Cyclosporine (CsA), a widely used immunosuppressive drug, is an effective treatment of sight-threatening posterior idiopathic uveitis. CsA's main side effect is nephrotoxicity. The aim of this single-center prospective cohort study (conducted in a tertiary care teaching hospital in Paris, France) was to assess the long-term renal tolerance of a low-dose CsA treatment in patients with previously healthy kidneys on clinical, biologic, and pathologic criteria. Forty-one patients treated with 4.3 +/- 1.6 mg/kg body wt per day CsA for 44.9 +/- 3.6 mo were included. Mean follow-up was 55.4 +/- 0.2 mo. BP, CsA trough level, and renal function were prospectively monitored together with blood urea, creatinine clearance, GFR, and effective renal plasma flow. Eleven patients underwent serial kidney biopsies before and after 2 yr of a 4 +/- 0.9 mg/kg daily CsA treatment. Sustained low-dose CsA treatment induced a significant increase in plasma creatinine (P < 0.0001), a significant decrease in creatinine clearance (P < 0.0001), and isotopic GFR (P < 0.0001) over time. The highest dose induced more severe alterations in any of the renal parameters than the lowest dose. Prevalence of hypertension was particularly high. Histopathologic data showed significant interstitial fibrosis (P < 0.003) and tubular atrophy (P < 0.003) after 2 yr. Low-dose long-term CsA treatment induces significant renal impairment and a high incidence of hypertension. Our study suggests that lowering daily dosage may prevent CsA-induced nephrotoxicity if a daily dose of < or =3 mg/kg is used. Whether once established it is reversible is still prospective, although the occurrence of interstitial fibrosis in the kidney would argue against reversibility.