• Evaluate for chronic kidney disease (CKD) anemia when a patient has a serum creatinine ≥2 mg/dL and hemoglobin <12 g/dL (adult males and postmenopausal females) or <11 g/dL (premenopausal females). A
• Before you treat CKD anemia, correct any underlying iron deficiency. A
• Start anemia therapy with erythropoietin-stimulating agents when hemoglobin is ≤10 g/dL, and maintain target hemoglobin levels between 11 and 12 g/dL, in accordance with National Kidney Foundation guidelines. A
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
CASE Mary J, a 65-year-old woman with stage 3 chronic kidney disease (CKD), is in your office for a follow-up appointment. Over the past 6 months, she has noticed a decrease in her energy level. On her routine blood work, you see that her hemoglobin has been slowly declining over the past year. It is now 9 g/dL and her estimated glomerular filtration rate (GFR) is 40 mL/min.
How would you evaluate Mary’s anemia, and would you suspect that it was related to her CKD?
Most physicians are aware that CKD—which affects approximately 10% of the US population1—has a deleterious effect on cardiovascular disease, but many fail to recognize the impact it has on the hematopoietic system. Managing the anemia that accompanies CKD in patients like Mary requires a finely tuned diagnostic approach and treatment strategy. This article will help toward that end.
Anemia of CKD: A common problem
Anemia of CKD is one of the first signs of kidney dysfunction, yet it often goes undetected because of its insidious onset. Anemia develops gradually as kidney function declines and the GFR drops to 70 mL/min in male patients and 50 mL/min in females.2 Epidemiologic data indicate that two-thirds of patients in the early stages of kidney failure are also anemic, with a hemoglobin level of less than 11 g/dL, yet only one-third of these patients have ever received erythropoietin-stimulating agents (ESAs) to treat their anemia.1 The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) guidelines recommend that the evaluation of anemia of CKD begin in patients with a serum creatinine ≥2 mg/dL when the hemoglobin is <12 g/dL in adult males and postmenopausal females and <11 g/dL in premenopausal females.3
How kidney failure leads to anemia
Patients like Mary develop anemia of CKD because failing kidneys produce less erythropoietin (EPO) than the body requires for the production of red blood cells. EPO is an endogenous hormone produced by peritubular fibroblasts in the renal cortex.4 Most of this hormone (90%) is produced in the kidney, with the remainder manufactured by hepatocytes.
Erythropoiesis is stimulated by blood loss, decreased oxygen tension, and an increase in oxygen affinity, which leads to an increase in EPO production via upregulation of the EPO gene. In healthy individuals, detection of hypoxia by the kidney can result in a 1000-fold increase in EPO production.5 Patients with CKD don’t have that kind of robust response, and their EPO levels remain normal or below normal even when challenged by lack of oxygen. Anemia in CKD can also be caused by nutritional deficiencies, decreased red blood cell survival because of uremic toxins, oxidative stress, inflammation, and the use of angiotensin-converting enzyme (ACE) inhibitors.
Chronic anemia, CKD, and CV disease: A deadly triad
The leading cause of death in patients with CKD is cardiovascular disease. Patients with cardiorenal anemia syndrome develop a self-perpetuating triad that increases the risk of death when all 3 conditions are present. Anemic patients double their relative risk of death when CKD is present and triple their risk if they have anemia, CKD, and cardiovascular disease.6
Epidemiologic studies suggest an association among anemia, left ventricular hypertrophy (LVH), mortality, and cardiovascular outcomes. One study evaluated 2423 stage 3 and 4 CKD patients with anemia, defined as hemoglobin <13 g/dL in males and <12 g/dL in females. The results showed an increase in composite outcomes of myocardial infarction, stroke, and death.7 A prospective study evaluating 246 people with stages 2 to 4 CKD reported anemia to be an independent risk factor for the development of LVH.8 The stages of CKD are shown in the TABLE.
Suspected mechanisms of cardiovascular disease progression due to chronic anemia include tissue hypoxia, free radical formation, endothelial dysfunction, and vascular damage. Compensatory neurohumeral adaptations result in an increased sympathetic response and upregulation of the reninangiotensin-aldosterone system.9