A multi-center, phase-2 trial of losartan for the nephropathy of sickle cell anemia

Background: Sickle nephropathy (SN) is a common and progressive manifestation of sickle cell anemia (SCA). Albuminuria indicates glomerular injury and portends renal failure. In a murine model of SCA, we found that increased TGF-β signaling underlies SN, and its downregulation by losartan, an angiotensin receptor blocker, reduced albuminuria and SN progression. The effect of losartan in humans with SCA is unknown.   Objectives: Determine the effect of losartan on SN in a phase-2, open-label study to inform the design of a phase-3 randomized trial.   Design/Method: Oral losartan was administered for 6 months to individuals with SCA (HbSS or S/β0-thalassemia) >=6 years of age. Main exclusion criteria: chronic transfusions, GFR<60 mL/min/1.73m2, hyperkalemia, and contraindications to losartan. Enrollment was in 3 groups defined by urinary albumin-to-creatinine ratio (UACR): no albuminuria (NoA: <30mg/g); microalbuminuria (MicroA: 30-300); and macroalbuminuria (MacroA: >300). The primary endpoint was a >=25% reduction UACR from baseline. Sample size was calculated to detect the primary endpoint in >=30% of the MicroA group with >80% power. Secondary endpoints: urine osmolality, GFR, UACR classification and toxicity.   Results: There were 36 participants (mean age 24.1y; 53% female) in 3 groups (NoA=15; MicroA=13; MacroA=8). Four were non-evaluable (marked non-compliance and/or early termination). The primary endpoint (>=25% reduction in UACR) was met in 41% (13/32) overall [83% (5/6) of MacroA; 58% (7/12) of MicroA; 7% (1/14) of NoA]. Among MacroA and MicroA participants, 67% (12/18) met the primary endpoint. Overall, UACR classification improved in 28% but worsened in 9%. In MacroA and MicroA participants, UACR classification improved in 50% but worsened in 11%. Mean UACR was 202 mg/g (S.E.M. 59, median 50) before and 137 (S.E.M. 47, median 16) after losartan (P=0.29). Urine osmolality and GFR did not change significantly (393 vs 370 mosm/kg•H20, P=0.11; 147 vs 139 mL/min/1.73m2, P=0.43). Losartan was discontinued for leg cramps (N=1); GFR decline >25% (N=1); and serum creatinine rise >50% (N=1).   Abstract source