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Effect of Recombinant Human Erythropoietin Therapy on Serum Erythropoietin Levels in Anemic CKD Patients in Baghdad City

Mohanad Yasir Al-Radeef*, Sajida Hussein Ismail, Ali Abdul-Majid Dyab Allawi

Department of Clinical Pharmacy, College of Pharmacy, Baghdad University, Iraq

Abstract: Anemia is a common complication associated with chronic kidney disease (CKD). It develops early in the course of the disease increasing its frequency with the reduction in renal function. Methoxy polyethylene glycol-epoetin beta (MPGE-β) is a chemically synthesized recombinant human erythropoietin (rHuEPO) with a much longer half-life than endogenous erythropoietin (EPO). This study aimed to determine the influence of rHuEPO therapy on serum EPO levels in anemic CKD patients on maintenance hemodialysis. Seventy patients with CKD on maintenance hemodialysis receiving MPGE-β and twenty healthy subjects without medical illnesses were enrolled in this case-control prospective study. Patients had significantly lower serum EPO levels as compared to control healthy group because of relative EPO deficiency in renal anemic patients. Moreover, a significant rHuEPO dose adjustment was done during the first three months which results in a significant elevation in serum EPO levels in patients during the study. Relative EPO deficiency is common in CKD patients and the administration of rHuEPO usually leads to a significant elevation in serum EPO levels in these patients.

Keywords: chronic kidney disease, serum erythropoietin, anemia, rHuEPO

Citation: Mohanad Yasir Al-Radeef, Sajida Hussein Ismail, Ali Abdul-Majid Dyab Allawi, Effect of Recombinant Human Erythropoietin Therapy on Serum Erythropoietin Levels in Anemic CKD Patients in Baghdad City. American Journal of Pharmacological Sciences, 4 (4). 46-50. January 2016. doi:10.12691/ajps-4-4-1

1. Introduction

Chronic kidney disease (CKD) is defined as kidney damage for three or more months, as described by abnormalities in structure or function of the kidney with or without decreased glomerular filtration rate (GFR) that manifested by pathologic abnormalities or markers of kidney damage involving abnormalities in the composition of the blood or urine and/or abnormalities in imaging tests [1], while end stage renal disease (ESRD) is a progressive and irreversible deterioration in the function of kidney in which the body’s ability to maintain metabolic and fluid and electrolyte balance fails, leading to uremia or azotemia (retention of urea and other nitrogenous wastes in the blood) [2]. For maintaining life, ESRD patients require regular courses of dialysis or kidney transplantation, and dialysis is only temporary that does not replace all of the renal functions [3].

According to the National Kidney Foundation Kidney-Disease Outcomes Quality Initiative (NKF-KDOQI), anemia can be defined as hemoglobin concentrations of less than 13.5g/dl for men and less than 12.0g/dl for women [4]. Conversely, the European Best Practices Guidelines for the Management of Anemia in Patients with Chronic Renal Failure defines anemia according to the age and sex. Anemia is defined as a hemoglobin level of less than 11.5 g/dl in women, less than 13.5 g/dl in men ≤ 70 years of age, and less than 12 g/dl in men > 70 years of age [5]. Regardless of the definition, anemia is a common complication that associated with CKD [5] that is typically normocytic, normochromic, and hypoproliferative [6]. Anemia develops early in the course of the disease increasing its frequency with the reduction in renal function. The incidence of anemia is less than 2 % in CKD stage 1 and stage 2, about 5% in CKD stage 3, 44% in CKD stage 4 and more than 70% in the ESRD [7].

Anemia is twice as prevalent in individuals with CKD (15.4%) as in the general population (7.6%) [8].

Optimal treatment of anemia due to CKD requires appropriate diagnosis, erythropoietin and iron therapy, and close monitoring of response [5]. This intervention has replaced transfusions as the cornerstone of treatment and improved the survival of CKD anemic patients [9].

Human erythropoietin (EPO) is an indispensable endogenous glycoprotein hormone that synthesized particularly in specific epithelial cells which line renal peritubular capillaries [10]. It is a cytokine for erythrocyte precursors in the bone marrow, and the glycoprotein hormone which regulates RBC production [11]. On the other hand, methoxy polyethylene glycol-epoetin beta (MPGE-β) is a chemically synthesized rHuEPO with a much longer half-life than erythropoietin. It can be produced by recombinant DNA technology in Chinese hamster ovary cells [12]. Like endogenous EPO, rHuEPO stimulates the proliferation and differentiation of erythroid progenitor cells in bone marrow. MPGE-β shows different activity to other rHuEPO at the receptor level. It is characterized by slower association to EPO receptor and slightly faster dissociation, resulting in a lower affinity for the receptor, and this lower affinity can result in less receptor-mediated endocytosis and contribute together with reduced subsequent lysosomal degradation and/or improved recycling to the slower elimination [13]. MPGE-β; therefore, has a longer half-life than EPO which enables MPGE-β to be administered or injected in a once-monthly dosing regimen [14].

This study is designed to determine the influence of treatment with rHuEPO on serum levels of EPO in anemic CKD patients on maintenance hemodialysis.

2. Materials and Methods

This case-control prospective study was carried out at Medical City Complex, Baghdad Teaching Hospital, Iraqi center of kidney dialysis under the supervision of consultant nephrologist from November 2015 until June 2016. Only (90) subjects completed the courses of the study successfully. These subjects were recruited into the following groups:

Patient Group: Includes 70 patients with CKD receiving rHuEPO (methoxy polyethylene glycol epoetin beta (MIRCERA®) pre-filled syringe containing 50, 100 or 200 µg in 0.3 ml supplied by Roche Diagnostics GmbH, Mannheim, Germany). The dose was individualized to achieve and maintain hemoglobin levels between 10-12 g/dl.

Control Group: Includes 20 healthy subjects without medical illnesses such as diabetes mellitus, hypertension, or renal disease including current or prior history of renal stone.

The primary inclusion criteria involved patients with chronic renal failure on maintenance hemodialysis for at least six months. Exclusion criteria involve the following: acute renal failure, age <18 years, inadequate data, hypertensive crises (diastolic blood pressure > 120mm Hg), psychiatric disorders and CNS diseases, renal carcinoma, and recent symptoms and signs of bleeding that required a blood transfusion.

Five milliliters of venous blood sample were drawn from each patient in the morning at 6:00 AM – 8:00 AM just prior to the start of the dialysis session after an overnight fasting from the hemodialysis needle puncture site 48–72 hours after the last dialysis. Samples were drawn from each patient at the beginning of the study (as baseline sample), then after 3 months and after 6 months of baseline sample to follow-up the changes in the studied parameters. During this time all the patients continued to receive MPGE-β. The blood sample was transferred into clean gel tube (that contains clot activator), left at room temperature for at least 30 minutes for clotting, centrifuged for 5 – 10 minutes at 3000 rpm to obtain serum. Serum then was stored at (–40°C) until time for the assay. A single blood sample was drawn from each subject of the control group.

Serum EPO is determined by using the DEMEDITEC erythropoietin immunoassay that is a two-site ELISA for the measurement of the biologically active 165 amino acid chain of EPO.

The study protocol was approved by the local ethics committee in the college of pharmacy, Baghdad University, Iraq but without specific informed consent from patients.

Statistical calculations were performed using the SPSS (version 20.0) program (SPSS Inc., Chicago, Illinois, USA) and Minitab version 17 software. In all comparisons, a p value <0.05 was considered statistically significant. Anderson-Darling test was performed to test the adherence of continuous variables to the normal distribution. Normally distributed variables presented using their mean and standard deviation and parametric tests were used, while non-normally distributed variables described by their median and their interquartile range (IQR) and non-parametric tests were used. Discrete variables presented using their number and percentages. The chi-square test was used for comparisons of discrete variables between each study group.

3. Result

Demographic data of the study groups are expressed in Table 1. The subjects enrolled in the present study were matched. However, clinically there was significant (p<0.05) elevation in serum urea, creatinine, and uric acid in patients group as compared to control group. Medications history was positive as the majority of these patients were taking folic acid, multivitamins, calcium carbonate or sevelamer, alfacalcidol and some of them were treating with antihypertensive agents and some of them were receiving antidiabetic drugs.

Table 1. Demographic Data of the Study Groups

Figure 1. Box plot of the median of serum erythropoietin levels (mIU/ml) in study groups at baseline

Results presented in Table 2 and Figure 1 showed that patients group had significantly (p<0.05) lower serum levels of EPO as compared to control healthy group.

Table 2. Serum Erythropoietin Level (mIU/ml) in Patients and Control Groups

During this study, the dose of rHuEPO received by patients was adjusted according to hemoglobin response and as shown in Table 3, the dose was increased significantly (p<0.05) from baseline toward 3 months, while this elevation was non-significant from 3 to 6 months.

According to this dose adjustment, there was a significant difference in serum EPO level in patients from the beginning of the study till the 6 months period, and for each 3 months interval, the change was significant. This means as the time increase the median change become more significant (p <0.05). These data are illustrated in Table 4 and Table 5 and in Figure 2.

Table 3. Dose of rHuEPO (µg/kg/week) Received by Patients Group during the Study

Figure 2. Box plot of median of serum erythropoietin level (mIU/ml) in patients group thought-out study

Table 4. Serum Erythropoietin Levels (mIU/ml) in Patients Group during the Study. Data Expressed as Median (IQR)

Table 5. Comparison between Each Subsequent Month for Serum Erythropoietin Levels in Patients Group during the study

4. Discussion

The use of rHuEPO in patients with renal failure has resulted in anemia correction and improvement in the quality of life for the majority of patients. The present study showed that in patients with CKD EPO level was significantly reduced as compared with normal healthy subjects. Such finding was seen by others [15,16]. EPO production is mainly triggered by anemia and tissue hypoxia. In CKD patient, EPO levels are inappropriately low for the degree of anemia. This reduction is explained primarily by the destruction of the EPO-producing fibroblasts of the kidney interstitial fibrosis during the natural history of CKD, and the overall reduction in renal mass [15,16]. In addition to that, anemia in dialysis patients sometimes is attributed mainly to reduce bone marrow sensitivity to EPO, probably as a result of accumulation and retention of uremic toxins as well as inhibitors of erythropoiesis [17].

These data demonstrate clearly that there is a relative EPO deficiency in renal anemic patients rather than an absolute lack; even in patients with severe renal failure (CKD stage 5) concentrations of EPO were neither lower than the values from renal patients without anemia nor different from the normal range. However, EPO remains detectable even in the most advanced stages of CKD maintaining the minimal rate of erythropoiesis. This might be attributed to the residual renal function or alternatively hepatic production [18].

The current study also evaluated the dose of rHuEPO (MPGE-β) that had been given to the patients during the study and it found that a significant initial dose adjustment (p<0.001) depending on hemoglobin levels had been made in these patients at the first follow-up as compared with their baseline dose. This dose adjustment became non-significant (p=0.667) at the second follow-up.

These dose adjustments were done according to KDIGO guideline as it states that in initiating and maintaining rHuEPO therapy, it is recommended to balancing the potential benefits of decreasing blood transfusions and anemia-related symptoms against the risks of injury in individual patients (e.g., stroke, hypertension, and vascular access loss). In addition to that, for adult patients with stage 5 CKD on hemodialysis, it is suggested that rHuEPO therapy should be used to avoid having hemoglobin concentration falls below 9.0 g/dl, besides that, rHuEPO therapy should not be used to maintain hemoglobin concentration above 11.5 g/dl in these patients, as well as, rHuEPO dose adjustments should be made based on the patient’s hemoglobin concentration, rate of change in hemoglobin concentration, current rHuEPO dose and clinical circumstances [19]. It has been found that rHuEPO and its analogs were considered beneficial at normal doses; however, at high doses, they seem to exert toxic effects. rHuEPO toxicity has been associated with the numerous extra-hematopoietic actions of EPO and mainly with its effect on arterial pressure, the coagulation system, and vascular endothelium [20].

After these dose adjustments, the current study showed that serum levels of EPO were significantly increased in CKD patients during the study. The measured EPO levels in serum of these patients may be attributed mainly to the exogenous source of EPO rather than an endogenous source of EPO as high levels of circulating rHuEPO may result in suppression of endogenous EPO synthesis secondary to a decrease in intra-renal oxygen consumption. Mechanism involves:

(1) EPO decreases reabsorption of sodium and fluid in the proximal tubule, thus directly reducing the major oxygen-consuming process in the kidney;

(2) Increase in end-proximal tubular delivery to the macula densa reduces renin release and subsequent angiotensin II- and aldosterone-dependent reabsorption in more distal segments of nephron;

(3) Decreased proximal tubular reabsorption activates the tubule-glomerular feedback mechanism generating a fall in GFR and reduction of the filtered load;

(4) The resulting increase in renal oxygen partial pressure inside the environment of interstitial fibroblast-like cells down-regulates the HIF-2-dependent production of endogenous EPO [21].

In conclusion the relative EPO deficiency is common in CKD patients and the administration of rHuEPO (MPGE-β) usually leads to a significant elevation in serum EPO levels in these patients. A large and multi-centers study is required to confirm these findings.

Acknowledgments

The authors acknowledge the participation and cooperation of the patients enrolled in the study.

Conflict of Interest

None declared.

References

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