THE EFFECT OF IRON AND ERYTHROPOIETIN TREATMENT ON THE HBA 1 C OF HEMODIALYSIS PATIENTS WITH DIABETES

Ayman M. El-Badawy, Mohamed YehiaSeddek and Mohamed Shawky El-sayed Samira Marawan Hassan. Internal medicine department,Faculty of medicine, Banha University ,Qalyubia, Egypt.  ......................................................................................................................  Manuscript Info Abstract ......................... ........................................................................  Manuscript History

Background & Aims:: The aim of this thesis is tovalidate the effect of iron and erythropoietin treatment on theHbA1c of hemodialysis patients with diabetes. Methods:This study was conducted on 50 HD patients withtype-2 diabetes.All patients were selected from those under going regular HD in nephrology and dialysis unit inBanha University Hospitals. .the diagnosis of diabetes was based on a history of diabetes or on the ADA criteria. The patients classified into two groups (each consists of 25 patients).The first group (group A) are patients selected for iron therapy according to clinical need.The second group (group B) consisted of patients required ESA treatment.Glycemic control in both patient groups were assessed using HbA1c in the month leading up to treatment and once again for a 4-week period 4 months after therapy. Results:A1C value falls after four months of therapy inboth groups(iron and ESA group) compared to before therapy .this change was independent on glycemic control. Conclusions: This study showed that iron and ESA treatments resulted a significant fall in A1C, which was independent on glycemic changes in patients with diabetes and CKD.

…………………………………………………………………………………………………….... Introduction:-
A1c is the most widely accepted and used method of assessing chronic glycemia in patients with diabetes. It is formed by the irreversible binding of glucose to hemoglobin over the lifespan of the erythrocytes (Goldstien et al, 2004).Patients with Chronic kidney disease (CKD) are commonly anemic due to a variety of reasons, including functional or absolute iron deficiency and erythropoietin insufficiency. Treatment of anemia in patients with CKD using iron replacement therapy and erythropoietin-stimulating agents (ESAs) has resulted in significant improvements to quality of life and the correction of anemia without the need for blood transfusions(Nissenson et al, 1999).

Statistical analysis:-
The collected data were tabulated and analyzed using SPSS version 16 soft ware (SpssInc, Chicago, ILL Company) and. Categorical data were presented as number and percentages while quantitative data were expressed as mean ± standard deviation, and range. Categorical variables were analyzed using Chi square test (X2) and Fisher's exact test (FET). Quantitative data were tested for normality using Shapiro-Wilks test, assuming normality at P>0.05. St."t test was used to analyze the difference between 2 independent groups regarding normal variables, non parametric variables were analyzed using Man Whitney U test (MWU) for 2 independent groups and Friedman test which was used to test the differences between matched variables considering P value significant at 0.05. Significant Friedman test was followed by post hoc multiple comparisons using Bonferroni adjusted Wilcoxon test to detect the significant pairs at adjusted P =0.017         Among studied groups In group A mean serum ferritin before treatment 85.18 µg /l compared with one month later 515.77 µg /l and four months later 360.73 µg /lwich was highly significant( p<0.001)

Results:-
In group B mean serum ferritin before treatment 1039.9 µg /l compared with one month later 885 µg /l and four months later 950.3 µg /lwich was highly significant( p<0.001)In group B mean values of serum ferretin were significant high compared with group A in whole duration of study (p <0.001 )  In group A mean value of Hb% before treatment 8.8% compared with one month later 10.05% and four months later 11.06% which was highly significant (p<0.001)

S. Ferretin
In group B mean value of Hb% before treatment 9.26 % compared with one month later 10.32% and four months later 11.01 which was highly significant (p< 0.001) In group B mean value of Hb%before treatment and one month later and four months later compared with that of group A was non significant     ---------------Among studied groups,mean values of T. Protein in group A and group B along course of treatment were non significant.

6.9
T. protein 6       ESAs and intra venous iron are commonly used therapies in the management of anemia in patients with CKD. Patients with both diabetes and CKD have a higher prevalence of severe anemia compared with patients with CKD alone (Thomas et al.,2003).

The aim of this thesis was to evaluate:-
The effect of iron and erythropoietin treatment on the HbA1c of hemodialysis patient with diabetes. This study was conducted on 50 HD patients with type-2 diabetes. All patients was chosen from those attending Banha University Hospitals. The diagnosis of diabetes was based on a history of diabetes or on the ADA criteria. Information collected from participants included demographic data, height, weight (dry weight in HD patients), duration of diabetes and duration of HD. Patients with diabetes was restricted to those with stable blood glucose and whose diabetes treatment had not been altered during the preceding 6 months before the determination of HbA1c.
The patients was classified into two groups (each consists of 25 patients).
The first group (group A): It included patients selected for iron therapy with serum ferritin values <200 µg/l. All patients had hemoglobin ≤ 10.5 g/dl. Patients in this group were not on previous or concurrent ESA therapy and were vitamin B12 and folate replete. Intravenous iron was given as a single dose in the form of low-molecular weight iron dextran dependent on the patient's body weight. This was delivered as an initial intravenous test infusion of 100 mg of iron over 1 h followed by the remaining dose over the next 2-4 h.
The second group (group B):It consisted of patients who needed ESA treatment with serum ferritin value >200 µg /l. All patients receiving ESA therapy had hemoglobin < or =10.5 g/dl and were considered iron, vitamin B12, and folate replete prior to initiation. Patients were considered iron replete following a serum ferritin value >200 µg /l or having received intravenous iron at least 6 weeks prior to ESA therapy.The dose of ESA was titrated monthly to achieve target hemoglobin 10.5-12 g/dl.
All patients were subjected to complete history taking( age, sex , type of diabetes ,medications and duration of HD ) , complete physical examination investigated for HA1C, rondom blood glucose, S.Ferretin, T.Protein, albumin,BUN, creatinine before treatment, one month later and four month later.
The result of this work were tabulated and statistically analysed using suitable statistical tests. The results of this study were that, in group A patients, parentral iron administration was attended with a significant rise of serum ferretin after four months.in group B, serum ferretin showed a significant fall four months after ESA therapy.  Fig(4).
In this study, there was significant improvement in haemoglobin level in both groups( in group A mean hemoglobin after four months 11.06% compared with before therapy8.85% (p<0.001), in group B mean hemoglobin after four months 11.01% compared with before therapy 9.26% (p<0.001) ) with treatment and a decrease in the number of patients requiring blood transfusions. Table( On the other hand, the CHOIR trial studied the outcomes of anemia treatment in over 1400 CKD patients who had a hemoglobin < 11 g/dl at entry. Enrolled subjects were randomly assigned to EPO therapy treatment protocols designed to achieve a target hemoglobin levels of either 13.5 (n=715) or 11.3 g/dl (n= 717). The study was terminated prematurely due to higher mortality rates adverse events in the group with higher targeted Hb levels (Pfeffer et al., 2009 )reported that despite the increased usage of ESA agents, his findings had shown that the correction of anemia to levels of hemoglobin in excess of 12.5 g/dl in patients with type 2 diabetes using this therapy had not led to an improvement in mortality but rather an increased risk of stroke. This study showed that iron and ESA treatments result in a significant fall in A1C in patients with diabetes and CKD , the change was independent of glycemic changes. Table (11).In group A mean value of HbA1C before treatment was 6.7% compared withHbA1C four months after which was 5.95%. In group B the mean value of HbA1C before treatment was 6.42 % whereas HbA1C after four months was 5.41 %. Table (10) Fig(8).This study showed no significant change occur in fasting and post prandial levels among groups during course of treatment. Table (8,9) Fig (6,7).This study showed non significant Correlation between HbA1c and FBG, PP blood glucose among groups during the course of the study. Table ( 11).This results came in coordination with (Sunil et al., 2010) who achieved a similar study and reported that despite a lack of change of glycemic control in the both groups, A1C concentrations fell significantly (P<0.001 and 0.013, respectively, for groups A and B).The effect of the lowering of the A1c values following either treatment has been postulated to be secondary to the formation of new erythrocytes in the blood stream, causing a change of proportion of young to old cells, and also from an alteration in the red-cell glycation rates (Brooks et al, 1980,  Good glycemic control in patients with diabetes and CKD has been shown to be associated with better survival rates (Morioka, 2001).
The results of our study showed statistically significant falls in the A1C following iron and ESA treatment (mean 5.95% following iron and 5.41% following ESA) in the absence of a change in glycemic control. It showed that A1C can be unreliable and can fall following treatment with both iron and ESA therapy. (Sunil et al., 2010).Fluctuations of A1C that can occur in this patient group(patients with diabetes and CKD who were treated with iron or ESA therapy)so alternative methods for measuring glycemic control such as capillary glucose testing and CGM should be used, and therapy should not be based on the A1C value alone.
It has been shown that 62% of the population variance in HbA1c level is genetically determined (Jeffcoate, 2004). et al.,2007).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 pre-ESA compared with patients post therapy It is known that glycation among various proteins is increased in diabetic patients compared with non -diabetic subjects. Currently, among these glycated proteins, glycated hemoglobin (HbA1C) is used as the gold standard index of glycemic control in clinical practice for diabetes treatment. However, HbA1C does not accurately reflect the actual status of glycemic control in some conditions where plasma glucose changes during short term, and in patients who have diseases such as anemia and variant hemoglobin. In comparison, another index of glycemic control, glycated albumin (GA), more accurately reflects changes in plasma glucose during short term and also postprandial plasma glucose. Although GA is not influenced by disorders of hemoglobin metabolism, it is affected by disorders of albumin metabolism. Some diseases and pathological conditions where GA measurement is useful. These include the status of glycemic control changes during short term, diseases which cause postprandial hyperglycemia, iron deficiency anemia, pregnancy, chronic liver disease (liver cirrhosis), chronic renal failure (diabetic nephropathy), and variant hemoglobin (Masafumi and Soji, 2010).