Sirolimus (Rapamycin) Induced Proteinuria in a Patient Undergoing Allogeneic Hematopoietic Stem Cell Transplant

Abstract

Proteinuria and renal dysfunction have been reported in patients receiving sirolimus after renal (1) or islet cell transplants (2). We report the case of a 28-year-old man undergoing allogeneic hematopoietic stem cell transplantation who suffered acute kidney injury with nephrotic range proteinuria after initiation of sirolimus. This patient with anaplastic large cell lymphoma in complete remission by positron emission tomography scan was admitted for an allogeneic hematopoietic stem cell transplant from a molecularly human leukocyte antigen-matched unrelated female donor. Four months before admission, the patient had a creatinine clearance (24 hr urine collection) of 106 mL/min and 1 month before admission had a clearance of 115 mL/min. During those outpatient visits, the patient had no protein detected by urinalysis. As part of his treatment for lymphoma, the patient received 4 monthly treatments with cisplatin and cytarabine. The last dose of cisplatin was administered 30 days before admission. Graft-versus-host disease prophylaxis consisted of sirolimus (12 mg load followed by 4 mg orally per day) and tacrolimus (0.3 mg/kg intravenous continuous infusion). At the time graft-versus-host disease prophylaxis was initiated, the patient had been on the following antibiotics in the hospital: piperacillin/ tazobactam, amikacin, and micafungin for 4 days; voriconazole for 2 days and vancomycin for 1 day. Eight days after initiation of sirolimus, blood urea nitrogen rose from 9 to 29 mg/dL and creatinine from 0.8 to 1.5 mg/dL. The tacrolimus level initially was 1.8 ng/mL, peaked at 8.6 ng/mL, but was 3.6 ng/mL during the time of acute kidney injury. The sirolimus level was initially 2.1 ng/mL, and 4.3 ng/mL during the time of acute kidney injury. The urine was cloudy and foamy and contained a jelly-like substance. Urinalysis showed 3+ protein and few white cells, and a random urine protein-to-creatinine ratio was 17. Triglycerides increased from 148 to 327 mg/dL. Albumin fell from 4.6 to 3.0 g/dL. After addition of sulfosalicylic acid the urine precipitated proteinaceous casts within seconds. Urine protein electrophoresis displayed a nonselective pattern with all fractions elevated. The creatinine peaked at 3.6 mg/dL. Sirolimus was discontinued, while tacrolimus prophylaxis was maintained. The blood urea nitrogen and creatinine improved over 3 to 4 days. The urinary protein-to-creatinine ratio declined from 17 to less than 0.5 over 2 days. Currently, patient is maintained on tacrolimus without any proteinuria and a creatinine of 0.9 mg/dL. Sirolimus has been associated with high-range proteinuria when used as replacement therapy for calcineurin inhibitors in chronic allograft nephropathy (3). Urinary protein loss presumably results from reduced tubular protein reabsorption (1). A specific pattern of renal injury has also been noted in rat models with increased intratubular cast formation, increased tubular epithelial cell proliferation, and protein endocytosis, causing massive proteinuria (4). Renal transplant patients treated with sirolimus have rarely developed intratubular casts indistinguishable from myeloma cast nephropathy. Histologically, these casts have been composed of renal tubular epithelial cells (1). Alternatively, there is speculation that sirolimus induced proteinuria is related to collapsing focal segmental glomerulosclerosis associated with vascular endothelial growth factor over-expression in podocytes (5). Senior et al. (2) have reported sirolimus related proteinuria in a nontransplanted kidney before. There was resolution of proteinuria from the native kidneys when sirolimus was discontinued in some patients with islet cell transplant. We present another case of sirolimus-related renal dysfunction and proteinuria but in a patient undergoing allogeneic hematopoietic stem cell transplantation. There was no evidence of underlying kidney disease in this patient given normal creatinine clearance and absence of proteinuria before administration of sirolimus. This patient did receive other medications that could be nephrotoxic, including tacrolimus, cisplatin, and several antibiotics. Though these medications could have contributed to the patient’s renal toxicity, the time course and dosages were not consistent with their being the primary cause of his nephrotic syndrome and acute onset of kidney injury. Because the tacrolimus levels were in the lower range of normal during the kidney insult, and because renal function recovered after cessation of sirolimus while the tacrolimus was maintained, this drug was not considered a major contributor. Similar reports of sirolimus-induced proteinuria have occurred only in renal transplant cases where the diagnosis often has been confounded by graft rejection or recurrence of the primary kidney disease. This case demonstrates a direct toxic effect of sirolimus on a nontransplanted kidney without prior tubular or glomerular disease. Kenar D. Jhaveri Division of Nephrology and Hypertension New York Presbyterian Hospital at Weill Cornell Medical Center New York, NY Jonathan H. Schatz Medical Oncology-Department Memorial Sloan-Kettering Cancer Center New York, NY James W. Young Division of Bone Marrow Transplantation Memorial Sloan-Kettering Cancer Center New York, NY Carlos Flombaum Division of Nephrology Memorial Sloan-Kettering Cancer Center New York, NY