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Advisory Committee on Organ Transplantation
Fifteenth ACOT Meeting
May 5-6, 2008
May 5, 2008
Welcome & Introductions
Ms. Agrawal welcomed the group and introduced the newest member, Dr. Robert Ettenger. She also announced that she would be able to continue to chair the ACOT.
Pediatric Transplantation: Overview, Problems in Non-adherence, Transitioning from Pediatric-Adolescent Care to Adult Care -- Dr. Robert Ettenger, Chief of Medical Staff, Department of Pediatrics, UCLA Medical Center
Dr. Ettenger recognized the group members have wide-ranging expertise and apologized for any information that was not new to the members. He began by noting that pediatric transplantation will always be the “flea on the hair of the tail of the dog” – there are only small numbers of transplants, but the numbers are constant. Most transplants are either kidney or liver. (Kidney patients tend to live longer, so the prevalence rates of pediatric kidney transplants are greater.)
Pediatric transplantation has improved. Twenty years ago, graft survival was a miserable 50 percent, but the current 2-year survival rate is over 90 percent. This improvement has provided a lot of hope, but many challenges remain. Transplantation confers more remaining lifetime years than dialysis, which is particularly true for children. However, looking at the general population, lifetime survival rates are still lower, even for pediatric patients.
New rules have placed pediatric patients at the top of the lists for transplantation, and the recipients’ increases are mainly among adolescents (for kidneys). The majority of pediatric transplant patients are, or will become, adolescents: two-thirds of non-adult recipients are 11-17 years of age. Dr. Ettenger joked that the two words that define adolescence are “me” and “now” – it is a time of emerging autonomy and multiple crises, many of which may be undetected. This affects compliance and patients’ ability and willingness to take care of themselves.
This is an issue because, in looking at graft survival by recipient age, adolescents have best outcomes at year 1. However, at 5 years, except for the very old recipients, adolescents have the worst outcomes. As they move into adolescence, they do worse. This is a problem with the population in terms of long-term graft outcome. Looking at kidney survival in pediatric recipients: among youngest patients (age 0-5), there is a declination point in graft outcome that they emerge from after 7-8 years, which is when they are around 13. They start falling off of the projected half-life. The 6-12 year olds have a similar declination, but it’s after 2-3 years – when they are the same age as those described above. There is not much declination seen in 13-18 years because they age out of adolescence. It is important to remember that patients are growing and changing over time.
This may not all be about non-compliance, however. A new National Institute of Allergy and Infectious Diseases-funded Clinical Trials in Organ Transplantation in Children indicates that adolescents may have heightened immune responsiveness. Antiviral responses may increase global immune response to alloantigens, and this may differ from patient to patient depending upon viral exposure (children have more exposure as they age and become adolescents). Differences exist in patients’ immunobiological reactivity as well. Therefore, the survival rates may result from an unfortuitous intersection of immune maturation with the developmental variability of the adolescent. It’s a bad conjunction in terms of non-adherence, however.
Non-adherence is an issue for this population. In a study of physicians’ reports about patient non-compliance, 54 percent of patients who were declared “noncompliant” were adolescents. If you combine those aged 11-15 and 16-20, the rates are well over 50 percent.
Patient characteristics that correlate to non-adherence in pediatric End Stage Renal Disease (ESRD) include: adolescence, female, family instability, insufficient social or emotional support, depression and anxiety, single-parent family, low SES, low self-esteem, poor interfamily communication, deficient acceptance of ESRD diagnosis, and poor communication and socialization skills. In fact, the situation of having ESRD is so stressful that it gives patients Post-Traumatic Stress Disorder.
Dr. Ettenger provided some definitions. Compliance is when the patient follows the medical team’s dictated orders without necessarily buying into the reasons for these orders. Adherence is when the patient understands the reasons for the medical team’s orders and participates in their execution by following these orders. Lastly, concordance is when the patient’s desires and incentives are aligned with those of the medical teams (the patient wants to do those things that will benefit him/her). The goal is establish concordance for each patient.
Dr. Ettenger noted that variability in operational definitions of non-adherence hinders the ability to compare study results. Definitions of non-adherence include: (1) when the patient misses, forgets, alters, or delays a dose at least once per month; (2) when the patient misses at least 10% of doses (6 doses per month); or (3) when the patient misses at least 20% of doses (12 doses per month). Dr. Ettenger said that he was attempting to popularize the term “chronic renal allograft pathology” (CRAP) because it describes where a lot of the research is. The field does not do a good job of tracking long-term co-morbidities (diabetes, hypertension). In fact, more needs to be learned about these issues.
Regardless of how it is measured it, however, non-adherence affects graft outcome and is expensive. A recent meta-analysis of 10 cohort studies found a 36% graft loss associated with non-adherence (a rate seven-fold higher than in adherent recipients) and a $15-$100 million annual impact -- just in solid organs.
In 2008, a consensus conference was held in Tampa with a range of organizations invested in non-adherence. Individual topics were addressed in six workgroup focusing on (1) pre-transplant assessment; (2) pre-transplant interventions; (3) post-transplant non-adherence monitoring and interventions to decrease non-adherence and increase adherence; (4) transitions from pediatric to adult health care provider; (5) issues in assessment and treatment of non-adherence in the elderly transplant patient; and (6) NIH support and initiatives for adherence/non-adherence research in adolescent and elderly transplant recipients.
There are seven multidisciplinary areas where non-adherence may be influenced:
For pre-transplant assessment, validated tools are needed in all areas: identification of pre-transplant adherence problems; identification of pre-transplant skill deficits (e.g., pill swallowing problems, memory/organizational difficulties); identification of pre-transplant emotional, behavioral or learning problems (e.g., depression, PTSD, anxiety, substance abuse); assessment methods for identification of provider factors that could hinder adherence; identification of potential post-transplant social/emotional support; and identification of medical team characteristics that may contribute to non-adherence.
In addition, validated “Toolboxes” are necessary for effective pre-transplant interventions, including: educational intervention methods to instruct adolescent and their caregiver(s) about post-transplant medical regimen and importance of consistent, long-term adherence; interventions to remediate skill deficits (e.g., organizational strategies, public transportation use, thermometer reading, lab value interpretations); treatment of identified emotional and/or behavioral problems; interventions to improve provider/patient relationship and communication; and interventions to increase/optimize social/emotional support for adolescent. The risk factors of non-adherence include being an adolescent; however, there are other issues, too, many which interact, including poor physician communication.
Dr. Ettenger stated that “care” does not mean transplanting the patient and turning him or her out into life unsupported. We have to modify what we do to coach and work with the kids to ensure that they stay healthy. Pre-transplant interventions are woefully inadequate. For pre-transplant interventions, we need to provide information using several different educators. This information should specifically address issues of medication knowledge, side-effects, and timing. It is important to try to emphasize reconciling health beliefs between patients and their parents, and health providers, and to stress that medications are life-long. The goal is to address non-adherence “patterns” in the educational activities.
For post-transplant non-adherence monitoring and interventions to improve adherence, Dr. Ettenger noted that we need to improve how we measure adherence; identify barriers to adherence; assess post-transplant emotional and behavioral adjustments; decrease the patient’s non-adherence potential; improve provider/patient communication; and develop patients’ abilities to problem-solve, self-monitor, and reinforce adherence. We need better interventions to increase adherence and may also benefit from exploring parenteral medications.
It is necessary to address any psychological and emotional problems that arise; and patients have to be seen frequently to succeed on this. The field does not do well at finding patients when they fail to come in. Dr. Ettenger noted that improved diagnoses of PTSD can significantly decrease non-adherence in transplant patients. Parents and patients are both susceptible to PTSD; however, parents have better compliance records.
There are ways to modify medications that would help deal with non-adherence, including simplifying medications and/or using drugs that have long half-lives and can be taken less often. There is a need to develop drugs that will last for a week or a year (like Norplant does). Pill counts and pharmacy monitoring only work if the patient is using a pharmacy associated with the program. This is difficult when many insurance companies restrict which pharmacy their beneficiaries can use in order to still be covered.
This is particularly an issue for patients who are in transition. At the time of transition, one-third of patients blew their creatinine levels up in 12-15 months. A new GAO report looked at patients (pediatric, transitioning, adults) and found that the percentage of recipients where the treatment failed was always higher in transitional patients – they do worse than both pediatrics and adults. In addition, they cost CMS a lot of money. The largest increase in the number of transitional patients who lost their grafts was among those 1-3 years post-transplant. As they transition, something happens to these patients; and this issue must be explored. Transition should be based on developmental guidelines rather than arbitrarily on age.
The issue of adolescents is critical, Dr. Ettenger stated, to whom we are and what kind of society we have. He would like to direct the ACOT’s attention to some of the underserved issues. The goal is to make these patients functional members of society who live life according to a game plan that integrates them into society.
Ms. Suzanne Conrad said she would play the devils’ advocate and asked if the field should be preferentially directing kidneys to this group, since they are just going to lose them. Dr. Ettenger responded that some have actually recommended not transplanting kids between the ages of 12 and 19 for this very reason. But it’s not all or nothing, he added. The expectation is that the patient is ready for transplantation when he or she is put on the list. Our task is to help and nurture them; and, he added, problems that come from being on dialysis are also overwhelming. There is a need to get caregivers up to speed and to find better ways to address this problem. The answer is not to deny the transplant, but to proceed in a sound and intelligent way.
Dr. Lewis Low said this was timely for him. He has a 20-year old patient who is on her third transplant. She is emotionally about 15, and her parents treated her as if she were that age. It was clear that her parents thought of her as a child, and the entire family’s emotional growth was stunted. Dr. Low concluded that there is a need to train families, too. Dr. Ettenger said that this situation occurs frequently. In his opinion, these patients are psycho-socially 3-7 years younger than their chronological age. Tools that can help include therapy, working with the schools, bringing them up to speed; and it’s essential not to transplant the person until he or she is ready. The problems occur because there are no tools to measure readiness. Dr. Ettenger’s UCLA program can assess this just from experience; but many centers lack this experience, have no plan for addressing non-adherence, and do not educate parents and kids. He noted that if a child fails the first transplant, it’s essential that the donor look at that case very closely.
Dr. Russell Wiesner asked if it was even possible to change adolescent behavior, and the response was that it is possible to teach appropriate behavior. In restricted situations, the goal is for adolescents to be able to handle themselves. The provider is not, however, there to run their life. Dr. Wiesner asked about the role of the nurse coordinator, adding that, at Mayo, the relationship with the pediatric nurse coordinator remained throughout the patient’s transition and into adulthood. For liver, at least, this seems to be very important for the patients. Dr. Ettenger stated the pediatric nurse coordinators are indispensable. Children see them like parents. The coordinators may be, in fact, the only parental figure in the kids’ lives. They are critical to a functional program.
Dr. Mildred Solomon thinks the goal is less to change adolescence, and more to help these patients transition. She described her involvement in social marketing campaigns targeted at different age groups, and the finding that teens require an uncomfortable level of fear in their messages. In terms of message design, she asked if teens needed more graphic information. The response was that there are at least three phases of adolescence, and each phase has a different need in term of messages that will work. For those with PTSD, however, fear-based messages are difficult. A one-size-fits-all program will not be effective.
Dr. Susie Leffell commented that this is very important because when kids lose their graft, they become highly sensitized, which affects both costs and treatment plans. She asked if the data on graft loss took into account the age of the allograft and where it was in the natural allograft life span. Dr. Ettenger said this was a good point, but one that is hard to study. The GAO study involved large, raw numbers; and the study suffered as a result. It did not adjust the multivariate analysis to really see those operant issues. Dr. David Vega asked if graft loss was related to lack of insurance, since experience at Emory indicates that graft loss is related to lack of coverage. Dr. Ettenger said that the patients in the GAO study were insured, but he concurred that California also sees this problem. He added another problem that pediatric patients’ public insurance ends when they are one day over 21. The insurance problems are catastrophic; and when patients approach 21, it’s a death sentence. It’s hard to get these patients onto Medicaid, too.
Ms. Agrawal noted that ACOT has limited authority. However, the group can make recommendations to the Secretary. She asked members to consider what ACOT could suggest to address these sorts of issue.
Update on Kidney Disease Outcome Quality Initiative/Early Kidney Transplantation Conference -- Dr. Steven Bartlett, Conference Co-Chair, University of Maryland Medical Center
Dr. Bartlett reported on the Kidney Foundation’s March 2007 conference on early transplantation. ESRD cases have been rising (although they have been leveling off in the last year or so). This conference was held to address several questions about early transplantation: is it desirable; are there benefits of preemptive transplantation that make it the preferred approach to renal replacement therapy; what barriers prevent early or preemptive transplantation; can these barriers be surmounted; and, if so, what interventions are necessary to do so. Dr. Bartlett shared the results from the conference workgroups.
Work Group 1 addressed transplantation and the Chronic Kidney Disease (CKD) paradigm and asked how we can incorporate transplant education, referral, and identification of living donors into the evolving paradigm of CKD management, given that rates vary at which different races learn about transplant before beginning dialysis and are referred for evaluation.
Work Group 2 addressed training and education for early kidney transplantation, looking at how to address the educational needs of all involved in the process, as well as what can be learned from the pediatric model.
Work Group 3 explored the financial implications and removal of disincentives, examining why the finances of early renal replacement therapy are easier to navigate on the dialysis side of the equation.
As background to these work groups, Dr. Bartlett noted that ESRD consumes about seven percent of the Medicare budget and CKD consumes sixteen percent of the Medicare budget. Thus, ESRD and “recognized CKD” appear to consume close to 25 percent of the Medicare budget, which has considerable health care implications. Moreover, ESRD incidence rates are down except among younger, African American individuals with DM, yet death rates in the first year of HD have not changed in 11 years. The utilization of dialysis catheters, known for their complication rates, is very high. There are major issues related to the transition from CKD to ESRD, which may contribute to the high early mortality, yet there is currently no program to address the preparation of individuals for ESRD.
Prevention of ESRD is emerging as an important public health policy issue. The high death rate in the first year of HD needs to be addressed through an education program that increases awareness of the modalities to treat ESRD; better dialysis access planning before ESRD; appropriate assessment of vessels and processes to promote effective fistula maturation; increased utilization of early transplantation, thereby avoiding the use of a dialysis catheter; and reduction of disincentives to early transplantation.
As part of the work to address factors associated with this situation, 4,000 nephrologists were surveyed and the following conclusions were reached: nephrologists need guidance to refer patients for preemptive transplantation; post-transplant care training; there is a financial impact of preemptive transplantation on dialysis centers; they should report patient referral and education issues; and they should have a positive attitude toward preemptive transplantation. In terms of listing, there is a fairly slow trickle of referrals from nephrologists; but once the patient gets onto the list, they move more quickly.
Among all patients starting ESRD therapy from 1996-2005, 6 percent were waitlisted before, or without, starting dialysis; and 2.5 percent received a preemptive living donor or deceased donor kidney transplant. About two-thirds of all preemptive transplants are from living donors and one-third are from deceased donors. Among patients with ESRD, wait-listing and transplantation rates, both overall and preemptive, are lower among older patients; patients with diabetes or hypertension; African Americans, Hispanics, Asians and Native Americans; and those relying solely or principally on public insurance. There is also marked geographic variation in overall and preemptive wait-listing and transplantation rates.
The question is, however, “what happens if a patient went right to transplant without getting dialysis”? Peer-reviewed information suggests that these patients have higher employment rates, lower unemployment rates, and a reduced family care giving burden. Follow-up questions include whether preemptive transplant has specific quality-of-life benefits; whether ESRD-related quality-of-life problems are preventable with preemptive transplant; and whether ESRD patients must first undergo dialysis in order to “appreciate” a transplant recipient’s quality-of-life and follow a transplant regimen.
Dr. Bartlett reported that early transplant can prevent losses associated with long-term dialysis. The short-term benefits of a scheduled transplant include the ability to plan work absences, recovery support, and dependent care. There is also reduced anxiety that can be associated with transplant timing unpredictability. There are better outcomes after preemptive transplants, including lower delayed graft function rates, lower acute rejection rates, and higher graft survival rates.
There are economic benefits as well, since the monthly cost of maintenance dialysis is greater than that of maintaining a transplant. The savings accrue for time periods when a functioning transplant allows the patient to avoid dialysis. Also, preemptive transplantation avoids the high costs of maintenance dialysis during the onset of ESRD. The cost spike during the transition from CKD to dialysis is avoided by preemptive transplantation. Economic benefits also include reductions in transplant complications arising from lower rates of delayed graft function, acute rejections, or graft failure. Dr. Bartlett described the per-person/month expenditures for ESRD patients on Medicare.
The risks of preemptive kidney transplantation are that the process may waste native kidney function by hastening the transition to renal replacement therapy, and the cost of care shifts from a CKD rate to a higher ESRD rate. Preemptive transplantation may increase the chance that a patient with renal function recovery (RFR) will have an unnecessary transplant. There are financial losses associated with the costs of such a transplant. Dr. Bartlett concluded that policies to perform preemptive transplant may result in cost savings by reducing costs associated with the transition through dialysis, and reducing the rate of costly post-operative complications.
Returning to the conference work groups, Dr. Bartlett summarized their recommendations
Work group 1 (Transplant and the CKD paradigm) established several goals:
Work Group 1 recommended referral to a nephrologist by early Stage III CKD by a patient’s primary care doctor; referral and evaluation at the transplant center by early Stage IV, and that patients be waitlisted at a GFR = 20 or when they become clinically symptomatic.
Work Group 2 addressed training and education for early kidney transplantation. Goals included the following. Through education, increase transplant rates, increase preemptive transplant rates, and increase early transplant. Target audiences for education were described as practicing community nephrologists, dialysis unit medical directors, nephrology fellowship training directors, nephrology fellows, primary care physicians, and financial stakeholders (commercial and government payers). These audiences need information on who to refer for early transplantation, when to when to transplant, and why preemptive transplantation is recommended.
As part of this work, the Metropolitan Nephrology Associates opened their books and let the work group explore its revenue sources. It was found that about 25 percent of its revenue stemmed from medical directors; 27 percent from hospital-based consultations; and 32 percent from in-center patients. It appeared that doctors may be unwilling to spend a lot of time with post-transplant patients, as this is a complicated process. In addition, the organization only gained 12 percent of its income from seeing these patients. The reimbursement is low for this type of work. Reimbursement codes need to be improved so that nephrologists can view those cases as being on a par with dialysis patients. If nephrologists could see a post-transplant patient as having the same income effect as a dialysis patient, it would help. It would be necessary to change transplant reimbursement, however.
The work group concluded that there is a need to increase awareness of the benefits of preemptive/early transplant by nephrology, primary care physician, physician extenders, and organizations delivering CKD and dialysis care. Barriers to early transplantation and post-transplantation care include both financial and practice patterns concerns. As living donors will likely be the means through which preemptive transplant will occur, there must be support for the United Network for Organ Sharing (UNOS) living donor activities and living donor follow-up. There needs to be a living donor registry to provide long-term data about donor safety. This would encourage more donors, protect the field, and deter risky subgroups from donating.
Work Group 3 explored the financial implications and removal of disincentives, examining why the finances of early renal replacement therapy are easier to navigate on the dialysis side of the equation. For hospitals, the incentive is that preemptive transplant is less costly (with higher margins), there are decreased operational and administrative costs, and outcomes are better. The disincentives are around increased administrative burden and potential risk, as well as the fact that the procedure is only viable with a Medicaid population. For transplant physicians, the incentive is EGHP (lower percentage discount than Medicare/Medicaid), but the disincentive is that if the patient does not sign up for Part B there is no doctor reimbursement for the donor nephrectomy procedure. There are no incentives for a non-transplant nephrologist (i.e., one who is not part of the transplant team) and many disincentives, including lost revenue, poor reimbursement, complex cases, and a lack of education benefit for transplant education of the CKD patient.
For a recipient, preemptive transplant is less disruptive to his or her earning potential, and enables the patient to maintain EGHP. It also has less impact on lifetime maximums, as the patient is not accruing costs from dialysis. Disincentives are that this applies only to Medicare beneficiaries unless the patient can meet the out-of-pocket requirements; and it may entail lost wages, travel, and other costs. Patients may also not perceive the urgency of the timing of their transplant.
For EGHP, preemptive transplants avoid dialysis’ costs and complications. It has lower costs and fulfills the companies’ obligations and social responsibilities, as well as affirming an interest in patient care. It saves other types of insurance claims (disability and reinsurance). The disincentives include the myth of 2-year payer turnover (e.g., member churn), which reduces the company’s savings opportunity and the fear of transplanting prematurely given member churn.
Work group 3 made several recommendations:
Dr. Bartlett reviewed next steps, which are to publish the findings of the Consensus Conference (upcoming in Clin J Am Soc Neph) and to begin the process of changing Medicare payer policy through analysis and action with ACOT, Congress, and the National Kidney Foundation Board. It will be necessary to balance the political power of large dialysis organizations, which seek to maintain the status quo.
Dr. Wiesner asked if the new Life Years from Transplant (LYFT) calculation system was considering pre-transplantation. The response was that it did give the patient some points because of the benefits in life years. Dr. Robert Wolfe with the SRTR added that the status of being preemptive or on dialysis generates some benefits, with the results surprising and worth discussion. Preemptive transplantation leads to better post-transplant outcomes (compared to those who were transplanted after dialysis had started). However, the question remained whether, for someone who hasn’t started dialysis, if it was better to get a transplant or not. He noted that the answer seemed to be that a person who has not yet started dialysis has a higher death rate with a transplant than without one. This is time-dependent, in the first year as well as in years 3 and 4. So, it seems as if the patient who has not had dialysis does better without it. There is a bias, however, because the ones who do not do either (transplant or dialysis) are the healthy ones. A related study shows that starting dialysis is a marker for having problems and getting sicker. Dr. Wolfe added that it was not known how to fix this bias. The LYFT calculation showed that the person who has yet to start dialysis does better to wait than to get the transplant.
Dr. Ettenger responded that a person with CKD 3 or 4 was going to progress and get worse. It was not as if they would not get sicker if they did not have the procedure. Dr. Wolfe agreed that it was unclear how to interpret the data when just looking at the evidence. Dr. Wiesner asked if the impact on graft survival of the time a person spent on dialysis had been adjusted and the response was that it had been, by time and age. Dr. Wiesner commented that the entire argument was based on the fact that the allocation system should be changed, and so the data have to be adjusted to know that it is not just part of the spectrum. Dr. Wolfe concurred that there is no biological reason why this should be, yet it seemed to be.
Dr. Marc Lorber agreed with Dr. Ettenger that it was important to stratify by CKD stage to see when a person might clearly benefit from transplantation. Dr. Wolfe said there were some longitudinal studies that looked at this. He had GFR at the time of listing, but did not think that this was available serially. Dr. Lorber suggested this be collected to assess whether preemptive transplant had the best benefit after dialysis had begun, or before it started.
Mr. Samuel Holtzman added that early transplant appears to be more disadvantageous for African Americans. The field has started trying to look at this and the education modalities needed to get this population into transplant, better identify living donors, and overcome disparities. He stated that the population de-selected out and assumed they would not get the transplant. There is a need for more education on this issue. Dr. Solomon added that there have been studies to look at this, which specifically held patient preferences steady, to see if African Americans de-selected or if they had different cultural beliefs about transplantation. In fact, the research showed that, even among those who wanted to have a transplant, African Americans were not referred at the same rates as Whites were. The study found major referral discrepancies.
Dr. Velma Scantlebury added that more work needs to be done. As an African American, she knows there is a lack of awareness about preemptive transplantation among people of color. There is also a bias in terms of getting patients from dialysis to transplantation. Having dialysis is better than not having dialysis, and preemptive transplantation is better than spending more time on dialysis. She applauded Dr. Bartlett’s efforts and stressed that the field needed to make headway in this area.
Dr. Solomon added that the financial incentives are perverse: non-transplant nephrologists seem to have a preference for dialysis. Dr. Bartlett suggested that increasing reimbursement for post-transplant care was a good idea. However, if the code were reimbursed at a high enough level, the cost savings could be lost. Dr. Bartlett clarified that there are other cost savings in terms of life benefits, reductions in dialysis, and increased work function. Preemptive transplantation had the opportunity to mitigate a health care disparity, he concluded.
Dr. Ettenger spoke on behalf of nephrologists and addressed the misperception that they were not ready to refer or care for transplant patients. He expressed the belief that these providers are willing and ready, since their job is to care for patients. He noted that he was struck by Dr. Wolfe’s comments about the survival and CKD data. He believed the variables which have to be included in order to make an assessment about this have not been included. There needs to be better reimbursement for nephrologists and more data, he concluded. Dr. Wiesner added that the issues raised also apply to other fields. He has had difficulty getting gastroenterologists to focus on his patients because these practitioners have other things they would rather do. Reimbursement is inadequate for liver patients, too.
Recovery/Allocation/Transplantation Practices Outside the U.S. -- Dr. Nicholas Tilney, President, The Transplant Society
Dr. Tilney described the worldwide need for, and availability of, organs, particularly kidneys. He described countries with notable practices around transplantation. For example, in Spain, both Madrid and Barcelona have very good ambulance services trained in donation after cardiac death (DCD). If someone falls dead on the street, the ambulance crews start infusing the patient right away to increase viability for DCD. Belgium and Austria both have required request laws specifying that, if a person has not opted out, he or she is a potential donor. The United States does quite well, and is in the top rank of countries. Most European countries do well and keep up with their demand. The systems are good in most of these countries.
The World Health Organization (WHO) has stated that about 10 percent of all organs in the world are bought. Dr. Tilney showed a slide of the host countries, which include China, India, and Columbia.
The Transplant Society just completed a summit in Istanbul on transplant commercialism, transplant tourism, and organ trafficking, terms which he defined for the ACOT members. Over 160 representatives from 71 countries came together at this event to produce guidelines that will be widely promulgated. In addition, the Transplantation Society, International Society of Nephrology, and WHO have initiatives that work with health authorities for accountability and oversight of transplantation practices.
Dr. Tilney described transplant tourism in China, noting that, in 2005, 11,000 kidneys and 8,000 livers were transplanted in that country. He said that people “come from far and wide to get these organs,” which were fresh, and originated with executed prisoners. There was no free will involved in the donation. The prisoners were shot in a field, and a field ambulance collected the organs and took them to military hospitals. A patient could get a good organ the day after arriving in China, as the executions were scheduled to fit the patient’s needs. Dr. Delmonico has been working with the Chinese government on this issue and has had some success, due to the courage of one minister, in particular. In 2007, the number of kidneys transplanted declined to 5,000. International pressure on the Chinese government seems to be helping but it is unclear what will happen after the Olympics.
The Middle East is also problematic. Renal failure is a big issue in the region, due to the heat, but brain death is not a widely accepted concept. There are a small number of living, related donors. In Egypt, the situation is hugely problematic. Since there is no central databank or organization, the information is very piecemeal. There is a large market in the sale of liver lobes from living donors. Many Israelis go abroad for transplantation (mainly to Turkey). The Israeli government may soon create new laws in Israel to address this situation, such as defining brain death.
Dr. Tilney showed a map of trafficking patterns, describing a patient from the United States who received a kidney from a donor in Brazil, in an operation performed in South Africa, and coordinated out of Israel. Pakistan is also very problematic. There are instances of bonded servants “donating” a kidney; this is exploitation. There is a new law that has reduced the organ trade, although it continues. Not much is known about the situation in India. Dr. Tilney described the situation in the Philippines, where efforts to legalize organ sales garnered Vatican opposition that seems to have succeeded. Recently, the Philippine Department of Health rescinded the approval and banned kidney transplants in foreigners. The government had been pushing legalization because it was making so much money, and Dr. Tilney described this ban as an amazing accomplishment. As the volume decreased in the Philippines, however, Columbia is increasing its volume. A lot of organs are available there due to traffic accidents and the drug wars.
The American Society of Transplant Surgeons (ASTS) opposes payments for living and deceased organs. Payment exploits the most vulnerable members of our society and arbitrarily assigns a market value to body parts (conceivably differentiated by gender, ethnicity, and the social status of the vendor). ASTS objects to payment for donor organs as against the very core of a democratic society that considers all to be created equal. Yet, wherever money speaks and there is a need, this activity will continue.
Dr. Tilney concluded by stating that it is necessary to speak out against these practices. Organ trafficking is unethical and illegal because it does not involve any choice or accountability for the donor, and has a high potential for transmitted disease.
Mrs. Rhonda Boone expressed her view that donors in the United States are also exploited given the lack of funding for long-term follow up. Dr. Jim Burdick, Director of the Division of Transplantation, agreed there is no money currently designated for long-term follow up but that the Division is working with NIH and within the Division to address this issue.
Dr. Ettenger stated that he was impressed with what Dr. Tilney and Dr. Delmonico have done. It was alarming to him that transplant tourism was addressed in one place only to pop up elsewhere. Dr. Tilney responded that regulation and compensation issues are complicated wherever there is a need and money to be made. There is a need to be creative in addressing it, and the way to proceed is unclear. Dr. Ettenger stated that Dr. Delmonico had raised the idea of implementing passport controls for those who travel for transplantation.
Dr. Low noted that ACOT had heard presentations on the dangers of transplant tourism before and asked what the ACOT could do, beyond getting an update. Dr. Wiesner added that the last presentation on this subject had included information about U.S. surgeons going overseas to train and practice. He wondered, however, how one could justify selling women’s eggs as any different from selling cells. The response was that there is no additional information about U.S. surgeons leaving the country for this purpose. The American Society of Transplantation has never discussed the egg issue but, according to Dr. Tilney, cells were different from eggs.
Dr. Scantlebury asked about regulations in place for patients who leave the United States for an organ but return home for care. The response was that it was illegal to buy or sell organs in the United States, but it is not illegal to leave the country in order to do so. Dr. Solomon added that the issue of covering patients who return home had been debated by many insurers. The insurer on whose ethics board she serves stated that it will care for their beneficiaries. The group noted that issues of young adults losing their Medicare coverage when they turn 21 may be more significant than those arising from the occasional patient getting a kidney in Pakistan.
Dr. Lorber concluded by suggesting that the group focus on how ACOT could address this problem in a recommendation to the U.S. Secretary of Health and Human Services.
Dr. Mark Uknis stated that he is a transplant surgeon by training and currently the medical director of ViroPharma. As a member of ASTS, he is aware there is continued controversy over reimbursement of donors; and this affected organ trafficking. He said that people can bury their heads and say that it’s wrong, but everyone has to realize that trafficking is occurring. He recently had a patient who went to Pakistan and paid $40,000 for a kidney and then came home with an infection. This patient was self-pay at the emergency room and ended up receiving 3 months of care. Dr. Uknis said he was trained at the University of Minnesota and had been opposed to paying donors until he looked at the implications. Payment does not necessarily mean monetary compensation, he argued. It goes back to NOTA, which was designed to prevent brokerage. Organ donation can, and should, be regulated so that brokering was prevented, but in a way that donors get compensation such as guaranteed lifetime health coverage. Every day, the number of people waiting for organs increases, and this issue had to be addressed.
Dr. Uknis’ second point concerned infectious diseases. He asked the ACOT to form a panel on the impact of infectious disease. Cytomegalovirus (CMV) Disease, while rarely fatal, has clear indirect effects on survival. There is a huge drop-off of graft survival if the patient gets CMV, as much as 50 percent mortality, over 5 years, from infectious diseases. Addressing infectious diseases would also limit the number of patients needing multiple transplants, which would improve waiting time by making more organs available for transplant.
Dr. Uknis’ third point was that CMS functions on a zero-sum game. Increasing payment for one code takes funds from somewhere else. There is little chance to increase reimbursement in one place without decreasing it elsewhere. Money can be saved if a proper organ donor reimbursement process was created. He thanked ACOT for the presentations and for having the public at the meeting.
Kimberly Tracy stated that she was both a living donor and a registered nurse. On the subject of pre-emptive transplant, the living donor advocacy group had seen many donors with financial problems. The Social Security Act stated that living donors would receive Part A and Part B from Medicare, but CMS has said that this is comparative. Often, a donor submitted his or her insurance information to the transplant center to coordinate the recipient’s and donor’s insurance. It was not the fault of the transplant center, but many donors did receive bills from their insurance companies. She described a particular transplant case (in which the donor should never have been allowed to donate) where the donor eventually had a breakdown. She now had no therapy and faced very real emotional issues. She closed by stating that there was a need for better informed consent procedures.
ACOT Next Steps
Ms. Agrawal noted that Dr. Mark Schnitzler was unable to attend the meeting to make his presentation on the economic impact of transplantation. The allotted time would be used to discuss ACOT’s future direction. Members were provided copies of the ACOT charter. Ms. Agrawal reviewed the charter and led a discussion about issues of concern and plans for the future.
The ACOT was initially created pursuant to statute, and its first members were named by Secretary Shalala, who sought an Advisory Committee to help her with issues surrounding OPTN issues. Before the first meeting was held, however, a change in administration occurred and the new Secretary, Tommy Thompson, was more interested in increasing organ donations. Thus, ACOT looked at education programs, informed consent, and changes to the Uniform Anatomical Gift Act. Since the current Secretary is less focused on organ procurement and transplantation, the Committee lacks clear directives on what to focus on.
However, Ms. Agrawal noted, ACOT has a broad, regulatory charge. She asked the members what they saw as the most significant issues facing the field on which the members could reasonably and profitably focus ACOT’s attention, in light of the power of the Secretary and the kinds of authority and actions he can take or facilitate. ACOT has an advisory capacity and should focus on matters of important policy, around which it can advise the Secretary in an informed way. Ms. Agrawal did not recommend that ACOT focus on reimbursement for codes, or reforming private health care, however.
Mrs. Boone suggested a recommendation to the Secretary to appropriate funds for a living donor registry and address insurance issues that have surfaced. Ms. Agrawal summarized by stating that one function of ACOT was to look at issues that arise in the context of living donors (e.g., registry, informed consent). There was consensus among the group to examine ACOT’s previous recommendations around living donors, and to identify gaps and assess what it could do next in that area.
Dr. Ettenger suggested addressing economic and financial issues (aging out of insurance, selling organs, living donors needing insurance). Ms. Agrawal said that ACOT might want to think about having speakers address the group on coverage issues affecting CMS, State plans, and private carriers.
Ms. Mary Kelleher added that ACOT could explore variations in access to care that are based on economics, race, educational level, and/or geography. Ms. Agrawal summarized that ACOT could explore those sorts of barriers and make recommendations to the Secretary about what he can do to address them. Dr. Lorber echoed the suggestion, adding that ACOT would be remiss if it did not, at some point, address the access issue. Equitable distribution has been on the table since the Organ Procurement and Transplantation Network (OPTN) was formed, he continued, and remains a key problem that has yet to be solved. Ms. Agrawal agreed that ensuring equitable distribution was part of the Secretary’s function; thus, it was within ACOT’s scope. She suggested that the OPTN provide information on this matter at a future meeting.
Mr. Mark McGinnis, J.D., HHS Office of the General Counsel, stressed Ms. Agrawal’s use of the word “profitably” in directing ACOT’s actions. The “bully pulpit” function of an Advisory Committee can be useful, he said, but ACOT can really only make legislative recommendations and then sit back and see what happens. There are some things that the Secretary can do, in terms of regulation, although they take time and are quite involved. He encouraged the ACOT to work within its parameters. ACOT can advocate for grants or contracts, such as programs to support nurse coordinator positions, for example, or for funding for a donor registry – both are non-legislative changes. ACOT cannot, however, do much about Blue Cross coverage in the States. With respect to Medicaid, ACOT can have a voice. However, it may not turn that voice into a fiat. Interesting and controversial issues may not be within the ACOT charter, including preventing people from engaging in transplant tourism.
Dr. Yiliang Zhu stated that the impact of medical tourism is self-evident. He believes there is a need for ACOT members to gain an understanding of global issues, and he suggested that the ACOT continue to look at this issue. The complexity of the issue makes it difficult, yet it is an important issue. Dr. Ettenger commented that all of the issues come back to donors and that ACOT needed to stay current and aware of global issues that impact donor numbers.
Mr. Holtzman said that the Organ Donation and Transplantation Breakthrough Collaborative has had a remarkable impact but there was more to be done, such as preventing medical examiners from blocking donations, ensuring that Level 1 and Level II trauma centers have active organ recovery programs, the issue of DCD donors. He felt that ACOT should also explore split livers in pediatric cases, since splitting livers had the potential to eliminate deaths on the pediatric waiting list and was something ACOT should encourage.
Ms. Agrawal thanked the group for their recommendations and said that she had asked staff to also provide their thoughts. Dr. Fant’s list for the ACOT to consider included:
Dr. Vega added that, in terms of safety, there was a burden on centers to comply with regulations that did not really protect anyone. Dr. Solomon suggested the addition of research on ways to maximize donation and transplantation, increase adherence, and assess DCD. Dr. Wiesner agreed that research was particularly essential for the DCD area.
Organ Allocation: Geographic Boundaries -- Dr. Robert Wolfe, Project Director, Scientific Registry for Transplant Recipients
Dr. Wolfe presented an overview of geographic issues in transplantation. He cautioned that there was a lot of information that takes time to grasp, including the policy implications. He began by describing the type of metrics SRTR developed to describe access to transplantation. The focus was not just on access, however. Processes that occur at varying centers lead to differences in access, including factors such as the rate of accepting or rejecting organs.
The country can be divided geographically into units in many ways, including by region (OPTN, CMS); DSA or OPO; state, county, ZIP code; transplant center or hospital; distance or travel time; exposure levels; and number of organ failure treatment providers. Likewise, differences can be measured in varying ways, including the providers’ perspective of outcomes and/or
Dr. Wolfe showed a table on kidney transplantation that illustrated the impact of insurance, race, and geography, in which characteristics with larger Chi-square contain more variance. The larger the number, the greater the impact by that characteristic. In the end, geography matters; it had a bigger impact than either race or insurance status. This was the same in liver and heart transplantation. Once a patient was on the list, geography had a larger impact than anything else.
Dr. Wolfe showed a chart about acute liver failure that compared getting on the waiting list versus dying of markers that could be associated with liver failure. It seemed that the regions vary in terms of whether it was easier or harder for a patient to get on the list if he or she had experienced organ failure. While it was not extremely accurate, this suggested that there were differences in being listed if a person had organ failure, depending on where he or she lived.
Looking at the relative mortality rates of transplantation vs. waiting list by Model End-stage Liver Disease (MELD), in the first 2 years of follow-up, those who had a MELD greater than 15 had death rates less than those who did not get a transplant. With a MELD of over 15, there was more benefit than those with a MELD below 15. An analysis of changing allocation due to this finding indicated that almost all OPOs would see an increase in the number of organs going to patients with high medical necessity.
For heart failure, an analysis of the rate of getting onto the list vs. the rate of dying of causes associated with heart failure indicated that there may be geographic differences in getting onto the wait list. SRTR explored what would happen if individuals with Status 1a and Status 1b were moved ahead of the local Status 2 candidates. While some regions had more transplants, and some had fewer, every region benefited in terms of mortality. This change was subsequently implemented.
For kidney, there are several different metrics. Substantial variations exist, depending on the patient’s OPO, in the rate of getting a donation. Dr. Wolfe showed a map that illustrated the overall rate of getting a transplant among all of those with ESRD (not just those who were wait-listed). The map showed that OPOs differed in the number of eligible deaths they saw; some also find more eligible deaths than others do. The more waiting list candidates an OPO has per potential donor, the less access there was, because the candidates outnumbered the donors. Some OPOs had four times as many candidates as donors.
SRTR calculated how long it took for 25 percent of candidates to get a transplant within a DSA. Among 59 OPOs, the worst took 5 years for 25 percent of the patients to be transplanted. There are OPO differences in recruiting living donors with the fraction of those with living donors ranging from 30-80 percent. There are also differences in the rates of related vs. unrelated living donors – OPOs range from 15-45 percent.
In terms of what kind of organ the patient received, one OPO showed 20 percent better outcomes than another one. Access to transplantation was an issue, as was access to the type of organ transplanted and both vary. Another factor was the odds of discard for non-ECD kidneys. This discard rate ranged among OPOs by about a four-fold rate.
Dr. Wolfe summarized by stating that for every single metric examined, there were two- to six-fold differences, depending on where the patient lived. When exploring the issue of race, African Americans had a kidney transplant rate that was 60 percent compared to Whites; Hispanics were at 61 percent; Asians were at 60 percent, and Native Americans were also at 60 percent. Part of the African American deficit stemmed from age and gender, i.e., factors other than geography.
Dr. Wolfe concluded by stating that there were differences in access to wait listing and to transplantation. Many, but not all, of these differences could be measured and characterized with existing SRTR metrics. Some differences were highly dependent on existing geographic boundaries, and others on practice patterns.
Ms. Conrad commented that on the issue of kidney discards and the Extended Criteria Donor (ECD), ECD did not explain why one might have to discard a kidney. This was an instance in which size does matter. It might not be possible to place little kidneys or, when the donor was opened up, cysts or some other problem could be identified. ECD only accounted for issues such as hypertension or age, so it was not a good descriptor to explain organ functions. Dr. Wolfe thanked her for the comment.
Dr. Wiesner asked if the data on reallocations showed improved survival or decreased deaths on the waiting list. The response was that definitive and clear data did not exist for MELD. Listing practices had changed and there were fewer low-MELD patients, so the denominator had changed. Dr. Wiesner said that, if this saved lives, it had implications for generalized sharing. Dr. Vega is the current chair of the OPTN Thoracic Committee; and he stated the change in allocation occurred in July 2006. There had been good early data since then which indicated a 60 percent reduction in wait list mortality for 1a and 1b patients, without an increase in mortality for 2a patients. It had not been long enough to assess survival after transplantation, however.
Dr. Solomon referenced the map of geographic variations and the fact that, over 5 years, the rates had worsened quite badly. It made her consider ACOT’s focus and the need to address the epidemic of huge predictors of ESRD that increased demand. The larger context for this was the change in public health status related to obesity and other preventable issues. Without scope creep, she asked if it was possible for ACOT to address this issue. Dr. Wolfe concurred that much of the increase was from type II diabetes. Mr. McGinnis commented that obesity prevention spanned the whole country and included multiple departments at HHS. It would be difficult, in his opinion, for ACOT to have an impact in this area. Dr. Lorber disagreed, noting that HHS focused on disease control and prevention and, thus, this was an appropriate issue for ACOT to consider.
Dr. Ettenger asked if ACOT could do something constructive in terms of discussing UNOS regions. Dr. Wolfe agreed that this was an area where policies had a big impact on candidates. Dr. Ettenger commented that location matters to a large extent and that geographic issues may have changed since the regions were originally created. The group discussed the fact that the OPTN Final Rule stated that geography should not make a difference and neither the OPTN Final Rule nor other regulations decreed that allocation be based on DSA. Ms. Conrad said that the V.A. had many Centers of Excellence and moved patients all over the country for treatment and transplantation. Her Iowa facility transplanted people who were not from Iowa, for example. Ms. Kelleher suggested that this reflected internal transplant tourism and indicated that people moved around, when they had the resources to do so, to be listed in a place with shorter waiting times.
Reports from Workgroups/Discussion/Recommendations
Ms. Agrawal -- Accreditation of Establishments Required to be Registered with the FDA
Ms. Agrawal led the reports from the workgroups. After the last meeting, there was a consensus that there should be a more formalized process with respect to entities involved in tissue. She and Ms. Emily Marcus Levine, J.D., HHS Office of the General Counsel, drafted the following recommendation:
The ACOT recommends that the Secretary take action to require accreditation of all establishments required to be registered with the FDA as manufacturers of human cells, tissues, and cellular- and tissue-based products.
Ms. Conrad asked how this would affect those who do not recover. Dr. Keith Wonnacutt of the FDA responded that the ACOT recommendation would capture organizations that manufacture as well as those that recover. Tissue rules described in detail what entities had to register. This definition simply stated that, if an entity had to register, it was party to this. Ms. Agrawal said that was also her understanding of the language. ACOT knows these entities are registered with the FDA, and it was ACOT’s opinion that registration is insufficient and that accreditation was desirable. ACOT did not state which entity should be the accrediting agency, however. The Secretary would decide if he was going to act on this and which entity would accredit.
Dr. Leffell asked what standards would be used to measure accreditation, and the response was that there was no single set of standards. The requirement for accreditation included the Secretary specifying the accreditor, as well as the accreditation basis that entity would use.
Ms. Agrawal called the question; the motion was moved and seconded, and the vote was unanimous.
Dr. Wiesner reported that the workgroup held a conference call on this issue and that members expressed concern about both the accuracy of data and the need for oversight. Many entities used the data but did not pay for the data. Data collection requirements presented a huge burden for transplant centers, and more data were needed in order to keep making evidence-based decisions. Yet, OPTN representatives indicated that the organization looked at MELD and not at the rest of the data. The work group members talked about the sorts of data needed (including levels of insulin required during transplant).
The group was interested in exploring funding to underwrite some of the data collected. Suggestions included adding a fee to list registration for data collection, or charging insurance and pharmaceutical companies for use of the data. Mr. McGinnis added that this subject came up at the April 28-29 Advisory Council on Blood Stem Cell Transplantation (ACBSCT) meeting. (The recently re-enacted statute required many data on blood and stem cell transplantations.) Everyone was thinking about it, but no perfect model had yet been created or suggested. The Secretary can set the fee schedule, but this could be problematic. Ms. Agrawal said that it might be interesting to have someone talk to ACOT about what the statute and the final Rule specify in terms of data collection about organ transplantation and procurement, so they could be compared with requirements for blood and stem cell.
Dr. Low suggested that the work group craft a recommendation around funding for data collection describing the entity’s use and payment of data. The ACOT did not need to solve the problem, merely to highlight it and to note that there are potential external sources of funding. Mr. McGinnis added that the OPTN Final Rule specified that the data must be provided, but it would be acceptable to charge at a reasonable rate to use the data. Ms. Agrawal suggested that the work group might need to get information from HRSA about the OPTN Final Rule’s specifications on data collection and availability. It would be good, she commented, if the work group could suggest the data needed.
Dr. Fant added that there is a process in place within OPTN to determine the committees’ data needs to support policy developments, and to collect and use these data, once identified. The issue was how ACOT could support the OPTN’s efforts to better identify data needs. Some members commented that there was nothing in the OPTN Final Rule limiting the type of data required to be submitted. It was whatever the Secretary felt was needed. The issue of how to pay for the data remained, however. Dr. Wiesner stated that the data provision burden overwhelmed transplant centers, and the OPTN Final Rule did not provide for a fee or reimbursement process for these programs. The group discussed the fact that data were no longer being collected on some long-term survival indicators (e.g., immunosuppression data). Dr. Fant clarified that, while the data reduction process eliminated data on tumors and cancers post-transplant, some questions were retained about post-transplant cancers. Thus, those questions were only asked when it was appropriate.
The work group will continue to consider this issue.
Dr. Leffell – Xenotransplantation
Dr. Leffell reported that part of the work group’s report would be presented by Dr. Wonnacott. The work group was charged with considering issues around xenotransplantion. The members had a few conference calls and reviewed materials to examine the scope of ACOT’s interest and whether there was any need for ACOT to pursue this issue further.
As part of this work, Dr. Fant conversed with the former Executive Secretary from the Secretary’s Advisory Committee on Xenotransplantation (SACX). The work group also reviewed a lot of work that they had not known had occurred, or was occurring. In the end, the work group determined that there was no current, pressing need for ACOT to pursue xenotransplantation issues. The work group did discuss several ethical issues, some of which were also raised in the morning session of this meeting.
Thus, the work group’s recommendation was that, with on-going oversight, there was no need for duplication of efforts. ACOT’s role should be simply to monitor progress in xenotransplantation.
Dr. Wonnacott updated the group on ongoing activities in this area. He stated that he was the Branch Chief for cell therapy, which oversees regulation of xenotransplantation. The FDA definition did not include non-living tissues. As such, all studies that used xenotransplantation products had to be performed under Investigational New Drug application (IND) process and were subject to premarket approval requirements prior to distribution for sale.
Guidelines on xenotransplantation include: the 2001 PHS Guideline on Infectious Disease Issues in Xenotransplantation; the 2003 FDA Guidance for Industry: Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of Xenotransplantation Products in Humans; the 1999 FDA Guidance for Industry: Public Health Issues Posed by the Use of Non-Human Primate Xenografts in Humans. These guidelines include information on source animal characterization and controls; manufacturing and product testing considerations; preclinical considerations; clinical considerations; protocol review, site and medical team, patient selection, informed consent/patient education, screening/surveillance, future blood donation; records management; and archiving samples.
Xenotransplantation policy has been a collaborative effort across DHHS and the scientific community, including advisory committees on xenotransplantation. These include the Secretary’s Advisory Committee on Xenotransplantation (SACX), and the Xenotransplantation Subcommittee of the Biological Response Modifiers Advisory Committee.
Dr. Leffell thanked Dr. Wonnacott for his overview. The work group felt that the ACOT’s role should be to monitor the issue. The work group members felt that there was not enough substantial clinical activity to do more. The work group will revisit the issue later, if needed. There was no active role for ACOT at this time.
Ms. Principe – Living donor advocacy/post-donation complications
Ms. Principe reported that the work group’s goal was to explore opportunities to promote and advance living organ donor advocacy and to assist in decreasing adverse events for those who are potential and/or actual living donors. In their conference calls, the members discussed the Living Donor Bill of Rights, informed consent issues, health and life insurance, quality-of-life issues, and living donor registries.
One relevant document the group discussed was from the New York State Transplant Council Committee on Quality Improvement in Living Kidney Donation, chaired by Dr. David Conti (an ACOT member). The Committee’s report was completed in December 2007; and Dr. Conti had offered to present on it at the November ACOT meeting, if desired.
The group also discussed the 2006 “Living Donor Bill of Rights,” created by the Live Organ Donor Education and Protection Program (LODEPP) and authored by Mrs. Boone (ACOT member), Vickie Hurewitz, and Donna L. Luebke. ACOT work group members expressed an interest in working with LODEPP to promote this document. Mrs. Boone added that the document should be reviewed again and that ACOT had offered to help with that. The work group also planned to communicate with the OPTN Living Donor Committee on its activities around this issue.
As part of its work, the work group received an update from SRTR on living donors who have been wait-listed for kidney transplantation. The data indicated that 177 former donor candidates had been waitlisted since 1993 (although data were not complete on all donors, particularly those from longer ago). In terms of demographics of live kidney donors who were wait-listed for transplantation, 63% were male, 42% were White, and 45% were African American. The mean age of those on the list was 47 years, compared to previous donors, who had a mean age of 51. SRTR found that the time from making a donation to being listed was about 18-20 years.
The work group’s future actions were to ask Dr. Conti to present on the Live Kidney Donor Guidelines in November 2008; to circulate the “Live Donor Bill of Rights” to ACOT members for comment; to acquire additional donor data; and to revisit live donor registry issues including funding, mandatory data submission, data analysis, and data reporting.
Mr. Holtzman – Reducing pediatric deaths on the waitlist
Mr. Holtzman presented for Dr. Reyes. The work group has had a lot of discussion about how to affect pediatric deaths, and the discussion focused on split livers. While there was discussion about the efficacy and value of doing this for pediatric cases, the data have not been received from SRTR yet. Questions include how to identify livers that can be split; whether to mandate splitting livers, if possible; and other appropriate incentives in this area.
Mr. Holtzman reported that his OPO had an allocation variance from UNOS to split livers and that this idea might be nationalized. The splitting transplant center would be able to transplant both lobes: one to the pediatric case and the other to any other patient the center chose. The index patient had to be an adult. ACOT might consider supporting the extension of this variance to those other than adult patients on the index. This might be a good incentive.
Dr. Fant stated that a major consideration was assessing how to maximize the ability to split the liver for different recipients. He suggested that members look at the past ACOT recommendation on this matter and compare with the OPTN’s current actions. ACOT had made a recommendation in favor of splitting livers in the past, but members may wish to make a new recommendation. Splitting the liver should be incentivized, in Dr. Fant’s opinion. Right now, however, surgeons were punished because they could only use half of the liver. Moreover, splitting the organ required special skills. The widespread lack of such skills might have a negative impact if a mandate was passed in this area, although incentives could be useful. Dr. Wiesner noted that the minute the liver is split, it became an ECD with lower graft survival. Dr. Ettenger added that it also takes a lot of skill to even recognize when a liver can be split.
Ms. Agrawal summarized by noting that ACOT had this exact discussion under its first chair, and ended up in an identical situation. The earlier recommendation was to incentivize rather than mandate this. The work group will continue to think about this issue. It was not ready for a recommendation at this time.
Administrative Matters and Adjournment
Dr. Fant reported that there were no administrative matters. The meeting was adjourned for the day.
May 6, 2008
Further Discussion and Vote on Work Group Recommendations
There was no further discussion needed on the work group recommendations.
Ms. Agrawal noted that the ACOT has existed for a while and has addressed many issues and made a large number of recommendations to the Secretary, some of which were acted on, others which were not. ACOT’s role is to give advice; it cannot make anyone take it. The ACOT’s charge was to provide advice to the Secretary on major issues around procurement and transplantation and, when asked, on OPTN policies. The current ACOT group had not been asked to do the latter, so this was not on the table.
Ms. Agrawal stated she wanted ACOT members to create a roadmap to use in going forward. The Secretary had not given ACOT a statement of interest, so the group had to decide on what to focus. One way to do that was to think in terms of broad, sub-categories, and prioritize within those sub-categories. While this carries the risk of becoming broad and unfocused, ACOT members could divide into subgroups, create problem statements on issues of concern, and triage them via recommendations. Ms. Agrawal suggested creating broad sub-groups on:
(1) Access issues: listing, disparities, coverage;
Dr. Low added that speakers could also be asked to tie their presentations back to one of these themes and specify what the ACOT could do. He said it was hard to generate a potential action right after hearing a presentation. Ms. Kelleher added that it would be helpful to hear about which entities already address the issues so ACOT members could ensure that the group worked with them as well.
Dr. Leffell suggested asking other relevant organizations (like AST and UNOS) what issues they would like to raise. Ms. Agrawal asked the staff if a meeting could be planned for these representatives to present key areas and big picture issues. Dr. Fant reminded the group that ACOT is a Federal committee with the role of helping assess the best direction for the Nation.
One idea was to ask members and other key stakeholders to provide lists of priority issues. It was felt that this could be done before November, but not at present. The members discussed various ideas for priority areas, including updating the OPTN Final Rule, although some felt that the OPTN Final Rule was very flexible and that broad policy changes could be made by OPTN.
The group discussed issues of allocation, including geography, disparities, and safety. Dr. Ettenger expressed the opinion that “the 800-pound gorilla” was that the allocation system had not been changed. He felt that ACOT could ask questions about this to assess whether the public’s health was being aided or whether recommendations were needed to protect it. He believed that ACOT’s asking questions would generate attention and focus. The group discussed differences in OPOs and whether it was possible to make them more uniform and standardized. Ms. Agrawal stated that ACOT was initiated primarily to provide advice about allocation policies, and this may be a turning point for ACOT to go back to its beginnings and look seriously at allocation.
Mrs. Boone added that she believed the safety of living organ donors must be a priority. Dr. Leffell supplemented the issue of living donors and allocation by stating the larger issue of geographic variation. Dr. Wiesner added that geography was a vague concept until the MELD scores illustrated how real its impact was and demonstrated that one place might have a MELD of 30, while another location had a MELD of 15. He recommended working with Dr. Wolfe to publish a paper exposing access and other differences. He felt that The LA Times should not be the only ones publishing on this subject.
Ms. Kelleher stated that she was concerned about how education and outreach occurred in the United States. They are added on to the OPOs’ responsibilities, but those organizations should focus on procurement. OPOs are not communications outreach professionals. Dr. Scantlebury added the issue of whether the field was maximizing scarce resources in terms of geography, e.g., if every hospital did everything possible around organs and donations, and how to maximize their efforts. Mr. Holtzman suggested hearing from Donate Life America about efforts to get people into State registries. This is about education. Once a person makes a pre-determination to be a donor, they will be a donor, he said.
Dr. Ettenger suggested getting information on post-transplant issues connected with the loss of insurance, CMS’ 36-month limit, etc. These are access issues (and, according to him, losing insurance was an access issue) in which case an ACOT recommendation could be useful. Ms. Peggy Rosenzweig suggested that some successful OPOs could talk about best practices. She also expressed the view that ACOT should speak out on international abuses in transplantation, commenting that the group had the moral need to attempt to curtail those practices.
Mr. Holtzman suggested looking at the past ACOT recommendations and getting an update on what, if anything, happened as a result of them. Ms. Agrawal agreed that staff could present this at the November meeting. In summary, Ms. Agrawal suggested that, at the November meeting, ACOT members would spend a chunk of time on allocation issues. She asked members to give Dr. Fant their ideas about which speakers to invite to the meeting. The living donor piece was completely different from allocation. The final issue was public education, which concerned increasing donors and educating people about donation (registry, living donors).
Revised Informed Consent Recommendation
Living Donor Consent – OPTN Perspective -- Maureen McBride, Ph.D., Director of Research, UNOS
Dr. McBride spoke on the OPTN’s perspectives on living donor consent. The June 16, 2006, Federal Register notice stated that OPTN living donor guidelines should be given the same status as those for deceased donor organs. The Secretary directed OPTN to develop policies regarding living donor organs and living donor recipients, including policies for equitable allocation. Noncompliance in this area is subject to the same consequences as deceased donor policies under the OPTN Final Rule. The living donor bylaws were developed by the Joint Subcommittee of Living Donor Committee and Membership and Professional Standards Committee. The bylaw modifications, which applied to Program Criteria for programs that perform living donor kidney and living donor liver transplants, went into effect on October 18, 2007.
The new Living Donor Kidney Bylaws required transplant programs to demonstrate they meet various requirements regarding personnel and resources. They must have the following specific protocols: living donation process, independent donor advocate, medical evaluation, and informed consent. The programs must develop (and once developed, must comply with) written protocols which include, at a minimum: discussion of the potential risks of the procedure including the medical, psychological, and financial risks associated with being a living donor; assurance that all communication between the potential donor and the transplant center will remain confidential; discussion of the potential donor’s right to opt out at any time during the donation process; discussion that the medical evaluation or donation may impact the potential donor’s ability to obtain health, life, and disability insurance; and disclosure by the transplant center that it is required, at a minimum, to submit Living Donor Follow-up forms addressing the health information of each living donor at 6 months, 1-year, and 2-years post-donation. The protocol must include a plan to collect the information about each donor.
A resource document regarding informed consent for living donors was posted at Transplantliving.org , along with recommendations from the OPTN/UNOS Living Donor Committee, to help transplant professionals obtain informed consent of all living donors.
In terms of the medical evaluation of living kidney donors, the Living Donor Committee has worked to finalize a set of recommendations that can be used by transplant programs in their own program-specific living donor kidney medical and psychosocial evaluation protocols. Kidney programs that perform living donor transplants will be asked to submit applications documenting that they meet all requirements for living donor transplantation. Programs will be notified when this process is ready to begin. Staff will review the following during site visits to the programs: the program’s written protocol and a sample of living donor/recipient records; and documentation in the record to verify that all phases of the living donation process were performed according to the program’s protocol.
Mrs. Boone asked about enforcement and was told that problems are reported as are other policy violations.
Dr. Solomon stated that poor IC for research is often found in examinations and commented that Dr. McBride had described procedures around, but not the content of, informed consent procedures. Nor had she described any attempts to ensure that the donor understood the consent process and contents. She stated that it was extraordinary that the new bylaws did not include any substance on what constitutes substantive informed consent and expressed the view that this failed to protect people’s choices.
Dr. Leffell added that the bylaws state that the risk of donation needs to be disclosed to the donor and that the Board had fallen short in delineating the specific risks. Some believed the bylaws were not as stringent as possible, she added, but the Board did not believe it could dictate practice to transplant centers since they varied to such an extent. Dr. Leffell agreed with Dr. Solomon’s point that there was a lack of follow-up to ensure that the donor understood the information provided. Dr. Solomon noted that assessment of understanding is key to informed consent and described many creative ways this can be done, and urged OPTN to explore this area. The Joint Commission itself had found, in its reviews, that merely focusing on hospitals’ record-keeping and medical records presents a misleading picture. The Commission had added conversations with patients in the waiting room to get more information.
Ms. Kelleher asked about the living donor advocate’s role and whether that individual has the job of documenting that the informed consent occurred. Dr. Scantlebury clarified that they act on behalf of the donor to make sure they are well-informed about the procedure.
CMS Requirements for Informed Consent -- Karen Tritz, Centers for Medicare and Medicaid Services, Survey and Certification Group
Ms. Tritz reviewed the informed consent requirements for transplant patients and for living donors, as well as the role of the Living Donor Advocate and the informed consent process during the survey process. Transplant centers must implement written transplant patient informed consent policies that identify who was responsible for discussing the informed consent process; where the discussions concerning the informed consent process were documented in the medical record; the methods used by the program to ensure and document patient understanding; and when the discussion will take place. There must be a written informed consent process that includes multiple discussions with the prospective transplant recipient and the living donor. Transplant patients must be given an opportunity to ask questions, and there must be a process to assess the patient’s understanding.
The informed consent must be specific enough so that the patient knows the general risk factors he or she may, or may not, have to be tested for, and what might happen in the transplant. This was to be revisited with the specific organ in order to describe whether it was an ECD or had other high-risk factors, so the patient can decide whether or not to accept the organ. Eight areas must be discussed with transplant patients:
There are nine topics that must be addressed to gain informed consent for living donors. CMS did not proscribe the process, but it must be a thorough, written process that covered all of these nine areas. All types of living donors, for any type of organ, must receive information on:
It is a primary responsibility of the living donor advocate to ensure that the donor has received information and provided informed consent. The donor advocate did not have to provide all of the information directly. The expectation was rather that the advocate would facilitate the process to ensure that the donor received full information (e.g., sit in on discussions with other medical personnel, ensure that the donor’s questions answered). Questions that the surveyors will ask the living donor advocate(s) include:
The review of the informed consent process includes a review of educational materials provided as part of the informed consent process; review of medical records and interviews to validate that timely and appropriate discussions were held; interviews with a sample of available post-transplant patients or living donors (or with representatives if not available); and assessment of evidence that the practitioner assessed the person’s understanding.
Ms. Rosenzweig asked for clarification on how CMS handled the issue of health care coverage for the living donor 1 or 2 years post-transplant. The response was that this was not specified in the regulations, in terms of a specific script to use for informed consent. CMS looked at the transplant center to ensure that this was part of the discussion, but the process varied based on the specific circumstances. It was expected that they would discuss effects of donation on insurance, however. CMS did not require that a specific tool be used, or developed. CMS believed that those who work on the ground directly with patients know best how to accomplish this.
Ms. Rosenzweig asked if, under Medicare/Medicaid, it was Ms. Tritz’s understanding that there be continuing coverage for donors. The response was that for living donors, CMS covered the immediate, post-donation expenses. For on-going or follow-up expenses secondary to the donation, primary insurance was relied upon. Ms. Tritz and Ms. Diane Corning, the CMS ex officio member on ACOT, said they would look at the issue of coverage for complications arising from the donation and provide information to Ms. Agrawal on this issue, as well as on the other reimbursement questions that came up during the meeting. Dr. Scantlebury asked if CMS recommended any specific length of follow-up on donors. The response was that there was no specific time-frame in the regulation, but CMS did expect there to be continuity of care and proper discharge, which included appropriate follow-up. This issue will be reviewed in the evaluation of the program.
Dr. Solomon commented that these informed consent processes were more substantive and included more content information. She asked what the relationship was between the CMS and UNOS guidelines. Ms. Tritz responded that they operate in parallel. CMS kept an eye on recommendations and other matters coming from UNOS. The purposes were different, however. CMS reviewed for Medicare’s requirements, while UNOS had broader responsibilities. Both guidelines applied, however. If a center wanted to participate in Medicaid, it had to comply with the CMS requirements.
The final guidelines are in the agency’s clearance process and will be released shortly.
Ms. Luebke spoke from the audience and recommended that the ACOT and others attending the meeting review Section 1881 of the Social Security Act, which stated that donors “shall be entitled to Medicare A and B coverage.” In Chapter 11 of the Manual, it defined “recovery” as lasting until there are no longer symptoms. She commented that she had discussed this with CMS. She stated that this is Federal legislation and the intent of Congress should be complied with in this area. Ms. Agrawal asked staff to follow up with her on this subject.
SRTR/OPTN Living Donors Long-term Follow Up
Living Donor Long-term Follow-up – OPTN Activities -- Maureen A. McBride, Ph.D., Director of Research, United Network for Organ Sharing
Dr. McBride reported that the OPTN contract included a requirement that it collect living donor data “annually for at least 1 years post-donation.” In June 2006, the Secretary of HHS directed OPTN to develop living donor policies and in June 2007, the Board approved the Policy Oversight Committee’s resolution: “Resolved, that a joint OPTN Committee be established to evaluate the use of living donor data.”
The Living Donor Data Task Force’s (LDDTF) charge was to “identify the purposes for which living donation-related data are needed and to recommend appropriate approaches for obtaining and/or reporting data for each purpose.” The Task Force had 20 members, including representatives from OPTN/UNOS (Living Donor and Policy Oversight Committees, KPD Working Group, Board of Directors); ASTS; AST; Adult to Adult Living Donor Transplantation Cohort Study (A2ALL); NIH Retrospective Living Donor Outcomes Study; NYCLT; LODN; NKF; as well as clinical, social work, and psychology experts.
The problem is that there are many questions about living donation, including its risks, costs, and psychosocial impacts. OPTN data are limited for addressing many important questions, however. This results from the fact that the donor is not a patient of the transplant center for very long; the lack of long-term follow-up data; “gaps” in the data; and limitations resulting from UNetSM forms data. OPTN’s approach was to take leadership role by articulating the questions being asked; directing the community to where answers can be found; and deciding which gaps the OPTN should be responsible for (and which are appropriate for others).
To date, the LDDTF has reviewed the current OPTN data collection system, and timeline of data collection (pre-donation, surgical, post-op, through 6 weeks, and follow-up at 6 months, 1 and 2 years). Dr. McBride showed a slide that illustrated recovery centers’ 1-year follow-up forms. The majority has followed less than half of the patients, and many had less than 50 percent follow-up for its donors.
Primary areas of interest include: questions about the donation process, the short- and long-term risks; recovery and return to ADLs; donor follow-up; psychosocial impacts; costs and insurance issues; and questions about paired donation. The Task Force needed to assess what it would like to know, as well as what data the OPTN should collect. Specific areas of concern included those around pre-donation (are donors properly evaluated, is risk properly assessed and communicated); peri-operative complications and long-term complications (including CCD, renal disease, and surgical complications); psychiatric complications and Quality of Life (QOL) issues; financial implications and issues surrounding health insurance.
The LDDTF will review ongoing studies of living donor outcome and will continue to review other possible sources of data. It will also consider other questions that need to be answered, as well as possible solutions to obtaining the necessary data. The goal is to create a set of living donor data-related recommendations to guide the OPTN/UNOS Board in planning approaches to living donor issues. Proposals may recommend approaches to be taken by the OPTN, other organizations, and/or a combination of both. The target is to have the recommendations by the end of 2008.
Living Donor Long-term Follow-up – SRTR Activities, Robert M. Merion, M.D., Clinical Transplant Director, SRTR
Dr. Merion began by noting that making living donation completely safe was probably impossible. The goal was to define the risks, focus on reducing short- and long-term risks, and communicating those risks as part of the informed consent process.
The goals of long-term follow-up of living donors were to estimate the risk of progression to organ failure, and to compare the level of risk of organ failure and/or death between donors and non-donors. Problems in assessing these issues included that the OPTN/SRTR data have been reported by transplant centers for a limited time frame. Data prior to 1995 were generally non-existent or incomplete with respect to living donors. There were high rates of loss-to-follow-up because it was hard to get donors (especially healthy donors) to return for long-term follow-up. Dr. Merion noted that some donors did not return due to bad experiences, which meant that the center could not help them with their problems. Finally, data have not been collected on the development of co-morbidities between donation and organ failure.
A recent article in Transplantation suggested that African Americans who were kidney donors had a higher rate of needing transplantation compared to donors of other race/ethnicities. The article appeared while SRTR was conducting a study, led by Dr. Ojo, looking at ESRD among prior living donors. As noted earlier, Dr. Ojo’s study identified 112 cases of ESRD among prior living donors. SRTR is collecting more information on an additional 65 individuals on the waiting list who received points for having made a prior donation, but for whom no record of donation has been found. One known non-donor was identified and 24 of the 112 cases were pending final confirmation. SRTR then looked at the rate of development of ESRD for the population as a whole (ESRD rate per million person-years). Dr. Merion described initial findings and next steps for the SRTR analysis.
There were other studies underway, too, including those being conducted by the NIH such as Renal and Lung Living Donor Evaluation Study (RELIVE) and the Adult to Adult Living Donor Liver Transplantation Cohort Study (A2ALL). The RELIVE consortium looked at informed consent in living kidney and lung donors. A preliminary analysis from RELIVE indicated that throughout almost 50 years of transplantation, kidney donors had good survival rates and did better than the norm for the U.S. population. Dr. Merion commented, however, that these were healthy individuals, and the question remained what their outcomes would have been if they had not made the donation.
The A2ALL Study included 11 participating organizations in 9 locations. The Study hypothesis was that receipt of a live donor liver allograft conferred superior long-term outcomes, compared to deceased donor liver transplantation. In addition, A2ALL explored whether donation of the right liver lobe was acceptably safe in properly selected donors. The A2ALL will evaluate donor and recipient outcomes from 1998-2000 and will include both cohort and ancillary studies.
One of the cohort’s primary aims was to determine the short- and long-term health and QOL impact made by donation, including morbidity, and long-term, health-related, QOL of donors. As part of this, A2ALL will assess the role of informed consent in affecting the decision to donate and the satisfaction after donation. It was hard, Dr. Merion, commented, to measure informed consent. One key element of understanding was the donor’s knowledge that he or she can refuse to donate, and all of those assessed performed well on that question. Some donors, however, had less than a perfect understanding of the risks, benefits, evaluation, and purpose of donation.
In terms of donor medical outcomes, there have been four deaths among the population, one could have been related to the donation; one was clearly accidental; and the other two may have been psychiatric in nature. There were some living donors who developed psychiatric issues after donation, and a few suicides and suicide attempts were seen, which was very concerning. There were 12 instances in which the operation was stopped, either because the donor was unstable or unsuitable, or because the recipient became unstable. Thirteen percent of donors were re-hospitalized in subsequent months or years after the donation.
Dr. Merion concluded by reiterating that living organ donation cannot be made totally safe. Hence, the unfinished business in this area was to define the long-term risks and benefits of living organ donation.
Ms. Rosenzweig asked, since it was unsafe and there were people who develop ESRD, whether they were in a better position to move to the top of the line or if they go into the queue. The response was that these patients get more points and go to the top of the list.
Because some attending members of the public had to leave the meeting early, this additional period was allotted for public comment.
Dr. Mark Uknis announced that he was a transplant surgeon and the medical director of Viralpharma; he also commented yesterday. He read an open letter to the ACOT members:
Donna Luebke thanked the Council for the opportunity to speak. She said she was a living kidney donor from 1994 and was doing well. She thanked the living donor subcommittee, on behalf of living donors, as well as New York and North Carolina, for putting forward guidelines for living donors. She asked the ACOT members to please publish on this subject.
She said that the number of those on the waiting list with ESRD had risen over the last 7 to 8 years. Earlier, Ms. Luebke had commented on the Section 1881 amendment to the Social Security Act and its promise that living donors would receive Medicare Part A and Part B coverage. She said that the key issue is that this legislation preceded the NOTA. Attorneys would have to look at “valuable consideration;” however, it was Congress’ intent to protect donors and to provide long-term Medicare benefits to them. She encouraged ACOT to examine the fact that legislation like the Kidney Donation Clarification Act (HR 710, on paired donation) had no funding attached to it. She asked how it could be implemented without funding and still develop, implement, and protect the pairs. She encouraged ACOT members to support the Everson Walls and Ron Springs Act (HR 3635), which established organ and tissue donor registries and included safeguards and protections for living donors. She closed by thanking the Act’s main sponsor, Rep. William Clay (D-MO).
Overview of NCI/HRSA Project to Study Post-Transplant Tumors and Cancers in the United States -- Eric Engels, M.D., MPH, Medical Epidemiologist Division of Cancer Epidemiology and Genetics, National Cancer Institute
Dr. Engels began by noting that solid organ transplantation was life-sustaining therapy for end-stage organ disease, but one that was associated with high morbidity. Cancer risk was elevated in transplant recipients (by two- to four-fold) due to cancer risk factors that included immunosuppression, infections, and transmission from the organ donor. Some viruses caused cancer; normally those cells were cleared away or otherwise prevented from proliferating in the body. Because transplant patients experienced more frequent infections, and immunosuppression, they were more susceptible to cancer.
The example of Kaposi Sarcoma (KS) demonstrated the rich understanding of virus-caused cancers. Dr. Engels showed a slide with KS incidence in the general population, among those living with HIV/AIDS, and in transplant recipients. He then discussed Merkel cell carcinoma, which was increased among those with transplants as well as people living with HIV. There was a polyomavirus present and it seemed like a cancer-causing virus.
The unanswered question was whether other, common, cancers were more common in transplant recipients. There were complicating issues that hampered interpretation of past studies and stem from inaccuracies in making a cancer ascertainment, and the differences in risk factors (e.g., smoking) between transplant patients and the general population. Other issues were that a history of cancer was a contraindication for donation, but living donors could manifest cancer for the first time after they made a donation.
Major studies of cancer in transplant recipients in the last 30 years have been limited to kidney donors, and there was little information for other groups of recipients. Only some used data from cancer registries, which was a problem. Under-ascertainment of cancers may stem from the reliance on OPTN reports in which for recipients that were most closely followed in the first years after transplant, cancers were likely to be treated at outside institutions, resulting in incomplete reporting by transplant centers. The effects of under-ascertainment in studies of cancer risk meant that the risk may be underestimated, especially for some cancers.
The transplant cancer match study linked the U.S. transplant registry with multiple cancer registries to systematically identify cancers in transplant recipients, transplant candidates, and donors. It is a collaboration between the NCI, HRSA, and SRTR. There were three objectives:
The approach used a computerized linkage of SRTR and 18 cancer registries (both State and regional) to assess risk among roughly half of the transplant population. There were a number of challenges to this project, however. For example, it took 10 months to get a Memorandum of Understanding between NCI and HRSA, and the study protocol was still under review at the eight cancer registries approached to date (all of which have different processes for managing data requests). The project had been hampered by the lack of a centralized process, concerns over confidentiality and data security, bureaucracy, and under-staffing. Dr. Engels illustrated the language from one of the proposed data use agreements to demonstrate the complexities in creating such State-level agreements.
The Transplant Cancer Match Study was not a substitute for continuing OPTN data collection on malignant outcomes. It was not designed for surveillance and only covered about half (46%) of transplant recipients, and only with a one-time match. It was likely to miss some outcomes due to incomplete reporting to cancer registries; early-stage post-transplant lymphoproliferative disorder; and squamous cell skin cancers.
Dr. Wiesner asked how accuracy and completeness of the registries was assessed and Dr. Engels responded that an accrediting body (North American Association of Central Cancer Registries) reviewed the registries and assigned levels of accreditation.
Dr. Wiesner asked why the study was not looking at the most common cancers. The response was that PTLD was a spectrum that ranged from proliferative lesions up to cancer (NHL). While it was correct that the study framework did not capture early stage disease, all of the outcomes like lymphomas were captured and the SRTR had early stage lesion information. The group discussed the issue of PTLD and the fact that it was related to transplantation. Because PTLD was so related to transplantation, the transplant centers tended to know about these events and were likely report them to the OPTN. The SRTR will provide its data on this to the Study. Reporting on this was better than the reporting for other solid cancers.
Dr. Wisener asked if genetic studies were being conducted to determine if the cancer came from the donor. The response was that the tumors would not be HLA typed. The goal was to compare risk between two groups: recipients whose donors did have cancer versus those whose donors did not. It was impossible to “fingerprint” the cancer and link it to one or the other.
Public Comment & Adjournment
Pearl Lewis stated that she was on the Malignancy Advisory Board of the National Kidney Foundation. She had two children, one who had been on dialysis for 19 years, and the other who had been transplanted. Earlier today, the group asked what the ACOT’s purpose was; she asked if it was not to enable transplant recipients to live long, healthier lives. People who had transplants were living longer, which is why there was more cancer in this group. In 1996, she worked with a patient who received a transplant from his sister. He had a colonoscopy in 1999 that was clear. Five years later, he had another one that revealed Stage 3 colon cancer. Dr. Penn has recommended that transplant recipients be screened for cancer 20-30 years earlier than members of the general population. This was not about age, it was about immunosuppression.
The patient she mentioned had no history of cancer. He was her husband, and he died last October at the age of 52. Her daughter had a transplant in 2004, in a small town in Texas, and she had been screened the first year post-transplant and every 2 years since then. Her husband, on the other hand, was transplanted in one of the major centers in Maryland, but he was never screened and never told of his cancer risk. When Ms. Lewis questioned the head of her husband’s transplant center about this, he said there was no time or money to do patient education. She asked if they could at least place a sign in the clinic about this and was told that there was no time to do so. She did succeed in putting free pamphlets out for new patients. The fact was, she said, no one says anything to those who are most at risk, yet people are on immunosuppressants for longer and longer amounts of time.
There were a lot of statistics that showed, from year 1 to year 3, colon cancer risk increases each year. It was the same with other cancers. Ms. Lewis quoted Elie Wiesel: “The opposite of love is not hate, it’s indifference. The opposite of art is not ugliness, it’s indifference. The opposite of faith is not heresy, it’s indifference. And the opposite of life is not death, it’s indifference.” She said that it was critical to tell patients about the risks and ensure that they get screened. People should be screened individually and looked at as individuals. Unless this happened, we make the patient’s life unbearable and have traded one cause of death for another that occurs years later. That would be unethical.
The meeting was adjourned.