Transplant

PHILADELPHIA – A 3-month course of levofloxacin after kidney transplant didn’t prevent BK virus from colonizing the urine, setting the stage for viremia in these immunosuppressed patients.

However, the antibiotic was associated with a significant 75% increase in the risk of developing a quinolone-resistant infection, compared with placebo, Dr. Greg A. Knoll and his colleagues reported in the Nov. 15 issue of JAMA (2014 [doi:10.1001/jama.2014.14721]).In a randomized trial of 154 kidney transplant patients, BK virus developed in 29% of those taking levofloxacin and in 33% of those taking placebo, a nonsignificant difference, coauthor Greg Knoll said at a late-breaking poster session during Kidney Week 2014, where the study was simultaneously presented.Levofloxacin, a quinolone antibiotic, has been shown to have some antiviral properties, especially against polyomaviruses – including BK virus, said Dr. Knoll of the University of Ottawa and the Ottawa Hospital.

Almost everyone harbors latent BK virus, Dr. Knoll said in an interview. It sometimes causes mild cold symptoms when first contracted, but often there’s no indication of illness at all. “If you’re otherwise healthy, it goes dormant and stays that way,” he noted.

But it can cause serious problems in immunocompromised patients, especially those with a kidney transplant. “BK virus tends to live in the bladder and urinary tract,” Dr. Knoll said, “So, when it reactivates, that’s the site where it does its damage.”

The virus will first appear in the urine, and then follow a logical progression through the ureters and into the kidney. If it remains unchecked, it causes very severe kidney inflammation. That inflammation “looks a lot like rejection,” Dr. Knoll said. “In fact, for years, we were very confused about this and ended up giving patients with BK viremia more immunosuppressants – when we actually should have been giving them less.”

It’s been tough to find the right balance of treatment to combat BK infections and immunosuppressants to maintain the allograft, he said.

Some retrospective studies suggested that quinolone antibiotics – including levofloxacin – could help fight cytomegalovirus infections and viral pneumonia, and decrease inflammatory markers in the urine of kidney transplant patients. “This was the little bit of evidence we needed to launch this study,” Dr. Knoll said.

The study investigators examined the time to first occurrence of BK viruria within the first year of transplant. Secondary outcomes included BK viremia, peak viral load, rejection, and patient and allograft survival.

Patients’ mean age was 48 years. They had undergone kidney transplant for a variety of reasons, including glomerulonephritis, polycystic kidney disease, diabetes, and hypertension. Comorbidities were common and included diabetes, history of cancer, cardiovascular disease, and hepatitis C and B infections. Most had received a living donor transplant (60%); the rest had kidneys from deceased donors.

Treatment began soon after transplantation. Patients were randomized to a target dose of 500 mg/day levofloxacin for 3 months. The mean length of follow-up was 46 weeks.

The primary outcome of BK viruria occurred in 46 patients – 29% of those in the levofloxacin group and 33.3% of those in the placebo group. That translated to a nonsignificant increased viruria risk of about 4%.

The time to viruria was not significantly different between the groups, with nearly 25% of each group developing it by 25 weeks. Nor was there a between-group difference in the occurrence of sustained viruria.

The secondary endpoint of BK viremia occurred in 7.9% of the levofloxacin group and 11.5% of the placebo group, also a nonsignificant finding. Infections were similar in both group, occurring in 59% of those taking levofloxacin and 45% of those taking placebo. The types of infections were similar: urinary tract/pyelonephritis (37% active vs. 38% placebo); cytomegalovirus (35% vs. 33%); pneumonia (3.5% vs. 1.7%); cellulitis (2.7% vs. 0.8%); and line infections and bacteremias, which were less than 1% in each group. No patient developed a Clostridium difficile infection.

However, patients taking levofloxacin developed significantly more quinolone-resistant infections (46.7% vs. 32.6%). Among isolates that are usually sensitive to quinolones, those patients taking the study drug were 75% more likely than were placebo patients to have a resistant strain (58.3% vs. 33.3%).

Because quinolones are an important part of infection prophylaxis in kidney transplant patients, “This would have significant implications for the management of common infections after transplantation,” Dr. Knoll said. “Our results don’t support the use of levofloxacin for preventing infections in patients with kidney transplants.”

The researchers were disappointed in the outcomes, “but there were people doing this already, and now we have the evidence to tell them to stop,” Dr. Knoll explained. “Of course, we are back to square one, with no proven treatment.”

He added that the quinolones remain critical antibiotics for kidney transplant patients – and that the study in no way suggests that should change.

“We were using these daily for 3 months, and that’s where we got into the resistance trouble,” he said. “That’s not anything like a 7- to 10-day course for a urinary tract infection.”

Dr. Knoll reported receiving investigator-initiated research grants from Astellas Canada and Pfizer Canada. The other coauthors had a number of financial relationships with pharmaceutical companies.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

PHILADELPHIA – A 3-month course of levofloxacin after kidney transplant didn’t prevent BK virus from colonizing the urine, setting the stage for viremia in these immunosuppressed patients.

However, the antibiotic was associated with a significant 75% increase in the risk of developing a quinolone-resistant infection, compared with placebo, Dr. Greg A. Knoll and his colleagues reported in the Nov. 15 issue of JAMA (2014 [doi:10.1001/jama.2014.14721]).In a randomized trial of 154 kidney transplant patients, BK virus developed in 29% of those taking levofloxacin and in 33% of those taking placebo, a nonsignificant difference, coauthor Greg Knoll said at a late-breaking poster session during Kidney Week 2014, where the study was simultaneously presented.Levofloxacin, a quinolone antibiotic, has been shown to have some antiviral properties, especially against polyomaviruses – including BK virus, said Dr. Knoll of the University of Ottawa and the Ottawa Hospital.

Almost everyone harbors latent BK virus, Dr. Knoll said in an interview. It sometimes causes mild cold symptoms when first contracted, but often there’s no indication of illness at all. “If you’re otherwise healthy, it goes dormant and stays that way,” he noted.

But it can cause serious problems in immunocompromised patients, especially those with a kidney transplant. “BK virus tends to live in the bladder and urinary tract,” Dr. Knoll said, “So, when it reactivates, that’s the site where it does its damage.”

The virus will first appear in the urine, and then follow a logical progression through the ureters and into the kidney. If it remains unchecked, it causes very severe kidney inflammation. That inflammation “looks a lot like rejection,” Dr. Knoll said. “In fact, for years, we were very confused about this and ended up giving patients with BK viremia more immunosuppressants – when we actually should have been giving them less.”

It’s been tough to find the right balance of treatment to combat BK infections and immunosuppressants to maintain the allograft, he said.

Some retrospective studies suggested that quinolone antibiotics – including levofloxacin – could help fight cytomegalovirus infections and viral pneumonia, and decrease inflammatory markers in the urine of kidney transplant patients. “This was the little bit of evidence we needed to launch this study,” Dr. Knoll said.

The study investigators examined the time to first occurrence of BK viruria within the first year of transplant. Secondary outcomes included BK viremia, peak viral load, rejection, and patient and allograft survival.

Patients’ mean age was 48 years. They had undergone kidney transplant for a variety of reasons, including glomerulonephritis, polycystic kidney disease, diabetes, and hypertension. Comorbidities were common and included diabetes, history of cancer, cardiovascular disease, and hepatitis C and B infections. Most had received a living donor transplant (60%); the rest had kidneys from deceased donors.

Treatment began soon after transplantation. Patients were randomized to a target dose of 500 mg/day levofloxacin for 3 months. The mean length of follow-up was 46 weeks.

The primary outcome of BK viruria occurred in 46 patients – 29% of those in the levofloxacin group and 33.3% of those in the placebo group. That translated to a nonsignificant increased viruria risk of about 4%.

The time to viruria was not significantly different between the groups, with nearly 25% of each group developing it by 25 weeks. Nor was there a between-group difference in the occurrence of sustained viruria.

The secondary endpoint of BK viremia occurred in 7.9% of the levofloxacin group and 11.5% of the placebo group, also a nonsignificant finding. Infections were similar in both group, occurring in 59% of those taking levofloxacin and 45% of those taking placebo. The types of infections were similar: urinary tract/pyelonephritis (37% active vs. 38% placebo); cytomegalovirus (35% vs. 33%); pneumonia (3.5% vs. 1.7%); cellulitis (2.7% vs. 0.8%); and line infections and bacteremias, which were less than 1% in each group. No patient developed a Clostridium difficile infection.

However, patients taking levofloxacin developed significantly more quinolone-resistant infections (46.7% vs. 32.6%). Among isolates that are usually sensitive to quinolones, those patients taking the study drug were 75% more likely than were placebo patients to have a resistant strain (58.3% vs. 33.3%).

Because quinolones are an important part of infection prophylaxis in kidney transplant patients, “This would have significant implications for the management of common infections after transplantation,” Dr. Knoll said. “Our results don’t support the use of levofloxacin for preventing infections in patients with kidney transplants.”

The researchers were disappointed in the outcomes, “but there were people doing this already, and now we have the evidence to tell them to stop,” Dr. Knoll explained. “Of course, we are back to square one, with no proven treatment.”

He added that the quinolones remain critical antibiotics for kidney transplant patients – and that the study in no way suggests that should change.

“We were using these daily for 3 months, and that’s where we got into the resistance trouble,” he said. “That’s not anything like a 7- to 10-day course for a urinary tract infection.”

Dr. Knoll reported receiving investigator-initiated research grants from Astellas Canada and Pfizer Canada. The other coauthors had a number of financial relationships with pharmaceutical companies.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

PHILADELPHIA – A 3-month course of levofloxacin after kidney transplant didn’t prevent BK virus from colonizing the urine, setting the stage for viremia in these immunosuppressed patients.

However, the antibiotic was associated with a significant 75% increase in the risk of developing a quinolone-resistant infection, compared with placebo, Dr. Greg A. Knoll and his colleagues reported in the Nov. 15 issue of JAMA (2014 [doi:10.1001/jama.2014.14721]).In a randomized trial of 154 kidney transplant patients, BK virus developed in 29% of those taking levofloxacin and in 33% of those taking placebo, a nonsignificant difference, coauthor Greg Knoll said at a late-breaking poster session during Kidney Week 2014, where the study was simultaneously presented.Levofloxacin, a quinolone antibiotic, has been shown to have some antiviral properties, especially against polyomaviruses – including BK virus, said Dr. Knoll of the University of Ottawa and the Ottawa Hospital.

Almost everyone harbors latent BK virus, Dr. Knoll said in an interview. It sometimes causes mild cold symptoms when first contracted, but often there’s no indication of illness at all. “If you’re otherwise healthy, it goes dormant and stays that way,” he noted.

But it can cause serious problems in immunocompromised patients, especially those with a kidney transplant. “BK virus tends to live in the bladder and urinary tract,” Dr. Knoll said, “So, when it reactivates, that’s the site where it does its damage.”

The virus will first appear in the urine, and then follow a logical progression through the ureters and into the kidney. If it remains unchecked, it causes very severe kidney inflammation. That inflammation “looks a lot like rejection,” Dr. Knoll said. “In fact, for years, we were very confused about this and ended up giving patients with BK viremia more immunosuppressants – when we actually should have been giving them less.”

It’s been tough to find the right balance of treatment to combat BK infections and immunosuppressants to maintain the allograft, he said.

Some retrospective studies suggested that quinolone antibiotics – including levofloxacin – could help fight cytomegalovirus infections and viral pneumonia, and decrease inflammatory markers in the urine of kidney transplant patients. “This was the little bit of evidence we needed to launch this study,” Dr. Knoll said.

The study investigators examined the time to first occurrence of BK viruria within the first year of transplant. Secondary outcomes included BK viremia, peak viral load, rejection, and patient and allograft survival.

Patients’ mean age was 48 years. They had undergone kidney transplant for a variety of reasons, including glomerulonephritis, polycystic kidney disease, diabetes, and hypertension. Comorbidities were common and included diabetes, history of cancer, cardiovascular disease, and hepatitis C and B infections. Most had received a living donor transplant (60%); the rest had kidneys from deceased donors.

Treatment began soon after transplantation. Patients were randomized to a target dose of 500 mg/day levofloxacin for 3 months. The mean length of follow-up was 46 weeks.

The primary outcome of BK viruria occurred in 46 patients – 29% of those in the levofloxacin group and 33.3% of those in the placebo group. That translated to a nonsignificant increased viruria risk of about 4%.

The time to viruria was not significantly different between the groups, with nearly 25% of each group developing it by 25 weeks. Nor was there a between-group difference in the occurrence of sustained viruria.

The secondary endpoint of BK viremia occurred in 7.9% of the levofloxacin group and 11.5% of the placebo group, also a nonsignificant finding. Infections were similar in both group, occurring in 59% of those taking levofloxacin and 45% of those taking placebo. The types of infections were similar: urinary tract/pyelonephritis (37% active vs. 38% placebo); cytomegalovirus (35% vs. 33%); pneumonia (3.5% vs. 1.7%); cellulitis (2.7% vs. 0.8%); and line infections and bacteremias, which were less than 1% in each group. No patient developed a Clostridium difficile infection.

However, patients taking levofloxacin developed significantly more quinolone-resistant infections (46.7% vs. 32.6%). Among isolates that are usually sensitive to quinolones, those patients taking the study drug were 75% more likely than were placebo patients to have a resistant strain (58.3% vs. 33.3%).

Because quinolones are an important part of infection prophylaxis in kidney transplant patients, “This would have significant implications for the management of common infections after transplantation,” Dr. Knoll said. “Our results don’t support the use of levofloxacin for preventing infections in patients with kidney transplants.”

The researchers were disappointed in the outcomes, “but there were people doing this already, and now we have the evidence to tell them to stop,” Dr. Knoll explained. “Of course, we are back to square one, with no proven treatment.”

He added that the quinolones remain critical antibiotics for kidney transplant patients – and that the study in no way suggests that should change.

“We were using these daily for 3 months, and that’s where we got into the resistance trouble,” he said. “That’s not anything like a 7- to 10-day course for a urinary tract infection.”

Dr. Knoll reported receiving investigator-initiated research grants from Astellas Canada and Pfizer Canada. The other coauthors had a number of financial relationships with pharmaceutical companies.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

Women who donate a kidney are almost two and a half times more likely than are nondonors to have preeclampsia or gestational hypertension in pregnancy, according to a study presented at Kidney Week 2014 and published online simultaneously in the New England Journal of Medicine.

“Information on this potential risk should be included in clinical practice guidelines, shared in the informed-consent processes for potential donors and their recipients when a woman has reproductive potential, and used to guide the care of pregnant donors,” wrote the study authors, led by Dr. Amit X. Garg at the London Kidney Research Unit in London, Ont. (N. Engl. J. Med. 2014 Nov. 14 [doi:10.1056/NEJMoa1408932]).

©Chuhail/thinkstockphotos.com

The Canadian retrospective study matched 85 living kidney donors in a 1:6 ratio with 510 healthy nondonors and followed them for almost 11 years. During this time, 131 pregnancies occurred in the donor group and 788 in the nondonor group.

Gestational hypertension or preeclampsia was diagnosed in 15 donors and 38 nondonors (11% vs. 5%, odds ratio for donors, 2.4; 95% confidence interval, 1.2 to 5.0; P = .01), the investigators reported.

No significant differences were observed between groups for other maternal or fetal outcomes, and there were no maternal or perinatal deaths in the study that was part of the Donor Nephrectomy Outcomes Research Network (DONOR).

However, they noted that the study included limitations, such as not recording body mass index, medication use, or the race of study participants.

Confidence intervals for risk estimates also were wide, and physicians used clinical judgment when applying accepted diagnostic criteria for gestational hypertension and preeclampsia.

“It remains possible that gestational hypertension and preeclampsia were more likely to be diagnosed and recorded among donors than nondonors despite similar clinical presentations in two groups,” the investigators wrote.

“There may be a role for government programs to cover the costs of recommended pregnancy care for donors who lack health insurance, including any costs related to the treatment of hypertension,” they added.

The meeting was sponsored by the American Society of Nephrology. The study was supported by a grant from the Canadian Institute of Health Research as well as several other research institutions. Dr. Garg received grants from Astellas and Roche outside this study. Several other authors received grants from a number companies outside this study, while the remainder of the authors had no relevant disclosures.

Women who donate a kidney are almost two and a half times more likely than are nondonors to have preeclampsia or gestational hypertension in pregnancy, according to a study presented at Kidney Week 2014 and published online simultaneously in the New England Journal of Medicine.

“Information on this potential risk should be included in clinical practice guidelines, shared in the informed-consent processes for potential donors and their recipients when a woman has reproductive potential, and used to guide the care of pregnant donors,” wrote the study authors, led by Dr. Amit X. Garg at the London Kidney Research Unit in London, Ont. (N. Engl. J. Med. 2014 Nov. 14 [doi:10.1056/NEJMoa1408932]).

©Chuhail/thinkstockphotos.com

The Canadian retrospective study matched 85 living kidney donors in a 1:6 ratio with 510 healthy nondonors and followed them for almost 11 years. During this time, 131 pregnancies occurred in the donor group and 788 in the nondonor group.

Gestational hypertension or preeclampsia was diagnosed in 15 donors and 38 nondonors (11% vs. 5%, odds ratio for donors, 2.4; 95% confidence interval, 1.2 to 5.0; P = .01), the investigators reported.

No significant differences were observed between groups for other maternal or fetal outcomes, and there were no maternal or perinatal deaths in the study that was part of the Donor Nephrectomy Outcomes Research Network (DONOR).

However, they noted that the study included limitations, such as not recording body mass index, medication use, or the race of study participants.

Confidence intervals for risk estimates also were wide, and physicians used clinical judgment when applying accepted diagnostic criteria for gestational hypertension and preeclampsia.

“It remains possible that gestational hypertension and preeclampsia were more likely to be diagnosed and recorded among donors than nondonors despite similar clinical presentations in two groups,” the investigators wrote.

“There may be a role for government programs to cover the costs of recommended pregnancy care for donors who lack health insurance, including any costs related to the treatment of hypertension,” they added.

The meeting was sponsored by the American Society of Nephrology. The study was supported by a grant from the Canadian Institute of Health Research as well as several other research institutions. Dr. Garg received grants from Astellas and Roche outside this study. Several other authors received grants from a number companies outside this study, while the remainder of the authors had no relevant disclosures.

Women who donate a kidney are almost two and a half times more likely than are nondonors to have preeclampsia or gestational hypertension in pregnancy, according to a study presented at Kidney Week 2014 and published online simultaneously in the New England Journal of Medicine.

“Information on this potential risk should be included in clinical practice guidelines, shared in the informed-consent processes for potential donors and their recipients when a woman has reproductive potential, and used to guide the care of pregnant donors,” wrote the study authors, led by Dr. Amit X. Garg at the London Kidney Research Unit in London, Ont. (N. Engl. J. Med. 2014 Nov. 14 [doi:10.1056/NEJMoa1408932]).

©Chuhail/thinkstockphotos.com

The Canadian retrospective study matched 85 living kidney donors in a 1:6 ratio with 510 healthy nondonors and followed them for almost 11 years. During this time, 131 pregnancies occurred in the donor group and 788 in the nondonor group.

Gestational hypertension or preeclampsia was diagnosed in 15 donors and 38 nondonors (11% vs. 5%, odds ratio for donors, 2.4; 95% confidence interval, 1.2 to 5.0; P = .01), the investigators reported.

No significant differences were observed between groups for other maternal or fetal outcomes, and there were no maternal or perinatal deaths in the study that was part of the Donor Nephrectomy Outcomes Research Network (DONOR).

However, they noted that the study included limitations, such as not recording body mass index, medication use, or the race of study participants.

Confidence intervals for risk estimates also were wide, and physicians used clinical judgment when applying accepted diagnostic criteria for gestational hypertension and preeclampsia.

“It remains possible that gestational hypertension and preeclampsia were more likely to be diagnosed and recorded among donors than nondonors despite similar clinical presentations in two groups,” the investigators wrote.

“There may be a role for government programs to cover the costs of recommended pregnancy care for donors who lack health insurance, including any costs related to the treatment of hypertension,” they added.

The meeting was sponsored by the American Society of Nephrology. The study was supported by a grant from the Canadian Institute of Health Research as well as several other research institutions. Dr. Garg received grants from Astellas and Roche outside this study. Several other authors received grants from a number companies outside this study, while the remainder of the authors had no relevant disclosures.

An oral, interferon-free drug regimen produced a 97% rate of sustained virologic response in liver transplant recipients who had recurrent hepatitis C viral infection – “an historically difficult-to-treat population” at high risk of death who have extremely limited treatment options, according to a study reported at the annual meeting of the American Association for the Study of Liver Diseases.

In an industry-sponsored, open-label phase II trial involving 34 adults with recurrent HCV infection following liver transplantation, 24 weeks of daily ombitasvir plus the ritonavir-boosted protease inhibitor ABT-450 (ABT-50/r), added to dasabuvir and ribavirin, eradicated every patient’s HCV RNA levels within 4 months. Only one patient had a relapse during a further 24 weeks of follow-up, said Dr. Parvez Mantry of the Liver Institute at Methodist Dallas, who presented the data at the meeting.*

Results of the study, which was conducted at 10 transplant centers in the United States and Spain, were presented at the meeting and simultaneously published online Nov. 11 in the New England Journal of Medicine (N. Engl. J. Med. 2014 Nov. 11 [doi: 10.1056/NEJMoa1408921]).

The standard of care for treating recurrent HCV infection after liver transplantation has been 48 weeks of peginterferon with ribavirin, but response rates are relatively low (13%-43%) because of interferon’s toxic effects. Moreover, the agent is known to induce graft injury, reducing both graft and patient survival.

The investigators assessed the safety and efficacy of a tablet formulation combining ombitasvir, a potent NS5A inhibitor, with ABT-50/r, a protease inhibitor that increases peak, trough, and overall drug exposure and allows once-daily dosing. To this was added standard dasabuvir and ribavirin, with ribavirin dosing adjusted according to the treating physician’s discretion to avert adverse hematologic effects in these immunosuppressed transplant recipients. Modified doses of standard calcineurin inhibitors (cyclosporine or tacrolimus) also were recommended for all patients, and low-dose glucocorticoids were permitted as needed.

The study participants were 18-70 years of age (mean age, 59.6 years) and had received liver transplants because of chronic HCV infection a minimum of 1 year previously. They had no or only mild liver fibrosis, were receiving stable cyclosporine- or tacrolimus-based immunosuppression, and were not coinfected with HIV or hepatitis B.

The primary efficacy endpoint was a sustained virologic response (SVR) 12 weeks after treatment was completed. All the study participants achieved an SVR by week 4 of treatment, which persisted in all of them until treatment was completed. At that time, 1 patient relapsed, so the overall SVR rate was 97%. This same SVR rate was sustained through final follow-up at post-treatment week 24.

In the patient who relapsed, HCV DNA showed resistance-associated genetic variants that had not been present at baseline. This patient also had been unresponsive to previous peginterferon-ribavirin therapy.

Adverse events were common, although the majority were mild or moderate in severity. Fatigue, headache, and cough were the most frequent adverse events. Grade 2 elevations in total bilirubin developed in two patients (6%), with no jaundice or scleral icterus. Nine patients showed grade 2 decreases in hemoglobin; none required a blood transfusion, and five required erythropoietin. There were no deaths and no cases of graft rejection.

One patient discontinued the study drug at week 18 after developing moderate rash, memory impairment, and anxiety deemed to be possibly drug related. However, that patient had already achieved an SVR before discontinuing treatment, and that SVR persisted at final follow-up 12 weeks later.

However, this study was not large enough to allow adequate assessment of adverse event rates or comparison of them with rates for other treatments, the investigators noted.

The researchers also noted that these study participants were easier to treat than the general population of liver transplant recipients with recurrent HCV, because they did not have advanced fibrosis or comorbid infections. In addition, patients with early, aggressive forms of recurrent HCV, such as fibrosing cholestatic hepatitis, were excluded from this study, as were patients maintained on immunosuppressive agents other than cyclosporine or tacrolimus.

This trial was sponsored by AbbVie, whose employees also designed the study, gathered and analyzed the data, and wrote the report. Study investigator Dr. Paul Y. Kwo reported receiving personal fees and grants from, and serving on advisory boards for, AbbVie, Bristol-Myers Squibb, and other companies. His associates reported ties to numerous industry sources.

*Clarification, 11/11/14: A previous version of this story did not state that the data were presented by Dr. Mantry

An oral, interferon-free drug regimen produced a 97% rate of sustained virologic response in liver transplant recipients who had recurrent hepatitis C viral infection – “an historically difficult-to-treat population” at high risk of death who have extremely limited treatment options, according to a study reported at the annual meeting of the American Association for the Study of Liver Diseases.

In an industry-sponsored, open-label phase II trial involving 34 adults with recurrent HCV infection following liver transplantation, 24 weeks of daily ombitasvir plus the ritonavir-boosted protease inhibitor ABT-450 (ABT-50/r), added to dasabuvir and ribavirin, eradicated every patient’s HCV RNA levels within 4 months. Only one patient had a relapse during a further 24 weeks of follow-up, said Dr. Parvez Mantry of the Liver Institute at Methodist Dallas, who presented the data at the meeting.*

Results of the study, which was conducted at 10 transplant centers in the United States and Spain, were presented at the meeting and simultaneously published online Nov. 11 in the New England Journal of Medicine (N. Engl. J. Med. 2014 Nov. 11 [doi: 10.1056/NEJMoa1408921]).

The standard of care for treating recurrent HCV infection after liver transplantation has been 48 weeks of peginterferon with ribavirin, but response rates are relatively low (13%-43%) because of interferon’s toxic effects. Moreover, the agent is known to induce graft injury, reducing both graft and patient survival.

The investigators assessed the safety and efficacy of a tablet formulation combining ombitasvir, a potent NS5A inhibitor, with ABT-50/r, a protease inhibitor that increases peak, trough, and overall drug exposure and allows once-daily dosing. To this was added standard dasabuvir and ribavirin, with ribavirin dosing adjusted according to the treating physician’s discretion to avert adverse hematologic effects in these immunosuppressed transplant recipients. Modified doses of standard calcineurin inhibitors (cyclosporine or tacrolimus) also were recommended for all patients, and low-dose glucocorticoids were permitted as needed.

The study participants were 18-70 years of age (mean age, 59.6 years) and had received liver transplants because of chronic HCV infection a minimum of 1 year previously. They had no or only mild liver fibrosis, were receiving stable cyclosporine- or tacrolimus-based immunosuppression, and were not coinfected with HIV or hepatitis B.

The primary efficacy endpoint was a sustained virologic response (SVR) 12 weeks after treatment was completed. All the study participants achieved an SVR by week 4 of treatment, which persisted in all of them until treatment was completed. At that time, 1 patient relapsed, so the overall SVR rate was 97%. This same SVR rate was sustained through final follow-up at post-treatment week 24.

In the patient who relapsed, HCV DNA showed resistance-associated genetic variants that had not been present at baseline. This patient also had been unresponsive to previous peginterferon-ribavirin therapy.

Adverse events were common, although the majority were mild or moderate in severity. Fatigue, headache, and cough were the most frequent adverse events. Grade 2 elevations in total bilirubin developed in two patients (6%), with no jaundice or scleral icterus. Nine patients showed grade 2 decreases in hemoglobin; none required a blood transfusion, and five required erythropoietin. There were no deaths and no cases of graft rejection.

One patient discontinued the study drug at week 18 after developing moderate rash, memory impairment, and anxiety deemed to be possibly drug related. However, that patient had already achieved an SVR before discontinuing treatment, and that SVR persisted at final follow-up 12 weeks later.

However, this study was not large enough to allow adequate assessment of adverse event rates or comparison of them with rates for other treatments, the investigators noted.

The researchers also noted that these study participants were easier to treat than the general population of liver transplant recipients with recurrent HCV, because they did not have advanced fibrosis or comorbid infections. In addition, patients with early, aggressive forms of recurrent HCV, such as fibrosing cholestatic hepatitis, were excluded from this study, as were patients maintained on immunosuppressive agents other than cyclosporine or tacrolimus.

This trial was sponsored by AbbVie, whose employees also designed the study, gathered and analyzed the data, and wrote the report. Study investigator Dr. Paul Y. Kwo reported receiving personal fees and grants from, and serving on advisory boards for, AbbVie, Bristol-Myers Squibb, and other companies. His associates reported ties to numerous industry sources.

*Clarification, 11/11/14: A previous version of this story did not state that the data were presented by Dr. Mantry

An oral, interferon-free drug regimen produced a 97% rate of sustained virologic response in liver transplant recipients who had recurrent hepatitis C viral infection – “an historically difficult-to-treat population” at high risk of death who have extremely limited treatment options, according to a study reported at the annual meeting of the American Association for the Study of Liver Diseases.

In an industry-sponsored, open-label phase II trial involving 34 adults with recurrent HCV infection following liver transplantation, 24 weeks of daily ombitasvir plus the ritonavir-boosted protease inhibitor ABT-450 (ABT-50/r), added to dasabuvir and ribavirin, eradicated every patient’s HCV RNA levels within 4 months. Only one patient had a relapse during a further 24 weeks of follow-up, said Dr. Parvez Mantry of the Liver Institute at Methodist Dallas, who presented the data at the meeting.*

Results of the study, which was conducted at 10 transplant centers in the United States and Spain, were presented at the meeting and simultaneously published online Nov. 11 in the New England Journal of Medicine (N. Engl. J. Med. 2014 Nov. 11 [doi: 10.1056/NEJMoa1408921]).

The standard of care for treating recurrent HCV infection after liver transplantation has been 48 weeks of peginterferon with ribavirin, but response rates are relatively low (13%-43%) because of interferon’s toxic effects. Moreover, the agent is known to induce graft injury, reducing both graft and patient survival.

The investigators assessed the safety and efficacy of a tablet formulation combining ombitasvir, a potent NS5A inhibitor, with ABT-50/r, a protease inhibitor that increases peak, trough, and overall drug exposure and allows once-daily dosing. To this was added standard dasabuvir and ribavirin, with ribavirin dosing adjusted according to the treating physician’s discretion to avert adverse hematologic effects in these immunosuppressed transplant recipients. Modified doses of standard calcineurin inhibitors (cyclosporine or tacrolimus) also were recommended for all patients, and low-dose glucocorticoids were permitted as needed.

The study participants were 18-70 years of age (mean age, 59.6 years) and had received liver transplants because of chronic HCV infection a minimum of 1 year previously. They had no or only mild liver fibrosis, were receiving stable cyclosporine- or tacrolimus-based immunosuppression, and were not coinfected with HIV or hepatitis B.

The primary efficacy endpoint was a sustained virologic response (SVR) 12 weeks after treatment was completed. All the study participants achieved an SVR by week 4 of treatment, which persisted in all of them until treatment was completed. At that time, 1 patient relapsed, so the overall SVR rate was 97%. This same SVR rate was sustained through final follow-up at post-treatment week 24.

In the patient who relapsed, HCV DNA showed resistance-associated genetic variants that had not been present at baseline. This patient also had been unresponsive to previous peginterferon-ribavirin therapy.

Adverse events were common, although the majority were mild or moderate in severity. Fatigue, headache, and cough were the most frequent adverse events. Grade 2 elevations in total bilirubin developed in two patients (6%), with no jaundice or scleral icterus. Nine patients showed grade 2 decreases in hemoglobin; none required a blood transfusion, and five required erythropoietin. There were no deaths and no cases of graft rejection.

One patient discontinued the study drug at week 18 after developing moderate rash, memory impairment, and anxiety deemed to be possibly drug related. However, that patient had already achieved an SVR before discontinuing treatment, and that SVR persisted at final follow-up 12 weeks later.

However, this study was not large enough to allow adequate assessment of adverse event rates or comparison of them with rates for other treatments, the investigators noted.

The researchers also noted that these study participants were easier to treat than the general population of liver transplant recipients with recurrent HCV, because they did not have advanced fibrosis or comorbid infections. In addition, patients with early, aggressive forms of recurrent HCV, such as fibrosing cholestatic hepatitis, were excluded from this study, as were patients maintained on immunosuppressive agents other than cyclosporine or tacrolimus.

This trial was sponsored by AbbVie, whose employees also designed the study, gathered and analyzed the data, and wrote the report. Study investigator Dr. Paul Y. Kwo reported receiving personal fees and grants from, and serving on advisory boards for, AbbVie, Bristol-Myers Squibb, and other companies. His associates reported ties to numerous industry sources.

*Clarification, 11/11/14: A previous version of this story did not state that the data were presented by Dr. Mantry

The Food and Drug Administration has approved the use of sofosbuvir in combination with simeprevir for treatment of patients with chronic hepatitis C virus. It is a ribavirin- and interferon-free regimen.

The approval is reflected in changes to the label of simeprevir (Olysio), an HCV NS3/4A protease inhibitor, which was approved in 2013 for chronic hepatitis C genotype 1 infection “as a component of a combination antiviral treatment regimen.”

The new label summarizes the results of COSMOS, an open label, randomized phase II trial of HCV genotype 1–infected prior null responders with a METAVIR fibrosis score of F0 F2 or treatment naive subjects and prior null responders with a METAVIR fibrosis score of F3 F4 and compensated liver disease. The sustained virologic response rates 12 weeks after planned end of treatment was 93% among those treated with the combination for 12 weeks, and 97% among those treated for 24 weeks. The study was published online (Lancet 2014 July [doi:10.1016/S0140-6736(14)61036-9]).

In COSMOS, the most common adverse reactions reported by more than 10% of treated patients during 12 weeks of combination treatment were fatigue in 25%, headache (21%), nausea (21%), insomnia (14%), pruritus (11%), rash (11%), and photosensitivity (7%). Among those treated for 24 weeks, dizziness (16%) and diarrhea (16%) were reported, according to the revised label.

When combined with sofosbuvir, treatment of treatment-naive and treatment-experienced patients is recommended for 12 weeks (for patients without cirrhosis) or 24 weeks (for patients with cirrhosis).

Simeprevir is marketed by Janssen Therapeutics. Sofosbuvir, an HCV nucleotide analog NS5B polymerase inhibitor approved in December 2013 for treatment of chronic hepatitis C as a component of a combination antiviral treatment regimen, is marketed as Sovaldi by Gilead Sciences. The combination was approved Nov. 5.

emechcatie@frontlinemedcom.com

The Food and Drug Administration has approved the use of sofosbuvir in combination with simeprevir for treatment of patients with chronic hepatitis C virus. It is a ribavirin- and interferon-free regimen.

The approval is reflected in changes to the label of simeprevir (Olysio), an HCV NS3/4A protease inhibitor, which was approved in 2013 for chronic hepatitis C genotype 1 infection “as a component of a combination antiviral treatment regimen.”

The new label summarizes the results of COSMOS, an open label, randomized phase II trial of HCV genotype 1–infected prior null responders with a METAVIR fibrosis score of F0 F2 or treatment naive subjects and prior null responders with a METAVIR fibrosis score of F3 F4 and compensated liver disease. The sustained virologic response rates 12 weeks after planned end of treatment was 93% among those treated with the combination for 12 weeks, and 97% among those treated for 24 weeks. The study was published online (Lancet 2014 July [doi:10.1016/S0140-6736(14)61036-9]).

In COSMOS, the most common adverse reactions reported by more than 10% of treated patients during 12 weeks of combination treatment were fatigue in 25%, headache (21%), nausea (21%), insomnia (14%), pruritus (11%), rash (11%), and photosensitivity (7%). Among those treated for 24 weeks, dizziness (16%) and diarrhea (16%) were reported, according to the revised label.

When combined with sofosbuvir, treatment of treatment-naive and treatment-experienced patients is recommended for 12 weeks (for patients without cirrhosis) or 24 weeks (for patients with cirrhosis).

Simeprevir is marketed by Janssen Therapeutics. Sofosbuvir, an HCV nucleotide analog NS5B polymerase inhibitor approved in December 2013 for treatment of chronic hepatitis C as a component of a combination antiviral treatment regimen, is marketed as Sovaldi by Gilead Sciences. The combination was approved Nov. 5.

emechcatie@frontlinemedcom.com

The Food and Drug Administration has approved the use of sofosbuvir in combination with simeprevir for treatment of patients with chronic hepatitis C virus. It is a ribavirin- and interferon-free regimen.

The approval is reflected in changes to the label of simeprevir (Olysio), an HCV NS3/4A protease inhibitor, which was approved in 2013 for chronic hepatitis C genotype 1 infection “as a component of a combination antiviral treatment regimen.”

The new label summarizes the results of COSMOS, an open label, randomized phase II trial of HCV genotype 1–infected prior null responders with a METAVIR fibrosis score of F0 F2 or treatment naive subjects and prior null responders with a METAVIR fibrosis score of F3 F4 and compensated liver disease. The sustained virologic response rates 12 weeks after planned end of treatment was 93% among those treated with the combination for 12 weeks, and 97% among those treated for 24 weeks. The study was published online (Lancet 2014 July [doi:10.1016/S0140-6736(14)61036-9]).

In COSMOS, the most common adverse reactions reported by more than 10% of treated patients during 12 weeks of combination treatment were fatigue in 25%, headache (21%), nausea (21%), insomnia (14%), pruritus (11%), rash (11%), and photosensitivity (7%). Among those treated for 24 weeks, dizziness (16%) and diarrhea (16%) were reported, according to the revised label.

When combined with sofosbuvir, treatment of treatment-naive and treatment-experienced patients is recommended for 12 weeks (for patients without cirrhosis) or 24 weeks (for patients with cirrhosis).

Simeprevir is marketed by Janssen Therapeutics. Sofosbuvir, an HCV nucleotide analog NS5B polymerase inhibitor approved in December 2013 for treatment of chronic hepatitis C as a component of a combination antiviral treatment regimen, is marketed as Sovaldi by Gilead Sciences. The combination was approved Nov. 5.

emechcatie@frontlinemedcom.com

AUSTIN, TEX. – The risk of death at 1 year after lung transplantation with organs donated either after cardiac arrest or after brain death was virtually the same, an analysis of the literature has shown.

“Donation after cardiac death appears to be a safe and effective method to expand the donor pool,” said Dr. Dustin Krutsinger of the University of Iowa, Iowa City, who presented the findings during the Hot Topics in Pulmonary Critical Care session at the annual meeting of the American College of Chest Physicians.

Over the years, the demand for organ donations for lung transplant candidates has steadily increased while the number of available organs has remained static. This is due, in part, to physicians being concerned about injury to the organs during the ischemic period, as well as what can often be as much as an hour before organ procurement after withdrawal of life support. However, Dr. Krutsinger said the similarities between the two cohorts could result from the fact that before procurement, systemic circulation allows the lungs to oxygenate by perfusion, and so there is less impact during the ischemic period.

“There is also a thought that the ischemic period might actually protect the lungs and the liver from reperfusion injury. And we’re avoiding brain death, which is not a completely benign state,” he told the audience.

After conducting an extensive review of the literature for 1-year survival rates post lung transplantation, the investigators found 519 unique citations, including 58 citations selected for full text review, 10 observational cohort studies for systematic review, and another 5 such studies for meta-analysis.

Dr. Krutsinger and his colleagues found no significant difference in 1-year survival rates between the donation after cardiac death and the donation after brain death cohorts (P = .658). In a pooled analysis of the five studies, no significant difference in risk of death was found at 1 year after either transplantation procedure (relative risk, 0.66; 95% confidence interval, 0.38-1.15; P = .15). Although he thought the findings were limited by shortcomings in the data, such as the fact that the study was a retrospective analysis of unmatched cohorts and that the follow-up period was short, Dr. Krutsinger said in an interview that he thought the data were compelling enough for institutions to begin rethinking organ procurement and transplantation protocols. In addition to his own study, he cited a 2013 study which he said indicated that if lungs donated after cardiac arrest were included, the pool of available organs would increase by as much as 50% (Ann. Am. Thorac. Soc. 2013;10:73-80).

But challenges remain.

“There are some things you can do to the potential donors that are questionable ethicswise, such as administering heparin premortem, which would be beneficial to the actual recipients. But, up until they are pronounced dead, they are still a patient. You don’t really have that complication with a donation after brain death, since once brain death is determined, the person is officially dead. Things you then do to them to benefit the eventual recipients aren’t being done to a ‘patient.’ ”

Still, Dr. Krutsinger said that if organs procured after cardiac arrest were to become more common than after brain death, he would be “disappointed” since the data showed “the outcomes are similar, not inferior.”

Dr. Krutsinger said he had no relevant disclosures.

wmcknight@frontlinemedcom.com 


On Twitter @whitneymcknight

AUSTIN, TEX. – The risk of death at 1 year after lung transplantation with organs donated either after cardiac arrest or after brain death was virtually the same, an analysis of the literature has shown.

“Donation after cardiac death appears to be a safe and effective method to expand the donor pool,” said Dr. Dustin Krutsinger of the University of Iowa, Iowa City, who presented the findings during the Hot Topics in Pulmonary Critical Care session at the annual meeting of the American College of Chest Physicians.

Over the years, the demand for organ donations for lung transplant candidates has steadily increased while the number of available organs has remained static. This is due, in part, to physicians being concerned about injury to the organs during the ischemic period, as well as what can often be as much as an hour before organ procurement after withdrawal of life support. However, Dr. Krutsinger said the similarities between the two cohorts could result from the fact that before procurement, systemic circulation allows the lungs to oxygenate by perfusion, and so there is less impact during the ischemic period.

“There is also a thought that the ischemic period might actually protect the lungs and the liver from reperfusion injury. And we’re avoiding brain death, which is not a completely benign state,” he told the audience.

After conducting an extensive review of the literature for 1-year survival rates post lung transplantation, the investigators found 519 unique citations, including 58 citations selected for full text review, 10 observational cohort studies for systematic review, and another 5 such studies for meta-analysis.

Dr. Krutsinger and his colleagues found no significant difference in 1-year survival rates between the donation after cardiac death and the donation after brain death cohorts (P = .658). In a pooled analysis of the five studies, no significant difference in risk of death was found at 1 year after either transplantation procedure (relative risk, 0.66; 95% confidence interval, 0.38-1.15; P = .15). Although he thought the findings were limited by shortcomings in the data, such as the fact that the study was a retrospective analysis of unmatched cohorts and that the follow-up period was short, Dr. Krutsinger said in an interview that he thought the data were compelling enough for institutions to begin rethinking organ procurement and transplantation protocols. In addition to his own study, he cited a 2013 study which he said indicated that if lungs donated after cardiac arrest were included, the pool of available organs would increase by as much as 50% (Ann. Am. Thorac. Soc. 2013;10:73-80).

But challenges remain.

“There are some things you can do to the potential donors that are questionable ethicswise, such as administering heparin premortem, which would be beneficial to the actual recipients. But, up until they are pronounced dead, they are still a patient. You don’t really have that complication with a donation after brain death, since once brain death is determined, the person is officially dead. Things you then do to them to benefit the eventual recipients aren’t being done to a ‘patient.’ ”

Still, Dr. Krutsinger said that if organs procured after cardiac arrest were to become more common than after brain death, he would be “disappointed” since the data showed “the outcomes are similar, not inferior.”

Dr. Krutsinger said he had no relevant disclosures.

wmcknight@frontlinemedcom.com 


On Twitter @whitneymcknight

AUSTIN, TEX. – The risk of death at 1 year after lung transplantation with organs donated either after cardiac arrest or after brain death was virtually the same, an analysis of the literature has shown.

“Donation after cardiac death appears to be a safe and effective method to expand the donor pool,” said Dr. Dustin Krutsinger of the University of Iowa, Iowa City, who presented the findings during the Hot Topics in Pulmonary Critical Care session at the annual meeting of the American College of Chest Physicians.

Over the years, the demand for organ donations for lung transplant candidates has steadily increased while the number of available organs has remained static. This is due, in part, to physicians being concerned about injury to the organs during the ischemic period, as well as what can often be as much as an hour before organ procurement after withdrawal of life support. However, Dr. Krutsinger said the similarities between the two cohorts could result from the fact that before procurement, systemic circulation allows the lungs to oxygenate by perfusion, and so there is less impact during the ischemic period.

“There is also a thought that the ischemic period might actually protect the lungs and the liver from reperfusion injury. And we’re avoiding brain death, which is not a completely benign state,” he told the audience.

After conducting an extensive review of the literature for 1-year survival rates post lung transplantation, the investigators found 519 unique citations, including 58 citations selected for full text review, 10 observational cohort studies for systematic review, and another 5 such studies for meta-analysis.

Dr. Krutsinger and his colleagues found no significant difference in 1-year survival rates between the donation after cardiac death and the donation after brain death cohorts (P = .658). In a pooled analysis of the five studies, no significant difference in risk of death was found at 1 year after either transplantation procedure (relative risk, 0.66; 95% confidence interval, 0.38-1.15; P = .15). Although he thought the findings were limited by shortcomings in the data, such as the fact that the study was a retrospective analysis of unmatched cohorts and that the follow-up period was short, Dr. Krutsinger said in an interview that he thought the data were compelling enough for institutions to begin rethinking organ procurement and transplantation protocols. In addition to his own study, he cited a 2013 study which he said indicated that if lungs donated after cardiac arrest were included, the pool of available organs would increase by as much as 50% (Ann. Am. Thorac. Soc. 2013;10:73-80).

But challenges remain.

“There are some things you can do to the potential donors that are questionable ethicswise, such as administering heparin premortem, which would be beneficial to the actual recipients. But, up until they are pronounced dead, they are still a patient. You don’t really have that complication with a donation after brain death, since once brain death is determined, the person is officially dead. Things you then do to them to benefit the eventual recipients aren’t being done to a ‘patient.’ ”

Still, Dr. Krutsinger said that if organs procured after cardiac arrest were to become more common than after brain death, he would be “disappointed” since the data showed “the outcomes are similar, not inferior.”

Dr. Krutsinger said he had no relevant disclosures.

wmcknight@frontlinemedcom.com 


On Twitter @whitneymcknight

Patients who received lung transplants from donors who died of asphyxiation or drowning had similar survival rates and clinical outcomes as those whose donors died of other causes, according to a large registry analysis in the October issue of The Annals of Thoracic Surgery.

“Asphyxiation or drowning as a donor cause of death should not automatically exclude the organ from transplant consideration,” said Dr. Bryan A. Whitson of Ohio State University, Columbus, and his associates. Donor death from asphyxiation or drowning did not significantly affect rates of airway dehiscence, transplant rejection, posttransplant stroke or dialysis, or long-term survival.

Lungs donated after asphyxiation or drowning should be carefully evaluated for parenchymal injury, microbial contamination, and the possibility of primary graft dysfunction, the researchers cautioned. For example, asphyxiation and drowning can alter lung surfactant levels (Ann. Thorac. Surg. 2014;98:1145-51).

The analysis included 18,205 U.S. adults who underwent lung transplantation between 1987 and 2010, including 309 patients whose donors had reportedly died from drowning or asphyxiation. Patients were identified from the UNOS/OPTN STAR (United Network for Organ Sharing/Organ Procurement and Transplantation Network Standard Transplant Analysis and Research) database, which is overseen by the U.S. Department of Health & Human Services.

Ten-year survival curves did not vary based on donor cause of death, either when analyzed individually or when asphyxiation or drowning was compared with all other causes (P = .52), the researchers said. In fact, pulmonary deaths were significantly less common (5.8%) among recipients whose donors had died of asphyxiation or drowning compared with other causes (9.5%; P = .02).

Donor death from drowning and asphyxiation also did not significantly affect rates of treatment for transplant rejection within the first year after surgery (50.8% vs. 47.4% for all other causes of donor death), or posttransplant rates of stroke (0.7% vs. 2.1%) or dialysis (5.4% vs. 5.2%), the investigators said. However, hospital length of stay averaged 0.8 days longer when donors had died of asphyxiation or drowning compared with other causes (27.3 vs. 26.5 days; P < 0.001).

Patients who received lung transplants from donors who died of asphyxiation or drowning had similar survival rates and clinical outcomes as those whose donors died of other causes, according to a large registry analysis in the October issue of The Annals of Thoracic Surgery.

“Asphyxiation or drowning as a donor cause of death should not automatically exclude the organ from transplant consideration,” said Dr. Bryan A. Whitson of Ohio State University, Columbus, and his associates. Donor death from asphyxiation or drowning did not significantly affect rates of airway dehiscence, transplant rejection, posttransplant stroke or dialysis, or long-term survival.

Lungs donated after asphyxiation or drowning should be carefully evaluated for parenchymal injury, microbial contamination, and the possibility of primary graft dysfunction, the researchers cautioned. For example, asphyxiation and drowning can alter lung surfactant levels (Ann. Thorac. Surg. 2014;98:1145-51).

The analysis included 18,205 U.S. adults who underwent lung transplantation between 1987 and 2010, including 309 patients whose donors had reportedly died from drowning or asphyxiation. Patients were identified from the UNOS/OPTN STAR (United Network for Organ Sharing/Organ Procurement and Transplantation Network Standard Transplant Analysis and Research) database, which is overseen by the U.S. Department of Health & Human Services.

Ten-year survival curves did not vary based on donor cause of death, either when analyzed individually or when asphyxiation or drowning was compared with all other causes (P = .52), the researchers said. In fact, pulmonary deaths were significantly less common (5.8%) among recipients whose donors had died of asphyxiation or drowning compared with other causes (9.5%; P = .02).

Donor death from drowning and asphyxiation also did not significantly affect rates of treatment for transplant rejection within the first year after surgery (50.8% vs. 47.4% for all other causes of donor death), or posttransplant rates of stroke (0.7% vs. 2.1%) or dialysis (5.4% vs. 5.2%), the investigators said. However, hospital length of stay averaged 0.8 days longer when donors had died of asphyxiation or drowning compared with other causes (27.3 vs. 26.5 days; P < 0.001).

Patients who received lung transplants from donors who died of asphyxiation or drowning had similar survival rates and clinical outcomes as those whose donors died of other causes, according to a large registry analysis in the October issue of The Annals of Thoracic Surgery.

“Asphyxiation or drowning as a donor cause of death should not automatically exclude the organ from transplant consideration,” said Dr. Bryan A. Whitson of Ohio State University, Columbus, and his associates. Donor death from asphyxiation or drowning did not significantly affect rates of airway dehiscence, transplant rejection, posttransplant stroke or dialysis, or long-term survival.

Lungs donated after asphyxiation or drowning should be carefully evaluated for parenchymal injury, microbial contamination, and the possibility of primary graft dysfunction, the researchers cautioned. For example, asphyxiation and drowning can alter lung surfactant levels (Ann. Thorac. Surg. 2014;98:1145-51).

The analysis included 18,205 U.S. adults who underwent lung transplantation between 1987 and 2010, including 309 patients whose donors had reportedly died from drowning or asphyxiation. Patients were identified from the UNOS/OPTN STAR (United Network for Organ Sharing/Organ Procurement and Transplantation Network Standard Transplant Analysis and Research) database, which is overseen by the U.S. Department of Health & Human Services.

Ten-year survival curves did not vary based on donor cause of death, either when analyzed individually or when asphyxiation or drowning was compared with all other causes (P = .52), the researchers said. In fact, pulmonary deaths were significantly less common (5.8%) among recipients whose donors had died of asphyxiation or drowning compared with other causes (9.5%; P = .02).

Donor death from drowning and asphyxiation also did not significantly affect rates of treatment for transplant rejection within the first year after surgery (50.8% vs. 47.4% for all other causes of donor death), or posttransplant rates of stroke (0.7% vs. 2.1%) or dialysis (5.4% vs. 5.2%), the investigators said. However, hospital length of stay averaged 0.8 days longer when donors had died of asphyxiation or drowning compared with other causes (27.3 vs. 26.5 days; P < 0.001).

Delaying kidney transplantation to allow for quiescence of systemic lupus erythematosus–related immune activity in patients with lupus nephritis and end-stage renal disease does not appear to improve graft outcomes, according to an analysis of national surveillance data.

Of 4,743 transplant recipients with lupus nephritis and end-stage renal disease (LN-ESRD), 1,239 experienced graft failure. Overall, wait times of 3-12 months and 12-24 months were associated with 25% and 37% increased risk of graft failure, respectively, compared with wait times of less than 3 months, after adjustment for age, race, insurance, hemoglobin, and donor type.

A similar pattern was seen in white patients, except that wait times of more than 36 months in white patients were associated with a near doubling of graft failure risk (hazard ratio, 1.98), Laura C. Plantinga of Emory University, Atlanta, and her colleagues reported (Arthritis Care Res. 2014 Sept. 23 [doi:10.1002/acr.22482]).

Among black patients, longer wait times were not associated with graft failure in the adjusted analysis, and, in fact, there was a nonstatistically significant suggestion of a protective effect for wait time of 2 years or more. This finding may reflect unexplained differences in disease pathology between white and black LN-ESRD patients, the investigators said, adding that there was no increased risk of graft failure in black patients who were transplanted early.

“Our results suggest U.S. recommendations for transplantation in LN-ESRD may not align with evidence from the target population,” they said, noting that the results should be considered hypotheses-generating because of the limitations of the study and that additional study is needed to examine the potential confounding effects of clinically recognized SLE activity on the associations observed in this study.

Some of the investigators were supported through grants from the National Institutes of Health.

Delaying kidney transplantation to allow for quiescence of systemic lupus erythematosus–related immune activity in patients with lupus nephritis and end-stage renal disease does not appear to improve graft outcomes, according to an analysis of national surveillance data.

Of 4,743 transplant recipients with lupus nephritis and end-stage renal disease (LN-ESRD), 1,239 experienced graft failure. Overall, wait times of 3-12 months and 12-24 months were associated with 25% and 37% increased risk of graft failure, respectively, compared with wait times of less than 3 months, after adjustment for age, race, insurance, hemoglobin, and donor type.

A similar pattern was seen in white patients, except that wait times of more than 36 months in white patients were associated with a near doubling of graft failure risk (hazard ratio, 1.98), Laura C. Plantinga of Emory University, Atlanta, and her colleagues reported (Arthritis Care Res. 2014 Sept. 23 [doi:10.1002/acr.22482]).

Among black patients, longer wait times were not associated with graft failure in the adjusted analysis, and, in fact, there was a nonstatistically significant suggestion of a protective effect for wait time of 2 years or more. This finding may reflect unexplained differences in disease pathology between white and black LN-ESRD patients, the investigators said, adding that there was no increased risk of graft failure in black patients who were transplanted early.

“Our results suggest U.S. recommendations for transplantation in LN-ESRD may not align with evidence from the target population,” they said, noting that the results should be considered hypotheses-generating because of the limitations of the study and that additional study is needed to examine the potential confounding effects of clinically recognized SLE activity on the associations observed in this study.

Some of the investigators were supported through grants from the National Institutes of Health.

Delaying kidney transplantation to allow for quiescence of systemic lupus erythematosus–related immune activity in patients with lupus nephritis and end-stage renal disease does not appear to improve graft outcomes, according to an analysis of national surveillance data.

Of 4,743 transplant recipients with lupus nephritis and end-stage renal disease (LN-ESRD), 1,239 experienced graft failure. Overall, wait times of 3-12 months and 12-24 months were associated with 25% and 37% increased risk of graft failure, respectively, compared with wait times of less than 3 months, after adjustment for age, race, insurance, hemoglobin, and donor type.

A similar pattern was seen in white patients, except that wait times of more than 36 months in white patients were associated with a near doubling of graft failure risk (hazard ratio, 1.98), Laura C. Plantinga of Emory University, Atlanta, and her colleagues reported (Arthritis Care Res. 2014 Sept. 23 [doi:10.1002/acr.22482]).

Among black patients, longer wait times were not associated with graft failure in the adjusted analysis, and, in fact, there was a nonstatistically significant suggestion of a protective effect for wait time of 2 years or more. This finding may reflect unexplained differences in disease pathology between white and black LN-ESRD patients, the investigators said, adding that there was no increased risk of graft failure in black patients who were transplanted early.

“Our results suggest U.S. recommendations for transplantation in LN-ESRD may not align with evidence from the target population,” they said, noting that the results should be considered hypotheses-generating because of the limitations of the study and that additional study is needed to examine the potential confounding effects of clinically recognized SLE activity on the associations observed in this study.

Some of the investigators were supported through grants from the National Institutes of Health.

SAN FRANCISCO – The practice of preferentially using left instead of right kidneys in living donor kidney transplantation may no longer be justified in the era of contemporary laparoscopic surgery, suggests a national study reported at the 2014 World Transplant Congress.

"The current approach in many centers is to prefer left living donor nephrectomy due to longer vessel length...Right donor nephrectomy, at least in our center and I think in most centers, has generally been reserved for cases of multiple or complex vessels on the left or incidental anatomical abnormalities on the right like cysts or stones," commented presenting author Dr. Tim E. Taber of Indiana University in Indianapolis.

© London_England /Thinkstockphotos.com

Only one in seven of the roughly 59,000 living donor kidney transplants studied was performed using a right kidney. However, most short- and long-term outcomes were statistically indistinguishable between recipients of left and right kidneys, and the differences that were significant were small, he reported at the congress sponsored by the American Society of Transplant Surgeons.

"Our [study] is the largest national analysis or most recent large data analysis done on this subject in today’s surgical era of established laparoscopic living donor nephrectomies. There may be a minor risk for slightly inferior outcomes with right versus left kidneys," Dr. Taber concluded.

"Right-donor nephrectomy continues to be performed with great reluctance," he added. Yet, "under the accepted principles of live-donor nephrectomy, with enough surgical expertise, right-donor nephrectomy can be performed successfully. Right kidneys seem to have a very small difference, if any, in outcomes as compared to left kidneys. Surgical expertise and experience should be tailored toward this aspect."

A session attendee from Brazil commented, "We [prefer] to choose the right kidney in situations where we have one artery on the right side and multiple arteries on the left side." In these cases, his group uses an approach to the vasculature adopted from pancreas transplantation. "We have identical results with the right and left side," he reported.

Dr. Lloyd E. Ratner, director of renal and pancreatic transplantation at Columbia University Medical Center in New York, who also attended the session, said, "I feel somewhat responsible for causing this problem with the right kidney because we were the ones that originally described the higher thrombosis rate with the right kidney with the laparoscopic donor nephrectomies. And I think it scared everyone off from this topic."

As several attendees noted, "there are surgical ways of getting around this," he agreed, offering two more options. "The first is that if we get a short vein, we’re not reluctant at all to put a piece of Dacron onto it, so you don’t even need to dig out the saphenous and cause additional time or morbidity to the patient. And the nice thing about the Dacron grafts is that they are corrugated and they don’t collapse. They also stretch, so you don’t need to cut them exactly precisely," he said.

"And number two is when you are stapling ... it’s often useful to be able to staple onto the cava and not get the vein in one staple byte." By using two passes in the appropriate configuration, "you actually get a cuff of cava, then you have plenty of vein," he explained.

In the study, Dr. Taber and colleagues retrospectively analyzed data from 58,599 adult living donor kidney transplants performed during 2000-2009 and captured in the United Network for Organ Sharing (UNOS) database. In 86% of cases, surgeons used the donor’s left kidney.

Recipients of left and right kidneys were statistically indistinguishable with respect to hospital length of stay, treatment for acute rejection within 6 months, acute rejection as a cause of graft failure, inadequate urine production in the first 24 hours, primary graft failure, graft thrombosis or surgical complication as a contributory cause of graft failure, and 1-year graft survival.

Those receiving a right kidney did have significant but small increases in rates of delayed graft function, as defined by the need for dialysis within 7 days of transplantation (5.7% vs. 4.2%), lack of decline in serum creatinine in the first 24 hours (19.7% vs. 16.4%), treatment for acute rejection within 1 year (12.7% vs. 11.8%), and graft thrombosis as the cause of graft failure (1.1% vs. 0.8%).

The Kaplan-Meier cumulative rate of graft survival was better for left kidneys than for right kidneys (P = .006), but "these are essentially superimposed numbers," said Dr. Taber, who disclosed no conflicts of interest related to the research.

The study had limitations, such as its retrospective design, lack of more detailed information about donor and recipient outcomes, and reliance on data as reported by centers, he acknowledged. Also, such large studies may pick up small differences that are not clinically meaningful.

"With ever-increasing demands for living donor transplantation, right-donor nephrectomies are being considered more often. Every effort should be made to leave the donor with the higher-functioning kidney, but at the same time maximizing the living donor pool," Dr. Taber concluded.

Dr. Taber disclosed no relevant conflicts of interest.

SAN FRANCISCO – The practice of preferentially using left instead of right kidneys in living donor kidney transplantation may no longer be justified in the era of contemporary laparoscopic surgery, suggests a national study reported at the 2014 World Transplant Congress.

"The current approach in many centers is to prefer left living donor nephrectomy due to longer vessel length...Right donor nephrectomy, at least in our center and I think in most centers, has generally been reserved for cases of multiple or complex vessels on the left or incidental anatomical abnormalities on the right like cysts or stones," commented presenting author Dr. Tim E. Taber of Indiana University in Indianapolis.

© London_England /Thinkstockphotos.com

Only one in seven of the roughly 59,000 living donor kidney transplants studied was performed using a right kidney. However, most short- and long-term outcomes were statistically indistinguishable between recipients of left and right kidneys, and the differences that were significant were small, he reported at the congress sponsored by the American Society of Transplant Surgeons.

"Our [study] is the largest national analysis or most recent large data analysis done on this subject in today’s surgical era of established laparoscopic living donor nephrectomies. There may be a minor risk for slightly inferior outcomes with right versus left kidneys," Dr. Taber concluded.

"Right-donor nephrectomy continues to be performed with great reluctance," he added. Yet, "under the accepted principles of live-donor nephrectomy, with enough surgical expertise, right-donor nephrectomy can be performed successfully. Right kidneys seem to have a very small difference, if any, in outcomes as compared to left kidneys. Surgical expertise and experience should be tailored toward this aspect."

A session attendee from Brazil commented, "We [prefer] to choose the right kidney in situations where we have one artery on the right side and multiple arteries on the left side." In these cases, his group uses an approach to the vasculature adopted from pancreas transplantation. "We have identical results with the right and left side," he reported.

Dr. Lloyd E. Ratner, director of renal and pancreatic transplantation at Columbia University Medical Center in New York, who also attended the session, said, "I feel somewhat responsible for causing this problem with the right kidney because we were the ones that originally described the higher thrombosis rate with the right kidney with the laparoscopic donor nephrectomies. And I think it scared everyone off from this topic."

As several attendees noted, "there are surgical ways of getting around this," he agreed, offering two more options. "The first is that if we get a short vein, we’re not reluctant at all to put a piece of Dacron onto it, so you don’t even need to dig out the saphenous and cause additional time or morbidity to the patient. And the nice thing about the Dacron grafts is that they are corrugated and they don’t collapse. They also stretch, so you don’t need to cut them exactly precisely," he said.

"And number two is when you are stapling ... it’s often useful to be able to staple onto the cava and not get the vein in one staple byte." By using two passes in the appropriate configuration, "you actually get a cuff of cava, then you have plenty of vein," he explained.

In the study, Dr. Taber and colleagues retrospectively analyzed data from 58,599 adult living donor kidney transplants performed during 2000-2009 and captured in the United Network for Organ Sharing (UNOS) database. In 86% of cases, surgeons used the donor’s left kidney.

Recipients of left and right kidneys were statistically indistinguishable with respect to hospital length of stay, treatment for acute rejection within 6 months, acute rejection as a cause of graft failure, inadequate urine production in the first 24 hours, primary graft failure, graft thrombosis or surgical complication as a contributory cause of graft failure, and 1-year graft survival.

Those receiving a right kidney did have significant but small increases in rates of delayed graft function, as defined by the need for dialysis within 7 days of transplantation (5.7% vs. 4.2%), lack of decline in serum creatinine in the first 24 hours (19.7% vs. 16.4%), treatment for acute rejection within 1 year (12.7% vs. 11.8%), and graft thrombosis as the cause of graft failure (1.1% vs. 0.8%).

The Kaplan-Meier cumulative rate of graft survival was better for left kidneys than for right kidneys (P = .006), but "these are essentially superimposed numbers," said Dr. Taber, who disclosed no conflicts of interest related to the research.

The study had limitations, such as its retrospective design, lack of more detailed information about donor and recipient outcomes, and reliance on data as reported by centers, he acknowledged. Also, such large studies may pick up small differences that are not clinically meaningful.

"With ever-increasing demands for living donor transplantation, right-donor nephrectomies are being considered more often. Every effort should be made to leave the donor with the higher-functioning kidney, but at the same time maximizing the living donor pool," Dr. Taber concluded.

Dr. Taber disclosed no relevant conflicts of interest.

SAN FRANCISCO – The practice of preferentially using left instead of right kidneys in living donor kidney transplantation may no longer be justified in the era of contemporary laparoscopic surgery, suggests a national study reported at the 2014 World Transplant Congress.

"The current approach in many centers is to prefer left living donor nephrectomy due to longer vessel length...Right donor nephrectomy, at least in our center and I think in most centers, has generally been reserved for cases of multiple or complex vessels on the left or incidental anatomical abnormalities on the right like cysts or stones," commented presenting author Dr. Tim E. Taber of Indiana University in Indianapolis.

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Only one in seven of the roughly 59,000 living donor kidney transplants studied was performed using a right kidney. However, most short- and long-term outcomes were statistically indistinguishable between recipients of left and right kidneys, and the differences that were significant were small, he reported at the congress sponsored by the American Society of Transplant Surgeons.

"Our [study] is the largest national analysis or most recent large data analysis done on this subject in today’s surgical era of established laparoscopic living donor nephrectomies. There may be a minor risk for slightly inferior outcomes with right versus left kidneys," Dr. Taber concluded.

"Right-donor nephrectomy continues to be performed with great reluctance," he added. Yet, "under the accepted principles of live-donor nephrectomy, with enough surgical expertise, right-donor nephrectomy can be performed successfully. Right kidneys seem to have a very small difference, if any, in outcomes as compared to left kidneys. Surgical expertise and experience should be tailored toward this aspect."

A session attendee from Brazil commented, "We [prefer] to choose the right kidney in situations where we have one artery on the right side and multiple arteries on the left side." In these cases, his group uses an approach to the vasculature adopted from pancreas transplantation. "We have identical results with the right and left side," he reported.

Dr. Lloyd E. Ratner, director of renal and pancreatic transplantation at Columbia University Medical Center in New York, who also attended the session, said, "I feel somewhat responsible for causing this problem with the right kidney because we were the ones that originally described the higher thrombosis rate with the right kidney with the laparoscopic donor nephrectomies. And I think it scared everyone off from this topic."

As several attendees noted, "there are surgical ways of getting around this," he agreed, offering two more options. "The first is that if we get a short vein, we’re not reluctant at all to put a piece of Dacron onto it, so you don’t even need to dig out the saphenous and cause additional time or morbidity to the patient. And the nice thing about the Dacron grafts is that they are corrugated and they don’t collapse. They also stretch, so you don’t need to cut them exactly precisely," he said.

"And number two is when you are stapling ... it’s often useful to be able to staple onto the cava and not get the vein in one staple byte." By using two passes in the appropriate configuration, "you actually get a cuff of cava, then you have plenty of vein," he explained.

In the study, Dr. Taber and colleagues retrospectively analyzed data from 58,599 adult living donor kidney transplants performed during 2000-2009 and captured in the United Network for Organ Sharing (UNOS) database. In 86% of cases, surgeons used the donor’s left kidney.

Recipients of left and right kidneys were statistically indistinguishable with respect to hospital length of stay, treatment for acute rejection within 6 months, acute rejection as a cause of graft failure, inadequate urine production in the first 24 hours, primary graft failure, graft thrombosis or surgical complication as a contributory cause of graft failure, and 1-year graft survival.

Those receiving a right kidney did have significant but small increases in rates of delayed graft function, as defined by the need for dialysis within 7 days of transplantation (5.7% vs. 4.2%), lack of decline in serum creatinine in the first 24 hours (19.7% vs. 16.4%), treatment for acute rejection within 1 year (12.7% vs. 11.8%), and graft thrombosis as the cause of graft failure (1.1% vs. 0.8%).

The Kaplan-Meier cumulative rate of graft survival was better for left kidneys than for right kidneys (P = .006), but "these are essentially superimposed numbers," said Dr. Taber, who disclosed no conflicts of interest related to the research.

The study had limitations, such as its retrospective design, lack of more detailed information about donor and recipient outcomes, and reliance on data as reported by centers, he acknowledged. Also, such large studies may pick up small differences that are not clinically meaningful.

"With ever-increasing demands for living donor transplantation, right-donor nephrectomies are being considered more often. Every effort should be made to leave the donor with the higher-functioning kidney, but at the same time maximizing the living donor pool," Dr. Taber concluded.

Dr. Taber disclosed no relevant conflicts of interest.

SAN FRANCISCO – The type of liver graft used in transplantation plays a large role in early development of new-onset diabetes, according to a retrospective study of 430 patients from the United Kingdom.

A team led by Dr. Hermien Hartog, an honorary clinical fellow in the Liver Unit, Queen Elizabeth Hospital, Birmingham, England, studied patients undergoing primary liver transplant between 2008 and 2012. Patients were excluded from the study if they had preexisting diabetes, had died, or had undergone retransplantation within 90 days.

The investigators assessed both the development of new-onset diabetes after transplant (NODAT), using criteria adapted from a published article (Transplantation 2013;96:58-64), and its resolution, defined as the date of cessation of antihyperglycemic therapy or the last episode of hyperglycemia.

Seventy-nine percent of the patients received grafts donated after brain death (DBD), Dr. Hartog reported at the annual meeting of the 2014 World Transplant Congress. Among the recipients of grafts donated after circulatory death (DCD), the mean warm ischemic time was 21 minutes.

With a median follow-up of 2.5 years, the cumulative 1-year incidence of NODAT was 19% in the entire cohort, with a median time to onset of 30 days. In the 44% of affected patients whose NODAT resolved, the median time to resolution was 150 days post transplantation, Dr. Hartog reported at the congress, which was sponsored by the American Society of Transplant Surgeons.

The cumulative 1-year incidence of NODAT was 23% in DCD graft recipients and 18% in DBD graft recipients, a nonsignificant difference. But when patients were stratified by graft type, "we saw an early occurrence and high peak incidence of NODAT in DCD graft recipients. Also, a larger proportion of these patients resolved their NODAT over time," she commented.

The overall temporal pattern suggested that "the effect that we see of graft type seems to be temporary and [lessens] over time when multifactorial factors come into play," according to Dr. Hartog.

In multivariate analyses, the risk of NODAT within 90 days of transplantation was higher for patients who received a DCD graft (hazard ratio, 1.8). More detailed analysis showed that the elevation of risk was greatest within the first 15 days.

"Our study confirms known associations with NODAT after liver transplantation but identifies DCD graft as a novel risk factor. This causes a temporary effect in the early post-transplant period that is independent from known risk factors," Dr. Hartog commented.

"Based on our observations, we hypothesize that hyperglycemia may be related to liver graft function through ischemia-reperfusion–induced hepatic insulin resistance," she added. "We are currently trying to confirm our data in an independent data set, which will also include postreperfusion glucose levels and correlation with the insulin receptor pathway in time-zero liver biopsies."

"The clinical relevance of our findings is as yet unknown," she acknowledged. However, they may help inform new approaches for graft optimization and selection.

Session cochair Dr. Darius Mirza, also of the University of Birmingham, asked, "Why does the pattern of recovery seem to be different in the DCDs versus the DBDs? Also, why are the cumulative incidence and the time frame so different?"

"Actually, in the literature, I have not seen any reports looking at the early post-transplant period. So most reports look at one time point, normally 1 year," Dr. Hartog replied. "What I think is that there is an early peak caused by DCD grafts that would explain why there is an early peak, but also why those patients recover later on. I think this peak is a bit obscure because there are also other factors that come into play, maybe after a while, that will obscure that first peak. If you would take those other factors out of the equation, I think you would just see a peak in the early period."

Dr. Mirza also wondered about the role of using DCD grafts that are accepted under extended criteria. "So you start off using mainly young, fit DCD livers. Now, the vast majority are extended-criteria DCD livers. Do you think that plays a role, or is it too early to say?"

"Yes, I think so," Dr. Hartog said, while adding that this phenomenon is likely not restricted to DCD grafts. "From earlier literature, there is a clear difference between a living donated graft and deceased donation. And it might also be that the extended grafts or the more steatotic grafts may exhibit this effect more than the better grafts."

Dr. Hartog disclosed no conflicts of interest relevant to the research.

SAN FRANCISCO – The type of liver graft used in transplantation plays a large role in early development of new-onset diabetes, according to a retrospective study of 430 patients from the United Kingdom.

A team led by Dr. Hermien Hartog, an honorary clinical fellow in the Liver Unit, Queen Elizabeth Hospital, Birmingham, England, studied patients undergoing primary liver transplant between 2008 and 2012. Patients were excluded from the study if they had preexisting diabetes, had died, or had undergone retransplantation within 90 days.

The investigators assessed both the development of new-onset diabetes after transplant (NODAT), using criteria adapted from a published article (Transplantation 2013;96:58-64), and its resolution, defined as the date of cessation of antihyperglycemic therapy or the last episode of hyperglycemia.

Seventy-nine percent of the patients received grafts donated after brain death (DBD), Dr. Hartog reported at the annual meeting of the 2014 World Transplant Congress. Among the recipients of grafts donated after circulatory death (DCD), the mean warm ischemic time was 21 minutes.

With a median follow-up of 2.5 years, the cumulative 1-year incidence of NODAT was 19% in the entire cohort, with a median time to onset of 30 days. In the 44% of affected patients whose NODAT resolved, the median time to resolution was 150 days post transplantation, Dr. Hartog reported at the congress, which was sponsored by the American Society of Transplant Surgeons.

The cumulative 1-year incidence of NODAT was 23% in DCD graft recipients and 18% in DBD graft recipients, a nonsignificant difference. But when patients were stratified by graft type, "we saw an early occurrence and high peak incidence of NODAT in DCD graft recipients. Also, a larger proportion of these patients resolved their NODAT over time," she commented.

The overall temporal pattern suggested that "the effect that we see of graft type seems to be temporary and [lessens] over time when multifactorial factors come into play," according to Dr. Hartog.

In multivariate analyses, the risk of NODAT within 90 days of transplantation was higher for patients who received a DCD graft (hazard ratio, 1.8). More detailed analysis showed that the elevation of risk was greatest within the first 15 days.

"Our study confirms known associations with NODAT after liver transplantation but identifies DCD graft as a novel risk factor. This causes a temporary effect in the early post-transplant period that is independent from known risk factors," Dr. Hartog commented.

"Based on our observations, we hypothesize that hyperglycemia may be related to liver graft function through ischemia-reperfusion–induced hepatic insulin resistance," she added. "We are currently trying to confirm our data in an independent data set, which will also include postreperfusion glucose levels and correlation with the insulin receptor pathway in time-zero liver biopsies."

"The clinical relevance of our findings is as yet unknown," she acknowledged. However, they may help inform new approaches for graft optimization and selection.

Session cochair Dr. Darius Mirza, also of the University of Birmingham, asked, "Why does the pattern of recovery seem to be different in the DCDs versus the DBDs? Also, why are the cumulative incidence and the time frame so different?"

"Actually, in the literature, I have not seen any reports looking at the early post-transplant period. So most reports look at one time point, normally 1 year," Dr. Hartog replied. "What I think is that there is an early peak caused by DCD grafts that would explain why there is an early peak, but also why those patients recover later on. I think this peak is a bit obscure because there are also other factors that come into play, maybe after a while, that will obscure that first peak. If you would take those other factors out of the equation, I think you would just see a peak in the early period."

Dr. Mirza also wondered about the role of using DCD grafts that are accepted under extended criteria. "So you start off using mainly young, fit DCD livers. Now, the vast majority are extended-criteria DCD livers. Do you think that plays a role, or is it too early to say?"

"Yes, I think so," Dr. Hartog said, while adding that this phenomenon is likely not restricted to DCD grafts. "From earlier literature, there is a clear difference between a living donated graft and deceased donation. And it might also be that the extended grafts or the more steatotic grafts may exhibit this effect more than the better grafts."

Dr. Hartog disclosed no conflicts of interest relevant to the research.

SAN FRANCISCO – The type of liver graft used in transplantation plays a large role in early development of new-onset diabetes, according to a retrospective study of 430 patients from the United Kingdom.

A team led by Dr. Hermien Hartog, an honorary clinical fellow in the Liver Unit, Queen Elizabeth Hospital, Birmingham, England, studied patients undergoing primary liver transplant between 2008 and 2012. Patients were excluded from the study if they had preexisting diabetes, had died, or had undergone retransplantation within 90 days.

The investigators assessed both the development of new-onset diabetes after transplant (NODAT), using criteria adapted from a published article (Transplantation 2013;96:58-64), and its resolution, defined as the date of cessation of antihyperglycemic therapy or the last episode of hyperglycemia.

Seventy-nine percent of the patients received grafts donated after brain death (DBD), Dr. Hartog reported at the annual meeting of the 2014 World Transplant Congress. Among the recipients of grafts donated after circulatory death (DCD), the mean warm ischemic time was 21 minutes.

With a median follow-up of 2.5 years, the cumulative 1-year incidence of NODAT was 19% in the entire cohort, with a median time to onset of 30 days. In the 44% of affected patients whose NODAT resolved, the median time to resolution was 150 days post transplantation, Dr. Hartog reported at the congress, which was sponsored by the American Society of Transplant Surgeons.

The cumulative 1-year incidence of NODAT was 23% in DCD graft recipients and 18% in DBD graft recipients, a nonsignificant difference. But when patients were stratified by graft type, "we saw an early occurrence and high peak incidence of NODAT in DCD graft recipients. Also, a larger proportion of these patients resolved their NODAT over time," she commented.

The overall temporal pattern suggested that "the effect that we see of graft type seems to be temporary and [lessens] over time when multifactorial factors come into play," according to Dr. Hartog.

In multivariate analyses, the risk of NODAT within 90 days of transplantation was higher for patients who received a DCD graft (hazard ratio, 1.8). More detailed analysis showed that the elevation of risk was greatest within the first 15 days.

"Our study confirms known associations with NODAT after liver transplantation but identifies DCD graft as a novel risk factor. This causes a temporary effect in the early post-transplant period that is independent from known risk factors," Dr. Hartog commented.

"Based on our observations, we hypothesize that hyperglycemia may be related to liver graft function through ischemia-reperfusion–induced hepatic insulin resistance," she added. "We are currently trying to confirm our data in an independent data set, which will also include postreperfusion glucose levels and correlation with the insulin receptor pathway in time-zero liver biopsies."

"The clinical relevance of our findings is as yet unknown," she acknowledged. However, they may help inform new approaches for graft optimization and selection.

Session cochair Dr. Darius Mirza, also of the University of Birmingham, asked, "Why does the pattern of recovery seem to be different in the DCDs versus the DBDs? Also, why are the cumulative incidence and the time frame so different?"

"Actually, in the literature, I have not seen any reports looking at the early post-transplant period. So most reports look at one time point, normally 1 year," Dr. Hartog replied. "What I think is that there is an early peak caused by DCD grafts that would explain why there is an early peak, but also why those patients recover later on. I think this peak is a bit obscure because there are also other factors that come into play, maybe after a while, that will obscure that first peak. If you would take those other factors out of the equation, I think you would just see a peak in the early period."

Dr. Mirza also wondered about the role of using DCD grafts that are accepted under extended criteria. "So you start off using mainly young, fit DCD livers. Now, the vast majority are extended-criteria DCD livers. Do you think that plays a role, or is it too early to say?"

"Yes, I think so," Dr. Hartog said, while adding that this phenomenon is likely not restricted to DCD grafts. "From earlier literature, there is a clear difference between a living donated graft and deceased donation. And it might also be that the extended grafts or the more steatotic grafts may exhibit this effect more than the better grafts."

Dr. Hartog disclosed no conflicts of interest relevant to the research.

SAN FRANCISCO – Monitoring plasma vascular endothelial growth factor A (VEGF-A) may help identify pediatric heart transplant patients who are at increased risk for poor outcomes, according to a study reported at the 2014 World Transplant Congress.

"Cardiac allograft vasculopathy [CAV] remains the leading cause of chronic allograft failure after heart transplantation. ... Therefore, it’s important for us to be able to anticipate the development of CAV and open up a therapeutic window," said Dr. Kevin P. Daly of Harvard Medical School and Boston Children’s Hospital.

"Our pilot data suggest that plasma VEGF-A levels below 90 pg/mL identify a low-risk patient population in whom a decreased frequency of coronary angiography can be considered. Future studies are needed to determine if using plasma VEGF-A levels to modify CAV screening frequency results in equivalent patient outcomes, with decreased resource utilization and improved quality of life," Dr. Daly commented at the congress, which was sponsored by the American Society of Transplant Surgeons.

As the vascular endothelium is the primary target of the immune response in CAV, the researchers hypothesized that VEGF-A likely contributes to an inflammatory cycle that leads to vascular damage and occlusion in the graft.

Participants in the single-center prospective cohort study were 44 consecutive children aged 2 years or older who were at least 18 months (median, 6 years) out from heart transplantation. They were scheduled for routine annual screening coronary angiography during 2009, and had no or mild CAV.

Moderate or severe CAV developed in 32% of patients who had VEGF-A values above the median value at baseline (90 pg/mL), compared with 5% of patients who had VEGF-A values below the median level (P = .02). Patients who developed this vasculopathy were more likely to die (38% vs. 0%), undergo retransplantation (38% vs. 0%), experience a myocardial infarction (12% vs. 0%), and be listed for retransplantation (12% vs. 0%).

"While this is a biomarker and we have shown it is associated with CAV, we have not shown that it is causal," Dr. Daly cautioned. Any treatment directed against VEGF would have to be conducted in the context of a clinical trial to assess its impact.

A subset of patients becomes nonadherent to therapy; a subset that is highly sensitized before transplant may have donor-specific antibody, Dr. Daly said. So "we don’t think we fully understand the inciting event, ... [but] VEGF-A has been shown before to be elevated in antibody-mediated rejection, so it’s not surprising to see this association."

"We didn’t have these data available clinically because it was all a research study, so we didn’t intervene on any of the patients in this cohort. But we have started to think about whether or not we could use VEGF-A levels at least in our ... patients who might not have arterial access, and it might be difficult to survey them for CAV. I think in order to really understand the appropriate way to use it, we would need a larger study," he remarked.

Dr. Daly disclosed that he had no conflicts of interest relevant to the study.

SAN FRANCISCO – Monitoring plasma vascular endothelial growth factor A (VEGF-A) may help identify pediatric heart transplant patients who are at increased risk for poor outcomes, according to a study reported at the 2014 World Transplant Congress.

"Cardiac allograft vasculopathy [CAV] remains the leading cause of chronic allograft failure after heart transplantation. ... Therefore, it’s important for us to be able to anticipate the development of CAV and open up a therapeutic window," said Dr. Kevin P. Daly of Harvard Medical School and Boston Children’s Hospital.

"Our pilot data suggest that plasma VEGF-A levels below 90 pg/mL identify a low-risk patient population in whom a decreased frequency of coronary angiography can be considered. Future studies are needed to determine if using plasma VEGF-A levels to modify CAV screening frequency results in equivalent patient outcomes, with decreased resource utilization and improved quality of life," Dr. Daly commented at the congress, which was sponsored by the American Society of Transplant Surgeons.

As the vascular endothelium is the primary target of the immune response in CAV, the researchers hypothesized that VEGF-A likely contributes to an inflammatory cycle that leads to vascular damage and occlusion in the graft.

Participants in the single-center prospective cohort study were 44 consecutive children aged 2 years or older who were at least 18 months (median, 6 years) out from heart transplantation. They were scheduled for routine annual screening coronary angiography during 2009, and had no or mild CAV.

Moderate or severe CAV developed in 32% of patients who had VEGF-A values above the median value at baseline (90 pg/mL), compared with 5% of patients who had VEGF-A values below the median level (P = .02). Patients who developed this vasculopathy were more likely to die (38% vs. 0%), undergo retransplantation (38% vs. 0%), experience a myocardial infarction (12% vs. 0%), and be listed for retransplantation (12% vs. 0%).

"While this is a biomarker and we have shown it is associated with CAV, we have not shown that it is causal," Dr. Daly cautioned. Any treatment directed against VEGF would have to be conducted in the context of a clinical trial to assess its impact.

A subset of patients becomes nonadherent to therapy; a subset that is highly sensitized before transplant may have donor-specific antibody, Dr. Daly said. So "we don’t think we fully understand the inciting event, ... [but] VEGF-A has been shown before to be elevated in antibody-mediated rejection, so it’s not surprising to see this association."

"We didn’t have these data available clinically because it was all a research study, so we didn’t intervene on any of the patients in this cohort. But we have started to think about whether or not we could use VEGF-A levels at least in our ... patients who might not have arterial access, and it might be difficult to survey them for CAV. I think in order to really understand the appropriate way to use it, we would need a larger study," he remarked.

Dr. Daly disclosed that he had no conflicts of interest relevant to the study.

SAN FRANCISCO – Monitoring plasma vascular endothelial growth factor A (VEGF-A) may help identify pediatric heart transplant patients who are at increased risk for poor outcomes, according to a study reported at the 2014 World Transplant Congress.

"Cardiac allograft vasculopathy [CAV] remains the leading cause of chronic allograft failure after heart transplantation. ... Therefore, it’s important for us to be able to anticipate the development of CAV and open up a therapeutic window," said Dr. Kevin P. Daly of Harvard Medical School and Boston Children’s Hospital.

"Our pilot data suggest that plasma VEGF-A levels below 90 pg/mL identify a low-risk patient population in whom a decreased frequency of coronary angiography can be considered. Future studies are needed to determine if using plasma VEGF-A levels to modify CAV screening frequency results in equivalent patient outcomes, with decreased resource utilization and improved quality of life," Dr. Daly commented at the congress, which was sponsored by the American Society of Transplant Surgeons.

As the vascular endothelium is the primary target of the immune response in CAV, the researchers hypothesized that VEGF-A likely contributes to an inflammatory cycle that leads to vascular damage and occlusion in the graft.

Participants in the single-center prospective cohort study were 44 consecutive children aged 2 years or older who were at least 18 months (median, 6 years) out from heart transplantation. They were scheduled for routine annual screening coronary angiography during 2009, and had no or mild CAV.

Moderate or severe CAV developed in 32% of patients who had VEGF-A values above the median value at baseline (90 pg/mL), compared with 5% of patients who had VEGF-A values below the median level (P = .02). Patients who developed this vasculopathy were more likely to die (38% vs. 0%), undergo retransplantation (38% vs. 0%), experience a myocardial infarction (12% vs. 0%), and be listed for retransplantation (12% vs. 0%).

"While this is a biomarker and we have shown it is associated with CAV, we have not shown that it is causal," Dr. Daly cautioned. Any treatment directed against VEGF would have to be conducted in the context of a clinical trial to assess its impact.

A subset of patients becomes nonadherent to therapy; a subset that is highly sensitized before transplant may have donor-specific antibody, Dr. Daly said. So "we don’t think we fully understand the inciting event, ... [but] VEGF-A has been shown before to be elevated in antibody-mediated rejection, so it’s not surprising to see this association."

"We didn’t have these data available clinically because it was all a research study, so we didn’t intervene on any of the patients in this cohort. But we have started to think about whether or not we could use VEGF-A levels at least in our ... patients who might not have arterial access, and it might be difficult to survey them for CAV. I think in order to really understand the appropriate way to use it, we would need a larger study," he remarked.

Dr. Daly disclosed that he had no conflicts of interest relevant to the study.