Evaluation of renal injury and function biomarkers, including symmetric dimethylarginine (SDMA), in the rat passive Heymann nephritis (PHN) model

Michael J Coyne; A Eric Schultze; Donald J McCrann 3rd; Rachel E Murphy; Julie Cross; Marilyn Strong-Townsend; Corie Drake; Rebekah Mack

doi:10.1371/journal.pone.0269085

Evaluation of renal injury and function biomarkers, including symmetric dimethylarginine (SDMA), in the rat passive Heymann nephritis (PHN) model

PLoS One. 2022 May 27;17(5):e0269085. doi: 10.1371/journal.pone.0269085. eCollection 2022.

Authors

Michael J Coyne¹, A Eric Schultze², Donald J McCrann 3rd¹, Rachel E Murphy¹, Julie Cross¹, Marilyn Strong-Townsend¹, Corie Drake¹, Rebekah Mack¹

Affiliations

¹ IDEXX Laboratories, Inc., Westbrook, Maine, United States of America.
² Pathology Department, Toxicology Division, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Arginine / analogs & derivatives
Biomarkers
Creatinine
Cystatin C
Dogs
Glomerulonephritis, Membranous*
Kidney / physiology
Lipocalin-2
Nitrogen
Rats
Sheep

Substances

Biomarkers
Cystatin C
Lipocalin-2
symmetric dimethylarginine
Arginine
Creatinine
Nitrogen

Grants and funding

This work was funded by IDEXX Laboratories, Inc., Westbrook, Maine, USA.The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.