The future of liver transplantation.

Over the last 50 years, liver transplantation has evolved into a procedure routinely performed in many countries worldwide. Those able to access this therapy frequently experience a miraculous risk-benefit ratio, particularly if they face the imminently life-threatening disease. Over the decades, the success of liver transplantation, with dramatic improvements in early posttransplant survival, has aggressively driven demand. However, despite the emergence of living donors to augment deceased donors as a source of organs, supply has lagged far behind demand. As a result, rationing has been an unfortunate focus in recent decades. Recent shifts in the epidemiology of liver disease combined with transformative innovations in liver preservation suggest that the underlying premise of organ shortage may erode in the foreseeable future. The focus will sharpen on improving equitable access while mitigating constraints related to workforce training, infrastructure for organ recovery and rehabilitation, and their associated costs. Research efforts in liver preservation will undoubtedly blossom with the aim of optimizing both the timing and conditions of transplantation. Coupled with advances in genetic engineering, regenerative biology, and cellular therapies, the portfolio of innovation, both broad and deep, offers the promise that, in the future, liver transplantation will not only be broadly available to those in need but also represent a highly durable life-saving therapy.

The type, duration, and severity of pretransplant kidney injury predict prolonged kidney dysfunction after liver transplantation.

Chronic kidney disease (CKD) is a major complication of liver transplantation (LT) associated with substantial morbidity and mortality. Knowing the drivers of post-LT kidney dysfunction-with a granular focus on the type, duration, and severity of pre-LT kidney disease-can highlight intervention opportunities and inform dual-organ allocation policies. We retrospectively analyzed predictors of safety net kidney after liver transplant (KALT) eligibility and kidney replacement therapy (KRT) for > 14 days after LT. Among 557 recipients of adult deceased-donor LT, 49% had normal kidney function, 25% had acute kidney injury (AKI), and 25% had CKD±AKI at the time of LT. A total of 36 (6.5%) qualified for KALT and 63 (11%) required KRT > 14 days. In univariable analysis, factors associated with KALT eligibility and KRT > 14 days, respectively, included stage 3 AKI (OR 7.87; OR 7.06), CKD±AKI (OR 4.58; OR 4.22), CKD III-V duration (OR 1.10 per week; OR 1.06 per week), and increasing CKD stage (stage III: OR 3.90, IV: OR 5.24, V: OR 16.8; stage III: OR 2.23, IV: OR 3.62, V: OR 19.4). AKI stage I-II and AKI duration in the absence of CKD were not associated with the outcomes. Pre-LT KRT had a robust impact on KALT eligibility (OR 4.00 per week) and prolonged post-LT KRT (OR 5.22 per week), with 19.8% of patients who received any pre-LT KRT ultimately qualifying for KALT. Eligibility for KALT was similar between those who received 0 days and ≤ 14 days of KRT after LT (2.1% vs. 2.9%, p = 0.53). In conclusion, the type, duration, and severity of pre-LT kidney dysfunction have unique impacts on post-LT kidney-related morbidity, and future research must use these novel classifications to study mitigation strategies.

Change in Body Mass Index and Attributable Risk of New-Onset Hypertension Among Obese Living Kidney Donors.

OBJECTIVE: To examine whether body mass index (BMI) changes modify the association between kidney donation and incident hypertension. BACKGROUND: Obesity increases hypertension risk in both general and living kidney donor (LKD) populations. Donation-attributable risk in the context of obesity, and whether weight change modifies that risk, is unknown. METHODS: Nested case-control study among 1558 adult LKDs (1976-2020) with obesity (median follow-up: 3.6 years; interquartile range: 2.0-9.4) and 3783 adults with obesity in the Coronary Artery Risk Development in Young Adults (CARDIA) and Atherosclerosis Risk in Communities (ARIC) studies (9.2 y; interquartile range: 5.3-15.8). Hypertension incidence was compared by donor status using conditional logistic regression, with BMI change investigated for effect modification. RESULTS: Overall, LKDs and nondonors had similar hypertension incidence [incidence rate ratio (IRR): 1.16, 95% confidence interval (95% CI): 0.94-1.43, P =0.16], even after adjusting for BMI change (IRR: 1.25, 95% CI: 0.99-1.58, P =0.05). Although LKDs and nondonors who lost >5% BMI had comparable hypertension incidence (IRR: 0.78, 95% CI: 0.46-1.34, P =0.36), there was a significant interaction between donor and >5% BMI gain (multiplicative interaction IRR: 1.62, 95% CI: 1.15-2.29, P =0.006; relative excess risk due to interaction: 0.90, 95% CI: 0.24-1.56, P =0.007), such that LKDs who gained weight had higher hypertension incidence than similar nondonors (IRR: 1.83, 95% CI: 1.32-2.53, P <0.001). CONCLUSIONS: Overall, LKDs and nondonors with obesity had similar hypertension incidence. Weight stability and loss were associated with similar hypertension incidence by donor status. However, LKDs who gained >5% saw increased hypertension incidence versus similar nondonors, providing support for counseling potential LKDs with obesity on weight management postdonation.

Advances and innovations in living donor liver transplant techniques, matching and surgical training: Meeting report from the living donor liver transplant consensus conference.

The practice of LDLT currently delivers limited impact in western transplant centers. The American Society of Transplantation organized a virtual consensus conference in October 2021 to identify barriers and gaps to LDLT growth, and to provide evidence-based recommendations to foster safe expansion of LDLT in the United States. This article reports the findings and recommendations regarding innovations and advances in approaches to donor-recipient matching challenges, the technical aspects of the donor and recipient operations, and surgical training. Among these themes, the barriers deemed most influential/detrimental to LDLT expansion in the United States included: (1) prohibitive issues related to donor age, graft size, insufficient donor remnant, and ABO incompatibility; (2) lack of acknowledgment and awareness of the excellent outcomes and benefits of LDLT; (3) ambiguous messaging regarding LDLT to patients and hospital leadership; and (4) a limited number of proficient LDLT surgeons across the United States. Donor-recipient mismatching may be circumvented by way of liver paired exchange. The creation of a national registry to generate granular data on donor-recipient matching will guide the practice of liver paired exchange. The surgical challenges to LDLT are addressed herein and focuses on the development of robust training pathways resulting in proficiency in donor and recipient surgery. Utilizing strong mentorship/collaboration programs with novel training practices under the auspices of established training and certification bodies will add to the breadth and depth of training.

A Multi-Modal Approach to Islet and Pancreas Transplantation With Calcineurin-Sparing Immunosuppression Maintains Long-Term Insulin Independence in Patients With Type I Diabetes.

Long-term success in beta-cell replacement remains limited by the toxic effects of calcineurin inhibitors (CNI) on beta-cells and renal function. We report a multi-modal approach including islet and pancreas-after-islet (PAI) transplant utilizing calcineurin-sparing immunosuppression. Ten consecutive non-uremic patients with Type 1 diabetes underwent islet transplant with immunosuppression based on belatacept (BELA; n = 5) or efalizumab (EFA; n = 5). Following islet failure, patients were considered for repeat islet infusion and/or PAI transplant. 70% of patients (four EFA, three BELA) maintained insulin independence at 10 years post-islet transplant, including four patients receiving a single islet infusion and three patients undergoing PAI transplant. 60% remain insulin independent at mean follow-up of 13.3 ± 1.1 years, including one patient 9 years after discontinuing all immunosuppression for adverse events, suggesting operational tolerance. All patients who underwent repeat islet transplant experienced graft failure. Overall, patients demonstrated preserved renal function, with a mild decrease in GFR from 76.5 ± 23.1 mL/min to 50.2 ± 27.1 mL/min (p = 0.192). Patients undergoing PAI showed the greatest degree of renal impairment following initiation of CNI (56% ± 18.7% decrease in GFR). In our series, repeat islet transplant is ineffective at maintaining long-term insulin independence. PAI results in durable insulin independence but is associated with impaired renal function secondary to CNI dependence.

Simultaneous thoracic and abdominal donation after circulatory death organ recovery: the abdominal surgeon's perspective.

PURPOSE OF THE REVIEW: To summarize the international experience with heart-liver (joint) donation after circulatory death (DCD) procurements and to explore the technical challenges in joint abdominal and thoracic DCD procurement. RECENT FINDINGS: Following completion of the Donors After Circulatory Death Heart Trial in the US, combined thoracic and abdominal DCD is poised to become the standard of care, expanding access to life-saving heart and lung allografts. DCD heart procurement relies on collection of donor blood for priming of the normothermic perfusion pump, which delays cooling of abdominal organs and increases risk of ischemic injury. We review the effect of donor ischemia time on abdominal organs, with several proposed technical solutions to optimize transplant outcomes for all organs. SUMMARY: The strategies reviewed in this manuscript may inform clinical decision-making, preoperative coordination between thoracic and abdominal procurement teams, and surgical technique for joint DCD procurements. Several approaches to organ procurement organization (OPO) and national policy, as well as future areas of focus for research are proposed.

Risk aversion in the use of complex kidneys in paired exchange programs: Opportunities for even more transplants?

This retrospective review of the largest United States kidney exchange reports characteristics, utilization, and recipient outcomes of kidneys with simple compared to complex anatomy and extrapolates reluctance to accept these kidneys. Of 3105 transplants performed, only 12.8% were right kidneys and 23.1% had multiple renal arteries. 59.3% of centers used fewer right kidneys than expected and 12.1% transplanted zero right kidneys or kidneys with more than 1 artery. Five centers transplanted a third of these kidneys (35.8% of right kidneys and 36.7% of kidneys with multiple renal arteries). 22.5% and 25.5% of centers currently will not entertain a match offer for a left or right kidney with more than one artery, respectively. There were no significant differences in all-cause graft failure or death-censored graft loss for kidneys with multiple arteries, and a very small increased risk of graft failure for right kidneys versus left of limited clinical relevance for most recipients. Kidneys with complex anatomy can be used with excellent outcomes at many centers. Variation in use (lack of demand) for these kidneys reduces the number of transplants, so systems to facilitate use could increase demand. We cannot know how many donors are turned away because perceived demand is limited.

Kidney transplant candidacy evaluation and waitlisting practices in the United States and their association with access to transplantation.

There are limited data on the degree of variability in practices surrounding prioritization of referrals for transplant evaluation and criteria for transplant candidacy and their association with transplantation rates. We surveyed transplant programs across the United States between January 2020 and May 2020 to determine current pre-transplantation practices. We examined the relation between these reported practices and the outcomes of waitlisted patients at responding programs between January 2015 and March 2021 using Scientific Registry of Transplant Recipients data. We used adjusted Cox models with random effects to accommodate clustering by program. Primary outcomes included living or deceased donor transplantation. Of 172 surveyed programs, 90 participated. Substantial variations were noted in when the candidacy evaluation began (13% reported when eGFR was <30 mL/min/1.73 m2 and 17% reported no set policy) and the approach to pre-transplantation cardiac workup (multi-modality [58%], stress echocardiogram [20%]). Using adjusted models, a program policy of using other measures of body habitus to determine transplant candidacy rather than requiring patients to meet a body mass index (BMI) threshold of ≤35 kg/m2 (reference group) for candidacy was associated with a higher hazard of living donor transplantation (HR 1.83 [95% CI 1.10-3.03]). Pre-transplant practices vary substantially across the United States, and select practices were associated with transplantation rates.

Motivations and outcomes of compatible living donor-recipient pairs in paired exchange.

Increasing numbers of compatible pairs are choosing to enter paired exchange programs, but motivations, outcomes, and system-level effects of participation are not well described. Using a linkage of the Scientific Registry of Transplant Recipients and National Kidney Registry, we compared outcomes of traditional (originally incompatible) recipients to originally compatible recipients using the Kaplan-Meier method. We identified 154 compatible pairs. Most pairs sought to improve HLA matching. Compared to the original donor, actual donors were younger (39 vs. 50 years, p < .001), less often female (52% vs. 68%, p < .01), higher BMI (27 vs. 25 kg/m², p = .03), less frequently blood type O (36% vs. 80%, p < .001), and had higher eGFR (99 vs. 94 ml/min/1.73 m², p = .02), with a better LKDPI (median 7 vs. 22, p < .001). We observed no differences in graft failure or mortality. Compatible pairs made 280 additional transplants possible, many in highly sensitized recipients with long wait times. Compatible pair recipients derived several benefits from paired exchange, including better donor quality. Living donor pairs should receive counseling regarding all options available, including kidney paired donation. As more compatible pairs choose to enter exchange programs, consideration should be given to optimizing compatible pair and hard-to-transplant recipient outcomes.

Which recipient pretransplant factors, such as MELD, renal function, sarcopenia, and recent sepsis influence suitability for and outcome after living donor liver transplantation? A systematic review of the literature and expert panel recommendations.

BACKGROUND: Varied access to deceased donors across the globe has resulted in differential living donor liver transplant (LDLT) practices and lack of consensus over the influence of models for end stage liver disease (MELD), renal function, sarcopenia, or recent infection on short-term outcomes. OBJECTIVES: Consider these risk factors in relation to patient selection and provide recommendations. DATA SOURCES: Ovid MEDLINE, Embase, Scopus, Google Scholar, Cochrane Central. METHODS: PRIMSA systematic review and GRADE. PROSPERO ID: RD42021260809 RESULTS: MELD >25-30 alone is not a contraindication to LDLT, and multiple studies found no increase in short term mortality in high MELD patients. Contributing factors such as muscle mass, acute physiologic assessment and chronic health evaluation score, donor age, graft weight/recipient weight ratio, and inclusion of the middle hepatic vein in a right lobe graft influence morbidity and mortality in high MELD patients. Higher mortality is observed with pretransplant renal dysfunction, but short-term mortality is rare. Sarcopenia and recent infection are not contraindications to LDLT. Morbidity and prolonged LOS are common, and more frequent in patients with renal dysfunction, nutritional deficiency or recent infection. CONCLUSIONS: When individual risk factors are studied mortality is low and graft loss is infrequent, but morbidity is common. MELD, especially with concomitant risk factors, had the greatest influence on short term outcome, and recent infection had the least. A multidisciplinary team of experts should carefully assess patients with multiple risk factors, and an optimal graft is recommended.

Association between Longer Travel Distance for Transplant Care and Access to Kidney Transplantation and Graft Survival in the United States.

BACKGROUND: Transplant candidates may gain an advantage by traveling to receive care at a transplant center that may have more favorable characteristics than their local center. Factors associated with longer travel distance for transplant care and whether the excess travel distance (ETD) is associated with access to transplantation or with graft failure are unknown. METHODS: This study of adults in the United States wait-listed for kidney transplantation in 1995-2015 used ETD, defined as distance a patient traveled beyond the nearest transplant center for initial waiting list registration. We used linear regression to examine patient and center characteristics associated with ETD and Fine-Gray models to examine the association between ETD (modeled as a spline) and time to deceased or living donor transplantation or graft failure. RESULTS: Of 373,365 patients, 11% had an ETD≥50 miles. Traveling excess distance was more likely among patients who were of non-Black race or those whose nearest transplant center had lower annual living donor transplant volume. At an ETD of 50 miles, we observed a lower likelihood of deceased donor transplantation (subhazard ratio [SHR], 0.85; 95% confidence interval [95% CI], 0.84 to 0.87) but higher likelihood of living donor transplantation (SHR, 1.14; 95% CI, 1.12 to 1.16) compared with those who received care at their nearest center. ETD was weakly associated with higher risk of graft failure. CONCLUSIONS: Patients who travel excess distances for transplant care have better access to living donor but not deceased donor transplantation and slightly higher risk of graft failure. Traveling excess distances is not clearly associated with better outcomes, especially if living donors are unavailable.

Bariatric surgery prior to transplantation and risk of early hospital re-admission, graft failure, or death following kidney transplantation.

Bariatric surgery has been shown to be safe in the dialysis population. Whether bariatric surgery before kidney transplantation influences posttransplant outcomes has not been examined nationally. We included severely obese (BMI >35) dialysis patients between 18 and 70 years who received a kidney transplant according to the US Renal Data System. We determined the association between history of bariatric surgery and risk of 30-day readmission, graft failure, or death after transplantation using multivariable logistic, Fine-Gray, and Cox models. We included 12 573 patients, of whom 503 (4%) received bariatric surgery before transplantation. Median age at transplant was 53 years; 42% were women. Overall, history of bariatric surgery was not statistically significantly associated with graft failure (HR 1.02; 95% CI 0.77-1.35) or death (HR 1.10; 95% CI 0.84-1.45). However, sleeve gastrectomy (vs. no bariatric surgery) was associated with lower risk of graft failure (HR 0.39; 95% CI 0.16-0.95). In conclusion, history of bariatric surgery prior to kidney transplantation was not associated with allograft or patient survival, but findings varied by surgery type. Sleeve gastrectomy was associated with better graft survival and should be considered in severely obese transplant candidates receiving dialysis.

Understanding the Final Disposition of Livers Declined After the Start of Procurement: A Nationwide Organ Procurement Organization Effort.

Declining a liver offer during organ procurement likely increases the risk of discard, but the specifics around late reallocation remain obscure. This voluntarily submitted, prospectively collected data describe late declines and the ultimate disposition of 893 livers. Once a liver suffered an intraoperative decline, only 49% of recovered livers were transplanted. Livers declined ≥80 minutes prior to cross-clamp were transplanted 80% of the time versus livers declined ≥80 minutes after cross-clamp, which were transplanted 45% of the time. The final disposition of these livers was into a predetermined backup patient (51%) or required an out-of-sequence expedited allocation (42%). Prerecovery imaging and prerecovery biopsy did not influence the ability to reallocate a liver, and livers from donors after circulatory death are rarely successfully reallocated. In conclusion, this study begins to shed light on this seemingly common practice. A total of 85% of centers had an intraoperative decline, but 4% of centers accounted for 25% of the declines. Organ procurement organizations often enter expedited liver allocation, and instituting a cross-clamp delay to allow for reallocation may influence the disposition of these liver grafts. Expedited allocation was more time consuming than allocation into a predetermined backup. Although a certain number of intraoperative declines probably suggests a healthy amount of donor selection aggressiveness at the time of the initial organ offer, the 47% risk of discard of livers declined intraoperatively suggests that United Network for Organ Sharing should consider systematically collecting data about intraoperative declines so we can learn more about this event that influences organ utilization.

Standardizing Discharge Opioid Prescriptions in Kidney Transplant Patients Decreases Opioid Usage.

BACKGROUND: Kidney transplant recipients are frequently prescribed excess opioids at discharge relative to their inpatient requirements. Recipients who fill prescriptions after transplant have an increased risk of death and graft loss. This study examined the impact of standardized prescriptions on discharge amount and number of outpatient refills. MATERIALS AND METHODS: A historical cohort (Group 1) was compared to a cohort without patient-controlled analgesia (Group 2) and a cohort in which providers prescribed no opioids to patients who required none on the day prior to discharge, and 10 pills to those who required opioids on the day prior (Group 3). Demographics, oral morphine equivalents (OMEs) prescribed on the day prior to and at discharge, and outpatient refills were collected. RESULTS: 270 recipients were included. There was a nonsignificant trend towards lower OMEs on the day prior to discharge in Groups 2 and 3. Nonopioid adjunct use increased (P < 0.001). Discharge OMEs significantly decreased (mean 87.2 in Group 1, 62.8 in Group 2, 26.6 in Group 3, P< 0.001). The number of patients discharged without opioids increased (23.8% of Group 1, 37.5% of Group 2, 60.6% of Group 3, P < 0.001). Group 3, Asian descent, and lower OMEs on the day prior were factors significantly associated with decreased discharge OMEs on multivariable linear regression. Twelve percent of Group 2 and 2% of Group 3 patients received an outpatient refill (P = 0.02). CONCLUSIONS: A protocol targeting discharge opioids significantly reduced the amount of opioids prescribed in kidney transplant recipients; most patients subsequently received no opioids at discharge.

Discrepant subtyping of blood type A2 living kidney donors: Missed opportunities in kidney transplantation.

BACKGROUND: Despite the institution of a new Kidney Allocation System in 2014, A2/A2B to B transplantation has not increased as expected. The current Organ Procurement and Transplantation Network policy requires subtyping on two separate occasions, and in the setting of discrepant results, defaulting to the A1 subtype. However, there is significant inherent variability in the serologic assays used for blood group subtyping and genotyping is rarely done. METHODS: The National Kidney Registry, a kidney paired donation (KPD) program, performs serological typing on all A/AB donors, and in cases of non-A1/non-A1B donors, confirmatory genotyping is performed. RESULTS: Between 2/18/2018 and 9/15/2020, 13.0% (145) of 1,111 type A donors registered with the NKR were ultimately subtyped as A2 via genotyping. Notably, 49.6% (72) of these were subtyped as A1 at their donor center, and in accordance with OPTN policy, ineligible for allocation as A2. CONCLUSION: Inaccurate A2 subtyping represents a significant lost opportunity in transplantation, especially in KPD where A2 donors can not only facilitate living donor transplantation for O and highly sensitized candidates, but can also facilitate additional living donor transplants. This study highlights the need for improved accuracy of subtyping technique, and the need for policy changes encouraging optimal utilization of A2 donor kidneys.

Long-term follow-up of beta cell replacement therapy in 10 HIV-infected patients with renal failure secondary to type 1 diabetes mellitus.

The approach to transplantation in human immunodeficiency virus (HIV)-positive patients has been conservative due to fear of exacerbating an immunocompromised condition. As a result, HIV-positive patients with diabetes were initially excluded from beta cell replacement therapy. Early reports of pancreas transplant in patients with HIV described high rates of early graft loss with limited follow-up. We report long-term follow-up of islet or pancreas transplantation in HIV-positive type 1 diabetic patients who received a kidney transplant concurrently or had previously undergone kidney transplantation. Although 4 patients developed polyoma viremia, highly active antiretroviral therapy and adequate infectious prophylaxis were successful in providing protection until CD4+ counts recovered. Coordination with HIV providers is critical to reduce the risk of rejection by minimizing drug-drug interactions. Also, protocols for prophylaxis of opportunistic infections and strategies for monitoring and treating BK viremia are important given the degree of immunosuppression required. This series demonstrates that type 1 diabetic patients with well-controlled HIV and renal failure can be appropriate candidates for beta cell replacement, with a low rate of infectious complications, early graft loss, and rejection, so excellent long-term graft survival is possible. Additionally, patients with HIV and cardiovascular contraindications can undergo islet infusion.

The effect of an organ procurement experience on preclinical medical student perceptions of transplant surgery.

Transplant surgery is a predominantly male specialty with high burnout rates. There are currently limited data regarding how programs can attract a diverse applicant pool to the field of transplant surgery. This study evaluated the effect of an Organ Procurement Experience elective on preclinical medical students' perceptions of transplant surgery in a prospective, longitudinal study. Preclinical medical students were anonymously surveyed before and after attending a deceased donor organ procurement. Questions focused on the following themes: Personal Beliefs, Personal/Professional Life, Diversity, and Gender Equality. Responses were rated on a five-point Likert scale. Ninety-nine and 45 students completed pre/post-procurement survey, respectively. Post-procurement responses demonstrated increased education about the field (2.1/5 vs 3.89/5, P < 0.001) and perceptions of the personalities and collegiality between surgeons (3.06/5 vs 3.73/5, P = 0.005). Post-procurement, women were less likely to feel that female transplant surgeons are treated differently (3.98/5 vs. 3.45/5, P < 0.017). Post-procurement, 19% agreed that transplant surgeons have a high quality of life. One percent of respondents felt the current gender distribution in transplant surgery is satisfactory. The Organ Procurement Experience significantly improved preclinical students' perceptions of the field. However, there remains a strong concern about quality of life and gender diversity within the field.

Central venous pressure monitoring in living donor kidney recipients does not affect immediate graft function: A propensity score analysis.

BACKGROUND: During kidney transplantation, intraoperative fluid management can affect post-transplant graft function. It is unclear whether or not central venous pressure (CVP) monitoring is required to guide fluid therapy during kidney transplantation. METHODS: We compared post-transplant graft function in recipients of living donor kidney transplants between August 2006 and March 2009 based on the use or absence of intraoperative CVP monitoring. Graft function, assessed using the creatinine reduction ratio on postoperative day 2 (CCR2), was evaluated by multivariable linear regression analysis and in a propensity-matched cohort. RESULTS: Two hundred and ninety patients were included in the analysis. Central venous pressure was monitored in 84 patients (29%). There was no difference in post-transplant graft function, as measured by CCR2, between patients with and without CVP monitoring in both unadjusted and multivariable-adjusted analyses. There were also no statistically significant differences in CCR2, delayed graft function, or 3-month renal function between those monitored with CVP and those without, in the propensity-matched cohort. CONCLUSIONS: In this single-center analysis, immediate post-transplant renal function was not associated with the use of intraoperative CVP monitoring.