Kidney Paired Donation

Kidney Paired Donation (KPD) or Paired Exchange, is an approach to living donor kidney transplantation where patients with incompatible donors swap kidneys to receive a compatible kidney. KPD is used in situations where a potential donor is incompatible. Because better donor HLA and age matching are correlated with lower lifetime mortality[1] and longer lasting kidney transplants,[2] many compatible pairs are also participating in swaps to find better matched kidneys. In the United States, the National Kidney Registry organizes the majority of U.S. KPD transplants,[3][4][5] including the largest swaps. The first large swap was a 60 participant chain in 2012 that appeared on the front page of the New York Times[6] and the second, even larger swap, included 70 participants and was completed in 2014.[7] Other KPD programs in the U.S. include the UNOS program which was launched in 2010[8] and completed it's 100th KPD transplant in 2014[9] and the Alliance for Paired Donation.[10]

Problem

More than one-third of potential living kidney donors who want to donate their kidney to a friend or family member cannot donate due to blood type or antibody incompatibility.[11] Historically, these donors would be turned away and the patient would lose the opportunity to receive a life-saving transplant. KPD overcomes donor-recipient incompatibility by swapping kidneys between multiple donor-recipient pairs. KPD is also being used to find better donor-recipient matches for compatible pairs who want a lower lifetime mortality[1][12] and longer lasting transplant.[2]

History

Year Event
1986 KPD first suggested by Rapaport[13]
1991 First KPD program started in South Korea by Dr. Park[8]
1999 First European KPD transplants performed in Switzerland[8]
2000 First KPD transplants performed in USA at the Rhode Island Hospital[8]
2001 Hopkins completes KPD transplants and begins first KPD program in USA[14]
2004 Dutch established first national KPD program[8]
2007 NEAD chain started by APD utilizing first bridge donor[15]
2007 Charlie Norwood Living Organ Donation Act clarifies legality of KPD in USA [16]
2008 National Kidney Registry organizes its first transplants on Valentine's Day[17]
2009 Hopkins leads first 16 patient multicenter Domino Chain [18][19]
2010 UNOS organizes its first KPD transplants[8]
2012 National Kidney Registry completes largest chain involving 60 participants[6]
2014 National Kidney Registry sets new record with 70 participant chain[7]

Early Days

The first paper outlining the concept of paired exchange was authored by Rappaport and published in 1986.[13] The first recorded paired exchange transplants were organized in South Korea by Dr. Park beginning in 1991.[8] For nearly a decade, only Dr. Park and his team in South Korea utilized this novel approach to facilitate transplants for incompatible donor - recipient pairs. In 1999, the first KPD transplants were performed in Europe[8] followed by the first KPD transplants in the United States in 2000.[8] Over the next ten years the United States would become the most competitive KPD market in the world with more than a dozen KPD programs commencing operations and many KPD programs failing. Outside of the United States, most of the KPD programs have been organized or sponsored by governments which has limited innovation in these programs. Three of the important early KPD programs in the U.S. were the Hopkins program led by Dr. Montgomery and Dr. Segev,[20] the New England Paired Kidney Exchange (NEPKE) led by Dr. Delmonico and Professor Alvin Roth[21] and the Ohio Organ Consortium which later reorganized as two competing programs, the Paired Donation Network (PDN) led by Dr. Woodle[22] and the Alliance for Paired Exchange (APD) led by Dr. Rees.[23]

The Hopkins program, which was based out of the Johns Hopkins Hospital, led the industry in early innovations including the critical "Domino Chain" breakthrough which allowed Good Samaritan donors to start chains,[24] dramatically increasing the number of pairs that could be matched in a swap compared to the loop approach that was used previously. Once the Hopkins team began organizing Domino Chains, these swaps became larger and began attracting national media attention due to the massive complexity and significant impact of these large swaps. Unlike the Hopkins program that was hospital based, NEPKE was launched within the New England Organ Procurement Organization which served several states in the North East. The PDN and APD organizations were founded by transplant surgeons but attempted to create networks of transplant centers that would work together to pool their incompatible pairs, much like NEPKE but without OPO support.

In 2006, the APD conceived of a critically important innovation called "NEAD Chains" that amplified the matching power of Domino Chains by allowing Bridge Donors to extend chains. Prior to the utilization of Bridge Donors, a chain of transplant surgeries would be completed in one day, which limited the number of transplants that could be performed. A bridge Donor is someone whose paired recipient has received a kidney but does not donate for some period of time (generally 1 week to 3 months). Just like Domino Chains increased KPD transplants, the utilization of bridge donors also dramatically increased KPD transplants because chains could now be organized over several months and avoid the logistical limitations of performing all surgeries on one day. In 2007, the APD completed the first NEAD chain.[15] That same year, the U.S. Congress passed the Charlie Norwood Act[16] which clarified that paired exchange was legal. Prior to the passage of this law, many in the U.S. transplant community feared that KPD was unlawful due to the prohibition of "valuable consideration" as articulated in the NOTA laws that govern the U.S. transplant industry.[25] With the passage of the Charlie Norwood Act, many more KPD programs were launched in the USA including the UNOS KPD program which was government sponsored[26] with funding from deceased donor registration fees and charitable contributions.

Break Out Phase

In 2007 Garet & Jan Hil founded the National Kidney Registry (NKR) after their daughter (age 10) lost her kidney function and needed a transplant. Both parents were incompatible and could not donate to their daughter, who later, after an extensive donor search, received a living donor kidney from her compatible cousin. Mr. Hil was the first non-physician to start/lead a KPD program and the first KPD leader to donate one of his kidneys, starting a chain that facilitated 8 transplants. In 2008 the National Kidney Registry completed its first KPD transplants and implemented the next major innovation, the shipment of kidneys on commercial airlines. This breakthrough in logistics further expanded KPD. The first living donor kidney that was shipped on a commercial airline went from New York to Los Angeles[27] and started NKR's second chain which facilitated eight transplants utilizing several bridge donors. Initially NKR provided donors with the option of traveling to the matched recipient's hospital or donating locally and having their kidney shipped. Recipients could also choose if they would accept a shipped kidney or require the donor to travel to their center to donate. Over a two-year period, these preferences shifted until nearly all recipients would accept shipped kidneys with very few donors willing to travel. By 2010 the option to have a donor travel was phased out and all kidneys that needed to be moved between centers were shipped. After several near misses and with the UNOS reporting that 1% - 2% of deceased donor kidney lost or mis-routed, the NKR developed the first GPS tracking systems for human organs to monitor the location of all NKR kidney shipments.[28] The utilization of GPS tracking devices is now mandatory for all NKR shipped kidneys.

In 2009 several more key innovations were yielding results at a single center KPD program, the Methodist Transplant Institute, in San Antonio led by Dr. Adam Bingaman. Prior to Dr. Bingaman's work, KPD was built on the notion that the results of a cross match test to determine donor-recipient compatibility are generally predictable and to ensure the prediction is accurate, a cross match test must be completed prior to the swap. In 5% - 10% of the cases, these cross match tests result in an unexpected positive cross match (bad) which causes a swap to fail. These swap failures are costly in terms of wasted time and testing but they are also demoralizing for the patients and donors involved in the cancelled swap. The Methodist program implemented the first donor blood cryo-preservation allowing the rapid cross matching of pairs in a swap without requiring fresh blood from donors. This approach accelerates the matching process, reduces swap failure rates and provides the ability to speculatively cross match potential donors for highly sensitized patients, leading to shorter wait times and more transplants for highly sensitized patients. Although the merits of using cryo-preserved donor blood for cross matching were clear, it proved difficult for multi-center KPD programs to implement cryo-preservation due to the complexity of the multi-center environment. The only U.S. multi-center KPD program that successfully implemented cryo-preservation was the National Kidney Registry[29] but only after establishing a central lab and investing three years in software development. The second important innovation implemented in San Antonio was the re-engineering of the donor/patient intake process to educate and enroll compatible pairs in KPD so that the compatible recipient can get a better matched donor kidney. The development of cryo-preservation based cross matching and the systematic enrollment of compatible pairs has helped make San Antonio one of the leading KPD centers in the U.S.

By 2010 the UNOS KPD program had completed its first swap[30] and the NEPKE and PDN programs folded due to funding issues and increased regulatory requirements imposed on U.S. KPD programs by CMS and UNOS. During this time, the NKR developed the first donor preselect system that allowed donors to be accepted or declined before a match was offered. This innovation was taken from the brokerage industry, essentially porting the limit order concept to KPD. The preselect concept eliminated the need to use supercomputers for match runs because the number of valid one-ways was dramatically reduced. The donor preselect concept developed by the NKR was quickly copied by other major KPD programs and changed the nature of the mathematics needed to support KPD by dramatically reducing the number of one-way match possibilities.

In 2012 the National Kidney registry organized the largest swap in history which included 60 surgeries, completed over five months.[6] That same year the NKR initiated the Advanced Donation Program (ADP) which inverted the role of the bridge donor - now donors were donating in advance of their paired recipient transplants[31] which further alleviated scheduling challenges for paired donors. In 2014, the National Kidney Registry set a new record by organizing a swap that included 70 surgeries completing over two months.[7] That same year, the NKR completed its first long term Advanced Donation whereby a donor donated on behalf of his grandson who may develop kidney failure 10 – 20 years in the future.[32] Mr. Hil, the founder of the NKR, was the second donor to donate his kidney through this program. In 2015, the National Kidney Registry completed 360 KPD transplants which accounted for 62% of all U.S. KPD transplants and more than the combined volume of all other KPD programs in world.

KPD Outcomes

Concerns regarding the negative impact that Cold Ischemic Time (CIT) may have on graft survival, due to the shipment of the kidneys, initially caused concern in the transplant industry and slowed the adoption of KPD. This concern regarding CIT originated from deceased donor transplant experiences where greater CIT is correlated with lower graft survival rates.[33] Prior to KPD, there was no reason to ship living donor kidneys and therefor, there was no understanding of the impact of CIT on outcomes. This concern proved to be unfounded as more living donor kidneys were shipped and the research demonstrated that CIT had no negative impact on KPD outcomes.[34][35]

After completing over 1,000 KPD transplants, it was discovered that NKR's graft survival rates were actually better than the graft survival rates of the typical U.S. non-KPD living donor transplants.[36] Researchers are working to better understand why NKR KPD transplants have superior outcomes and believe it may be driven by better HLA and donor age matching and/or better avoidance of recipient antibodies. Researchers have determined that the improved outcomes from NKR are not driven by a center effect although most of the top U.S. transplant centers participate in KPD via NKR. The improved outcomes from KPD transplants are opening the door for more compatible pair participation in KPD, allowing patient with compatible living donor to essentially trade-up and get a better matched kidney. The increasing enrollment of compatible pairs in KPD is shortening the wait times for incompatible pairs with hard to match blood type combinations (e.g. "O" patients with "A" donors) and driving more matches for highly sensitized patients (e.g. cPRAs > 90%).

Researchers have also discovered that better HLA matching not only leads to longer lasting transplants,[2] but is also correlated with lower patient mortality rates[1][12][37] because better matched kidneys require less immunosuppression and less immunosuppression reduces nephrotoxicity and other negative side effects from post-transplant anti-rejection medications. Equally important, better HLA matching reduces the number of antibodies that a transplant recipient will create making it easier to get a second, third or fourth transplant.[38] This issue is critical for young transplant recipients who have a life expectancy that is longer than the expected graft survival (i.e. how long a transplanted kidney lasts). Deceased donor kidneys typically last 5 – 15 years[39] and living donor kidneys typically last 10 – 30 years.[39]

Compatible Pairs

When KPD first started, the focus was only on enrolling incompatible donor-recipient pairs. As paired exchange grew and the process became faster and more reliable, patients with compatible donors that wanted a better match, began enrolling in KPD. Researchers have identified that a better matched kidney is correlated with better outcomes. Specifically a better matched kidney lasts longer[2] and may allow for a lower dosage of post-transplant immunosuppressive medications.[2] Also a better matched kidney transplant is correlated with a lower lifetime mortality rate.[1][12][37]

For compatible pairs, not only does a better match lead to a better outcome, but it also directly helps other patients with incompatible donors find a match and get transplanted. A favorable blood type compatible pair (i.e. O donor with non-O recipient) will facilitate at least 1 and as many as 6 additional transplants.[36] Compatible pair participation is the fastest growing segment of KPD[36] and holds the promise of facilitating better matches for patients with compatible donors while limiting KPD wait times to less than 12 months for patients that have a cPRA less than 98%.

Further reading

The following academic publications highlight the most significant innovations and results in the field of KPD.[40]

  1. ABO-Incompatible Kidney Transplants: Twice as Expensive, Half as Good
  2. The Incorporation of an Advanced Donation Program into Kidney Paired Exchange
  3. Equipoise: Ethical, Scientific, and Clinical Trial Design Considerations for Compatible Pair Participation in Kidney Exchange Programs
  4. Optimizing HLA matching in a highly sensitized pediatric patient using ABO-incompatible and paired exchange kidney transplantation
  5. Demographic and Clinical Characteristics of 207 Non-Directed Donors Participating in Paired Exchange through the National Kidney Registry
  6. Outcomes of shipped live donor kidney transplants compared with traditional living donor kidney transplants
  7. A Systematic Review of Kidney Paired Donation: Applying Lessons From Historic and Contemporary Case Studies to Improve the US Model
  8. Center-Defined Unacceptable HLA Antigens Facilitate Transplants for Sensitized Patients in a Multi-Center Kidney Exchange Program
  9. Kidney Transplant Chains Amplify Benefit of Nondirected Donors
  10. Chain Transplantation: Initial Experience of a Large Multicenter Program
  11. The National Kidney Registry: 175 Transplants in One Year
  12. Living donor kidney paired donation transplantation: experience as a founding member center of the National Kidney Registry
  13. Boosting Renal Transplantation with Kidney Paired Donation
  14. Kidney Paired Donation: Something Special
  15. Managing Finances of Shipping Living Donor Kidneys
  16. National Kidney Registry: 213 Transplants in Three Years
  17. The National Kidney Registry: Transplant Chains - Beyond Paired Kidney Donation
  18. Asynchronous, Out-of-Sequence, Transcontinental Chain Kidney Transplantation: A Novel Concept
  19. Does flow cytometry crossmatch predict renal allograft outcome in patients with a negative antiglobulin crossmatch?

References

  1. 1 2 3 4 2007, Taoti Enterprises International | Web Design and Marketing | www.taoti.com - August. "Compatible Pairs - National Kidney Registry - Facilitating Living Donor Transplants". kidneyregistry.org. Retrieved 2016-08-26.
  2. 1 2 3 4 5 Milner; Melcher; Lee; Veale; Ronin; D'Alessandro; Hil; Fry; Shannon (2016-07-15). "HLA Matching Trumps Donor Age: Donor-Recipient Pairing Characteristics that Impact Long-Term Success In Living Donor Kidney Transplantation in the Era of Paired Kidney Exchange". Transplantation Direct. Transplantation Direct.
  3. ↑ Kidney Transplant Activity from Living Donors in 2010 (Absolute Numbers, 81 Countries) (Report). Global Observatory on Donation and Transplantation. Retrieved 1 Jun 2016.
  4. ↑ Transplant:Donor Relation by Transplant Center (Report). Organ Procurement and Transplantation Network. Retrieved 6 Apr 2016.
  5. ↑ Paired Exchange Results Quarterly Report (Report). National Kidney Registry. 2015.
  6. 1 2 3 Sack, Kevin (18 Feb 2012). "60 Lives, 30 Kidneys, All Linked". New York Times.
  7. 1 2 3 Pitts; Louszko; Cappetta; Effron; Valiente (15 Apr 2015). "Changing Lives Through Donating Kidneys to Strangers". ABC News Nightline.
  8. 1 2 3 4 5 6 7 8 9 Ellison, Blake (2014-05-16). "A Systematic Review of Kidney Paired Donation: Applying Lessons From Historic and Contemporary Case Studies to Improve the US Model". Wharton Research Scholars Journal. 107. Retrieved 2016-08-23.
  9. ↑ "100th living donor kidney transplant arranged through OPTN/UNOS KPDPP | UNOS". www.unos.org. Retrieved 2016-09-12.
  10. ↑ "About Alliance for Paired Kidney Donation : Matching Donors". paireddonation.org. Retrieved 2016-09-12.
  11. ↑ Segev; Gentry; Warren; Reeb; Montgomery (20 Apr 2005). "Kidney Paired Donation and Optimizing the Use of Live Donor Organs" (PDF). JAMA. Original Contribution. 293 (15): 1883–1890.
  12. 1 2 3 Opelz, G.; Döhler, B. (2012-11-01). "Association of HLA mismatch with death with a functioning graft after kidney transplantation: a collaborative transplant study report". American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 12 (11): 3031–3038. doi:10.1111/j.1600-6143.2012.04226.x. ISSN 1600-6143. PMID 22900931.
  13. 1 2 Wallis; Samy; Roth; Rees (31 Mar 2011). "Kidney paired donation" (PDF). Nephrol Dial Transplant (2011): 2091–2099.
  14. ↑ "Johns Hopkins Gazette | November 27, 2006". pages.jh.edu. Retrieved 2016-08-26.
  15. 1 2 Rees, Michael A.; Kopke, Jonathan E.; Pelletier, Ronald P.; Segev, Dorry L.; Rutter, Matthew E.; Fabrega, Alfredo J.; Rogers, Jeffrey; Pankewycz, Oleh G.; Hiller, Janet (2009-03-12). "A Nonsimultaneous, Extended, Altruistic-Donor Chain". New England Journal of Medicine. 360 (11): 1096–1101. doi:10.1056/NEJMoa0803645. ISSN 0028-4793. PMID 19279341.
  16. 1 2 "H.R. 710 (110^th): Charlie W. Norwood Living Organ Donation Act". govtrack. 21 Dec 2007.
  17. ↑ "National Kidney Registry". 2008-02-20. Retrieved 2016-08-26.
  18. ↑ "Johns Hopkins Leads First 16-Patient, Multicenter "Domino Donor" Kidney Transplant". Johns Hopkins Medicine. 7 Jul 2009.
  19. ↑ "16 patients, 8 'new' kidneys, 4 hospitals: Johns Hopkins surgeons lead largest-ever 'domino donor' kidney transplant". The JHU Gazette. 20 Jul 2009.
  20. ↑ "Hopkins Medicine Magazine - Circling the Dome". www.hopkinsmedicine.org. Retrieved 2016-08-26.
  21. ↑ "Alvin Roth". 2008-09-01. Retrieved 2016-08-26.
  22. ↑ "Steve Woodle, MD". www.cecentral.com. Retrieved 2016-08-26.
  23. ↑ "About Alliance for Paired Kidney Donation : Matching Donors". paireddonation.org. Retrieved 2016-08-26.
  24. ↑ "Hopkins Performs Historic "Six-Way Domino" Kidney Transplant - 04/08/2008". Retrieved 2016-08-25.
  25. ↑ "National Organ Transplant Act" (PDF). 1984-10-19. Retrieved 2016-08-23.
  26. ↑ "United Network for Organ Sharing" (PDF). Retrieved 2016-08-25.
  27. ↑ "First NY–to–LA living-donor transplant chain results in triple kidney transplant". www.uclahealth.org. Retrieved 2016-08-25.
  28. ↑ "NKR Introduces GPS Tracking Technology". National Kidney Registry. Retrieved 2016-08-23.
  29. ↑ "National Kidney Registry Initiates Donor Blood Cryo-Preservation". National Kidney Registry. 2014-12-02.
  30. ↑ "United Network for Organ Sharing" (PDF). Retrieved 2016-08-26.
  31. ↑ Flechner, S. M.; Leeser, D.; Pelletier, R.; Morgievich, M.; Miller, K.; Thompson, L.; McGuire, S.; Sinacore, J.; Hil, G. (2015-10-01). "The Incorporation of an Advanced Donation Program Into Kidney Paired Exchange: Initial Experience of the National Kidney Registry". American Journal of Transplantation. 15 (10): 2712–2717. doi:10.1111/ajt.13339. ISSN 1600-6143.
  32. ↑ Rivero, Enrique. "'Gift certificate' enables kidney donation when convenient and transplant when needed". UCLA Newsroom. Retrieved 2016-08-25.
  33. ↑ Debout, Foucher, Trebern-Launay, Legendre, Kreis, Mourad, Garrigue, Morelon, Buron, Rostaing, Kamar, Kessler, Ladrie, Poignas, Blidi, Soulillou, Giral, Dantan (2014-09-17). "Each additional hour of cold ischemia time significantly increases the risk of graft failure and mortality following renal transplantation". Kidney International. Retrieved 2016-08-23.
  34. ↑ Butt, F. K.; Gritsch, H. A.; Schulam, P.; Danovitch, G. M.; Wilkinson, A.; Del Pizzo, J.; Kapur, S.; Serur, D.; Katznelson, S. (2009-09-01). "Asynchronous, out-of-sequence, transcontinental chain kidney transplantation: a novel concept". American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 9 (9): 2180–2185. doi:10.1111/j.1600-6143.2009.02730.x. ISSN 1600-6143. PMID 19563335.
  35. ↑ Treat, Miller, Kwan, Connon, Maliski, Hicks, Williams, Whitted, Gritsch, McGuire, Mone, Veale (2014-09-22). "Outcomes of shipped live donor kidney transplants compared with traditional living donor kidney transplants". Transplant International. PMID 25052215.
  36. 1 2 3 "National Kidney Registry". Retrieved 2016-08-23.
  37. 1 2 Cecka, J Michael (2007-04-01). "Does flow cytometry crossmatch predict renal allograft outcome in patients with a negative antiglobulin crossmatch?". Nature Clinical Practice Nephrology. 3 (3): 136–137. doi:10.1038/ncpneph0405. ISSN 1745-8331.
  38. ↑ Meier-Kriesche, Herwig-Ulf; Scornik, Juan C.; Susskind, Brian; Rehman, Shehzad; Schold, Jesse D. (2009-07-15). "A lifetime versus a graft life approach redefines the importance of HLA matching in kidney transplant patients". Transplantation. 88 (1): 23–29. doi:10.1097/TP.0b013e3181a9ec89. ISSN 1534-6080. PMID 19584676.
  39. 1 2 "Organ Procurement and Transplantation Network and Scientific Registry of Transplant Recipients 2010 Data Report". American Journal of Transplantation. 12: 1–156. 2012-01-01. doi:10.1111/j.1600-6143.2011.03886.x. ISSN 1600-6143.
  40. ↑ "Academic Publications". www.kidneyregistry.org. National Kidney Registry. Retrieved 7 Apr 2016.
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