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We present a case of life-threatening refractory hypertension (rHTN) in a patient with stage 3b chronic kidney disease that was unresponsive to open surgical renal denervation (RDN) but responded to bilateral nephrectomy (BLN). Both RDN and BLN reduce the increased sympathetic activation in rHTN. However, RDN has yet to show reductions in blood pressure adequate for the average patient with rHTN, and BLN has thus far been reserved for patients with preexisting end-stage kidney disease (ESKD). Our case suggests that there are patients with rHTN that warrant consideration of BLN prior to developing ESKD.

Background COVID‐19 epidemiologic studies comparing immunosuppressed and immunocompetent patients may provide insight into the impact of immunosuppressants on outcomes. Methods In this retrospective cohort study, we assembled kidney or kidney‐pancreas transplant recipients who underwent transplant from January 1, 2010, to June 30, 2020, and kidney or kidney‐pancreas waitlisted patients who were ever on the waitlist from January 1, 2019, to June 30, 2020. We identified laboratory‐confirmed COVID‐19 until January 31, 2021, and tracked its outcomes by leveraging informatics infrastructure developed for an outcomes research network. Results COVID‐19 was identified in 62 of 887 kidney or kidney‐pancreas transplant recipients and 20 of 434 kidney or kidney‐pancreas waitlisted patients (7.0% vs. 4.6%, p = .092). Of these patients with COVID‐19, hospitalization occurred in 48 of 62 transplant recipients and 8 of 20 waitlisted patients (77% vs. 40%, p = .002); intensive care unit admission occurred in 18 of 62 transplant recipients and 2 of 20 waitlisted patients (29% vs. 10%, p = .085); and 7 transplant recipients were mechanically ventilated and died, whereas no waitlisted patients were mechanically ventilated or died (11% vs. 0%, p = .116). Conclusions Our study provides single‐center data and an informatics approach that can be used to inform the design of multicenter studies.

Background The extent of liver resection for tumours is limited by the expected functional reserve of the future liver remnant (FRL), so hypertrophy may be induced by portal vein embolization (PVE), taking 6 weeks or longer for growth. This study assessed the hypothesis that simultaneous embolization of portal and hepatic veins (PVE/HVE) accelerates hypertrophy and improves resectability. Methods All centres of the international DRAGON trials study collaborative were asked to provide data on patients who had PVE/HVE or PVE on 2016–2019 (more than 5 PVE/HVE procedures was a requirement). Liver volumetry was performed using OsiriX MD software. Multivariable analysis was performed for the endpoints of resectability rate, FLR hypertrophy and major complications using receiver operating characteristic (ROC) statistics, regression, and Kaplan–Meier analysis. Results In total, 39 patients had undergone PVE/HVE and 160 had PVE alone. The PVE/HVE group had better hypertrophy than the PVE group (59 versus 48 per cent respectively; P = 0.020) and resectability (90 versus 68 per cent; P = 0.007). Major complications (26 versus 34 per cent; P = 0.550) and 90-day mortality (3 versus 16 per cent respectively, P = 0.065) were comparable. Multivariable analysis confirmed that these effects were independent of confounders. Conclusion PVE/HVE achieved better FLR hypertrophy and resectability than PVE in this collaborative experience.

BACKGROUND Patient compliance with immunosuppressive therapy after transplant has impacts on both graft and patient outcomes. For diabetic end-stage renal disease (ESRD) patients who are undergoing evaluation for kidney transplantation in our program, hemoglobin A1c (HbA1c) level of >10% is used as a flag that the patient may be at risk for noncompliance and that more comprehensive psychosocial screening is needed prior to transplant. We evaluated the association between pre-transplant HbA1c level and post-transplant compliance, as no study to date has looked at this in the transplant population. MATERIAL AND METHODS The charts of 392 patients who received a kidney transplant at a single institution between July 2008 and June 2012 were retrospectively reviewed. One hundred and sixty-five diabetic patients who received a kidney transplant alone were included in the final analysis. Our predictive variable was HbA1c level greater than 7.7% based on previous reports in the diabetic population. Outcome measures were graft survival, rejection episodes, unexplained low immunosuppressant levels, and documented noncompliance. RESULTS There were no statistically significant differences between the HbA1c groups of ≤7.7% and >7.7% in outcomes of failed grafts (22.0% and 17.8%, p=0.2), rejection episodes (15.0% and 6.7%, p=0.3), unexplained low immunosuppressant level (46.6% and 37.9%, p=0.3), and documented noncompliance (25.0% and 16.7%, p=0.4). CONCLUSIONS In diabetic ESRD patients selected for renal transplantation, elevated pre-transplant HbA1c levels, defined as HbA1c >7.7%, are not predictive of post-transplant medication compliance. We advocate that this group of patients should not be denied transplant solely on their elevated pre-transplant HbA1c.

Heat stroke is a multiple organ dysfunction syndrome of poorly understood pathogenesis. Exertional heat stroke with acute liver failure is a rarely reported condition. Liver transplant has been recommended as treatment in cases of severe liver dysfunction; however, there are only 5 described cases of long-term survival after this procedure in patients with heat stroke. Here, we present 2 cases of young athletes who developed heat stroke. Both patients developed acute liver failure and were listed for liver transplant. Liver function tests of one patient improved, and he was discharged on postoperative day 13. The other patient showed no signs of improvement and liver biopsy showed massive necrosis. The patient underwent combined kidney-liver transplant and was discharged on postoperative day 17. After a follow-up of longer than 6 years, both patients are doing well with normal liver function and no neurologic sequelae. We also reviewed all published cases of hepatic failure associated with heat stroke and found 9 published cases of liver transplant for heat stroke in the English literature. Conservative management appears to be justified in heat stroke-associated liver failure, even in the presence of accepted criteria for emergency liver transplant. If the liver does not show signs of recovery and hepatic decompensation progresses, liver transplant should be performed.

Since the first attempt of pig-to-primate liver xenotransplantation (LXT) in 1968, survival has been limited. We evaluated a model utilizing α-1,3-galactosyltransferase knockout donors, continuous posttransplant infusion of human prothrombin concentrate complex, and immunosuppression including anti-thymocyte globulin, FK-506, methylprednisone, and costimulation blockade (belatacept, n = 3 or anti-CD40 mAb, n = 1) to extend survival. Baboon 1 remained well until postoperative day (POD) 25, when euthanasia was required because of cholestasis and plantar ulcers. Baboon 2 was euthanized following a seizure on POD 5, despite normal liver function tests (LFTs) and no apparent pathology. Baboon 3 demonstrated initial stable liver function but was euthanized on POD 8 because of worsening LFTs. Pathology revealed C4d positivity, extensive hemorrhagic necrosis, and a focal cytomegalovirus inclusion. Baboon 4 was clinically well with stable LFTs until POD29, when euthanasia was again necessitated by plantar ulcerations and rising LFTs. Final pathology was C4d negative and without evidence of rejection, inflammation, or thrombotic microangiopathy. Thus, nearly 1-mo rejection-free survival has been achieved following LXT in two of four consecutive recipients, demonstrating that the porcine liver can support life in primates for several weeks and has encouraging potential for clinical application as a bridge to allotransplantation for patients with acute-on-chronic or fulminant hepatic failure.

Introduction The decision for isolated kidney transplant (KT) vs. combined liver–kidney transplant (CLKT) in patients with end-stage renal disease (ESRD) with compensated cirrhosis remains controversial. We sought to determine outcomes of patients requiring listing for a liver transplant (LT) following either a cadaveric or living donor KT and compare these outcomes to similar patients receiving a CLKT. Methods Our dataset included the United Network for Organ Sharing (UNOS)/Standard Transplant and Analysis and Research (STAR) kidney files from 1987 to 2012 after being joined with the liver files from 2002 to 2012. Outcomes of patients who received a CLKT with an international normalized ratio (INR) ≤1 and total bilirubin ≤1 were compared to patients who received a primary KT and subsequently required listing for LT between zero and five yr or after five yr. Results For the three groups, 244 patients had a CLKT, 216 were wait-listed for LT between zero and five yr after KT (0–5 WL), and 320 were wait-listed five yr after KT (+5 WL). From the time of KT, the 0–5 WL group had significantly worse survival than the CLKT group and the +5 WL group. The +5 WL had the best survival of all groups. For the 0–5 WL group, 45% underwent LT and 40% died while waiting compared to the +5 WL group with 53% having LT and 26% died while waiting. At the time of LT, the 0–5 WL group had a higher model for end-stage liver disease (MELD) score, higher incidence of being in the ICU at the time of transplant, and higher incidence of requiring life support. From the time of LT, the CLKT trended toward better survival (p = 0.0549) than both the 0–5 WL and +5 WL groups, which had equivalent survival. Conclusion The 0–5 WL group is a higher risk group with poorer survival due to a higher incidence of dying on the waitlist. Better identification of patients with a high risk for hepatic decompensation following KT and agreement for regional exception for LT in the event of decompensation may improve utilization of organs and better survival for those patients.

Background Pig to baboon liver xenotransplantation typically results in severe thrombocytopenia and coagulation disturbances, culminating in death from hemorrhage within 9 days, in spite of continuous transfusions. We studied the contribution of anticoagulant production and clotting pathway deficiencies to fatal bleeding in baboon recipients of porcine livers. Methods By transplanting liver xenografts from α1,3-galactosyltransferase gene-knockout (GalT-KO) miniature swine donors into baboons as auxiliary organs, leaving the native liver in place, we provided the full spectrum of primate clotting factors and allowed in vivo mixing of porcine and primate coagulation systems. Results Recipients of auxiliary liver xenografts develop severe thrombocytopenia, comparable to recipients of conventional orthotopic liver xenografts and consistent with hepatic xenograft sequestration. However, baboons with both pig and native livers do not exhibit clinical signs of bleeding and maintain stable blood counts without transfusion for up to 8 consecutive days post-transplantation. Instead, recipients of auxiliary liver xenografts undergo graft failure or die of sepsis, associated with thrombotic microangiopathy in the xenograft, but not the native liver. Conclusion Our data indicate that massive hemorrhage in the setting of liver xenotransplantation might be avoided by supplementation with primate clotting components. However, coagulation competent hepatic xenograft recipients may be predisposed to graft loss related to small vessel thrombosis and ischemic necrosis.

Background The development of genetically modified pigs, which lack the expression of alpha 1-3 galactosyl transferase, (GalT-KO pigs) has facilitated the xenogeneic transplantation of porcine organs and tissues into primates by avoiding hyperacute rejection due to pre-existing antibodies against the Gal epitope. However, antibodies against other antigens (anti-non-Gal antibodies), are found at varying levels in the pre-transplant sera of most primates. We have previously found that baboons with high levels of pre-transplant anti-non-Gal IgG, conditioned with a non-myeloablative conditioning regimen, failed to engraft following pig-to-baboon bone marrow transplantation (Xenotransplantation, 17, 2010 and 300). Two baboons with low levels of pre-transplant anti-non-Gal IgG, conditioned with the same regimen, showed porcine bone marrow progenitors at 28 days following transplantation, suggesting engraftment. These baboons also showed evidence of donor-specific hyporesponsiveness. This observation led us to investigate the hypothesis that selecting for baboon recipients with low pre-transplant anti-non-Gal IgG levels might improve engraftment levels following GalT-KO pig-to-baboon bone marrow transplantation. Methods Five baboons, with low pre-transplant anti-non-Gal IgG levels, received transplantation of bone marrow cells (1–5 × 109/kg of recipient weight) from GalT-KO pigs. They received a non-myeloablative conditioning regimen consisting of low-dose total body irradiation (TBI) (150 cGy), thymic irradiation (700 cGy), anti-thymocyte globulin (ATG), and tacrolimus. In addition, two baboons received Rituximab and Bortezomib (Velcade) treatment as well as extra-corporeal immunoadsorption using GalT-KO pig livers. Bone marrow engraftment was assessed by porcine-specific PCR on colony forming units (CFU) of day 28 bone marrow aspirates. Anti-non-Gal antibody levels were assessed by serum binding toward GalT-KO PBMC using flow cytometry (FACS). Peripheral macro-chimerism was measured by FACS using pig and baboon-specific antibodies and baboon anti-pig cellular responses were assessed by mixed lymphocyte reactions (MLR). Results As previously reported, two of five baboons demonstrated detectable bone marrow engraftment at 4 weeks after transplantation. Engraftment was associated with lack of an increase in anti-non-Gal IgG levels as well as cellular hyporesponsiveness toward pig. Three subsequent baboons with similarly low levels of pre-existing anti-non-Gal IgG showed no engraftment and an increase in anti-non-Gal IgG antibody levels following transplantation. Peripheral macrochimerism was only seen for a few days following transplantation regardless of antibody development. Conclusions Selecting for baboon recipients with low levels of pre-transplant anti-non-Gal IgG did not ensure bone marrow engraftment. Failure to engraft was associated with an increase in anti-non-Gal IgG levels following transplantation. These results suggest that anti-non-Gal-IgG is likely involved in early bone marrow rejection and that successful strategies for combating anti-non-Gal IgG development may allow better engraftment. Since engraftment was only low and transient regardless of antibody development, innate immune, or species compatibility mechanisms will likely also need to be addressed to achieve long term engraftment.

Type 1 primary hyperoxaluria (PH1) causes renal failure, for which isolated kidney transplantation (KT) is usually unsuccessful treatment due to early oxalate stone recurrence. Although hepatectomy and liver transplantation (LT) corrects PH1 enzymatic defect, simultaneous auxiliary partial liver transplantation (APLT) and KT have been suggested as an alternative approach. APLT advantages include preservation of the donor pool and retention of native liver function in the event of liver graft loss. However, APLT relative mass may be inadequate to correct the defect. We here report the first case of native portal vein embolization (PVE) to increase APLT to native liver mass ratio (APLT/NLM-R). Following initial combined APLT-KT, both allografts functioned well, but oxalate plasma levels did not normalize. We postulated the inadequate APLT/NLM-R could be corrected by trans-hepatic native PVE. The resulting increased APLT/NLM-R decreased serum oxalate to normal levels within 1 month following PVE. We conclude that persistently elevated oxalate levels after combined APLT-KT for PH1 treatment, results from inadequate relative functional capacity. This can be reversed by partial native PVE to decrease portal flow to the native liver. This approach might be applicable to other scenarios where partial grafts have been transplanted to replace native liver function.

Rates of transmission of hepatitis B virus (HBV) infection from organ donors with HBV markers to recipients along with reactivation of HBV during immunosuppression following transplantation have fallen significantly with the advent of hepatitis B immune globulin (HBIg) and effective antiviral therapy. Although the availability of potent antiviral agents and HBIg has highly impacted the survival rate of HBV-infected patients after transplantation, the high cost associated with this practice represents a major financial burden. The availability of potent antivirals with high genetic barrier to resistance and minimal side effects have made it possible to recommend an HBIg-free prophylactic regimen in selected patients with low viral burden prior to transplant. Significant developments over the last two decades in the understanding and treatment of HBV infection necessitate a re-appraisal of the guidelines for prophylaxis of HBV infection in solid organ transplant recipients.

Purpose: Ureteroneocystostomy (UCN) is the most widely used urinary reconstruction technique during kidney transplantation. Disadvantages of this technique include a high incidence of hematuria and reflux, plus the potential for obstruction resulting from distal ureteral fibrosis. Pyeloureterostomy (PU) avoids these complications but increases the technical complexity. Methods: Between January 1990 and December 2005, 1066 adults patients underwent kidney transplantations; 768 patients (72.1%) had urinary reconstruction by PU and 298 (27.9%) underwent UNC. Results: Patients in the PU group underwent simultaneous ipsilateral native nephrectomy. The operative time was longer in the PU group compared with the UNC group: 210 � 36 min versus 182 � 24 min (P < 0.001). Overall surgical complications in the PU group were comparable to those in the UNC group (9.5% versus 12.3%). The urinary complication rate was also comparable in both groups: 3.2% (25 of 768) in the PU group and 5% (15 of 298) in the UNC group. However, urinary obstruction comprised 60% of urinary complications in the UNC group, compared with 32% in the PU group (P < 0.01). We treated most urinary complications non-operatively. However, 24% of patients (six of 25) in the PU group needed operative intervention or revision for ureteral reconstruction, compared with 46.6% (seven of 15) in the UNC group (P < 0.01). Conclusions: Pyeloureterostomy is a safe and effective method for urinary tract reconstruction in renal transplantation. Pyeloureterostomy should be part of every transplant surgeon’s armamentarium.

As patients with end-stage renal disease are receiving renal allografts at older ages, the number of male renal transplant recipients (RTRs) being diagnosed with prostate cancer (CaP) is increasing. Historically, the literature regarding the management of CaP in RTR's is limited to case reports and small case series. To date, there are no standardized guidelines for screening or management of CaP in these complex patients. To better understand the unique characteristics of CaP in the renal transplant population, we performed a literature review of PubMed, without date limitations, using a combination of search terms including prostate cancer, end stage renal disease, renal transplantation, prostate cancer screening, prostate specific antigen kinetics, immuno-suppression, prostatectomy, and radiation therapy. Of special note, teams facilitating the care of these complex patients must carefully and meticulously consider the altered anatomy for surgical and radiotherapeutic planning. Active surveillance, though gaining popularity in the general low risk prostate cancer population, needs further study in this group, as does the management of advance disease. This review provides a comprehensive and contemporary understanding of the incidence, screening measures, risk stratification, and treatment options for CaP in RTRs.

Cytomegalovirus (CMV)-seronegative kidney transplant (KTx) recipients of organs from CMV-seropositive donors (D+/R-) are at increased risk for CMV infection. Despite valganciclovir (VGCV) prophylaxis (900 mg daily for 200 days), late-onset CMV (LO-CMV) occurs at excessive rates. VGCV-associated cost and toxicities remain problematic.We retrospectively evaluated 50 D+/R- adult KTx recipients from August 2008 to August 2014 who received low-dose VGCV (450 mg daily) prophylaxis for an extended duration. The primary outcome was occurrence of CMV disease.All patients received depletion induction and underwent ABO-compatible KTx. Mean prophylaxis and follow-up durations were 22.8 and 40.7 months, respectively. Eight patients developed CMV: 5 breakthrough cases (1 case of colitis [2%] and 4 cases of infection [8%]) and 3 cases of LO-CMV (1 syndrome [2.9%] and 2 cases of infection [5.7%]). On logistic regression, longer duration of VGCV prophylaxis was protective against CMV infection or disease (P = .044; odds ratio, 1.12 [95% confidence interval, 1.03-1.29]). None of 19 recipients with prophylaxis for ≥12 months developed LO-CMV compared with 3 of 16 recipients with prophylaxis for 12 months (18.8%) (P = .086). Four patients had recurrence of CMV, and 1 patient developed resistance. CMV was not responsible for graft or patient loss and did not affect survival.Low-dose VGCV is an effective prophylaxis for D+/R- KTx recipients despite depleting induction. Longer prophylaxis is more protective, and receiving VGCV for ≥12 months nearly eradicated LO-CMV without increasing antiviral resistance.

Kim K, Schuetz C, Elias N, Veillette GR, Wamala I, Varma M, Smith RN, Robson SC, Cosimi AB, Sachs DH, Hertl M. Up to 9-day survival and control of thrombocytopenia following GalT-KO swine liver xenotransplantation in baboons. Xenotransplantation 2012; 19: 256–264.. © 2012 John Wiley & Sons A/S. Abstract: Background: With standard miniature swine donors, survivals of only 3 days have been achieved in primate liver-transplant recipients. The recent production of alpha1,3-galactosyl transferase knockout (GalT-KO) miniature swine has made it possible to evaluate xenotransplantation of pig organs in clinically relevant pig-to-non-human primate models in the absence of the effects of natural anti-Gal antibodies. We are reporting our results using GalT-KO liver grafts. Methods: We performed GalT-KO liver transplants in baboons using an immunosuppressive regimen previously used by our group in xeno heart and kidney transplantation. Post-operative liver function was assessed by laboratory function tests, coagulation parameters and histology. Results: In two hepatectomized recipients of GalT-KO grafts, post-transplant liver function returned rapidly to normal. Over the first few days, the synthetic products of the donor swine graft appeared to replace those of the baboon. The first recipient survived for 6 days and showed no histopathological evidence of rejection at the time of death from uncontrolled bleeding, probably caused by transfusion-refractory thrombocytopenia. Amicar treatment of the second and third recipients led to maintenance of platelet counts of over 40 000 per μl throughout their 9- and 8-day survivals, which represents the longest reported survival of pig-to-primate liver transplants to date. Both of the last two animals nevertheless succumbed to bleeding and enterococcal infection, without evidence of rejection. Conclusions: These observations suggest that thrombocytopenia after liver xenotransplantation may be overcome by Amicar therapy. The coagulopathy and sepsis that nevertheless occurred suggest that additional causes of coagulation disturbance must be addressed, along with better prevention of infection, to achieve long-term survival.

Background The shortage in donor livers has led to increased use of allografts derived from donation after cardiac death (DCD). The compromised viability in these livers leads to inferior post-transplantation allograft function and survival compared with donation after brain death (DBD) donor grafts. In this study, we reconditioned DCD livers using an optimized normothermic machine perfusion system. Methods Livers from 12 Yorkshire pigs (20–30 kg) were subjected to either 0 min (WI-0 group, n = 6) or 60 min (WI-60 group, n = 6) of warm ischemia and 2 h of cold storage in UW solution, followed by 4 h of oxygenated sanguineous normothermic machine perfusion. Liver viability and metabolic function were analyzed hourly. Results Warm ischemic livers showed elevated transaminase levels and reduced ATP concentration. After the start of machine perfusion, transaminase levels stabilized and there was recovery of tissue ATP, coinciding with an increase in bile production. These parameters reached comparable levels to the control group after 1 h of machine perfusion. Histology and gross morphology confirmed recovery of the ischemic allografts. Conclusion Our data demonstrate that metabolic and functional parameters of livers with extended warm ischemic time (60 min) can be significantly improved using normothermic machine perfusion. We hereby compound the existing body of evidence that machine perfusion is a viable solution for reconditioning marginal organs.

Protein S deficiency is a thrombophilia associated with increased risk of thromboembolic episodes in affected patients. Traditionally, protein S deficiency in a potential donor was considered an absolute contraindication to living donor liver transplantation, both due to the increased risk incurred by the thrombophilic donor as well as the risk of transmitting the thrombophilia to the liver recipient, as protein S is predominantly produced by the liver. We present the first successful case of living donor liver transplantation using a donor with asymptomatic protein S deficiency. Interestingly, whereas the donor continued to have protein S levels approximately 50% of normal, the recipient maintained normal levels of protein S post-transplant, potentially due to compensation by extra-hepatic protein S production. We discuss the prior literature of protein S deficiency acquired via liver transplantation, and we evaluate potential criteria by which the safety of transplants utilizing this pool of donors may be enhanced.

Introduction The gold standard in organ preservation is static cold storage (SCS) using University of Wisconsin solution (UW). Although it is well-known that there is a finite limit to SCS preservation, and that there is a correlation between the adenosine triphosphate (ATP) levels and organ function post-preservation, a quantitative relationship has not been established, which is important in understanding the fundamental limitations to preservation, minimizing cold ischemic injury, and hence maximizing use of the donor organ pool. Aim This study determines the time limits of cellular viability and metabolic function during SCS, and characterizes the relationship between cellular viability and energetic state using clinically relevant techniques in organ preservation. Methods Rat livers were procured and stored using conventional storage in UW solution at 4°C. Viability was assessed by determining the amount of viable hepatocytes and intracellular ATP content after 0, 24, 48, 72, and 120 hours of storage. Results Numbers of viable hepatocytes that were isolated from these livers decreased steadily during SCS. After 5 days, viable hepatocytes decreased from 25.95 × 10 6 to 0.87 × 10 6 cells/gram tissue. Intracellular ATP content decreased from 9.63 to 0.93 moles/g tissue. Statistical analysis of variance established a linear relation for both parameters as a function of time ( P Conclusion The linear correlation between hepatocyte viability, ATP content, and storage time suggests a shared physiological foundation. These findings confirm ATP as direct predictor for organ quality in the context of liver preservation, which will aid quantitative assessment of donor organs for various applications.

Donors after cardiac death present a significant pool of untapped organs for transplantation, and use of machine perfusion strategies has been an active focus area in experimental transplantation. However, despite 2 decades of research, a gold standard has yet to emerge for machine perfusion systems and protocols. Whole blood reperfusion has been used as a surrogate for organ transplantation, especially as a model for the short-term response posttransplantation, and for optimization of perfusion systems. Although it is known that there is a strong correlation between liver function in whole-blood reperfusion and survival, the exact nature of these correlations, and to what extent they can be considered as an indicator of viability for transplantation/recipient survival, remain unclear. In this work, we demonstrate that diluted whole-blood reperfusion can be used as a direct model for transplantation of ischemic rat liver grafts. Specifically, we show that recipient survival can be predicted based simply on the value of alanine aminotransferase during perfusion, providing quantitative criteria of viability for use in this animal model. These results indicate that in the rat model graft survival is highly correlated with hepatocellular damage.

Elimination of galactose-α( 1 , 3 )galactose (Gal) expression in pig organs has been previously shown to prevent hyperacute xenograft rejection. However, naturally present antibodies to non-Gal epitopes activate endothelial cells, leading to acute humoral xenograft rejection. Still, it is unknown whether xenogeneic pig liver sinusoidal endothelial cells (LSECs) from α( 1 , 3 )galactosyltransferase (GalT)-deficient pigs are damaged by antibody and complement-mediated mechanisms. The present study examined the xeno-antibody response of LSECs from GalT-deficient and wild pigs. Isolated LSEC from wild-type and GalT pigs were expose to human and baboon sera; IgM and IgG binding was analyzed by flow cytometry. Complement activation (C3a and CH50) was quantified in vitro from serum-exposed LSEC cultures using Enzyme-Linked ImmunoSorbent assay (ELISA). Levels of complement-activated cytotoxicity (CAC) were also determined by a fluorescent Live-Dead Assay and by the quantification of LDH release. IgM binding to GalT knockout (KO) LSECs was significantly lower (80% human and 87% baboon) compare to wild-type pig LSEC. IgG binding was low in all groups. Moreover, complement activation (C3a and CH50) levels released following exposure to human or baboon sera were importantly reduced (42% human and 52% baboon), CAC in GalT KO LSECs was reduced by 60% in human serum and by 72% in baboon serum when compared to wild-type LSECs, and LDH release levels were reduced by 37% and 57%, respectively. LSECs from GalT KO pigs exhibit a significant protection to humoral-induced cell damage compared to LSECs from wild pigs when exposed to human serum. Although insufficient to inhibit xenogeneic reactivity completely, transgenic GalT KO expression on pig livers might contribute to a successful application of clinical xenotransplantation in combination with other protective strategies.

There is a paucity of data on long-term outcomes of older kidney recipients. Our aim was to compare the early and long-term outcomes of deceased donor kidney transplantation in patients agedor=60 years with outcomes in younger recipients.From 1998 to 2005, we performed 271 deceased donor kidney transplants. There were 76 recipients (28.1%)60 years old. Older candidates were carefully selected based on their physiologic, cardiac, and performance status. Demographic data, including clinical characteristics, early complications, mortality, and patient and graft survival rates, were collected and analyzed.Older patients had comparable perioperative mortality and morbidity, incidence of delayed graft function (DGF), length of stay, and readmissions compared with younger patients. The rates of acute rejection and major infections were also comparable between the 2 study groups. Among older recipients, 25/76 (32.1%) patients received extended criteria donor kidneys compared with only 35/195 (17.9%) of younger patients (P.001). Nevertheless, equivalent 1-, 3-, and 5-year allograft survival rates were observed in elderly and young patients; 91.5% versus, 92.5%, 78.5% versus 81.9%, and 75.6% versus 78.5%, respectively. Overall patient survival was also comparable in both groups.Kidney transplantation in appropriately selected elderly recipients provides equivalent outcomes compared with those observed in younger patients. These observations support the notion that older recipients should not lose access to deceased donor kidney transplantation in the effort to achieve a perceived gain in social utility.

Background. The PHS increased risk donor (IRD) is underutilized in liver transplantation. We aimed to examine the posttransplant outcomes in recipients of increased-risk organs.Methods. We analyzed 228,040 transplants in the Organ Procurement and Transplantation Network database from 2004 to 2013. Endpoints were graft failure and death. Results were controlled for demographics and comorbidities. Statistical analysis utilized Fisher’s test and logistic regression.Results. 58,816 patients were identified (5,534 IRD, 53,282 non-IRD). IRDs were more frequently male (69.2% versus 58.3%,p<0.001), younger (34 versus 39,p<0.001), and less likely to have comorbidities (p<0.001). Waitlist time was longer for IRD graft recipients (254 versus 238 days,p<0.001). All outcomes were better in the IRD group. Graft failure (23.6 versus 27.3%,p<0.001) and mortality (20.4 versus 22.3%,p=0.001) were decreased in IRD graft recipients. However, in multivariate analysis, IRD status was not a significant indicator of outcomes.Conclusion. This is the first study to describe IRD demographics in liver transplantation. Outcomes are improved in IRD organ recipients; however, controlling for donor and recipient comorbidities, ischemia time, and MELD score, the differences lose significance. In multivariate analysis, use of IRD organs is noninferior, with similar graft failure and mortality despite the infectious risk.

We sought to determine the effects of exogenous administration of human coagulation factors following pig-to-baboon liver xenotransplantation (LXT) using GalT-KO swine donors. After LXT, baboons received no coagulation factors (historical control, n = 1), bolus administration of a human prothrombin concentrate complex (hPCC; 2.5 mL/kg, n = 2), continuous infusion of hPCC (1.0 mL/h, n = 1) or continuous infusion of human recombinant factor VIIa (1 µg/kg per hour, n = 3). The historical control recipient demonstrated persistent thrombocytopenia despite platelet administration after transplant, along with widespread thrombotic microangiopathy (TMA). In contrast, platelet levels were maintained in bolus hPCC recipients; however, these animals quickly developed large-vessel thrombosis and TMA, leading to graft failure with shortened survival. Recipients of continuous coagulation factor administration experienced either stabilization or an increase in their circulating platelets with escalating doses. Furthermore, transfusion requirements were decreased, and hepatic TMA was noticeably absent in recipients of continuous coagulation factor infusions compared with the historical control and bolus hPCC recipients. This effect was most profound with a continuous, escalating dose of factor VIIa. Further studies are warranted because this regimen may allow for prolonged survival following LXT.

Awareness of smoking complications in liver transplantation patients is increasing. No study in the past 15 years has addressed attitudes toward offering transplantation to smokers. Our aim was to determine smoking policies nationwide. We conducted a survey of liver transplantation centers. The seven-question survey was sent to medical and surgical directors of liver transplantation. Results were analyzed in R 3.1.1 using two-tailed t testing and ANOVA. Fifty one of 110 centers (46 %) responded. Volume transplanted annually ranged from 10 to 190. Most respondents acknowledged a policy on smoking (38/51, 75 %). Most centers with policies required cessation (32/38, 84 %). All other centers did encourage attempts at cessation (19/19, 100 %). Whether smoking cessation was required differed by region (p = 0.02). Southern programs more commonly required smoking cessation (87.5 vs. 38.4 %, p

Organ transplantation is increasingly available to the thousands of patients who suffer from end-organ failure. There has been an attendant increase in demand for living donor participation. This combined with a bioethical focus on autonomy increases the burden of decision on donor candidates. The authors review the history of living donor participation in organ transplantation and explore the psychological dynamics of the clinical encounter between donor and transplant surgeon. The field of communication psychology lends to the understanding of coercion and to the importance of donors possessing a status of patient-hood in the classical Hippocratic condition.

The incidence of hepatocellular carcinoma (HCC), a frequent and incurable complication of cirrhosis, continues to rise. Orthotopic liver transplantation (OLT) has been proposed as a treatment for unresectable, intrahepatic HCC limited in extent to the Milan criteria adopted by the United Network of Organ Sharing (UNOS) in 1998. More recently, somewhat less restrictive University of California, San Francisco (UCSF)10, criteria were proposed. To examine the long-term outcomes of OLT for HCC patients and to assess the UNOS policy of assigning weighted allocation points to patients with HCC, we retrospectively analyzed 144 patients (113 after 1998) with HCC who underwent OLT over an 11-year period at 3 institutions from UNOS Region 1. We compared their outcomes with 525 patients (272 after 1998) who underwent OLT for nonmalignant liver disease. The 1- and 5-year survival rates were 80.3% and 46.7%, respectively, for patients with HCC and 81.5% and 70.6%, respectively, for patients without HCC (P = .020). However, there was no difference in survival between HCC and non-HCC patients after implementation of disease-specific allocation for HCC in 1998. A higher proportion of the HCC cohort was older and male and had chronic HCV infection and alcoholic liver disease. In univariate analysis, having alpha-fetoprotein (AFP) levels of 10 ng/mL or less and meeting clinical and pathologic UCSF criteria were each significant predictors of improved survival (P = .005, P = .02, and P = .03, respectively). AFP greater than 10 ng/mL and exceeding pathologic UCSF criteria were also significant predictors of recurrence (P = .003 and P = .02, respectively). In conclusion, taken together, our data suggest that OLT is an acceptable option for patients with early HCC and that UCSF criteria predict outcome better than Milan or UNOS criteria. Regardless of which criteria are adopted to define eligibility, strict adherence to the criteria is important to achieve acceptable outcomes.

Background and aims: Bile duct complications are the modern Achilles' heel of adult-to-adult living donor liver transplantation. A duct-to-duct anastomosis is currently performed in the presence of single graft ducts, while cholangiojejunostomy is used to drain multiple ducts. Our aim is to describe the feasibility of duct-to-duct anastomoses independent of the presence of one or multiple graft bile ducts. Methods: The probe technique for right bile duct dissection in donors and a proximal hilar bile duct division in recipients are illustrated. The BARIGA LDLT (biliary anastomosis in right graft for adult living donor liver transplantation recipients) with end-to-side or end-to-end hepatico-hepaticostomy was used in five recipients of right grafts (segments 5–8). Results: All donors and recipients are doing well; all grafts are functional at 13 months. Duct-to-duct anastomoses to single, double, or triple graft ducts have been performed. Two early anastomotic stenoses at 5 and 10 weeks were successfully treated endoscopically. Conclusion: The duct-to-duct anastomosis represents a valid alternative to the standard hepaticojejunostomy for right living donor liver grafts. Using this method, biliary complications can be treated endoscopically. End-to-side or end-to-end BARIGA LDLT has the potential to become a standard method in segmental transplantation, including split liver.

The main obstacle to a expansion of human liver transplantation is the lack of donor organs. At present mortality reported for pediatric and adult patients on the waiting list is 10%to 20%. This article focuses on several techniques to alleviate this problem. Several years ago, application of reduced-size liver transplantation overcame the donor shortage among small infants through the use of grafts shaped to almost any size needed. Today reduced-size grafts are only rarely used, most commonly with traumatized donor livers or particularly small pediatric donor livers. Split liver transplantation also yields a net gain of organs, in that it uses one organ to save either an adult and a child or, recently, two adults. The technique of ex situ splitting is progressively being replaced by the in situ splitting technique, which yields better preserved grafts,optimization of graft/donor matching by pretransplant manipulation(preconditioning), avoidance of early rejection in the recipient,portal decompression, temporary liver support, if necessary, and induction of fast regeneration. In acute hepatic failure, auxiliary heterotopic liver transplantation might be sufficient to support liver function until regeneration of the native liver has begun. Domino transplantation in some patients with inborn errors of metabolism or storage disease should be considered. This article focuses on increasing the organ supply by using split liver transplantation techniques and living-donor liver transplantation.

La transplantation des organes comme le coeur, le poumon, le foie, le pancreas, l'intestin grele et le rein, est la seule facon de traiter radicalement certaines maladies qui menacent le pronostic vital. La transplantation necessite un equipement specifique non seulement pour realiser le procede mais aussi pour assurer les soins pre et postoperatoires, ainsi que des connaissances specifiques d'une equipe experimentee de chirurgiens ou de medecins d'autres specialites pouvant intervenir aupres d'un transplante potentiel (cardiologues, nephrologues, hepatologues, pour n'en citer que quelques-uns). La transplantation est un effort d'equipe, seul garant pour obtenir les bons resultats que nous connaissons aujourd'hui. Il arrive que quelques individus essaient de monter, pratiquement tout seul un centre de transplantation. Aucun ne peut reussir sans une aide institutionnelle, financiere avec un soutien continu, et en particulier on ne peut y arriver sans une structure organisationnelle efficace. Cet article resume ce qui est necessaire pour creer un centre de transplantation du foie; il traite egalement des considerations ethiques.

Background Prophylaxis against hepatitis B virus (HBV) recurrence after orthotopic liver transplantation (OLT) includes lifelong hepatitis B immunoglobulin (HBIG) and oral antiviral agent(s). In the presence of high-genetic-barrier nucleos(t)ide analogues, the need for lifelong HBIG is questioned. We evaluated the safety and cost-effectiveness of a limited HBIG course. Methods OLT from 2006 to 2013 were reviewed. Patients with pre-OLT hepatitis B virus surface antigen who received HBV prophylaxis with 2 HBIG doses (anhepatic and first post-operative day; 10,000 units/dose) and potent nucleos(t)ide analogues were included. The primary end point was HBV recurrence (HBV-DNA detection). Results Thirteen patients (primary transplants) were included, median Model for End-Stage Liver Disease score was 18, and there was no fulminant failure; HBV-DNA was detected in 4 patients at OLT. After OLT, 10 patients received entecavir and/or tenofovir. Median follow-up was 23 months. One recurrence occurred (7.7%) at month 13 (HBV-DNA: 14 IU/mL); the graft maintained excellent function. This minimal viremic expression is related to hepatocellular carcinoma recurrence with neoplastic replication carrying integrated HBV-DNA; thus, there is no defined HBV viral recurrence. No graft loss or patient death was related to HBV recurrence. The 1-year patient and graft survival rate was 84.6%. Cost-savings in the first year was $178,100 per patient when compared with Food and Drug Administration–approved HBIG dosing. Conclusions In the era of potent oral nucleos(t)ide analogues, a limited HBIG course appears to be cost-effective in preventing HBV recurrence.

Prolonged graft preservation is associated with postoperative bile duct strictures after liver transplantation. We previously showed that hydrophilic bile salts mitigate bile duct preservation injury in a pig model. Because this injury occurs at the epithelial level, scanning electron microscopy was performed to further characterize this effect in vitro. Swine livers were harvested after the intravenous infusion of 1 of 3 solutions: saline (n = 7), tauroursodeoxycholate ([TUDC] hydrophilic; n = 4), or taurodeoxycholate ([TDC] hydrophobic; n = 4). Livers were perfused with University of Wisconsin solution. The bile ducts were flushed retrograde, and the liver was stored at 0 degrees C to 1 degrees C for 20 hours. Bile duct samples were obtained at the time of harvest and 8, 12, 16, and 20 hours thereafter. In saline-infused controls at time 0, the epithelium was intact and composed of uniform cuboidal cells covered with fine regular microvilli. There were no spaces between individual cells. After 8 to 12 hours of preservation, cells were more irregular in shape, with loss of cell-cell contact. The cell surfaces showed fewer microvilli. Surface erosions suggested loss of cell-wall integrity. TUDC was protective, evidenced by normal-appearing cells with uniform microvilli after 16 hours. In contrast, TDC accelerated the injury process, causing cell-surface erosions, blebs, and loss of microvilli as early as time 0. Scanning electron microscopy is an excellent tool to study injury to bile duct epithelium. This study supports the hypothesis that hydrophilic bile salts protect bile ducts during preservation. To determine whether treatment with hydrophilic bile salts can prevent postoperative stricture, in vivo transplantation studies are needed.

Introduction: Tauroursodeoxycholate (TUDC) is used routinely in the treatment of cholestatic liver disease. The present study was designed to determine whether it would mitigate ischemia/reperfusion injury in an in vivo pig liver-transplantation model. Methods: Transplantation was performed in 12 animals after a preservation time of 8 h. In the control group (n=6), 0.9% saline was infused into the donor. In the experimental group (n=6), TUDC was given intravenously at a rate of 2 µmol/kg body weight per minute. In the recipient, infusion was started at the time of reperfusion; saline was infused for 400 min in the control group, TUDC for the same duration at a rate of 0.2 µmol/kg body weight per minute in the experimental group. Blood was drawn for determination of liver enzymes. Bile samples were collected and bile flow (BF) and bile salt secretion rate (BSSR) were determined. Results: One-week survival was 92% and not different among groups. Liver enzymes were lower in the TUDC group than the saline group. Prior to TUDC infusion in the donor animals, there were no differences in BF and BSSR. After infusion of TUDC, BF and BSSR were highly significantly different than the control group. Discussion: Infusion of TUDC in pig livers protects against ischemia/reperfusion injury in vivo. This might be due to the membrane-stabilizing effect of TUDC. Preconditioning of liver grafts with TUDC could potentially lead to improved liver function post-transplantation.

Rapid allograft infection complicates liver transplantation (LT) in patients with hepatitis C virus (HCV). Pegylated interferon-α and ribavirin therapy after LT has significant toxicity and limited efficacy. The effect of a human monoclonal antibody targeting the HCV E2 glycoprotein (MBL-HCV1) on viral clearance was examined in a randomized, double-blind, placebo-controlled pilot study in patients infected with HCV genotype 1a undergoing LT. Subjects received 11 infusions of 50 mg/kg MBL-HCV1 (n = 6) or placebo (n = 5) intravenously with three infusions on day of transplant, a single infusion on days 1 through 7 and one infusion on day 14 after LT. MBL-HCV1 was well-tolerated and reduced viral load for a period ranging from 7 to 28 days. Median change in viral load (log10 IU/mL) from baseline was significantly greater (p = 0.02) for the antibody-treated group (range −3.07 to −3.34) compared to placebo group (range −0.331 to −1.01) on days 3 through 6 posttransplant. MBL-HCV1 treatment significantly delayed median time to viral rebound compared to placebo treatment (18.7 days vs. 2.4 days, p < 0.001). As with other HCV monotherapies, antibody-treated subjects had resistance-associated variants at the time of viral rebound. A combination study of MBL-HCV1 with a direct-acting antiviral is underway.

Background The goal of this study was to review the results of 279 laparoscopic living donor nephrectomies (LLDN) regarding outcomes of using the left or the right kidney. Methods Among 279 patients who underwent LLDN between August 1998 and April 2009, 260 underwent a left (group L) and 19, a right (group R) nephrectomy. The two groups were compared regarding intra- and postoperative parameters, including pre- and postoperative renal function, length of surgery, conversion to an open approach, delayed graft function, and complications. Results There were no significant differences between the two groups regarding preoperative glomerular filtration rate (L = 129.5 ± 32 mL/min versus group R = 127.3 ± 26 mL/min), length of surgery (group L = 228 ± 58 minutes versus group R = 226 ± 62 minutes group), postoperative donor creatinine (group L = 1.36 ± 0.9 mg/dL versus group R = 1.48 ± 0.8 mg/dL), conversion to open (group L = 6.6% versus group R = 5.3%), delayed graft function (group L = 7.2% versus group R = 6.3%) and recipient postoperative creatinine at 1 month (group L = 1.54 ± 1.4 mg/dL versus group R = 1.32 ± 1.1 mg/dL). There were three intraoperative donor complications in group L (bleeding in one donor required transfusion), and none in group R. Similarly, there was a great albeit not a significant difference in the number of major postoperative donor complications among group L ( n = 16) versus group R ( n = 2). The right kidney was chosen because of the number of vessels ( n = 5), presence of cysts ( n = 5), size and renal function ( n = 6), presence of renal stones ( n = 2), and tortuous ureter ( n = 1). The reasons for conversion to open included bleeding, anatomic issues, and presence of adhesions. It should be noted that during the last 3 years there were no conversions to open, whereas the only conversion among group R was the first case. Conclusions Intra- and postoperative parameters were comparable between the groups. Considering the limitations of the small sample size of right LLDNs in this study, it appears that it is as safe and effective as a left procedure. The learning curve is extremely important, as can be seen by the lack of conversion in the last 3 years.

Donation after cardiac death (DCD) has proven effective at increasing the availability of organs for transplantation. We performed a retrospective examination of Massachusetts General Hospital (MGH) records of all 201 donors from 1/1/98 to the 11/2008, including 54 DCD, 115 DBD and 32 DCD candidates that did not progress to donation (DCD-dnp). Comparing three time periods, era 1 (01/98–12/02), era 2 (01/03–12/05) and era 3 (01/06–11/08), DCD's comprised 14.8, 48.4% and 60% of donors, respectively (p = 0.002). A significant increase in the incidence of cardiovascular/cerebrovascular as cause of death was evident in era 3 versus eras 1 and 2; 74% versus 57.1% (p < 0.001), as was a corresponding decrease in the incidence of traumatic death. Interestingly, we noted an increase in utilization of aggressive neurological management over time, especially in the DCD group. We detected significant changes in the make-up of the donor pool over the past decade. That the changes in diagnosis over time did not differ between DCD and DBD groups suggests this difference is not responsible for the increase in DCD rates. Instead, we suggest that changes in clinical practice, especially in management of patients with severe brain injury may account for the increased proportion of DCD.

Five patients with end-stage renal disease received combined bone marrow and kidney transplants from HLA single-haplotype mismatched living related donors, with the use of a nonmyeloablative preparative regimen. Transient chimerism and reversible capillary leak syndrome developed in all recipients. Irreversible humoral rejection occurred in one patient. In the other four recipients, it was possible to discontinue all immunosuppressive therapy 9 to 14 months after the transplantation, and renal function has remained stable for 2.0 to 5.3 years since transplantation. The T cells from these four recipients, tested in vitro, showed donor-specific unresponsiveness and in specimens from allograft biopsies, obtained after withdrawal of immunosuppressive therapy, there were high levels of P3 (FOXP3) messenger RNA (mRNA) but not granzyme B mRNA.

Expanded criteria donors (ECDs) and donation after cardiac death (DCD) provide more kidneys in the donor pool. However, the financial impact and the long-term benefits of these kidneys have been questioned. From 1998 to 2005, we performed 271 deceased donor kidney transplants into adult recipients. There were 163 (60.1%) SCDs, 44 (16.2%) ECDs, 53 (19.6%) DCDs and 11 (4.1%) ECD/DCDs. The mean follow-up was 50 months. ECD and DCD kidneys had a significantly higher incidence of delayed graft function, longer time to reach serum creatinine below 3 (mg/dL), longer length of stay and more readmissions compared to SCDs. The hospital charge was also higher for ECD, ECD/DCD and DCD kidneys compared to SCDs, primarily due to the longer length of stay and increased requirement for dialysis (70,030 dollars, 72,438 dollars, 72,789 dollars and 47,462 dollars, respectively, p < 0.001). Early graft survival rates were comparable among all groups. However, after a mean follow-up of 50 months, graft survival was significantly less in the ECD group compared to other groups. Although our observations support the utilization of ECD and DCD kidneys, these transplants are associated with increased costs and resource utilization. Revised reimbursement guidelines will be required for centers that utilize these organs.

Adult-to-adult living donor liver transplantation (LDLT) for patients with decompensated end-stage liver disease (DELD) is controversial. Nevertheless, these patients are most in need of a timely liver transplant. We present the results of 7 patients who underwent transplantation with this procedure and discuss the rationale for its possible broader application. Seven of 51 patients who underwent right LDLT (segments 5 to 8) between August 1998 and April 2001 had DELD, defined as Child-Pugh-Turcotte score greater than 13 or Model for End-Stage Liver Disease score greater than 30. All patients also were listed for cadaveric liver transplantation. Mean age of the 7 transplant recipients was 54 years (range, 44 to 63 years). Three patients had ethyltoxic cirrhosis; 2 patients, hepatitis C; 1 patient, hepatitis B; and 1 patient, autoimmune hepatitis cirrhosis. The average intensive care unit stay was 23 days (range, 3 to 88 days), and average hospital stay was 77 days (range, 27 to 132 days). Three patients are alive 31, 21, and 17 months after LDLT. At a mean follow-up of 15.1 ± 10 months, patient and graft survival rates are 43%. Four transplant recipients died day 30, 60, 117, and 180 after transplantation. Three of the seven donors (43%) experienced a complication. At present, all donors are well and have returned to their normal activities. No donors had regrets about the procedure, and all donors stated that they would donate again if presented with the same decision. In conclusion, with the lack of other therapeutic options, LDLT represents a timely and effective alternative to cadaveric liver transplantation. Better outcome is foreseeable with a decrease in posttransplantation complications and more experience in predicting survival of these critical patients. ( Liver Transpl 2002;8:340-346 .)