Nephrology

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.

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.

[email protected]

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.

[email protected]

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.

[email protected]

To the Editor: I read with great interest the article by Thomas et al, “Interpreting SPRINT: How low should you go?”¹

Hypertension is the most prevalent modifiable risk factor, affecting almost one in every three people in the United States.² Moreover, only half of people with hypertension have their blood pressure under control to the current standard of lower than 140/90 mm Hg.² The Systolic Blood Pressure Intervention Trial (SPRINT) tested a lower goal systolic pressure, ie, less than 120 mm Hg, and found it more beneficial than the standard goal of less than 140 mm Hg.³

A drawback of SPRINT that Thomas et al did not address in their interpretation of the trial is that the two study groups were not homogeneous in terms of the antihypertensive drugs used. Antihypertensive drugs do not only lower blood pressure—some of them have additional pleiotropic effects, making their use more advantageous in special situations. For example, renin-angiotensin-aldosterone system (RAAS) blockers—ie, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and mineralocorticoid receptor antagonists—are disease-modfying drugs in heart failure, as are certain beta-blockers.⁴ The cardiovascular benefit seen in the intensive-treatment group in SPRINT compared with the standard-therapy group was primarily due to a reduction in heart failure (a 38% relative risk reduction, P = .0002),³ for which RAAS blockers and beta-adrenergic blocking drugs have been shown consistently to be beneficial. But the intensive- and standard-therapy groups were not homogeneous in terms of the use of RAAS blockers and beta-blockers.

So, was the cardiovascular benefit attained in the intensive-treatment group in SPRINT due to the benefit of lower blood pressure or to the drugs used?

To the Editor: I read with great interest the article by Thomas et al, “Interpreting SPRINT: How low should you go?”¹

Hypertension is the most prevalent modifiable risk factor, affecting almost one in every three people in the United States.² Moreover, only half of people with hypertension have their blood pressure under control to the current standard of lower than 140/90 mm Hg.² The Systolic Blood Pressure Intervention Trial (SPRINT) tested a lower goal systolic pressure, ie, less than 120 mm Hg, and found it more beneficial than the standard goal of less than 140 mm Hg.³

A drawback of SPRINT that Thomas et al did not address in their interpretation of the trial is that the two study groups were not homogeneous in terms of the antihypertensive drugs used. Antihypertensive drugs do not only lower blood pressure—some of them have additional pleiotropic effects, making their use more advantageous in special situations. For example, renin-angiotensin-aldosterone system (RAAS) blockers—ie, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and mineralocorticoid receptor antagonists—are disease-modfying drugs in heart failure, as are certain beta-blockers.⁴ The cardiovascular benefit seen in the intensive-treatment group in SPRINT compared with the standard-therapy group was primarily due to a reduction in heart failure (a 38% relative risk reduction, P = .0002),³ for which RAAS blockers and beta-adrenergic blocking drugs have been shown consistently to be beneficial. But the intensive- and standard-therapy groups were not homogeneous in terms of the use of RAAS blockers and beta-blockers.

So, was the cardiovascular benefit attained in the intensive-treatment group in SPRINT due to the benefit of lower blood pressure or to the drugs used?

To the Editor: I read with great interest the article by Thomas et al, “Interpreting SPRINT: How low should you go?”¹

Hypertension is the most prevalent modifiable risk factor, affecting almost one in every three people in the United States.² Moreover, only half of people with hypertension have their blood pressure under control to the current standard of lower than 140/90 mm Hg.² The Systolic Blood Pressure Intervention Trial (SPRINT) tested a lower goal systolic pressure, ie, less than 120 mm Hg, and found it more beneficial than the standard goal of less than 140 mm Hg.³

A drawback of SPRINT that Thomas et al did not address in their interpretation of the trial is that the two study groups were not homogeneous in terms of the antihypertensive drugs used. Antihypertensive drugs do not only lower blood pressure—some of them have additional pleiotropic effects, making their use more advantageous in special situations. For example, renin-angiotensin-aldosterone system (RAAS) blockers—ie, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and mineralocorticoid receptor antagonists—are disease-modfying drugs in heart failure, as are certain beta-blockers.⁴ The cardiovascular benefit seen in the intensive-treatment group in SPRINT compared with the standard-therapy group was primarily due to a reduction in heart failure (a 38% relative risk reduction, P = .0002),³ for which RAAS blockers and beta-adrenergic blocking drugs have been shown consistently to be beneficial. But the intensive- and standard-therapy groups were not homogeneous in terms of the use of RAAS blockers and beta-blockers.

So, was the cardiovascular benefit attained in the intensive-treatment group in SPRINT due to the benefit of lower blood pressure or to the drugs used?

To the Editor: In their review,¹ Thomas et al noted that the benefits of intensive blood pressure lowering seen in the SPRINT study² were not observed in the Action to Control Cardiovascular Risk in Diabetes-Blood pressure (ACCORD BP) trial³ or in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial.⁴ In addition to the reasons discussed in their review, the discrepancy may be due to the surprisingly low rate of statin use in the patients enrolled in SPRINT. Even though 61% of the patients in SPRINT had a 10-year Framingham risk score greater than 15%, only 44% of the patients were on statin therapy. In comparison, rates of statin use in ACCORD BP and SPS3 were 65% and 83%, respectively.

A possible interaction between statin use and intensive blood pressure lowering is consistent with previous data on angiotensin-converting enzyme (ACE) inhibitor use in high-risk populations.

The Heart Outcomes Prevention Evaluation (HOPE) trial,⁵ in which only 29% of patients received lipid-lowering therapy, found that ACE inhibitor use was associated with a significant reduction in a composite cardiovascular outcome, whereas the Prevention of Events With Angiotensin-Converting Enzyme Inhibitor Therapy (PEACE) trial,⁶ in which 70% of patients were on lipid-lowering therapy, did not show a benefit for ACE inhibitor therapy. In addition, there are many drug interactions between statins and calcium channel blockers, potentially limiting options for simultaneous aggressive treatment of lipid levels and blood pressure.

In summary, aggressive use of statins may confer sufficient cardiovascular protection when aggressive antihypertensive therapy provides little or no incremental benefit. Hopefully, further analyses of these trials will shed light on this important question.

To the Editor: In their review,¹ Thomas et al noted that the benefits of intensive blood pressure lowering seen in the SPRINT study² were not observed in the Action to Control Cardiovascular Risk in Diabetes-Blood pressure (ACCORD BP) trial³ or in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial.⁴ In addition to the reasons discussed in their review, the discrepancy may be due to the surprisingly low rate of statin use in the patients enrolled in SPRINT. Even though 61% of the patients in SPRINT had a 10-year Framingham risk score greater than 15%, only 44% of the patients were on statin therapy. In comparison, rates of statin use in ACCORD BP and SPS3 were 65% and 83%, respectively.

A possible interaction between statin use and intensive blood pressure lowering is consistent with previous data on angiotensin-converting enzyme (ACE) inhibitor use in high-risk populations.

The Heart Outcomes Prevention Evaluation (HOPE) trial,⁵ in which only 29% of patients received lipid-lowering therapy, found that ACE inhibitor use was associated with a significant reduction in a composite cardiovascular outcome, whereas the Prevention of Events With Angiotensin-Converting Enzyme Inhibitor Therapy (PEACE) trial,⁶ in which 70% of patients were on lipid-lowering therapy, did not show a benefit for ACE inhibitor therapy. In addition, there are many drug interactions between statins and calcium channel blockers, potentially limiting options for simultaneous aggressive treatment of lipid levels and blood pressure.

In summary, aggressive use of statins may confer sufficient cardiovascular protection when aggressive antihypertensive therapy provides little or no incremental benefit. Hopefully, further analyses of these trials will shed light on this important question.

To the Editor: In their review,¹ Thomas et al noted that the benefits of intensive blood pressure lowering seen in the SPRINT study² were not observed in the Action to Control Cardiovascular Risk in Diabetes-Blood pressure (ACCORD BP) trial³ or in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial.⁴ In addition to the reasons discussed in their review, the discrepancy may be due to the surprisingly low rate of statin use in the patients enrolled in SPRINT. Even though 61% of the patients in SPRINT had a 10-year Framingham risk score greater than 15%, only 44% of the patients were on statin therapy. In comparison, rates of statin use in ACCORD BP and SPS3 were 65% and 83%, respectively.

A possible interaction between statin use and intensive blood pressure lowering is consistent with previous data on angiotensin-converting enzyme (ACE) inhibitor use in high-risk populations.

The Heart Outcomes Prevention Evaluation (HOPE) trial,⁵ in which only 29% of patients received lipid-lowering therapy, found that ACE inhibitor use was associated with a significant reduction in a composite cardiovascular outcome, whereas the Prevention of Events With Angiotensin-Converting Enzyme Inhibitor Therapy (PEACE) trial,⁶ in which 70% of patients were on lipid-lowering therapy, did not show a benefit for ACE inhibitor therapy. In addition, there are many drug interactions between statins and calcium channel blockers, potentially limiting options for simultaneous aggressive treatment of lipid levels and blood pressure.

In summary, aggressive use of statins may confer sufficient cardiovascular protection when aggressive antihypertensive therapy provides little or no incremental benefit. Hopefully, further analyses of these trials will shed light on this important question.

In Reply: We thank the readers for their important and insightful comments and questions.

Dr. Yilmaz raises the point that there was no mandate in the SPRINT trial to preferentially use any specific class of antihypertensive medications in either group. However, there was greater use of all drug classes (including diuretics and renin-angiotensin-aldosterone blockers) in the intensive-treatment group.¹ (This information was included as a supplementary appendix in the main paper, and as Table 1 in our review.) Could this have contributed to the primary cardiovascular outcome benefit seen in the intensive-therapy group, largely driven by a decreased incidence of heart failure, or could it even have masked the symptoms of heart failure rather than preventing it^2,3? While this is plausible, since the SPRINT trial was designed as a “treat to target” study and not as an antihypertensive medication efficacy study, it is difficult to conclusively answer the question of potential pleiotropic effects of antihypertensive medications influencing the trial results. The authors did not comment on this in the main paper, and we agree that further analysis would be helpful in exploring this important question.

Dr. Edwards raises the question whether antihypertensive therapy confers additional cardiovascular benefit over aggressive use of statins. Statin use in the SPRINT cohort (both intensive and standard groups) was low at baseline, despite this being a population at high cardiovascular risk.¹ It is unclear whether treatment practices pertaining to lipid management could have changed during the course of the trial in participants within the SPRINT cohort, particularly after the new lipid guidelines were published. The recently published HOPE-3 trial indicated cardiovascular benefit with statins used as a primary prevention strategy in older persons with intermediate cardiovascular risk.^4,5 Notably, outcomes with combination therapy in this trial using a statin plus antihypertensive therapy were not significantly better than with statin alone, except in the subgroup of participants who were in the upper third of systolic blood pressure levels, where combination appeared to benefit more. This study, of course, was done in a population with lower cardiovascular risk than in SPRINT, and the antihypertensive medications used (candesartan and hydrochlorothiazide) were not at maximal doses. There is also a question of whether use of chlorthalidone in HOPE-3 may have been more effective.

We agree with Dr. Edwards that this is an important question that merits further exploration, especially in the broader context of treatment based on cardiovascular risk.

In Reply: We thank the readers for their important and insightful comments and questions.

Dr. Yilmaz raises the point that there was no mandate in the SPRINT trial to preferentially use any specific class of antihypertensive medications in either group. However, there was greater use of all drug classes (including diuretics and renin-angiotensin-aldosterone blockers) in the intensive-treatment group.¹ (This information was included as a supplementary appendix in the main paper, and as Table 1 in our review.) Could this have contributed to the primary cardiovascular outcome benefit seen in the intensive-therapy group, largely driven by a decreased incidence of heart failure, or could it even have masked the symptoms of heart failure rather than preventing it^2,3? While this is plausible, since the SPRINT trial was designed as a “treat to target” study and not as an antihypertensive medication efficacy study, it is difficult to conclusively answer the question of potential pleiotropic effects of antihypertensive medications influencing the trial results. The authors did not comment on this in the main paper, and we agree that further analysis would be helpful in exploring this important question.

Dr. Edwards raises the question whether antihypertensive therapy confers additional cardiovascular benefit over aggressive use of statins. Statin use in the SPRINT cohort (both intensive and standard groups) was low at baseline, despite this being a population at high cardiovascular risk.¹ It is unclear whether treatment practices pertaining to lipid management could have changed during the course of the trial in participants within the SPRINT cohort, particularly after the new lipid guidelines were published. The recently published HOPE-3 trial indicated cardiovascular benefit with statins used as a primary prevention strategy in older persons with intermediate cardiovascular risk.^4,5 Notably, outcomes with combination therapy in this trial using a statin plus antihypertensive therapy were not significantly better than with statin alone, except in the subgroup of participants who were in the upper third of systolic blood pressure levels, where combination appeared to benefit more. This study, of course, was done in a population with lower cardiovascular risk than in SPRINT, and the antihypertensive medications used (candesartan and hydrochlorothiazide) were not at maximal doses. There is also a question of whether use of chlorthalidone in HOPE-3 may have been more effective.

We agree with Dr. Edwards that this is an important question that merits further exploration, especially in the broader context of treatment based on cardiovascular risk.

In Reply: We thank the readers for their important and insightful comments and questions.

Dr. Yilmaz raises the point that there was no mandate in the SPRINT trial to preferentially use any specific class of antihypertensive medications in either group. However, there was greater use of all drug classes (including diuretics and renin-angiotensin-aldosterone blockers) in the intensive-treatment group.¹ (This information was included as a supplementary appendix in the main paper, and as Table 1 in our review.) Could this have contributed to the primary cardiovascular outcome benefit seen in the intensive-therapy group, largely driven by a decreased incidence of heart failure, or could it even have masked the symptoms of heart failure rather than preventing it^2,3? While this is plausible, since the SPRINT trial was designed as a “treat to target” study and not as an antihypertensive medication efficacy study, it is difficult to conclusively answer the question of potential pleiotropic effects of antihypertensive medications influencing the trial results. The authors did not comment on this in the main paper, and we agree that further analysis would be helpful in exploring this important question.

Dr. Edwards raises the question whether antihypertensive therapy confers additional cardiovascular benefit over aggressive use of statins. Statin use in the SPRINT cohort (both intensive and standard groups) was low at baseline, despite this being a population at high cardiovascular risk.¹ It is unclear whether treatment practices pertaining to lipid management could have changed during the course of the trial in participants within the SPRINT cohort, particularly after the new lipid guidelines were published. The recently published HOPE-3 trial indicated cardiovascular benefit with statins used as a primary prevention strategy in older persons with intermediate cardiovascular risk.^4,5 Notably, outcomes with combination therapy in this trial using a statin plus antihypertensive therapy were not significantly better than with statin alone, except in the subgroup of participants who were in the upper third of systolic blood pressure levels, where combination appeared to benefit more. This study, of course, was done in a population with lower cardiovascular risk than in SPRINT, and the antihypertensive medications used (candesartan and hydrochlorothiazide) were not at maximal doses. There is also a question of whether use of chlorthalidone in HOPE-3 may have been more effective.

We agree with Dr. Edwards that this is an important question that merits further exploration, especially in the broader context of treatment based on cardiovascular risk.

LONDON – Updated management recommendations for patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis from the European League Against Rheumatism and the European Renal Association-European Dialysis and Transplant Association aim to provide clinicians with reliable guidance on the best approach to treatment.

The update, presented at the European Congress of Rheumatology and recently published online in Annals of the Rheumatic Diseases (Ann Rheum Dis. 2016 Jun 23. doi:10.1136/annrheumdis-2016-209133), reassessed items in the 2009 recommendations for the management of primary systemic vasculitis and focused only on the management of ANCA-associated vasculitis (AAV), according to recommendations task force member Dr. Max Yates.

“In the past 5 years, 1,691 papers have been published on primary systemic vasculitis in internal medicine, rheumatology, and nephrology journals. Together with the licensing of rituximab for AAV, it was an opportune time to update the recommendations with an AAV focus,” Dr. Yates explained. The revised guidance is based on a systematic literature review from January 2007 to February 2015, focusing in particular on specific items that needed updating, such as the importance of ANCA testing and biopsy in diagnosis and follow-up, disease staging at diagnosis, the choices for remission-induction and remission-maintenance therapies, and the drug choices for relapsing and refractory disease. The task force considered for the first time the choice of immunosuppressive drugs and biologic agents (principally rituximab) and immunologic monitoring. They identified patient education as another priority.

“These updated recommendations provide a framework of practice and should apply to the majority of patients with AAV,” added Dr. Yates, who is a clinical fellow at Norwich Medical School at the University of East Anglia and works in the department of rheumatology at the Norfolk and Norwich (England) University Hospital.

The 22-member task force included rheumatologists, internists, nephrologists, a clinical immunologist, an otorhinolaryngologist, a chest physician, an ophthalmologist, a vasculitis nurse, and a patient with vasculitis from 11 countries in Europe and the United States. The task force was convened by rheumatologist Dr. Chetan Mukhtyar of the Norfolk and Norwich University Hospital on behalf of EULAR and by vasculitis and renal specialist Dr. David Jayne of Addenbrooke’s Hospital in Cambridge (England) on behalf of the European Renal Association-European Dialysis and Transplant Association.

The recommendations now contain one single, simple overarching principle, Dr. Mukhtyar said at the congress. That is, the need for shared decision making between the patient and the clinician. This principle is also included as the first point in many of the other recently updated EULAR recommendations on the management of rheumatic diseases.

Both previous and updated versions of the vasculitis recommendations contain 15 recommendations, with some changed and others combined. One key recommendation is about who should treat patients with AAV; it states that patients “should be managed in close collaboration with, or at, centers of expertise,” Dr. Mukhtyar said.“Patients with ANCA-associated vasculitis have often very complex presentations that involve several different specialties, and it is always worthwhile that these patients are looked after by people who commonly see them, because these are rare conditions,” he observed.

Deciding when to perform a biopsy is also covered, with the recommendation being that it can be used to establish a new diagnosis and to further evaluate cases of suspected relapsing vasculitis. “When do you do a biopsy?” Dr. Mukhtyar asked. “Well, every time you can, every time it is clinically feasible,” he suggested.

As for treatment, there are different recommendations depending on whether the aim is to induce or maintain remission and whether there has been a major relapse. In patients with organ- or life-threatening disease, for example, the advice is to use glucocorticoids and either cyclophosphamide or rituximab to induce remission, Dr. Mukhtyar said. The specific dosing or administration of glucocorticoids is not specified as this will depend on the clinical situation, but the advice is to taper down when possible, somewhere between month 3 and 5.

For remission induction in less severe (non–organ threatening) disease, the recommendation is to use glucocorticoids plus either methotrexate or mycophenolate mofetil. Situations when methotrexate or mycophenolate mofetil should and should not be used are specified, notably when cyclophosphamide or rituximab are not available or are contraindicated.

For maintenance of remission, the task force advised using low-dose glucocorticoids plus azathioprine, rituximab, methotrexate, or mycophenolate mofetil.

Guidance on when to use plasma exchange is given for patients with severe disease and options following failure of remission-induction therapy, and when to switch therapy is also covered.

There are also several follow-up recommendations, such as the periodic assessment of cardiovascular risk, and patient-focused recommendations on awareness of the nature, benefits, and risks of therapy. 

The recommendations should provide clinicians with reliable guidance on the best approach to treating AAV, according to Dr. Yates. “From the patients’ point of view, these recommendations should provide useful insight into which treatments they are likely to be offered and when. They also emphasize that as a patient, you should have a voice in your treatment and if you have any questions or concerns, be sure to speak with your specialist.” 

Dr. Yates and Dr. Mukhtyar did not report having any relevant disclosures.

LONDON – Updated management recommendations for patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis from the European League Against Rheumatism and the European Renal Association-European Dialysis and Transplant Association aim to provide clinicians with reliable guidance on the best approach to treatment.

The update, presented at the European Congress of Rheumatology and recently published online in Annals of the Rheumatic Diseases (Ann Rheum Dis. 2016 Jun 23. doi:10.1136/annrheumdis-2016-209133), reassessed items in the 2009 recommendations for the management of primary systemic vasculitis and focused only on the management of ANCA-associated vasculitis (AAV), according to recommendations task force member Dr. Max Yates.

“In the past 5 years, 1,691 papers have been published on primary systemic vasculitis in internal medicine, rheumatology, and nephrology journals. Together with the licensing of rituximab for AAV, it was an opportune time to update the recommendations with an AAV focus,” Dr. Yates explained. The revised guidance is based on a systematic literature review from January 2007 to February 2015, focusing in particular on specific items that needed updating, such as the importance of ANCA testing and biopsy in diagnosis and follow-up, disease staging at diagnosis, the choices for remission-induction and remission-maintenance therapies, and the drug choices for relapsing and refractory disease. The task force considered for the first time the choice of immunosuppressive drugs and biologic agents (principally rituximab) and immunologic monitoring. They identified patient education as another priority.

“These updated recommendations provide a framework of practice and should apply to the majority of patients with AAV,” added Dr. Yates, who is a clinical fellow at Norwich Medical School at the University of East Anglia and works in the department of rheumatology at the Norfolk and Norwich (England) University Hospital.

The 22-member task force included rheumatologists, internists, nephrologists, a clinical immunologist, an otorhinolaryngologist, a chest physician, an ophthalmologist, a vasculitis nurse, and a patient with vasculitis from 11 countries in Europe and the United States. The task force was convened by rheumatologist Dr. Chetan Mukhtyar of the Norfolk and Norwich University Hospital on behalf of EULAR and by vasculitis and renal specialist Dr. David Jayne of Addenbrooke’s Hospital in Cambridge (England) on behalf of the European Renal Association-European Dialysis and Transplant Association.

The recommendations now contain one single, simple overarching principle, Dr. Mukhtyar said at the congress. That is, the need for shared decision making between the patient and the clinician. This principle is also included as the first point in many of the other recently updated EULAR recommendations on the management of rheumatic diseases.

Both previous and updated versions of the vasculitis recommendations contain 15 recommendations, with some changed and others combined. One key recommendation is about who should treat patients with AAV; it states that patients “should be managed in close collaboration with, or at, centers of expertise,” Dr. Mukhtyar said.“Patients with ANCA-associated vasculitis have often very complex presentations that involve several different specialties, and it is always worthwhile that these patients are looked after by people who commonly see them, because these are rare conditions,” he observed.

Deciding when to perform a biopsy is also covered, with the recommendation being that it can be used to establish a new diagnosis and to further evaluate cases of suspected relapsing vasculitis. “When do you do a biopsy?” Dr. Mukhtyar asked. “Well, every time you can, every time it is clinically feasible,” he suggested.

As for treatment, there are different recommendations depending on whether the aim is to induce or maintain remission and whether there has been a major relapse. In patients with organ- or life-threatening disease, for example, the advice is to use glucocorticoids and either cyclophosphamide or rituximab to induce remission, Dr. Mukhtyar said. The specific dosing or administration of glucocorticoids is not specified as this will depend on the clinical situation, but the advice is to taper down when possible, somewhere between month 3 and 5.

For remission induction in less severe (non–organ threatening) disease, the recommendation is to use glucocorticoids plus either methotrexate or mycophenolate mofetil. Situations when methotrexate or mycophenolate mofetil should and should not be used are specified, notably when cyclophosphamide or rituximab are not available or are contraindicated.

For maintenance of remission, the task force advised using low-dose glucocorticoids plus azathioprine, rituximab, methotrexate, or mycophenolate mofetil.

Guidance on when to use plasma exchange is given for patients with severe disease and options following failure of remission-induction therapy, and when to switch therapy is also covered.

There are also several follow-up recommendations, such as the periodic assessment of cardiovascular risk, and patient-focused recommendations on awareness of the nature, benefits, and risks of therapy. 

The recommendations should provide clinicians with reliable guidance on the best approach to treating AAV, according to Dr. Yates. “From the patients’ point of view, these recommendations should provide useful insight into which treatments they are likely to be offered and when. They also emphasize that as a patient, you should have a voice in your treatment and if you have any questions or concerns, be sure to speak with your specialist.” 

Dr. Yates and Dr. Mukhtyar did not report having any relevant disclosures.

LONDON – Updated management recommendations for patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis from the European League Against Rheumatism and the European Renal Association-European Dialysis and Transplant Association aim to provide clinicians with reliable guidance on the best approach to treatment.

The update, presented at the European Congress of Rheumatology and recently published online in Annals of the Rheumatic Diseases (Ann Rheum Dis. 2016 Jun 23. doi:10.1136/annrheumdis-2016-209133), reassessed items in the 2009 recommendations for the management of primary systemic vasculitis and focused only on the management of ANCA-associated vasculitis (AAV), according to recommendations task force member Dr. Max Yates.

“In the past 5 years, 1,691 papers have been published on primary systemic vasculitis in internal medicine, rheumatology, and nephrology journals. Together with the licensing of rituximab for AAV, it was an opportune time to update the recommendations with an AAV focus,” Dr. Yates explained. The revised guidance is based on a systematic literature review from January 2007 to February 2015, focusing in particular on specific items that needed updating, such as the importance of ANCA testing and biopsy in diagnosis and follow-up, disease staging at diagnosis, the choices for remission-induction and remission-maintenance therapies, and the drug choices for relapsing and refractory disease. The task force considered for the first time the choice of immunosuppressive drugs and biologic agents (principally rituximab) and immunologic monitoring. They identified patient education as another priority.

“These updated recommendations provide a framework of practice and should apply to the majority of patients with AAV,” added Dr. Yates, who is a clinical fellow at Norwich Medical School at the University of East Anglia and works in the department of rheumatology at the Norfolk and Norwich (England) University Hospital.

The 22-member task force included rheumatologists, internists, nephrologists, a clinical immunologist, an otorhinolaryngologist, a chest physician, an ophthalmologist, a vasculitis nurse, and a patient with vasculitis from 11 countries in Europe and the United States. The task force was convened by rheumatologist Dr. Chetan Mukhtyar of the Norfolk and Norwich University Hospital on behalf of EULAR and by vasculitis and renal specialist Dr. David Jayne of Addenbrooke’s Hospital in Cambridge (England) on behalf of the European Renal Association-European Dialysis and Transplant Association.

The recommendations now contain one single, simple overarching principle, Dr. Mukhtyar said at the congress. That is, the need for shared decision making between the patient and the clinician. This principle is also included as the first point in many of the other recently updated EULAR recommendations on the management of rheumatic diseases.

Both previous and updated versions of the vasculitis recommendations contain 15 recommendations, with some changed and others combined. One key recommendation is about who should treat patients with AAV; it states that patients “should be managed in close collaboration with, or at, centers of expertise,” Dr. Mukhtyar said.“Patients with ANCA-associated vasculitis have often very complex presentations that involve several different specialties, and it is always worthwhile that these patients are looked after by people who commonly see them, because these are rare conditions,” he observed.

Deciding when to perform a biopsy is also covered, with the recommendation being that it can be used to establish a new diagnosis and to further evaluate cases of suspected relapsing vasculitis. “When do you do a biopsy?” Dr. Mukhtyar asked. “Well, every time you can, every time it is clinically feasible,” he suggested.

As for treatment, there are different recommendations depending on whether the aim is to induce or maintain remission and whether there has been a major relapse. In patients with organ- or life-threatening disease, for example, the advice is to use glucocorticoids and either cyclophosphamide or rituximab to induce remission, Dr. Mukhtyar said. The specific dosing or administration of glucocorticoids is not specified as this will depend on the clinical situation, but the advice is to taper down when possible, somewhere between month 3 and 5.

For remission induction in less severe (non–organ threatening) disease, the recommendation is to use glucocorticoids plus either methotrexate or mycophenolate mofetil. Situations when methotrexate or mycophenolate mofetil should and should not be used are specified, notably when cyclophosphamide or rituximab are not available or are contraindicated.

For maintenance of remission, the task force advised using low-dose glucocorticoids plus azathioprine, rituximab, methotrexate, or mycophenolate mofetil.

Guidance on when to use plasma exchange is given for patients with severe disease and options following failure of remission-induction therapy, and when to switch therapy is also covered.

There are also several follow-up recommendations, such as the periodic assessment of cardiovascular risk, and patient-focused recommendations on awareness of the nature, benefits, and risks of therapy. 

The recommendations should provide clinicians with reliable guidance on the best approach to treating AAV, according to Dr. Yates. “From the patients’ point of view, these recommendations should provide useful insight into which treatments they are likely to be offered and when. They also emphasize that as a patient, you should have a voice in your treatment and if you have any questions or concerns, be sure to speak with your specialist.” 

Dr. Yates and Dr. Mukhtyar did not report having any relevant disclosures.

Q) One of my diabetic patients read about finerenone in The New York Times. Apparently, it’s the “newest cure for albuminuria”! Is this just hype, or do the trials on this medication really show progress against kidney disease? Should I buy stock in the company?

Albuminuria (> 500 mg/d) associated with diabetic nephropathy and other glomerular diseases increases patient risk for chronic kidney disease (CKD) and its progression to end-stage renal disease (ESRD). Reduction of albuminuria has been shown to slow the progression of CKD.

Renin-angiotensin-aldosterone system (RAAS) blockers, such as ACE inhibitors or angiotensin receptor blockers, are considered firstline therapy to reduce albuminuria. Additional treatment modalities include diuretics, nondihydropyridine calcium channel blockers, ß-blockers, and aldosterone antagonist therapy. Limiting dietary sodium helps control blood pressure, thus slowing disease progression. In addition, some studies show that limiting phosphorus and protein (for the latter, intake of no more than 0.7 g/kg ideal body weight per day) may slow the progression of CKD. Unfortunately, despite these interventions, patients may still advance to ESRD.¹

The aldosterone and steroidal mineralocorticoid receptor antagonists (MRA) spironolactone and eplerenone have been found to reduce albuminuria when used in conjunction with RAAS blockade. However, patients using this combination are up to eight times more likely to experience hyperkalemia—a serious, potentially life-threatening adverse condition—than those not using an MRA.² The presence of hyperkalemia requires discontinuation of the RAAS blocker and the MRA, at least temporarily.

Finerenone, a nonsteroidal MRA with “greater receptor selectivity than spironolactone and better receptor affinity than eplerenone in vitro,” is in phase III trials for the treatment of systolic and diastolic dysfunction and reduction of morbidity and mortality associated with heart failure.² One study has already demonstrated that finerenone (5 to 10 mg/d) is at least as effective as spironolactone (25 mg/d) for heart failure patients.³

The Mineralocorticoid Receptor Antagonist Tolerability Study-Diabetic Nephropathy (ARTS-DN) found that finerenone at 10 to 20 mg/d was superior to spironolactone and eplerenone, partly due to the decreased incidence of hyperkalemia. However, it should be noted that the lower incidence of hyperkalemia may be attributable to the fact that 66% of the study participants had an estimated glomerular filtration rate (eGFR) greater than 60 mL/min and that potential participants with a serum potassium level of more than 4.8 mEq/L were not included in the study.²

Additional research is needed to confirm superiority of finerenone over spironolactone and eplerenone, in conjunction with RAAS blockers, in the treatment of albuminuria and hyperkalemia. Including subjects with lower eGFR (such as patients with stage IV CKD who are at higher risk for hyperkalemia) would give a better indication of finerenone’s efficacy. In the meantime, it’s probably too soon to corner the market on this stock! —SEB

Susan E. Brown, MS, ARNP, ACNP-BC, CCRN
Great River Nephrology, West Burlington, Iowa

References
1. Parikh SV, Haddad NJ, Hebert LA. Retarding progression of kidney disease. In: Johnson RJ, Feehally J, Floege J, eds. Comprehensive Clinical Nephrology. 5th ed. Philadelphia, PA: Saunders; 2015:931-940.
2. Bakris GL, Agarwal R, Chan JC, et al. Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial. JAMA. 2015;314(9):884-894.
3. Kolkhof P, Delbeck M, Kretschmer A, et al. Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist, protects from rat cardiorenal injury. J Cardiovasc Pharmacol. 2014;64(1):69-78.

Q) One of my diabetic patients read about finerenone in The New York Times. Apparently, it’s the “newest cure for albuminuria”! Is this just hype, or do the trials on this medication really show progress against kidney disease? Should I buy stock in the company?

Albuminuria (> 500 mg/d) associated with diabetic nephropathy and other glomerular diseases increases patient risk for chronic kidney disease (CKD) and its progression to end-stage renal disease (ESRD). Reduction of albuminuria has been shown to slow the progression of CKD.

Renin-angiotensin-aldosterone system (RAAS) blockers, such as ACE inhibitors or angiotensin receptor blockers, are considered firstline therapy to reduce albuminuria. Additional treatment modalities include diuretics, nondihydropyridine calcium channel blockers, ß-blockers, and aldosterone antagonist therapy. Limiting dietary sodium helps control blood pressure, thus slowing disease progression. In addition, some studies show that limiting phosphorus and protein (for the latter, intake of no more than 0.7 g/kg ideal body weight per day) may slow the progression of CKD. Unfortunately, despite these interventions, patients may still advance to ESRD.¹

The aldosterone and steroidal mineralocorticoid receptor antagonists (MRA) spironolactone and eplerenone have been found to reduce albuminuria when used in conjunction with RAAS blockade. However, patients using this combination are up to eight times more likely to experience hyperkalemia—a serious, potentially life-threatening adverse condition—than those not using an MRA.² The presence of hyperkalemia requires discontinuation of the RAAS blocker and the MRA, at least temporarily.

Finerenone, a nonsteroidal MRA with “greater receptor selectivity than spironolactone and better receptor affinity than eplerenone in vitro,” is in phase III trials for the treatment of systolic and diastolic dysfunction and reduction of morbidity and mortality associated with heart failure.² One study has already demonstrated that finerenone (5 to 10 mg/d) is at least as effective as spironolactone (25 mg/d) for heart failure patients.³

The Mineralocorticoid Receptor Antagonist Tolerability Study-Diabetic Nephropathy (ARTS-DN) found that finerenone at 10 to 20 mg/d was superior to spironolactone and eplerenone, partly due to the decreased incidence of hyperkalemia. However, it should be noted that the lower incidence of hyperkalemia may be attributable to the fact that 66% of the study participants had an estimated glomerular filtration rate (eGFR) greater than 60 mL/min and that potential participants with a serum potassium level of more than 4.8 mEq/L were not included in the study.²

Additional research is needed to confirm superiority of finerenone over spironolactone and eplerenone, in conjunction with RAAS blockers, in the treatment of albuminuria and hyperkalemia. Including subjects with lower eGFR (such as patients with stage IV CKD who are at higher risk for hyperkalemia) would give a better indication of finerenone’s efficacy. In the meantime, it’s probably too soon to corner the market on this stock! —SEB

Susan E. Brown, MS, ARNP, ACNP-BC, CCRN
Great River Nephrology, West Burlington, Iowa

References
1. Parikh SV, Haddad NJ, Hebert LA. Retarding progression of kidney disease. In: Johnson RJ, Feehally J, Floege J, eds. Comprehensive Clinical Nephrology. 5th ed. Philadelphia, PA: Saunders; 2015:931-940.
2. Bakris GL, Agarwal R, Chan JC, et al. Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial. JAMA. 2015;314(9):884-894.
3. Kolkhof P, Delbeck M, Kretschmer A, et al. Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist, protects from rat cardiorenal injury. J Cardiovasc Pharmacol. 2014;64(1):69-78.

Q) One of my diabetic patients read about finerenone in The New York Times. Apparently, it’s the “newest cure for albuminuria”! Is this just hype, or do the trials on this medication really show progress against kidney disease? Should I buy stock in the company?

Albuminuria (> 500 mg/d) associated with diabetic nephropathy and other glomerular diseases increases patient risk for chronic kidney disease (CKD) and its progression to end-stage renal disease (ESRD). Reduction of albuminuria has been shown to slow the progression of CKD.

Renin-angiotensin-aldosterone system (RAAS) blockers, such as ACE inhibitors or angiotensin receptor blockers, are considered firstline therapy to reduce albuminuria. Additional treatment modalities include diuretics, nondihydropyridine calcium channel blockers, ß-blockers, and aldosterone antagonist therapy. Limiting dietary sodium helps control blood pressure, thus slowing disease progression. In addition, some studies show that limiting phosphorus and protein (for the latter, intake of no more than 0.7 g/kg ideal body weight per day) may slow the progression of CKD. Unfortunately, despite these interventions, patients may still advance to ESRD.¹

The aldosterone and steroidal mineralocorticoid receptor antagonists (MRA) spironolactone and eplerenone have been found to reduce albuminuria when used in conjunction with RAAS blockade. However, patients using this combination are up to eight times more likely to experience hyperkalemia—a serious, potentially life-threatening adverse condition—than those not using an MRA.² The presence of hyperkalemia requires discontinuation of the RAAS blocker and the MRA, at least temporarily.

Finerenone, a nonsteroidal MRA with “greater receptor selectivity than spironolactone and better receptor affinity than eplerenone in vitro,” is in phase III trials for the treatment of systolic and diastolic dysfunction and reduction of morbidity and mortality associated with heart failure.² One study has already demonstrated that finerenone (5 to 10 mg/d) is at least as effective as spironolactone (25 mg/d) for heart failure patients.³

The Mineralocorticoid Receptor Antagonist Tolerability Study-Diabetic Nephropathy (ARTS-DN) found that finerenone at 10 to 20 mg/d was superior to spironolactone and eplerenone, partly due to the decreased incidence of hyperkalemia. However, it should be noted that the lower incidence of hyperkalemia may be attributable to the fact that 66% of the study participants had an estimated glomerular filtration rate (eGFR) greater than 60 mL/min and that potential participants with a serum potassium level of more than 4.8 mEq/L were not included in the study.²

Additional research is needed to confirm superiority of finerenone over spironolactone and eplerenone, in conjunction with RAAS blockers, in the treatment of albuminuria and hyperkalemia. Including subjects with lower eGFR (such as patients with stage IV CKD who are at higher risk for hyperkalemia) would give a better indication of finerenone’s efficacy. In the meantime, it’s probably too soon to corner the market on this stock! —SEB

Susan E. Brown, MS, ARNP, ACNP-BC, CCRN
Great River Nephrology, West Burlington, Iowa

References
1. Parikh SV, Haddad NJ, Hebert LA. Retarding progression of kidney disease. In: Johnson RJ, Feehally J, Floege J, eds. Comprehensive Clinical Nephrology. 5th ed. Philadelphia, PA: Saunders; 2015:931-940.
2. Bakris GL, Agarwal R, Chan JC, et al. Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial. JAMA. 2015;314(9):884-894.
3. Kolkhof P, Delbeck M, Kretschmer A, et al. Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist, protects from rat cardiorenal injury. J Cardiovasc Pharmacol. 2014;64(1):69-78.