NEPHROLOGY

2002; 7, S46–S47

Meeting Proceedings: Review

Blackwell Science, LtdOxford, UKNEPNephrology1320-53582002 Asian Pacific Society of Nephrology

7Suppl.June 2002

14Tacrolimus in children

D Lewis10.1046/j.1320-5358.2002.00014.x

Meeting Proceedings: ReviewS46S47BEES SGML

Correspondence: Dr Deborah Lewis, The Children’s Hospital atWestmead, Locked Bag 4001, Westmead, NSW 2145, Australia.Email: DeborahL@chw.edu.au

The trials and tribulations of tacrolimus in children

D

eborah

LEWIS

The Children’s Hospital at Westmead, Sydney, New South Wales, Australia

Although tacrolimus has been used in clinical transplan-tation in the United States for over 10 years, and in pae-diatric renal and liver transplantation in Australia, since1996, only one randomized controlled trial on tacrolimusin paediatric patients has been recently completed.

1

Available data have come mainly from a cohort studyby the University of Pittsburgh, Thomas E. Starzl Trans-plantation Institute of 82 paediatric renal transplantsperformed over a 7-year period (1989–1996) usingtacrolimus-based immunosuppression without inductionantilymphocyte antibody therapy.

2,3

Patient and graft sur-vival rates of 99% and 94% after 1 year, and 98% and84% after 4 years were reported, with unproblematicrenal function, and ability to taper corticosteroids inmost patients. The results encouraged a strongly optimis-tic approach to tacrolimus by paediatric nephrologistsassociated with the Pittsburgh study – an approachsupported by the randomised European study

1

and theAustralian experience.

INDICATIONS

Tacrolimus was initially introduced as rescue immuno-suppressive therapy for steroid resistant rejection or whenanti-lymphocyte antibody therapy was unsuccessful. Itwas subsequently used as a cyclosporin-sparing agent andis currently used as first line immunosuppressive therapyin combination with an interleukin-2 receptor inhibitor,mycophenolate and prednisolone.

TACROLIMUS ADVERSE EVENTS

Some of the adverse events associated with tacrolimusinclude neurotoxicity, nephrotoxicity, diabetes and gas-trointestinal symptoms. Infections include bronchiecta-sis, cholangitis in children with authosomal dominantpolycystic kidney disease and rotavirus gastroenteritis.

Incidence of gastrointestinal symptoms have markedlydecreased since the interaction between tacrolimus and

mycophenolate was recognized, and dosages of the twodrugs adjusted.

Post-transplant diabetes mellitus (PTDM), which usu-ally occurs early after transplantation, has been linkedwith both prednisone dose and tacrolimus blood concen-trations. A meta-analysis of the available literature byKnoll and Bell

4

suggested that even after 1 year, patientstreated with tacrolimus still had about five times the riskof PTDM compared with those treated with cyclosporin.The University of Pittsburgh Medical Center cohortstudy

2

observed a PTDM incidence initially of 9% in pae-diatric transplant recipients, which was reduced to 1%with reduction of tacrolimus doses and corticosteroidtapering. The Australian experience suggests that forpatients converted from cyclosporin to tacrolimus whodevelop diabetes, re-conversion back to cyclosporinimproves the situation.

Perhaps the greatest concern with the use of tacroli-mus in paediatric renal transplantation has been the rel-atively high incidence of EBV-related post-transplantlymphoproliferative disorders (PTLD) reported. In theearlier years (1989–1992) of the cohort study undertakenby the University of Pittsburgh Medical Centre, the inci-dence of PTLD was 17% (five cases in 29 patients). Witha more judicious approach to the early reduction oftacrolimus levels in the postoperative period during thelatter years of the study, this incidence was reduced to 4%(two cases in 53 patients).

2

When all paediatric plusadult renal transplants at the Centre between the years1989–1997 were considered (1316 total transplants), theincidence of PTLD in adult patients was found to be1.2%, compared with 10.1% in children. However, themost recent data, from the North American PediatricRenal Transplant database, suggests that the incidenceof PTLD in USA paediatric patients overall (includingboth cyclosporin and tacrolimus-treated patients) is cur-rently about 1.2%, which is nearer the adult incidence.The FK506 Kidney Transplant Study Group has alsoreported, based on the US multicentre randomized trialof FK506 (tacrolimus) versus cyclosporin, that tacroli-mus was not associated with an increased risk of PTLDcompared with cyclosporin.

5

However, others reportfindings suggesting the incidence of PTLD to be substan-tially higher in tacrolimus-treated recipients compared tothose treated with cyclosporin,

6

and that the highest

Tacrolimus in children

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incidence is reported from centres that use tacrolimusexclusively.

7

BENEFITS

The randomised European study in paediatric renaltransplants showed a lower incidence of acute rejectionin those using tacrolimus compared with cyclosporinand there were fewer episodes of steroid resistance andrejection in the patients treated with tacrolimus. Thesepatients were on triple therapy using a calcineurininhibitor, azathioprine and corticosteroids. More recentexperience has been in the use of quadruple therapy withan interleukin 2 inhibitor, tacrolimus, mycophenolateand corticosteroid.

As cyclosporin absorption in young paediatric patients(< 2 years of age) is highly variable, tacrolimus hasbeen especially beneficial for this group. Tacrolimus hashelped children with cyclosporin-related neurotoxicityand in the avoidance of cyclosporin-related adverseeffects. Graft disease recurrence in patients with atypicalhaemolytic–uraemic syndrome (HUS) is reported to beaided by tacrolimus, although others,

8,9

have previouslyreported no effect between tacrolimus and cyclosporinwith regard to this.

Unsightly adverse events associated with cyclosporinsuch as gingival enlargement and hirsutism are anecdot-ally suggested to form obstacles to compliance in adoles-cent renal transplant populations. Tacrolimus has beenshown to significantly reduce both these events whenpatients are converted to it from cyclosporin.

10

CONCLUSION

Tacrolimus is now a widely used first line immunosup-pressive agent for both renal and liver transplantation.Over time, by adjusting dosages to trough levels (seeTable 1), a more efficacious regimen has been established,diminishing some of the more adverse effects initiallyencountered. Tacrolimus is especially beneficial amongadolescent populations where issues of non-complianceare a major concern.

REFERENCES

1. Trompeter RE, Filler G, Webb NJA

et al.

Randomised trial oftacrolimus versus cyclosporin microemulsion in renal transplan-tation.

Paediatic Nephrol.

2002;

17

: 141–9.2. Jordon ML, Shapiro R, Scantlebury V

et al.

Tacrolimus-basedimmunosuppression in pediatric renal transplantation.

Transplan-tation Proc.

1999;

31

: 29S–30S.3. Shapiro R, Scantlebury V, Jordan ML

et al.

Pediatric transplanta-tion under tacrolimus-based immunosuppression.

Transplantation

1999;

67

: 299–303.4. Knoll GA, Bell RC. Tacrolimus versus cyclosporin for immunosup-

pression in renal transplantation: meta-analysis of randomized tri-als.

BMJ

1999;

318

: 1104–17.5. Pirsch JD. Cytomegalovirus infection and posttransplant lymphop-

roliferative disease in renal transplant recipients: results of the USMulticenter Fk506 Kidney Transplant Study Group.

Transplanta-tion

1999;

68

: 1203–5.6. Shapiro R, Nalesnik M, McAuley J

et al.

Posttransplant lymphop-roliferative disorders in adult and pediatric renal transplantpatients receiving tacrolimus-based immunosupression.

Transplan-tation

1999;

68

: 1851–4.7. Harmon WE, Dharnidharka VR. Lymphoproliferative disease in

children.

Transplantation Proc.

1999;

31

: 1268–9.8. Scantlebury VP, Shapiro R, McCauley J

et al.

Renal transplanta-tion under cyclospirone and FK 506 for hemolytic uremic syn-drome.

Transplantation Proc.

1995;

27

: 842–3.9. Grupp C, Schmidt F, Braun F

et al.

Haemolytic uraemic syndrome(HUS) during treatment with cyclosporin A after renal transplan-tation—is tacrolimus the answer?

Nephrol. Dial. Transplant

1998;

13

: 1629–31.10. Spade M, Corno V, Colledan M et al. Rejection and tacrolimus

conversion therapy in paediatric liver transplantation.

TransplantInt.

2000;

13

(Suppl. 1): 5341–4.

Table 1

Tacrolimus levels, 1993 to 2001 (trough level ng/mL)

Before 1993 1993–1996 1996–2001(Quadruple therapy)

2 weeks 20–25 15–25 7–121 month 15–20 10–15 7–122 months 10–15 5–10 5–10> 3 months 5–9 4–71 year 3–7