Nephrology

The oral multitargeted tyrosine kinase inhibitor cabozantinib is more efficacious than everolimus as therapy for advanced renal cell carcinoma across a wide range of patients, suggests a subgroup analysis of the phase III METEOR trial being reported at the genitourinary cancers symposium.

Trial participants were 658 patients with advanced renal cell carcinoma and clear cell histology who had experienced progression on a tyrosine kinase inhibitor targeting the vascular endothelial growth factor receptor (VEGFR). There was no limit on the number of prior therapies.

Wikimedia Commons/Patho/Public Domain

The patients were randomized evenly to cabozantinib (Cometriq), which inhibits the VEGFR, MET, and AXL tyrosine kinases – all of which are up-regulated in this cancer – or to everolimus (Afinitor), an inhibitor of the mammalian target of rapamycin that is considered a standard of care. (At present, cabozantinib is approved by the Food and Drug Administration for the treatment of medullary thyroid cancer.)

Results for the entire trial population showed that patients in the cabozantinib group were about half as likely as were their counterparts in the everolimus group to experience progression-free survival events, lead author Dr. Bernard Escudier reported in a press briefing held before the 2016 genitourinary cancers symposium sponsored by the American Society of Clinical Oncology. All patients appeared to derive benefit, with the reduction in risk ranging from 16% to 78% depending on the specific subgroup.

“Cabozantinib improved progression-free survival, compared to one of our standard therapies, everolimus, in advanced renal cell carcinoma,” concluded Dr. Escudier, who is chair of the Genitourinary Oncology Committee at the Institut Gustave Roussy in Villejuif, France. “Benefit was observed across prespecified subgroups,” including a small subgroup who had previously received immunotherapies targeting the programmed death 1 (PD-1) signaling pathway.

Toxicity was somewhat problematic with cabozantinib, despite starting the drug at a lower dose than has typically been used in the past, he acknowledged. The most common side effects were diarrhea, fatigue, nausea, decreased appetite, and hand-foot syndrome, and they often necessitated further dose reductions.

“Benefit with cabozantinib treatment is supported by a trend in overall survival, and hopefully, we will give this final overall survival analysis at ASCO this year,” Dr. Escudier added. Findings of an interim analysis reported last year were very promising with respect to this outcome (hazard ratio, 0.67; P = .005) (N Engl J Med. 2015 Nov 5;373:1814-23).

“This study is unique compared to others in that it allowed a broad range of patients: Patients could have had spread of cancer to the brain, they could have received any number of prior therapies, and they could have been exposed to immune-based treatments,” commented ASCO spokesperson and moderator of the press briefing Dr. Sumanta K. Pal. “The magnitude of benefit that patients got from cabozantinib far exceeds, in my opinion, what we have seen to date in this setting in terms of both delay in tumor growth and improving survival.”

In fact, for some oncologists, the findings may be strong enough to prompt use of cabozantinib as second-line therapy, according to Dr. Pal, who is a medical oncologist at the City of Hope in Duarte, Calif.

“Given the fact that cabozantinib has a very compelling benefit in terms of both delay in tumor growth and a hint toward a benefit in terms of overall survival, I would perhaps tend to favor that as a second-line option as compared to other comparators, such as nivolumab (Opdivo), in that setting,” he said, referring to an antibody that targets the cell surface receptor PD-1. “Now that’s a personal opinion. I certainly think there are some merits with nivolumab, such as the toxicity profile. But, in broad terms, patients are very focused on clinical efficacy, and with that in mind, the data for cabozantinib truly speaks for itself.”

But Dr. Escudier offered a more-reserved perspective. “I think what people are going to do will be to use nivolumab as second-line [therapy] in most patients and keep cabozantinib for nivolumab failure,” he predicted. “Based on that, this subgroup, although small, is of importance. I don’t think it’s good enough to say we should use cabozantinib or nivolumab in second line based on the subgroup analyses we have.”

The eagerly awaited overall survival results will also help determine cabozantinib’s position in treatment sequence, he added. “If we get a survival advantage [that] is the same magnitude that we have with nivolumab, with such an impressive improvement in progression-free survival, maybe despite the toxicity with cabozantinib, people will be willing to use cabozantinib early on.”

In the new analysis, median progression-free survival in the entire trial population was 7.4 months with cabozantinib and 3.9 months with everolimus, translating to a near halving of the risk of events (hazard ratio, 0.52; P less than .001).

Subgroup analyses showed that patients in the cabozantinib group consistently had a lower risk of events, with hazard ratios ranging from 0.22 to 0.84, regardless of their Memorial Sloan Kettering Cancer Center risk group, number of organs with metastases, presence of both visceral and bone metastases, number of prior VEGFR tyrosine kinase inhibitors, the specific VEGFR tyrosine kinase inhibitor in patients who had received only one, and prior immunotherapy targeting the programmed death pathway.

The 42 patients who had previously received immunotherapy targeting that pathway were among those seeming to derive most benefit, Dr. Escudier reported. “Of course, this is a small number, but certainly an observation [of interest] when many patients are going to receive nivolumab as second-line in kidney cancer. This drug is still very active after PD-1 or PD-L1 antibodies.”

The oral multitargeted tyrosine kinase inhibitor cabozantinib is more efficacious than everolimus as therapy for advanced renal cell carcinoma across a wide range of patients, suggests a subgroup analysis of the phase III METEOR trial being reported at the genitourinary cancers symposium.

Trial participants were 658 patients with advanced renal cell carcinoma and clear cell histology who had experienced progression on a tyrosine kinase inhibitor targeting the vascular endothelial growth factor receptor (VEGFR). There was no limit on the number of prior therapies.

Wikimedia Commons/Patho/Public Domain

The patients were randomized evenly to cabozantinib (Cometriq), which inhibits the VEGFR, MET, and AXL tyrosine kinases – all of which are up-regulated in this cancer – or to everolimus (Afinitor), an inhibitor of the mammalian target of rapamycin that is considered a standard of care. (At present, cabozantinib is approved by the Food and Drug Administration for the treatment of medullary thyroid cancer.)

Results for the entire trial population showed that patients in the cabozantinib group were about half as likely as were their counterparts in the everolimus group to experience progression-free survival events, lead author Dr. Bernard Escudier reported in a press briefing held before the 2016 genitourinary cancers symposium sponsored by the American Society of Clinical Oncology. All patients appeared to derive benefit, with the reduction in risk ranging from 16% to 78% depending on the specific subgroup.

“Cabozantinib improved progression-free survival, compared to one of our standard therapies, everolimus, in advanced renal cell carcinoma,” concluded Dr. Escudier, who is chair of the Genitourinary Oncology Committee at the Institut Gustave Roussy in Villejuif, France. “Benefit was observed across prespecified subgroups,” including a small subgroup who had previously received immunotherapies targeting the programmed death 1 (PD-1) signaling pathway.

Toxicity was somewhat problematic with cabozantinib, despite starting the drug at a lower dose than has typically been used in the past, he acknowledged. The most common side effects were diarrhea, fatigue, nausea, decreased appetite, and hand-foot syndrome, and they often necessitated further dose reductions.

“Benefit with cabozantinib treatment is supported by a trend in overall survival, and hopefully, we will give this final overall survival analysis at ASCO this year,” Dr. Escudier added. Findings of an interim analysis reported last year were very promising with respect to this outcome (hazard ratio, 0.67; P = .005) (N Engl J Med. 2015 Nov 5;373:1814-23).

“This study is unique compared to others in that it allowed a broad range of patients: Patients could have had spread of cancer to the brain, they could have received any number of prior therapies, and they could have been exposed to immune-based treatments,” commented ASCO spokesperson and moderator of the press briefing Dr. Sumanta K. Pal. “The magnitude of benefit that patients got from cabozantinib far exceeds, in my opinion, what we have seen to date in this setting in terms of both delay in tumor growth and improving survival.”

In fact, for some oncologists, the findings may be strong enough to prompt use of cabozantinib as second-line therapy, according to Dr. Pal, who is a medical oncologist at the City of Hope in Duarte, Calif.

“Given the fact that cabozantinib has a very compelling benefit in terms of both delay in tumor growth and a hint toward a benefit in terms of overall survival, I would perhaps tend to favor that as a second-line option as compared to other comparators, such as nivolumab (Opdivo), in that setting,” he said, referring to an antibody that targets the cell surface receptor PD-1. “Now that’s a personal opinion. I certainly think there are some merits with nivolumab, such as the toxicity profile. But, in broad terms, patients are very focused on clinical efficacy, and with that in mind, the data for cabozantinib truly speaks for itself.”

But Dr. Escudier offered a more-reserved perspective. “I think what people are going to do will be to use nivolumab as second-line [therapy] in most patients and keep cabozantinib for nivolumab failure,” he predicted. “Based on that, this subgroup, although small, is of importance. I don’t think it’s good enough to say we should use cabozantinib or nivolumab in second line based on the subgroup analyses we have.”

The eagerly awaited overall survival results will also help determine cabozantinib’s position in treatment sequence, he added. “If we get a survival advantage [that] is the same magnitude that we have with nivolumab, with such an impressive improvement in progression-free survival, maybe despite the toxicity with cabozantinib, people will be willing to use cabozantinib early on.”

In the new analysis, median progression-free survival in the entire trial population was 7.4 months with cabozantinib and 3.9 months with everolimus, translating to a near halving of the risk of events (hazard ratio, 0.52; P less than .001).

Subgroup analyses showed that patients in the cabozantinib group consistently had a lower risk of events, with hazard ratios ranging from 0.22 to 0.84, regardless of their Memorial Sloan Kettering Cancer Center risk group, number of organs with metastases, presence of both visceral and bone metastases, number of prior VEGFR tyrosine kinase inhibitors, the specific VEGFR tyrosine kinase inhibitor in patients who had received only one, and prior immunotherapy targeting the programmed death pathway.

The 42 patients who had previously received immunotherapy targeting that pathway were among those seeming to derive most benefit, Dr. Escudier reported. “Of course, this is a small number, but certainly an observation [of interest] when many patients are going to receive nivolumab as second-line in kidney cancer. This drug is still very active after PD-1 or PD-L1 antibodies.”

The oral multitargeted tyrosine kinase inhibitor cabozantinib is more efficacious than everolimus as therapy for advanced renal cell carcinoma across a wide range of patients, suggests a subgroup analysis of the phase III METEOR trial being reported at the genitourinary cancers symposium.

Trial participants were 658 patients with advanced renal cell carcinoma and clear cell histology who had experienced progression on a tyrosine kinase inhibitor targeting the vascular endothelial growth factor receptor (VEGFR). There was no limit on the number of prior therapies.

Wikimedia Commons/Patho/Public Domain

The patients were randomized evenly to cabozantinib (Cometriq), which inhibits the VEGFR, MET, and AXL tyrosine kinases – all of which are up-regulated in this cancer – or to everolimus (Afinitor), an inhibitor of the mammalian target of rapamycin that is considered a standard of care. (At present, cabozantinib is approved by the Food and Drug Administration for the treatment of medullary thyroid cancer.)

Results for the entire trial population showed that patients in the cabozantinib group were about half as likely as were their counterparts in the everolimus group to experience progression-free survival events, lead author Dr. Bernard Escudier reported in a press briefing held before the 2016 genitourinary cancers symposium sponsored by the American Society of Clinical Oncology. All patients appeared to derive benefit, with the reduction in risk ranging from 16% to 78% depending on the specific subgroup.

“Cabozantinib improved progression-free survival, compared to one of our standard therapies, everolimus, in advanced renal cell carcinoma,” concluded Dr. Escudier, who is chair of the Genitourinary Oncology Committee at the Institut Gustave Roussy in Villejuif, France. “Benefit was observed across prespecified subgroups,” including a small subgroup who had previously received immunotherapies targeting the programmed death 1 (PD-1) signaling pathway.

Toxicity was somewhat problematic with cabozantinib, despite starting the drug at a lower dose than has typically been used in the past, he acknowledged. The most common side effects were diarrhea, fatigue, nausea, decreased appetite, and hand-foot syndrome, and they often necessitated further dose reductions.

“Benefit with cabozantinib treatment is supported by a trend in overall survival, and hopefully, we will give this final overall survival analysis at ASCO this year,” Dr. Escudier added. Findings of an interim analysis reported last year were very promising with respect to this outcome (hazard ratio, 0.67; P = .005) (N Engl J Med. 2015 Nov 5;373:1814-23).

“This study is unique compared to others in that it allowed a broad range of patients: Patients could have had spread of cancer to the brain, they could have received any number of prior therapies, and they could have been exposed to immune-based treatments,” commented ASCO spokesperson and moderator of the press briefing Dr. Sumanta K. Pal. “The magnitude of benefit that patients got from cabozantinib far exceeds, in my opinion, what we have seen to date in this setting in terms of both delay in tumor growth and improving survival.”

In fact, for some oncologists, the findings may be strong enough to prompt use of cabozantinib as second-line therapy, according to Dr. Pal, who is a medical oncologist at the City of Hope in Duarte, Calif.

“Given the fact that cabozantinib has a very compelling benefit in terms of both delay in tumor growth and a hint toward a benefit in terms of overall survival, I would perhaps tend to favor that as a second-line option as compared to other comparators, such as nivolumab (Opdivo), in that setting,” he said, referring to an antibody that targets the cell surface receptor PD-1. “Now that’s a personal opinion. I certainly think there are some merits with nivolumab, such as the toxicity profile. But, in broad terms, patients are very focused on clinical efficacy, and with that in mind, the data for cabozantinib truly speaks for itself.”

But Dr. Escudier offered a more-reserved perspective. “I think what people are going to do will be to use nivolumab as second-line [therapy] in most patients and keep cabozantinib for nivolumab failure,” he predicted. “Based on that, this subgroup, although small, is of importance. I don’t think it’s good enough to say we should use cabozantinib or nivolumab in second line based on the subgroup analyses we have.”

The eagerly awaited overall survival results will also help determine cabozantinib’s position in treatment sequence, he added. “If we get a survival advantage [that] is the same magnitude that we have with nivolumab, with such an impressive improvement in progression-free survival, maybe despite the toxicity with cabozantinib, people will be willing to use cabozantinib early on.”

In the new analysis, median progression-free survival in the entire trial population was 7.4 months with cabozantinib and 3.9 months with everolimus, translating to a near halving of the risk of events (hazard ratio, 0.52; P less than .001).

Subgroup analyses showed that patients in the cabozantinib group consistently had a lower risk of events, with hazard ratios ranging from 0.22 to 0.84, regardless of their Memorial Sloan Kettering Cancer Center risk group, number of organs with metastases, presence of both visceral and bone metastases, number of prior VEGFR tyrosine kinase inhibitors, the specific VEGFR tyrosine kinase inhibitor in patients who had received only one, and prior immunotherapy targeting the programmed death pathway.

The 42 patients who had previously received immunotherapy targeting that pathway were among those seeming to derive most benefit, Dr. Escudier reported. “Of course, this is a small number, but certainly an observation [of interest] when many patients are going to receive nivolumab as second-line in kidney cancer. This drug is still very active after PD-1 or PD-L1 antibodies.”

While editing this month’s Renal Consult, I noted the mention of “paired kidney exchange” with particular interest. In 2005, I heard about a relatively new concept: matching two or more incompatible kidney donor-recipient pairs to create compatible matches. After conducting some research and interviewing experts, I wrote an article on paired kidney exchange for our sister publication, Clinician News. In the subsequent decade, the concept of paired exchange has expanded to the point that as many as 70 people have participated in a 35-kidney exchange. —AMH

Last year, almost 27,000 Americans received an organ transplant—a new national record, according to the US Department of Health and Human Services. Donations from living persons reached nearly 7,000, an increase of 2.3% from 2003. But despite these positive numbers, nearly 88,000 people are on the waiting list for an organ, and about 6,200 died last year before one became available.

But in some areas of the country, an innovative program is gaining momentum: paired kidney exchange, which puts together two or more incompatible donor-recipient pairs to create compatible matches. And while it will not close the gap between patients in need and those who receive, experts believe it could help thousands of people each year.

The real struggle is finding more willing donors. But Francis Delmonico, MD, Medical Director, New England Organ Bank, Newton, Massachusetts, says paired exchange is “an adjunct. When it can be of help, it’s helped a number of people already. And as with any of this, it’s a lot of work but it’s a tactic that we ought to try and apply anytime we can.”

“There are about 10,000 people who could be put into a program like this,” says Michael A. Rees, MD, PhD, Associate Professor, Department of Urology, Medical College of Ohio, Toledo. “Once you put them into the program, we would hope that 2,000 to 3,000 per year could be matched up and we could do that many extra kidney transplants a year. And that would certainly help to close the gap.”

Continue for how it works >>

HOW IT WORKS
Paired kidney exchange got its start in the US at Johns Hopkins Comprehensive Transplant Center, Baltimore, in 2001. The concept is simple: Recipient A needs a kidney and has a family member or friend, Donor A, who is willing to give. However, testing reveals that Donor A and Recipient A are incompatible. Meanwhile, Recipient B and Donor B find themselves with the same problem. But, it turns out, Donor B could give to Recipient A and Donor A could give to Recipient B. The patients and their donors are approached with the idea of an exchange, and if they agree, two people receive needed organs.

Twenty-two patients have received kidneys through the Johns Hopkins program, according to Robert A. Montgomery, MD, PhD, Director, Incompatible Kidney Transplant Programs (InKTP). Surgeons at Johns Hopkins have also expanded the exchange to three donor-recipient pairs; “triple swap” operations were performed at the hospital in 2003 and 2004.

“Everyone, when they come for an incompatible transplant, is offered the option of a paired exchange, because … if there’s any way to get a compatible kidney, that’s what you try for first,” says Janet Hiller, RN, MSN, Clinical Nurse Specialist, InKTP. “We’ve only had probably two out of a hundred [patients] who have thought, ‘No, I’d rather just get the kidney from my spouse or loved one.’”

“Patients are surprisingly open to this option, and almost all of them … request it when they are initially seen by me,” Montgomery told Clinician News via e-mail. “Some [recipients] have expressed apprehension about not knowing the donor and not being sure they have taken good care of their kidney. The donors have rarely expressed any concerns; they just want their loved one to receive a kidney…. It has universally been a positive experience.”

Ohio’s Rees first heard about paired exchange at a conference in 2001. He returned to his institution and consulted with the living donor coordinator to see if any pairs could be formed from people who had been willing to donate but unable due to blood type or other incompatibility problems. After identifying two pairs (out of 10 possibilities) for whom an exchange might work, Rees brought the patients and donors in for testing. But alas, the match wasn’t quite right.

“It became clear to me that if I really wanted to make this work, I needed a lot more than 10 pairs [to start with],” Rees says. “The numbers—if you try to match up people—go up logarithmically the more pairs that you have. So the chances you have of creating pairs go up exponentially.”

With this realization in mind, Rees set out to find someone willing to write a computer program that could identify potential matches from a larger bank of people pooled from several facilities. After some false starts—no computer programmer would work on the project for academic glory, the only reward Rees could offer—he convinced his father, Alan, to help. The senior Rees’ prototype was the basis for the current system, which links 10 transplant centers in Ohio.

Working with a larger pool of colleagues required numerous teleconference calls to iron out details for the statewide program. Among the questions were, “Are we going to make the donor travel, or are we going to cut the kidney out at home and ship the kidney in a box of ice to the place where it’s going to be transplanted?” he recalls. “And we decided that the donor has to travel.”

The first kidney exchange in the state of Ohio was performed in early November 2004. The third was scheduled for mid-April.

Creating one system to be shared by medical institutions that would normally be competitors took some work. “Trying to get us all to play in the same sandbox was very difficult,” Rees acknowledges. “But we did that; we stuck it out. And we all agreed to come up with something that we all think is a great idea and should help our patients.”

Delmonico, who is also a Professor of Surgery at Harvard Medical School and Visiting Surgeon in the Transplant Unit at Massachusetts General Hospital, Boston, has also seen the gratifying cooperation between medical professionals. “Institutions are competitive in terms of medical care—that’s no mystery,” he says. “But in this instance, the physicians have been simply magnificent in trying to help patients. Innovative programs can be developed and sustained through the kind of collaboration that is going on here.”

The New England paired exchange program, dating back to 2002, is a collaboration involving a dozen hospitals. It started with a paper-and-pen effort (blood type–incompatible patients would be brought to the attention of Delmonico, who would then contact each transplant center, seeking others) but now has its own computer system.

New England also has another variation on the exchange program that is unique to the region, according to Delmonico. “Let’s say I wanted to give to you but I can’t. I’ll give to somebody on the list, and as a result of that donation, you would get a priority for the next available deceased donor kidney in New England,” he explains. “We’ve done that about 20 times now.”

Continue for going national >>

GOING NATIONAL
So where does paired exchange go from here? Johns Hopkins’ Montgomery organized a consensus meeting in March to discuss the possibility of creating a national network; Hiller, Rees, and Delmonico attended.

“I think our goal should be to one day have a national program,” Rees says. “But shipping somebody from Toledo down to Cincinnati is a lot easier to sell to a patient than shipping somebody from Toledo to Los Angeles. And the logistics of trying to do that when you have a whole different set of insurance companies … would be a lot more complicated. So, I think the way to begin is to do it on a more regional basis and prove that the concept works, that people can be satisfied with it, and then begin to expand it.”

Delmonico also thinks a national program is essential. “We need to enlarge the possibility of paired donation and exchange,” he says. “It will not happen successfully in a regional system. There aren’t enough patients that can be identified.” Questions to be answered before such a program could exist, Delmonico notes, include where the system will be based and who will administer it.

“There was a lot of agreement—though not total consensus—on the fact that UNOS, the United Network for Organ Sharing, would be the most likely place to ‘house’ and to manage the data,” Hiller reports. “They have all those systems in place already [and] are capable of managing this large database.”

Delmonico, as Vice President of UNOS, points out, “We have no authority to do that yet. Whether or not the country wants us to do that also remains to be determined.” But the UNOS Board of Directors is open to the idea; last year, they endorsed the concept of establishing a national paired exchange program with the understanding that details would have to be worked out over time, according to a UNOS spokesperson.

Another obstacle to widespread paired donation may be perceptions of it in the eyes of the government and critics: Could it be construed as a violation of the 1984 National Organ Transplant Act, which says that an organ should not be transplanted for a “value consideration”? Legal experts have assured Delmonico that paired exchanges can be interpreted as a gift.

“The government is also, properly, not wanting to see this as a slope toward buying and selling organs,” Delmonico says. “And I am adamantly opposed to that. In the instances that we’ve done paired exchange here, that’s not in the mix. That’s not our motivation, nor has it been the motivation of these donors. We wouldn’t do it if we felt that was the case.”

Montgomery says it will take several years to get a national system set up. But the bottom line for transplant surgeons is that a national paired kidney exchange program would do a world of good, two people at a time. “This is clearly what is best for our patients,” Montgomery says.

“The bigger we can get, if we can spread it nationally, the more people it will help,” Rees says. “And so we have to think of a way to do this so that we’re all satisfied that it’s moving forward in a way that will make everyone happy.”

Reprinted from Clinician News. 2005;9(5):cover, 3, 15.

While editing this month’s Renal Consult, I noted the mention of “paired kidney exchange” with particular interest. In 2005, I heard about a relatively new concept: matching two or more incompatible kidney donor-recipient pairs to create compatible matches. After conducting some research and interviewing experts, I wrote an article on paired kidney exchange for our sister publication, Clinician News. In the subsequent decade, the concept of paired exchange has expanded to the point that as many as 70 people have participated in a 35-kidney exchange. —AMH

Last year, almost 27,000 Americans received an organ transplant—a new national record, according to the US Department of Health and Human Services. Donations from living persons reached nearly 7,000, an increase of 2.3% from 2003. But despite these positive numbers, nearly 88,000 people are on the waiting list for an organ, and about 6,200 died last year before one became available.

But in some areas of the country, an innovative program is gaining momentum: paired kidney exchange, which puts together two or more incompatible donor-recipient pairs to create compatible matches. And while it will not close the gap between patients in need and those who receive, experts believe it could help thousands of people each year.

The real struggle is finding more willing donors. But Francis Delmonico, MD, Medical Director, New England Organ Bank, Newton, Massachusetts, says paired exchange is “an adjunct. When it can be of help, it’s helped a number of people already. And as with any of this, it’s a lot of work but it’s a tactic that we ought to try and apply anytime we can.”

“There are about 10,000 people who could be put into a program like this,” says Michael A. Rees, MD, PhD, Associate Professor, Department of Urology, Medical College of Ohio, Toledo. “Once you put them into the program, we would hope that 2,000 to 3,000 per year could be matched up and we could do that many extra kidney transplants a year. And that would certainly help to close the gap.”

Continue for how it works >>

HOW IT WORKS
Paired kidney exchange got its start in the US at Johns Hopkins Comprehensive Transplant Center, Baltimore, in 2001. The concept is simple: Recipient A needs a kidney and has a family member or friend, Donor A, who is willing to give. However, testing reveals that Donor A and Recipient A are incompatible. Meanwhile, Recipient B and Donor B find themselves with the same problem. But, it turns out, Donor B could give to Recipient A and Donor A could give to Recipient B. The patients and their donors are approached with the idea of an exchange, and if they agree, two people receive needed organs.

Twenty-two patients have received kidneys through the Johns Hopkins program, according to Robert A. Montgomery, MD, PhD, Director, Incompatible Kidney Transplant Programs (InKTP). Surgeons at Johns Hopkins have also expanded the exchange to three donor-recipient pairs; “triple swap” operations were performed at the hospital in 2003 and 2004.

“Everyone, when they come for an incompatible transplant, is offered the option of a paired exchange, because … if there’s any way to get a compatible kidney, that’s what you try for first,” says Janet Hiller, RN, MSN, Clinical Nurse Specialist, InKTP. “We’ve only had probably two out of a hundred [patients] who have thought, ‘No, I’d rather just get the kidney from my spouse or loved one.’”

“Patients are surprisingly open to this option, and almost all of them … request it when they are initially seen by me,” Montgomery told Clinician News via e-mail. “Some [recipients] have expressed apprehension about not knowing the donor and not being sure they have taken good care of their kidney. The donors have rarely expressed any concerns; they just want their loved one to receive a kidney…. It has universally been a positive experience.”

Ohio’s Rees first heard about paired exchange at a conference in 2001. He returned to his institution and consulted with the living donor coordinator to see if any pairs could be formed from people who had been willing to donate but unable due to blood type or other incompatibility problems. After identifying two pairs (out of 10 possibilities) for whom an exchange might work, Rees brought the patients and donors in for testing. But alas, the match wasn’t quite right.

“It became clear to me that if I really wanted to make this work, I needed a lot more than 10 pairs [to start with],” Rees says. “The numbers—if you try to match up people—go up logarithmically the more pairs that you have. So the chances you have of creating pairs go up exponentially.”

With this realization in mind, Rees set out to find someone willing to write a computer program that could identify potential matches from a larger bank of people pooled from several facilities. After some false starts—no computer programmer would work on the project for academic glory, the only reward Rees could offer—he convinced his father, Alan, to help. The senior Rees’ prototype was the basis for the current system, which links 10 transplant centers in Ohio.

Working with a larger pool of colleagues required numerous teleconference calls to iron out details for the statewide program. Among the questions were, “Are we going to make the donor travel, or are we going to cut the kidney out at home and ship the kidney in a box of ice to the place where it’s going to be transplanted?” he recalls. “And we decided that the donor has to travel.”

The first kidney exchange in the state of Ohio was performed in early November 2004. The third was scheduled for mid-April.

Creating one system to be shared by medical institutions that would normally be competitors took some work. “Trying to get us all to play in the same sandbox was very difficult,” Rees acknowledges. “But we did that; we stuck it out. And we all agreed to come up with something that we all think is a great idea and should help our patients.”

Delmonico, who is also a Professor of Surgery at Harvard Medical School and Visiting Surgeon in the Transplant Unit at Massachusetts General Hospital, Boston, has also seen the gratifying cooperation between medical professionals. “Institutions are competitive in terms of medical care—that’s no mystery,” he says. “But in this instance, the physicians have been simply magnificent in trying to help patients. Innovative programs can be developed and sustained through the kind of collaboration that is going on here.”

The New England paired exchange program, dating back to 2002, is a collaboration involving a dozen hospitals. It started with a paper-and-pen effort (blood type–incompatible patients would be brought to the attention of Delmonico, who would then contact each transplant center, seeking others) but now has its own computer system.

New England also has another variation on the exchange program that is unique to the region, according to Delmonico. “Let’s say I wanted to give to you but I can’t. I’ll give to somebody on the list, and as a result of that donation, you would get a priority for the next available deceased donor kidney in New England,” he explains. “We’ve done that about 20 times now.”

Continue for going national >>

GOING NATIONAL
So where does paired exchange go from here? Johns Hopkins’ Montgomery organized a consensus meeting in March to discuss the possibility of creating a national network; Hiller, Rees, and Delmonico attended.

“I think our goal should be to one day have a national program,” Rees says. “But shipping somebody from Toledo down to Cincinnati is a lot easier to sell to a patient than shipping somebody from Toledo to Los Angeles. And the logistics of trying to do that when you have a whole different set of insurance companies … would be a lot more complicated. So, I think the way to begin is to do it on a more regional basis and prove that the concept works, that people can be satisfied with it, and then begin to expand it.”

Delmonico also thinks a national program is essential. “We need to enlarge the possibility of paired donation and exchange,” he says. “It will not happen successfully in a regional system. There aren’t enough patients that can be identified.” Questions to be answered before such a program could exist, Delmonico notes, include where the system will be based and who will administer it.

“There was a lot of agreement—though not total consensus—on the fact that UNOS, the United Network for Organ Sharing, would be the most likely place to ‘house’ and to manage the data,” Hiller reports. “They have all those systems in place already [and] are capable of managing this large database.”

Delmonico, as Vice President of UNOS, points out, “We have no authority to do that yet. Whether or not the country wants us to do that also remains to be determined.” But the UNOS Board of Directors is open to the idea; last year, they endorsed the concept of establishing a national paired exchange program with the understanding that details would have to be worked out over time, according to a UNOS spokesperson.

Another obstacle to widespread paired donation may be perceptions of it in the eyes of the government and critics: Could it be construed as a violation of the 1984 National Organ Transplant Act, which says that an organ should not be transplanted for a “value consideration”? Legal experts have assured Delmonico that paired exchanges can be interpreted as a gift.

“The government is also, properly, not wanting to see this as a slope toward buying and selling organs,” Delmonico says. “And I am adamantly opposed to that. In the instances that we’ve done paired exchange here, that’s not in the mix. That’s not our motivation, nor has it been the motivation of these donors. We wouldn’t do it if we felt that was the case.”

Montgomery says it will take several years to get a national system set up. But the bottom line for transplant surgeons is that a national paired kidney exchange program would do a world of good, two people at a time. “This is clearly what is best for our patients,” Montgomery says.

“The bigger we can get, if we can spread it nationally, the more people it will help,” Rees says. “And so we have to think of a way to do this so that we’re all satisfied that it’s moving forward in a way that will make everyone happy.”

Reprinted from Clinician News. 2005;9(5):cover, 3, 15.

While editing this month’s Renal Consult, I noted the mention of “paired kidney exchange” with particular interest. In 2005, I heard about a relatively new concept: matching two or more incompatible kidney donor-recipient pairs to create compatible matches. After conducting some research and interviewing experts, I wrote an article on paired kidney exchange for our sister publication, Clinician News. In the subsequent decade, the concept of paired exchange has expanded to the point that as many as 70 people have participated in a 35-kidney exchange. —AMH

Last year, almost 27,000 Americans received an organ transplant—a new national record, according to the US Department of Health and Human Services. Donations from living persons reached nearly 7,000, an increase of 2.3% from 2003. But despite these positive numbers, nearly 88,000 people are on the waiting list for an organ, and about 6,200 died last year before one became available.

But in some areas of the country, an innovative program is gaining momentum: paired kidney exchange, which puts together two or more incompatible donor-recipient pairs to create compatible matches. And while it will not close the gap between patients in need and those who receive, experts believe it could help thousands of people each year.

The real struggle is finding more willing donors. But Francis Delmonico, MD, Medical Director, New England Organ Bank, Newton, Massachusetts, says paired exchange is “an adjunct. When it can be of help, it’s helped a number of people already. And as with any of this, it’s a lot of work but it’s a tactic that we ought to try and apply anytime we can.”

“There are about 10,000 people who could be put into a program like this,” says Michael A. Rees, MD, PhD, Associate Professor, Department of Urology, Medical College of Ohio, Toledo. “Once you put them into the program, we would hope that 2,000 to 3,000 per year could be matched up and we could do that many extra kidney transplants a year. And that would certainly help to close the gap.”

Continue for how it works >>

HOW IT WORKS
Paired kidney exchange got its start in the US at Johns Hopkins Comprehensive Transplant Center, Baltimore, in 2001. The concept is simple: Recipient A needs a kidney and has a family member or friend, Donor A, who is willing to give. However, testing reveals that Donor A and Recipient A are incompatible. Meanwhile, Recipient B and Donor B find themselves with the same problem. But, it turns out, Donor B could give to Recipient A and Donor A could give to Recipient B. The patients and their donors are approached with the idea of an exchange, and if they agree, two people receive needed organs.

Twenty-two patients have received kidneys through the Johns Hopkins program, according to Robert A. Montgomery, MD, PhD, Director, Incompatible Kidney Transplant Programs (InKTP). Surgeons at Johns Hopkins have also expanded the exchange to three donor-recipient pairs; “triple swap” operations were performed at the hospital in 2003 and 2004.

“Everyone, when they come for an incompatible transplant, is offered the option of a paired exchange, because … if there’s any way to get a compatible kidney, that’s what you try for first,” says Janet Hiller, RN, MSN, Clinical Nurse Specialist, InKTP. “We’ve only had probably two out of a hundred [patients] who have thought, ‘No, I’d rather just get the kidney from my spouse or loved one.’”

“Patients are surprisingly open to this option, and almost all of them … request it when they are initially seen by me,” Montgomery told Clinician News via e-mail. “Some [recipients] have expressed apprehension about not knowing the donor and not being sure they have taken good care of their kidney. The donors have rarely expressed any concerns; they just want their loved one to receive a kidney…. It has universally been a positive experience.”

Ohio’s Rees first heard about paired exchange at a conference in 2001. He returned to his institution and consulted with the living donor coordinator to see if any pairs could be formed from people who had been willing to donate but unable due to blood type or other incompatibility problems. After identifying two pairs (out of 10 possibilities) for whom an exchange might work, Rees brought the patients and donors in for testing. But alas, the match wasn’t quite right.

“It became clear to me that if I really wanted to make this work, I needed a lot more than 10 pairs [to start with],” Rees says. “The numbers—if you try to match up people—go up logarithmically the more pairs that you have. So the chances you have of creating pairs go up exponentially.”

With this realization in mind, Rees set out to find someone willing to write a computer program that could identify potential matches from a larger bank of people pooled from several facilities. After some false starts—no computer programmer would work on the project for academic glory, the only reward Rees could offer—he convinced his father, Alan, to help. The senior Rees’ prototype was the basis for the current system, which links 10 transplant centers in Ohio.

Working with a larger pool of colleagues required numerous teleconference calls to iron out details for the statewide program. Among the questions were, “Are we going to make the donor travel, or are we going to cut the kidney out at home and ship the kidney in a box of ice to the place where it’s going to be transplanted?” he recalls. “And we decided that the donor has to travel.”

The first kidney exchange in the state of Ohio was performed in early November 2004. The third was scheduled for mid-April.

Creating one system to be shared by medical institutions that would normally be competitors took some work. “Trying to get us all to play in the same sandbox was very difficult,” Rees acknowledges. “But we did that; we stuck it out. And we all agreed to come up with something that we all think is a great idea and should help our patients.”

Delmonico, who is also a Professor of Surgery at Harvard Medical School and Visiting Surgeon in the Transplant Unit at Massachusetts General Hospital, Boston, has also seen the gratifying cooperation between medical professionals. “Institutions are competitive in terms of medical care—that’s no mystery,” he says. “But in this instance, the physicians have been simply magnificent in trying to help patients. Innovative programs can be developed and sustained through the kind of collaboration that is going on here.”

The New England paired exchange program, dating back to 2002, is a collaboration involving a dozen hospitals. It started with a paper-and-pen effort (blood type–incompatible patients would be brought to the attention of Delmonico, who would then contact each transplant center, seeking others) but now has its own computer system.

New England also has another variation on the exchange program that is unique to the region, according to Delmonico. “Let’s say I wanted to give to you but I can’t. I’ll give to somebody on the list, and as a result of that donation, you would get a priority for the next available deceased donor kidney in New England,” he explains. “We’ve done that about 20 times now.”

Continue for going national >>

GOING NATIONAL
So where does paired exchange go from here? Johns Hopkins’ Montgomery organized a consensus meeting in March to discuss the possibility of creating a national network; Hiller, Rees, and Delmonico attended.

“I think our goal should be to one day have a national program,” Rees says. “But shipping somebody from Toledo down to Cincinnati is a lot easier to sell to a patient than shipping somebody from Toledo to Los Angeles. And the logistics of trying to do that when you have a whole different set of insurance companies … would be a lot more complicated. So, I think the way to begin is to do it on a more regional basis and prove that the concept works, that people can be satisfied with it, and then begin to expand it.”

Delmonico also thinks a national program is essential. “We need to enlarge the possibility of paired donation and exchange,” he says. “It will not happen successfully in a regional system. There aren’t enough patients that can be identified.” Questions to be answered before such a program could exist, Delmonico notes, include where the system will be based and who will administer it.

“There was a lot of agreement—though not total consensus—on the fact that UNOS, the United Network for Organ Sharing, would be the most likely place to ‘house’ and to manage the data,” Hiller reports. “They have all those systems in place already [and] are capable of managing this large database.”

Delmonico, as Vice President of UNOS, points out, “We have no authority to do that yet. Whether or not the country wants us to do that also remains to be determined.” But the UNOS Board of Directors is open to the idea; last year, they endorsed the concept of establishing a national paired exchange program with the understanding that details would have to be worked out over time, according to a UNOS spokesperson.

Another obstacle to widespread paired donation may be perceptions of it in the eyes of the government and critics: Could it be construed as a violation of the 1984 National Organ Transplant Act, which says that an organ should not be transplanted for a “value consideration”? Legal experts have assured Delmonico that paired exchanges can be interpreted as a gift.

“The government is also, properly, not wanting to see this as a slope toward buying and selling organs,” Delmonico says. “And I am adamantly opposed to that. In the instances that we’ve done paired exchange here, that’s not in the mix. That’s not our motivation, nor has it been the motivation of these donors. We wouldn’t do it if we felt that was the case.”

Montgomery says it will take several years to get a national system set up. But the bottom line for transplant surgeons is that a national paired kidney exchange program would do a world of good, two people at a time. “This is clearly what is best for our patients,” Montgomery says.

“The bigger we can get, if we can spread it nationally, the more people it will help,” Rees says. “And so we have to think of a way to do this so that we’re all satisfied that it’s moving forward in a way that will make everyone happy.”

Reprinted from Clinician News. 2005;9(5):cover, 3, 15.

SAN DIEGO – The oral opioid nalbuphine was safe and significantly reduced itching intensity in hemodialysis patients with uremic pruritus, a randomized, placebo-controlled trial showed.

“Uremic pruritus is a common problem in dialysis patients,” Dr. Vandana S. Mathur said during a press briefing at a meeting sponsored by the American Society of Nephrology. “A recent study in over 73,000 patients found that 60% of them experience pruritus, and 30% of them experience moderate to severe pruritus. Uremic pruritus is associated with worsening quality of life, sleep, mood, social functioning, higher use of IV antibiotics, higher erythropoiesis-stimulating agent and iron doses, and higher mortality.”

Endogenous opioids are important in the pathogenesis of itch, including itch related to systemic disease, noted Dr. Mathur, a nephrologist and clinical and regulatory drug development consultant based in Woodside, Calif.

“Mu receptors mediate mast cell degranulation and have direct central and peripheral pruritogenic effects, while kappa receptors mediate opposing, antipruritic effects,” she said. “Hemodialysis patients have an increased ratio of beta-endorphin to dynorphin A, and the ratio is associated with increased itch intensity.”

Extended-release nalbuphine is a mu receptor antagonist and a kappa receptor agonist being developed by Trevi Therapeutics. “This dual mechanism of action suggests that it may be effective in the treatment of uremic pruritus,” Dr. Mathur said.

The researchers enrolled 373 hemodialysis patients at 46 sites who had moderate or severe uremic pruritus in a phase II/III study. The primary objectives were to evaluate the drug’s effects on itching intensity as assessed by the Worst Itching Numerical Rating Scale (NRS), as well as safety and tolerability. The patients were randomized 1:1:1 to nalbuphine 60 mg b.i.d., nalbuphine 120 mg b.i.d., or placebo b.i.d. for 8 weeks.

Patients’ mean age was 55 years, and 57% were male. They had been on hemodialysis for nearly 5 years and had experienced pruritus for an average of 3.2 years.

The mean NRS in the 120-mg nalbuphine group declined by 3.5 (from 6.9) on the 10-point scale, which represented a 49% decrease in symptoms and was statistically significant from the least squares mean NRS observed in the placebo group (P = .017), Dr. Mathur reported.

The mean NRS in the 60-mg nalbuphine group declined by 3.1 (from 6.9), which was not statistically different from the least squares mean NRS in the placebo group (P = .432).

“The effect of 120-mg nalbuphine b.i.d. was evident within 1 week following titration and was durable for the full 8-week treatment period,” Dr. Mathur said.

The most common adverse events resulting in discontinuation were nausea, vomiting, somnolence, dizziness, and hallucination, with the incidence rate of these events quickly approaching that of placebo after the first week of titration.

The study’s secondary endpoints of itch-related quality of life and sleep were not significantly improved, “but directional trends supported the primary endpoint findings,” she said.

Trevi Therapeutics supported the study. Dr. Mathur disclosed that she is a consultant for the company.

[email protected]

SAN DIEGO – The oral opioid nalbuphine was safe and significantly reduced itching intensity in hemodialysis patients with uremic pruritus, a randomized, placebo-controlled trial showed.

“Uremic pruritus is a common problem in dialysis patients,” Dr. Vandana S. Mathur said during a press briefing at a meeting sponsored by the American Society of Nephrology. “A recent study in over 73,000 patients found that 60% of them experience pruritus, and 30% of them experience moderate to severe pruritus. Uremic pruritus is associated with worsening quality of life, sleep, mood, social functioning, higher use of IV antibiotics, higher erythropoiesis-stimulating agent and iron doses, and higher mortality.”

Endogenous opioids are important in the pathogenesis of itch, including itch related to systemic disease, noted Dr. Mathur, a nephrologist and clinical and regulatory drug development consultant based in Woodside, Calif.

“Mu receptors mediate mast cell degranulation and have direct central and peripheral pruritogenic effects, while kappa receptors mediate opposing, antipruritic effects,” she said. “Hemodialysis patients have an increased ratio of beta-endorphin to dynorphin A, and the ratio is associated with increased itch intensity.”

Extended-release nalbuphine is a mu receptor antagonist and a kappa receptor agonist being developed by Trevi Therapeutics. “This dual mechanism of action suggests that it may be effective in the treatment of uremic pruritus,” Dr. Mathur said.

The researchers enrolled 373 hemodialysis patients at 46 sites who had moderate or severe uremic pruritus in a phase II/III study. The primary objectives were to evaluate the drug’s effects on itching intensity as assessed by the Worst Itching Numerical Rating Scale (NRS), as well as safety and tolerability. The patients were randomized 1:1:1 to nalbuphine 60 mg b.i.d., nalbuphine 120 mg b.i.d., or placebo b.i.d. for 8 weeks.

Patients’ mean age was 55 years, and 57% were male. They had been on hemodialysis for nearly 5 years and had experienced pruritus for an average of 3.2 years.

The mean NRS in the 120-mg nalbuphine group declined by 3.5 (from 6.9) on the 10-point scale, which represented a 49% decrease in symptoms and was statistically significant from the least squares mean NRS observed in the placebo group (P = .017), Dr. Mathur reported.

The mean NRS in the 60-mg nalbuphine group declined by 3.1 (from 6.9), which was not statistically different from the least squares mean NRS in the placebo group (P = .432).

“The effect of 120-mg nalbuphine b.i.d. was evident within 1 week following titration and was durable for the full 8-week treatment period,” Dr. Mathur said.

The most common adverse events resulting in discontinuation were nausea, vomiting, somnolence, dizziness, and hallucination, with the incidence rate of these events quickly approaching that of placebo after the first week of titration.

The study’s secondary endpoints of itch-related quality of life and sleep were not significantly improved, “but directional trends supported the primary endpoint findings,” she said.

Trevi Therapeutics supported the study. Dr. Mathur disclosed that she is a consultant for the company.

[email protected]

SAN DIEGO – The oral opioid nalbuphine was safe and significantly reduced itching intensity in hemodialysis patients with uremic pruritus, a randomized, placebo-controlled trial showed.

“Uremic pruritus is a common problem in dialysis patients,” Dr. Vandana S. Mathur said during a press briefing at a meeting sponsored by the American Society of Nephrology. “A recent study in over 73,000 patients found that 60% of them experience pruritus, and 30% of them experience moderate to severe pruritus. Uremic pruritus is associated with worsening quality of life, sleep, mood, social functioning, higher use of IV antibiotics, higher erythropoiesis-stimulating agent and iron doses, and higher mortality.”

Endogenous opioids are important in the pathogenesis of itch, including itch related to systemic disease, noted Dr. Mathur, a nephrologist and clinical and regulatory drug development consultant based in Woodside, Calif.

“Mu receptors mediate mast cell degranulation and have direct central and peripheral pruritogenic effects, while kappa receptors mediate opposing, antipruritic effects,” she said. “Hemodialysis patients have an increased ratio of beta-endorphin to dynorphin A, and the ratio is associated with increased itch intensity.”

Extended-release nalbuphine is a mu receptor antagonist and a kappa receptor agonist being developed by Trevi Therapeutics. “This dual mechanism of action suggests that it may be effective in the treatment of uremic pruritus,” Dr. Mathur said.

The researchers enrolled 373 hemodialysis patients at 46 sites who had moderate or severe uremic pruritus in a phase II/III study. The primary objectives were to evaluate the drug’s effects on itching intensity as assessed by the Worst Itching Numerical Rating Scale (NRS), as well as safety and tolerability. The patients were randomized 1:1:1 to nalbuphine 60 mg b.i.d., nalbuphine 120 mg b.i.d., or placebo b.i.d. for 8 weeks.

Patients’ mean age was 55 years, and 57% were male. They had been on hemodialysis for nearly 5 years and had experienced pruritus for an average of 3.2 years.

The mean NRS in the 120-mg nalbuphine group declined by 3.5 (from 6.9) on the 10-point scale, which represented a 49% decrease in symptoms and was statistically significant from the least squares mean NRS observed in the placebo group (P = .017), Dr. Mathur reported.

The mean NRS in the 60-mg nalbuphine group declined by 3.1 (from 6.9), which was not statistically different from the least squares mean NRS in the placebo group (P = .432).

“The effect of 120-mg nalbuphine b.i.d. was evident within 1 week following titration and was durable for the full 8-week treatment period,” Dr. Mathur said.

The most common adverse events resulting in discontinuation were nausea, vomiting, somnolence, dizziness, and hallucination, with the incidence rate of these events quickly approaching that of placebo after the first week of titration.

The study’s secondary endpoints of itch-related quality of life and sleep were not significantly improved, “but directional trends supported the primary endpoint findings,” she said.

Trevi Therapeutics supported the study. Dr. Mathur disclosed that she is a consultant for the company.

[email protected]

SAN DIEGO – High-dose perioperative atorvastatin treatment did not reduce acute kidney injury following elective cardiac surgery, and it may increase risk in patients with chronic kidney disease (CKD) who are naive to statin treatment, results from a large, randomized trial showed.

“Despite advances in patient management that have reduced mortality during cardiac surgery, acute kidney injury continues to complicate the postoperative course in 20%-30% of patients,” Dr. Frederic Tremaine Billings said during a press briefing at a meeting sponsored by the American Society of Nephrology.

“Its diagnosis is independently associated with a fivefold increase in mortality following the surgery,” Dr. Tremaine added. “Statins affect several mechanisms underlying postoperative acute kidney injury. Widely prescribed to reduce cholesterol synthesis, these drugs also reduce lipid modification of intracellular signaling molecules, which have been shown to improve perfusion and reduce oxidative stress – both mechanisms important in acute kidney injury following cardiac surgery.”

Dr. Billings of the department of anesthesiology and critical care medicine at Vanderbilt University Medical Center, Nashville, Tenn., and his associates tested the hypothesis that short-term, high-dose perioperative (preoperative, intraoperative, and postoperative) atorvastatin reduces acute kidney injury (AKI) following elective cardiac surgery.

The researchers randomly assigned preoperative statin-naive patients to 80 mg of atorvastatin on the morning before surgery, 40 mg on the morning of surgery, and 40 mg daily throughout hospitalization, or to a matching placebo regimen. In addition, they randomly assigned patients who were already using statins prior to surgery to 80 mg of atorvastatin the morning of surgery, and 40 mg on the morning after surgery, or to a matching placebo regimen.

“We felt it was important to not withhold statin treatment in patients already using statins prior to surgery, beyond what is typically done in clinical practice,” Dr. Billings explained. “For this reason, preoperative statin–using subjects continued their statin up until the day before surgery, and then resumed their statin use on postoperative day 2.”

The primary endpoint of the study was the incidence of AKI as determined by Acute Kidney Injury Network criteria (a 0.3 mg/dL increase in serum creatinine concentrations within 48 hours of surgery). Secondary endpoints included the maximum creatinine increase from baseline to 48 hours after surgery, ICU delirium diagnosed by the Confusion Assessment Method for the ICU, myocardial injury, and the incidence of atrial fibrillation, pneumonia, and stroke. Safety endpoints included liver toxicity, muscle toxicity, and adverse events.

The study was limited to adults having elective cardiac surgery and excluded those with statin intolerance, acute coronary syndrome, liver dysfunction, use of CYP3A4 inhibitors, kidney transplant recipients, those currently on dialysis, and those who were pregnant.

From November 2009 to October 2014, the researchers recruited 653 patients. But the trial was halted on recommendation of Vanderbilt’s data and safety monitoring board because of futility and an increased incidence of AKI among statin-naive patients with CKD randomized to atorvastatin.

Among all patients, AKI occurred in 20.8% of those randomized to atorvastatin, compared with 19.5% of those randomized to placebo, a difference that was neither clinically nor statistically significant (P = .75), Dr. Billings reported.

However, among the 199 patients who were statin naive, AKI occurred in 21.6% of those randomized to atorvastatin, compared with 13.4% of those randomized to placebo (P = .14). “An 8% difference in the incidence of AKI is of clinical importance, if true,” he said.

Among the 36 statin-naive patients with CKD, AKI occurred in 52.9% of those randomized to atorvastatin, compared with 15.8% of those randomized to placebo (P = .03). “While the number of patients in this subgroup is small, the magnitude of effect is striking,” Dr. Billings said.

Among the 416 patients who were using statins prior to surgery, AKI occurred in 20.4% of those randomized to atorvastatin, compared with 22.4% of those randomized to placebo (P = .63). Results were similar among the subset of those patients who had CKD (31.3% vs. 36.3%; P = .59).

Safety endpoints were similar between the two groups.

Strengths of the study, Dr. Billings said, include the fact that it’s the largest randomized, controlled trial to date to test this hypothesis, the pragmatic design of the protocol, and rigorous methodology.

Limitations include the “small number of patients in the statin-naive CKD subgroup,” he noted. “And the short duration of treatment among prestudy statin-using patients could limit the observation that short-term withdrawal is not harmful – although we felt it appropriate not to limit statins beyond what’s typical in clinical practice, based on prior reports that even short-term statin withdrawal may be harmful.”

The National Institutes of Health and the department of anesthesiology at Vanderbilt University supported the study. Dr. Billings reported having no financial disclosures.

[email protected]

SAN DIEGO – High-dose perioperative atorvastatin treatment did not reduce acute kidney injury following elective cardiac surgery, and it may increase risk in patients with chronic kidney disease (CKD) who are naive to statin treatment, results from a large, randomized trial showed.

“Despite advances in patient management that have reduced mortality during cardiac surgery, acute kidney injury continues to complicate the postoperative course in 20%-30% of patients,” Dr. Frederic Tremaine Billings said during a press briefing at a meeting sponsored by the American Society of Nephrology.

“Its diagnosis is independently associated with a fivefold increase in mortality following the surgery,” Dr. Tremaine added. “Statins affect several mechanisms underlying postoperative acute kidney injury. Widely prescribed to reduce cholesterol synthesis, these drugs also reduce lipid modification of intracellular signaling molecules, which have been shown to improve perfusion and reduce oxidative stress – both mechanisms important in acute kidney injury following cardiac surgery.”

Dr. Billings of the department of anesthesiology and critical care medicine at Vanderbilt University Medical Center, Nashville, Tenn., and his associates tested the hypothesis that short-term, high-dose perioperative (preoperative, intraoperative, and postoperative) atorvastatin reduces acute kidney injury (AKI) following elective cardiac surgery.

The researchers randomly assigned preoperative statin-naive patients to 80 mg of atorvastatin on the morning before surgery, 40 mg on the morning of surgery, and 40 mg daily throughout hospitalization, or to a matching placebo regimen. In addition, they randomly assigned patients who were already using statins prior to surgery to 80 mg of atorvastatin the morning of surgery, and 40 mg on the morning after surgery, or to a matching placebo regimen.

“We felt it was important to not withhold statin treatment in patients already using statins prior to surgery, beyond what is typically done in clinical practice,” Dr. Billings explained. “For this reason, preoperative statin–using subjects continued their statin up until the day before surgery, and then resumed their statin use on postoperative day 2.”

The primary endpoint of the study was the incidence of AKI as determined by Acute Kidney Injury Network criteria (a 0.3 mg/dL increase in serum creatinine concentrations within 48 hours of surgery). Secondary endpoints included the maximum creatinine increase from baseline to 48 hours after surgery, ICU delirium diagnosed by the Confusion Assessment Method for the ICU, myocardial injury, and the incidence of atrial fibrillation, pneumonia, and stroke. Safety endpoints included liver toxicity, muscle toxicity, and adverse events.

The study was limited to adults having elective cardiac surgery and excluded those with statin intolerance, acute coronary syndrome, liver dysfunction, use of CYP3A4 inhibitors, kidney transplant recipients, those currently on dialysis, and those who were pregnant.

From November 2009 to October 2014, the researchers recruited 653 patients. But the trial was halted on recommendation of Vanderbilt’s data and safety monitoring board because of futility and an increased incidence of AKI among statin-naive patients with CKD randomized to atorvastatin.

Among all patients, AKI occurred in 20.8% of those randomized to atorvastatin, compared with 19.5% of those randomized to placebo, a difference that was neither clinically nor statistically significant (P = .75), Dr. Billings reported.

However, among the 199 patients who were statin naive, AKI occurred in 21.6% of those randomized to atorvastatin, compared with 13.4% of those randomized to placebo (P = .14). “An 8% difference in the incidence of AKI is of clinical importance, if true,” he said.

Among the 36 statin-naive patients with CKD, AKI occurred in 52.9% of those randomized to atorvastatin, compared with 15.8% of those randomized to placebo (P = .03). “While the number of patients in this subgroup is small, the magnitude of effect is striking,” Dr. Billings said.

Among the 416 patients who were using statins prior to surgery, AKI occurred in 20.4% of those randomized to atorvastatin, compared with 22.4% of those randomized to placebo (P = .63). Results were similar among the subset of those patients who had CKD (31.3% vs. 36.3%; P = .59).

Safety endpoints were similar between the two groups.

Strengths of the study, Dr. Billings said, include the fact that it’s the largest randomized, controlled trial to date to test this hypothesis, the pragmatic design of the protocol, and rigorous methodology.

Limitations include the “small number of patients in the statin-naive CKD subgroup,” he noted. “And the short duration of treatment among prestudy statin-using patients could limit the observation that short-term withdrawal is not harmful – although we felt it appropriate not to limit statins beyond what’s typical in clinical practice, based on prior reports that even short-term statin withdrawal may be harmful.”

The National Institutes of Health and the department of anesthesiology at Vanderbilt University supported the study. Dr. Billings reported having no financial disclosures.

[email protected]

SAN DIEGO – High-dose perioperative atorvastatin treatment did not reduce acute kidney injury following elective cardiac surgery, and it may increase risk in patients with chronic kidney disease (CKD) who are naive to statin treatment, results from a large, randomized trial showed.

“Despite advances in patient management that have reduced mortality during cardiac surgery, acute kidney injury continues to complicate the postoperative course in 20%-30% of patients,” Dr. Frederic Tremaine Billings said during a press briefing at a meeting sponsored by the American Society of Nephrology.

“Its diagnosis is independently associated with a fivefold increase in mortality following the surgery,” Dr. Tremaine added. “Statins affect several mechanisms underlying postoperative acute kidney injury. Widely prescribed to reduce cholesterol synthesis, these drugs also reduce lipid modification of intracellular signaling molecules, which have been shown to improve perfusion and reduce oxidative stress – both mechanisms important in acute kidney injury following cardiac surgery.”

Dr. Billings of the department of anesthesiology and critical care medicine at Vanderbilt University Medical Center, Nashville, Tenn., and his associates tested the hypothesis that short-term, high-dose perioperative (preoperative, intraoperative, and postoperative) atorvastatin reduces acute kidney injury (AKI) following elective cardiac surgery.

The researchers randomly assigned preoperative statin-naive patients to 80 mg of atorvastatin on the morning before surgery, 40 mg on the morning of surgery, and 40 mg daily throughout hospitalization, or to a matching placebo regimen. In addition, they randomly assigned patients who were already using statins prior to surgery to 80 mg of atorvastatin the morning of surgery, and 40 mg on the morning after surgery, or to a matching placebo regimen.

“We felt it was important to not withhold statin treatment in patients already using statins prior to surgery, beyond what is typically done in clinical practice,” Dr. Billings explained. “For this reason, preoperative statin–using subjects continued their statin up until the day before surgery, and then resumed their statin use on postoperative day 2.”

The primary endpoint of the study was the incidence of AKI as determined by Acute Kidney Injury Network criteria (a 0.3 mg/dL increase in serum creatinine concentrations within 48 hours of surgery). Secondary endpoints included the maximum creatinine increase from baseline to 48 hours after surgery, ICU delirium diagnosed by the Confusion Assessment Method for the ICU, myocardial injury, and the incidence of atrial fibrillation, pneumonia, and stroke. Safety endpoints included liver toxicity, muscle toxicity, and adverse events.

The study was limited to adults having elective cardiac surgery and excluded those with statin intolerance, acute coronary syndrome, liver dysfunction, use of CYP3A4 inhibitors, kidney transplant recipients, those currently on dialysis, and those who were pregnant.

From November 2009 to October 2014, the researchers recruited 653 patients. But the trial was halted on recommendation of Vanderbilt’s data and safety monitoring board because of futility and an increased incidence of AKI among statin-naive patients with CKD randomized to atorvastatin.

Among all patients, AKI occurred in 20.8% of those randomized to atorvastatin, compared with 19.5% of those randomized to placebo, a difference that was neither clinically nor statistically significant (P = .75), Dr. Billings reported.

However, among the 199 patients who were statin naive, AKI occurred in 21.6% of those randomized to atorvastatin, compared with 13.4% of those randomized to placebo (P = .14). “An 8% difference in the incidence of AKI is of clinical importance, if true,” he said.

Among the 36 statin-naive patients with CKD, AKI occurred in 52.9% of those randomized to atorvastatin, compared with 15.8% of those randomized to placebo (P = .03). “While the number of patients in this subgroup is small, the magnitude of effect is striking,” Dr. Billings said.

Among the 416 patients who were using statins prior to surgery, AKI occurred in 20.4% of those randomized to atorvastatin, compared with 22.4% of those randomized to placebo (P = .63). Results were similar among the subset of those patients who had CKD (31.3% vs. 36.3%; P = .59).

Safety endpoints were similar between the two groups.

Strengths of the study, Dr. Billings said, include the fact that it’s the largest randomized, controlled trial to date to test this hypothesis, the pragmatic design of the protocol, and rigorous methodology.

Limitations include the “small number of patients in the statin-naive CKD subgroup,” he noted. “And the short duration of treatment among prestudy statin-using patients could limit the observation that short-term withdrawal is not harmful – although we felt it appropriate not to limit statins beyond what’s typical in clinical practice, based on prior reports that even short-term statin withdrawal may be harmful.”

The National Institutes of Health and the department of anesthesiology at Vanderbilt University supported the study. Dr. Billings reported having no financial disclosures.

[email protected]

SAN DIEGO – The use of hormone therapy was associated with a lower urine albumin-to-creatinine ratio and a decreased risk of albuminuria, results from a cross-sectional study suggest.

“This may be useful information for providers taking care of menopausal women who are considering the use of hormone therapy for vasomotor symptoms and are worried about the systemic effects of these medications,” lead study author Dr. Andrea G. Kattah said in an interview after the annual meeting of the American Society of Nephrology. “Though our data only show an association and not cause and effect, hormone therapy is associated with better kidney function in this study.”

Results from many animal studies suggest that estrogen can have beneficial effects on the kidneys, noted Dr. Kattah, who conducted the research with Dr. Vesna D. Garovic and colleagues in the division of hypertension and nephrology at the Mayo Clinic, Rochester, Minn.

“In addition, in human studies of chronic kidney disease, premenopausal women tend to have slower progression of kidney disease than men,” she said. “Studies on the effects of hormone therapy on kidney function in women have had variable results. We wanted to look at the association of hormone therapy and renal function in a large, multiethnic cohort with well-defined health conditions that may confound the relationship between hormone therapy and renal disease.”

Study participants included 2,217 women enrolled in the Family Blood Pressure Program, a multinetwork effort to study the genetics of hypertension. During a study visit between 2000 and 2004, the women completed questionnaires about medical history, menopausal status, and use of hormone therapy (HT) in the past month. Clinicians also took their blood pressure, measured their body mass index, and drew blood to determine levels of serum creatinine and urine albumin-to-creatinine ratio (UACR).

Of the 2,217 women, 673 were on HT and 1,544 were not, and their mean ages were 60 years and 63 years, respectively.

In unadjusted analysis, Dr. Kattah and her associates found that UACR was significantly lower in those on HT, compared with those who were not (3.5 mg/g creatinine vs. 5.2 mg/g creatinine, respectively, P less than .001), as was the number of women with an estimated glomerular filtration rate (eGFR) of less than 60 mL/min per 1.73 m² (7% vs. 10%, P = .003).

After adjusting for renal and cardiovascular risk factors including age, race, smoking, diabetes, hypertension, and family history of hypertension, the use of HT was still significantly associated with a lower UACR and decreased risk of microalbuminuria (odds ratio, 0.61). The association between HT and eGFR of less than 60 mL/min per 1.73 m² was no longer significant after adjustment, but there was a trend toward higher eGFR and fewer women with an eGFR of less than 60 mL/min per 1.73 m² among those on HT.

“Not surprisingly, the women taking hormone therapy were different than those who were not, and they generally had fewer health problems, such as diabetes and hyperlipidemia,” Dr. Kattah said. “However, after taking these differences into account in our models, we still found a significant decrease in the risk of having microalbuminuria in those on hormone therapy.”

Dr. Kattah acknowledged certain limitations of the study, including the fact that its design is “cross-sectional and cannot answer the question of whether or not hormone therapy can improve kidney function.

In addition, “we do not have data on how long women were taking hormone therapy, which other studies have suggested is an important factor.”

The researchers reported having no financial disclosures.

SAN DIEGO – The use of hormone therapy was associated with a lower urine albumin-to-creatinine ratio and a decreased risk of albuminuria, results from a cross-sectional study suggest.

“This may be useful information for providers taking care of menopausal women who are considering the use of hormone therapy for vasomotor symptoms and are worried about the systemic effects of these medications,” lead study author Dr. Andrea G. Kattah said in an interview after the annual meeting of the American Society of Nephrology. “Though our data only show an association and not cause and effect, hormone therapy is associated with better kidney function in this study.”

Results from many animal studies suggest that estrogen can have beneficial effects on the kidneys, noted Dr. Kattah, who conducted the research with Dr. Vesna D. Garovic and colleagues in the division of hypertension and nephrology at the Mayo Clinic, Rochester, Minn.

“In addition, in human studies of chronic kidney disease, premenopausal women tend to have slower progression of kidney disease than men,” she said. “Studies on the effects of hormone therapy on kidney function in women have had variable results. We wanted to look at the association of hormone therapy and renal function in a large, multiethnic cohort with well-defined health conditions that may confound the relationship between hormone therapy and renal disease.”

Study participants included 2,217 women enrolled in the Family Blood Pressure Program, a multinetwork effort to study the genetics of hypertension. During a study visit between 2000 and 2004, the women completed questionnaires about medical history, menopausal status, and use of hormone therapy (HT) in the past month. Clinicians also took their blood pressure, measured their body mass index, and drew blood to determine levels of serum creatinine and urine albumin-to-creatinine ratio (UACR).

Of the 2,217 women, 673 were on HT and 1,544 were not, and their mean ages were 60 years and 63 years, respectively.

In unadjusted analysis, Dr. Kattah and her associates found that UACR was significantly lower in those on HT, compared with those who were not (3.5 mg/g creatinine vs. 5.2 mg/g creatinine, respectively, P less than .001), as was the number of women with an estimated glomerular filtration rate (eGFR) of less than 60 mL/min per 1.73 m² (7% vs. 10%, P = .003).

After adjusting for renal and cardiovascular risk factors including age, race, smoking, diabetes, hypertension, and family history of hypertension, the use of HT was still significantly associated with a lower UACR and decreased risk of microalbuminuria (odds ratio, 0.61). The association between HT and eGFR of less than 60 mL/min per 1.73 m² was no longer significant after adjustment, but there was a trend toward higher eGFR and fewer women with an eGFR of less than 60 mL/min per 1.73 m² among those on HT.

“Not surprisingly, the women taking hormone therapy were different than those who were not, and they generally had fewer health problems, such as diabetes and hyperlipidemia,” Dr. Kattah said. “However, after taking these differences into account in our models, we still found a significant decrease in the risk of having microalbuminuria in those on hormone therapy.”

Dr. Kattah acknowledged certain limitations of the study, including the fact that its design is “cross-sectional and cannot answer the question of whether or not hormone therapy can improve kidney function.

In addition, “we do not have data on how long women were taking hormone therapy, which other studies have suggested is an important factor.”

The researchers reported having no financial disclosures.

SAN DIEGO – The use of hormone therapy was associated with a lower urine albumin-to-creatinine ratio and a decreased risk of albuminuria, results from a cross-sectional study suggest.

“This may be useful information for providers taking care of menopausal women who are considering the use of hormone therapy for vasomotor symptoms and are worried about the systemic effects of these medications,” lead study author Dr. Andrea G. Kattah said in an interview after the annual meeting of the American Society of Nephrology. “Though our data only show an association and not cause and effect, hormone therapy is associated with better kidney function in this study.”

Results from many animal studies suggest that estrogen can have beneficial effects on the kidneys, noted Dr. Kattah, who conducted the research with Dr. Vesna D. Garovic and colleagues in the division of hypertension and nephrology at the Mayo Clinic, Rochester, Minn.

“In addition, in human studies of chronic kidney disease, premenopausal women tend to have slower progression of kidney disease than men,” she said. “Studies on the effects of hormone therapy on kidney function in women have had variable results. We wanted to look at the association of hormone therapy and renal function in a large, multiethnic cohort with well-defined health conditions that may confound the relationship between hormone therapy and renal disease.”

Study participants included 2,217 women enrolled in the Family Blood Pressure Program, a multinetwork effort to study the genetics of hypertension. During a study visit between 2000 and 2004, the women completed questionnaires about medical history, menopausal status, and use of hormone therapy (HT) in the past month. Clinicians also took their blood pressure, measured their body mass index, and drew blood to determine levels of serum creatinine and urine albumin-to-creatinine ratio (UACR).

Of the 2,217 women, 673 were on HT and 1,544 were not, and their mean ages were 60 years and 63 years, respectively.

In unadjusted analysis, Dr. Kattah and her associates found that UACR was significantly lower in those on HT, compared with those who were not (3.5 mg/g creatinine vs. 5.2 mg/g creatinine, respectively, P less than .001), as was the number of women with an estimated glomerular filtration rate (eGFR) of less than 60 mL/min per 1.73 m² (7% vs. 10%, P = .003).

After adjusting for renal and cardiovascular risk factors including age, race, smoking, diabetes, hypertension, and family history of hypertension, the use of HT was still significantly associated with a lower UACR and decreased risk of microalbuminuria (odds ratio, 0.61). The association between HT and eGFR of less than 60 mL/min per 1.73 m² was no longer significant after adjustment, but there was a trend toward higher eGFR and fewer women with an eGFR of less than 60 mL/min per 1.73 m² among those on HT.

“Not surprisingly, the women taking hormone therapy were different than those who were not, and they generally had fewer health problems, such as diabetes and hyperlipidemia,” Dr. Kattah said. “However, after taking these differences into account in our models, we still found a significant decrease in the risk of having microalbuminuria in those on hormone therapy.”

Dr. Kattah acknowledged certain limitations of the study, including the fact that its design is “cross-sectional and cannot answer the question of whether or not hormone therapy can improve kidney function.

In addition, “we do not have data on how long women were taking hormone therapy, which other studies have suggested is an important factor.”

The researchers reported having no financial disclosures.