Renal & Genitourinary

The Food and Drug Administration has approved difelikefalin for treatment of moderate to severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis, the first agent approved from a novel class of kappa opioid receptor agonists.

Olivier Le Moal/Getty Images

Some nephrologists welcomed the Aug. 23 approval of this new option for treating pruritus, a relatively common and often hard-to-resolve complication of dialysis in patients with chronic kidney disease (CKD) that can substantially impinge on quality of life for some patients, but also voiced uncertainty about the role of a new agent with a modest trial track record that may be expensive and face insurance-coverage hurdles.

“Uptake of difelikefalin will depend on awareness of itch among patients dependent on hemodialysis, and on payment policies,” predicted Daniel E. Weiner, MD, a nephrologist at Tufts Medical Center in Boston. “Pruritus is underdiagnosed among people with kidney failure, and in some patients ongoing pruritus can be highly impactful on sleep and quality of life. The clinical trial results were very encouraging that difelikefalin is effective and safe,” which makes recognition of pruritus as a significant issue for patients a key factor in uptake of the new drug, Dr. Weiner, an investigator in a difelikefalin clinical study, said in an interview.

Other nephrologists acknowledged the substantial problem that itch can pose for many patients with CKD on dialysis but questioned the weight of evidence behind difelikefalin’s approval.
 

Two pivotal trials with fewer than 900 total randomized patients

The data considered by the FDA primarily featured results from two pivotal trials, KALM-1 and KALM-2. KALM-1 randomized 378 patients with CKD and on hemodialysis and with moderate to severe pruritus to intravenous treatment with difelikefalin or placebo three times a week for 12 weeks with a primary endpoint of an improvement (decrease) of at least 3 points from baseline in their Worst Itching Intensity Numerical Rating Scale (WI-NRS) score, which averaged just over 7 points at baseline. After 12 weeks on treatment, 52% of patients who received difelikefalin had at least a 3-point drop, compared with 31% of patients who received placebo, a significant difference. The results appeared in a 2020 report in the New England Journal of Medicine.

Confirmatory results came in the second pivotal trial, KALM-2, a similarly designed, 12-week study that randomized 473 patients, with 54% of those in the active arm achieving at least a 3-point cut in their baseline WI-NRS score, compared with 42% of patients who received placebo, a significant difference. A report at the Kidney Week meeting sponsored by the National Kidney Foundation in October 2020 presented the KALM-2 results, but the findings have not yet appeared in a published article.

In sum, the data suggest that treatment with difelikefalin will, on average, produce a clinically meaningful effect on itch compared with placebo in about 20% of patients, with nearly half the patients who receive the active drug having a less robust response and many patients who receive no active treatment also show a meaningful cut in their pruritus severity in a trial setting, noted Paul Palevsky, MD, professor of medicine at the University of Pittsburgh and chief of the renal section at the Veterans Affairs Pittsburgh Healthcare System.

The upshot is that questions linger over which patients are the best candidates for this drug and how it might perform in real-world practice given difelikefalin’s limited track record, Dr. Palevsky said in an interview.

In addition, the labeling specifies the indication is for patients with moderate to severe pruritus, but itching severity is not routinely quantified in these patients in current practice, added Dr. Palevsky, who is also president of the National Kidney Foundation.

Dr. Weiner noted that another unknown is the appropriate duration of treatment in real-world use.
 

What will it cost, and will it be covered?

The drug’s price and insurance coverage will likely be a major factor in uptake of the new drug, agreed both Dr. Weiner and Dr. Palevsky, especially the coverage decision for Medicare patients by the Centers for Medicare & Medicaid Services. A corollary is whether or not coverage for difelikefalin, which patients receive as an intravenous infusion during each of their usual three-times-a-week dialysis sessions, will lie outside of the bundled dialysis reimbursement payment. If is no mechanism exists to pay for difelikefalin separately beyond the current bundled dialysis rate, “I suspect it will not get used very much unless it is very inexpensive,” predicted Dr. Weiner.

Another issue is where difelikefalin fits within the lineup of standard treatment options. “A lot of people receiving hemodialysis suffer from pruritus and have not been successfully treated. For these individuals difelikefalin could be a game changer,” Dr. Weiner said.

Other nephrologists have a more positive take on the existing treatment options.

“Start systemic therapy for patients with itch that is significantly affecting quality of life; stepping up from topical therapy just delays effective treatment,” advised Hugh C. Rayner, MD, a nephrologist affiliated with Birmingham (England) Heartland’s Hospital who was lead author on a review of pruritus treatments for patients with CKD on hemodialysis.

“Standard systemic therapy is gabapentin or pregabalin,” an approach “supported by robust evidence confirmed in a Cochrane review,” he said in an interview. The impact of difelikefalin “will be limited as its effectiveness in reducing itch is modest at best and far inferior to gabapentin and pregabalin,” Dr. Rayner added. Difelikefalin’s “main downsides will be its cost, compared with gabapentin, and its gastrointestinal side effects.”
 

Adverse-event profiles

In KALM-1, the most frequent adverse effects from difelikefalin treatment was diarrhea, in 10% of patients, compared with a 4% rate among patients who received placebo. Vomiting occurred at a 5% incidence on difelikefalin and in 3% of patients on placebo. All serious adverse events occurred in 26% of patients on difelikefalin and in 22% of those who received placebo. Discontinuations because of an adverse event occurred in 8% of patients on difelikefalin and in 5% of the placebo patients.

An editorial that accompanied the published KALM-1 report in 2020 said “the findings are compelling, although diarrhea, dizziness, and vomiting were frequent side effects.”

Both Dr. Weiner and Dr. Palevsky were more reserved than Dr. Rayner in their appraisal of gabapentin and pregabalin, although Dr. Palevsky admitted that he has prescribed one or the other of these two drugs to “lots of patients,” especially gabapentin. “But they are not completely benign drugs,” he cautioned, a concern echoed by Dr. Weiner.

“Antihistamines, gabapentin, and pregabalin have a high side-effect burden in patients on hemodialysis and limited efficacy, and are poor options for chronic pruritus management,” explained Dr. Weiner. “I would favor difelikefalin to chronic prescription of these other agents” because difelikefalin “appears effective and has a very low side effect burden. Very few effective treatments for pruritus do not have side effects.”

Difelikefalin is a peripherally restricted, selective kappa opioid receptor agonist that exerts antipruritic effects by activating kappa opioid receptors on peripheral neurons and immune cells. The drug’s hydrophilic, small-peptide structure restricts passive diffusion across membranes, which limits the drug’s access to kappa opioid receptors in the central nervous system and hence reduces potential adverse effects.

The FDA made this approval decision without consulting an advisory committee. The companies that will market difelikefalin (Korsuva), Cara Therapeutics and Vifor Pharma, announced that their U.S. promotional launch of the drug starts early in 2022.

The KALM-1 and KALM-2 studies were sponsored by Cara Therapeutics and Vifor Pharma, the two companies that have been jointly developing difelikefalin. Dr. Pavelsky and Dr. Rayner had no relevant disclosures. Dr. Weiner was previously an adviser to Cara and Vifor and participated as an investigator in a difelikefalin clinical study, but more recently has had no relationships with the companies.

[email protected]

The Food and Drug Administration has approved difelikefalin for treatment of moderate to severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis, the first agent approved from a novel class of kappa opioid receptor agonists.

Olivier Le Moal/Getty Images

Some nephrologists welcomed the Aug. 23 approval of this new option for treating pruritus, a relatively common and often hard-to-resolve complication of dialysis in patients with chronic kidney disease (CKD) that can substantially impinge on quality of life for some patients, but also voiced uncertainty about the role of a new agent with a modest trial track record that may be expensive and face insurance-coverage hurdles.

“Uptake of difelikefalin will depend on awareness of itch among patients dependent on hemodialysis, and on payment policies,” predicted Daniel E. Weiner, MD, a nephrologist at Tufts Medical Center in Boston. “Pruritus is underdiagnosed among people with kidney failure, and in some patients ongoing pruritus can be highly impactful on sleep and quality of life. The clinical trial results were very encouraging that difelikefalin is effective and safe,” which makes recognition of pruritus as a significant issue for patients a key factor in uptake of the new drug, Dr. Weiner, an investigator in a difelikefalin clinical study, said in an interview.

Other nephrologists acknowledged the substantial problem that itch can pose for many patients with CKD on dialysis but questioned the weight of evidence behind difelikefalin’s approval.
 

Two pivotal trials with fewer than 900 total randomized patients

The data considered by the FDA primarily featured results from two pivotal trials, KALM-1 and KALM-2. KALM-1 randomized 378 patients with CKD and on hemodialysis and with moderate to severe pruritus to intravenous treatment with difelikefalin or placebo three times a week for 12 weeks with a primary endpoint of an improvement (decrease) of at least 3 points from baseline in their Worst Itching Intensity Numerical Rating Scale (WI-NRS) score, which averaged just over 7 points at baseline. After 12 weeks on treatment, 52% of patients who received difelikefalin had at least a 3-point drop, compared with 31% of patients who received placebo, a significant difference. The results appeared in a 2020 report in the New England Journal of Medicine.

Confirmatory results came in the second pivotal trial, KALM-2, a similarly designed, 12-week study that randomized 473 patients, with 54% of those in the active arm achieving at least a 3-point cut in their baseline WI-NRS score, compared with 42% of patients who received placebo, a significant difference. A report at the Kidney Week meeting sponsored by the National Kidney Foundation in October 2020 presented the KALM-2 results, but the findings have not yet appeared in a published article.

In sum, the data suggest that treatment with difelikefalin will, on average, produce a clinically meaningful effect on itch compared with placebo in about 20% of patients, with nearly half the patients who receive the active drug having a less robust response and many patients who receive no active treatment also show a meaningful cut in their pruritus severity in a trial setting, noted Paul Palevsky, MD, professor of medicine at the University of Pittsburgh and chief of the renal section at the Veterans Affairs Pittsburgh Healthcare System.

The upshot is that questions linger over which patients are the best candidates for this drug and how it might perform in real-world practice given difelikefalin’s limited track record, Dr. Palevsky said in an interview.

In addition, the labeling specifies the indication is for patients with moderate to severe pruritus, but itching severity is not routinely quantified in these patients in current practice, added Dr. Palevsky, who is also president of the National Kidney Foundation.

Dr. Weiner noted that another unknown is the appropriate duration of treatment in real-world use.
 

What will it cost, and will it be covered?

The drug’s price and insurance coverage will likely be a major factor in uptake of the new drug, agreed both Dr. Weiner and Dr. Palevsky, especially the coverage decision for Medicare patients by the Centers for Medicare & Medicaid Services. A corollary is whether or not coverage for difelikefalin, which patients receive as an intravenous infusion during each of their usual three-times-a-week dialysis sessions, will lie outside of the bundled dialysis reimbursement payment. If is no mechanism exists to pay for difelikefalin separately beyond the current bundled dialysis rate, “I suspect it will not get used very much unless it is very inexpensive,” predicted Dr. Weiner.

Another issue is where difelikefalin fits within the lineup of standard treatment options. “A lot of people receiving hemodialysis suffer from pruritus and have not been successfully treated. For these individuals difelikefalin could be a game changer,” Dr. Weiner said.

Other nephrologists have a more positive take on the existing treatment options.

“Start systemic therapy for patients with itch that is significantly affecting quality of life; stepping up from topical therapy just delays effective treatment,” advised Hugh C. Rayner, MD, a nephrologist affiliated with Birmingham (England) Heartland’s Hospital who was lead author on a review of pruritus treatments for patients with CKD on hemodialysis.

“Standard systemic therapy is gabapentin or pregabalin,” an approach “supported by robust evidence confirmed in a Cochrane review,” he said in an interview. The impact of difelikefalin “will be limited as its effectiveness in reducing itch is modest at best and far inferior to gabapentin and pregabalin,” Dr. Rayner added. Difelikefalin’s “main downsides will be its cost, compared with gabapentin, and its gastrointestinal side effects.”
 

Adverse-event profiles

In KALM-1, the most frequent adverse effects from difelikefalin treatment was diarrhea, in 10% of patients, compared with a 4% rate among patients who received placebo. Vomiting occurred at a 5% incidence on difelikefalin and in 3% of patients on placebo. All serious adverse events occurred in 26% of patients on difelikefalin and in 22% of those who received placebo. Discontinuations because of an adverse event occurred in 8% of patients on difelikefalin and in 5% of the placebo patients.

An editorial that accompanied the published KALM-1 report in 2020 said “the findings are compelling, although diarrhea, dizziness, and vomiting were frequent side effects.”

Both Dr. Weiner and Dr. Palevsky were more reserved than Dr. Rayner in their appraisal of gabapentin and pregabalin, although Dr. Palevsky admitted that he has prescribed one or the other of these two drugs to “lots of patients,” especially gabapentin. “But they are not completely benign drugs,” he cautioned, a concern echoed by Dr. Weiner.

“Antihistamines, gabapentin, and pregabalin have a high side-effect burden in patients on hemodialysis and limited efficacy, and are poor options for chronic pruritus management,” explained Dr. Weiner. “I would favor difelikefalin to chronic prescription of these other agents” because difelikefalin “appears effective and has a very low side effect burden. Very few effective treatments for pruritus do not have side effects.”

Difelikefalin is a peripherally restricted, selective kappa opioid receptor agonist that exerts antipruritic effects by activating kappa opioid receptors on peripheral neurons and immune cells. The drug’s hydrophilic, small-peptide structure restricts passive diffusion across membranes, which limits the drug’s access to kappa opioid receptors in the central nervous system and hence reduces potential adverse effects.

The FDA made this approval decision without consulting an advisory committee. The companies that will market difelikefalin (Korsuva), Cara Therapeutics and Vifor Pharma, announced that their U.S. promotional launch of the drug starts early in 2022.

The KALM-1 and KALM-2 studies were sponsored by Cara Therapeutics and Vifor Pharma, the two companies that have been jointly developing difelikefalin. Dr. Pavelsky and Dr. Rayner had no relevant disclosures. Dr. Weiner was previously an adviser to Cara and Vifor and participated as an investigator in a difelikefalin clinical study, but more recently has had no relationships with the companies.

[email protected]

The Food and Drug Administration has approved difelikefalin for treatment of moderate to severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis, the first agent approved from a novel class of kappa opioid receptor agonists.

Olivier Le Moal/Getty Images

Some nephrologists welcomed the Aug. 23 approval of this new option for treating pruritus, a relatively common and often hard-to-resolve complication of dialysis in patients with chronic kidney disease (CKD) that can substantially impinge on quality of life for some patients, but also voiced uncertainty about the role of a new agent with a modest trial track record that may be expensive and face insurance-coverage hurdles.

“Uptake of difelikefalin will depend on awareness of itch among patients dependent on hemodialysis, and on payment policies,” predicted Daniel E. Weiner, MD, a nephrologist at Tufts Medical Center in Boston. “Pruritus is underdiagnosed among people with kidney failure, and in some patients ongoing pruritus can be highly impactful on sleep and quality of life. The clinical trial results were very encouraging that difelikefalin is effective and safe,” which makes recognition of pruritus as a significant issue for patients a key factor in uptake of the new drug, Dr. Weiner, an investigator in a difelikefalin clinical study, said in an interview.

Other nephrologists acknowledged the substantial problem that itch can pose for many patients with CKD on dialysis but questioned the weight of evidence behind difelikefalin’s approval.
 

Two pivotal trials with fewer than 900 total randomized patients

The data considered by the FDA primarily featured results from two pivotal trials, KALM-1 and KALM-2. KALM-1 randomized 378 patients with CKD and on hemodialysis and with moderate to severe pruritus to intravenous treatment with difelikefalin or placebo three times a week for 12 weeks with a primary endpoint of an improvement (decrease) of at least 3 points from baseline in their Worst Itching Intensity Numerical Rating Scale (WI-NRS) score, which averaged just over 7 points at baseline. After 12 weeks on treatment, 52% of patients who received difelikefalin had at least a 3-point drop, compared with 31% of patients who received placebo, a significant difference. The results appeared in a 2020 report in the New England Journal of Medicine.

Confirmatory results came in the second pivotal trial, KALM-2, a similarly designed, 12-week study that randomized 473 patients, with 54% of those in the active arm achieving at least a 3-point cut in their baseline WI-NRS score, compared with 42% of patients who received placebo, a significant difference. A report at the Kidney Week meeting sponsored by the National Kidney Foundation in October 2020 presented the KALM-2 results, but the findings have not yet appeared in a published article.

In sum, the data suggest that treatment with difelikefalin will, on average, produce a clinically meaningful effect on itch compared with placebo in about 20% of patients, with nearly half the patients who receive the active drug having a less robust response and many patients who receive no active treatment also show a meaningful cut in their pruritus severity in a trial setting, noted Paul Palevsky, MD, professor of medicine at the University of Pittsburgh and chief of the renal section at the Veterans Affairs Pittsburgh Healthcare System.

The upshot is that questions linger over which patients are the best candidates for this drug and how it might perform in real-world practice given difelikefalin’s limited track record, Dr. Palevsky said in an interview.

In addition, the labeling specifies the indication is for patients with moderate to severe pruritus, but itching severity is not routinely quantified in these patients in current practice, added Dr. Palevsky, who is also president of the National Kidney Foundation.

Dr. Weiner noted that another unknown is the appropriate duration of treatment in real-world use.
 

What will it cost, and will it be covered?

The drug’s price and insurance coverage will likely be a major factor in uptake of the new drug, agreed both Dr. Weiner and Dr. Palevsky, especially the coverage decision for Medicare patients by the Centers for Medicare & Medicaid Services. A corollary is whether or not coverage for difelikefalin, which patients receive as an intravenous infusion during each of their usual three-times-a-week dialysis sessions, will lie outside of the bundled dialysis reimbursement payment. If is no mechanism exists to pay for difelikefalin separately beyond the current bundled dialysis rate, “I suspect it will not get used very much unless it is very inexpensive,” predicted Dr. Weiner.

Another issue is where difelikefalin fits within the lineup of standard treatment options. “A lot of people receiving hemodialysis suffer from pruritus and have not been successfully treated. For these individuals difelikefalin could be a game changer,” Dr. Weiner said.

Other nephrologists have a more positive take on the existing treatment options.

“Start systemic therapy for patients with itch that is significantly affecting quality of life; stepping up from topical therapy just delays effective treatment,” advised Hugh C. Rayner, MD, a nephrologist affiliated with Birmingham (England) Heartland’s Hospital who was lead author on a review of pruritus treatments for patients with CKD on hemodialysis.

“Standard systemic therapy is gabapentin or pregabalin,” an approach “supported by robust evidence confirmed in a Cochrane review,” he said in an interview. The impact of difelikefalin “will be limited as its effectiveness in reducing itch is modest at best and far inferior to gabapentin and pregabalin,” Dr. Rayner added. Difelikefalin’s “main downsides will be its cost, compared with gabapentin, and its gastrointestinal side effects.”
 

Adverse-event profiles

In KALM-1, the most frequent adverse effects from difelikefalin treatment was diarrhea, in 10% of patients, compared with a 4% rate among patients who received placebo. Vomiting occurred at a 5% incidence on difelikefalin and in 3% of patients on placebo. All serious adverse events occurred in 26% of patients on difelikefalin and in 22% of those who received placebo. Discontinuations because of an adverse event occurred in 8% of patients on difelikefalin and in 5% of the placebo patients.

An editorial that accompanied the published KALM-1 report in 2020 said “the findings are compelling, although diarrhea, dizziness, and vomiting were frequent side effects.”

Both Dr. Weiner and Dr. Palevsky were more reserved than Dr. Rayner in their appraisal of gabapentin and pregabalin, although Dr. Palevsky admitted that he has prescribed one or the other of these two drugs to “lots of patients,” especially gabapentin. “But they are not completely benign drugs,” he cautioned, a concern echoed by Dr. Weiner.

“Antihistamines, gabapentin, and pregabalin have a high side-effect burden in patients on hemodialysis and limited efficacy, and are poor options for chronic pruritus management,” explained Dr. Weiner. “I would favor difelikefalin to chronic prescription of these other agents” because difelikefalin “appears effective and has a very low side effect burden. Very few effective treatments for pruritus do not have side effects.”

Difelikefalin is a peripherally restricted, selective kappa opioid receptor agonist that exerts antipruritic effects by activating kappa opioid receptors on peripheral neurons and immune cells. The drug’s hydrophilic, small-peptide structure restricts passive diffusion across membranes, which limits the drug’s access to kappa opioid receptors in the central nervous system and hence reduces potential adverse effects.

The FDA made this approval decision without consulting an advisory committee. The companies that will market difelikefalin (Korsuva), Cara Therapeutics and Vifor Pharma, announced that their U.S. promotional launch of the drug starts early in 2022.

The KALM-1 and KALM-2 studies were sponsored by Cara Therapeutics and Vifor Pharma, the two companies that have been jointly developing difelikefalin. Dr. Pavelsky and Dr. Rayner had no relevant disclosures. Dr. Weiner was previously an adviser to Cara and Vifor and participated as an investigator in a difelikefalin clinical study, but more recently has had no relationships with the companies.

[email protected]

Kidney transplantation has recently been happening at a record pace and with unprecedented success despite patients having more risk factors than ever before.

HYWARDS/Thinkstock

During 2016-2019, U.S. centers performed kidney transplants in nearly 77,000 patients, a jump of almost 25% compared with 4-year averages of about 62,000 patients throughout 2004-2015. That works out to about 15,000 more patients receiving donor kidneys, Sundaram Hariharan, MD, and associates reported in the New England Journal of Medicine in a review of all U.S. renal transplantations performed during 1996-2019.

Coupled with the volume uptick during this 24-year period were new lows in graft losses and patient deaths. By 2018, mortality during the first year following transplantation occurred at about a 1% rate among patients who had received a kidney from a living donor, and at about a 3% rate when the organ came from a deceased donor, nearly half the rate of 2 decades earlier, in 1996. Rates of first-year graft loss during 2017 were also about half of what they had been in 1996, occurring in about 2% of patients who received a living donor organ and in about 6% of those who got a kidney from a deceased donor during 2017.

“Twenty years ago, kidney transplantation was the preferred option compared with dialysis, and even more so now,” summed up Dr. Hariharan, a senior transplant nephrologist and professor of medicine and surgery at the University of Pittsburgh Medical Center and first author of the report. Kidney transplantation survival at U.S. centers “improved steadily over the past 24 years, despite patient variables becoming worse,” he said in an interview.
 

Kidney recipients are older, more obese, and have more prevalent diabetes

During the period studied, kidney transplant recipients became on average older and more obese, and had a higher prevalence of diabetes; the age of organ donors grew as well. The prevalence of diabetes among patients who received a kidney from a deceased donor increased from 24% during 1996-1999 to 36% during 2016-2019, while diabetes prevalence among recipients of an organ from a living donor rose from 25% in 1996-1999 to 29% during 2016-2019.

The improved graft and patient survival numbers “are very encouraging trends,” said Michelle A. Josephson, MD, professor and medical director of kidney transplantation at the University of Chicago, who was not involved with the report. “We have been hearing for a number of years that short-term graft survival had improved, but I’m thrilled to learn that long-term survival has also improved.”

The report documented 10-year survival of graft recipients during 2008-2011 of 67%, up from 61% during 1996-1999, and a 10-year overall graft survival rate of 54% in the 2008-2011 cohort, an improvement from the 42% rate in patients who received their organs in 1996-1999, changes Dr. Hariharan characterized as “modest.”

These improvements in long-term graft and patient survival are “meaningful, and particularly notable that outcomes improved despite increased complexity of the transplant population,” said Krista L. Lentine, MD, PhD, professor and medical director of living donation at Saint Louis University. But “despite these improvements, long-term graft survival remains limited,” she cautioned, especially because of risks for substantial complications from chronic immunosuppressive treatment including infection, cancer, glucose intolerance, and dyslipidemia.

The analysis reported by Dr. Hariharan and his associates used data collected by the Scientific Registry of Transplant Patients, run under contract with the U.S. Department of Health and Human Services, which has tracked all patients who have had kidney transplants at U.S. centers since the late 1980s, said Dr. Hariharan. The database included just over 362,000 total transplants during the 24-year period studied, with 36% of all transplants involving organs from living donors with the remaining patients receiving kidneys from deceased donors.

Living donations still stagnant; deceased-donor kidneys rise

The data showed that the rate of transplants from living donors was stagnant for 2 decades, with 22,525 patients transplanted during 2000-2003, and 23,746 transplanted during 2016-2019, with very similar rates during the intervening years. The recent spurt in transplants during 2016-2019 compared with the preceding decade depended almost entirely on kidneys from deceased donors. This rate jumped from the steady, slow rise it showed during 1996-2015, when deceased-donor transplants rose from about 30,000 during 1996-1999 to about 41,000 during 2012-2015, to a more dramatic increase of about 12,000 additional transplants during the most recent period, adding up to a total of more than 53,000 transplants from deceased donors during 2016-2019.

“I strongly recommend organs from living donors” when feasible, said Dr. Hariharan. “At some centers, a high proportion of transplants use living donors, but not at other centers,” he said.

It’s unknown why transplants using organs from deceased donors has shown this growth, but Dr. Hariharan suggested a multifactorial explanation. Those factors include growth in the number of patients with end-stage renal disease who require dialysis, increased numbers of patients listed for kidney transplant, new approaches that allow organs from older donors and those infected with pathogens such as hepatitis C virus or HIV, greater numbers of people and families agreeing to donate organs, and possibly the opioid crisis that may have led to increased organ donation. The number of U.S. centers performing kidney transplants rose from fewer than 200 about a quarter of a century ago to about 250 today, he added.

‘Immuno Bill’ guarantees Medicare coverage for immunosuppression

Dr. Hariharan voiced optimism that graft and patient survival rates will continue to improve going forward. One factor will likely be the passage in late 2020 of the “Immuno Bill” by the U.S. Congress, which among other things mandated ongoing coverage starting in 2023 for immunosuppressive drugs for all Medicare beneficiaries with a kidney transplant. Until then, Medicare provides coverage for only 36 months, a time limit that has resulted in nearly 400 kidney recipients annually losing coverage of their immunosuppression medications.

Dr. Hariharan and coauthors called the existing potential for discontinuation of immunosuppressive drug an “unnecessary impediment to long-term survival for which patients and society paid a heavy price.”

“Kidney transplantation, especially from living donors, offers patients with kidney failure the best chance for long-term survival and improved quality of life, with lower cost to the health care system,” Dr. Lentine said in an interview. Despite the many positive trends detailed in the report from Dr. Hariharan and coauthors, “the vast majority of the more than 700,000 people in the United States with kidney failure will not have an opportunity to receive a transplant due to limitations in organ supply.” And many patients who receive a kidney transplant eventually must resume dialysis because of “limited long-term graft survival resulting from allograft nephropathy, recurrent native disease, medication nonadherence, or other causes.” Plus many potentially transplantable organs go unused.

Dr. Lentine cited a position statement issued in July 2021 by the National Kidney Foundation that made several recommendations on how to improve access to kidney transplants and improve outcomes. “Expanding opportunities for safe living donation, eliminating racial disparities in living-donor access, improving wait-list access and transport readiness, maximizing use of deceased-donor organs, and extending graft longevity are critical priorities,” said Dr. Lentine, lead author on the statement.

“For many or even most patients with kidney failure transplantation is the optimal form of renal replacement. The better recent outcomes and evolving management strategies make transplantation an even more attractive option,” said Dr. Josephson. Improved outcomes among U.S. transplant patients also highlights the “importance of increasing access to kidney transplantation” for all people with kidney failure who could benefit from this treatment, she added.

Dr. Hariharan and Dr. Lentine had no relevant disclosures. Dr. Josephson has been a consultant to UCB and has an ownership interest in Seagen.

[email protected]

Kidney transplantation has recently been happening at a record pace and with unprecedented success despite patients having more risk factors than ever before.

HYWARDS/Thinkstock

During 2016-2019, U.S. centers performed kidney transplants in nearly 77,000 patients, a jump of almost 25% compared with 4-year averages of about 62,000 patients throughout 2004-2015. That works out to about 15,000 more patients receiving donor kidneys, Sundaram Hariharan, MD, and associates reported in the New England Journal of Medicine in a review of all U.S. renal transplantations performed during 1996-2019.

Coupled with the volume uptick during this 24-year period were new lows in graft losses and patient deaths. By 2018, mortality during the first year following transplantation occurred at about a 1% rate among patients who had received a kidney from a living donor, and at about a 3% rate when the organ came from a deceased donor, nearly half the rate of 2 decades earlier, in 1996. Rates of first-year graft loss during 2017 were also about half of what they had been in 1996, occurring in about 2% of patients who received a living donor organ and in about 6% of those who got a kidney from a deceased donor during 2017.

“Twenty years ago, kidney transplantation was the preferred option compared with dialysis, and even more so now,” summed up Dr. Hariharan, a senior transplant nephrologist and professor of medicine and surgery at the University of Pittsburgh Medical Center and first author of the report. Kidney transplantation survival at U.S. centers “improved steadily over the past 24 years, despite patient variables becoming worse,” he said in an interview.
 

Kidney recipients are older, more obese, and have more prevalent diabetes

During the period studied, kidney transplant recipients became on average older and more obese, and had a higher prevalence of diabetes; the age of organ donors grew as well. The prevalence of diabetes among patients who received a kidney from a deceased donor increased from 24% during 1996-1999 to 36% during 2016-2019, while diabetes prevalence among recipients of an organ from a living donor rose from 25% in 1996-1999 to 29% during 2016-2019.

The improved graft and patient survival numbers “are very encouraging trends,” said Michelle A. Josephson, MD, professor and medical director of kidney transplantation at the University of Chicago, who was not involved with the report. “We have been hearing for a number of years that short-term graft survival had improved, but I’m thrilled to learn that long-term survival has also improved.”

The report documented 10-year survival of graft recipients during 2008-2011 of 67%, up from 61% during 1996-1999, and a 10-year overall graft survival rate of 54% in the 2008-2011 cohort, an improvement from the 42% rate in patients who received their organs in 1996-1999, changes Dr. Hariharan characterized as “modest.”

These improvements in long-term graft and patient survival are “meaningful, and particularly notable that outcomes improved despite increased complexity of the transplant population,” said Krista L. Lentine, MD, PhD, professor and medical director of living donation at Saint Louis University. But “despite these improvements, long-term graft survival remains limited,” she cautioned, especially because of risks for substantial complications from chronic immunosuppressive treatment including infection, cancer, glucose intolerance, and dyslipidemia.

The analysis reported by Dr. Hariharan and his associates used data collected by the Scientific Registry of Transplant Patients, run under contract with the U.S. Department of Health and Human Services, which has tracked all patients who have had kidney transplants at U.S. centers since the late 1980s, said Dr. Hariharan. The database included just over 362,000 total transplants during the 24-year period studied, with 36% of all transplants involving organs from living donors with the remaining patients receiving kidneys from deceased donors.

Living donations still stagnant; deceased-donor kidneys rise

The data showed that the rate of transplants from living donors was stagnant for 2 decades, with 22,525 patients transplanted during 2000-2003, and 23,746 transplanted during 2016-2019, with very similar rates during the intervening years. The recent spurt in transplants during 2016-2019 compared with the preceding decade depended almost entirely on kidneys from deceased donors. This rate jumped from the steady, slow rise it showed during 1996-2015, when deceased-donor transplants rose from about 30,000 during 1996-1999 to about 41,000 during 2012-2015, to a more dramatic increase of about 12,000 additional transplants during the most recent period, adding up to a total of more than 53,000 transplants from deceased donors during 2016-2019.

“I strongly recommend organs from living donors” when feasible, said Dr. Hariharan. “At some centers, a high proportion of transplants use living donors, but not at other centers,” he said.

It’s unknown why transplants using organs from deceased donors has shown this growth, but Dr. Hariharan suggested a multifactorial explanation. Those factors include growth in the number of patients with end-stage renal disease who require dialysis, increased numbers of patients listed for kidney transplant, new approaches that allow organs from older donors and those infected with pathogens such as hepatitis C virus or HIV, greater numbers of people and families agreeing to donate organs, and possibly the opioid crisis that may have led to increased organ donation. The number of U.S. centers performing kidney transplants rose from fewer than 200 about a quarter of a century ago to about 250 today, he added.

‘Immuno Bill’ guarantees Medicare coverage for immunosuppression

Dr. Hariharan voiced optimism that graft and patient survival rates will continue to improve going forward. One factor will likely be the passage in late 2020 of the “Immuno Bill” by the U.S. Congress, which among other things mandated ongoing coverage starting in 2023 for immunosuppressive drugs for all Medicare beneficiaries with a kidney transplant. Until then, Medicare provides coverage for only 36 months, a time limit that has resulted in nearly 400 kidney recipients annually losing coverage of their immunosuppression medications.

Dr. Hariharan and coauthors called the existing potential for discontinuation of immunosuppressive drug an “unnecessary impediment to long-term survival for which patients and society paid a heavy price.”

“Kidney transplantation, especially from living donors, offers patients with kidney failure the best chance for long-term survival and improved quality of life, with lower cost to the health care system,” Dr. Lentine said in an interview. Despite the many positive trends detailed in the report from Dr. Hariharan and coauthors, “the vast majority of the more than 700,000 people in the United States with kidney failure will not have an opportunity to receive a transplant due to limitations in organ supply.” And many patients who receive a kidney transplant eventually must resume dialysis because of “limited long-term graft survival resulting from allograft nephropathy, recurrent native disease, medication nonadherence, or other causes.” Plus many potentially transplantable organs go unused.

Dr. Lentine cited a position statement issued in July 2021 by the National Kidney Foundation that made several recommendations on how to improve access to kidney transplants and improve outcomes. “Expanding opportunities for safe living donation, eliminating racial disparities in living-donor access, improving wait-list access and transport readiness, maximizing use of deceased-donor organs, and extending graft longevity are critical priorities,” said Dr. Lentine, lead author on the statement.

“For many or even most patients with kidney failure transplantation is the optimal form of renal replacement. The better recent outcomes and evolving management strategies make transplantation an even more attractive option,” said Dr. Josephson. Improved outcomes among U.S. transplant patients also highlights the “importance of increasing access to kidney transplantation” for all people with kidney failure who could benefit from this treatment, she added.

Dr. Hariharan and Dr. Lentine had no relevant disclosures. Dr. Josephson has been a consultant to UCB and has an ownership interest in Seagen.

[email protected]

Kidney transplantation has recently been happening at a record pace and with unprecedented success despite patients having more risk factors than ever before.

HYWARDS/Thinkstock

During 2016-2019, U.S. centers performed kidney transplants in nearly 77,000 patients, a jump of almost 25% compared with 4-year averages of about 62,000 patients throughout 2004-2015. That works out to about 15,000 more patients receiving donor kidneys, Sundaram Hariharan, MD, and associates reported in the New England Journal of Medicine in a review of all U.S. renal transplantations performed during 1996-2019.

Coupled with the volume uptick during this 24-year period were new lows in graft losses and patient deaths. By 2018, mortality during the first year following transplantation occurred at about a 1% rate among patients who had received a kidney from a living donor, and at about a 3% rate when the organ came from a deceased donor, nearly half the rate of 2 decades earlier, in 1996. Rates of first-year graft loss during 2017 were also about half of what they had been in 1996, occurring in about 2% of patients who received a living donor organ and in about 6% of those who got a kidney from a deceased donor during 2017.

“Twenty years ago, kidney transplantation was the preferred option compared with dialysis, and even more so now,” summed up Dr. Hariharan, a senior transplant nephrologist and professor of medicine and surgery at the University of Pittsburgh Medical Center and first author of the report. Kidney transplantation survival at U.S. centers “improved steadily over the past 24 years, despite patient variables becoming worse,” he said in an interview.
 

Kidney recipients are older, more obese, and have more prevalent diabetes

During the period studied, kidney transplant recipients became on average older and more obese, and had a higher prevalence of diabetes; the age of organ donors grew as well. The prevalence of diabetes among patients who received a kidney from a deceased donor increased from 24% during 1996-1999 to 36% during 2016-2019, while diabetes prevalence among recipients of an organ from a living donor rose from 25% in 1996-1999 to 29% during 2016-2019.

The improved graft and patient survival numbers “are very encouraging trends,” said Michelle A. Josephson, MD, professor and medical director of kidney transplantation at the University of Chicago, who was not involved with the report. “We have been hearing for a number of years that short-term graft survival had improved, but I’m thrilled to learn that long-term survival has also improved.”

The report documented 10-year survival of graft recipients during 2008-2011 of 67%, up from 61% during 1996-1999, and a 10-year overall graft survival rate of 54% in the 2008-2011 cohort, an improvement from the 42% rate in patients who received their organs in 1996-1999, changes Dr. Hariharan characterized as “modest.”

These improvements in long-term graft and patient survival are “meaningful, and particularly notable that outcomes improved despite increased complexity of the transplant population,” said Krista L. Lentine, MD, PhD, professor and medical director of living donation at Saint Louis University. But “despite these improvements, long-term graft survival remains limited,” she cautioned, especially because of risks for substantial complications from chronic immunosuppressive treatment including infection, cancer, glucose intolerance, and dyslipidemia.

The analysis reported by Dr. Hariharan and his associates used data collected by the Scientific Registry of Transplant Patients, run under contract with the U.S. Department of Health and Human Services, which has tracked all patients who have had kidney transplants at U.S. centers since the late 1980s, said Dr. Hariharan. The database included just over 362,000 total transplants during the 24-year period studied, with 36% of all transplants involving organs from living donors with the remaining patients receiving kidneys from deceased donors.

Living donations still stagnant; deceased-donor kidneys rise

The data showed that the rate of transplants from living donors was stagnant for 2 decades, with 22,525 patients transplanted during 2000-2003, and 23,746 transplanted during 2016-2019, with very similar rates during the intervening years. The recent spurt in transplants during 2016-2019 compared with the preceding decade depended almost entirely on kidneys from deceased donors. This rate jumped from the steady, slow rise it showed during 1996-2015, when deceased-donor transplants rose from about 30,000 during 1996-1999 to about 41,000 during 2012-2015, to a more dramatic increase of about 12,000 additional transplants during the most recent period, adding up to a total of more than 53,000 transplants from deceased donors during 2016-2019.

“I strongly recommend organs from living donors” when feasible, said Dr. Hariharan. “At some centers, a high proportion of transplants use living donors, but not at other centers,” he said.

It’s unknown why transplants using organs from deceased donors has shown this growth, but Dr. Hariharan suggested a multifactorial explanation. Those factors include growth in the number of patients with end-stage renal disease who require dialysis, increased numbers of patients listed for kidney transplant, new approaches that allow organs from older donors and those infected with pathogens such as hepatitis C virus or HIV, greater numbers of people and families agreeing to donate organs, and possibly the opioid crisis that may have led to increased organ donation. The number of U.S. centers performing kidney transplants rose from fewer than 200 about a quarter of a century ago to about 250 today, he added.

‘Immuno Bill’ guarantees Medicare coverage for immunosuppression

Dr. Hariharan voiced optimism that graft and patient survival rates will continue to improve going forward. One factor will likely be the passage in late 2020 of the “Immuno Bill” by the U.S. Congress, which among other things mandated ongoing coverage starting in 2023 for immunosuppressive drugs for all Medicare beneficiaries with a kidney transplant. Until then, Medicare provides coverage for only 36 months, a time limit that has resulted in nearly 400 kidney recipients annually losing coverage of their immunosuppression medications.

Dr. Hariharan and coauthors called the existing potential for discontinuation of immunosuppressive drug an “unnecessary impediment to long-term survival for which patients and society paid a heavy price.”

“Kidney transplantation, especially from living donors, offers patients with kidney failure the best chance for long-term survival and improved quality of life, with lower cost to the health care system,” Dr. Lentine said in an interview. Despite the many positive trends detailed in the report from Dr. Hariharan and coauthors, “the vast majority of the more than 700,000 people in the United States with kidney failure will not have an opportunity to receive a transplant due to limitations in organ supply.” And many patients who receive a kidney transplant eventually must resume dialysis because of “limited long-term graft survival resulting from allograft nephropathy, recurrent native disease, medication nonadherence, or other causes.” Plus many potentially transplantable organs go unused.

Dr. Lentine cited a position statement issued in July 2021 by the National Kidney Foundation that made several recommendations on how to improve access to kidney transplants and improve outcomes. “Expanding opportunities for safe living donation, eliminating racial disparities in living-donor access, improving wait-list access and transport readiness, maximizing use of deceased-donor organs, and extending graft longevity are critical priorities,” said Dr. Lentine, lead author on the statement.

“For many or even most patients with kidney failure transplantation is the optimal form of renal replacement. The better recent outcomes and evolving management strategies make transplantation an even more attractive option,” said Dr. Josephson. Improved outcomes among U.S. transplant patients also highlights the “importance of increasing access to kidney transplantation” for all people with kidney failure who could benefit from this treatment, she added.

Dr. Hariharan and Dr. Lentine had no relevant disclosures. Dr. Josephson has been a consultant to UCB and has an ownership interest in Seagen.

[email protected]

U.S. prescribing data from 160,000 adults with type 2 diabetes and diabetic kidney disease showed a notable uptick in new prescriptions for sodium-glucose cotransporter 2 inhibitors and less dramatic gains for glucagonlike peptide–1 receptor agonists during 2019 and continuing into early 2020, compared with prior years, with usage levels of both classes during the first quarter of 2020 rivaling those of more traditional agents including metformin and insulin.

During the first 3 months of 2020, initiation of a SGLT2 inhibitor constituted 13% of all new starts of an antidiabetes drug among adults with type 2 diabetes and diabetic kidney disease (DKD). This compared with initiation rates during the same early 2020 period of 17% for GLP-1 receptor agonists, 19% for metformin, 16% for sulfonylureas, 15% for insulins, 14% for thiazolidinediones, and 6% for dipeptidyl peptidase–4 inhibitors, the seven drug classes examined in a study published in Diabetes Care.

Early 2020 was the first time that starts of a GLP-1 receptor agonist ranked second (behind only metformin) among these seven drug classes in the studied U.S. population, and early 2020 also marked an unprecedentedly high start rate for SGLT2 inhibitors that nearly tripled the roughly 5% rate in place as recently as 2018.
 

Rises are ‘what we expected’

The recent rise of SGLT2 inhibitors and GLP-1 receptor agonists in these patients “was what we expected,” given the evidence for both classes in slowing progression of DKD, said Julie M. Paik, MD, senior author on the study and a nephrologist and pharmacoepidemiologist at Brigham and Women’s Hospital in Boston.

“We’ve seen other beneficial drugs slow on the uptake, so it’s not surprising to see it here, and I’m optimistic” about further increases going forward, she said in an interview.

Both drug classes “were originally marketed as diabetes drugs,” and it is only since 2019, with the publication of trials showing dramatic renal benefits from canagliflozin (Invokana) in CREDENCE, and from dapagliflozin (Farxiga) in DAPA-CKD in 2020 that the evidence became truly compelling for SGLT2 inhibitors. This evidence also led to new renal-protection indications approved by the Food and Drug Administration for canagliflozin and for dapagliflozin, noted Dr. Paik.

Evidence for renal protection also emerged in 2017 for the GLP-1 receptor agonist liraglutide (Victoza) in the LEADER trial, and for dulaglutide (Trulicity) in the AWARD-7 trial, although neither drug has received a renal indication in its labeling.

By 2020, guidelines for managing patients with type 2 diabetes and chronic kidney disease from the influential Kidney Disease: Improving Global Outcomes organization had identified agents from the SGLT2 inhibitor class as top-tier options, along with metformin, for treating these patients, with agents from the GLP-1 receptor agonist class as the top third class to add in patients who require additional glycemic control.

Additional analyses Dr. Paik and associates ran showed how this played out in terms of which specialists prescribed these drugs during the full period studied beginning in 2013. Throughout this roughly 7-year span, about 70% of the prescriptions written for either SGLT2 inhibitors or for GLP-1 receptor agonists were from internal medicine physicians, followed by about 20% written by endocrinologists. Prescriptions from nephrologists, as well as from cardiologists, have hovered at about 5% each, but seem poised to start rising based on the recently added indications and newer treatment recommendations.

“It’s good to see the recent uptick in use since 2019,” Katherine R. Tuttle, MD, commented in an interview. It’s a positive development for U.S. public health, “but we need to do more to disseminate and implement these life-, kidney-, and heart-saving therapies.”

Future use could approach 80% of DKD patients

Dr. Tuttle estimated that “target” levels of use for SGLT2 inhibitors and for GLP-1 receptor agonists “could reasonably approach 80%” for patients with type 2 diabetes and diabetic kidney disease.

“We will likely move to combination therapy” with simultaneous use of agents from both classes in a targeted way using “precision phenotyping based on clinical characteristics, and eventually perhaps by biomarkers, kidney biopsies, or both.” Combined treatment with both an SGLT2 inhibitor and a GLP-1 receptor agonist may be especially suited to patients with type 2 diabetes, atherosclerotic cardiovascular disease, low estimated glomerular filtration rate, and need for better glycemic control and weight loss, a profile that is “pretty typical” in real-world practice, said Dr. Tuttle, a nephrologist and endocrinologist and executive director for research at Providence Healthcare in Spokane, Wash.
 

Study included patients with commercial or Medicare Advantage coverage

The study used information in an Optum database that included patients enrolled in either commercial or in Medicare Advantage health insurance plans from 2013 to the first quarter of 2020. This included 160,489 adults with type 2 diabetes and DKD who started during that period at least one agent from any of the seven included drug classes.

This focus may have biased the findings because, overall, U.S. coverage of the relatively expensive agents from the SGLT2 inhibitor and GLP-1 receptor agonist classes has often been problematic.

“There are issues of cost, coverage, and access” using these medications, as well as limited data on cost-effectiveness, Dr. Paik acknowledged. Additional issues that have helped generate prescribing lags include concerns about possible adverse effects, low familiarity by providers with these drugs early on, and limited trial experience using them in older patients. The process of clinicians growing more comfortable prescribing these new agents has depended on their “working through the evidence,” she explained.

The FDA’s approval in July 2021 of finerenone (Kerendia) for treating patients with type 2 diabetes and chronic kidney disease threw yet another new variable into the prescribing mix for these patients.

“SGLT2 inhibitors are here to stay as a new standard of care for patients with diabetic kidney disease, but combination with finerenone might be especially useful for patients with diabetic kidney disease and heart failure,” Dr. Tuttle suggested. A new generation of clinical trials will likely soon launch to test these combinations, she predicted.

Dr. Paik had no disclosures. Dr. Tuttle has been a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Gilead, Goldfinch Bio, Eli Lilly, and Novo Nordisk.

[email protected]

U.S. prescribing data from 160,000 adults with type 2 diabetes and diabetic kidney disease showed a notable uptick in new prescriptions for sodium-glucose cotransporter 2 inhibitors and less dramatic gains for glucagonlike peptide–1 receptor agonists during 2019 and continuing into early 2020, compared with prior years, with usage levels of both classes during the first quarter of 2020 rivaling those of more traditional agents including metformin and insulin.

During the first 3 months of 2020, initiation of a SGLT2 inhibitor constituted 13% of all new starts of an antidiabetes drug among adults with type 2 diabetes and diabetic kidney disease (DKD). This compared with initiation rates during the same early 2020 period of 17% for GLP-1 receptor agonists, 19% for metformin, 16% for sulfonylureas, 15% for insulins, 14% for thiazolidinediones, and 6% for dipeptidyl peptidase–4 inhibitors, the seven drug classes examined in a study published in Diabetes Care.

Early 2020 was the first time that starts of a GLP-1 receptor agonist ranked second (behind only metformin) among these seven drug classes in the studied U.S. population, and early 2020 also marked an unprecedentedly high start rate for SGLT2 inhibitors that nearly tripled the roughly 5% rate in place as recently as 2018.
 

Rises are ‘what we expected’

The recent rise of SGLT2 inhibitors and GLP-1 receptor agonists in these patients “was what we expected,” given the evidence for both classes in slowing progression of DKD, said Julie M. Paik, MD, senior author on the study and a nephrologist and pharmacoepidemiologist at Brigham and Women’s Hospital in Boston.

“We’ve seen other beneficial drugs slow on the uptake, so it’s not surprising to see it here, and I’m optimistic” about further increases going forward, she said in an interview.

Both drug classes “were originally marketed as diabetes drugs,” and it is only since 2019, with the publication of trials showing dramatic renal benefits from canagliflozin (Invokana) in CREDENCE, and from dapagliflozin (Farxiga) in DAPA-CKD in 2020 that the evidence became truly compelling for SGLT2 inhibitors. This evidence also led to new renal-protection indications approved by the Food and Drug Administration for canagliflozin and for dapagliflozin, noted Dr. Paik.

Evidence for renal protection also emerged in 2017 for the GLP-1 receptor agonist liraglutide (Victoza) in the LEADER trial, and for dulaglutide (Trulicity) in the AWARD-7 trial, although neither drug has received a renal indication in its labeling.

By 2020, guidelines for managing patients with type 2 diabetes and chronic kidney disease from the influential Kidney Disease: Improving Global Outcomes organization had identified agents from the SGLT2 inhibitor class as top-tier options, along with metformin, for treating these patients, with agents from the GLP-1 receptor agonist class as the top third class to add in patients who require additional glycemic control.

Additional analyses Dr. Paik and associates ran showed how this played out in terms of which specialists prescribed these drugs during the full period studied beginning in 2013. Throughout this roughly 7-year span, about 70% of the prescriptions written for either SGLT2 inhibitors or for GLP-1 receptor agonists were from internal medicine physicians, followed by about 20% written by endocrinologists. Prescriptions from nephrologists, as well as from cardiologists, have hovered at about 5% each, but seem poised to start rising based on the recently added indications and newer treatment recommendations.

“It’s good to see the recent uptick in use since 2019,” Katherine R. Tuttle, MD, commented in an interview. It’s a positive development for U.S. public health, “but we need to do more to disseminate and implement these life-, kidney-, and heart-saving therapies.”

Future use could approach 80% of DKD patients

Dr. Tuttle estimated that “target” levels of use for SGLT2 inhibitors and for GLP-1 receptor agonists “could reasonably approach 80%” for patients with type 2 diabetes and diabetic kidney disease.

“We will likely move to combination therapy” with simultaneous use of agents from both classes in a targeted way using “precision phenotyping based on clinical characteristics, and eventually perhaps by biomarkers, kidney biopsies, or both.” Combined treatment with both an SGLT2 inhibitor and a GLP-1 receptor agonist may be especially suited to patients with type 2 diabetes, atherosclerotic cardiovascular disease, low estimated glomerular filtration rate, and need for better glycemic control and weight loss, a profile that is “pretty typical” in real-world practice, said Dr. Tuttle, a nephrologist and endocrinologist and executive director for research at Providence Healthcare in Spokane, Wash.
 

Study included patients with commercial or Medicare Advantage coverage

The study used information in an Optum database that included patients enrolled in either commercial or in Medicare Advantage health insurance plans from 2013 to the first quarter of 2020. This included 160,489 adults with type 2 diabetes and DKD who started during that period at least one agent from any of the seven included drug classes.

This focus may have biased the findings because, overall, U.S. coverage of the relatively expensive agents from the SGLT2 inhibitor and GLP-1 receptor agonist classes has often been problematic.

“There are issues of cost, coverage, and access” using these medications, as well as limited data on cost-effectiveness, Dr. Paik acknowledged. Additional issues that have helped generate prescribing lags include concerns about possible adverse effects, low familiarity by providers with these drugs early on, and limited trial experience using them in older patients. The process of clinicians growing more comfortable prescribing these new agents has depended on their “working through the evidence,” she explained.

The FDA’s approval in July 2021 of finerenone (Kerendia) for treating patients with type 2 diabetes and chronic kidney disease threw yet another new variable into the prescribing mix for these patients.

“SGLT2 inhibitors are here to stay as a new standard of care for patients with diabetic kidney disease, but combination with finerenone might be especially useful for patients with diabetic kidney disease and heart failure,” Dr. Tuttle suggested. A new generation of clinical trials will likely soon launch to test these combinations, she predicted.

Dr. Paik had no disclosures. Dr. Tuttle has been a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Gilead, Goldfinch Bio, Eli Lilly, and Novo Nordisk.

[email protected]

U.S. prescribing data from 160,000 adults with type 2 diabetes and diabetic kidney disease showed a notable uptick in new prescriptions for sodium-glucose cotransporter 2 inhibitors and less dramatic gains for glucagonlike peptide–1 receptor agonists during 2019 and continuing into early 2020, compared with prior years, with usage levels of both classes during the first quarter of 2020 rivaling those of more traditional agents including metformin and insulin.

During the first 3 months of 2020, initiation of a SGLT2 inhibitor constituted 13% of all new starts of an antidiabetes drug among adults with type 2 diabetes and diabetic kidney disease (DKD). This compared with initiation rates during the same early 2020 period of 17% for GLP-1 receptor agonists, 19% for metformin, 16% for sulfonylureas, 15% for insulins, 14% for thiazolidinediones, and 6% for dipeptidyl peptidase–4 inhibitors, the seven drug classes examined in a study published in Diabetes Care.

Early 2020 was the first time that starts of a GLP-1 receptor agonist ranked second (behind only metformin) among these seven drug classes in the studied U.S. population, and early 2020 also marked an unprecedentedly high start rate for SGLT2 inhibitors that nearly tripled the roughly 5% rate in place as recently as 2018.
 

Rises are ‘what we expected’

The recent rise of SGLT2 inhibitors and GLP-1 receptor agonists in these patients “was what we expected,” given the evidence for both classes in slowing progression of DKD, said Julie M. Paik, MD, senior author on the study and a nephrologist and pharmacoepidemiologist at Brigham and Women’s Hospital in Boston.

“We’ve seen other beneficial drugs slow on the uptake, so it’s not surprising to see it here, and I’m optimistic” about further increases going forward, she said in an interview.

Both drug classes “were originally marketed as diabetes drugs,” and it is only since 2019, with the publication of trials showing dramatic renal benefits from canagliflozin (Invokana) in CREDENCE, and from dapagliflozin (Farxiga) in DAPA-CKD in 2020 that the evidence became truly compelling for SGLT2 inhibitors. This evidence also led to new renal-protection indications approved by the Food and Drug Administration for canagliflozin and for dapagliflozin, noted Dr. Paik.

Evidence for renal protection also emerged in 2017 for the GLP-1 receptor agonist liraglutide (Victoza) in the LEADER trial, and for dulaglutide (Trulicity) in the AWARD-7 trial, although neither drug has received a renal indication in its labeling.

By 2020, guidelines for managing patients with type 2 diabetes and chronic kidney disease from the influential Kidney Disease: Improving Global Outcomes organization had identified agents from the SGLT2 inhibitor class as top-tier options, along with metformin, for treating these patients, with agents from the GLP-1 receptor agonist class as the top third class to add in patients who require additional glycemic control.

Additional analyses Dr. Paik and associates ran showed how this played out in terms of which specialists prescribed these drugs during the full period studied beginning in 2013. Throughout this roughly 7-year span, about 70% of the prescriptions written for either SGLT2 inhibitors or for GLP-1 receptor agonists were from internal medicine physicians, followed by about 20% written by endocrinologists. Prescriptions from nephrologists, as well as from cardiologists, have hovered at about 5% each, but seem poised to start rising based on the recently added indications and newer treatment recommendations.

“It’s good to see the recent uptick in use since 2019,” Katherine R. Tuttle, MD, commented in an interview. It’s a positive development for U.S. public health, “but we need to do more to disseminate and implement these life-, kidney-, and heart-saving therapies.”

Future use could approach 80% of DKD patients

Dr. Tuttle estimated that “target” levels of use for SGLT2 inhibitors and for GLP-1 receptor agonists “could reasonably approach 80%” for patients with type 2 diabetes and diabetic kidney disease.

“We will likely move to combination therapy” with simultaneous use of agents from both classes in a targeted way using “precision phenotyping based on clinical characteristics, and eventually perhaps by biomarkers, kidney biopsies, or both.” Combined treatment with both an SGLT2 inhibitor and a GLP-1 receptor agonist may be especially suited to patients with type 2 diabetes, atherosclerotic cardiovascular disease, low estimated glomerular filtration rate, and need for better glycemic control and weight loss, a profile that is “pretty typical” in real-world practice, said Dr. Tuttle, a nephrologist and endocrinologist and executive director for research at Providence Healthcare in Spokane, Wash.
 

Study included patients with commercial or Medicare Advantage coverage

The study used information in an Optum database that included patients enrolled in either commercial or in Medicare Advantage health insurance plans from 2013 to the first quarter of 2020. This included 160,489 adults with type 2 diabetes and DKD who started during that period at least one agent from any of the seven included drug classes.

This focus may have biased the findings because, overall, U.S. coverage of the relatively expensive agents from the SGLT2 inhibitor and GLP-1 receptor agonist classes has often been problematic.

“There are issues of cost, coverage, and access” using these medications, as well as limited data on cost-effectiveness, Dr. Paik acknowledged. Additional issues that have helped generate prescribing lags include concerns about possible adverse effects, low familiarity by providers with these drugs early on, and limited trial experience using them in older patients. The process of clinicians growing more comfortable prescribing these new agents has depended on their “working through the evidence,” she explained.

The FDA’s approval in July 2021 of finerenone (Kerendia) for treating patients with type 2 diabetes and chronic kidney disease threw yet another new variable into the prescribing mix for these patients.

“SGLT2 inhibitors are here to stay as a new standard of care for patients with diabetic kidney disease, but combination with finerenone might be especially useful for patients with diabetic kidney disease and heart failure,” Dr. Tuttle suggested. A new generation of clinical trials will likely soon launch to test these combinations, she predicted.

Dr. Paik had no disclosures. Dr. Tuttle has been a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Gilead, Goldfinch Bio, Eli Lilly, and Novo Nordisk.

[email protected]

The presence of chronic kidney disease (CKD) or end-stage renal disease (ESRD) is associated with worse in-hospital and short-term outcomes after left atrial appendage (LAA) closure, a nationwide study shows.

Patients with ESRD were particularly vulnerable, having about 6.5-fold higher odds of in-hospital mortality than those without CKD and about 11.5-fold higher odds than those with CKD, even after adjustment for potential confounders.

Patients with CKD had higher rates of stroke or transient ischemic attack (TIA) and more short-term readmissions for bleeding, Keerat Rai Ahuja, MD, Reading Hospital-Tower Health, West Reading, Pennsylvania, and colleagues reported August 16 in JACC: Cardiovascular Interventions.

CKD and ESRD are known to be associated with an increased risk for stroke and bleeding in patients with atrial fibrillation (AFib), yet data are limited on the safety and efficacy of LAA closure for stroke prevention in AFib patients with CKD or ESRD, they note.  

“It’s important to know about CKD and understand that there may be an association with worse levels of CKD and worse outcomes, but the data that strikes me is really that for end-stage renal disease,” Matthew Sherwood, MD, MHS, who was not involved with the study, said in an interview.

He noted that data have not been published for patients with CKD and ESRD enrolled in the pivotal PROTECT-AF and PREVAIL trials of Boston Scientific’s Watchman device or from large clinical registries such as EWOLUTION and the company’s continued access protocol registries.

Further, it’s not well understood what the best strategy is to prevent stroke in AFib patients with ESRD and whether they benefit from anticoagulation with warfarin or any of the newer agents. “Thus, it’s hard to then say: ‘Well they have worse outcomes with Watchman,’ which is true as shown in this study, but they may not have any other options based upon the lack of data for oral anticoagulants in end-stage kidney disease patients,” said Dr. Sherwood, from the Inova Heart and Vascular Institute, Falls Church, Virginia.

The lack of clarity is concerning, given rising atrial fibrillation cases and the prevalence of abnormal renal function in everyday practice. In the present study – involving 21,274 patients undergoing LAA closure between 2016 and 2017 in the Nationwide Readmissions Database – 18.6% of patients had CKD stages I to V and 2.7% had ESRD based on ICD-10 codes.

In-hospital mortality was increased only in patients with ESRD. In all, 3.3% of patients with ESRD and 0.4% of those with no CKD died in hospital (adjusted odds ratio [aOR], 6.48), as did 0.5% of patients with CKD (aOR, 11.43; both P <.001).

“These patients represent a sicker population at baseline and have an inherent greater risk for mortality in cardiac interventions, as noted in other studies of structural heart interventions,” Dr. Ahuja and colleagues write.

Patients with CKD had a higher risk for in-hospital stroke or TIA than patients with no CKD (1.8% vs. 1.3%; aOR, 1.35; P = .038) and this risk continued up to 90 days after discharge (1.7% vs. 1.0%; aOR, 1.67; P = .007).

The in-hospital stroke rate was numerically higher in patients with ESRD compared with no CKD (aOR, 1.18; P = .62).

The authors point out that previous LAA closure and CKD studies have reported no differences in in-hospital or subsequent stroke/TIA rates in patients with and without CKD. Possible explanations are that patients with CKD in the present study had higher CHA2DS2-VASc scores than those without CKD (4.18 vs. 3.62) and, second, patients with CKD and AFib are known to have higher risk for thromboembolic events than those with AFib without CKD.

CKD patients were also more likely than those without CKD to experience in-hospital acute kidney injury or hemodialysis (aOR, 5.02; P <.001).

CKD has been shown to be independently associated with acute kidney injury (AKI) after LAA closure. AKI may have long-term thromboembolic consequences, the authors suggest, with one study reporting higher stroke risk at midterm follow-up in patients with AKI.

“As with other cardiac interventions in patients with CKD, efforts should be made to optimize preoperative renal function, minimize contrast volume, and avoid abrupt hemodynamic changes such as hypotension during the procedure to prevent AKI,” Dr. Ahuja and colleagues write.

Patients with CKD and ESRD had longer index length of stay than those without CKD but had similar rates of other in-hospital complications, such as systemic embolization, bleeding/transfusion, vascular complications, and pericardial tamponade requiring intervention.

Among the short-term outcomes, 30- and 90-day all-cause readmissions were increased in patients with CKD and ESRD compared with those without CKD, and 30-day bleeding readmissions were increased within the CKD cohort.

“With Watchman and left atrial appendage closure, what we see is that they have higher rates of readmission and other problems,” Dr. Sherwood said. “I think we understand that that’s probably related not to the procedure itself, not because the Watchman doesn’t work for end-stage kidney disease, but because the patients themselves are likely higher risk.”

Commonly used risk scores for atrial fibrillation, however, don’t take into account advanced kidney disease, he added.

Besides the inherent limitations of observational studies, Dr. Sherwood and the authors point to the lack of laboratory variables and procedural variables in the database, the fact that CKD was defined using ICD-10 codes, that outcomes were not clinically adjudicated, that unmeasured confounders likely still exist, and that long-term follow-up is lacking.

Dr. Sherwood, who wrote an editorial accompanying the study, said that the release of outcomes data from CKD and ESRD patients in the major clinical trials would be helpful going forward, as would possible involvement with the Kidney Disease Improving Global Outcomes organization.

“One of the main points of this study is that we just need a lot more research diving into this patient population,” he said.

The authors report no relevant financial relationships. Dr. Sherwood reports honoraria from Janssen and Medtronic. Editorial coauthor Sean Pokorney reports research grant support from Gilead, Boston Scientific, Pfizer, Bristol Myers Squibb, Janssen, and the Food and Drug Administration; and advisory board, consulting, and honoraria supports from Medtronic, Boston Scientific, Pfizer, Bristol Myers Squibb, Philips, and Zoll.

A version of this article first appeared on Medscape.com.

The presence of chronic kidney disease (CKD) or end-stage renal disease (ESRD) is associated with worse in-hospital and short-term outcomes after left atrial appendage (LAA) closure, a nationwide study shows.

Patients with ESRD were particularly vulnerable, having about 6.5-fold higher odds of in-hospital mortality than those without CKD and about 11.5-fold higher odds than those with CKD, even after adjustment for potential confounders.

Patients with CKD had higher rates of stroke or transient ischemic attack (TIA) and more short-term readmissions for bleeding, Keerat Rai Ahuja, MD, Reading Hospital-Tower Health, West Reading, Pennsylvania, and colleagues reported August 16 in JACC: Cardiovascular Interventions.

CKD and ESRD are known to be associated with an increased risk for stroke and bleeding in patients with atrial fibrillation (AFib), yet data are limited on the safety and efficacy of LAA closure for stroke prevention in AFib patients with CKD or ESRD, they note.  

“It’s important to know about CKD and understand that there may be an association with worse levels of CKD and worse outcomes, but the data that strikes me is really that for end-stage renal disease,” Matthew Sherwood, MD, MHS, who was not involved with the study, said in an interview.

He noted that data have not been published for patients with CKD and ESRD enrolled in the pivotal PROTECT-AF and PREVAIL trials of Boston Scientific’s Watchman device or from large clinical registries such as EWOLUTION and the company’s continued access protocol registries.

Further, it’s not well understood what the best strategy is to prevent stroke in AFib patients with ESRD and whether they benefit from anticoagulation with warfarin or any of the newer agents. “Thus, it’s hard to then say: ‘Well they have worse outcomes with Watchman,’ which is true as shown in this study, but they may not have any other options based upon the lack of data for oral anticoagulants in end-stage kidney disease patients,” said Dr. Sherwood, from the Inova Heart and Vascular Institute, Falls Church, Virginia.

The lack of clarity is concerning, given rising atrial fibrillation cases and the prevalence of abnormal renal function in everyday practice. In the present study – involving 21,274 patients undergoing LAA closure between 2016 and 2017 in the Nationwide Readmissions Database – 18.6% of patients had CKD stages I to V and 2.7% had ESRD based on ICD-10 codes.

In-hospital mortality was increased only in patients with ESRD. In all, 3.3% of patients with ESRD and 0.4% of those with no CKD died in hospital (adjusted odds ratio [aOR], 6.48), as did 0.5% of patients with CKD (aOR, 11.43; both P <.001).

“These patients represent a sicker population at baseline and have an inherent greater risk for mortality in cardiac interventions, as noted in other studies of structural heart interventions,” Dr. Ahuja and colleagues write.

Patients with CKD had a higher risk for in-hospital stroke or TIA than patients with no CKD (1.8% vs. 1.3%; aOR, 1.35; P = .038) and this risk continued up to 90 days after discharge (1.7% vs. 1.0%; aOR, 1.67; P = .007).

The in-hospital stroke rate was numerically higher in patients with ESRD compared with no CKD (aOR, 1.18; P = .62).

The authors point out that previous LAA closure and CKD studies have reported no differences in in-hospital or subsequent stroke/TIA rates in patients with and without CKD. Possible explanations are that patients with CKD in the present study had higher CHA2DS2-VASc scores than those without CKD (4.18 vs. 3.62) and, second, patients with CKD and AFib are known to have higher risk for thromboembolic events than those with AFib without CKD.

CKD patients were also more likely than those without CKD to experience in-hospital acute kidney injury or hemodialysis (aOR, 5.02; P <.001).

CKD has been shown to be independently associated with acute kidney injury (AKI) after LAA closure. AKI may have long-term thromboembolic consequences, the authors suggest, with one study reporting higher stroke risk at midterm follow-up in patients with AKI.

“As with other cardiac interventions in patients with CKD, efforts should be made to optimize preoperative renal function, minimize contrast volume, and avoid abrupt hemodynamic changes such as hypotension during the procedure to prevent AKI,” Dr. Ahuja and colleagues write.

Patients with CKD and ESRD had longer index length of stay than those without CKD but had similar rates of other in-hospital complications, such as systemic embolization, bleeding/transfusion, vascular complications, and pericardial tamponade requiring intervention.

Among the short-term outcomes, 30- and 90-day all-cause readmissions were increased in patients with CKD and ESRD compared with those without CKD, and 30-day bleeding readmissions were increased within the CKD cohort.

“With Watchman and left atrial appendage closure, what we see is that they have higher rates of readmission and other problems,” Dr. Sherwood said. “I think we understand that that’s probably related not to the procedure itself, not because the Watchman doesn’t work for end-stage kidney disease, but because the patients themselves are likely higher risk.”

Commonly used risk scores for atrial fibrillation, however, don’t take into account advanced kidney disease, he added.

Besides the inherent limitations of observational studies, Dr. Sherwood and the authors point to the lack of laboratory variables and procedural variables in the database, the fact that CKD was defined using ICD-10 codes, that outcomes were not clinically adjudicated, that unmeasured confounders likely still exist, and that long-term follow-up is lacking.

Dr. Sherwood, who wrote an editorial accompanying the study, said that the release of outcomes data from CKD and ESRD patients in the major clinical trials would be helpful going forward, as would possible involvement with the Kidney Disease Improving Global Outcomes organization.

“One of the main points of this study is that we just need a lot more research diving into this patient population,” he said.

The authors report no relevant financial relationships. Dr. Sherwood reports honoraria from Janssen and Medtronic. Editorial coauthor Sean Pokorney reports research grant support from Gilead, Boston Scientific, Pfizer, Bristol Myers Squibb, Janssen, and the Food and Drug Administration; and advisory board, consulting, and honoraria supports from Medtronic, Boston Scientific, Pfizer, Bristol Myers Squibb, Philips, and Zoll.

A version of this article first appeared on Medscape.com.

The presence of chronic kidney disease (CKD) or end-stage renal disease (ESRD) is associated with worse in-hospital and short-term outcomes after left atrial appendage (LAA) closure, a nationwide study shows.

Patients with ESRD were particularly vulnerable, having about 6.5-fold higher odds of in-hospital mortality than those without CKD and about 11.5-fold higher odds than those with CKD, even after adjustment for potential confounders.

Patients with CKD had higher rates of stroke or transient ischemic attack (TIA) and more short-term readmissions for bleeding, Keerat Rai Ahuja, MD, Reading Hospital-Tower Health, West Reading, Pennsylvania, and colleagues reported August 16 in JACC: Cardiovascular Interventions.

CKD and ESRD are known to be associated with an increased risk for stroke and bleeding in patients with atrial fibrillation (AFib), yet data are limited on the safety and efficacy of LAA closure for stroke prevention in AFib patients with CKD or ESRD, they note.  

“It’s important to know about CKD and understand that there may be an association with worse levels of CKD and worse outcomes, but the data that strikes me is really that for end-stage renal disease,” Matthew Sherwood, MD, MHS, who was not involved with the study, said in an interview.

He noted that data have not been published for patients with CKD and ESRD enrolled in the pivotal PROTECT-AF and PREVAIL trials of Boston Scientific’s Watchman device or from large clinical registries such as EWOLUTION and the company’s continued access protocol registries.

Further, it’s not well understood what the best strategy is to prevent stroke in AFib patients with ESRD and whether they benefit from anticoagulation with warfarin or any of the newer agents. “Thus, it’s hard to then say: ‘Well they have worse outcomes with Watchman,’ which is true as shown in this study, but they may not have any other options based upon the lack of data for oral anticoagulants in end-stage kidney disease patients,” said Dr. Sherwood, from the Inova Heart and Vascular Institute, Falls Church, Virginia.

The lack of clarity is concerning, given rising atrial fibrillation cases and the prevalence of abnormal renal function in everyday practice. In the present study – involving 21,274 patients undergoing LAA closure between 2016 and 2017 in the Nationwide Readmissions Database – 18.6% of patients had CKD stages I to V and 2.7% had ESRD based on ICD-10 codes.

In-hospital mortality was increased only in patients with ESRD. In all, 3.3% of patients with ESRD and 0.4% of those with no CKD died in hospital (adjusted odds ratio [aOR], 6.48), as did 0.5% of patients with CKD (aOR, 11.43; both P <.001).

“These patients represent a sicker population at baseline and have an inherent greater risk for mortality in cardiac interventions, as noted in other studies of structural heart interventions,” Dr. Ahuja and colleagues write.

Patients with CKD had a higher risk for in-hospital stroke or TIA than patients with no CKD (1.8% vs. 1.3%; aOR, 1.35; P = .038) and this risk continued up to 90 days after discharge (1.7% vs. 1.0%; aOR, 1.67; P = .007).

The in-hospital stroke rate was numerically higher in patients with ESRD compared with no CKD (aOR, 1.18; P = .62).

The authors point out that previous LAA closure and CKD studies have reported no differences in in-hospital or subsequent stroke/TIA rates in patients with and without CKD. Possible explanations are that patients with CKD in the present study had higher CHA2DS2-VASc scores than those without CKD (4.18 vs. 3.62) and, second, patients with CKD and AFib are known to have higher risk for thromboembolic events than those with AFib without CKD.

CKD patients were also more likely than those without CKD to experience in-hospital acute kidney injury or hemodialysis (aOR, 5.02; P <.001).

CKD has been shown to be independently associated with acute kidney injury (AKI) after LAA closure. AKI may have long-term thromboembolic consequences, the authors suggest, with one study reporting higher stroke risk at midterm follow-up in patients with AKI.

“As with other cardiac interventions in patients with CKD, efforts should be made to optimize preoperative renal function, minimize contrast volume, and avoid abrupt hemodynamic changes such as hypotension during the procedure to prevent AKI,” Dr. Ahuja and colleagues write.

Patients with CKD and ESRD had longer index length of stay than those without CKD but had similar rates of other in-hospital complications, such as systemic embolization, bleeding/transfusion, vascular complications, and pericardial tamponade requiring intervention.

Among the short-term outcomes, 30- and 90-day all-cause readmissions were increased in patients with CKD and ESRD compared with those without CKD, and 30-day bleeding readmissions were increased within the CKD cohort.

“With Watchman and left atrial appendage closure, what we see is that they have higher rates of readmission and other problems,” Dr. Sherwood said. “I think we understand that that’s probably related not to the procedure itself, not because the Watchman doesn’t work for end-stage kidney disease, but because the patients themselves are likely higher risk.”

Commonly used risk scores for atrial fibrillation, however, don’t take into account advanced kidney disease, he added.

Besides the inherent limitations of observational studies, Dr. Sherwood and the authors point to the lack of laboratory variables and procedural variables in the database, the fact that CKD was defined using ICD-10 codes, that outcomes were not clinically adjudicated, that unmeasured confounders likely still exist, and that long-term follow-up is lacking.

Dr. Sherwood, who wrote an editorial accompanying the study, said that the release of outcomes data from CKD and ESRD patients in the major clinical trials would be helpful going forward, as would possible involvement with the Kidney Disease Improving Global Outcomes organization.

“One of the main points of this study is that we just need a lot more research diving into this patient population,” he said.

The authors report no relevant financial relationships. Dr. Sherwood reports honoraria from Janssen and Medtronic. Editorial coauthor Sean Pokorney reports research grant support from Gilead, Boston Scientific, Pfizer, Bristol Myers Squibb, Janssen, and the Food and Drug Administration; and advisory board, consulting, and honoraria supports from Medtronic, Boston Scientific, Pfizer, Bristol Myers Squibb, Philips, and Zoll.

A version of this article first appeared on Medscape.com.

Background

Urinary tract infections (UTIs), one of the most common human bacterial infections, affect approximately 150 million people annually worldwide.^1,2 In the United States, UTIs account for approximately 1% of all outpatient clinic visits and about 2 to 3 million ED visits annually.^1,3-5

Although the urine pH level is frequently assessed in urinalysis, it is rarely considered in the management of a patient with a UTI.

Reports correlating urine pH with urine culture data from ED patients with UTIs are lacking. While poorly studied, there are multiple factors that could potentially alter the urine pH of patients with a UTI, including blood pH, diabetes, dehydration, ketosis, drugs, and renal function, as well as factors related to the infecting microorganism. For instance, Proteus mirabilis produces urease, an enzyme that hydrolyzes urea to ammonia and carbon dioxide.^6-8

Objective

The objective of this study is to assess the relationship between the urine pH and the infecting microbe in ED patients diagnosed with UTIs, and to determine if P mirabilis is associated with alkaline urine.

Methods

We obtained approval from our Institutional Review Board to retrospectively obtain electronic medical record data from patients aged 18 years and older who presented to our institution’s ED and who were diagnosed with either cystitis or a UTI between January 1, 2012 and March 31, 2015. Both urine pH level and a urine culture were obtained for all patients.

The results of all of the patients’ urinary cultures in our study were positive for one bacterial species or genera (≥100,000 CFU/mL). The International Classification of Disease, Ninth Revision/Tenth Revision codes used to identify patients with cystitis and UTI were as follows: 595.0, 595.1, 595.9, 599.0, N30.91, N30.90, N30.80, N30.81, N30.00, N30.01, N30.20, N30.20, and N39.0.

To ensure that the focus of our study was limited to cystitis and UTIs, we excluded patients who were diagnosed with pyelonephritis, sexually transmitted infection, pelvic inflammatory disease, or vaginal discharge. The urine pH values reported from the clinical laboratory were 5.0, 5.5, 6.0, 6.5, 7.0. 7.5, 8.0, 8.5, and 9.0. Our dataset contained 1,331 clinical encounters. We used descriptive statistics and unpaired t-tests to evaluate the associations between urine pH values and the different microbes.

Results

Data were categorized into 16 different bacterial genera or species. Acinetobacter (n = 1), Kluyvera ascorbata (n = 2), and Stenotrophomonas maltophilia (n = 3) were underrepresented in the dataset and therefore were not included in the data analysis. The data are summarized in the Table.

In our dataset, the most common bacteria associated with UTI, irrespective of urine pH, were Escherichia coli (n = 818/1,331; 62%), Klebsiella (n = 167/1,331; 13%), and P mirabilis (n = 88/1,331; 7%). The mean urine pH in our cohort was 6.1 (range, 5.0-9.0; SD, 0.88; median, 6; and mode, 6), and 1,194/1,331 (90%) of all urine samples had a urine pH of 5.0 to 7.0. Among patients who had a urine pH of 7.5 to 9.0, E coli was the cause of UTI in 39% (53/137) and P mirabilis was the cause of UTI in 28% (38/137). Likewise, among patients who had a urine pH of 8.0 to 9.0, E coli was the cause of UTI in 36% (30/83), and P mirabilis was the cause of UTI in 31% (26/83). Lastly, in patients who had a urine pH of 8.5 to 9.0, P mirabilis was the most common cause of UTI, present in 35% (9/26) patients.

The mean urine pH in our dataset for P mirabilis (n = 88) was 7.0, with a standard deviation (SD) of 1.03 and the standard error of the mean (SEM) of 0.11. The majority, 50/88 (57%) of P mirabilis UTIs were associated with a urine pH of 5.0 to 7.0. However, the urine pH for P mirabilis was significantly more alkaline than the combined urine pH from all of the other bacterial genera and species in our cohort (P < .0001). The mean urine pH in our cohort, excluding the P mirabilis data, was 6.01 with an SD of 0.828 and a SEM of 0.023.

Limitations

Our data were obtained retrospectively from a single ED, and did not include the following information: patient age and gender, and mode in which urine samples were obtained (eg, Foley catheter, clean catch). In addition, no reports were available regarding the sensitivity of the urine cultures with respect to urine pH.

Discussion

While alkaline urine was present in only 10% of patients, a high percentage of alkaline UTIs were associated with P mirabilis, an organism with intrinsic resistance to nitrofurantoin. Therefore, health care providers could consider obtaining a urine culture and/or prescribing an antibiotic other than nitrofurantoin for treating uncomplicated UTIs with alkaline urine. In addition, nitrofurantoin has been shown to be less effective against otherwise susceptible organisms in an alkaline urine.⁹

Conclusion

Our data demonstrates that urine pH of UTIs diagnosed in ED patients varied with the associated bacterial pathogen, and thus urine pH potentially could affect ED provider choice of antibiotics for the treatment of UTIs. Additional research is needed to confirm our results from a larger, more diverse dataset before changes in practice are recommended.

Background

Urinary tract infections (UTIs), one of the most common human bacterial infections, affect approximately 150 million people annually worldwide.^1,2 In the United States, UTIs account for approximately 1% of all outpatient clinic visits and about 2 to 3 million ED visits annually.^1,3-5

Although the urine pH level is frequently assessed in urinalysis, it is rarely considered in the management of a patient with a UTI.

Reports correlating urine pH with urine culture data from ED patients with UTIs are lacking. While poorly studied, there are multiple factors that could potentially alter the urine pH of patients with a UTI, including blood pH, diabetes, dehydration, ketosis, drugs, and renal function, as well as factors related to the infecting microorganism. For instance, Proteus mirabilis produces urease, an enzyme that hydrolyzes urea to ammonia and carbon dioxide.^6-8

Objective

The objective of this study is to assess the relationship between the urine pH and the infecting microbe in ED patients diagnosed with UTIs, and to determine if P mirabilis is associated with alkaline urine.

Methods

We obtained approval from our Institutional Review Board to retrospectively obtain electronic medical record data from patients aged 18 years and older who presented to our institution’s ED and who were diagnosed with either cystitis or a UTI between January 1, 2012 and March 31, 2015. Both urine pH level and a urine culture were obtained for all patients.

The results of all of the patients’ urinary cultures in our study were positive for one bacterial species or genera (≥100,000 CFU/mL). The International Classification of Disease, Ninth Revision/Tenth Revision codes used to identify patients with cystitis and UTI were as follows: 595.0, 595.1, 595.9, 599.0, N30.91, N30.90, N30.80, N30.81, N30.00, N30.01, N30.20, N30.20, and N39.0.

To ensure that the focus of our study was limited to cystitis and UTIs, we excluded patients who were diagnosed with pyelonephritis, sexually transmitted infection, pelvic inflammatory disease, or vaginal discharge. The urine pH values reported from the clinical laboratory were 5.0, 5.5, 6.0, 6.5, 7.0. 7.5, 8.0, 8.5, and 9.0. Our dataset contained 1,331 clinical encounters. We used descriptive statistics and unpaired t-tests to evaluate the associations between urine pH values and the different microbes.

Results

Data were categorized into 16 different bacterial genera or species. Acinetobacter (n = 1), Kluyvera ascorbata (n = 2), and Stenotrophomonas maltophilia (n = 3) were underrepresented in the dataset and therefore were not included in the data analysis. The data are summarized in the Table.

In our dataset, the most common bacteria associated with UTI, irrespective of urine pH, were Escherichia coli (n = 818/1,331; 62%), Klebsiella (n = 167/1,331; 13%), and P mirabilis (n = 88/1,331; 7%). The mean urine pH in our cohort was 6.1 (range, 5.0-9.0; SD, 0.88; median, 6; and mode, 6), and 1,194/1,331 (90%) of all urine samples had a urine pH of 5.0 to 7.0. Among patients who had a urine pH of 7.5 to 9.0, E coli was the cause of UTI in 39% (53/137) and P mirabilis was the cause of UTI in 28% (38/137). Likewise, among patients who had a urine pH of 8.0 to 9.0, E coli was the cause of UTI in 36% (30/83), and P mirabilis was the cause of UTI in 31% (26/83). Lastly, in patients who had a urine pH of 8.5 to 9.0, P mirabilis was the most common cause of UTI, present in 35% (9/26) patients.

The mean urine pH in our dataset for P mirabilis (n = 88) was 7.0, with a standard deviation (SD) of 1.03 and the standard error of the mean (SEM) of 0.11. The majority, 50/88 (57%) of P mirabilis UTIs were associated with a urine pH of 5.0 to 7.0. However, the urine pH for P mirabilis was significantly more alkaline than the combined urine pH from all of the other bacterial genera and species in our cohort (P < .0001). The mean urine pH in our cohort, excluding the P mirabilis data, was 6.01 with an SD of 0.828 and a SEM of 0.023.

Limitations

Our data were obtained retrospectively from a single ED, and did not include the following information: patient age and gender, and mode in which urine samples were obtained (eg, Foley catheter, clean catch). In addition, no reports were available regarding the sensitivity of the urine cultures with respect to urine pH.

Discussion

While alkaline urine was present in only 10% of patients, a high percentage of alkaline UTIs were associated with P mirabilis, an organism with intrinsic resistance to nitrofurantoin. Therefore, health care providers could consider obtaining a urine culture and/or prescribing an antibiotic other than nitrofurantoin for treating uncomplicated UTIs with alkaline urine. In addition, nitrofurantoin has been shown to be less effective against otherwise susceptible organisms in an alkaline urine.⁹

Conclusion

Our data demonstrates that urine pH of UTIs diagnosed in ED patients varied with the associated bacterial pathogen, and thus urine pH potentially could affect ED provider choice of antibiotics for the treatment of UTIs. Additional research is needed to confirm our results from a larger, more diverse dataset before changes in practice are recommended.

Background

Urinary tract infections (UTIs), one of the most common human bacterial infections, affect approximately 150 million people annually worldwide.^1,2 In the United States, UTIs account for approximately 1% of all outpatient clinic visits and about 2 to 3 million ED visits annually.^1,3-5

Although the urine pH level is frequently assessed in urinalysis, it is rarely considered in the management of a patient with a UTI.

Reports correlating urine pH with urine culture data from ED patients with UTIs are lacking. While poorly studied, there are multiple factors that could potentially alter the urine pH of patients with a UTI, including blood pH, diabetes, dehydration, ketosis, drugs, and renal function, as well as factors related to the infecting microorganism. For instance, Proteus mirabilis produces urease, an enzyme that hydrolyzes urea to ammonia and carbon dioxide.^6-8

Objective

The objective of this study is to assess the relationship between the urine pH and the infecting microbe in ED patients diagnosed with UTIs, and to determine if P mirabilis is associated with alkaline urine.

Methods

We obtained approval from our Institutional Review Board to retrospectively obtain electronic medical record data from patients aged 18 years and older who presented to our institution’s ED and who were diagnosed with either cystitis or a UTI between January 1, 2012 and March 31, 2015. Both urine pH level and a urine culture were obtained for all patients.

The results of all of the patients’ urinary cultures in our study were positive for one bacterial species or genera (≥100,000 CFU/mL). The International Classification of Disease, Ninth Revision/Tenth Revision codes used to identify patients with cystitis and UTI were as follows: 595.0, 595.1, 595.9, 599.0, N30.91, N30.90, N30.80, N30.81, N30.00, N30.01, N30.20, N30.20, and N39.0.

To ensure that the focus of our study was limited to cystitis and UTIs, we excluded patients who were diagnosed with pyelonephritis, sexually transmitted infection, pelvic inflammatory disease, or vaginal discharge. The urine pH values reported from the clinical laboratory were 5.0, 5.5, 6.0, 6.5, 7.0. 7.5, 8.0, 8.5, and 9.0. Our dataset contained 1,331 clinical encounters. We used descriptive statistics and unpaired t-tests to evaluate the associations between urine pH values and the different microbes.

Results

Data were categorized into 16 different bacterial genera or species. Acinetobacter (n = 1), Kluyvera ascorbata (n = 2), and Stenotrophomonas maltophilia (n = 3) were underrepresented in the dataset and therefore were not included in the data analysis. The data are summarized in the Table.

In our dataset, the most common bacteria associated with UTI, irrespective of urine pH, were Escherichia coli (n = 818/1,331; 62%), Klebsiella (n = 167/1,331; 13%), and P mirabilis (n = 88/1,331; 7%). The mean urine pH in our cohort was 6.1 (range, 5.0-9.0; SD, 0.88; median, 6; and mode, 6), and 1,194/1,331 (90%) of all urine samples had a urine pH of 5.0 to 7.0. Among patients who had a urine pH of 7.5 to 9.0, E coli was the cause of UTI in 39% (53/137) and P mirabilis was the cause of UTI in 28% (38/137). Likewise, among patients who had a urine pH of 8.0 to 9.0, E coli was the cause of UTI in 36% (30/83), and P mirabilis was the cause of UTI in 31% (26/83). Lastly, in patients who had a urine pH of 8.5 to 9.0, P mirabilis was the most common cause of UTI, present in 35% (9/26) patients.

The mean urine pH in our dataset for P mirabilis (n = 88) was 7.0, with a standard deviation (SD) of 1.03 and the standard error of the mean (SEM) of 0.11. The majority, 50/88 (57%) of P mirabilis UTIs were associated with a urine pH of 5.0 to 7.0. However, the urine pH for P mirabilis was significantly more alkaline than the combined urine pH from all of the other bacterial genera and species in our cohort (P < .0001). The mean urine pH in our cohort, excluding the P mirabilis data, was 6.01 with an SD of 0.828 and a SEM of 0.023.

Limitations

Our data were obtained retrospectively from a single ED, and did not include the following information: patient age and gender, and mode in which urine samples were obtained (eg, Foley catheter, clean catch). In addition, no reports were available regarding the sensitivity of the urine cultures with respect to urine pH.

Discussion

While alkaline urine was present in only 10% of patients, a high percentage of alkaline UTIs were associated with P mirabilis, an organism with intrinsic resistance to nitrofurantoin. Therefore, health care providers could consider obtaining a urine culture and/or prescribing an antibiotic other than nitrofurantoin for treating uncomplicated UTIs with alkaline urine. In addition, nitrofurantoin has been shown to be less effective against otherwise susceptible organisms in an alkaline urine.⁹

Conclusion

Our data demonstrates that urine pH of UTIs diagnosed in ED patients varied with the associated bacterial pathogen, and thus urine pH potentially could affect ED provider choice of antibiotics for the treatment of UTIs. Additional research is needed to confirm our results from a larger, more diverse dataset before changes in practice are recommended.

According to the National Institute of Diabetes and Digestive and Kidney Diseases, approximately 468,000 persons in the United States are on dialysis—a number that continues to grow annually.¹ The 1-year rate for hemorrhagic complications from arteriovenous fistulas (AVFs) is estimated to be 0.4%.² One study by Ellingson et al³ reported 1,654 deaths secondary to fatal vascular access hemorrhage over a 6-year period, accounting for 0.4% of all deaths of hemodialysis (HD) patients in that study.³

Nonhemorrhagic vascular access-related complications also contribute to the morbidity and mortality associated with AVFs and arteriovenous grafts (AVGs). Venous stenosis resulting in thrombosis has been estimated to occur in 24.7% of AVGs and 9.0% of AVFs, both of which are common causes of access failure.

Infection is reported to be the second leading cause of death in dialysis patients, and vascular access-related infection rates are reported to occur in 9.5% of AVGs vs 0.4% to 0.9% of AVFs.^2,4 Pseudoaneurysms and aneurysms range from 30% to 60% for AVFs,^2,5 and contribute to morbidity by limiting available areas to cannulate for dialysis, occasionally requiring surgical revision to restore access function or prevent access rupture.

Steal phenomena, including dialysis access-induced steal syndrome (DASS) and ischemic monomelic neuropathy, as well as heart failure secondary to high output are additional contributors to morbidity and mortality.

With the growing rate of end-stage renal disease (ESRD) in the United States and the contribution to morbidity and mortality by bleeding and other complications, it is essential to understand how to evaluate and treat these patients in the ED. This article reviews the evaluation and treatment of vascular access emergencies, as well as risk factors that contribute to complications in the ESRD patient population.

Hemorrhagic Complications of Vascular Access

Risk Factors

Many patients with ESRD have multiple comorbidities such as coronary artery disease and atrial fibrillation that require anticoagulation, antiplatelet medications, or both. Studies have shown that ESRD patients taking warfarin have an increase in major bleeding episodes of 3.1% per person-year and 4.4% per person-year for those taking aspirin alone, while those taking both medications have an increased bleeding risk of 6.3% per person-year.⁶ A recent systematic review by Elliott et al⁷ has suggested a 2-fold increase in bleeding rates in HD patients anticoagulated with warfarin as compared to HD patients not on warfarin.

While uremia secondary to chronic kidney disease (CKD) is a well-known facilitator of bleeding complications, the underlying pathophysiology is not yet completely delineated. However, there are some general underlying principles that may help in understanding the best treatment modalities available at this time. As the kidneys fail, uremic toxins accumulate in the bloodstream. These toxins include urea, creatinine, and phenolic acids, which are believed to interfere with primary hemostasis by effecting platelet adherence to endothelium, platelet activation, and aggregation.⁸ Functional defects are created in the interactions between the glycoprotein Ib (GPIb) receptor and von Willebrand factor (vWF), which are essential to endothelial adhesion of platelets.⁹ Additionally, these toxins impair the up regulation of the GPIIbIIIa receptor which is integral to platelet aggregation.¹⁰ Platelet activation normally leads to platelet aggregation by increasing production of thromboxane A2 (TXA2) and serotonin that are released from storage granules.¹⁰ Some toxins may increase nitric oxide (NO) synthesis, effectively reducing aggregation by decreasing TXA2 and adenosine diphosphate (ADP) levels.¹¹ In addition, elevated levels of fibrinogen fragments have also recently been shown to inhibit platelet function by competing with fibrinogen for the GPIIbIIIa receptor with decreasing levels demonstrated after HD.¹²

Finally, increased pressure in the venous outflow segment also increases persistent bleeding from puncture sites. These pressures may be exaggerated secondary to venous thrombosis, venous stenosis, pseudoaneurysm, aneurysm, or infection.¹³ The following sections further describe the evaluation and treatment of these complications.

Clinical Presentation

Patients presenting with bleeding from the vascular access site may present with slow continuous oozing from the needle puncture-site itself or with life-threatening hemorrhage secondary to AVF or AVG rupture.¹⁴ The incidence of vascular access rupture is unknown, but it appears the majority of ruptures occur in patients with AVG vs AVF.³ However, several case reports have also described hemorrhagic complications of AVF ruptures.^15-17 The risk of rupture may be associated with the development of aneurysms or pseudoaneuryms.¹⁸ Possible impending perforation may be signaled by skin thinning or a shiny appearance overlying the aneurysm, or evidence of infection overlying the access site.³ Many patients were shown to have complications such as stenosis, thrombosis, or infection within 6 months prior to rupture.³ Education of patients is also important as most hemorrhages occur prior to hospital arrival.^3,19

Evaluation in the ED

As with any patient presenting to the ED, the initial evaluation of an unstable patient experiencing bleeding from a vascular access site includes assessing the airway, breathing, and circulation as a first priority—paying special attention to the area of bleeding while simultaneously preparing for possible intervention. It is also important to determine when the patient last underwent dialysis and if he or she was able to complete HD. This information will identify patients who are candidates for reversing the heparin load likely given during dialysis.

It is also important to note that some patients undergoing HD who have already been identified as having an increased risk of bleeding may not receive heparin or may undergo local heparinization, minimal heparinization, or regional citrate anticoagulation during dialysis, in which case protamine is not indicated.¹⁴ The emergency physician (EP) must also determine if the patient is on any antiplatelet or anticoagulation agents.

The vascular access site should be inspected for evidence of aneurysmal changes, infection, and skin thinning as these factors increase the risk of bleeding and vascular rupture. Additionally auscultation and palpation of the vascular access site should be performed to evaluate for other potential complications such as stenosis and thrombosis. Lastly, the EP should anticipate the patient’s need for HD in the setting of a potentially unavailable AVG or AVF to determine whether the patient may need an alternative access.

Treatment and Management

The primary responsibility during the initial treatment of a bleeding access site is to stop further blood loss by utilizing methods that employ direct pressure or, in extreme cases, application of a tourniquet, followed by other interventions such as fluid and blood-product resuscitation; coagulopathy reversal; consideration of desmopressin, cryoprecipitate, tranexamic acid (TXA); HD; and vascular repair.

Control of a bleeding dialysis access-site is a balancing act of adequately controlling the bleeding while maintaining the integrity of the fistula. Overly aggressive management may cause thrombosis in the vascular access site, which is associated with morbidity—eg, site revisions, potential for the need to create a new access site. On the opposite end of the spectrum, failing to adequately control bleeding can lead to significant anemia ranging from minimal symptoms to hemodynamic compromise and death.

Peripheral Venous Access

While peripheral venous access is notoriously difficult in patients with ESRD, it is essential for the resuscitation of hemorrhaging patients. Ideally, two large bore peripheral intravenous (IV) lines should be placed in the proximal upper extremities. If peripheral venous access is not achieved, central venous access or interosseous access placement is indicated (Figure).

Direct Pressure

With low-volume bleeding, the first attempt to control the bleeding is simple direct pressure. Except in the instance of trauma or self-inflicted injury, bleeding usually occurs at the site of cannulation of the vascular access post-HD. Direct pressure should be light and limited to as small of an area as possible to prevent thrombosis; the force and area encompassed by direct pressure can be expanded as needed for bleeding that is more difficult to control. In cases of higher volume bleeding, pressure should be placed both proximally and distally to the shunt due to its bidirectional flow. Another possible temporizing measure is to place an upright gallipot or cup over the bleeding site on top of a folded piece of gauze and then securing it with tape.²¹

Topical Hemostatic Agents

Second simple direct pressure, topical hemostatic agents may be a good adjunct to help obtain hemostasis. There is a wide range of products available, from procoagulants (eg, Combat Gauze, topical thrombin) to factor concentrators (eg, QuikClot). These can be used directly on the bleeding site and only in conjunction with direct pressure.

In addition to topical hemostatic agents, another option is skin glue, which should be applied generously after bleeding has been temporized, with pressure both proximally and distally to the site.

Anticoagulation Reversal

As previously mentioned, it is important to determine when the patient’s last HD was. Heparin is used during dialysis to prevent clotting within the circuit, and although clotting times are monitored during dialysis to guide anticoagulation, it is possible that a patient bleeding after dialysis could still have therapeutic levels of heparin requiring reversal with protamine.

The recommended dose of protamine is 1 mg for every 100 U of heparin given during dialysis; protamine should be administered over 10 minutes. Alternatively, a 10- to 20-mg dose of protamine can be given if the amount of heparin administered during HD is unknown. Additionally, the patient’s medication list, as with any ED presentation, should be carefully reviewed as many dialysis patients have comorbidities requiring anticoagulation with potentially reversible agents.

Hemodialysis to Improve Platelet Dysfunction

It is thought that long-term exposure of platelets to the dialysis membrane can lead to chronic platelet activation leading to platelet dysfunction. There is conflicting data regarding the effects of HD on improving bleeding in renal patients.^9,22,23 Hemodialysis is thought to be beneficial, at least partially, through reversing uremia, thus improving platelet function.²⁴ Therefore, in the stable bleeding patient who missed a scheduled dialysis, initiating HD in the ED setting could be beneficial. If the vascular access site is deemed unsafe for HD, another access site must be obtained, for example, by placing a temporary central venous catheter that will allow for successful HD.

Desmopressin

Desmopressin acetate has been shown to reduce bleeding time in uremic patients by releasing vWF and factor VIII into plasma, taking effect within 1 hour and lasting 4 to 8 hours.^25-27 Desmopressin has also been shown to reduce blood loss and bleeding times in patients with platelet dysfunction undergoing cardiac surgery.²⁸ While the underlying mechanism is unclear, desmopressin acetate is thought to help with platelet adhesion to the endothelial wall.

Alternatively, one study by Soslau et al²⁹ has suggested that desmopressin may increase serotonin uptake by platelets and increase adenosine triphosphate release, thereby facilitating platelet aggregation. The dosing of desmopressin is 0.2 to 0.3 mcg/kg IV.³⁰ Adverse effects include facial flushing, mild headache, and transient small decrease in blood pressure (BP) with increase in heart rate. Historically, it was thought that desmopressin could lead to water retention, volume overload, congestive heart failure, and hyponatremia; however, these adverse effects have not been seen in uremic patients.³⁰ Tachyphylaxis may occur after just a few doses of desmopressin are given.³¹ Additionally, hyponatremia and seizures have been seen after repeated administration in children.³¹

Anemia and Low Hematocrit

As mentioned earlier, anemia and low hematocrit (HCT) may actually exacerbate bleeding tendencies by decreasing the number of platelets exposed to the vessel wall. Red blood cells (RBCs) also produce TXA2 and ADP, both of which play vital roles in normal platelet aggregation. Secondly, RBCs have been shown to increase NO uptake. Nitric oxide is a potent vasodilator and inhibitor of platelet aggregation. The degree of uptake appears to be augmented by increasing HCT levels.³² A goal HCT of greater than 30% has been suggested and demonstrated benefit.³³

Cryoprecipitate

Cryoprecipitate is rich in fibrinogen and vWF. Its mechanism is thought to be secondary to increasing functional vWF levels and possibly fibrinogen levels. While the overall effects appear to be variable, studies suggest 10 U of cryoprecipitate is adequate to reverse significant bleeding with resolution of effect at 24 hours.^34,35 Given the risks of adverse reactions, variable responses, and risks of hepatitis C and HIV transmission, this therapy must be used cautiously with risk-benefit analysis.

Tranexamic Acid

Tranexamic acid is an antifibrinolytic agent that binds to fibrinogen as a competitive inhibitor of plasmin, inhibiting plasminogen activation. The trauma literature has shown TXA to significantly reduce all-cause mortality.³⁶ It has also been shown to be beneficial in the bleeding uremic patient.^37-39

However, it is important to keep in mind that the clearance of TXA in patients with renal disease is unclear. One study by Andersson et al⁴⁰ demonstrated that TXA has increased plasma concentrations in patients with renal impairment, and a generally accepted practice is to renal-dose this medication. This study recommended a dose of 10 mg/kg IV at varying intervals, such as once daily, twice daily, or every 48 hours depending on the creatinine value, compared to patients with no renal impairment.⁴⁰ Another study by Sabovic et al³⁹ that evaluated the effects of TXA on gastrointestinal bleeding in patients with renal impairment used a 20-mg IV loading dose of TXA followed by 10 mg/kg orally every 48 hours. Though no adverse events occurred in this study, the study group was small. Other studies have not shown an increase in thromboembolic risk in patients who have no renal disease.^36,41

At this time, there is no consensus on the exact dosing of TXA in this patient population. Therefore, this therapy should only be considered if others have failed and the patient continues to have significant blood loss.

Life-threatening Hemorrhage

If a patient is experiencing life-threatening blood loss, more aggressive measures must be employed regardless of risk of damage to the access. In such cases, a consultation with vascular surgery services should be obtained as early as possible. If none of the previously discussed measures are ineffective, the EP may be required to place sutures in the vascular access itself or apply a tourniquet. Again, these interventions may cause permanent damage to the access; however, in the setting of life-threatening hemorrhage such interventions clearly outweigh the risks associated with continued blood loss.

As blood can flow bidirectionally within a fistula, a tourniquet should be placed both proximally and distally to the fistula to obtain adequate hemostasis. Once the tourniquets are in place, if there is no immediate surgical consultation available, the EP may need to temporarily repair the defect to allow minimal tourniquet time. There are a few considerations when placing sutures. Ideally, a noncutting needle should be used to minimize damage. An adequate-sized suture, such as a 3-0 nylon suture, should be used to maintain strength in the high-pressure system. A figure-8 suture or purse-string suture may be placed around the defect. Adequate repair should allow for tourniquet removal.

Hemodynamic Status

The EP must remain aware of the patient’s hemodynamic status. Massive transfusion protocols may need to be initiated. Best current evidence dictates that this should be done in a 1:1:1 ratio of packed red blood cells, platelets, and fresh frozen plasma respectively.⁴² In our experience, the EP should consider permissive hypotension as aggressive resuscitation and increasing BP can compromise the vascular repair.

Lastly, transfer for definitive management should be arranged if not available at the EP’s institution. The patient should travel with tourniquets in place (although not tightened) in the event of further bleeding.

Nonhemorrhagic Complications of AVF or AVG

Stenosis/Thrombosis

Prolonged bleeding from the cannulation site may suggest outflow stenosis.⁴³ Stenosis with or without subsequent thrombosis is a common cause of vascular access failure. Access failure has also been implicated secondary to poor vascular mapping, resulting in undetected pre-existing stenosis of the inflow artery, outflow vein, or juxta-anastomosis. However, development of stenosis may occur at any time throughout the life of the vascular access. One study by Schild et al⁴ reported thrombosis rates of 24.7% for grafts and 9.0% for fistula. Additionally, AVGs have a higher reported stenosis rate than AVFs, which is a risk factor for thrombosis.^44,45

There has been much debate regarding routine surveillance to prevent clinically significant stenosis with subsequent thrombosis. Surveillance includes a clinical examination, Doppler imaging studies, and flow measurements during dialysis. A recent systematic review from 2016 by Ravani et al,⁴⁶ demonstrated no difference in risk of access loss in preemptive stenosis correction in AVF or AVG without evidence of access dysfunction. However, on subgroup analysis this review did demonstrate a small benefit regarding risk of thrombosis and access loss in the AVF group.⁴⁶

The physical examination may indicate evidence of vascular access stenosis or thrombosis. Evidence of stenosis may be indicated by failure of the outflow vein to collapse on arm raise test (distal stenosis), hyperpulsatility or hypopulsatility, loss of the diastolic component of the normal continuous thrill and bruit with only systolic components appreciated, and arm edema (central vein stenosis).^43,47 Thrombosis of the vein may be evidenced by complete loss of the thrill and pulsatility on palpation. Sensitivity and specificity of the physical examination for inflow or outflow stenosis has been reported to be between 70% to 92% and 71% to 100%, respectively.^48-50

While evidence may or may not support preemptive correction of stenosis, interventions are usually required when the stenosis is more than 50% and interferes with dialysis, decreased flow, abnormal physical examination, or elevated venous pressures.⁵¹ If stenosis is associated with interference of effective dialysis or thrombosis is suspected, ultrasound imaging and consultation with a vascular surgeon or interventional radiologist are indicated. Treatment of AVF or AVG stenosis and thrombosis includes percutaneous and surgical interventions.⁵²

A systematic review by Tanner and da Silva⁵³ evaluating adjuvant medical treatments for increasing patency rates of AVF and AVG found no therapy had any improvement in patency rates at 1 month. Another review from 2015 by Palmer et al⁵⁴ suggested antiplatelet therapy may be protective for stenosis and thrombosis in AVF, but not AVG.

Infection

Infection in patients with ESRD is a major cause of morbidity and mortality, and 24% of these infections may be attributed to the vascular access itself, including central venous catheters (CVC).⁵⁵ Central venous catheters are associated with the highest rate of infection, followed by AVGs, then AVFs.^4,54 Studies have reported 9.5% vs 0.4% to 0.9% infection rates for AVG and AVF, respectively.^2,4 These infections are usually due to gram-positive organisms, with the Staphylococcus species being the most common organism involved.^55-57 However, infections caused by gram-negative organisms are possible, and broad-spectrum antibiotics should be initiated in the ED if infection is suspected. Patients may present with localized infection with increased risk of rupture of access to profound sepsis. Definitive treatment of an infected graft or fistula usually requires removal of the infected access or at least partial excision with possible interposition of additional graft material.⁵⁸

Pseudoaneurysm/Aneurysm

Pseudoaneuryms are usually caused by hematoma development after needle puncture or in juxta-anastomic segments postoperatively. Pseudoaneurysms do not have a true wall and may secondarily become infected.⁵⁹ Pseudoaneurysms occur more frequently in AVG, and are usually reported along with true aneurysms. One study by Al-Thani et al⁶⁰ detected pseudoaneurysms in 15% of clinically significant aneurysms.

Approximately 30% to 60% of patients with AVFs will develop an aneurysm.^2,5 One study by Al-Thani et al⁶⁰ reported the need for surgical intervention in 31% of patients with an AVF in whom an aneurysm was detected. The risk for developing an aneurysm is highest for those patients on high flux membrane type HD and polycystic kidney disease.⁵ As discussed earlier in this article, cannulation sites and techniques may also influence aneurysmal changes in the fistula. Aneurysm formation at the site of previous cannulation site should not be re-cannulated.¹⁸ Aneurysmal changes can contribute to other complications including high-output heart failure, thrombosis with fistula or graft failure, increased risk of bleeding, ineffective HD when associated with thrombosis or stenosis, pain and peripheral neuropathies secondary to compression of nearby nerves, and interference with functional HD.

Many asymptomatic aneurysmal changes to vascular access may not compromise access function. If a patient is identified with a vascular access pseudoaneurysm or aneurysmal changes with high-risk features, early referral to vascular surgeon for surgical interventions is imperative. High-risk features include any of the complications previously discussed—infection, threatened overlying skin, or shiny appearance. The EP should consider duplex imaging to assist with evaluation. Treatment may include ligation of the AVF, partial resection, stenting, or grafting of the aneurysm with hopes of salvaging the vascular access.^61,62

Ischemic Monomelic Neuropathy

Ischemic monomelic neuropathy may result secondary to a type of steal phenomenon, thereby inducing ischemia to supplied nerves. Ischemic monomelic neuropathy has been described in many case reports and narrative reviews.^63-67 It has been described as ischemia or infarction of the blood supply to the nerves (vasa nervosa) in the lower arm.⁶⁸ Ischemic monomelic neuropathy typically occurs immediately after the vascular access creation in the postoperative period. Therefore, it is unlikely to be seen in the ED but as patients may have sequelae of this complication, EPs should be aware of its existence. Patients with ischemic monomelic neuropathy will have severe pain, paresthesia, and weakness immediately after placement of a vascular access. Patients also typically have sensorimotor deficits in the radial, ulnar, and median nerves. Pulses should be preserved. Severe neuropathic pain will develop and may limit the examination. Clinical diagnosis may be difficult immediately after surgery because patients will often have minor deficits secondary to the surgical procedure itself or secondary to the regional block provided by anesthesia, but nerve-conduction studies usually reveal the diagnosis. The treatment is ligation of the access immediately and prognosis is variable, depending on the severity and duration of ischemia, and may result in complete loss of function of the hand.

Steal Syndrome

Dialysis access-associated steal syndrome is a type of distal ischemia secondary to the vascular access site with a reported incidence of 6.2%, and appears to occur more frequently in AVF than AVGs.^69,70 Diabetes appears to be a strong risk factor for developing DASS.⁷¹ Patients with DASS can present with classic ischemic symptoms such as pain, paresthesia, claudication, pallor, and diminished or absent arterial pulse. Pain may be present only while undergoing dialysis or exercising, or symptoms may be persistent.^68,72 There are several possible causes of DASS, including arterial occlusion or insufficiency proximal or distal to the anastomosis, increased flow through the conduit (true steal), or increased flow diverted through collateral vessels.^73,74 One clue to the diagnosis is a diminished or absent radial pulse that should improve with compression of the access site.

Once DASS is suspected, diagnosis should be confirmed using venous duplex scanning with finger pressure waveform analysis or arteriogram. Definitive management is surgical intervention with ligation of the access or banding.

High-Output Heart Failure

Changes in cardiac output (CO) are a well-documented effect of AVF placement, with one small study by Korsheed et al⁷⁵ demonstrating an average increase in CO of 17% only 2 weeks after AVF placement. The increase in CO is thought to be secondary to alterations in systemic vascular resistance and sympathetic activity. While an increase in CO can ultimately lead to high-output heart failure, this is typically only seen in patients with pre-existing cardiac dysfunction.⁷⁶ Patients are at an increased risk of high-output heart failure when flow through the AVF exceeds 2 L/min; flows below this rate are typically not associated with adverse cardiac effects.⁷⁷ Another objective measurement for identifying patients at risk of high-output heart failure is the ratio of flow in the fistula (Qa) to cardiac output ratio. Patients with a Qa:CO ratio greater than 0.3 have a significantly increased risk of high-output heart failure.⁷⁸ There is thought to be no difference in risk of heart failure between AVF and AVG.⁷⁹

Once overt heart failure has developed, it should be treated in the usual fashion, with IV fluid management and standard pharmacological therapies. If standard conservative heart failure treatment is ineffective, several surgical options are available, including banding, changing the location of the anastomosis, and ultimately closing the fistula.⁸⁰

Conclusion

While life-threatening bleeding and vascular access rupture are uncommon complications of AVFs and AVGs, it is essential for the EP to rapidly treat the potentially catastrophic hemorrhagic vascular access complications. Depending on the severity and stability of the patient, it is reasonable to begin in a stepwise fashion as presented in this article for patients with minor bleeding, while more severe or persistent bleeding may require several interventions simultaneously to gain control of the bleeding.

Patients with hemodynamic instability requiring transfusion will need a vascular surgery consult and admission. Disposition for stable patients, without evidence of impending aneurysmal related rupture and concern for overlying infection or other complication requiring immediate intervention, will depend on clinical judgment, patient-specific factors and family support, follow-up, and proximity of the patient to medical care.

According to the National Institute of Diabetes and Digestive and Kidney Diseases, approximately 468,000 persons in the United States are on dialysis—a number that continues to grow annually.¹ The 1-year rate for hemorrhagic complications from arteriovenous fistulas (AVFs) is estimated to be 0.4%.² One study by Ellingson et al³ reported 1,654 deaths secondary to fatal vascular access hemorrhage over a 6-year period, accounting for 0.4% of all deaths of hemodialysis (HD) patients in that study.³

Nonhemorrhagic vascular access-related complications also contribute to the morbidity and mortality associated with AVFs and arteriovenous grafts (AVGs). Venous stenosis resulting in thrombosis has been estimated to occur in 24.7% of AVGs and 9.0% of AVFs, both of which are common causes of access failure.

Infection is reported to be the second leading cause of death in dialysis patients, and vascular access-related infection rates are reported to occur in 9.5% of AVGs vs 0.4% to 0.9% of AVFs.^2,4 Pseudoaneurysms and aneurysms range from 30% to 60% for AVFs,^2,5 and contribute to morbidity by limiting available areas to cannulate for dialysis, occasionally requiring surgical revision to restore access function or prevent access rupture.

Steal phenomena, including dialysis access-induced steal syndrome (DASS) and ischemic monomelic neuropathy, as well as heart failure secondary to high output are additional contributors to morbidity and mortality.

With the growing rate of end-stage renal disease (ESRD) in the United States and the contribution to morbidity and mortality by bleeding and other complications, it is essential to understand how to evaluate and treat these patients in the ED. This article reviews the evaluation and treatment of vascular access emergencies, as well as risk factors that contribute to complications in the ESRD patient population.

Hemorrhagic Complications of Vascular Access

Risk Factors

Many patients with ESRD have multiple comorbidities such as coronary artery disease and atrial fibrillation that require anticoagulation, antiplatelet medications, or both. Studies have shown that ESRD patients taking warfarin have an increase in major bleeding episodes of 3.1% per person-year and 4.4% per person-year for those taking aspirin alone, while those taking both medications have an increased bleeding risk of 6.3% per person-year.⁶ A recent systematic review by Elliott et al⁷ has suggested a 2-fold increase in bleeding rates in HD patients anticoagulated with warfarin as compared to HD patients not on warfarin.

While uremia secondary to chronic kidney disease (CKD) is a well-known facilitator of bleeding complications, the underlying pathophysiology is not yet completely delineated. However, there are some general underlying principles that may help in understanding the best treatment modalities available at this time. As the kidneys fail, uremic toxins accumulate in the bloodstream. These toxins include urea, creatinine, and phenolic acids, which are believed to interfere with primary hemostasis by effecting platelet adherence to endothelium, platelet activation, and aggregation.⁸ Functional defects are created in the interactions between the glycoprotein Ib (GPIb) receptor and von Willebrand factor (vWF), which are essential to endothelial adhesion of platelets.⁹ Additionally, these toxins impair the up regulation of the GPIIbIIIa receptor which is integral to platelet aggregation.¹⁰ Platelet activation normally leads to platelet aggregation by increasing production of thromboxane A2 (TXA2) and serotonin that are released from storage granules.¹⁰ Some toxins may increase nitric oxide (NO) synthesis, effectively reducing aggregation by decreasing TXA2 and adenosine diphosphate (ADP) levels.¹¹ In addition, elevated levels of fibrinogen fragments have also recently been shown to inhibit platelet function by competing with fibrinogen for the GPIIbIIIa receptor with decreasing levels demonstrated after HD.¹²

Finally, increased pressure in the venous outflow segment also increases persistent bleeding from puncture sites. These pressures may be exaggerated secondary to venous thrombosis, venous stenosis, pseudoaneurysm, aneurysm, or infection.¹³ The following sections further describe the evaluation and treatment of these complications.

Clinical Presentation

Patients presenting with bleeding from the vascular access site may present with slow continuous oozing from the needle puncture-site itself or with life-threatening hemorrhage secondary to AVF or AVG rupture.¹⁴ The incidence of vascular access rupture is unknown, but it appears the majority of ruptures occur in patients with AVG vs AVF.³ However, several case reports have also described hemorrhagic complications of AVF ruptures.^15-17 The risk of rupture may be associated with the development of aneurysms or pseudoaneuryms.¹⁸ Possible impending perforation may be signaled by skin thinning or a shiny appearance overlying the aneurysm, or evidence of infection overlying the access site.³ Many patients were shown to have complications such as stenosis, thrombosis, or infection within 6 months prior to rupture.³ Education of patients is also important as most hemorrhages occur prior to hospital arrival.^3,19

Evaluation in the ED

As with any patient presenting to the ED, the initial evaluation of an unstable patient experiencing bleeding from a vascular access site includes assessing the airway, breathing, and circulation as a first priority—paying special attention to the area of bleeding while simultaneously preparing for possible intervention. It is also important to determine when the patient last underwent dialysis and if he or she was able to complete HD. This information will identify patients who are candidates for reversing the heparin load likely given during dialysis.

It is also important to note that some patients undergoing HD who have already been identified as having an increased risk of bleeding may not receive heparin or may undergo local heparinization, minimal heparinization, or regional citrate anticoagulation during dialysis, in which case protamine is not indicated.¹⁴ The emergency physician (EP) must also determine if the patient is on any antiplatelet or anticoagulation agents.

The vascular access site should be inspected for evidence of aneurysmal changes, infection, and skin thinning as these factors increase the risk of bleeding and vascular rupture. Additionally auscultation and palpation of the vascular access site should be performed to evaluate for other potential complications such as stenosis and thrombosis. Lastly, the EP should anticipate the patient’s need for HD in the setting of a potentially unavailable AVG or AVF to determine whether the patient may need an alternative access.

Treatment and Management

The primary responsibility during the initial treatment of a bleeding access site is to stop further blood loss by utilizing methods that employ direct pressure or, in extreme cases, application of a tourniquet, followed by other interventions such as fluid and blood-product resuscitation; coagulopathy reversal; consideration of desmopressin, cryoprecipitate, tranexamic acid (TXA); HD; and vascular repair.

Control of a bleeding dialysis access-site is a balancing act of adequately controlling the bleeding while maintaining the integrity of the fistula. Overly aggressive management may cause thrombosis in the vascular access site, which is associated with morbidity—eg, site revisions, potential for the need to create a new access site. On the opposite end of the spectrum, failing to adequately control bleeding can lead to significant anemia ranging from minimal symptoms to hemodynamic compromise and death.

Peripheral Venous Access

While peripheral venous access is notoriously difficult in patients with ESRD, it is essential for the resuscitation of hemorrhaging patients. Ideally, two large bore peripheral intravenous (IV) lines should be placed in the proximal upper extremities. If peripheral venous access is not achieved, central venous access or interosseous access placement is indicated (Figure).

Direct Pressure

With low-volume bleeding, the first attempt to control the bleeding is simple direct pressure. Except in the instance of trauma or self-inflicted injury, bleeding usually occurs at the site of cannulation of the vascular access post-HD. Direct pressure should be light and limited to as small of an area as possible to prevent thrombosis; the force and area encompassed by direct pressure can be expanded as needed for bleeding that is more difficult to control. In cases of higher volume bleeding, pressure should be placed both proximally and distally to the shunt due to its bidirectional flow. Another possible temporizing measure is to place an upright gallipot or cup over the bleeding site on top of a folded piece of gauze and then securing it with tape.²¹

Topical Hemostatic Agents

Second simple direct pressure, topical hemostatic agents may be a good adjunct to help obtain hemostasis. There is a wide range of products available, from procoagulants (eg, Combat Gauze, topical thrombin) to factor concentrators (eg, QuikClot). These can be used directly on the bleeding site and only in conjunction with direct pressure.

In addition to topical hemostatic agents, another option is skin glue, which should be applied generously after bleeding has been temporized, with pressure both proximally and distally to the site.

Anticoagulation Reversal

As previously mentioned, it is important to determine when the patient’s last HD was. Heparin is used during dialysis to prevent clotting within the circuit, and although clotting times are monitored during dialysis to guide anticoagulation, it is possible that a patient bleeding after dialysis could still have therapeutic levels of heparin requiring reversal with protamine.

The recommended dose of protamine is 1 mg for every 100 U of heparin given during dialysis; protamine should be administered over 10 minutes. Alternatively, a 10- to 20-mg dose of protamine can be given if the amount of heparin administered during HD is unknown. Additionally, the patient’s medication list, as with any ED presentation, should be carefully reviewed as many dialysis patients have comorbidities requiring anticoagulation with potentially reversible agents.

Hemodialysis to Improve Platelet Dysfunction

It is thought that long-term exposure of platelets to the dialysis membrane can lead to chronic platelet activation leading to platelet dysfunction. There is conflicting data regarding the effects of HD on improving bleeding in renal patients.^9,22,23 Hemodialysis is thought to be beneficial, at least partially, through reversing uremia, thus improving platelet function.²⁴ Therefore, in the stable bleeding patient who missed a scheduled dialysis, initiating HD in the ED setting could be beneficial. If the vascular access site is deemed unsafe for HD, another access site must be obtained, for example, by placing a temporary central venous catheter that will allow for successful HD.

Desmopressin

Desmopressin acetate has been shown to reduce bleeding time in uremic patients by releasing vWF and factor VIII into plasma, taking effect within 1 hour and lasting 4 to 8 hours.^25-27 Desmopressin has also been shown to reduce blood loss and bleeding times in patients with platelet dysfunction undergoing cardiac surgery.²⁸ While the underlying mechanism is unclear, desmopressin acetate is thought to help with platelet adhesion to the endothelial wall.

Alternatively, one study by Soslau et al²⁹ has suggested that desmopressin may increase serotonin uptake by platelets and increase adenosine triphosphate release, thereby facilitating platelet aggregation. The dosing of desmopressin is 0.2 to 0.3 mcg/kg IV.³⁰ Adverse effects include facial flushing, mild headache, and transient small decrease in blood pressure (BP) with increase in heart rate. Historically, it was thought that desmopressin could lead to water retention, volume overload, congestive heart failure, and hyponatremia; however, these adverse effects have not been seen in uremic patients.³⁰ Tachyphylaxis may occur after just a few doses of desmopressin are given.³¹ Additionally, hyponatremia and seizures have been seen after repeated administration in children.³¹

Anemia and Low Hematocrit

As mentioned earlier, anemia and low hematocrit (HCT) may actually exacerbate bleeding tendencies by decreasing the number of platelets exposed to the vessel wall. Red blood cells (RBCs) also produce TXA2 and ADP, both of which play vital roles in normal platelet aggregation. Secondly, RBCs have been shown to increase NO uptake. Nitric oxide is a potent vasodilator and inhibitor of platelet aggregation. The degree of uptake appears to be augmented by increasing HCT levels.³² A goal HCT of greater than 30% has been suggested and demonstrated benefit.³³

Cryoprecipitate

Cryoprecipitate is rich in fibrinogen and vWF. Its mechanism is thought to be secondary to increasing functional vWF levels and possibly fibrinogen levels. While the overall effects appear to be variable, studies suggest 10 U of cryoprecipitate is adequate to reverse significant bleeding with resolution of effect at 24 hours.^34,35 Given the risks of adverse reactions, variable responses, and risks of hepatitis C and HIV transmission, this therapy must be used cautiously with risk-benefit analysis.

Tranexamic Acid

Tranexamic acid is an antifibrinolytic agent that binds to fibrinogen as a competitive inhibitor of plasmin, inhibiting plasminogen activation. The trauma literature has shown TXA to significantly reduce all-cause mortality.³⁶ It has also been shown to be beneficial in the bleeding uremic patient.^37-39

However, it is important to keep in mind that the clearance of TXA in patients with renal disease is unclear. One study by Andersson et al⁴⁰ demonstrated that TXA has increased plasma concentrations in patients with renal impairment, and a generally accepted practice is to renal-dose this medication. This study recommended a dose of 10 mg/kg IV at varying intervals, such as once daily, twice daily, or every 48 hours depending on the creatinine value, compared to patients with no renal impairment.⁴⁰ Another study by Sabovic et al³⁹ that evaluated the effects of TXA on gastrointestinal bleeding in patients with renal impairment used a 20-mg IV loading dose of TXA followed by 10 mg/kg orally every 48 hours. Though no adverse events occurred in this study, the study group was small. Other studies have not shown an increase in thromboembolic risk in patients who have no renal disease.^36,41

At this time, there is no consensus on the exact dosing of TXA in this patient population. Therefore, this therapy should only be considered if others have failed and the patient continues to have significant blood loss.

Life-threatening Hemorrhage

If a patient is experiencing life-threatening blood loss, more aggressive measures must be employed regardless of risk of damage to the access. In such cases, a consultation with vascular surgery services should be obtained as early as possible. If none of the previously discussed measures are ineffective, the EP may be required to place sutures in the vascular access itself or apply a tourniquet. Again, these interventions may cause permanent damage to the access; however, in the setting of life-threatening hemorrhage such interventions clearly outweigh the risks associated with continued blood loss.

As blood can flow bidirectionally within a fistula, a tourniquet should be placed both proximally and distally to the fistula to obtain adequate hemostasis. Once the tourniquets are in place, if there is no immediate surgical consultation available, the EP may need to temporarily repair the defect to allow minimal tourniquet time. There are a few considerations when placing sutures. Ideally, a noncutting needle should be used to minimize damage. An adequate-sized suture, such as a 3-0 nylon suture, should be used to maintain strength in the high-pressure system. A figure-8 suture or purse-string suture may be placed around the defect. Adequate repair should allow for tourniquet removal.

Hemodynamic Status

The EP must remain aware of the patient’s hemodynamic status. Massive transfusion protocols may need to be initiated. Best current evidence dictates that this should be done in a 1:1:1 ratio of packed red blood cells, platelets, and fresh frozen plasma respectively.⁴² In our experience, the EP should consider permissive hypotension as aggressive resuscitation and increasing BP can compromise the vascular repair.

Lastly, transfer for definitive management should be arranged if not available at the EP’s institution. The patient should travel with tourniquets in place (although not tightened) in the event of further bleeding.

Nonhemorrhagic Complications of AVF or AVG

Stenosis/Thrombosis

Prolonged bleeding from the cannulation site may suggest outflow stenosis.⁴³ Stenosis with or without subsequent thrombosis is a common cause of vascular access failure. Access failure has also been implicated secondary to poor vascular mapping, resulting in undetected pre-existing stenosis of the inflow artery, outflow vein, or juxta-anastomosis. However, development of stenosis may occur at any time throughout the life of the vascular access. One study by Schild et al⁴ reported thrombosis rates of 24.7% for grafts and 9.0% for fistula. Additionally, AVGs have a higher reported stenosis rate than AVFs, which is a risk factor for thrombosis.^44,45

There has been much debate regarding routine surveillance to prevent clinically significant stenosis with subsequent thrombosis. Surveillance includes a clinical examination, Doppler imaging studies, and flow measurements during dialysis. A recent systematic review from 2016 by Ravani et al,⁴⁶ demonstrated no difference in risk of access loss in preemptive stenosis correction in AVF or AVG without evidence of access dysfunction. However, on subgroup analysis this review did demonstrate a small benefit regarding risk of thrombosis and access loss in the AVF group.⁴⁶

The physical examination may indicate evidence of vascular access stenosis or thrombosis. Evidence of stenosis may be indicated by failure of the outflow vein to collapse on arm raise test (distal stenosis), hyperpulsatility or hypopulsatility, loss of the diastolic component of the normal continuous thrill and bruit with only systolic components appreciated, and arm edema (central vein stenosis).^43,47 Thrombosis of the vein may be evidenced by complete loss of the thrill and pulsatility on palpation. Sensitivity and specificity of the physical examination for inflow or outflow stenosis has been reported to be between 70% to 92% and 71% to 100%, respectively.^48-50

While evidence may or may not support preemptive correction of stenosis, interventions are usually required when the stenosis is more than 50% and interferes with dialysis, decreased flow, abnormal physical examination, or elevated venous pressures.⁵¹ If stenosis is associated with interference of effective dialysis or thrombosis is suspected, ultrasound imaging and consultation with a vascular surgeon or interventional radiologist are indicated. Treatment of AVF or AVG stenosis and thrombosis includes percutaneous and surgical interventions.⁵²

A systematic review by Tanner and da Silva⁵³ evaluating adjuvant medical treatments for increasing patency rates of AVF and AVG found no therapy had any improvement in patency rates at 1 month. Another review from 2015 by Palmer et al⁵⁴ suggested antiplatelet therapy may be protective for stenosis and thrombosis in AVF, but not AVG.

Infection

Infection in patients with ESRD is a major cause of morbidity and mortality, and 24% of these infections may be attributed to the vascular access itself, including central venous catheters (CVC).⁵⁵ Central venous catheters are associated with the highest rate of infection, followed by AVGs, then AVFs.^4,54 Studies have reported 9.5% vs 0.4% to 0.9% infection rates for AVG and AVF, respectively.^2,4 These infections are usually due to gram-positive organisms, with the Staphylococcus species being the most common organism involved.^55-57 However, infections caused by gram-negative organisms are possible, and broad-spectrum antibiotics should be initiated in the ED if infection is suspected. Patients may present with localized infection with increased risk of rupture of access to profound sepsis. Definitive treatment of an infected graft or fistula usually requires removal of the infected access or at least partial excision with possible interposition of additional graft material.⁵⁸

Pseudoaneurysm/Aneurysm

Pseudoaneuryms are usually caused by hematoma development after needle puncture or in juxta-anastomic segments postoperatively. Pseudoaneurysms do not have a true wall and may secondarily become infected.⁵⁹ Pseudoaneurysms occur more frequently in AVG, and are usually reported along with true aneurysms. One study by Al-Thani et al⁶⁰ detected pseudoaneurysms in 15% of clinically significant aneurysms.

Approximately 30% to 60% of patients with AVFs will develop an aneurysm.^2,5 One study by Al-Thani et al⁶⁰ reported the need for surgical intervention in 31% of patients with an AVF in whom an aneurysm was detected. The risk for developing an aneurysm is highest for those patients on high flux membrane type HD and polycystic kidney disease.⁵ As discussed earlier in this article, cannulation sites and techniques may also influence aneurysmal changes in the fistula. Aneurysm formation at the site of previous cannulation site should not be re-cannulated.¹⁸ Aneurysmal changes can contribute to other complications including high-output heart failure, thrombosis with fistula or graft failure, increased risk of bleeding, ineffective HD when associated with thrombosis or stenosis, pain and peripheral neuropathies secondary to compression of nearby nerves, and interference with functional HD.

Many asymptomatic aneurysmal changes to vascular access may not compromise access function. If a patient is identified with a vascular access pseudoaneurysm or aneurysmal changes with high-risk features, early referral to vascular surgeon for surgical interventions is imperative. High-risk features include any of the complications previously discussed—infection, threatened overlying skin, or shiny appearance. The EP should consider duplex imaging to assist with evaluation. Treatment may include ligation of the AVF, partial resection, stenting, or grafting of the aneurysm with hopes of salvaging the vascular access.^61,62

Ischemic Monomelic Neuropathy

Ischemic monomelic neuropathy may result secondary to a type of steal phenomenon, thereby inducing ischemia to supplied nerves. Ischemic monomelic neuropathy has been described in many case reports and narrative reviews.^63-67 It has been described as ischemia or infarction of the blood supply to the nerves (vasa nervosa) in the lower arm.⁶⁸ Ischemic monomelic neuropathy typically occurs immediately after the vascular access creation in the postoperative period. Therefore, it is unlikely to be seen in the ED but as patients may have sequelae of this complication, EPs should be aware of its existence. Patients with ischemic monomelic neuropathy will have severe pain, paresthesia, and weakness immediately after placement of a vascular access. Patients also typically have sensorimotor deficits in the radial, ulnar, and median nerves. Pulses should be preserved. Severe neuropathic pain will develop and may limit the examination. Clinical diagnosis may be difficult immediately after surgery because patients will often have minor deficits secondary to the surgical procedure itself or secondary to the regional block provided by anesthesia, but nerve-conduction studies usually reveal the diagnosis. The treatment is ligation of the access immediately and prognosis is variable, depending on the severity and duration of ischemia, and may result in complete loss of function of the hand.

Steal Syndrome

Dialysis access-associated steal syndrome is a type of distal ischemia secondary to the vascular access site with a reported incidence of 6.2%, and appears to occur more frequently in AVF than AVGs.^69,70 Diabetes appears to be a strong risk factor for developing DASS.⁷¹ Patients with DASS can present with classic ischemic symptoms such as pain, paresthesia, claudication, pallor, and diminished or absent arterial pulse. Pain may be present only while undergoing dialysis or exercising, or symptoms may be persistent.^68,72 There are several possible causes of DASS, including arterial occlusion or insufficiency proximal or distal to the anastomosis, increased flow through the conduit (true steal), or increased flow diverted through collateral vessels.^73,74 One clue to the diagnosis is a diminished or absent radial pulse that should improve with compression of the access site.

Once DASS is suspected, diagnosis should be confirmed using venous duplex scanning with finger pressure waveform analysis or arteriogram. Definitive management is surgical intervention with ligation of the access or banding.

High-Output Heart Failure

Changes in cardiac output (CO) are a well-documented effect of AVF placement, with one small study by Korsheed et al⁷⁵ demonstrating an average increase in CO of 17% only 2 weeks after AVF placement. The increase in CO is thought to be secondary to alterations in systemic vascular resistance and sympathetic activity. While an increase in CO can ultimately lead to high-output heart failure, this is typically only seen in patients with pre-existing cardiac dysfunction.⁷⁶ Patients are at an increased risk of high-output heart failure when flow through the AVF exceeds 2 L/min; flows below this rate are typically not associated with adverse cardiac effects.⁷⁷ Another objective measurement for identifying patients at risk of high-output heart failure is the ratio of flow in the fistula (Qa) to cardiac output ratio. Patients with a Qa:CO ratio greater than 0.3 have a significantly increased risk of high-output heart failure.⁷⁸ There is thought to be no difference in risk of heart failure between AVF and AVG.⁷⁹

Once overt heart failure has developed, it should be treated in the usual fashion, with IV fluid management and standard pharmacological therapies. If standard conservative heart failure treatment is ineffective, several surgical options are available, including banding, changing the location of the anastomosis, and ultimately closing the fistula.⁸⁰

Conclusion

While life-threatening bleeding and vascular access rupture are uncommon complications of AVFs and AVGs, it is essential for the EP to rapidly treat the potentially catastrophic hemorrhagic vascular access complications. Depending on the severity and stability of the patient, it is reasonable to begin in a stepwise fashion as presented in this article for patients with minor bleeding, while more severe or persistent bleeding may require several interventions simultaneously to gain control of the bleeding.

Patients with hemodynamic instability requiring transfusion will need a vascular surgery consult and admission. Disposition for stable patients, without evidence of impending aneurysmal related rupture and concern for overlying infection or other complication requiring immediate intervention, will depend on clinical judgment, patient-specific factors and family support, follow-up, and proximity of the patient to medical care.

According to the National Institute of Diabetes and Digestive and Kidney Diseases, approximately 468,000 persons in the United States are on dialysis—a number that continues to grow annually.¹ The 1-year rate for hemorrhagic complications from arteriovenous fistulas (AVFs) is estimated to be 0.4%.² One study by Ellingson et al³ reported 1,654 deaths secondary to fatal vascular access hemorrhage over a 6-year period, accounting for 0.4% of all deaths of hemodialysis (HD) patients in that study.³

Nonhemorrhagic vascular access-related complications also contribute to the morbidity and mortality associated with AVFs and arteriovenous grafts (AVGs). Venous stenosis resulting in thrombosis has been estimated to occur in 24.7% of AVGs and 9.0% of AVFs, both of which are common causes of access failure.

Infection is reported to be the second leading cause of death in dialysis patients, and vascular access-related infection rates are reported to occur in 9.5% of AVGs vs 0.4% to 0.9% of AVFs.^2,4 Pseudoaneurysms and aneurysms range from 30% to 60% for AVFs,^2,5 and contribute to morbidity by limiting available areas to cannulate for dialysis, occasionally requiring surgical revision to restore access function or prevent access rupture.

Steal phenomena, including dialysis access-induced steal syndrome (DASS) and ischemic monomelic neuropathy, as well as heart failure secondary to high output are additional contributors to morbidity and mortality.

With the growing rate of end-stage renal disease (ESRD) in the United States and the contribution to morbidity and mortality by bleeding and other complications, it is essential to understand how to evaluate and treat these patients in the ED. This article reviews the evaluation and treatment of vascular access emergencies, as well as risk factors that contribute to complications in the ESRD patient population.

Hemorrhagic Complications of Vascular Access

Risk Factors

Many patients with ESRD have multiple comorbidities such as coronary artery disease and atrial fibrillation that require anticoagulation, antiplatelet medications, or both. Studies have shown that ESRD patients taking warfarin have an increase in major bleeding episodes of 3.1% per person-year and 4.4% per person-year for those taking aspirin alone, while those taking both medications have an increased bleeding risk of 6.3% per person-year.⁶ A recent systematic review by Elliott et al⁷ has suggested a 2-fold increase in bleeding rates in HD patients anticoagulated with warfarin as compared to HD patients not on warfarin.

While uremia secondary to chronic kidney disease (CKD) is a well-known facilitator of bleeding complications, the underlying pathophysiology is not yet completely delineated. However, there are some general underlying principles that may help in understanding the best treatment modalities available at this time. As the kidneys fail, uremic toxins accumulate in the bloodstream. These toxins include urea, creatinine, and phenolic acids, which are believed to interfere with primary hemostasis by effecting platelet adherence to endothelium, platelet activation, and aggregation.⁸ Functional defects are created in the interactions between the glycoprotein Ib (GPIb) receptor and von Willebrand factor (vWF), which are essential to endothelial adhesion of platelets.⁹ Additionally, these toxins impair the up regulation of the GPIIbIIIa receptor which is integral to platelet aggregation.¹⁰ Platelet activation normally leads to platelet aggregation by increasing production of thromboxane A2 (TXA2) and serotonin that are released from storage granules.¹⁰ Some toxins may increase nitric oxide (NO) synthesis, effectively reducing aggregation by decreasing TXA2 and adenosine diphosphate (ADP) levels.¹¹ In addition, elevated levels of fibrinogen fragments have also recently been shown to inhibit platelet function by competing with fibrinogen for the GPIIbIIIa receptor with decreasing levels demonstrated after HD.¹²

Finally, increased pressure in the venous outflow segment also increases persistent bleeding from puncture sites. These pressures may be exaggerated secondary to venous thrombosis, venous stenosis, pseudoaneurysm, aneurysm, or infection.¹³ The following sections further describe the evaluation and treatment of these complications.

Clinical Presentation

Patients presenting with bleeding from the vascular access site may present with slow continuous oozing from the needle puncture-site itself or with life-threatening hemorrhage secondary to AVF or AVG rupture.¹⁴ The incidence of vascular access rupture is unknown, but it appears the majority of ruptures occur in patients with AVG vs AVF.³ However, several case reports have also described hemorrhagic complications of AVF ruptures.^15-17 The risk of rupture may be associated with the development of aneurysms or pseudoaneuryms.¹⁸ Possible impending perforation may be signaled by skin thinning or a shiny appearance overlying the aneurysm, or evidence of infection overlying the access site.³ Many patients were shown to have complications such as stenosis, thrombosis, or infection within 6 months prior to rupture.³ Education of patients is also important as most hemorrhages occur prior to hospital arrival.^3,19

Evaluation in the ED

As with any patient presenting to the ED, the initial evaluation of an unstable patient experiencing bleeding from a vascular access site includes assessing the airway, breathing, and circulation as a first priority—paying special attention to the area of bleeding while simultaneously preparing for possible intervention. It is also important to determine when the patient last underwent dialysis and if he or she was able to complete HD. This information will identify patients who are candidates for reversing the heparin load likely given during dialysis.

It is also important to note that some patients undergoing HD who have already been identified as having an increased risk of bleeding may not receive heparin or may undergo local heparinization, minimal heparinization, or regional citrate anticoagulation during dialysis, in which case protamine is not indicated.¹⁴ The emergency physician (EP) must also determine if the patient is on any antiplatelet or anticoagulation agents.

The vascular access site should be inspected for evidence of aneurysmal changes, infection, and skin thinning as these factors increase the risk of bleeding and vascular rupture. Additionally auscultation and palpation of the vascular access site should be performed to evaluate for other potential complications such as stenosis and thrombosis. Lastly, the EP should anticipate the patient’s need for HD in the setting of a potentially unavailable AVG or AVF to determine whether the patient may need an alternative access.

Treatment and Management

The primary responsibility during the initial treatment of a bleeding access site is to stop further blood loss by utilizing methods that employ direct pressure or, in extreme cases, application of a tourniquet, followed by other interventions such as fluid and blood-product resuscitation; coagulopathy reversal; consideration of desmopressin, cryoprecipitate, tranexamic acid (TXA); HD; and vascular repair.

Control of a bleeding dialysis access-site is a balancing act of adequately controlling the bleeding while maintaining the integrity of the fistula. Overly aggressive management may cause thrombosis in the vascular access site, which is associated with morbidity—eg, site revisions, potential for the need to create a new access site. On the opposite end of the spectrum, failing to adequately control bleeding can lead to significant anemia ranging from minimal symptoms to hemodynamic compromise and death.

Peripheral Venous Access

While peripheral venous access is notoriously difficult in patients with ESRD, it is essential for the resuscitation of hemorrhaging patients. Ideally, two large bore peripheral intravenous (IV) lines should be placed in the proximal upper extremities. If peripheral venous access is not achieved, central venous access or interosseous access placement is indicated (Figure).

Direct Pressure

With low-volume bleeding, the first attempt to control the bleeding is simple direct pressure. Except in the instance of trauma or self-inflicted injury, bleeding usually occurs at the site of cannulation of the vascular access post-HD. Direct pressure should be light and limited to as small of an area as possible to prevent thrombosis; the force and area encompassed by direct pressure can be expanded as needed for bleeding that is more difficult to control. In cases of higher volume bleeding, pressure should be placed both proximally and distally to the shunt due to its bidirectional flow. Another possible temporizing measure is to place an upright gallipot or cup over the bleeding site on top of a folded piece of gauze and then securing it with tape.²¹

Topical Hemostatic Agents

Second simple direct pressure, topical hemostatic agents may be a good adjunct to help obtain hemostasis. There is a wide range of products available, from procoagulants (eg, Combat Gauze, topical thrombin) to factor concentrators (eg, QuikClot). These can be used directly on the bleeding site and only in conjunction with direct pressure.

In addition to topical hemostatic agents, another option is skin glue, which should be applied generously after bleeding has been temporized, with pressure both proximally and distally to the site.

Anticoagulation Reversal

As previously mentioned, it is important to determine when the patient’s last HD was. Heparin is used during dialysis to prevent clotting within the circuit, and although clotting times are monitored during dialysis to guide anticoagulation, it is possible that a patient bleeding after dialysis could still have therapeutic levels of heparin requiring reversal with protamine.

The recommended dose of protamine is 1 mg for every 100 U of heparin given during dialysis; protamine should be administered over 10 minutes. Alternatively, a 10- to 20-mg dose of protamine can be given if the amount of heparin administered during HD is unknown. Additionally, the patient’s medication list, as with any ED presentation, should be carefully reviewed as many dialysis patients have comorbidities requiring anticoagulation with potentially reversible agents.

Hemodialysis to Improve Platelet Dysfunction

It is thought that long-term exposure of platelets to the dialysis membrane can lead to chronic platelet activation leading to platelet dysfunction. There is conflicting data regarding the effects of HD on improving bleeding in renal patients.^9,22,23 Hemodialysis is thought to be beneficial, at least partially, through reversing uremia, thus improving platelet function.²⁴ Therefore, in the stable bleeding patient who missed a scheduled dialysis, initiating HD in the ED setting could be beneficial. If the vascular access site is deemed unsafe for HD, another access site must be obtained, for example, by placing a temporary central venous catheter that will allow for successful HD.

Desmopressin

Desmopressin acetate has been shown to reduce bleeding time in uremic patients by releasing vWF and factor VIII into plasma, taking effect within 1 hour and lasting 4 to 8 hours.^25-27 Desmopressin has also been shown to reduce blood loss and bleeding times in patients with platelet dysfunction undergoing cardiac surgery.²⁸ While the underlying mechanism is unclear, desmopressin acetate is thought to help with platelet adhesion to the endothelial wall.

Alternatively, one study by Soslau et al²⁹ has suggested that desmopressin may increase serotonin uptake by platelets and increase adenosine triphosphate release, thereby facilitating platelet aggregation. The dosing of desmopressin is 0.2 to 0.3 mcg/kg IV.³⁰ Adverse effects include facial flushing, mild headache, and transient small decrease in blood pressure (BP) with increase in heart rate. Historically, it was thought that desmopressin could lead to water retention, volume overload, congestive heart failure, and hyponatremia; however, these adverse effects have not been seen in uremic patients.³⁰ Tachyphylaxis may occur after just a few doses of desmopressin are given.³¹ Additionally, hyponatremia and seizures have been seen after repeated administration in children.³¹

Anemia and Low Hematocrit

As mentioned earlier, anemia and low hematocrit (HCT) may actually exacerbate bleeding tendencies by decreasing the number of platelets exposed to the vessel wall. Red blood cells (RBCs) also produce TXA2 and ADP, both of which play vital roles in normal platelet aggregation. Secondly, RBCs have been shown to increase NO uptake. Nitric oxide is a potent vasodilator and inhibitor of platelet aggregation. The degree of uptake appears to be augmented by increasing HCT levels.³² A goal HCT of greater than 30% has been suggested and demonstrated benefit.³³

Cryoprecipitate

Cryoprecipitate is rich in fibrinogen and vWF. Its mechanism is thought to be secondary to increasing functional vWF levels and possibly fibrinogen levels. While the overall effects appear to be variable, studies suggest 10 U of cryoprecipitate is adequate to reverse significant bleeding with resolution of effect at 24 hours.^34,35 Given the risks of adverse reactions, variable responses, and risks of hepatitis C and HIV transmission, this therapy must be used cautiously with risk-benefit analysis.

Tranexamic Acid

Tranexamic acid is an antifibrinolytic agent that binds to fibrinogen as a competitive inhibitor of plasmin, inhibiting plasminogen activation. The trauma literature has shown TXA to significantly reduce all-cause mortality.³⁶ It has also been shown to be beneficial in the bleeding uremic patient.^37-39

However, it is important to keep in mind that the clearance of TXA in patients with renal disease is unclear. One study by Andersson et al⁴⁰ demonstrated that TXA has increased plasma concentrations in patients with renal impairment, and a generally accepted practice is to renal-dose this medication. This study recommended a dose of 10 mg/kg IV at varying intervals, such as once daily, twice daily, or every 48 hours depending on the creatinine value, compared to patients with no renal impairment.⁴⁰ Another study by Sabovic et al³⁹ that evaluated the effects of TXA on gastrointestinal bleeding in patients with renal impairment used a 20-mg IV loading dose of TXA followed by 10 mg/kg orally every 48 hours. Though no adverse events occurred in this study, the study group was small. Other studies have not shown an increase in thromboembolic risk in patients who have no renal disease.^36,41

At this time, there is no consensus on the exact dosing of TXA in this patient population. Therefore, this therapy should only be considered if others have failed and the patient continues to have significant blood loss.

Life-threatening Hemorrhage

If a patient is experiencing life-threatening blood loss, more aggressive measures must be employed regardless of risk of damage to the access. In such cases, a consultation with vascular surgery services should be obtained as early as possible. If none of the previously discussed measures are ineffective, the EP may be required to place sutures in the vascular access itself or apply a tourniquet. Again, these interventions may cause permanent damage to the access; however, in the setting of life-threatening hemorrhage such interventions clearly outweigh the risks associated with continued blood loss.

As blood can flow bidirectionally within a fistula, a tourniquet should be placed both proximally and distally to the fistula to obtain adequate hemostasis. Once the tourniquets are in place, if there is no immediate surgical consultation available, the EP may need to temporarily repair the defect to allow minimal tourniquet time. There are a few considerations when placing sutures. Ideally, a noncutting needle should be used to minimize damage. An adequate-sized suture, such as a 3-0 nylon suture, should be used to maintain strength in the high-pressure system. A figure-8 suture or purse-string suture may be placed around the defect. Adequate repair should allow for tourniquet removal.

Hemodynamic Status

The EP must remain aware of the patient’s hemodynamic status. Massive transfusion protocols may need to be initiated. Best current evidence dictates that this should be done in a 1:1:1 ratio of packed red blood cells, platelets, and fresh frozen plasma respectively.⁴² In our experience, the EP should consider permissive hypotension as aggressive resuscitation and increasing BP can compromise the vascular repair.

Lastly, transfer for definitive management should be arranged if not available at the EP’s institution. The patient should travel with tourniquets in place (although not tightened) in the event of further bleeding.

Nonhemorrhagic Complications of AVF or AVG

Stenosis/Thrombosis

Prolonged bleeding from the cannulation site may suggest outflow stenosis.⁴³ Stenosis with or without subsequent thrombosis is a common cause of vascular access failure. Access failure has also been implicated secondary to poor vascular mapping, resulting in undetected pre-existing stenosis of the inflow artery, outflow vein, or juxta-anastomosis. However, development of stenosis may occur at any time throughout the life of the vascular access. One study by Schild et al⁴ reported thrombosis rates of 24.7% for grafts and 9.0% for fistula. Additionally, AVGs have a higher reported stenosis rate than AVFs, which is a risk factor for thrombosis.^44,45

There has been much debate regarding routine surveillance to prevent clinically significant stenosis with subsequent thrombosis. Surveillance includes a clinical examination, Doppler imaging studies, and flow measurements during dialysis. A recent systematic review from 2016 by Ravani et al,⁴⁶ demonstrated no difference in risk of access loss in preemptive stenosis correction in AVF or AVG without evidence of access dysfunction. However, on subgroup analysis this review did demonstrate a small benefit regarding risk of thrombosis and access loss in the AVF group.⁴⁶

The physical examination may indicate evidence of vascular access stenosis or thrombosis. Evidence of stenosis may be indicated by failure of the outflow vein to collapse on arm raise test (distal stenosis), hyperpulsatility or hypopulsatility, loss of the diastolic component of the normal continuous thrill and bruit with only systolic components appreciated, and arm edema (central vein stenosis).^43,47 Thrombosis of the vein may be evidenced by complete loss of the thrill and pulsatility on palpation. Sensitivity and specificity of the physical examination for inflow or outflow stenosis has been reported to be between 70% to 92% and 71% to 100%, respectively.^48-50

While evidence may or may not support preemptive correction of stenosis, interventions are usually required when the stenosis is more than 50% and interferes with dialysis, decreased flow, abnormal physical examination, or elevated venous pressures.⁵¹ If stenosis is associated with interference of effective dialysis or thrombosis is suspected, ultrasound imaging and consultation with a vascular surgeon or interventional radiologist are indicated. Treatment of AVF or AVG stenosis and thrombosis includes percutaneous and surgical interventions.⁵²

A systematic review by Tanner and da Silva⁵³ evaluating adjuvant medical treatments for increasing patency rates of AVF and AVG found no therapy had any improvement in patency rates at 1 month. Another review from 2015 by Palmer et al⁵⁴ suggested antiplatelet therapy may be protective for stenosis and thrombosis in AVF, but not AVG.

Infection

Infection in patients with ESRD is a major cause of morbidity and mortality, and 24% of these infections may be attributed to the vascular access itself, including central venous catheters (CVC).⁵⁵ Central venous catheters are associated with the highest rate of infection, followed by AVGs, then AVFs.^4,54 Studies have reported 9.5% vs 0.4% to 0.9% infection rates for AVG and AVF, respectively.^2,4 These infections are usually due to gram-positive organisms, with the Staphylococcus species being the most common organism involved.^55-57 However, infections caused by gram-negative organisms are possible, and broad-spectrum antibiotics should be initiated in the ED if infection is suspected. Patients may present with localized infection with increased risk of rupture of access to profound sepsis. Definitive treatment of an infected graft or fistula usually requires removal of the infected access or at least partial excision with possible interposition of additional graft material.⁵⁸

Pseudoaneurysm/Aneurysm

Pseudoaneuryms are usually caused by hematoma development after needle puncture or in juxta-anastomic segments postoperatively. Pseudoaneurysms do not have a true wall and may secondarily become infected.⁵⁹ Pseudoaneurysms occur more frequently in AVG, and are usually reported along with true aneurysms. One study by Al-Thani et al⁶⁰ detected pseudoaneurysms in 15% of clinically significant aneurysms.

Approximately 30% to 60% of patients with AVFs will develop an aneurysm.^2,5 One study by Al-Thani et al⁶⁰ reported the need for surgical intervention in 31% of patients with an AVF in whom an aneurysm was detected. The risk for developing an aneurysm is highest for those patients on high flux membrane type HD and polycystic kidney disease.⁵ As discussed earlier in this article, cannulation sites and techniques may also influence aneurysmal changes in the fistula. Aneurysm formation at the site of previous cannulation site should not be re-cannulated.¹⁸ Aneurysmal changes can contribute to other complications including high-output heart failure, thrombosis with fistula or graft failure, increased risk of bleeding, ineffective HD when associated with thrombosis or stenosis, pain and peripheral neuropathies secondary to compression of nearby nerves, and interference with functional HD.

Many asymptomatic aneurysmal changes to vascular access may not compromise access function. If a patient is identified with a vascular access pseudoaneurysm or aneurysmal changes with high-risk features, early referral to vascular surgeon for surgical interventions is imperative. High-risk features include any of the complications previously discussed—infection, threatened overlying skin, or shiny appearance. The EP should consider duplex imaging to assist with evaluation. Treatment may include ligation of the AVF, partial resection, stenting, or grafting of the aneurysm with hopes of salvaging the vascular access.^61,62

Ischemic Monomelic Neuropathy

Ischemic monomelic neuropathy may result secondary to a type of steal phenomenon, thereby inducing ischemia to supplied nerves. Ischemic monomelic neuropathy has been described in many case reports and narrative reviews.^63-67 It has been described as ischemia or infarction of the blood supply to the nerves (vasa nervosa) in the lower arm.⁶⁸ Ischemic monomelic neuropathy typically occurs immediately after the vascular access creation in the postoperative period. Therefore, it is unlikely to be seen in the ED but as patients may have sequelae of this complication, EPs should be aware of its existence. Patients with ischemic monomelic neuropathy will have severe pain, paresthesia, and weakness immediately after placement of a vascular access. Patients also typically have sensorimotor deficits in the radial, ulnar, and median nerves. Pulses should be preserved. Severe neuropathic pain will develop and may limit the examination. Clinical diagnosis may be difficult immediately after surgery because patients will often have minor deficits secondary to the surgical procedure itself or secondary to the regional block provided by anesthesia, but nerve-conduction studies usually reveal the diagnosis. The treatment is ligation of the access immediately and prognosis is variable, depending on the severity and duration of ischemia, and may result in complete loss of function of the hand.

Steal Syndrome

Dialysis access-associated steal syndrome is a type of distal ischemia secondary to the vascular access site with a reported incidence of 6.2%, and appears to occur more frequently in AVF than AVGs.^69,70 Diabetes appears to be a strong risk factor for developing DASS.⁷¹ Patients with DASS can present with classic ischemic symptoms such as pain, paresthesia, claudication, pallor, and diminished or absent arterial pulse. Pain may be present only while undergoing dialysis or exercising, or symptoms may be persistent.^68,72 There are several possible causes of DASS, including arterial occlusion or insufficiency proximal or distal to the anastomosis, increased flow through the conduit (true steal), or increased flow diverted through collateral vessels.^73,74 One clue to the diagnosis is a diminished or absent radial pulse that should improve with compression of the access site.

Once DASS is suspected, diagnosis should be confirmed using venous duplex scanning with finger pressure waveform analysis or arteriogram. Definitive management is surgical intervention with ligation of the access or banding.

High-Output Heart Failure

Changes in cardiac output (CO) are a well-documented effect of AVF placement, with one small study by Korsheed et al⁷⁵ demonstrating an average increase in CO of 17% only 2 weeks after AVF placement. The increase in CO is thought to be secondary to alterations in systemic vascular resistance and sympathetic activity. While an increase in CO can ultimately lead to high-output heart failure, this is typically only seen in patients with pre-existing cardiac dysfunction.⁷⁶ Patients are at an increased risk of high-output heart failure when flow through the AVF exceeds 2 L/min; flows below this rate are typically not associated with adverse cardiac effects.⁷⁷ Another objective measurement for identifying patients at risk of high-output heart failure is the ratio of flow in the fistula (Qa) to cardiac output ratio. Patients with a Qa:CO ratio greater than 0.3 have a significantly increased risk of high-output heart failure.⁷⁸ There is thought to be no difference in risk of heart failure between AVF and AVG.⁷⁹

Once overt heart failure has developed, it should be treated in the usual fashion, with IV fluid management and standard pharmacological therapies. If standard conservative heart failure treatment is ineffective, several surgical options are available, including banding, changing the location of the anastomosis, and ultimately closing the fistula.⁸⁰

Conclusion

While life-threatening bleeding and vascular access rupture are uncommon complications of AVFs and AVGs, it is essential for the EP to rapidly treat the potentially catastrophic hemorrhagic vascular access complications. Depending on the severity and stability of the patient, it is reasonable to begin in a stepwise fashion as presented in this article for patients with minor bleeding, while more severe or persistent bleeding may require several interventions simultaneously to gain control of the bleeding.

Patients with hemodynamic instability requiring transfusion will need a vascular surgery consult and admission. Disposition for stable patients, without evidence of impending aneurysmal related rupture and concern for overlying infection or other complication requiring immediate intervention, will depend on clinical judgment, patient-specific factors and family support, follow-up, and proximity of the patient to medical care.

Case

A 39-year-old woman presented to the ED with a chief complaint of intermittent right flank pain that radiated into her groin area. She stated the pain had begun suddenly, 4 hours prior to arrival, and was accompanied by nausea and vomiting. The patient said that she had taken acetaminophen for the pain, but had received no relief. Regarding history, according to the patient, her last menstrual period ended 2 days earlier. She denied any urinary symptoms, diarrhea, or constipation. She had no history of abdominal surgery and was currently not on any medications.

The patient’s vital signs at presentation were: temperature 98.7°F; blood pressure, 130/90 mm Hg; heart rate, 110 beats/minute; and respiratory rate, 18 breaths/minute. Oxygen saturation was 98% on room air. On physical examination, she appeared to be in mild distress, pacing around the room. There was moderate right costovertebral tenderness on percussion; the abdomen was soft and nontender.

Incidence

As ED visits for nephrolithiasis are increasing, so too are the health-care costs associated with this condition. Between 1992 and 2009, emergent-care presentations for nephrolithiasis rose from 178 to 340 visits per 100,000 individuals.¹ Approximately 1 in 11 people in the United States will be affected by nephrolithiasis during their lifetime.² Estimated health-care costs associated with these complaints were roughly $2 billion in 2000—an increase of 50% since 1994.²

Evaluation and Diagnosis

Laboratory Evaluation
Urinalysis is one of the initial studies for patients with suspected nephrolithiasis. Although hematuria is a classic finding associated with renal calculi, its sensitivity on microscopic analysis is around 84%. Therefore, the absence of hematuria does not exclude renal colic in the differential diagnosis.³

In addition to detecting hematuria, urinalysis can also reveal an underlying infection. One study by Abrahamian et al⁴ found that roughly 8% of patients presenting with acute nephrolithiasis had a urinary tract infection (UTI)—many without any clinical findings of infection. The presence of pyuria, however, has only moderate accuracy in identifying UTIs in patients with kidney stones.⁴ If an infected stone cannot be excluded clinically, computed tomography (CT) is indicated.

Mild leukocytosis (ie, <15,000 cells/mcL) is another common finding in patients with acute renal colic.⁵ A leukocyte count >15,000 cells/mcL is suspicious for infection or other pathology. A blood-chemistry panel to evaluate renal function is appropriate as a baseline—particularly for patients in whom treatment with a nonsteroidal anti-inflammatory (NSAID) drug is anticipated.

Despite the increase in CT imaging to evaluate patients presenting to the ED with nephrolithiasis/flank pain, the proportion of patients diagnosed with a kidney stone remained the same between 2000 and 2008, with no significant change in outcomes.^10-12 Moreover, the use of CT as an initial imaging modality in patients presenting with flank pain—but with no sign of infection—is unlikely to reveal important alternative findings.¹³

Regarding the sensitivity of CT in detecting nephrolithiasis, one study demonstrates a sensitivity of 100% and a specificity of 94% for noncontrast CT.¹⁴ Controversy, however, still exists regarding the necessity and utility of CT in diagnosing nephrolithiasis,¹⁵ and CT is one of the top 10 tests included in the American College of Emergency Physicians (ACEP) 2014 Choosing Wisely campaign. In this campaign, ACEP recommended emergency physicians (EPs) avoid abdominal and pelvic CT in otherwise healthy patients younger than age 50 years who present with symptoms consistent with uncomplicated renal colic and who have a known history of nephrolithiasis or ureterolithiasis.¹⁵ The ACEP also noted that CTs in this context do not often change treatment decisions and are associated with unnecessary radiation exposure and cost.¹⁵

While keeping the aforementioned recommendations in mind, if an EP intends to refer a renal colic patient to a urologist a CT scan is necessary either in the ED or as an outpatient. In all cases (except perhaps in patients in whom there is a history of renal stones), the urologist will need this study to determine the size and location of the stone in order to provide recommendations for management.

Ultrasound

Clinical Decision Score

Moore et al,¹⁷ authors of the Size, Topography, Location, Obstruction, Number of stones, and Evaluation (STONE) scoring system, developed a classification system for patients with suspected nephrolithiasis. This system places patients into low-, moderate-, and high-score groups, with corresponding probabilities of ureteral stone based on symptoms and epidemiological classifications.

The intent of the STONE system is to accurately predict, based on classification, the likelihood of a patient having a simple ureteral stone versus a more significant, complicated stone and to help guide which, if any, imaging studies are indicated. For example, a lower STONE score would help guide the decision to defer advanced imaging studies that would be unlikely to reveal an alternate serious diagnosis. Likewise, an individual with a high STONE score could potentially receive ultrasonography, reduced-dose CT, or no further imaging.

The STONE score performs fairly well and appears to be superior to physician gestalt, with an area under the receiver operating characteristic curve (AUC) of .78 compared to .68 with physician gestalt. This system, however, is not always accurate in its classification and has been shown to have 87% specificity at the high end to rule in stone and 96% sensitivity rate at the low end to rule out a stone. Of course, when using a clinical decision rule to rule in or rule out a stone, a tool with a very high specificity is preferred. Although the STONE scoring system does show promise, further studies are needed before it can be applied clinically.¹⁷

Treatment

Analgesia
By inhibiting prostaglandin synthesis, NSAIDs reduce inflammation and ureteral muscular hyperactivity.¹⁸ A recent Cochrane review of over 50 studies concluded that NSAIDs were effective in relieving acute renal colic pain.¹⁹ A systematic review by Holdgate and Pollock²⁰ shows that patients treated with NSAIDs achieve greater reductions in pain scores and are less likely to require additional analgesia in the short term compared to patients treated with opioids. Although opioid medications are effective in relieving pain associated with nephrolithiasis, this class of drugs can exacerbate the nausea often associated with this condition. This same study also showed that patients who were prescribed NSAIDs following an ED visit for renal colic required less medication for pain control, experienced less nausea, and had greater improvements in their pain.²⁰

Nevertheless, the utility of opiates as an adjunct therapy should not be overlooked. For example, in patients with renal colic, numerous studies show treatment with a combination of an NSAID and opiate provides superior pain relief compared to either treatment modality in isolation.²¹ Opioid analgesia may be indicated in patients in whom NSAIDs are not recommended or contraindicated (eg, elderly patients, patients with renal disease). While NSAIDs address the underlying pathophysiology associated with renal colic, they are sometimes not the best treatment option. Depending on the situation, treatment with an opioid should instead be considered.

Intravenous Fluid Therapy
A 2012 Cochrane Review of randomized control trials (RCT) on intravenous (IV) fluid therapy hydration/diuretic use concluded that there was “no reliable evidence in the literature to support the use of diuretics and high-volume fluid therapy for people with acute ureteric colic.” The review, however, did note that further investigation is warranted for a definitive answer.²² Another study by Springhart et al²³ showed no difference in pain or stone expulsion between large-volume (2 L IV fluids over 2 hours) and small-volume fluid administration (20 mL/h). Regarding administration, the use of IV fluids in renal colic is no different than the usual indications for fluid therapy in the ED and should be restricted to patients with signs of dehydration or kidney injury.

Many patients with renal colic will have decreased oral intake from the pain and nausea associated with the stone and may be vomiting. Under these circumstances, it is reasonable to rehydrate the patients, even though large-volume hydration with the intent of aiding stone expulsion or improving pain has not been shown efficacious. Conversely, in addition to the perceived benefit of rehydrating patients, a small amount of fluid hydration may improve the visualization of hydronephrosis on ultrasound.²⁴

Medical Expulsive Therapy
For many years, clinicians have considered the use of tamsulosin, an α1-receptor blocker, as well as nifedipine, a calcium channel blocker, in treating renal colic due to the theoretical benefit of reducing ureteral smooth muscle spasm/constriction thus expediting stone passage. Over the years, dozens of studies showed positive benefit in the use of medical expulsive therapy (MET). A 2014 Cochrane Review demonstrated that patients treated with α1-blockers experienced a higher stone-free rate and shorter time to stone expulsion, and concluded that α1-blockers should be offered as one of the primary treatment modalities in MET.²⁵ This review, however, has been criticized for using a number of studies with very small patient samples, non-peer-reviewed abstracts, and low-quality study designs.²⁶

More recently, in April 2015, Lancet published a large RCT from 24 hospitals in the United Kingdom, comparing placebo versus 400 mcg tamsulosin and 30 mg nifedipine. The authors concluded that “tamsulosin 400 mcg and nifedipine 30 mg are not effective at decreasing the need for further treatment to achieve stone clearance in 4 weeks for patients with expectantly managed ureteric colic.”²⁷ Another large double-blind, placebo-controlled, randomized, multicenter trial by Furyk et al²⁸ in July 2015 went a step further and evaluated distal stones, which have historically caused complications requiring intervention. They concluded that there was “no benefit overall of 0.4 mg of tamsulosin daily for patients with distal ureteric calculi less than or equal to 10 mm in terms of spontaneous passage, time to stone passage, pain, or analgesia requirements. In the subgroup with large stones (5 to 10 mm), tamsulosin did increase passage and should be considered.”²⁸ Based on these recent studies, the use of tamsulosin in patients with stones larger than 5 mm—but not those with smaller stones—appears to be an appropriate treatment option.

Patient Disposition

The American Urological Association cited indications for urgent/emergent urological interventions necessitating the need for inpatient admission and further workup.²⁹ Patients who do not fall into any of the categories outlined in the Table may be seen on an outpatient basis. These patients may be treated symptomatically until they can follow up with a urologist, who will determine expectant management versus intervention.

Prognosis

The majority of stones <5mm will pass spontaneously.³⁰ Larger stones may still pass spontaneously but are more likely to require lithotripsy or other urologic intervention; therefore, patients with stones >5 mm should be referred to urology services.³⁰

Recurrence
Patients with a first-time kidney stone have a 30% to 50% chance of disease recurrence within 5 years,³¹ and a 60% to 80% chance of recurrence during their lifetime.³² Those with a family history of nephrolithiasis are likely to develop an earlier onset of stones as well as experience more frequent recurrent episodes.³³ Patients with recurrent disease should undergo outpatient risk stratification, including stone-composition analysis and assessment for modifiable risk factors.

Case Conclusion

The patient’s urinalysis demonstrated microscopic hematuria; blood urea nitrogen and creatinine levels were within normal limits. As the patient was tachycardic and appeared mildly dehydrated, an IV infusion of 1 L normal saline was initiated, along with ketorolac and ondansetron for symptomatic relief. A POC ultrasound of the right kidney revealed mild-to-moderate hydronephrosis; the left kidney appeared sonographically normal. Since this patient had no history of nephrolithiasis, a nonenhanced CT of the abdomen was obtained, which revealed moderate, right-sided hydronephrosis and a 3-mm distal ureteral stone. Once the patient’s symptoms were controlled, she was discharged home with a prescription for ibuprofen for symptomatic relief and instructions to follow up with her PCP.

Conclusion

The evaluation and treatment of nephrolithiasis is important due to its increasing prevalence, as well as implications on costs to the health-care system and to patients themselves. The workup and treatment of nephrolithiasis has been and continues to be the subject of much controversy. Until very recently, treatment recommendations were founded on physiological theories more so than robust research. In an era where improved imaging technology is becoming more readily available in the ED, EPs should weigh the pros and cons of its utilization for common ED complaints such as nephrolithiasis.

Dr Parsa is an assistant professor in the department of emergency medicine, Texas Tech University Health Sciences Center, El Paso. Dr Khafi is a resident in the department of emergency medicine, Texas Tech University Health Sciences Center, El Paso.

Case

A 39-year-old woman presented to the ED with a chief complaint of intermittent right flank pain that radiated into her groin area. She stated the pain had begun suddenly, 4 hours prior to arrival, and was accompanied by nausea and vomiting. The patient said that she had taken acetaminophen for the pain, but had received no relief. Regarding history, according to the patient, her last menstrual period ended 2 days earlier. She denied any urinary symptoms, diarrhea, or constipation. She had no history of abdominal surgery and was currently not on any medications.

The patient’s vital signs at presentation were: temperature 98.7°F; blood pressure, 130/90 mm Hg; heart rate, 110 beats/minute; and respiratory rate, 18 breaths/minute. Oxygen saturation was 98% on room air. On physical examination, she appeared to be in mild distress, pacing around the room. There was moderate right costovertebral tenderness on percussion; the abdomen was soft and nontender.

Incidence

As ED visits for nephrolithiasis are increasing, so too are the health-care costs associated with this condition. Between 1992 and 2009, emergent-care presentations for nephrolithiasis rose from 178 to 340 visits per 100,000 individuals.¹ Approximately 1 in 11 people in the United States will be affected by nephrolithiasis during their lifetime.² Estimated health-care costs associated with these complaints were roughly $2 billion in 2000—an increase of 50% since 1994.²

Evaluation and Diagnosis

Laboratory Evaluation
Urinalysis is one of the initial studies for patients with suspected nephrolithiasis. Although hematuria is a classic finding associated with renal calculi, its sensitivity on microscopic analysis is around 84%. Therefore, the absence of hematuria does not exclude renal colic in the differential diagnosis.³

In addition to detecting hematuria, urinalysis can also reveal an underlying infection. One study by Abrahamian et al⁴ found that roughly 8% of patients presenting with acute nephrolithiasis had a urinary tract infection (UTI)—many without any clinical findings of infection. The presence of pyuria, however, has only moderate accuracy in identifying UTIs in patients with kidney stones.⁴ If an infected stone cannot be excluded clinically, computed tomography (CT) is indicated.

Mild leukocytosis (ie, <15,000 cells/mcL) is another common finding in patients with acute renal colic.⁵ A leukocyte count >15,000 cells/mcL is suspicious for infection or other pathology. A blood-chemistry panel to evaluate renal function is appropriate as a baseline—particularly for patients in whom treatment with a nonsteroidal anti-inflammatory (NSAID) drug is anticipated.

Despite the increase in CT imaging to evaluate patients presenting to the ED with nephrolithiasis/flank pain, the proportion of patients diagnosed with a kidney stone remained the same between 2000 and 2008, with no significant change in outcomes.^10-12 Moreover, the use of CT as an initial imaging modality in patients presenting with flank pain—but with no sign of infection—is unlikely to reveal important alternative findings.¹³

Regarding the sensitivity of CT in detecting nephrolithiasis, one study demonstrates a sensitivity of 100% and a specificity of 94% for noncontrast CT.¹⁴ Controversy, however, still exists regarding the necessity and utility of CT in diagnosing nephrolithiasis,¹⁵ and CT is one of the top 10 tests included in the American College of Emergency Physicians (ACEP) 2014 Choosing Wisely campaign. In this campaign, ACEP recommended emergency physicians (EPs) avoid abdominal and pelvic CT in otherwise healthy patients younger than age 50 years who present with symptoms consistent with uncomplicated renal colic and who have a known history of nephrolithiasis or ureterolithiasis.¹⁵ The ACEP also noted that CTs in this context do not often change treatment decisions and are associated with unnecessary radiation exposure and cost.¹⁵

While keeping the aforementioned recommendations in mind, if an EP intends to refer a renal colic patient to a urologist a CT scan is necessary either in the ED or as an outpatient. In all cases (except perhaps in patients in whom there is a history of renal stones), the urologist will need this study to determine the size and location of the stone in order to provide recommendations for management.

Ultrasound

Clinical Decision Score

Moore et al,¹⁷ authors of the Size, Topography, Location, Obstruction, Number of stones, and Evaluation (STONE) scoring system, developed a classification system for patients with suspected nephrolithiasis. This system places patients into low-, moderate-, and high-score groups, with corresponding probabilities of ureteral stone based on symptoms and epidemiological classifications.

The intent of the STONE system is to accurately predict, based on classification, the likelihood of a patient having a simple ureteral stone versus a more significant, complicated stone and to help guide which, if any, imaging studies are indicated. For example, a lower STONE score would help guide the decision to defer advanced imaging studies that would be unlikely to reveal an alternate serious diagnosis. Likewise, an individual with a high STONE score could potentially receive ultrasonography, reduced-dose CT, or no further imaging.

The STONE score performs fairly well and appears to be superior to physician gestalt, with an area under the receiver operating characteristic curve (AUC) of .78 compared to .68 with physician gestalt. This system, however, is not always accurate in its classification and has been shown to have 87% specificity at the high end to rule in stone and 96% sensitivity rate at the low end to rule out a stone. Of course, when using a clinical decision rule to rule in or rule out a stone, a tool with a very high specificity is preferred. Although the STONE scoring system does show promise, further studies are needed before it can be applied clinically.¹⁷

Treatment

Analgesia
By inhibiting prostaglandin synthesis, NSAIDs reduce inflammation and ureteral muscular hyperactivity.¹⁸ A recent Cochrane review of over 50 studies concluded that NSAIDs were effective in relieving acute renal colic pain.¹⁹ A systematic review by Holdgate and Pollock²⁰ shows that patients treated with NSAIDs achieve greater reductions in pain scores and are less likely to require additional analgesia in the short term compared to patients treated with opioids. Although opioid medications are effective in relieving pain associated with nephrolithiasis, this class of drugs can exacerbate the nausea often associated with this condition. This same study also showed that patients who were prescribed NSAIDs following an ED visit for renal colic required less medication for pain control, experienced less nausea, and had greater improvements in their pain.²⁰

Nevertheless, the utility of opiates as an adjunct therapy should not be overlooked. For example, in patients with renal colic, numerous studies show treatment with a combination of an NSAID and opiate provides superior pain relief compared to either treatment modality in isolation.²¹ Opioid analgesia may be indicated in patients in whom NSAIDs are not recommended or contraindicated (eg, elderly patients, patients with renal disease). While NSAIDs address the underlying pathophysiology associated with renal colic, they are sometimes not the best treatment option. Depending on the situation, treatment with an opioid should instead be considered.

Intravenous Fluid Therapy
A 2012 Cochrane Review of randomized control trials (RCT) on intravenous (IV) fluid therapy hydration/diuretic use concluded that there was “no reliable evidence in the literature to support the use of diuretics and high-volume fluid therapy for people with acute ureteric colic.” The review, however, did note that further investigation is warranted for a definitive answer.²² Another study by Springhart et al²³ showed no difference in pain or stone expulsion between large-volume (2 L IV fluids over 2 hours) and small-volume fluid administration (20 mL/h). Regarding administration, the use of IV fluids in renal colic is no different than the usual indications for fluid therapy in the ED and should be restricted to patients with signs of dehydration or kidney injury.

Many patients with renal colic will have decreased oral intake from the pain and nausea associated with the stone and may be vomiting. Under these circumstances, it is reasonable to rehydrate the patients, even though large-volume hydration with the intent of aiding stone expulsion or improving pain has not been shown efficacious. Conversely, in addition to the perceived benefit of rehydrating patients, a small amount of fluid hydration may improve the visualization of hydronephrosis on ultrasound.²⁴

Medical Expulsive Therapy
For many years, clinicians have considered the use of tamsulosin, an α1-receptor blocker, as well as nifedipine, a calcium channel blocker, in treating renal colic due to the theoretical benefit of reducing ureteral smooth muscle spasm/constriction thus expediting stone passage. Over the years, dozens of studies showed positive benefit in the use of medical expulsive therapy (MET). A 2014 Cochrane Review demonstrated that patients treated with α1-blockers experienced a higher stone-free rate and shorter time to stone expulsion, and concluded that α1-blockers should be offered as one of the primary treatment modalities in MET.²⁵ This review, however, has been criticized for using a number of studies with very small patient samples, non-peer-reviewed abstracts, and low-quality study designs.²⁶

More recently, in April 2015, Lancet published a large RCT from 24 hospitals in the United Kingdom, comparing placebo versus 400 mcg tamsulosin and 30 mg nifedipine. The authors concluded that “tamsulosin 400 mcg and nifedipine 30 mg are not effective at decreasing the need for further treatment to achieve stone clearance in 4 weeks for patients with expectantly managed ureteric colic.”²⁷ Another large double-blind, placebo-controlled, randomized, multicenter trial by Furyk et al²⁸ in July 2015 went a step further and evaluated distal stones, which have historically caused complications requiring intervention. They concluded that there was “no benefit overall of 0.4 mg of tamsulosin daily for patients with distal ureteric calculi less than or equal to 10 mm in terms of spontaneous passage, time to stone passage, pain, or analgesia requirements. In the subgroup with large stones (5 to 10 mm), tamsulosin did increase passage and should be considered.”²⁸ Based on these recent studies, the use of tamsulosin in patients with stones larger than 5 mm—but not those with smaller stones—appears to be an appropriate treatment option.

Patient Disposition

The American Urological Association cited indications for urgent/emergent urological interventions necessitating the need for inpatient admission and further workup.²⁹ Patients who do not fall into any of the categories outlined in the Table may be seen on an outpatient basis. These patients may be treated symptomatically until they can follow up with a urologist, who will determine expectant management versus intervention.

Prognosis

The majority of stones <5mm will pass spontaneously.³⁰ Larger stones may still pass spontaneously but are more likely to require lithotripsy or other urologic intervention; therefore, patients with stones >5 mm should be referred to urology services.³⁰

Recurrence
Patients with a first-time kidney stone have a 30% to 50% chance of disease recurrence within 5 years,³¹ and a 60% to 80% chance of recurrence during their lifetime.³² Those with a family history of nephrolithiasis are likely to develop an earlier onset of stones as well as experience more frequent recurrent episodes.³³ Patients with recurrent disease should undergo outpatient risk stratification, including stone-composition analysis and assessment for modifiable risk factors.

Case Conclusion

The patient’s urinalysis demonstrated microscopic hematuria; blood urea nitrogen and creatinine levels were within normal limits. As the patient was tachycardic and appeared mildly dehydrated, an IV infusion of 1 L normal saline was initiated, along with ketorolac and ondansetron for symptomatic relief. A POC ultrasound of the right kidney revealed mild-to-moderate hydronephrosis; the left kidney appeared sonographically normal. Since this patient had no history of nephrolithiasis, a nonenhanced CT of the abdomen was obtained, which revealed moderate, right-sided hydronephrosis and a 3-mm distal ureteral stone. Once the patient’s symptoms were controlled, she was discharged home with a prescription for ibuprofen for symptomatic relief and instructions to follow up with her PCP.

Conclusion

The evaluation and treatment of nephrolithiasis is important due to its increasing prevalence, as well as implications on costs to the health-care system and to patients themselves. The workup and treatment of nephrolithiasis has been and continues to be the subject of much controversy. Until very recently, treatment recommendations were founded on physiological theories more so than robust research. In an era where improved imaging technology is becoming more readily available in the ED, EPs should weigh the pros and cons of its utilization for common ED complaints such as nephrolithiasis.

Dr Parsa is an assistant professor in the department of emergency medicine, Texas Tech University Health Sciences Center, El Paso. Dr Khafi is a resident in the department of emergency medicine, Texas Tech University Health Sciences Center, El Paso.

Case

A 39-year-old woman presented to the ED with a chief complaint of intermittent right flank pain that radiated into her groin area. She stated the pain had begun suddenly, 4 hours prior to arrival, and was accompanied by nausea and vomiting. The patient said that she had taken acetaminophen for the pain, but had received no relief. Regarding history, according to the patient, her last menstrual period ended 2 days earlier. She denied any urinary symptoms, diarrhea, or constipation. She had no history of abdominal surgery and was currently not on any medications.

The patient’s vital signs at presentation were: temperature 98.7°F; blood pressure, 130/90 mm Hg; heart rate, 110 beats/minute; and respiratory rate, 18 breaths/minute. Oxygen saturation was 98% on room air. On physical examination, she appeared to be in mild distress, pacing around the room. There was moderate right costovertebral tenderness on percussion; the abdomen was soft and nontender.

Incidence

As ED visits for nephrolithiasis are increasing, so too are the health-care costs associated with this condition. Between 1992 and 2009, emergent-care presentations for nephrolithiasis rose from 178 to 340 visits per 100,000 individuals.¹ Approximately 1 in 11 people in the United States will be affected by nephrolithiasis during their lifetime.² Estimated health-care costs associated with these complaints were roughly $2 billion in 2000—an increase of 50% since 1994.²

Evaluation and Diagnosis

Laboratory Evaluation
Urinalysis is one of the initial studies for patients with suspected nephrolithiasis. Although hematuria is a classic finding associated with renal calculi, its sensitivity on microscopic analysis is around 84%. Therefore, the absence of hematuria does not exclude renal colic in the differential diagnosis.³

In addition to detecting hematuria, urinalysis can also reveal an underlying infection. One study by Abrahamian et al⁴ found that roughly 8% of patients presenting with acute nephrolithiasis had a urinary tract infection (UTI)—many without any clinical findings of infection. The presence of pyuria, however, has only moderate accuracy in identifying UTIs in patients with kidney stones.⁴ If an infected stone cannot be excluded clinically, computed tomography (CT) is indicated.

Mild leukocytosis (ie, <15,000 cells/mcL) is another common finding in patients with acute renal colic.⁵ A leukocyte count >15,000 cells/mcL is suspicious for infection or other pathology. A blood-chemistry panel to evaluate renal function is appropriate as a baseline—particularly for patients in whom treatment with a nonsteroidal anti-inflammatory (NSAID) drug is anticipated.

Despite the increase in CT imaging to evaluate patients presenting to the ED with nephrolithiasis/flank pain, the proportion of patients diagnosed with a kidney stone remained the same between 2000 and 2008, with no significant change in outcomes.^10-12 Moreover, the use of CT as an initial imaging modality in patients presenting with flank pain—but with no sign of infection—is unlikely to reveal important alternative findings.¹³

Regarding the sensitivity of CT in detecting nephrolithiasis, one study demonstrates a sensitivity of 100% and a specificity of 94% for noncontrast CT.¹⁴ Controversy, however, still exists regarding the necessity and utility of CT in diagnosing nephrolithiasis,¹⁵ and CT is one of the top 10 tests included in the American College of Emergency Physicians (ACEP) 2014 Choosing Wisely campaign. In this campaign, ACEP recommended emergency physicians (EPs) avoid abdominal and pelvic CT in otherwise healthy patients younger than age 50 years who present with symptoms consistent with uncomplicated renal colic and who have a known history of nephrolithiasis or ureterolithiasis.¹⁵ The ACEP also noted that CTs in this context do not often change treatment decisions and are associated with unnecessary radiation exposure and cost.¹⁵

While keeping the aforementioned recommendations in mind, if an EP intends to refer a renal colic patient to a urologist a CT scan is necessary either in the ED or as an outpatient. In all cases (except perhaps in patients in whom there is a history of renal stones), the urologist will need this study to determine the size and location of the stone in order to provide recommendations for management.

Ultrasound

Clinical Decision Score

Moore et al,¹⁷ authors of the Size, Topography, Location, Obstruction, Number of stones, and Evaluation (STONE) scoring system, developed a classification system for patients with suspected nephrolithiasis. This system places patients into low-, moderate-, and high-score groups, with corresponding probabilities of ureteral stone based on symptoms and epidemiological classifications.

The intent of the STONE system is to accurately predict, based on classification, the likelihood of a patient having a simple ureteral stone versus a more significant, complicated stone and to help guide which, if any, imaging studies are indicated. For example, a lower STONE score would help guide the decision to defer advanced imaging studies that would be unlikely to reveal an alternate serious diagnosis. Likewise, an individual with a high STONE score could potentially receive ultrasonography, reduced-dose CT, or no further imaging.

The STONE score performs fairly well and appears to be superior to physician gestalt, with an area under the receiver operating characteristic curve (AUC) of .78 compared to .68 with physician gestalt. This system, however, is not always accurate in its classification and has been shown to have 87% specificity at the high end to rule in stone and 96% sensitivity rate at the low end to rule out a stone. Of course, when using a clinical decision rule to rule in or rule out a stone, a tool with a very high specificity is preferred. Although the STONE scoring system does show promise, further studies are needed before it can be applied clinically.¹⁷

Treatment

Analgesia
By inhibiting prostaglandin synthesis, NSAIDs reduce inflammation and ureteral muscular hyperactivity.¹⁸ A recent Cochrane review of over 50 studies concluded that NSAIDs were effective in relieving acute renal colic pain.¹⁹ A systematic review by Holdgate and Pollock²⁰ shows that patients treated with NSAIDs achieve greater reductions in pain scores and are less likely to require additional analgesia in the short term compared to patients treated with opioids. Although opioid medications are effective in relieving pain associated with nephrolithiasis, this class of drugs can exacerbate the nausea often associated with this condition. This same study also showed that patients who were prescribed NSAIDs following an ED visit for renal colic required less medication for pain control, experienced less nausea, and had greater improvements in their pain.²⁰

Nevertheless, the utility of opiates as an adjunct therapy should not be overlooked. For example, in patients with renal colic, numerous studies show treatment with a combination of an NSAID and opiate provides superior pain relief compared to either treatment modality in isolation.²¹ Opioid analgesia may be indicated in patients in whom NSAIDs are not recommended or contraindicated (eg, elderly patients, patients with renal disease). While NSAIDs address the underlying pathophysiology associated with renal colic, they are sometimes not the best treatment option. Depending on the situation, treatment with an opioid should instead be considered.

Intravenous Fluid Therapy
A 2012 Cochrane Review of randomized control trials (RCT) on intravenous (IV) fluid therapy hydration/diuretic use concluded that there was “no reliable evidence in the literature to support the use of diuretics and high-volume fluid therapy for people with acute ureteric colic.” The review, however, did note that further investigation is warranted for a definitive answer.²² Another study by Springhart et al²³ showed no difference in pain or stone expulsion between large-volume (2 L IV fluids over 2 hours) and small-volume fluid administration (20 mL/h). Regarding administration, the use of IV fluids in renal colic is no different than the usual indications for fluid therapy in the ED and should be restricted to patients with signs of dehydration or kidney injury.

Many patients with renal colic will have decreased oral intake from the pain and nausea associated with the stone and may be vomiting. Under these circumstances, it is reasonable to rehydrate the patients, even though large-volume hydration with the intent of aiding stone expulsion or improving pain has not been shown efficacious. Conversely, in addition to the perceived benefit of rehydrating patients, a small amount of fluid hydration may improve the visualization of hydronephrosis on ultrasound.²⁴

Medical Expulsive Therapy
For many years, clinicians have considered the use of tamsulosin, an α1-receptor blocker, as well as nifedipine, a calcium channel blocker, in treating renal colic due to the theoretical benefit of reducing ureteral smooth muscle spasm/constriction thus expediting stone passage. Over the years, dozens of studies showed positive benefit in the use of medical expulsive therapy (MET). A 2014 Cochrane Review demonstrated that patients treated with α1-blockers experienced a higher stone-free rate and shorter time to stone expulsion, and concluded that α1-blockers should be offered as one of the primary treatment modalities in MET.²⁵ This review, however, has been criticized for using a number of studies with very small patient samples, non-peer-reviewed abstracts, and low-quality study designs.²⁶

More recently, in April 2015, Lancet published a large RCT from 24 hospitals in the United Kingdom, comparing placebo versus 400 mcg tamsulosin and 30 mg nifedipine. The authors concluded that “tamsulosin 400 mcg and nifedipine 30 mg are not effective at decreasing the need for further treatment to achieve stone clearance in 4 weeks for patients with expectantly managed ureteric colic.”²⁷ Another large double-blind, placebo-controlled, randomized, multicenter trial by Furyk et al²⁸ in July 2015 went a step further and evaluated distal stones, which have historically caused complications requiring intervention. They concluded that there was “no benefit overall of 0.4 mg of tamsulosin daily for patients with distal ureteric calculi less than or equal to 10 mm in terms of spontaneous passage, time to stone passage, pain, or analgesia requirements. In the subgroup with large stones (5 to 10 mm), tamsulosin did increase passage and should be considered.”²⁸ Based on these recent studies, the use of tamsulosin in patients with stones larger than 5 mm—but not those with smaller stones—appears to be an appropriate treatment option.

Patient Disposition

The American Urological Association cited indications for urgent/emergent urological interventions necessitating the need for inpatient admission and further workup.²⁹ Patients who do not fall into any of the categories outlined in the Table may be seen on an outpatient basis. These patients may be treated symptomatically until they can follow up with a urologist, who will determine expectant management versus intervention.

Prognosis

The majority of stones <5mm will pass spontaneously.³⁰ Larger stones may still pass spontaneously but are more likely to require lithotripsy or other urologic intervention; therefore, patients with stones >5 mm should be referred to urology services.³⁰

Recurrence
Patients with a first-time kidney stone have a 30% to 50% chance of disease recurrence within 5 years,³¹ and a 60% to 80% chance of recurrence during their lifetime.³² Those with a family history of nephrolithiasis are likely to develop an earlier onset of stones as well as experience more frequent recurrent episodes.³³ Patients with recurrent disease should undergo outpatient risk stratification, including stone-composition analysis and assessment for modifiable risk factors.

Case Conclusion

The patient’s urinalysis demonstrated microscopic hematuria; blood urea nitrogen and creatinine levels were within normal limits. As the patient was tachycardic and appeared mildly dehydrated, an IV infusion of 1 L normal saline was initiated, along with ketorolac and ondansetron for symptomatic relief. A POC ultrasound of the right kidney revealed mild-to-moderate hydronephrosis; the left kidney appeared sonographically normal. Since this patient had no history of nephrolithiasis, a nonenhanced CT of the abdomen was obtained, which revealed moderate, right-sided hydronephrosis and a 3-mm distal ureteral stone. Once the patient’s symptoms were controlled, she was discharged home with a prescription for ibuprofen for symptomatic relief and instructions to follow up with her PCP.

Conclusion

The evaluation and treatment of nephrolithiasis is important due to its increasing prevalence, as well as implications on costs to the health-care system and to patients themselves. The workup and treatment of nephrolithiasis has been and continues to be the subject of much controversy. Until very recently, treatment recommendations were founded on physiological theories more so than robust research. In an era where improved imaging technology is becoming more readily available in the ED, EPs should weigh the pros and cons of its utilization for common ED complaints such as nephrolithiasis.

Dr Parsa is an assistant professor in the department of emergency medicine, Texas Tech University Health Sciences Center, El Paso. Dr Khafi is a resident in the department of emergency medicine, Texas Tech University Health Sciences Center, El Paso.

SAN DIEGO – The prevalence of kidney stone disease appears to be rising in the United States.

According to an analysis of responses from the 2007-2012 National Health and Nutrition Examination Survey (NHANES), 8.8% of people in the United States have kidney stone disease (Eur Urol. 2012 Jul;62[1]:160-5), up from a prevalence of 5.2% observed in the 1988-1994 NHANES.

“There’s also been a marked increase in emergency room visits for kidney stones: 91% between 1994 and 2006,” Dr. Anna L. Zisman said at the meeting sponsored by the American Society of Nephrology.

“Unfortunately, it doesn’t only affect adults. There has been an increased incidence in ER visits for kids as well.” Though good national data on the incidence of kidney stone disease in children are lacking, one study conducted in South Carolina found that the incidence of ER visits in children rose from 8 per 100,000 in 1996 to more than 18 per 100,000 in 2007 (J Pediatr. 2010 Jul;157[1]:132-7).

What’s driving these increases? Dr. Zisman, a nephrologist at the University of Chicago, discussed a “recipe” for how to create a kidney stone, with heredity as the first step.

“Pick your parents well,” she said. “The familial clustering index is higher for nephrolithiasis than for diabetes and hypertension. A family history of stone disease is present in 16%-37% of stone formers, compared with 4%-12% of healthy controls. And the heritability estimates – how much of a given disease or trait can be attributable to genetic predisposition – is somewhere between 46% and 63%.”

According to Mayo Clinic researchers, heritable traits for kidney stone disease based on 24-hour urine measurements, adjusted for diet, include calcium, magnesium, pH, and citrate (Clin J Am Soc Nephrol. 2014 May;9[5]:943-50).

“Hypercalciuria is the most well-established risk factor for stone disease,” Dr. Zisman said. “Up to 50% of subjects with stones have a history of hypercalciuria, and 43% of first-degree relatives of hypercalciuric patients have hypercalciuria.”

Race and gender are two factors people can’t control in their risk for kidney stone disease. NHANES data suggest that non-Hispanic whites are at highest risk for stone formation, compared with Hispanics and non-Hispanic blacks. However, among whites and all of the racial categories, males have a higher risk than females.

Step two in the recipe for stone formation is timing: Age matters.

According to an analysis of 49,976 men who participated in the Health Professionals Follow-Up Study, the highest risk of stone formation was in male patients in their 40s (J Am Soc Nephrol. 2004 Dec;15[12]:3225-32). By the time white males reach their 70s, the prevalence is almost 19%, while the prevalence for white women in their 70s is 9.4% (Eur Urol. 2012 Jul;62[1]:160-5).

Step three in the recipe is location. According to Dr. Zisman, the prevalence of kidney stone disease across the world is quite varied. “That likely has to do with both genetic predispositions as well as environmental factors,” she noted. “For example, Iran, which has a pretty warm climate, has a prevalence of 5.7%, Greece 15.2%, whereas Argentina only 4%. In the United States, data suggest that the highest incidence of stone disease is in the south. It is suspected that this is due to more men working outside in manual labor in the heat, but that’s just a hypothesis.”

Step four in the recipe involves the role of certain nutrients. For example, a higher daily calcium intake is associated with a lower risk of kidney stone formation. “The theory is that with higher dietary calcium, your urine oxalate tends to drop,” she said. Increased intake of magnesium, protein, potassium, and fluid are also associated with decreased stone formation.

On the other hand, a higher daily vitamin C intake is associated with an increased risk of stone formation. Specifically, a daily intake of more than 1,000 mg confers a 41% increased risk, compared with a lower intake. “The theory there is that vitamin C intake, once absorbed, results in a higher urine oxalate,” Dr. Zisman said.

Current epidemiology literature draws no clear association between a high-sodium diet and the development of kidney stones. From a clinical standpoint, however, “I think everyone would recommend a low-sodium diet because of the physiologic mechanisms leading to higher urine calcium,” she said.

Higher body mass index and increased waist circumference also impact the risk of developing kidney stones, especially among women. “The higher [they are], the greater the risk,” Dr. Zisman said. “We know that as weight goes up, urinary pH drops. Another potential reason is that as body weight goes up, urinary oxalate goes up as well.”

Step five in the recipe for stone formation is occupation. A study from Israel found that lifeguards in that country faced about a 20-fold increased risk of kidney stones, compared with that of the general population (Adv Exp Med Biol. 1980;128:467-72). Meanwhile, a study of glass factory workers in Italy found that the prevalence of kidney stones was 8.5% among those exposed to blast furnace sites, compared with 2.4% among those who worked in ambient temperatures (P = .03) (J Urol 1993 Dec;150[6]:1757-60). A similar finding was observed in a more recent study of steel factory workers in Brazil (Urology 2005;65[5]:858-61).

Variations to the “recipe” for kidney stones include certain genetic diseases such as primary hyperoxaluria and Dent disease; anatomic variations such as horseshoe kidney and ileal conduits; coexisting disease such as inflammatory bowel disease and primary hyperparathyroidism; and effects from medication such as acetazolamide/topiramate and prednisone.

“Mix up genetic predisposition, environmental factors, and dietary/lifestyle factors and add the magic ingredient,” Dr. Zisman concluded. “There is something that is affecting some people and not others. We don’t know what that is, and we clearly need more research.”

Dr. Zisman reported having no financial disclosures.

[email protected]

SAN DIEGO – The prevalence of kidney stone disease appears to be rising in the United States.

According to an analysis of responses from the 2007-2012 National Health and Nutrition Examination Survey (NHANES), 8.8% of people in the United States have kidney stone disease (Eur Urol. 2012 Jul;62[1]:160-5), up from a prevalence of 5.2% observed in the 1988-1994 NHANES.

“There’s also been a marked increase in emergency room visits for kidney stones: 91% between 1994 and 2006,” Dr. Anna L. Zisman said at the meeting sponsored by the American Society of Nephrology.

“Unfortunately, it doesn’t only affect adults. There has been an increased incidence in ER visits for kids as well.” Though good national data on the incidence of kidney stone disease in children are lacking, one study conducted in South Carolina found that the incidence of ER visits in children rose from 8 per 100,000 in 1996 to more than 18 per 100,000 in 2007 (J Pediatr. 2010 Jul;157[1]:132-7).

What’s driving these increases? Dr. Zisman, a nephrologist at the University of Chicago, discussed a “recipe” for how to create a kidney stone, with heredity as the first step.

“Pick your parents well,” she said. “The familial clustering index is higher for nephrolithiasis than for diabetes and hypertension. A family history of stone disease is present in 16%-37% of stone formers, compared with 4%-12% of healthy controls. And the heritability estimates – how much of a given disease or trait can be attributable to genetic predisposition – is somewhere between 46% and 63%.”

According to Mayo Clinic researchers, heritable traits for kidney stone disease based on 24-hour urine measurements, adjusted for diet, include calcium, magnesium, pH, and citrate (Clin J Am Soc Nephrol. 2014 May;9[5]:943-50).

“Hypercalciuria is the most well-established risk factor for stone disease,” Dr. Zisman said. “Up to 50% of subjects with stones have a history of hypercalciuria, and 43% of first-degree relatives of hypercalciuric patients have hypercalciuria.”

Race and gender are two factors people can’t control in their risk for kidney stone disease. NHANES data suggest that non-Hispanic whites are at highest risk for stone formation, compared with Hispanics and non-Hispanic blacks. However, among whites and all of the racial categories, males have a higher risk than females.

Step two in the recipe for stone formation is timing: Age matters.

According to an analysis of 49,976 men who participated in the Health Professionals Follow-Up Study, the highest risk of stone formation was in male patients in their 40s (J Am Soc Nephrol. 2004 Dec;15[12]:3225-32). By the time white males reach their 70s, the prevalence is almost 19%, while the prevalence for white women in their 70s is 9.4% (Eur Urol. 2012 Jul;62[1]:160-5).

Step three in the recipe is location. According to Dr. Zisman, the prevalence of kidney stone disease across the world is quite varied. “That likely has to do with both genetic predispositions as well as environmental factors,” she noted. “For example, Iran, which has a pretty warm climate, has a prevalence of 5.7%, Greece 15.2%, whereas Argentina only 4%. In the United States, data suggest that the highest incidence of stone disease is in the south. It is suspected that this is due to more men working outside in manual labor in the heat, but that’s just a hypothesis.”

Step four in the recipe involves the role of certain nutrients. For example, a higher daily calcium intake is associated with a lower risk of kidney stone formation. “The theory is that with higher dietary calcium, your urine oxalate tends to drop,” she said. Increased intake of magnesium, protein, potassium, and fluid are also associated with decreased stone formation.

On the other hand, a higher daily vitamin C intake is associated with an increased risk of stone formation. Specifically, a daily intake of more than 1,000 mg confers a 41% increased risk, compared with a lower intake. “The theory there is that vitamin C intake, once absorbed, results in a higher urine oxalate,” Dr. Zisman said.

Current epidemiology literature draws no clear association between a high-sodium diet and the development of kidney stones. From a clinical standpoint, however, “I think everyone would recommend a low-sodium diet because of the physiologic mechanisms leading to higher urine calcium,” she said.

Higher body mass index and increased waist circumference also impact the risk of developing kidney stones, especially among women. “The higher [they are], the greater the risk,” Dr. Zisman said. “We know that as weight goes up, urinary pH drops. Another potential reason is that as body weight goes up, urinary oxalate goes up as well.”

Step five in the recipe for stone formation is occupation. A study from Israel found that lifeguards in that country faced about a 20-fold increased risk of kidney stones, compared with that of the general population (Adv Exp Med Biol. 1980;128:467-72). Meanwhile, a study of glass factory workers in Italy found that the prevalence of kidney stones was 8.5% among those exposed to blast furnace sites, compared with 2.4% among those who worked in ambient temperatures (P = .03) (J Urol 1993 Dec;150[6]:1757-60). A similar finding was observed in a more recent study of steel factory workers in Brazil (Urology 2005;65[5]:858-61).

Variations to the “recipe” for kidney stones include certain genetic diseases such as primary hyperoxaluria and Dent disease; anatomic variations such as horseshoe kidney and ileal conduits; coexisting disease such as inflammatory bowel disease and primary hyperparathyroidism; and effects from medication such as acetazolamide/topiramate and prednisone.

“Mix up genetic predisposition, environmental factors, and dietary/lifestyle factors and add the magic ingredient,” Dr. Zisman concluded. “There is something that is affecting some people and not others. We don’t know what that is, and we clearly need more research.”

Dr. Zisman reported having no financial disclosures.

[email protected]

SAN DIEGO – The prevalence of kidney stone disease appears to be rising in the United States.

According to an analysis of responses from the 2007-2012 National Health and Nutrition Examination Survey (NHANES), 8.8% of people in the United States have kidney stone disease (Eur Urol. 2012 Jul;62[1]:160-5), up from a prevalence of 5.2% observed in the 1988-1994 NHANES.

“There’s also been a marked increase in emergency room visits for kidney stones: 91% between 1994 and 2006,” Dr. Anna L. Zisman said at the meeting sponsored by the American Society of Nephrology.

“Unfortunately, it doesn’t only affect adults. There has been an increased incidence in ER visits for kids as well.” Though good national data on the incidence of kidney stone disease in children are lacking, one study conducted in South Carolina found that the incidence of ER visits in children rose from 8 per 100,000 in 1996 to more than 18 per 100,000 in 2007 (J Pediatr. 2010 Jul;157[1]:132-7).

What’s driving these increases? Dr. Zisman, a nephrologist at the University of Chicago, discussed a “recipe” for how to create a kidney stone, with heredity as the first step.

“Pick your parents well,” she said. “The familial clustering index is higher for nephrolithiasis than for diabetes and hypertension. A family history of stone disease is present in 16%-37% of stone formers, compared with 4%-12% of healthy controls. And the heritability estimates – how much of a given disease or trait can be attributable to genetic predisposition – is somewhere between 46% and 63%.”

According to Mayo Clinic researchers, heritable traits for kidney stone disease based on 24-hour urine measurements, adjusted for diet, include calcium, magnesium, pH, and citrate (Clin J Am Soc Nephrol. 2014 May;9[5]:943-50).

“Hypercalciuria is the most well-established risk factor for stone disease,” Dr. Zisman said. “Up to 50% of subjects with stones have a history of hypercalciuria, and 43% of first-degree relatives of hypercalciuric patients have hypercalciuria.”

Race and gender are two factors people can’t control in their risk for kidney stone disease. NHANES data suggest that non-Hispanic whites are at highest risk for stone formation, compared with Hispanics and non-Hispanic blacks. However, among whites and all of the racial categories, males have a higher risk than females.

Step two in the recipe for stone formation is timing: Age matters.

According to an analysis of 49,976 men who participated in the Health Professionals Follow-Up Study, the highest risk of stone formation was in male patients in their 40s (J Am Soc Nephrol. 2004 Dec;15[12]:3225-32). By the time white males reach their 70s, the prevalence is almost 19%, while the prevalence for white women in their 70s is 9.4% (Eur Urol. 2012 Jul;62[1]:160-5).

Step three in the recipe is location. According to Dr. Zisman, the prevalence of kidney stone disease across the world is quite varied. “That likely has to do with both genetic predispositions as well as environmental factors,” she noted. “For example, Iran, which has a pretty warm climate, has a prevalence of 5.7%, Greece 15.2%, whereas Argentina only 4%. In the United States, data suggest that the highest incidence of stone disease is in the south. It is suspected that this is due to more men working outside in manual labor in the heat, but that’s just a hypothesis.”

Step four in the recipe involves the role of certain nutrients. For example, a higher daily calcium intake is associated with a lower risk of kidney stone formation. “The theory is that with higher dietary calcium, your urine oxalate tends to drop,” she said. Increased intake of magnesium, protein, potassium, and fluid are also associated with decreased stone formation.

On the other hand, a higher daily vitamin C intake is associated with an increased risk of stone formation. Specifically, a daily intake of more than 1,000 mg confers a 41% increased risk, compared with a lower intake. “The theory there is that vitamin C intake, once absorbed, results in a higher urine oxalate,” Dr. Zisman said.

Current epidemiology literature draws no clear association between a high-sodium diet and the development of kidney stones. From a clinical standpoint, however, “I think everyone would recommend a low-sodium diet because of the physiologic mechanisms leading to higher urine calcium,” she said.

Higher body mass index and increased waist circumference also impact the risk of developing kidney stones, especially among women. “The higher [they are], the greater the risk,” Dr. Zisman said. “We know that as weight goes up, urinary pH drops. Another potential reason is that as body weight goes up, urinary oxalate goes up as well.”

Step five in the recipe for stone formation is occupation. A study from Israel found that lifeguards in that country faced about a 20-fold increased risk of kidney stones, compared with that of the general population (Adv Exp Med Biol. 1980;128:467-72). Meanwhile, a study of glass factory workers in Italy found that the prevalence of kidney stones was 8.5% among those exposed to blast furnace sites, compared with 2.4% among those who worked in ambient temperatures (P = .03) (J Urol 1993 Dec;150[6]:1757-60). A similar finding was observed in a more recent study of steel factory workers in Brazil (Urology 2005;65[5]:858-61).

Variations to the “recipe” for kidney stones include certain genetic diseases such as primary hyperoxaluria and Dent disease; anatomic variations such as horseshoe kidney and ileal conduits; coexisting disease such as inflammatory bowel disease and primary hyperparathyroidism; and effects from medication such as acetazolamide/topiramate and prednisone.

“Mix up genetic predisposition, environmental factors, and dietary/lifestyle factors and add the magic ingredient,” Dr. Zisman concluded. “There is something that is affecting some people and not others. We don’t know what that is, and we clearly need more research.”

Dr. Zisman reported having no financial disclosures.

[email protected]