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EPS meetingEPS meeting
Guido GarosiU.O.C. Nefrologia, Dialisi e TrapiantoAzienda Ospedaliera Universitaria SeneseSiena, Italy
Guido GarosiU.O.C. Nefrologia, Dialisi e TrapiantoAzienda Ospedaliera Universitaria SeneseSiena, Italy
Post-transplant EPSPost-transplant EPS
Naarden, The NetherlandsFebruary 4th 2010
Naarden, The NetherlandsFebruary 4th 2010
is post-transplant EPSa remarkable problem?is post-transplant EPSa remarkable problem?
46 EPS casesAt diagnosis:12 on PD13 after switch to HD22 after transplantation
46 EPS casesAt diagnosis:12 on PD13 after switch to HD22 after transplantation
50% of EPS cases after transplantation50% of EPS cases after transplantation
The overall incidence of EPS is stableThe incidence during PD seems to decreaseThe incidence after PD seems to increase
The overall incidence of EPS is stableThe incidence during PD seems to decreaseThe incidence after PD seems to increase
13 EPS cases during 2004-2005in Rotterdam + Utrecht:- 7 post-transplant- 3 after shift to HD- 3 during PD
13 EPS cases during 2004-2005in Rotterdam + Utrecht:- 7 post-transplant- 3 after shift to HD- 3 during PD
>50% of EPS cases after transplantation>50% of EPS cases after transplantation
During last years post-transplant EPS seems to bethe most frequent form of the disease,exceeding the cases of EPS during PD or after shift to HD, at least in the countries with a high transplantation rate
During last years post-transplant EPS seems to bethe most frequent form of the disease,exceeding the cases of EPS during PD or after shift to HD, at least in the countries with a high transplantation rate
The greater incidence of post-transplant EPSwith respect to HD cases seems to suggesta pathogenetic role of transplantation itself,independent from PD withdrawal
The greater incidence of post-transplant EPSwith respect to HD cases seems to suggesta pathogenetic role of transplantation itself,independent from PD withdrawal
This seems to be confirmed if we considerthat usually patients shifting from PD to HDshould be in greater numberwith respect to PD patients undergoing transplantation
This seems to be confirmed if we considerthat usually patients shifting from PD to HDshould be in greater numberwith respect to PD patients undergoing transplantation
is post-transplant EPS a remarkable problem?
is post-transplant EPS a remarkable problem?
Yes !Yes !
is the frequencyof post-transplant EPS
increasing?
is the frequencyof post-transplant EPS
increasing?
the incidence ofpost-transplant EPS
is actually increasingwith respect to
previous epidemiological
studies
prospective
transplant centers
transplant centers
Nomoto Y et al: Sclerosing encapsulating peritonitis in patients undergoing continuous ambulatory peritoneal dialysis: A report of the Japanese Sclerosing Encapsulating Peritonitis Study Group. Am J Kidney Dis 1996;20:420-7Rigby RJ et al: Sclerosing peritonitis: The experience in Australia. Nephrol Dial Transplant 1998;13:154-9Lee HJ et al: Sclerosing encapsulating peritonitis as a complication of long term continuous ambulatory peritoneal dialysis in Korea. Nephrol (Carlton) 2003;8:S33-9Kawanishi H: Long-Term Peritoneal Dialysis Study Group: Encapsulating Peritoneal Sclerosis in Japan: Prospective multicenter controlled study. Perit Dial Int 2001;21:S67-71Kawanishi H et al: Encapsulating peritoneal sclerosis in Japan: A prospective, controlled, multicenter study. Am J Kidney Dis 2004;44:729-37Summers AM et al: Single-center experience of encapsulating peritoneal sclerosis in patients on peritoneal dialysis for end stage renal failure. Kidney Int 2005;68:2381-8
Nomoto Y et al: Sclerosing encapsulating peritonitis in patients undergoing continuous ambulatory peritoneal dialysis: A report of the Japanese Sclerosing Encapsulating Peritonitis Study Group. Am J Kidney Dis 1996;20:420-7Rigby RJ et al: Sclerosing peritonitis: The experience in Australia. Nephrol Dial Transplant 1998;13:154-9Lee HJ et al: Sclerosing encapsulating peritonitis as a complication of long term continuous ambulatory peritoneal dialysis in Korea. Nephrol (Carlton) 2003;8:S33-9Kawanishi H: Long-Term Peritoneal Dialysis Study Group: Encapsulating Peritoneal Sclerosis in Japan: Prospective multicenter controlled study. Perit Dial Int 2001;21:S67-71Kawanishi H et al: Encapsulating peritoneal sclerosis in Japan: A prospective, controlled, multicenter study. Am J Kidney Dis 2004;44:729-37Summers AM et al: Single-center experience of encapsulating peritoneal sclerosis in patients on peritoneal dialysis for end stage renal failure. Kidney Int 2005;68:2381-8
Previous studies were usually retrospective and did not involve only transplant centers,so there is the possibility that they did not considerall post-transplant EPS patients
Previous studies usually did not make a clear distinction between EPS arising during PD, after switch to HD,and post-transplantation
is the frequencyof post-transplant EPS
increasing?
is the frequencyof post-transplant EPS
increasing?
likely !
Hypothesis:acceleration of inflammatory-fibroticprocesses due to increased peritonealconcentration of fibrin, IL1, TGFβ, VEGF(lack of peritoneal lavage)
Hypothesis:acceleration of inflammatory-fibroticprocesses due to increased peritonealconcentration of fibrin, IL1, TGFβ, VEGF(lack of peritoneal lavage)
Kawanishi H et al: Encapsulating peritoneal sclerosis in Japan: A prospective, controlled, multicenter study. Am J Kidney Dis 2004;44:729-37Margetts PJ et al: Inflammatory cytokines, angiogenesis, and fibrosis in the rat peritoneum. Am J Pathol 2002;160:2285-94Fieren MWJA et al: Endotoxin-stimulated peritoneal macrophages obtained from continuous ambulatory peritoneal dialysis patients show an increased capacity to release interleukin-1β in vitro during infectious peritonitis. Eur J Clin Invest 1990;20:453-7
Kawanishi H et al: Encapsulating peritoneal sclerosis in Japan: A prospective, controlled, multicenter study. Am J Kidney Dis 2004;44:729-37Margetts PJ et al: Inflammatory cytokines, angiogenesis, and fibrosis in the rat peritoneum. Am J Pathol 2002;160:2285-94Fieren MWJA et al: Endotoxin-stimulated peritoneal macrophages obtained from continuous ambulatory peritoneal dialysis patients show an increased capacity to release interleukin-1β in vitro during infectious peritonitis. Eur J Clin Invest 1990;20:453-7
Pathogenesis of EPSafter PD withdrawal
Pathogenesis of EPSafter PD withdrawal
Proposal:to continue exchanges of fluidsa few times per week after PD withdrawal
Proposal:to continue exchanges of fluidsa few times per week after PD withdrawal
Kawanishi H et al: Encapsulating peritoneal sclerosis in Japan: A prospective, controlled, multicenter study.Am J Kidney Dis 2004;44:729-37
Kawanishi H et al: Encapsulating peritoneal sclerosis in Japan: A prospective, controlled, multicenter study.Am J Kidney Dis 2004;44:729-37
Pathogenesis of EPSafter PD withdrawal
Pathogenesis of EPSafter PD withdrawal
Result:so far, no convincing evidenceof a beneficial effecton the development or course of EPS
Result:so far, no convincing evidenceof a beneficial effecton the development or course of EPS
ultrafiltration failure and peritonitisare risk factors for EPS
very often associated to HD shift,never to transplantation
ultrafiltration failure and peritonitisare risk factors for EPS
very often associated to HD shift,never to transplantation
post-transplant EPS usually showsan acute-onset presentation,
at variance withthe more commonly describedinsidious and chronic course
post-transplant EPS usually showsan acute-onset presentation,
at variance withthe more commonly describedinsidious and chronic course
Pathogenetic differences betweenHD and post-transplant EPS
Pathogenetic differences betweenHD and post-transplant EPS
transplantationper se
does playa role in the development
of EPS
transplantationper se
does playa role in the development
of EPS
Transplantation
Japanese studies, at variance with Europe, show much more EPS cases
after shift to PD than post-transplantation
Japanese studies, at variance with Europe, show much more EPS cases
after shift to PD than post-transplantation
Hypothesis:- Lower transplantation rate in Japan- Differences in inflammatory reactivity- Genetic differences
Hypothesis:- Lower transplantation rate in Japan- Differences in inflammatory reactivity- Genetic differences
no significant inflammation, calcification, and vasculopathy in EPS
no significant inflammation, calcification, and vasculopathy in EPS
Japanese studiesJapanese studies
inflammation could be differentbetween populations
inflammation could be differentbetween populations
Pathogenetic role of transplantation“per se” in post-transplant EPS
Pathogenetic role of transplantation“per se” in post-transplant EPS
Pivotal role of the modality of immunosuppressive therapyPivotal role of the modality of immunosuppressive therapy
Reliable scheme of the pro-fibrotic and anti-fibrotic properties of eachimmunosuppressive drug
Reliable scheme of the pro-fibrotic and anti-fibrotic properties of eachimmunosuppressive drug
EPS cases recovering after kidneytransplantation
EPS cases recovering after kidneytransplantation
Junor BJ, McMillan MA:Immunosuppression in sclerosing peritonitis.Adv Perit Dial 1993;9:187-9
Junor BJ, McMillan MA:Immunosuppression in sclerosing peritonitis.Adv Perit Dial 1993;9:187-9
Hawley CM, Wall DR, Johnson DW, Campbell SB, Griffin AD, Rigby RJ, Petrie JJB:Recovery of gastrointestinal function after renal transplantation in a patients with sclerosing peritonitis secondary to continuousambulatory peritoneal dialysis.Am J Kidney Dis 1995;26:658-61
Hawley CM, Wall DR, Johnson DW, Campbell SB, Griffin AD, Rigby RJ, Petrie JJB:Recovery of gastrointestinal function after renal transplantation in a patients with sclerosing peritonitis secondary to continuousambulatory peritoneal dialysis.Am J Kidney Dis 1995;26:658-61
immunosuppressive protocolswith high-dose steroids
immunosuppressive protocolswith high-dose steroids
kidney transplantation:tacrolimus, mycophenolate mofetil, low-dose steroidkidney transplantation:tacrolimus, mycophenolate mofetil, low-dose steroid
post-transplant EPSpost-transplant EPS
high-dose steroidhigh-dose steroid
successsuccess steroid taperingsteroid tapering
relapse of EPSrelapse of EPS
increase in steroid doseincrease in steroid dose
successsuccess
Several reports from Japan confirm thatsteroids alone may be efficacious in EPSSeveral reports from Japan confirm thatsteroids alone may be efficacious in EPS
Kawanishi H, Kawagushi Y, Fukui H, Hara S, Imada A, Kubo H, Kin M, Nakamoto M, Ohira S, Shoji T:Encapsulating peritoneal sclerosis in Japan: A prospective, controlled, multicenter study.Am J Kidney Dis 2004;44:729-37
Kawanishi H, Kawagushi Y, Fukui H, Hara S, Imada A, Kubo H, Kin M, Nakamoto M, Ohira S, Shoji T:Encapsulating peritoneal sclerosis in Japan: A prospective, controlled, multicenter study.Am J Kidney Dis 2004;44:729-37
Kuriyama S, Tomonari H:Corticosteroid theraphy in encapsulating peritoneal sclerosis.Nephrol Dial Transplant 2001;16:1304-5
Kuriyama S, Tomonari H:Corticosteroid theraphy in encapsulating peritoneal sclerosis.Nephrol Dial Transplant 2001;16:1304-5
Mori Y, Matsuo S, Sutoh H, Toriyama T, Kawahara H, Hotta N:A case of a dialysis patient with sclerosing peritonitis successfullytreated with corticosteroid therapy alone.Am J Kidney Dis 1997;30:275-8
Mori Y, Matsuo S, Sutoh H, Toriyama T, Kawahara H, Hotta N:A case of a dialysis patient with sclerosing peritonitis successfullytreated with corticosteroid therapy alone.Am J Kidney Dis 1997;30:275-8
Steroid theraphy is useful in EPSSteroid theraphy is useful in EPS
the present trend to reduce or abolish steroids after transplantation
could be associated to a growingtendency in post-transplant EPS
the present trend to reduce or abolish steroids after transplantation
could be associated to a growingtendency in post-transplant EPS
Whenever the immunosuppressiveregimen at diagnosis isreported,it is always basedon CNI (cyclosporinor tacrolimus)in all patients, without exception
Whenever the immunosuppressiveregimen at diagnosis isreported,it is always basedon CNI (cyclosporinor tacrolimus)in all patients, without exception
CNI in post-transplant EPSCNI in post-transplant EPS
CNI:- Induce nephrotoxicity with interstitial fibrosis- Increase TGF-β transcription in human T lymphocytes- Modulate expression of TGF-β and other growth factors- Upregulate expression of VEGF (mRNA and protein)- Upregulate expression of VEGF receptors
CNI:- Induce nephrotoxicity with interstitial fibrosis- Increase TGF-β transcription in human T lymphocytes- Modulate expression of TGF-β and other growth factors- Upregulate expression of VEGF (mRNA and protein)- Upregulate expression of VEGF receptors
Profibrotic effects of CNIProfibrotic effects of CNI
Van Nieuwenhoven FA et al: Imbalance of growth factors signalling in diabetic kidneydisease: is connective tissue growth factor (CTGF, CCN2) the perfect intervention point? Nephrol Dial Transplant 2005;20:6-10Myers BD et al: Cyclosporine-associated chronic nephropathy. N Eng J Med 1984;31:699-705Shibab FS et al: Role of transforming growth factor-β1 in experimental chronic cyclosporinnephropathy. Kidney Int 1996;49:1141-51Shin GT et al: In vivo expression of transforming growth factor-β in humans. Transplantation1998;65:3313-18Shibab FS et al: Expression of vascular endothelial growth factor and its receptors Flt-1 and KDR/FLK-1 in chronic cyclosporin nephrotoxicity. Transplantation 2001;72:164-168
Van Nieuwenhoven FA et al: Imbalance of growth factors signalling in diabetic kidneydisease: is connective tissue growth factor (CTGF, CCN2) the perfect intervention point? Nephrol Dial Transplant 2005;20:6-10Myers BD et al: Cyclosporine-associated chronic nephropathy. N Eng J Med 1984;31:699-705Shibab FS et al: Role of transforming growth factor-β1 in experimental chronic cyclosporinnephropathy. Kidney Int 1996;49:1141-51Shin GT et al: In vivo expression of transforming growth factor-β in humans. Transplantation1998;65:3313-18Shibab FS et al: Expression of vascular endothelial growth factor and its receptors Flt-1 and KDR/FLK-1 in chronic cyclosporin nephrotoxicity. Transplantation 2001;72:164-168
CNI as a trigger for post-transplant EPS: a quite obvious role
CNI as a trigger for post-transplant EPS: a quite obvious role
in rats treatedwith PD,
peritonealfibrosis is
significantlyincreased by
CNI and prevented by
steroids
in rats treatedwith PD,
peritonealfibrosis is
significantlyincreased by
CNI and prevented by
steroids
inefficacy of azathioprineinefficacy of azathioprine
MMF as a way to reduce CNIMMF as a way to reduce CNI
- Block of T-cell cycle at late G1 phase by inhibiting IL2- Inhibition of growth-factor stimulated proliferation in
vascular smooth muscle cells, liver and lung fibrosis- Inhibition of mesenchimal cell proliferation- Down-regulation of lipopolysaccharide- and
interferon-γ-induced inflammatory gene transcription
- Block of T-cell cycle at late G1 phase by inhibiting IL2- Inhibition of growth-factor stimulated proliferation in
vascular smooth muscle cells, liver and lung fibrosis- Inhibition of mesenchimal cell proliferation- Down-regulation of lipopolysaccharide- and
interferon-γ-induced inflammatory gene transcription
Effects of mTOR-I (sirolimus, everolimus):inhibition of fibrosis, angiogenesis, inflammation
Effects of mTOR-I (sirolimus, everolimus):inhibition of fibrosis, angiogenesis, inflammation
Schuller W et al: SDZ RAD, a new rapamycin derivative. Pharmacological properties in vitro and in vivo. Transplantation 1997;64:36-42Cao W et al: Effects of rapamycin on growth-factor stimulated vascular smooth muscle cellsDNA synthesis. Transplantation 1995;59:390-5Neef M et al: Low-dose oral rapamycin treatment reduces fibrogenesis, improves liverfunction, and prolongs survival in rats with established liver cirrhosis. J Hepatol2006;45:786-96Simler NR et al: The rapamycin analgue SDZ RAD attenuates bleomycin-induced pulmonaryfibrosis in rats. Eur Respir J 2002;19:1124-7Kristof AS: Stimulation of signal transducer and activator of transcription-1 (STAT-1)-dependent gene transcription by lipopolysaccharide and interferon-γ is regulated bymammalian target of rapamycin. J Biol Chem 2003;278:33637-44
Schuller W et al: SDZ RAD, a new rapamycin derivative. Pharmacological properties in vitro and in vivo. Transplantation 1997;64:36-42Cao W et al: Effects of rapamycin on growth-factor stimulated vascular smooth muscle cellsDNA synthesis. Transplantation 1995;59:390-5Neef M et al: Low-dose oral rapamycin treatment reduces fibrogenesis, improves liverfunction, and prolongs survival in rats with established liver cirrhosis. J Hepatol2006;45:786-96Simler NR et al: The rapamycin analgue SDZ RAD attenuates bleomycin-induced pulmonaryfibrosis in rats. Eur Respir J 2002;19:1124-7Kristof AS: Stimulation of signal transducer and activator of transcription-1 (STAT-1)-dependent gene transcription by lipopolysaccharide and interferon-γ is regulated bymammalian target of rapamycin. J Biol Chem 2003;278:33637-44
Clinical use of mTOR-IClinical use of mTOR-I
mTOR-I as the most rational basisfor immunosuppressive therapy
in ex-PD transplant patients
mTOR-I as the most rational basisfor immunosuppressive therapy
in ex-PD transplant patients
- Endovascular medicine: drug-eluting stents- Oncology: antiproliferative agents- Transplantation: alternative agents for CNI toxicity,
namely to prevent CNI-associated fibrosis;association with delayed healing of surgical wounds
- Endovascular medicine: drug-eluting stents- Oncology: antiproliferative agents- Transplantation: alternative agents for CNI toxicity,
namely to prevent CNI-associated fibrosis;association with delayed healing of surgical wounds
No case of post-transplant EPShas ever been reported in mTOR-I based
immunosuppressive therapy, devoid of CNI
No case of post-transplant EPShas ever been reported in mTOR-I based
immunosuppressive therapy, devoid of CNI
How to prevent EPS?
Stopping PD at 5 years in order to avoid EPS:is it rational?
We do not think soIt may actually increase the incidence of EPS
The “precautionary principle” suggesting “to anticipate harm before itoccurs when the absence of scientific certainty makes it difficult to predictthe likelihood of harm occurring” seems reasonable with etiological factors, not with risk factors
Epidemiology shows thatEPS cases during PD are just ¼EPS cases after PD stopping are ¾
Which is the risk of shifting patients to HD without definite indications?Negative impact on quality of life
(2009) 41:903-907
(2009) 41:903-907
What to do to prevent EPS?
Use of new biocompatible PD solutions
Inhibition of renin-angiotensin systemas the elective therapy of hypertension in PD
Prophylaxis with tamoxifen 10 mg/die in:- patients in PD after 5 years- patients in PD with ultrafiltration failureor increased peritoneal transport
What to do to prevent post-transplant EPS?To treat ex-PD patients at transplantationwith mTOR-I, mycophenolate mofetil and steroids,with avoidance or minimization of CNI
(2009) 41:903-907
Aim: such a specific immunosuppressive protocolfor PD patients receiving kidney transplantation
Many immunosuppressive protocols based on mTOR-I and mycophenolatemofetil have already been successfully developed to prevent or to minimize the nephrotoxic effect of CNI, without any significant increase in rejection rateThe trend to decrease or avoid steroidscould not be pursued rigorously in ex-PD patients
in collaboration with transplantation centers, surveyin all post-transplant ex-PD patients in order to clarifythe development of post-transplant EPS with respect
to the detailed modalities of immunosuppression
mTOR-I
CNI
specific immunosuppressive protocol for PD patients receiving kidney transplantation:
large doses of mTOR-I, possible use of mycophenolate mofetil, judicious dosage of steroids,
avoidance or minimization of CNI
it seems extremely important to haveas much data as possible
from any center throughout the world
mTOR-I
CNI
it should be wonderfulto collect data
from many countries!
it seems extremely important to haveas much data as possible
from any center throughout the world
mTOR-I
CNI
Join in!
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