Anemia Is a Common Complication of CKD Kausz and colleagues published results of a study in 2002, which demonstrates that, as the level of serum creatinine increases, the prevalence of CKD patients defined as anemic increases. In this study, anemia was defined as at least two Hct values below the gender-specific norm (Hct value <42% for males; Hct value <36% for females) that were at least 30 days apart. The results of this study show that anemia often develops early in the course of CKD and worsens as CKD progresses. . Reference Kausz AT, Steinberg EP, Nissenson AR, et al. Prevalence and management of anemia among patients with chronic kidney disease in a health maintenance organization. Dis Manage Health Outcomes. 2002;10:505-513.
Effect of Diabetes on Anemia* Prevalence (KEEP) El-Achkar and colleagues reported results from the Kidney Early Evaluation Program (KEEP) demonstrating that, at different levels of glomerular filtration rate (GFR), the prevalence of anemia in patients with diabetes is higher compared to patients without diabetes. Anemia develops earlier in CKD patients with diabetes, and at any given level of GFR, the prevalence of anemia is greater in patients with diabetes. Reference El-Achkar TM, Ohmit SE, McCullough PA, et al. Higher prevalence of anemia with diabetes mellitus in moderate kidney insufficiency: The Kidney Early Evaluation Program. Kidney Int . 2005;67:1483-1488.
Untreated Anemia Is Associated With Increased Hospitalizations In a retrospective analysis of 362 patients with CKD (who were not treated with erythropoietin-stimulating agents), the presence of anemia was independently associated with an increased likelihood of hospitalization. Patients with anemia were hospital free for a median of 13.3 months, compared with a median of 21.5 months for patients with higher Hb levels ( P= 0.0593). Reference Holland DC, Lam M. Predictors of hospitalization and death among pre-dialysis patients: a retrospective cohort study. Nephrol Dial Transplant. 2000;15:650-658.
Benefits of Treatment With Erythropoiesis-Stimulating Agents (ESAs) Treatment with ESAs to achieve partial correction of Hb levels is associated with improved quality of life, 1 reduced risk for mortality, 2 and reduced risk of hospitalization. 3 References 1. Eschbach JW, Abdulhadi MH, Browne JK, et al. Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multicenter clinical trial. Ann Intern Med . 1989;111:992-1000. 2. Collins AJ, Ma JZ, Ebben J. Impact of hematocrit on morbidity and mortality. Semin Nephrol . 2000;20:345-349. 3. Collins AJ, Li S, St Peter W, et al. Death, hospitalization, and economic associations among incident hemodialysis patients with hematocrit values of 36 to 39%. J Am Soc Nephrol. 2001;12:2465–2473.
Epoetin The first therapeutic agent to be used for the stimulation of erythropoiesis was recombinant human erythropoietin ( Epoetin ). Recombinant human erythropoietin acts by stimulating the proliferation, survival, and differentiation of erythroid progenitors so that they will survive and enter the circulation as reticulocytes. 1-4 Epoetins are approved for either intravenous or subcutaneous administration 2 to 3 times per week; however, in clinical practice they are often given less frequently. 5 The frequency of administration is dictated partly by the short biologic half-life of these drugs. 1-4 References 1. Egrie JC, Strickland TW, Lane J, et al. Characterization and biological effects of recombinant human erythropoietin. Immunobiology . 1986;172:213-224. 2. Graber SE, Krantz SB. Erythropoietin and the Control of Red Cell Production. Ann Rev Med . 1978;29:51-66. 3. Eschbach JW, Egrie JC, Downing MR, et al. Correction of the Anemia of End-Stage Renal Disease with Recombinant Human Erythropoietin. NEJM . 1987;316:73-78. 4. Eschbach JW, Abdulhadi MH, Browne JK, et al. Recombinant Human Erythropoietin in Anemic Patients with End-Stage Renal Disease. Ann Intern Med . 1989;111:992-1000. 5. Papatheofanis FJ, McKenzie RS, Mody SH, et al. Dosing patterns, hematologic outcomes, and costs of erythropoietic agents in predialysis chronic kidney disease patients with anemia. Curr Med Res Opin . 2006;22:837-842.
Darbepoetin alfa At the turn of this century, darbepoetin alfa became available. Darbepoetin alfa contains two additional N-linked carbohydrate chains and up to 8 more sialic acid residues than epoetin. These modifications extend the half life of the drug by at least three fold and may allow for a decreased frequency of administration. Reference Egrie JC, Browne JK. Development and characterization of novel erythropoiesis stimulating protein (NESP). Nephrol Dial Transplant . 2001;16 Suppl 3:3-13. Macdougall IC, Gray SJ, Elston O, et al. Pharmacokinetics of novel erythropoiesis stimulating protein compared with epoetin alfa in dialysis patients. J Am Soc Nephrol. 1999;10:2392–2395.
Hypertension Up to 80% of patients with CKD have a history of hypertension. 1,2 Hypertension has been a well-established adverse consequence related to EPO therapy, with new-onset hypertension or a worsening in blood pressure occurring in an estimated one-quarter of patients receiving EPO treatment. 3 Blood pressure should be controlled adequately before initiation of ESA therapy. 4 References Kerr DN. Chronic Renal Failure. In: Beeson PB, McDermott W, Wyngaarden JB, eds. Cecil Textbook of Medicine . Philadelphia, PA: W.B. Saunders; 1979:1351-1367. Agarwal R, Nissenson AR, Batlle D, et al. Prevalence, treatment, and control of hypertension in chronic hemodialysis patients in the United States. Am J Med. 2003;115: 291-297. National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. Am J Kidney Dis. 2006;47(suppl 3):S1-S146. Agarwal R. Overcoming barriers that inhibit proper treatment of anemia. Kidney Int Suppl. 2006;(101):S9-12. Macdougall IC, Eckardt KU. Novel strategies for stimulating erythropoiesis and potential new treatments foranaemia. Lancet . 2006;368:947-953.
Iron Deficiency in CKD In patients beginning ESA treatment, iron deficiency occurs due to increased iron consumption during erythropoiesis. Iron deficiency will develop in most dialysis patients receiving ESAs. Iron deficiency is the most common reason for resistance to the effect of ESAs. Reference National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. Am J Kidney Dis. 2006;47(suppl 3):S1-S146.
Importance of Iron Sufficiency During ESA Initiation The importance of maintaining sufficient iron stores during the initiation of ESA therapy is made clear by the study by McDougall and colleagues that was published in 1996. Results from this study showed that, over 16 weeks of treatment, patients who received intravenous iron had an increase in hemoglobin levels from approximately 7 g/dL to 12 g/dL. In patients treated with either no iron or with oral iron therapy, a substantial decrease in the effectiveness of ESA treatment was seen, which was related to the development of iron deficiency in a large number of patients. Reference Macdougall IC, Tucker B, Thompson J, et al. A randomized controlled study of iron supplementation in patients treated with erythropoietin. Kidney Int . 1996;50:1694-1699.
Evaluating Iron Status in Anemic Patients With CKD Iron status test results reflect either the level of iron in tissue stores or the adequacy of iron for erythropoiesis. Serum ferritin level is the only available blood marker of storage iron. Tests that reflect adequacy of iron for erythropoiesis include TSAT, percentage of hypochromic red blood cells (PHRC) and content of Hb in reticulocytes (CHr). Reference National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. Am J Kidney Dis. 2006;47(suppl 3):S1-S146.
Avoiding Iron Deficiency The 2006 KDOQI guidelines recommend specific targets (goals) of iron therapy during administration of ESAs. For hemodialysis (HD) patients, the guidelines recommend iron be administered if transferrin saturation (TSAT) is higher than 20% AND if the s erum ferritin concentration higher than 200 ng/mL. For non-HD patients, the guidelines recommend iron be administered if TSAT is higher than 20% AND serum ferritin concentration is higher than 100 ng/mL. Reference National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. Am J Kidney Dis. 2006;47(suppl 3):S1-S146.
Avoiding Iron Overload According to the 2006 KDOQI guidelines, when serum ferritin is >500 ng/mL, decisions regarding IV iron administration should weigh ESA responsiveness, Hb and TSAT levels, and the patient’s clinical status. For the patient who is feeling well and has a satisfactory Hb level, the decision may be to not intensify iron treatment. However, in patients who require very high doses of ESA and have low Hb levels, IV iron or other methods of iron intensification might be required. Reference National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. Am J Kidney Dis. 2006;47(suppl 3):S1-S146.
How to Initiate ESA Therapy According to the prescribing information, Epoetin should be initiated at 50-100 units/kg administered either IV or SC, 3 times per week. 1,2 In clinical practice, however, . . . According to the prescribing information, darbepoetin alfa should be initiated at 0.45 g/kg, administered as a single IV or SC injection once weekly. 5 In clinical practice, however, . . . According to the prescribing information, C.E.R.A. should be initiated at 0.6 g/kg administered as a single IV or SC injection once every 2 weeks8 In clinical practice, however, . . . References Epogen (epoetin alfa) prescribing information, Amgen, Inc, Thousand Oaks, Calif. Procrit (epoetin alfa) prescribing information, Ortho Biotech Products, L.P., Raritan, New Jersey. 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;64:113-123. Provenzano R, Garcia-Mayol L, Suchinda P, et al. Once-weekly epoetin alfa for treating the anemia of chronic kidney disease. Clin Nephrol . 2004;61:392-405. Aranesp (darbopoetin alfa) prescribing information, Amgen, Inc., Thousand Oaks, Calif. Suryani MG, et al. Am J Kidney Dis . 2003;23:106-111 Ling B, Walczyk M, Agarwal A, Carroll W, Liu W, Brenner R. Darbapoetin alfa administered once monthly maintains hemoglobin concentrations in patients with chronic kidney disease. Clin Nephrol. 2005; 63:327-334.
Monitoring Rate of Hb Response It is recommended that the dose of ESA be decreased if the Hb increase exceeds 1.0 g/dL in any 2-week period. In clinical trials, increases in Hb >1.0 g/dL during any 2-week period were associated with increased incidence of cardiac arrest, neurologic events (including seizures and stroke), exacerbations of hypertension, congestive heart failure, vascular thrombosis/ischemia/infarction, acute myocardial infarction, and fluid overload/edema. References Epogen (epoetin alfa) prescribing information, Amgen, Inc, Thousand Oaks, Calif. Procrit (epoetin alfa) prescribing information, Ortho Biotech Products, L.P., Raritan, New Jersey. Aranesp (darbopoetin alfa) prescribing information, Amgen, Inc., Thousand Oaks, Calif.
Target Hb Level The KDOQI 2001 anemia guidelines recommended a target Hb range of 11-12 g/dL. The 2006 published anemia guidelines recommended Hb level of greater than or equal to 11 g/dL≥11 g/dL, but urged caution when intentionally maintaining Hb >13 g/dL. The prescribing information for the ESAs recommends a target Hb level of 10-12 g/dL. There is considerable controversy regarding the optimal hemoglobin level. References 1. National Kidney Foundation. Am J Kidney Dis. 2006;47(suppl 3):S1-S146. 2. Epogen (epoetin alfa) prescribing information, Amgen, Inc, Thousand Oaks, Calif. 3. Procrit (epoetin alfa) prescribing information, Ortho Biotech Products, L.P., Raritan, New Jersey. 4. Aranesp (darbopoetin alfa) prescribing information, Amgen, Inc., Thousand Oaks, Calif. 5. 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;355:2071-2084. 6. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med . 2006;355:2085-2098.
Normalization of Hb Has Increased Risk To determine whether targeting higher Hb concentrations when treating CKD patients with anemia puts them at increased risk of death, a meta-analysis of several studies examined the risk of all-cause mortality associated with a higher Hb target in the normal physiological range (defined here as between 12-16 g/dL) compared with a lower Hb target. Results showed that the risk ratio for the higher Hb target was 1.17 (95% CI 1.01-1.35), indicating that targeting higher Hb concentrations does put patients at increased risk. There was no heterogeneity between these studies and the data from the HD pataients and the non-HD patients were similar. References Phrommintikul A, Haas SJ, Elsik M, et al. Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis. Lancet . 2007;369:381-388. Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med . 1998;339:584-590. Foley RN, Parfrey PS, Morgan J, et al. Effect of hemoglobin levels in hemodialysis patients with asymptomatic cardiomyopathy. Kidney Int . 2000;58:1325-35. Furuland H, Linde T, Ahlmen J, et al. A randomized controlled trial of haemoglobin normalization with epoetin alfa in pre-dialysis and dialysis patients. Nephrol Dial Transplant . 2003;18:353-361. Levin A, Djurdjev O, Thompson C, et al. Canadian randomized trial of hemoglobin maintenance to prevent or delay left ventricular mass growth in patients with CKD. Am J Kidney Dis . 2005;46:799-811. Parfrey PS, Foley RN, Wittreich BH, et al. Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease. J Am Soc Nephrol . 2005;16:2180-2189. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med . 2006;355:2085-2098. 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;355:2071-2084. Rossert J, Levin A, Roger SD, et al. Effect of early correction of anemia on the progression of CKD. Am J Kidney Dis . 2006;47:738-750.
Key Points 1,25-dihydroxyvitamin D (1,25(OH) 2 D 3 ) levels start falling much earlier in CKD before the rise in PTH is observed. The changes in 1,25(OH) 2 D 3 have not previously been described given the lack of data in this earlier population. 1 Note that secondary HPT begins to occur at eGFR levels of approximately 45 mL/min/1.73 m 2 , similar to the point where the median value of 1,25(OH) 2 D 3 begins to approach values deemed ‘deficient’ (22 pg/mL) when using the values in the lowest tertile for this population. 1 Background The S tudy for the E valuation of E arly K idney Disease (SEEK) was a prospective, observational, multicenter study. 1 This was a cross-sectional analyses of baseline data. The primary objective was to determine the relationship of circulating vitamin D, PTH, calcium, and phosphorus in CKD patients who were not receiving prescribed vitamin D. This study was an initial attempt to help better define the role of vitamin D deficiency as it relates to eGFR and the development of hyperparathyroidism. Patients were enrolled from June to October 2004. 5,255 patients were screened of which 1,903 were enrolled, and 1,814 were analyzed. A large number could not be enrolled due to eGFR levels or analyzed due to missing serum creatinine levels. 1 Levin A, et al. Kidney Int . 2007;71:31-38.
Key Points In 2005, KDIGO ® proposed the term CKD–Mineral and Bone Disease (CKD–MBD) to refer to a broad clinical syndrome due to CKD associated with abnormalities in bone and mineral metabolism, and extra-skeletal calcification. 1 This Venn diagram illustrates how the consequences of CKD-MBD interact to produce poor outcomes for patients in the later stages of renal disease. 2 Background Recognizing that CKD is a worldwide public health problem, KDIGO ® sponsored a Controversies Conference on Renal Osteodystrophy, at which it was recommended that the term CKD-MBD should be used to describe the syndrome of biochemical, bone, and extra-skeletal calcification abnormalities that occur in CKD; these include abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism; abnormalities in bone turnover, mineralization, volume, linear growth, or strength; and vascular or other soft tissue calcification. 1 Chronic kidney disease involves disorders of both mineral and bone metabolism which are associated with significant morbidity, decreased quality of life, and extra-skeletal calcification that can lead to increased cardiovascular mortality. These disturbances have classically been termed renal osteodystrophy and classified based on bone biopsy. 1 KDIGO ® is a registered trademark of Kidney Disease: Improving Global Outcomes, Inc. 1 Moe S, et al. Kidney Int. 2006;69:1945-1953. 2 KDIGO ® Overview slide presentation at: http://www.kdigo.org/speaker_center.php. Accessed September 11, 2008.