Urinary Biomarkers for Acute Kidney Injury in Dogs

Routinely, kidney dysfunction and decreased glomerular filtration rate (GFR) are diagnosed by the evaluation of changes in the serum creatinine (SCr) and blood urea nitrogen (BUN) concentrations. However, neither of these tests is sensitive or specific enough for the early diagnosis of impaired kidney function because they are both affected by other renal and nonrenal factors. Furthermore, kidney injury can be present in the absence of kidney dysfunction. Renal reserve enables normal GFR even when nephrons are damaged. Renal biomarkers, especially those present in urine, may be useful for the study of both acute and chronic nephropathies. The aim of this review is to describe the current status of urinary biomarkers as diagnostic tools for kidney injury in dogs with particular focus on acute kidney injury (AKI). The International Renal Interest Society (IRIS) canine AKI grading system and the implementation of urinary biomarkers in this system also are discussed. The discovery of novel urinary biomarkers has emerged from hypotheses about the pathophysiology of kidney injury, but few proteomic urine screening approaches have been described in dogs. Lack of standardization of biomarker assays further complicates the comparison of novel canine urinary biomarker validation results among studies. Future research should focus on novel biomarkers of renal origin and evaluate promising biomarkers in different clinical conditions. Validation of selected urinary biomarkers in the diagnosis of canine kidney diseases must include dogs with both renal and nonrenal diseases to evaluate their sensitivity, specificity as well as their negative and positive predictive values.     

Urinary Markers in Healthy Young and Aged Dogs and Dogs with Chronic Kidney Disease

Background: Blood urea nitrogen and serum creatinine concentrations only detect a decrease of >75% of renal functional mass. Therefore, there is a need for markers that allow early detection and localization of renal damage.
Hypothesis: Urinary albumin (uALB), C-reactive protein (uCRP), retinol binding protein (uRBP), and N -acetyl-β- d -glucosaminidase (uNAG) concentrations are increased in dogs with chronic kidney disease (CKD) compared with healthy controls and in healthy older dogs compared with young dogs.
Animals: Ten dogs with CKD, 10 healthy young dogs (age 1–3 years), and 10 healthy older dogs (age > 7 years) without clinically relevant abnormalities on physical examination, hematology, biochemistry, and urinalysis.
Methods: Urinary markers were determined using an ELISA (uALB, uCRP, and uRBP) or a colorimetric test (uNAG). Results were related to urinary creatinine (c). The fixed effects model or the Wilcoxon rank sum test were used to compare the different groups of dogs.
Results: uALB/c, uRBP/c, and uNAG/c were significantly higher in CKD dogs than in healthy dogs. No significant difference was found for uCRP, which was not detectable in the healthy dogs and only in 3 of the CKD dogs. Between the healthy young and older dogs, no significant difference was detected for any of the markers.
Conclusion: The urinary markers uALB/c, uRBP/c, and uNAG/c were significantly increased in dogs with CKD compared with healthy controls. Additional studies are needed to evaluate the ability of these markers to detect renal disease before the onset of azotemia.     

Comparison of Serum Concentrations of Symmetric Dimethylarginine and Creatinine as Kidney Function Biomarkers in Cats with Chronic Kidney Disease

Background

Symmetric dimethylarginine (SDMA) has been shown to be an accurate and precise biomarker for calculating estimated glomerular filtration rate (GFR) in humans, as well as a more sensitive biomarker than serum creatinine concentration (sCr) for assessing renal dysfunction.

Objectives

The purpose of this retrospective study was to report on the utility of measuring serum SDMA concentrations in cats for detection of chronic kidney disease (CKD) before diagnosis by conventional measurement of sCr.

Animals

Chronic kidney disease cats (n = 21) included those persistently azotemic for ≥3 months (n = 15), nonazotemic cats with GFR >30% decreased from median GFR of normal cats (n = 4), and nonazotemic cats with calcium oxalate kidney stones (n = 2). Healthy geriatric cats (n = 21) were selected from the same colony.

Methods

Symmetric dimethylarginine concentrations (liquid chromatography‐mass spectroscopy) and sCr (enzymatic colorimetry) were determined retrospectively from historical data or banked serum samples in azotemic cats or at the time GFR (iohexol clearance) was measured in nonazotemic cats.

Results

Serum SDMA (r = −0.79) and sCr (r = −0.77) concentrations were significantly correlated to GFR (both P < .0001). Symmetric dimethylarginine became increased before sCr in 17/21 cats (mean, 17.0 months; range, 1.5–48 months). Serum SDMA had higher sensitivity (100%) compared with sCr (17%), but lower specificity (91% versus 100%) and positive predictive value (86% versus 100%).

Conclusion and Clinical Importance

Using serum SDMA as a biomarker for CKD allows earlier detection of CKD in cats compared with sCr, which may be desirable for initiating renoprotective interventions that slow progression of CKD.     

Relationship between Serum Symmetric Dimethylarginine Concentration and Glomerular Filtration Rate in Cats

Background

Direct measurement of glomerular filtration rate (GFR) is the preferred method to assess renal function in cats, but it is not widely used in the diagnosis of chronic kidney disease (CKD). In cats with CKD, symmetric dimethylarginine (SDMA) has been shown to increase and to correlate with plasma creatinine concentrations.

Hypothesis

In cats, reduced GFR corresponds with increased serum SDMA concentration.

Animals

The study group consisted of ten client‐owned cats whose GFR had been measured previously. Cats ranged in age from 11.1 to 16.9 years; both azotemic and nonazotemic animals were included.

Methods

Glomerular filtration rate was determined for each cat by plasma iohexol clearance using the three sample slope‐intercept method, and serum SDMA concentration was measured by liquid chromatography‐mass spectrometry.

Results

A linear relationship was observed between GFR and the reciprocal of serum SDMA concentration (R ² = 0.82, P < .001). A similar relationship was found between GFR and the reciprocal of plasma creatinine concentration (R ² = 0.81, P < .001).

Conclusions and Clinical Importance

Increased serum SDMA concentrations were observed in cats with reduced renal function as determined by direct measurement of GFR. This finding indicates that SDMA could have clinical applications in the diagnosis of CKD in cats.     

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

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.