Biomedical subjects
Publications and source records attributed to D Scholz.
Tuberculosis is an uncommon infectious complication after kidney transplantation, but such an infection carries a significant mortality and morbidity and may jeopardize the function of the renal allograft. Herein we report our experience in the treatment of mycobacterial infections in 4 renal transplant recipients and review the literature.
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68 cases of autopsy of 950 patients who underwent a kidney transplantation in Berlin from 1970 to 1986 were analysed with regard to their main disease, the disease directly leading to death and secondary disease. The average age of the deceased was 39.6 years (15-56 years), the duration between kidney transplantation and death was 51.2 months (1-192 months). In the first place there are diseases of the liver (30 times primary disease, 28 times secondary disease), in which cases 24 times a liver cirrhosis was existing and in 11 cases a coma hepaticum caused death. Apart from this septic-septicopyaemic processes (23 times) were of great importance for the exitus, in which cases there were frequently close relations to liver diseases (10 times liver diseases primary disease, 12 times secondary disease). Furthermore are important for the occurrence of death the renal hypertension as well as hemorrhages particularly in the gastrointestinal tract. 15 times a diabetes mellitus was stated, in 13 cases severe changes of bones and joints were diagnosed. 4 times a neoplasia was present (3 times immunocytoma, once liver carcinoma). The diseases diagnosed are to be regarded as a sequela of the primary disease, above all, however, caused by the long-lasting immunosuppressive therapy and the influence on the endocrine system.
The sugar-modified dTTP analogues 2',3'-didehydro-2',3'-dideoxy-thymidine 5'-triphosphate (ddeTTP), 2',3'-dideoxythymidine 5'-triphosphate (ddTTP), 3'-fluorothymidine 5'-triphosphate (FdTTP), and 3'-azidothymidine 5'-triphosphate (N3dTTP) are demonstrated to be very effective and selective inhibitors of the HIV-associated reverse transcriptase (HIV-RT). This conclusion is based on a comparison of the ID50 values of the compounds for the HIV-RT (ranging from 0.03 microM for ddeTTP to 0.1 microM for ddTTP) and the cellular DNA polymerase alpha (greater than 200 microM). DNA polymerase beta is partially affected by N3dTTP (ID50 = 31 microM) and by the other analogues (ID50 = 1-2.2 microM). FdTTP has proved as effective as N3dTTP (ID50 = 0.05 microM) in suppressing the HIV-RT activity. Kinetic analysis revealed for both dTTP analogues a competitive type of inhibition and the same K1 values (about 0.05 microM).
Extended experimental experience with the efficacy of pretreating the kidney donor and the allograft by means of photochemotherapy (photosensitizer + UVA irradiation = PUVA) was adopted in clinical kidney transplantation. In a preliminary unrandomized study similar patient populations were treated by generally uniform methods. Thirty-three PUVA-pretreated kidneys (group A) were compared with the experience regarding 26 non-pretreated kidney allografts (group B). The number of rejection episodes was significantly lower in the first 3 months in group A (p less than 0.05 vs group B) and fewer grafts failed because of irreversible rejection (2 vs 5). Furthermore, in group A the rate of infectious complications was lower (18% vs 34%). The cumulative allograft survival at 3 months was improved from 65% in group B to 81% in group A and at 12 months from 65% 76%, respectively. These differences were not significant. Therefore, our preliminary clinical experience with a photochemical donor pretreatment is encouraging and further use in a randomized study seems to be necessary.
NMR-spectroscopy and electron microscopy were applied in order to find out whether nephrotoxic effects of cyclosporine A in combination with ischaemia on rat kidney are of significance for the energy metabolism of the organ. CSA was administered in daily doses of 15 mg/kg rat over 20 days. Use was made of the particular advantage of 31P-NMR-spectroscopy to follow up the dynamics of high-energy phosphate concentrations in the same tissue. Ultrastructural changes were observed in the region of the proximal tubule. Some mitochondria showed degenerative changes, others increased density of cristae. The total number of mitochondria was increased. This observation together with the coexistence of vacuolarly degenerated mitochondria and mitochondria with increased activity after CSA treatment is interpreted as expression of a compensatory mechanism that keeps constant the totality of high-energy phosphates despite damage to some mitochondria.
The effect of cyclosporin A (CYA) on the respiration and phosphorylation in rat kidney mitochondria was studied. When CYA (50 mg/kg/day) was subcutaneously administered to rats for 4 days, the state 3 respiration and uncoupled respiration of succinate and glutamate/malate respiration was decreased. The respiratory control index was decreased in glutamate/malate respiration. These ex vivo effects of mitochondrial dysfunction are discussed as CYA effects on kidney mitochondria occurring in the intact cell. The nephrotoxic effect of CYA could be demonstrated by increased excretions of urinary enzymes.
An analysis of 68 autopsy cases from a total of 950 patients with renal transplantation in Berlin in 1970-1986 shows an average age at death of 39,6 years (15-56 years). The period between renal transplantation and death averaged 51,2 months (range: 1-912 months). Liver failure was the immediate cause of death in 30 cases. In 28 cases the liver disease was a secondary disease. The risk of dying from a liver disease rose with the interval between renal transplantation and death. 61-192 months after renal transplantation, liver disease was the cause of death in 70% of the deceased. Liver cirrhosis was observed in 24 patients (age 21-56 years) after a period from 24-192 months. In 1 case a liver carcinoma developed in a cirrhotic liver. 11 patients died in coma hepaticum, 29 patients had a chronic hepatitis. The findings are compared with clinical studies and individual autopsy reports and contrasted to causes of death in patients with chronic dialysis.
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Dose-response studies of cyclosporin (CsA) established that doses of 2 mg/kg body weight on 4 consecutive days (0-3) or higher gave complete suppression of rejection and permanent survival of all rat kidney allografts, while a dose of 2 mg/kg body weight on day 0 was much less effective in preventing deleterious rejection (30% permanent survival). Photochemical pretreatment of the kidney donor with 8-methoxypsoralen (8-MOP) and direct long-wave ultraviolet irradiation (UVA) of the kidney (PUVA) therapy) significantly prolonged the subsequent graft survival in allogeneic recipients. Forty per cent of the animals survived more than 100 days. However, when PUVA-treated kidney allografts were transplanted into temporary CsA immunosuppressed recipients (2 mg/kg on day 0) the graft survival rate was further improved. Seventy per cent of the PUVA + CsA-treated recipients survived permanently. Therefore, a synergistic effect of PUVA pretreatment and low-dose CsA therapy on rat renal allograft survival was demonstrated. The results suggested a possible clinical application of this treatment regimen in order to avoid high nephrotoxic CsA doses.
For monitoring the immunosuppressive drug cyclosporin A by radioimmunoassay (Sandoz Ltd.) we propose a simple method of sampling in which 20 microL of capillary blood is dried on filter paper. Patients can collect their own samples and mail or bring them to the laboratory. Results for such samples, and their variability, correspond to those for conventional methods of sampling (collection of venous or capillary blood into buffer). Capillary blood can be stored on paper at room temperature for more than four weeks with no effect on assay results.
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Pretreatment of the kidney donor with 8-methoxy-psoralen (8-MOP) and direct longwave ultraviolet (UVA) irradiation of the kidney graft (PUVA therapy) significantly prolonged survival in allogeneic recipients. 40% of the recipients survived more than 100 days with normal transplant function. The addition of standard clinical immunosuppressive agents azathioprine and prednisolone (both at dosages of 15 mg/kg body weight/day for 21 days) to the PUVA therapy further improved graft survival rate, with a recipient survival rate of 62.5%. The two drugs alone were less effective in prolonging graft survival rate (28.5%). A synergistic effect of PUVA therapy and standard immunosuppressive treatment with azathioprine and prednisolone was demonstrated. This suggested a possible clinical application of this type of immunosuppression and immunoregulation.
We compared the diagnostic validity of five urinary enzymes--alanine aminopeptidase (EC 3.4.11.2), alkaline phosphatase (EC 3.1.3.1), gamma-glutamyltransferase (EC 2.3.2.2), N-acetyl-beta-D-glucosaminidase (EC 3.2.1.30), and lysozyme (EC 3.2.1.17)--as indicators of acute rejection crises in renal-transplant recipients. In 82 patients (group A), the excretion of each of these five enzymes was measured daily from transplantation until discharge from hospital. In another 69 patients (group B), enzyme determinations were made when the patient came for regular checkups (about every four to eight weeks). We used an "activity ratio" (the activity measured at a particular time compared with the activity on the preceding determination) value of 1.5 as the decision point. In group A, use of this discrimination point for alanine aminopeptidase, gamma-glutamyltransferase, and N-acetyl-beta-D-glucosaminidase yielded a specificity and sensitivity of about 90%. In group B, only alanine aminopeptidase had a greater diagnostic sensitivity than creatinine alone. Evidently, measurement of alanine aminopeptidase can be a helpful indicator of acute rejection crises, when interpreted in combination with other available relevant clinical, biochemical, and immunological data.
Plasma membranes of cells from lymph nodes of bovine leukaemia virus (BLV)-free cattle and of cells from tumorous lymph nodes of BLV-infected cattle have been investigated for their reactivity with iodine labelled BLV antigens gp51 and p24. It has been found that only the plasma membranes from cells of tumorous lymph nodes bound gp51 and p24. The binding could be abolished by addition of nonlabelled antigens. It has been calculated from Scatchard plot analysis that 10(5) molecules of gp51 or 10(4) molecules of p24 can be bound per tumour cell. The findings led to the conclusion that tumour cells of BLV-infected cattle are endowed with receptors for the BLV antigens gp51 and p24.
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