Monograph: Anemia & Diabetes

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Key Points
  • 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.

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 levels.1 Approximately 800,000 new cases of diabetes are diagnosed each year, with 90% to 95% being type 2 diabetes.2,3 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 years.1 Many factors have contributed to the rising incidence of type 2 diabetes, including the aging population, greater prevalence of obesity, and increase in sedentary lifestyles.3 Diabetes is now the seventh leading cause of death in this nation.3

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 nephropathy.4 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 States.5

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 CKD.6 As CKD progresses, anemia typically worsens.7

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 anemia. 8 They found that erythropoietin concentrations were significantly lower in diabetic patients than in nondiabetic patients with similar decreases in Hb (P <0.001). 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.

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 failure.6,8-11

Recently, Bosman and colleagues evaluated the presence of anemia in patients with persistent proteinuria and glomerulonephritis and those with type 1 diabetes.6 They found that 13 of 27 patients with diabetes were anemic (mean Hb of 10.6 g/dL) compared to none of the 26 patients with glomerulonephritis (mean Hb of 13.7 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 development.11 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 anemia.9 Three of the 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 anemia. 10 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 11.6 g/dL was followed for 2 years and demonstrated marked clinical improvement, including the ability to return to a normal active life.12

Consequences of Anemia in Patients with Diabete
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 causes.13 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 population.14 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 deaths.17,18 Recently, Shoji and colleagues demonstrated that diabetes increases aortic stiffness and is an independent predictor of mortality in patients with ESRD.19 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, 2.0; 95% CI, 1.2-3.3).20 Furthermore, patients with retinopathy and low Hb levels were more than five times as likely to have severe rather than mild retinopathy (OR, 5.3; 95% CI, 2.3- 12.6), suggesting that anemia plays a significant role in retinopathy development and progression.

Beneficial Effects of Anemia Management
Anemia Management In studies in which investigators explored the connection between diabetic neuropathy and anemia, the Hb levels of patients with diabetes improved with epoetin administration.9,11,12 Also, both diabetic retinopathy and macular edema have been shown to respond to epoetin therapy.21

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 function.22 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.

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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://www.hhs.gov/news/press/2002pres/20020327.html. Accessed April 10, 2002.
  2. Mokdad AH, Bowman BA, Ford ES, et al. The continuing epidemics of obesity and diabetes in the United States. JAMA. 2001;286:1195-1200.
  3. American Diabetes Association. Basic diabetes information. Available at: http://www.diabetes. org. Accessed January 4, 2002.
  4. 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.
  5. 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.
  6. Bosman DR, Winkler AS, Marsden JT, et al. Anemia with erythropoietin deficiency occurs early in diabetic nephropathy. Diabetes Care. 2001;24:495-499.
  7. Levin A. Prevalence of cardiovascular damage in early renal disease. Nephrol Dial Transplant. 2001;16(suppl 2):7-11.
  8. 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.
  9. 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.
  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: www.diabetes.org/main/info/link. Accessed January 5, 2002.
  14. Sarnak MJ, Levey AS. Cardiovascular disease and chronic renal disease: a new paradigm.
    15. Am J Kidney Dis. 2000;35(suppl 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.
    23.

Last Updated: May 29, 2008