Calcineurin inhibitor induced nephrotoxicity in steroid resistant nephrotic syndrome

Prolonged therapy with calcineurin inhibitors (CNI) is effective in patients with difficult nephrotic syndrome. However, information on prevalence and risk factors for nephrotoxicity in children with steroid-resistant nephrotic syndrome is limited. This retrospective observational study was conducted on 40 patients with steroid-resistant nephrotic syndrome treated with cyclosporine (CyA) (n = 28) or tacrolimus (n = 12) for more than 2 years. Nephrotoxicity was defined by the presence of striped fibrosis involving ≥10% of the interstitium or nodular hyalinosis in more than one arteriole. Ten additional parameters were graded semi-quantitatively. Continuous data are presented as median and interquartile range (IQR). The median (IQR) age at onset of nephrotic syndrome and CNI therapy were 30 (21-45) and 49.5 (40-102.5) months. A second renal biopsy, following 30 (26-35) months of CNI therapy, showed histological toxicity in 10 (25%) patients. Toxicity was seen in 7 and 3 patients receiving CyA and tacrolimus, respectively, and 5 patients each with minimal change and focal segmental glomerulosclerosis. Therapy with CNI was associated with significant increases in scores for global glomerulosclerosis, tubular atrophy, interstitial fibrosis, nonnodular arteriolar hyalinosis (P < -0.001 for all), arteriolar smooth-muscle vacuolization (P = -0.02), juxtaglomerular hyperplasia (P = -0.002), and tubular microcalcinosis (P = -0.06). Risk factors for nephrotoxicity were initial resistance (OR 9; 95% CI 1.0-80.1; P = -0.049); dose of CyA (OR 9.2; 95% CI 1.1-74.6; P = -0.037); duration of heavy proteinuria (OR 1.2; 95% CI 1.0-1.4; P = -0.023); and hypertension during therapy (OR 6; 95% CI 1.3-28.3; P = -0.023). Following prolonged CNI therapy, one in four biopsies show features of toxicity. Prolonged duration of heavy proteinuria, hypertension, initial steroid resistance and high CyA dose predict the occurrence of nephrotoxicity.