Extracorporeal membrane oxygenation for cardiopulmonary failure in organ donation: Assessing liver transplant outcomes.

Liver transplantation continues to face significant organ shortages and efficient utilization of marginal donors is paramount. This study evaluates the practice patterns and outcomes in liver transplantation when utilizing allografts from marginal donors who required extracorporeal membrane oxygenation (ECMO) support. We performed a retrospective review of the Gift of Life (PA, NJ, DE) organ-procuring organization database for transplants performed using donors supported on ECMO for nondonation purposes. These were cross-referenced to the transplant recipients within the Organ Procurement and Transplantation Network database, and the outcomes of liver transplants using donors on ECMO support were compared with those not requiring ECMO. Organ use and nonuse patterns were then evaluated in ECMO-supported donors, identifying the factors associated with nonuse compared with the factors associated with graft failure. Thirty-nine of the 84 ECMO-supported donors contributing at least one intra-abdominal organ for transplant donated a liver. Graft survival and patient survival up to 5 years were comparable between transplants from ECMO and non-ECMO-supported donors, and no cases of primary nonfunction were seen in the ECMO group. ECMO support was not associated with 1-year graft failure on regression modeling. Additional regression analyses within the ECMO donor population identified bacteremia (HR: 19.81) and elevated total bilirubin at donation (HR: 2.44) as predictive of post-transplant graft failure. Livers from donors supported on ECMO before donation appear safe to use in select transplant settings. Better understanding of the impact of predonation ECMO on liver allograft function will help guide the optimal use of these scarcely used donors.

Evaluating Outcomes Related to Donor and Recipient Metabolic Environment: Macrosteatotic Allografts and Nonalcoholic Steatohepatitis.

The increasing prevalence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) affects both recipient and donor populations in liver transplantation. Presently, it is unclear whether transplantation of macrosteatotic allografts is affected by the metabolic milieu of liver transplant recipients. This study investigates fatty liver disease at the intersection of donor and recipient. A retrospective review of the Organ Procurement and Transplantation database identified 5167 NASH and 26,289 non-NASH transplant recipients who received transplants from January 1, 2004, to June 12, 2020. A total of 12,569 donors had allografts with no macrosteatosis (<5%), 16,140 had mild macrosteatosis (5%-29%), and 2747 had moderate to severe macrosteatosis (≥30%). Comparing recipients with NASH to propensity score-matched (PSM) recipients without NASH demonstrated noninferior graft and patient survival up to 10 years in patients with NASH. Similar trends were observed in subgroup analyses of transplants within each strata of allograft macrosteatosis. Assessing allograft macrosteatosis specifically in the NASH population demonstrated that allografts with ≥30% macrosteatosis were associated with reduced early graft survival (30 days, 93.32% versus 96.54% [P = 0.02]; 1 year, 84.53% versus 88.99% [P = 0.05]) compared with PSM grafts with <30% macrosteatosis. Long-term graft survival at 5 and 10 years, however, was similar. The use of carefully selected macrosteatotic allografts can be successful in both recipients with NASH and recipients without NASH. The metabolic environment of patients with NASH does not appear to adversely affect outcomes with regard to the allograft when controlled for numerous confounders. It is, however, important to remain cognizant of the potential for high-risk macrosteatotic allografts to negatively affect outcomes.

Simultaneous liver kidney allocation policy and the Safety Net: an early examination of utilization and outcomes in the United States.

Rates of simultaneous liver kidney (SLK) transplantation in the United States have progressively risen. On 8/10/17, the Organ Procurement and Transplantation Network implemented a policy defining criteria for SLK, with a "Safety Net" to prioritize kidney allocation to liver recipients with ongoing renal failure. We performed a retrospective review of the United Network for Organ Sharing (UNOS) database to evaluate policy impact on SLK, kidney after liver (KAL) and kidney transplant alone (KTA). Rates and outcomes of SLK and KAL transplants were compared, as was utilization of high-quality kidney allografts with Kidney Donor Profile Indices (KDPI) <35%. Here, SLK transplants comprised 9.0% and 4.5% of total postpolicy liver and kidney transplants compared to 10.2% and 5.5% prior. Policy enactment did not affect 1-year graft or patient survival for SLK and KAL populations. Less postpolicy SLK transplants utilized high-quality kidney allografts; in all transplant settings, outcomes using high-quality grafts remained stable. These findings suggest that policy implementation has reduced kidney allograft use in SLK transplantation, although both SLK and KAL rates have recently increased. Despite decreased high-quality kidney allograft use, SLK and KAL outcomes have remained stable. Additional studies and long-term follow-up will ensure optimal organ access and sharing.

The adipose tissue production of adiponectin is increased in end-stage renal disease.

Adiponectin has antidiabetic properties, and patients with obesity, diabetes, and insulin resistance have low plasma adiponectin levels. However, although kidney disease is associated with insulin resistance, adiponectin is elevated in end-stage renal disease. Here we determine whether adipose tissue production of adiponectin is increased in renal disease in a case-control study of 36 patients with end-stage renal disease and 23 kidney donors. Blood and tissue samples were obtained at kidney transplantation and donation. The mean plasma adiponectin level was significantly increased to 15.6 mg/ml in cases compared with 8.4 mg/ml in controls. Plasma levels of the inflammatory adipokines tumor necrosis factor α, interleukin 6, and high-sensitivity C-reactive protein were significantly higher in cases compared with controls. Adiponectin mRNA and protein expression in visceral and subcutaneous fat were significantly higher in cases than controls, while adiponectin receptor-1 mRNA expression was significantly increased in peripheral blood cells, muscle, and adipose tissue in cases compared with controls. Thus, our study suggests that adipose tissue production of adiponectin contributes to the high plasma levels seen in end-stage renal disease.

Completely steroid-free immunosuppression in liver transplantation: a randomized study.

INTRODUCTION: Corticosteroids (CS) have been standard immunosuppression to prevent and treat rejection. However, CS are associated with increased risk of infection, obesity, hypertension, hyperlipidemia, diabetes, and accelerated hepatitis C virus (HCV) recurrence post-orthotopic liver transplantation (OLT). This study assesses the safety and efficacy of CS-free immunosuppressive regimen in adult OLT. METHODS: A two-yr, prospective, randomized study of CS with delayed withdrawal (CS) or CS-free regimen with basiliximab, tacrolimus, and enteric-coated mycophenolate sodium (EC-MPS) was performed in 39 patients (CS=20; CS-free=19). CS group received intra-operative methylprednisolone weaned by six months. HCV patients had HCV PCR pre-OLT and 0.5, one, three, and six months post-OLT. Protocol liver biopsies were performed at OLT, 2 and 24 wk post-OLT or when indicated. RESULTS: Rejection occurred in two patients. Patient survival at one yr (100% vs. 95%), three yr (85% vs. 63%), and five yr (80% vs. 63%) post-OLT were similar between CS and CS-free group, respectively. Death-censored graft survival at one yr (100% vs. 95%), three yr (85% vs. 63%), and five yr (75% vs. 63%) were also similar. The risk of new-onset DM, hypertension, hypercholesterolemia, and weight gain was similar between groups. CONCLUSION: CS avoidance with basiliximab, calcineurin inhibitor, and EC-MPS is safe and effective as CS- containing immunosuppression in adult OLT.

Assessing Kidney Transplantation Using ECMO-Supported Donors Within a KDPI-Based Allocation System.

Background: Organ donors supported by extracorporeal membrane oxygenation (ECMO) have historically been considered high-risk and are judiciously utilized. This study examines transplant outcomes using renal allografts from donors supported on ECMO for nondonation purposes. Methods: Retrospective review of the Gift of Life (Pennsylvania, New Jersey, Delaware) organ procurement organization database, cross-referenced to the Organ Procurement and Transplantation Network database, assessed kidney transplants using donors supported on venoarterial (VA) and venovenous (VV) ECMO for nondonation purposes. Transplants using VA- and VV-ECMO donors were compared with Kidney Donor Profile Index (KDPI)-stratified non-ECMO donors. Regression modeling of the entire ECMO and non-ECMO populations assessed ECMO as predictive of graft survival. Additional regression of the ECMO population alone assessed for donor features associated with graft survival. Results: Seventy-eight ECMO donors yielded 128 kidney transplants (VA: 80, VV: 48). Comparing outcomes using these donors to kidney transplants using organs from KDPI-stratified non-ECMO donors, VA- and VV-ECMO donor grafts conferred similar rates of delayed graft function and posttransplant renal function to KDPI-matched non-ECMO counterparts. VA-ECMO kidneys demonstrated superior graft survival compared with the lowest-quality (KDPI 86%-100%) non-ECMO kidneys and similar graft survival to KDPI <85% non-ECMO kidneys. VV-ECMO showed inferior graft survival to all but the lowest-quality (KDPI 86%-100%) non-ECMO kidneys. VV-ECMO, but not VA-ECMO, was associated with increased risk of graft loss on multivariable regression (hazard ratios-VA: 1.02, VV: 2.18). Higher KDPI, advanced age, increased body mass index, hypertension, and diabetes were identified as high-risk features of ECMO donors. Conclusions: Kidney transplantation using appropriately selected ECMO donors can safely expand the donor pool. Ongoing studies are necessary to determine best practice patterns using kidneys from these donors.

Peritransplant kidney biopsies: comparison of pathologic interpretations and practice patterns of organ procurement organizations.

The preimplantation kidney biopsy affects utilization by diagnosing glomerulosclerosis, interstitial fibrosis (IF), arteriosclerosis, and arteriolar hyalinosis. Organ procurement organizations (OPOs) determine whether a donor warrants this biopsy and the donor hospital pathologists (DHPs) report on an OPO-specific pathology interpretation form. Biopsy slides from 40 deceased donor kidneys transplanted at our institution were used to compare interpretations between our transplant pathologist and the DHPs. Thirty-three of these kidneys also had post-perfusion biopsies (PPB). All 58 OPOs were queried for criteria used to request a preimplantation biopsy, and their pathology interpretation forms were also analyzed. The transplant and DHPs had substantial agreement for percent glomerulosclerosis with 75% of biopsies being interpreted within five percentage points. Concordance for IF was poor. The DHP rarely reported arterial pathology. Seventy percent of preimplantation and PPB were read similarly for glomerulosclerosis; concordance for other lesions was weaker. There were no cues for arterial disease on our OPO's pathology interpretation form. Criteria for obtaining a preimplantation biopsy lacked uniformity for the 21 OPOs with a self-generated policy. The pathology interpretation forms varied widely among the OPOs. Current OPO practices with regard to the preimplantation biopsy should be improved.

A retrospective analysis of the use of caspofungin in recipients of liver transplant with a modified high index of suspicion for fungal infection. A critical review of mortality, acute cellular rejection, infections, and changes in the liver function tests while on caspofungin.

This study is a retrospective analysis of death, adverse events (AE), fungal infections, and hepatic function among recipients of liver transplantation at high risk of fungal infection who received prophylactic treatment with caspofungin. After reviewing data of 105 patients who had received isolated liver transplant between January 2003 and April 2007, we identified and analyzed 82 high-risk patients. Post-transplant patients at high risk for fungal infection are commonly defined by the presence of at least one of the following: (i) re-transplantation; (ii) re-operation; (iii) renal dysfunction. However, in our practice, patients are also considered at high risk for developing fungal infections if they present with the following: (iv) fever of unknown origin; (v) hypothermia; (vi) positive random culture for fungus at the time of transplant (bile and/or ascites); (vii) sepsis; (viii) use of vasopressors; (ix) re-intubation, during the first hospitalization after liver transplant; (x) prolonged intubation (>24 h), and (xi) acute respiratory distress syndrome, until negative fungal cultures are obtained. Exact conditional logistic regression was used to compare the risk of death, AEs, and fungal infections between patients who received caspofungin, other antifungal drugs, and no antifungal drugs. Analyses were then performed with SAS 9.1 (SAS Institute Inc., Cary, NC, USA). Patients were between 27 and 72 yr old (mean = 55), with two-thirds male and three-quarters Caucasian. Sixteen patients received caspofungin (11 preventively), and 32 received other antifungal (26 preventively). There were no proven fungal infections among the patients who received caspofungin, three infections among patients who received other antifungal (3/26 = 12%), and 14 infections among patients who were not preventively treated (14/45 = 31%). These infection rates were significantly different across the three groups (p = 0.029), with caspofungin and other antifungal preventive treatment comparable (p = 0.540), and both better than no preventive treatment at all (OR = 0.15, p = 0.049, for caspofungin versus no preventive treatment; OR = 0.29, p = 0.085, for other antifungal versus no preventive treatment). Caspofungin appears to be an effective preventive agent against fungal infections when used in recipients of liver transplant designated as high risk for fungal infection. Usage of caspofungin in these patients does not carry an apparent increase in risk of death or acute cellular rejection, although we observed a significantly higher risk of AEs, especially acute renal failure (p = 0.001), in patients who received this agent.

Use of enteric-coated mycophenolate sodium in liver transplant patients with intestinal intolerance caused by mycophenolate mofetil.

BACKGROUND: Post-transplant gastrointestinal (GI) side effects can impair a patient's quality of life (QoL). This study investigates the improvement in GI side effects and related QoL changes in recipients of liver transplantation (OLT) after converting patients from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS). METHODS: Thirty-four patients who underwent OLT and suffered from GI intolerability were included in this study. Infectious causes of GI intolerability were excluded. QoL assessed by the Gastrointestinal Quality of Life Index was evaluated before conversion and at months 3, 6 and 12 post-conversion. All patients received baseline immunosuppression of one calcineurin inhibitor, MMF, with or without steroids. Patients were converted from MMF to EC-MPS on an equimolar basis. Paired t-test was used to assess differences in mean score changes over time. RESULTS: Conversion from MMF to EC-MPS for GI intolerability post-OLT shows statistically significant improvement in GI-related QoL at 3, 6, and 12 months when compared to baseline assessments (p < 0.05 for total mean score); nonetheless, one-third of patients discontinued EC-MPS. No rejection episodes, deaths or graft loss were seen during the study period. CONCLUSION: OLT recipients who develop GI side effects caused by MMF can be safely converted to EC-MPS with improvement to their QoL.

Pregnancy after liver transplantation.

Women constitute >30% of patients undergoing liver transplantation (orthotopic liver transplantation, OLT) and about 8% are of reproductive age, and 5% are pediatric females who will mostly survive into adulthood and will consider pregnancy. Although pregnancy in OLT recipients is associated with an increased incidence of hypertension, preeclampsia, anemia, preterm deliveries, and cesarean section, acute rejection and liver allograft loss do not appear to be increased and pregnancy-related maternal death is uncommon. The incidence of structural malformations in the newborn of liver transplant recipients is reported to be 4.4%, which is similar to the rate of 3-5% in the US general population. Patients are advised to defer conception for at least 1-2 years after OLT, while maintaining effective contraception. Pregnancy after OLT usually results in a favorable maternal and neonatal outcome when there is coordinated pre- and perinatal care by a multidisciplinary team composed of obstetric-gynecologists, and a transplant team.

Expanded criteria donor kidneys where the paired kidney is discarded owing to biopsy results: a concept that needs revision.

OBJECTIVES: We explored the categorizing of expanded criteria donors based on systemic disease processes linked to symmetric bilateral renal injury. MATERIALS AND METHODS: We evaluated expanded criteria donor kidneys where the paired kidney was discarded owing to biopsy results, termed the discard group compared with those expanded criteria donors (where both were transplanted), termed the nondiscard group. Analysis of the Organ Procurement and Transplant Network data was completed focusing on the effect of glomerulosclerosis. RESULTS: Our investigation revealed 754 and 9575 recipients in the discard group and nondiscard groups. Fewer glomerulosclerosis was seen the nondiscard group. An assessment revealed improved 1-, 3-, and 5-year graft (P < .001) and patient (P < .05) survivals in the nondiscard group compared with the discard group. However, multivariate analysis demonstrated glomerulosclerosis had little to no effect on graft and patient survival. Expanded criteria donor kidneys with 0% to 5% glomerulosclerosis had no significant differences in graft function as compared with expanded criteria donor kidneys that had > 10% glomerulosclerosis. In fact, expanded criteria donor kidneys with 0% to 5% glomerulosclerosis showed no statistically significantly protective effect over any biopsy with > 5% glomerulosclerosis in patient survival. CONCLUSIONS: Owing to the limited supply of biopsy results in predicting outcomes when controlled for pertinent variables, relying on biopsy findings for kidney allocation may result in many valuable kidneys being discarded.

An alternative surgical technique for caval preservation in liver transplantation.

INTRODUCTION: The results of orthotopic liver transplantation in patients with end-stage liver disease continue to improve. Refinements in surgical techniques represent an important part of this improvement. MATERIALS AND METHODS: With the advent of split-liver and living-donor liver transplantation, inferior vena cava (IVC) preservation transitioned from being a potential option to being mandatory for many cases. Preserving the IVC can be a demanding technical maneuver in many liver transplants and several different approaches have been developed. When utilizing IVC preservation, there are several options for implantation of the graft. The piggyback technique, when feasible, is considered safe and provides hemodynamic stability for the recipient. RESULTS AND DISCUSSION: In some cases it may be difficult to perform the piggyback technique if intense inflammatory adhesions and severe significant collateral circulation exist between the IVC and the posterior segments of the liver. In these cases, the retro-hepatic dissection can be carried out with a different approach: the infrahepatic vena cava and the confluence of the three hepatic veins can be cross-clamped en-bloc without dissection. CONCLUSION: This technique broadens the transplant surgeons' armamentarium and can be used in the setting of a very difficult retro-hepatic dissection. It is safe, and allows a shorter anhepatic phase with caval preservation.

Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation.

With the constant advent of new developments and modifications in immunosuppressive regimens, clinicians are responsible for providing pregnancy counseling to all pre and posttransplant recipients of childbearing age. As individual physicians and centers accrue experience with these major therapeutic decisions, it is critical that both positive and negative outcomes be reported in appropriate settings-symposia, meetings, publications, and registries. The NTPR has acquired experience with 2000 pregnancy outcomes in female transplant recipients. For the NTPR's largest group, female kidney recipients, 71-76% of the pregnancies produce a livebirth. For the other organs combined, the livebirth likelihood ranges from 50-86%. The incidence of birth defects in the liveborn appears similar to the general population, except for pregnancies with MPA exposure that have a 23% incidence of birth defects. Long-term follow-up of the offspring of transplant recipients has provided reassurance after 20 years of observation. The continued recording of data in registries such as the NTPR is essential for assessing the safety of pregnancy in solid organ transplant recipients. Key benefits of the NTPR are the personal contact between registry staff and participants, the wide range of pregnancy-related variables that are analyzed, and the opportunity for health-care providers to obtain information that helps them care for transplant recipients on a case-by-case basis.

Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation.

With the constant advent of new developments and modifications in immunosuppressive regimens, clinicians are responsible for providing pregnancy counseling in all pre- and post-transplant recipients of childbearing age. As individual physicians and centers accrue experience with these major therapeutic decisions, it is critical that both positive and negative outcomes be reported in appropriate settings-symposia, meetings, publications, and registries. Future analyses from the NTPR are directed at potential effects of newer immunosuppressive regimens, not only from immediate exposure, but also from continued exposures such as may occur from breastfeeding. As the registry study design allows for contact between registry staff and recipients and their health care providers, efforts are ongoing to analyze long-term outcomes of parent and child. Continued close collaboration among specialists will help to better identify potential pregnancy risks in these populations, particularly as new immunosuppressive agents are developed. Therefore, centers are encouraged to report all pregnancy exposures in transplant recipients to the NTPR.

Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation.

With the constant advent of new developments and modifications in immunosuppressive regimens, clinicians are responsible for providing pregnancy counseling in all pre and post-transplant patients of childbearing age. As individual physicians and centers accrue experience with these major therapeutic decisions, it is critical that both positive and negative outcomes be reported in appropriate settings-symposia, meetings, publications, and registries. Future analyses from the NTPR are directed at potential effects of newer immunosuppressive regimens, not only from immediate exposure, but also from continued exposures such as may occur from breastfeeding. As the registry study design allows for contact between registry staff and recipients and their health care providers, efforts are ongoing to analyze long-term outcomes of parent and child. Continued close collaboration among specialists will help to identify potential pregnancy risks in these populations, particularly as new immunosuppressive agents are developed. Therefore, centers are encouraged to report all pregnancy exposures in transplant recipients to the NTPR. The 50th anniversary of the first post-transplant pregnancy (reported by Joseph Murray et al. (32)) that occurred in March of 2008 helped to raise awareness of the need for continued worldwide cooperation for data collection. Enhanced assessment of pregnancy safety is essential to the development of guidelines for counseling and management of pregnancy in the transplant population.

The role of basiliximab induction therapy in organ transplantation.

Basiliximab is a chimeric monoclonal antibody that selectively binds to the alpha-subunit (CD25) of IL-2 receptors on the surface of activated T lymphocytes, and is a highly effective prophylaxis agent against rejection in organ transplant recipients. Its pharmacokinetic profile is characterized by a biphasic and slow clearance with long terminal half-life and a volume of distribution within the central compartment and outside the circulatory system. Basiliximab induction demonstrated an excellent safety profile, with no increase in the incidence of malignancy, infections or death. It has also been used effectively in high-risk recipients, steroid-sparing and steroid-minimization protocols, and in post-transplant patients with renal dysfunction who would benefit from delayed introduction of calcineurin inhibitors. Basiliximab induction therapy given at days 0 and 4 after transplantation appears to be safe and cost-effective for immunoprophylaxis in solid organ transplant recipients, specifically in kidney and liver transplantation, when given in conjunction with dual or triple immunosuppressive therapy.

Anti-IL2 induction in liver transplantation with 93% rejection-free patient and graft survival at 18 months.

BACKGROUND: Induction with the use of monoclonal antibodies targeting the alpha-chain (CD25) of the high-affinity IL2 receptor may avoid many of the adverse events associated with polyclonal antibodies and significantly impact on rejection-free long-term survival in orthotopic liver transplantation (OLT). METHODS: Forty-two consecutive deceased donor primary OLT were retrospectively analyzed. All patients received two 20-mg doses of basiliximab (days 0 and 4 after OLT) followed by tacrolimus (0.15 mg/kg/day; 10-15 ng/mL target trough levels), and steroids (methylprednisolone 1 g intraoperatively followed by tapering doses). Mycophenolate mofetil (MMF) 1 g every 12 h was added to the drug combination as needed. The mean follow-up period was 19.3 months (range: 4.8-35.9 months). RESULTS: The average Model for End-Stage Liver Disease score was 26 (range: 15-40). A total of 39 patients (93%) remained rejection-free during follow-up with an actuarial rejection-free probability of 95% within 3 months. The actuarial patient and graft survival rate (Kaplan-Meier estimated) at 2 years was 93%. Twenty-five patients (60%) were completely off steroids within 3 months post-OLT (mean: 51.1 days, range: 10-90 days). By the 10th month post-OLT, 30/39 (77%) of the patients were completely off steroids. At last follow-up, 30/39 (77%) are on tacrolimus monotherapy with an average dose of 4 mg per day. Six patients (15%) are on double therapy, receiving a combination of tacrolimus and prednisone (two patients) or tacrolimus and MMF (two patients) or tacrolimus and mycophenolic acid (two patients). Only three patients (8%) are receiving triple therapy at last follow-up. Nine patients (21%) experienced at least one episode of infection. Only six (26%) of a total of 23 hepatitis C virus (HCV) recipients developed histology-proven HCV recurrence, with a mean onset of recurrence post-OLT of 3.2 months (range: 1.3-6.3 months). Of these six patients, two are presently undergoing treatment with interferon and ribavirin, one was treated and became HCV RNA negative, one was not treated, one declined treatment, and two died of HCV recurrence. None of the 42 study patients developed cytomegalovirus infection or posttransplant lymphoproliferative disease. CONCLUSIONS: These preliminary data suggest that basiliximab, given in combination with a tacrolimus-based immunosuppressive regimen, is safe and associated with a low incidence of acute rejection and excellent short-term rejection-free graft and patient survival rate after OLT.