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| ORIGINAL ARTICLE |
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| Year : 2022 | Volume
: 22
| Issue : 4 | Page : 209-215 |
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Serum hepcidin levels and cardiovascular outcomes in patients on maintenance hemodialysis: a study from South India
Kankokaran Vadakkeveetil Anupama, Manjusha Yadla
Department of Nephrology, Gandhi Medical College, Hyderabad, Telangana, India
| Date of Submission | 16-Aug-2021 |
| Date of Acceptance | 08-Mar-2022 |
| Date of Web Publication | 22-Sep-2022 |
Correspondence Address:
Dr. Manjusha Yadla
Department of Nephrology, Gandhi Medical College, Hyderabad 500071, Telangana
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jesnt.jesnt_20_21
Background Cardiovascular mortality is high in patients on maintenance hemodialysis. Different factors and plausible mechanisms have been explained for the increased risk. A recent concept of iron dysregulation and the related biomarker serum hepcidin was thought to be one of the novel markers of cardiovascular disease. We undertook this study to study the fatal and nonfatal cardiovascular events in dialysis population. Patients and methods All the patients who satisfied inclusion criteria were included in the study. All the patients have been on either twice-/thrice-weekly dialysis with polysulfone membrane of 1.3-m2 surface area. Serum hepcidin levels were estimated in blood samples using the appropriate techniques. All the patients were followed up for 18 months to assess the fatal and nonfatal cardiovascular outcomes. Results A total of 80 patients satisfied the criteria and were followed up. Mean serum hepcidin levels were 116.3 ± 32 ng/ml. On univariate analysis of factors influencing mortality, age, sex, and presence of comorbidities did not show significant association, but the levels of serum bicarbonate, albumin, creatinine, cholesterol, triglycerides, and the high-sensitivity C-reactive protein, hepcidin, showed a significant association with mortality. Serum hepcidin level of 120 ng/ml predicted mortality with a sensitivity of 100% and specificity of 85%. Conclusions Serum hepcidin is associated with all-cause mortality and cardiovascular mortality in patients on hemodialysis. Hepcidin levels may serve a good predictor of cardiovascular outcomes in patients on hemodialysis. Keywords: cardiovascular outcomes, hepcidin, maintenance hemodialysis
How to cite this article:
Anupama KV, Yadla M. Serum hepcidin levels and cardiovascular outcomes in patients on maintenance hemodialysis: a study from South India. J Egypt Soc Nephrol Transplant 2022;22:209-15 |
How to cite this URL:
Anupama KV, Yadla M. Serum hepcidin levels and cardiovascular outcomes in patients on maintenance hemodialysis: a study from South India. J Egypt Soc Nephrol Transplant [serial online] 2022 [cited 2023 Jun 8];22:209-15. Available from: http://www.jesnt.eg.net/text.asp?2022/22/4/209/356686 |
| Introduction | |  |
The prevalence of cardiovascular morbidity and mortality is high in patients on hemodialysis [1]. Various mechanisms have been identified for increased risk of CVD in these patients, of which iron accumulation and iron overdose has gained recent importance. Hepcidin, a key peptide of iron metabolism, is regulated under hypoxia, iron deficiency, iron infusion, and inflammation [2–4]. Higher levels of serum hepcidin were observed in patients with chronic kidney disease (CKD) and those on dialysis. The possible mechanisms of increased risk of cardiovascular disease due to serum hepcidin were explained based on increased oxidative stress and formation of atherosclerotic plaques.
The aim of this study was to assess serum hepcidin levels in patients on hemodialysis and correlate with 1-year fatal and nonfatal cardiovascular outcomes.
| Patients and methodology | | |
Study design
Prospective observational study.
Sample size
In total, 80 patients on maintenance hemodialysis.
Setting
Patients on maintenance hemodialysis attending the Outpatient Hemodialysis Unit of Nephrology Department at Tertiary Care Government Teaching Hospital under cashless Government scheme. All our patients are on twice-weekly or thrice-weekly dialysis. All patients are given single-use dialyzers with 1.3-m2 surface area along with injection of erythropoietin and other regular medications including oral iron. Investigations are done as per the Government protocols.
Study duration
18 months.
Inclusion criteria:
- (1) Patients who are on maintenance haemodialysis for a minimum period of 3 months.
- (2) Patients who gave informed consent.
Exclusion criteria:
- (1) Patients who were noncompliant to the prescription of dialysis.
- (2) Patients with a past history of cardiovascular disease or history of cerebrovascular accident or prior history of peripheral vascular disease.
- (3) Patients who did not give consent.
Consent
Written informed consent was obtained from all the eligible dialysis patients.
Analysis
All the responses were tabulated and graphically represented as and wherever necessary. All data were entered into Statistical Package for Social Sciences (SPSS, IBM Inc., Armonk, NY, USA), Version 20 (statistical method of analysis), and statistical tools like mean, SD, and χ2 test were applied.
Study procedure
The protocol was submitted to Institute Ethical Committee (IEC).
| Results | | |
During the study period over 18 months, a total number of 80 patients were included in the study.
Mean age of the patients of the study group was 50.05 ± 10.01 years. Males were 57 (71.3%) and females 23 (28.7%). Hypertension was the most common comorbidity seen in 76 (95%) patients. Twenty-six (32.5%) patients had diabetes mellitus. Etiology for end-stage renal disease was presumed chronic glomerulonephritis seen in 54 (67.5%) and presumed chronic interstitial nephritis in 26 (32.5%) patients. The mean vintage of hemodialysis is 1.89 ± 1.08 years. Arterio venous fistula (AV) fistula was the common access in the study group, of whom, left radiocephalic AV fistula in 31 (38.7%) and left brachiocephalic AV fistula in 25 (31.2%) patients. Cardiac evaluation included electrocardiogram and echocardiogram. 2D echocardiogram was done in all the patients at baseline and regularly at a period of 6 months.. The most common finding on echocardiogram was concentric left ventricular hypertrophy LVH in 45 (56.2%) patients, left-ventricular (LV) diastolic dysfunction in 18 (22.5%) patients. Mild LV dysfunction was seen in eight (10%) patients, while moderate LV dysfunction was seen in three (3.8%) patients and one (1.2%) patient had LV dysfunction with concentric left ventricular hypertrophy (LVH). Four (5%) patients had mild pericardial effusion, while one (1.2%) patient had pericardial effusion along with concentric LVH ([Fig. 1]).
Baseline characteristics of the cohort are tabulated in [Table 1].
Serum hepcidin levels and high-sensitivity C-reactive protein (hs-CRP) were estimated as mentioned above. The mean hs-CRP levels are less than 24 mg/dl in 60 patients and more than 24 mg/dl in 20 patients. The mean hepcidin of the study population is 111.64 ± 32.71 ng/ml ([Table 2]).
Primary composite outcome
Of the 80 patients, 13 (16.2%) patients expired. On analysis of the factors influencing survival, it was observed that age, sex, duration, or frequency of dialysis did not show a statistically significant association with mortality. Laboratory parameters such as total leukocyte counts, serum albumin, cholesterol, high density cholesterol (HDL), serum-triglyceride urea levels, and creatinine levels showed significant association with mortality. Higher serum hs-CRP and higher serum hepcidin levels were associated with mortality (P<0.05) ([Table 3]).
Secondary composite outcome
We observed nine cardiovascular events in nine patients at the end of 6 months and four cardiovascular events in four patients at the end of 12 months. At the follow-up period of 18 months, there was no cardiovascular event in 67 patients. Adverse outcome leading to death was observed in 13 (16.2%) patients in the form of sudden cardiac arrest in nine (11.2%) patients, cerebro vascular accident in three (3.8%) patients, and acute coronary syndrome with severe LV dysfunction in one (1.2%) patient. On further analysis of composite outcome of cardiovascular morbidity and mortality, it was observed that the presence of diabetes was associated with sudden cardiac arrest (P<0.006) ([Table 4]).
Factors influencing serum hepcidin levels
Serum hepcidin levels were found to be high in patients of more than 60 years, female sex, and in those with diabetes and hypertension (although P>0.05). On further analysis, serum albumin, serum calcium, and serum bicarbonate levels showed negative correlation with serum hepcidin levels. Levels of hs-CRP showed a significant positive correlation with serum hepcidin levels ([Table 5], [Fig. 2]). Sensitivity and specificity of serum hepcidin level were assessed. The best cutoff of 118 ng/ml showed a sensitivity of 100% and specificity of 85% in predicting mortality.
Area under the curve for hs-CRP and hepcidin ([Table 6]) ([Fig 3][Fig 4][Fig 5]). | Table 6: Sensitivity and specificity of hepcidin in relation to mortality
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 | Figure 4: ROC of hs-CRP. hs-CRP, high-sensitivity C-reactive protein; ROC, receiver operating characteristic.
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 | Figure 5: ROC of serum hepcidin. ROC, receiver operating characteristic.
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| Discussion | | |
Hepcidin plays an important role in iron metabolism. Serum hepcidin is known to prevent mobilization of iron from macrophages forming atherosclerotic iron traps in macrophages increasing oxidative inflammation, atherogenicity, and thus enhancing the chances of cardiovascular disease.
Few positive findings in our study are: (a) serum hepcidin is strongly associated with all-cause mortality and cardiovascular outcomes. (b) Serum hepcidin level of 118 ng/ml had a sensitivity of 100% and specificity of 85% in predicting cardiovascular outcomes.
Recent studies assessed whether serum hepcidin is a cardiovascular marker in patients with CKD and on hemodialysis [5–7]. Kali et al. [8] in a study of 82 hemodialysis patients showed that serum hepcidin levels were associated with atherosclerosis and cardiovascular disease. Van der Weerd et al. [9] studied serum hepcidin levels in an randomised control trial involving 405 hemodialysis patients, and it was observed that serum hepcidin levels were associated with fatal and nonfatal cardiovascular events even after adjustment of cardiovascular mortality. In a study of 75 hemodialysis patients, Xu et al. observed that serum hepcidin levels correlated with cardiovascular outcomes [10]. Although the relation between serum hepcidin and left-ventricular mass index is inverse in CKD patients, the same was not proven in hemodialysis patients [11,12]. In our study, we did not assess the relation between serum hepcidin levels and Left Ventricular Mass Index. In a Chinese study of 159 patients, it was shown that serum hepcidin levels were associated with all-cause mortality [13].
In our study, the mean serum hepcidin levels were 111.6 ± 32 ng/ml. About 71% of the group had serum hepcidin levels less than 120 ng/ml and 30% of the patients had higher than the mean level. It was observed that there was no influence of age, sex, and presence of comorbidities on serum hepcidin levels. It was also observed that factors such as serum albumin, calcium, and bicarbonate showed a negative correlation with serum hepcidin levels. Levels of hs-CRP showed a significant positive correlation with serum hepcidin levels. This finding suggests the presence of inflammatory status in patients on dialysis. Several studies have shown an association of hepcidin levels with hs-CRP and ferritin levels [14]. We could not assess serum ferritin levels in our group.
On assessment of sensitivity of hepcidin levels with mortality, levels below 118 ng/ml had sensitivity of 100% and specificity of 85%. On univariate analysis, total leukocyte counts, serum albumin, cholesterol, HDL, serum triglycerides, urea, and creatinine levels showed significant association with mortality.
In our group, we observed both fatal and nonfatal cardiovascular events. There were no deaths related to infections or noncardiovascular events during the study period. Van der Weerd et al. studied serum hepcidin in chronic hemodialysis patients and concluded that hepcidin was associated with fatal and nonfatal cardiovascular events even after adjustment of inflammation [9]. Sonkar et al. [15] in a study of 80 patients showed that serum hepcidin was markedly increased along with hs-CRP, thus linking inflammation and poor cardiovascular outcomes.
| Conclusion | | |
In our study, the acute-phase reactant, hs-CRP, and hepcidin levels showed a statistically significant association with mortality. We could not analyze the inflammatory independent effect of serum hepcidin levels. It is well known that hepcidin is an acute inflammatory marker, and thus it may be understood that serum hepcidin levels in dialysis patients are associated with fatal and nonfatal cardiovascular events.
Financial support and sponsorship
Nil.
Conflicts of interest
Authors hereby declare that there is no conflict of interest.
| References | | |
| 1. | Tahir MA, Dmitrieva O, de Lusignan S, van Vlymen J, Chan T, Golmohamad R, et al. Confidence and quality in managing CKD compared with other cardiovascular diseases and diabetes mellitus: a linked study of questionnaire and routine primary care data. BMC Fam Pract 2011; 12:83.  |
| 2. | Bakris G, Vassalotti J, Ritz E, Wanner C, Stergiou G, Molitch M, et al. National Kidney Foundation consensus conference on cardiovascular and kidney diseases and diabetes risk: an integrated therapeutic approach to reduce events. Kidney Int 2010; 78:726–736. |
| 3. | Mejía-Rodríguez O, Herrera-Abarca JE, Ceballos-Reyes G, Avila-Diaz M, Prado-Uribe C, Belio-Caro F, et al. Cardiovascular and renal effects of bromocriptine in diabetic patients with stage 4 chronic kidney disease. Biomed Res Int 2013; 2013:104059. |
| 4. | Ohsawa M, Tanno K, Itai K, Turin TC, Okamura T, Ogawa A, et al. Comparison of predictability of future cardiovascular events between chronic kidney disease (CKD) stage based on CKD epidemiology collaboration equation and that based on modification of diet in renal disease equation in the Japanese general population – Iwate KENCO Study. Circ J 2013; 77:1315–1325. |
| 5. | Nakanishi T, Hasuike Y, Otaki Y, Kida A, Nonoguchi H, Kuragano T Hepcidin: another culprit for complications in patients with chronic kidney disease?. Nephrol Dial Transplant 2011; 26:3092–3100. |
| 6. | Zaritsky J, Young B, Gales B, Wang HJ, Rastogi A, Westerman M, et al. Reduction of serum hepcidin by hemodialysis in pediatric and adult patients. Clin J Am Soc Nephrol 2010; 5:1010–1014. |
| 7. | Ulu SM, Yuksel S, Altuntaş A, Kacar E, Ahsen A, Altug A, Celik S, Sezer MT Associations between serum hepcidin level, FGF-21 level and oxidative stress with arterial stiffness in CAPD patients. Int Urol Nephrol 2014; 46:2409–2414. |
| 8. | Kali A, Yayar O, Erdogan B, Eser B, Buyukbakkal M, Ercan Z, Merhametsiz O, et al. Is hepcidin-25 a predictor of atherosclerosis in hemodialysis patients?. Hemodial Int 2016; 20:191–197. |
| 9. | Van der Weerd NC, Grooteman MP, Bots ML, van den Dorpel MA, den Hoedt CH, et al. CONTRAST Investigators. Hepcidin-25 is related to cardiovascular events in chronic haemodialysis patients. Nephrol Dial Transplant 2013; 28:3062–3071. |
| 10. | Xu Y, Wang Y, Hu H, Li J, Tian T. Relationship between serum hepcidin levels and cardiovascular disease in patients with maintenance hemodialysis. Physiol Int 2020; 107:491–500. |
| 11. | Hsieh YP, Huang CH, Lee CY, Chen HL, Lin CY, Chang CC Hepcidin-25 negatively predicts left ventricular mass index in chronic kidney disease patients. World J Nephrol 2013; 2:38–43. |
| 12. | Mostovaya IM, Bots ML, van den Dorpel MA, Goldschmeding R, den Hoedt CH, Kamp O, et al. Left ventricular mass in dialysis patients, determinants and relation with outcome. Results from the COnvective TRansport STudy (CONTRAST). PLoS ONE 2014; 9:e84587. |
| 13. | Ling S, Xi L, Yan L, Yan L, Na D, Hui XW. Effect of serum hepcidin on predicting mortality in hemodialysis patients: a prospective cohort study. Iran Red Crescent Med J 2019; 21:3. |
| 14. | Roy JE, Shanthi B, Selvi VSK Serum hepcidin as an inflammatory marker in chronic kidney disease. J Pharma Res Int 2020; 32:40–45. |
| 15. | 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; 30:315–324. |
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]
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