Transplantation: Pump it up: conserving a precious resource?

News and Views

Nature Reviews Nephrology 5, 433-434 (August 2009) | doi:10.1038/nrneph.2009.110

Subject Category: Transplant
Transplantation: Pump it up: conserving a precious resource?

Choli Hartono1 & Manikkam Suthanthiran1
Abstract

Determining the optimal method for preserving deceased-donor kidneys is crucial for improving long-term transplant success. A randomized, controlled trial has compared two methods—hypothermic machine perfusion and cold storage preservation.

Optimizing the preservation of deceased-donor kidneys remains an important objective. The two main methods of preservation, hypothermic machine perfusion (Figure 1) and static cold storage, have each had ardent advocates for the past three decades. The results from an international, randomized, controlled trial comparing machine perfusion with cold storage demonstrated that hypothermic machine perfusion is associated with a reduced risk of delayed graft function and improved renal graft survival.1 These findings seem to tilt the balance, albeit gently, towards machine preservation of deceased-donor kidneys.
Figure 1 | LifePort™ Kidney Transporter machine used for hypothermic machine perfusion.
Figure 1 : LifePort|[trade]| Kidney Transporter machine used for hypothermic machine perfusion. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.comImage supplied by Organ Recovery Systems on request of the journal.

* High resolution image and legend (54 KB)
* Figures and tables index
* Download Power Point slide (192 KB)

The transplant community has much to celebrate in the spectacular transformation of organ transplantation from an extremely risky experimental procedure to a safe and successful clinical endeavor in a relatively short timespan of five decades.2 However, there is an oft-repeated lament that the improvement in short-term outcome has not been effectively translated into long-term success.3

What are the perceived obstacles to successful long-term functioning of kidney transplants? Delayed graft function, recalcitrant acute rejection, and chronic allograft nephropathy are all important contributors, and could be mechanistically linked. Delayed graft function is likely to become a greater threat in the future as we continue to liberalize deceased-donor kidney acceptance criteria in our attempts to mitigate the ever-increasing disparity between organ supply and demand.

How should we minimize the incidence and influence of delayed graft function? A number of factors contribute to delayed graft function, currently defined as a requirement for dialysis therapy, irrespective of the cause or indication, in the first week after transplantation. A number of studies, including a recent one by Moers et al., suggest that both donor-related and recipient-related factors are associated with delayed graft function.1, 4, 5

What can we glean from the well-executed, randomized, controlled trial of Moers and colleagues? The investigators randomly assigned one kidney from 336 consecutive deceased donors to machine perfusion and the other kidney from each of these donors to cold storage. Recipients of these kidneys were followed for 1 year. Delayed graft function was observed in 70 of 336 recipients in the machine perfusion group (20.8%) and 89 of 336 recipients in the cold-storage group (26.5%; P = 0.05), and the adjusted odds ratio for delayed graft function was 0.57 (P = 0.01) favoring machine preservation.1 In addition, machine perfusion was associated with a better 1-year graft survival rate (94% versus 90%, P = 0.04), a shorter duration of delayed graft function (P = 0.04), and a lower incidence of primary non-function (2.1% versus 4.8%, P = 0.08), compared with cold storage.

Should the observations of Moers et al.—particularly when viewed together with earlier reports, including a meta-analysis,6 which suggested that preservation of deceased-donor kidneys using hypothermic machine perfusion is associated with a reduced incidence of delayed graft function compared with preservation by cold static storage—sway us to pump henceforth every deceased-donor kidney? Should static cold storage, the prevailing method of deceased-donor kidney preservation7 (used for 80% of deceased-donor kidneys in the USA, and almost 100% of deceased-donor kidneys in Eurotransplant countries) be abandoned? We believe that the existing data should serve as a potent stimulus to perform mechanistic studies to resolve why a subset of deceased-donor kidneys exhibit delayed graft function, and whether the subset that would benefit from hypothermic machine perfusion could be identified in a clinically meaningful fashion. We note that in the controlled trial of Moers et al., more than 70% of the recipients, irrespective of the method of preservation of their deceased-donor kidneys, did not need dialysis therapy in the first week following transplantation. A total of 19 of 338 recipients in the machine perfusion group seemed to have benefited from machine preservation (89 recipients in the cold storage group compared with 70 recipients in the machine perfusion group were treated with dialysis therapy in the first week after transplantation).

Deceased-donor kidneys are currently classified on the basis of whether the kidneys were procured from patients declared brain dead (that is, donated after brain death [DBD]) or donated after cardio-circulatory death (DCD).6 The term expanded criteria donor (ECD) is currently applied when the deceased donor is aged 60 years and older or aged 50–59 years with at least two of the following characteristics: history of hypertension, serum creatinine >133 micromol/l, or cerebrovascular cause of death.8 Existing data suggest that delayed graft function is more frequent in kidneys from DCD donors than in kidneys from DBD donors, and more frequent in kidneys from ECD donors than in kidneys from standard criteria donors (SCD). Hypothermic machine perfusion would be predicted to be beneficial in these high-risk groups, and indeed the observed trend towards a lower incidence of delayed graft function with machine perfusion than with cold storage of kidneys from DCD donors and kidneys from ECD donors supports this hypothesis.1

What are the down-sides of preserving deceased-donor kidneys using machine perfusion? Static cold storage is a technically simpler and cheaper method of preservation than machine perfusion (which in the US costs approximately $3,000 more than cold storage). However, costs over the life-time of a transplant could be lower with machine preservation owing to a lower incidence of delayed graft function (which results in a decreased likelihood of dialysis), shorter hospital stays, and better graft survival rates.9

In a thoughtful editorial on the report of Moers et al., Tullius and García-Cardeña10 emphasized the need for research on the quality of donor organs and the mechanisms contributing to the beneficial effects associated with pulsatile perfusion. We fully subscribe to the view that the pioneering contributions of Folkert Belzer, the inventor of the modern day machine pulsatile preservation method, can be better realized by refining the current classification of deceased donors as SCD and ECD, and investigation of kidney status with greater precision. We need to develop robust criteria for 'discarding' donor organs. In this regard, it would be important to resolve the contributions of donor factors and recipient factors to impaired kidney function following transplantation.

Development of biomarkers that are predictive and prognostic of delayed graft function could assist the design of interventional trials. We are hopeful that mechanistic biomarker studies and further refinement of preservation fluids and pulsatile strategies would minimize organ wastage and optimize post-transplantation function. We look forward to further scrutiny of deceased-donor organ preservation methods in controlled trials complemented by mechanistic studies.
Competing interests statement

The authors declare no competing interests.
Top of page
References

1.

Moers, C. et al. Machine perfusion or cold storage in deceased-donor kidney transplantation. N. Engl. J. Med. 360, 7–29 (2009).
* Article
* PubMed
* ChemPort
2.

Morris, P. J. Transplantation—a medical miracle of the 20th century. N. Engl. J. Med. 351, 2678–2680 (2004).
* Article
* PubMed
* ChemPort
3.

Meier-Kriesche, H. U. et al. Long-term renal allograft survival: Have we made significant progress or is it time to rethink our analytic and therapeutic strategies? Am. J. Transplant. 4, 1289–1295 (2004).
* Article
* PubMed
* ISI
4.

Peeters, P., Terryn, W., Vanholder, R. & Lameire, N. Delayed graft function in renal transplantation. Curr. Opin. Crit. Care 10, 489–498 (2004).
* Article
* PubMed
5.

Patel, S. J. et al. Risk factors and consequences of delayed graft function in deceased donor renal transplant patients receiving antithymocyte globulin induction. Transplantation 86, 313–320 (2008).
* Article
* PubMed
6.

Wight, J. P., Chilcott, J. B., Holmes, M. W. & Brewer, N. Pulsatile machine perfusion vs. cold storage of kidneys for transplantation: a rapid and systematic review. Clin. Transplant. 17, 293–307 (2003).
* Article
* PubMed
7.

Opelz, G. & Döhler, B. Multicenter analysis of kidney preservation. Transplantation 83, 247–253 (2007).
* Article
* PubMed
8.

Port, F. K. et al. Donor characteristics associated with reduced graft survival: an approach to expanding the pool of kidney donors. Transplantation 74, 1281–1286 (2002).
* Article
* PubMed
* ISI
9.

Buchanan, P. M. et al. Association of lower costs of pulsatile machine perfusion in renal transplantation from expanded criteria donors. Am. J. Transplant. 8, 2391–2401 (2008).
* Article
* PubMed
* ChemPort
10.

Tullius, S. G. & García-Cardeña, G. Organ procurement and perfusion before transplantation. N. Engl. J. Med. 360, 78–80 (2009).
* Article
* PubMed
* ChemPort

Top of page
Author affiliations

1. New York Presbyterian Hospital–Weill Cornell Medical Center, NY, USA.

Correspondence to: M. Suthanthiran, New York Presbyterian Hospital–Weill Cornell Medical Center, 525 East 68th Street, Box 3, New York, NY 10065, USA
Email: msuthan@med.cornell.edu

http://www.nature.com/nrneph/journal/v5/n8/full/nrneph.2009.110.html
...........