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Background: Traversing the stricture with a guidewire is a prerequisite for the endoscopic treatment of biliary strictures after living donor liver transplantation. We aimed to evaluate the effect of variations in the biliary anastomosis and strictures on the success of endoscopic treatment and suggest a cholangiographic classification., Methods: The 125 strictures among the 104 patients with right-lobe living donor liver transplantation were reviewed. The strictures were classified by the anastomosis pattern according to the number (1, 2, or >2), location (common bile, hepatic, or cystic duct), the angle between the proximal and distal sites of the anastomosis, and the contrast enhancement pattern. The relationship between the success rate of traversing the anastomosis and the classification was evaluated., Results: Of the 125 biliary strictures, 86 (68.8%) could be passed via endoscopically. Thirty-three strictures were managed either percutaneously (n = 13) or by magnetic compression anastomosis (n = 20). Compared with the round, the triangular (odds ratio [OR], 6.5), the intermediate form (OR, 17.7), and the end-to-side anastomosis (OR, 5.1) were associated with an increased chance of traversing. The contrast enhancement pattern of the strictures and the bile ducts was also related to the successful rate of the endoscopic treatment (P < 0.001). The success rate was higher in the patients with the angle between the proximal and distal sites of the anastomosis approximated was small (0°-30° = 74%, 30°-60° = 69%, 60°-90° = 63%, >90° = 41%)., Conclusions: The type of biliary anastomoses and stricture affect the success rate of endoscopic treatment. These data may play role in making decision about the type of anastomosis during the surgery., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: The authors declare no funding or conflicts of interest.

Background: To analyze the risk factors affecting the development of infection in artificial vascular grafts (AVGs) used for reconstruction of middle hepatic vein (MHV) tributaries in living donor liver transplantation (LDLT)., Methods: Between January 2009 and January 2018, 1253 right lobe LDLTs were performed at our Transplant Institute, and MHV tributaries of the 640 right lobe liver grafts were reconstructed with AVG. Reconstructed MHV tributaries were removed due to AVG infection in 25 of these patients (case group; n = 25). To determine risk factors for AVG infection, right lobe LDLT patients without AVG infections were selected as control group (n = 615). Both groups were compared about demographic parameter, transcystic catheter usage, bile leakage, type of biliary anastomosis (duct-to-duct, telescopic duct-to-duct), number of graft biliary duct (=1 versus >1), number of biliary anastomosis (=1 versus >1), AVG thrombosis, AVG types (Dacron versus polytetrafluoroethylene). Univariate analyses were used for comparison of different variables, and variables with P ≤ 0.20 were taken into logistic regression model., Results: Univariate analysis shows that statistically significant differences were found between groups regarding bile leakage (P < 0.001), graft thrombosis (P = 0.002), transcystic catheter (P = 0.049), and AVG types (P = 0.013). Variables with P ≤ 0.20 were taken into logistic regression model. Multivariate analysis shows that bile leakage (odds ratio, 13.3) and AVG thrombosis (odds ratio, 9.8) were determined as independent and strong risk factors for development of AVG infection., Conclusions: This study revealed that bile leakage and graft thrombosis are independent and strong risk factors for infections of AVGs used for anterior sector drainage reconstruction.

Background: Liver transplantation is the most extreme form of surgical management of patients with hepatic trauma, with very limited literature data supporting its use. The aim of this study was to assess the results of liver transplantation for hepatic trauma., Methods: This retrospective analysis based on European Liver Transplant Registry comprised data of 73 recipients of liver transplantation for hepatic trauma performed in 37 centers in the period between 1987 and 2013. Mortality and graft loss rates at 90 days were set as primary and secondary outcome measures, respectively., Results: Mortality and graft loss rates at 90 days were 42.5% and 46.6%, respectively. Regarding general variables, cross-clamping without extracorporeal veno-venous bypass was the only independent risk factor for both mortality (P = 0.031) and graft loss (P = 0.034). Regarding more detailed factors, grade of liver trauma exceeding IV increased the risk of mortality (P = 0.005) and graft loss (P = 0.018). Moreover, a tendency above the level of significance was observed for the negative impact of injury severity score (ISS) on mortality (P = 0.071). The optimal cut-off for ISS was 33, with sensitivity of 60.0%, specificity of 80.0%, positive predictive value of 75.0%, and negative predictive value of 66.7%., Conclusions: Liver transplantation seems to be justified in selected patients with otherwise fatal severe liver injuries, particularly in whom cross-clamping without extracorporeal bypass can be omitted. The ISS cutoff less than 33 may be useful in the selection process.

Background: Renal transplant patients have been shown to have a higher risk of bone disease than the general population. The aim of this study was to examine vitamin D status, a modifiable risk factor in bone disease, in the renal transplant population in a northern climate., Methods: This retrospective observational study included 331 subjects and analyzed demographic, biochemical, and medication information for associations with vitamin D., Results: Of the study population, 45.3% were vitamin D deficient. The percentage of deficient subjects increases to 76.5% if those receiving supplementation are excluded. The mean daily dose of vitamin D was 1275 IU for sufficient patients. For every 1000 IU of vitamin D daily, the risk of deficiency is decreased by 40.3%. Time from transplantation had a significant positive association (P<0.001) in which every year out of transplantation decreased the risk of deficiency by 9.1%. Body mass index had a significant negative association (P=0.012) with vitamin D in which the risk of deficiency increased by 6% for each kilogram per meter squared. Ethnicity was found to be statistically significant on univariate analysis (P=0.034), with white patients having 9.1% decreased risk of deficiency., Conclusion: Despite a high rate of supplementation of vitamin D, close to half of the renal transplant population was still deficient. Those who were receiving over 1000 IU daily were more likely to be vitamin D sufficient. Early supplementation after transplantation along with higher doses for non-white patients or patients with a high body mass index may be warranted for normalization of vitamin D status.

Background: Infiltration of inflammatory cells into the renal allograft interstitium is the biologic hallmark of alloimmune responses that leads to tubulointerstitial injury and subsequent interstitial fibrosis and chronic allograft failure. The proliferation, stimulation, and infiltration of these inflammatory cells are governed by various proinflammatory and regulatory cytokines. We assessed whether the differences in the genes encoding cytokines (producing low, moderate, or high expression profiles) may affect the infiltration of inflammatory cells into the renal allograft and the histologic changes characteristics of chronic allograft failure., Methods: A total of 218 kidney transplant recipients were genotyped for 15 single-nucleotide polymorphisms located in the gene promoter or exonic regions of 10 different cytokines or their receptors. Six- to 12-month posttransplant surveillance biopsies were scored using 11 individual histologic parameters and the combined grade of interstitial fibrosis and tubular atrophy (IF/TA). B-cell, T-cell, and macrophage infiltrates were quantified by immunostaining., Results: The low-expressing interleukin (IL)-10 gene promoter genotypes were found significantly associated with high IF/TA grade (IL-10 -819 TT; P=0.035; odds ratio=3.27; 95% confidence interval 1.1-9.8). At individual histologic indices, recipients carrying low-expressing IL-10 genotypes showed 2.5-fold higher scores for interstitial fibrosis, inflammation, and tubular atrophy. High infiltration of T cells and macrophages but not B cells into the renal allograft interstitium was found strongly associated with the carriage of low-expressing IL-10 genotypes., Conclusions: The results suggest that renal transplant recipients genetically predisposed to low expression of the regulatory cytokine IL-10 are more susceptible to high grades of IF/TA scores, graft inflammation, and high influx of inflammatory cells into the graft interstitium.

Background: We recently reported a randomized study in renal transplant patients (RTP) receiving tacrolimus, mycophenolate mofetil, and prednisone in which patients who had early protocol biopsies (PBx) derived no benefit compared with controls (no PBx) at 6 months, likely due to the low prevalence of subclinical rejection. We report on the follow-up of these patients to 24 months at which time a repeat PBx and tests of renal function were performed., Methods: Of the 240 RTP randomized, 22 were excluded for a protocol violation. Approximately 75% of the remaining 218 (111 PBx and 107 controls) completed the study., Results: At 24 months, graft function was excellent with a mean creatinine clearance of approximately 74 mL/min and negligible proteinuria; however, the prevalence of interstitial fibrosis and tubular atrophy (IF/TA)-ci + ct more than or equal to 2-increased from approximately 3% at baseline to up to 40% to 50%. By logistic regression analysis, the only independent positive correlate of IF/TA was transplantation with a deceased donor. However, by post hoc analysis, use of angiotensin-II-converting enzyme inhibitors or angiotensin II receptor blockers was negatively correlated with both the prevalence of IF/TA at 24 months and its progression between 6 and 24 months in RTP that had paired biopsies., Conclusions: A regimen of tacrolimus, mycophenolate mofetil, and prednisone results in excellent renal function at 24 months posttransplant but with a progressive increase in IF/TA. A potential inhibitory effect of angiotensin-II-converting enzyme inhibitor/angiotensin II receptor blockers on IF/TA is suggested that requires confirmation in a randomized study.

Background: Chronic allograft nephropathy is the most frequent cause of long-term kidney allograft loss. Studies are desperately needed to improve long-term survival. Tacrolimus has been associated with less rejection and better kidney function compared with cyclosporine in clinical trials. This study tested the hypothesis that conversion from cyclosporine to tacrolimus might improve long-term outcomes in patients with chronic allograft damage., Methods: In this multicenter Canadian clinical trial, cyclosporine-treated patients with biopsy-proven chronic allograft nephropathy and impaired renal function were randomly assigned (2:1) to convert to tacrolimus or continue on cyclosporine therapy. A total of 106 (70 tacrolimus and 36 cyclosporine treated) patients were followed-up for up to 5 years. The primary outcome was graft survival., Results: In an intention to treat analysis, subsequent graft (73% vs. 81%, P=0.2835, log-rank test) and patient survival (91% vs. 92%, P=0.8668, log-rank test) were not different between the tacrolimus and cyclosporine groups, respectively. Changes in Chronic Allograft Damage Index scores on protocol biopsies from baseline to 3 years were not different (+0.4+/-1.8 vs. +1.3+/-3.2, P=0.5910, cyclosporine vs. tacrolimus, respectively). There were no significant differences in biopsy-proven acute rejection (6 [8.6%] vs. 2 [5.6%], tacrolimus vs. cyclosporine, respectively, P=0.5906)., Conclusions: In this study, patients with chronic allograft damage converted from cyclosporine to tacrolimus demonstrated no apparent benefit.

Background: Microscopic colitis (MC) has not been recognized as a complication of transplantation because patients are on immunosuppressant medications. The objective of this work was to describe the risk of developing MC after solid-organ transplantation., Methods: This population-based cohort study identified all cases of MC diagnosed after kidney, kidney and pancreas, or liver transplantation using pathology and transplantation databases. The annual incidence and point prevalence of MC after transplantation was calculated. The incidence rate of MC among transplantation patients was compared with the general population and presented as a Standardized Incidence Ratio (SIR) with 95% confidence intervals., Results: Seven cases (0.9%) of MC were diagnosed in kidney (n=2), kidney and pancreas (n=1), and liver (n=4) transplantation recipients. The point prevalence of MC was 8.8 per 1000 transplantation recipients. The annual incidence rate of MC in solid-organ transplantation patients was 5.0 cases per 1000 person-years. The SIR of developing MC after transplantation was 50.5 (95% confidence interval 13.6-131.8). The average age of diagnosis of MC was 49.4+/-5.3 years, average time of onset from transplantation was 67.4+/-27.0 months, and the average latency period was 30.1+/-9.0 months. Once diagnosed, all patients responded to MC-specific therapy., Conclusion: Physicians should have a low threshold to investigate for MC in solid-organ transplantation recipients who present with chronic diarrhea because this population is at an increased risk of developing MC.

Background: Progressive injury that is refractory to conventional immunosuppression remains the major hurdle to indefinite survival of transplanted organs. Several clinical risk factors of chronic renal allograft rejection have been identified; although some (e.g., acute rejection) are direct manifestations of immunological injury, others (e.g., donor age) have been more difficult to conceptually link with graft dysfunction., Methods: We conducted formal multivariate statistical analyses to reveal associations between established clinical risk factors and allograft histopathology. In a multicenter protocol biopsy-controlled study, 17 clinical risk factors were studied in relation to either the composite Chronic Allograft Damage Index (CADI) score or, to each of eight individual histological indices, using multiple linear regression with forward selection., Results: Nine clinical risk factors were not significantly associated with any histopathological index. Four (donor age, acute rejection, recipient age, and cold ischemia time) were associated both with the total CADI score and, to varying extents, with the individual histopathological indices. In our analysis, clinical risk factors accounted for, at best, only about 60% of the interindividual variation in histopathological score., Conclusions: Our study reveals a missing link between specific clinical risk factors and early histopathological findings that are known to presage accelerated failure of clinically healthy grafts. Given the complex relationship between clinical risk factors, early histopathological changes, and graft outcome, we conclude that composite, quantitative histological indices are best suited to for evaluation of the histological status of the transplant.

Background: Laparoscopic donor nephrectomy (LDN) is associated with prolonged warm ischemia, which could potentially increase oxidative stress in the graft. Because pneumoperitoneum (Pp) used to facilitate LDN impairs renal perfusion, it could augment the effects of warm ischemia. Our experimental, randomized, controlled study with blind outcome assessment is the first to address this possibility., Methods: Wistar-Albino rats were randomized to 4 groups. Controls were subjected to a sham operation; the remainder were subjected to Pp with or without warm ischemia of differing durations. The kidneys were removed at the end of each experiment. The concentrations of malondialdehyde (MDA), protein carbonyl, and sulfhydryl groups and the activities of superoxide dismutase (SOD) and catalase were measured in renal samples as markers of oxidative stress. Renal samples were also evaluated histopathologically using light microscopy., Results: Pp promoted oxidative stress in renal tissues, with an increase of MDA and protein carbonyls and a decrease in protein sulfhydryls and SOD activity. Warm ischemia exerted an additive effect on Pp-associated oxidative stress only when sustained for 10 minutes. These changes occurred in the absence of light-microscopic evidence of overt tissue damage., Conclusion: In an experimental model resembling LDN, Pp and 10 minutes of warm ischemia emerged as additive factors with respect to causing increased oxidative stress in the kidney. Because these effects imply subtle injury not only in the harvested kidneys of live donors but also in the kidneys the donors retain, avoiding Pp and warm ischemia above 5 minutes during LDN appears advisable.

Background: An association has been found between transplant glomerulopathy (TG) and reduplication of peritubular capillary basement membranes (PTCR). Although such an association is of practical and theoretical importance, only one prospective study has tried to confirm it., Methods: We examined 278 consecutive renal specimens (from 135 transplants and 143 native kidneys) for ultrastructural evidence of PTCR. In addition to renal allografts with TG, we also examined grafts with acute rejection, recurrent glomerulonephritis, chronic allograft nephropathy and stable grafts ("protocol biopsies"). Native kidney specimens included a wide range of glomerulopathies as well as cases of thrombotic microangiopathy, malignant hypertension, acute interstitial nephritis, and acute tubular necrosis., Results: We found PTCR in 14 of 15 cases of TG, in 7 transplant biopsy specimens without TG, and in 13 of 143 native kidney biopsy specimens. These 13 included cases of malignant hypertension, thrombotic microangiopathy, lupus nephritis, Henoch-Schonlein nephritis, crescentic glomerulonephritis, and cocaine-related acute renal failure. Mild PTCR in allografts without TG did not predict renal failure or significant proteinuria after follow-up periods of between 3 months and 1 year., Conclusions: We conclude that in transplants, there is a strong association between well-developed PTCR and TG, while the significance of mild PTCR and its predictive value in the absence of TG is unclear. PTCR also occurs in certain native kidney diseases, though the association is not as strong as that for TG. We suggest that repeated endothelial injury, including immunologic injury, may be the cause of this lesion both in allografts and native kidneys.

We have investigated the evolution of chronic glomerular changes in the absence of the recurrence of original disease in an experimental rat model of chronic renal allograft rejection. Using serial graft needle biopsies and serum creatinine levels, we were able to focus on early glomerular changes that are associated with good graft function. The recipient rats were divided into 5 groups, 2 with allogeneic (DA to WF) transplants and 3 with syngeneic (DA to DA) transplants. In the first 2 allogeneic groups, one group received cyclosporine (CsA) for 2 weeks (n = 7) and the other received CsA for 12 weeks (n = 5). In the 2-week treatment group, all allografts developed chronic rejection, compared with none in the 12-week group. Syngeneic controls received CsA for 2 (n = 3) and 12 weeks (n = 3), or no immunosuppression (n = 2) in order to exclude the effects of CsA. The first detectable ultrastructural event was slight deposition of electron lucent material in the glomerular basement membrane. Contrary to previous morphological studies, the initial deposition was not subendothelial, but was within the lamina densa itself. Examination of allogeneic grafts with good graft function and syngeneic grafts showed glomerular alterations that were similar to the early changes preceding chronic rejection. The intensity of changes in optimally immunosuppressed allografts was mild, and they were arrested early in the evolving stage of glomerular basement membrane changes. In the suboptimally immunosuppressed allografts with chronic rejection, the glomerular basement membrane changes became more pronounced and extensive in subsequent biopsies. Thus, all recipients in different groups showed similar glomerular alterations, but to different intensities. These results suggest a common pathogenetic mechanism which might be endothelial damage. In chronic rejection, the endothelial damage might be immunologically mediated by rejection episodes and progressive, whereas in syngeneic grafts and in allografts without chronic rejection, perioperative trauma, ischemia, and graft reperfusion may be responsible for the self-limiting glomerular changes.

15-deoxyspergualin (DSG) is an immunosuppressive drug that suppresses monocyte/macrophage function and/or T cell induction and early differentiation of B lymphocytes. It is as effective as cyclosporine in the prevention of acute rejection. We have investigated the effects of DSG on rat aortic allograft arteriosclerosis (chronic rejection). DSG was administered to the recipient rat at a dose of 0.3-10 mg/kg/day i.p. for 1-3 months, after which recipients were sacrificed. Histological changes were quantitated from paraffin sections. DSG is effective in chronic rejection in rat aortic allografts and reduces all three manifestations in the vascular wall--adventitial inflammation, media necrosis, and intimal thickening. At the dose of 1.0 mg/kg/day we demonstrated significant inhibition of adventitial inflammation from 10.6 point score units (psu) to 4.7 psu (P < 0.05), of media necrosis (P = 0.004) and of intimal thickening from 2.9 psu to 0.8 psu (P = 0.008). The therapeutic window was small in the long-term experiment. Doses of 3-10 mg/kg/day were toxic and 0.3 mg/kg/day was ineffective. In vitro smooth muscle cell proliferation was not inhibited by DSG and in the in vivo carotic denudation model DSG had no inhibitory effects either. These results suggest that DSG works via suppression of the immune/inflammatory response rather than via a direct antiproliferative effect on smooth muscle cells.

We have investigated the impact of the frequency of acute rejection episodes on the generation of chronic rejection in long-surviving rat renal allografts. A total of 33 renal transplantations was performed from DA to WF rats, receiving different cyclosporine-based immunosuppressive regimens. As a consequence, different numbers of acute rejection episodes were recorded in the recipients, all of which were successfully treated with cyclosporine. Upon sacrifice at 12 weeks posttransplantation, the frequency of acute rejection episodes was correlated with the major histological parameters of chronic rejection and with graft function. The intensity of the major histological parameters of chronic rejection, exemplified by vascular intimal proliferation and glomerular mesangial matrix increase, and the decline in graft function between the no-rejection vs. rejection groups, were directly proportional to the number of acute rejection episodes. Vascular intimal proliferation increased from 0.5 +/- 0.4 (arbitrary units) in the no-rejection group to 1.7 +/- 0.9 (P = 0.0093) after one rejection episode, to 2.2 +/- 0.3 (P = 0.0001) after two, and to 2.2 +/- 0.5 (P = 0.0014) after three or four rejection episodes. Glomerular mesangial matrix increased from 1.2 +/- 0.3 (arbitrary units) in the no-rejection group to 1.9 +/- 0.6 (P = 0.017) after one, to 2.2 +/- 0.5 (P = 0.0005) after two, and to 2.1 +/- 0.4 (P = 0.003) after three or four rejection episodes. Serum creatinine increased from 93 +/- 24 mumol/L in the no-rejection group to 196 +/- 92 mumol/L (P = 0.016) after one, to 238 +/- 38 mumol/L (P = 0.0001) after two, and to 308 +/- 85 mumol/L (P = 0.0016) after three or four rejection episodes. Prolongation of the preoperative ischemia time from 30-60 min correlated with an increase in the number of acute rejection episodes as well as an increase in chronic changes. To conclude, in the rat renal allograft model, acute allograft rejection carries a highly significant correlation with the development of chronic rejection.

The effect of prolonged ischemia time on the generation of chronic rejection was investigated in long-surviving rat renal allografts. Three groups of rats were compared: allografts with a 30-min ischemia time, allografts with a 60-min ischemia time, and syngeneic grafts with a 60-min ischemia time. All transplants were initially immunosuppressed with 5 mg/kg/day of cyclosporine i.m. for 3 weeks postoperatively. The CsA trough levels were similar in the three rat groups. All groups demonstrated an initial rise and fall in serum creatinine; a simultaneous biopsy confirmed acute CsA toxicity. Thereafter the serum creatinine level remained on the normal control level both in the 30-min ischemia allografts and in the 60-min ischemia syngeneic grafts. After the initial decline, the serum creatinine level steadily increased in the 60-min ischemia allograft group and was 181 +/- 64 mumol/L at the end of the observation period, 12 weeks postoperatively, compared with 85 +/- 21 mumol/L in the 30-min ischemia allografts and 89 +/- 25 mumol/L in the 60-min ischemia syngeneic grafts. Quantitative histology that was performed upon autopsy demonstrated that the 60-min ischemia allografts showed persistent inflammation, inflammatory cell pyroninophilia, vascular arteriosclerosis and obliteration, and glomerular sclerosis, which were significantly stronger than in similarly immunosuppressed syngeneic transplants. Reduction of the ischemia time from 60 to 30 min significantly ameliorated the vascular and glomerular changes in the allografts but not the inflammatory alterations. This experimental study confirms previous clinical observations and demonstrates that prolonged ischemia contributes to chronic rejection in renal allografts. The results suggest that the effect of prolonged ischemia on chronic rejection is directed primarily to the parenchymal components of the graft, possibly to the graft vascular endothelium. As prolonged ischemia did not significantly affect the inflammation in the transplants, we conclude that the effect is not directed to the intensity of the host antigraft immune response.