Outcomes of Therapeutic Hypothermia in Deceased Organ Donors on Delayed Graft Function

Published - Written by Andrea Merrill

Hypothermia 2 7-29-2015While many think of surgery as messy, gory, or even medieval at times, there are certain operations that are simply beautiful to observe and perform, requiring both elegance and finesse. For me, kidney transplants fall into this category, demanding gentle handling of the arterial, venous and ureteral anastomoses by the surgeon with the help of special magnifying lenses (surgical loupes).

The first time I had the privilege to participate as a surgeon in a kidney transplant was also my most memorable. Mr. X was in his 50s with end stage renal disease from IgA nephropathy. He had been on dialysis and waiting for a kidney transplant for several years. He was finally called in, late one Sunday night, to receive the kidney that would unchain him from the thrice-weekly dialysis sessions essential to keep him alive. I briefly introduced myself, performed a routine physical exam and then pulled out a consent form for him to sign before surgery. He would be getting a kidney from a donor after neurologic determination of death (formerly called brain dead donors). In fact, it was a kidney I had helped harvest earlier that morning, from a brave adolescent girl who had suffered brain death from what had become fatal status asthmaticus. There was a pervasive somber mood in the operating room that morning as we removed her liver and kidneys, moving quickly to reduce cold ischemia time.

Although the grief of that morning was still present several hours later, there I was offering life, or at least an improved quality of life, to this grateful man. The operation went well, and I was allowed to carefully sew the delicate veno-venous anastomosis. I rotated off service the next day but continued to follow my patient from afar. Two days later, I was dismayed to find out that, despite our careful surgical dexterity, he had experienced delayed graft function requiring dialysis. His new kidney eventually began functioning, but only after several rounds of dialysis and an extended postoperative course.

Unfortunately, delayed graft function is not uncommon in patients who receive kidneys from deceased donors. Given the long wait list times and shortage of organs, many patients opt to receive kidneys from deceased donors after neurologic determination of death, from donors after cardiac death and, in some cases, from extended-criteria donors (any donor > 60 yo, or any donor > 50 yo with 2 of the following: a history of hypertension, a creatinine > 1.5, or death resulting from a stroke). Efforts to improve outcomes in kidney transplantation from deceased donors are needed, given the ever-growing number of patients awaiting a transplant.

An article by Niemann et al. in this week’s issue of NEJM details the results of a randomized controlled trial that studied the effect of therapeutic hypothermia on delayed graft function in patients who received kidneys from donors after neurologic determination of death.  Current organ donor management protocols require normothermia during harvesting of organs; however, retrospective studies of hypothermia in cardiac arrest patients have demonstrated renal protection. Thus, the authors of this study hypothesized that hypothermia in organ donors might improve outcomes in deceased donor transplants.

The investigators randomized donors in two organ donation service areas—in California and Nevada. Donors were assigned by computer randomization to either mild hypothermia (34-35°C) or normothermia (36.5-37.5°C), stratified according to organ procurement organ, standard or expanded criteria donor status and whether or not they had received therapeutic hypothermia prior to neurologic death. The primary outcome was delayed graft function, defined as need for dialysis during the first week after transplantation.

In total, 370 donors were randomized– 180 assigned to hypothermia and 190 to normothermia; and 583 kidneys were transplanted, 290 from the hypothermia group and 293 from the normothermia group.  Baseline characteristics were similar between the two groups.  Additionally, recipient characteristics known to affect outcomes were balanced between the two groups.  The trial was stopped early because of overwhelming efficacy following after a preplanned interim analysis.

Delayed graft function occurred in about 40% of transplants from the normothermia group in contrast to just over 28% from the hypothermia group (a statistically significant difference, p=0.008). The primary efficacy analysis used a multivariable model logistic analysis and found that hypothermia significantly reduced the risk of delayed graft function by about 40%.

This difference was more pronounced in pre-planned subgroup analysis of extended criteria donors.  Among recipients of extended criteria donor kidneys, delayed graft function occurred in about 30% of hypothermic group compared to just over 50% of the normothermic group, representing a risk reduction of about 70%.  While there was also less delayed graft function in the standard criteria hypothermic group, it was not statistically significant.  Only a small proportion of recipients (11) received dual kidneys, but there was a significant advantage in those patients who received kidneys from the hypothermia group (0% delayed graft function vs. about 80%). There were minimal adverse events and no differences between the two arms.

The accompanying editorial by Jochmans and Watson notes several concerns and limitations.  While immediate outcomes are improved, longer term outcomes such as acute rejection or graft survival were not studied.  Additionally, outcomes of the other organs transplanted (livers and pancreases) were not reported.  Regardless of these limitations, the Niemann et al. study is important, and the editorialists applaud the authors for a potentially simple, cheap, and non-technological intervention in the organ donor “that can have dramatic therapeutic effects” in the recipient.  One hopes that mild hypothermia is a new step towards improving outcomes in transplants in every Mr. and Ms. X on the organ waiting list.