Nephrology

A 54-year-old woman with chronic renal disease was diagnosed with gout and prescribed allopurinol. Two days later, she was evaluated by her nephrologist, whom she informed about her new medication.

Subsequently, the patient developed fever and rash. Laboratory analysis indicated elevated transaminase levels and eosinophilia. She was admitted to the hospital.

During her stay, an infectious disease consultation was obtained, and the allopurinol was discontinued. When the patient’s condition improved, she was discharged.

Following discharge, the patient resumed taking allopurinol, and her rash returned. Eleven days later, she returned to the hospital, where she was diagnosed with toxic epidermal necrolysis. She was found to have a desquamating rash covering 62% of her body. The patient was transferred to a burn center but eventually succumbed to multi-organ failure.

The patient’s estate filed a medical malpractice lawsuit against the nephrologist alleging negligence—specifically, failure to diagnose toxic epidermal necrolysis and failure to review her medications more carefully.

Continue for the outcome >>

OUTCOME
A $5.1 million verdict was returned against the nephrologist.

COMMENT
Many medications cause rash and are subsequently withdrawn; in a few cases, the effects are life threatening. Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are relatively uncommon but potentially fatal examples.

From the limited facts presented, we know that a 54-year-old woman with established renal disease of unknown magnitude was prescribed allopurinol for gout and consulted the nephrologist two days later. It is unclear if the patient had the rash during the first visit with her nephrologist. But we do know that she was eventually admitted and maintained on allopurinol while she had the rash, pending infectious disease consultation. At some point, the allopurinol was apparently stopped and the rash improved. After discharge, the patient resumed taking allopurinol. The rash not only returned but also worsened, necessitating her readmission to a burn center.

TEN, like SJS, is often induced by certain medications, including sulfonamides, macrolides, penicillins, and quinolones. Allopur­inol, phenobarbital, phenytoin, carbamazepine, valproic acid, and lamotrigine are frequently implicated as well.

TEN is rare but serious. The initial presentation may be subtle, with influenza-like symptoms such as malaise, fever, cough, rhinitis, headache, and arthralgia—and the most discriminating sign: rash.

The rash begins as a poorly defined, erythematous macular rash with purpuric centers. The lesions predominate on the torso and face, sparing the scalp. Mucosal membranes are involved in more than 90% of cases.¹ Pain at the site of the skin lesions is often the predominate symptom and is often out of proportion to physical findings. Over a period of hours to days, the rash coalesces to form flaccid blisters and sheetlike epidermal detachment.² In established cases, patients will nearly universally demonstrate Nikolsky’s sign: Mild frictional contact with the skin results in epithelial desquamation and immediate blistering.

Management involves immediate withdrawal of the offending agent and hospitalization for aggressive management. The mortality rate is high (30% to 60%³) and generally attributed to sepsis or multi-organ failure.

As clinicians, we are sometimes hesitant to label a rash allergic—thereby forever disqualifying an entire class of useful agents from that patient. However, in this case, the fact that the rash occurred simultaneously with a constellation of signs and symptoms perhaps made the rash appear to be part of an infectious process and not a drug-induced reaction. That is the challenge with TEN and SJS: The symptoms are subtle, flu-like, and confounding.

Here, the nephrologist apparently did not take action to stop the allopurinol after the patient first developed the rash. The jury was persuaded that a reasonably prudent clinician would have recognized the clinical presentation and stopped the allopurinol—and certainly not restarted it following discharge (especially after the allopurinol was stopped in the hospital and the rash began to improve).

This case brings to mind two physicians from my training who made an impression. The first was a second-year internal medicine resident. I remember quietly remarking to another student during rounds, “He is really good.” Overhearing, an attending physician answered, “He is really good because in his workup he always considers a presentation as a function of an underlying process, and walks through each of those processes in formulating his differential.”

“Walking through” various disease categories forces the clinician to consider them all: infectious, autoimmune, neoplastic, environmental/toxic, vascular, traumatic, metabolic, inflammatory. In challenging cases, I’ve found it helpful to step backward into those broad basic categories of disease and reconsider the clinical picture.

Here, doing so may have allowed the clinician to reconsider inflammatory and autoimmune processes and revisit the possibility of iatrogenic toxic/environmental causes (ie, the allopurinol). Perhaps the outcome of this case would have been different.

The second physician was a nephrology fellow, who left me with this piece of wisdom: “When in doubt, blame the drug.” Since nephrologists are expert drug-blamers, I suspect the early stages of this unfortunate case presented a clinical challenge.

IN SUM 
Before you “missile lock” onto a diagnosis, take a mental step back to consider broad categories of disease. —DML

REFERENCES
1. Letko E, Papaliodis DN, Papaliodis GN, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: a review of the literature. Ann Allergy Asthma Immunol. 2005;94(4):419-436.
2. Cohen V, Jellinek SP, Schwartz RA, et al. Toxic epidermal necrolysis.  Medscape; 2013. emedicine.medscape.com/article/229698-overview. Accessed September 16, 2015.
3. Schulz JT, Sheridan RL, Ryan CM, et al. A 10-year experience with toxic epidermal necrolysis. J Burn Care Rehabil. 2000;21(3): 199-204.

A 54-year-old woman with chronic renal disease was diagnosed with gout and prescribed allopurinol. Two days later, she was evaluated by her nephrologist, whom she informed about her new medication.

Subsequently, the patient developed fever and rash. Laboratory analysis indicated elevated transaminase levels and eosinophilia. She was admitted to the hospital.

During her stay, an infectious disease consultation was obtained, and the allopurinol was discontinued. When the patient’s condition improved, she was discharged.

Following discharge, the patient resumed taking allopurinol, and her rash returned. Eleven days later, she returned to the hospital, where she was diagnosed with toxic epidermal necrolysis. She was found to have a desquamating rash covering 62% of her body. The patient was transferred to a burn center but eventually succumbed to multi-organ failure.

The patient’s estate filed a medical malpractice lawsuit against the nephrologist alleging negligence—specifically, failure to diagnose toxic epidermal necrolysis and failure to review her medications more carefully.

Continue for the outcome >>

OUTCOME
A $5.1 million verdict was returned against the nephrologist.

COMMENT
Many medications cause rash and are subsequently withdrawn; in a few cases, the effects are life threatening. Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are relatively uncommon but potentially fatal examples.

From the limited facts presented, we know that a 54-year-old woman with established renal disease of unknown magnitude was prescribed allopurinol for gout and consulted the nephrologist two days later. It is unclear if the patient had the rash during the first visit with her nephrologist. But we do know that she was eventually admitted and maintained on allopurinol while she had the rash, pending infectious disease consultation. At some point, the allopurinol was apparently stopped and the rash improved. After discharge, the patient resumed taking allopurinol. The rash not only returned but also worsened, necessitating her readmission to a burn center.

TEN, like SJS, is often induced by certain medications, including sulfonamides, macrolides, penicillins, and quinolones. Allopur­inol, phenobarbital, phenytoin, carbamazepine, valproic acid, and lamotrigine are frequently implicated as well.

TEN is rare but serious. The initial presentation may be subtle, with influenza-like symptoms such as malaise, fever, cough, rhinitis, headache, and arthralgia—and the most discriminating sign: rash.

The rash begins as a poorly defined, erythematous macular rash with purpuric centers. The lesions predominate on the torso and face, sparing the scalp. Mucosal membranes are involved in more than 90% of cases.¹ Pain at the site of the skin lesions is often the predominate symptom and is often out of proportion to physical findings. Over a period of hours to days, the rash coalesces to form flaccid blisters and sheetlike epidermal detachment.² In established cases, patients will nearly universally demonstrate Nikolsky’s sign: Mild frictional contact with the skin results in epithelial desquamation and immediate blistering.

Management involves immediate withdrawal of the offending agent and hospitalization for aggressive management. The mortality rate is high (30% to 60%³) and generally attributed to sepsis or multi-organ failure.

As clinicians, we are sometimes hesitant to label a rash allergic—thereby forever disqualifying an entire class of useful agents from that patient. However, in this case, the fact that the rash occurred simultaneously with a constellation of signs and symptoms perhaps made the rash appear to be part of an infectious process and not a drug-induced reaction. That is the challenge with TEN and SJS: The symptoms are subtle, flu-like, and confounding.

Here, the nephrologist apparently did not take action to stop the allopurinol after the patient first developed the rash. The jury was persuaded that a reasonably prudent clinician would have recognized the clinical presentation and stopped the allopurinol—and certainly not restarted it following discharge (especially after the allopurinol was stopped in the hospital and the rash began to improve).

This case brings to mind two physicians from my training who made an impression. The first was a second-year internal medicine resident. I remember quietly remarking to another student during rounds, “He is really good.” Overhearing, an attending physician answered, “He is really good because in his workup he always considers a presentation as a function of an underlying process, and walks through each of those processes in formulating his differential.”

“Walking through” various disease categories forces the clinician to consider them all: infectious, autoimmune, neoplastic, environmental/toxic, vascular, traumatic, metabolic, inflammatory. In challenging cases, I’ve found it helpful to step backward into those broad basic categories of disease and reconsider the clinical picture.

Here, doing so may have allowed the clinician to reconsider inflammatory and autoimmune processes and revisit the possibility of iatrogenic toxic/environmental causes (ie, the allopurinol). Perhaps the outcome of this case would have been different.

The second physician was a nephrology fellow, who left me with this piece of wisdom: “When in doubt, blame the drug.” Since nephrologists are expert drug-blamers, I suspect the early stages of this unfortunate case presented a clinical challenge.

IN SUM 
Before you “missile lock” onto a diagnosis, take a mental step back to consider broad categories of disease. —DML

REFERENCES
1. Letko E, Papaliodis DN, Papaliodis GN, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: a review of the literature. Ann Allergy Asthma Immunol. 2005;94(4):419-436.
2. Cohen V, Jellinek SP, Schwartz RA, et al. Toxic epidermal necrolysis.  Medscape; 2013. emedicine.medscape.com/article/229698-overview. Accessed September 16, 2015.
3. Schulz JT, Sheridan RL, Ryan CM, et al. A 10-year experience with toxic epidermal necrolysis. J Burn Care Rehabil. 2000;21(3): 199-204.

A 54-year-old woman with chronic renal disease was diagnosed with gout and prescribed allopurinol. Two days later, she was evaluated by her nephrologist, whom she informed about her new medication.

Subsequently, the patient developed fever and rash. Laboratory analysis indicated elevated transaminase levels and eosinophilia. She was admitted to the hospital.

During her stay, an infectious disease consultation was obtained, and the allopurinol was discontinued. When the patient’s condition improved, she was discharged.

Following discharge, the patient resumed taking allopurinol, and her rash returned. Eleven days later, she returned to the hospital, where she was diagnosed with toxic epidermal necrolysis. She was found to have a desquamating rash covering 62% of her body. The patient was transferred to a burn center but eventually succumbed to multi-organ failure.

The patient’s estate filed a medical malpractice lawsuit against the nephrologist alleging negligence—specifically, failure to diagnose toxic epidermal necrolysis and failure to review her medications more carefully.

Continue for the outcome >>

OUTCOME
A $5.1 million verdict was returned against the nephrologist.

COMMENT
Many medications cause rash and are subsequently withdrawn; in a few cases, the effects are life threatening. Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are relatively uncommon but potentially fatal examples.

From the limited facts presented, we know that a 54-year-old woman with established renal disease of unknown magnitude was prescribed allopurinol for gout and consulted the nephrologist two days later. It is unclear if the patient had the rash during the first visit with her nephrologist. But we do know that she was eventually admitted and maintained on allopurinol while she had the rash, pending infectious disease consultation. At some point, the allopurinol was apparently stopped and the rash improved. After discharge, the patient resumed taking allopurinol. The rash not only returned but also worsened, necessitating her readmission to a burn center.

TEN, like SJS, is often induced by certain medications, including sulfonamides, macrolides, penicillins, and quinolones. Allopur­inol, phenobarbital, phenytoin, carbamazepine, valproic acid, and lamotrigine are frequently implicated as well.

TEN is rare but serious. The initial presentation may be subtle, with influenza-like symptoms such as malaise, fever, cough, rhinitis, headache, and arthralgia—and the most discriminating sign: rash.

The rash begins as a poorly defined, erythematous macular rash with purpuric centers. The lesions predominate on the torso and face, sparing the scalp. Mucosal membranes are involved in more than 90% of cases.¹ Pain at the site of the skin lesions is often the predominate symptom and is often out of proportion to physical findings. Over a period of hours to days, the rash coalesces to form flaccid blisters and sheetlike epidermal detachment.² In established cases, patients will nearly universally demonstrate Nikolsky’s sign: Mild frictional contact with the skin results in epithelial desquamation and immediate blistering.

Management involves immediate withdrawal of the offending agent and hospitalization for aggressive management. The mortality rate is high (30% to 60%³) and generally attributed to sepsis or multi-organ failure.

As clinicians, we are sometimes hesitant to label a rash allergic—thereby forever disqualifying an entire class of useful agents from that patient. However, in this case, the fact that the rash occurred simultaneously with a constellation of signs and symptoms perhaps made the rash appear to be part of an infectious process and not a drug-induced reaction. That is the challenge with TEN and SJS: The symptoms are subtle, flu-like, and confounding.

Here, the nephrologist apparently did not take action to stop the allopurinol after the patient first developed the rash. The jury was persuaded that a reasonably prudent clinician would have recognized the clinical presentation and stopped the allopurinol—and certainly not restarted it following discharge (especially after the allopurinol was stopped in the hospital and the rash began to improve).

This case brings to mind two physicians from my training who made an impression. The first was a second-year internal medicine resident. I remember quietly remarking to another student during rounds, “He is really good.” Overhearing, an attending physician answered, “He is really good because in his workup he always considers a presentation as a function of an underlying process, and walks through each of those processes in formulating his differential.”

“Walking through” various disease categories forces the clinician to consider them all: infectious, autoimmune, neoplastic, environmental/toxic, vascular, traumatic, metabolic, inflammatory. In challenging cases, I’ve found it helpful to step backward into those broad basic categories of disease and reconsider the clinical picture.

Here, doing so may have allowed the clinician to reconsider inflammatory and autoimmune processes and revisit the possibility of iatrogenic toxic/environmental causes (ie, the allopurinol). Perhaps the outcome of this case would have been different.

The second physician was a nephrology fellow, who left me with this piece of wisdom: “When in doubt, blame the drug.” Since nephrologists are expert drug-blamers, I suspect the early stages of this unfortunate case presented a clinical challenge.

IN SUM 
Before you “missile lock” onto a diagnosis, take a mental step back to consider broad categories of disease. —DML

REFERENCES
1. Letko E, Papaliodis DN, Papaliodis GN, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: a review of the literature. Ann Allergy Asthma Immunol. 2005;94(4):419-436.
2. Cohen V, Jellinek SP, Schwartz RA, et al. Toxic epidermal necrolysis.  Medscape; 2013. emedicine.medscape.com/article/229698-overview. Accessed September 16, 2015.
3. Schulz JT, Sheridan RL, Ryan CM, et al. A 10-year experience with toxic epidermal necrolysis. J Burn Care Rehabil. 2000;21(3): 199-204.

THE CASE

A 71-year-old woman came to our clinic with a left subconjunctival hemorrhage. She had a history of atrial flutter and had received a liver transplant approximately 10 years ago. The patient reported having a procedure 2 weeks before her visit with us to remove a basal cell carcinoma on her lower left eyelid, but had no recent changes in vision or physical damage to the eye.

In the past year, she had been started on dabigatran 150 mg twice daily after developing symptomatic atrial fibrillation. Our patient had also been receiving tacrolimus 3 mg twice daily since her transplant. Other medications she was taking included hydroxychloroquine 200 mg/d for rheumatoid arthritis, propafenone 225 mg twice daily for atrial fibrillation, valsartan 80 mg/d for hypertension, and ranitidine 150 mg/d for reflux.

Venipuncture coagulation tests showed a partial thromboplastin time (PTT) of 75.1 seconds, a prothrombin time (PT) of 46.1 seconds, and an elevated international normalized ratio (INR) of 4.5 (normal range: 0.8-1.2). Point-of-care INR results were not obtained.

A complete blood count (CBC) was unremarkable with the exception of a low platelet count and high red blood cell distribution width (RDW). Our patient’s aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were both within normal limits.

Kidney function tests told another story. The patient’s serum creatinine (SCr) and blood urea nitrogen (BUN) levels were elevated (1.54 mg/dL and 29 mg/dL, respectively) and her creatinine clearance (CrCl; 30.2 mL/min) suggested moderate to severe renal dysfunction.

The patient’s CHADS₂ score was calculated as 1, suggesting she had a low-to-moderate risk of stroke.

THE DIAGNOSIS

Our patient had a left subconjunctival hemorrhage and an elevated venipuncture INR. Based on her renal dysfunction, we suspected that her elevated INR was likely due to an excessive dose of dabigatran, as well as an interaction between dabigatran and tacrolimus.

DISCUSSION

Dabigatran is an oral direct thrombin inhibitor approved for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. An important advantage of dabigatran compared to warfarin is that the fixed-dose regimen does not require routine anticoagulation monitoring. In cases where anticoagulation monitoring is needed, PTT is the preferred method.¹

While PT and INR have generally not been shown to accurately reflect the degree of anticoagulation with dabigatran at therapeutic doses, there have been in vitro reports of elevated INRs with supratherapeutic dabigatran levels.^2,3 At a typical peak therapeutic dabigatran concentration of approximately 184 ng/mL, the INR generally ranged from 1.1 to 1.7.² However, at a dabigatran concentration of 1000 ng/mL, the INR was elevated to 4.5,^2,3 which is the same venipuncture INR recorded in our patient. While there have been published reports of falsely elevated point-of-care INR results compared to corresponding venipuncture INR results in patients taking dabigatran,^4,5 a literature review found only a case of an elevated venipuncture INR in an end-stage renal disease patient receiving hemodialysis.⁶

Concurrent use of any P-gp inhibitor (such as tacrolimus) and dabigatran is contraindicated in patients with severe renal dysfunction.

In the case noted above, as well as our patient, an accumulation of dabigatran due to the patient’s renal dysfunction likely resulted in high plasma concentrations and therefore an elevated venipuncture INR. The elimination half-life for dabigatran is approximately 14 hours in patients with normal renal function; in a patient with severe renal impairment, the half-life can be up to 28 hours.⁷ Our patient’s CrCl at the time of presentation was 30.2 mL/min, which indicated moderate to severe renal dysfunction. Based on dabigatran prescribing recommendations, a dose adjustment to 75 mg bid might be appropriate.¹ (Our patient was taking 150 mg bid.)

We do not believe our patient’s elevated INR was due to her liver transplant because there were no clinical signs of liver dysfunction. A more likely contributing factor was a drug interaction with tacrolimus. Dabigatran is a moderate affinity P-glycoprotein (P-gp) substrate and tacrolimus is both a P-gp substrate and inhibitor. While an interaction between tacrolimus and dabigatran has not been studied directly, concurrent use of any P-gp inhibitor and dabigatran is contraindicated in patients with severe renal dysfunction (CrCl: 15-30 mL/min).¹ For these theoretical interactions, the Drug Interaction Probability Scale (DIPS) has been developed.⁸ In our patient’s case, the calculated DIPS score of 5 suggests a probable interaction, likely due to P-gp inhibition. The other medications our patient was taking did not have this interaction and were unlikely to contribute to the elevated INR and subconjunctival hemorrhage.

Our patient was instructed to stop taking dabigatran and return in 3 days for additional lab tests. At her follow-up visit, the lab results were PTT, 34.3 seconds; PT, 11.6 seconds; and venipuncture INR, 1.1. Her CBC was unremarkable and unchanged. Shortly after the follow-up visit, our patient was assessed by her cardiologist. Due to her renal dysfunction, risk of bleeding, and relatively low CHADS₂ score, the cardiologist decided to discontinue dabigatran and start her on aspirin.

THE TAKEAWAY

Dabigatran may cause elevated INR levels in patients with renal dysfunction and/or those taking other medications that could interact with dabigatran. Concurrent use of any P-gp inhibitor (such as tacrolimus) and dabigatran is contraindicated in patients with severe renal dysfunction. Despite the lack of required routine laboratory monitoring, renal function and drug interactions associated with dabigatran therapy should be monitored closely.

THE CASE

A 71-year-old woman came to our clinic with a left subconjunctival hemorrhage. She had a history of atrial flutter and had received a liver transplant approximately 10 years ago. The patient reported having a procedure 2 weeks before her visit with us to remove a basal cell carcinoma on her lower left eyelid, but had no recent changes in vision or physical damage to the eye.

In the past year, she had been started on dabigatran 150 mg twice daily after developing symptomatic atrial fibrillation. Our patient had also been receiving tacrolimus 3 mg twice daily since her transplant. Other medications she was taking included hydroxychloroquine 200 mg/d for rheumatoid arthritis, propafenone 225 mg twice daily for atrial fibrillation, valsartan 80 mg/d for hypertension, and ranitidine 150 mg/d for reflux.

Venipuncture coagulation tests showed a partial thromboplastin time (PTT) of 75.1 seconds, a prothrombin time (PT) of 46.1 seconds, and an elevated international normalized ratio (INR) of 4.5 (normal range: 0.8-1.2). Point-of-care INR results were not obtained.

A complete blood count (CBC) was unremarkable with the exception of a low platelet count and high red blood cell distribution width (RDW). Our patient’s aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were both within normal limits.

Kidney function tests told another story. The patient’s serum creatinine (SCr) and blood urea nitrogen (BUN) levels were elevated (1.54 mg/dL and 29 mg/dL, respectively) and her creatinine clearance (CrCl; 30.2 mL/min) suggested moderate to severe renal dysfunction.

The patient’s CHADS₂ score was calculated as 1, suggesting she had a low-to-moderate risk of stroke.

THE DIAGNOSIS

Our patient had a left subconjunctival hemorrhage and an elevated venipuncture INR. Based on her renal dysfunction, we suspected that her elevated INR was likely due to an excessive dose of dabigatran, as well as an interaction between dabigatran and tacrolimus.

DISCUSSION

Dabigatran is an oral direct thrombin inhibitor approved for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. An important advantage of dabigatran compared to warfarin is that the fixed-dose regimen does not require routine anticoagulation monitoring. In cases where anticoagulation monitoring is needed, PTT is the preferred method.¹

While PT and INR have generally not been shown to accurately reflect the degree of anticoagulation with dabigatran at therapeutic doses, there have been in vitro reports of elevated INRs with supratherapeutic dabigatran levels.^2,3 At a typical peak therapeutic dabigatran concentration of approximately 184 ng/mL, the INR generally ranged from 1.1 to 1.7.² However, at a dabigatran concentration of 1000 ng/mL, the INR was elevated to 4.5,^2,3 which is the same venipuncture INR recorded in our patient. While there have been published reports of falsely elevated point-of-care INR results compared to corresponding venipuncture INR results in patients taking dabigatran,^4,5 a literature review found only a case of an elevated venipuncture INR in an end-stage renal disease patient receiving hemodialysis.⁶

Concurrent use of any P-gp inhibitor (such as tacrolimus) and dabigatran is contraindicated in patients with severe renal dysfunction.

In the case noted above, as well as our patient, an accumulation of dabigatran due to the patient’s renal dysfunction likely resulted in high plasma concentrations and therefore an elevated venipuncture INR. The elimination half-life for dabigatran is approximately 14 hours in patients with normal renal function; in a patient with severe renal impairment, the half-life can be up to 28 hours.⁷ Our patient’s CrCl at the time of presentation was 30.2 mL/min, which indicated moderate to severe renal dysfunction. Based on dabigatran prescribing recommendations, a dose adjustment to 75 mg bid might be appropriate.¹ (Our patient was taking 150 mg bid.)

We do not believe our patient’s elevated INR was due to her liver transplant because there were no clinical signs of liver dysfunction. A more likely contributing factor was a drug interaction with tacrolimus. Dabigatran is a moderate affinity P-glycoprotein (P-gp) substrate and tacrolimus is both a P-gp substrate and inhibitor. While an interaction between tacrolimus and dabigatran has not been studied directly, concurrent use of any P-gp inhibitor and dabigatran is contraindicated in patients with severe renal dysfunction (CrCl: 15-30 mL/min).¹ For these theoretical interactions, the Drug Interaction Probability Scale (DIPS) has been developed.⁸ In our patient’s case, the calculated DIPS score of 5 suggests a probable interaction, likely due to P-gp inhibition. The other medications our patient was taking did not have this interaction and were unlikely to contribute to the elevated INR and subconjunctival hemorrhage.

Our patient was instructed to stop taking dabigatran and return in 3 days for additional lab tests. At her follow-up visit, the lab results were PTT, 34.3 seconds; PT, 11.6 seconds; and venipuncture INR, 1.1. Her CBC was unremarkable and unchanged. Shortly after the follow-up visit, our patient was assessed by her cardiologist. Due to her renal dysfunction, risk of bleeding, and relatively low CHADS₂ score, the cardiologist decided to discontinue dabigatran and start her on aspirin.

THE TAKEAWAY

Dabigatran may cause elevated INR levels in patients with renal dysfunction and/or those taking other medications that could interact with dabigatran. Concurrent use of any P-gp inhibitor (such as tacrolimus) and dabigatran is contraindicated in patients with severe renal dysfunction. Despite the lack of required routine laboratory monitoring, renal function and drug interactions associated with dabigatran therapy should be monitored closely.

THE CASE

A 71-year-old woman came to our clinic with a left subconjunctival hemorrhage. She had a history of atrial flutter and had received a liver transplant approximately 10 years ago. The patient reported having a procedure 2 weeks before her visit with us to remove a basal cell carcinoma on her lower left eyelid, but had no recent changes in vision or physical damage to the eye.

In the past year, she had been started on dabigatran 150 mg twice daily after developing symptomatic atrial fibrillation. Our patient had also been receiving tacrolimus 3 mg twice daily since her transplant. Other medications she was taking included hydroxychloroquine 200 mg/d for rheumatoid arthritis, propafenone 225 mg twice daily for atrial fibrillation, valsartan 80 mg/d for hypertension, and ranitidine 150 mg/d for reflux.

Venipuncture coagulation tests showed a partial thromboplastin time (PTT) of 75.1 seconds, a prothrombin time (PT) of 46.1 seconds, and an elevated international normalized ratio (INR) of 4.5 (normal range: 0.8-1.2). Point-of-care INR results were not obtained.

A complete blood count (CBC) was unremarkable with the exception of a low platelet count and high red blood cell distribution width (RDW). Our patient’s aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were both within normal limits.

Kidney function tests told another story. The patient’s serum creatinine (SCr) and blood urea nitrogen (BUN) levels were elevated (1.54 mg/dL and 29 mg/dL, respectively) and her creatinine clearance (CrCl; 30.2 mL/min) suggested moderate to severe renal dysfunction.

The patient’s CHADS₂ score was calculated as 1, suggesting she had a low-to-moderate risk of stroke.

THE DIAGNOSIS

Our patient had a left subconjunctival hemorrhage and an elevated venipuncture INR. Based on her renal dysfunction, we suspected that her elevated INR was likely due to an excessive dose of dabigatran, as well as an interaction between dabigatran and tacrolimus.

DISCUSSION

Dabigatran is an oral direct thrombin inhibitor approved for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. An important advantage of dabigatran compared to warfarin is that the fixed-dose regimen does not require routine anticoagulation monitoring. In cases where anticoagulation monitoring is needed, PTT is the preferred method.¹

While PT and INR have generally not been shown to accurately reflect the degree of anticoagulation with dabigatran at therapeutic doses, there have been in vitro reports of elevated INRs with supratherapeutic dabigatran levels.^2,3 At a typical peak therapeutic dabigatran concentration of approximately 184 ng/mL, the INR generally ranged from 1.1 to 1.7.² However, at a dabigatran concentration of 1000 ng/mL, the INR was elevated to 4.5,^2,3 which is the same venipuncture INR recorded in our patient. While there have been published reports of falsely elevated point-of-care INR results compared to corresponding venipuncture INR results in patients taking dabigatran,^4,5 a literature review found only a case of an elevated venipuncture INR in an end-stage renal disease patient receiving hemodialysis.⁶

Concurrent use of any P-gp inhibitor (such as tacrolimus) and dabigatran is contraindicated in patients with severe renal dysfunction.

In the case noted above, as well as our patient, an accumulation of dabigatran due to the patient’s renal dysfunction likely resulted in high plasma concentrations and therefore an elevated venipuncture INR. The elimination half-life for dabigatran is approximately 14 hours in patients with normal renal function; in a patient with severe renal impairment, the half-life can be up to 28 hours.⁷ Our patient’s CrCl at the time of presentation was 30.2 mL/min, which indicated moderate to severe renal dysfunction. Based on dabigatran prescribing recommendations, a dose adjustment to 75 mg bid might be appropriate.¹ (Our patient was taking 150 mg bid.)

We do not believe our patient’s elevated INR was due to her liver transplant because there were no clinical signs of liver dysfunction. A more likely contributing factor was a drug interaction with tacrolimus. Dabigatran is a moderate affinity P-glycoprotein (P-gp) substrate and tacrolimus is both a P-gp substrate and inhibitor. While an interaction between tacrolimus and dabigatran has not been studied directly, concurrent use of any P-gp inhibitor and dabigatran is contraindicated in patients with severe renal dysfunction (CrCl: 15-30 mL/min).¹ For these theoretical interactions, the Drug Interaction Probability Scale (DIPS) has been developed.⁸ In our patient’s case, the calculated DIPS score of 5 suggests a probable interaction, likely due to P-gp inhibition. The other medications our patient was taking did not have this interaction and were unlikely to contribute to the elevated INR and subconjunctival hemorrhage.

Our patient was instructed to stop taking dabigatran and return in 3 days for additional lab tests. At her follow-up visit, the lab results were PTT, 34.3 seconds; PT, 11.6 seconds; and venipuncture INR, 1.1. Her CBC was unremarkable and unchanged. Shortly after the follow-up visit, our patient was assessed by her cardiologist. Due to her renal dysfunction, risk of bleeding, and relatively low CHADS₂ score, the cardiologist decided to discontinue dabigatran and start her on aspirin.

THE TAKEAWAY

Dabigatran may cause elevated INR levels in patients with renal dysfunction and/or those taking other medications that could interact with dabigatran. Concurrent use of any P-gp inhibitor (such as tacrolimus) and dabigatran is contraindicated in patients with severe renal dysfunction. Despite the lack of required routine laboratory monitoring, renal function and drug interactions associated with dabigatran therapy should be monitored closely.

Sickle cell disease is a common genetic disorder in the United States that disproportionately affects people of African ancestry. The characteristic sickling of red blood cells under conditions of reduced oxygen tension leads to intravascular hemolysis and vaso-occlusive events, which in turn cause tissue ischemia-reperfusion injury affecting multiple organs, including the genitourinary system.^1–3

In this paper, we review the genitourinary effects of sickle cell disease, focusing on sickle cell nephropathy, priapism, and renal medullary carcinoma.

THE WIDE-RANGING EFFECTS OF SICKLE CELL DISEASE

In the United States, sickle cell disease affects 1 of every 500 blacks and 1 of every 36,000 Hispanics.¹ The term describes hemoglobinopathies associated with sickling of red blood cells.

Sickling of red blood cells results from a single base-pair change in the beta-globin gene from glutamic acid to valine at position 6, causing abnormal hemoglobin (hemoglobin S), which polymerizes under conditions of reduced oxygen tension and alters the biconcave disk shape into a rigid, irregular, unstable cell. The sickle-shaped cells are prone to intravascular hemolysis,² causing intermittent vaso-occlusive events that result in tissue ischemia-reperfusion injury. Genitourinary problems include impaired ability to concentrate urine, hematuria, renal medullary carcinoma, and increased frequency of urinary tract infection.

SICKLE CELL NEPHROPATHY

Signs of kidney involvement may appear in early childhood

The kidney is one of the most frequently affected organs in sickle cell disease. Renal manifestations begin to appear in early childhood, with impaired medullary concentrating ability and ischemic damage to the tubular cells caused by sickling within the vasa recta renis precipitated by the acidic, hypoxic, and hypertonic environment in the renal medulla.

As in early diabetic nephropathy, renal blood flow is enhanced and the glomerular filtration rate (GFR) is increased. Increased cardiac output as a result of anemia, localized release of prostaglandins, and a hypoxia-induced increase in nitric oxide synthesis all play a role in the increase in GFR.^4,5

Oxidative stress, an increase in markers of inflammation, and local activation of the renin-angiotensin system contribute to renal damage in sickle cell disease.^5–7 The resulting hyperfiltration injury leads to microalbuminuria, which occurs in 20% to 40% of children with sickle cell anemia^8,9 and in as many as 60% of adults.

The glomerular lesions associated with sickle cell disease vary from glomerulopathy in the early stages to secondary focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, and glomerular thrombotic microangiopathy.¹⁰

Clinical presentations and workup

Clinical presentations are not limited to glomerular disease but include hyperchloremic metabolic acidosis and hyperkalemia resulting from defects in potassium secretion and renal acidification.

Hyperphosphatemia—a result of increased reabsorption of phosphorus, increased secretion of uric acid, and increased creatinine clearance—is seen in patients with sickle cell disease.^11,12 About 10% of patients can develop an acute kidney injury as a result of volume depletion, rhabdomyolysis, renal vein thrombosis, papillary necrosis, and urinary tract obstruction secondary to blood clots.^11,13

Up to 30% of adult patients with sickle cell disease develop chronic kidney disease. Predictors include severe anemia, hypertension, proteinuria, nephrotic syndrome, and microscopic hematuria.¹⁴ From 4% to 12% of patients go on to develop end-stage renal disease, but with a 1-year mortality rate three times higher than in patients without sickle cell disease.¹⁵

In general, patients with sickle cell anemia have blood pressures below those of age- and sex-matched individuals, but elevated blood pressure and low GFR are not uncommon in affected children. In a cohort of 48 children ages 3 to 18, 8.3% had an estimated GFR less than 90 mL/min/1.73 m², and 16.7% had elevated blood pressure (prehypertension and hypertension).¹⁶

In patients with sickle cell disease, evaluation of proteinuria, hematuria, hypertension, and renal failure should take into consideration the unique renal physiologic and pathologic processes involved. Recent evidence^17,18 suggests that the Chronic Kidney Disease Epidemiology Collaboration equation provides a better estimate of GFR than the Modification of Diet in Renal Disease and Cockcroft-Gault equations, although all three creatinine-based methods overestimate GFR in patients with sickle cell disease when compared with GFR measured with technetium-99m-labeled diethylenetriamine penta-acetic acid renal scanning.

Treatment options

Treatment of sickle cell nephropathy includes adequate fluid intake (given the loss of concentrating ability), adequate blood pressure control, use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) in patients who have microalbuminuria or proteinuria (or both)^9,11,19 and hydroxyurea. Treatment with enalapril has been shown to decrease proteinuria in patients with sickle cell nephropathy.⁹ In a cohort of children with sickle cell disease, four of nine patients treated with an ACE inhibitor developed hyperkalemia, leading to discontinuation of the drug in three patients.⁹

ACE inhibitors and ARBs must be used cautiously in these patients because they have defects in potassium secretion. Hydroxyurea has also been shown to decrease hyperfiltration and microalbuminuria in recent studies,^20,21 and this could protect against the development of overt nephropathy.

Higher mortality rates have been reported in patients with sickle cell disease who developed end-stage renal disease than in patients with end-stage renal disease without sickle cell disease. Sickle cell disease also increases the risk of pulmonary hypertension and the vaso-occlusive complication known as acute chest syndrome, contributing to increased mortality rates. Of note, in a study that looked at the association between mortality rates and pre-end-stage care of renal disease using data from the Centers for Medicare and Medicaid Services, patients with sickle cell disease who had had predialysis nephrology care had lower mortality rates.¹⁵

Treatments for end-stage renal disease are also effective in patients with sickle cell disease and include hemodialysis, peritoneal dialysis, and transplantation

Treatments for end-stage renal disease are also effective in patients with sickle cell disease and include hemodialysis, peritoneal dialysis, and renal transplantation. Data from the Organ Procurement and Transplantation Network and the United Network for Organ Sharing show that from 2000 to 2011, African American kidney recipients with sickle cell disease had better survival rates than patients who had undergone transplantation from 1988 to 1999, although rates of long-term survival and graft survival were lower than in transplant recipients with other diagnoses.²²

It is important to note that complications as a result of vaso-occlusive events and thrombosis can lead to graft loss; therefore, sickle cell crisis after transplantation requires careful management.

Take-home messages

• Loss of urine-concentrating ability and hyperfiltration are the earliest pathologic changes in sickle cell disease.
• Microalbuminuria as seen in diabetic nephropathy is the earliest manifestation of sickle cell nephropathy, and the prevalence increases as these patients get older and live longer.
• ACE inhibitors or ARBs should be used with caution, given the heightened risk of hyperkalemia in sickle cell disease.
• Recent results with hydroxyurea in decreasing hyperfiltration and microalbuminuria are encouraging.
• Early referral for predialysis nephrologic care is needed in sickle cell patients with chronic kidney disease.

PRIAPISM IN SICKLE CELL DISEASE

Priapism was formerly defined as a full, painful erection lasting more than 4 hours and unrelated to sexual stimulation or orgasm. But priapism is now recognized as two separate disorders—ischemic (veno-occlusive, low-flow) priapism and nonischemic (arterial, high-flow) priapism. The new definition includes both disorders: ie, a full or partial erection lasting more than 4 hours and unrelated to sexual stimulation or orgasm.

Ischemic priapism

Hematologic disorders are major contributors to ischemic priapism and include sickle cell disease, multiple myeloma, fat emboli (hyperalimentation),²³ glucose-6-phosphate dehydrogenase deficiency, and hemoglobin Olmsted variant.²⁴

Ischemic priapism is often seen in sickle cell disease and is considered an emergency. It is characterized by an abnormally rigid erection not involving the glans penis. Entrapment of blood in the corpora cavernosa leads to hypoxia, hypercarbia, and acidosis, which in turn leads to a painful compartment syndrome that, if untreated, results in smooth muscle necrosis and subsequent fibrosis. The results are a smaller penis and erectile dysfunction that is unresponsive to any treatment other than implantation of a penile prosthesis. However, scarring of the corpora cavernosa can make this procedure exceedingly difficult, requiring advanced techniques such as corporeal excavation.²⁵

Men with a subtype of ischemic priapism called “stuttering” priapism²⁶ suffer recurrent prolonged erections during sleep. The patient awakens with a painful erection that usually subsides, but sometimes only after several hours. Patients with this disorder suffer from sleep deprivation. Stuttering priapism may lead to full-blown ischemic priapism that does not resolve without intervention.

Nonischemic priapism

In nonischemic priapism, the corpora are engorged but not rigid. The condition results from unregulated arterial inflow and thus is not painful and does not result in damage to the corporeal smooth muscle.

Most cases of nonischemic priapism follow blunt perineal trauma or trauma associated with needle insertion into the corpora. This form of priapism is not associated with sickle cell disease. Because tissue damage does not occur, nonischemic or arterial priapism is not considered an emergency.

Treatment guidelines

Differentiating ischemic from nonischemic priapism is usually straightforward, based on the history, physical examination, corporeal blood gases, and duplex ultrasonography.²⁷

Ischemic priapism is an emergency. After needle aspiration of blood from the corpora cavernosa, phenylephrine is diluted with normal saline to a concentration of 100 to 500 µg/mL and is injected in 1-mL amounts repeatedly at 3- to 5-minute intervals until the erection subsides or until a 1-hour time limit is reached. Blood pressure and pulse are monitored during these injections. If aspiration and phenylephrine irrigation fail, surgical shunting is performed.²⁷

Measures to treat sickle cell disease (hydration, oxygen, exchange transfusions) may be employed simultaneously but should never delay aspiration and phenylephrine injections.²⁵

Early referral for predialysis nephrologic care is needed in sickle cell patients with chronic kidney disease

As nonischemic priapism is not considered an emergency, management begins with observation. Patients eventually become dissatisfied with their constant partial erection, and they then present for treatment. Most cases resolve after selective catheterization of the internal pudendal artery and embolization of the fistula with absorbable material. If this fails, surgical exploration with ligation of the vessels leading to the fistula is indicated.

Prevalence in sickle cell trait vs sickle cell disease

Ischemic priapism is uncommon in men with sickle cell trait, but prevalence rates in men with sickle cell disease are as high as 42%.²⁸ In a study of 130 men with sickle cell disease, 35% had a history of prolonged ischemic priapism, 72% had a history of stuttering priapism, and 75% of men with stuttering priapism had their first episode before age 20.²⁹

Rates of erectile dysfunction increase with the duration of ischemic episodes and range from 20% to 90%.^28,30 In childhood, sickle cell disease accounts for 63% of the cases of ischemic priapism, and in adults it accounts for 23% of cases.³¹

Take-home messages

• Sickle cell disease accounts for two-thirds of cases of ischemic priapism in children, and one-fourth of adult cases.
• Ischemic priapism is a medical emergency.
• Treatment with aspiration and phenylephrine injections should begin immediately and should not await treatment measures for sickle cell disease (hydration, oxygen, exchange transfusions).

OTHER UROLOGIC COMPLICATIONS OF SICKLE CELL DISEASE

Other urologic complications of sickle cell trait and sickle cell disease include microscopic hematuria, gross hematuria, and renal colic. A formal evaluation of any patient with persistent microscopic hematuria or gross hematuria should consist of urinalysis, computed tomography, and cystoscopy. This approach assesses the upper and lower genitourinary system for treatable causes. Renal ultrasonography can be used instead of computed tomography but tends to provide less information.

Special considerations

In patients with sickle cell trait and sickle cell disease, chronic hypoxia and subsequent sickling of erythrocytes in the renal medulla can lead to papillary hypertrophy and papillary necrosis. In papillary hypertrophy, friable blood vessels can rupture, resulting in microscopic and gross hematuria. In papillary necrosis, the papilla can slough off and become lodged in the ureter.

Nevertheless, hematuria and renal colic in patients with sickle cell disease or trait are most often attributable to common causes such as infection and stones. A finding of hydronephrosis in the absence of a stone, however, suggests obstruction due to a clot or a sloughed papilla. Ureteroscopy, fulguration, and ureteral stent placement can stop the bleeding and alleviate obstruction in these cases.

Renal medullary carcinoma

Another important reason to order imaging in patients with sickle cell disease or trait who present with urologic symptoms is to rule out renal medullary carcinoma, a rare but aggressive cancer that arises from the collecting duct epithelium. This cancer is twice as likely to occur in males than in females; it has been reported in patients ranging in age from 10 to 40, with a median age at presentation of 26.³²

When patients present with symptomatic renal medullary cancer, in most cases the cancer has already metastasized.

On computed tomography, the tumor tends to occupy a central location in the kidney and appears to infiltrate and replace adjacent kidney tissue. Retroperitoneal lymphadenopathy and metastasis are common.

Treatment typically entails radical nephrectomy, chemotherapy, and in some circumstances, radiotherapy. Case reports have shown promising tumor responses to carboplatin and paclitaxel regimens.^33,34 Also, a low threshold for imaging in patients with sickle cell disease and trait may increase the odds of early detection of this aggressive cancer.

Sickle cell disease is a common genetic disorder in the United States that disproportionately affects people of African ancestry. The characteristic sickling of red blood cells under conditions of reduced oxygen tension leads to intravascular hemolysis and vaso-occlusive events, which in turn cause tissue ischemia-reperfusion injury affecting multiple organs, including the genitourinary system.^1–3

In this paper, we review the genitourinary effects of sickle cell disease, focusing on sickle cell nephropathy, priapism, and renal medullary carcinoma.

THE WIDE-RANGING EFFECTS OF SICKLE CELL DISEASE

In the United States, sickle cell disease affects 1 of every 500 blacks and 1 of every 36,000 Hispanics.¹ The term describes hemoglobinopathies associated with sickling of red blood cells.

Sickling of red blood cells results from a single base-pair change in the beta-globin gene from glutamic acid to valine at position 6, causing abnormal hemoglobin (hemoglobin S), which polymerizes under conditions of reduced oxygen tension and alters the biconcave disk shape into a rigid, irregular, unstable cell. The sickle-shaped cells are prone to intravascular hemolysis,² causing intermittent vaso-occlusive events that result in tissue ischemia-reperfusion injury. Genitourinary problems include impaired ability to concentrate urine, hematuria, renal medullary carcinoma, and increased frequency of urinary tract infection.

SICKLE CELL NEPHROPATHY

Signs of kidney involvement may appear in early childhood

The kidney is one of the most frequently affected organs in sickle cell disease. Renal manifestations begin to appear in early childhood, with impaired medullary concentrating ability and ischemic damage to the tubular cells caused by sickling within the vasa recta renis precipitated by the acidic, hypoxic, and hypertonic environment in the renal medulla.

As in early diabetic nephropathy, renal blood flow is enhanced and the glomerular filtration rate (GFR) is increased. Increased cardiac output as a result of anemia, localized release of prostaglandins, and a hypoxia-induced increase in nitric oxide synthesis all play a role in the increase in GFR.^4,5

Oxidative stress, an increase in markers of inflammation, and local activation of the renin-angiotensin system contribute to renal damage in sickle cell disease.^5–7 The resulting hyperfiltration injury leads to microalbuminuria, which occurs in 20% to 40% of children with sickle cell anemia^8,9 and in as many as 60% of adults.

The glomerular lesions associated with sickle cell disease vary from glomerulopathy in the early stages to secondary focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, and glomerular thrombotic microangiopathy.¹⁰

Clinical presentations and workup

Clinical presentations are not limited to glomerular disease but include hyperchloremic metabolic acidosis and hyperkalemia resulting from defects in potassium secretion and renal acidification.

Hyperphosphatemia—a result of increased reabsorption of phosphorus, increased secretion of uric acid, and increased creatinine clearance—is seen in patients with sickle cell disease.^11,12 About 10% of patients can develop an acute kidney injury as a result of volume depletion, rhabdomyolysis, renal vein thrombosis, papillary necrosis, and urinary tract obstruction secondary to blood clots.^11,13

Up to 30% of adult patients with sickle cell disease develop chronic kidney disease. Predictors include severe anemia, hypertension, proteinuria, nephrotic syndrome, and microscopic hematuria.¹⁴ From 4% to 12% of patients go on to develop end-stage renal disease, but with a 1-year mortality rate three times higher than in patients without sickle cell disease.¹⁵

In general, patients with sickle cell anemia have blood pressures below those of age- and sex-matched individuals, but elevated blood pressure and low GFR are not uncommon in affected children. In a cohort of 48 children ages 3 to 18, 8.3% had an estimated GFR less than 90 mL/min/1.73 m², and 16.7% had elevated blood pressure (prehypertension and hypertension).¹⁶

In patients with sickle cell disease, evaluation of proteinuria, hematuria, hypertension, and renal failure should take into consideration the unique renal physiologic and pathologic processes involved. Recent evidence^17,18 suggests that the Chronic Kidney Disease Epidemiology Collaboration equation provides a better estimate of GFR than the Modification of Diet in Renal Disease and Cockcroft-Gault equations, although all three creatinine-based methods overestimate GFR in patients with sickle cell disease when compared with GFR measured with technetium-99m-labeled diethylenetriamine penta-acetic acid renal scanning.

Treatment options

Treatment of sickle cell nephropathy includes adequate fluid intake (given the loss of concentrating ability), adequate blood pressure control, use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) in patients who have microalbuminuria or proteinuria (or both)^9,11,19 and hydroxyurea. Treatment with enalapril has been shown to decrease proteinuria in patients with sickle cell nephropathy.⁹ In a cohort of children with sickle cell disease, four of nine patients treated with an ACE inhibitor developed hyperkalemia, leading to discontinuation of the drug in three patients.⁹

ACE inhibitors and ARBs must be used cautiously in these patients because they have defects in potassium secretion. Hydroxyurea has also been shown to decrease hyperfiltration and microalbuminuria in recent studies,^20,21 and this could protect against the development of overt nephropathy.

Higher mortality rates have been reported in patients with sickle cell disease who developed end-stage renal disease than in patients with end-stage renal disease without sickle cell disease. Sickle cell disease also increases the risk of pulmonary hypertension and the vaso-occlusive complication known as acute chest syndrome, contributing to increased mortality rates. Of note, in a study that looked at the association between mortality rates and pre-end-stage care of renal disease using data from the Centers for Medicare and Medicaid Services, patients with sickle cell disease who had had predialysis nephrology care had lower mortality rates.¹⁵

Treatments for end-stage renal disease are also effective in patients with sickle cell disease and include hemodialysis, peritoneal dialysis, and transplantation

Treatments for end-stage renal disease are also effective in patients with sickle cell disease and include hemodialysis, peritoneal dialysis, and renal transplantation. Data from the Organ Procurement and Transplantation Network and the United Network for Organ Sharing show that from 2000 to 2011, African American kidney recipients with sickle cell disease had better survival rates than patients who had undergone transplantation from 1988 to 1999, although rates of long-term survival and graft survival were lower than in transplant recipients with other diagnoses.²²

It is important to note that complications as a result of vaso-occlusive events and thrombosis can lead to graft loss; therefore, sickle cell crisis after transplantation requires careful management.

Take-home messages

• Loss of urine-concentrating ability and hyperfiltration are the earliest pathologic changes in sickle cell disease.
• Microalbuminuria as seen in diabetic nephropathy is the earliest manifestation of sickle cell nephropathy, and the prevalence increases as these patients get older and live longer.
• ACE inhibitors or ARBs should be used with caution, given the heightened risk of hyperkalemia in sickle cell disease.
• Recent results with hydroxyurea in decreasing hyperfiltration and microalbuminuria are encouraging.
• Early referral for predialysis nephrologic care is needed in sickle cell patients with chronic kidney disease.

PRIAPISM IN SICKLE CELL DISEASE

Priapism was formerly defined as a full, painful erection lasting more than 4 hours and unrelated to sexual stimulation or orgasm. But priapism is now recognized as two separate disorders—ischemic (veno-occlusive, low-flow) priapism and nonischemic (arterial, high-flow) priapism. The new definition includes both disorders: ie, a full or partial erection lasting more than 4 hours and unrelated to sexual stimulation or orgasm.

Ischemic priapism

Hematologic disorders are major contributors to ischemic priapism and include sickle cell disease, multiple myeloma, fat emboli (hyperalimentation),²³ glucose-6-phosphate dehydrogenase deficiency, and hemoglobin Olmsted variant.²⁴

Ischemic priapism is often seen in sickle cell disease and is considered an emergency. It is characterized by an abnormally rigid erection not involving the glans penis. Entrapment of blood in the corpora cavernosa leads to hypoxia, hypercarbia, and acidosis, which in turn leads to a painful compartment syndrome that, if untreated, results in smooth muscle necrosis and subsequent fibrosis. The results are a smaller penis and erectile dysfunction that is unresponsive to any treatment other than implantation of a penile prosthesis. However, scarring of the corpora cavernosa can make this procedure exceedingly difficult, requiring advanced techniques such as corporeal excavation.²⁵

Men with a subtype of ischemic priapism called “stuttering” priapism²⁶ suffer recurrent prolonged erections during sleep. The patient awakens with a painful erection that usually subsides, but sometimes only after several hours. Patients with this disorder suffer from sleep deprivation. Stuttering priapism may lead to full-blown ischemic priapism that does not resolve without intervention.

Nonischemic priapism

In nonischemic priapism, the corpora are engorged but not rigid. The condition results from unregulated arterial inflow and thus is not painful and does not result in damage to the corporeal smooth muscle.

Most cases of nonischemic priapism follow blunt perineal trauma or trauma associated with needle insertion into the corpora. This form of priapism is not associated with sickle cell disease. Because tissue damage does not occur, nonischemic or arterial priapism is not considered an emergency.

Treatment guidelines

Differentiating ischemic from nonischemic priapism is usually straightforward, based on the history, physical examination, corporeal blood gases, and duplex ultrasonography.²⁷

Ischemic priapism is an emergency. After needle aspiration of blood from the corpora cavernosa, phenylephrine is diluted with normal saline to a concentration of 100 to 500 µg/mL and is injected in 1-mL amounts repeatedly at 3- to 5-minute intervals until the erection subsides or until a 1-hour time limit is reached. Blood pressure and pulse are monitored during these injections. If aspiration and phenylephrine irrigation fail, surgical shunting is performed.²⁷

Measures to treat sickle cell disease (hydration, oxygen, exchange transfusions) may be employed simultaneously but should never delay aspiration and phenylephrine injections.²⁵

Early referral for predialysis nephrologic care is needed in sickle cell patients with chronic kidney disease

As nonischemic priapism is not considered an emergency, management begins with observation. Patients eventually become dissatisfied with their constant partial erection, and they then present for treatment. Most cases resolve after selective catheterization of the internal pudendal artery and embolization of the fistula with absorbable material. If this fails, surgical exploration with ligation of the vessels leading to the fistula is indicated.

Prevalence in sickle cell trait vs sickle cell disease

Ischemic priapism is uncommon in men with sickle cell trait, but prevalence rates in men with sickle cell disease are as high as 42%.²⁸ In a study of 130 men with sickle cell disease, 35% had a history of prolonged ischemic priapism, 72% had a history of stuttering priapism, and 75% of men with stuttering priapism had their first episode before age 20.²⁹

Rates of erectile dysfunction increase with the duration of ischemic episodes and range from 20% to 90%.^28,30 In childhood, sickle cell disease accounts for 63% of the cases of ischemic priapism, and in adults it accounts for 23% of cases.³¹

Take-home messages

• Sickle cell disease accounts for two-thirds of cases of ischemic priapism in children, and one-fourth of adult cases.
• Ischemic priapism is a medical emergency.
• Treatment with aspiration and phenylephrine injections should begin immediately and should not await treatment measures for sickle cell disease (hydration, oxygen, exchange transfusions).

OTHER UROLOGIC COMPLICATIONS OF SICKLE CELL DISEASE

Other urologic complications of sickle cell trait and sickle cell disease include microscopic hematuria, gross hematuria, and renal colic. A formal evaluation of any patient with persistent microscopic hematuria or gross hematuria should consist of urinalysis, computed tomography, and cystoscopy. This approach assesses the upper and lower genitourinary system for treatable causes. Renal ultrasonography can be used instead of computed tomography but tends to provide less information.

Special considerations

In patients with sickle cell trait and sickle cell disease, chronic hypoxia and subsequent sickling of erythrocytes in the renal medulla can lead to papillary hypertrophy and papillary necrosis. In papillary hypertrophy, friable blood vessels can rupture, resulting in microscopic and gross hematuria. In papillary necrosis, the papilla can slough off and become lodged in the ureter.

Nevertheless, hematuria and renal colic in patients with sickle cell disease or trait are most often attributable to common causes such as infection and stones. A finding of hydronephrosis in the absence of a stone, however, suggests obstruction due to a clot or a sloughed papilla. Ureteroscopy, fulguration, and ureteral stent placement can stop the bleeding and alleviate obstruction in these cases.

Renal medullary carcinoma

Another important reason to order imaging in patients with sickle cell disease or trait who present with urologic symptoms is to rule out renal medullary carcinoma, a rare but aggressive cancer that arises from the collecting duct epithelium. This cancer is twice as likely to occur in males than in females; it has been reported in patients ranging in age from 10 to 40, with a median age at presentation of 26.³²

When patients present with symptomatic renal medullary cancer, in most cases the cancer has already metastasized.

On computed tomography, the tumor tends to occupy a central location in the kidney and appears to infiltrate and replace adjacent kidney tissue. Retroperitoneal lymphadenopathy and metastasis are common.

Treatment typically entails radical nephrectomy, chemotherapy, and in some circumstances, radiotherapy. Case reports have shown promising tumor responses to carboplatin and paclitaxel regimens.^33,34 Also, a low threshold for imaging in patients with sickle cell disease and trait may increase the odds of early detection of this aggressive cancer.

Sickle cell disease is a common genetic disorder in the United States that disproportionately affects people of African ancestry. The characteristic sickling of red blood cells under conditions of reduced oxygen tension leads to intravascular hemolysis and vaso-occlusive events, which in turn cause tissue ischemia-reperfusion injury affecting multiple organs, including the genitourinary system.^1–3

In this paper, we review the genitourinary effects of sickle cell disease, focusing on sickle cell nephropathy, priapism, and renal medullary carcinoma.

THE WIDE-RANGING EFFECTS OF SICKLE CELL DISEASE

In the United States, sickle cell disease affects 1 of every 500 blacks and 1 of every 36,000 Hispanics.¹ The term describes hemoglobinopathies associated with sickling of red blood cells.

Sickling of red blood cells results from a single base-pair change in the beta-globin gene from glutamic acid to valine at position 6, causing abnormal hemoglobin (hemoglobin S), which polymerizes under conditions of reduced oxygen tension and alters the biconcave disk shape into a rigid, irregular, unstable cell. The sickle-shaped cells are prone to intravascular hemolysis,² causing intermittent vaso-occlusive events that result in tissue ischemia-reperfusion injury. Genitourinary problems include impaired ability to concentrate urine, hematuria, renal medullary carcinoma, and increased frequency of urinary tract infection.

SICKLE CELL NEPHROPATHY

Signs of kidney involvement may appear in early childhood

The kidney is one of the most frequently affected organs in sickle cell disease. Renal manifestations begin to appear in early childhood, with impaired medullary concentrating ability and ischemic damage to the tubular cells caused by sickling within the vasa recta renis precipitated by the acidic, hypoxic, and hypertonic environment in the renal medulla.

As in early diabetic nephropathy, renal blood flow is enhanced and the glomerular filtration rate (GFR) is increased. Increased cardiac output as a result of anemia, localized release of prostaglandins, and a hypoxia-induced increase in nitric oxide synthesis all play a role in the increase in GFR.^4,5

Oxidative stress, an increase in markers of inflammation, and local activation of the renin-angiotensin system contribute to renal damage in sickle cell disease.^5–7 The resulting hyperfiltration injury leads to microalbuminuria, which occurs in 20% to 40% of children with sickle cell anemia^8,9 and in as many as 60% of adults.

The glomerular lesions associated with sickle cell disease vary from glomerulopathy in the early stages to secondary focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, and glomerular thrombotic microangiopathy.¹⁰

Clinical presentations and workup

Clinical presentations are not limited to glomerular disease but include hyperchloremic metabolic acidosis and hyperkalemia resulting from defects in potassium secretion and renal acidification.

Hyperphosphatemia—a result of increased reabsorption of phosphorus, increased secretion of uric acid, and increased creatinine clearance—is seen in patients with sickle cell disease.^11,12 About 10% of patients can develop an acute kidney injury as a result of volume depletion, rhabdomyolysis, renal vein thrombosis, papillary necrosis, and urinary tract obstruction secondary to blood clots.^11,13

Up to 30% of adult patients with sickle cell disease develop chronic kidney disease. Predictors include severe anemia, hypertension, proteinuria, nephrotic syndrome, and microscopic hematuria.¹⁴ From 4% to 12% of patients go on to develop end-stage renal disease, but with a 1-year mortality rate three times higher than in patients without sickle cell disease.¹⁵

In general, patients with sickle cell anemia have blood pressures below those of age- and sex-matched individuals, but elevated blood pressure and low GFR are not uncommon in affected children. In a cohort of 48 children ages 3 to 18, 8.3% had an estimated GFR less than 90 mL/min/1.73 m², and 16.7% had elevated blood pressure (prehypertension and hypertension).¹⁶

In patients with sickle cell disease, evaluation of proteinuria, hematuria, hypertension, and renal failure should take into consideration the unique renal physiologic and pathologic processes involved. Recent evidence^17,18 suggests that the Chronic Kidney Disease Epidemiology Collaboration equation provides a better estimate of GFR than the Modification of Diet in Renal Disease and Cockcroft-Gault equations, although all three creatinine-based methods overestimate GFR in patients with sickle cell disease when compared with GFR measured with technetium-99m-labeled diethylenetriamine penta-acetic acid renal scanning.

Treatment options

Treatment of sickle cell nephropathy includes adequate fluid intake (given the loss of concentrating ability), adequate blood pressure control, use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) in patients who have microalbuminuria or proteinuria (or both)^9,11,19 and hydroxyurea. Treatment with enalapril has been shown to decrease proteinuria in patients with sickle cell nephropathy.⁹ In a cohort of children with sickle cell disease, four of nine patients treated with an ACE inhibitor developed hyperkalemia, leading to discontinuation of the drug in three patients.⁹

ACE inhibitors and ARBs must be used cautiously in these patients because they have defects in potassium secretion. Hydroxyurea has also been shown to decrease hyperfiltration and microalbuminuria in recent studies,^20,21 and this could protect against the development of overt nephropathy.

Higher mortality rates have been reported in patients with sickle cell disease who developed end-stage renal disease than in patients with end-stage renal disease without sickle cell disease. Sickle cell disease also increases the risk of pulmonary hypertension and the vaso-occlusive complication known as acute chest syndrome, contributing to increased mortality rates. Of note, in a study that looked at the association between mortality rates and pre-end-stage care of renal disease using data from the Centers for Medicare and Medicaid Services, patients with sickle cell disease who had had predialysis nephrology care had lower mortality rates.¹⁵

Treatments for end-stage renal disease are also effective in patients with sickle cell disease and include hemodialysis, peritoneal dialysis, and transplantation

Treatments for end-stage renal disease are also effective in patients with sickle cell disease and include hemodialysis, peritoneal dialysis, and renal transplantation. Data from the Organ Procurement and Transplantation Network and the United Network for Organ Sharing show that from 2000 to 2011, African American kidney recipients with sickle cell disease had better survival rates than patients who had undergone transplantation from 1988 to 1999, although rates of long-term survival and graft survival were lower than in transplant recipients with other diagnoses.²²

It is important to note that complications as a result of vaso-occlusive events and thrombosis can lead to graft loss; therefore, sickle cell crisis after transplantation requires careful management.

Take-home messages

• Loss of urine-concentrating ability and hyperfiltration are the earliest pathologic changes in sickle cell disease.
• Microalbuminuria as seen in diabetic nephropathy is the earliest manifestation of sickle cell nephropathy, and the prevalence increases as these patients get older and live longer.
• ACE inhibitors or ARBs should be used with caution, given the heightened risk of hyperkalemia in sickle cell disease.
• Recent results with hydroxyurea in decreasing hyperfiltration and microalbuminuria are encouraging.
• Early referral for predialysis nephrologic care is needed in sickle cell patients with chronic kidney disease.

PRIAPISM IN SICKLE CELL DISEASE

Priapism was formerly defined as a full, painful erection lasting more than 4 hours and unrelated to sexual stimulation or orgasm. But priapism is now recognized as two separate disorders—ischemic (veno-occlusive, low-flow) priapism and nonischemic (arterial, high-flow) priapism. The new definition includes both disorders: ie, a full or partial erection lasting more than 4 hours and unrelated to sexual stimulation or orgasm.

Ischemic priapism

Hematologic disorders are major contributors to ischemic priapism and include sickle cell disease, multiple myeloma, fat emboli (hyperalimentation),²³ glucose-6-phosphate dehydrogenase deficiency, and hemoglobin Olmsted variant.²⁴

Ischemic priapism is often seen in sickle cell disease and is considered an emergency. It is characterized by an abnormally rigid erection not involving the glans penis. Entrapment of blood in the corpora cavernosa leads to hypoxia, hypercarbia, and acidosis, which in turn leads to a painful compartment syndrome that, if untreated, results in smooth muscle necrosis and subsequent fibrosis. The results are a smaller penis and erectile dysfunction that is unresponsive to any treatment other than implantation of a penile prosthesis. However, scarring of the corpora cavernosa can make this procedure exceedingly difficult, requiring advanced techniques such as corporeal excavation.²⁵

Men with a subtype of ischemic priapism called “stuttering” priapism²⁶ suffer recurrent prolonged erections during sleep. The patient awakens with a painful erection that usually subsides, but sometimes only after several hours. Patients with this disorder suffer from sleep deprivation. Stuttering priapism may lead to full-blown ischemic priapism that does not resolve without intervention.

Nonischemic priapism

In nonischemic priapism, the corpora are engorged but not rigid. The condition results from unregulated arterial inflow and thus is not painful and does not result in damage to the corporeal smooth muscle.

Most cases of nonischemic priapism follow blunt perineal trauma or trauma associated with needle insertion into the corpora. This form of priapism is not associated with sickle cell disease. Because tissue damage does not occur, nonischemic or arterial priapism is not considered an emergency.

Treatment guidelines

Differentiating ischemic from nonischemic priapism is usually straightforward, based on the history, physical examination, corporeal blood gases, and duplex ultrasonography.²⁷

Ischemic priapism is an emergency. After needle aspiration of blood from the corpora cavernosa, phenylephrine is diluted with normal saline to a concentration of 100 to 500 µg/mL and is injected in 1-mL amounts repeatedly at 3- to 5-minute intervals until the erection subsides or until a 1-hour time limit is reached. Blood pressure and pulse are monitored during these injections. If aspiration and phenylephrine irrigation fail, surgical shunting is performed.²⁷

Measures to treat sickle cell disease (hydration, oxygen, exchange transfusions) may be employed simultaneously but should never delay aspiration and phenylephrine injections.²⁵

Early referral for predialysis nephrologic care is needed in sickle cell patients with chronic kidney disease

As nonischemic priapism is not considered an emergency, management begins with observation. Patients eventually become dissatisfied with their constant partial erection, and they then present for treatment. Most cases resolve after selective catheterization of the internal pudendal artery and embolization of the fistula with absorbable material. If this fails, surgical exploration with ligation of the vessels leading to the fistula is indicated.

Prevalence in sickle cell trait vs sickle cell disease

Ischemic priapism is uncommon in men with sickle cell trait, but prevalence rates in men with sickle cell disease are as high as 42%.²⁸ In a study of 130 men with sickle cell disease, 35% had a history of prolonged ischemic priapism, 72% had a history of stuttering priapism, and 75% of men with stuttering priapism had their first episode before age 20.²⁹

Rates of erectile dysfunction increase with the duration of ischemic episodes and range from 20% to 90%.^28,30 In childhood, sickle cell disease accounts for 63% of the cases of ischemic priapism, and in adults it accounts for 23% of cases.³¹

Take-home messages

• Sickle cell disease accounts for two-thirds of cases of ischemic priapism in children, and one-fourth of adult cases.
• Ischemic priapism is a medical emergency.
• Treatment with aspiration and phenylephrine injections should begin immediately and should not await treatment measures for sickle cell disease (hydration, oxygen, exchange transfusions).

OTHER UROLOGIC COMPLICATIONS OF SICKLE CELL DISEASE

Other urologic complications of sickle cell trait and sickle cell disease include microscopic hematuria, gross hematuria, and renal colic. A formal evaluation of any patient with persistent microscopic hematuria or gross hematuria should consist of urinalysis, computed tomography, and cystoscopy. This approach assesses the upper and lower genitourinary system for treatable causes. Renal ultrasonography can be used instead of computed tomography but tends to provide less information.

Special considerations

In patients with sickle cell trait and sickle cell disease, chronic hypoxia and subsequent sickling of erythrocytes in the renal medulla can lead to papillary hypertrophy and papillary necrosis. In papillary hypertrophy, friable blood vessels can rupture, resulting in microscopic and gross hematuria. In papillary necrosis, the papilla can slough off and become lodged in the ureter.

Nevertheless, hematuria and renal colic in patients with sickle cell disease or trait are most often attributable to common causes such as infection and stones. A finding of hydronephrosis in the absence of a stone, however, suggests obstruction due to a clot or a sloughed papilla. Ureteroscopy, fulguration, and ureteral stent placement can stop the bleeding and alleviate obstruction in these cases.

Renal medullary carcinoma

Another important reason to order imaging in patients with sickle cell disease or trait who present with urologic symptoms is to rule out renal medullary carcinoma, a rare but aggressive cancer that arises from the collecting duct epithelium. This cancer is twice as likely to occur in males than in females; it has been reported in patients ranging in age from 10 to 40, with a median age at presentation of 26.³²

When patients present with symptomatic renal medullary cancer, in most cases the cancer has already metastasized.

On computed tomography, the tumor tends to occupy a central location in the kidney and appears to infiltrate and replace adjacent kidney tissue. Retroperitoneal lymphadenopathy and metastasis are common.

Treatment typically entails radical nephrectomy, chemotherapy, and in some circumstances, radiotherapy. Case reports have shown promising tumor responses to carboplatin and paclitaxel regimens.^33,34 Also, a low threshold for imaging in patients with sickle cell disease and trait may increase the odds of early detection of this aggressive cancer.

Q)  I am getting calls from patients saying they heard a “stomach medicine” would hurt their kidneys. What is the basis, and how should I respond?

Emerging evidence is suggestive of a causal association between proton pump inhibitor (PPI) use and acute kidney injury/interstitial nephritis. Acute kidney injury is defined as either a decrease in urine output to less than 0.5 mL/kg/h for six hours, a rise in serum creatinine of 0.3 mg/dL or more within 48 hours, or an increase in creatinine of 50% or more above baseline within a week. Acute interstitial nephritis is often definitively diagnosed by renal biopsy, with findings of acute inflammatory cells, interstitial edema, and infiltration. Medications are the most common etiology for acute interstitial nephritis and account for more than 75% of cases.⁵

According to results published in the American Journal of Kidney Diseases, a retrospective study of 133 biopsy-proven cases of acute interstitial nephritis found 70% were associated with medication use. Of these, 14% were linked to use of a PPI (other drug culprits included antibiotics and NSAIDs, responsible for 49% and 11% of cases, respectively). Overall, omeprazole was the top drug cause, at 12%.⁶

In a nested case-control study of 572,661 subjects (mean age, 65.4) taking either lansoprazole, omeprazole, or pantoprazole, 46 definite cases and 26 probable cases of first-time acute interstitial nephritis were identified. Omeprazole was the most commonly dispensed PPI in this study. The crude incidence rate per 100,000 person-years for current use of a PPI was 11.98 and for past use, 1.68.⁷

Another nested case-control study of 184,480 subjects (ages 18 and older) reported 854 ­cases of acute kidney injury, with a positive association between use of a PPI and development of renal disease, even after controlling for confounding factors (P < .0001). Of note, no significant relationship was found between acute renal injury and use of H₂ blocker therapy.⁸—CAS 

Cynthia A. Smith, DNP, APRN, FNP-BC
Renal Consultants PLLC, South Charleston, West Virginia

REFERENCES
1. Velazquez H, Perazella MA, Wright FS, Ellison DH. Renal mechanism of trimethoprim-induced hyperkalemia. Ann Intern Med. 1993;119:296-301.
2. Horn JR, Hansten PD. Trimethoprim and potassium-sparing drugs: a risk for hyperkalemia. www.pharmacytimes.com/publications/issue/2011/February2011/DrugInteractions-0211. Accessed August 24, 2015.
3. Medina I, Mills J, Leoung G, et al. Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a controlled trial of trimethoprim-sulfamethoxazole versus trimethoprim-dapsone. N Engl J Med. 1990;323:776-782.
4. Fralick M, Macdonald EM, Gomes T, et al. Co-trimoxazole and sudden death in patients receiving inhibitors of renin-angiotensin system: population based study. BMJ. 2014;349:g6196.
5. Gilbert SJ, Weiner DE, Gipson DS, et al. National Kidney Foundation’s Primer on Kidney Diseases. Philadelphia, PA: Elsevier; 2014.
6. Muriithi AK, Leung N, Valeri AM, et al. Biopsy-proven acute interstitial nephritis, 1993-2011: a case series. Am J Kidney Dis. 2014;64(4):558-566.
7. Blank ML, Parkin L, Paul C, Herbison P. A nationwide nested case-control study indicates an increased risk of acute interstitial nephritis with proton pump inhibitor use. Kidney Int. 2014;86(4):837-844.
8. Klepser DG, Collier DS, Cochran GL. Proton pump inhibitors and acute kidney injury: a nested case-control study.  BMC Nephrology. 2013;14:150.

Q)  I am getting calls from patients saying they heard a “stomach medicine” would hurt their kidneys. What is the basis, and how should I respond?

Emerging evidence is suggestive of a causal association between proton pump inhibitor (PPI) use and acute kidney injury/interstitial nephritis. Acute kidney injury is defined as either a decrease in urine output to less than 0.5 mL/kg/h for six hours, a rise in serum creatinine of 0.3 mg/dL or more within 48 hours, or an increase in creatinine of 50% or more above baseline within a week. Acute interstitial nephritis is often definitively diagnosed by renal biopsy, with findings of acute inflammatory cells, interstitial edema, and infiltration. Medications are the most common etiology for acute interstitial nephritis and account for more than 75% of cases.⁵

According to results published in the American Journal of Kidney Diseases, a retrospective study of 133 biopsy-proven cases of acute interstitial nephritis found 70% were associated with medication use. Of these, 14% were linked to use of a PPI (other drug culprits included antibiotics and NSAIDs, responsible for 49% and 11% of cases, respectively). Overall, omeprazole was the top drug cause, at 12%.⁶

In a nested case-control study of 572,661 subjects (mean age, 65.4) taking either lansoprazole, omeprazole, or pantoprazole, 46 definite cases and 26 probable cases of first-time acute interstitial nephritis were identified. Omeprazole was the most commonly dispensed PPI in this study. The crude incidence rate per 100,000 person-years for current use of a PPI was 11.98 and for past use, 1.68.⁷

Another nested case-control study of 184,480 subjects (ages 18 and older) reported 854 ­cases of acute kidney injury, with a positive association between use of a PPI and development of renal disease, even after controlling for confounding factors (P < .0001). Of note, no significant relationship was found between acute renal injury and use of H₂ blocker therapy.⁸—CAS 

Cynthia A. Smith, DNP, APRN, FNP-BC
Renal Consultants PLLC, South Charleston, West Virginia

REFERENCES
1. Velazquez H, Perazella MA, Wright FS, Ellison DH. Renal mechanism of trimethoprim-induced hyperkalemia. Ann Intern Med. 1993;119:296-301.
2. Horn JR, Hansten PD. Trimethoprim and potassium-sparing drugs: a risk for hyperkalemia. www.pharmacytimes.com/publications/issue/2011/February2011/DrugInteractions-0211. Accessed August 24, 2015.
3. Medina I, Mills J, Leoung G, et al. Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a controlled trial of trimethoprim-sulfamethoxazole versus trimethoprim-dapsone. N Engl J Med. 1990;323:776-782.
4. Fralick M, Macdonald EM, Gomes T, et al. Co-trimoxazole and sudden death in patients receiving inhibitors of renin-angiotensin system: population based study. BMJ. 2014;349:g6196.
5. Gilbert SJ, Weiner DE, Gipson DS, et al. National Kidney Foundation’s Primer on Kidney Diseases. Philadelphia, PA: Elsevier; 2014.
6. Muriithi AK, Leung N, Valeri AM, et al. Biopsy-proven acute interstitial nephritis, 1993-2011: a case series. Am J Kidney Dis. 2014;64(4):558-566.
7. Blank ML, Parkin L, Paul C, Herbison P. A nationwide nested case-control study indicates an increased risk of acute interstitial nephritis with proton pump inhibitor use. Kidney Int. 2014;86(4):837-844.
8. Klepser DG, Collier DS, Cochran GL. Proton pump inhibitors and acute kidney injury: a nested case-control study.  BMC Nephrology. 2013;14:150.

Q)  I am getting calls from patients saying they heard a “stomach medicine” would hurt their kidneys. What is the basis, and how should I respond?

Emerging evidence is suggestive of a causal association between proton pump inhibitor (PPI) use and acute kidney injury/interstitial nephritis. Acute kidney injury is defined as either a decrease in urine output to less than 0.5 mL/kg/h for six hours, a rise in serum creatinine of 0.3 mg/dL or more within 48 hours, or an increase in creatinine of 50% or more above baseline within a week. Acute interstitial nephritis is often definitively diagnosed by renal biopsy, with findings of acute inflammatory cells, interstitial edema, and infiltration. Medications are the most common etiology for acute interstitial nephritis and account for more than 75% of cases.⁵

According to results published in the American Journal of Kidney Diseases, a retrospective study of 133 biopsy-proven cases of acute interstitial nephritis found 70% were associated with medication use. Of these, 14% were linked to use of a PPI (other drug culprits included antibiotics and NSAIDs, responsible for 49% and 11% of cases, respectively). Overall, omeprazole was the top drug cause, at 12%.⁶

In a nested case-control study of 572,661 subjects (mean age, 65.4) taking either lansoprazole, omeprazole, or pantoprazole, 46 definite cases and 26 probable cases of first-time acute interstitial nephritis were identified. Omeprazole was the most commonly dispensed PPI in this study. The crude incidence rate per 100,000 person-years for current use of a PPI was 11.98 and for past use, 1.68.⁷

Another nested case-control study of 184,480 subjects (ages 18 and older) reported 854 ­cases of acute kidney injury, with a positive association between use of a PPI and development of renal disease, even after controlling for confounding factors (P < .0001). Of note, no significant relationship was found between acute renal injury and use of H₂ blocker therapy.⁸—CAS 

Cynthia A. Smith, DNP, APRN, FNP-BC
Renal Consultants PLLC, South Charleston, West Virginia

REFERENCES
1. Velazquez H, Perazella MA, Wright FS, Ellison DH. Renal mechanism of trimethoprim-induced hyperkalemia. Ann Intern Med. 1993;119:296-301.
2. Horn JR, Hansten PD. Trimethoprim and potassium-sparing drugs: a risk for hyperkalemia. www.pharmacytimes.com/publications/issue/2011/February2011/DrugInteractions-0211. Accessed August 24, 2015.
3. Medina I, Mills J, Leoung G, et al. Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a controlled trial of trimethoprim-sulfamethoxazole versus trimethoprim-dapsone. N Engl J Med. 1990;323:776-782.
4. Fralick M, Macdonald EM, Gomes T, et al. Co-trimoxazole and sudden death in patients receiving inhibitors of renin-angiotensin system: population based study. BMJ. 2014;349:g6196.
5. Gilbert SJ, Weiner DE, Gipson DS, et al. National Kidney Foundation’s Primer on Kidney Diseases. Philadelphia, PA: Elsevier; 2014.
6. Muriithi AK, Leung N, Valeri AM, et al. Biopsy-proven acute interstitial nephritis, 1993-2011: a case series. Am J Kidney Dis. 2014;64(4):558-566.
7. Blank ML, Parkin L, Paul C, Herbison P. A nationwide nested case-control study indicates an increased risk of acute interstitial nephritis with proton pump inhibitor use. Kidney Int. 2014;86(4):837-844.
8. Klepser DG, Collier DS, Cochran GL. Proton pump inhibitors and acute kidney injury: a nested case-control study.  BMC Nephrology. 2013;14:150.

Q) At a lecture I recently attended, the speaker said sulfamethoxazole/trimethoprim is a potentially dangerous medication. I use it all the time. Is there any data to support her comments? Where did she get her information?

Sulfamethoxazole/trimethoprim (SMX/TMP) is a combination of two antibiotics, each of which has the potential to interact with other substances.

It is well documented that sulfamethoxazole can inhibit the metabolism of cytochrome P450 2C9 substrates. Frequently prescribed medications that also use the cytochrome substrate include warfarin and oral antihypoglycemic agents.

Trimethoprim’s distinct properties also lead to drug interactions. Trimethoprim inhibits sodium uptake by the appropriate channels in the distal tubule of the kidney, preventing reabsorption and altering the electrical balance of the tubular cells. As a result, the amount of potassium excreted into the urine is reduced, yielding an accumulation of serum potassium.¹

High serum potassium retention can manifest as hyperkalemia in patients with chronic kidney disease (CKD). Use of potassium-sparing drugs by patients with comorbidities, including CKD, can increase risk for hyperkalemia; concurrent use of these drugs with ACE inhibitors or angiotensin II receptor blockers (ARBs) compounds the risk.² The first reports of hyperkalemia with trimethoprim use occurred in HIV patients treated with large doses for Pneumocystis carinii infection.³

In a population-based case-control study, the results of which were published in the British Medical Journal, Fralick and colleagues analyzed data on older patients (age 66 or older) who were taking either ACE inhibitors or ARBs in combination with an antibiotic.⁴ They found a significantly increased risk for sudden death within seven days of prescription of SMX/TMP, compared to amoxicillin; a secondary analysis also revealed an increased risk for sudden death within 14 days with SMX/TMP. The researchers speculated that this excess risk, which translated to 3 sudden deaths in 1,000 patients taking SMX/TMP versus 1 sudden death in 1,000 patients taking amoxicillin, “reflects unrecognized arrhythmic death due to hyperkalemia.”

Since more than 250 million prescriptions for ACE inhibitors/ARBs and 20 million prescriptions for SMX/TMP are written each year, there will be instances of overlap. The prudent clinician would prescribe a different antibiotic or, if avoidance is not possible, use the lowest effective dose and duration of SMX/TMP. Close monitoring of serum potassium levels is warranted in patients with comorbidities, especially CKD, who are taking ACE inhibitors or ARBs—and of course, in our geriatric population. —DLC

Debra L. Coplon, DNP, DCC
City of Memphis Wellness Clinic, Tennessee

REFERENCES
1. Velazquez H, Perazella MA, Wright FS, Ellison DH. Renal mechanism of trimethoprim-induced hyperkalemia. Ann Intern Med. 1993;119:296-301.
2. Horn JR, Hansten PD. Trimethoprim and potassium-sparing drugs: a risk for hyperkalemia. www.pharmacytimes.com/publications/issue/2011/February2011/DrugInteractions-0211. Accessed August 24, 2015.
3. Medina I, Mills J, Leoung G, et al. Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a controlled trial of trimethoprim-sulfamethoxazole versus trimethoprim-dapsone. N Engl J Med. 1990;323:776-782.
4. Fralick M, Macdonald EM, Gomes T, et al. Co-trimoxazole and sudden death in patients receiving inhibitors of renin-angiotensin system: population based study. BMJ. 2014;349:g6196.
5. Gilbert SJ, Weiner DE, Gipson DS, et al. National Kidney Foundation’s Primer on Kidney Diseases. Philadelphia, PA: Elsevier; 2014.
6. Muriithi AK, Leung N, Valeri AM, et al. Biopsy-proven acute interstitial nephritis, 1993-2011: a case series. Am J Kidney Dis. 2014;64(4):558-566.
7. Blank ML, Parkin L, Paul C, Herbison P. A nationwide nested case-control study indicates an increased risk of acute interstitial nephritis with proton pump inhibitor use. Kidney Int. 2014;86(4):837-844.
8. Klepser DG, Collier DS, Cochran GL. Proton pump inhibitors and acute kidney injury: a nested case-control study.  BMC Nephrology. 2013;14:150.

Q) At a lecture I recently attended, the speaker said sulfamethoxazole/trimethoprim is a potentially dangerous medication. I use it all the time. Is there any data to support her comments? Where did she get her information?

Sulfamethoxazole/trimethoprim (SMX/TMP) is a combination of two antibiotics, each of which has the potential to interact with other substances.

It is well documented that sulfamethoxazole can inhibit the metabolism of cytochrome P450 2C9 substrates. Frequently prescribed medications that also use the cytochrome substrate include warfarin and oral antihypoglycemic agents.

Trimethoprim’s distinct properties also lead to drug interactions. Trimethoprim inhibits sodium uptake by the appropriate channels in the distal tubule of the kidney, preventing reabsorption and altering the electrical balance of the tubular cells. As a result, the amount of potassium excreted into the urine is reduced, yielding an accumulation of serum potassium.¹

High serum potassium retention can manifest as hyperkalemia in patients with chronic kidney disease (CKD). Use of potassium-sparing drugs by patients with comorbidities, including CKD, can increase risk for hyperkalemia; concurrent use of these drugs with ACE inhibitors or angiotensin II receptor blockers (ARBs) compounds the risk.² The first reports of hyperkalemia with trimethoprim use occurred in HIV patients treated with large doses for Pneumocystis carinii infection.³

In a population-based case-control study, the results of which were published in the British Medical Journal, Fralick and colleagues analyzed data on older patients (age 66 or older) who were taking either ACE inhibitors or ARBs in combination with an antibiotic.⁴ They found a significantly increased risk for sudden death within seven days of prescription of SMX/TMP, compared to amoxicillin; a secondary analysis also revealed an increased risk for sudden death within 14 days with SMX/TMP. The researchers speculated that this excess risk, which translated to 3 sudden deaths in 1,000 patients taking SMX/TMP versus 1 sudden death in 1,000 patients taking amoxicillin, “reflects unrecognized arrhythmic death due to hyperkalemia.”

Since more than 250 million prescriptions for ACE inhibitors/ARBs and 20 million prescriptions for SMX/TMP are written each year, there will be instances of overlap. The prudent clinician would prescribe a different antibiotic or, if avoidance is not possible, use the lowest effective dose and duration of SMX/TMP. Close monitoring of serum potassium levels is warranted in patients with comorbidities, especially CKD, who are taking ACE inhibitors or ARBs—and of course, in our geriatric population. —DLC

Debra L. Coplon, DNP, DCC
City of Memphis Wellness Clinic, Tennessee

REFERENCES
1. Velazquez H, Perazella MA, Wright FS, Ellison DH. Renal mechanism of trimethoprim-induced hyperkalemia. Ann Intern Med. 1993;119:296-301.
2. Horn JR, Hansten PD. Trimethoprim and potassium-sparing drugs: a risk for hyperkalemia. www.pharmacytimes.com/publications/issue/2011/February2011/DrugInteractions-0211. Accessed August 24, 2015.
3. Medina I, Mills J, Leoung G, et al. Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a controlled trial of trimethoprim-sulfamethoxazole versus trimethoprim-dapsone. N Engl J Med. 1990;323:776-782.
4. Fralick M, Macdonald EM, Gomes T, et al. Co-trimoxazole and sudden death in patients receiving inhibitors of renin-angiotensin system: population based study. BMJ. 2014;349:g6196.
5. Gilbert SJ, Weiner DE, Gipson DS, et al. National Kidney Foundation’s Primer on Kidney Diseases. Philadelphia, PA: Elsevier; 2014.
6. Muriithi AK, Leung N, Valeri AM, et al. Biopsy-proven acute interstitial nephritis, 1993-2011: a case series. Am J Kidney Dis. 2014;64(4):558-566.
7. Blank ML, Parkin L, Paul C, Herbison P. A nationwide nested case-control study indicates an increased risk of acute interstitial nephritis with proton pump inhibitor use. Kidney Int. 2014;86(4):837-844.
8. Klepser DG, Collier DS, Cochran GL. Proton pump inhibitors and acute kidney injury: a nested case-control study.  BMC Nephrology. 2013;14:150.

Q) At a lecture I recently attended, the speaker said sulfamethoxazole/trimethoprim is a potentially dangerous medication. I use it all the time. Is there any data to support her comments? Where did she get her information?

Sulfamethoxazole/trimethoprim (SMX/TMP) is a combination of two antibiotics, each of which has the potential to interact with other substances.

It is well documented that sulfamethoxazole can inhibit the metabolism of cytochrome P450 2C9 substrates. Frequently prescribed medications that also use the cytochrome substrate include warfarin and oral antihypoglycemic agents.

Trimethoprim’s distinct properties also lead to drug interactions. Trimethoprim inhibits sodium uptake by the appropriate channels in the distal tubule of the kidney, preventing reabsorption and altering the electrical balance of the tubular cells. As a result, the amount of potassium excreted into the urine is reduced, yielding an accumulation of serum potassium.¹

High serum potassium retention can manifest as hyperkalemia in patients with chronic kidney disease (CKD). Use of potassium-sparing drugs by patients with comorbidities, including CKD, can increase risk for hyperkalemia; concurrent use of these drugs with ACE inhibitors or angiotensin II receptor blockers (ARBs) compounds the risk.² The first reports of hyperkalemia with trimethoprim use occurred in HIV patients treated with large doses for Pneumocystis carinii infection.³

In a population-based case-control study, the results of which were published in the British Medical Journal, Fralick and colleagues analyzed data on older patients (age 66 or older) who were taking either ACE inhibitors or ARBs in combination with an antibiotic.⁴ They found a significantly increased risk for sudden death within seven days of prescription of SMX/TMP, compared to amoxicillin; a secondary analysis also revealed an increased risk for sudden death within 14 days with SMX/TMP. The researchers speculated that this excess risk, which translated to 3 sudden deaths in 1,000 patients taking SMX/TMP versus 1 sudden death in 1,000 patients taking amoxicillin, “reflects unrecognized arrhythmic death due to hyperkalemia.”

Since more than 250 million prescriptions for ACE inhibitors/ARBs and 20 million prescriptions for SMX/TMP are written each year, there will be instances of overlap. The prudent clinician would prescribe a different antibiotic or, if avoidance is not possible, use the lowest effective dose and duration of SMX/TMP. Close monitoring of serum potassium levels is warranted in patients with comorbidities, especially CKD, who are taking ACE inhibitors or ARBs—and of course, in our geriatric population. —DLC

Debra L. Coplon, DNP, DCC
City of Memphis Wellness Clinic, Tennessee

REFERENCES
1. Velazquez H, Perazella MA, Wright FS, Ellison DH. Renal mechanism of trimethoprim-induced hyperkalemia. Ann Intern Med. 1993;119:296-301.
2. Horn JR, Hansten PD. Trimethoprim and potassium-sparing drugs: a risk for hyperkalemia. www.pharmacytimes.com/publications/issue/2011/February2011/DrugInteractions-0211. Accessed August 24, 2015.
3. Medina I, Mills J, Leoung G, et al. Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a controlled trial of trimethoprim-sulfamethoxazole versus trimethoprim-dapsone. N Engl J Med. 1990;323:776-782.
4. Fralick M, Macdonald EM, Gomes T, et al. Co-trimoxazole and sudden death in patients receiving inhibitors of renin-angiotensin system: population based study. BMJ. 2014;349:g6196.
5. Gilbert SJ, Weiner DE, Gipson DS, et al. National Kidney Foundation’s Primer on Kidney Diseases. Philadelphia, PA: Elsevier; 2014.
6. Muriithi AK, Leung N, Valeri AM, et al. Biopsy-proven acute interstitial nephritis, 1993-2011: a case series. Am J Kidney Dis. 2014;64(4):558-566.
7. Blank ML, Parkin L, Paul C, Herbison P. A nationwide nested case-control study indicates an increased risk of acute interstitial nephritis with proton pump inhibitor use. Kidney Int. 2014;86(4):837-844.
8. Klepser DG, Collier DS, Cochran GL. Proton pump inhibitors and acute kidney injury: a nested case-control study.  BMC Nephrology. 2013;14:150.

In March 2009, a 63-year-old man was diagnosed with stage IV gastric carcinoma with metastasis to the liver. His treating oncologist gave him a prognosis of about 10 months’ life expectancy with chemotherapy. The patient’s family searched for alternative treatment options and found a natural alternative treatment center claiming the ability to cure the patient.

The patient and his family decided to defer chemotherapy, and he was admitted to the alternative treatment center for three to four weeks of inpatient care. The treatment consisted of “colonic hydrotherapy,” supplements designed to cleanse the body, and a diet restricted to seed milk, vegetable juice, and spinach soup. 

After six days, the patient developed severe diarrhea, confusion, and profound weakness. He was taken to a local hospital and admitted with a diagnosis of acute renal failure. Dialysis attempts were unsuccessful, and the man died of respiratory distress secondary to acute renal failure a week later.

The plaintiff claimed that the treatment provided by the defendants was contraindicated and caused acute renal failure, noting that the patient’s kidney function had been relatively normal when he entered the treatment facility. The plaintiff claimed that defendant Dr N., a chiropractor, never reviewed any of the decedent’s medical records, did not discuss the proposed treatment plan with his treating physicians, and failed to properly monitor the patient’s condition, notice his deterioration, and provide timely transfer to a hospital.

The defendant claimed that the treatment given had no adverse effects on the decedent and that the acute renal failure was due to hepatorenal syndrome due to his advanced metastatic liver cancer.

What was the outcome? >>

OUTCOME 
A $2.5 million verdict was returned. An appeal was pending.

COMMENT 
This is a case against a chiropractor, so why discuss it in a journal dedicated to NP and PA practice? Because it involves scope of practice, alternative medicine, the safety of “natural” treatments, and the ethical and legal problems of making unsupportable promises to patients.

Know your scope of practice, and don’t overextend. Clinicians trained as specialists (eg, in pediatrics, midwifery, or anesthesia) should use caution departing from that area. Those trained as “generalists” need to be careful as well; even if you were trained in a family practice program, if you are a PA who  has worked in dermatology for the past 10 years, think twice about giving treatment or advice to your friend with a neurologic complaint. In the event of a lawsuit, the plaintiff will spend a great deal of time building your resume as an expert in your discipline, only to attack you as inexperienced and unqualified in the case in which you extended yourself.

Here a chiropractor, without ever examining the patient, directed the treatment of a very sick man in an area in which he was not qualified. While chiropractors may claim the ability to treat outside their traditional scope, the jury’s verdict in this case proves that they were not persuaded he was right to do so. The chiropractor, Dr N., eventually lost his license, based in part on the false promises he made about his ability to cure patients of “any and all diseases, including cancer, by restoring the body to its natural state ….” This opportunistic preying upon the most ill and vulnerable in our society likely irked the jurors, who returned a substantial award, considering that the patient’s short life expectancy was uncontested.

Handle alternative medicine with particular care, because an alternative treatment may not qualify as “medicine” at all. If we define medicine as the application of scientific principles to health care, an alternative that is unproven, unstudied, and unknown does not qualify. Rather, it is guesswork—with potentially devastating consequences.

In this case, through his company, the chiropractor based his treatment plan on guesswork that colonic hydrotherapy and severe dietary restrictions would help a patient with stage IV metastatic gastric carcinoma. He was wrong, and the jury concluded that these alternatives injured the patient and hastened his death.

Certainly, Western medicine has been rightly and fairly criticized for failing to promote wellness through a healthy lifestyle, including diet, exercise, safety, emotional well-being, and stress management. However, when venturing from generally accepted health promotion strategies to a specific recommendation that an alternative agent “is good for” a specific problem, be careful. You may believe lavender oil is an effective antibiotic—but can you prove it?

If you choose lavender oil over a demonstrably effective antibiotic to treat pneumonia, and the patient deteriorates, you will be held accountable. The plaintiff will demand answers, and the jury will await your explanation. Reliance on vague concepts, not generally accepted in the literature (eg, “energy management,” detoxifying, unblocking “clogged” nervous systems), will be ridiculed by the plaintiff’s experts, and you will be skewered on cross-examination. It is not enough to personally “believe” in the alternative; you must be able to support your treatment decisions through the best evidence possible.

To be fair, this cuts both ways: Some Western medical practices are based on anecdotal evidence with minimal scientific support.  There was a time when a corneal abrasion was patched, a fractured clavicle was stabilized with a figure-of-eight dressing, and narcotics were withheld from a suffering patient with acute abdomen because it would “mask signs.” Our “Western” system is not immune from the impact of poor research, group-think, dogmas leading to inappropriate practice, and other sources of logical fallacy.

As NPs and PAs, we will be held to a scientific evidentiary standard. The standard of care will be based upon the care a reasonably prudent clinician would deliver in a similar situation. At trial, you will be confronted with a PA or NP on the stand testifying against you regarding what is reasonably prudent, acceptable care. Make sure your actions are scientifically defensible.

Interestingly, the standard for admitting a scientific opinion as expert testimony has changed. In 1923, Frye v United States¹ established that, for an expert opinion to be admissible, the testimony had to be based on what is “generally accepted in the scientific community.” In 1993, the Supreme Court case Daubert v Merrell Dow Pharmaceuticals² determined that the opinion need not be “generally accepted” but must be based on scientific method and must be relevant to the case; the judge serves as a “gatekeeper” to be sure the opinions flow from “scientific knowledge.”

Medical malpractice cases are based on state law. Some follow Frye, some Daubert. The latter is a more relaxed standard, but even in states following Daubert, an expert witness who purports to testify on an alternative treatment must follow the scientific method. For example, the webpage of the defendant chiropractor’s institute (still in business) currently claims that “Heart/Brain Entrainment Therapy balances frequencies of organs/glands/tissues. Everything in the universe resonates at a particular frequency—light, sound, and every cell, organ, gland, and tissue in you.”³

So, whatever Heart/Brain Entrainment Therapy is, for that theory to be admissible in a Frye jurisdiction it would likely have to be “generally accepted” in the medical community. To be admissible in a Daubert jurisdiction, proponents of the testimony would have to show evidence of a scientific methodology supporting the theory before the jury could hear any testimony about it. In either case, strategically, the defense attorney would likely file a motion to block either certain parts of the testimony or the testimony entirely.

IN SUM
Jurors expect sound scientific methodology supporting medical decisions; use care when selecting treatment for patients. Robustly adopt health promotion and general wellness strategies. However, if you use alternatives directed toward a specific therapy solving a specific problem, use them cautiously and with an awareness that the indication for the therapy should be scientifically defensible. —DML 

REFERENCES
1. Frye v United States, 293 F. 1013 (D.C. Cir. 1923).
2. Daubert v Merrell Dow Pharmaceuticals, 509 U.S. 579 (1993).
3. Total Health Institute. Bioelectrical Energy, Quantum Frequency Resonance. www.totalhealthinstitute.com/about. Accessed July 14, 2015.

In March 2009, a 63-year-old man was diagnosed with stage IV gastric carcinoma with metastasis to the liver. His treating oncologist gave him a prognosis of about 10 months’ life expectancy with chemotherapy. The patient’s family searched for alternative treatment options and found a natural alternative treatment center claiming the ability to cure the patient.

The patient and his family decided to defer chemotherapy, and he was admitted to the alternative treatment center for three to four weeks of inpatient care. The treatment consisted of “colonic hydrotherapy,” supplements designed to cleanse the body, and a diet restricted to seed milk, vegetable juice, and spinach soup. 

After six days, the patient developed severe diarrhea, confusion, and profound weakness. He was taken to a local hospital and admitted with a diagnosis of acute renal failure. Dialysis attempts were unsuccessful, and the man died of respiratory distress secondary to acute renal failure a week later.

The plaintiff claimed that the treatment provided by the defendants was contraindicated and caused acute renal failure, noting that the patient’s kidney function had been relatively normal when he entered the treatment facility. The plaintiff claimed that defendant Dr N., a chiropractor, never reviewed any of the decedent’s medical records, did not discuss the proposed treatment plan with his treating physicians, and failed to properly monitor the patient’s condition, notice his deterioration, and provide timely transfer to a hospital.

The defendant claimed that the treatment given had no adverse effects on the decedent and that the acute renal failure was due to hepatorenal syndrome due to his advanced metastatic liver cancer.

What was the outcome? >>

OUTCOME 
A $2.5 million verdict was returned. An appeal was pending.

COMMENT 
This is a case against a chiropractor, so why discuss it in a journal dedicated to NP and PA practice? Because it involves scope of practice, alternative medicine, the safety of “natural” treatments, and the ethical and legal problems of making unsupportable promises to patients.

Know your scope of practice, and don’t overextend. Clinicians trained as specialists (eg, in pediatrics, midwifery, or anesthesia) should use caution departing from that area. Those trained as “generalists” need to be careful as well; even if you were trained in a family practice program, if you are a PA who  has worked in dermatology for the past 10 years, think twice about giving treatment or advice to your friend with a neurologic complaint. In the event of a lawsuit, the plaintiff will spend a great deal of time building your resume as an expert in your discipline, only to attack you as inexperienced and unqualified in the case in which you extended yourself.

Here a chiropractor, without ever examining the patient, directed the treatment of a very sick man in an area in which he was not qualified. While chiropractors may claim the ability to treat outside their traditional scope, the jury’s verdict in this case proves that they were not persuaded he was right to do so. The chiropractor, Dr N., eventually lost his license, based in part on the false promises he made about his ability to cure patients of “any and all diseases, including cancer, by restoring the body to its natural state ….” This opportunistic preying upon the most ill and vulnerable in our society likely irked the jurors, who returned a substantial award, considering that the patient’s short life expectancy was uncontested.

Handle alternative medicine with particular care, because an alternative treatment may not qualify as “medicine” at all. If we define medicine as the application of scientific principles to health care, an alternative that is unproven, unstudied, and unknown does not qualify. Rather, it is guesswork—with potentially devastating consequences.

In this case, through his company, the chiropractor based his treatment plan on guesswork that colonic hydrotherapy and severe dietary restrictions would help a patient with stage IV metastatic gastric carcinoma. He was wrong, and the jury concluded that these alternatives injured the patient and hastened his death.

Certainly, Western medicine has been rightly and fairly criticized for failing to promote wellness through a healthy lifestyle, including diet, exercise, safety, emotional well-being, and stress management. However, when venturing from generally accepted health promotion strategies to a specific recommendation that an alternative agent “is good for” a specific problem, be careful. You may believe lavender oil is an effective antibiotic—but can you prove it?

If you choose lavender oil over a demonstrably effective antibiotic to treat pneumonia, and the patient deteriorates, you will be held accountable. The plaintiff will demand answers, and the jury will await your explanation. Reliance on vague concepts, not generally accepted in the literature (eg, “energy management,” detoxifying, unblocking “clogged” nervous systems), will be ridiculed by the plaintiff’s experts, and you will be skewered on cross-examination. It is not enough to personally “believe” in the alternative; you must be able to support your treatment decisions through the best evidence possible.

To be fair, this cuts both ways: Some Western medical practices are based on anecdotal evidence with minimal scientific support.  There was a time when a corneal abrasion was patched, a fractured clavicle was stabilized with a figure-of-eight dressing, and narcotics were withheld from a suffering patient with acute abdomen because it would “mask signs.” Our “Western” system is not immune from the impact of poor research, group-think, dogmas leading to inappropriate practice, and other sources of logical fallacy.

As NPs and PAs, we will be held to a scientific evidentiary standard. The standard of care will be based upon the care a reasonably prudent clinician would deliver in a similar situation. At trial, you will be confronted with a PA or NP on the stand testifying against you regarding what is reasonably prudent, acceptable care. Make sure your actions are scientifically defensible.

Interestingly, the standard for admitting a scientific opinion as expert testimony has changed. In 1923, Frye v United States¹ established that, for an expert opinion to be admissible, the testimony had to be based on what is “generally accepted in the scientific community.” In 1993, the Supreme Court case Daubert v Merrell Dow Pharmaceuticals² determined that the opinion need not be “generally accepted” but must be based on scientific method and must be relevant to the case; the judge serves as a “gatekeeper” to be sure the opinions flow from “scientific knowledge.”

Medical malpractice cases are based on state law. Some follow Frye, some Daubert. The latter is a more relaxed standard, but even in states following Daubert, an expert witness who purports to testify on an alternative treatment must follow the scientific method. For example, the webpage of the defendant chiropractor’s institute (still in business) currently claims that “Heart/Brain Entrainment Therapy balances frequencies of organs/glands/tissues. Everything in the universe resonates at a particular frequency—light, sound, and every cell, organ, gland, and tissue in you.”³

So, whatever Heart/Brain Entrainment Therapy is, for that theory to be admissible in a Frye jurisdiction it would likely have to be “generally accepted” in the medical community. To be admissible in a Daubert jurisdiction, proponents of the testimony would have to show evidence of a scientific methodology supporting the theory before the jury could hear any testimony about it. In either case, strategically, the defense attorney would likely file a motion to block either certain parts of the testimony or the testimony entirely.

IN SUM
Jurors expect sound scientific methodology supporting medical decisions; use care when selecting treatment for patients. Robustly adopt health promotion and general wellness strategies. However, if you use alternatives directed toward a specific therapy solving a specific problem, use them cautiously and with an awareness that the indication for the therapy should be scientifically defensible. —DML 

REFERENCES
1. Frye v United States, 293 F. 1013 (D.C. Cir. 1923).
2. Daubert v Merrell Dow Pharmaceuticals, 509 U.S. 579 (1993).
3. Total Health Institute. Bioelectrical Energy, Quantum Frequency Resonance. www.totalhealthinstitute.com/about. Accessed July 14, 2015.

In March 2009, a 63-year-old man was diagnosed with stage IV gastric carcinoma with metastasis to the liver. His treating oncologist gave him a prognosis of about 10 months’ life expectancy with chemotherapy. The patient’s family searched for alternative treatment options and found a natural alternative treatment center claiming the ability to cure the patient.

The patient and his family decided to defer chemotherapy, and he was admitted to the alternative treatment center for three to four weeks of inpatient care. The treatment consisted of “colonic hydrotherapy,” supplements designed to cleanse the body, and a diet restricted to seed milk, vegetable juice, and spinach soup. 

After six days, the patient developed severe diarrhea, confusion, and profound weakness. He was taken to a local hospital and admitted with a diagnosis of acute renal failure. Dialysis attempts were unsuccessful, and the man died of respiratory distress secondary to acute renal failure a week later.

The plaintiff claimed that the treatment provided by the defendants was contraindicated and caused acute renal failure, noting that the patient’s kidney function had been relatively normal when he entered the treatment facility. The plaintiff claimed that defendant Dr N., a chiropractor, never reviewed any of the decedent’s medical records, did not discuss the proposed treatment plan with his treating physicians, and failed to properly monitor the patient’s condition, notice his deterioration, and provide timely transfer to a hospital.

The defendant claimed that the treatment given had no adverse effects on the decedent and that the acute renal failure was due to hepatorenal syndrome due to his advanced metastatic liver cancer.

What was the outcome? >>

OUTCOME 
A $2.5 million verdict was returned. An appeal was pending.

COMMENT 
This is a case against a chiropractor, so why discuss it in a journal dedicated to NP and PA practice? Because it involves scope of practice, alternative medicine, the safety of “natural” treatments, and the ethical and legal problems of making unsupportable promises to patients.

Know your scope of practice, and don’t overextend. Clinicians trained as specialists (eg, in pediatrics, midwifery, or anesthesia) should use caution departing from that area. Those trained as “generalists” need to be careful as well; even if you were trained in a family practice program, if you are a PA who  has worked in dermatology for the past 10 years, think twice about giving treatment or advice to your friend with a neurologic complaint. In the event of a lawsuit, the plaintiff will spend a great deal of time building your resume as an expert in your discipline, only to attack you as inexperienced and unqualified in the case in which you extended yourself.

Here a chiropractor, without ever examining the patient, directed the treatment of a very sick man in an area in which he was not qualified. While chiropractors may claim the ability to treat outside their traditional scope, the jury’s verdict in this case proves that they were not persuaded he was right to do so. The chiropractor, Dr N., eventually lost his license, based in part on the false promises he made about his ability to cure patients of “any and all diseases, including cancer, by restoring the body to its natural state ….” This opportunistic preying upon the most ill and vulnerable in our society likely irked the jurors, who returned a substantial award, considering that the patient’s short life expectancy was uncontested.

Handle alternative medicine with particular care, because an alternative treatment may not qualify as “medicine” at all. If we define medicine as the application of scientific principles to health care, an alternative that is unproven, unstudied, and unknown does not qualify. Rather, it is guesswork—with potentially devastating consequences.

In this case, through his company, the chiropractor based his treatment plan on guesswork that colonic hydrotherapy and severe dietary restrictions would help a patient with stage IV metastatic gastric carcinoma. He was wrong, and the jury concluded that these alternatives injured the patient and hastened his death.

Certainly, Western medicine has been rightly and fairly criticized for failing to promote wellness through a healthy lifestyle, including diet, exercise, safety, emotional well-being, and stress management. However, when venturing from generally accepted health promotion strategies to a specific recommendation that an alternative agent “is good for” a specific problem, be careful. You may believe lavender oil is an effective antibiotic—but can you prove it?

If you choose lavender oil over a demonstrably effective antibiotic to treat pneumonia, and the patient deteriorates, you will be held accountable. The plaintiff will demand answers, and the jury will await your explanation. Reliance on vague concepts, not generally accepted in the literature (eg, “energy management,” detoxifying, unblocking “clogged” nervous systems), will be ridiculed by the plaintiff’s experts, and you will be skewered on cross-examination. It is not enough to personally “believe” in the alternative; you must be able to support your treatment decisions through the best evidence possible.

To be fair, this cuts both ways: Some Western medical practices are based on anecdotal evidence with minimal scientific support.  There was a time when a corneal abrasion was patched, a fractured clavicle was stabilized with a figure-of-eight dressing, and narcotics were withheld from a suffering patient with acute abdomen because it would “mask signs.” Our “Western” system is not immune from the impact of poor research, group-think, dogmas leading to inappropriate practice, and other sources of logical fallacy.

As NPs and PAs, we will be held to a scientific evidentiary standard. The standard of care will be based upon the care a reasonably prudent clinician would deliver in a similar situation. At trial, you will be confronted with a PA or NP on the stand testifying against you regarding what is reasonably prudent, acceptable care. Make sure your actions are scientifically defensible.

Interestingly, the standard for admitting a scientific opinion as expert testimony has changed. In 1923, Frye v United States¹ established that, for an expert opinion to be admissible, the testimony had to be based on what is “generally accepted in the scientific community.” In 1993, the Supreme Court case Daubert v Merrell Dow Pharmaceuticals² determined that the opinion need not be “generally accepted” but must be based on scientific method and must be relevant to the case; the judge serves as a “gatekeeper” to be sure the opinions flow from “scientific knowledge.”

Medical malpractice cases are based on state law. Some follow Frye, some Daubert. The latter is a more relaxed standard, but even in states following Daubert, an expert witness who purports to testify on an alternative treatment must follow the scientific method. For example, the webpage of the defendant chiropractor’s institute (still in business) currently claims that “Heart/Brain Entrainment Therapy balances frequencies of organs/glands/tissues. Everything in the universe resonates at a particular frequency—light, sound, and every cell, organ, gland, and tissue in you.”³

So, whatever Heart/Brain Entrainment Therapy is, for that theory to be admissible in a Frye jurisdiction it would likely have to be “generally accepted” in the medical community. To be admissible in a Daubert jurisdiction, proponents of the testimony would have to show evidence of a scientific methodology supporting the theory before the jury could hear any testimony about it. In either case, strategically, the defense attorney would likely file a motion to block either certain parts of the testimony or the testimony entirely.

IN SUM
Jurors expect sound scientific methodology supporting medical decisions; use care when selecting treatment for patients. Robustly adopt health promotion and general wellness strategies. However, if you use alternatives directed toward a specific therapy solving a specific problem, use them cautiously and with an awareness that the indication for the therapy should be scientifically defensible. —DML 

REFERENCES
1. Frye v United States, 293 F. 1013 (D.C. Cir. 1923).
2. Daubert v Merrell Dow Pharmaceuticals, 509 U.S. 579 (1993).
3. Total Health Institute. Bioelectrical Energy, Quantum Frequency Resonance. www.totalhealthinstitute.com/about. Accessed July 14, 2015.

No. In patients with severe atherosclerotic renal artery stenosis and hypertension or chronic kidney disease, renal artery stenting offers no additional benefit when added to comprehensive medical therapy.

See related editorial

In these patients, renal artery stenting in addition to antihypertensive drug therapy can improve blood pressure control modestly but has no significant effect on outcomes such as adverse cardiovascular events and death. And because renal artery stenting carries a risk of complications, medical management should continue to be the first-line therapy.

RENAL ARTERY STENOSIS

Renal artery stenosis is a common form of peripheral artery disease. Atherosclerosis is the most common cause, but it can also be caused by fibromuscular dysplasia or vasculitis (eg, Takayasu arteritis). It is most often unilateral, but bilateral disease has also been reported.

The prevalence of atherosclerotic renal vascular disease in the US Medicare population is 0.5%, and 5.5% in those with chronic kidney disease.¹ Furthermore, renal artery stenosis is found in 6.8% of adults over age 65.² The prevalence increases with age and is higher in patients with hyperlipidemia, peripheral arterial disease, and hypertension. The prevalence of renal artery stenosis in patients with atherosclerotic disease and renal dysfunction is as high as 50%.³

Patients with peripheral artery disease may be five times more likely to develop renal artery stenosis than people without peripheral artery disease.⁴ Significant stenosis can result in resistant arterial hypertension, renal insufficiency, left ventricular hypertrophy, and congestive heart failure.⁵

Renal artery stenting added to drug therapy can modestly improve blood pressure control, but has no significant effect on outcomes

Nephropathy due to renal artery stenosis is complex and is caused by hypoperfusion and chronic microatheroembolism. Renal artery stenosis leads to oxidative stress, inflammation, fibrosis in the stenotic kidney, and, over time, loss of kidney function. Hypoperfusion also leads to activation of the renin-angiotensin-aldosterone system, which plays a role in development of left ventricular hypertrophy.^5,6

Adequate blood pressure control, goal-directed lipid-lowering therapy, smoking cessation, and other preventive measures are the foundation of management.

RENAL ARTERY STENOSIS AND HYPERTENSION

Renal artery stenosis is a cause of secondary hypertension. The stenosis decreases renal perfusion pressure, activating the release of renin and the production of angiotensin II, which in turn raises the blood pressure by two mechanisms (Figure 1): directly, by causing generalized vasoconstriction, and indirectly, by stimulating the release of aldosterone, which in turn increases the reabsorption of sodium and causes hypervolemia. These two mechanisms play a major role in renal vascular hypertension when renal artery stenosis is bilateral. In unilateral renal artery stenosis, pressure diuresis in the unaffected kidney compensates for the reabsorption of sodium in the affected kidney, keeping the blood pressure down. However, with time, the unaffected kidney will develop hypertensive nephropathy, and pressure diuresis will be lost.^7,8 In addition, the activation of the renin-angiotensin-aldosterone system results in structural heart disease, such as left ventricular hypertrophy,⁵ and may shorten survival.

STENTING PLUS ANTIHYPERTENSIVE DRUG THERAPY

Because observational studies showed improvement in blood pressure control after endovascular stenting of atherosclerotic renal artery stenosis,^9,10 this approach became a treatment option for uncontrolled hypertension in these patients. The 2005 joint guidelines of the American College of Cardiology and the American Heart Association¹¹ considered percutaneous revascularization a reasonable option (level of evidence B) for patients who meet one of the following criteria:

• Hemodynamically significant stenosis and accelerated, resistant, or malignant hypertension, hypertension with an unexplained unilateral small kidney, or hypertension with intolerance to medication
• Renal artery stenosis and progressive chronic kidney disease with bilateral stenosis or stenosis in a solitary functioning kidney
• Hemodynamically significant stenosis and recurrent, unexplained congestive heart failure or sudden, unexplained pulmonary edema or unstable angina.¹¹

However, no randomized study has shown a direct benefit of renal artery stenting on rates of cardiovascular events or renal function compared with drug therapy alone.

TRIALS OF STENTING VS MEDICAL THERAPY ALONE

Technical improvements have led to more widespread use of diagnostic and interventional endovascular tools for renal artery revascularization. Studies over the past 10 years examined the impact of stenting in patients with uncontrolled hypertension.

The STAR trial

In the Stent Placement and Blood Pressure and Lipid-lowering for the Prevention of Progression of Renal Dysfunction Caused by Atherosclerotic Ostial Stenosis of the Renal Artery (STAR) trial,⁹ patients with creatinine clearance less than 80 mL/min/1.73 m², renal artery stenosis greater than 50%, and well-controlled blood pressure were randomized to either renal artery stenting plus medical therapy or medical therapy alone. The authors concluded that stenting had no effect on the progression of renal dysfunction but led to a small number of significant, procedure-related complications. The study was criticized for including patients with mild stenosis (< 50% stenosis) and for being underpowered for the primary end point.

The ASTRAL study

The Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) study¹⁰ was a similar comparison with similar results, showing no benefit from stenting with respect to renal function, systolic blood pressure control, cardiovascular events, or death.

HERCULES

The Herculink Elite Cobalt Chromium Renal Stent Trial to Demonstrate Efficacy and Safety (HERCULES)¹² was a prospective multicenter study of the effects of renal artery stenting in 202 patients with significant renal artery stenosis and uncontrolled hypertension. It showed a reduction in systolic blood pressure from baseline (P < .0001). However, follow-up was only 9 months, which was insufficient to show a significant effect on long-term cardiovascular and cerebrovascular outcomes.

The CORAL trial

The Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial¹³ used more stringent definitions and longer follow-up. It randomized 947 patients to either stenting plus medical therapy or medical therapy alone. Patients had atherosclerotic renal artery stenosis, defined as stenosis of at least 80% or stenosis of 60% to 80% with a gradient of at least 20 mm Hg in the systolic pressure), and either systolic hypertension while taking two or more antihypertensive drugs or stage 3 or higher chronic kidney disease (glomerular filtration rate < 60 mL/min/1.73 m² as calculated by the Modification of Diet in Renal Disease formula).

Complications of renal artery stenting are a limiting factor compared with drug therapy alone

Participants were followed for 43 months to detect the occurrence of adverse cardiovascular and renal events. There was no significant difference in primary outcome between stenting plus drug therapy and drug therapy alone (35.1% and 35.8%, respectively; P = .58). However, stenting plus drug therapy was associated with modestly lower systolic pressures compared with drug therapy alone (−2.3 mm Hg, 95% confidence interval −4.4 to −0.2 mm Hg, P = .03).¹³ This study provided strong evidence that renal artery stenting offers no significant benefit to patients with moderately severe atherosclerotic renal artery stenosis, and that stenting may actually pose an unnecessary risk.

COMPLICATIONS OF RENAL ARTERY STENTING

Complications of renal artery stenting are a limiting factor compared with drug therapy alone, especially since the procedure offers no significant benefit in outcome. Procedural complication rates of 10% to 15% have been reported.^9,10,12 The CORAL trial reported arterial dissection in 2.2%, branch-vessel occlusion in 1.2%, and distal embolization in 1.2% of patients undergoing stenting.¹³ Other reported complications have included stent misplacement requiring an additional stent, access-vessel damage, stent embolization, renal artery thrombosis or occlusion, and death.^10,12

No. In patients with severe atherosclerotic renal artery stenosis and hypertension or chronic kidney disease, renal artery stenting offers no additional benefit when added to comprehensive medical therapy.

See related editorial

In these patients, renal artery stenting in addition to antihypertensive drug therapy can improve blood pressure control modestly but has no significant effect on outcomes such as adverse cardiovascular events and death. And because renal artery stenting carries a risk of complications, medical management should continue to be the first-line therapy.

RENAL ARTERY STENOSIS

Renal artery stenosis is a common form of peripheral artery disease. Atherosclerosis is the most common cause, but it can also be caused by fibromuscular dysplasia or vasculitis (eg, Takayasu arteritis). It is most often unilateral, but bilateral disease has also been reported.

The prevalence of atherosclerotic renal vascular disease in the US Medicare population is 0.5%, and 5.5% in those with chronic kidney disease.¹ Furthermore, renal artery stenosis is found in 6.8% of adults over age 65.² The prevalence increases with age and is higher in patients with hyperlipidemia, peripheral arterial disease, and hypertension. The prevalence of renal artery stenosis in patients with atherosclerotic disease and renal dysfunction is as high as 50%.³

Patients with peripheral artery disease may be five times more likely to develop renal artery stenosis than people without peripheral artery disease.⁴ Significant stenosis can result in resistant arterial hypertension, renal insufficiency, left ventricular hypertrophy, and congestive heart failure.⁵

Renal artery stenting added to drug therapy can modestly improve blood pressure control, but has no significant effect on outcomes

Nephropathy due to renal artery stenosis is complex and is caused by hypoperfusion and chronic microatheroembolism. Renal artery stenosis leads to oxidative stress, inflammation, fibrosis in the stenotic kidney, and, over time, loss of kidney function. Hypoperfusion also leads to activation of the renin-angiotensin-aldosterone system, which plays a role in development of left ventricular hypertrophy.^5,6

Adequate blood pressure control, goal-directed lipid-lowering therapy, smoking cessation, and other preventive measures are the foundation of management.

RENAL ARTERY STENOSIS AND HYPERTENSION

Renal artery stenosis is a cause of secondary hypertension. The stenosis decreases renal perfusion pressure, activating the release of renin and the production of angiotensin II, which in turn raises the blood pressure by two mechanisms (Figure 1): directly, by causing generalized vasoconstriction, and indirectly, by stimulating the release of aldosterone, which in turn increases the reabsorption of sodium and causes hypervolemia. These two mechanisms play a major role in renal vascular hypertension when renal artery stenosis is bilateral. In unilateral renal artery stenosis, pressure diuresis in the unaffected kidney compensates for the reabsorption of sodium in the affected kidney, keeping the blood pressure down. However, with time, the unaffected kidney will develop hypertensive nephropathy, and pressure diuresis will be lost.^7,8 In addition, the activation of the renin-angiotensin-aldosterone system results in structural heart disease, such as left ventricular hypertrophy,⁵ and may shorten survival.

STENTING PLUS ANTIHYPERTENSIVE DRUG THERAPY

Because observational studies showed improvement in blood pressure control after endovascular stenting of atherosclerotic renal artery stenosis,^9,10 this approach became a treatment option for uncontrolled hypertension in these patients. The 2005 joint guidelines of the American College of Cardiology and the American Heart Association¹¹ considered percutaneous revascularization a reasonable option (level of evidence B) for patients who meet one of the following criteria:

• Hemodynamically significant stenosis and accelerated, resistant, or malignant hypertension, hypertension with an unexplained unilateral small kidney, or hypertension with intolerance to medication
• Renal artery stenosis and progressive chronic kidney disease with bilateral stenosis or stenosis in a solitary functioning kidney
• Hemodynamically significant stenosis and recurrent, unexplained congestive heart failure or sudden, unexplained pulmonary edema or unstable angina.¹¹

However, no randomized study has shown a direct benefit of renal artery stenting on rates of cardiovascular events or renal function compared with drug therapy alone.

TRIALS OF STENTING VS MEDICAL THERAPY ALONE

Technical improvements have led to more widespread use of diagnostic and interventional endovascular tools for renal artery revascularization. Studies over the past 10 years examined the impact of stenting in patients with uncontrolled hypertension.

The STAR trial

In the Stent Placement and Blood Pressure and Lipid-lowering for the Prevention of Progression of Renal Dysfunction Caused by Atherosclerotic Ostial Stenosis of the Renal Artery (STAR) trial,⁹ patients with creatinine clearance less than 80 mL/min/1.73 m², renal artery stenosis greater than 50%, and well-controlled blood pressure were randomized to either renal artery stenting plus medical therapy or medical therapy alone. The authors concluded that stenting had no effect on the progression of renal dysfunction but led to a small number of significant, procedure-related complications. The study was criticized for including patients with mild stenosis (< 50% stenosis) and for being underpowered for the primary end point.

The ASTRAL study

The Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) study¹⁰ was a similar comparison with similar results, showing no benefit from stenting with respect to renal function, systolic blood pressure control, cardiovascular events, or death.

HERCULES

The Herculink Elite Cobalt Chromium Renal Stent Trial to Demonstrate Efficacy and Safety (HERCULES)¹² was a prospective multicenter study of the effects of renal artery stenting in 202 patients with significant renal artery stenosis and uncontrolled hypertension. It showed a reduction in systolic blood pressure from baseline (P < .0001). However, follow-up was only 9 months, which was insufficient to show a significant effect on long-term cardiovascular and cerebrovascular outcomes.

The CORAL trial

The Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial¹³ used more stringent definitions and longer follow-up. It randomized 947 patients to either stenting plus medical therapy or medical therapy alone. Patients had atherosclerotic renal artery stenosis, defined as stenosis of at least 80% or stenosis of 60% to 80% with a gradient of at least 20 mm Hg in the systolic pressure), and either systolic hypertension while taking two or more antihypertensive drugs or stage 3 or higher chronic kidney disease (glomerular filtration rate < 60 mL/min/1.73 m² as calculated by the Modification of Diet in Renal Disease formula).

Complications of renal artery stenting are a limiting factor compared with drug therapy alone

Participants were followed for 43 months to detect the occurrence of adverse cardiovascular and renal events. There was no significant difference in primary outcome between stenting plus drug therapy and drug therapy alone (35.1% and 35.8%, respectively; P = .58). However, stenting plus drug therapy was associated with modestly lower systolic pressures compared with drug therapy alone (−2.3 mm Hg, 95% confidence interval −4.4 to −0.2 mm Hg, P = .03).¹³ This study provided strong evidence that renal artery stenting offers no significant benefit to patients with moderately severe atherosclerotic renal artery stenosis, and that stenting may actually pose an unnecessary risk.

COMPLICATIONS OF RENAL ARTERY STENTING

Complications of renal artery stenting are a limiting factor compared with drug therapy alone, especially since the procedure offers no significant benefit in outcome. Procedural complication rates of 10% to 15% have been reported.^9,10,12 The CORAL trial reported arterial dissection in 2.2%, branch-vessel occlusion in 1.2%, and distal embolization in 1.2% of patients undergoing stenting.¹³ Other reported complications have included stent misplacement requiring an additional stent, access-vessel damage, stent embolization, renal artery thrombosis or occlusion, and death.^10,12

No. In patients with severe atherosclerotic renal artery stenosis and hypertension or chronic kidney disease, renal artery stenting offers no additional benefit when added to comprehensive medical therapy.

See related editorial

In these patients, renal artery stenting in addition to antihypertensive drug therapy can improve blood pressure control modestly but has no significant effect on outcomes such as adverse cardiovascular events and death. And because renal artery stenting carries a risk of complications, medical management should continue to be the first-line therapy.

RENAL ARTERY STENOSIS

Renal artery stenosis is a common form of peripheral artery disease. Atherosclerosis is the most common cause, but it can also be caused by fibromuscular dysplasia or vasculitis (eg, Takayasu arteritis). It is most often unilateral, but bilateral disease has also been reported.

The prevalence of atherosclerotic renal vascular disease in the US Medicare population is 0.5%, and 5.5% in those with chronic kidney disease.¹ Furthermore, renal artery stenosis is found in 6.8% of adults over age 65.² The prevalence increases with age and is higher in patients with hyperlipidemia, peripheral arterial disease, and hypertension. The prevalence of renal artery stenosis in patients with atherosclerotic disease and renal dysfunction is as high as 50%.³

Patients with peripheral artery disease may be five times more likely to develop renal artery stenosis than people without peripheral artery disease.⁴ Significant stenosis can result in resistant arterial hypertension, renal insufficiency, left ventricular hypertrophy, and congestive heart failure.⁵

Renal artery stenting added to drug therapy can modestly improve blood pressure control, but has no significant effect on outcomes

Nephropathy due to renal artery stenosis is complex and is caused by hypoperfusion and chronic microatheroembolism. Renal artery stenosis leads to oxidative stress, inflammation, fibrosis in the stenotic kidney, and, over time, loss of kidney function. Hypoperfusion also leads to activation of the renin-angiotensin-aldosterone system, which plays a role in development of left ventricular hypertrophy.^5,6

Adequate blood pressure control, goal-directed lipid-lowering therapy, smoking cessation, and other preventive measures are the foundation of management.

RENAL ARTERY STENOSIS AND HYPERTENSION

Renal artery stenosis is a cause of secondary hypertension. The stenosis decreases renal perfusion pressure, activating the release of renin and the production of angiotensin II, which in turn raises the blood pressure by two mechanisms (Figure 1): directly, by causing generalized vasoconstriction, and indirectly, by stimulating the release of aldosterone, which in turn increases the reabsorption of sodium and causes hypervolemia. These two mechanisms play a major role in renal vascular hypertension when renal artery stenosis is bilateral. In unilateral renal artery stenosis, pressure diuresis in the unaffected kidney compensates for the reabsorption of sodium in the affected kidney, keeping the blood pressure down. However, with time, the unaffected kidney will develop hypertensive nephropathy, and pressure diuresis will be lost.^7,8 In addition, the activation of the renin-angiotensin-aldosterone system results in structural heart disease, such as left ventricular hypertrophy,⁵ and may shorten survival.

STENTING PLUS ANTIHYPERTENSIVE DRUG THERAPY

Because observational studies showed improvement in blood pressure control after endovascular stenting of atherosclerotic renal artery stenosis,^9,10 this approach became a treatment option for uncontrolled hypertension in these patients. The 2005 joint guidelines of the American College of Cardiology and the American Heart Association¹¹ considered percutaneous revascularization a reasonable option (level of evidence B) for patients who meet one of the following criteria:

• Hemodynamically significant stenosis and accelerated, resistant, or malignant hypertension, hypertension with an unexplained unilateral small kidney, or hypertension with intolerance to medication
• Renal artery stenosis and progressive chronic kidney disease with bilateral stenosis or stenosis in a solitary functioning kidney
• Hemodynamically significant stenosis and recurrent, unexplained congestive heart failure or sudden, unexplained pulmonary edema or unstable angina.¹¹

However, no randomized study has shown a direct benefit of renal artery stenting on rates of cardiovascular events or renal function compared with drug therapy alone.

TRIALS OF STENTING VS MEDICAL THERAPY ALONE

Technical improvements have led to more widespread use of diagnostic and interventional endovascular tools for renal artery revascularization. Studies over the past 10 years examined the impact of stenting in patients with uncontrolled hypertension.

The STAR trial

In the Stent Placement and Blood Pressure and Lipid-lowering for the Prevention of Progression of Renal Dysfunction Caused by Atherosclerotic Ostial Stenosis of the Renal Artery (STAR) trial,⁹ patients with creatinine clearance less than 80 mL/min/1.73 m², renal artery stenosis greater than 50%, and well-controlled blood pressure were randomized to either renal artery stenting plus medical therapy or medical therapy alone. The authors concluded that stenting had no effect on the progression of renal dysfunction but led to a small number of significant, procedure-related complications. The study was criticized for including patients with mild stenosis (< 50% stenosis) and for being underpowered for the primary end point.

The ASTRAL study

The Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) study¹⁰ was a similar comparison with similar results, showing no benefit from stenting with respect to renal function, systolic blood pressure control, cardiovascular events, or death.

HERCULES

The Herculink Elite Cobalt Chromium Renal Stent Trial to Demonstrate Efficacy and Safety (HERCULES)¹² was a prospective multicenter study of the effects of renal artery stenting in 202 patients with significant renal artery stenosis and uncontrolled hypertension. It showed a reduction in systolic blood pressure from baseline (P < .0001). However, follow-up was only 9 months, which was insufficient to show a significant effect on long-term cardiovascular and cerebrovascular outcomes.

The CORAL trial

The Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial¹³ used more stringent definitions and longer follow-up. It randomized 947 patients to either stenting plus medical therapy or medical therapy alone. Patients had atherosclerotic renal artery stenosis, defined as stenosis of at least 80% or stenosis of 60% to 80% with a gradient of at least 20 mm Hg in the systolic pressure), and either systolic hypertension while taking two or more antihypertensive drugs or stage 3 or higher chronic kidney disease (glomerular filtration rate < 60 mL/min/1.73 m² as calculated by the Modification of Diet in Renal Disease formula).

Complications of renal artery stenting are a limiting factor compared with drug therapy alone

Participants were followed for 43 months to detect the occurrence of adverse cardiovascular and renal events. There was no significant difference in primary outcome between stenting plus drug therapy and drug therapy alone (35.1% and 35.8%, respectively; P = .58). However, stenting plus drug therapy was associated with modestly lower systolic pressures compared with drug therapy alone (−2.3 mm Hg, 95% confidence interval −4.4 to −0.2 mm Hg, P = .03).¹³ This study provided strong evidence that renal artery stenting offers no significant benefit to patients with moderately severe atherosclerotic renal artery stenosis, and that stenting may actually pose an unnecessary risk.

COMPLICATIONS OF RENAL ARTERY STENTING

Complications of renal artery stenting are a limiting factor compared with drug therapy alone, especially since the procedure offers no significant benefit in outcome. Procedural complication rates of 10% to 15% have been reported.^9,10,12 The CORAL trial reported arterial dissection in 2.2%, branch-vessel occlusion in 1.2%, and distal embolization in 1.2% of patients undergoing stenting.¹³ Other reported complications have included stent misplacement requiring an additional stent, access-vessel damage, stent embolization, renal artery thrombosis or occlusion, and death.^10,12