Kidney allograft offers: Predictors of turndown and the impact of late organ acceptance on allograft survival.

There is growing interest in understanding patterns of organ acceptance and reducing discard. Little is known about how donor factors, timing of procurement, and geographic location affect organ offer decisions. We performed a retrospective cohort study of 47 563 deceased donor kidney match-runs from 2007 to 2013. Several characteristics unrelated to allograft quality were independently associated with later acceptance in the match-run: Public Health Service increased-risk donor status (adjusted odds ratio [aOR] 2.49, 95% confidence interval [CI] 2.29-2.69), holiday or weekend procurement (aOR 1.11, 95% CI 1.07-1.16), shorter donor stature (aOR 1.53 for <150 cm vs reference >180 cm, 95% CI 1.28-1.94), and procurement in an area with higher intensity of market competition (aOR 1.71, 95% CI 1.62-1.78) and with the longest waiting times (aOR 1.41, 95% CI 1.34-1.49). Later acceptance in the match-run was associated with delayed graft function but not all-cause allograft failure (adjusted hazard ratio 1.01, 95% CI 0.96-1.07). Study limitations include a lack of match-run data for discarded organs and the possibility of sequence inaccuracies for some nonlocal matches. Interventions are needed to reduce turndowns of viable organs, especially when decisions are driven by infectious risk, weekend or holiday procurement, geography, or other donor characteristics unrelated to allograft quality.

Healthcare utilization after liver transplantation is highly variable among both centers and recipients.

The relationship between healthcare utilization before and after liver transplantation (LT), and its association with center characteristics, is incompletely understood. This was a retrospective cohort study of 34 402 adult LTs between 2002 and 2013 using Vizient inpatient claims data linked to the United Network for Organ Sharing (UNOS) database. Multivariable mixed-effects linear regression models evaluated the association between hospitalization 90 days pre-LT and the number of days alive and out of the hospital (DAOH) 1 year post-LT. Of those patients alive at LT discharge, 24.7% spent ≥30 days hospitalized during the first year. Hospitalization in the 90 days pre-LT was inversely associated with DAOH (ß = -3.4 DAOH/week hospitalized pre-LT; P = .002). Centers with >30% of their liver transplant recipients hospitalized ≥30 days in the first LT year were typically smaller volume and/or transplanting higher risk recipients (Model for End-Stage Liver Disease [MELD] score ≥35, inpatient or ventilated pre-LT). In conclusion, pre-LT hospitalization predicts 1-year post-LT hospitalization independent of MELD score at the patient-level, whereas center-specific post-LT healthcare utilization is associated with certain center behaviors and selection practices.

Sustained Posttransplantation Diabetes Is Associated With Long-Term Major Cardiovascular Events Following Liver Transplantation.

Cardiovascular disease is a leading cause of death among liver transplant (LT) recipients. With a rising burden of posttransplantation metabolic disease, increases in cardiovascular-related morbidity and mortality may reduce life expectancy after LT. It is unknown if the risk of long-term major cardiovascular events (MCEs) differs among LT recipients with varying diabetic states. We performed a retrospective cohort study of LT recipients from 2003 through 2013 to compare the incidence of MCEs among patients (1) without diabetes, (2) with pretransplantation diabetes, (3) with de novo transient posttransplantation diabetes, and (4) with de novo sustained posttransplantation diabetes. We analyzed 994 eligible patients (39% without diabetes, 24% with pretransplantation diabetes, 16% with transient posttransplantation diabetes, and 20% with sustained posttransplantation diabetes). Median follow-up was 54.7 months. Overall, 12% of patients experienced a MCE. After adjustment for demographic and clinical variables, sustained posttransplantation diabetes was the only state associated with a significantly increased risk of MCEs (subdistribution hazard ratio 1.95, 95% confidence interval 1.20-3.18). Patients with sustained posttransplantation diabetes mellitus had a 13% and 27% cumulative incidence of MCEs at 5 and 10 years, respectively. While pretransplantation diabetes has traditionally been associated with cardiovascular disease, the long-term risk of MCEs is greatest in LT recipients with sustained posttransplantation diabetes mellitus.

Outcomes of organ transplants when the donor is a prior recipient.

Organ shortage continues to challenge the field of transplantation. One potential group of donors are those who have been transplant recipients themselves, or Organ Donation After Transplant (ODAT) donors. We conducted a retrospective cohort study to describe ODAT donors and to compare outcomes of ODAT grafts versus conventional grafts. From October 1, 1987 to June 30, 2015, 517 former recipients successfully donated 803 organs for transplant. Former kidney recipients generally survived a median of approximately 4 years before becoming an ODAT donor whereas liver, lung, and heart recipients generally survived less than a month prior to donation. In the period June 1, 2005 to December 31, 2014, liver grafts from ODAT donors had a significantly higher risk of graft failure compared to non-ODAT liver transplants (P = .008). Kidney grafts donated by ODAT donors whose initial transplant occurred >1 year prior were associated with significantly increased graft failure (P = .012). Despite increased risk of graft failure amongst certain ODAT grafts, 5-year survival was still high. ODAT donors should be considered another form of expanded criteria donor under these circumstances.

Sociodemographic Determinants of Waitlist and Posttransplant Survival Among End-Stage Liver Disease Patients.

While regional organ availability dominates discussions of distribution policy, community-level disparities remain poorly understood. We studied micro-geographic determinants of survival risk and their distribution across Donor Service Areas (DSAs). Scientific Registry of Transplant Recipients records for all adults waitlisted for liver transplantation 2002-2014 were reviewed. The primary exposure variables were county-level sociodemographic risk, as measured by the Community Health Score (CHS), a previously-validated composite index local health conditions, and distance to listing transplant center. Among 114 347 patients, the median CHS was 19.4 (range: 0-40). Compared the lowest risk counties (CHS 1-10), highest-risk counties (CHS 31-40) had more black (14.6% vs. 5.4%), publicly insured (44.9% vs. 33.0), and remote candidates (34.0% vs. 15.1% living >100 miles away). Higher-CHS candidates had greater waitlist mortality in Cox multivariable (HR 1.16 for CHS 31-40, 95% CI 1.11-1.21) and competing risks analysis (sHR 1.07, 95% CI 0.99-1.14). Post-transplant survival was similar across CHS quartiles. Living >25 miles from the transplant center conferred excess mortality risk (sHR 1.08, 95% CI 1.03-1.12). Proposed distribution changes would disproportionately impact DSAs with more high-CHS or distant candidates. Low-income, rural and minority patients experience excess mortality while awaiting transplant, and risk disproportionately worse outcomes with reduced organ availability under current proposals.

When Living Donor Liver Allografts Fail: Exploring the Outcomes of Retransplantation Using Deceased Donors.

Outcomes of retransplantation after initial living donor liver transplantation (LDLT) are poorly understood. The aim of this study is to better understand the indications, timing, and outcomes of retransplantation after initial LDLT when compared to after initial deceased donor transplantation (DDLT). From 2002 to 2013, 209 retransplant recipients after initial LDLT and 2893 after initial DDLT were identified in Organ Procurement and Transplantation Network/United Network for Organ Sharing. Multivariable logistic models evaluated the association between initial transplant type and 1-year mortality. The most frequent reason for early graft failure (≤14 days) in LDLT recipients was vascular thrombosis (63.6%) versus primary graft failure in initial DDLT recipients (59.1%). LDLT recipients were more often acutely and/or critically ill with a greater proportion of Status 1 (42.6% vs. 27.3%; p < 0.001) and intensive care unit (52.2% vs. 39.9%; p = 0.001) recipients at the time of retransplantation. There was no difference in adjusted 1-year mortality between retransplant recipients after initial LDLT versus DDLT (odds ratio 0.74; 95% confidence interval 0.51-1.08). The proportion of recipients who ultimately required retransplantation for a third time was not different between the two groups (4.8%). Retransplantation outcomes after LDLT are not different from other retransplant procedures, despite recipients having greater acuity of illness and different indications.

Improving Organ Utilization to Help Overcome the Tragedies of the Opioid Epidemic.

Death rates from drug overdoses have nearly doubled since 2003, with over 47 000 deaths in 2014. This is largely attributable to the opioid epidemic. If the unfortunate deaths of otherwise healthy people have yielded an increase in organ donors, then this might serve as perhaps the only comforting factor among this tragic and unnecessary loss of life. In this viewpoint, we present data from the Organ Procurement and Transplantation Network (OPTN) that show how the greatest relative increases in the mechanism of death among deceased donors from 2003 to 2014 were drug overdoses. Unfortunately, despite the absolute increase in the number of donors who died from a drug overdose, the mean organ yield was significantly lower than in other categories, in part due to concerns about disease transmission. In this paper, we present data on the changes in donation from donors with a drug overdose as a result of the opioid epidemic and discuss the need to educate transplant candidates and their physicians about the low risk of disease transmission compared to the greater risk of dying on a transplant waitlist.

Use of Population-based Data to Demonstrate How Waitlist-based Metrics Overestimate Geographic Disparities in Access to Liver Transplant Care.

Liver allocation policies are evaluated by how they impact waitlisted patients, without considering broader outcomes for all patients with end-stage liver disease (ESLD) not on the waitlist. We conducted a retrospective cohort study using two nationally representative databases: HealthCore (2006-2014) and five-state Medicaid (California, Florida, New York, Ohio and Pennsylvania; 2002-2009). United Network for Organ Sharing (UNOS) linkages enabled ascertainment of waitlist- and transplant-related outcomes. We included patients aged 18-75 with ESLD (decompensated cirrhosis or hepatocellular carcinoma) using validated International Classification of Diseases, Ninth Revision (ICD-9)-based algorithms. Among 16 824 ESLD HealthCore patients, 3-year incidences of waitlisting and transplantation were 15.8% (95% confidence interval [CI] : 15.0-16.6%) and 8.1% (7.5-8.8%), respectively. Among 67 706 ESLD Medicaid patients, 3-year incidences of waitlisting and transplantation were 10.0% (9.7-10.4%) and 6.7% (6.5-7.0%), respectively. In HealthCore, the absolute ranges in states' waitlist mortality and transplant rates were larger than corresponding ranges among all ESLD patients (waitlist mortality: 13.6-38.5%, ESLD 3-year mortality: 48.9-62.0%; waitlist transplant rates: 36.3-72.7%, ESLD transplant rates: 4.8-13.4%). States' waitlist mortality and ESLD population mortality were not positively correlated: ρ = -0.06, p-value = 0.83 (HealthCore); ρ = -0.87, p-value = 0.05 (Medicaid). Waitlist and ESLD transplant rates were weakly positively correlated in Medicaid (ρ = 0.36, p-value = 0.55) but were positively correlated in HealthCore (ρ = 0.73, p-value = 0.001). Compared to population-based metrics, waitlist-based metrics overestimate geographic disparities in access to liver transplantation.

Increasing the Number of Organ Transplants in the United States by Optimizing Donor Authorization Rates.

While recent policies have focused on allocating organs to patients most in need and lessening geographic disparities, the only mechanism to increase the actual number of transplants is to maximize the potential organ supply. We conducted a retrospective cohort study using OPTN data on all "eligible deaths" from 1/1/08 to 11/1/13 to evaluate variability in donor service area (DSA)-level donor authorization rates, and to quantify the potential gains associated with increasing authorization rates. Despite adjustments for donor demographics (age, race/ethnicity, cause of death) and geographic factors (rural/urban status of donor hospital, statewide participation in deceased-donor registries) among 52 571 eligible deaths, there was significant variability (p < 0.001) in donor authorization rates across the 58 DSAs. Overall DSA-level adjusted authorization rates ranged from 63.5% to 89.5% (median: 72.7%). An additional 773-1623 eligible deaths could have been authorized, yielding 2679-5710 total organs, if the DSAs with authorization rates below the median and 75th percentile, respectively, implemented interventions to perform at the level of the corresponding reference DSA. Opportunities exist within the current organ acquisition framework to markedly improve DSA-level donor authorization rates. Such initiatives would mitigate waitlist mortality while increasing the number of transplants.

An Assessment of HIV-Infected Patients Dying in Care for Deceased Organ Donation in a United States Urban Center.

Organ transplantation is an acceptable option for human immunodeficiency virus (HIV)-infected patients with end-stage kidney or liver disease. With worse outcomes on the waitlist, HIV-infected patients may actually be disproportionately affected by the organ shortage in the United States. One potential solution is the use of HIV-infected deceased donors (HIVDD), recently legalized by the HIV Organ Policy Equity (HOPE) Act. This is the first analysis of patient-specific data from potential HIVDD, retrospectively examining charts of HIV-infected patients dying in care at six HIV clinics in Philadelphia, Pennsylvania from January 1, 2009 to June 30, 2014. Our data suggest that there are four to five potential HIVDD dying in Philadelphia annually who might yield two to three kidneys and three to five livers for transplant. Extrapolated nationally, this would approximate 356 potential HIVDD yielding 192 kidneys and 247 livers annually. However, several donor risk indices raise concerns about the quality of kidneys that could be recovered from HIVDD as a result of older donor age and comorbidities. On the other hand, livers from these potential HIVDD are of similar quality to HIV-negative donors dying locally, although there is a high prevalence of positive hepatitis C antibody.

The Risk of End-Stage Renal Disease Among Living Donor Liver Transplant Recipients in the United States.

Since initiation of model for end-stage liver disease (MELD)-based allocation for liver transplantation, the risk of posttransplant end-stage renal disease (ESRD) has increased. Recent US data have demonstrated comparable, if not superior survival, among recipients of living donor liver transplants (LDLT) when compared to deceased donor liver transplant (DDLT) recipients. However, little is known about the incidence of ESRD post-LDLT. We analyzed linked Scientific Registry of Transplant Recipients (SRTR) and US Renal Data System (USRDS) data of first-time liver-alone transplant recipients from February 27, 2002 to March 1, 2011, and restricted the cohort to recipients with a laboratory MELD score ≤25 not on dialysis prior to transplantation, in order to evaluate the incidence of ESRD post-LDLT, and to compare the incidence among LDLT versus DDLT recipients. There were 28 707 DDLT and 1917 LDLT recipients included in the analyses. The 1-, 3- and 5-year unadjusted risk of ESRD was 1.7%, 2.9% and 3.4% in LDLT recipients, compared with 1.5%, 3.0% and 4.8% in DDLT recipients (p > 0.05), respectively. In multivariable competing risk Cox regression models, there was no association between receiving an LDLT and risk of ESRD (sub-hazard ratio: 0.99, 95% CI: 0.77-1.26, p = 0.92). In conclusion, the incidence of ESRD post-LDLT in the United States is low, and there are no significant differences among LDLT and DDLT recipients with MELD scores ≤25 at transplantation.

Hepatocellular carcinoma surveillance rates in commercially insured patients with noncirrhotic chronic hepatitis B.

American association for the study of liver diseases (AASLD) and European Association for the Study of the Liver (EASL) guidelines recommend biannual hepatocellular carcinoma (HCC) screening for noncirrhotic patients with chronic hepatitis B infection (HBV), yet there are no data estimating surveillance rates or factors associated with surveillance. We performed a retrospective cohort study of US patients using the Truven Health Analytics databases from 2006 to 2010 and identified patients with noncirrhotic chronic HBV. Surveillance patterns were characterized using categorical and continuous outcomes, with the continuous measure of the proportion of time 'up to date' with surveillance (PUTDS), with the 6-month interval following each ultrasound categorized as 'up to date'. During a median follow-up of 26.0 (IQR: 16.2-40.0) months among 4576 noncirrhotic patients with chronic HBV (median age: 44 years, IQR: 36-52), only 306 (6.7%) had complete surveillance (one ultrasound every 6-month interval), 2727 (59.6%) incomplete (≥1 ultrasound) and 1543 (33.7%) none. The mean PUTDS was 0.34 ± 0.29, and the median was 0.32 (IQR: 0.03-0.52). In multinomial logistic regression models, patients diagnosed by a nongastroenterologist were significantly less likely to have complete surveillance (P < 0.001), as were those coinfected with HBV/HIV (P < 0.001). In linear regression models, nongastroenterologist provider, health insurance subtype, HBV/HIV coinfection, rural status and metabolic syndrome were independently associated with decreased surveillance. Patients with HIV had an absolute decrease in the PUTDS of 0.24, while patients in less populated rural areas had an absolute decrease of 0.10. HCC surveillance rates in noncirrhotic patients with chronic HBV in the United States are poor and lower than reported rates of HCC surveillance in cirrhotic patients.

MELD exceptions for portopulmonary hypertension: current policy and future implementation.

Since 2006, waitlist candidates with portopulmonary hypertension (POPH) have been eligible for standardized Model for End-Stage Liver Disease (MELD) exception points. However, there are no data evaluating the current POPH exception policy and its implementation. We used Organ Procurement and Transplantation Network (OPTN) data to compare outcomes of patients with approved POPH MELD exceptions from 2006 to 2012 to all nonexception waitlist candidates during this period. Since 2006, 155 waitlist candidates had approved POPH MELD exceptions, with only 73 (47.1%) meeting the formal OPTN exception criteria. Furthermore, over one-third of those with approved POPH exceptions either did not fulfill hemodynamic criteria consistent with POPH or had missing data, with 80% of such patients receiving a transplant based on receiving exception points. In multivariable multistate survival models, waitlist candidates with POPH MELD exceptions had an increased risk of death compared to nonexception waitlist candidates, regardless of whether they did (hazard ratio [HR]: 2.46, 95% confidence interval [CI]: 1.73-3.52; n = 100) or did not (HR: 1.60, 95% CI: 1.04-2.47; n = 55) have hemodynamic criteria consistent with POPH. These data highlight the need for OPTN/UNOS to reconsider not only the policy for POPH MELD exceptions, but also the process by which such points are awarded.

Improving outcomes in DCDD liver transplantation: there can only be strength in numbers.

In the United States, liver transplantation using donation after circulatory determination of death (DCDD) donors is challenged by persistently inferior graft survival compared with donation after neurological death (DND), along with declining rates of liver transplantation relative to the total number of DCDD donors. Advances in adult-to-adult living donor liver transplantation graft survival temporally related to the Adult-to-Adult Living Donor Liver Transplantation Cohort Study consortium suggest that a similarly focused collaborative effort may serve to stimulate evolution within DCDD liver transplantation. Without a multi-center consortium to support innovative trials, the current state of DCDD liver transplantation is unlikely to progress.

Angiotensin I-converting enzyme antisense gene therapy causes permanent antihypertensive effects in the SHR.

The renin-angiotensin system plays a critical role in the control of blood pressure (BP), and its hyperactivity is associated with the development and maintenance of hypertension. Although traditional pharmacological therapies targeted toward the inhibition of the renin-angiotensin system are effective in the control of this disease, they pose significant limitations. We used an antisense gene delivery strategy to circumvent these limitations and established that a single intracardiac administration of angiotensin type 1 receptor antisense (AT(1)R-AS) causes permanent prevention of hypertension in the spontaneously hypertensive rat (SHR), an animal model of primary human hypertension. Our objectives in this study were 2-fold: to determine (1) whether the targeting of angiotensin I-converting enzyme (ACE) mRNA by a similar antisense strategy would prevent the SHR from developing hypertension and (2) whether the antihypertensive phenotype is transmitted to the offspring from the antisense-treated parents. Administration of a retroviral vector containing ACE antisense (LNSV-ACE-AS) caused a modest yet significant attenuation of high BP ( approximately 15+/-2 mm Hg) exclusively in the SHR. This was associated with a complete prevention of cardiac and renovascular pathophysiological alterations that are characteristic of hypertension. Like their parents, the F(1) generation offspring of the LNSV-ACE-AS-treated SHR expressed lower BP, decreased cardiac hypertrophy, and normalization of renal arterial excitation-coupling compared with offspring derived from the LNSV-ACE-tS (truncated sense)-treated SHR. In addition, the endothelial dysfunction commonly observed in the SHR renal arterioles was significantly prevented in both parents and offspring of the LNSV-ACE-AS-treated SHR. Polymerase chain reaction followed by Southern analysis revealed that the ACE-AS was integrated into the SHR genome and transmitted to the offspring. These observations suggest that transmission of ACE-AS by retroviral vector may be responsible for the transference of normotensive phenotypes in the SHR offspring.