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

Abstract

Rationale & 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±4.7mL/min/1.73m² 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 gelatinase-associated 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≥140mm 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.

Trial registration: ClinicalTrials.gov NCT00304148.

Keywords: CKD progression; CXCL12; Chronic kidney disease (CKD); N-terminal pro-B-type natriuretic peptide (NTproBNP); diabetes; eGFR slope; end-stage renal disease (ESRD); estimated glomerular filtration rate (eGFR); halving of eGFR; inflammatory chemokines; kidney replacement therapy (KRT); neutrophil gelatinase-associated lipocalin (NGAL); renal function trajectory; risk stratification.

Figure 1.

Rates and patterns of chronic kidney disease progression for Chronic Renal Insufficiency Cohort participants with and without diabetes. Panel A: Annual change in estimated glomerular filtration rate (eGFR) in mL/min/1.73m²/year and percentage within categories of eGFR change by diabetes status. Percentages do not add up to 100%, as the tails of the distributions were truncated. Panel B: Unadjusted event rates of kidney replacement therapy (KRT) or eGFR halving per 1,000 person-years by diabetes status and level of baseline eGFR.

Figure 2.

Summary of the statistical significance of chronic kidney disease progression risk factors in the Chronic Renal Insufficiency Cohort Study Panel A: Demographic, kidney function, and blood pressure risk factors for estimated glomerular filtration rate (eGFR) slope and the composite renal outcome of kidney replacement therapy (KRT) and eGFR halving. Panel B: Clinical, socioeconomic, behavioral, body composition, vascular, anemia, inflammatory, mineral or carbohydrate metabolism, cardiac, acidosis, urinary electrolyte, kidney injury, and RAAS factors for estimated glomerular filtration rate (eGFR) slope and the composite renal outcome of kidney replacement therapy (KRT) and eGFR halving.

Figure 3.

Summary of final variable selection of chronic kidney disease progression risk factors among CRIC participants without or with diabetes before and after exclusion of albuminuria measure UACR. Variables selected in modeling without exclusion of albuminuria indicated in blue, with exclusion of albuminuria indicated in orange, and selected both with and without albuminuria indicated in gray. Panel A: Demographic, kidney function, and blood pressure risk factors for estimated glomerular filtration rate (eGFR) slope and the composite renal outcome of kidney replacement therapy (KRT) and eGFR halving. Panel B: Clinical, socioeconomic, behavioral, body composition, vascular, anemia, inflammatory, mineral or carbohydrate metabolism, cardiac, acidosis, urinary electrolyte, kidney injury, and RAAS factors for estimated glomerular filtration rate (eGFR) slope and the composite renal outcome of kidney replacement therapy (KRT) and eGFR halving. Tables 2 and 3 provide the specific magnitude and direction of the risk factor associations, which include both linear and non-linear associations.