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. Author manuscript; available in PMC: 2022 Nov 1.
Published in final edited form as: Am J Kidney Dis. 2021 May 27;78(5):719–727. doi: 10.1053/j.ajkd.2021.03.026

The Promise of Tubule Biomarkers in Kidney Disease: A Review

Joachim H Ix 1,2,3, Michael G Shlipak 4,5
PMCID: PMC8545710  NIHMSID: NIHMS1709020  PMID: 34051308

Abstract

For over 70 years, serum creatinine has remained the primary index for detection and monitoring of kidney disease. Tubulo-interstitial damage and fibrosis are highly prognostic for subsequent kidney failure in biopsy studies, yet this pathology is invisible to the clinician in the absence of a biopsy. Recent discovery of biomarkers that reflect distinct aspects of kidney tubule disease have led to investigations of whether these markers can provide additional information on risk of CKD progression and associated adverse clinical endpoints, above and beyond eGFR and albuminuria. These biomarkers can be loosely grouped into those that mark tubule cell injury (e.g. KIM-1, MCP-1), and those that mark tubule cell dysfunction (e.g. α1M, UMOD). These kidney tubule biomarkers provide new opportunities to monitor response to therapeutics used to treat CKD patients. In this review, we describe results from some unique contributions in this area, and discuss current challenges and requirements in the field to bring these markers to clinical practice. We advocate for a broader assessment of kidney health that moves beyond a focus on the glomerulus, and we highlight how such tools can improve diagnostic accuracy and earlier assessment of therapeutic efficacy or harm in CKD patients.

INTRODUCTION

For over 70 years, serum creatinine, and its derivative equations to estimate glomerular filtration rate (eGFR) have been the primary index of chronic kidney disease (CKD) prevalence and severity, despite its many limitations. In 2013, the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines committee recommended addition of the albumin to creatinine ratio (ACR) to CKD staging and prognostication, as ACR provided powerful and complementary information on CKD and cardiovascular disease (CVD) prognosis, independent of eGFR and other CKD risk factors.(1) Although both measures predominantly reflect the health of glomeruli, this evolution in CKD staging provided a critical transition in nephrology, as the international community embraced a broader assessment of kidney health that encompasses measures of both kidney function (eGFR) and injury (ACR).

The kidney has many biological functions carried out by tubule cells, and the vast majority of energy expenditure within the kidney is devoted to the processes of electrolyte transport, acid-base homeostasis, and endocrine functions in kidney tubules. Damage to the kidney is also not limited to the glomerulus; rather, on kidney biopsy, tubular atrophy and tubulointerstitial fibrosis are common findings in virtually all forms of CKD,(2–4) and their severity have consistently proven to be reliable features for prediction of progression to end stage kidney disease (ESKD).(2,5,6) These important components of kidney damage are not fully captured by either lower eGFR or greater ACR. For example, a study of over 1200 biopsies from healthy kidney donor candidates found that tubulointerstitial fibrosis was present in 28% overall, ranging from 3% in the 20–29 age group to 73% in those aged 70–79 years. However, the severity of tubular atrophy and fibrosis on biopsy had no association with iothalamate GFR accounting for age.(4) Therefore, despite its prognostic importance, tubular disease cannot be reliably detected by the standard clinical measures of glomerular health (eGFR and ACR) and is invisible to the clinician except in the rare instances when biopsies are obtained.

In the past decade, investigators began exploring individual biomarkers that could give insights to unique aspects of kidney tubule health. Similar to the clinically available biomarkers of glomerular health (eGFR and ACR), these newer biomarkers could be characterized into two broad groups reflecting aspects of tubule injury and tubule dysfunction. Evaluating individual biomarkers, investigators consistently observed signals with clinically important outcomes including CKD progression, CVD, and mortality that were evident even after accounting for eGFR, ACR, and traditional CKD risk factors. These studies initially evaluated one tubule marker at a time; more recently, however, we and others are exploring the paradigm that we need a global assessment of kidney health using multiple measures concurrently in order to maximize the diagnosis, treatment, and prevention of CKD (Figure 1). This might improve risk assessment for not only for kidney outcomes but also related end-points including CVD and heart failure. Moreover, we hypothesized that these markers could provide new tools to monitor CKD therapy. In this review, we summarize how these hypotheses have been advanced over the past decade, and the challenges faced by this area of research. Finally, we propose next steps that will be required to make these measurements available and useful to the practicing clinician.

Figure 1.

Figure 1.

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A comprehensive kidney health biomarker panel would capture not only glomerular function (eGFR) and injury (albuminuria), but also kidney tubule function and injury concurrently. An example list of biomarkers marking each category is provided.

Abbreviations: *α1M for alpha 1 microglobulin, UMOD for uromodulin, EGF for epidermal growth factor. Endogenous secretion markers reflects a panel of 13 biomarkers measured in paired blood and urine that mark the kidney tubule secretory capacity.(40)

† KIM-1 for kidney injury molecule 1, IL-18 for interleukin-18, NGAL for neutrophil gelatinase-associated lipocalin, MCP-1 for monocyte chemoattractant protein-1, and PIIINP for procollagen type 3 amino terminal pro-peptide.

MEASURES OF TUBULE INJURY AND DYSFUNCTION

Kidney tubule biomarkers can be generally classified as either reflecting the processes of direct tissue injury and repair in the tubulointerstitium, or as measuring unique functions that are performed by kidney tubule cells. While some require blood measurements, most can be measured in urine. Although the kidney damage biomarkers were initially pursued as early indicators of acute kidney injury (AKI) in hospitalized patients, it has been subsequently demonstrated that they can be measured reliably in the ambulatory setting. Collectively, this initial group of biomarkers quantify the severity of tubule cell injury (e.g. Kidney injury marker [KIM] 1) the capacity for the tubules to repair themselves from injury (e.g. epidermal growth factor [EGF]), and the extent of inflammation and fibrotic activity (e.g. monocyte chemoattractant protein [MCP] 1) within the tubulo-interstitial space. However, the exact pathological correspondence of each biomarker has not been fully elucidated. Unique biomarkers that are fit for purpose are also emerging; for example, evaluating unique cytokines to differentiate the inflammatory response in acute interstitial nephritis (AIN) vs. acute tubule necrosis (ATN).(7)

The functions of the kidney tubules are broad, as they are critical to homeostatic control. For example, serum sodium, potassium and calcium concentrations largely reflect aspects of the kidney tubules’ ability to regulate each of these electrolytes in response to unique hormonal control. Additional functions of the kidney tubules are not routinely measured clinically, but are measurable by research assays. These include assessment of the proximal tubules’ capacity to reabsorb filtered small molecular weight proteins (e.g. alpha-1 microglobulin [α1M]);(8) the capacity of the proximal tubule to secrete endogenous metabolites (e.g. Hippurate)(9) or exogenous compounds (e.g. furosemide);(10) the production of proteins required to maintain impermeability of water to distal tubule segments and to protect against infection (e.g. uromodulin);(11) and ammonium production as a marker of the kidney tubules’ ability to excrete acid.(12)

These tubule biomarkers should have direct relevance to prognosis for kidney specific endpoints, and also for CKD complications like CVD, heart failure, and mortality. Demonstrating such relationships is a critical first step to demonstrate these markers are truly reflective of they kidney’s health status, even if their intended ultimate clinical utility extends far beyond predicting prognosis. Thus, investigators have used epidemiological studies to learn inductively of their importance as risk factors for CKD adverse outcomes. The usual design for studying novel CKD prognostic biomarkers is to measure one or more in stored frozen specimens and to compare associations with longitudinal adverse outcomes. Promising biomarkers can then be tested for other potential uses, for example in facilitating selection of the most appropriate treatments, monitoring of effectiveness, monitoring for safety, and distinguishing causes of changes in eGFR (Figure 2).

Figure 2.

Figure 2.

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The figure provides examples of potential use cases for kidney tubule injury and dysfunction biomarkers in clinical practice. Examples in the literature of each are provided here for the purposes of prognosis,(20,27,37) treatment selection,(36) monitoring for treatment effectiveness,(41,42) monitoring for medication safety,(29,43) and distinguishing injury from hemodynamic causes of declining eGFR.(33–35)

TUBULE INJURY AND DYSFUNCTION MARKERS AND SUBSEQUENT RISK OF CKD ADVERSE OUTCOMES

Some of the initial investigations of kidney tubule biomarkers as risk factors for declining kidney function began in studies among persons living with human immunodeficiency virus (HIV) infection. For example, Jotwani and colleagues found strong and independent associations of both markers of proximal tubule dysfunction (higher urine α1M) and proximal tubule injury (higher urine KIM-1) markers with eGFR decline and incident CKD, independent of eGFR, ACR, and other CKD and HIV related risk factors (Figure 3). It is notable from this early study that the associations of these tubule function and injury markersappeared more strongly associated with loss of kidney function over time than urine ACR itself, even though their associations were adjusted for urine ACR. They also provided prognostic information about future loss of kidney function independently from one another. The investigators went on to demonstrated that α1M, KIM-1, and ACR were all independently associated with mortality risk in this HIV cohort.(13)

Figure 3.

Figure 3.

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The figure compares the highest to the lowest tertile of each biomarker, to provide an even reference for comparison. Models are adjusted for age, race, HTN, DM, HCV coinfection, smoking, LDL, triglycerides, BMI, HIV viral load, CD4 count, anti-retroviral use, and all biomarkers shown concurrently. Reproduced from Jotwani et al13 with permission of the American Society of Nephrology; original graphic © 2015 American Society of Nephrology.

As the HIV-infected participants, on average, had well preserved eGFR, subsequent investigations evaluated a contrasting cohort of stable kidney transplant recipients from the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) trial. Among four urine tubule markers evaluated, the investigators found strong associations for proximal tubule dysfunction and fibrosis biomarkers with risk of allograft failure, as captured by higher urine a1M (HR per two-fold higher: 1.76; 1.27 – 2.44) and MCP-1 (1.49; 1.17 – 1.89) concentrations, respectively. Once more, these associations were independent of eGFR, ACR, transplant and CKD related risk factors, and of one another.(14) Furthermore, Park and colleagues demonstrated that these tubule function and injury markers had independent associations with risk for CVD and mortality in FAVORIT, as in HIV.(15) These findings, confirmed across two different settings, suggested not only that assessing tubule health could inform prognosis above and beyond eGFR and ACR, but also that assessment of both tubule function and injury could provide distinct and potentially additive information on prognosis.

Additional studies have evaluated urine biomarkers in the high-risk ambulatory settings of diabetes and hypertension. For example, in the Action to Control Cardiovascular Disease Trial (ACCORD) trial, Nadkarni and colleagues conducted a case-control study with cases defined by a 40% reduction in eGFR over 5-years among adults with type 2 diabetes. The tubule inflammation and fibrosis marker MCP-1 was again strongly associated with reductions in eGFR (2.27 per two-fold higher; 1.44 – 3.58), yet the tubule injury biomarkers (IL-18 and KIM-1) were not associated with that outcome in this study.(16) However, these investigators subsequently explored kidney tubule injury (plasma KIM-1) measured in the blood rather than the urine, and found that higher levels were strongly associated with CKD progression; these findings suggested that plasma concentrations of biomarkers specific to the kidney tubules may have stronger associations than urine concentrations in some settings.(17)

In the SPRINT trial, which recruited participants with hypertension and high CVD risk, investigators identified participants with eGFR<60 ml/min/1.73m2 at baseline and measured a panel of eight urine biomarkers as risk factors for CKD progression. Jotwani and colleagues demonstrated that, among tubule function measures, higher urine uromodulin (UMOD) concentrations (a marker of distal kidney tubule synthetic function) were strongly associated with slower decline in eGFR; among the injury markers, higher levels of urine KIM-1, IL-18, and MCP-1 were each individually associated with elevated risk for CKD progression in adjusted analyses.(18,19) Additionally, Garimella and colleagues demonstrated that two measures of reduced tubule function, (higher α1M and lower UMOD) were strongly and independently associated with risk of CVD events in SPRINT; in fact, these two biomarkers improved CVD risk prediction above and beyond traditional CVD risk factors, eGFR, and ACR.(20)

An additional novel marker of tubule dysfunction is epidermal growth factor (EGF). EGF messenger RNA transcripts are selectively expressed in distal tubular epithelial cells, and higher levels are thought to reflect functional tubular mass and regeneration potential.(21) Kidney biopsy studies have correlated lower urine EGF concentrations with more severe tubule atrophy and interstitial fibrosis.(21) EGF is only minimally detectable in plasma, thus urine EGF excretion may be specific to kidney tubule damage and fibrosis.(21,22) Recent studies have demonstrated that lower urine EGF is associated with CKD progression in populations with CKD at baseline,(23) persons with diabetes,(24) and more recently in a general population cohort with preserved eGFR at baseline, on average.(25) However, unlike the other biomarkers, most studies evaluated urine EGF individually, so its performance and inter-relationship with other tubule function biomarkers are less well established, and warrant further research. Nonetheless, the strong signals observed with urine EGF independent of baseline eGFR, albuminuria, and other risk factors make it a promising new addition among markers characterizing tubule cell dysfunction.

Some kidney tubule health biomarkers are detectable in the bloodstream, and as summarized previously, preliminary findings suggested that blood levels may be more informative than urine levels for some markers, perhaps because of greater precision, regulation, or less influence from changes in urine tonicity. Recent studies extended this work, evaluating blood levels of soluble urokinase-type plasminogen activator receptor (suPAR), tumor necrosis factor receptor (TNFR) 1, TNFR2, and KIM-1. Plasma suPAR was found to have strong associations with incident CKD in a community-based cohort of persons undergoing cardiac catheterization.(26) In two trials of persons with diabetes, higher plasma TNFR1, TNFR2, and KIM-1 were each associated with risks for progressive loss of kidney function with effect sizes of approximately two-fold risk per two-fold higher biomarker concentration.(17) These findings were confirmed for TNFR1 and TNFR2 with similarly strong findings among persons with diabetes and CKD in the CRIC cohort. Finally, among children with CKD in the CKiD cohort, these same plasma biomarkers were prognostic for CKD progression, with the strongest associations observed for plasma TNFR1 and plasma KIM-1.(27) These findings are exciting for their utility to predict prognosis. However, because these circulating proteins have strong correlations to eGFR, it can be more challenging to distinguish their pathological connection to kidney tubule damage independent from their linkage to the underlying true GFR. This important area requires additional research to determine what unique insights these blood biomarkers provide to tubule health and their clinical utility.

TUBULE DYSFUNCTION, RISK OFACUTE KIDNEY INJURY, AND DIFFERENTIATION OF ACUTE KIDNEY INJURY ETIOLOGY

In addition to CKD progression, kidney tubule function biomarkers have been associated with risk for future AKI events in the SPRINT trial. Interrogating why some individuals develop AKI in response to hemodynamic stressors whereas others do not, Bullen and colleagues hypothesized that worse kidney tubule function may identify kidneys more susceptible to injury that might be missed by assessment of eGFR and ACR alone. The team hypothesized that tubule dysfunction may manifest as AKI events when the kidneys are stressed by hypotension or other insults. Among SPRINT participants with eGFR<60 at their baseline ambulatory visit, the investigators demonstrated that worse proximal tubule reabsorptive function (higher urine α1M) and reduced tubule synthetic function (lower urine UMOD) had mutually independent associations with future development of AKI during the trial. Interestingly, in contrast to these markers of tubule function, the ambulatory measures of kidney tubule injury did not have associations with risks for future AKI.(28) These injury markers were elevated only after the AKI episodes, as was expected.

Investigators are also harnessing the unique pathologies evident in different etiologies of CKD and AKI. For example, Moledina and colleagues recently evaluated inflammatory markers in the urine among persons admitted with AKI who underwent kidney biopsies for diagnosis of the etiology. Harnessing the unique inflammatory infiltrate of patients with AIN, they demonstrated that patients with biopsy confirmed AIN had higher urine concentrations interleukin-9 (IL-9) and tumor necrosis factor α (TNFα) compared with patients who had acute tubule necrosis, glomerular etiologies, or diabetic nephropathy on biopsy. Higher urine concentrations of these two biomarkers also improved the ability to distinguishing AIN from acute tubular necrosis. Moreover, among the subset with AIN, higher urine IL-9 was associated with greater interstitial infiltration at the time of kidney biopsy.(7)

In summary, markers of tubule injury and dysfunction demonstrate the potential of these groups of biomarkers to improve characterization and prognostication for persons at risk for, or with established CKD. Plasma biomarkers have augmented the strength of these associations, but perhaps with less specificity for representing intrinsic kidney damage. Consistently, across biomarkers and across different settings, markers of kidney tubule function and injury have provided additional relevant and prognostic information on risk of CKD and related outcomes above and beyond eGFR, ACR, and clinical risk factors, as we predicted based on prior biopsy studies. These findings confirm that these biomarkers provide novel information about kidney health not captured by eGFR and ACR, which is a critical first step. Yet, their ultimately clinical utility will likely be much broader than prognostication for kidney failure (Figure 2).

TUBULE INJURY AND DYSFUNCTION BIOMARKERS FOR MONITORING THERAPEUTIC RESPONSES

The biomarkers reflecting tubule injury and dysfunction have provided new opportunities for monitoring drug therapy in CKD patients. Once more, work in this area began with research in the setting of HIV. Tenofovir disoproxil fumarate (TDF) is a widely prescribed, highly effective anti-retroviral medication, but is known to cause both AKI and more rapid CKD progression. TDF induces mitochondrial dysfunction in proximal tubule cells, and can cause Fanconi syndrome, which is manifest by the proximal tubule’s failure to reabsorb nutrients and small proteins. Zhang and colleagues hypothesized that TDF may impair proximal tubule reabsorptive capacity, which would be marked by higher urine concentrations of α1M and similar proteins in the urine. They identified 198 HIV-infected individuals who had urine specimens obtained both before they initiated TDF and 1-year after, and measured a panel of tubule health biomarkers at both timepoints.(29) Among this panel, two biomarkers that represent proximal tubule reabsorptive function were the most dramatically elevated after initiation of TDF; concentrations of trefoil factor 3 increased by 78% and α1M increased by 32%, and these elevations were associated with subsequent declining eGFR.(30) Results were similar in men using TDF as part of HIV pre-exposure prophylaxis, among whom urine α1Mconcentrations increased by 21% after 6 months among TDF users.(31)

In the SPRINT trial, hypertensive participants with high risk of CVD were randomized to intensive systolic blood pressure (SBP) lowering (target < 120mmHg) vs. a standard SBP target (< 140mmHg). The trial showed that intensive SBP lowering resulted in reductions in a composite CVD endpoint and mortality, but also resulted in more rapid loss of eGFR.(32) This has led to concern that intensive SBP lowering may increase long-term kidney risk. An alternative hypothesis is that this acute reduction in eGFR may reflect hemodynamic changes rather than intrinsic injury to the kidney. Investigators recently developed kidney tubule biomarkers to gain insights into the kidney’s response to intensive SBP lowering. Among a subset of 978 SPRINT trial participants with eGFR < 60 ml/min/1.73m2, Malhotra and colleagues measured a panel of 8 biomarkers of kidney tubule injury and dysfunction at baseline and after 1 year. Some of these markers (urine ACR, β2 microglobulin [β2M] and α1M) are filtered at the glomerulus, while others are produced within the kidney tissue in response to injury, inflammation, or repair (urine NGAL, KIM-1, IL-18, MCP-1, and YKL-40). Despite the acute decline in eGFR, the investigators found that none of these measures showed significant increases in the intensive vs. the standard arm; therefore, intensive SBP lowering did not appear to cause intrinsic tubule cell injury despite the eGFR decline (Figure 4). Among the panel, the 3 biomarkers that are filtered at the glomerulus (urine albumin, β2M, and α1M) were all significantly decreased in response to intensive SBP lowering (Figure 4; red box), whereas none of the biomarkers that are produced within the kidney tissue were significantly different between study arms (Figure 4; blue box).(33) These findings support the hypothesis that the acute reduction in eGFR in response to intensive SBP lowering is due to hemodynamic changes rather than intrinsic kidney injury in most patients. In a separate analysis of SPRINT participants who developed incident CKD during intensive SBP lowering, investigators similarly found no evidence of intrinsic kidney injury.(34) Finally, a parallel analysis in the ACCORD trial of participants with diabetes, Nadkarni and colleagues demonstrated that intensive SBP lowering also acutely lowered eGFR without raising any of the biomarkers that would indicate intrinsic kidney tubule cell injury.(35)

Figure 4.

Figure 4.

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Figure depicts changes in biomarkers over 1 year in the intensive vs. the standard arm among 978 SPRINT participants with CKD at baseline. Biomarkers that are small molecules that are filtered at the glomerulus were all decreased in the intensive vs. the standard arm (red box). In contrast, biomarkers that are produced within kidney tissue and found in higher concentrations in the urine in response to kidney tubule injury, repair, or inflammation were all similar in the intensive vs. the standard arm (blue box). Collectively, the data suggest that changes in eGFR in response to intensive SBP lowering are predominantly driven by hemodynamic changes. Adapted from Malhotra et al33.

Other investigators are making important parallel discoveries utilizing kidney tubule biomarkers for therapeutic monitoring. Above, we described the recent discovery of the diagnostic utility of urine IL-9 and TNF-α concentrations in patients with biopsy verified AIN vs. other causes of AKI. The authors also reported that higher urine IL-9 was associated with greater interstitial infiltration as the time of biopsy among the subset with AIN. Recently these authors reported that higher baseline IL-9 concentrations at the time of biopsy were associated with a greater response to treatment with corticosteroids. Among the AIN patients who received corticosteroids, there were larger improvements in eGFR over 6 months follow-up in the subgroup of patients with higher urine IL-9 levels at baseline, whereas the subgroup with lower IL-9 levels had less interstitial infiltration and did not have improvements in eGFR with corticosteroid treatment over the subsequent 6 months.(36)

In summary, the etiologies for reductions in eGFR are heterogeneous, and clinicians do not currently have tools to differentiate their causes in clinical practice. Given their concerns for intrinsic kidney injury, clinicians often feel compelled to interrupt beneficial medications, such as anti-hypertensive or anti-retroviral medications, and then rely upon observation time to determine whether the kidney “recovers” based upon the eGFR response. In the case of AIN, many patients require kidney biopsy for definitive diagnosis, which is invasive, expensive, and carries risks of bleeding. By leveraging the unique pathological signatures provided by individual tubule injury and dysfunction biomarkers, emerging evidence suggests that a panel of kidney tubule measures can aid in the non-invasive diagnosis of the etiology of eGFR decline. Even when kidney biopsies are obtained, they are rarely done repeatedly. Thus, observing changes in biomarkers longitudinally may ultimately provide useful tools to monitor changes in kidney health non-invasively in response to drug therapy, as has now been demonstrated using strored urine specimens in the examples of TDF treatment in HIV, intensive SBP lowering, and with corticosteroid treatment for AIN.

CURRENT CHALLENGES AND DEVELOPMENTAL NEEDS REQUIRED TO MOVE KIDNEY TUBULE INJURY AND DYSFUNCTION BIOMARKERS TO THE BEDSIDE

Although these associations of kidney tubule biomarkers with CKD onset and progression have launched a new paradigm for research, the magnitude of the findings have not consistently been strong enough to distinguish categories of risk for future outcomes. One approach to overcome the limits of individual markers will be to combine them into panels that collectively improve prediction. Indeed, several recent studies have found improvements in the area under the receiver operator curve (AUC) on the order of 0.02–0.07 for both CKD progression and CVD endpoints when evaluating biomarker combinations.(17,37,38) Moving forward, a given population of patients, the biomarker panel could be selected to include those that indicate both kidney tubule dysfunction and injury while also providing the strongest signals for CKD progression and CVD prognosis. Once a set of relevant biomarkers has been finalized, groups of measurements that have overlapping physiology may be combined using data reduction strategies.(38) This review has described data wherein kidney tubule biomarkers have shown promise for therapeutic monitoring in HIV, hypertension, and AIN, yet there are many other exciting opportunities to utilize these markers for similar purposes in other common clinical settings. Additional research is needed to determine the utility of the biomarkers in each of these use cases, and to confirm that changes in biomarkers correlate to contemporaneous changes in kidney pathology.

For clinical application, commercial entities will need to develop precise, high throughput assays that could be performed in many clinical laboratories affiliated with both ambulatory practices and hospitals. It will be essential that novel testing strategies are not only widely available to clinicians, but also reproducible across diverse settings. Finally, if a panel of markers is to be utilized, it will be important that strategies are developed to integrate the information and guide the clinician to utilize the information in an unbiased way that will best guide clinical decision making.

SUMMARY

The limitations of serum creatinine as the cornerstone of clinical diagnosis and monitoring of kidney disease have been widely described. Beyond the consequences of its influence by muscle mass, diet, and tubule secretion, serum creatinine changes cannot differentiate between benign hemodynamic changes versus intrinsic kidney injury. Whereas oncology, cardiology, and other fields in medicine have transformed clinical care by embracing biomarkers that provide new pathological insights, nephrology has been slow to adopt and integrate new markers. Within nephrology, each new biomarker is typically held to the standard of whether it, as an individual marker, can improve clinical decision making and quantify prognosis for ESKD.(39) However, single biomarkers rarely are able to achieve that standard of risk discrimination or diagnostic utility, and estimating prognosis is one of many challenges facing the nephrologist in clinical practice. Arguably, refining diagnosis, and monitoring response to therapy are more commonly needed and utilizable in the clinic.

Collectively, biomarkers of kidney tubule injury and dysfunction hold considerable promise, and provide an opportunity to characterize the health of the kidney more fully. Consider the analogy to a liver function panel. Using 6 different biomarkers (aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, alkaline phosphatase, serum albumin, and the prothrombin time) the clinician can quickly review the blood concentrations both in absolute terms, and in relation to the other 5 markers, and infer the likely cause and severity of liver injury. For example, a patient with hypotension and the combination of marked elevations in AST and ALT but relatively preserved total bilirubin and prothrombin time will lead the clinician to deduce that the patient has likely experienced ischemic liver injury. The combination of elevated total bilirubin and alkaline phosphatase with relatively lower concentrations of the other liver biomarkers in a patient may lead the clinician to obtain imaging to evaluate for etiologies of obstructive jaundice or infiltrative liver disease. Finally, a patient with elevated prothrombin time and low serum albumin may have synthetic dysfunction from chronic cirrhosis. It is inconceivable that clinicians would be willing to diagnose liver diseases while relying solely on the serum albumin concentration, even though costs may be lower and albumin might predict liver failure better than the other markers if compared head to head. The appropriate clinical question is not whether albumin predicts liver-related death independently of the AST concentration; rather the relative pattern of liver function tests allows the clinician to move quickly toward definitive diagnostic tests for the benefit of the patient.

Nephrology clinical practice should be no different, and is now within reach. Clinicians should demand improvements in diagnostic tests to capture the complexity of kidney diseases. 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. Wider testing will provide new insights to patterns of diseases, which will facilitate our diagnostic evaluations, and will, in all likelihood, improve patient care. For these reasons, our curiosity and our desire to characterize the breath of kidney disease should be adequate justification to introduce novel biomarkers into CKD care, as it is in other fields of medicine. Although additional research and refinements are needed, kidney tubule biomarkers will be essential to provide a global kidney health panel that can improve diagnosis and management for patients at risk or suffering from kidney diseases.

Support:

Drs. Ix and Shlipak’s work in kidney tubule biomarkers is supported through grants (R01 DK098234) and contracts (U01 DK102730) from the National Institutes of Diabetes and Digestive and Kidney Diseases. Dr. Shlipak was additionally supported by R01 AG034853 from the National Institutes on Aging.

Financial Disclosure:

Dr. Ix is principal investigator of an investigator initiated research grant from Baxter International, serves as a data safety monitoring board member for Sanifit International, and has served on advisory boards for Alpha Young, AstraZeneca, Ardelyx Inc., and Jnana Inc. Dr. Shlipak has served as a consultant for Cricket Health and Intercept Pharmaceuticals.

Footnotes

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References

  • 1.Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013. January;3(1):1–150. [Google Scholar]
  • 2.Nath KA. Tubulointerstitial changes as a major determinant in the progression of renal damage. Am J Kidney Dis Off J Natl Kidney Found. 1992. July;20(1):1–17. [DOI] [PubMed] [Google Scholar]
  • 3.Ong AC, Fine LG. Loss of glomerular function and tubulointerstitial fibrosis: cause or effect? Kidney Int. 1994. February;45(2):345–51. [DOI] [PubMed] [Google Scholar]
  • 4.Rule AD, Amer H, Cornell LD, Taler SJ, Cosio FG, Kremers WK, et al. The association between age and nephrosclerosis on renal biopsy among healthy adults. Ann Intern Med. 2010. May 4;152(9):561–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Howie AJ, Ferreira MA, Adu D. Prognostic value of simple measurement of chronic damage in renal biopsy specimens. Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc - Eur Ren Assoc. 2001. June;16(6):1163–9. [DOI] [PubMed] [Google Scholar]
  • 6.Takebayashi S, Kiyoshi Y, Hisano S, Uesugi N, Sasatomi Y, Meng J, et al. Benign nephrosclerosis: incidence, morphology and prognosis. Clin Nephrol. 2001. May;55(5):349–56. [PubMed] [Google Scholar]
  • 7.Moledina DG, Wilson FP, Pober JS, Perazella MA, Singh N, Luciano RL, et al. Urine TNF-α and IL-9 for clinical diagnosis of acute interstitial nephritis. JCI Insight. 2019. May 16;4(10). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Jotwani V, Scherzer R, Estrella MM, Jacobson LP, Witt MD, Palella FJ, et al. HIV Infection, Tenofovir, and Urine α1-Microglobulin: A Cross-sectional Analysis in the Multicenter AIDS Cohort Study. Am J Kidney Dis Off J Natl Kidney Found. 2016. October;68(4):571–81. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Sirich TL, Aronov PA, Plummer NS, Hostetter TH, Meyer TW. Numerous protein-bound solutes are cleared by the kidney with high efficiency. Kidney Int. 2013. September;84(3):585–90. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Rivero J, Rodríguez F, Soto V, Macedo E, Chawla LS, Mehta RL, et al. Furosemide stress test and interstitial fibrosis in kidney biopsies in chronic kidney disease. BMC Nephrol. 2020. March 6;21(1):87. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Garimella PS, Bartz TM, Ix JH, Chonchol M, Shlipak MG, Devarajan P, et al. Urinary Uromodulin and Risk of Urinary Tract Infections: The Cardiovascular Health Study. Am J Kidney Dis Off J Natl Kidney Found. 2016. October 28; [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Raphael KL, Isakova T, Ix JH, Raj DS, Wolf M, Fried LF, et al. A Randomized Trial Comparing the Safety, Adherence, and Pharmacodynamics Profiles of Two Doses of Sodium Bicarbonate in CKD: the BASE Pilot Trial. J Am Soc Nephrol JASN. 2020. January;31(1):161–74. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Jotwani V, Scherzer R, Abraham A, Estrella MM, Bennett M, Cohen MH, et al. Association of urine α1-microglobulin with kidney function decline and mortality in HIV-infected women. Clin J Am Soc Nephrol CJASN. 2015. January 7;10(1):63–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Ix JH, Katz R, Bansal N, Foster M, Weiner DE, Tracy R, et al. Urine Fibrosis Markers and Risk of Allograft Failure in Kidney Transplant Recipients: A Case-Cohort Ancillary Study of the FAVORIT Trial. Am J Kidney Dis Off J Natl Kidney Found. 2016. December 23; [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Park M, Katz R, Shlipak MG, Weiner D, Tracy R, Jotwani V, et al. Urinary Markers of Fibrosis and Risk of Cardiovascular Events and Death in Kidney Transplant Recipients: The FAVORIT Trial. Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg. 2017. October;17(10):2640–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Nadkarni GN, Rao V, Ismail-Beigi F, Fonseca VA, Shah SV, Simonson MS, et al. Association of Urinary Biomarkers of Inflammation, Injury, and Fibrosis with Renal Function Decline: The ACCORD Trial. Clin J Am Soc Nephrol CJASN. 2016. August 8;11(8):1343–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Coca SG, Nadkarni GN, Huang Y, Moledina DG, Rao V, Zhang J, et al. Plasma Biomarkers and Kidney Function Decline in Early and Established Diabetic Kidney Disease. J Am Soc Nephrol JASN. 2017. September;28(9):2786–93. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Jotwani V, Garimella PS, Katz R, Malhotra R, Bates J, Cheung AK, et al. Tubular Biomarkers and Chronic Kidney Disease Progression in SPRINT Participants. Am J Nephrol. 2020;51(10):797–805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Malhotra R, Katz R, Jotwani V, Ambrosius WT, Raphael KL, Haley W, et al. Urine Markers of Kidney Tubule Cell Injury and Kidney Function Decline in SPRINT Trial Participants with CKD. Clin J Am Soc Nephrol CJASN. 2020. March 6;15(3):349–58. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Garimella PS, Lee AK, Ambrosius WT, Bhatt U, Cheung AK, Chonchol M, et al. Markers of kidney tubule function and risk of cardiovascular disease events and mortality in the SPRINT trial. Eur Heart J. 2019. November 1;40(42):3486–93. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Ju W, Nair V, Smith S, Zhu L, Shedden K, Song PXK, et al. Tissue transcriptome-driven identification of epidermal growth factor as a chronic kidney disease biomarker. Sci Transl Med. 2015. December 2;7(316):316ra193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Gesualdo L, Di Paolo S, Calabró A, Milani S, Maiorano E, Ranieri E, et al. Expression of epidermal growth factor and its receptor in normal and diseased human kidney: an immunohistochemical and in situ hybridization study. Kidney Int. 1996. March;49(3):656–65. [DOI] [PubMed] [Google Scholar]
  • 23.Torres DD, Rossini M, Manno C, Mattace-Raso F, D’Altri C, Ranieri E, et al. The ratio of epidermal growth factor to monocyte chemotactic peptide-1 in the urine predicts renal prognosis in IgA nephropathy. Kidney Int. 2008. February;73(3):327–33. [DOI] [PubMed] [Google Scholar]
  • 24.Wu L, Li X-Q, Chang D-Y, Zhang H, Li J-J, Wu S-L, et al. Associations of urinary epidermal growth factor and monocyte chemotactic protein-1 with kidney involvement in patients with diabetic kidney disease. Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc - Eur Ren Assoc. 2020. February 1;35(2):291–7. [DOI] [PubMed] [Google Scholar]
  • 25.Norvik JV, Harskamp LR, Nair V, Shedden K, Solbu MD, Eriksen BO, et al. Urinary excretion of epidermal growth factor and rapid loss of kidney function. Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc - Eur Ren Assoc. 2020. October 17; [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Hayek SS, Leaf DE, Samman Tahhan A, Raad M, Sharma S, Waikar SS, et al. Soluble Urokinase Receptor and Acute Kidney Injury. N Engl J Med. 2020. January 30;382(5):416–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Schrauben SJ, Shou H, Zhang X, Anderson AH, Bonventre JV, Chen J, et al. Association of Multiple Plasma Biomarker Concentrations with Progression of Prevalent Diabetic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study. J Am Soc Nephrol JASN. 2021. January;32(1):115–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Bullen AL, Katz R, Lee AK, Anderson CAM, Cheung AK, Garimella PS, et al. The SPRINT trial suggests that markers of tubule cell function in the urine associate with risk of subsequent acute kidney injury while injury markers elevate after the injury. Kidney Int. 2019. August;96(2):470–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Zhang WR, Scherzer R, Estrella MM, Ascher SB, Muiru A, Jotwani V, et al. Tenofovir disoproxil fumarate initiation and changes in urinary biomarker concentrations among HIV-infected men and women. AIDS Lond Engl. 2019. March 15;33(4):723–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Ascher SB, Scherzer R, Estrella MM, Zhang WR, Muiru AN, Jotwani V, et al. Association of Urinary Biomarkers of Kidney Injury with Estimated GFR Decline in HIV-Infected Individuals following Tenofovir Disoproxil Fumarate Initiation. Clin J Am Soc Nephrol CJASN. 2018. September 7;13(9):1321–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Jotwani V, Scherzer R, Glidden DV, Mehrotra M, Defechereux P, Liu A, et al. Pre-exposure Prophylaxis With Tenofovir Disoproxil Fumarate/Emtricitabine and Kidney Tubular Dysfunction in HIV-Uninfected Individuals. J Acquir Immune Defic Syndr 1999. 2018. June 1;78(2):169–74. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Cheung AK, Rahman M, Reboussin DM, Craven TE, Greene T, Kimmel PL, et al. Effects of Intensive BP Control in CKD. J Am Soc Nephrol JASN. 2017. September;28(9):2812–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Malhotra R, Craven T, Ambrosius WT, Killeen AA, Haley WE, Cheung AK, et al. Effects of Intensive Blood Pressure Lowering on Kidney Tubule Injury in CKD: A Longitudinal Subgroup Analysis in SPRINT. Am J Kidney Dis Off J Natl Kidney Found. 2019. January;73(1):21–30. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Zhang WR, Craven TE, Malhotra R, Cheung AK, Chonchol M, Drawz P, et al. Kidney Damage Biomarkers and Incident Chronic Kidney Disease During Blood Pressure Reduction: A Case-Control Study. Ann Intern Med. 2018. November 6;169(9):610–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Nadkarni GN, Chauhan K, Rao V, Ix JH, Shlipak MG, Parikh CR, et al. Effect of Intensive Blood Pressure Lowering on Kidney Tubule Injury: Findings From the ACCORD Trial Study Participants. Am J Kidney Dis Off J Natl Kidney Found. 2019. January;73(1):31–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Moledina DG, Wilson FP, Kukova L, Obeid W, Luciano R, Kuperman M, et al. Urine interleukin-9 and tumor necrosis factor-α for prognosis of human acute interstitial nephritis. Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc - Eur Ren Assoc. 2020. October 28; [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Greenberg JH, Abraham AG, Xu Y, Schelling JR, Feldman HI, Sabbisetti VS, et al. Plasma Biomarkers of Tubular Injury and Inflammation Are Associated with CKD Progression in Children. J Am Soc Nephrol JASN. 2020. May;31(5):1067–77. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Lee AK, Katz R, Jotwani V, Garimella PS, Ambrosius WT, Cheung AK, et al. Distinct Dimensions of Kidney Health and Risk of Cardiovascular Disease, Heart Failure, and Mortality. Hypertens Dallas Tex 1979. 2019;74(4):872–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Hsu C-Y, Xie D, Waikar SS, Bonventre JV, Zhang X, Sabbisetti V, et al. Urine biomarkers of tubular injury do not improve on the clinical model predicting chronic kidney disease progression. Kidney Int. 2017. January;91(1):196–203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Chen Y, Zelnick LR, Wang K, Hoofnagle AN, Becker JO, Hsu C-Y, et al. Kidney Clearance of Secretory Solutes Is Associated with Progression of CKD: The CRIC Study. J Am Soc Nephrol JASN. 2020. April;31(4):817–27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Heerspink HJL, Greene T, Tighiouart H, Gansevoort RT, Coresh J, Simon AL, et al. Change in albuminuria as a surrogate endpoint for progression of kidney disease: a meta-analysis of treatment effects in randomised clinical trials. Lancet Diabetes Endocrinol. 2019. February;7(2):128–39. [DOI] [PubMed] [Google Scholar]
  • 42.Jardine M, Zhou Z, Lambers Heerspink HJ, Hockham C, Li Q, Agarwal R, et al. Kidney, Cardiovascular, and Safety Outcomes of Canagliflozin according to Baseline Albuminuria: A CREDENCE Secondary Analysis. Clin J Am Soc Nephrol CJASN. 2021. February 22; [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Ascher SB, Scherzer R, Estrella MM, Shigenaga J, Spaulding KA, Glidden DV, et al. HIV preexposure prophylaxis with tenofovir disoproxil fumarate/emtricitabine and changes in kidney function and tubular health. AIDS Lond Engl. 2020. April 1;34(5):699–706. [DOI] [PMC free article] [PubMed] [Google Scholar]

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