Are Transplant Chains the Answer to Our Kidney Deficit?

Today, 99,478 of the 120,001(83%) of patients on the organ transplant waiting list in the United States still await a kidney transplant.¹

In 2015, US surgeons transplanted only 17,800 kidneys.²More patients remain on the waiting list than those receiving a transplant, and approximately 15% of those on the waiting list will die waiting.

Finding ways to improve the number of organ donors would increase the size of the deceased donor pool. Targeting the living donor pool by increasing the length and number of kidney transplant chains is another option.

To start these chains, altruistic individuals donate kidneys to complete strangers. This sets off a domino reaction, in which recipients’ loved ones donate to others in gratitude.³In recent years, these chains have gained momentum, changing many patients’ lives.^4,5

Transplant Types

Kidneys can come from living or deceased donors. Kidney registries use living donors in 3ways (Table 1⁸) and prefer them because of long-term results and lower risks of complications and rejection.⁶

Kidneys from live donors last twice as long as those from deceased donors.⁷In addition, identifying a living donor significantly shortens wait times. Although recipients may wait on the deceased donor waiting list (DDWL) for more than 5 years, the average wait time for a living donor match from the National Kidney Registry (NKR) is 5 months.^1,8

Table 1: Living Kidney Donation Types⁸

Type

Description

Direct

· Occurs when the donor knows the recipient, is a compatible match, and donates to that individual

Paired exchange

· Occurs if a potential donor is not a match for his or her intended recipient; an alternative known as paired exchange donation is possible.

· Donor #1 donates his or her kidney to another recipient who will provide a compatible donor for recipient #1

· Two incompatible pairs are matched to allow 2 otherwise-impossible transplants to occur

Altruistic

· Occurs when a donor gives a kidney to a stranger, initiating a chain

· Synonymous terms include nondirected and Good Samaritan donation

Transplant Surgery

It’s a fairly straightforward procedure. For donors, the operation can be performed laparoscopically with small incisions, a camera, and instruments that remove the kidney.⁹It only takes 2 to 3 hours and patients are usually discharged after 2 nights in the hospital.⁸The donor’s remaining kidney performs the work that both kidneys had prior, with no long-term health consequences.⁶

For the recipient, the operation is usually 2 to 4 hours.⁹Once the kidney is placed into the abdomen, the surgeon sews the donor kidney’s renal artery and vein to the recipient’s external iliac artery and vein, allowing blood to flow properly. Then, the surgeon connects the donor ureter to the recipient’s bladder, allowing urine to pass through the kidney.¹⁰Hospital recovery time is usually around 3 to 7 days, during which time the health care team monitors for kidney function and graft rejection. Patients also begin a regimen of antirejection medications for life.⁹

Among organ transplants, kidney transplants have some of the highest success rates. Ninety-seven percent of transplanted kidneys function normally after one month, and 83% function normally 3 years post-transplant.

Matching for Transplants

Several blood tests ensure donor-recipient compatibility. The first is blood type (A, B, O, or AB positive or negative),⁹which must be either identical or compatible. Blood type O-negative is the universal donor, so any patient can receive a kidney from an O-negative donor. AB-positive is the universal recipient, so patients with AB-positive blood can receive a kidney from anyone.

After blood type is matched, the pathology lab performs tissue typing by identifying human leukocyte antigens (genetic markers on cells) in blood samples.⁹Transplants with the best and longest success rates have perfect matches for all 6 antigens, but some degree of mismatch is allowed.

The pathology lab also conducts percent reactive antibody tests to assure compatibility, evaluating the recipient for antibodies that may have formed from a previous exposure to antigens. The more antibodies present, the more difficult it is to find a match.

A serum crossmatch determines if the donor and recipient are compatible. Donor cells are incubated in the recipient’s serum and if the recipient has antibodies against the donor’s cells, those cells will be destroyed and it will be termed a positive crossmatch. If this happens, the individuals are incompatible and a transplant is impossible. If, however, a patient’s samples pass all of these tests, then the pair is a match and the transplant can occur.

The transplant team considers many factors during the match process. One-third of willing donors are incompatible with their intended recipients.¹⁰Traditional paired kidney donation has the potential to leave many of these pairs unmatched. Kidney chains can be a solution to this problem.¹¹Paired exchange and altruistic donation not only increase the size of the kidney donor pool, but also stimulate additional compatible matches.⁵

History of Transplant Chains

The first successful living donor kidney transplant occurred in 1954 between identical twins in Boston. The first living unrelated and nondirected donor transplants occurred about a decade later, but it took many years for the living donor pool to grow.¹²

Before chains were possible, transplantation programs and specialists made numerous improvements to organ donation policy and procedure. Kidney chains evolved in a step-wise manner from other types of living donation. Direct donation first began in the 1950s. Although the idea of paired exchange was first published in 1986, it wasn’t until 2000 that the first recorded exchange occurred in the United States.¹²

Paired exchange programs emerged to facilitate matches, first within a single transplant program, and then between different programs across the country. Dr. Robert Montgomery, renowned transplant surgeon and director of NYU Langone Medical Center’s Transplant Institute, suggested domino paired kidney donation in 2006.¹³In domino exchange, altruistic donors are matched to recipients with incompatible donors, and the incompatible donors promise to donate to a patient on the DDWL.

The formation of the first never-ending altruistic donor chain was the next milestone in living kidney donation.¹⁴Rather than donating to patients on the DDWL, kidneys are donated to patients who are incompatible with willing donors. Those willing donors become “bridge donors” who continue the chain as recipients of incompatible pairs match with bridge donors.

Theoretically, such chains could go on forever. The first chain was launched by Michael Rees, a transplant doctor at the University of Toledo Medical Center and founder of the Alliance for Paired Kidney Donation in 2000. The chain occurred in 2007 and yielded 10 kidney transplants.¹⁴Garet Hil, president of Hil & Company LLC and founder of the NKR in 2007, has also been instrumental in organizing matches and chains throughout the country.⁸

Benefits of Transplant Chains

The most obvious is the expansion of the donor pool and higher-quality matches for the greatest number of patients. When the exchange is between 2 pairs, one recipient may receive a much higher-quality match than the other. Even though both exchanges are compatible, better HLA matches could exist and be found using chain donation techniques.¹⁵

Even more beneficial is when compatible pairs with blood type O donors and A, B, or AB recipients enter a chain.¹⁶Traditionally, type O patients on the waiting list have longer wait times because type O kidneys can be allocated to all blood types.¹⁷When such compatible pairs participate in a chain, the intended recipient can find a stronger match, and the type O donor can match to a type O recipient in need.

Another advantage over paired exchange is that chains eliminate the need for simultaneous transplant surgeries. Paired exchange transplants need to be performed simultaneously to prevent donor withdrawal.¹²If the surgeries aren’t completed at the same time, one donor could back out of the exchange, leaving a recipient without a kidney and without their original intended donor. Chains don’t exhibit this problem because they start with altruistic donors who expect nothing in return. Surgeries within chains can be scheduled more flexibly and at the patients’ convenience.

An additional concern with paired exchange is the repercussions of swap failures.⁸If a procedural complication occurs, surgeons are unable to complete the transplant. This is termed a swap failure. In paired exchange, a recipient has lost a compatible kidney and may also have lost their incompatible donor as the procedures are done simultaneously. In a chain, swap failures end the chain, but recipients aren’t further harmed by the loss of their incompatible donor. They still have the opportunity to participate in a different chain because their intended donor has not donated a kidney yet.

Finally, chains are particularly advantageous for highly sensitized and blood type O recipients.⁵Sensitized individuals have high levels of HLA antibodies as a result of a previous exposure through blood transfusions, pregnancy, or prior transplants.¹⁸Sensitized patients wait on the DDWL significantly longer than other patients due to the difficulty in finding a compatible donor. Kidney chains produce more transplants for these 2 groups by increasing the donor pool.⁵

Problems with Transplant Chains

One concern is the risk of breaking a chain.¹²Theoretically, these chains could endure forever, but realistically, they don’t. Eventually, chains end when a compatible pair is not available or a donor is difficult to match. They also end if donors have extended wait times.

Although donors may change their minds at any moment and back out of chains, it is unlikely.¹⁹Most donors are so grateful that their loved one received a kidney, they can’t way to “pay the gift forward.”¹²The NKR reported only one broken chain out of 83 in 2015, and zero broken chains out of 20 as of March 31, 2016.⁸Some chains also end intentionally when a recipient qualifies for a kidney from the DDWL.¹³The living chain ends, but the final recipient benefits by receiving a needed kidney that he or she may not have received otherwise.

The real debate is over the ethics of kidney chains. When altruistic donors come forward, their kidneys could start chains or be given to individuals on the DDWL. The popularity of chains diverts potential living donor kidneys, which have significantly longer graft survival times, away from patients who lack living donors.¹⁹However, some argue that chains are beneficial for the DDWL by preventing kidney transplant chain recipients from competing with other patients on the list.²⁰Those who remain on the DDWL will be more likely to receive a transplant. Blood type O patients on the DDWL are at even more of a disadvantage. Recipients with this blood type already have the longest wait times, with kidney chains further increasing these wait times.²¹

Altruistic donors’ motives also need to be considered. Large kidney transplant chains tend to attract media coverage. Some individuals only consider becoming altruistic donors for media attention. Maintaining the anonymity of transplant chain participants could combat this issue. It’s equally important to ensure that potential donors aren’t coerced, exploited, or given financial compensation as these raise further ethical concerns. Careful screening, education, and informed consent of potential altruistic donors help maintain ethical standards in chain transplants.¹⁹

Another concern is the kidney allocation process.²²Lacking government regulation, kidney registries are able to weigh certain factors more heavily than others. When determining individual patients’ transplant needs, kidney registries may consider HLA and ABO status, wait time, match difficulty, age, other health conditions, time until or duration on dialysis, history of kidney transplant, previous organ donation, and formation of the longest chain possible.^{16, 23}

A Massive Undertaking

Several nonprofit agencies facilitate the formation of chains. Registries use complex software algorithms to find the best match for each patient. Some organ transplant centers conduct exchanges exclusively at their center. The use of national registries, however, expands the donor pool and provides patients with a greater likelihood of successful transplant and increased graft survival times. The NKR has the largest donor pool in the world, prompting better matches and more opportunities to repair failed swaps.⁸Registry software is designed to optimize ABO and HLA compatibility. Other patient-specific characteristics are factored in, such as age and travel preference.¹²

One potential problem that arises from national registries is location. If donor-recipient matches span the country, the donor or the organ will need to travel. Many donors prefer to stay at home where they can recover near friends and family; in these cases, organ shipment is usually preferred. Organs can be shipped on commercial airlines at minimal cost. Local organ procurement organizations deal with these transactions’ details.²⁴Such organizations also manage the transportation of deceased donor organs successfully. Some experts have reservations about the function of kidneys that have prolonged cold ischemic times. This may be why some transplant specialists prefer conducting local exchanges at the same center, even if the match isn’t as strong.¹²However, studies have shown that prolonged cold ischemia time does not affect graft function.²⁵

Leaders in the field of kidney transplants attended a conference in Herndon, Virginia, in 2012 to discuss the formation of a national registry. Opinions were split between establishing one registry or having multiple registries (the current arrangement) to manage the matching and allocation processes. Mathematically, one large pool of donors creates more potential matches than 2 smaller pools do. In addition, including pairs in multiple registries could create problems with chain construction if two registries want to use the same donor. However, competing registries prefer remaining separate. Competition fuels innovation, which unification of the registries may destroy. The general consensus was to work toward the formation of single national registry in the future.²⁶

Successful Chains

The benefits of kidney transplant chains are already being realized. They multiply the impact that altruistic donors create.¹⁶Currently, the longest living kidney donor chain is the University of Alabama at Birmingham Kidney Chain. Started in December 2013, it has since grown to include 112 individuals, yielding a total of 56 kidney transplants as of December 2015.²⁷

The longest multihospital chain to date involved 68 individuals, 34 kidneys, and 26 hospitals across the United States.²⁸It happened over the course of 3 months, ending on March 26, 2015.²⁹Kathy Hart was the Good Samaritan who started this chain, ending with Mitzi Neyens. After living with kidney disease for 30 years, Neyens’ condition began to rapidly decline at the age of 77, but her age precluded her from being added to the DDWL. Living organ donation was her only option, and without this chain, she probably wouldn’t have found a donor. This particular chain included 16 highly-sensitized individuals who could have waited years on the DDWL before a compatible match was identified.²⁸

Many multicenter transplant chains wouldn’t be possible without the efforts of national registries. The NKR alone has initiated 329 chains, facilitating 1513 kidney transplants. It has also arranged 83 loops (a series of swaps without an altruistic donor), facilitating 194 transplants. The NKR is responsible for organizing a total of 1827 kidney transplants as of July 2016.Table 2lists the longest and most successful chains/swaps from the NKR. The longest chain to date is Chain #357, which enabled 35 transplants.

Table 2: Longest National Kidney Registry Chains

Chain Number

Transplants Facilitated

(multiply by 2 for total number of participants)

5

21

10

11

18

12

19

12

20

10

21

10

61

11

69

10

95

16

122

11

124

30

178

10

187

12

192

12

221

28

225

10

266

12

268

10

282

10

293

13

306

11

313

11

330

16

357*

35

412

16

459

19

464

13

476

13

494

10

* = longest chain

Future Possibilities

Kidney transplant chains aren’t only saving lives; they’re also saving money, as a national registry could save $750 million every year.²²Kidney disease treatments consume 7% of the total Medicare budget, costing $30 billion every year. Medicare spending in 2013 on hemodialysis was $84,550 per patient per year (PPPY), peritoneal dialysis was $69,919 PPPY, and transplant was $29,920 PPPY.³⁰Compared with the average cost of Medicare coverage for a kidney failure patient on dialysis, the surgery is considerably less expensive. Each patient who exits dialysis due to a kidney transplant saves Medicare $500,000 to $1 million.²³Increasing the number of kidney transplants produces savings that can be used for other health conditions.

These chains hold great potential for the 100,000 patients currently in need of kidney transplants. Research and computer models show that thousands more transplants could be possible annually if transplant specialists, donors, and recipients understood paired exchange and chain donation better. A national registry listing all donors and recipients also has the potential to improve donation.²⁶

Convenient care clinicians can educate patients about kidney transplants, specifically the different types of living donation. By increasing public awareness about kidney registries and chains, they can improve these processes and increase the number of kidney transplants.

References

1. HHS. Organ Procurement and Transplantation Network. optn.transplant.hrsa.gov. Accessed July 26, 2016.

2. United Network for Organ Sharing. Working together, saving lives. unos.org. Accessed July 26, 2016.

3. Roodnat JI, Zuidema W, van de Wetering J, de Klerk M, Erdman RA, Massey EK,

Hilhorst MT, Ijzermans JN, Weimar W. Altruistic donor triggered domino-paired

kidney donation for unsuccessful couples from the kidney-exchange program.Am J

Transplant. 2010 Apr;10(4):821-827.

4. Roodnat JI, Kal-van Gestel JA, Zuidema W, van Noord MA, van de Wetering J,

IJzermans JN, Weimar W. Successful expansion of the living donor pool by

alternative living donation programs.Am J Transplant. 2009 Sep;9(9):2150-2156.

5. Ashlagi I, Gilchrist DS, Roth AE, Rees MA. Nonsimultaneous chains and dominos

in kidney- paired donation-revisited.Am J Transplant. 2011 May;11(5):984-994.

6. Davis CL, Delmonico FL. Living-donor kidney transplantation: a review of the

current practices for the live donor.J Am Soc Nephrol. 2005 Jul;16(7):2098-2110.

7. Organ Procurement and Transplantation Network and Scientific Registry of

Transplant Recipients 2010 data report.Am J Transplant. 2012 Jan;12 Suppl

1:1-156.

8. National Kidney Registry. Facilitating living donor transplants. kidneyregistry.org. Accessed July 26, 2016.

9. University of California San Francisco. Kidney transplantation. transplant.surgery.ucsf.edu/conditions--procedures/kidney-transplantation.aspx. Accessed July 26, 2016.

10. Melcher ML, Veale JL, Javaid B, Leeser DB, Davis CL, Hil G, Milner JE. Kidney

transplant chains amplify benefit of nondirected donors.JAMA Surg. 2013;148(2):165-169.

11. Gentry SE, Montgomery RA, Swihart BJ, Segev DL. The roles of dominos and

nonsimultaneous chains in kidney paired donation.Am J Transplant. 2009

Jun;9(6):1330-1336.

12. Veale J, Hil G. The National Kidney Registry: transplant chains--beyond paired

kidney donation.Clin Transpl. 2009:253-264.

13. Montgomery RA, Gentry SE, Marks WH, Warren DS, Hiller J, Houp J, Zachary AA,

Melancon JK, Maley WR, Rabb H, Simpkins C, Segev DL. Domino paired kidney

donation: a strategy to make best use of live non-directed donation.Lancet. 2006

Jul 29;368(9533):419-421.

14. Rees MA, Kopke JE, Pelletier RP, Segev DL, Rutter ME, Fabrega AJ, Rogers J,

Pankewycz OG, Hiller J, Roth AE, Sandholm T, Unver MU, Montgomery RA. A

nonsimultaneous, extended, altruistic-donor chain.N Engl J Med. 2009 Mar

12;360(11):1096-1101.

15. Gentry SE, Segev DL, Simmerling M, Montgomery RA. Expanding kidney paired

donation through participation by compatible pairs. Am J Transplant. 2007

Oct;7(10):2361-70.

16. Lee YJ, Lee SU, Chung SY, Cho BH, Kwak JY, Kang CM, Park JT, Han DJ, Kim DJ.

Clinical outcomes of multicenter domino kidney paired donation. Am J Transplant.

2009 Oct;9(10):2424-8.

17. Glander P, Budde K, Schmidt D, Fuller TF, Giessing M, Neumayer HH, Liefeldt L.

The 'blood group O problem' in kidney transplantation--time to change?Nephrol

Dial Transplant. 2010 Jun;25(6):1998-2004.

18. Yabu JM, Siebert JC, Maecker HT. Immune profiles to predict response to

desensitization therapy in highly HLA-sensitized kidney transplant candidates.

PLoS One. 2016 14;11(4):e0153355.

19. Woodle ES, Daller JA, Aeder M, Shapiro R, Sandholm T, Casingal V, Goldfarb D,

Lewis RM, Goebel J, Siegler M; Paired Donation Network. Ethical considerations

for participation of nondirected living donors in kidney exchange programs.Am J

Transplant. 2010 Jun;10(6):1460-1467.

20. Delmonico FL, Morrissey PE, Lipkowitz GS, Stoff JS, Himmelfarb J, Harmon W,

Pavlakis M, Mah H, Goguen J, Luskin R, Milford E, Basadonna G, Chobanian M,

Bouthot B, Lorber M, Rohrer RJ. Donor kidney exchanges.Am J Transplant. 2004

Oct;4(10):1628-1634.

21. Ross LF, Zenios S. Practical and ethical challenges to paired exchange

programs.Am J Transplant. 2004 Oct;4(10):1553-1554.

22. Wallis CB, Samy KP, Roth AE, Rees MA. Kidney paired donation.Nephrol Dial

Transplant. 2011 Jul;26(7):2091-2099.

23. Alliance for Paired Kidney Donation. Provide hope and healing. paireddonation.org. Accessed July 26, 2016.

24. Melcher ML, Leeser DB, Gritsch HA, Milner J, Kapur S, Busque S, Roberts JP,

Katznelson S, Bry W, Yang H, Lu A, Mulgaonkar S, Danovitch GM, Hil G, Veale JL.

Chain transplantation: initial experience of a large multicenter program.Am J

Transplant. 2012 Sep;12(9):2429-2436.

25. Butt FK, Gritsch HA, Schulam P, Danovitch GM, Wilkinson A, Del Pizzo J, Kapur

S, Serur D, Katznelson S, Busque S, Melcher ML, McGuire S, Charlton M, Hil G,

Veale JL. Asynchronous, out-of-sequence, transcontinental chain kidney

transplantation: a novel concept.Am J Transplant. 2009 Sep;9(9):2180-2185.

26. Melcher ML, Blosser CD, Baxter-Lowe LA, Delmonico FL, Gentry SE, Leishman R,

Knoll GA, Leffell MS, Leichtman AB, Mast DA, Nickerson PW, Reed EF, Rees MA,

Rodrigue JR, Segev DL, Serur D, Tullius SG, Zavala EY, Feng S. Dynamic challenges

inhibiting optimal adoption of kidney paired donation: findings of a consensus

conference.Am J Transplant. 2013 Apr;13(4):851-860.

27. University of Alabama at Birmingham. UAB medicine. uab.edu/kidneychain. Accessed July 26, 2016.

28. Longest kidney chain ever completed wraps up at UW hospital and clinics. University of Wisconsin School of Medicine and Public Health. uwhealth.org/news/longest-kidney-chain-ever-completed-wraps-up-at-uw-hospital-and-clinics/45549. Accessed July 26, 2016.

29. Pitts B, Louszko A, Cappetta M, Effron L, Valiente A. Donating a kidney to a complete stranger in order to save a loved one. ABC News Network. abcnews.go.com/Health/donating-kidney-complete-stranger-order-save-loved/story?id=30288400. Accessed July 26, 2016.

30. United States Renal Data System. USRDS Annual Data Reports. usrds.org/Default.aspx. Accessed July 26, 2016.