Associations of Plasma Biomarkers of Inflammation, Fibrosis, and Kidney Tubular Injury With Progression of Diabetic Kidney Disease: A Cohort Study

Orlando M. Gutiérrez, Michael G. Shlipak, Ronit Katz, Sushrut S. Waikar, Jason H. Greenberg, Sarah J. Schrauben, Steven Coca, Chirag R. Parikh, Ramachandran S. Vasan, Harold I. Feldman, Paul L. Kimmel, Mary Cushman, Joseph V. Bonventre, Mark J. Sarnak, Joachim H. Ix

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Rationale & Objective: Most circulating biomarkers of chronic kidney disease (CKD) progression focus on factors reflecting glomerular filtration. Few biomarkers capture nonglomerular pathways of kidney injury or damage, which may be particularly informative in populations at high risk for CKD progression such as individuals with diabetes. Study Design: Cohort study. Setting & Participants: 594 participants (mean age, 70 years; 53% women) of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study who had diabetes and an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 at baseline. Exposures: Plasma biomarkers of inflammation/fibrosis (TNFR1 and TNFR2, suPAR, MCP-1, YKL-40) and tubular injury (KIM-1) measured at the baseline visit. Outcomes: Incident kidney failure with replacement therapy (KFRT). Analytical Approach: Cox proportional hazards regression and least absolute shrinkage and selection operator regression adjusted for established risk factors for kidney function decline, baseline eGFR, and urinary albumin-creatinine ratio (UACR). Results: A total of 98 KFRT events were observed over a mean of 6.2 ± 3.5 (standard deviation) years of follow-up. Plasma biomarkers were modestly associated with baseline eGFR (correlation coefficients ranging from −0.08 to −0.65) and UACR (0.14 to 0.56). In individual biomarker models adjusted for eGFR, UACR, and established risk factors, hazard ratios for incident KFRT per 2-fold higher biomarker concentrations were 1.52 (95% CI, 1.25-1.84) for plasma KIM-1, 1.54 (95% CI, 1.08-2.21) for TNFR1, 1.91 (95% CI, 1.16-3.14) for TNFR2, and 1.39 (95% CI, 1.05-1.84) for YKL-40. In least absolute shrinkage and selection operator regression models accounting for biomarkers in parallel, plasma KIM-1 and TNFR1 remained associated with incident KFRT. Limitations: Single biomarker measurement, lack of follow-up eGFR assessments. Conclusions: Individual plasma markers of inflammation/fibrosis (TNFR1, TNFR2, YKL-40) and tubular injury (KIM-1) were associated with risk of incident KFRT in adults with diabetes and an eGFR <60 mL/min/1.73 m2 after adjustment for established risk factors.

Original languageEnglish (US)
Pages (from-to)849-857.e1
JournalAmerican Journal of Kidney Diseases
Issue number6
StatePublished - Jun 2022
Externally publishedYes


  • CKD progression
  • End-stage kidney disease (ESKD)
  • TNFR2
  • biomarkers
  • chitinase 3–like 1 (YKL-40)
  • chronic kidney disease (CKD)
  • diabetes
  • dialysis
  • end-stage renal disease (ESRD)
  • fibrosis
  • inflammation
  • kidney injury marker 1 (KIM-1)
  • kidney tubule injury
  • monocyte chemotactic protein 1 (MCP-1)
  • prognosis
  • renal failure
  • soluble urokinase-type plasminogen activator receptor (suPAR)
  • tumor necrosis factor receptor 1 (TNFR1)

ASJC Scopus subject areas

  • Nephrology


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