Department of Urology, Aalborg University Hospital, Aalborg, Denmark.
Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
Pflugers Arch. 2021 Apr;473(4):595-610. doi: 10.1007/s00424-021-02555-w. Epub 2021 Apr 12.
With variable potencies atrial-, brain-type and c-type natriuretic peptides (NP)s, best documented for ANP and its analogues, promote sodium and water excretion, renal blood flow, lipolysis, lower blood pressure, and suppress renin and aldosterone secretion through interaction predominantly with cGMP-coupled NPR-A receptor. Infusion of especially ANP and its analogues up to 50 ng/kg/min in patients with high risk of acute kidney injury (cardiac vascular bypass surgery, intraabdominal surgery, direct kidney surgery) protects kidney function (GFR, plasma flow, medullary flow, albuminuria, renal replacement therapy, tissue injury) at short term and also long term and likely additively with the diuretic furosemide. This documents a pharmacologic potential for the pathway. Neprilysin (NEP, neutral endopeptidase) degrades NPs, in particular ANP, and angiotensin II. The drug LCZ696, a mixture of the neprilysin inhibitor sacubitril and the ANGII-AT1 receptor blocker valsartan, was FDA approved in 2015 and marketed as Entresto®. In preclinical studies of kidney injury, LCZ696 and NPs lowered plasma creatinine, countered hypoxia and oxidative stress, suppressed proinflammatory cytokines, and inhibited fibrosis. Few randomized clinical studies exist and were designed with primary cardiac outcomes. The studies showed that LCZ696/entresto stabilized and improved glomerular filtration rate in patients with chronic kidney disease. LCZ696 is safe to use concerning kidney function and stabilizes or increases GFR. In perspective, combined AT1 and neprilysin inhibition is a promising approach for long-term renal protection in addition to AT1 receptor blockers in acute kidney injury and chronic kidney disease.
具有不同效力的心房肽、脑型和 C 型利钠肽（NP），以心房肽及其类似物最为人所知，通过与 cGMP 偶联的 NPR-A 受体主要相互作用，促进钠和水排泄、肾血流量、脂肪分解、降低血压，并抑制肾素和醛固酮分泌。在有发生急性肾损伤风险的患者（心脏血管旁路手术、腹腔内手术、直接肾脏手术）中输注特别是心房肽及其类似物高达 50ng/kg/min，可在短期内保护肾功能（GFR、血浆流量、髓质流量、白蛋白尿、肾脏替代治疗、组织损伤），长期来看也可能与利尿剂呋塞米具有累加效应。这证明了该途径具有药理学潜力。中性内肽酶（NEP，中性内肽酶）降解 NP，特别是心房肽和血管紧张素 II。药物 LCZ696 是 Neprilysin 抑制剂 sacubitril 和血管紧张素 II-AT1 受体阻滞剂 valsartan 的混合物，于 2015 年获得 FDA 批准并以 Entresto®上市。在肾损伤的临床前研究中，LCZ696 和 NP 降低了血浆肌酐，对抗了缺氧和氧化应激，抑制了促炎细胞因子，并抑制了纤维化。目前仅有少数随机临床试验存在，且主要设计用于心脏终点。这些研究表明，LCZ696/Entresto 稳定并改善了慢性肾脏病患者的肾小球滤过率。LCZ696 在肾功能方面使用安全，并稳定或增加了 GFR。从前景来看，联合 AT1 和 Neprilysin 抑制是一种有前途的方法，除了在急性肾损伤和慢性肾脏病中使用 AT1 受体阻滞剂外，还可长期保护肾脏。
