Utilization of Deceased Donor Kidneys to Initiate Living Donor Chains.

We propose that some deceased donor (DD) kidneys be allocated to initiate nonsimultaneous extended altruistic donor chains of living donor (LD) kidney transplants to address, in part, the huge disparity between patients on the DD kidney waitlist and available donors. The use of DD kidneys for this purpose would benefit waitlisted candidates in that most patients enrolled in kidney paired donation (KPD) systems are also waitlisted for a DD kidney transplant, and receiving a kidney through the mechanism of KPD will decrease pressure on the DD pool. In addition, a LD kidney usually provides survival potential equal or superior to that of DD kidneys. If KPD chains that are initiated by a DD can end in a donation of an LD kidney to a candidate on the DD waitlist, the quality of the kidney allocated to a waitlisted patient is likely to be improved. We hypothesize that a pilot program would show a positive impact on patients of all ethnicities and blood types.

Planning for Uncertainty and Fallbacks Can Increase the Number of Transplants in a Kidney-Paired Donation Program.

A kidney-paired donation (KPD) pool consists of transplant candidates and their incompatible donors, along with nondirected donors (NDDs). In a match run, exchanges are arranged among pairs in the pool via cycles, as well as chains created from NDDs. A problem of importance is how to arrange cycles and chains to optimize the number of transplants. We outline and examine, through example and by simulation, four schemes for selecting potential matches in a realistic model of a KPD system; proposed schemes take account of probabilities that chosen transplants may not be completed as well as allowing for contingency plans when the optimal solution fails. Using data on candidate/donor pairs and NDDs from the Alliance for Paired Donation, the simulations extend over 8 match runs, with 30 pairs and 1 NDD added between each run. Schemes that incorporate uncertainties and fallbacks into the selection process yield substantially more transplants on average, increasing the number of transplants by as much as 40% compared to a standard selection scheme. The gain depends on the degree of uncertainty in the system. The proposed approaches can be easily implemented and provide substantial advantages over current KPD matching algorithms.

Historical Matching Strategies in Kidney Paired Donation: The 7-Year Evolution of a Web-Based Virtual Matching System.

Failure to convert computer-identified possible kidney paired donation (KPD) exchanges into transplants has prohibited KPD from reaching its full potential. This study analyzes the progress of exchanges in moving from "offers" to completed transplants. Offers were divided into individual segments called 1-way transplants in order to calculate success rates. From 2007 to 2014, the Alliance for Paired Donation performed 243 transplants, 31 in collaboration with other KPD registries and 194 independently. Sixty-one of 194 independent transplants (31.4%) occurred via cycles, while the remaining 133 (68.6%) resulted from nonsimultaneous extended altruistic donor (NEAD) chains. Thirteen of 35 (37.1%) NEAD chains with at least three NEAD segments accounted for 68% of chain transplants (8.6 tx/chain). The "offer" and 1-way success rates were 21.9 and 15.5%, respectively. Three reasons for failure were found that could be prospectively prevented by changes in protocol or software: positive laboratory crossmatch (28%), transplant center declined donor (17%) and pair transplanted outside APD (14%). Performing a root cause analysis on failures in moving from offer to transplant has allowed the APD to improve protocols and software. These changes have improved the success rate and the number of transplants performed per year.

Demographic, metabolic, and blood pressure characteristics of living kidney donors spanning five decades.

While cautious criteria for selection of living kidney donors are credited for favorable outcomes, recent practice changes may include acceptance of less than ideal donors. To characterize trends in donor acceptance, the Renal and Lung Living Donors Evaluation (RELIVE) Study evaluated 8,951 kidney donors who donated between 1963 and 2007 at three major U.S. transplant centers. Over the study interval, there was an increase in the percentage of donors >40 years old from 38% to 51%; donors >60 years varied between 1% and 4%. The proportion of donors with obesity increased from 8% to 26% and with glucose intolerance from 9% to 25%. The percentage of hypertensive donors was consistent (5-8%). Accepted donors ≥60 years old were more likely to have obesity, glucose intolerance, and/or hypertension compared to younger donors (p<0.0001). Our results demonstrate important trends in acceptance of older and more obese donors. The fraction of older donors accepted with glucose intolerance or hypertension remains small and for the majority includes mild elevations in glucose or blood pressure that were previously classified as within normal limits.

Dynamic challenges inhibiting optimal adoption of kidney paired donation: findings of a consensus conference.

While kidney paired donation (KPD) enables the utilization of living donor kidneys from healthy and willing donors incompatible with their intended recipients, the strategy poses complex challenges that have limited its adoption in United States and Canada. A consensus conference was convened March 29-30, 2012 to address the dynamic challenges and complexities of KPD that inhibit optimal implementation. Stakeholders considered donor evaluation and care, histocompatibility testing, allocation algorithms, financing, geographic challenges and implementation strategies with the goal to safely maximize KPD at every transplant center. Best practices, knowledge gaps and research goals were identified and summarized in this document.

Utilization of kidneys with similar kidney donor risk index values from standard versus expanded criteria donors.

With the shortage of standard criteria donor (SCD) kidneys, efficient expanded criteria donor (ECD) kidney utilization has become more vital. We investigated the effects of the ECD label on kidney recovery, utilization and outcomes. Using data from the Scientific Registry of Transplant Recipients from November 2002 to May 2010, we determined recovery and transplant rates, and modeled discard risk, for kidneys within a range of kidney donor risk index (KDRI) 1.4-2.1 that included both SCD and ECD kidneys. To further compare similar quality kidneys, these kidneys were again divided into three KDRI intervals. Overall, ECD kidneys had higher recovery rates, but lower transplant rates. However, within each KDRI interval, SCD and ECD kidneys were transplanted at similar rates. Overall, there was increased risk for discard for biopsied kidneys. SCD kidneys in the lower two KDRI intervals had the highest risk of discard if biopsied. Pumped kidneys had a lower risk of discard, which was modulated by KDRI for SCD kidneys but not ECD kidneys. Although overall ECD graft survival was worse than SCD, there were no differences within individual KDRI intervals. Thus, ECD designation adversely affects neither utilization nor outcomes beyond that predicted by KDRI.

Call to develop a standard acquisition charge model for kidney paired donation.

We propose a Medicare Demonstration Project to develop a standard acquisition charge for kidney paired donation. A new payment strategy is required because Medicare and commercial insurance companies may not directly pay living donor costs intended to lead to transplantation of a beneficiary of a different insurance provider. Until the 1970s, when organ procurement organizations were empowered to serve as financial intermediaries to pay the upfront recovery expenses for deceased donor kidneys before knowing the identity of the recipient, there existed similar limitations in the recovery and placement of deceased donor organs. Analogous to the recovery of deceased donor kidneys, kidney paired donation requires the evaluation of living donors before identifying their recipient. Tissue typing, crossmatching and transportation of living donors or their kidneys represent additional financial barriers. Finally, the administrative expenses of the organizations that identify and coordinate kidney paired donation transplantation require reimbursement akin to that necessary for organ procurement organizations. To expand access to kidney paired donation for more patients, we propose a model to reimburse paired donation expenses analogous to the proven strategy used for over 30 years to pay for deceased donor solid organ transplantation in America.

Transplanting kidneys without points for HLA-B matching: consequences of the policy change.

In 2003, the US kidney allocation system was changed to eliminate priority for HLA-B similarity. We report outcomes from before and after this change using data from the Scientific Registry of Transplant Recipients (SRTR). Analyses were based on 108 701 solitary deceased donor kidney recipients during the 6 years before and after the policy change. Racial/ethnic distributions of recipients in the two periods were compared (chi-square); graft failures were analyzed using Cox models. In the 6 years before and after the policy change, the overall number of deceased donor transplants rose 23%, with a larger increase for minorities (40%) and a smaller increase for non-Hispanic whites (whites) (8%). The increase in the proportion of transplants for non-whites versus whites was highly significant (p < 0.0001). Two-year graft survival improved for all racial/ethnic groups after implementation of this new policy. Findings confirmed prior SRTR predictions. Following elimination of allocation priority for HLA-B similarity, the deficit in transplantation rates among minorities compared with that for whites was reduced but not eliminated; furthermore, there was no adverse effect on graft survival.

Access and outcomes among minority transplant patients, 1999-2008, with a focus on determinants of kidney graft survival.

Coincident with an increasing national interest in equitable health care, a number of studies have described disparities in access to solid organ transplantation for minority patients. In contrast, relatively little is known about differences in posttransplant outcomes between patients of specific racial and ethnic populations. In this paper, we review trends in access to solid organ transplantation and posttransplant outcomes by organ type, race and ethnicity. In addition, we present an analysis of categories of factors that contribute to the racial/ethnic variation seen in kidney transplant outcomes. Disparities in minority access to transplantation among wait-listed candidates are improving, but persist for those awaiting kidney, simultaneous kidney and pancreas and intestine transplantation. In general, graft and patient survival among recipients of solid organ transplants is highest for Asians and Hispanic/Latinos, intermediate for whites and lowest for African Americans. Although much of the difference in outcomes between racial/ethnic groups can be accounted for by adjusting for patient characteristics, important observed differences remain. Age and duration of pretransplant dialysis exposure emerge as the most important determinants of survival in an investigation of the relative impact of center-related versus patient-related variables on kidney graft outcomes.

Predictability of survival models for waiting list and transplant patients: calculating LYFT.

'Life years from transplant' (LYFT) is the extra years of life that a candidate can expect to achieve with a kidney transplant as compared to never receiving a kidney transplant at all. The LYFT component survival models (patient lifetimes with and without transplant, and graft lifetime) are comparable to or better predictors of long-term survival than are other predictive equations currently in use for organ allocation. Furthermore, these models are progressively more successful at predicting which of two patients will live longer as their medical characteristics (and thus predicted lifetimes) diverge. The C-statistics and the correlations for the three LYFT component equations have been validated using independent, nonoverlapping split-half random samples. Allocation policies based on these survival models could lead to substantial increases in the number of life years gained from the current donor pool.

Kidney and pancreas transplantation in the United States, 1998-2007: access for patients with diabetes and end-stage renal disease.

Although the number of candidates on the kidney transplant waiting list at year-end rose from 40 825 to 76 070 (86%) between 1998 and 2007, recent growth principally reflects increases in the number of patients in inactive status. The number of active patients increased by 'only' 4510 between 2002 and 2007, from 44 263 to 48 773. There were 6037 living donor and 10 082 deceased donor kidney transplants in 2007. Patient and allograft survival was best for recipients of living donor kidneys, least for expanded criteria donor (ECD) deceased donor kidneys, and intermediate for non-ECD deceased donor kidneys. The total number of pancreas transplants peaked at 1484 in 2004 and has since declined to 1331. Among pancreas recipients, those with simultaneous pancreas-kidney (SPK) transplants experienced the best pancreas graft survival rates: 86% at 1 year and 53% at 10 years. Between 1998 and 2006, among diabetic patients with end-stage renal disease (ESRD) who were under the age of 50 years, 23% of all and 62% of those waitlisted received a kidney-alone or SPK transplant. In contrast, 6% of diabetic patients aged 50-75 years with ESRD were transplanted, representing 46% of those waitlisted from this cohort. Access to kidney-alone or SPK transplantation varies widely by state.

Determinants of discard of expanded criteria donor kidneys: impact of biopsy and machine perfusion.

We examined factors associated with expanded criteria donor (ECD) kidney discard. Scientific Registry of Transplant Recipients (SRTR)/Organ Procurement and Transplantation Network (OPTN) data were examined for donor factors using logistic regression to determine the adjusted odds ratio (AOR) of discard of kidneys recovered between October 1999 and June 2005. Logistic and Cox regression models were used to determine associations with delayed graft function (DGF) and graft failure. Of the 12,536 recovered ECD kidneys, 5139 (41%) were discarded. Both the performance of a biopsy (AOR = 1.21, p = 0.02) and the degree of glomerulosclerosis (GS) on biopsy were significantly associated with increased odds of discard. GS was not consistently associated with DGF or graft failure. The discard rate of pumped ECD kidneys was 29.7% versus 43.6% for unpumped (AOR = 0.52, p < 0.0001). Among pumped kidneys, those with resistances of 0.26-0.38 and >0.38 mmHg/mL/min were discarded more than those with resistances of 0.18-0.25 mmHg/mL/min (AOR = 2.5 and 7.9, respectively). Among ECD kidneys, pumped kidneys were less likely to have DGF (AOR = 0.59, p < 0.0001) but not graft failure (RR = 0.9, p = 0.27). Biopsy findings and machine perfusion are important correlates of ECD kidney discard; corresponding associations with graft failure require further study.

Kidney and pancreas transplantation in the United States, 1997-2006: the HRSA Breakthrough Collaboratives and the 58 DSA Challenge.

Growth in the number of active patients on the kidney transplant waiting list has slowed. Projections based on the most recent 5-year data suggest the total waiting list will grow at a rate of 4138 registrations per year, whereas the active waiting list will increase at less than one-sixth that rate, or 663 registrations per year. The last 5 years have seen a small trend toward improved unadjusted allograft survival for living and deceased donor kidneys. Since 2004 the overall number of pancreas transplants has declined. Among pancreas recipients, those with simultaneous kidney-pancreas transplants experienced the highest pancreas graft survival rates. In response to the ongoing shortage of deceased donor organs, the US Health Resources and Services Administration launched the Organ Donation Breakthrough Collaborative in September 2003 and the Organ Transplantation Breakthrough Collaborative (OTBC) in October 2005. The 58 DSA Challenge is prominent among the goals adopted by the OTBC. Its premise: were each of the 58 existing donation service areas to increase the number of kidney transplants performed within their boundaries by 10 per month, an additional 7000 transplants over current annual levels would result. Such an increase could potentially eliminate the national kidney transplantation waiting list by 2030.

Calculating life years from transplant (LYFT): methods for kidney and kidney-pancreas candidates.

The Organ Procurement and Transplantation Network (OPTN) Kidney Committee is considering a proposal for a new deceased donor kidney allocation system. Among the components under consideration is a strategy to rank candidates in part by the estimated incremental years of life that are expected to be achieved with a transplant from a specific available deceased donor, computed as the difference in expected median lifespan with that transplant compared with remaining on dialysis. This concept has been termed life years from transplant or LYFT. Median lifespans could be calculated, based on objective medical criteria, for each candidate when a deceased donor kidney becomes available, based on Cox regression models using current candidate and donor medical information. The distribution of the calculated LYFT scores for an average nonexpanded criteria donor kidney is similar across candidate sex, race/ethnicity, insurance status and, with the exception of diabetes, diagnosis. LYFT scores tend to be higher for younger candidates and lower for diabetics receiving a kidney-alone rather than a simultaneous kidney-pancreas transplant. Prioritizing candidates with higher LYFT scores for each available kidney could substantially increase total years of life among both transplant candidates and recipients. LYFT is also a powerful metric for assessing trends in allocation outcomes and for comparing alternative allocation systems.

Should pediatric patients wait for HLA-DR-matched renal transplants?

Graft survival rates from deceased donors aged 35 years or less among all primary pediatric kidney transplant recipients in the United States between 1996 and 2004 were retrospectively examined to determine the effect of HLA-DR mismatches on graft survival. Zero HLA-DR-mismatched kidneys had statistically comparable 5-year graft survival (71%), to 1-DR-mismatched kidneys (69%) and 2-DR-mismatched kidneys (71%). When compared to donors less than 35 years of age, the relative rate of allograft failure was 1.32 (p = 0.0326) for donor age greater than or equal to age 35. There was no statistical increase in the odds of developing a panel-reactive antibody (PRA) greater than 30% at the time of second waitlisting, based upon the degree of HLA-A, -B or -DR mismatch of the first transplant, nor was there a 'dose effect' when more HLA antigens were mismatched between the donor and recipient. Therefore, pediatric transplant programs should utilize the recently implemented Organ Procurement and Transplantation Network's (OPTN)allocation policy, which prioritizes pediatric recipients to receive kidneys from deceased donors less than 35 years of age, and should not turn down such kidney offers to wait for a better HLA-DR-matched kidney.

Erythromycin breath test predicts oral clearance of cyclosporine in kidney transplant recipients.

It has been shown recently that cyclosporine is largely metabolized by P450IIIA (CYP3A), an enzyme whose catalytic activity varies significantly among patients. To determine whether heterogeneity in P450IIIA activity contributes to interpatient differences in cyclosporine dosing requirements, the oral pharmacokinetics of the drug were determined in 20 stable kidney transplant recipients. P450IIIA activity was then measured in each patient by use of the erythromycin breath test. In the 16 patients who were at steady state, the logarithm of the apparent oral clearance of cyclosporine correlated significantly with the rate of 14CO2 exhaled in breath after intravenous administration of [14C N-methyl]erythromycin (r = 0.55, p = 0.03). No significant correlations existed between apparent oral clearance and age, high-density lipoprotein cholesterol or low-density lipoprotein cholesterol, or hematocrit in these patients. We conclude that heterogeneity in P450IIIA activity significantly contributes to interpatient differences in dosing requirements of cyclosporine in kidney transplant patients.

P450 3A activity and cyclosporine dosing in kidney and heart transplant recipients.

Interpatient differences in the kinetics of cyclosporine appear to result in part from interindividual differences in the catalytic activity of an enzyme termed P450 3A. We investigated the relationship between P450 3A activity, as measured by the erythromycin breath test (ERMBT), and the appropriate stable daily dose of cyclosporine as currently determined by physicians at our institution. The ERMBT was administered to kidney and heart allograft recipients who had attended at least two monthly clinic visits without having their daily cyclosporine dose changed. There was a significant positive correlation between the ERMBT result and the daily cyclosporine doses (in milligrams per kilogram) in both the heart (r = 0.68; p = 0.04; n = 9) and kidney (r = 0.68; p = 0.03; n = 10) recipients. To confirm our findings, we prospectively administered the ERMBT on multiple occasions to 20 patients who were undergoing kidney transplantation. Although the transplant physicians were blinded to the ERMBT results, the test predicted the stable daily doses of cyclosporine that they ultimately prescribed to the patients (r = 0.54; p = 0.015). When data from all 39 patients were pooled and subjected to multiple regression analysis, the ERMBT was the only variable examined that significantly correlated with the stable daily cyclosporine dose (r = 0.63; p < 0.001; n = 39). In the 20 patients prospectively studied, the prescribed daily dose of cyclosporine generally decreased during the months after surgery and the percentage changes in cyclosporine daily dose correlated with changes in P450 3A activity during this period (r = 0.47; p = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine.

Interpatient differences in the oral clearance of cyclosporine (INN, ciclosporin) have been partially attributed to variation in the activity of a single liver enzyme termed CYP3A4. Recently it has been shown that small bowel also contains CYP3A4, as well as P-glycoprotein, a protein able to transport cyclosporine. To assess the importance of these intestinal proteins, the oral pharmacokinetics of cyclosporine were measured in 25 kidney transplant recipients who each had their liver CYP3A4 activity quantitated by the intravenous [14C-N-methyl]-erythromycin breath test and who underwent small bowel biopsy for measurement of CYP3A4 and P-glycoprotein. Forward multiple regression revealed that 56% (i.e., r2 = 0.56) and 17% of the variability in apparent oral clearance [log (dose/area under the curve)] were accounted for by variation in liver CYP3A4 activity (p < 0.0001) and intestinal P-glycoprotein concentration (p = 0.0059), respectively. For peak blood concentration, liver CYP3A4 activity accounted for 32% (p = 0.0002) and P-glycoprotein accounted for an additional 30% (p = 0.0024) of the variability. Intestinal levels of CYP3A4, which varied tenfold, did not appear to influence any cyclosporine pharmacokinetic parameter examined. We conclude that intestinal P-glycoprotein plays a significant role in the first-pass elimination of cyclosporine, presumably by being a rate-limiting step in absorption. Drug interactions with cyclosporine previously ascribed to intestinal CYP3A4 may instead be mediated by interactions with intestinal P-glycoprotein.

Blocking of T cell activation at the G1A/G1B interface of the cell cycle and prevention of expression of interleukin 2 receptors by alloactivated suppressor T lymphocytes.

Suppressor T (Ts) leukocytes affect various immune reactions including the activation of T cells by alloantigens. It is, however, not known where Ts interfere with the sequence of events supporting T cell activation and proliferation. In the present studies, alloantigen selective Ts were activated by in vitro priming with heat-inactivated allogeneic leukocytes in the mixed leukocyte reaction (MLR). Such Ts, or a soluble factor thereof, were shown to interfere with the progression of MLR responder cells from the G1A to the G1B phase of the cell cycle. In the presence of Ts, most MLR responder cells did not express interleukin 2 receptors, although a small minority of cells constantly escaped Ts inhibition. Moreover, Ts modified MLR contained only minor interleukin 2 (IL-2) bioactivity suggesting also an effect of Ts cells on IL-2 synthesis. The addition of exogenous IL-2 to Ts modified MLR increased 3H-thymidine incorporation although Ts retained the capacity to regulate the proliferative response in a dose-dependent fashion. Phenotypic analysis of allostimulated T cells proliferating in the presence of preformed Ts and exogenous IL-2 revealed a conspicuous failure of T helper cells to proliferate in response to alloantigen despite the presence of very high IL-2 concentrations.