IDEXX Laboratories, Inc., Westbrook, Maine, United States of America.
Pathology Department, Toxicology Division, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America.
PLoS One. 2022 May 27;17(5):e0269085. doi: 10.1371/journal.pone.0269085. eCollection 2022.
Symmetric dimethylarginine (SDMA) is a serum biomarker of excretory renal function which consistently correlates with glomerular filtration rate (GFR) across multiple species including rats, dogs, and humans. In human and veterinary clinical settings SDMA demonstrates enhanced sensitivity for detection of declining renal function as compared to other serum biomarkers, but application in preclinical study designs thus far has been limited. The purpose of this study was to determine the performance of serum SDMA in a rat passive Heyman nephritis model of glomerulopathy. In addition to SDMA other biomarkers of excretory renal function were measured including serum creatinine (sCr), blood urea nitrogen (BUN), and cystatin C along with creatinine clearance. Urinary renal biomarkers including microalbumin (μALB), clusterin (CLU), cystatin C, kidney injury marker-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin (OPN) were also measured. PHN was induced using commercial sheep anti-Fx1A serum. Tissue, serum, and urine were collected from groups of control and anti-Fx1A-treated animals for biomarker evaluation, hematology, urinalysis, serum biochemistry, and histologic examination of kidney. Over the course of a 28-day study, concentrations of the urinary biomarkers μALB, CLU, cystatin C, NGAL, KIM-1 and the serum biomarker cystatin C increased significantly in anti-Fx1A-treated rats as compared to controls but no significant increase in serum SDMA, sCr, BUN, or creatinine clearance were noted in anti-Fx1A-treated rats. Given lack of direct GFR measurement or significant change in the renal function biomarkers sCr, BUN, and creatinine clearance, it is unclear if GFR differed significantly between control and anti-Fx1A-treated rats in this study, though urinary biomarkers and histopathologic findings supported renal injury in anti-Fx1A-treated rats over the time course investigated. This study is among the first to investigate serum SDMA in a rat model relevant to preclinical safety assessment and serves to inform future experimental designs and biomarker selection when evaluation of glomerular injury is of priority.
对称二甲基精氨酸（SDMA）是一种反映肾脏排泄功能的血清生物标志物，在包括大鼠、犬和人类在内的多种物种中，SDMA 与肾小球滤过率（GFR）始终具有相关性。在人类和兽医临床环境中，与其他血清生物标志物相比，SDMA 检测肾脏功能下降的敏感性更高，但迄今为止，其在临床前研究设计中的应用有限。本研究旨在确定血清 SDMA 在大鼠被动性海曼肾炎肾小球病变模型中的表现。除了 SDMA 外，还测量了其他反映肾脏排泄功能的生物标志物，包括血清肌酐（sCr）、血尿素氮（BUN）和胱抑素 C 以及肌酐清除率。还测量了尿液中的肾脏生物标志物，包括微量白蛋白（μALB）、簇蛋白（CLU）、胱抑素 C、肾损伤标志物-1（KIM-1）、中性粒细胞明胶酶相关脂质运载蛋白（NGAL）和骨桥蛋白（OPN）。使用商业绵羊抗 FX1A 血清诱导 PHN。从对照组和抗 FX1A 处理组动物中采集组织、血清和尿液，用于生物标志物评估、血液学、尿液分析、血清生化和肾脏组织学检查。在为期 28 天的研究过程中，与对照组相比，抗 FX1A 处理组大鼠尿液生物标志物μALB、CLU、胱抑素 C、NGAL、KIM-1 和血清生物标志物胱抑素 C 的浓度显著升高，但在抗 FX1A 处理组大鼠中未观察到血清 SDMA、sCr、BUN 或肌酐清除率显著增加。由于缺乏直接的 GFR 测量或反映肾功能的生物标志物 sCr、BUN 和肌酐清除率的显著变化，因此尚不清楚在本研究中，与对照组相比，抗 FX1A 处理组大鼠的 GFR 是否存在显著差异，尽管尿液生物标志物和组织病理学发现支持抗 FX1A 处理组大鼠在研究过程中存在肾脏损伤。本研究是首批在与临床前安全性评估相关的大鼠模型中研究血清 SDMA 的研究之一，为今后评估肾小球损伤时的实验设计和生物标志物选择提供了信息。
