eMedicine Specialties > Hematology > Red Blood Cells and Disorders

Anemia of Chronic Disease and Renal Failure

Author: Edgar V Lerma, MD, Clinical Associate Professor of Medicine, Section of Nephrology, Department of Medicine, University of Illinois at Chicago College of Medicine; Consulting Staff, Associates in Nephrology, SC
Coauthor(s): Robert Stein, MD, Chief, Section of Hematology, Department of Internal Medicine, Vice President, Medical Management, Advocate Christ Medical Center
Contributor Information and Disclosures

Updated: Jun 12, 2009

Introduction

Background

By definition, anemia refers to an absolute reduction of the total number of circulating red blood cells (RBCs). For practical purposes, anemia is considered when one or more of the following are decreased: hemoglobin, hematocrit, or RBC count. Anemia is a laboratory finding that signifies the presence of illness or disease; it should not be considered a diagnosis.

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center and Kidneys and Urinary System Center. Also, see eMedicine's patient education articles Anemia and Chronic Kidney Disease.

Pathophysiology

Based upon the mechanism causing anemia, this condition can be divided into 3 broad categories, namely: decreased RBC production, increased RBC destruction, and blood loss. At times, however, anemia can be due to a combination of 2 or more mechanisms.

Anemia of chronic illness and anemia of chronic kidney disease both fall under the first category, that of decreased RBC production.

Another classification of anemia is based on the morphology of the RBCs. Using this classification system, both anemia of chronic illness and chronic kidney disease usually fall under the classification of normochromic, normocytic anemia.

Anemia of chronic illness traditionally encompassed any inflammatory, infectious, or malignant disease of a long-standing nature. The modern definition includes rheumatoid arthritis, severe trauma, heart disease, or diabetes mellitus. In these conditions, there is primarily a decreased availability of iron, relatively decreased levels of erythropoietin, and a mild decrease in the lifespan of RBCs to 70-80 days (normally 120 days).1

Relatively recently, hepcidin, an endogenous antimicrobial peptide, has been identified.2,3,4 Secreted by the liver, hepcidin controls the level of plasma iron by regulating the intestinal absorption of dietary iron, as well as the release of iron from macrophages and the transfer of iron stored in the hepatocytes. Increase in hepcidin level in the course of inflammatory disease may be a significant mediator of the accompanying anemia.2,3,4

Another proposed mechanism for anemia of chronic illness deals with cytokines, such as interleukins (IL-1 and IL-6), and tumor necrosis factor (TNF-alpha), which are believed to cause the destruction of RBC precursors and decrease the number of erythropoietin receptors on progenitor cells.5,6,7  

Whereas hypoxia in the individual with normal functioning kidneys leads to erythropoietin gene transcription, and hence increased RBC production, in those with anemia of chronic kidney disease, there is primary deficiency of erythropoietin production by the interstitial fibroblasts, also known as type I interstitial cells, thereby leading to anemia. The anemia that develops is directly related to the amount of residual renal function.8 The kidneys are responsible for approximately 90% of erythropoietin production in an individual.

Frequency

United States

Anemia is common in patients with chronic kidney disease. Although it is not as common in earlier stages of chronic kidney disease, patients with stage III have a prevalence of concurrent anemia of 5.2%, whereas those with stage IV disease have a prevalence of concurrent anemia of 44.1%.9

International

Anemia is more common in third world countries, as compared with the US. Several factors affect the true incidence of anemia, making it very difficult to truly estimate. These factors include: heterogeneity of patient population, geographic locations, socioeconomic status, various "normal" reference ranges, and the limitation in the ability to actually screen for the presence of anemia.

Mortality/Morbidity

Morbidity and mortality depend greatly on the underlying etiology of the patient's anemia as well as the stage of the disease, whether early or advanced. In fact, in individuals with advanced stages of chronic kidney disease, the etiology of anemia tends to be multifactorial (eg, decreased RBC production due to lack of erythropoietin, increased RBC destruction due to hemolysis [intravascular or extravascular], as well as increased blood loss due to multiple venipunctures for an array of indications).

Race

Blacks have a 4-fold increased risk of developing develop chronic kidney disease relative to whites.10 Similarly, anemia has been shown to have an increased prevalence in blacks as compared to whites.

With regard to prevalence among predialysis patients, the landmark study by Obrador et al showed that 68% of patients with advanced chronic kidney disease who required renal replacement therapy had a hematocrit <30 mg/dL; of these, 51% of patients had a hematocrit <28 mg/dL.11

Two major surveys attempted to identify the prevalence and associations of anemia of chronic kidney disease; they were the targeted, community-based screening program KEEP (Kidney Early Evaluation Program) and the generalizable population health survey NHANES (National Health and Nutrition Examination Survey) 1999-2004.

There has been a lower prevalence of anemia in current smokers, which has been attributed to secondary erythrocytosis.

Sex

In general, anemia is more common in women, in particular, those in their childbearing years. In the latter decades of life, anemia tends to occur without any particular sex predilection.

However, in anemia of chronic kidney disease, males have a 30% greater risk of developing anemia as compared to their female counterparts. Although males have higher hemoglobin values, they also have higher rates of advanced chronic kidney disease.

Age

There is a greater prevalence of anemia of chronic kidney disease in those older than 60 years, as compared to those aged between 46 and 60 years (see the eMedicine article Anemia in Elderly Persons). This is probably secondary to the greater rate of chronic kidney disease in older individuals, as well as the lower estimated glomerular filtration rates (GFRs) that are associated with aging.

Clinical

History

Aside from the obvious concomitant diseases that present with anemia, such as an underlying malignancy or chronic kidney disease, the symptoms that occur with anemia tend to be quite nonspecific:

  • Generalized weakness or malaise, easy fatigability
  • Generalized body aches, or myalgias
  • Orthostatic symptoms (eg, lightheadedness, dizziness)
  • Syncope or near-syncope
  • Decreased exercise tolerance
  • Chest discomfort
  • Palpitations
  • Cold intolerance
  • Sleep disturbances
  • Inability to concentrate
  • Loss of appetite

Although it is true that many of the symptoms attributable to anemia and chronic kidney disease are nonspecific, clinicians must be wary in that several of these symptoms can be easily attributed to the state of being elderly and thereby diminishing the value of such symptoms to serve as alarming signals of disease or pathology.

Physical

  • Skin: Pallor
  • Neurovascular: Decreased cognitive ability
  • Eyes: Pale conjunctivae
  • Cardiovascular: Orthostatic hypotension, tachyarrhythmias
  • Pulmonary: Tachypnea
  • Abdomen: Ascites, hepatosplenomegaly

Causes

In the clinical approach to a patient with anemia, aside from reviewing the RBC indices and the peripheral smear, another important test is the reticulocyte count. A low reticulocyte count usually points to decreased RBC production as the primary mechanism responsible for anemia, whereas an elevated reticulocyte count points to increased RBC destruction or hemolysis as the most likely cause.

Note: Although decreased RBC production is the main mechanism in both anemia of chronic illness and anemia of chronic kidney disease, oftentimes, the anemia is due to a combination of things, including concomitant blood loss. Therefore, a reticulocyte count should always be interpreted with caution.

More on Anemia of Chronic Disease and Renal Failure

Overview: Anemia of Chronic Disease and Renal Failure
Differential Diagnoses & Workup: Anemia of Chronic Disease and Renal Failure
Treatment & Medication: Anemia of Chronic Disease and Renal Failure
Follow-up: Anemia of Chronic Disease and Renal Failure
Multimedia: Anemia of Chronic Disease and Renal Failure
References
Further Reading
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References

  1. Besarab A, Levin A. Defining a renal anemia management period. Am J Kidney Dis. Dec 2000;36(6 suppl 3):S13-23. [Medline].

  2. Deicher R, Horl WH. New insights into the regulation of iron homeostasis. Eur J Clin Invest. May 2006;36(5):301-9. [Medline].

  3. Roy CN, Mak HH, Akpan I, et al. Hepcidin antimicrobial peptide transgenic mice exhibit features of the anemia of inflammation. Blood. May 1 2007;109(9):4038-44. [Medline]. [Full Text].

  4. Zaritsky J, Young B, Wang HJ, et al. Hepcidin--a potential novel biomarker for iron status in chronic kidney disease. Clin J Am Soc Nephrol. Jun 2009;4(6):1051-6. [Medline].

  5. Wang CQ, Udupa KB, Lipschitz DA. Interferon-gamma exerts its negative regulatory effect primarily on the earliest stages of murine erythroid progenitor cell development. J Cell Physiol. Jan 1995;162(1):134-8. [Medline].

  6. Taniguchi S, Dai CH, Price JO, Krantz SB. Interferon gamma downregulates stem cell factor and erythropoietin receptors but not insulin-like growth factor-I receptors in human erythroid colony-forming cells. Blood. Sep 15 1997;90(6):2244-52. [Medline]. [Full Text].

  7. Means RT Jr. Recent developments in the anemia of chronic disease. Curr Hematol Rep. Mar 2003;2(2):116-21. [Medline].

  8. McClellan W, Aronoff SL, Bolton WK, et al. The prevalence of anemia in patients with chronic kidney disease. Curr Med Res Opin. Sep 2004;20(9):1501-10. [Medline].

  9. Centers for Disease Control and Prevention. Prevalence of chronic kidney disease and associated risk factors--United States, 1999-2004. MMWR Morb Mortal Wkly Rep. Mar 2 2007;56(8):161-5. [Medline]. [Full Text].

  10. National Kidney Disease Education Program. African Americans & kidney disease fact sheet. Bethesda, Md: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), U.S. Department of Health & Human Services. NIH publication no. 04-5577. August 2004 (rev April 2006). Available at http://nkdep.nih.gov/news/campaign/african_americans_508.pdf. Accessed October 21, 2008.

  11. Obrador GT, Ruthazer R, Arora P, Kausz AT, Pereira BJ. Prevalence of and factors associated with suboptimal care before initiation of dialysis in the United States. J Am Soc Nephrol. Aug 1999;10(8):1793-800. [Medline]. [Full Text].

  12. VanWyck DB, Eckardt K-U, and the National Kidney Foundation KDOQI Work Group. KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease: 2007 Update of Hemoglobin Target. National Kidney Foundation. Available at http://www.kidney.org/professionals/KDOQI/guidelines_anemiaUP/index.htm. Accessed June 12, 2009.

  13. Grabe DW, Manley HJ, Barton Pai A. Therapeutic advances in chronic kidney disease: management of anemia and the role of pharmacy (slides with transcript) (CME/CE). Medscape [serial online]. June 29, 2007;Accessed October 21, 2008. Available at http://www.medscape.com/viewarticle/561198.

  14. Silverberg DS, Wexler D, Blum M, et al. The correction of anemia in severe resistant heart failure with erythropoietin and intravenous iron prevents the progression of both the heart and the renal failure and markedly reduces hospitalization. Clin Nephrol. Jul 2002;58 suppl 1:S37-45. [Medline].

  15. Levin A, Singer J, Thompson CR, Ross H, Lewis M. Prevalent left ventricular hypertrophy in the predialysis population: identifying opportunities for intervention. Am J Kidney Dis. Mar 1996;27(3):347-54. [Medline].

  16. Foley RN, Parfrey PS, Harnett JD, et al. The impact of anemia on cardiomyopathy, morbidity, and and mortality in end-stage renal disease. Am J Kidney Dis. Jul 1996;28(1):53-61. [Medline].

  17. Sarnak MJ, Levey AS. Epidemiology of cardiac disease in dialysis patients: uremia-related risk factors. Semin Dial. 1999;12:69-76.

  18. Pisoni RL, Bragg-Gresham JL, Young EW, et al. Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis. Jul 2004;44(1):94-111. [Medline].

  19. Ofsthun NJ, LaBrecque J, Keen M, et al. The association of mortality and hospitalization with hemoglobin (Hb) and missed dialysis treatments in stage 5 chronic kidney disease (CKD) patients with and without cardiac comorbidities [abstract]. Nephrol Dial Transplant. 2005;20(suppl 5):v268.

  20. Drueke TB, Locatelli F, Clyne N, et al, for the CREATE Investigators. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. Nov 16 2006;355(20):2071-84. [Medline].

  21. [Best Evidence] Singh AK, Szczech L, Tang KL, et al, for the CHOIR Investigators. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. Nov 16 2006;355(20):2085-98. [Medline].

  22. US Food and Drug Administration. FDA strengthens boxed warnings, approves other safety labeling changes for erythropoiesis-stimulating agents (ESAs). November 8, 2007. [news release]. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm109024.htm. Accessed June 12, 2009.

  23. Mostafa S, Tagboto S, Robinson M, Burden A, Davies S. Over-representation of diabetic patients with renal anaemia in the primary care setting. Fam Pract. Jun 2009;26(3):180-2. [Medline].

  24. [Best Evidence] Navaneethan SD, Nigwekar SU, Sehgal AR, Strippoli GF. Aldosterone antagonists for preventing the progression of chronic kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol. Mar 2009;4(3):542-51. [Medline].

  25. [Best Evidence] Pizzi LT, Bunz TJ, Coyne DW, Goldfarb DS, Singh AK. Ferric gluconate treatment provides cost savings in patients with high ferritin and low transferrin saturation. Kidney Int. Dec 2008;74(12):1588-95. [Medline].

  26. Schmidt RJ. Methoxy polyethylene glycol-epoetin beta: worth waiting for or a novelty worn off?. Expert Opin Pharmacother. Jun 2009;10(9):1509-14. [Medline].

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Further Reading

Related eMedicine Topics

Clinical Trials
National Guideline Clearinghouse

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Keywords

anemia of chronic disease, anemia, anemia of chronic illness, renal failure, kidney failure, chronic renal disease, chronic kidney disease, CKD, chronic anemia, chronic renal failure

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Contributor Information and Disclosures

Author

Edgar V Lerma, MD, Clinical Associate Professor of Medicine, Section of Nephrology, Department of Medicine, University of Illinois at Chicago College of Medicine; Consulting Staff, Associates in Nephrology, SC
Edgar V Lerma, MD is a member of the following medical societies: American Heart Association, American Medical Association, American Society of Hypertension, American Society of Nephrology, Chicago Medical Society, Illinois State Medical Society, National Kidney Foundation, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Coauthor(s)

Robert Stein, MD, Chief, Section of Hematology, Department of Internal Medicine, Vice President, Medical Management, Advocate Christ Medical Center
Robert Stein, MD is a member of the following medical societies: American Medical Association, American Society of Hematology, Chicago Medical Society, and Eastern Cooperative Oncology Group
Disclosure: Nothing to disclose.

Medical Editor

Pradyumna D Phatak, MBBS, MD,, Chair, Division of Hematology and Medical Oncology, Rochester General Hospital; Clinical Professor of Oncology, Roswell Park Cancer Institute
Pradyumna D Phatak, MBBS, MD, is a member of the following medical societies: American Society of Hematology
Disclosure: Novartis Honoraria Speaking and teaching

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

 
 
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