Losartan for the nephropathy of sickle cell anemia: A phase-2, multicenter trial

Abstract

Nephropathy is a common and progressive complication of sickle cell anemia (SCA). In SCA mice, we found that hyperangiotensinemia in the absence of hypertension underlies nephropathy, and its downregulation by losartan, an angiotensin-II-receptor-1 blocker, reduced albuminuria and progression of nephropathy. Therefore, we performed a phase-2 trial of oral losartan, given for 6 months, to explore whether it reduced albuminuria in children and adults with SCA. Participants were allocated to groups defined by class of baseline urinary albumin-to-creatinine ratio (UACR): no albuminuria (NoA), microalbuminuria (MicroA), and macroalbuminuria (MacroA). The primary endpoint was a ≥25% reduction UACR from baseline. There were 32 evaluable participants (mean age 24 years; NoA = 14, MicroA = 12, MacroA = 6). The primary endpoint was met in 83% of the MacroA group (P < 0.0001) and 58% of the MicroA group (P < 0.0001). Median fold-change in UACR was -0.74 for MacroA and -0.46 for MicroA. In MacroA and MicroA, UACR classification improved in 50% but worsened in 11%. Urine osmolality and estimated glomerular filtration rate (eGFR) did not change significantly. Losartan was discontinued in three participants [leg cramps, N = 1; decline in eGFR >25% (142➝104 mL/minute/1.73 m² ), N = 1; rise in serum creatinine >50% (0.2➝0.3 mg/dL), N = 1]. Albuminuria was associated with diastolic dysfunction and impaired functional capacity, although cardiopulmonary status was unchanged after 6 months of losartan therapy. In summary, losartan decreased urinary albumin excretion in most participants with albuminuria. Those with macroalbuminuria had the greatest benefit. This study forms the basis for a phase-3, randomized, placebo-controlled trial of losartan for the nephropathy of SCA.

Figure 1. Percent of participants meeting the primary endpoint by baseline class of albuminuria

The primary endpoint of a ≥25% reduction in urinary albumin-to-creatinine ratio (UACR) from baseline was met in 67% (12/18) of participants with albuminuria and 41% (13/32) of all participants. Most participants in the MicroA and MacroA groups met the primary endpoint. The dotted line indicates 30% of participants having a ≥25%reduction in UACR, which was the minimum anticipated proportion of participants with ≥25% reduction in UACR in the MicroA group used for calculation of sample size. P-values are from a two-sided binominal test, assuming that the proportion of significant reduction (≥25%) in UACR without losartan was ≤5%.

Figure 2. Fold-change in albuminuria, glomerular filtration rate (eGFR), and urinary osmolality after losartan therapy by baseline class of albuminuria

For all panels, a negative fold-change indicates a reduction in the value of the outcome at the final study visit compared to the baseline value. The boxes are Tukey’s hinges, the line is the median value, the whiskers are 5^th and 95^th percentiles, and the dots are outliers. Panel A: Urinary albumin-to-creatinine ratio (UACR) on first morning void. The light, dotted line indicates a 25% reduction in UACR, the primary outcome measure. For the MicroA and MacroA groups, the median fold-change is below this line (indicating a ≥25% reduction for most participants in those groups). Panel B: eGFR by creatinine clearance on 24-hour urine collection. Panel C: eGFR by measurement of cystatin C. Panel D: Urinary osmolality on first morning void. For each panel, the P-value is from an independent samples Kruskal-Wallis test of the distribution of the outcome across the three classes of baseline albuminuria.

Figure 3. Longitudinal analysis of UACR by class of baseline albuminuria

The natural log of the fold-change in the UACR by number of weeks following initiation of losartan is shown (the natural log of a fold-change of 1 equals 0). Statistically significant differences are indicated by asterisks. In the MiA group, 6 participants had missing week 26 values.