Cleveland Clinic Journal of Medicine

In Reply: We would like to thank Dr. Lichtenberg for giving us the opportunity to clarify and expand on questions regarding HPV vaccine efficacy.

Our statement “HPV immunization can prevent up to 70% of cases of cervical cancer due to HPV as well as 90% of genital warts” was based on a statement by Thaxton and Waxman, ie, that immunization against HPV types 16 and 18 has the potential to prevent 70% of cancers of the cervix plus a large percentage of other lower anogenital tract cancers.¹ This was meant to describe the prevention potential of the quadrivalent vaccine. The currently available Gardasil 9 targets the HPV types that account for 90% of cervical cancers,² with projected effectiveness likely to vary based on geographic variation in HPV subtypes, ranging from 86.5% in Australia to 92% in North America.³ It is difficult to precisely calculate the effectiveness of HPV vaccination alone, given that cervical cancer prevention is twofold, with primary vaccination and secondary screening (with several notable updates to US national screening guidelines during the same time frame as vaccine development).⁴

It is true that the 29% decrease in US cervical cancer incidence rates during the years 2011–2014 compared with 2003–2006 is less than the predicted 70%.⁵ However, not all eligible US females are vaccinated; according to reports from the US Centers for Disease Control and Prevention, 49% of adolescents were appropriately immunized against HPV in 2017, an increase over the rate of only 35% in 2014.⁶ Low vaccination rates undoubtedly negatively impact any benefits from herd immunity, though the exact benefits of this population immunity are difficult to quantify.⁷

In Australia, a national school-based HPV vaccination program was initiated in 2007, making the vaccine available for free. Over 70% of girls ages 12 and 13 were vaccinated, and follow-up within the same decade showed a greater than 90% reduction in genital warts, as well as a reduction in high-grade cervical lesions.⁸ In addition, the incidence of genital warts in unvaccinated heterosexual males during the prevaccination vs the vaccination period decreased by up to 81% (a marker of herd immunity).⁹

In the US, the HPV subtypes found in the quadrivalent vaccine decreased by 71% in those ages 14 to 19, within 8 years of vaccine introduction.¹⁰ An analysis of US state cancer registries between 2009 and 2012 showed that in Michigan, the rates of high-grade, precancerous lesions declined by 37% each year for women ages 15 to 19, thought to be due to changes in screening and vaccination guidelines.¹¹ Similarly, an analysis of 9 million privately insured US females showed that the presence of high-grade precancerous lesions significantly decreased between the years 2007 and 2014 in those ages 15 to 24 (vaccinated individuals), but not in those ages 25 to 39 (unvaccinated individuals).¹² Most recently, a study of 10,206 women showed a 21.9% decrease in cervical intraepithelial neoplasia grade 2 or worse lesions due to HPV subtypes 16 or 18 in those who have received at least 1 dose of the vaccine; reduced rates in unvaccinated women were also seen, representing first evidence of herd immunity in the United States.¹³ In contrast, the rates of high-grade lesions due to nonvaccine HPV subtypes remained constant. Given that progression to cervical cancer can take 10 to 15 years or longer after HPV infection, true vaccine benefits will emerge once increased vaccination rates are achieved and after at least a decade of follow-up.

We applaud Dr. Lichtenberg’s efforts to clarify vaccine efficacy for appropriate counseling, as this is key to ensuring patient trust. Immunization fears have fueled the re-emergence of vaccine-preventable illnesses across the world. Given the wave of vaccine misinformation on the Internet, we all face patients and family members skeptical of vaccine efficacy and safety. Those requesting more information deserve an honest, informed discussion with their provider. Interestingly, however, among 955 unvaccinated women, the belief of not being at risk for HPV was the most common reason for not receiving the vaccine.¹⁴ Effective education can be achieved by focusing on the personal risks of HPV to the patient, as well as the overall favorable risk vs benefits of vaccination. Quoting an exact rate of cancer reduction is likely a less effective counseling strategy, and these efficacy estimates will change as vaccination rates and HPV prevalence within the population change over time.

In Reply: We would like to thank Dr. Lichtenberg for giving us the opportunity to clarify and expand on questions regarding HPV vaccine efficacy.

Our statement “HPV immunization can prevent up to 70% of cases of cervical cancer due to HPV as well as 90% of genital warts” was based on a statement by Thaxton and Waxman, ie, that immunization against HPV types 16 and 18 has the potential to prevent 70% of cancers of the cervix plus a large percentage of other lower anogenital tract cancers.¹ This was meant to describe the prevention potential of the quadrivalent vaccine. The currently available Gardasil 9 targets the HPV types that account for 90% of cervical cancers,² with projected effectiveness likely to vary based on geographic variation in HPV subtypes, ranging from 86.5% in Australia to 92% in North America.³ It is difficult to precisely calculate the effectiveness of HPV vaccination alone, given that cervical cancer prevention is twofold, with primary vaccination and secondary screening (with several notable updates to US national screening guidelines during the same time frame as vaccine development).⁴

It is true that the 29% decrease in US cervical cancer incidence rates during the years 2011–2014 compared with 2003–2006 is less than the predicted 70%.⁵ However, not all eligible US females are vaccinated; according to reports from the US Centers for Disease Control and Prevention, 49% of adolescents were appropriately immunized against HPV in 2017, an increase over the rate of only 35% in 2014.⁶ Low vaccination rates undoubtedly negatively impact any benefits from herd immunity, though the exact benefits of this population immunity are difficult to quantify.⁷

In Australia, a national school-based HPV vaccination program was initiated in 2007, making the vaccine available for free. Over 70% of girls ages 12 and 13 were vaccinated, and follow-up within the same decade showed a greater than 90% reduction in genital warts, as well as a reduction in high-grade cervical lesions.⁸ In addition, the incidence of genital warts in unvaccinated heterosexual males during the prevaccination vs the vaccination period decreased by up to 81% (a marker of herd immunity).⁹

In the US, the HPV subtypes found in the quadrivalent vaccine decreased by 71% in those ages 14 to 19, within 8 years of vaccine introduction.¹⁰ An analysis of US state cancer registries between 2009 and 2012 showed that in Michigan, the rates of high-grade, precancerous lesions declined by 37% each year for women ages 15 to 19, thought to be due to changes in screening and vaccination guidelines.¹¹ Similarly, an analysis of 9 million privately insured US females showed that the presence of high-grade precancerous lesions significantly decreased between the years 2007 and 2014 in those ages 15 to 24 (vaccinated individuals), but not in those ages 25 to 39 (unvaccinated individuals).¹² Most recently, a study of 10,206 women showed a 21.9% decrease in cervical intraepithelial neoplasia grade 2 or worse lesions due to HPV subtypes 16 or 18 in those who have received at least 1 dose of the vaccine; reduced rates in unvaccinated women were also seen, representing first evidence of herd immunity in the United States.¹³ In contrast, the rates of high-grade lesions due to nonvaccine HPV subtypes remained constant. Given that progression to cervical cancer can take 10 to 15 years or longer after HPV infection, true vaccine benefits will emerge once increased vaccination rates are achieved and after at least a decade of follow-up.

We applaud Dr. Lichtenberg’s efforts to clarify vaccine efficacy for appropriate counseling, as this is key to ensuring patient trust. Immunization fears have fueled the re-emergence of vaccine-preventable illnesses across the world. Given the wave of vaccine misinformation on the Internet, we all face patients and family members skeptical of vaccine efficacy and safety. Those requesting more information deserve an honest, informed discussion with their provider. Interestingly, however, among 955 unvaccinated women, the belief of not being at risk for HPV was the most common reason for not receiving the vaccine.¹⁴ Effective education can be achieved by focusing on the personal risks of HPV to the patient, as well as the overall favorable risk vs benefits of vaccination. Quoting an exact rate of cancer reduction is likely a less effective counseling strategy, and these efficacy estimates will change as vaccination rates and HPV prevalence within the population change over time.

In Reply: We would like to thank Dr. Lichtenberg for giving us the opportunity to clarify and expand on questions regarding HPV vaccine efficacy.

Our statement “HPV immunization can prevent up to 70% of cases of cervical cancer due to HPV as well as 90% of genital warts” was based on a statement by Thaxton and Waxman, ie, that immunization against HPV types 16 and 18 has the potential to prevent 70% of cancers of the cervix plus a large percentage of other lower anogenital tract cancers.¹ This was meant to describe the prevention potential of the quadrivalent vaccine. The currently available Gardasil 9 targets the HPV types that account for 90% of cervical cancers,² with projected effectiveness likely to vary based on geographic variation in HPV subtypes, ranging from 86.5% in Australia to 92% in North America.³ It is difficult to precisely calculate the effectiveness of HPV vaccination alone, given that cervical cancer prevention is twofold, with primary vaccination and secondary screening (with several notable updates to US national screening guidelines during the same time frame as vaccine development).⁴

It is true that the 29% decrease in US cervical cancer incidence rates during the years 2011–2014 compared with 2003–2006 is less than the predicted 70%.⁵ However, not all eligible US females are vaccinated; according to reports from the US Centers for Disease Control and Prevention, 49% of adolescents were appropriately immunized against HPV in 2017, an increase over the rate of only 35% in 2014.⁶ Low vaccination rates undoubtedly negatively impact any benefits from herd immunity, though the exact benefits of this population immunity are difficult to quantify.⁷

In Australia, a national school-based HPV vaccination program was initiated in 2007, making the vaccine available for free. Over 70% of girls ages 12 and 13 were vaccinated, and follow-up within the same decade showed a greater than 90% reduction in genital warts, as well as a reduction in high-grade cervical lesions.⁸ In addition, the incidence of genital warts in unvaccinated heterosexual males during the prevaccination vs the vaccination period decreased by up to 81% (a marker of herd immunity).⁹

In the US, the HPV subtypes found in the quadrivalent vaccine decreased by 71% in those ages 14 to 19, within 8 years of vaccine introduction.¹⁰ An analysis of US state cancer registries between 2009 and 2012 showed that in Michigan, the rates of high-grade, precancerous lesions declined by 37% each year for women ages 15 to 19, thought to be due to changes in screening and vaccination guidelines.¹¹ Similarly, an analysis of 9 million privately insured US females showed that the presence of high-grade precancerous lesions significantly decreased between the years 2007 and 2014 in those ages 15 to 24 (vaccinated individuals), but not in those ages 25 to 39 (unvaccinated individuals).¹² Most recently, a study of 10,206 women showed a 21.9% decrease in cervical intraepithelial neoplasia grade 2 or worse lesions due to HPV subtypes 16 or 18 in those who have received at least 1 dose of the vaccine; reduced rates in unvaccinated women were also seen, representing first evidence of herd immunity in the United States.¹³ In contrast, the rates of high-grade lesions due to nonvaccine HPV subtypes remained constant. Given that progression to cervical cancer can take 10 to 15 years or longer after HPV infection, true vaccine benefits will emerge once increased vaccination rates are achieved and after at least a decade of follow-up.

We applaud Dr. Lichtenberg’s efforts to clarify vaccine efficacy for appropriate counseling, as this is key to ensuring patient trust. Immunization fears have fueled the re-emergence of vaccine-preventable illnesses across the world. Given the wave of vaccine misinformation on the Internet, we all face patients and family members skeptical of vaccine efficacy and safety. Those requesting more information deserve an honest, informed discussion with their provider. Interestingly, however, among 955 unvaccinated women, the belief of not being at risk for HPV was the most common reason for not receiving the vaccine.¹⁴ Effective education can be achieved by focusing on the personal risks of HPV to the patient, as well as the overall favorable risk vs benefits of vaccination. Quoting an exact rate of cancer reduction is likely a less effective counseling strategy, and these efficacy estimates will change as vaccination rates and HPV prevalence within the population change over time.

To the Editor: I read with great interest the article “Aleukemic leukemia cutis” by Abraham et al,¹ as we recently had a case of this at my institution. The case is unique and quite intriguing; however, I found the pathologic description confusing and imprecise.

The authors state, “The findings were consistent with leukemic T cells with monocytic differentiation.”¹ This is based on their findings that the tumor cells expressed CD4, CD43, CD68, and lysozyme. However, the cells were negative for CD30, ALK-1, CD2, and CD3.

First, I must contest the authors’ claim that “the cells co-expressed T-cell markers (CD4 and CD43)”: CD4 and CD43 are not specific for T cells and are almost invariably seen on monocytes, especially in acute monoblastic/monocytic leukemia (AMoL; also known as M5 in the French-American-British classification system).^2,3 Therefore, the immunophenotype is perfect for an AMoL, but since there was no significant blood or bone marrow involvement and it was limited to the skin, this would best fit with a myeloid sarcoma, which frequently has a monocytic immunoprofile.^3,4

Additionally, this would not be a mixed-phenotype acute leukemia, T/myeloid, not otherwise specified, as that requires positivity for cytoplasmic CD3 or surface CD3, and that was conspicuously absent.⁵ Therefore, the appropriate workup and treatment should have essentially followed the course for acute myeloid leukemia,⁴ which is unclear from the present report as there is no mention of a molecular workup (eg, for FLT3 and NPM1 mutations). This would, in turn, have important treatment and prognostic implications.⁶

The reason for my comments is to bring to light the importance of exact pathologic diagnosis, especially when dealing with leukemia. We currently have a host of treatment options and prognostic tools for the various types of acute myeloid leukemia, but only when a clear and precise pathologic diagnosis is given.⁵

To the Editor: I read with great interest the article “Aleukemic leukemia cutis” by Abraham et al,¹ as we recently had a case of this at my institution. The case is unique and quite intriguing; however, I found the pathologic description confusing and imprecise.

The authors state, “The findings were consistent with leukemic T cells with monocytic differentiation.”¹ This is based on their findings that the tumor cells expressed CD4, CD43, CD68, and lysozyme. However, the cells were negative for CD30, ALK-1, CD2, and CD3.

First, I must contest the authors’ claim that “the cells co-expressed T-cell markers (CD4 and CD43)”: CD4 and CD43 are not specific for T cells and are almost invariably seen on monocytes, especially in acute monoblastic/monocytic leukemia (AMoL; also known as M5 in the French-American-British classification system).^2,3 Therefore, the immunophenotype is perfect for an AMoL, but since there was no significant blood or bone marrow involvement and it was limited to the skin, this would best fit with a myeloid sarcoma, which frequently has a monocytic immunoprofile.^3,4

Additionally, this would not be a mixed-phenotype acute leukemia, T/myeloid, not otherwise specified, as that requires positivity for cytoplasmic CD3 or surface CD3, and that was conspicuously absent.⁵ Therefore, the appropriate workup and treatment should have essentially followed the course for acute myeloid leukemia,⁴ which is unclear from the present report as there is no mention of a molecular workup (eg, for FLT3 and NPM1 mutations). This would, in turn, have important treatment and prognostic implications.⁶

The reason for my comments is to bring to light the importance of exact pathologic diagnosis, especially when dealing with leukemia. We currently have a host of treatment options and prognostic tools for the various types of acute myeloid leukemia, but only when a clear and precise pathologic diagnosis is given.⁵

To the Editor: I read with great interest the article “Aleukemic leukemia cutis” by Abraham et al,¹ as we recently had a case of this at my institution. The case is unique and quite intriguing; however, I found the pathologic description confusing and imprecise.

The authors state, “The findings were consistent with leukemic T cells with monocytic differentiation.”¹ This is based on their findings that the tumor cells expressed CD4, CD43, CD68, and lysozyme. However, the cells were negative for CD30, ALK-1, CD2, and CD3.

First, I must contest the authors’ claim that “the cells co-expressed T-cell markers (CD4 and CD43)”: CD4 and CD43 are not specific for T cells and are almost invariably seen on monocytes, especially in acute monoblastic/monocytic leukemia (AMoL; also known as M5 in the French-American-British classification system).^2,3 Therefore, the immunophenotype is perfect for an AMoL, but since there was no significant blood or bone marrow involvement and it was limited to the skin, this would best fit with a myeloid sarcoma, which frequently has a monocytic immunoprofile.^3,4

Additionally, this would not be a mixed-phenotype acute leukemia, T/myeloid, not otherwise specified, as that requires positivity for cytoplasmic CD3 or surface CD3, and that was conspicuously absent.⁵ Therefore, the appropriate workup and treatment should have essentially followed the course for acute myeloid leukemia,⁴ which is unclear from the present report as there is no mention of a molecular workup (eg, for FLT3 and NPM1 mutations). This would, in turn, have important treatment and prognostic implications.⁶

The reason for my comments is to bring to light the importance of exact pathologic diagnosis, especially when dealing with leukemia. We currently have a host of treatment options and prognostic tools for the various types of acute myeloid leukemia, but only when a clear and precise pathologic diagnosis is given.⁵

In Reply: We greatly appreciate our reader’s interest and response. He brings up a very good point. We have reviewed the reports and discussed it with our pathologists. On page 85, the sentence that begins, “The findings were consistent with leukemic T cells with monocytic differentiation” should actually read, “The findings were consistent with leukemic cells with monocytic differentiation.” The patient was appropriately treated for acute myeloid leukemia.

In Reply: We greatly appreciate our reader’s interest and response. He brings up a very good point. We have reviewed the reports and discussed it with our pathologists. On page 85, the sentence that begins, “The findings were consistent with leukemic T cells with monocytic differentiation” should actually read, “The findings were consistent with leukemic cells with monocytic differentiation.” The patient was appropriately treated for acute myeloid leukemia.

In Reply: We greatly appreciate our reader’s interest and response. He brings up a very good point. We have reviewed the reports and discussed it with our pathologists. On page 85, the sentence that begins, “The findings were consistent with leukemic T cells with monocytic differentiation” should actually read, “The findings were consistent with leukemic cells with monocytic differentiation.” The patient was appropriately treated for acute myeloid leukemia.

A 12-lead electrocardiogram (Figure 1) showed ST-segment elevation of more than 2 mm in leads V₂, V₃, V₄, and V₅, with no reciprocal changes.

Based on the classic angiographic appearance and the absence of atherosclerotic disease in other coronary arteries, type 2 spontaneous coronary artery dissection (SCAD) was diagnosed.

CORONARY ARTERY WALL SEPARATION

SCAD is defined as a nontraumatic, noniatrogenic intramural hemorrhage leading to separation of the coronary arterial wall and the formation of a false lumen. The separation can occur between any of the coronary artery wall layers and may or may not involve an intimal tear. The bleeding may result in an intramural hematoma and possible narrowing of the arterial lumen. Depending on the severity of narrowing, blood supply to the myocardium could be compromised, resulting in symptoms of ischemia.¹

SCAD usually involves a single coronary artery, although multiple coronary artery involvement has been reported.²

CASE CONTINUED: MANAGEMENT

The patient recovered completely and was discharged home with plans to return for outpatient imaging for fibromuscular dysplasia.

SCAD appears to be a rare cause of acute coronary syndrome, but it is likely underdiagnosed and is becoming increasingly recognized worldwide. Typically, it affects women younger than 50, with women in general outnumbering men 9 to 1.³ Overall, SCAD causes up to 4% of acute myocardial infarctions, but in women age 50 or younger, it is responsible for 24% to 35% of acute myocardial infarctions, and the proportion is even higher in pregnant women.⁴

Not just pregnancy-associated    

SCAD was previously thought to be mainly idiopathic and mostly affecting women peripartum. Current understanding paints a different picture: pregnancy-associated SCAD does not account for the majority of cases. That said, SCAD is the most common cause of myocardial infarction peripartum, with the third trimester and early postpartum period being the times of highest risk.⁵ SCAD development at those times is believed to be related to hormonal changes causing weakening of coronary artery walls.⁶

Weakening of the coronary artery wall also may occur in the setting of fibromuscular dysplasia, connective tissue disease, recurrent pregnancies, systemic inflammatory disease, hormonal therapy, and other disease states that cause arteriopathy. Exposure to a stressor in a patient with underlying risk factors can lead to either an intimal tear or rupture of the vasa vasorum, with subsequent formation of intramural hemorrhage and eventually SCAD.⁷ Stressors can be emotional or physical and can include labor and delivery, intense physical exercise, the Valsalva maneuver, and drug abuse.⁸

Presentation is variable

SCAD presentation depends on the degree of flow limitation and extent of the dissection. Presentation can range from asymptomatic to sudden cardiac death and can include signs and symptoms of acute coronary syndrome caused by ST-segment elevation or non-ST-segment elevation myocardial infarction.

DIAGNOSIS BY ANGIOGRAPHY    

SCAD can be diagnosed by coronary angiography. There are 3 angiographic types:

Type 1 (about 25% of SCAD cases) has typical contrast dye staining of the arterial wall and multiple radiolucent luminal abnormalities, with or without dye hang-up.

Type 2 (about 70%) has diffuse, smooth narrowing of the coronary artery, with the left anterior descending artery the most frequently affected.⁸

Type 3 (about 5%) mimics atherosclerosis, with focal or tubular stenosis.⁹

Types 1 and 2 are usually easy to recognize. To diagnose type 2, intravenous nitroglycerin should first be administered to rule out coronary spasm.

Type 3 SCAD is more challenging to diagnose because its appearance on angiography is similar to that of atherosclerosis. For equivocal findings in any type, but especially in type 3, intravascular ultrasonography or optical coherence tomography can help.¹⁰ Optical coherence tomography is preferred because of superior image resolution, although ultrasonography offers better tissue penetration.¹¹ 

MANAGE MOST CASES CONSERVATIVELY

Management algorithms for SCAD are available.^8,12

The initial and most critical step is to make the correct diagnosis. Although the presentation of acute coronary syndrome caused by SCAD is often identical to that of atherosclerosis, the conditions have different pathophysiologies and thus require different management. Theoretically, systemic anticoagulation may worsen an intramural hemorrhage.

First-line therapy for most patients with SCAD is conservative management and close inpatient monitoring for 3 to 5 days.¹³ More aggressive management is indicated for any of the following:

• Left main or severe proximal 2-vessel dissection
• Hemodynamic instability
• Ongoing ischemic symptoms.

In a prospective cohort of 168 patients, 134 (80%) were initially treated conservatively; of those, in-hospital myocardial infarction recurred in 4.5%, a major cardiac event occurred within 2 years in 17%, and SCAD recurred in 13%.⁸

Observational data on patients with SCAD who had repeat angiography weeks to months after the initial event has shown that lesions heal in 70% to 97% of patients.¹²

WHEN TO CONSIDER AGGRESSIVE MANAGEMENT

Under the circumstances listed above, revascularization with PCI or coronary artery bypass grafting (CABG) should be considered, with choice of procedure determined by feasibility, technical considerations, and local expertise.

The American Heart Association recommendations are as follows¹²:     

• For left main or severe proximal 2-vessel dissection in clinically stable patients, consider CABG
• For active ischemia or hemodynamic instability, consider PCI if feasible or perform urgent CABG.

A few series have shown that the prognosis with conservative management or CABG is better than with PCI.^8,13,14 The success rate for revascularization with PCI is only about 60% because of challenges including risk of inducing iatrogenic dissection, passing the wire into the false lumen and worsening a dissection, and propagating an intramural hematoma with stenting and further compromising coronary blood flow. In addition, dissection tends to extend into distal arteries that are difficult to stent. There is also the risk of stent malapposition after resorption of the intramural hematoma, causing late stent thrombosis.⁷ 

SCREEN FOR OTHER VASCULAR PROBLEMS

Imaging of the renal, iliac, and cerebral vasculature is recommended for all patients with SCAD.¹² Screening for fibromuscular dysplasia can be done with angiography, computed tomographic angiography (CTA), or magnetic resonance angiography (MRA).¹² 

Multifocal fibromuscular dysplasia in extracoronary arteries occurs with SCAD in 25% to 86% of cases. In a single-center series of 115 patients with confirmed SCAD who underwent CTA from 2010 to 2014, extracoronary vascular abnormalities were found in 66%, with fibromuscular dysplasia being the most common type (45%).¹⁵ In another single-center study, 327 patients with SCAD were prospectively followed from 2012 to 2016 with screening for cerebrovascular, renal, and iliac fibromuscular dysplasia using CTA or catheter angiography. Fibromuscular dysplasia was found in 63%, and intracranial aneurysm was found in 14% of patients with fibromuscular dysplasia.⁹ 

SCAD can also be associated with connective tissue disorders such as Ehlers-Danlos syndrome type IV and Marfan syndrome.^16,17

LONG-TERM MANAGEMENT

Patients with SCAD should start long-term aspirin and 1 year of clopidogrel. Statins are indicated for patients with hyperlipidemia^8,18 but otherwise offer no clear benefit for SCAD alone. If there are no contraindications, a beta-adrenergic blocker should be considered, especially if left ventricular dysfunction or arrhythmias are present. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers should also be considered with concomitant left ventricular dysfunction. Antianginal therapy can be used for post-SCAD chest pain syndromes.¹²

Repeat angiography is recommended only to evaluate recurrent symptoms, to confirm an unclear initial diagnosis, to assess for atherosclerosis-related stenosis, or to evaluate high-risk anatomy, eg, involvement of the left main coronary artery.¹²

Genetic testing is reserved for patients with a high clinical suspicion of connective tissue disease or systemic arteriopathy.¹⁹

A 12-lead electrocardiogram (Figure 1) showed ST-segment elevation of more than 2 mm in leads V₂, V₃, V₄, and V₅, with no reciprocal changes.

Based on the classic angiographic appearance and the absence of atherosclerotic disease in other coronary arteries, type 2 spontaneous coronary artery dissection (SCAD) was diagnosed.

CORONARY ARTERY WALL SEPARATION

SCAD is defined as a nontraumatic, noniatrogenic intramural hemorrhage leading to separation of the coronary arterial wall and the formation of a false lumen. The separation can occur between any of the coronary artery wall layers and may or may not involve an intimal tear. The bleeding may result in an intramural hematoma and possible narrowing of the arterial lumen. Depending on the severity of narrowing, blood supply to the myocardium could be compromised, resulting in symptoms of ischemia.¹

SCAD usually involves a single coronary artery, although multiple coronary artery involvement has been reported.²

CASE CONTINUED: MANAGEMENT

The patient recovered completely and was discharged home with plans to return for outpatient imaging for fibromuscular dysplasia.

SCAD appears to be a rare cause of acute coronary syndrome, but it is likely underdiagnosed and is becoming increasingly recognized worldwide. Typically, it affects women younger than 50, with women in general outnumbering men 9 to 1.³ Overall, SCAD causes up to 4% of acute myocardial infarctions, but in women age 50 or younger, it is responsible for 24% to 35% of acute myocardial infarctions, and the proportion is even higher in pregnant women.⁴

Not just pregnancy-associated    

SCAD was previously thought to be mainly idiopathic and mostly affecting women peripartum. Current understanding paints a different picture: pregnancy-associated SCAD does not account for the majority of cases. That said, SCAD is the most common cause of myocardial infarction peripartum, with the third trimester and early postpartum period being the times of highest risk.⁵ SCAD development at those times is believed to be related to hormonal changes causing weakening of coronary artery walls.⁶

Weakening of the coronary artery wall also may occur in the setting of fibromuscular dysplasia, connective tissue disease, recurrent pregnancies, systemic inflammatory disease, hormonal therapy, and other disease states that cause arteriopathy. Exposure to a stressor in a patient with underlying risk factors can lead to either an intimal tear or rupture of the vasa vasorum, with subsequent formation of intramural hemorrhage and eventually SCAD.⁷ Stressors can be emotional or physical and can include labor and delivery, intense physical exercise, the Valsalva maneuver, and drug abuse.⁸

Presentation is variable

SCAD presentation depends on the degree of flow limitation and extent of the dissection. Presentation can range from asymptomatic to sudden cardiac death and can include signs and symptoms of acute coronary syndrome caused by ST-segment elevation or non-ST-segment elevation myocardial infarction.

DIAGNOSIS BY ANGIOGRAPHY    

SCAD can be diagnosed by coronary angiography. There are 3 angiographic types:

Type 1 (about 25% of SCAD cases) has typical contrast dye staining of the arterial wall and multiple radiolucent luminal abnormalities, with or without dye hang-up.

Type 2 (about 70%) has diffuse, smooth narrowing of the coronary artery, with the left anterior descending artery the most frequently affected.⁸

Type 3 (about 5%) mimics atherosclerosis, with focal or tubular stenosis.⁹

Types 1 and 2 are usually easy to recognize. To diagnose type 2, intravenous nitroglycerin should first be administered to rule out coronary spasm.

Type 3 SCAD is more challenging to diagnose because its appearance on angiography is similar to that of atherosclerosis. For equivocal findings in any type, but especially in type 3, intravascular ultrasonography or optical coherence tomography can help.¹⁰ Optical coherence tomography is preferred because of superior image resolution, although ultrasonography offers better tissue penetration.¹¹ 

MANAGE MOST CASES CONSERVATIVELY

Management algorithms for SCAD are available.^8,12

The initial and most critical step is to make the correct diagnosis. Although the presentation of acute coronary syndrome caused by SCAD is often identical to that of atherosclerosis, the conditions have different pathophysiologies and thus require different management. Theoretically, systemic anticoagulation may worsen an intramural hemorrhage.

First-line therapy for most patients with SCAD is conservative management and close inpatient monitoring for 3 to 5 days.¹³ More aggressive management is indicated for any of the following:

• Left main or severe proximal 2-vessel dissection
• Hemodynamic instability
• Ongoing ischemic symptoms.

In a prospective cohort of 168 patients, 134 (80%) were initially treated conservatively; of those, in-hospital myocardial infarction recurred in 4.5%, a major cardiac event occurred within 2 years in 17%, and SCAD recurred in 13%.⁸

Observational data on patients with SCAD who had repeat angiography weeks to months after the initial event has shown that lesions heal in 70% to 97% of patients.¹²

WHEN TO CONSIDER AGGRESSIVE MANAGEMENT

Under the circumstances listed above, revascularization with PCI or coronary artery bypass grafting (CABG) should be considered, with choice of procedure determined by feasibility, technical considerations, and local expertise.

The American Heart Association recommendations are as follows¹²:     

• For left main or severe proximal 2-vessel dissection in clinically stable patients, consider CABG
• For active ischemia or hemodynamic instability, consider PCI if feasible or perform urgent CABG.

A few series have shown that the prognosis with conservative management or CABG is better than with PCI.^8,13,14 The success rate for revascularization with PCI is only about 60% because of challenges including risk of inducing iatrogenic dissection, passing the wire into the false lumen and worsening a dissection, and propagating an intramural hematoma with stenting and further compromising coronary blood flow. In addition, dissection tends to extend into distal arteries that are difficult to stent. There is also the risk of stent malapposition after resorption of the intramural hematoma, causing late stent thrombosis.⁷ 

SCREEN FOR OTHER VASCULAR PROBLEMS

Imaging of the renal, iliac, and cerebral vasculature is recommended for all patients with SCAD.¹² Screening for fibromuscular dysplasia can be done with angiography, computed tomographic angiography (CTA), or magnetic resonance angiography (MRA).¹² 

Multifocal fibromuscular dysplasia in extracoronary arteries occurs with SCAD in 25% to 86% of cases. In a single-center series of 115 patients with confirmed SCAD who underwent CTA from 2010 to 2014, extracoronary vascular abnormalities were found in 66%, with fibromuscular dysplasia being the most common type (45%).¹⁵ In another single-center study, 327 patients with SCAD were prospectively followed from 2012 to 2016 with screening for cerebrovascular, renal, and iliac fibromuscular dysplasia using CTA or catheter angiography. Fibromuscular dysplasia was found in 63%, and intracranial aneurysm was found in 14% of patients with fibromuscular dysplasia.⁹ 

SCAD can also be associated with connective tissue disorders such as Ehlers-Danlos syndrome type IV and Marfan syndrome.^16,17

LONG-TERM MANAGEMENT

Patients with SCAD should start long-term aspirin and 1 year of clopidogrel. Statins are indicated for patients with hyperlipidemia^8,18 but otherwise offer no clear benefit for SCAD alone. If there are no contraindications, a beta-adrenergic blocker should be considered, especially if left ventricular dysfunction or arrhythmias are present. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers should also be considered with concomitant left ventricular dysfunction. Antianginal therapy can be used for post-SCAD chest pain syndromes.¹²

Repeat angiography is recommended only to evaluate recurrent symptoms, to confirm an unclear initial diagnosis, to assess for atherosclerosis-related stenosis, or to evaluate high-risk anatomy, eg, involvement of the left main coronary artery.¹²

Genetic testing is reserved for patients with a high clinical suspicion of connective tissue disease or systemic arteriopathy.¹⁹

A 12-lead electrocardiogram (Figure 1) showed ST-segment elevation of more than 2 mm in leads V₂, V₃, V₄, and V₅, with no reciprocal changes.

Based on the classic angiographic appearance and the absence of atherosclerotic disease in other coronary arteries, type 2 spontaneous coronary artery dissection (SCAD) was diagnosed.

CORONARY ARTERY WALL SEPARATION

SCAD is defined as a nontraumatic, noniatrogenic intramural hemorrhage leading to separation of the coronary arterial wall and the formation of a false lumen. The separation can occur between any of the coronary artery wall layers and may or may not involve an intimal tear. The bleeding may result in an intramural hematoma and possible narrowing of the arterial lumen. Depending on the severity of narrowing, blood supply to the myocardium could be compromised, resulting in symptoms of ischemia.¹

SCAD usually involves a single coronary artery, although multiple coronary artery involvement has been reported.²

CASE CONTINUED: MANAGEMENT

The patient recovered completely and was discharged home with plans to return for outpatient imaging for fibromuscular dysplasia.

SCAD appears to be a rare cause of acute coronary syndrome, but it is likely underdiagnosed and is becoming increasingly recognized worldwide. Typically, it affects women younger than 50, with women in general outnumbering men 9 to 1.³ Overall, SCAD causes up to 4% of acute myocardial infarctions, but in women age 50 or younger, it is responsible for 24% to 35% of acute myocardial infarctions, and the proportion is even higher in pregnant women.⁴

Not just pregnancy-associated    

SCAD was previously thought to be mainly idiopathic and mostly affecting women peripartum. Current understanding paints a different picture: pregnancy-associated SCAD does not account for the majority of cases. That said, SCAD is the most common cause of myocardial infarction peripartum, with the third trimester and early postpartum period being the times of highest risk.⁵ SCAD development at those times is believed to be related to hormonal changes causing weakening of coronary artery walls.⁶

Weakening of the coronary artery wall also may occur in the setting of fibromuscular dysplasia, connective tissue disease, recurrent pregnancies, systemic inflammatory disease, hormonal therapy, and other disease states that cause arteriopathy. Exposure to a stressor in a patient with underlying risk factors can lead to either an intimal tear or rupture of the vasa vasorum, with subsequent formation of intramural hemorrhage and eventually SCAD.⁷ Stressors can be emotional or physical and can include labor and delivery, intense physical exercise, the Valsalva maneuver, and drug abuse.⁸

Presentation is variable

SCAD presentation depends on the degree of flow limitation and extent of the dissection. Presentation can range from asymptomatic to sudden cardiac death and can include signs and symptoms of acute coronary syndrome caused by ST-segment elevation or non-ST-segment elevation myocardial infarction.

DIAGNOSIS BY ANGIOGRAPHY    

SCAD can be diagnosed by coronary angiography. There are 3 angiographic types:

Type 1 (about 25% of SCAD cases) has typical contrast dye staining of the arterial wall and multiple radiolucent luminal abnormalities, with or without dye hang-up.

Type 2 (about 70%) has diffuse, smooth narrowing of the coronary artery, with the left anterior descending artery the most frequently affected.⁸

Type 3 (about 5%) mimics atherosclerosis, with focal or tubular stenosis.⁹

Types 1 and 2 are usually easy to recognize. To diagnose type 2, intravenous nitroglycerin should first be administered to rule out coronary spasm.

Type 3 SCAD is more challenging to diagnose because its appearance on angiography is similar to that of atherosclerosis. For equivocal findings in any type, but especially in type 3, intravascular ultrasonography or optical coherence tomography can help.¹⁰ Optical coherence tomography is preferred because of superior image resolution, although ultrasonography offers better tissue penetration.¹¹ 

MANAGE MOST CASES CONSERVATIVELY

Management algorithms for SCAD are available.^8,12

The initial and most critical step is to make the correct diagnosis. Although the presentation of acute coronary syndrome caused by SCAD is often identical to that of atherosclerosis, the conditions have different pathophysiologies and thus require different management. Theoretically, systemic anticoagulation may worsen an intramural hemorrhage.

First-line therapy for most patients with SCAD is conservative management and close inpatient monitoring for 3 to 5 days.¹³ More aggressive management is indicated for any of the following:

• Left main or severe proximal 2-vessel dissection
• Hemodynamic instability
• Ongoing ischemic symptoms.

In a prospective cohort of 168 patients, 134 (80%) were initially treated conservatively; of those, in-hospital myocardial infarction recurred in 4.5%, a major cardiac event occurred within 2 years in 17%, and SCAD recurred in 13%.⁸

Observational data on patients with SCAD who had repeat angiography weeks to months after the initial event has shown that lesions heal in 70% to 97% of patients.¹²

WHEN TO CONSIDER AGGRESSIVE MANAGEMENT

Under the circumstances listed above, revascularization with PCI or coronary artery bypass grafting (CABG) should be considered, with choice of procedure determined by feasibility, technical considerations, and local expertise.

The American Heart Association recommendations are as follows¹²:     

• For left main or severe proximal 2-vessel dissection in clinically stable patients, consider CABG
• For active ischemia or hemodynamic instability, consider PCI if feasible or perform urgent CABG.

A few series have shown that the prognosis with conservative management or CABG is better than with PCI.^8,13,14 The success rate for revascularization with PCI is only about 60% because of challenges including risk of inducing iatrogenic dissection, passing the wire into the false lumen and worsening a dissection, and propagating an intramural hematoma with stenting and further compromising coronary blood flow. In addition, dissection tends to extend into distal arteries that are difficult to stent. There is also the risk of stent malapposition after resorption of the intramural hematoma, causing late stent thrombosis.⁷ 

SCREEN FOR OTHER VASCULAR PROBLEMS

Imaging of the renal, iliac, and cerebral vasculature is recommended for all patients with SCAD.¹² Screening for fibromuscular dysplasia can be done with angiography, computed tomographic angiography (CTA), or magnetic resonance angiography (MRA).¹² 

Multifocal fibromuscular dysplasia in extracoronary arteries occurs with SCAD in 25% to 86% of cases. In a single-center series of 115 patients with confirmed SCAD who underwent CTA from 2010 to 2014, extracoronary vascular abnormalities were found in 66%, with fibromuscular dysplasia being the most common type (45%).¹⁵ In another single-center study, 327 patients with SCAD were prospectively followed from 2012 to 2016 with screening for cerebrovascular, renal, and iliac fibromuscular dysplasia using CTA or catheter angiography. Fibromuscular dysplasia was found in 63%, and intracranial aneurysm was found in 14% of patients with fibromuscular dysplasia.⁹ 

SCAD can also be associated with connective tissue disorders such as Ehlers-Danlos syndrome type IV and Marfan syndrome.^16,17

LONG-TERM MANAGEMENT

Patients with SCAD should start long-term aspirin and 1 year of clopidogrel. Statins are indicated for patients with hyperlipidemia^8,18 but otherwise offer no clear benefit for SCAD alone. If there are no contraindications, a beta-adrenergic blocker should be considered, especially if left ventricular dysfunction or arrhythmias are present. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers should also be considered with concomitant left ventricular dysfunction. Antianginal therapy can be used for post-SCAD chest pain syndromes.¹²

Repeat angiography is recommended only to evaluate recurrent symptoms, to confirm an unclear initial diagnosis, to assess for atherosclerosis-related stenosis, or to evaluate high-risk anatomy, eg, involvement of the left main coronary artery.¹²

Genetic testing is reserved for patients with a high clinical suspicion of connective tissue disease or systemic arteriopathy.¹⁹

Total hip or knee replacement (also called total joint arthroplasty) is highly successful at relieving pain and restoring function, but at the risk of acute kidney injury, which is a sudden loss of renal function. Various factors have been associated with this risk, some of which are potentially modifiable, notably, the use of nephrotoxic antibiotics and other drugs.

This review examines the incidence of acute kidney injury using current criteria in total joint arthroplasty of the hip or knee in general, and in the setting of revision surgery for prosthetic joint infection in particular, in which the risk is higher. We identify risk factors for acute kidney injury and propose ways to lower the risk.

MILLIONS OF PROCEDURES ANNUALLY

Total replacement of the hip^1,2 or knee³ is being done more and more. Kurtz et al⁴ estimate that by the year 2030, we will see approximately 3.5 million primary total knee and 500,000 primary total hip replacements every year. In addition, revision total knee procedures are expected to exceed 250,000 per year, and revision total hip procedures are expected to exceed 90,000 per year.⁴

Chronic infection may complicate up to 2% of these procedures and is associated with significant morbidity, death, and financial costs. Currently, it may be the reason for 25% of total joint arthroplasty revisions,⁵ but by the year 2030, it is projected to account for 66% of revision total knee arthroplasties and 48% of revision total hip arthroplasties.⁶

PRIMARY TOTAL JOINT ARTHROPLASTY AND ACUTE KIDNEY INJURY

Study designs, findings varied widely

The incidence of acute kidney injury varied markedly among the studies of primary total joint arthroplasty or revision for aseptic reasons. Numerous factors explain this heterogeneity.

Designs ranged from single-center studies with relatively small numbers of patients to large regional and national samples based on administrative data.

Almost all of the studies were retrospective. We are not aware of any randomized controlled trials.

Discharge diagnosis may miss many cases

Several studies based the diagnosis of acute kidney injury on International Classification of Diseases, Ninth Revision (ICD-9) coding from hospital discharge summaries.

Nadkarni et al,²⁹ in the largest study published to date, used the nationwide inpatient sample database of more than 7 million total joint arthroplasties and found an incidence of acute kidney injury based on ICD-9 coding of 1.3% over the years 2002 to 2012, although this increased to 1.8% to 1.9% from 2010 to 2012.

Lopez-de-Andres et al,³⁰ in a similar study using the Spanish national hospital discharge database, evaluated 20,188 patients who underwent revision total hip or knee arthroplasty and found an overall incidence of acute kidney injury of 0.94%, also using ICD-9 coding.

Gharaibeh et al³¹ used similar methods to diagnose acute kidney injury in a single-center study of 8,949 patients and found an incidence of 1.1%.

Although these 3 studies suggest that the incidence of acute kidney injury is relatively low, Grams et al³⁵ found the sensitivity of ICD-9 coding from hospital records for the diagnosis of acute kidney injury to be only 11.7% compared with KDIGO serum creatinine and urine output criteria. This suggests that the true incidence in these studies may be many times higher, possibly near 10%.

Do all stages of kidney injury count?

Jafari et al,⁷ in a large series from a single medical center, used only the “I” (injury) and “F” (failure) levels of the RIFLE criteria (corresponding to stages 2 and 3 of the KDIGO criteria) and found an incidence of 0.55% in more than 17,000 total joint arthroplasties.

Jamsa et al⁸ used the same criteria for acute kidney injury (only “I” and “F”) and found 58 cases in 5,609 patients in whom postoperative serum creatinine was measured, for an incidence of 1%; the remaining 14,966 patients in their cohort did not have serum creatinine measured, and it was assumed they did not have acute kidney injury. Neither of these studies included the most common “R” (risk) stage of acute kidney injury.

Parr et al³⁶ recently studied a nationwide sample of 657,840 hospitalized veterans and found that of 90,614 who developed acute kidney injury based on KDIGO creatinine criteria, 84% reached only stage R. This suggests that if all stages were considered, the true incidence of acute kidney injury would have been higher—possibly 4% in the Jafari series and possibly 7% in the Jamsa series.

Smaller studies had higher rates

Smaller, single-center series reported much higher incidences of acute kidney injury.

Kimmel et al¹¹ found an incidence of 14.8% in 425 total joint arthroplasties using RIFLE creatinine criteria.

Johansson et al²⁵ found an incidence of 19.9% in 136 total joint arthroplasties using KDIGO creatinine criteria.

Sehgal et al⁹ found an incidence of 21.9% in 659 total joint arthroplasties using AKIN creatinine criteria.

Challagundla et al²⁴ found an incidence of 23.7% in 198 procedures using RIFLE creatinine criteria.

Weingarten et al,¹⁰ in a single-center series of 7,463 total joint arthroplasties, found an incidence of acute kidney injury of only 2.2% using AKIN criteria, although 12% of the patients with acute kidney injury did not return to their baseline serum creatinine levels by 3 months.

Our estimate: Nearly 10%

In total, in the 20 studies in Table 1 that included all stages of acute kidney injury, there were 1,909 cases of acute kidney injury in 34,337 patients, for an incidence of 5.6%. Considering that all studies but one were retrospective and none considered urine output criteria for acute kidney injury, we believe that using current KDIGO criteria, the true incidence of acute kidney injury complicating primary lower-extremity total joint arthroplasties is really closer to 10%.

Various factors have been associated with development of acute kidney injury by multivariate analysis in these studies. Some are modifiable, while others are not, at least in the short term.

Nonmodifiable risk factors

Older age is often significant in studies assessing primary total joint arthroplasty or revision total joint arthroplasty not specifically for infection.^{11,12,16,17,26,28}

Obesity is also a major factor in the development of acute kidney injury,^{7,10–12,17,18} and, along with age, is a major factor contributing to the need for joint replacement in the first place.

Male sex may increase risk.²⁹

Diabetes mellitus was identified as a risk factor in several studies,^10,12,17,20 and hypertension in a few.^7,10,24

Other comorbidities and factors such as cardiovascular disease,^7,10 liver disease,⁷ pulmonary disease,⁷ high American Society of Anesthesiology score,^8,19 and benign heart murmurs preoperatively by routine physical examination have also been linked to acute kidney injury after joint arthroplasty.²⁸

Chronic kidney disease as a risk factor

Chronic kidney disease at baseline was associated with acute kidney injury in several of these series.^{7,11–13,15,19,29}

Warth et al¹² studied 1,038 patients and found an incidence of acute kidney injury of 11% in the 135 with chronic kidney disease (defined as serum creatinine > 1.2 mg/dL) and who received acetaminophen or narcotics for pain control, compared with 4.8% in the remaining 903 patients without chronic kidney disease, who received ketorolac or celecoxib.

Perregaard et al¹³ studied 3,410 patients who underwent total hip arthroplasty and found an incidence of acute kidney injury (per KDIGO creatinine criteria) of 2.2% overall, but 7% in the 134 patients with chronic kidney disease based on KDIGO creatinine criteria.

Nowicka et al¹⁵ found an incidence of acute kidney injury of 16.7% in the 48 patients with chronic kidney disease (defined as a glomerular filtration rate estimated by the Cockroft-Gault formula of less than 60 mL/min/1.73 m²), compared with 4.5% in the remaining 289.

Modifiable risk factors

Modifiable risk factors that should be considered in high-risk cases include anemia, perioperative blood transfusion, perioperative use of renin-angiotensin-aldosterone system inhibitors such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), particular antibiotics used for prophylaxis, and nonsteroidal anti-inflammatory drugs used postoperatively.

Anemia and blood transfusion

Preoperative anemia has been associated with postoperative acute kidney injury in various surgical settings such as cardiac surgery.^37,38 Perioperative red blood cell transfusions have also been associated with acute kidney injury in cardiac surgery; similar results may apply to total joint arthroplasty.

Choi et al,¹⁷ in 2,467 patients undergoing hip replacement, found a significant risk for acute kidney injury if postoperative hemoglobin was consistently below 10 g/dL compared with consistently above this level, with an inverse probability-of-treatment weighted odds ratio of 1.817 (P = .011).

Others have found a significant association of perioperative blood transfusion with acute kidney injury in total joint arthroplasty.^10,29

Nadkarni et al,²⁹ for example, used the nationwide inpatient sample database and found by multivariate analysis that perioperative blood transfusion was strongly associated with acute kidney injury, with an adjusted odds ratio of 2.28 (95% confidence interval [CI] 2.15–2.42, P < .0001).

Comment. A higher incidence of acute kidney injury may represent confounding by indication bias, as sicker patients or complicated surgeries may require transfusion, and this risk may not be completely accounted for by multivariate analysis. It is also possible, however, that transfusions per se may contribute to acute kidney injury. Possible direct or indirect mechanisms mediating acute kidney injury include hemolytic reactions, circulatory overload, acute lung injury, and immunomodulatory effects.³⁹

Preoperative transfusion in anemic patients undergoing cardiac surgery may also reduce the incidence of postoperative acute kidney injury both by correcting the anemia and by limiting the need for perioperative transfusions.⁴⁰ It remains to be determined whether elective preoperative transfusion to correct anemia would reduce postoperative development of acute kidney injury in total joint arthroplasty. As an aside, perioperative transfusion has also been linked to development of periprosthetic joint infection.⁴¹

Renin-angiotensin-aldosterone system inhibitors

Several studies found perioperative use of renin-angiotensin-aldosterone system inhibitors to be a risk factor for acute kidney injury.

Kimmel et al¹¹ reported adjusted odds ratios of 2.70 (95% CI 1.12–6.48) for ACE inhibitor use and 2.64 (95% CI 1.18–5.93) for ARB use in a study of 425 primary total joint arthroplasties.

Challagundla et al²⁴ found an odds ratio of 3.07 (95% CI 1.40–6.74) with ACE inhibitor or ARB use by multivariate analysis in 198 total joint arthroplasties.

Nielson et al¹⁸ studied 798 patients who underwent total joint arthroplasty and found that preoperative use of renin-angiotensin system inhibitors was associated with a significantly higher rate of postoperative acute kidney injury (8.3% vs 1.7% without inhibition), which was statistically significant by multivariate analysis (odds ratio 2.6, 95% CI 1.04–6.51).

We recommend holding renin-angiotensin-aldosterone system inhibitors 7 days before surgery through the postoperative period in high-risk cases.

Aminoglycoside use as a risk factor

Prophylactic administration of systemic antibiotics is the standard of care. In a systematic review of 26 studies and meta-analysis of 7 studies (3,065 patients), prophylactic antibiotics reduced the relative risk of wound infection by 81% with an absolute risk reduction of 8%.⁴²

A modifiable risk factor for acute kidney injury is the specific antibiotic used for prophylaxis. Multiple studies assessed the risk of acute kidney injury comparing regimens containing an aminoglycoside (typically gentamicin) with regimens lacking these agents.^20–26 In general, these studies found a significantly higher risk of acute kidney injury when gentamicin was used.

Challagundla et al²⁴ found an incidence of acute kidney injury of 52% using RIFLE creatinine criteria in 52 patients receiving 8 g total of flucloxacillin plus 160 mg of gentamicin (120 mg if they weighed less than 60 kg) compared with 8% in 48 patients given cefuroxime (3 g total) and 14% in an additional 52 patients also given cefuroxime.

Johansson et al²⁵ found an incidence of KDIGO creatinine-based acute kidney injury of 13% in 70 patients given dicloxacillin alone prophylactically compared with 27% given dicloxacillin and gentamicin, with a relative risk of 3.

Bell et al,²¹ in a large registry-based analysis from Scotland involving 7,666 elective orthopedic procedures, found that use of flucloxacillin 2 g plus a single dose of gentamicin 4 mg/kg was significantly associated with a 94% higher risk of acute kidney injury (KDIGO creatinine criteria) compared with a cefuroxime-based regimen, with absolute rates increasing from 6.2% to 10.8%.

Dubrovskaya et al²⁰ and Ferguson et al,²⁶ in contrast, found no increased risk with addition of gentamicin.

We recommend avoiding aminoglycosides for prophylaxis in primary lower-extremity total joint arthroplasty in patients at higher risk unless required for specific microbiologic reasons.

Vancomycin may also increase risk

Courtney et al¹⁹ assessed the risk of adding vancomycin to cefazolin for routine prophylaxis in a retrospective series of 1,828 total hip or knee arthroplasties and found a significantly higher rate of acute kidney injury, using AKIN criteria (13% vs 8%, odds ratio by multivariate analysis 1.82, P = .002).¹⁹

Other agents shown to be effective in treating periprosthetic joint infections or complicated skin and soft-tissue infections with resistant organisms include daptomycin⁴³ and linezolid.⁴⁴ These nonnephrotoxic alternatives to vancomycin may be a consideration if prophylaxis for methicillin-resistant Staphylococcus aureus is deemed necessary in patients at risk for acute kidney injury.

Deep infection may complicate nearly 1% of total hip⁴⁵ and 2% of total knee arthroplasties.⁴⁶ Kurtz et al^4,6 have projected that by 2030, infection will be the cause of two-thirds of the estimated 268,000 revision total knee arthroplasties and about half of the estimated 96,700 revision total hip arthroplasties.

The most common method of treating a chronically infected replacement joint is a 2-stage procedure.⁵ First, the prosthesis is removed, all infected bone and soft tissue is debrided, and an antibiotic-loaded cement spacer is implanted. Systemic antibiotics are given concurrently, typically for about 6 weeks. After the infection is brought under control, perhaps 2 to 3 months later, the spacer is removed and a new joint is implanted with antibiotic-loaded cement. A 1-stage procedure may be an option in selected cases and would obviate the need for an antibiotic-loaded cement spacer.^47,48

Of obvious relevance to development of acute kidney injury is the choice and amount of antibiotics embedded in the cement used for spacers and in implantation. Very high antibiotic levels are achieved within the joint space, usually with little systemic absorption, although significant systemic exposure has been documented in some cases.

The polymethylmethacrylate cement used for these purposes comes in 40-g bags. Multiple bags are typically required per joint, perhaps 2 to 4.⁴⁹

The rate of elution of antibiotics is determined by several factors, including surface area, porosity, and the number of antibiotics. In general, elution is greatest early on, with exponential decline lasting perhaps 1 week,  followed by slow, sustained release over weeks to months.⁵⁰ However, several in vitro studies have indicated that only about 5%^50,51 of the total antibiotic actually elutes over time.

Initially, multiple antibiotic-laden cement beads were used to fill the joint space, but this significantly limited function and mobility.⁵² Now, cement spacers are used, and they can be nonarticulating or articulating for maximal joint mobility.⁵³ Although much greater antibiotic elution occurs from beads due to their high surface area-to-volume ratio, spacers still provide an adequate dose.

ANTIBIOTIC-LOADED CEMENT: DOSAGE AND ELUTION CHARACTERISTICS

Antibiotic-loaded cement can be either low-dose or high-dose.

Low-dose cement

Low-dose cement typically consists of 0.5 to 1.0 g of antibiotic per 40-g bag of cement, usually an aminoglycoside (gentamicin or tobramycin) or vancomycin, and can be purchased premixed by the manufacturer. Such cement is only used prophylactically with primary total joint arthroplasty or revision for aseptic reasons, a practice common in Europe but less so in the United States. Some American authors propose antibiotic-loaded cement prophylaxis for patients at high risk, eg, those with immunosuppression, inflammatory cause of arthritis, or diabetes.⁵⁴

Vrabec et al,⁵⁵ in a study of low-dose tobramycin-loaded cement used for primary total knee arthroplasty, found a peak median intra-articular tobramycin concentration of 32 mg/L at 6 hours, declining to 6 mg/L at 48 hours with all serum levels 0.3 mg/L or less (unmeasureable) at similar time points.

Sterling et al,⁵⁶ studying primary total hip arthroplasties with low-dose tobramycin-loaded cement, found mean levels in drainage fluid of 103 mg/L at 6 hours, declining to 15 mg/L at 48 hours. Serum levels peaked at 0.94 mg/L at 3 hours, declining to 0.2 mg/L by 48 hours.

Although most of the antibiotic elution occurs early (within the first week), antibiotic can be found in joint aspirates up to 20 years later.⁵⁷ We are unaware of any well-documented cases of acute kidney injury ascribable to low-dose antibiotic-loaded cement used prophylactically. One case report making this assertion did not determine serum levels of aminoglycoside.⁵⁸

High-dose cement

High-dose antibiotic-loaded cement typically contains about 4 to 8 g of antibiotic per 40-g bag of cement and is used in the treatment of prosthetic joint infection to form the spacers. The antibiotic must be mixed into the cement powder by the surgeon in the operating room.

There is no standard combination or dosage. The choice of antibiotic can be tailored to the infecting organism if known. Otherwise, gram-positive organisms are most common, and vancomycin and aminoglycosides are often used together. This particular combination will enhance the elution of both antibiotics when studied in vitro, a process termed “passive opportunism.”⁵⁹ Other antibiotics in use include aztreonam, piperacillin, teicoplanin, fluoroquinolones, cephalosporins, and daptomycin, among others.

About 8 g of antibiotic total per 40-g bag is the maximum to allow easy molding.⁵² As an example, this may include 4 g of vancomycin and 3.6 g of tobramycin per 40 g. Given that 3 to 4 such bags are often used per joint, there is significant risk of systemic exposure.

Kalil et al⁶⁰ studied 8 patients who received high-dose tobramycin-loaded cement to treat periprosthetic joint infections of the hip or knee and found that 7 had detectable serum levels (mean 0.84 mg/L, highest 2.0 mg/L), including 1 with a level of 0.9 mg/L on day 38; 4 of these 8 developed acute kidney injury by AKIN criteria, although other risk factors for acute kidney injury existed. Nearly all had concomitant vancomycin (3 to 8 g) added to the cement as well.

Hsieh et al⁶¹ studied 46 patients with infected total hip arthroplasties treated with high-dose antibiotic-loaded cement spacers (vancomycin 4 g and aztreonam 4 g per 40-g bag) and found vancomycin levels in joint drainage higher than 1,500 mg/L on day 1, decreasing to 571 mg/L on day 7; serum levels were low (range 0.1–1.6 mg/L at 24 hours), falling to undetectable by 72 hours.

Case reports have associated high-dose antibiotic-loaded cement spacers with acute kidney injury.

Curtis et al⁶² described an 85-year-old patient with stage 3 chronic kidney disease who was treated for an infected total knee arthroplasty with an antibiotic-loaded cement spacer (containing 3.6 g of tobramycin and 3 g of cefazolin per 40-g bag, 3 bags total) and developed stage 3 acute kidney injury. After 16 days and 3 hemodialysis sessions, the patient’s serum tobramycin level was still 2 mg/L despite receiving no systemic tobramycin.

Wu et al⁶³ reported a case of acute kidney injury that required dialysis after implantation of a tobramycin- and vancomycin-loaded spacer, with persistent serum tobramycin levels despite repeated hemodialysis sessions until the spacer was removed.

Chalmers et al⁶⁴ described 2 patients with acute kidney injury and persistently elevated serum tobramycin levels (3.9 mg/L on day 39 in 1 patient and 2.0 mg/L on day 24 in the other patient) despite no systemic administration.

In these and other case reports,^65–67 dialysis and spacer explantation were usually required. 


Comment. It is intuitive that acute kidney injury would more likely complicate revision total joint arthroplasties for infection than for primary total joint arthroplasties or revisions for aseptic reasons, given the systemic effects of infection and exposure to nephrotoxic or allergenic antibiotics. And the available data suggest that the risk of acute kidney injury is higher with revision for prosthetic joint infection than with revision for aseptic reasons. However, many of the studies were retrospective, relatively small, single-center series and used different definitions of acute kidney injury.

Luu et al⁸³ performed a systematic review of studies published between January 1989 and June 2012 reporting systemic complications (including acute kidney injury) of 2-stage revision arthroplasties including placement of an antibiotic-loaded cement spacer for treatment of periprosthetic joint infection. Overall, 10 studies were identified with 544 total patients. Five of these studies, with 409 patients, reported at least 1 case of acute kidney injury for a total of 27 patients, giving an incidence of 6.6% in these studies.^68–71 The remaining 5 studies, totaling 135 patients, did not report any cases of acute kidney injury,^{50,61,76–78} although that was not the primary focus of any of those trials.

Most notable from this systematic review, the study of Menge et al⁶⁹ retrospectively determined the incidence of acute kidney injury (defined as a 50% rise in serum creatinine to > 1.4 mg/dL within 90 days of surgery) to be 17% in 84 patients with infected total knee arthroplasties treated with antibiotic-loaded cement spacers. A mean of 3.5 bags of cement per spacer were used in the 35 articulating spacers, compared with 2.9 per nonarticulating spacer. These spacers contained vancomycin in 82% (median 4.0 g, range 1–16 g) and tobramycin in 94% (median 4.8 g, range 1–12 g), among others in small percentages. The dose of tobramycin in the spacer considered either as a dichotomous variable (> 4.8 g, OR 5.87) or linearly (OR 1.24 per 1-g increase) was significantly associated with acute kidney injury, although systemic administration of aminoglycosides or vancomycin was not.

Additional single-center series that were published subsequent to this review have generally used more current diagnostic criteria.

Noto et al⁷² found that 10 of 46 patients treated with antibiotic-loaded cement spacers had a greater than 50% rise in serum creatinine (average increase 260%). All spacers contained tobramycin (mean dose 8.2 g), and 9 of 10 also contained vancomycin (mean 7.6 g). All of the 9 patients with acute kidney injury with follow-up data recovered renal function.

Reed et al⁷⁵ found 26 cases of acute kidney injury (based on RIFLE creatinine criteria) in 306 patients with antibiotic-loaded cement spacers treating various periprosthetic joint infections (including hips, knees, shoulders, and digits) and compared them with 74 controls who did not develop acute kidney injury. By multivariable analysis, receipt of an ACE inhibitor within 7 days of surgery and receipt of piperacillin-tazobactam within 7 days after surgery were both significantly more common in cases with acute kidney injury than in controls without acute kidney injury.

Aeng et al⁷³ prospectively studied 50 consecutive patients receiving antibiotic-loaded spacers containing tobramycin (with or without vancomycin) for treatment of infected hip or knee replacements. Using RIFLE creatinine criteria, they found an incidence of acute kidney injury of 20% (10 of 50). Factors significantly associated with acute kidney injury included cement premixed by the manufacturer with gentamicin (0.5 g per 40-g bag) in addition to the tobramycin they added, intraoperative blood transfusions, and postoperative use of nonsteroidal anti-inflammatory drugs.

Geller et al,⁷⁴ in a multicenter retrospective study of 247 patients with prosthetic joint infections (156 knees and 91 hips) undergoing antibiotic-loaded cement spacer placement, found an incidence of acute kidney injury of 26% based on KDIGO creatinine criteria. Significant risk factors included higher body mass index, lower preoperative hemoglobin level, drop in hemoglobin after surgery, and comorbidity (hypertension, diabetes, chronic kidney disease, or cardiovascular disease). Most of the spacers contained a combination of vancomycin and either tobramycin (81%) or gentamicin (13%). The spacers contained an average of 5.3 g (range 0.6–18 g) of vancomycin (average 2.65 g per 40-g bag) and an average of 5.2 g (range 0.5–16.4 g) of tobramycin (average 2.6 g per bag).

As in Menge et al,⁶⁹ this study illustrates the wide range of antibiotic dosages in use and the lack of standardization. In contrast to the study by Menge et al, however, development of acute kidney injury was not related to the amount of vancomycin or tobramycin contained in the spacers. Eventual clearance of infection (at 1 and 2 years) was significantly related to increasing amounts of vancomycin. Multiple different systemic antibiotics were used, most commonly vancomycin (44%), and systemic vancomycin was not associated with acute kidney injury.

Yadav et al,⁸¹ in a study of 3,129 consecutive revision procedures of the knee or hip, found an incidence of acute kidney injury by RIFLE creatinine criteria of 29% in the 197 patients who received antibiotic-loaded cement spacers for periprosthetic joint infection compared with 3.4% in the 2,848 who underwent revision for aseptic reasons. In 84 patients with prosthetic joint infection having various surgeries not including placement of a spacer, the acute kidney injury rate at some point in their course was an alarmingly high 82%. In the group that received spacers, only age and comorbidity as assessed by Charlson comorbidity index were independently associated with acute kidney injury by multivariate analysis. Surprisingly, modest renal impairment was protective, possibly because physicians of patients with chronic kidney disease were more vigilant and took appropriate measures to prevent acute kidney injury.

Overall, the risk of acute kidney injury appears to be much higher during treatment of prosthetic joint infection with a 2-stage procedure using an antibiotic-loaded cement spacer than after primary total joint arthroplasty or revision for aseptic reasons, and may complicate up to one-third of cases.

As in primary total joint arthroplasty in general, higher-risk cases should be identified based on age, body mass index, chronic kidney disease, comorbidities (hypertension, diabetes, established cardiovascular disease), and anemia.

Preoperative transfusion can be considered case by case depending on degree of anemia and associated risk factors.

All renin-angiotensin-aldosterone system inhibitors should be withheld starting 1 week before surgery.

Both nonselective and cyclooxygenase-2 selective nonsteroidal anti-inflammatory drugs should be avoided, if possible.

Strict attention should be paid to adequate intraoperative and postoperative fluid resuscitation.

Kidney function should be monitored closely in the early postoperative period, including urine output and daily creatinine for at least 72 hours.

Systemic administration of potentially nephrotoxic antibiotics should be minimized, especially the combination of vancomycin with piperacillin-tazobactam.⁸⁴ Daptomycin is a consideration.⁴³

If acute kidney injury should develop, serum levels of vancomycin or aminoglycosides should be measured if the spacer contains these antibiotics. The spacer may need to be removed if toxic serum levels persist.

TAKE-HOME POINTS

Acute kidney injury may complicate up to 10% of primary lower-extremity total joint arthroplasties and up to 25% of periprosthetic joint infections treated with a 2-stage procedure including placement of an antibiotic-loaded cement spacer in the first stage.

Risk factors for acute kidney injury include older age, obesity, chronic kidney disease, and overall comorbidity. Potentially modifiable risk factors include anemia, perioperative transfusions, aminoglycoside prophylaxis, perioperative renin-angiotensin system blockade, and postoperative nonsteroidal anti-inflammatory drugs. These should be mitigated when possible.

In patients with periprosthetic joint infection who receive antibiotic-loaded cement spacers, especially patients  with additional risk factors for acute kidney injury, strict attention should be paid to the dose of antibiotic in the spacer, with levels checked postoperatively if necessary. Nonnephrotoxic antibiotics should be chosen for systemic administration when possible.

Prospective randomized controlled trials are needed to guide therapy after total joint arthroplasty, and to verify the adverse long-term outcomes of acute kidney injury in this setting.

Total hip or knee replacement (also called total joint arthroplasty) is highly successful at relieving pain and restoring function, but at the risk of acute kidney injury, which is a sudden loss of renal function. Various factors have been associated with this risk, some of which are potentially modifiable, notably, the use of nephrotoxic antibiotics and other drugs.

This review examines the incidence of acute kidney injury using current criteria in total joint arthroplasty of the hip or knee in general, and in the setting of revision surgery for prosthetic joint infection in particular, in which the risk is higher. We identify risk factors for acute kidney injury and propose ways to lower the risk.

MILLIONS OF PROCEDURES ANNUALLY

Total replacement of the hip^1,2 or knee³ is being done more and more. Kurtz et al⁴ estimate that by the year 2030, we will see approximately 3.5 million primary total knee and 500,000 primary total hip replacements every year. In addition, revision total knee procedures are expected to exceed 250,000 per year, and revision total hip procedures are expected to exceed 90,000 per year.⁴

Chronic infection may complicate up to 2% of these procedures and is associated with significant morbidity, death, and financial costs. Currently, it may be the reason for 25% of total joint arthroplasty revisions,⁵ but by the year 2030, it is projected to account for 66% of revision total knee arthroplasties and 48% of revision total hip arthroplasties.⁶

PRIMARY TOTAL JOINT ARTHROPLASTY AND ACUTE KIDNEY INJURY

Study designs, findings varied widely

The incidence of acute kidney injury varied markedly among the studies of primary total joint arthroplasty or revision for aseptic reasons. Numerous factors explain this heterogeneity.

Designs ranged from single-center studies with relatively small numbers of patients to large regional and national samples based on administrative data.

Almost all of the studies were retrospective. We are not aware of any randomized controlled trials.

Discharge diagnosis may miss many cases

Several studies based the diagnosis of acute kidney injury on International Classification of Diseases, Ninth Revision (ICD-9) coding from hospital discharge summaries.

Nadkarni et al,²⁹ in the largest study published to date, used the nationwide inpatient sample database of more than 7 million total joint arthroplasties and found an incidence of acute kidney injury based on ICD-9 coding of 1.3% over the years 2002 to 2012, although this increased to 1.8% to 1.9% from 2010 to 2012.

Lopez-de-Andres et al,³⁰ in a similar study using the Spanish national hospital discharge database, evaluated 20,188 patients who underwent revision total hip or knee arthroplasty and found an overall incidence of acute kidney injury of 0.94%, also using ICD-9 coding.

Gharaibeh et al³¹ used similar methods to diagnose acute kidney injury in a single-center study of 8,949 patients and found an incidence of 1.1%.

Although these 3 studies suggest that the incidence of acute kidney injury is relatively low, Grams et al³⁵ found the sensitivity of ICD-9 coding from hospital records for the diagnosis of acute kidney injury to be only 11.7% compared with KDIGO serum creatinine and urine output criteria. This suggests that the true incidence in these studies may be many times higher, possibly near 10%.

Do all stages of kidney injury count?

Jafari et al,⁷ in a large series from a single medical center, used only the “I” (injury) and “F” (failure) levels of the RIFLE criteria (corresponding to stages 2 and 3 of the KDIGO criteria) and found an incidence of 0.55% in more than 17,000 total joint arthroplasties.

Jamsa et al⁸ used the same criteria for acute kidney injury (only “I” and “F”) and found 58 cases in 5,609 patients in whom postoperative serum creatinine was measured, for an incidence of 1%; the remaining 14,966 patients in their cohort did not have serum creatinine measured, and it was assumed they did not have acute kidney injury. Neither of these studies included the most common “R” (risk) stage of acute kidney injury.

Parr et al³⁶ recently studied a nationwide sample of 657,840 hospitalized veterans and found that of 90,614 who developed acute kidney injury based on KDIGO creatinine criteria, 84% reached only stage R. This suggests that if all stages were considered, the true incidence of acute kidney injury would have been higher—possibly 4% in the Jafari series and possibly 7% in the Jamsa series.

Smaller studies had higher rates

Smaller, single-center series reported much higher incidences of acute kidney injury.

Kimmel et al¹¹ found an incidence of 14.8% in 425 total joint arthroplasties using RIFLE creatinine criteria.

Johansson et al²⁵ found an incidence of 19.9% in 136 total joint arthroplasties using KDIGO creatinine criteria.

Sehgal et al⁹ found an incidence of 21.9% in 659 total joint arthroplasties using AKIN creatinine criteria.

Challagundla et al²⁴ found an incidence of 23.7% in 198 procedures using RIFLE creatinine criteria.

Weingarten et al,¹⁰ in a single-center series of 7,463 total joint arthroplasties, found an incidence of acute kidney injury of only 2.2% using AKIN criteria, although 12% of the patients with acute kidney injury did not return to their baseline serum creatinine levels by 3 months.

Our estimate: Nearly 10%

In total, in the 20 studies in Table 1 that included all stages of acute kidney injury, there were 1,909 cases of acute kidney injury in 34,337 patients, for an incidence of 5.6%. Considering that all studies but one were retrospective and none considered urine output criteria for acute kidney injury, we believe that using current KDIGO criteria, the true incidence of acute kidney injury complicating primary lower-extremity total joint arthroplasties is really closer to 10%.

Various factors have been associated with development of acute kidney injury by multivariate analysis in these studies. Some are modifiable, while others are not, at least in the short term.

Nonmodifiable risk factors

Older age is often significant in studies assessing primary total joint arthroplasty or revision total joint arthroplasty not specifically for infection.^{11,12,16,17,26,28}

Obesity is also a major factor in the development of acute kidney injury,^{7,10–12,17,18} and, along with age, is a major factor contributing to the need for joint replacement in the first place.

Male sex may increase risk.²⁹

Diabetes mellitus was identified as a risk factor in several studies,^10,12,17,20 and hypertension in a few.^7,10,24

Other comorbidities and factors such as cardiovascular disease,^7,10 liver disease,⁷ pulmonary disease,⁷ high American Society of Anesthesiology score,^8,19 and benign heart murmurs preoperatively by routine physical examination have also been linked to acute kidney injury after joint arthroplasty.²⁸

Chronic kidney disease as a risk factor

Chronic kidney disease at baseline was associated with acute kidney injury in several of these series.^{7,11–13,15,19,29}

Warth et al¹² studied 1,038 patients and found an incidence of acute kidney injury of 11% in the 135 with chronic kidney disease (defined as serum creatinine > 1.2 mg/dL) and who received acetaminophen or narcotics for pain control, compared with 4.8% in the remaining 903 patients without chronic kidney disease, who received ketorolac or celecoxib.

Perregaard et al¹³ studied 3,410 patients who underwent total hip arthroplasty and found an incidence of acute kidney injury (per KDIGO creatinine criteria) of 2.2% overall, but 7% in the 134 patients with chronic kidney disease based on KDIGO creatinine criteria.

Nowicka et al¹⁵ found an incidence of acute kidney injury of 16.7% in the 48 patients with chronic kidney disease (defined as a glomerular filtration rate estimated by the Cockroft-Gault formula of less than 60 mL/min/1.73 m²), compared with 4.5% in the remaining 289.

Modifiable risk factors

Modifiable risk factors that should be considered in high-risk cases include anemia, perioperative blood transfusion, perioperative use of renin-angiotensin-aldosterone system inhibitors such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), particular antibiotics used for prophylaxis, and nonsteroidal anti-inflammatory drugs used postoperatively.

Anemia and blood transfusion

Preoperative anemia has been associated with postoperative acute kidney injury in various surgical settings such as cardiac surgery.^37,38 Perioperative red blood cell transfusions have also been associated with acute kidney injury in cardiac surgery; similar results may apply to total joint arthroplasty.

Choi et al,¹⁷ in 2,467 patients undergoing hip replacement, found a significant risk for acute kidney injury if postoperative hemoglobin was consistently below 10 g/dL compared with consistently above this level, with an inverse probability-of-treatment weighted odds ratio of 1.817 (P = .011).

Others have found a significant association of perioperative blood transfusion with acute kidney injury in total joint arthroplasty.^10,29

Nadkarni et al,²⁹ for example, used the nationwide inpatient sample database and found by multivariate analysis that perioperative blood transfusion was strongly associated with acute kidney injury, with an adjusted odds ratio of 2.28 (95% confidence interval [CI] 2.15–2.42, P < .0001).

Comment. A higher incidence of acute kidney injury may represent confounding by indication bias, as sicker patients or complicated surgeries may require transfusion, and this risk may not be completely accounted for by multivariate analysis. It is also possible, however, that transfusions per se may contribute to acute kidney injury. Possible direct or indirect mechanisms mediating acute kidney injury include hemolytic reactions, circulatory overload, acute lung injury, and immunomodulatory effects.³⁹

Preoperative transfusion in anemic patients undergoing cardiac surgery may also reduce the incidence of postoperative acute kidney injury both by correcting the anemia and by limiting the need for perioperative transfusions.⁴⁰ It remains to be determined whether elective preoperative transfusion to correct anemia would reduce postoperative development of acute kidney injury in total joint arthroplasty. As an aside, perioperative transfusion has also been linked to development of periprosthetic joint infection.⁴¹

Renin-angiotensin-aldosterone system inhibitors

Several studies found perioperative use of renin-angiotensin-aldosterone system inhibitors to be a risk factor for acute kidney injury.

Kimmel et al¹¹ reported adjusted odds ratios of 2.70 (95% CI 1.12–6.48) for ACE inhibitor use and 2.64 (95% CI 1.18–5.93) for ARB use in a study of 425 primary total joint arthroplasties.

Challagundla et al²⁴ found an odds ratio of 3.07 (95% CI 1.40–6.74) with ACE inhibitor or ARB use by multivariate analysis in 198 total joint arthroplasties.

Nielson et al¹⁸ studied 798 patients who underwent total joint arthroplasty and found that preoperative use of renin-angiotensin system inhibitors was associated with a significantly higher rate of postoperative acute kidney injury (8.3% vs 1.7% without inhibition), which was statistically significant by multivariate analysis (odds ratio 2.6, 95% CI 1.04–6.51).

We recommend holding renin-angiotensin-aldosterone system inhibitors 7 days before surgery through the postoperative period in high-risk cases.

Aminoglycoside use as a risk factor

Prophylactic administration of systemic antibiotics is the standard of care. In a systematic review of 26 studies and meta-analysis of 7 studies (3,065 patients), prophylactic antibiotics reduced the relative risk of wound infection by 81% with an absolute risk reduction of 8%.⁴²

A modifiable risk factor for acute kidney injury is the specific antibiotic used for prophylaxis. Multiple studies assessed the risk of acute kidney injury comparing regimens containing an aminoglycoside (typically gentamicin) with regimens lacking these agents.^20–26 In general, these studies found a significantly higher risk of acute kidney injury when gentamicin was used.

Challagundla et al²⁴ found an incidence of acute kidney injury of 52% using RIFLE creatinine criteria in 52 patients receiving 8 g total of flucloxacillin plus 160 mg of gentamicin (120 mg if they weighed less than 60 kg) compared with 8% in 48 patients given cefuroxime (3 g total) and 14% in an additional 52 patients also given cefuroxime.

Johansson et al²⁵ found an incidence of KDIGO creatinine-based acute kidney injury of 13% in 70 patients given dicloxacillin alone prophylactically compared with 27% given dicloxacillin and gentamicin, with a relative risk of 3.

Bell et al,²¹ in a large registry-based analysis from Scotland involving 7,666 elective orthopedic procedures, found that use of flucloxacillin 2 g plus a single dose of gentamicin 4 mg/kg was significantly associated with a 94% higher risk of acute kidney injury (KDIGO creatinine criteria) compared with a cefuroxime-based regimen, with absolute rates increasing from 6.2% to 10.8%.

Dubrovskaya et al²⁰ and Ferguson et al,²⁶ in contrast, found no increased risk with addition of gentamicin.

We recommend avoiding aminoglycosides for prophylaxis in primary lower-extremity total joint arthroplasty in patients at higher risk unless required for specific microbiologic reasons.

Vancomycin may also increase risk

Courtney et al¹⁹ assessed the risk of adding vancomycin to cefazolin for routine prophylaxis in a retrospective series of 1,828 total hip or knee arthroplasties and found a significantly higher rate of acute kidney injury, using AKIN criteria (13% vs 8%, odds ratio by multivariate analysis 1.82, P = .002).¹⁹

Other agents shown to be effective in treating periprosthetic joint infections or complicated skin and soft-tissue infections with resistant organisms include daptomycin⁴³ and linezolid.⁴⁴ These nonnephrotoxic alternatives to vancomycin may be a consideration if prophylaxis for methicillin-resistant Staphylococcus aureus is deemed necessary in patients at risk for acute kidney injury.

Deep infection may complicate nearly 1% of total hip⁴⁵ and 2% of total knee arthroplasties.⁴⁶ Kurtz et al^4,6 have projected that by 2030, infection will be the cause of two-thirds of the estimated 268,000 revision total knee arthroplasties and about half of the estimated 96,700 revision total hip arthroplasties.

The most common method of treating a chronically infected replacement joint is a 2-stage procedure.⁵ First, the prosthesis is removed, all infected bone and soft tissue is debrided, and an antibiotic-loaded cement spacer is implanted. Systemic antibiotics are given concurrently, typically for about 6 weeks. After the infection is brought under control, perhaps 2 to 3 months later, the spacer is removed and a new joint is implanted with antibiotic-loaded cement. A 1-stage procedure may be an option in selected cases and would obviate the need for an antibiotic-loaded cement spacer.^47,48

Of obvious relevance to development of acute kidney injury is the choice and amount of antibiotics embedded in the cement used for spacers and in implantation. Very high antibiotic levels are achieved within the joint space, usually with little systemic absorption, although significant systemic exposure has been documented in some cases.

The polymethylmethacrylate cement used for these purposes comes in 40-g bags. Multiple bags are typically required per joint, perhaps 2 to 4.⁴⁹

The rate of elution of antibiotics is determined by several factors, including surface area, porosity, and the number of antibiotics. In general, elution is greatest early on, with exponential decline lasting perhaps 1 week,  followed by slow, sustained release over weeks to months.⁵⁰ However, several in vitro studies have indicated that only about 5%^50,51 of the total antibiotic actually elutes over time.

Initially, multiple antibiotic-laden cement beads were used to fill the joint space, but this significantly limited function and mobility.⁵² Now, cement spacers are used, and they can be nonarticulating or articulating for maximal joint mobility.⁵³ Although much greater antibiotic elution occurs from beads due to their high surface area-to-volume ratio, spacers still provide an adequate dose.

ANTIBIOTIC-LOADED CEMENT: DOSAGE AND ELUTION CHARACTERISTICS

Antibiotic-loaded cement can be either low-dose or high-dose.

Low-dose cement

Low-dose cement typically consists of 0.5 to 1.0 g of antibiotic per 40-g bag of cement, usually an aminoglycoside (gentamicin or tobramycin) or vancomycin, and can be purchased premixed by the manufacturer. Such cement is only used prophylactically with primary total joint arthroplasty or revision for aseptic reasons, a practice common in Europe but less so in the United States. Some American authors propose antibiotic-loaded cement prophylaxis for patients at high risk, eg, those with immunosuppression, inflammatory cause of arthritis, or diabetes.⁵⁴

Vrabec et al,⁵⁵ in a study of low-dose tobramycin-loaded cement used for primary total knee arthroplasty, found a peak median intra-articular tobramycin concentration of 32 mg/L at 6 hours, declining to 6 mg/L at 48 hours with all serum levels 0.3 mg/L or less (unmeasureable) at similar time points.

Sterling et al,⁵⁶ studying primary total hip arthroplasties with low-dose tobramycin-loaded cement, found mean levels in drainage fluid of 103 mg/L at 6 hours, declining to 15 mg/L at 48 hours. Serum levels peaked at 0.94 mg/L at 3 hours, declining to 0.2 mg/L by 48 hours.

Although most of the antibiotic elution occurs early (within the first week), antibiotic can be found in joint aspirates up to 20 years later.⁵⁷ We are unaware of any well-documented cases of acute kidney injury ascribable to low-dose antibiotic-loaded cement used prophylactically. One case report making this assertion did not determine serum levels of aminoglycoside.⁵⁸

High-dose cement

High-dose antibiotic-loaded cement typically contains about 4 to 8 g of antibiotic per 40-g bag of cement and is used in the treatment of prosthetic joint infection to form the spacers. The antibiotic must be mixed into the cement powder by the surgeon in the operating room.

There is no standard combination or dosage. The choice of antibiotic can be tailored to the infecting organism if known. Otherwise, gram-positive organisms are most common, and vancomycin and aminoglycosides are often used together. This particular combination will enhance the elution of both antibiotics when studied in vitro, a process termed “passive opportunism.”⁵⁹ Other antibiotics in use include aztreonam, piperacillin, teicoplanin, fluoroquinolones, cephalosporins, and daptomycin, among others.

About 8 g of antibiotic total per 40-g bag is the maximum to allow easy molding.⁵² As an example, this may include 4 g of vancomycin and 3.6 g of tobramycin per 40 g. Given that 3 to 4 such bags are often used per joint, there is significant risk of systemic exposure.

Kalil et al⁶⁰ studied 8 patients who received high-dose tobramycin-loaded cement to treat periprosthetic joint infections of the hip or knee and found that 7 had detectable serum levels (mean 0.84 mg/L, highest 2.0 mg/L), including 1 with a level of 0.9 mg/L on day 38; 4 of these 8 developed acute kidney injury by AKIN criteria, although other risk factors for acute kidney injury existed. Nearly all had concomitant vancomycin (3 to 8 g) added to the cement as well.

Hsieh et al⁶¹ studied 46 patients with infected total hip arthroplasties treated with high-dose antibiotic-loaded cement spacers (vancomycin 4 g and aztreonam 4 g per 40-g bag) and found vancomycin levels in joint drainage higher than 1,500 mg/L on day 1, decreasing to 571 mg/L on day 7; serum levels were low (range 0.1–1.6 mg/L at 24 hours), falling to undetectable by 72 hours.

Case reports have associated high-dose antibiotic-loaded cement spacers with acute kidney injury.

Curtis et al⁶² described an 85-year-old patient with stage 3 chronic kidney disease who was treated for an infected total knee arthroplasty with an antibiotic-loaded cement spacer (containing 3.6 g of tobramycin and 3 g of cefazolin per 40-g bag, 3 bags total) and developed stage 3 acute kidney injury. After 16 days and 3 hemodialysis sessions, the patient’s serum tobramycin level was still 2 mg/L despite receiving no systemic tobramycin.

Wu et al⁶³ reported a case of acute kidney injury that required dialysis after implantation of a tobramycin- and vancomycin-loaded spacer, with persistent serum tobramycin levels despite repeated hemodialysis sessions until the spacer was removed.

Chalmers et al⁶⁴ described 2 patients with acute kidney injury and persistently elevated serum tobramycin levels (3.9 mg/L on day 39 in 1 patient and 2.0 mg/L on day 24 in the other patient) despite no systemic administration.

In these and other case reports,^65–67 dialysis and spacer explantation were usually required. 


Comment. It is intuitive that acute kidney injury would more likely complicate revision total joint arthroplasties for infection than for primary total joint arthroplasties or revisions for aseptic reasons, given the systemic effects of infection and exposure to nephrotoxic or allergenic antibiotics. And the available data suggest that the risk of acute kidney injury is higher with revision for prosthetic joint infection than with revision for aseptic reasons. However, many of the studies were retrospective, relatively small, single-center series and used different definitions of acute kidney injury.

Luu et al⁸³ performed a systematic review of studies published between January 1989 and June 2012 reporting systemic complications (including acute kidney injury) of 2-stage revision arthroplasties including placement of an antibiotic-loaded cement spacer for treatment of periprosthetic joint infection. Overall, 10 studies were identified with 544 total patients. Five of these studies, with 409 patients, reported at least 1 case of acute kidney injury for a total of 27 patients, giving an incidence of 6.6% in these studies.^68–71 The remaining 5 studies, totaling 135 patients, did not report any cases of acute kidney injury,^{50,61,76–78} although that was not the primary focus of any of those trials.

Most notable from this systematic review, the study of Menge et al⁶⁹ retrospectively determined the incidence of acute kidney injury (defined as a 50% rise in serum creatinine to > 1.4 mg/dL within 90 days of surgery) to be 17% in 84 patients with infected total knee arthroplasties treated with antibiotic-loaded cement spacers. A mean of 3.5 bags of cement per spacer were used in the 35 articulating spacers, compared with 2.9 per nonarticulating spacer. These spacers contained vancomycin in 82% (median 4.0 g, range 1–16 g) and tobramycin in 94% (median 4.8 g, range 1–12 g), among others in small percentages. The dose of tobramycin in the spacer considered either as a dichotomous variable (> 4.8 g, OR 5.87) or linearly (OR 1.24 per 1-g increase) was significantly associated with acute kidney injury, although systemic administration of aminoglycosides or vancomycin was not.

Additional single-center series that were published subsequent to this review have generally used more current diagnostic criteria.

Noto et al⁷² found that 10 of 46 patients treated with antibiotic-loaded cement spacers had a greater than 50% rise in serum creatinine (average increase 260%). All spacers contained tobramycin (mean dose 8.2 g), and 9 of 10 also contained vancomycin (mean 7.6 g). All of the 9 patients with acute kidney injury with follow-up data recovered renal function.

Reed et al⁷⁵ found 26 cases of acute kidney injury (based on RIFLE creatinine criteria) in 306 patients with antibiotic-loaded cement spacers treating various periprosthetic joint infections (including hips, knees, shoulders, and digits) and compared them with 74 controls who did not develop acute kidney injury. By multivariable analysis, receipt of an ACE inhibitor within 7 days of surgery and receipt of piperacillin-tazobactam within 7 days after surgery were both significantly more common in cases with acute kidney injury than in controls without acute kidney injury.

Aeng et al⁷³ prospectively studied 50 consecutive patients receiving antibiotic-loaded spacers containing tobramycin (with or without vancomycin) for treatment of infected hip or knee replacements. Using RIFLE creatinine criteria, they found an incidence of acute kidney injury of 20% (10 of 50). Factors significantly associated with acute kidney injury included cement premixed by the manufacturer with gentamicin (0.5 g per 40-g bag) in addition to the tobramycin they added, intraoperative blood transfusions, and postoperative use of nonsteroidal anti-inflammatory drugs.

Geller et al,⁷⁴ in a multicenter retrospective study of 247 patients with prosthetic joint infections (156 knees and 91 hips) undergoing antibiotic-loaded cement spacer placement, found an incidence of acute kidney injury of 26% based on KDIGO creatinine criteria. Significant risk factors included higher body mass index, lower preoperative hemoglobin level, drop in hemoglobin after surgery, and comorbidity (hypertension, diabetes, chronic kidney disease, or cardiovascular disease). Most of the spacers contained a combination of vancomycin and either tobramycin (81%) or gentamicin (13%). The spacers contained an average of 5.3 g (range 0.6–18 g) of vancomycin (average 2.65 g per 40-g bag) and an average of 5.2 g (range 0.5–16.4 g) of tobramycin (average 2.6 g per bag).

As in Menge et al,⁶⁹ this study illustrates the wide range of antibiotic dosages in use and the lack of standardization. In contrast to the study by Menge et al, however, development of acute kidney injury was not related to the amount of vancomycin or tobramycin contained in the spacers. Eventual clearance of infection (at 1 and 2 years) was significantly related to increasing amounts of vancomycin. Multiple different systemic antibiotics were used, most commonly vancomycin (44%), and systemic vancomycin was not associated with acute kidney injury.

Yadav et al,⁸¹ in a study of 3,129 consecutive revision procedures of the knee or hip, found an incidence of acute kidney injury by RIFLE creatinine criteria of 29% in the 197 patients who received antibiotic-loaded cement spacers for periprosthetic joint infection compared with 3.4% in the 2,848 who underwent revision for aseptic reasons. In 84 patients with prosthetic joint infection having various surgeries not including placement of a spacer, the acute kidney injury rate at some point in their course was an alarmingly high 82%. In the group that received spacers, only age and comorbidity as assessed by Charlson comorbidity index were independently associated with acute kidney injury by multivariate analysis. Surprisingly, modest renal impairment was protective, possibly because physicians of patients with chronic kidney disease were more vigilant and took appropriate measures to prevent acute kidney injury.

Overall, the risk of acute kidney injury appears to be much higher during treatment of prosthetic joint infection with a 2-stage procedure using an antibiotic-loaded cement spacer than after primary total joint arthroplasty or revision for aseptic reasons, and may complicate up to one-third of cases.

As in primary total joint arthroplasty in general, higher-risk cases should be identified based on age, body mass index, chronic kidney disease, comorbidities (hypertension, diabetes, established cardiovascular disease), and anemia.

Preoperative transfusion can be considered case by case depending on degree of anemia and associated risk factors.

All renin-angiotensin-aldosterone system inhibitors should be withheld starting 1 week before surgery.

Both nonselective and cyclooxygenase-2 selective nonsteroidal anti-inflammatory drugs should be avoided, if possible.

Strict attention should be paid to adequate intraoperative and postoperative fluid resuscitation.

Kidney function should be monitored closely in the early postoperative period, including urine output and daily creatinine for at least 72 hours.

Systemic administration of potentially nephrotoxic antibiotics should be minimized, especially the combination of vancomycin with piperacillin-tazobactam.⁸⁴ Daptomycin is a consideration.⁴³

If acute kidney injury should develop, serum levels of vancomycin or aminoglycosides should be measured if the spacer contains these antibiotics. The spacer may need to be removed if toxic serum levels persist.

TAKE-HOME POINTS

Acute kidney injury may complicate up to 10% of primary lower-extremity total joint arthroplasties and up to 25% of periprosthetic joint infections treated with a 2-stage procedure including placement of an antibiotic-loaded cement spacer in the first stage.

Risk factors for acute kidney injury include older age, obesity, chronic kidney disease, and overall comorbidity. Potentially modifiable risk factors include anemia, perioperative transfusions, aminoglycoside prophylaxis, perioperative renin-angiotensin system blockade, and postoperative nonsteroidal anti-inflammatory drugs. These should be mitigated when possible.

In patients with periprosthetic joint infection who receive antibiotic-loaded cement spacers, especially patients  with additional risk factors for acute kidney injury, strict attention should be paid to the dose of antibiotic in the spacer, with levels checked postoperatively if necessary. Nonnephrotoxic antibiotics should be chosen for systemic administration when possible.

Prospective randomized controlled trials are needed to guide therapy after total joint arthroplasty, and to verify the adverse long-term outcomes of acute kidney injury in this setting.

Total hip or knee replacement (also called total joint arthroplasty) is highly successful at relieving pain and restoring function, but at the risk of acute kidney injury, which is a sudden loss of renal function. Various factors have been associated with this risk, some of which are potentially modifiable, notably, the use of nephrotoxic antibiotics and other drugs.

This review examines the incidence of acute kidney injury using current criteria in total joint arthroplasty of the hip or knee in general, and in the setting of revision surgery for prosthetic joint infection in particular, in which the risk is higher. We identify risk factors for acute kidney injury and propose ways to lower the risk.

MILLIONS OF PROCEDURES ANNUALLY

Total replacement of the hip^1,2 or knee³ is being done more and more. Kurtz et al⁴ estimate that by the year 2030, we will see approximately 3.5 million primary total knee and 500,000 primary total hip replacements every year. In addition, revision total knee procedures are expected to exceed 250,000 per year, and revision total hip procedures are expected to exceed 90,000 per year.⁴

Chronic infection may complicate up to 2% of these procedures and is associated with significant morbidity, death, and financial costs. Currently, it may be the reason for 25% of total joint arthroplasty revisions,⁵ but by the year 2030, it is projected to account for 66% of revision total knee arthroplasties and 48% of revision total hip arthroplasties.⁶

PRIMARY TOTAL JOINT ARTHROPLASTY AND ACUTE KIDNEY INJURY

Study designs, findings varied widely

The incidence of acute kidney injury varied markedly among the studies of primary total joint arthroplasty or revision for aseptic reasons. Numerous factors explain this heterogeneity.

Designs ranged from single-center studies with relatively small numbers of patients to large regional and national samples based on administrative data.

Almost all of the studies were retrospective. We are not aware of any randomized controlled trials.

Discharge diagnosis may miss many cases

Several studies based the diagnosis of acute kidney injury on International Classification of Diseases, Ninth Revision (ICD-9) coding from hospital discharge summaries.

Nadkarni et al,²⁹ in the largest study published to date, used the nationwide inpatient sample database of more than 7 million total joint arthroplasties and found an incidence of acute kidney injury based on ICD-9 coding of 1.3% over the years 2002 to 2012, although this increased to 1.8% to 1.9% from 2010 to 2012.

Lopez-de-Andres et al,³⁰ in a similar study using the Spanish national hospital discharge database, evaluated 20,188 patients who underwent revision total hip or knee arthroplasty and found an overall incidence of acute kidney injury of 0.94%, also using ICD-9 coding.

Gharaibeh et al³¹ used similar methods to diagnose acute kidney injury in a single-center study of 8,949 patients and found an incidence of 1.1%.

Although these 3 studies suggest that the incidence of acute kidney injury is relatively low, Grams et al³⁵ found the sensitivity of ICD-9 coding from hospital records for the diagnosis of acute kidney injury to be only 11.7% compared with KDIGO serum creatinine and urine output criteria. This suggests that the true incidence in these studies may be many times higher, possibly near 10%.

Do all stages of kidney injury count?

Jafari et al,⁷ in a large series from a single medical center, used only the “I” (injury) and “F” (failure) levels of the RIFLE criteria (corresponding to stages 2 and 3 of the KDIGO criteria) and found an incidence of 0.55% in more than 17,000 total joint arthroplasties.

Jamsa et al⁸ used the same criteria for acute kidney injury (only “I” and “F”) and found 58 cases in 5,609 patients in whom postoperative serum creatinine was measured, for an incidence of 1%; the remaining 14,966 patients in their cohort did not have serum creatinine measured, and it was assumed they did not have acute kidney injury. Neither of these studies included the most common “R” (risk) stage of acute kidney injury.

Parr et al³⁶ recently studied a nationwide sample of 657,840 hospitalized veterans and found that of 90,614 who developed acute kidney injury based on KDIGO creatinine criteria, 84% reached only stage R. This suggests that if all stages were considered, the true incidence of acute kidney injury would have been higher—possibly 4% in the Jafari series and possibly 7% in the Jamsa series.

Smaller studies had higher rates

Smaller, single-center series reported much higher incidences of acute kidney injury.

Kimmel et al¹¹ found an incidence of 14.8% in 425 total joint arthroplasties using RIFLE creatinine criteria.

Johansson et al²⁵ found an incidence of 19.9% in 136 total joint arthroplasties using KDIGO creatinine criteria.

Sehgal et al⁹ found an incidence of 21.9% in 659 total joint arthroplasties using AKIN creatinine criteria.

Challagundla et al²⁴ found an incidence of 23.7% in 198 procedures using RIFLE creatinine criteria.

Weingarten et al,¹⁰ in a single-center series of 7,463 total joint arthroplasties, found an incidence of acute kidney injury of only 2.2% using AKIN criteria, although 12% of the patients with acute kidney injury did not return to their baseline serum creatinine levels by 3 months.

Our estimate: Nearly 10%

In total, in the 20 studies in Table 1 that included all stages of acute kidney injury, there were 1,909 cases of acute kidney injury in 34,337 patients, for an incidence of 5.6%. Considering that all studies but one were retrospective and none considered urine output criteria for acute kidney injury, we believe that using current KDIGO criteria, the true incidence of acute kidney injury complicating primary lower-extremity total joint arthroplasties is really closer to 10%.

Various factors have been associated with development of acute kidney injury by multivariate analysis in these studies. Some are modifiable, while others are not, at least in the short term.

Nonmodifiable risk factors

Older age is often significant in studies assessing primary total joint arthroplasty or revision total joint arthroplasty not specifically for infection.^{11,12,16,17,26,28}

Obesity is also a major factor in the development of acute kidney injury,^{7,10–12,17,18} and, along with age, is a major factor contributing to the need for joint replacement in the first place.

Male sex may increase risk.²⁹

Diabetes mellitus was identified as a risk factor in several studies,^10,12,17,20 and hypertension in a few.^7,10,24

Other comorbidities and factors such as cardiovascular disease,^7,10 liver disease,⁷ pulmonary disease,⁷ high American Society of Anesthesiology score,^8,19 and benign heart murmurs preoperatively by routine physical examination have also been linked to acute kidney injury after joint arthroplasty.²⁸

Chronic kidney disease as a risk factor

Chronic kidney disease at baseline was associated with acute kidney injury in several of these series.^{7,11–13,15,19,29}

Warth et al¹² studied 1,038 patients and found an incidence of acute kidney injury of 11% in the 135 with chronic kidney disease (defined as serum creatinine > 1.2 mg/dL) and who received acetaminophen or narcotics for pain control, compared with 4.8% in the remaining 903 patients without chronic kidney disease, who received ketorolac or celecoxib.

Perregaard et al¹³ studied 3,410 patients who underwent total hip arthroplasty and found an incidence of acute kidney injury (per KDIGO creatinine criteria) of 2.2% overall, but 7% in the 134 patients with chronic kidney disease based on KDIGO creatinine criteria.

Nowicka et al¹⁵ found an incidence of acute kidney injury of 16.7% in the 48 patients with chronic kidney disease (defined as a glomerular filtration rate estimated by the Cockroft-Gault formula of less than 60 mL/min/1.73 m²), compared with 4.5% in the remaining 289.

Modifiable risk factors

Modifiable risk factors that should be considered in high-risk cases include anemia, perioperative blood transfusion, perioperative use of renin-angiotensin-aldosterone system inhibitors such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), particular antibiotics used for prophylaxis, and nonsteroidal anti-inflammatory drugs used postoperatively.

Anemia and blood transfusion

Preoperative anemia has been associated with postoperative acute kidney injury in various surgical settings such as cardiac surgery.^37,38 Perioperative red blood cell transfusions have also been associated with acute kidney injury in cardiac surgery; similar results may apply to total joint arthroplasty.

Choi et al,¹⁷ in 2,467 patients undergoing hip replacement, found a significant risk for acute kidney injury if postoperative hemoglobin was consistently below 10 g/dL compared with consistently above this level, with an inverse probability-of-treatment weighted odds ratio of 1.817 (P = .011).

Others have found a significant association of perioperative blood transfusion with acute kidney injury in total joint arthroplasty.^10,29

Nadkarni et al,²⁹ for example, used the nationwide inpatient sample database and found by multivariate analysis that perioperative blood transfusion was strongly associated with acute kidney injury, with an adjusted odds ratio of 2.28 (95% confidence interval [CI] 2.15–2.42, P < .0001).

Comment. A higher incidence of acute kidney injury may represent confounding by indication bias, as sicker patients or complicated surgeries may require transfusion, and this risk may not be completely accounted for by multivariate analysis. It is also possible, however, that transfusions per se may contribute to acute kidney injury. Possible direct or indirect mechanisms mediating acute kidney injury include hemolytic reactions, circulatory overload, acute lung injury, and immunomodulatory effects.³⁹

Preoperative transfusion in anemic patients undergoing cardiac surgery may also reduce the incidence of postoperative acute kidney injury both by correcting the anemia and by limiting the need for perioperative transfusions.⁴⁰ It remains to be determined whether elective preoperative transfusion to correct anemia would reduce postoperative development of acute kidney injury in total joint arthroplasty. As an aside, perioperative transfusion has also been linked to development of periprosthetic joint infection.⁴¹

Renin-angiotensin-aldosterone system inhibitors

Several studies found perioperative use of renin-angiotensin-aldosterone system inhibitors to be a risk factor for acute kidney injury.

Kimmel et al¹¹ reported adjusted odds ratios of 2.70 (95% CI 1.12–6.48) for ACE inhibitor use and 2.64 (95% CI 1.18–5.93) for ARB use in a study of 425 primary total joint arthroplasties.

Challagundla et al²⁴ found an odds ratio of 3.07 (95% CI 1.40–6.74) with ACE inhibitor or ARB use by multivariate analysis in 198 total joint arthroplasties.

Nielson et al¹⁸ studied 798 patients who underwent total joint arthroplasty and found that preoperative use of renin-angiotensin system inhibitors was associated with a significantly higher rate of postoperative acute kidney injury (8.3% vs 1.7% without inhibition), which was statistically significant by multivariate analysis (odds ratio 2.6, 95% CI 1.04–6.51).

We recommend holding renin-angiotensin-aldosterone system inhibitors 7 days before surgery through the postoperative period in high-risk cases.

Aminoglycoside use as a risk factor

Prophylactic administration of systemic antibiotics is the standard of care. In a systematic review of 26 studies and meta-analysis of 7 studies (3,065 patients), prophylactic antibiotics reduced the relative risk of wound infection by 81% with an absolute risk reduction of 8%.⁴²

A modifiable risk factor for acute kidney injury is the specific antibiotic used for prophylaxis. Multiple studies assessed the risk of acute kidney injury comparing regimens containing an aminoglycoside (typically gentamicin) with regimens lacking these agents.^20–26 In general, these studies found a significantly higher risk of acute kidney injury when gentamicin was used.

Challagundla et al²⁴ found an incidence of acute kidney injury of 52% using RIFLE creatinine criteria in 52 patients receiving 8 g total of flucloxacillin plus 160 mg of gentamicin (120 mg if they weighed less than 60 kg) compared with 8% in 48 patients given cefuroxime (3 g total) and 14% in an additional 52 patients also given cefuroxime.

Johansson et al²⁵ found an incidence of KDIGO creatinine-based acute kidney injury of 13% in 70 patients given dicloxacillin alone prophylactically compared with 27% given dicloxacillin and gentamicin, with a relative risk of 3.

Bell et al,²¹ in a large registry-based analysis from Scotland involving 7,666 elective orthopedic procedures, found that use of flucloxacillin 2 g plus a single dose of gentamicin 4 mg/kg was significantly associated with a 94% higher risk of acute kidney injury (KDIGO creatinine criteria) compared with a cefuroxime-based regimen, with absolute rates increasing from 6.2% to 10.8%.

Dubrovskaya et al²⁰ and Ferguson et al,²⁶ in contrast, found no increased risk with addition of gentamicin.

We recommend avoiding aminoglycosides for prophylaxis in primary lower-extremity total joint arthroplasty in patients at higher risk unless required for specific microbiologic reasons.

Vancomycin may also increase risk

Courtney et al¹⁹ assessed the risk of adding vancomycin to cefazolin for routine prophylaxis in a retrospective series of 1,828 total hip or knee arthroplasties and found a significantly higher rate of acute kidney injury, using AKIN criteria (13% vs 8%, odds ratio by multivariate analysis 1.82, P = .002).¹⁹

Other agents shown to be effective in treating periprosthetic joint infections or complicated skin and soft-tissue infections with resistant organisms include daptomycin⁴³ and linezolid.⁴⁴ These nonnephrotoxic alternatives to vancomycin may be a consideration if prophylaxis for methicillin-resistant Staphylococcus aureus is deemed necessary in patients at risk for acute kidney injury.

Deep infection may complicate nearly 1% of total hip⁴⁵ and 2% of total knee arthroplasties.⁴⁶ Kurtz et al^4,6 have projected that by 2030, infection will be the cause of two-thirds of the estimated 268,000 revision total knee arthroplasties and about half of the estimated 96,700 revision total hip arthroplasties.

The most common method of treating a chronically infected replacement joint is a 2-stage procedure.⁵ First, the prosthesis is removed, all infected bone and soft tissue is debrided, and an antibiotic-loaded cement spacer is implanted. Systemic antibiotics are given concurrently, typically for about 6 weeks. After the infection is brought under control, perhaps 2 to 3 months later, the spacer is removed and a new joint is implanted with antibiotic-loaded cement. A 1-stage procedure may be an option in selected cases and would obviate the need for an antibiotic-loaded cement spacer.^47,48

Of obvious relevance to development of acute kidney injury is the choice and amount of antibiotics embedded in the cement used for spacers and in implantation. Very high antibiotic levels are achieved within the joint space, usually with little systemic absorption, although significant systemic exposure has been documented in some cases.

The polymethylmethacrylate cement used for these purposes comes in 40-g bags. Multiple bags are typically required per joint, perhaps 2 to 4.⁴⁹

The rate of elution of antibiotics is determined by several factors, including surface area, porosity, and the number of antibiotics. In general, elution is greatest early on, with exponential decline lasting perhaps 1 week,  followed by slow, sustained release over weeks to months.⁵⁰ However, several in vitro studies have indicated that only about 5%^50,51 of the total antibiotic actually elutes over time.

Initially, multiple antibiotic-laden cement beads were used to fill the joint space, but this significantly limited function and mobility.⁵² Now, cement spacers are used, and they can be nonarticulating or articulating for maximal joint mobility.⁵³ Although much greater antibiotic elution occurs from beads due to their high surface area-to-volume ratio, spacers still provide an adequate dose.

ANTIBIOTIC-LOADED CEMENT: DOSAGE AND ELUTION CHARACTERISTICS

Antibiotic-loaded cement can be either low-dose or high-dose.

Low-dose cement

Low-dose cement typically consists of 0.5 to 1.0 g of antibiotic per 40-g bag of cement, usually an aminoglycoside (gentamicin or tobramycin) or vancomycin, and can be purchased premixed by the manufacturer. Such cement is only used prophylactically with primary total joint arthroplasty or revision for aseptic reasons, a practice common in Europe but less so in the United States. Some American authors propose antibiotic-loaded cement prophylaxis for patients at high risk, eg, those with immunosuppression, inflammatory cause of arthritis, or diabetes.⁵⁴

Vrabec et al,⁵⁵ in a study of low-dose tobramycin-loaded cement used for primary total knee arthroplasty, found a peak median intra-articular tobramycin concentration of 32 mg/L at 6 hours, declining to 6 mg/L at 48 hours with all serum levels 0.3 mg/L or less (unmeasureable) at similar time points.

Sterling et al,⁵⁶ studying primary total hip arthroplasties with low-dose tobramycin-loaded cement, found mean levels in drainage fluid of 103 mg/L at 6 hours, declining to 15 mg/L at 48 hours. Serum levels peaked at 0.94 mg/L at 3 hours, declining to 0.2 mg/L by 48 hours.

Although most of the antibiotic elution occurs early (within the first week), antibiotic can be found in joint aspirates up to 20 years later.⁵⁷ We are unaware of any well-documented cases of acute kidney injury ascribable to low-dose antibiotic-loaded cement used prophylactically. One case report making this assertion did not determine serum levels of aminoglycoside.⁵⁸

High-dose cement

High-dose antibiotic-loaded cement typically contains about 4 to 8 g of antibiotic per 40-g bag of cement and is used in the treatment of prosthetic joint infection to form the spacers. The antibiotic must be mixed into the cement powder by the surgeon in the operating room.

There is no standard combination or dosage. The choice of antibiotic can be tailored to the infecting organism if known. Otherwise, gram-positive organisms are most common, and vancomycin and aminoglycosides are often used together. This particular combination will enhance the elution of both antibiotics when studied in vitro, a process termed “passive opportunism.”⁵⁹ Other antibiotics in use include aztreonam, piperacillin, teicoplanin, fluoroquinolones, cephalosporins, and daptomycin, among others.

About 8 g of antibiotic total per 40-g bag is the maximum to allow easy molding.⁵² As an example, this may include 4 g of vancomycin and 3.6 g of tobramycin per 40 g. Given that 3 to 4 such bags are often used per joint, there is significant risk of systemic exposure.

Kalil et al⁶⁰ studied 8 patients who received high-dose tobramycin-loaded cement to treat periprosthetic joint infections of the hip or knee and found that 7 had detectable serum levels (mean 0.84 mg/L, highest 2.0 mg/L), including 1 with a level of 0.9 mg/L on day 38; 4 of these 8 developed acute kidney injury by AKIN criteria, although other risk factors for acute kidney injury existed. Nearly all had concomitant vancomycin (3 to 8 g) added to the cement as well.

Hsieh et al⁶¹ studied 46 patients with infected total hip arthroplasties treated with high-dose antibiotic-loaded cement spacers (vancomycin 4 g and aztreonam 4 g per 40-g bag) and found vancomycin levels in joint drainage higher than 1,500 mg/L on day 1, decreasing to 571 mg/L on day 7; serum levels were low (range 0.1–1.6 mg/L at 24 hours), falling to undetectable by 72 hours.

Case reports have associated high-dose antibiotic-loaded cement spacers with acute kidney injury.

Curtis et al⁶² described an 85-year-old patient with stage 3 chronic kidney disease who was treated for an infected total knee arthroplasty with an antibiotic-loaded cement spacer (containing 3.6 g of tobramycin and 3 g of cefazolin per 40-g bag, 3 bags total) and developed stage 3 acute kidney injury. After 16 days and 3 hemodialysis sessions, the patient’s serum tobramycin level was still 2 mg/L despite receiving no systemic tobramycin.

Wu et al⁶³ reported a case of acute kidney injury that required dialysis after implantation of a tobramycin- and vancomycin-loaded spacer, with persistent serum tobramycin levels despite repeated hemodialysis sessions until the spacer was removed.

Chalmers et al⁶⁴ described 2 patients with acute kidney injury and persistently elevated serum tobramycin levels (3.9 mg/L on day 39 in 1 patient and 2.0 mg/L on day 24 in the other patient) despite no systemic administration.

In these and other case reports,^65–67 dialysis and spacer explantation were usually required. 


Comment. It is intuitive that acute kidney injury would more likely complicate revision total joint arthroplasties for infection than for primary total joint arthroplasties or revisions for aseptic reasons, given the systemic effects of infection and exposure to nephrotoxic or allergenic antibiotics. And the available data suggest that the risk of acute kidney injury is higher with revision for prosthetic joint infection than with revision for aseptic reasons. However, many of the studies were retrospective, relatively small, single-center series and used different definitions of acute kidney injury.

Luu et al⁸³ performed a systematic review of studies published between January 1989 and June 2012 reporting systemic complications (including acute kidney injury) of 2-stage revision arthroplasties including placement of an antibiotic-loaded cement spacer for treatment of periprosthetic joint infection. Overall, 10 studies were identified with 544 total patients. Five of these studies, with 409 patients, reported at least 1 case of acute kidney injury for a total of 27 patients, giving an incidence of 6.6% in these studies.^68–71 The remaining 5 studies, totaling 135 patients, did not report any cases of acute kidney injury,^{50,61,76–78} although that was not the primary focus of any of those trials.

Most notable from this systematic review, the study of Menge et al⁶⁹ retrospectively determined the incidence of acute kidney injury (defined as a 50% rise in serum creatinine to > 1.4 mg/dL within 90 days of surgery) to be 17% in 84 patients with infected total knee arthroplasties treated with antibiotic-loaded cement spacers. A mean of 3.5 bags of cement per spacer were used in the 35 articulating spacers, compared with 2.9 per nonarticulating spacer. These spacers contained vancomycin in 82% (median 4.0 g, range 1–16 g) and tobramycin in 94% (median 4.8 g, range 1–12 g), among others in small percentages. The dose of tobramycin in the spacer considered either as a dichotomous variable (> 4.8 g, OR 5.87) or linearly (OR 1.24 per 1-g increase) was significantly associated with acute kidney injury, although systemic administration of aminoglycosides or vancomycin was not.

Additional single-center series that were published subsequent to this review have generally used more current diagnostic criteria.

Noto et al⁷² found that 10 of 46 patients treated with antibiotic-loaded cement spacers had a greater than 50% rise in serum creatinine (average increase 260%). All spacers contained tobramycin (mean dose 8.2 g), and 9 of 10 also contained vancomycin (mean 7.6 g). All of the 9 patients with acute kidney injury with follow-up data recovered renal function.

Reed et al⁷⁵ found 26 cases of acute kidney injury (based on RIFLE creatinine criteria) in 306 patients with antibiotic-loaded cement spacers treating various periprosthetic joint infections (including hips, knees, shoulders, and digits) and compared them with 74 controls who did not develop acute kidney injury. By multivariable analysis, receipt of an ACE inhibitor within 7 days of surgery and receipt of piperacillin-tazobactam within 7 days after surgery were both significantly more common in cases with acute kidney injury than in controls without acute kidney injury.

Aeng et al⁷³ prospectively studied 50 consecutive patients receiving antibiotic-loaded spacers containing tobramycin (with or without vancomycin) for treatment of infected hip or knee replacements. Using RIFLE creatinine criteria, they found an incidence of acute kidney injury of 20% (10 of 50). Factors significantly associated with acute kidney injury included cement premixed by the manufacturer with gentamicin (0.5 g per 40-g bag) in addition to the tobramycin they added, intraoperative blood transfusions, and postoperative use of nonsteroidal anti-inflammatory drugs.

Geller et al,⁷⁴ in a multicenter retrospective study of 247 patients with prosthetic joint infections (156 knees and 91 hips) undergoing antibiotic-loaded cement spacer placement, found an incidence of acute kidney injury of 26% based on KDIGO creatinine criteria. Significant risk factors included higher body mass index, lower preoperative hemoglobin level, drop in hemoglobin after surgery, and comorbidity (hypertension, diabetes, chronic kidney disease, or cardiovascular disease). Most of the spacers contained a combination of vancomycin and either tobramycin (81%) or gentamicin (13%). The spacers contained an average of 5.3 g (range 0.6–18 g) of vancomycin (average 2.65 g per 40-g bag) and an average of 5.2 g (range 0.5–16.4 g) of tobramycin (average 2.6 g per bag).

As in Menge et al,⁶⁹ this study illustrates the wide range of antibiotic dosages in use and the lack of standardization. In contrast to the study by Menge et al, however, development of acute kidney injury was not related to the amount of vancomycin or tobramycin contained in the spacers. Eventual clearance of infection (at 1 and 2 years) was significantly related to increasing amounts of vancomycin. Multiple different systemic antibiotics were used, most commonly vancomycin (44%), and systemic vancomycin was not associated with acute kidney injury.

Yadav et al,⁸¹ in a study of 3,129 consecutive revision procedures of the knee or hip, found an incidence of acute kidney injury by RIFLE creatinine criteria of 29% in the 197 patients who received antibiotic-loaded cement spacers for periprosthetic joint infection compared with 3.4% in the 2,848 who underwent revision for aseptic reasons. In 84 patients with prosthetic joint infection having various surgeries not including placement of a spacer, the acute kidney injury rate at some point in their course was an alarmingly high 82%. In the group that received spacers, only age and comorbidity as assessed by Charlson comorbidity index were independently associated with acute kidney injury by multivariate analysis. Surprisingly, modest renal impairment was protective, possibly because physicians of patients with chronic kidney disease were more vigilant and took appropriate measures to prevent acute kidney injury.

Overall, the risk of acute kidney injury appears to be much higher during treatment of prosthetic joint infection with a 2-stage procedure using an antibiotic-loaded cement spacer than after primary total joint arthroplasty or revision for aseptic reasons, and may complicate up to one-third of cases.

As in primary total joint arthroplasty in general, higher-risk cases should be identified based on age, body mass index, chronic kidney disease, comorbidities (hypertension, diabetes, established cardiovascular disease), and anemia.

Preoperative transfusion can be considered case by case depending on degree of anemia and associated risk factors.

All renin-angiotensin-aldosterone system inhibitors should be withheld starting 1 week before surgery.

Both nonselective and cyclooxygenase-2 selective nonsteroidal anti-inflammatory drugs should be avoided, if possible.

Strict attention should be paid to adequate intraoperative and postoperative fluid resuscitation.

Kidney function should be monitored closely in the early postoperative period, including urine output and daily creatinine for at least 72 hours.

Systemic administration of potentially nephrotoxic antibiotics should be minimized, especially the combination of vancomycin with piperacillin-tazobactam.⁸⁴ Daptomycin is a consideration.⁴³

If acute kidney injury should develop, serum levels of vancomycin or aminoglycosides should be measured if the spacer contains these antibiotics. The spacer may need to be removed if toxic serum levels persist.

TAKE-HOME POINTS

Acute kidney injury may complicate up to 10% of primary lower-extremity total joint arthroplasties and up to 25% of periprosthetic joint infections treated with a 2-stage procedure including placement of an antibiotic-loaded cement spacer in the first stage.

Risk factors for acute kidney injury include older age, obesity, chronic kidney disease, and overall comorbidity. Potentially modifiable risk factors include anemia, perioperative transfusions, aminoglycoside prophylaxis, perioperative renin-angiotensin system blockade, and postoperative nonsteroidal anti-inflammatory drugs. These should be mitigated when possible.

In patients with periprosthetic joint infection who receive antibiotic-loaded cement spacers, especially patients  with additional risk factors for acute kidney injury, strict attention should be paid to the dose of antibiotic in the spacer, with levels checked postoperatively if necessary. Nonnephrotoxic antibiotics should be chosen for systemic administration when possible.

Prospective randomized controlled trials are needed to guide therapy after total joint arthroplasty, and to verify the adverse long-term outcomes of acute kidney injury in this setting.