| Abstract|| |
We aimed in this study to assess the opinion of medical directors of dialysis centers in the Kingdom of Saudi Arabia (KSA) about updates of strategies for treatment of anemia in patients with chronic kidney disease (CKD). A questionnaire was sent to the medical directors of the 174 active dialysis centers in the KSA including centers under the Ministry of Health (MOH) (67 %), the governmental non-MOH sector (12%) and private hospitals (21 %) that together care for a population of more than 11,300 chronic dialysis patients. The study was performed between November 2008 and March 2009. A total of 143 of the 174 (82.1%) medical directors answered the questionnaire. This covered 9563 (84%) dialysis patients in the KSA. There were 95 (68.8%) respondents who believed that the mechanism of action of ESAs is due to both blood concentration and direct action on the stem cells that form red cells. Only 81 (57%) respondents believed that the half-life of the short-acting ESAs is less than one day, 67 (46.9%) believed the half-life of darbepoetin is 2-4 days, and 52 (36.6%) believed the half-life of CERA is 5-10 days; 79 (55.6%) respondents believed that the interval of dosing of darbepoetin is once biweekly, and 92 (71.9%) believed that the interval of dosing of CERA is once a month. There were 110 (76.9%) respondents who believed the CKD should receive a long-acting than short-acting ESAs for the more stable hemoglobin levels, 64 (44.8%) believed that pharmacodynamics of the CERA are better than other ESAs and warrant its use over all of them, and 115 (80.6%) believed that the target hemoglobin is 11-13 g/dL in CKD patients is well established. Finally, 65 (51.5%) respondents would request more than 30% of the stock of ESAs in the future as short-acting ESAs vs 71 (55%) for darbepoetin and 40 (37.4%) for CERA. There were no statistically significant differences among the respondents according to their affiliations (MOH, non MOH and private sector) on any of the issues in the questionnaire. We conclude that our results showed inadequate awareness of the medical directors of the dialysis centers in the KSA of the mechanisms of action of ESAs and the new agents such as the CERA. However, they were well informed about the limits of the targeted hemoglobin levels and showed a trend toward using the long-acting ESAs.
Keywords: Chronic, Kidney, Disease, Renal, Dialysis, Anemia, Darbepoetin, Stages
|How to cite this article:|
Souqiyyeh MZ, Shaheen FA. Survey of attitude of physicians on updates in the management of anemia in chronic kidney disease patients. Saudi J Kidney Dis Transpl 2009;20:410-6
|How to cite this URL:|
Souqiyyeh MZ, Shaheen FA. Survey of attitude of physicians on updates in the management of anemia in chronic kidney disease patients. Saudi J Kidney Dis Transpl [serial online] 2009 [cited 2020 Nov 29];20:410-6. Available from: https://www.sjkdt.org/text.asp?2009/20/3/410/50771
| Introduction|| |
Surveys of opinion are a useful tool to communicate current routine practices and approaches in the nephrology community concerning major issues related to patients' care. ,,
Cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD) is related to the control of the risk factors such as anemia, ,,,,, which is also a risk factor for the progression of CKD.  Erythropoietin stimulation agents (ESAs) are established as the drugs of choice for anemia in the CKD patients with great advantages for decreasing morbidity and mortality in this population. 
There are available short and long-acting ESAs for treatment of anemia, and some are considered major advances in this field such as darbepoetin and continuous receptor stimulatingagent (CERA). ,,,,,,, The long-acting ESAs have advantages such as the less time and drug waste that impact positively on the cost of ESAs. The pharmacodynamics (the direct me-chanism of action) have been implicated as a major determinant of the action of ESAs than the pharmacokinetics (bioavailability of the pharmaceutical preparation). ,
| Aim of the Study|| |
The aim of this study is to survey the attitude of the physicians in the dialysis centers in Saudi Arabia towards the choice of the ESAs and the properties that help them in their decision making such as the mechanism of action of the ESAs.
| Materials and Methods|| |
A questionnaire was sent from the Saudi Center for Organ Transplantation, Riyadh, Saudi Arabia to the medical directors of the 175 active dialysis centers in the KSA. This covered decision makers in 118 (67 %) centers in the Ministry of Health (MOH), 21 (12%) centers in the governmental non-MOH sector and 36 (21 %) centers in private hospitals that care for a population of more than 11,300 chronic dialysis patients. The study was performed between November 2008 and March 2009. The questionnaire was intended to evaluate the following aspects of practice of physicians who manage CKD patients in the KSA:
- The perception of the physicians about the mechanism of action of the ESAs.
- The dissociation between the half-life and the dosing interval of the ESAs that may reflect more pharmacodynamic than pharmacokinetic mechanism of action.
- The knowledge of the physicians about the other agents that are being developed such as the hematids and the hypoxia inducible factor (HIF) stabilizing agents.
- The perception of the physicians about the targeted hemoglobin in the CKD patients.
- The preferences of the physicians of the ESA that is most efficient in its pharma cokinetics and pharmacodynamics.
We considered the best answers as those in accordance with the common denominator of the established guidelines and practices in the United States of America (USA) and Europe and the facts about the mechanism of action of the ESAs and preferred agents for use in the CKD patients. ,
Data were entered in a Microsoft Excel file. However, the description of data and analysis were done using the statistical program SPSS. The valid percent of the answers was considered according to the frequency of the answers to each corresponding question. Pearson ChiSquare test was used throughout the analysis to test the significance of differences between groups and sub-groups. Significance was set as P< 0.05.
| Results|| |
A total of 143 medical directors of the 174 (82.1%) dialysis centers answered the questionnaire. This covered 8951 (87%) dialysis patients in the KSA. There were 108 (93.1%) respondents of 116 MOH centers, 12 of 21 (57.1%) governmental non-MOH centers and 22 of 36 (61%) private centers.
[Table 1] shows the answers related to the evaluation of mechanism of action and dosing of ESAs in CKD patients. There were 95 respondents (68.8%) who believed that the mechanism of action of ESAs is due to both blood concentration and direct action on the stem cells that form red cells. The rest of the respondents believed of one mechanism responsible for the action of the ESAs. Only 81 (57%) respondents believed that the half-life of the short-acting ESAs is less than one day, 67 (46.9%) believed the half-life of darbepoetin is 2-4 days, and 52 (36.6%) believed the half-life of CERA is 5-10 days. In contrast to beliefs on half-lives and for keeping stability of hemoglobin, 120 (83.9%) believed that the interval of dosing of shortacting ESAs is once a week, 79 (55.6%) believed that the interval of dosing of darbepoetin is once biweekly, and 92 (71.9%) believed that the interval of dosing of CERA is once a month.
[Table 2] shows preferences of the respondents of ESAs for CKD patients. There were 64 (44.8%) respondents who believed the pharmacokinetics of the ESAs were less important than their pharmacodynamics to affect the red cells forming stem cells, 110 (76.9%) believed the CKD should receive a long-acting than shortacting ESAs for the more stable hemoglobin levels, and 64 (44.8%) believed that pharmacodynamics of the CERA are better than other ESAs and warrant its use over all of them. There were 82 (58.6%) respondents who believed that other products than protein ESAs such as hematids and hypoxia inducible factor (HIF) stabilizing agent are still experimental in treating anemia in CKD patients, and 115 (80.6%) believed that the target hemoglobin 1113 g/dL in CKD patients is well established according to the recent US and European studies. Finally, 65 (51.5%) respondents would request more than 30% of the stock of ESAs in the future as short-acting ESAs vs 71 (55%) for darbepoetin and 40 (37.4%) for CERA. Most of the respondents believed that the stock could be a mixture of both short and long-acting ESAs.
There were no statistically significant differences among the respondents according to their affiliations (MOH, non MOH and private sector) on any of the issues in the questionnaire.
| Discussion|| |
The results of our study demonstrate inadequate perception of the physicians of the mechanism of action of the protein ESAs, the dissociation between the half-life and the dosing interval of the ESAs that may reflect more pharmacodynamic than pharmacokinetic mechanism of action, and data of the other nonprotein agents that are being developed such as the hematids and the hypoxia inducible factor (HIF) stabilizing agent. However, the respondents showed adequate knowledge about the targeted hemoglobin in the CKD patients. Furthermore, the choices of the respondents of the future stocks of ESAs reflected a trend toward long rather than short-acting agents including the new agent CERA.
The mechanism of action of endogenous erythropoietin in stimulating the stem cells in the bone marrow has been demonstrated to involve saturation of the receptors in the blasts forming red cells. This binding to the receptors is onetime stimulation for the process that continues relentlessly after the first contact of the stem cells with the erythropoietin. Some investigators suggested that the concentration and availability of erythropoietin after the first stimulation of the stem cells is not necessary for the maturation of red cells. It seems that the action of the endogenous erythropoeitin is regulated by the body to resist further stimulation till the next batches of the blast cells that will be stimulated at 15-21 days intervals including the phenomenon of neocytolysis, which involves the stimulation of the phagocytes by the vascular endothelial cells to destroy the newly formed red cells in order to stabilize the red cell mass if it was exceeded. ,
The response of the stem cells to the pharmacological administration of the ESAs is suggested to be similar to the behavior toward the endogenous erythropoietin. There are several points that raise question about the mechanism of action of the ESAs. There is much shorter half-life compared to the dosing interval of the ESAs. The usual dosing of the short-acting erythropoietin for example is two to three times per week, and even longer dosing intervals could maintain the hemoglobin in the CKD patients of different stages. It seems that the pharmacodynamics of the ESAs are more important than their pharmacokinetics. , Further more, some studies questioned the importance of the long-acting ESAs in comparison with the short-acting ones. They suggested that high dose of short-acting ESAs at long intervals could be equivalent to the long acting ESAs in stabilizing the hemoglobin levels at the target levels. ,,,, Other studies in the past failed to show such effect in HD patients. The prospective comparative clinical studies should elucidate the differences. Some comparative studies of darbepoetin and CERA and darbepoetin and short-acting ESA have been published and support this notion. ,,
The updates of information about the ESAs are important, since we are still trying to adjust our practices in the management of anemia in CKD. ,,, The new ESAs such as the CERA have shown ability to stabilize hemoglobin levels in the CKD patients at longer intervals. It is administered in the HD patients at monthly intervals and has peculiar longer stimulation of the stem cells receptors. Whatever the mechanism of action of the CERA (pharmacokinetic and/or pharmacodynamics) the agent is promising in terms of stabilizing the hemoglobin at long intervals.
Other agents that are being developed such as the hematids and the hypoxia inducible factor (HIF) stabilizers, however, they are still in the experimental phases leaving us, and the recombinant protein ESAs are still the only established replacement therapy for the deficient endogenous erythropoeitin. 
The minimal targeted hemoglobin level in the CKD patients is 11 g/L and the maximal suggested level is 12 g/L.  This is due to the recent studies CHOIR  and CREATE,  which demonstrated that high levels above 13 g/L were associated with increased cardiovascular morbidity and mortality in the CKD patients.
Stabilizing the hemoglobin levels in the narrow therapeutic window is suggested to be more important than the choice of the ESA. Not only convenience, but safety also should modify the physicians' strategies to cautiously administer the ESAs to CKD patients and avoid variability of the hemoglobin and overshooting to dangerous levels.,
The choices of the respondents of the future stocks of ESAs reflected a trend toward long rather than short-acting agents. This is justified by the convenience of administration of these agents to save time of staff and hopefully costeffectiveness. The word of caution, however, is whatever the choices of the ESAs might be, stabilizing the hemoglobin level within the therapeutic limits is prudent and requires diligent practice.
We conclude that our results showed inadequate awareness of the medical directors of the dialysis centers in the KSA of the mechanisms of action of ESAs and the new agents such as the CERA. However, they were well informed about the limits of the targeted hemoglobin levels and showed a trend toward using the long-acting ESAs.
| Acknowledgement|| |
We would like to thank Roche Pharmaceuticals in Saudi Arabia for their grant that made this study possible.
| References|| |
|1.||Powe NR, Thamer M, Hwang W, et al. Cost quality trade-offs in dialysis care: A national survey of dialysis facility administrators. Am J Kidney Dis 2002;39(1):116-26. |
|2.||Zimmerman DL, Selick A, Singh R, Mendelssohn DC. Attitudes of Canadian nephrologists, family physicians and patients with kidney failure toward primary care delivery for chronic dialysis patients. Nephrol Dial Transplant 2003; 18(2):305-9. |
|3.||Van Waeleghem JP, Elseviers MM, De Weerdt DL, et al. A survey of nephrology nursing care and treatments in Belgium. Nephrol News Issue 1998;12(11):53-6 |
|4.||Locatelli F, Pozzoni P, Del Vecchio L. Anemia and heart failure in chronic kidney disease. Semin Nephrol 2005;25(6):392-6. |
|5.||Foley RN, Murray AM, Li S, et al. Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States Medicare population, 1998 to 1999. J Am Soc Nephrol 2005;16(2):489-95. |
|6.||Besarab A, Soman S. Anemia management in chronic heart failure: Lessons learnt from chronic kidney disease. Kidney Blood Press Res 2005;28(5-6):363-71. |
|7.||Foley RN. Anaemia: Cardiovascular adaptations and maladaptive responses in chronic kidney disease. Nephrol Dial Transplant 2002;17(Suppl 11):32-4. [PUBMED] [FULLTEXT]|
|8.||Locatelli F, Pisoni RL, Combe C, et al. Anaemia in hemodialysis patients of five European countries: Association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant 2004;19(1):121-32. |
|9.||Stevens LA, Levin A. Anaemia, cardiovascular disease and kidney disease: Integrating new knowledge in 2002. Curr Opin Nephrol Hypertens 2003;12(2):133-8. |
|10.||Deicher R, Horl WH. Anaemia as a risk factor for the progression of chronic kidney disease. Curr Opin Nephrol Hypertens 2003;12(2):139-43. |
|11.||Canaud B, Mingardi G, Braun J, et al. Intravenous C.E.R.A. maintains stable haemoglobin levels in patients on dialysis previously treated with darbepoetin alfa: results from STRIATA, a randomized phase III study. Nephrol Dial Transplant 2008;23(11):3654-61. |
|12.||Macdougall IC, Walker R, Provenzano R, et al. C.E.R.A. corrects anemia in patients with chronic kidney disease not on dialysis: results of a randomized clinical trial. Clin J Am Soc Nephrol 2008;3(2):337-47. |
|13.||McGahan L. Continuous erythropoietin receptor activator (Mircera) for renal anemia. Issues Emerg Health Technol 2008;113:1-6. [PUBMED] |
|14.||Topf JM. CERA: third-generation erythropoiesisstimulating agent. Expert Opin Pharmacother 2008;9(5):839-49. |
|15.||Scott SD. Dose conversion from recombinant human erythropoietin to darbepoetin alfa: Recommendations from clinical studies. Pharmacotherapy 2002;22(9.2):160S-5S. |
|16.||Glaspy J. Phase III clinical trials with darbepoetin: implications for clinicians. Best Pract Res Clin Haematol 2005;18(3):407-16. |
|17.||Macdougall IC. CERA (Continuous Erythropoietin Receptor Activator): a new erythropoiesisstimulating agent for the treatment of anemia. Curr Hematol Rep. 2005;4(6):436-40. |
|18.||Macdougall IC, Robson R, Opatrna S, et al. Pharmacokinetics and pharmacodynamics of intravenous and subcutaneous continuous erythropoietin receptor activator (C.E.R.A.) in patients with chronic kidney disease. Clin J Am Soc Nephrol 2006;1(6):1211-5. |
|19.||McGowan T, Vaccaro NM, Beaver JS, Massarella J, Wolfson M. Pharmacokinetic and pharmacodynamic profiles of extended dosing of epoetin alfa in anemic patients who have chronic kidney disease and are not on dialysis. Clin J Am Soc Nephrol 2008;3(4):1006-14. |
|20.||Levey AS, Coresh J, Balk E, et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 2003;139(2): 137-47. |
|21.||Grabe DW. Update on clinical practice recommendations and new therapeutic modalities for treating anemia in patients with chronic kidney disease. Am J Health Syst Pharm. 2007;64 (13Suppl 8):S8-14; quiz S23-5. |
|22.||Scharte M, Fink MP. Red blood cell physiology in critical illness. Crit Care Med 2003;31(12 Suppl):S651-7. |
|23.||Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med 2005;352(10):1011-23. |
|24.||Arroliga AC, Guntupalli KK, Beaver JS, Langholff W, Marino K, Kelly K. Pharmacokinetics and pharmacodynamics of six epoetin alfa dosing regimens in anemic critically ill patients without acute blood loss. Crit Care Med 2009 Feb 24. [Epub ahead of print] |
|25.||Provenzano R, Bhaduri S, Singh AK; PROMPT Study Group. Extended epoetin alfa dosing as maintenance treatment for the anemia of chronic kidney disease: the PROMPT study. Clin Nephrol 2005;64(2):113-23. |
|26.||Provenzano R, Singh AK. Hemoglobin maintenance with use of extended dosing of epoetin alfa in patients with diabetes and anemia of chronic kidney disease. Endocr Pract 2007;13 (3):251-9. |
|27.||Spinowitz B, Germain M, Benz R, et al. A randomized study of extended dosing regimens for initiation of epoetin alfa treatment for anemia of chronic kidney disease. Clin J Am Soc Nephrol 2008;3(4):935-7. |
|28.||Pussell BA, Walker R; Australian Renal Anaemia Group. Australian haemodialysis patients on intravenous epoetin alfa or intravenous darbepoetin alfa: how do they compare? Nephrology (Carlton) 2007;12(2):126-9. |
|29.||Nurko S, Spirko R, Law A, Dennis VW. Dosing intervals and hemoglobin control in patients with chronic kidney disease and anemia treated with epoetin alfa or darbepoetin alfa: a retrospective cohort study. Clin Ther 2007;29(9): 2010-21. |
|30.||Walker R, Pussell BA; Australian Renal Anaemia Group. Fluctuations in haemoglobin levels in haemodialysis patients receiving intravenous epoetin alfa or intravenous darbe-poetin alfa. Nephrology (Carlton) 2007;12(5): 448-51. |
|31.||Stevens P. Optimizing renal anaemia management-benefits of early referral and treatment. Nephrol Dial Transplant 2005;20(Suppl 8): viii22-6. [PUBMED] [FULLTEXT]|
|32.||Locatelli F, Del Vecchio L. Optimizing the management of renal anemia: challenges and new opportunities. Kidney Int Suppl 2008;111: S33-7. [PUBMED] |
|33.||Deray G. Achieving therapeutic targets in renal anaemia: considering cost efficacy. Curr Med Res Opin 2004;20(7):1095-101. |
|34.||Basile JN. Clinical considerations and practical recommendations for the primary care practitioner in the management of anemia of chronic kidney disease. South Med J 2007;100(12): 1200-7. |
|35.||Macdougall IC. Recent advances in erythropoietic agents in renal anemia. Semin Nephrol 2006;26(4):313-8. |
|36.||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(3):471-530. |
|37.||Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006;355(20): 2085-98. |
|38.||Drueke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006;355(20):2071-84. |
|39.||Singh AK, Milford E, Fishbane S, Keithi-Reddy SR. Managing anemia in dialysis patients: Hemoglobin cycling and overshoot. Kidney Int 2008;74(5):679-83. |
|40.||Yang W, Israni RK, Brunelli SM, Joffe MM, Fishbane S, Feldman HI. Hemoglobin variability and mortality in ESRD. J Am Soc Nephrol 2007;18(12):3164-70. |
Muhammad Ziad Souqiyyeh
The Saudi Center for Organ Transplantation, P.O. Box 27049, Riyadh, 11417
[Table 1], [Table 2]