Rabbit anti-thymocyte globulin treatment of steroid resistant rejection in renal allograft recipients immunosuppressed with cyclosporine A.
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Biomedical subjects
Publications and source records attributed to R W Johnson.
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This study investigated the relationships among family environment, demographic measures, the decisions made by unintentionally pregnant adolescents regarding postdelivery plans and the certainty with which these decisions were made. Subjects were 175 pregnant adolescents, ages 14 through 22, who intended to carry their pregnancies to term. Greater uncertainty was associated with living with both natural parents or with mother only. Higher levels of negative affect were related to lower levels of perceived family cohesion, independence, expressiveness, and intellectual-cultural orientation. Age, trimester of pregnancy, and family constellation also were related to levels of negative affect. Discriminant analysis revealed that subjects choosing adoption were more likely to be older and to be white than were those choosing to keep the child. They also tended to perceive higher levels of expressiveness and independence in their families. The implications of these findings for the delivery of services and for future research efforts in this area are discussed.
On the basis that unbound concentration better correlates with response than total plasma or blood concentration, the inter- and intra-subject variability in the distribution of cyclosporin within blood and to plasma components was studied in renal transplant patients. Pharmacokinetic aspects were also studied. Blood samples were analysed from patients who received the drug both by a 72-h i.v. infusion and orally (7 mg.kg-1 twice daily). Steady-state was reached within 18 h of starting the i.v. infusion; the plasma data were best fitted by a biexponential equation with half-times of 0.13-1.02 h and 4.3-13.9 h, associated with the two phases. The mean plasma clearance was 700 ml/min. Concentrations during the infusions measured by RIA and HPLC were comparable. Oral profiles showed rapid and extensive absorption. The peak plasma concentrations were 1460-1880 micrograms.l-1 and occurred 2-4 h after dosing, with bioavailability estimates of 41-113%. Concentrations measured by RIA were higher than by HPLC. Blood-to-plasma concentration ratio measurements of cyclosporin at 37 degrees C decreased with increasing plasma concentration and increased with haematocrit. Fraction unbound, measured by ultra-centrifugation, was in the range 0.042-0.122 with an average of 0.068, and varied little in some patients but showed systematic changes with time in others. Cyclosporin binding was found to be related not only to the triglyceride but, more particularly, to the cholesterol-related lipoproteins in plasma. Monitoring cholesterol may be helpful in identifying patients with extremes in binding or with widely varying binding.
Thermodilution measurements of clinically important cardiac parameters, such as cardiac output and stroke volume, are subject to many sources of error. The temperature fluctuations (thermal noise) normally found in the pulmonary artery constitute one of these sources of errors. To improve the signal-to-noise ratio of thermodilution flow measurements rather than increase the signal level, we investigated four signal processing strategies designed to reduce the thermal noise power. We applied the noise reduction strategies to thermal noise data, containing simulated thermodilution curves, obtained in a mock circulatory loop. We compared the accuracy and reproducibility of the curve area estimates produced by the algorithms to the area estimates obtained by numerical integration of the thermal signal. Our results show that a bandpass (BP) integration technique combined with a noise canceler can improve thermodilution curve area estimate reproducibility and accuracy. The BP integration technique improved the reproducibility of cardiac output measurements by roughly 16 dB and is directly applicable to most thermodilution hardware currently in use. The more accurate noise cancelers, combined with the BP integration technique, provided correspondingly improved signal-to-noise ratios, with the improvement ranging up to 50 dB.
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Loss of an allograft caused by anti-GBM antibody-mediated nephritis is a rare complication of renal transplantation in Alport's syndrome. We describe a patient in whom this occurred. He belongs to the subgroup of patients with hereditary nephritis and deafness with an abnormal Goodpasture antigen, and he developed a high level of circulating anti-GBM antibodies within 20 days of transplantation of a kidney with a presumably normal Goodpasture antigen. The antibody titer fell, only to rise again when he developed evidence of acute infection with CMV. Coincident with this second rise in antibody titer he developed an anti-GBM antibody-mediated crescentic nephritis with resultant loss of graft function and transplant nephrectomy. This case provides support for the hypothesis that the abnormality in the basement membrane in some patients with Alport's syndrome involves the Goodpasture antigen, and raises the possibility that viral infection may have triggered autoantibody production.
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An enzyme-linked immunosorbent assay (ELISA) for rabbit immunoglobulin (Ig) was developed in order to investigate serum levels achieved by therapeutic doses of rabbit antithymocyte globulin (ATG) and their relationship to in vitro serum lymphocytotoxic activity. Twenty renal allograft recipients treated for acute steroid resistant rejection with ATG were studied, where possible, before, during and following their treatment with ATG. During therapy, peak serum levels of rabbit Ig were in the range 20-101 micrograms/ml with one exception of 404 micrograms/ml. After treatment, levels gradually declined to zero within 12 weeks. All sera with lymphocytotoxic activity were absorbed with platelets and treated with dithiothreitol so that reactivity due to anti-HLA antibodies and autoantibodies produced by the patient could be differentiated from each other and from serum ATG. Nine patients had detectable serum ATG associated with in vitro lymphocytotoxic activity. In two cases the lymphocytotoxicity was attributed solely to ATG; two had only anti-HLA antibodies; in one patient the lymphocytotoxicity was due to a combination of ATG and anti-HLA antibodies; two had autoantibodies; and for two, cytotoxicity was initially due to ATG and subsequently to the development of autoantibodies. The serum levels of ATG achieved during treatment could thus be quantified, and the important distinction between anti-HLA antibodies, autoantibodies and ATG clearly made.
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Pulmonary artery blood temperature manifests large variations which obscure the measurement of cardiac parameters by thermodilution techniques. We have created three mathematical models of heat flow through the heart in order to better understand the origins of the temperature fluctuations in the pulmonary artery. These lumped parameter models are based on a serial connection of two mixing chambers, which correspond to the atrium and ventricle of the heart. We have used the models to predict temperature fluctuations in the outlet, based on measurements of inlet flow, inlet temperature, and the timing of the cardiac cycle, of a mechanical right artificial heart in a mock circulatory loop. The most complex model accurately predicts the outflow temperature from the input variables and provides a quantitative description of heat transport across the heart under many operating conditions. The simplified models illustrate the conditions under which is possible to predict the outflow temperature from the inflow temperatures alone.
Serial serum samples from 266 recipients of primary renal allografts were monitored posttransplant for the presence of panel reactive lymphocytotoxic antibodies (PRA). The minimum posttransplant follow-up period was 18 months. Patients were classified according to whether or not they produced PRA before and/or after transplantation. The groups were as follows: PRA negative before and after transplant, -/-, 171; PRA positive before and negative after transplant, +/-, 5; PRA positive before and positive after transplant, +/+, 27; PRA negative before and positive after transplant, -/+, 63. Actuarial graft survival at 1 year for each group was 81.3%, 100%, 70.4%, 47.6%, respectively. Fifty-five of the 63 -/+ recipients were retrospectively crossmatched with posttransplant sera against stored donor lymphocytes. Of these, 50 (91%) were posttransplant cross match positive, and 37 (67%) have lost their grafts. In 23 of the 26 cases where an anti-HLA specificity was defined, the antibody was directed against antigens present in the donor but not in the recipient. These results clearly indicate that the production of PRA in recipients of renal transplants is associated with antidonor reactivity and poor graft outcome. The fact that these PRA were often directed against donor HLA antigens emphasizes one of the hazards of mismatching for HLA at transplantation.
The response of excised stem segments of several tree species to freezing and thawing cycles was studied. All species studied (Thuja occidentalis, Fagus grandifolia, and Betula papyrifera) except maple (Acer spp.) exuded sap while freezing and absorbed on thawing. Maple stems absorbed sap while freezing and exuded sap during the thaw only when sucrose was present in the vessel solution. Increased concentration of sucrose in the vessel sap led to increased exudation. In the absence of sucrose, maple stems absorbed sap on thawing. The presence of sucrose enhanced sap absorption during freezing cycles in maples. In general, large sugars, disaccharides and larger, could substitute for sucrose in the maple exudation response while sugar hexoses could not. The results are discussed in relation to the O'Malley-Milburn model (1983 Can J Bot 61: 3100-3106) of sap flow in maples.
1 The pharmacokinetics of cyclosporin were studied in 12 renal transplant patients. Five patients received a constant rate (7 mg kg-1 day-1) intravenous infusion over 72 h and the remainder received rates of 7, 4 and 10 mg kg-1 day-1, consecutively each for at least 24 h. 2 Plasma, separated at 37 degrees C, was analysed by h.p.l.c. 3 The data were best described by a biexponential model. 4 Following the 72 h infusion, a plateau was reached by 24 h and clearance was 0.60 l h-1 kg-1. 5 Clearance associated with the 10 mg kg-1 day-1 infusion rate (0.43 l h-1 kg-1) was estimated to be lower than that following the 4 and 7 mg kg-1 day-1 rates (0.52 and 0.54 l h-1 kg-1 respectively) but the difference is unlikely to be of clinical significance.
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Ultrasound was compared with histology in 66 cases to assess the accuracy of sonography in demonstrating abnormality in renal allografts. Patients with suspected acute, chronic or acute and chronic rejection, acute tubular necrosis and glomerulonephritis in the transplant kidney were included in the study. It was noted in this trial that ultrasound is less accurate at demonstrating abnormality in the grafted kidney than has been suggested previously in the literature. It was concluded that, where doubt exists, even when ultrasound examination is normal, biopsy should be considered.