End-stage renal disease (ESRD) affects millions worldwide, posing a growing public health challenge due to increasing incidence, rising healthcare costs, and its profound impact on quality of life. Kidney transplantation is recognized as the gold standard treatment for ESRD, offering superior patient survival, lower morbidity, and better health-related quality of life compared to long-term dialysis (1, 2). Despite these benefits, a persistent gap exists between the number of patients needing kidney transplants and the availability of suitable donors (3). Living donor kidney transplantation provides an opportunity to bridge this gap, but immunologic barriers often preclude direct transplantation.

The most significant immunologic challenges include ABO blood group incompatibility and the presence of donor-specific anti-HLA antibodies (DSAs), particularly in highly sensitized patients. Sensitization may arise from previous transplants, blood transfusions, or pregnancies and can drastically reduce the likelihood of finding a compatible donor (4). The presence of DSAs, especially with high mean fluorescence intensity (MFI) or positive crossmatches, is associated with increased risk of antibody-mediated rejection (AMR) and subsequent graft loss (5–7).

In addition to incompatibility, suboptimal HLA matching has emerged as an important determinant of long-term transplant outcomes. Numerous studies have demonstrated that inadequate HLA class II compatibility, particularly at the DQ locus, contributes to the formation of de novo DSAs and chronic AMR (8–10). Moreover, a growing body of evidence supports the use of molecular-level matching through eplet-based algorithms to more accurately predict immunologic risk and improve graft survival (11–13).

Kidney paired donation (KPD) programs have revolutionized the field by enabling incompatible donor-recipient pairs to exchange kidneys with other pairs, thus achieving immunologic compatibility through logistical optimization rather than biological matching alone (14, 15). KPD programs have evolved further to incorporate compatible pairs with poor HLA matching, allowing them to access better-matched donors, improve graft longevity, and increase the overall transplant opportunities within the system (16).

Global experiences with KPD vary. The National Kidney Registry (NKR) in the United States and national programs in the UK, Canada, Australia, and the Netherlands have successfully demonstrated that large-scale, multi-institutional KPD networks can efficiently facilitate high-volume exchanges, including chains initiated by non-directed altruistic donors (17) (18–21). However, centralized programs are often constrained by geographic, logistical, and regulatory challenges—particularly in regions with fragmented healthcare systems.

In contrast, single-center KPD programs offer greater agility, control, and faster execution of exchanges. When supported by a robust matching algorithm, clinical expertise, and desensitization protocols, these programs can achieve outcomes comparable to national networks, particularly in high-volume transplant centers.

Our institution, a high-volume kidney transplant center in Saudi Arabia, has implemented a dynamic, multi-strategy KPD program that includes HLA-incompatible (HLAi), ABO-incompatible (ABOi), and compatible pairs with suboptimal immunologic profiles. In 2024 alone, our center performed 135 KPD transplants—the highest known single-center annual volume to date. This study describes the design, evolution, and outcomes of our single-center KPD program, offering a practical framework for other institutions facing similar challenges in donor compatibility and transplant access.

This study highlights the feasibility, flexibility, and effectiveness of a high-volume, single-center kidney paired donation (KPD) program in addressing immunologic barriers to transplantation, especially in regions without access to large-scale national registries. Our center’s ability to facilitate 135 KPD transplants in one year—including HLA-incompatible (HLAi), ABO-incompatible (ABOi), and compatible pairs—demonstrates the value of a pragmatic, inclusive strategy that balances immunologic risk with clinical opportunity.

To our knowledge, this represents the highest single-center volume of kidney paired donation transplants reported globally within a calendar year. While national and regional registries such as the National Kidney Registry (NKR) in the United States, United Kingdom Living Kidney Sharing Scheme, or the Canadian Living Donor Paired Exchange Program facilitate hundreds of KPD transplants annually across multiple centers, the number of KPD procedures performed at any one institution typically ranges from several dozen to less than 100 per year. The NKR reported that 116 KPD transplants were performed in Penn Medical Institute in the past 12 months (24).On the other hand a total of 70 KPD transplants were carried out in Canada (25). In the whole UK, 179 kidney transplants were performed through KPD (17). In contrast, our program facilitated 135 transplants in 2024 alone, underscoring the operational capacity, algorithmic optimization, and institutional commitment required to achieve such high-volume performance. This volume reflects not only clinical throughput but also the success of our inclusive matching strategy and streamlined coordination within a single-center framework.

As one of the largest transplant centers in Saudi Arabia, our center performed 511 kidney transplants in 2024, of which 453 were from living donors. KPD accounted for nearly 30% of our living donor transplants. Through targeted strategies — notably the inclusion of compatible pairs into the KPD program — we successfully maintained a balanced ABO blood group distribution between donors and recipients. Individuals with blood group O comprise 55% of recipients and 48% of donors in our pool, encompassing matched, unmatched, and transplanted pairs. This achievement addresses a significant concern previously raised in the literature, where the unbalanced representation of blood group O donors in the donor pool was associated with declining match rates (26, 27). By proactively managing ABO representation, we have thus far been able to preserve match rates and optimize transplant opportunities for patients across all blood groups.

Match rates in KPD programs are influenced by multiple factors. A study by the NKR demonstrated that both cPRA levels and blood group type significantly impact the likelihood of matching (28).Specifically, potential recipients with cPRA >80% or those with blood group O were less likely to find suitable matches within the KPD pool. Since the inception of our KPD program in 2016, we have successfully transplanted 694 patients through different strategies (unpublished data). Our data show a match rate of 73% for ABOi patients and 79% for patients with cPRA >80%. Importantly, among very highly sensitized patients with cPRA between 95–100%, the match rate remained favorable at 74%, highlighting the effectiveness of our program in addressing the challenges associated with difficult to match recipients. However, 118 patients remain unmatched. Of these, 84 (71%) are potential recipients with blood group O, whereas only 29% of the potential donor pool has blood group O. In addition, 64% of patients in the unmatched group have a cPRA >80%.

Not all KPD programs include compatible pairs in their pool. Several reasons have been cited for this, including concerns about creating imbalanced exchanges, fears of weakening the emotional bond through indirect donation, and logistical challenges. However, with appropriate counseling, many compatible pairs may choose to participate in KPD programs (29). The key question is how to provide benefit to compatible patients. They should ideally achieve better HLA matching, improved Class II matching, lower LKDPI scores, and reduced class II eplet mismatch loads. Better HLA matching has been associated with improved graft survival (30). Additionally, a higher eplet mismatch load, particularly in Class II, has been linked to poorer graft outcomes (31, 32). We prioritize securing better HLA matching, lower LKDPI scores, and reduced class II eplet mismatches for compatible pairs compared to their original donors. This approach can also be adopted by newly developing KPD programs or used to strengthen single-center KPD initiatives.

Another strategy in our program involves converting high-risk HLA incompatibility to low-risk incompatibility and then offering desensitization using rituximab and IVIG. Prior studies have shown that desensitized patients have significantly better survival outcomes compared to those who remain on dialysis (33, 34). Almost 25% of our cohort consisted of very highly sensitized patients (cPRA >95%), whom we were able to transplant through a combination of targeted strategies. This approach enabled us to expand transplant opportunities for patients who would otherwise have had limited or no access to transplantation.

A major strength of our study is the successful implementation of a high-volume, single-center KPD model that accommodates a diverse array of clinical scenarios. Unlike national programs constrained by geography and coordination complexity, our program offered agility and continuity of care, particularly valuable in regions with limited transplant infrastructure for KPD. Furthermore, our structured inclusion of compatible pairs not only enhanced individual outcomes but also increased overall exchange opportunities, amplifying the network effect within our center.

Nonetheless, several limitations merit consideration. First, this was a single-center study with a relatively short follow-up period, which limits the ability to assess long-term outcomes such as graft survival, chronic rejection, and the development of DSAs. While early post-transplant outcomes are encouraging, extended follow-up is essential to confirm durability. However, the favorable immunologic profiles of our cohort—reflected in improved HLA class II matching, reduced class II eplet mismatch loads, and low LKDPI scores—suggest a strong potential for superior long-term outcomes. Second, the generalizability of our findings may be limited, particularly for lower-volume centers or those without established desensitization protocols and strong immunologic infrastructure.

In conclusion, our experience demonstrates the operational feasibility of a high-volume, single-center kidney paired donation program as a strategy to address immunologic incompatibilities in kidney transplantation. Through the structured inclusion of HLA-incompatible pairs, ABO-incompatible pairs, and selected compatible pairs seeking improved matching, together with the use of desensitization protocols when required, such programs can expand transplant opportunities for patients with elevated immunologic risk. While longer follow-up and broader comparative analyses are warranted, our findings suggest that this model may provide a practical framework for other high-capacity centers seeking to increase transplant activity and manage complex donor–recipient incompatibilities.