Characterizing the risk of human leukocyte antigen-incompatible living donor kidney transplantation in older recipients.

Older compatible living donor kidney transplant (CLDKT) recipients have higher mortality and death-censored graft failure (DCGF) compared to younger recipients. These risks may be amplified in older incompatible living donor kidney transplant (ILDKT) recipients who undergo desensitization and intense immunosuppression. In a 25-center cohort of ILDKT recipients transplanted between September 24, 1997, and December 15, 2016, we compared mortality, DCGF, delayed graft function (DGF), acute rejection (AR), and length of stay (LOS) between 234 older (age ≥60 years) and 1172 younger (age 18-59 years) recipients. To investigate whether the impact of age was different for ILDKT recipients compared to 17 542 CLDKT recipients, we used an interaction term to determine whether the relationship between posttransplant outcomes and transplant type (ILDKT vs CLDKT) was modified by age. Overall, older recipients had higher mortality (hazard ratio: 1.632.072.65, P < .001), lower DCGF (hazard ratio: 0.360.530.77, P = .001), and AR (odds ratio: 0.390.540.74, P < .001), and similar DGF (odds ratio: 0.461.032.33, P = .9) and LOS (incidence rate ratio: 0.880.981.10, P = 0.8) compared to younger recipients. The impact of age on mortality (interaction P = .052), DCGF (interaction P = .7), AR interaction P = .2), DGF (interaction P = .9), and LOS (interaction P = .5) were similar in ILDKT and CLDKT recipients. Age alone should not preclude eligibility for ILDKT.

Impact of Portable Normothermic Machine Perfusion for Liver Transplantation From Adult Deceased Donors.

OBJECTIVE: To assess how liver allografts preserved using portable normothermic machine perfusion (NMP) compare against those that underwent ischemic cold storage (ICS) in the setting of donation after brain death (DBD) and donation after circulatory death (DCD) liver transplantation (LT). BACKGROUND: Compared with conventional ICS, NMP may offer more homeostatic preservation, permit physiological assessment of organ function, and provide opportunities for graft improvement/modification. We report a single-center US experience of liver NMP. METHODS: A single-center, retrospective analysis of collected data on 541 adult whole LTs from 469 DBD donors [NMP (n = 58) vs ICS (n = 411)] and 72 DCD donors [NMP (n = 52) vs ICS (n = 20)] between January 2016 and December 2022. RESULTS: In DBD LT, male sex [odds ratio (95% CI): 1.83 (1.08-3.09)] and >10% macrosteatosis of the donor liver [1.85 (1.10-3.10)] were statistically significant independent risk factors of early allograft dysfunction (EAD). Donor age >40 years and cold ischemia time >7 hours were independent risk factors of reperfusion syndrome (RPS). One-year, 3-year, and 5-year incidences of ischemic cholangiopathy (IC) did not differ significantly in DBD cases between the NMP and ICS cohorts. In DCD LT, NMP was an independent protective factor against EAD [0.11 (0.03-0.46)] and RPS [0.04 (0.01-0.25)]. The incidence of IC in the DCD cases at 1-year and 3-year time points was significantly lower in the NMP cohort (1.9% compared with 20% in the ICS group). CONCLUSIONS: Compared with conventional ICS, NMP can significantly reduce the incidence of EAD, RPS, and IC after DCD LT.

Impact of donor sex on hepatocellular carcinoma recurrence in liver transplantation after brain death.

BACKGROUND: Hepatocellular carcinoma (HCC) is predominantly seen in males but has a better prognosis in females. No prior studies have investigated HCC recurrence based on sex combination following liver transplant donated after brain death (DBDLT). This study sought to elucidate the effects of donor and recipient sex on HCC recurrence rates. METHODS: 9232 adult recipients from the United Network for Organ Sharing (UNOS) database who underwent DBDLT for HCC from 2012 to 2018 were included. Donor-recipient pairs were divided into (1) female donor/female recipient (F-F) (n = 1089); (2) male donor/female recipient (M-F) (n = 975); (3) female donor/male recipient (F-M) (n = 2691); (4) male donor/male recipient (M-M) (n = 4477). The primary prognostic outcome was HCC recurrence. A multivariable competing risk regression analysis was used to assess prognostic influences. RESULTS: The median recipient age and model for end-stage liver disease (MELD) scores were similar among the four groups. Livers of male recipients demonstrated greater in size and number of HCC (both p-values were <.0001). There was also a higher rate of vascular invasion in male recipients compared to female (p < .0001). Competing risk analyses showed that the cumulative HCC recurrence rate was significantly lower in the M-F group (p = .013). After adjusting for tumor characteristics, liver grafts from male donors were associated with a lower HCC recurrence rate in female recipients (HR: .62 95%CI: .42-.93) (p = .021). CONCLUSION: In DBDLT, male donor to female recipient pairing exhibited lower HCC recurrence rates. SUMMARY: Lowest rates of HCC recurrence were confirmed among the female recipients of male donor grafts group in the deceased donor LT cohort. A competing risk multivariable regression analysis demonstrated that male donor sex was significantly associated with low HCC recurrence in female but not male recipients.

Resection of NAFLD/NASH-related Hepatocellular Carcinoma (HCC): Clinical Features and Outcomes Compared with HCC Due to Other Etiologies.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are the leading causes of hepatocellular carcinoma (HCC) worldwide. Limited data exist on surgical outcomes for NAFLD/NASH-related HCC compared with other HCC etiologies. We evaluated differences in clinicopathological characteristics and outcomes of patients undergoing surgical resection for NAFLD/NASH-associated HCC compared with other HCC etiologies. METHODS: Demographic, clinicopathological features, and survival outcomes of patients with surgically resected HCC were collected. NAFLD activity score (NAS) and fibrosis score were assessed by focused pathologic review in a subset of patients. RESULTS: Among 492 patients screened, 260 met eligibility (NAFLD/NASH [n = 110], and other etiologies [n = 150]). Median age at diagnosis was higher in the NAFLD/NASH HCC cohort compared with the other etiologies cohort (66.7 vs. 63.4 years, respectively, P = .005), with an increased percentage of female patients (36% vs. 18%, P = .001). NAFLD/NASH-related tumors were more commonly >5 cm (66.0% vs. 45%, P = .001). There were no significant differences in rates of lymphovascular or perineural invasion, histologic grade, or serum AFP levels. The NAFLD/NASH cohort had lower rates of background liver fibrosis, lower AST and ALT levels, and higher platelet counts (P < .01 for all). Median overall survival (OS) was numerically shorter in NAFLD/NASH vs other etiology groups, however, not statistically significant. CONCLUSIONS: Patients with NAFLD/NASH-related HCC more commonly lacked liver fibrosis and presented with larger HCCs compared with patients with HCC from other etiologies. No differences were seen in rates of other high-risk features or survival. With the caveat of sample size and retrospective analysis, this supports a similar decision-making approach regarding surgical resection for NAFLD/NASH and other etiology-related HCCs.

Resolution of Severe Graft Steatosis Before Living-Donor Liver Transplant After 86 Pounds of Weight Loss.

Living-donor liver transplant allows for expedited transplant, with outcomes shown to be superior compared with deceased-donor liver transplant due to earlier intervention, with reduced hospital costs. However, they only comprise about 5% of liver transplants nationally. This is due to a limited pool of willing donors and donor exclusions for medical and psycho-social reasons. The leading reason for why potential living liver donors are not eligible is nonalcoholic fatty liver disease. Donor hepatic steatosis limits the number of potential living-donor liver transplants because it is associated with perioperative complications in both donors and recipients. Here, we describe a 37-year-old male potential living donor who presented with hepatic steatosis based on preoperative imaging. Over a 1-year period, he was able to completely reverse his hepatic steatosis by losing about 86 pounds (from 279 to 193 pounds), reducing his body mass index from 40 to 28.55 kg/m². Computed tomography and biopsy results after his weight loss showed that he had no hepatic steatosis, allowing him to become a living donor for his mother. Postoperative periods for both the donor and recipient were uncomplicated. This case suggests that the pool of living liver donors could be expanded through dietary and behavior modifications, thus increasing the number of potential living donors and providing potential recipients with more transplant options. Enlarging this pool of donors will also improve transplant outcomes for donors and recipients and lower overall health care costs compared with deceased-donor liver transplant.

Treatment of Acute Graft-versus-Host Disease in Liver Transplant Recipients.

Acute graft-versus-host disease (aGvHD) is a rare complication of liver transplantation associated with high morbidity and mortality. Death typically occurs due to complications related to severe infection, shock, and multiorgan failure. The clinical presentation involves dysfunction of multiple organ systems with overlapping symptoms that often results in a diagnostic delay. As there are a limited number of cases reported in the literature, there are no clear guidelines for treatment. Many different therapeutic measures have been utilized that target various immune system pathways, but steroids remain the first line of therapy. We report on two patients who developed aGvHD after liver transplantation who were treated with ruxolitinib, a novel Janus kinase 1/2 (JAK) inhibitor that has been shown to improve outcomes in steroid refractory cases of aGvHD after allogenic hematopoietic stem cell transplantation. We reviewed the literature to discuss various therapeutic options currently available for aGvHD after liver transplantation.

Transplantation of Renal Allograft After Removal of Renal Cell Carcinoma: Case Report and Review of the Literature.

With the rising incidence of end-stage renal disease in the United States, patients needing renal transplants are waiting longer for increasingly scarce grafts. Formerly, the general practice was to avoid organs with tumors for transplant because of the risk of malignancy transmission to the recipient. However, with comprehensive donor selection and a small-sized primary tumor, the positive outcomes of transplant outweigh the risks of transmission after a partial nephrectomy. In our case, a 31-year-old woman, the daughter of the recipient, underwent a laparoscopic nephrectomy with an existing 8-mm tumor later confirmed as renal cell carcinoma. An ex vivo tumor enucleation was performed before the allograft was transplanted into the 69-year-old patient with endstage renal disease. At last follow-up, graft function has remained excellent with no evidence of local recurrence or metastasis in both the donor and recipient. Here, we describe our case and perform a literature review on the incidence and management of renal allografts with incidentally detected renal cell carcinoma during transplant.

Center-level Variation in HLA-incompatible Living Donor Kidney Transplantation Outcomes.

BACKGROUND: Desensitization protocols for HLA-incompatible living donor kidney transplantation (ILDKT) vary across centers. The impact of these, as well as other practice variations, on ILDKT outcomes remains unknown. METHODS: We sought to quantify center-level variation in mortality and graft loss following ILDKT using a 25-center cohort of 1358 ILDKT recipients with linkage to Scientific Registry of Transplant Recipients for accurate outcome ascertainment. We used multilevel Cox regression with shared frailty to determine the variation in post-ILDKT outcomes attributable to between-center differences and to identify any center-level characteristics associated with improved post-ILDKT outcomes. RESULTS: After adjusting for patient-level characteristics, only 6 centers (24%) had lower mortality and 1 (4%) had higher mortality than average. Similarly, only 5 centers (20%) had higher graft loss and 2 had lower graft loss than average. Only 4.7% of the differences in mortality (P < 0.01) and 4.4% of the differences in graft loss (P < 0.01) were attributable to between-center variation. These translated to a median hazard ratio of 1.36 for mortality and 1.34 of graft loss for similar candidates at different centers. Post-ILDKT outcomes were not associated with the following center-level characteristics: ILDKT volume and transplanting a higher proportion of highly sensitized, prior transplant, preemptive, or minority candidates. CONCLUSIONS: Unlike most aspects of transplantation in which center-level variation and volume impact outcomes, we did not find substantial evidence for this in ILDKT. Our findings support the continued practice of ILDKT across these diverse centers.

Pleural Effusions Following Liver Transplantation: A Single-Center Experience.

INTRODUCTION: This was a single-center retrospective study to evaluate incidence, prognosis, and risk factors in patients with postoperative pleural effusions, a common pulmonary complication following liver transplantation. METHODS: A retrospective review was performed on 374 liver transplantation cases through a database within the timeframe of January 1, 2009 through December 31, 2015. Demographics, pulmonary and cardiac function testing, laboratory studies, intraoperative transfusion/infusion volumes, postoperative management, and outcomes were analyzed. RESULTS: In the immediate postoperative period, 189 (50.5%) developed pleural effusions following liver transplantation of which 145 (76.7%) resolved within 3 months. Those who developed pleural effusions demonstrated a lower fibrinogen (149.6 ± 66.3 mg/dL vs 178.4 ± 87.3 mg/dL; P = .009), total protein (5.8 ± 1.0 mg/dL vs 6.1 ± 1.2 mg/dL; P = .04), and hemoglobin (9.8 ± 1.8 mg/dL vs 10.3 ± 1.9 mg/dL; P = .004). There was not a statistically significant difference in 1-year all-cause mortality and in-hospital mortality between liver transplant recipients with and without pleural effusions. Liver transplant recipients who developed pleural effusions had a longer hospital length of stay (16.4 ± 10.9 days vs 14.0 ± 16.5 days; P = .1), but the differences were not statistically significant. However, there was a significant difference in tracheostomy rates (11.6% vs 5.4%; P = .03) in recipients who developed pleural effusions compared to recipients who did not. CONCLUSIONS: In summary, pleural effusions are common after liver transplantation and are associated with increased morbidity. Pre- and intraoperative risk factors can offer both predictive and prognostic value for post-transplantation pleural effusions. Further prospective studies will be needed to further evaluate the relevance of these findings to limit instances of postoperative pleural effusions.

Liver transplant evaluation for fulminant liver failure due to acute hepatitis A infection: Case series and literature review.

Hepatitis A virus can cause liver damage ranging from mild illness to fulminant hepatic failure, constituting 0.35% of all cases of fulminant liver failure. While rates of spontaneous remission are higher for hepatitis A, recent outbreaks attributable to vaccine shortages in highly populated urban cities plagued by insufficient affordable housing and inaccessible sanitation, and changes in the epidemiology of viral strains have resulted in increased hospitalizations and deaths. While the prognosis for patients with FHF has improved since the introduction of transplantation, the decision to transplant is often difficult to reach. We present five patients with HAV and subsequent FHF, one of whom successfully received a liver transplant. We have reviewed all published cases of HAV FHF in the literature and report ten patients, seven of whom received liver transplantation. There are few predictive models that attempt to distinguish between fulminant hepatitis A and spontaneous recovery. Patients found to have positive hepatitis A IgM, encephalopathy, worsening LFT's and coagulation should be monitored closely and referred to transplant centers urgently for management.

Delayed graft function and acute rejection following HLA-incompatible living donor kidney transplantation.

Incompatible living donor kidney transplant recipients (ILDKTr) have pre-existing donor-specific antibody (DSA) that, despite desensitization, may persist or reappear with resulting consequences, including delayed graft function (DGF) and acute rejection (AR). To quantify the risk of DGF and AR in ILDKT and downstream effects, we compared 1406 ILDKTr to 17 542 compatible LDKT recipients (CLDKTr) using a 25-center cohort with novel SRTR linkage. We characterized DSA strength as positive Luminex, negative flow crossmatch (PLNF); positive flow, negative cytotoxic crossmatch (PFNC); or positive cytotoxic crossmatch (PCC). DGF occurred in 3.1% of CLDKT, 3.5% of PLNF, 5.7% of PFNC, and 7.6% of PCC recipients, which translated to higher DGF for PCC recipients (aOR = 1.03 1.682.72 ). However, the impact of DGF on mortality and DCGF risk was no higher for ILDKT than CLDKT (p interaction > .1). AR developed in 8.4% of CLDKT, 18.2% of PLNF, 21.3% of PFNC, and 21.7% of PCC recipients, which translated to higher AR (aOR PLNF = 1.45 2.093.02 ; PFNC = 1.67 2.403.46 ; PCC = 1.48 2.243.37 ). Although the impact of AR on mortality was no higher for ILDKT than CLDKT (p interaction = .1), its impact on DCGF risk was less consequential for ILDKT (aHR = 1.34 1.621.95 ) than CLDKT (aHR = 1.96 2.292.67 ) (p interaction = .004). Providers should consider these risks during preoperative counseling, and strategies to mitigate them should be considered.

Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma in Patients With Child-Pugh B or C Cirrhosis.

PURPOSE: Our purpose was to report outcomes in patients with Child-Pugh B or C (CP B/C) hepatocellular carcinoma (HCC) treated with stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: Patients with HCC suitable for SBRT were prospectively enrolled in the study from 2012 to 2018. Outcomes in patients with CP B/C were analyzed. Cox proportional hazard models were used to compare survival outcomes between baseline CP score and post-SBRT CP score. RESULTS: Twenty-three patients with CP B/C with a total of 29 HCC tumors were treated with SBRT. Eighty-seven percent of patients were CP B8-C10. Median tumor size was 3.1 cm (range, 1-10 cm). Median dose delivered was 40 Gy in a median of 5 fractions. Eighteen of 23 patients (78.3%) had been previously treated with transarterial chemoembolization. Median follow-up was 14.5 months. Rates of 6- and 12-month local control were 100% and 92.3%, respectively. Six- and 12-month survival rates were 73.9% and 56.5%, respectively. Median survival was 14.5 months overall and 9.2, 22.5, 14.5, and 14.4 months for patients with CP B7, B8, B9, and C10, respectively. No patients exhibited symptoms of classic radiation-induced liver disease. However, 10 patients had CP score progression, with 4 patients (17%) having a ≥2-point increase in CP score by 6 months (or time of censor). There were 7 liver-related deaths, and based on independent review by a hepatologist, 1 of these deaths may have been attributable to SBRT-related liver injury. Fifteen of 23 patients were listed for liver transplant (LT) at the time of SBRT and 9 went on to receive LT with a pathologic complete response rate of 63.6%. Median survival, excluding patients who received LT, was 7.3 months. CONCLUSIONS: SBRT is a reasonable treatment option for carefully selected patients with CP B7-C10. In our small cohort, there was no detectable difference between local control or overall survival and baseline CP score.

Candida auris outbreak involving liver transplant recipients in a surgical intensive care unit.

Candida auris is a yeast that is difficult to eradicate and has caused outbreaks in health care facilities. We report a cluster of 5 patients in 1 intensive care unit who were colonized or infected in 2017. The initial 2 patients were recipients of liver transplants who had cultures that grew C auris within 3 days of each other in June 2017 (days 43 and 30 posttransplant). Subsequent screening cultures identified 2 additional patients with C auris colonization. Respiratory and urine cultures from a fifth patient yielded C auris. All isolates were fluconazole resistant but susceptible to echinocandins. Whole genome sequencing showed the strains were clonal, suggesting in-hospital transmission, and related but distinct from New York/New Jersey strains, consistent with a separate introduction. However, no source or contact was found. Two of the 5 patients died. C auris infection likely contributed to 1 patient death by infecting a vascular aneurysm at the graft anastomosis. Strict infection control precautions were initiated to control the outbreak. Our experience reveals that although severe disease from C auris can occur in transplant recipients, outbreaks can be controlled using recommended infection control practices. We have had no further patients infected with C auris to date.

Therapeutics administered during ex vivo liver machine perfusion: An overview.

Although the use of extended criteria donors has increased the pool of available livers for transplant, it has also introduced the need to develop improved methods of protection against ischemia-reperfusion injury (IRI), as these "marginal" organs are particularly vulnerable to IRI during the process of procurement, preservation, surgery, and post-transplantation. In this review, we explore the current basic science research investigating therapeutics administered during ex vivo liver machine perfusion aimed at mitigating the effects of IRI in the liver transplantation process. These various categories of therapeutics are utilized during the perfusion process and include invoking the RNA interference pathway, utilizing defatting cocktails, and administering classes of agents such as vasodilators, anti-inflammatory drugs, human liver stem cell-derived extracellular vesicles, and δ-opioid agonists in order to reduce the damage of IRI. Ex vivo machine perfusion is an attractive alternative to static cold storage due to its ability to continuously perfuse the organ, effectively deliver substrates and oxygen required for cellular metabolism, therapeutically administer pharmacological or cytoprotective agents, and continuously monitor organ viability during perfusion. The use of administered therapeutics during machine liver perfusion has demonstrated promising results in basic science studies. While novel therapeutic approaches to combat IRI are being developed through basic science research, their use in clinical medicine and treatment in patients for liver transplantation has yet to be explored.

Impact of recipient functional status on 1-year liver transplant outcomes.

BACKGROUND: The Karnofsky Performance Status (KPS) scale has been widely validated for clinical practice for over 60 years. AIM: To examine the extent to which poor pre-transplant functional status, assessed using the KPS scale, is associated with increased risk of mortality and/or graft failure at 1-year post-transplantation. METHODS: This study included 38278 United States adults who underwent first, non-urgent, liver-only transplantation from 2005 to 2014 (Scientific Registry of Transplant Recipients). Functional impairment/disability was categorized as severe, moderate, or none/normal. Analyses were conducted using multivariable-adjusted Cox survival regression models. RESULTS: The median age was 56 years, 31% were women, median pre-transplant Model for End-Stage for Liver Disease score was 18. Functional impairment was present in 70%; one-quarter of the sample was severely disabled. After controlling for key recipient and donor factors, moderately and severely disabled patients had a 1-year mortality rate of 1.32 [confidence interval (CI): 1.21-1.44] and 1.73 (95%CI: 1.56-1.91) compared to patients with no impairment, respectively. Subjects with moderate and severe disability also had a multivariable-adjusted 1-year graft failure rate of 1.13 (CI: 1.02-1.24) and 1.16 (CI: 1.02-1.31), respectively. CONCLUSION: Pre-transplant functional status is a useful prognostic indicator for 1-year post-transplant patient and graft survival.

Hepatic Epithelioid Angiomyolipoma Treated with Laparoscopic Resection: Case Report and Review of the Literature.

Hepatic angiomyolipoma is a rare primary liver tumor, with a radiographic appearance very similar to hepatocellular carcinoma. We present the case of a noncirrhotic patient with a liver tumor suspicious for HCC by imaging features. Liver biopsy demonstrated angiomyolipoma, and the patient successfully underwent a laparoscopic liver resection.

Association Between Sarcopenia and Functional Status in Liver Transplant Patients.

OBJECTIVES: A growing body of evidence shows that frailty and functional performance predict liver transplant outcomes. The Organ Procurement and Transplant Network uses the Karnofsky Performance Status scale to adjust for transplant center case mix in assessing quality measures. This study explores the strength of the relationship between Karnofsky Performance Status scores and objective measures of frailty. MATERIALS AND METHODS: This observational study includes 136 adult, first-time liver transplant recipients at UMass Memorial (2006-2015) who had 2 abdominal computed tomography scans available (at ≤ 90 days pretransplant and ≥ 7 days before that). We analyzed the relationship between Karnofsky Performance Status and muscle wasting using absolute and change in psoas muscle size and quality pretransplant. RESULTS: The mean age was 55 years, mean Model for End-Stage Liver Disease was 22, and 34% of patients were women. In the study group, 50% of patients had sarcopenia pretransplant and 71.3% demonstrated declined lean psoas area at an average rate of 11% per month. Patients who experienced muscle wasting at a rate of ≥ 1% per month had 2.83 times the risk (95% confidence interval, 1.18-6.80) of being severely impaired/disabled pretransplant. The risk increased by 2.32-fold (95% confidence interval, 1.44-3.75) for every standard deviation decrease in pretransplant lean psoas area. CONCLUSIONS: Provider-assessed physical health status moderately correlates with objective measures of frailty.