Jon W. Jones

Successful Hand Transplantation — One-Year Follow-up

Background On the basis of positive results in studies of the transplantation of pig extremities and the information exchanged at an international symposium on composite-tissue transplantation, we developed a protocol for human hand transplantation. Methods After a comprehensive pretransplantation evaluation and informed-consent process, the left hand of a 58-year-old cadaveric donor, matched for size, sex, and skin tone, was transplanted to a 37-year-old man who had lost his dominant left hand 13 years earlier. Immunosuppression consisted of basiliximab for induction therapy and tacrolimus, mycophenolate mofetil, and prednisone for maintenance therapy. Results The cold-ischemia time of the donor hand was 310 minutes. There were no intraoperative or early postoperative complications. Moderate acute cellular rejection of the skin of the graft developed 6, 20, and 27 weeks after transplantation. All three episodes resolved completely after treatment with intravenous methylprednisolone and topical tacrolimus...

Long-term survival of an extremity composite tissue allograft with FK506-mycophenolate mofetil therapy.

BACKGROUND High-dose tacrolimus (FK506) monotherapy has significantly prolonged rat hindlimb allograft survival. With an eye toward direct clinical application, we used a large-animal extremity composite tissue allograft model to assess the antirejection efficacy and systemic toxicity of combination FK506-mycophenolate mofetil (MMF) treatment. METHODS Radial forelimb osteomyocutaneous flap transplants were performed between size-matched outbred pigs assigned to one of two groups: 5 control pigs received no immunosuppression and 9 animals received a once-daily oral FK506-MMF-prednisone regimen. Rejection was assessed by visual inspection of flap skin and was correlated with serial histopathologic examination of skin biopsy specimens. RESULTS In all control pigs the flap was completely rejected on day 7. Of the 9 pigs receiving treatment, 3 died from pneumonia on days 29, 30, and 83 without signs of rejection and another died from gastric rupture on day 42 with persistent mild rejection. The remaining 5 animals were free of rejection at the end of the 90-day follow-up period (P < 0.005 vs controls). Overall, 5 pigs had pneumonia, 4 septic arthritis, 3 toe abscesses, and 5 diarrhea and decreased weight gain. CONCLUSIONS Combination oral FK506-MMF treatment provided a superior antirejection effect but more produced more toxicity than that previously demonstrated with cyclosporin A-MMF therapy in our model. Our results suggest that reduction of FK506 or MMF doses might decrease both infectious and drug-specific side effects while still providing adequate prophylaxis against rejection.

Long-term composite tissue allograft survival, in a porcine model with cyclosporine/mycophenolate mofetil therapy

BACKGROUND Low-dose cyclosporine (CsA)/mycophenolate mofetil (MMF) therapy has significantly reduced the frequency of rejection and drug-induced side effects in rat hindlimb allograft recipients. With an eye toward direct clinical application, we developed a large-animal extremity composite tissue allograft model to assess the antirejection efficacy and systemic toxicity of combination CsA/MMF treatment. METHODS Radial forelimb osteomyocutaneous flap transplants were performed between size-matched, outbred pigs assigned to one of two groups: 5 control pigs received no immunosuppression, and 10 pigs received a once-daily oral CsA/MMF/prednisone regimen. Rejection was assessed by visual inspection of flap skin and correlated with serial histopathologic examination of skin biopsies. RESULTS In all control pigs, the flap was completely rejected on day 7. Of the 10 pigs receiving treatment, one died from pneumonia and an another from an anesthetic complication on days 19 and 30, respectively, without signs of rejection. Two flaps were lost on days 25 and 29 from severe rejection. Three pigs were free of rejection at the end of the 90-day follow-up period, and three had stable mild-to-moderate rejection at 90 days (P= 0.0007 vs. controls). White blood cell and platelet counts, serum creatinine values, and liver function tests remained normal in all animals receiving immunosuppressive therapy. CONCLUSIONS Our results, to our knowledge, demonstrate for the first time that rejection can be significantly delayed in a large-animal composite tissue allograft model including skin using only orally administered agents dosed according to clinically relevant strategies without significant drug-specific systemic side effects.

Survival transplantation of preserved non???heart-beating donor rat livers: preservation by hypothermic machine perfusion1

Background. Non–heart-beating donor (NHBD) livers are an untapped source with the potential to provide relief to the current donor shortage problem. Hypothermic machine perfusion (MP) has the potential to reclaim and preserve these marginal donor organs. Methods. This study compared 5-day survival in a rat NHBD liver transplantation model with simple cold storage (SCS) and MP-preserved tissues that had experienced 30 min of warm ischemia followed by a 5-hr preservation period with the University of Wisconsin solution. Total release of lactate dehydrogenase (LDH) and alanine aminotransferase (ALT) were determined at major time points. Bilirubin levels and histology were examined after 5-day survival. Results. Six of seven control livers and five of six MP livers survived, whereas SCS tissues had survival in zero of seven. The results showed that MP livers had reduced release of LDH and ALT after 5 hr of storage, 5.07±1.42 and 2.02±0.69 U (mean±SE), respectively, compared with SCS, 15.54±0.81 and 3.41.3±0.73 U, respectively. Bilirubin values after 5-day survival of MP livers (1.17±0.49 mg/dL) were comparable to controls (0.91±0.36 mg/dL). Histology confirms that SCS displayed increased necrosis and MP tissue showed regions of near normal hepatic structure. Conclusions. These results suggest that MP for 5 hr improves survival and reduces cellular damage of liver tissue that has experienced 30 min of warm ischemia when compared with SCS tissues. Further studies need to be conducted, but this study suggests that MP preservation has the potential to reclaim and preserve NHBD liver tissues.

Use of Intravenous Immunoglobulin in Sensitized LVAD Recipients

HEART transplantation remains standard surgical therapy for select patients with end-stage heart failure. Due to longer waiting list times, an increasing number of potential recipients require mechanical circulatory support as a bridge to transplantation. However, placement of mechanical cardiac assist devices often leads to the use of multiple blood products and results in high levels of preformed cytotoxic alloantibodies to MHC class I antigen. We hypothesized that the use of intravenous immune gamma globulin (IVIG) would decrease the level of preformed cytotoxic alloantibodies. We report the use of IVIG in these highly sensitized patients awaiting heart transplantation on mechanical circulatory support.

A Facilitated Technique for Hepatectomy of Porcine Liver

The swine liver has been used for experimental transplantation and as an ex vivo support system for patients with fulminant hepatic failure. Preservation of liver function after the cold storage period can be accomplished by complying with several key steps during the procurement: Keep the procedure short, provide extensive exposure, allow only minimal dissection, irrigate the portal system through the splenic vein and thereby obtain regular blood flow through the organ up to the clamping point, and ice the liver abruptly in situ. This retrieval technique was used and evaluated in 10 pigs. The method allowed a short and successful organ procurement while preserving normal function of the liver ex vivo.

Success and complications of pancreatic transplantation at one institution.

OBJECTIVE The authors report the results and complications of the first 59 pancreas transplantation procedures performed at one institution. SUMMARY BACKGROUND DATA Pancreas transplantation is performed at relatively few centers. Results have improved in the past few years. METHODS A retrospective review was completed of the results and complications after pancreas transplantation at one institution. Pancreas transplantation was indicated for patients with insulin-dependent diabetes mellitus and who were younger than 50 years of age. The results were divided into era I (March 1987-December 1992) and era II (January 1993-October 1995). RESULTS Fifty-nine transplants were performed since March 1987. There were 45 combined kidney/pancreas transplants and 13 pancreas transplants. Graft survival at 1 year was 57% for those in era I versus 79% in era II. Rejection occurred in 74% of the patients in era I and 48% in era II. Eighty-five percent of all rejection episodes in both eras were steroid resistant and required antibody therapy. Complications were not different from eras I and II. CONCLUSIONS Pancreas transplantation is a successful procedure with a number of significant complications. Rejection episodes are most often steroid resistant.

Recovery of Energy Stores of Non-Heart-Beating Donor Livers Following Preservation by Hypothermic Machine Perfusion

The shortage of donor organs for liver transplantation requires investigations into expanding the donor pool. Non-heart beating donor (NHBD) livers are an untapped source of organs. NHBD organs are those that have had a period of warm ischemia prior to cold preservation. A main concern of NHBD livers is that there is a depletion of energy stores during the warm ischemia and subsequent cold storage. This study is to investigate the use of hypothermic machine perfusion to regenerate energy stores in the liver during 5hr storage and after 1hr rewarming in a rat transplantation model. Results will be compared with control. (no warm ischemia) and simple cold stored tissues.Copyright

HYPOTHERMIC MACHINE PERFUSION OF RAT LIVERS PRESERVES ENDOTHELIAL CELL FUNCTION

This study was conducted to investigate the effect of starch in the preservation solution during hypothermic machine perfusion (HMP) on endothelial cell and hepatocyte functions in an isolated perfused rat liver model. Livers isolated from male Sprague-Dawley rats were perfused with the University of Wisconsin (UW) solution (HMP + starch group); modified UW solution (starch omitted) (HMP - starch group) at 0.4 mL/min per g liver; or simply stored in the UW solution (SCS group) at 4 degrees C for 24 hours. Following preservation, livers from HMP + starch, HMP - starch, SCS, and control group (without preservation) were perfused with Krebs-Henseleit Buffer solution at 37 degrees C for 30 minutes. Samples were taken every 10 minutes during 30-minute warm perfusion to assess hepatocyte and endothelial cell function and damage. After 24 hours of hypothermic preservation and 30 minutes rewarming, livers in the HMP + starch group displayed significantly lower lactate dehydrogenase levels and higher bile production. Endothelial cell function was also improved as indicated by hyaluronic acid uptake and shorter transient time for albumin observed in a multiple indicator dilution study. Liver wet and dry ratio and histological findings confirmed reduced edema formation in the tissue of the HMP + starch group livers compared with that of the HMP - starch and SCS group livers. These results suggest that HMP with the UW solution containing starch improve endothelial cell function and induce less hepatocellular damage following 24-hour preservation compared to SCS and HMP with the starch-free UW solution. These results also suggest that oncotic support may be an important component in preserving hepatic microcirculation in HMP.

Successful long-term outcome with 0-haplotype-matched living-related kidney donors

The waiting list for cadaver kidney transplantation continues to grow. Yet there has been little increase in the number of living-donor transplants. At many centers, willing relatives are turned down as potential donors because of poor HLA ABDR matching with the recipient. It has been our policy to accept the 0-haplotype-match (0-HTM) living-related donor. We studied long-term (6-year) outcome of 0-HTM transplants compared with the outcome of transplants from 1- and 2-HTM recipients and from cadaver donors. Since 1984, 352 adults have received primary living-related renal transplants, and had a minimum of 1 year of follow-up: 92 2-HTM, 216 1-HTM, and 44 0-HTM. In the same period and with the same follow-up, 362 adults have received primary cadaver (CAD) renal transplants. Immunosuppression consisted of cyclosporine, azathioprine, and prednisone (triple therapy) for living-donor and sequential therapy for CAD recipients. ABDR match (mean +/- SD) for 0 HTM was 1.3 +/- 8; CAD, 2.0 +/- 1.6; % peak panel-reactive antibodies (PRA) for 0 HTM was 1.2 +/- 5.3; 1 HTM, 6.7 +/- 20; 2 HTM, 7.5 +/- 21; CAD, 15.5 +/- 30. The percentage of PRA at the time of transplant for 0 HTM was .7 +/- 4.4; 1 HTM, 4.1 +/- 1.6; 2 HTM, 6 +/- 18; CAD, 7.2 +/- 20. While the number of ABDR matches was significantly fewer for 0 HTM than for the other groups, the % PRA at transplant and the peak % PRA were less in the 0-HTM group. Other demographics were not significantly different. Patient survival was significantly lower in the CAD group vs. 2-HTM recipients (P < .05). The living-related grafts had significantly greater survival than the CAD grafts (P < .05), but there was no significant difference between 0-, 1-, and 2-HTM graft survival. The most common causes of graft loss in all groups were death and chronic rejection. In our experience, the long-term graft survivals of 0-HTM and 1-HTM transplants are the same, and both are superior to CAD results, using 0-HTM living-related donor transplants should be continued and encouraged.