consequences of diabetes is not completely understood, it is chronic kidney disease in patients with diabetes. type 2 diabetes, including the aging …
While the contribution of anemia to the development of the consequences of diabetes is not completely understood, it is imperative that both be managed to limit negative outcomes
IV
Anemia
Key Points
Diabetes
Both diabetic nephropathy and neuropathy likely contribute to the development of anemia in patients with diabetes Anemia often develops early in the course of chronic kidney disease in patients with diabetes Anemia likely contributes to the high incidence of cardiovascular disease observed in patients with diabetes Anemia in patients with diabetes is associated with an increased incidence of retinopathy and macular edema Anemia in patients with diabetes responds to erythropoietin therapy
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Anemia: A Hidden Epidemic
Diabetes Rate Still Increasing The prevalence and incidence of diabetes continues to increase in the United States Recently, Health and Human Services HHS Secretary Tommy G Thompson released updated figures, estimating the prevalence of diabetes mellitus at 17 million, an 8 increase from 1997 levels1 Approximately 800,000 new cases of diabetes are diagnosed each year, with 90 to 95 being type 2 diabetes2,3 The HHS Secretary also announced that 16
million Americans have prediabetes, which will lead to the development of type 2 diabetes in these individuals within 10 years1 Many factors have contributed to the rising incidence of type 2 diabetes, including the aging population, greater prevalence of obesity, and increase in sedentary lifestyles3 Diabetes is now the seventh leading cause of death in this nation3 Diabetes Leads to Serious Comorbidities Long-standing diabetes is associated with a multitude of consequences, including neuropathy motor-sensory and autonomic and nephropathy Approximately 50 of patients with diabetes eventually develop diabetic neuropathy and 35 develop diabetic nephropathy4 Of all new end-stage renal disease ESRD cases from 1994 through 1998, about 43 were attributed to diabetic nephropathy, making diabetes the leading cause of ESRD in the United States5 The common denominator of diabetes complications is hyperglycemia of any degree Hyperglycemia affects the function of nerves and muscles acutely and
possibly all other tissues as well Therefore, erythropoietin responses to anemia in diabetes may also be disturbed An example of such a mechanism would be the glycosylation of both low-density
lipoprotein LDL and the LDL receptor, which results in a failure of mutual recognition Diabetic Nephropathy and Anemia As diabetes progresses, the basement membrane of the glomeruli thickens as a result of glycosylation, leading to increased intrarenal pressure This damage ultimately results in chronic kidney disease CKD, decreased production of erythropoietin, and anemia In patients with diabetic nephropathy, the onset of anemia can occur early in the course of CKD, in marked contrast to nondiabetic patients, who do not develop anemia at the same stage of CKD6 As CKD progresses, anemia typically worsens7 Yun and colleagues compared the characteristics and erythropoietin levels of 35 diabetic patients with anemia but without overt renal disease to those of nondiabetic patients with anemia8 They found that erythropoietin concentrations were significantly lower in diabetic patients than in nondiabetic patients with similar decreases in Hb P 0001 Hb concentrations in the diabetic patients were related to creatinine clearance, serum creatinine, and albumin excretion rate, suggesting that the blunted erythropoietin response in patients with diabetes but without overt renal disease may
be due to early renal interstitial damage or the glycosylation mechanism described above
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Normal
Kidney
Erythropoietin
Diabetic Kidney Disease
Erythroid precursors
oxygen available
Erythropoietin Erythroid precursors
Bone Marrow
Red blood cells Red blood cells
Bone Marrow
Figure 4-1 As diabetes progresses the kidneys become damaged, resulting in decreased production of erythropoietin and the development of anemia
Diabetic Neuropathy and Anemia The relationship between diabetic neuropathy and anemia is just emerging, with early studies suggesting that diabetic neuropathy may trigger the development of anemia in patients before the onset of advanced renal failure6,8-11 Recently, Bosman and colleagues evaluated the presence of anemia in patients with persistent proteinuria and glomerulonephritis and those with type 1 diabetes6 They found that 13 of 27 patients with diabetes were anemic mean Hb of 106 g/dL compared to none of the 26 patients with glomerulonephritis mean Hb of 137 g/dL, despite similar renal status The anemia was associated with low levels of erythropoietin Comparison of the characteristics of the anemic and nonanemic patients with
diabetes revealed that while serum creatinine levels were similar in both groups, proteinuria and sympathetic dysfunction were more severe in the anemic group The researchers
postulated that autonomic neuropathy with subsequent renal denervation, combined with damaged erythropoietinproducing fibroblasts in the renal cortex, may have contributed to the early development of anemia in the patients with diabetes Similarly, a recent case report by Hadjadj and colleagues described anemia in a patient with type 1 diabetes, proliferative retinopathy, autonomic neuropathy, microalbuminuria, and only moderate renal failure, suggesting that factors other than CKD contributed to anemia development11 The patient had a low erythropoietin response to anemia and responded to treatment with epoetin Similar findings were reported in a number of small studies published prior to the Bosman study and Hadjadj case report Cotroneo and colleagues reported that 10 of 13 patients with anemia and type 1 diabetes had autonomic neuropathy and a blunted erythropoietin response to anemia9 Three of the
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Anemia: A Hidden Epidemic
patients were treated with epoetin, which resulted in improvement of the anemia
Winkler and colleagues examined the relationships between anemia, autonomic neuropathy, and erythropoietin response among patients with diabetes and autonomic neuropathy, patients with diabetes without autonomic neuropathy, and nondiabetic patients with and without anemia10 All patients with diabetes had diabetic nephropathy but normal serum creatinine The researchers found that more patients with diabetes and neuropathy had anemia than those who had diabetes but no neuropathy They also showed that erythropoietin increased in response to anemia in nondiabetic patients, but not in diabetic patients with neuropathy, suggesting that diabetic neuropathy blunts the erythropoietin response Again 
, treatment with epoetin in five of the patients with diabetes, anemia, and autonomic neuropathy led to improved Hb concentrations One patient treated with epoetin to maintain a Hb of 116 g/dL was followed for 2 years and demonstrated marked clinical improvement, including the ability to return to a normal active life12 Consequences of Anemia in Patients with Diabetes Separately, diabetes and anemia are each associated with significant morbidity and mortality While the contribution of anemia to
the development of the consequences of diabetes is not completely understood, it is imperative that both be managed to limit negative outcomes Anemia in diabetic patients likely contributes to the high incidence of cardiovascular disease CVD observed in these patients People with diabetes are two to
four times more likely to have heart disease or suffer a stroke than people without diabetes, and approximately 75 of patients with diabetes die of CVD-related causes13 Separately, both ESRD and anemia are known to contribute to the development of CVD Patients with ESRD are 10 to 20 times more likely to develop CVD than the normal population14 Anemia is associated with a greater incidence of left ventricular hypertrophy,15,16 de novo or recurrent cardiac failure,17 and increased cardiac-related hospitalizations and deaths17,18 Recently, Shoji and colleagues demonstrated that diabetes increases aortic stiffness and is an independent predictor of mortality in patients with ESRD19 Since many patients with diabetes develop both anemia and eventually ESRD, they are at an even greater risk for the development of cardiac complications than either group alone Anemia in patients with diabetes
is also associated with diabetic retinopathy20,21 and macular edema,21 both of which result in accelerated vision loss Patients with Hb 12 g/dL have been found to have double the risk of diabetic retinopathy compared with those with Hb 12 g/dL OR, 20; 95 CI, 12-3320 Furthermore, patients with retinopathy and low Hb levels were more than five times as likely to have severe rather than mild retinopathy OR, 53; 95 CI, 23126, suggesting that anemia plays a significant role in retinopathy development and progression Beneficial Effects of Anemia Management In studies in which investigators explored the connection between diabetic neuropathy and anemia, the Hb levels
IV Anemia Diabetes
31
of patients with diabetes improved with epoetin administration9,11,12 Also, both diabetic retinopathy and macular edema have been shown to respond to epoetin therapy21 Rarick and colleagues showed that the administration of epoetin improves Hct values and quality of life in patients with diabetes, anemia, and clinically normal renal function22 All six patients
had near-normal serum creatinine levels 2 mg/dL and Hct 32 Two of the patients had retinopathy, one had neuropathy, and one had proteinuria
Although this study was too small to determine the causes of early anemia in patients with diabetes, it provides further evidence of the need for early anemia screening and treatment in patients with diabetes
References
DIABETES References
1
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://wwwhhsgov/news/press/2002pres/20020327html Accessed April 10, 2002 Mokdad AH, Bowman BA, Ford ES, et al The continuing epidemics of obesity and diabetes in the United States JAMA 2001;286:1195-1200 American Diabetes Association Basic diabetes information Available at: http://wwwdiabetesorg Accessed January 4, 2002 Steil CF Diabetes Mellitus In: DiPiro JT, Talbert RL, Yee GC, et al, eds Pharmacotherapy, A Pathophysiologic Approach 4th ed Stamford, CT: Appleton and Lange; 1999:1219-1244 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 Bosman DR, Winkler AS, Marsden JT, et al Anemia with erythropoietin deficiency occurs early in diabetic nephropathy
Diabetes Care 2001;24:495-499 Levin A Prevalence of cardiovascular damage in early renal disease Nephrol Dial Transplant 2001;16suppl 2:7-11 Yun YS, Lee HC, Yoo NC, et al Reduced erythropoietin responsiveness to anemia in diabetic patients before advanced diabetic nephropathy Diabetes Res Clin Pract 1999;46:223-229 Cotroneo P, Maria Ricerca B, Todaro L, et al Blunted erythropoietin response to anemia in patients with Type 1 diabetes Diabetes Metab Res Rev 2000;16:172-176
2 3 4 5 6 7 8 9
10 Winkler AS, Marsden J, Chaudhuri KR, et al Erythropoietin depletion and anaemia in diabetes mellitus Diabet Med 1999;16:813-819 11 Hadjadj S, Torremocha F, Fanelli A, et al Erythropoietin-dependent anaemia: a possible complication of diabetic neuropathy Diabetes Metab 2001;27:383-385
12 Winkler AS, Watkins PJ Long-term treatment of the anaemia in Type 1 diabetes mellitus with erythropoietin Diabet Med 2000;17:250-251 13 American Diabetes Association The link between diabetes and cardiovascular disease Available at: wwwdiabetesorg/main/info/link Accessed January 5, 2002 14 Sarnak MJ, Levey AS Cardiovascular disease and chronic renal disease: a new paradigm Am J Kidney Dis 2000;35suppl
1:S117-S131 15 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 16 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 17 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 18 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 19 Shoji T, Emoto M, Shinohara K, et al Diabetes mellitus, aortic stiffness, and cardiovascular mortality in end-stage renal disease J Am Soc Nephrol 2001;12:2117-2124 20 Qiao Q, Keinanen-Kiukaanniemi S, Laara E The relationship between hemoglobin levels and diabetic retinopathy J Clin Epidemiol 1997;50:153-158 21 Friedman EA, Brown CD, Berman DH Erythropoietin in diabetic macular edema and renal insufficiency Am J Kidney Dis 1995;26:202-208 22 Rarick MU, Espina BM,
Colley DT, et al Treatment of a unique anemia in patients with IDDM with epoetin alfa Diabetes Care 1998;21:423-426
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