Kidney Paired Donation

Abstract

Kidney paired donation (KPD) offers a crucial solution to the challenges of organ transplantation, particularly for patients with immunological incompatibilities. By allowing incompatible donor-recipient pairs to exchange donors with other pairs, KPD significantly expands the donor pool, enhancing the likelihood of successful transplants. Advanced algorithms and desensitization techniques further optimize matching and compatibility. The ethical challenges, including equitable access and donor autonomy, require robust guidelines and transparency. As KPD programs evolve, incorporating strategies like altruistic donations and international collaborations can further enhance transplant success, making kidney transplants more accessible and equitable globally.

1. Introduction

Kidney transplantation is the optimal treatment for patients with end-stage renal disease (ESRD), offering significantly better outcomes compared to dialysis [1]. However, the field of kidney transplantation faces numerous challenges, particularly in the area of living kidney donation. One of the most pressing issues is the shortage of compatible donors, exacerbated by the increasing demand for transplants [2].

Living donors are preferable to deceased donors due to better survival rates and shorter wait times [3]. Still, the discrepancy in transplant accessibility between male and female patients further complicates the landscape [4]. Women, often more likely to donate than receive, face additional barriers to transplantation, leading to disparities in outcomes [5].

Highly sensitized patients (HSP) who have developed high antibodies against human leukocyte antigens (HLA) due to previous transplants, blood transfusions, or pregnancies present another significant challenge. These antibodies make it exceedingly difficult to find compatible donors, substantially reducing the likelihood of successful transplantation for these individuals [6, 7]. Compatibility issues, particularly immunological barriers, remain one of the significant obstacles in kidney transplantation [8]. Certain groups, such as blood group O recipients, face specific challenges in finding compatible donors [9]. Blood group O recipients can only receive kidneys from blood group O donors, which limits their options and increases their wait times.

Developing effective strategies for expanding the donor pool is crucial to addressing these challenges. This includes leveraging innovative approaches like kidney paired donation (KPD), which can provide viable solutions for patients with incompatible donors. KPD allows for the creation of donation chains and exchanges that can match incompatible pairs with other pairs in similar situations, ultimately increasing the number of transplants.

Furthermore, unconventional strategies, such as incorporating non-directed altruistic donors (NDAD), facilitating ABO incompatible (ABOi) transplants, and exploring cross-organ exchanges like liver-kidney swaps can significantly enhance donor availability. The potential for international kidney exchange programs also offers a promising avenue for expanding the donor pool.

Overcoming the challenges of living kidney donation requires a multifaceted approach that includes understanding the unique needs of difficult-to-match recipients, addressing compatibility issues, and implementing innovative strategies to expand the donor pool. By doing so, we can move closer to ensuring that every patient, regardless of their immunological or demographic barriers, has access to life-saving kidney transplants [10].

2. Strategies to overcome immunological barriers in living kidney transplantation

In the field of living kidney transplantation (LKT), overcoming immunological barriers is crucial for ensuring successful outcomes. Desensitization and kidney paired donation (KPD) are crucial strategies for addressing the challenge of transplanting patients with donor-specific antibodies (DSAs).

2.1 Desensitization

Desensitization is a critical process for transplant candidates with donor-specific antibodies (DSAs) [11] to mitigate the risk of antibody-mediated rejection (AMR) and expand their access to potential donors. Traditional desensitization protocols involve a combination of plasmapheresis (PLEX), intravenous immunoglobulin (IVIG), and immunosuppressive agents, such as rituximab, which targets B cells, and daratumumab, which depletes plasma cells. These treatments aim to reduce preformed antibodies, making it feasible to perform transplants that would otherwise be contraindicated due to positive crossmatches. Despite their effectiveness, these methods are resource-intensive, require meticulous monitoring, and carry significant risks, including a higher incidence of AMR and decreased long-term graft survival. Studies from 2000 to 2010 involving 725 patients reported a 95% patient survival and 86% graft survival at two years, although acute rejection rates were 36% [12].

The heterogeneity in patient responses to desensitization necessitates individualized approaches, considering patients’ immunological profiles and the type of allo-sensitizing events, such as previous transplants or pregnancies. Emerging strategies [13] use novel therapeutics like bispecific antibodies (anti-BCMA-CD3) and co-stimulation blockade agents like Belatacept, requiring further validation. Integrating immune-modulatory therapies, such as IL-6 inhibitors like tocilizumab, shows promise in reducing inflammation and supporting desensitization. Combining these with existing therapies could enhance DSA reduction and prevent rebound post-transplant. Adaptive clinical trial designs and standardized endpoints, like cPRA titers, are essential for refining desensitization protocols, improving transplant success rates and patient outcomes.

2.2 Kidney paired donation

KPD is an innovative solution that matches incompatible donor-recipient pairs with other pairs in similar situations, effectively creating chains of compatible transplants. This method increases the donor pool and enables more patients to receive transplants without the need for extensive desensitization. While KPD is generally less expensive and associated with lower risks of rejection and infection compared to desensitization, it comes with logistical challenges. Coordinating multiple simultaneous transplantations and addressing last-moment cancelations can be complex and require meticulous planning.

2.3 ABO incompatible versus paired donation

Both strategies have demonstrated significant success over the past decade, and emerging data supports their combined use. Comparing ABOitransplants to KPD, several factors stand out. ABOi transplants are generally less expensive and pose higher risk of rejection and infection due to advances in desensitization protocols. Long-term outcomes for ABOi transplants have also improved, making this a viable option for many patients. However, the logistical challenges inherent in KPD, such as the need for synchronized transplant surgeries and potential last-minute issues, make ABOi transplants an attractive alternative in certain scenarios. Desensitization and paired exchange are complementary strategies. Montgomery’s proposed modality algorithm helps identify which donor/recipient phenotypes benefit from each approach. Patients who are easy to match but difficult to desensitize should opt for paired exchange, while those who are difficult to match but easy to desensitize should undergo desensitization. For those who are both difficult to match and desensitize, a combination of paired exchange and desensitization with an immunologically suited donor is recommended (Figure 1).

Figure 1.

Strategic approach for managing incompatible live donors based on matchability and antibody titers. It categorizes patients by ease of match and desensitization difficulty, guiding the choice between kidney paired donation (KPD), KPD with desensitization, or desensitization alone.

3. History of kidney paired donation

The concept of kidney paired donation (KPD) was first proposed by Felix Rapaport in 1986 [14]. He introduced the innovative idea of matching incompatible donor-recipient pairs with other such pairs to facilitate compatible transplants. This concept saw its first successful application in 1991 in South Korea, where the first KPD transplant was performed [15]. By 1999, the first paired exchange in Europe occurred at University Hospital in Basel, Switzerland. The United States conducted its first KPD transplant in 2000 [10], initially in New England and shortly after that by the Johns Hopkins team, further validating this approach and setting the stage for broader adoption.

Between 2000 and 2006 [16, 17, 18, 19] KPD programs were established worldwide, creating multicenter and national registries. The Netherlands set a precedent in 2004 by successfully launching the first national KPD program globally, followed by establishing other national registries in many different countries. These registries have been instrumental in expanding the pool of potential matches, improving coordination, and increasing the success rates of KPD transplants. By the third quarter of 2010, over 1000 KPD transplants had been performed in the USA [10].

The academic and scientific community’s recognition of the significance of KPD was solidified in 2012 when Alvin Roth was honored with the Nobel Prize in Economic Sciences for his contributions to the theory of stable allocations and market design [20], which included the development of matching algorithms used in KPD programs. In 2014 [21], the United States implemented advanced algorithms and software, significantly enhancing the efficiency of KPD matching processes. These technological advancements have transformed KPD into a more reliable and effective option for patients with incompatible donors, further validating its importance in the field.

As of 2024, improvements in KPD programs continue, focusing on refining matching algorithms, expanding donor pools, and increasing transplant accessibility and success rates. The evolution of KPD highlights the collaborative efforts of medical professionals, economists, and researchers to improve kidney transplantation outcomes for patients worldwide.

4. Modalities of kidney paired donation

The evolution of kidney paired donation (KPD) has introduced several innovative modalities to address donor-recipient incompatibilities. These advanced strategies improve match rates and transplant outcomes, particularly for highly sensitized patients and those with challenging blood types. Each modality offers unique advantages and faces specific challenges, enhancing the overall effectiveness and reach of KPD in providing life-saving transplants. By adopting these innovative approaches, KPD programs can significantly expand the donor pool and improve access to kidney transplantation for a broader range of patients.

4.1 Conventional KPD: closed loops and simultaneous transplants

A kidney transplant is deemed compatible if both the ABO blood group of the donor and recipient are matched and the crossmatch test is negative, which can be determined through either the Complement-Dependent Cytotoxicity (CDC) test or virtually (no donor-specific antibodies, DSA).

Conventional kidney-paired donation (KPD) involves direct exchanges between incompatible donor-recipient pairs, forming closed loops where transplants are conducted simultaneously. The simplest form is the two-way loop, where two incompatible pairs exchange kidneys such that each recipient receives a kidney from the donor of the other pair. This setup is straightforward and ensures both transplants occur simultaneously, minimizing the risk of donors backing out after their recipient has received a kidney. This is the simplest form of KPD, which requires pairs to have reciprocal or complementary incompatibilities (Figure 2).

Figure 2.

This diagram illustrates a scenario in kidney paired donation where two incompatible donor-recipient pairs swap donors to facilitate transplants. In this example, Brother (Donor 1) and Daughter (Donor 2) are unable to donate directly to their respective siblings, Patient 1 and Patient 2, due to incompatibility. However, by swapping, Donor 1 donates to Patient 2 and Donor 2 donates to Patient 1, allowing both patients to receive compatible kidneys.

As the number of participating pairs increases, the complexity of the exchanges can grow significantly. Entering more pairs into an exchange, such as 3-way or even up to 10-way loops, not only facilitates more transplants but also increases options for difficult-to-match patients, as complementary incompatibilities are not required. This means that donors do not necessarily have to give their kidney directly to the recipient of the donor who is giving a kidney to their intended recipient. Instead, through a larger pool, more suitable matches can be found across different pairs, optimizing compatibility and outcomes (Figure 3).

Figure 3.

An illustration of kidney paired donation exchanges, showing two-way, three-way, and four-way exchanges, increasing the number of successful transplants.

The Dutch program reported that the 3-way exchange increases match rates from 54–66% [22], making it the most optimal length of kidney-paired donation to achieve reasonable match rates and simultaneous kidney transplants, especially for newly starting single-center programs. Longer chains do not lead to significantly more kidney transplants and add logistical burdens on the transplant team, requiring stringent and careful coordination.

One of the important examples of the progression of kidney paired donation (KPD) programs is the experience of an Indian center. This center started with a basic 2-way loop in 2000 and, after 13 years of gaining experience and confidence, progressed to a 3-way loop [23]. By 2020, they had further advanced to conducting a 10-way loop. This gradual evolution underscores the growing sophistication and effectiveness of KPD programs, demonstrating how incremental advancements in complexity can significantly enhance transplant facilitation.

One of the concerns in kidney paired Donation (KPD) programs is the potential for donors to renege in the middle of a chain. However, an analysis of 1748 transplants facilitated by the National Kidney Registry (NKR) found that broken chains are uncommon [24].

4.2 Expanding KPD: key strategies

Relying solely on conventional kidney paired donation (KPD) limits the potential for successful transplants, especially for patients with complex incompatibilities. Traditional methods cannot fully address the challenges posed by highly sensitized patients and those with difficult blood types, such as blood group O recipients. Expanding KPD strategies is essential for increasing match rates, improving transplant outcomes, and maximizing the donor pool. By incorporating innovative approaches, such as desensitization, ABO-incompatible transplants, and altruistic donor chains, KPD programs can better meet diverse patient needs and reduce wait times.

4.2.1 Incorporating compatible pairs in KPD

Incorporating compatible pairs into kidney paired donation (KPD) programs has proven to be a transformative strategy to expand the donor pool and improve matching opportunities for difficult-to-transplant recipients. Compatible donor-recipient pairs, when included in KPD, significantly enhance the match rate for incompatible pairs, effectively addressing the challenge of balancing blood-type mismatches and sensitized recipients. Studies, such as those by Gentry et al. [25], have demonstrated that including compatible pairs can nearly double the match rates, highlighting the efficiency of this approach in optimizing donor-recipient matching.

Recipients in KPD programs involving compatible pairs often receive kidneys from younger and healthier donors, improving post-transplant outcomes. Research by Chipman et al. [26] and Basu et al. [27] has shown that recipients benefit from kidneys with better Living Kidney Donor Profile Index (LKDPI) scores compared to their original donors. This improvement in donor quality not only enhances the immediate post-transplant outcomes but also contributes to the long-term success of the transplant.

The inclusion of compatible pairs also helps address issues related to sensitization and infectious mismatches. For instance, many compatible pairs enter KPD to avoid cytomegalovirus (CMV) or Epstein-Barr virus (EBV) mismatches, successfully mitigating these risks. This approach ensures better immunological compatibility and reduces post-transplant complications related to infectious diseases, as studies from Bingaman et al. [28] demonstrated (Figure 4).

Figure 4.

This diagram illustrates a kidney paired donation (KPD) scenario involving two incompatible donor-recipient pairs. Recipient 1 (husband) and Donor 2 (wife) share compatibility in blood group A and CMV status, while Recipient 2 (husband) and Donor 1 (wife) share compatibility in blood group O and CMV status. The exchange allows both patients to receive kidneys from compatible donors, overcoming initial incompatibilities in their respective pairs.

Despite the clear benefits, ethical and logistical considerations must be addressed to optimize the implementation of compatible pairs in KPD. Fortin et al. [29] found that motivations for participation included the potential for optimal matching and policies ensuring prioritization for repeat transplantation. However, concerns about chain breaks, donor reneging, and delays in transplantation need systematic solutions. Overall, incorporating compatible pairs into KPD programs maximizes the potential of living donor kidney transplantation and provides equitable transplant opportunities for all patients.

4.2.2 A2 blood group in KPD

Blood group B candidates, especially among ethnic minorities, have historically faced significant barriers in accessing kidney transplantation, particularly in regions with a lower prevalence of blood group B [30]. Utilizing non-A1 kidneys, including the A2 subtype, has opened new opportunities for these patients. The A2 subtype expresses lower levels of A antigen on cell surfaces than the A1 subtype, making it less immunogenic and allowing it to act as a universal donor similar to blood group O [31].

A2 kidneys can be transplanted into blood type B and even O recipients using standard immunosuppression protocols, provided that the recipient’s anti-A titers are sufficiently low. While most centers consider anti-A titers of less than 8 acceptable for transplantation [23], increasing this threshold to 16 could potentially expand the pool of eligible recipients, thereby improving access within KPD.

Studies on the long-term outcomes of A2 to O and B kidney transplants have demonstrated excellent graft survival rates comparable to those of ABO-compatible transplants. From 1986 through 2006, several blood group B and O patients received kidneys from blood group A2 donors. The data showed that graft survival rates for B recipients of A2/A2B kidneys were equivalent to those for B recipients of B kidneys.

A2 kidneys have already started to be utilized in the kidney allocation system (KAS) for deceased donors; incorporating them into KPD could further enhance the effectiveness and reach of these programs.

The accuracy of subtyping is crucial in ensuring that A2 donors are correctly identified and utilized. Between February 2018 and September 2020, the National Kidney Registry (NKR) performed serological typing on all A/AB donors and confirmed non-A1/non-A1B donors through genotyping. They discovered that 13.0% of type A donors registered with the NKR were ultimately subtyped as A2 via genotyping. Notably, 49.6% of these donors had initially been subtyped as A1 at their donor centers, making them ineligible for allocation as A2 according to OPTN policy. This inaccuracy represents a significant lost opportunity in transplantation, especially in KPD, where A2 donors can facilitate additional living donor transplants and benefit highly sensitized candidates.

4.2.3 KPD combined with incompatible ABO transplantation

Advances in immunosuppressive protocols and antibody removal techniques, such as plasmapheresis and immunoadsorption, have made ABO-incompatible transplants more feasible. These methods allow patients with low to moderate anti-blood group antibody (ABGAb) titers to receive kidneys from ABO-incompatible donors, achieving outcomes comparable to those of ABO-compatible transplants. This approach is particularly beneficial in kidney-paired donation (KPD) programs, where combining KPD with ABO-incompatible transplants can further expand the pool of available donors, thereby increasing the number of successful transplants.

For example, a patient-donor pairs with high ABO titers [pair 1: patient 1 (O group) and donor 1 (A group) with an anti-A isoagglutinin titer >512; pair 2: patient 2 (O group) and donor 2 (B group) with an anti-B isoagglutinin titer >512] can exchange kidneys to receive a donor with low ABO titers [pair 1: patient 1 (O group) and donor 2 (B group) with an anti-B isoagglutinin titer <64; pair 2: patient 2 (O group) and donor 1 (A group) with an anti-A isoagglutinin titer <64]. This strategy minimizes costs, reduces the need for intensive immunosuppression, and enhances long-term outcomes for ABO-incompatible kidney transplantation while increasing match rates for sensitized patients. Studies have shown that ABO-incompatible transplantation, in the absence of donor-specific antibodies and with low baseline ABO titers (< 1:64), has good outcomes (Figure 5).

Figure 5.

The figure shows a blood group-based kidney exchange between two incompatible pairs. Pair 1 involves a patient with blood group O and high anti-A titers (>512) receiving a kidney from Pair 2’s donor with blood group B and low anti-B titers (<64). Simultaneously, Pair 2’s patient with blood group O and high anti-B titers (>512) receives a kidney from Pair 1’s donor with blood group A and low anti-A titers (<64). This exchange enables successful transplantation without extensive desensitization.

Integrating ABO incompatibility solutions within KPD programs enhances their flexibility and efficacy. By including ABO-incompatible pairs, KPD programs can form more extensive and complex chains, optimizing the use of available donors and expanding the pool of compatible recipients. This approach maximizes transplant opportunities and addresses disparities in access to transplantation, particularly benefiting highly sensitized patients. The Australian KPD program’s success in accepting ABO-incompatible donors [32], which resulted in a significant increase in transplant rates, demonstrates the potential of such integrated strategies to improve the effectiveness and reach of KPD programs globally.

4.2.4 Desensitization combinations

Desensitization has shown good outcomes when starting donor-specific antibody strength is low. For broadly sensitized patients with a high-strength cross-match, a better donor can often be found in a KPD pool, facilitating safer and more successful desensitization [33].

Combining kidney-paired donation (KPD) with desensitization strategies significantly enhances transplant rates for highly sensitized patients. These patients often face substantial barriers to finding compatible donors due to ABO or HLA incompatibilities. The integration of desensitization protocols with KPD broadens the pool of potential donors, particularly benefiting those with high calculated panel-reactive antibody (cPRA) levels. This combined approach has shown a 66% increase in transplant rates, addressing the critical issue of long wait times for highly sensitized patients [34].

Sensitized patients comprise 30% of the kidney transplant waiting list, yet fewer than 15% of highly sensitized patients are transplanted each year. Traditional options for these patients include desensitization or KPD, but these methods alone may not be sufficient for recipients with cumulative cPRA >95%. Combining both approaches maximizes the likelihood of finding a compatible match with a more immunologically favorable donor through a kidney exchange program. This combined approach was successfully used in five highly sensitized patients, all with cPRA 100%, who received compatible living and deceased donor kidney transplants [35].

The integration of KPD with desensitization protocols has become increasingly common, particularly for highly sensitized patients. In a study of 170 kidney recipients transplanted by KPD, 75 received concomitant desensitization. The outcomes of KPD combined with desensitization were comparable to those of compatible transplants. Kaplan–Meier estimates showed no significant difference in patient survival, death-censored graft survival, and overall graft survival between the two strategies [36]. This demonstrates that incompatible pairs, which do not benefit from KPD or desensitization alone, achieve similar outcomes when both modalities are combined.

4.2.5 Altruistic chains: NDAD and NEAD

Incorporating altruistic donors, often called “Good Samaritans,” “anonymous”, or “benevolent community donors”, into kidney-paired donation (KPD) systems significantly enhances the potential for successful transplants. Altruistic donors are individuals who donate a kidney without a designated recipient, motivated purely by the desire to help someone needing a transplant. Their contributions can initiate a “Domino Effect” within the KPD framework, where a single altruistic donation sets off a chain of transplants, exponentially increasing the number of recipients who can benefit.

One of the pioneering reports [37] of such a chain in the United States documented a series of 10 transplants initiated by a single altruistic donor in July 2007. This chain, which concluded in 2009, involved six transplantation centers across five states and included simultaneous and non-simultaneous surgeries. Notably, 6 of the 10 recipients had a panel reactive antibody (PRA) level greater than 60%, highlighting the effectiveness of this approach in assisting highly sensitized patients.

In the non-directed altruistic donor (NDAD) model, a non-directed donor starts a sequence where each recipient’s donor subsequently donates to the following recipient in the chain, potentially ending with a donation to the waitlist. An advancement of this model is the non-simultaneous extended altruistic donor (NEAD) chain, where the final donor in the sequence, known as a bridge donor, waits to initiate another chain, thus creating a continuous cycle of donations. Since 2008, kidney exchange in America has grown significantly due to the incorporation of non-directed donors in transplant chains rather than simple exchanges. It is controversial whether these chains should be performed simultaneously as “domino-paired donation” (DPD) or non-simultaneously as NEAD chains. NEAD chains create “bridge donors” whose incompatible recipients receive kidneys before the bridge donor donates, risking reneging by bridge donors, but offering the opportunity to create more transplants by overcoming logistical barriers inherent in simultaneous chains [38].

Gentry et al. [37] conducted simulations to compare the effectiveness of domino-paired donation (DPD) and non-simultaneous extended altruistic donor (NEAD) chains in producing transplants. When limiting the chain segment length to three transplants, their findings showed that DPD performed as well as NEAD chains. However, this contrasts with the experiences of several kidney-paired donation groups. Simulations that allowed for longer chain segments (4–6 transplants) and used real patient data from the Alliance for Paired Donation demonstrated that NEAD chains resulted in more transplants than DPD. Additionally, NEAD chains were particularly effective in producing transplants for highly sensitized and blood type O recipients.

Altruistic donor chains, particularly those initiated by donors with blood type O, have proven exceptionally beneficial. A study involving 77 non-directed donors demonstrated that these donors-initiated chains averaging nearly five transplants each, with blood type O donors facilitating even longer chains [39]. Additionally, a multicenter study [40] involving 16 transplant centers showed that 70 domino chains initiated by altruistic donors resulted in 179 kidney transplants, with impressive one-year and five-year graft survival rates of 98.3% and 87.7%, respectively. These chains are crucial for matching highly sensitized patients and those with blood type O, who typically face longer wait times.

In a list exchange (LE), an intended recipient in an incompatible pair receives priority on the deceased donor waitlist after their paired incompatible donor gives a kidney to a waitlist candidate, thus optimizing the transplant process [41]. Similarly, incorporating deceased donor (DD) kidneys to initiate transplant chains within a KPD pool has been shown to increase the number of transplants by at least 447 over two years (Figure 6) [42].

Figure 6.

This diagram compares two kidney paired donation chain strategies. In (A) the NDAD chain, an altruistic non-directed donor initiates the chain, with the final donor in the sequence donating to a patient on the waitlist. In (B) the NEAD chain, an altruistic donor starts the chain, but the final donor becomes a bridge donor, creating potential for further transplants in subsequent chains. Both strategies aim to maximize transplant opportunities, but NEAD chains extend the chain’s impact over time.

However, incorporating altruistic donors into KPD systems also presents challenges. The NEAD model, for instance, often faces difficulties with AB blood type bridge donors due to the smaller pool of compatible recipients, which can lead to prolonged waiting periods and an increased risk of bridge donors reneging. Despite these challenges, simulations have shown that NEAD chains can result in more transplants compared to traditional simultaneous domino-paired donations [43].

The flexibility and potential for extended chains make the incorporation of altruistic donors a vital strategy in KPD. These chains not only increase the number of transplants but also optimize the use of available donors, leading to improved outcomes for a broader set of recipients. By expanding the donor pool and facilitating complex matching scenarios, altruistic donors play a pivotal role in addressing the organ shortage crisis and enhancing the effectiveness of kidney paired donation programs.

5. Expanding horizons in kidney paired donation

5.1 International KPD

International kidney paired donation (IKPD) offers a promising avenue to expand the donor pool and improve matching opportunities on a global scale. This approach not only addresses biological incompatibilities but also bridges financial barriers, facilitating transplants for patients across both high-income and low- to middle-income countries. By connecting donor-recipient pairs from different countries, international KPD leverages the diverse genetic pool and varying availability of donors globally, thus increasing the chances of finding suitable matches for highly sensitized patients or those with rare blood types [44].

One notable initiative in this domain is the Global Kidney Exchange (GKE), which aims to overcome financial incompatibilities that often prevent transplants in lower-income countries. GKE involves entering international pairs into a US-based kidney exchange program, which provides long-term financial support and facilitates suitable exchanges for both international pairs and US citizens. The first GKE transplant, conducted with a Filipino husband and wife, successfully provided a kidney for the husband while integrating the couple into a non-simultaneous extended altruistic chain, benefiting multiple recipients in the United States [45]. Furthermore, the first international KPD transplantation from India involved a two-way kidney exchange between pairs from Portugal and India. This initiative underscored the feasibility and benefits of cross-border exchanges, particularly for highly sensitized and ABO-incompatible patients. Both pairs underwent simultaneous transplant surgeries with successful outcomes [46].

However, international KPD faces criticism for the potential exploitation of financially disadvantaged donors, healthcare inequities in post-transplant care, and the risk of diverting resources from developing local transplant programs. Ethical concerns include ensuring voluntary and informed consent and managing the disparity in healthcare standards across countries. Addressing these challenges through stringent ethical guidelines, equitable care protocols, and robust international agreements can help mitigate risks and enhance the efficacy of international KPD programs.

5.2 Trans-organ exchange (liver-kidney exchange)

Trans-organ paired exchange is an innovative concept that expands the potential for organ donation by allowing donors who are unsuitable for donating one organ to contribute to the transplant system by donating another organ. This approach enables donors who may be ruled out for kidney-specific reasons to donate a liver and vice versa. For instance [47], a person with a mild reduction in glomerular filtration rate (GFR) or complex kidney anatomy may be ruled out as a kidney donor but can still be a viable liver donor. Conversely, a potential liver donor with aberrant liver anatomy might be a suitable kidney donor.

To date, only a few trans-organ paired exchanges have been reported. One notable case [48] involved a 19-year-old who was ruled out as a kidney donor but requested to donate her liver in exchange for a kidney for her mother, who had end-stage renal disease (ESRD). This pair was matched with another donor-recipient pair where the potential liver donor had an anatomical issue precluding liver donation but was suitable for kidney donation. Despite initial donor incompatibilities, this swap enabled both recipients to receive the needed organs.

Trans-organ paired exchange raises several ethical and legal questions. The National Organ Transplant Act (NOTA) allows for organ-paired donation but does not specify that the organs must be the same, making trans-organ exchanges legally permissible. However, ethical concerns include the disparity in risk between kidney and liver donations. Kidney donation carries a mortality risk of approximately 1 in 3000, while liver donation’s risk is about 1 in 500. Additionally, liver donors face a longer recovery period and more immediate postoperative risks compared to kidney donors. Ensuring that donors provide informed and voluntary consent is crucial. Potential donors must understand the differential risks and benefits involved, and transplant teams must protect donors from coercion and ensure they have the opportunity to withdraw consent without feeling undue pressure.

6. Criteria for KPD entry and advanced algorithms and software

The criteria for kidney paired donation (KPD) include HLA incompatibility, ABO incompatibility, significant age differences (more than 10 years if the donor is under 50), size mismatch (donor’s Iothalamate GFR corrected for recipient’s body surface area divided by 2 is less than 35), CMV/EBV mismatch, and altruistic reasons [27].

As KPD programs evolve, the number of potential donor-recipient combinations grows exponentially, presenting a significant mathematical challenge. This graph illustrates how combinations increase as more pairs participate. With 100 pairs, potential matches are relatively small, but approaching 500 pairs, combinations skyrocket to tens of thousands. To manage this complexity, advanced algorithmic software designed for organ matching is utilized. This software inputs each participant’s medical data, including blood type, tissue compatibility, and immunological factors, to generate compatibility scores for every possible pair.

Modern KPD programs significantly benefit from integrating advanced algorithms and sophisticated software. These innovations optimize the matching process, ensuring efficient and accurate pairings between donors and recipients. The software used in KPD registries manages and analyzes vast amounts of data, incorporating immunological data, such as HLA typing and crossmatch results to create compatibility matrices. By assigning point scores to potential matches, the software generates optimized solutions, efficiently identifying the best donor-recipient pairings. Advanced algorithms and software optimize both closed-loop conventional exchanges and chain strategies based on the likelihood of better transplants, prioritizing sensitized recipients, avoiding viral mismatches, and focusing on chain length for maximum efficiency.

Additionally, KPD guidelines emphasize that less compatible kidneys should never be offered. Pre-emptive transplantation is prioritized, especially if the recipient is near needing dialysis, and decisions are re-evaluated every three months. ABO/HLA compatible pairs always have the option to proceed directly to transplantation outside of KPD.

Centralized databases and real-time updates in the software enable seamless coordination between multiple transplant centers, minimizing delays, and improving overall process efficiency. For instance, the Alliance for Paired Donation (APD) [49] uses a web-based virtual matching system that has evolved over seven years to improve conversion rates from computer-identified matches to successful transplants. This system not only proposes optimal matches but also helps track and manage offers, perform crossmatches, and handle logistical details effectively.

In practical application, advanced algorithmic software dynamically adapts to changes such as new pairs joining the pool or updates in a recipient’s medical condition, ensuring the matching process remains efficient and adaptable. For example, with 10 incompatible pairs, arranging them into a single chain could potentially facilitate up to seven transplants if all goes perfectly. However, this is often not the most efficient or feasible scenario due to various compatibility and logistical challenges. With sophisticated algorithmic software, alternative arrangements can be explored to increase the total number of successful transplants. The software might suggest splitting the 10 pairs into two shorter chains or loops, maximizing the use of available donors and enhancing the chances for patients to receive transplants faster and with better matches.

In summary, the software does not just seek to match pairs—it aims to optimize the entire system to maximize successful transplants. It creates multiple chains and loops, ensuring that as many patients as possible receive the kidneys they need. The dynamic nature of the software allows it to adapt to changes, such as new pairs joining the pool or updates in a recipient’s medical condition, ensuring the matching process remains efficient and adaptable (Figure 7).

Figure 7.

Graph showing the exponential increase in possible combinations as the number of pairs in a kidney-paired donation program increases, illustrating the complexity and potential of matching algorithms in such programs.

7. Ethical challenges in KPD programs

Kidney-paired donation (KPD) programs face numerous ethical challenges [50], primarily ensuring equitable access to kidney transplants. Socioeconomic disparities often hinder fair access, especially for individuals in poverty or without medical insurance. Addressing these financial and logistical barriers is crucial for ethical integrity. Additionally, maintaining donor autonomy is vital, requiring comprehensive informed consent and clear communication about the risks and implications involved in the donation process.

Another significant challenge is safeguarding patient data, ensuring privacy, and protection against unauthorized access. Balancing financial incentives to support donors while preventing organ commercialization is also critical. Furthermore, managing expectations and preparing patients and families for potential negative outcomes through thorough counseling and support is essential. Logistical issues, such as ensuring donor anonymity, addressing concerns about age differences and kidney quality, and coordinating simultaneous operations to prevent donor reneging, are integral to the program’s ethical success.

8. Key requirements and strategies for implementing a successful KPD program

Establishing a successful kidney-paired donation (KPD) program involves several critical components. Firstly, a robust KPD registry is essential for efficiently tracking participants and outcomes. Uniform evaluations and care protocols across all facilities ensure consistent and fair treatment. Standardizing HLA laboratory testing is crucial for accurate donor-recipient matching. Ensuring similar quality kidneys are exchanged maintains equity in transplantation outcomes. Simultaneous surgeries prevent donors from withdrawing post-nephrectomy of the recipient. Finally, a non-anonymous allocation process enhances transparency and trust among participants.

The strategy for developing a kidney-paired exchange (KPE) program [48] emphasizes gradual growth, starting with centralization and standardization. Establishing a National Transplant Centre is central to this strategy, coordinating all components of the KPE program and facilitating improved collaboration between healthcare sectors. Standardizing protocols for preparing donors and recipients simplifies the exchange process and sets a foundation for future expansion.

Building community confidence through adherence to high ethical standards is crucial, aligning with international principles on organ donation and transplantation. Robust legal frameworks must protect participants and prevent organ trafficking. Engaging public opinion and gaining stakeholder consensus are critical steps in this phase. This foundational work ensures the KPE program operates with integrity and public trust.

Continuous monitoring through analysis of transplant rates, graft survival, and patient quality of life provides crucial insights into the program’s effectiveness. As the National Transplant Centre gains experience, particularly with simpler 2-way exchanges, the program can strategically expand to more complex exchange types. This methodical expansion ensures the program remains adaptable and scalable, maintaining high-quality service without compromising the integrity or outcomes of the exchanges. By continuously evaluating and refining the process, the KPE program can achieve sustainable growth and success.

Acknowledgments

The authors extend their gratitude to Yasmeen Jamal Alabdallat, a distinguished student at Hashemite University, for her invaluable assistance in creating the figures and diagrams presented in this work.

Appendices and nomenclature

KPD (Kidney paired donation)	A transplant option where incompatible donor-recipient pairs are matched with other pairs in similar situations to enable kidney exchanges
NDAD (Non-directed altruistic donor)	An individual who donates a kidney without a designated recipient, often initiating a chain of transplants
cPRA (Calculated panel reactive antibody)	A measure of a patient’s sensitization to potential donors, expressed as a percentage