Benjamin Hippen, M.D.

1
University of Alberta Transplant Grand
Rounds Conventional and Controversial Solutions
to the Shortage of Kidneys
Benjamin Hippen, M.D. Metrolina Nephrology
Associates, P.A. and the Carolinas Medical
Center Charlotte, North Carolina
2
Declarations and Disclaimers

• I have received no funding from a pharmaceutical
  company or medical device manufacturer.
• I will not discuss off-label use of any
  medication.
• In the last 5 years, I have received fixed
  remuneration for services rendered from
• The American Enterprise Institute
• The Cato Institute
• Roche Organ Transplant Research Foundation
• I have never been remunerated for any paper
  ultimately published in a peer-reviewed journal.

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• Justice is when people receive what they are due
• David Schmitz

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Learning Objectives

• Understand the magnitude, causes and implications
  of the shortage of transplantable kidneys.
• Become familiar with conventional and
  controversial solutions to the shortage, past and
  present, and the limitations of these solutions.
• Develop an informed basis for speculation on
  future trends in organ procurement policy

5
Today - USA

• 2006 Total federal expenditures on ESRD 22.7
  billion
• 5-year patient survival on dialysis 35
• 2006 Total federal expenditures on kidney
  transplantation 2.2 billion
• 5-year patient survival with a transplant 75
• 2006 Total federal expenditures on ESAs 2
  billion

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Projected Growth in the Waiting List for Deceased
Donor Kidneys, and Projected Growth in Prevalent
Dialysis Patients
(712,000) Comb DT
(591,000) combined DT
(Predicted) ESRD
Actual (Predicted) Wt list
Aug 09 80,384
Sources 2008 OPTN/SRTR Annual Report, Table 5.1.
Predicted values for 2004-2010 based on slope of
the line from 1994-2003, and JASN 122753, JASN
163736. Non-referred projections AJT 8(1)58.
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Inactive The rest of the story

• Delmonico McDiarmid Status 7 is
• (a) Misleading with regard to organ demand
• (b) Accounts for much of the vaunted death on
  the list
• (c ) Imposes undue burdens on transplant centers
• The percentage of patients who died categorized
  as inactive on the kidney waiting list has also
  increased markedly from 31 (1,197) in 2003 to
  52 (2,431) in 2007.
• Total deaths reported as such on Wt list 2007
  4,452

Transplantation 86 (12) 1678-1683
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Inactive The rest of the story(2)

• 2007 - 24,624 inactive candidates (32.8)
• 10,961 (45) inactivated within 30 days of
  listing
• Why should this be so? Data not illuminating
• Candidates with GFR lt 20, not ready for Tx
• Accumulate time while completing evaluation
• Insurance hold
• Uncertainty about available/qualified living
  donors
• Longer median waiting times

Table 2 - Transplantation 86 (12) 1678-1683
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Inactive 12/06 Disposition 4/08

• Total (Inactive 12/06) 20,334
• Still Waiting/Inactive 9,797 (48.2)
• Other Removal 3,330 (16.4)
• Death 2,845 (14.0)
• Still Waiting/Active 2,344 (11.5)
• Deceased Donor Transplant 1,481 (7.3)
• Living Donor Transplant 537 (2.6)

Table 4 - Transplantation 86 (12) 1678-1683
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Reasons for removal (UNOS)

• Total removal from list 2008 26,673
• Deceased donor transplant 39.5
• Living donor transplant 18.5
• Death 17.5
• Other 11.5
• Too sick - 7.2
• Other and Too sick are not counted as Death
• Total removed, not transplanted 9,252

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Inactive The rest of the story(3)

• Insinuation Most patients inactive arent
  (ever) really candidates
• Problem Lack of granularity in data
• Data doesnt describe disposition of specific
  cohorts of patients listed inactive under
  specific conditions.
• Doesnt demonstrate substantial center
  variability in how Status 7 is used.
• Other and Too sick confuses removals for
  death on both active and inactive list

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Projected Growth in the Waiting List for Deceased
Donor Kidneys, and Projected Growth in Prevalent
Dialysis Patients
(712,000) Comb DT
(591,000) combined DT
(Predicted) ESRD
Actual (Predicted) Wt list
Aug 09 80,384
Sources 2008 OPTN/SRTR Annual Report, Table 5.1.
Predicted values for 2004-2010 based on slope of
the line from 1994-2003, and JASN 122753, JASN
163736. Non-referred projections AJT 8(1)58.
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Unintended Consequences

• Waiting time which exceeds median life span
• Older and sicker recipients, including young
  recipients with extended vintage on dialysis
• Increasing emotional pressure on any available
  living donor
• Increased reliance on extended criteria donors
• An upsurge in international organ trafficking
• Erosion of trust in the transplant community.

Hippen, B. JMP 30593
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Alternative solutions

• Prevention
• Presumed consent
• Extended criteria donors
• Controlled donors after cardiac death
• Uncontrolled donors after cardiac death
• Swaps and list-paired donation
• Utility models KPSAM/LYFT/KARS

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Hippen, B. Kidney International (2006) 70,
606607. Preventive measures may not reduce the
demand for kidney transplantation.
NHANES III Data (2007)
CKD 3 gt 15,000,000
CKD 4 1,200,000
CKD 5 390,000
MMWR Weekly, 56(08)161-165
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Presumed consent

• Existing presumed consent laws in Europe havent
  increased organ procurement rates.
• Even 100 conversion wouldnt solve the problem.
• 10,500-13,800 potential BDDs/year.
• Weak vs. Strong versions
• Weak opt-out versions more or less synonymous
  with tenacious solicitation
• Strong versions flirt with conflicts of interest
• Special problem of donation after cardiac death

Healy, K. Depaul Law Rev. 551017 Sheehy, E.
NEJM 349667.
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Healy, K. Depaul Law Rev. 551017.
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Extended criteria donors
of ECDs
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Schold, et.al. AJT 5757
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Reasonable short-term outcomes from controlled DCD
Bernat AJT 6281
Table 5 Summary of adjusted kidney graft
survival results by donor type and delayed graft
function (DGF)
Table 5 Summary of adjusted kidney graft
survival results by donor type and delayed graft
function (DGF)
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But

• Estimated number of controlled donors after
  cardiac death by 2013 (HRSA)
• 2,016

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Uncontrolled DCD The signature solution of the
IOM

• Correctly identifying a candidate in the field
• IOM - 7.6 of all out-of-hospital cardiac arrests
• Transfer to an ER with available personnel and
  capability for cardiopulmonary bypass within
  90-120 minutes of cessation of CPR
• Limited knowledge regarding decedents medical
  history
• Identifying and evaluating recipient in short
  order
• Non-trivial cost of circulatory preservation with
  failed conversion
• (Forthcoming study in AJT Testing the publics
  trust?)
• UCLA study higher primary non-function and DGF
• (2.7 vs. 1.4, 51 vs. 25 Plt0.0001)
• Recent AIM study from Spain w/ better outcomes

Ganadeep AJT1682, Sanchez-Fructuoso AIM 145157
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Other issues with DCD

• Scepticism about veracity of criteria for death
  by whole-brain criteria exacerbated by DCD
• Alan Shewmon, Chronic "brain death"
  meta-analysis and conceptual consequences.
  Neurology 51(6)1538-1545, 1998.
• Heterogeneous practices
• How long to wait? Why?
• IOMs basis for 5 minute wait based on 6 small
  studies of autoresuscitation, from 1915 -
  present.

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Paired and List-paired Exchange
Paired exchange A1 B2 B1 A2 Potential for
many iterations!
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Challenges of Paired Exchange

• Standardization of immunologic evaluation
• Transportation of organs from living donors
• Unbalanced altruism
• Donor age
• Highly-sensitized or less physiologically robust
  recipient
• New pressures on previously unavailable living
  donors
• Too many O-recipients

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List-Paired Exchange
A Waiting list Waiting Time B A1 C
D E F ..
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O
Delmonico, F. AJT 41628
O-list 550 days added over 3 years
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Utility Model Maximize LYFT
Objective Maximize the total number of
life-years saved of candidates on the waiting
list for a deceased donor kidney Survival
Benefit Candidate survival with SCD transplant
minus Candidate survival without a kidney
transplant on the waiting list KARS Combination
of LYFT and Dialysis Years
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Variables in Survival Benefit Model
Center-specific data

• Age
• Time exposed to ESRD
• Albumin
• BMI
• Diagnosis
• HTN
• Polycystic
• Diabetic
• Other
• Previous Transplant
• Peak PRA
• Ethnicity/Race
• Angina

• Peripheral Vascular Disease
• Calendar Year of Listing
• Gender
• NYHA Functional Class
• Primary Insurance Status
• Drug Treated Hypertension
• Type of Dialysis
• DSA (Surrogate for Geography)

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Methodological criticisms of LYFT

• No prospective testing of the model based
  entirely on retrospective data
• Ability to correctly predict waitlist, patient
  and graft survival for individuals is poor
• IOC (index of concordance) 0.5 chance
• Waitlist survival 0.6
• Patient survival 0.68
• Graft survival 0.57
• Zero granularity to diagnostic categories
• Type II diabetes 1 year 35 years

Wolfe RA, et.al. AJT 2008 8 (Part 2) 9971011
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What we thought vs. What we now know
Meier-Kriesche AJT 41289
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Moral Concerns

• Which patients would be disadvantaged by the new
  system?
• Balancing harms and benefits
• Variability in interpersonal comparisons of
  utility
• Competing claims for special dispensation
• Unintended, forseeable consequences

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Moral Concerns (1)

• Who loses ?
• Utility involves benefits and harms
• No assessment of harms to balance claims of
  benefit from LYFT
• If LYFT-gains are a benefit, then surely
  additional time on dialysis and death is a harm.
  How to balance these harms with the purported
  benefits?

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Moral Concerns (2)

• Interpersonal comparisons of utility
• LYFT includes a discount QALY for time on
  dialysis, but otherwise a year a year
• Value of 15th -gt 20th year off dialysis in a
  young recipient gtgt value of 0 -gt 4th year off
  dialysis for an older recipient.
• Dont older recipients have some morally
  compelling claims about additional years at the
  end of their lives?

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Moral Concerns (3)

• Variability in interpersonal comparisons of
  utility is hard to measure
• There is good-faith disagreement about how
  charitably a crude, universal metric such as LYFT
  provides an answer to the question What is
  kidney transplantation for? We will probably
  never agree on a single answer.
• Reference to sound medical judgment, best use
  of resources, etc. is an exercise is
  self-serving circularity.

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Unintended consequences (1)

• Paradoxical effect of KAS on living donation
  trends (the pediatric exception lesson)
• Homogenization of the waiting list
• Raising the importance of previously minor
  variables, which encourages gaming

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The pediatric exception
Groups with higher LYFT scores Less living
donor transplantation Groups with lower LYFT
scores More living donor transplantation
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Unintended consequences (2)

• Homogenization of the waiting list
• The youngest (18-34) cohort on the waiting list
  is small, and the incident rate is low
• Eliminating a significant fraction of the 18-34
  cohort will homogenize the LYFT scores of the
  remaining candidates
• Narrow margins of error become important
• Minor variables ? Major variables
• Gaming KAS at the margins to gain a crucial
  advantage

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• Disparity between demand for and supply of
  transplantable organs
• Unintended consequences of (1)
• Alternative solutions
• The moral defensibility of incentives.

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Autonomy

• as a primary value
• Operational freedom is typically better for
  individuals and societies compared to the
  opposite
• But not always When and where that is the case
  is hotly disputed
• .as a side constraint
• Given the vast moral pluralism of even stable,
  peaceful societies, valuing autonomy as a
  side-constraint on interference by others.

Engelhardt HT. Foundations of Bioethics, 2nd ed.
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Four side-constraints on incentives

• The priority of safety of the donor and
  recipient
• Transparency regarding risks to the donor and
  recipient, and regarding institutional outcomes
  and follow-up care
• Institutional integrity with regard to
  establishing guidelines which broadly reflect the
  conditions under which institutions and
  individuals will participate
• Operation under a rule of law providing
  enforceable redress.

Hippen B. JMP 30593
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Safety Moral and market value

• Moral value of safety
• Non-maleficence
• Market value of safety
• Disincentive to engage in the risks of organ
  trafficking for organ sellers and recipients.
• Organ markets may be safer than donation
• Incentives to avoid short- and long-term harms
• Avoid emotional pressures to use marginal related
  living donors.

Hippen B. JMP 30593
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Transparency

• Criteria for evaluation should apply equally to
  compensated and uncompensated donors.
• Ample potential supply of potential living donors
  offers opportunity for even more stringent
  acceptance criteria
• If donor compensation included a comprehensive
  health benefit ? longitudinal outcomes studies.

Hippen B. JMP 30593
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Institutional integrity

• Moral pluralism Hallmark of a free society.
• Institutions and individuals should not be
  obligated to participate in incentives.
• The solidarity of moral communities
• Some donors will refuse compensation
• Some recipients will refuse to engage with
  compensated donors
• Some MDs, institutions will agree
• Centers of Authentic Altruism
• Free-rider problem indirect beneficiaries of
  markets.

Hippen B. JMP 30593
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Rule of law

• Productive function
• Facilitates agreed-to arrangements between
  individuals and institutions
• Protective function
• Protects contractual and forebearance rights of
  all
• Sample contracts
• Mechanisms for adjudication and mediation
• Standards for tort liability

Hippen B. JMP 30593
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Valuable consideration

• Compensation need not be limited to money
• Lifetime health insurance and drug benefit
• Meaning of exchange not reduced to cash-value
• Contribution to charity, retirement, college ed.
• Proscribed consideration limits fungibility
  HSAs, 401k, 529
• Reimbursement for otherwise noble endeavors
  Firefighters and soldiers still get paid.

Gaston RS. AJT 62548
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Other advantages of incentives for organs

• Reduce economic support for international organ
  trafficking
• Permits altruistic donors to donate free of
  emotional and psychological pressures
• Increase in pre-emptive transplantation
• Fewer complications, shorter hospital stays,
  better outcomes
• The leisure and safety value of time
• More chances for highly-sensitized recipients.

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Per-patient break-even and cost-effectiveness
costs of incentives for organs
134,659
47,290
Matas A. AJT 4216
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Objections to a regulated organ market

• Damage to living and deceased donation
• The lessons of organ trafficking harm to
  sellers
• Chicken or Egg - Shortage leads to economic
  support for organ trafficking.
• Crowding out Richard Titmuss and his
  descendents
• Authentic altruism will not be crowded out, but
  inauthentic altruism might be.
• Corrosive to the virtue of altruism
• Current system is damaging altruism Tyranny of
  the Gift
• Markets can (and should) coexist with donation
• Markets clarify altruism That which can be sold
  can also be donated.

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Objections to a regulated organ market

• Exploitation of the poor
• Excluding the poorest among us for other reasons
• Poverty as a risk for CKD
• Vending/Donating as a right of forebearance
• Organ markets versus organ trafficking
• Commercialization as offensive to human dignity
• Little consensus as to what constitutes human
  dignity
• Even less consensus on whether human dignity
  should represent a supervenient political concept
  (moral pluralism)
• Few proponents draw out these consequences
  entirely
• Well-remunerated athletes, entertainers, runway
  models
• The whole of non-reconstructive cosmetic surgery
• A wide array of commonplace market arrangements.

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If only there were some data out there
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Long term recipient outcomes Graft survival rates
in HLA-identical, one HLA-haplotype match and
living unrelated renal transplant in Hahemi Nehad
Hospital, Tehran from 1986 to 2000
Ghods, A. J. Nephrol. Dial. Transplant. 2002
17222-228
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Trafficking Recipient outcomes
It remains likely, however, that with the severe
organ shortage and ever-increasing waiting times
for an organ, a greater number of patients will
present to Canadian transplant centers in this
manner.
Prasad GVR. Transplantation 821130
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Vendor outcomes

• Mixed, anecdotal data.but very worrisome
• Malakoutian, et.al.
• 91 satisfied with the exchange
• 53 would recommend vending to others
• Zargooshi a different story
• 38 lost job from post-op complications
• 39 severe social ostracism
• 84 difficulty securing employment
• 60 fully expected to be dialysis-dependent

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Trends in Kidney Transplantation in Iran 1967-2005
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Projected Growth in the Waiting List for Deceased
Donor Kidneys, and Projected Growth in Prevalent
Dialysis Patients
(712,000) Comb DT
(591,000) combined DT
(Predicted) ESRD
Actual (Predicted) Wt list
Aug 09 80,384
Sources 2008 OPTN/SRTR Annual Report, Table 5.1.
Predicted values for 2004-2010 based on slope of
the line from 1994-2003, and JASN 122753, JASN
163736. Non-referred projections AJT 8(1)58.
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What if nothing happens?

• Policy
• More pressure to revise allocation policies
• More efforts to revise demand downward
• More pressure to push ethical boundaries with
  donors
• Organ trafficking may evolve into equilibrium
• Centers may improve on recipient outcomes out of
  pure self-interest, even if incentives to improve
  donor outcomes not robust.
• Is this already happening?

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Iran?

• 1967-1985 100-110 transplants
• 1988 Legalization of market in organs from
  living vendors
• 1999 Elimination of the waiting list for
  kidneys in Iran

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How it works

• Recipient counseled that LRD the best option
• If no LRD willing/available
• Waiting list for deceased donor organ
• If not available, or gt 6 months waiting -gt Vendor
• Separation of responsibilities
• Vendor candidates identified by patient-run
  charity initial screening done as well
• Responsibility for evaluation and approval of
  vendor candidacy rests with transplant center

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How it works (2)

• Vendors remunerated in two ways
• Fixed compensation from State 1200 US
• Negotiated compensation from recipient/family
  2300-4600 US
• If recipient impoverished, second payment
  negotiated and paid by patient-run charity
• Vendors receive health coverage for 1 year, only
  for conditions related to organ procurement

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Vendor Demographics

• Caveat Studies of vendors are paltry
• Ghods, et.al. 500 vendors, random
• 90.2 male
• 84 poor, 16 middle class
• 6 illiterate, 24 elementary education
• Zargooshi, et.al. 301 vendors
• 71 male 27 unemployed 18 confined to home
  duties 35 illiterate 25 elementary education

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Long-term vendor outcomes

• ?