Balancing Equity and HLA Matching in Deceased-Donor Kidney Allocation with Eplet Mismatch.

Background: Prioritization of HLA antigen-level matching in the US kidney allocation system intends to improve post-transplant survival but causes racial disparities and thus has been substantially de-emphasized. Recently, molecular matching based on eplets has been found to improve risk stratification compared to antigen matching. Methods: To assign eplets unambiguously, we utilized a cohort of 5193 individuals with high resolution allele-level HLA genotypes from the National Kidney Registry. Using repeated random sampling to simulate donor-recipient genotype pairings based on the ethnic composition of the historical US deceased donor pool, we profiled the percentage of well-matched donors for candidates by ethnicity. Results: The percentage of well-matched donors with zero-DR/DQ eplet mismatch was 3-fold less racially disparate for Black and Asian candidates than percentage of donors with zero-ABDR antigen mismatches, and 2-fold less racially disparate for Latino candidates. For other HLA antigen and eplet mismatch thresholds, the percentage of well-matched donors was more similar across candidate ethnic groups. Conclusions: Compared to the current zero-ABDR antigen mismatch, prioritizing a zero-DR/DQ eplet mismatch in allocation would decrease racial disparities and increase the percentage of well-matched donors. High resolution HLA deceased donor genotyping would enable unambiguous assignment of eplets to operationalize molecular mismatch metrics in allocation. Key Points: Question: What is the impact of prioritizing low molecular mismatch transplants on racial and ethnic disparities in US deceased-donor kidney allocation, compared to the current prioritization of antigen-level matching?Findings: The lowest-risk eplet mismatch approach decreases racial disparities up to 3-fold compared to lowest-risk antigen mismatch and identifies a larger number of the lowest allo-immune risk donors.Meaning: Prioritizing eplet matching in kidney transplant allocation could both improve outcomes and reduce racial disparities compared to the current antigen matching.

Heterogeneous donor circles for fair liver transplant allocation.

The United States (U.S.) Department of Health and Human Services is interested in increasing geographical equity in access to liver transplant. The geographical disparity in the U.S. is fundamentally an outcome of variation in the organ supply to patient demand (s/d) ratios across the country (which cannot be treated as a single unit due to its size). To design a fairer system, we develop a nonlinear integer programming model that allocates the organ supply in order to maximize the minimum s/d ratios across all transplant centers. We design circular donation regions that are able to address the issues raised in legal challenges to earlier organ distribution frameworks. This allows us to reformulate our model as a set-partitioning problem. Our policy can be viewed as a heterogeneous donor circle policy, where the integer program optimizes the radius of the circle around each donation location. Compared to the current policy, which has fixed radius circles around donation locations, the heterogeneous donor circle policy greatly improves both the worst s/d ratio and the range between the maximum and minimum s/d ratios. We found that with the fixed radius policy of 500 nautical miles (NM), the s/d ratio ranges from 0.37 to 0.84 at transplant centers, while with the heterogeneous circle policy capped at a maximum radius of 500 NM, the s/d ratio ranges from 0.55 to 0.60, closely matching the national s/d ratio average of 0.5983. Our model matches the supply and demand in a more equitable fashion than existing policies and has a significant potential to improve the liver transplantation landscape.

Accelerating kidney allocation: Simultaneously expiring offers.

Using nonideal kidneys for transplant quickly might reduce the discard rate of kidney transplants. We studied changing kidney allocation to eliminate sequential offers, instead making offers to multiple centers for all nonlocally allocated kidneys, so that multiple centers must accept or decline within the same 1 hour. If more than 1 center accepted an offer, the kidney would go to the highest-priority accepting candidate. Using 2010 Kidney-Pancreas Simulated Allocation Model-Scientific Registry for Transplant Recipients data, we simulated the allocation of 12 933 kidneys, excluding locally allocated and zero-mismatch kidneys. We assumed that each hour of delay decreased the probability of acceptance by 5% and that kidneys would be discarded after 20 hours of offers beyond the local level. We simulated offering kidneys simultaneously to small, medium-size, and large batches of centers. Increasing the batch size increased the percentage of kidneys accepted and shortened allocation times. Going from small to large batches increased the number of kidneys accepted from 10 085 (92%) to 10 802 (98%) for low-Kidney Donor Risk Index kidneys and from 1257 (65%) to 1737 (89%) for high-Kidney Donor Risk Index kidneys. The average number of offers that a center received each week was 10.1 for small batches and 16.8 for large batches. Simultaneously expiring offers might allow faster allocation and decrease the number of discards, while still maintaining an acceptable screening burden.

Restructuring the Organ Procurement and Transplantation Network contract to achieve policy coherence and infrastructure excellence.

The Organ Procurement and Transplantation Network (OPTN) went up for competitive bid again this year, yet this contract has been held by only 1 entity since its inception. The OPTN's scope has grown steadily, and it now embraces several disparate missions: to operate the computing and coordination infrastructure that maintains waitlists and makes organ offers in priority order, to regulate transplant centers and organ procurement organizations, to follow and protect living donors, and to decide organ allocation policy in concert with the many voices of the transplant community. The contracting process and performance work statement continue to discourage both innovative approaches to the OPTN and competitive bids outside of United Network for Organ Sharing (UNOS), with evaluation criteria that either disqualify or strongly disadvantage new applicants. The performance work statement also emphasizes bureaucratic tasks while obligating the OPTN contractor to the specific committee structure that has impeded decision-making and tended to preserve the status quo in controversial matters. Finally, the UNOS computing infrastructure is antiquated and requires months to years to implement small changes. Restructuring the OPTN contract to separate the information technology requirements from the policy/regulatory responsibilities might allow more nimble and effective specialty contractors to offer their capabilities in service of the national transplant enterprise.

Geographic disparities in lung transplant rates.

In November 2017, in response to a lawsuit from a New York City lung transplant candidate, an emergency change to the lung allocation policy eliminated the donation service area (DSA) as the first geographic tier of allocation. The lawsuit claimed that DSA borders are arbitrary and that allocation should be based on medical priority. We investigated whether deceased-donor lung transplant (LT) rates differed substantially between DSAs in the United States before the policy change. We estimated LT rates per active person-year using multilevel Poisson regression and empirical Bayes methods. We found that the median incidence rate ratio (MIRR) of transplant rates between DSAs was 2.05, meaning a candidate could be expected to double their LT rate by changing their DSA. This can be compared directly to a 1.54-fold increase in LT rate that we found associated with an increase in lung allocation score (LAS) category from 38-42 to 42-50. Changing a candidate's DSA would have had a greater impact on the candidate's LT rate than changing LAS categories from 38-42 to 42-50. In summary, we found that the DSA of listing was a major determinant of LT rate for candidates across the country before the emergency lung allocation change.

Geographic disparity in kidney transplantation under KAS.

The Kidney Allocation System fundamentally altered kidney allocation, causing a substantial increase in regional and national sharing that we hypothesized might impact geographic disparities. We measured geographic disparity in deceased donor kidney transplant (DDKT) rate under KAS (6/1/2015-12/1/2016), and compared that with pre-KAS (6/1/2013-12/3/2014). We modeled DSA-level DDKT rates with multilevel Poisson regression, adjusting for allocation factors under KAS. Using the model we calculated a novel, improved metric of geographic disparity: the median incidence rate ratio (MIRR) of transplant rate, a measure of DSA-level variation that accounts for patient casemix and is robust to outlier values. Under KAS, MIRR was 1.75 1.811.86 for adults, meaning that similar candidates across different DSAs have a median 1.81-fold difference in DDKT rate. The impact of geography was greater than the impact of factors emphasized by KAS: having an EPTS score ≤20% was associated with a 1.40-fold increase (IRR = 1.35 1.401.45 , P < .01) and a three-year dialysis vintage was associated with a 1.57-fold increase (IRR = 1.56 1.571.59 , P < .001) in transplant rate. For pediatric candidates, MIRR was even more pronounced, at 1.66 1.922.27 . There was no change in geographic disparities with KAS (P = .3). Despite extensive changes to kidney allocation under KAS, geography remains a primary determinant of access to DDKT.

Liver sharing and organ procurement organization performance under redistricted allocation.

Concerns have been raised that optimized redistricting of liver allocation areas might have the unintended result of shifting livers from better-performing to poorer-performing organ procurement organizations (OPOs). We used liver simulated allocation modeling to simulate a 5-year period of liver sharing within either 4 or 8 optimized districts. We investigated whether each OPO's net liver import under redistricting would be correlated with 2 OPO performance metrics (observed to expected liver yield and liver donor conversion ratio), along with 2 other potential correlates (eligible deaths and incident listings above a Model for End-Stage Liver Disease score of 15). We found no evidence that livers would flow from better-performing OPOs to poorer-performing OPOs in either redistricting scenario. Instead, under these optimized redistricting plans, our simulations suggest that livers would flow from OPOs with more-than-expected eligible deaths toward those with fewer-than-expected eligible deaths and that livers would flow from OPOs with fewer-than-expected incident listings to those with more-than-expected incident listings; the latter is a pattern that is already established in the current allocation system. Redistricting liver distribution to reduce geographic inequity is expected to align liver allocation across the country with the distribution of supply and demand rather than transferring livers from better-performing OPOs to poorer-performing OPOs.

Liver sharing and organ procurement organization performance.

Whether the liver allocation system shifts organs from better performing organ procurement organizations (OPOs) to poorer performing OPOs has been debated for many years. Models of OPO performance from the Scientific Registry of Transplant Recipients make it possible to study this question in a data-driven manner. We investigated whether each OPO's net liver import was correlated with 2 performance metrics [observed to expected (O:E) liver yield and liver donor conversion ratio] as well as 2 alternative explanations [eligible deaths and incident listings above a Model for End-Stage Liver Disease (MELD) score of 15]. We found no evidence to support the hypothesis that the allocation system transfers livers from better performing OPOs to centers with poorer performing OPOs. Also, having fewer eligible deaths was not associated with a net import. However, having more incident listings was strongly correlated with the net import, both before and after Share 35. Most importantly, the magnitude of the variation in OPO performance was much lower than the variation in demand: although the poorest performing OPOs differed from the best ones by less than 2-fold in the O:E liver yield, incident listings above a MELD score of 15 varied nearly 14-fold. Although it is imperative that all OPOs achieve the best possible results, the flow of livers is not explained by OPO performance metrics, and instead, it appears to be strongly related to differences in demand.

The interaction among donor characteristics, severity of liver disease, and the cost of liver transplantation.

Accurate assessment of the impact of donor quality on liver transplant (LT) costs has been limited by the lack of a large, multicenter study of detailed clinical and economic data. A novel, retrospective database linking information from the University HealthSystem Consortium and the Organ Procurement and Transplantation Network registry was analyzed using multivariate regression to determine the relationship between donor quality (assessed through the Donor Risk Index [DRI]), recipient illness severity, and total inpatient costs (transplant and all readmissions) for 1 year following LT. Cost data were available for 9059 LT recipients. Increasing MELD score, higher DRI, simultaneous liver-kidney transplant, female sex, and prior liver transplant were associated with increasing cost of LT (P < 0.05). MELD and DRI interact to synergistically increase the cost of LT (P < 0.05). Donors in the highest DRI quartile added close to $12,000 to the cost of transplantation and nearly $22,000 to posttransplant costs in comparison to the lowest risk donors. Among the individual components of the DRI, donation after cardiac death (increased costs by $20,769 versus brain dead donors) had the greatest impact on transplant costs. Overall, 1-year costs were increased in older donors, minority donors, nationally shared organs, and those with cold ischemic times of 7-13 hours (P < 0.05 for all). In conclusion, donor quality, as measured by the DRI, is an independent predictor of LT costs in the perioperative and postoperative periods. Centers in highly competitive regions that perform transplantation on higher MELD patients with high DRI livers may be particularly affected by the synergistic impact of these factors.

Kidney paired donation: fundamentals, limitations, and expansions.

Incompatibility between the candidate recipient and the prospective donor is a major obstacle to living donor kidney transplant. Kidney paired donation (KPD) can circumvent the incompatibility by matching them to another candidate and living donor for an exchange of transplants such that both transplants are compatible. KPD has faced legal, logistical, and ethical challenges since its inception in the 1980s. Although the full potential of this modality for facilitating transplant for individuals with incompatible donors is unrealized, great strides have been made. In this review article, we detail how several impediments to KPD have been overcome to the benefit of ever greater numbers of patients. Limitations and questions that have been addressed include blood group type O imbalance, reciprocal match requirements, simultaneous donor nephrectomy requirements, combining KPD with desensitization, the role of list-paired donation, geographic barriers, legal barriers, concerns regarding living donor safety, fragmented registries, and inefficient matching algorithms.

The interplay of socioeconomic status, distance to center, and interdonor service area travel on kidney transplant access and outcomes.

BACKGROUND AND OBJECTIVES: Variation in kidney transplant access across the United States may motivate relocation of patients with ability to travel to better-supplied areas. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We examined national transplant registry and U.S. Census data for kidney transplant candidates listed in 1999 to 2009 with a reported residential zip code (n = 203,267). Cox's regression was used to assess associations of socioeconomic status (SES), distance from residence to transplant center, and relocation to a different donation service area (DSA) with transplant access and outcomes. RESULTS: Patients in the highest SES quartile had increased access to transplant compared with those with lowest SES, driven strongly by 76% higher likelihood of living donor transplantation (adjusted hazard ratio [aHR] 1.76, 95% confidence interval [CI] 1.70 to 1.83). Waitlist death was reduced in high compared with low SES candidates (aHR 0.86, 95% CI 0.84 to 0.89). High SES patients also experienced lower mortality after living and deceased donor transplant. Patients living farther from the transplant center had reduced access to deceased donor transplant and increased risk of post-transplant death. Inter-DSA travel was associated with a dramatic increase in deceased donor transplant access (HR 1.94, 95% CI 1.88 to 2.00) and was predicted by high SES, white race, and longer deceased-donor allograft waiting time in initial DSA. CONCLUSIONS: Ongoing disparities exist in kidney transplantation access and outcomes on the basis of geography and SES despite near-universal insurance coverage under Medicare. Inter-DSA travel improves access and is more common among high SES candidates.

Kidney paired donation and optimizing the use of live donor organs.

CONTEXT: Blood type and crossmatch incompatibility will exclude at least one third of patients in need from receiving a live donor kidney transplant. Kidney paired donation (KPD) offers incompatible donor/recipient pairs the opportunity to match for compatible transplants. Despite its increasing popularity, very few transplants have resulted from KPD. OBJECTIVE: To determine the potential impact of improved matching schemes on the number and quality of transplants achievable with KPD. DESIGN, SETTING, AND POPULATION: We developed a model that simulates pools of incompatible donor/recipient pairs. We designed a mathematically verifiable optimized matching algorithm and compared it with the scheme currently used in some centers and regions. Simulated patients from the general community with characteristics drawn from distributions describing end-stage renal disease patients eligible for renal transplantation and their willing and eligible live donors. MAIN OUTCOME MEASURES: Number of kidneys matched, HLA mismatch of matched kidneys, and number of grafts surviving 5 years after transplantation. RESULTS: A national optimized matching algorithm would result in more transplants (47.7% vs 42.0%, P<.001), better HLA concordance (3.0 vs 4.5 mismatched antigens; P<.001), more grafts surviving at 5 years (34.9% vs 28.7%; P<.001), and a reduction in the number of pairs required to travel (2.9% vs 18.4%; P<.001) when compared with an extension of the currently used first-accept scheme to a national level. Furthermore, highly sensitized patients would benefit 6-fold from a national optimized scheme (2.3% vs 14.1% successfully matched; P<.001). Even if only 7% of patients awaiting kidney transplantation participated in an optimized national KPD program, the health care system could save as much as $750 million. CONCLUSIONS: The combination of a national KPD program and a mathematically optimized matching algorithm yields more matches with lower HLA disparity. Optimized matching affords patients the flexibility of customizing their matching priorities and the security of knowing that the greatest number of high-quality matches will be found and distributed equitably.

Assessment of the VEGF, bFGF, aFGF and IL8 angiogenic activity in urinary bladder carcinoma, using the mice cutaneous angiogenesis test.

Development of new blood vessels in solid tumors depends on changes in equilibrium between angiogenic stimulators and inhibitors. Overexpression of angiogenic growth factors has been shown in bladder carcinoma. The 'mice cutaneous angiogenesis test' is a good method for assessment of the total angiogenic potential of bladder cancer tissue. The analysis of the levels of proangiogenic factors could be useful for the choice of properly directed angiogenesis inhibitors. The aim of our study was to investigate the influence of blocking some angiogenic factors on the angiogenic activity of bladder cancer tissue. Tumor tissue obtained from 12 patients with invasive bladder carcinoma was used. Cancer tissue homogenates were incubated in the presence of specific antibodies against VEGF, bFGF, Il-8 and aFGF. Cytokine levels were determined using the ELISA test. Cutaneous angiogenesis assay in Balb/c mice was performed to detect the angiogenic activity of the tumor tissue. VEGF, bFGF and Il-8 were present in all examined cancer tissues (aFGF level was not estimated). Cytokine concentration and angiogenic activity of bladder cancer tissue showed individual variation. There was no correlation between the cytokines content in tumor tissue and the ability of this tissue to induce angiogenesis. Absorption caused significant reduction in cytokines level. The reduction of angiogenic activity was observed in the cancer tissue of 1 patient after VEGF absorption, in 3 patients' tissue homogenates after incubation with anti-aFGF and in 2 patients' homogenates after bFGF absorption. There was no reduction of angiogenic activity after Il-8 absorption.