A propensity score matched analysis of liver transplantation outcomes in the setting of preservation solution shortage.

The recent shortage of the University of Wisconsin (UW) solution prompted increased utilization of histidine-tryptophan-ketoglutarate (HTK) solution for liver graft preservation. This contemporary study analyzed deceased donor liver transplant outcomes following preservation with HTK vs UW. Patients receiving deceased donor liver transplantations between January 1, 2019, and June 30, 2022, were retrospectively identified utilizing the Organ Procurement and Transplant Network database, stratified by preservation with HTK vs UW, and a propensity score matching analysis was performed. Outcomes assessed included rates of primary nonfunction, graft survival, and patient survival. There were 4447 patients in each cohort. Primary nonfunction occurred in 60 (1.35%) patients in the HTK group vs 25 (0.54%) in the UW group (P < .001). HTK was associated with lower 90-day graft survival (94.39% vs 96.09%; P < .001) and 90-day patient survival (95.97% vs 97.38%; P = .001). Unmatched donation after cardiac death-specific analysis of HTK vs UW demonstrated respective rates of primary nonfunction of 1.63% vs 0.82% (P = .20), 90-day graft survival of 92.50% vs 95.29% (P = .069), and 90-day patient survival of 93.90% vs 96.35% (P = .077). These results suggest that HTK may not be an equivalent preservation solution for deceased donor liver transplantation.

Kidney transplant program specific reporting and transplant metrics.

PURPOSE OF REVIEW: Kidney transplantation is a heavily regulated medical procedure with the Secretary of HHS ultimately responsible for oversight and authority derived from the NOTA and the Final Rule. Transplant Programs undergo publicly reported evaluations every 6 months based on outcomes from a 2-and-a-half-year period. The current Bayesian metrics for kidney transplant programs were created such that over ten percentage of programs are deemed underperformers, or 'flag', every 6 months. Newly suggested transplant metrics have been released for public comment in Summer 2021. In addition to graft outcomes, waiting list mortality and organ acceptance rate ratios are proposed. RECENT FINDINGS: Under the newly proposed kidney transplant metrics, over 10% of programs are expected to be deemed underperformers or 'flagged'. Transplant Center flagging is well correlated with decreased transplantation due to the transplant centres move to more conservative organ and patient acceptance. Death on the waiting list is a proposed metric over which transplant centres have little influence. SUMMARY: In the USA, the harsh regulation continued by Health Resources and Services Administration (HRSA) through the national organ procurement and transplant network (OPTN) and Scientific Registry for Transplant Recipients (SRTR) leads directly to high organ discard rates and limitations to transplanting patients with perceived unadjusted risks. Instead of loosening regulation in a highly functioning industry that achieves remarkable outcomes in end stage kidney patients, the OPTN with the SRTR persist in increasing potential penalties through more proposed metrics that continue to deem 10% of US kidney transplant programs as underperformers. HRSA must establish a reasonable regulatory environment that allows for innovation and increased transplant opportunities for US end-stage renal disease patients.

The demise of islet allotransplantation in the United States: A call for an urgent regulatory update.

Islet allotransplantation in the United States (US) is facing an imminent demise. Despite nearly three decades of progress in the field, an archaic regulatory framework has stymied US clinical practice. Current regulations do not reflect the state-of-the-art in clinical or technical practices. In the US, islets are considered biologic drugs and "more than minimally manipulated" human cell and tissue products (HCT/Ps). In contrast, across the world, human islets are appropriately defined as "minimally manipulated tissue" and not regulated as a drug, which has led to islet allotransplantation (allo-ITx) becoming a standard-of-care procedure for selected patients with type 1 diabetes mellitus. This regulatory distinction impedes patient access to islets for transplantation in the US. As a result only 11 patients underwent allo-ITx in the US between 2016 and 2019, and all as investigational procedures in the settings of a clinical trials. Herein, we describe the current regulations pertaining to islet transplantation in the United States. We explore the progress which has been made in the field and demonstrate why the regulatory framework must be updated to both better reflect our current clinical practice and to deal with upcoming challenges. We propose specific updates to current regulations which are required for the renaissance of ethical, safe, effective, and affordable allo-ITx in the United States.

Now is the time for the Organ Procurement and Transplantation Network to change regulatory policy to effectively increase transplantation in the United States; Carpe Diem.

With the Centers for Medicare and Medicaid Services proposing to remove outcome measures from the transplant centers' renewal for Conditions of Participation an exciting opportunity surfaces for the Organ Procurement and Transplantation Network to make an equally bold change and allow for increased transplantation options for patients in the United States.

Time for reform in transplant program-specific reporting: AST/ASTS transplant metrics taskforce.

In accordance with the National Organ Transplant Act and Department of Health and Human Services' Final Rule, the Scientific Registry of Transplant Recipients (SRTR) publicly releases biannual program-specific reports that include analyses of transplant centers' risk-adjusted waitlist mortality, organ acceptance ratios, transplant rates, and graft and patient survival. Since the inception of these center metrics, 1-year posttransplant graft and patient survival have improved, and center variation has decreased, casting uncertainty on their clinical relevance. The SRTR has recently modified center evaluations by ranking centers into 5 tiers rather than 3 tiers in an attempt to discriminate between programs performing within a tight range, further exacerbating this uncertainty. The American Society of Transplantation/American Society of Transplant Surgeons convened an expert taskforce to examine both the utility and unintended consequences of transplant center metrics. Estimates of center variation in outcomes in adjacent tiers are imprecise and fleeting, but can result in consequential changes in clinician and center behavior. The taskforce has concerns that current metrics, based principally on 1-year graft and patient survival, provide minimal if any benefit in informing patient choice and access to transplantation, with the untoward effect of decreased utilization of organs and restriction of research and innovation.

Expanding clarity or confusion? Volatility of the 5-tier ratings assessing quality of transplant centers in the United States.

Outcomes of patients receiving solid organ transplants in the United States are systematically aggregated into bi-annual Program-Specific Reports (PSRs) detailing risk-adjusted survival by transplant center. Recently, the Scientific Registry of Transplant Recipients (SRTR) issued 5-tier ratings evaluating centers based on risk-adjusted 1-year graft survival. Our primary aim was to examine the reliability of 5-tier ratings over time. Using 10 consecutive PSRs for adult kidney transplant centers from June 2012 to December 2016 (n = 208), we applied 5-tier ratings to center outcomes and evaluated ratings over time. From the baseline period (June 2012), 47% of centers had at least a 1-unit tier change within 6 months, 66% by 1 year, and 94% by 3 years. Similarly, 46% of centers had at least a 2-unit tier change by 3 years. In comparison, 15% of centers had a change in the traditional 3-tier rating at 3 years. The 5-tier ratings at 4 years had minimal association with baseline rating (Kappa 0.07, 95% confidence interval [CI] -0.002 to 0.158). Centers had a median of 3 different 5-tier ratings over the period (q1 = 2, q3 = 4). Findings were consistent for center volume, transplant rate, and baseline 5-tier rating. Cumulatively, results suggest that 5-tier ratings are highly volatile, limiting their utility for informing potential stakeholders, particularly transplant candidates given expected waiting times between wait listing and transplantation.

Rethinking the advantage of zero-HLA mismatches in unrelated living donor kidney transplantation: implications on kidney paired donation.

The OPTN/UNOS Kidney Paired Donation (KPD) Pilot Program allocates priority to zero-HLA mismatches. However, in unrelated living donor kidney transplants (LDKT)-the same donor source in KPD-no study has shown whether zero-HLA mismatches provide any advantage over >0 HLA mismatches. We hypothesize that zero-HLA mismatches among unrelated LDKT do not benefit graft survival. This retrospective SRTR database study analyzed LDKT recipients from 1987 to 2012. Among unrelated LDKT, subjects with zero-HLA mismatches were compared to a 1:1-5 matched (by donor age ±1 year and year of transplantation) control cohort with >0 HLA mismatches. The primary endpoint was death-censored graft survival. Among 32,654 unrelated LDKT recipients, 83 had zero-HLA mismatches and were matched to 407 controls with >0 HLA mismatches. Kaplan-Meier analyses for death-censored graft and patient survival showed no difference between study and control cohorts. In multivariate marginal Cox models, zero-HLA mismatches saw no benefit with death-censored graft survival (HR = 1.46, 95% CI 0.78-2.73) or patient survival (HR = 1.43, 95% CI 0.68-3.01). Our data suggest that in unrelated LDKT, zero-HLA mismatches may not offer any survival advantage. Therefore, particular study of zero-HLA mismatching is needed to validate its place in the OPTN/UNOS KPD Pilot Program allocation algorithm.

Changing landscape of liver transplant in the United States-time for a new innovative way to define and utilize the "non-standard liver allograft"-a proposal.

Since the first liver transplant was performed over six decades ago, the landscape of liver transplantation in the US has seen dramatic evolution. Numerous advancements in perioperative and operative techniques have resulted in major improvements in graft and patient survival rates. Despite the increase in transplants performed over the years, the waitlist mortality rate continues to remain high. The obesity epidemic and the resultant metabolic sequelae continue to result in more marginal donors and challenging recipients. In this review, we aim to highlight the changing characteristics of liver transplant recipients and liver allograft donors. We focus on issues relevant in successfully transplanting a high model for end stage liver disease recipient. We provide insights into the current use of terms and definitions utilized to discuss marginal allografts, discuss the need to look into more consistent ways to describe these organs and propose two new concepts we coin as "Liver Allograft Variables" (LAV) and "Liver Allograft Composite Score" (LACS) for this. We discuss the development of spectrum of risk indexes as a dynamic tool to characterize an allograft in real time. We believe that this concept has the potential to optimize the way we allocate, utilize and transplant livers across the US.

Personalized Tacrolimus Dosing After Liver Transplantation: A Randomized Clinical Trial.

Background: Inter- and intra-individual variability in tacrolimus dose requirements mandates empirical clinician-titrated dosing that frequently results in deviation from a narrow target range. Improved methods to individually dose tacrolimus are needed. Our objective was to determine whether a quantitative, dynamically-customized, phenotypic-outcome-guided dosing method termed Phenotypic Personalized Medicine (PPM) would improve target drug trough maintenance. Methods: In a single-center, randomized, pragmatic clinical trial ( NCT03527238 ), 62 adults were screened, enrolled, and randomized prior to liver transplantation 1:1 to standard-of-care (SOC) clinician-determined or PPM-guided dosing of tacrolimus. The primary outcome measure was percent days with large (>2 ng/mL) deviation from target range from transplant to discharge. Secondary outcomes included percent days outside-of-target-range and mean area-under-the-curve (AUC) outside-of-target-range per day. Safety measures included rejection, graft failure, death, infection, nephrotoxicity, or neurotoxicity. Results: 56 (29 SOC, 27 PPM) patients completed the study. The primary outcome measure was found to be significantly different between the two groups. Patients in the SOC group had a mean of 38.4% of post-transplant days with large deviations from target range; the PPM group had 24.3% of post-transplant days with large deviations; (difference -14.1%, 95% CI: -26.7 to -1.5 %, P=0.029). No significant differences were found in the secondary outcomes. In post-hoc analysis, the SOC group had a 50% longer median length-of-stay than the PPM group [15 days (Q1-Q3: 11-20) versus 10 days (Q1-Q3: 8.5-12); difference 5 days, 95% CI: 2-8 days, P=0.0026]. Conclusions: PPM guided tacrolimus dosing leads to better drug level maintenance than SOC. The PPM approach leads to actionable dosing recommendations on a day-to-day basis. Lay Summary: In a study on 62 adults who underwent liver transplantation, researchers investigated whether a new dosing method called Phenotypic Personalized Medicine (PPM) would improve daily dosing of the immunosuppression drug tacrolimus. They found that PPM guided tacrolimus dosing leads to better drug level maintenance than the standard-of-care clinician-determined dosing. This means that the PPM approach leads to actionable dosing recommendations on a day-to-day basis and can help improve patient outcomes.

Impact of antibody induction on the outcomes of new onset diabetes after kidney transplantation: a registry analysis.

PURPOSE: We conducted this observational study to examine the impact of antibody inductions administered at kidney transplant (KT) on outcomes of 5 year exposure to post-transplant diabetes (PTDM) in adult deceased-donor kidney transplant recipients (DDKTRs). We also studied the risk of PTDM associated with antibody inductions. METHODS: Using 2000-2016 Organ Procurement Transplantation Network data, we employed multivariable Cox models to determine the adjusted hazard ratios (HR) of death, and overall and death-censored graft loss (OAGL, DCGL; respectively) at the 5 year landmark period in antibody induction cohorts with and without PTDM at the 1 year post-transplant index time point. We used multivariable logistic regression in determining the risk factors for PTDM. All multivariable analyses were adjusted for the potential confounding effects of maintenance immunosuppression, steroid regimens, and other relevant covariates. RESULTS: 48,031 adult DDKTRs were classified into cohorts based on antibody induction at transplant: (anti-thymocyte globulin) ATG (n = 26, 788); (alemtuzumab) ALM (n = 5916); and interleukin-2 receptor antagonist (IL-2RA) (n = 15,327). PTDM was a risk factor for 5 year OAGL and death, not DCGL [(HR = 1.25, CI = 1.16-1.36), (HR = 1.13, CI = 1.06-1.21), and (HR = 1.05, CI = 0.96-1.16); respectively]. Induction regimens were not risk factors for 5 year outcomes in DDKTRs with and without PTDM. Risk factors for PTDM included DDKTR obesity, age > / = 50 years, acute rejection, and ATG induction, among others. CONCLUSIONS: In adult DDKTRs, after controlling the confounding effects of clinically relevant variables including maintenance and steroid regimens, PTDM at 1 year post-transplant is associated with death and OAGL, not DCGL in the following 5 years: induction received at KT did not modify these associations.

Arguments against the Requirement of a Biological License Application for Human Pancreatic Islets: The Position Statement of the Islets for US Collaborative Presented during the FDA Advisory Committee Meeting.

The Food and Drug Administration (FDA) has been regulating human islets for allotransplantation as a biologic drug in the US. Consequently, the requirement of a biological license application (BLA) approval before clinical use of islet transplantation as a standard of care procedure has stalled the development of the field for the last 20 years. Herein, we provide our commentary to the multiple FDA's position papers and guidance for industry arguing that BLA requirement has been inappropriately applied to allogeneic islets, which was delivered to the FDA Cellular, Tissue and Gene Therapies Advisory Committee on 15 April 2021. We provided evidence that BLA requirement and drug related regulations are inadequate in reassuring islet product quality and potency as well as patient safety and clinical outcomes. As leaders in the field of transplantation and endocrinology under the "Islets for US Collaborative" designation, we examined the current regulatory status of islet transplantation in the US and identified several anticipated negative consequences of the BLA approval. In our commentary we also offer an alternative pathway for islet transplantation under the regulatory framework for organ transplantation, which would address deficiencies of in current system.

The high-risk recipient: the Eighth Annual American Society of Transplant Surgeons' State-of-the-Art Winter Symposium.

The evolution of organ transplantation has produced results so successful that many transplant programs commonly see recipients with medical risks, which in the past, would have prohibited transplantation. The Eighth Annual American Society of Transplant Surgeons State-of-the-Art Winter Symposium focused on the high-risk recipient. The assessment of risk has evolved over time, as transplantation has matured. The acceptance of risk associated with a given candidate today is often made in consideration of the relative value of the organ to other candidates, the regulatory environment, and philosophical notions of utility, equity, and fairness. In addition, transplant programs must balance outcomes, transplant volume, and the costs of organ transplantation, which are impacted by high-risk recipients. Discussion focused on various types of high-risk recipients, such as those with coronary artery disease, morbid obesity, and hepatitis C; strategies to reduce risk, such as down-staging of hepatocellular carcinoma and treatment of pulmonary hypertension; the development of alternatives to transplantation; and the degree to which risk can or should be used to define candidate selection. These approaches can modify the impact of recipient risk on transplant outcomes and permit transplantation to be applied successfully to a greater variety of patients.

Presence of urinary Haufen accurately predicts polyomavirus nephropathy.

There are no accurate, noninvasive tests to diagnose BK polyomavirus nephropathy, a common infectious complication after renal transplantation. This study evaluated whether the qualitative detection of cast-like, three-dimensional polyomavirus aggregates ("Haufen") in the urine accurately predicts BK polyomavirus nephropathy. Using negative-staining electron microscopy, we sought Haufen in 194 urine samples from 139 control patients and in 143 samples from 21 patients with BK polyomavirus nephropathy. Haufen detection was correlated with pathology in concomitant renal biopsies and BK viruria (decoy cell shedding and viral load assessments by PCR) and BK viremia (viral load assessments by PCR). Haufen originated from renal tubules containing virally lysed cells, and the detection of Haufen in the urine correlated tightly with biopsy confirmed BK polyomavirus nephropathy (concordance rate 99%). A total of 77 of 143 urine samples from 21 of 21 patients with BK polyomavirus nephropathy (disease stages A-C) contained Haufen, and during follow-up (3 to 120 wk), their presence or absence closely mirrored the course of renal disease. All controls were Haufen-negative, however, high viremia or viruria were detected in 8% and 41% of control samples, respectively. kappa statistics showed fair to good agreement of viruria and viremia with BK polyomavirus nephropathy or with Haufen shedding and demonstrated an excellent agreement between Haufen and polyomavirus nephropathy (kappa 0.98). Positive and negative predictive values of Haufen for BK polyomavirus nephropathy were 97% and 100%, respectively. This study shows that shedding of urinary Haufen and not BK viremia and viruria accurately mark BK polyomavirus nephropathy. It suggests that the detection of Haufen may serve as a noninvasive means to diagnose BK polyomavirus nephropathy in the urine.

Evaluation of Flagging Criteria of United States Kidney Transplant Center Performance: How to Best Define Outliers?

BACKGROUND: Scientific Registry of Transplant Recipients report cards of US organ transplant center performance are publicly available and used for quality oversight. Low center performance (LP) evaluations are associated with changes in practice including reduced transplant rates and increased waitlist removals. In 2014, Scientific Registry of Transplant Recipients implemented new Bayesian methodology to evaluate performance which was not adopted by Center for Medicare and Medicaid Services (CMS). In May 2016, CMS altered their performance criteria, reducing the likelihood of LP evaluations. METHODS: Our aims were to evaluate incidence, survival rates, and volume of LP centers with Bayesian, historical (old-CMS) and new-CMS criteria using 6 consecutive program-specific reports (PSR), January 2013 to July 2015 among adult kidney transplant centers. RESULTS: Bayesian, old-CMS and new-CMS criteria identified 13.4%, 8.3%, and 6.1% LP PSRs, respectively. Over the 3-year period, 31.9% (Bayesian), 23.4% (old-CMS), and 19.8% (new-CMS) of centers had 1 or more LP evaluation. For small centers (<83 transplants/PSR), there were 4-fold additional LP evaluations (52 vs 13 PSRs) for 1-year mortality with Bayesian versus new-CMS criteria. For large centers (>183 transplants/PSR), there were 3-fold additional LP evaluations for 1-year mortality with Bayesian versus new-CMS criteria with median differences in observed and expected patient survival of -1.6% and -2.2%, respectively. CONCLUSIONS: A significant proportion of kidney transplant centers are identified as low performing with relatively small survival differences compared with expected. Bayesian criteria have significantly higher flagging rates and new-CMS criteria modestly reduce flagging. Critical appraisal of performance criteria is needed to assess whether quality oversight is meeting intended goals and whether further modifications could reduce risk aversion, more efficiently allocate resources, and increase transplant opportunities.

Inhibition of human cytomegalovirus signaling and replication by the immunosuppressant FK778.

FK778 (Fujisawa Healthcare Inc.) is an immunosuppressant structurally similar to A771726, the active metabolite of leflunomide (Aventis Pharmaceuticals), but with a clinically relevant shorter serum half-life. Leflunomide, a tolerated and efficacious immunosuppressive agent in patients receiving allograft transplantations, was reported to be active against HCMV and HSV-1. Here we report that FK778 is a potent and effective inhibitor of HCMV, and that its mode of antiviral action appears to mirror the biochemical mechanisms elsewhere described to be responsible for its immunosuppressive properties: inhibition of protein tyrosine phosphorylation and inhibition of cellular de novo pyrimidine biosynthesis. Initial HCMV-mediated activation of the EGF receptor/phosphatidylinositol 3-kinase (PI3-K) pathways and Sp1 and NF-kappaB were partially inhibited by FK778. The second tier (phase) of PI3-K, Sp1, and NF-kappaB induction by HCMV was more sensitive to FK778. Treatment of HCMV-infected cells with FK778 prevented the appearance of HCMV proteins some 12-24h post infection, and inhibited viral DNA synthesis. In our assays, leflunomide also reduced HCMV DNA levels. The antiviral activity of FK778 was reversed in cell culture by treatment with uridine, consistent with specific inhibition of dihydroorotate dehydrogenase (DHODH), a required enzyme in the de novo biosynthesis of pyrimidines. This report substantiates the clinical possibility of a single drug treatment to achieve immunosuppression and inhibit opportunistic herpesvirus infections. Our results differ from descriptions of leflunomide acting as an inhibitor of HCMV cytoplasmic capsid formation. Additionally, this study indicates that DHODH may be an effective cellular antiviral target.