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

Abstract

BackgroundAlthough 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.MethodsIn 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.ResultsMedian 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.ConclusionsHigher 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.

Plasma and urine biomarkers in chronic kidney disease: closer to clinical application

“…The biomarker is produced by cleavage of membrane-bound suPAR as a result of inflammatory stimuli such as viruses, and cardiovascular risk factors such as smoking and diabetes mellitus. In the aforementioned CRIC and CKiD cohorts, the independent association between suPAR was modest (adjusted hazard ratio 1.4, 95% CI 1.1–1.7 in CRIC [ 9 ▪▪ ]) or not significant (hazard ratio 1.2, 95% CI 0.7–2.2 for quartile 4 vs. quartile 1 in CKiD [ 11 ▪ ]). In a Chinese cohort of 2391 individuals with CKD, plasma suPAR was modestly associated with ESRD (adjusted hazard ratio 1.53, 95% CI 1.10–2.12) [ 13 ].…”

Current Challenges and Future Perspectives of Renal Tubular Dysfunction in Diabetic Kidney Disease

“…More recent evidence still emphasizes the important role of KIM-1 in DKD. In 2020, a multicenter and prospective cohort within the CRIC Study suggested that higher plasma KIM-1 levels were associated with DKD progression and yearly decline in eGFR ( 9 ). Kammer et al.…”

“…More convincing results were obtained from a multicenter, prospective, large-sample cohort within the CRIC Study, providing new insights on YKL-40 as a plasma marker of DKD progression. Increased plasma YKL-40 concentrations were associated with DKD progression and decline in eGFR over time, even after adjustment for potential confounders and other plasma biomarkers ( 9 ).…”

“…The 2020 CRIC Study first reported an association of plasma MCP-1 concentrations and DKD progression among individuals with moderate to severe kidney disease. Higher plasma MCP-1 levels were associated with an increased risk of DKD progression only among patients with baseline eGFR<45 ml/min per 1.73 m 2 ( 9 ).…”

“…Urinary tubular injury markers may increase in patients with diabetes even before the onset of microalbuminuria ( 7 , 8 ). Plasma tubular markers, which may reflect inflammatory and fibrotic responses, oxidative stress, and capacity of reabsorption in DKD, were also reported to be associated with early renal function decline and DKD progression ( 9 , 10 ). Moreover, the biomarkers of tubulointerstitial function and structural changes were ultimately proven to be better predictors of disease progression and long-term prognosis than the current markers ( 11 ).…”