Urinary Biomarkers for Acute Kidney Injury in Dogs

Abstract

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.

Correlation of Urine and Serum Biomarkers with Renal Damage and Survival in Dogs with Naturally Occurring Proteinuric Chronic Kidney Disease

“…N‐acetyl‐β‐D‐glucosaminidase is a tubular lysosomal enzyme recognized as a marker of tubular injury, wherein tubular damage causes release of NAG and subsequent increases in enzyme activity in urine 31, 32. N‐acetyl‐β‐D‐glucosaminidase, which is approximately the size of IgG, does not pass through a normal glomerular filtration barrier, and the upper reference limit for uNAG/c in healthy dogs (3.63 U/g)27 is well below the mean in this study.…”

Is Progressive Chronic Kidney Disease a Slow Acute Kidney Injury?

“…4,24,25,26 Similar efforts are underway in veterinary medicine and show great promise. [28][29][30][31][32][33][34][35][36] (See also, Yerramilli in this issue) An AKI biomarker should be detectable in urine and/or plasma such that it can be assessed routinely and serve as an indicator of kidney function or dysfunction or response to injury. The ideal marker should reflect kidney specific events, be unique and specific to the kidney, and reflect very early and potentially sustained phases of the pathogenesis and repair processes.…”

“…Many candidate serum and urinary biomarkers have been assessed in human 28,37 This linkage to tubular dysfunction has established RBP as a candidate for early identification of kidney injury. Retinal binding protein has been evaluated in dogs associated with a variety AKI models, and its appearance precedes routine clinical predictors as an early marker of AKI.…”

“…However, urinary RBP is only loosely associated with proximal tubular dysfunction and is nonspecific for active injury to the tubular epithelium. 28,37 Cystatin C is a 13 kDA cysteine protease inhibitor constitutively produced by most cells and subsequently circulated in blood after release from the cells. It is freely filtered across the glomerulus and subject to proximal tubular reabsorption from the filtrate and degradation in the proximal epithelia.…”

“…Like RBP, dysfunction of megalin-mediated endocytosis from acute injury or decreased reabsorptive capacity results in urinary detection of cystatin C, and its increased renal excretion. 28 Cystatin C has been proposed as an early predictor of kidney dysfunction. However, it also lacks specificity for active kidney injury, is not uniquely produced by kidney cells, and, as for any freely filtered protein, is confounded by excessive proteinuria which might promote its urinary excretion without substantive active or ongoing tubular injury.…”