Hector Ramos

Systemic chimerism in human female recipients of male livers

We have previously reported data from clinical and laboratory animal observations which suggest that organ tolerance after transplantation depends on a state of balanced lymphodendritic cell chimerism between the host and donor graft. We have sought further evidence to support this hypothesis by investigating HLA-mismatched liver allograft recipients. 9 of 9 female recipients of livers from male donors had chimerism in their allografts and extrahepatic tissues, according to in-situ hybridisation and molecular techniques 10 to 19 years posttransplantation. In 8 women with good graft function, evidence of the Y chromosome was found in the blood (6/8), skin (8/8), and lymph nodes (7/8). A ninth patient whose transplant failed after 12 years from recurrent chronic viral hepatitis had chimerism in her lymph nodes, skin, jejunum, and aorta at the time of retransplantation. Although cell migration is thought to take place after all types of transplantation, the large population of migratory cells in, and the extent of their seeding from, hepatic grafts may explain the privileged tolerogenicity of the liver compared with other organs.

Chimerism and donor-specific nonreactivity 27 to 29 years after kidney allotransplantation

Chimerism was demonstrated with immunocytochemical and/or polymerase chain reaction techniques in kidney allografts and in the native skin, lymph nodes, or blood of 5 of 5 patients who received continuously functioning renal transplants from 1 or 2 haplotype HLA mismatched consanguineous donors (4 parents, 1 aunt) 27–29 years ago. In the 4 cases where the kidney donor still was alive to provide stimulator lymphocytes for testing, these provoked no (n=2) or modest (n=2) MLR in contrast to vigorous MLR to third party lymphocytes. In all 4 cases, the donor cells failed to generate in vitro cytotoxic effector cells (cell-mediated lymphocytotoxicity). These findings are in accord with the hypothesis that cell migration, repopulation, and chimerism are seminal events that define graft acceptance and ultimately can lead to acquired donor-specific nonresponsiveness (tolerance).

Weaning of immunosuppression in long-term liver transplant recipients.

Seventy-two long-surviving liver transplant recipients were evaluated prospectively, including a baseline allograft biopsy for weaning off of immunosuppression. Thirteen were removed from candidacy because of chronic rejection (n = 4), hepatitis (n = 2), patient anxiety (n = 5), or lack of cooperation by the local physician (n = 2). The other 59, aged 12-68 years, had stepwise drug weaning with weekly or biweekly monitoring of liver function tests. Their original diagnoses were PBC (n = 9), HCC (n = 1), Wilsons disease (n = 4), hepatitides (n = 15), Laennecs cirrhosis (n = 1), biliary atresia (n = 16), cystic fibrosis (n = 1), hemochromatosis (n = 1), hepatic trauma (n = 1), alpha-1-antitrypsin deficiency (n = 9), and secondary biliary cirrhosis (n = 1). Most of the patients had complications of long-term immunosuppression, of which the most significant were renal dysfunction (n = 8), squamous cell carcinoma (n = 2) or verruca vulgaris of skin (n = 9), osteoporosis and/or arthritis (n = 12), obesity (n = 3), hypertension (n = 11), and opportunistic infections (n = 2). When azathioprine was a third drug, it was stopped first. Otherwise, weaning began with prednisone, using the results of corticotropin stimulation testing as a guide. If adrenal insufficiency was diagnosed, patients reduced to < 5 mg/day prednisone were considered off of steroids. The baseline agents (azathioprine, cyclosporine, or FK506) were then gradually reduced in monthly decrements. Complete weaning was accomplished in 16 patients (27.1%) with 3-19 months drug-free follow-up, is progressing in 28 (47.4%), and failed in 15 (25.4%) without graft losses or demonstrable loss of graft function from the rejections. This and our previous experience with self-weaned and other patients off of immunosuppression indicate that a significant percentage of appropriately selected long-surviving liver recipients can unknowingly achieve drug-free graft acceptance. Such attempts should not be contemplated until 5-10 years posttransplantation and then only with careful case selection, close monitoring, and prompt reinstitution of immunosuppression when necessary.

Single-center experience with primary orthotopic liver transplantation with FK 506 immunosuppression.

OBJECTIVE The efficacy for primary orthotopic liver transplantation of a new immunosuppressive agent, FK 506 (tacrolimus, Prograf, Fujisawa USA, Deerfield, IL), was determined. SUMMARY BACKGROUND DATA After 3 years of preclinical research, a clinical trial of FK 506 for orthotopic liver transplantation was begun in February 1989, first as a rescue therapy for patients with intractable rejection with conventional immunosuppression, then as a primary drug. METHODS Between August 1989 and December 1993, 1391 recipients (1188 adult and 203 pediatric) of primary liver allografts were treated with FK 506 from the outset. Results from these patients were analyzed and compared with those of 1212 historical control patients (971 adult and 241 pediatric) given cyclosporine-based immunosuppression. RESULTS Actuarial survival at 4 years was 86.2% with FK 506 versus 65.5% with cyclosporine in the pediatric patients (p < 0.0000) and 71.4% versus 65.5% in the adults (p < 0.0005). The need for retransplantation was reduced significantly for FK 506 patients. Four-year graft survival was 77.0% with FK 506 versus 48.4% with cyclosporine in the pediatric patients (p < 0.0000), and 61.9% with FK 506 versus 51.4% with cyclosporine in the adult recipients (p < 0.0000). Regression analysis revealed that reduction in mortality or graft loss from uncontrollable rejection, sepsis, technical failure, and recurrent original liver disease were responsible for the improved results with FK 506 therapy. CONCLUSIONS FK 506 is a potent and superior immunosuppressive agent for orthotopic liver transplantation.

Combined liver-kidney transplantation and the effect of preformed lymphocytotoxic antibodies.

Thirty-eight sequentially placed liver and kidney allografts were evaluated with respect to patient and graft survival, and the influence of preformed lymphocytotoxic antibodies was analysed. The results suggest that the survival rate of combined liver and kidney transplantation is similar to the survival rate of liver transplantation alone. Sequentially placed kidney allografts may be protected from hyperacute rejection in the presence of donor specific lymphocytotoxic antibodies, but not in all instances. Both patient and kidney allograft survival was lower in positive crossmatch patients (33% and 17% respectively) than in negative crossmatch patients (78% and 75%). High levels of panel reactive antibodies (> 10%) also appeared to have a deleterious effect on survival, although the majority of the patients who failed also had a positive crossmatch. Although performed lymphocytotoxic antibodies are not an absolute contraindication to combined liver-kidney transplantation, they do appear to have a deleterious effect on long-term graft survival. However, more correlation with clinical parameters is needed.

Early tolerance in pediatric liver allograft recipients.

The authors report on six pediatric liver transplant recipients for whom allograft tolerance occurred shortly after transplantation (ie, less than 1.5 years). All the patients had associated life-threatening viral complications. They are currently immunocompetent. The tolerant state may be related to the development of a TH2 cytokine pattern.

Dissecting pseudoaneurysm of the hepatic artery: A delayed complication of angioplasty in a liver transplant

We report a 59-year-old female with a dissecting pseudoaneurysm of the allograft hepatic artery, as a delayed complication of percutaneous transluminal angioplasty (PTA). PTA of a severe anastomotic stenosis was successful, but complicated by a dissection involving the allograft hepatic artery. A large dissecting pseiidoaneurysm developed and was incidentally detected during routine sonographic evaluation 14 months after PTA. Because of the extent of the pseudoaneurysm, percutaneous repair or surgical reconstruction was considered impossible. The patient underwent successful retransplantation 1 week after diagnosis. Key words: Liver, transplantation-Hepatic arteries, stenosis or obstruction-Transluminal angioplasty-Aneurysm, hepatic

Allografts surviving for 26 to 29 years following living-related kidney transplantation: analysis by light microscopy, in situ hybridization for the Y chromosome, and anti-HLA antibodies.

We studied seven patients aged 14 to 40 years who received living-related kidney transplants and had allograft survivals of 26 to 29 years. The blood urea and creatinine were either within normal limits or marginally elevated. Histopathologic examination showed only mild mesangial expansion, interstitial fibrosis, and arteriosclerosis. Immunoperoxidase staining with anti-HLA antibodies or in situ hybridization with a Y chromosome probe showed persistence of donor tubular epithelium and vascular endothelium within the graft. Recipient-derived glomerular cells were seen in one case, and interstitial lymphocytic infiltrates were seen in all cases. A review of the clinicopathologic data available for these cases indicated that both central and peripheral immunologic mechanisms contributed to the maintenance of prolonged graft survival. This extended survival was independent of six antigen matching, down-regulation of donor HLA antigen expression, and ingrowth of host epithelium/endothelium into the allograft.

Transluminal ligation of bleeding angiodysplasia of the small bowel without need for surgical resection

SummaryThe use of intraoperative endoscopy to localize a site of recurrent intestinal bleeding is reported wherein, once identified, the lesion was managed surgically without an enterostomy but with transluminal suture ligation. This technique is particularly attractive for use in debilitated or elderly patients and those with advanced decompensated liver disease complicated by portal hypertension.