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.