Podocyte Biomarkers in Urine: Relevance and Potential

Introduction

In considering potential biomarkers to improve outcomes for kidney diseases it is important to identify specific clinical goals of a biomarker, since no biomarker can serve all needs. We can define progression of kidney diseases as a condition where nephrons are progressively lost over time and replaced by polymerized cross-linked matrix proteins (scar), and where the combination of reduced nephron mass and scar accumulation causes progressive loss of kidney function. Biomarkers aimed at measuring these processes for the clinician can take several forms. Measures of kidney function are still widely used to monitor kidney diseases but are insensitive because the kidney has substantial reserve function so that before kidney function becomes measurably abnormal more than 50% of nephrons have to become nonfunctional. Therefore any screening strategy that relies on functional measurements will be insensitive and will tend to identify late stage disease. Similarly, hypertension and measures of kidney size and shape only become measurably abnormal in late stage kidney disease.

Abstract

Proteinuria and/or albuminuria are widely used for noninvasive assessment of kidney diseases. However, proteinuria is a nonspecific indicator of many forms of kidney injury, systemic disease, and physiologic alteration in glomerular filtration of proteins. This includes diabetic nephropathy and causes of proteinuria that progress to end-stage kidney disease (ESKD) and those that do not. Therefore proteinuria per se is not considered to be sufficiently precise an endpoint to serve either as a diagnostic tool for specific diseases of the kidney or as a surrogate for ESKD in clinical trials, although within a defined disease setting proteinuria is a powerful monitoring tool. Progression of glomerular diseases is the mechanism by which cumulative glomerular injury results in progressive loss of kidney structure and function eventually causing ESKD. Several lines of evidence strongly suggest that a major cause of glomerulosclerosis is podocyte depletion from glomeruli. Since podocytes are resident on the outer surface of the glomerular basement membrane, when they or their products detach they can be detected in urine. This potentially provides a noninvasive mechanism for monitoring podocyte well-being and raises the possibility that biomarkers of podocyte injury, stress, or loss could be used in combination with proteinuria to more reliably detect and monitor progression and response to treatment. Several potential urine podocyte biomarkers have been described including podocytes themselves and fragments of podocytes, podocyte proteins and mRNAs, and exosomes. Here we review recent urine podocyte biomarkers that could potentially complement proteinuria for monitoring the progression process in the clinic.

Keywords

urine biomarker, proteinuria, albuminuria, podocyturia, glomerular disease