Novel Risk Factors for Progression of Diabetic and Nondiabetic CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study

Abstract

on behalf of the CRIC Study InvestigatorsRationale & Objective: Identification of novel risk factors for chronic kidney disease (CKD) progression may inform mechanistic investigations and improve identification of high-risk subgroups. The current study aimed to characterize CKD progression across levels of numerous risk factors and identify independent risk factors for CKD progression among those with and without diabetes.Study Design: The Chronic Renal Insufficiency Cohort (CRIC) Study is a prospective cohort study of adults with CKD conducted at 7 US clinical centers.Setting & Participants: Participants (N = 3,379) had up to 12.3 years of follow-up; 47% had diabetes.Predictors: 30 risk factors for CKD progression across sociodemographic, behavioral, clinical, and biochemical domains at baseline.Outcomes: Study outcomes were estimated glomerular filtration rate (eGFR) slope and the composite of halving of eGFR or initiation of kidney replacement therapy. Analytical Approach:Stepwise selection of independent risk factors was performed stratified by diabetes status using linear mixed-effects and Cox proportional hazards models.Results: Among those without and with diabetes, respectively, mean eGFR slope was −1.4 ± 3.3 and −2.7 ± 4.7 mL/min/1.73 m 2 per year. Among participants with diabetes, multivariable-adjusted hazard of the composite outcome was approximately 2-fold or greater with higher levels of the inflammatory chemokine CXCL12, the cardiac marker N-terminal pro-B-type natriuretic peptide (NT-proBNP), and the kidney injury marker urinary neutrophil gelatinaseassociated lipocalin (NGAL). Among those without diabetes, low serum bicarbonate and higher high-sensitivity troponin T, NT-proBNP, and urinary NGAL levels were all significantly associated with a 1.5-fold or greater rate of the composite outcome. Limitations:The observational study design precludes causal inference.Conclusions: Strong associations for cardiac markers, plasma CXCL12, and urinary NGAL are comparable to that of systolic blood pressure ≥ 140 mm Hg, a well-established risk factor for CKD progression. This warrants further investigation into the potential mechanisms that these markers indicate and opportunities to use them to improve risk stratification.

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

“…It is an early sensitive biomarker for kidney injury. Urinary NGAL showed association with eGFR decline and kidney transplant in nondiabetic CRIC population (hazard ratio 1.6, 95% CI 1.1–2.3) [ 20 ], whereas the association was not significant in those with diabetes [ 20 ]. Urine NGAL was not a predictor of CKD progression in the SPRINT substudy [ 16 ].…”

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

“…Consistently, our cohort study found that the best predictive cutoff value of urinary NGAL to creatine ratio (uNCR) for DKD diagnosis was 60.685 ng/mg, and T2DM patients with the increased level of uNCR had a higher risk of nephrotic-range proteinuria and worse renal outcome ( 82 ). Furthermore, a more recent report from the CRIC study conducted at seven US clinical centers provided solid evidence that higher urinary NGAL levels were not only strongly associated with cardiac markers, but were also linked to an approximately twofold or greater risk of CKD progression in patients with DM ( 10 ). It has been postulated that NGAL captures some of the variability in the rate of kidney function decline independently of albuminuria or other risk factors and reflects tubular injury and inflammation in the setting of DKD ( 10 , 85 ).…”

“…Furthermore, a more recent report from the CRIC study conducted at seven US clinical centers provided solid evidence that higher urinary NGAL levels were not only strongly associated with cardiac markers, but were also linked to an approximately twofold or greater risk of CKD progression in patients with DM ( 10 ). It has been postulated that NGAL captures some of the variability in the rate of kidney function decline independently of albuminuria or other risk factors and reflects tubular injury and inflammation in the setting of DKD ( 10 , 85 ).…”

“…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 ).…”

“…Summary of principal tubular biomarkers of DKD in clinical use.NGALincreased when acute tubular damage of various causes occurred; correlated with CKD progression urine (77, 78) associated with urinary albumin excretion, rapid decline of eGFR, and increased serum creatinine urine (79-82) associated with renal progression to ESKD, progressive tubular structural and functional impairment urine(10,(83)(84)(85) best predictive cutoff value of urinary NGAL to creatine ratio (uNCR) for T2DKD diagnosis was 60.685 ng/mg; urine (82) 7.595 times higher risk of nephrotic-range proteinuria in T2DKD patients with uNCR >60.685 vs.≤60.685 ng/mg. twofold or greater risk for CKD progression in patients with diabetes; urine (10) 1.5-fold or greater risk for CKD progression in patients without diabetes tubular cells in areas with tubulointerstitial damage induced by overload proteinuria; upregulated in proteinuric nephropathy and associated with renal fibrosis and inflammation.…”