Graft-versus-host disease following liver transplantation: A systematic review of literature.

BACKGROUND: Graft-versus-host disease following liver transplantation is a serious and usually fatal complication. Data identifying the risk factors and specifying the diagnosis and treatment options of the disease are scarce and contentious. Moreover, recommendations for therapeutic approaches are similarly sparse. METHODS: A systematic review of the literature from 1988 to 2020 on graft-versus-host disease following liver transplantation was performed using the PubMed and MEDLINE databases. Medical subject headings, such as graft-versus-host disease and GvHD were used in combination with solid organ transplant, transplantation, or liver transplant. Following duplicate removal, 9298 articles were screened for suitability. A total of 238 full-text articles were analyzed for eligibility, resulting in 130 eligible articles for meta-analysis. Two hundred twenty-five patients developing graft-versus-host disease following liver transplantation reported herein were mainly published in case reports and case series. RESULTS: Graft-versus-host disease occurred with an incidence of 1.2%. 85% developed following deceased donor liver transplant and 15% following living-related donor liver transplantation. The median follow-up period following liver transplantation was 84 days (interquartile range, 45-180). The median time from liver transplantation to graft-versus-host disease onset was 30 days (interquartile range, 21-42). The main clinical features included skin rash (59%), fever (43%), diarrhea (36%), and pancytopenia (30%). The overall mortality rate was 71%. Neither univariate (HR = 0.999; 95% CI, 0.493-2.023; p = 1.0) nor multivariate Cox regression analysis revealed a significant correlation between adaptation of immunosuppression and survival probability (HR = 1.475; 95% CI, 0.659-3.303; p = 0.3). CONCLUSIONS: This systematic review suggests that an increase in immunosuppressive regimen does not yield any survival benefit in patients suffering from graft-versus-host disease following liver transplantation.

Outcomes of Kidney Transplantation in Older Recipients.

BACKGROUND Access to kidney transplantation is limited for elderly patients with end-stage renal disease (ESRD), who often die while on the waiting list or receive kidneys from marginal deceased donors. In our transplantation center, most donated kidneys were from younger living relatives, in whom donations to elderly outcomes were not previously studied. In this study, we aimed to determine the short- and long-term outcomes of patients aged ³65 years to justify the use of kidneys from younger donors in older recipients. We also compared the outcomes between those who received kidneys from living donors (LDs) and deceased donors (DDs). MATERIAL AND METHODS We analyzed the patients' demographic data and the 1-, 5-, and 10-year patient and graft survival rates of patients aged ≥65 years who received kidney transplants between January 2005 and December 2020. RESULTS Among 158 patients, 136 received kidneys from LD and 22 from DD. The mean age was 69 years old. In this cohort, the most common cause of ESRD was diabetes. The graft survival rates were 99%, 96%, and 94% after 1, 5, and 10 years, respectively. Patient survival was 94%, 83%, and 61% after 1, 5, and 10 years, respectively. Delayed graft function rates, 1-year patient survival, and 5- and 10-year graft survival rates were lower in the DD group. Ischemic heart disease and transplantation from DD were independent risk factors for mortality. CONCLUSIONS Our study demonstrated reasonably good patient and graft survival rates in older patients. Outcomes were better in patients who received kidneys from LD.

Ex situ arterial reconstruction prior normothermic machine perfusion of liver grafts.

PURPOSE: Atypical variants of the hepatic artery are common and pose a technical challenge for normothermic machine perfusion (NMP). The transplant surgeon has three options when confronted with hepatic arterial variation in a liver graft to be subjected to NMP: to perform arterial reconstruction (i) prior, (ii) during, or (iii) following NMP. METHODS: Herein, we report our experience and technical considerations with pre-NMP reconstruction. Out of 52 livers, 9 had an atypical hepatic artery (HA): 3 replaced right HA, 3 replaced left HA, 1 accessory left HA, 1 accessory left and right HA, and 1 replaced left and right HA. RESULTS: Reconstruction was conducted during back-table preparation. A single vascular conduit was created in all grafts to allow single arterial cannulation for NMP, necessitating only one arterial anastomosis within the recipient. All grafts were subjected to NMP and subsequently successfully transplanted. CONCLUSION: Our approach is being advocated for as it preserves the ability to alter the reconstruction in case of problems resulting from the reconstruction itself, thereby allowing functional evaluation of the reconstruction prior transplantation, permitting simultaneous reperfusion in the recipient, and providing the shortest possible duration for vascular reconstruction once the graft is rewarming non-perfused within the recipient. In addition, in light of the frequency of technically demanding reconstructions with very small vessels, we consider our technique beneficial as the procedure can be performed under ideal conditions at the back-table.

Bryostatin-1 Attenuates Ischemia-Elicited Neutrophil Transmigration and Ameliorates Graft Injury after Kidney Transplantation.

Ischemia reperfusion injury (IRI) is a form of sterile inflammation whose severity determines short- and long-term graft fates in kidney transplantation. Neutrophils are now recognized as a key cell type mediating early graft injury, which activates further innate immune responses and intensifies acquired immunity and alloimmunity. Since the macrolide Bryostatin-1 has been shown to block neutrophil transmigration, we aimed to determine whether these findings could be translated to the field of kidney transplantation. To study the effects of Bryostatin-1 on ischemia-elicited neutrophil transmigration, an in vitro model of hypoxia and normoxia was equipped with human endothelial cells and neutrophils. To translate these findings, a porcine renal autotransplantation model with eight hours of reperfusion was used to study neutrophil infiltration in vivo. Graft-specific treatment using Bryostatin-1 (100 nM) was applied during static cold storage. Bryostatin-1 dose-dependently blocked neutrophil activation and transmigration over ischemically challenged endothelial cell monolayers. When applied to porcine renal autografts, Bryostatin-1 reduced neutrophil graft infiltration, attenuated histological and ultrastructural damage, and improved renal function. Our novel findings demonstrate that Bryostatin-1 is a promising pharmacological candidate for graft-specific treatment in kidney transplantation, as it provides protection by blocking neutrophil infiltration and attenuating functional graft injury.

[Chronic intestinal failure]. / Chronisches Darmversagen.

The term intestinal failure (IF) is understood as the transient or irreversible loss of the resorptive capacity of the bowels. This includes a multitude of diseases, some of which have anatomical causes and others functional causes. The functional capacity (absorption and motility) of the remaining digestive tract and the bacterial overgrowth and false colonization of the small bowel are of prognostic importance. After exclusion of pathological intestinal findings, such as stenosis and dilatation, initially conservative treatment is employed with the aim of intestinal adaptation. Before failure or complications, initially conservative surgery and then organ replacement by transplantation should be considered. The IF is a temporary or permanent condition. For adults a length of 100cm small bowel without the colon, 60cm still with continuity to the colon and 35cm small bowel with complete preservation of the colon including the ileocecal valve are potentially sufficient for intestinal autonomy.

Tumor Recurrence and Graft Survival in Renal Transplant Recipients with a History of Pretransplant Malignancy: A Matched Pair Analysis.

Organ scarcity demands critical decision-making regarding eligible transplant candidates and graft allocation to ensure best benefit from renal transplantation (RTx). Among the controversial relative contraindications is a history of pretransplant malignancy (PTM). While oncological outcomes of PTM-RTx recipients are well described, data on graft-specific outcome are scarce. A retrospective double case control matched pair analysis (60 months follow-up) was carried out and RTx-recipients were stratified for history of PTM. First, PTM-RTx recipients were matched according to age, sex and duration of immunosuppressive therapy. Next, PTM-RTx recipients were matched 1:1 for age, sex and cause of end-stage renal disease. Five-year patient and graft survival as well as oncological outcomes were analyzed. A total of 65 PTM-RTx recipients were identified. Post-RTx recurrence rate was 5%, while 20% developed second de novo malignancy, comparable to 14% in the control group. PTM-RTx recipients had a noticeable lower five-year death-censored as well as overall graft survival and Cox proportional hazard modeling showed a correlation between PTM and inferior graft survival. Although underlying reasons remain not fully understood, this study is the first to show inferior graft survival in PTM-RTx recipients and advocates necessity to focus on more meticulous graft monitoring in PTM recipients in addition to heightened surveillance for cancer recurrence.

Short- and Long-Term Outcomes of Different Reperfusion Sequences in Liver Transplantation.

BACKGROUND Although most centers perform primary portal vein reperfusion (PV) in orthotopic liver transplantation (OLT) for historical reasons, there is so far no sound evidence as to whether this technique is superior. The present study evaluated the long-term outcome of 3 different reperfusion sequences: PV vs primary arterial (A) vs simultaneous reperfusion (SIM). MATERIAL AND METHODS All patients at our center who underwent OLT (who received a primary, whole-organ liver graft) from 2006 to 2007 were evaluated for analysis. RESULTS A total of 61 patients were found eligible (PV: 25, A: 22, SIM: 14). Twenty-one patients (35%) were still alive after the follow-up period of 12 years. Despite poorer starting conditions such as higher recipient age (59 y (SIM) vs 55 y (A) vs 50 y (PV), P=0.01) and donor age (56 y (SIM) vs 51 y (PV) vs 50 y (A), n.s.), higher MELD scores (22 vs 19 (PV) vs 17 (A), n.s.), as well as a higher number of marginal donor organs (79% (SIM) vs 36% (A/PV), P=0.02), SIM-recipients demonstrated superior outcomes. Overall survival was 8.1 y (SIM), 4.8 y (PV), and 5.9 y (A, n.s.)). None of the SIM-recipients underwent re-transplantation, while the rate was 32% in the PV-group. The 8.1 y graft survival in SIM-recipients was significantly longer than in the other 2 groups, which were 3.3 y (PV) and 5.5 y (A, P=0.013). CONCLUSIONS Although SIM-reperfused recipients were the oldest and received grafts of inferior quality, these recipients showed superior results in terms of overall patient and graft survival. Multicentric randomized controlled trials with larger study populations are required to confirm this finding.

Donor-derived vancomycin-resistant enterococci transmission and bloodstream infection after intestinal transplantation.

BACKGROUND: Transplant recipients are at high risk for infections. However, donor-recipient transmission of multidrug-resistant organisms (MDROs) remains mostly unaddressed in the protocols of pre-transplant infection and colonization screening. Vancomycin-resistant enterococci (VRE) are MDROs that colonize the gastrointestinal tract and are associated with a significant burden of disease. Besides the high mortality of invasive VRE infections, chronic colonization leads to costly isolation measures in the hospital setting. Whereas most post-transplantation VRE infections are endogenous and thus preceded by colonization of the recipient, conclusive evidence of VRE transmission via allograft in the context of intestinal transplantation is lacking. CASE PRESENTATION: We describe a donor-derived VRE infection after intestinal transplantation including small bowel and right hemicolon. The recipient, a 54-year old male with history of mesenteric ischemia and small bowel perforation due to generalized atherosclerosis and chronic stenosis of the celiac trunk and the superior mesenteric artery, developed an intra-abdominal infection and bloodstream infection after transplantation. VRE isolates recovered from the patient as well as from the allograft prior to transplantation were analyzed via whole genome sequencing. Isolates showed to be genetically identical, thus confirming the transmission from donor to recipient. CONCLUSIONS: This case underlines the relevance of donor-recipient VRE transmission and invasive infection in the context of intestinal transplantation, highlighting the need for preoperative MDRO screening that facilitates the prompt and effective treatment of possible infections as well as the timely establishment of contact precautions to prevent further spread.

HTK-N: Modified Histidine-Tryptophan-Ketoglutarate Solution-A Promising New Tool in Solid Organ Preservation.

To ameliorate ischemia-induced graft injury, optimal organ preservation remains a critical hallmark event in solid organ transplantation. Although numerous preservation solutions are in use, they still have functional limitations. Here, we present a concise review of a modified Histidine-Tryptophan-Ketoglutarate (HTK) solution, named HTK-N. Its composition differs from standard HTK solution, carrying larger antioxidative capacity and providing inherent toxicity as well as improved tolerance to cold aiming to attenuate cold storage injury in organ transplantation. The amino acids glycine, alanine and arginine were supplemented, N-acetyl-histidine partially replaced histidine, and aspartate and lactobionate substituted chloride. Several in vitro studies confirmed the superiority of HTK-N in comparison to HTK, being tested in vivo in animal models for liver, kidney, pancreas, small bowel, heart and lung transplantation to adjust ingredients for required conditions, as well as to determine its innocuousness, applicability and potential advantages. HTK-N solution has proven to be advantageous especially in the preservation of liver and heart grafts in vivo and in vitro. Thus, ongoing clinical trials and further studies in large animal models and consequently in humans are inevitable to show its ability minimizing ischemia-induced graft injury in the sequel of organ transplantation.

Sulforaphane Elicits Protective Effects in Intestinal Ischemia Reperfusion Injury.

Intestinal ischemia reperfusion injury (IRI) is an inherent, unavoidable event of intestinal transplantation, contributing to allograft failure and rejection. The inflammatory state elicited by intestinal IRI is characterized by heightened leukocyte recruitment to the gut, which is amplified by a cross-talk with platelets at the endothelial border. Sulforaphane (SFN), a naturally occurring isothiocyanate, exhibits anti-inflammatory characteristics and has been shown to reduce platelet activation and block leukocyte adhesion. Thus, the aim of this study was to investigate protective effects and mechanism of action of SFN in a murine model of intestinal IRI. Intestinal IRI was induced by superior mesenteric artery occlusion for 30 min, followed by reperfusion for 2 h, 8 h or 24 h. To investigate cellular interactions, leukocytes were in vivo stained with rhodamine and platelets were harvested from donor animals and ex vivo stained. Mice (C57BL/6J) were divided into three groups: (1) control, (2) SFN treatment 24 h prior to reperfusion and (3) SFN treatment 24 h prior to platelet donation. Leukocyte and platelet recruitment was analyzed via intravital microscopy. Tissue was analyzed for morphological alterations in intestinal mucosa, barrier permeability, and leukocyte infiltration. Leukocyte rolling and adhesion was significantly reduced 2 h and 8 h after reperfusion. Mice receiving SFN treated platelets exhibited significantly decreased leukocyte and platelet recruitment. SFN showed protection for intestinal tissue with less damage observed in histopathological and ultrastructural evaluation. In summary, the data presented provide evidence for SFN as a potential therapeutic strategy against intestinal IRI.

Severe hyponatremia after donor nephrectomy.

Living kidney donation is safe and established but can lead to short- and long-term complications. Hyponatremia is the most common disorder of body fluid and electrolyte balance in clinical practice, associated with increased morbidity, mortality, and the length of hospital stay. A correct diagnosis of the etiology of hyponatremia is critical, both to determine correct management and prognosis. Here, we present a case of a severe hyponatremia following left- sided donor nephrectomy with a physical examination suggestive of mild hypovolemia. Laboratory tests revealed high urine osmolality and sodium concentration mimicking syndrome of inappropriate antidiuretic hormone secretion (SIADH), in the setting of abnormally blunted response to Synacthen. The patient responded well to hydrocortisone replacement. Differentiating between primary adrenal insufficiency and SIADH as a cause of severe hyponatremia was the key to successfully treating this patient. Hyponatremia following donor nephrectomy is unusual and could be explained in this case by hypocortisolism.

Urinary Biomarkers α-GST and π-GST for Evaluation and Monitoring in Living and Deceased Donor Kidney Grafts.

The aim of this study was to analyze the value of urine α- and π-GST in monitoring and predicting kidney graft function following transplantation. In addition, urine samples from corresponding organ donors was analyzed and compared with graft function after organ donation from brain-dead and living donors. Urine samples from brain-dead (n = 30) and living related (n = 50) donors and their corresponding recipients were analyzed before and after kidney transplantation. Urine α- and π-GST values were measured. Kidney recipients were grouped into patients with acute graft rejection (AGR), calcineurin inhibitor toxicity (CNI), and delayed graft function (DGF), and compared to those with unimpaired graft function. Urinary π-GST revealed significant differences in deceased kidney donor recipients with episodes of AGR or DGF at day one after transplantation (p = 0.0023 and p = 0.036, respectively). High π-GST values at postoperative day 1 (cutoff: >21.4 ng/mg urine creatinine (uCrea) or >18.3 ng/mg uCrea for AGR or DGF, respectively) distinguished between rejection and no rejection (sensitivity, 100%; specificity, 66.6%) as well as between DGF and normal-functioning grafts (sensitivity, 100%; specificity, 62.6%). In living donor recipients, urine levels of α- and π-GST were about 10 times lower than in deceased donor recipients. In deceased donors with impaired graft function in corresponding recipients, urinary α- and π-GST were elevated. α-GST values >33.97 ng/mg uCrea were indicative of AGR with a sensitivity and specificity of 77.7% and 100%, respectively. In deceased donor kidney transplantation, evaluation of urinary α- and π-GST seems to predict different events that deteriorate graft function. To elucidate the potential advantages of such biomarkers, further analysis is warranted.

Impact of nighttime procedures on outcomes after liver transplantation.

BACKGROUND: Sleep deprivation is a well-known risk factor for the performance of medical professionals. Solid organ transplantation (especially orthotopic liver transplantation (oLT)) appears to be vulnerable since it combines technically challenging operative procedures with an often unpredictable start time, frequently during the night. Aim of this study was to analyze whether night time oLT has an impact on one-year graft and patient survival. MATERIAL AND METHODS: Deceased donor oLTs between 2006 and 2017 were retrospectively analyzed and stratified for recipients with a start time at day (8 a.m. and 6 p.m.) or at night (6 p.m. to 8 a.m.). We examined donor as well as recipient demographics and primary outcome measure was one-year patient and graft survival. RESULTS: 350 oLTs were conducted in the study period, 154 (44%) during daytime and 196 (56%) during nighttime. Donor and recipient variables were comparable. One-year patient survival (daytime 75.3% vs nighttime 76.5%, p = 0.85) as well as graft survival (daytime 69.5% vs nighttime 73.5%, p = 0.46) were similar between the two groups. Frequencies of reoperation (daytime 53.2% vs nighttime 55.1%, p = 0.74) were also not significantly different. CONCLUSION: Our retrospective single center data derived from a German transplant center within the Eurotransplant region provides evidence that oLT is a safe procedure irrespective of the starting time. Our data demonstrate that compared to daytime surgery nighttime liver transplantation is not associated with a greater risk of surgical complications. In addition, one-year graft and patient survival do not display inferior results in patients undergoing nighttime transplantation.

Solid organ transplantation following allogeneic haematopoietic cell transplantation: experience from a referral organ transplantation center and systematic review of literature.

Solid organ transplantation (SOT) following haematopoietic cell transplantation (HCT) is a rare event. Uncertainty exists whether such recipients are at higher risk of relapse of underlying haematological disease or at increased risk of developing infectious or immunological complications and malignancies following SOT. The experience at our referral organ transplantation center and the present literature of SOT (n = 198) in recipients following previous HCT was systematically reviewed. Outcome analysis of 206 SOT recipients following HCT challenges the validity of the frequently stated comparable outcome with recipients without prior HCT. SOT recipients after HCT are younger and have a higher mortality and morbidity in comparison with "standard" recipients. Rejection rates for SOT recipients following HCT appear to be lower for all organs, except for liver transplantation. In the setting of liver transplantation following HCT, mortality for recipients of deceased donor grafts appears to be exceptionally high, although experience with grafts of living donors are favourable. Morbidity was mostly associated with infectious and malignant complications. Of note some SOT recipients who received solid organ donation from the same HCT donor were able to achieve successful withdrawal of immune suppression. Despite limited follow-up, recipients with prior HCT show a different course after SOT, necessitating attention and closer follow-up.

Hand-assisted living-donor nephrectomy: a retrospective comparison of two techniques.

BACKGROUND: Living-donor nephrectomy (LDN) is challenging, as surgery is performed on healthy individuals. Minimally invasive techniques for LDN have become standard in most centers. Nevertheless, numerous techniques have been described with no consensus on which is the superior approach. Both hand-assisted retroperitoneoscopic (HARS) and hand-assisted laparoscopic (HALS) LDNs are performed at Zurich University Hospital. The aim of this study was to compare these two surgical techniques in terms of donor outcome and graft function. METHOD: Retrospective single-center analysis of 60 consecutive LDNs (HARS n = 30; HALS n = 30) from June 2010 to May 2012, including a one-year follow-up of the recipients. RESULTS: There was no mortality in either group and little difference in the overall complication rates. Median warm ischemia time (WIT) was significantly shorter in the HARS group. The use of laxatives and the incidence of postoperative vomiting were significantly greater in the HALS group. There was no difference between right- and left-sided nephrectomies in terms of donor outcome and graft function. CONCLUSIONS: Both techniques appear safe for both donors and donated organs. The HARS technique is associated with a shorter WIT and a reduced incidence of postoperative paralytic ileus. Therefore, we consider HARS LDN a valuable alternative to HALS LDN.

Successful transplantation of porcine liver grafts following 48-hour normothermic preservation.

Current cold storage organ preservation technique fails to preserve marginal donor grafts sufficiently. Evidence from large animal experiments suggests superiority of normothermic machine preservation of liver allografts. Long-term organ preservation using normothermic perfusion might not only allow organ viability assessment before transplantation, but also provide the means for further organ modifications under physiologic conditions. Previous research has shown that porcine livers can be transplanted successfully after normothermic preservation of 20 hours. In the present study we investigate whether similar methodology is capable of further extending the safe limit to 48 hours. In this study, livers from White Landrace pigs were preserved by normothermic, oxygenated sanguineous perfusion. After a 48-hour period of preservation, livers were transplanted into recipient pigs and followed for 5 days. Outcome parameters measured included markers of synthetic and metabolic liver function as well as hepatocellular injury and blood gas analysis during perfusion and follow-up. Histological assessment of morphological liver integrity was performed. All livers showed sustained bile production and metabolic activity throughout the preservation period. Low levels of hepatocellular damage were found. Following transplantation all liver grafts revealed excellent graft function and death-censored graft survival was 100%. Porcine livers were transplanted successfully following 48 hours normothermic machine preservation.

The 24-hour normothermic machine perfusion of discarded human liver grafts.

Donor organ shortage necessitates use of less than optimal donor allografts for transplantation. The current cold storage preservation technique fails to preserve marginal donor grafts sufficiently. Evidence from large animal experiments suggests superiority of normothermic machine preservation (NMP) of liver allografts. In this study, we analyze discarded human liver grafts that underwent NMP for the extended period of 24 hours. Thirteen human liver grafts which had been discarded for transplantation were entered into this study. Perfusion was performed with an automated device using an oxygenated, sanguineous perfusion solution at normothermia. Automated control was incorporated for temperature-, flow-, and pressure-regulation as well as oxygenation. All livers were perfused for 24 hours; parameters of biochemical and synthetic liver function as well as histological parameters of liver damage were analyzed. Livers were stratified for expected viability according to the donor's medical history, procurement data, and their macroscopic appearance. Normothermic perfusion preservation of human livers for 24 hours was shown to be technically feasible. Human liver grafts, all of which had been discarded for transplantation, showed levels suggesting organ viability with respect to metabolic and synthetic liver function (to varying degrees). There was positive correlation between instantly available perfusion parameters and generally accepted predictors of posttransplant graft survival. In conclusion, NMP is feasible reliably for periods of at least 24 hours, even in highly suboptimal donor organs. Potential benefits include not only viability testing (as suggested in recent clinical implementations), but also removal of the time constraints associated with the utilization of high-risk livers, and recovery of ischemic and other preretrieval injuries (possibly by enabling therapeutic strategies during NMP). Liver Transplantation 23 207-220 2017 AASLD.

Aorto-hepatic bypass in liver transplantation in the MELD-era: outcomes after supraceliac and infrarenal bypasses.

PURPOSE: Poor arterial inflow during orthotopic liver transplantation (OLT) may necessitate arterial revascularisation using aorto-hepatic bypasses with supraceliac (SC) or infrarenal (IR) allografts. This study compared both techniques focusing on the patients' preoperative conditions, postoperative graft/organ function, complications and survival. METHODS: Fifteen out of 114 OLT patients underwent revascularisation (7 IR/8 SC) between 2005 and 2008 and were included in the study. The patients' records were reviewed retrospectively. RESULTS: IR patients presented with a higher BMI, received more male donor organs and their reperfusion sequence was predominately portal venous (SC: primary arterial). SC patients presented a significantly worse preoperative creatinine clearance and a trend towards a higher MELD score. The postoperative graft/organ function, morbidity and mortality did not differ between the groups despite a trend towards a worse survival in the SC group. A deteriorated preoperative creatinine clearance and higher MELD score negatively impacted the survival. Postoperative bleeding episodes and major re-interventions also affected the outcome. CONCLUSIONS: We found no evidence for superiority of either bypass technique in our OLT patients. The trend toward a worse survival in SC patients was most likely caused by the worse preoperative conditions of these patients and highlights the importance of the impact of the MELD score on the outcome after OLT.