Evaluation of Renal Biomarkers, Including Symmetric Dimethylarginine, following Gentamicin-Induced Proximal Tubular Injury in the Rat

Abstract

Symmetric dimethylarginine (SDMA) is an excretory renal function biomarker shown to correlate well with glomerular filtration rate in dogs, cats, humans, and rats. The objectives of this study were to determine utility of serum SDMA as a renal biomarker in a rat model of gentamicin-induced renal injury and provide validation of a commercially available SDMA immunoassay for rat serum. Rats were randomly assigned to one of three dose levels of gentamicin (20, 50, or 100 mg/kg) or a vehicle control group and dosed once daily by subcutaneous injection for either four or ten days. Serum and urine renal biomarker evaluation including serum SDMA, hematologic and serum biochemical analysis, urinalysis, and histologic examination of kidney were performed. Prior to biologic validation, analytic validation of the SDMA immunoassay for rat serum was performed including assessment of assay accuracy, precision, analytical sensitivity, linearity, analyte stability, and interference testing. Among markers of excretory renal function SDMA and serum creatinine increased earliest and at the lowest gentamicin concentrations and were significantly increased in both the 50 mg/kg and the 100 mg/kg dosage levels in the 4 and 10-dose treatment groups compared to controls. Time- and dose-dependent increases were noted for all urinary biomarkers investigated in this study, with µALB being most responsive and OPN least responsive for detection of gentamicin-induced injury across dose levels and schedules investigated. The SDMA immunoassay met all set quality requirements assessed in analytical validation. This study is the first to investigate performance of serum SDMA as compared to other excretory renal function markers in a rat gentamicin acute toxicity model. In this study serum SDMA was an earlier biomarker for detection of gentamicin-induced toxicity than serum cystatin C, BUN, and creatinine clearance. The SDMA immunoassay provides a reliable commercially available assay for future renal investigations in rat models.

Utilizing liposomal encapsulation approach to address nephrotoxic challenges of colistimethate sodium through a preclinical study

“…The results of this experiment further support the potential risk of acute kidney injury, as shown by the significant increase in SDMA levels. This finding is consistent with previous research that demonstrated the effectiveness of serum SDMA as a biomarker of renal excretory function in a rat model of gentamicin-induced proximal tubular injury, as well as the validation of a high-throughput SDMA immunoassay for rat serum (Hamlin et al, 2022).…”

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

“…The urine KIM-1 and urine OPN were performed using R&D Systems ELISAs (RKM100 for KIM-1 and MOST00 for OPN) (R&D Systems, Inc. Minneapolis, MN USA) [18,19]. Serum SDMA was measured using the IDEXX SDMA1 Test (IDEXX Laboratories, Inc, Westbrook, ME, USA) [11].…”

“…Investigations of SDMA in the peer-reviewed literature predominately focus either on utility as a diagnostic biomarker in naturally occurring renal disease or basic science research, while evaluations of SDMA as a renal safety biomarker in relevant preclinical species and study designs are not as well represented. Recent validation of a high through put immunoassay for measurement of serum SDMA in rats, however, allows for increased opportunities to investigate SDMA as a safety biomarker in this species [11]. The purpose of this study was to evaluate the utility of serum SDMA as a biomarker of renal excretory function within a rat passive Heymann nephritis (PHN) model of glomerulopathy.…”

Simultaneous magnetic resonance imaging of pH, perfusion and renal filtration using hyperpolarized 13C-labelled Z-OMPD

“…Renal biomarkers in blood serum reveal mildly increased creatinine- ( l ) and strongly elevated urea levels ( m ), while SDMA values are not clinically evident ( n) ( l , m , n : n = 8 individual blood samples). Reference ranges (dashed lines) were obtained from animal suppliers for creatinine and urea 97 or literature for SDMA 98 – 100 . o Urine pH is unobtrusive in hydronephrotic models ( n = 10 healthy and n = 11 individual hydronephrosis urine samples).…”