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

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.

Novel renal injury markers in dogs with ehrlichiosis

“…In this study, there were no differences in SDMA concentrations at the time of inclusion between groups and over time within EG or CG. These results were similar to recent reports that did not find an increase in SDMA levels in early AKI following snake bite envenomation, nor in a rat passive Heyman nephritis model of glomerulopathy [ 20 , 24 , 37 ]. SDMA has previously been shown to be useful in the detection of increased risk of CKD in dogs with Ehrlichia spp.…”

“…At this stage, regardless of the subtle decline of GFR, sCr concentrations (and hypothetically SDMA concentrations) will not increase as rapidly because of its curvilinear, hyperbolic, exponential relationship with GFR, as compared to active kidney injury biomarkers [ 1 – 3 , 6 , 38 – 40 ]. However, as the injury persists in association with the ‘extension’ stage of the disease, azotemia arises and an increase in SDMA concentrations is also expected [ 1 , 2 , 37 , 40 ]. In this study, there were no differences in SDMA concentrations at the time of inclusion between groups and over time within EG or CG.…”

Ergothioneine promotes longevity and healthy aging in male mice

“…In particular, the plasma levels of creatinine, SDMA, urea, and ADMA, which are markers of renal dysfunction were suppressed by daily ERGO intake (Fig. 4a-d) [27][28][29]. This finding may be compatible with the previous reports indicating that ERGO modulates oxidative damage of the kidney in rats and that decreased ERGO levels may contribute to chronic kidney disease progression implying beneficial roles of ERGO in the kidney [80,81].…”

“…The bar graph data represent mean ± SEM. CXCL9, chemokine (CXC motif) ligand 9; SIRT6, NAD + -dependent protein deacetylase sirtuin-6; TBARS, thiobarbituric acid-reactive substances may also be a marker of endothelial damage [27][28][29]. The levels of these markers in the control group increased significantly between 28 and 92 weeks (P < 0.01; Fig.…”

“…Cellular senescence and oxidative stress were assessed by western blotting (WB) and ELISA for representative markers (liver p16, SIRT6, TBARS, and plasma CXCL9) [1,[24][25][26]. Systemic senescence was evaluated by CE-MS for renal function, strongly associated with aging and inflammaging markers (creatinine, urea, ADMA, SDMA, quinolinic acid, kynurenine, and tryptophan) [27][28][29][30]. Cognitive impairment was determined using the novel object recognition test (NORT), a commonly used behavioral assay for investigating various aspects of learning and memory in mice [31].…”