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

https://doi.org/10.1053/j.ajkd.2021.09.018Get rights and content

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.

Section snippets

Study Overview

REGARDS is a population-based, longitudinal cohort study designed to examine underlying causes for racial and regional differences in stroke rates in the United States. Details of the study design have been published elsewhere.14 Briefly, the study was designed to provide approximately equal representation of men and women and oversampled Black individuals as well as those living in the southeastern United States. Trained interviewers conducted computer-assisted telephone interviews to obtain

Study Population

Of the 594 participants, 47% were men and 53% were Black individuals; baseline mean age was 70 years, and mean eGFR was 44 mL/min/1.73 m2. Other baseline characteristics of the study sample are depicted overall and by quartiles of plasma KIM-1 level in Table 1. Baseline characteristics across quartiles of other biomarkers largely aligned with KIM-1 and are depicted in Tables S1-S5. In general, participants in higher quartiles of KIM-1 level were younger, were more likely to be Black, were more

Discussion

In this study of older adults with diabetes and CKD, plasma markers of inflammation/fibrosis (TNFR1, TNFR2, and YKL-40) and tubular injury (KIM-1) were associated with higher risk of KFRT independent of established risk factors, including baseline eGFR and UACR.

Prior studies have shown that higher concentrations of TNFR1 and TNFR2 are associated with greater risk of kidney function decline in individuals with diabetes and CKD.8,9,11 The results of the present study are in accordance with these

Article Information

Authors’ Full Names and Academic Degrees

Orlando M. Gutiérrez, MD, MMSc, Michael G. Shlipak, MD, MPH, Ronit Katz, DPhil, Sushrut S. Waikar, MD, MPH, Jason H. Greenberg, MD, MHS, Sarah J. Schrauben, MD, MSCE, Steven Coca, DO, MS, Chirag R. Parikh, MBBS, PhD, Ramachandran S. Vasan, MD, Harold I. Feldman, MD, MSCE, Paul L. Kimmel, MD, Mary Cushman, MD, MSc, Joseph V. Bonventre, MD, PhD, Mark J. Sarnak, MD, MS, and Joachim H. Ix, MD, MAS.

Authors’ Contributions

Research idea and study design: OMG, MGS, MJS, JHI; data acquisition: OMG, MGS, MJS, JHI; data

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    • Biomarkers of Kidney Tubule Disease and Risk of End-Stage Kidney Disease in Persons With Diabetes and CKD

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      Using blood rather than urine, prior studies demonstrated that higher plasma concentrations reflecting both inflammation and tubule injury—particularly tumor necrosis factor receptor-1, tumor necrosis factor receptor-2, and plasma KIM-1—were independently associated with progression of kidney disease in diabetes.39,40 Our CKD Biomarkers Consortium collaborators have built on these prior studies, finding that plasma KIM-1, YKL-40, tumor necrosis factor receptor-1, and tumor necrosis factor receptor-2 were independently associated with incident ESKD among REGARDS participants with diabetes and CKD.41 The present study complements this work by reinforcing the importance of tubulointerstitial disease in persons with diabetes and CKD, but it has the important distinction of measuring novel biomarkers in urine rather than plasma.

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