Losartan for the nephropathy of sickle cell anemia: A phase-2, multicenter trial.
Losartan for the nephropathy of sickle cell anemia: A phase-2, multicenter trial.
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氯沙坦治疗镰状细胞性贫血肾病：一项 2 期、多中心试验。
DOI：
10.1002/ajh.24810
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发表时间：
2017
影响因子：
12.8
通讯作者：
Taylor,Michae
中科院分区：
文献类型：
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作者：
Quinn,CharlesT;Saraf,SantoshL;Gordeuk,VictorR;Fitzhugh,CourtneyD;Creary,SusanE;Bodas,Prasad;George,Alex;Raj,AshokB;Nero,AleciaC;Terrell,CatherineE;McCord,Lisa;Lane,Adam;Ackerman,HansC;Yang,Yu;Niss,Omar;Taylor,Michae
肾病是镰状细胞性贫血 (SCA) 的常见且进行性并发症。在 SCA 小鼠中，我们发现在没有高血压的情况下，高血管紧张素血症是肾病的基础，而氯沙坦（一种血管紧张素 II 受体 1 阻滞剂）可下调高血管紧张素血症，从而减少蛋白尿和肾病的进展。因此，我们进行了一项为期 6 个月的口服氯沙坦的 2 期试验，以探讨它是否可以减少患有 SCA 的儿童和成人的蛋白尿。参与者被分配到根据基线尿白蛋白与肌酐比值（UACR）类别定义的组中：无白蛋白尿（NoA）、微量白蛋白尿（MicroA）和大量白蛋白尿（MacroA）。主要终点是 UACR 较基线降低 ≥25%。有 32 名可评估参与者（平均年龄 24 岁；NoA = 14，MicroA = 12，MacroA = 6）。 MacroA 组中有 83% 的人达到了主要终点（P<0.0001），MicroA 组的有 58% 的人达到了主要终点（P<0.0001）。 MacroA 的 UACR 中位倍数变化为 -0.74，MicroA 的中位变化倍数为 -0.46。在 MacroA 和 MicroA 中，UACR 分类改善了 50%，但恶化了 11%。尿液渗透压和估计肾小球滤过率（eGFR）没有显着变化。三名参与者中止了氯沙坦治疗[腿部抽筋，N= 1； eGFR下降>25%（142➝104 mL/分钟/1.73 m2），N= 1；血清肌酐升高>50% (0.2➝0.3 mg/dL),N= 1]。尽管氯沙坦治疗 6 个月后心肺状态没有变化，但蛋白尿与舒张功能障碍和功能受损有关。总之，氯沙坦减少了大多数白蛋白尿参与者的尿白蛋白排泄。那些患有大量白蛋白尿的人受益最大。这项研究为氯沙坦治疗 SCA 肾病的 3 期随机安慰剂对照试验奠定了基础。
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.