Practical Approach to the Diagnosis and Treatment of Anemia Associated With CKD in Elderly

Anil K. Agarwal, MD Anemia is a frequent complication of chronic kidney disease (CKD). Inadequate production of erythropoietin by the failing kidneys leads to decreased stimulation of the bone marrow to produce red blood cells (RBCs). Anemia of CKD develops early and worsens with progressive renal insufciency. Although over 40% of patients with CKD are anemic, anemia in this population is underrecognized and undertreated. Of considerable importance, anemia is a risk factor for cardiovascular disease and is associated with higher rates of hospitalization and mortality. Despite the availability of erythropoiesis-stimulating proteins (ESPs) to stimulate RBC production in CKD patients, approximately three fourths of patients initiating dialysis have a hemoglobin 11 g/dL. The recognition of anemia of CKD begins with an estimation of glomerular ltration rate (GFR), which can be far lower than a normal serum creatinine might suggest, especially in the elderly and in those with poor nutrition and muscle mass. If GFR is 60 mL/min/1.73 m2, hemoglobin should be checked. The anemia is diagnosed when the hemoglobin is 12 g/dL in a man or a postmenopausal woman, or 11 g/dL in a premenopausal woman. The cause of anemia should be investigated in these individuals; this can range from erythropoietin deciency due to CKD, to deciency of vitamin B12 and/or folate, iron deciency, blood loss, inammation, malignancy, and aluminum intoxication. After other causes of anemia have been excluded, CKD is the most likely etiology, and it should be treated with an ESP. Currently, epoetin alfa and darbepoetin alfa are the only 2 ESPs approved for use in the United States. Extended dosing of ESP has potential advantages for the patient and may also improve resource utilization. Consequently, both agents have been tested for dosing at extended intervals. Adequate iron stores dened as transferrin saturation 20% and ferritin 100 mgas well as ESP administration are needed to produce an appropriate increase in hemoglobin. Poor response to treatment with ESP can be due to many factors, including presence of iron deciency, inammation, continued blood loss, and hemoglobinopathy. (J Am Med Dir Assoc 2006; 7: S7S12) Keywords: Anemia; erythropoiesis-stimulating protein (ESP); treatment; hemoglobin; treatment strategies; chronic kidney disease

INTRODUCTION Accurate determination of the stage of chronic kidney disease (CKD) based on estimated glomerular ltration rate (eGFR) is fundamental to the appropriate and timely treatment of anemia associated with CKD. Estimation of GFR, rather than reliance on measured serum creatinine to determine the stage of CKD, is especially important because the eGFR level correlates directly with cardiovascular morbidity and mortality. Similar to the conventional cardiovascular risk factors such as older age, male sex, increased body weight, and smoking, the presence of CKD by itself heightens the risk of cardiovascular morbidity and mortality.1
The Ohio State University, Internal Medicine, Division of Nephrology, Columbus, OH. Address correspondence to Anil K. Agarwal, MD, The Ohio State University, Internal Medicine, Division of Nephrology, N210 Means, 1654 Upham Drive, Columbus, OH 43210. E-mail: aagarwal@pol.net

Copyright 2006 American Medical Directors Association DOI: 10.1016/j.jamda.2006.09.005 SUPPLEMENT

Recognition of the presence of CKD itself may sometimes be difcult owing to the absence of a grossly abnormal value of serum creatinine. Direct measurement of GFR by radioiothalamate test provides the best accuracy of kidney function and is considered the gold standard but is neither required nor recommended for a routine, uncomplicated determination of kidney function. Serum creatinine (SCr) level has been the traditional marker of renal function, but used alone it does not give a complete picture of renal function and is often fallacious. Levels of SCr are inuenced by many factors: muscle mass, absorption of dietary creatinine, medications, sex, ethnicity, and age. Equations that take into account some of these factors more accurately estimate actual GFR.2 Thus, actual kidney function can vary widely among individuals for a given SCr level. This is readily depicted by the following example. Two individualsa black man and a white womanare the same age (70 years), the same weight (70 kg), and have the same SCr (1.5 mg/dL). Both appear to have relatively normal renal function, until either the creatinine clearance (CrCl) is calculated with the Cockcroft-Gault forAgarwal S7

Fig. 1. When a patient develops CKD, anemia may develop as a result of the presence of any one or the combination of multiple factors.

mula or the GFR is estimated with the Modication of Diet in Renal Disease (MDRD) equation. Applying the CockcroftGault formula, that is, (140 age) weight / (SCr 72), multiplied by 0.85 for females, the man has an estimated CrCl of 45 mL/min, while the womans sex factor alone brings her estimated CrCl down to 39 mL/min. When these same laboratory values are factored into the MDRD equation, the mans eGFR is 60 mL/min/1.73 m2 and the womans is 36 mL/min/1.73 m2. Based on the eGFR, the womans kidney function is much lower than the mans. This is very important to recognize because women generally have less muscle mass than men; therefore, their SCr will not be as high. Although the MDRD equation and Cockcroft-Gault formula provide estimates that may not be as precise as a measured GFR, they give a more accurate idea of kidney function than does serum creatinine alone. The estimation of GFR for the diagnosis and staging of kidney disease has been recommended by the National Kidney Foundation (NKF). In fact, many laboratories are starting to report the eGFR using the MDRD formula along with the SCr. CAUSES OF ANEMIA IN CKD When a patient develops CKD, anemia develops as a result of the presence of any one or the combination of multiple factors that include: decreased erythropoietin production, bone marrow suppression by uremia, shortened red blood cell (RBC) life span, blood loss, deciency of vitamin B12 and/or folate, iron deciency, inammation, infection, osteitis brosa cystica secondary to hyperparathyroidism in CKD, and aluminum toxicity (Figure 1). The evidence suggests that, as renal function is lost in CKD, the kidney produces less erythropoietin, which is essential to stimulate the bone marrow to produce RBCs. Additionally, uremia is associated with shorter life span of RBCs from 4 months to 30 or 40 days.3 Presence of uremic toxins such as polyamines also leads to suppression of RBC producS8 Agarwal

tion.4 Further, secondary hyperparathyroidism may develop and brosis of the bone marrow can ensue. In addition, more than a third of the people with CKD become iron decient; in some, the iron deciency results from a decline in platelet function and loss of blood from the gastrointestinal tract. In CKD, increased inammatory cytokines, common in chronic diseases, can also block iron release from the reticuloendothelial system, causing a functional iron deciency.5 While several factors contribute to anemia associated with CKD, the most important factors responsible for anemia are deciency of erythropoietin production and iron deciency. After a study of the impact of human recombinant erythropoietin (epoetin alfa) therapy in nearly 1000 hemodialysis patients, Eschbach and his group6 reported that their results suggest that erythropoietin deciency is still the main cause of the anaemia of CKD. Not only is anemia typically linked with CKD, but the anemia develops early in the course of CKD, as revealed in the classic study by Radtkes group7 that examined the relationship between CrCl and hematocrit levels in 59 healthy subjects and 117 patients who had various stages of chronic renal failure. Their data illustrate that as renal function starts to decline, so too does hematocrit; the decrease in hematocrit is more gradual in the early stages and faster in the later stages of kidney disease. Anemia often appears when CrCl falls below 40 mL/min/1.73 m2 (25 40% function). Between 2 and 40 mL/min/1.73 m2, declining CrCl and hematocrit are highly and signicantly correlated (r 0.69, P .0001). No signicant correlation to hematocrit was found in CrCl levels of 41 to 91 mL/min/1.73 m2.8 Similarly, when calculating the eGFR, anemia often appears when the eGFR falls below 60 mL/min/m2.5,9 Anemia associated with CKD is underrecognized and undertreated.10 This is of concern, since almost three fourths of the patients presenting for dialysis have a hemoglobin level lower than 11 g/dL.8 This may be the result of not only the poor recognition of anemia but also the poor recognition of CKD itself. DILEMMA OF DIAGNOSING ANEMIA To avoid the high degree of cardiovascular morbidity and mortality in people who have CKD-related anemia, both the anemia and the CKD need to be recognized and treated early. Low hemoglobin levels are so common in CKD that some clinicians might be erroneously tempted to consider these acceptable in CKD. However, as the NKFs Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) guideline points out, The low hemoglobin level that is often seen in chronic kidney disease should not lead to the acceptance of lower than normal hemoglobin levels as appropriate in patients with chronic kidney disease. All patients with CKD who have hemoglobin levels lower than physiological norms should be considered anemic.11 Using the hemoglobin level to identify anemia is complicated, however, by the lack of a single accepted level of hemoglobin that denes anemia. In the United States, the NKF-K/DOQI recommends anemia workup when the hemoglobin is 12 g/dL in adult men and postmenopausal women,
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or 11 g/dL in prepubertal children (hemoglobin tends to be lower in children than in adults) and premenopausal women (who normally lose blood in their menses).11 The European Best Practice Guidelines for the management of anemia in patients with CKD, in contrast, identify a much higher level of hemoglobin for men and a slightly higher level of hemoglobin for women. The guidelines recommend an anemia workup when the hemoglobin level drops below 13.5 g/dL in men 70 years or younger, 12 g/dL in men older than 70 years, or 11.5 g/dL in women.12 The World Health Organization (WHO) denes anemia as a hemoglobin level below 13 g/dL in men older than 15 years, below 12 g/dL in women older than 15 years, and below 11 g/dL in pregnant women. No differentiation is made for elderly or menopausal status. The WHO has pointed out that hemoglobin levels vary not only with age and sex, but also with altitude, smoking, and perhaps genetic factors. The WHO also advises considering that high altitude and smoking can raise hemoglobin.13 For example, hemoglobin of 12.5 g/dL in a woman who smokes and lives in the mountains could easily mask the presence of anemia. EVALUATION AND TREATMENT According to the NKF-K/DOQI guidelines, when stage 3 CKD is identied (by the clinicians calculation or the laboratorys report of eGFR 60 mL/min/1.73 m2), the next step is to assess the hemoglobin level (since in most cases it will have already been checked). The hemoglobin value is the generally accepted, preferred way to assess anemia since it is a measured value unlike hematocrit, which is a calculated value that is affected greatly by shifts in plasma water. If the hemoglobin is above the dened value cutoff for anemia, the clinician only needs to continue monitoring the person until the hemoglobin value declines below the recommended levels. If the hemoglobin level is 12 g/dL in a man or postmenopausal woman or 11 g/dL in a premenopausal woman, the NKF-K/DOQI recommends an anemia workup, including RBC indices, reticulocyte count, and iron parameters.2 The anemia of CKD is typically normocytic and normochromic, while iron deciency anemia is usually microcytic and hypochromic, and vitamin B12 and folate deciency anemia are most often macrocytic.11 As part of the anemia workup, the patients stool is checked for occult blood to rule out anemia caused by gastrointestinal bleeding, which is especially common in an older population. If the workup reveals iron deciency, the patient should be treated with iron, either orally or intravenously. If iron therapy corrects the anemia, the NKF-K/DOQI guidelines recommend no further treatment, only periodic follow-up. If the hematologic indices are abnormal and the person does not have an iron deciency, a hematologic evaluation to rule out blood dyscrasia or a bone marrow abnormality is in order. MONITORING AND REPLACING IRON Effective therapy for CKD anemia requires monitoring and, when necessary, replacing iron stores. Iron status should be evaluated before and during ESP therapy. If the patient has an iron deciency, the ESP will not be able to effectively stimSUPPLEMENT

Fig. 2. The NKF-K/DOQI Clinical Practice Guidelines outline the evaluation of iron status, which includes checking iron saturation, TIBC, serum ferritin level, and TSAT.11

ulate production of hemoglobin. Supplemental iron is recommended at any point that the transferrin saturation (TSAT) falls below 20% or the serum ferritin drops below 100 ng/mL in CKD. Evaluating Iron The evaluation of iron status includes checking iron saturation, total iron binding capacity (TIBC), serum ferritin level, and TSAT (Figure 2). Knowing the TSAT is essential as it is the indicator of iron that is readily available to the bone marrow for erythropoiesis. The TIBC and ferritin levels are indirect measures of the availability of iron for hemoglobin synthesis but may not provide an accurate assessment of the adequacy of iron supply to the erythron. Nevertheless, use of the 3 resultsTIBC, TSAT, and ferritinin combination provides a more accurate assessment of iron status than any measure used alone. The TSAT is calculated by dividing the TIBC by the serum iron level, then multiplying by 100 to calculate the percentage. No single TSAT or serum ferritin level is optimal for all patients. NKF-K/DOQI guidelines recommend that TSAT be 20% and serum ferritin 100 ng/mL.11 Other indices of iron deciency include a serum iron level of 65 mg/dL in a man or 50 mg/dL in a woman and a TIBC 425 mg/dL. The usual recommendation is to withhold iron if the ferritin rises above 800 ng/mL because that could signify iron overload. However, ferritin is an acutephase reactant and can be high in the presence of infection and inammation, hence the importance of using transferrin saturation to evaluate iron level.11 Iron Supplementation The preferred route of iron supplementation is oral. The patient needs to be given at least 200 mg of elemental iron a day (eg, ferrous sulfate 325-mg tablets, which contain about 65 mg of elemental iron, 3 times daily) because patients
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Frequency of Administration of ESP in Older Patients While the Food and Drug Administration (FDA) has not approved initial dosing for once-weekly epoetin alfa, or beyond once a week for darbepoetin alfa, researchers have been investigating extended dosing.20,21 Fink and colleagues22 performed a subset analysis comparing hemoglobin response of elderly and young patients to once-weekly epoetin alfa. Of the 1338 patients, 717 were 65 years of age or older and 621 were younger than 65 years; all had entry hemoglobin levels of less than 10 g/dL. All received an epoetin alfa starting dose of 10,000 U subcutaneously (SC) once weekly for 16 weeks. If hemoglobin level did not rise by 1 g/dL after 4 weeks, epoetin alfa was titrated to 20,000 U SC once weekly. Similar responses were seen in weeks 4 and 8 for both elderly patients and younger patients. A total of 637 (88.8%) elderly patients and 564 (90.8%) younger patients responded to weekly doses of epoetin alfa. Provenzano et al23 studied response of xed doses of epoetin alfa given at 1-, 2-, 3-, or 4-week intervals. The follow up was short and data in older patients were not analyzed separately.23 Hertel and colleagues24 investigated the effect of darbepoetin alfa SC administration at every 2-week interval in patients with CKD not receiving dialysis who were previously treated with once-weekly epoetin alfa. The subanalysis of the investigation compared elderly (65 years) and younger patients (65 years). Darbepoetin alfa was titrated to doses that would maintain hemoglobin levels no higher than 12 g/dL. The study lasted 52 weeks, with an evaluation period at 20 to 32 weeks. The mean twice-weekly dose of darbepoetin alfa in the elderly patients was 42.86 g every 2 weeks. The subanalysis found that every 2-week administration of darbepoetin alfa can effectively maintain hemoglobin levels in elderly patients when converting from once-weekly epoetin alfa. More recently, Ling et al25 (Figure 4) examined the effect of extending the darbepoetin alfa dosing to once a month in patients with CKD stage 3 or 4 who were not on dialysis. In a multicenter trial, 97 patients whose hemoglobin was stable between 10 and 12 g/dL on SC darbepoetin alfa administered every 2 weeks were converted to monthly dosing. Over a period of 20 weeks, the darbepoetin dose was titrated and the interval between doses was doubled from every 2 to every 4 weeks. Hemoglobin levels remained at about 11 g/dL up to 29 weeks on the monthly dosing regimen. Of all patients who completed the study receiving monthly administration of darbepoetin alfa, hemoglobin remained in the target range for 85% (95% condence interval [CI], 78 93%). Seventy-nine percent of those over 65 years of age and 80% of those over 75 years maintained hemoglobin in the target range. The researchers concluded that Patients with CKD who are clinically stable on darbepoetin alfa administered once every 2 weeks can be safely and effectively converted to darbepoetin alfa administered once monthly.26 Recommended Dosing While the studies evaluating extended dosing for both epoetin and darbepoetin continue, the clinician beginning
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Fig. 3. With the incorporation of 2 additional carbohydrate chains, the half life of darbepoetin alfa is 3 times longer than the rHuEPO.1719 Reprinted with permission from Nature Biotechnology.17 Copyright 2003, Nature Publishing Group.

generally absorb only about 10% of elemental iron.14 Although this is the recommended dosage, clinical judgment is necessary for use in elderly patients who tend to be more vulnerable to the dose-dependent adverse gastrointestinal effects of iron.15 Iron status should be monitored every 2 to 6 months in people who are not receiving ESP and even more frequently in those who are being treated with ESP to ensure that the storage iron is not depleted and that target hemoglobin levels are maintained.14 It has been observed that the oral absorption in patients with CKD is often inadequate.11 Therefore, if oral iron therapy fails, it will be necessary to give the patient intravenous (IV) iron. Additionally, poor availability of iron (as in the presence of infection or inammation) can limit hemoglobin synthesis as a result of functional iron deciency, which is distinct from absolute iron deciency.16 Treatment of the underlying cause of inammation is warranted in such cases. INITIATING ESP THERAPY If no iron deciency is detected, or the anemia persists after iron deciency is adequately corrected with iron supplementation, therapy with ESP is required.11 Currently, 2 such products are available and approved in the United States for treatment of anemia of CKD: epoetin alfa and darbepoetin alfa. Both of these agents are effective in correcting anemia of CKD. The 2 molecules are structurally similar to the natural erythropoietin that healthy kidneys produce (Figure 3).17 Epoetin alfa has 3 carbohydrate side chains, and darbepoetin is hyperglycosylated with 5 such chains.18 Darbepoetin has longer terminal half life than epoetin alfa because of this hyperglycosylation. In theory, the longer terminal half life of darbepoetin should reduce the frequency of its administration, resulting in more comfort and convenience to the patient. The extended dosing may also be useful to non-dialysis patients in community and long-term care settings by decreasing resource utilization.19
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often been reported in patients taking darbepoetin alfa or epoetin alfa. If a patient has uncontrolled hypertension, ESP is not recommended until after the blood pressure is controlled. For example, in a patient who had stage 1 hypertension controlled by a single medication, the clinician may wish to consider adding another antihypertensive before starting an ESP. Initially, there was some concern that ESP therapy might increase seizure activity or thrombotic events, but that has not proven to be the case when used in accordance with the dosing guidelines mentioned previously.11 Measuring ESP Response An adequate hemoglobin response can be expected within 4 to 6 weeks in about 70% of patients who are treated with ESP therapy. If the patients hemoglobin does not rise after 2 months at a dose of 300 U/kg/wk SC or 450 U/kg/wk IV, it is considered an inadequate response. These recommendations are for epoetin alfa only and do no apply to darbepoetin alfa. The causes of inadequate response include inadequate dose of ESP, iron deciency, infection/ inammation, chronic blood loss, osteitis brosa, aluminum toxicity, vitamin B12 or folate deciency, hemoglobinopathy, hemolysis, multiple myeloma, malnutrition, and pure red cell aplasia (PRCA). Iron deciency is present in 25% to 37.5% of patients, and is a common cause of ESP nonresponse. The NKF-K/ DOQI guidelines caution that epoetin therapy itself, by stimulating erythropoiesis to high levels, can lead to functional iron deciencythat is, while the absolute iron level may appear acceptable, there is too little iron available for the large number of RBCs being produced. The guidelines advise that functional (and absolute) iron deciency be prevented by administering 100 to 125 mg iron via IV especially in patients on hemodialysis once a week to improve hemoglobin-rich erythropoiesis. In patients not receiving iron supplementation, the TSAT and serum ferritin levels should be checked every month.5 It is important to look for and treat any infection or inammation that can cause ineffective erythropoiesis, secondary hyperparathyroidism, aluminum toxicity, and other illnesses that could impair bone marrow function. It should be ensured that the patient does not have vitamin B12 or folate deciency, blood dyscrasia, or hemolysis. Infrequently, ESP nonresponse has been caused by appearance of PRCA. Pure red cell aplasia is rather uncommon in the United States and most cases of PRCA have been linked to a neutralizing antibody that was produced in the patient when they received a particular SC epoetin formulation (epoetin alfa), a formulation not available in the United States. The clinician should investigate for PRCA if a patient previously well controlled with epoetin or darbepoetin begins to show a decline in hemoglobin requiring higher doses without improvement. In that case, the patients blood can be tested for PRCA and it would be appropriate for a primary care physician to consult a nephrologist or hematologist.
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Fig. 4. Lings group examined the effect of extending the darbepoetin alfa dosing to once a month in patients with CKD stages 3 or 4 who were not on dialysis. Researchers concluded that Patients with CKD who are clinically stable on darbepoetin alfa administered once every two weeks can be safely and effectively converted to darbepoetin alfa administered once monthly.25

ESP in a patient with CKD needs to keep in mind the dosing recommended in the NKF-K/DOQI treatment guidelines, as well as the dosing approved by the FDA. The recommended epoetin alfa starting dose in the product information approved by the FDA is 50 to 100 U/kg IV or SC 3 times weekly.18 For comparable patients beginning treatment with darbepoetin alfa, the recommended dose is a weekly injection starting with 0.45 g/kg, although some patients may need an every-2week schedule.19 MONITORING AND CAUTIONS In patients receiving epoetin or darbepoetin, hemoglobin should be checked every 1 to 2 weeks until the hemoglobin stabilizes at the target level. If the iron stores are adequate, the expected rise each week is about 0.3 g/dL for the hemoglobin (about 1% for the hematocrit). Despite the frequent monitoring of hemoglobin level, the clinician needs to keep in mind that it can take 2 to 6 weeks of treatment before the effect is seen in the hemoglobin level. Therefore, the dosage should generally not be changed any more frequently than every 4 weeks. If the hemoglobin rise is less than 1 g/dL in 4 weeks, the ESP dose should be increased by 25%. On the other hand, if hemoglobin has risen more than 1 g/dL in 2 weeks, it is recommended that the dose be reduced by 25%.11 It is important that the hemoglobin not rise too high or too fast. Expanding the red cell volume too much may lead to thrombosis, seizures, or cerebrovascular events. Adverse Effects The reported adverse effects for both ESP products are similar. For both medications, it is important to monitor blood pressure closely, because a rise in blood pressure has
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CONCLUSIONS To summarize, anemia occurs early in CKD. Anemia can begin in some people who have a GFR as high as 60 mL/min/ 1.73m2. Yet, only a minority of patients who have CKD and anemia ever receive a single dose of an ESP before their kidney function declines enough to require dialysis. CKD is a cardiovascular risk factor and it is very important not to wait for a patient to be on dialysis before treating anemiaalthough that is so often the scenario. A huge potential for making a positive impact exists for the 8 million CKD patients at stage 3 and higher who are not yet requiring dialysis but who have signicant anemia. Diagnosis of CKD-associated anemia involves recognition of a GFR 60 mL/min/1.73 m2 with no other evident cause of anemia in this population. Both currently approved ESPs epoetin alfa and darbepoetin alfa can very effectively treat the anemia of kidney disease. In fact, it is much easier to treat anemia than to treat hypertension, which is another signicant cardiovascular risk factor commonly present in this population. Adequate iron levels are essential for the correction of anemia by the use of ESPs. The availability of extended dosing regimens in anemic patients with CKD may actually reduce resource utilization and potentially improve compliance, which may benet older patients in the community and long-term care settings.27 While not currently proven in randomized, controlled, prospective trials, early recognition and correction of anemia in patients with CKD may play an important role in ultimately improving outcomes and delaying progression to end-stage renal disease.28 REFERENCES
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10. Brenner BM, Cooper ME, de Zeeuw D. The losartan renal protection study: rationale, study design and baseline characteristics of RENAAL (Reduction of Endpoints in NIDDM with Angiotensin II Antagonist Losartan). J Ren Ang Ald Sys 2000;1:328 335. 11. NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease: update 2000. Am J Kidney Dis 2001;37(1 Suppl 1):S182 S238. 12. Locatelli F, Aljama P, Brny P, et al. European Best Practice Guidelines Working Group. Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant 2004;19(Suppl 2):ii1ii5. 13. WHO/UNICEF/UNU. Iron deciency anaemia: assessment, prevention, and control. Geneva, Switzerland: WHO; 2001. 14. Schwartz A, Prasad V, Garcha J. Anemia of chronic kidney disease: A combined effect of marginal iron stores and erythropoietin deciency. Dialysis Transplant 2004;33:758 767. 15. Rimon E, Kagansky N, Kagansky M, et al. Are we giving too much iron? Low-dose iron therapy is effective in octogenarians. Am J Med 2005; 118:11421147. 16. Schaefer RM, Bahner U. Iron metabolism in rhEPO-treated hemodialysis patients. Clin Nephrol 2000;53(Suppl):S65S68. 17. Elliot S, Lorenzini T, Asher S, et al. Enhancement of therapeutic protein in vivo activities through glycoengineering. Nat Biotechnol 2003;21: 414 421. 18. Erythropoetin (Epogen/Procrit) [package insert]. Raritan (NJ): Ortho Biotech Products, LP; 2005. Available at: http://www.epogen.com/pdf/ epogen_pi.pdf. Accessed August 16, 2006. 19. Darbepoetin (Aranesp) [package insert]. Thousand Oaks (CA): Amgen Inc.; 2005. Available at: http://www.aranesp.com/pdf/aranesp_PI.pdf. Accessed August 16, 2006. 20. Jadoul M, Vanrenterghem Y, Foret M, et al, for the Darbepoetin Alfa 20000144 Study Group. Darbepoetin alfa administered once monthly maintains haemoglobin levels in stable dialysis patients. Nephrol Dial Transplant 2004;19:898 903. 21. Agarwal A, Ling B, Wacky M, et al. Aranesp (darbepoetin alfa) administered once monthly maintains hemoglobin levels in patient with chronic kidney disease (CKD). Presented at: Annual Meeting of the National Kidney Foundation Clinical Nephrology; April 28 May 2, 2004; Chicago, IL. 22. Fink J, Provenzano R, Woodman R, Hill K, et al. Comparative analysis of efcacy and safety of once-weekly (QW) epoetin alfa (EPO) in elderly (65) and non-elderly (65) patients with anemia due to chronic kidney disease (CKD). J Am Geriatr Soc 2004;52(Suppl 1):s25. 23. 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;64:113123. 24. Hertel J, Locay H, Scarlata D, et al. Darbepoetin alfa administered every other week maintains hemoglobin levels over 52 weeks in patients with chronic kidney disease converting from once-weekly recombinant human erythropoietin: results from Simplify the Treatment of Anemia with Aranesp (STAAR). Am J Nephrol 2006;26:149 156. 25. Ling B, Agarwal A, Scarlata D, Liu W, Brenner R, Audhya P. Oncemonthly Aranesp (darbepoetin alfa) maintains hemoglobin in elderly chronic kidney disease patients. Poster presented at: American Geriatrics Society Annual Scientic Meeting; 2005; Orlando, FL. 26. Ling B, Walczyk M, Agarwal A, et al. Darbepoetin alfa administered once monthly maintains hemoglobin concentrations in patients with chronic kidney disease. Clin Nephrol 2005;63:327334. 27. Agarwal A, Silver MR, Walczyk M, Liu W, Audhy P. Once-monthly darbepoetin alfa for maintaining hemoglobin levels in older patients with chronic kidney disease. J Am Med Dir Assoc; in press. 28. Radtke HW, Claussner A, Erbes PM. Serum erythropoietin concentration in chronic renal failure: Relationship to degree of anemia and excretory function. Blood 1979;54:877 884.

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