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. 2023 Sep 1;4(9):e1257-e1264.
doi: 10.34067/KID.0000000000000226. Epub 2023 Aug 3.

Urinary Biomarkers of Kidney Tubule Health and Mortality in Persons with CKD and Diabetes Mellitus

George Vasquez-Rios  1 , Ronit Katz  2 , Emily B Levitan  3 , Mary Cushman  4 , Chirag R Parikh  5 , Paul L Kimmel  6 , Joseph V Bonventre  7 , Sushrut S Waikar  8 , Sarah J Schrauben  9 , Jason H Greenberg  10 , Mark J Sarnak  11 , Joachim H Ix  12   13 , Michael G Shlipak  14 , Orlando M Gutierrez  15
Affiliations

Urinary Biomarkers of Kidney Tubule Health and Mortality in Persons with CKD and Diabetes Mellitus

George Vasquez-Rios et al. Kidney360. .

Abstract

Key Points:

  1. Among adults with diabetes and CKD, biomarkers of kidney tubule health were associated with a greater risk of death, independent of eGFR, albuminuria, and additional risk factors.

  2. Higher urine levels of YKL-40 and KIM-1 were associated with a greater risk of death. For cause-specific death, UMOD was independently and inversely associated with the risk of cardiovascular death.

Background: Kidney disease assessed by serum creatinine and albuminuria are strongly associated with mortality in diabetes. These markers primarily reflect glomerular function and injury. Urine biomarkers of kidney tubule health were recently associated with the risk of kidney failure in persons with CKD and diabetes. Associations of these biomarkers with risk of death are poorly understood.

Methods: In 560 persons with diabetes and eGFR ≤60 ml/min per 1.73 m2 from the Reasons for Geographic and Racial Differences in Stroke study (47% male, 53% Black), we measured urine biomarkers of kidney tubule health at baseline: monocyte chemoattractant protein-1 (MCP-1), alpha-1-microglobulin, kidney injury molecule-1 (KIM-1), EGF, chitinase-3-like protein 1 (YKL-40), and uromodulin (UMOD). Cox proportional hazards regression was used to examine the associations of urine biomarkers with all-cause and cause-specific mortality in nested models adjusted for urine creatinine, demographics, mortality risk factors, eGFR, and urine albumin.

Results: The mean (SD) age was 70 (9.6) years, and baseline eGFR was 40 (3) ml/min per 1.73 m2. There were 310 deaths over a mean follow-up of 6.5 (3.2) years. In fully adjusted models, each two-fold higher urine concentration of KIM-1 and YKL-40 were associated with all-cause mortality (hazard ratio [HR] 1.15, 95% confidence interval [CI], 1.01 to 1.31 and 1.13, 95% CI, 1.07 to 1.20, respectively). When examining cause-specific mortality, higher UMOD was associated with a lower risk of cardiovascular death (adjusted HR per two-fold higher concentration 0.87, 95% CI, 0.77 to 0.99), and higher MCP-1 was associated with higher risk of cancer death (HR per two-fold higher concentration 1.52, 95% CI, 1.05 to 2.18).

Conclusion: Among persons with diabetes and CKD, higher urine KIM-1 and YKL-40 were associated with a higher risk of all-cause mortality independently of established risk factors. Urine UMOD and MCP-1 were associated with cardiovascular and cancer-related death, respectively.

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Conflict of interest statement

M. Cushman reports the following: Advisory or Leadership Role: International Society on Thrombosis and Haemostasis—journal editor, Research and Practice in Thrombosis and Haemostasis; honorarium; Hemostasis and Thrombosis Research Society—board member. Unpaid; International Society on Thrombosis and Haemostasis; board member, unpaid. O.M. Gutierrez reports the following: Consultancy: QED; Research Funding: Amgen; and Honoraria: Akebia, Amgen, Ardelyx, AstraZeneca; and QED therapeutics. J.H. Ix reports the following: Consultancy: Akebia, AstraZeneca, Bayer, Cincor, and Sanifit; Research Funding: Baxter International and Juvenile Diabetes Research Foundation; Honoraria: Akebia, AstraZeneca, Bayer, Cincor, and Sanifit; Advisory or Leadership Role: AlphaYoung; and Other Interests or Relationships: Executive Board for Kidney Disease: Improving Global Outcomes (KDIGO). R. Katz reports the following: Consultancy: UCSD and UPenn; and Advisory or Leadership Role: CJASN Editorial Board. P.L. Kimmel reports the following: Employer: National Institute of Diabetes and Digestive Kidney Diseases (NIDDK); Ownership Interest: As a Federal Employee at NIDDK, my holdings are reviewed each year for potential conflict of interest. At this time, my only stock holding related in any fashion to health care is CVS; Patents or Royalties: Elsevier: Royalties for coediting Chronic Renal Disease and Psychosocial Aspects of Chronic Kidney Disease. Mayo Clinic Press: Royalties for The Body's Keepers; Advisory or Leadership Role: Unpaid member of Board of Directors of the Academy of Medicine of Washington, DC; and Other Interests or Relationships: Co-Editor, Chronic Renal Disease Academic Press; Co-Editor, Psychosocial Aspects of Chronic Kidney Disease. Academic Press; Mayo Clinic Press. Royalties. E.B. Levitan reports the following: Research Funding: Amgen, Inc.; and Advisory or Leadership Role: University of Pittsburgh. C.R. Parikh reports the following: Consultancy: Genfit Biopharmaceutical Company; Ownership Interest: Renaltix AI; Research Funding: National Heart, Lung and Blood Institute (NHLBI) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); and Advisory or Leadership Role: Genfit Biopharmaceutical Company and Renalytix. M.J. Sarnak reports the following: Employer: Spouse works for Eli Lilly; Consultancy: Akebia. On the Steering Committee of a trial. Funds payed to Cardurian; Tufts Medical Center. Consultant: Boehringer Ingelheim. Advisory Board; Ownership Interest: spouse is employee of Lilly; and Research Funding: NIH. M.G. Shlipak reports the following: Research Funding: Bayer Pharmaceuticals; Honoraria: AstraZeneca; Bayer; Boehringer Ingelheim; Patents or Royalties: Kidney Health Monitoring in Hypertension Patients; Advisory or Leadership Role: American Journal of Kidney Disease; Circulation; Journal of the American Society of Nephrology; Board Member, Northern California Institute for Research and Education; and Other Interests or Relationships: Committee Member—KDIGO Guidelines Committee. S.S. Waikar reports the following: Advanced Clinical (spouse); Consultancy: Bain, BioMarin, CANbridge, Goldfinch, Google, GSK, Ikena, NovoNordisk, PepGen, Sironax, Strataca, Wolters Kluwer; Research Funding: JNJ, Pfizer, Natera, and Vertex; and Other Interests or Relationships: expert witness for litigation related to dialysis lab testing (Davita), PPIs (Pfizer), PFAO exposure (Dechert), voclosporin patent (Aurinia). All remaining authors have nothing to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
Forest plot analysis showing association between biomarkers and all-cause death and their respective adjusted hazard ratios (95% CI). Adjusted hazard ratios (fully adjusted models): adjusted for age, sex, race, education, and urine creatinine, systolic BP, use of hypertension meds, body mass index, smoking, history of coronary heart disease, history of stroke, C-reactive protein, eGFR, and urine albumin. α1m, alpha-1-microglobulin; CI, confidence interval; KIM-1, kidney injury molecule-1; MCP-1, monocyte chemoattractant protein-1; UMOD, uromodulin; YKL-40, chitinase-3-like protein 1.
See this image and copyright information in PMC

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