Symmetric Dimethylarginine Assay Validation, Stability, and Evaluation as a Marker for the Early Detection of Chronic Kidney Disease in Dogs

Abstract

Background: Symmetric dimethylarginine (SDMA) is a small molecule formed by methylation of arginine, and released into blood during protein degradation. SDMA is primarily eliminated by renal excretion and is a promising endogenous marker of glomerular filtration rate (GFR).

Objectives: To validate an assay for SDMA measurement, determine stability of SDMA in blood, and compare SDMA with serum creatinine concentration (sCr) and GFR for early detection of decreasing kidney function in dogs with chronic kidney disease (CKD).

Animals: Eight male dogs affected with X-linked hereditary nephropathy and 4 unaffected male littermates.

Methods: Prospective study validating SDMA measurement using liquid chromatography-mass spectrometry, assessing stability of SDMA in serum and plasma, and serially determining sCr, SDMA, and GFR (using iohexol clearance) in dogs during progression from preclinical disease to end-stage renal failure. Correlations were determined using linear regression. Timepoints at which sCr, SDMA, and GFR identified decreased renal function were compared using defined cutoffs, trending in an individual dog, and comparison with unaffected littermates.

Results: Symmetric dimethylarginine was highly stable in serum and plasma, and the assay demonstrated excellent analytical performance. In unaffected dogs, SDMA remained unchanged whereas in affected dogs, SDMA increased during disease progression, correlating strongly with an increase in sCr (r = 0.95) and decrease in GFR (r = -0.95). Although trending improved sCr's sensitivity, SDMA identified, on average, <20% decrease in GFR, which was earlier than sCr using any comparison method.

Conclusions and clinical importance: Symmetric dimethylarginine is useful for both early identification and monitoring of decreased renal function in dogs with CKD.

Keywords: X-linked hereditary nephropathy; canine; glomerular filtration rate; serum creatinine.

Figure 1

Correlations of serum creatinine (sCr), SDMA and GFR in dogs affected with X‐linked hereditary nephropathy (n = 8; graphs A, C, and E) and unaffected littermates (n = 4; graphs B, D, and F).

Figure 2

Difference in weeks between comparisons of various methods for the analysis of serum creatinine (sCr), SDMA, and GFR for detecting initial decline in renal function in dogs affected with X‐linked hereditary nephropathy (n = 8). Age difference was calculated by subtracting the age at which a decrease in renal function was identified by method (2) from that identified by method (1). “(1) Better” indicates that method (1) detected a decline in renal function earlier than method (2); “(2) Better” indicates that method (2) detected this decline earlier than method (1). sCr cutoff: sCr ≥ 1.2 mg/dL; GFR cutoff: GFR <2 mL/min/kg; SDMA cutoff: SDMA≥14 μg/dL; sCr and SDMA trending refer to detection of a clinically relevant difference in the rate of change from prior values in an individual dog.