A normochromic normocytic anemia is a well-known complication of CKD (4, 5). Recent findings from the NHANES III study (in which the mean age was 48 years) indicate that Hgb levels typically begin to decline as the GFR falls below 70 mL/min in men and 50 mL/min in women, and that the prevalence and severity of anemia increase as kidney function falls below a level of about 60 mL/min. The prevalence of Hgb levels below 11 g/dL increases as GFR falls below about 30 mL/min/1.73 m2 (5, 14, 23-25). The principal underlying etiology of CKD-related anemia is impaired synthesis of the glycoprotein hormone erythropoietin, which is produced primarily in peritubular cells of the kidneys. Other important contributing factors include the presence of inhibitors of erythropoiesis, reduced red cell lifespan, iron deficiency, vitamin B12 and folate deficiency, blood loss due to phlebotomy and surgery, other underlying disease processes such as infection, inflammation, poor nutritional status, hemol-ysis, multiple myeloma, malignancy, HIV infection, and among dialysis patients, dialysis-related blood losses and severe hyperparathyroidism. Many of these conditions are likely to be more prevalent in the elderly than in younger subjects (26).
CKD has been reported to be the principal cause of anemia in more than 8% of older subjects, and a contributing cause in others (27). The pathophysiologic basis for anemia related to CKD in older individuals is likely similar to that of younger subjects, complicated perhaps by a greater impact of underlying inflammatory processes, and in men, an age-related decline in testosterone levels (28). Although information is conflicting, data from the Baltimore Longitudinal Study on Aging revealed a rise in serum erythropoietin level over time in that sample of older adults, regardless of the presence or absence of anemia (29, 30). The increase in erythropoietin levels was less marked in subjects with hypertension or diabetes mellitus, perhaps reflecting some underlying CKD, either age-related or due to these other conditions. While some studies suggest that the erythropoietin production in response to anemia and erythropoietin responsiveness is blunted in healthy elderly subjects, others have found no difference comparing older and younger subjects, and most have not considered the effect of underlying CKD (25, 29-36).
One assessment of the association of anemia and CKD in the elderly comes from the InCHIANTI study, a prospective, population-based survey of older residents of Tuscany, Italy, who were 65 years older (mean 74.5 years; range 65-102 years) and in whom anemia was defined using the WHO criteria (Hgb < 12 g/dL in women and <13 g/dL in men) (37). Kidney function was measured with 24-h urine collections for creatinine clearance. In both men and women, the prevalence of anemia was greater at older ages, and both Hgb and creatinine clearance declined with increasing age. The mean age-related decline in Hgb and creatinine clearance was 0.75 g/dL and 19.4 mL/min per decade, respectively, in men, and 0.50 g/dL and 15.2 mL/min per decade, respectively, in women. The unadjusted prevalence of anemia, using WHO criteria, was higher among men and women at lower levels of creatinine clearance, particularly among subjects with creatinine clearance of 60 mL/min or less; 6.6% in subjects with creatinine clearance greater than 90%, 9.8% in those with creatinine clearance of 61-90 mL/min, 18.5% among those with creatinine clearance of 31-60 mL/min, and 65.4% in those with creatinine clearance of 30 mL/min or less. In age- and sex-adjusted comparisons, the prevalence of anemia was greater only in the group with creatinine clearance levels of 30 mL/min or less. Serum erythropoietin levels declined with lower levels of kidney function, although age- and Hgb-adjusted levels were significantly lower, compared to the group with creatinine clearance greater than 90 mL/min, only in subjects with creatinine clearance of 30 mL/min or less. The authors of this study concluded that among older individuals, the age-related decline in erythropoietin synthesis was an important contributing factor to anemia only when kidney function was severely impaired, i.e., when creatinine clearance was 30 mL/min or less.
In an earlier study of subjects between the ages of 49 and 97 years, there was also an inverse relationship between creatinine clearance (estimated with the Cockcroft-Gault formula) and prevalence of anemia (using WHO criteria), with a greater than fivefold risk of anemia among men and greater than threefold risk of anemia in women with creatinine clearance less than 50 mL/min compared to those with higher creatinine clearance (12). It was estimated that approximately 82% of cases of anemia in women and 68% of cases of anemia in men with CKD could be attributed to their CKD. In the entire study population, it was estimated that in approximately 17% of women and 22% of men, anemia could be attributed to renal impairment.
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