Risk factors for cyclosporin A nephrotoxicity in children with steroid-dependant nephrotic syndrome

Abstract

Background and objectives: Cyclosporin A (CsA) is a well-established treatment for steroid-dependent nephrotic syndrome (SDNS) that may, however, cause chronic ischemic renal lesions. The objective of the study was to assess the prevalence of CsA nephrotoxicity (CsAN) in protocol biopsies of children with SDNS.

Design, settings, participants, & measurements: From 1990 through 2008, we performed 71 renal biopsies in 53 patients with SDNS. The mean CsA C2 levels were 466 +/- 134 ng/ml, and the mean duration of treatment was 4.7 +/- 2.0 yr before biopsy (range 2.9 to 12.7 yr).

Results: CsAN was observed in 22 (31%) of 71 renal biopsies. Of these, 11 corresponded to isolated vascular or tubular lesions, and 11 corresponded to combined vascular and tubular lesions. The majority of CsAN lesions were mild (17 of 22). In no cases were lesions graded as severe. By regression analysis, CsAN was positively associated with the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and with hyperuricemia and negatively associated with minimal-change lesions. By multivariate analysis, only association with the use of ACEIs or ARBs retained significance. Stratification of the population according to CsA C2 levels showed increased risk for CsAN for C2 levels >600 ng/ml.

Conclusions: Mild to moderate CsAN occurs in approximately one third of patients who have SDNS and are treated with CsA for >3 yr. Our data suggest that patients who require high dosages of CsA or treatment for hypertension, in particular when ACEIs/ARBs are used, are at higher risk for CsAN.

Figure 1.

Timing of renal biopsies in individual patients, cyclosporin A (CsA) treatment, and CsA nephrotoxicity. Each line represents an individual patient. Each circle represents a renal biopsy and is filled to indicate the presence of CsA nephrotoxicity as indicated in the legend. Hashed lines indicate transient discontinuation of CsA treatment. Lines that end with a vertical bar indicate that the patient stopped CsA treatment; otherwise, each line ends at the time of the last follow-up.

Figure 2.

(A) Distribution of CsA nephrotoxicity lesions according to antihypertensive treatment and CsA C2 levels. Circles are filled to indicate the presence of CsA nephrotoxicity as indicated in the legend. ^cPatients with combined treatment with calcium channel blocker (CCB) and angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). (B) Odds ratios for the development of overt CsA toxicity. The population was divided using various cutoffs of CsA C2 levels. CsA C2 levels were calculated for each patient as the average of all levels measured during a period of 2 yr before each biopsy. Odds ratios are adjusted for the use of ACEIs or ARBs. Horizontal bars indicate low and high 95% confidence intervals. *P < 0.03.