Anemia is very common among end-stage renal fail LATEST STRATEGY IN RENAL ANEMIA MANAGEMENT IN PERITONEAL DIALYSIS PATIENTS.

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1 Proceedings of the 3rd Asian Chapter Meeting of the ISPD November 22 24, 2007, Hiroshima, Japan Peritoneal Dialysis International, Vol. 28 (2008), Supplement /08 $ Copyright 2008 International Society for Peritoneal Dialysis Printed in Canada. All rights reserved. LATEST STRATEGY IN RENAL ANEMIA MANAGEMENT IN PERITONEAL DIALYSIS PATIENTS Wai Kei Lo Tung Wah Hospital, The University of Hong Kong, Hong Kong SAR, PR China The target of renal anemia correction with erythropoietin stimulating agents (ESAs) has been traditionally set at a hemoglobin (Hb) level of g/dl. However, a trend has arisen of progressively increasing the Hb level to beyond 12 g/dl. Recent randomized control trials (RCTs) on correction of renal anemia in chronic kidney disease patients found that normalization of anemia to above 13 g/dl was associated with negative outcome parameters, echoing a previous RCT that showed increased death and myocardial infarction risk after normalization of hemoglobin level in hemodialysis patients. The latest consensus is to limit Hb to a level not exceeding 13 g/dl during renal anemia correction with ESAs. Currently, there are three ESAs available commercially. The choice of ESA should consider safety of subcutaneous administration, cost-effectiveness, and dosing frequency, all of which may affect compliance with ESA administration. Early identification of, and an early search for the causes of hyporesponsiveness to, ESAs is needed to avoid unnecessary escalation in the dose of ESAs. These approaches will help to improve the cost-effectiveness of ESA therapy and permit early detection of hidden problems. The current definitions of hyporesponsiveness are far too stringent and should be reviewed. Perit Dial Int 2008; 28(S3):S76 S80 S76 KEY WORDS: Renal anemia; erythropoietic agents Anemia is very common among end-stage renal fail ure patients on dialysis and has been shown to be associated with increased mortality and hospitalization. Many observational studies have demonstrated that, in hemodialysis (HD) and peritoneal dialysis (PD) patients alike, the higher the hemoglobin (Hb) level, the better the outcome in terms of survival rates, hospitalization rates, and quality of life (QOL) domains, with the effect starting to level off when the Hb level exceeds 12.5 g/dl (1 3). Major guidelines, including Correspondence to: Wai Kei Lo, Tung Wah Hospital, The University of Hong Kong, 12 Po Yan Street, Hong Kong SAR, PR China. wkloc@hkucc.hku.hk that from the Kidney Disease Outcomes Quality Initiative (K/DOQI) in 2006 and the European Best Practice Guideline (EBPG) published in 2004 (4,5), recommend a target Hb level of g/dl during therapy with erythropoietic stimulating agents (ESAs). TARGET HEMOGBIN LEVELS DURING CORRECTION OF RENAL ANEMIA IN DIALYSIS AND PD PATIENTS Reports from the United States Renal Data System (USRDS) have noted a progressively increasing averaged Hb level and ESA dosage over the years. The latest data showed that the average Hb in dialysis patients rose from 10 g/dl in 1993 to 12 g/dl in 2005, associated with a doubling in the dose of ESAs (6), meaning that roughly 50% of patients had a Hb level exceeding 12 g/dl. However, a more recent observational study by Regidor et al. showed a J-shaped relationship between Hb level and cardiovascular mortality in both incident and prevalent HD patients, with the lowest risk at g/dl and the risk significantly increased at a Hb level greater than 13.5 g/dl (7). Furthermore, all-cause and cardiovascular mortality risk increased with increasing doses of ESAs, possibly indicating the presence of factors leading to hyporesponsiveness to ESAs. The observation of higher mortality associated with a normalization of Hb level was echoed by two randomized controlled trials (RCTs) in chronic kidney disease (CKD) patients published in late 2006: the CRE- ATE (Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta) study and the CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) study (8,9). Both studies showed that complete normalization of Hb level by two different ESAs to above 13 g/dl was associated with a negative outcome as compared with maintenance of Hb levels at approximately 11 g/dl. In the CREATE study, 603 patients with an estimated glomerular filtration rate (egfr) of ml/min/ 1.73 m 2 were randomized into two groups. Epoetin beta

2 PDI JUNE 2008 VOL. 28, SUPPL 3 PROCEEDINGS OF THE 3RD ASIAN CHAPTER MEETING OF THE ISPD was given and adjusted to achieve a Hb level of g/dl in group 1 (normal Hb group) and an Hb level of g/dl in group 2 (Hb partially corrected group). The study endpoints included time to first cardiovascular event, cardiac and all-cause mortality, hospitalization, changes in left ventricular function parameters, QOL by SF-36 (Medical Outcomes Study 36- item Short Form), and decrease in egfr. Apart from better QOL in several domains, no significant benefit was observed for the normal Hb group over the Hb partially corrected group. In fact, the hazard ratio (HR) for cardiovascular events in group 1 as compared with group 2 was slightly increased (HR: 0.78; p = 0.20) and the time to initiation of dialysis was shorter at 18 months (p = 0.03). The CHOIR study had a similar design, but with some differences in the details. It randomized 1432 CKD patients with an egfr between 15 ml/min/1.73 m 2 and 50 ml/min/1.73 m 2 and an Hb level below 11 g/dl into two groups. The high-hb group was targeted to achieve a Hb level of 13.5 g/dl; the low-hb group was targeted to achieve a level of 11.3 g/dl. Both groups were treated with epoetin alpha. The study endpoints included time to death, myocardial infarction, and hospitalization for congestive heart failure or stroke. The HRs for primary composite outcome events and hospitalization for congestive heart failure were found to be significantly increased in the high Hb group, with a trend toward higher all-cause mortality risk (p = 0.07). As in the CREATE study, improvement in QOL was more noticeable in the high Hb group for certain domains. The higher risk of death and cardiac events in the high Hb groups actually echoes an earlier RCT on HD patients published in 1998 by Besarab et al. (10). In that study, 1233 HD patients with congestive heart failure or ischemic heart disease were treated with epoetin alpha to maintain high hematocrit values (42% ± 3%) or low hematocrit values (30% ± 3%). The high hematocrit group was found to have an increased risk [to 1.3; 95% confidence interval (CI): 0.9 to 1.9] of a primary endpoint event (death or myocardial infarction), but that risk did not reach a statistically significant level. Again, QOL scores were higher in certain domains in the high hematocrit group. These RCTs all showed that, apart from improvement in scores for certain QOL domains, complete normalization of Hb level in HD and CKD patients brings a higher mortality risk to those patients. In addition, among several other smaller-scale RCTs on the effect of normalization of Hb on various cardiac parameters such as left ventricular hypertrophy in HD patients, none has demonstrated definitive positive effects (11 13). At the same time, an increased mortality rate was reported with the use of ESAs to increase Hb levels to above 12 g/dl in patients with malignancy. These studies led to the release by the U.S. Food and Drug Administration (FDA) of a warning on the deleterious effects of a Hb level exceeding 12 g/dl with the use of ESAs in CKD and cancer patients (14). A new K/DOQI guideline on Hb targets published in September 2007 said that in dialysis and nondialysis patients with CKD receiving ESA therapy, the selected hemoglobin target should generally be in the range of 11.0 to 12.0 g/dl and that the hemoglobin target should not be greater than 13.0 g/dl (15). However, reports have noted that fluctuation of Hb levels in the form of cycles commonly occurs in up to 90% of HD patients. The annual mean of 3.1 cycles involving Hb excursions of 2.5 g/dl (16) suggests that Hb levels could easily exceed 13 g/dl if the target is set at 12 g/dl. Therefore, it seems safer to set a target of approximately 11 g/dl than 12 g/dl. Following a meeting and public hearing by the FDA Cardiovascular and Renal Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee, the FDA released an alert on 14 November 2007 which said that the dosing recommendations for anemic patients with chronic renal failure have been revised to recommend maintaining hemoglobin levels within 10 12g/dL. Directions are also provided for patients whose hemoglobin level does not increase to the recommended level after following appropriate dose titrations. In addition, quality of life claims in the previous labeling were removed, with the exception of improved exercise tolerance and functional ability for chronic renal failure patients (17). Notably, all of the foregoing RCTs were performed in HD and CKD patients. Would Hb levels in PD patients behave differently from those in HD and CKD patients? To date, there is no evidence of such. Therefore, unless new evidence arises, Hb targets should apply to PD patients as well. Given the RCT data, it is highly unlikely any similar RCT design can be approved by an ethics committee. It is not only worrisome that Hb level are rising among dialysis patients, but also that Hb levels commonly overshoot 12 g/dl. The USRDS reported that Hb levels exceeded 12 g/dl in 97% of dialysis patients and 14 g/dl in 42% of patients within 6 months after 11 g/dl had been achieved, although excess levels were less frequent in PD patients than HD patients (6). It is therefore high time that the new recommendation be widely publicized to avoid the unnecessary and potentially hazardous normalization of Hb levels. S77

3 PROCEEDINGS OF THE 3RD ASIAN CHAPTER MEETING OF THE ISPD JUNE 2008 VOL. 28, SUPPL 3 PDI COST-EFFECTIVENESS OF ESAs The ESAs are expensive drugs. Concerns are increasing regarding the expenditures on ESAs in dialysis patients in the United States (18). These concerns should also apply equally to other countries, particularly countries with developing economies. The RCTs mentioned earlier all indicated that raising a patient s Hb level from 11 g/dl to 13.5 g/dl requires at least double the ESA dose. The cost-effective use of ESAs should receive high priority in countries where cost is a major concern in the provision of dialysis therapy. Given that the only benefit of doubling the dose of ESA to achieve complete Hb normalization is an improvement in certain QOL domains, the doubling of the cost is not justified. The advantage of PD over HD in this circumstance is that PD patients require a lower ESA dose to achieve an equivalent Hb level (19). CHOICE OF ESA IN PD PATIENTS Three ESAs are currently commercially available: epoetin alpha, epoetin beta, and darbepoetin alpha. Not every ESA is available in every country, and their relative costs also vary by country. For example, darbepoetin is the most expensive ESA in the United States (18), but it is the cheapest alternative in Hong Kong. Other than cost, safety of subcutaneous (SC) administration and frequency of administration should also be considered as major criteria in choosing an ESA. Unlike the case with HD patients, intravenous (IV) administration of ESAs to PD patients is extremely inconvenient; SC injection is therefore almost the only convenient route of ESA administration in PD patients. The good point of SC administration is that it is more cost-effective than IV administration is (20), and the drug can be administered at home by patients or their caregivers after proper instruction. However, the epidemic of pure red cell aplasia (PRCA) arising from SC, but not IV, administration of the ESA Eprex (Janssen Pharmaceutica NV, Beerse, Belgium), which uses uncoated rubber stoppers in the pre-filled syringe containing polysorbate 80 as the stabilizer (21) should indicate caution in the SC administration of any ESA. Although the incidence of PRCA has been largely reduced since the Eprex stopper was changed to coated rubber, the safety of SC-administered ESAs should remain under close scrutiny, particularly given the sporadic reports of PRCA occurring with other forms of ESA, including epoetin beta, darbepoetin, and Eprex not containing polysorbate 80 (21 24). Education for patients is needed regarding strict adherence to the S78 recommended procedures in collecting the drug from the hospital pharmacy, transporting it home, and subsequently storing it. The three ESAs vary in half-life and dosing interval. The frequency of ESA administration may affect compliance. Noncompliance to ESA administration has been reported to occur in 58% 74% of patients, depending on the method used to assess compliance (25). Theoretically, compliance can be increased when the frequency of administration is reduced from the traditional frequency of 2 3 times weekly to once weekly or even to once monthly. Studies have considered prolonging the administration interval for all three ESAs, with the longest reported interval being once monthly for darbepoetin alpha, which has the longest half-life of the three ESAs (26). However, additional studies are needed to confirm whether the longer dosing interval improves compliance. The choice of interval should be determined based on setting and and patient preference. A further consideration in choosing a long dosing interval for an ESA is the rate of Hb decline when the drug is being withheld because of a high Hb level. Given that a high Hb level is now recognized to carry increased risk, it is important that the Hb level decrease after suspension of the ESA; a long half-life should not make the decline excessively slow. According to an earlier study in non dialysis CKD patients that compared SC epoetin alpha twice weekly with darbepoetin once weekly, the median time required for a drop in Hb level to 12 g/dl from 14 g/dl once the ESA was withheld was similar for both agents: 9 weeks for epoetin alpha and 7 weeks for darbepoetin (27). The same may not be true for an ESA given at longer intervals such as fortnightly or monthly. The rates of decline in PD and HD patients in such a situation should also be studied. IMPROVING COST-EFFECTIVENESS: TARGETING AT DETECTING AND TREATING HYPORESPONSIVENESS EARLY The most common way to improve the cost-effectiveness of ESA therapy in HD patients is to administer IV iron regularly albeit with caution, because excessive IV iron may increase the risk for mortality (28). In PD patients, maintenance IV iron administration is very inconvenient and is therefore seldom done. The use of IV iron in PD patients is confined mainly to treatment of either absolute or functional iron deficiency. Maintenance IV iron therapy should be studied before it is put into practice. Hyporesponsiveness is not uncommon. Other than absolute and functional iron deficiency, the causes

4 PDI JUNE 2008 VOL. 28, SUPPL 3 PROCEEDINGS OF THE 3RD ASIAN CHAPTER MEETING OF THE ISPD of hyporesponsiveness to ESAs include inadequate dialysis; thalassemia; occult gastrointestinal blood loss; deficiencies of vitamin B 12, folate, and L-carnitine; severe hyperparathyroidism; aluminum toxicity; presence of anti-erythropoietin antibodies; and underlying hematologic disease (29). The prevalence of the condition actually depends on how it is defined. The EBPG defines hyporesponsiveness as a weekly requirement for epoetin exceeding 300 IU/kg (or an equivalent dose of darbepoetin) to achieve the Hb target (30). The K/DOQI has an even stricter definition, which specifies a weekly requirement greater than 500 IU/kg to achieve a Hb level of 11 g/dl (31). Therefore, for a 70-kg man, the weekly epoetin dosage required for diagnosing hyporesponsiveness has to exceed either IU (EBPG definition) or IU (K/DOQI definition). According to the 2007 USRDS report, the average Hb level of U.S. dialysis patients (most on HD) was 12 g/dl, and the average weekly dose of erythropoietin administered was IU (6). The dose required for achieving a Hb level of 11 g/dl should be substantially lower overall, and even lower in PD patients, because PD patients require less ESA to achieve the same Hb level. Clearly, these definitions of hyporesponsiveness set the dose far too high, because if patients have an inadequate Hb response at the average dose, physicians would have to almost double the dose before embarking on an investigation into the potential causes of the suboptimal response and beginning to manage that suboptimal response. Raising the ESA dose would not only waste a great deal of money, but also lead to delay in the diagnosis of possibly serious underlying problems. Furthermore, because PD patients require less ESA to achieve the same Hb target, the definition of hyporesponsiveness to ESA therapy in PD patients should be different from that in HD patients. The FDA has already suggested the need to redefine hyporesponsiveness to ESA therapy (17). Prevention and early detection of hyporesponsiveness to ESA, and correction of the underlying causes are important. REFERENCES 1. Collins AJ, Li S, St. Peter W, Ebben J, Roberts R, Ma JZ, et al. Death, hospitalization, and economic associations among incident hemodialysis patients with hematocrit values of 36 to 39%. J Am Soc Nephrol 2001; 12: Li S, Collins AJ. Associations of hematocrit value with cardiovascular morbidity and mortality in incident hemodialysis patients. Kidney Int 2004; 65: Li S, Foley R, Collins AJ. Anemia, hospitalization, and mortality in patients receiving peritoneal dialysis in the United States. 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