The use of cyclosporin A and prednisone in cadaver kidney transplantation

Eighteen patients were treated with primary cadaveric renal transplantation using cyclosporin A therapy, and four more patients underwent cadaveric retransplantation. Eleven of the 22 recipients were conditioned with lymphoid depletion before transplantation, using thoracic duct drainage or lymphapheresis for two to eight and one-half weeks. cyclosporin A was begun a few hours before grafting. The other 11 patients were pretreated wtih cyclosporin A for from one day to 18 days. After transplantation, the majority of patients in both subgroups of 11 had rejection develop, but in most, the immunologic process was readily controlled with relatively small dosages of prednisone. After follow-up periods of two to four and one-half months, one patient has died of the complications of a coronary artery reconstruction that was not related to the transplantation. Another graft was lost from rejection, and a third organ was removed because of ureteral necrosis. Nineteen of the original 22 cadaveric kidneys are functioning, including 17 of the 18 kidneys given to patients who were undergoing transplantation for the first time. The only loss in the latter group of 18 patients was in the patient who died after an open heart operation. Results of these studies have shown that cyclosporin A is a superior and safe immunosuppressive drug but that, for optimal use in cadaveric transplantation, it usually should not be given alone. Steroid therapy greatly amplified the value of cyclosporin A. Unless major delayed morbidity develops which is not obvious so far, this drug combination should permit revolutionary advances ion the transplantation of all organs. Other adjunct to the cyclosporin A-steroid combination, including lymphoid depletion techniques, will require further investigation

Evolution of hepatitis B virus liver disease after hepatic replacement. Practical and theoretical considerations

The morphologic evolution of hepatitis B virus (HBV) liver disease in 45 hepatic allograft recipients who were HBV surface-antigen positive (HBs-Ag+) at the time of liver replacement and who survived for more than 60 days was studied by routine histologic and immunocytochemical analysis of serial pathology specimens. The findings in these patients were compared to a control group of 30 individuals who were immune to the HBV (anti-HBs antibody positive), but required hepatic replacement for other reasons. Eight of the forty-five (18%) HBsAg-positive patients have no serologic evidence of HBV reinfection after transplantation. All 37 remaining patients are reinfected; 21 (47%) developed chronic active hepatitis and/or cirhosis, 3 (7%) developed submassive necrosis, and 6 (14%) developed chronic lobular hepatitis. One patient lost her graft to chronic rejection, despite reinfection with the B virus. Four other patients (9%) developed a chronic carrier state. No long-term follow-up biopsies were available in the remaining two patients. The histologic features associated with dysfunction related to recurrent HBV infection evolved from an acute to chronic phase and were similar to hepatitis B seen in nonallografted livers. Furthermore HBV-related lesions could be separated from rejection using routine histology alone. The only exception to this conclusion was the occurrence of a peculiar HBV-related lesion in two recipients, described herein. Immunohistochemical analysis demonstrated the presence of viral antigens in almost all cases. Hepatic inflammation also was commonly present during HBV disease and consisted mostly of accessory cells and T lymphocytes. Analysis of the effect of major histocompatibility complex matching revealed no clear association between the number of class I or II matches or mismatches and the development, or pattern, of active hepatitis in the allograft. Peculiar pathologic alterations in several of the biopsies and failed allografts after HBV reinfection suggests that, under special circumstances, the B virus may by cytopathic

Lymphapheresis in organ transplantation: preliminary report.

Reduction of lymphoid tissue by splenectomy and/or thymectomy has been used as a part of immunosuppression in organ transplantation (4). More recently Walker (7), Johnson (2), Franksson (1) and Starzl (5,6) and their associates have shown that chronic depletion of lymphocytes by thoracic duct drainage decreases the incidence of rejection and hence increases renal graft survival. Mechanical removal of lymphocytes from circulation peripheral blood should theoretically achieve the same or similar effect on the immunity as thoracic duct drainage. Since September, 1979, five organ transplant recipients have received multiple lymphocytapheresis by IBM 2997 Blood Cell Separator as a mechanical pretransplant immunosuppression. The changes in cellular and humoral immunity and the clinical outcome are presented in this report

Why is the condensed phase of DNA preferred at higher temperature? DNA compaction in the presence of a multivalent cation

Upon the addition of multivalent cations, a giant DNA chain exhibits a large discrete transition from an elongated coil into a folded compact state. We performed single-chain observation of long DNAs in the presence of a tetravalent cation (spermine), at various temperatures and monovalent salt concentrations. We confirmed that the compact state is preferred at higher temperatures and at lower monovalent salt concentrations. This result is interpreted in terms of an increase in the net translational entropy of small ions due to ionic exchange between higher and lower valence ions.Comment: 4pages,3figure

PPARα contributes to protection against metabolic and inflammatory derangements associated with acute kidney injury in experimental sepsis

Abstract Sepsis‐associated acute kidney injury (AKI) is a significant problem in critically ill children and adults resulting in increased morbidity and mortality. Fundamental mechanisms contributing to sepsis‐associated AKI are poorly understood. Previous research has demonstrated that peroxisome proliferator‐activated receptor α (PPARα) expression is associated with reduced organ system failure in sepsis. Using an experimental model of polymicrobial sepsis, we demonstrate that mice deficient in PPARα have worse kidney function, which is likely related to reduced fatty acid oxidation and increased inflammation. Ultrastructural evaluation with electron microscopy reveals that the proximal convoluted tubule is specifically injured in septic PPARα deficient mice. In this experimental group, serum metabolomic analysis reveals unanticipated metabolic derangements in tryptophan‐kynurenine‐NAD+ and pantothenate pathways. We also show that a subgroup of children with sepsis whose genome‐wide expression profiles are characterized by repression of the PPARα signaling pathway has increased incidence of severe AKI. These findings point toward interesting associations between sepsis‐associated AKI and PPARα‐driven fatty acid metabolism that merit further investigation

Intestinal transplantation in children under FK 506 immunosuppression

Intestinal transplantation, solitary (n = 3) or in combination with the liver (n = 7), was performed in 10 pediatric patients with intestinal failure. The liver was only replaced if there was liver failure and portal hypertension. Immunosuppression was based on FK 506. Two patients died, one of graft-versus-host disease and one of lymphoproliferative disease. One patient was still in the intensive care unit 1 month posttransplantation due to perioperative complications. The function of the intestinal grafts in the remaining patients is normal. All nutrition and medications including immunosuppression are being administered enterally. This series indicates that small bowel transplantation, alone or in combination with the liver, is feasible in pediatric patients. © 1993

Effect of preoperative thoracic duct drainage on canine kidney transplantation

Chronic drainage of the thoracic duct to the esophagus was developed in dogs, and its efficacy in immunomodulation was tested using kidney transplantation. Compared to 9.7 days in the control, the mean animal survival was prolonged to 9.9 days, 17.8 days, and 18.5 days when TDD was applied preoperatively for 3 weeks, 6 weeks, and 9 weeks, respectively. Prolongation was significant after 6 weeks. Patency of the fistula was 93.5, 80.4, and 76.1% at respective weeks. Number of peripheral T-lymphocytes determined by a new monoclonal antibody diminished after 3 weeks. All animals were in normal health, requiring no special care for fluid, electrolyte, or protein replacement

Uterine selection of human embryos at implantation

Human embryos frequently harbor large-scale complex chromosomal errors that impede normal development. Affected embryos may fail to implant although many first breach the endometrial epithelium and embed in the decidualizing stroma before being rejected via mechanisms that are poorly understood. Here we show that developmentally impaired human embryos elicit an endoplasmic stress response in human decidual cells. A stress response was also evident upon in vivo exposure of mouse uteri to culture medium conditioned by low-quality human embryos. By contrast, signals emanating from developmentally competent embryos activated a focused gene network enriched in metabolic enzymes and implantation factors. We further show that trypsin, a serine protease released by pre-implantation embryos, elicits Ca2+ signaling in endometrial epithelial cells. Competent human embryos triggered short-lived oscillatory Ca2+ fluxes whereas low-quality embryos caused a heightened and prolonged Ca2+ response. Thus, distinct positive and negative mechanisms contribute to active selection of human embryos at implantation