First Things First: Laying the Ethical and Factual Groundwork for Living Kidney Donor Selection Standards

The recent article by Mandelbrot et al. (1Mandelbrot DA Pavlakis M Danovitch GM et al.The medical evaluation of living kidney donors: A survey of US transplant centers.Am J Transplant. 2007; 7: 2333-2343Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar) and the accompanying editorial by Davis (2Davis CL Variable evaluation and selection criteria for living kidney donors: Have we gotten the message yet.Am J Transplant. 2007; 7 (Editorial): 2219-2220Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar) addressed current transplant center practices in evaluating and accepting living kidney donors (1Mandelbrot DA Pavlakis M Danovitch GM et al.The medical evaluation of living kidney donors: A survey of US transplant centers.Am J Transplant. 2007; 7: 2333-2343Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar) and compared these findings with those of a similar survey done a decade ago (3Bia MJ Ramos EL Danovitch GM et al.Evaluation of living renal donors.Transplantation. 1995; 60: 322-327Crossref PubMed Scopus (221) Google Scholar). Both of those surveys depicted a wide spectrum of clinical practices, but they did not in themselves provide ethical or factual justifications for any specific donor selection policy. In viewing these substantial disparities, one might naturally ask—because of well-intentioned but confused ethics or because of errors in understanding medical facts—whether some centers are accepting donors who should be rejected. Or perhaps just as important, are some centers inappropriately rejecting donors who should be offered the chance to donate? In her editorial, Davis calls for a more standardized medical evaluation for prospective donors, for standardized acceptance criteria, and for a registry to follow outcomes after donation. Her important suggestions deserve a detailed analysis, and we wish to explore them in the next few paragraphs. Creating standards for donor selection will involve (1Mandelbrot DA Pavlakis M Danovitch GM et al.The medical evaluation of living kidney donors: A survey of US transplant centers.Am J Transplant. 2007; 7: 2333-2343Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar) making explicit the ethical rationale for setting particular standards and (2Davis CL Variable evaluation and selection criteria for living kidney donors: Have we gotten the message yet.Am J Transplant. 2007; 7 (Editorial): 2219-2220Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar) developing factual risk data that support the setting of any standard or threshold. Too often in the past, the transplant community has set out to formulate such standards without first addressing essential ethical and factual issues (as discussed below). Whether generated by individuals, committees, forums, or surveys, living kidney donor selection standards need to be defended ethically and factually. When this cannot be done, a strict standard cannot be justified and may do more harm than good. A number of ethical issues must be addressed as part of developing guidelines for donor acceptance. First, to keep our bearings, we must articulate why we are trying to set standards at all. For example, do we think that without these standards, some centers may act unethically, and if so, how? Do we think that donors may be misled or make unsupportable decisions, or that standards are necessary simply so that we can better withstand public scrutiny? Second, we must decide whether we can ever realistically promise to ‘do no harm’ or whether we always must accept that we might ‘do harm ethically’. A ‘safe’/‘unsafe’ dichotomy for donors is artificial and misleading (4Steiner RW Risk appreciation for living kidney donors: Another new subspecialty.Am J Transplant. 2004; 4: 694-697Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar), so our ethical positions will have to account for the continuums of risks that all donors face. The actual calculation of risk is a factual matter, but the need for risk data and risk estimation (however imperfect) is an ethical matter. Risks must be estimated, not just qualitatively as ‘high’ or ‘low’ but semiquantitatively (e.g. for the typical donor candidate, the 20-year risk of end-stage renal disease (ESRD) from mild hypertension is between 1 in several hundred and 1 in a thousand [7]). One approach to achieving ethical consensus is through analysis of paradigm examples, i.e. hypothetical cases where virtually all of us would agree on the ethical or unethical nature of donation (4Steiner RW Risk appreciation for living kidney donors: Another new subspecialty.Am J Transplant. 2004; 4: 694-697Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar). It is known that perioperative risks for older donors are greater than for young donors. Blacks have almost three times the long-term risk of ESRD than do whites (5Kiberd BA Clase CM Cumulative risk for developing end-stage renal disease in the US population.J Am Soc Nephrol. 2002; 13: 1635-1644Crossref PubMed Scopus (122) Google Scholar). The 20-year risk for end-organ damage for a patient with a blood pressure (BP) of 135/85 is different—but only slightly different—from the risk of a BP of 125/75, or a BP of 115/65, so that ‘there is no lower limit to risk’ (6Levy D Hypertension from Framingham to ALLHAT: Translating clinical trials into practice.Cleve Clin J Med. 2007; 61: 672-678Crossref Scopus (2) Google Scholar). As we attempt to estimate perioperative and long-term donor risks, we must try to decide where along these continuums the acceptable limit is to be set, and what ethical considerations might permit acceptance of greater risk, depending on the individual circumstances for any given donor. Of note, using the standards we apply in other major life decisions, we can offer approximate the common risks that our donors face (7Steiner RW Danovitch G The medical evaluation and risk estimation of end-stage renal disease for living kidney donors.in: Steiner RW Educating, Evaluating, and Selecting Living Kidney Donors. Kluwer Academic Publishers, Norwell, MA2004: 51-79Crossref Google Scholar). As centers still have to decide for themselves what risks are reasonable, formulating these risks does not in itself obligate a center to accept any donor, but these estimates are essential to rationally determine donor acceptance policy. We must formulate the risks of nephrectomy and ESRD. These risk estimates must be developed for ‘normal’ donors and for donors with potential increased risk (e.g. mild hypertension, nephrolithiasis), as we determine where to set the bar. If the risks are truly unknown, or only a cursory estimate is provided over a wide ‘low’ to ‘high’ range, then so-called reasonable donor counseling, decision making and center acceptance are indefensible. Prospective donors faced with truly unknown risk cannot rationally decide, cannot be taught or counseled about risk, and therefore cannot be accepted. In these situations, promulgating a standard of refusal would be justified as the risk of a given medical finding is unknown, not because it is known to be ‘high’. This is, in fact, the actual, but unarticulated, reason that some centers reject many donor candidates when a risk factor is identified. This distinction is important, because if a center had defensibly researched and defended its risk estimates, it would not be breaching this standard. Other ethical issues might also be clarified by discussion of the sometimes sound, but largely unarticulated, reasons for the variations among centers, or within centers, regarding donor exclusion policies. For example, a prospective donor with mild hypertension may be accepted only if no other donors are available. A younger (<30 years old) candidate with mild hypertension may be rejected, whereas an older person with the same degree of hypertension may be accepted. We also need to discuss how much autonomy over risk an otherwise acceptable prospective donor has in the decision-making process. Once we define the continuums of risks for different ‘normal’ donors, we need to decide whether there will be situations where we allow some informed donors to accept more risk than others. We need to articulate our shared ethical misgivings about granting autonomy to our very high risk, putatively heroic donors. We cannot forget that the decision to deny a prospective donor may have significant negative consequences. If there are no other donors, the potential recipient may have to spend more years on dialysis; unjustified rejection of, say, a spouse who wants to donate may have negative consequences for both the prospective donor and recipient. There is no doubt that a kidney transplant has significant advantages over long-term maintenance dialysis. And we recognize that many centers are currently doing living liver donor transplants; liver donors are at higher risk for perioperative and medium-term complications (there is not yet long-term follow-up) than kidney donors. Whether or not there should be a different level of acceptable risk for kidney vs liver donors should be part of the ethical discussion. In both instances, however, as long as the center determines that the donor meets defensible ethical criteria, then giving reasoned, informed consent to donation is still the donor’s choice. No abridgement of donor selection standards should be justified simply because donation greatly benefits the recipient. Once risk estimates have been developed, we need to discuss whether or not all centers need to adhere to identical standards and under what circumstances centers could deviate from any agreed-on risk levels. We would expect that, within limits, individual centers could ethically choose to have either more or less stringent acceptance criteria—as long as their policies were transparent. Importantly, if there are irreconcilable major differences in center acceptance practices, prospective donors must be informed of the alternatives. Finally, another of our ethical obligations is to ensure donor understanding of risk and benefit. We must agree on minimally acceptable teaching tools and explore the most effective methods to help ensure clear thinking and bona fide understanding in all prospective donors. The factual issues involve estimating the donor risks themselves. Currently, all centers do a relatively similar medical examination to assess the overall health and kidney function of prospective donors. What may differ is the interpretation of the data. We first need to define the risks for our ‘normal’ donors and then the risks for donors with the isolated medical abnormalities that the Mandelbrot survey addressed. Given the continuum between ‘normal’ and ‘abnormal’, we may debate what really is an abnormal finding and how seriously to take some mild ‘abnormalities’. Definitions of some risk factors have changed in the last 30 years (e.g. for diabetes and hypertension); other risk factors (e.g. obesity and the metabolic syndrome) have only recently been defined. As the ‘at-risk’ donor pool expands because of inclusion of more individuals with borderline disease, the risks for the pool become more heterogeneous. Certainly, the risks will be relatively lower in prospective donors with less severe abnormalities. Our overriding factual tasks are to estimate the lifetime risks of ‘normal’ donors, the risks of nephrectomy, and the real risks of various common isolated medical abnormalities. In the Mandelbrot survey (1Mandelbrot DA Pavlakis M Danovitch GM et al.The medical evaluation of living kidney donors: A survey of US transplant centers.Am J Transplant. 2007; 7: 2333-2343Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar), respondents were asked whether risks of certain isolated medical abnormalities (IMAs) in prospective donors were ‘nil’, ‘small’ or ‘large’, but were asked not to specify what they meant quantitatively by these terms, or to specify the number of years over which the risk was estimated. Differences in opinion abounded, illustrating the need to develop objective methodologies to estimate the actual risks. In order to have a meaningful discussion, we must replace the terms ‘high’ and ‘low’ risk with terms providing a numerical estimate of the risk over time. ‘High’ and ‘low’ risk may mean very different things to different people. In fact, the phrase ‘high risk’ is for many centers more of a recommendation not to donate than it is an actual quantitative risk estimate. It is critical to recognize that normal donor candidates have lifetime risks of renal disease (and death) that can be estimated from abundant existing data. Using available data, risk estimates can be determined for donors with any IMA. The questions that centers must address are whether or not this IMA (or combination of abnormalities) is associated with increased risk, and over what time period this increased risk occurs. As stated above, all donors, like nondonors, have a lifetime risk of developing ESRD. For example, many donors develop hypertension and other risk factors as they age (7Steiner RW Danovitch G The medical evaluation and risk estimation of end-stage renal disease for living kidney donors.in: Steiner RW Educating, Evaluating, and Selecting Living Kidney Donors. Kluwer Academic Publishers, Norwell, MA2004: 51-79Crossref Google Scholar, 8Najarian JS Chavers BM McHugh LE Matas AJ 20 years or more of follow-up of living kidney donors.Lancet. 1992; 340: 807-810Abstract PubMed Scopus (568) Google Scholar). Of 100 ‘healthy’ 25-year-old white males (with 2 kidneys) who live into their 70s, about 2 will develop ESRD, usually at an old age (5Kiberd BA Clase CM Cumulative risk for developing end-stage renal disease in the US population.J Am Soc Nephrol. 2002; 13: 1635-1644Crossref PubMed Scopus (122) Google Scholar). If the evaluation process in these young donors can identify even half of this 2%, which is doubtful, we still miss the other half, who will develop ESRD late in life, usually due to diabetes or hypertension (7Steiner RW Danovitch G The medical evaluation and risk estimation of end-stage renal disease for living kidney donors.in: Steiner RW Educating, Evaluating, and Selecting Living Kidney Donors. Kluwer Academic Publishers, Norwell, MA2004: 51-79Crossref Google Scholar). Few nephrologists would argue that uninephrectomy per se causes ESRD. But because all donors are at risk of ESRD late in life, we need now—not some date in the future—a ‘best estimate’ of the effect of uninephrectomy on the progression of ESRD late in life. Only then can we meaningfully discuss whether prospective donors with 1 or more risk factors (e.g. obesity, hypertension) should be accepted. In principle, it is hard to oppose a donor registry. A registry sounds attractive; after all, it would eventually provide relevant quantitative data for risk estimation. However, the data that we are looking for would take decades to develop. Most ESRD comes late in life (7Steiner RW Danovitch G The medical evaluation and risk estimation of end-stage renal disease for living kidney donors.in: Steiner RW Educating, Evaluating, and Selecting Living Kidney Donors. Kluwer Academic Publishers, Norwell, MA2004: 51-79Crossref Google Scholar), and many donors are young. Only a very small fraction of our older donors would develop ESRD, because they have little or nothing wrong with them when they donate, and they have less time left to live. Transplant centers do not now have the capability to take on such a major unfunded effort as a well-done long-term donor registry. And it is not clear that a registry, which would collect long-term data on the thousands of donors accepted each year (in the United States), would have any advantage over carefully done single- or multicenter analyses. Moreover, we cannot stop doing living donor transplants until long-term registry data are available. Even ‘mature’ donor registries would not settle all disagreements. A donor’s condition at donation and development of subsequent ESRD may not be meaningfully linked. How to apply registry data to some individual donors would inevitably inspire debate. Confidence limits would be wide. Registries are not the only way to estimate risk. Today, operative risk for a donor nephrectomy is well characterized, and numerous studies have analyzed short- and long-term outcome for donors (7Steiner RW Danovitch G The medical evaluation and risk estimation of end-stage renal disease for living kidney donors.in: Steiner RW Educating, Evaluating, and Selecting Living Kidney Donors. Kluwer Academic Publishers, Norwell, MA2004: 51-79Crossref Google Scholar, 8Najarian JS Chavers BM McHugh LE Matas AJ 20 years or more of follow-up of living kidney donors.Lancet. 1992; 340: 807-810Abstract PubMed Scopus (568) Google Scholar, 9Williams SL Oler J Jorkasky DK Long-term renal function in kidney donors: A comparison of donors and their siblings.Ann Intern Med. 1986; 105: 1-8Crossref PubMed Scopus (121) Google Scholar, 10Matas AJ Ibrahim H Long-term outcomes for the donor.in: HP Tan Marcos A Shapiro R Living Donor Transplantation. Informa Healthcare USA, New York2007: 87-100Google Scholar), some of whom become hypertensive after donation (8Najarian JS Chavers BM McHugh LE Matas AJ 20 years or more of follow-up of living kidney donors.Lancet. 1992; 340: 807-810Abstract PubMed Scopus (568) Google Scholar, 9Williams SL Oler J Jorkasky DK Long-term renal function in kidney donors: A comparison of donors and their siblings.Ann Intern Med. 1986; 105: 1-8Crossref PubMed Scopus (121) Google Scholar, 10Matas AJ Ibrahim H Long-term outcomes for the donor.in: HP Tan Marcos A Shapiro R Living Donor Transplantation. Informa Healthcare USA, New York2007: 87-100Google Scholar) and acquire other renal risk factors as they age. We can also currently estimate risks by extrapolating from the abundant, risk-relevant medical literature (7Steiner RW Danovitch G The medical evaluation and risk estimation of end-stage renal disease for living kidney donors.in: Steiner RW Educating, Evaluating, and Selecting Living Kidney Donors. Kluwer Academic Publishers, Norwell, MA2004: 51-79Crossref Google Scholar). Both previously published, and currently ongoing, long-term single- or multicenter studies (in effect, ‘miniregistries’) using donor outcome data could certainly help confirm estimates of donor risk within a reasonable confidence interval. Many of us have Davis’s desire to develop a broader consensus. Yet this consensus does not exist, even after numerous forums that have focused more on standards than on the process and justification for setting them. The efforts by UNOS committees show that consensus can be reached in many areas, but these committees have not addressed the ethically charged areas of the continuum of risks, risk formulations or development of tools to teach risk estimates to donors. Therefore, as we proceed, we must first agree on the ethical issues that we need to address and on the principles for donor acceptance; we then need to utilize the abundant available data to formulate risk and initiate new prospective studies to confirm risk estimates for normal donors and those with IMAs. Essentially all transplant centers (in the United States and Canada) do living kidney donor transplants; in that sense, we have already agreed to proceed in this endeavor, presumably all knowing that there are risks to the donor. So there should be much common ground as we begin this task. While we are defining any increased risk for young donors or potential donors with IMAs, we need to have meaningful discussions about what level of increased risk is acceptable (and what level is not), and thus provide a rationale for any decisions on standards for acceptance for living donors. Donor selection standards must be ethically and factually justified; otherwise they will be a set of free-floating and arbitrary rules. The transplant community owes it to our donors and recipients to begin this task.

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