Nephrology

Clinical experience and observational studies made us aware that African American patients responded differently to some treatments than the white male patients in the clinical trials. This awareness led to some interesting biologic hypotheses and, over the past 13 years, has led to trials focused on the treatment of heart failure and hypertension in African Americans. But a full biologic understanding of the apparent racial differences in clinical response to specific therapies has for the most part remained elusive.

Contributing to this understanding gap was that we historically did not fully appreciate the differences according to race (and likely sex) in the clinical progression of diseases such as hypertension, heart failure, and, as discussed in this issue of the Journal by Dr. Joseph V. Nally, Jr., chronic kidney disease. African Americans with congestive heart failure seem to fare worse than their white counterparts with the same disease. Given the strong link between heart failure and chronic kidney disease and the crosstalk between the heart and kidneys, it is no surprise that African Americans with chronic kidney disease progress to end-stage renal disease at a higher rate than whites. Yet, as Dr. Nally points out, once on dialysis, African Americans live longer—an intriguing observation that came from analysis of large databases devoted to the study of patients with chronic kidney disease.

As a patient’s self-defined racial identity may not be biologically accurate, using molecular genetic techniques to delve more deeply into the characteristics of patients in these chronic kidney disease registries is starting to yield fascinating results—and even more questions. Links between APOL1 gene polymorphisms and the occurrence of renal disease and the survival of transplanted kidneys is assuredly just the start of a journey of genomic discovery and understanding.

Readers will note the short editor’s note at the start of Dr. Nally’s article, indicating that it was based on a Medicine Grand Rounds lecture at Cleveland Clinic, the 14th annual Lawrence “Chris” Crain Memorial Lecture. In 1997, Chris became the first African American chief resident in internal medicine at Cleveland Clinic, and I had the pleasure of interacting with him while he was in that role. Chris was a natural leader. He was soft-spoken, curious, and passionate about delivering and understanding the basics of high-quality clinical care.

After his residency, with Byron Hoogwerf as the internal medicine program director, Chris trained with Joe Nally as his program director in nephrology, and further developed his interest in renal and cardiovascular disease in African Americans. He moved to Atlanta, where he died far too prematurely in July 2003. That year, in conjunction with Chris’s mother, wife, extended family, and other faculty, Drs. Hoogwerf and Nally established the Lawrence “Chris” Crain Memorial Lectureship, devoted to Chris’s passion of furthering our understanding and our ability to deliver optimal care to African American patients with cardiovascular and renal disease.

I am pleased to share this lecture with you.

Clinical experience and observational studies made us aware that African American patients responded differently to some treatments than the white male patients in the clinical trials. This awareness led to some interesting biologic hypotheses and, over the past 13 years, has led to trials focused on the treatment of heart failure and hypertension in African Americans. But a full biologic understanding of the apparent racial differences in clinical response to specific therapies has for the most part remained elusive.

Contributing to this understanding gap was that we historically did not fully appreciate the differences according to race (and likely sex) in the clinical progression of diseases such as hypertension, heart failure, and, as discussed in this issue of the Journal by Dr. Joseph V. Nally, Jr., chronic kidney disease. African Americans with congestive heart failure seem to fare worse than their white counterparts with the same disease. Given the strong link between heart failure and chronic kidney disease and the crosstalk between the heart and kidneys, it is no surprise that African Americans with chronic kidney disease progress to end-stage renal disease at a higher rate than whites. Yet, as Dr. Nally points out, once on dialysis, African Americans live longer—an intriguing observation that came from analysis of large databases devoted to the study of patients with chronic kidney disease.

As a patient’s self-defined racial identity may not be biologically accurate, using molecular genetic techniques to delve more deeply into the characteristics of patients in these chronic kidney disease registries is starting to yield fascinating results—and even more questions. Links between APOL1 gene polymorphisms and the occurrence of renal disease and the survival of transplanted kidneys is assuredly just the start of a journey of genomic discovery and understanding.

Readers will note the short editor’s note at the start of Dr. Nally’s article, indicating that it was based on a Medicine Grand Rounds lecture at Cleveland Clinic, the 14th annual Lawrence “Chris” Crain Memorial Lecture. In 1997, Chris became the first African American chief resident in internal medicine at Cleveland Clinic, and I had the pleasure of interacting with him while he was in that role. Chris was a natural leader. He was soft-spoken, curious, and passionate about delivering and understanding the basics of high-quality clinical care.

After his residency, with Byron Hoogwerf as the internal medicine program director, Chris trained with Joe Nally as his program director in nephrology, and further developed his interest in renal and cardiovascular disease in African Americans. He moved to Atlanta, where he died far too prematurely in July 2003. That year, in conjunction with Chris’s mother, wife, extended family, and other faculty, Drs. Hoogwerf and Nally established the Lawrence “Chris” Crain Memorial Lectureship, devoted to Chris’s passion of furthering our understanding and our ability to deliver optimal care to African American patients with cardiovascular and renal disease.

I am pleased to share this lecture with you.

Clinical experience and observational studies made us aware that African American patients responded differently to some treatments than the white male patients in the clinical trials. This awareness led to some interesting biologic hypotheses and, over the past 13 years, has led to trials focused on the treatment of heart failure and hypertension in African Americans. But a full biologic understanding of the apparent racial differences in clinical response to specific therapies has for the most part remained elusive.

Contributing to this understanding gap was that we historically did not fully appreciate the differences according to race (and likely sex) in the clinical progression of diseases such as hypertension, heart failure, and, as discussed in this issue of the Journal by Dr. Joseph V. Nally, Jr., chronic kidney disease. African Americans with congestive heart failure seem to fare worse than their white counterparts with the same disease. Given the strong link between heart failure and chronic kidney disease and the crosstalk between the heart and kidneys, it is no surprise that African Americans with chronic kidney disease progress to end-stage renal disease at a higher rate than whites. Yet, as Dr. Nally points out, once on dialysis, African Americans live longer—an intriguing observation that came from analysis of large databases devoted to the study of patients with chronic kidney disease.

As a patient’s self-defined racial identity may not be biologically accurate, using molecular genetic techniques to delve more deeply into the characteristics of patients in these chronic kidney disease registries is starting to yield fascinating results—and even more questions. Links between APOL1 gene polymorphisms and the occurrence of renal disease and the survival of transplanted kidneys is assuredly just the start of a journey of genomic discovery and understanding.

Readers will note the short editor’s note at the start of Dr. Nally’s article, indicating that it was based on a Medicine Grand Rounds lecture at Cleveland Clinic, the 14th annual Lawrence “Chris” Crain Memorial Lecture. In 1997, Chris became the first African American chief resident in internal medicine at Cleveland Clinic, and I had the pleasure of interacting with him while he was in that role. Chris was a natural leader. He was soft-spoken, curious, and passionate about delivering and understanding the basics of high-quality clinical care.

After his residency, with Byron Hoogwerf as the internal medicine program director, Chris trained with Joe Nally as his program director in nephrology, and further developed his interest in renal and cardiovascular disease in African Americans. He moved to Atlanta, where he died far too prematurely in July 2003. That year, in conjunction with Chris’s mother, wife, extended family, and other faculty, Drs. Hoogwerf and Nally established the Lawrence “Chris” Crain Memorial Lectureship, devoted to Chris’s passion of furthering our understanding and our ability to deliver optimal care to African American patients with cardiovascular and renal disease.

I am pleased to share this lecture with you.

Editor’s note: This Medical Grand Rounds was presented as the 14th Annual Lawrence “Chris” Crain Memorial Lecture, a series that has been dedicated to discussing kidney disease, hypertension, and health care disparities in the African American community. In 1997, Dr. Crain became the first African American chief medical resident at Cleveland Clinic, and was a nephrology fellow in 1998–1999. Dr. Nally was his teacher and mentor.

African Americans have a greater burden of chronic kidney disease than whites. They are more than 3 times as likely as whites to develop end-stage renal disease, even after adjusting for age, disease stage, smoking, medications, and comorbidities. Why this is so has been the focus of much speculation and research.

This article reviews recent advances in the understanding of the progression of chronic kidney disease, with particular scrutiny of the disease in African Americans. Breakthroughs in genetics that help explain the greater disease burden in African Americans are also discussed, as well as implications for organ transplant screening.

ADVANCING UNDERSTANDING OF CHRONIC KIDNEY DISEASE

In the 1990s, dialysis rolls grew by 8% to 10% annually. Unfortunately, many patients first met with a nephrologist on the eve of their first dialysis treatment; there was not yet an adequate way to recognize the disease earlier and slow its progression. And disease definitions were not yet standardized, which led to inadequate metrics and hampered the ability to move disease management forward.

Standardizing definitions

The situation improved in 2002, when the National Kidney Foundation published clinical practice guidelines for chronic kidney disease that included disease definitions and staging.¹ Chronic kidney disease was defined as a structural or functional abnormality of the kidney lasting at least 3 months, as manifested by either of the following:

• Kidney damage, with or without decreased glomerular filtration rate (GFR), as defined by pathologic abnormalities or markers of kidney damage in the blood, urine, or on imaging tests

• 

  GFR less than 60 mL/min/1.73 m², with or without kidney damage.

A subsequent major advance was the recognition that not only GFR but also albuminuria was important for staging of chronic kidney disease (Figure 1).²

Developing large databases

Surveillance and monitoring of chronic kidney disease have generated large databases that enable researchers to detect trends in disease progression.

US Renal Data System. The US Renal Data System has collected and reported on data for more than 20 years from the National Health and Nutrition Examination Survey and the Centers for Medicare and Medicaid Services about chronic and end-stage kidney disease in the United States.

Cleveland Clinic database. Cleveland Clinic has developed a validated chronic kidney disease registry based on its electronic health record.³ The data include demographics (age, sex, ethnic group), comorbidities, medications, and complete laboratory data.⁴

Alberta Kidney Disease Network. This Canadian research consortium links large laboratory and demographic databases to facilitate defining patient populations, such as those with kidney disease and other comorbidities.

Kaiser Permanente Renal Registry. Kaiser Permanente of Northern California insures more than one-third of adults in the San Francisco Bay Area. The renal registry includes all adults whose kidney function is known. Data on age, sex, and racial or ethnic group are available from the health-plan databases.

DEATHS FROM KIDNEY DISEASE

The mortality rate in patients with end-stage renal disease who are on dialysis has steadily fallen over the past 20 years, from an annual rate of about 25% in 1996 to 17% in 2014, suggesting that care improved during that time. Patients with transplants have a much lower mortality rate: less than 5% annually.⁵ But these data also highlight the persistent risk faced by patients with chronic kidney disease; even those with transplants have death rates comparable to those of patients with cancer, diabetes, or heart failure.

Death rates correlate with GFR

After the publication of definitions and staging by the National Kidney Foundation in 2002, Go et al⁶ studied more than 1 million patients with chronic kidney disease from the Kaiser Permanente Renal Registry and found that the rates of cardiovascular events and death from any cause increased with decreasing estimated GFR. These findings were confirmed in a later meta-analysis, which also found that an elevated urinary albumin-to-creatinine ratio (> 1.1 mg/mmol) is an independent predictor of all-cause mortality and cardiovascular mortality.⁷

Keith et al⁸ followed nearly 28,000 patients with chronic kidney disease (with an estimated GFR of less than 90 mL/min/1.73 m²) over 5 years. Patients with stage 3 disease (moderate disease, GFR = 30–59 mL/min/1.73 m²) were 20 times more likely to die than to progress to end-stage renal disease (24.3% vs 1.2%). Even those with stage 4 disease (severe disease, GFR = 15–29 mL/min/1.73 m²) were more than twice as likely to die as to progress to dialysis (45.7% vs 19.9%).

Similar observations were made by Thompson et al¹⁰ based on the Alberta Kidney Disease Network database. They tracked cardiovascular causes of death and found that regardless of estimated GFR, cardiovascular deaths were most often attributed to ischemic heart disease (about 55%). Other trends were also apparent: as the GFR fell, the incidence of stroke decreased, and heart failure and valvular heart disease increased.

AFRICAN AMERICANS WITH KIDNEY DISEASE: A DISTINCT GROUP

African Americans constitute about 12% of the US population but account for:

• 31% of end-stage renal disease
• 34% of the kidney transplant waiting list
• 28% of kidney transplants in 2015 (12% of living donor transplants, 35% of deceased donor transplants).

In addition, African Americans with chronic kidney disease tend to be:

• Younger and have more advanced kidney disease than whites¹¹
• Much more likely than whites to have diabetes, and somewhat more likely to have hypertension

• 

  Adapted from Navaneethan SD, Schold JD, Arrigain S, Jolly SE, Nally JV Jr. Cause-specific deaths in non-dialysis-dependent CKD. J Am Soc Nephrol 2015; 26:2512–2520.

  More likely than whites to die of cardiovascular disease (37.4% vs 34.2%) (Figure 2).⁹

Overall, the prevalence of chronic kidney disease is slightly higher in African Americans than in whites. Interestingly, African Americans are slightly less likely than whites to have low estimated GFR values (6.2% vs 7.6% incidence of < 60 mL/min/1.73 m²) but are about 50% more likely to have proteinuria (12.3% vs 8.4% incidence of urine albumin-to-creatinine ratio ≥ 30 mg/g).

More likely to be on dialysis, but less likely to die

Although African Americans have only a slightly higher prevalence of chronic kidney disease (about 15% increased prevalence) than whites,¹² they are 3 times more likely to be on dialysis.

Nevertheless, for unknown reasons, African American adults on dialysis have about a 26% lower all-cause mortality rate than whites.⁵ One proposed explanation for this survival advantage has been that the mortality rate in African Americans with chronic kidney disease before entering dialysis is higher than in whites, leading to a “healthier population” on dialysis.¹³ However, this theory is based on a small study from more than a decade ago and has not been borne out by subsequent investigation.

African Americans with chronic kidney disease: Death rates not increased

African Americans over age 65 with chronic kidney disease have all-cause mortality rates similar to those of whites: about 11% annually. Breaking it down by disease severity, death rates in stage 3 disease are about 10% and jump to more than 15% in higher stages in both African Americans and whites.⁵

However, African Americans with chronic kidney disease have more heart disease and much more end-stage renal disease than whites.

Disease advances faster despite care

The incidence of end-stage renal disease is consistently more than 3 times higher in African Americans than in whites in the United States.^5,14

Multiple investigations have tried to determine why African Americans are disproportionately affected by progression of chronic kidney disease to end-stage renal disease. We recently examined this question in our Cleveland Clinic registry data. Even after adjusting for 17 variables (including demographics, comorbidities, insurance, medications, smoking, and chronic kidney disease stage), African Americans with chronic kidney disease were found to have an increased risk of progressing to end-stage renal disease compared with whites (subhazard ratio 1.38, 95% confidence interval 1.19–1.60).

We examined care measures from the Cleveland Clinic database. In terms of the number of laboratory tests ordered, clinic visits, and nephrology referrals, African Americans had at least as much care as whites, if not more. Similarly, African Americans’ access to renoprotective medicines (angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, statins, beta-blockers) was the same as or more than for whites.

Although the frequently attributed reasons surrounding compliance and socioeconomic issues are worthy of examination, they do not appear to completely explain the differences in incidence and outcomes. This dichotomy of a marginally increased prevalence of chronic kidney disease in African Americans with mortality rates similar to those of whites, yet with a 3 times higher incidence of end-stage renal disease in African Americans, suggests a faster progression of the disease in African Americans, which may be genetically based.

In 2010, two variant alleles of the APOL1 gene on chromosome 22 were found to be associated with nondiabetic kidney disease.¹⁵ Three nephropathies are associated with being homozygous for these alleles:

• Focal segmental glomerulosclerosis, the leading cause of nephrotic syndrome in African Americans
• Hypertension-associated kidney disease with scarring of glomeruli in vessels, the primary cause of end-stage renal disease in African Americans
• Human immunodeficiency virus (HIV)- associated nephropathy, usually a focal segmental glomerulosclerosis type of lesion.

The first two conditions are about 3 to 5 times more prevalent in African Americans than in whites, and HIV-associated nephropathy is about 20 to 30 times more common. 

African sleeping sickness and chronic kidney disease

Retrospective analysis of biologic samples from trials of kidney disease in African Americans has revealed interesting results.

From Parsa A, Kao WH, Xie D, et al; AASK Study Investigators; CRIC Study Investigators. APOL1 risk variants, race, and progression of chronic kidney disease. N Engl J Med 2013; 369:2183–2196. Reprinted with permission from Massachusetts Medical Society.

The Chronic Renal Insufficiency Cohort (CRIC) observation study¹⁸ enrolled patients with an estimated GFR of 20 to 70 mL/min/1.73 m², with a preference for African Americans and patients with diabetes. Nearly 3,000 participants had adequate samples for DNA testing. They found that African Americans with the double variant allele had worse outcomes, whether or not they had diabetes, compared with whites and African Americans without the homozygous gene variant.

Mechanism not well understood

The mechanism of renal injury is not well understood. Apolipoprotein L1, the protein coded for by APOL1, is a component of high-density lipoprotein. It is found in a different distribution pattern in people with normal kidneys vs those with nondiabetic kidney disease, especially in the arteries, arterioles, and podocytes.^19,20 It can be detected in blood plasma, but levels do not correlate with kidney disease.²¹ Not all patients with the high-risk variant develop chronic kidney disease; a “second hit” such as infection with HIV may be required.

Investigators have recently developed knockout mouse models of APOL1-associated kidney diseases that are helping to elucidate mechanisms.^22,23

EFFECT OF GENOTYPE ON KIDNEY TRANSPLANTS IN AFRICAN AMERICANS

African Americans receive about 30% of kidney transplants in the United States and represent about 15% to 20% of all donors.

Lee et al²⁴ reviewed 119 African American recipients of kidney transplants, about half of whom were homozygous for an APOL1 variant. After 5 years, no differences were found in allograft survival between recipients with 0, 1, or 2 risk alleles.

However, looking at the issue from the other side, Reeves-Daniel et al²⁵ studied the fate of more than 100 kidneys that were transplanted from African American donors, 16% of whom had the high-risk, homozygous genotype. In this case, graft failure was much likelier to occur with the high-risk donor kidneys (hazard ratio 3.84, P = .008). Similar outcomes were shown in a study of 2 centers²⁶ involving 675 transplants from deceased donors, 15% of which involved the high-risk genotype. The hazard ratio for graft failure was found to be 2.26 (P = .001) with high-risk donor kidneys.

These studies, which examined data from about 5 years after transplant, found that kidney failure does not tend to occur immediately in all cases, but gradually over time. Most high-risk kidneys were not lost within the 5 years of the studies.

The fact that the high-risk kidneys do not all fail immediately also suggests that a second hit is required for failure. Culprits postulated include a bacterial or viral infection (eg, BK virus, cytomegalovirus), ischemia or reperfusion injury, drug toxicity, and immune-mediated allograft injury (ie, rejection). 

Genetic testing for APOL1 risk variants is on the horizon for kidney transplant. But at this point, providing guidance for patients can be tricky. Two case studies^27,28 and epidemiologic data suggest that donors homozygous for an APOL1 variant and those with a family history of end-stage kidney disease are at increased risk of chronic kidney disease. Even so, most recipients even of these high-risk organs have good outcomes. If an African American patient needs a kidney and his or her sibling offers one, it is difficult to advise against it when the evidence is weak for immediate risk and when other options may not be readily available. Further investigation is clearly needed into whether APOL1 variants and other biomarkers can predict an organ’s success as a transplant.

The National Institutes of Health are currently funding prospective longitudinal studies with the APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) to determine the impact of APOL1 genetic factors on transplant recipients as well as on living donors. Possible second hits will also be studied, as will other markers of renal dysfunction or disease in donors. Researchers are actively investigating these important questions.

KEEPING SCIENCE RELEVANT

In a recent commentary related to the murine knockout model of APOL1-associated kidney disease, O’Toole et al offered insightful observations regarding the potential clinical impact of these new genetic discoveries.²³

As we study the genetics of kidney disease in African American patients, we should keep in mind 3 critical questions of clinical importance:

Will findings identify better treatments for chronic kidney disease? The AASK trial found that knowing the genetics did not affect outcomes of routine therapy. However, basic science investigations are currently underway targeting APOL1 variants which might reduce the increased kidney disease risk among people of African descent.

Should patients be genotyped for APOL1 risk variants? For patients with chronic kidney disease, it does not seem useful at this time. But for renal transplant donors, the answer is probably yes.

How does this discovery help us to understand our patients better? The implications are enormous for combatting the assumptions that rapid chronic kidney disease progression reflects poor patient compliance or other socioeconomic factors. We now understand that genetics, at least in part, drives renal disease outcomes in African American patients.

Editor’s note: This Medical Grand Rounds was presented as the 14th Annual Lawrence “Chris” Crain Memorial Lecture, a series that has been dedicated to discussing kidney disease, hypertension, and health care disparities in the African American community. In 1997, Dr. Crain became the first African American chief medical resident at Cleveland Clinic, and was a nephrology fellow in 1998–1999. Dr. Nally was his teacher and mentor.

African Americans have a greater burden of chronic kidney disease than whites. They are more than 3 times as likely as whites to develop end-stage renal disease, even after adjusting for age, disease stage, smoking, medications, and comorbidities. Why this is so has been the focus of much speculation and research.

This article reviews recent advances in the understanding of the progression of chronic kidney disease, with particular scrutiny of the disease in African Americans. Breakthroughs in genetics that help explain the greater disease burden in African Americans are also discussed, as well as implications for organ transplant screening.

ADVANCING UNDERSTANDING OF CHRONIC KIDNEY DISEASE

In the 1990s, dialysis rolls grew by 8% to 10% annually. Unfortunately, many patients first met with a nephrologist on the eve of their first dialysis treatment; there was not yet an adequate way to recognize the disease earlier and slow its progression. And disease definitions were not yet standardized, which led to inadequate metrics and hampered the ability to move disease management forward.

Standardizing definitions

The situation improved in 2002, when the National Kidney Foundation published clinical practice guidelines for chronic kidney disease that included disease definitions and staging.¹ Chronic kidney disease was defined as a structural or functional abnormality of the kidney lasting at least 3 months, as manifested by either of the following:

• Kidney damage, with or without decreased glomerular filtration rate (GFR), as defined by pathologic abnormalities or markers of kidney damage in the blood, urine, or on imaging tests

• 

  GFR less than 60 mL/min/1.73 m², with or without kidney damage.

A subsequent major advance was the recognition that not only GFR but also albuminuria was important for staging of chronic kidney disease (Figure 1).²

Developing large databases

Surveillance and monitoring of chronic kidney disease have generated large databases that enable researchers to detect trends in disease progression.

US Renal Data System. The US Renal Data System has collected and reported on data for more than 20 years from the National Health and Nutrition Examination Survey and the Centers for Medicare and Medicaid Services about chronic and end-stage kidney disease in the United States.

Cleveland Clinic database. Cleveland Clinic has developed a validated chronic kidney disease registry based on its electronic health record.³ The data include demographics (age, sex, ethnic group), comorbidities, medications, and complete laboratory data.⁴

Alberta Kidney Disease Network. This Canadian research consortium links large laboratory and demographic databases to facilitate defining patient populations, such as those with kidney disease and other comorbidities.

Kaiser Permanente Renal Registry. Kaiser Permanente of Northern California insures more than one-third of adults in the San Francisco Bay Area. The renal registry includes all adults whose kidney function is known. Data on age, sex, and racial or ethnic group are available from the health-plan databases.

DEATHS FROM KIDNEY DISEASE

The mortality rate in patients with end-stage renal disease who are on dialysis has steadily fallen over the past 20 years, from an annual rate of about 25% in 1996 to 17% in 2014, suggesting that care improved during that time. Patients with transplants have a much lower mortality rate: less than 5% annually.⁵ But these data also highlight the persistent risk faced by patients with chronic kidney disease; even those with transplants have death rates comparable to those of patients with cancer, diabetes, or heart failure.

Death rates correlate with GFR

After the publication of definitions and staging by the National Kidney Foundation in 2002, Go et al⁶ studied more than 1 million patients with chronic kidney disease from the Kaiser Permanente Renal Registry and found that the rates of cardiovascular events and death from any cause increased with decreasing estimated GFR. These findings were confirmed in a later meta-analysis, which also found that an elevated urinary albumin-to-creatinine ratio (> 1.1 mg/mmol) is an independent predictor of all-cause mortality and cardiovascular mortality.⁷

Keith et al⁸ followed nearly 28,000 patients with chronic kidney disease (with an estimated GFR of less than 90 mL/min/1.73 m²) over 5 years. Patients with stage 3 disease (moderate disease, GFR = 30–59 mL/min/1.73 m²) were 20 times more likely to die than to progress to end-stage renal disease (24.3% vs 1.2%). Even those with stage 4 disease (severe disease, GFR = 15–29 mL/min/1.73 m²) were more than twice as likely to die as to progress to dialysis (45.7% vs 19.9%).

Similar observations were made by Thompson et al¹⁰ based on the Alberta Kidney Disease Network database. They tracked cardiovascular causes of death and found that regardless of estimated GFR, cardiovascular deaths were most often attributed to ischemic heart disease (about 55%). Other trends were also apparent: as the GFR fell, the incidence of stroke decreased, and heart failure and valvular heart disease increased.

AFRICAN AMERICANS WITH KIDNEY DISEASE: A DISTINCT GROUP

African Americans constitute about 12% of the US population but account for:

• 31% of end-stage renal disease
• 34% of the kidney transplant waiting list
• 28% of kidney transplants in 2015 (12% of living donor transplants, 35% of deceased donor transplants).

In addition, African Americans with chronic kidney disease tend to be:

• Younger and have more advanced kidney disease than whites¹¹
• Much more likely than whites to have diabetes, and somewhat more likely to have hypertension

• 

  Adapted from Navaneethan SD, Schold JD, Arrigain S, Jolly SE, Nally JV Jr. Cause-specific deaths in non-dialysis-dependent CKD. J Am Soc Nephrol 2015; 26:2512–2520.

  More likely than whites to die of cardiovascular disease (37.4% vs 34.2%) (Figure 2).⁹

Overall, the prevalence of chronic kidney disease is slightly higher in African Americans than in whites. Interestingly, African Americans are slightly less likely than whites to have low estimated GFR values (6.2% vs 7.6% incidence of < 60 mL/min/1.73 m²) but are about 50% more likely to have proteinuria (12.3% vs 8.4% incidence of urine albumin-to-creatinine ratio ≥ 30 mg/g).

More likely to be on dialysis, but less likely to die

Although African Americans have only a slightly higher prevalence of chronic kidney disease (about 15% increased prevalence) than whites,¹² they are 3 times more likely to be on dialysis.

Nevertheless, for unknown reasons, African American adults on dialysis have about a 26% lower all-cause mortality rate than whites.⁵ One proposed explanation for this survival advantage has been that the mortality rate in African Americans with chronic kidney disease before entering dialysis is higher than in whites, leading to a “healthier population” on dialysis.¹³ However, this theory is based on a small study from more than a decade ago and has not been borne out by subsequent investigation.

African Americans with chronic kidney disease: Death rates not increased

African Americans over age 65 with chronic kidney disease have all-cause mortality rates similar to those of whites: about 11% annually. Breaking it down by disease severity, death rates in stage 3 disease are about 10% and jump to more than 15% in higher stages in both African Americans and whites.⁵

However, African Americans with chronic kidney disease have more heart disease and much more end-stage renal disease than whites.

Disease advances faster despite care

The incidence of end-stage renal disease is consistently more than 3 times higher in African Americans than in whites in the United States.^5,14

Multiple investigations have tried to determine why African Americans are disproportionately affected by progression of chronic kidney disease to end-stage renal disease. We recently examined this question in our Cleveland Clinic registry data. Even after adjusting for 17 variables (including demographics, comorbidities, insurance, medications, smoking, and chronic kidney disease stage), African Americans with chronic kidney disease were found to have an increased risk of progressing to end-stage renal disease compared with whites (subhazard ratio 1.38, 95% confidence interval 1.19–1.60).

We examined care measures from the Cleveland Clinic database. In terms of the number of laboratory tests ordered, clinic visits, and nephrology referrals, African Americans had at least as much care as whites, if not more. Similarly, African Americans’ access to renoprotective medicines (angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, statins, beta-blockers) was the same as or more than for whites.

Although the frequently attributed reasons surrounding compliance and socioeconomic issues are worthy of examination, they do not appear to completely explain the differences in incidence and outcomes. This dichotomy of a marginally increased prevalence of chronic kidney disease in African Americans with mortality rates similar to those of whites, yet with a 3 times higher incidence of end-stage renal disease in African Americans, suggests a faster progression of the disease in African Americans, which may be genetically based.

In 2010, two variant alleles of the APOL1 gene on chromosome 22 were found to be associated with nondiabetic kidney disease.¹⁵ Three nephropathies are associated with being homozygous for these alleles:

• Focal segmental glomerulosclerosis, the leading cause of nephrotic syndrome in African Americans
• Hypertension-associated kidney disease with scarring of glomeruli in vessels, the primary cause of end-stage renal disease in African Americans
• Human immunodeficiency virus (HIV)- associated nephropathy, usually a focal segmental glomerulosclerosis type of lesion.

The first two conditions are about 3 to 5 times more prevalent in African Americans than in whites, and HIV-associated nephropathy is about 20 to 30 times more common. 

African sleeping sickness and chronic kidney disease

Retrospective analysis of biologic samples from trials of kidney disease in African Americans has revealed interesting results.

From Parsa A, Kao WH, Xie D, et al; AASK Study Investigators; CRIC Study Investigators. APOL1 risk variants, race, and progression of chronic kidney disease. N Engl J Med 2013; 369:2183–2196. Reprinted with permission from Massachusetts Medical Society.

The Chronic Renal Insufficiency Cohort (CRIC) observation study¹⁸ enrolled patients with an estimated GFR of 20 to 70 mL/min/1.73 m², with a preference for African Americans and patients with diabetes. Nearly 3,000 participants had adequate samples for DNA testing. They found that African Americans with the double variant allele had worse outcomes, whether or not they had diabetes, compared with whites and African Americans without the homozygous gene variant.

Mechanism not well understood

The mechanism of renal injury is not well understood. Apolipoprotein L1, the protein coded for by APOL1, is a component of high-density lipoprotein. It is found in a different distribution pattern in people with normal kidneys vs those with nondiabetic kidney disease, especially in the arteries, arterioles, and podocytes.^19,20 It can be detected in blood plasma, but levels do not correlate with kidney disease.²¹ Not all patients with the high-risk variant develop chronic kidney disease; a “second hit” such as infection with HIV may be required.

Investigators have recently developed knockout mouse models of APOL1-associated kidney diseases that are helping to elucidate mechanisms.^22,23

EFFECT OF GENOTYPE ON KIDNEY TRANSPLANTS IN AFRICAN AMERICANS

African Americans receive about 30% of kidney transplants in the United States and represent about 15% to 20% of all donors.

Lee et al²⁴ reviewed 119 African American recipients of kidney transplants, about half of whom were homozygous for an APOL1 variant. After 5 years, no differences were found in allograft survival between recipients with 0, 1, or 2 risk alleles.

However, looking at the issue from the other side, Reeves-Daniel et al²⁵ studied the fate of more than 100 kidneys that were transplanted from African American donors, 16% of whom had the high-risk, homozygous genotype. In this case, graft failure was much likelier to occur with the high-risk donor kidneys (hazard ratio 3.84, P = .008). Similar outcomes were shown in a study of 2 centers²⁶ involving 675 transplants from deceased donors, 15% of which involved the high-risk genotype. The hazard ratio for graft failure was found to be 2.26 (P = .001) with high-risk donor kidneys.

These studies, which examined data from about 5 years after transplant, found that kidney failure does not tend to occur immediately in all cases, but gradually over time. Most high-risk kidneys were not lost within the 5 years of the studies.

The fact that the high-risk kidneys do not all fail immediately also suggests that a second hit is required for failure. Culprits postulated include a bacterial or viral infection (eg, BK virus, cytomegalovirus), ischemia or reperfusion injury, drug toxicity, and immune-mediated allograft injury (ie, rejection). 

Genetic testing for APOL1 risk variants is on the horizon for kidney transplant. But at this point, providing guidance for patients can be tricky. Two case studies^27,28 and epidemiologic data suggest that donors homozygous for an APOL1 variant and those with a family history of end-stage kidney disease are at increased risk of chronic kidney disease. Even so, most recipients even of these high-risk organs have good outcomes. If an African American patient needs a kidney and his or her sibling offers one, it is difficult to advise against it when the evidence is weak for immediate risk and when other options may not be readily available. Further investigation is clearly needed into whether APOL1 variants and other biomarkers can predict an organ’s success as a transplant.

The National Institutes of Health are currently funding prospective longitudinal studies with the APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) to determine the impact of APOL1 genetic factors on transplant recipients as well as on living donors. Possible second hits will also be studied, as will other markers of renal dysfunction or disease in donors. Researchers are actively investigating these important questions.

KEEPING SCIENCE RELEVANT

In a recent commentary related to the murine knockout model of APOL1-associated kidney disease, O’Toole et al offered insightful observations regarding the potential clinical impact of these new genetic discoveries.²³

As we study the genetics of kidney disease in African American patients, we should keep in mind 3 critical questions of clinical importance:

Will findings identify better treatments for chronic kidney disease? The AASK trial found that knowing the genetics did not affect outcomes of routine therapy. However, basic science investigations are currently underway targeting APOL1 variants which might reduce the increased kidney disease risk among people of African descent.

Should patients be genotyped for APOL1 risk variants? For patients with chronic kidney disease, it does not seem useful at this time. But for renal transplant donors, the answer is probably yes.

How does this discovery help us to understand our patients better? The implications are enormous for combatting the assumptions that rapid chronic kidney disease progression reflects poor patient compliance or other socioeconomic factors. We now understand that genetics, at least in part, drives renal disease outcomes in African American patients.

Editor’s note: This Medical Grand Rounds was presented as the 14th Annual Lawrence “Chris” Crain Memorial Lecture, a series that has been dedicated to discussing kidney disease, hypertension, and health care disparities in the African American community. In 1997, Dr. Crain became the first African American chief medical resident at Cleveland Clinic, and was a nephrology fellow in 1998–1999. Dr. Nally was his teacher and mentor.

African Americans have a greater burden of chronic kidney disease than whites. They are more than 3 times as likely as whites to develop end-stage renal disease, even after adjusting for age, disease stage, smoking, medications, and comorbidities. Why this is so has been the focus of much speculation and research.

This article reviews recent advances in the understanding of the progression of chronic kidney disease, with particular scrutiny of the disease in African Americans. Breakthroughs in genetics that help explain the greater disease burden in African Americans are also discussed, as well as implications for organ transplant screening.

ADVANCING UNDERSTANDING OF CHRONIC KIDNEY DISEASE

In the 1990s, dialysis rolls grew by 8% to 10% annually. Unfortunately, many patients first met with a nephrologist on the eve of their first dialysis treatment; there was not yet an adequate way to recognize the disease earlier and slow its progression. And disease definitions were not yet standardized, which led to inadequate metrics and hampered the ability to move disease management forward.

Standardizing definitions

The situation improved in 2002, when the National Kidney Foundation published clinical practice guidelines for chronic kidney disease that included disease definitions and staging.¹ Chronic kidney disease was defined as a structural or functional abnormality of the kidney lasting at least 3 months, as manifested by either of the following:

• Kidney damage, with or without decreased glomerular filtration rate (GFR), as defined by pathologic abnormalities or markers of kidney damage in the blood, urine, or on imaging tests

• 

  GFR less than 60 mL/min/1.73 m², with or without kidney damage.

A subsequent major advance was the recognition that not only GFR but also albuminuria was important for staging of chronic kidney disease (Figure 1).²

Developing large databases

Surveillance and monitoring of chronic kidney disease have generated large databases that enable researchers to detect trends in disease progression.

US Renal Data System. The US Renal Data System has collected and reported on data for more than 20 years from the National Health and Nutrition Examination Survey and the Centers for Medicare and Medicaid Services about chronic and end-stage kidney disease in the United States.

Cleveland Clinic database. Cleveland Clinic has developed a validated chronic kidney disease registry based on its electronic health record.³ The data include demographics (age, sex, ethnic group), comorbidities, medications, and complete laboratory data.⁴

Alberta Kidney Disease Network. This Canadian research consortium links large laboratory and demographic databases to facilitate defining patient populations, such as those with kidney disease and other comorbidities.

Kaiser Permanente Renal Registry. Kaiser Permanente of Northern California insures more than one-third of adults in the San Francisco Bay Area. The renal registry includes all adults whose kidney function is known. Data on age, sex, and racial or ethnic group are available from the health-plan databases.

DEATHS FROM KIDNEY DISEASE

The mortality rate in patients with end-stage renal disease who are on dialysis has steadily fallen over the past 20 years, from an annual rate of about 25% in 1996 to 17% in 2014, suggesting that care improved during that time. Patients with transplants have a much lower mortality rate: less than 5% annually.⁵ But these data also highlight the persistent risk faced by patients with chronic kidney disease; even those with transplants have death rates comparable to those of patients with cancer, diabetes, or heart failure.

Death rates correlate with GFR

After the publication of definitions and staging by the National Kidney Foundation in 2002, Go et al⁶ studied more than 1 million patients with chronic kidney disease from the Kaiser Permanente Renal Registry and found that the rates of cardiovascular events and death from any cause increased with decreasing estimated GFR. These findings were confirmed in a later meta-analysis, which also found that an elevated urinary albumin-to-creatinine ratio (> 1.1 mg/mmol) is an independent predictor of all-cause mortality and cardiovascular mortality.⁷

Keith et al⁸ followed nearly 28,000 patients with chronic kidney disease (with an estimated GFR of less than 90 mL/min/1.73 m²) over 5 years. Patients with stage 3 disease (moderate disease, GFR = 30–59 mL/min/1.73 m²) were 20 times more likely to die than to progress to end-stage renal disease (24.3% vs 1.2%). Even those with stage 4 disease (severe disease, GFR = 15–29 mL/min/1.73 m²) were more than twice as likely to die as to progress to dialysis (45.7% vs 19.9%).

Similar observations were made by Thompson et al¹⁰ based on the Alberta Kidney Disease Network database. They tracked cardiovascular causes of death and found that regardless of estimated GFR, cardiovascular deaths were most often attributed to ischemic heart disease (about 55%). Other trends were also apparent: as the GFR fell, the incidence of stroke decreased, and heart failure and valvular heart disease increased.

AFRICAN AMERICANS WITH KIDNEY DISEASE: A DISTINCT GROUP

African Americans constitute about 12% of the US population but account for:

• 31% of end-stage renal disease
• 34% of the kidney transplant waiting list
• 28% of kidney transplants in 2015 (12% of living donor transplants, 35% of deceased donor transplants).

In addition, African Americans with chronic kidney disease tend to be:

• Younger and have more advanced kidney disease than whites¹¹
• Much more likely than whites to have diabetes, and somewhat more likely to have hypertension

• 

  Adapted from Navaneethan SD, Schold JD, Arrigain S, Jolly SE, Nally JV Jr. Cause-specific deaths in non-dialysis-dependent CKD. J Am Soc Nephrol 2015; 26:2512–2520.

  More likely than whites to die of cardiovascular disease (37.4% vs 34.2%) (Figure 2).⁹

Overall, the prevalence of chronic kidney disease is slightly higher in African Americans than in whites. Interestingly, African Americans are slightly less likely than whites to have low estimated GFR values (6.2% vs 7.6% incidence of < 60 mL/min/1.73 m²) but are about 50% more likely to have proteinuria (12.3% vs 8.4% incidence of urine albumin-to-creatinine ratio ≥ 30 mg/g).

More likely to be on dialysis, but less likely to die

Although African Americans have only a slightly higher prevalence of chronic kidney disease (about 15% increased prevalence) than whites,¹² they are 3 times more likely to be on dialysis.

Nevertheless, for unknown reasons, African American adults on dialysis have about a 26% lower all-cause mortality rate than whites.⁵ One proposed explanation for this survival advantage has been that the mortality rate in African Americans with chronic kidney disease before entering dialysis is higher than in whites, leading to a “healthier population” on dialysis.¹³ However, this theory is based on a small study from more than a decade ago and has not been borne out by subsequent investigation.

African Americans with chronic kidney disease: Death rates not increased

African Americans over age 65 with chronic kidney disease have all-cause mortality rates similar to those of whites: about 11% annually. Breaking it down by disease severity, death rates in stage 3 disease are about 10% and jump to more than 15% in higher stages in both African Americans and whites.⁵

However, African Americans with chronic kidney disease have more heart disease and much more end-stage renal disease than whites.

Disease advances faster despite care

The incidence of end-stage renal disease is consistently more than 3 times higher in African Americans than in whites in the United States.^5,14

Multiple investigations have tried to determine why African Americans are disproportionately affected by progression of chronic kidney disease to end-stage renal disease. We recently examined this question in our Cleveland Clinic registry data. Even after adjusting for 17 variables (including demographics, comorbidities, insurance, medications, smoking, and chronic kidney disease stage), African Americans with chronic kidney disease were found to have an increased risk of progressing to end-stage renal disease compared with whites (subhazard ratio 1.38, 95% confidence interval 1.19–1.60).

We examined care measures from the Cleveland Clinic database. In terms of the number of laboratory tests ordered, clinic visits, and nephrology referrals, African Americans had at least as much care as whites, if not more. Similarly, African Americans’ access to renoprotective medicines (angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, statins, beta-blockers) was the same as or more than for whites.

Although the frequently attributed reasons surrounding compliance and socioeconomic issues are worthy of examination, they do not appear to completely explain the differences in incidence and outcomes. This dichotomy of a marginally increased prevalence of chronic kidney disease in African Americans with mortality rates similar to those of whites, yet with a 3 times higher incidence of end-stage renal disease in African Americans, suggests a faster progression of the disease in African Americans, which may be genetically based.

In 2010, two variant alleles of the APOL1 gene on chromosome 22 were found to be associated with nondiabetic kidney disease.¹⁵ Three nephropathies are associated with being homozygous for these alleles:

• Focal segmental glomerulosclerosis, the leading cause of nephrotic syndrome in African Americans
• Hypertension-associated kidney disease with scarring of glomeruli in vessels, the primary cause of end-stage renal disease in African Americans
• Human immunodeficiency virus (HIV)- associated nephropathy, usually a focal segmental glomerulosclerosis type of lesion.

The first two conditions are about 3 to 5 times more prevalent in African Americans than in whites, and HIV-associated nephropathy is about 20 to 30 times more common. 

African sleeping sickness and chronic kidney disease

Retrospective analysis of biologic samples from trials of kidney disease in African Americans has revealed interesting results.

From Parsa A, Kao WH, Xie D, et al; AASK Study Investigators; CRIC Study Investigators. APOL1 risk variants, race, and progression of chronic kidney disease. N Engl J Med 2013; 369:2183–2196. Reprinted with permission from Massachusetts Medical Society.

The Chronic Renal Insufficiency Cohort (CRIC) observation study¹⁸ enrolled patients with an estimated GFR of 20 to 70 mL/min/1.73 m², with a preference for African Americans and patients with diabetes. Nearly 3,000 participants had adequate samples for DNA testing. They found that African Americans with the double variant allele had worse outcomes, whether or not they had diabetes, compared with whites and African Americans without the homozygous gene variant.

Mechanism not well understood

The mechanism of renal injury is not well understood. Apolipoprotein L1, the protein coded for by APOL1, is a component of high-density lipoprotein. It is found in a different distribution pattern in people with normal kidneys vs those with nondiabetic kidney disease, especially in the arteries, arterioles, and podocytes.^19,20 It can be detected in blood plasma, but levels do not correlate with kidney disease.²¹ Not all patients with the high-risk variant develop chronic kidney disease; a “second hit” such as infection with HIV may be required.

Investigators have recently developed knockout mouse models of APOL1-associated kidney diseases that are helping to elucidate mechanisms.^22,23

EFFECT OF GENOTYPE ON KIDNEY TRANSPLANTS IN AFRICAN AMERICANS

African Americans receive about 30% of kidney transplants in the United States and represent about 15% to 20% of all donors.

Lee et al²⁴ reviewed 119 African American recipients of kidney transplants, about half of whom were homozygous for an APOL1 variant. After 5 years, no differences were found in allograft survival between recipients with 0, 1, or 2 risk alleles.

However, looking at the issue from the other side, Reeves-Daniel et al²⁵ studied the fate of more than 100 kidneys that were transplanted from African American donors, 16% of whom had the high-risk, homozygous genotype. In this case, graft failure was much likelier to occur with the high-risk donor kidneys (hazard ratio 3.84, P = .008). Similar outcomes were shown in a study of 2 centers²⁶ involving 675 transplants from deceased donors, 15% of which involved the high-risk genotype. The hazard ratio for graft failure was found to be 2.26 (P = .001) with high-risk donor kidneys.

These studies, which examined data from about 5 years after transplant, found that kidney failure does not tend to occur immediately in all cases, but gradually over time. Most high-risk kidneys were not lost within the 5 years of the studies.

The fact that the high-risk kidneys do not all fail immediately also suggests that a second hit is required for failure. Culprits postulated include a bacterial or viral infection (eg, BK virus, cytomegalovirus), ischemia or reperfusion injury, drug toxicity, and immune-mediated allograft injury (ie, rejection). 

Genetic testing for APOL1 risk variants is on the horizon for kidney transplant. But at this point, providing guidance for patients can be tricky. Two case studies^27,28 and epidemiologic data suggest that donors homozygous for an APOL1 variant and those with a family history of end-stage kidney disease are at increased risk of chronic kidney disease. Even so, most recipients even of these high-risk organs have good outcomes. If an African American patient needs a kidney and his or her sibling offers one, it is difficult to advise against it when the evidence is weak for immediate risk and when other options may not be readily available. Further investigation is clearly needed into whether APOL1 variants and other biomarkers can predict an organ’s success as a transplant.

The National Institutes of Health are currently funding prospective longitudinal studies with the APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) to determine the impact of APOL1 genetic factors on transplant recipients as well as on living donors. Possible second hits will also be studied, as will other markers of renal dysfunction or disease in donors. Researchers are actively investigating these important questions.

KEEPING SCIENCE RELEVANT

In a recent commentary related to the murine knockout model of APOL1-associated kidney disease, O’Toole et al offered insightful observations regarding the potential clinical impact of these new genetic discoveries.²³

As we study the genetics of kidney disease in African American patients, we should keep in mind 3 critical questions of clinical importance:

Will findings identify better treatments for chronic kidney disease? The AASK trial found that knowing the genetics did not affect outcomes of routine therapy. However, basic science investigations are currently underway targeting APOL1 variants which might reduce the increased kidney disease risk among people of African descent.

Should patients be genotyped for APOL1 risk variants? For patients with chronic kidney disease, it does not seem useful at this time. But for renal transplant donors, the answer is probably yes.

How does this discovery help us to understand our patients better? The implications are enormous for combatting the assumptions that rapid chronic kidney disease progression reflects poor patient compliance or other socioeconomic factors. We now understand that genetics, at least in part, drives renal disease outcomes in African American patients.

WASHINGTON – Treatment with carvedilol reduced the incidence of sepsis and acute kidney injury and improved survival at 28 days but did not significantly reduce the progression of esophageal varices in patients with acute-on-chronic liver failure.

A total of 136 patients with acute-on-chronic liver failure with small or no esophageal varices and a hepatic venous pressure gradient (HVPG) of 12 mm Hg or greater were enrolled in a single center, prospective, open-label, randomized controlled trial: 66 were randomized to carvedilol and 70 to placebo, according to Sumeet Kainth, MD, of the Institute of Liver and Biliary Sciences in New Delhi.

The study was sponsored by Institute of Liver and Biliary Sciences. Dr. Kainth reported no relevant conflicts of interest.

dfulton@frontlinemedcom.com

On Twitter @denisefulton

WASHINGTON – Treatment with carvedilol reduced the incidence of sepsis and acute kidney injury and improved survival at 28 days but did not significantly reduce the progression of esophageal varices in patients with acute-on-chronic liver failure.

A total of 136 patients with acute-on-chronic liver failure with small or no esophageal varices and a hepatic venous pressure gradient (HVPG) of 12 mm Hg or greater were enrolled in a single center, prospective, open-label, randomized controlled trial: 66 were randomized to carvedilol and 70 to placebo, according to Sumeet Kainth, MD, of the Institute of Liver and Biliary Sciences in New Delhi.

The study was sponsored by Institute of Liver and Biliary Sciences. Dr. Kainth reported no relevant conflicts of interest.

dfulton@frontlinemedcom.com

On Twitter @denisefulton

WASHINGTON – Treatment with carvedilol reduced the incidence of sepsis and acute kidney injury and improved survival at 28 days but did not significantly reduce the progression of esophageal varices in patients with acute-on-chronic liver failure.

A total of 136 patients with acute-on-chronic liver failure with small or no esophageal varices and a hepatic venous pressure gradient (HVPG) of 12 mm Hg or greater were enrolled in a single center, prospective, open-label, randomized controlled trial: 66 were randomized to carvedilol and 70 to placebo, according to Sumeet Kainth, MD, of the Institute of Liver and Biliary Sciences in New Delhi.

The study was sponsored by Institute of Liver and Biliary Sciences. Dr. Kainth reported no relevant conflicts of interest.

dfulton@frontlinemedcom.com

On Twitter @denisefulton

Q) Recently, when I have sent my patients with chronic kidney disease (CKD) to the emergency department (ED) for complaints of chest pain or shortness of breath, their troponin levels are high. I know CKD increases risk for cardiovascular disease, but I find it hard to believe that every CKD patient is having an MI. What gives?

Cardiovascular disease remains the most common cause of death in patients with CKD, accounting for 45% to 50% of all deaths. Therefore, accurate diagnosis of acute myocardial infarction (AMI) in this patient population is vital to assure prompt identification and treatment.^1,2

Cardiac troponins are the gold standard for detecting myocardial injury in patients presenting to the ED with suggestive symptoms.¹ But the chronic baseline elevation in serum troponin levels among patients with CKD often results in a false-positive reading, making the detection of AMI difficult.¹

With the recent introduction of high-sensitivity troponin assays, as many as 97% of patients on hemodialysis exhibit elevated troponin levels; this is also true for patients with CKD, on a sliding scale (lower kidney function = higher baseline troponins).² The use of high-sensitivity testing has increased substantially in the past 15 years, and it is expected to become the benchmark for troponin evaluation. While older troponin tests had a false-positive rate of 30% to 85% in patients with stage 5 CKD, the newer troponin tests display elevated troponins in almost 100% of these patients.^1,2

Numerous studies have been conducted to determine the best way to interpret positive troponin tests in patients with CKD to ensure an accurate diagnosis of AMI.² One study determined that a 20% increase in troponin levels was a more accurate determinant of AMI in patients with CKD than one isolated positive level.³ Another study demonstrated that serial troponin measurements conducted over time yielded higher diagnostic accuracy than one measurement above the 99th percentile.⁴

The American College of Cardiology Foundation task force found that monitoring changes in troponin concentration over time (3-6 h) is more accurate than a single elevated troponin when diagnosing AMI in symptomatic patients.³ Correlation between elevated troponin levels and clinical suspicion proved helpful in determining the significance of troponin results and the probability of AMI in patients with CKD.²

The significance and interpretation of elevated troponin levels in patients with CKD remains an important topic for further study, as cardiovascular disease continues to be the leading cause of mortality in patients with kidney dysfunction.^1,2 More definitive studies need to be conducted on patients with CKD as high-sensitivity troponin assay testing becomes standard for diagnosing AMI.

So, the reason you see more positive troponin results in your CKD population is due to both the increased accuracy of the newer tests and the fact that CKD often causes a false-positive result. Monitoring your patients with serial troponins for at least three hours is essential to confirm or rule out an AMI. —MS-G

Marlene Shaw-Gallagher, MS, PA-C
University of Detroit Mercy, Michigan
Division of Nephrology, University of Michigan, Ann Arbor

Q) Recently, when I have sent my patients with chronic kidney disease (CKD) to the emergency department (ED) for complaints of chest pain or shortness of breath, their troponin levels are high. I know CKD increases risk for cardiovascular disease, but I find it hard to believe that every CKD patient is having an MI. What gives?

Cardiovascular disease remains the most common cause of death in patients with CKD, accounting for 45% to 50% of all deaths. Therefore, accurate diagnosis of acute myocardial infarction (AMI) in this patient population is vital to assure prompt identification and treatment.^1,2

Cardiac troponins are the gold standard for detecting myocardial injury in patients presenting to the ED with suggestive symptoms.¹ But the chronic baseline elevation in serum troponin levels among patients with CKD often results in a false-positive reading, making the detection of AMI difficult.¹

With the recent introduction of high-sensitivity troponin assays, as many as 97% of patients on hemodialysis exhibit elevated troponin levels; this is also true for patients with CKD, on a sliding scale (lower kidney function = higher baseline troponins).² The use of high-sensitivity testing has increased substantially in the past 15 years, and it is expected to become the benchmark for troponin evaluation. While older troponin tests had a false-positive rate of 30% to 85% in patients with stage 5 CKD, the newer troponin tests display elevated troponins in almost 100% of these patients.^1,2

Numerous studies have been conducted to determine the best way to interpret positive troponin tests in patients with CKD to ensure an accurate diagnosis of AMI.² One study determined that a 20% increase in troponin levels was a more accurate determinant of AMI in patients with CKD than one isolated positive level.³ Another study demonstrated that serial troponin measurements conducted over time yielded higher diagnostic accuracy than one measurement above the 99th percentile.⁴

The American College of Cardiology Foundation task force found that monitoring changes in troponin concentration over time (3-6 h) is more accurate than a single elevated troponin when diagnosing AMI in symptomatic patients.³ Correlation between elevated troponin levels and clinical suspicion proved helpful in determining the significance of troponin results and the probability of AMI in patients with CKD.²

The significance and interpretation of elevated troponin levels in patients with CKD remains an important topic for further study, as cardiovascular disease continues to be the leading cause of mortality in patients with kidney dysfunction.^1,2 More definitive studies need to be conducted on patients with CKD as high-sensitivity troponin assay testing becomes standard for diagnosing AMI.

So, the reason you see more positive troponin results in your CKD population is due to both the increased accuracy of the newer tests and the fact that CKD often causes a false-positive result. Monitoring your patients with serial troponins for at least three hours is essential to confirm or rule out an AMI. —MS-G

Marlene Shaw-Gallagher, MS, PA-C
University of Detroit Mercy, Michigan
Division of Nephrology, University of Michigan, Ann Arbor

Q) Recently, when I have sent my patients with chronic kidney disease (CKD) to the emergency department (ED) for complaints of chest pain or shortness of breath, their troponin levels are high. I know CKD increases risk for cardiovascular disease, but I find it hard to believe that every CKD patient is having an MI. What gives?

Cardiovascular disease remains the most common cause of death in patients with CKD, accounting for 45% to 50% of all deaths. Therefore, accurate diagnosis of acute myocardial infarction (AMI) in this patient population is vital to assure prompt identification and treatment.^1,2

Cardiac troponins are the gold standard for detecting myocardial injury in patients presenting to the ED with suggestive symptoms.¹ But the chronic baseline elevation in serum troponin levels among patients with CKD often results in a false-positive reading, making the detection of AMI difficult.¹

With the recent introduction of high-sensitivity troponin assays, as many as 97% of patients on hemodialysis exhibit elevated troponin levels; this is also true for patients with CKD, on a sliding scale (lower kidney function = higher baseline troponins).² The use of high-sensitivity testing has increased substantially in the past 15 years, and it is expected to become the benchmark for troponin evaluation. While older troponin tests had a false-positive rate of 30% to 85% in patients with stage 5 CKD, the newer troponin tests display elevated troponins in almost 100% of these patients.^1,2

Numerous studies have been conducted to determine the best way to interpret positive troponin tests in patients with CKD to ensure an accurate diagnosis of AMI.² One study determined that a 20% increase in troponin levels was a more accurate determinant of AMI in patients with CKD than one isolated positive level.³ Another study demonstrated that serial troponin measurements conducted over time yielded higher diagnostic accuracy than one measurement above the 99th percentile.⁴

The American College of Cardiology Foundation task force found that monitoring changes in troponin concentration over time (3-6 h) is more accurate than a single elevated troponin when diagnosing AMI in symptomatic patients.³ Correlation between elevated troponin levels and clinical suspicion proved helpful in determining the significance of troponin results and the probability of AMI in patients with CKD.²

The significance and interpretation of elevated troponin levels in patients with CKD remains an important topic for further study, as cardiovascular disease continues to be the leading cause of mortality in patients with kidney dysfunction.^1,2 More definitive studies need to be conducted on patients with CKD as high-sensitivity troponin assay testing becomes standard for diagnosing AMI.

So, the reason you see more positive troponin results in your CKD population is due to both the increased accuracy of the newer tests and the fact that CKD often causes a false-positive result. Monitoring your patients with serial troponins for at least three hours is essential to confirm or rule out an AMI. —MS-G

Marlene Shaw-Gallagher, MS, PA-C
University of Detroit Mercy, Michigan
Division of Nephrology, University of Michigan, Ann Arbor

BARCELONA – Oral anticoagulation had a net overall benefit for patients with atrial fibrillation and advanced chronic kidney disease, based on results of a large observational study reported at the annual congress of the European Society of Cardiology.

The novel direct-acting oral anticoagulants (NOACs) and warfarin were all similarly effective in this study of 39,241 patients who had stage 4 or 5 chronic kidney disease (CKD), atrial fibrillation, and were not on dialysis. Compared with no oral anticoagulation, the drugs cut in half the risk of stroke or systemic embolism, with no increased risk of major bleeding.

“In patients with advanced CKD, it appears that OACs [oral anticoagulants] are reasonable,” concluded Peter A. Noseworthy, MD, of the Mayo Clinic in Rochester, Minn.

bjancin@frontlinemedcom.com

BARCELONA – Oral anticoagulation had a net overall benefit for patients with atrial fibrillation and advanced chronic kidney disease, based on results of a large observational study reported at the annual congress of the European Society of Cardiology.

The novel direct-acting oral anticoagulants (NOACs) and warfarin were all similarly effective in this study of 39,241 patients who had stage 4 or 5 chronic kidney disease (CKD), atrial fibrillation, and were not on dialysis. Compared with no oral anticoagulation, the drugs cut in half the risk of stroke or systemic embolism, with no increased risk of major bleeding.

“In patients with advanced CKD, it appears that OACs [oral anticoagulants] are reasonable,” concluded Peter A. Noseworthy, MD, of the Mayo Clinic in Rochester, Minn.

bjancin@frontlinemedcom.com

BARCELONA – Oral anticoagulation had a net overall benefit for patients with atrial fibrillation and advanced chronic kidney disease, based on results of a large observational study reported at the annual congress of the European Society of Cardiology.

The novel direct-acting oral anticoagulants (NOACs) and warfarin were all similarly effective in this study of 39,241 patients who had stage 4 or 5 chronic kidney disease (CKD), atrial fibrillation, and were not on dialysis. Compared with no oral anticoagulation, the drugs cut in half the risk of stroke or systemic embolism, with no increased risk of major bleeding.

“In patients with advanced CKD, it appears that OACs [oral anticoagulants] are reasonable,” concluded Peter A. Noseworthy, MD, of the Mayo Clinic in Rochester, Minn.

bjancin@frontlinemedcom.com

Q) Is it true that PPI use can cause kidney disease?

Proton pump inhibitors (PPIs) have been available in the United States since 1990, with OTC options available since 2009. While these medications play a vital role in the treatment of gastrointestinal (GI) con­ditions, observational studies have linked PPI use to serious adverse events, including dementia, community-acquired pneumonia, hip fracture, and Clostridium difficile infection.^1-4

Studies have also found an association between PPI use and kidney problems such as acute kidney injury (AKI), acute interstitial nephritis, and incident chronic kidney disease (CKD).^5-7 One observational study used the Department of Veterans Affairs (VA) national databases to track the renal outcomes of 173,321 new PPI users and 20,270 new histamine H2 receptor antagonist (H2RA) users over the course of five years. Those who used PPIs demonstrated a significant risk for decreased renal function, lower estimated glomerular filtration rate (eGFR), doubled serum creatinine levels, and progression to end-stage renal disease (ESRD).⁸

Another study of 10,482 patients (322 PPI; 956 H2RA; 9,204 nonusers) and a replicate study of 248,751 patients (16,900 PPI; 6,640 H2RA; 225,211 nonusers) with an initial eGFR ≥ 60 mL/min/1.73m² also found an association between PPI use and incident CKD, which persisted when compared to the other groups. Additionally, twice-daily PPI use was associated with a higher CKD risk than once-daily use.⁹

The pathophysiology of PPI use and kidney deterioration is poorly understood at this point. It is known that AKI can increase the risk for CKD, and AKI has been an assumed precursor to PPI-associated CKD. However, a study by Xie and colleagues reported an association between PPI use and increased risk for CKD, progression of CKD, and ESRD in the absence of preceding AKI. Using the VA databases, the researchers identified 144,032 new users of acid-suppressing medications (125,596 PPI; 18,436 H2RA) who had no history of kidney disease and followed them for five years. PPI users were found to be at increased risk for CKD, and a graded association was discovered between length of PPI use and risk for CKD.¹⁰

While these studies are observational and therefore do not prove causation, they do suggest a need for attentive monitoring of kidney function in patients using PPIs. Evaluating the need for PPIs and inquiring about OTC use of these medications is highly recommended, as research has found 25% to 70% of PPI prescriptions are not prescribed for an appropriate indication.¹¹ Considerations regarding PPI use should include dosage, length of use, and whether alternate use of an H2RA is appropriate. —CAS

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

Q) Is it true that PPI use can cause kidney disease?

Proton pump inhibitors (PPIs) have been available in the United States since 1990, with OTC options available since 2009. While these medications play a vital role in the treatment of gastrointestinal (GI) con­ditions, observational studies have linked PPI use to serious adverse events, including dementia, community-acquired pneumonia, hip fracture, and Clostridium difficile infection.^1-4

Studies have also found an association between PPI use and kidney problems such as acute kidney injury (AKI), acute interstitial nephritis, and incident chronic kidney disease (CKD).^5-7 One observational study used the Department of Veterans Affairs (VA) national databases to track the renal outcomes of 173,321 new PPI users and 20,270 new histamine H2 receptor antagonist (H2RA) users over the course of five years. Those who used PPIs demonstrated a significant risk for decreased renal function, lower estimated glomerular filtration rate (eGFR), doubled serum creatinine levels, and progression to end-stage renal disease (ESRD).⁸

Another study of 10,482 patients (322 PPI; 956 H2RA; 9,204 nonusers) and a replicate study of 248,751 patients (16,900 PPI; 6,640 H2RA; 225,211 nonusers) with an initial eGFR ≥ 60 mL/min/1.73m² also found an association between PPI use and incident CKD, which persisted when compared to the other groups. Additionally, twice-daily PPI use was associated with a higher CKD risk than once-daily use.⁹

The pathophysiology of PPI use and kidney deterioration is poorly understood at this point. It is known that AKI can increase the risk for CKD, and AKI has been an assumed precursor to PPI-associated CKD. However, a study by Xie and colleagues reported an association between PPI use and increased risk for CKD, progression of CKD, and ESRD in the absence of preceding AKI. Using the VA databases, the researchers identified 144,032 new users of acid-suppressing medications (125,596 PPI; 18,436 H2RA) who had no history of kidney disease and followed them for five years. PPI users were found to be at increased risk for CKD, and a graded association was discovered between length of PPI use and risk for CKD.¹⁰

While these studies are observational and therefore do not prove causation, they do suggest a need for attentive monitoring of kidney function in patients using PPIs. Evaluating the need for PPIs and inquiring about OTC use of these medications is highly recommended, as research has found 25% to 70% of PPI prescriptions are not prescribed for an appropriate indication.¹¹ Considerations regarding PPI use should include dosage, length of use, and whether alternate use of an H2RA is appropriate. —CAS

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

Q) Is it true that PPI use can cause kidney disease?

Proton pump inhibitors (PPIs) have been available in the United States since 1990, with OTC options available since 2009. While these medications play a vital role in the treatment of gastrointestinal (GI) con­ditions, observational studies have linked PPI use to serious adverse events, including dementia, community-acquired pneumonia, hip fracture, and Clostridium difficile infection.^1-4

Studies have also found an association between PPI use and kidney problems such as acute kidney injury (AKI), acute interstitial nephritis, and incident chronic kidney disease (CKD).^5-7 One observational study used the Department of Veterans Affairs (VA) national databases to track the renal outcomes of 173,321 new PPI users and 20,270 new histamine H2 receptor antagonist (H2RA) users over the course of five years. Those who used PPIs demonstrated a significant risk for decreased renal function, lower estimated glomerular filtration rate (eGFR), doubled serum creatinine levels, and progression to end-stage renal disease (ESRD).⁸

Another study of 10,482 patients (322 PPI; 956 H2RA; 9,204 nonusers) and a replicate study of 248,751 patients (16,900 PPI; 6,640 H2RA; 225,211 nonusers) with an initial eGFR ≥ 60 mL/min/1.73m² also found an association between PPI use and incident CKD, which persisted when compared to the other groups. Additionally, twice-daily PPI use was associated with a higher CKD risk than once-daily use.⁹

The pathophysiology of PPI use and kidney deterioration is poorly understood at this point. It is known that AKI can increase the risk for CKD, and AKI has been an assumed precursor to PPI-associated CKD. However, a study by Xie and colleagues reported an association between PPI use and increased risk for CKD, progression of CKD, and ESRD in the absence of preceding AKI. Using the VA databases, the researchers identified 144,032 new users of acid-suppressing medications (125,596 PPI; 18,436 H2RA) who had no history of kidney disease and followed them for five years. PPI users were found to be at increased risk for CKD, and a graded association was discovered between length of PPI use and risk for CKD.¹⁰

While these studies are observational and therefore do not prove causation, they do suggest a need for attentive monitoring of kidney function in patients using PPIs. Evaluating the need for PPIs and inquiring about OTC use of these medications is highly recommended, as research has found 25% to 70% of PPI prescriptions are not prescribed for an appropriate indication.¹¹ Considerations regarding PPI use should include dosage, length of use, and whether alternate use of an H2RA is appropriate. —CAS

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

Since the first successful pregnancy in a kidney transplant recipient in 1958,¹ hundreds of kidney recipients have had successful pregnancies. Chronic kidney disease disrupts the hypothalamic-pituitary-gonadal axis, lead­ing to anovulation and infertility. However, within 6 months of kidney transplant, the hypothalamic-pituitary-gonadal axis and sex hormone levels return to normal,² and the renal allograft is able to adapt to the various physiologic changes of pregnancy.³

Successful pregnancy after kidney transplant requires a team approach to care that includes the primary care physician, a transplant nephrologist, and an obstetrician with expertise in high-risk pregnancies. But equally important is educating and counseling the patient about the risks and challenges. This should begin at the first pretransplant visit.⁴

Below are answers to questions often asked by renal transplant recipients who wish to become pregnant.

WHAT IS THE IDEAL TIME TO BECOME PREGNANT AFTER KIDNEY TRANSPLANT?

Mycophenolate mofetil and sirolimus are contraindicated in pregnancy and should be stopped at least 6 weeks before conception. Mycophenolate mofetil increases the risk of congenital malformations and spontaneous abortion. Data on sirolimus from clinical studies are limited, but in animal studies it is associated with delay in ossification of skeletal structure and with an increase in fetal mortality.⁷

WHAT INCREASES THE RISK OF A POOR PREGNANCY OUTCOME AFTER RENAL TRANSPLANT?

Risk factors for poor maternal and fetal outcomes include an elevated prepregnancy serum creatinine level (≥ 1.4 mg/dL), hypertension, and proteinuria (≥ 500 mg/24 hours). Younger age at transplant and at conception is associated with better pregnancy outcome.^5,8

WHAT ARE THE POSSIBLE MATERNAL COMPLICATIONS?

Kidney transplant recipients who become pregnant have a risk of developing preeclampsia 6 times higher than normal, and the incidence rate ranges between 24% and 38%.^9,10 The risk of cesarean delivery is 5 times higher  than in the general population, and the incidence rate is 43% to 64%.^10,11

Low-dose aspirin reduces the risk of preeclampsia and should be prescribed to all pregnant women who are kidney transplant recipients. Angiotensin-converting enzyme inhibitors are contraindicated due to the risk of teratogenic effects, ie, pulmonary hypoplasia and oligohydramnios.⁴

Women who become pregnant after kidney transplant are at greater risk of preterm delivery (40% to 60% higher risk), having a baby with low birth weight (42% to 46% higher risk), and intrauterine growth restriction (30% to 50% higher risk). But the risk of perinatal mortality is not increased in the absence of the above-mentioned risk factors.^10,11

DOES PREGNANCY INCREASE THE RISK OF GRAFT FAILURE?

Pregnancy does not increase the risk of allograft loss as long as the patient has a prepregnancy serum creatinine below 1.4 mg/dL, no hypertension, and urine protein excretion less than 500 mg/24 hours.¹²

WHAT CHANGES TO IMMUNE SUPPRESSION ARE REQUIRED BEFORE AND DURING PREGNANCY?

Careful management of immunosuppression is critical in renal transplant recipients before and during pregnancy because of the risks of teratogenicity and other adverse effects.

As stated above, mycophenolate mofetil and sirolimus are teratogenic and should be stopped 6 weeks before conception. The recommended maintenance immunosuppression during pregnancy includes calcineurin inhibitors (tacrolimus and cyclosporine), azathioprine, and low-dose prednisone.

A 20% to 25% increase in the dose of calcineurin inhibitor is required during pregnancy due to an increase in metabolic activity of cytochrome P450 and an increase in the volume of distribution.^5,6,13 However, this dosing increase requires more frequent monitoring throughout the pregnancy to ensure the safest possible therapeutic levels.

DOES PREGNANCY INCREASE THE RISK OF INFECTION?

Because of their immunosuppressed state, renal transplant recipients are prone to infection; the incidence rate of urinary tract infection is as high as 40% due to mild reflux and pregnancy-related dilation of ureters and collecting ducts.⁶ Women should be screened for urinary tract infection at every visit with urine dipstick testing and with urine culture every 4 weeks. Antibiotics such as nitrofurantoin, amoxicillin, and cephalexin are safe to treat urinary tract infection during pregnancy.⁶

IS BREAST-FEEDING SAFE IN RENAL TRANSPLANT RECIPIENTS?

Breast-feeding is considered safe for women with renal transplant who are on prednisone, azathioprine, cyclosporine, and tacrolimus. Women should avoid breast-feeding if they are taking mycophenolate mofetil, sirolimus, everolimus, or belatacept, as clinical data on safety are not adequate.¹⁴

Since the first successful pregnancy in a kidney transplant recipient in 1958,¹ hundreds of kidney recipients have had successful pregnancies. Chronic kidney disease disrupts the hypothalamic-pituitary-gonadal axis, lead­ing to anovulation and infertility. However, within 6 months of kidney transplant, the hypothalamic-pituitary-gonadal axis and sex hormone levels return to normal,² and the renal allograft is able to adapt to the various physiologic changes of pregnancy.³

Successful pregnancy after kidney transplant requires a team approach to care that includes the primary care physician, a transplant nephrologist, and an obstetrician with expertise in high-risk pregnancies. But equally important is educating and counseling the patient about the risks and challenges. This should begin at the first pretransplant visit.⁴

Below are answers to questions often asked by renal transplant recipients who wish to become pregnant.

WHAT IS THE IDEAL TIME TO BECOME PREGNANT AFTER KIDNEY TRANSPLANT?

Mycophenolate mofetil and sirolimus are contraindicated in pregnancy and should be stopped at least 6 weeks before conception. Mycophenolate mofetil increases the risk of congenital malformations and spontaneous abortion. Data on sirolimus from clinical studies are limited, but in animal studies it is associated with delay in ossification of skeletal structure and with an increase in fetal mortality.⁷

WHAT INCREASES THE RISK OF A POOR PREGNANCY OUTCOME AFTER RENAL TRANSPLANT?

Risk factors for poor maternal and fetal outcomes include an elevated prepregnancy serum creatinine level (≥ 1.4 mg/dL), hypertension, and proteinuria (≥ 500 mg/24 hours). Younger age at transplant and at conception is associated with better pregnancy outcome.^5,8

WHAT ARE THE POSSIBLE MATERNAL COMPLICATIONS?

Kidney transplant recipients who become pregnant have a risk of developing preeclampsia 6 times higher than normal, and the incidence rate ranges between 24% and 38%.^9,10 The risk of cesarean delivery is 5 times higher  than in the general population, and the incidence rate is 43% to 64%.^10,11

Low-dose aspirin reduces the risk of preeclampsia and should be prescribed to all pregnant women who are kidney transplant recipients. Angiotensin-converting enzyme inhibitors are contraindicated due to the risk of teratogenic effects, ie, pulmonary hypoplasia and oligohydramnios.⁴

Women who become pregnant after kidney transplant are at greater risk of preterm delivery (40% to 60% higher risk), having a baby with low birth weight (42% to 46% higher risk), and intrauterine growth restriction (30% to 50% higher risk). But the risk of perinatal mortality is not increased in the absence of the above-mentioned risk factors.^10,11

DOES PREGNANCY INCREASE THE RISK OF GRAFT FAILURE?

Pregnancy does not increase the risk of allograft loss as long as the patient has a prepregnancy serum creatinine below 1.4 mg/dL, no hypertension, and urine protein excretion less than 500 mg/24 hours.¹²

WHAT CHANGES TO IMMUNE SUPPRESSION ARE REQUIRED BEFORE AND DURING PREGNANCY?

Careful management of immunosuppression is critical in renal transplant recipients before and during pregnancy because of the risks of teratogenicity and other adverse effects.

As stated above, mycophenolate mofetil and sirolimus are teratogenic and should be stopped 6 weeks before conception. The recommended maintenance immunosuppression during pregnancy includes calcineurin inhibitors (tacrolimus and cyclosporine), azathioprine, and low-dose prednisone.

A 20% to 25% increase in the dose of calcineurin inhibitor is required during pregnancy due to an increase in metabolic activity of cytochrome P450 and an increase in the volume of distribution.^5,6,13 However, this dosing increase requires more frequent monitoring throughout the pregnancy to ensure the safest possible therapeutic levels.

DOES PREGNANCY INCREASE THE RISK OF INFECTION?

Because of their immunosuppressed state, renal transplant recipients are prone to infection; the incidence rate of urinary tract infection is as high as 40% due to mild reflux and pregnancy-related dilation of ureters and collecting ducts.⁶ Women should be screened for urinary tract infection at every visit with urine dipstick testing and with urine culture every 4 weeks. Antibiotics such as nitrofurantoin, amoxicillin, and cephalexin are safe to treat urinary tract infection during pregnancy.⁶

IS BREAST-FEEDING SAFE IN RENAL TRANSPLANT RECIPIENTS?

Breast-feeding is considered safe for women with renal transplant who are on prednisone, azathioprine, cyclosporine, and tacrolimus. Women should avoid breast-feeding if they are taking mycophenolate mofetil, sirolimus, everolimus, or belatacept, as clinical data on safety are not adequate.¹⁴

Since the first successful pregnancy in a kidney transplant recipient in 1958,¹ hundreds of kidney recipients have had successful pregnancies. Chronic kidney disease disrupts the hypothalamic-pituitary-gonadal axis, lead­ing to anovulation and infertility. However, within 6 months of kidney transplant, the hypothalamic-pituitary-gonadal axis and sex hormone levels return to normal,² and the renal allograft is able to adapt to the various physiologic changes of pregnancy.³

Successful pregnancy after kidney transplant requires a team approach to care that includes the primary care physician, a transplant nephrologist, and an obstetrician with expertise in high-risk pregnancies. But equally important is educating and counseling the patient about the risks and challenges. This should begin at the first pretransplant visit.⁴

Below are answers to questions often asked by renal transplant recipients who wish to become pregnant.

WHAT IS THE IDEAL TIME TO BECOME PREGNANT AFTER KIDNEY TRANSPLANT?

Mycophenolate mofetil and sirolimus are contraindicated in pregnancy and should be stopped at least 6 weeks before conception. Mycophenolate mofetil increases the risk of congenital malformations and spontaneous abortion. Data on sirolimus from clinical studies are limited, but in animal studies it is associated with delay in ossification of skeletal structure and with an increase in fetal mortality.⁷

WHAT INCREASES THE RISK OF A POOR PREGNANCY OUTCOME AFTER RENAL TRANSPLANT?

Risk factors for poor maternal and fetal outcomes include an elevated prepregnancy serum creatinine level (≥ 1.4 mg/dL), hypertension, and proteinuria (≥ 500 mg/24 hours). Younger age at transplant and at conception is associated with better pregnancy outcome.^5,8

WHAT ARE THE POSSIBLE MATERNAL COMPLICATIONS?

Kidney transplant recipients who become pregnant have a risk of developing preeclampsia 6 times higher than normal, and the incidence rate ranges between 24% and 38%.^9,10 The risk of cesarean delivery is 5 times higher  than in the general population, and the incidence rate is 43% to 64%.^10,11

Low-dose aspirin reduces the risk of preeclampsia and should be prescribed to all pregnant women who are kidney transplant recipients. Angiotensin-converting enzyme inhibitors are contraindicated due to the risk of teratogenic effects, ie, pulmonary hypoplasia and oligohydramnios.⁴

Women who become pregnant after kidney transplant are at greater risk of preterm delivery (40% to 60% higher risk), having a baby with low birth weight (42% to 46% higher risk), and intrauterine growth restriction (30% to 50% higher risk). But the risk of perinatal mortality is not increased in the absence of the above-mentioned risk factors.^10,11

DOES PREGNANCY INCREASE THE RISK OF GRAFT FAILURE?

Pregnancy does not increase the risk of allograft loss as long as the patient has a prepregnancy serum creatinine below 1.4 mg/dL, no hypertension, and urine protein excretion less than 500 mg/24 hours.¹²

WHAT CHANGES TO IMMUNE SUPPRESSION ARE REQUIRED BEFORE AND DURING PREGNANCY?

Careful management of immunosuppression is critical in renal transplant recipients before and during pregnancy because of the risks of teratogenicity and other adverse effects.

As stated above, mycophenolate mofetil and sirolimus are teratogenic and should be stopped 6 weeks before conception. The recommended maintenance immunosuppression during pregnancy includes calcineurin inhibitors (tacrolimus and cyclosporine), azathioprine, and low-dose prednisone.

A 20% to 25% increase in the dose of calcineurin inhibitor is required during pregnancy due to an increase in metabolic activity of cytochrome P450 and an increase in the volume of distribution.^5,6,13 However, this dosing increase requires more frequent monitoring throughout the pregnancy to ensure the safest possible therapeutic levels.

DOES PREGNANCY INCREASE THE RISK OF INFECTION?

Because of their immunosuppressed state, renal transplant recipients are prone to infection; the incidence rate of urinary tract infection is as high as 40% due to mild reflux and pregnancy-related dilation of ureters and collecting ducts.⁶ Women should be screened for urinary tract infection at every visit with urine dipstick testing and with urine culture every 4 weeks. Antibiotics such as nitrofurantoin, amoxicillin, and cephalexin are safe to treat urinary tract infection during pregnancy.⁶

IS BREAST-FEEDING SAFE IN RENAL TRANSPLANT RECIPIENTS?

Breast-feeding is considered safe for women with renal transplant who are on prednisone, azathioprine, cyclosporine, and tacrolimus. Women should avoid breast-feeding if they are taking mycophenolate mofetil, sirolimus, everolimus, or belatacept, as clinical data on safety are not adequate.¹⁴

The Food and Drug Administration has approved a biosimilar to bevacizumab (Avastin) for the treatment of certain colorectal, lung, brain, kidney, and cervical cancers.

Bevacizumab-awwb is the first biosimilar approved in the United States for the treatment of cancer, the FDA said in a press release.

Approval is based on structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrate bevacizumab-awwb is biosimilar to bevacizumab, the FDA said.

lnikolaides@frontlinemedcom.com

The Food and Drug Administration has approved a biosimilar to bevacizumab (Avastin) for the treatment of certain colorectal, lung, brain, kidney, and cervical cancers.

Bevacizumab-awwb is the first biosimilar approved in the United States for the treatment of cancer, the FDA said in a press release.

Approval is based on structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrate bevacizumab-awwb is biosimilar to bevacizumab, the FDA said.

lnikolaides@frontlinemedcom.com

The Food and Drug Administration has approved a biosimilar to bevacizumab (Avastin) for the treatment of certain colorectal, lung, brain, kidney, and cervical cancers.

Bevacizumab-awwb is the first biosimilar approved in the United States for the treatment of cancer, the FDA said in a press release.

Approval is based on structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrate bevacizumab-awwb is biosimilar to bevacizumab, the FDA said.

lnikolaides@frontlinemedcom.com

SAN FRANCISCO – Routine lab tests for estimating the average glomerular filtration rate (GFR) are too imprecise, according to Michael G. Shlipak, MD.

“If you study 100 patients, the average GFR based on creatinine is going to be pretty close to estimated GFR,” Dr. Shlipak said at the UCSF Annual Advances in Internal Medicine meeting. “But with individual patients, the average GFR is going to be plus or minus 30%, which is a lot. If the estimated GFR is 70 mL/min per 1.73 m², the real GFR could be between 50 and 90 mL/min per 1.73 m²; so that’s a wide range.”

dbrunk@frontlinemedcom.com

SAN FRANCISCO – Routine lab tests for estimating the average glomerular filtration rate (GFR) are too imprecise, according to Michael G. Shlipak, MD.

“If you study 100 patients, the average GFR based on creatinine is going to be pretty close to estimated GFR,” Dr. Shlipak said at the UCSF Annual Advances in Internal Medicine meeting. “But with individual patients, the average GFR is going to be plus or minus 30%, which is a lot. If the estimated GFR is 70 mL/min per 1.73 m², the real GFR could be between 50 and 90 mL/min per 1.73 m²; so that’s a wide range.”

dbrunk@frontlinemedcom.com

SAN FRANCISCO – Routine lab tests for estimating the average glomerular filtration rate (GFR) are too imprecise, according to Michael G. Shlipak, MD.

“If you study 100 patients, the average GFR based on creatinine is going to be pretty close to estimated GFR,” Dr. Shlipak said at the UCSF Annual Advances in Internal Medicine meeting. “But with individual patients, the average GFR is going to be plus or minus 30%, which is a lot. If the estimated GFR is 70 mL/min per 1.73 m², the real GFR could be between 50 and 90 mL/min per 1.73 m²; so that’s a wide range.”

dbrunk@frontlinemedcom.com

LISBON – Patients with type 2 diabetes mellitus who also have moderate-to-severe chronic kidney disease (CKD) may be as effectively treated with the glucagonlike peptide–1 receptor agonist dulaglutide (Trulicity) as insulin glargine, the results of an international study showed.

Although comparable effects on glycemic control were seen, patients who received dulaglutide rather than insulin glargine in conjunction with prandial insulin lispro (Humalog) exhibited greater weight loss, had fewer episodes of hypoglycemia, and experienced beneficial effects on two important renal parameters.

Sara Freeman/Frontline Medical News

This article was updated September 28, 2017.

LISBON – Patients with type 2 diabetes mellitus who also have moderate-to-severe chronic kidney disease (CKD) may be as effectively treated with the glucagonlike peptide–1 receptor agonist dulaglutide (Trulicity) as insulin glargine, the results of an international study showed.

Although comparable effects on glycemic control were seen, patients who received dulaglutide rather than insulin glargine in conjunction with prandial insulin lispro (Humalog) exhibited greater weight loss, had fewer episodes of hypoglycemia, and experienced beneficial effects on two important renal parameters.

Sara Freeman/Frontline Medical News

This article was updated September 28, 2017.

LISBON – Patients with type 2 diabetes mellitus who also have moderate-to-severe chronic kidney disease (CKD) may be as effectively treated with the glucagonlike peptide–1 receptor agonist dulaglutide (Trulicity) as insulin glargine, the results of an international study showed.

Although comparable effects on glycemic control were seen, patients who received dulaglutide rather than insulin glargine in conjunction with prandial insulin lispro (Humalog) exhibited greater weight loss, had fewer episodes of hypoglycemia, and experienced beneficial effects on two important renal parameters.

Sara Freeman/Frontline Medical News

This article was updated September 28, 2017.