Is Sirolimus a Nephrotoxic Drug? A Report of Five Cases A.A. Sabry, A.E. Elagroudy, K.F. El-dahshan, M.A.A. El-Rahim, and M.A. Sobh T HE CHOICE OF immunosuppression after organ transplantation is expanding. The past decade has seen the introduction of tacrolimus, mycophenolate mofetil (MMF), and an array of monoclonal antibodies. 1 Cal- cineurin inhibitors have been a cornerstone of transplant immunosuppression, beginning with the introduction of cyclosporine in 1978 and then tacrolimus in 1989, but nephrotoxicity limits their therapeutic benefit. 2 With the addition of mycophenolate mofetil in 1991, 1-year kidney graft survival rates have improved to greater than 90%. 3 Rapamycin (Rapa) is a new immunosuppressive medica- tion that prolongs allograft survival. It was initially investi- gated as an antifungal and antitumor agent; however, its lymphopenic properties heralded its role as an immunosup- pressant agent. The therapeutic effects of Rapa are derived from the inhibition of proliferation of fibroblasts, endothe- lial, mesangial and smooth muscle cells. 4 Sirolimus binds to the immunophilin FK506-binding protein-12 with greater avidity than tacrolimus. Animal studies have shown that sirolimus and tacrolimus act synergistically to prevent re- jection. 5 Herein we have presented five cases of focal segmental glomerulosclerosis (FSGS) in Egyptian renal transplant patients; both de novo and recurrent FSGS were associated with sirolimus-based immunosuppression. CASE REPORTS Case 1 A 34-year-old man with a biopsy-proven FSGS evolved to end- stage renal disease (ESRD) necessitating hemodialysis for 8 months before receiving a renal allograft from his 23-year-old wife whose HLA match was 3/6, DR 50%, and negative crossmatch, His immunosuppressive protocol consisted of: basiliximab (20 mg) at days 0 and 4, sirolimus 10 mg/d gradually adjusted to achieve a target level of 6 to 12 ng/mL, 2 g-MMF, 0.25 mg prednisone/d. His serum creatinine level fell promptly from preoperative values of 10.1 mg/dL to 1.3 mg/dL. The blood counts were normal with sirolimus levels within the therapeutic window (target 10 to 15 ng/mL). Fourteen months later the patient developed proteinuria (3.2 gm/d) with a serum albumin falling to 2.8 gm/dL and a creatinine increased from 1.3 mg/dL to 1.8 mg/dL and Rapa level of 9.8 ng/mL. Physical examination was normal apart from mild edema of the lower limbs and mild hypertension with no obvious cause for graft dysfunction. Ultrasound of the graft was unremarkable. Graft biopsy revealed recurrent FSGS. Two months later further deteri- oration of the graft function was evident by a serum creatinine rising to 2.8 mg/dL, necessitating a second biopsy, which revealed the same diagnosis—recurrent FSGS. Pulse steroid (500 mg/d for 5 days) was administered without a satisfactory response. In view of the increased serum creatinine to 5.2 mg/dL and worsening pro- teinuria (13 g/d), rapamycin was replaced by cyclosporine plus MMF 1.5 g/d with a partial initial response in the form of a fall in serum creatinine to 1.4 mg/dL and decreased proteinuria to 6 gm/d. However, further deterioration occurred and the patient returned back to hemodialysis 2 years after transplantation. Case 2 A 32-year-old male patient had ESRD presumed to be secondary to hypertension since a renal biopsy was not performed due to atrophic kidneys. He was maintained on chronic hemodialysis for a year before receiving a renal allograft from his 25-year-old sister whose HLA match was 3/6, DR 50% with a negative crossmatch. His immunosuppressive protocol consisted of Basiliximab on days 0 and 4, sirolimus (10 mg for 3 days reduced thereafter to 5 mg to achieve a target level between 6 and 12 ng/mL), tacrolimus (target level between 3 to 7 ng/mL) and prednisolone therapy. His serum creatinine dropped from 8.7 mg/dL to 1.3 mg/dL with a normal blood count and urinalysis. A month after transplanta- tion, the serum creatinine rose from 1.3 mg/dL to 1.6 mg/dL; dipstick revealed + proteinuria and a 24-hour protein of 1 g. A graft biopsy revealed acute rejection, which was successfully treated with pulse methylprednisolone (500 mg/d for 5 days). Twenty-six months later, he was admitted with graft impairment and a raised serum creatinine of 2.4 mg/dL, +++ proteinuria, 3.1 g protein in 24-hour urine. Sirolimus level was 7.5 ng/mL and tacrolimus level was 6 ng/mL. The graft biopsy showed a picture of FSGS (Fig 1). Rapa was replaced by MMF 1.5 g/d, with the current serum creatinine stabilized at 2.4 mg/dL and 24-hour urinary protein of 4 g. Case 3 A 36-year-old male patient developed ESRD presumably second- ary to hypertension because he was not biopsied due to atrophic kidneys. He received an allograft from his brother with HLA 3/6, DR 50%, and a negative crossmatch. The immunosuppressive protocol consisted of Basiliximab (days 0 and 4), cyclosporine (8 mg/kg/d aiming to a target level of 200 to 300 in the first month after transplantation), and azathioprine (2 mg/kg/d) that was replaced by MMF due to high liver enzymes with normal virological studies (negative hepatitis C virus antibodies, negative HBsAg, From the Department of Nephrology, Mansoura Urology and Nephrology Center, Mansoura, Egypt. Address reprint requests to Dr Alaa Albel-aziz Sabry, MD, Nephrology, Mansoura Urology and Nephrology Center, Elsoura Street, Mansoura 355555, Egypt. E-mail: asabry20@yahoo.com 0041-1345/07/$–see front matter © 2007 by Elsevier Inc. All rights reserved. doi:10.1016/j.transproceed.2007.03.020 360 Park Avenue South, New York, NY 10010-1710 1406 Transplantation Proceedings, 39, 1406 –1409 (2007)