Epidemiology of Chronic Kidney Disease and Anemia

Bruce E. Robinson, MD, MPH Anemia is a common comorbidity of chronic kidney disease (CKD). As the diseased kidney loses its ability to produce the erythropoietin essential to the production of hemoglobin, anemia ensues. The age-related rise in CKD makes anemia in CKD a problem of increasing prevalence among residents of long-term care facilities. CKD refers to the entire continuum of renal disease that progresses from mildly impaired kidney function (stage 1, glomerular ltration rate [GFR] 90 mL/min/1.73 m2) to signicant deterioration, requiring dialysis or kidney transplant in what is categorized as stage 5 (GFR 15 mL/min/1.73 m2). The denition of anemia is controversial. The WHO denes anemia as hemoglobin 13 g/dL for men and 12 g/dL for women. The National Kidney Foundations Kidney Disease Outcomes Quality Initiative, which is the criteria used for Medicare reimbursement, denes anemia in adult men and postmenopausal women as hemoglobin 12 g/dL, or 11 g/dL in a premenopausal woman. (J Am Med Dir Assoc 2006; 7: S3S6) Keywords: Prevalence; chronic kidney disease (CKD); anemia; glomerular ltration rate (GFR); Modication of Diet in Renal Disease (MDRD) formula; CockcroftGault formula

INTRODUCTION Epidemiologic studies have documented a dramatic agerelated rise in the prevalence of chronic kidney disease (CKD) and anemia.1,2 These 2 common chronic conditions are associated with increases in mortality and morbidity, functional decline, hospitalizations, and increased health care costs. Chronic Kidney Disease The incidence and prevalence of kidney disease worldwide and in the United States has risen markedly in the past decade.3 About 20 million Americans from 1988 to 1994 or approximately 11% of all US adultsare living with CKD (stages 15), and the incidence and prevalence of kidney disease are increasing.4 As the numbers have grown over the last few years, the nomenclature of CKD has evolved. In 2001, the National Kidney Foundation (NKF) issued a consensus statement recommending CKD as the preferred label and glomerular ltration rate (GFR) as the diagnostic test of choice.5 CKD refers to the entire continuum of renal disease that progresses from renal abnormality with normal GFR (stage 1) through mild CKD (stage 2, GFR 60 90 mL/min/1.73 m2) through moderate CKD (stage 3, GFR 30 60 mL/min/1.73 m2) to signicant deterioration requiring dialysis or kidney

transplant in stage 5 (GFR 15 mL/min/1.73 m2). End-stage renal disease is an administrative term that indicates that a patient is being treated with dialysis or kidney transplant. Traditionally, CKD in nursing home residents has only been thought of as those in stages 4 and 5. In fact, most people with CKD are asymptomatic. Stage 1 CKD is typically not detected and requires some other information, for example, the presence of proteinuria or hematuria, to bring it to the clinicians attention. Epidemiologically, a major observation of the last few years has been the recognition of the very large number of people who have GFR between 30 and 59 mL/min/1.73 m2, placing them at stage 3 CKD. They represent the bulk of patients who suffer most of the consequences of CKD in the United States. While approximately 400,000 patients in the United States have stage 4 (severe) CKD and about 300,000 are on dialysis, the majority of CKD patients (7.6 million) are in stage 3 (Figure 1).6 Signicance of declining GFR with age Why worry about the GFR in elders? At maturity, the average GFR is 120 mL/min/1.73 m2. As the years go by, adults lose about 1 mL/min/y. An 85-year-old person, then, can be expected to have a GFR just under 60 mL/min/1.73 m2 qualifying that person as having stage 3 CKD. One can argue that, on average, CKD is to be expected in older people who are not free of disease. Data from longitudinal studies in the last 20 years has demonstrated the phenomenon of successful aging. That is, even though usual aging means a progressive decline in GFR, that decline is not universal. A substantial number of people manage to go into late life with very good GFR and have no CKD. Those who develop even modest CKD, however, tend to experience cardiovascular morbidity and mortality above
Robinson S3

Florida State University College of Medicine, University of South Florida College of Medicine, Sarasota, FL. Address correspondence to Bruce E. Robinson, MD, MPH, University of South Florida College of Medicine, 1700 S. Tamiami Trail, Sarasota, FL 34239. E-mail: Bruce-Robinson@smh.com

Copyright 2006 American Medical Directors Association DOI: 10.1016/j.jamda.2006.09.004 SUPPLEMENT

Fig. 1. Epidemiologically, a major observation of the last few years has been the recognition of the very large number of people who have GFR between 30 and 59 mL/min/1.73 m2, placing them at stage 3 CKD. While approximately 400,000 patients in the United States have stage 4 (severe) CKD and about 300,000 are on dialysis, the majority of CKD patients (7.6 million) are in stage 3.6

Fig. 3. The Garg study estimated that 30% of the oldest residents had stage 3 or higher CKD. Reprinted with permission from Kidney International.1 Copyright 2004, Nature Publishing Group.

the norm. Decreased GFR is associated with complications in virtually all organ systems. Frequency and severity of complications worsen as GFR declines. Complications associated with CKD include high blood pressure, anemia, malnutrition, bone disease, and decreased overall physical functioning. Two major community studies (National Health and Nutrition Examination Survey [NHANES III] and the NKFs Kidney Early Evaluation Program [KEEP]) have documented that the prevalence of CKD rises with increasing age (Figure 2). The NHANES III was a large epidemiologic study performed to evaluate the health and nutrition of the US pop-

Fig. 2. In both the NHANES and KEEP studies, the prevalence of CKD, dened as a serum creatinine level 1.3 mg/dL in women and 1.5 mg/dL in men, rose rapidly in those aged 60 years and over. Reprinted with permission from American Journal of Kidney Disease.7 Copyright 2005, National Kidney Foundation. S4 Robinson

ulation. The NHANES III data demonstrate that CKD increases in individuals older than 60 years of age, and that the percentage of patients with CKD increases as one approaches 75 years of age.6 The KEEP is an ongoing community-based health-screening program that focuses on people at high risk for developing CKD. In the program, sponsored by the NKF, individuals are evaluated for CKD if they have a personal health history of hypertension or diabetes or have a family history of diabetes, hypertension, or CKD. This clinical population has a much higher prevalence of CKD.7,8 To determine the extent of renal insufciency among institutionalized elders, a group at risk based on age and frail health, Garg and colleagues1 carried out a large retrospective cross-sectional study of 9931 residents aged 65 years and older in 87 Canadian nursing homes. The Garg study, which represents the rst published report of CKD among long-term care patients based on GFR, estimated that nearly 40% of the residents had CKD (dened as GFR 60 mL/min/1.73 m2 using the modied Modication of Diet in Renal Disease [MDRD] Study Group equation).1 The mean age in the Garg study was 82 years for men and 85 years for women. This study showed how common CKD is in this nursing home population (Figure 3). Gargs group documented that about 30% of the oldest men and women in a nursing home population had CKD at stage 3 or higher. Gargs team also compared 2 commonly used methods for estimating GFR: the Cockcroft-Gault and MDRD formulas. Gargs group concluded that both equations may underestimate the gold-standard GFR in these elderly patients, with the underestimation being greater with the Cockcroft-Gault than the MDRD formula.1 Although both the CockcroftGault and the MDRD formulas have been used in the elderly population, neither has been validated in the elderly (Table 1).1,9 13 Ania and colleagues14 were among the rst to document that the prevalence of anemia in older adults rises with age.
JAMDA November 2006

Table 1. MDRD Versus Cockcroft-Gault in Older Adults Study Cirillo et al.

9

N 380 52 9931 52 7747 134

Age (y) 1888 82.3 Men 82 Women 85 79.7 77.8 71.3

Population Mix of age and BMI, as well as renal/nonrenal disease, and no disease Generally healthy patients; 67.7 mL/min/1.73 m2 Long-term care residents; mix of renal/nonrenal disease CKD; mean GFR 53.3 mL/min/ 1.73 m2 Admissions to acute care ward (65 y) Mix of age and BMI, mostly hypertensive; mean GFR 79.4 mL/min/1.73 m2

Results in Older Adults CG underestimated GFR more than MDRD MDRD had strongest correlation with actual GFR CG underestimates GFR more than MDRD CG had fewer misclassications than MDRD (10 vs 14) CG underestimates GFR more than MDRD CG underestimates GFR more than MDRD

Fehrman-Ekholm et al.10 Garg et al.1 Lamb et al.11 Pedone et al.12 Verhave et al.13

Anias group from the Mayo Clinic in Rochester, MN, evaluated 618 men and women aged 65 years or older in a Minnesota county. All elders were diagnosed with anemia using the World Health Organization (WHO) denition of hemoglobin of 13 g/dL for men and 12 g/dL for women. The group evaluated the cohort from 1986 until death or loss of clinical contact through 1994. The corrected annual incidence of anemia rose with age in this population-based study, with rates higher in men (90.3 per 1000; 95% condence interval [CI], 79.2101.4) than women (69.1 per 1000; 95% CI, 62.375.8) (Figure 4).14 In 465 cases (75%), anemia was detected in conjunction with a hospitalization, but admission was owing to anemia in only 57 instances. Half of the cases were caused by blood loss, two thirds of these as a result of surgery. The cause of anemia was uncertain in 102 cases (16%). One third of the patients were transfused with a

median of 3 units. Overall survival was worse than expected, but was better among those with anemia caused by blood loss. Mortality attributable to malignancy, mental disorders, circulatory and respiratory diseases, ill-dened conditions, and injuries was signicantly increased among these older patients with anemia.15 An analysis of data from NHANES III revealed that one third of the anemia in people aged 65 and older was due to a nutritional deciency; one third was nonnutritional anemia that could not be explained, and one third was caused by either renal insufciency or chronic inammation.16 Anemia in the Nursing Home In 2004, Andrew Artz and colleagues2 reported their investigation of the prevalence of anemia in chronically ill nursing home residents. In a multicenter study of 900 residents who had a mean age of 79 years and a median age of 82 years, Artzs team documented that the 6-month prevalence of anemia dened using the WHO values of 13 g/dL for men and 12 g/dL for womenwas 48%. Any residents in whom anemia was discovered at any point in the 6 months prior to chart review were considered positive for anemia. The 6-month hospitalization rate among patients with anemia was 30%, compared with 15.8% of those without anemia. What therapy was offered for the anemia? Among the 704 residents who had charts with reliably available dates, 2.3% had received a red cell transfusion. Among the 816 residents with documentation regarding use of recombinant human erythropoietin, 3% received this therapy. The researchers concluded, It is apparent that anemia is common in nursing homes, but directed therapy is not.2 Anemia and Chronic Kidney Disease Anemia is a common comorbidity of CKD. As the diseased kidney loses its ability to produce the erythropoietin essential to the production of hemoglobin, anemia ensues.5 In a study of 60 nursing home residents, Artz et al17 found that 10% of patients had both anemia and CKD. Anemia of chronic
Robinson S5

Fig. 4. Anias group was among the rst to document that the prevalence of anemia in older adults is high and rises with age. Reprinted with permission from Mayo Clinic Proceedings.14 Copyright 1994, Mayo Foundation for Medical Education and Research. SUPPLEMENT

disease was found in 13% of patients and idiopathic anemia, in 23%.17 Epidemiologic data from NHANES III and KEEP show an increase in prevalence of anemia (hemoglobin 12 g/dL) in those aged 61 years and older in the presence of stage 3 CKD or higher (GFR 60 mL/min/1.73 m2). More than half of those older than 75 years with stage 3 or higher CKD have anemia as well. Why Care About Anemia? While low hemoglobin is common in seniors, there is a growing body of evidence for moving away from a normative denition of anemia. The normative criteria developed in younger adults may not apply to older persons. The nding that anemia rises more dramatically in men than in women may be primarily related to the sex difference in how anemia is denedwhich has less relevance in older men than younger men. As men age and androgen levels decline, older men lose the hemoglobin advantage attributable to this sexrelated hormone. Also, older women lose the hemoglobin disadvantage related to iron loss through their menstrual periods. Because of these age-related changes, dening anemia below 12 g/dL in women and at the higher level of below 13 g/dL in men may not appropriately reect the biological concept of what is normal for older adults. Anemia is an important predictor of morbidity and mortality in older adults, with evidence for effects on a variety of clinically important events. The increased mortality associated with anemia in older persons has been shown in a number of studies.18 20 The study by Culleton et al20 found optimal mortality and morbidity in hemoglobin ranges of 130 to 150 g/L for women and 140 to 170 g/L for men. Anemia is also associated with diminished quality of life and physical function in older adults.2123 The lower the hemoglobin, the more serious the problem with increased hospitalization rates, mortality, morbidity, and serious adverse consequences to patients. CONCLUSIONS CKD stage 3 or greater may affect nearly 43% of residents in long-term care facilities. Anemia, by the WHO denition, affects nearly 60%. An association has been documented between anemia and CKD in long-term care residents, and it is prominent. Further work dening this association will help determine the size of the population that might be targeted for correction of anemia by erythropoiesis-stimulating protein treatment. This work is under way using a population of 6000 nursing home residents of a large national chain and will determine the prevalence of anemia, CKD, and the association between these 2 common chronic conditions. REFERENCES
1. Garg AX, Papaioannou A, Ferko N, et al. Estimating the prevalence of renal insufciency in seniors requiring long-term care. Kidney Int 2004; 65:649 653.

2. Artz AS, Fergusson D, Drinka PJ, et al. Prevalence of anemia in skilled-nursing home residents. Arch Gerontol Geriatr 2004;39:201 206. 3. Hamer RA, El Nahas AM. The burden of chronic kidney disease. Br Med J 2006;332:563564. 4. Levey AS, Coresh J, Balk E, et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classication, and stratication. Ann Intern Med 2003;139:137147. 5. National Kidney Foundation. NKF-K/DOQI clinical practice guidelines for anemia of chronic kidney disease: update 2000. Am J Kidney Dis 2001;37(suppl 1):S182S238. 6. Coresh J, Astor BC, Greene T, et al. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 2003;41:112. 7. National Kidney Foundation. KEEP 2004 annual data report. Am J Kidney Dis 2005;45(suppl 2):S1S80. 8. Brown WW, Peters RM, Ohmit SE, et al. Early detection of kidney disease in community settings: the Kidney Early Evaluation Program (KEEP). Am J Kidney Dis 2003;42:2235. 9. Cirillo M, Anastasio P, De Santo NG. Relationship of gender, age, and body mass index to errors in predicted kidney function. Nephrol Dial Transplant 2005;20:17911798. 10. Fehrman-Ekholm I, Skeppholm L. Renal function in the elderly (70 years old) measured by means of iohexol clearance, serum creatinine, serum urea and estimated clearance. Scand J Urol Nephrol 2004;38:73 77. 11. Lamb EJ, Webb MC, Simpson DE, Coakley AJ, Newman DJ, ORiordan SE. Estimation of glomerular ltration rate in older patients with chronic renal insufciency: is the Modication of Diet in Renal Disease formula an improvement? J Am Geriatr Soc 2003;51: 10121017. 12. Pedone C, Corsonello A, Incalzi RA, for the GIFA Investigators. Estimating renal function in older people: a comparison of three formulas. Age Ageing 2006;35:121126. 13. Verhave JC, Fesler P, Ribstein J, du Cailar G, Mimran A. Estimation of renal function in subjects with normal serum creatinine levels: inuence of age and body mass index. Am J Kidney Dis 2005;46:233241. 14. Ania BJ, Suman VJ, Fairbanks VF, et al. Prevalence of anemia in medical practice: community versus referral patients. Mayo Clinic Proc 1994;69: 730 735. 15. Ana BJ, Suman VJ, Fairbanks VF, et al. Incidence of anemia in older people: an epidemiologic study in a well dened population. J Am Geriatr Soc 1997;45:825 831. 16. Guralnik JM, Eisenstaedt RS, Ferrucci L, et al. Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia. Blood 2004;104:22632268. 17. Artz AS, Fergusson D, Drinka PJ, et al. Mechanisms of unexplained anemia in the nursing home. J Am Geriatr Soc 2004;52:423 427. 18. Izaks GJ, Westendorp RG, Knook DL. The denition of anemia in older persons. JAMA 1999;281:1714 1717. 19. Zakai NA, Katz R, Hirsch C, et al. A prospective study of anemia status, hemoglobin concentration, and mortality in an elderly cohort. Arch Intern Med 2005;165:2214 2220. 20. Culleton BF, Manns BJ, Zhang J, et al. Impact of anemia on hospitalization and mortality in older adults. Blood 2006;10:38413846. 21. Cesari M, Penninx BW, Lauretani F, et al. Hemoglobin levels and skeletal muscle: results from the InCHIANTI study. J Gerontol A Biol Sci Med Sci 2004;59:249 254. 22. Penninx BW, Pahor M, Cesari M, et al. Anemia is associated with disability and decreased physical performance and muscle strength in the elderly. J Am Geriatr Soc 2004;52:719 724. 23. Thomas DR. Anemia and quality of life: unrecognized and undertreated. J Gerontol A Biol Sci Med Sci 2004;59:238 241.

S6 Robinson

JAMDA November 2006