American Journal of Kidney Diseases
Volume 56, Issue 1 , Pages 10-13, July 2010

Donor Pretreatment With Dopamine and Graft Function Following Kidney Transplant: A Strategy to Improve Transplant Outcomes?

  • John S. Gill, MD, MS

      Affiliations

    • Corresponding Author InformationAddress correspondence to John S. Gill, MD, MS, Providence Bldg, St Paul's Hospital, Ward 6a, 1081 Burrard St, Vancouver, BC, Canada V6Z 1Y6
    • ,
  • William Gourlay, MD
    • ,
  • Jagbir Gill, MD, SM

Division of Nephrology and Urology, University of British Columbia, Vancouver, Canada

published online 18 March 2010.

Article Outline

 

Commentary on Schnuelle P, Gottmann U, Hoeger S, et al. Effects of donor pretreatment with dopamine on graft function after kidney transplantation: a randomized controlled trial. JAMA. 2009;302(10):1067-1075.

The seemingly inexorable increase in the number of patients wait-listed for kidney transplant, with more than 82,616 patients listed as of November 13, 2009, in the United States,1 highlights the urgent need to increase the number of organs available for transplant. Despite the efforts of the Organ Donation and Transplantation Collaboratives2 and the marked increases in deceased donors early in this effort, only 67 additional deceased donors were identified in 2007 compared with 2006.3 Decreased mortality in younger age groups together with public safety initiatives have decreased the number of potential deceased organ donors. Thus, organ donation programs must not only be highly efficient at identifying potential deceased organ donors and obtaining consent from their families, but also must preserve organ function before donation to ensure maximum use of all organs available for transplant. Deceased organ donors increasingly are of advanced age or have causes of death other than trauma. For example, in 1998-2007, the proportion of standard-criteria donors decreased from 78% to 65%.3 These changes in donor demographics potentially can compromise both initial transplant function and long-term transplant survival and require the development of strategies to maintain the safety and efficacy of solid-organ transplants from the available organ supply. The recent Centers for Medicare & Medicaid Services mandate that individual transplant program outcomes be within expected risk-adjusted limits has further heightened the need for evidence-based strategies to maximize outcomes from the existing supply of deceased donor organs.4 The need for strategies to increase organ viability is emphasized because a substantial proportion of available deceased donor organs currently are not used for transplant. Of the 15,793 potentially recoverable deceased donor kidneys in the United States in 2007, a total of 9% were not recovered, whereas 15% were recovered, but discarded.3

Efforts to improve the management of deceased organ donors before organ procurement have led to numerous advances in clinical practice, with often dramatic improvements in organ function and viability.5 Diligent management of the deceased organ donor, including maintenance of hemodynamic stability and treatment of electrolyte imbalances, hyperglycemia, coagulopathies, and hypothermia, are essential to ensure organ viability. The recent study by Schnuelle et al,6 published in 2009 by the Journal of the American Medical Association, examined whether the routine use of low-dose dopamine in deceased donors after brain death could improve initial kidney transplant function.

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What Does This Important Study Show? 

In this prospective open-label study conducted in Germany, 264 brain-dead donors were randomly assigned to receive a continuous infusion of dopamine at 4 μg/kg (n = 124) or not (n = 140). Included donors were required to be hemodynamically stable while receiving low-dose norepinephrine and have a prerandomization serum creatinine level <2 mg/dL, as well as a serum creatinine level <1.3 mg/dL at the time of hospital admission. Donors in both treatment groups were monitored closely, with predefined thresholds for intervention to maintain hemodynamic stability. Donors had a mean age of approximately 50 years, and trauma accounted for approximately one-quarter of all donor deaths.

Prerandomization donor characteristics were balanced between study groups, except for higher use of norepinephrine and a marginally higher systolic blood pressure in donors who received dopamine. A total of 487 kidney transplants were studied, including 227 in the dopamine group and 260 in the control group. All kidneys were transplanted as singletons; however, multiorgan transplants were included. Mean cold ischemic times in the dopamine and control groups were 13.7 and 14.2 hours, respectively (P = 0.25). Of the transplanted kidneys, a lower proportion was treated according to study protocol in the dopamine group (183 of 227) versus controls (258 of 260). Kidneys were allocated according to Eurotransplant standards, and the management of transplant recipients was not protocol driven. Transplant recipients were approximately 50 years of age and had been wait-listed for a mean of 3.9 years. There were few differences between recipients in the 2 study groups. Outcome measures included the requirement for dialysis during the first posttransplant week, routine serum creatinine values during the first posttransplant week, occurrence and severity of acute rejection during the first 30 days after transplant, and transplant and patient survival at 12 months after transplant. The frequency of multiple dialysis treatments during the first week after transplant was lower in recipients of dopamine-treated kidneys (35.4% vs 24.7%; P = 0.01). A multiple logistic regression analysis that included adjustment for the few baseline differences between study groups confirmed a lower odds ratio for the outcome of multiple dialysis treatments in the first week after transplant in recipients of dopamine-treated kidneys (odds ratio, 0.54; 95% confidence interval, 0.35-0.83). No differences in rejection or patient or transplant survival were identified. In a post hoc analysis, the benefit of dopamine was notable in the subgroup of donor kidneys transplanted after a mean cold ischemic time longer than 21.2 hours (range, 17.1-34.4 hours). The investigators concluded that donor pretreatment with low-dose dopamine decreased the requirement for dialysis after transplant and estimated that treatment of only 10 donors was required to prevent the need for multiple dialysis treatments after transplant in 2 transplant recipients.

This study was rigorously conducted and is internally valid. The unblinded treatment of donors was unlikely to have resulted in biased ascertainment of outcomes in transplant recipients. In addition, the intervention was feasible and would appear to be relatively safe, although 15 of 264 donors were withdrawn from dopamine treatment because of adverse circulatory effects and an additional 2 donors required a decrease in the rate of dopamine infusion. The clinical relevance of the main outcome measure (multiple dialysis treatments in the first week after transplant) is somewhat questionable because the indications for dialysis were not standardized and clinicians may have different thresholds for initiating dialysis therapy in the immediate posttransplant period.6 However, multiple dialysis treatments in the first week were associated strongly with decreased transplant survival in this study. Kaplan-Meier analysis (see Fig 2 in6) showed a high rate of early transplant failure in patients who received multiple dialysis treatments during the first week after transplant, suggesting that these early dialysis treatments were simply a marker of a failing transplant. The cause of these early transplant failures was not reported, and this information would have been useful in understanding the association of multiple early dialysis treatments in the first week with transplant failure. The relevance of multiple dialysis treatments in the first posttransplant week outside the setting of this study remains to be shown. Even if multiple dialysis treatments are not associated with decreased transplant survival outside this study, this surrogate outcome might still be considered clinically relevant if it is associated with increased perioperative morbidity or prolonged peritransplant hospitalization.

Whether the study findings can be generalized to clinical practice in the United States is unclear. The donor and recipient populations in the United States differ from those in this study, and variation in donor management practices likely is far greater in the United States than in the 2 regions of Germany that contributed donors to this study. In addition, the post hoc analysis suggesting that the benefit of dopamine may be modified by the duration of cold ischemia indicates the need to replicate these findings under a variety of clinical conditions.

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How Does This Study Compare with Prior Studies? 

Findings in this study conflict with findings in studies performed in critically ill patients with acute native kidney injury, in which “renal-dose” dopamine has failed to show an improvement in outcomes.7 Factors unique to organ donation and transplant may explain this apparent dichotomy. Deceased donor organs are exposed to numerous events, which may increase immunogenicity. In particular, factors related to brain death, such as hemodynamic instability and systemic release of cytokines, cold preservation, and reperfusion injury, may induce a proinflammatory state in the organ before transplant. The importance of individual proinflammatory mediators is yet to be determined; however, free oxygen radicals likely have an important role. The heme oxygenase system is an important mediator of oxidative stress. Upregulation of heme oxygenase 1 in transplants has prevented ischemia-reperfusion damage and improved long-term transplant survival in various transplant models.7 Dopamine is capable of stimulating the induction of heme oxygenase 1,7, 8, 9 potentially rendering the transplant more resistant to the insult of ischemia-reperfusion damage and inflammation. Catecholamines also can modulate cytokine production. Schnuelle et al10 previously published a single-center study that included 254 kidney transplant recipients. In this study, donor dopamine use was associated with a decreased requirement for hemodialysis after transplant and more rapid recovery of transplant function. An earlier case-control study from this same group showed that use of donor dopamine and noradrenalin was associated with fewer acute rejection episodes and better long-term transplant survival.11 These associations also were shown in an analysis of the Eurotransplant registry that included more than 2,400 kidney transplants performed in 47 centers in 1993.12

The optimal use of catecholamines in the overall management of potential organ donors requires further study. For example, the catecholamine surge at the time of brain death is associated with cardiac injury, including the formation of contraction bands, focal mononuclear cell infiltrates, and necrosis of cardiac myocytes, and thus may decrease the likelihood of successful heart transplant.13 Similarly, use of dopamine after kidney transplant is unclear. The dopamine-mediated increase in renal blood flow in native kidneys may not occur in the denervated transplant.14 However, improved renal hemodynamics with administration of low-dose dopamine in the early posttransplant period has been reported.15

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What Should Clinicians and Researchers Do? 

Deceased organ donors constitute a special subpopulation in the intensive care unit. In the United States, when an individual is identified as a potential donor and after brain death is declared, medical management is directed by transplant coordinators from local organ procurement organizations, rather than by the primary medical team that provided hospital care before death. The donor may remain under the care of the organ procurement organization for hours or even days before organs are procured for transplant. Because there are no universally applied guidelines, there can be considerable variation in practice between organ procurement organizations. Although sharing of best practices is common, continued efforts to standardize care are needed. The present study by Schnuelle et al6 offers a feasible and potentially safe strategy to improve initial kidney transplant function, and the efficacy of this strategy in clinical practice in both the United States and other countries with kidney transplant waitlists should be established. The importance of this strategy in relation to other evidence-based strategies to increase initial kidney transplant function, including the use of machine perfusion16 and calcium channel blockers,17 also needs to be determined. Although the primary goal of organ procurement should be ensuring timely transplants with minimal cold ischemic times, dopamine infusion and other strategies may be important adjunctive therapies to improve early transplant outcomes from deceased donors.

There is a clear and urgent need for research to maximize organ function from the available supply of deceased donor organs. A major accomplishment of the study by Schnuelle et al6 was that it included both brain-dead organ donors and subsequent transplant recipients in a randomized controlled trial. Critically, the investigators were able to include donors after brain death without separate consent from donor families and also were able to obtain outcomes in transplant recipients without consent. The ability to conduct high-quality studies in both brain-dead donors and donors after circulatory death in the United States is dependent on the establishment of clear guidelines that will enable the conduct of ethical trials. In the absence of this framework, the field will continue to be limited by small observational studies, and high-quality prospective controlled studies like that of Schnuelle et al6 will remain the exception rather than the rule.

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Acknowledgements 

Financial Disclosure: The authors declare that they have no relevant financial interests.

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References 

  1. United Network Of Organ Sharing. http://www.unos.orgAccessed November 13, 2009
  2. Leichtman AB, Cohen D, Keith D, et al. Kidney and pancreas transplantation in the United States, 1997-2006: the HRSA Breakthrough Collaboratives and the 58 DSA Challenge. Am J Transplant. 2008;8(4 pt 2):946–957
  3. Tuttle-Newhall JE, Krishnan SM, Levy MF, McBride V, Orlowski JP, Sung RS. Organ donation and utilization in the United States: 1998-2007. Am J Transplant. 2009;9(4 pt 2):879–893
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  6. Schnuelle P, Gottmann U, Hoeger S, et al. Effects of donor pretreatment with dopamine on graft function after kidney transplantation: a randomized controlled trial. JAMA. 2009;302(10):1067–1075
  7. Dunning J, Khasati N, Barnard J. Low dose (renal dose) dopamine in the critically ill patient. Interact Cardiovasc Thorac Surg. 2004;3(1):114–117
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  9. Katori M, Buelow R, Ke B, et al. Heme oxygenase-1 overexpression protects rat hearts from cold ischemia/reperfusion injury via an antiapoptotic pathway. Transplantation. 2002;73(2):287–292
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  11. Schnuelle P, Lorenz D, Mueller A, Trede M, Van Der Woude FJ. Donor catecholamine use reduces acute allograft rejection and improves graft survival after cadaveric renal transplantation. Kidney Int. 1999;56(2):738–746
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 Originally published online as doi:10.1053/j.ajkd.2010.01.007 on March 18, 2010.

PII: S0272-6386(10)00037-5

doi:10.1053/j.ajkd.2010.01.007

American Journal of Kidney Diseases
Volume 56, Issue 1 , Pages 10-13, July 2010

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