Monograph: Anemia & Chronic Kidney Disease

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DISCLAIMER
PLEASE NOTE: This monograph provides useful information for medical professionals, but treatment recommendations regarding erythropoiesis-stimulating agents (ESAs) use and monitoring have changed since this handbook was originally published. We are in the process of updating the chapters to reflect emerging data. Any questions about content can be submitted online through our Ask the Expert section. In the meantime, we recommend practitioners follow current clinical practice guidelines using ESAs with CKD patients, provided by the National Kidney Foundation (NKF).

Key points
  • Anemia is a common complication of chronic kidney disease (CKD), develops early, and worsens as CKD progresses.
  • CKD-related anemia has multiple adverse consequences, affecting quality of life, cognitive function, exercise capacity, immune response, and heart function.
  • Early identification and treatment of CKD-related anemia to prevent serious consequences is an idea promoted as the Renal Anemia Management Period (RAMP) by concerned nephrologists.
  • Benefits of anemia correction in patients with CKD include decreased morbidity, hospitalization, and mortality; and improvement in quality of life, exercise capacity, cognitive function, and sexual function.

CKD: An Insidious Disease
Chronic kidney disease (CKD) is an insidious disease that gradually impairs kidney function. In its earliest stages, patients may be unaware they have the disease, but over a period ranging from several years to several decades, CKD will often progress to end-stage renal disease (ESRD), requiring renal replacement therapy (dialysis or kidney transplantation) to sustain life.

CKD arises as a consequence of diabetes mellitus, hypertensive nephrosclerosis, chronic glomerulonephritis, polycystic kidney disease, and a host of other disorders.1 Diabetes and hypertension are the two leading causes of ESRD, accounting for approximately 43% and 27% of all new ESRD cases, respectively.2

Staging and Prevalence of CKD
While the terminology of the formal literature has been inconsistent and confusing, this monograph has adopted the CKD staging terminology recently proposed by the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) and uses the term chronic kidney disease to encompass the entire spectrum of kidney disease, from its earliest stages through ESRD.3,4

As serum creatinine (SCr) levels are an imperfect indicator of the severity of kidney disease, the NKF-K/DOQI staging and prevalence estimates are based on glomerular filtration rates (GFRs) derived using a formula developed by Levey and colleagues5 from data in the Modification of Diet in Renal Disease Study.

The resulting estimated total of 19.5 million people in the United States who have CKD marks the disease as a major public health concern, affecting more than the number of Americans with diabetes (estimated at 17 million)8 and nearly half the number of those with hypertension (estimated at 50 million).9 Because CKD typically progresses to its most severe form, ESRD, the public health concern is underscored by the most recent data from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD). The combined 1995 to 1999 prevalence of ESRD patients was 392,847 on dialysis and 8,287 with transplants.2 Expecting this alarming trend to continue, the NIDDKD has estimated that the prevalence of ESRD will reach over half a million by 2010.10

*Adapted and reprinted with permission from NKF-K/DOQI, 2002.6 Data for stages 1-4 from the Third National Health and Nutrition Examination Study (NHANES III, 1988-1984).7 Population of 177 million adults (age =18 years). CKD = chronic kidney disease, CVD = cardiovascular disease. Stages 1-5 represent individuals with CKD; first row represents individuals at risk for CKD.

The NKF-K/DOQI prevalence estimates, together with the high costs associated with CKD, prompted the National Institutes of Health to establish the National Kidney Disease Education Program (NKDEP), an aggressive public education campaign currently underway. The NKDEP initiative likely will recommend interventions based on this K/DOQI staging. For patients first diagnosed with CKD, a primary goal will be to slow progression through the use of angiotensin-converting enzyme inhibitors, blood pressure control, and, in patients with diabetes, blood sugar control. Emphasis will be given to preventive and therapeutic approaches related to uremic complications, malnutrition, anemia, bone disease, acidosis, and medical comorbidities, such as cardiovascular disease.

Anemia Common in CKD
Anemia is a common complication of CKD, mainly due to the inability of the kidneys to secrete enough erythropoietin to stimulate adequate hematopoiesis. Additional factors that may cause or contribute to CKD-related anemia include iron deficiency,11 severe hyperparathyroidism, 12 acute and chronic inflammatory conditions,13 aluminum toxicity,14 folate deficiency,15 shortened red blood cell survival, 16 hypothyroidism,17 and hemoglobinopathies such as a-thalassemia.18

Anemia often develops early in the course of CKD, well before the onset of ESRD (stage 5, on dialysis),10,12,14,18-21 and then worsens as CKD progresses. Anemia is thus an important clinical factor for millions of Americans with CKD stages 3 through 5.

Hb/Hct levels in dialysis patients (stage 5, on dialysis) are meticulously followed by the Medicare system, and detailed analyses of these levels and treatment results are readily available. Less is known, however, regarding Hb/Hct levels in the millions of Americans with CKD not requiring dialysis

One frequently cited paper that sheds light on the prevalence of anemia in CKD patients prior to ESRD—and the quality of their care—is a retrospective analysis by Obrador and colleagues21 of more than 130,000 US patients initiating dialysis between April 1995 and June 1997. Sixty-eight percent of these patients had a Hct value <30%, considered to indicate severe anemia, and 51% had a Hct value <28% immediately before starting dialysis. Of those with Hct <28%, epoetin had not been prescribed for 80%.

Obrador and colleagues based their analysis on information collected on Medicare’s Medical Evidence Form (MEF). A recent comparison of MEF data to actual Medicare claims22 (n = 89,193) suggests that the MEF overestimates epoetin use in CKD patients prior to ESRD. The percentage of untreated patients suggested by Obrador and colleagues, therefore, may be even higher. In any event, the evidence is clear that anemia related to CKD stages 1 through 4 is underrecognized and undertreated in the United States.

Consequences of CKD-Related Anemia
The clinical consequences of anemia have been studied more in CKD than in any other disease state. The condition affects almost every organ system. In addition to contributing to the development of left ventricular hypertrophy (LVH), as described below, anemia impairs cognitive function,23 decreases exercise capacity,24 erodes quality of life,25 and may weaken immune responses.26 In patients with ESRD, severe anemia is associated with increases in hospitalization,27 health care costs,28,29 and mortality.30-32

Cardiovascular disease (CVD) is the cause of death in nearly half of dialysis patients.33 Many of the risk factors for CVD are also risk factors for CKD, including hypertension, diabetes, and male gender. Complications of CKD create additional cardiovascular risk factors, such as volume overload, anemia, increased oxidant stress, hypoalbuminemia, divalent ion abnormalities, hypokalemia and hyperkalemia, and metabolic acidosis.34

LVH is a common finding in patients with CKD,35-37 resulting from alterations in left ventricular wall stress caused, at least in part, by hypertension and anemia.35,36 It has been shown to progress with the degree of CKD.38 LVH is a significant risk factor for cardiovascular events independent of blood pressure in hypertensive men,38 and for cardiac and all-cause mortality in patients who require dialysis or kidney transplant.39

Figure 2-1. The RAMP (Renal Anemic Management Period) calls for timely and appropriate treatment of CKD to prevent anemia and other comorbitities.40

Early Identification of Anemia Recommended
Concerned by the facts that anemia develops early in CKD and worsens as the disease progresses, a panel of nephrologists developed a concept called the Renal Anemia Management Period (RAMP). The RAMP model emphasizes the progressive nature of CKD and the need for timely and appropriate treatment—well before the development of ESRD—to prevent anemia and other comorbidities that can potentially lead to irreversible, physiological damage, such as LVH.40 Rather than representing data from a specific study, the RAMP model notes trends identified in many studies.

Guidelines from the NKF-K/DOQI recommend that an anemia work-up be initiated when the Hb/Hct value declines to approximately 80% of the mean value defined for healthy, normal subgroups, as anemia is likely to be present.6 For example, in adult men and postmenopausal women with CKD, an anemia work-up should be initiated at Hb =12.5 g/dL (Hct <37%); in premenopausal women and prepubertal CKD patients, the corresponding levels are Hb =11 g/dL (Hct <33%).

The NKF-K/DOQI guidelines recommend that Hb levels in patients with ESRD be maintained between 11 g/dL and 12 g/dL. The same target Hb range (11 g/dL to 12 g/dL) has come to apply also to patients with CKD who do not have ESRD, despite a lack of studies on the long-term effects of maintaining such a Hb range in this population.

A consensus on the optimal Hb levels at varying stages of CKD has not been reached, but the current Centers for Medicaid and Medicare Services policy restricts reimbursement for the initiation of anemia treatment to Hb =10 g/dL, even though evidence indicates that adverse anemia-related sequelae occur at Hb =11 g/dL.35,36

Figure 2-2. Anemia Work-Up for CKD Patients. Differences in average Hb/Hct values between adult men and women are likely due to differences in estrogen and testosterone production that emerge at puberty and subside after menopause.

Referral Concerns
Referral Concerns Many of the suboptimal outcomes related to CKD may result from late referral of patients with CKD to a nephrologist. Although guidelines from the National Institutes of Health 1993 Consensus Statement on Morbidity and Mortality of Dialysis41 recommend that patients be referred to nephrologists when SCr levels rise to 1.5 mg/dL for women and 2 mg/dL for men, a 1999 US Renal Data System report10 indicated that only 20% to 25% of patients with CKD are referred to a nephrologist before they need dialysis.

Arora and colleagues42 reported that, of 135 patients with CKD followed at a major tertiary medical center, 22% were referred less than 4 months before initiation of dialysis. Compared with earlier referrals, these late referrals were more likely to have Hct <28% (55% of patients referred late vs. 33% of patients referred early) and less likely to have received treatment with epoetin (17% of those referred late vs. 40% of those referred early).

One study of 1,658 patients with elevated serum creatinine levels, conducted by Nissenson and colleagues, found that patients with CKD tended to be transferred to a nephrologist only when levels reached 4.0 mg/dL. In addition, only 7.4% of patients received epoetin, which was unlikely to be prescribed unless the patient had visited a nephrologist.43

A multidisciplinary approach may facilitate patient identification and improve the management of CKD.44 One study of CKD patients prior to ESRD demonstrated that inclusion in a multidisciplinary CKD clinic program produced greater increases in time to renal replacement therapy, Hb levels, and epoetin treatment at initiation of dialysis compared to standard nephrology care or no care.45

The proposed NKF-K/DOQI staging of CKD, coupled with the National Kidney Disease Education Program, may promote a greater sensitivity on the part of primary care physicians to be alert for CKD and its complications in patients with a GFR <60 mL/min/1.73 m2 (stage 3). The evaluation of patients at stage 3 should include the measurement of dietary energy and protein intake, weight, Hb, serum albumin, serum total cholesterol, parathyroid hormone, calcium, and phosphorus, as well as patient functioning and well-being.46

Beneficial Effects of Anemia Management

Findings of several studies suggest that partial correction of anemia to Hb levels of 11 g/dL to 12 g/dL may decrease morbidity and reduce hospital ization and mortality among patients with CKD.26,27,47-52 Hayashi and colleagues found that 4 months of epoetin treatment increased the mean Hct and decreased the left ventricular mass index (LVMI) in CKD patients prior to ESRD,53 and similar progressive improvements were seen after 12 months. Another study of renal failure patients showed a trend of decreased left ventricular thickness and a significant decrease in LVMI as Hb levels were increased with epoetin therapy.54 Other study findings have shown that benefits of correcting anemia in patients with CKD include improvements in quality of life,51,54 exercise capacity,24,51 cognitive function,49 and sexual function.50

Since its introduction in the late 1980s, epoetin has become widely accepted as an effective and well-tolerated therapy for anemia. Its clinical benefits to thousands of patients with CKD (before and during dialysis) are well documented. Because of its relatively short half-life, however, it generally has to be administered two to three times per week.

Recently, darbepoetin alfa, a longer-acting erythropoietic agent than epoetin, has been approved by the Food and Drug Administration for the treatment of patients with the anemia of CKD whether on dialysis or not. Due to longer serum half-life (25 hours vs. 8.5 hours), darbepoetin alfa can be administered less frequently than epoetin alfa. For example, patients who had been receiving epoetin once weekly can often be administered darbepoetin alfa once every 2-4 weeks.55

Two large multicenter studies in dialysis patients who switched therapies demonstrated that darbepoetin alfa is as effective as epoetin in maintaining Hb levels.56,57 Similar comparability was demonstrated in a European multicenter study of CKD patients before the need for dialysis.58 In addition to less frequent dosing requirements, darbepoetin alfa appears to be well tolerated, with a safety profile comparable to that of epoetin.51,52

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References

  1. Pereira BJ, Besarab A. The renal anemia management period.Internal Medicine News. 2001;suppl:6-9.
  2. US Renal Data System. USRDS 2001 Annual Data Report. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; 2001.
  3. National Kidney Foundation. National Kidney Foundation Kidney Disease Outcomes Quality Initiative. Orlando, FL: National Kidney Foundation; April 17-22 2001.
  4. Eknoyan G, Levey AS, Levin NW, et al. The national epidemic of chronic kidney disease: what we know and what we can do. Postgrad Med. 2001;110:23-29.
  5. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med. 1999;130:461- 470.
  6. National Kidney Foundation. NKF-K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(suppl):S1-S266.
  7. Jones CA, McQuillan GM, Kusek JW. Serum creatinine levels in the US population: Third National Health and Nutrition Examination Survey (erratum in Am J Kidney Dis 2000;35:178). Am J Kidney Dis. 1998;32:992-999.
  8. US Department of Health and Human Services. HHS, ADA warn Americans of "pre-diabetes," encourage people to take healthy steps to reduce risks. March 27, 2002. Available at: http://www.hhs.gov/news/press/2002pres/20020327.html. Accessed April 10, 2002.
  9. Joint National Committee on Prevention Detection, Evaluation, and Treatment of High Blood Pressure. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Bethesda, MD: National Institutes of Health; 1997.
  10. US Renal Data System. USRDS 1999 Annual Data Report. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; 1999.
  11. Parker PA, Izard MW, Maher JF. Therapy of iron deficiency anemia in patients on maintenance dialysis. Nephron. 1979;23:181-186.
  12. Potasman I, Better OS. The role of secondary hyperparathyroidism in the anemia of chronic renal failure. Nephron. 1983;33:229-231.
  13. Adamson JW, Eschbach JW. Management of the anaemia of chronic renal failure with recombinant erythropoietin. Q J Med. 1989;73:1093-1101.
  14. Kaiser L, Schwartz KA. Aluminum-induced anemia. Am J Kidney Dis. 1985;6:348-352.
  15. Hampers CL, Streiff R, Nathan DG, et al. Megaloblastic hematopoiesis in uremia and in patients on long-term hemodialysis. N Engl J Med. 1967;276:551-554.
  16. Eschbach JW, Jr., Funk D, Adamson J, et al. Erythropoiesis in patients with renal failure undergoing chronic dialysis. N Engl J Med. 1967;276:653-658.
  17. Eschbach JW. The future of r-HuEPO. Nephrol Dial Transplant. 1995;10(suppl 2):96-109.
  18. Kausz AT, Khan SS, Abichandani R, et al. Management of patients with chronic renal insufficiency in the Northeastern United States. J Am Soc Nephrol. 2001;12:1501-1507.
  19. Kazmi WH, Kausz AT, Khan S, et al. Anemia: an early complication of chronic renal insufficiency. Am J Kidney Dis. 2001;38:803-812.
  20. Radtke HW, Claussner A, Erbes PM, et al. Serum erythropoietin concentration in chronic renal failure: relationship to degree of anemia and excretory renal function. Blood. 1979;54:877-884.
  21. Obrador GT, Ruthazer R, Arora P, et al. Prevalence of and factors associated with suboptimal care before initiation of dialysis in the United States. J Am Soc Nephrol. 1999;10:1793- 1800.
  22. St. Peter WL, Xue JL, Ebben J, et al. Is the Medical Evidence Form a reliable indicator of erythropoietin use in pre-end-stage renal disease (ESRD) patients? New Orleans: Annual meeting of the American Society of Nephrology: American Society of Nephrology; 2001.
  23. Nissenson AR. Epoetin and cognitive function. Am J Kidney Dis. 1992;20(suppl 1):21-24.
  24. Clyne N, Jogestrand T. Effect of erythropoietin treatment on physical exercise capacity and on renal function in predialytic uremic patients. Nephron. 1992;60:390-396.
  25. Revicki DA, Brown RE, Feeny DH, et al. Health-related quality of life associated with recombinant human erythropoietin therapy for predialysis chronic renal disease patients. Am J Kidney Dis. 1995;25:548-554.
  26. Gafter U, Kalechman Y, Orlin JB, et al. Anemia of uremia is associated with reduced in vitro cytokine secretion: immunopotentiating activity of red blood cells. Kidney Int. 1994;45:224- 231.
  27. Xia H, Ebben J, Ma JZ, et al. Hematocrit levels and hospitalization risks in hemodialysis patients. J Am Soc Nephrol. 1999;10:1309-1316.
  28. Collins AJ, Li S, Ebben J, et al. Hematocrit levels and associated Medicare expenditures. Am J Kidney Dis. 2000;36:282-293.
  29. 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.
  30. Harnett JD, Kent GM, Foley RN, et al. Cardiac function and hematocrit level. Am J Kidney Dis. 1995;25(suppl 1):S3-S7.
  31. Foley RN, Parfrey PS, Harnett JD, et al. The impact of anemia on cardiomyopathy, morbidity, and mortality in end-stage renal disease. Am J Kidney Dis. 1996;28:53-61.
  32. Ma JZ, Ebben J, Xia H, et al. Hematocrit level and associated mortality in hemodialysis patients. J Am Soc Nephrol. 1999;10:610-619.
  33. Parfrey PS, Foley RN, Harnett JD, et al. Outcome and risk factors for left ventricular disorders in chronic uraemia. Nephrol Dial Transplant. 1996;11:1277-1285.
  34. Parfrey PS, Foley RN. The clinical epidemiology of cardiac disease in chronic renal failure. J Am Soc Nephrol. 1999;10:1606-1615.
  35. Levin A, Singer J, Thompson CR, et al. Prevalent left ventricular hypertrophy in the predialysis population: identifying opportunities for intervention. Am J Kidney Dis. 1996;27:347-354.
  36. Levin A, Thompson CR, Ethier J, et al. Left ventricular mass index increase in early renal disease: impact of decline in hemoglobin. Am J Kidney Dis. 1999;34:125-134.
  37. Foley RN, Parfrey PS. Cardiovascular disease and mortality in ESRD. J Nephrol. 1998;11:239- 245.
  38. Casale PN, Devereux RB, Milner M, et al. Value of echocardiographic measurement of left ventricular mass in predicting cardiovascular morbid events in hypertensive men. Ann Intern Med. 1986;105:173-178.
  39. Silberberg JS, Barre PE, Prichard SS, et al. Impact of left ventricular hypertrophy on survival in end-stage renal disease. Kidney Int. 1989;36:286-290.
  40. Besarab A, Levin A. Defining a renal anemia management period. Am J Kidney Dis. 2000;36(suppl 3):S13-S23.
  41. National Institutes of Health. Morbidity and Mortality of Dialysis: An NIH Consensus Statement. Bethesda, MD: National Institutes of Health; 1993.
  42. Arora P, Obrador GT, Ruthazer R, et al. Prevalence, predictors, and consequences of late nephrology referral at a tertiary care center. J Am Soc Nephrol. 1999;10:1281-1286.
  43. Nissenson AR, Collins AJ, Hurley J, et al. Opportunities for improving the care of patients with chronic renal insufficiency: current practice patterns. J Am Soc Nephrol. 2001;12:1713- 1720.
  44. Valderrabano F, Golper T, Muirhead N, et al. Chronic kidney disease: why is current management uncoordinated and suboptimal? Nephrol Dial Transplant. 2001;16(suppl 7):61-64.
  45. Levin A. Identification of patients and risk factors in chronic kidney disease-evaluating risk factors and therapeutic strategies. Nephrol Dial Transplant. 2001;16(suppl 7):57-60.
  46. Johnson CA. Issues in anemia management: primary care perspective. Internal Medicine News. 2001:10-11.
  47. Kleinman KS, Schweitzer SU, Perdue ST, et al. The use of recombinant human erythropoietin in the correction of anemia in predialysis patients and its effect on renal function: a doubleblind, placebo-controlled trial. Am J Kidney Dis. 1989;14:486-495.
  48. Lim VS, DeGowin RL, Zavala D, et al. Recombinant human erythropoietin treatment in predialysis patients: a double-blind placebo-controlled trial. Ann Intern Med. 1989;110:108-114.
  49. Bedani PL, Verzola A, Bergami M, et al. Erythropoietin and cardiocirculatory condition in aged patients with chronic renal failure. Nephron. 2001;89:350-353.
  50. Wu SC, Lin SL, Jeng FR. Influence of erythropoietin treatment on gonadotropic hormone levels and sexual function in male uremic patients. Scand J Urol Nephrol. 2001;35:136-140.
  51. Nissenson AR. Novel erythropoiesis stimulating protein for managing the anemia of chronic kidney disease. Am J Kidney Dis. 2001;38:1390-1397.
  52. Sunder-Plassmann G, Horl WH. The clinical potential of novel erythropoiesis stimulating protein. Expert Opin Biol Ther. 2001;1:733-739.
  53. Hayashi T, Suzuki A, Shoji T, et al. Cardiovascular effect of normalizing the hematocrit level during erythropoietin therapy in predialysis patients with chronic renal failure. Am J Kidney Dis. 2000;35:250-256.
  54. Portoles J, Torralbo A, Martin P, et al. Cardiovascular effects of recombinant human erythropoietin in predialysis patients. Am J Kidney Dis. 1997;29:541-548.
  55. Amgen Inc. ARANESP (darbepoetin alfa) package insert, Thousand Oaks, CA: Amgen Inc.; 2001.
  56. VanRenterghem Y, Barany P, Mann J. Novel erythropoiesis stimulating protein (NESP) maintains Hb in ESRD patients when administered once weekly or once every other week. Paper
    57. presented at: American Society of Nephrology 32nd Annual Meeting, November 1-8, 1999.
  57. Nissenson AR, Swan SK, Lindberg JS. Novel erythropoiesis stimulating protein (NESP) safely maintains Hb concentration levels in hemodialysis patients as effectively as r-HuEPO when administered once weekly. J Am Soc Nephrol. 2000;11:1326A.
  58. Locatelli F, Olivares J, Walker R, et al. Novel erythropoiesis stimulating protein (NESP) administered subcutaneously corrects anemia in subjects with chronic renal insufficiency (CRI) when administered at a reduced frequency compared with recombinant human erythropoietin (r-HuEPO). J Am Soc Nephrol. 2000;11. Abstract 1486A.
    59.

Last Updated: May 29, 2008