ANEMIA

End Stage Renal Disease

CKD: An Insidious Disease

Chronic kidney disease (CKD) is an insidious disease that gradually impairs kidney function. In its earliest stages, patients may be unaware they have the disease, but over a period ranging from several years to several decades, CKD will often progress to end-stage renal disease (ESRD), requiring renal replacement therapy (dialysis or kidney transplantation) to sustain life.

CKD arises as a consequence of diabetes mellitus, hypertensive nephrosclerosis, chronic glomerulonephritis, polycystic kidney disease, and a host of other disorders.1 Diabetes and hypertension are the two leading causes of end-stage renal disease ESRD, accounting for approximately 43% and 27% of all new end-stage renal disease ESRD cases, respectively.

End Stage Renal Disease

Staging and Prevalence of CKD

While the terminology of the formal literature has been inconsistent and confusing, this monograph has adopted the CKD staging terminology recently proposed by the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) and uses the term chronic kidney disease to encompass the entire spectrum of kidney disease, from its earliest stages through end-stage renal disease ESRD.

As serum creatinine (SCr) levels are an imperfect indicator of the severity of kidney disease, the NKF-K/DOQI staging and prevalence estimates are based on glomerular filtration rates (GFRs) derived using a formula developed by Levey and colleagues5 from data in the Modification of Diet in Renal Disease Study.

The resulting estimated total of 19.5 million people in the United States who have CKD marks the disease as a major public health concern, affecting more than the number of Americans with diabetes (estimated at 17 million)8 and nearly half the number of those with hypertension (estimated at 50 million).9 Because CKD typically progresses to its most severe form, end-stage renal disease ESRD, the public health concern is underscored by the most recent data from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD). The combined 1995 to 1999 prevalence of end-stage renal disease ESRD patients was 392,847 on dialysis and 8,287 with transplants.2 Expecting this alarming trend to continue, the NIDDKD has estimated that the prevalence of end-stage renal disease ESRD will reach over half a million by 2010.10

The NKF-K/DOQI prevalence estimates, together with the high costs associated with CKD, prompted the National Institutes of Health to establish the National Kidney Disease Education Program (NKDEP), an aggressive public education campaign currently underway. The NKDEP initiative likely will recommend interventions based on this K/DOQI staging. For patients first diagnosed with CKD, a primary goal will be to slow progression through the use of angiotensin-converting enzyme inhibitors, blood pressure control, and, in patients with diabetes, blood sugar control. Emphasis will be given to preventive and therapeutic approaches related to uremic complications, malnutrition, anemia, bone disease, acidosis, and medical comorbidities, such as cardiovascular disease.

end-stage renal disease

One frequently cited paper that sheds light on the prevalence of anemia in CKD patients prior to end-stage renal disease ESRD—and the quality of their care—is a retrospective analysis by Obrador and colleagues21 of more than 130,000 US patients initiating dialysis between April 1995 and June 1997. Sixty-eight percent of these patients had a Hct value <30%, considered to indicate severe anemia, and 51% had a Hct value <28% immediately before starting dialysis. Of those with Hct <28%, epoetin had not been prescribed for 80%.

Concerned by the facts that anemia develops early in CKD and worsens as the disease progresses, a panel of nephrologists developed a concept called the Renal Anemia Management Period (RAMP). The RAMP model emphasizes the progressive nature of CKD and the need for timely and appropriate treatment—well before the development of end-stage renal disease ESRD—to prevent anemia and other comorbidities that can potentially lead to irreversible, physiological damage, such as LVH.40 Rather than representing data from a specific study, the RAMP model notes trends identified in many studies.

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 end-stage renal disease ESRD in the United States.

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 end-stage renal disease ESRD, they are at an even greater risk for the development of cardiac complications than either group alone.

In end-stage renal disease (ESRD), severe impairment of QOL may occur in as many as 31% of patients.

Darbepoetin

Epoetin treatment has also been found to improve QOL in cancer patients. In a randomized study of 180 patients with anemia due to hormone-refractory prostate cancer, Johansson and colleagues observed that epoetin therapy improved QOL, physical functioning, and fatigue in many of the treated patients.33 Quirt and colleagues found that, regardless of whether patients were receiving chemotherapy, Hb levels increased with administration of epoetin, and these increases were positively correlated with improved QOL.32 Glaspy and colleagues reported that mean energy level increased by 38%, activity increased by 32%, and overall QOL increased by 24% in over 1,000 patients with nonmyeloid malignancies who received 4 months of epoetin therapy while undergoing chemotherapy. In their controlled study of 375 patients receiving nonplatinum chemotherapy, Littlewood and colleagues determined that compared with those receiving placebo, the patients treated with epoetin showed increased Hb levels (P <0.001) and improvement in a number of QOL domains, including energy level, fatigue, and ability to perform daily activities (P <0.01).30 Similarly, Demetri and associates reported that Hb values increased and were associated with improved activity level, energy, and overall well-being in patients receiving epoetin therapy.

Treatment of anemia may also improve response to treatment. Frommhold and colleagues, in a study of nearly 900 head and neck cancer patients, found that anemic patients treated with epoetin and undergoing radiotherapy experienced better locoregional tumor control than patients not receiving epoetin.36 Similarly, Glaser and colleagues have noted improved response to chemoradiation for oral or oropharyngeal squamous cell carcinoma when patients are treated with epoetin.37,38 A Phase III trial is currently being conducted by the Gynecologic Oncology Group to evaluate the efficacy of maintaining Hb levels above 12 g/dL with erythropoietin versus above 10 g/dL without erythropoietin in anemic patients receiving concurrent radiation and cisplatin for cervical cancer.39 The Radiation Oncology Therapy Group is also conducting a randomized Phase III trial, assessing the effect of erythropoietin on local-regional control in anemic patients treated with radiotherapy for squamous cell carcinoma of the head and neck.40

While darbepoetin alfa (novel erythropoiesis stimulating protein, NESP) has been approved by the Food and Drug Administration (FDA) for treating anemia in patients with chronic kidney disease (CKD), findings of clinical trials have demonstrated positive results in cancer patients as well. As has been shown in patients with CKD, Heatherington and colleagues found that the half-life of darbepoetin alfa is three times greater than that of epoetin in cancer patients, suggesting that this erythropoietic agent can be administered less frequently.41

In 89 anemic patients with nonmyeloid malignancies who were not receiving chemotherapy, Smith and colleagues found that darbepoetin alfa was well

tolerated. Increasing doses corresponded with increased efficacy, and most patients responded to treatment.42 In a more recent dosing study, Smith and colleagues evaluated 96 patients with nonmyeloid malignancies and chronic anemia, who were not receiving chemotherapy or radiation therapy. Darbepoetin alfa again was found to be safe and effective, with increased doses resulting in shorter time to response. In patients who received 6.75 mcg/kg every 3 (Q3W) or 4 (Q4W) weeks, serum concentrations of darbepoetin alfa were maintained above baseline for up to 3 to 4 weeks post-dose, and the terminal half-life was about 60 hours.43

Glaspy and colleagues assessed the efficacy of darbepoetin alfa in 107 cancer patients with solid tumors who were receiving multicycle chemotherapy. In three dose cohorts, the medication was found to be well tolerated, safe, and effective in increasing Hb levels.6 In a

12-week study involving 122 anemic patients with solid tumors who were receiving multicycle chemotherapy, the same researchers recently compared the efficacy of darbepoetin alfa to epoetin alfa. Patients were randomized to receive darbepoetin alfa in a 4-week front load phase followed by an 8-week maintenance phase that involved less frequent dosing or epoetin alfa at 40,000 units per week as a starting dose. After 12 weeks, 61% of patients treated with darbepoetin alfa responded to treatment compared to 49% of the patients treated with epoetin alfa, even when doses were increased to 60,000 units per week for those patients whose initial responses were inadequate. darbepoetin doses were not increased for patients who did not respond.44

Kotasek and colleagues recently evaluated the efficacy of darbepoetin alfa administered Q3W or Q4W, the same time frequency of most chemotherapy regimens. Data on 414 anemic patients with solid tumors on chemotherapy, who participated in the placebo-controlled trial, indicate that darbepoetin alfa can be safely and effectively administered very infrequently, allowing once per cycle dosing in patients receiving chemotherapy.45

Darbepoetin alfa is currently undergoing FDA review for use in the treatment of anemia in cancer patients receiving chemotherapy.

Recently, darbepoetin alfa (novel erythropoiesis stimulating protein, NESP), a longer-acting erythropoietic agent than epoetin, has been approved by the Food and Drug Administration for the treatment of patients with the anemia of CKD whether on dialysis or not. Due to longer serum half-life (25 hours vs. 8.5 hours), darbepoetin alfa should be administered less frequently than epoetin alfa. For example, patients who had been receiving epoetin once weekly should be administered darbepoetin alfa once every 2 weeks.55

Two large multicenter studies in dialysis patients who switched therapies demonstrated that darbepoetin alfa is as effective as epoetin in maintaining Hb levels.Similar comparability was demonstrated in a European multicenter study of CKD patients before the need for dialysis. In addition to less frequent dosing requirements, darbepoetin alfa appears to be well tolerated, with a safety profile comparable to that of epoetin.

CRI

Anemia is a common complication of chronic renal insufficiency (CRI), develops early, and worsens as CRI progresses. CRI-related anemia has multiple adverse consequences, affecting quality of life, cognitive function, exercise capacity, immune response, and heart function. Early identification and treatment of CRI-related anemia to prevent serious consequences is an idea promoted as the Renal Anemia Management Period (RAMP) by concerned nephrologists. Benefits of anemia correction in patients with CRI include decreased morbidity, hospitalization, and mortality; and improvement in quality of life, exercise capacity, cognitive function, and sexual function.

CRI

Chronic renal insufficiency (CRI) is an insidious disease that gradually impairs kidney function. In its earliest stages, patients may be unaware they have the disease, but over a period ranging from several years to several decades, CRI will often progress to end-stage renal disease (ESRD), requiring renal replacement therapy (dialysis or kidney transplantation) to sustain life.

CRI arises as a consequence of diabetes mellitus, hypertensive nephrosclerosis, chronic glomerulonephritis, polycystic kidney disease, and a host of other disorders.1 Diabetes and hypertension are the two leading causes of ESRD, accounting for approximately 43% and 27% of all new ESRD cases, respectively.2

Staging and Prevalence of CRI

While the terminology of the formal literature has been inconsistent and confusing, this monograph has adopted the CRI staging terminology recently proposed by the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) and uses the term chronic renal insufficiency to encompass the entire spectrum of kidney disease, from its earliest stages through ESRD.3,4

The resulting estimated total of 19.5 million people in the United States who have CRI marks the disease as a major public health concern, affecting more than the number of Americans with diabetes (estimated at 17 million)8 and nearly half the number of those with hypertension (estimated at 50 million).9 Because CRI typically progresses to its most severe form, ESRD, the public health concern is underscored by the most recent data from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD). The combined 1995 to 1999 prevalence of ESRD patients was 392,847 on dialysis and 8,287 with transplants.2 Expecting this alarming trend to continue, the NIDDKD has estimated that the prevalence of ESRD will reach over half a million by 2010.10

The NKF-K/DOQI prevalence estimates, together with the high costs associated with CRI, prompted the National Institutes of Health to establish the National Kidney Disease Education Program (NKDEP), an aggressive public education campaign currently underway. The NKDEP initiative likely will recommend interventions based on this K/DOQI staging. For patients first diagnosed with CRI, a primary goal will be to slow progression through the use of angiotensin-converting enzyme inhibitors, blood pressure control, and, in patients with diabetes, blood sugar control. Emphasis will be given to preventive and therapeutic approaches related to uremic complications, malnutrition, anemia, bone disease, acidosis, and medical comorbidities, such as cardiovascular disease.

Anemia Common in CRI

Anemia is a common complication of CRI, mainly due to the inability of the kidneys to secrete enough erythropoietin to stimulate adequate hematopoiesis. Additional factors that may cause or contribute to CRI-related anemia include iron deficiency,11 severe hyperparathyroidism,12 acute and chronic inflammatory conditions,13 aluminum toxicity,14 folate deficiency,15 shortened red blood cell survival,16 hypothyroidism,17 and hemoglobinopathies such as a-thalassemia.18

Anemia often develops early in the course of CRI, well before the onset of ESRD (stage 5, on dialysis),10,12,14,18-21 and then worsens as CRI progresses. Anemia is thus an important clinical factor for millions of Americans with CRI stages 3 through 5.

Hb/Hct levels in dialysis patients (stage 5, on dialysis) are meticulously followed by the Medicare system, and detailed analyses of these levels and treatment results are readily available. Less is known, however, regarding Hb/Hct levels in the millions of Americans with CRI not requiring dialysis.

One frequently cited paper that sheds light on the prevalence of anemia in CRI patients prior to ESRD—and the quality of their care—is a retrospective analysis by Obrador and colleagues21 of more than 130,000 US patients initiating dialysis between April 1995 and June 1997. Sixty-eight percent of these patients had a Hct value <30%, considered to indicate severe anemia, and 51% had a Hct value <28% immediately before starting dialysis. Of those with Hct <28%, epoetin had not been prescribed for 80%.

CRI-Related Anemia

The clinical consequences of anemia have been studied more in CRI than in any other disease state. The condition affects almost every organ system. In addition to contributing to the development of left ventricular hypertrophy (LVH), as described below, anemia impairs cognitive function, decreases exercise capacity, erodes quality of life,25 and may weaken immune responses. In patients with ESRD, severe anemia is associated with increases in hospitalization, health care costs, and mortality.

Cardiovascular disease (CVD) is the cause of death in nearly half of dialysis patients.33 Many of the risk factors for CVD are also risk factors for CRI, including hypertension, diabetes, and male gender. Complications of CRI create additional cardiovascular risk factors, such as volume overload, anemia, increased oxidant stress, hypoalbuminemia, divalent ion abnormalities, hypokalemia and hyperkalemia, and metabolic acidosis.

LVH is a common finding in patients with CRI, resulting from alterations in left ventricular wall stress caused, at least in part, by hypertension and anemia. It has been shown to progress with the degree of CRI.38 LVH is a significant risk factor for cardiovascular events independent of blood pressure in hypertensive men,38 and for cardiac and all-cause mortality in patients who require dialysis or kidney transplant.

CKD

Anemia often develops early in the course of chronic kidney disease (CKD), well before the onset of end-stage renal disease, and then worsens as CKD progresses.

Anemia & Chronic Kidney Disease

Anemia is a common complication of chronic kidney disease (CKD), develops early, and worsens as CKD progresses. CKD-related anemia has multiple adverse consequences, affecting quality of life, cognitive function, exercise capacity, immune response, and heart function. Early identification and treatment of CKD-related anemia to prevent serious consequences is an idea promoted as the Renal Anemia Management Period (RAMP) by concerned nephrologists. Benefits of anemia correction in patients with CKD include decreased morbidity, hospitalization, and mortality; and improvement in quality of life, exercise capacity, cognitive function, and sexual function.

CKD: An Insidious Disease

CKD arises as a consequence of diabetes mellitus, hypertensive nephrosclerosis, chronic glomerulonephritis, polycystic kidney disease, and a host of other disorders.1 Diabetes and hypertension are the two leading causes of ESRD, accounting for approximately 43% and 27% of all new ESRD cases, respectively.2

Staging and Prevalence of CKD

The resulting estimated total of 19.5 million people in the United States who have CKD marks the disease as a major public health concern, affecting more than the number of Americans with diabetes (estimated at 17 million)8 and nearly half the number of those with hypertension (estimated at 50 million).9 Because CKD typically progresses to its most severe form, ESRD, the public health concern is underscored by the most recent data from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD). The combined 1995 to 1999 prevalence of ESRD patients was 392,847 on dialysis and 8,287 with transplants.2 Expecting this alarming trend to continue, the NIDDKD has estimated that the prevalence of ESRD will reach over half a million by 2010.10

be to slow progression through the

use of angiotensin-converting enzyme inhibitors, blood pressure control, and, in patients with diabetes, blood sugar control. Emphasis will be given to preventive and therapeutic approaches related to uremic complications, malnutrition, anemia, bone disease, acidosis, and medical comorbidities, such as cardiovascular disease.

Anemia Common in CKD

Anemia is a common complication of CKD, mainly due to the inability of the kidneys to secrete enough erythropoietin to stimulate adequate hematopoiesis. Additional factors that may cause or contribute to CKD-related anemia include iron deficiency,11 severe hyperparathyroidism,12 acute and chronic inflammatory conditions,13 aluminum toxicity,14 folate deficiency,15 shortened red blood cell survival,16 hypothyroidism,17 and hemoglobinopathies such as a-thalassemia.18

Anemia often develops early in the course of CKD, well before the onset of ESRD (stage 5, on dialysis),10,12,14,18-21 and then worsens as CKD progresses. Anemia is thus an important clinical factor for millions of Americans with CKD stages 3 through 5.

One frequently cited paper that sheds light on the prevalence of anemia in CKD patients prior to ESRD—and the quality of their care—is a retrospective analysis by Obrador and colleagues21 of more than 130,000 US patients initiating dialysis between April 1995 and June 1997. Sixty-eight percent of these patients had a Hct value <30%, considered to indicate severe anemia, and 51% had a Hct value <28% immediately before starting dialysis. Of those with Hct <28%, epoetin had not been prescribed for 80%.

Obrador and colleagues based their analysis on information collected on Medicare’s Medical Evidence Form (MEF). A recent comparison of MEF data to actual Medicare claims22 (n = 89,193) suggests that the MEF overestimates epoetin use in CKD patients prior to ESRD. The percentage of untreated patients suggested by Obrador and colleagues, therefore, may be even higher. In any event, the evidence is clear that anemia related to CKD stages 1 through 4 is underrecognized and undertreated in the United States.

Consequences of CKD-Related Anemia

The clinical consequences of anemia have been studied more in CKD than in any other disease state. The condition affects almost every organ system. In addition to contributing to the development of left ventricular hypertrophy (LVH), as described below, anemia impairs cognitive function,23 decreases exercise capacity,24 erodes quality of life,25 and may weaken immune responses.26 In patients with ESRD, severe anemia is associated with increases in hospitalization,27 health care costs,28,29 and mortality.30-32

Cardiovascular disease (CVD) is the cause of death in nearly half of dialysis patients.33 Many of the risk factors for CVD are also risk factors for CKD, including hypertension, diabetes, and male gender. Complications of CKD

create additional cardiovascular risk factors, such as volume overload, anemia, increased oxidant stress, hypoalbuminemia, divalent ion abnormalities, hypokalemia and hyperkalemia, and metabolic acidosis.34

LVH is a common finding in patients with CKD,35-37 resulting from alterations in left ventricular wall stress caused, at least in part, by hypertension and anemia.35,36 It has been shown to progress with the degree of CKD. LVH is a significant risk factor for cardiovascular events independent of blood pressure in hypertensive men,38 and for cardiac and all-cause mortality in patients who require dialysis or kidney transplant.

Chronic renal insufficiency

Anemia is a common complication of chronic renal insufficiency, develops early, and worsens as chronic renal insufficiency progresses. Chronic renal insufficiency-related anemia has multiple adverse consequences, affecting quality of life, cognitive function, exercise capacity, immune response, and heart function. Early identification and treatment of chronic renal insufficiency-related anemia to prevent serious consequences is an idea promoted as the Renal Anemia Management Period (RAMP) by concerned nephrologists. Benefits of anemia correction in patients with chronic renal insufficiency include decreased morbidity, hospitalization, and mortality; and improvement in quality of life, exercise capacity, cognitive function, and sexual function.

chronic renal insufficiency

Chronic renal insufficiency (chronic renal insufficiency) is an insidious disease that gradually impairs kidney function. In its earliest stages, patients may be unaware they have the disease, but over a period ranging from several years to several decades, chronic renal insufficiency will often progress to end-stage renal disease (ESRD), requiring renal replacement therapy (dialysis or kidney transplantation) to sustain life.

chronic renal insufficiency arises as a consequence of diabetes mellitus, hypertensive nephrosclerosis, chronic glomerulonephritis, polycystic kidney disease, and a host of other disorders.1 Diabetes and hypertension are the two leading causes of ESRD, accounting for approximately 43% and 27% of all new ESRD cases, respectively.2

Staging and Prevalence of chronic renal insufficiency

While the terminology of the formal literature has been inconsistent and confusing, this monograph has adopted the chronic renal insufficiency staging terminology recently proposed by the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) and uses the term chronic renal insufficiency to encompass the entire spectrum of kidney disease, from its earliest stages through ESRD.3,4

The resulting estimated total of 19.5 million people in the United States who have chronic renal insufficiency marks the disease as a major public health concern, affecting more than the number of Americans with diabetes (estimated at 17 million)8 and nearly half the number of those with hypertension (estimated at 50 million).9 Because chronic renal insufficiency typically progresses to its most severe form, ESRD, the public health concern is underscored by the most recent data from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD). The combined 1995 to 1999 prevalence of ESRD patients was 392,847 on dialysis and 8,287 with transplants.2 Expecting this alarming trend to continue, the NIDDKD has estimated that the prevalence of ESRD will reach over half a million by 2010.10

The NKF-K/DOQI prevalence estimates, together with the high costs associated with chronic renal insufficiency, prompted the National Institutes of Health to establish the National Kidney Disease Education Program (NKDEP), an aggressive public education campaign currently underway. The NKDEP initiative likely will recommend interventions based on this K/DOQI staging. For patients first diagnosed with chronic renal insufficiency, a primary goal will be to slow progression through the use of angiotensin-converting enzyme inhibitors, blood pressure control, and, in patients with diabetes, blood sugar control. Emphasis will be given to preventive and therapeutic approaches related to uremic complications, malnutrition, anemia, bone disease, acidosis, and medical comorbidities, such as cardiovascular disease.

Anemia common in chronic renal insufficiency

Anemia is a common complication of chronic renal insufficiency, mainly due to the inability of the kidneys to secrete enough erythropoietin to stimulate adequate hematopoiesis. Additional factors that may cause or contribute to chronic renal insufficiency-related anemia include iron deficiency,11 severe hyperparathyroidism,12 acute and chronic inflammatory conditions,13 aluminum toxicity,14 folate deficiency,15 shortened red blood cell survival,16 hypothyroidism,17 and hemoglobinopathies such as a-thalassemia.18

Anemia often develops early in the course of chronic renal insufficiency, well before the onset of ESRD (stage 5, on dialysis),10,12,14,18-21 and then worsens as chronic renal insufficiency progresses. Anemia is thus an important clinical factor for millions of Americans with chronic renal insufficiency stages 3 through 5.

One frequently cited paper that sheds light on the prevalence of anemia in chronic renal insufficiency patients prior to ESRD—and the quality of their care—is a retrospective analysis by Obrador and colleagues21 of more than 130,000 US patients initiating dialysis between April 1995 and June 1997. Sixty-eight percent of these patients had a Hct value <30%, considered to indicate severe anemia, and 51% had a Hct value <28% immediately before starting dialysis. Of those with Hct <28%, epoetin had not been prescribed for 80%.

Chronic renal insufficiency related anemia

The clinical consequences of anemia have been studied more in chronic renal insufficiency than in any other disease state. The condition affects almost every organ system. In addition to contributing to the development of left ventricular hypertrophy (LVH), as described below, anemia impairs cognitive function,23 decreases exercise capacity, rodes quality of life and may weaken immune responses.26 In patients with ESRD, severe anemia is associated with increases in hospitalization, health care costs and mortality.

Cardiovascular disease (CVD) is the cause of death in nearly half of dialysis patients.33 Many of the risk factors for CVD are also risk factors for chronic renal insufficiency, including hypertension, diabetes, and male gender. Complications of chronic renal insufficiency create additional cardiovascular risk factors, such as volume overload, anemia, increased oxidant stress, hypoalbuminemia, divalent ion abnormalities, hypokalemia and hyperkalemia, and metabolic acidosis.34

LVH is a common finding in patients with chronic renal insufficiency,35-37 resulting from alterations in left ventricular wall stress caused, at least in part, by hypertension and anemia. It has been shown to progress with the degree of chronic renal insufficiency.38 LVH is a significant risk factor for cardiovascular events independent of blood pressure in hypertensive men,38 and for cardiac and all-cause mortality in patients who require dialysis or kidney transplant.

Chronic Kidney Disease

Anemia often develops early in the course of chronic kidney disease (CKD), well before the onset of end-stage renal disease, and then worsens as CKD chronic kidney disease progresses.

Anemia & Chronic Kidney Disease

Anemia is a common complication of chronic kidney disease (CKD), develops early, and worsens as CKD chronic kidney disease progresses. CKD chronic kidney disease-related anemia has multiple adverse consequences, affecting quality of life, cognitive function, exercise capacity, immune response, and heart function. Early identification and treatment of CKD chronic kidney disease-related anemia to prevent serious consequences is an idea promoted as the Renal Anemia Management Period (RAMP) by concerned nephrologists. Benefits of anemia correction in patients with CKD chronic kidney disease include decreased morbidity, hospitalization, and mortality; and improvement in quality of life, exercise capacity, cognitive function, and sexual function.

Chronic Kidney Disease

Chronic kidney disease (CKD) is an insidious disease that gradually impairs kidney function. In its earliest stages, patients may be unaware they have the disease, but over a period ranging from several years to several decades, CKD chronic kidney disease will often progress to end-stage renal disease (ESRD), requiring renal replacement therapy (dialysis or kidney transplantation) to sustain life.

CKD chronic kidney disease arises as a consequence of diabetes mellitus, hypertensive nephrosclerosis, chronic glomerulonephritis, polycystic kidney disease, and a host of other disorders.1 Diabetes and hypertension are the two leading causes of ESRD, accounting for approximately 43% and 27% of all new ESRD cases, respectively.2

Staging and Prevalence of CKD chronic kidney disease

While the terminology of the formal literature has been inconsistent and confusing, this monograph has adopted the CKD chronic kidney disease staging terminology recently proposed by the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) and uses the term chronic kidney disease to encompass the entire spectrum of kidney disease, from its earliest stages through ESRD.3,4

The resulting estimated total of 19.5 million people in the United States who have CKD chronic kidney disease marks the disease as a major public health concern, affecting more than the number of Americans with diabetes (estimated at 17 million)8 and nearly half the number of those with hypertension (estimated at 50 million).9 Because CKD chronic kidney disease typically progresses to its most severe form, ESRD, the public health concern is underscored by the most recent data from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD). The combined 1995 to 1999 prevalence of ESRD patients was 392,847 on dialysis and 8,287 with transplants.2 Expecting this alarming trend to continue, the NIDDKD has estimated that the prevalence of ESRD will reach over half a million by 2010.10

The NKF-K/DOQI prevalence estimates, together with the high costs associated with CKD chronic kidney disease, prompted the National Institutes of Health to establish the National Kidney Disease Education Program (NKDEP), an aggressive public education campaign currently underway. The NKDEP initiative likely will recommend interventions based on this K/DOQI staging. For patients first diagnosed with CKD chronic kidney disease, a primary goal will be to slow progression through the use of angiotensin-converting enzyme inhibitors, blood pressure control, and, in patients with diabetes, blood sugar control. Emphasis will be given to preventive and therapeutic approaches related to uremic complications, malnutrition, anemia, bone disease, acidosis, and medical comorbidities, such as cardiovascular disease.

Anemia - CKD chronic kidney disease

Anemia is a common complication of CKD chronic kidney disease, mainly due to the inability of the kidneys to secrete enough erythropoietin to stimulate adequate hematopoiesis. Additional factors that may cause or contribute to CKD chronic kidney disease-related anemia include iron deficiency,11 severe hyperparathyroidism,12 acute and chronic inflammatory conditions,13 aluminum toxicity,14 folate deficiency,15 shortened red blood cell survival,16 hypothyroidism,17 and hemoglobinopathies such as a-thalassemia.18

Anemia often develops early in the course of CKD chronic kidney disease, well before the onset of ESRD (stage 5, on dialysis),10,12,14,18-21 and then worsens as CKD chronic kidney disease progresses. Anemia is thus an important clinical factor for millions of Americans with CKD chronic kidney disease stages 3 through 5.

One frequently cited paper that sheds light on the prevalence of anemia in CKD chronic kidney disease patients prior to ESRD—and the quality of their care—is a retrospective analysis by Obrador and colleagues21 of more than 130,000 US patients initiating dialysis between April 1995 and June 1997. Sixty-eight percent of these patients had a Hct value <30%, considered to indicate severe anemia, and 51% had a Hct value <28% immediately before starting dialysis. Of those with Hct <28%, epoetin had not been prescribed for 80%.

Obrador and colleagues based their analysis on information collected on Medicare’s Medical Evidence Form (MEF). A recent comparison of MEF data to actual Medicare claims22 (n = 89,193) suggests that the MEF overestimates epoetin use in CKD chronic kidney disease patients prior to ESRD. The percentage of untreated patients suggested by Obrador and colleagues, therefore, may be even higher. In any event, the evidence is clear that anemia related to CKD chronic kidney disease stages 1 through 4 is underrecognized and undertreated in the United States.

Consequences of CKD chronic kidney disease related Anemia

The clinical consequences of anemia have been studied more in CKD chronic kidney disease than in any other disease state. The condition affects almost every organ system. In addition to contributing to the development of left ventricular hypertrophy (LVH), as described below, anemia impairs cognitive function,23 decreases exercise capacity,24 erodes quality of life,25 and may weaken immune responses.26 In patients with ESRD, severe anemia is associated with increases in hospitalization,27 health care costs,28,29 and mortality.30-32

Cardiovascular disease (CVD) is the cause of death in nearly half of dialysis patients.33 Many of the risk factors for CVD are also risk factors for CKD chronic kidney disease, including hypertension, diabetes, and male gender. Complications of CKD chronic kidney disease

LVH is a common finding in patients with CKD chronic kidney disease,35-37 resulting from alterations in left ventricular wall stress caused, at least in part, by hypertension and anemia.35,36 It has been shown to progress with the degree of CKD chronic kidney disease.38 LVH is a significant risk factor for cardiovascular events independent of blood pressure in hypertensive men,38 and for cardiac and all-cause mortality in patients who require dialysis or kidney transplant.

Anemia symptoms

Symptoms of Anemia

Approximately 75% of all cancer patients report symptoms of fatigue,13,14 which can present as weakness, listlessness, low energy, trouble starting and finishing tasks, and the need to sleep during the day.9,14-17 While fatigue is the primary symptom of anemia in cancer patients, anemia can also cause a range of other symptoms, including palpitations, impaired cognitive function, nausea, reduced skin temperature, impaired immune function, dizziness, headache, chest pain, shortness of breath, and depression.

anemia symptoms

Anemia is often underrecognized and undertreated.
Anemia is associated with many chronic diseases and other conditions.
If left untreated, anemia can have serious consequences.
Anemia can be readily managed by current therapies.

Anemia symptoms may be vague, and it is present in a substantial number of patients with a variety of chronic and serious diseases. Frequently, however, anemia remains undetected because it is masked by symptoms of the diseases with which it is associated, including chronic kidney disease, cancer, diabetes, cardiovascular disease, HIV/AIDS, rheumatoid arthritis, and inflammatory bowel disease.

The Burden of Anemia

Because anemia affects the delivery of oxygen to all of the body’s organs, its signs and symptoms are varied.

It is generally accepted that the symptoms of anemia adversely affect quality of life (QOL), even when anemia is mild. In end-stage renal disease (ESRD), severe impairment of QOL may occur in as many as 31% of patients.13 Several factors contribute to poor QOL in these patients, including low Hb or Hct. Anemia in patients with cancer contributes to fatigue and may reduce patients’ ability to function normally, thus reducing QOL.12,14,15 The corollary to this is that the correction of anemia is associated with improved QOL. In fact, improved Hb and Hct values are associated with better scores on QOL assessments in a variety of disease states, including CKD,13,16,17 inflammatory bowel disease,18 rheumatoid arthritis,16,19 cancer,20,21 and HIV/AIDS.22-24

Anemia of chronic disease

Key Points

Anemia is common in rheumatoid arthritis (RA) and may constitute an important clinical problem for many patients. The two primary types of anemia in patients with RA are anemia of chronic disease and iron deficiency anemia. Erythropoietin therapy in combination with iron supplementation corrects anemia in most patients with RA, and may improve RA outcomes and quality of life. Erythropoietin is useful in facilitating autologous blood donation prior to elective surgery for patients with RA and in reducing transfusion requirements.

anemia of chronic disease

Anemia is the most common extra-articular manifestation of RA, estimated to occur in 30% to 60% of patients.17-19 Patients with RA who are anemic have evidence of more severe disease, with more involved joints and higher levels of functional disability and pain.19-21

Although any type of anemia may be seen in patients with RA, the two primary types of anemia in RA appear to be iron deficiency anemia and anemia of chronic disease. In their retrospective review of 225 patients with RA, Peeters and colleagues identified 64% as anemic. Of the group classified as anemic, 77% were found to have anemia of chronic disease and 23% to have iron deficiency anemia.19

Differential diagnosis may be difficult, as serum iron levels are low in both types of anemia, and bone marrow staining for iron stores may be required. However, serum ferritin testing usually distinguishes between iron deficiency and anemia of chronic disease. Patients with serum ferritin levels >50 µg/mL are likely to have anemia of chronic disease, while those with a lower value of serum ferritin are likely to be iron deficient.22-24

The most common causes of iron deficiency anemia in RA are blood loss through menstrual bleeding and/or gastrointestinal bleeding secondary to nonsteroidal anti-inflammatory drugs. Anemia of chronic disease is an “inflammatory anemia,” and its features in RA are similar to those seen in inflammatory bowel disease, HIV, aging, and cancer.

Impact of Inflammatory Cytokines

Development of anemia of chronic disease in patients with RA appears to be related to inflammatory cytokines, which cause joint inflammation and interfere with normal red blood cell formation and destruction.25-28

Patients with RA make erythropoietin in response to the inflammatory anemia, as expected. However, the response is blunted in these patients, with both inadequate production of erythropoietin and inadequate bone marrow responses compared to people with similar levels of anemia and no inflammation. Animal studies suggest that increased

levels of the inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-µ (TNF-µ) inhibit erythropoietin production and interfere with erythroid colony-forming units in the bone marrow.28,31,32

Iron Supplementation

Iron supplementation is of great importance in patients who have iron deficiency. Furthermore, iron deficiency may occur concomitantly with anemia of chronic disease.28,35 Iron repletion is almost always required as an adjunctive treatment to erythropoietin therapy, as erythroid production is increased.36-39

Anemia in chronic disease

Key Points

Anemia is common in rheumatoid arthritis (RA) and may constitute an important clinical problem for many patients. The two primary types of anemia in patients with RA are anemia in chronic disease and iron deficiency anemia. Erythropoietin therapy in combination with iron supplementation corrects anemia in most patients with RA, and may improve RA outcomes and quality of life. Erythropoietin is useful in facilitating autologous blood donation prior to elective surgery for patients with RA and in reducing transfusion requirements.

Anemia in chronic disease

Although any type of anemia may be seen in patients with RA, the two primary types of anemia in RA appear to be iron deficiency anemia and anemia in chronic disease. In their retrospective review of 225 patients with RA, Peeters and colleagues identified 64% as anemic. Of the group classified as anemic, 77% were found to have anemia of chronic disease and 23% to have iron deficiency anemia.19

Differential diagnosis may be difficult, as serum iron levels are low in both types of anemia, and bone marrow staining for iron stores may be required. However, serum ferritin testing usually distinguishes between iron deficiency and anemia of chronic disease. Patients with serum ferritin levels >50 µg/mL are likely to have anemia in chronic disease, while those with a lower value of serum ferritin are likely to be iron deficient.22-24

Impact of Inflammatory Cytokines

Development of anemia in chronic disease in patients with RA appears to be related to inflammatory cytokines, which cause joint inflammation and interfere with normal red blood cell formation and destruction.25-28

Iron Supplementation

Iron supplementation is of great importance in patients who have iron deficiency. Furthermore, iron deficiency may occur concomitantly with anemia in chronic disease.28,35 Iron repletion is almost always required as an adjunctive treatment to erythropoietin therapy, as erythroid production is increased.36-39

Anemia

Anemia: A Hidden Epidemic

First convened in November 2000, the National Anemia Action Council (NAAC) is a multispecialty consortium comprised of nearly 30 leading physicians who are experts in identifying and treating anemia. Their specialties include hematology, nephrology, oncology, cardiology, critical care, rheumatology, gastroenterology, infectious diseases, geriatrics, and surgery.

Based on scientific evidence, NAAC has identified anemia as a public health concern that requires concerted attention and action. One of NAAC’s primary objectives is to raise professional and public awareness of anemia, its consequences, and treatment options. NAAC is also dedicated to stimulating research and new therapeutic approaches to achieve better patient outcomes.

Written with the editorial input of a number of prestigious NAAC members and other anemia specialists, Anemia:

A Hidden Epidemic is designed to be an in-office handbook for primary care and specialty medical practitioners who may be seeing patients with undiagnosed anemia. In addition to providing a broad overview of the condition, the monograph contains chapters on the association of anemia with: chronic kidney disease, cardiovascular disease, diabetes, cancer, HIV/AIDS, inflammatory bowel disease, hepatitis C, rheumatoid arthritis, surgery, and aging.

Visit www.anemia.org, the official Web site of the National Anemia Action Council, to obtain additional copies of Anemia: A Hidden Epidemic and to access other scientific anemia information and CME materials.

“At least 3.4 million Americans have been diagnosed as

anemic, and millions more may be undiagnosed or at

increased risk of developing anemia.”

I Anemia Overview

Key Points

• Anemia is often underrecognized and undertreated.

• Anemia is associated with many chronic diseases and other conditions.

• If left untreated, anemia can have serious consequences.

• Anemia can be readily managed by current therapies.

A Hidden Epidemic

Traditionally, the health care community has not focused on anemia as a serious and common condition. However, findings from the National Center for Health Statistics and the recent identification of anemia as a significant public health concern by the United States Department of Health and Human Services in Healthy People 20101 have sounded a call for a re-examination of the impact of anemia on the health of Americans.

Based on a national household interview survey, the National Center for Health Statistics estimated in 1996 that 3.4 million Americans were living with anemia.2 The actual number of individuals with the condition may be far greater, as anemia is often underdiagnosed and undertreated. Anemia’s signs and symptoms may be vague, and it is present in a substantial number of patients with a variety of chronic and serious diseases. Frequently, however, anemia remains undetected because it is masked by symptoms of the diseases with which it is associated, including chronic kidney disease, cancer, diabetes, cardiovascular disease, HIV/AIDS, rheumatoid arthritis, and inflammatory bowel disease.

The National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) new clinical practice guideline on the classification system for chronic kidney disease (CKD) estimates that more than 19.5 million Americans have CKD.3 Anemia is a common and early complication of CKD4-8 and worsens as the disease progresses. The estimated 50 million Americans with hypertension9 and 17 million with diabetes10 are at increased risk for CKD—and subsequently anemia.

Not only is anemia a consequence of many diseases, it may also occur from the treatment of the disease itself, such as in patients with cancer, HIV/AIDS, and hepatitis C. Candidates for surgery may be anemic due to underlying disease or become so due to blood loss during the perioperative period. Anemia also occurs more frequently among the elderly, and its prevalence in this group is expected to increase as baby-boomers become senior citizens.

At least 3.4 million Americans have been diagnosed as anemic, and millions more may be undiagnosed or at increased risk of developing anemia. Anemia is a hidden epidemic in this nation, and a condition that can have serious consequences if left untreated. However, it is also a condition that can be readily managed by current therapies.

Anemia Defined

Anemia is defined as a reduction in the number of circulating red blood cells, the hemoglobin concentration, or the volume of packed red cells (hematocrit) in the blood. In the laboratory, anemia is identified when a patient’s hemoglobin (Hb)/hematocrit (Hct) values fall below the lower end of a normal range of values for age- and sex-matched subjects. The likelihood and severity of anemia is based on the patient’s deviation from normal values. Women in their childbearing years normally have a lower Hb value by about 1 gm/dL than men of the same age, likely due to hormonal influences. After menopause, the gender difference virtually disappears.

The three major categories of anemia are hypoproliferative, maturation defects, and hemolysis/blood loss. The most common anemia in the United States is hypoproliferative anemia, which includes iron deficiency, chronic kidney disease (CKD), and the inflammation-associated anemia of chronic disease, which is found in patients with chronic conditions, such as rheumatoid arthritis, inflammatory bowel disease, HIV/AIDS, and cancer. Anemia may be acquired (eg, through blood loss, inflammation, and malignancy) or inherited (eg, by patients with sickle cell disease, thalassemia, and other hemoglobinopathies).

The Burden of Anemia

Because anemia affects the delivery of oxygen to all of the body’s organs, its signs and symptoms are varied.

Impaired Quality of Life

Increased Cardiovascular Morbidity

Anemia is associated with significant cardiovascular morbidity and mortality. Compensatory hemodynamic changes that occur in anemia lead to increased cardiac output and blood flow, resulting in a variety of cardiovascular consequences.25,26 Decreased oxygenation of the heart muscle combined with increased cardiac workload may result in symptoms such as angina27,28 and palpitations,29 and, over time, result in cardiac enlargement and congestive heart failure.30,31

The relationship between anemia and cardiovascular disease has been the topic of much research in CKD, both in predialysis patients and those with ESRD on dialysis. This is partly because of the increased cardiovascular morbidity in CKD patients and the increased cardiovascular-associated mortality observed in dialysis patients. For example, left ventricular hypertrophy is associated with a 50% decrease in 4-year survival in ESRD.32 Similarly, dialysis patients with low Hct (<33%) have a significantly higher risk of cardiac death than patients with higher Hct (≥33% to <36%) at 1 year (RR, 1.74; 95% CI, 1.66-1.83).33 In cancer patients, cardiovascular symptoms and signs of anemia include tachycardia, palpitations, cardiac enlargement, increased pulse pressure, systolic ejection murmur, and risk of cardiac failure.34

Correction of anemia has been associated with significant improvements in cardiovascular morbidity and mortality. In patients with heart failure, the correction of mild anemia to a Hb level of 12.5 g/dL is associated with functional improvement, increased left ventricular ejection fraction, improved exercise capacity, and a decline in hospitalizations.29,35,36 In patients with CKD, partial correction of anemia is associated with improvements in left ventricular mass index,37-41 myocardial ischemia, and exercise duration.42

Hindered Cognitive Function

Researchers have shown a relationship between Hct and cognitive function. In patients with ischemic cerebrovascular disease, Hct correction to the normal range (40% to 45%) was shown to improve cerebral oxygen delivery.43 Similarly, in dialysis patients, Hct correction to normal was shown to improve neurophysiologic parameters indicative of cognitive function and memory.44 Even partial correction of anemia in CKD patients (to Hct of 36% to 36.5%) has been shown to improve cognitive function, including sustained attention and memory.45,46

The Hct values necessary to maintain optimal cognitive function, however, remain to be defined. For example, in dialysis patients, maximal oxygenation of the cerebral hemisphere was estimated to occur at a Hct of 35.2%, but the optimal level varied with the region of the brain explored (eg, a Hct of 33% provided maximal oxygen delivery in the occipital region, whereas a Hct of 45% was needed in the frontal region).47

Increased Hospitalization and Mortality Risk

In patients with CKD, anemia has been shown to correlate directly with the risk of hospitalization. In a recent study of more than 66,000 dialysis patients, those with Hct of 33% to <39% were found to have lower hospitalization rates than patients with Hct <33%.33 Findings of another study indicated that dialysis patients with Hct <30% had the highest risk of hospitalization, while those with Hct levels of 33% to 36% had the lowest hospitalization risk.48 Both fewer hospitalizations per year and shorter hospital stays were observed for new dialysis patients treated with recombinant human erythropoietin (epoetin) than for their untreated peers.49

anemia in dialysis patients is also associated with increased mortality, with higher 1-year mortality risk in patients with lower Hct.31,33 Similarly, 3-year mortality in dialysis patients increases with decreasing Hct, with the highest mortality at Hct <30%.51 Observational studies in dialysis patients show reductions in mortality with correction of anemia to Hct 33% to 36%.52

Such a relationship also has been noted between anemia and survival in cancer patients. In a systematic review of 60 published studies, researchers reported that the presence of anemia was asso ciated with an overall 65% increased relative risk of death, although the relative risk varied by cancer type.53

Results of a recent retrospective study of nearly 79,000 acute myocardial infarction patients ≥65 years indicated that a lower Hct at admission was associated with a higher 30-day mortality rate. Short-term mortality rates were lowered in patients with a Hct of ≤30% at admission who were given blood transfusions to correct anemia.54

Diagnosing Anemia

Since anemia is a sign of a wide range of underlying disorders, and, in itself, is associated with morbidity and even an increased risk of mortality, it is critical that the underlying pathophysiologic mechanism be identified for any given patient. The hyproproliferative anemias may be associated with inadequate erythroid marrow stimulation by erythropoietin for red blood cell production and with inadequate iron availability for Hb synthesis. Because it is the most common cause of anemia, iron deficiency must be ruled out in the evaluation of any anemic patient.

Anemia is almost always discovered through abnormal laboratory screening test results. It is unusual for patients to present with anemia so advanced that the clinical manifestations (eg, pallor, palpitations, weakness, etc.) predominate. With acute anemia, the only real considerations are blood loss or hemolysis.

An anemia work-up should include a routine complete blood count (CBC) with reticulocyte count (corrected for the Hct) and three red cell indices: mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC).

*All values from Wintrobe’s Clinical Hematology.55

In addition, measurements of iron supply [serum iron, total iron binding capacity (TIBC), percent transferrin saturation (TSAT), and serum ferritin] and a careful evaluation of the peripheral blood smear are necessary.

*Serum iron and TIBC values from Wintrobe’s Clinical Hematology.55 TSAT and serum ferritin values from Tietz Textbook of Clinical Chemistry.56

Marked alterations (either increased or decreased) in the red cell indices almost always reflect a maturation defect or iron deficiency. Iron deficiency is revealed by a low serum iron, low percent transferrin saturation, and low serum ferritin. A microcytic anemia in the presence of normal iron values suggests a defect (most commonly inherited) in Hb synthesis.

The algorithm in Figure 1-3 provides an overview of a diagnostic work-up for anemia. The World Health Organization defines anemia as Hb <12g/dL for premenopausal women and prepubertal patients, and Hb <13g/dL for men and postmenopausal women.57 Because Hb/Hct values below the normal age- and sex-adjusted values represent probabilities of anemia, they are more easily interpreted when they are compared to patients’ historic values.

Anemia Management

A correct diagnosis of the cause is key to managing anemia. Once the cause is determined, the approach is to implement the appropriate treatment to correct the anemia. In most medical practices, the identification of iron deficiency should be foremost, since it may be associated with occult bleeding or other serious conditions, and it can be quickly and easily treated with iron supplementation. Other less common but reversible anemias include vitamin B12 and folate deficiency, and some cases of anemia associated with inflammation. Each of these requires a slightly different therapeutic approach.

Iron deficiency in adult males and postmenopausal females must be considered due to chronic blood loss until proven otherwise. There are a variety of oral and parenteral iron preparations to choose from in treating iron deficiency. For most uncomplicated cases, an oral iron preparation will suffice. A total elemental iron dose of 200 mg/day will gradually reverse the iron deficiency anemia. Oral iron should be continued for some months after the reversal of the anemia in order to replenish body iron stores. A convenient rule of thumb is to continue iron replacement for 6 months after correction of the anemia. If oral iron is not absorbed well, or if the patient cannot tolerate the side effects of oral iron treatment, parenteral iron may be given.

For the other anemias, the same principles apply. Vitamin B12 deficiency must be corrected with parenteral B12 injections. Folate deficiency is generally due to poor dietary intake of the vitamin, and the deficiency state is generally rapidly reversed with improved nutrition. Chronic inflammatory states are more complex, depending on the underlying inflammatory process.

One of the most common and chronic hypoproliferative anemias is the anemia of CKD. This is a hormone deficiency state, in which the diseased kidney is incapable of meeting the endogenous erythropoietin needs of the patient. As a result of erythropoietin deficiency, the moderately shortened lifespan of the circulating red cells, and the obligatory blood loss that accompanies dialysis, CKD patients can experience profound, debilitating anemia. Such patients have benefited greatly from the availability of epoetin alfa, a recombinant human erythropoietin.

Epoetin alfa is a 165-amino-acid glycoprotein manufactured by recombinant DNA technology and is identical in structure and biological activity to native erythropoietin. Originally approved by the Food and Drug Administration (FDA) for the treatment of anemia in CKD patients on dialysis, epoetin alfa is currently indicated for treating anemia in CKD patients whether on dialysis or not, in cancer patients on chemotherapy, and in zidovudine-treated HIV-infected patients. It is also approved for reducing allogeneic blood transfusions in anemic patients undergoing elective, noncardiac, nonvascular surgery.60

Epoetin beta and epoetin omega are other forms of recombinant human erythropoietin used outside of the United States. Because European researchers sometimes include data on epoetin beta, epoetin in this monograph refers to epoetin alfa and epoetin beta.

For more than a decade, epoetin has been used successfully to manage the anemia of patients with CKD or cancer-related anemia. Epoetin therapy has dramatically reduced the need for transfusions in these patient groups, has led to an improvement in QOL for those who have responded, and has decreased anemia-associated morbidity.61 Epoetin has also been shown to be of benefit in managing anemia in patients with HIV/AIDS,22-24 inflammatory bowel disease,18 and rheumatoid arthritis.16,62 The anemia of the elderly and those undergoing surgery63,64 has also been responsive to therapy with epoetin. In some cases, epoetin is given with supplemental iron, a strategy that has been of proven value for a variety of patients, including patients with ESRD on dialysis, patients with rheumatoid arthritis, and some surgical patients.

Epoetin, however, has a relatively short circulating half-life and, consequently, it is usually administered several times a week or at least weekly. Most recently, a novel erythropoiesis-stimulating protein (NESP) has been developed that addresses some of the inconvenience of frequent epoetin dosing. Engineered specifically for increased biological activity, darbepoetin alfa has the same number of amino acids as epoetin alfa, but they have been molecularly modified to add two additional

N-linked glycosylation sites to the molecule, bringing the total number to five, instead of the usual three. This results in a threefold increase in terminal elimination half-life (23.5 hours vs. 8.5 hours). As a result, darbepoetin alfa allows less frequent dosing than epoetin alfa and is well tolerated. Darbepoetin alfa was approved by the FDA in 2001 for the treatment of patients with the anemia of CKD whether on dialysis or not.65 Study findings to date have shown the medication also to be of benefit in patients with nonmyeloid hematological malignancies or solid tumors.66,67 Darbepoetin alfa is currently undergoing FDA review for use in the treatment of anemia in cancer patients receiving chemotherapy.

Replacement therapy, whether it is iron or epoetin, takes time to correct the anemia. Thus, if the anemia is severe and the patient is symptomatic, transfusion therapy with packed red blood cells is an option. Although the safety of blood transfusions has been brought to an extremely high level, exposure to red cell transfusions still carries a measurable risk of allosensitization, and in some patient groups, such as those with HIV/AIDS and cancer, it can have an adverse effect on mortality.

Figure 1-1 The amount of deviation from age- and sex-matched normal subjects indicates the probability and severity of anemia. Reprinted with permission from Harrison’s Textbook of Internal Medicine.11

Figure 1-2 Symptoms and signs occur when the oxygen carrying capacity of the blood is unable to meet the oxygen requirements of body tissues. Adapted and reprinted with permission from Semin Oncol.12

(sidebar)

Anemia Labs

Reticulocyte Count

The reticulocyte count estimates the rate of red cell production. An elevated reticulocyte count generally indicates that the marrow is responding to endogenous erythropoietin stimulation. The reticulocyte count must be corrected for the degree of anemia in order to have a valid estimate of the rate of red cell production. A normal reticulocyte count in the presence of anemia suggests impaired erythropoietin production or an impaired response to erythropoietin by the erythroid marrow.

An elevated reticulocyte count and slightly increased MCV suggest a hemolytic process. An elevated MCV can reflect a very high reticulocyte production or a nuclear maturation defect (eg, vitamin B12 or folic acid deficiency).

Iron Supply Parameters

The serum iron level and percent transferrin saturation reflect the iron available for Hb synthesis. When the serum iron falls (true iron deficiency or acute inflammation), Hb synthesis is impaired and microcytic, hypochromic red cells are produced. The serum ferritin reflects total body iron stores and is decreased in iron deficiency, but normal or increased in states of acute or chronic inflammation. This is a useful laboratory test to distinguish between true iron deficiency and chronic inflammatory states.

Red Cell Indices

The red cell indices reflect the state of red cell production. anemia with normal red cell indices is almost always hypoproliferative in nature. Microcytic red cells can be seen with true iron deficiency as well as chronic severe inflammation. In the latter, the inflammatory process impairs iron release from storage sites, resulting in a low serum iron value, despite normal or increased iron stores. Macrocytic red cells are most commonly seen with the nuclear maturation disorders, such as vitamin B12 or folic acid deficiency.

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Erythropoiesis

Hematopoiesis is the process by which the formed elements of the blood are regulated through a series of steps, beginning with the pluripotent stem cell. Once stem cells are committed to specific differentiated cell lineages, hematopoietic precursor cells come under increasing regulation by growth factors and hormones. The physiologic regulator of red cell (erythrocyte) production is the glycoprotein hormone erythropoietin, of which >90% is made in the kidney.

The machinery responsible for red cell production (erythropoiesis) resides in the bone marrow. The erythropoietin molecule interacts and binds to specific receptors on the surface of marrow erythroid progenitor cells, inducing them to proliferate and mature. The key to erythropoietin production is the availability of oxygen, which is transported to tissues in a form bound to the Hb molecule contained within the red cells.

The fundamental stimulus for erythropoietin production is oxygen availability to the kidney. Impaired oxygen delivery to the kidney is caused by a decrease in the number of circulating red cells (anemia), impaired oxygen loading of the red cell Hb or, rarely, impaired flow of red cells to the kidney because of renal artery stenosis.

Erythropoietin not only is responsible for the day-to-day regulation of erythropoiesis, but it also responds dramatically to increase red cell production in the face of an inadequate oxygen supply, thereby meeting tissue oxygen needs. When the Hb concentration falls below 10 g/dL to 12 g/dL, and if kidney function is normal, plasma erythropoietin levels rise logarithmically in inverse proportion to the level of Hb. Under the stimulus of erythropoietin, red blood cell production can increase four- to fivefold within 1 to 2 weeks. However, this can occur only in the presence of adequate substrates, most particularly iron. In order for this feedback system to function properly, there must be normal renal production of erythropoietin, a functioning erythroid marrow, and an adequate supply of substrates for Hb synthesis. A defect in any of these key components can lead to anemia.58

Figure 1-4. Inadequate oxygen delivery to the kidney stimulates erythropoietin production. BFU-E= Burst-forming units-erythroid; CFU-E= Colony forming units-erythroid. Adapted and reprinted with permission from N Eng J Med.59

Figure 1-3. Overview of anemia diagnostic work-up using WHO anemia definitions.

“Anemia often develops early in the course of chronic kidney

disease (CKD), well before the onset of end-stage renal disease,

and then worsens as CKD progresses.”

II anemia & Chronic Kidney Disease

Key Points

• anemia is a common complication of chronic

kidney disease (CKD), develops early, and

worsens as CKD progresses.

• CKD-related anemia has multiple adverse

consequences, affecting quality of life, cognitive function, exercise capacity, immune response, and heart function.

• Early identification and treatment of CKD-related anemia to prevent serious consequences is an idea promoted as the Renal Anemia Management Period (RAMP) by concerned nephrologists.

• Benefits of anemia correction in patients with CKD include decreased morbidity, hospitalization,

and mortality; and improvement in quality of

life, exercise capacity, cognitive function, and

sexual function.

CKD: An Insidious Disease

CKD arises as a consequence of diabetes mellitus, hypertensive nephrosclerosis, chronic glomerulonephritis, polycystic kidney disease, and a host of other disorders.1 Diabetes and hypertension are the two leading causes of ESRD, accounting for approximately 43% and 27% of all new ESRD cases, respectively.2

Staging and Prevalence of CKD

The resulting estimated total of 19.5 million people in the United States who have CKD marks the disease as a major public health concern, affecting more than the number of Americans with diabetes (estimated at 17 million)8 and nearly half the number of those with hypertension (estimated at 50 million).9 Because CKD typically progresses to its most severe form, ESRD, the public health concern is underscored by the most recent data from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD). The combined 1995 to 1999 prevalence of ESRD patients was 392,847 on dialysis and 8,287 with transplants.2 Expecting this alarming trend to continue, the NIDDKD has estimated that the prevalence of ESRD will reach over half a million by 2010.10

be to slow progression through the

Anemia Common in CKD

Consequences of

CKD-Related Anemia

LVH is a common finding in patients with CKD,35-37 resulting from alterations in left ventricular wall stress caused, at least in part, by hypertension and anemia.35,36 It has been shown to progress with the degree of CKD.38 LVH is a significant risk factor for cardiovascular events independent of blood pressure in hypertensive men,38 and for cardiac and all-cause mortality in patients who require dialysis or kidney transplant.39

Early Identification of

Anemia Recommended

Concerned by the facts that anemia develops early in CKD and worsens as the disease progresses, a panel of nephrologists developed a concept called the Renal Anemia Management Period (RAMP). The RAMP model emphasizes the progressive nature of CKD and the need for timely and appropriate treatment—well before the development of ESRD—to prevent anemia and other comorbidities that can potentially lead to irreversible, physiological damage, such as LVH.40 Rather than

representing data from a specific study, the RAMP model notes trends identified in many studies.

Guidelines from the NKF-K/DOQI recommend that an anemia work-up be initiated when the Hb/Hct value declines to approximately 80% of the mean value defined for healthy, normal subgroups, as anemia is likely to be present.6 For example, in adult men and postmenopausal women with CKD, an anemia work-up should be initiated at Hb ≤12.5 g/dL (Hct <37%); in premenopausal women and prepubertal CKD patients, the corresponding levels are Hb ≤11 g/dL (Hct <33%).

The NKF-K/DOQI guidelines recommend that Hb levels in patients with ESRD be maintained between 11 g/dL and 12 g/dL. The same target Hb range (11 g/dL to 12 g/dL) has come to apply also to patients with CKD who do not have ESRD, despite a lack of studies on the long-term effects of maintaining such a Hb range in this population.

A consensus on the optimal Hb levels at varying stages of CKD has not been reached, but the current Centers for Medicaid and Medicare Services policy restricts reimbursement for the initiation of anemia treatment to Hb ≤10 g/dL, even though evidence indicates that adverse anemia-related sequelae occur at Hb ≤11 g/dL.35,36

Referral Concerns

Many of the suboptimal outcomes related to CKD may result from late referral of patients with CKD to a nephrologist. Although guidelines from the National Institutes of Health 1993 Consensus Statement on Morbidity and Mortality of Dialysis41 recommend that patients be referred to nephrologists when SCr levels rise to 1.5 mg/dL for women and 2 mg/dL for men, a 1999 US Renal Data System report10 indicated that only 20% to 25% of patients with CKD are referred to a nephrologist before they need dialysis.

Arora and colleagues42 reported that, of 135 patients with CKD followed at a major tertiary medical center, 22% were referred less than 4 months before initiation of dialysis. Compared with earlier referrals, these late referrals were more likely to have Hct <28% (55% of patients referred late vs. 33% of patients referred early) and less likely to have received treatment with epoetin (17% of those referred late vs. 40% of those referred early).

One study of 1,658 patients with elevated serum creatinine levels, conducted by Nissenson and colleagues, found that patients with CKD tended to be transferred to a nephrologist only when levels reached 4.0 mg/dL. In addition, only 7.4% of patients received epoetin, which was unlikely to be prescribed unless the patient had visited a nephrologist.43

A multidisciplinary approach may facilitate patient identification and improve the management of CKD.44 One study of CKD patients prior to ESRD demonstrated that inclusion in a multidisciplinary CKD clinic program produced greater increases in time to renal replacement therapy, Hb levels, and epoetin treatment at initiation of dialysis compared to standard nephrology care or no care.45

The proposed NKF-K/DOQI staging of CKD, coupled with the National Kidney Disease Education Program, may promote a greater sensitivity on the part of primary care physicians to be alert for CKD and its complications in patients with a GFR <60 mL/min/1.73 m2 (stage 3). The evaluation of patients at stage 3 should include the measurement of dietary energy and protein intake, weight, Hb, serum albumin, serum total cholesterol, parathyroid hormone, calcium, and phosphorus, as well as patient functioning and well-being.46

Beneficial Effects of

Anemia Management

Findings of several studies suggest that partial correction of anemia to Hb levels of 11 g/dL to 12 g/dL may decrease morbidity and reduce hospitalization and mortality among patients with CKD.26,27,47-52 Hayashi and colleagues found that 4 months of epoetin treatment increased the mean Hct and decreased the left ventricular mass index (LVMI) in CKD patients prior to ESRD,53 and similar progressive improvements were seen after 12 months. Another study of renal failure patients showed a trend of decreased left ventricular thickness and a significant decrease in LVMI as Hb levels were increased with epoetin therapy.54 Other study findings have shown that benefits of correcting anemia in patients with CKD include improvements in quality of life,51,54 exercise capacity,24,51 cognitive function,49 and sexual function.50

Since its introduction in the late 1980s, epoetin has become widely accepted as an effective and well-tolerated therapy for anemia. Its clinical benefits to thousands of patients with CKD (before and during dialysis) are well documented. Because of its relatively short half-life, however, it generally has to be administered two to three times per week.

Two large multicenter studies in dialysis patients who switched therapies demonstrated that darbepoetin alfa is as effective as epoetin in maintaining Hb levels.56,57 Similar comparability was demonstrated in a European multicenter study of CKD patients before the need for dialysis.58 In addition to less frequent dosing requirements, darbepoetin alfa appears to be well tolerated, with a safety profile comparable to that of epoetin.51,52

Table 2-1

NKF-K/DOQI Classification and Prevalence Estimates for Chronic Kidney Disease

Stages Description GFR Prevalence in Action

(mL/min/1.73m2) US Population*

(in millions)

At increased risk ≥90 N/A Screening, CKD

(with CKD risk factors) risk reduction

1 Kidney ≥90 5.9 (3.3%) Diagnosis and

damage with treatment; Treatment of

normal or ≠ GFR comorbid conditions;

Slowing progression of CVD

2 Kidney damage 60-89 5.3 (3.0%) Estimating

with mild Ø GFR progression

3 Moderate 30-59 7.6 (4.3%) Evaluating and

Ø GFR treating complications

4 Severe Ø GFR 15-29 0.4 (0.2%) Preparation for

kidney replacement therapy

5 Kidney failure <15 (or dialysis) 0.3 (0.1%) Replacement

(if uremia present)

*Adapted and reprinted with permission from NKF-K/DOQI, 2002.6 Data for stages 1-4 from the Third National Health and Nutrition Examination Study (NHANES III, 1988-1984).7 Population of 177 million adults (age ≥18 years). CKD = chronic kidney disease, CVD = cardiovascular disease. Stages 1-5 represent individuals with CKD; first row represents individuals at risk for CKD.

Figure 2-1. The RAMP (Renal Anemic Management Period) calls for timely and appropriate treatment of CKD to prevent anemia and other comorbitities.40

Figure 2-2. Anemia Work-Up for CKD Patients. Differences in average Hb/Hct values between adult men and women are likely due to differences in estrogen and testosterone production that emerge at puberty and subside after menopause.

“The adverse cardiovascular effects of anemia in chronic kidney disease have been well established. New data are now emerging to suggest this condition may represent an important treatable cause of cardiac

morbidity and mortality in patients with heart failure as well.”

III Anemia & Cardiovascular Disease

Key Points

• Anemia is a common condition that may promote or exacerbate cardiovascular disease (CVD).

• Low Hb and Hct values are associated with increased CVD morbidity and mortality in

patients with end-stage renal disease and

congestive heart failure (CHF).

• Clinical studies suggest that regression of

left ventricular hypertrophy is possible with

correction of anemia.

• Early evidence suggests that correction of anemia may improve exercise capacity and decrease adverse outcomes in patients with CHF.

• Anemia is common in elderly patients hospitalized with acute myocardial infarction, and transfusion may improve outcome.

Anemia and Cardiac Risk

Hypertension is well recognized for its role not only as an etiologic factor for cardiovascular diseases, such as myocardial infarction and angina, but also for its ability to aggravate the course of many established cardiovascular diseases. Early diagnosis and aggressive treatment of hypertension at any point has become a critical component in the prevention and management of cardiac disease. Anemia, which is often untreated or inadequately treated, is emerging as another potentially common contributor to the development and progression of cardiovascular disease (CVD).1 Although the complete picture of anemia’s role in CVD is currently unknown, hemodynamic changes brought about by this condition have cardiovascular consequences that could both predispose toward and aggravate existing cardiac disease.

Anemia and Cardiac Pathophysiology

Anemia provokes a series of cardiovascular alterations that may result in a compensatory increase in cardiac output and blood flow in the short term. These initially favorable adaptations, however, may lead to cardiac structural changes, which could predispose to CVD over time.2,3 For patients with known CVD, anemia may be particularly problematic. It is well established that anemia has adverse effects on myocardial oxygenation that result in the provocation or acceleration of angina, and anemia may worsen congestive heart failure (CHF).4

Inadequate tissue oxygenation resulting from anemia appears to be the initial trigger for a number of specific hemodynamic adjustments.5,6 Systemic arterial dilatation leads to decreased systemic vascular resistance and reduced afterload, which may improve stroke volume.7 Anemia decreases blood viscosity, which may improve venous return and thus augment preload. Anemia also activates the sympathetic nervous system, which induces an increase in heart rate.8 These changes in the heart and circulation act to raise cardiac output in the short term.

In contrast, over the long term, adaptations that initially increase cardiac output may lead to left ventricular enlargement and left ventricular hypertrophy (LVH). These two forms of cardiac remodeling predispose to heart failure and may aggravate coronary artery disease. The sustained sympathetic activation that accompanies anemia may be particularly problematic when accompanied by ventricular enlargement and LVH. Sympathetic activation is now

recognized to play a major role in the pathophysiology of heart failure and beta blockade has emerged as a major form of therapy for this syndrome.9,10

Chronic anemia may have adverse effects on the vasculature as well. Arterial hypertrophy and remodeling may occur as a result of sustained increases in cardiac output. This may reverse the early vasodilation characteristic of anemia and lead to increased systemic vascular resistance, which further contributes to the development of LVH and poor cardiac function. Early on these changes may be reversible; however, in conditions such as chronic kidney disease (CKD), they may become permanent.5

Anemia and Cardiac

Morbidity and Mortality

The adverse cardiovascular effects of anemia in (CKD) have been well established. New data are now emerging to suggest this condition may represent an important treatable cause of cardiac morbidity and mortality in patients with heart failure as well. Anemia also appears to contribute to the development of cardiac symptoms in cancer patients.

CKD

The relationship between anemia and CVD has been well established in patients with CKD. Two studies in patients with predialysis CKD, conducted by Levin and colleagues, demonstrated that anemia is an independent risk factor for the development of LVH. Specifically, decreasing Hb was associated with increasing risk of LVH. The first study showed a 6% increase in the risk of LVH for each 1 g/dL decrease in Hb.11 The second, larger study showed an even greater risk: an increase of 32% in LVH risk for each 0.5-g/dL decrease in Hb

(P = 0.004).2 This study identified three risk factors that contributed to the development of LVH in patients with CKD: Hb concentration, systolic blood pressure, and baseline left ventricular mass index. Similarly, in patients with end-stage renal disease (ESRD) undergoing dialysis, left ventricular end-diastolic volume and left ventricular mass both were found to increase with decreasing Hb levels.12 Decreasing Hb levels have also been associated with a greater risk of the development of de novo or recurrent heart failure and increased mortality in this population.3

Collins and colleagues, in their study of nearly 67,000 ESRD patients starting dialysis, demonstrated that lower Hct is associated with higher cardiac-related hospitalizations and mortality at 1 year.13 Patients with Hct <30% or 30% to <33% were found to have a significantly higher risk of cardiac death than patients with Hct ≥33% to <36% at 1 year [RR 1.74 (95% CI, 1.66-1.83) and RR 1.25 (95% CI, 1.20-1.30), respectively]. The risk of cardiac-related hospitalization was also significantly higher in patients with Hct <30% or 30% to <33% than in those with Hct ≥33% to <36% [RR 1.3 (95% CI, 1.21-1.38) and RR 1.17 (95% CI, 1.11-1.18), respectively]. Interestingly, those with Hct ≥36% to <39% had even lower cardiac-hospitalization risk than did those in the benchmark ≥33% to <36% Hct group (RR, 0.75; 95% CI, 0.71-0.82).

CHF

In the last two decades, CHF has become a serious public health problem in western industrialized countries, and its prevalence continues to increase throughout the world. An estimated 5 million patients currently suffer from this condition in the United States, with approximately 400,000 new cases reported annually.14-16 Despite treatment advances, CHF is associated with a high rate of morbidity and mortality.17-19

The incidence and prevalence of anemia in CHF patients cannot be precisely determined from existing data, but retrospective studies suggest that reduced Hb is common in this syndrome. Patients hospitalized with CHF have been reported to have a mean Hb level of approximately 12 g/dL, and it has been demonstrated that the Hb level decreases as the severity of heart failure progresses.16,17 For example, a retrospective analysis of 142 patients with CHF revealed that the prevalence of a Hb level <12 g/dL increased with the severity of the disease, reaching a prevalence of 79.1% in patients with New York Heart Association (NYHA) functional classification IV.20 In addition, endogenous erythropoietin levels have been shown to increase with increasing severity of CHF.16,18,19

Several potential mechanisms have been proposed to explain the relationship between anemia and CHF. Heart failure is often complicated by impaired renal function, which may result in decreased production of endogenous erythropoietin. Some evidence suggests that low cardiac output, especially likely in severe CHF, may impair bone marrow function.21 For example, a recent report using a mouse model demonstrated a 40% to 50% reduction in progenitor cells in the bone marrow of animals with infarcts, which appeared to be due to apoptosis, possibly induced by cytokines.22

Another potential mechanism is right-sided heart failure with passive congestion, which may cause sufficient malabsorption and nutritional deficits to result in reduced Hb.23 The use of angiotensin-converting enzyme inhibitors, while important in heart failure management, may inhibit the synthesis of endogenous erythropoietin.24 Additionally, a systemic inflammatory state with activation of cytokines is increasingly recognized as an important part of the maladaptive neurohormonal activation that occurs in CHF. Cytokines and other mediators of this systemic inflammatory response may be involved in the development and progression of anemia. Finally, the increased levels of unbound iron seen in anemia can theoretically catalyze the peroxidation of lipids, thus enhancing oxidative stress and proinflammatory responses and potentially aggravating anemia.25

Epidemiological data from several large heart failure clinical trials have demonstrated an association between anemia and adverse outcomes in this syndrome. Lower Hct and Hb values in patients with CHF have been associated with increased mortality risk. A recent retrospective analysis of the Studies of Left Ventricular Dysfunction (SOLVD) trial showed that in several thousand patients, reduced Hct was an independent risk factor for mortality.26 A retrospective cross-sectional analysis of 1,734 patients with advanced CHF, referred to UCLA Medical Center between 1983 and 1999, confirmed an inverse correlation between Hb level and mortality. In addition, a lower Hb level is associated with a greater need for urgent status for heart transplantation.27

Acute Myocardial Infarction

Many treatment advances have improved outcome in acute myocardial infarction (AMI), but this disease continues to have a high mortality risk in the elderly. The potential for anemia to worsen AMI outcome is clear, but the frequency and impact of reduced Hct in this condition had not been well investigated until the recent work of Wu and colleagues.28 These investigators noted a strong adverse association between 30-day mortality and admission Hct in a retrospective study of 78,984 Medicare beneficiaries ≥65 years. Both adjusted and unadjusted analysis suggested that patients with admission Hct values of 39.1% to 48% had a substantially lower 30-day mortality rate than did patients with lower admission Hct values. For example, the 30-day survival rate was 82.8% in patients with the highest admission Hct values, 70% for patients with admission Hct values of 30.1% to 33.0%, and 64.1% for patients with admission Hct values of 27.1% to 30%. In addition, anemia sufficient to affect prognosis was found to be much more common than previously reported. By the criteria of Hct <39%, 43.4% were anemic, and 4.2% had Hct <30%. These findings suggest that anemia may be an important and underrecognized risk factor in patients with AMI.29

Cancer

Symptomatic cardiovascular disease is not uncommon in patients with cancer. Signs and symptoms of cardiac disease in patients with cancer include exertional dyspnea, tachycardia, palpitations, and increased pulse pressure.30 Structural changes, namely cardiac enlargement and eccentric hypertrophy, have also been reported. Anemia is common in patients with cancer and appears to play a major role in the development of cardiac symptoms in patients with malignancy. The severity of these symptoms is dependent not only on the degree of anemia but also on other patient characteristics, such as age, type of malignancy, and underlying pulmonary and cardiac function.30

Beneficial Effects of

Anemia Management

CKD

A number of favorable cardiovascular effects have been observed in patients with CKD whose anemia has been treated. A recent report by London and colleagues demonstrated that treatment directed toward lowering blood pressure and reversing anemia was associated with a reduction in left ventricular mass and favorable outcomes during long-term follow-up in a cohort of 153 patients receiving dialysis.31 Augmentation of Hct to within the normal range, target 40%, was associated with significant reductions in left ventricular mass index (LVMI), a measure of LVH, that were superior to those observed with partial anemia correction, target 30% (P <0.01).32 The relationship between anemia treatment and improvements in LVMI was also observed in several small studies that used Hb as a measure of anemia.33-36

Treatment of anemia in ESRD patients undergoing dialysis has also been associated with improvements in myocardial ischemia. Results of a small study conducted by Wizemann and colleagues showed that correction of Hct from 25% to 35% led to an 81% reduction in

ST-segment depression during stress testing, as well as to significant increases in exercise duration (mean 362 s to 489 s,

P <0.01) and maximum workload achieved (mean 79 W to 104 W, P <0.01).37

CHF

Preliminary studies show that correction of mild anemia in patients with severe CHF has beneficial effects. In an uncontrolled study, Silverberg and colleagues used a combination of subcutaneous epoetin (mean dose 5,227 IU/week) and intravenous iron (mean dose 185.1 mg/week) to correct anemia in 26 patients with persistent, severe heart failure (all NYHA class III or IV).38 Treatment resulted in improvements in mean Hct (from 30.1% to 35.9%, P <0.001) and mean Hb (from 10.2 g/dL to 12.1 g/dL, P <0.001). Serum iron and iron saturation levels improved as well. Twenty-four of the 26 patients experienced functional improvement, with the mean NYHA functional class decreasing from 3.7 prior to treatment to 2.7 at the end of the study. Patients also showed improved renal function and decreased use of oral and intravenous furosemide. Furthermore, patients required fewer hospitalizations, with an overall decline in hospitalizations of 91% when compared to a similar time period prior to study treatment.

In a second controlled but unblinded study by these investigators, correction of anemia with epoetin and intravenous iron was compared to no anemia correction in 32 patients with moderate to severe heart failure. In this study, correction of anemia to a Hb level of ≥12.5 mg/dL improved NYHA functional classification (mean increase of 42%), reduced the need for oral and intravenous diuretics (91% and 51%, respectively), and reduced the number of hospitalization days by 79%. In contrast, patients with untreated anemia showed a decline in NYHA functional class (mean decrease of 11%), increased need for oral and intravenous diuretics (mean increases of 29% and 28%, respectively), and a 58% increase in hospitalizations.20

Preliminary data in a pilot study of patients with severe heart failure by Mancini and colleagues demonstrated that correction of anemia with epoetin improved exercise capacity.39 This controlled study involved 22 anemic patients (mean baseline Hb of 10.9 g/dL) with severe left ventricular dysfunction (LVEF22 ± 4%) who were randomized in a 2:1 fashion to either no treatment or 5,000 to 10,000 units of epoetin given subcutaneously per week for 3 months. From baseline to the end of study, these investigators demonstrated a significant improvement (P <0.05) in maximal oxygen consumption during exercise treadmill testing in the 14 patients who received erythropoietin therapy. In contrast, no change was found in maximal oxygen consumption during a similar period of follow-up of eight control patients. Favorable trends were also noted in the treated group on 6-minute-walk testing and assessment of quality of life by the Minnesota Living with Heart Failure questionnaire. The augmentation of exercise performance in the patients treated with erythropoietin was associated with a change in Hb from 10.9 g/dL at baseline to 14.3 g/dL after 3 months of therapy. In contrast, Hb concentration was stable in the control group.

AMI

The data of Wu and colleagues suggest that transfusion, presumably by improving anemia, may be beneficial in elderly patients hospitalized for AMI.28 Although the study was retrospective and the results must be interpreted with caution, the findings of benefit from transfusion were striking. Transfusion was associated with a reduced mortality rate in patients with Hct <30% and may be effective even in patients with Hct as high as 33%. Additional studies are needed, but these findings provide evidence that treatment of anemia may be an important component of therapy for AMI in certain patients.

Figure 3-1. Adverse cardiovascular effects of anemia.

“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 & Diabetes

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.

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 erythropoietin-producing 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 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 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

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.

Figure 4-1. As diabetes progresses the kidneys become damaged, resulting in decreased production of erythropoietin and the development of anemia.

“While fatigue is the primary symptom of anemia in cancer patients, anemia can also cause a range of other symptoms…”

V Anemia & Cancer

Key Points

• Because anemia is a common complication of cancer and its treatment, all cancer patients should be assessed for anemia.

• Anemia causes debilitating symptoms, with fatigue being the most prevalent.

• Anemia may have an adverse effect on cancer outcomes.

• Erythropoietin therapy has been shown to decrease transfusion requirements, improve quality of life, and improve cancer treatment outcomes.

Multifactoral Causes of

Cancer-Related Anemia

Many factors contribute to cancer-related anemia, some associated with the progression of cancer and others associated with cancer therapy.1 Factors likely to increase the risk of anemia include the type, stage, and duration of disease; treatment regimen and intensity; presence of infection; and the need for surgical intervention.1

Disease-Related Anemia

Anemia related to the progression of cancer can result from activation of the immune and inflammatory systems, leading to an increased release of cytokines, including tumor necrosis factor, interferon-gamma, and interleukin-1.2,3 At least three mechanisms participate in the cytokine-mediated failure of erythropoiesis: impaired iron utilization, suppression of erythroid progenitor cell differentiation, and inadequate erythropoietin production.2 Patients with cancer have been shown to have inappropriately low levels of circulating erythropoietin for their degree of anemia,4 which could reflect a disruption of homeostatic mechanisms due to the inflammatory state associated with malignancy.5 In addition, the life span of red blood cells is shortened in cancer-related anemia, and production of new cells cannot compensate for the shortened survival time.2 Bleeding from the tumor bed or bleeding due to systemic coagulopathy may also contribute to anemia in these patients.6

The prevalence of anemia due to cancer progression varies based on the definition of anemia and the type of cancer involved. A survey of 38 studies, most of which evaluated anemia prevalence in cancer patients before treatment, found that the prevalence ranged from 5% (prostate cancer) to as high as 90% (multiple myeloma).7 The prevalence of anemia appears to be especially high in patients with uterine-cervical cancers, advanced multiple myeloma, and those suffering from cancer-related renal impairment.8,9

Treatment-Related Anemia

In contrast to disease-related anemia, anemia due to chemotherapy or radiation therapy results mainly from myelosuppression, but it can also occur because of the destruction of red blood cells due to treatment.10 At least one chemotherapy drug, cisplatin, appears to blunt erythropoietin production and cause prolonged anemia,3 and repeated cycles of this and other types of chemotherapy may cumulatively impair erythropoiesis.6

A broad review of clinical trials noted that mild anemia after chemotherapy can occur in 100% of patients, and the incidence of more severe anemia can reach 80%.11 The incidence of chemotherapy-related anemia varies depending on tumor type and regimen. Cisplatin and etoposide, a combination frequently used for the treatment of non-small-cell lung cancer, causes severe anemia in 16% to 55% of patients; however, treatment of advanced colorectal cancer with 5-fluorouracil and leucovorin causes severe anemia in only 2% to 5% of patients.12

Radiation therapy can also increase the incidence of anemia in cancer patients. In one study of nearly 600 randomly selected cancer patients, radiation therapy increased the overall percentage of anemic patients from 41% before therapy to 54% after therapy.8 In patients with lung/bronchus cancer, radiation increased the prevalence from 55% to 77%, and in patients with colorectal cancer, the prevalence increased from 44% to 63%.8

Table 5-1.

CAUSES OF CANCER-RELATED ANEMIA

Neoplastic process: chronic anemia of cancer

Chemotherapy and radiation therapy

Intercurrent infections

Clonal disorders of hematopoiesis

Gastrointestinal blood loss

Autoimmune hemolysis

Microangiopathy

Excessive marrow fibrosis and displacement

Iron, folate, vitamin B12 deficiency

Renal impairment

Reprinted with permission from Semin Oncol.9

Symptoms of Anemia

Clinical Consequences of Anemia

Fatigue and Decreased Quality of Life

Cancer-related fatigue can have a profound effect on quality of life (QOL) for cancer patients. One study found that fatigue is associated with significant physical, emotional, psychological, and emotional consequences, which impact virtually every aspect of daily life.13 Vogelzang and colleagues, in a Fatigue Coalition survey of more than 400 cancer patients, noted that 61% of the patients reported that fatigue adversely affected their lives more than cancer-related pain.18

Work schedules are also affected, with Curt reporting that employed cancer patients take an average of 4.2 days off per month during or immediately after treatment, due to fatigue.13 In one study, none of the patients with low-level fatigue and high Hb levels reported the inability to work, whereas 30% of patients with low Hb levels reported that they could not work, even though they did not complain of more fatigue relative to the rest of the patient groups.14 Other side effects associated with anemia, although not necessarily with fatigue, include dizziness, headaches, dyspnea, chest pain, and decreased libido.14

Increased Mortality

Anemia also increases the risk of mortality in cancer patients. In a systematic review of 60 papers, Caro and colleagues examined the survival of cancer patients according to either Hb levels or the presence of anemia and found that the relative risk of death varied by cancer type. Overall, the presence of anemia in cancer patients increased the relative risk of death by 65% (Adjusted HRR, 1.65; 95% CI, 1.54-1.77). Anemic patients with head and neck carcinoma, and those with lymphoma experienced the greatest risk, 75% (Adjusted HRR, 1.75; 95% CI, 1.37-2.23) and 67% (Adjusted HHR, 1.67; 95% CI, 1.54-1.77), respectively.19

Decreased Treatment Efficacy

One of the ways anemia increases mortality is by influencing treatment efficacy. Anemia influences response to radiation therapy because it limits the oxygen-transporting capacity of the blood and consequently tissue oxygenation. Thus, anemia can contribute to tumor hypoxia, which makes solid tumors resistant to sparsely ionizing radiation and some forms of chemotherapy.20 Hypoxia also influences the number of cells destroyed following therapy by modulating the proliferation and cell cycle position of tumor cells.20 In contrast, well-oxygenated tumors have a greater chance of being controlled.21-23 Many studies have documented the association between anemia and poor outcome in cancers of the head and neck, respiratory tract, pelvis, and genitourinary organs.24

Pretreatment anemia has been identified in more than 40 studies as an adverse prognosticator in patients receiving radiotherapy or chemoradiation for solid tumors.22 For example, researchers studying a group of patients with head and neck cancer receiving intra-arterial high-dose cisplatin and radiation therapy found that pretreatment Hb level was significantly predictive of complete response at primary and nodal sites, local-regional failure-free survival, and overall survival.24 Findings of a study of more than 200 head and neck cancer patients indicated that moderate anemia was an independent prognostic factor for failure of local-regional control in squamous cell carcinoma of the head and neck treated with radiation therapy (RR, 1.6; 95% CI, 1.0-2.7).25 A retrospective chart review of more than 600 patients with carcinoma of the cervix found that although pretreatment anemia was not a significant predictor, Hb levels ≥12 g/dL during radiotherapy were predictive of successful treatment and disease-free survival.26

Beneficial Effects of

Anemia Management

Because of the detrimental effects of anemia on QOL and prognosis of cancer patients, treatment of anemia would be expected to improve outcomes. Findings of a number of studies have demonstrated reduced transfusion requirements and improved QOL when the anemia of cancer patients is treated with epoetin.

While transfusions are a rapid and reliable method of correcting anemia, especially in life-threatening situations, they do present risks for cancer patients. Along with allergic/febrile reactions, transfusion-associated immunosuppression may influence postoperative infection rates and long-term prognosis.9,27,28

A review of 22 trials of patients with treatment-related anemia, by Seidenfeld and colleagues, found that epoetin therapy reduced the percentage of patients transfused by 7% to 47%.29 In a controlled trial of 375 patients, Littlewood and colleagues noted significantly decreased transfusion requirements in patients receiving nonplatinum chemotherapy and epoetin compared to those receiving only the chemotherapy (P = 0.006).30 Dunphy and colleagues found a 50% reduced need for transfusions in patients treated with epoetin compared to those not receiving the therapy, in a randomized controlled study of 30 patients with advanced head and neck or lung carcinoma who were treated with paclitaxel and carboplatin.31 The effect appears to occur regardless of whether patients are undergoing chemotherapy. According to findings by Quirt and colleagues, when 401 anemic patients were administered epoetin, the need for transfusions decreased, both in the 218 patients receiving chemotherapy and the 183 patients not receiving chemotherapy.32

Epoetin treatment has also been found to improve QOL in cancer patients. In a randomized study of 180 patients with anemia due to hormone-refractory prostate cancer, Johansson and colleagues observed that epoetin therapy improved QOL, physical functioning, and fatigue in many of the treated patients.33 Quirt and colleagues found that, regardless of whether patients were receiving chemotherapy, Hb levels increased with administration of epoetin, and these increases were positively correlated with improved QOL.32 Glaspy and colleagues reported that mean energy level increased by 38%, activity increased by 32%, and overall QOL increased by 24% in over 1,000 patients with nonmyeloid malignancies who received 4 months of epoetin therapy while undergoing chemotherapy.34 In their controlled study of 375 patients receiving nonplatinum chemotherapy, Littlewood and colleagues determined that compared with those receiving placebo, the patients treated with epoetin showed increased Hb levels (P <0.001) and improvement in a number of QOL domains, including energy level, fatigue, and ability to perform daily activities (P <0.01).30 Similarly, Demetri and associates reported that Hb values increased and were associated with improved activity level, energy, and overall well-being in patients receiving epoetin therapy.35

In 89 anemic patients with nonmyeloid malignancies who were not receiving chemotherapy, Smith and colleagues found that darbepoetin alfa was well

12-week study involving 122 anemic patients with solid tumors who were receiving multicycle chemotherapy, the same researchers recently compared the efficacy of darbepoetin alfa to epoetin alfa. Patients were randomized to receive darbepoetin alfa in a 4-week front load phase followed by an 8-week maintenance phase that involved less frequent dosing or epoetin alfa at 40,000 units per week as a starting dose. After 12 weeks, 61% of patients treated with darbepoetin alfa responded to treatment compared to 49% of the patients treated with epoetin alfa, even when doses were increased to 60,000 units per week for those patients whose initial responses were inadequate. Darbepoetin doses were not increased for patients who did not respond.44

Darbepoetin alfa is currently undergoing FDA review for use in the treatment of anemia in cancer patients receiving chemotherapy.

“Anemia has been associated with progression to AIDS and

shorter survival times for HIV+ patients.”

VI Anemia & HIV/AIDS

Key Points

• Multiple factors, both disease-related and

treatment-related, can cause anemia during

HIV infection.

• Although some HIV drugs may increase the risk of anemia, HAART may prevent or ameliorate anemia in HIV+ patients.

• The prevalence of anemia is higher in HIV+ patients with more severe disease.

• Anemia has been associated with shorter survival times and diminished quality of life in HIV+ patients.

• Management of anemia has been shown

to improve survival and quality of life in

HIV+ patients.

Multiple Factors Contribute to Anemia

Multiple factors, both disease-related and treatment-related, can cause anemia during HIV infection. HIV plasma viral load appears to correlate inversely with all hematologic values, suggesting a causative role of HIV in hematologic disorders.1 The disease can cause anemia by influencing cytokine production and suppressing hematopoiesis; decreasing erythropoietin concentrations; and increasing the risk of opportunistic infection with agents, such as Mycobacterium avium complex and parvovirus B-19.2

HIV infection also causes immunosuppression. In a recent longitudinal study of 797 HIV-infected patients, Semba and colleagues demonstrated that a CD4+ T-lymphocyte count <200 cells/µL is independently associated with the development of anemia. In the period prior to the widespread use of highly active antiretroviral therapy (HAART), 1993 to 1996, patients with CD4+ counts <200 cells/µL had an 86% increased risk of developing anemia (OR, 1.86; 95% CI, 1.51-2.30). Moreover, this study noted that this relationship was maintained in the first years of the HAART era, 1996 to 2000 (OR, 1.62; 95% CI, 1.35-1.94).3

Less common mechanisms for HIV-associated anemia include vitamin B12 deficiency and the autoimmune destruction of red blood cells.2,4 According to findings of a cohort study of about 200 consecutive HIV+ patients, circulating autoantibodies to endogenous erythropoietin were present in about a quarter of the patients, and this subgroup was at a 5- to 10-fold increased risk of anemia compared to HIV+ patients without autoantibodies.4

In addition to anemia caused by

disease, therapies used to treat HIV have been implicated as a cause of anemia. Sullivan and colleagues found in their study of nearly 33,000 HIV+ patients that 22% of those diagnosed with anemia were identified by physicians as having treatment-related anemia.2 Many HIV therapies have significant myelotoxic side effects, with the nucleoside reverse transcriptase inhibitor zidovudine (AZT) generally considered to be more myelotoxic compared with other drugs in its class and the protease inhibitors.5 In the pre-HAART era, AZT at a dose of 600 mg/day was associated with transfusion-dependent anemia in approximately 30% of patients with AIDS and 1% of patients with asymptomatic HIV disease.6 In the study by Semba and colleagues, patients taking AZT in the pre-HAART era had a 28% greater chance of developing anemia than those not taking the drug (OR, 1.28; 95% CI, 1.05-1.56). This association, however, did not hold true in the HAART era (OR, 1.02; 95% CI, 0.87-1.22).3

Didanosine (ddI) and stavudine (d4T) have been associated with anemia as well, but less frequently and less strongly than AZT.2,7 Lamivudine (3TC) has also been associated with anemia, although primarily in conjunction with AZT.8,9 Interestingly, however, a case report has suggested that 3TC without AZT can cause anemia.10

Several reports indicate that HAART prevents or ameliorates anemia in some HIV+ patients.1,11,12 Servais and colleagues have shown that HIV-associated hematologic disorders improve with HAART regimens containing at least one protease inhibitor.1 Another report notes that prior to the introduction of HAART, anemia developed in close to 90% of HIV+ patients, but that the prevalence of anemia in the HAART era has decreased to about 46%.11 However, according to a longitudinal study of 2,078 HIV+ women, improvements in anemia are negated when AZT is included in the HAART regimen.12

While not proving cause and effect, some studies have shown that HIV/AIDS patients with anemia are more likely to demonstrate certain characteristics than those without anemia. One longitudinal study of over 1,100 HIV+ and HIV- women, who were enrolled between 1993 and 1995 and followed for at least 2 years, noted that factors associated with an increased risk of anemia were African American race, increased age, lower body mass index, history of pneumonia, oral candidiasis, CD4+ count <200 cells/µL, history of fever, and zidovudine use.3 Similarly, findings of another study of more than 2,500 HIV+ and HIV- women, enrolled between 1994 and 1995, indicated that factors predicting anemia in HIV+ women included African American race, mean corpuscular volume <80 fL, CD4+ count <200 cells/µL, increased HIV RNA in plasma, current use of zidovudine, and history of clinical AIDS.13 HIV- women who were African American and/or had low MCV values were also at increased risk for anemia. Thus, numerous factors related to genetics, disease progression, and treatment may contribute to the anemia associated with HIV/AIDS.

Anemia Prevalence Increases with Disease Progression

In general, patients who are in the beginning stages of HIV infection have a lower prevalence of anemia than those with more advanced stages of the disease. For example, the Multistate Adult and Adolescent Spectrum of HIV Disease Project, which evaluated nearly 33,000 patients between 1990 and 1996, identified anemia in 28% of men with HIV infection, in 55% of men with AIDS due to a CD4+ count <200 cells/µL, and in 87% of men with AIDS due to the presence of opportunistic infections.2 A similar trend of increasing prevalence of anemia with progression of HIV disease was also observed in women.2 Findings of a study of nearly 800 HIV+ women found that the prevalence of anemia at enrollment (between 1993 and 1995) was 28.1%. The cumulative incidence of anemia in this study over a 5.4-year follow-up was more than 60%, with higher rates of anemia seen in patients with lower CD4+ counts (P <0.0001).3 The EuroSIDA study, a European prospective observational study of 6,725 patients enrolled during the HAART era, showed that 59.6% of HIV+ patients evaluated were anemic and that Hb levels correlated with CD4+ counts (P <0.0001).14

Anemia Associated with Increased Morbidity and Mortality

Anemia has been associated with progression to AIDS and shorter survival times for HIV+ patients.15 In the Multistate Adult and Adolescent Spectrum of HIV Disease Surveillance Project, lower Hb levels were associated with decreased survival at all levels of CD4+ counts.2 In HIV+ patients with a CD4+ count of ≥200 cells/µL at the beginning of the survival analysis, the risk of death for those with anemia was 48% greater than for those without anemia (OR, 1.48; 99% CI, 114%-188%). For patients whose CD4+ count was <200 cells/µL, the risk of death for those who developed anemia was 56% greater than for those without anemia (OR; 1.56, 99% CI, 43%-71%). Additionally, for patients who did not recover from anemia, the risk of death was 70% greater than for those who did recover (OR; 1.70, 99% CI, 132%-203%).

The EuroSIDA study also evaluated Hb level and its association with mortality in more than 6,700 HIV-infected patients.16 At 12 months after recruitment, the proportion of patients estimated to have died was 3.1% for patients without anemia, 15.9% for patients with mild anemia, and 40.8% for patients with severe anemia. Although severe anemia was present in only 1.4% of the patients at the time of recruitment, it was associated with a much faster rate of disease progression. Among patients with similar viral load and CD4+ counts, Hb value was a strong independent predictor of death.16 Furthermore, the Multicenter AIDS Cohort Study, a prospective pre-HAART study of more than 700 AIDS-free patients initiating AZT therapy, identified baseline levels of CD4+ lymphocytes, platelets, and Hb as significant predictors of AIDS and death.17

In addition to influencing disease progression and mortality, HIV-related anemia dramatically influences quality of life (QOL), especially because of its contribution to fatigue,18,19 and it also appears to increase the requirement for transfusions.20,21

Beneficial Effects of

Anemia Management

The effects of anemia on morbidity and mortality suggest that anemia management may dramatically benefit HIV+ patients and that treatment of anemia improves survival rates in patients with HIV disease.21,22

An important step in the treatment of anemia in HIV+ patients is to address and correct the underlying cause of the anemia (eg, infection, tumor, hemolysis, drugs).23,24 However, if immediate treatment is warranted or anemia persists, then several non-mutually exclusive options should be considered.

Transfusions may be indicated in the setting of acute hemorrhage; however, this approach is not without potential risks.25 A retrospective study of 2,348 HIV+ patients has demonstrated that blood transfusions are independently associated with an increased risk of death.22 Other study findings have shown that blood transfusions may transiently increase HIV RNA levels,26 increase the risk of opportunistic infections,27 transmit blood borne infections, result in adverse reactions secondary to blood borne product incompatibilities, and cause iron overload.25

Initiation or continuation of HAART without AZT or HAART with a lower dose of AZT is another option,24 as HAART has been shown to ameliorate anemia in many HIV+ anemic patients.1,11,12

Erythropoietin therapy may be appropriate for selected HIV+ patients, in particular those with baseline endogenous serum erythropoietin levels ≤500 IU/L.28,29 A review of four 12-week randomized controlled trials noted that administration of epoetin to HIV+ patients with anemia results in an increase in mean Hct and a decrease in transfusion requirements.29 Use of epoetin is also associated with a decreased risk of death for HIV+ patients with anemia. In one retrospective study, 91 HIV+ patients who received epoetin were found to have a decreased hazard of dying (RH, 0.57; 95% CI, 0.40-0.81).22

Anemia management may also improve QOL in HIV+ patients. By increasing Hb levels, anemia management can decrease fatigue. In one open-label observational study involving 251 anemic AIDS patients receiving epoetin, researchers analyzed 12 QOL indicators, such as energy level, fatigue, and the ability to be cared for at home.30 After 12 and 24 weeks, patients who responded to epoetin had significantly better scores for several QOL indicators compared to nonresponders. Similarly, in a combined analysis of four randomized, double-blind, controlled clinical trials of AIDS patients receiving AZT, epoetin responders showed significant increases in a number of QOL measures after 12 weeks of treatment.29 Abrams and colleagues, who conducted a 4-month open-label, nonrandomized trial assessing the effect of epoetin on the QOL of 221 HIV+ patients, found that transfusion requirements were significantly reduced, from 20% to 5% (P <0.01), and mean total QOL scores improved significantly

(P <0.05) after epoetin administration.20

As treatment for HIV/AIDS improves and lifespan increases among these patients, the need for awareness of anemia will also increase. Management of anemia has been shown to improve not only survival rates, but also the QOL of HIV/AIDS patients.

Table 6-1 Risk Factors In HIV+ Patients

CD4+ counts <200 cells/µL

MCV <80 fL

African American race

Increased age

Lower body mass index

Oral candidiasis

History of clinical AIDS

History of pneumonia

History of fever

Zidovudine use

Increased HIV RNA in plasma

3, 13

“Anemia is the most common extra-articular manifestation of rheumatoid arthritis, estimated to occur in 30% to 60% of patients.”

VII Anemia & Rheumatoid Arthritis

Key Points

• Anemia is common in rheumatoid arthritis

(RA) and may constitute an important clinical problem for many patients.

• The two primary types of anemia in patients with RA are anemia of chronic disease and iron deficiency anemia.

• Erythropoietin therapy in combination with iron supplementation corrects anemia in most patients with RA, and may improve RA outcomes and quality of life.

• Erythropoietin is useful in facilitating autologous blood donation prior to elective surgery for patients with RA and in reducing transfusion requirements.

RA: A Chronic Inflammatory Disease

Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects an estimated 2.1 million Americans.1 Although patients who meet diagnostic criteria for RA for less than 6 months may enjoy a spontaneous remission,2,3 patients with persistent inflammation over a year or longer generally have a chronic progressive disease.4-6 Most patients with RA experience joint destruction, radiographic damage, functional declines, work disability after 10 years of disease,7,8 and premature death by 10 to 15 years.4,9

RA remains a source of significant morbidity in the United States, estimated to involve costs of 1% of the gross domestic product,10,11 much of which are indirect costs secondary to work disability.12 The goal of therapy is to control inflammation in order to prevent long-term joint damage.13-16 The variables that best identify and predict severe outcomes, including work disability, high costs, and premature mortality, are poor functional status, comorbidities, old age, and low socioeconomic status, and, to a lesser degree, high radiographic scores and rheumatoid factor titer.6

Anemia Common in RA

Impact of Inflammatory Cytokines

Treatment of Anemia in RA

Antirheumatic Drugs

The first principle of treating anemia in RA is to reduce inflammation to as low a level as possible with disease-modifying antirheumatic drugs (DMARDs),13-16 using methotrexate as an anchor drug in combination with additional DMARDs and biologic agents, including leflunomide, etanercept, infliximab, and anakinra.33 Treatment of patients with RA with infliximab (an anti–TNF-µ agent) and anakinra

(an IL-1 receptor antagonist) led to improvement in anemia not seen in patients treated with placebo,34 although improvement of clinical features of RA was not correlated significantly with improvement of anemia.

Iron Supplementation

Erythropoietin Therapy

Erythropoietin therapy is effective in correcting anemia of chronic disease in patients with RA.37,40,41 However, the doses of erythropoietin required are higher than those needed by patients with anemia from noninflammatory

causes, such as renal failure.

In most early studies, the increase in Hb levels was not accompanied by improvement of functional status, as measured by capacity to perform activities of daily living and pain scores on patient questionnaires.42-44 As in the studies noted above, patients who were treated with epoetin generally required high doses of iron to maintain erythrocyte production. When the erythropoietin was discontinued, the Hb level declined.

More recent studies have indicated that treatment of patients with RA with epoetin does lead to functional improvement. Peeters and colleagues noted that patients with RA who were treated with epoetin experienced improvement in joint tenderness and swelling, in addition to improvement in Hct.40,41 Another report noted improvement in Nottingham Health Profile scores for energy in patients treated with epoetin.20 Kaltwasser and colleagues found that combined treatment with epoetin and intravenous iron in patients with RA with anemia of chronic disease led to increased Hb levels, decreased disease activity, and improved quality of life (decreased fatigue and increased vitality and muscle strength).37 The beneficial effects of anemia treatment with epoetin appear to extend to children with juvenile RA, improving both quality of life and growth rates in children who are still in their growing phase.45

Treatment with epoetin may also facilitate autologous blood donation by patients with RA prior to total hip or knee arthroplasty.21,46-48 This therapy has also been shown to reduce transfusion requirements in patients with RA who undergo elective joint replacement surgery.33,48,49

Figure 7-1. Patients with RA exhibit a blunted erythropoietin response compared to patients without RA. Adapted and reprinted with permission from Brit J Hematol.17

“Preliminary data suggest that anemia in inflammatory bowel

disease (IBD) correlates with disease severity and that anemia treatment may improve IBD outcomes.”

VIII Anemia & Inflammatory Bowel Disease

Key Points

• Anemia affects many patients with inflammatory bowel disease (IBD).

• Multiple factors contribute to anemia in patients with IBD, including blood loss, inadequate nutrient intake/absorption, and the underlying inflammatory disease process.

• Early evidence suggests that there is a relationship between anemia, disease severity, and quality of life in patients with IBD.

• Erythropoietin therapy may be useful in treating the anemia associated with Crohn’s disease and ulcerative colitis.

Inflammation and Anemia

The etiology of inflammatory bowel disease (IBD) is multifactoral. Chronic blood loss from the colon and intestines, along with poor nutrient and iron absorption, can lead to iron deficiency anemia.1 A number of inflammatory cytokines, such as tumor necrosis factor-a, interferon-g, interleukin-1a,

and interleukin-1b, contribute to disease progression.2,3 As with rheumatoid arthritis, it is likely that in addition to causing the characteristic signs and symptoms of IBD, these cytokines trigger anemia of chronic disease.

The enhanced production of these proinflammatory mediators may both inhibit the production of erythropoietin and the stimulatory effect of erythropoietin on the proliferation and maturation of erythroid precursors.4 When Schreiber and colleagues performed a linear regression analysis of serum erythropoietin levels measured prior to treatment in 52 IBD patients with anemia, 18 patients with anemia but no IBD, and 24 healthy volunteers, they found that patients with anemia and IBD had inadequate serum erythropoietin levels in relation to the degree of anemia they exhibited.4

Anemia in IBD

Many of the more than 1 million people in the United States who have IBD5 also suffer from anemia. Although the exact number of IBD patients with anemia is not known, prevalence reports suggest that anemia may actually be very common among patients with ulcerative colitis and Crohn’s disease. Researchers assessing anemia in patients with Crohn’s disease have reported its presence in 10.2% to 72.7% of patients,3,4,6-12 whereas those who limited their study to patients with ulcerative colitis have reported anemia in 8.8% to 73.7% of patients.4,7,13-16 In studies where the type of IBD was not specified, the prevalence ranged from 17.5% to 41.3%.17,18

Beneficial Effects of

Anemia Management

Preliminary data suggest that anemia in IBD correlates with disease severity4 and that anemia treatment may improve IBD outcomes.19 Schreiber and colleagues reported a significant relationship between anemia and clinical disease activity in a study of 334 patients with Crohn’s disease, 25% of whom were anemic, and 332 patients with ulcerative colitis, 37% of whom were anemic (P = 0.02 and P = 0.04, respectively).4 Their findings showed that the presence of anemia was associated with significantly higher scores on disease activity indices and that lower Hb concentrations were associated with higher levels of interleukin-1b (P = 0.007). Treatment of anemia with epoetin plus oral iron improved Hb concentrations to a greater extent than iron alone in these patients; however, the effect on disease outcomes was not reported.

Similarly, Gasché and colleagues showed that erythropoietin therapy effectively treats anemia in both patients with Crohn’s disease19 and those with ulcerative colitis.20 Furthermore, they examined the effects of anemia treatment with intravenous iron saccharate plus either epoetin or placebo in 40 patients with severe anemia (Hb ≤10.5 g/dL) and Crohn’s disease.19 The group that received epoetin showed significant increases in Hb levels (P = 0.004). Anemia correction in these patients improved scores on the Crohn’s Disease Activity Index, primarily due to changes in Hct and general well-being levels. The epoetin-treated patients also demonstrated significant positive changes (P = 0.020) in quality of life indicators, primarily attributed to improvements in physical ability, social activities, mood, and feeling of well-being.

Erythropoietin therapy may also benefit children with IBD. Dohil and colleagues showed that the administration of epoetin three times weekly to three children with Crohn’s disease and anemia corrected Hb concentrations to within normal within 6 to 12 weeks.21 Anemia correction in these patients was associated with improved appetite, and less lethargy and irritability.

Figure 8-1: Patients with IBD and anemia exhibit a blunted erythropoietic response compared to non-IBD controls. Adapted and reprinted with permission from N Engl J Med.4

“While combined-therapy dose reduction or treatment discontinuation has been shown to alleviate hemolytic anemia in some patients, the use of erythropoietin may achieve the same goal.”

IX Anemia & Hepatitis C

Key Points

• Hemolytic anemia is a major side effect of ribavirin therapy in patients with hepatitis C.

• Pernicious anemia may be induced in patients with hepatitis C by long-term

interferon therapy.

• Erythropoietin therapy may be useful in

managing anemia in patients with hepatitis C.

HCV Infection Common

Hepatitis C virus (HCV) infection is the most common chronic blood borne infection in the United States. Although the incidence of HCV infection has declined to 36,000 new infections per year since 1996,1 an estimated 3.9 million Americans are or have been infected.1 Of those, 2.7 million are chronically infected.2

HCV is primarily transmitted by large or repeated direct percutaneous exposures to blood, such as by injection drug use, which currently accounts for most HCV transmission in the United States.1 Coinfection of HIV patients with HCV is a serious clinical problem, occurring in approximately one quarter of HIV patients.3 Other risk factors associated with transmission of HCV include employment in patient care or clinical laboratories, exposure to an infected sex partner or multiple sex partners, and low socioeconomic level.

Before the 1990s, transfusions contributed substantially to the incidence of HCV infections, but improved screening practices have lowered the incidence to a negligible rate of about 1 in 100,000 per unit transfused.4 In dialysis patients, however, infections are common, with the prevalence of HCV infection ranging from 10% to 30%.5

Treatment for HCV Infection

Two regimens have been approved for the treatment of HCV infection in the United States: monotherapy with alpha interferon and combination therapy of alpha interferon and the oral antiviral agent ribavirin.6 Studies of patients treated with combination therapy have demonstrated a substantial increase in sustained response rates, about 40% to 50%, compared with response rates of 15% to 25% with alpha interferon alone.7 Pegylated forms of interferon, which have a prolonged half-life and a lower rate of clearance compared to unmodified interferon, are now being used with ribavirin, and this combination is becoming the standard of care.8

Ribavirin-induced Hemolytic Anemia

While combined therapy has proven more effective than monotherapy for patients with HCV infection, hemolytic anemia is a major side effect of therapy with ribavirin. Hct values generally reach their lowest values within 2 to 3 weeks after therapy has commenced.8

Anemia associated with ribavirin treatment has been attributed to the accumulation of ribavirin triphosphate in erythrocytes, which interferes with cells’ function.9 Ribavirin causes red cell hemolysis to a variable degree in almost all patients6 and necessitates dose reduction in an estimated 7% to 9% of patients receiving combination therapy.10,11 Consequently, patients with preexisting hemolysis or anemia (Hb <11 g/dL or Hct <33%) should not receive ribavirin. Similarly, neither should patients who have significant coronary or cerebral vascular disease, since anemia caused by treatment can trigger significant ischemia.6

Little is known about the variables influencing hemolytic anemia in patients treated for HCV infection, but a recent study of 244 chronically infected HCV patients indicates that ribavirin-induced hemolysis is significantly influenced by three factors: pretreatment platelet level (P = 0.01), the amount of alpha interferon administered (P = 0.001), and the haptoglobin phenotype (P = 0.01).12 Haptoglobins bind to Hb and are present in three phenotypes that have differing binding properties. In this study, Van Vlierbergh and colleagues found that anemia occurred in 67% of the patients. Patients who began therapy with lower platelet counts had a significantly higher drop in Hb level with treatment than those with higher counts. Low platelet counts were especially common in older male patients with cirrhosis, which appeared to be a risk factor for ribavirin-induced anemia. Alpha interferon, known to be myelosuppressive when given in higher doses, also contributed to anemia in patients receiving high doses.13 As a potential explanation for the third factor influencing anemia in these patients, haptoglobin phenotype, the researchers suggest that there are differences in uptake or competition in uptake of ribavirin between the different haptoglobin phenotypes.11

Pernicious Anemia in

Patients with HCV

The immunomodulatory effects of interferon therapy may induce pernicious anemia.14 Although the association between HCV infection and pernicious anemia has not been well studied, reports indicate that the longer-term schedules of interferon, used for treatment of cancer, induced pernicious anemia in some patients.13 Careful monitoring of these effects in long-term HCV maintenance therapy appears to be necessary, whether interferon is used alone or in combination with ribavirin, as the drugs may contribute to pernicious anemia.

Management of Anemia in

Patients with HCV

While combined-therapy dose reduction or treatment discontinuation has been shown to alleviate hemolytic anemia in some patients,10 the use of erythropoietin may achieve the same goal. A few clinicians have explored the use of epoetin, primarily in patients undergoing liver transplants.14-17 A recent Swedish pilot study investigated epoetin’s use in dialysis patients undergoing combined interferon-ribavarin therapy. The study was conducted in patients with chronic HCV infection, of whom five were receiving hemodialysis and one was receiving peritoneal dialysis. The results showed that ribavirin-induced hemolytic anemia could be managed with high doses of epoetin (20,000 to 30,000 IU/week), and close monitoring of plasma ribavirin and Hb concentrations.15

The direct cost of treating clinically significant ribavirin-induced hemolytic anemia is low in comparison to the cost of treatment with combination therapy. In a review of the literature, Devine and colleagues estimated the costs at 1% of total drug treatment costs.16 In their review of 26 studies, they included three studies17-19 in which epoetin was used 11% of the time, mainly in patients undergoing liver transplants. In these patients, the erythropoietin therapy increased the average cost slightly, but it still accounted for only 1.7% of the total drug treatment costs.

Multiple Causes of Anemia

in Surgical Patients

Anemia is a concern for the surgical patient in two phases of treatment: before surgery and in the immediate perioperative period, which includes both the surgery itself and the time spent in the hospital during postoperative recovery. Surgery patients may develop preoperative anemia from acute or chronic blood loss (eg, trauma or peptic ulcer oozing), iron deficiency caused by poor nutrition or menstrual bleeding, renal insufficiency, malignancy, or chronic disease (eg, rheumatoid arthritis or inflammatory bowel

disease).1,2

Catastrophic bleeding during surgery may occur, but this is uncommon and usually can be controlled before significant anemia develops. Coagulation defects, either congenital or acquired, such as trauma-induced disseminated intravascular coagulation, may lead to anemia. Frequent phlebotomies and untreated bleeding episodes can also cause blood loss and contribute to anemia during surgery and recovery.2 Furthermore, after surgery, the erythropoietic response may be severely blunted in anemic patients because of diminished iron availability and the inhibitory actions of inflammatory cytokines.1 Reduced red cell life span and occult gastrointestinal bleeding may also contribute to anemia in surgical patients.

Anemia Prevalence Varies

in Surgical Patients

It is difficult to estimate an overall prevalence of anemia in surgery patients, in part because of variations among patients undergoing different types of surgery as well as the variability in investigators’ anemia definitions. A recent review of the literature found 10 studies reporting the prevalence of anemia among surgery patients.3 In these studies, the prevalence ranged from a low of 5% (in female geriatric hip fracture patients) to almost 76% (in patients with Dukes’ stage D colon cancer). Clemens and Spivak found that 56% (49% of the women and 63% of the men) in a group of 84 elective surgery patients were anemic before surgery. Moreover, 66% of the women and 88% of the men were anemic after surgery. On postoperative day 5, the anemia frequency increased to 90% (80% of the women and all of the men), probably due to a blunted erythropoietic response.4 Dunne and colleagues recently reported that 33.9% of 6,301 patients scheduled for noncardiac surgery were anemic before surgery and 84.1% were anemic in the postoperative period.5

Some patients may be more susceptible than others to perioperative anemia. Clemens and Spivak reported that female or African American patients were more susceptible to surgery-induced suppression of erythropoiesis.4 In a study of nearly 7,000 patients undergoing coronary artery bypass graft (CABG) surgery, DeFoe and colleagues found that female patients and those with smaller body surface area were at increased risk of anemia compared to males and larger patients.6 Gruson and colleagues found that 180 of 395 patients (45.6%) who entered their hospital for repair of a hip fracture were anemic, suggesting that recent blood loss from a hip fracture may be superimposed on chronic anemia.7

Increased Postoperative

Risk of Anemia

Findings of several studies suggest that perioperative anemia may increase the risk of postoperative morbidity and mortality.8-10 However, the exact relationships among preoperative, intraoperative, and postoperative factors and how to measure anemia remain unclear. Below-normal preoperative Hb levels may or may not be a deciding factor.

Carson and colleagues demonstrated that the degree of anemia as measured by Hb and Hct values was associated with postoperative mortality in the nontransfused patient.11 However, in the same patients the research group showed that the amount of surgical blood loss was more important than preoperative Hb or Hct value.12 Upon analysis of a larger patient population, these researchers found that among patients with low preoperative Hb (<6 g/dL), the risk of death was more pronounced in those with cardiovascular disease than in those without (interaction P <0.03).13 Subsequent analyses have called into question the validity of preoperative Hb and Hct values as predictors of outcome other than an increased need for transfusion.14-16

Other researchers have shown that preoperative Hb and Hct values can be used as predictors of outcome for specific types of patients, namely those undergoing CABG or orthopedic surgery.17,18 The Northern New England Cardiovascular Disease Study Group has shown an association between nadir Hct during cardiopulmonary bypass and postoperative morbidity and mortality in 6,980 patients who underwent CABG.6 Female patients and those with a smaller body size were most susceptible to low intraoperative Hct, suggesting that excessive hemodilution may contribute to this problem. This same group previously showed that hemorrhage leading to re-exploration after CABG was associated with increased mortality, as one would expect.19 The findings of another study, which involved nearly 1,000 patients undergoing CABG, revealed that a measure combining age and red blood cell volume was an important determinant of postoperative morbidity, as indicated by either serious complications or increased length of hospital stay. The researchers concluded that older patients with preoperative anemia, low blood volume, and comorbidities were at increased risk for postoperative complications.8

Dunne and colleagues point out the clinical significance of perisurgical anemia by demonstrating a statistical relationship between anemia and increased morbidity, mortality, and length of stay.5 Overall length of stay and mortality up to 12 months after surgery were higher in the anemic group of patients in Gruson and colleagues’ study of hip fracture patients.7

In addition to influencing survival and morbidity in surgical patients, perioperative anemia may adversely affect quality of life (QOL), especially because of its contribution to fatigue.20,21

Of particular relevance to surgery patients is the relationship between lowered Hb levels and the safety of general anesthesia. Some patients with lower perioperative Hb levels may be at increased risk of hypoxemia; therefore, the issue of safety should be considered in anemic patients undergoing anesthesia.22 Anemia might also be one of several factors that can contribute to delirium during surgery.23 In addition, red blood cells might play an important role as a supplier of phospholipids in the blood coagulation pathway; thus, anemia could represent a risk factor for hemorrhagic tendency.24

Presurgical Strategies to

Correct Anemia

Multiple strategies can be used to correct perioperative anemia. These include allogeneic blood transfusion, the use of single transfusion alternatives, or combinations of the alternatives.25,26 Allogeneic blood transfusion should be avoided whenever possible, not only because of associated risks but also because transfusion has not been proven to improve postoperative outcomes.27 Transfusion risks include reactions, disease transmission, and immunomodulation.28,29 Transfusion decisions must focus on patient characteristics, not Hb or Hct values alone.30

The simplest approach is to avoid transfusion regardless of the level of preoperative anemia. This may be necessary in emergency cases or in patients who refuse transfusion. Ott and Cooley’s landmark report of successful cardiac surgery without blood transfusion in 542 Jehovah’s Witness patients was the first demonstration that surgery could be done using this strategy without excessive blood loss or mortality.31 The sine qua non of success using this approach is meticulous surgery to eliminate or reduce operative blood loss. This strategy entails accepting a lowered transfusion threshold, or trigger, and has been proven to be safe by several surgical groups.25,32,33 The use of autologous blood either through preoperative donation or autotransfusion to return shed blood is also helpful.28,29

In surgeries with an expected high blood loss (>1,000 mL), one of the major anesthetic techniques for avoiding allogeneic blood use is acute normovolemic hemodilution (ANH). ANH is a procedure that reduces the patient’s red blood cell mass by the controlled removal of whole blood and the simultaneous replacement with colloid, crystalloid, or both to maintain essential adequate circulatory volume. The purpose of ANH is to avoid allogeneic blood transfusions during and after surgery. ANH is a point-of-care technique that results in acute anemia, decreased blood viscosity, and preserved tissue perfusion.34

While ANH is one cornerstone, other necessary blood conservation practices are pharmaceuticals (primarily erythropoietin plus iron) for enhancing Hb production, preoperative autologous donation, minimally invasive surgical techniques, new techniques for hemostasis, the staging of difficult surgical procedures, and intraoperative cell salvage. These are used selectively or in combination. Along with these specific techniques, a reasoned approach is necessary for a greater understanding of the implications of tolerating acute anemia.

Preoperative anemia often goes unrecognized and untreated unless the surgeon makes a particular effort to order Hb and Hct tests for review in advance of a planned operation. Therefore, the first step to be taken with the anemic patient is to establish the presence of the problem early enough to do something about it, if the risk is to be decreased by avoiding allogeneic blood.

Although alternative therapies have their own risks, these are typically minimal when compared to transfusion. Autologous predonation can be very effective in reducing reliance on allogeneic blood, but it has been shown to increase overall exposure to transfusion and to increase the chance of perioperative anemia.28,29,35 This problem can be avoided by the use of iron replenishment and erythropoietin to facilitate autologous blood procurement before surgery.36-38

Use of erythropoietin alone may eliminate the need for transfusion in some surgical patients, but when transfusion is indicated, the most effective approach may be to combine preoperative erythropoietin administration with procurement of autologous blood by methods such as ANH.39

Erythropoietin use is also helpful in the postoperative period because it accelerates Hct recovery.40 Erythropoietin has also been used in bloodless surgery, protecting patients from the possible hazards of allogeneic blood transfusion.1,21,41,42 In addition to reducing the need for transfusion, management of anemia with erythropoietin has been shown to accelerate erythropoiesis and to enhance QOL in surgery patients.43,44

Beneficial Effects of

Anemia Management

Early recognition of anemia allows the surgeon to offer patients proven, safe alternatives to allogeneic blood, thereby reducing risk. Blood transfusion has not been shown to reduce morbidity and mortality in surgical patients, but alternatives such as erythropoietin have. Sound management of anemia with combinations of alternatives avoids risk and appears to provide better outcomes.

Figure 10-1. Preoperative anemia is common, and prevalence dramatically increases

postoperatively.4,5

“Failure to evaluate anemia in the elderly could lead to delayed diagnosis of potentially treatable conditions.”

XI Anemia & Aging

Key Points

• Anemia is not a normal consequence of aging.

• Failure to evaluate anemia in the elderly could lead to delayed diagnosis of potentially treatable conditions.

• Untreated geriatric anemia is associated with increased mortality, increased prevalence of various comorbidities, and decreased function.

• Treatment of anemia in the elderly has been shown to improve outcomes.

Multifactoral Causes of Anemia

in the Elderly

Anemia should not be accepted as an inevitable consequence of aging, as a cause is identified in about 80% of elderly patients.1 In ambulatory elderly patients, the most common causes of anemia are chronic disease (kidney disease, infections, malignancies, and chronic inflammatory disorders), iron deficiency, and nutritional and metabolic disorders. Blood loss as a causal factor (from surgery, injuries, and gastrointestinal and genitourinary bleeding) is more common in hospitalized patients.1-5 Frequently, multiple factors contribute to the problem in the individual patient. Approximately 20% of geriatric anemias, however, do defy classification, and their pathogenesis remains speculative. Proposed mechanisms include the presence of inflammatory cytokines and abnormal cytokine modulation of erythropoiesis, due both to abnormal production of stimulatory cytokines and decreased responsiveness of the erythroid precursors.3,5-12 An increased amount of fatty marrow tissue, possibly related to atherosclerotic changes in the bone marrow feeding arteries, may also play a role.13

Anemia Prevalence

Increases with Age

A recent review of studies of anemia in elderly patients found a wide variation in prevalence, ranging from 2.9% to 61% in men and 3.3% to 41% in women.14 As expected, higher rates are found in hospitalized patients than in community dwellers, and in the oldest patients. For example, a retrospective chart review of 151 elderly hospitalized patients by Sahadevan and colleagues found that slightly more than a third of the patients were anemic. The prevalence of anemia was significantly higher in those ≥75 years old, 42.9%, compared to those 65 to 74 years old, 25% (P <0.05).15 Similarly, a retrospective chart review of 183 hospitalized patients by Smieja and associates found 36% were anemic.16 In a study of 56 persons in good condition, aged 90 to 99 years, 29% were found to be anemic.17 Outpatient studies of more heterogeneous geriatric populations report prevalences of anemia between 5.2% and 13.6%.4,18,19

Diagnosing Anemia in the Elderly

Although the prevalence of anemia does increase with age, successful aging is not usually associated with anemia. Therefore, failure to evaluate anemia in the elderly could lead to delayed diagnosis of potentially treatable conditions.

It is a common perception that Hb

levels lower than reference values are acceptable in older individuals. However, most experts recommend using the same reference values for Hb as are used in younger individuals. Indeed, a review of 73 studies of mixed elderly populations indicates that the most frequently used anemia definition for men was Hb <13 g/dL and Hb <12 g/dL for women, the same values suggested by the World Health Organization for younger adults.20

An accurate history and focused physical examination, together with a limited, noninvasive laboratory evaluation (complete blood count with reticulocyte count, tests of hepatic and renal function, serum ferritin, vitamin B12 level, stools for occult blood), are frequently sufficient to determine the cause of geriatric anemia and to direct management.

The differentiation between anemia of chronic disease and iron deficiency may be more challenging in older individuals because the hallmarks of iron deficiency, microcytosis, and reduced serum ferritin level are somewhat less likely to be present.21 Microcytosis may be masked by coexistent conditions usually associated with macrocytosis (eg, folate and vitamin B12 deficiency, hypothyroidism, HIV infections, and use of drugs such as phenytoin or methotrexate). Serum ferritin, in addition to being a marker for iron stores, is an acute phase reactant. Therefore, low levels due to iron deficiency could be masked by elevations due to the presence of other comorbidities. The clinical context helps in the interpretation of equivocal laboratory results.22,23 Determination of total iron binding capacity and measurement of the soluble transferrin receptor concentration24 or the C-reactive protein concentration may contribute to the differential diagnosis.25

Pernicious anemia affects approximately 2% of the population older than 60 years and could be present in the absence of macrocytosis.26 The prevalence of anemia due to vitamin B12 deficiency may be much higher than that of pernicious anemia. With aging, the most common cause of vitamin B12 deficiency is achylia, which prevents proper digestion of food.27

Consequences of Untreated

Anemia in the Elderly

Untreated geriatric anemia has been associated with increased mortality, increased prevalence of various comorbid conditions, and decreased function. Low Hb concentration was found to predict early death in one study of 63 nursing home residents, aged 70 to 99 years.28 In individuals aged 70 to 79 years, the

5-year survival rate was 67% in normal controls and 48% in anemic individuals. For those aged 80 to 89 years, the 5-year survival rate was 62% for normal controls and 41% for anemic patients. Those in the oldest group, 90 to 99 years, had 5-year survival rates of 25% for patients with normal Hb and 13% for anemic patients. Chaves and colleagues, who followed 1,002 disabled community-dwelling women, aged ≥65 years, found that women with a Hb of 12 g/dL had a significantly higher mortality risk than did women with a Hb of 13.9 g/dL (OR, 1.6; 95% CI, 1.1-2.4). The odds of dying decreased 24% (OR, 0.76; 95% CI, 0.62-0.93) for each 1-g/dL increase in Hb between 8.0 g/dL and 13.9 g/dL.29

Several studies have addressed the impact of anemia on cognitive function. Argyriadou and colleagues found significant differences in cognitive impairment in anemic versus nonanemic patients. They reported cognitive impairment in anemic males of 55.6% compared to 34.4% in nonanemic males (P = 0.016). Similarly, the proportions were 47.5% in anemic females versus 40.1% in nonanemic females (P = 0.016).30

Beard and colleagues, who compared 302 patients with Alzheimer’s disease (AD) with healthy age- and gender-matched controls aged ≥65 years, found an almost twofold increase in the incidence of AD when anemia was present (OR, 1.88; 95% CI, 1.11-3.47). However, an associated retrospective cohort study by the same researchers of 618 community residents found no overall increase of AD risk.31 Milward and colleagues failed to confirm an association between anemia and AD but noted a significant association between anemia and vascular dementia (VAD). Nearly 45% of VAD subjects were anemic compared with 17% of nonanemic controls enrolled in a community-based study of elderly individuals.32 In-hospital delirium was increased in older patients with postoperative anemia, according to findings of a study conducted by Marcantonio and colleagues. In the study group of 1,341 patients ≥50 years admitted for major elective noncardiac surgery, postoperative Hct <30% was associated with a nearly twofold increased risk of death (OR, 1.7; 95% CI, 1.1-2.7).33

Other researchers have noted the association between anemia and functional ability and common comorbidities found in the elderly. Kamenetz and colleagues, in an investigation of 48 elderly subjects, ages 65 to 90 years, found patients with mild anemia to be impaired on a test of functional independence.34 Iron deficiency anemia and also iron deficiency without anemia have been associated with restless legs syndrome.35 In their review of 94 cohort and 72 case-control studies, Espallargues and colleagues found pernicious anemia to be one of several important risk factors for osteoporotic fracture.36

Beneficial Effects of

Anemia Management

Treatment of anemia may improve outcomes in elderly patients with chronic diseases as much as in younger patients. One study of 11 aged patients with chronic renal failure found that early correction of anemia with epoetin improved the quality of life, exercise performance, and cognitive function.37 Treatment also reduced transfusion need. In most patients, partial regression of left ventricular hypertrophy occurred, and no congestive heart failure was documented. Moreno and colleagues reported that 23 elderly patients with end-stage renal disease who were on dialysis showed an increase of Hct from 21% to 29% in response to epoetin therapy. These patients improved in quality of life measures as much as did the younger patients included in the study.38 Elderly cancer patients with cisplatin-associated anemia were found to respond to epoetin administration, with an increase in Hb levels and a need for blood transfusions comparable to that of younger individuals.39

Wu and colleagues, in their retrospective study of nearly 79,000 acute myocardial infarction patients ≥65 years, found that the prevalence of anemia at admission was 43.4% and that a lower Hct was associated with a higher 30-day mortality rate. Mortality rates were highest among the patients with the lowest Hct values and decreased as Hct values increased. Blood transfusion lowered short-term mortality rates in patients with a Hct ≤30% and might be effective in patients with a Hct as high as 33% at admission.

Anemia and Cancer

Because anemia is a common complication of cancer and its treatment, all cancer patients should be assessed for anemia.
Anemia causes debilitating symptoms, with fatigue being the most prevalent.
Anemia may have an adverse effect on cancer outcomes.
Erythropoietin therapy has been shown to decrease transfusion requirements, improve quality of life, and improve cancer treatment outcomes.

Multifactoral causes of anemia and cancer

Many factors contribute to cancer-related anemia, some associated with the progression of cancer and others associated with cancer therapy. Factors likely to increase the risk of anemia include the type, stage, and duration of disease; treatment regimen and intensity; presence of infection; and the need for surgical intervention.

Cancer-Related Anemia

Treatment-Related Anemia

CAUSES OF ANEMIA IN CANCER

Neoplastic process: chronic anemia of cancer
Chemotherapy and radiation therapy
Intercurrent infections
Clonal disorders of hematopoiesis
Gastrointestinal blood loss
Autoimmune hemolysis
Microangiopathy
Excessive marrow fibrosis and displacement
Iron, folate, vitamin B12 deficiency
Renal impairment
Reprinted with permission from Semin Oncol.

Symptoms of Anemia

Approximately 75% of all cancer patients report symptoms of fatigue, which can present as weakness, listlessness, low energy, trouble starting and finishing tasks, and the need to sleep during the day.9,14-17 While fatigue is the primary symptom of anemia in cancer patients, anemia can also cause a range of other symptoms, including palpitations, impaired cognitive function, nausea, reduced skin temperature, impaired immune function, dizziness, headache, chest pain, shortness of breath, and depression.

Fatigue and Decreased Quality of Life

Increased Mortality

Decreased Treatment Efficacy

Beneficial Effects of Anemia Management

Anemia

The three major categories of anemia are hypoproliferative, maturation defects, and hemolysis/blood loss. The most common anemia in the United States is hypoproliferative anemia, which includes iron deficiency, chronic kidney disease (CKD), and the inflammation-associated anemia of chronic disease, which is found in patients with chronic conditions, such as rheumatoid arthritis, inflammatory bowel disease, HIV / AIDS, and cancer. Anemia may be acquired (eg, through blood loss, inflammation, and malignancy) or inherited (eg, by patients with sickle cell disease, thalassemia, and other hemoglobinopathies).

Anemia: A Hidden Epidemic

Written with the editorial input of a number of prestigious NAAC members and other anemia specialists, Anemia:

“At least 3.4 million Americans have been diagnosed as anemic, and millions more may be undiagnosed or at increased risk of developing anemia.”

Anemia

Anemia is often underrecognized and undertreated.
Anemia is associated with many chronic diseases and other conditions.
If left untreated, anemia can have serious consequences.
Anemia can be readily managed by current therapies.

Anemia

ACD

Key Points

Anemia is common in rheumatoid arthritis (RA) and may constitute an important clinical problem for many patients. The two primary types of anemia in patients with RA are acd and iron deficiency anemia. Erythropoietin therapy in combination with iron supplementation corrects anemia in most patients with RA, and may improve RA outcomes and quality of life. Erythropoietin is useful in facilitating autologous blood donation prior to elective surgery for patients with RA and in reducing transfusion requirements.

acd

Although any type of anemia may be seen in patients with RA, the two primary types of anemia in RA appear to be iron deficiency anemia and acd. In their retrospective review of 225 patients with RA, Peeters and colleagues identified 64% as anemic. Of the group classified as anemic, 77% were found to have acd and 23% to have iron deficiency anemia.19

Differential diagnosis may be difficult, as serum iron levels are low in both types of anemia, and bone marrow staining for iron stores may be required. However, serum ferritin testing usually distinguishes between iron deficiency and acd. Patients with serum ferritin levels >50 µg/mL are likely to have acd, while those with a lower value of serum ferritin are likely to be iron deficient.22-24

The most common causes of iron deficiency anemia in RA are blood loss through menstrual bleeding and/or gastrointestinal bleeding secondary to nonsteroidal anti-inflammatory drugs. ACD is an “inflammatory anemia,” and its features in RA are similar to those seen in inflammatory bowel disease, HIV, aging, and cancer.

Impact of Inflammatory Cytokines

Development of acd in patients with RA appears to be related to inflammatory cytokines, which cause joint inflammation and interfere with normal red blood cell formation and destruction.25-28

Iron Supplementation

Iron supplementation is of great importance in patients who have iron deficiency. Furthermore, iron deficiency may occur concomitantly with acd.28,35 Iron repletion is almost always required as an adjunctive treatment to erythropoietin therapy, as erythroid production is increased.36-39

Low Hematocrit

Anemia is defined as a reduction in the number of circulating red blood cells, the hemoglobin concentration, or the volume of packed red cells hematocrit in the blood. In the laboratory, anemia is identified when a patient’s hemoglobin (Hb)/hematocrit (hematocrit) values fall below the lower end of a normal range of values for age- and sex-matched subjects. The likelihood and severity of anemia is based on the patient’s deviation from normal values. Women in their childbearing years normally have a lower Hb value by about 1 gm/dL than men of the same age, likely due to hormonal influences. After menopause, the gender difference virtually disappears.

Hindered Cognitive Function

Researchers have shown a relationship between Hct and cognitive function. In patients with ischemic cerebrovascular disease, Hct correction to the normal range (40% to 45%) was shown to improve cerebral oxygen delivery. Similarly, in dialysis patients, hematocrit correction to normal was shown to improve neurophysiologic parameters indicative of cognitive function and memory.44 Even partial correction of anemia in CKD patients (to hematocrit of 36% to 36.5%) has been shown to improve cognitive function, including sustained attention and memory.

The hematocrit values necessary to maintain optimal cognitive function, however, remain to be defined. For example, in dialysis patients, maximal oxygenation of the cerebral hemisphere was estimated to occur at a hematocrit of 35.2%, but the optimal level varied with the region of the brain explored (eg, a hematocrit of 33% provided maximal oxygen delivery in the occipital region, whereas a hematocrit of 45% was needed in the frontal region).

low hematocrit

Increased Hospitalization and Mortality Risk

In patients with CKD, anemia has been shown to correlate directly with the risk of hospitalization. In a recent study of more than 66,000 dialysis patients, those with hematocrit of 33% to <39% were found to have lower hospitalization rates than patients with hematocrit <33%.33 Findings of another study indicated that dialysis patients with hematocrit <30% had the highest risk of hospitalization, while those with hematocrit levels of 33% to 36% had the lowest hospitalization risk.48 Both fewer hospitalizations per year and shorter hospital stays were observed for new dialysis patients treated with recombinant human erythropoietin (epoetin) than for their untreated peers.

Anemia in dialysis patients is also associated with increased mortality, with higher 1-year mortality risk in patients with low hematocrit.31,33 Similarly, 3-year mortality in dialysis patients increases with low hematocrit, with the highest mortality at hematocrit <30%. Observational studies in dialysis patients show reductions in mortality with correction of anemia to hematocrit 33% to 36%.

Such a relationship also has been noted between anemia and survival in cancer patients. In a systematic review of 60 published studies, researchers reported that the presence of anemia was associated with an overall 65% increased relative risk of death, although the relative risk varied by cancer type.

Low hematocrit

Results of a recent retrospective study of nearly 79,000 acute myocardial infarction patients ≥65 years indicated that a low hematocrit at admission was associated with a higher 30-day mortality rate. Short-term mortality rates were lowered in patients with a hematocrit of ≤30% at admission who were given blood transfusions to correct anemia.

Hb/Hct levels in dialysis patients (stage 5, on dialysis) are meticulously followed by the Medicare system, and detailed analyses of these levels and treatment results are readily available. Less is known, however, regarding Hb/hematocrit levels in the millions of Americans with CKD not requiring dialysis.

LOW HEMATOCRIT

There seems to be a large number of menstruating women (ages 15 to 50), who complain of fatigue, whose hemoglobins/hematocrits are normal. However, if you check their serum ferritins, they are strikingly low. If you treat with iron, they often improve. Often doctors are not checking serum ferritin unless the hemoglobin is low.

By NAAC Hematologist John W. Adamson, MD
Years ago, studies by Finch and colleagues at the University of Washington in Seattle, demonstrated that rats with tissue iron deficiency (but no anemia) had impaired maximum exercise tolerance. This impairment improved dramatically when the animals were treated with iron. This improvement was seen despite the fact that there was no change in the hemoglobin or hematocrit as a result of iron administration. These investigators demonstrated that the defect likely was due to mitochondrial dysfunction brought about by the tissue iron deficiency. Other anecdotal reports have appeared of similar improvement in patients with polycythemia vera whose disease was being managed by phlebotomy. Symptoms of fatigue were reversed with iron replacement - again in the absence of anemia.

In an otherwise healthy patient >50 years old, what should be included in the work-up of a normochromic microcytic state and the absence of low hemoglobin or hematocrit?

By NAAC Hematologist John W. Adamson, MD
There are two points to be made. Is this an acquired finding (ie, did this patient have a documented normal MCV in the past) or is this chronic and, therefore, perhaps congenital? If the latter, then thalassemia trait is a likely possibility. If this is acquired, and the iron status of the patient is normal, then a defect of heme synthesis might be considered. A bone marrow exam to look at the marrow precursors for their content and distribution of iron might be helpful. One would not like to miss an early sideroblastic process.

What is the best way to approach a patient with a low hematocrit but normal hemoglobin?

By NAAC Hematologist John W. Adamson, MD
This is a difficult question without actually seeing the values. However, it is important to remember that most automated cell counters measure the hemoglobin directly, but that the hematocrit is calculated. Generally, therefore, it is probably more reliable to base clinical decisions on the hemoglobin concentration.

Hematocrit

Is the ferritin level also increased in states of chronic inflammation?

A8. By NAAC Hematologist John W. Adamson, MD
Typically, yes. Although imperfect, the serum ferritin level is the best laboratory test available to evaluate the body's iron stores. It is probably the best single test to differentiate the anemia of chronic disease and true iron deficiency anemia.

Why do MCV and MCH stay elevated years after alcoholics stop drinking?

A9. By NAAC Hematologist John W. Adamson, MD
It is not at all clear. Usually, the macrocytosis in the nonanemic patient with liver disease reflects the toxic effects of alcohol on the bone marrow, but persistent macrocytosis in the absence of folate deficiency and megaloblastic marrow changes is not uncommon. One should always rule out folate deficiency or an elevated reticulocyte count as contributing to the macrocytosis in this setting.

Iron Deficiency

In most medical practices, the identification of iron deficiency should be foremost, since it may be associated with occult bleeding or other serious conditions, and it can be quickly and easily treated with iron supplementation. Other less common but reversible anemias include vitamin B12 and folate deficiency, and some cases of anemia associated with inflammation. Each of these requires a slightly different therapeutic approach.

When the serum iron falls (true iron deficiency or acute inflammation), Hb synthesis is impaired and microcytic, hypochromic red cells are produced. The serum ferritin reflects total body iron stores and is decreased in iron deficiency, but normal or increased in states of acute or chronic inflammation. This is a useful laboratory test to distinguish between true iron deficiency and chronic inflammatory states.

Iron-deficiency Anemia Common During Long-term Total Parenteral Nutrition

LOS ANGELES (National Anemia Action Council) - Patients receiving long-term home total parenteral nutrition (HPN) should be routinely screened for iron-deficiency anemia, Massachusetts investigators recommend. If iron deficiency is detected, regular administration of low-dose iron is safer than total dose infusion, they have found.

Only 13 of the 30 patients with iron-deficiency anemia had episodes of acute blood loss. The researchers note in their paper that each milliliter of blood contains 0.5 mg of iron, so "even minor chronic blood loss can be clinically important."

In 10 of the patients, iron-deficiency anemia was diagnosed when HPN was initiated. In the others it developed two to 97 months later (mean 28.8 months).

"For the first year after initiation of total parenteral nutrition, iron studies should be done every 3 months," Dr. Bistrian's group suggests. "If no problem is found during that examination, yearly assessment is sufficient. If iron deficiency is found, treatment should be proposed and monitored every 3 months until a stable iron regimen is defined, and then monitored every 6 months thereafter."

Twenty of the patients with iron-deficiency anemia received IV iron rather than a blood transfusion or oral iron supplementation. Of these, eight received iron doses of 100 to 500 mg by total dose infusion or multiple infusions; seven received low doses of iron in HPN, 10 mg to 75 mg at a time for up to 6 months; and five were treated with both regimens.

Rash, urticaria, and/or shortness of breath developed in four of the 13 patients who received total dose infusion, the authors report. Low-dose iron was not associated with such events. One patient with shortness of breath after total dose infusion subsequently responded well to repeated dosing with 10 mg of iron in HPN. Total dose infusion is "a perfectly acceptable therapy," Dr. Bistrian said. "But you're a little more likely, if you give large doses, 400 or 500 milligrams, to have mild, self-limited symptoms from it. If you give less than 75 milligrams, there's really no reaction."

"And occasionally, less than 1% of the time, you'll get a severe reaction with a total dose infusion," Dr. Bistrian continued. "To my knowledge it's not been shown with low-dose infusions that you can get anaphylactic reactions that are very severe."

He pointed out that most people who develop iron-deficiency anemia have an ongoing loss and require iron permanently. "To us it's more reasonable to find out how much more iron they need and just give it to them all the time, rather than give them a big dose. As they get further and further away from the dose, they redevelop the anemia."

In their report, Dr. Bistrian and his associates share their method of estimating how much iron should be replaced. They determine "the iron equivalent of rate of hematocrit or hemoglobin drop over time by means of the following equation: iron (mg) = 0.3 x weight (lbs) [100 (actual Hb (g/dL) 100/desired Hb]."

Symptoms of anemia

Symptoms of Anemia

Approximately 75% of all cancer patients report symptoms of fatigue,13,14 which can present as weakness, listlessness, low energy, trouble starting and finishing tasks, and the need to sleep during the day. While fatigue is the primary symptom of anemia in cancer patients, anemia can also cause a range of other symptoms, including palpitations, impaired cognitive function, nausea, reduced skin temperature, impaired immune function, dizziness, headache, chest pain, shortness of breath, and depression.

symptoms of anemia

Anemia is often underrecognized and undertreated.
Anemia is associated with many chronic diseases and other conditions.
If left untreated, anemia can have serious consequences.
Anemia can be readily managed by current therapies.

Anemia symptoms and signs may be vague, and it is present in a substantial number of patients with a variety of chronic and serious diseases. Frequently, however, anemia remains undetected because it is masked by symptoms of the diseases with which it is associated, including chronic kidney disease, cancer, diabetes, cardiovascular disease, HIV/AIDS, rheumatoid arthritis, and inflammatory bowel disease.

The Burden of Anemia

Because anemia affects the delivery of oxygen to all of the body’s organs, its signs and symptoms of anemia are varied.

It is generally accepted that the symptoms of anemia adversely affect quality of life (QOL), even when anemia is mild. In end-stage renal disease (ESRD), severe impairment of QOL may occur in as many as 31% of patients. Several factors contribute to poor QOL in these patients, including low Hb or Hct. Anemia in patients with cancer contributes to fatigue and may reduce patients’ ability to function normally, thus reducing QOL. The corollary to this is that the correction of anemia is associated with improved QOL. In fact, improved Hb and Hct values are associated with better scores on QOL assessments in a variety of disease states, including CKD, inflammatory bowel disease,18 rheumatoid arthritis, cancer, and HIV/AIDS.

Hemoglobin

Anemia is defined as a reduction in the number of circulating red blood cells, the hemoglobin concentration, or the volume of packed red cells (hematocrit) in the blood. In the laboratory, anemia is identified when a patient’s hemoglobin (Hb)/hematocrit (Hct) values fall below the lower end of a normal range of values for age- and sex-matched subjects. The likelihood and severity of anemia is based on the patient’s deviation from normal values. Women in their childbearing years normally have a low hemoglobin value by about 1 gm/dL than men of the same age, likely due to hormonal influences. After menopause, the gender difference virtually disappears.

In end-stage renal disease (ESRD), severe impairment of QOL may occur in as many as 31% of patients.13 Several factors contribute to poor QOL in these patients, including low hemoglobin or Hct. Anemia in patients with cancer contributes to fatigue and may reduce patients’ ability to function normally, thus reducing QOL.12,14,15 The corollary to this is that the correction of anemia is associated with improved QOL. In fact, improved hemoglobin and Hct values are associated with better scores on QOL assessments in a variety of disease states, including CKD, inflammatory bowel disease,18 rheumatoid arthritis, cancer, and HIV/AIDS.

The key to erythropoietin production is the availability of oxygen, which is transported to tissues in a form bound to the hemoglobin molecule contained within the red cells.

low hemoglobin

The fundamental stimulus for erythropoietin production is oxygen availability to the kidney. Impaired oxygen delivery to the kidney is caused by a decrease in the number of circulating red cells (anemia), impaired oxygen loading of the red cell hemoglobin or, rarely, impaired flow of red cells to the kidney because of renal artery stenosis.

Erythropoietin not only is responsible for the day-to-day regulation of erythropoiesis, but it also responds dramatically to increase red cell production in the face of an inadequate oxygen supply, thereby meeting tissue oxygen needs. When the hemoglobin concentration falls below 10 g/dL to 12 g/dL, and if kidney function is normal, plasma erythropoietin levels rise logarithmically in inverse proportion to the level of hemoglobin. Under the stimulus of erythropoietin, red blood cell production can increase four- to fivefold within 1 to 2 weeks. However, this can occur only in the presence of adequate substrates, most particularly iron. In order for this feedback system to function properly, there must be normal renal production of erythropoietin, a functioning erythroid marrow, and an adequate supply of substrates for hemoglobin synthesis. A defect in any of these key components can lead to anemia.

Guidelines from the NKF-K/DOQI recommend that an anemia work-up be initiated when the hemoglobin/Hct value declines to approximately 80% of the mean value defined for healthy, normal subgroups, as anemia is likely to be present.6 For example, in adult men and postmenopausal women with CKD, an anemia work-up should be initiated at hemoglobin ≤12.5 g/dL (Hct <37%); in premenopausal women and prepubertal CKD patients, the corresponding levels are hemoglobin ≤11 g/dL (Hct <33%).

The NKF-K/DOQI guidelines recommend that hemoglobin levels in patients with ESRD be maintained between 11 g/dL and 12 g/dL. The same target hemoglobin range (11 g/dL to 12 g/dL) has come to apply also to patients with CKD who do not have ESRD, despite a lack of studies on the long-term effects of maintaining such a hemoglobin range in this population.

A consensus on the optimal hemoglobin levels at varying stages of CKD has not been reached, but the current Centers for Medicaid and Medicare Services policy restricts reimbursement for the initiation of anemia treatment to hemoglobin ≤10 g/dL, even though evidence indicates that adverse anemia-related sequelae occur at hemoglobin ≤11 g/dL.

Low Hemoglobin

Specifically, decreasing hemoglobin was associated with increasing risk of LVH. The first study showed a 6% increase in the risk of LVH for each 1 g/dL decrease in hemoglobin.11 The second, larger study showed an even greater risk: an increase of 32% in LVH risk for each 0.5-g/dL decrease in hemoglobin (P = 0.004).2 This study identified three risk factors that contributed to the development of LVH in patients with CKD: hemoglobin concentration, systolic blood pressure, and baseline left ventricular mass index. Similarly, in patients with end-stage renal disease (ESRD) undergoing dialysis, left ventricular end-diastolic volume and left ventricular mass both were found to increase with low hemoglobin levels. Decreasing hemoglobin levels have also been associated with a greater risk of the development of de novo or recurrent heart failure and increased mortality in this population.

The incidence and prevalence of anemia in CHF patients cannot be precisely determined from existing data, but retrospective studies suggest that low hemoglobin is common in this syndrome. Patients hospitalized with CHF have been reported to have a mean hemoglobin level of approximately 12 g/dL, and it has been demonstrated that the hemoglobin level decreases as the severity of heart failure progresses.16,17 For example, a retrospective analysis of 142 patients with CHF revealed that the prevalence of a hemoglobin level <12 g/dL increased with the severity of the disease, reaching a prevalence of 79.1% in patients with New York Heart Association (NYHA) functional classification IV.20 In addition, endogenous erythropoietin levels have been shown to increase with increasing severity of CHF.

Hemoglobin

Anemia is defined as a reduction in the number of circulating red blood cells, the hemoglobin concentration, or the volume of packed red cells (hematocrit) in the blood. In the laboratory, anemia is identified when a patient’s hemoglobin (Hb)/hematocrit (Hct) values fall below the lower end of a normal range of values for age- and sex-matched subjects. The likelihood and severity of anemia is based on the patient’s deviation from normal values. Women in their childbearing years normally have a lower hemoglobin value by about 1 gm/dL than men of the same age, likely due to hormonal influences. After menopause, the gender difference virtually disappears.

In end-stage renal disease (ESRD), severe impairment of QOL may occur in as many as 31% of patients.13 Several factors contribute to poor QOL in these patients, including low hemoglobin or Hct. Anemia in patients with cancer contributes to fatigue and may reduce patients’ ability to function normally, thus reducing QOL.12,14,15 The corollary to this is that the correction of anemia is associated with improved QOL. In fact, improved hemoglobin and Hct values are associated with better scores on QOL assessments in a variety of disease states, including CKD,13,16,17 inflammatory bowel disease,18 rheumatoid arthritis,16,19 cancer,20,21 and HIV/AIDS.

The key to erythropoietin production is the availability of oxygen, which is transported to tissues in a form bound to the hemoglobin molecule contained within the red cells.

hemoglobin

The fundamental stimulus for erythropoietin production is oxygen availability to the kidney. Impaired oxygen delivery to the kidney is caused by a decrease in the number of circulating red cells (anemia), impaired oxygen loading of the red cell hemoglobin or, rarely, impaired flow of red cells to the kidney because of renal artery stenosis.

Erythropoietin not only is responsible for the day-to-day regulation of erythropoiesis, but it also responds dramatically to increase red cell production in the face of an inadequate oxygen supply, thereby meeting tissue oxygen needs. When the hemoglobin concentration falls below 10 g/dL to 12 g/dL, and if kidney function is normal, plasma erythropoietin levels rise logarithmically in inverse proportion to the level of hemoglobin. Under the stimulus of erythropoietin, red blood cell production can increase four- to fivefold within 1 to 2 weeks. However, this can occur only in the presence of adequate substrates, most particularly iron. In order for this feedback system to function properly, there must be normal renal production of erythropoietin, a functioning erythroid marrow, and an adequate supply of substrates for hemoglobin synthesis. A defect in any of these key components can lead to anemia.

Hemoglobin

Specifically, decreasing hemoglobin was associated with increasing risk of LVH. The first study showed a 6% increase in the risk of LVH for each 1 g/dL decrease in hemoglobin.11 The second, larger study showed an even greater risk: an increase of 32% in LVH risk for each 0.5-g/dL decrease in hemoglobin (P = 0.004).2 This study identified three risk factors that contributed to the development of LVH in patients with CKD: hemoglobin concentration, systolic blood pressure, and baseline left ventricular mass index. Similarly, in patients with end-stage renal disease (ESRD) undergoing dialysis, left ventricular end-diastolic volume and left ventricular mass both were found to increase with decreasing hemoglobin levels.12 Decreasing hemoglobin levels have also been associated with a greater risk of the development of de novo or recurrent heart failure and increased mortality in this population.

The incidence and prevalence of anemia in CHF patients cannot be precisely determined from existing data, but retrospective studies suggest that reduced hemoglobin is common in this syndrome. Patients hospitalized with CHF have been reported to have a mean hemoglobin level of approximately 12 g/dL, and it has been demonstrated that the hemoglobin level decreases as the severity of heart failure progresses.16,17 For example, a retrospective analysis of 142 patients with CHF revealed that the prevalence of a hemoglobin level <12 g/dL increased with the severity of the disease, reaching a prevalence of 79.1% in patients with New York Heart Association (NYHA) functional classification IV.20 In addition, endogenous erythropoietin levels have been shown to increase with increasing severity of CHF.

Hematopoiesis

Anemia is a common complication of CKD, mainly due to the inability of the kidneys to secrete enough erythropoietin to stimulate adequate hematopoiesis. Additional factors that may cause or contribute to CKD-related anemia include iron deficiency, severe hyperparathyroidism,12 acute and chronic inflammatory conditions, aluminum toxicity, folate deficiency, shortened red blood cell survival, hypothyroidism, and hemoglobinopathies such as a-thalassemia.

hematopoiesis

CAUSES OF CANCER-RELATED ANEMIA

Neoplastic process: chronic anemia of cancer
Chemotherapy and radiation therapy
Intercurrent infections
Clonal disorders of hematopoiesis
Gastrointestinal blood loss
Autoimmune hemolysis
Microangiopathy
Excessive marrow fibrosis and displacement
Iron, folate, vitamin B12 deficiency
Renal impairment
Reprinted with permission from Semin Oncol.

Hematopoiesis

Multiple Factors Contribute to Anemia

Multiple factors, both disease-related and treatment-related, can cause anemia during HIV infection. HIV plasma viral load appears to correlate inversely with all hematologic values, suggesting a causative role of HIV in hematologic disorders. The disease can cause anemia by influencing cytokine production and suppressing hematopoiesis; decreasing erythropoietin concentrations; and increasing the risk of opportunistic infection with agents, such as Mycobacterium avium complex and parvovirus B-19.

Hematocrit

Hindered Cognitive Function

Researchers have shown a relationship between Hct and cognitive function. In patients with ischemic cerebrovascular disease, Hct correction to the normal range (40% to 45%) was shown to improve cerebral oxygen delivery. Similarly, in dialysis patients, hematocrit correction to normal was shown to improve neurophysiologic parameters indicative of cognitive function and memory.44 Even partial correction of anemia in CKD patients (to hematocrit of 36% to 36.5%) has been shown to improve cognitive function, including sustained attention and memory.

hematocrit

Increased Hospitalization and Mortality Risk

Anemia in dialysis patients is also associated with increased mortality, with higher 1-year mortality risk in patients with lower hematocrit.31,33 Similarly, 3-year mortality in dialysis patients increases with decreasing hematocrit, with the highest mortality at hematocrit <30%. Observational studies in dialysis patients show reductions in mortality with correction of anemia to hematocrit 33% to 36%.

Such a relationship also has been noted between anemia and survival in cancer patients. In a systematic review of 60 published studies, researchers reported that the presence of anemia was associated with an overall 65% increased relative risk of death, although the relative risk varied by cancer type.

hematocrit

Results of a recent retrospective study of nearly 79,000 acute myocardial infarction patients ≥65 years indicated that a lower hematocrit at admission was associated with a higher 30-day mortality rate. Short-term mortality rates were lowered in patients with a hematocrit of ≤30% at admission who were given blood transfusions to correct anemia.

Hb/Hct levels in dialysis patients (stage 5, on dialysis) are meticulously followed by the Medicare system, and detailed analyses of these levels and treatment results are readily available. Less is known, however, regarding Hb/hematocrit levels in the millions of Americans with CKD not requiring dialysis.

Hematocrit

ESRD

Staging and Prevalence of CKD

The resulting estimated total of 19.5 million people in the United States who have CKD marks the disease as a major public health concern, affecting more than the number of Americans with diabetes (estimated at 17 million)8 and nearly half the number of those with hypertension (estimated at 50 million).9 Because CKD typically progresses to its most severe form, ESRD, the public health concern is underscored by the most recent data from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD). The combined 1995 to 1999 prevalence of ESRD patients was 392,847 on dialysis and 8,287 with transplants.2 Expecting this alarming trend to continue, the NIDDKD has estimated that the prevalence of ESRD will reach over half a million by 2010.10

esrd

Concerned by the facts that anemia develops early in CKD and worsens as the disease progresses, a panel of nephrologists developed a concept called the Renal Anemia Management Period (RAMP). The RAMP model emphasizes the progressive nature of CKD and the need for timely and appropriate treatment—well before the development of ESRD —to prevent anemia and other comorbidities that can potentially lead to irreversible, physiological damage, such as LVH.40 Rather than representing data from a specific study, the RAMP model notes trends identified in many studies.

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.

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.

In ESRD, severe impairment of QOL may occur in as many as 31% of patients.

Epotein

Epotein alfa is a 165-amino-acid glycoprotein manufactured by recombinant DNA technology and is identical in structure and biological activity to native erythropoietin. Originally approved by the Food and Drug Administration (FDA) for the treatment of anemia in CKD patients on dialysis, epotein alfa is currently indicated for treating anemia in CKD patients whether on dialysis or not, in cancer patients on chemotherapy, and in zidovudine-treated HIV-infected patients. It is also approved for reducing allogeneic blood transfusions in anemic patients undergoing elective, noncardiac, nonvascular surgery.

Epotein beta and epotein omega are other forms of recombinant human erythropoietin used outside of the United States. Because European researchers sometimes include data on epotein beta, epotein in this monograph refers to epotein alfa and epoetin beta.

Epotein

For more than a decade, epoetin has been used successfully to manage the anemia of patients with CKD or cancer-related anemia. epotein therapy has dramatically reduced the need for transfusions in these patient groups, has led to an improvement in QOL for those who have responded, and has decreased anemia-associated morbidity.61 epoetin has also been shown to be of benefit in managing anemia in patients with HIV/AIDS,22-24 inflammatory bowel disease,18 and rheumatoid arthritis.16,62 The anemia of the elderly and those undergoing surgery63,64 has also been responsive to therapy with epotein. In some cases, epoetin is given with supplemental iron, a strategy that has been of proven value for a variety of patients, including patients with ESRD on dialysis, patients with rheumatoid arthritis, and some surgical patients.

Epotein, however, has a relatively short circulating half-life and, consequently, it is usually administered several times a week or at least weekly. Most recently, a novel erythropoiesis-stimulating protein (NESP) has been developed that addresses some of the inconvenience of frequent epoetin dosing. Engineered specifically for increased biological activity, darbepoetin alfa has the same number of amino acids as epotein alfa, but they have been molecularly modified to add two additional

Replacement therapy, whether it is iron or epotein, takes time to correct the anemia. Thus, if the anemia is severe and the patient is symptomatic, transfusion therapy with packed red blood cells is an option. Although the safety of blood transfusions has been brought to an extremely high level, exposure to red cell transfusions still carries a measurable risk of allosensitization, and in some patient groups, such as those with HIV/AIDS and cancer, it can have an adverse effect on mortality.

Erythropoietin

Erythropoietin alfa is a 165-amino-acid glycoprotein manufactured by recombinant DNA technology and is identical in structure and biological activity to native erythropoietin. Originally approved by the Food and Drug Administration (FDA) for the treatment of anemia in CKD patients on dialysis, erythropoietin alfa is currently indicated for treating anemia in CKD patients whether on dialysis or not, in cancer patients on chemotherapy, and in zidovudine-treated HIV-infected patients. It is also approved for reducing allogeneic blood transfusions in anemic patients undergoing elective, noncardiac, nonvascular surgery.

Erythropoietin beta and erythropoietin omega are other forms of recombinant human erythropoietin used outside of the United States. Because European researchers sometimes include data on erythropoietin beta, erythropoietin in this monograph refers to erythropoietin alfa and epoetin beta.

For more than a decade, epoetin has been used successfully to manage the anemia of patients with CKD or cancer-related anemia. erythropoietin therapy has dramatically reduced the need for transfusions in these patient groups, has led to an improvement in QOL for those who have responded, and has decreased anemia-associated morbidity.61 epoetin has also been shown to be of benefit in managing anemia in patients with HIV/AIDS,22-24 inflammatory bowel disease,18 and rheumatoid arthritis.16,62 The anemia of the elderly and those undergoing surgery63,64 has also been responsive to therapy with erythropoietin. In some cases, epoetin is given with supplemental iron, a strategy that has been of proven value for a variety of patients, including patients with ESRD on dialysis, patients with rheumatoid arthritis, and some surgical patients.

Erythropoietin, however, has a relatively short circulating half-life and, consequently, it is usually administered several times a week or at least weekly. Most recently, a novel erythropoiesis-stimulating protein (NESP) has been developed that addresses some of the inconvenience of frequent epoetin dosing. Engineered specifically for increased biological activity, darbepoetin alfa has the same number of amino acids as erythropoietin alfa, but they have been molecularly modified to add two additional

Replacement therapy, whether it is iron or erythropoietin, takes time to correct the anemia. Thus, if the anemia is severe and the patient is symptomatic, transfusion therapy with packed red blood cells is an option. Although the safety of blood transfusions has been brought to an extremely high level, exposure to red cell transfusions still carries a measurable risk of allosensitization, and in some patient groups, such as those with HIV/AIDS and cancer, it can have an adverse effect on mortality.

Epoetin Alfa

epoetin alfa

EPO

One of the most common and chronic hypoproliferative anemia is the anemia of CKD. This is a hormone deficiency state, in which the diseased kidney is incapable of meeting the endogenous erythropoietin needs of the patient. As a result of erythropoietin deficiency, the moderately shortened lifespan of the circulating red cells, and the obligatory blood loss that accompanies dialysis, CKD patients can experience profound, debilitating anemia. Such patients have benefited greatly from the availability of epo, a recombinant human erythropoietin.

Epo is a 165-amino-acid glycoprotein manufactured by recombinant DNA technology and is identical in structure and biological activity to native erythropoietin. Originally approved by the Food and Drug Administration (FDA) for the treatment of anemia in CKD patients on dialysis, epo is currently indicated for treating anemia in CKD patients whether on dialysis or not, in cancer patients on chemotherapy, and in zidovudine-treated HIV-infected patients. It is also approved for reducing allogeneic blood transfusions in anemic patients undergoing elective, noncardiac, nonvascular surgery.

Epo beta and epo omega are other forms of recombinant human erythropoietin used outside of the United States. Because European researchers sometimes include data on epo beta, epo in this monograph refers to epo and epo beta.

For more than a decade, epo has been used successfully to manage the anemia of patients with CKD or cancer-related anemia. epo therapy has dramatically reduced the need for transfusions in these patient groups, has led to an improvement in QOL for those who have responded, and has decreased anemia-associated morbidity.61 epo has also been shown to be of benefit in managing anemia in patients with HIV/AIDS,22-24 inflammatory bowel disease,18 and rheumatoid arthritis.16,62 The anemia of the elderly and those undergoing surgery63,64 has also been responsive to therapy with epo. In some cases, epo is given with supplemental iron, a strategy that has been of proven value for a variety of patients, including patients with ESRD on dialysis, patients with rheumatoid arthritis, and some surgical patients.

epo

Epo, however, has a relatively short circulating half-life and, consequently, it is usually administered several times a week or at least weekly. Most recently, a novel erythropoiesis-stimulating protein (NESP) has been developed that addresses some of the inconvenience of frequent epo dosing. Engineered specifically for increased biological activity, darbepo has the same number of amino acids as epo, but they have been molecularly modified to add two additional

N-linked glycosylation sites to the molecule, bringing the total number to five, instead of the usual three. This results in a threefold increase in terminal elimination half-life (23.5 hours vs. 8.5 hours). As a result, darbepoetin alfa allows less frequent dosing than epo and is well tolerated. Darbepoetin alfa was approved by the FDA in 2001 for the treatment of patients with the anemia of CKD whether on dialysis or not.65 Study findings to date have shown the medication also to be of benefit in patients with nonmyeloid hematological malignancies or solid tumors.66,67 Darbepoetin alfa is currently undergoing FDA review for use in the treatment of anemia in cancer patients receiving chemotherapy.

Replacement therapy, whether it is iron or epo, takes time to correct the anemia. Thus, if the anemia is severe and the patient is symptomatic, transfusion therapy with packed red blood cells is an option. Although the safety of blood transfusions has been brought to an extremely high level, exposure to red cell transfusions still carries a measurable risk of allosensitization, and in some patient groups, such as those with HIV/AIDS and cancer, it can have an adverse effect on mortality.