[The flavonoids effect against vinblastine, cyclophosphamide and paracetamol toxicity by inhibition of lipid-peroxydation and increasing liver glutathione concentration]. / Effect protecteur des flavonoïdes contre la toxicité de la vinblastine, du cyclophosphamide et du paracétamol par inhibition de la peroxydation lipidique et augmentation du glutathion hépatique.

The paracetamol and cyclophosphamid are metabolized in the liver by the cytochrome P450. The formed reactive intermediates are responsible of a hepatocyte depletion of the glutathion and a lipoperoxydation. the vinblastine is also a chemotherapeutic agent hepatotoxic and hematotoxic. Otherwise, flavonoïds are polyphenols substances of plant origin having some biological and anti-oxydative properties. However no information is available on their effects on glutathion and glutathion-s-transferases. In our research, we valued the effect of oral administration of flavonoids (diosmine and quercetine) under shape of propolis extract to 60 mg/kg daily during 14 days, on hematological and hepatic toxicity of a single dose of cyclophosphamide 80 mg/kg by intravenous way, vinblastine 2 mg/kg by intravenous way and the hepatic toxicity of the paracetamol managed by oral way to 200 mg/kg corresponding to 2/3 the DL50 at the rat female albinos wistar. We did a blood numeration, an assessment of serum activities of transaminases and alkali phosphatases as well as quantification of the glutathion and the malondialdehyde (MDA) in liver homogenats of rats treated. Analyses are done at regular intervals; 1, 3, 7 and 14 days after the administration of drugs. In the group of rats treated by the cyclophosphamid paracetamol alone we observed since the 1st day, an increase of lipid peroxide (MDA) of 120% and a downfall of hepatic glutathion including the group receiving the vinblastine (until 210% of reduction). In the same way a severe leucopenia and a thrombopenia (70% of reduction) are observed between the 3rd and the 14th day at rats treated by the chemotherapeutic agents alone (cyclophosphamide and vinblastine). The combination of flavonoids with drugs have clearly reduced the effect of drugs toxicity. Indeed, the aplasic observed with the vinblastine, as well as the leucopenia and thrombopenia of the cyclophosphamide are corrected entirely. In the same way, we noted a restoration of rates of peroxide and glutathion. Flavonoïds seem to act by activation of the turn over of the glutathion and enzymes stimulating particularly glutathion-s-transferases permitting the captation of the reactive metabolites of the studied drugs.

[Is it possible to reduce the incidence of aminoglycoside-induced nephrotoxicity?]. / Peut-on diminuer l'incidence de la néphrotoxicité des aminoglycosides.

The incidence of nephrotoxicity due to aminoglycosides should be sharply reduced. The indications for prescribing these antibiotics should be limited to infectious disorders induced by aerobic Gram-negative bacteria and by some Gram-positive bacteria requiring treatment in specialized hospital units using an association of aminoglycosides and another antibiotic. Daily doses should not exceed those indicated by the manufacturer, and the length of treatment should be as short as possible, with a relay to other antibiotics that are not or are less nephrotoxic. The possibilities for reducing the incidence of nephrotoxicity are few. It is not possible to prevent the antibiotic from entering the renal tubular cell or from producing deleterious effects therein. However, by using short-term intravenous infusion as the administration route, prolonged contact between the antibiotic and its receptors on the brush borders of the proximal tubular cells can be avoided, particularly since the process of cellular absorption is saturable. Essentially, doses should be adapted according to the age and the glomerular filtration of the patient, since renal function usually decreases with age. Volemic and hydroelectrolytic disorders favour nephrotoxicity and should be corrected. Associations with other nephrotoxic drugs should either be avoided or used with increased caution. The same is true in special situations such as endotoxaemia, severe renal parenchymatous infections and cholestasis. In any case, given the well-known insidious onset of nephropathy, aminoglycoside treatment always requires laboratory follow-up consisting of repeated testing of creatinemia during the two weeks of treatment.

[A priority mission: prevention, early detection, identification of risk factors of progression of chronic renal insufficiency]. / Une mission prioritaire: la prévention, le dépistage précoce, l'identification des facteurs de risque de progression de l'insuffisance rénale chronique.

The prevalence of chronic renal failure is continuously increasing. The reasons are the lengthening life expectancy of the general population, the increasing age of the patient population benefitting from renal replacement therapy and the growing number of vascular and diabetic nephropathies leading to end-stage renal disease. The financial burden of treating renal failure is considerable, estimated at nearly 2 percent of the national health budget. A priority for French departments of nephrology is to initiate and participate in epidemiological studies on renal failure in order to eradicate the present pitfalls: lack of exhaustiveness and non-validation of information. The need is to create networks for patient care and management, grouping specialists such as cardiologists, diabetologists, rheumatologists and gerontologists, who face the problems stemming from renal failure, for early identification of problems, in order to apply appropriate measures to slow disease progression and to initiate renal management at the optimal time. Active participation in research is indispensable, not only in multicentric studies but also in "nephrosurveillance" and for development of guidelines for good clinical practice and good prescription practice. Many tools are available for undertaking varied experimental research. This research can lead to identification of the cellular and molecular mechanisms underlying nephron destruction and to development of effective strategies to slow or halt the progression of lesions. Identification of genetic factors that favor the appearance or progression of renal failure is in its early stages and will continue to develop. All these efforts require communication and teaching. A last point: the need to revamp hospital organization to better respond to the needs of patients requiring only a few hours in specialized units.

[Massive poisoning by African bee stings]. / Envenimation massive après piqûres d'abeilles africaines.

BACKGROUND: Bee stings can cause severe toxic effects when envenomation is massive. CASE REPORT: While touring in Casamance (Southern Senegal) a white male was severely stung by a swarm of African bees. The massive envenomation caused rhabdomyolysis, hemolysis and acute renal failure. Pathology examination of kidney and bladder specimens showed vasculitis affecting both arteries and veins. The patient was treated with several hemodialysis sessions and renal function returned to normal three months after the incident. DISCUSSION: Bees in Africa, known as "killer bees", are particularly aggressive. They have recently been imported from tropical zones in America where a large number of deaths have been reported. Most cases of massive envenomation have shown acute tubular necrosis or renal involvement with myoglobinuria or hemoglobinuria. The renal pathology observed in our case is not usually described.

[Extracapillary glomerulonephritis secondary to D-penicillamine. Apropos of 1 case and review of the literature]. / Glomérulonéphrites extracapillaires secondaires à la D-pénicillamine. A propos d'une observation et revue de la littérature.

Extracapillary glomerulonephritis was diagnosed in a 51-year-old woman after 11 months of D-Penicillamine treatment given for systemic sclerosis. Antineutrophil cytoplasmic antibodies specific for myeloperoxydase were detected. Penicillamine was stopped and the patient was treated with plasma exchanges, cyclophosphamide and corticosteroids. The renal function progressively deteriorated leading to end stage requiring dialysis. Previous reports of extracapillary glomerulonephritis after D-penicillamine are analysed. Several cases with alveolar haemorrhage are consistent with the diagnosis of microscopic polyangiitis.

Autoantibodies against a kidney--liver protein associated with quinolone-induced acute interstitial nephritis or hepatitis.

In the present study we report on four cases of acute interstitial nephritis (AIN) and two cases of hepatitis induced by quinolone. We show by immunoblotting analysis that all sera from these patients contained autoantibodies that recognize a 65-kDa protein expressed in normal human kidney and liver microsomes. Only 6% of sera from healthy individuals who did not ingest quinolone recognized the same protein. These findings suggest that the presence of autoantibodies could be used as a sensitive marker and that a modification of microsomal proteins by quinolone itself or by a metabolite could generated an autoimmune response.

[Interstitial nephropathies of toxic or drug origin. New causes, new prospects]. / Néphropathies interstitielles d'origine médicamenteuse ou toxique. De nouvelles causes, de nouvelles perspectives.

PHENOTYPING INTERSTITIAL INFILTRATIONS: Recent progress has led to the distinction between type I and type II fibroblasts in the renal interstitium. The cellular phenotype of pathological infiltrations can be identified with monoclonal antibodies. DRUG-INDUCED INTERSTITIAL NEPHROPATHIES: Extrarenal manifestations (skin eruptions, fever, joint pain) often suggests the diagnosis but may be absent, in which case renal histology is required. CAUSAL DRUGS: Among the different causal agents, nonsteroid anti-inflammatory drugs cause abnormal leakage from glomerular capillaries favoring the development of a nephrotic syndrome associated with renal failure and major cell infiltration into the interstitial tissue. CHRONIC DISEASE: Chronic interstitial nephropathy is nearly asymptomatic and may only be discovered at an advanced stage. Briefly, there are three categories which result from long-term administration of 5-aminosalicylate, use of Chinese herbal medicines to lose weight, and chronic intoxication with ochratoxin (a mycotoxin). COMPLEX PHYSIOPATHOLOGY: Immunological mechanisms are involved although it is not always easy to distinguish between manifestations of humoral and cellular reactions. Both could be implicated as indicated in recent experimental animal models which throw more light on the pathological process in humans. RENAL PROGNOSIS: Different strategies can be used to halt or limit the development of fibrosis and thus improve prognosis of toxic interstitial nephropathies: counteract cellular immunity reactions, inhibit fibroblast proliferation and activation, reduce synthesis and stimulate degradation of the extracellular matrix, and inhibit collagen formation.

Efficacy and Tolerability of Fosinopril 10mg and Hydrochlorothiazide 12.5mg Combination in Elderly Patients with Mild to Moderate Hypertension : A French Multicentre Study.

The objective of the study was to evaluate the efficacy and tolerability of the combination of fosinopril l0mg (FOS) and hydrochlorothiazide (HCTZ) 12.5mg versus placebo in the treatment of elderly patients with mild to moderate hypertension. The study included two distinct phases: Phase I was a short-term phase consisting of a 4-week single-blind, placebo lead-in period followed by a randomised, double-blind, parallel group where patients were treated with either a combination tablet of FOS 10mg with HCTZ 12.5mg or placebo given once daily for 8 weeks. A total of 150 patients, ranging from 60 to 91 years of age, were included in this study. Phase II was a long-term extension of phase I and was a 12-month open-label follow-up in which all patients started therapy with FOS l0mg/HCTZ 12.5mg. After 4 weeks of initial therapy, escalation to FOS 20mg/HCTZ 12.5mg was allowed for seated diastolic blood pressure (SeDBP) > 90mm Hg. Clinic visits were scheduled at months 1, 3, 6, 9 and 12. Data from 118 patients were analysed. The mean SeDBP decreased from baseline more in the FOS/HCTZ group (-12.2mm Hg) than in the placebo group (-6.4mm Hg). Similar results were observed for supine diastolic and systolic blood pressure. After 8 weeks of treatment, 58.2% of patients showed normalised (≤ 90mm Hg) SeDBP with Fos/HCTZ vs 30.3% in the placebo group (p < 0.001). The mean decrease from baseline in SeDBP was -14.3mm Hg and -18.4mm Hg at 1 month and 12 months, respectively, demonstrating efficacy of the lower dose combination (10/12.5mg). The mean seated systolic blood pressure (SeSBP) also decreased from baseline and was -24.5mm Hg and -28.5mm Hg at months 1 and 12, respectively. The results for supine blood pressure corroborated the findings for seated blood pressure. Four patients died either during (2) or shortly after (2) long-term therapy, 5 patients discontinued long-term therapy because of adverse events, 14 patients experienced 16 serious adverse events. Cough was the most common adverse effect reported in 10.4% of patients. No symptomatic orthostatic hypotension was reported.Fosinopril 10 or 20mg when administered in combination with hydrochlorothiazide 12.5mg once daily for 12 months was found to be an effective antihypertensive treatment in elderly patients with mild to moderate hypertension.

Altered flow-dependent vasodilatation of conduit arteries in maintenance haemodialysis.

BACKGROUND: An altered arterial nitric oxide (NO) pathway could partly explain the damage to arteries observed in haemodialyzed (HD) patients. The present study was designed to non-invasively evaluate the NO pathway of peripheral conduit arteries in HD patients. METHODS: Twelve normotensive, non-diabetic HD patients treated with erythropoietin and 12 matched healthy controls (C) were included in the study. The effect of endogenous release of NO was assessed by measuring the flow-dependent vasodilatation of the radial artery (post-ischaemic hyperaemia), and the response to exogenous NO assessed using sublingual glyceryl trinitrate administration (GTN). RESULTS: Radial artery diameter (echo-tracking), radial blood flow (RBF: Doppler) and mean arterial pressure (Finapres) were identical at baseline in HD patients and in healthy subjects. The flow-dependent vasodilatation of the radial artery was decreased in HD patients (C: 9 +/- 1% vs HD: 3 +/- 05%, P < 0.05). The decrease in radial vascular resistance (C: -44 +/- 4% vs HD: -24 +/- 2%, P < 0.05) and the increase in radial diameter (C: 31 +/- 2% vs HD: 25 +/- 2%, P < 0.05) after GTN administration were less in HD patients than in controls. The ratio between the increase in diameter after hyperaemia to the increase in diameter after GTN, was also diminished in HD patients (C: 30 +/- 3% vs HD: 13 +/- 2%, P < 0.001). CONCLUSIONS: The flow-dependent vasodilatation of peripheral conduit arteries is altered in HD patients and is associated with a slight but significant decrease in the vasodilating response to exogenous NO. These results suggest, in the absence of changes in basal radial vascular resistance and arterial diameter, more a decrease in endothelial NO bioavailability, than an increase in basal vascular tone.

[Experimental and human nephrotoxicity induced by ochratoxins]. / Néphrotoxicité expérimentale et humaine des ochratoxines.

Ochratoxin A is a mycotoxin: a dihydroisocoumarin derivative linked to L. beta phenylalanine. Ochratoxin A is produced by a number of Aspergillus and Penicillium species. This mycotoxin is a carcinogenic, teratogenic, mutagenic and immunosuppressive substance. Ochratoxin A is a common contaminant found in a variety of foods for human nutrition as well as animal feeds. The aim of this study is to discuss nephrotoxic properties of this mycotoxin in humans. Nephrotoxicity has been reported in many animals after exposure to ochratoxin A. Porcine nephropathy due to this mycotoxin is a well known disease characterized by impairment of proximal renal function. Renal damage is also confined to the proximal tubule in other animal species. A good correlation is found between renal function abnormalities and the location of the lesions along the nephron. Of particular interest is the presence of nuclear abnormalities of the epithelial cells with pyknosis, karyorrhexis and karyomegaly. The question is to know if ochratoxin is nephrotoxic in humans. Acute nephrotoxicity seems to be very rare and we found only one case report suggesting such a possibility. We observed the occurrence of chronic renal failure in two patients with a possible responsibility of a chronic ochratoxin A intoxication. Clinical and histologic findings in these two patients were quite similar to those described in several cases of karyomegalic interstitial nephritis. Striking similarities between the changes in renal structure and function seen in ochratoxin A-induced experimental nephropathies and in Balkan endemic nephropathy suggest a common etiologic agent. This mycotoxin could be also responsible for interstitial nephropathies in North Africa.

Crescentic glomerulonephritis in juvenile chronic arthritis.

Juvenile chronic arthritis (JCA) was diagnosed in 2 young girls. In one of them, antinuclear antibodies (ANA) were strongly positive during the course of erosive polyarthritis. After 5 years followup, severe renal insufficiency occurred. Antineutrophil cytoplasmic antibodies (ANCA) were positive with a perinuclear pattern on indirect immunofluorescence (IIF) and antimyeloperoxidase (MPO) specificity. Renal biopsy showed severe crescentic glomerulonephritis without significant deposits on IIF. Treatment consisted of prednisone and monthly intravenous cyclophosphamide pulse. Renal failure worsened and hemodialysis was necessary. A 2nd patient was referred for polyarthritis with positive rheumatoid factors without positive ANA. The presence of microscopic hematuria led to the discovery of crescentic glomerulonephritis with positive ANCA of anti-MPO specificity. At latest examination, after prednisone for 10 months and azathioprine for 6 months, the patient had moderate proteinuria with normal renal function. These observations emphasize that in juvenile onset chronic polyarthritis, renal microscopic angiitis with ANCA of anti-MPO specificity may occur.

Pharmacokinetics of netivudine, a potent anti-varicella zoster virus drug, in patients with renal impairment.

The pharmacokinetics of a single oral 200 mg dose of netivudine (1-(beta-D-arabinofuranosyl)-5-(1-propynyl)uracil), a nucleoside analogue under development for use in varicella zoster virus infections, were studied in 12 renal failure (RF) subjects (creatinine clearance 15 +/- 7 mL/min) and 12 age-matched healthy subjects with normal creatinine clearance. Blood and urine samples were collected up to nine days after drug administration. Concentrations of netivudine and of its main metabolite, the pyrimidine base 5-(1-propynyl)uracil (5 PU), were determined by a specific high performance liquid chromatography assay. The mean peak plasma concentrations of netivudine, Tmax, and volume of distribution were not significantly affected by RF. The elimination half-life of netivudine was approximately 15 h in subjects with normal renal function and 60 h in RF patients. Plasma and renal clearances of netivudine were significantly reduced in RF patients and AUC was three to four times higher in these patients. Cmax and AUC of 5 PU were higher in RF patients, and the half-life was also significantly longer. However, the half-life of this metabolite was much lower than that of the parent compound. Tmax and the lag time were similar in the two groups. There were highly significant correlations for netivudine and 5 PU between half-life and creatinine clearance and between renal clearance and creatinine clearance. These findings suggest that netivudine dosage may need to be reduced in patients with severe renal failure, and confirm that formation of the 5 PU is independent of the elimination of netivudine from plasma.

Kinetics, safety, and efficacy of ramipril after long-term administration in hemodialyzed patients.

We studied the efficacy and safety of ramipril and the kinetics of its active moiety ramiprilat in 12 hypertensive patients receiving regular hemodialysis, after a single dose and after long-term (28 days) administration. Patients received 2.5 mg ramipril after each hemodialysis. On days 1 and 29, ramipril was administered 4 h before the hemodialysis and serial blood samples were obtained for 9 h for determination of pharmacokinetic parameters. Tolerability was good, and all patients completed the study. There was a high degree of angiotensin-converting enzyme (ACE) inhibition throughout the study. Ramipril had a clear-cut antihypertensive effect. Long-term administration of ramipril did not modify the time to peak ramiprilat concentration, but increased the mean maximal concentration significantly: 20.2 +/- 12.7 vs. 10.4 +/- 7.1 ng center dot ml-1. The mean accumulation ratio was 2.2. Ramiprilat hemodialysis clearance was 31.7 ml/min (range 4.2-64.9 ml/min) on day 1 and 21.0 ml/min (range 7.9-56.5 ml/min) on day 29. Ramipril 2.5 mg, administered after hemodialysis, appears to be safe and effective in hypertensive patients receiving periodic hemodialysis. Despite an increase in ramiprilat concentration from day 1 to day 29, the steady state was reached. We describe the role of nonrenal clearance of ramiprilat.

The cellular toxicity of two antitumoural agents derived from platinum, cisplatinum versus oxaliplatinum, on cultures of tubular proximal cells.

There is a large scope for the use for cisplatin and its derivatives in the treatment of human malignancies. Nephrotoxicity is their most important use-limiting factor. The aim of this study has been to compare cisplatin (CDDP) and oxaliplatin (1-OHP), a new derivative, on cultures of tubular proximal cells. Three cells models were used: primary culture of rabbit kidney, proximal tubular cells (RPTC) and established opossum kidney (OK) and pig kidney (LLC-PK1) epithelial cell lines. Results indicate that in these three culture systems, the cytotoxicity-ranking of the two molecules were in agreement with their in vivo nephrotoxicity (CDDP > 1-OHP), but were less cytotoxic for OK and LLC-PK1 cells than for RPTC. Functional and biochemical evaluations in RPTC indicate that toxic effects of platinum derivates are exerted on DNA, protein synthesis and glucose uptake. 1-OHP effect on DNA synthesis seems to be more effective, but induced a more progressive cytotoxicity. Alteration of glutathione-dependent detoxication activities may reflect the occurrence of a lipid peroxidation process. The present study showed that 1) RPTC are more suitable that LLC-PK1 or OK cells for investigating the nephrotoxicity of platinum derivatives; 2) 1-OHP seems to have a more powerful pharmacological effect than CDDP. The toxic effect ratio seems to promise greater safety with 1-OHP than with CDDP.