Blog entry by Arif Khwaja
Despite the plethora of publications regarding kidney transplantation outcomes, immunosuppression remains remarkable similar in most centres. CNIs (usually tacrolimus), anti-metabolites (usually) MMF and steroids with IL2-receptor antagonism remaining the cornerstone of immunosuppression for most transplant centres. Of course there are variations on this (some centres maybe steroid free, others may use ATG induction) but broadly speaking graft outcomes are similar across most large transplant centres. Consequently there have been few interventions that have made any difference to graft outcomes in that last 10 years. Recently there has been increasing interest in donor interventions than can impact on graft outcomes - e.g. machine perfusion of kidneys from deceased donors has been shown to reduce delayed graft function (DGF -defined as the need for dialysis within the week after transplant) and possibly improve allograft function at one year.
In this weeks NEJM, Niemann and colleagues publish data looking at the effect of therapeutic hypothermia in patients transplanted in California and Nevada. In essence donors who had been declared brain dead according to neurological criteria were randomised to two target temperatures: hypothermia (34-35 C) or normothermia (36.5-37.5 C). Hypothermia was achieved either by not actively warming patients or through the use of ‘forced air-systems or passive cooling devices’ ( there is no further detail on what this actually is in practice).
The headline figures show that the trial was terminated early after the independent safety board saw a clear benefit of induced hypothermia. A total of 572 patients received a kidney from 370 donors. DGF developed in 28% of the hypothermia group and 39% of normothermia group - there was a significant difference (p=0.02). This was based on a multivariable analysis that accounted for variables that can influence DGF such as donor type (expanded vs standard-criteria), donor creatinine and age and cold ischaemia time. The beneficial effect of hypothermia was particularly striking in the expanded criteria donors (adjusted odds ratio 0.31;CI 0.15-0.68; p=0.003) whereas in the standard criteria group although hypothermia reduced DGF this did not reach statistical significance. The authors reasonably conclude that this may reflect the benefit of hypothermia is via mitigation of ischaemia-reperfusion injury.
As well as normothermia other statistically significant factors assocaied with an increased risk of DGF included donor age, cold ischaemia time, donor creatinine and donor age.
A few things worth pointing out. As the investigators could not control all donor variables it is worth noting that the cold ischaemia time in the hypothermia group was slightly (but significantly) less than in the normothermia group. This may of course skew the data in favour of hypothermia but it was accounted for in the multi-variate analysis. Furthermore although there were no safety signals, no long term data is presented so we don’t know whether this reduction in DGF translates into graft function at 1 year or any other longterm meaninful outcome. Finally there is little information presented on how hypothermia was achieved so I’m not quite clear how costly such an intervention would be.
In summary this is a really interesting study that suggests a relatively safe and presumably easy to deliver intervention (hypothermia) can have a meaningful impact graft outcomes particular in kidneys from expanded criteria donors. It will be interesting to see how quickly this intervention is taken up by the broader transplant community