Sirolimus in Pediatric Renal Transplantation

Sirolimus in Pediatric Renal Transplantation J.P. Ibáñez, M.L. Monteverde, J. Goldberg, M.A. Diaz, and A. Turconi ABSTRACT Side effects of calcineurin inhibitors (CNIs) include nephrotoxicity and hypertension. Moreover, children have a higher risk of infections and posttransplantation lymphoproliferative disorders. We retrospectively evaluated the efficacy and safety of Sirolimus (SRL) in 18 patients, who were 10.52 ⫾ 5.03 years at time of transplantation and received a CNI as the core immunosuppression. The most common indications for starting SRL therapy were chronic allograft nephropathy, Epstein-Barr virus–associated neoplasia, and thrombotic microangiopathy. The patients were converted to SRL at 49.14 ⫾ 45.9 months posttransplantation. Mean follow-up after the switch to SRL was 13.83 ⫾ 7.24 months. All patients who began SRL therapy remained on that medication. We observed a significant improvement (P ⬍ .05) in glomerular filtration rate assessed using the Schwartz formula at 3 months, which was sustained thereafter. There were no changes in proteinuria, plasma lipids, and platelet number. Although the prevalence of hypertensive patients decreased during follow-up, it was not significant. There was one steroid-sensitive, acute rejection episode. Serious adverse events included 1 death due to a relapse of B lymphoma, 1 sepsis, and 1 pancreatic pseudo-cyst. Adverse events were present in 17% of patients: 3 Herpes Simplex infections, and 1 dose-related lymphedema. Further studies are necessary to assess the impact of adverse events in the pediatric transplant population receiving SRL as immunosuppression.

D

URING the past 20 years, the introduction of calcineurin inhibitors (CNIs) has contributed to lower acute rejection rates and improved 12-month graft survival rates in renal transplantation (RTx).1 The use of drug monitoring for these immunosuppressive agents, mainly cyclosporin A (CsA), also has been associated with improvement in graft half-life in recent years.2 Despite these maneuvers, nephrotoxicity and hypertension remain problems of concern.3,4 Furthermore, children have a higher risk of infections and posttransplantation lymphoproliferative disorders (PTLD) than adults.5,6 Sirolimus (SRL) is a potent immunosuppressor agent that acts selectively blocking cytokine signal transduction and inhibiting cell division and proliferation.7,8 Several trials have demonstrated that SRL lacks nephrotoxicity.9 –11 The aim of this study was to evaluate retrospectively SRL efficacy and safety as a rescue agent in pediatric renal transplant recipients receiving a CNI as core immunosuppression. METHODS From December 1988 to June 2004, 420 RTx were performed in 401 pediatric recipients who received immunosuppression with 0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2004.12.242 682

CsA, steroids, and azathioprine (AZA) or mycophenolate mofetil (MMF). Since September 2001, when SRL was available in our country, 18 children were selected for conversion from CsA to SRL. Their demographic data are summarized in Table 1. The reasons for the change were as follows: chronic allograft nephropathy (CAN) (n ⫽ 9; 50%), Epstein-Barr virus (EBV)–associated neoplasia (n ⫽ 4; 22%), thrombotic microangiopathy (n ⫽ 3;

Table 1. Demographic Characteristics of the Study Patients Characteristic

Mean ⫾ SD

Range

Age at RTx time (y) Switch time after RTx (mo) Follow-up postswitch (mo) Weight (kg) Body surface area (m2)

10.52 ⫾ 5.03 49.14 ⫾ 45.9 13.83 ⫾ 7.24 41.46 ⫾ 12.97 1.26 ⫾ 0.31

2.86–16.20 0.33–1.28 3–30 17–58 0.62–1.65

From the Division of Nephrology and Pathology, Hospital de Pediatria “Dr. Juan P. Garrahan,” Buenos Aires, Argentina. Address reprint requests to Dr Juan Ibáñez, Hospital de Pediatria “Dr. Juan P. Garrahan” Combate de los Pozos 1880, CP 1245, Buenos Aires, Argentina. E-mail: juanibanez@ sinectis.com.ar © 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 37, 682– 684 (2005)

SIROLIMUS

683 Table 2. Reasons for Change

Reasons

Chronic allograft nephropathy EBV-associated neoplasia Thrombotic microangiopathy Severe hypertension Gingival hypertrophy Total

No. of Patients

%

9

50

4 3 1 1 18

22.3 16.7 5.5 5.5 100

16.7%), severe hypertension (n ⫽ 1; 5.5%), and gingival hypertrophy (n ⫽ 1; 5.5%, Table 2). Seven patients were on CsA plus AZA plus steroids, 8 patients were on CsA plus MMF plus steroids, and 3 patients were on CsA plus steroids. The mean (⫾ SD) daily dose of CsA was 209.72 ⫾ 59.76 and the mean (⫾ SD) trough level was 150.61 ⫾ 74.76 ng/mL. In the patients with thrombotic microangiopathy, the entire CsA dose was abruptly stopped and full-dose SRL begun the next day. The remaining 15 patients initially received full-dose SRL while CsA was reduced by 30% each week over 3 weeks. Then the SRL dose was adjusted according to its trough level. The mean (⫾ SD) dose of SRL administered after conversion was 2.76 ⫾ 0.96 mg/m2 body surface area, and the mean (⫾ SD) trough level was 7.05 ⫾ 2.64 ng/mL. The results were analyzed using one-way analysis of variance (ANOVA) test for continuous variables and chi-square test for 2 categorical variables. Efficacy was assessed by the incidence of rejection and safety by the incidence/severity of adverse events.

RESULTS

The glomerular filtration rate (GFR) estimated using the Schwartz formula showed significant improvement (P ⬍ .05) at 3 months after CNI withdrawal, which was sustained thereafter (Fig 1). Mean values (⫾ SD) for proteinuria, serum cholesterol, triglycerides, and platelet counts showed no significant change. The prevalence of hypertensive patients decreased (Table 3). One patient with severe hypertension receiving 3 antihypertensive drugs became normotensive with only 2 medications within the first 3 months after conversion. Gingival hypertrophy present in 1 patient disappeared. One patient (5.6%) experienced a steroid-sensitive acute rejection episode (Banff Ib) in the early posttransplantation period, with SRL trough levels below the therapeutic range. Three patients (17%) experienced 1 serious adverse event (SAE) each; 1 child was switched to SRL because of central nervous system relapse of EBV-related B lymphoma. Al-

Fig 1.

GFR estimated using the Schwartz formula.

though the number of EBV copies in the peripheral blood decreased to ⬍1, he died 8 months later with widespread lung metastasis and a functioning graft. A girl showed sepsis in the course of an acute pyelonephritis episode. Blood and urine cultures were positive for the same bacteria. She was successfully treated with antibiotics. The third patient had an asymptomatic pancreatic tumor detected during abdominal surveillance ultrasonography, which was successfully resected. The microscopic examination revealed a pancreatic pseudo-cyst. There were 4 adverse events (AEs) in 3 children (17%): three Herpes Simplex infections were treated with oral acyclovir with no change in immunosuppression. One girl showed mild lymphedema in both legs that improved by lowering the SRL dose. Twelve patients remained free of events under SRL therapy. No patient discontinued the drug. DISCUSSION

Our results in children who underwent kidney transplantation receiving a CNI who were switched to SRL suggest that this agent is effective for prophylaxis of rejection, as many trials have already demonstrated.9 –13 Only 1 adolescent experienced a steroid-sensitive acute rejection episode (Banff Ib) at 79 days posttransplantation. She received SRL as the core immunosuppression drug, twice a day, from the 8th posttransplantation day because of CsA-related microangiopathic thrombotic nephropathy. On day 70, the same SRL dose was prescribed once a day, to simplify drug administration. Then, her 24-hour trough level decreased to less than therapeutic range. She returned to a b.i.d SRL dose schedule, as Schachter et al recommended in their

Table 3. Results (Mean ⴞ SD) Variables

Baseline n ⫽ 18

3 mo n ⫽ 18

6 mo n ⫽ 14

12 mo n ⫽ 11

P

GFR by Schwartz (mL/min ⫻ 1.73m2) Proteinuria (mg/kg/d) Cholesterolemia (mg/dL) Triglyceridemia (mg/dL) Platelets count (⫻103 mm3) Hypertensive patients (%)

41.67 ⫾ 14.85

58.44 ⫾ 16.97

57.50 ⫾ 13.53

57.13 ⫾ 18.00

⬍.05

9.45 ⫾ 11.38 207 ⫾ 46.93 132 ⫾ 63.98 266 ⫾ 53 38.9

10.22 ⫾ 9.50 211 ⫾ 29.34 155 ⫾ 93.03 284 ⫾ 80 16.7

13.35 ⫾ 13.55 214 ⫾ 35.87 155 ⫾ 81.62 279 ⫾ 54 13.3

10.23 ⫾ 10.48 208 ⫾ 37.48 141 ⫾ 54.75 288 ⫾ 62 0

NS NS NS NS NS

Abbreviation: NS, not significant.

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recent article.14 We also observed a significant improvement of GFR in our patients probably because the renal vasoconstrictor effect of CsA was diminished. Due to the same fact, the prevalence of our hypertensive patients was reduced. Laboratory abnormalities reported significantly more often with SRL— hypertriglyceridemia, hypercholesterolemia, and thrombocytopenia—in de novo transplant recipients15 were not seen in our children. It is worth mentioning that except for 1 patient, the desired SRL trough level for our group was lower due to the long time elapsed after transplantation.14 In our experience, the number of SAEs and AEs observed in this small sample size receiving SRL was no different from those in patients receiving CsA. As a matter of fact, a MEDLINE search reveals few reports concerning the use of SRL in pediatric transplant populations. Therefore, further studies with larger sample sizes are necessary to assess SRL efficacy and safety. REFERENCES 1. Hariharan S, Johnson C, Bresnahan B, et al: Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med 342:605, 2000 2. Mahalati K, Belitsky P, Sketris I, et al: Neoral monitoring by simplified sparse sampling area under the concentration-time curve: Its relationship to acute rejection and Cyclosporine nephrotoxicity early after kidney transplantation. Clin Transplant 68:55, 1999 3. De Mattos A, Olvaei A, Bennett W: Nephrotoxicity of immunosuppressive drugs: long-term consequences and challenges for the future. Am J Kidney Dis 35:333, 2000 4. Ponticelli C: Progression of renal damage in chronic rejection. Kidney Int 57:(suppl 75):S-62, 2000

IBÁÑEZ, MONTEVERDE, GOLDBERG ET AL 5. Dharnidharka V, Sullivan E, Tejani A, et al: Risk factors for post-transplant lymphoproliferative disorder (PTLD) in pediatric kidney transplantation: a report of the North American Pediatric Cooperative Study (NAPRTCS). Transplantation 71:1065, 2001 6. Harmon W, Dharnidharka V: Lymphoproliferative disease in children. Transplant Proc 31:1268, 1999 7. Sehgal S, Camardo J, Scarola J, et al: Rapamycin (sirolimus, rapamune). Curr Opin Nephrol Hyperten 4:482, 1995 8. Sehgal S: Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem 31:335, 1998 9. Long-term improvement in renal function with Sirolimus after early Cyclosporine withdrawal in renal transplant recipients: 2-year results of the Rapamune maintenance regimen study. Transplantation 76:364, 2003 10. Flechner S, Goldfarb D, Modlin C, et al: Kidney transplantation without calcineurin inhibitor drugs: a prospective, randomized trial of Sirolimus versus Cyclosporine. Transplantation 74: 1070, 2002 11. Sirolimus-based therapy following early Cyclosporine withdrawal provides significantly improved renal histology and function at 3 years. Am J Transplant 4:953, 2004 12. Sindhi R: Sirolimus in pediatric transplant recipients. Transplant Proc 35 (suppl 3A):S113, 2003 13. MacDonald A for the Rapamune Global Study Group: A worldwide, phase III, randomized, controlled, safety and efficacy study of a Sirolimus/Cyclosporine regimen for prevention of acute rejection in recipients of primary mismatched renal allograft. Transplantation 71:271, 2001 14. Schachter A, Meyers K, Spaneas L, et al: Short sirolimus half-life in pediatric renal transplant recipients on a calcineurin inhibitor-free protocol. Pediatr Transplant 8:171, 2004 15. Groth C, Bäckman L, Morales J, et al: Sirolimus (Rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with Cyclosporine. Clin Transplant 67:1036, 1999