Association of Multiple Plasma Biomarker Concentrations with Progression of Prevalent Diabetic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study.

Abstract

BACKGROUND:

Although diabetic kidney disease is the leading cause of ESKD in the United States, identifying those patients who progress to ESKD is difficult. Efforts are under way to determine if plasma biomarkers can help identify these high-risk individuals.

METHODS:

In our case-cohort study of 894 Chronic Renal Insufficiency Cohort Study participants with diabetes and an eGFR of <60 ml/min per 1.73 m2 at baseline, participants were randomly selected for the subcohort; cases were those patients who developed progressive diabetic kidney disease (ESKD or 40% eGFR decline). Using a multiplex system, we assayed plasma biomarkers related to tubular injury, inflammation, and fibrosis (KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40). Weighted Cox regression models related biomarkers to progression of diabetic kidney disease, and mixed-effects models estimated biomarker relationships with rate of eGFR change.

RESULTS:

Median follow-up was 8.7 years. Higher concentrations of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were each associated with a greater risk of progression of diabetic kidney disease, even after adjustment for established clinical risk factors. After accounting for competing biomarkers, KIM-1, TNFR-2, and YKL-40 remained associated with progression of diabetic kidney disease; TNFR-2 had the highest risk (adjusted hazard ratio, 1.61; 95% CI, 1.15 to 2.26). KIM-1, TNFR-1, TNFR-2, and YKL-40 were associated with rate of eGFR decline.

CONCLUSIONS:

Higher plasma levels of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were associated with increased risk of progression of diabetic kidney disease; TNFR-2 had the highest risk after accounting for the other biomarkers. These findings validate previous literature on TNFR-1, TNFR-2, and KIM-1 in patients with prevalent CKD and provide new insights into the influence of suPAR and YKL-40 as plasma biomarkers that require validation.

• Authors: Sarah J Schrauben, Haochang Shou, Xiaoming Zhang, Amanda Hyre Anderson, Joseph V Bonventre, Jing Chen, Steven Coca, Susan L Furth, Jason H Greenberg, Orlando M Gutierrez, Joachim H Ix, James P Lash, Chirag R Parikh, Casey M Rebholz, Venkata Sabbisetti, Mark J Sarnak, Michael G Shlipak, Sushrut S Waikar, Paul L Kimmel, Ramachandran S Vasan, Harold I Feldman, Jeffrey R Schelling, CKD Biomarkers Consortium and the Chronic Renal Insufficiency Cohort (CRIC) Study Investigators
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 32 Issue 1 Pg. 115-126 (01 2021) ISSN: 1533-3450 [Electronic] United States
• PMID: 33122288 (Publication Type: Journal Article, Multicenter Study, Observational Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 by the American Society of Nephrology.

Chemical References

• Biomarkers
• CCL2 protein, human
• CHI3L1 protein, human
• Chemokine CCL2
• Chitinase-3-Like Protein 1
• HAVCR1 protein, human
• Hepatitis A Virus Cellular Receptor 1
• Receptors, Tumor Necrosis Factor, Type I
• Receptors, Tumor Necrosis Factor, Type II
• Receptors, Urokinase Plasminogen Activator

Topics

• Adult
• Aged
• Biomarkers (blood)
• Chemokine CCL2 (blood)
• Chitinase-3-Like Protein 1 (blood)
• Cohort Studies
• Diabetic Nephropathies (blood, genetics)
• Disease Progression
• Female
• Glomerular Filtration Rate
• Hepatitis A Virus Cellular Receptor 1 (blood)
• Humans
• Kidney Failure, Chronic (blood, genetics)
• Male
• Middle Aged
• Phenotype
• Prevalence
• Receptors, Tumor Necrosis Factor, Type I (blood)
• Receptors, Tumor Necrosis Factor, Type II (blood)
• Receptors, Urokinase Plasminogen Activator (blood)
• Renal Insufficiency, Chronic (blood, genetics)
• Risk
• Young Adult