| Abstract|| |
Darbepoetin due to longer half life is convenient and effective for long term. This study was done to assess the efficacy of darbepoetin in the treatment of patients on high doses of erythropoietin (EPO) and to compare its efficacy in patients resistant and responsive to EPO. This is a prospective, controlled open label study assessing the efficacy of darbepoetin in 55 hemodialysis patients on high dose EPO and comparing its efficacy in the patients who were "EPO -resistant" (group 1, n= 28) and in those who were "EPO-responsive" (group 2, n= 27). The initial conversion ratio was 380 mcg darbepoetin: 1 U EPO/ week and the dose of darbepoetin was adjusted thereafter at fortnightly intervals with the aim of achieving and maintaining the hemoglobin level between 11-12 g/dL. The patients were followed up for 12 weeks following the introduction of darbepoetin. The impact of gender, baseline PTH, age, Kt/V, duration on dialysis, initial EPO dose on the response to darbepoetin was investigated. Continuous variables were compared using two tailed t-test and non-parametric by Fisher exact test. Overall darbepoetin was effective with 85.5 % of the patients responding and 21.8 % of the patients' able to maintain their hemoglobin with once fortnightly dose by the end of the study. Mean darbepoetin dose and the mean EPO to darbepoetin conversion ratio on completion of the study were 58.2 (42.4) mcg/week (0.983 (0.87) mcg/kg/week) and 384:1 respectively. Hemoglobin levels in groups 1 improved from 9.8 ± 0.9 g/dL to 12.0 ± 1.4 g/dL (0.0001) and 2 were and maintained it in group 2 at 11.9 ± 1.3 g/dL (P= 0.79). The doses of darbepoetin required in groups 1 and 2 were similar (54.3 ± 33 and 53.9 ± 47 mcg/week (P= 0.97) respectively and 0.89 ± 0.6 and 0.98 ± 1.0 mcg/kg/week (P= 0.8). 22 (78.6 %) of the EPO resistant patients responded to darbepoetin. In conclusion conversion from high dose EPO to darbepoetin proved successful even in patients who were resistant to EPO. The darbepoetin dose required in the EPO resistant and EPO responsive groups did not differ significantly and age, duration on dialysis and baseline PTH level had no impact on responsiveness to EPO or darbepoetin.
Keywords: Darbepoetin, Hemodialysis, Resistance to Epo
|How to cite this article:|
Hejaili F. The efficacy of darbepoetin alpha in hemodialysis patients resistant to human recombinant erythropoietin (rHuEpo). Saudi J Kidney Dis Transpl 2009;20:590-5
|How to cite this URL:|
Hejaili F. The efficacy of darbepoetin alpha in hemodialysis patients resistant to human recombinant erythropoietin (rHuEpo). Saudi J Kidney Dis Transpl [serial online] 2009 [cited 2019 May 21];20:590-5. Available from: http://www.sjkdt.org/text.asp?2009/20/4/590/53246
| Introduction|| |
There is good evidence that darbepoetin alfa is effective in the treatment of anemia in dialysis patients when given once weekly or once every two weeks. ,, Erythropoietin (EPO) has proven its efficacy over the number of years but because of shorter half life requires to be given twice or three times weekly.  In 5% to 10% of patients resistance to EPO is documented  even in the presence of adequate iron stores and absence of on going inflammatory process. 
Women and elderly patients have been reported previously to require higher doses of EPO.  Another factor causing EPO hypo-responsiveness is suboptimal dialysis and a 10% rise in urea reduction ratio leading to small but significant linear rise in hemoglobin of 0.10 g/dL. 
The Kidney Disease Outcomes Quality Initiative (KDOQI) Guidelines and the European Best Practice Guideline (EBPG)  defines epoetin hyporesponsiveness as failure to attain the target hemoglobin despite receiving > 300 IU/kg/week EPO or 1.5 mcg/kg of darbepoetin (100 mcg/ week) (given subcutaneously), or a continued need for such high doses to maintain target hemoglobin). When administered intravenously, the threshold for diagnosing EPO resistance is raised to 400 or 450 IU/kg per week. 
In this study we investigate the responsiveness to darbepoetin when given to hemodialysis patients on high doses of epoetin and to compare the outcome in an EPO resistant group and an EPO-responsive group.
| Methods|| |
This is a prospective, controlled open label study assessing the efficacy of darbepoetin in 55 hemodialysis patients on high dose EPO and comparing its efficacy in the patients who were "EPO-resistant" (group 1, n= 28) and in those who were "EPO-responsive" (group 2, n= 27). Resistance to EPO was defined as inability to achieve a hemoglobin level of > 11.0 g/dL despite high dose of EPO (> 300 U/Kg/week) in the absence of iron deficiency, active infection, malignancy or blood loss.
All patients were being treated with EPO for over one year prior to conversion to darbepoetin. The initial conversion ratio was 200 mcg darbepoetin: 1 U EPO/week and the dose of darbepoetin was adjusted thereafter at fortnightly intervals with the aim of achieving and maintaining the hemoglobin level between 11 to 12 g/dL. The patients were followed for 12 weeks following the introduction of darbepoetin.
We also investigated the impact of gender, baseline PTH, age, Kt/V, duration on dialysis and initial EPO dose on the response to darbepoetin.
Diet, dialysis regimen, dry weights, type of dialyzer and anti hypertensive medications were kept the same before and after conversion to darbepoetin.
Parametric variables were compared using paired and two tailed t-test and non parametric by using Fisher exact test.
| Results|| |
A) In all the patients as a group overall
Darbepoetin was effective with 85.5% of the patients responding and 21.8% of the patients' were able to maintain their hemoglobin with once fortnightly dose by the end of the study. This later group of patients required significantly lower darbepoetin dose/week 22.3 ± 9.8 versus 72.5 ± 32.3 mcg/week (P= 0.0001) and the achieved hemoglobin level was higher 13.5 ± 0.2 versus 11.5 ± 1.2 (P= 0.0001) respectively. Other characteristics are shown in [Table 1].
At the completion of the study following the conversion to darbepoetin, there was no change seen in systolic blood pressure, a slight drop ion diastolic blood pressure (P= 0.012) and a significant rise in mean hemoglobin level from 11.1 ± 1.6 to 11.9 ± 1.3 g/dL (P= 0.0037 [Table 1].
Overall the mean darbepoetin dose on completion of the study was 58.2 ± 42.4 mcg/week (0.983 ± 0.87 mcg/kg/week). The mean EPO to darbepoetin conversion ratio at the beginning and at the completion of the study were 388:1 and 384:1 respectively [Table 1].
Age, duration on dialysis and baseline PTH level had no impact on initial and final hemoglobin levels or on the doses of rHuEpo and darbepoetin per kilogram body weight [Table 2].
The dose of darbepoetin per kg required was not statistically different between male and female patients. However, female patients required higher doses of EPO than males (396 ± 204 and 284 ± 145 IU/kg/week respectively (P= 0.027). The final hemoglobin levels, following conversion to darbepoetin were comparable however (11.7 ± 1.5 vs 12.0 ± 1.2 g/dL (P= 0.46) [Table 3].
B) Comparison of EPO-resistant patients (group 1) and EPO-responsive patients (group 2)
The mean pre-conversion dose of EPO in group 1 and group 2 were 22576 ± 8509 U/week and 18074.1 ± 6293 U/week (P= 0.065) and the mean EPO doses/kg/week were (442 ± 168 and 205 ± 63 (P= 0.0001) U/kg/week respectively. The mean age, years on dialysis and mean PTH levels were not different between the groups.
Similarly, both groups had adequate iron stores.
The EPO: darbepoetin ratio was significantly higher in group 1 than group 2 (432:1 and 338:1 respectively (P= 0.003) and the resistance index (ratio between weekly dose per kilogram of weight/level of hemoglobin) was higher in group 1 [Table 4].
The mean pre-conversion dose of EPO in group 1 and group 2 were similar whereas the mean EPO doses/kg/week were significantly higher in group 1 [Table 5].
The pre-conversion hemoglobin levels in group 1 were significantly lower which increased after Darbepoetin conversion, however the doses required in each group was similar [Table 5].
[Table 6] shows that 78.6% of the EPO resistant patients responded to darbepoetin raising the hemoglobin level significantly (from10 g/dL to 12.5 g/dL (P= 0.0001).
We found no significant differences between the darbepoetin responsive subgroup and the darbepoetin-resistant subgroup among the EPOresistant patient in terms of age, duration on dialysis, the EPO dose required or darbepoetin dose required or the baseline levels of ferritin (P> 0.05).
| Discussion|| |
For our study we have selected a group of hemodialysis patients who required high dose of EPO. Half of these patients achieved the required hemoglobin levels and half did not and we investigated the efficacy of darbepoetin in these groups.
Besides improving the quality of life,  , the use of recombinant human erythropoietin (epoetin) also improves survival  and reduce morbidity in CKD patients.  In a study in 998 hemodialysis patients followed up for six months, (EPIBACDIAL Study), anemia was associated with at least one episode of bacteremia. 
Despite the availability and use of EPO, anemia remains common in dialysis patients due to a variety of reasons including sup-optimal dosing in order to save costs or due to non attendance to factors known to cause hypo-respon siveness to epoetin.  ,
The European Survey on Anaemia Management (ESAM) 2 estimtes that 34% of the patients treated with ESA do not achieve a hemoglobin level of 11 g/dL. 
The most common cause of suboptimal response to epoetin is absolute iron deficiency (ferritin concentration less than 100 mg/L with or without reduced transferrin saturation) or functional iron deficiency (ferritin concentration greater than 100 mg/L associated with a TSAT < 20%).  ,
Iron deficiency is thought to be the cause of hyporesponsive to ESA in 51.6% of cases. 
Serum ferritin level of 400 ng/mL was associated with higher Hb levels at lower EPO levels when compared with 200 ng/mL.  The ferritin levels in our study were high before and after conversion suggesting that the observed resistance to EPO in some of the patients was not related to iron deficiency. Parathyroidectomy has been reported to be associated with fewer requirements of EPO and at the same time rise in hemoglobin. 
There are a number of reports that confirmed a negative association between dialysis adequacy and EPO dose and a positive association between dialysis adequacy and hemoglobin level.  Our patients were being adequately dialyzed with mean Kt/V before and after conversion was >1.5 .
We have noted that the EPO to darbepoetin dose ratio to achieve optimal hemoglobin level increased with time. Similar observation was made by other others.  , Indeed in 21.2% of our patients, darbepoetin dose dropped form once weekly to once fortnightly. Similar results were obtained by others. 
As has been shown in other reports,  we find that female patients require higher doses of EPO to achieve comparable hemoglobin levels. Unlike other reports which suggested reduced response to EPO in elderly patients  we have not found this to be the case in our patients.
Of the 28 patients with EPO resistance, 22 (78.6%) responded to darbepoetin.
Darbepoetin was equally effective in both epoetin resistant and epoetin responsive patients. The darbepoetin doses required in both groups were similar with the resistant group requiring 0.98 mcg/kg/week and the responsive group requiring 0.89 mcg/kg/week (P= 0.8). However there was markedly higher EPO: darbepoetin ratio in the resistant group (432: 1 versus 338:1 (P= 0.003). These figures also suggest that besides its efficacy in patients requiring high doses of EPO as well as those resistant to EPO, darbepoetin could be a source of cost saving in these patients.
In conclusion, conversion from high dose EPO to darbepoetin proved successful even in patients resistant to EPO without any significant difference in darbepoetin dose between the EPO-resistant and EPO-responsive groups. The response rates in males and females were similar although the dose requirement in females was higher.
Age, duration on dialysis and baseline PTH level had no impact on responsiveness to EPO or darbepoetin.
| Acknowledgement|| |
The author thanks Nader Omran and Karen Newsham for collecting data and support.[Table 3]
| References|| |
|1.||Shaheen FA, Akeel N, Alfi A, Harbi A, Tarif N, Souqiyyeh M. Darbepoetin use for the treatment of anemia in hemodialysis patients in Saudi Arabia. Saudi J Kidney Dis Transpl 2006;17(3): 365-72 |
|2.||Locatelli F, Canaud B, Giacardy F, Martin-Malo A, Baker N, Wilson J. Treatment of anaemia in dialysis patients with unit dosing of darbepoetin alfa at a reduced dose frequency relative to recombinant human erythropoietin (rHuEpo). Nephrol Dial Transplant 2003;18(2):362-9. |
|3.||MacDougall I. Once weekly erythropoietin therapy: is there a difference between the avaiable preparations? Nephrol Dial Transplant 2002; 7:2047-51. |
|4.||Johnson D, Pollock C and Macdougall I. Erythropoietin stimulating agent hyporesponsiveness. Nephrology 2007;12,321-30. |
|5.||Devita MV, Frumkin D, Mittal S, Kamran A, Fishbane S, Michelis MF. Targeting higher ferritin concentrations with intravenous iron dextran lowers erythropoietin requirement in hemodialysis patients. Clin. Nephrol. 2003;60: 335-40. |
|6.||Richardson D. Clinical factors influencing sensitivity and response to epoetin. Nephrol Dial Transplant 2002;17 Suppl 1:53-9. [PUBMED] [FULLTEXT]|
|7.||Locatelli F, Del Vecchio L. Dialysis adequacy and response to erythropoietic agents: What is the evidence base? Nephrol. Dial. Transplant. 2003;18 (Suppl 8): viii29-35. |
|8.||Locatelli F, Aljama P, Barany P. et al. Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol. Dial. Transplant. 2004;19 (Suppl 2):ii1-47. |
|9.||KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. Am. J. Kidney Dis. 2006;47: S11-45. |
|10.||Barany P, Pettersson E, Konarski-Svensson JK. Long term effects on quality of life in haemodialysis patients of correction of anaemia with erythropoietin. Nephrol Dial Transplant 1993; 8:426-32. |
|11.||Moreno F, Aracil FJ, Perez R, Valderrabano F. Controlled study on the improvement of quality of life in elderly hemodialysis patients after correcting end-stage renal disease-related anemia with erythropoietin. Am J Kidney Dis 1996;27:548-56. |
|12.||Mocks J, Franke W, Ehmer B, Scigalla P, Quarder O. Analysis of safety database for long term epoetin beta treatment. A meta analysis covering 3697 patients. In: Koch KM, Stein G, eds. Pathogenetic and Therapeutic Aspects of Chronic Renal Failure.Marcel Dekker, New York, 1997;163-79. |
|13.||Consensus Development Conference Panel. Morbidity and mortality of renal disease: an NIH consensus conference statement. Ann Intern Med 1994;121:62-70. [PUBMED] [FULLTEXT]|
|14.||Hoen B, Paul-Dauphin A, Hestin D, Kessler M. EPIBACDIAL: A multicenter prospective study of risk factors for bacteremia in chronic hemodialysis patients. J Am Soc. Nephrol. 1998;9:869-76. |
|15.||Jacobs C, Frei D, Perkins AC. Results of the European Survey on Anaemia Management 2003 (ESAM 2003): Current status of anaemia management in dialysis patients, factors affectting epoetin dosage and changes in anaemia management over the last 5 years. Nephrol. Dial. Transplant. 2005;20(Suppl 3):iii3-24. |
|16.||Lee CT, Chou FF, Chang HW, et al. Effects of parathyroidectomy on iron homeostasis and erythropoiesis in hemodialysis patients with severe hyperparathyroidism. Blood Purif. 2003; 21:369-75. |
Department of Medicine, King Saud Bin Abdulaziz University King Abdulaziz Medical City Kingdom of Saudi Arabia
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]