Serelaxin as a potential treatment for renal dysfunction in cirrhosis: Preclinical evaluation and results of a randomized phase 2 trial.
Serelaxin as a potential treatment for renal dysfunction in cirrhosis: Preclinical evaluation and results of a randomized phase 2 trial.
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DOI：
10.1371/journal.pmed.1002248
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发表时间：
2017-02
期刊：
影响因子：
15.8
通讯作者：
Fallowfield JA
中科院分区：
文献类型：
--
作者：
Snowdon VK;Lachlan NJ;Hoy AM;Hadoke PW;Semple SI;Patel D;Mungall W;Kendall TJ;Thomson A;Lennen RJ;Jansen MA;Moran CM;Pellicoro A;Ramachandran P;Shaw I;Aucott RL;Severin T;Saini R;Pak J;Yates D;Dongre N;Duffield JS;Webb DJ;Iredale JP;Hayes PC;Fallowfield JA
任何原因造成的慢性肝瘢痕形成可导致肝硬化、门静脉高压、肾血流量和肾功能进行性下降。严重的肾血管收缩是肝肾综合征的特征，是晚期肝硬化患者急性肾损伤的一种功能性和潜在可逆形式，但目前使用全身血管收缩剂治疗在很大比例的患者中无效，并且受到缺血性不良事件的限制。Serelaxin（重组人松弛素-2）是一种具有抗纤维化和血管保护特性的肽分子，与松弛素家族肽受体-1 （RXFP1）结合，已被证明可以增加健康人类志愿者的肾脏灌注。我们假设血清舒张素可以改善肝硬化和门静脉高压症患者的肾血管收缩和肾功能障碍。为了建立临床前概念证明，我们开发了两个独立的肝硬化大鼠模型，其特征是肾血流量和肾小球滤过率进行性减少，并显示肾内皮功能障碍的证据。然后，我们开始在一项针对酒精相关性肝硬化和门脉高压的男性和女性患者的2期随机开放标签平行组研究中进一步探索和验证我们的假设。40例患者按1:1随机分组，分别给予静脉输注色拉欣（80 μg/kg/d, 60 min, 30 μg/kg/d, 60 min）或特利加压素（单次2 mg，静脉滴注）治疗，并在基线和120 min后通过相对比磁共振血管造影量化局部血流动力学影响。主要终点是与基线相比肾动脉总血流的变化。在大鼠模型中，用七色拉素靶向治疗肾血管收缩，通过降低肾血管阻力、逆转内皮功能障碍和增加肾脏中AKT/eNOS/NO信号通路的激活，增加肾脏灌注、氧合和功能。在随机临床研究中，输注selelaxin 120 min使肾动脉总血流量较基线增加65% （95% CI 40%, 95%; p < 0.001）。使用舍拉辛是安全且耐受性良好的，对全身血压或肝脏灌注无不良影响。临床研究的主要局限性是样本量相对较小，人群稳定，补偿良好。我们在大鼠模型和人类肝硬化的探索性研究中发现的机制表明，选择性肾血管舒张使用舍拉辛作为肝硬化肾功能障碍的新治疗方法的治疗潜力，尽管需要在更晚期的肝硬化和肾功能障碍患者中进一步验证。在一篇研究文章中，Jonathan Fallowfield和他的同事研究了血清松弛素作为肝硬化肾血管收缩的可能治疗方法。1型肝肾综合征是肝硬化患者发生的一种快速进展但可能可逆的急性肾损伤形式，其特征是严重的肾血管收缩，预后很差。对于一种被广泛批准、安全有效的药物治疗，有一个显著的未被满足的需求。舒张素是人类肽激素松弛素-2的重组形式，已被证明可以增加健康人类志愿者的肾脏灌注。我们测试了血清舒张素是否可以改善肝硬化患者的肾血管收缩和肾功能障碍。在两种独立的肝硬化动物模型中，通过逆转内皮功能障碍和增加肾脏一氧化氮信号的激活，给药血清舒张素改善肾脏血流、氧合和功能。在一项针对肝硬化和门脉高压症患者的探索性2期临床试验中，输注色拉辛诱导肾血流量显著增加，且安全且耐受性良好，对全身血压或肝脏灌注无不良影响。我们的数据表明，选择性靶向肾血管收缩使用色拉辛可以调节肾功能障碍的肝硬化而不影响全身血压。需要对晚期肝硬化和肾功能不全患者进行进一步的研究，以确认是否对肾功能和患者预后有有益的影响。
Chronic liver scarring from any cause leads to cirrhosis, portal hypertension, and a progressive decline in renal blood flow and renal function. Extreme renal vasoconstriction characterizes hepatorenal syndrome, a functional and potentially reversible form of acute kidney injury in patients with advanced cirrhosis, but current therapy with systemic vasoconstrictors is ineffective in a substantial proportion of patients and is limited by ischemic adverse events. Serelaxin (recombinant human relaxin-2) is a peptide molecule with anti-fibrotic and vasoprotective properties that binds to relaxin family peptide receptor-1 (RXFP1) and has been shown to increase renal perfusion in healthy human volunteers. We hypothesized that serelaxin could ameliorate renal vasoconstriction and renal dysfunction in patients with cirrhosis and portal hypertension. To establish preclinical proof of concept, we developed two independent rat models of cirrhosis that were characterized by progressive reduction in renal blood flow and glomerular filtration rate and showed evidence of renal endothelial dysfunction. We then set out to further explore and validate our hypothesis in a phase 2 randomized open-label parallel-group study in male and female patients with alcohol-related cirrhosis and portal hypertension. Forty patients were randomized 1:1 to treatment with serelaxin intravenous (i.v.) infusion (for 60 min at 80 μg/kg/d and then 60 min at 30 μg/kg/d) or terlipressin (single 2-mg i.v. bolus), and the regional hemodynamic effects were quantified by phase contrast magnetic resonance angiography at baseline and after 120 min. The primary endpoint was the change from baseline in total renal artery blood flow. Therapeutic targeting of renal vasoconstriction with serelaxin in the rat models increased kidney perfusion, oxygenation, and function through reduction in renal vascular resistance, reversal of endothelial dysfunction, and increased activation of the AKT/eNOS/NO signaling pathway in the kidney. In the randomized clinical study, infusion of serelaxin for 120 min increased total renal arterial blood flow by 65% (95% CI 40%, 95%; p < 0.001) from baseline. Administration of serelaxin was safe and well tolerated, with no detrimental effect on systemic blood pressure or hepatic perfusion. The clinical study’s main limitations were the relatively small sample size and stable, well-compensated population. Our mechanistic findings in rat models and exploratory study in human cirrhosis suggest the therapeutic potential of selective renal vasodilation using serelaxin as a new treatment for renal dysfunction in cirrhosis, although further validation in patients with more advanced cirrhosis and renal dysfunction is required. ClinicalTrials.gov NCT01640964 In a Research Article, Jonathan Fallowfield and colleagues study serelaxin as a possible treatment for renal vasoconstriction in liver cirrhosis. Hepatorenal syndrome type 1 is a rapidly progressive, but potentially reversible, form of acute kidney injury occurring in patients with liver cirrhosis, characterized by severe renal vasoconstriction and a very poor prognosis. There is a significant unmet need for a widely approved, safe, and effective pharmacological treatment. Serelaxin, a recombinant form of the human peptide hormone relaxin-2, has been shown to increase renal perfusion in healthy human volunteers. We tested whether serelaxin could ameliorate renal vasoconstriction and renal dysfunction in cirrhosis. Administration of serelaxin improved renal blood flow, oxygenation, and function in two independent animal models of cirrhosis through reversal of endothelial dysfunction and increased activation of nitric oxide signaling in the kidney. In an exploratory phase 2 clinical trial in patients with cirrhosis and portal hypertension, serelaxin infusion induced a significant increase in renal blood flow and was safe and well tolerated, with no adverse effects on systemic blood pressure or hepatic perfusion. Our data indicate that selective targeting of renal vasoconstriction using serelaxin may modulate renal dysfunction in cirrhosis without affecting systemic blood pressure. Further studies in patients with more advanced cirrhosis and renal dysfunction are required to confirm whether there are beneficial effects on renal function and patient outcomes.