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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2009  |  Volume : 20  |  Issue : 3  |  Page : 410-416
Survey of attitude of physicians on updates in the management of anemia in chronic kidney disease patients


Saudi Center for Organ Transplantation, Riyadh, Saudi Arabia

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   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 Sep 20];20:410-6. Available from: http://www.sjkdt.org/text.asp?2009/20/3/410/50771

   Introduction Top


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. [1],[2],[3]

Cardiovascular morbidity and mortality in pa­tients with chronic kidney disease (CKD) is re­lated to the control of the risk factors such as anemia, [4],[5],[6],[7],[8],[9] which is also a risk factor for the progression of CKD. [10] 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. [9]

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). [11],[12],[13],[14],[15],[16],[17],[18] 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). [18],[19]


   Aim of the Study Top


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 Top


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:

  1. The perception of the physicians about the mechanism of action of the ESAs.
  2. The dissociation between the half-life and the dosing interval of the ESAs that may reflect more pharmacodynamic than phar­macokinetic mechanism of action.
  3. 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.
  4. The perception of the physicians about the targeted hemoglobin in the CKD patients.
  5. 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. [20],[21]

Statistical Analysis

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 Top


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 Top


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. [22],[23]

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. [18],[19] 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. [23],[24],[25],[26],[27] 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. [28],[29],[30]

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. [31],[32],[33],[34] 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. [35]

The minimal targeted hemoglobin level in the CKD patients is 11 g/L and the maximal sug­gested level is 12 g/L. [36] This is due to the recent studies CHOIR [37] and CREATE, [38] 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.[39],[40]

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.[40]


   Acknowledgement Top


We would like to thank Roche Pharmaceu­ticals in Saudi Arabia for their grant that made this study possible.

 
   References Top

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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.  Back to cited text no. 18    
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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.  Back to cited text no. 40    

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Correspondence Address:
Muhammad Ziad Souqiyyeh
The Saudi Center for Organ Transplantation, P.O. Box 27049, Riyadh, 11417
Saudi Arabia
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    Abstract
    Introduction
    Aim of the Study
    Materials and Me...
    Results
    Discussion
    Acknowledgement
    References
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