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Сalcineurin inhibitors (CNI) is currently being considered as the first line immunosuppressive treatment for steroid-resistant nephrotic syndrome (SRNS) in children. However, CNI-induced nephrotoxicity is potential adverse effect of the treatment. The aim of the study was to identify risk factors for progression from acute to chronic CNI-induced nephrotoxicity in children with SRNS due to FSGS.
We conducted retrospective longitudinal study of 20 children (13F/7M) with SRNS due to FSGS treated with therapeutic dosage (5.1 (4.4-5.4) mg/kg) of cyclosporine (CsA) for 24.0 (IQR: 14.9-38.1) months who had acute (n=8) and chronic (n=12) CNI-induced nephrotoxicity. Therapeutic drug monitoring was performed in all patients by measuring trough CsA blood levels. Acute CNI-nephrotoxicity was defined by reversible increasing of serum creatinine more than 30% from baseline level. Chronic CNI-induced nephrotoxicity was defined by continued decline of eGFR after CNI withdrawal. The first kidney biopsy undertaken in all patients before starting treatment with CNI revealed FSGS in all children.
Among children with SRNS due to FSGS with acute or chronic CNI-induced nephrotoxicity there were no significant differences in the age at SRNS onset, duration before starting CNI, baseline serum creatinine and eGFR; CNI dosage, trough blood levels and dosage/C₀ ratio, ACE inhibitors dosage at the start of CNI treatment and at the time of acute CNI-mediated nephrotoxicity (р>0.05). Children with chronic CNI-mediated nephrotoxicity compared with patients who had acute CNI-induced nephrotoxicity had significantly higher duration of CNI treatment (32.5 vs 20.5 months; p = 0.01); proportion of serum creatinine increasing (63.4% vs 32.7%; p = 0.004) and eGFR declining (36.2% vs 20.0%; p = 0.004) from baseline levels at the time of acute CNI-mediated nephrotoxicity. The proportion of serum creatinine increasing (39.3% vs 8.7%; p = 0.043) and eGFR declining (24% vs 1.2%; p = 0.029) from baseline levels after CNI dosage adjustment, and duration of CNI-mediated toxicity before the treatment withdrawal (18.0 vs 1.5 months; p = 0.0004) were also significantly higher in the patients with chronic CNI-mediated nephrotoxicity compared with patients who had acute CNI-induced nephrotoxicity. The second kidney biopsy performed in 6 (30%) children at 31.0 (IQR: 21.4-36.1) months after the 1st kidney biopsy revealed histopathological features of CNI-induced nephrotoxicity in 3 (50%) patients who had clinical features of chronic CNI-nephrotoxicity.
High level of serum creatinine increasing and eGFR declining at the time of acute CNI-mediated nephrotoxicity and after CNI dosage adjustment, prolonged duration of CNI treatment and CNI-mediated toxicity might be considered as risk factors for progression from acute to chronic CNI-induced nephrotoxicity in children with SRNS due to FSGS.