Update on preservation of liver grafts.
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Biomedical subjects
Publications and source records attributed to M Kalayoglu.
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Venoocclusive disease of the liver (VOD) is a well-described complication following chemotherapy. It is manifested by jaundice and signs of portal hypertension and carries a mortality rate approaching 50%. There is no known treatment for the disease itself, although several recent reports suggest portacaval diversion may be effective in treating its sequelae. A 6.75-kg 8-month-old boy with VOD following bone marrow ablation and bone marrow transplantation (BMT) for juvenile chronic myelogenous leukemia (JCML) is presented. Over a 6-week period following bone marrow ablation he developed ascites refractory to diuretics, jaundice, and hematemasis with normal hepatocellular function. Splenectomy with a central splenorenal shunt was performed, which resulted in a significant reduction in portal pressures and complete resolution of his ascites and hematemasis without resultant encephalopathy. We propose that central end-to-side splenorenal shunting is an acceptable treatment for portal hypertension due to VOD and can be successfully performed in infants.
The development of the University of Wisconsin (UW) cold storage solution has extended safe preservation of the liver and pancreas from 6 to 24 hours or more. From May 1987 until November 1991, 288 livers and 163 simultaneous pancreas/kidney transplants were performed using UW solution. The mean preservation times were: liver, 12.7 +/- 4.4 hours, pancreas 17.2 +/- 4.4 hours, and kidney, 19.2 +/- 4.3 hours. Included in this series were 35 reduced-sized liver transplants, 7 cluster transplants, and 132 combined liver/pancreas retrievals. No differences in allograft function or graft-related complications were seen in organs preserved for less than or longer than 12 hours or in grafts from combined liver/pancreas retrievals. All pancreas/kidney transplants and most liver transplants were performed semi-electively. Actuarial 1-month patient and graft survival after liver transplantation was 91.4% and 80.2%, and at 4 years was 74.0% and 62.0%, respectively. After pancreas/kidney transplantation, the actuarial patient survival at 1 month and 4 years was 99.4% and 90.5%, respectively, whereas pancreatic and renal allograft survival at 1 month was 97.5% and 96.8%, and at 4 years was 83.0% and 83.4%, respectively. The ability to extend preservation times with UW solution has many advantages; however, the most important contribution of UW solution to clinical transplantation has been the increased utilization of scarce donor organs for more recipients because the previously imposed constraints on preservation time have been removed.
We retrospectively analyzed 526 primary cadaver recipients transplanted at a single center to identify pretransplant variables that predict long-term survival with multivariate analysis. All recipients received at least three random blood transfusions and were treated under a quadruple-therapy protocol consisting of ALG, azathioprine, prednisone, and cyclosporine. Of 526 consecutive transplants, 86 grafts were lost from acute or chronic rejection. Thirteen grafts were lost for nonimmunologic reasons and 35 recipients died with a functioning graft. A total of 273 patients (52%) experienced at least one episode of acute rejection. Donor age ranged from 3 to 64 years, with 62% of donors less than 30 years of age and 9% of donors over 50 years of age. Donor age was not predictive of long-term graft survival and neither was the difference between donor and recipient age. Recipient age was predictive of subsequent immunologic graft less, with younger recipients at greater risk (P = 0.011). The rate of first rejection was also inversely related to recipient age, with younger recipients rejecting earlier (P = 0.0001). The degree of DR mismatch was the only other significant predictor of long-term graft success (P = 0.013). Transplant survival correlated with the degree of DR mismatch: 2 DR mismatch was the worst, 1 DR mismatch was intermediate and 0 DR mismatch was the best (P = 0.02). A, B, AB, and BDR did not influence long-term graft outcome. In our center, donor age does not predict graft failure. Younger recipients have a higher rate of early rejection and, combined with a poor DR match, are at higher risk for long-term graft failure.
Hyperlipidemia is a well-recognized complication of renal transplantation. In long-term survivors of renal transplantation, cardiovascular disease accounts for the majority of patient deaths. In the cyclosporine era, cardiovascular disease has surpassed infection as the number one cause of death. Risk factors in the transplant population for hyperlipidemia include age, male sex, diabetes, prednisone dose, graft impairment, obesity, and antihypertensive therapy. Recently, cyclosporine has been implicated as an aggravating factor in the development of hyperlipidemia after transplantation, although its role has been controversial. Because renal transplant recipients have other significant risk factors for the development of coronary artery disease, the amelioration of hyperlipidemia may improve long-term patient survival. Because most late deaths occur in patients with a functioning graft, long-term graft survival could also be improved. The role of corticosteroids in the development of hyperlipidemia is well established. Recent studies employing corticosteroid withdrawal after transplantation have shown a marked reduction in cholesterol despite the use of cyclosporine. Data on corticosteroid withdrawal in living related transplants at our center show a significant reduction in total cholesterol after steroid withdrawal. Data from heart transplant recipients under corticosteroid-free protocols show a similar reduction in total cholesterol. Other treatments for hyperlipidemia include diet and cholesterol-lowering agents, such as Mevacor (lovastatin; Merck Sharp & Dohme, West Point, PA). The efficacy of lowering cholesterol in this high-risk population is unknown.
BACKGROUND: Alcoholism is the leading cause of end-stage liver failure in the United States, but the application of liver transplantation to the treatment of alcoholic liver disease remains controversial because of medical and ethical concerns. Information about the outcome of patients who undergo transplantation for alcoholic cirrhosis would help to resolve these concerns. METHODS: The results of 41 patients (Group 1) with alcoholic liver disease were compared with those of patients who underwent liver transplantation for other medical problems (group 2) at this center. Thirty of the 32 survivors from group 1 and 30 matched subjects from group 2 were interviewed to assess substance dependence, recidivism, and activity level. RESULTS: Compared with control subjects, patients with alcoholic liver disease had equivalent patient and graft survival rates and achieved an equal level of postoperative health. These results were achieved even though patients with alcoholic liver disease had significantly worse liver failure and more morbidity before surgery, and one third of the patients in this group were not abstinent before transplantation. CONCLUSIONS: We conclude that patients with alcoholic liver disease merit equal consideration for liver transplantation compared with other causes of liver failure. Treatment of the addictive disorder should be included before and after surgery.
BACKGROUND: Bladder drainage has become the procedure of choice for 94% of transplant centers in North America. Bladder drainage is superior to other techniques as far as graft survival and technical success are concerned; however, the procedure is associated with significant urologic problems that might necessitate conversion to enteric drainage. This review summarizes the indications and results for enteric conversion at this institution. METHODS: Between June 1982 and January 1992 a total of 240 pancreas transplantations were performed at our center. In 229 cases exocrine secretions were drained into the bladder. These cases were reviewed, and those with enteric conversions were further analyzed to delineate indications, complications, and results. RESULTS: Sixteen (7%) were converted to enteric drainage (side-to-side duodenojejunostomy). The reasons for conversion were urethral disruption (six), recurrent urine leaks (five), bleeding (four), and chronic urinary tract infection (one). Enteric conversions were performed between 1 1/2 and 32 months after the initial transplantation. With the exception of one anastomotic leak resulting in an intraabdominal abscess, no complications occurred. All patients undergoing enteric conversions had resolution of their problems and, in addition, were able to discontinue use of oral bicarbonate. CONCLUSIONS: We conclude that enteric conversion after pancreas transplantation with bladder drainage is safe and effective in the correction of urologic problems. Based on our experience, we recommend early enteric conversion if urologic problems do not resolve after an appropriate period of conservative therapy.
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The current role of liver transplantation in treating malignant tumors of the liver is uncertain, except for select histologic types. Pooled data on the results of liver transplantation in 12 children with hepatoblastoma is presented here. One half of the children are alive 24 to 70 (44 +/- 19) months after transplantation with no evidence of recurrence. Three patients (25%) died of tumor recurrence and three (25%) died of other causes. Unifocal and intrahepatic tumors were associated with better prognosis compared to the multifocal tumors and tumors with extrahepatic spread (p = 0.04 and 0.13). Microscopically vascular invasion and the predominance of embryonal and/or anaplastic epithelium were associated with a poor prognosis compared to the tumors with no vascular invasion and with predominantly fetal epithelium (p = 0.08 and 0.1). It is concluded that continued efforts to treat unresectable hepatoblastomas by liver transplantation is justified and the role of adjuvant chemotherapy in improving the results needs to be better defined.
From December 1985 to December 1989, 100 consecutive simultaneous pancreas-kidney (SPK) transplants were performed at the University of Wisconsin Hospital and Clinics. Bladder drainage technique was used for all grafts. One- and three-year patient survival was 93% and 90%; kidney survival, 90% and 85%; and pancreas survival, 86% and 84%. Quadruple immunosuppressive therapy was used in all patients and consisted of either MALG or OKT3 induction, and cyclosporine, prednisone, and azathioprine maintenance therapy. OKT3 induction therapy was used in 42 patients and Minnesota antilymphocyte globule in 58 patients, with equivalent results except for more opportunistic infection with OKT3. The duodenal button technique was used in the first 17 patients with systemic anticoagulation and was associated with significantly more postoperative bleeding and infection compared with the duodenal segment technique. The most common surgical complication of the duodenal segment technique was urine leak (13%), which usually occurred from the distal duodenal segment. The most common urologic complication of bladder drainage was hematuria (13%), which was usually self-limited. Within 6 months of transplantation, 84% of patients developed urinary tract infections, and 25% of patients had opportunistic infections. The surgical techniques and immunosuppressive methods used in this series are reviewed, and strategies for preventing medical and surgical complications are outlined.
Methods of accurately assessing the suitability of donor livers prior to transplantation are required if the incidence of primary nonfunction (PNF) is to be reduced. This study evaluated the ability of donor liver biopsies to predict the development of primary nonfunction after transplantation. From June 1987 until May 1990, 170 liver transplants were performed in 147 patients. A total of 124 donor liver biopsies were obtained and divided into three groups. Group 1 biopsies (n = 77) were obtained after revascularization of the liver, group 2 biopsies (n = 19) were obtained prior to donor hepatectomy but examined only after implantation, and group 3 biopsies (n = 28) were obtained as in group 2, but were examined prior to implantation. Three of 89 (3.4%) livers interpreted as having normal histology developed primary nonfunction, while one of 26 (3.8%) biopsies interpreted as having a minimal or moderate amount of fatty infiltration developed primary nonfunction. PNF occurred in 7 of 8 livers with severe fatty infiltration (3), hydropic degeneration (3), and centrilobular necrosis (1). A fourth liver with hydropic degeneration and poor function ultimately failed requiring retransplantation 8 weeks later. Analysis of liver function revealed progressive elevation in aspartate-aminotransferase, alanine-aminotransferase, lactate dehydrogenase, and serum ammonia (NH3) with increasing degrees of fatty infiltration. Donor age and weight was also found to be significantly higher in livers with fatty infiltration. This study suggests that donor liver biopsies demonstrating normal histology or minimal-to-moderate fatty infiltration function adequately, but that donor livers with severe fatty infiltration or hydropic degeneration function poorly and should not be transplanted.
A total of 127 haploidentical living-related transplants have been performed at our institution since March 1986. A donor-specific transfusion plus azathioprine protocol was used until July 1988 (n = 74) and a random transfusion (RT) protocol without AZA used thereafter (n = 53) in an effort to decrease risk of recipient sensitization and reduce the burden on the prospective donor. All patients were given cyclosporine 8 mg/kg/day orally beginning 1 week prior to transplantation. Immunosuppression was similar in both groups and consisted of triple induction therapy with prednisone, CsA, and AZA. A positive T cell crossmatch eliminated the potential donor. Seven individuals (9.6%) were sensitized in the DST group and 1 (1.9%) in the RT group, leaving 67 and 52 patients in the two groups of the study, respectively. Groups were similar with respect to age, sex, history of pregnancy in female patients, peak and baseline panel-reactive antibody (PRA), DR match, and prior transplants. The groups differed slightly with respect to AB antigens shared, with an advantage in the RT group. Actuarial graft survival was not statistically significantly different between the two groups, with 2-year graft survival of 95% in the DST and 91% in the RT group (log rank, P = 0.16). Patients in the RT group had significantly more rejection episodes and had them sooner than their counterparts in the DST group. At the end of 1 year, 50% of patients in the DST group had at least 1 rejection episode, compared with 75% of patients in the RT group (P = 0.0008). Multivariate (Poisson) analysis of 10 variables was performed, with an overall model P-value of 0.0001. Only DST (P = 0.0001) and pregnancy (P = 0.015) were significant predictors of rejection episodes, both protective. The difference in rejection episodes and the timing with which they occur has not yet translated into a significant difference in graft survival between DST and RT groups.
Cyclosporine appears to have abrogated age as a contraindication to kidney transplantation in the elderly, although it is unclear whether this is true for other types of solid organ transplantation. We performed a retrospective analysis of liver transplant recipients who were 60 years of age and older (n = 23) versus recipients of primary transplants who were 18 to 59 years of age (n = 84). Indications in recipients over 60 included alcoholism (6), postnecrotic cirrhosis (6), cancer (4), primary biliary cirrhosis (3), sclerosing cholangitis (2), and one patient with polycystic liver disease. There were no important differences in the initial transplant hospitalization or the incidence of infection and rejection between the two groups. No patient in the over-60 population required retransplantation. Actuarial patient survival is 83% at 2 years for recipients 60 years of age and above compared to 76% patient survival in adult recipients who are under the age of 60. Liver transplant recipients over the age of 60 years have excellent patient and graft survival and the same postoperative morbidity as recipients who are under 60 years of age. Therefore, advanced age does not appear to be a contraindication to orthotopic liver transplantation.
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