Nephrology

The article “Anemia of chronic kidney disease: Treat it, but not too aggressively” by Drs. Georges Nakhoul and James F. Simon (Cleve Clin J Med 2016; 83:613–624) contained a typographical error. In Table 2, the target ferritin level in chronic kidney disease is given as greater than 100 ng/dL, and for end-stage renal disease 200 to 1,200 ng/dL. Ferritin levels are measured in ng/mL, not ng/dL.

The article “Anemia of chronic kidney disease: Treat it, but not too aggressively” by Drs. Georges Nakhoul and James F. Simon (Cleve Clin J Med 2016; 83:613–624) contained a typographical error. In Table 2, the target ferritin level in chronic kidney disease is given as greater than 100 ng/dL, and for end-stage renal disease 200 to 1,200 ng/dL. Ferritin levels are measured in ng/mL, not ng/dL.

The article “Anemia of chronic kidney disease: Treat it, but not too aggressively” by Drs. Georges Nakhoul and James F. Simon (Cleve Clin J Med 2016; 83:613–624) contained a typographical error. In Table 2, the target ferritin level in chronic kidney disease is given as greater than 100 ng/dL, and for end-stage renal disease 200 to 1,200 ng/dL. Ferritin levels are measured in ng/mL, not ng/dL.

ROME – The use of coronary artery bypass graft surgery for revascularization in patients with multivessel CAD and comorbid diabetes plus chronic kidney disease was associated with a significantly lower risk of major cardiovascular and cerebrovascular events than was PCI with first-generation drug-eluting stents in a new secondary analysis from the landmark FREEDOM trial.

“The reason for this presentation is that even though chronic kidney disease is common in patients with diabetes, until now there has not been a large study of the efficacy and safety of coronary revascularization with drug-eluting stents versus CABG in this population in a randomized trial cohort,” explained Usman Baber, MD, who reported the results at the annual congress of the European Society of Cardiology.

Bruce Jancin/Frontline Medical News

FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) randomized 1,900 diabetic patients with multivessel CAD to PCI or CABG. As previously reported, CABG proved superior to PCI, with a significantly lower rate of the composite primary endpoint composed of all-cause mortality, MI, or stroke (N Engl J Med. 2012 Dec 20;367[25]:2375-84).

Dr. Baber presented a post hoc analysis of the 451 FREEDOM participants with baseline comorbid chronic kidney disease (CKD). Their mean SYNTAX score was 27, and their mean baseline estimated glomerular filtration rate was 44 mL/min per 1.73 m², indicative of mild to moderate CKD.

“Only 28 patients in the FREEDOM trial had an estimated GFR below 30, therefore we can’t make any inferences about revascularization in that setting, which I think is a completely different population,” he noted.

The 5-year rate of major adverse cardiovascular and cerebrovascular events in patients with CKD was 26% in the CABG group, an absolute 9.4% less than the 35.6% rate in subjects randomized to PCI.

Roughly one-quarter of FREEDOM participants had CKD. They fared significantly worse than did those without CKD. The 5-year incidence of major adverse cardiovascular and cerebrovascular events was 30.8% in patients with CKD and 20.1% in patients without renal impairment. In a multivariate analysis adjusted for age, gender, hypertension, peripheral vascular disease, and other potential confounders, the risk of all-cause mortality was twofold higher in the CKD group. Their risk of cardiac death was increased 1.8-fold, and they were at 1.9-fold increased risk for stroke. Interestingly, however, the acute MI risk did not differ between patients with or without CKD, Dr. Baber observed.

Drilling deeper into the data, the cardiologist reported that CABG was associated with significantly lower rates of MI and a nonsignificant trend for fewer deaths, but with a significantly higher stroke rate than PCI.

One audience member rose to complain that this information won’t be helpful in counseling his diabetic patients with CKD and multivessel CAD because the choices look so grim: a higher risk of MI with percutaneous therapy, and a greater risk of stroke with surgery.

Dr. Baber replied by pointing out that the 10.8% absolute reduction in the risk of MI with CABG compared with PCI was more than twice as large as the absolute 4.6% increase in stroke risk with surgery.

“Most people would say that a heart attack is an inconvenience, and a stroke is a life-changing experience for them and their family,” said session cochair Kim A. Williams, MD, professor of medicine and chairman of cardiology at Rush University Medical Center in Chicago.

At that, Dr. Baber backtracked a bit, observing that since this was a post hoc analysis, the FREEDOM findings in patients with CKD must be viewed as hypothesis-generating rather than definitive. And, of course, contemporary second-generation drug-eluting stents have a better risk/benefit profile than do those used in FREEDOM.

“The number needed to treat/number needed to harm ratio for CABG and PCI probably ends up being roughly equal. The pertinence of an analysis like this is if you look at real-world registry-based data, you find a therapeutic nihilism that’s highly prevalent in CKD patients, where many patients who might benefit are not provided with revascularization therapy. It’s clear that we as clinicians – either because we don’t know there is a benefit or we are too concerned about potential harm – deprive patients of a treatment that might be beneficial. This analysis makes clinicians who might be concerned feel somewhat comforted that there is not unacceptable harm and that there is benefit,” Dr. Baber said.

Follow-up of FREEDOM participants continues and will be the subject of future reports, he added.

The FREEDOM trial was sponsored by the National Heart, Lung and Blood Institute. Dr. Baber reported having no financial conflicts of interest.

[email protected]

ROME – The use of coronary artery bypass graft surgery for revascularization in patients with multivessel CAD and comorbid diabetes plus chronic kidney disease was associated with a significantly lower risk of major cardiovascular and cerebrovascular events than was PCI with first-generation drug-eluting stents in a new secondary analysis from the landmark FREEDOM trial.

“The reason for this presentation is that even though chronic kidney disease is common in patients with diabetes, until now there has not been a large study of the efficacy and safety of coronary revascularization with drug-eluting stents versus CABG in this population in a randomized trial cohort,” explained Usman Baber, MD, who reported the results at the annual congress of the European Society of Cardiology.

Bruce Jancin/Frontline Medical News

FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) randomized 1,900 diabetic patients with multivessel CAD to PCI or CABG. As previously reported, CABG proved superior to PCI, with a significantly lower rate of the composite primary endpoint composed of all-cause mortality, MI, or stroke (N Engl J Med. 2012 Dec 20;367[25]:2375-84).

Dr. Baber presented a post hoc analysis of the 451 FREEDOM participants with baseline comorbid chronic kidney disease (CKD). Their mean SYNTAX score was 27, and their mean baseline estimated glomerular filtration rate was 44 mL/min per 1.73 m², indicative of mild to moderate CKD.

“Only 28 patients in the FREEDOM trial had an estimated GFR below 30, therefore we can’t make any inferences about revascularization in that setting, which I think is a completely different population,” he noted.

The 5-year rate of major adverse cardiovascular and cerebrovascular events in patients with CKD was 26% in the CABG group, an absolute 9.4% less than the 35.6% rate in subjects randomized to PCI.

Roughly one-quarter of FREEDOM participants had CKD. They fared significantly worse than did those without CKD. The 5-year incidence of major adverse cardiovascular and cerebrovascular events was 30.8% in patients with CKD and 20.1% in patients without renal impairment. In a multivariate analysis adjusted for age, gender, hypertension, peripheral vascular disease, and other potential confounders, the risk of all-cause mortality was twofold higher in the CKD group. Their risk of cardiac death was increased 1.8-fold, and they were at 1.9-fold increased risk for stroke. Interestingly, however, the acute MI risk did not differ between patients with or without CKD, Dr. Baber observed.

Drilling deeper into the data, the cardiologist reported that CABG was associated with significantly lower rates of MI and a nonsignificant trend for fewer deaths, but with a significantly higher stroke rate than PCI.

One audience member rose to complain that this information won’t be helpful in counseling his diabetic patients with CKD and multivessel CAD because the choices look so grim: a higher risk of MI with percutaneous therapy, and a greater risk of stroke with surgery.

Dr. Baber replied by pointing out that the 10.8% absolute reduction in the risk of MI with CABG compared with PCI was more than twice as large as the absolute 4.6% increase in stroke risk with surgery.

“Most people would say that a heart attack is an inconvenience, and a stroke is a life-changing experience for them and their family,” said session cochair Kim A. Williams, MD, professor of medicine and chairman of cardiology at Rush University Medical Center in Chicago.

At that, Dr. Baber backtracked a bit, observing that since this was a post hoc analysis, the FREEDOM findings in patients with CKD must be viewed as hypothesis-generating rather than definitive. And, of course, contemporary second-generation drug-eluting stents have a better risk/benefit profile than do those used in FREEDOM.

“The number needed to treat/number needed to harm ratio for CABG and PCI probably ends up being roughly equal. The pertinence of an analysis like this is if you look at real-world registry-based data, you find a therapeutic nihilism that’s highly prevalent in CKD patients, where many patients who might benefit are not provided with revascularization therapy. It’s clear that we as clinicians – either because we don’t know there is a benefit or we are too concerned about potential harm – deprive patients of a treatment that might be beneficial. This analysis makes clinicians who might be concerned feel somewhat comforted that there is not unacceptable harm and that there is benefit,” Dr. Baber said.

Follow-up of FREEDOM participants continues and will be the subject of future reports, he added.

The FREEDOM trial was sponsored by the National Heart, Lung and Blood Institute. Dr. Baber reported having no financial conflicts of interest.

[email protected]

ROME – The use of coronary artery bypass graft surgery for revascularization in patients with multivessel CAD and comorbid diabetes plus chronic kidney disease was associated with a significantly lower risk of major cardiovascular and cerebrovascular events than was PCI with first-generation drug-eluting stents in a new secondary analysis from the landmark FREEDOM trial.

“The reason for this presentation is that even though chronic kidney disease is common in patients with diabetes, until now there has not been a large study of the efficacy and safety of coronary revascularization with drug-eluting stents versus CABG in this population in a randomized trial cohort,” explained Usman Baber, MD, who reported the results at the annual congress of the European Society of Cardiology.

Bruce Jancin/Frontline Medical News

FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) randomized 1,900 diabetic patients with multivessel CAD to PCI or CABG. As previously reported, CABG proved superior to PCI, with a significantly lower rate of the composite primary endpoint composed of all-cause mortality, MI, or stroke (N Engl J Med. 2012 Dec 20;367[25]:2375-84).

Dr. Baber presented a post hoc analysis of the 451 FREEDOM participants with baseline comorbid chronic kidney disease (CKD). Their mean SYNTAX score was 27, and their mean baseline estimated glomerular filtration rate was 44 mL/min per 1.73 m², indicative of mild to moderate CKD.

“Only 28 patients in the FREEDOM trial had an estimated GFR below 30, therefore we can’t make any inferences about revascularization in that setting, which I think is a completely different population,” he noted.

The 5-year rate of major adverse cardiovascular and cerebrovascular events in patients with CKD was 26% in the CABG group, an absolute 9.4% less than the 35.6% rate in subjects randomized to PCI.

Roughly one-quarter of FREEDOM participants had CKD. They fared significantly worse than did those without CKD. The 5-year incidence of major adverse cardiovascular and cerebrovascular events was 30.8% in patients with CKD and 20.1% in patients without renal impairment. In a multivariate analysis adjusted for age, gender, hypertension, peripheral vascular disease, and other potential confounders, the risk of all-cause mortality was twofold higher in the CKD group. Their risk of cardiac death was increased 1.8-fold, and they were at 1.9-fold increased risk for stroke. Interestingly, however, the acute MI risk did not differ between patients with or without CKD, Dr. Baber observed.

Drilling deeper into the data, the cardiologist reported that CABG was associated with significantly lower rates of MI and a nonsignificant trend for fewer deaths, but with a significantly higher stroke rate than PCI.

One audience member rose to complain that this information won’t be helpful in counseling his diabetic patients with CKD and multivessel CAD because the choices look so grim: a higher risk of MI with percutaneous therapy, and a greater risk of stroke with surgery.

Dr. Baber replied by pointing out that the 10.8% absolute reduction in the risk of MI with CABG compared with PCI was more than twice as large as the absolute 4.6% increase in stroke risk with surgery.

“Most people would say that a heart attack is an inconvenience, and a stroke is a life-changing experience for them and their family,” said session cochair Kim A. Williams, MD, professor of medicine and chairman of cardiology at Rush University Medical Center in Chicago.

At that, Dr. Baber backtracked a bit, observing that since this was a post hoc analysis, the FREEDOM findings in patients with CKD must be viewed as hypothesis-generating rather than definitive. And, of course, contemporary second-generation drug-eluting stents have a better risk/benefit profile than do those used in FREEDOM.

“The number needed to treat/number needed to harm ratio for CABG and PCI probably ends up being roughly equal. The pertinence of an analysis like this is if you look at real-world registry-based data, you find a therapeutic nihilism that’s highly prevalent in CKD patients, where many patients who might benefit are not provided with revascularization therapy. It’s clear that we as clinicians – either because we don’t know there is a benefit or we are too concerned about potential harm – deprive patients of a treatment that might be beneficial. This analysis makes clinicians who might be concerned feel somewhat comforted that there is not unacceptable harm and that there is benefit,” Dr. Baber said.

Follow-up of FREEDOM participants continues and will be the subject of future reports, he added.

The FREEDOM trial was sponsored by the National Heart, Lung and Blood Institute. Dr. Baber reported having no financial conflicts of interest.

[email protected]

Q) I work in a cardiology practice. Recently, a patient on dialysis mentioned that her nephrology practitioner recommended either home therapy or nocturnal dialysis. Why would someone recommend these, and what are the differences between home, nocturnal, and regular daytime dialysis?

Patients usually require dialysis when 90% or more of their renal function is lost.⁵ This can happen acutely or result from a chronic process. Dialysis performs many of the functions of a kidney, such as removing waste and fluid buildup that damaged kidneys cannot. It also helps maintain electrolyte balance.

There are several forms of hemodialysis including home, incenter, and nocturnal; the most frequently used is in-center hemodialysis.⁵ Patients on in-center hemodialysis visit the center three times a week, and their treatments last from three to five hours; the nationwide average is four hours. These patients have very restricted schedules and must maintain their appointments with limited flexibility. Food, drinks, and nonmedical personnel may not be allowed in the treatment area. Between treatments, patients must follow a diet that restricts fluid, sodium, and potassium intake.

Home dialysis has become a popular alternative, since it may be done in a location and at a time that is convenient for the patient. With more flexibility, many patients are able to continue working and feel like they have a more “normal” life. Types of home dialysis include home hemodialysis (HHD) or peritoneal dialysis (PD). A relative or friend may need to assist the patient during HHD, which is undergone more frequently (between five and seven days per week) and for a shorter duration of time than in-center dialysis. PD is done every day, either at night or multiple times throughout the day. Although no partner is needed for PD, a medical provider is available by phone to address any concerns that may arise during treatment.

Nocturnal hemodialysis is similar to daytime in-center hemodialysis, but it occurs while the patient is asleep. The treatment duration is longer (an average of eight hours per treatment). The slower blood flow allows for gentler dialysis. Patients who undergo nocturnal hemodialysis have higher survival and lower hospitalization rates, with better phosphorus control and blood pressure.⁶ This is attributed to the slower removal of excess fluid and more effective clearance of toxins.

So, why is your patient being encouraged to consider home or nocturnal dialysis? Studies have shown that for the cardiac patient, slower, gentler dialysis is preferable.⁷ The clinician who recommended it has the patient’s best interest in mind. —TAH

Tricia A. Howard, MHS, PA-C, DFAAPA
PA Program, South University, Savannah, Georgia

Q) I work in a cardiology practice. Recently, a patient on dialysis mentioned that her nephrology practitioner recommended either home therapy or nocturnal dialysis. Why would someone recommend these, and what are the differences between home, nocturnal, and regular daytime dialysis?

Patients usually require dialysis when 90% or more of their renal function is lost.⁵ This can happen acutely or result from a chronic process. Dialysis performs many of the functions of a kidney, such as removing waste and fluid buildup that damaged kidneys cannot. It also helps maintain electrolyte balance.

There are several forms of hemodialysis including home, incenter, and nocturnal; the most frequently used is in-center hemodialysis.⁵ Patients on in-center hemodialysis visit the center three times a week, and their treatments last from three to five hours; the nationwide average is four hours. These patients have very restricted schedules and must maintain their appointments with limited flexibility. Food, drinks, and nonmedical personnel may not be allowed in the treatment area. Between treatments, patients must follow a diet that restricts fluid, sodium, and potassium intake.

Home dialysis has become a popular alternative, since it may be done in a location and at a time that is convenient for the patient. With more flexibility, many patients are able to continue working and feel like they have a more “normal” life. Types of home dialysis include home hemodialysis (HHD) or peritoneal dialysis (PD). A relative or friend may need to assist the patient during HHD, which is undergone more frequently (between five and seven days per week) and for a shorter duration of time than in-center dialysis. PD is done every day, either at night or multiple times throughout the day. Although no partner is needed for PD, a medical provider is available by phone to address any concerns that may arise during treatment.

Nocturnal hemodialysis is similar to daytime in-center hemodialysis, but it occurs while the patient is asleep. The treatment duration is longer (an average of eight hours per treatment). The slower blood flow allows for gentler dialysis. Patients who undergo nocturnal hemodialysis have higher survival and lower hospitalization rates, with better phosphorus control and blood pressure.⁶ This is attributed to the slower removal of excess fluid and more effective clearance of toxins.

So, why is your patient being encouraged to consider home or nocturnal dialysis? Studies have shown that for the cardiac patient, slower, gentler dialysis is preferable.⁷ The clinician who recommended it has the patient’s best interest in mind. —TAH

Tricia A. Howard, MHS, PA-C, DFAAPA
PA Program, South University, Savannah, Georgia

Q) I work in a cardiology practice. Recently, a patient on dialysis mentioned that her nephrology practitioner recommended either home therapy or nocturnal dialysis. Why would someone recommend these, and what are the differences between home, nocturnal, and regular daytime dialysis?

Patients usually require dialysis when 90% or more of their renal function is lost.⁵ This can happen acutely or result from a chronic process. Dialysis performs many of the functions of a kidney, such as removing waste and fluid buildup that damaged kidneys cannot. It also helps maintain electrolyte balance.

There are several forms of hemodialysis including home, incenter, and nocturnal; the most frequently used is in-center hemodialysis.⁵ Patients on in-center hemodialysis visit the center three times a week, and their treatments last from three to five hours; the nationwide average is four hours. These patients have very restricted schedules and must maintain their appointments with limited flexibility. Food, drinks, and nonmedical personnel may not be allowed in the treatment area. Between treatments, patients must follow a diet that restricts fluid, sodium, and potassium intake.

Home dialysis has become a popular alternative, since it may be done in a location and at a time that is convenient for the patient. With more flexibility, many patients are able to continue working and feel like they have a more “normal” life. Types of home dialysis include home hemodialysis (HHD) or peritoneal dialysis (PD). A relative or friend may need to assist the patient during HHD, which is undergone more frequently (between five and seven days per week) and for a shorter duration of time than in-center dialysis. PD is done every day, either at night or multiple times throughout the day. Although no partner is needed for PD, a medical provider is available by phone to address any concerns that may arise during treatment.

Nocturnal hemodialysis is similar to daytime in-center hemodialysis, but it occurs while the patient is asleep. The treatment duration is longer (an average of eight hours per treatment). The slower blood flow allows for gentler dialysis. Patients who undergo nocturnal hemodialysis have higher survival and lower hospitalization rates, with better phosphorus control and blood pressure.⁶ This is attributed to the slower removal of excess fluid and more effective clearance of toxins.

So, why is your patient being encouraged to consider home or nocturnal dialysis? Studies have shown that for the cardiac patient, slower, gentler dialysis is preferable.⁷ The clinician who recommended it has the patient’s best interest in mind. —TAH

Tricia A. Howard, MHS, PA-C, DFAAPA
PA Program, South University, Savannah, Georgia

Q)

I’ve received mixed messages about whom to screen for chronic kidney disease (CKD). The US Preventive Services Task Force (USPSTF) recommends screening only patients at high risk, but kidney experts advise screening everyone. Who is right? What does the data show?

In 2012, the USPSTF stated that there was insufficient evidence to assess the benefit, or harm, of regularly screening asymptomatic adults for CKD.¹ Other expert medical panels have come to this conclusion as well, and therefore only recommend screening highrisk patients.²

The National Kidney Foundation (NKF) encourages clinicians to assess all patients for risk factors of CKD. Diabetes and hypertension are strongly established risk factors for kidney disease; others include family history of kidney disease; cardiovascular disease; obesity; and older age.

If a patient is at risk for CKD, the NKF recommends testing serum creatinine levels to estimate glomerular filtration rate and testing urine for protein (microalbuminuria or macroalbuminuria). These tests are readily accessible in a primary care setting. It should be noted that one-time testing of serum creatinine and/or urine has not been studied for sensitivity or specificity in the diagnosis of CKD. Diagnosis should be based on decreased renal function or kidney damage occurring over a three-month span.³

In May 2016, Canadian researchers published results from the See Kidney Disease Targeted Screening Program for CKD, comparing CKD screening in the general population with a targeted, at-risk individual population.⁴ The study, which included more than 6,000 participants, revealed a higher rate of unrecognized CKD in the at-risk population than in the general population (21.9% and 14.7%, respectively).

These findings support the idea that screening at-risk patients identifies more cases of CKD than screening the general patient population does.⁴ Early diagnosis of CKD, through recognition of risk factors, provides an opportunity to decrease complications and manage conditions that contribute to the progression of renal disease.^2,3 —RVR

Rebecca V. Rokosky, MSN, APRN, FNP
Renal Associates Clinical Advancement Center in San Antonio, Texas

Q)

I’ve received mixed messages about whom to screen for chronic kidney disease (CKD). The US Preventive Services Task Force (USPSTF) recommends screening only patients at high risk, but kidney experts advise screening everyone. Who is right? What does the data show?

In 2012, the USPSTF stated that there was insufficient evidence to assess the benefit, or harm, of regularly screening asymptomatic adults for CKD.¹ Other expert medical panels have come to this conclusion as well, and therefore only recommend screening highrisk patients.²

The National Kidney Foundation (NKF) encourages clinicians to assess all patients for risk factors of CKD. Diabetes and hypertension are strongly established risk factors for kidney disease; others include family history of kidney disease; cardiovascular disease; obesity; and older age.

If a patient is at risk for CKD, the NKF recommends testing serum creatinine levels to estimate glomerular filtration rate and testing urine for protein (microalbuminuria or macroalbuminuria). These tests are readily accessible in a primary care setting. It should be noted that one-time testing of serum creatinine and/or urine has not been studied for sensitivity or specificity in the diagnosis of CKD. Diagnosis should be based on decreased renal function or kidney damage occurring over a three-month span.³

In May 2016, Canadian researchers published results from the See Kidney Disease Targeted Screening Program for CKD, comparing CKD screening in the general population with a targeted, at-risk individual population.⁴ The study, which included more than 6,000 participants, revealed a higher rate of unrecognized CKD in the at-risk population than in the general population (21.9% and 14.7%, respectively).

These findings support the idea that screening at-risk patients identifies more cases of CKD than screening the general patient population does.⁴ Early diagnosis of CKD, through recognition of risk factors, provides an opportunity to decrease complications and manage conditions that contribute to the progression of renal disease.^2,3 —RVR

Rebecca V. Rokosky, MSN, APRN, FNP
Renal Associates Clinical Advancement Center in San Antonio, Texas

Q)

I’ve received mixed messages about whom to screen for chronic kidney disease (CKD). The US Preventive Services Task Force (USPSTF) recommends screening only patients at high risk, but kidney experts advise screening everyone. Who is right? What does the data show?

In 2012, the USPSTF stated that there was insufficient evidence to assess the benefit, or harm, of regularly screening asymptomatic adults for CKD.¹ Other expert medical panels have come to this conclusion as well, and therefore only recommend screening highrisk patients.²

The National Kidney Foundation (NKF) encourages clinicians to assess all patients for risk factors of CKD. Diabetes and hypertension are strongly established risk factors for kidney disease; others include family history of kidney disease; cardiovascular disease; obesity; and older age.

If a patient is at risk for CKD, the NKF recommends testing serum creatinine levels to estimate glomerular filtration rate and testing urine for protein (microalbuminuria or macroalbuminuria). These tests are readily accessible in a primary care setting. It should be noted that one-time testing of serum creatinine and/or urine has not been studied for sensitivity or specificity in the diagnosis of CKD. Diagnosis should be based on decreased renal function or kidney damage occurring over a three-month span.³

In May 2016, Canadian researchers published results from the See Kidney Disease Targeted Screening Program for CKD, comparing CKD screening in the general population with a targeted, at-risk individual population.⁴ The study, which included more than 6,000 participants, revealed a higher rate of unrecognized CKD in the at-risk population than in the general population (21.9% and 14.7%, respectively).

These findings support the idea that screening at-risk patients identifies more cases of CKD than screening the general patient population does.⁴ Early diagnosis of CKD, through recognition of risk factors, provides an opportunity to decrease complications and manage conditions that contribute to the progression of renal disease.^2,3 —RVR

Rebecca V. Rokosky, MSN, APRN, FNP
Renal Associates Clinical Advancement Center in San Antonio, Texas

A 72-year-old woman with type 2 diabetes mellitus, hypertension, and atrial fibrillation on anticoagulation was brought to the emergency department by her husband after 1 day of altered mental status with acute onset. Her husband reported that she had been minimally arousable, and the physical examination revealed that she was stuporous and withdrew extremities only from noxious stimuli.

Results of initial laboratory tests revealed a creatinine level of 2.4 mg/dL (reference range 0.7–1.4), hemoglobin 12.1 g/dL (12–16), platelet count 16 × 10⁹/L (150–400), white blood cell count of 7.7 × 10⁹/L (3.7–11), and international normalized ratio of 2.1. A peripheral blood smear is shown in Figure 1.

Computed tomography showed evidence of chronic small vascular ischemia. Magnetic resonance imaging of the brain showed numerous foci of restricted diffusion within the supratentorial and infratentorial areas, suggesting microembolic phenomena.

The peripheral blood smear was compatible with microangiopathic hemolytic anemia, which can occur in thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome, malignant hypertension, scleroderma, antiphospholipid antibody syndrome, systemic lupus erythematosus, eclampsia, renal allograft rejection, hematopoietic stem cell transplant, and severe sepsis.^1,2

In addition to hemolytic anemia, the patient also had neurologic abnormalities, renal involvement, and thrombocytopenia. The hemolytic anemia and thrombocytopenia were sufficient to raise our suspicion of TTP and to consider initiation of plasma exchange. Only 5% of patients with TTP demonstrate the classic pentad of clinical features,¹ ie, thrombocytopenia, microangiopathic hemolytic anemia, fluctuating neurologic signs, renal impairment, and fever.

In 1991, when plasma exchange was introduced for TTP, the survival rate of patients increased from 10% to 78%.^1,3 Thus, the diagnosis of TTP is an urgent indication for plasma exchange. We normally do plasma exchange daily until the platelet levels improve.

Our patient received methylprednisone 125 mg intravenously every 12 hours and plasma exchange daily. After three cycles of plasma exchange, she regained normal consciousness, and her platelet count had increased to 20.5 × 10⁹/L on the day of discharge from our hospital.

TTP is a life-threatening hematologic disorder. Evidence of microangiopathic hemolytic anemia on a peripheral blood smear is vital to the suspicion of TTP. The diagnosis should be confirmed by ADAMTS13 testing, which should show decreased activity (< 10%) or increased inhibition, or both. Rapid management with plasma exchange and steroids can lead to a satisfactory outcome.

Acknowledgment: We are particularly grateful to Dr. Vivian Arguello (Director of Flow Cytometry, Department of Pathology, Einstein Medical Center, Philadelphia) for her kind support with the blood smear image.

A 72-year-old woman with type 2 diabetes mellitus, hypertension, and atrial fibrillation on anticoagulation was brought to the emergency department by her husband after 1 day of altered mental status with acute onset. Her husband reported that she had been minimally arousable, and the physical examination revealed that she was stuporous and withdrew extremities only from noxious stimuli.

Results of initial laboratory tests revealed a creatinine level of 2.4 mg/dL (reference range 0.7–1.4), hemoglobin 12.1 g/dL (12–16), platelet count 16 × 10⁹/L (150–400), white blood cell count of 7.7 × 10⁹/L (3.7–11), and international normalized ratio of 2.1. A peripheral blood smear is shown in Figure 1.

Computed tomography showed evidence of chronic small vascular ischemia. Magnetic resonance imaging of the brain showed numerous foci of restricted diffusion within the supratentorial and infratentorial areas, suggesting microembolic phenomena.

The peripheral blood smear was compatible with microangiopathic hemolytic anemia, which can occur in thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome, malignant hypertension, scleroderma, antiphospholipid antibody syndrome, systemic lupus erythematosus, eclampsia, renal allograft rejection, hematopoietic stem cell transplant, and severe sepsis.^1,2

In addition to hemolytic anemia, the patient also had neurologic abnormalities, renal involvement, and thrombocytopenia. The hemolytic anemia and thrombocytopenia were sufficient to raise our suspicion of TTP and to consider initiation of plasma exchange. Only 5% of patients with TTP demonstrate the classic pentad of clinical features,¹ ie, thrombocytopenia, microangiopathic hemolytic anemia, fluctuating neurologic signs, renal impairment, and fever.

In 1991, when plasma exchange was introduced for TTP, the survival rate of patients increased from 10% to 78%.^1,3 Thus, the diagnosis of TTP is an urgent indication for plasma exchange. We normally do plasma exchange daily until the platelet levels improve.

Our patient received methylprednisone 125 mg intravenously every 12 hours and plasma exchange daily. After three cycles of plasma exchange, she regained normal consciousness, and her platelet count had increased to 20.5 × 10⁹/L on the day of discharge from our hospital.

TTP is a life-threatening hematologic disorder. Evidence of microangiopathic hemolytic anemia on a peripheral blood smear is vital to the suspicion of TTP. The diagnosis should be confirmed by ADAMTS13 testing, which should show decreased activity (< 10%) or increased inhibition, or both. Rapid management with plasma exchange and steroids can lead to a satisfactory outcome.

Acknowledgment: We are particularly grateful to Dr. Vivian Arguello (Director of Flow Cytometry, Department of Pathology, Einstein Medical Center, Philadelphia) for her kind support with the blood smear image.

A 72-year-old woman with type 2 diabetes mellitus, hypertension, and atrial fibrillation on anticoagulation was brought to the emergency department by her husband after 1 day of altered mental status with acute onset. Her husband reported that she had been minimally arousable, and the physical examination revealed that she was stuporous and withdrew extremities only from noxious stimuli.

Results of initial laboratory tests revealed a creatinine level of 2.4 mg/dL (reference range 0.7–1.4), hemoglobin 12.1 g/dL (12–16), platelet count 16 × 10⁹/L (150–400), white blood cell count of 7.7 × 10⁹/L (3.7–11), and international normalized ratio of 2.1. A peripheral blood smear is shown in Figure 1.

Computed tomography showed evidence of chronic small vascular ischemia. Magnetic resonance imaging of the brain showed numerous foci of restricted diffusion within the supratentorial and infratentorial areas, suggesting microembolic phenomena.

The peripheral blood smear was compatible with microangiopathic hemolytic anemia, which can occur in thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome, malignant hypertension, scleroderma, antiphospholipid antibody syndrome, systemic lupus erythematosus, eclampsia, renal allograft rejection, hematopoietic stem cell transplant, and severe sepsis.^1,2

In addition to hemolytic anemia, the patient also had neurologic abnormalities, renal involvement, and thrombocytopenia. The hemolytic anemia and thrombocytopenia were sufficient to raise our suspicion of TTP and to consider initiation of plasma exchange. Only 5% of patients with TTP demonstrate the classic pentad of clinical features,¹ ie, thrombocytopenia, microangiopathic hemolytic anemia, fluctuating neurologic signs, renal impairment, and fever.

In 1991, when plasma exchange was introduced for TTP, the survival rate of patients increased from 10% to 78%.^1,3 Thus, the diagnosis of TTP is an urgent indication for plasma exchange. We normally do plasma exchange daily until the platelet levels improve.

Our patient received methylprednisone 125 mg intravenously every 12 hours and plasma exchange daily. After three cycles of plasma exchange, she regained normal consciousness, and her platelet count had increased to 20.5 × 10⁹/L on the day of discharge from our hospital.

TTP is a life-threatening hematologic disorder. Evidence of microangiopathic hemolytic anemia on a peripheral blood smear is vital to the suspicion of TTP. The diagnosis should be confirmed by ADAMTS13 testing, which should show decreased activity (< 10%) or increased inhibition, or both. Rapid management with plasma exchange and steroids can lead to a satisfactory outcome.

Acknowledgment: We are particularly grateful to Dr. Vivian Arguello (Director of Flow Cytometry, Department of Pathology, Einstein Medical Center, Philadelphia) for her kind support with the blood smear image.

Patients with highly active lupus nephritis who took the investigational oral calcineurin inhibitor voclosporin plus mycophenolate mofetil and tapered corticosteroids were twice as likely to achieve complete remission by 24 weeks, compared against placebo-treated patients who also received standard of care treatment in a phase IIb study trial reported by Aurinia Pharmaceuticals.

The 24-week complete remission primary endpoint of the AURA-LV(Aurinia Urinary Protein Reduction Active–Lupus With Voclosporin) study – defined as a urine protein/creatinine ratio of 0.5 mg/mg or less as well as normal stable renal function (estimated glomerular filtration rate of 60 mL/min per 1.73 m² or greater or no confirmed decrease from baseline in eGFR of 20% or greater) – occurred in 32.6% of patients who were randomized to take 23.7 mg of voclosporin twice daily, which was significantly higher than the 19.3% rate observed in the placebo-treated group. The rate was 27.3% in a higher-dose group that received 39.5 mg of voclosporin twice daily.

©London_England/Thinkstock

Serious adverse events occurred at higher rates in both voclosporin arms of the trial than in the placebo arm, but Aurinia said in its statement announcing the results that the nature of the events was consistent with highly active lupus nephritis. A total of 13 deaths occurred, including 2 in the high-dose arm, 10 in the low-dose arm, and 1 in the placebo arm, but the company said that the investigator deemed the deaths as unrelated to voclosporin. Eleven of the deaths occurred in Asia.

Both low- and high-dose voclosporin arms attained a partial response by 24 weeks (50% drop in urine protein per creatinine ratio) in a significantly higher percentage of patients than did the placebo arm (69.7% and 65.9%, respectively, vs. 49.4%).

The Lupus Research Alliance welcomed the results of the study but noted that more needs to be known about the risk-benefit profile of the drug, specifically in reference to the 12 deaths reported in those who took voclosporin. “The magnitude of benefit is quite striking and unprecedented in lupus nephritis, but the number of deaths is a concern that must be taken seriously. We are very hopeful that further analysis of the safety data will confirm that voclosporin can provide a safe and effective treatment,” Margaret G. Dowd, co–chief executive officer of the Lupus Research Alliance, said in a statement.

The trial enrolled and randomized 265 patients diagnosed with highly active lupus nephritis (according to clinical signs and renal biopsy features) across centers in more than 20 countries. Besides being randomized to either active treatment arm or placebo, all patients received mycophenolate mofetil (CellCept) and oral corticosteroids that started at 20-25 mg/daily and then tapered down to 5 mg daily by week 8 and 2.5 mg daily by week 16. All patients also had an initial 500-1,000 mg intravenous dose of steroids.

Aurinia said that the study will continue to 48 weeks, and these data will be available in early 2017.

[email protected]

Patients with highly active lupus nephritis who took the investigational oral calcineurin inhibitor voclosporin plus mycophenolate mofetil and tapered corticosteroids were twice as likely to achieve complete remission by 24 weeks, compared against placebo-treated patients who also received standard of care treatment in a phase IIb study trial reported by Aurinia Pharmaceuticals.

The 24-week complete remission primary endpoint of the AURA-LV(Aurinia Urinary Protein Reduction Active–Lupus With Voclosporin) study – defined as a urine protein/creatinine ratio of 0.5 mg/mg or less as well as normal stable renal function (estimated glomerular filtration rate of 60 mL/min per 1.73 m² or greater or no confirmed decrease from baseline in eGFR of 20% or greater) – occurred in 32.6% of patients who were randomized to take 23.7 mg of voclosporin twice daily, which was significantly higher than the 19.3% rate observed in the placebo-treated group. The rate was 27.3% in a higher-dose group that received 39.5 mg of voclosporin twice daily.

©London_England/Thinkstock

Serious adverse events occurred at higher rates in both voclosporin arms of the trial than in the placebo arm, but Aurinia said in its statement announcing the results that the nature of the events was consistent with highly active lupus nephritis. A total of 13 deaths occurred, including 2 in the high-dose arm, 10 in the low-dose arm, and 1 in the placebo arm, but the company said that the investigator deemed the deaths as unrelated to voclosporin. Eleven of the deaths occurred in Asia.

Both low- and high-dose voclosporin arms attained a partial response by 24 weeks (50% drop in urine protein per creatinine ratio) in a significantly higher percentage of patients than did the placebo arm (69.7% and 65.9%, respectively, vs. 49.4%).

The Lupus Research Alliance welcomed the results of the study but noted that more needs to be known about the risk-benefit profile of the drug, specifically in reference to the 12 deaths reported in those who took voclosporin. “The magnitude of benefit is quite striking and unprecedented in lupus nephritis, but the number of deaths is a concern that must be taken seriously. We are very hopeful that further analysis of the safety data will confirm that voclosporin can provide a safe and effective treatment,” Margaret G. Dowd, co–chief executive officer of the Lupus Research Alliance, said in a statement.

The trial enrolled and randomized 265 patients diagnosed with highly active lupus nephritis (according to clinical signs and renal biopsy features) across centers in more than 20 countries. Besides being randomized to either active treatment arm or placebo, all patients received mycophenolate mofetil (CellCept) and oral corticosteroids that started at 20-25 mg/daily and then tapered down to 5 mg daily by week 8 and 2.5 mg daily by week 16. All patients also had an initial 500-1,000 mg intravenous dose of steroids.

Aurinia said that the study will continue to 48 weeks, and these data will be available in early 2017.

[email protected]

Patients with highly active lupus nephritis who took the investigational oral calcineurin inhibitor voclosporin plus mycophenolate mofetil and tapered corticosteroids were twice as likely to achieve complete remission by 24 weeks, compared against placebo-treated patients who also received standard of care treatment in a phase IIb study trial reported by Aurinia Pharmaceuticals.

The 24-week complete remission primary endpoint of the AURA-LV(Aurinia Urinary Protein Reduction Active–Lupus With Voclosporin) study – defined as a urine protein/creatinine ratio of 0.5 mg/mg or less as well as normal stable renal function (estimated glomerular filtration rate of 60 mL/min per 1.73 m² or greater or no confirmed decrease from baseline in eGFR of 20% or greater) – occurred in 32.6% of patients who were randomized to take 23.7 mg of voclosporin twice daily, which was significantly higher than the 19.3% rate observed in the placebo-treated group. The rate was 27.3% in a higher-dose group that received 39.5 mg of voclosporin twice daily.

©London_England/Thinkstock

Serious adverse events occurred at higher rates in both voclosporin arms of the trial than in the placebo arm, but Aurinia said in its statement announcing the results that the nature of the events was consistent with highly active lupus nephritis. A total of 13 deaths occurred, including 2 in the high-dose arm, 10 in the low-dose arm, and 1 in the placebo arm, but the company said that the investigator deemed the deaths as unrelated to voclosporin. Eleven of the deaths occurred in Asia.

Both low- and high-dose voclosporin arms attained a partial response by 24 weeks (50% drop in urine protein per creatinine ratio) in a significantly higher percentage of patients than did the placebo arm (69.7% and 65.9%, respectively, vs. 49.4%).

The Lupus Research Alliance welcomed the results of the study but noted that more needs to be known about the risk-benefit profile of the drug, specifically in reference to the 12 deaths reported in those who took voclosporin. “The magnitude of benefit is quite striking and unprecedented in lupus nephritis, but the number of deaths is a concern that must be taken seriously. We are very hopeful that further analysis of the safety data will confirm that voclosporin can provide a safe and effective treatment,” Margaret G. Dowd, co–chief executive officer of the Lupus Research Alliance, said in a statement.

The trial enrolled and randomized 265 patients diagnosed with highly active lupus nephritis (according to clinical signs and renal biopsy features) across centers in more than 20 countries. Besides being randomized to either active treatment arm or placebo, all patients received mycophenolate mofetil (CellCept) and oral corticosteroids that started at 20-25 mg/daily and then tapered down to 5 mg daily by week 8 and 2.5 mg daily by week 16. All patients also had an initial 500-1,000 mg intravenous dose of steroids.

Aurinia said that the study will continue to 48 weeks, and these data will be available in early 2017.

[email protected]

DURBAN, SOUTH AFRICA – The optimal frequency of kidney safety monitoring in patients using oral daily tenofovir/emtricitabine for pre-exposure prophylaxis against HIV infection is every 6 months, but less frequent monitoring may be reasonable in most low-risk patients, Renee Heffron, PhD, said at the 21st International AIDS Conference.

The occurrence and pattern of detection of a drop in creatinine clearance to less than 60 mL/min during the first 12 months of therapy didn’t differ significantly regardless of whether monitoring was done at 3- or 6-month intervals. The risk of a clinically relevant decline in creatinine clearance during the first 12 months of therapy appears to be largely confined to the subgroup of patients on tenofovir/emtricitabine (Truvada) for pre-exposure prophylaxis (PrEP) who weigh 55 kg or less, have a baseline creatinine clearance rate of 60-90 mL/min, or are at least 45 years old, according to Dr. Heffron of the University of Washington, Seattle.

Bruce Jancin/Frontline Medical News

The question of how frequently to monitor renal function is a key issue as PrEP with tenofovir/emtricitabine is ramped up to scale in sub-Saharan Africa and other parts of the developing world where the majority of new HIV infections occur – and where laboratory resources are often limited. The randomized clinical trials that led to marketing approval of tenofovir/emtricitabine for PrEP in the United States and elsewhere monitored creatinine clearance every 3 months. But the confirmatory demonstration projects used a range of kidney monitoring schedules, she explained.

She presented an analysis of clinically relevant kidney toxicity in 4,404 initially HIV-negative subjects on tenofovir/emtricitabine in the Partners PrEP Study, in which creatinine clearance was measured every 3 months, and in 955 participants in the Partners Demonstration Study, in which monitoring was performed every 6 months. All participants were at high risk for HIV acquisition because they were members of serodiscordant couples.

The occurrence and pattern of detection of a drop in creatinine clearance to less than 60 mL/min during the first 12 months of therapy didn’t differ significantly regardless of whether monitoring was done at 3- or 6-month intervals. The cumulative rate in the randomized trial was 0.4%, 0.5%, and 0.7% at 3, 6, and 12 months, and it was 0.2% at both 6 and 12 months in the demonstration project, Dr. Heffron reported.

These renal events were not only rare, they were reassuringly nonprogressive and resolved within a few weeks of PrEP discontinuation, she added.

Her analysis of the combined 5,359 subjects in the two Partners studies identified three independent predictors of a fall in creatinine clearance to below 60 mL/min during the first 12 months of therapy. A baseline age of 45 years or more was associated with an adjusted 2.5-fold increase, compared with younger patients. Subjects with a creatinine clearance of 60-90 mL/min at enrollment were 74 times more likely to experience a significant drop in creatinine clearance than those who started on PrEP with a creatinine clearance rate in excess of 90 mL/min. And patients weighing 55 kg or less had a 2.7-fold greater risk than those weighing more. But fewer than 5% of patients with any of these three predictors actually experienced a drop in creatinine clearance to below 60 mL/min.

The data from the two Partners studies support guidelines from the Centers for Disease Control and Prevention recommending creatinine monitoring every 6 months for people on oral daily PrEP. Still, patients with one of the defined risk factors might logically be candidates for targeted monitoring, Dr. Heffron observed.

The Partners studies were funded by the National Institutes of Health, the Bill and Melinda Gates Foundation, and the U.S. Agency for International Development. Dr. Heffron reported having no financial conflicts of interest.

[email protected]

DURBAN, SOUTH AFRICA – The optimal frequency of kidney safety monitoring in patients using oral daily tenofovir/emtricitabine for pre-exposure prophylaxis against HIV infection is every 6 months, but less frequent monitoring may be reasonable in most low-risk patients, Renee Heffron, PhD, said at the 21st International AIDS Conference.

The occurrence and pattern of detection of a drop in creatinine clearance to less than 60 mL/min during the first 12 months of therapy didn’t differ significantly regardless of whether monitoring was done at 3- or 6-month intervals. The risk of a clinically relevant decline in creatinine clearance during the first 12 months of therapy appears to be largely confined to the subgroup of patients on tenofovir/emtricitabine (Truvada) for pre-exposure prophylaxis (PrEP) who weigh 55 kg or less, have a baseline creatinine clearance rate of 60-90 mL/min, or are at least 45 years old, according to Dr. Heffron of the University of Washington, Seattle.

Bruce Jancin/Frontline Medical News

The question of how frequently to monitor renal function is a key issue as PrEP with tenofovir/emtricitabine is ramped up to scale in sub-Saharan Africa and other parts of the developing world where the majority of new HIV infections occur – and where laboratory resources are often limited. The randomized clinical trials that led to marketing approval of tenofovir/emtricitabine for PrEP in the United States and elsewhere monitored creatinine clearance every 3 months. But the confirmatory demonstration projects used a range of kidney monitoring schedules, she explained.

She presented an analysis of clinically relevant kidney toxicity in 4,404 initially HIV-negative subjects on tenofovir/emtricitabine in the Partners PrEP Study, in which creatinine clearance was measured every 3 months, and in 955 participants in the Partners Demonstration Study, in which monitoring was performed every 6 months. All participants were at high risk for HIV acquisition because they were members of serodiscordant couples.

The occurrence and pattern of detection of a drop in creatinine clearance to less than 60 mL/min during the first 12 months of therapy didn’t differ significantly regardless of whether monitoring was done at 3- or 6-month intervals. The cumulative rate in the randomized trial was 0.4%, 0.5%, and 0.7% at 3, 6, and 12 months, and it was 0.2% at both 6 and 12 months in the demonstration project, Dr. Heffron reported.

These renal events were not only rare, they were reassuringly nonprogressive and resolved within a few weeks of PrEP discontinuation, she added.

Her analysis of the combined 5,359 subjects in the two Partners studies identified three independent predictors of a fall in creatinine clearance to below 60 mL/min during the first 12 months of therapy. A baseline age of 45 years or more was associated with an adjusted 2.5-fold increase, compared with younger patients. Subjects with a creatinine clearance of 60-90 mL/min at enrollment were 74 times more likely to experience a significant drop in creatinine clearance than those who started on PrEP with a creatinine clearance rate in excess of 90 mL/min. And patients weighing 55 kg or less had a 2.7-fold greater risk than those weighing more. But fewer than 5% of patients with any of these three predictors actually experienced a drop in creatinine clearance to below 60 mL/min.

The data from the two Partners studies support guidelines from the Centers for Disease Control and Prevention recommending creatinine monitoring every 6 months for people on oral daily PrEP. Still, patients with one of the defined risk factors might logically be candidates for targeted monitoring, Dr. Heffron observed.

The Partners studies were funded by the National Institutes of Health, the Bill and Melinda Gates Foundation, and the U.S. Agency for International Development. Dr. Heffron reported having no financial conflicts of interest.

[email protected]

DURBAN, SOUTH AFRICA – The optimal frequency of kidney safety monitoring in patients using oral daily tenofovir/emtricitabine for pre-exposure prophylaxis against HIV infection is every 6 months, but less frequent monitoring may be reasonable in most low-risk patients, Renee Heffron, PhD, said at the 21st International AIDS Conference.

The occurrence and pattern of detection of a drop in creatinine clearance to less than 60 mL/min during the first 12 months of therapy didn’t differ significantly regardless of whether monitoring was done at 3- or 6-month intervals. The risk of a clinically relevant decline in creatinine clearance during the first 12 months of therapy appears to be largely confined to the subgroup of patients on tenofovir/emtricitabine (Truvada) for pre-exposure prophylaxis (PrEP) who weigh 55 kg or less, have a baseline creatinine clearance rate of 60-90 mL/min, or are at least 45 years old, according to Dr. Heffron of the University of Washington, Seattle.

Bruce Jancin/Frontline Medical News

The question of how frequently to monitor renal function is a key issue as PrEP with tenofovir/emtricitabine is ramped up to scale in sub-Saharan Africa and other parts of the developing world where the majority of new HIV infections occur – and where laboratory resources are often limited. The randomized clinical trials that led to marketing approval of tenofovir/emtricitabine for PrEP in the United States and elsewhere monitored creatinine clearance every 3 months. But the confirmatory demonstration projects used a range of kidney monitoring schedules, she explained.

She presented an analysis of clinically relevant kidney toxicity in 4,404 initially HIV-negative subjects on tenofovir/emtricitabine in the Partners PrEP Study, in which creatinine clearance was measured every 3 months, and in 955 participants in the Partners Demonstration Study, in which monitoring was performed every 6 months. All participants were at high risk for HIV acquisition because they were members of serodiscordant couples.

The occurrence and pattern of detection of a drop in creatinine clearance to less than 60 mL/min during the first 12 months of therapy didn’t differ significantly regardless of whether monitoring was done at 3- or 6-month intervals. The cumulative rate in the randomized trial was 0.4%, 0.5%, and 0.7% at 3, 6, and 12 months, and it was 0.2% at both 6 and 12 months in the demonstration project, Dr. Heffron reported.

These renal events were not only rare, they were reassuringly nonprogressive and resolved within a few weeks of PrEP discontinuation, she added.

Her analysis of the combined 5,359 subjects in the two Partners studies identified three independent predictors of a fall in creatinine clearance to below 60 mL/min during the first 12 months of therapy. A baseline age of 45 years or more was associated with an adjusted 2.5-fold increase, compared with younger patients. Subjects with a creatinine clearance of 60-90 mL/min at enrollment were 74 times more likely to experience a significant drop in creatinine clearance than those who started on PrEP with a creatinine clearance rate in excess of 90 mL/min. And patients weighing 55 kg or less had a 2.7-fold greater risk than those weighing more. But fewer than 5% of patients with any of these three predictors actually experienced a drop in creatinine clearance to below 60 mL/min.

The data from the two Partners studies support guidelines from the Centers for Disease Control and Prevention recommending creatinine monitoring every 6 months for people on oral daily PrEP. Still, patients with one of the defined risk factors might logically be candidates for targeted monitoring, Dr. Heffron observed.

The Partners studies were funded by the National Institutes of Health, the Bill and Melinda Gates Foundation, and the U.S. Agency for International Development. Dr. Heffron reported having no financial conflicts of interest.

[email protected]

Certain children are more highly predisposed to contracting a urinary tract infection caused by a pathogen other than Escherichia coli, which is typically the most common cause of UTIs, a study showed.

“It may be clinically important to predict which children have UTIs caused by organisms other than E. coli because these organisms differ in their patterns of antimicrobial susceptibility,” wrote the study authors led by Nader Shaikh, MD, of the University of Pittsburgh. “Furthermore, some guidelines have suggested that screening for vesicoureteral reflux (VUR) with a voiding cystourethrogram (VCUG) should, at least in part, be based on whether an organism other than E. coli is recovered,” they wrote.

Dr. Shaikh and his coinvestigators examined the medical records of children in the Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR) trial and the Careful Urinary Tract Infection Evaluation (CUTIE), both of which were prospective multicenter studies. Children included in both studies were 2-71 months of age; RIVUR subjects had VUR grades 1-4 and presented with either a first or second febrile or symptomatic UTI, while CUTIE subjects presented with either their first or second UTI but not VUR (Ped Inf Dis J. 2016. doi:10.1097/INF.0000000000001301).

In total, 769 children from 19 centers were included from both studies, of which 703 (91%) were female and 596 (78%) were white. Nine percent of all the children had UTIs that were not caused by E. coli. Circumcised males had the highest odds ratio associated with non–E. coli UTIs, with an OR of 5.5 (95% CI, 1.18-17.1; P = .003). significantly higher than the 1.6 odds ratio for uncircumcised males (95% CI, 0.6-4.6; P = .35).

Hispanic children also had a higher risk (OR = 2.3; 95% CI, 1.1-4.6; P = .02) than either non-Hispanic children or females, which were reference cohorts. Other groups found to be at higher-than-normal risk for non–E. coli UTIs were children without fever (OR = 2.8; 95% CI, 1.2-6.6; P = .02) and children with VUR grade 3 or 4 (OR = 2.2; 95% CI, 1.2-4.1; P = .01).

While more than 90% of children’s UTIs were caused by E. coli, the most common pathogens causing UTIs, causative organisms in the other 70 children were Proteus species (21 children, 30%), Klebsiella species (16, 23%), Enterococcus species (14, 20%), Enterobacter species (8, 11%), and “other species” (11, 16%).

“Children with UTIs caused by organisms other than E. coli were twice as likely to have high-grade VUR (grade 3 and 4), which is consistent with prior studies,” Dr. Shaikh and his coauthors noted, adding, “the association between Hispanic ethnicity and non-E. coli pathogens is novel and may be due to differences in genes involved with susceptibility to UTIs.”

There were no disclosures or sources of funding provided.

[email protected]

Certain children are more highly predisposed to contracting a urinary tract infection caused by a pathogen other than Escherichia coli, which is typically the most common cause of UTIs, a study showed.

“It may be clinically important to predict which children have UTIs caused by organisms other than E. coli because these organisms differ in their patterns of antimicrobial susceptibility,” wrote the study authors led by Nader Shaikh, MD, of the University of Pittsburgh. “Furthermore, some guidelines have suggested that screening for vesicoureteral reflux (VUR) with a voiding cystourethrogram (VCUG) should, at least in part, be based on whether an organism other than E. coli is recovered,” they wrote.

Dr. Shaikh and his coinvestigators examined the medical records of children in the Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR) trial and the Careful Urinary Tract Infection Evaluation (CUTIE), both of which were prospective multicenter studies. Children included in both studies were 2-71 months of age; RIVUR subjects had VUR grades 1-4 and presented with either a first or second febrile or symptomatic UTI, while CUTIE subjects presented with either their first or second UTI but not VUR (Ped Inf Dis J. 2016. doi:10.1097/INF.0000000000001301).

In total, 769 children from 19 centers were included from both studies, of which 703 (91%) were female and 596 (78%) were white. Nine percent of all the children had UTIs that were not caused by E. coli. Circumcised males had the highest odds ratio associated with non–E. coli UTIs, with an OR of 5.5 (95% CI, 1.18-17.1; P = .003). significantly higher than the 1.6 odds ratio for uncircumcised males (95% CI, 0.6-4.6; P = .35).

Hispanic children also had a higher risk (OR = 2.3; 95% CI, 1.1-4.6; P = .02) than either non-Hispanic children or females, which were reference cohorts. Other groups found to be at higher-than-normal risk for non–E. coli UTIs were children without fever (OR = 2.8; 95% CI, 1.2-6.6; P = .02) and children with VUR grade 3 or 4 (OR = 2.2; 95% CI, 1.2-4.1; P = .01).

While more than 90% of children’s UTIs were caused by E. coli, the most common pathogens causing UTIs, causative organisms in the other 70 children were Proteus species (21 children, 30%), Klebsiella species (16, 23%), Enterococcus species (14, 20%), Enterobacter species (8, 11%), and “other species” (11, 16%).

“Children with UTIs caused by organisms other than E. coli were twice as likely to have high-grade VUR (grade 3 and 4), which is consistent with prior studies,” Dr. Shaikh and his coauthors noted, adding, “the association between Hispanic ethnicity and non-E. coli pathogens is novel and may be due to differences in genes involved with susceptibility to UTIs.”

There were no disclosures or sources of funding provided.

[email protected]

Certain children are more highly predisposed to contracting a urinary tract infection caused by a pathogen other than Escherichia coli, which is typically the most common cause of UTIs, a study showed.

“It may be clinically important to predict which children have UTIs caused by organisms other than E. coli because these organisms differ in their patterns of antimicrobial susceptibility,” wrote the study authors led by Nader Shaikh, MD, of the University of Pittsburgh. “Furthermore, some guidelines have suggested that screening for vesicoureteral reflux (VUR) with a voiding cystourethrogram (VCUG) should, at least in part, be based on whether an organism other than E. coli is recovered,” they wrote.

Dr. Shaikh and his coinvestigators examined the medical records of children in the Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR) trial and the Careful Urinary Tract Infection Evaluation (CUTIE), both of which were prospective multicenter studies. Children included in both studies were 2-71 months of age; RIVUR subjects had VUR grades 1-4 and presented with either a first or second febrile or symptomatic UTI, while CUTIE subjects presented with either their first or second UTI but not VUR (Ped Inf Dis J. 2016. doi:10.1097/INF.0000000000001301).

In total, 769 children from 19 centers were included from both studies, of which 703 (91%) were female and 596 (78%) were white. Nine percent of all the children had UTIs that were not caused by E. coli. Circumcised males had the highest odds ratio associated with non–E. coli UTIs, with an OR of 5.5 (95% CI, 1.18-17.1; P = .003). significantly higher than the 1.6 odds ratio for uncircumcised males (95% CI, 0.6-4.6; P = .35).

Hispanic children also had a higher risk (OR = 2.3; 95% CI, 1.1-4.6; P = .02) than either non-Hispanic children or females, which were reference cohorts. Other groups found to be at higher-than-normal risk for non–E. coli UTIs were children without fever (OR = 2.8; 95% CI, 1.2-6.6; P = .02) and children with VUR grade 3 or 4 (OR = 2.2; 95% CI, 1.2-4.1; P = .01).

While more than 90% of children’s UTIs were caused by E. coli, the most common pathogens causing UTIs, causative organisms in the other 70 children were Proteus species (21 children, 30%), Klebsiella species (16, 23%), Enterococcus species (14, 20%), Enterobacter species (8, 11%), and “other species” (11, 16%).

“Children with UTIs caused by organisms other than E. coli were twice as likely to have high-grade VUR (grade 3 and 4), which is consistent with prior studies,” Dr. Shaikh and his coauthors noted, adding, “the association between Hispanic ethnicity and non-E. coli pathogens is novel and may be due to differences in genes involved with susceptibility to UTIs.”

There were no disclosures or sources of funding provided.

[email protected]

Vasopressin was no better than norepinephrine in preventing kidney failure when used as a first-line treatment for septic shock, according to a report published online Aug. 2 in JAMA.

In a multicenter, double-blind, randomized trial comparing the two approaches in 408 ICU patients with septic shock, the early use of vasopressin didn’t reduce the number of days free of kidney failure, compared with standard norepinephrine.

©decade3d/thinkstockphotos.com

However, “the 95% confidence intervals of the difference between [study] groups has an upper limit of 5 days in favor of vasopressin, which could be clinically important,” said Anthony C. Gordon, MD, of Charing Cross Hospital and Imperial College London, and his associates. “Therefore, these results are still consistent with a potentially clinically important benefit for vasopressin; but a larger trial would be needed to confirm or refute this.”

Norepinephrine is the recommended first-line vasopressor for septic shock, but “there has been a growing interest in the use of vasopressin” ever since researchers described a relative deficiency of vasopressin in the disorder, Dr. Gordon and his associates noted.

“Preclinical and small clinical studies have suggested that vasopressin may be better able to maintain glomerular filtration rate and improve creatinine clearance, compared with norepinephrine,” the investigators said, and other studies have suggested that combining vasopressin with corticosteroids may prevent deterioration in organ function and reduce the duration of shock, thereby improving survival.

To examine those possibilities, they performed the VANISH (Vasopressin vs. Norepinephrine as Initial Therapy in Septic Shock) trial, assessing patients age 16 years and older at 18 general adult ICUs in the United Kingdom during a 2-year period. The study participants were randomly assigned to receive vasopressin plus hydrocortisone (100 patients), vasopressin plus matching placebo (104 patients), norepinephrine plus hydrocortisone (101 patients), or norepinephrine plus matching placebo (103 patients).

The primary outcome measure was the number of days alive and free of kidney failure during the 28 days following randomization. There was no significant difference among the four study groups in the number or the distribution of kidney-failure–free days, the investigators said (JAMA. 2016 Aug 2. doi: 10.1001/jama.2016.10485).

In addition, the percentage of survivors who never developed kidney failure was not significantly different between the two groups who received vasopressin (57.0%) and the two who received norepinephrine (59.2%). And the median number of days free of kidney failure in the subgroup of patients who died or developed kidney failure was not significantly different between those receiving vasopressin (9 days) and those receiving norepinephrine (13 days).

The quantities of IV fluids administered, the total fluid balance, serum lactate levels, and heart rate were all similar across the four study groups. There also was no significant difference in 28-day mortality between patients who received vasopressin (30.9%) and those who received norepinephrine (27.5%). Adverse event profiles also were comparable.

However, the rate of renal replacement therapy was 25.4% with vasopressin, significantly lower than the 35.3% rate in the norepinephrine group. The use of such therapy was not controlled in the trial and was initiated according to the treating physicians’ preference. “It is therefore not possible to know why renal replacement therapy was or was not started,” Dr. Gordon and his associates noted.

The use of renal replacement therapy wasn’t a primary outcome of the trial. Nevertheless, it is an important patient-centered outcome and may be a factor to consider when treating adults who have septic shock, the researchers added.

The study was supported by the U.K. National Institute for Health Research and the U.K. Intensive Care Foundation. Dr. Gordon reported ties to Ferring, HCA International, Orion, and Tenax Therapeutics; his associates reported having no relevant financial disclosures.

Vasopressin was no better than norepinephrine in preventing kidney failure when used as a first-line treatment for septic shock, according to a report published online Aug. 2 in JAMA.

In a multicenter, double-blind, randomized trial comparing the two approaches in 408 ICU patients with septic shock, the early use of vasopressin didn’t reduce the number of days free of kidney failure, compared with standard norepinephrine.

©decade3d/thinkstockphotos.com

However, “the 95% confidence intervals of the difference between [study] groups has an upper limit of 5 days in favor of vasopressin, which could be clinically important,” said Anthony C. Gordon, MD, of Charing Cross Hospital and Imperial College London, and his associates. “Therefore, these results are still consistent with a potentially clinically important benefit for vasopressin; but a larger trial would be needed to confirm or refute this.”

Norepinephrine is the recommended first-line vasopressor for septic shock, but “there has been a growing interest in the use of vasopressin” ever since researchers described a relative deficiency of vasopressin in the disorder, Dr. Gordon and his associates noted.

“Preclinical and small clinical studies have suggested that vasopressin may be better able to maintain glomerular filtration rate and improve creatinine clearance, compared with norepinephrine,” the investigators said, and other studies have suggested that combining vasopressin with corticosteroids may prevent deterioration in organ function and reduce the duration of shock, thereby improving survival.

To examine those possibilities, they performed the VANISH (Vasopressin vs. Norepinephrine as Initial Therapy in Septic Shock) trial, assessing patients age 16 years and older at 18 general adult ICUs in the United Kingdom during a 2-year period. The study participants were randomly assigned to receive vasopressin plus hydrocortisone (100 patients), vasopressin plus matching placebo (104 patients), norepinephrine plus hydrocortisone (101 patients), or norepinephrine plus matching placebo (103 patients).

The primary outcome measure was the number of days alive and free of kidney failure during the 28 days following randomization. There was no significant difference among the four study groups in the number or the distribution of kidney-failure–free days, the investigators said (JAMA. 2016 Aug 2. doi: 10.1001/jama.2016.10485).

In addition, the percentage of survivors who never developed kidney failure was not significantly different between the two groups who received vasopressin (57.0%) and the two who received norepinephrine (59.2%). And the median number of days free of kidney failure in the subgroup of patients who died or developed kidney failure was not significantly different between those receiving vasopressin (9 days) and those receiving norepinephrine (13 days).

The quantities of IV fluids administered, the total fluid balance, serum lactate levels, and heart rate were all similar across the four study groups. There also was no significant difference in 28-day mortality between patients who received vasopressin (30.9%) and those who received norepinephrine (27.5%). Adverse event profiles also were comparable.

However, the rate of renal replacement therapy was 25.4% with vasopressin, significantly lower than the 35.3% rate in the norepinephrine group. The use of such therapy was not controlled in the trial and was initiated according to the treating physicians’ preference. “It is therefore not possible to know why renal replacement therapy was or was not started,” Dr. Gordon and his associates noted.

The use of renal replacement therapy wasn’t a primary outcome of the trial. Nevertheless, it is an important patient-centered outcome and may be a factor to consider when treating adults who have septic shock, the researchers added.

The study was supported by the U.K. National Institute for Health Research and the U.K. Intensive Care Foundation. Dr. Gordon reported ties to Ferring, HCA International, Orion, and Tenax Therapeutics; his associates reported having no relevant financial disclosures.

Vasopressin was no better than norepinephrine in preventing kidney failure when used as a first-line treatment for septic shock, according to a report published online Aug. 2 in JAMA.

In a multicenter, double-blind, randomized trial comparing the two approaches in 408 ICU patients with septic shock, the early use of vasopressin didn’t reduce the number of days free of kidney failure, compared with standard norepinephrine.

©decade3d/thinkstockphotos.com

However, “the 95% confidence intervals of the difference between [study] groups has an upper limit of 5 days in favor of vasopressin, which could be clinically important,” said Anthony C. Gordon, MD, of Charing Cross Hospital and Imperial College London, and his associates. “Therefore, these results are still consistent with a potentially clinically important benefit for vasopressin; but a larger trial would be needed to confirm or refute this.”

Norepinephrine is the recommended first-line vasopressor for septic shock, but “there has been a growing interest in the use of vasopressin” ever since researchers described a relative deficiency of vasopressin in the disorder, Dr. Gordon and his associates noted.

“Preclinical and small clinical studies have suggested that vasopressin may be better able to maintain glomerular filtration rate and improve creatinine clearance, compared with norepinephrine,” the investigators said, and other studies have suggested that combining vasopressin with corticosteroids may prevent deterioration in organ function and reduce the duration of shock, thereby improving survival.

To examine those possibilities, they performed the VANISH (Vasopressin vs. Norepinephrine as Initial Therapy in Septic Shock) trial, assessing patients age 16 years and older at 18 general adult ICUs in the United Kingdom during a 2-year period. The study participants were randomly assigned to receive vasopressin plus hydrocortisone (100 patients), vasopressin plus matching placebo (104 patients), norepinephrine plus hydrocortisone (101 patients), or norepinephrine plus matching placebo (103 patients).

The primary outcome measure was the number of days alive and free of kidney failure during the 28 days following randomization. There was no significant difference among the four study groups in the number or the distribution of kidney-failure–free days, the investigators said (JAMA. 2016 Aug 2. doi: 10.1001/jama.2016.10485).

In addition, the percentage of survivors who never developed kidney failure was not significantly different between the two groups who received vasopressin (57.0%) and the two who received norepinephrine (59.2%). And the median number of days free of kidney failure in the subgroup of patients who died or developed kidney failure was not significantly different between those receiving vasopressin (9 days) and those receiving norepinephrine (13 days).

The quantities of IV fluids administered, the total fluid balance, serum lactate levels, and heart rate were all similar across the four study groups. There also was no significant difference in 28-day mortality between patients who received vasopressin (30.9%) and those who received norepinephrine (27.5%). Adverse event profiles also were comparable.

However, the rate of renal replacement therapy was 25.4% with vasopressin, significantly lower than the 35.3% rate in the norepinephrine group. The use of such therapy was not controlled in the trial and was initiated according to the treating physicians’ preference. “It is therefore not possible to know why renal replacement therapy was or was not started,” Dr. Gordon and his associates noted.

The use of renal replacement therapy wasn’t a primary outcome of the trial. Nevertheless, it is an important patient-centered outcome and may be a factor to consider when treating adults who have septic shock, the researchers added.

The study was supported by the U.K. National Institute for Health Research and the U.K. Intensive Care Foundation. Dr. Gordon reported ties to Ferring, HCA International, Orion, and Tenax Therapeutics; his associates reported having no relevant financial disclosures.

Anemia is a frequent complication of chronic kidney disease, occurring in over 90% of patients receiving renal replacement therapy. It is associated with significant morbidity and mortality. While its pathogenesis is typically multifactorial, the predominant cause is failure of the kidneys to produce enough endogenous erythropoietin. The clinical approval of recombinant human erythropoietin in 1989 dramatically changed the treatment of anemia of chronic kidney disease, but randomized controlled trials yielded disappointing results when erythropoiesis-stimulating agents (ESAs) were used to raise hemoglobin to normal levels.

This article reviews the epidemiology and pathophysiology of anemia of chronic kidney disease and discusses the complicated and conflicting evidence regarding its treatment.

DEFINITION AND PREVALENCE

Anemia is defined as a hemoglobin concentration less than 13.0 g/dL for men and less than 12.0 g/dL for premenopausal women.¹ It is more common in patients with impaired kidney function, especially when the glomerular filtration rate (GFR) falls below 60 mL/min. It is rare at GFRs higher than 80 mL/min,² but as the GFR falls, the severity of the anemia worsens³ and its prevalence increases: almost 90% of patients with a GFR less than 30 mL/min are anemic.⁴

RENAL ANEMIA IS ASSOCIATED WITH BAD OUTCOMES

Anemia in chronic kidney disease is independently associated with risk of death. It is also an all-cause mortality multiplier, ie, it magnifies the risk of death from other disease states.⁵

In observational studies, anemia was associated with faster progression of left ventricular hypertrophy, inflammation, and increased myocardial and peripheral oxygen demand, thereby leading to worse cardiac outcomes with increased risk of myocardial infarction, coronary revascularization, and readmission for heart failure.^6–8 Anemia is also associated with fatigue, depression, reduced exercise tolerance, stroke, and increased risk of rehospitalization.^9–13

RENAL ANEMIA IS MULTIFACTORIAL

Anemia of chronic kidney disease is typically attributed to the decrease of erythropoietin production that accompanies the fall in GFR. However, the process is multifactorial, with several other contributing factors: absolute and functional iron deficiency, folate and vitamin B₁₂ deficiencies, reduced red blood cell life span, and suppression of erythropoiesis by the uremic milieu.¹⁴

While it was once thought that chronic kidney disease leads to loss of erythropoietin-producing cells, it is now known that downregulation of hypoxia-inducible factor (HIF; a transcription factor) is at least partially responsible for the decrease in erythropoietin production^15,16 and that this downregulation is reversible (see below).

ERYTHROPOIETIN, IRON, AND RED BLOOD CELLS

Erythropoietin production is triggered by hypoxia, mediated by HIF

Erythropoietin is produced primarily in the deep cortex and outer medulla of the kidneys by a special population of peritubular interstitial cells.¹⁷ The parenchymal cells of the liver also produce erythropoietin, but much less.¹⁸

The rate of renal erythropoietin synthesis is determined by tissue oxygenation rather than by renal blood flow; production increases as the hemoglobin concentration drops and the arterial oxygen tension decreases (Figure 1).¹⁹

The gene for erythropoietin is located on chromosome 7 and is regulated by HIF. HIF molecules are composed of an alpha subunit, which is unstable at high Po₂, and a beta subunit, constitutively present in the nucleus.²⁰

In hypoxic conditions, the HIF dimer is transcriptionally active and binds to specific DNA recognition sequences called hypoxia-response elements. Gene transcription is upregulated, leading to increased production of erythropoietin.²¹

Under normal oxygen tension, on the other hand, the proline residue of the HIF alpha subunit is hydroxylated. The hydroxylated HIF alpha subunit is then degraded by proteasomal ubiquitylation, which is mediated by the von Hippel-Lindau tumor-suppressor gene pVHL.²² Degradation of HIF alpha prevents formation of the HIF heterodimers. HIF therefore cannot bind to the hypoxia-response elements, and erythropoietin gene transcription does not occur.²³

Thus, in states of hypoxia, erythropoietin production is upregulated, whereas with normal oxygen tension, production is downregulated.

Erythropoietin is essential for terminal maturation of erythrocytes

Erythropoietin is essential for terminal maturation of erythrocytes.²⁴ It is thought to stimulate the growth of erythrogenic progenitors: burst-forming units-erythroid (BFU-E) and colony-forming units-erythroid (CFU-E). In the absence of erythropoietin, BFU-E and CFU-E fail to differentiate into mature erythrocytes.²⁵

Binding of erythropoietin to its receptor sets off a series of downstream signals, the most important being the signal transducer and activator of transcription 5 (STAT5). In animal studies, STAT5 was found to inhibit apoptosis through the early induction of an antiapoptotic gene, Bcl-xL.²⁶

Iron metabolism is controlled by several proteins

Iron is characterized by its capacity to accept or donate electrons. This unique property makes it a crucial element in many biochemical reactions such as enzymatic activity, DNA synthesis, oxygen transport, and cell respiration.

Iron metabolism is under the control of several proteins that play different roles in its absorption, recycling, and loss (Figure 2).²⁷

Dietary iron exists primarily in its poorly soluble trivalent ferric form (Fe³⁺), and it needs to be reduced to its soluble divalent ferrous form (Fe²⁺) by ferric reductase to be absorbed. Ferrous iron is taken up at the apical side of enterocytes by a divalent metal transporter (DMT1) and is transported across the brush border.²⁸

To enter the circulation, iron has to be transported across the basolateral membrane by a transporter called ferroportin.²⁹ Ferroportin is also found in placental syncitiotrophoblasts, where it transfers iron from mother to fetus, and in macrophages, where it allows recycling of iron scavenged from damaged cells back into the circulation.³⁰ Upon its release, the ferrous iron is oxidized to the ferric form and loaded onto transferrin. This oxidation process involves hephaestin, a homologue of the ferroxidase ceruloplasmin.³¹

In the plasma, iron is bound to transferrin, and under normal circumstances one-third of transferrin is saturated with iron.³² Transferrin receptors are present on most cells but are most dense on erythroid precursors. Each transferrin receptor can bind two transferrin molecules. After binding to transferrin, the transferrin receptor is endocytosed, and the iron is released into acidified vacuoles. The transferrin-receptor complex is then recycled to the surface.³³

Ferritin is the cellular storage protein for iron, and it can store up to 4,500 atoms of iron within its spherical cavity.³⁴ The serum level of ferritin reflects overall storage, with 1 ng/mL of ferritin indicating 10 mg of total iron stores.³⁵ Ferritin is also an acute-phase reactant, and plasma levels can increase in inflammatory states such as infection or malignancy. As such, elevated ferritin does not necessarily indicate elevated iron stores.

Iron is lost in sweat, shed skin cells, and sloughed intestinal mucosal cells. However, there is no specific mechanism of iron excretion from the human body. Thus, iron is mainly regulated at the level of intestinal absorption. The iron exporter ferroportin is upregulated by the amount of available iron and is degraded by hepcidin.³⁶

Hepcidin is a small cysteine-rich cationic peptide that is primarily produced in the liver, with some minor production also occurring in the kidneys.³⁷ Transcription of the gene encoding hepcidin is downregulated by anemia and hypoxia and upregulated by inflammation and elevated iron levels.³⁸ Transcription of hepcidin leads to degradation of ferroportin and a decrease in intestinal iron absorption. On the other hand, anemia and hypoxia inhibit hepcidin transcription, which allows ferroportin to facilitate intestinal iron absorption.

TREATMENT OF RENAL ANEMIA

Early enthusiasm for erythropoietin agents

Androgens started to be used to treat anemia of end-stage renal disease in 1970,^39,40 and before the advent of recombinant human erythropoietin, they were a mainstay of nontransfusional therapy for anemic patients on dialysis.

The approval of recombinant human erythropoietin in 1989 drastically shifted the treatment of renal anemia. While the initial goal of treating anemia of chronic kidney disease with erythropoietin was to prevent blood transfusions,⁴¹ subsequent studies showed that the benefits might be far greater. Indeed, an initial observational trial showed that erythropoiesis-stimulating agents (ESAs) were associated with improved quality of life,⁴² improved neurocognitive function,^43,44 and even cost savings.⁴⁵ The benefits also extended to major outcomes such as regression of left ventricular hypertrophy,⁴⁶ improvement in New York Heart Association class and cardiac function,⁴⁷ fewer hospitalizations,⁴⁸ and even reduction of cardiovascular mortality rates.⁴⁹

As a result, ESA use gained popularity, and by 2006 an estimated 90% of dialysis patients were receiving these agents.⁵⁰ The target and achieved hemoglobin levels also increased, with mean hemoglobin levels in hemodialysis patients being raised from 9.7 to 12 g/dL.⁵¹

Disappointing results in clinical trials of ESAs to normalize hemoglobin

To prospectively study the effects of normalized hemoglobin targets, four randomized controlled trials were conducted (Table 1):

• The Normal Hematocrit Study (NHCT)⁵²
• The Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial⁵³
• The Cardiovascular Risk Reduction by Early Anemia Treatment (CREATE) trial⁵⁴
• The Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT).⁵⁵

These trials randomized patients to either higher “normal-range” hemoglobin targets or to lower target hemoglobin levels.

Their findings were disappointing and raised several red flags about excessive use of ESAs. The trials found no benefit in higher hemoglobin targets, and in fact, some of them demonstrated harm in patients randomized to higher targets. Notably, higher hemoglobin targets were associated with significant side effects such as access-site  thrombosis,⁵² strokes,⁵⁵ and possibly cardiovascular events.^54,55 Only the CREATE trial was able to demonstrate a quality-of-life benefit for the high-target group.⁵⁴ 

It remains unclear whether these adverse events were from the therapy itself or from an increased morbidity burden in the treated patients. Erythropoietin use is associated with hypertension,⁵⁶ thought to be related to endothelin-mediated vasoconstriction.⁵⁷ In our experience, this is most evident when hemoglobin levels are normalized with ESA therapy. Cycling of erythropoietin levels between extreme levels can lead to vascular remodeling, which may also be related to its cardiovascular effects.⁵⁷

A noticeable finding in several of these trials was that patients failed to achieve the higher hemoglobin target despite the use of very high doses of ESA. Reanalysis of data from the CHOIR and CREATE trials showed that the patients who had worse outcomes were more likely to have required very high doses without achieving their target hemoglobin.^58,59 Indeed, patients who achieved the higher target hemoglobin levels, usually at lower ESA doses, had better outcomes. This suggested that the need for a higher dose was associated with poorer outcomes, either as a marker of comorbidity or due to yet undocumented side effects of such high doses.

General approach to therapy

Before attributing anemia to chronic kidney disease, a thorough evaluation should be conducted to look for any reversible process that could be contributing to the anemia.

The causes of anemia are numerous and beyond the scope of this review. However, among the common causes of anemia in chronic kidney disease are deficiencies of iron, vitamin B₁₂, and folate. Therefore, guidelines recommend checking iron, vitamin B₁₂, and folate levels in the initial evaluation of anemia.⁶⁰

Iron deficiency in particular is very common in chronic kidney disease patients and is present in nearly all dialysis patients.⁶¹ Hemodialysis patients are estimated to lose 1 to 3 g of iron per year as a result of blood loss in the dialysis circuit and increased iron utilization secondary to ESA therapy.⁶²

However, in contrast to the general population, in which the upper limits of normal for iron indices are well defined, high serum ferritin levels appear to be poorly predictive of hemoglobin responsiveness in dialysis patients.^63,64 Thus, the cutoffs that define iron responsiveness are much higher than standard definitions for iron deficiency.^65,66 The Dialysis Patients’ Response to IV Iron With Elevated Ferritin (DRIVE) study showed that dialysis patients benefit from intravenous iron therapy even if their ferritin is as high as 1,200 ng/mL, provided their transferrin saturation is below 30%.⁶⁷

Of note, erythropoietin levels cannot be used to distinguish renal anemia from other causes of anemia. Indeed, patients with renal failure may have “relative erythropoietin deficiency,” ie, “normal” erythropoietin levels that are actually too low in view of the degree of anemia.^68,69 In addition to the decreased production capacity by the kidney, there appears to be a component of resistance to the action of erythropoietin in the bone marrow.

For these reasons, there is no erythropoietin level that can be considered “inadequate” or defining of renal anemia. Thus, measuring erythropoietin levels is not routinely recommended in the evaluation of renal anemia.

Two ESA preparations

The two ESAs that have traditionally been used in the treatment of renal anemia are recombinant human erythropoietin and darbepoietin alfa. They appear to be equivalent in terms of safety and efficacy.⁷⁰ However, darbepoietin alfa has more sialic acid molecules, giving it a higher potency and longer half-life and allowing for less-frequent injections.^71,72

In nondialysis patients, recombinant human erythropoietin is typically given every 1 to 2 weeks, whereas darbepoietin alfa can be given every 2 to 4 weeks. In dialysis patients, recombinant human erythropoietin is typically given 3 times per week with every dialysis treatment, while darbepoietin alfa is given once a week.

Target hemoglobin levels: ≤ 11.5 g/dL

In light of the four trials described in Table 1, the international Kidney Disease: Improving Global Outcomes (KDIGO) guidelines⁶⁰ recommend the following (Table 2):

For patients with chronic kidney disease who are not on dialysis, ESA therapy should not be initiated if the hemoglobin level is higher than 10 g/dL. If the hemoglobin level is lower than 10 g/dL, ESA therapy can be initiated, but the decision needs to be individualized based on the rate of fall of hemoglobin concentration, prior response to iron therapy, the risk of needing a transfusion, the risks related to ESA therapy, and the presence of symptoms attributable to anemia.

For patients on dialysis, ESA therapy should be used when the hemoglobin level is between 9 and 10 g/dL to avoid having the hemoglobin fall below 9 g/dL.

In all adult patients, ESAs should not be used to intentionally increase the hemoglobin level above 13 g/dL but rather to maintain levels no higher than 11.5 g/dL. This target is based on the observation that adverse outcomes were associated with ESA use with hemoglobin targets higher than 13 g/dL (Table 1).

Target iron levels

Regarding iron stores, the guidelines recommend the following:

For adult patients with chronic kidney disease who are not on dialysis, iron should be given to keep transferrin saturation above 20% and ferritin above 100 ng/mL. Transferrin saturation should not exceed 30%, and ferritin levels should not exceed 500 ng/mL.

For adult patients on dialysis, iron should be given to maintain transferrin saturation above 30% and ferritin above 200 ng/mL.

The upper limits of ferritin and transferrin saturation are somewhat controversial, as the safety of intentionally maintaining respective levels greater than 30% and 500 ng/mL has been studied in very few patients. Transferrin saturation should in general not exceed 50%.

High ferritin levels are associated with higher death rates, but whether elevation of ferritin levels is a marker of excessive iron administration rather than a nonspecific acute-phase reactant is not clear. The 2006 guidelines⁶⁰ cited upper ferritin limits of 500 to 800 ng/mL. However, the more recent DRIVE trial⁶⁷ showed that patients with ferritin levels of 500 to 1,200 ng/mL will respond to intravenous administration of iron with an increase in their hemoglobin levels. This has led many clinicians to adopt a higher ferritin limit of 1,200 ng/mL.

Hemosiderosis, or excess iron deposition, was a known consequence of frequent transfusions in patients with end-stage renal disease before ESA therapy was available. However, there have been no documented cases of clinical iron overload from iron therapy using current guidelines.⁷³

These algorithms are nuanced, and the benefit of giving intravenous iron should always be weighed against the risks of short-term acute toxicity and infection. Treatment of renal anemia not only requires in-depth knowledge of the topic, but also familiarity with the patient’s specific situation. As such, it is not recommended that clinicians unfamiliar with the treatment of renal anemia manage its treatment.

PARTICULAR CIRCUMSTANCES

Inflammation and ESA resistance

While ESAs are effective in treating anemia in many cases, in many patients the anemia fails to respond. This is of particular importance, since ESA hyporesponsiveness has been found to be a powerful predictor of cardiovascular events and death.⁷⁴ It is unclear, however, whether high doses of ESA are inherently toxic or whether hyporesponsiveness is a marker of adverse outcomes related to comorbidities.

KDIGO defines initial hyporesponsiveness as having no increase in hemoglobin concentration after the first month of appropriate weight-based dosing, and acquired hyporesponsiveness as requiring two increases in ESA doses up to 50% beyond the dose at which the patient had originally been stable.⁶⁰ Identifying ESA hyporesponsiveness should lead to an intensive search for potentially correctable factors.

The two major factors accounting for the state of hyporesponsiveness are inflammation and iron deficiency.^75,76

Inflammation. High C-reactive protein levels have been shown to predict resistance to erythropoietin in dialysis patients.⁷⁷ The release of cytokines such as tumor necrosis factor alpha, interleukin 1, and interferon gamma has an inhibitory effect on erythropoiesis.⁷⁸ Additionally, inflammation can alter the response to ESAs by disrupting the metabolism of iron⁷⁹ through the release of hepcidin, as previously discussed.³⁸ These reasons likely account for the observed lower response to ESAs in the setting of acute illness and explain why ESAs are not recommended for correcting acute anemia.⁸⁰

Iron deficiency also can blunt the response to ESAs. Large amounts of iron are needed for effective erythropoietic bursts. As such, iron supplementation is now a recognized treatment of renal anemia.⁸¹

Other factors associated with hyporesponsiveness include chronic occult blood loss, aluminum toxicity, cobalamin or folate deficiencies, testosterone deficiency, inadequate dialysis, hyperparathyroidism, and superimposed primary bone marrow disease,^82,83 and these should be addressed in patients whose anemia does not respond as expected to ESA therapy. A summary of the main causes of ESA hyporesponsiveness, their reversibility, and recommended treatments is presented in Table 3.

Antibody-mediated pure red-cell aplasia. Rarely, patients receiving ESA therapy develop antibodies that neutralize both the ESA and endogenous erythropoietin. The resulting syndrome, called antibody-mediated pure red-cell aplasia, is characterized by the sudden development of severe transfusion-dependent anemia. This has historically been connected to epoetin beta, a formulation not in use in the United States. However, cases have been documented with epoetin alfa and darbepoetin. The incidence rate is low with subcutaneous ESA use, estimated at 0.5 cases per 10,000 patient-years⁸⁴ and anecdotal with intravenous ESA.⁸⁵ The definitive diagnosis requires demonstration of neutralizing antibodies against erythropoietin. Parvovirus infection should be excluded as an alternative cause of pure red­cell aplasia.

ANEMIA IN CANCER PATIENTS

ESAs are effective in raising hemoglobin levels and reducing transfusion requirements in patients with chemotherapy-induced anemia.⁸⁶ However, there are data linking the use of ESAs to shortened survival in patients who have a variety of solid tumors.⁸⁷

Several mechanisms have been proposed to explain this rapid disease progression, most notably acceleration in tumor growth^88–90 by stimulation of erythropoietin receptors on the surface of the tumor cells, leading to increased tumor angiogenesis.^91,92

For these reasons, treatment of renal anemia in the setting of active malignancy should be referred to an oncologist.

NOVEL TREATMENTS

Several new agents for treating renal anemia are currently under review.

Continuous erythropoiesis receptor activator

Continuous erythropoiesis receptor activator is a pegylated form of recombinant human erythropoietin that has the ability to repeatedly activate the erythropoietin receptor. It appears to be similar to the other forms of erythropoietin in terms of safety and efficacy in both end-stage renal disease⁹³ and chronic kidney disease.⁹⁴ It has the advantage of an extended serum half-life, which allows for longer dosing intervals, ie, every 2 weeks. Its use is currently gaining popularity in the dialysis community.

HIF stabilizers

Our growing understanding of the physiology of erythropoietin offers new potential treatment targets. As previously described, production of erythropoietin is stimulated by HIFs. In order to be degraded, these HIFs are hydroxylated at their proline residues by a prolyl hydroxylase. A new category of drugs called prolyl-hydroxylase inhibitors (PDIs) offers the advantage of stabilizing the HIFs, leading to an increase in erythropoietin production.

In phase 1 and 2 clinical trials, these agents have been shown to increase hemoglobin in both end-stage renal disease and chronic kidney disease patients^15,16 but not in anephric patients, demonstrating a renal source of the erythropoietin production even in nonfunctioning kidneys. The study of one PDI agent (FG 2216) was halted temporarily after a report of death from fulminant hepatitis, but the other (FG 4592) continues to be studied in a phase 2 clinical trial.^95,96

TAKE-HOME POINTS

• Anemia of renal disease is a common condition that is mainly caused by a decrease in erythropoietin production by the kidneys.
• While anemia of renal disease can be corrected with ESAs, it is necessary to investigate and rule out underlying treatable conditions such as iron or vitamin deficiencies before giving an ESA.
• Anemia of renal disease is associated with significant morbidity such as increased risk of left ventricular hypertrophy, myocardial infarction, and heart failure, and has been described as an all-cause mortality multiplier.
• Unfortunately, the only undisputed benefit of treatment to date remains the avoidance of blood transfusions. Furthermore, the large randomized controlled trials that looked at the benefits of ESA have shown that their use can be associated with increased risk of cardiovascular events. Therefore, use of an ESA in end-stage renal disease should never target a normal hemoglobin levels but rather aim for a hemoglobin level of no more than 11.5 g/dL.
• Use of an ESA in chronic kidney disease should be individualized and is not recommended to be started unless the hemoglobin level is less than 10 g/dL.
• Several newer agents for renal anemia are currently under review. A pegylated form of recombinant human erythropoietin has an extended half-life, and a new and promising category of drugs called HIF stabilizers is currently under study.

Anemia is a frequent complication of chronic kidney disease, occurring in over 90% of patients receiving renal replacement therapy. It is associated with significant morbidity and mortality. While its pathogenesis is typically multifactorial, the predominant cause is failure of the kidneys to produce enough endogenous erythropoietin. The clinical approval of recombinant human erythropoietin in 1989 dramatically changed the treatment of anemia of chronic kidney disease, but randomized controlled trials yielded disappointing results when erythropoiesis-stimulating agents (ESAs) were used to raise hemoglobin to normal levels.

This article reviews the epidemiology and pathophysiology of anemia of chronic kidney disease and discusses the complicated and conflicting evidence regarding its treatment.

DEFINITION AND PREVALENCE

Anemia is defined as a hemoglobin concentration less than 13.0 g/dL for men and less than 12.0 g/dL for premenopausal women.¹ It is more common in patients with impaired kidney function, especially when the glomerular filtration rate (GFR) falls below 60 mL/min. It is rare at GFRs higher than 80 mL/min,² but as the GFR falls, the severity of the anemia worsens³ and its prevalence increases: almost 90% of patients with a GFR less than 30 mL/min are anemic.⁴

RENAL ANEMIA IS ASSOCIATED WITH BAD OUTCOMES

Anemia in chronic kidney disease is independently associated with risk of death. It is also an all-cause mortality multiplier, ie, it magnifies the risk of death from other disease states.⁵

In observational studies, anemia was associated with faster progression of left ventricular hypertrophy, inflammation, and increased myocardial and peripheral oxygen demand, thereby leading to worse cardiac outcomes with increased risk of myocardial infarction, coronary revascularization, and readmission for heart failure.^6–8 Anemia is also associated with fatigue, depression, reduced exercise tolerance, stroke, and increased risk of rehospitalization.^9–13

RENAL ANEMIA IS MULTIFACTORIAL

Anemia of chronic kidney disease is typically attributed to the decrease of erythropoietin production that accompanies the fall in GFR. However, the process is multifactorial, with several other contributing factors: absolute and functional iron deficiency, folate and vitamin B₁₂ deficiencies, reduced red blood cell life span, and suppression of erythropoiesis by the uremic milieu.¹⁴

While it was once thought that chronic kidney disease leads to loss of erythropoietin-producing cells, it is now known that downregulation of hypoxia-inducible factor (HIF; a transcription factor) is at least partially responsible for the decrease in erythropoietin production^15,16 and that this downregulation is reversible (see below).

ERYTHROPOIETIN, IRON, AND RED BLOOD CELLS

Erythropoietin production is triggered by hypoxia, mediated by HIF

Erythropoietin is produced primarily in the deep cortex and outer medulla of the kidneys by a special population of peritubular interstitial cells.¹⁷ The parenchymal cells of the liver also produce erythropoietin, but much less.¹⁸

The rate of renal erythropoietin synthesis is determined by tissue oxygenation rather than by renal blood flow; production increases as the hemoglobin concentration drops and the arterial oxygen tension decreases (Figure 1).¹⁹

The gene for erythropoietin is located on chromosome 7 and is regulated by HIF. HIF molecules are composed of an alpha subunit, which is unstable at high Po₂, and a beta subunit, constitutively present in the nucleus.²⁰

In hypoxic conditions, the HIF dimer is transcriptionally active and binds to specific DNA recognition sequences called hypoxia-response elements. Gene transcription is upregulated, leading to increased production of erythropoietin.²¹

Under normal oxygen tension, on the other hand, the proline residue of the HIF alpha subunit is hydroxylated. The hydroxylated HIF alpha subunit is then degraded by proteasomal ubiquitylation, which is mediated by the von Hippel-Lindau tumor-suppressor gene pVHL.²² Degradation of HIF alpha prevents formation of the HIF heterodimers. HIF therefore cannot bind to the hypoxia-response elements, and erythropoietin gene transcription does not occur.²³

Thus, in states of hypoxia, erythropoietin production is upregulated, whereas with normal oxygen tension, production is downregulated.

Erythropoietin is essential for terminal maturation of erythrocytes

Erythropoietin is essential for terminal maturation of erythrocytes.²⁴ It is thought to stimulate the growth of erythrogenic progenitors: burst-forming units-erythroid (BFU-E) and colony-forming units-erythroid (CFU-E). In the absence of erythropoietin, BFU-E and CFU-E fail to differentiate into mature erythrocytes.²⁵

Binding of erythropoietin to its receptor sets off a series of downstream signals, the most important being the signal transducer and activator of transcription 5 (STAT5). In animal studies, STAT5 was found to inhibit apoptosis through the early induction of an antiapoptotic gene, Bcl-xL.²⁶

Iron metabolism is controlled by several proteins

Iron is characterized by its capacity to accept or donate electrons. This unique property makes it a crucial element in many biochemical reactions such as enzymatic activity, DNA synthesis, oxygen transport, and cell respiration.

Iron metabolism is under the control of several proteins that play different roles in its absorption, recycling, and loss (Figure 2).²⁷

Dietary iron exists primarily in its poorly soluble trivalent ferric form (Fe³⁺), and it needs to be reduced to its soluble divalent ferrous form (Fe²⁺) by ferric reductase to be absorbed. Ferrous iron is taken up at the apical side of enterocytes by a divalent metal transporter (DMT1) and is transported across the brush border.²⁸

To enter the circulation, iron has to be transported across the basolateral membrane by a transporter called ferroportin.²⁹ Ferroportin is also found in placental syncitiotrophoblasts, where it transfers iron from mother to fetus, and in macrophages, where it allows recycling of iron scavenged from damaged cells back into the circulation.³⁰ Upon its release, the ferrous iron is oxidized to the ferric form and loaded onto transferrin. This oxidation process involves hephaestin, a homologue of the ferroxidase ceruloplasmin.³¹

In the plasma, iron is bound to transferrin, and under normal circumstances one-third of transferrin is saturated with iron.³² Transferrin receptors are present on most cells but are most dense on erythroid precursors. Each transferrin receptor can bind two transferrin molecules. After binding to transferrin, the transferrin receptor is endocytosed, and the iron is released into acidified vacuoles. The transferrin-receptor complex is then recycled to the surface.³³

Ferritin is the cellular storage protein for iron, and it can store up to 4,500 atoms of iron within its spherical cavity.³⁴ The serum level of ferritin reflects overall storage, with 1 ng/mL of ferritin indicating 10 mg of total iron stores.³⁵ Ferritin is also an acute-phase reactant, and plasma levels can increase in inflammatory states such as infection or malignancy. As such, elevated ferritin does not necessarily indicate elevated iron stores.

Iron is lost in sweat, shed skin cells, and sloughed intestinal mucosal cells. However, there is no specific mechanism of iron excretion from the human body. Thus, iron is mainly regulated at the level of intestinal absorption. The iron exporter ferroportin is upregulated by the amount of available iron and is degraded by hepcidin.³⁶

Hepcidin is a small cysteine-rich cationic peptide that is primarily produced in the liver, with some minor production also occurring in the kidneys.³⁷ Transcription of the gene encoding hepcidin is downregulated by anemia and hypoxia and upregulated by inflammation and elevated iron levels.³⁸ Transcription of hepcidin leads to degradation of ferroportin and a decrease in intestinal iron absorption. On the other hand, anemia and hypoxia inhibit hepcidin transcription, which allows ferroportin to facilitate intestinal iron absorption.

TREATMENT OF RENAL ANEMIA

Early enthusiasm for erythropoietin agents

Androgens started to be used to treat anemia of end-stage renal disease in 1970,^39,40 and before the advent of recombinant human erythropoietin, they were a mainstay of nontransfusional therapy for anemic patients on dialysis.

The approval of recombinant human erythropoietin in 1989 drastically shifted the treatment of renal anemia. While the initial goal of treating anemia of chronic kidney disease with erythropoietin was to prevent blood transfusions,⁴¹ subsequent studies showed that the benefits might be far greater. Indeed, an initial observational trial showed that erythropoiesis-stimulating agents (ESAs) were associated with improved quality of life,⁴² improved neurocognitive function,^43,44 and even cost savings.⁴⁵ The benefits also extended to major outcomes such as regression of left ventricular hypertrophy,⁴⁶ improvement in New York Heart Association class and cardiac function,⁴⁷ fewer hospitalizations,⁴⁸ and even reduction of cardiovascular mortality rates.⁴⁹

As a result, ESA use gained popularity, and by 2006 an estimated 90% of dialysis patients were receiving these agents.⁵⁰ The target and achieved hemoglobin levels also increased, with mean hemoglobin levels in hemodialysis patients being raised from 9.7 to 12 g/dL.⁵¹

Disappointing results in clinical trials of ESAs to normalize hemoglobin

To prospectively study the effects of normalized hemoglobin targets, four randomized controlled trials were conducted (Table 1):

• The Normal Hematocrit Study (NHCT)⁵²
• The Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial⁵³
• The Cardiovascular Risk Reduction by Early Anemia Treatment (CREATE) trial⁵⁴
• The Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT).⁵⁵

These trials randomized patients to either higher “normal-range” hemoglobin targets or to lower target hemoglobin levels.

Their findings were disappointing and raised several red flags about excessive use of ESAs. The trials found no benefit in higher hemoglobin targets, and in fact, some of them demonstrated harm in patients randomized to higher targets. Notably, higher hemoglobin targets were associated with significant side effects such as access-site  thrombosis,⁵² strokes,⁵⁵ and possibly cardiovascular events.^54,55 Only the CREATE trial was able to demonstrate a quality-of-life benefit for the high-target group.⁵⁴ 

It remains unclear whether these adverse events were from the therapy itself or from an increased morbidity burden in the treated patients. Erythropoietin use is associated with hypertension,⁵⁶ thought to be related to endothelin-mediated vasoconstriction.⁵⁷ In our experience, this is most evident when hemoglobin levels are normalized with ESA therapy. Cycling of erythropoietin levels between extreme levels can lead to vascular remodeling, which may also be related to its cardiovascular effects.⁵⁷

A noticeable finding in several of these trials was that patients failed to achieve the higher hemoglobin target despite the use of very high doses of ESA. Reanalysis of data from the CHOIR and CREATE trials showed that the patients who had worse outcomes were more likely to have required very high doses without achieving their target hemoglobin.^58,59 Indeed, patients who achieved the higher target hemoglobin levels, usually at lower ESA doses, had better outcomes. This suggested that the need for a higher dose was associated with poorer outcomes, either as a marker of comorbidity or due to yet undocumented side effects of such high doses.

General approach to therapy

Before attributing anemia to chronic kidney disease, a thorough evaluation should be conducted to look for any reversible process that could be contributing to the anemia.

The causes of anemia are numerous and beyond the scope of this review. However, among the common causes of anemia in chronic kidney disease are deficiencies of iron, vitamin B₁₂, and folate. Therefore, guidelines recommend checking iron, vitamin B₁₂, and folate levels in the initial evaluation of anemia.⁶⁰

Iron deficiency in particular is very common in chronic kidney disease patients and is present in nearly all dialysis patients.⁶¹ Hemodialysis patients are estimated to lose 1 to 3 g of iron per year as a result of blood loss in the dialysis circuit and increased iron utilization secondary to ESA therapy.⁶²

However, in contrast to the general population, in which the upper limits of normal for iron indices are well defined, high serum ferritin levels appear to be poorly predictive of hemoglobin responsiveness in dialysis patients.^63,64 Thus, the cutoffs that define iron responsiveness are much higher than standard definitions for iron deficiency.^65,66 The Dialysis Patients’ Response to IV Iron With Elevated Ferritin (DRIVE) study showed that dialysis patients benefit from intravenous iron therapy even if their ferritin is as high as 1,200 ng/mL, provided their transferrin saturation is below 30%.⁶⁷

Of note, erythropoietin levels cannot be used to distinguish renal anemia from other causes of anemia. Indeed, patients with renal failure may have “relative erythropoietin deficiency,” ie, “normal” erythropoietin levels that are actually too low in view of the degree of anemia.^68,69 In addition to the decreased production capacity by the kidney, there appears to be a component of resistance to the action of erythropoietin in the bone marrow.

For these reasons, there is no erythropoietin level that can be considered “inadequate” or defining of renal anemia. Thus, measuring erythropoietin levels is not routinely recommended in the evaluation of renal anemia.

Two ESA preparations

The two ESAs that have traditionally been used in the treatment of renal anemia are recombinant human erythropoietin and darbepoietin alfa. They appear to be equivalent in terms of safety and efficacy.⁷⁰ However, darbepoietin alfa has more sialic acid molecules, giving it a higher potency and longer half-life and allowing for less-frequent injections.^71,72

In nondialysis patients, recombinant human erythropoietin is typically given every 1 to 2 weeks, whereas darbepoietin alfa can be given every 2 to 4 weeks. In dialysis patients, recombinant human erythropoietin is typically given 3 times per week with every dialysis treatment, while darbepoietin alfa is given once a week.

Target hemoglobin levels: ≤ 11.5 g/dL

In light of the four trials described in Table 1, the international Kidney Disease: Improving Global Outcomes (KDIGO) guidelines⁶⁰ recommend the following (Table 2):

For patients with chronic kidney disease who are not on dialysis, ESA therapy should not be initiated if the hemoglobin level is higher than 10 g/dL. If the hemoglobin level is lower than 10 g/dL, ESA therapy can be initiated, but the decision needs to be individualized based on the rate of fall of hemoglobin concentration, prior response to iron therapy, the risk of needing a transfusion, the risks related to ESA therapy, and the presence of symptoms attributable to anemia.

For patients on dialysis, ESA therapy should be used when the hemoglobin level is between 9 and 10 g/dL to avoid having the hemoglobin fall below 9 g/dL.

In all adult patients, ESAs should not be used to intentionally increase the hemoglobin level above 13 g/dL but rather to maintain levels no higher than 11.5 g/dL. This target is based on the observation that adverse outcomes were associated with ESA use with hemoglobin targets higher than 13 g/dL (Table 1).

Target iron levels

Regarding iron stores, the guidelines recommend the following:

For adult patients with chronic kidney disease who are not on dialysis, iron should be given to keep transferrin saturation above 20% and ferritin above 100 ng/mL. Transferrin saturation should not exceed 30%, and ferritin levels should not exceed 500 ng/mL.

For adult patients on dialysis, iron should be given to maintain transferrin saturation above 30% and ferritin above 200 ng/mL.

The upper limits of ferritin and transferrin saturation are somewhat controversial, as the safety of intentionally maintaining respective levels greater than 30% and 500 ng/mL has been studied in very few patients. Transferrin saturation should in general not exceed 50%.

High ferritin levels are associated with higher death rates, but whether elevation of ferritin levels is a marker of excessive iron administration rather than a nonspecific acute-phase reactant is not clear. The 2006 guidelines⁶⁰ cited upper ferritin limits of 500 to 800 ng/mL. However, the more recent DRIVE trial⁶⁷ showed that patients with ferritin levels of 500 to 1,200 ng/mL will respond to intravenous administration of iron with an increase in their hemoglobin levels. This has led many clinicians to adopt a higher ferritin limit of 1,200 ng/mL.

Hemosiderosis, or excess iron deposition, was a known consequence of frequent transfusions in patients with end-stage renal disease before ESA therapy was available. However, there have been no documented cases of clinical iron overload from iron therapy using current guidelines.⁷³

These algorithms are nuanced, and the benefit of giving intravenous iron should always be weighed against the risks of short-term acute toxicity and infection. Treatment of renal anemia not only requires in-depth knowledge of the topic, but also familiarity with the patient’s specific situation. As such, it is not recommended that clinicians unfamiliar with the treatment of renal anemia manage its treatment.

PARTICULAR CIRCUMSTANCES

Inflammation and ESA resistance

While ESAs are effective in treating anemia in many cases, in many patients the anemia fails to respond. This is of particular importance, since ESA hyporesponsiveness has been found to be a powerful predictor of cardiovascular events and death.⁷⁴ It is unclear, however, whether high doses of ESA are inherently toxic or whether hyporesponsiveness is a marker of adverse outcomes related to comorbidities.

KDIGO defines initial hyporesponsiveness as having no increase in hemoglobin concentration after the first month of appropriate weight-based dosing, and acquired hyporesponsiveness as requiring two increases in ESA doses up to 50% beyond the dose at which the patient had originally been stable.⁶⁰ Identifying ESA hyporesponsiveness should lead to an intensive search for potentially correctable factors.

The two major factors accounting for the state of hyporesponsiveness are inflammation and iron deficiency.^75,76

Inflammation. High C-reactive protein levels have been shown to predict resistance to erythropoietin in dialysis patients.⁷⁷ The release of cytokines such as tumor necrosis factor alpha, interleukin 1, and interferon gamma has an inhibitory effect on erythropoiesis.⁷⁸ Additionally, inflammation can alter the response to ESAs by disrupting the metabolism of iron⁷⁹ through the release of hepcidin, as previously discussed.³⁸ These reasons likely account for the observed lower response to ESAs in the setting of acute illness and explain why ESAs are not recommended for correcting acute anemia.⁸⁰

Iron deficiency also can blunt the response to ESAs. Large amounts of iron are needed for effective erythropoietic bursts. As such, iron supplementation is now a recognized treatment of renal anemia.⁸¹

Other factors associated with hyporesponsiveness include chronic occult blood loss, aluminum toxicity, cobalamin or folate deficiencies, testosterone deficiency, inadequate dialysis, hyperparathyroidism, and superimposed primary bone marrow disease,^82,83 and these should be addressed in patients whose anemia does not respond as expected to ESA therapy. A summary of the main causes of ESA hyporesponsiveness, their reversibility, and recommended treatments is presented in Table 3.

Antibody-mediated pure red-cell aplasia. Rarely, patients receiving ESA therapy develop antibodies that neutralize both the ESA and endogenous erythropoietin. The resulting syndrome, called antibody-mediated pure red-cell aplasia, is characterized by the sudden development of severe transfusion-dependent anemia. This has historically been connected to epoetin beta, a formulation not in use in the United States. However, cases have been documented with epoetin alfa and darbepoetin. The incidence rate is low with subcutaneous ESA use, estimated at 0.5 cases per 10,000 patient-years⁸⁴ and anecdotal with intravenous ESA.⁸⁵ The definitive diagnosis requires demonstration of neutralizing antibodies against erythropoietin. Parvovirus infection should be excluded as an alternative cause of pure red­cell aplasia.

ANEMIA IN CANCER PATIENTS

ESAs are effective in raising hemoglobin levels and reducing transfusion requirements in patients with chemotherapy-induced anemia.⁸⁶ However, there are data linking the use of ESAs to shortened survival in patients who have a variety of solid tumors.⁸⁷

Several mechanisms have been proposed to explain this rapid disease progression, most notably acceleration in tumor growth^88–90 by stimulation of erythropoietin receptors on the surface of the tumor cells, leading to increased tumor angiogenesis.^91,92

For these reasons, treatment of renal anemia in the setting of active malignancy should be referred to an oncologist.

NOVEL TREATMENTS

Several new agents for treating renal anemia are currently under review.

Continuous erythropoiesis receptor activator

Continuous erythropoiesis receptor activator is a pegylated form of recombinant human erythropoietin that has the ability to repeatedly activate the erythropoietin receptor. It appears to be similar to the other forms of erythropoietin in terms of safety and efficacy in both end-stage renal disease⁹³ and chronic kidney disease.⁹⁴ It has the advantage of an extended serum half-life, which allows for longer dosing intervals, ie, every 2 weeks. Its use is currently gaining popularity in the dialysis community.

HIF stabilizers

Our growing understanding of the physiology of erythropoietin offers new potential treatment targets. As previously described, production of erythropoietin is stimulated by HIFs. In order to be degraded, these HIFs are hydroxylated at their proline residues by a prolyl hydroxylase. A new category of drugs called prolyl-hydroxylase inhibitors (PDIs) offers the advantage of stabilizing the HIFs, leading to an increase in erythropoietin production.

In phase 1 and 2 clinical trials, these agents have been shown to increase hemoglobin in both end-stage renal disease and chronic kidney disease patients^15,16 but not in anephric patients, demonstrating a renal source of the erythropoietin production even in nonfunctioning kidneys. The study of one PDI agent (FG 2216) was halted temporarily after a report of death from fulminant hepatitis, but the other (FG 4592) continues to be studied in a phase 2 clinical trial.^95,96

TAKE-HOME POINTS

• Anemia of renal disease is a common condition that is mainly caused by a decrease in erythropoietin production by the kidneys.
• While anemia of renal disease can be corrected with ESAs, it is necessary to investigate and rule out underlying treatable conditions such as iron or vitamin deficiencies before giving an ESA.
• Anemia of renal disease is associated with significant morbidity such as increased risk of left ventricular hypertrophy, myocardial infarction, and heart failure, and has been described as an all-cause mortality multiplier.
• Unfortunately, the only undisputed benefit of treatment to date remains the avoidance of blood transfusions. Furthermore, the large randomized controlled trials that looked at the benefits of ESA have shown that their use can be associated with increased risk of cardiovascular events. Therefore, use of an ESA in end-stage renal disease should never target a normal hemoglobin levels but rather aim for a hemoglobin level of no more than 11.5 g/dL.
• Use of an ESA in chronic kidney disease should be individualized and is not recommended to be started unless the hemoglobin level is less than 10 g/dL.
• Several newer agents for renal anemia are currently under review. A pegylated form of recombinant human erythropoietin has an extended half-life, and a new and promising category of drugs called HIF stabilizers is currently under study.

Anemia is a frequent complication of chronic kidney disease, occurring in over 90% of patients receiving renal replacement therapy. It is associated with significant morbidity and mortality. While its pathogenesis is typically multifactorial, the predominant cause is failure of the kidneys to produce enough endogenous erythropoietin. The clinical approval of recombinant human erythropoietin in 1989 dramatically changed the treatment of anemia of chronic kidney disease, but randomized controlled trials yielded disappointing results when erythropoiesis-stimulating agents (ESAs) were used to raise hemoglobin to normal levels.

This article reviews the epidemiology and pathophysiology of anemia of chronic kidney disease and discusses the complicated and conflicting evidence regarding its treatment.

DEFINITION AND PREVALENCE

Anemia is defined as a hemoglobin concentration less than 13.0 g/dL for men and less than 12.0 g/dL for premenopausal women.¹ It is more common in patients with impaired kidney function, especially when the glomerular filtration rate (GFR) falls below 60 mL/min. It is rare at GFRs higher than 80 mL/min,² but as the GFR falls, the severity of the anemia worsens³ and its prevalence increases: almost 90% of patients with a GFR less than 30 mL/min are anemic.⁴

RENAL ANEMIA IS ASSOCIATED WITH BAD OUTCOMES

Anemia in chronic kidney disease is independently associated with risk of death. It is also an all-cause mortality multiplier, ie, it magnifies the risk of death from other disease states.⁵

In observational studies, anemia was associated with faster progression of left ventricular hypertrophy, inflammation, and increased myocardial and peripheral oxygen demand, thereby leading to worse cardiac outcomes with increased risk of myocardial infarction, coronary revascularization, and readmission for heart failure.^6–8 Anemia is also associated with fatigue, depression, reduced exercise tolerance, stroke, and increased risk of rehospitalization.^9–13

RENAL ANEMIA IS MULTIFACTORIAL

Anemia of chronic kidney disease is typically attributed to the decrease of erythropoietin production that accompanies the fall in GFR. However, the process is multifactorial, with several other contributing factors: absolute and functional iron deficiency, folate and vitamin B₁₂ deficiencies, reduced red blood cell life span, and suppression of erythropoiesis by the uremic milieu.¹⁴

While it was once thought that chronic kidney disease leads to loss of erythropoietin-producing cells, it is now known that downregulation of hypoxia-inducible factor (HIF; a transcription factor) is at least partially responsible for the decrease in erythropoietin production^15,16 and that this downregulation is reversible (see below).

ERYTHROPOIETIN, IRON, AND RED BLOOD CELLS

Erythropoietin production is triggered by hypoxia, mediated by HIF

Erythropoietin is produced primarily in the deep cortex and outer medulla of the kidneys by a special population of peritubular interstitial cells.¹⁷ The parenchymal cells of the liver also produce erythropoietin, but much less.¹⁸

The rate of renal erythropoietin synthesis is determined by tissue oxygenation rather than by renal blood flow; production increases as the hemoglobin concentration drops and the arterial oxygen tension decreases (Figure 1).¹⁹

The gene for erythropoietin is located on chromosome 7 and is regulated by HIF. HIF molecules are composed of an alpha subunit, which is unstable at high Po₂, and a beta subunit, constitutively present in the nucleus.²⁰

In hypoxic conditions, the HIF dimer is transcriptionally active and binds to specific DNA recognition sequences called hypoxia-response elements. Gene transcription is upregulated, leading to increased production of erythropoietin.²¹

Under normal oxygen tension, on the other hand, the proline residue of the HIF alpha subunit is hydroxylated. The hydroxylated HIF alpha subunit is then degraded by proteasomal ubiquitylation, which is mediated by the von Hippel-Lindau tumor-suppressor gene pVHL.²² Degradation of HIF alpha prevents formation of the HIF heterodimers. HIF therefore cannot bind to the hypoxia-response elements, and erythropoietin gene transcription does not occur.²³

Thus, in states of hypoxia, erythropoietin production is upregulated, whereas with normal oxygen tension, production is downregulated.

Erythropoietin is essential for terminal maturation of erythrocytes

Erythropoietin is essential for terminal maturation of erythrocytes.²⁴ It is thought to stimulate the growth of erythrogenic progenitors: burst-forming units-erythroid (BFU-E) and colony-forming units-erythroid (CFU-E). In the absence of erythropoietin, BFU-E and CFU-E fail to differentiate into mature erythrocytes.²⁵

Binding of erythropoietin to its receptor sets off a series of downstream signals, the most important being the signal transducer and activator of transcription 5 (STAT5). In animal studies, STAT5 was found to inhibit apoptosis through the early induction of an antiapoptotic gene, Bcl-xL.²⁶

Iron metabolism is controlled by several proteins

Iron is characterized by its capacity to accept or donate electrons. This unique property makes it a crucial element in many biochemical reactions such as enzymatic activity, DNA synthesis, oxygen transport, and cell respiration.

Iron metabolism is under the control of several proteins that play different roles in its absorption, recycling, and loss (Figure 2).²⁷

Dietary iron exists primarily in its poorly soluble trivalent ferric form (Fe³⁺), and it needs to be reduced to its soluble divalent ferrous form (Fe²⁺) by ferric reductase to be absorbed. Ferrous iron is taken up at the apical side of enterocytes by a divalent metal transporter (DMT1) and is transported across the brush border.²⁸

To enter the circulation, iron has to be transported across the basolateral membrane by a transporter called ferroportin.²⁹ Ferroportin is also found in placental syncitiotrophoblasts, where it transfers iron from mother to fetus, and in macrophages, where it allows recycling of iron scavenged from damaged cells back into the circulation.³⁰ Upon its release, the ferrous iron is oxidized to the ferric form and loaded onto transferrin. This oxidation process involves hephaestin, a homologue of the ferroxidase ceruloplasmin.³¹

In the plasma, iron is bound to transferrin, and under normal circumstances one-third of transferrin is saturated with iron.³² Transferrin receptors are present on most cells but are most dense on erythroid precursors. Each transferrin receptor can bind two transferrin molecules. After binding to transferrin, the transferrin receptor is endocytosed, and the iron is released into acidified vacuoles. The transferrin-receptor complex is then recycled to the surface.³³

Ferritin is the cellular storage protein for iron, and it can store up to 4,500 atoms of iron within its spherical cavity.³⁴ The serum level of ferritin reflects overall storage, with 1 ng/mL of ferritin indicating 10 mg of total iron stores.³⁵ Ferritin is also an acute-phase reactant, and plasma levels can increase in inflammatory states such as infection or malignancy. As such, elevated ferritin does not necessarily indicate elevated iron stores.

Iron is lost in sweat, shed skin cells, and sloughed intestinal mucosal cells. However, there is no specific mechanism of iron excretion from the human body. Thus, iron is mainly regulated at the level of intestinal absorption. The iron exporter ferroportin is upregulated by the amount of available iron and is degraded by hepcidin.³⁶

Hepcidin is a small cysteine-rich cationic peptide that is primarily produced in the liver, with some minor production also occurring in the kidneys.³⁷ Transcription of the gene encoding hepcidin is downregulated by anemia and hypoxia and upregulated by inflammation and elevated iron levels.³⁸ Transcription of hepcidin leads to degradation of ferroportin and a decrease in intestinal iron absorption. On the other hand, anemia and hypoxia inhibit hepcidin transcription, which allows ferroportin to facilitate intestinal iron absorption.

TREATMENT OF RENAL ANEMIA

Early enthusiasm for erythropoietin agents

Androgens started to be used to treat anemia of end-stage renal disease in 1970,^39,40 and before the advent of recombinant human erythropoietin, they were a mainstay of nontransfusional therapy for anemic patients on dialysis.

The approval of recombinant human erythropoietin in 1989 drastically shifted the treatment of renal anemia. While the initial goal of treating anemia of chronic kidney disease with erythropoietin was to prevent blood transfusions,⁴¹ subsequent studies showed that the benefits might be far greater. Indeed, an initial observational trial showed that erythropoiesis-stimulating agents (ESAs) were associated with improved quality of life,⁴² improved neurocognitive function,^43,44 and even cost savings.⁴⁵ The benefits also extended to major outcomes such as regression of left ventricular hypertrophy,⁴⁶ improvement in New York Heart Association class and cardiac function,⁴⁷ fewer hospitalizations,⁴⁸ and even reduction of cardiovascular mortality rates.⁴⁹

As a result, ESA use gained popularity, and by 2006 an estimated 90% of dialysis patients were receiving these agents.⁵⁰ The target and achieved hemoglobin levels also increased, with mean hemoglobin levels in hemodialysis patients being raised from 9.7 to 12 g/dL.⁵¹

Disappointing results in clinical trials of ESAs to normalize hemoglobin

To prospectively study the effects of normalized hemoglobin targets, four randomized controlled trials were conducted (Table 1):

• The Normal Hematocrit Study (NHCT)⁵²
• The Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial⁵³
• The Cardiovascular Risk Reduction by Early Anemia Treatment (CREATE) trial⁵⁴
• The Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT).⁵⁵

These trials randomized patients to either higher “normal-range” hemoglobin targets or to lower target hemoglobin levels.

Their findings were disappointing and raised several red flags about excessive use of ESAs. The trials found no benefit in higher hemoglobin targets, and in fact, some of them demonstrated harm in patients randomized to higher targets. Notably, higher hemoglobin targets were associated with significant side effects such as access-site  thrombosis,⁵² strokes,⁵⁵ and possibly cardiovascular events.^54,55 Only the CREATE trial was able to demonstrate a quality-of-life benefit for the high-target group.⁵⁴ 

It remains unclear whether these adverse events were from the therapy itself or from an increased morbidity burden in the treated patients. Erythropoietin use is associated with hypertension,⁵⁶ thought to be related to endothelin-mediated vasoconstriction.⁵⁷ In our experience, this is most evident when hemoglobin levels are normalized with ESA therapy. Cycling of erythropoietin levels between extreme levels can lead to vascular remodeling, which may also be related to its cardiovascular effects.⁵⁷

A noticeable finding in several of these trials was that patients failed to achieve the higher hemoglobin target despite the use of very high doses of ESA. Reanalysis of data from the CHOIR and CREATE trials showed that the patients who had worse outcomes were more likely to have required very high doses without achieving their target hemoglobin.^58,59 Indeed, patients who achieved the higher target hemoglobin levels, usually at lower ESA doses, had better outcomes. This suggested that the need for a higher dose was associated with poorer outcomes, either as a marker of comorbidity or due to yet undocumented side effects of such high doses.

General approach to therapy

Before attributing anemia to chronic kidney disease, a thorough evaluation should be conducted to look for any reversible process that could be contributing to the anemia.

The causes of anemia are numerous and beyond the scope of this review. However, among the common causes of anemia in chronic kidney disease are deficiencies of iron, vitamin B₁₂, and folate. Therefore, guidelines recommend checking iron, vitamin B₁₂, and folate levels in the initial evaluation of anemia.⁶⁰

Iron deficiency in particular is very common in chronic kidney disease patients and is present in nearly all dialysis patients.⁶¹ Hemodialysis patients are estimated to lose 1 to 3 g of iron per year as a result of blood loss in the dialysis circuit and increased iron utilization secondary to ESA therapy.⁶²

However, in contrast to the general population, in which the upper limits of normal for iron indices are well defined, high serum ferritin levels appear to be poorly predictive of hemoglobin responsiveness in dialysis patients.^63,64 Thus, the cutoffs that define iron responsiveness are much higher than standard definitions for iron deficiency.^65,66 The Dialysis Patients’ Response to IV Iron With Elevated Ferritin (DRIVE) study showed that dialysis patients benefit from intravenous iron therapy even if their ferritin is as high as 1,200 ng/mL, provided their transferrin saturation is below 30%.⁶⁷

Of note, erythropoietin levels cannot be used to distinguish renal anemia from other causes of anemia. Indeed, patients with renal failure may have “relative erythropoietin deficiency,” ie, “normal” erythropoietin levels that are actually too low in view of the degree of anemia.^68,69 In addition to the decreased production capacity by the kidney, there appears to be a component of resistance to the action of erythropoietin in the bone marrow.

For these reasons, there is no erythropoietin level that can be considered “inadequate” or defining of renal anemia. Thus, measuring erythropoietin levels is not routinely recommended in the evaluation of renal anemia.

Two ESA preparations

The two ESAs that have traditionally been used in the treatment of renal anemia are recombinant human erythropoietin and darbepoietin alfa. They appear to be equivalent in terms of safety and efficacy.⁷⁰ However, darbepoietin alfa has more sialic acid molecules, giving it a higher potency and longer half-life and allowing for less-frequent injections.^71,72

In nondialysis patients, recombinant human erythropoietin is typically given every 1 to 2 weeks, whereas darbepoietin alfa can be given every 2 to 4 weeks. In dialysis patients, recombinant human erythropoietin is typically given 3 times per week with every dialysis treatment, while darbepoietin alfa is given once a week.

Target hemoglobin levels: ≤ 11.5 g/dL

In light of the four trials described in Table 1, the international Kidney Disease: Improving Global Outcomes (KDIGO) guidelines⁶⁰ recommend the following (Table 2):

For patients with chronic kidney disease who are not on dialysis, ESA therapy should not be initiated if the hemoglobin level is higher than 10 g/dL. If the hemoglobin level is lower than 10 g/dL, ESA therapy can be initiated, but the decision needs to be individualized based on the rate of fall of hemoglobin concentration, prior response to iron therapy, the risk of needing a transfusion, the risks related to ESA therapy, and the presence of symptoms attributable to anemia.

For patients on dialysis, ESA therapy should be used when the hemoglobin level is between 9 and 10 g/dL to avoid having the hemoglobin fall below 9 g/dL.

In all adult patients, ESAs should not be used to intentionally increase the hemoglobin level above 13 g/dL but rather to maintain levels no higher than 11.5 g/dL. This target is based on the observation that adverse outcomes were associated with ESA use with hemoglobin targets higher than 13 g/dL (Table 1).

Target iron levels

Regarding iron stores, the guidelines recommend the following:

For adult patients with chronic kidney disease who are not on dialysis, iron should be given to keep transferrin saturation above 20% and ferritin above 100 ng/mL. Transferrin saturation should not exceed 30%, and ferritin levels should not exceed 500 ng/mL.

For adult patients on dialysis, iron should be given to maintain transferrin saturation above 30% and ferritin above 200 ng/mL.

The upper limits of ferritin and transferrin saturation are somewhat controversial, as the safety of intentionally maintaining respective levels greater than 30% and 500 ng/mL has been studied in very few patients. Transferrin saturation should in general not exceed 50%.

High ferritin levels are associated with higher death rates, but whether elevation of ferritin levels is a marker of excessive iron administration rather than a nonspecific acute-phase reactant is not clear. The 2006 guidelines⁶⁰ cited upper ferritin limits of 500 to 800 ng/mL. However, the more recent DRIVE trial⁶⁷ showed that patients with ferritin levels of 500 to 1,200 ng/mL will respond to intravenous administration of iron with an increase in their hemoglobin levels. This has led many clinicians to adopt a higher ferritin limit of 1,200 ng/mL.

Hemosiderosis, or excess iron deposition, was a known consequence of frequent transfusions in patients with end-stage renal disease before ESA therapy was available. However, there have been no documented cases of clinical iron overload from iron therapy using current guidelines.⁷³

These algorithms are nuanced, and the benefit of giving intravenous iron should always be weighed against the risks of short-term acute toxicity and infection. Treatment of renal anemia not only requires in-depth knowledge of the topic, but also familiarity with the patient’s specific situation. As such, it is not recommended that clinicians unfamiliar with the treatment of renal anemia manage its treatment.

PARTICULAR CIRCUMSTANCES

Inflammation and ESA resistance

While ESAs are effective in treating anemia in many cases, in many patients the anemia fails to respond. This is of particular importance, since ESA hyporesponsiveness has been found to be a powerful predictor of cardiovascular events and death.⁷⁴ It is unclear, however, whether high doses of ESA are inherently toxic or whether hyporesponsiveness is a marker of adverse outcomes related to comorbidities.

KDIGO defines initial hyporesponsiveness as having no increase in hemoglobin concentration after the first month of appropriate weight-based dosing, and acquired hyporesponsiveness as requiring two increases in ESA doses up to 50% beyond the dose at which the patient had originally been stable.⁶⁰ Identifying ESA hyporesponsiveness should lead to an intensive search for potentially correctable factors.

The two major factors accounting for the state of hyporesponsiveness are inflammation and iron deficiency.^75,76

Inflammation. High C-reactive protein levels have been shown to predict resistance to erythropoietin in dialysis patients.⁷⁷ The release of cytokines such as tumor necrosis factor alpha, interleukin 1, and interferon gamma has an inhibitory effect on erythropoiesis.⁷⁸ Additionally, inflammation can alter the response to ESAs by disrupting the metabolism of iron⁷⁹ through the release of hepcidin, as previously discussed.³⁸ These reasons likely account for the observed lower response to ESAs in the setting of acute illness and explain why ESAs are not recommended for correcting acute anemia.⁸⁰

Iron deficiency also can blunt the response to ESAs. Large amounts of iron are needed for effective erythropoietic bursts. As such, iron supplementation is now a recognized treatment of renal anemia.⁸¹

Other factors associated with hyporesponsiveness include chronic occult blood loss, aluminum toxicity, cobalamin or folate deficiencies, testosterone deficiency, inadequate dialysis, hyperparathyroidism, and superimposed primary bone marrow disease,^82,83 and these should be addressed in patients whose anemia does not respond as expected to ESA therapy. A summary of the main causes of ESA hyporesponsiveness, their reversibility, and recommended treatments is presented in Table 3.

Antibody-mediated pure red-cell aplasia. Rarely, patients receiving ESA therapy develop antibodies that neutralize both the ESA and endogenous erythropoietin. The resulting syndrome, called antibody-mediated pure red-cell aplasia, is characterized by the sudden development of severe transfusion-dependent anemia. This has historically been connected to epoetin beta, a formulation not in use in the United States. However, cases have been documented with epoetin alfa and darbepoetin. The incidence rate is low with subcutaneous ESA use, estimated at 0.5 cases per 10,000 patient-years⁸⁴ and anecdotal with intravenous ESA.⁸⁵ The definitive diagnosis requires demonstration of neutralizing antibodies against erythropoietin. Parvovirus infection should be excluded as an alternative cause of pure red­cell aplasia.

ANEMIA IN CANCER PATIENTS

ESAs are effective in raising hemoglobin levels and reducing transfusion requirements in patients with chemotherapy-induced anemia.⁸⁶ However, there are data linking the use of ESAs to shortened survival in patients who have a variety of solid tumors.⁸⁷

Several mechanisms have been proposed to explain this rapid disease progression, most notably acceleration in tumor growth^88–90 by stimulation of erythropoietin receptors on the surface of the tumor cells, leading to increased tumor angiogenesis.^91,92

For these reasons, treatment of renal anemia in the setting of active malignancy should be referred to an oncologist.

NOVEL TREATMENTS

Several new agents for treating renal anemia are currently under review.

Continuous erythropoiesis receptor activator

Continuous erythropoiesis receptor activator is a pegylated form of recombinant human erythropoietin that has the ability to repeatedly activate the erythropoietin receptor. It appears to be similar to the other forms of erythropoietin in terms of safety and efficacy in both end-stage renal disease⁹³ and chronic kidney disease.⁹⁴ It has the advantage of an extended serum half-life, which allows for longer dosing intervals, ie, every 2 weeks. Its use is currently gaining popularity in the dialysis community.

HIF stabilizers

Our growing understanding of the physiology of erythropoietin offers new potential treatment targets. As previously described, production of erythropoietin is stimulated by HIFs. In order to be degraded, these HIFs are hydroxylated at their proline residues by a prolyl hydroxylase. A new category of drugs called prolyl-hydroxylase inhibitors (PDIs) offers the advantage of stabilizing the HIFs, leading to an increase in erythropoietin production.

In phase 1 and 2 clinical trials, these agents have been shown to increase hemoglobin in both end-stage renal disease and chronic kidney disease patients^15,16 but not in anephric patients, demonstrating a renal source of the erythropoietin production even in nonfunctioning kidneys. The study of one PDI agent (FG 2216) was halted temporarily after a report of death from fulminant hepatitis, but the other (FG 4592) continues to be studied in a phase 2 clinical trial.^95,96

TAKE-HOME POINTS

• Anemia of renal disease is a common condition that is mainly caused by a decrease in erythropoietin production by the kidneys.
• While anemia of renal disease can be corrected with ESAs, it is necessary to investigate and rule out underlying treatable conditions such as iron or vitamin deficiencies before giving an ESA.
• Anemia of renal disease is associated with significant morbidity such as increased risk of left ventricular hypertrophy, myocardial infarction, and heart failure, and has been described as an all-cause mortality multiplier.
• Unfortunately, the only undisputed benefit of treatment to date remains the avoidance of blood transfusions. Furthermore, the large randomized controlled trials that looked at the benefits of ESA have shown that their use can be associated with increased risk of cardiovascular events. Therefore, use of an ESA in end-stage renal disease should never target a normal hemoglobin levels but rather aim for a hemoglobin level of no more than 11.5 g/dL.
• Use of an ESA in chronic kidney disease should be individualized and is not recommended to be started unless the hemoglobin level is less than 10 g/dL.
• Several newer agents for renal anemia are currently under review. A pegylated form of recombinant human erythropoietin has an extended half-life, and a new and promising category of drugs called HIF stabilizers is currently under study.