Living Donor Kidney Transplantation: Opportunities and Challenges

1
Living Donor Kidney Transplantation
Opportunities and Challenges

• Robert Montgomery, MD
• Associate Professor of Surgery
• Director of the Incompatible Kidney Transplant
  Program
• Chief of the Division of Transplantation
• Director of the Comprehensive Transplant Center
• John Hopkins University and Hospital

2
Renal Transplantation in the United States,
1990-2003
Candidates on waiting list, deaths on waiting
list, and transplants by donor type
60,000
50,000
40,000
Number of patients
30,000
20,000
10,000
0
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
Year
Based on OPTN data as of October 8, 2004.
www.optn.org
3
Cadaveric vs. Live Donor

• Shorter waiting period and hospitalization
• Preemptive transplant
• Optimize medical status of recipient
• Better HLA matching
• Shorter cold ischemic times
• No brain death injury to organ
• Lower incidence of DGF and rejection
• Superior graft and patient survival

4
Time on Dialysis Strongest Modifiable Risk
Factor for Renal Transplant Outcome
Meier-Kriesche H, Kaplan B. Transplantation
74,13772002
5
Timeline for Expansion of Live Donation

• 1954 Identical Twins
• 1962 Living Related
• 1990 Living Unrelated/Emotionally Related
• 1995 Laparoscopic Donor Nephrectomy
• 1998 Positive Crossmatch/ABO Incompatible
• 1999 Nondirected Donation
• 2000 Kidney Paired Donation

6
Changes in Types of Kidney Donors
7
Risks of Living Kidney Donation

• Mortality 1/3000
• Major complications 1/500
• Chronic kidney disease 1/500
• Increase in BP approx 5mm/hg

.In view of the available evidence,
living donor kidney transplantation is reasonably
safe, reliable, and effective.
Nguyen et al. Lancet 200736987.
8
Living Kidney Donors Listed For Renal
Transplantation

• 56 previous donors listed at UNOS
• Over a total of 35 years (20 since 1987)
• Out of 48,000 since 1987 (0.04)
• 86 siblings

9
Psychosocial Health of Living Kidney Donors

• 5,139 donors in 51 studies 4 years post-op
• Anxiety and depression uncommon (5-20)
• Stable or improved relationships (82-100)
• Increased self esteem
• No change in attractiveness (83-93)
• Most scored high on QoL measures
• Most report improved psychosocial health

Clemens et al. Am J Transplant 200662965.
10
The Laproscopic Donor Nephrectomy
12 mm
12 mm
5 cm
5 mm
11
Laparoscopic Live Donor Nephrectomy Goals

• Reduce disincentives to donation
• Decreased length of stay
• Shorter convalescence
• Less invasive operation
• Less pain
• Less morbidity
• Favorable cosmetic result

12
Trends in Complications Hopkins Experience

13
Donor Nephrectomy in the U.S. 1999-2001
Matas et al. Am J Transplantation, 2003
14
Barriers to Expansion of LDRT

• 30 of DD list is sensitized
• Patients become sensitized from exposure to
  disparate HLA due to pregnancies, transfusions,
  or transplants
• About 7000 patients on DD list are highly
  sensitized (PRA gt 80)
• Highly sensitized patients on average wait twice
  as long as unsensitized patients for a DD organ
• Very broadly sensitized patients may not ever
  receive an organ offer
• Several thousand of these patient have willing
  living donors who are excluded due to a () XM

15
Barriers to Expansion of LDRT

• Based on blood group frequencies in the USA,
  there is a 35 chance that any 2 individuals will
  be ABO incompatible
• Up to 1/3 of potential live donors are excluded
  on the basis of ABO incompatibility
• This translates into lost opportunities for many
  patients with willing donors
• Blood type incompatible recipients have natural
  occurring antibodies against carbohydrate
  epitopes on disparate blood group molecules which
  can result in hyperacute rejection

16
Patients with Incompatible Donors

• Confront the incompatibility directly
• Desensitization Plasmapheresis/IVIg
• Montgomery et al. Transplantation 2000
  70(6)887.
• Gloor et al. Am J Transplant 2003 31017.
• Avoid the incompatibility
• Kidney or domino paired donation (KPD or DPD)
• Montgomery et al. JAMA 2005 2941655.
• Montgomery et al. Lancet 2006 368 419.
• Lessen the incompatibility
• KPD or DPD followed by desensitization
• Montgomery et al. JAMA 2005 2941655.

17
Assessing Risk and Difficulty of a () XM Tx

• Factors Determining Degree of Difficulty of Ab
  Removal
• DSA Titer of plasmapheresis treatments to
  arrive at a safe level for transplantation
• Factors Contributing to Immunologic Risk
• Breadth of anti-HLA Ab--estimated by (PRA)
• of previous transplants
• Previous early graft losses
• of repeat mismatches
• Multiple sensitizing events--Ab response to each
• High risk donor/recipient combination
• IVIg nonresponder
• High titer DSA

18
Assessing Difficulty and Risk of ABOi Transplant
Between a Donor and Recipient

• Factors determining degree of difficulty
• Isohemagglutinin Titer of plasmapheresis
  treatments to get to a titer of 16
• Factors contributing to immunologic risk
• Donor blood type (risk for A1 gt B gt A2)
• High Isoagglutinin titer
• History of sensitization, previous transplant,
  high risk donor/recipient pair

19
Matching Donor/Recipient Pair to Transplant
Modality

• Easy-to-match pair
• O donor
• A/B, B/A
• Low PRA
• Difficult-to-desensitize
• A1 donor
• High titer DSA
• High immunologic risk

• Difficult-to-match pair
• AB donor
• A/O
• Broad Sensitization
• Easy-to-desensitize
• B or A2 donor
• Low titer DSA
• Low immunologic risk

20
Matching Donor/Recipient Pair to Transplant
Modality

• KPD/DPD followed by desensitization
• Difficult-to-match pair
• AB donor
• A/O
• Broad Sensitization
• Difficult-to-desensitize
• High immunologic risk
• A1 donor
• High titer DSA

21
Kidney Paired Donation

• The goal of pairing is to eliminate the
  incompatibility for all parties in the exchange
• Conventional PD involves exchanges between A/B
  and B/A pairs. This is the rarest blood type
  combination and only effects 3 of patients
• The concept of the unconventional KPD greatly
  expands the value of matching through the
  participation of blood type O patients
• Likelihood of finding a match pair is substrate
  dependent the larger the pool, the more likely
  the match

22
Kidney Paired Donation
Conventional- only ABO I pairs A/B or B/A (lt3 of
donor/recipient pairs eligible)
Donor
Recipient
A
B
B
A
23
Kidney Paired Donation
Unconventional (all ABOI and XM
donor/recipient pairs eligible)
Donor
Recipient
O
24
Desensitization afterKidney Paired Donation

• In cases where patients are difficult-to-match
  (broadly sensitized or undesirable blood types)
  and not thought to be good candidates for
  desensitization, relaxing restrictions for a (-)
  XM and ABOc can generate matches that are a lower
  immunologic risk
• The goal is not to find a blood type compatible
  or (-) XM pairing but rather to find a better
  donor

25
Triple Exchange With () XM Only
Donor
Recipient
O
Pair 1
A
XM gt1024
XM titer 4
O
Pair 2
O
XM gt1024
-XM
XM gt1024
-XM
Pair 3
O
O
26
Domino Paired Donation
Donor 1 NDD
Incompatible
Donor 2
Recipient 1
Recipient 2
1st eligible recipient From UNOS match run
Montgomery et al. Lancet. 2006368419.
27
DPD After Desensitization
Donor
Recipient
ND Donor
AB
- cyto XM, Anti-AB titer 64
XM, PRA
O
Pair 1
O
A
O
Pair 2
ABOi
ABOc
-cyto XM
Wait List
A
PRA
28
Hopkins Single Center Experience

• 145 patients transplanted through KPD in the US
  (UNOS 1/12/07)
• 43 patients transplanted
• Conventional 6 x 2-way
• Unconventional 5 x 2-way, 2 x 3-way
• Domino 2 x 2-way, 2 x 3-way, 1 x 5-way
• 1 graft loss
• 2 deaths with functioning grafts
• 1 heart and 1 pulmonary failure

Montgomery et al. JAMA 2005.
29
Desensitization for () XM
Anti-CD20 Splenectomy
FK 506 MMF
Steroids Daclizumab
Anti-CD20
Tx
PP/Ig
PP/Ig
PP/Ig
PP/Ig
PP/Ig
PP/Ig
PP/Ig
PP/Ig
0
1
2
3
4
5
6
-1
-2
-3
-4
-5
-6
-7
-8
-9
-10
-40
Time in days
30
Johns Hopkins ABOi Transplantation Protocol
Overview
Anti-CD20 And/or Splenectomy
FK 506 MMF
Steroids Daclizumab
Tx
PP/Ig
PP/Ig
PP/Ig
PP/Ig
PP/Ig
PP/Ig
PP/Ig
PP/Ig
PP/Ig
0
1
2
3
4
5
6
-1
-2
-3
-4
-5
-6
-7
-8
-9
-10
8
7
Time in days
lt116
116
1128
31
Goals of Preconditioning for Incompatible Kidney
Engraftment

• Pre-transplant plasmapheresis (PP) and IVIg
• PP reduces DSA titer to a level in which
  hyperacute
• rejection is unlikely to occur.
• Low dose IVIg suppresses endogenous Ab synthesis
  and may have some immunomodulatory activity.
• Post-transplant PP and IVIg
• PP prevents rebound, maintaining DSA at a safe
  level until tolerance or accommodation occurs.
• IVIg repletes antibody lost from PP and may have
  some role in tolerance/accommodation

32
Goals of Preconditioning for Incompatible Kidney
Engraftment

• B-cell ablative therapy
• Splenectomy reduces plasma cell burden, precursor
  cells, B-cell immune surveillance capabilities
• Anti-CD20 rapidly depletes the peripheral B-cell
  compartment but not plasma cells
• Induction
• Agents like ATG and anti-IL-2 receptor Ab reduce
  T-cell responsiveness and T-cell help
• Maintenance immunosuppression
• Fk 506, Rapamycin, MMF/DSG, and steroids, reduce
  the risk of cellular rejection and some have
  anti-B-cell properties

33
The Effect of Anti-CD20 on B-cell Expression in
Spleen
CD20
CD20
Normal Spleen
1 Week After Anti-CD20
34
Death-censored Graft Survival 1yr 3yr 5yr
n ABOi 97.7 94.3 87.1 50 XM 85.6 84.1 81.1 13
8 XM/ABOi 100 100 - 10
35
New Registrants 3584/yr
ABOi and XM () 6000
Matched 47 or 2820
Unmatched 53 or 3180
Tx
List Donation 3180
Desensitization 2940
KPD for Better Match
Tx
Tx 4 or 240
Montgomery et al. Transplantation. 200682164.
Segev et al. Am J Transplant. 2005 51914.
36
Transplantation TourismThe Canadian Experience
11 of 20 patients had serious post-transplant
opportunistic infection
Ramesh P et al Transplantation 2006821130.
37
An Australian Perspective

• Outcome of commercial kidney transplantation 16
  patients
• 2 HBVdeath
• 3 serious CMV
• 1 aspergillus death
• Poor patient and graft survival
• High incidence of infection in literature review

Kennedy et al. MJA 2005182224..
38
A Call for Action

• Why we should develop a regulated system of organ
  sales
• Payment by government or insurance
• Fixed sum (50,000?)/insurance/tax breaks
• Allocation per UNOS algorithm
• Evaluation/consent/oversight/follow-up
• Limit to fixed geographic areas
• Treat donor with dignity

Matas A. CJASN 200611129
39
Iranian Model

• Paid and regulated living-unrelated kidney
  donation
• Approx 20,000 performed
• Kidney waiting list eliminated
• Award (1200)/Insurance/Gift
• No brokers
• 84 of donors are poor
• Long term dissatisfaction of some donors

Ghods A. CJASN 200611136
40
Summary and Conclusions

• The deceased donor list continues to grow at an
  alarming pace
• Live donation is the area where expansion is most
  likely to occur
• Live kidney donation is safe and can be done
  using minimally invasive techniques, reducing the
  disincentives to donation
• HLA and ABO incompatibilities are the most
  significant barriers to further expansion of live
  donation

41
Summary and Conclusions

• KPD and DPD are the most effective method of
  managing patients with incompatible live donors
  and could eliminate the need for desensitization
  in over 50 of patients
• Excellent results can be achieved through
  desensitization of () XM and ABOi patients
• Organ vending is receiving a lot of attention in
  the lay press as well as the transplant community
  as a possible solution to the crisis