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

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

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

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

[In vitro evidence for pancreatic lineage: Ngn3 positive cells are endocrine progenitors derived from cultured islets].

OBJECTIVE: Further studies have been conducted to evaluate the roles of Ngn3 in adult islet maintenance and renewal. METHODS: Islets were isolated from 6 - 8 week old male C57BL/6 mice. After common bile duct cannulation, the pancreas was resected and digested in collagenase V (2.5 mg/ml). Islets were then handpicked and 10 - 12 islets were plated in 60 mm culture dish and cultivated with RPMI-1640, which contained 12.5 mmol/L HEPES, 5.2 mmol/L glucose and 2% fetal bovine serum (FBS). Islet cells were analyzed by immunocytochemistry methods for A6, insulin, glucagon, nestin, Ngn3 and 5-bromo-2'-deoxy-uridine (BrdU). RESULTS: The results of these studies indicated that less than 15 percent of proliferated islet cells were Ngn3 expressing cells, in which about one third of the Ngn3 positive cells co-expressed A6. The existence of Ngn3 in cultured islet cells is consistent with the results from other's findings both in embryogenesis and adult islet studies. A significant finding of our study is that the existence of A6 and Ngn3 co-expressing cells in the cultured islet. A6 is a marker for identifying bile duct epithelial cell oriented hepatic progenitor cells. Islet-derived A6 cells are possibly born in the adult pancreatic duct and migrate into islets. A6 cells co-express Ngn3 when these cells commit to endocrine lineage within the islets. More interestingly, islet-derived A6 positive cells have the potential to transdifferentiate into hepatic cells. CONCLUSION: The presence of Ngn3(+) and A6(+) cells in the cultured islets suggests that the four established islet cell types arise from a common endocrine lineage residing within the adult islets. A6 and Ngn3 are useful markers for understanding intra-islet adult stem cell lineages in our future studies. This approach may allow for significant advances in understanding the IPC proliferation and differentiation, and open the possibility of using intra-islet adult stem cells for diabetes treatment.

A model utilizing adult murine stem cells for creation of personalized islets for transplantation.

Clinical islet cell transplantation has demonstrated great promise for diabetes treatment. Two major obstacles are the organ donor shortage and the immunoresponse. The purpose of this study was to create a model using the patient's own adult stem cell sources, possibly in combination with non-self cells, such as pancreatic, hepatic, or embryonic stem cells, to create "personalized" islets. We hypothesize that the reconstructed islets have the normal capability to produce insulin and glucagon with reduced immunoresponses after transplantation. Stem cells are a proliferating population of master cells that have the ability for self-renewal and multilineage differentiation. The recently developed photolithograph-based, biologic, microelectromechanic system (BioMEMS) technique supplies a useful tool for biomedical applications. Our lab has developed a novel method that integrates the adult stem cell and BioMEMS to reconstruct personalized islets. We selected islet-derived progenitor cells (IPC) for repairing and reconstructing STZ-diabetic islets. A6(+)/PYY(+) or A6(+)/ngn3(+) cells were selected to manipulate the neoislets. After 3 to 4 weeks in culture, the reconstructed cells formed islet-like clusters containing insulin or glucagon producing cells. The pilot results showed the ability of these reconstructed islets to correct hyperglycemia when transplanted into a STZ-diabetic isograft mouse model. Although several technical problems remain with the mouse model, namely, the difficulty to collect enough islets from a single mouse because of animal size, the mouse isograft model is suitable for personalized islet development.

Hepatocellular carcinoma recurrence and death following living and deceased donor liver transplantation.

We examined mortality and recurrence of hepatocellular carcinoma (HCC) among 106 transplant candidates with cirrhosis and HCC who had a potential living donor evaluated between January 1998 and February 2003 at the nine centers participating in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL). Cox regression models were fitted to compare time from donor evaluation and time from transplant to death or HCC recurrence between 58 living donor liver transplant (LDLT) and 34 deceased donor liver transplant (DDLT) recipients. Mean age and calculated Model for End-Stage Liver Disease (MELD) scores at transplant were similar between LDLT and DDLT recipients (age: 55 vs. 52 years, p = 0.21; MELD: 13 vs. 15, p = 0.08). Relative to DDLT recipients, LDLT recipients had a shorter time from listing to transplant (mean 160 vs. 469 days, p < 0.0001) and a higher rate of HCC recurrence within 3 years than DDLT recipients (29% vs. 0%, p = 0.002), but there was no difference in mortality or the combined outcome of mortality or recurrence. LDLT recipients had lower relative mortality risk than patients who did not undergo LDLT after the center had more experience (p = 0.03). Enthusiasm for LDLT as HCC treatment is dampened by higher HCC recurrence compared to DDLT.

Isolated donor specific alloantibody-mediated rejection after ABO compatible liver transplantation.

Antibody-mediated rejection (AMR) after liver transplantation is recognized in ABO incompatible and xeno-transplantation, but its role after ABO compatible liver transplantation is controversial. We report a case of ABO compatible liver transplantation that demonstrated clinical, serological and histological signs of AMR without evidence of concurrent acute cellular rejection. AMR with persistently high titers of circulating donor specific antibodies resulted in graft injury with initial centrilobular hepatocyte necrosis, fibroedematous portal expansion mimicking biliary tract outflow obstruction, ultimately resulting in extensive bridging fibrosis. Immunofluorescence microscopy demonstrated persistent, diffuse linear C4d deposits along sinusoids and central veins. Despite intense therapeutic intervention including plasmapheresis, IVIG and rituximab, AMR led to graft failure. We present evidence that an antibody-mediated alloresponse to an ABO compatible liver graft can cause significant graft injury independent of acute cellular rejection. AMR shows distinct histologic changes including a characteristic staining profile for C4d.

Suprarenal mesocaval shunt.

A new technique for performing a mesocaval shunt above the level of the renal veins is described. It should be considered an option for those patients with perirenal vena caval occlusion or obstruction who require surgical decompression of the portal venous system.

Comparison of Gianturco Z stents and Wallstents in a hemodialysis access graft animal model.

PURPOSE: To compare the primary patency of two structurally different metallic stents in an animal model of hemodialysis access grafts. MATERIAL AND METHODS: Nineteen synthetic femorofemoral arteriovenous shunts were created in 10 dogs. After a 1-month period of maturation (during which one graft thrombosed), stents were placed spanning the venous anastomosis. The grafts were divided into two treatment groups (Wallstent, n = 6, and Gianturco stent, n = 6) and a control group with no stent (n = 6). Fistulograms and pressure measurements were obtained at monthly intervals for 6 months or until thrombosis of the graft. RESULTS: Mean graft patency in the Wallstent group (112 days +/- 30) was significantly shorter than in the control (157 days +/- 32, P < .03) or Gianturco (157 days +/- 32, P < .05) groups. Patency in the Gianturco stent group was no different from that in the control group. Stenosis due to intimal hyperplasia within the stents appeared greater in the Wallstent group but did not achieve statistical significance. One Wallstent migration, three Gianturco stents shifts, and two Gianturco stent breakages occurred. Histologic examination revealed a necrotizing vasculitis in the portion of vein containing the stent in all grafts treated with the Gianturco stent but not in any other grafts. CONCLUSION: In an animal model of hemodialysis access grafts, the Gianturco stent had longer primary patency than the Wallstent when placed across the venous anastomosis. However, stent fractures and focal necrotizing inflammation may limit the use of the Gianturco stent in hemodialysis access.

Relationship between deciduoma formation and uterine blood flow in the pseudopregnant rat.

The relationships between experimentally induced deciduoma formation, circulating estradiol (E) and progesterone (P) levels and alterations in uterine blood flow (UBF) were studied between days 4 and 15 of pseudopregnancy (PSP: day 0 = ovulation) in rats. Blood flow was measured with an electromagnetic blood flow monitor and serum analyzed for E and P levels by radioimmunoassay. Neither uterine trauma on day 4 of PSP nor the site of trauma had any direct influence on altering UBF. A dramatic increase in UBF occurred in response to stromal proliferation on days 5-6 and continued to remain above sham-operated control levels through day 9. These vascular changes correlated temporally with the day 9 peak in uterine weight resulting from deciduoma formation. Both uterine weight and vascular fluctuations in deciduoma-bearing rats were related to the cyclic changes in E/P ratios between days 5 and 8 of PSP. A decline in UBF preceded deciduoma regression between days 9 and 15 of PSP. These results suggest that an increase in UBF is causally associated with the formation and maintenance of deciduoma in the PSP rat and that deciduoma regression may result from a subsequent decline in UBF rates. Both factors may be directly dependent on fluctuating E/P ratios.

The living donor experience: donor health assessment and outcomes after living donor liver transplantation.

Despite the increasing use of living donor liver transplantation, little is known about donor needs, concerns, and experiences. The goal of this study is to assess morbidity associated with living donation from a donor perspective, functional status after donation, and overall satisfaction with the donation process. We surveyed all living donors (LDs) from our center. Demographics, perioperative experience, and satisfaction with donation were assessed. The Medical Outcomes Study 12-Item Short-Form Survey (SF-12), a well-validated tool, measured overall health-related quality of life. Of 27 subjects eligible for the study, 27 subjects (100%) participated. Forty percent reported an event they deemed an immediate complication, of which 60% were recorded in the medical record. Complications requiring readmission were reported by 22%. Mean recovery time was 12 weeks (range, 1 to 52 weeks). No significant change was reported in physical activity, social activity, or emotional stability, and 92% of donors resumed their predonation occupation. Regardless of recipient outcome, 100% of donors would donate again and recommend donation to someone in contemplation. All surveyed LDs at our institution are satisfied with their donation decision. Morbidity in the first year after donation may be greater than previously appreciated. Despite complications, postoperative functional status of donors is equal to or better than population norms.

Payer status, but not race, affects the cost of liver transplantation.

Prior studies evaluating the impact of race and payer on cost of liver transplantation did not adjust for clinical factors known to increase cost. We analyzed the impact of race and payer on the cost of liver transplantation after controlling for clinical factors. We analyzed data obtained on patient and graft survival, cost, race, age, sex, payer, and United Network for Organ Sharing (UNOS) status from 153 consecutive liver transplants in 130 patients performed at University of North Carolina Hospitals from September 1991 through December 1996. Race was classified as white or nonwhite, and payer status was classified as commercial or Medicare/Medicaid. Multivariate linear regression was used to compare costs, adjusting for age, sex, race, payer, and UNOS status. For the 130 patients, 1-year patient and graft survival rates were 88% and 82%, respectively. There were no significant differences in patient and graft survival or in the unadjusted average cost of liver transplantation by race or payer. After adjusting for demographic and clinical factors, the cost of transplantation was $28,494 more for Medicare/Medicaid recipients compared with the commercial insurance recipients (P = .02). The Medicare/Medicaid group had higher intensive care unit costs compared with the commercial insurance group ($17,807 and $9,359, respectively; P = .03), and a longer length of stay (41 and 31 days, respectively; P = .04). There was no significant difference in cost between whites and nonwhites adjusting for these factors. Medicare or Medicaid patients had a higher cost of transplantation compared with those with commercial insurance. The cost of liver transplantation was similar for whites and nonwhites.

Use of transjugular intrahepatic portosystemic shunt as a bridge to liver transplantation in a patient with severe hepatopulmonary syndrome.

Hepatopulmonary syndrome (HPS) is defined by the presence of the triad of liver disease, arterial hypoxemia, and intrapulmonary vascular dilatation. The clinical implication of this disorder is impairment of gas exchange. Numerous reports in the literature show that this condition is reversible with orthotopic liver transplantation (OLT). However, patients with HPS often present with PaO(2) levels that are quite low. OLT with a preoperative PaO(2) less than 50 mm Hg is associated with unacceptably high mortality and morbidity. We report a case of severe HPS in which a transjugular intrahepatic portosystemic shunt was successfully used to improve oxygenation, thus allowing a successful elective OLT.

Primary Gianturco stent placement for inferior vena cava abnormalities following liver transplantation.

PURPOSE: To determine the efficacy of primary Gianturco stent placement for patients with inferior vena caval (IVC) abnormalities following liver transplantation. MATERIALS AND METHODS: From August 1996 through March 1999, nine adult patients developed significant IVC abnormalities following liver transplantation. Patients were referred for vena cavography on the basis of abnormal clinical findings, laboratory values, liver biopsy results, Doppler findings, or a combination. Those patients demonstrating a significant caval or hepatic venous gradient were treated with primary Gianturco stent placement. Patients were followed clinically (nine patients), with duplex ultrasound (nine patients), vena cavography (four patients), and biopsy (seven patients). RESULTS: Original pressure gradients ranged from 3 to 14 mm Hg, with a mean of 9 mm Hg. Gradients were reduced to 3 mm Hg or less in all nine patients; presenting signs and symptoms either resolved or improved in eight of nine patients. The ninth patient required repeated transplantation 2 days later. A second patient died 433 days after stent placement of recurrent hepatitis C. Another initially improved following caval stent placement, but underwent repeated transplantation 7 days later due to hepatic necrosis from hepatic arterial thrombosis. Follow-up for the remaining six patients has averaged 491 days, with no clinical, venographic, or ultrasound evidence for recurrent caval stenosis. CONCLUSIONS: Intermediate term results suggest that primary Gianturco stent placement for IVC stenosis, compression, or torsion resulting after liver transplantation is safe and effective.

Technique of right laparoscopic donor nephrectomy: a single center experience.

The majority of laparoscopic donor nephrectomies (LDNs) are limited to the left side due to technical and allograft concerns in using the right. We review our experience with right LDNs. Since June 1997, 15 right LDNs were performed and the records retrospectively reviewed for demographics, operative time, transfusions, complications, and length of stay. Recipient records were also reviewed for delayed graft function, complications, and serum creatinine levels. Overall donor, recipient and graft survivals at 6 months are 100%. Mean operative time was 317 +/- 11.0 min, length of stay was 4.2 +/- 0.2 d, and mean serum creatinine levels at discharge, 1, 3, and 6 months were 1.74 +/- 0.19, 1.59 +/- 0.13, 1.72 +/- 0.13, and 1.68 +/- 0.13 mg/dL, respectively. No transfusions were required. There were no operative or hospital complications. Two recipients (13.3%) experienced delayed graft function, defined as requiring hemodialysis post-transplantation. With hand-assisted laparoscopy, the right laparoscopic donor nephrectomy is safe and allows excellent allograft function.