Pre-treating deceased heart-beating donors with low-dose dopamine reduces the need for dialysis after kidney transplantation, reported a randomized study published in the Journal of the American Medical Association (2009;302: 1067–1075).
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Higher doses of dopamine are traditionally used to increase blood pressure in donors who are brain-dead, noted study author Martin Zeier, MD, PhD, speaking in a phone interview. Dr. Zeier is Head of the Department of Nephrology at the University of Heidelberg in Heidelberg, Germany.
“It is thought that dopamine increases blood pressure, and many donors are in shock and need to keep the blood pressure up,” Dr. Zeier said. “In this case we used only a low dose, which is not relevant for the circulatory system, but still it has a protective effect on the donated kidneys.
“This is a very inexpensive measure to improve kidney function posttransplantation. Dopamine is not expensive, it is very easy to give to the donor, there are practically no side effects, and I think it's very useful.”
Dialysis during the first week after transplantation, categorized as single or multiple sessions, was the primary outcome of this prospective, open-label study.
The need for multiple sessions was considered a better indicator of more deteriorated kidney graft function, as a single session is more suggestive of a recipient's overall health and the physician's clinical judgment, the authors wrote.
A total of 264 deceased heart-beating donors who were stable while receiving norepinephrine at a dose of 0.4 µg/kg/ min or lower, had a serum creatinine concentration less than 2 mg/dL, and had an admission serum creatinine concentration below 1.3 mg/dL were randomized to a dopamine infusion at a standard dose of 4 µg/kg/min for a median of 344 minutes or to the control group.
Included in the primary analysis were 487 subsequent renal transplants (227 using kidneys from donors in the dopamine group and 260 using kidneys from donors in the control group) performed at 60 European centers between March 2004 and August 2007. Recipients younger than 18 were excluded.
Fewer recipients of kidneys from the dopamine-treated group needed multiple dialyses before the recovery of renal function compared with recipients of kidneys from the control group—56 of 227 (24.7%) and 92 of 260 patients (35.4%), respectively—translating to a relative risk of 0.86 and a risk difference of 10.7%.
The study authors think that the influence of dopamine on reactive oxygen species is behind this protective effect, Dr. Zeier said.
“We believe that reactive oxygen species—free radicals and things like that—are reduced or bioregulated when the patients receive low-dose dopamine,” restoring endothelial function.
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“That could be a reason why these kidneys start working earlier, these patients need less dialysis after transplantation, and hopefully these kidneys will last longer in these patients.”
No Effect on Rejection or Survival
On the other hand, there were no significant differences between the two groups in incidence and severity of acute rejection at 30 days or patient and graft survival at three years.
“Obviously we have to do a long-term observation, and we'll do that and come back with the results in a couple of years and see whether the kidneys in these patients do better or not,” Dr. Zeier said.
In addition, more kidneys from the dopamine-treated group than from the control group were rated as suboptimal by the surgeons—13.9% versus 6.5%. As this rating is based on the opinion of the transplant surgeon rather than hard clinical evidence, Dr. Zeier said, the difference is a minor point.
“Even though the organs in the dopamine group were not estimated to be as well as the ones in the non-dopamine group, they did better in the follow-up. I would say they were more or less the same, but the dopamine group did much better.”
Dopamine-treated donors also presented with statistically significant but clinically meaningless increases in systolic blood pressure and urine production before organ recovery, the authors noted.
Protocols for managing potential donors vary across different regions, and this study provides support for a more consistent approach, said Bryan N. Becker, MD, who was not involved in the study. Dr. Becker is Professor in the Department of Medicine at the University of Wisconsin–Madison, as well as President of the National Kidney Foundation.
“I think it's the best-structured study to date that has looked at an intervention in the potential organ donor to determine the effects of that intervention on outcomes of the organs. That's a tremendous strength.
“There is tremendous variability among donor populations across the world. This certainly can't account for that, and I think that has to be a consideration.”
The study has a couple other important implications, Dr. Becker added.
“First of all, it's excellent to have better data that tells us how to manage the potential donor with the greatest benefit to the person who is going to receive the organ. We now have better data to suggest that this is an agent that should be used.
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“The second aspect is that it opens up a number of questions as to how it's working, which leads to the potential for additional insight in understanding how to better procure organs with less damage and how those organs get transplanted into people and last longer and indeed function better.”
Potential mechanisms for the observed effect of dopamine on dialysis requirement after transplantation are the effect of the agent on blood pressure, the interaction between dopamine and its receptors in the kidney, and the potential influence of dopamine on the immune system, Dr. Becker said.
‘Not Strictly Comparable to US’
On the other hand, there are some concerns over how applicable the results are to practice in the United States.
“It's most likely not going to affect my practice,” said Anthony M. D'Alessandro, MD, who was not involved in the study. Dr. D'Alessandro is Professor of Surgery in the Division of Transplantation at the University of Wisconsin School of Medicine and Public Health, as well as Medical Director and Interim Chair of the Organ Procurement Organization there.
“This is a European study. I think there are a number of potential issues with the study. Dopamine is our first choice as a pressor when we are working with a brain-dead donor, and we usually add other pressors as needed, such as norepinephrine, rarely epinephrine, and even more rarely dobutamine.
“Usually our dopamine dose is somewhere between 5 and 10 micrograms per kilo and not just at what we refer to as the renal dose. The dose that they chose, 4 micrograms per kilo, would be considered to be renal-dose dopamine.”
While the need for multiple dialyses after transplantation is a good indicator of delayed graft function, the study does not take into account a number of variables that could affect that measure, Dr. D'Alessandro added.
“In Europe they are not using the definition of extended-criteria donor [ECD], so while they do say they control for age, and although they say later on in the study that they control for creatinine and hypertension in the donors, they really don't show any data to that effect.
“One of my concerns is that if one of these groups—say, for instance, the no-dopamine group—had a higher percentage of patients with what we would define as ECD kidneys, they would clearly have a higher need for dialysis.”
Recipient characteristics also need to be taken into consideration, Dr. D'Alessandro added, noting that 11.9% of patients in the dopamine group and 18.1% of patients in the non-dopamine group had previously had transplants.
“If you have more retransplants in one group or the other, you're going to have a higher dialysis rate for immunologic reasons.”
In the study, the need for multiple dialysis sessions posttransplant translated to significantly worse graft survival only in those patients whose organs were preserved for a mean of 21.2 hours, Dr. D'Alessandro noted.
“My question still remains: In that particular group was there a higher preponderance of retransplant patients or extended-criteria donors?”
Overall, preservation time in the study was consistent with clinical practice in the United States—a median of 13.7 hours in the dopamine-treated group and 14.2 hours in the non-dopamine-treated group.
The preservation methods did differ, though, with kidneys cold stored in the study as opposed to machine perfused, which is becoming more common in the United States, Dr. D'Alessandro said.
“We obviously need to do whatever we can to reduce delayed graft function, and machine perfusion is one way to do so. Reducing the preservation time, whether its cold storage or machine perfusion, is probably the biggest thing we can control for reducing delayed graft function.”
Despite the study's limitations, there's probably enough evidence to say that low-dose dopamine might be helpful and can be used in conjunction with the other measures aimed at reducing delayed graft function, he added.
“There have been a number of studies that clearly show that delayed graft function affects your long-term graft survival, so if you can further reduce delayed graft function by using a combination of low-dose dopamine and norepinephrine to maintain blood pressure in brain-dead donors, then I think, why not?”
TO REACH CIRCULATION
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© 2009 Lippincott Williams & Wilkins, Inc.