Nephrology

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.

A breakthrough in understanding the pathogenesis of thrombotic thrombocytopenic purpura (TTP) came with the discovery of ADAMTS13 (an abbreviation for “a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13”), a plasma protein that cleaves von Willebrand factor, which interacts with platelets to promote blood clotting. If ADAMTS13 is lacking, unusually large multimers of von Willebrand factor can accumulate and trigger intravascular platelet aggregation and microthrombosis, causing the signs and symptoms of TTP.^1–3

This knowledge has practical applications: we can now measure ADAMTS13 activity, ADAMTS13 inhibitor, and antibodies against ADAMTS13 to help us diagnose TTP and distinguish it from other forms of thrombotic microangiopathy, such as hemolytic-uremic syndrome, that have similar symptoms but require different treatment.

Using case studies, this article describes typical presentations of acute and relapsing TTP; the role of laboratory testing, including the ADAMTS13 assay; how to distinguish TTP from other conditions that present similarly; and how to manage this condition.

A HIGH RISK OF DEATH WITHOUT PLASMA EXCHANGE

TTP is characterized by disseminated microthrombi composed of agglutinated platelets and von Willebrand factor in small vessels. Tissue damage by microthrombi can cause thrombocytopenia (platelet deficiency), microangiopathic hemolytic anemia (loss of red blood cells caused by destructive conditions in small vessels), and multiorgan failure.¹

Untreated TTP has a mortality rate of about 90%.¹ As shown in Case 1, Case 2, and Table 1, rapid diagnosis and prompt initiation of daily therapeutic plasma exchange can improve this grave outlook.⁴

ADAMTS13 DEFICIENCY CAN BE ACQUIRED OR CONGENITAL

Two major forms of TTP with ADAMTS13 deficiency and microvascular thrombosis are recognized:

Acquired TTP, the more common form, peaks in incidence between ages 30 and 50.^2,5 It more often affects women, particularly during and after pregnancy (its estimated prevalence is 1 in 25,000 pregnancies), and African Americans.⁶ Acquired TTP may be:

• Primary (idiopathic or autoantibody-mediated), associated with severely decreased ADAMTS13 and the presence of ultra-large von Willebrand factor multimers, or
• Secondary (23%–67% of cases), arising from a variety of conditions, including autoimmune disorders (eg, systemic lupus erythematosus, rheumatoid arthritis), solid organ or hematopoietic cell transplant, malignancy, drugs, and pregnancy (Table 2).^1,5–8 Secondary TTP has a worse prognosis than idiopathic TTP.^5,9

Congenital TTP (Upshaw-Shulman syndrome) is a rare autosomal-recessive disease caused by compound heterozygous or homozygous mutations of the ADAMTS13 gene, producing nonfunctional ADAMTS13 protein. Patients have severely deficient ADAMTS13 activity but usually do not develop autoantibodies. There is a high risk of chronic, relapsing episodes; identified triggers include pregnancy and heavy alcohol intake.^2,10 About half of patients with congenital TTP have an early onset, usually presenting with acute TTP between birth and age 5, and about half have a late onset, usually remaining without symptoms until age 20 to 40.

THE CLINICAL PICTURE OF TTP IS NOT ALWAYS CLASSIC

TTP is primarily diagnosed clinically, but diagnosis is often difficult because of various nonspecific symptoms. Typical TTP presents with the “classic pentad”:

• Severe thrombocytopenia (70%–100% of patients)
• Microangiopathic hemolytic anemia with multiple schistocytes (70%–100%) (Figure 1)
• Neurologic involvement (50%–90%)
• Renal abnormalities (about 50%)
• Fever (25%).

However, the entire picture often does not emerge in a single patient.^2,6 Waiting for the entire pentad to develop before diagnosing TTP can have grave clinical consequences,^1,2,5 and the presence of thrombocytopenia and unexplained microangiopathic hemolytic anemia are considered clinically sufficient to suspect TTP.⁵

Neurologic symptoms usually fluctuate. They can include mild abnormalities such as weakness, dizziness, headache, blurred vision, ataxia, and transient mental status changes, as well as severe abnormalities including stroke, seizure, and coma.^2,6

Most patients have normal findings on computed tomography and magnetic resonance imaging at the onset of neurologic symptoms or with a history of TTP. Some patients (8%–39%) show reversible acute brain lesions, including ischemic changes.^11–13

Other signs and symptoms may result from multiorgan failure due to microthrombosis; ischemia in retinal, coronary, and abdominal circulations; and unconjugated hyperbilirubinemia.²

Atypical presentations. About 18% of patients have cardiac involvement from microvascular occlusion, with arrhythmia, angina, or congestive heart failure. Abdominal pain and pancreatitis occur in 5% to 13%, and visual disturbances in 8% to 10%.

Patients with an atypical presentation may not have laboratory evidence of microangiopathic hemolytic anemia, but an ADAMTS13 assay will show severely decreased activity. Therapeutic plasma exchange can improve atypical symptoms.^2,3,10,14,15

ADAMTS13 ASSAY IS KEY TO DIAGNOSIS

Laboratory evidence typically includes hemolytic anemia (reticulocytosis, schistocytes, elevated indirect bilirubin, reduced haptoglobin, elevated lactate dehydrogenase) and thrombocytopenia.³ There are no significant abnormalities in prothrombin time, international normalized ratio, activated partial thromboplastin time, fibrinogen, or D-dimer level.

Measuring the levels of ADAMTS13 activity, ADAMTS13 inhibitor, and ADAMTS13 antibody is becoming standard to confirm the diagnosis of TTP, to determine if it is congenital or acquired, and to distinguish it from thrombocytopenic conditions such as hemolytic-uremic syndrome, idiopathic thrombocytopenic purpura, and heparin-induced thrombocytopenia.^4,5 A newer ADAMTS13 assay based on fluorescence energy transfer (FRET) technology with a synthetic amino acid-von Willebrand factor peptide substrate has a faster turnaround time and less test variability.^6,16,17 This FRET assay can give the result of ADAMTS13 activity within 2 hours. In comparison, the assay based on multimeric von Willebrand factor takes 2 to 3 days, and mass spectrometry to measure the cleavage products of a synthetic von Willebrand factor molecule takes about 4 hours.^3,10,16

About two-thirds of patients with the clinical diagnosis of idiopathic TTP have ADAMTS13 activity levels lower than 10%.^5,14,18 In the appropriate clinical setting, this threshold level is highly sensitive (89%–100%) and specific (99%–100%) in differentiating TTP from other thrombotic angiopathies.^2,3,18

Note: The ADAMTS13 assay was needed for early correct diagnosis in Case 1 and Case 2.

Inhibitors provide more clues

Autoantibodies can be classified according to whether they inhibit ADAMTS13 activity.

Neutralizing inhibitors. Most cases of acquired, idiopathic TTP with severe ADAMTS13 deficiency are related to circulating autoantibodies that neutralize ADAMTS13 activity. This ADAMTS13 inhibitor level is obtained by measuring residual ADAMTS13 activity after mixing equal amounts of patient plasma with normal pooled plasma. ADAMTS13 inhibitor is detectable in 44% to 93% of patients with severely deficient ADAMTS13 activity.^3,6,19

Nonneutralizing inhibitors. From 10% to 15% of patients with TTP with severe ADAMTS13 deficiency lack ADAMTS13 autoantibodies measured by enzyme immunoassay but have nonneutralizing immunoglobulin G (IgG) or IgM autoantibodies. In such cases, ADAMTS13 deficiency may be related to increased antibody-mediated clearance or other unknown mechanisms.

Neutralizing inhibitors and nonneutralizing inhibitors may be present simultaneously in some patients.^3,10,19,20

Blood factors affect ADAMTS13 activity

Specimen factors can affect ADAMTS13 activity and antibody levels.

Hemoglobin is a potent inhibitor of ADAMTS13, so an elevated plasma level of free hemoglobin (> 2 g/dL) can reduce ADAMTS13 activity, as can hyperbilirubinemia (> 15 mg/dL).

High levels of endogenous von Willebrand factor, lipids, thrombin, or other proteases that may cleave ADAMTS13 can also reduce ADAMTS13 activity.³ Conversely, recent plasma exchange or transfusion can mask the diagnosis of TTP because of false normalization of ADAMTS13 activity. In addition, ADAMTS13 autoantibody can be detected in other immune-mediated disorders (eg, systemic lupus erythematosus, antiphospholipid syndrome), and hypergammaglobulinemia, as well as in 10% to 15% of healthy individuals.¹⁹

CONSIDER OTHER CONDITIONS

Before diagnosing TTP, other conditions causing thrombocytopenia and hemolytic anemia should be excluded by taking a careful clinical, laboratory, and medication history (Table 2). Of these conditions, the most challenging to differentiate from TTP—and often indistinguishable from it at presentation—is hemolytic-uremic syndrome (Table 3).

Hemolytic-uremic syndrome

Hemolytic-uremic syndrome presents with a triad of thrombocytopenia, acute renal failure, and microangiopathic hemolytic anemia, with increased lactate dehydrogenase levels. Renal dysfunction from ischemia or tissue injury by microvascular thrombi predominates. Hemolytic-uremic syndrome most often occurs in children and is often related to hemorrhagic enterocolitis caused by infection with Escherichia coli O157:H7 or Shigella species (90%–95% of cases).^1,2,5

From 5% to 10% of cases of hemolytic- uremic syndrome are atypical. These cases are not associated with diarrhea, and many are caused by genetic mutations that result in chronic excessive complement activation. Implicated genes regulate complement regulator factor H (20%–30% of cases) or CD46 (10%) and other cofactors, or autoantibodies against factor H (10%), which affect the alternate complement pathway.^6,21–23

Initial therapeutic plasma exchange is commonly undertaken for atypical hemolytic- uremic syndrome, particularly for patients at risk of rapid progression to end-stage renal failure. But despite such treatment, about 60% of these patients die or develop permanent renal damage within 1 year.^2,3,24

Eculizumab, a monoclonal antibody against complement component C5, has been approved by the US Food and Drug Administration for atypical hemolytic-uremic syndrome and may improve quality of life.^25–27

PLASMA EXCHANGE IS THE MAINSTAY OF THERAPY

In 2012, the British Society for Haematology published revised guidelines for managing TTP and other thrombotic microangiopathies.²⁸

Acquired idiopathic TTP with reduced ADAMTS13 activity requires immediate therapeutic plasma exchange. Daily plasma exchange combines plasmapheresis to remove circulating ultralarge von Willebrand factor-platelet strings and autoantibodies against ADAMTS13, and infusion of fresh-frozen plasma to replace ADAMTS13.¹⁸ This procedure is the mainstay of therapy and brings 70% to 90% of patients with idiopathic TTP to remission.^1,2,5,6 However, the optimal duration of daily plasma exchange and the number of procedures required is highly variable according to clinical condition. Therapeutic plasma exchange can also cause plasma-related adverse reactions.^9,28 Congenital TTP requires plasma infusion or exchange depending on the patient’s severity of ADAMTS13 deficiency.

Corticosteroids are used in combination with daily therapeutic plasma exchange, although evidence from controlled trials of their efficacy in this setting is lacking. Patients with severely decreased ADAMTS13 activity or low titers of ADAMTS13 autoantibodies tend to respond to the therapy.^5,8,29

An ADAMTS13 assay with a short turn-around time can help guide the decision to initiate therapeutic plasma exchange. However, if there is a strong clinical suspicion of TTP, plasma exchange should be initiated immediately without waiting for test results.^5,30 Monitoring ADAMTS13 activity or inhibitor during initial plasma exchange therapy has had conflicting results in several studies and is generally not recommended for patients with acquired TTP.^8,30,31

RELAPSE IS COMMON

About 20% to 50% of patients with idiopathic TTP experience a relapse (Case 2). Most relapses occur within the first 2 years after the initial episode, with an estimated risk of 43% for relapse at 7.5 years.^5,9

Factors that predict a higher risk of relapse include persistently severely decreased ADAMTS13 activity, positive inhibitor, and high titers of autoantibodies to ADAMTS13 during symptomatic TTP. During clinical remission, persistence of autoantibodies also indicates increased risk.^1,3,5,6,9

Patients who have a relapse and whose disease is refractory to therapeutic plasma exchange (10%–20% of cases) have been treated with corticosteroids, splenectomy, or immunosuppressive agents (cyclosporine, azathioprine, or cyclophosphamide) with varying rates of success. Rituximab (monoclonal anti-CD20) has recently been used as second-line therapy in refractory or relapsing immune-mediated TTP or idiopathic TTP with neurologic or cardiac symptoms associated with a poor prognosis. Therapy including rituximab results in improved response and progression-free survival.³² Other potential therapies, including recombinant active ADAMTS13, are under investigation.^{9,23,28,30,33,34}

A breakthrough in understanding the pathogenesis of thrombotic thrombocytopenic purpura (TTP) came with the discovery of ADAMTS13 (an abbreviation for “a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13”), a plasma protein that cleaves von Willebrand factor, which interacts with platelets to promote blood clotting. If ADAMTS13 is lacking, unusually large multimers of von Willebrand factor can accumulate and trigger intravascular platelet aggregation and microthrombosis, causing the signs and symptoms of TTP.^1–3

This knowledge has practical applications: we can now measure ADAMTS13 activity, ADAMTS13 inhibitor, and antibodies against ADAMTS13 to help us diagnose TTP and distinguish it from other forms of thrombotic microangiopathy, such as hemolytic-uremic syndrome, that have similar symptoms but require different treatment.

Using case studies, this article describes typical presentations of acute and relapsing TTP; the role of laboratory testing, including the ADAMTS13 assay; how to distinguish TTP from other conditions that present similarly; and how to manage this condition.

A HIGH RISK OF DEATH WITHOUT PLASMA EXCHANGE

TTP is characterized by disseminated microthrombi composed of agglutinated platelets and von Willebrand factor in small vessels. Tissue damage by microthrombi can cause thrombocytopenia (platelet deficiency), microangiopathic hemolytic anemia (loss of red blood cells caused by destructive conditions in small vessels), and multiorgan failure.¹

Untreated TTP has a mortality rate of about 90%.¹ As shown in Case 1, Case 2, and Table 1, rapid diagnosis and prompt initiation of daily therapeutic plasma exchange can improve this grave outlook.⁴

ADAMTS13 DEFICIENCY CAN BE ACQUIRED OR CONGENITAL

Two major forms of TTP with ADAMTS13 deficiency and microvascular thrombosis are recognized:

Acquired TTP, the more common form, peaks in incidence between ages 30 and 50.^2,5 It more often affects women, particularly during and after pregnancy (its estimated prevalence is 1 in 25,000 pregnancies), and African Americans.⁶ Acquired TTP may be:

• Primary (idiopathic or autoantibody-mediated), associated with severely decreased ADAMTS13 and the presence of ultra-large von Willebrand factor multimers, or
• Secondary (23%–67% of cases), arising from a variety of conditions, including autoimmune disorders (eg, systemic lupus erythematosus, rheumatoid arthritis), solid organ or hematopoietic cell transplant, malignancy, drugs, and pregnancy (Table 2).^1,5–8 Secondary TTP has a worse prognosis than idiopathic TTP.^5,9

Congenital TTP (Upshaw-Shulman syndrome) is a rare autosomal-recessive disease caused by compound heterozygous or homozygous mutations of the ADAMTS13 gene, producing nonfunctional ADAMTS13 protein. Patients have severely deficient ADAMTS13 activity but usually do not develop autoantibodies. There is a high risk of chronic, relapsing episodes; identified triggers include pregnancy and heavy alcohol intake.^2,10 About half of patients with congenital TTP have an early onset, usually presenting with acute TTP between birth and age 5, and about half have a late onset, usually remaining without symptoms until age 20 to 40.

THE CLINICAL PICTURE OF TTP IS NOT ALWAYS CLASSIC

TTP is primarily diagnosed clinically, but diagnosis is often difficult because of various nonspecific symptoms. Typical TTP presents with the “classic pentad”:

• Severe thrombocytopenia (70%–100% of patients)
• Microangiopathic hemolytic anemia with multiple schistocytes (70%–100%) (Figure 1)
• Neurologic involvement (50%–90%)
• Renal abnormalities (about 50%)
• Fever (25%).

However, the entire picture often does not emerge in a single patient.^2,6 Waiting for the entire pentad to develop before diagnosing TTP can have grave clinical consequences,^1,2,5 and the presence of thrombocytopenia and unexplained microangiopathic hemolytic anemia are considered clinically sufficient to suspect TTP.⁵

Neurologic symptoms usually fluctuate. They can include mild abnormalities such as weakness, dizziness, headache, blurred vision, ataxia, and transient mental status changes, as well as severe abnormalities including stroke, seizure, and coma.^2,6

Most patients have normal findings on computed tomography and magnetic resonance imaging at the onset of neurologic symptoms or with a history of TTP. Some patients (8%–39%) show reversible acute brain lesions, including ischemic changes.^11–13

Other signs and symptoms may result from multiorgan failure due to microthrombosis; ischemia in retinal, coronary, and abdominal circulations; and unconjugated hyperbilirubinemia.²

Atypical presentations. About 18% of patients have cardiac involvement from microvascular occlusion, with arrhythmia, angina, or congestive heart failure. Abdominal pain and pancreatitis occur in 5% to 13%, and visual disturbances in 8% to 10%.

Patients with an atypical presentation may not have laboratory evidence of microangiopathic hemolytic anemia, but an ADAMTS13 assay will show severely decreased activity. Therapeutic plasma exchange can improve atypical symptoms.^2,3,10,14,15

ADAMTS13 ASSAY IS KEY TO DIAGNOSIS

Laboratory evidence typically includes hemolytic anemia (reticulocytosis, schistocytes, elevated indirect bilirubin, reduced haptoglobin, elevated lactate dehydrogenase) and thrombocytopenia.³ There are no significant abnormalities in prothrombin time, international normalized ratio, activated partial thromboplastin time, fibrinogen, or D-dimer level.

Measuring the levels of ADAMTS13 activity, ADAMTS13 inhibitor, and ADAMTS13 antibody is becoming standard to confirm the diagnosis of TTP, to determine if it is congenital or acquired, and to distinguish it from thrombocytopenic conditions such as hemolytic-uremic syndrome, idiopathic thrombocytopenic purpura, and heparin-induced thrombocytopenia.^4,5 A newer ADAMTS13 assay based on fluorescence energy transfer (FRET) technology with a synthetic amino acid-von Willebrand factor peptide substrate has a faster turnaround time and less test variability.^6,16,17 This FRET assay can give the result of ADAMTS13 activity within 2 hours. In comparison, the assay based on multimeric von Willebrand factor takes 2 to 3 days, and mass spectrometry to measure the cleavage products of a synthetic von Willebrand factor molecule takes about 4 hours.^3,10,16

About two-thirds of patients with the clinical diagnosis of idiopathic TTP have ADAMTS13 activity levels lower than 10%.^5,14,18 In the appropriate clinical setting, this threshold level is highly sensitive (89%–100%) and specific (99%–100%) in differentiating TTP from other thrombotic angiopathies.^2,3,18

Note: The ADAMTS13 assay was needed for early correct diagnosis in Case 1 and Case 2.

Inhibitors provide more clues

Autoantibodies can be classified according to whether they inhibit ADAMTS13 activity.

Neutralizing inhibitors. Most cases of acquired, idiopathic TTP with severe ADAMTS13 deficiency are related to circulating autoantibodies that neutralize ADAMTS13 activity. This ADAMTS13 inhibitor level is obtained by measuring residual ADAMTS13 activity after mixing equal amounts of patient plasma with normal pooled plasma. ADAMTS13 inhibitor is detectable in 44% to 93% of patients with severely deficient ADAMTS13 activity.^3,6,19

Nonneutralizing inhibitors. From 10% to 15% of patients with TTP with severe ADAMTS13 deficiency lack ADAMTS13 autoantibodies measured by enzyme immunoassay but have nonneutralizing immunoglobulin G (IgG) or IgM autoantibodies. In such cases, ADAMTS13 deficiency may be related to increased antibody-mediated clearance or other unknown mechanisms.

Neutralizing inhibitors and nonneutralizing inhibitors may be present simultaneously in some patients.^3,10,19,20

Blood factors affect ADAMTS13 activity

Specimen factors can affect ADAMTS13 activity and antibody levels.

Hemoglobin is a potent inhibitor of ADAMTS13, so an elevated plasma level of free hemoglobin (> 2 g/dL) can reduce ADAMTS13 activity, as can hyperbilirubinemia (> 15 mg/dL).

High levels of endogenous von Willebrand factor, lipids, thrombin, or other proteases that may cleave ADAMTS13 can also reduce ADAMTS13 activity.³ Conversely, recent plasma exchange or transfusion can mask the diagnosis of TTP because of false normalization of ADAMTS13 activity. In addition, ADAMTS13 autoantibody can be detected in other immune-mediated disorders (eg, systemic lupus erythematosus, antiphospholipid syndrome), and hypergammaglobulinemia, as well as in 10% to 15% of healthy individuals.¹⁹

CONSIDER OTHER CONDITIONS

Before diagnosing TTP, other conditions causing thrombocytopenia and hemolytic anemia should be excluded by taking a careful clinical, laboratory, and medication history (Table 2). Of these conditions, the most challenging to differentiate from TTP—and often indistinguishable from it at presentation—is hemolytic-uremic syndrome (Table 3).

Hemolytic-uremic syndrome

Hemolytic-uremic syndrome presents with a triad of thrombocytopenia, acute renal failure, and microangiopathic hemolytic anemia, with increased lactate dehydrogenase levels. Renal dysfunction from ischemia or tissue injury by microvascular thrombi predominates. Hemolytic-uremic syndrome most often occurs in children and is often related to hemorrhagic enterocolitis caused by infection with Escherichia coli O157:H7 or Shigella species (90%–95% of cases).^1,2,5

From 5% to 10% of cases of hemolytic- uremic syndrome are atypical. These cases are not associated with diarrhea, and many are caused by genetic mutations that result in chronic excessive complement activation. Implicated genes regulate complement regulator factor H (20%–30% of cases) or CD46 (10%) and other cofactors, or autoantibodies against factor H (10%), which affect the alternate complement pathway.^6,21–23

Initial therapeutic plasma exchange is commonly undertaken for atypical hemolytic- uremic syndrome, particularly for patients at risk of rapid progression to end-stage renal failure. But despite such treatment, about 60% of these patients die or develop permanent renal damage within 1 year.^2,3,24

Eculizumab, a monoclonal antibody against complement component C5, has been approved by the US Food and Drug Administration for atypical hemolytic-uremic syndrome and may improve quality of life.^25–27

PLASMA EXCHANGE IS THE MAINSTAY OF THERAPY

In 2012, the British Society for Haematology published revised guidelines for managing TTP and other thrombotic microangiopathies.²⁸

Acquired idiopathic TTP with reduced ADAMTS13 activity requires immediate therapeutic plasma exchange. Daily plasma exchange combines plasmapheresis to remove circulating ultralarge von Willebrand factor-platelet strings and autoantibodies against ADAMTS13, and infusion of fresh-frozen plasma to replace ADAMTS13.¹⁸ This procedure is the mainstay of therapy and brings 70% to 90% of patients with idiopathic TTP to remission.^1,2,5,6 However, the optimal duration of daily plasma exchange and the number of procedures required is highly variable according to clinical condition. Therapeutic plasma exchange can also cause plasma-related adverse reactions.^9,28 Congenital TTP requires plasma infusion or exchange depending on the patient’s severity of ADAMTS13 deficiency.

Corticosteroids are used in combination with daily therapeutic plasma exchange, although evidence from controlled trials of their efficacy in this setting is lacking. Patients with severely decreased ADAMTS13 activity or low titers of ADAMTS13 autoantibodies tend to respond to the therapy.^5,8,29

An ADAMTS13 assay with a short turn-around time can help guide the decision to initiate therapeutic plasma exchange. However, if there is a strong clinical suspicion of TTP, plasma exchange should be initiated immediately without waiting for test results.^5,30 Monitoring ADAMTS13 activity or inhibitor during initial plasma exchange therapy has had conflicting results in several studies and is generally not recommended for patients with acquired TTP.^8,30,31

RELAPSE IS COMMON

About 20% to 50% of patients with idiopathic TTP experience a relapse (Case 2). Most relapses occur within the first 2 years after the initial episode, with an estimated risk of 43% for relapse at 7.5 years.^5,9

Factors that predict a higher risk of relapse include persistently severely decreased ADAMTS13 activity, positive inhibitor, and high titers of autoantibodies to ADAMTS13 during symptomatic TTP. During clinical remission, persistence of autoantibodies also indicates increased risk.^1,3,5,6,9

Patients who have a relapse and whose disease is refractory to therapeutic plasma exchange (10%–20% of cases) have been treated with corticosteroids, splenectomy, or immunosuppressive agents (cyclosporine, azathioprine, or cyclophosphamide) with varying rates of success. Rituximab (monoclonal anti-CD20) has recently been used as second-line therapy in refractory or relapsing immune-mediated TTP or idiopathic TTP with neurologic or cardiac symptoms associated with a poor prognosis. Therapy including rituximab results in improved response and progression-free survival.³² Other potential therapies, including recombinant active ADAMTS13, are under investigation.^{9,23,28,30,33,34}

A breakthrough in understanding the pathogenesis of thrombotic thrombocytopenic purpura (TTP) came with the discovery of ADAMTS13 (an abbreviation for “a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13”), a plasma protein that cleaves von Willebrand factor, which interacts with platelets to promote blood clotting. If ADAMTS13 is lacking, unusually large multimers of von Willebrand factor can accumulate and trigger intravascular platelet aggregation and microthrombosis, causing the signs and symptoms of TTP.^1–3

This knowledge has practical applications: we can now measure ADAMTS13 activity, ADAMTS13 inhibitor, and antibodies against ADAMTS13 to help us diagnose TTP and distinguish it from other forms of thrombotic microangiopathy, such as hemolytic-uremic syndrome, that have similar symptoms but require different treatment.

Using case studies, this article describes typical presentations of acute and relapsing TTP; the role of laboratory testing, including the ADAMTS13 assay; how to distinguish TTP from other conditions that present similarly; and how to manage this condition.

A HIGH RISK OF DEATH WITHOUT PLASMA EXCHANGE

TTP is characterized by disseminated microthrombi composed of agglutinated platelets and von Willebrand factor in small vessels. Tissue damage by microthrombi can cause thrombocytopenia (platelet deficiency), microangiopathic hemolytic anemia (loss of red blood cells caused by destructive conditions in small vessels), and multiorgan failure.¹

Untreated TTP has a mortality rate of about 90%.¹ As shown in Case 1, Case 2, and Table 1, rapid diagnosis and prompt initiation of daily therapeutic plasma exchange can improve this grave outlook.⁴

ADAMTS13 DEFICIENCY CAN BE ACQUIRED OR CONGENITAL

Two major forms of TTP with ADAMTS13 deficiency and microvascular thrombosis are recognized:

Acquired TTP, the more common form, peaks in incidence between ages 30 and 50.^2,5 It more often affects women, particularly during and after pregnancy (its estimated prevalence is 1 in 25,000 pregnancies), and African Americans.⁶ Acquired TTP may be:

• Primary (idiopathic or autoantibody-mediated), associated with severely decreased ADAMTS13 and the presence of ultra-large von Willebrand factor multimers, or
• Secondary (23%–67% of cases), arising from a variety of conditions, including autoimmune disorders (eg, systemic lupus erythematosus, rheumatoid arthritis), solid organ or hematopoietic cell transplant, malignancy, drugs, and pregnancy (Table 2).^1,5–8 Secondary TTP has a worse prognosis than idiopathic TTP.^5,9

Congenital TTP (Upshaw-Shulman syndrome) is a rare autosomal-recessive disease caused by compound heterozygous or homozygous mutations of the ADAMTS13 gene, producing nonfunctional ADAMTS13 protein. Patients have severely deficient ADAMTS13 activity but usually do not develop autoantibodies. There is a high risk of chronic, relapsing episodes; identified triggers include pregnancy and heavy alcohol intake.^2,10 About half of patients with congenital TTP have an early onset, usually presenting with acute TTP between birth and age 5, and about half have a late onset, usually remaining without symptoms until age 20 to 40.

THE CLINICAL PICTURE OF TTP IS NOT ALWAYS CLASSIC

TTP is primarily diagnosed clinically, but diagnosis is often difficult because of various nonspecific symptoms. Typical TTP presents with the “classic pentad”:

• Severe thrombocytopenia (70%–100% of patients)
• Microangiopathic hemolytic anemia with multiple schistocytes (70%–100%) (Figure 1)
• Neurologic involvement (50%–90%)
• Renal abnormalities (about 50%)
• Fever (25%).

However, the entire picture often does not emerge in a single patient.^2,6 Waiting for the entire pentad to develop before diagnosing TTP can have grave clinical consequences,^1,2,5 and the presence of thrombocytopenia and unexplained microangiopathic hemolytic anemia are considered clinically sufficient to suspect TTP.⁵

Neurologic symptoms usually fluctuate. They can include mild abnormalities such as weakness, dizziness, headache, blurred vision, ataxia, and transient mental status changes, as well as severe abnormalities including stroke, seizure, and coma.^2,6

Most patients have normal findings on computed tomography and magnetic resonance imaging at the onset of neurologic symptoms or with a history of TTP. Some patients (8%–39%) show reversible acute brain lesions, including ischemic changes.^11–13

Other signs and symptoms may result from multiorgan failure due to microthrombosis; ischemia in retinal, coronary, and abdominal circulations; and unconjugated hyperbilirubinemia.²

Atypical presentations. About 18% of patients have cardiac involvement from microvascular occlusion, with arrhythmia, angina, or congestive heart failure. Abdominal pain and pancreatitis occur in 5% to 13%, and visual disturbances in 8% to 10%.

Patients with an atypical presentation may not have laboratory evidence of microangiopathic hemolytic anemia, but an ADAMTS13 assay will show severely decreased activity. Therapeutic plasma exchange can improve atypical symptoms.^2,3,10,14,15

ADAMTS13 ASSAY IS KEY TO DIAGNOSIS

Laboratory evidence typically includes hemolytic anemia (reticulocytosis, schistocytes, elevated indirect bilirubin, reduced haptoglobin, elevated lactate dehydrogenase) and thrombocytopenia.³ There are no significant abnormalities in prothrombin time, international normalized ratio, activated partial thromboplastin time, fibrinogen, or D-dimer level.

Measuring the levels of ADAMTS13 activity, ADAMTS13 inhibitor, and ADAMTS13 antibody is becoming standard to confirm the diagnosis of TTP, to determine if it is congenital or acquired, and to distinguish it from thrombocytopenic conditions such as hemolytic-uremic syndrome, idiopathic thrombocytopenic purpura, and heparin-induced thrombocytopenia.^4,5 A newer ADAMTS13 assay based on fluorescence energy transfer (FRET) technology with a synthetic amino acid-von Willebrand factor peptide substrate has a faster turnaround time and less test variability.^6,16,17 This FRET assay can give the result of ADAMTS13 activity within 2 hours. In comparison, the assay based on multimeric von Willebrand factor takes 2 to 3 days, and mass spectrometry to measure the cleavage products of a synthetic von Willebrand factor molecule takes about 4 hours.^3,10,16

About two-thirds of patients with the clinical diagnosis of idiopathic TTP have ADAMTS13 activity levels lower than 10%.^5,14,18 In the appropriate clinical setting, this threshold level is highly sensitive (89%–100%) and specific (99%–100%) in differentiating TTP from other thrombotic angiopathies.^2,3,18

Note: The ADAMTS13 assay was needed for early correct diagnosis in Case 1 and Case 2.

Inhibitors provide more clues

Autoantibodies can be classified according to whether they inhibit ADAMTS13 activity.

Neutralizing inhibitors. Most cases of acquired, idiopathic TTP with severe ADAMTS13 deficiency are related to circulating autoantibodies that neutralize ADAMTS13 activity. This ADAMTS13 inhibitor level is obtained by measuring residual ADAMTS13 activity after mixing equal amounts of patient plasma with normal pooled plasma. ADAMTS13 inhibitor is detectable in 44% to 93% of patients with severely deficient ADAMTS13 activity.^3,6,19

Nonneutralizing inhibitors. From 10% to 15% of patients with TTP with severe ADAMTS13 deficiency lack ADAMTS13 autoantibodies measured by enzyme immunoassay but have nonneutralizing immunoglobulin G (IgG) or IgM autoantibodies. In such cases, ADAMTS13 deficiency may be related to increased antibody-mediated clearance or other unknown mechanisms.

Neutralizing inhibitors and nonneutralizing inhibitors may be present simultaneously in some patients.^3,10,19,20

Blood factors affect ADAMTS13 activity

Specimen factors can affect ADAMTS13 activity and antibody levels.

Hemoglobin is a potent inhibitor of ADAMTS13, so an elevated plasma level of free hemoglobin (> 2 g/dL) can reduce ADAMTS13 activity, as can hyperbilirubinemia (> 15 mg/dL).

High levels of endogenous von Willebrand factor, lipids, thrombin, or other proteases that may cleave ADAMTS13 can also reduce ADAMTS13 activity.³ Conversely, recent plasma exchange or transfusion can mask the diagnosis of TTP because of false normalization of ADAMTS13 activity. In addition, ADAMTS13 autoantibody can be detected in other immune-mediated disorders (eg, systemic lupus erythematosus, antiphospholipid syndrome), and hypergammaglobulinemia, as well as in 10% to 15% of healthy individuals.¹⁹

CONSIDER OTHER CONDITIONS

Before diagnosing TTP, other conditions causing thrombocytopenia and hemolytic anemia should be excluded by taking a careful clinical, laboratory, and medication history (Table 2). Of these conditions, the most challenging to differentiate from TTP—and often indistinguishable from it at presentation—is hemolytic-uremic syndrome (Table 3).

Hemolytic-uremic syndrome

Hemolytic-uremic syndrome presents with a triad of thrombocytopenia, acute renal failure, and microangiopathic hemolytic anemia, with increased lactate dehydrogenase levels. Renal dysfunction from ischemia or tissue injury by microvascular thrombi predominates. Hemolytic-uremic syndrome most often occurs in children and is often related to hemorrhagic enterocolitis caused by infection with Escherichia coli O157:H7 or Shigella species (90%–95% of cases).^1,2,5

From 5% to 10% of cases of hemolytic- uremic syndrome are atypical. These cases are not associated with diarrhea, and many are caused by genetic mutations that result in chronic excessive complement activation. Implicated genes regulate complement regulator factor H (20%–30% of cases) or CD46 (10%) and other cofactors, or autoantibodies against factor H (10%), which affect the alternate complement pathway.^6,21–23

Initial therapeutic plasma exchange is commonly undertaken for atypical hemolytic- uremic syndrome, particularly for patients at risk of rapid progression to end-stage renal failure. But despite such treatment, about 60% of these patients die or develop permanent renal damage within 1 year.^2,3,24

Eculizumab, a monoclonal antibody against complement component C5, has been approved by the US Food and Drug Administration for atypical hemolytic-uremic syndrome and may improve quality of life.^25–27

PLASMA EXCHANGE IS THE MAINSTAY OF THERAPY

In 2012, the British Society for Haematology published revised guidelines for managing TTP and other thrombotic microangiopathies.²⁸

Acquired idiopathic TTP with reduced ADAMTS13 activity requires immediate therapeutic plasma exchange. Daily plasma exchange combines plasmapheresis to remove circulating ultralarge von Willebrand factor-platelet strings and autoantibodies against ADAMTS13, and infusion of fresh-frozen plasma to replace ADAMTS13.¹⁸ This procedure is the mainstay of therapy and brings 70% to 90% of patients with idiopathic TTP to remission.^1,2,5,6 However, the optimal duration of daily plasma exchange and the number of procedures required is highly variable according to clinical condition. Therapeutic plasma exchange can also cause plasma-related adverse reactions.^9,28 Congenital TTP requires plasma infusion or exchange depending on the patient’s severity of ADAMTS13 deficiency.

Corticosteroids are used in combination with daily therapeutic plasma exchange, although evidence from controlled trials of their efficacy in this setting is lacking. Patients with severely decreased ADAMTS13 activity or low titers of ADAMTS13 autoantibodies tend to respond to the therapy.^5,8,29

An ADAMTS13 assay with a short turn-around time can help guide the decision to initiate therapeutic plasma exchange. However, if there is a strong clinical suspicion of TTP, plasma exchange should be initiated immediately without waiting for test results.^5,30 Monitoring ADAMTS13 activity or inhibitor during initial plasma exchange therapy has had conflicting results in several studies and is generally not recommended for patients with acquired TTP.^8,30,31

RELAPSE IS COMMON

About 20% to 50% of patients with idiopathic TTP experience a relapse (Case 2). Most relapses occur within the first 2 years after the initial episode, with an estimated risk of 43% for relapse at 7.5 years.^5,9

Factors that predict a higher risk of relapse include persistently severely decreased ADAMTS13 activity, positive inhibitor, and high titers of autoantibodies to ADAMTS13 during symptomatic TTP. During clinical remission, persistence of autoantibodies also indicates increased risk.^1,3,5,6,9

Patients who have a relapse and whose disease is refractory to therapeutic plasma exchange (10%–20% of cases) have been treated with corticosteroids, splenectomy, or immunosuppressive agents (cyclosporine, azathioprine, or cyclophosphamide) with varying rates of success. Rituximab (monoclonal anti-CD20) has recently been used as second-line therapy in refractory or relapsing immune-mediated TTP or idiopathic TTP with neurologic or cardiac symptoms associated with a poor prognosis. Therapy including rituximab results in improved response and progression-free survival.³² Other potential therapies, including recombinant active ADAMTS13, are under investigation.^{9,23,28,30,33,34}

A 53-year-old woman presented with extensive, nonulcerated, painful plaques on both calves. She had long-standing diabetes mellitus and had recently started hemodialysis. She had no fever or trauma and did not appear to be in shock.

On physical examination, she had extensive, well-demarcated, nonulcerated, indurated dark eschar over the right calf (Figure 1). Her left calf had similar lesions that appeared as focal, discrete, nonulcerated, violaceous plaques, with associated tenderness. No significant erythema, edema, drainage, or fluctuance was noted.

A broad-spectrum antibiotic was started empirically but was discontinued when routine blood testing and magnetic resonance imaging showed no evidence of infection. Histologic study of a full-thickness skin biopsy specimen (Figure 2) showed tissue necrosis, ulceration, and concentric calcification of small and medium-sized blood vessels, many with luminal thrombi, all of which together were diagnostic for calciphylaxis.

Treatment was started with cinacalcet, low-calcium dialysis baths, phosphate binders, and sodium thiosulfate. However, within a few days of the biopsy procedure, an infection developed at the biopsy site, and the patient developed sepsis and septic shock. She received broad-spectrum antibiotics and underwent extensive debridement with wound care. After a protracted hospital course, the infection resolved.

CALCIPHYLAXIS RISK FACTORS

Calciphylaxis, also referred to as calcific uremic arteriolopathy, is a rare and often fatal condition in patients with end-stage renal disease who are on hemodialysis (1% to 4% of dialysis patients).^1–3 It is also seen in patients who have undergone renal transplant and in patients with chronic kidney disease who have a chronic inflammatory disease or who have been exposed to corticosteroids or warfarin. However, it can also occur in patients without chronic kidney disease or end-stage renal disease.

The term “calcific uremic arteriolopathy” is a misnomer, as this condition can occur in patients with normal renal function (nonuremic calciphylaxis). Also, despite what the term calciphylaxis implies, there is no systemic anaphylaxis.^3–5

Documented risk factors include obesity; female sex; use of warfarin, corticosteroids, or vitamin D analogues; low serum albumin; hypercoagulable states; hyperparathyroidism; alcoholic liver disease; elevated calcium-phosphorus product; inflammation; connective tissue disease; and cancer.^4–6

DIAGNOSTIC CLUES

There are no strict guidelines for the diagnosis of calciphylaxis, and the exact pathophysiology of calciphylaxis is not understood.^1–4

Ulceration is considered the clinical hallmark, but there are increasing reports of patients presenting with nonulcerated plaques, as in our patient. The literature suggests a mortality rate of 33% at 6 months in these patients, but ulceration increases the risk of death to over 80%, and sepsis is the leading cause of death.^7,8

Histologic features identified on full-thickness biopsy specimens are intravascular deposition of calcium in the media of the blood vessels, as well as fibrin thrombi formation, intimal proliferation, tissue necrosis, and resultant ischemia. However, as in our patient and as discussed below, the biopsy procedure can induce or exacerbate ulceration, increasing the risk of sepsis, and is thus controversial.⁷

In the early stages, lesions of calciphylaxis are focal and appear as erythema or livedo reticularis with or without subcutaneous plaques or ulcers. As the disease progresses, the ischemic changes coalesce to form denser violaceous, painful, plaquelike subcutaneous nodules with eschar. In the advanced stages, the eschar or ulceration involves an extensive area.

Diagnosis in the early stages is challenging because of the focal nature of involvement. The differential diagnosis includes potentially fatal conditions such as systemic vasculitis, nephrogenic systemic fibrosis, pyoderma gangrenosum, gangrene from peripheral arterial disease, cholesterol embolization, warfarin-induced necrosis, purpura fulminans, and oxalate vasculopathy.⁷

In the advanced stages, the diagnosis of calciphylaxis is clinically more evident, and the differential diagnosis usually narrows. Well-demarcated, necrotic, indurated lesions that are bilateral in a patient with end-stage renal disease without shock makes the diagnosis very likely.

The dangers of biopsy

As seen in our patient, biopsy for histologic confirmation of calciphylaxis can increase the risk of infection and sepsis.⁷ Also, the efficacy and clinical utility are uncertain because the quantity or depth of tissue obtained may not be enough for diagnosis. Deep incisional cutaneous biopsy is needed rather than punch biopsy to provide ample subcutaneous tissue for histologic study.³

Further, the biopsy procedure induces ulceration in the region of the incision, increasing the risk of infection and poor healing and escalating the risk of sepsis and death.^7–9 Since extensive necrosis predisposes to a negative biopsy, a high clinical suspicion should drive early treatment of calciphylaxis.¹⁰ Noninvasive imaging studies such as plain radiography and bone scintigraphy can aid the diagnosis by detecting moderate to severe soft-tissue vascular calcification in these areas.^7–11

DEBRIDEMENT IS CONTROVERSIAL

Conservative measures are the mainstay of care and include dietary alterations, noncalcium and nonaluminum phosphate binders, and low-calcium bath dialysis. There is mounting evidence for the use of calcimimetics and sodium thiosulfate.^7,12–14

The role of wound debridement is controversial, as concomitant poor peripheral vascular perfusion can delay wound healing and, if ulceration ensues, there is a dramatic escalation of mortality risk. The decision for wound debridement is determined case by case, based on an assessment of the comorbidities, vascular perfusion, and status of the eschar.

Extensive wound debridement should be considered immediately after biopsy or with any signs of ulceration or infection—this in addition to meticulous wound care, which will  promote healing and prevent serious complications secondary to infection.¹⁵

A TEAM APPROACH IMPROVES OUTCOMES

A multidisciplinary approach involving surgeons, nephrologists, dermatologists, dermatopathologists, wound or burn care team, nutrition team, pain management team, and infectious disease team is important to improve outcomes.⁷

Management mainly involves controlling pain; avoiding local trauma; treating and preventing infection; stopping causative agents such as warfarin and corticosteroids; intensive hemodialysis with an increase in both frequency and duration; intravenous sodium thiosulphate; non-calcium-phosphorus binders and cinacalcet in patients with elevated parathyroid hormone; and hyperbaric oxygen.^12–14 There are also reports of success with oral etidronate and intravenous pamidronate.^16,17

A 53-year-old woman presented with extensive, nonulcerated, painful plaques on both calves. She had long-standing diabetes mellitus and had recently started hemodialysis. She had no fever or trauma and did not appear to be in shock.

On physical examination, she had extensive, well-demarcated, nonulcerated, indurated dark eschar over the right calf (Figure 1). Her left calf had similar lesions that appeared as focal, discrete, nonulcerated, violaceous plaques, with associated tenderness. No significant erythema, edema, drainage, or fluctuance was noted.

A broad-spectrum antibiotic was started empirically but was discontinued when routine blood testing and magnetic resonance imaging showed no evidence of infection. Histologic study of a full-thickness skin biopsy specimen (Figure 2) showed tissue necrosis, ulceration, and concentric calcification of small and medium-sized blood vessels, many with luminal thrombi, all of which together were diagnostic for calciphylaxis.

Treatment was started with cinacalcet, low-calcium dialysis baths, phosphate binders, and sodium thiosulfate. However, within a few days of the biopsy procedure, an infection developed at the biopsy site, and the patient developed sepsis and septic shock. She received broad-spectrum antibiotics and underwent extensive debridement with wound care. After a protracted hospital course, the infection resolved.

CALCIPHYLAXIS RISK FACTORS

Calciphylaxis, also referred to as calcific uremic arteriolopathy, is a rare and often fatal condition in patients with end-stage renal disease who are on hemodialysis (1% to 4% of dialysis patients).^1–3 It is also seen in patients who have undergone renal transplant and in patients with chronic kidney disease who have a chronic inflammatory disease or who have been exposed to corticosteroids or warfarin. However, it can also occur in patients without chronic kidney disease or end-stage renal disease.

The term “calcific uremic arteriolopathy” is a misnomer, as this condition can occur in patients with normal renal function (nonuremic calciphylaxis). Also, despite what the term calciphylaxis implies, there is no systemic anaphylaxis.^3–5

Documented risk factors include obesity; female sex; use of warfarin, corticosteroids, or vitamin D analogues; low serum albumin; hypercoagulable states; hyperparathyroidism; alcoholic liver disease; elevated calcium-phosphorus product; inflammation; connective tissue disease; and cancer.^4–6

DIAGNOSTIC CLUES

There are no strict guidelines for the diagnosis of calciphylaxis, and the exact pathophysiology of calciphylaxis is not understood.^1–4

Ulceration is considered the clinical hallmark, but there are increasing reports of patients presenting with nonulcerated plaques, as in our patient. The literature suggests a mortality rate of 33% at 6 months in these patients, but ulceration increases the risk of death to over 80%, and sepsis is the leading cause of death.^7,8

Histologic features identified on full-thickness biopsy specimens are intravascular deposition of calcium in the media of the blood vessels, as well as fibrin thrombi formation, intimal proliferation, tissue necrosis, and resultant ischemia. However, as in our patient and as discussed below, the biopsy procedure can induce or exacerbate ulceration, increasing the risk of sepsis, and is thus controversial.⁷

In the early stages, lesions of calciphylaxis are focal and appear as erythema or livedo reticularis with or without subcutaneous plaques or ulcers. As the disease progresses, the ischemic changes coalesce to form denser violaceous, painful, plaquelike subcutaneous nodules with eschar. In the advanced stages, the eschar or ulceration involves an extensive area.

Diagnosis in the early stages is challenging because of the focal nature of involvement. The differential diagnosis includes potentially fatal conditions such as systemic vasculitis, nephrogenic systemic fibrosis, pyoderma gangrenosum, gangrene from peripheral arterial disease, cholesterol embolization, warfarin-induced necrosis, purpura fulminans, and oxalate vasculopathy.⁷

In the advanced stages, the diagnosis of calciphylaxis is clinically more evident, and the differential diagnosis usually narrows. Well-demarcated, necrotic, indurated lesions that are bilateral in a patient with end-stage renal disease without shock makes the diagnosis very likely.

The dangers of biopsy

As seen in our patient, biopsy for histologic confirmation of calciphylaxis can increase the risk of infection and sepsis.⁷ Also, the efficacy and clinical utility are uncertain because the quantity or depth of tissue obtained may not be enough for diagnosis. Deep incisional cutaneous biopsy is needed rather than punch biopsy to provide ample subcutaneous tissue for histologic study.³

Further, the biopsy procedure induces ulceration in the region of the incision, increasing the risk of infection and poor healing and escalating the risk of sepsis and death.^7–9 Since extensive necrosis predisposes to a negative biopsy, a high clinical suspicion should drive early treatment of calciphylaxis.¹⁰ Noninvasive imaging studies such as plain radiography and bone scintigraphy can aid the diagnosis by detecting moderate to severe soft-tissue vascular calcification in these areas.^7–11

DEBRIDEMENT IS CONTROVERSIAL

Conservative measures are the mainstay of care and include dietary alterations, noncalcium and nonaluminum phosphate binders, and low-calcium bath dialysis. There is mounting evidence for the use of calcimimetics and sodium thiosulfate.^7,12–14

The role of wound debridement is controversial, as concomitant poor peripheral vascular perfusion can delay wound healing and, if ulceration ensues, there is a dramatic escalation of mortality risk. The decision for wound debridement is determined case by case, based on an assessment of the comorbidities, vascular perfusion, and status of the eschar.

Extensive wound debridement should be considered immediately after biopsy or with any signs of ulceration or infection—this in addition to meticulous wound care, which will  promote healing and prevent serious complications secondary to infection.¹⁵

A TEAM APPROACH IMPROVES OUTCOMES

A multidisciplinary approach involving surgeons, nephrologists, dermatologists, dermatopathologists, wound or burn care team, nutrition team, pain management team, and infectious disease team is important to improve outcomes.⁷

Management mainly involves controlling pain; avoiding local trauma; treating and preventing infection; stopping causative agents such as warfarin and corticosteroids; intensive hemodialysis with an increase in both frequency and duration; intravenous sodium thiosulphate; non-calcium-phosphorus binders and cinacalcet in patients with elevated parathyroid hormone; and hyperbaric oxygen.^12–14 There are also reports of success with oral etidronate and intravenous pamidronate.^16,17

A 53-year-old woman presented with extensive, nonulcerated, painful plaques on both calves. She had long-standing diabetes mellitus and had recently started hemodialysis. She had no fever or trauma and did not appear to be in shock.

On physical examination, she had extensive, well-demarcated, nonulcerated, indurated dark eschar over the right calf (Figure 1). Her left calf had similar lesions that appeared as focal, discrete, nonulcerated, violaceous plaques, with associated tenderness. No significant erythema, edema, drainage, or fluctuance was noted.

A broad-spectrum antibiotic was started empirically but was discontinued when routine blood testing and magnetic resonance imaging showed no evidence of infection. Histologic study of a full-thickness skin biopsy specimen (Figure 2) showed tissue necrosis, ulceration, and concentric calcification of small and medium-sized blood vessels, many with luminal thrombi, all of which together were diagnostic for calciphylaxis.

Treatment was started with cinacalcet, low-calcium dialysis baths, phosphate binders, and sodium thiosulfate. However, within a few days of the biopsy procedure, an infection developed at the biopsy site, and the patient developed sepsis and septic shock. She received broad-spectrum antibiotics and underwent extensive debridement with wound care. After a protracted hospital course, the infection resolved.

CALCIPHYLAXIS RISK FACTORS

Calciphylaxis, also referred to as calcific uremic arteriolopathy, is a rare and often fatal condition in patients with end-stage renal disease who are on hemodialysis (1% to 4% of dialysis patients).^1–3 It is also seen in patients who have undergone renal transplant and in patients with chronic kidney disease who have a chronic inflammatory disease or who have been exposed to corticosteroids or warfarin. However, it can also occur in patients without chronic kidney disease or end-stage renal disease.

The term “calcific uremic arteriolopathy” is a misnomer, as this condition can occur in patients with normal renal function (nonuremic calciphylaxis). Also, despite what the term calciphylaxis implies, there is no systemic anaphylaxis.^3–5

Documented risk factors include obesity; female sex; use of warfarin, corticosteroids, or vitamin D analogues; low serum albumin; hypercoagulable states; hyperparathyroidism; alcoholic liver disease; elevated calcium-phosphorus product; inflammation; connective tissue disease; and cancer.^4–6

DIAGNOSTIC CLUES

There are no strict guidelines for the diagnosis of calciphylaxis, and the exact pathophysiology of calciphylaxis is not understood.^1–4

Ulceration is considered the clinical hallmark, but there are increasing reports of patients presenting with nonulcerated plaques, as in our patient. The literature suggests a mortality rate of 33% at 6 months in these patients, but ulceration increases the risk of death to over 80%, and sepsis is the leading cause of death.^7,8

Histologic features identified on full-thickness biopsy specimens are intravascular deposition of calcium in the media of the blood vessels, as well as fibrin thrombi formation, intimal proliferation, tissue necrosis, and resultant ischemia. However, as in our patient and as discussed below, the biopsy procedure can induce or exacerbate ulceration, increasing the risk of sepsis, and is thus controversial.⁷

In the early stages, lesions of calciphylaxis are focal and appear as erythema or livedo reticularis with or without subcutaneous plaques or ulcers. As the disease progresses, the ischemic changes coalesce to form denser violaceous, painful, plaquelike subcutaneous nodules with eschar. In the advanced stages, the eschar or ulceration involves an extensive area.

Diagnosis in the early stages is challenging because of the focal nature of involvement. The differential diagnosis includes potentially fatal conditions such as systemic vasculitis, nephrogenic systemic fibrosis, pyoderma gangrenosum, gangrene from peripheral arterial disease, cholesterol embolization, warfarin-induced necrosis, purpura fulminans, and oxalate vasculopathy.⁷

In the advanced stages, the diagnosis of calciphylaxis is clinically more evident, and the differential diagnosis usually narrows. Well-demarcated, necrotic, indurated lesions that are bilateral in a patient with end-stage renal disease without shock makes the diagnosis very likely.

The dangers of biopsy

As seen in our patient, biopsy for histologic confirmation of calciphylaxis can increase the risk of infection and sepsis.⁷ Also, the efficacy and clinical utility are uncertain because the quantity or depth of tissue obtained may not be enough for diagnosis. Deep incisional cutaneous biopsy is needed rather than punch biopsy to provide ample subcutaneous tissue for histologic study.³

Further, the biopsy procedure induces ulceration in the region of the incision, increasing the risk of infection and poor healing and escalating the risk of sepsis and death.^7–9 Since extensive necrosis predisposes to a negative biopsy, a high clinical suspicion should drive early treatment of calciphylaxis.¹⁰ Noninvasive imaging studies such as plain radiography and bone scintigraphy can aid the diagnosis by detecting moderate to severe soft-tissue vascular calcification in these areas.^7–11

DEBRIDEMENT IS CONTROVERSIAL

Conservative measures are the mainstay of care and include dietary alterations, noncalcium and nonaluminum phosphate binders, and low-calcium bath dialysis. There is mounting evidence for the use of calcimimetics and sodium thiosulfate.^7,12–14

The role of wound debridement is controversial, as concomitant poor peripheral vascular perfusion can delay wound healing and, if ulceration ensues, there is a dramatic escalation of mortality risk. The decision for wound debridement is determined case by case, based on an assessment of the comorbidities, vascular perfusion, and status of the eschar.

Extensive wound debridement should be considered immediately after biopsy or with any signs of ulceration or infection—this in addition to meticulous wound care, which will  promote healing and prevent serious complications secondary to infection.¹⁵

A TEAM APPROACH IMPROVES OUTCOMES

A multidisciplinary approach involving surgeons, nephrologists, dermatologists, dermatopathologists, wound or burn care team, nutrition team, pain management team, and infectious disease team is important to improve outcomes.⁷

Management mainly involves controlling pain; avoiding local trauma; treating and preventing infection; stopping causative agents such as warfarin and corticosteroids; intensive hemodialysis with an increase in both frequency and duration; intravenous sodium thiosulphate; non-calcium-phosphorus binders and cinacalcet in patients with elevated parathyroid hormone; and hyperbaric oxygen.^12–14 There are also reports of success with oral etidronate and intravenous pamidronate.^16,17

A 54-year-old man with a history of cirrhosis secondary to hepatitis C virus (HCV) infection has had a progressive decline in kidney function. He was diagnosed with hepatitis C 15 years ago; he tried interferon treatment, but this failed. He received a transjugular intrahepatic shunt 10 years ago after an episode of esophageal variceal bleeding. He has since been taking furosemide and spironolactone as maintenance treatment for ascites, and he has no other medical concerns such as hypertension or diabetes.

Two weeks ago, routine laboratory tests in the clinic showed that his serum creatinine level had increased from baseline. He was asked to stop his diuretics and increase his fluid intake. Nevertheless, his kidney function continued to decline (Table 1), and he was admitted to the hospital for further evaluation.

On admission, he appeared comfortable. He denied recent use of any medications, including nonsteroidal anti-inflammatory drugs, antibiotics, and diuretics, and he had no genitourinary symptoms. His temperature was normal, blood pressure 170/90 mm Hg, pulse rate 72 per minute, and respiratory rate 16. His skin and sclerae were not jaundiced; his abdomen was not tender, but it was grossly distended with ascites. He also had +3 pedal edema (on a scale of 4) extending to both knees. The rest of his physical examination was unremarkable. Results of further laboratory tests are shown in in Table 2.

Ultrasonography of the liver demonstrated cirrhosis with patent flow through the shunt, and ultrasonography of the kidneys showed that both were slightly enlarged with increased cortical echogenicity but no hydronephrosis or obstruction.

EXPLORING THE CAUSE OF RENAL FAILURE

1. Given this information, what is the likely cause of our patient’s renal failure?

• Volume depletion
• Acute tubular necrosis
• Hepatorenal syndrome 
• HCV glomerulopathy

Renal failure is a common complication in cirrhosis and portends a higher risk of death.¹ The differential diagnosis is broad, but a systematic approach incorporating data from the history, physical examination, and laboratory tests can help identify the cause and is essential in determining the prognosis and proper treatment.

Volume depletion

Volume depletion is a common cause of renal failure in cirrhotic patients. Common precipitants are excessive diuresis and gastrointestinal fluid loss from bleeding, vomiting, and diarrhea. Despite having ascites and edema, patients may have low fluid volume in the vascular space. Therefore, the first step in a patient with acute kidney injury is to withhold diuretics and give fluids. The renal failure usually rapidly reverses if the patient does not have renal parenchymal disease.²

Our patient did not present with any fluid losses, and his high blood pressure and normal heart rate did not suggest volume depletion. And most importantly, withholding his diuretics and giving fluids did not reverse his renal failure. Thus, volume depletion was an unlikely cause.

Acute tubular necrosis

The altered hemodynamics caused by cirrhosis predispose patients to acute tubular necrosis. Classically, this presents as muddy brown casts and renal tubular epithelial cells on urinalysis and as a fractional excretion of sodium greater than 2%.¹ However, these microscopic findings lack sensitivity, and patients with cirrhosis may have marked sodium avidity and low urine sodium excretion despite tubular injury.³

This diagnosis must still be considered in patients with renal failure, especially after an insult such as hemorrhagic or septic shock or intake of nephrotoxins. However, because our patient did not have a history of any of these and because his renal failure had been progressing over weeks, acute tubular necrosis was considered unlikely.

Hepatorenal syndrome

Hepatorenal syndrome is characterized by progressive renal failure in the absence of renal parenchymal disease. It is a functional disorder, ie, the decreased glomerular filtration rate results from renal vasoconstriction, which in turn is due to decreased systemic vascular resistance and increased compensatory activity of the renin-angiotensin-aldosterone axis and of antiduretic hormone release (Figure 1).

Hepatorenal syndrome often occurs in patients with advanced liver disease. These patients typically have a hyperdynamic circulation (systemic vasodilation, low blood pressure, and increased blood volume) with a low mean arterial pressure and increased renin and norepinephrine levels. Other frequent findings include hyponatremia, low urinary sodium excretion (< 2 mmol/day), and low free water clearance,⁴ all of which mark the high systemic levels of antidiuretic hormone and aldosterone.

Importantly, while hepatorenal syndrome is always considered in the differential diagnosis because of its unique prognosis and therapy, it remains a diagnosis of exclusion. The International Ascites Club⁵ has provided diagnostic criteria for hepatorenal syndrome:

• Cirrhosis and ascites
• Serum creatinine greater than 1.5 mg/dL
• Failure of serum creatinine to fall to less than 1.5 mg/dL after at least 48 hours of diuretic withdrawal and volume expansion with albumin (recommended dose 1 g/kg body weight per day up to a maximum of 100 g per day)
• Absence of shock
• No current or recent treatment with nephrotoxic drugs
• No signs of parenchymal kidney disease such as proteinuria (protein excretion > 500 mg/day), microhematuria (> 50 red blood cells per high-power field), or abnormalities on renal ultrasonography.

While these criteria are not perfect,⁶ they remind clinicians that there are other important causes of renal insufficiency in cirrhosis.

Clinically, our patient had no evidence of a hyperdynamic circulation and was instead hypertensive. He was eunatremic and did not have marked renal sodium avidity. His pyuria, proteinuria (his protein excretion was approximately 1.9 g/day as determined by urine spot protein-to-creatinine ratio), and results of ultrasonography also suggested underlying renal parenchymal disease. Therefore, hepatorenal syndrome was not the likely diagnosis.

HCV glomerulopathy

Intrinsic renal disease is likely, given our patient’s proteinuria, active urine sediment (ie, containing red blood cells, white blood cells, and protein), and abnormal findings on ultrasonography. In patients with HCV infection and no other cause of intrinsic kidney disease, immune complex deposition leading to glomerulonephritis is the most common pattern.⁷ Despite the intrinsic renal disease, fractional excretion of sodium may be less than 1% in glomerulonephritis. Hypertension in a patient such as ours with cirrhosis and renal insufficiency raises suspicion for glomerular disease, as hypertension is unlikely in advanced cirrhosis.⁸

Glomerulonephritis in patients with cirrhosis is often clinically silent and may be highly prevalent; some studies have shown glomerular involvement in 55% to 83% of patients with cirrhosis.^9,10 This increases the risk of end-stage renal disease, and the Kidney Disease Improving Global Outcomes guideline recommends that HCV-infected patients be tested at least once a year for proteinuria, hematuria, and estimated glomerular filtration rate to detect possible HCV-associated kidney disease.¹¹ According to current guidelines of the Infectious Diseases Society of America (IDSA) and American Association for the Study of Liver Diseases (AASLD) , detection of glomerulonephritis in HCV patients puts them in the highest priority class for treatment of HCV.¹²

HISTOLOGIC FINDINGS

Because of the high likelihood of glomerulopathy, our patient underwent renal biopsy.

2. What is the classic pathologic finding in HCV kidney disease?

• Focal segmental glomerulosclerosis
• Crescentic glomerulonephritis
• Membranoproliferative glomerulonephritis
• Membranous glomerulonephritis

A number of pathologic patterns have been described in HCV kidney disease, including membranous glomerulonephritis, immunoglobulin A nephropathy, and focal segmental glomerulosclerosis. However, by far the most common pattern is type 1 membranoproliferative glomerulonephritis.¹³ (Types 2 and 3 are much less common, and we will not discuss them here.) In type 1, light microscopy shows increased mesangial cells and thickened capillary walls (lobular glomeruli), staining of the basement membrane reveals double contours (“tram tracking”) or splitting due to mesangial deposition, and immunofluorescence demonstrates immunoglobulin G and complement C3 deposition. All of these findings were seen in our patient (Figure 2, Figure 3).

Membranoproliferative glomerulonephritis in patients with HCV is most commonly associated with cryoglobulins, a mixture of monoclonal or polyclonal immunoglobulin (Ig) M that have antiglobulin (rheumatoid factor) activity and bind to polyclonal IgG. They reversibly precipitate at less than 37°C, (98.6°F), hence their name. Only 50% to 70% of patients with cryoglobulinemic membranoproliferative glomerulonephritis have detectable serum cryoglobulins; however, kidney biopsy may show globular accumulations of eosinophilic material and prominent hypercellularity due to infiltration of glomerular capillaries with mononuclear and polymorphonuclear leukocytes.

Noncryoglobulinemic membranoproliferative glomerulonephritis is also found in patients with HCV infection. Its histologic features are similar, but on biopsy, there is less prominent leukocytic infiltration and no eosinophilic material. Although the pathogenesis of glomerulonephritis in HCV infection is poorly understood, it is thought to result from deposition of circulating immune complexes of HCV, anti-HCV, and rheumatoid factor in the glomeruli.

3. What laboratory finding is often seen in membranoproliferative glomerulonephritis?

• Positive cytoplasmic antineutrophil cytoplasmic antibody
• serum complement Low levels 
• Antiphospholipase A2 receptor antibodies

Cytoplasmic antineutrophil cytoplasmic antibody is seen in granulomatosis with polyangiitis, while antiphospholipid A2 receptor antibodies are seen in idiopathic membranous nephritis.

Low serum complement levels are frequently found in membranoproliferative glomerulonephritis. It is believed that immune complex deposition leads to glomerular damage through activation of the complement pathway and the subsequent influx of inflammatory cells, release of cytokines and proteases, and damage to capillary walls. When repair ensues, new mesangial matrix and basement membrane are deposited, leading to mesangial expansion and duplicated basement membrane.¹⁴

In cryoglobulinemic membranoproliferative glomerulonephritis, the complement C4 level is often much lower than C3, but in noncryoglobulinemic forms C3 is lower. A mnemonic to remember nephritic syndromes with low complement levels is “hy-PO-CO-MP-L-EM-ents”; PO for postinfectious, CO for cryoglobulins, MP for membranoproliferative glomerulonephritis, L for lupus, and EM for embolic.

BACK TO OUR PATIENT

In addition to kidney biopsy, we tested our patient for serum cryoglobulins, rheumatoid factor, and serum complements. Results from these tests (Table 3), in addition to the lack of cryoglobulins on his biopsy, led to the conclusion that he had noncryoglobulinemic membranoproliferative glomerulonephritis.

WHO SHOULD RECEIVE TREATMENT FOR HCV?

4. According to the current IDSA/AASLD guidelines, which of the following patients should not receive direct-acting antiviral therapy for HCV?

• Patients with HCV and only low-stage fibrosis
• Patients with decompensated cirrhosis
• Patients with a glomerular filtration rate less than 30 mL/minute
• None of the above—nearly all patients with HCV infection should receive treatment for it

While certain patients have compelling indications for HCV treatment, such as advanced fibrosis, severe extrahepatic manifestations of HCV (eg, glomerulonephritis, cryoglobulinemia), and posttransplant status, current guidelines recommend treatment for nearly all patients with HCV, including those with low-stage fibrosis.¹²

Patients with Child-Pugh grade B or C decompensated cirrhosis, even with hepatocellular carcinoma, may be considered for treatment. Multiple studies have demonstrated the efficacy and safety of direct-acting antiviral drugs in this patient population. In one randomized controlled trial,¹⁵ the combination of ledipasvir, sofosbuvir, and ribavirin resulted in high sustained virologic response rates at 12 weeks in patients infected with HCV genotype 1 or 4 with advanced liver disease, irrespective of transplant status (86% to 89% of patients were pretransplant). Sustained virologic response was associated with improvements in Model for End-Stage Liver Disease and Child-Pugh scores largely due to decreases in bilirubin and improvement in synthetic function (ie, albumin).

Similarly, even patients with a glomerular filtration rate less than 30 mL/min are candidates for treatment. Those with a glomerular filtration rate above 30 mL/min need no dosage adjustments for the most common regimens, while regimens are also available for those with a rate less than 30 mL/min. Although patients with low baseline renal function have a higher frequency of anemia (especially with ribavirin), worsening renal dysfunction, and more severe adverse events, treatment responses remain high and comparable to those without renal impairment.

The Hepatitis C Therapeutic Registry and Research Network (HCV-TARGET) is conducting an ongoing prospective study evaluating real-world use of direct-acting antiviral agents. The study has reported the safety and efficacy of sofosbuvir-containing regimens in patients with varying severities of kidney disease, including glomerular filtration rates less than 30 mL/min). The patients received different regimens that included sofosbuvir. The regimens were reportedly tolerated, and the rate of sustained viral response at 12 weeks remained high.¹⁶

The efficacy of direct-acting antiviral agents for HCV-associated glomerulonephritis remains to be studied but is promising. Earlier studies found that antiviral therapy based on interferon alfa with or without ribavirin can significantly decrease proteinuria and stabilize renal function.^17–20 HCV RNA clearance has been found to best predict renal improvement.

OUR PATIENT’S COURSE

Unfortunately, our patient’s kidney function declined further over the next 3 months, and he is currently on dialysis awaiting simultaneous liver and kidney transplant.

A 54-year-old man with a history of cirrhosis secondary to hepatitis C virus (HCV) infection has had a progressive decline in kidney function. He was diagnosed with hepatitis C 15 years ago; he tried interferon treatment, but this failed. He received a transjugular intrahepatic shunt 10 years ago after an episode of esophageal variceal bleeding. He has since been taking furosemide and spironolactone as maintenance treatment for ascites, and he has no other medical concerns such as hypertension or diabetes.

Two weeks ago, routine laboratory tests in the clinic showed that his serum creatinine level had increased from baseline. He was asked to stop his diuretics and increase his fluid intake. Nevertheless, his kidney function continued to decline (Table 1), and he was admitted to the hospital for further evaluation.

On admission, he appeared comfortable. He denied recent use of any medications, including nonsteroidal anti-inflammatory drugs, antibiotics, and diuretics, and he had no genitourinary symptoms. His temperature was normal, blood pressure 170/90 mm Hg, pulse rate 72 per minute, and respiratory rate 16. His skin and sclerae were not jaundiced; his abdomen was not tender, but it was grossly distended with ascites. He also had +3 pedal edema (on a scale of 4) extending to both knees. The rest of his physical examination was unremarkable. Results of further laboratory tests are shown in in Table 2.

Ultrasonography of the liver demonstrated cirrhosis with patent flow through the shunt, and ultrasonography of the kidneys showed that both were slightly enlarged with increased cortical echogenicity but no hydronephrosis or obstruction.

EXPLORING THE CAUSE OF RENAL FAILURE

1. Given this information, what is the likely cause of our patient’s renal failure?

• Volume depletion
• Acute tubular necrosis
• Hepatorenal syndrome 
• HCV glomerulopathy

Renal failure is a common complication in cirrhosis and portends a higher risk of death.¹ The differential diagnosis is broad, but a systematic approach incorporating data from the history, physical examination, and laboratory tests can help identify the cause and is essential in determining the prognosis and proper treatment.

Volume depletion

Volume depletion is a common cause of renal failure in cirrhotic patients. Common precipitants are excessive diuresis and gastrointestinal fluid loss from bleeding, vomiting, and diarrhea. Despite having ascites and edema, patients may have low fluid volume in the vascular space. Therefore, the first step in a patient with acute kidney injury is to withhold diuretics and give fluids. The renal failure usually rapidly reverses if the patient does not have renal parenchymal disease.²

Our patient did not present with any fluid losses, and his high blood pressure and normal heart rate did not suggest volume depletion. And most importantly, withholding his diuretics and giving fluids did not reverse his renal failure. Thus, volume depletion was an unlikely cause.

Acute tubular necrosis

The altered hemodynamics caused by cirrhosis predispose patients to acute tubular necrosis. Classically, this presents as muddy brown casts and renal tubular epithelial cells on urinalysis and as a fractional excretion of sodium greater than 2%.¹ However, these microscopic findings lack sensitivity, and patients with cirrhosis may have marked sodium avidity and low urine sodium excretion despite tubular injury.³

This diagnosis must still be considered in patients with renal failure, especially after an insult such as hemorrhagic or septic shock or intake of nephrotoxins. However, because our patient did not have a history of any of these and because his renal failure had been progressing over weeks, acute tubular necrosis was considered unlikely.

Hepatorenal syndrome

Hepatorenal syndrome is characterized by progressive renal failure in the absence of renal parenchymal disease. It is a functional disorder, ie, the decreased glomerular filtration rate results from renal vasoconstriction, which in turn is due to decreased systemic vascular resistance and increased compensatory activity of the renin-angiotensin-aldosterone axis and of antiduretic hormone release (Figure 1).

Hepatorenal syndrome often occurs in patients with advanced liver disease. These patients typically have a hyperdynamic circulation (systemic vasodilation, low blood pressure, and increased blood volume) with a low mean arterial pressure and increased renin and norepinephrine levels. Other frequent findings include hyponatremia, low urinary sodium excretion (< 2 mmol/day), and low free water clearance,⁴ all of which mark the high systemic levels of antidiuretic hormone and aldosterone.

Importantly, while hepatorenal syndrome is always considered in the differential diagnosis because of its unique prognosis and therapy, it remains a diagnosis of exclusion. The International Ascites Club⁵ has provided diagnostic criteria for hepatorenal syndrome:

• Cirrhosis and ascites
• Serum creatinine greater than 1.5 mg/dL
• Failure of serum creatinine to fall to less than 1.5 mg/dL after at least 48 hours of diuretic withdrawal and volume expansion with albumin (recommended dose 1 g/kg body weight per day up to a maximum of 100 g per day)
• Absence of shock
• No current or recent treatment with nephrotoxic drugs
• No signs of parenchymal kidney disease such as proteinuria (protein excretion > 500 mg/day), microhematuria (> 50 red blood cells per high-power field), or abnormalities on renal ultrasonography.

While these criteria are not perfect,⁶ they remind clinicians that there are other important causes of renal insufficiency in cirrhosis.

Clinically, our patient had no evidence of a hyperdynamic circulation and was instead hypertensive. He was eunatremic and did not have marked renal sodium avidity. His pyuria, proteinuria (his protein excretion was approximately 1.9 g/day as determined by urine spot protein-to-creatinine ratio), and results of ultrasonography also suggested underlying renal parenchymal disease. Therefore, hepatorenal syndrome was not the likely diagnosis.

HCV glomerulopathy

Intrinsic renal disease is likely, given our patient’s proteinuria, active urine sediment (ie, containing red blood cells, white blood cells, and protein), and abnormal findings on ultrasonography. In patients with HCV infection and no other cause of intrinsic kidney disease, immune complex deposition leading to glomerulonephritis is the most common pattern.⁷ Despite the intrinsic renal disease, fractional excretion of sodium may be less than 1% in glomerulonephritis. Hypertension in a patient such as ours with cirrhosis and renal insufficiency raises suspicion for glomerular disease, as hypertension is unlikely in advanced cirrhosis.⁸

Glomerulonephritis in patients with cirrhosis is often clinically silent and may be highly prevalent; some studies have shown glomerular involvement in 55% to 83% of patients with cirrhosis.^9,10 This increases the risk of end-stage renal disease, and the Kidney Disease Improving Global Outcomes guideline recommends that HCV-infected patients be tested at least once a year for proteinuria, hematuria, and estimated glomerular filtration rate to detect possible HCV-associated kidney disease.¹¹ According to current guidelines of the Infectious Diseases Society of America (IDSA) and American Association for the Study of Liver Diseases (AASLD) , detection of glomerulonephritis in HCV patients puts them in the highest priority class for treatment of HCV.¹²

HISTOLOGIC FINDINGS

Because of the high likelihood of glomerulopathy, our patient underwent renal biopsy.

2. What is the classic pathologic finding in HCV kidney disease?

• Focal segmental glomerulosclerosis
• Crescentic glomerulonephritis
• Membranoproliferative glomerulonephritis
• Membranous glomerulonephritis

A number of pathologic patterns have been described in HCV kidney disease, including membranous glomerulonephritis, immunoglobulin A nephropathy, and focal segmental glomerulosclerosis. However, by far the most common pattern is type 1 membranoproliferative glomerulonephritis.¹³ (Types 2 and 3 are much less common, and we will not discuss them here.) In type 1, light microscopy shows increased mesangial cells and thickened capillary walls (lobular glomeruli), staining of the basement membrane reveals double contours (“tram tracking”) or splitting due to mesangial deposition, and immunofluorescence demonstrates immunoglobulin G and complement C3 deposition. All of these findings were seen in our patient (Figure 2, Figure 3).

Membranoproliferative glomerulonephritis in patients with HCV is most commonly associated with cryoglobulins, a mixture of monoclonal or polyclonal immunoglobulin (Ig) M that have antiglobulin (rheumatoid factor) activity and bind to polyclonal IgG. They reversibly precipitate at less than 37°C, (98.6°F), hence their name. Only 50% to 70% of patients with cryoglobulinemic membranoproliferative glomerulonephritis have detectable serum cryoglobulins; however, kidney biopsy may show globular accumulations of eosinophilic material and prominent hypercellularity due to infiltration of glomerular capillaries with mononuclear and polymorphonuclear leukocytes.

Noncryoglobulinemic membranoproliferative glomerulonephritis is also found in patients with HCV infection. Its histologic features are similar, but on biopsy, there is less prominent leukocytic infiltration and no eosinophilic material. Although the pathogenesis of glomerulonephritis in HCV infection is poorly understood, it is thought to result from deposition of circulating immune complexes of HCV, anti-HCV, and rheumatoid factor in the glomeruli.

3. What laboratory finding is often seen in membranoproliferative glomerulonephritis?

• Positive cytoplasmic antineutrophil cytoplasmic antibody
• serum complement Low levels 
• Antiphospholipase A2 receptor antibodies

Cytoplasmic antineutrophil cytoplasmic antibody is seen in granulomatosis with polyangiitis, while antiphospholipid A2 receptor antibodies are seen in idiopathic membranous nephritis.

Low serum complement levels are frequently found in membranoproliferative glomerulonephritis. It is believed that immune complex deposition leads to glomerular damage through activation of the complement pathway and the subsequent influx of inflammatory cells, release of cytokines and proteases, and damage to capillary walls. When repair ensues, new mesangial matrix and basement membrane are deposited, leading to mesangial expansion and duplicated basement membrane.¹⁴

In cryoglobulinemic membranoproliferative glomerulonephritis, the complement C4 level is often much lower than C3, but in noncryoglobulinemic forms C3 is lower. A mnemonic to remember nephritic syndromes with low complement levels is “hy-PO-CO-MP-L-EM-ents”; PO for postinfectious, CO for cryoglobulins, MP for membranoproliferative glomerulonephritis, L for lupus, and EM for embolic.

BACK TO OUR PATIENT

In addition to kidney biopsy, we tested our patient for serum cryoglobulins, rheumatoid factor, and serum complements. Results from these tests (Table 3), in addition to the lack of cryoglobulins on his biopsy, led to the conclusion that he had noncryoglobulinemic membranoproliferative glomerulonephritis.

WHO SHOULD RECEIVE TREATMENT FOR HCV?

4. According to the current IDSA/AASLD guidelines, which of the following patients should not receive direct-acting antiviral therapy for HCV?

• Patients with HCV and only low-stage fibrosis
• Patients with decompensated cirrhosis
• Patients with a glomerular filtration rate less than 30 mL/minute
• None of the above—nearly all patients with HCV infection should receive treatment for it

While certain patients have compelling indications for HCV treatment, such as advanced fibrosis, severe extrahepatic manifestations of HCV (eg, glomerulonephritis, cryoglobulinemia), and posttransplant status, current guidelines recommend treatment for nearly all patients with HCV, including those with low-stage fibrosis.¹²

Patients with Child-Pugh grade B or C decompensated cirrhosis, even with hepatocellular carcinoma, may be considered for treatment. Multiple studies have demonstrated the efficacy and safety of direct-acting antiviral drugs in this patient population. In one randomized controlled trial,¹⁵ the combination of ledipasvir, sofosbuvir, and ribavirin resulted in high sustained virologic response rates at 12 weeks in patients infected with HCV genotype 1 or 4 with advanced liver disease, irrespective of transplant status (86% to 89% of patients were pretransplant). Sustained virologic response was associated with improvements in Model for End-Stage Liver Disease and Child-Pugh scores largely due to decreases in bilirubin and improvement in synthetic function (ie, albumin).

Similarly, even patients with a glomerular filtration rate less than 30 mL/min are candidates for treatment. Those with a glomerular filtration rate above 30 mL/min need no dosage adjustments for the most common regimens, while regimens are also available for those with a rate less than 30 mL/min. Although patients with low baseline renal function have a higher frequency of anemia (especially with ribavirin), worsening renal dysfunction, and more severe adverse events, treatment responses remain high and comparable to those without renal impairment.

The Hepatitis C Therapeutic Registry and Research Network (HCV-TARGET) is conducting an ongoing prospective study evaluating real-world use of direct-acting antiviral agents. The study has reported the safety and efficacy of sofosbuvir-containing regimens in patients with varying severities of kidney disease, including glomerular filtration rates less than 30 mL/min). The patients received different regimens that included sofosbuvir. The regimens were reportedly tolerated, and the rate of sustained viral response at 12 weeks remained high.¹⁶

The efficacy of direct-acting antiviral agents for HCV-associated glomerulonephritis remains to be studied but is promising. Earlier studies found that antiviral therapy based on interferon alfa with or without ribavirin can significantly decrease proteinuria and stabilize renal function.^17–20 HCV RNA clearance has been found to best predict renal improvement.

OUR PATIENT’S COURSE

Unfortunately, our patient’s kidney function declined further over the next 3 months, and he is currently on dialysis awaiting simultaneous liver and kidney transplant.

A 54-year-old man with a history of cirrhosis secondary to hepatitis C virus (HCV) infection has had a progressive decline in kidney function. He was diagnosed with hepatitis C 15 years ago; he tried interferon treatment, but this failed. He received a transjugular intrahepatic shunt 10 years ago after an episode of esophageal variceal bleeding. He has since been taking furosemide and spironolactone as maintenance treatment for ascites, and he has no other medical concerns such as hypertension or diabetes.

Two weeks ago, routine laboratory tests in the clinic showed that his serum creatinine level had increased from baseline. He was asked to stop his diuretics and increase his fluid intake. Nevertheless, his kidney function continued to decline (Table 1), and he was admitted to the hospital for further evaluation.

On admission, he appeared comfortable. He denied recent use of any medications, including nonsteroidal anti-inflammatory drugs, antibiotics, and diuretics, and he had no genitourinary symptoms. His temperature was normal, blood pressure 170/90 mm Hg, pulse rate 72 per minute, and respiratory rate 16. His skin and sclerae were not jaundiced; his abdomen was not tender, but it was grossly distended with ascites. He also had +3 pedal edema (on a scale of 4) extending to both knees. The rest of his physical examination was unremarkable. Results of further laboratory tests are shown in in Table 2.

Ultrasonography of the liver demonstrated cirrhosis with patent flow through the shunt, and ultrasonography of the kidneys showed that both were slightly enlarged with increased cortical echogenicity but no hydronephrosis or obstruction.

EXPLORING THE CAUSE OF RENAL FAILURE

1. Given this information, what is the likely cause of our patient’s renal failure?

• Volume depletion
• Acute tubular necrosis
• Hepatorenal syndrome 
• HCV glomerulopathy

Renal failure is a common complication in cirrhosis and portends a higher risk of death.¹ The differential diagnosis is broad, but a systematic approach incorporating data from the history, physical examination, and laboratory tests can help identify the cause and is essential in determining the prognosis and proper treatment.

Volume depletion

Volume depletion is a common cause of renal failure in cirrhotic patients. Common precipitants are excessive diuresis and gastrointestinal fluid loss from bleeding, vomiting, and diarrhea. Despite having ascites and edema, patients may have low fluid volume in the vascular space. Therefore, the first step in a patient with acute kidney injury is to withhold diuretics and give fluids. The renal failure usually rapidly reverses if the patient does not have renal parenchymal disease.²

Our patient did not present with any fluid losses, and his high blood pressure and normal heart rate did not suggest volume depletion. And most importantly, withholding his diuretics and giving fluids did not reverse his renal failure. Thus, volume depletion was an unlikely cause.

Acute tubular necrosis

The altered hemodynamics caused by cirrhosis predispose patients to acute tubular necrosis. Classically, this presents as muddy brown casts and renal tubular epithelial cells on urinalysis and as a fractional excretion of sodium greater than 2%.¹ However, these microscopic findings lack sensitivity, and patients with cirrhosis may have marked sodium avidity and low urine sodium excretion despite tubular injury.³

This diagnosis must still be considered in patients with renal failure, especially after an insult such as hemorrhagic or septic shock or intake of nephrotoxins. However, because our patient did not have a history of any of these and because his renal failure had been progressing over weeks, acute tubular necrosis was considered unlikely.

Hepatorenal syndrome

Hepatorenal syndrome is characterized by progressive renal failure in the absence of renal parenchymal disease. It is a functional disorder, ie, the decreased glomerular filtration rate results from renal vasoconstriction, which in turn is due to decreased systemic vascular resistance and increased compensatory activity of the renin-angiotensin-aldosterone axis and of antiduretic hormone release (Figure 1).

Hepatorenal syndrome often occurs in patients with advanced liver disease. These patients typically have a hyperdynamic circulation (systemic vasodilation, low blood pressure, and increased blood volume) with a low mean arterial pressure and increased renin and norepinephrine levels. Other frequent findings include hyponatremia, low urinary sodium excretion (< 2 mmol/day), and low free water clearance,⁴ all of which mark the high systemic levels of antidiuretic hormone and aldosterone.

Importantly, while hepatorenal syndrome is always considered in the differential diagnosis because of its unique prognosis and therapy, it remains a diagnosis of exclusion. The International Ascites Club⁵ has provided diagnostic criteria for hepatorenal syndrome:

• Cirrhosis and ascites
• Serum creatinine greater than 1.5 mg/dL
• Failure of serum creatinine to fall to less than 1.5 mg/dL after at least 48 hours of diuretic withdrawal and volume expansion with albumin (recommended dose 1 g/kg body weight per day up to a maximum of 100 g per day)
• Absence of shock
• No current or recent treatment with nephrotoxic drugs
• No signs of parenchymal kidney disease such as proteinuria (protein excretion > 500 mg/day), microhematuria (> 50 red blood cells per high-power field), or abnormalities on renal ultrasonography.

While these criteria are not perfect,⁶ they remind clinicians that there are other important causes of renal insufficiency in cirrhosis.

Clinically, our patient had no evidence of a hyperdynamic circulation and was instead hypertensive. He was eunatremic and did not have marked renal sodium avidity. His pyuria, proteinuria (his protein excretion was approximately 1.9 g/day as determined by urine spot protein-to-creatinine ratio), and results of ultrasonography also suggested underlying renal parenchymal disease. Therefore, hepatorenal syndrome was not the likely diagnosis.

HCV glomerulopathy

Intrinsic renal disease is likely, given our patient’s proteinuria, active urine sediment (ie, containing red blood cells, white blood cells, and protein), and abnormal findings on ultrasonography. In patients with HCV infection and no other cause of intrinsic kidney disease, immune complex deposition leading to glomerulonephritis is the most common pattern.⁷ Despite the intrinsic renal disease, fractional excretion of sodium may be less than 1% in glomerulonephritis. Hypertension in a patient such as ours with cirrhosis and renal insufficiency raises suspicion for glomerular disease, as hypertension is unlikely in advanced cirrhosis.⁸

Glomerulonephritis in patients with cirrhosis is often clinically silent and may be highly prevalent; some studies have shown glomerular involvement in 55% to 83% of patients with cirrhosis.^9,10 This increases the risk of end-stage renal disease, and the Kidney Disease Improving Global Outcomes guideline recommends that HCV-infected patients be tested at least once a year for proteinuria, hematuria, and estimated glomerular filtration rate to detect possible HCV-associated kidney disease.¹¹ According to current guidelines of the Infectious Diseases Society of America (IDSA) and American Association for the Study of Liver Diseases (AASLD) , detection of glomerulonephritis in HCV patients puts them in the highest priority class for treatment of HCV.¹²

HISTOLOGIC FINDINGS

Because of the high likelihood of glomerulopathy, our patient underwent renal biopsy.

2. What is the classic pathologic finding in HCV kidney disease?

• Focal segmental glomerulosclerosis
• Crescentic glomerulonephritis
• Membranoproliferative glomerulonephritis
• Membranous glomerulonephritis

A number of pathologic patterns have been described in HCV kidney disease, including membranous glomerulonephritis, immunoglobulin A nephropathy, and focal segmental glomerulosclerosis. However, by far the most common pattern is type 1 membranoproliferative glomerulonephritis.¹³ (Types 2 and 3 are much less common, and we will not discuss them here.) In type 1, light microscopy shows increased mesangial cells and thickened capillary walls (lobular glomeruli), staining of the basement membrane reveals double contours (“tram tracking”) or splitting due to mesangial deposition, and immunofluorescence demonstrates immunoglobulin G and complement C3 deposition. All of these findings were seen in our patient (Figure 2, Figure 3).

Membranoproliferative glomerulonephritis in patients with HCV is most commonly associated with cryoglobulins, a mixture of monoclonal or polyclonal immunoglobulin (Ig) M that have antiglobulin (rheumatoid factor) activity and bind to polyclonal IgG. They reversibly precipitate at less than 37°C, (98.6°F), hence their name. Only 50% to 70% of patients with cryoglobulinemic membranoproliferative glomerulonephritis have detectable serum cryoglobulins; however, kidney biopsy may show globular accumulations of eosinophilic material and prominent hypercellularity due to infiltration of glomerular capillaries with mononuclear and polymorphonuclear leukocytes.

Noncryoglobulinemic membranoproliferative glomerulonephritis is also found in patients with HCV infection. Its histologic features are similar, but on biopsy, there is less prominent leukocytic infiltration and no eosinophilic material. Although the pathogenesis of glomerulonephritis in HCV infection is poorly understood, it is thought to result from deposition of circulating immune complexes of HCV, anti-HCV, and rheumatoid factor in the glomeruli.

3. What laboratory finding is often seen in membranoproliferative glomerulonephritis?

• Positive cytoplasmic antineutrophil cytoplasmic antibody
• serum complement Low levels 
• Antiphospholipase A2 receptor antibodies

Cytoplasmic antineutrophil cytoplasmic antibody is seen in granulomatosis with polyangiitis, while antiphospholipid A2 receptor antibodies are seen in idiopathic membranous nephritis.

Low serum complement levels are frequently found in membranoproliferative glomerulonephritis. It is believed that immune complex deposition leads to glomerular damage through activation of the complement pathway and the subsequent influx of inflammatory cells, release of cytokines and proteases, and damage to capillary walls. When repair ensues, new mesangial matrix and basement membrane are deposited, leading to mesangial expansion and duplicated basement membrane.¹⁴

In cryoglobulinemic membranoproliferative glomerulonephritis, the complement C4 level is often much lower than C3, but in noncryoglobulinemic forms C3 is lower. A mnemonic to remember nephritic syndromes with low complement levels is “hy-PO-CO-MP-L-EM-ents”; PO for postinfectious, CO for cryoglobulins, MP for membranoproliferative glomerulonephritis, L for lupus, and EM for embolic.

BACK TO OUR PATIENT

In addition to kidney biopsy, we tested our patient for serum cryoglobulins, rheumatoid factor, and serum complements. Results from these tests (Table 3), in addition to the lack of cryoglobulins on his biopsy, led to the conclusion that he had noncryoglobulinemic membranoproliferative glomerulonephritis.

WHO SHOULD RECEIVE TREATMENT FOR HCV?

4. According to the current IDSA/AASLD guidelines, which of the following patients should not receive direct-acting antiviral therapy for HCV?

• Patients with HCV and only low-stage fibrosis
• Patients with decompensated cirrhosis
• Patients with a glomerular filtration rate less than 30 mL/minute
• None of the above—nearly all patients with HCV infection should receive treatment for it

While certain patients have compelling indications for HCV treatment, such as advanced fibrosis, severe extrahepatic manifestations of HCV (eg, glomerulonephritis, cryoglobulinemia), and posttransplant status, current guidelines recommend treatment for nearly all patients with HCV, including those with low-stage fibrosis.¹²

Patients with Child-Pugh grade B or C decompensated cirrhosis, even with hepatocellular carcinoma, may be considered for treatment. Multiple studies have demonstrated the efficacy and safety of direct-acting antiviral drugs in this patient population. In one randomized controlled trial,¹⁵ the combination of ledipasvir, sofosbuvir, and ribavirin resulted in high sustained virologic response rates at 12 weeks in patients infected with HCV genotype 1 or 4 with advanced liver disease, irrespective of transplant status (86% to 89% of patients were pretransplant). Sustained virologic response was associated with improvements in Model for End-Stage Liver Disease and Child-Pugh scores largely due to decreases in bilirubin and improvement in synthetic function (ie, albumin).

Similarly, even patients with a glomerular filtration rate less than 30 mL/min are candidates for treatment. Those with a glomerular filtration rate above 30 mL/min need no dosage adjustments for the most common regimens, while regimens are also available for those with a rate less than 30 mL/min. Although patients with low baseline renal function have a higher frequency of anemia (especially with ribavirin), worsening renal dysfunction, and more severe adverse events, treatment responses remain high and comparable to those without renal impairment.

The Hepatitis C Therapeutic Registry and Research Network (HCV-TARGET) is conducting an ongoing prospective study evaluating real-world use of direct-acting antiviral agents. The study has reported the safety and efficacy of sofosbuvir-containing regimens in patients with varying severities of kidney disease, including glomerular filtration rates less than 30 mL/min). The patients received different regimens that included sofosbuvir. The regimens were reportedly tolerated, and the rate of sustained viral response at 12 weeks remained high.¹⁶

The efficacy of direct-acting antiviral agents for HCV-associated glomerulonephritis remains to be studied but is promising. Earlier studies found that antiviral therapy based on interferon alfa with or without ribavirin can significantly decrease proteinuria and stabilize renal function.^17–20 HCV RNA clearance has been found to best predict renal improvement.

OUR PATIENT’S COURSE

Unfortunately, our patient’s kidney function declined further over the next 3 months, and he is currently on dialysis awaiting simultaneous liver and kidney transplant.

NEW ORLEANS – Insulin glargine 300 U/mL provided comparable glycemic control to that seen with insulin glargine 100 U/mL and consistently reduced the risk of nocturnal hypoglycemia in patients with type 2 diabetes, regardless of their renal function, results from a large post hoc meta-analysis showed.

The EDITION I, II, and III studies showed that over a period of 6 months, Gla-300 provided comparable glycemic control to Gla-100 with less hypoglycemia in patients with type 2 diabetes. However, “renal impairment increases the risk of hypoglycemia in people with type 2 diabetes, and may limit glucose-lowering therapy options,” Javier Escalada, M.D., said at the annual scientific sessions of the American Diabetes Association. “Therefore, it may be more challenging to manage diabetes in this population than in people with normal renal function.”

Dr. Escalada of the department of endocrinology and nutrition at Clinic University of Navarra, Pamplona, Spain, and his associates set out to investigate the impact of renal function on hemoglobin A_1c reduction and hypoglycemia in a post hoc meta-analysis of 2,468 patients aged 18 years and older with type 2 diabetes who were treated with Gla-300 or Gla-100 for 6 months in the EDITION I, II, and III studies. Treatment consisted of once-daily evening doses of Gla-300 or Gla-100 titrated to a fasting self-measured plasma glucose of 80-100 mg/dL. Patients were classified by their renal function as having moderate loss (30 to less than 60 mL/min per 1.73 m³; 399 patients), mild loss (60 to less than 90; 1,386 patients), or normal function (at least 90; 683 patients).

Outcomes of interest were change in HbA_1c from baseline to month 6, and the percentages of patients achieving an HbA_1c target of lower than 7.0% and lower than 7.5% at month 6. The researchers also assessed the cumulative number of hypoglycemic events, the relative risk of at least one confirmed or severe hypoglycemic event, and the nocturnal and at any time event rate per participant year.

Slightly more than half of participants (56%) had a baseline estimated glomerular filtration rate of 60 to less than 90 mL/min per 1.73 m³. Dr. Escalada reported that noninferiority for HbA1c reduction was shown for Gla-300 and Gla-100 regardless of renal function, and that evidence of heterogeneity of treatment effect across subgroups was observed (P = .46). However, the risk of confirmed or severe hypoglycemia was significantly lower for nocturnal events in the Gla-300 group, compared with the Gla-100 group (30% vs. 40% overall, respectively), while the risk of anytime hypoglycemia events in a 24-hour period was comparable to or lower in the Gla-300 group, compared with the Gla-100 group. Renal function did not affect the lower rate of nocturnal or anytime hypoglycemia. “Severe hypoglycemia was rare, and renal function did not affect the rate of severe events,” he said.

The trial was sponsored by Sanofi. Dr. Escalada disclosed that he is a member of the advisory panel for Sanofi and for Merck Sharp & Dohme. He is also a member of the speakers bureau for both companies as well as for AstraZeneca, Boehringer Ingelheim, Eli Lilly, and Novo Nordisk.

NEW ORLEANS – Insulin glargine 300 U/mL provided comparable glycemic control to that seen with insulin glargine 100 U/mL and consistently reduced the risk of nocturnal hypoglycemia in patients with type 2 diabetes, regardless of their renal function, results from a large post hoc meta-analysis showed.

The EDITION I, II, and III studies showed that over a period of 6 months, Gla-300 provided comparable glycemic control to Gla-100 with less hypoglycemia in patients with type 2 diabetes. However, “renal impairment increases the risk of hypoglycemia in people with type 2 diabetes, and may limit glucose-lowering therapy options,” Javier Escalada, M.D., said at the annual scientific sessions of the American Diabetes Association. “Therefore, it may be more challenging to manage diabetes in this population than in people with normal renal function.”

Dr. Escalada of the department of endocrinology and nutrition at Clinic University of Navarra, Pamplona, Spain, and his associates set out to investigate the impact of renal function on hemoglobin A_1c reduction and hypoglycemia in a post hoc meta-analysis of 2,468 patients aged 18 years and older with type 2 diabetes who were treated with Gla-300 or Gla-100 for 6 months in the EDITION I, II, and III studies. Treatment consisted of once-daily evening doses of Gla-300 or Gla-100 titrated to a fasting self-measured plasma glucose of 80-100 mg/dL. Patients were classified by their renal function as having moderate loss (30 to less than 60 mL/min per 1.73 m³; 399 patients), mild loss (60 to less than 90; 1,386 patients), or normal function (at least 90; 683 patients).

Outcomes of interest were change in HbA_1c from baseline to month 6, and the percentages of patients achieving an HbA_1c target of lower than 7.0% and lower than 7.5% at month 6. The researchers also assessed the cumulative number of hypoglycemic events, the relative risk of at least one confirmed or severe hypoglycemic event, and the nocturnal and at any time event rate per participant year.

Slightly more than half of participants (56%) had a baseline estimated glomerular filtration rate of 60 to less than 90 mL/min per 1.73 m³. Dr. Escalada reported that noninferiority for HbA1c reduction was shown for Gla-300 and Gla-100 regardless of renal function, and that evidence of heterogeneity of treatment effect across subgroups was observed (P = .46). However, the risk of confirmed or severe hypoglycemia was significantly lower for nocturnal events in the Gla-300 group, compared with the Gla-100 group (30% vs. 40% overall, respectively), while the risk of anytime hypoglycemia events in a 24-hour period was comparable to or lower in the Gla-300 group, compared with the Gla-100 group. Renal function did not affect the lower rate of nocturnal or anytime hypoglycemia. “Severe hypoglycemia was rare, and renal function did not affect the rate of severe events,” he said.

The trial was sponsored by Sanofi. Dr. Escalada disclosed that he is a member of the advisory panel for Sanofi and for Merck Sharp & Dohme. He is also a member of the speakers bureau for both companies as well as for AstraZeneca, Boehringer Ingelheim, Eli Lilly, and Novo Nordisk.

NEW ORLEANS – Insulin glargine 300 U/mL provided comparable glycemic control to that seen with insulin glargine 100 U/mL and consistently reduced the risk of nocturnal hypoglycemia in patients with type 2 diabetes, regardless of their renal function, results from a large post hoc meta-analysis showed.

The EDITION I, II, and III studies showed that over a period of 6 months, Gla-300 provided comparable glycemic control to Gla-100 with less hypoglycemia in patients with type 2 diabetes. However, “renal impairment increases the risk of hypoglycemia in people with type 2 diabetes, and may limit glucose-lowering therapy options,” Javier Escalada, M.D., said at the annual scientific sessions of the American Diabetes Association. “Therefore, it may be more challenging to manage diabetes in this population than in people with normal renal function.”

Dr. Escalada of the department of endocrinology and nutrition at Clinic University of Navarra, Pamplona, Spain, and his associates set out to investigate the impact of renal function on hemoglobin A_1c reduction and hypoglycemia in a post hoc meta-analysis of 2,468 patients aged 18 years and older with type 2 diabetes who were treated with Gla-300 or Gla-100 for 6 months in the EDITION I, II, and III studies. Treatment consisted of once-daily evening doses of Gla-300 or Gla-100 titrated to a fasting self-measured plasma glucose of 80-100 mg/dL. Patients were classified by their renal function as having moderate loss (30 to less than 60 mL/min per 1.73 m³; 399 patients), mild loss (60 to less than 90; 1,386 patients), or normal function (at least 90; 683 patients).

Outcomes of interest were change in HbA_1c from baseline to month 6, and the percentages of patients achieving an HbA_1c target of lower than 7.0% and lower than 7.5% at month 6. The researchers also assessed the cumulative number of hypoglycemic events, the relative risk of at least one confirmed or severe hypoglycemic event, and the nocturnal and at any time event rate per participant year.

Slightly more than half of participants (56%) had a baseline estimated glomerular filtration rate of 60 to less than 90 mL/min per 1.73 m³. Dr. Escalada reported that noninferiority for HbA1c reduction was shown for Gla-300 and Gla-100 regardless of renal function, and that evidence of heterogeneity of treatment effect across subgroups was observed (P = .46). However, the risk of confirmed or severe hypoglycemia was significantly lower for nocturnal events in the Gla-300 group, compared with the Gla-100 group (30% vs. 40% overall, respectively), while the risk of anytime hypoglycemia events in a 24-hour period was comparable to or lower in the Gla-300 group, compared with the Gla-100 group. Renal function did not affect the lower rate of nocturnal or anytime hypoglycemia. “Severe hypoglycemia was rare, and renal function did not affect the rate of severe events,” he said.

The trial was sponsored by Sanofi. Dr. Escalada disclosed that he is a member of the advisory panel for Sanofi and for Merck Sharp & Dohme. He is also a member of the speakers bureau for both companies as well as for AstraZeneca, Boehringer Ingelheim, Eli Lilly, and Novo Nordisk.