Magnetic resonance imaging of kidney and pancreatic transplants.
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Biomedical subjects
Publications and source records attributed to G Tufveson.
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Monoclonal antibodies reactive with different T lymphocyte antigens were administered to rats receiving heart allografts. Ox 19 antibodies (directed to the rat Ly 1 equivalent) and Ox 8 antibodies (directed to the rat CD8 equivalent) both prolonged graft survival, whereas W3/25 (anti-CD4), Ox 6 (anti-Ia), and W3/13 (anti-pan T) antibodies did not affect graft rejection. Immunohistological studies were carried out on spleen and graft specimens in order to analyse further the mechanisms behind the prolongation of graft survival. The observed almost complete absence of Ox 8-reactive cells in the spleen after treatment with Ox 8 antibodies corroborates earlier observations that injection of moderate amounts of Ox 8 antibodies leads to complete elimination of suppressor/cytotoxic T cells from peripheral lymphoid organs and blood. The present data on graft survival therefore both support the notion that suppressor/cytotoxic T cells are involved in graft rejection, and suggest that these cells are not the only ones involved. An unexpected and as yet unexplained finding was that Ox 8-reactive molecules were found in large numbers on various inflammatory cells as well as on certain myocytes in the grafted hearts that had experienced a prolonged graft survival due to treatment with Ox 8 or Ox 19 antibodies.
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With a low dose, triple drug protocol for immunosuppression, more frequent and severe rejection episodes, and lower, kidney graft survival appeared after combined kidney and pancreas transplantation than after kidney transplantation alone. With increased immunosuppression using the quadruple drug protocol that includes prophylactic ATG treatment, the results after combined transplantations improved.
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The pharmacokinetics of azathioprine (AZA) and 6-mercaptopurine (6-MP) was studied in uremic patients after 100 mg AZA intravenously (fifteen patients) and orally (eight patients). 6-MP was analysed with gas chromatography mass spectrometry following extractive alkylation. AZA was determined indirectly assuming quantitative conversion to 6-MP in whole blood. The plasma concentration of AZA fell rapidly after i.v. administration. The mean half-time of elimination for the first rapid phase (t1/2 alpha) was 6.1 min (S.D. +/- 4.1) and for the terminal phase (t1/2 beta) 50 min (+/- 31). The total plasma clearance (Cl) was 6.9 1./min (+/- 3.0). AZA was rapidly converted to 6-MP in vivo, and maximal plasma concentrations of 6-MP were found as early as 5 min after i.v. injection of AZA. The mean t1/2 alpha was 4.6 min (+/- 2.2), t1/2 beta 74 min (+/- 58) and Cl 8.0 1./min (+/- 5.8). The plasma levels of both AZA and 6-MP were either low or undetectable 4-6 h after dose. In erythrocytes AZA levels were low or undetectable indicating rapid conversion to 6-MP in these cells. 6-MP concentration - time curve in erythrocytes was similar to that in plasma, except for a somewhat slower terminal phase of elimination. Oral administration of AZA generated flat plasma curves for AZA and 6-MP. The area under the concentration - time curve (AUC) was considerably smaller than after i.v. administration, 18 and 41% for AZA and 6-MP, respectively. There seems to be little danger of accumulation of AZA/6-MP in uremia. We also studied inhibition of Leucoagglutin (LA) stimulated lymphocyte proliferation by patient plasma at different times in six of the patients following AZA i.v. Sera drawn at 5, 10 and 30 min significantly inhibited the LA-induced proliferation, with an estimated minimum effective concentration of 6-MP in the cultures of about 0.02-0.04 microM. This suggests the possibility of a therapeutic effect even of the low plasma levels of 6-MP obtained after AZA orally. The combined use of sensitive pharmacokinetic and immunological assays as described should be useful in studying the relationship between plasma levels of AZA/6-MP and their immunosuppressive effect and toxicity.
A potentially lethal case of "air-borne" adult respiratory distress syndrome, most likely consequent to cytomegalovirus (CMV) pneumonitis, is described in a kidney transplant patient. It was characterized by confluent densities on both lung fields with peripheral zones of normal radiographic pattern and with one of the highest values of extravascular lung water reported in the literature, in the presence of a normal pulmonary capillary wedge pressure. When specific conservative therapy for curing a potentially lethal CMV pneumonitis after kidney transplantation fails, we suggest that transplantectomy should be considered.
Measurement of deoxythymidine kinase activity (S-TK) in serum is used as a marker for cytomegalovirus (CMV) infection following transplant surgery. A case is presented where a kidney transplant patient suffered a fatal CMV infection. The new antiviral drug Foscarnet was used to treat the infection. Retrospective analysis of S-TK showed a good correlation with the course of the disease, its treatment, recurrence and final outcome.
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Twenty patients, cadaveric renal transplant recipients, were retrospectively analysed for serum levels of deoxythymidine kinase. Special reference was made to the thymidine kinase level in relation to rejection, and viral infection. Seven of the patients experienced clinically suspected cytomegalovirus infection. All these patients had elevated levels of serum thymidine kinase during the period of clinical disease. Usually the thymidine kinase level parallelled the severity of the disease. All patients with irreversible rejection had increased levels of serum thymidine kinase, but normally not as high, as seen in patients with severe cytomegalovirus infection. There was also some correlation between clinically suspected rejection, that lead to rejection treatment, and moderate increase in thymidine kinase. However, not all rejection episodes were accompanied by a thymidine kinase increase. Serum thymidine kinase was analysed and compared in patients with self-healing cytomegalovirus disease, and those treated with phosphonoformate. A rapid decline in thymidine kinase level was found in connection with successful antiviral therapy, when compared to the decline in untreated patients. Some bone marrow transplanted patients were also included in this analysis.
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In a rat kidney transplantation model, DA kidneys were transplanted into Lewis rats. Syngeneic Lewis transplantations were studied as controls. Histologic evaluation was made, and immunohistochemical staining with a single-staining peroxidase-antiperoxidase technique on frozen sections was performed after 2, 4, 6, and 8 days. Antibodies for Ia antigen (Ox 6), 'suppressor/cytotoxic' cells (Ox 8), pan-T cells (W 3/13), and 'helper/inducer' cells (W 3/25) were used. Allogeneic grafts were almost completely rejected in 8 days. Syngeneic grafts also showed lymphocyte infiltrates, somewhat later than allogeneic ones, but were not rejected. In these infiltrates W 3/25-positive cells dominated, being even more numerous than W 3/13-positive cells. Relatively fewer Ox 8-positive cells were seen in the infiltrates of syngeneic than in allogeneic transplants. Infiltrates occurred later in the renal medulla than in the cortex. Perivascular infiltrates with cells of all investigated phenotypes were seen earlier in allogeneic grafts than in syngeneic ones. All tubular cells within one renal tubule appeared either Ox 6-positive or -negative. With time, all tubules in the allogeneic transplants became Ox 6-positive. Some increase of Ox 6-positive tubules was also seen in syngeneic transplants.
The urologic complications were reviewed in 159 consecutive renal transplantations. There were 23 major complications (14%) in 22 patients. One patient died as a consequence of urologic complications and two other grafts were lost. In the remaining cases the grafts could be saved by surgical revision or conservative treatment. The principles of diagnosis and treatment of these complications are discussed.
Fine-needle aspiration biopsy( FNAB) of renal allograft transplants has been used at Uppsala University Hospital for 3 years. Experience from 51 consecutive patients (from 1 1/2 years) with 333 FNAB was reviewed. Representative material was obtained in more than 70% of the biopsies. Eleven rejection episodes in 12 patients were confirmed with this method. One was not recognized. Significant inflammation in the kidney without clinical rejection was found in 22 patients. The possible causes of such inflammation are discussed. Repeatedly recorded inflammation in the kidney with minor or no effect on graft function may sometimes be caused by viral infection. The clinical value of FNAB in various immunosuppressive regimens is discussed.
Sera collected from a majority (15/16) of recipients of renal transplants occasionally contained low, but significant, levels of antiviral activity, maximally corresponding to 25-50 units of interferon-alpha per milliliter of serum in a bioassay. The exception was the only transplanted patient with a known cytomegalovirus infection, who demonstrated persistent high levels of antiviral activity corresponding to 200-400 interferon units/ml. Only the latter antiviral activity was sufficiently high for a partial characterization. It was pH 2 labile, did not have antigenic properties of interferon-alpha or beta, and may correspond to the lymphokine interferon-gamma. In consecutive serum samples from individual patients, the peaks of the antiviral activity occurred preponderantly in connection with clinical signs and consequent treatment of graft rejections. Interferon may, therefore, be a useful marker (at the serum level) of incipient graft rejection, and of certain viral infections, at least, provided that a more rapid sensitive and precise assay of this lymphokine is developed.