Late Conversion From Calcineurin Inhibitor-Based to Sirolimus-Based Immunosuppression Due to Chronic Toxicity: A Prospective Study With Protocol Biopsy Amendment

Background. There is an emerging consensus on conversion from calcineurin inhibitor (CNI)-based regimens to proliferation signal inhibitor (PSI)-based protocols for the prevention of a progressive decline in graft function due to CNI toxicity. Methods. Thirty-one primary renal transplant recipients within 17-48 years of age (mean, 32.2 +/- 1.6) were enrolled in this dual-center Study. Eligible patients had a baseline (pre-engraftment) biopsy and completed at least 12 months of follow-up with deteriorating graft function indicative of chronic CNI toxicity with or without nonspecific interstitial fibrosis/tubular atrophy (IF/TA) on a biopsy specimen. A fast conversion protocol, being defined as a 50% initial reduction followed by complete withdrawal of CNI drug within 2 weeks of introducing rapamycin was performed in all patients. A sirolimus (SRL) loading dose was not prescribed; all subjects directly received maintenance (2-5 mg/d) doses of the drug. The primary endpoint of this study was assessement of renal function using cGFR and renal histology by protocol biopsy at I year after conversion. Results. The mean follow-up after conversion was 21.6 months. The difference between cGFR before compared with cGFR after 12 months after conversion (40.8 +/- 2.36 mL/min vs 55.7 +/- 3.6 mL/min; P < .000) and at the last follow-up (40.8 +/- 2.36 mL/min vs 53.8 +/- 2.96 mL/min; P < .000) was significant. The mean IF/TA with glomerulosclerosis and chronic vasculopathy scores of biopsy specimens at baseline, during conversion, and at 12 months of the study were 2.25 +/- 0.3, 3.30 +/- 0.24, and 3.0 +/- 0.30, respectively. The change in scores was indicative of mild progression; however, the difference was not significant. IF/TA, glomerulosclerosis, and chronic vasculopathy scores improved in 8 (30%) Subjects, remained unchanged in 11 (42%) and worsened in 7 (28%) after 1 year of SRL therapy. After conversion there was no patient or graft loss in this group. Moreover, SCr and GFR improved in 21 or 29 patients (72%) remained stable in 4 (14%), and decreased in 4 (14%) patients. The predictors of successful conversion in our Study were GFR 40.6 mL/min, SCr <= 2.34 mg/dL, and histological allograft damage score <= 3. Conclusion. SRL-MPA/MMF-ST combination may be a good therapeutic strategy against chronic CNI toxicity, particularly for patients whose conversion biopsy specimens demonstrated mild IF/TA, glomerulosclerosis, and chronic vasculopathy scores (<= 3.1 +/- 0.3).