Effects of Dopamine Donor Pretreatment on Graft Survival after Kidney Transplantation: A Randomized Trial

Abstract

Background and objectives: Donor dopamine improves initial graft function after kidney transplantation due to antioxidant properties. We investigated if a 4 µg/kg per minute continuous dopamine infusion administered after brain-death confirmation affects long-term graft survival and examined the exposure-response relationship with treatment duration.

Design, setting, participants, & measurements: Five-year follow-up of 487 renal transplant patients from 60 European centers who had participated in the randomized, multicenter trial of dopamine donor pretreatment between 2004 and 2007 (ClinicalTrials.gov identifier: NCT00115115).

Results: Follow-up was complete in 99.2%. Graft survival was 72.6% versus 68.7% (P=0.34), and 83.3% versus 80.4% (P=0.42) after death-censoring in treatment and control arms according to trial assignment. Although infusion times varied substantially in the treatment arm (range 0-32.2 hours), duration of the dopamine infusion and all-cause graft failure exhibited an exposure-response relationship (hazard ratio, 0.96; 95% confidence interval [95% CI], 0.92 to 1.00, per hour). Cumulative frequency curves of graft survival and exposure time of the dopamine infusion indicated a maximum response rate at 7.10 hours (95% CI, 6.99 to 7.21), which almost coincided with the optimum infusion time for improvement of early graft function (7.05 hours; 95% CI, 6.92 to 7.18). Taking infusion time of 7.1 hours as threshold in subsequent graft survival analyses indicated a relevant benefit: Overall, 81.5% versus 68.5%; P=0.03; and 90.3% versus 80.2%; P=0.04 after death-censoring.

Conclusions: We failed to show a significant graft survival advantage on intention-to-treat. Dopamine infusion time was very short in a considerable number of donors assigned to treatment. Our finding of a significant, nonlinear exposure-response relationship disclosed a threshold value of the dopamine infusion time that may improve long-term kidney graft survival.

Keywords: arm; brain; brain death; brain-dead donor; cadaver organ transplantation; confidence intervals; death; donor pretreatment; dopamine; follow-up studies; graft survival; humans; intention to treat analysis; ischemia-reperfusion; kidney transplantation; outcomes; renal protection; renal transplantation; survival analysis; tissue donors; transplants.

Figure 1.

Study flow diagram.

Figure 2.

Kaplan–Meier estimates of kidney graft survival until 5 years after transplantation according to trial group assignment failed to show a significant benefit of dopamine. (A) Overall graft survival. (B) Death-censored graft survival.

Figure 3.

Frequency graphs of the trial efficacy endpoints and dopamine infusion time displayed an effective treatment duration of around 7.1 hours which was achieved only in one third of donors assigned to dopamine. Cumulative percentage frequency of (A) freedom from multiple dialyses requirement immediately after transplantation, and (B) survival with functioning graft 5 years after transplantation, by dopamine infusion time. Vertical dashed lines denote the infusion time at the inflection point. (C) Frequency distribution of dopamine infusion time. (D) Adjusted hazard ratios (HR) of all-cause graft failure 5 years after transplantation and related 95% confidence intervals (95% CI) according to rising thresholds of exposure to the continuous dopamine infusion.

Figure 4.

Kaplan–Meier estimates of kidney graft survival until 5 years after transplantation according to dopamine infusion time ≥7.1 hours indicated a relevant benefit of dopamine. (A) Overall graft survival. (B) Death-censored graft survival.