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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 18  |  Issue : 2  |  Page : 40-45

Effect of recombinant human erythropoietin treatment on left ventricular hypertrophy and cardiac function in dialysis patients


Internal Medicine Department, Faculty of Medicine, Banha University, Banha, Egypt

Date of Submission18-Dec-2017
Date of Acceptance20-Feb-2018
Date of Web Publication4-Sep-2018

Correspondence Address:
Ahmed E Mansour
Internal Medicine Department, Faculty of Medicine, Banha University, Banha, 11311
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jesnt.jesnt_29_17

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  Abstract 


Background Cardiovascular disease is a significant complication in chronic kidney disease and a major cause of death in dialysis patients. Anemia is associated with reduced survival in patients with renal disease, and anemia is independently associated with an increased risk of cardiovascular disease. The body adapts to anemia by increasing cardiac output, which may result in cardiac remodeling and progression of left ventricular (LV) growth.
Aim The aim of this study was to shed light on the effects of correction of anemia after therapy with recombinant human erythropoietin (rHuEPO) on left ventricular hypertrophy (LVH) and consequently LV function in dialysis patients. So we studied 40 hemodialysis patients with hemoglobin (Hb) less than 10 g/dl as well as 10 age-matched and sex-matched hemodialysis patients with Hb more than 11 g/dl who never received erythropoietin as a control group.
Patients and methods All participants of the study were subjected to full medical history, thorough medical examination, and investigations including complete blood count, serum ferritin, and echocardiography.
Results A significant increase in Hb, packed cell volume (PCV%), and red blood cells (RBCs) count was seen at all months of the study period, with mean Hb at the start of the study being 7.96±0.72 g/dl and at the end of treatment being 10.67±0.83 g/dl. There is a significant increase in ejection fraction (EF%) with significant reduction in left ventricular mass index (LVMI) after treatment in comparison with pretreatment, which means improvement of cardiac function and reduction of LVH after treatment with rHuEPO.
Conclusion This prospective study showed that correction of anemia with rHuEPO in the patients undergoing hemodialysis with Hb level less than 10 g/dl led to correction of LVH, with improvement of the cardiac function.

Keywords: anemia, chronic kidney disease, erythropoietin, left ventricular hypertrophy


How to cite this article:
El-Badawy AM, Mansour AE, Abdelmoniem RO, Rabee AE. Effect of recombinant human erythropoietin treatment on left ventricular hypertrophy and cardiac function in dialysis patients. J Egypt Soc Nephrol Transplant 2018;18:40-5

How to cite this URL:
El-Badawy AM, Mansour AE, Abdelmoniem RO, Rabee AE. Effect of recombinant human erythropoietin treatment on left ventricular hypertrophy and cardiac function in dialysis patients. J Egypt Soc Nephrol Transplant [serial online] 2018 [cited 2018 Sep 21];18:40-5. Available from: http://www.jesnt.eg.net/text.asp?2018/18/2/40/240584




  Introduction Top


Chronic kidney disease (CKD) is a growing public health epidemic that is associated with markedly increased risk of cardiovascular disease (CVD) and mortality [1].

The prevalence of CVD is increased among patients in all stages of CKD. The Cardiovascular Health Study analysis demonstrated that per every 10 ml/min/1.73 m2 decrease in glomerular filtration rate, the risk of CVD and all-cause mortality increased by 5 and 6%, respectively. In end-stage renal failure, the CVD is by far the leading cause of morbidity and mortality causing 40–50% of hospitalizations and deaths [2].

There is a high prevalence of left ventricular hypertrophy (LVH) in CKD. In fact, LVH is present in more than 70% of patients commencing dialysis (Dharawat et al., 2009) [3].

Anemia is a severe complication of CKD that is seen in more than 80% of patients with impaired renal function [3]. Although there are many mechanisms involved in the pathogenesis of renal anemia, the primary cause is inadequate production of erythropoietin (EPO) by the damaged kidneys. EPO is produced in the peritubular cells of the kidney and is the major hormone involved in the synthesis of red blood cells (EPO). When EPO levels are low, an inadequate number of oxygen-carrying red blood cells are produced. Anemia decreases oxygen supply all over the body and causes decreased exercise capacity, cognitive impairment, and diminished quality of life [3].

Anemia has also been implicated in the development of congestive heart failure and LVH [4]. Although treatment with recombinant EPO has improved the management of anemia in CKD, anemia persists as a significant problem in the disease [5].

The aim of this study was to shed light on the effects of correction of anemia after therapy with recombinant human erythropoietin (rHuEPO) on LVH and consequently left ventricular (LV) function in dialysis patients as regarding assessment of systolic function and LV measurements.


  Patients and methods Top


This cohort prospective study was conducted on 40 hemodialysis patients with hemoglobin (Hb) less than 10 g/dl as case group and 10 age-matched and sex-matched hemodialysis patients with Hb more than 11 g/dl who never received EPO as a control group.

All participants of this study were submitted to full medical history with focus on manifestations of CKD, manifestations of heart failure, manifestations of anemia, and cause of renal failure, either diabetes mellite (DM), hypertension (HTN), or any other cause.

Medical examination focused on signs of CKD, signs of heart failure, and signs of anemia. Complete blood count and serum ferritin were measured.

For all participants, a baseline investigation was done before treatment, including complete blood picture with focusing on red blood cells (RBCs) count, packed cell volume (PCV%), serum ferritin, and echocardiography.

Echocardiography was done for all participants at the start of the study. Complete blood count was done monthly for 6 months. At the end of the study, complete blood count and echocardiography were again done for all participants.

Statistical analysis

The clinical data were recorded on a report form. These data were tabulated and analyzed using the computer program statistical package for the social sciences (SPSS) version 20 (Oracle Corporation, Chicago, United States).

Descriptive data

Descriptive statistics were calculated for the data in the following form:
  1. Mean and SD for quantitative data.
  2. Frequency and distribution for qualitative data.


Analytical statistics

In the statistical comparison between the different groups, the significance of difference was tested using one of the following tests:
  1. Student’s t-test used to compare means of two groups of quantitative data.
  2. Paired t-test used to compare mean of variables in different time periods of quantitative data.
  3. Intergroup comparison of categorical data was performed by using Fisher exact test.


P value less than 0.05 was considered statistically significant, whereas more than 0.05 was considered statistically insignificant.


  Results Top


The age of the studied group ranges from 18 to 70 years, with mean age of 52.2±12.44 years. Overall, 48% were males and 52% were females. The weight of the studied group ranges from 54 to 110 kg, with mean weight of 77.44±15.18 kg; height ranges from 150 to 190 cm, with mean height of 169.4±7.79 cm; and BMI ranges from 19 to 35.75 kg/m2, with mean BMI of 26.92±4.29 kg/m2 ([Table 1]). This study shows nonsignificant difference between case and control regarding age, sex, weight, height, BMI, HTN, and DM ([Table 2]).
Table 1 Distribution of the studied group

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Table 2 Comparison between case and control regarding age, sex, weight, height, and BMI

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There is a significant increase in Hb level, PCV%, and RBCs count at all months of the study period ([Table 3],[Table 4],[Table 5]), and there is also a significant reduction in Hb, PCV%, and RBCs count in cases in comparison with control in all months of the study ([Table 6],[Table 7],[Table 8]).
Table 3 Hemoglobin difference at different follow-up periods from baseline among case group

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Table 4 PCV% difference at different follow-up periods from baseline among case group

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Table 5 RBCs count difference at different follow-up periods from baseline among case group

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Table 6 Comparison between case and control group regarding hemoglobin level at different follow-up periods

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Table 7 Comparison between case and control group regarding PCV% at different follow-up periods

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Table 8 Comparison between case and control group regarding RBCs count at different follow-up periods

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A significant reduction in serum ferritin in cases in comparison with control is seen at the start of the study ([Table 9]).
Table 9 Comparison between case and control group regarding ferritin level at start of the study

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There is a significant increase in EF% in cases after treatment in comparison with before treatment, and also a significant reduction is seen in left ventricular end systolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), interventricular septal diameter (IVSD), posterior wall thickness diameter (PWtD), LVM, and left ventricular mass index (LVMI) in cases after treatment in comparison with before treatment. Significant increase is seen in LVESD, left atrial diameter (LAD), IVSD, PWtD, LVM, and LVMI in cases before treatment in comparison with control, a significant increase in LAD in cases after treatment in comparison with control, and also a significant reduction in ejection fraction (EF%) in cases before treatment in comparison with control ([Table 10]).
Table 10 Echocardiographic findings

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  Discussion Top


Anemia in patients with CKD is associated with cardiovascular complications. Anemia has been independently associated with the development of LVH [6].

The use of erythropiotin (ESAs) in the management of renal anemia has been shown to improve survival, reduce cardiovascular morbidity, and enhance quality of life [7].

This study shows significant reduction in Hb, PCV%, and RBCs count in cases in comparison with control in all months of the study, and this indicates high prevalence of anemia in hemodialysis (HD) patients. This finding is consistent with the population-based study using National Health And Nutrition Examination Survey conducted in the USA that exhibited prevalence of anemia increases progressively as the estimated glomerular filtration rate decreases to less than 60 ml/min/1.73 m2 [8].

Recently, large population-based studies about the prevalence of anemia in nondialysis CKD were reported. The recent National Health And Nutrition Examination Survey report showed that the prevalence of anemia was 15.4% in patients with CKD stages 1–5 compared with 7.5% in non-CKD population (Stauffer et al. 2014) [9]. A Chinese report showed that 51.5% of patients with CKD stages 1–5 had anemia (Li et al. 2016) [10].

This study also shows significant increase in Hb concentration, PCV%, and RBCs count at all follow-up periods of the study. The mean Hb at baseline in our study was 7.96±0.72 g/dl and the mean Hb at the end of the study was 10.67±0.83 g/dl. This means that all cases of the study responded well to treatment with rHuEPO and achieved the target Hb of 11–12 g/dl. These results were consistent with the study of Abdu et al. [11] which shows that all patients of the study responded well to treatment with rHuEPO, and all patients achieved the target Hb of 11 g/dl [11].

Moreover, these results are consistent with the results of a multicenter study by Dimković et al. [12], which showed that Hb was significantly increased by increasing the dose of EPO B during the study compared with the baseline values. This significant increase was recorded after the third month of therapy, and it continued up to the 12th month. Although at the end of the study, 52% of patients achieved the target Hb level, a higher percentage of patients (83%) achieved Hb levels more than 11 g/dl, which is in accordance with the current guidelines (10–12 g/dl) [12].

These results are consistent with the data from a study by Al-Shohaib et al. [13] which re-enforced the previous conclusion with Julphar’s Epotin. Efficacy and tolerability to correct anemia and to maintain Hb within the target range of 11–12 g/dl in 80% of patients with ESKD on maintenance hemodialysis was achieved as per KDOQI Working Group on Anemia [14].

The target Hb in the present study was assigned to limit between 11 and 12 g/dl, and this is consistent with the study by Al-Shohaib et al. [13] which showed that this is the optimal target hemoglobin level in patients with ESRD who are under dialysis, and current guidelines recommended that Hb should not be increased more than 12 g/dl in high-risk patients with CVDs [13].

Finally, the KDOQI clinical practice recommendation clearly addressed that the Hb target should generally be in the range of 11–12 g/dl in dialysis and nondialysis patients with CKD receiving EPO stimulating agent therapy [15].

The echocardiographic findings in our study show a significant reduction in LVEDD and LVESD in cases after treatment in comparison with pretreatment and significant increase in LVESD and LAD in cases before treatment in comparison with control. These results are consistent with the study done by Wirginia Tomczak et al. [16], which shows a reduction in LV end-diastolic diameter, which also suggest a decrease in preload. These results are also consistent with a study done by Prasert and Siriwiwatanakul [17], which shows that there was a significant regression of LV end-diastolic diameter and LVMI especially in the highest tertile of basal LVMI.

Our results also show significant increase in EF% in cases after treatment in comparison with cases before treatment and significant reduction in EF% in cases before treatment in comparison with control, and this demonstrate that correction of anemia in hemodialysis patients by EPO resulted in significant improvement in LVEF. This is consistent with the study done by Hampl et al. [18] which showed that correction of anemia by rHuEPO resulted in significant improvement in NYHA class and LVEF, which is also consistent across high-risk subgroups [18].

In contrary to our results, data from the study by Tomczac-Watras et al. (2009) showed that the increase in Hb level did not significantly influence the EF% in the analyzed group of patients. Moreover, in contrary to our results, a study by Dimkovic et al. [12] showed that during their study, the LVEF values were not significantly changed, thus indicating the preserved LV function after the correction of hyperdynamic state, but this study had certain limitations. Its design was predominantly focused on the correction of anemia as an important risk factor for the development of LVH, whereas other risk factors were not investigated [12].

A significant reduction was seen in IVSD, PWtd, LVM, and LVMI in cases after treatment in comparison with before treatment, and this indicates an improvement in LVH in cases after correction of anemia by rHuEPO. These results are consistent with the study done by Ayus et al. [19] which showed that among patients with advanced chronic renal insufficiency, a reduction in Hb level is associated with increased odds of having echocardiographic LVH, and administration of EPO in patients with anemia with Hb less than 10 g/dl with severe renal insufficiency reduced LVMI after 6 months of therapy [19].

Our results also are consistent with the study by Hampl et al. [18]. We were able to demonstrate that regression and prevention of LVH is possible. Even in the high-risk subgroup of HD patients, namely, those with CAD, diabetes mellitus, hypertension, or those with very low LVEF, regression of LVH was achieved [18].

In contrary to our study results, a prospective Canadian study reported that normalization of the Hb, after a 48-week trial of erythropoietin therapy, did not lead to echocardiographic evidence of regression of LVH or LV dilatation [20].

In contrary to our study results, data from a study by Roger et al. [21] showed that only 33% of anemic participants had LVH. The lower prevalence of LVH noted by Roger et al. [21] compared with ours may be owing to enrolment of younger patients with more preserved levels of renal function and higher Hb levels [21].

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Gutiérrez OM, James L, Januzzi JL, Isakova T, Laliberte K, Smith K et al. Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation 2009; 119:2545–2552.  Back to cited text no. 1
    
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Melnikova I. Anaemiatherapies. Nat Rev Drug Discov 2006; 5:627–628.  Back to cited text no. 3
    
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Rao M, Pereira BJG. Prospective trials on anemia of chronic kidney disease: the trial to reduce cardiovascular events with Aranesp therapy. Business Briefing: North Am Pharmacol 2006; 64:97–103.  Back to cited text no. 4
    
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Obrador GT, Pereira BJ. Anemia of chronic kidney disease: an under-recognized and under-treated problem. Nephrol Dial Transplant 2002; 17(Suppl 11):44–46.  Back to cited text no. 5
    
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Astor BC, Muntner P, Levin A, Eustaca JA, Coresh J et al. Association of kidney function with anemia: the Third National Health and Nutrition Examination Survey (1988–1994). Arch Intern Med 2002; 162:1401–1408.  Back to cited text no. 8
    
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Stauffer MFT.Prevalence of anemia in chronic kidney disease patients in united states. Plos One 2014; e84943.  Back to cited text no. 9
    
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Li Y, Shi H, Wang WM, Peng A, Jiang GR, Zhang JY et al. Prevalence and awareness and treatment of anemia in chinese patients with non dialysis chronic kidney disease, first multicenter cross sectional study. Med (Baltimore) 2016; 95:e3872.  Back to cited text no. 10
    
11.
Abdu A, Arogundade F, Adamu B et al. Anaemia and its response to treatment with recombinant human erythropoietin in chronic kidney disease patients. West Afr J Med 2009; 28:295–299.  Back to cited text no. 11
    
12.
Dimković N, Mitić3 I, Andrić B et al. Complete correction of anemia with recormon ®(erythropoietin β) in patients on chronic hemodialysis. Med Pregl 2015; 68:324–330.  Back to cited text no. 12
    
13.
Al-Shohaib S, Shaker DS, Ghaedi BB, Alyarim M, Emara S, Behairy M et al. The hematopoietic effect of epotin (recombinant human erythropoietin-β) on maintenance hemodialysis end-stage kidney disease patients. Transplant Proc 2010; 42:753–759.  Back to cited text no. 13
    
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KDOQI Working Group on Anemia. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. CPR. Identifying patients and initiating evaluation. Am J Kidney Dis 2006; 47(Suppl 3): S17–S27.  Back to cited text no. 14
    
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KDOQI. KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target. Am J Kidney Dis 2007; 50:471–530.  Back to cited text no. 15
    
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Prasert T, Siriwiwatanakul N. Hemoglobin response and influence on left ventricular hypertrophy after 24-week treatment of a biosimilar epoetin-alfa in hemodialysis patients with anemia. J Med Assoc Thai 2007; 90:2574–2586.  Back to cited text no. 17
    
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Hampl H, Hennig L, Rosenberger CH, Amirkhalily M, Gogoll L, Riedel E et al. Effects of optimized heart failure therapyand anemia correction with epoetin beta on leftventricular mass in hemodialysis patients. Am J Nephrol 2005; 25:211–220.  Back to cited text no. 18
    
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Ayus JC, Go AS, Valderrabano F. Effects of erythropoietinon left ventricular hypertrophy in adults withsevere chronic renal failure and hemoglobin <10 g/dl. Kidney Int 2005; 68:788–795.  Back to cited text no. 19
    
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Foley RN, Parfrey PS, Morgan J, Barre PE, Campell P, Cartier P et al. Effect of hemoglobin levels inhemodialysis patients with asymptomatic cardiomyopathy. Kidney Int 2000; 58:1325–1335.  Back to cited text no. 20
    
21.
Roger SD, McMahon LP, Clarkson A. Effects ofearly and late intervention with epoetin alpha on leftventricular mass among patients with chronic kidneydisease (stage 3 or 4): results of a randomized clinicaltrial. J Am Soc Nephrol 2004; 15:148–156.  Back to cited text no. 21
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]



 

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