The effect of serum hepcidin levels on the clinical outcomes in patients with chronic kidney disease

Abstract

165 (8.6%) patients with functional deterioration and 275 (14.4%) patients with dialysis initiation. In penalized smoothing splines curve analysis, the hazard of renal events steadily increased with the increase of serum hepcidin levels. In multivariate Cox-proportional hazard regression analysis, the hazard ratio and its 95% CI in the third and the forth serum hepcidin quartile were 1.514 (1.025-2.237, P = 0.037) and 1.752 (1.183-2.596, P = 0.005), respectively, compared to the first serum hepcidin quartile. In subgroup analysis, increased serum hepcidin levels were associated with increased hazard of future renal events development, particularly in diabetic male patients with lower levels of Hb, TSAT, ferritin, inflammation, and kidney function.

Conclusions Investigator observed that kidney function was an independent factor of serum hepcidin levels. Increased serum hepcidin levels with the increase of ESA dosage may suggest the key role of hepcidin in ESA resistance. Although ferritin was not associated with anemia in CKD patients, regardless of kidney function, TSAT was associated with less severe anemia in early CKD patients, whereas serum hepcidin was associated with more severe anemia in advanced CKD patients. In this study, increased serum hepcidin levels independently predict the progression of CKD in non-dialysis CKD patients. Diabetic male patients with lower levels of Hb, TSAT, ferritin, inflammation, and kidney function may need to be treated more meticulously with special attention to the development of CKD progression.

Background Anemia is common problem in patients with chronic kidney disease (CKD) and contributes to increased risk of poor clinical outcomes. In treating anemia in CKD patients, erythropoiesis stimulating agents (ESA) resistance is an important issue and hepcidin is suggested as a key peptide of ESA resistance. However, the clinical characteristics of hepcidin and its role on ESA resistance have not been validated in large-scaled multicenter cohort. Moreover, the relative contribution of hepcidin and iron indices on anemia severity in CKD has been studied little. Therefore investigator designed and performed this study to confirm the known association between hepcidin, kidney function, ESA resistance, and anemia, and to identify the effect of hepcidin on clinical outcomes in non-dialysis CKD patients.

Methods Investigator reviewed data of 2238 patients from a large-scale multicenter prospective Korean study (2011–2016). Among 2238 patients whose mean age was 54.2 years, serum of 2113 patients were analyzed to measure serum hepcidin levels using competitive enzyme-linked immunosorbent assay. Iron indices were transferrin saturation (TSAT) and ferritin. Anemia was defined as hemoglobin (Hb) <13.0 g/dl in men and <12.0 g/dl in women. Mild, moderated, and severe anemia were defined as Hb <13.0 g/dl, <11.5 g/dl, and <10.0 g/dl, respectively. The studied clinical outcomes were renal events, defined as a >50% decrease in kidney function from the baseline values, doubling of serum creatinine, or dialysis initiation, which were detected and adjudicated annually. Results Markers of inflammation and iron status were positively associated with serum hepcidin levels, regardless of CKD stage. However, estimated glomerular filtration rate was inversely associated with serum hepcidin levels (beta -0.007, P < 0.001), particularly in patients with CKD stages 3b–5, but not in those with CKD stages 1–3a. Iron supplementation was associated with increased serum hepcidin levels (beta 0.306, P = 0.001), particularly in patients with CKD stages 1–3a, but not in those with CKD stages 3b–5. Use of ESA was associated with increased serum hepcidin levels (beta 0.802, P <0.001), particularly in patients with CKD stages 3b–5, but not in those with CKD stages 1–3a, and ESA dosage positively correlated with serum hepcidin levels. In subgroup analysis according to the causes of CKD, kidney function was negatively associated with serum hepcidin levels in patients with hypertensive nephropathy and glomerulonephritis. The positive association between ESA use and serum hepcidin levels was not affected by causes of CKD. TSAT and serum hepcidin were significantly associated with anemia status, whereas serum ferritin was not, regardless of anemia severity. In patients with CKD1-3a, a 10% increase of TSAT was associated with severe anemia [odds ratio (OR) 0.628, 95% confidence interval (CI) 0.515-0.765

P <0.001] and moderate anemia (OR 0.672, 95% CI 0.476-0.950

P = 0.024), whereas a 10-ng/ml increase of serum hepcidin was associated with mild anemia (OR 1.360, 95% CI 1.115-1.659

P=0.002) and moderate anemia (OR 1.379, 95% CI 1.173-1.620

P <0.001) in patients with CKD 3b-5 on multivariate logistic analysis. During a mean of 2.4 years, 333 patients developed renal events (17.4%)