volume iv • number 3 • september-december 2010 …...ing isolation and engraftment is the main...

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Beta-Cell Replacement by Transplantation in Diabetes Mellitus: When Pancreas, When Islets, and How To Allocate the Pancreas?David E.R. Sutherland and Dixon B. Kaufmann99Cytomegalovirus and Development of Cardiac Allograft Vasculopathy: Evidences and Therapeutic ImplicationsLuciano Potena and Hannah A. Valantine108Calcineurin Inhibitor-Free Maintenance Therapy After Liver Transplantation I: Mycophenolate Mofetil and Renal FunctionLydia Barrera-Pulido, José María Álamo-Martínez, Miguel Ángel Gómez-Bravo, Carmen Bernal-Bellido, Luis Miguel Marín-Gómez, Gonzalo Suárez-Artacho, Juan Serrano-Díez Canedo and Francisco Javier Padillo-Ruiz117Kidney Transplantation from Donors with a Positive Serology for Hepatitis C: The Facts and the ChallengesBeatriz Domínguez-Gil, Nuria Esforzado, Amado Andrés, Jose M Campistol and Jose M Morales129Living Donor Liver TransplantationJuan Carlos García-Valdecasas, Itxarone Bilbao Aguirre, Ramón Charco Torra, Constantino Fondevila Campo, Josep Fuster Obregón, Juan Carlos García-Valdecasas, Paloma Jara Vega, Rafael López Andújar, Pedro López Cillero, Juan Carlos Meneu-Díaz, Miguel Navasa Anadón and Fernando Pardo Sánchez138

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Volume IV • Number 3 • September-December 2010ISSN: 1887-455X

2.328

1.099

219

274

2009

05.1

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Mucho por vivir, mucho por recorrer

Con Valcyte® comprimidos y solución oral hemos dado un paso adelante, ampliando las soluciones frente al CMV.

Frente al CMV

Desde su lanzamiento hace más de cinco años, hemos demostrado la eficacia de Valcyte®, y seguimos avanzando. Tenemos mucho por recorrer, mucho por investigar, y mucha ilusión por seguir cumpliendo nuestro compromiso en la lucha frente al CMV.

03.0

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David e.R. Sutherland and Dixon B. Kaufmann: Beta-Cell Replacement by Transplantation in Diabetes Mellitus

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Beta-Cell Replacement by Transplantation in Diabetes Mellitus: When Pancreas, When Islets, and How To Allocate the Pancreas?David E.R. Sutherland1 and Dixon B. Kaufmann2

1Division of Transplantation, Schulz Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, USA; 2Division of Transplantation, Department of Surgery, Comprehensive Transplant Center Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA

trends in transplant. 2010;4:99-107

Correspondence to:

David e.R. Sutherland

Division of transplantation

Department of Surgery

University of minnesota

420 Delaware St.

minneapolis, mN 55455, USA

e-mail:[email protected]

Abstract

A successful pancreas or islet transplantation produces an insulin-independent, euglycemic state that normalizes hemoglobin A1C levels for as long as the graft functions. Pancreas transplantation has been shown to definitely influence the progression of many secondary complications of diabetes. Islet transplants, even if they do not function well enough to induce insulin independence, still improve quality of life and reduce the frequency of hypo-glycemic episodes in those with unawareness. Currently, approximately 1,300 pancreas transplants are performed annually in the USA, a frequency about 20-times that of islet al-lotransplants. The insulin-independence rates over time are definitely higher in the simulta-neous pancreas/kidney transplantation category than in any islet recipient category. How-ever, the insulin-independence rates are somewhat closer when comparing solitary pancreas transplants to recent islet transplant, a consequence of improved immunosuppres-sion and islet isolation. Currently, five-year solitary pancreas graft survival rates are ap-proximately 55% versus at best approximately 40% for islets. However, islet transplantation has a low morbidity and thus remains attractive as a minimally invasive procedure. For widespread application it needs to be made more efficient. The attrition of viable islets dur-ing isolation and engraftment is the main problem. The failure to obtain a high yield of vi-able islets from some donor pancreases creates the need to use more than one donor to provide a sufficient beta-cell mass to achieve insulin-independence in many recipients. Ef-forts are being made to increase the efficiency of islet isolation and engraftment so islet transplantation can become the form of beta-cell replacement therapy used in the majority of candidates. A deceased donor pancreas allocation policy for beta-cell replacement should be designed to foster efficiency and access to the most candidates for pancreas or islet transplantation. Current United Network for Organ Sharing policy in the USA on pancreas and islet transplants reflects the efficiency and durability of pancreas transplants, so candi-dates for a whole organ are given preference for donors < 50 years old and with a body

trends in transplantation 2010;4

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Hyperglycemia is the most important factor in the development and progression of secondary complications of diabetes. The Diabetes Control and Complication Trial (DCCT) demonstrated that the microvascular and possibly macrovascular complications of diabetes may be prevented by maintaining euglycemia1,2. This study gave further support to the application of beta-cell replacement as an alternative to exogenous insulin adminis-tration in efforts to achieve optimal glycemic control so that the progression of long-term complications can be altered without the risk of hypoglycemia. The only treatments other than intensive insulin therapy that can influ-ence the progression of secondary complica-tions is beta-cell replacement by either pan-creas or islet transplantation. Since diabetes is not a rapidly fatal disease, and because transplant procedures require the patient to receive life-long immunosuppression, the re-sults of islet or pancreas transplantation must be sufficiently efficacious and safe to warrant their application in place of standard medical management of the primary disease. Even though pancreas transplantation has a high

success rate, it is associated with surgical morbidity. Pancreas transplantation is a prov-en therapeutic treatment option for diabetes and is superior to manual intensive insulin therapy with regard to the efficacy of achiev-ing glycemic control and beneficial effects on diabetic secondary complications. Islet trans-plantation is an alternative method of beta-cell replacement therapy.

Currently, islet transplantation is an in-vestigational procedure for highly selective cases. An obvious advantage of islet trans-plantation is that it is minimally invasive for the recipient, but logistically it is more difficult3-5.

A successful pancreas or islet trans-plant produces a euglycemic, insulin-inde-pendent state that normalizes hemoglobin A1C levels for as long as the graft functions. Transplantation also has the added physio-logical properties of pro-insulin and C-peptide release, not possible with intensive insulin therapy6. Through improved metabolic control by pancreas transplantation, many secondary complications of diabetes, including diabetic

mass index < 30. The United Network for Organ Sharing is now in the process of revising pan-creas allocation for both solid organ and islet transplantation. The new allocation system will reduce the geographic inequities related to pancreas utilization, access to transplantation, and how long the candidates wait. It will maximize capacity by improving the opportunity for pan-creas and islet candidates to receive a transplant. It will enhance efficiency and minimize the complexity of implementing and maintaining the operational requirements of a new allocation system. However, no matter how much the deceased donor organ allocation system is refined, there will never be enough human pancreases to provide beta-cell replacement therapy for all who could benefit. To do so will require the use of xenografts or insulin-producing, expand-ed autologous or allogeneic cell lines. These new modalities hold great promise for clinical application because of the unlimited supply and modifiable or intrinsic potential to escape some of the immunological consequences that plague solid organ xenografts as well as con-ventional allogeneic beta-cell replacement therapies. (Trends in Transplant. 2010;4:99-107)

Corresponding author: David E.R. Sutherland, [email protected]

Key words

Pancreas and islet transplantation. Pancreas allocation. Diabetes.


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neuropathy7, autonomic neuropathy-associat-ed sudden death8, and diabetic nephropathy, in both uremic and nonuremic patients9,10, may be markedly improved. A successful pancreas transplant significantly improves quality of life11 and life expectancy12,13. The effect of islet transplantation on secondary complications has not undergone as rigorous a study on secondary complications as pan-creas transplantation, but preliminary studies suggest the same effect14. Islet transplanta-tion improves quality of life and has a signifi-cant ameliorating effect on the frequency of episodes of hypoglycemia15. One prospective study showed that islet transplantation not only reduced HbA1c levels more than inten-sive medical therapy, but was also associated with less progression of retinopathy during three years of follow-up16.

Approximately 1,300 pancreas trans-plants are performed annually in the USA, about 20-times more than islet allotransplants. Of the pancreas transplants, 65-70% involves a simul-taneous pancreas and kidney (SPK) transplant for patients with type 1 diabetes and chronic renal failure. These individuals are excellent candidates for an SPK transplant from the same donor because the immunosuppressive medi-cations that are needed are similar to those for a kidney transplant alone and the surgical risk of adding the pancreas is low. The benefits of adding a pancreas transplant to ameliorate diabetes are profound–transplantation saves lives12,13,17. Simultaneous islet/kidney trans-plants are rarely performed, in part because of difficult logistics and because a successful is-let isolation occurs at best in 50% of cases.

The second category for pancreas and islet transplantation consists of patients with type 1 diabetes who have received a previous kidney transplant from either a living or de-ceased donor18-20. This pancreas after kidney transplant category accounts for approximately 20% of patients receiving pancreas transplants, while approximately 15% of islet transplantations

are done after a kidney transplant. The impor-tant consideration is that of technical risk21, since the risk of immunosuppression has al-ready been assumed for both groups22.

The third category for pancreas and is-let transplantation is composed of non-uremic patients with type 1 diabetes23. Candidates are those in whom the risk of immunosuppres-sion is judged to be less than the risk of re-maining diabetic on exogenous insulin thera-py. Most of the candidates for a pancreas transplant alone have extremely labile diabe-tes and have difficulty managing day-to-day, with frequent emergency room visits or inpa-tient hospitalizations for hypoglycemia or dia-betes. Other patients have significant diffi-culty with hypoglycemic unawareness that results in unconsciousness without warning, need assistance from those around them, and never should be left alone. For select patients, this state can be a devastating problem that affects their employment and their ability to keep a driver’s license and creates concern about lethal hypoglycemia while asleep, as well as imposing an emotional toll on family members. Pretransplant evaluation often in-corporates an assessment of the Clarke Score24 to semi-quantitatively determine the severity of hypoglycemic complications in an effort to more fully understand the risk/benefit relationship for undergoing a pancreas or islet transplantation. Only about 15% of pancreas transplants are performed for this scenario (be-cause so many pancreas transplants are done in renal allograft recipients who are already obligated to immunosuppression and thus the indications for beta-cell replacement are much more liberal), whereas for islet transplant, it accounts for about 85% of cases since almost all to date are in nonrenal allograft recipients.

The outcomes currently favor pancreas transplants in the SPK transplant group over any islet group. However, the results are much closer when solitary pancreas transplants are compared to islet transplants as immunosuppression


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protocols have improved for islet transplantation. Currently, five-year solitary pancreas graft sur-vival rates are approximately 55% in this group and at best approximately 40% for islets25.

Importantly, islet transplantation has a low morbidity. Unfortunately, it is also ineffi-cient because of the attrition of viable islets during isolation and engraftment. This prob-lem results in failed attempts to obtain a suf-ficient yield of islets for transplants from some donor pancreases, and creates the need for more than one donor (retransplantation) to achieve a sufficient beta-cell mass in many recipients. Ideally, beta-cell replacement should be done by the least invasive means possible. However, if one is to maximize the number of recipients in the face of a scarce resource, deceased donor organ allocation for pancreas and islet allotransplantation has to be integrated in a way that balances the two objectives: treating as many as possible and minimizing morbidity26.

The decision as to whether a beta-cell replacement candidate should receive an im-mediately vascularized solitary pancreas graft or an injection of isolated islets can be dic-tated, in part, by recipient characteristics27, to circumvent the limitations of islet graft ineffi-ciency. Exogenous insulin requirements are a rough guide to the number of beta-cells re-quired to induce insulin-independence; the lower the requirement, the fewer islets that will be needed. Thus, beta-cell replacement can-didates with high insulin requirements would be better suited for a pancreas transplant, while those with low insulin requirements might get by with a single-donor islet transplant.

A deceased donor pancreas allocation policy for beta-cell replacement should be de-signed to foster efficiency, and thus minimize the use of multiple islet donors (euphemism for retransplantation) for a single recipient. In the USA, organ allocation policies are set by the United Network for Organ Sharing (UNOS).

The current pancreas allocation is complicat-ed by the need for two lists: one for those only in need of beta-cell replacement, and one for those who also need a kidney. Currently, the priority varies according to the policies of lo-cal organ procurement organizations. In some organizations, uremic diabetic patients wait-ing for a kidney/pancreas transplant have no priority over uremic patients waiting for a kid-ney alone; a kidney/pancreas is allocated only when a uremic diabetic is at the top of the list. In other organ procurement organizations, the highest ranked uremic diabetic gets priority for a kidney/pancreas, no matter what the rank; in others, however, a level of rank is specified above which the highest ranked kid-ney/pancreas gets priority. In all organ pro-curement organizations, if no kidney/pancreas candidate is ranked high enough for an offer of both organs, the pancreas is offered to the highest ranked candidate for solitary pancre-as or islet transplantation.

In regard to UNOS policy on pan-creas and islet transplants, organs from donors < 50 years old are first offered to pan-creas candidates, and those from donors > 50 first to islet candidates, primarily because intact pancreas transplants from donors over 50 years of age have increased technical complication rates at most pancreas programs. Pancreases from obese donors (BMI > 30) are also prefer-entially for islets, both because of the increased technical complication rate with pancreas trans-plants from such donors and the fact that the absolute number of islets isolated is propor-tional to donor size28. We know that nondiabetic, obese individuals have more islets than lean individuals because the beta-cell mass increas-es to cope with the increased insulin needs associated with obesity. This means that pan-creases from obese donors could be assigned preferentially to recipients suitable to receive islet transplants because of their low insulin re-quirements, while pancreases from lean donors would be used for whole pancreas transplants to recipients with high insulin requirements.


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Currently, UNOS is in the process of designing the pancreas allocation for both solid organ and islet transplantation29. UNOS is interested in a new national pancreas allo-cation system that will better address the needs of patients with diabetes with and with-out concurrent renal failure. There are several concerns with the way pancreases are cur-rently allocated. First, there is no nationally established allocation practice for patients with diabetes and renal failure. Current pan-creas allocation policy allows organ procure-ment organizations several choices on pan-creas (pancreas alone) allocation practice. The candidates can be listed on separate or combined SPK/pancreas-alone waiting lists. The kidney may be allocated to SPK candi-dates based upon the kidney/pancreas match run, the kidney-alone match run, or a combi-nation of match runs. Consequently, waiting times for SPK transplants vary widely across the country because of local or regional allo-cation decisions. Furthermore, current prac-tice does not seek to maximize the utilization of the pancreas. Simultaneous pancreas and kidney transplants receive offers after other renal/extrarenal multiorgan transplants, kid-ney paybacks, and zero mismatch kidney-alone candidates. This allocation order leads to discarding of grafts that would likely be used if offered in the context of SPK trans-plantation but are declined for pancreas-alone transplants. Under the current system, 66% of pancreases are used for SPK transplant can-didates. However, there are no specific listing criteria for SPK transplants with respect to the degree of pancreas dysfunction necessary to qualify to receive waiting time for an SPK trans-plant, it is only the criteria for a kidney that is used: glomerular filtration rate (GFR) or creati-nine clearance (CrCl) of 20 ml/min or less.

A revised system is needed to improve the current pancreas allocation process. It should be consistent with the Organ Procure-ment Transplantation Network’s long-range stra-tegic goals and priorities: geographic equity in

access and waiting time to deceased donor organs for transplantation; maximizing capac-ity of deceased donor organ transplantation; achieving operational efficiency and cost-ef-fectiveness in implementing and maintaining the organ allocation system.

Depending on where a transplant can-didate lives, some candidates may have to wait longer than others for a pancreas trans-plant. The first goal of the proposed pancreas allocation system reduces the geographic in-equities related to deceased donor pancreas utilization, access to transplantation, and how long the candidates wait. Accomplishing these goals would mean instituting a consis-tent national system. Under this system, if a diabetic, uremic candidate on the list for an SPK transplant is allocated a pancreas from a local deceased donor and accepts it, then that candidate would also receive a kidney from the same deceased donor.

The second goal is to maximize capac-ity by improving the opportunity for pancreas candidates to receive a transplant. This would be accomplished by combining SPK and pan-creas-alone candidates onto a single match run list. On a single list, candidates for both categories of pancreas transplants would have an equal opportunity to receive offers of high quality organs. A single list for all pan-creas candidates would be operationally ef-ficient for organ procurement organizations. It would also retain some high quality kidneys for the kidney allocation system in the situa-tions in which a pancreas graft is allocated for pancreas-alone transplantation. Right now, diabetic, uremic candidates are not fully in-centivized to receive a kidney from a living donor if they will subsequently be put on a wait list for a solitary pancreas in a donation service area that allocates organs to SPK can-didates before allocating them to pancreas-alone candidates. In this situation, if a candi-date chooses to take a living donor kidney and then wait on the list for a pancreas, that


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candidate would receive a local pancreas of-fer only if all the local SPK candidates had turned down that pancreas. This process re-sults in additional waiting time for pancreas after kidney transplantation compared to de-clining a living donor kidney and continuing to wait for the SPK transplant. Also, in many circumstances these pancreases that are re-fused by all the SPK candidates are of lower quality than the pancreases the candidate would be able to receive if he or she had waited for an SPK rather than taking the living donor kidney. This situation might discourage candidates who need both a kidney and a pan-creas from taking a living donor kidney followed by a deceased donor pancreas. The proposed allocation change would mean that candidates may be more inclined to accept a kidney from a living donor, knowing they subsequently will get a good quality solitary pancreas offer.

On the other hand, for pancreas trans-plant programs that readily accept regional and national solitary pancreas offers, the wait-ing time for a pancreas after kidney transplant may be relatively short. Thus, in these pro-grams or donation service areas, a living do-nor kidney followed by a solitary deceased donor pancreas transplantation can actually reduce the time of being both dialysis-free and insulin-independent for uremic diabetics over those on the SPK waiting list. Thus, the value on survival of preempting dialysis with a living donor kidney transplant offsets the negative aspects of waiting for a solitary pan-creas transplant and having two opera-tions18-20. And of course, there is the option of a living donor SPK transplant30,31.

The third goal is to enhance efficiency and minimize the complexity of implementing and maintaining the operational requirements of a new pancreas allocation system. The pro-posed method would allocate deceased do-nor pancreases separately from the current kidney allocation system. This method would effectively disentangle the system of

a pancreas allocation from kidney allocation. There appears to be enough deceased donor kidneys (both standard and expanded crite-ria) available to accommodate this allocation change without adversely affecting pediatric or adult kidney transplant activity. Importantly, this process would result in a faster and more effi-cient method of allocating organs. It would also be less costly to implement and maintain.

The fourth goal is to optimize pancreas transplant access without adversely affecting kidney transplantation. Specifically, a new pan-creas allocation system would not affect trans-plant volume for adult and pediatric kidney recipients as well as ethnicity, age, and gender of recipients. This goal would be accomplished by instituting objective medical qualifying cri-teria relating to renal dysfunction and diabetes for SPK candidates. These candidates would be eligible to accrue SPK waiting time only if they meet qualifying criteria based on renal and metabolic function. The kidney function criteria for qualifying includes either being on dialysis, having a GFR or CrCl ≤ 20 ml/min. Qualifying pancreas function criteria includes either being on insulin and having a C-peptide value ≤ 2 ng/ml or being on insulin with glycemic intolerance with a C-peptide value > 2 ng/ml and a body mass index (BMI) ≤ 30 kg/m2. In addition, a single list for all pancreas transplant candidates would retain some high quality kid-neys for the kidney allocation system. Finally, the proposal includes a system to monitor al-location of standard criteria deceased donor kidneys for pediatric and adult kidney alone recipients and SPK recipients with respect to donor ages ≤ 35 and > 35 years. It should be noted that pancreas transplantation is effective in inducing insulin-independence in diabetic pa-tients (including type 2), regardless of the pres-ence or absence of C-peptide or the levels32; nevertheless, C-peptide is being used in the policy formulations.

Advances are being made in the isola-tion of islets to increase the proportion of islets


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that remain viable for transplantation; for ex-ample, the use of agents that prevent apop-tosis after isolation33. As these advances are applied clinically, the insulin requirement threshold below which a single-donor islet transplant would be sufficient to induce insulin independence could be raised, increasing the proportion of beta-cell replacements done by the minimally invasive technique. Conversely, the BMI requirements to be an islet donor could be progressively lowered as the islet isolation efficiency increases in terms of via-bility. Ultimately, such improvements would result in a fully integrated list of pancreas and islet candidates, each being able to accept nearly all donors regardless of characteristics, and most beta-cell replacement therapy would be done by islet transplantation. We are, of course, not at that point yet.

Besides improving the efficiency of islet isolation, other alterations in strategies may al-low a lower number of isolated islets to induce insulin-independence in recipients than is cur-rently the case, for example, using a truly non-diabetogenic immunosuppressive regime (even the Edmonton protocol is diabetogenic with its inclusion of a calcineurin inhibitor). In many pan-creas transplant programs, the immunosup-pressive regimen is free of steroids22,34.

By combining several aspects of the recipient and donor selection criteria, techni-cal improvements in islet isolation and immu-nosuppressant selection, as outlined above, has allowed insulin independence to be achieved with islets from a single donor35. There are several recent reviews on islet transplantation that show the promise of islet transplantation to eventually be the nearly sole method of beta-cell replacement thera-py14,36,37. However, to be truly a treatment for all diabetics, an unlimited source of islets is needed, and this could only be met by islet xenotransplantation, as recently reviewed38, or through development of glucose-respon-sive, insulin-producing expanded cell line.

If one deceased donor pancreas could consistently yield enough islets to induce in-sulin independence in a diabetic recipient, regardless of donor characteristics or recipi-ent’s exogenous insulin requirements, islet transplantation would largely replace pancre-as transplantation. An exception would be candidates who also have exocrine deficien-cy, for example, those who became diabetic as a result of pancreatectomy for benign dis-ease39. Islet autotransplantation performed at the time of pancreatectomy for chronic pan-creatitis can preserve insulin independence in some patients40,41, but for those in whom it does not, or in whom it was never attempted, it makes sense to transplant a pancreas (rath-er than simply islets) with enteric drainage of the exocrine secretions so that normal intesti-nal absorption can also be restored39.

The shortage of deceased donors for those in need of organ replacement therapy of all kinds has led to the use of living donors, including for the pancreas. Segmental pan-creas transplants from living donors have been done since 1979 at the University of Minnesota31, and this institution had an even earlier experience with two cases of islet al-lografts from living donors42. In countries where deceased organ donors are in even shorter supply, the incentive to use living do-nors is particularly strong. For example, in Japan the number of living donor liver trans-plants greatly exceeds that from deceased donors, and the transplant group in Kyoto also did a living donor islet transplantation a few years ago43,44. However, it is unlikely that the use of both deceased and living donors can meet the demand for beta-cell replacement therapy any better than it has for any other or-gan, even in countries with relatively high num-bers of both types. Thus, in the long term, either islet xenografts or induction of endogenous beta-cell regeneration will be the answer26,38.

Meanwhile, we must use the resource at hand: a limited number of allogeneic donor


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pancreases for beta-cell replacement therapy. To answer the questions posed in the title, beta-cell replacement therapy should be done in insulin-dependent diabetic patients who are either obligated to immunosuppression (near-ly all diabetic renal allograft recipients should be candidates) or in those whose problems with achieving sufficient metabolic control of diabetes using exogenous insulin (primarily those with hypoglycemic unawareness) ex-ceed the potential side effects of immunosup-pression. For candidates in whom the insulin requirements are low enough so that islets isolated from a single donor would predictably induce insulin independence, perform an islet transplant; in those whose requirements are so high that more than one donor would be need-ed for the islet approach, and who are not at high risk for surgical complications, carry out a pancreas transplant. If the surgical risk is unacceptable in high insulin-requiring candi-dates, then perform an islet transplant, with the exception that islet retransplantation can be done over time to eventually achieve insulin independence. With this approach, beta-cell replacement can be done in the most patients with the highest insulin-independent rate pos-sible, while allowing minimally invasive surgery to be done in some candidates at no expense to those who require more (a solid organ).

Finally, a word about the mortality risk of beta-cell replacement therapy versus remain-ing on insulin for a diabetic patient. The mortal-ity risk of pancreas transplantation, in absolute terms, is very low, with patient survival rates at one year ranging from 95 to 98% in all three (simultaneous pancreas/kidney, pancreas after kidney, pancreas alone) recipient categories45. However, Venstrom, et al., in an analysis of UNOS data from 1995 through 2000, found that the posttransplant mortality rate of solitary pan-creas transplant recipients (pancreas alone or pancreas after kidney transplant) was higher than for candidates who remained on the wait-ing list46. Analyses of this type are very difficult to perform, and in a separate analysis by

Gruessner, et al.47, but this time counting pa-tients only once that were multiply listed or changed centers, the mortality rate for solitary pancreas transplant recipients was not higher than for wait-listed patients.

Thus, it appears that pancreas transplan-tation and exogenous insulin treatment are at least equal in survival probabilities for the dia-betic patients accepted as transplant candi-dates. As reviewed by Robertson48, every study that has been done on quality of life favors pan-creas transplantation over exogenous insulin for such patients, most of whom have significant problems with the latter (such as hypoglycemic unawareness). What is needed now is to increase the efficiency of islet isolation and engraftment so beta-cell replacement therapy can be done by the minimally invasive technique in the major-ity, rather than the minority, of candidates.

References 1. Epidemiology of Diabetes Interventions and Complications

(EDIC) Research Group. Effect of intensive diabetes treat-ment on carotid artery wall thickness in the epidemiology of diabetes interventions and complications. Epidemiology of Diabetes Interventions and Complications (EDIC) Research Group. Diabetes. 1999;48:383-90.

2. DCCT/EDIC Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA. 2002;287:2563-9.

3. Stock P. Beta-cell replacement for type 1 diabetes mellitus - islet versus solid organ pancreas. Curr Opin Organ Trans-plant. 2005;10:70-4.

4. Deng S, Markmann JF, Rickels M, et al. Islet alone versus islet after kidney transplantation: metabolic outcomes and islet graft survival. Transplantation 2009;88:820-5.

5. Markmann JF, Kaufman DB, Ricordi C, Schwab PM, Stock PG. Financial issues constraining the use of pancreata re-covered for islet transplantation: a white paper. Am J Trans-plant. 2008;8:1588-92.

6. Morel P, Goetz F, Moudry-Munns KC, et al. Long term met-abolic control in patients with pancreatic transplants. Ann Intern Med. 1991;115:694-9.

7. Navarro X, Kennedy WR, Loewenson RB, et al. Influence of pancreas transplantation on cardiorespiratory reflexes, nerve conduction, and mortality in diabetes mellitus. Diabe-tes. 1990;39:802-6.

8. Kennedy WR, Navarro X, Goetz FC, et al. Effects of pancre-atic transplantation on diabetic neuropathy. N Engl J Med. 1990;322:1031-7. *This study was the first to definitively show that a pancreas transplant could reverse clinical manifestations of neuropathy or prevent progression in diabetic patients.

9. Fioretto P, Mauer SM, Bilous RW, et al. Effects of pancreas transplantation on glomerular structure in insulin-dependent diabetic patients with their own kidneys. Lancet. 1993;342:1193-6. *This study was the first to definitively show that a pancreas transplant alone could reverse histo-logical manifestations of nephropathy in native kidneys of diabetic patients, though renal function may not improve because of the nephrotoxic effect of calcineurin-inhibitor immunosuppression.


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10. Bilous RW, Mauer SM, Sutherland DE, et al. The effects of pancreas transplantation on the glomerular structure of renal allografts in patients with insulin-dependent diabetes. N Engl J Med. 1989;321:80-5.

11. Zehr PS, Milde FK, Hart LK, et al. Pancreas transplantation: assessing secondary complications and life quality. Diabe-tologia. 1991;34(Suppl 1):S138-40.

12. Ojo AO, Meier-Kriesche HU, Hanson JA, et al. Impact of simultaneous pancreas-kidney transplantation on long-term patient survival. Transplantation. 2001;71:82-90.

13. Mohan P, Safi K, Little DM, et al. Improved patient survival in recipients of simultaneous pancreas-kidney transplant compared with kidney transplant alone in patients with type 1 diabetes mellitus and end-stage renal disease. Br J Surg. 2003;90:1137-41.

14. Fioriana P, Shapiro AM, Ricordi C, Secchi A. The clinical impact of islet transplantation. Am J Transplant. 2008;8:1990-7. *Excel-lent review on every aspect of clinical islet transplantation.

15. Tharavanij T, Betancourt A, Messinger S, et al. Improved long-term health-related quality of life after islet transplanta-tion. Transplantation. 2008;86:1161-7.

16. Warnock GL, Thompson DM, Meloche RM, et al. A multi-year analysis of islet transplantation compared with intensive medical therapy on progression of complications in type 1 diabetes. Transplantation. 2008;86:1762-6.

17. Sollinger HW, Odorico JS, Becker YT, et al. One thousand simultaneous pancreas-kidney transplants at a single center with 22-year follow-up. Ann Surg. 2009;250:618-30. *Largest series of SPK transplants from a single institution.

18. Sutherland DE, Gruessner AC, Radosevich DM. Transplanta-tion: kidney or kidney-pancreas transplant for the uremic diabetic? Nat Rev Nephrol. 2009;5:554-6.

19. Kleinclauss F, Fauda M, Sutherland DE, et al. Pancreas after living donor kidney transplants in diabetic patients: impact on long-term kidney graft function. Clin Transplant. 2009;23:437-46. *This article shows the attractiveness of do-ing a LD kidney transplant to preempt dialysis followed by a deceased donor pancreas transplant in uremic diabetics.

20. Kaufmann D. Pancreas-after-kidney transplantation: to have and to have not. Clin Transplant. 2009;23:435-6.

21. Boggi U, Vistoli F, DelChiaro M, et al. Surgical techniques for pancreas transplantation. Curr Opin Organ Transplant. 2005;10:75-87.

22. Kaufmann D, Salvalaggio PR. Immunosuppression for pancreas transplantation. Curr Opin Organ Transplant. 2005;10:88-94.

23. Gruessner R, Sutherland DE, Kandaswamy R, Gruessner A. Over 500 solitary pancreas transplants in nonuremic pa-tients with brittle diabetes mellitus. Transplantation. 2008;85:42-7. *Largest series of pancreas transplants alone from a single institution.

24. Clarke WL, Cox DJ, Gonder-Frederick LA, et al. Reduced awareness of hypoglycemia in adults with IDDM. A prospec-tive study of hypoglycemic frequency and associated symp-toms. Diabetes Care. 1995;18:517-22.

25. White SA, Shaw JA, Sutherland DE. Pancreas transplanta-tion. Lancet. 2009;373:1808-17. *Most up to date review on current status of pancreas transplantation.

26. Sutherland DE, Gruessner A, Hering J. Beta-cell replacement therapy (pancreas and islet transplantation): an integrated approach. Endocr Metab Clin N Amer. 2004;33:135-48.

27. Sutherland DER. Pancreas and Islet Transplant Population. Transplantation of the Pancreas. Gruessner RW, Sutherland DE (eds). New York: Springer-Verlag, 2004:91-2.

28. Matsumoto I, Sawada T, Nakano M, et al. Improvements in islet yield from obese donors for human islet transplants. Transplantation. 2004;78:880-5.

29. http://www.unos.org/CommitteeReports/board_main_Pan-creasTransplantationCommittee_6_24_2010_9_59.pdf - ap-plication/pdf

30. Sutherland D, Najarian J. Living Donor Pancreas Transplan-tation. In Living Related Transplantation. Hakim NS, Canelo R, Papalois V (eds). Imperial College Press, London. 2010:95-117.

31. Sutherland DE, Gruessner RW, Dunn DL, et al. Lessons learned from more than 1,000 pancreas transplants at a single institution. Ann Surg. 2001;233:463-501.

32. Nath DS, Gruessner A, Kandaswamy R, Gruessner R, Sutherland DER, Humar A. Outcomes of pancreas trans-

plants for patients with type 2 diabetes mellitus. Clin Trans-plant. 2005;19:792-7.

33. Nakano M, Matsumoto I, Sawada T, et al. Capsase-3 inhibitor prevents apoptosis of human islets immediately after isolation and improves graft function. Pancreas. 2004;29:104-9.

34. Sutherland DE, Kandaswamy R, Humar A, Gruessner RW. Calcineurin-inhibitor-free protocols: Use of the anti-T-cell agent Campath H-1 for maintenance immunosuppression in pancreas and pancreas/kidney recipients. Clin Transplant. 2010;18:14-15.

35. Hering BJ, Kandaswamy R, Ansite J, et al. Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes mellitus. J Am Med Assoc. 2005;293:830-5.

36. Korsgren O, Nilsson B. Improving islet transplantation: a road map for a widespread application for the cure of per-sons with type I diabetes. Curr Opin Organ Transplant. 2009;14:683-7. *Most up to date review on current status of islet transplantation.

37. Robertson RP. Islet transplantation a decade later and strate-gies for filling a half-full glass. Diabetes. 2010;59:1285-91.

38. Hering BJ, Walawalkar N. Pig-to-nonhuman primate islet xenotransplantation. Transpl Immunol. 2009;21:81-6. *This article reviews the promise of islet xenotransplantation for solving the human organ shortage problem, and how close this is to clinical reality.

39. Gruessner RW, Sutherland DE, Dunn DL, et al. Transplant options for patients undergoing total pancreatectomy. J Am Coll Surg. 2004;198:559-67.

40. Blondet J, Carlson A, Kobayashi T, et al. The role of total pancreatectomy and islet autotransplantation for chronic pancreatitis. Surg Clin North Am. 2007;87:1477-501.

41. Sutherland DE, Gruessner AC, Carlson AM, et al. Islet auto-transplant outcomes after total pancreatectomy: A contrast to islet allograft outcomes. Transplantation. 2008;86:1799-802.

42. Sutherland DE, Gores PF, Farney AC, et al. Evolution of kidney, pancreas, and islet transplantation for patients with diabetes at the University of Minnesota. Am J Surg. 1993;166:456-91.

43. Matsumoto S, Okitsu T, Iwanaga Y, et al. Insulin indepen-dence after living-donor distal pancreatectomy and islet al-lotransplantation. Lancet. 2005;365:1642-4.

44. Matsumoto S, Okitsu T, Iwanaga Y, et al. Insulin indepen-dence of unstable diabetic patient after single living donor islet transplantation. Transplant Proc. 2005;37:3427-9.

45. Gruessner AC, Sutherland DE. Pancreas transplant out-comes for United States (US) and non-US cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of June 2004. Clin Transplant. 2005;19:433-55.

46. Venstrom JM, McBride MA, Rother KI, Hirshberg B, Orchard TJ, Harlan DM. Survival after pancreas transplantation in patients with diabetes and preserved kidney function. J Am Med Assoc. 2003;290:2817-23.

47. Gruessner RD, Sutherland DE, Gruessner AC. Mortality assess-ment for pancreas transplants. Am J Transplant. 2004;4:2018-26. *This article and the one preceding both definitively show the great beneficial effect of kidney-pancreas transplant on survival of uremic diabetics over those who remain on the wait list. What is controversial is whether the mortality risk of a soli-tary pancreas transplant exceeds that of not being transplant-ed and in the article by Gruessner, et al. the answer is no.

48. Robertson RP. Impact of pancreas and islet transplantation on acute and chronic complications of diabetes. Curr Opin Organ Transplant. 2005;10:95-9.

Suggested ReadingsSutherland DER. Beta-cell replacement by transplantation in dia-

betes mellitus: which patients at what risk, which way (when pancreas, when islets), and how to allocate deceased donor pancreases. Curr Opin Organ Transplant. 2005;10:147-9. *This issue has several articles, besides the one cited, on all aspects of pancreas and islet transplantation. The article cited has formed the basis of the current discussion adding Dr. Kaufman’s perspective as current Chairman of the UNOS Pancreas Allocation Committee.


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Cytomegalovirus and Development of Cardiac Allograft Vasculopathy: Evidences and Therapeutic ImplicationsLuciano Potena1 and Hannah A. Valantine2

1Cardiovascular Department of the University of Bologna, Bologna, Italy; 2Division of Cardiovascular Medicine, Stanford University, Palo Alto, USA


Correspondence to:

Luciano Potena

Cardiovascular Department

Heart Failure and Heart transplant Program

University of Bologna

Padiglione 21

Via massarenti, 9

40138 Bologna, Italy

e-mail: [email protected]

Abstract

Cardiac allograft vasculopathy remains the major cause of long-term failure of heart trans-plantation. Cytomegalovirus infection was identified as a major risk factor for cardiac allograft vasculopathy development in pioneering studies, even though the possibility that the virus is only an innocent bystander was not completely excluded. Only recently, convincing clinical and experimental evidences support the hypothesis of a direct involvement of cytomegalovi-rus in cardiac allograft vasculopathy pathogenesis. In this article, we review the mechanisms and clinical evidences supporting the hypothesis that subclinical cytomegalovirus infection leads to adverse long-term graft outcome by favoring cardiac allograft vasculopathy develop-ment. In addition, we discuss data pointing to the need for antiviral approaches designed to suppress subclinical cytomegalovirus activation as a long-term strategy to prevent cardiac allograft vasculopathy and chronic allograft damage. (Trends in Transplant. 2010;4:108-16)

Corresponding author: Luciano Potena, [email protected]

Key words

Heart transplant. Cytomegalovirus. Cardiac allograft vasculopathy.

Introduction

Short-term survival after heart trans-plantation has greatly improved over the last three decades as a consequence of advanc-es in immunosuppressive therapy and periop-erative management. However, improvement

in long-term outcome is still significantly im-peded by the consequences of chronic al-lograft vasculopathy (CAV), the major cause of late failure of the transplanted heart1. Al-though numerous immune-mediated and met-abolic risk factors have been identified for CAV progression2, to date no effective treat-ment is available to fully eliminate its related adverse outcomes. Therefore, the main thera-peutic strategy against CAV is the prevention and treatment of the factors known to trigger or accelerate the disease3. Among these known risk factors is cytomegalovirus (CMV) infection, which plays a key role in CAV pro-gression, possibly through its complex inter-action with the host immune system4,5. Impor-tantly, strategies that target CMV offer the

Luciano Potena and Hannah A. Valantine: CMV and Cardiac Allograft Vasculopathy

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possibility of effective prevention of CAV while also advancing our understanding of its patho-genesis. However, the efficacy of distinct anti-CMV strategies in limiting CAV requires further evaluation, in concert with studies that identify the specific mechanisms by which CMV medi-ates graft injury. This knowledge is necessary to advance the field and settle the much-de-bated controversy of whether CMV is an inno-cent bystander or directly involved in CAV pathogenesis6.

This article reviews recent studies that provide evidence in support of the involve-ment of CMV in the pathogenesis of CAV. Specifically discussed are the implication of new clinical data and mechanistic pathways potentially implicated in CMV-induced al-lograft damage. Also discussed are the impli-cations of these data that point to the need for chronic suppression of subclinical viral activa-tion as a long-term strategy to prevent CAV and chronic allograft damage.

Relevance of cytomegalovirus infection in heart transplantation

Cytomegalovirus is a member of the β-Herpesviridae family that includes human herpesvirus-6 (HHV-6) and HHV-77. In the gen-eral population, CMV is present in peripheral blood monocytes of 50-90% of individuals, but does not normally cause symptomatic disease. In contrast, CMV is the most clinically relevant posttransplant infectious agent, affecting up to 80% of heart transplant recipients, depending on donor-recipient serostatus, intensity of the immunosuppressive regimen, and the diagnos-tic system used to assay CMV replication8,9.

Following transplantation, immunosup-pression causes the reactivation of latent vi-rus, or allows de novo transmission of CMV from a seropositive donor to a seronegative recipient (D+/R–)10. Bidirectional interaction between the suppressed host immune system

and the immune modulating virus itself increas-es the risk of infection and CMV disease11.

Cytomegalovirus infection has both di-rect and indirect effects. Direct effects, attrib-uted to the CMV syndrome, typically present as prolonged high fever, fatigue, malaise, an-orexia, arthralgias and myalgias, and the leu-kopenia and thrombocytopenia symptomatic of myelosuppression12. Tissue-invasive dis-ease manifests as nephritis, hepatitis, carditis, pneumonitis, pancreatitis, colitis, or rarely as retinitis, seen more frequently among patients coinfected with HIV13. Indirect effects of CMV include allograft injury and rejection, and in-creased risk for the development of Epstein-Barr virus-associated posttransplant lymphop-roliferative disorder12. Viral disruption of immune responses and damage to endothelial cells are believed to be responsible for many of the indirect effects of CMV14,15.

Transplant recipients who develop CMV infection are at increased risk of mortality. Of note, increased risk for overall mortality ap-pears associated not only with tissue-invasive CMV disease, but also with asymptomatic in-fection, as detected by pp65 antigenemia16, supporting the concept that CMV is capable to indirectly promote graft dysfunction.

Taken together, the evidence supports the conclusion that acute CMV disease follow-ing transplantation is a predictor of acute mor-bidity, and is likely to predispose to chronic long-term graft dysfunction. Thus, strategies di-rected to prevent CMV disease and to balance the burden of immunosuppressive therapy are mandatory for an optimal posttransplant care.

Clinical evidence associating cytomegalovirus with chronic allograft vasculopathy

The association of CMV infection with CAV was first reported over two decades ago,


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in the pre-ganciclovir era17-19. These early ob-servational studies were conducted at a time when the methods for detection of CMV infec-tion were relatively insensitive, relying pre-dominantly on clinical manifestations of viral disease and confirmation by histology or viral culture. From these observations developed the concept that CMV may not only cause an organ-specific or systemic disease due to di-rect viral damage, but is also capable of in-ducing immune activation that targets the al-lograft and thus indirectly results in acute rejection and CAV20.

The advent of antiviral drugs, particu-larly ganciclovir, led to effective therapeutic strategies for preventing CMV disease and to a reduction in virus-related graft failure, both in experimental models and in heart transplant recipients21-23. These advances in antiviral therapy were paralleled by the de-velopment of highly sensitive diagnostic tools to detect CMV infection, enabling the identification of a large number of patients who developed subclinical viral infection, hitherto unrecognized by prior methods24,25. By monitoring asymptomatic CMV activation in peripheral blood, Emery, et al. reported that the risk of overt CMV disease is propor-tional to the level of viral DNA detected26. These observations linking viral load with acute disease raised the question of wheth-er asymptomatic viral replication may also predict the long-term consequences of CMV infection. Several studies, summa-rized below, provide confirmatory evidence for this link.

In a large retrospective analysis includ-ing more than 400 kidney recipients16, Saged-al, et al. showed that in absence of either prophylaxis or preemptive strategies, CMV infection at a subclinical level as detected by pp65 antigenemia was associated with in-creased risk for overall and cardiovascular mortality. The authors additionally showed that subclinical CMV disease during the first

100 days after transplantation increased the risk for subsequent rejection27.

As opposed to a universal prophylaxis strategy, the preemptive strategy involves the administration of antiviral drugs only in those patients who reach a certain threshold level of viral activity28. Thus, patients managed by a preemptive strategy develop significantly higher levels of subclinical CMV replication compared to those managed by a prophy-laxis strategy. These two distinct approaches have allowed for the comparison of outcomes with respect to asymptomatic infection29.

We have shown that in heart transplant recipients managed by a preemptive strategy, asymptomatic CMV infection was associated with increased risk of developing CAV, de-fined as abnormal coronary remodeling one year after transplantation30. In this study, an-tiviral treatment was administered only to pa-tients who developed > 30 pp65 positive cells per 105 polymorphonuclear cells, consistent with the preemptive approach. In a subse-quent prospective study undertaken at Stan-ford, despite universal antiviral prophylaxis with ganciclovir, CMV DNA indicating active infection was detected in over 90% of the patients, who however remained asymptom-atic. In the majority of patients developing CMV infection (80%), CMV was detected only after discontinuing prophylaxis, raising the question of the importance of the duration and type of CMV prophylaxis. To address this question, we compared the outcomes in pa-tients receiving a “standard regimen” of intra-venous ganciclovir for 28-days, compared to D+/R– patients who received a more aggres-sive regimen consisting in three months of (val-)ganciclovir and CMV hyperimmune se-rum (CMVIG)31. Despite being at higher risk for CMV activation because of the serological mismatch, recipients treated with the aggres-sive regimen showed delayed and reduced CMV infection rates and, most importantly, a reduced risk of acute rejection and CAV as


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compared to patients treated with the stan-dard regimen.

More recently, pursuing the hypothesis that an aggressive anti-CMV strategy could reduce CAV development in CMV-positive re-cipients, we compared the outcomes of pa-tients managed with a preemptive strategy with a consecutive cohort receiving a 40-day course of valganciclovir, followed by CMV monitoring and additional treatment when patients developed > 30 pp65 positive cells per 105 polymorphonuclear cells. In this study, the aggressive strategy led to a delayed and reduced magnitude of CMV infection. Most importantly, the prophylaxis-based strategy was associated with a reduced increase in coronary maximal intimal thickness one year after transplantation (Fig. 1)29.

Taken together, the findings of these studies suggest a pathophysiological role of CMV in chronic graft failure, limiting long-term outcome in heart transplant recipients. Most important, the recent data suggest that such chronic damage to the graft may progress unabated, even in the absence of overt clini-cal CMV disease32. Randomized clinical trials are required to confirm these observations.

Possible mechanisms of cytomegalovirus-mediated injury

Cytomegalovirus drives a complex in-teraction with the recipient immune system that, under conditions of iatrogenic immuno-suppression, can promote a local proinflam-matory milieu, disrupt tolerogenic mecha-nisms, and exert immunosuppressive effects. These consequences of CMV infection di-rectly influence the alloimmune response in the transplant recipient and may explain the pathogenesis of CMV-induced CAV.

Interaction of CMV with the host in-flammatory response sets the stage for viral

replication and active CMV infection. Viral gly-coprotein B-mediated virion entry and interac-tion with host leukocyte toll-like receptors leads to activation of the transcription factor nuclear factor kappa B (NFκB), required for CMV transcription, even in the absence of complete viral particle33,34. The NFκB regu-lates many inflammatory cytokine genes and adhesion molecules and has recognition sites for the CMV major immediate early promoter35. Virus-cell interaction is sufficient for activation of NFκB, which is required to initiate the CMV transcription machinery33,35. In addition, trig-gering of NFκB by immuno-inflammatory stim-uli (e.g. infections or allograft recognition) contributes to CMV activation in cells harbor-ing latent infection, including monocytes dif-ferentiating into macrophages36. Of note, al-lograft transplantation, but not isograft transplantation, induces CMV reactivation in a murine model of latent infection37, and phar-macologic inhibition of NFκB may reduce en-dothelial cell replication of CMV in vitro38. Ac-tivation of NFκB stimulates endothelial cell

0.9

p = 0.001

0.8

0.7

0.6

0.5

0.4

0.3

0.2Cha

nge

in M

IT (

mm

)

0.1

0.0

–0.1Preemptive group

(n = 21)

MIT: maximal intimal thickness

Prophylaxis group(n = 19)

Figure 1. Changes in coronary maximal intimal thickness in patients treated with valganciclovir prophylaxis and in those followed by preemptive approach (reproduced with permission from elsevier)29.


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replication of CMV. Cytokines and chemok-ines induced by CMV and released over the course of the immune response activate en-dothelial cells, resulting in upregulation of ad-hesion molecules, increased class II major histocompatibility complex protein expres-sion, and the production of cytokines exacer-bating allograft inflammation39-43. In turn, these events are associated with the development of allograft vascular disease20,44.

In addition to stimulating the synthesis of inflammatory mediators by host cells, CMV encodes for chemokine and cytokine ho-mologs. Cytokine homolog genes are believed to favor viral spreading by inducing cell mi-gration and cell proliferation4. Particular im-portance has been ascribed to US28, a viral gene encoding a G-protein-coupled chemokine receptor homolog that induces smooth muscle cell proliferation45. In a rat model, deletion of the functional homolog of US28 rCMV led to reduced CMV-dependent transplant vascul-opathy46. It must be noted, however, that these CMV-dependent inflammatory mecha-nisms require allogeneic responses to accel-erate graft rejection because infected animals receiving syngeneic organs do not develop disease47. Therefore, interplay between CMV and the host immune system appears to be a crucial factor in CMV-associated graft injury.

A direct vascular effect of the activation of inflammatory mediators in the graft vascular system is reduced nitric oxide (NO) synthesis by endothelial layer, which rapidly becomes dysfunctional, impairing NO-mediated vasodi-lation48. Endothelial dysfunction is a mecha-nism preceding and associated with systemic and graft atherosclerosis49,50. Of note, CMV infection has been linked to endothelial dys-function of both graft coronary arteries and systemic vasculature in heart recipients51,52. Indeed, chronic endothelial dysfunction, and thus abnormal vascular response to injury, may explain the consistent finding of coronary lumen loss associated with negative remodeling,

instead of intimal hyperplasia, shown by CMV-infected patients53. A possible process in-volved in the induction of endothelial dysfunc-tion by CMV takes into account asymmetric dimethylarginine (ADMA)53,54. This ADMA is an endogenous inhibitor of endothelial NO synthesis, increases in conditions of intracel-lular oxidative stress, amplifies the disruption of endothelial homeostasis and thus may be regarded as a systemic marker of impaired endothelial function48,55,56. Cytomegalovirus infection is capable of increasing ADMA in cultured endothelial cells, and patients with CMV DNA detected in peripheral blood were shown to have higher ADMA plasma concen-trations and were more likely to develop CAV than recipients with no CMV detection53,54.

In addition to being associated with CAV pathogenesis, further negative effects of asymptomatic CMV infection on the periph-eral vascular system have been hypothesized by the group from the Great Ormond Street Children’s Hospital in London. In pediatric heart transplant recipients, these investigators show that children who experience asymptom-atic CMV infection develop chronic endothe-lial dysfunction in the systemic circulation. These data suggest that the consequences of CMV infection after transplantation may not only be limited to the allograft, and reinforce the concept that subclinical CMV replication may negatively influence later vascular health globally, even when it is no longer detectable in the circulation51.

The negative effect of CMV infection on graft tolerance has been elegantly investigat-ed in a recent study by Cook, et al.37. In a murine model of heart transplantation where tolerance may be effectively achieved with gallium nitrate treatment, recipients harboring latent CMV not only reactivate the virus, but also develop graft rejection leading to 80% of graft loss, as opposed to the 8% graft loss in CMV-negative recipients. Interestingly, while infiltrating the graft, CMV does not disrupt


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graft expression of regulatory genes, nor stim-ulate allograft-specific immunity, but induces intra-graft inflammatory response mediated by type I interferon upregulation, ultimately lead-ing to graft rejection37.

In addition to mechanisms inducing in-flammation, CMV exerts several effects relevant to immune-system escape and suppression of cellular immunity4, which, paradoxically, may be involved in acute rejection and CAV patho-genesis. In particular, the lack of CMV-specif-ic CD4-positive immunity in CMV-seropositive heart recipients appears to favor earlier onset and magnitude of CMV infection57-59. Further-more, recipients with delayed CMV-specific immunity had also an increased incidence of acute rejection and a more accelerated pro-gression of CAV detected by intravascular ultrasound (IVUS), as compared with those with early CMV-specific immunity57. Interest-ingly, similar findings have been reported also in kidney transplant recipients60. Taken togeth-er, these data suggest that CMV-specific im-munity is protective for preserving graft func-tion, and not induce allograft cross-reactivity. Moreover, we may speculate that the lack of CD4-positive activation is the consequence of a successful CMV strategy of immune sys-tem escape that indirectly favors graft injury.

Antiviral strategies to prevent transplant atherosclerosis

Two strategies are commonly recom-mended for the prevention of CMV infection and disease: universal prophylaxis and pre-emptive therapy28. Their rationales are based on two different preventive assumptions. Pro-phylaxis almost abolishes viral replication dur-ing the first weeks/months after transplanta-tion, when the burden of immunosuppression is higher, thereby delaying the eventual ap-pearance of the infection until a later phase of follow-up, by which time the immunosuppres-sive burden and risk of rejection is expected

to be lower. As opposed to prophylaxis, a preemptive strategy permits early low-grade viral replication in the belief that it may stimu-late the host’s own immune response against the virus and will reduce the number of pa-tients needing anti-CMV drugs61. A key issue in identifying the optimal strategy for preven-tion of CMV infection is the choice to limit or to allow asymptomatic CMV replication. In this paragraph, we discuss evidences supporting the graft-related benefit of approaches de-signed to suppress and prevent asymptom-atic CMV replication.

A large meta-analysis of randomized tri-als evaluating the effect of CMV prophylaxis in solid organ recipients showed that in addi-tion to a clear prevention of CMV disease, the universal prophylaxis strategy was associated to superior survival and lower rejection epi-sodes as compared to placebo62. This con-trasted with the observations from a meta-analysis of preemptive strategy trials in which the preemptive approach was shown to be effective in preventing CMV disease, but failed to demonstrate any effect on survival or graft-related endpoints63. Although it must be noted that in this systematic review, the small sam-ple size of preemptive studies may have hid-den its long-term efficacy; in two recent ran-domized studies, secondary analyses of graft-related endpoints suggested prolonged graft survival in kidney recipients receiving prophylaxis as compared with those followed with a preemptive approach64,65. In heart transplant recipients, with a non-randomized design, we have shown that aggressive anti-CMV approaches – based either on a pro-longed (val)ganciclovir and CMVIG regimen, or on valganciclovir prophylaxis followed by CMV monitoring and adjunctive treatment – are associated with lower progression of CAV as reflected by vascular remodeling66 and of intimal hyperplasia29.

In addition to antiviral drugs, new lines of evidence regarding the anti-CMV effect of


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inhibitors of the mammalian target of rapamy-cin (mTOR), such as sirolimus and everoli-mus, offer new strategies to limit the impact of CMV infection on graft function. These two drugs, approved for prevention of acute rejec-tion, have both been shown to reduce the occurrence of CMV infection in solid organ transplant recipients when compared with tacrolimus or mycophenolate67-70. Most impor-tantly, both drugs also reduce the progression of CAV by IVUS measurement of coronary artery intimal hyperplasia71,72. Of note, the anti-CMV effect of mTOR inhibitors depends on their ability to inhibit the cell proliferation machinery, and not on a direct effect on CMV proteins. Nevertheless, the magnitude of mTOR inhibitors’ action in limiting CMV infec-tion appears to exceed the protective effect of valganciclovir prophylaxis. Indeed, in a preliminary observational study73 including patients receiving valganciclovir prophylaxis or followed by preemptive strategy, we found that those receiving a maintenance immuno-suppression regimen that included everolimus developed less CMV infection than those re-ceiving mycophenolate. Importantly, while prophylaxis was effective in reducing CMV infection in mycophenolate-treated patients, patients receiving everolimus had such a low incidence of CMV infection that the advantage of prophylaxis over a preemptive strategy was no longer apparent. Thus, the use of mTOR inhibitors may represent a potent approach to minimize the risk of CMV reactivation and to limit CAV progression.

Immunomodulatory agents provide yet another strategy for preventing CMV infection, reducing its effects on allograft injury. We and others have shown that the combination of ganciclovir with CMVIG appears superior to ganciclovir alone in preventing acute rejection and CAV31,74,75. Although we cannot exclude that different durations of prophylaxis may be even more important, there is evidence that hyperimmune sera can provide an additional beneficial immunomodulation of host responses,

thereby reducing the risk of both acute CMV disease and rejection76,77. In addition to the effects of improved humoral immunomodula-tion associated with CMVIG therapy, modula-tion of CMV-specific cellular immunity appears to play a role in preventing CMV reactivation and CMV-mediated graft injury57. These data raise the hypothesis that interventions de-signed to augment increasing CMV-specific immunity (e.g. by development of a vaccine) may provide yet another strategy for protec-tion from CMV infection and CAV.

Taken together, these studies under-score the concept that aggressive limitation of even subclinical CMV infection with strate-gies based on prophylaxis with antiviral agents and/or hyperimmune sera and on maintenance immunosuppression regimens may effectively protect long-term graft function.

Conclusions

Although modern antiviral strategies significantly limit the immediate negative im-pact of CMV disease in heart transplant re-cipients, a growing body of evidence sug-gests that subclinical CMV infection leads to adverse long-term graft outcome. Several ex-perimental studies support the hypothesis that the mechanism of CMV-dependent graft dys-function is mediated by an active disruption of the interplay between graft and host’s im-mune system. Anti-CMV strategies aggres-sively targeting subclinical infection may ef-fectively limit these effects by means of prophylaxis with antiviral drugs, immune-sys-tem reconstitution approaches, or even by the selection of maintenance immunosuppres-sion. However, well designed randomized controlled studies are needed to confirm ob-servational data regarding the benefits of ag-gressive anti-CMV approaches and to ascer-tain whether such expected benefits outweigh cost and toxicity.


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References 1. Taylor DO, Edwards LB, Boucek MM, et al. Registry of the

International Society for Heart and Lung Transplantation: twenty-third official adult heart transplantation report–2006. J Heart Lung Transplant. 2006;25:869-79.

2. Valantine HA. Cardiac allograft vasculopathy: central role of endothelial injury leading to transplant “atheroma”. Trans-plantation. 2003;76:891-9.

3. Mehra M. Contemporary concepts in prevention and treat-ment of cardiac allograft vasculopathy. Am J Transplant. 2006;6:1248-56.

4. Mocarski E. Immune escape and exploitation strategies of cytomegaloviruses: impact on and imitation of the major histocompatibility system. Cell Microbiol. 2004;6:707-17.

5. Abate D, Watanabe S, Mocarski E. Major human cytomega-lovirus structural protein pp65 (ppUL83) prevents interferon response factor 3 activation in the interferon response. J Virol. 2004;78:10995-1006. *This paper dissects one of the mechanisms through which CMV induces immune evasion by modulating cellular gene-expression.

6. Vamvakopoulos J, Hayry P. Cytomegalovirus and transplant arteriopathy: evidence for a link is mounting, but the jury is still out. Transplantation. 2003;75:742-3.

7. Naraqi S. Cytomegalovirus. In: Textbook of Human Virology. Edited by: Mosby-Year Book inc. 1991;2:889-924.

8. Pescovitz MD. Is low-dose valganciclovir the same as appro-priate-dose valganciclovir? Transplantation. 2007;84:126.

9. Potena L, Holweg CT, Vana ML, et al. Frequent occult infection with Cytomegalovirus in cardiac transplant recipients despite antiviral prophylaxis. J Clin Microbiol. 2007;45:1804-10.

10. Rowshani AT, Bemelman FJ, van Leeuwen EM, van Lier RA, ten Berge IJ. Clinical and immunologic aspects of cyto-megalovirus infection in solid organ transplant recipients. Transplantation. 2005;79:381-6.

11. Steininger C. Clinical relevance of cytomegalovirus infection in patients with disorders of the immune system. Clin Micro-biol Infect. 2007;13:953-63.

12. Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med. 2007;357:2601-14.

13. Yust I, Fox Z, Burke M, et al. Retinal and extraocular cyto-megalovirus end-organ disease in HIV-infected patients in Europe: a EuroSIDA study, 1994-2001. Eur J Clin Microbiol Infect Dis. 2004;23:550-9.

14. Kas-Deelen AM, de Maar EF, Harmsen MC, Driessen C, van Son WJ, The TH. Uninfected and cytomegalic endothelial cells in blood during cytomegalovirus infection: effect of acute rejection. J Infect Dis. 2000;181:721-4.

15. Grefte A, van der Giessen M, van Son W, The TH. Circulat-ing cytomegalovirus (CMV)-infected endothelial cells in patients with an active CMV infection. J Infect Dis. 1993;167: 270-7.

16. Sagedal S, Hartmann A, Nordal KP, et al. Impact of early cytomegalovirus infection and disease on long-term recipi-ent and kidney graft survival. Kidney Int. 2004;66:329-37. *This is the first paper raising the hypothesis of adverse outcome caused by subclinical CMV infection.

17. Grattan M, Moreno-Cabral C, Starnes V, Oyer P, Stinson E, Shumway N. Cytomegalovirus infection is associated with cardiac allograft rejection and atherosclerosis. JAMA. 1989;261:3561-6.

18. Loebe M, Schuler S, Zais O, Warnecke H, Fleck E, Hetzer R. Role of cytomegalovirus infection in the development of coronary artery disease in the transplanted heart. J Heart Lung Transplant. 1990;9:707-11.

19. Mc Donald K, Rector S, Braunlin E, Kubo S, Olivari M. As-sociation of coronary artery disease in cardiac transplant recipients with cytomegalovirus infection. Am J Cardiol. 1989;64:359-62.

20. Koskinen P, Lemstrom K, Bruggeman C, Lautenschlager I, Hayry P. Acute cytomegalovirus infection induces a suben-dothelial inflammation (endothelialitis) in the allograft vascu-lar wall. Am J Pathol. 1994;144:41-50.

21. Merigan T, Renlund D, Keay S, et al. A controlled trial of ganciclovir to prevent cytomegalovirus disease after heart transplantation. N Engl J Med. 1992;326:1182-6.

22. Lemstrom K, Sihvola R, Bruggeman C, Hayry P, Koskinen P. Cytomegalovirus infection-enhanced cardiac allograft

vasculopathy is abolished by DHPG prophylaxis in the rat. Circulation. 1997;95:2614-16.

23. Valantine H, Gao S, Menon S, et al. Impact of prophylactic immediate posttransplant ganciclovir on development of transplant atherosclerosis. A post hoc analysis of a random-ized, placebo-controlled study. Circulation. 1999;100:61-6.

24. Gerna G, Percivalle E, Baldanti F, et al. Diagnostic signifi-cance and clinical impact of quantitative assays for diagno-sis of human cytomegalovirus infection/disease in immuno-compromised patients. New Microbiol. 1998;21:293-308.

25. Boeckh M, Huang M, Ferrenberg J, et al. Optimization of quantitative detection of cytomegalovirus DNA in plasma by real-time PCR. J Clin Microbiol. 2004;42:1142-8.

26. Emery VC, Sabin CA, Cope AV, Gor D, Hassan-Walker AF, Griffiths PD. Application of viral-load kinetics to identify pa-tients who develop cytomegalovirus disease after transplan-tation. Lancet. 2000;355:2032-6.

27. Sageda S, Nordal KP, Hartmann A, et al. The impact of cyto-megalovirus infection and disease on rejection episodes in renal allograft recipients. Am J Transplant. 2002;2:850-6.

28. Preiksaitis JK, Brennan DC, Fishman J, Allen U. Canadian society of transplantation consensus workshop on cytomeg-alovirus management in solid organ transplantation final report. Am J Transplant. 2005;5:218-27.

29. Potena L, Grigioni F, Magnani G, et al. Prophylaxis versus preemptive anti-cytomegalovirus approach for prevention of allograft vasculopathy in heart transplant recipients. J Heart Lung Transplant. 2009;28:461-7. *This is the first study com-paring prophylaxis with preemptive approach in heart trans-plant recipients towards a graft-related outcome.

30. Potena L, Grigioni F, Ortolani P, et al. Relevance of cyto-megalovirus infection and coronary-artery remodeling in the first year after heart transplantation: a prospective three-di-mensional intravascular ultrasound study. Transplantation. 2003;75:839-43.

31. Potena L, Holweg C, Chin C, et al. Acute rejection and cardiac allograft vascular disease is reduced by suppres-sion of subclinical cytomegalovirus infection. Transplanta-tion. 2006;82:398-405. *This study shows that suppression of subclinical CMV infection is associated with a slower CAV progression.

32. Thomas LD, Milstone AP, Miller GG, Loyd JE, Stephen Dummer J. Long-term outcomes of cytomegalovirus infec-tion and disease after lung or heart-lung transplantation with a delayed ganciclovir regimen. Clin Transplant. 2009; 23:476-83.

33. Compton T, Kurt-Jones EA, Boehme KW, et al. Human cy-tomegalovirus activates inflammatory cytokine responses via CD14 and Toll-like receptor 2. J Virol. 2003;77:4588-96.

34. Stassen FR, Vega-Cordova X, Vliegen I, Bruggeman CA. Immune activation following cytomegalovirus infection: more important than direct viral effects in cardiovascular disease? J Clin Virol. 2006;35:349-53.

35. Kowalik T, Wing B, Haskill J, Azizkhan J, Baldwin A, Huang E. Multiple mechanisms are implicated in the regulation of NFκB activity during human cytomegalovirus infection. Proc Natl Acad Sci USA. 1992;90:1107-11.

36. Laegreid A, Medvedev A, Nonstad U, et al. Tumor necrosis factor receptor p75 mediates cell-specific activation of nu-clear factor kappa B and induction of human cytomegalovi-rus enhancer. J Biol Chem. 1994;269:7785-91.

37. Cook CH, Bickerstaff AA, Wang JJ, et al. Disruption of mu-rine cardiac allograft acceptance by latent cytomegalovirus. Am J Transplant. 2009;9:42-53. *This paper shows an ele-gant experimental demonstration of a possible mechanism implicated in CMV-dependent graft injury.

38. Potena L, Frascaroli G, Grigioni F, et al. Hydroxymethyl-glutaryl coenzyme a reductase inhibition limits cytomegalo-virus infection in human endothelial cells. Circulation. 2004;109:532-6.

39. Sedmak DD, Knight DA, Vook NC, Waldman JW. Divergent patterns of ELAM-1, ICAM-1, and VCAM-1 expression on cytomegalovirus-infected endothelial cells. Transplantation. 1994;58:1379-85.

40. Knight DA, Waldman WJ, Sedmak DD. Cytomegalovirus-mediated modulation of adhesion molecule expression by human arterial and microvascular endothelial cells. Trans-plantation. 1999;68:1814-18.


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41. Waldman WJ, Knight DA. Cytokine-mediated induction of endothelial adhesion molecule and histocompatibility leuko-cyte antigen expression by cytomegalovirus-activated T cells. Am J Pathol. 1996;148:105-19.

42. Almeida GD, Porada CD, St Jeor S, Ascensao JL. Human cytomegalovirus alters interleukin-6 production by endothe-lial cells. Blood. 1994;83:370-6.

43. Smith PD, Saini SS, Raffeld M, Manischewitz JF, Wahl SM. Cytomegalovirus induction of tumor necrosis factor-alpha by human monocytes and mucosal macrophages. J Clin Invest. 1992;90:1642-8.

44. Lemstrom K, Koskinen P, Krogerus L, Daemen M, Brugge-man C, Hayry P. Cytomegalovirus antigen expression, en-dothelial cell proliferation, and intimal thickening in rat car-diac allografts after cytomegalovirus infection. Circulation. 1995;92:2594-604.

45. Melnychuk RM, Streblow DN, Smith PP, Hirsch AJ, Panche-va D, Nelson JA. Human cytomegalovirus-encoded G pro-tein-coupled receptor US28 mediates smooth muscle cell migration through Galpha12. J Virol. 2004;78:8382-91.

46. Streblow DN, Kreklywich CN, Smith P, et al. Rat cytomega-lovirus-accelerated transplant vascular sclerosis is reduced with mutation of the chemokine-receptor R33. Am J Trans-plant. 2005;5:436-42. *This paper shows the relevance of CMV genes encoding for cytokine homologues in the patho-genesis of CAV.

47. Orloff SL, Streblow DN, Soderberg-Naucler C, et al. Elimina-tion of donor-specific alloreactivity prevents cytomegalovi-rus-accelerated chronic rejection in rat small bowel and heart transplants. Transplantation. 2002;73:679-88.

48. Weis M, Cooke JP. Cardiac allograft vasculopathy and dys-regulation of the NO synthase pathway. Arterioscler Thromb Vasc Biol. 2003;23:567-75.

49. Tona F, Caforio A, Montisci R, et al. Coronary flow reserve by contrast-enhanced echocardiography: a new noninvasive diagnostic tool for cardiac allograft vasculopathy. Am J Transplant. 2006;6:998-1003.

50. Hollenberg SM, Klein LW, Parrillo JE, et al. Coronary en-dothelial dysfunction after heart transplantation predicts al-lograft vasculopathy and cardiac death. Circulation. 2001;104:3091-6.

51. Simmonds J, Fenton M, Dewar C, et al. Endothelial dysfunc-tion and cytomegalovirus replication in pediatric heart trans-plantation. Circulation. 2008;117:2657-61. *This study sug-gests that CMV subclinical infection may cause damage also to extra-graft vascular system.

52. Petrakopoulou P, Kubrich M, Pehlivanli S, et al. Cytomegalo-virus infection in heart transplant recipients is associated with impaired endothelial function. Circulation. 2004;110:207-12.

53. Potena L, Fearon WF, Sydow K, et al. Asymmetric dimethy-larginine and cardiac allograft vasculopathy progression: modulation by sirolimus. Transplantation. 2008;85:827-33.

54. Weis M, Kledal TN, Lin KY, et al. Cytomegalovirus infection impairs the nitric oxide synthase pathway: role of asymmet-ric dimethylarginine in transplant arteriosclerosis. Circula-tion. 2004;109:500-5.

55. Sydow K, Munzel T. ADMA and oxidative stress. Atheroscler Suppl. 2003;4:41-51.

56. Ito A, Tsao PS, Adimoolam S, Kimoto M, Ogawa T, Cooke JP. Novel mechanism for endothelial dysfunction: dysregula-tion of dimethylarginine dimethylaminohydrolase. Circula-tion. 1999;99:3092-5.

57. Tu W, Potena L, Stepick-Biek P, et al. T-cell immunity to subclinical cytomegalovirus infection reduces cardiac al-lograft disease. Circulation. 2006;114:1608-15. *This study raise the hypothesis that increased CMV specific immunity may effectively prevent CMV-mediated allograft dysfunction.

58. Westall G, Kotsimbos T, Brooks A. CMV-specific CD8 T-cell dynamics in the blood and the lung allograft reflect viral reactivation following lung transplantation. Am J Transplant. 2006;6:577-84.

59. Gerna G, Lilleri D, Fornara C, et al. Monitoring of human cytomegalovirus-specific CD4 and CD8 T-cell immunity in

patients receiving solid organ transplantation. Am J Trans-plant. 2006;6:2356-64.

60. Nickel P, Bold G, Presber F, et al. High levels of CMV-IE-1-specific memory T cells are associated with less alloimmu-nity and improved renal allograft function. Transpl Immunol. 2009;20:238-42.

61. Emery VC. Prophylaxis for CMV should not now replace pre-emptive therapy in solid organ transplantation. Rev Med Virol. 2001;11:83-6.

62. Hodson EM, Jones CA, Webster AC, et al. Antiviral medica-tions to prevent cytomegalovirus disease and early death in recipients of solid-organ transplants: a systematic review of randomised controlled trials. Lancet. 2005;365:2105-15.

63. Strippoli GF, Hodson EM, Jones C, Craig JC. Preemptive treatment for cytomegalovirus viremia to prevent cytomega-lovirus disease in solid organ transplant recipients. Trans-plantation. 2006;81:139-45.

64. Kliem V, Fricke L, Wollbrink T, Burg M, Radermacher J, Rohde F. Improvement in long-term renal graft survival due to CMV prophylaxis with oral ganciclovir: results of a ran-domized clinical trial. Am J Transplant. 2008;8:975-83.

65. Reischig T, Jindra P, Hes O, Svecova M, Klaboch J, Treska V. Valacyclovir prophylaxis versus preemptive valganciclovir therapy to prevent cytomegalovirus disease after renal transplantation. Am J Transplant. 2008;8:69-77.

66. Potena L, Holweg CT, Chin C, et al. Acute rejection and cardiac allograft vascular disease is reduced by suppres-sion of subclinical cytomegalovirus infection. Transplanta-tion. 2006;82:398-405.

67. Hill JA, Hummel M, Starling RC, et al. A lower incidence of cytomegalovirus infection in de novo heart transplant re-cipients randomized to everolimus. Transplantation. 2007;84: 1436-42.

68. Vigano M, Dengler T, Mattei MF, et al. Lower incidence of cytomegalovirus infection with everolimus versus mycophe-nolate mofetil in de novo cardiac transplant recipients: a randomized, multicenter study. Transpl Infect Dis 2009 [Epub ahead of print].

69. Demopoulos L, Polinsky M, Steele G, et al. Reduced risk of cytomegalovirus infection in solid organ transplant recipients treated with sirolimus: a pooled analysis of clinical trials. Transplant Proc. 2008;40:1407-10.

70. Haririan A, Morawski K, West MS, et al. Sirolimus exposure during the early post-transplant period reduces the risk of CMV infection relative to tacrolimus in renal allograft recipi-ents. Clin Transplant. 2007;21:466-71.

71. Eisen HJ, Tuzcu EM, Dorent R, et al. Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med. 2003;349:847-58.

72. Keogh A, Richardson M, Ruygrok P, et al. Sirolimus in de novo heart transplant recipients reduces acute rejection and prevents coronary artery disease at 2 years: a randomized clinical trial. Circulation. 2004;110:2694-700.

73. Potena L, D’Agostino C, Abate D, et al. Interaction of CMV prophylaxis and preemptive strategies with immunosuppres-sive therapy: potential antiviral effect of everolimus. J Heart Lung Transplant. 2010;29:S155-6.

74. Valantine H, Luikart H, Doyle R, et al. Impact of cytomega-lovirus hyperimmune globulin on outcome after cardiotho-racic transplantation. Transplantation. 2001;72:1647-52.

75. Ruttmann E, Geltner C, Bucher B, et al. Combined CMV prophylaxis improves outcome and reduces the risk for bronchiolitis obliterans syndrome (BOS) after lung transplan-tation. Transplantation. 2006;81:1415-20.

76. Toyoda M, Petrosyan A, Pao A, Jordan SC. Immunomodu-latory effects of combination of pooled human gamma-globulin and rapamycin on cell proliferation and apoptosis in the mixed lymphocyte reaction. Transplantation. 2004;78: 1134-8.

77. Jordan SC, Vo A, Bunnapradist S, et al. Intravenous immune globulin treatment inhibits crossmatch positivity and allows for successful transplantation of incompatible organs in liv-ing-donor and cadaver recipients. Transplantation. 2003;76: 631-6.

Lydia Barrera Pulido, et al.: Calcineurin Inhibitor-Free Maintenance with MMF

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Calcineurin Inhibitor-Free Maintenance Therapy After Liver Transplantation I: Mycophenolate Mofetil and Renal FunctionLydia Barrera-Pulido, José María Álamo-Martínez, Miguel Ángel Gómez-Bravo, Carmen Bernal-Bellido, Luis Miguel Marín-Gómez, Gonzalo Suárez-Artacho, Juan Serrano-Díez Canedo and Francisco Javier Padillo-Ruiz

Hepatobiliopancreatic Surgery and Liver Transplant Unit, Virgen del Rocio University Hospital, Seville, Spain


Lydia Barrera Pulido

Unidad de Cirugía Hepato Bilio Pancreática

y trasplantes

Hospital Universitario Virgen del Rocío

Av. manuel Siurot s/n, 41013

Sevilla, españa


Abstract

It has been widely reported that continued therapy with calcineurin inhibitors can cause an up to fourfold increase in morbidity and mortality in long-term liver transplant patients due to the development of chronic renal failure as well as neurotoxicity, arterial hypertension, hyperglycemia, hyperlipidemia, and increased risk of de novo tumors.These side effects have led to the development of other treatment options that allow these drugs to be minimized or withdrawn.Mycophenolate mofetil is one of the immunosuppressive drugs that has made it possible to discontinue calcineurin inhibitors in liver transplantation. Its side effects are mainly related to the gastrointestinal tract and bone marrow. Furthermore, it lacks nephrotoxic, metabolic, and neurological effects.In the last decade numerous papers have been published, based on the study of liver trans-plant patients treated with mycophenolate mofetil monotherapy in different countries. They analyzed the safety and efficacy of this therapy, focusing primarily on its effect on chronic renal failure, metabolic complications, and incidence of graft rejection.After reviewing all these works we know that mycophenolate mofetil therapy reduces cal-cineurin inhibitor-induced renal damage by allowing minimization of the doses of these drugs and their subsequent withdrawal. It has been widely shown that the switch to mycophenolate mofetil monotherapy improves and maintains stable serum creatinine and creatinine clear-ance values as well as improving hypertension and hyperlipidemia in the long term.On the other hand, most studies found that the improvement in the clinical variables analyzed occurred in the first three months after conversion, so it is clear that a large part of the renal damage and other side effects are induced by the calcineurin inhibitors because it is in that period when the largest reduction is made in the dose of these drugs until their complete withdrawal.


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Introduction

In 1980, a new class of immunosup-pressive agents called calcineurin inhibitors (CNI) was developed. This allowed the safety of the immunosuppressive regimens used in liver transplantation (LTx) to be improved, since the use of these CNI provided a consid-erable reduction in the risk of suffering rejec-tion and also increased short-term survival1. As a result, CNI, either tacrolimus or cy-closporine, are a key element in all baseline immunosuppression therapies.

However, it has been widely reported that continued use of these drugs can cause up to a fourfold increase in morbidity and mor-tality in long-term liver transplant patients due to the development of chronic renal failure (CRF), as well as neurotoxicity, arterial hyper-tension, hyperglycemia, hyperlipidemia and increased risk of de novo tumors2-4.

The incidence of CRF at five years post-transplantation is high, and although its origin

is multifactorial, in over 70% of cases renal damage is directly related to the CNI dose.

It is also known that hemodialysis and even renal transplantation is required in nearly 10% of patients with end-stage renal disease; this was analyzed in detail in a study of 834 patients with 13 years of post-LTx follow-up5.

The nephrotoxic impact, among others, caused by these CNI has led to the develop-ment of other treatment options that allow these drugs to be minimized or withdrawn, mainly in the maintenance phase, and thus reduce the incidence and prevalence of CRF.

One of the immunosuppressive drugs that has made it possible to discontinue these CNI in LTx is mycophenolate mofetil (MMF). This is a semi-synthetic ester of mycophenolic acid, which acts as a potent inhibitor of the proliferation of B and T lymphocytes6. Its side effects are mainly related to the gastrointestinal tract (diarrhea, nausea, abdominal pain, etc.)

However, these variables continue to improve after withdrawal so we should consider that the long-term effect of mycophenolate mofetil monotherapy is beneficial.The disparity in the incidence of rejection in the different studies presented should be high-lighted, but nevertheless, they all have in common the fact that rejections occurred in the majority of cases in the first three months after the start of conversion.The side effects of mycophenolate mofetil, such as gastrointestinal complications and he-matological problems, were reversed in most cases simply by a temporary reduction in the drug dose, so we can consider that the benefits outweigh the risks in this regard.Based on all the studies analyzed, we can infer that the ideal patient for long-term with-drawal of calcineurin inhibitors is a patient who clearly has calcineurin inhibitor-induced chronic renal failure and is not on dialysis, who has not suffered severe acute rejection episodes in the last year, and who has not shown intolerance to mycophenolate mofetil previously. (Trends in Transplant. 2010;4:117-28)

Corresponding author: Lydia Barrera Pulido, [email protected]

Key words

Calcineurin inhibitor. Chronic renal failure. Mycophenolate mofetil. Monotherapy. Acute rejection.


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and bone marrow (leukopenia, thrombopenia, and anemia). Furthermore, it lacks nephro-toxic, metabolic, and neurological effects.

The first steps towards MMF monother-apy were made in studies where MMF was introduced due to CNI-induced renal toxicity, with the consequent reduction in the doses of these CNI7-9.

Pfitzmann, et al. conducted a study in a series of 101 patients receiving both tacrolimus and cyclosporine as CNI, who developed CNI-induced CRF and were treated by reducing the dose of CNI and adding MMF to treatment.

The results obtained were a reduction in serum creatinine (SCr 0.4 mg/dl; p < 0.001) after a mean follow-up of 40 months. Of these 101 patients, 56 also had graft dys-function, and it was found that they also showed improvements versus baseline in bilirubin (p < 0.019) and alkaline phos-phatase (p < 0.002) from 2.9 ± 0.8 to 1.3 ± 0.3 mg/dl and from 321 ± 41 to 208 ± 18 UI/l, respectively. It should be noted that there were two patient deaths from sepsis and renal dys-function and that MMF therapy was associated with a high rate of side effects (37 patients): gastrointestinal (n = 26), bone marrow toxicity (n = 9), and infections (n = 2). However, the rate of acute rejection did not increase with respect to standard full-dose CNI therapy7.

On the other hand, Cantarovich, et al. analyzed 19 LTx patients receiving cy-closporine who developed posttransplant renal dysfunction induced by this drug. They reported a clear improvement in renal func-tion evaluation parameters with the intro-duction of MMF and reduction in cyclosporine dose, since mean creatinine clearance (CrCl) increased by 18 ml/min (p < 0.02) and mean glomerular filtration rate by 24 ml/min (p = 0.002); in addition, 71% of patients who were receiving antihypertensive therapy were able to discontinue it. However, the rate of

acute rejection as a result of the treatment change was high (29%)8.

A third study on CNI dose reduction for CRF by the introduction of MMF was published by Beckebaum, et al.9. It was randomized study (2:1) in which all patients were diagnosed with CRF and it compared the changes in different clinical variables (mainly related to renal func-tion) between the control group, which contin-ued with normal doses of CNI monotherapy, versus the case group in which MMF was in-troduced and CNI doses were minimized.

After three months of follow-up, signifi-cant improvements were observed in the group receiving low-dose CNI but not in the group receiving standard therapy.

Mean values of SCr decreased from 1.88 ± 0.36 to 1.58 ± 0.33 mg/dl (p < 0.001) and CrCl increased from 51.4 ± 10.8 to 61.6 ± 14.1 ml/min (p < 0.001).

The authors also suggested that de-spite the fact that the mean time from LTx to the start of treatment was 5.6 ± 3.6 years, CNI-induced renal damage appeared to be partially reversible.

They also found that the group of pa-tients with low-dose CNI and MMF improved their lipid profile and blood pressures at three months, and more importantly, they found that transaminases were significantly reduced.

The efficacy of MMF therapy in im-proving CRF and its safety on liver graft function was thus demonstrated in patients with CNI-induced toxicity.

Mycophenolate mofetil monotherapy

Since numerous studies have shown that use of MMF allows CNI doses to be minimized


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safely and effectively in LTx, the next step to achieve CNI-free therapies would be to con-sider immunosuppressive regimens without them7-9.

A long-term treatment option could be MMF monotherapy, as this would largely avoid the side effects of CNI, mainly chronic renal disease, arterial hypertension, hyperlipidemia, hyperglycemia, and de novo tumors.

In the last decade, a considerable num-ber of studies have been generated on this topic, where it can be seen that there are some authors with results favorable to MMF monotherapy as a safe, long-term treatment in LTx, while others found that the risk was greater than the benefit (Table 1).

One of the first published studies on this problem was that of Herrero, et al., who attempt-ed conversion to MMF monotherapy in a group of 11 patients with CRF (SCr > 1.5 mg/dl), stable liver function, and no episodes of acute rejection within one year before the treatment change. All patients were started on full doses of MMF (2 g/day), simultaneously slowly re-ducing the dose of cyclosporine. After a mean time of 15 months, seven patients had achieved CNI-free therapy with MMF, with SCr decreasing from 2.22 ± 0.13 mg/dl at baseline to 1.90 ± 0.19 mg/dl and CrCl increasing from 38.16 ± 5.60 to 47.01 ± 6.76 ml/min (p = 0.005). In addition, these patients experienced an im-provement in control of arterial hypertension, with a reduction in the number of antihyper-tensive drugs, as only two of seven patients required antihypertensive treatment at the end of follow-up.

The side effects observed were those expected for MMF, and in six patients the dose had to be reduced due to mild anemia.

Complete conversion to MMF was not achieved in four of 11 patients as two patients were switched to tacrolimus due to acute re-

jection (18%) and another two continued with low-dose cyclosporine.

The results seemed quite promising since the patients considerably improved re-nal function and tolerance of MMF was good. The incidence of rejection was also accept-able since it was easily reversed and no graft loss or patient death occurred10.

However, several years later two stud-ies were published with the same objectives of conversion to MMF monotherapy to mini-mize CRF from CNI, with very unpromising results since despite improving renal function the incidence of acute rejection increased alarmingly11,12.

The first study was conducted by Stew-art, et al. and consisted of a case-control study. The study enrolled patients with CRF who in some cases also had associated arte-rial hypertension. The initially estimated num-ber of patients was 18, of which nine would be the control group (treated with azathioprine and CNI) and the case group would be com-posed of another nine patients treated with MMF monotherapy with slow CNI tapering.

However, when five patients had al-ready been enrolled, the study had to be dis-continued because of the high rate of severe organ rejection (two chronic rejections and one acute rejection). The consequence was that two of the five patients had to be re-transplanted soon (mean 4 months) after start-ing the study and one patient received steroid therapy for acute rejection. Therefore, the risk posed by this treatment was unacceptable, independently of whether it improved renal function parameters11.

Schlitt, et al. obtained similar results to the previous group. They designed a case-control study with 28 patients; 14 patients continued with standard CNI therapy and the other 14 patients in the case group were con-


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verted to MMF monotherapy. Eight patients from the latter group continued with steroids combined with MMF, so only six were treated with MMF monotherapy. Of these, three pa-tients suffered recurrence of hepatitis C virus accompanied by mild rejection, one patient stopped treatment due to intolerable diarrhea, and the two remaining patients also devel-oped moderate acute cellular rejection12.

This discrepancy of results between the different groups led to the generation of more controlled studies with larger numbers of pa-tients in which it was attempted to analyze long-term MMF monotherapy, taking special care due to the high risk of rejection and con-sequent organ loss. Fortunately, the studies that were published in successive years pre-sented results of series with rejection inci-dence rates not superior, in the majority of cases, to 10-15%13-15,17-20.

In 2003, the data from Raimondo, et al. were published. They conducted a study with 45 patients, all with CRF associated with CNI; one of the treatment arms was formed by pa-tients on MMF monotherapy (n = 16) in doses of 2 g/day. The mean follow-up period was 24 months, SCr values improved in five of eight patients who completed the two years of treatment from 1.79 mg/dl (1.20-3.36) at baseline to 1.22 mg/dl (97-2.15) at the end of the study13.

Four patients died from causes not di-rectly related to immunosuppression with MMF monotherapy. Only one case of acute rejection (6%) was diagnosed in the 16 pa-tients included, and interestingly, it was the only patient who had had rejection prior to inclusion in the study. The authors concluded that the presence of rejection episodes could be a risk factor to be considered when decid-ing on monotherapy.

This may be what occurred in the stud-ies by Stewart and Schlitt, as it is not defined

if the patients randomized in their studies had previously suffered any episode of acute re-jection. Perhaps this, among other factors, explains their high rate of rejection.

Therefore, the fact that MMF monother-apy is clearly beneficial in improving renal function in patients who only have CNI neph-rotoxicity is unquestionable, even if therapy is started several years after LTx, because al-though in many cases normalized values of SCr or CrCl are not achieved, an improvement in renal function is obtained.

One year later, three new studies were published that help to improve our learning about CNI-free therapy with MMF monothera-py through the experience of different centers performing LTx14-16.

The first study carried out by Koch, et al. included 32 patients with CRF who were split into two groups according to time since LTx. Thus, one group was formed by pa-tients less than six months posttransplanta-tion (n = 14) and the other by patients who were transplanted more than six months previ-ously (n = 18)14.

In 88% of patients, there was a signifi-cant reduction in SCr values from 2.63 ± 0.39 to 1.74 ± 0.34 mg/dl. Furthermore, a higher proportion of patients normalized SCr values in the group with early MMF conversion: 64% versus 22% in the second group. As a nega-tive point, it should be noted that three pa-tients had to be entered in hemodialysis, but it should be clarified that none of them had diabetic nephropathy.

As in previous studies, the rejection rate was minimal at 6% (2/32 patients), and may have been because patients with previous episodes of severe rejection were not exclud-ed. Special mention should be made of the fact that five patients died in this study: two from cardiovascular problems, one from de novo


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Table 1. Studies about treatment in monotherapy with MMF in LTx with CRF induced by CNIs

Author Year of publication,city

Type of study Number of

patients

Follow-up from LTx to

conversion (months)

Indication for conversion

Type of CNI

MMF daily dose (grams)

Patients on MMF

monotherapy at the end

of the study

Acute rejection

Follow-up time

(months)

Adverse effects of MMF

Patients who developed

intolerance to MMF

Improvement of renal function

Improvement of arterial

hypertension

Death

Herrero, et al.10 1999, Pamplona

Prospective 11 32 CRF CsA 2 6/11 (55%) 2/11 (18%) 15 6/11 (55%) 0/11 (0%) 10/11 (91%) 6/7 (86%) 0/11 (0%)

Stewart, et al.11 2001, Newcastle

Prospective randomized case-control

5 Not specified CRFHypertension

CsA 2 2/5 (40%) 3/5(60%) 0 – – – – 0/5 (0%)

Schlitt, et al.12 2001, Hannover


14 76 CRF CsA/Tac 2 6/14 (42.8%) 5/14 (36%) 6 8/14 (57%) 0/14 (0%) 11/14 (79%) 14/14 (100%) 0/14 (0%)

Raimondo, et al.13 2003, London

Retrospective 16 45 CRF CsA/Tac 2 8/16 (50%) 1/16 (6%) 33 2/16 (13%) 0/16 (0%) 5/8 (63%) – 4/16 (25%): 3 recurrences,

1 alcoholic, 1 HCV

and 1 HCC.1 de novo tumor

Moreno-Planas, et al.15

2004, Madrid

Prospective 50 81 CRFHypertension

CsA/Tac 2 39/50 (78%) 5/50 (10%) 18 26/50 (52%)

3/50 (6%) 32/40 (80%) 24/32 (75%) 2/50 (4%): alcoholic recurrence

Koch, et al.14 2004, Innsbruck

Prospective 32 25.6 CRF CsA/Tac 2 9/32 (28%) 2/32 (6%) 57 17/32 (53%)

0/32 (0%) 8/9 (88%) – 5/32 (16%): 2 cardiovascular

problem, 1 de novo neoplasm, 1 tumor

recurrence, 1 sepsis

Fairbanks and Thuluvath16

2004, Baltimore

Retrospective 13 69 CRFHistoplasmosis

CsA/Tac Not specified 11/13 (85%) 3/13 (23%) 22 Minimal 0/13 (0%) No significant improvement

– 3/13 (23%): 2 severe liver failure

due to alcoholic recurrence,

1 HCV recurrence

Pierini, et al.17 2005, Turin

Retrospective 32 50 CRFDe novo tumor

CsA/Tac 1.5 32/32 (100%) 1/32 (3%) 17.9 9/32 (28%) 0/32 (0%) Significant improvement

(% not specified)

– 0/32 (0%)

Orlando, et al.18 2007, Rome

Prospective 42 70.5 CRFHypertensionHyperlipidemiaHyperuricemiaGingival hyperplasia

CsA/Tac 1.5 41/42 (98%) 9/42 (21%) 24 7/42 (17%) 0/42 (0%) 31/36 (89%) 4/5 (80%) 0/42 (0%)

Barrera-Pulido, et al.20

2008, Seville

Prospective 31 87 CRF CsA/Tac 2 31/31 (100%) 0/31 (0%) 12 5/31 (16%) 0/31 (0%) 21/31 (67.7%) – 0/31 (0%)

Ko, et al.19 2008, Vancouver

Retrospective 15 135 CRF CsA/Tac 2 12/15 (80%) 1/15 (7%) 10 5/15 (33%) 3/15 (20%) 13/15 (87%) – 0/15 (0%)

Kamphues, et al.21 2009, Berlin

Retrospective 123 91 CRF CsA/Tac 2 123/123 (100%)

0/123 (0%) 12 Minimal 0/123 (0%) Significant improvement

(% not specified)

– 0/123 (0%)

LTx: liver transplantation; CNI: calcineurin inhibitor; MMF: mycophenolate mofetil; CRF: chronic renal failure; CsA: cyclosporin A; Tac: tacrolimus; HCV: hepatitis C virus; HCC: hepatocellular carcinoma.


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Table 1. Studies about treatment in monotherapy with MMF in LTx with CRF induced by CNIs

Author Year of publication,city

Type of study Number of

patients

Follow-up from LTx to

conversion (months)

Indication for conversion

Type of CNI

MMF daily dose (grams)

Patients on MMF

monotherapy at the end

of the study

Acute rejection

Follow-up time

(months)

Adverse effects of MMF

Patients who developed

intolerance to MMF

Improvement of renal function

Improvement of arterial

hypertension

Death

Herrero, et al.10 1999, Pamplona

Prospective 11 32 CRF CsA 2 6/11 (55%) 2/11 (18%) 15 6/11 (55%) 0/11 (0%) 10/11 (91%) 6/7 (86%) 0/11 (0%)

Stewart, et al.11 2001, Newcastle


5 Not specified CRFHypertension

CsA 2 2/5 (40%) 3/5(60%) 0 – – – – 0/5 (0%)

Schlitt, et al.12 2001, Hannover


14 76 CRF CsA/Tac 2 6/14 (42.8%) 5/14 (36%) 6 8/14 (57%) 0/14 (0%) 11/14 (79%) 14/14 (100%) 0/14 (0%)

Raimondo, et al.13 2003, London

Retrospective 16 45 CRF CsA/Tac 2 8/16 (50%) 1/16 (6%) 33 2/16 (13%) 0/16 (0%) 5/8 (63%) – 4/16 (25%): 3 recurrences,

1 alcoholic, 1 HCV

and 1 HCC.1 de novo tumor

Moreno-Planas, et al.15

2004, Madrid

Prospective 50 81 CRFHypertension

CsA/Tac 2 39/50 (78%) 5/50 (10%) 18 26/50 (52%)

3/50 (6%) 32/40 (80%) 24/32 (75%) 2/50 (4%): alcoholic recurrence

Koch, et al.14 2004, Innsbruck

Prospective 32 25.6 CRF CsA/Tac 2 9/32 (28%) 2/32 (6%) 57 17/32 (53%)

0/32 (0%) 8/9 (88%) – 5/32 (16%): 2 cardiovascular

problem, 1 de novo neoplasm, 1 tumor

recurrence, 1 sepsis

Fairbanks and Thuluvath16

2004, Baltimore

Retrospective 13 69 CRFHistoplasmosis

CsA/Tac Not specified 11/13 (85%) 3/13 (23%) 22 Minimal 0/13 (0%) No significant improvement

– 3/13 (23%): 2 severe liver failure

due to alcoholic recurrence,

1 HCV recurrence

Pierini, et al.17 2005, Turin

Retrospective 32 50 CRFDe novo tumor

CsA/Tac 1.5 32/32 (100%) 1/32 (3%) 17.9 9/32 (28%) 0/32 (0%) Significant improvement

(% not specified)

– 0/32 (0%)

Orlando, et al.18 2007, Rome

Prospective 42 70.5 CRFHypertensionHyperlipidemiaHyperuricemiaGingival hyperplasia

CsA/Tac 1.5 41/42 (98%) 9/42 (21%) 24 7/42 (17%) 0/42 (0%) 31/36 (89%) 4/5 (80%) 0/42 (0%)

Barrera-Pulido, et al.20

2008, Seville

Prospective 31 87 CRF CsA/Tac 2 31/31 (100%) 0/31 (0%) 12 5/31 (16%) 0/31 (0%) 21/31 (67.7%) – 0/31 (0%)

Ko, et al.19 2008, Vancouver

Retrospective 15 135 CRF CsA/Tac 2 12/15 (80%) 1/15 (7%) 10 5/15 (33%) 3/15 (20%) 13/15 (87%) – 0/15 (0%)

Kamphues, et al.21 2009, Berlin

Retrospective 123 91 CRF CsA/Tac 2 123/123 (100%)

0/123 (0%) 12 Minimal 0/123 (0%) Significant improvement

(% not specified)

– 0/123 (0%)

LTx: liver transplantation; CNI: calcineurin inhibitor; MMF: mycophenolate mofetil; CRF: chronic renal failure; CsA: cyclosporin A; Tac: tacrolimus; HCV: hepatitis C virus; HCC: hepatocellular carcinoma.


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pancreatic neoplasm, one from recurrence of cholangiocarcinoma, and one from sepsis due to cholangitis.

The second study, published in 2004 with optimum results in terms of rejection with MMF monotherapy, was that of Moreno, et al.15. Fifty patients were converted to this treatment because of CNI-associated toxicity: 45 had CRF (in 11 associated with arterial hypertension) and five had hypertension as the only complication.

At 18 months, 78% of patients were no longer receiving CNI as immunosuppressive treatment. The SCr values decreased from 1.81 to 1.49 mg/dl (p < 0.0001), CrCl in-creased from 44.7 to 55.1 ml/min (p < 0.0001); therefore, 80% of patients achieved an im-provement in renal function.

An acute rejection rate seen was 10% (five patients). Side effects occurred in 52% of patients and consisted mainly of asthenia, diarrhea, and viral infections.

In conclusion, this study reinforces the idea that MMF monotherapy late after LTx is well tolerated and safe and clearly improves CNI-induced CRF and hypertension.

In contrast to the two previous studies is a third retrospective study published in the same year and including 13 patients with CRF16. The results obtained for the incidence of rejection in this series were rather more dangerous at 28% (three of the 13 patients included). In addition to these three patients, two died due to rejection and another had to be re-transplanted.

With regard to renal function, even though conversion to MMF was indicated for CRF, MMF therapy was not effective in some cases as four patients required dialysis. How-ever, in those not requiring dialysis, SCr val-ues were decreased from 2.51 ± 1.12 to 1.85

± 0.58 mg/dl (p = 0.01), as has been widely reported in the studies we are analyzing.

These data led to the use of MMF mono-therapy being questioned again as this study attributed a 19% risk of death to treatment with MMF alone.

The results lead us to think that special care should be taken when selecting patients and the time of conversion to be sure that the benefit outweighs the risk associated with the use of this therapy.

Fortunately, in the previous year the re-sults of the study by Italian group from Turin were published in which they retrospectively analyzed their experience with MMF mono-therapy17.

Conversion to MMF was at a median of 50 months post-LTx in 32 patients (for CRF in 30 and de novo tumors in two), and over 90% were receiving cyclosporine as the CNI. Unlike the regimens of the other centers, the mean dose of MMF administered was 1.5 g/day.

Once more, the positive effect of MMF monotherapy on renal function was confirmed, with baseline SCr values decreasing from 2.02 to 1.7 mg/dl (p = 0.0001). The rejection rate was also minimal as only one case was diagnosed among the 32 patients (3%).

Obviously, the treatment change was not free of side effects, as was also reported by other authors, such as diarrhea (12.5%) and leukopenia (15.6%).

Two years later, Orlando, et al. pub-lished their experience with 42 patients18. In this case, they attempted to optimize MMF monotherapy in order to avoid the high inci-dence of MMF-related side effects. Therefore, they converted all patients to MMF therapy at initial doses of 1.5 g/day instead of 2 g/day (standard therapy).


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Another novel feature of this study is the expansion of the indications for monotherapy: only for CRF (n = 22), CRF associated with hyperlipidemia (n = 10), hypercholesterolemia (n = 4), CRF associated with hyperlipidemia and hypertension (n = 2), hypercholesterolemia associated with hypertension (n = 1) and gin-gival hyperplasia (n = 1).

Calcineurin inhibitors were reduced by 25% monthly until permanent withdrawal (mean of 4.5 months).

Of the 35 patients included for CRF, 31 improved their renal function at one year, as SCr decreased from 1.8 ± 0.4 to 1.56 ± 0.4 mg/dl and CrCl increased from 47.8 ± 10.4 to 57.6 ± 17 ml/min (p < 0.05). They also ob-tained considerable improvements in patients converted for hyperlipidemia, as triglycerides decreased in 14 of 17 patients (82%) and cholesterol in 12 of 13 patients (92%) at one year and the reductions were maintained at two years of follow-up. In addition, three of the five patients who were being treated with sta-tins were able to discontinue this treatment.

Conversion also allowed blood pres-sure to be controlled and improved (80%), as two of the four patients who were receiving antihypertensive treatment were able to dis-continue it at five and seven months after con-version to MMF.

However, it should be noted that there was a high incidence of suspected rejection episodes, all within the first six months after conversion, since they occurred in nine of the 42 patients studied (21%). In any case, the au-thors state that this does not represent an im-portant clinical problem as no graft loss or un-treatable rejection occurred. In fact, all rejections were reversed by increasing the MMF dose to 2 g/day and/or optimizing the CNI dose.

A very positive finding of this study was the considerable reduction in side effects

related to MMF. Only seven of 42 patients (16%) experienced any side effect: nausea and vomiting in two patients, asthenia in two, leuko-thrombopenia in three, and herpes zoster skin infection in one patient. It should be stressed that no case required treatment discontinuation.

This article demonstrated the efficacy of MMF monotherapy in doses of 1.5 g/day to improve renal function, dyslipidemia, and hy-pertension as well as its relative safety. How-ever, the authors stress that it was at three months from the start of conversion when a frank improvement was observed in most pa-tients, that is when CNI had been reduced by 75%. Therefore, they propose the idea that perhaps it is not necessary to completely with-draw the CNI, but rather to reduce them to a minimum and simultaneously administer MMF in doses of 1.5 g/day, with the consequent reduction in undesirable effects.

Subsequently, in 2008, the experiences of another two centers were published who treated their long-term liver transplant patients with CNI-free therapies based on MMF19,20.

The first study conducted by Ko, et al. in Vancouver has a clear limitation because the sample size is small (18 patients) and the median follow-up time is very short, in addition to being done retrospectively19.

No dialysis patients were included who had suffered a rejection episode in the year previous to conversion, nor patients who had CRF induced by any other cause than CNI toxicity.

Nevertheless, the results obtained pro-vide quite a lot of information since they ana-lyzed the effect of conversion to MMF mono-therapy at three and six months post conversion and, like other authors, conclud-ed that a significant improvement occurred in the different clinical variables during the


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first three months, with no differences be-tween the third and sixth month. Median SCr values at baseline were 1.44 mg/dl: 1.29 mg/dl at three months (p = 0.001) and 1.39 mg/dl at six months (p = 0.008).

Side effects were those usually seen with MMF. Three patients experienced gastro-intestinal intolerance (one had to discontinue MMF), one had anemia (also discontinued MMF), and one had atrial fibrillation (despite being unrelated to MMF, it was discontinued as a precaution).

In terms of graft function, only one pa-tient experienced elevated liver enzymes, which was considered acute rejection (6.7%), although biopsy was not performed, and was treated by adding sirolimus to immunosup-pressive treatment.

The second published series was car-ried out prospectively at our institution, Virgen del Rocio University Hospital in Seville20. Like the other groups, we made the switch to MMF monotherapy in patients with CNI-induced CRF, slowly reducing the CNI dose by 25% every 2-3 months up to complete withdrawal. Unlike the experiences of other authors, our patients were not on CNI monotherapy and subsequently switched to MMF, but were al-ready receiving this dual therapy previously.

Like the previous authors, we excluded from the study patients who were on dialysis, patients with CRF not induced by CNI, pa-tients with chronic rejection or any episode of acute rejection in the last year, and finally we excluded patients who were receiving dual immunosuppressive therapy (CNI plus MMF) and who had shown intolerance to MMF in full doses (2 g/day).

The mean time from LTx to monothera-py was 87 months (range 14-186 months) and the minimum follow-up time post conversion was 12 months.

The different clinical variables analyzed improved significantly between three and six months posttransplantation and remained stable at 12 months. Thus, mean SCr values were reduced from 1.63 ± 0.47 mg/dl at baseline to 1.49 ± 0.33 mg/dl at six months (p < 0.05).

No significant side effects were record-ed, although we had to change the dose of MMF in three cases due to gastrointestinal disturbances and reduce the dose in two pa-tients because of mild leukopenia.

With regard to graft function, there was no case of graft loss or rejection.

Therefore, we also concluded that this therapy based on MMF is effective and safe provided that patients are carefully selected and closely monitored. Nevertheless, we must continue longer-term evaluation of these pa-tients because most currently continue on this immunosuppressive therapy.

The last study published in 2009 on CNI-free therapy based on MMF was conduct-ed by the group of Kamphues, et al. in Berlin21. It is a retrospective analysis of 123 liver trans-plant patients in whom MMF monotherapy was carried out effectively for CNI-induced CRF. They only included patients who com-pleted conversion to MMF and did not suffer acute rejection episodes in the first three months after conversion from CNI to MMF. They present and analyze the experience of other groups in terms of the incidence of re-jection and the results they obtained showed that most rejections occur at three months after the switch to monotherapy11,12,18; there-fore, if they eliminate this group of patients from the start they can evaluate the real effect of treatment with MMF alone.

They also included another novelty with respect to previous studies, since in 59 of the 123 patients they performed biopsies before


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and after conversion (although not at a spe-cific time pre- and post-LTx) to evaluate the histopathological changes that might be caused by the drug in the organ, including acute rejection, chronic rejection, fibrosis, ste-atosis, etc.

The results obtained were very positive as no episode of chronic or acute rejection was recorded in 12 months of follow-up post conversion. Fibrosis was observed in eight of 59 patients (13%), a lower grade of fibrosis was detected in 14 patients (24%), and fibro-sis remained stable versus the pre conversion MMF biopsy in 37 patients (63%).

On the other hand, an increase in liver fat content was detected in 24 of the 59 patients (41%). In addition, mean fat content of all patients analyzed by biopsy (n = 59) was significantly increased from 9.8 ± 15.9% before conversion to MMF monotherapy to 16.1 ± 21.0% after conver-sion (p < 0.05).

The authors were unable to explain this pathophysiological effect of increased fat in the liver, and were also unable to compare their experience with that of other groups because this was the first study in which bi-opsy was done before and after the start of treatment.

As this effect of MMF on liver tissue has not been reported by other authors, it would be of great utility to design a prospective study with protocol biopsies before and after conversion to see if the results are repeated in patients from other groups; this would help us to further advance our knowledge on the safety of this CNI-free therapy.

In their study, as in the rest of the previously mentioned studies, renal function was significantly improved from baseline SCr values of 1.54 ± 0.59 to 1.47 ± 0.61 mg/dl at 12 months.

Conclusions

After reviewing all the above studies, we know that MMF therapy reduces CNI-in-duced renal damage by allowing minimization of the doses of these drugs and their subse-quent withdrawal. It has been widely shown that the switch to MMF monotherapy improves and maintains stable SCr and CrCl values as well as improving hypertension and hyperlipi-demia in the long term.

On the other hand, most studies found that the improvement in the clinical variables analyzed occurred in the first three months after conversion, so it is clear that a large part of the renal damage and other side effects are induced by the CNI because it is in that pe-riod when the largest reduction is made in the dose of these drugs until their complete with-drawal. However, these variables continue to improve after withdrawal so we should con-sider that the long-term effect of MMF mono-therapy is beneficial.

The disparity in the incidence of rejec-tion in the different studies presented should be highlighted, but, nevertheless, they all have in common that rejections occurred in the majority of cases in the first three months after the start of conversion.

The side effects of MMF, such as gas-trointestinal complications and hematological problems, were reversed in most cases sim-ply by a temporary reduction in the drug dose so we can consider that the benefits outweigh the risks in this regard.

Therefore, special care should be taken to have an adequate degree of immunosup-pression, to analyze well as to when after LTx we should consider the switch to MMF mono-therapy and when we should completely with-draw the CNI because we must select very carefully the patients who may benefit from this therapy.


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Based on all the studies analyzed, we can infer that the ideal patient for long-term withdrawal of CNI is a patient who clearly has CNI-induced CRF and is not on dialysis, who has not suffered severe acute rejection epi-sodes in the last year, and who has not shown intolerance to MMF previously.

References 1. Olyaei AJ, De Mattos AM, Bwnnett WM. Nephrotoxicity of

immunosuppressive drugs: new insight and preventive strat-egies. Curr Opin Crit Care. 2001;7:384.

2. Danovitch GM. Immunosuppressant-induced metabolic tox-icities. Transplant Rev. 2000;14:65-81.

3. Monsour HP, Wood RP, Dyer CH, et al: Renal insufficiency and hypertension as long-term complications in liver trans-plantation. Semin Liver Dis. 1995;15:123.

4. Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med. 2003;349:931. **Interesting paper, with a very large cohort of nonrenal transplant patients, which concludes that the development of chronic renal failure increases the risk of death fourfold.

5. Gonwa TA, Mai ML, Melton LB, et al. End-stage renal disease (ESRD) after orthotopic liver transplantation (OLTX) using calcineurin-based immunotherapy: risk of development and treatment. Transplantation. 2001;72:1934-9. *Role of CNI in the long-term develop-ment of end-stage renal disease with required dialysis and renal transplantation.

6. Ascher NL. Immunosuppressant substitutes in liver trans-plantation. Lancet. 2001;357:571-2.

7. Pfitzmann R, Klupp J, Langrehr JM, et al. Mycophenolate mofetil reduces calcineurin inhibitor-induced side effects after liver transplantation. Transplant Proc. 2002;34: 2936.

8. Cantarovich M, Tzimas GN, Barkun J, Deschenes M, Alpert E, Tchervenkov J. Efficacy of mycophenolate mofetil com-bined with very low-dose cyclosporine microemulsion in long-term liver-transplant patients with renal dysfunction. Transplantation. 2003;76:98-102.

9. Beckebaum S, Cicinnati VR, Klein CG, et al. Impact of com-bined mycophenolate mofetil and low-dose calcineurin in-hibitor therapy on renal function, cardiovascular risk factors, and graft function in liver transplant patients: preliminary results of an open prospective study. Transplant Proc. 2004;36:2671-4. *Suggests that the renal damage caused by CNI is partially reversible.

10. Herrero JI, Quiroga J, Sangro B, et al. Conversion of liver transplant recipients on cyclosporine with renal impairment to mycophenolate mofetil. Liver Transpl Surg. 1999; 5:414-20. *First study that demonstrates the efficacy and safety of the monotherapy with MMF in LTx patients.

11. Stewart SF, Hudson M, Talbot D, et al. Mycophenolate mofetil monotherapy in liver transplantation. Lancet. 2001;357:609-11. *This paper shows a high risk of rejection using MMF in monotherapy.

12. Schlitt HJ, Barkmann A, Böker KH, et al. Replacement of calcineurin inhibitors with mycophenolate mofetil in liver-transplant patients with renal dysfunction: a randomised controlled study. Lancet. 2001;357:587-91.

13. Raimondo ML, Dagher L, Papatheodoridis GV, et al. Long-term mycophenolate mofetil in combination with calcineurin inhibitors for chronic renal dysfunction after liver transplanta-tion. Transplantation. 2003;75:186-90. **Indicates that previ-ous rejection events prior to monotherapy with MMF, in-creases the risk of other acute rejection.

14. Koch RO, Gaziadei IW, Schulz F, et al. Long-term efficacy and safety of mycophenolate mofetil in liver transplant re-cipients with calcineurin-induce renal dysfunction. Trans-plant Int. 2004;17:518-24. *Introduces the concept of early conversion to MMF monotherapy to reverse kidney failure.

15. Moreno JM, Cuervas-Mons V, Rubio E, et al. Mycophenolate mofetil can be used as monotherapy late after liver trans-plantation. Am J Transplant. 2004;4:1650-5. *Shows the suc-cess of monotherapy with MMF in improving CRF and hy-pertension induced by CNI.

16. Fairbanks KD, Thuluvath PJ. Mycophenolate mofetil mono-therapy in liver transplant recipients: a single center experi-ence. Liver Transpl. 2004;10:1189-94.

17. Pierini A, Mirabella S, Brunati A, Ricchiuti A, Franchello A, Salizzoni M. Mycophenolate mofetil monotherapy in liver transplantation. Transpl Proc. 2005;37:2614-15.

18. Orlando G, Baiocchi L, Cardillo A, et al. Switch to 1.5 grams MMF monotherapy for CNI-related toxicity in liver transplan-tation is safe and improves renal function, dyslipidemia and hypertension. Liver Transpl. 2007;13:46-54. **Extends the indication of the use of the monotherapy of MMF at doses of 1.5 g/day in case of metabolic syndrome. Furthermore, adverse drug effects were substantially reduced.

19. Ko HH, Greanya E, Lee TK, Steinbrecher UP, Erb SR, Yoshi-da EM. Mycophenolate mofetil in liver transplant patients with calcineurin-inhibitor-induced renal impairment. Ann He-patol. 2008;7:376-80.

20. Barrera Pulido L, Alamo Martínez JM, Pareja Ciuró F, et al. Efficacy and safety of mycophenolate mofetil monotherapy in liver transplant patients with renal failure induced by cal-cineurin inhibitors. Transplant Proc. 2008;40:2985-7.

21. Kamphues C, Bova R, Röcken C, et al. Safety of mycophe-nolate mofetil monotherapy in patients after liver transplanta-tion. Ann Transplant. 2009;14:40-6. *Confirms that most rejec-tions occur three months after the change to monotherapy.

Beatriz Domínguez-Gil, et al.: Kidney Transplantation from Donors with a Positive Serology for Hepatitis C

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Kidney Transplantation from Donors with a Positive Serology for Hepatitis C: The Facts and the ChallengesBeatriz Domínguez-Gil 1, Nuria Esforzado 2, Amado Andrés 3, Jose M Campistol 2 and Jose M Morales 3

1National Transplant Organization, Madrid, Spain; 2Nephrology Service, Clinic i Provincial Hospital, Barcelona, Spain; 3Nephrology Service, 12 de Octubre Hospital, Madrid, Spain


Correspondence to:

Beatriz Domínguez-Gil

Organización Nacional de trasplantes

C/ Sinesio Delgado 6, pabellón 3

28029 madrid, españa


Abstract

The use of kidneys from donors with a positive serology for hepatitis C virus into recipients with anti-HCV-positive antibodies seems to be a safe approach in the long term. Results provided by center-based experiences show a favorable outcome of HCV-positive recipients in terms of graft survival, patient survival, and HCV-related liver disease with kidneys trans-planted from HCV-positive donors. Registry studies have raised doubts on the safety of this approach, but do not represent a standardized policy. The safety of this policy can be im-proved by limiting the transplantation of these kidneys to patients with a positive HCV RNA before transplantation and, ideally, by matching donors and recipients according to the HCV genotype. Kidneys from HCV-positive donors are being lost today because of remaining doubts that seem to be reasonably overcome nowadays and by the lack of appropriate re-cipients. Organizational measures, such as devising preemptive transplantation for HCV RNA-positive recipients accepting to be transplanted with kidneys from HCV-positive donors, and international cooperation seem essential to avoid the loss of these organs at a moment of dramatic organ shortage. (Trends in Transplant. 2010;4:129-37)

Corresponding author: Beatriz Domínguez-Gil, [email protected]

Key words

Kidney transplantation. Hepatitis C. Interferon. Liver disease. Donors.

Introduction

Organ transplantation has become a con-solidated therapy which saves the lives or im-proves the qualities of life of about 100,000 pa-tients worldwide every year1. However, one of

the main obstacles that preclude the full de-velopment of transplantation is the shortage of organs to satisfy the need. At the end of 2009 there were 63,000 patients in the waiting list for an organ in the European Union, while only about 28,000 transplant procedures were performed during that entire year2. The UNOS registry shows a rather similar dramatic situa-tion for the USA. In November 2010 more than 100,000 patients were registered in the wait-ing list, but the number of transplant proce-dures performed annually in that country is about 28,0003. As a consequence of short-age, patients with low survival expectancies


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might not be included in the lists and many will deteriorate or die while waiting to be trans-planted. Added to the unequal distribution of wealth in the world, organ shortage is the root case for unacceptable practices such as or-gan trafficking and transplant tourism4.

Different strategies have been devised to increase organ availability, including the use of organs from expanded criteria donors5 and from non standard risk donors. A hazard of a decreased graft survival is assumed in the first case and a hazard of donor-derived diseases in the second. Since hepatitis C vi-rus (HCV) infection is transmitted through or-gan transplantation, donors with a positive serology for hepatitis C virus (HCVD+) are included in the latter group6-12. Controversies regarding the safety of transplanting kidneys from HCVD+ have been overcome at least partially in the last years through the evidence provided by center-based experiences. How-ever, some centers do not accept kidneys from HCVD+ for transplantation yet. Moreover, there are countries with technical or legal pro-visions in place that preclude the transplanta-tion of organs from these donors13. In parallel, progress in the therapeutic approach to end-stage renal disease patients with an HCV in-fection raises doubts about the usefulness of policies for the transplantation of kidneys from HCVD+. This article intends to provide an up-date on the facts about the use of kidneys from these donors and the related challenges for the coming years.

Transmission of HCV infection through kidney transplantation

Soon after the description of HCV in 198914, several units published their experi-ences in the transplantation of kidneys from HCV RNA-positive donors6-12,15. The HCV in-fection was transmitted through kidney trans-plantation, although the rate of transmission ranged between 1410 and 100%8, depending

on the series. Moreover, the clinical conse-quences of the transmission of HCV infection were also variable. Pereira, et al.8 showed that 50% of the patients acquiring HCV infection through kidney transplantation developed cri-teria of chronic liver disease (CLD), something otherwise infrequent in the experience of the Columbus University12. Variability among the se-ries with regards to the viral load in the trans-planted organ, the infectivity of the HCV strain involved, the volume of the preservation solu-tion, the preservation method used, and the diagnostic tests applied might justify these heterogeneous results9,16.

These experiences lead to the general consensus that kidneys from HCVD+, regard-less of HCV RNA, should not be transplanted into recipients with a negative HCV serology (HCVR–)16. In parallel, the question to be an-swered was whether these organs could be safely transplanted into HCVR+. There were arguments against this approach: (i) anti-HCV antibodies are not protective and not indica-tive of a viremic state, and (ii) several HCV genotypes have been described, so superin-fection with another HCV genotype could po-tentially occur17. But there were also strong arguments in favor of this policy: (i) the preva-lence of HCV antibodies among organ donors may be high in specific countries or geograph-ical areas, so universally discarding these or-gans could exacerbate organ shortage; (ii) cardiovascular-related rather than liver-related morbidity and mortality is by far the most fre-quent after kidney transplantation; and (iii) there is still today a residual risk of discarding a do-nor with a false positivity for HCV antibodies.

Experiences with the use of kidneys from HCV-positive donors into HCV-positive recipients

Based on the abovementioned argu-ments in favor of their use, in March 1990 two Spanish kidney transplant units initiated a


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pilot experience with the transplantation of kidneys from HCVD+ into HCVR+. First results revealed the short-term safety of this policy. Graft and patient survival of HCVR+ was sim-ilar regardless of HCV serology of their do-nors. A similar percentage of patients in both groups developed biochemical criteria con-sistent with CLD (ALT levels > 2.5 times the upper normal limit during more than six con-secutive months)18,19. Nonetheless, the policy did not prevent the transmission of HCV infec-tion. Retrospectively, HCV RNA was assessed in donors and recipients through the poly-merase chain reaction (PCR) technique. Three different situations were described when us-ing kidneys from HCVD+ into HCVR+19. First, when HCV RNA was detectable in both the donor and the recipient, no negative clinical consequences were apparent in the post-transplant period. As expected, also no nega-tive consequences were observed if the donor was HCV RNA negative and the recipient ex-hibited a positive HCV RNA. The situation to be avoided was when the donor was HCV RNA positive and the recipient HCV RNA neg-ative, a circumstance described in five pa-tients within the series. Four of them became HCV RNA positive after transplantation and two developed CLD, as previously defined. As a result of these findings, in March 1993 both Spanish groups modified their policy of using kidneys from HCVD+ by limiting their use to those patients in the waiting list who exhibited a positive HCV RNA before transplantation. This approach was then nationally adopted with the support of the Spanish National Trans-plant Organization.

Other single-center experiences with the same approach as the Spanish one have later been published (Table 1)20-25. Conclusions are rather similar among these groups: no out-standing differences are observed in HCVR+ who have received a kidney transplant from an HCVD+ compared to those transplanted from an HCVD-, at least in the short term. Moreover, some of these series have demonstrated that

time in the waiting list for HCVR+ is signifi-cantly shorter when these patients are trans-planted from HCVD+21,22,24. Furthermore, ac-cording to these experiences in kidney transplantation, livers from HCVD+ have been transplanted into HCVR+ with good results26.

The information derived from these pre-viously described experiences have been the basis for international guidelines and recom-mendations on the use of kidneys from HCVD+ for transplantation in a safe way, avoiding their loss at a moment of organ shortage27-29.

In contrast to the positive results ob-tained in center-based experiences, registry studies have offered contradictory results. By using the U.S. Renal Data System registry, Abbot, et al. evaluated the outcome of recipi-ents transplanted from HCVD+ versus HCVD-30,31. No apparent differences were noticed in terms of graft survival. However, patient sur-vival was significantly worse in recipients transplanted from HCVD+, irrespective of HCV serology of the recipient. The increased risk of death among recipients of HCVD+ kid-neys was delayed for two years, which sug-gested the development of an intermediate complication that resulted in a later increased risk of death32. The observed higher incidence of posttransplant diabetes mellitus (PTDM) among recipients of kidneys from HCVD+ could be the reason behind this32. These data made the authors conclude that caution should be paid to the use of organs from HCVD+ and that careful and complete infor-mation should be provided to the potential recipient of these organs before transplanta-tion33. However, when taking a careful look at these papers it is important to note that kid-neys from HCVD+ had been used into pa-tients with a worse baseline clinical and im-munological situation compared to recipients of kidneys from HCVD-. Factors associated with the use of kidneys from HCVD+ were advanced donor and recipient age, African American race, and a high rate of dialysis


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Table 1. Main results of the center-based experiences with the use of kidneys from HCV-positive versus HCV-negative donors in HCV-positive recipients

Ali20 Kasprzyk25 Mandal21 Morales35 Veroux24 Woodside22

D+/R+ D-/R+ D+/R+ D-/R+ D+/R+ D-/R+ D+/R+ D-/R+ D+/R+ D-/R+ D+/R+ D-/R+

Number 28 16 60 199 19 10 162 306 28 16 20 20

Follow-up (months)

36 (12-60) 12-156 15.4 (SD = 2)

74.5 23 26.3 34.9

Acute rejection

50% 68% – 42% 50% 42.1% 37.2% 10% 14.2% 20% 25%

Graft survival

86% 78% 70% 89% 70% 47%(10 yr)

58.5%(10 yr)

90% 88% 89%(1 yr)

79%(1 yr)

Patient survival

86% 95% 85% 89% 90% 72.7% 76.5% 100% 94% 89%(1 yr)

94%(1 yr)

Acute liver dysfunction

16%* – – 16%‡ 10%‡ 16.1%* 11.6%* – – – –

Chronic liver dysfunction

9%† 11%§ 10%§ 9.8%¶ 6.2%¶ – – – –

Time in the waiting list (months)

– – – – 9 (SD = 3)**

29 (SD = 3)**

– – 9 24 9.9 (SD = 1.8)**

17.8 (SD = 3.3)**

D: donor; R: recipient; SD: standard deviation.*ALT > 2.5 times the upper normal limit for more than 2 weeks, but less than 6 months. †ALT > 2.5 times the upper normal limit for more than 6 consecutive months.‡ALT > 2 times the upper normal limit. §ALT > 2 times the upper normal limit for more than 3 months. ¶Decompensated liver disease: At least one episode of ascites, hepatic encephalopathy and/or gastrointestinal bleeding due to ruptured gastrointestinal varices. **p < 0.05.

access complications31,32. It is also important to note that the previously described studies reflected a lack of a specific policy on the use of organs from HCVD+, since they were also used into HCVR-, and there was no informa-tion available on the HCV RNA status of the recipients at the time of transplantation. Fi-nally, also by using the U.S. Renal Data Sys-tem registry, it has been shown that receiving a kidney from an HCVD+ is independently associated with improved patient survival compared with remaining in the waiting list (adjusted HR: 0.76; 95% CI: 0.60-0.96)34.

Latest evidence on the safety of trans-planting kidneys from HCVD+ into HCVR+ has been offered by the Spanish groups pilot-ing the first experiences (Table 1)35. For the very first time, information has been offered

on the long-term outcome (mean follow-up 74.5 months) of 162 HCVR+ transplanted from HCVD+ (group 1) versus 306 HCVR+ trans-planted from HCVD- (group 2). No differences were observed in patient survival. Only three deaths in group 1 and two deaths in group 2 were liver disease related. On the contrary, there was a trend towards a lower death-cen-sored graft survival and a significantly lower non censored for death graft survival in pa-tients transplanted from HCVD+. This could be due to differences in baseline demograph-ic and clinical variables: group 1 exhibited a higher donor and recipient age and, as ex-pected, a more frequent recipient pretrans-plant viremic state (HCV RNA positive), result-ing from the allocation policy applied since 1993. This theory is supported by Mahmoud, et al. who have described a higher frequency


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of chronic allograft nephropathy among HCV RNA-positive recipients36. Nevertheless, the Cox-regression analysis performed in the Span-ish experience (Table 2) could not identify the donor HCV-positive serology as a significant risk factor for death or graft loss. Moreover, decompensated CLD (at least one episode of ascites, hepatic encephalopathy and/or gas-trointestinal bleeding due to ruptured gastro-intestinal varices) occurred in 10.3 vs. 6.2% of the patients (p = ns), respectively in both groups. Donor HCV-positive serology was not an independent risk factor for the evolution towards a situation of advanced liver disease, as previously defined (Table 2). Although de novo PTDM occurred more frequently in group 1, HCVD+ was not identified as an independent risk factor in the multivariate analysis. No dif-ferences were observed in the incidence of posttransplant glomerular disease between the two groups.

Limitations of this latest experience are challenges for research in the near future:

Information on HCV RNA among HCVD+ –was lacking, but the practice of testing do-nors with nucleic acid testing has only been recently suggested27. Knowledge about the HCV RNA of donors, however, should not substantially modify the alloca-tion strategy applied to the use of kidneys from HCVD+.

No information has been provided on the –HCV genotype of both donors and recipi-ents, something important to evaluate the incidence of superinfection and its conse-quences.

Information on the evaluation of HCV liver –disease has been assessed clinically but not histologically. Because liver biopsies were not routinely performed in the series, whether the histological outcome of HCV-related liver disease is different (stable or progressive liver fibrosis)37 in HCVR+ transplanted from HCVD+ versus HCVD- still remains to be answered.

Table 2. Factors independently associated to patient death, graft loss, and decompensated chronic liver disease in the multivariate analysis performed in the Spanish experience35

Patient death* Graft loss* Decompensated CLD†

P OR 95% CI P OR 95% CI P OR 95% CI

HCVD+ 0.22 0.709 0.412-1.223 0.18 1.248 0.902-1.726 0.92 1.048 0.429-2.560

Donor age – – – < 0.001 1.022 1.012-1.032 – – –

Recipient age < 0.001 1.075 1.049-1.102 – – – – – –

PRA ≥ 50% – – – < 0.001 1.912 1.367-2.674 – – –

Pretransplantcardiovascular disease

0.05 1.850 0.997-3.432 – – – – – –

Delayed graft function – – – 0.03 1.417 1.031-1.949 – – –

Acute rejection – – – < 0.001 1.778 1.304-2.425 – – –

NODAT 0.003 2.883 1.447-5.746 – – – – – –

Moderate CLD‡ – – – – – – < 0.001 9.462 3.887-23.030

Decompensated CLD§ 0.03 2.883 1.447-5.746 – – – – – –

CLD: chronic liver disease; HCVD+: positive serology for HCV; PRA: panel-reactive antibody; NODAT: new onset diabetes after transplantation.*Cox regression analysis. †Logistic regression analysis. ‡ALT > 2.5 times the upper normal limit for more than 6 consecutive months. §At least one episode of ascites, hepatic encephalopathy and/or gastrointestinal bleeding due to ruptured gastrointestinal varices.


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Decreasing the risk of HCV transmission when using kidneys from HCV-positive donors into HCV-positive recipients

As demonstrated by the Spanish groups, the policy of transplanting kidneys from HCVD+ into HCVR+ does not complete-ly prevent the transmission of HCV infection. Hence, this option should be limited to those candidates for kidney transplantation with a positive HCV RNA in the waiting list. This means that patients with a positive serology for HCV and a positive HCV RNA are the ones to be offered the possibility of receiving a kidney from an HCVD+, always with appropri-ate information on the special characteristics of these potential donors.

In a very elegant exercise, Natov and Pereira analyzed the consequences of four different approaches to the use of kidneys from HCVD+38. The following assumptions were made: 2.4% prevalence of HCV antibod-ies among deceased donors, second genera-tion ELISA test with 100% sensitivity and 98% specificity, 100% transmission of infection with the use of kidneys from HCV RNA-posi-tive donors, 20% prevalence of HCV infection among patients under dialysis therapy, and absence of clinical consequences of HCV su-perinfection. No restriction on the use of or-gans from HCVD+ (all organs used irrespec-tive of HCV serology of the recipients) would be related to 0% of graft losses, but 2.4% of transmission of the infection and 2% of new infections. With a universal restriction on the use of these organs (no organ used irrespec-tive of HCV serology of the recipient), no transmission or new infection would occur but 4.2% of organs would be lost. By using or-gans from HCVD+ into HCVR+, 0% of graft losses would occur but a risk of transmission (2.4%) and new infection (0.5%) would per-sist. The best balance seemed to be achieved with the restriction of organs from these do-nors to recipients with a positive HCV RNA

before transplantation, with a theoretical occur-rence of 2.4% of transmission of HCV infection but 0% of new infections and no graft losses.

Therefore, the policy of using kidneys from HCVD+ into HCVR+ seems to be safer when the organs are exclusively placed into recipients with a positive HCV RNA before transplantation. But superinfection with a dif-ferent HCV genotype may still occur. Studies in a posttransfusion hepatitis C infection mod-el in chimpanzees have demonstrated that a preexisting infection with HCV did not protect from reinfection with a different genotype or even the same viral genotype39. Likewise, kid-ney transplant patients with a baseline HCV infection are not protected from a superinfec-tion with a new HCV genotype17. Although mixed infection has not been associated with an increased mortality in a recent study40, at least one clinical report on a severe liver dis-ease has been published when using a kid-ney from an HCVD+ into an HCVR+, when donor and recipient were infected by a differ-ent HCV genotype (genotype 1 to genotype 2)41. Therefore, matching donor and recipient according to the HCV genotypes involved should still improve results by reducing the risk of HCV transmission, although limited by obvious time constraints. Besides, depending on the HCV genomic heterogenicity within a specific geographical area, the possibilities of a mismatch between donor and recipient should be balanced.

Is there a place today for the use of HCV-positive donors into HCV-positive recipients: making this policy compatible with interferon therapy before transplantation

It has been documented that survival of HCVR+ is significantly better than that of matched patients who remain in the waiting list34,42,43. Therefore, kidney transplantation is


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the best therapy for patients with HCV infection and end-stage renal disease. However, HCVR+ have proven to exhibit a worse long-term graft and patient survival than HCVR-44-50. Also, HCV infection has been related to the development of posttransplant complications, such as de novo PTDM51, posttransplant glomerulone-phritis52-54, proteinuria and chronic allograft nephropathy55, after kidney transplantation.

Notably, treatment with interferon (IFN) before kidney transplantation may be related to a decreased incidence of posttransplant HCV-related glomerulonephritis56. Interferon therapy in 50 HCV RNA-positive patients sig-nificantly decreased the incidence of chronic allograft nephropathy57. In spite of this, treat-ment with IFN before transplantation in HCV-infected patients has not been related yet to benefits in terms of graft or patient survival.

The problem of anti-HCV therapy is that IFN increases the risk of allograft dysfunction and therefore its use in kidney transplant pa-tients is contraindicated, with the exception of patients with fibrosing cholestatic hepati-tis15,27,58,59. Therefore, the best strategy is to treat HCV infection in patients on dialysis before transplantation15,27,52,58-62. While in the past rec-ommendations on end-stage renal disease pa-tients with HCV infection were based on the liver clinical and histological situation15, the neg-ative clinical consequences of HCV infection after kidney transplantation constitute the basis to indicate therapy with IFN, independently of the stage of the liver disease, in order to im-prove the outcomes after transplantation27.

Treatment of HCV infection before trans-plantation with the aim of a sustained viro-logic response is obviously not compatible with the use of HCVD+ into HCVR+. However, the limitations of HCV antiviral therapy should be taken into consideration: a wide range of adverse events has been described with IFN therapy, the rate of nonresponding patients is not negligible63,64, the treatment is long and

during this time the patients should be ex-cluded from the waiting list, and finally it is an expensive treatment not universally afford-able. Therefore, a group of end-stage renal disease HCV RNA-positive patients would not be candidates for antiviral treatment, some will refuse to be treated, or will not respond or withdraw the therapy. These patients, despite presenting a positive HCV RNA before trans-plantation should be placed into the waiting list since their outcome will be better than re-maining under dialysis34,65-67. It is in this con-text where the possibility of being transplanted with a kidney from an HCVD+ could be of-fered, with the potential advantage of reducing the time in the waiting list. Even the possibility of preemptive kidney transplantation with or-gans from HCVD+ for these recipients could be offered. The rationale behind this is simple. The prevalence and the incidence of HCV in-fection is decreasing among patients with end-stage renal disease. The number of HCV RNA-positive patients in the list is progressively less and most of them are immunologically high-risk patients. Hence, there are a number of kidneys from HCVD+ which are not transplant-ed because of the lack of an appropriate re-cipient. Organizational measures should hence be developed in order to allow preemptive transplantation in these exceptional cases.

Finally, some countries may probably not consider the universal approach of treat-ing HCV RNA-positive patients under dialysis because of economic reasons. Unfortunately, these countries are usually those with a high-er prevalence of HCV infection among their donors and their recipients. The policy of us-ing HCVD+ for HCVR+ could be a safe ap-proach in these populations.

Conclusions

The use of kidneys from HCVD+ into HCVR+ seems to be a safe approach in the long term and a way of using these kidneys


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that otherwise would be lost. Results provided by center-based experiences show a favor-able outcome of HCVR+ in terms of graft sur-vival, patient survival, and HCV-related liver disease when transplanted from HCVD+. Registry studies have raised doubts on safety but do not represent a standardized policy. The safety of this approach can be improved by limiting the transplantation of these kidneys to patients with a positive HCV RNA before transplantation and, ideally, by matching do-nors and recipients according to their HCV genotype. Donor HCV-positive kidneys are be-ing lost today because of remaining doubts that seem to be reasonably overcome nowadays and by the lack of appropriate recipients. Or-ganizational measures such as devising pre-emptive transplantation for HCV RNA-positive recipients accepting to be transplanted with HCVD+ kidneys and international cooperation seem essential to avoid the loss of these organs at a moment of dramatic organ shortage.

References 1. Global Observatory on Donation and Transplantation. Avail-

able at: http://www.transplant-observatory.org/pages/home.aspx. Last access: November 2010.

2. International figures on donation and transplantation 2009. Newsletter Transplant 2010; 15 (1). Website of the Orga-nización Nacional de Trasplantes. Avaialable at: http://www.ont.es/publicaciones/Documents/Newsletter2010.pdf. Last access: November 2010. **Most comprehensive publication on international donation and transplantation activities.

3. Organ Procurement and Transplant Network website. Avail-able at: http://optn.transplant.hrsa.gov/latestData/step2.asp?. Last access: November 2010.

4. Steering Committee of the Istanbul Summit. Organ traffick-ing and transplant tourism and commercialism: the Declara-tion of Istanbul. Lancet 2008; 372(9632): 5-6. **Land-mark reference international professional statement on organ traf-ficking.

5. Port FK, Bragg-Gresham JL, Metzger RA, Dykstra DM, Gillespie BW, Young EW, Delmonico FL, Wynn JJ, Merion RM, Wolfe RA, Held PJ. Donor characteristics associated with reduced graft survival: an approach to expanding the pool of kidney donors. Transplantation 2002;74(9):1281-1286. **Key reference on the definition of expanded criteira donor, base don the analysis of UNOS data.

6. Pereira BJG, Milford EL, Kirkman RL, Levey AS. Transmis-sion of hepatitis C virus by organ transplantation. N Engl J Med 1991;325:454-460.

7. Diethelm AG, Roth D, Ferguson RM, Schiff ER, Hardy MA, Starzl TE et al. Transmission of HCV by organ transplanta-tion. N Engl J Med 1992; 326: 410ñ411.

8. Pereira BJG, Milford EL, Kirkman RL. Prevalence of HCV RNA in hepatitis C antibody-positive cadaver organ donors and their recipients. N Engl J Med 1992; 327: 910ñ915.

9. Roth D, Fernandez JA, Babischkin S, De Mattos A, Buck BE, Quan S, et al. Detection of hepatitis C infection among organ donors: evidence for low transmission of disease. Ann Intern Med 1992; 117:470-475.

10. Vincenti F, Lake J, Wright T, Kuo G, Weber P, Stempel C. Nontransmission of hepatitis C from cadaver kidney donors to transplant recipients. Transplantation 1993; 55: 674-675.

11. Aeder MI, Shield CF, Tegtmeier GE, Bayer W, Luger AM, Nelson PW, et al. Incidence and clinical impact of hepatitis C virus (HCV) positive donors in cadaveric transplantation. Transplant Proc 1993;25:1469-1471.

12. Tesi RJ, Waller K, Morgan CJ, Delaney S, Elkhammas EA, Henry ML, et al. Transmission of hepatitis C by kidney trans-plantation: the risks. Transplantation 1994; 57:826-831.

13. DOPKI WP 5 Statistical analysis. Pages: 155-172. DOPKI web-site. Available at: http://www.dopki.eu/dmdocuments/WP5_Statistical%20Report.pdf. Last access: November 2010.

14. Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989; 88: 359-362.

15. Morales JM, Campistol JM. Transplantation in the Patient with Hepatitis C. Morales JM, Campistol JM. J Am Soc Ne-phrol 2000; 11: 1343ñ1353.

16. Morales JM, Rodicio JL. Should hepatitis C positive donors be accepted for renal transplantation? Curr Opin Nephrol Hypertens 1996; 5:199-201.

17. Widell A, Mansson S, Persson NH, Thysell H, Hermodsson S, Blohme I. Hepatitis C superinfection in hepatitis C virus (HCV) infected patients transplanted with an HCV infected kidney. Transplantation 1995;60:642-647.

18. Morales JM, Andres A, Campistol JM. Hepatitis C virus and organ transplantation. N Engl J Med 1993; 328: 511-512.

19. Morales JM, Campistol JM, Castellano G, Andres A, Colina F, Fuertes A et al. Transplantation of kidneys from donors with hepatitis C antibody into recipients with pre-transplan-tation anti-HCV. Kidney Int 1995; 47: 236-240. *First com-prehensive study on the short-term results of transplantation of kidneys from hepatitis C antibody positive donors into hepatitis C positive recipients.

20. Ali MK, Light JA, Barhyte DY, Sasaki TM, Currier CB Jr, Grandas O, et al. Donor hepatitis C virus status does not adversely affect short-term outcomes in HCV+ recipients in renal transplantation. Transplantation 1998; 66:1694-1697.

21. Mandal AK, Kraus ES, Samaniego M, Rai R, Humphreys SL, Ratner LE, et al. Shorter waiting times for hepatitis C virus seropositive recipients of cadaveric renal allografts from hepatitis C virus seropositive donors. Clin Transplant 2000; 14:679 391-396.

22. Woodside KJ, Ishihara K, Theisen JE, Early MG, Covert LG, Hunter GC, et al. Use of kidneys from hepatitis C seroposi-tive donors shortens waitlist time but does not alter one-yr outcome. Clin Transplant 2003;17: 433-437.

23. Veroux P, Veroux M, Puliatti C, Cappello D, Macarone M, Gagliano M, et al. Kidney transplantation from hepatitis C virusñpositive donors into hepatitis C virusñpositive recipi-ents: a safe way to expand the donor Pool? Transplant Proc 2005;37:2571-1573.

24. Veroux P, Veroux M, Sparacino V, Giuffrida G, Puliatti C, Macarone M, et al. Kidney transplantation from donors with viral B and C hepatitis. Transplant Proc 2006;38: 996-998.

25. Kasprzyk T, Kwiatkowski A, Wszola M, Ostrowski K, Daniele-wicz R, Domagala P, et al. Long-term results of kidney trans-plantation from HCV-positive donors. Transplant Proc 2007; 39(9):2701-2703.

26. Testa G, Goldstein RM, Netto G, Abbasoglu O, Brooks BK, Levy MF, et al. Long-term outcome of patients transplanted with livers from hepatitis C-positive donors. Transplantation 1998; 65: 925-9.

27. Kidney Disease: Improving Global Outcomes. KDIGO clini-cal practice guidelines for the prevention, diagnosis, evalu-ation, and treatment of Hepatitis C in chronic kidney dis-ease. Kidney Int 2008; 73(Suppl 109):S1ñS99. *KDIGO evidence based guidelines for a holistic approach to the patient with kidney disease and hepatitis C virus infection.

28. Covic A, Abramowicz D, Bruchfeld A, Leroux-Roels G, Sam-uel D, van Biesen W, et al. Endorsement of the Kidney Disease Improving Global Outcomes (KDIGO) hepatitis C guidelines: a European Renal Best Practice (ERBP) position statement. Nephrol Dial Transplant (2009) 24: 719ñ727.

29. Gordon CE, Balk EM, Becker BN, Crooks PA, Jaber BL, Johnson CA, et al. KDOQI US commentary on the KDIGO


137

clinical practice guideline for the prevention, diagnosis, evaluation and treatment of hepatitis C in CKD. Am J Kid Dis 2008; 52(5): 811-825

30. Bucci JR, Matsumoto CS, Swanson SJ, Agodoa LY, Holtz-muller KC, Peters TG, Abbott KC. Donor hepatitis C serop-ositivity: clinical correlates and effect on early graft and patient survival in adult cadaveric kidney transplantation. J Am Soc Nephrol 2002; 13: 2974-2982

31. Abbott KC, Bucci JR, Matsumoto CS, Swanson SJ, Agodoa LY, Holtzmuller KC et al. Hepatitis C and renal transplanta-tion in the era of modern immunosuppression. J Am Soc Nephrol. 2003 Nov;14(11):2908-18. **UNOS registry based study observing an increased mortality among kidney re-cipients transplanted from donors with a positive serology for hepatitis C.

32. Bucci JR, Lentine KL, Agodoa LY, Peters TG, Schnitzler MA, Abbott KC. Outcomes associated with recipient and donor hepatitis C serology status after kidney transplantation in the United States: analysis of the USRDS/UNOS database. Clin Transpl. 2004;51-61.

33. Abbott KC. Response to ìViral Hepatitis Guidelines for Trans-plant Recipientsî. Am J Transplant 2005; 5: 1577-1578.

34. Abbott KC, Lentine KL, Bucci JR, Agodoa LY, Peters TG, Schnitzler MA. The impact of transplantation with deceased donor hepatitis Cñpositive kidneys on survival in wait-listed long-term dialysis patients. Am J Transplant 2004;4:2032-7.

35. Morales JM, Campistol JM, Domínguez-Gil B, Andrés A, Esforzado N, Oppenheimer F, Castellano G, Fuertes A, Bru-guera M, Praga M. Long-term experience with kidney trans-plantation from Hepatitis C positive donors into Hepatitis C positive recipients. Am J Transplant 2010 (11): 2453-2462. *Most comprehensive study on the long-term outcome of kidney recipients transplanted from donors with a positive serology for hepatitis C into recipients with a hepatitis C positive serology.

36. Mahmoud IM, Elhabashi AF, Elsawy E, El-Husseini AA, Sheha GE, Sobh MA. The impact of hepatitis C virus viremia on renal graft and patient survival: a 9-year prospective study. Am J Kid Dis 2004; 43:131-139.

37. Kamar N, Rostaing L, Selves J, Sandres-Saune K, Alric L, Durand D, et al. Natural history of hepatitis C virus-related liver fibrosis after renal transplantation. Am J Transplant 2005; 5: 1704-1712.

38. Natov SN, Pereira BJG. Transmission of viral hepatitis by kidney transplantation: donor evaluation and transplant policies (Part 2: hepatitis C virus). Transpl Infect Dis 2002; 4: 124-131.

39. Farci P, Alter HJ, Govindarajan S, et al. Lack of protective immunity against reinfection with hepatitis C virus. Science 1992;258:135-40.

40. Natov SN, Lau JY, Ruthazer R, Schmid CH, Levey AS, Perei-ra BJ. Hepatitis C virus genotype does not affect patient survival among renal transplant candidates. The New Eng-land Organ Bank Hepatitis C Study Group. Kidney Int 1999; 56: 700-706.

41. Schussler T, Staffeld-Coit C, Eason J, Nair S. Severe hepa-titis C infection in a renal transplant recipient following hepatitis C genotype mismatch transplant. Am J Transplant 2004;4: 1375-1378.

42. Pereira BJ, Levey AS. Hepatitis C virus infection in dialysis and renal transplantation. Kidney Int 1997;51:981-999.

43. Knoll GA, Tankersley MR, Lee JY, Julian BA, Curtis JJ. The impact of renal transplantation on survival in hepatitis C positive end-stage renal disease patients. Am J Kidney Dis 1997;29: 606-614.

44. Morales JM, Domínguez-Gil B, Sanz-Guajardo D, Fernandez J, Escuin F. The influence of hepatitis B and hepatitis C virus infection in the recipient on late renal allograft failure. Neph-rol Dial Transplant 2004; 19(Suppl 3):72-76.

45. Legendre C, Garrigue V, Le Bihan C, et al. Harmful long-term impact of hepatitis C virus infection in kidney transplant recipients. Transplantation 1998;65:667-670.

46. Mathurin P, Mouquet C, Poynard T, et al. Impact of hepatitis B and C virus on kidney transplantation outcome. Hepatol-ogy 1999;29:257-263.

47. Gentil MA, Rocha JL, Rodríguez-Algarra G, et al. Impaired kidney transplant survival in patients with antibodies to hep-atitis C virus. Nephrol Dial Transplant 1999;14:2455-2459.

48. Breitenfeldt MK, Rasenak J, Berthold H, et al. Impact of hepatitis B and C on graft loss and mortality of patients after kidney transplantation. Clin Transplant 2002;16:130-136.

49. Aroldi A, Lampertico P, Montagnino G, et al. Natural history of hepatitis B and C in renal allograft recipients. Transplan-tation 2005;15:1132-1136.

50. Fabrizi F, Martin P, Dixit V, Bunnapradist S, Dulai G. Hepa-titis C virus antibody status and survival after renal trans-plantation: meta-analysis of observational studies. Am J Transplant 2005;5:1452-1461. *Metanalysis on observation-al studies demonstrating a significant negative impact of hepatitis C virus antibody status on graft and patient sur-vival after kidney transplantation.

51. Fabrizi F, Martin P, Dixit V, Bunnapradist S, Kanwal F, Dulai G. Posttransplant diabetes mellitus and HCV seropositive status after renal transplantation: meta-analysis of clinical studies. Am J Transplant 2005; 5: 2433-2440.

52. Cruzado JM, Gil-Vernet S, Ercilla G, et al. Hepatitis C virus-ñassociated membranoproliferative glomerulonephritis in renal allografts. J Am Soc Nephrol 1996;7:2469-75.

53. Roth D, Cirocco R, Zucker K, et al. De novo membranopro-liferative glomerulonephritis in hepatitis C virusñinfected re-nal allografts recipients. Transplantation 1995;59:1676-82.

54. Morales JM, Pascual-Capdevila J, Campistol JM, et al. Mem-branous glomerulonephritis associated with hepatitis virus infection in renal transplant patients. Transplantation 1997;63:1634-9

55. Hestin D, Guillemin F, Castin N, Le Faou A, Champigneulles J, Kessler M. Pre-transplant hepatitis C virus infection: a predictor of proteinuria after renal transplantation. Trans-plantation 1998;65:741-4.

56. Cruzado JM, Casanovas-Taltabull T, Torras J, Baliellas G, Gil-Vernet S, Grinyo JM. Pretransplant Interferon prevents hepatitis C virusñ associated glomerulonephritis in renal al-lografts by HCV-RNA clearance. Am J Transplant 2003;3:357-60. **Elegant series on the impact of Interferon treatment before transplantation on a decreased incidence of hepatitis C related glomerulonephritis after kidney transplantation.

57. Mahmoud IM, Sobh MA, El-Habashi AF, et al. Interferon therapy in hemodialysis patients with chronic hepatitis C: study of tolerance, efficacy and posttransplantation course. Nephron Clin Pract 2005;100:c133-9.

58. Kamar N, Ribes D, Izopet J, Rostaing L. Treatment of hepa-titis C virus infection (HCV) after renal transplantation: impli-cations for HCVpositive dialysis awaiting a kidney transplant. Transplantation 2006;82:853-6.

59. Fabrizi F, Lunghi G, Dixit V, Martin P. Meta-analysis: antiviral therapy of hepatitis C virusñrelated liver disease in renal trans-plant patients. Aliment Pharmacol Ther 2006;24:1413-22.

60. Campistol JM, Esforzado N, Morales JM. Hepatitis C virusñ-positive patients on the waiting list for renal transplantation. Semin Nephrol 2002;22:361-4.

61. Rostaing L, Chatelut E, Payen JL, et al. Pharmacokinetics of alfaIFN-2b in chronic hepatitis C virus patients undergoing chronic haemodialysis or with normal renal function: clinical implications.J Am Soc Nephrol 1998;9:2344-8.

62. Kamar N, Toupamce O, Buchler M, et al. Evidence that clearance of hepatitis C virus RNA after alpha interferon therapy in dialysis patients is sustainted after renal trans-plantation. J Am Soc Nephrol 2003; 14: 2092-2098.

63. Fabrizi F, Dixit V, Messa P, Martin P. Pegylated interferon monotherapy of chronic hepatitis C in dialysis patients: Meta-analysis of clinical trials. J Med Virol 2010; 82(5):768-775.

64. Gordon CE, Uhlig K, Lau J, Schmid CH, Levey AS, Wong JB. Interferon for hepatitis C virus in hemodialysis--an indi-vidual patient meta-analysis of factors associated with sus-tained virological response. Clin J Am Soc Nephrol 2009;4(9):1449-1458.

65. Knoll GA, Tankersley MR, Lee JY et al. The impact of renal transplantation on survival in hepatitis C-positive end-stage renal disease patients. Am J Kidney Dis 1997; 29: 608ñ614.

66. Pereira BJ, Natov SN, Bouthot BA et al. Effects of hepatitis C infection and renal transplantation on survival in end-stage renal disease. The New England Organ Bank Hepatitis C Study Group. Kidney Int 1998; 53: 1374ñ1381.

67. Bloom RD, Sayer G, Fa K et al. Outcome of hepatitis C virus-infected kidney transplant candidates who remain on the waiting list. Am J Transplant 2005; 5: 139ñ144.


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Living Donor Liver TransplantationJuan Carlos García-Valdecasas1, Itxarone Bilbao Aguirre2, Ramón Charco Torra3, Constantino Fondevila Campo4, Josep Fuster Obregón5, Juan Carlos García-Valdecasas1, Paloma Jara Vega6, Rafael López Andújar7, Pedro López Cillero8, Juan Carlos Meneu-Díaz9, Miguel Navasa Anadón5 and Fernando Pardo Sánchez10

1Department of Surgery, Hospital Clínic i Provincial, Barcelona, Spain; 2Liver Transplant Unit, Hospital Vall d´Hebron, Barcelona, Spain; 3Department of HPB and Transplant Surgery, Hospital Vall d’Hebron, Barcelona, Spain; 4Division of Gastroenterology and General Surgery, Hospital Clínic i Provincial, Barcelona, Spain; 5Liver Surgery and Transplantation Unit, Institute of Digestive and Metabolic Diseases,Hospital Clínic i Provincial, Barcelona, Spain; 6Pediatric Liver Care and Transplant Center, Children’s University Hospital, La Paz, Madrid, Spain; 7Liver Transplantation Unit, Hospital Universitario La Fe, Valencia, Spain; 8Division of General and Gastrointestinal Surgery, Hospital Reina Sofía, Córdoba, Spain; 9Division of Gastroenterology and General Surgery, Hospital 12 de Octubre, Madrid, Spain; 10Department of HPB and Liver Transplant Surgery, Clínica Universidad de Navarra, Pamplona, Spain


Correspondence to:

Juan Carlos García-Valdecasas

Servicio de Cirugía General y Digestiva

Hospital Clinic de Barcelona

c/ Villarroel, 170

08036 Barcelona, españa


Abstract

Living donor liver transplantation was introduced for the purposes of increasing the number of donors, reducing mortality and morbidity rates, and improving long-term survival of the recipients. The procedure for living donor liver transplantation is the same as for cadaveric liver transplantation. The suitability of potential donors is established following exhaustive evaluations of the donor’s liver and overall health.In adult transplantation cases, living donor liver transplantation outcomes are as good as in cadaveric transplants, but donor morbidity continues to be significant as are biliary com-plications, whereas outcomes in pediatric liver transplants from living donors are more successful than those from cadaveric liver grafts.Living donor liver transplantation is a valid alternative to cadaveric transplantation that can offer improvement of survival rates in the future if we manage to select suitable candidates and overcome a few technical difficulties. (Trends in Transplant. 2010;4:138-44)

Corresponding author: Juan Carlos García-Valdecasas, [email protected]

Key words

Liver transplantation. Living donor. Pediatric liver transplatation. Adult liver transplatation. Trends in liver transplantation.

Juan Carlos García-Valdecasas, et al.: Living Donor Liver Transplantation

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Introduction

The main objective of living donor liver transplantation (LDLT) is to increase the num-ber of organs available for transplantation. Although the potential risks to the donor’s life are low, they very much govern the perfor-mance of this type of transplantation. Never-theless, the mortality rate for patients on the waiting list for a donor justifies the use of this procedure. This document details the out-comes of discussions held at the consensus meeting of the Spanish groups, whose objec-tive was to detect problems and provide pos-sible solutions.

Donation process

Trends in living donor transplantation

Over the past few years, advances in liver transplantation have allowed the survival rate after one year to rise to nearly 95%. Al-though Spain has one of the highest trans-plant rates in the world, availability of cadav-eric organs for transplantation is not sufficient at this time to cover existing needs. Waiting list mortality has hovered around 7-8% for the last few years; the probability of undergoing transplantation was 51% in 2008.

While in recent years a slight increase in living donor kidney transplantations has been observed1, in LDLT the trend has been in the opposite direction2. One of the reasons for this decline has been the fact that applica-tion of the model for end stage liver disease (MELD) causes the urgency for donations to decrease as patients with a higher risk of death are identified.

Other reasons are donor mortality and morbidity rates, the risk of worse outcomes in recipients according to their etiology or the seriousness of their illness, the potential donor

evaluation process itself, which means only between 9 and 17% are accepted for dona-tion, as well as issues related to the donors’ quality of life following transplantation.

At this time, LDLT continues to be a complex procedure that involves morbidity and mortality risks for donors as well as risks for recipients due to the need for complex vascular and biliary reconstruction. Neverthe-less, the general opinion is that this type of transplantation is justified due to the fact that the waiting list mortality rate still remains too high3. In addition, the prevalence of hepato-cellular carcinoma (HCC) means it is impos-sible to cover all of the need for liver trans-plants so that HCC should be considered as an indication criterion for LDLT.

Improvement of LDLT requires proper identification of appropriate candidates, such as MELD exceptions or those with HCC, re-duction of donor morbidity and mortality and improvement in their quality of life following the donation, compensation for financial loss and, lastly, the introduction of more aggres-sive options such as programs for cross-matching donor and recipient or programs for use from donors with blood group incompat-ibility.

The majority of LDLT that take place in Spain are being performed in pediatric re-cipients4. So far, more than 2,000 implanta-tions of left lateral segment grafts, which is an option that parents frequently request, have been performed worldwide. Selection of po-tential recipients is based on pediatric end-stage liver disease criteria that predict mortal-ity within three months of being included on the waiting list. This modification of the adult “score” does not appear to identify all of the children in urgent need of transplantation. Those in exceptional situations or serious cases account for approximately 50% of those who receive a transplant. In addition, children over the age of 12 compete with adults, which


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makes giving them priority more difficult. The solution would be to systematically prioritize pediatric patients, giving status as a child whenever necessary and making it an obliga-tion for this pediatric grouping to make divi-sion of the graft a priority so as to be able to transplant into both an adult and a child at the same time. The graft will thus have been as-signed to two patients and there would be no predominance of one group over the other which, in the majority of cases, is a source of conflict. To maintain the offer of a living dona-tion is also a duty for those parents or relatives who are willing to make a donation.

In some cases, LDLT has been proven to have survival outcomes that are equivalent5 or superior to full grafts. However, and in spite of being associated with a somewhat greater survival rate, the risk of graft loss is somewhat higher for divided or split grafts than for full ones.

Incentives for live donations

In order to encourage living donations, the objective must be to reduce to the mini-mum the negative impact that transplantation has on the donor, as much physically as psy-chologically or even financially.

One of the main drawbacks is the scar, which can be resolved through the use of laparoscopic surgery6,7. Economic obstacles for the donor could be solved through the creation of protection mechanisms that would guarantee employment maintenance or pro-vide access to long-term care insurance.

The majority of hospitals are not candid with patients on the waiting list about the pos-sibility of opting for a LDLT. To improve on this situation in the future, informing patients on the waiting list about this option should be mandatory, as should advising them about referral centers when need be.

Donor evaluation

The key to LDLT lies mainly in the con-sideration of the risk to the donor, which should be minimal, and the benefit for the recipient. The donor must weigh the risk of possible mortality, aftereffects, and social, economic, and work aspects. The importance of these factors may vary according to sur-vival of the recipient. The risk of minor com-plications for the donor is about 27%, that for potentially serious complications that are suc-cessfully resolved is 26%, about 2% for life-threatening conditions, and 0.8% for death8.

Extensive evaluation of the donors is key to achieving good short- and long-term outcomes. The risk of complications in the do-nor is currently about 37%, about half of which are minor while the remainder are considered to be potentially serious, according to the Cla-vien classification system. Therefore, one of the most pressing objectives is to try and re-duce this number by means of thorough prior testing and a meticulous surgical technique to ensure the highest standard of quality of life for the donor following the operation.

Table 1 shows the factors that deter-mine the selection of donors and table 2 shows the protocols for the selection of poten-

Table 1. Characteristics of the ideal live donor

– Age: 18-55 years

– BMI: < 30 kg/m2

– No cardiopulmonary, renal or metabolic disease

– Residual liver volume (LLL): > 40%

– Graft (RLL): > 0,8% recipient weight

– Steatosis < 20%

– Favorable anatomical suitability

– Donor/recipient must be ABO-compatible

– Significant relationship with the recipient

– Independence and competence of the donor


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tial donors. The donor must be informed of the risks and drawbacks associated with trans-plantation before giving consent.

Despite all this, a comprehensive pre-operative evaluation does not guarantee the absence of postoperative morbidity in the do-nor. The mortality risk for donors is five times greater in LDLT than in living kidney dona-tion9,10. Progressive experience and im-provements in donor selection may reduce mortality and morbidity rates in the future, although they are not expected to ever be as low as in living donor kidney transplan-tation.

The need for total transparency regard-ing outcomes for donors and awareness that

morbidity and mortality rates will never be zero justify the need for establishing a pro-spective donor morbidity registry and estab-lishing a standard system for recording com-plications in donors. In the meantime, surgery complications should be recorded following the Clavien classification system or one of the recent adaptations based on it11.

Follow-up of donors is essential and should be made, at the very least, for the first three years following surgery, at a rate of once every three months during the first year and at 12-month intervals after that. It is recom-mended that the tests to be required should include complete lab tests and volume calcu-lations using magnetic resonance imaging. It is necessary to have a long time of follow-up

Table 2. Phases in the process of donor evaluation

Preliminary general health evaluation

First informed consent formDetailed medical historyPhysical examinationBlood tests, blood group, hepatitis serology

Psychological evaluation Mental stabilityVoluntary nature and willingness Relationship between donor and recipientInforming the donor sufficiently about the surgical procedure

Anatomy Cholangio-MRICT angiographyAll-in-one MeVis®

Overall risks of the surgical procedure

Lab tests: biochemical, lipid profile, iron, ferritin, transferrin, α1-antitrypsin, ceruloplasmin, immunoglobulin levels, thyroid function tests, tumor markers, coagulation factorsHyper-coagulation profile*Chest X-RayLung function testStress test-ECGEchocardiogram

Liver biopsy† Presence of steatosis (contraindicated: if > 20% or if 10-20% and RLVBWR < 0,8)Discovery of other histologic findings: (portal and sinusoidal fibrosis; NASH; portal inflammation and necroinflammatory changes)

Preparation for surgery Autologous blood donationSecond psychological evaluation Evaluation by hepatologistAssessment by anesthetistFinal consentEthics committeeCivil registry

RLVBWR: remnant liver volume body weight ratio; NASH: nonalcoholic steatohepatitis.*If donor has a history of deep vein thrombosis.†in patients with abnormal liver function test results, radiologic abnormalities (steatosis and others), BMI > 30 kg/m2, or relatives of recipients with primary biliary cirrhosis, primary sclerosing cholangitis or autoimmune disease.


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of all donors because we don’t know what the long-term complications could be. The major-ity of programs consider that during the first year, follow-up should be performed every three months.

Evaluation of the liver

The liver is an organ that has surgically important vascular variations, both venous and arterial, in addition to the biliary tract, which makes evaluating it very complex. Cur-rent imaging technology is extremely efficient and allows the anatomic distribution of all of its structures, including the biliary tract, to be described with great exactitude. Helical com-puted tomography with multiplanar recon-struction and magnetic resonance imaging allow the visualization of all of these structures in a single exploration. In addition, the pos-sibility of including a reconstruction of the liver through use of a special program (Me-Vis®) allows three-dimensional images to be obtained that further increase safety in surgi-cal planning. Even so, imaging during the surgical intervention itself must be used to guarantee the anatomical orientation suggest-ed by the preoperative evaluation. In a major surgical procedure, such as that performed on the donor, where meticulous dissection of the hilum of the liver is required, there is no room for guesswork and each step of the pro-cess must be performed with the maximum possible safety and knowledge of the possible consequences.

Selection of candidates for liver transplantation

The ideal candidate for LDLT is a per-son who would benefit from receiving a ca-daveric liver, but who has a low probability of receiving one for transplantation because of the seriousness of their disease, and in addition, is someone who has not previously

suffered from significant deterioration in qual-ity of life.

At present, the MELD system is able to identify and prioritize those patients with the highest probability of pretransplant death. That is why LDLT currently targets all those patients who are not correctly identified and therefore not prioritized.

From our point of view, HCC repre-sents a leading indication for LDLT, both for patients who meet the Milan criteria and for those who exceed these criteria but are known to have a relatively good prognosis (Barcelona criteria, Kyoto criteria, etc.)12, or those who respond following chemoembo-lization or radiofrequency ablation and sur-vive for at least three months within the Milan criteria.

Donor operation in adult-to-adult and adult-to-child living donor liver transplantation

Donor surgery in adult-to-adult procedures

In the majority of cases, the surgical technique for the adult donor consists of a right hepatectomy including segments V-VIII, and in which the middle hepatic vein remains with the donor.

Donor surgery in adult-to-pediatric recipient procedures

The surgical technique for the adult donor normally includes resection of liver segments II and III. Anatomical variability is significantly lower, especially where the bile duct, which is unique in 90% of cases, is concerned. This makes the surgery easier to perform and minimizes the need for banked-blood.


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Recipient operation in adult-to-adult and adult-to-child living donor liver transplantation

Recipient surgery in adult-to-adult procedures

Vascular reconstruction depends on achieving the best possible venous drainage, which means not only performing anastomo-sis of the right hepatic vein, but also recon-structing all of the veins, whether they be ac-cessory veins of the right lobe or tributaries of the middle hepatic vein, for which cryopre-served grafts are frequently necessary. Al-though the artery is small (only 3-5 mm in diameter) its reconstruction rarely causes problems. Continuous hemodynamic monitor-ing is needed to ensure adequate arterial flow. Last of all come the bile ducts, which have a diameter between 2 and 4 mm and are the “Achilles heel” of this type of trans-plantation. The ideal is to perform a system-atic duct-to-duct biliary reconstruction, and when this is not possible, to perform a hepa-ticojejunostomy.

Recipient surgery in adult-to-pediatric recipient procedures

Surgical techniques in pediatric living donor transplantation depend largely on the patient’s original disease. Vascular recon-struction is essentially the same as in adults, although in this case the size of the liver is always larger than required so that it is not necessary to maneuver to ensure venous drainage. On the contrary, because of its as-sociation with congenital anomalies, insuffi-cient portal flow must be ruled out (due to hypoplasia of the portal vein). On the other hand, the size of the bile ducts, which is fre-quently insufficient, make it necessary to al-ways perform a hepaticojejunostomy, some-thing that is absolutely necessary in cases of biliary atresia.

Results

Adults

As has already been mentioned, the objective of LDLT is to increase the number of donors, reduce mortality and morbidity rates among donors, and improve the long-term survival of recipients.

Outcomes for LDLT have improved in the last few years. Although survival rates are now comparable to those from cadaveric do-nors, the incidence of biliary complications affects long-term outcomes. Nevertheless, according to follow-ups for periods of more than five years in the USA as well as in Eu-rope, the presence of these complications does not appear to affect long-term out-comes.

The current trend in Western countries towards progressive reduction of this type of transplantation is not due to poor outcomes, but rather to sporadic cases of donor death, which have led to the closing of LDLT pro-grams at hospitals where these have oc-curred. There have been a variety causes, from those due to the absence of an appropri-ate level of care to those where the pressure on the medical staff has had an impact on care delivery.

A total of 232 adult and 91 pediatric LDLT were performed in Europe during 2007. Both patient and graft survival rates are better in LDLT. Since MELD scores in LDLT patients are lower than in patients receiving cadaveric transplants, there is a need for caution when comparing figures.

The experience in Spain is small, al-though at present the absence of donor mor-tality associated with good outcomes in both pediatric and adult recipients allow for the consideration of the need for joint action by those hospitals where LDLT is performed in


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order to increase activity. The identification of those patients in need of LDLT is of para-mount importance as are systematic infor-mation and referral of patients to those cen-ters with the experience, when the case arises.

In the last 15 years, 188 LDLT have been performed in Spain13. As yet no deaths have been recorded, although there has been an 8.3% rate of reoperations to solve compli-cations. Graft survival is similar in patients who are living donor recipients (80% at one year and 65% at five years) as in those who are cadaveric donor recipients (82 and 66%, respectively). The big problem in this type of donation is the high number of complications involved.

Living donor liver transplantation in the pediatric population

Outcomes in the pediatric age group cause many fewer problems. The family rela-tionship with the child is more reasonable and outcomes are better than those obtained with grafts that come from cadaveric donors. Only the systematic division of all liver grafts would reduce the need for this type of transplanta-tion. Even so, at present living donation allows ensuring absence of mortality on the waiting list, something unthinkable in the 1990s when mortality on the waiting list was around 30%. Between 1993 and 2009, survival of pediatric recipients of living donor transplants in Spain was 84.8% at one year and 79.8% at five years.

Final considerations

The most important aspects to be re-solved in LDLT are the establishment of stan-dardized registries, the resolution of technical difficulties, shortening the learning curve, and improving quality of life for the donor and the efficiency of the procedure. It is also neces-sary to assess the possibility of expanding indications for LDLT, allowing expected sur-vival in recipients of up to 30%.

References 1. Steinbrook R. Public solicitation of organ donors. N Engl J

Med. 2005;353:441-4. 2. Clavien PA, Dutkowski P, Trotter JF. Requiem for a cham-

pion? Living donor liver transplantation. J Hepatol. 2009;51:635-7.

3. García-Valdecasas JC, Fuster J, Fondevila C, Calatayud D. Adult living-donor liver transplantation. Gastroenterol Hepa-tol. 2009;32:577-83

4. ONT. Registro Español de Trasplante Hepático. Memoria de resultados 2009. [Spanish Hepatic Transplant Registry. His-tory of results 2009]. Available at: http://www.ont.es/infesp/Registros/MEMORIA_RETH_2009.pdf

5. Bourdeaux C, Darwish A, Jamart J, et al. Living-related versus deceased donor pediatric liver transplantation: a multivariate analysis of technical and immunological compli-cations in 235 recipients. Am J Transplant. 2007;7:440-7.

6. Baker TB, Jay CL, Ladner DP, et al. Laparoscopy-assisted and open living donor right hepatectomy: a comparative study of outcomes. Surgery. 2009;146:817-23.

7. Suh KS, Yi NJ, Kim T, et al. Laparoscopy-assisted donor right hepatectomy using a hand port system preserving the mid-dle hepatic vein branches. World J Surg. 2009;33:526-33.

8. Ghobrial RM, Freise CE, Trotter JF, et al. Donor morbidity after living donation for liver transplantation. Gastroenterol-ogy. 2008;135:468-76.

9. Brown RS. Live donors in liver transplantation. Gastroenter-ology. 2008;134:1802-13

10. Cotler SJ, McNutt R, Patil R, et al. Adult living donor liver transplantation: Preferences about donation outside the medical community. Liver Transpl. 2001;7:335-40.

11. Hata T, Fujimoto Y, Suzuki K, et al. Two cases of central ve-nous catheter-related thrombosis in living liver donors: how can the risk be minimized? Clin Transplant. 2009;23:289-93.

12. Mazzaferro V, Llovet JM, Miceli R et al. Predicting survival after liver transplantation in patients with hepatocellular car-cinoma beyond the Milan criteria: a retrospective, explor-atory analysis. Lancet Oncol. 2009;10:35-43.

13. SETH-ONT. Memoria de resultados 1984-2008. [History of results 1984-2008]. Available from: http://www.sethepati-co.org.

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VALCYTE 50 mg/ml polvo para solución oral. VALCYTE 450 mg comprimidos con cubierta pelicular. COMPOSICIÓN CUALITATIVA Y CUANTITATIVA: VALCYTE polvo para solución oral: cada frasco contiene 5,5 g de hidrocloruro de valganciclovir, por 12 g de polvo para solución oral. La solución reconstituida contiene 50 mg por ml de valganciclovir (como hidrocloruro). VALCYTE comprimidos con cubierta pelicular: cada comprimido contiene 496,3 mg de hidrocloruro de valganciclovir, equivalente a 450 mg de valganciclovir (base libre). Para consultar la lista completa de excipientes, ver apartado lista de excipientes. FORMA FARMACÉUTICA: VALCYTE polvo para solución oral: polvo para solución oral. El polvo es un granulado de color blanco a ligeramente amarillento. Cuando el polvo es disuelto, la solución es clara, de incolora a parda. VALCYTE comprimidos con cubierta pelicular: comprimidos con cubierta pelicular. Comprimidos con cubierta pelicular de color rosa, convexo y ovalado, con el grabado “VGC” en una cara y “450” en la otra. DATOS CLÍNICOS: Indicaciones terapéuticas VALCYTE está indicado para el tratamiento de inducción y mantenimiento de la retinitis por citomegalovirus (CMV) en pacientes con síndrome de inmunodeficiencia adquirida (SIDA). VALCYTE está indicado para la prevención de la enfermedad por CMV en pacientes seronegativos al CMV que han recibido un trasplante de órgano sólido de un donante seropositivo. Posología y forma de administración: Advertencia – se deben seguir estrictamente las recomendaciones sobre la posología para evitar sobredosificación (ver apartados Advertencias y precauciones especiales de empleo y Sobredosis). Después de su administración oral, el valganciclovir se metaboliza de forma rápida y extensa a ganciclovir. 900 mg de valganciclovir por vía oral, dos veces al día, es equivalente terapéuticamente a 5 mg/kg de ganciclovir administrado dos veces al día. La exposición sistémica a ganciclovir con 900 mg de valganciclovir solución oral es equivalente a 900 mg de valganciclovir en comprimidos. Posología habitual en adultos: Tratamiento de inducción de la retinitis por CMV: La dosis recomendada para los pacientes con retinitis activa por CMV es de 900 mg de valganciclovir dos veces al día durante 21 días (en el caso de Valcyte comprimidos con cubierta pelicular: dos comprimidos de 450 mg). Un tratamiento prolongado de inducción puede incrementar el riesgo de toxicidad para la médula ósea (ver apartado Advertencias y precauciones especiales de empleo). Tratamiento de mantenimiento de la retinitis por CMV: Después del tratamiento de inducción, o si se trata de pacientes con retinitis inactiva por CMV, se recomienda administrar una dosis de 900 mg de valganciclovir una vez al día (en el caso de Valcyte comprimidos con cubierta pelicular: dos comprimidos de 450 mg). Se puede repetir el tratamiento de inducción en aquellos pacientes en los que la retinitis empeore; sin embargo, se debe tener en cuenta la posibilidad de resistencia viral al fármaco. Prevención de la enfermedad por CMV en el trasplante de órgano sólido: La dosis recomendada en pacientes que han recibido un trasplante es de 900 mg una vez al día (en el caso de Valcyte comprimidos con cubierta pelicular: dos comprimidos de 450 mg), comenzando dentro de los 10 días del trasplante y continuando hasta los 100 días post-trasplante. Instrucciones posológicas especiales: Pacientes con insuficiencia renal: Los niveles séricos de creatinina o el aclaramiento de creatinina se deben vigilar cuidadosamente. El aclaramiento estimado de creatinina (ml/min) se puede calcular según la creatinina sérica mediante las siguientes fórmulas: para los varones = (140 – edad [años]) x (peso corporal [kg])/(72) x (0,011 x creatinina sérica [micromoles/l]). Para las mujeres = 0,85 x valor de los varones. VALCYTE polvo para solución oral: hay que ajustar la posología según el aclaramiento de creatinina, tal y como se indica en la siguiente tabla (ver apartado Advertencias y precauciones especiales de empleo).

VALCYTE comprimidos con cubierta pelicular: Hay que ajustar la posología según el aclaramiento de creatinina, tal y como se indica en la siguiente tabla (ver apartado Advertencias y precauciones especiales de empleo).

Pacientes sometidos a hemodiálisis: VALCYTE polvo para solución oral: es necesario ajustar la dosis para pacientes en hemodiálisis (CrCl < 10 ml/min) (ver apartado Advertencias y precauciones especiales de empleo) en la tabla anterior se da una recomendación de dosis. VALCYTE comprimidos con cubierta pelicular: para pacientes en hemodiálisis (CrCl < 10 ml/min) no se puede dar una recomendación de dosis. Por consiguiente, Valcyte comprimidos con cubierta pelicular no se debe emplear en estos pacientes (ver apartado Advertencias y precauciones especiales de empleo). Pacientes con disfunción hepática: La seguridad y eficacia de VALCYTE no ha sido estudiada en pacientes con disfunción hepática (ver apartado Advertencias y precauciones especiales de empleo). Niños y adolescentes (menores de 18 años): VALCYTE no está recomendado para uso en niños menores de 18 años debido a la escasez de datos sobre seguridad y eficacia en esta población de pacientes.( ver apartado Advertencias y precauciones especiales de empleo). Pacientes ancianos: La seguridad y la eficacia de VALCYTE se desconocen en esta población. Pacientes con leucopenia, neutropenia, anemia, trombocitopenia y pancitopenia graves: Antes de comenzar el tratamiento, ver apartado Advertencias y precauciones especiales de empleo. Si se produce un deterioro significativo del recuento de células sanguíneas durante el tratamiento con VALCYTE, se deberá considerar el empleo de factores de crecimiento hematopoyético y/o una suspensión de la medicación (ver apartado Advertencias y precauciones especiales de empleo). Forma de administración: VALCYTE se administra por vía oral, y siempre que sea posible, debe tomarse con alimentos. VALCYTE polvo para solución oral: requiere ser reconstituido antes de su administración oral (ver apartado Precauciones especiales de eliminación y otras manipulaciones ). Se incluye dos dispensadores orales con graduación desde 25 mg hasta 500 mg. Se recomienda que el paciente use el dispensador. VALCYTE comprimidos con cubierta pelicular: Los comprimidos no se deben romper ni triturar. Contraindicaciones: VALCYTE está contraindicado en pacientes con hipersensibilidad a valganciclovir, ganciclovir o a alguno de los excipientes. Debido a la semejanza en la estructura química de VALCYTE y de aciclovir y valaciclovir, es posible que ocurra una reacción de hipersensibilidad cruzada entre estos medicamentos. Por lo tanto, VALCYTE está contraindicado en pacientes con hipersensibilidad a aciclovir y valaciclovir. VALCYTE está contraindicado durante la lactancia (ver apartado Embarazo y lactancia). Advertencias y precauciones especiales de empleo: Debido a su carácter teratogénico, el polvo de VALCYTE y la solución reconstituida deben manejarse con precaución. Si el polvo o la solución contactan directamente con la piel, esta zona debe lavarse a fondo con agua y jabón. Si la solución entra en los ojos, los ojos deben lavarse de forma inmediata con agua abundante. Antes de iniciar el tratamiento de valganciclovir, se debe advertir a los pacientes del riesgo potencial para el feto. En estudios con animales, se ha observado el poder mutágeno, teratógeno, espermatogénico, carcinógeno, y supresor de la fertilidad femenina del ganciclovir. Por tanto, VALCYTE debe considerarse como un potencial teratógeno y carcinógeno para el ser humano, con potencial para ocasionar malformaciones congénitas y cáncer. Además, es probable que VALCYTE inhiba la espermatogénesis de forma transitoria o permanente. Se debe recomendar a las mujeres en edad de procrear que empleen medidas anticonceptivas eficaces durante el tratamiento. Y se debe recomendar a los hombres que utilicen anticonceptivos de barrera durante y hasta, por lo menos, 90 días después del tratamiento, a menos que exista la seguridad de que la pareja femenina no corre el riesgo de quedarse embarazada (ver apartados Embarazo y lactancia y Reacciones adversas). Se han descrito casos graves de leucopenia, neutropenia, anemia, trombocitopenia, pancitopenia, mielosupresión y anemia aplásica en pacientes tratados con VALCYTE (y con ganciclovir). No debe iniciarse este tratamiento si el recuento absoluto de neutrófilos es menor de 500 células/μl, el recuento de plaquetas es menor de 25.000/μl o el nivel de hemoglobina es menor de 8 g/dl (ver apartados Posología y forma de administración y Reacciones adversas). VALCYTE debe emplearse con precaución en pacientes con citopenia hematológica preexistente, o con antecedentes de citopenia relacionada con la administración de medicamentos, y en pacientes que estén recibiendo radioterapia. Se recomienda vigilar el hemograma completo y las plaquetas durante el tratamiento. En pacientes con alteración renal se debe garantizar un aumento de la monitorización hematológica. Se recomienda considerar el empleo de factores de crecimiento hematopoyético y/o una suspensión de la medicación en pacientes que desarrollen leucopenia, neutropenia, anemia y/o trombocitopenia grave (ver apartados Posología y forma de administración y Reacciones adversas). La biodisponibilidad del ganciclovir tras una dosis única de 900 mg de valganciclovir es del 60% aproximadamente, en comparación con aproximadamente el 6 % tras la administración de 1000 mg de ganciclovir oral (como cápsulas). Una exposición excesiva a ganciclovir puede estar asociada a reacciones adversas con riesgo para la vida. Por consiguiente, se aconseja un estricto seguimiento de las recomendaciones posológicas al inicio de la terapia, cuando se cambie del tratamiento de inducción al de mantenimiento, y en pacientes que cambien de ganciclovir oral a valganciclovir, ya que no se puede reemplazar las cápsulas de ganciclovir por los comprimidos de Valcyte según una relación de uno a uno. Hay que advertir a los pacientes que tomaban con anterioridad cápsulas de ganciclovir del riesgo de sobredosis si ingieren un número de comprimidos de Valcyte mayor del prescrito (ver apartados Posología y forma de administración y Sobredosis). El ajuste posológico para los pacientes con insuficiencia renal debe basarse en el aclaramiento de creatinina (ver apartados Posología y forma de administración). Valcyte comprimidos con cubierta pelicular no debe usarse en pacientes sometidos a hemodiálisis (ver Posología y forma de administración).Se han descrito convulsiones entre pacientes tratados con imipenem-cilastatina y ganciclovir. VALCYTE no debe administrarse al mismo tiempo que imipenem-cilastatina, a menos que los posibles beneficios excedan los riesgos potenciales (ver apartado Interacción con otros medicamentos y otras formas de interacción). Los pacientes tratados con VALCYTE y (a) didanosina, (b) medicamentos con efecto mielosupresor conocido (ej. zidovudina) o (c) sustancias que afecten a la función renal, deben vigilarse estrechamente por si aparecen signos añadidos de toxicidad (ver apartado Interacción con otros medicamentos y otras formas de interacción). El estudio clínico controlado con valganciclovir para el tratamiento profiláctico de la enfermedad por CMV en pacientes trasplantados no incluyó pacientes con trasplante de pulmón e intestino. Por ello, la experiencia en estos pacientes es limitada. VALCYTE polvo para solución oral: Para pacientes con una dieta controlada en sodio, este medicamento contiene 0,188 mg/ml de sodio. Interacción con otros medicamentos y otras formas de interacción: Interacciones farmacológicas con valganciclovir: No se han realizado estudios in vivo de interacción farmacológica con VALCYTE. Debido a que valganciclovir se metaboliza a ganciclovir de manera amplia y rápida, cabe esperar para valganciclovir las mismas interacciones farmacológicas que se asocian con el ganciclovir. Interacciones farmacológicas con ganciclovir: Imipenem-cilastatina: Se han descrito convulsiones en pacientes tratados con ganciclovir e imipenem-cilastatina al mismo tiempo. Estos medicamentos no deben administrarse a la vez, a menos que los posibles beneficios excedan los riesgos potenciales (ver apartado Advertencias y precauciones especiales de empleo). Probenecid: El probenecid, administrado junto con el ganciclovir por vía oral, disminuye significativamente el aclaramiento renal del ganciclovir (20%), aumentando la exposición a este medicamento de manera estadísticamente significativa (40%). Estos cambios son compatibles con un mecanismo de interacción que implica una competición por la secreción tubular renal. Por lo tanto, hay que vigilar con cuidado la posible toxicidad de ganciclovir entre los pacientes que tomen probenecid y VALCYTE. Zidovudina: Cuando se administró zidovudina junto con ganciclovir por vía oral, el AUC de la zidovudina experimentó un incremento pequeño (17%), pero estadísticamente significativo. Asimismo, se advierte una tendencia al descenso de las concentraciones de ganciclovir, cuando se administra simultáneamente zidovudina, aunque sin alcanzar significación estadística. De cualquier manera, puesto que tanto la zidovudina como el ganciclovir pueden inducir neutropenia y anemia, es posible que algunos pacientes no toleren el tratamiento concomitante en dosis plenas (ver apartado Advertencias y precauciones especiales de empleo). Didanosina: Se ha observado que las concentraciones plasmáticas de didanosina aumentan siempre que se administra con ganciclovir (ya sea por vía intravenosa como oral). Cuando se administran dosis orales de ganciclovir de 3 y 6 g/día, se observa un aumento del AUC de didanosina, que varía entre 84 y 124%, y cuando se aplican dosis intravenosas de 5 y 10 mg/kg/día, el incremento observado del AUC de didanosina fluctúa entre 38 y 67%. No se ha observado ninguna modificación clínicamente significativa de las concentraciones de ganciclovir. Hay que vigilar de cerca la posible toxicidad de la didanosina para estos pacientes (ver apartado Advertencias y precauciones especiales de empleo). Micofenolato mofetilo: Considerando los resultados de un estudio de administración de dosis orales únicas recomendadas de micofenolato mofetilo (MMF) y de ganciclovir por vía i.v. y los efectos conocidos de la insuficiencia renal en la farmacocinética de MMF y de ganciclovir, se puede prever que la administración simultánea de ambos medicamentos (que tienen potencial para competir por la secreción tubular renal) determine aumentos del glucurónido fenólico del ácido micofenólico (MPAG) y de la concentración de ganciclovir. La farmacocinética del ácido micofenólico (MPA) apenas se altera y no es necesario ajustar la dosis de MMF. Sin embargo, los pacientes con insuficiencia renal que reciban al mismo tiempo MMF y ganciclovir deberán respetar las recomendaciones posológicas de ganciclovir y requieren una estrecha vigilancia. Ya que el MMF y el ganciclovir pueden causar neutropenia, y leucopenia, se deberá vigilar a los pacientes por si presentaran toxicidad acumulada. Zalcitabina: No se han observado cambios farmacocinéticos clínicamente significativos después de la administración conjunta de ganciclovir y zalcitabina. Tanto valganciclovir como zalcitabina tienen el potencial de producir neuropatía periférica, por lo que se debe vigilar la aparición de esta clase de acontecimientos en los pacientes. Estavudina: Cuando se administran conjuntamente estavudina y ganciclovir por vía oral no se observaron interacciones clínicamente significativas. Trimetoprim: No se observó ninguna interacción farmacocinética clínicamente significativa cuando se administraron conjuntamente trimetoprim y ganciclovir oral. Sin embargo, existe el potencial de incremento de la toxicidad ya que los dos fármacos son mielosupresores, por lo que, ambos fármacos deben usarse de forma concomitante únicamente si los posibles beneficios superan los riesgos. Otros antirretrovirales: A concentraciones clínicamente relevantes, es improbable que se produzca un efecto antagónico o sinérgico de la inhibición del virus de la inmunodeficiencia humana (VIH) en presencia de ganciclovir o del CMV en presencia de fármacos antirretrovirales. No es probable que se produzcan interacciones metabólicas con, por ejemplo, inhibidores de la proteasa o inhibidores de la transcriptasa inversa no nucleosídicos (ITIANNs) debido a la falta de implicación del P450 en el metabolismo tanto del valganciclovir como del ganciclovir. Otras interacciones farmacológicas potenciales: La toxicidad puede verse aumentada cuando valganciclovir se administra junto con, o se da inmediatamente antes o después que, otros fármacos que inhiben la replicación de poblaciones celulares que se dividen rápidamente, tal y como ocurre en la médula ósea, testículos, capas germinales de la piel y mucosa gastrointestinal. Ejemplos de estos tipos de fármacos son dapsona, pentamidina, flucitosina, vincristina, vinblastina, adriamicina, anfotericina B, trimetropim/derivados de sulfamidas, análogos de nucleósidos e hidroxiurea. Debido a que el ganciclovir es excretado a través del riñón, la toxicidad puede verse aumentada cuando valganciclovir se administra junto con fármacos que podrían reducir el aclaramiento renal de ganciclovir y, por lo tanto aumentar su exposición. El aclaramiento renal del ganciclovir puede inhibirse por dos mecanismos: (a) nefrotoxicidad, causada por fármacos como cidofovir y foscarnet, y (b) inhibición competitiva de la secreción tubular activa en el riñón como, por ejemplo, otros análogos de nucleósidos. Por lo tanto, se debe considerar el uso concomitante de todos estos fármacos con valganciclovir sólo si los posibles beneficios superan a los riesgos potenciales (ver apartado Advertencias y precauciones especiales de empleo). Embarazo y lactancia No hay datos del empleo de VALCYTE en mujeres embarazadas. Su metabolito activo, ganciclovir, pasa fácilmente a través de la placenta humana. Existe un riesgo teórico de teratogenicidad en humanos, en base a su mecanismo de acción farmacológico y la toxicidad reproductiva observada en estudios en animales con ganciclovir. VALCYTE no debe emplearse en el embarazo, a menos que los beneficios para la madre superen el riesgo potencial de daño teratogénico para el niño. Las mujeres en edad de procrear deben utilizar medidas anticonceptivas eficaces durante el tratamiento. Se debe aconsejar a los varones que utilicen

CrCl (ml/min)

≥ 6040 – 5925 – 3910 – 24

<10

Dosis de inducción de valganciclovir

900 mg dos veces al día450 mg dos veces al día450 mg una vez al día225 mg una vez al día200 mg tres veces a la semana tras diálisis

Dosis de mantenimiento/Dosis de prevención de valganciclovir

900 mg una vez al día450 mg una vez al día225 mg una vez al día125 mg una vez al día100 mg tres veces a la semana tras diálisis

CrCl (ml/min)

≥ 6040 – 5925 – 3910 – 24

Dosis de inducción de valganciclovir

900 mg (2 comprimidos) dos veces al día450 mg (1 comprimido) dos veces al día450 mg (1 comprimido) una vez al día450 mg (1 comprimido) cada 2 días

Dosis de mantenimiento/Dosis de prevención de valganciclovir

900 mg (2 comprimidos) una vez al día450 mg (1 comprimido) una vez al día450 mg (1 comprimido) cada 2 días450 mg (1 comprimido) dos veces por semana

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medidas anticonceptivas de barrera durante y hasta, por lo menos, 90 días después del tratamiento con VALCYTE, a menos que exista la seguridad de que la pareja femenina no corra el riesgo de quedarse embarazada. Se desconoce si el ganciclovir se excreta en la leche materna pero no se puede descartar esta posibilidad, con las reacciones adversas graves consiguientes para el bebé lactante. Por eso, debe interrumpirse la lactancia (ver apartado Contraindicaciones). Efectos sobre la capacidad para conducir y utilizar máquinas: No se han realizado estudios de los efectos sobre la capacidad para conducir y utilizar máquinas. El uso de VALCYTE y/o de ganciclovir se ha asociado con convulsiones, sedación, mareos, ataxia y/o confusión. Si aparece cualquiera de estas reacciones, podrían alterar las tareas que exigen un estado de alerta, como la capacidad para conducir vehículos y utilizar máquinas. Reacciones adversas: El valganciclovir es un profármaco del ganciclovir, que se metaboliza de manera rápida y extensa a ganciclovir después de su administración oral. Valganciclovir debería asociarse con las mismas reacciones adversas conocidas para el ganciclovir. Todas las reacciones adversas observadas en los estudios clínicos con valganciclovir se habían observado antes con ganciclovir. Las reacciones adversas más comunes comunicadas tras la administración de valganciclovir son neutropenia, anemia y diarrea. Valganciclovir, se asocia a un mayor riesgo de diarrea comparado con ganciclovir i.v. Además, valganciclovir se asocia con un riesgo más alto de neutropenia y leucopenia comparado con ganciclovir oral. Se observa con más frecuencia neutropenia grave (< 500 recuento total de neutrófilos/μl) en pacientes con retinitis por CMV en tratamiento con valganciclovir que en pacientes con trasplante de órgano sólido recibiendo valganciclovir. En la siguiente tabla se detalla la frecuencia de las reacciones adversas notificadas en los ensayos clínicos con valganciclovir, ganciclovir oral, o ganciclovir intravenoso. Las reacciones adversas reflejadas en la tabla se comunicaron en ensayos clínicos para el tratamiento de inducción y mantenimiento de la retinitis por CMV en pacientes con SIDA, o para la profilaxis de la enfermedad por CMV en pacientes con trasplante de corazón, riñón o hígado. El término (grave) que aparece en paréntesis en la tabla indica que la reacción adversa se ha comunicado en pacientes tanto de intensidad leve/moderada como intensidad grave/amenazante para la vida en esa frecuencia específica. Las reacciones adversas se enumeran en orden decreciente de gravedad dentro de cada intervalo de frecuencia.

Se puede asociar la trombocitopenia grave con amenaza de la vida por una hemorragia. Sobredosis: Experiencia con sobredosis de valganciclovir. Un adulto que recibió durante varios días dosis 10 veces mayores de las recomendadas para su grado de insuficiencia renal (disminución del aclaramiento de creatinina) sufrió una mielosupresión mortal (aplasia medular). Cabe esperar que la sobredosis de valganciclovir pueda aumentar también la toxicidad renal de este compuesto (ver apartados Posología y forma de administración y Advertencias y precauciones especiales de empleo). La hemodiálisis y la hidratación pueden resultar beneficiosos para reducir los niveles plasmáticos de los pacientes que reciben sobredosis de valganciclovir. Experiencia con sobredosis de ganciclovir por vía intravenosa: Se han recibido notificaciones de sobredosis de ganciclovir por vía intravenosa sucedidas en ensayos clínicos y durante la comercialización de este medicamento. En algunos de estos casos no se observó ningún tipo de acontecimiento adverso. La mayoría de los enfermos presentaron uno o más de los siguientes acontecimientos adversos: Toxicidad hematológica: pancitopenia, mielosupresión, aplasia medular, leucopenia, neutropenia, granulocitopenia. Toxicidad hepática: hepatitis, trastornos de la función hepática. Toxicidad renal: empeoramiento de la hematuria de un paciente con alteraciones previas de la función renal, insuficiencia renal aguda, elevación de la creatinina. Toxicidad digestiva: dolor abdominal, diarrea, vómitos. Neurotoxicidad: temblor generalizado, convulsiones. DATOS FARMACÉUTICOS: Lista de excipientes: VALCYTE polvo para solución oral: povidona, ácido fumárico, benzoato sódico (E211), sacarina sódica, manitol. Sabor Tutti-frutti: maltodextrina (maíz), propilenglicol, goma arábiga E414 y sustancias naturales que dan sabor principalmente de plátano, piña y melocotón. VALCYTE comprimidos con cubierta pelicular: Núcleo de los comprimidos: Povidona K30, Crospovidona, Celulosa microcristalina, Ácido esteárico. Recubrimiento pelicular de los comprimidos: Opadry Rosa 15B24005 que contiene: Hipromellosa, Dióxido de titanio (E171), Macrogol 400, Óxido de hierro rojo (E172), Polisorbato 80. Incompatibilidades: No aplicable. Periodo de validez: VALCYTE polvo para solución oral: Polvo para solución oral: 2 años. Solución reconstituida: 49 días. Conservar en nevera (2ºC - 8ºC). VALCYTE comprimidos con cubierta pelicular: 3 años. Precauciones especiales de conservación: Este medicamento no requiere condiciones especiales de conservación. Para las condiciones de conservación del medicamento reconstituido, ver apartado Periodo de validez. Naturaleza y contenido del envase: VALCYTE polvo para solución oral: La caja contiene un frasco de cristal ámbar de 100 ml, con un tapón de plástico a prueba de niños, un adaptador de plástico para el frasco y una bolsa de plástico que contiene 2 dispensadores orales de plástico graduados hasta 500 mg, con graduaciones de 25 mg. Cada frasco contiene 12 g de polvo para solución oral. Cuando se reconstituye, el volumen de la solución es 100 ml, proporcionando el volumen mínimo utilizable, 88 ml. VALCYTE comprimidos con cubierta pelicular: Frascos de polietileno de alta densidad (HDPE), con cierre de polipropileno a prueba de niños y algodón. 60 comprimidos. Precauciones especiales de eliminación y otras manipulaciones: VALCYTE polvo para solución oral: debe manipularse con precaución tanto el polvo como la solución reconstituida, ya que es considerado un potencial agente teratógeno y carcinógeno en humanos (ver apartado Advertencias y precauciones especiales de empleo). Evite la inhalación y el contacto directo del polvo y de la solución en piel y membranas mucosas. Si ocurriese tal contacto, lávese a fondo con jabón y agua. Si el polvo o la solución entran en los ojos, aclare los ojos a fondo con agua. Se recomienda que VALCYTE polvo para solución oral sea reconstituida por un farmacéutico antes de dispensarse al paciente. Preparación de la solución: 1. Medir 91 ml de agua en una probeta graduada. 2. Quitar el tapón a prueba de niños, añadir el agua en el frasco y cierre el frasco con el tapón a prueba de niños. Agitar el frasco cerrado hasta que se disuelva todo el polvo formando una solución clara, de incolora a parda. 3. Quitar el tapón a prueba de niños y poner el adaptador en el cuello del frasco. 4.Cerrar bien fuerte el frasco con el tapón a prueba de niños. Esto asegurará el asentamiento apropiado del adaptador al frasco y la función del tapón a prueba de niños. 5. Escribir la fecha de caducidad de la solución reconstituida en la etiqueta del frasco (ver apartado Periodo de validez ). La eliminación del medicamento no utilizado y de todos los materiales que hayan estado en contacto con él, se realizará de acuerdo con la normativa local. TITULAR DE LA AUTORIZACIÓN DE COMERCIALIZACIÓN: Roche Farma, S.A. Eucalipto, no 33. 28016 Madrid. NÚMERO(S) DE AUTORIZACIÓN DE COMERCIALIZACIÓN: VALCYTE polvo para solución oral: Número de registro: 69.760 VALCYTE comprimidos con cubierta pelicular: Número de registro: 64.829. FECHA DE LA PRIMERA AUTORIZACIÓN/RENOVACIÓN DE LA AUTORIZACIÓN. VALCYTE polvo para solución oral: Abril 2008. VALCYTE comprimidos con cubierta pelicular: Fecha de la primera autorización: 5 de marzo de 2002. Renovación de la autorización: 12 de abril de 2007. FECHA DE LA REVISIÓN DEL TEXTO: Abril 2008. PRECIOS AUTORIZADOS: Valcyte, 50 mg polvo para solución oral. P.V.L.: 258,18 €. P.V.P.: 304,09 €. P.V.P (IVA): 316,25 €. Valcyte 450 mg (60 comprimidos). P.V.L.: 1.267 €. P.V.P (IVA): 1.364,82 €. CONDICIONES DE DISPENSACIÓN: Valcyte polvo para solución oral: Especialidad farmacéutica de uso hospitalario. Valcyte comprimidos con cubierta pelicular: Especialidad de diagnóstico hospitalario. Para cualquier información adicional: Roche Farma, Tel.: 91 324 81 00

Sistema corporal Muy frecuentes Frecuentes Poco frecuentes Raras (≥ 1/10) (≥ 1/100, < 1/10) (≥ 1/1.000, < 1/100) (≥ 1/10.000, < 1/1.000) Solo para Valcyte POSExploraciones complementarias aumento de creatinina en sangre, pérdida de peso Trastornos cardiacos arritmias Trastornos de la sangre neutropenia (grave), Pancitopenia (grave), mielosupresión anemia aplásicay del sistema linfático anemia leucopenia (grave), anemia (grave), trombocitopenia (grave) Trastornos del sistema nervioso convulsiones, neuropatía temblores periférica, insomnio, hipoestesia, parestesia, mareos (sin vértigo), disgeusia (trastorno del gusto), dolor de cabeza Trastornos oculares desprendimiento de retina, visión anormal, edema macular, dolor ocular, conjuntivitis moscas flotantes Trastornos del oído y del laberinto dolor de oídos sordera Trastornos respiratorios, torácicos disnea tosy mediastínicos Trastornos gastrointestinales diarrea náuseas, vómitos, dolor pancreatitis, abdominal, dolor abdominal distensión abdominal, superior, estreñimiento, disfagia, ulceraciones orales dispepsia, flatulencia Trastornos renales y urinarios disfunción renal, disminución del Insuficiencia renal, hematuria aclaramiento de la creatinina renal Trastornos de la piel y del dermatitis, sudores alopecia, urticaria,tejido subcutáneo nocturnos, prurito sequedad de la piel Trastornos muscoloesqueléticos dolor de espalda, mialgia, y del tejido conjuntivo y óseo artralgia, calambres musculares(para Valcyte comprimidos) Trastornos del metabolismo anorexia, pérdida del apetitoy de la nutrición Infecciones e infestaciones sepsis (bacteriemia, viremia), celulitis, infección del tracto urinario, candidiasis oral Trastornos vasculares hipotensión Trastornos generales y fatiga, fiebre, rigidez, dolor, alteraciones en el lugar dolor torácico, malestar, astenia, de administración escalofríos (solo valcyte comprimidos) Trastornos del sistema inmunológico reacción anafilácticaTrastornos hepatobiliares función hepática anormal (grave), aumento de la alanina aumento de la fosfatasa alcalina aminotransferasa en sangre, aumento del aspartato aminotransferasa Trastornos del aparato reproductor Infertilidad masculinay de la mama Trastornos psiquiátricos depresión, ansiedad, confusión, Alteración psicótica, pensamientos perturbados agitación, alucinaciones

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1. NOMBRE DEL MEDICAMENTO CellCept 500 mg, comprimidos; CellCept 250 mg, cápsulas; CellCept, 500 mg, polvo paraconcentrado para solución para perfusión; CellCept 1 g/5 ml polvo para suspensión oral. 2. COMPOSICIÓN CUALITATIVA YCUANTITATIVA Cada comprimido contiene 500 mg de micofenolato mofetilo. Cada cápsula contiene 250 mg de micofenolatomofetilo. Cada vial contiene el equivalente a 500 mg de micofenolato mofetilo (clorhidrato). Cada frasco contiene 35 g demicofenolato mofetilo en 110 g de polvo para suspensión oral. Excipientes: Para la lista completa, ver sección 6.1. 3. FORMAFARMACÉUTICA Comprimidos recubiertos con película Comprimidos CellCept: oblongos, de color azul espliego, con el grabado“CellCept 500” en una cara y el “logotipo de la Empresa” en la otra. Cápsulas duras Cápsulas CellCept: oblongas, de colorazul/marrón, con la inscripción “CellCept 250” en la mitad superior y el “logotipo de la Compañía” en la mitad inferior. Polvo paraconcentrado para solución para perfusión. CellCept 500 mg polvo para concentrado para solución para perfusión debe serreconstituido y posteriormente diluido con una solución para perfusión intravenosa de glucosa al 5 %, antes de la administraciónal paciente (ver sección 6.6). Polvo para suspensión oral. CellCept 1 g/5 ml polvo para suspensión oral: cada frasco contiene 35 gde micofenolato mofetilo en 110 g de polvo para suspensión oral. 5 ml de la suspensión reconstituida contiene 1 g de micofenolatomofetilo. 4. DATOS CLÍNICOS 4.1. Indicaciones terapéuticas CellCept, en combinación con ciclosporina y corticosteroides, estáindicado para la pro�laxis del rechazo agudo de trasplante en pacientes sometidos a trasplante alogénico renal, cardíaco o hepático.4.2 Posología y forma de administración El tratamiento con CellCept debe ser iniciado y mantenido por especialistasdebidamente cuali�cados en trasplantes. ADVERTENCIA: LA SOLUCIÓN INTRAVENOSA DE CELLCEPT NUNCA DEBE SERADMINISTRADA MEDIANTE INYECCIÓN INTRAVENOSA RÁPIDA O EN BOLUS. CellCept 500 mg polvo para concentrado parasolución para perfusión es una forma farmacéutica alternativa a las formas orales de CellCept (cápsulas, comprimidos y polvopara suspensión oral) que puede ser administrada durante 14 días. La dosis inicial de CellCept 500 mg polvo para concentradopara solución para perfusión debe administrarse, dentro de las 24 horas siguientes al trasplante.Tras la reconstitución hasta unaconcentración de 6 mg/mL, CellCept 500 mg polvo para concentrado para solución para perfusión se debe administrar medianteperfusión intravenosa lenta en un período superior a 2 horas, bien en vena periférica o en vena central (ver sección 6.6). Nota Sies preciso, CellCept 1 g/5 ml polvo para suspensión oral se puede administrar a través de un tubo nasogástrico con un tamañomínimo de 8º franceses (diámetro interior mínimo de 1,7 mm). Uso en trasplante renal: Adultos: el inicio de la administración deCellCept por vía oral debe realizarse en las 72 horas siguientes al trasplante. La dosis recomendada en trasplantados renales esde 1 g administrado dos veces al día (dosis diaria total = 2 g). Niños y adolescentes (entre 2 y 18 años): la dosis recomendada demicofenolato mofetilo es de 600 mg/m2, administrada dos veces al día por vía oral (hasta un máximo de 2 g diarios). Loscomprimidos de CellCept deben prescribirse únicamente a pacientes con una super�cie corporal mayor de 1,5 m2, deben recibiruna dosis de 1 g dos veces al día (dosis diaria total = 2 g). Debido a que algunas reacciones adversas ocurren con una mayorfrecuencia en este grupo de edad (ver sección 4.8), en comparación con los adultos, es posible que sea necesario efectuarreducciones de dosis temporales o interrupción del tratamiento; esto deberá tener en cuenta factores clínicos relevantes incluyendola gravedad del evento. Niños (< 2 años): existen datos limitados de seguridad y e�cacia en niños con una edad inferior a los2 años. Estos son insu�cientes para realizar recomendaciones posológicas y por consiguiente, no se recomienda su uso en estegrupo de edad. Uso en trasplante cardíaco: Adultos: el inicio de la administración de CellCept por vía oral debe realizarse en los5 días siguientes al trasplante. La dosis recomendada en los pacientes sometidos a trasplante cardíaco es de 1,5 g administradados veces al día (dosis diaria total = 3 g). Niños: No hay datos disponibles en pacientes pediátricos con trasplante cardíaco. Usoen trasplante hepático: Adultos: se debe administrar CellCept IV durante los 4 días siguientes al trasplante hepático, posteriormentese comenzará la administración de CellCept oral, tan pronto como ésta sea tolerada. La dosis oral recomendada en los pacientessometidos a trasplante hepático es de 1,5 g administrados dos veces al día (dosis total diaria = 3 g).Niños: No hay datos disponiblesen pacientes pediátricos con trasplante hepático. Uso en ancianos (≥ 65 años): la dosis recomendada en ancianos es de 1 gadministrado dos veces al día en el trasplante renal y 1,5 g dos veces al día en los trasplantes cardíaco y hepático. Uso en pacientescon insu�ciencia renal: en pacientes sometidos a trasplante renal con insu�ciencia renal crónica grave (�ltración glomerular< 25 mL·min-1·1,73 m-2), deben evitarse dosis superiores a 1 g dos veces al día fuera del período inmediatamente posterior altrasplante. Se debe observar cuidadosamente a estos pacientes. No son necesarios ajustes posológicos en pacientes con retrasofuncional del riñón trasplantado en el postoperatorio (ver sección 5.2).No existen datos sobre los pacientes sometidos a trasplantecardíaco o hepático con insu�ciencia renal crónica grave. Uso en pacientes con insu�ciencia hepática grave: los pacientes sometidosa trasplante renal con enfermedad grave del parénquima hepático, no precisan ajuste de dosis. No existen datos sobre los pacientessometidos a trasplante cardíaco con enfermedad grave del parénquima hepático. Tratamiento durante episodios de rechazo: elácido micofenólico (MPA) es el metabolito activo del micofenolato mofetilo. El rechazo del riñón trasplantado no provoca cambiosen la farmacocinética del MPA; no es necesario reducir la dosis o interrumpir el tratamiento con CellCept. No hay fundamentospara ajustar la dosis de CellCept tras el rechazo del corazón transplantado. No se dispone de datos farmacocinéticos durante elrechazo del hígado trasplantado.4.3 Contraindicaciones Se han descrito reacciones de hipersensibilidad a CellCept (ver sección4.8). Por consiguiente, este medicamento está contraindicado en pacientes con hipersensibilidad al micofenolato mofetilo o alácido micofenólico. CellCept está contraindicado en mujeres en periodo de lactancia (ver el sección 4.6). Para información sobresu uso durante el embarazo así como las medidas contraceptivas a adoptar ver sección 4.6. 4.4 Advertencias y precaucionesespeciales de empleo Los pacientes que reciben CellCept como parte de un tratamiento inmunosupresor en combinación conotros medicamentos, presentan un mayor riesgo de desarrollar linfomas y otros tumores malignos, en especial de la piel (versección 4.8). El riesgo parece estar relacionado con la intensidad y la duración de la inmunosupresión más que con el uso de unfármaco determinado. Como norma general para minimizar el riesgo de cáncer de piel, se debe limitar la exposición a la luz solary a la luz UV mediante el uso de ropa protectora y el empleo de pantalla solar con factor de protección alto. Se debe indicar a lospacientes que reciben tratamiento con CellCept que comuniquen inmediatamente cualquier evidencia de infección, contusionesno esperadas, hemorragias o cualquier otra manifestación de depresión de la médula ósea. La supresión excesiva del sistemainmunitario aumenta la vulnerabilidad a las infecciones, incluyendo infecciones oportunistas, infecciones mortales y sepsis (versección 4.8). En pacientes tratados con Cellcept se han noti�cado casos, alguno de ellos mortales, de Leucoencefalopatía MultifocalProgresiva (LMP). En general, los casos noti�cados presentaban factores de riesgo para la LMP, como tratamiento inmunosupresory función inmune deteriorada. En pacientes inmunodeprimidos que presenten síntomas neurológicos, los clínicos deben tener encuenta la LMP a la hora de realizar un diagnostico diferencial, y estaría indicado desde un punto de vista clínico realizar unaconsulta con el neurólogo. En los pacientes que desarrollen LPM, se debe considerar reducir la inmunosupresión total. Sin embargo,en pacientes trasplantados, reducir la inmunosupresión puede suponer un riesgo de rechazo del injerto. Se debe monitorizar a lospacientes en tratamiento con CellCept debido a la neutropenia, la cual podría estar relacionada con el propio CellCept, conmedicamentos concomitantes, con infecciones virales, o con la combinación de estas causas. En los pacientes tratados conCellCept se deben realizar hemogramas completos una vez por semana durante el primer mes, dos veces al mes durante losmeses segundo y tercero de tratamiento y, a continuación, una vez al mes durante todo el resto del primer año. Se deberíainterrumpir o �nalizar el tratamiento con CellCept si se desarrollase la neutropenia (recuento absoluto de neutró�los< 1,3 x 10³/microlitro). Se han reportado casos de aplasia pura de células rojas (APCR) en pacientes tratados con Cellcept encombinación con otros inmunosupresores. El mecanismo de inducción de APCR por parte de micofenolato mofetilo es desconocido;así mismo, la contribución relativa de otros inmunosupresores y su combinación en un régimen inmunosupresor es tambiéndesconocida. En algunos casos la APCR es reversible con disminución de dosis o cese del tratamiento con Cellcept. Sin embargo,en los pacientes trasplantados la reducción de inmunosupresión puede aumentar el riesgo de rechazo. Se debe informar a lospacientes que durante el tratamiento con CellCept las vacunaciones pueden ser menos e�caces y que se debe evitar el empleode vacunas atenuadas de organismos vivos (ver sección 4.5).Se debe considerar la vacunación contra la gripe. El médico deberáobservar las directrices nacionales para la vacunación contra la gripe. Se ha relacionado CellCept con un aumento en la incidenciade eventos adversos en el aparato digestivo, entre los que se incluyen casos poco frecuentes de ulceraciones en el tractogastrointestinal, hemorragias y perforaciones. Por este motivo CellCept debe administrarse con precaución en pacientes conenfermedad activa grave del aparato digestivo. CellCept es un inhibidor de la inosin monofosfato deshidrogenasa (IMPDH). Por loque, en teoría, debe evitarse su empleo en pacientes con de�ciencia hereditaria rara de la hipoxantina-guanina fosforribosiltransferasa (HGPRT) como es el caso de los Síndromes de Lesch-Nyhan y Kelley-Seegmiller.No se recomienda administrar CellCeptal mismo tiempo que azatioprina, ya que su administración concomitante no se ha estudiado. Teniendo en cuenta la reducciónsigni�cativa del AUC del MPA que produce la colestiramina, la administración concomitante de CellCept y medicamentos queinter�eran en la recirculación enterohepática debe llevarse a cabo con precaución, dada la posibilidad de que disminuya la e�caciade CellCept. No se ha establecido el balance bene�cio-riesgo de micofenolato mofetilo en combinación con tacrolimus o sirolimus(ver también sección 4.5). Se han reportado casos de aplasia pura de células rojas (APCR) en pacientes tratados con Cellcept encombinación con otros agentes inmunosupresores. El mecanismo por el que micofenolato mofetilo induce APCR se desconoce;la contribución relativa de otros inmunosupresores y sus combinaciones en un régimen inmunosupresor es también desconocida.En algunos casos APCR fue reversible con reducción de dosis o supresión de Cellcept. Sin embargo, en pacientes trasplantadosreducir la inmunosupresión puede aumentar el riesgo de rechazo.4.5 Interacción con otros medicamentos y otras formas deinteracción Los estudios de interacciones se han realizado sólo en adultos.Aciclovir: se observaron concentraciones plasmáticasde aciclovir más altas cuando se administra con micofenolato mofetilo que cuando se administra aciclovir solo. Los cambios enla farmacocinética del MPAG (el glucurónido fenólico del MPA) fueron mínimos (aumento del MPAG entorno al 8 %) y no seconsideran clínicamente signi�cativos. Dado que las concentraciones plasmáticas de MPAG y aciclovir aumentan cuando estádeteriorada la función renal, existe la posibilidad de que micofenolato mofetilo y aciclovir, o sus profármacos, ej. valaciclovircompitan en la secreción tubular y se eleve aún más la concentración de ambas sustancias.Antiácidos con hidróxidos de magnesioy aluminio: la absorción del micofenolato mofetilo disminuyó tras su administración con antiácidos. Colestiramina: tras laadministración de una dosis única de 1,5 g de micofenolato mofetilo a sujetos sanos tratados previamente con 4 g de colestiramina,tres veces al día, durante 4 días, se observó la disminución del AUC del MPA (ver secciones 4.4, y 5.2). Se deberá tener precaucióncuando se administren conjuntamente, debido a su potencial para reducir la e�cacia de CellCept. Medicamentos que inter�erencon la circulación enterohepática: se debe tener precaución cuando se empleen medicamentos que inter�eran con la circulaciónenterohepática debido a su potencial para reducir la e�cacia de CellCept. Ciclosporina A: la farmacocinética de la ciclosporina A

(CsA) no experimenta variaciones debidas a micofenolato mofetilo. Sin embargo, si se cesa la administración concomitante deciclosporina, es previsible un aumento del AUC del MPA entorno al 30%. Ganciclovir: teniendo en cuenta los resultados de unestudio de administración de dosis única a las dosis recomendadas de micofenolato oral y ganciclovir intravenoso, así como losconocidos efectos de la insu�ciencia renal en la farmacocinética del CellCept (ver sección 4.2) y del ganciclovir, se prevé que laadministración conjunta de estos fármacos (que compiten por los mismos mecanismos de la secreción tubular renal) de lugar aun aumento de la concentración del MPAG y del ganciclovir. Como no hay indicios de que se produzca una alteración sustancialde la farmacocinética del MPA no es necesario ajustar la dosis de CellCept. Se debería considerar las recomendaciones de dosisde ganciclovir, así como llevar a cabo una estrecha vigilancia en aquellos pacientes con insu�ciencia renal y que estén siendotratados con CellCept y ganciclovir simultáneamente o sus profármacos, ej. valganciclovir.Anticonceptivos orales:la farmacocinéticay la farmacodinamia de los anticonceptivos orales no se vieron modi�cadas por la administración simultánea de CellCept (verademás sección 5.2). Rifampicina: En pacientes no tratados con ciclosporina, la administración concomitante de Cellcept yrifampicina dió lugar a una disminución en la exposición al MPA del 18% al 70% (AUC 0-12h). Por lo tanto, se recomienda vigilarlos niveles de exposición al MPA y ajustar las dosis de CellCept en consecuencia para mantener la e�cacia clínica cuando seadministra rifampicina de forma concomitante. Sirolimus: en pacientes sometidos a trasplante renal, la administración concomitantede Cellcept con ciclosporina redujo la exposición al MPA en un 30-50% en comparación con los pacientes que habían recibido lacombinación de sirolimus y dosis similares de Cellcept (ver además sección 4.4). Sevelamer: la administración concomitante deCellcept con sevelamer disminuyó la Cmax del MPA y del AUC 0-12 en un 30% y 25%, respectivamente, sin consecuenciasclínicas (ej: rechazo del injerto). Sin embargo, se recomendó administrar Cellcept al menos una hora antes o tres horas despuésdel uso de sevelamer para minimizar el impacto sobre la absorción del MPA. .Con respecto a los ligantes de fosfasto solo existendatos de Cellcept con sevelamer. Trimetoprim/sulfametoxazol: no se observó ningún efecto sobre la biodisponibilidad del MPA.Nor�oxacino y metronidazol: no se ha observado interacción signi�cativa en la administración concomitante separada de Cellceptcon nor�oxacina o con metronidazol en voluntarios sanos. Sin embargo, nor�oxacina y metronidazol combinados redujeron laexposición al MPA en aproximadamente un 30% tras una dosis única de Cellcept Tacrolimus:En los pacientes sometidos a trasplantehepático que comenzaron con Cellcept y tacrolimus, el AUC y la Cmáx del MPA no se vieron afectados de forma signi�cativa porla administración conjunta con tacrolimus. Por el contrario, hubo un aumento de aproximadamente un 20% en el AUC de tacrolimuscuando se administraron dosis múltiples de Cellcept (1,5 g dos veces al día) a pacientes tratados con tacrolimus. Sin embargo,en pacientes con transplante renal, la concentración de tacrolimus no pareció verse alterada por Cellcept (ver además sección4.4). Otras interacciones: la administración conjunta de probenecid y micofenolato mofetilo en mono eleva al triple el valor delAUC del MPAG. En consecuencia, otras sustancias con secreción tubular renal pueden competir con el MPAG y provocar así unaumento de las concentraciones plasmáticas del MPAG o de la otra sustancia sujeta a secreción tubular. Vacunas de organismosvivos: las vacunas de organismos vivos no deben administrarse a pacientes con una respuesta inmune deteriorada. La respuestade anticuerpos a otras vacunas puede verse disminuida. (ver también sección 4.4).4.6 Embarazo y lactancia Se recomienda noiniciar tratamiento con CellCept hasta disponer de una prueba de embarazo negativa. Se debe utilizar un tratamiento anticonceptivoefectivo antes de comenzar el tratamiento, a lo largo del mismo, y durante las seis semanas siguientes a la terminación deltratamiento con CellCept (ver sección 4.5). Debe indicarse a los pacientes que consulten inmediatamente a su médico en caso dequedar embarazadas. No se recomienda el uso de CellCept durante el embarazo, quedando reservado solo para aquellos casosen los que no haya disponible un tratamiento alternativo más adecuado. CellCept solo se debería usar durante el embarazo si elbene�cio para la madre supera el riesgo potencial para el feto. Se dispone de datos limitados del uso de CellCept en mujeresembarazadas. No obstante, se han noti�cado casos de malformaciones congénitas en hijos de pacientes tratados durante elembarazo con Cellcept en combinación con otros inmunosupresores, incluyendo malformaciones en oidos, p.ej. carencia del oídoexterno/medio o con anomalía en la formación.Se han noti�cado casos de abortos espontáneos en pacientes tratados conCellcept.Los estudios en animales han mostrado toxicidad reproductiva (ver sección 5.3). En ratas lactantes se ha demostradoque el micofenolato mofetilo se elimina en la leche. No se sabe si esta sustancia se elimina en la leche humana. CellCept estácontraindicado en mujeres durante el periodo de lactancia, debido al riesgo potencial de reacciones adversas graves al micofenolatomofetilo en niños lactantes (ver sección 4.3). 4.7 Efectos sobre la capacidad para conducir y utilizar máquinas No se hanrealizado estudios sobre la capacidad para conducir y utilizar máquinas. El per�l farmacodinámico y las reacciones adversasdescritas indican que es improbable tal efecto. 4.8 Reacciones adversas Entre las siguientes reacciones adversas se incluyenlas reacciones adversas ocurridas durante los ensayos clínicos: Las principales reacciones adversas, asociadas a la administraciónde CellCept en combinación con ciclosporina y corticosteroides, consisten en diarrea, leucopenia, sepsis y vómitos; se hanobservado, además, indicios de una frecuencia más alta de ciertos tipos de infección (ver sección 4.4). Neoplasias malignos: Lospacientes bajo tratamiento inmunosupresor con asociaciones de medicamentos, que incluyen CellCept tienen mayor riesgo dedesarrollar linfomas y otras neoplasias malignas, principalmente en la piel (ver sección 4.4). Se desarrollaron enfermedadeslinfoproliferativas o linfomas en el 0,6 % de los pacientes que recibían CellCept (2 g ó 3 g diarios) en combinación con otrosinmunosupresores, en ensayos clínicos controlados de pacientes con transplante renal (datos con 2 g), cardíaco y hepático, a losque se les hizo seguimiento durante por lo menos 1 año. Se observó cáncer de piel, excluyendo al melanoma, en el 3,6 % de lospacientes; se observaron otros tipos de neoplasias malignas en el 1,1 % de los pacientes. Los datos de seguridad a tres años enpacientes con transplante renal y cardíaco no mostraron ningún cambio inesperado en la incidencia de neoplasias malignas encomparación con los datos a 1 año. El seguimiento de los pacientes con transplante hepático fue de al menos 1 año pero inferiora 3 años. Infecciones oportunistas: Todos los pacientes transplantados tienen mayor riesgo de padecer infecciones oportunistas,este riesgo aumenta con la carga inmunosupresora total (ver sección 4.4). Las infecciones oportunistas más comunes en pacientestratados con CellCept (2 g ó 3 g diarios) juntos con otros inmunosupresores, detectadas en los ensayos clínicos controlados depacientes con transplante renal (datos con 2 g), cardíaco y hepático, a los que se les hizo un seguimiento de al menos 1 año,fueron candida mucocutánea, viremia/síndrome por CMV y Herpes simplex. La proporción de pacientes con viremia/síndrome porCMV fue del 13,5 %. Niños y adolescentes (entre 2 y 18 años): En un ensayo clínico, que incluía a 92 pacientes pediátricos deedades comprendidas entre los 2 y los 18 años, tratados dos veces al día con 600 mg/m2 de micofenolato mofetilo administradopor vía oral, el tipo y la frecuencia de las reacciones adversas fueron, por lo general, similares a aquellas observadas en pacientesadultos tratados con 1 g de CellCept dos veces al día. No obstante, las siguientes reacciones adversas relacionadas con eltratamiento fueron más frecuentes en la población pediátrica, particularmente en niños menores de 6 años de edad, que en la deadultos: diarreas, sepsis, leucopenia, anemia e infección. Pacientes ancianos (≥ 65 años): Los pacientes ancianos (≥ 65 años) engeneral pueden presentar mayor riesgo de reacciones adversas debido a la inmunosupresión. Los pacientes ancianos, que recibenCellCept como parte de un régimen inmunosupresor en combinación, podrían tener mayor riesgo de padecer ciertas infecciones(incluyendo la enfermedad hística invasiva por citomegalovirus), posibles hemorragias gastrointestinales y edema pulmonar, encomparación con individuos jóvenes. Otras reacciones adversas: En la siguiente tabla se indican las reacciones adversas,probablemente o posiblemente relacionadas con CellCept, noti�cadas en ≥1/10 y en ≥1/100 a <1/10 de los pacientes tratadoscon CellCept en los ensayos clínicos controlados de pacientes con transplante renal (datos con 2 g), cardíaco y hepático.Reacciones Adversas, Probablemente o Posiblemente Relacionadas con CellCept, Noti�cadas en Pacientes Tratados conCellCept en los Ensayos Clínicos en Transplante Renal, Cardíaco y Hepático cuando se Usa en Asociación con Ciclosporinay Corticosteroides Dentro de la clasi�cación por órganos y sistemas, las reacciones adversas se presentan bajo el encabezamientode frecuencia, usando las siguientes categorías: muy frecuentes (≥ 1/10); frecuentes (≥ 1/100 < 1/10); poco frecuentes (≥ 1/1.000< 1/100); raras (≥ 1/10.000 ≤1/1.000); muy raras (≤1/10.000), no conocidas (no se puede estimar a partir de los datos disponibles).Las reacciones adversas se presentan en orden decreciente de gravedad dentro de cada frecuencia.

Clasi�cación por órgano y sistema Reacciones adversas al fármaco Infecciones e infestaciones Muy frecuentes Sepsis, candidiasis gastrointestinal, infección del tracto urinario, herpes simplex, herpes zoster Frecuentes Neumonía, síndrome gripal, infección del tracto respiratorio, moniliasis respiratoria, infección gastrointestinal, candidiasis,

gastroenteritis, infección, bronquitis, faringitis, sinusitis, dermatitis micótica, candidiasis en piel, candidiasis vaginal, rinitis Neoplasias benignas, malignas y no especi�cadas (incl quistes y pólipos) Muy frecuentes - Frecuentes Cáncer cutáneo, tumor benigno de piel Trastorno de la sangre y del sistema linfático Muy frecuentes Leucopenia, trombocitopenia, anemia Frecuentes Pancitopenia, leucocitosis Trastornos del metabolismo y de la nutrición Muy frecuentes - Frecuentes Acidosis, hiperpotasemia, hipopotasemia, hiperglicemia,hipomagnesemia, hipocalcemia, hipercolesterolemia, hiperlipide-

mia, hipofosfatemia, hiperuricemia, gota, anorexia Trastornos psiquiátricos Muy frecuentes - Frecuentes Agitación,confusión, depresión, ansiedad, alteración del pensamiento, insomnio

Trastornos del sistema nervioso Muy frecuentes - Frecuentes Convulsión, hipertonía, temblor, somnolencia, síndrome miasténico, mareos, dolor de cabeza, parestesia, disgeusia Trastornos cardíacos Muy frecuentes - Frecuentes Taquicardia

148

Los siguientes efectos adversos incluyen las reacciones adversas ocurridas durante la experiencia posterior a lacomercialización: Los tipos de reacciones adversas, noti�cadas tras la comercialización de CellCept, son similares a lasobservadas en los ensayos controlados en transplante renal, cardíaco y hepático. A continuación se describen reaccionesadversas al fármaco adicionales, noti�cadas tras la comercialización, con las correspondientes frecuencias si se conocen,dentro de paréntesis. Aparato digestivo: colitis incluyen colitis por citomegalovirus, (≥1/100 <1/10), pancreatitis (≥1/100<1/10), y atro�a de las vellosidades intestinales. Alteraciones relacionadas con la inmunosupresión: Se han comunicadoocasionalmente casos de infecciones graves con riesgo para la vida como meningitis, endocarditis infecciosa, tuberculosise infección micobacteriana atípica.En pacientes tratados con Cellcept se han noti�cado casos, alguno de ellos mortales,de Leucoencefalopatía Multifocal Progresiva (LMP). En general, los casos noti�cados presentaban factores de riesgo parala LMP, como tratamiento inmunosupresor y función inmune deteriorada.. Se ha comunicado agranulocitosis(≥1/1000<1/100), y neutropenia en algunos pacientes, por lo que se aconseja monitorizar regularmente a los pacientes en tratamientocon CellCept (ver sección 4.4 ) Se han noti�cado casos de anemia aplásica y depresión de médula ósea en pacientestratados con CellCept, algunos de los cuales han provocado la muerte. Hipersensibilidad: Se han noti�cado reacciones dehipersensibilidad, incluyendo edema angioneurótico y reacción ana�lactica. Se han reportado casos de aplasia pura decélulas rojas (APCR) en pacientes tratados con Cellcept en combinación con otros agentes inmunosupresores. 4.9Sobredosis Se han noti�cado casos de sobredosis con micofenolato mofetilo en ensayos clínicos y durante la experienciapostcomercialización. En muchos de estos casos, no se noti�caron reacciones adversas. En los casos de sobredosis en loscuales se noti�caron reacciones adversas, estas reacciones estaban dentro del per�l de seguridad conocido delmedicamento. Se cree que una sobredosis de micofenolato mofetilo posiblemente podría producir una sobresupresión delsistema inmune y aumentar la susceptibilidad a infecciones y una supresión de la médula ósea (ver sección 4.4). Si sedesarrolla neutropenia, se debería interrumpir o reducir la dosis de CellCept (ver sección 4.4). No se preveé la eliminaciónde cantidades clínicamente signi�cativas de MPA o MPAG por hemodiálisis. Los secuestradores de ácidos biliares, comola colestiramina, pueden eliminar el MPA disminuyendo la re-circulación enterohepática del fármaco (ver sección 5.2). 5.PROPIEDADES FARMACOLÓGICAS 5.1 Propiedades farmacodinámicas Grupo farmacoterapéutico: agentesinmunosupresores código ATC L04AA06 El micofenolato mofetilo es el éster 2-morfolinoetílico del MPA. El MPA es uninhibidor potente, selectivo, no competitivo y reversible de la inosinmonofosfato-deshidrogenasa; inhibe, por tanto, la síntesisde novo del nucleótido guanosina, sin incorporación al ADN. El MPA tiene unos efectos citostáticos más potentes en loslinfocitos que en otras células ya que los linfocitos T y B dependen de una manera decisiva para su proliferación de lasíntesis de novo de purinas, mientras que otros tipos de células pueden utilizar mecanismos de recuperación de purinas.5.2 Propiedades farmacocinéticas Tras la administración oral, el micofenolato mofetilo se absorbe rápida y ampliamente;a continuación se transforma en MPA, su metabolito activo, en un proceso de metabolización presistémica completa. Laactividad inmunosupresora de CellCept está correlacionada con la concentración del MPA, según ha quedado demostradopor la supresión del rechazo agudo a continuación del trasplante renal. La biodisponibilidad media del micofenolato mofetilopor vía oral, determinada mediante el AUC del MPA, es del 94 % en comparación con la del micofenolato mofetilointravenoso. Los alimentos no tuvieron ningún efecto en el grado de absorción (AUC del MPA) del micofenolato mofetiloadministrado a dosis de 1,5 g, dos veces al día, a transplantados renales. Sin embargo, se produjo una disminución deaproximadamente el 40 % en la Cmáx del MPA en presencia de alimentos. El micofenolato mofetilo no es detectablesistémicamente en el plasma tras su administración oral. El MPA, a concentraciones clínicamente relevantes, se une a laalbúmina plasmática en un 97 %. Tras la administración intravenosa, el micofenolato mofetilo experimenta unametabolización rápida y completa a MPA, su metabolito activo. El MPA, a concentraciones clínicamente relevantes, se unea la albúmina plasmática en un 97 %. La sustancia de origen, el micofenolato mofetilo, puede ser detectado sistémicamentedurante la perfusión intravenosa; sin embargo, tras la administración oral permanece por debajo del límite de cuanti�cación(0,4 microgramo/mL). Como consecuencia de la recirculación enterohepática, se suelen observar aumentos secundariosde la concentración plasmática de MPA después de aproximadamente 6 - 12 horas de la administración. Con lacoadministración de colestiramina (4 g tres veces al día), se produce una reducción del AUC del MPA del orden del 40 %,lo que es indicativo de una recirculación enterohepática importante. El MPA se metaboliza principalmente por la glucuronil-transferasa, para formar el glucurónido fenólico del MPA (MPAG), sin actividad farmacológica. La cantidad de sustanciaque se excreta en forma de MPA con la orina es despreciable (< 1 % de la dosis). Tras la administración por vía oral demicofenolato mofetilo radiomarcado, la recuperación de la dosis administrada es completa. Un 93 % de la dosis se recuperóen la orina y un 6 % en las heces. La mayor parte de la dosis administrada (alrededor del 87 %) se excreta por la orina enforma de MPAG. El MPA y el MPAG no se eliminan por hemodiálisis a las concentraciones encontradas a nivel clínico. Sinembargo, a concentraciones plasmáticas elevadas de MPAG (> 100 microgramo/mL), se eliminan pequeñas cantidadesdel mismo. En el postoperatorio inmediato (< 40 días posteriores al trasplante), los pacientes sometidos a trasplante renal,cardíaco y hepático tienen unos valores medios del AUC del MPA aproximadamente un 30 % mas bajo y una Cmaxaproximadamente un 40 % mas baja que en el periodo postoperatorio tardío (3-6 meses posteriores al trasplante).Insu�ciencia renal: En un ensayo a dosis única (6 individuos/grupo), se observó que para los individuos con insu�cienciarenal crónica grave (�ltración glomerular < 25 mL·min-1·1,73 m-2), el valor medio del AUC para el MPA plasmático fue deun 28 – 75 % superior que para individuos sanos normales o en pacientes con menor deterioro renal. Sin embargo, el valormedio del AUC del MPAG tras una dosis única en los sujetos con insu�ciencia renal grave, fue 3 - 6 veces superior alpresentado en los pacientes con deterioro renal leve o en los voluntarios sanos, lo que concuerda con la eliminación renalconocida del MPAG. No se ha estudiado la administración de dosis múltiples de micofenolato mofetilo en pacientes coninsu�ciencia renal crónica grave. No existen datos sobre los pacientes sometidos a trasplante cardíaco o hepático coninsu�ciencia renal crónica grave. Retraso de la función renal del injerto: En pacientes con retraso funcional del riñóntrasplantado, el valor medio del AUC (0-12) del MPA fue comparable al observado en los pacientes sin retraso funcionalpostrasplante. Asimismo, el valor medio del AUC (0-12) del MPAG fue 2 - 3 veces superior al de los pacientes trasplantadossin retraso de la función del órgano. Puede darse un aumento transitorio de la fracción libre y la concentración en plasmadel MPA en pacientes con retraso de la función renal del injerto. No se considera necesario realizar un ajuste de la dosisde CellCept. Insu�ciencia hepática: En voluntarios con cirrosis alcohólica se comprobó que los procesos de glucuronidaciónhepática del MPA estaban relativamente poco afectados por la enfermedad del parénquima hepático. Los efectos de lahepatopatía en este proceso dependen probablemente de la enfermedad concreta de que se trate. Sin embargo, unahepatopatía con predominio de la afectación biliar, como la cirrosis biliar primaria, puede tener un efecto diferente. Niñosy adolescentes (entre 2 y 18 años): Se han evaluado los parámetros farmacocinéticos de 49 pacientes pediátricos contrasplante renal, tratados dos veces al día con 600 mg/m2 de micofenolato mofetilo administrado por vía oral. Con esta

dosis se alcanzaron valores del AUC del MPA similares a los observados en pacientes adultos con trasplante renal, tratadoscon 1 g de CellCept dos veces al día, en los periodos post-trasplante inicial y tardío. Los valores del AUC del MPA en todoslos grupos de edad fueron similares en los periodos post-trasplante inicial y tardío. Pacientes ancianos (≥ 65 años): No seha evaluado formalmente el comportamiento farmacocinético de CellCept en pacientes ancianos. Anticonceptivos orales:La farmacocinética de los anticonceptivos orales no se vio afectada por la administración conjunta con CellCept (ver ademássección 4.5). En un ensayo realizado en 18 mujeres (que no tomaban otro inmunosupresor), durante 3 ciclos menstrualesconsecutivos, en el que se administraban conjuntamente CellCept (1 g, dos veces al día) y anticonceptivos oralescombinados, que contenían etinilestradiol (de 0,02 mg a 0,04 mg) y levonorgestrel (de 0,05 mg a 0,15 mg), desogestrel(0,15 mg) o gestodeno (de 0,05 mg a 0,10 mg), no se puso de mani�esto una in�uencia clínicamente relevante de CellCeptsobre la capacidad de los anticonceptivos orales para suprimir la ovulación. Los niveles séricos de LH, FSH y progesteronano se vieron afectados signi�cativamente. 5.3 Datos preclínicos sobre seguridad En modelos experimentales, elmicofenolato mofetilo no fue carcinogénico. La dosis más alta ensayada en los estudios de carcinogénesis en animalesresultó ser aproximadamente de 2 a 3 veces la exposición sistémica (AUC o Cmáx) observada en pacientes trasplantadosrenales a la dosis clínica recomendada de 2 g/ día, y de 1,3 a 2 veces la exposición sistémica (AUC o Cmáx) observada enpacientes sometidos a trasplante cardíaco con la dosis clínica recomendada de 3 g/ día. Dos estudios de genotoxicidad(ensayo in vitro de linfoma de ratón y ensayo in vivo del test del micronúcleo en médula ósea de ratón) indicaron que elmicofenolato mofetilo tenía potencial para causar aberración cromosómica. Estos efectos pueden estar relacionados conel mecanismo de acción, p.ej. inhibición de la síntesis de nucleótidos en células sensibles. No se demostró actividadgenotóxica en otros ensayos in vitro para la detección de la mutación de genes. El micofenolato mofetilo no tuvo efectoalguno en la fertilidad de las ratas macho a dosis orales de hasta 20 mg·kg-1·día-1. La exposición sistémica a esta dosisrepresenta de 2- 3 veces la exposición clínica a la dosis recomendada de 2 g/ día en los pacientes sometidos a trasplanterenal y de 1,3 a 2 veces la exposición clínica con la dosis recomendada de 3 g/ día en los pacientes sometidos a trasplantecardíaco. En un estudio de la reproducción y la fertilidad llevado a cabo en ratas hembra, dosis orales de 4,5 mg·kg-1·día-

1 causaron malformaciones (incluyendo anoftalmia, agnatia, e hidrocefalia) en la primera generación de crías, sin que sedetectara toxicidad en las madres. La exposición sistémica a esta dosis fue aproximadamente 0,5 veces la exposiciónclínica a la dosis recomendada de 2 g/ día en los pacientes sometidos a trasplante renal y de 0,3 veces la exposición clínicacon la dosis recomendada de 3 g/ día en los pacientes sometidos a trasplante cardíaco. No se evidenció ningún efecto enla fertilidad y la reproducción de las ratas madre ni en la generación siguiente. En los estudios de teratogenia se produjeronresorciones fetales y malformaciones en ratas con dosis de 6 mg·kg-1· día-1 (incluyendo anoftalmia, agnatia, e hidrocefalia)y en conejos con dosis de 90 mg·kg-1·día-1 (incluyendo anormalidades cardiovasculares y renales, como ectopia del corazóny riñones ectópicos, y hernia diafragmática y umbilical), sin que se registrara toxicidad materna. La exposición sistémica aestos niveles es aproximadamente equivalente o menor a 0,5 veces la exposición clínica a la dosis recomendada de 2 g/día en los pacientes sometidos a trasplante renal y en torno a 0,3 veces la exposición clínica con la dosis recomendada de3 g/ día en los pacientes sometidos a trasplante cardíaco. Ver sección 4.6. Los sistemas hematopoyético y linfoide fueronlos primeros órganos afectados en los estudios toxicológicos realizados con micofenolato mofetilo en la rata, ratón, perroy mono. Estos efectos se observaron con valores de exposición sistémica equivalentes o inferiores a la exposición clínicacon la dosis recomendada de 2 g/ día en trasplantados renales. En el perro se observaron efectos gastrointestinales aniveles de exposición sistémica equivalentes o menores a la exposición clínica a las dosis recomendadas. En el mono, a ladosis más alta (niveles de exposición sistémica equivalente a o mayor que la exposición clínica), también se observaronefectos gastrointestinales y renales que concuerdan con la deshidratación. El per�l toxicológico no clínico de micofenolatomofetilo parece estar de acuerdo con los acontecimientos adversos observados en los ensayos clínicos humanos que ahoraproporcionan datos de seguridad de mas relevancia para la población de pacientes. (ver sección 4.8). 6. DATOSFARMACÉUTICOS 6.1 Lista de excipientes Comprimidos de CellCept: celulosa microcristalina povidona (K-90)croscarmelosa sódica estearato magnésico Recubrimiento de los comprimidos: hipromellosa hidroxipropil celulosa dióxidode titanio (E171) polietilenglicol 400 índigo carmín en laca alumínica (E132) óxido de hierro rojo (E172) Cápsulas de CellCept:almidón de maíz pregelatinizado croscarmelosa sódica povidona (K-90) estearato magnésico Envoltura de la cápsula:gelatina índigo carmín (E132) óxido de hierro amarillo (E172) óxido de hierro rojo (E172) dióxido de titanio (E171) óxido dehierro negro (E172) hidróxido de potasio goma laca. CellCept 500 mg polvo para concentrado para solución para perfusiónPolisorbato 80 ácido cítrico ácido clorhídrico cloruro sódico CellCept 1 g/5 ml polvo para suspensión oral: sorbitol sílicecoloidal anhidra citrato sódico lecitina de soja sabor compuesto de frutas goma xantam aspartamo (E951)parahidroxibenzoato de metilo (E218) ácido cítrico anhidro *contiene una cantidad de fenilalanina equivalente a 2,78 mg/5 mlde suspensión. 6.2 Incompatibilidades No procede en caso de comprimidos y cápsulas. La solución para perfusión deCellCept 500 mg polvo para concentrado para solución para perfusión no debe ser mezclada o administrada de formaconcurrente a través del mismo catéter con otros medicamentos intravenosos u otras mezclas para perfusión.6.3 Periodode validez 3 años para comprimidos y cápsulas. Polvo para concentrado para solución para perfusión: 3 años. Soluciónreconstituida y solución para perfusión: Si la solución para perfusión no se prepara inmediatamente antes de laadministración, el comienzo de la administración de la solución para perfusión debe ser dentro de las 3 horas siguientes ala reconstitución y dilución del medicamento. El polvo para suspensión oral tiene un periodo de validez de 2 años. Lasuspensión reconstituida tiene un periodo de validez de 2 meses. 6.4 Precauciones especiales de conservación Noconservar a temperatura superior a 30ºC.Conservar en el embalaje original para protegerlo de la humedad. Polvo paraconcentrado para solución para perfusión: No conservar a temperatura superior a 30ºC. Solución reconstituida y soluciónde perfusión: Conservar entre 15 y 30ºC. 6.5 Naturaleza y contenido del envase CellCept 500 mg comprimidos: 1 estuchecontiene 50 comprimidos (en blísters de 10 unidades). 1 estuche contiene 150 comprimidos (en blísters de 10 unidades).CellCept 250 mg cápsulas: 1 estuche contiene 100 cápsulas (en blísters de 10 unidades). 1 estuche contiene 300 cápsulas(en blísters de 10 unidades). Viales de vidrio transparente tipo I de 20 mL con tapón de caucho butílico gris y precinto dealuminio con cápsulas de plástico de fácil apertura. CellCept 500 mg polvo para concentrado para solución para perfusiónestá disponible en envases de 4 viales. Cada frasco contiene 110 g de polvo para suspensión oral. El volumen de lasuspensión cuando se reconstituye es de 175 ml, proporcionando un volumen útil de 160-165 ml. También se incluyen unadaptador del frasco y 2 dispensadores orales. 6.6 Precauciones especiales de eliminación y otras manipulacionesDado que se ha observado efecto teratogénico para el micofenolato mofetilo en la rata y el conejo, no deben triturarse loscomprimidos de CellCept, no deben abrirse o triturarse las cápsulas de CellCept. Evítese la inhalación del polvo contenidoen las cápsulas de CellCept, así como el contacto directo con la piel o las mucosas. En caso de contacto, lávese la parteafectada con abundante agua y jabón; los ojos deben lavarse con agua corriente. La eliminación del medicamento noutilizado y de todos los materiales que hayan estado en contacto con él se realizará de acuerdo con las normativas locales.Preparación de la Solución de Perfusión (6 mg/mL) CellCept 500 mg polvo para concentrado para solución para perfusiónno contiene conservantes antibacterianos; por tanto, la reconstitución y dilución del producto debe realizarse bajocondiciones asépticas. CellCept 500 mg polvo para concentrado para solución para perfusión debe prepararse en dospasos: el primer lugar reconstituir con una solución para perfusión intravenosa de glucosa al 5 % y el segundo lugar diluircon una solución para perfusión intravenosa de glucosa al 5 %. A continuación se da una descripción detallada de lapreparación: Paso 1. a. Para cada dosis de 1 g se emplean dos viales de CellCept 500 mg polvo para concentrado parasolución para perfusión. Reconstituir el contenido de cada vial mediante una inyección de 14 mL de solución para perfusiónintravenosa de glucosa al 5 %. b. Agitar suavemente el vial para disolver el medicamento, se produce una soluciónligeramente amarilla. c. Antes de seguir diluyendo, inspeccionar la solución resultante en lo relativo a partículas y alteracióndel color. Descartar el vial si se observan partículas o alteración del color. Paso 2. a. Posteriormente diluir el contenido dedos viales reconstituidos (aprox. 2 x 15 mL) en 140 mL de solución para perfusión intravenosa de glucosa al 5 %. Laconcentración �nal de la solución es de 6 mg/mL de micofenolato mofetilo. b. Inspeccionar la solución para perfusión enlo relativo a partículas o alteración del color. Si se observan partículas o alteración del color desechar la solución paraperfusión. Si la solución para perfusión no se prepara inmediatamente antes de la administración, el comienzo de laadministración de la solución debe efectuarse dentro de las 3 horas siguientes a la reconstitución y dilución delmedicamento. Mantener las soluciones entre 15 y 30ºC. Preparación de la Suspensión oral Se recomienda que antes dela dispensación al paciente, CellCept 1 g/5 ml polvo para suspensión oral sea reconstituida por el farmacéutico. Preparaciónde la suspensión 1. Golpear ligeramente el frasco cerrado varias veces para soltar el polvo. 2. Medir 94 ml de agua puri�cadaen una probeta. 3. Añadir al frasco aproximadamente la mitad de la cantidad total de agua puri�cada y agitar bien el frascocerrado durante 1 minuto aproximadamente. 4. Añadir el resto de agua y agitar bien el frasco cerrado durante 1 minutoaproximadamente. 5. Quitar el cierre a prueba de niños y acoplar el adaptador en el cuello del frasco. 6. Cerrar el frascoherméticamente con el cierre a prueba de niños. Esto asegurará la colocación correcta del adaptador en el frasco y elestado del cierre a prueba de niños. 7. Escribir en la etiqueta del frasco la fecha de caducidad de la solución reconstituida.(El periodo de validez de la suspensión reconstituida es de dos meses) 7. TITULAR DE LA AUTORIZACIÓN DECOMERCIALIZACIÓN Roche Registration Limited 6 Falcon Way Shire Park Welwyn Garden City AL7 1TW Reino Unido 8.NÚMERO(S) DE AUTORIZACIÓN DE COMERCIALIZACIÓN EU/1/96/005/002 CellCept (50 comprimidos) EU/1/96/005/004CellCept (150 comprimidos) EU/1/96/005/001 CellCept (100 cápsulas) EU/1/96/005/003 CellCept (300 cápsulas)EU/1/96/005/006 (1 frasco de 110 g) EU/1/96/005/005 CellCept (4 viales) 9. FECHA DE LA PRIMERAAUTORIZACIÓN/RENOVACIÓN DE LA AUTORIZACIÓN Fecha de la primera autorización: 14 de febrero de 1996 Fecha dela última renovación: 14 de febrero de 2006 10. FECHA DE LA REVISIÓN DEL TEXTO 28 de febrero de 2008 La informacióndetallada de este medicamento está disponible en la página web de la Agencia Europea del Medicamento (EMEA)http://www.emea.europa.eu/ PRECIO CellCept 500 mg (50 comprimidos) y CellCept 250 mg (100 cápsulas): PVL 99,26euros; PVP IVA 150,98 euros. CellCept 500 mg, polvo para concentrado para solución para perfusión: PVL 49,81 euros;PVP IVA 77,76 euros. Cellcept polvo para suspensión oral: PVL 138,98 euros; PVP IVA 192,29 euros.

Trastornos vasculares Muy frecuentes - Frecuentes Hipotensión, hipertensión, vasodilatación Trastornos respiratorios, torácicos y mediastínicos Muy frecuentes - Frecuentes Derrame pleural, disnea, tos Trastornos gastrointestinales Muy frecuentes Vómitos, dolor abdominal, diarrea, náuseas Frecuentes Hemorragia gastrointestinal, peritonitis, íleo, colitis, úlcera gástrica, úlcera duodenal, gastritis, esofagitis, estomatitis, estre-

ñimiento, dispepsia, �atulencia, eructos. Trastornos hepatobiliares Muy frecuentes - Frecuentes Hepatitis, ictericia, hiperbilirrubinemia

Trastornos de la piel y del tejido subcutáneo Muy frecuentes - Frecuentes Hipertro�a cutánea, rash, acné, alopecia Trastornos musculoesqueléticos y del tejido conjuntivo Muy frecuentes - Frecuentes Artralgia Trastornos renales y urinarios Muy frecuentes - Frecuentes Alteración renal Trastornos generales y alteraciones en el lugar de administración Muy frecuentes - Frecuentes Edema, pirexia, escalofríos, dolor, malestar general, astenia Exploraciones complementarias Muy frecuentes - Frecuentes Aumento de los niveles enzimáticos, aumento de creatinina sérica, aumento de lactato deshidrogenasa sérica, aumento de

urea sérica, aumento de fosfatasa alcalina sérica, pérdida de peso Nota: 501 (2 g diarios de CellCept), 289 (3 g diarios de CellCept) y 277 (2 g diarios de CellCept IV/3 g diarios de CellCept oral) pacientes fue-ron tratados en ensayos en fase III para la prevención del rechazo en trasplante renal, cardíaco y hepático respectivamente.