Late-onset proteinuria after antithymocyte globulin induction and de novo sirolimus monotherapy in kidney transplant recipients.

Current immunosuppressive regimens reduce rejection rates and improve graft survival after kidney transplantation. But calcineurin inhibitors (CNIs) and steroids have long-term side effects, increasing the risks of cardiovascular events and chronic allograft nephropathy. In addition, overimmunosuppression increases the risk of opportunistic infections (1) and malignant diseases (2). Therefore, steroidand CNI-free protocols (1, 3– 6) are being tested. Five nonsensitized recipients of human leukocyte antigen-nonidentical postmortal kidney grafts were enrolled in a prospective Institutional Review Board-approved trial to test de novo sirolimus monotherapy following antithymocyte globulin induction (Reference No: UKF 000105). Inclusion criteria were a first kidney transplantation, negative T/B crossmatch, panel reactive antibody level less than 10%, serum CD 30 negative ( 100 U/mL), IgG anti-human leukocyte antigen class I/II negative ( 300), and IgA anti-Fab more than 1000. Patients received 3 mg/kg of rabbit antithymocyte globulin (rATG) (Thymoglobulin, Genzyme, Cambridge, MA) on day 0 and 2 mg/kg on day 1. rATG doses on day 2 to 10 were adjusted to lymphocyte counts. Five hundred milligram of prednisolone was applied on day 0 and 250 mg on day 1 and 2. Sirolimus was started on day 4 or 5, if serum creatinine was less than 3 mg/dL. A fixed sirolimus dose of 1.0 mg/kg body weight was given for 3 days to reach a target level of 12 to 15 ng/mL by day 8. Concomitantly, patients received pravastatin, valganciclovir, fluconazole (for 90 days), and trimethoprim/sulfamethoxazole (for 180 days). Adverse events included serum sickness (two), mouth ulcer (one), postoperative (three) and recurrent urinary tract infection (one), and one graft loss on day 33, which lead our local Ethics Committee to abort the pilot study. The remaining grafts currently function. Serum creatinine was 70.8, 79.65, 106.2, and 177 mol/L. Glomerular filtration rates were 77, 67, 67, and 45 mL/min, respectively. No patient showed signs of clinical rejection during follow-up.  A 49-year-old woman developed proteinuria with 1.31 g/24 hr 18 months after transplantation. Therefore tacrolimus was added to her regimen.  A 64-year-old woman was restarted on 5 mg prednisolone 5 months after transplantation due to preexistent rheumatoid arthritis with persistent joint pain. Current graft function is stable with a proteinuria of 110 mg/24 hr.  A 48-year-old man developed severe proteinuria of 3.5 g/24 hr 18 months after kidney transplantation. A graft biopsy showed no signs of immunologic damage. This patient’s regimen was converted to the standard triple therapy of tacrolimus, mycophenolate mofetil, and prednisolone. Under this regimen, proteinuria improved to 945 mg/24 hr in December 2008.  A 48-year-old woman had postoperative bleeding and required surgical revision on day 1, resulting in two warm ischemic periods and delayed graft function. For this reason, sirolimus was discontinued, and the patient was transferred to the standard triple therapy with tacrolimus, mycophenolate mofetil, and prednisolone on day 20. Once the graft function stabilized, the patient was retransferred to sirolimus monotherapy after 6 months. The patient had severe recurrent urinary tract infections. Current serum creatinine is stable approximately 2.0 mg/dL with no signs of increased proteinuria (707 mg/24 hr).  A 46-year-old man with nephrosclerosis lost his graft due to therapy-resistant thrombotic microangiopathy on postoperative day 33. The initial graft function was excellent up to day 14. Repeated graft biopsies revealed no signs of rejection. On postoperative day 24, fibrinogenic thrombi were detected in three of nine glomeruli. On day 33, diagnostic imaging revealed complete thrombosis of the graft, which was therefore removed. Later on, the patient developed Guillain-Barré-syndrome with severe paralysis. After recovery, the patient had a myocardial infarction. Coronary angiography revealed severe arteriosclerosis of the coronary arteries, thus excluding interventional treatment options. A coronary artery bypass operation was rejected by the patient. During rehabilitation, the patient had a second myocardial infarction and died. In the 1-year follow-up, four patients were maintained on a CNI-free immunosuppression protocol. Three patients received only sirolimus, and one patient received a combination therapy of sirolimus and prednisolone. This study confirms that de novo sirolimus monotherapy after rATG induction therapy in renal transplant recipients is feasible and probably not associated with an increased risk of rejection episodes in patients with a lowrisk immunologic profile. All patients tolerated this protocol well. Despite this study’s strong limitations due to the small patient population, the authors conclude, in accordance to Swanson et al. (3), Diekmann et al. (5), and Arellano et al. (7), that in well-selected immunologically low-risk patients sirolimus monotherapy is safe. However, because of severe, late-onset proteinuria, we cannot recommend de novo sirolimus monotherapy for renal transplantation.