摘要:

The critical injury of cold preservation is to the hepatic microcirculation. Oxygen free radical injury and cell swelling have been proposed to be causes of allograft failure, and new solutions such as Marshall's isotonic citrate and University of Wisconsin (UW) solutions were designed to prevent cell swelling and free radical injury. Experiments were done to determine whether Marshall's solution and UW solution protect the microcirculation, and whether they do so by preventing cell swelling or free radical—induced injury. To determine if the new solutions reduce sinusoidal lining cell injury, rat livers were examined after preservation at 4°C in NaCl 0.9% and CaCl22 mM for 4 hr and 8 hr, in Collins' solution for 8 hr, and in both UW and isotonic citrate solutions for 8 hr and 16 hr. Next, the role of cell swelling in preservation injury was studied by storing livers in hypotonic solutions that accelerate liver weight gain, and in a choline chloride-based preservation solution. Finally, to evaluate the role of active oxygen species, SOD, catalase, and allopurinol were added to preservation solutions. The effect of allopurinol alone was also studied. In a related study, sucrose was substituted for the free radical scavenger, mannitol, in isotonic citrate solution. All livers were studied by light microscopy after perfusion-fixation. Storage in UW and isotonic citrate solutions resulted in clear improvement in the morphology of the sinusoidal lining. Increasing the rate of liver weight gain by the use of hypotonic solutions did not accelerate the endothelial injury. Choline chloride-based solution prevented weight gain during preservation, but unlike UW or isocitrate solutions it did not retard the microcirculatory injury. After preservation in the presence of SOD and catalase, or allopurinol, no improvement in the defined morphological features of the endothelial injury was noted when compared with respective controls; nor was the benefit of isotonic citrate solution lessened by the removal of the free radical scavenger mannitol. We conclude that microvascular injury produced by cold injury is due neither to free radical-mediated injury nor to cell swelling. As both UW and isotonic citrate solutions provide significant protection to the microcirculation, they must do so by a yet-undetermined mechanism.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

The present study was performed to estimate the optimal serum trough levels of FK506 (FK) for prophylactic use and for the treatment of acute rejection in renal allotransplantation of the beagle dog. The serum trough levels of an immunosuppressive dose of FK 1.0 mg/kg p.o. ranged from 0.1 to 0.4 ng/ml. The data indicate that the effective serum trough level is about 100 times lower than that of cyclosporine, as was already observed in previous in vitro studies. Combining treatment with a nonimmunosuppressive dose of cyclosporine of 2.5 mg/kg could lower the effective trough levels of FK. By the combining treatment, 2 out of 5 renal recipient dogs survived with well-functioning grafts as long as 60 days with the trough levels between 0.04 and 0.07 ng/ml. High-dose 5-day i.m. FK treatment of 0.5 or 1.0 mg/kg was effective in the reversal of acute rejection, with peak serum trough levels during successful rejection therapy ranging between 0.28 and 3.7 ng/ml. Two dogs died of malaise or pneumonia with peak trough levels of 2.25 and 2.78 ng/ml. Among the wide range of the effective trough levels for successful acute rejection therapy, those above 2.0 ng/ml seem to be toxic in some renal-transplanted dogs.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

In our previous experiments studying the effects of FK506 on renal allografting in the dog, we encountered two major problems. One problem was anorexia and the other problem was vascular changes mainly in the recipient heart. Anorexia was generally dose dependent, but the vascular changes were seen to be more prominent at lower doses rather than at higher immunosuppressive doses. The present study was undertaken to study these two problems. A nonanorexic, vascular change-related, nonimmunosuppressive dose of FK506 was combined with a low dose of cyclosporine or prednisolone in beagle dogs after renal allografting.Treatment with either FK506 alone at a dose of 0.32 mg/kg or cyclosporine alone at 2.5 mg/kg was not effective in prolonging renal recipient survival. The recipient dogs died of rejection, and a variety of vascular changes were observed in the hearts of both groups. Combined treatment with FK506 and cyclosporine at these same doses resulted in statitsitcally significant prolongation of the survival time of the renal recipient (P<0.01), and histologic studies showed that the frequency and severity of the vascular changes were suppressed in the recipient receiving the combined treatment. The combination of FK506 and prednisolone at 0.5 mg/kg was not effective in prolonging survival. Furthermore, the extent of vascular changes was similar to those found in recipients receiving FK506 alone.The data suggest that combined treatment with low doses of both FK506 and cyclosporine acted synergistically in prolonging canine renal allografts and that the vascular changes frequently seen at low doses of FK506 were reduced by additional immunosuppression with a low dose of cyclosporine.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Oxidation-reduction changes in pyridine nucleotide fluorescence were investigated in perfused and preserved porcine liver. A fluorocarbon emulsion (FC-43) was administered to the perfusate as an oxygen carrier to obtain full oxidation level by portal perfusion at a physiological low flow rate. A satisfactory reading was obtained by portal perfusion with EuroCollins' solution containing 10% v/v FC-43 at a rate of 0.5 ml/min/g liver. The amplitude (R×A) and the changing velocity (R×V) from full oxidation to full reduction were determined in the resultant trace curve. Both R×A and R×V decreased in inverse proportion to the duration of preservation period (3, 6, 12 hr). Adenine nucleotide content, hepatic energy charge level, and ketone body ratio in the tissue were simultaneously measured, and they also decreased proportionally to the duration of preservation. There were close positive correlations between R×A and total adenine nucleotide concentration (r=0.841,P<0.01), between R×V and energy charge (r=0.787,P<0.01), and between R×V and tissue ketone body ratio (r=0.881,P<0.01). These results suggest that pyridine nucleotide fluorometry can accurately follow the cellular function of isolated porcine liver by administration of FC-43 in perfusate. This fluorometry may also have potential application in evaluating viability of a large organ like the human liver graft.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Experiments were designed to test the hypothesis that renal medulla is more sensitive to hypoxia than is the cortex. Using the one-dimensional phase encoding technique to perform31phosphorus magnetic resonance spectroscopy in a perfused porcine kidney preparation, cortex and medulla were differentiated on the basis of the unique resonance at 3 ppm found only in medulla. Hypotension-induced hypoxia reduced total renal oxygen consumption by 60%, and urine flow by 44%. Nonlocalized31P MRS spectra showed that [ATP]/[Pi] ratio fell by 40%, and intrarenal pH by 0.1 unit. Virtually all of these changes could be accounted for by changes in the renal cortex, where initial [ATP]/[Pi] was higher than in medulla (1.16 vs. 0.68). In medulla [ATP]/[Pi] fell only 29% (n.s. versus control) and pH remained unchanged during hypotension.Thus the cortex appears to be more sensitive to hypoxia in this preparation, and observations fail to support the proposed hypothesis. They are consistent, however, with the greater capacity of medulla for anaerobic glycolysis. Localized31P MRS provides improved non-invasive metabolic assessment of cold-preserved kidneys.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Vascular perfusion of gaseous oxygen has been used to prolong the in vitro survival of a number of isolated organs, and has been shown to improve the hypothermic preservation of ischemically injured kidneys that were subsequently transplanted. We have investigated the mechanism of this effect. Rabbit kidneys were subjected to 60 min of warm ischemia prior to preservation for 24 hr with Ross, Marshall, and Escott's hypertonic citrate solution, with or without retrograde oxygen persufflation (ROP) via the renal vein. It was found that adenine nucleotide levels were almost doubled in the ROP-pre-served kidneys, principally due to higher adenosine tri-phosphate (ATP) concentrations. It was shown that cytochrome oxidase activity was unaffected by ischemia or preservation method, but studies with the metabolic inhibitors ouabain and a mixture of cyanide and iodoacetate suggested that ATP was being synthesized during the storage period but was also being utilized to power the active volume-regulating pump. Morphological examination revealed a much greater degree of cell swelling and cytological injury in the kidneys not subject to ROP, and the interstitial space appeared much reduced in the latter group. At the ultrastructural level, the ROP-treated kidneys showed generally well-preserved mitochondria, mostly in the energized “orthodox” configuration. In contrast, the mitochondria in the nonpersufflated kidneys were generally in the “condensed” deenergized state. We conclude that the provision of sufficient oxygen by ROP allows the continued production of ATP in sufficient quantities to permit improved maintenance of cellular volume and morphology under the conditions of low-temperature storage that we have studied.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

The goal of endocrine pancreas transplants should be the prevention of diabetic complications. The differential effect of grafts of organ-cultured fetal mouse pancreas on diabetic complications in the retina and kidney was tested by comparing capillary basement membrane thickness (BMT) in mice made diabetic with streptozotocin and transplanted either early or late, or treated with insulin. BALB/c female mice were grafted with a single organ-cultured syngeneic fetal pancreas at either 3 weeks or 7 months after induction of diabetes. Controls were sex- and age-matched nondiabetic; diabetic untreated; and diabetic insulin-treated mice. All mice were killed at 20 months of age and their eyes and kidneys fixed for electron microscopy. BMT was measured on coded micrographs. In all mice glomerular capillary BM were thicker than retinal capillary BM. Mice grafted early after the induction of diabetes had normal BMT in both sites, while those transplanted after 6 months of disease had normal retinal, but thickened glomerular, capillary BM. In each case the late-transplanted animals had BM thickness significantly less than the insulin-treated or untreated diabetics.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

The influence of continuous immunosuppression on the immune system of 2 neonates born to heart-lung transplant recipients was analyzed. T cells, T cell sub-populations, B cells and cyclosporine levels were measured in maternal and cord blood at the time of delivery. Cyclosporine, both parent compound, and metabolites were found in cord blood but in lower amounts than that in the mother. This discrepancy was more pronounced for parent compound than metabolites. Infants born to immunosuppressed mothers had more T and B cells than the mother and had similar numbers of T and B cells to that found in cord blood from 10 babies born to nonimmunosuppressed mothers. One infant had fewer activated T cells and a higher CD4/CD8 ratio due to increased numbers of CD4 cells than normal. In conclusion, neither of these babies had a lymphocyte profile suggestive of chronic immunosuppression.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Molecules responsible for adhesion between cells are known to play an important role in the immune response. The expression of one of these molecules, intercellular adhesion molecule-1 (ICAM-1), was examined on normal and allografted kidneys using a specific monoclonal antibody and an indirect immunoperoxidase technique. The expression of this molecule was compared to that of HLA class II antigens. On normal kidneys and most allograft biopsies taken immediately before implantation, ICAM-1 was expressed only on vascular endothelial cells (VEC) and parietal epithelium of Bowman's capsule. In the 11 kidneys where biopsies were available before and after transplantation, the appearance of rejection was associated withde novoexpression of ICAM-1 on renal tubular epithelial cells that closely paralleled that of HLA class II antigens. In addition, an increase in endothelial cell expression of these molecules was also seen in rejection. In 23 random allograft biopsies, most of those with rejection showed tubular expression of both HLA class II antigens and ICAM-1. However, the presence of these molecules on tubules in several biopsies that did not show rejection limits the clinical usefulness of monitoring these antigens in posttransplant biopsies. The upregulation of these molecules is presumed to be secondary to the release of cytokines by cells infiltrating the allograft, although other mechanisms may be operating that explain the expression of these molecules in nonrejecting grafts.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Data from 7436 cases of first-cadaver transplants between 1981 and 1986 from 50 transplant follow-up centers within Eurotransplant, were analyzed with respect to the effect of HLA-DR matching on graft prognosis within the first year posttransplant. The use of cyclosporine was allowed for as well as the variation in graft survival rate between transplant follow-up centers. After adjustment for these variables, HLA-DR matching was still very significant. The effect of CsA on graft survival varied between centers—i.e., interaction was observed—but the effect of HLA-DR mismatching did not vary significantly between centers. Over all the centers there was a 1.4-fold increase in relative risk for each increase in HLA-DR mismatch, corresponding to predicted one-year graft survivals of 86.5%, 81.9%, and 75.4% for 0, 1, and 2 HLA-DR mismatches respectively, in patients receiving CsA, and 72.5%, 64.2%, and 53.6% in patients not receiving CsA.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID