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Nine Things You Might Not Say or Hear in Transplantation

2008; Elsevier BV; Volume: 9; Issue: 1 Linguagem: Inglês

10.1111/j.1600-6143.2008.02502.x

1600-6143

Jonathan S. Bromberg, Philip F. Halloran,

Renal Transplantation Outcomes and Treatments

It is time to stir up some debate on areas of organ transplantation that need sharper focus. As an exercise, the editorial board of the AJT put together a long list of important, hot or cutting edge areas in transplantation research. As we examined the topics, categorized them and played with their relative merits, it became apparent that this process of analyzing science and research sometimes disguises some uncomfortable truths and realities. In the spirit of the late George Carlin and his 'seven words you can never say on television', we now offer some uncomfortable conclusions about the current state of transplantation. These topics represent our personal favorite bete noires among a large list of many important issues, some of which truly cannot be said or heard. The sine qua non of transplantation is organ donation. There have been extensive efforts and discussions around both deceased and living donation with the Donor Collaborative, paired exchange programs, extended criteria donors and ethical issues involving both types of donors. Yet, we seem to be at an impasse. The gains of the Collaborative have plateaued and some have argued that the gains are at the expense of worse outcomes and higher costs through the use of ever more marginal organs (1). Efforts to increase living donation have been stymied by acrimonious debates about risk, ethics and costs (2, 3). Too often, instead of taking a strong position and negotiating minimally, the organ procurement community always takes a weak position and then backtracks further. When will the transplant societies, government agencies or society as a whole realize that we are mired in old paradigms and that resource allocation and attitudinal changes must take place to truly increase donation of high quality living and deceased organs to make an impact on the mortality rate of those waiting for organs? Will we be able to say that organ donation is a requirement, not an expectation? There are many current opportunities for changes in organ allocation, such as a utility-based approach for kidneys, stratification for the sensitized population, tweaking the MELD exception formulae, toying with geographical radii of distribution and new methods for assigning HLA matching. However, given the shortage of organs, the long waiting times and the mortalities on the waitlist, these considerations often are tantamount to rearranging the deck chairs on the Titanic. For example, some portray their favorite allocation system as if it is capable of allocating life in an 'equitable manner', sparing some and allowing others to die. At times people have claimed allocation systems have 'saved' lives, leaving the impression that it is a highly effective donor organ 'generator'. Despite the claims, donor organs are not a 'product' conferred by an allocation strategy. Depending on whose modeling one believes, the gains from these allocation studies may be, at best, modest to the overall picture; and often disguise from patients and families that allocation is really rationing (4) and does not produce more organs or solve their personal needs. Changes in the allocation systems expend huge amounts of time, effort and money on the part of every single OPO and transplant center and afford innumerable opportunities for UNOS/OPTN and CMS to find these organizations out of compliance and cite them for real or perceived deficits, initiating a new round of expensive corrective actions that ultimately divert resources from patient care and redistribute them to purely administrative and punitive actions. Unremitting changes in allocation waste valuable resources that would be better spent on solutions to the donor shortage. Organ assessment and preservation is largely based on 1960s practices. The basic and translational scientific analyses of ischemia-reperfusion injury, extended criteria donor (ECD) organ assessment, organ preservation and management of organ injury remain persuasive and fascinating areas, as recent basic advances suggest many important targets for study and therapy. There is even more urgency to these fields as a result of the Collaborative increasing the yield of ECD organs, and as a result of the ever increasing recipient waiting lists. Yet, Federal rules on human subjects protection and approval for consent during emergent operations have stymied translational and clinical research. The decreasing NIH budget and ever more complex rules and expenses for animal experimentation (such as providing an enriching environment for mice and fish) have all but precluded significant new research in this field. The recent recognition that B cells and antibodies may be participating in a variety of immune phenomena, such as acute and chronic rejection and immune regulation, has posed a number of important questions. What is the mechanism of late antibody-mediated graft loss, and why is it so often class II? How can antibody-mediated rejection be diagnosed and treated? What is the significance of B cells and plasma cells in organ allografts? Given the ease of collecting and measuring antibodies, and then correlating their profile over time with graft clinical and pathologic outcomes, the time seems ripe for a large multi-centered trial to answer these important questions. Perhaps the resources devoted to CMS re-certification would be better spent and result in better patient outcomes for such a research project, rather than being wasted on consultants and administration. In the T-cell universe of immune regulation, recent discoveries now allow us to ask incisive questions. But, many of these questions make little sense if we do not understand what processes they are regulating. What is the mechanism of T-cell-mediated rejection in vascularized organs across MHC disparities? What is the phenotype of the grafts that are being lost, and what immunologic mechanisms are responsible? How much do non-immunologic mechanisms really play? How can we identify and quantify memory T cells that cross-react with donor MHC, and how do these T cells mediate graft damage? However, the elephant in the room that receives little discussion is the nature of tolerance. What adaptive mechanisms actually operate (as opposed to theories) in humans with organ transplants that keep them stable on relatively little immunosuppression? What are the relative roles of deletion, anergy and suppression in transplant stability? What is the risk/benefit of immunosuppression withdrawal? Who would donate a kidney to their wife/child and then enroll them in a tolerance trial involving total withdrawal of immunosuppression? Are we ready to admit that we are very far from inducing or maintaining something that looks like tolerance? We can't even agree on what it is (5, 6). Like the Supreme Court and pornography, we can't define it, but believe we know what it is when we see it. Major changes in healthcare structure and financing will undoubtedly have protean effects on all aspects of transplantation, both in the USA and elsewhere. In the USA, we must rethink the structure and finances of transplantation: the impending collapse of support for academic medical centers due to changes in medicare, medicaid, NIH, biotechnology and the U.S. economy; the unfunded burden of documentation for and compliance with multiple organizations (JCAHO, CMS, UNOS/OPTN, individual state departments of health) conducting independent and politically competitive reviews; and questions whether traditional departmental lines versus commonality of purpose within transplant centers will result in the best patient care, training environment, research incubator and financial stability of the whole medical center. Many of the so-called innovations in transplantation, such as the use of DCDs and ECDs, essentially drive up the costs associated with transplantation, while undermining the benefits. Thus, in effect, transplantation is becoming less cost-effective at precisely the time when public policy is dictating that health care should be increasingly cost-effective. The competing interests on federal, state and university levels make addressing these problems extraordinarily difficult (7). However, the alternative is to remain mired in inactivity and defeat. In a time when big pharma seems to be curtailing support for transplantation, there is no clear mechanism to make advances in immunosuppression that are clearly needed. While the future of therapeutics is bright from an intellectual and theoretical standpoint, we need more discussion about where is the field of immunosuppression going, both in industry and academia. Is therapeutic use of T-cell populations as 'drugs' (e.g. infusion of regulatory cells) realistic? Would this be better than conventional immunosuppression, and what kinds of trials would be necessary? What is the role of stem cell therapy? Will we have individualized therapies? However, there are numerous roadblocks to any progress at present: decreasing NIH budget; recessionary economy; insuperable IRB and religious hurdles; and paralyzed, politicized and contradictory FDA policies. Powerful technologies that were only a dream a decade ago are ready to advance diagnostics (8), but we have not yet defined a critical pathway to bring them to the clinic. From the intellectual standpoint, there are important questions: How do we incorporate the power of 'omics' into clinical transplantation? What are the validation strategies for new technologies? These questions would be easier to answer if the actual mechanisms of rejection were defined, permitting measurement of the actual processes operating in T-cell-mediated rejection, B-cell-mediated rejection, allograft vasculopathy, atrophy and fibrosis and other biological processes contributing to late graft loss. In other words, the search for biomarkers must be combined with the definition of mechanisms. These areas are poised to make huge contributions, but political and administrative roadblocks impede much research or make it too difficult or too expensive to contemplate. Furthermore, there are major financial impediments to answering these questions. First, the tests are expensive, yet research and development expenditures ultimately need to 'show a profit.' Second, companies may be confused as to who actually benefits from the tests. Clearly, patients benefit from noninvasive testing. However, companies lobby payers in hopes of favorable coverage and reimbursement policies. Yet, the transplant center is more realistically the marketing target due to prospective or fixed payment methods. Unfortunately, once the payment is fixed and if the new test although patient-friendly is vastly more expensive, there is minimal reason for the transplant center to adopt it. Therefore, companies are making substantial investments while laboring under an old sales paradigm. Important and productive research is not being done, not because it is intellectually unsatisfying or clinically irrelevant, but because it has been regulated out of our reach. There is not enough investment in risk reduction in the long-term organ transplant patient. New knowledge in protective immunity to viruses and new approaches to chemotherapy for pathogens promise to revolutionize the treatment of important infections in transplantation, including HCV, Polyoma and emerging pathogens. Questions regarding immunity, vaccines, clearance, viral load and recurrence are now approachable with a precision and finesse not available even a few years ago. We should now be asking how to evaluate and quantify the trade-offs in long-term immunosuppressive management between infections, malignancy and components of the metabolic syndrome versus adequate immune protection. We should be asking how to measure those components for individual patients, and how to improve the therapeutic index for all patients and for all drugs and combinations. Organ transplantation started over 50 years ago and needs new directions. In every country, the systems that led to the successes of transplantation may not be the systems needed to achieve the successes of the next generation. Systems become stale. Effective organizations become bureaucratic and fossilized. Regulations and regulators increase, at the expense of people and resources needed for 'production', i.e. bureaucrats seem to proliferate when what we need is more people and resources for actually looking after donors and recipients and achieving research advances. This is a problem in all human systems, and requires a serious strategic reassessment of all aspects of the system and possibly drastic changes. The above nine areas are only examples: it is time to shake up the field with some new forces that examine every aspect of our systems. We must return to the spirit of the pioneers of transplantation science and practice, who built the successes of the past half-century by refusing to accept the limitations of an unsatisfactory status quo. Over the next year, the AJT editorial board will be inviting leaders in our field to comment on the issues noted above and on other important consequences of our current uncomfortable realities. Our goal is to start a dialogue that will result in important consensus conferences to make bold and difficult decisions about the direction of transplantation.