Department of Nephrology, The Central Hospital of Putuo District, Shanghai, China.
Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, California, USA.
Am J Nephrol. 2019;50(2):92-104. doi: 10.1159/000501059. Epub 2019 Jul 3.
Previous animal experiments and small human studies suggest that urinary plasmin can activate the epithelial sodium channel (ENaC) and contribute to sodium retention in nephrotic syndrome (NS), but this however is not well studied in clinical settings, and its relevance to edema formation is not well characterized in humans. We have investigated the association between urinary plasmin and clinical phenotypes in a large group of patients with NS from multiple etiologies, aiming to assess the role of urinary plasmin in sodium handling and edema formation.
Two hundred and three NS patients with urine and blood samples were divided into mild and severe symptom groups based on their edema severity. Twenty six of them had serial samples collected during the course of immunosuppressive therapy. The plasminogen-plasmin level and other key parameters were assayed, and their association with clinical manifestations were analyzed.
One hundred and one of the 203 patients had renal biopsies performed, the results of which had included all the common types of primary NS and various types of secondary NS. Quantitative comparison and multivariate logistic regression analysis identified urinary plasminogen-plasmin to creatinine ratio (uPLG-PL/C), serum albumin, D-Dimer, and cardiac dysfunction history, but not albuminuria or 24-h urine protein, as independent risk factors for edema (p < 0.01). In patients who were treated and had serial samples, a decrease in uPLG-PL/C was identified as an independent influencing factor of edema remission (p < 0.01). Finally, the urinary fractional excretion of sodium (FENa) in patients was inversely correlated with the fractional excretion of potassium (FEK; p< 0.001), and FEK/FENa ratio was positively correlated with uPLG-PL/C (p < 0.001), suggesting a close association between uPLG-PL and ENaC activation.
Our study identifies uPLG-PL abundance as an independent influencing factor of edema in adult NS patients, and supports the conclusion that plasmin-dependent ENaC activation is an important pathophysiological mechanism of sodium retention and edema formation in humans with NS.
先前的动物实验和小型人体研究表明，尿纤溶酶可激活上皮钠通道（ENaC），并导致肾病综合征（NS）中的钠潴留，但在临床环境中对此研究甚少，且其与水肿形成的相关性在人类中尚未得到充分描述。我们在一组来自多种病因的大量 NS 患者中研究了尿纤溶酶与临床表型之间的关联，旨在评估尿纤溶酶在钠处理和水肿形成中的作用。
将 203 名具有尿液和血液样本的 NS 患者根据其水肿严重程度分为轻度和重度症状组。其中 26 名患者在免疫抑制治疗过程中采集了系列样本。测定纤溶酶原-纤溶酶水平和其他关键参数，并分析其与临床表现的关系。
203 名患者中有 101 名进行了肾活检，结果包括所有常见的原发性 NS 类型和各种继发性 NS 类型。定量比较和多变量逻辑回归分析确定尿纤溶酶原-纤溶酶与肌酐比值（uPLG-PL/C）、血清白蛋白、D-二聚体和心脏功能障碍史，而不是蛋白尿或 24 小时尿蛋白，是水肿的独立危险因素（p<0.01）。在接受治疗并采集系列样本的患者中，uPLG-PL/C 的降低被确定为水肿缓解的独立影响因素（p<0.01）。最后，患者的尿钠排泄分数（FENa）与尿钾排泄分数（FEK；p<0.001）呈负相关，FEK/FENa 比值与 uPLG-PL/C 呈正相关（p<0.001），提示 uPLG-PL 与 ENaC 激活密切相关。
我们的研究确定了尿纤溶酶原-纤溶酶的丰度是成人 NS 患者水肿的独立影响因素，并支持纤溶酶依赖性 ENaC 激活是 NS 患者钠潴留和水肿形成的重要病理生理机制的结论。
