|Year : 2019 | Volume
| Issue : 3 | Page : 86-94
Effect of erythropoietin treatment on hemoglobin A1c levels in diabetic patients with chronic kidney disease
Ahmed Z EL Okel1, Ahmed R El-Arbagy2, Yassein S Yassein2, Seham Z Khodir3, Heba El Sayed Kasem2
1 Department of Nephrology, Naser Institute, Cairo, Egypt
2 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
|Date of Submission||12-Jan-2019|
|Date of Acceptance||19-Mar-2019|
|Date of Web Publication||2-Aug-2019|
MSc Ahmed Z EL Okel
MSc student, Department of Nephrology, Naser Institute, 32511
Source of Support: None, Conflict of Interest: None
Introduction Chronic kidney disease is a universal escalating health issue of many etiologies. It affects millions across the world from all racial and ethnic groups.
Objective The purpose of this study is to assess the influence of erythropoietin (EPO) therapy on glycated hemoglobin (HbA1c) levels while excluding conditions that cause changes in the blood glucose concentration.
Patients and methods Clinical data were collected from 60 Egyptian patients with chronic kidney disease; of these, 30 patients had a history for diabetes mellitus and 30 nondiabetic controls. Serum urea, creatinine, complete blood count, fasting and postprandial blood glucose levels, and HbA1c were measured by means of column chromatography before and 3 months later after a course of recombinant EPO treatment for anemia.
Results This study revealed that EPO medication had a significant effect on HbA1c levels, and the more erythropoiesis fluctuated by altering the dose of EPO, the more HbA1c levels changed, though there were no significant changes in blood glucose levels throughout the study period. The changes in HbA1c during the 3-month period were inversely correlated with the changes in Hb%.
Conclusion The change in Hb% should be kept in mind when the HbA1c level is evaluated in EPO-treated patients and formula should be proposed to correct HbA1c levels based on the change in hematocrit or the reticulocyte count.
Keywords: chronic kidney diseases, erythropoietin, glycated hemoglobin
|How to cite this article:|
EL Okel AZ, El-Arbagy AR, Yassein YS, Khodir SZ, Kasem HE. Effect of erythropoietin treatment on hemoglobin A1c levels in diabetic patients with chronic kidney disease. J Egypt Soc Nephrol Transplant 2019;19:86-94
|How to cite this URL:|
EL Okel AZ, El-Arbagy AR, Yassein YS, Khodir SZ, Kasem HE. Effect of erythropoietin treatment on hemoglobin A1c levels in diabetic patients with chronic kidney disease. J Egypt Soc Nephrol Transplant [serial online] 2019 [cited 2020 May 28];19:86-94. Available from: http://www.jesnt.eg.net/text.asp?2019/19/3/86/263899
| Introduction|| |
Chronic kidney disease (CKD) is an escalating health issue. It is delineated as kidney damage or glomerular filtration rate (GFR) less than 60 ml/min/1.73 m2 for more than 3 months. CKD rose up from the 27th leading cause of mortality in 1990, to become the 18th leading cause of mortality in 2010 and lastly to the 12th one in 2015, with death numbers approaching ∼1.1 million globally ,. Yet, epidemiological data in developing countries are still sparse or of limited quality .
The persistent surge in the incidence of diabetic kidney disease, together with a global inequity between over-nutrition and physical inactivity triggering overweight and obesity, is the crucial driver of the CKD burden . Between 2005 and 2015, the prevalence of diabetic kidney disease increased by 39.5% worldwide .
A frequent complication in CKD is anemia, causing various adverse clinical consequences , including an increased risk for hospitalization and mortality, and the development or the deterioration of cardiovascular disease risk factors, comprising left ventricular hypertrophy .
Although there is a complex mixture of factors responsible for the decreasing hemoglobin (Hb) levels in patients with progressive CKD, diminished EPO production by deteriorating kidneys is a decisive cause .
Human erythropoietin (EPO), which is the product of the EPO gene on chromosome 7, is a 30.4-kDa glycoprotein hormone composed of a single 165 amino acid residue chain to which four glycans are connected. The kidneys are the crucial sources of EPO; its synthesis is regulated by hypoxia-inducible transcription factors ,.
Circulating EPO binds to specific transmembrane receptors on erythroblasts to regulate erythroid proliferation and survival through an antiapoptotic mechanism, and also it serves as a growth factor to enhance red blood cell (RBC) maturation .
Glycated hemoglobin (HbA1c) is a term used to designate a series of stable minor Hb components formed slowly and nonenzymatically from Hb and glucose .
HbA1c measures the extent of HbA1c in the blood. HbA1c can be differentiated into three distinct fractions: A1a, A1b, and A1c. A1c is the most plentiful. It is considered the gold standard of measuring glycemic control over the past 3–4 months, because once a Hb molecule is glycated, it continues to persist in the RBC for the rest of its lifespan (120 days) .
Likewise, shortening the lifespan of RBCs via any cause will falsely lessen A1c level. The A1c level has been revealed to be falsely diminished in patients with hemolysis, such as thalassemia or sickle cell anemia, and in those who have undergone blood transfusions .
Conditions that may cause the A1c level to be falsely elevated include uremia, chronic alcohol intake, splenectomy, chronic renal failure, iron-deficiency anemia, and hypertriglyceridemia .
The aim of this study was to estimate changes in HbA1c levels after EPO medication in diabetic patients with CKD and to evaluate the reliability of HbA1c as a marker for assessment of glycemic control in those patients treated with recombinant EPO as an anemia therapy.
| Patients and methods|| |
This study included 60 patients presented to Menoufia University Hospitals with CKD at stages III and IV during the period from January 2017 to November 2018. Patients were divided into two groups (30 patients each).
- Group I: 30 patients with CKD associated with diabetes mellitus.
- Group II: 30 patients with CKD without diabetes mellitus. All patients started EPO treatment for 3 months starting from the start of March 2017 till the end of May 2017. The weekly dose of EPO ranged from 4000 to 12000 IU/week, with mean EPO dose of 8.8 and 8.4 in both groups I and II, respectively.
We excluded patients with advanced liver disease; previous EPO treatment chronic alcohol intake; chronic salicylates intake; opiate addiction; splenomegaly and splenectomy; iron, vitamin B12 and folate deficiency; blood transfusion; hemoglobinopathies; serological evidence of autoimmune diseases; hypertriglyceridemia; hyperbilirubinemia; and drug-induced hematological disease based on history and laboratory.
The study was approved by the Local Ethics Committee of the Ministry of Health and Population. An informed consent was taken from each individual who participated in this study, and all were fully informed concerning the nature of the disease and the diagnostic procedures.
All patients were subjected to thorough history taking, clinical examination including BMI (calculated as weight in kilograms divided by height in meters squared), assessment of vital signs, chest examination, heart examination, abdominal examination, neurological examination, and echocardiography before and after treatment with EPO.
Samples collection and biochemical analysis
Blood samples were drawn in the morning after a 12-h fast (from 8 p.m. to 8 a.m.); a portion of the blood was collected in EDTA tube for the determination of HbA1c. The other portion was left to clot at room temperature. Serum was separated by centrifuging for 10 min at 3000 rpm. Sera were divided into several aliquots and stored at −70°C until the time of the assay.
Moreover, laboratory investigations including complete blood count and liver and kidney functions were determined. Serum creatinine was measured according to the colorimetric kinetic method described by Jaffe  using a commercial assay kit obtained from Diamond Diagnostics (Cairo, Egypt). Uric acid was determined using kits provided by Biodiagnostic Co. (Cairo, Egypt). Serum albumin concentration was determined colorimetrically by BCG method  using a kit obtained from Human Biochemica und Diagnostica GmbH (Wiesbaden, Germany).
Fasting serum levels of total cholesterol, triglycerides, and high-density lipoprotein (HDL) were measured with an enzymatic colorimetric method (Stanbio Laboratory, Boerna, Texas, USA). Low-density lipoprotein (LDL) was calculated using Friedewald’s formula as follows: LDL-C (mg/dl)=TC−HDL-C−TG/5 .
Serum iron, ferritin, and total iron-binding capacity were assessed according to the method described by Peter and Wang .
In addition, fasting and 2-h postprandial serum blood sugar (PPBS) levels were determined by the enzymatic colorimetric method performed according to Trinder reaction . HbA1c level before and after 3-month course of recombinant EPO treatment for anemia was measured according to the cation exchange resin method described by Trivelli et al. , using a commercial assay kit obtained from Intermedical (Villaricca, Italy).
Erythrocyte sedimentation rate was determined, and C-reactive protein levels were also estimated by reagents purchased from DRG International Inc. (Springfield Township, New Jersey, USA).
Data management and statistical analysis were performed using statistical package for social sciences, version 23.0 (SPSS, Chicago, IL, United States).
All data were tested for Gaussian distribution, using the Shapiro–Wilks normality test.
Descriptive statistics were summarized as the frequency and percentage for categorical data and mean with SDs for continuous variables with approximately normal distributions. Between-group comparisons of the baseline characteristics were achieved by Student’s t-test for normally distributed variables and by χ2-tests for categorical variables. Comparison of all laboratory parameters before and after EPO therapy was performed by using the paired t-test.
For categorical variables, differences were analyzed with χ2-test and Fisher’s exact test when appropriate. Furthermore, the correlation of HbA1c with fasting blood sugar (FBS) and other parameters was determined by calculation of correlation coefficients. All P values are two sided. P values less than 0.05 were considered significant.
| Results|| |
The study group enrolled 60 patients with CKD with and without diabetes. Their age ranged from 40 to 76 years. Among those patients, 37 (61.67%) were males and 23 (38.33%) were females. Clinical and demographic characteristics of the patients enrolled in this study are summarized in [Table 1].
|Table 1 Comparison of demographic and metabolic characteristic of chronic kidney disease patients with or without diabetes at the beginning of the study|
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The mean age of patients who had CKD associated with diabetes was nearly identical to that of patients who did not have diabetes, and the percentage of men in each group was not significantly different. Moreover, BMI, systolic blood pressure, diastolic blood pressure, infection with hepatitis, total bilirubin, and GFR levels showed no significant difference between the studied groups.
The clinical parameters in both groups were comparable at the beginning of the study ([Table 1]).
The mean Hb levels in group I patients before treatment were 9.39 g/dl, whereas it was 9.46 g/dl in group II, without statistical difference (P=0.542). After 3 months of treatment, the Hb levels increased in both groups (I and II) to 10.86 and 10.93 g/dl, respectively, as shown in [Table 2] and
[Figure 1]. Other hematological parameters, such as white blood cells, were significantly reduced after 3 months of treatment in both groups (I and II) (from 7.73 to 6.37 103/μl, P<0.001, and from 8.36 to 6.6 103/μl, P<0.001, respectively). In contrast, no effect of treatment was observed on platelets count. Regarding the kidney function tests (creatinine, sodium, potassium, and uric acid), they were significantly higher values before treatment, which improved on receiving EPO in both groups ([Table 2]).
|Table 2 Clinical and laboratory data of the studied groups before and after administration of a therapy|
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|Figure 1 Hemoglobin level in groups I and II before and after treatment with erythropoietin.|
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The results showed that serum levels of albumin were significantly increased after receiving treatment in patients in both groups (I and II) compared with its levels before therapy (P≤0.001).
The recent study showed that there was a slight and nonsignificant increase in the fasting and PPBS in sera of patients administered EPO in group I as compared with baseline (P=0.381 and 0.359, respectively), whereas low and insignificant decrease in both parameters was detected in group II after administration of therapy (P=0.069 and 0.294, respectively) ([Table 2], [Figure 2] and [Figure 3]).
|Figure 2 Fasting blood sugar in groups I and II before and after treatment with erythropoietin.|
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|Figure 3 Postprandial blood sugar in groups I and II before and after treatment with erythropoietin.|
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In addition, HbA1c percentage was significantly decreased after receiving treatment in both groups compared with its level before therapy (P<0.001) ([Table 2] and [Figure 4]).
|Figure 4 Glycated hemoglobin level in groups I and II before and after treatment with erythropoietin.|
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Although the mean concentration of ferritin was significantly increased in group I patients after receiving therapy than its level before the treatment (P=0. 0.017), no effect of therapy was observed on serum level of ferritin in group II patients, with a slight nonsignificant decrease detected after receiving treatment (P=0.864).
The transferrin saturation percentage was elevated in both group patients (I and II) after 3 months of treatment (17.03±9.02–28.7±5.62%, P<0.001, and 21.45±8.57–28.37±4.44%, P<0.001), as compared with baseline.
Finally, both groups showed a statistically significant decrease in the percentage of left ventricular mass index after obtaining the treatment compared with its percentage at the beginning of the study (140.5±5.04–124.2±4.25%, P<0.001, and 141.2±6.14–121.8±5.43%, P<0.001, respectively).
In this study, the decline in HbA1c after EPO therapy showed a significant negative correlation with the increase of Hb levels in both groups I and II (r=−0.879, P<0.001 and r=−0.883, P<0.001, respectively). No correlation was found between HbA1c and other parameters in both groups ([Table 3]).
|Table 3 Correlation between changes in glycated hemoglobin and changes in other parameters in both groups|
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| Discussion|| |
CKD is increasingly classified as a worldwide public health issue with adverse outcomes on patients’ health and carries a huge financial burden. Diabetes and hypertension confer the highest risks for acquiring CKD .
Assay of HbA1c in blood is an important indicator of long-term cumulative glycemic control with the ability to reflect the average blood glucose levels throughout the preceding 2–3 months, which is the predicted half-life of RBCs .
Patients with CKD are commonly anemic owing to a variety of reasons. Treatment of anemia in patients with CKD using iron replacement therapy and EPO stimulating agents has resulted in significant improvement of the quality of life and anemia correction without need for blood transfusion .
Thus, this study aimed to evaluate HbA1c as a marker for the assessment of glycemic control in patients treated with recombinant EPO for anemia correction.
This study included 60 patients known to have CKD at stage IIIB or IV. They were divided into two groups. Thirty patients in group I had diabetes mellitus on regular follow-up for blood glucose levels and with no previous history of EPO. The remaining thirty patients in group II were free of diabetes but had CKD stage IIIB or IV with no previous history of EPO.
There was a statistically significant improvement in Hb levels (P<0.001) in both patient groups 3 months after EPO therapy. This improvement resulted from EPO influence on erythroid lineage in the bone marrow as EPO is the main regulator of erythropoiesis. It acts through binding to EPO receptor on the early erythroid precursor cells and stimulates their survival, proliferation, and differentiation .
In our study, the dose of EPO was adjusted to accomplish target Hb of 10.5–12 g/dl, and this resulted in correction of anemia and improvement of kidney function tests, albumin, and cardiac functions significantly after EPO therapy. In agreement with this study, numerous studies have demonstrated that anemia correction in patients with CKD improves the quality of life and reduces the need for transfusion ,.
Evidence suggesting that the correction of anemia improves cardiovascular outcomes has largely been derived from observational studies and small interventional trials associating a high level of Hb (about 12.0 g/dl) with a lower rate of complications and death from cardiovascular causes ,.
The 2006 NKF KDOQI counseled that the target Hb concentration is ∼11–12 g/dl, with recommendations against routinely maintaining Hb concentrations of more than 13 g/dl in patients with CKD . Moreover, CHOIR Study published that the relative risk for death, stroke, myocardial infarction, and hospitalization for congestive heart failure was statistically higher in patients receiving epoetin α with the aim to achieve Hb levels of 13.5 g/dl than patients whose target Hb was 11.3 g/dl, with a strong trend toward increased mortality and rate of hospitalization for CHF reported in the high Hb group, as well as an increased rate of serious adverse events such as thrombotic events .
Furthermore, the results of this study revealed that there were no statistically significant changes in both fasting and PPBS levels in both groups. However, results showed a statistically significant decline in HbA1c level (P<0.001) in both studied groups. The aforementioned results were in accordance with Inaba et al.  as well as Ng et al.  who demonstrated a meaningful reduction in HbA1c levels after EPO therapy without changes in glycemic control in patients with type 2 diabetes and CKD.
In a similar Egyptian study, Abdel-Aziz et al.  reported a significant decrease in both HbA1c and FBS levels after 3 months of EPO treatment to diabetic patients with CKD. They elucidated that the cause for this correction in FBS levels is unclear. However, they explained that the fall in HbA1c levels after EPO therapy was a false decline via the new RBCs added to the existing pool, with less circulating time and hence lower glycation rate. Besides, the proportion of novel RBCs to old ones after EPO therapy is considered to surge, thus falsely decreasing HbA1c levels.
This is evidenced by the significant negative correlation found between HbA1c and Hb%. This means that HbA1c is inversely proportional to Hb% levels, in a linear fashion. The decline in HbA1c is associated with improvement in hematocrit.
HbA1c is influenced by RBCs survival because the average lifespan of RBC is 120 days. These results propose that the effect of EPO on HbA1c causing its decrease is possibly mediated via its influence on bone marrow erythroid lineage, and subsequent change in the RBCs turnover and formation of new erythrocytes in the bloodstream, causing a change of proportion of young to old RBCs, and this change was independent of glycemic changes .
Moreover, the results of this study showed no correlation between changes in HbA1c levels and other laboratory data such as serum albumin, GFR, and electrolytes. This further excludes that the significant decline noted in HbA1c after EPO treatment might be owing to the effect of other variables.
The lack of direct correlation between HbA1c and FBS and PPBS in both study groups provides a proof that HbA1c is not a reliable biomarker for glycemic control in such patients.
Discordantly, high A1c values paralleled to glucose readings have been reported in previous studies and case reports on nondiabetic patients with iron deficiency and in patients with type 1 diabetes in childhood and pregnancy ,.
Moreover, these results were in contrast with Katz et al. , who reported the effect of EPO on the reduction of blood glucose level.
So alternative methods for measuring glycemic control such as capillary glucose testing and glycated albumin should be used, and therapy should not be based on the A1c value alone . Glycated albumin has been suggested as an alternative marker to represent glycemic control, as it was noted to be similar (in contrast to A1c, which was higher) in patients with iron deficiency and in pre-ESA administration period compared with patients after therapy ,.
| Conclusion|| |
Currently, HbA1c is the gold-standard index of glycemic control for diabetes treatment in clinical practice. However, HbA1c does not accurately reflect the actual status of glycemic control in some circumstances where plasma glucose level changes during short term, and in patients who have diseases such as anemia and variant Hb. It was concluded that the changes in Hb% should be kept in mind when the HbA1c level is evaluated when EPO is used in the management of anemia in patients with both diabetes mellitus and CKD.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]