Independent risk factors for chronic cyclosporine induced nephropathy in children with nephrotic syndrome

Abstract

Background: Cyclosporine A (CsA) has been widely used in children with steroid dependent and steroid resistant nephrotic syndrome (NS) because of its efficacy in relieving these patients from systemic side effects of steroids. However, its long term use is controversial, since chronic CsA induced nephropathy (CsAN) may develop in a considerable number of patients. Aims and Methods: In order to clarify the risk factors for the development of CsAN, the clinical characteristics of children with steroid dependent or steroid resistant NS taking CsA (target blood trough levels 50-150 ng/ml) for more than six months, managed at a single centre, were retrospectively analysed. Results: Thirteen of 30 children (24 boys and 6 girls) taking CsA (mean duration 43 months, range 6-144) had CsAN defined as the presence of CsA associated arteriopathy with or without striped tubulointerstitial lesions. The multivariate analysis revealed that CsA treatment for more than 36 months and an age younger than 5 years at the start of CsA treatment were independent risk factors for the development of CsAN. The univariate analysis also showed that patients with CsAN had more frequent relapses during CsA treatment than those without CsAN. Conclusion: An alternative treatment should be seriously considered after a 36 month administration of CsA in order to prevent CsAN. Data also suggest that CsA treatment in children younger than 5 years should be avoided if possible.

Risk Factors for Cyclosporin A Nephrotoxicity in Children with Steroid-Dependant Nephrotic Syndrome

“…CsAN is primarily caused by chronic ischemic insult to the kidney, resulting in arteriolar hyalination and tubulointerstitial changes, including striped interstitial fibrosis, tubular vacuolization, and atrophy (11). Because these lesions may be difficult to distinguish from the underlying renal disease, criteria have been developed to stage CsA-induced renal lesions (11,12); however, even when using these criteria, the diagnosis of CsAN may be uncertain. Progressive interstitial fibrosis can develop with time in patients who have NS and are not treated with CsA, although less frequently and to a lesser extent (4,13,14).…”

“…Numerous studies have documented the prevalence of CsAN in patients who were treated for idiopathic nephrotic syndrome. Since 1986, Ͼ200 follow-up biopsies in patients who were treated with CsA for SDNS have been reported in the literature (1,(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). These studies are difficult to compare because they vary in the number of biopsies, underlying renal pathology, duration of follow-up, dosages of CsA, and criteria to define CsAN.…”

“…Various clinical and pathology risk factors for the development of CsAN have been inconsistently reported in the literature (12,14,17,18,27). These include steroid resistance, low GFR, high proteinuria, FSGS lesions, high relapse rate, prolonged CsA treatment, and CsA serum levels.…”

“…A link between CsAN and the number of relapses or the duration of proteinuria was therefore unlikely. Likewise, it is generally accepted that longer treatments with CsA increase the risk for nephrotoxicity (4,12,16). This was not observed in our cohort.…”

Protective Effects of Mizoribine on Cyclosporine A Nephropathy in Rats

“…This has relieved children with steroid dependent and resistant nephrotic syndrome from steroid toxicity (1). However, there is controversy concerning its long-term treatment because of the potential toxicity by chronic CsA nephropathy, which is characterized by tubular atrophy, interstitial fibrosis, and progressive renal impairment (2).…”