Time To Think Out Of The (Ice) Box

17 February 2011  //  News

Reproduced with permission from Wolters Kluwer Health: Pirenne J. Time to think out of the (ice) box. Current Opinion in Organ Transplantation 2010;15 (2):147–149.

In most transplant centers, and for most organs, cold storage remains the standard preservation method. The concept – and its application – are simple: at low temperature, metabolism is reduced and organs can be sustained, despite the lack of oxygen and metabolic substrates, for longer periods than at normal temperature. However, after 40 years of development, cold storage has reached its limit and it is time to think out of the (ice) box! There are two reasons for this.

First, cold storage has its intrinsic limitations. In an era of high technology, and emphasis on safety and control issues, simple cold storage increasingly appears to be an unsophisticated method of organ preservation. There is little control and usually no monitoring of the temperature during organ transportation. Second, the type of organs that are procured and transplanted are completely different compared with 40 years ago. Grafts originating from ‘expanded criteria donors’ are increasingly being used and are more susceptible to cold ischemic and preservation injury. In addition, use of grafts from nonheart-beating donors is increasing. These are exposed to warm ischemia prior to procurement and tolerate cold ischemia very poorly. The warm does not like the cold! And yet we still accept these ‘marginal’ grafts in the absence of objective and quantifiable predictive information regarding their viability and function. Most of the time, the final decision to transplant or not to transplant is taken empirically and based on experience, but not on reliable surrogates, simply because in the era of cold storage, these surrogates do not exist.

Whatever the complexity of the biology behind preservation injury, we should not forget that an adequate preservation starts with an efficient surgical procurement technique. This is a largely underestimated area. Procurement operations should be performed by dedicated and well trained surgeons. Credit should be given to professional transplant organizations that are organizing master classes and educational courses in organ procurement to make sure that the surgical standards of procurement remain high.

So, what needs to change?

We need to ‘switch gear’ and reappraise our approach to organ preservation.

Continuously perfusing an organ is – a priori – a more physiological method of preserving it. The concept was invented and developed experimentally by Carrel and Lindbergh. The clinical application was pioneered by Belzer in Madison, but the precise merits of machine perfusion have been questioned ever since. It is only a few months ago that a randomized control trial ended decades of controversy by clearly documenting the superiority of pulsatile machine perfusion over static cold storage1. Machine-perfused kidneys function better, experience less delayed graft function and survive longer2. Also, of major importance in an era of financial constraints, machine perfusion reduces transplant-associated costs. An additional advantage of machine perfusion is that it provides biochemical and hemodynamic tools to assess the quality of the graft. These perfusion parameters, in concert with other relevant donor and recipient parameters, may eventually lead to a more objective prediction of graft function and guide the clinician in selecting the graft, the recipient for a given graft, and the optimal post-transplant immunosuppressive regimen for this particular donor/recipient pair.

Cold pumping may not be the end of the story, but just the start. Currently used hypothermic perfusion systems can probably be optimized by enhansing preservation solutions, adding oxygen and perhaps pharmalogical agents to the perfusate. But cold remains cold, and human organs, even in the presence of oxygen, do not tolerate long periods of hypothermia. For these reasons, warm perfusion has become a ‘hot’ topic and several teams have embarked on warm perfusion in vivo (using ECMO systems) or ex vivo. Until recently, maintaining solid organ viability ex vivo, under near-to-normal physiological conditions, and transplanting them successfully, would have sounded like science fiction, but in fact has been recently performed successfully in large animals (liver) and in humans (lung and heart). Needless to say, this concept – the complete opposite of cold storage – brings major logistical, engineering and surgical challenges.

Time has come to translate this accumulated evidence into the clinics, and instead of using single interventions and targeting single phases of the procurement and transplant process, we should probably be acting simultaneously on different mechanisms and at different stages (donor, preservation, recipient) of the transplantation process.

 

1. Moers C, Smits JM, Maathuis M-HJ, et al. Machine perfusion or cold storage in deceased-donor kidney transplantation. N Engl J Med 2009;360:7–19.
2. Kawai M, Kitade H, Koshiba T, et al. Intestinal ischemia reperfusion and lipopolysaccharide transform a tolerogenic signal into a sensitizing signal and trigger rejection. Transplantation 2009;87:1464–1467.