Effect of mitomycin C on prostacyclin synthesis by human endothelial cells.

The effect of mitomycin C (MMC) on the biosynthesis of prostacyclin was tested in culture of human umbilical cord vein endothelial cells. A 30% inhibition of the thrombin-stimulated prostacyclin synthesis by MMC was observed at concentrations of the same order as those found in MMC-treated patients (3 micrograms/ml as compared with the peak plasma concentration varying between 0.4 and 3.2 micrograms/ml (J. Den Hartigh et al., Cancer Res 40:5017-5021, 1983)). This inhibition was found for incubation times ranging from 15 to 30 min during which the cell viability was unaltered. Under these conditions it was found that the release of von Willebrand factor by the endothelial cell was unaffected. Since MMC toxicity in man is expressed by a chronic haemolytic and uraemic syndrome, the inhibitory capacity of MMC on prostacyclin synthesis favours the hypothesis that a deficiency in prostacyclin synthesis leads to the development of this syndrome in man.

[Primary microvascular lesions of the kidney or pre-hypertensive nephroangiosclerosis. 25 cases]. / Lésions microvasculaires primitives du rein ou néphroangiosclérose pré-hypertensive. 25 observations.

Isolated non inflammatory lesions of renal microarteries (eventually with mild thickening of tubular basement membranes, but with negative immunofluorescent glomerular studies) were observed in 25 patients (22 males) in whom renal biopsy have been performed for proteinuria (P). Selection criteria were: pathological lesions by definition; absence of hypertension (HT) in clinical and at the time of biopsy; minimum follow up of 4 years after the first statement of the proteinuria (4 to 29 years; mean 14 years). Three groups have been isolated: 1. 3 patients have had an acute glomerulonephritis followed by disappearance of proteinuria. It reappears 1 to 5 years later. HT was discovered 2, 8 and 11 years after the proteinuria. Renal failure occurred 1 and 3 years after HT. 2. 14 patients had hereditary or acquired vascular risk factors (obesity, smoking, ethylism). In 7, HT occurred 3 to 15 years after P. In 2, renal failure occurred 4 to 8 years later. 3. 8 patients had no vascular risk factor; in 3 of them Ht developed 7, 13 and 20 years after the first statement. A positive immunofluorescence with IgM or C3 on renal arterioles had been found in only 3 of the 10 patients who in group 2 and 3 became hypertensive. A proteinuria may precede the occurrence of HT without being induced by glomerulonephritis. Group 2 and 3 suggest that these renal lesions of arterial sclerosis precede and may be a factor of HT. Indeed, this entity may be considered as a prehypertensive condition.

[Hypocomplementary membrano-proliferative glomerulonephritis in a Malagasy patient with schistosomiasis mansoni (detection of bilharzial antigen on glomerular basement membrane using monoclonal antibodies)]. / Glomérulonéphrite membranoproliférative hypocomplémentaire chez un Malgache atteint de bilharziose à Schistosoma mansoni (détection d'antigène bilharzien sur les membranes basales glomérulaires par anticorps monoclonal).

Schistosomiasis due to Schistosoma mansoni affects more than 40 millions people all over the world. Renal involvement is observed mainly in endemic areas. We report a case of hypocomplementemic membrano-proliferative glomerulonephritis in a malagasy man who suffered also from hepatosplenic bilharziosis. The relation between Schistosoma mansoni and the nephropathy was proved by indirect immunofluorescence test using a monoclonal antibody directed against the caecum of adult Schistosoma mansoni.

[Nephrotoxicity of mitomycin C (apropos of 25 case reports). Results of a multicenter survey organized by the Society of Nephrology]. / La néphrotoxicité de la mitomycine C (à propos de 25 observations). Résultats d'une enquête multicentrique organisée par la Société de néphrologie.

We have studied 25 cases of hemolytic and uremic syndrome (H.U.S.) induced by mitomycin C, collected from 1976 to 1982 in 12 Nephrology Centers. Mitomycin C was administered in successive cures at a cumulative dose higher than 50 mg/m2. This H.U.S. is characterized by its slow and late occurrence, by extra-renal, mainly respiratory, manifestations that may reveal the disease, and finally by its pathological aspects. Mesangiolysis and endothelial or mesangial enlarged and atypical nuclei are observed in addition to the usual lesions of thrombotic micro-angiopathy. The prognosis was very poor in the first cases reported. It was better, however, in the patients studied more recently, because the cumulative dose was lower. In severe cases, plasma exchange might improve long-term prognosis. The disease might be due to a direct toxic effect of mitomycin C on the vascular endothelium.

[Nephrotoxicity of antitumor chemotherapy]. / Néphrotoxicité des chimiothérapies antitumorales.

The renal toxicity of antitumoral drugs is an increasingly disturbing problem. These drugs are now prescribed in an ever wider variety of cases, and delayed renal reactions, previously unknown, are revealed by the longer survivals obtained. For a number of years, patients whose cancer had been cured have been placed under haemodialysis on account of drug-induced renal failure. The renal toxicity of cisplatinum, nitrosoureas and methotrexate is well-known, but mitomycin C is also capable of inducing permanent renal failure; the delayed toxicity of this drug explains that it has long been underestimated. This example emphasizes the need for close co-operation between oncologists, nephrologists and pharmacologists in order to determine, for each patient, the most effective treatment with the minimum of side effects.