eGFR decrease during antiviral C therapy with first generation protease inhibitors: a clinical significance?

BACKGROUND & AIMS: Renal toxicity of first generation protease inhibitors (PIs) was not a safety signal in phase III clinical trials, but was recently reported in recent studies. It appeared important to determine the clinical significance of these findings. METHODS: We retrospectively analysed 101 HCV patients receiving triple therapy with telaprevir (n = 36) or boceprevir (n = 26) or double therapy (n = 39) with peginterferon and ribavirin and having a close monitoring of eGFR (MDRD formula) during and after treatment. EGFR decline over time was assessed by a linear mixed-effects model (LMEM) with search for possible explanatory covariates. RESULTS: Patients treated with telaprevir presented a significant decrease of eGFR with the same kinetics: initial decrease at W (week) 4, nadir at W8 (mean decrease 17.0 ± 18.9 ml/min/1.73 m(2)) and return to baseline at W16. The W8 eGFR was correlated with the D0 eGFR (R(2) = 0.49). The LMEM showed that interindividual variability in the slope of eGFR vs time between D0 and W8 was non-significant and eGFR nadir could be predicted from eGFR obtained at D0. In multivariate analysis, eGFR intercept (i.e. baseline value) was associated with older age and male sex. CONCLUSION: The eGFR significantly varied in telaprevir group only. Our model showed that eGFR nadir mainly depended on initial eGFR. As telaprevir has been shown to inhibit mostly the drug transporter OCT2 which interacts with creatinine transport, the early decrease of eGFR observed could be a benign phenomenon. However, as unpredictable true renal toxicity may occur during therapy, we recommend a thorough follow-up of eGFR.

Clinical characteristics and outcomes of childhood-onset ANCA-associated vasculitis: a French nationwide study.

BACKGROUND: Data on anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis are scarce in children. The current study is aimed at describing the clinical features and outcomes of childhood-onset ANCA-associated vasculitis (AAV). METHODS: We conducted a retrospective French multicentre study involving patients in whom AAV was diagnosed before the age of 18 years. Inclusion criteria were (i) granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) according to classification criteria of the European League Against Rheumatism/Paediatric Rheumatology European Society, and (ii) ANCA positivity. Patient and renal survival were analysed. RESULTS: Among 66 children included, 80% were female, 42% had GPA and 58% MPA including renal-limited vasculitis, 67% were pANCA+ and 33% cANCA+. The mean incidence of reported cases increased to 0.45 per million children/year in the period 2006-10. Median age at diagnosis was 11.5 years, and median time to diagnosis was 1 month. Initial symptoms included fever and fatigue (79%), skin lesions (41%), arthritis (42%), pulmonary (45%) and renal involvement (88%). Clinical features were similar between GPA and MPA with the exception of upper airway impairment (28%) specific of GPA. Ninety percent of the patients achieved remission after induction treatment. After a median follow-up of 5.2 years, 4 patients (6%) died, corresponding to a mortality rate of 1.2 per 100 person-years, and 22 patients (34%) developed end-stage renal disease (ESRD). Renal survival was 74, 70 and 59% at 1, 5 and 10 years, respectively. In a multivariable Cox regression model, baseline glomerular filtration rate, ethnic origin, histopathological classification and era of treatment were associated with the occurrence of ESRD. Relapse-free survival was 57% at 5 years and 34% at 10 years of follow-up. Patient and renal outcome did not significantly differ between GPA and MPA. CONCLUSION: Childhood-onset AAV is a rare disease characterized by female predominance, delayed diagnosis, frequent renal impairment and a high remission rate. Baseline GFR and new histopathological classification system are strong predictors of ESRD. Renal survival in childhood AAV has improved over time.