No country for old livers? Examining and optimizing the utilization of elderly liver grafts.

Of the 1.6 million patients >70 years of age who died of stroke since 2002, donor livers were retrieved from only 2402 (0.15% yield rate). Despite reports of successful liver transplantation (LT) with elderly grafts (EG), advanced donor age is considered a risk for poor outcomes. Centers for Medicare and Medicaid Services definitions of an "eligible death" for donation excludes patients >70 years of age, creating disincentives to donation. We investigated utilization and outcomes of recipients of donors >70 through analysis of a United Network for Organ Sharing Standard Transplant Analysis and Research-file of adult LTs from 2002 to 2014. Survival analysis was conducted using Kaplan-Meier curves, and Cox regression was used to identify factors influencing outcomes of EG recipients. Three thousand one hundred four livers from donors >70, ≈40% of which were used in 2 regions: 2 (520/3104) and 9 (666/3104). Unadjusted survival was significantly worse among recipients of EG compared to recipients of younger grafts (P < .0001). Eight independent negative predictors of survival in recipients of EG were identified on multivariable analysis. Survival of low-risk recipients who received EG was significantly better than survival of recipients of younger grafts (P = .04). Outcomes of recipients of EG can therefore be optimized to equal outcomes of younger grafts. Given the large number of stroke deaths in patients >70 years of age, the yield rate of EGs can be maximized and disincentives removed to help resolve the organ shortage crisis.

Social and Financial Outcomes of Living Liver Donation: A Prospective Investigation Within the Adult-to-Adult Living Donor Liver Transplantation Cohort Study 2 (A2ALL-2).

Because results from single-center (mostly kidney) donor studies demonstrate interpersonal relationship and financial strains for some donors, we conducted a liver donor study involving nine centers within the Adult-to-Adult Living Donor Liver Transplantation Cohort Study 2 (A2ALL-2) consortium. Among other initiatives, A2ALL-2 examined the nature of these outcomes following donation. Using validated measures, donors were prospectively surveyed before donation and at 3, 6, 12, and 24 mo after donation. Repeated-measures regression models were used to examine social relationship and financial outcomes over time and to identify relevant predictors. Of 297 eligible donors, 271 (91%) consented and were interviewed at least once. Relationship changes were positive overall across postdonation time points, with nearly one-third reporting improved donor family and spousal or partner relationships and >50% reporting improved recipient relationships. The majority of donors, however, reported cumulative out-of-pocket medical and nonmedical expenses, which were judged burdensome by 44% of donors. Lower income predicted burdensome donation costs. Those who anticipated financial concerns and who held nonprofessional positions before donation were more likely to experience adverse financial outcomes. These data support the need for initiatives to reduce financial burden.

Hypothermic machine preservation facilitates successful transplantation of "orphan" extended criteria donor livers.

Hypothermic machine preservation (HMP) remains investigational in clinical liver transplantation. It is widely used to preserve kidneys for transplantation with improved results over static cold storage (SCS). At our center, we have used HMP in 31 adults receiving extended criteria donor (ECD) livers declined by the originating United Network for Organ Sharing region ("orphan livers"). These cases were compared to ECD SCS cases in a matched cohort study design. Livers were matched for donor age, recipient age, cold ischemic time, donor risk index and Model for End-Stage Liver Disease (MELD) score. HMP was performed for 3-7 h at 4-8 °C using our previously published protocol. Early allograft dysfunction rates were 19% in the HMP group versus 30% in the control group (p = 0.384). One-year patient survival was 84% in the HMP group versus 80% in the SCS group (p = NS). Post hoc analysis revealed significantly less biliary complications in the HMP group versus the SCS group (4 vs. 13, p = 0.016). Mean hospital stay was significantly shorter in the HMP group (13.64 ± 10.9 vs. 20.14 ± 11.12 days in the SCS group, p = 0.001). HMP provided safe and reliable preservation in orphan livers transplanted at our center.

Totally laparoscopic full left hepatectomy for living donor liver transplantation in adolescents and adults.

In recent years different minimal access strategies have been designed in order to perform living donor liver surgery for adult recipients with less morbidity. Techniques involve shortening the length of the incision with or without previous laparoscopic mobilization of the liver. Herein we present two cases of totally laparoscopic living donor left hepatectomy, with and without removal of the middle hepatic vein, respectively. We describe in detail the anatomical and technical aspects of the procedure focusing on relevant points to enhance safety.

Prevalence of high-risk human papilloma virus among women with hepatitis C virus before liver transplantation.

BACKGROUND: We sought to assess the prevalence and risk factors for high-risk human papillomavirus (HPV) infection among female liver transplant (LT) candidates. Traditional health screening before LT listing has included Pap smear and is typically carried out by the patient's local provider. The prevalence of high-risk HPV in this population has not been studied. METHODS: With Institutional Review Board approval, 62 LT candidates received a liquid-based Pap smear with high-risk HPV testing as part of their pre-transplant evaluation by a single provider. Clinical variables included age, ethnicity, insurance status, prior Pap smear, and HPV results, HPV risk factors including age of first intercourse, number of lifetime partners, last sexual activity, smoking, birth control pill use, history of sexually transmitted infections, human immunodeficiency virus status, immunosuppressive medication, medical diagnoses, prescribed medications, and history of hepatitis A, B, C, or D. RESULTS: The 62 women had a median age of 56 years, and 39% had high-risk behavior known to be associated with HPV. Ten of 62 patients (16.1%) had high-risk HPV at baseline screening, 5 of whom had atypical cytology. All of the patients who were positive for high-risk HPV had an etiology of hepatitis C virus (HCV) as the underlying cause of liver disease, with the majority (90%) having no history of high-risk behavior for HPV. In contrast, all patients with high-risk behavior who were HCV negative were HPV negative. Fisher's exact test demonstrated a statistically significant relationship between HPV and HCV; odds ratio = 24.4, 95% confidence interval, 1.4, 438.7, P-value = 0.0013. None of the other potential risk factors were associated with HPV in this cohort. CONCLUSIONS: In this study, we provide evidence of a strong association between HCV and HPV in LT candidates, which has not been previously reported. HPV positivity was observed in non-sexually active women, suggesting a reactivation of dormant HPV. An association between hepatitis C and high-risk HPV could involve impairment of T-cell function by hepatitis C. These data support close surveillance in women's health screening for LT candidates. Further studies to characterize immune responses in these patients will be in order.

Hypothermic machine preservation reduces molecular markers of ischemia/reperfusion injury in human liver transplantation.

Hypothermic machine perfusion (HMP) is in its infancy in clinical liver transplantation. Potential benefits include diminished preservation injury (PI) and improved graft function. Molecular data to date has been limited to extrapolation of animal studies. We analyzed liver tissue and serum collected during our Phase 1 trial of liver HMP. Grafts preserved with HMP were compared to static cold stored (SCS) transplant controls. Reverse transcription polymerase chain reaction (RT-PCR), immunohistochemistry and transmission electron microscopy (TEM) were performed on liver biopsies. Expression of inflammatory cytokines, adhesion molecules and chemokines, oxidation markers, apoptosis and acute phase proteins and the levels of CD68 positive macrophages in tissue sections were evaluated. RT-PCR of reperfusion biopsy samples in the SCS group showed high expression of inflammatory cytokines, adhesion molecules and chemokines, oxidative markers and acute phase proteins. This upregulation was significantly attenuated in livers that were preserved by HMP. Immunofluorescence showed larger numbers of CD68 positive macrophages in the SCS group when compared to the HMP group. TEM samples also revealed ultrastructural damage in the SCS group that was not seen in the HMP group. HMP significantly reduced proinflammatory cytokine expression, relieving the downstream activation of adhesion molecules and migration of leukocytes, including neutrophils and macrophages when compared to SCS controls.

The deceased organ donor with an "open abdomen": proceed with caution.

In solid organ transplantation, the disparity between donor supply and patients awaiting transplant continues to increase. The organ shortage has led to relaxation of historic contraindications to organ donation. A large percentage of deceased organ donors have been subjected to traumatic injuries, which can often result in intervention that leads to abdominal packing and intensive care unit resuscitation. The donor with this "open abdomen" (OA) presents a situation in which the risk of organ utilization is difficult to quantify. There exists a concern for the potential of a higher risk for both bacterial and fungal infections, including multidrug-resistant (MDR) pathogens because of the prevalence of antibiotic use and critical illness in this population. No recommendations have been established for utilization of organs from these OA donors, because data are limited. Herein, we report a case of a 21-year-old donor who had sustained a gunshot wound to his abdomen, resulting in a damage-control laparotomy and abdominal packing. The donor subsequently suffered brain death, and the family consented to organ donation. A multiorgan procurement was performed with respective transplantation of the procured organs (heart, liver, and both kidneys) into 4 separate recipients. Peritoneal swab cultures performed at the time of organ recovery grew out MDR Pseudomonas aeruginosa on the day after procurement, subsequently followed by positive blood and sputum cultures as well. All 4 transplant recipients subsequently developed infections with MDR P. aeruginosa, which appeared to be donor-derived with similar resistance patterns. Appropriate antibiotic coverage was initiated in all of the patients. Although 2 of the recipients died, mortality did not appear to be clearly associated with the donor-derived infections. This case illustrates the potential infectious risk associated with organs from donors with an OA, and suggests that aggressive surveillance for occult infections should be pursued.

Process of care events in transplantation: effects on the cost of hospitalization.

Deviations in the processes of healthcare delivery that affect patient outcomes are recognized to have an impact on the cost of hospitalization. Whether deviations that do not affect patient outcome affects cost has not been studied. We have analyzed process of care (POC) events that were reported in a large transplantation service (n = 3,012) in 2005, delineating whether or not there was a health consequence of the event and assessing the impact on hospital resource utilization. Propensity score matching was used to adjust for patient differences. The rate of POC events varied by transplanted organ: from 10.8 per 1000 patient days (kidney) to 17.3 (liver). The probability of a POC event increased with severity of illness. The majority (81.5%) of the POC events had no apparent effect on patients' health (63.6% no effect and 17.9% unknown). POC events were associated with longer length of stay (LOS) and higher costs independent of whether there was a patient health impact. Multiple events during the same hospitalization were associated with the highest impact on LOS and cost. POC events in transplantation occur frequently, more often in sicker patients and, although the majority of POC events do not harm the patient, their effect on resource utilization is significant.

Hypothermic machine preservation in human liver transplantation: the first clinical series.

Hypothermic machine perfusion (HMP) is widely used to preserve kidneys for transplantation with improved results over cold storage (CS). To date, successful transplantation of livers preserved with HMP has been reported only in animal models. In this, the first prospective liver HMP study, 20 adults received HMP-preserved livers and were compared to a matched group transplanted with CS livers. HMP was performed for 3-7 h using centrifugal perfusion with Vasosol solution at 4-6 degrees C. There were no cases of primary nonfunction in either group. Early allograft dysfunction rates were 5% in the HMP group versus 25% in controls (p = 0.08). At 12 months, there were two deaths in each group, all unrelated to preservation or graft function. There were no vascular complications in HMP livers. Two biliary complications were observed in HMP livers compared with four in the CS group. Serum injury markers were significantly lower in the HMP group. Mean hospital stay was shorter in the HMP group (10.9 +/- 4.7 days vs. 15.3 +/- 4.9 days in the CS group, p = 0.006). HMP of donor livers provided safe and reliable preservation in this pilot case-controlled series. Further multicenter HMP trials are now warranted.

The impact of hepatitis C and biliary complications on patient and graft survival following liver transplantation.

Recurrent hepatitis C (HCV) and biliary complications (BC) are major causes of post liver transplant morbidity and mortality. The impact of these complications may be additive or synergistic. We performed a retrospective cohort study to analyze the effects of HCV and BC on all patients transplanted at two institutions over 6 years. BC was defined by imaging findings in the setting of abnormal liver function tests that required intervention. The primary outcomes were graft and patient survival over a mean 3.4 years. 709 patients (619 deceased, 90 living donor) were included, 337 with HCV and 372 without. BC was diagnosed more frequently in patients with HCV, 26% versus 18% (p = 0.008). One-year and overall patient and graft survival were significantly lower in patients with HCV, but BC impacted only 1-year graft survival. The combination of BC and HCV had no additional impact on survival or fibrosis rates on 1-year protocol biopsies. Multivariate analysis revealed HCV (HR 2.1) and HCC (HR 1.9) to be independent predictors of mortality. Since BC are diagnosed more frequently in HCV patients and only affect early graft loss, it is likely that recurrent HCV rather than BC accounts for the majority of adverse graft outcomes.

Resource utilization of living donor versus deceased donor liver transplantation is similar at an experienced transplant center.

Although living donor liver transplantation (LDLT) has been shown to decrease waiting-list mortality, little is known of its financial impact relative to deceased donor liver transplantation (DDLT). We performed a retrospective cohort study of the comprehensive resource utilization, using financial charges as a surrogate measure-from the pretransplant through the posttransplant periods-of 489 adult liver transplants (LDLT n = 86; DDLT n = 403) between January 1, 2000, through December 31, 2006, at a single center with substantial experience in LDLT. Baseline characteristics differed between LDLT versus DDLT with regards to age at transplantation (p = 0.02), male gender (p < 0.01), percentage Caucasians (p < 0.01) and transplant model for end-stage liver disease (MELD) score (p < 0.01). In univariate analysis, there was a trend toward decreased total transplant charges with LDLT (p = 0.06), despite increased surgical charges associated with LDLT (p < 0.01). After adjustment for the covariates that were associated with financial charges, there was no significant difference in total transplant charges (p = 0.82). MELD score at transplant was the strongest driver of resource utilization. We conclude that at an experienced transplant center, LDLT imposes a similar overall financial burden than DDLT, despite the increased complexity of living donor surgery and the addition of the costs of the living donor. We speculate that LDLT optimizes transplantation by transplanting healthier and younger recipients.

Incidence and severity of acute cellular rejection in recipients undergoing adult living donor or deceased donor liver transplantation.

Living donor liver transplantation (LDLT) may have better immunological outcomes compared to deceased donor liver transplantation (DDLT). The aim of this study was to analyze the incidence of acute cellular rejection (ACR) after LDLT and DDLT. Data from the adult-to-adult living donor liver transplantation (A2ALL) retrospective cohort study on 593 liver transplants done between May 1998 and March 2004 were studied (380 LDLT; 213 DDLT). Median LDLT and DDLT follow-up was 778 and 713 days, respectively. Rates of clinically treated and biopsy-proven ACR were compared. There were 174 (46%) LDLT and 80 (38%) DDLT recipients with >/=1 clinically treated episodes of ACR, whereas 103 (27%) LDLT and 58 (27%) DDLT recipients had >/=1 biopsy-proven ACR episode. A higher proportion of LDLT recipients had clinically treated ACR (p = 0.052), but this difference was largely attributable to one center. There were similar proportions of biopsy-proven rejection (p = 0.97) and graft loss due to rejection (p = 0.16). Longer cold ischemia time was associated with a higher rate of ACR in both groups despite much shorter median cold ischemia time in LDLT. These data do not show an immunological advantage for LDLT, and therefore do not support the application of unique posttransplant immunosuppression protocols for LDLT recipients.

Recipient morbidity after living and deceased donor liver transplantation: findings from the A2ALL Retrospective Cohort Study.

Patients considering living donor liver transplantation (LDLT) need to know the risk and severity of complications compared to deceased donor liver transplantation (DDLT). One aim of the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) was to examine recipient complications following these procedures. Medical records of DDLT or LDLT recipients who had a living donor evaluated at the nine A2ALL centers between 1998 and 2003 were reviewed. Among 384 LDLT and 216 DDLT, at least one complication occurred after 82.8% of LDLT and 78.2% of DDLT (p = 0.17). There was a median of two complications after DDLT and three after LDLT. Complications that occurred at a higher rate (p < 0.05) after LDLT included biliary leak (31.8% vs. 10.2%), unplanned reexploration (26.2% vs. 17.1%), hepatic artery thrombosis (6.5% vs. 2.3%) and portal vein thrombosis (2.9% vs. 0.0%). There were more complications leading to retransplantation or death (Clavien grade 4) after LDLT versus DDLT (15.9% vs. 9.3%, p = 0.023). Many complications occurred more commonly during early center experience; the odds of grade 4 complications were more than two-fold higher when centers had performed 40). In summary, complication rates were higher after LDLT versus DDLT, but declined with center experience to levels comparable to DDLT.

Survival outcomes following liver transplantation (SOFT) score: a novel method to predict patient survival following liver transplantation.

It is critical to balance waitlist mortality against posttransplant mortality. Our objective was to devise a scoring system that predicts recipient survival at 3 months following liver transplantation to complement MELD-predicted waitlist mortality. Univariate and multivariate analysis on 21,673 liver transplant recipients identified independent recipient and donor risk factors for posttransplant mortality. A retrospective analysis conducted on 30,321 waitlisted candidates reevaluated the predictive ability of the Model for End-Stage Liver Disease (MELD) score. We identified 13 recipient factors, 4 donor factors and 2 operative factors (warm and cold ischemia) as significant predictors of recipient mortality following liver transplantation at 3 months. The Survival Outcomes Following Liver Transplant (SOFT) Score utilized 18 risk factors (excluding warm ischemia) to successfully predict 3-month recipient survival following liver transplantation. This analysis represents a study of waitlisted candidates and transplant recipients of liver allografts after the MELD score was implemented. Unlike MELD, the SOFT score can accurately predict 3-month survival following liver transplantation. The most significant risk factors were previous transplantation and life support pretransplant. The SOFT score can help clinicians determine in real time which candidates should be transplanted with which allografts. Combined with MELD, SOFT can better quantify survival benefit for individual transplant procedures.

Select utilization of obese donors in living donor liver transplantation: implications for the donor pool.

Living donor liver transplantation evolved in response to donor shortage. Current guidelines recommend potential living donors (LD) have a body mass index (BMI) <30. With the current obesity epidemic, locating nonobese LD is difficult. From September 1999 to August 2003, 68 LD with normal liver function test (LFTs) and without significant comorbidities underwent donor hepatectomy at our center. Post-operative complications were collected, including wound infection, pneumonia, hernia, fever, ileus, biliary leak, biliary stricture, thrombosis, bleeding, hepatic dysfunction, thrombocytopenia, deep venous thrombosis, pulmonary embolism, difficult to control pain, depression and anxiety. Complication rates for LD with BMI >30 (n = 16) and BMI <30 (n = 52) were compared. The incidence of wound infection increased with BMI, 4% for nonobese and 25% for obese LD (p = 0.024). There were no statistically significant differences for all other complications. No LD died. Recipient survival was 100% with obese LD and 80% with nonobese LD (p = 0.1). Select donors with a BMI >30 may undergo donor hepatectomy with acceptable morbidity and excellent recipient results. Updating current guidelines to include select LD with BMI >30 has the potential to safely increase the donor pool.

Posttransplantation growth in pediatric liver recipients.

The aim of this retrospective analysis was to evaluate the growth of 96 pediatric liver transplant recipients from February 1988 to June 1999. Inclusion criteria were the following: age younger than 18 years, follow-up longer than 1 year, transplantation for a nontumor indication, and no retransplantation. Linear height and growth velocity SD scores were correlated to age, sex, indication for transplantation, immunosuppression, and graft type. Transplant recipients of all ages and indications and both sexes were growth retarded at transplantation. Recipients aged younger than 24 months showed growth within the first year to achieve a height distribution equal to that of an age-matched population. Posttransplantation growth inversely correlated with height standard score at transplantation. Children older than 2 years at transplantation established new growth curves, but remained growth retarded. As children approached the prepubertal growth acceleration, growth deficits frequently were erased. Transplant recipients with biliary atresia and alpha(1)-antitrypsin deficiency showed increased growth performance compared with those who underwent transplantation for chronic hepatitis or fulminant hepatic failure. Boys were less growth retarded at transplantation and showed improved posttransplantation growth performance versus girls. No correlation to immunosuppression or graft type was identified. We conclude that early transplantation of children who show growth retardation is optimal for restoration of growth potential, whereas delaying transplantation in older children impedes potential growth.