For decades, estimation of GFR, i.e., eGFR and albuminuria, has served as the only clinical tool to assess kidney health. The value of eGFR and albuminuria in prognosticating CKD and risk stratification for cardiovascular disease (CVD) and mortality1 is undisputable, but the challenges in measuring and interpreting eGFR and its lack of sensitivity in diagnosing kidney injury are well known to clinicians. GFR is, for the most part, dependent on the renal blood flow and, of course, the integrity of glomeruli. Kidney function, however, encompasses more than GFR. The tubulointerstitial compartment has vital roles in clearance of certain molecules, reabsorption of fluid and electrolytes, and production of peptides and hormones. Currently, kidney biopsy is the only clinical tool to assess the extent of tubulointerstitial injury, because GFR correlates poorly with severity of nephrosclerosis.2 Therefore, identification of novel biomarkers of kidney health, such as markers of tubular dysfunction or injury measurable in urine or blood specimens, has the potential to revolutionize the approach to diagnosis and management of CKD.
In recent years, several investigators have reported encouraging results demonstrating associations between biomarkers of tubular function or injury and renal disease outcomes, and, in some cases, cardiovascular events and overall mortality.3 These studies investigated the utility of measuring urinary excretion of molecules secreted or reabsorbed by the proximal tubular (PT) epithelial cells, or secreted by the epithelial cells in the distal nephron, as markers of tubular health in prognosticating CKD and determining the risk for CVD and death. Such markers include organic acids that the PT cells mainly secrete into the lumen of the nephron, α1 microglobulin or β2 microglobulin that are filtered in the glomeruli and and reabsorbed by PT cells, and uromodulin that the epithelial cells in the loop of Henle secrete. Tubular dysfunction, at least theoretically, can be identified by demonstrating reduced organic acid secretion or increased excretion of α1 microglobulin, β2 microglobulin, or uromodulin (Figure 1). Previous studies demonstrated associations between interstitial fibrosis and tubular atrophy and functional markers of the distal nephron segments4 or proximal tubules.5
Figure 1.
Normal handling of markers of tubular function within the nephron. α1M, α1 microglobulin; β2M, β2 microglobulin; Alb., albumin; OAT, organic anion transporter; TAL, thick ascending limb of the loop of Henle.
In this issue of JASN, Ascher et al. report a strong association between a composite of markers of PT function and adverse events among participants with CKD (eGFR <60 ml/min per 1.73 m2) in the Systolic Blood Pressure Intervention Trial (SPRINT).
These important findings will help guide application of SPRINT findings in CKD patients.6 In a related study these authors examined the correlation between biomarkers of tubular function and CKD progression and mortality in the same population.7 The researchers demonstrate an association between lower average baseline secretion score of ten biomarkers of tubular function and faster decline in eGFR after adjustments for several risk factors, including eGFR and albuminuria. However, their data did not show any associations between the secretion scores of tubular function markers and CKD progression, CVD, and mortality after adjustments for other risk factors, specifically, baseline eGFR and albuminuria. Previous studies of the SPRINT cohort or the Chronic Renal Insufficiency Cohort (CRIC) study participants had also demonstrated associations between individual biomarkers of tubular function and outcomes of GFR decline, CKD progression, and, in some studies, CVD and mortality.8–11
Although the new findings are intriguing and may potentially change the approach to diagnosis and management of CKD, a few issues need to be addressed, and further research is needed to advance our understanding of the utility of tubular function markers. The published studies have taken a variety of approaches to assess tubular function, from studying markers of PT or distal nephron function individually, to looking at aggregate secretion scores for several markers, to a combination of markers of PT and distal nephron function. It is also worth considering that secretion of tubular function markers correlated only modestly with one another,11,12 which adds to the complexity of interpreting results. A question in the design on the future studies is whether it would be advantageous to include several markers of PT and distal nephron function, individually or in combination, or to limit the number of tubular markers to those with the strongest associations with clinical outcomes shown in previous studies. Additionally, because the current evidence is from individuals with GFR values <60 ml/min per 1.73 m2, studies are needed to investigate the generalizability of these results in individuals who are healthy or have less severe renal disease.
The findings of this and previous studies do not undermine the value of GFR estimation and albuminuria. Instead, they call for the design of future studies to determine the value of combining these measures with biomarkers of tubular function and possibly injury, inflammation, and repair in developing a better tool to assess kidney health and to prognosticate CKD.
Disclosures
None.
Funding
None.
Acknowledgments
The content of this article reflects the personal experience and views of the author and should not be considered medical advice or recommendations. The content does not reflect the views or opinions of the American Society of Nephrology (ASN) or JASN. Responsibility for the information and views expressed herein lies entirely with the author.
Footnotes
Published online ahead of print. Publication date available at www.jasn.org.
See related article, “Markers of Kidney Tubular Secretion and Risk of Adverse Events in SPRINT Participants with CKD,” on pages 1915–1926.
Author Contributions
K. Kalantari conceptualized the study, was responsible for data curation, wrote the original draft, and reviewed and edited the manuscript.
References
- 1.van der Velde M, Matsushita K, Coresh J, Astor BC, Woodward M, Levey A, et al. : Chronic Kidney Disease Prognosis Consortium: Lower estimated glomerular filtration rate and higher albuminuria are associated with all-cause and cardiovascular mortality. A collaborative meta-analysis of high-risk population cohorts. Kidney Int 79: 1341–1352, 2011 [DOI] [PubMed] [Google Scholar]
- 2.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 152: 561–567, 2010 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Ix JH, Shlipak MG: The promise of tubule biomarkers in kidney disease: A review. Am J Kidney Dis 78: 719–727, 2021 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Melchinger H, Calderon-Gutierrez F, Obeid W, Xu L, Shaw MM, Luciano RL, et al. : Urine uromodulin as a biomarker of kidney tubulointerstitial fibrosis. Clin J Am Soc Nephrol: CJN.04360422, 2022 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Garimella PS, Katz R, Waikar SS, Srivastava A, Schmidt I, Hoofnagle A, et al. : Kidney tubulointerstitial fibrosis and tubular secretion. Am J Kidney Dis 79: 709–716, 2022 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Bullen AL, Ascher SB, Scherzer R, Garimella PS, Katz R, Hallan SI, et al. : Markers of kidney tubular secretion and risk of adverse events in SPRINT participants with CKD. J Am Soc Nephrol 33: 1915–1926, 2022 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Ascher SB, Shlipak MG, Katz R, et al. : Estimated kidney tubular secretion and kidney, cardiovascular, and mortality outcomes in CKD: The systolic blood pressure intervention trial (SPRINT). Kidney Med, 2022 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Suchy-Dicey AM, Laha T, Hoofnagle A, Newitt R, Sirich TL, Meyer TW, et al. : Tubular secretion in CKD. J Am Soc Nephrol 27: 2148–2155, 2016 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Chen Y, Zelnick LR, Wang K, Katz R, Hoofnagle AN, Becker JO, et al. : CRIC Study Investigators: Association of tubular solute clearances with the glomerular filtration rate and complications of chronic kidney disease: The Chronic Renal Insufficiency Cohort study. Nephrol Dial Transplant 36: 1271–1281, 2020 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Jotwani V, Garimella PS, Katz R, Malhotra R, Bates J, Cheung AK, et al. : SPRINT Research Group: Tubular biomarkers and chronic kidney disease progression in SPRINT participants. Am J Nephrol 51: 797–805, 2020 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.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 40: 3486–3493, 2019 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Chen Y, Zelnick LR, Wang K, Hoofnagle AN, Becker JO, Hsu CY, et al. : CRIC Study Investigators: Kidney clearance of secretory solutes is associated with progression of CKD: The CRIC Study. J Am Soc Nephrol 31: 817–827, 2020 [DOI] [PMC free article] [PubMed] [Google Scholar]