Feature Articles

Anemia from Declining Kidney Function in Diabetic and Hypertensive Patients

November 19, 2009

Kidney illustration

Erythropoietin and Declining Kidney Function

As kidney function declines due to accumulating damage from diabetes, hypertension and possibly from obesity, less erythropoietin is produced. Lower levels of circulating erythropoietin – the hormone produced by the kidneys which stimulates red blood cell production in the bone marrow – can eventually lead to decreasing hemoglobin levels and anemia.

“Anemia is more common in patients with diabetes at every stage of CKD for reasons that aren’t completely clear,” said Dr. McGill, an endocrinologist and Associate Professor of Medicine at Washington University in St. Louis. “And anemia that remains an under-recognized and under-treated condition in diabetic patients can seriously affect their health and well-being.”

The occurrence of anemia in patients with stage 3 CKD is well documented, but damage to the kidneys from diabetes and hypertension can contribute to lowered hemoglobin levels before estimated glomerular filtration rate (eGFR) readings dip below 60 mL/minute – a well accepted threshold for CKD diagnosis. This is because diabetes is associated with protein in the urine which contributes to losses of key nutrients required for the body to be able to make red blood cells, and because diabetes damages the part of the kidney responsible for making erythropoietin. CKD patients with diabetes, on average, develop anemia in the earlier stages of the disease. Traditionally, anemia worsens as CKD progresses toward end stage renal disease (ESRD), with 28% of patients having anemia in early stages (1&2) and 87% of patients having anemia in later stages (3-5).1 In diabetic patients these numbers are increased.

Progressive Complications of Diabetes

There are several complications that can emerge over time with diabetes and the associated elevated blood sugar levels including CKD, hypertension and cardiovascular disease. Additionally, diabetic retinopathy and diabetic neuropathy are prevalent in patients who have had diabetes for many years. Many complications, either directly or indirectly, may contribute to anemia and worsening of clinical outcomes for patients with diabetes as described below.

Chronic Kidney Disease – Diabetes is the leading cause of CKD and kidney failure in the United States, attributing for about 44% of new cases diagnosed annually.2,3 And those at-risk for acquiring CKD include the increasing number of patients with diabetes mellitus, roughly 24 million, and the approximately 16 million patients with pre-diabetes, as defined below.4,5 “It’s important to remember that people with diabetes get kidney disease more often than patients without, and anemia among those patients may be more prevalent and more severe as well,” said Dr. McGill.

Defining Pre-diabetes By IFG and IGT Levels

Hyperglycemia not sufficient to meet the diagnostic criteria for diabetes is categorized as either impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), depending on whether it is identified through the fasting plasma glucose (FPG) or the oral glucose tolerance test (OGTT):

  • IFG = FPG 100 mg/dl (5.6 mmol/l) to 125 mg/dl (6.9 mmol/l)
  • IGT = 2-h plasma glucose 140 mg/dl (7.8 mmol/l) to 199 mg/dl (11.0 mmol/l)

IFG and IGT have been officially termed “pre-diabetes.” Both categories of pre-diabetes are risk factors for future diabetes and for cardiovascular disease (CVD).

From publication: Nathan DM et al. Diabetes Care. 2007.6

Hypertension – Hypertension affects 65 million people in the United States and causes more than 25,000 new cases of kidney failure every year.7,3 Both type 1 and type 2 diabetes can contribute to kidney disease that is predominantly caused by hypertension. Hypertension can damage blood vessels throughout the body, and damaged vessels in the kidney can reduce their ability to remove waste from the blood.8

Cardiovascular Conditions – The high incidence of cardiovascular disease in patients with diabetes may well stem, in part, from the additional burdens CKD and anemia can place on the heart.9 For instance, patients with anemia are more likely to suffer the effects of left ventricular hypertrophy (LVH). One study showed an increase of 32% in LVH risk for each 0.5-g/dL decrease in Hb (P = 0.004), and identified Hb concentration, systolic blood pressure, and baseline left ventricular mass index as risk factors in patients with CKD.10 About 75% of diabetic patients die from CVD-related causes.11

Diabetic Nephropathy – Eventually, 35% of diabetics will develop nephropathy, in which glomeruli can thicken as a result of glycosylation and can lead to an increased intrarenal pressure.12,9 This state can over time damage the kidney and reduce production of erythropoietin, as outlined in the diagram below.

Diabetic Neuropathy – The relationship between diabetic neuropathy and anemia is not as well known, but some research studies have suggesting that impaired autonomic interactions may blunt the erythropoietic response which signals the production of red blood cells.13 Approximately 50% of patients with diabetes will develop neuropathy.12

Slowing the Progression Toward Renal Failure

At-risk for Pre-diabetes & Diabetes
  • Family history of diabetes
  • Cardiovascular disease
  • Overweight or obese state
  • Sedentary lifestyle
  • Latino/Hispanic, Non–Hispanic Black, Asian American, Native American, or Pacific Islander ethnicity
  • Previously identified impaired glucose tolerance or impaired fasting glucose
  • Hypertension
  • Increased levels of triglycerides, low concentrations of high-density lipoprotein cholesterol, or both
  • History of gestational diabetes
  • History of delivery of an infant with a birth weight >9 pounds
  • Polycystic ovary syndrome
  • Psychiatric illness
From: Rodbard HW. Endocr Pract. 2007.18

Proper diagnosis and management of diabetes, hypertension, kidney disease and anemia may help slow a patient’s progressive damage to the kidneys and heart which can eventually lead to kidney failure and/or cardiovascular disease.

“The progression of CKD in diabetic patients can be significantly impacted by early diagnosis, aggressive treatment of hypertension, and tight control of blood glucose,” said Dr. Allen Nissenson, a nephrologist and the Chief Medical Officer for DaVita Inc. “Early diagnosis may be beneficial at all stages of diabetic nephropathy, while tight management is particularly effective in the early stages. Recent evidence suggests that diabetic nephropathy may even be arrested in some cases.”

Guidelines and Recommendations

Several different professional organizations have produced a variety of guidelines which address the care of patients with diabetes, hypertension and kidney disease. Some recommendations from these publications are outlined below.

The National Kidney Foundation (NKF) offers several guidelines for treatment of patients with kidney disease, including the KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease: 2006 Guide14 and 2007 Update.15

The National Heart, Lung, and Blood Institute (NHLBI) recommends that patients with hypertension contain their blood pressure below 130/80 mmHg using appropriate diet, exercise and medicines.8,16 Notable are the use of angiotensin-converting enzymes (ACE) inhibitors and angiotensin receptor blockers (ARBs) which may help protect the kidneys from hypertensive damage but which also contribute to the suppression of erythropoiesis and to development of anemia.6,17 Read more about the possibility that ACE inhibitors and ARBs may lead to anemia in the article Outlining Drug-Induced Anemia and Select Medications. More information about managing hypertension can be found in NHLBI’s Seventh Report on High Blood Pressure.

For all patients with diabetes, the American Diabetes Association (ADA) recommends in their 2009 edition of Standards of Medical Care in Diabetes that cardiovascular risk factors – including dyslipidemia, hypertension, smoking, a positive family history of premature coronary disease, and the presence of micro- or macroalbuminuria – be assessed at least annually.19

Causes and Control of Anemia

Regarding anemia and its potential causes, “It is well within the purview of the primary care physician to check for and replace nutritional deficiencies which tend to aggravate other disease processes,” said Dr. McGill. For diabetic patients, the cause of anemia can be multi-factorial resulting from the complications of kidney disease, nutritional deficiencies or inflammation from chronic disease.

Dr. McGill also recommends that health professionals check a CBC when proteinuria is detected or when the eGFR is below 60 mL/minute in order to detect anemia. “Management of anemia in the CKD patient includes replacing micronutrients such as iron and vitamin B12, monitoring response and considering the use of erythropoietin in conjunction with referral to a nephrologist,” said Dr. McGill.

Vigilance Against Kidney Disease

For patients with diabetes and hypertension, reduced kidney function can contribute to anemia and cardiovascular disease and events, but early detection and proper management of these conditions can yield improved health and reduced risks for patients. With increasingly more Americans being diagnosed with diabetes, hypertension and kidney disease, it is important for you to monitor patients’ health, diet and behavior to reduce both the chances of developing concomitant conditions and to reduce the progression of kidney disease.

References

  1. Guralnik JM, Ershler WB, Schrier SL, Picozzi VJ. Anemia in the elderly: a public health crisis in hematology. Hematology Am Soc Hematol Educ Program. 2005:528-32. Link.
  2. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Kidney Disease of Diabetes. Link. Accessed: November 3, 2009.
  3. United States Renal Data System. USRDS 2007 Annual Data Report. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, U.S. Department of Health and Human Services; 2007. Link.
  4. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). National Diabetes Statistics, 2007. Link. Accessed: November 17, 2009.
  5. 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. Link. Accessed: April 10, 2002.
  6. Nathan DM, Davidson MB, DeFronzo RA, Heine RJ, Henry RR, Pratley R, Zinman B; American Diabetes Association. Impaired fasting glucose and impaired glucose tolerance: implications for care. Diabetes Care. 2007 Mar;30(3):753-59. Link. (Text)
  7. Fields LE, Burt VL, Cutler JA, Hughes J, Roccella EJ, Sorlie P. The burden of adult hypertension in the United States 1999 to 2000: a rising tide. Hypertension. 2004 Oct;44(4):398-404. Link.
  8. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). High Blood Pressure and Kidney Disease. Link. Accessed: November 3, 2009.
  9. [Cited source redacted; replace with a supporting citation.]
  10. Levin A, Thompson CR, Ethier J, Carlisle EJ, Tobe S, Mendelssohn D, Burgess E, Jindal K, Barrett B, Singer J, Djurdjev O. Left ventricular mass index increase in early renal disease: impact of decline in hemoglobin. Am J Kidney Dis. 1999 Jul;34(1):125-34. Link.
  11. American Diabetes Association. The Link Between Diabetes And Cardiovascular Disease. Accessed January 5, 2002.
  12. 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.
  13. Winkler AS, Marsden J, Chaudhuri KR, Hambley H, Watkins PJ. Erythropoietin depletion and anaemia in diabetes mellitus. Diabet Med. 1999 Oct;16(10):813-19. Link.
  14. KDOQI; National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis. 2006 May;47(5 Suppl 3):S11-145. Link. (Text)
  15. KDOQI. KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target. Am J Kidney Dis. 2007 Sep;50(3):471-530. Link. (Text)
  16. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ; Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003 Dec;42(6):1206-52. Link. (PDF)
  17. Macdougall IC. The role of ACE inhibitors and angiotensin II receptor blockers in the response to epoetin. Nephrol Dial Transplant. 1999 Aug;14(8):1836-41. Link.
  18. Rodbard HW, Blonde L, Braithwaite SS, Brett EM, Cobin RH, Handelsman Y, Hellman R, Jellinger PS, Jovanovic LG, Levy P, Mechanick JI, Zangeneh F; AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract. 2007 May-Jun;13 Suppl 1:1-68. Link. (PDF)
  19. American Diabetes Association. Standards of medical care in diabetes--2009. Diabetes Care. 2009 Jan;32 Suppl 1:S13-61. Link. (PDF)