Tubule or Not Tubule?

It is widely accepted that estimated glomerular filtration rate (eGFR) and urine albumin creatinine ratio have been used as measures in chronic kidney disease (CKD) staging and prognosis. These measures reflect the health of the glomerulus by measuring kidney function and injury, respectively. However, damage involving the glomerulus is not the only predictor of kidney failure and in fact can sometimes be unreliable.

Recognizing some of the major limitations of using serum creatinine for diagnosis and monitoring of kidney disease (eg, muscle mass, tubular secretion, etc), differentiating benign hemodynamic change from intrinsic kidney injury becomes particularly imprecise. Determining the etiology of the decline in eGFR poses another challenge. Tubulointerstitial damage and fibrosis are known and well-validated prognosticators of kidney failure, but are typically only demonstrated by performing a kidney biopsy. Although a kidney biopsy may provide a definitive diagnosis, there are inherent limitations to performing it (ie, cost, invasive nature, attendant risks and complications, etc).

The identification of unique serum and urine biomarkers has been the subject of interest for many decades. Beyond bench research, there is the potential for utilizing these biomarkers in the clinical setting, particularly in the diagnosis and prognostication of various chronic diseases, and eventually for impacting clinical decision making and potential future treatment targets.

In general, kidney tubule biomarkers can be divided into 2 categories.  The first are biomarkers that reflect direct tissue injury and repair.  Examples include KIM-1 (Kidney Injury Marker – 1), EGF (Epidermal Growth Factor), and MCP-1 (Monocyte Chemoattractant – 1). Other biomarkers measure unique functions that are performed by the tubular cells, and include α1-microglobulin (A1M), hippurate, and uromodulin.  A recently published AJKD article from Ix and Shlipak reviews these biomarkers, their current use, and their potential future impact.

A study from Malhotra et al that highlights the utility of these tubule biomarkers looked at a subset of 978 participants in the SPRINT cohort, with an eGFR < 60 mL/min/1.73 m2. They authors examined a panel of 8 biomarkers at baseline and after 1 year. An analysis of their results showed that none of the biomarkers significantly increased in both arms (intensive systolic blood pressure [SBP] lowering and standard SBP lowering), thereby leading them to conclude that the acute decline in eGFR that was noted in the intensive SBP lowering group was associated with “hemodynamic alterations” as opposed to intrinsic kidney injury in most of the subjects.  Similar findings were noted in an analysis of participants in the ACCORD study.

Figure 4 from Ix and Shlipak, This is a US Government Work. There are no restrictions on its use.

While there is data on individual biomarkers, it is difficult to achieve diagnostic utility and prognosis estimation with a single test alone. The authors propose that a panel of select biomarkers could be potentially useful in guiding clinical decision making and prognostication. Other disciplines including cardiology and oncology have adopted biomarkers as an aid in clinical decision making. These markers would be analogous to a liver function panel in distinguishing different etiologies of liver disease.  However, to make this applicable in clinical settings, reliable assays would need to be developed by commercial entities. Education should be provided for providers on proper utilization and interpretation of these results. Once enough data is gathered, future studies can investigate cost benefit analysis of using these biomarkers in conjunction with current standard of care. We can imagine a world where a kidney health panel would be created to improve patient care in the setting of kidney disease.

From the clinical practice standpoint, while these biomarkers seem to offer us a glimpse into the holy grail of fully understanding the AKI-to-CKD continuum, they are not yet ready for primetime. At this time, they are primarily being utilized in basic and clinical research.  As the authors nicely put it, “Curiosity is the hallmark of the diagnostician, and the limitations of current diagnostic testing in nephrology derail our quests for the satisfaction to truly understanding the pathophysiology of our patients’ diseases.”

– Post prepared by Norhan Elsayed, PGY-2 at Franciscan Health in Olympia Fields (AJKDBlog Guest Contributor) and Edgar V. Lerma @edgarvlermamd, AJKD Social Media Advisory Board member. 


To view Ix and Shlipak [FREE] please visit AJKD.org.

Title: The Promise of Tubule Biomarkers in Kidney Disease: A Review
Authors: Joachim H. Ix and Michael G. Shlipak
DOI: 10.1053/j.ajkd.2021.03.026


Review articles cover clinical, translational, or basic science topics of interest to practitioners. Reviews published in the last two years are freely available.


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