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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2019  |  Volume : 30  |  Issue : 2  |  Page : 315-324
Association of hepcidin and anemia in early chronic kidney disease


1 Department of Medicine, King George's Medical University, Lucknow, Uttar Pradesh, India
2 Department of Biochemistry, King George's Medical University, Lucknow, Uttar Pradesh, India
3 Department of Nephrology, King George's Medical University, Lucknow, Uttar Pradesh, India
4 Department of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India

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Date of Submission14-Feb-2018
Date of Acceptance18-Mar-2018
Date of Web Publication23-Apr-2019
 

   Abstract 


Hepcidin is being extensively studied for anemia and inflammation in chronic kidney disease (CKD) patients. Hepcidin is thought to regulate iron metabolism by iron blockade through various mechanisms. Patients with CKD have early cardiac mortality due to anemia and subclinical inflammation; hence, we studied hepcidin as a biomarker in patients with early stage of CKD in relation to anemia and inflammation. In our cross-sectional study, a total of 80 patients were enrolled of whom, there were 25, 26, and 29 patients in CKD stages 1, 2, and 3, respectively. Patients were divided into normal iron level (39), functional iron deficiency (FID) (18), and absolute iron deficiency (AID) (23) based on transferrin saturation and ferritin. We found significantly high level of hepcidin (P <0.05) and high-sensitivity C-reactive protein (hsCRP) (P <0.05) in FID as compared to AID as well as normal iron level. We also found other inflammatory markers such as albumin, transferrin, and ferritin to be significantly associated with FID. In univariate analysis, hemoglobin (Hb) varied significantly with serum total iron-binding capacity (r = 0.40, P <0.001), log hsCRP (r = -0.32, P <0.01), and log ferritin (r = -0.23, P <0.05); however, Hb was not affected significantly with log hepcidin (r = -0.07, P >0.05). The study indicates that among early CKD patients with FID, there was high level of hepcidin along with other inflammatory parameters, which may be associated with poor cardiovascular disease outcome due to increased inflammation.

How to cite this article:
Sonkar SK, Singh NK, Sonkar GK, Pandey S, Bhosale V, Kumar A, Usman K. Association of hepcidin and anemia in early chronic kidney disease. Saudi J Kidney Dis Transpl 2019;30:315-24

How to cite this URL:
Sonkar SK, Singh NK, Sonkar GK, Pandey S, Bhosale V, Kumar A, Usman K. Association of hepcidin and anemia in early chronic kidney disease. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2019 Jul 21];30:315-24. Available from: http://www.sjkdt.org/text.asp?2019/30/2/315/256838



   Introduction Top


Early chronic kidney disease (CKD) is a worldwide public health problem due to increasing incidence and prevalence of diabetes and hypertension which has poor outcomes and are associated with subclinical inflammation.[1],[2] Outcomes of CKD include not only kidney failure but also complications of decreased kidney function such as hyporesponsive anemia and cardiovascular disease (CVD) leading to premature mortality.[2],[3]

Anemia is highly prevalent in CKD and the severity increases as the disease advances and is associated with poor prognosis and increased mortality. Moreover, the leading cause of death in CKD is CVD and hence, there exists a relationship for such adverse outcome in CKD patients.[4]

Hepcidin is being extensively studied for its association with anemia in CKD where it has also been associated with inflammation. Hepcidin is thought to be the major regulator of dietary iron absorption and cellular iron release from macrophages, and it exerts its regulatory function by counteracting the function of ferroportin, the major cellular iron exporter. Hepcidin induces internalization and degradation of ferroportin, which results in increased intracellular iron stores, decreased dietary iron absorption and decreased circulating iron levels which may be the cause for functional iron deficiency (FID).[5]

At a certain concentration, hepcidin may improve host defense by reducing iron concentrations. Since iron is required for microbial growth, low iron levels are thought to be bacteriostatic. Hepcidin has also been found to modulate lipopolysaccharide-induced transcription in cultured macrophages and in vivo mouse models, suggesting that hepcidin plays a role in modulating acute inflammatory responses to bacterial infections.[6],[7]

Hepcidin is upregulated in the setting of chronic inflammation and cancer due to stimulation by cytokines of which interleukin-6 is the most important.[8] Inflammation is associated with increased levels of serum markers of inflammation including serum C-reactive protein (CRP);[9] erythrocyte sedimentation rate (ESR)[10] and other parameters of inflammation, including reduced production of serum albumin[11] and transferrin.[12]

In this study, we assessed the role of hepcidin compared to iron indices and inflammation in early CKD as a prognostic marker.


   Material and Methods Top


A cross-sectional study of one year’s duration was conducted in the Department of Medicine and Nephrology, King George’s Medical University, Lucknow. Adult patients (>18 years) in stable clinical state in the 1st, 2nd, and 3rd stage of CKD, with estimated glomerular filtration rate (eGFR) >90 mL/min, 60–89, and 30–59 mL/min, respectively, calculated from equation from the Modification of Diet in Renal Disease, were enrolled after obtaining consent. Patients having active infection, active cancer, on any hemopoetic drug, thrombosis, blood transfusions within three months preceding the study, immunosuppressive therapy and acute cardiovascular complications (uncontrolled hypertension, acute coronary syndrome, and acute heart failure), were excluded from the study.

Patients with transferrin saturation (TSAT) >20% were considered having normal iron level. Absolute iron deficiency (AID) was taken when TSAT was <20% and the serum ferritin concentration was <100 μg/L, while FID was defined as TSAT <20% and serum ferritin 100–300 μg/L.

All venous blood samples were taken in the morning after an overnight rest. Hematological measurements were made in fresh EDTA venous blood and clotted blood. The plasma and serum obtained after centrifugation was then frozen at –70°C until further laboratory analysis. Hemoglobin (Hb) concentration, red blood count (RBC), hematocrit (HCT), platelet count, iron profile, lipid profile, creatinine, urea, and uric acid were measured using standard laboratory methods (automated system) in a central laboratory. Commercially available kits were used to measure the following: hepcidin-25 (by sandwich enzyme-linked immunosorbent assay (ELISA) method kit of sunred biotech, Shanghai), high-sensitivity CRP (hsCRP) (by sandwich ELISA method kit of sunred biotech, Shanghai). The study was approved by the Institutional Ethical Committee.


   Statistical Analysis Top


Baseline characteristics were assessed with standard descriptive statistics. Normalcy of data was tested by the Kolmogorov–Smirnov test. If the normalcy was rejected then nonparametric test was used. Continuous variables were presented as mean ± standard deviation (SD) and median with interquartile range (as applicable). Quantitative variables were compared using the independent t-test and Mann–Whitney test (for nonparametric data) between two groups. Qualitative variables were compared using the Chi-square test/Fisher’s exact test. Pearson correlation coefficient was used to find correlation between various variables. For nonparametric data, log of data was used to find the correlation.

Multivariate regression analysis was performed to examine the relationship between various parameters after adjusting for confounders. The data were entered into Microsoft Excel spreadsheet, and analysis was performed using Statistical software (MS Excel statistical tool package). P <0.05 was considered statistically significant.


   Results Top


A total of 80 patients were enrolled for this study. Majority (70%) of the patients were diabetic, 10% had hypertension, 12% had chronic glomerulonephritis, and 8% had chronic interstitial nephiritis. Among diabetics, 26% of the patients had hypertension in addition. In CKD stages 1, 2, and 3, there were 25, 26, and 29 patients, respectively. With the advanced stage of CKD, Hb decreased significantly [Table 1]. Serum iron and hepcidin levels did not vary significantly between early stages of CKD, but serum ferritin and hsCRP increased significantly. In our study, by using univariate analysis (data not shown), log hepcidin did not show any significant relation with eGFR (r = 0.06, P >0.05). However, the serum total iron-binding capacity (TIBC) (r = 0.45, P <0.001), log hsCRP (r = –0.36, P <0.001), and log ferritin (r = –0.29, P <0.05) showed significant correlation with eGFR.
Table 1: Various parameters in early stage of chronic kidney disease.

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We looked for the factors affecting the Hb level which defined the severity of anemia with respect to TIBC, TSAT, log ferritin, log hsCRP, and log hepcidin. In univariate analysis, Hb varied significantly with TIBC (r = 0.40, P <0.001), log hsCRP (r = -0.32, P <0.005) and log ferritin (r = -0.23, P <0.05) while Hb was not affected significantly with serum hepcidin (r = -0.07, P >0.05).

On multiple sequential regression analysis, Hb was more affected with eGFR, followed by log hsCRP and log ferritin; hence, hepcidin did not play an important role in determining Hb level [Table 2].
Table 2: Sequential multivariate regression of hemoglobin with various parameters.

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On multiple regression, log normalized hepcidin correlated significantly with log ferritin but not with log hsCRP [Table 3]. However, on dividing hepcidin values into four quartiles, we found that log hepcidin in Q4 (Q1 lowest and Q4 the highest) significantly correlated with log hsCRP (r = 0.48, P <0.05).
Table 3: Multivariate regression for log hepcidin with different variable.

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Patients were also divided into three different groups according to iron status; those with normal iron level (39), functional iron deficiency (FID, 18) and AID (23) based on TSAT and ferritin. Thirty-one percent of the patients in stage 3 CKD had FID when compared with 20% in stage 1 and 16% in stage 2 (P >0.05). Hence, FID was present irrespective of the stage of early CKD [Table 4].
Table 4: Number and percentage of patients according to iron status in CKD stages 1, 2, and 3.

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In the FID group, serum hepcidin was markedly increased along with hsCRP as compared to AID and normal iron level [Table 5]. Similarly, in Q4 (highest quartile of hepcidin), we found significant correlation with loghsCRP (r = 0.48, P <0.05) and 56% of patients had FID vs 6% of patients who had FID in Q1.
Table 5: Various parameters according to iron status in early stage of chronic kidney disease.

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   Discussion Top


The kidney is the major route of hepcidin clearance, but in early stages of CKD, eGFR does not affect hepcidin level and similar results were observed in this study;[12] however, in some studies, hepcidin correlated with eGFR.[13],[14] In the study of Uehata et al, they found no significant difference of hepcidin in the early stage of CKD but significant difference was found in stage 4 and 5 of CKD.[15] Serum TIBC, ferritin, and hsCRP showed significant correlation with the eGFR suggestive of sub-clinical inflammation/uremic toxins [Table 1]. Abraham et al.[16] found inverse correlation between hsCRP and eGFR, but in some studies, no such correlation was found.[17]

This study searched for factors such as various iron parameters and hepcidin for better prediction of anemia in early CKD patients. Studies on anemia in Indian CKD patients identified iron deficiency as a major problem.[18],[19] Iron deficiency is common in the Indian population, with the prevalence of anemia being 33–98%.[20],[21] In addition to true iron deficiency, many CKD patients have FID. These patients have low serum TSAT (a measure of circulating iron) and normal or high serum ferritin (a marker of body iron stores).[22] We found that despite increased TSAT and adequate iron store, with increasing stage of CKD, there was a significant reduction of Hb level. This decreased Hb level could be attributed to reticuloendothelial cell iron blockage due to inflammation. Inflammation has been implicated in many complications in CKD, including malnutrition, atherosclerosis, and decreased iron utilization. Several other studies also have reported the above findings.[23] Decreased Hb was significantly associated with serum total iron binding capacity, hsCRP, ferritin, and eGFR (uremic toxin), which is suggestive of chronic inflammation and also supported by other studies.[24],[25],[26]

Anemia guidelines for CKD patients consider that TSAT and ferritin are important markers of anemia in CKD, and iron replacement is based according to TSAT and serum ferritin levels.[25] Hepcidin lowers the available serum iron levels by limiting iron efflux from the body’s iron stores;[26] therefore, it is plausible that iron might be sequestrated in iron stores as the serum hepcidin level increases. This may cause bone marrow iron deficiency despite sufficient iron in storage sites,[27] suggesting that sufficient serum levels of TSAT and ferritin may not guarantee sufficient production of RBC when the serum hepcidin level is increased. Four mechanisms play a role in determining the value of hepcidin, i.e., regulation by iron status, hypoxia, inflammation, and erythropoietic signals.[28] Previous studies on hepcidin levels revealed a strong positive correlation between serum hepcidin and ferritin concentrations in CKD patients. The serum hepcidin levels in CKD patients have also been shown to be associated with ironrestricted erythropoiesis, as reflected by the relation of high serum hepcidin levels and low Hb concentrations and/or reticulocyte counts.[29],[30] Hepcidin is thought to regulate iron metabolism by counteracting the function of ferroportin, the major cellular iron exporter.[31] In this study, we found a significant correlation between log hepcidin and log ferritin but not with log hepcidin and Hb. Although serum hepcidin levels are correlated with iron status, they have a high short-term interpatient coefficient of variation and are influenced by inflammation.[32] Eleftheriadis et al also found that hepcidin is increased and correlated with ferritin but not with TSAT. In that study, ferroportin in monocytes of HD patients was decreased and did not correlate with hepcidin, an observation that denotes that erythropoiesis disturbances are multifactorial in this population making the use of hepcidin as a marker problematic.[33] Other studies also suggest that hepcidin is not correlated to anemia in the early stage of CKD where Hb was greater than 10 g/dL. However, in later stages of CKD, hepcidin correlated with anemia better than TSAT and ferritin.[26] There is the difficulty of using hepcidin as a marker of iron metabolism in HD and CKD, in general, as found in this study and also supported by other clinical studies.[34],[35] In this study, Hb decreased significantly with decreasing GFR. Hb varied significantly with s. TIBC, s. Ferritin, and hsCRP but not with serum hepcidin. Regarding correlation of Hb with serum hepcidin, our results are consistent with the results of other studies in dialysis patients[34],[36] as well as with studies in nondialysis CKD patients,[26],[37] but not consistent with other studies.[38] These conflicting results may be attributed to difference in iron status of the population studied, difference in inflammatory state or sample size.

CRP has a relatively long half-life of 18 to 20 hours, owing to its stable pentraxin structure. In addition, CRP levels are stable as they do not exhibit diurnal variations or variations in relation to food intake. High-sensitivity ELISA can detect CRP with a sensitivity range of 0.01 to 10 mg/L.[39] These high-sensitivity assays help quantify low grades of systemic inflammation, in the absence of overt systemic inflammatory or immunologic disorders. The hsCRP assays have been standardized.[40] The hsCRP is a widely evaluated biomarker in the search for an ideal biomarker for global CVD risk prediction. It has been incorporated into the various risk scoring system for global CVD risk prediction.[41] On the basis of data obtained from population-based studies, the American Heart Association/Centres for Disease Control Working Group on markers of inflammation in CVD has classified serum hsCRP levels <1, 1–3, and >3 mg/L as low-, intermediate-, and high-risk groups for global CVD, respectively. In this study, we found universally high hsCRP level in the early stage of CKD since 70% of patients in our study were diabetic. On dividing patients into four quartiles based on hepcidin level, we found significant correlation between hsCRP and hepcidin in the fourth quartile (Q4: the highest quartile); hence, high level of hepcidin could be marker of poor CVD outcome.[38]

Based on iron level, we classified the patient groups into FID group, AID group and normal iron level. We observed that established markers of inflammation such as CRP and ferritin were higher and negative markers of inflammation such as transferrin and albumin were lower in FID group and other studies also suggest the same.[23],[42] In this study patients with FID, when compared to patients with AID or normal iron level, had significantly higher level of hepcidin along with hsCRP which suggests the role of inflammation in regulation of hepcidin and consistent with other studies.[43] Oral drug like roxadustat (FG-4592) which is HIF-PH inhibitor, increases the production of endogenous erythropoietin (EPO), increases iron mobilization and utilization, and overcomes the suppressive effects of inflammation on red blood cell production. This drug, by reducing hepcidin, would not only improve anemia but also prevent the hazards of injectable erythropoietin and hence, improving overall cardiac outcome.[44],[45] Although Hb was not significantly lowered in FID, as the disease progresses, this group may develop hypo-responsive anemia along with increased cardiovascular mortality.


   Conclusion Top


FID is a major concern in early CKD patients. Hepcidin value has to be standardized universally so that in future it could be clinically used routinely. High level of hepcidin in early CKD patients may be a vital early predictor of hypo-responsive anemia and poor CVD outcome.

Conflict of interest: None declared.



 
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Correspondence Address:
Satyendra Kumar Sonkar
Department of Medicine, King George's Medical University, Lucknow, Uttar Pradesh
India
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DOI: 10.4103/1319-2442.256838

PMID: 31031367

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