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Fifteenth ACOT
Meeting
Rockville, MD
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:
- Pre-transplant
Prediction and/or Recognition
- Pre-transplant
– Optimize Support, Provide Adequate Information and
Modify Behavior
- Post-Transplant
– Prevention/Treatment
- Post-Transplant
– Medication Modifications
- Post-Transplant
– Recognition / Assessment
- Transition
- Research
Initiatives
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.
Discussion
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
below.
Work group
1 (Transplant and the CKD paradigm) established several goals:
- Increase
access to preemptive transplants for all patients by limiting
pre-wait-listing dialysis exposure;
- Reduce
disparity in access to transplantation based on age, ethnicity,
geography, and SES and increase providers’ cultural
competence and patient educational materials (e.g., language);
- Promote
early referral of patients with CKD such as by co-management
by primary M.D. and nephrologists of patients in Stage III,
and evaluation by transplant centers at entry to Stage IV
(prior to or at the time of vascular access referral);
- Provide
comprehensive education for CKD patients at the time of
nephrology referral (Stage III) that emphasizes the potential
for transplantation;
- Conduct
timely evaluation by transplant centers (with a target of
6 weeks from referral to initial visit; expeditious completion
of work-up of candidates; and early identification, screening,
and evaluation of potential donors);
- Increase
the percent of living donation performed preemptively from
the current rate 26% to a goal of 50%; and
- Raise
awareness of the benefit of preemptive transplant among
the public, patients, physicians, nephrologists, dialysis
providers, transplant centers, and the payer community.
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:
- Provide
a White Paper that articulates the financial incentives
for payers for preemptive transplant;
- Accelerate
the processing time for Medicare enrollment;
- Create
uniform minimum coverage requirements for Medicaid programs
to include reimbursement for organ acquisition and adequate
medication coverage including immunosuppressants;
- Support
Part B premium reimbursement by third-party payers (similar
to dialysis and COBRA payments);
- Create
a reimbursement structure that recognizes the complexity
of post-transplant care (this will enhance long-term outcomes);
- Support
legislation that provides funding for CKD education/modality
selection (pending legislation);
- Support
appropriation of funds to the Organ Donation Recovery and
Improvement Act (3-year period);
- Support
pending legislation that provides extended entitlement for
immunosuppressive medication coverage from 36 months to
lifetime of the graft;
- Support
legislation to extend existing state laws and introduce
a national program to allow for a Federal tax credit to
cover living donor expenses (consistent with current NOTA
language); and
- Modify
Medicare eligibility criteria to include patients who have
reached Stage 5 CKD.
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.
Discussion
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.
Dr. Tilney described the Transplantation Society, which began
in 1966. One of its Guiding Principles (#5) is that: “Organ,
tissue and cells should only be donated freely and without
monetary reward. The sale of organs, tissues and cells for
transplantation by living persons, or by the next of kin for
deceased persons, should be banned. The prohibition of sale
or purchase of cells, tissue and organs does not affect reimbursing
for reasonable expenses incurred by the donor, including loss
of income, or the payment of other expenses relating to the
costs of recovering, processing, preserving and supplying
human cells, tissues or organs for transplantation.”
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.
Discussion
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.
Public
Comment
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:
- Efforts
to increase donation and living donors safeguards
- DCD:
declaration of death vs. retrieval
- Patient
safety issues
- NIH
projects: recommending and following up on items for study
- Access
to transplantation (including geography, minorities)
- Composite,
vascularized transplants
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
process or the candidate’s perspective of access (e.g.,
access to the list, to transplant after listing, average MELD
score, donor characteristics, transplant characteristics).
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.
Discussion
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 – Funding Sources for Additional Data
Collection
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.
Ms. Agrawal summarized by stating that there were three issues.
The first was, “what data should be collected?”
The second (and related) question was, “what does the
OPTN require in the way of data and why – and should
ACOT have some oversight over this?” (It was part of
ACOT’s original charge.) The third question was about
reimbursement. The ACOT could recommend that reimbursement
was insufficient and suggest that, if people were asked to
provide more data, they should be paid for this process. ACOT
cannot, however, set a fee schedule. Mr. McGinnis added that
the ACBSCT made a recommendation at the April meeting that
the data collection efforts be fully funded. ACOT could recommend
that full funding be available for data collection sources,
or that NIH award grants in this area.
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.
The FDA also engages in international collaborations and sharing
approaches among multi-national and national entities, including
the World Health Organization (WHO), the Organization for
Economic Cooperation and Development (OECD), the Council of
Europe, the European Medicines Agency (EMEA), and regulatory
bodies of individual countries. These entities engage in consensus-building,
information-sharing, and cooperation.
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;
(2) Donor issues: protecting, incentivizing; and
(3) Outcomes: quality-of-life, data collection, research,
follow-up.
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
- Maureen
McBride, Ph.D., Director of Research, UNOS
- Karen
Tritz, Centers for Medicare and Medicaid Services, Survey
and Certification Group
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.
Discussion
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:
- The
evaluation process;
- The
surgical procedure;
- Alternative
treatments;
- Potential
medical or psychosocial risks;
- National
and transplant center-specific outcomes, from the most recent
SRTR center-specific report, including (but not limited
to) the transplant center’s observed and expected
1-year patient and graft survival, national 1-year patient
and graft survival, and notification about all Medicare
outcome requirements not being met by the transplant center);
- Organ
donor risk factors that could affect the success of the
graft or the health of the patient including, but not limited
to, the donor’s history, condition or age of the organs
used, or the patient’s potential risk of contracting
the human immunodeficiency virus and other infectious diseases
if the disease cannot be detected in an infected donor;
- His
or her right to refuse transplantation; and
- The
fact that if his or her transplant is not provided in a
Medicare-approved transplant center, it could affect the
transplant recipient’s ability to have his or her
immunosuppressive drugs paid for under Medicare Part B.
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:
- The
fact that communication between the donor and the transplant
center will remain confidential, in accordance with the
requirements at 45 CFR parts 160 and 164;
- The
evaluation process;
- The
surgical procedure, including post-operative treatment;
- The
availability of alternative treatments for the transplant
recipient;
- The
potential medical or psychosocial risks to the donor;
- Transplant
center-specific outcomes for recipients, and the national
and center-specific outcomes for living donors, as data
are available;
- The
possibility that future health problems related to the donation
may not be covered by the donor’s insurance and that
the donor’s ability to obtain health, disability,
or life insurance may be affected;
- The
donor’s right to opt out of donation at any time during
the donation process; and
- The
fact that if a transplant is not provided in a Medicare-approved
transplant center it could affect the transplant recipient’s
ability to have his or her immunosuppressive drugs paid
for under Medicare Part B.
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:
- What
role do you play in the informed consent process for living
donors?
- Explain
the discussion you have with the donor related to emotional/psychological,
physical, financial aspects.
- How
do you ensure that the donor understands the donation process?
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.
Discussion
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
- Maureen
A. McBride, Ph.D., Director of Research, United Network
for Organ Sharing
- Robert
M. Merion, M.D., Clinical Transplant Director
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.
Discussion
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.
Public
Comment
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:
May
6, 2008
Dear
Committee,
The
mission of the ACOT is not to address the multitudes
of inherent problems with organ transplantation, but
rather to make thoughtful recommendations for action
items to the Secretary of Health and Human Services
that would be most “profitable”; that is
the recommendations that would supplant current standards
and lead to changes in policy that would most positively
impact not only the field of transplantation, but ultimately
result in better quality of medical care for our patients
and living donors. It is in this regard that the following
issues and solutions are suggested to the members of
ACOT for careful consideration and recommendation to
the Secretary:
The
issue of supply and demand: Dr. Wolfe presented sobering
data yesterday that shows (sic) not only the appearance
of geographic disparities, but also an incredible rise
in the incidence of renal failure. The scope of the
epidemic in morbid obesity and Type 2 diabetes remains
beyond the mission of the ACOT; however, the looming
issues of increasing demand on an already-unbalanced
supply and demand problem in organ transplantation appears
to be worsening. We must address the two factors at
the base of the issue:
Supply:
There were a total of 8,091 deceased donors in the U.S.
for the year 2007. This is the highest number in history,
yet we can do better. The most thoughtful recommendation
from a member of ACOT yesterday was to mandate that
certification of Trauma centers necessarily require
an action plan addressing the manner to which the institution
will move to enhance access for families of trauma victims
that choose to donate loved one’s organs. It is
in this regard that the greatest improvement in deceased
donor organs be achieved.
With
regard to living donation: in 2007, there were 6,308
living donors… the lowest number of living donors
since 2004. This is an unfortunate decline, since during
that same time period, the number of patients on liver
and kidney wait lists have increased dramatically. Dr.
Tilney presented sobering issues of living donor exploitation
in other nations that have led to a transplant tourism
trade that must be curtailed. This tourism and trade
will continue until we address the issue in a manner
that will disincentivize U.S. citizens from seeking
such unethical care that results in poor outcomes and
exploitation of less fortunate people. Black markets
can only be curtailed by legalization and regulation
of the contraband; in this case, live donor organs.
A compromise must necessarily be established between
the two extremes on the issue of compensation of living
donors. Acknowledging that the National Organ Transplantation
Act was enacted to protect donors from exploitation
and profit of intermediaries, we must allow for a form
of compensation that would exclude intermediary gain.
Alan Greenspan has commented that the most important
determinant of success of a free market is protection
under the rule of law of personal property rights. If
a kidney is considered one’s property and by extension
their health, then in the case of the live organ donor,
a mandate assuring life-long health care benefits would
be one such means of protecting living donors from exploitation
by necessarily excluding the intermediary. Insurance
carriers, both public and private, should be mandated
to provide lifetime health healthcare benefits to living
organ donors. This is palatable because, by definition,
a living donor is healthy and literature suggests that
living kidney donors may live longer lives (of course
these results likely represent a selection bias). Fair
compensation for expenses incurred, including some period
of time off work, may be helpful financial incentives.
Strict law prohibiting intermediaries would need to
be established.
Protection
of living donors must also occur to prevent exploitation[,]
and this can only occur only (sic) through the establishment
of carefully constructed principles for acceptance of
people for live organ donation. It is my recommendation
that an ad hoc committee be tasked with developing the
guidelines that would necessarily be implemented across
all Medicare[-]approved centers of Transplantation.
With
regards to compensation of families of deceased donors,
a modest payment that would address burial costs and
some additional money to incentivize families toward
donation of deceased (next of kin) organs is certainly
warranted.
It
is not unreasonable to expect that such changes may
lead to an increase in 5,000 kidney transplants being
performed each year. At a cost savings of $45,000 per
person per year off dialysis, savings to Medicare would
be nearly 250 million dollars a year. Such cost savings
can be shifted to increase reimbursements to healthcare
providers that deserve such an increase and will improve
the quality of care given to our citizens by these providers.
Demand:
Demand for organs can only be addressed by decreasing
the waiting list. This can best be achieved by mandating
a removal of those deemed to benefit less from kidney
transplantation than hemodialysis, for example. This
may include kidney donors over the age of 70 with cardiovascular
morbidity or MELD score 40 liver failure patients.
Additionally,
the wait list can be decreased 15% by working to extend
years of graft function and this can only be achieved
by understanding the pathophysiology if short[-] and
long[-]term graft failure. Currently, the highest impact
would be achieved by development of less toxic immunosuppression
regimens or curtailing ever[-]present opportunistic
infections. Ad hoc committees on immunosuppression and
infectious diseases should be established to make advice
to ACOT for recommendations to the Secretary.
Improving
Access to Transplantation: We must address the issue
of the 30[-]month time limit on immunosuppression and
anti-infection medication coverage for transplant patients.
The data is (sic) striking that inner[-]city and economically
disadvantaged have less access to Transplantation. This
may be the result of the prohibitive cost incurred after
the 30[-]month window. Remaining on hemodialysis carries
the least financial burden to an economically disadvantaged
person with end[-]stage renal failure as these patients
carry Medicare entitlement for life. The window, therefore,
must be extended to pay for Transplant[-]related medications
for the life of the allograft. Private insurance carriers
must be mandated to follow suit as patients with failed
allografts will end up on the disabled rolls of Medicare.
These
are just a few of the recommendations which I hope the
Committee finds useful. I remain committed to improving
the lives of patients with end[-]stage organ disease
and offer my services to ACOT in any way I can be most
helpful.
Sincerely,
Marc
E. Uknis, MD
Member:
American Society of Transplant Surgeons
The Transplant Society
Fellow of the American College of Surgeons
Medical
Director
ViroPharma Inc.
397 Eagleview Blvd
Exton, PA 19341 |
Dr. Uknis referred to a recent article on outcomes in liver
transplant in the U.S. vs. the United Kingdom and said that
the latter had better long-term outcomes. The reason for this
is that the UK paid for life-long medication for patients
for the life of the allograft. If adopted in the U.S., this
policy would incentivize transplantation.
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:
- Assess
cancer risk in transplant recipients (for common malignancies,
subtypes of cancer, immunosuppressive regimens, and epidemiology
of virus-related cancers);
- Assess
transmission of cancer from donors (prevalence of cancer
among deceased donors, incidence of cancer among living
donors, cancer risk in recipients related to cancer in donors,
by cancer type and time from donation); and
- Assess
the completeness of OPTN’s cancer data.
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.
Discussion
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.
Ms. Agrawal thanked Ms. Lewis for her comments.
The meeting
was adjourned.
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