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

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; on behalf of the CKD Biomarkers Consortium and the Chronic Renal Insufficiency Cohort (CRIC) Study Investigators

doi:10.1681/ASN.2020040487

This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.

Visual Abstract

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.

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.

View Full Text

Log in through your institution

Purchase access

You will have access to the article for 24 hours.

If you do not have an account, you will need to create one and you will be asked for your name, email address and other information. Just like commercial web sites, we do need details from you in order to complete your purchase of an article. Select the "Create an Account" link to create your account.

You will then be asked to register a user name, email address and you will need to create a password that is at least eight characters in length. As you move through the registration page, you will have to verify you are a person by completing a Captcha request. Lastly, your first and last name will be required.

Once your information is successfully saved, the system will redisplay the home page of the journal. From there, navigate back to the article to purchase. Select the article and at the bottom of the page, use the credentials you just created to login. The article will be added to your shopping cart. You can continue to navigate across JASN and CJASN adding to your cart from both journals. When you are ready to complete your purchse, select the Shopping Cart from the upper right hand corner of the page and follow the onscreen instructions.