Schnuelle, P. et al. Effects of donor pretreatment with dopamine on graft function after kidney transplantation: a randomized controlled trial. JAMA 302, 1067–1075 (2009).

Renal transplant recipients who experience delayed graft function and acute rejection are known to be at an increased risk of chronic renal dysfunction. Peter Schnuelle and colleagues have now reported that administering dopamine to kidney donors before transplantation reduces the need for multiple dialysis sessions in organ recipients soon after transplantation, before organ function recovers.

About 10 years ago, Schnuelle's research group reported that treatment of deceased heart-beating kidney donors with catechols—and with the neurotransmitter dopamine in particular—is associated with improved long-term graft survival following transplantation. Data from subsequent experimental work by the same research group indicated that the beneficial effects of dopamine and related compounds on renal graft function are not the result of any hemodynamic improvement achieved in the donors. Instead these compounds seem to exert their influence by protecting the renal graft from preservation injury during cold storage after the organ has been removed. Evidence shows that catecholamines such as dopamine prevent hypothermia-induced cell death by improving cellular redox balance, by preventing intracellular influx and accumulation of calcium ions and by delaying depletion of intracellular ATP.

In their latest study, Schnuelle et al. randomly assigned 124 deceased heart-beating kidney donors to receive a 4 µg/kg per min continuous infusion of dopamine until the implementation of aortic cross-clamping and assigned 140 heart-beating kidney donors to not receive dopamine. Median duration of dopamine administration was 344 min. Ultimately, 227 kidneys removed from donors in the treatment group were transferred to adult recipients; 183 of these kidneys were from donors who had received the full dopamine infusion according to the protocol; the rest of the kidneys were from donors who had been prematurely withdrawn from dopamine (n = 30), had received a reduced dose (n = 4) or had received no dopamine at all (n = 10). Among the 260 kidneys removed from donors in the control group that were transferred to adult transplant recipients, two had been treated with dopamine after randomization.

The necessity of more than one dialysis session in the immediate aftermath of kidney transplantation is considered a better marker of organ deterioration than a single instance of dialysis. The researchers found that, on an intention-to-treat basis, multiple dialyses were required in significantly fewer recipients of renal grafts from donors in the dopamine treatment group in the first week after transplantation than in recipients of grafts removed from donors in the control group (24.7% versus 35.4%). No significant differences were observed between groups in the incidence of biopsy-proven allograft rejection in the first 30 days after transplantation. However, when only data on kidneys transplanted after the mean cold ischemic time of 21.2 h were analyzed, donor treatment with dopamine was associated with improved 3-year graft survival compared with non-dopamine treatment (90.5% versus 73.5%). This evidence seems to corroborate the findings from Schnuelle et al.'s experimental studies that the graft-protecting effects of dopamine are the result of its ability to retard cell death while the organ is stored at a low temperature.

Although Schnuelle and colleagues conclude that “Donor pretreatment with low-dose dopamine reduces the need for dialysis after kidney transplantation”, Terry Strom from the Beth Israel Deaconess Medical Center points out that this trial was not blinded, as physicians who prescribed dialysis were aware of whether or not the grafts had been obtained from donors treated with dopamine. “The results can only be regarded as tentative”, Strom concludes.

Schnuelle et al. chose to use dopamine in their clinical trial because this compound is an approved drug; experimental evidence suggests, however, that dopamine derivatives with increased lipophilicity are more effective than dopamine in protecting tissues from hypothermia damage. Schnuelle and his colleagues are now focusing on these novel dopamine-derived agents, which could “limit organ injury during transplantation through pharmacological donor pretreatment.” As an example, Schnuelle mentions octanyl-dopamine, the product of the reaction of dopamine with octanoic acid. This compound seems unable to bind the dopaminergic or adrenergic receptors—which could reduce its unwanted ability to act as a neurotransmitter. In addition, owing to its hydrophobicity, the cellular uptake of octanyl-dopamine seems increased compared with dopamine, a characteristic that might enhance its ability to prevent hypothermia-induced tissue injury.