American Journal of Kidney Diseases
Volume 55, Issue 5 , Pages 813-816, May 2010

Urinary Tubular Biomarkers of Kidney Damage: Potential Value in Clinical Practice

  • Femke Waanders, MD, PhD

      Affiliations

    • Corresponding Author InformationAddress correspondence to Femke Waanders, MD, PhD, University Medical Center Groningen, Kidney Center, PO Box 30.001, 9700 RB Groningen, The Netherlands
    • ,
  • Gerjan Navis, MD, PhD
    • ,
  • Harry van Goor, PhD

University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Article Outline

 

Related Article, p. 824

Chronic kidney disease (CKD) is a worldwide public health problem leading to a steadily increasing number of patients with end-stage renal disease.1 According to current guidelines, renoprotective intervention aims at decreasing blood pressure and proteinuria. Whereas proteinuria reduction is a main predictor for long-term outcome, this predictive value is far from perfect because even responders to antiproteinuric treatment may still show progressive loss of kidney function. This notion was recently emphasized by the results of ONTARGET (Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial), in which greater decreases in blood pressure and albuminuria using dual renin-angiotensin-aldosterone system (RAAS) blockade were associated with worse kidney outcomes.2 In line with this evidence, we reported pronounced progression of tubulointerstitial damage during RAAS blockade despite better proteinuria reduction in experimental proteinuria.3 Therefore, during therapy, proteinuria and tubulointerstitial damage may dissociate considerably. Importantly, in most kidney diseases, long-term outcome is determined by the severity of tubulointerstitial involvement.4, 5 Accordingly, the possibility to monitor tubulointerstitial damage might be crucial to allow further advances in renoprotective interventions. This would imply the possibility of monitoring the extent of tubulointerstitial damage before and during treatment,6 preferably using noninvasive methods that allow repeated measurements during follow-up without the need for a kidney biopsy. Urinary biomarkers meet these criteria.

What conditions should be fulfilled for urinary tubular biomarkers to be of value in clinical practice? First, it is important that urinary markers specifically and quantitatively reflect the presence of tubulointerstitial damage. Compartment specificity would be an advantage (Fig 1). Second, tubular markers should adequately predict progression of kidney disease. Third, to be of use for monitoring therapy response, tubular biomarkers should respond to therapeutic intervention, and their response should have prognostic impact. Finally, to identify new targets for therapy, biomarkers should reflect specific pathophysiologic processes, such as fibrosis and inflammation.

  • View full-size image.
  • Figure 1. 

    Urinary biomarkers of chronic kidney disease, categorized by nephron segment. Abbreviations: AGEs, advanced glycation end products; CTGF, connective tissue growth factor; G, glomerulus; KIM-1, kidney injury molecule 1; MCP-1, monocyte chemoattractant protein 1; NAG, N-acetyl-β-d-glucosaminidase; NGAL, neutrophil gelatinase-associated lipocalin; TGF-β, transforming growth factor β.

In this issue of the American Journal of Kidney Diseases, Kern et al7 evaluated the predictive value of albuminuria and tubular injury markers on the onset of micro- or macroalbuminuria in patients with type 1 diabetes mellitus participating in the Diabetes Control and Complication Trial (DCCT) in a nested case-control study. These investigators show that baseline urinary N-acetyl-β-d-glucosaminidase (NAG) and submicroalbuminuric levels of albuminuria, as well as an increase in NAG levels, are independently associated with the subsequent occurrence of both micro- and macroalbuminuria. The lack of data about the use of angiotensin-converting enzyme inhibition is a drawback to this study. Nevertheless, interesting inferences can be made from its results. The independent predictive value of urinary NAG excretion in particular suggests that tubular alterations might either be a first sign of diabetic kidney involvement or predispose to the development of diabetic nephropathy. This result further reinforces the rationale for better exploration of the potential of urinary biomarkers for tubulointerstitial damage.

Several urinary biomarkers have potential value in the management of CKD. For more than a decade, it has been known that greater urinary excretion of low-molecular-weight (“tubular”) proteins is associated with progression of CKD.8 More recently, it was shown that KIM-1 (kidney injury molecule 1) is expressed selectively by injured proximal tubular cells.9 KIM-1 expression is related to tubulointerstitial damage and correlates with the severity of kidney function impairment.10 Urinary KIM-1 levels are strongly related to tubular KIM-1 expression.10 In nondiabetic proteinuria, antiproteinuric treatment decreases urinary KIM-1 excretion irrespective of the mode of intervention and in proportion to proteinuria reduction, suggesting amelioration of tubular dysfunction.11 Of note, if proteinuria decreased to protein excretion <1 g/d in that same study, urinary KIM-1 levels did not normalize in 88% (14 of 16) of patients, suggesting ongoing tubular damage.11 Thus, the interpretation of the tubulointerstitial marker KIM-1 sharply contrasts with the interpretation of the glomerular marker proteinuria. It would be highly important to compare the prognostic impact of the two, as well as their combination, for long-term outcome. This could provide a basis for using urinary KIM-1 levels in clinical practice. Finally, to meet the criterion of reflecting pathophysiologic pathways, KIM-1 facilitates repair of tubular damage by its role in removing dying cells from injured tubules, suggesting that it also could guide the development of new targets for therapy.9, 12

Other markers may be of value as well. In one study, urinary neutrophil gelatinase-associated lipocalin (NGAL) excretion is associated with loss of kidney function in patients with CKD.13 NGAL has potential for monitoring therapy response because increased urinary NGAL levels decrease in response to successful treatment.14 Remarkably, high urinary excretion of the brush border lysosomal enzyme NAG predicts progression of CKD better than proteinuria in patients with membranous nephropathy.15 Urinary NAG levels also decrease with antiproteinuric treatment, albeit only when proteinuria is decreased considerably.11 Whether urinary NGAL and NAG levels specifically and quantitatively reflect the presence of tubulointerstitial damage is not established. Moreover, they are unlikely to have a role in the pathophysiologic process of tubular damage and/or repair. In contrast, several studies support a pathophysiologic role for advanced glycation end products (AGEs) in CKD.16 The AGE pentosidine accumulates in damaged proximal tubules in experimental nephrotic syndrome, which is ameliorated by antiproteinuric treatment.17 However, in the study by Kern et al,7 pentosidine and AGE fluorescence had no association with either micro- or macroalbuminuria after adjustment for NAG levels. Theoretically, they might be of value in the development of specific interventions aimed at decreasing AGE levels; however, to date, these strategies have been disappointing in clinical trials.18 Other urinary biomarkers reflect the pathophysiologic processes of inflammation and fibrosis. Monocyte chemoattractant protein 1 (MCP-1) has prognostic impact in diabetic nephropathy since urinary MCP-1 levels correlate with the rate of kidney function decline.19 Levels of urinary transforming growth factor β and connective tissue growth factor are increased in patients with diabetic nephropathy and ameliorated by RAAS blockade,20, 21 suggesting that they might be of additional value in the management of CKD. Recent findings highlight uromodulin (Tamm-Horsfall protein), a well-known biomarker, that is produced exclusively in the distal tubule (Fig 1), a region susceptible to ischemic damage. Increased excretion of uromodulin precedes the development of CKD.22 Moreover, lower uromodulin concentrations are associated with the protective allele C at a single-nucleotide polymorphism in the uromodulin region.22 Ongoing and future studies should establish its value as a biomarker of genetic and environmental triggers relevant to CKD.

Interestingly, tubular biomarker levels are increased not only in primary kidney parenchymal damage, but also in heart failure, in which urinary KIM-1, NGAL, and NAG levels are strongly increased independent of glomerular filtration rate.23 Remarkably, urinary NAG and KIM-1 levels predict the combined cardiovascular end point of death, heart failure, hospitalizations, and heart transplant.23 Thus, tubular dysfunction predicts cardiovascular prognosis, re-emphasizing the clinical potential of tubular biomarkers. The mechanism of tubular dysfunction in patients with heart failure without primary CKD is unknown, but might be related to impaired kidney perfusion and hypoxia-induced tubulointerstitial damage. Consistent with this idea, in (non-CKD) patients undergoing cardiac surgery, urinary KIM-1, NAG, and NGAL levels are increased well before an increase in serum creatinine level,24 suggesting that tubular biomarkers are sensitive to detect ischemia-induced kidney injury. Together with the data from Kern et al,7 this suggests that tubular alterations may identify patients at risk of further kidney damage.

For future use in clinical practice, “biomarker panels” to monitor intrarenal pathophysiologic processes and adequately predict therapy response and kidney outcome may be more fruitful than single markers. Combining KIM-1, NAG, and NGAL improved the sensitivity for early detection of postoperative kidney injury compared with either individual biomarker.24 Kern et al7 recommend combining albuminuria and urinary NAG for better prediction of diabetic nephropathy, but without providing data that support this recommendation. Long-term studies should validate specific biomarker panels in cohorts of patients with CKD across different diseases. Furthermore, it should be investigated whether glomerular (proteinuria), tubulointerstitial biomarkers and biomarkers of fibrosis/inflammation have independent prognostic impact and consequently could provide independent treatment targets. If so, it might be relevant to study whether targeting treatment on urinary biomarkers can improve outcome. Aggressive treatment aimed at proteinuria may occur only at the expense of tubulointerstitial ischemic damage, resulting in an unfavorable long-term kidney outcome.2, 3 A more balanced approach, also taking tubulointerstitial factors into account, might be a better option.

In conclusion, urinary tubular markers have potential value in the early diagnosis and management of kidney damage. Urinary excretion of tubular markers might show renal changes before they are identified using conventional measurements, such as changes in glomerular filtration rate or proteinuria. It will be exciting to study the prognostic impact of tubular biomarkers relative to proteinuria. Studies are warranted to evaluate whether targeting conventional treatment on urinary tubular markers leads to improved outcome in the next few years.

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Acknowledgements 

We thank Mieneke Rook and Gemma Mulder for contributions in graphical design.

Financial Disclosure: The authors declare that they have no relevant financial interests.

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References 

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PII: S0272-6386(10)00122-8

doi:10.1053/j.ajkd.2010.02.002

Refers to article:

  • Early Urinary Markers of Diabetic Kidney Disease: A Nested Case-Control Study From the Diabetes Control and Complications Trial (DCCT) , 08 February 2010

    Elizabeth F.O. Kern, Penny Erhard, Wanjie Sun, Saul Genuth, Miriam F. Weiss
    American Journal of Kidney Diseases May 2010 (Vol. 55, Issue 5, Pages 824-834)

American Journal of Kidney Diseases
Volume 55, Issue 5 , Pages 813-816, May 2010

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