The Chronic Renal Insufficiency Cohort (CRIC) study measured hepcidin, cardiovascular, kidney and metabolic outcomes in chronic kidney disease.

INTRODUCTION

Abnormal iron homeostasis plays a critical role in extra-hematopoietic disorders. The relationship of hepcidin, the master iron regulator, to clinical outcomes, has not been characterized in a large cohort of chronic kidney disease (CKD).

METHODS

To determine if plasma hepcidin level predicts cardiovascular (CV), kidney, and metabolic outcomes in patients with CKD, we studied 3826 patients enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study. Hazard ratios for hepcidin tertiles were estimated from Cox Proportional Hazards regression for primary outcomes of incident heart failure (HF), end stage kidney disease (kidney failure) or halving of the estimated glomerular filtration rate (eGFR), and new onset diabetes or prediabetes. Secondary outcomes included atherosclerotic events and all-cause and CV mortality.

RESULTS

The median and interquartile range of plasma hepcidin level was 43 (22, 77) ng/mL. Higher plasma hepcidin levels were associated with older age, male sex, non-Hispanic Black race, diabetes, lower eGFR, higher albuminuria, increased plasma levels of iron indices, C-terminal fibroblast growth factor 23, and markers of inflammation (high-sensitivity C-reactive protein and interleukin-6). We found no association between plasma hepcidin level and the risk for incident HF or prediabetes/diabetes. However, compared to the middle tertile, the highest hepcidin tertile was independently associated with increased risk for kidney outcomes (hazard ratio 1.19; 95% confidence interval 1.09, 1.30) and atherosclerotic events (hazard ratio 1.34; 95% confidence interval 1.09, 1.64), while the lowest hepcidin tertile was associated with increased risk for all-cause and CV mortality in fully adjusted multivariable models including iron indices and inflammation.

CONCLUSION

Both low and high plasma levels of hepcidin are associated with adverse clinical outcomes.