Kidney Paired Donation Chains Initiated by Deceased Donors.

Introduction: Rather than generating 1 transplant by directly donating to a candidate on the waitlist, deceased donors (DDs) could achieve additional transplants by donating to a candidate in a kidney paired donation (KPD) pool, thereby, initiating a chain that ends with a living donor (LD) donating to a candidate on the waitlist. We model outcomes arising from various strategies that allow DDs to initiate KPD chains. Methods: We base simulations on actual 2016 to 2017 US DD and waitlist data and use simulated KPD pools to model DD-initiated KPD chains. We also consider methods to assess and overcome the primary criticism of this approach, namely the potential to disadvantage blood type O-waitlisted candidates. Results: Compared with shorter DD-initiated KPD chains, longer chains increase the number of KPD transplants by up to 5% and reduce the number of DDs allocated to the KPD pool by 25%. These strategies increase the overall number of blood type O transplants and make LDs available to candidates on the waitlist. Restricting allocation of blood type O DDs to require ending KPD chains with LD blood type O donations to the waitlist markedly reduces the number of KPD transplants achieved. Conclusion: Allocating fewer than 3% of DD to initiate KPD chains could increase the number of kidney transplants by up to 290 annually. Such use of DDs allows additional transplantation of highly sensitized and blood type O KPD candidates. Collectively, patients of each blood type, including blood type O, would benefit from the proposed strategies.

Deceased donors as nondirected donors in kidney paired donation.

As proof of concept, we simulate a revised kidney allocation system that includes deceased donor (DD) kidneys as chain-initiating kidneys (DD-CIK) in a kidney paired donation pool (KPDP), and estimate potential increases in number of transplants. We consider chains of length 2 in which the DD-CIK gives to a candidate in the KPDP, and that candidate's incompatible donor donates to theDD waitlist. In simulations, we vary initial pool size, arrival rates of candidate/donor pairs and (living) nondirected donors (NDDs), and delay time from entry to the KPDP until a candidate is eligible to receive a DD-CIK. Using data on candidate/donor pairs and NDDs from the Alliance for Paired Kidney Donation, and the actual DDs from the Scientific Registry of Transplant Recipients (SRTR) data, simulations extend over 2 years. With an initial pool of 400, respective candidate and NDD arrival rates of 2 per day and 3 per month, and delay times for access to DD-CIK of 6 months or less, including DD-CIKs increases the number of transplants by at least 447 over 2 years, and greatly reduces waiting times of KPDP candidates. Potential effects on waitlist candidates are discussed as are policy and ethical issues.

Life and expectations post-kidney transplant: a qualitative analysis of patient responses.

BACKGROUND: The effect of a kidney transplant on a recipient extends beyond the restoration of kidney function. However, there is limited qualitative analysis of recipient perspectives on life following transplantation, particularly in the United States. To understand the full patient experience, it is necessary to understand recipient views on life adjustments after kidney transplantation, medical management, and quality of life. This could lead to improvements in recipient care and sense of well-being. METHODS: We conducted a paper-based survey from March 23 to October 1, 2015 of 476 kidney transplant recipients at the University of Michigan Health System in Ann Arbor, Michigan. We analyzed their open-ended responses using qualitative research methods. This is a companion analysis to a previous quantitative report on the closed-ended responses to that survey. RESULTS: Common themes relating to changes following transplantation included: improvements in quality of life, a return to normalcy, better health and more energy. Concerns included: duration of graft survival, fears about one day returning to dialysis or needing to undergo another kidney transplant, comorbidities, future quality of life, and the cost and quality of their healthcare. Many recipients were grateful for their transplant, but some were anxious about the burdens transplantation placed on their loved ones. CONCLUSIONS: While most recipients reported meaningful improvements in health and lifestyle after kidney transplantation, a minority of participants experienced declines in energy or health status. Worries about how long the transplant will function, future health, and cost and quality of healthcare are prevalent. Future research could study the effects of providing additional information, programs, and interventions following transplantation that target these concerns. This may better prepare and support kidney recipients and lead to improvements in the patient experience.

KPDGUI: An interactive application for optimization and management of a virtual kidney paired donation program.

BACKGROUND AND OBJECTIVES: The aim in kidney paired donation (KPD) is typically to maximize the number of transplants achieved through the exchange of donors in a pool comprising incompatible donor-candidate pairs and non-directed (or altruistic) donors. With many possible options in a KPD pool at any given time, the most appropriate set of exchanges cannot be determined by simple inspection. In practice, computer algorithms are used to determine the optimal set of exchanges to pursue. Here, we present our software application, KPDGUI (Kidney Paired Donation Graphical User Interface), for management and optimization of KPD programs. METHODS: While proprietary software platforms for managing KPD programs exist to provide solutions to the standard KPD problem, our application implements newly investigated optimization criteria that account for uncertainty regarding the viability of selected transplants and arrange for fallback options in cases where potential exchanges cannot proceed, with intuitive resources for visualizing alternative optimization solutions. RESULTS: We illustrate the advantage of accounting for uncertainty and arranging for fallback options in KPD using our application through a case study involving real data from a paired donation program, comparing solutions produced under different optimization criteria and algorithmic priorities. CONCLUSIONS: KPDGUI is a flexible and powerful tool for offering decision support to clinicians and researchers on possible KPD transplant options to pursue under different user-specified optimization schemes.

Secular Trends in the Cost of Immunosuppressants after Solid Organ Transplantation in the United States.

BACKGROUND AND OBJECTIVES: Immunosuppressive medications are critical for maintenance of graft function in transplant recipients but can represent a substantial financial burden to patients and their insurance carriers. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: To determine whether availability of generic immunosuppressive medications starting in 2009 may have alleviated some of that burden, we used Medicare Part D prescription drug events between 2008 and 2013 to estimate the average annualized per-patient payments made by patients and Medicare in a large national sample of kidney, liver, and heart transplant recipients. Repeated measures linear regression was used to determine changes in payments over the study period. RESULTS: Medicare Part D payments for two commonly used immunosuppressive medications, tacrolimus and mycophenolic acid (including mycophenolate mofetil and mycophenolate sodium), decreased overall by 48%-67% across organs and drugs from 2008 to 2013, reflecting decreasing payments for brand and generic tacrolimus (21%-54%), and generic mycophenolate (72%-74%). Low-income subsidy payments, which are additional payments made under Medicare Part D, also decreased during the study period. Out-of-pocket payments by patients who did not receive the low-income subsidy decreased by more than those who did receive the low-income subsidy (63%-79% versus 24%-44%). CONCLUSIONS: The decline in payments by Medicare Part D and by transplant recipients for tacrolimus and mycophenolate between 2008 and 2013 suggests that the introduction of generic immunosuppressants during this period has resulted in substantial cost savings to Medicare and to patients, largely reflecting the transition from brand to generic products.

Comparison of patient and provider goals, expectations, and experiences following kidney transplantation.

OBJECTIVE: This study examined whether kidney transplant recipients' post-transplant goals and expectations align with those as perceived by their healthcare providers. METHODS: Post-transplant goals and expectations across four domains were assessed via a descriptive survey of healthcare providers (N=72) and kidney transplant recipients (N=476) at the University of Michigan from March 23 - October 1, 2015. Demographic and transplant-related data were collected via a retrospective review of medical records, and survey responses were compared using Chi-square tests, Wilcoxon two-sample tests, and logistic regression. RESULTS: Patients expressed higher quality of life (mean Neuro-QOL T-score 60.2 vs. 52.7), were less likely to report that they were currently experiencing complications (11% vs. 24%), and anticipated their transplants to last longer (median 25 vs. 15 years) and to live longer (median 80 vs. 71 years) than providers expected for their typical patient. However, provider perceptions of patients' future ability to feel well, perform daily activities and work were significantly higher than those expressed by patients (all p<0.05). CONCLUSION: Kidney transplant patient and provider expectations differ in significant ways. PRACTICE IMPLICATIONS: Identified areas of discordance may provide opportunities for patients and providers to better evaluate treatment option tradeoffs in post-transplant clinical interactions.

A Kidney Graft Survival Calculator that Accounts for Mismatches in Age, Sex, HLA, and Body Size.

BACKGROUND AND OBJECTIVES: Outcomes for transplants from living unrelated donors are of particular interest in kidney paired donation (KPD) programs where exchanges can be arranged between incompatible donor-recipient pairs or chains created from nondirected/altruistic donors. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using Scientific Registry of Transplant Recipients data, we analyzed 232,705 recipients of kidney-alone transplants from 1998 to 2012. Graft failure rates were estimated using Cox models for recipients of kidney transplants from living unrelated, living related, and deceased donors. Models were adjusted for year of transplant and donor and recipient characteristics, with particular attention to mismatches in age, sex, human leukocyte antigens (HLA), body size, and weight. RESULTS: The dependence of graft failure on increasing donor age was less pronounced for living-donor than for deceased-donor transplants. Male donor-to-male recipient transplants had lower graft failure, particularly better than female to male (5%-13% lower risk). HLA mismatch was important in all donor types. Obesity of both the recipient (8%-18% higher risk) and donor (5%-11% higher risk) was associated with higher graft loss, as were donor-recipient weight ratios of <75%, compared with transplants where both parties were of similar weight (9%-12% higher risk). These models are used to create a calculator of estimated graft survival for living donors. CONCLUSIONS: This calculator provides useful information to donors, candidates, and physicians of estimated outcomes and potentially in allowing candidates to choose among several living donors. It may also help inform candidates with compatible donors on the advisability of joining a KPD program.

HLA Amino Acid Polymorphisms and Kidney Allograft Survival.

BACKGROUND: The association of HLA mismatching with kidney allograft survival has been well established. We examined whether amino acid (AA) mismatches (MMs) at the antigen recognition site of HLA molecules represent independent and incremental risk factors for kidney graft failure (GF) beyond those MMs assessed at the antigenic (2-digit) specificity. METHODS: Data on 240 024 kidney transplants performed between 1987 and 2009 were obtained from the Scientific Registry of Transplant Recipients. We imputed HLA-A, -B, and -DRB1 alleles and corresponding AA polymorphisms from antigenic specificity through the application of statistical and population genetics inferences. GF risk was evaluated using Cox proportional-hazards regression models adjusted for covariates including patient and donor risk factors and HLA antigen MMs. RESULTS: We show that estimated AA MMs at particular positions in the peptide-binding pockets of HLA-DRB1 molecule account for a significant incremental risk that was independent of the well-known association of HLA antigen MMs with graft survival. A statistically significant linear relationship between the estimated number of AA MMs and risk of GF was observed for HLA-DRB1 in deceased donor and living donor transplants. This relationship was strongest during the first 12 months after transplantation (hazard ratio, 1.30 per 15 DRB1 AA MM; P < 0.0001). CONCLUSIONS: This study shows that independent of the well-known association of HLA antigen (2-digit specificity) MMs with kidney graft survival, estimated AA MMs at peptide-binding sites of the HLA-DRB1 molecule account for an important incremental risk of GF.

Why do we have the kidney allocation system we have today? A history of the 2014 kidney allocation system.

"Those who do not know the past are destined to repeat it". The current system for the allocation of deceased donor kidneys that was implemented in December 2014 (termed the kidney allocation system (KAS)) was the culmination of a decade-long process. Thus, many people involved in transplantation today may not be aware of the underlying concepts and early debates that resulted in KAS. Others who were involved might not remember the details (or have chosen to forget). The goal of this manuscript is to outline the history of the process in order to shed light on why KAS has its current format.

Coagulation status after therapeutic plasma exchange using citrate in kidney transplant recipients.

BACKGROUND: Therapeutic plasma exchange (TPE) is increasingly used for treatment of antibody-mediated rejection (AMR) after solid organ transplants. There is concern that TPE may increase risk of bleeding, although data are limited. After TPE, clot-based coagulation tests may not accurately represent the levels of coagulation factors due to the effect of citrate. We investigated protein levels of fibrinogen using antigen detection method (FibAg) and correlated results with a clot-based fibrinogen activity test (Fib). STUDY DESIGN AND METHODS: Nine kidney transplant recipients who received TPE for AMR were investigated. Fib, FibAg, prothrombin time/international normalized ratio (PT/INR), partial thromboplastin time (PTT), coagulation factor X chromogenic activity (CFX), and ionized calcium (iCa) were measured at pre- and post-TPE and 1, 3, 6, 9, 24, and 48 hours after the first TPE. RESULTS: Mean Fib/FibAg ratio before TPE was 1.08; therefore, all Fib values were normalized (n) by dividing by 1.08. Overall, the mean normalized Fib (nFib)/FibAg ratio at post-TPE was 0.89 and returned to close to 1.0 at 6 hours after the first TPE. Decreases in nFib, FibAg, and CFX and increases in PT/INR and PTT post-TPE were observed. The lowest Fib, FibAg, CFX, platelet, and iCa levels were still at levels that would be considered sufficient for hemostasis at all time points. CONCLUSION: The mean nFib/FibAg ratio after TPE was 0.89 and normalized in 6 hours, which demonstrates a persistent effect of citrate for up to 6 hours. Therefore, similar data observed in clot-based tests of PT/INR and PTT may be falsely elevated up to 6 hours after TPE due to the citrate effect.

Efficacy of plasmapheresis on donor-specific antibody reduction by HLA specificity in post-kidney transplant recipients.

BACKGROUND: Donor-specific antibodies (DSAs) to HLA antigens can cause acute antibody-mediated rejection (AMR) after kidney transplantation (Txp). Therapeutic plasma exchange (TPE) has been used for AMR treatment; however, DSA reduction rates are inconsistent. We investigated DSA reduction rates by HLA specificity and clinical outcome. STUDY DESIGN AND METHODS: Sixty-four courses of TPE for 56 kidney Txp recipients with high DSA were investigated. Dates of TPE procedures and Txp, patients' age, sex, race, creatinine (Cr), and mean fluorescent intensity (MFI) of DSA were retrieved. MFI reduction rate after one to three TPE and four to six TPE procedures were calculated by HLA DSA specificity in each patient, and the mean reduction rates were compared. The relationship of TPE treatment, MFI or Cr improvement rate, and graft age was also investigated. RESULTS: Patients received a mean 6.0 TPE procedures. Most received intravenous immunoglobulin after TPE and immunosuppressives. Forty-two cases (65.6%) had DSA to HLA Class I and 54 cases (84.4%) to Class II, including 32 cases (50.0%) to both. Mean MFI reduction rates after one to three TPE and four to six TPE procedures were 25.7 and 37.1% in HLA Class I, 25.1 and 34.2% in Class II, and 14.3 and 19.9% in DR51-53. The mean Cr improvements at the end of TPE and 3 and 6 months after TPE were 3.41, -0.37, and -0.72%, respectively. CONCLUSION: Six TPE procedures decreased DSA more than three TPE procedures, but reduction rate was lower by the second three TPE procedures than the first three TPE procedures. Although the mean Cr improvement was minimal, the treatment has good potential to stop further deterioration of kidney function. Better Cr improvement rate is correlated with the graft age.

Patient selection and volume in the era surrounding implementation of Medicare conditions of participation for transplant programs.

OBJECTIVE: To evaluate evidence of practice changes affecting kidney transplant program volumes, and donor, recipient and candidate selection in the era surrounding the introduction of Centers for Medicare and Medicaid Services (CMS) conditions of participation (CoPs) for organ transplant programs. DATA: Scientific Registry of Transplant Recipients; CMS ESRD and Medicare claims databases. DESIGN: Retrospective analysis of national registry data. METHODS: A Cox proportional hazards model of 1-year graft survival was used to derive risks associated with deceased-donor kidney transplants performed from 2001 to 2010. FINDINGS: Among programs with ongoing noncompliance with the CoPs, kidney transplant volumes declined by 38 percent (n = 766) from 2006 to 2011, including a 55 percent drop in expanded criteria donor transplants. Volume increased by 6 percent (n = 638) among programs remaining in compliance. Aggregate risk of 1-year graft failure increased over time due to increasing recipient age and obesity, and longer ESRD duration. CONCLUSIONS: Although trends in aggregate risk of 1-year kidney graft loss do not indicate that the introduction of the CoPs has systematically reduced opportunities for marginal candidates or that there has been a systematic shift away from utilization of higher risk deceased donor kidneys, total volume and expanded criteria donor utilization decreased overall among programs with ongoing noncompliance.

Decision Making in Kidney Paired Donation Programs with Altruistic Donors.

In recent years, kidney paired donation (KPD) has been extended to include living non-directed or altruistic donors, in which an altruistic donor donates to the candidate of an incompatible donor-candidate pair with the understanding that the donor in that pair will further donate to the candidate of a second pair, and so on; such a process continues and thus forms an altruistic donor-initiated chain. In this paper, we propose a novel strategy to sequentially allocate the altruistic donor (or bridge donor) so as to maximize the expected utility; analogous to the way a computer plays chess, the idea is to evaluate different allocations for each altruistic donor (or bridge donor) by looking several moves ahead in a derived look-ahead search tree. Simulation studies are provided to illustrate and evaluate our proposed method.

Satisfaction With Life Among Living Kidney Donors: A RELIVE Study of Long-Term Donor Outcomes.

BACKGROUND: Little is known about living kidney donors' satisfaction with life (SWL) after donation. We compared donors' SWL to previously reported general population samples and investigated predictors of donors' SWL. METHODS: Three transplant centers mailed questionnaires to assess SWL, physical health, optimism, retrospective evaluation of the donation experience, and demographic characteristics to living kidney donors' homes between 2010 and 2012. Two thousand four hundred fifty-five donors who were between 5 and 48 years from the time of their donor surgery completed the questionnaire. RESULTS: Eighty-four percent of donors were satisfied with their lives (scores ≥ 20 on the Satisfaction With Life Scale). Donors were at least as satisfied with their lives as previously reported general population samples. After adjusting for physical health, optimism, and demographics, donors' SWL was significantly associated with donors' recalled experience of donation. Social support and positive effects of the donation on relationships predicted greater SWL. Financial difficulties associated with donation and longer recovery times predicted lower SWL. Recipient outcomes were not significantly related to donor SWL. DISCUSSION: Limitations include the lack of predonation SWL data, potential bias in postdonation SWL because of the situational context of the questionnaire, and a sample that is not representative of all U.S. living kidney donors. Nonetheless, strategies focused on improving the donation experience, particularly related to recovery time, financial issues, and social support, may result in greater SWL after donation.

Optimal Decisions for Organ Exchanges in a Kidney Paired Donation Program.

The traditional concept of barter exchange in economics has been extended in the modern era to the area of living-donor kidney transplantation, where one incompatible donor-candidate pair is matched to another pair with a complementary incompatibility, such that the donor from one pair gives an organ to a compatible candidate in the other pair and vice versa. Kidney paired donation (KPD) programs provide a unique and important platform for living incompatible donor-candidate pairs to exchange organs in order to achieve mutual benefit. In this paper, we propose novel organ allocation strategies to arrange kidney exchanges under uncertainties with advantages, including (i) allowance for a general utility-based evaluation of potential kidney transplants and an explicit consideration of stochastic features inherent in a KPD program; and (ii) exploitation of possible alternative exchanges when the originally planned allocation cannot be fully executed. This allocation strategy is implemented using an integer programming (IP) formulation, and its implication is assessed via a data-based simulation system by tracking an evolving KPD program over a series of match runs. Extensive simulation studies are provided to illustrate our proposed approach.

Kidney transplantation as primary therapy for end-stage renal disease: a National Kidney Foundation/Kidney Disease Outcomes Quality Initiative (NKF/KDOQITM) conference.

BACKGROUND AND OBJECTIVES: Kidney transplantation is the most desired and cost-effective modality of renal replacement therapy for patients with irreversible chronic kidney failure (end-stage renal disease, stage 5 chronic kidney disease). Despite emerging evidence that the best outcomes accrue to patients who receive a transplant early in the course of renal replacement therapy, only 2.5% of incident patients with end-stage renal disease undergo transplantation as their initial modality of treatment, a figure largely unchanged for at least a decade. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The National Kidney Foundation convened a Kidney Disease Outcomes Quality Initiative (KDOQI) conference in Washington, DC, March 19 through 20, 2007, to examine the issue. Fifty-two participants representing transplant centers, dialysis providers, and payers were divided into three work groups to address the impact of early transplantation on the chronic kidney disease paradigm, educational needs of patients and professionals, and finances of renal replacement therapy. RESULTS: Participants explored the benefits of early transplantation on costs and outcomes, identified current barriers (at multiple levels) that impede access to early transplantation, and recommended specific interventions to overcome those barriers. CONCLUSIONS: With implementation of early education, referral to a transplant center coincident with creation of vascular access, timely transplant evaluation, and identification of potential living donors, early transplantation can be an option for substantially more patients with chronic kidney disease.

Insurance type and minority status associated with large disparities in prelisting dialysis among candidates for kidney transplantation.

BACKGROUND AND OBJECTIVES: Disparities in time to placement on the waiting list on the basis of socioeconomic factors decrease access to deceased-donor renal transplantation for some groups of patients with end-stage renal disease. This study was undertaken to determine candidate factors that influence duration of dialysis before placement on the waiting list among candidates for deceased-donor renal transplantation in the United States from January 2001 to December 2004 and the impact of Medicare eligibility rules on access. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Access to the waiting list was measured as the percentage of all wait-listed candidates in the Scientific Registry of Transplant Recipients database who were listed before dialysis and by the duration of dialysis before placement on the waiting list. Multivariate logistic and linear regressions were used to determine variables that were predictive of preemptive listing and the duration of dialysis before listing. RESULTS: The odds for preemptive placement on the waiting list improved during the course of the study period, whereas the median duration of prelisting dialysis did not. The candidate factors that were associated with low rates of preemptive listing and prolonged exposure to prelisting dialysis included Medicare insurance, minority race/ethnicity, and low educational attainment. In patients who were listed after the age of 64 yr, the adverse effect of Medicare insurance on access largely disappeared. CONCLUSIONS: The disparity in dialysis exposure could potentially be diminished by concerted efforts on the part of the nephrology and transplant communities to promote early referral and preemptive placement on the waiting list, by calculating waiting time from the date of initiation of dialysis for patients who are on dialysis at the time of referral, and by relaxing Medicare eligibility requirements.