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

key information

source: The American Society of Pediatric Hematology/Oncology

year: 2016

authors: Charles T. Quinn, Santosh Saraf, Victor Gordeuk, Courtney Fitzhugh, Susan Creary, Prasad Bodas, Alex George, Ashok B. Raj, Alecia Nero, Catherine Terell, Lisa McCord, Omar Niss, Rubina Dosani, Michael D. Taylor, Prasad Devarajan, Punam Malik

summary/abstract:

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).

 

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