Bomback Andrew S, Rekhtman Yelena, Klemmer Philip J, Canetta Pietro A, Radhakrishnan Jai, Appel Gerald B
Department of Medicine, Division of Nephrology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
J Am Soc Hypertens. 2012 Sep-Oct;6(5):338-45. doi: 10.1016/j.jash.2012.07.003.
Aldosterone levels increase in 30%-40% of patients on angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers over the long term. This "aldosterone breakthrough" may carry important clinical consequences given aldosterone's nonepithelial, pro-fibrotic actions. The renin inhibitor, aliskiren, by suppressing the renin-angiotensin-aldosterone system (RAAS) proximally, may limit breakthrough compared to conventional RAAS blockade. This open-label study (NCT01129557) randomized subjects to aliskiren 300 mg daily (A), valsartan 320 mg daily (V), or aliskiren 150 mg + valsartan 160 mg daily (A+V) for 9 months. Eligible subjects had proteinuria >300 mg/day, estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m(2), and systolic blood pressure (BP) >130 or diastolic BP >80 mm Hg. Serum and 24-hour urine aldosterone (indexed to 24-hour urine Na) were checked before initiation of therapy and at 3, 6, and 9 months. Aldosterone breakthrough was defined as a sustained increase from baseline aldosterone by study end. The study was intended to enroll 120 subjects but was terminated early by the sponsor. We present here the results of 33 subjects who completed the protocol, of which 12 were randomized to A, 11 were randomized to V, and 10 were randomized to A+V. Mean baseline eGFR was 75.5 (±23.3) mL/min/1.73 m(2); baseline proteinuria was 3104 (±2943) mg/day; and baseline BP was 134.7 (±10.5)/84.8 (±8.4) mm Hg. Three (27%) subjects on V, three (25%) subjects on A, and three (30%) subjects on A+V had aldosterone breakthrough. Mean proteinuria reduction was 31% from baseline in all subjects: 30% in subjects with breakthrough vs. 32% in subjects without breakthrough. Mean BP reduction was 11.0/8.8 mm Hg in all subjects: 8.4/6.1 mm Hg in subjects with breakthrough vs. 12.0/9.8 mm Hg in subjects without breakthrough. Aliskiren, alone or in combination with valsartan, did not reduce the incidence of aldosterone breakthrough in subjects with hypertension and proteinuria compared with conventional RAAS blockade.
长期使用血管紧张素转换酶抑制剂和/或血管紧张素受体阻滞剂的患者中，30%-40%的患者醛固酮水平会升高。鉴于醛固酮的非上皮性、促纤维化作用，这种“醛固酮突破”可能会带来重要的临床后果。肾素抑制剂阿利吉仑通过在近端抑制肾素-血管紧张素-醛固酮系统（RAAS），与传统的RAAS阻断相比，可能会限制醛固酮突破。这项开放标签研究（NCT01129557）将受试者随机分为每日服用300 mg阿利吉仑（A组）、每日服用320 mg缬沙坦（V组）或每日服用150 mg阿利吉仑+160 mg缬沙坦（A+V组），为期9个月。符合条件的受试者蛋白尿>300 mg/天，估计肾小球滤过率（eGFR）>45 mL/min/1.73 m²，收缩压（BP）>130或舒张压>80 mmHg。在治疗开始前以及治疗3、6和9个月时检查血清和24小时尿醛固酮（以24小时尿钠为指标）。醛固酮突破定义为研究结束时醛固酮水平较基线持续升高。该研究计划招募120名受试者，但主办方提前终止了研究。我们在此展示了33名完成方案的受试者的结果，其中12名被随机分配到A组，11名被随机分配到V组，10名被随机分配到A+V组。平均基线eGFR为75.5（±23.3）mL/min/1.73 m²；基线蛋白尿为3104（±2943）mg/天；基线血压为134.7（±10.5）/84.8（±8.4）mmHg。V组中有3名（27%）受试者、A组中有3名（25%）受试者、A+V组中有3名（30%）受试者出现醛固酮突破。所有受试者的蛋白尿平均较基线降低31%：有醛固酮突破的受试者降低30%，无醛固酮突破的受试者降低32%。所有受试者的平均血压降低11.0/8.8 mmHg：有醛固酮突破的受试者降低8.4/6.1 mmHg，无醛固酮突破的受试者降低12.0/9.8 mmHg。与传统的RAAS阻断相比，阿利吉仑单独使用或与缬沙坦联合使用并未降低高血压和蛋白尿患者醛固酮突破的发生率。
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