Association of Multiple Plasma Biomarker Concentrations with Progression of Prevalent Diabetic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study
Authors: Schrauben Sarah J. , Shou Haochang , Zhang Xiaoming , Anderson Amanda Hyre , Bonventre Joseph V. , Chen Jing , Coca Steven , Furth Susan L. , Greenberg Jason H. , Gutierrez Orlando M. , Ix Joachim H. , Lash James P. , Parikh Chirag R. , Rebholz Casey M. , Sabbisetti Venkata , Sarnak Mark J. , Shlipak Michael G. , Waikar Sushrut S. , Kimmel Paul L. , Vasan Ramachandran S. , Feldman Harold I. , Schelling Jeffrey R. ,   on behalf of the CKD Biomarkers Consortium and the Chronic Renal Insufficiency Cohort (CRIC) Study Investigators
Published: October 2020

Significance Statement
In diabetic kidney disease, ascertaining which patients will progress to ESKD is difficult. Efforts are under way to determine whether plasma biomarkers can identify these high-risk individuals; such biomarkers may inform development of therapies and selection of individuals for clinical trials. In this case-cohort study of well-phenotyped individuals with diabetic kidney disease, increased concentrations of plasma biomarkers related to tubular injury, inflammation, and fibrosis (kidney injury molecule 1 [KIM-1], TNF receptor 1 [TNFR-1], TNFR-2, monocyte chemotactic protein-1, soluble urokinase-type plasminogen activator receptor [suPAR], and YKL-40) were associated with increased risk of progression of diabetic kidney disease. After accounting for the other biomarkers, higher TNFR-2 levels were most strongly associated with disease progression. These findings validate the previous literature on TNFR-1, TNFR-2, and KIM-1, and provide new insights on suPAR and YKL-40 as plasma markers of diabetic kidney disease progression that require validation.

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.