Pharmacokinetics and metabolism of cyclosporine A in 19 hemodialysis patients.
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Biomedical subjects
Publications and source records attributed to J Kovarik.
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A 56-year-old patient received a cadaveric renal allograft because of primary cystic kidney disease. The donor was a 28-year-old man who died from head trauma. No other major illnesses were present at the time of transplantation. Immunosuppression was performed with cyclosporine A and steroids. After 3 months, the patient presented with fever and abdominal pain which was located in the region of the allograft. Ultrasonography demonstrated a tumor mass at the renal transplant hilus that was suspected to be an infected hematoma. Kidney biopsy from the cortex revealed only severe morphologic signs of cyclosporine A toxicity which was due to high cyclosporine A levels during the first 2 months after transplantation. The patient died from pulmonary embolism 6 months posttransplant. Histologic evaluation of the tumor specimens obtained at autopsy showed an extensive infiltration of the renal hilus and the medulla by a peripheral T cell lymphoma of the large-cell type. The T cell origin was confirmed by immunohistochemistry using the T cell-associated monoclonal antibodies UCHL-1 and MT1.
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The differential diagnosis of thrombocytopenia and leukocytopenia in renal allograft recipient can be troublesome. We report on a patient in whom the rare case of portal hypertension with secondary hypersplenism due to Caroli syndrome was detected to be the cause for the hematological disturbance. The management of the thereby complicated immunosuppressive regimen is discussed.
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Pathophysiological histological and radiological findings in renal osteodystrophy are described. Special emphasis is laid on secondary hyperparathyroidism. Preliminary results of the authors' investigations show a good correlation between radiological findings in the phalanges of the hand and the concentration of parathyroid hormone (PTH) in 14 patients. The concentration of the hormone in the blood was measured by a new "two-site" immunoradiometric assay, which is specific for the intact, biologically active hormone. Patients with high concentrations of PTH in the blood tended to have more severe radiological changes. In 4 patients for whom radiographs of the hands revealed no pathologic findings, normal PTH concentrations in the blood were measured by this method, whereas the conventional assay gave elevated hormone concentrations for the same patients. This is due to the lack of specificity of the conventional method for the intact, biologically active hormone. Nevertheless, further investigations are needed to confirm these findings.
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A retrospective analysis was undertaken of the renal transplantation results in diabetic nephropathy over the past 10 years. Out of 428 kidney transplants in 348 patients, 22 transplants were performed in 20 diabetic patients during the observation period. Patient survival for diabetics after 1, 2, and 3 years in contrast to non-diabetic controls was significantly different (70%, 50.9%, 50.9%, respectively versus 93.9%, 89.5%, 83.3% in the non-diabetic control group) (p less than 0.001). Transplant survival was 55%, 42%, 34.4%, versus 74.7%, 67.4%, 57.6% after 1, 2, and 3 years, respectively (p less than 0.08). During the posttransplant period the incidence of cardiovascular and infectious complications, as well as the rate of amputation was much higher than in the pretransplant phase. Main causes of death were cardiovascular or infectious complications. Improvement of the still poor results in diabetic transplant recipients is certainly a challenge for the future.
The presence of antibodies against ethylene oxide, which is used for sterilization of dialyzers, was evaluated in 52 hemodialysis patients (30 male, 22 female). The aim of the prospective study was to evaluate a possible correlation of these antibodies with hypersensitivity reactions during hemodialysis. By means of a radio-allergo-sorbent-test (RAST) only 3.9% (2 patients) were detected to have ethylene oxide antibodies. There was no significant correlation between antibodies on the one hand, and symptoms, eosinophilia and IgE-elevation on the other hand. We could not find ETO-induced hypersensitivity reactions in our study population. Thorough rinsing and sufficient storage time of the dialyzers might be the reasons for these findings.
During antirejection treatment with antithymocyte globulin (ATG), a 48-year-old male kidney graft recipient was erroneously given 30 mg/kg ATG on day 5 of the treatment course. Clinically, the patient presented with abdominal pain, profuse diarrhea, and fever. Initially, the platelet count dropped to 94 x 10(3)/microliters and showed a further decrease to 65 x 10(3)/microliters 2 days thereafter. Plasmapheresis carried out about 12 h after the end of ATG infusion resulted in a decrease in serum levels of total rabbit immunoglobulin as well as the antibody fraction reactive with human T lymphocytes. Within 10 days after the discontinuation of ATG treatment, the relative and absolute number of the T-cell subpopulations, which had disappeared from the circulation at the time of antirejection therapy, returned to normal values. In addition, at this time both platelet and lymphocyte counts were again found to be in the normal range. Kidney function had recovered from the rejection crisis such that the patient could be discharged 26 days posttransplantation.
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A prospective study was carried out in 81 patients to compare the ability of colour coded Doppler sonography (angiodynography) and Tc bolus examination for demonstrating renal blood supply. In patients with normal transplant function both methods performed equally well. In anuric patients angiodynography was superior to the Tc bolus examination: In three cases angiodynography was able to provide important additional information such as absence of blood flow in peripheral intrarenal vessels or missing blood supply of a transplant pole. Angiodynography seems to be able to replace the Tc bolus examination; this statement excludes very obese patients until low-frequency probes for angiodynography will be available.
Two monoclonal antibodies, DA7 and DC10, were obtained from fusions of mouse myeloma cells with splenic lymphocytes from mice immunized with human breast cancer cells of PMC 42 line. The indirect immunofluorescence studies performed on established tumor cell lines together with immunoperoxidase staining of normal human tissues showed that the components reacting with the antibodies were cytokeratins. Positive reaction was noted in all epithelia derived cultured cells and in all simple epithelial tissues known to express keratin 18. Immunoblotting performed on various cytoskeletal preparations demonstrated strong staining of a single band with a mobility corresponding to that of cytokeratin 18 (45 kD). The negative immunoperoxidase reaction found in different epithelial tissues of seven animal species suggests that both antibodies are specific for human keratin 18. It was shown that DA7 and DC10 antibodies exhibited strong reaction in paraffin embedded tissues fixed in either methacarn or standard formalin. These characteristics predetermine both antibodies as suitable reagents for the specialized histopathological work.
The incidence and clinical relevance of cytomegalovirus (CMV) infection has been investigated in 120 consecutive renal allograft recipients receiving cyclosporin A and low-dose steroid (CsA/LDS) immunosuppression. Forty patients (33.3%) showed serological evidence of recent CMV infection; 21 patients (17%) developed clinically symptomatic infection. A seronegative recipient status and an aggressive additional immunosuppressive therapy were significant risk factors for the development of serological infection. There was, however, no difference with regard to these or any other relevant parameters (HLA matching; pretransplant history) between the symptomatic and asymptomatic group. Furthermore there was no influence of CMV infection, whether symptomatic or not, on graft outcome. During the study CMV infection prophylaxis consisted of single-shot CMV hyperimmunoglobulin in 72 patients immediately before grafting, recombinant interferon alpha 2 in 28 patients, and placebo in 20 patients. There was no beneficial effect of either interferon or hyperimmunoglobulin on the incidence and severity of CMV infection. However, steroid-resistant vascular rejections were much more common in the interferon group. We conclude that the incidence of CMV infection after kidney transplantation using CsA/LDS immunosuppression is lower when compared to kidney grafting with conventional immunosuppression. Prophylactic treatment with single-shot hyperimmunoglobulin is not effective, and recombinant interferon alpha 2 prophylaxis may even exert deleterious effects on graft survival by inducing steroid-resistant vascular rejection.
Since infections with Herpetoviridae after kidney transplantation still remain a major clinical problem, we conducted a double-blind, placebo-controlled trial using low-dose recombinant interferon-alpha-2C (rIFNa2C) prophylaxis in 50 renal graft recipients immunosuppressed with cyclosporine and methylprednisolone. Ten patients were excluded from further analysis because of graft loss due to surgical complications, side effects of rIFNa2C, and because of lack of compliance. There was a significant difference in graft loss due to irreversible rejections between the verum and the placebo group (6 vs. 0; P less than 0.05), whereas no difference was observed with regard to the occurrence of viral infections. We conclude, that low-dose rIFNa2C prophylaxis is harmful in renal allograft recipients treated with cyclosporine in view of the high incidence of irreversible transplant rejections without beneficial effects on the occurrence of viral infections.