Conversion to sirolimus for chronic allograft nephropathy and calcineurin inhibitor toxicity and the adverse effects of sirolimus after conversion.

BACKGROUND: Chronic allograft nephropathy and calcineurin inhibitor toxicity may cause graft loss. After kidney transplantation, especially among those patients with chronic allograft nephropathy, sirolimus may be a good alternative to calcineurin inhibitors. Unlike calcineurin inhibitors, sirolimus is devoid of significant nephrotoxicity, but approximately 30% to 50% of patients on sirolimus therapy display mild or severe adverse effects. We sought to report our experience with sirolimus conversion among patients with chronic allograft nephropathy as well as the mild versus severe adverse effects that limit the drug's use.

MATERIALS AND METHODS: We analyzed the outcomes of 88 patients (64 men and 24 women) of overall mean age of 35.9 +/- 9.9 years (range, 21-59 years) who had undergone kidney transplantation. Immunosuppressive therapy had been converted from a calcineurin inhibitor to sirolimus because of biopsy-proven chronic allograft nephropathy, calcineurin inhibitor toxicity, or presence of malignancy. We excluded patients with prior acute rejection episodes. Subjects were divided into two groups with respect to their creatinine levels: Group A < 2 mg/dL and Group B >or= 2 mg/dL. After conversion to sirolimus, possible adverse effects of sirolimus were evaluated at the follow-up inset. Each patient underwent a physical examination, and estimation of serum lipid and electrolyte levels as well as hemoglobin concentration.

RESULTS: At the time of conversion of the 88 renal transplant patients, their mean duration after grafting was 48 +/- 15 months (range, 4-296). The prior treatment consisted of a calcineurin inhibitor, prednisolone, and mycophenolate mofetil. After conversion, the calcineurin inhibitor was stopped and sirolimus was begun. The 48 Group 2 patients (34 men, 14 women) of overall mean posttransplant time of 22.7 +/- 14.6 months who underwent conversion displayed a mean serum creatinine increase to 3.2 +/- 1.4 mg/dL, including 17 subjects who underwent rejection. The 40 Group 1 patients (30 men, 10 women) with a mean overall posttransplant period of 67.6 +/- 49.9 months showed an fall in serum creatinine level to 1.4 +/- 0.5 mg/dL among only 3 patients. While 5/88 patients showed no increase in proteinuria (5.6%); 83 (94.4%) did experience it. Proteinuria increased from a mean of 192 +/- 316 to 449 +/- 422 mg/d. Only three patients displayed heavy proteinuria (>3 g/d); sirolimus was discontinued for this reason. Proteinuria was well controlled in the other patients with angiotensin-converting enzyme and/or angiotensin II receptor inhibitor agents. After sirolimus conversion, serum cholesterol levels increased from 187 +/- 42 to 214 +/- 52 mg/dL, and serum triglyceride levels increased from 161 +/- 61 to 194 +/- 102 mg/dL. All but four patients responded to statin therapy, with serum lipid levels falling to acceptable levels. Another four patients developed unilateral lower extremity edema with sirolimus discontinued for this reason. One patient displayed generalized arthralgia.

CONCLUSION: Chronic allograft nephropathy or calcineurin inhibitor toxicity can lead to loss of graft kidney function. Calcineurin inhibitor toxicity can lead to chronic allograft nephropathy. Patients with a low baseline serum creatinine level who undergo sirolimus conversion showed stabilized kidney function. Late conversion of patients with a serum creatinine above 2 mg/dL face a risk of graft failure. Sirolimus displayed a limited incidence of serious adverse effects; mild or moderate adverse effects, such as hyperlipidemia and proteinuria, were easily controlled with countermeasure therapy.