Live Donor Kidney Transplantation: Updates in Paired Kidney Exchange

1. Live Donor Kidney Transplantation: Updates in Paired Kidney Exchange Miguel Tan, MD, FRCSC Surgical Director, Kidney & Pancreas Transplantation Piedmont Transplant Institute

2. Outline • Current statistics for kidney transplantation in the United States • Living donor outcomes • Paired exchange, impact, logistics and challenges

3. Patients on the waiting list on December 31 of the year (active listings only) Organ supply continues to be a problem in kidney transplantation Almost 100 000 patients on waiting list Average waiting time to transplant 4- 5 years 4% of potential recipients die while waiting on list annually Transplants performed during the year (adult & pediatric combined)

4. Deceased kidney donation rates

5. Organ discard rate for organs recovered for transplantation

6. Possible reasons for lack of growth of supply include • -lack of education on donation options ie. living donation, paired exchange, desensitization • Increasing rate of morbid obesity and diabetes resulting poorer quality of organs

7. Advantages of Live Donor Kidney Transplant • To address the issue of long wait times and organ shortage there has been an effort to increase living donation • Advantages: • If recipient has living donor there is no wait time • Quality of organs and long term outcome are superior • Allows opportunity for desensitization in highly sensitized recipients • eg. plasmapheresis, biologic agents( bortezomib, rituximab)

8. Advantages of Live Donor Kidney Transplant • Death-censored graft failure within 90 days among adult kidney transplant recipients

9. Delayed graft function among adult kidney transplant recipients

10. Incidence of first acute rejection among adult patients receiving a kidney transplant in 2005–2009

11. Long Term Deceased Donor Transplant Outcomes Long Term Living Donor Transplant Outcomes

12. Half-lives for adult kidney transplant recipients

13. Paired Exchange • It is clear that living kidney donation is superior to deceased donor transplant from an outcomes standpoint • A third of intended donor recipient pairs are incompatible • Paired exchange allows transplants to occur for ABO incompatible and highly sensitized patients by ‘swapping’ for an ABO compatible donor or a donor that the recipient is not as highly sensitized • Paired exchange transplants are fastest growing source of transplantable kidneys over the last decade

14. Paired Exchange • Example of simple 2 way paired exchange. • Logistically complex if more than 2 pairs as all cases need to happen simultaneously • Resource intensive • –need multiple OR • -multiple surgeons and OR staff • -coordinating OR between multiple • hospitals in different geographic • regions difficult

15. Domino chain transplantation • Requires an altruistic or non-directed donor (NDD) • Advantages- • cases need to occur in sequence but not necessarily at same time • - easier to manage from a resource standpoint • - chains can last indefinitely with use of a bridge donor • Longest chain on record is 30 transplants - 17 hospitals across 11 states over 4 months (NKR chain 124)

17. Open Chain or Non-simultaneous extended altruistic donor (NEAD) chain

19. History of Paired Exchange • Felix Rapaport first advocated for a “living emotionally related international kidney-donor exchange registry “ in 1986 • First donor exchange program was initiated in Korea in 1991 • Single center • 129 transplants in 11 years Netherlands paired exchange program first to use computer algorithms in 2004 - 7 centers - 128 transplants in 5 years US, Canada, United Kingdom, Netherlands and Korea have multi center paired exchange registries

20. In the United Statesthere are 7 active multicenter paired exchange registries plus many single center programs

21. Exchange programs in the US are fragmented • Ideally, a national program with a single pool would allow maximum exposure of patients to potential donors • Kidney Paired Donation Pilot Program (UNOS-KPD) was started by UNOS in 2010 in order to unify and standardize the process of paired kidney donation

22. How does the paired exchange process work?

23. Optimization Optimization is a branch of applied mathematics • “In the simplest case, an optimization problem consists of maximizing or minimizing a real function by systematically choosing input values from within an allowed set and computing the value of the function. “ • Optimization algorithms are used for airline scheduling, medical school and residency matching, online dating services, artificial intelligence research… • Alvin Roth (Nobel Memorial Prize in Economic Science 2012) • developed the algorithms that are used by a number of paired • exchange registries including Alliance for Paired Donation • In the context of KPD, the main problem is how to optimize for maximum number of transplants or how to transplant the most highly sensitized patients, or some combination of both Photo: U. Montan

24. Optimization Example Schematic of incompatible pairs and reciprocal compatibility shows 2-way paired donation possibilities. Each numbered circle represents a transplant candidate/incompatible donor pair. A connecting line is shown if the donor from each pair can donate to the candidate of the other pair. Optimal matching. The bold lines denote optimal matching of incompatible pairs for 2-way paired donations; for example, pair 1 matches with pair 15. Using an appropriate mathematical algorithm guarantees that the largest number of transplants or best set of transplants using some other criterion will be chosen. For instance, if incompatible pair 1 and incompatible pair 3 were matched for paired donation, neither pair 14 nor pair 15 could undergo transplant

25. Paired exchange logistics • After match run is completed, participating centers review medical histories or donor and recipient as well as crossmatch data • Age matching • CMV status • Willingness of donor to travel • Size match • OR times, surgeons, resources need to be coordinated amongst centers • - can be very tricky in simultaneous paired exchange with multiple pairs • Currently, payment and financial issues need to be coordinated between centers on a case by case basis • For donor convenience and comfort, many donors stay at local center and kidney is shipped • Segev et al (AJT 2011) demonstrated that cold ischemia time less than 14 hours does not adversely affect rate of delayed graft function (3.5% vs 3.6% for nonshipped kidneys)

26. At the end of the day, we need to do what is best for the donor.

27. Potential impact of Paired Exchange • Each year up to 3500 potential living donors cannot donate to intended recipient due to incompatibility • Hopkins study using mathematical simulation based on probability data and the UNOS database (Segev DL et al JAMA 2005, 293: 1883) to predict impact of KPD • In an efficiency national program 4000 pairs but be enrolled with 750 added per year • Rees et al AJT 2012 suggest that an well implemented standardized KPD program could yield an additional 1000 live donor transplants at a cost savings of 250-500 million to the healthcare system • Various models predict 2-10% increase in overall kidney transplant volumes

28. Domino chain donation is particularly interesting (Segev et al AJT 2009;9:1330) • Using montecarlosimulations* comparing altruistic donors donating directly to waitlist vs donating to a domino paired exchange yields 20% more transplants. Open ended chains even more efficient and leads to more sensitized patients receiving transplant.(Ashlagi et al . AJT, 2011(11,)5:984 *Monte Carlo methods are a broad class of computational algorithms that rely on repeated random sampling to obtain numerical results; i.e., by running simulations many times over in order to calculate those same probabilities heuristically just like actually playing and recording your results in a real casino situation: hence the name.

29. JAMA 2005

30. Current Challenges in KPDfrom The 2012 KPD consensus conference

31. Donor Evaluation and Care How Do we ensure health and safety of the living kidney donor?

32. Histocompability recommendations for KPD How do we account for lab-to-lab variation and KPD acceptance criteria between centers ?

33. Geographic Barriers Increasing size of KPD pools results in pairs that are geographically distant How do we balance achieving higher transplant rates with these larger pools while limiting complexity and costs of geographic expansion?

34. Financial Challenges KPD incurs unique financial costs that are challenging to recover under current reimbursement practices

35. Financial Challenges • Currently these issues are negotiated on a center-to-center and case by case basis which is problematic as there is too much variability. • Standardizing payments is desirable as it would allow simpler administration by eliminating individual negotiations, guarantees payment for all involved parties, provides predictability from payer standpoint and allows them to predictably underwrite their transplant risk portfolio • The current solution is to develop a national KPD Standard Acquisition Charge (SAC) • Alliance for Paired Donation has received a grant from AHRQ to develop this model

36. Financial Challenges • In order to be viable the following criteria need to be addressed

37. Financial Challenges Proposed National KPD-SAC would: Aggregate all costs associated with donor evaluation and be paid out by a single administrative center Geographic difference in cost accounted for by multiplying a predetermined CMS approved rate by a factor accounting for cost-of-care differences among hospitals and regions. Aggregated national costs would then be used to derived a KPD SAC charged to recipient centers at the time of transplant. Recalculated annually

38. KPD Implementation Strategies Implementing KPD protocols can be difficult and problems amplified in multicenter exchanges How do we establish and operate a successful KPD program?

39. Summary • Living kidney donation is an important modality to address the stagnant rate of kidney transplantation • Paired exchange allows transplantation of otherwise incompatible or hard to match pairs and an increasingly important source of transplantable kidneys and has the potential to increase overall kidney transplant volumes • A unified national program will maximize exposure to pairs registered in KPD this is in the initial stages with the UNOS pilot program • There is economic value to paired exchange with some estimates suggesting a benefit to the overall healthcare system of 250-500 million annually

40. References • 1. Serur, D and Charlton, M. Kidney Paired Donation 2011. Progress in Transplant 21(3) :215 • 2. Gentry, S Montgomery RA, Segev DL. Kidney Paired Donation: Fundamentals, Limitations, and Expansions. AJKD 2011;57(1): 144 • 3. Gentry SE, Montgomery RA, Swihart BJ, Segev DL. The Roles of Dominos and Nonsimultaneous Chains in Kidney Paired Donation. AJT 2009;9:1330 • 4. Rees MA et al. Call to Develop a Standard Acquisition Charge Model for Kidney Paired Donation. AJT 2012; 12: 1392 • 5.Melcher ML et al. Dynamic Challenges Inhibiting Optimal Adoption of Kidney Paired Donation: Findings of a Consensus Conference. AJT 2013;13:851 • 6. Segev DL, Gentry SE, Warren DS, Reeb B, Montgomery RA. Kidney Paired Donation and Optimizing the Use of Live Donor Organs . JAMA 2005, 293(15):1883