Since Campath 1H (C1H) has been successfully used in adult liver transplant recipients since 2001... more Since Campath 1H (C1H) has been successfully used in adult liver transplant recipients since 2001 in our program, we started to use it in children. C1H induction was employed in 10 children with autoimmune hepatitis (AIH) (n = 6), primary sclerosing cholangitis (PSC) (n = 1), biliary atresia (n = 1), glycogen storage disease (n = 1), and Wilson's disease. Eight were primary transplants, and two retransplants. Patients ages ranged from 5 to 17 years. C1H was administered at a dose of 0.3 mg/kg on days 0, 4, and 7. Tacrolimus level was maintained at 5 to 10 ng/mL. No patient received maintenance steroids posttransplantation except two who were on steroid therapy at the time transplant. They were prescribed small doses of maintenance steroids. Median follow-up of C1H recipients was 679 days (range 115-1143). Postoperative courses were mostly uneventful except for one retransplant recipient who required prolonged hospitalization (40 days) for rehabilitation. Median hospital stay was...
Documented causes of biliary complications following orthotopic liver transplantation have been r... more Documented causes of biliary complications following orthotopic liver transplantation have been related to technical imperfections or insufficient arterial supply. Although anatomical variations of the extrahepatic biliary system are not infrequent, neither their incidence, surgical management nor possible association with complications have been reported in liver transplantation. At our institution, the global incidence of biliary complications following 357 consecutive liver transplants performed in 324 patients over a 2-yr period was 15.4% (55/357). Anomalous donor extrahepatic ducts were verified in 10 cases (2.8%) and they were recognized intraoperatively, prior to biliary reconstruction, in 7 cases. Technical complications occurred in 1 of these 7 and in 3 other cases where the anomalous ducts were not identified until later in the postoperative period when serious clinical problems ensued. We herein present a description of these 10 cases, with reference to the techniques emp...
Intestinal motility disorder is one major cause of intestinal failure. Sever case such as idiopat... more Intestinal motility disorder is one major cause of intestinal failure. Sever case such as idiopathic pseud-obstruction is a life threatening illness. Causes of intestinal motility disorders seem to be multifactorial, and only a few have been figured out. The prognosis is poor for patients with severe illness. Progress of intestinal transplant has been made and improved survival has been noted. Intestinal transplantation is a treatment for severe motility disorder with irreversible intestinal failure. However prevalence of severe motility disorder is unknown. We performed national survey to figure out the patients with intestinal motility disorder and find out the patients who require intestinal transplant. Methods: National survey was performed to 302 institutions that take care of motility disorders of intestine. Questionnaire was sent to the institutions. Patients were collected for intestinal failure who were treated in the institutions from 2006 to 2011. 354 patients were reported from 69 institutions. The factor to indication for intestinal transplantation: diagnosis, patient age, age of onset, sex, patient's outcome, total parental nutrition, liver function test and central line access were accessed. Results: 132 patients who have motility disorder were reported from 45 institutions. The prevalence was about one out of one million in this survey. Male was 48 patients and female was 84 patients. The female to male ratio was about 2: 1. Mean patient age was 12.1 year old (ranged 0.3 to 77.5 year old). The mean age of onset was 3.0 year old (raged 0.0 to 68.8 years old). Diagnoses were idiopathic pseud-obstruction, Hirshsprung's disease, Megacystis micro-colon intestinal hypoperistalsis syndrome (MMIHS) and others. They were 84 cases, 28 cases, 14 cases and 6 cases respectively. 114 patients survived and 18 patients were died during last 5 years. Mortality rate was 13.6%. 105 cases experienced catheter related infection at least once a year. 43 cases have had central vein thrombosis. 83 patients (63%) were not able to discontinue total parental nutrition. They were defined as irreversible intestinal failure. Among surviving patients with irreversible intestinal failure, 8 patients (10 %) developed hepatic failure with jaundice. 23 patients (28%) developed 2 or more central vein thrombosis. Total 31 patients (37%) may be candidate for intestinal transplantation among irreversible intestinal failure with motility disorder of intestine. Conclusion: The prevalence of the severe motility disorder was figure out in Japan. 38% patients with irreversible intestinal failure from intestinal motility disorder may be candidate for intestinal transplantation. The severe case of motility disorder should be referred to the transplant facility. Farther investigations were required.
Endoscopic biopsies of intestinal allografts are limited to the superficial layers of the bowel. ... more Endoscopic biopsies of intestinal allografts are limited to the superficial layers of the bowel. We investigated whether the presence of mucosal fibrosis in graft biopsies was indicative of chronic allograft rejection. We examined graft biopsies of 182 intestinal transplant recipients for the presence of mucosal fibrosis. Kaplan-Meier analysis showed that within 5 years posttransplantation 33% of intestinal transplant patients had graft biopsies positive for mucosal fibrosis. Although the presence of mucosal fibrosis did not affect patient or graft survival, patients with this lesion were at higher risk of developing chronic allograft enteropathy.
Introduction. Panel reactive antibodies (PRA) to class I and II HLA molecules have been associate... more Introduction. Panel reactive antibodies (PRA) to class I and II HLA molecules have been associated with acute kidney graft rejection, but their role in small bowel transplantation has not been characterized. Methods. Since 1994, 324 SBT, alone or as multivisceral transplantation (MVT), have been performed in 286 patients. Routine and surveillance biopsies were performed to rule out or confirm acute rejection (AR), and PRA quantification was performed at varying intervals. We obtained data from 110 patients and 651 PRA measurements. While AR grade (mild to severe, grades 1-3) was determined by histopathological analysis, the status of no AR was determined also by clinical data. When biopsy samples or PRA measurements were frequent around an AR episode within periods of 7 days, the highest value was used. Results. A comparison could be made between 259 instances in which there was a PRA measurement and simultaneous rejection evaluation. Positive PRA showed association with AR (P Ͻ 0.001). The positive and negative predictive values were 44% and 79%, respectively. No correlation was found in the severity of rejection. Conclusion. The presence of increased levels of PRA is a risk factor of rejection in small bowel transplantation. Alloantibody-mediated injury to the graft contributes frequently to acute rejection of small bowel, and it is associated with cell-mediated immunity in variable proportion.
Uterine transplantation in the sheep model has been described as a partial or whole orthotopic gr... more Uterine transplantation in the sheep model has been described as a partial or whole orthotopic graft from a living donor with vascular anastomoses. As an alternative to surrogate pregnancy or adoption uterus transplantation might be indicated for cases of infertility of uterine origin. The main complications might be rejection and thrombosis. The objective of this work was to develop a model of whole uterus transplantation that was applicable to the human setting, using grafts obtained from brain-dead donors, and suitable for immunologic and viability follow-up with a reduced risk of thrombosis. Two donors and 1 recipient were operated. The first graft was used for an anatomic study; the second was used for transplantation. The donor operation consisted of an en bloc harvest of the uterus, adnexa, and proximal vagina with the distal aorta and cava. After harvest the donor sheep was humanely killed. In the recipient ewe, heterotopic implantation was performed in the lower abdomen. An End-to-side anastomoses of aorta and cava were performed below the recipient's renal vessels. A cutaneous vaginal stoma was performed in the right lower quadrant. The recipient ewe was humanely killed for an autopsy study. The anatomy of uterine veins of the ewe differs from the human. The uterine and ovarian veins join, forming the utero-ovarian vein, which drains at the confluence of the common iliac to the cava. En bloc harvesting allows for rapid graft preparation, with vascular cuffs easily anastomosed with a low risk of thrombosis. The vaginal stoma seems appropriate to facilitate follow-up and graft biopsy. This approach can be a suitable experimental model applicable to humans using grafts from brain-dead donors.
Background: Transplantation of the stomach has been done as part of multivisceral transplantation... more Background: Transplantation of the stomach has been done as part of multivisceral transplantation at our institution. In this study, we review our results of function, pathology and complications regarding the gastric allograft. Methods: A retrospective review of the recipients who received allograft stomach as part of as part of the multivisceral graft. Results: 146 patients received the stomach as part of the multivisceral graft during 1994-2007. 124 received it with a standard multivisceral graft (liver, stomach, pancreas and intestine) and 22 received it with a modifi ed multivisceral graft (stomach, pancreas and intestine). The gastric allograft was anastomosed to the native esophagus (esophagogastrostomy) in 78 and to the small rim of the native stomach (gastro-gastric anastomosis) in 68. All received pyloroplasty at the time of transplant. 71 patients who received gastric allograft are currently alive. The gastric emptying were normal to near normal in most cases except for 3 cases who exhibit signifi cant gastropalasis after the transplant both of those cases had dysmotility disease as a cause of transplant. The rejection of the gastric allograft was seen in xxx cases. All of those occurred concurrently with the intestinal rejection. No isolated gastric rejection was seen. Signifi cant gastro esophageal refl ux was seen in 10 patients. 8 of those had esophagogastrostomy and 2 gastro gastrostomy. Fudoplication surgery was performed in 3 cases. No anastomotic leak from the gastric anasomosis was seen in primary multivisceral transplant; in 2 case, leak was seen after the second multivisceral transplant. Conclusion: The gastric allograft as part of the multivisceral graft seemed to show good emptying function. Gastric rejection seemed to be a rare occurrence and other complication rate pertaining to the gastric allograft is rare as well.
Introduction: Subclinical acute rejection (SCR) is a recognized notion in various organ transplan... more Introduction: Subclinical acute rejection (SCR) is a recognized notion in various organ transplants and is defi ned as histopathologically proven acute cellular rejection (ACR) without concurrent clinical indications of ACR. We recently characterized SCR in small intestinal transplantation (Itx) and found it has a negative impact on graft survival. The purpose of this study was to investigate the histomorphological characteristics of SCR in Itx in comparison with clinically signifi cant acute cellular rejection (CSR). Methods: SCR in Itx was defi ned as a biopsy showing histopathological ACR without any clinical signs of ACR, including endoscopical fi ndings, and not treated with adjuvant immunosuppression. Histopathologically proven ACR with clinical signs for ACR were defi ned as clinically signifi cant ACR (CSR). A total of 100 cases (50 cases for SCR and CSR) from 32 patients, which showed histopathologically grade 1 ACR, were blindly reviewed without information of rejection status and compared for the following histopathological factors: number of apoptotic bodies in 10 representative crypts, "macroscopic apoptosis", infl ammatory infi ltrate in lamina propria, mucosal edema, blunting of villi, vascular congestion and red blood cell extravasation. We used a semiquantitative scoring system which assigned a numerical score of 0-3 for each histopathological factor. Using a 3-color immunofl uorescence technique, we also evaluated the population of CD4 (+) Foxp3 (+) regulatory T cells in the infl ammatory infi ltrate. Results: Among a total of 32 patients, 12 were male and 20 were female. Median age was 1.3 year old, ranging from 0.26 to 52.5. The types of grafts used in Itx were as follows: isolated intestine (n=6). liver-intestine (n=1). multivisceral transplant (n=22) and multivisceral transplant without liver (modifi ed multivisceral transplant, n=3). The median number of biopsies from each patient was 3, ranging from 1 to 14. SCR cases showed "big apoptosis" more frequently than CSR cases (42% vs. 14%; p=0.004). CSR cases showed severe blunting of villi (p<0.001). There were not signifi cant differences between SCR and CSR in the number of apoptotic bodies in 10 representative crypts, infl ammatory infi ltrate in lamina propria, mucosal edema, vascular congestion and red blood cell extravasation in lamina propria and submucosa. Immunohistochemical staining for CD4 and Foxp3 revealed CD4 (+) Foxp3 (+) regulatory T cell populations in both SCR and CSR cases. Conclusion: There were only minor differences in morphology between SCR and CSR in Itx and regulatory cell subpopulations were seen in both situations. Therefore, histopathological evaluation of biopsies by routine methodology shows SCR cases having features compatible with a vigorous alloimmune response and without other novel changes.
Background: It is hypothesized that immune deficiency has a negative impact on the re-infection o... more Background: It is hypothesized that immune deficiency has a negative impact on the re-infection of hepatitis C after liver transplantation. Previous studies have shown that major surgical complications may have a negative interference with the immune system. The aim of this study was to evaluate the impact of major surgical complications of liver transplantation on the clinical relevant re-infection of hepatitis C. Methods: The study population consists of all patients who underwent a liver transplantation for hepatitis C liver cirrhoses between 2004 and 2008. The records of these patients were retrospectively reviewed. Postoperative complications were graded using the Clavien Classification system. Major complications were defined as ≥ Grade IIIb. Patients with positive hepatitis C serology and admission to the hospital due to poor liver function were defined as patients with clinical relevant re-infection. Results: There were 114 patients included to the study with a median age of 54 years and a median follow-up of 35 month. All patients underwent orthotopic liver transplantation. Surgical complications of the liver transplantation were seen in 84 patients (73%). Complications were Clavian Grade I-IIIa in 29 (25%) and Grade IIIb or IV in 55 (48%). Of these 114 patients, 21 patients (18%) died during the hospital stay within the first three month after transplantation and were excluded from further analyses. There were no significant differences in median age, comorbidities, severity of the cirrhoses and rate of acute rejection between patients with and without major complications. Of these 55 patients with major complications, 22 (40%) had a re-infection in a median time of 12 month. Of the 59 patients with none or minor complications, 10 (17%) had a re-infection after a median time of 18 month (p< 0.001). Conclusion: The results of the study indicate that the time to clinical relevant hepatitis C re-infections is significantly shorter in patients with major surgical complications of the liver transplantation.
Individualization of MMF therapy has been advocated to minimize the incidence of acute rejection.... more Individualization of MMF therapy has been advocated to minimize the incidence of acute rejection. Pre-existing disease state may contribute to the variability in MPA exposure. This is a retrospective analysis of the impact of pre-existing diabetes on MPA exposure in kidney transplant patients. Methods: 141 kidney transplant patients had three full MPA pharmacokinetics (PK) profiles (0 to 12 hours) on days 3, 7, and 11; and five abbreviated (0 to 2 hours) PK profiles on Weeks 3, 4, 8, 12, and 20. Diabetic status was determined based on medical history and / or reported use of anti-diabetics at study entry. Diabetics and nondiabetics were compared using repeated measures in a linear mixed effects model. Log transformed AUC 0-12 and C max were compared adjusting for treatment group, sex, age, donor age, and average daily dose of MMF, cyclosporine, and corticosteroids. The ratio of the least squares of the means (LSM) and the 90% confidence interval (C.I.) were compared to the (0.8, 1.25) equivalency range. Individual time concentration points were also compared. Results: AUC 0-12 increased over time in both diabetic and nondiabetic patients, almost doubling by Week 12. MPA exposure during 20 weeks of therapy, expressed as MPA AUC 0-12 , was not significantly different in the diabetic and non-diabetic groups. Selected MPA AUC 0-12 (mg.h/L) by Diabetic Status C max was not significantly different for all periods except for days 7 and 11. However, AUC 0-12 was not significantly different for all periods. Conclusion: The data suggest that pre-existing diabetic status does not influence MPA exposure as measured by AUC 0-12 after MMF administration to kidney transplant patients. MPA AUC's were similar in all groups including days 7 and 11.
Introduction. We investigated the putative candidate biomarkers of graft rejection in peripheral ... more Introduction. We investigated the putative candidate biomarkers of graft rejection in peripheral blood of intestinal transplant patients. Materials and Methods. Peripheral blood gene expression analysis was performed in intestinal transplant patients. The results were matched with concurrent graft biopsies using bioinformatics. Results. Peripheral blood samples (nϭ11), of 3 adult patients [transplant day (nϭ1), no rejection (nϭ1), minimal rejection (nϭ2), mild rejection (nϭ5) and severe rejection (nϭ2)] were collected. Bioinformatics: Enrichment Analysis: The three most affected pathways differentially expressed in rejection versus a pool of healthy volunteers were related to protein translation: translation initiation, translation elongation termination, and translation in mitochondria, with p-values for all rejection stages in all patients in the 10-4 to 10-18 range. No significant enrichment was observed for these categories in the day of transplant sample. In addition to translation, significant enrichment of several immune response categories was observed in rejection samples. Subsequent gene set enrichment analysis verified these results. The level of enrichment was very high (p-values of 10-5-10-60) and increased with the level of rejection in all patients. Genes significantly down-regulated in translation related gene sets included ribosomal proteins RPL13A, RP L22, RPS23, RPL13 and RPL10A, that could be used as potential biomarkers for future experiments. Conclusion. In this pilot study we found a list of genes (involved in translation) significantly downregulated in the peripheral blood of three intestinal transplant patients during rejection. These results will be verified in further studies with increased number of patients and with isolation of peripheral blood subpopulations.
Hepatitis C infection recurs after orthotopic liver transplantation for hepatitis C virus (HCV)-r... more Hepatitis C infection recurs after orthotopic liver transplantation for hepatitis C virus (HCV)-related end-stage liver disease. Overlapping histopathologic features may present difficulties in differentiating recurrent HCV in the allograft from other conditions, especially rejection. In this study, we evaluated the presence of HCV-RNA by reverse transcriptase in situ polymerase chain reaction (RT in situ RCR) in hepatic tissue, after orthotopic liver transplantation for HCV-related liver disease. Further, detection of HCV-RNA was correlated with the serum HCV-RNA levels, histopathology, and clinical outcome. Twenty-five patients were part of this study. Seventeen patients were transplanted for HCV cirrhosis and eight for an underlying disease other than HCV. None of the patients in the non-HCV group had in situ RT-PCR detection of HCV-RNA. Positive RT in situ PCR for HCV was found in 9 of 17 HCV patients, and the patients had a clinical course consistent with recurrent hepatitis C disease. Four of these nine patients had an initial histologic diagnosis of rejection. The other eight patients in the HCV group had negative RT in situ PCR, and none of them had a course compatible with recurrent HCV disease, although four patients were histologically diagnosed as having chronic C hepatitis. The mean HCV-RNA level (log/mL) in the patients who had in situ detection of HCV-RNA was 7.01+/-0.26. Although RT-PCR was negative in 8 of 17 HCV patients, the patients were serologically viremic and the mean HCV-RNA level was 6.05+/-0.33 (P=0.03). Our findings indicate that the HCV in situ RT-PCR assay may be helpful in the differentiation of recurrent hepatitis C disease from rejection. This may further help in the adjustment of immunosuppression.
We wanted to determine if parametric cause-specific hazard modeling, including log-linear general... more We wanted to determine if parametric cause-specific hazard modeling, including log-linear generalizations of underlying parameters to incorporate covariate effects, would provide accurate representations, particularly with nonproportional hazards. Nonparametric ...
Since Campath 1H (C1H) has been successfully used in adult liver transplant recipients since 2001... more Since Campath 1H (C1H) has been successfully used in adult liver transplant recipients since 2001 in our program, we started to use it in children. C1H induction was employed in 10 children with autoimmune hepatitis (AIH) (n = 6), primary sclerosing cholangitis (PSC) (n = 1), biliary atresia (n = 1), glycogen storage disease (n = 1), and Wilson's disease. Eight were primary transplants, and two retransplants. Patients ages ranged from 5 to 17 years. C1H was administered at a dose of 0.3 mg/kg on days 0, 4, and 7. Tacrolimus level was maintained at 5 to 10 ng/mL. No patient received maintenance steroids posttransplantation except two who were on steroid therapy at the time transplant. They were prescribed small doses of maintenance steroids. Median follow-up of C1H recipients was 679 days (range 115-1143). Postoperative courses were mostly uneventful except for one retransplant recipient who required prolonged hospitalization (40 days) for rehabilitation. Median hospital stay was...
Documented causes of biliary complications following orthotopic liver transplantation have been r... more Documented causes of biliary complications following orthotopic liver transplantation have been related to technical imperfections or insufficient arterial supply. Although anatomical variations of the extrahepatic biliary system are not infrequent, neither their incidence, surgical management nor possible association with complications have been reported in liver transplantation. At our institution, the global incidence of biliary complications following 357 consecutive liver transplants performed in 324 patients over a 2-yr period was 15.4% (55/357). Anomalous donor extrahepatic ducts were verified in 10 cases (2.8%) and they were recognized intraoperatively, prior to biliary reconstruction, in 7 cases. Technical complications occurred in 1 of these 7 and in 3 other cases where the anomalous ducts were not identified until later in the postoperative period when serious clinical problems ensued. We herein present a description of these 10 cases, with reference to the techniques emp...
Intestinal motility disorder is one major cause of intestinal failure. Sever case such as idiopat... more Intestinal motility disorder is one major cause of intestinal failure. Sever case such as idiopathic pseud-obstruction is a life threatening illness. Causes of intestinal motility disorders seem to be multifactorial, and only a few have been figured out. The prognosis is poor for patients with severe illness. Progress of intestinal transplant has been made and improved survival has been noted. Intestinal transplantation is a treatment for severe motility disorder with irreversible intestinal failure. However prevalence of severe motility disorder is unknown. We performed national survey to figure out the patients with intestinal motility disorder and find out the patients who require intestinal transplant. Methods: National survey was performed to 302 institutions that take care of motility disorders of intestine. Questionnaire was sent to the institutions. Patients were collected for intestinal failure who were treated in the institutions from 2006 to 2011. 354 patients were reported from 69 institutions. The factor to indication for intestinal transplantation: diagnosis, patient age, age of onset, sex, patient's outcome, total parental nutrition, liver function test and central line access were accessed. Results: 132 patients who have motility disorder were reported from 45 institutions. The prevalence was about one out of one million in this survey. Male was 48 patients and female was 84 patients. The female to male ratio was about 2: 1. Mean patient age was 12.1 year old (ranged 0.3 to 77.5 year old). The mean age of onset was 3.0 year old (raged 0.0 to 68.8 years old). Diagnoses were idiopathic pseud-obstruction, Hirshsprung's disease, Megacystis micro-colon intestinal hypoperistalsis syndrome (MMIHS) and others. They were 84 cases, 28 cases, 14 cases and 6 cases respectively. 114 patients survived and 18 patients were died during last 5 years. Mortality rate was 13.6%. 105 cases experienced catheter related infection at least once a year. 43 cases have had central vein thrombosis. 83 patients (63%) were not able to discontinue total parental nutrition. They were defined as irreversible intestinal failure. Among surviving patients with irreversible intestinal failure, 8 patients (10 %) developed hepatic failure with jaundice. 23 patients (28%) developed 2 or more central vein thrombosis. Total 31 patients (37%) may be candidate for intestinal transplantation among irreversible intestinal failure with motility disorder of intestine. Conclusion: The prevalence of the severe motility disorder was figure out in Japan. 38% patients with irreversible intestinal failure from intestinal motility disorder may be candidate for intestinal transplantation. The severe case of motility disorder should be referred to the transplant facility. Farther investigations were required.
Endoscopic biopsies of intestinal allografts are limited to the superficial layers of the bowel. ... more Endoscopic biopsies of intestinal allografts are limited to the superficial layers of the bowel. We investigated whether the presence of mucosal fibrosis in graft biopsies was indicative of chronic allograft rejection. We examined graft biopsies of 182 intestinal transplant recipients for the presence of mucosal fibrosis. Kaplan-Meier analysis showed that within 5 years posttransplantation 33% of intestinal transplant patients had graft biopsies positive for mucosal fibrosis. Although the presence of mucosal fibrosis did not affect patient or graft survival, patients with this lesion were at higher risk of developing chronic allograft enteropathy.
Introduction. Panel reactive antibodies (PRA) to class I and II HLA molecules have been associate... more Introduction. Panel reactive antibodies (PRA) to class I and II HLA molecules have been associated with acute kidney graft rejection, but their role in small bowel transplantation has not been characterized. Methods. Since 1994, 324 SBT, alone or as multivisceral transplantation (MVT), have been performed in 286 patients. Routine and surveillance biopsies were performed to rule out or confirm acute rejection (AR), and PRA quantification was performed at varying intervals. We obtained data from 110 patients and 651 PRA measurements. While AR grade (mild to severe, grades 1-3) was determined by histopathological analysis, the status of no AR was determined also by clinical data. When biopsy samples or PRA measurements were frequent around an AR episode within periods of 7 days, the highest value was used. Results. A comparison could be made between 259 instances in which there was a PRA measurement and simultaneous rejection evaluation. Positive PRA showed association with AR (P Ͻ 0.001). The positive and negative predictive values were 44% and 79%, respectively. No correlation was found in the severity of rejection. Conclusion. The presence of increased levels of PRA is a risk factor of rejection in small bowel transplantation. Alloantibody-mediated injury to the graft contributes frequently to acute rejection of small bowel, and it is associated with cell-mediated immunity in variable proportion.
Uterine transplantation in the sheep model has been described as a partial or whole orthotopic gr... more Uterine transplantation in the sheep model has been described as a partial or whole orthotopic graft from a living donor with vascular anastomoses. As an alternative to surrogate pregnancy or adoption uterus transplantation might be indicated for cases of infertility of uterine origin. The main complications might be rejection and thrombosis. The objective of this work was to develop a model of whole uterus transplantation that was applicable to the human setting, using grafts obtained from brain-dead donors, and suitable for immunologic and viability follow-up with a reduced risk of thrombosis. Two donors and 1 recipient were operated. The first graft was used for an anatomic study; the second was used for transplantation. The donor operation consisted of an en bloc harvest of the uterus, adnexa, and proximal vagina with the distal aorta and cava. After harvest the donor sheep was humanely killed. In the recipient ewe, heterotopic implantation was performed in the lower abdomen. An End-to-side anastomoses of aorta and cava were performed below the recipient's renal vessels. A cutaneous vaginal stoma was performed in the right lower quadrant. The recipient ewe was humanely killed for an autopsy study. The anatomy of uterine veins of the ewe differs from the human. The uterine and ovarian veins join, forming the utero-ovarian vein, which drains at the confluence of the common iliac to the cava. En bloc harvesting allows for rapid graft preparation, with vascular cuffs easily anastomosed with a low risk of thrombosis. The vaginal stoma seems appropriate to facilitate follow-up and graft biopsy. This approach can be a suitable experimental model applicable to humans using grafts from brain-dead donors.
Background: Transplantation of the stomach has been done as part of multivisceral transplantation... more Background: Transplantation of the stomach has been done as part of multivisceral transplantation at our institution. In this study, we review our results of function, pathology and complications regarding the gastric allograft. Methods: A retrospective review of the recipients who received allograft stomach as part of as part of the multivisceral graft. Results: 146 patients received the stomach as part of the multivisceral graft during 1994-2007. 124 received it with a standard multivisceral graft (liver, stomach, pancreas and intestine) and 22 received it with a modifi ed multivisceral graft (stomach, pancreas and intestine). The gastric allograft was anastomosed to the native esophagus (esophagogastrostomy) in 78 and to the small rim of the native stomach (gastro-gastric anastomosis) in 68. All received pyloroplasty at the time of transplant. 71 patients who received gastric allograft are currently alive. The gastric emptying were normal to near normal in most cases except for 3 cases who exhibit signifi cant gastropalasis after the transplant both of those cases had dysmotility disease as a cause of transplant. The rejection of the gastric allograft was seen in xxx cases. All of those occurred concurrently with the intestinal rejection. No isolated gastric rejection was seen. Signifi cant gastro esophageal refl ux was seen in 10 patients. 8 of those had esophagogastrostomy and 2 gastro gastrostomy. Fudoplication surgery was performed in 3 cases. No anastomotic leak from the gastric anasomosis was seen in primary multivisceral transplant; in 2 case, leak was seen after the second multivisceral transplant. Conclusion: The gastric allograft as part of the multivisceral graft seemed to show good emptying function. Gastric rejection seemed to be a rare occurrence and other complication rate pertaining to the gastric allograft is rare as well.
Introduction: Subclinical acute rejection (SCR) is a recognized notion in various organ transplan... more Introduction: Subclinical acute rejection (SCR) is a recognized notion in various organ transplants and is defi ned as histopathologically proven acute cellular rejection (ACR) without concurrent clinical indications of ACR. We recently characterized SCR in small intestinal transplantation (Itx) and found it has a negative impact on graft survival. The purpose of this study was to investigate the histomorphological characteristics of SCR in Itx in comparison with clinically signifi cant acute cellular rejection (CSR). Methods: SCR in Itx was defi ned as a biopsy showing histopathological ACR without any clinical signs of ACR, including endoscopical fi ndings, and not treated with adjuvant immunosuppression. Histopathologically proven ACR with clinical signs for ACR were defi ned as clinically signifi cant ACR (CSR). A total of 100 cases (50 cases for SCR and CSR) from 32 patients, which showed histopathologically grade 1 ACR, were blindly reviewed without information of rejection status and compared for the following histopathological factors: number of apoptotic bodies in 10 representative crypts, "macroscopic apoptosis", infl ammatory infi ltrate in lamina propria, mucosal edema, blunting of villi, vascular congestion and red blood cell extravasation. We used a semiquantitative scoring system which assigned a numerical score of 0-3 for each histopathological factor. Using a 3-color immunofl uorescence technique, we also evaluated the population of CD4 (+) Foxp3 (+) regulatory T cells in the infl ammatory infi ltrate. Results: Among a total of 32 patients, 12 were male and 20 were female. Median age was 1.3 year old, ranging from 0.26 to 52.5. The types of grafts used in Itx were as follows: isolated intestine (n=6). liver-intestine (n=1). multivisceral transplant (n=22) and multivisceral transplant without liver (modifi ed multivisceral transplant, n=3). The median number of biopsies from each patient was 3, ranging from 1 to 14. SCR cases showed "big apoptosis" more frequently than CSR cases (42% vs. 14%; p=0.004). CSR cases showed severe blunting of villi (p<0.001). There were not signifi cant differences between SCR and CSR in the number of apoptotic bodies in 10 representative crypts, infl ammatory infi ltrate in lamina propria, mucosal edema, vascular congestion and red blood cell extravasation in lamina propria and submucosa. Immunohistochemical staining for CD4 and Foxp3 revealed CD4 (+) Foxp3 (+) regulatory T cell populations in both SCR and CSR cases. Conclusion: There were only minor differences in morphology between SCR and CSR in Itx and regulatory cell subpopulations were seen in both situations. Therefore, histopathological evaluation of biopsies by routine methodology shows SCR cases having features compatible with a vigorous alloimmune response and without other novel changes.
Background: It is hypothesized that immune deficiency has a negative impact on the re-infection o... more Background: It is hypothesized that immune deficiency has a negative impact on the re-infection of hepatitis C after liver transplantation. Previous studies have shown that major surgical complications may have a negative interference with the immune system. The aim of this study was to evaluate the impact of major surgical complications of liver transplantation on the clinical relevant re-infection of hepatitis C. Methods: The study population consists of all patients who underwent a liver transplantation for hepatitis C liver cirrhoses between 2004 and 2008. The records of these patients were retrospectively reviewed. Postoperative complications were graded using the Clavien Classification system. Major complications were defined as ≥ Grade IIIb. Patients with positive hepatitis C serology and admission to the hospital due to poor liver function were defined as patients with clinical relevant re-infection. Results: There were 114 patients included to the study with a median age of 54 years and a median follow-up of 35 month. All patients underwent orthotopic liver transplantation. Surgical complications of the liver transplantation were seen in 84 patients (73%). Complications were Clavian Grade I-IIIa in 29 (25%) and Grade IIIb or IV in 55 (48%). Of these 114 patients, 21 patients (18%) died during the hospital stay within the first three month after transplantation and were excluded from further analyses. There were no significant differences in median age, comorbidities, severity of the cirrhoses and rate of acute rejection between patients with and without major complications. Of these 55 patients with major complications, 22 (40%) had a re-infection in a median time of 12 month. Of the 59 patients with none or minor complications, 10 (17%) had a re-infection after a median time of 18 month (p< 0.001). Conclusion: The results of the study indicate that the time to clinical relevant hepatitis C re-infections is significantly shorter in patients with major surgical complications of the liver transplantation.
Individualization of MMF therapy has been advocated to minimize the incidence of acute rejection.... more Individualization of MMF therapy has been advocated to minimize the incidence of acute rejection. Pre-existing disease state may contribute to the variability in MPA exposure. This is a retrospective analysis of the impact of pre-existing diabetes on MPA exposure in kidney transplant patients. Methods: 141 kidney transplant patients had three full MPA pharmacokinetics (PK) profiles (0 to 12 hours) on days 3, 7, and 11; and five abbreviated (0 to 2 hours) PK profiles on Weeks 3, 4, 8, 12, and 20. Diabetic status was determined based on medical history and / or reported use of anti-diabetics at study entry. Diabetics and nondiabetics were compared using repeated measures in a linear mixed effects model. Log transformed AUC 0-12 and C max were compared adjusting for treatment group, sex, age, donor age, and average daily dose of MMF, cyclosporine, and corticosteroids. The ratio of the least squares of the means (LSM) and the 90% confidence interval (C.I.) were compared to the (0.8, 1.25) equivalency range. Individual time concentration points were also compared. Results: AUC 0-12 increased over time in both diabetic and nondiabetic patients, almost doubling by Week 12. MPA exposure during 20 weeks of therapy, expressed as MPA AUC 0-12 , was not significantly different in the diabetic and non-diabetic groups. Selected MPA AUC 0-12 (mg.h/L) by Diabetic Status C max was not significantly different for all periods except for days 7 and 11. However, AUC 0-12 was not significantly different for all periods. Conclusion: The data suggest that pre-existing diabetic status does not influence MPA exposure as measured by AUC 0-12 after MMF administration to kidney transplant patients. MPA AUC's were similar in all groups including days 7 and 11.
Introduction. We investigated the putative candidate biomarkers of graft rejection in peripheral ... more Introduction. We investigated the putative candidate biomarkers of graft rejection in peripheral blood of intestinal transplant patients. Materials and Methods. Peripheral blood gene expression analysis was performed in intestinal transplant patients. The results were matched with concurrent graft biopsies using bioinformatics. Results. Peripheral blood samples (nϭ11), of 3 adult patients [transplant day (nϭ1), no rejection (nϭ1), minimal rejection (nϭ2), mild rejection (nϭ5) and severe rejection (nϭ2)] were collected. Bioinformatics: Enrichment Analysis: The three most affected pathways differentially expressed in rejection versus a pool of healthy volunteers were related to protein translation: translation initiation, translation elongation termination, and translation in mitochondria, with p-values for all rejection stages in all patients in the 10-4 to 10-18 range. No significant enrichment was observed for these categories in the day of transplant sample. In addition to translation, significant enrichment of several immune response categories was observed in rejection samples. Subsequent gene set enrichment analysis verified these results. The level of enrichment was very high (p-values of 10-5-10-60) and increased with the level of rejection in all patients. Genes significantly down-regulated in translation related gene sets included ribosomal proteins RPL13A, RP L22, RPS23, RPL13 and RPL10A, that could be used as potential biomarkers for future experiments. Conclusion. In this pilot study we found a list of genes (involved in translation) significantly downregulated in the peripheral blood of three intestinal transplant patients during rejection. These results will be verified in further studies with increased number of patients and with isolation of peripheral blood subpopulations.
Hepatitis C infection recurs after orthotopic liver transplantation for hepatitis C virus (HCV)-r... more Hepatitis C infection recurs after orthotopic liver transplantation for hepatitis C virus (HCV)-related end-stage liver disease. Overlapping histopathologic features may present difficulties in differentiating recurrent HCV in the allograft from other conditions, especially rejection. In this study, we evaluated the presence of HCV-RNA by reverse transcriptase in situ polymerase chain reaction (RT in situ RCR) in hepatic tissue, after orthotopic liver transplantation for HCV-related liver disease. Further, detection of HCV-RNA was correlated with the serum HCV-RNA levels, histopathology, and clinical outcome. Twenty-five patients were part of this study. Seventeen patients were transplanted for HCV cirrhosis and eight for an underlying disease other than HCV. None of the patients in the non-HCV group had in situ RT-PCR detection of HCV-RNA. Positive RT in situ PCR for HCV was found in 9 of 17 HCV patients, and the patients had a clinical course consistent with recurrent hepatitis C disease. Four of these nine patients had an initial histologic diagnosis of rejection. The other eight patients in the HCV group had negative RT in situ PCR, and none of them had a course compatible with recurrent HCV disease, although four patients were histologically diagnosed as having chronic C hepatitis. The mean HCV-RNA level (log/mL) in the patients who had in situ detection of HCV-RNA was 7.01+/-0.26. Although RT-PCR was negative in 8 of 17 HCV patients, the patients were serologically viremic and the mean HCV-RNA level was 6.05+/-0.33 (P=0.03). Our findings indicate that the HCV in situ RT-PCR assay may be helpful in the differentiation of recurrent hepatitis C disease from rejection. This may further help in the adjustment of immunosuppression.
We wanted to determine if parametric cause-specific hazard modeling, including log-linear general... more We wanted to determine if parametric cause-specific hazard modeling, including log-linear generalizations of underlying parameters to incorporate covariate effects, would provide accurate representations, particularly with nonproportional hazards. Nonparametric ...
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Papers by Andreas Tzakis