Renal transplantation: can we reduce calcineurin inhibitor/stop steroids? Evidence based on protocol biopsy findings

Abstract

How to combine antirejection drugs and which is the optimal dose of steroids and calcineurin inhibitors beyond the first year after kidney transplantation to maintain adequate immunosuppression without major side effects are far from clear. Kidney transplant patients on steroid, cyclosporine (CsA), and azathioprine were randomized to per-protocol biopsy (n = 30) or no-biopsy (n = 29) 1 to 2 yr posttransplant. Steroid or CsA were discontinued or reduced on the basis of biopsy to establish effects on drug-related complications, acute rejection, and graft function over 3 yr of follow-up. Serum creatinine, GFR (plasma clearance of iohexol), RPF (renal clearance of p-aminohippurate), CsA pharmacokinetics, and adverse events were monitored yearly. At the end, patients underwent a second biopsy. Per-protocol biopsy histology revealed no lesions (n = 5, steroid withdrawal), CsA nephropathy (n = 13, CsA discontinuation/reduction), or chronic rejection (n = 12, standard therapy). Reducing the drug regimen led to overall fewer side effects related to immunosuppression as compared with standard therapy or no-biopsy. Steroids were safely stopped with no acute rejection or graft loss. Complete CsA discontinuation was associated with acute rejection in the first four patients. Lowering CsA to low target CsA trough (30 to 70 ng/ml) never led to acute rejection or major renal function deterioration. Biopsy patients on conventional regimen had no acute rejection, one graft loss, no significant change in GFR, and significant RPF decline. No-biopsy controls: no acute rejection, one graft loss, significant decline of GFR and RPF. By serial biopsy analysis, severe lesions did not develop in patients with steroid discontinuation in contrast to patients on standard therapy over follow-up. CsA reduction did not adversely affect histology. Per-protocol biopsy more than 1 yr after kidney transplantation is a safe procedure to guide change of drug regimen and to lower the risk of major side effects.