Biomedical subjects
P McMaster
Publications and source records attributed to P McMaster.
Use of grafts procured from organ transplant recipients.
BACKGROUND: Massive intracerebral bleeding may cause brain stem death in transplant (Tx) recipients early or late postTx. We addressed the question as to whether Tx recipients may safely be used as organ donors. In particular, it is feared that exposure to immunosuppressive drugs may render those organs unsuitable for Tx. METHODS: We reviewed two case reports of liver grafts procured from Tx patients. In addition, we conducted a survey within United Kingdom Transplant Support Service Authority (UKTSSA) to delineate the UK experience in that area. RESULTS: Donor 1 was an 50-year-old heart Tx recipient who became brain stem dead due to cerebral bleeding 8 months postTx. His liver was used in an 55-year-old patient with PBC who is alive and well more than 22 months postTx. Donor 2 was a 22-year-old kidney Tx patient who developed cerebral bleeding 4 years postTx. His liver was used in a 65-year-old patient with PBC who is doing well more than 27 months postTx. During the study period of 1989-1995, 13 organs (9 kidneys, 3 hearts, 1 liver) were procured from 6 brain stem dead Tx patients (3 long, 2 heart, and 1 kidney Tx patients). Seven recipients are enjoying satisfactory graft function 1 to 7 years postTx; one kidney Tx recipient was relisted 4 years postTx due to chronic rejection; five functionning grafts were lost to patient death; primary nonfunction was seen in one heart Tx recipient. CONCLUSIONS: Tx patients can be successfully used as organ donors. In particular, chronic exposure to immunosuppression is not per se a contraindication to donation. Tx physicians confronted with the rare and tragic event of brain stem death in a Tx patient should not a priori exclude these patients from donation.
Immunosuppressive effect of combination schedules of brequinar with leflunomide or tacrolimus on rat cardiac allotransplantation.
Drug toxicity is one of the major problems in clinical immunosuppression. Combining two immunosuppressants in low or ineffective doses is an attractive strategy if it helps to reduce drug-related toxicity. We examined the immunosuppressive efficacy of brequinar (BQR) in combination with leflunomide (Lef) or tacrolimus (FK) in a heterotopic rat cardiac allotransplantation model. Abdominal heterotopic heart grafts (DA x LEW) were immunosuppressed from the time of transplantation and continued until the ninth posttransplant day (POD) in experiments examining prophylaxis of rejection treatment (PRT). In a separate series of experiments designed to test rescue treatment (RT), immunosuppression was begun on POD 4 and continued for 10 days; transplanted rats were sacrificed the following day intentionally. Cardiac rejection was monitored by palpation and documented by light microscopy. Immunosuppressive drugs (BQR 3 mg/kg and 12 mg/kg; BQR 3 mg/kg + Lef 5 mg/kg; BQR 3 mg/kg + FK 0.5 mg/kg) were given orally by gavage; thrice weekly according to the monotherapy or dual-therapy dosing protocol. Median survival time of the cardiac graft for controls (no treatment) was 5 days. BQR monotherapy 3 mg/kg (low dose) improved graft survival (P = 0.003); graft histology showed moderate acute rejection. BQR monotherapy 12 mg/kg (therapeutic dose) application in the PRT or RT treatment arms of the study design resulted in aortic-graft ruptures and clinical toxicity in each treatment arm due to overimmunosuppression; normal graft morphology was maintained. Successful rescue of rejecting grafts was histologically documented. Combining BQR with Lef or FK in the PRT protocol showed prolonged graft survival in both drug combination groups (median survival time, 14 days; P = 0.009 and 0.014, respectively). Using an identical combination protocol for RT, all grafts achieved a 14-day graft survival; cardiac histology showed reversible moderate acute rejection. BQR given in the presence of Lef or FK not only prevented acute rejection but intercepted it so long as it was administered; grafts were rejected within 4 days of stopping immunosuppression in the PRT study. These combinations using low or subtherapeutic doses may be important for controlling transplant rejection and rescuing ongoing graft rejection. The need for continuing treatment in this strongly allogeneic model is highlighted.
Outcome of liver retransplantation in children.
Irreversible liver graft failure is a life-threatening complication. We reviewed the first 200 pediatric liver transplantations in Birmingham. Forty-one children developed primary graft failure, 9 of whom developed secondary graft failure. The main indications for graft failure were primary nonfunction (PRNF; 8 patients), vascular complications (VASC; 23 patients), and chronic rejection (CHRE; 19 patients). Thirty-two children underwent retransplantation (ReTx) (21 children received reduced grafts; 11 children, whole hepatic grafts). Patient survival was significantly worse for retransplant recipients compared with children receiving a single graft (63% v 76. 5% actuarial patient survival at 1 year; P <.05). Primary graft 1-year actuarial survival was 74% in first grafts compared with 47% for regrafts (P <.05), but improved with time. The graft 1-year survival rate was 55% for whole grafts and 45% for reduced and/or split grafts in the first 100 grafts compared with 83% and 66% in the second 100 grafts, respectively (P <.01). Emergency ReTx within a month of transplantation was associated with more complications and a worse outcome (1-year survival rate, 37%) compared with patients who underwent ReTx later (1-year survival rate, 72%; P <. 01). The incidence of primary graft failure decreased from 33% in the first 100 grafts to 16% in the second 100 grafts (P <.01), as did the incidence of PRNF, which decreased from 8% to 0% (P <.05). Although the rates of graft failure from VASC decreased from 15% to 8% (P =.2) and CHRE decreased from 11% to 8% (P =.6), neither reached statistical significance. The improved results overall are because of advances in surgical techniques, intensive care management, and graft preservation and refinements in immunosuppression. We conclude that ReTx for a child with primary graft failure is justified.
Energy storage and cytokine response in patients undergoing liver transplantation.
Overproduction of pro-inflammatory cytokines during surgery has been known to exert tissue-damaging and lethal effects on the host. Hypermetabolism-associated malnutrition, a common feature of patients with end-stage liver diseases, is related to the presence of a systemic inflammatory response, as reflected by enhanced levels of proinflammatory cytokines. The present study was designed to evaluate energy status of 29 liver transplant recipients, and to assess the relation of energy storage to post-operative cytokine response. The glycogen contents of the graft, and the recipient's abdominal muscle and old liver were measured. The plasma concentrations of tumour necrosis factor alpha, interleukin 1beta, interleukin 6, lactate, pyruvate and total ketone bodies were determined during and after surgery. In undernourished patients, ketone bodies seemed to be the major fuel available to muscle. The concentration of ketone bodies decreased rapidly after the incision, and remained at a low level after reperfusion. These patients had higher plasma levels of lactate/pyruvate ratio and aromatic amino acids during the anhepatic phase, followed by an exaggerated response of cytokines. Depletion of energy storage of the recipients may be involved in the deterioration of peri-operative energy metabolism and the exaggerated post-operative cytokine response.
Effect of donor-specific transfusion in combination with FK 506 in rat cardiac allotransplantation.
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High pre-treatment serum hepatitis B virus titre predicts failure of lamivudine prophylaxis and graft re-infection after liver transplantation.
BACKGROUND/AIMS: Orthotopic liver transplantation has an established role for the treatment of patients with chronic liver failure secondary to hepatitis B virus (HBV) infection. Unfortunately, recurrent infection of the graft can be associated with aggressive disease, and with diminished graft and patient survival. Currently, the role of nucleoside analogues for prevention of graft re-infection is being evaluated. Preliminary results are encouraging, but treatment failure has been associated with emergence of drug-resistant virus. METHODS: We have studied ten consecutive patients who received lamivudine prophylaxis for prevention of HBV graft reinfection. Sequential sera, collected prelamivudine then during treatment before and after liver transplantation, were examined. Conventional serological markers were measured, as were serum viral DNA levels with a sensitive quantitative polymerase chain reaction assay. RESULTS: Lamivudine treatment effected a reduction in serum HBV levels, but six patients still had measurable viral DNA at the time of transplantation. Five patients developed graft re-infection with lamivudine-resistant virus. Resistant virus emerged 8 to 15 months post-transplant. The likelihood of emergence of resistant virus was related to the pre-treatment serum HBV titre. Persistent serum viral DNA positivity and evidence of graft re-infection during the early post-transplant period did not predict the subsequent emergence of resistant virus. CONCLUSIONS: Our observations suggest that the resistant species may be present in the viral quasispecies in the serum and liver of patients with high-level replication prior to lamivudine exposure. The resistant species can persist during lamivudine treatment prior to transplantation, and emerge following transplantation. These observations suggest strategies which might prevent the emergence of drug-resistant species, and imply that graft re-infection may be a preventable phenomenon.
Hyperekplexia: a rare differential of neonatal fits described in a developing country.
Hyperekplexia is a rare condition in which there is an exaggerated startle response. We report how a case presented in Papua New Guinea (PNG) and was diagnosed with international support. This is the first reported case in PNG. It is an important diagnosis to make to prevent sudden death and inappropriate treatment. The case illustrates the benefit of having a link with an international specialist and we discuss the importance of communication between developing and industrialized countries.
Serum hepatocyte growth factor as an index of extensive catabolism of patients awaiting liver transplantation.
BACKGROUND: Whole body catabolism as the result of intrahepatic metabolic derangement is common in liver transplant candidates. However, individual nutritional assessment parameters lack sensitivity and specificity in determining energy status of these patients. Recently, serum hepatocyte growth factor (HGF) has been shown to reflect the recovery of hepatic energy metabolism after liver transplantation. AIMS: The relation between preoperative levels of serum HGF and metabolic variables was investigated to clarify the clinical value of measuring HGF in evaluations of the catabolism. PATIENTS/METHODS: Blood samples were obtained from 30 liver transplant recipients, and biopsy specimens were taken from each recipient's rectus muscle and the explanted liver. Preoperative serum concentration of HGF was determined. Whole body energy metabolism was assessed by measuring glycogen contents of biopsy specimens and plasma or serum levels of glucose, insulin, total ketone bodies, total carnitine, and amino acids. RESULTS: Serum HGF concentration was elevated in 22 of 30 patients and correlated with the Child-Pugh score. It showed a negative association with muscle glycogen content, and a positive correlation with serum levels of glucose, total carnitine, and total ketone bodies. Patients with elevated serum HGF concentrations had higher preoperative plasma levels of aromatic amino acids and branched chain amino acids, associated with lower branched chain to aromatic amino acid ratios. CONCLUSIONS: The elevated serum concentration of HGF in liver transplant candidates reflected inhibition of peripheral glucose storage, enhanced lipid oxidation, and increased peripheral release of branched chain amino acids, and thus extensive energy catabolism.
Withdrawal of immunosuppression in liver allograft recipients.
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Hepatocellular cancer: resection or transplantation.
Surgery remains the treatment of choice for hepatocellular carcinoma (HCC). For HCC without underlying cirrhosis resection remains the mainstay treatment option. Prognosis depends on the stage of the tumor. Survival appears to be better for small (less than 5 cm) solitary tumors with negative resection margins and absence of vascular invasion. At present, liver transplantation does not have an established role in the treatment of HCC in a non-cirrhotic liver. Because of the high recurrence rate, it should not be considered for more advanced disease which is not amenable to resection. The surgical approach in cirrhotics depends not only on the stage of the tumor but also on the liver functional reserve. Tumor size, presence of multifocal disease, and vascular invasion determine the risk of HCC recurrence after resection, and the functional stability of the liver determines both resectability and outcome. In societies in which transplantation is not available, small tumors will be treated with liver resection. The outcome in patients with well preserved liver function is relatively good, at least in the medium term. However, recurrent tumor and progressive hepatic decompensation have significant adverse effects on long-term survival. Poor functional reserve may be associated with significant perioperative mortality and lower survival due to progressive liver failure. In our opinion, for small cirrhosis-related HCCs, liver transplantation offers better long-term prospects than resection. Therefore, if liver transplantation is available as an option it should be considered as the treatment of choice, particularly for younger patients with otherwise good life expectancy.
Effect of peritransplant FTY720 alone or in combination with post-transplant tacrolimus in a rat model of cardiac allotransplantation.
FTY720 is a recently discovered compound that is derived from the fungus Isaria sinclairii. Using a DA donor-to-LEW recipient rat combination, we assessed the efficacy of peritransplant FTY720 alone or in combination with post-transplant tacrolimus on the survival of cardiac allografts. Peritransplant FTY720 given orally at a dose of 5 mg/kg on days-1 and 0 prolonged graft survival from 5 to 13 days (P < 0.05). Combining peritransplant FTY720 with post-transplant tacrolimus resulted in a further prolongation of allograft survival. The lymphocyte count in transplanted rats decreased within 24 h to 46.6%. Analysis of lymphocyte subsets by FACS revealed that FTY720 affected the total population of CD3-bearing T cells while the ratio of CD4 to CD8 cells remained unchanged. Kidney and liver biochemistry remained elevated for 2 weeks. In conclusion, FTY720 is a powerful immunosuppressive agent when used as induction therapy and may have an additive effect--perhaps a synergistic one--with post-transplant tacrolimus.
Repeat orthotopic liver transplantation in the 1990s: is it justified?
Repeat orthotopic liver transplantation (ReOLT) is controversial because of limited donor organ availability and increasing health care costs. The purpose of this study is to analyse and compare the outcome of reOLT in the 1990s and the 1980s. Prospective data of 1077 adult OLT from the Liver Unit database were used for the study. The log-rank test was used for statistical analysis. Between January 1982 and December 1996, a total of 1077 adult OLTs were performed including 107 reOLTs. The proportion of retransplants decreased from 13% in the 1980s to 9% in the 1990s. There was a significant improvement in outcome; the overall 1-year graft and patient survival for reOLT was 60% and 74% in the 1990s compared to 29% (P < 0.0001) and 51% (P < 0.0001) in the 1980s. In the second half of the study between January 1990 and December 1996, 732 adult OLTs were undertaken including 70 (9%) reOLTs which consisted of 62 second, 7 third and 1 fourth grafts. The main indications for retransplantation were chronic rejection (31%), hepatic artery thrombosis (30%), primary non-function (16%), ischaemic injury (11%), recurrent disease (6%) and biliary complications (6%). During this period, the 1-year graft survival for all reOLTs was significantly lower than for primary OLTs (67% vs 78%, P < 0.001). The timing of reOLT was found to be associated with graft survival; 1-year graft survival for early reOLT (< 30 days) was 50% compared to 73% for late reOLT (P < 0.001). The worse outcome associated with early reOLT is explained by the poor preoperative medical condition of patients who were retransplanted from intensive care. Subgroup analysis of indications for reOLT revealed 1-year graft survival of 81% for late vascular complications, 75% for early vascular complications, 69% for chronic rejection and 30% for primary non-function. One-year graft survival rates for third and fourth grafts were 42% and 0%, respectively. Graft survival and resource utilisation in patients who received a late regraft for the first time is now comparable to that for primary OLT. The favourable overall results should not preclude this group of patients from consideration for reOLT.
Maintained function of primary human hepatocytes by cellular interactions in coculture: implications for liver support systems.
The application of primary hepatocytes in hybrid artificial liver systems has been hampered by the gradual loss of differentiated morphology and function in vitro. Therefore, we have established a coculture model of autologous human hepatocytes and biliary epithelial cells (BEC) in collagen gel in the presence of hepatotrophic growth factors. Furthermore, we examined the effect of hepatocyte cell perfusion in a women multicompartment capillary membrane system. Normal hepatocytes isolated from human liver produced albumin for more than 2 weeks in serum-free media, and were further stimulated by conditioned medium. When cocultured with BEC, albumin secretion was greatly enhanced, suggesting that cellular interactions promote tissue-specific differentiation. When perfused in bioreactors, albumin levels were maintained at steady state for longer than 2 weeks. These data indicate that differentiation of primary hum hepatocytes can be maintained by coculture interactions and three-dimensional hybrid organ devices, providing appropriate growth factors and matrix for tissue regeneration.
Donor-specific blood transfusion does not enhance the effect of FTY720 in rat cardiac allotransplantation.
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Liver transplantation: changing goals in immunosuppression.
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Perihepatic packing in liver transplantation.
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FTY720 compares with FK 506 as rescue therapy in rat heterotopic cardiac transplantation.
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