Updated meta-analytical approach to the efficacy of antihypertensive drugs in reducing blood pressure.

BACKGROUND AND OBJECTIVE: Despite advances in the treatment of hypertension, control rates continue to be suboptimal in both Europe and the US. Strategies that improve hypertension control are therefore urgently needed. This study aimed to assess the relative efficacies of various antihypertensive drugs commonly used in France in reducing systolic and diastolic blood pressure (SBP and DBP) by using a meta-analytical approach. This update of a previously published meta-analytical approach extends the number of drugs evaluated from 13 to 19. METHODS: A total of 80 randomised, controlled trials published between 1973 and 2007 involving 10 818 patients were selected for inclusion in the meta-analytical approach. Data were examined for 19 drugs, and 16 drugs were included in the analysis: hydrochlorothiazide, indapamide sustained-release (SR), atenolol, amlodipine, lercanidipine, manidipine, enalapril, ramipril, trandolapril, candesartan cilexetil, irbesartan, losartan, olmesartan medoxomil, telmisartan, valsartan and aliskiren. Weighted average reductions in SBP and DBP over a period of 8-12 weeks were calculated for each drug from information on both the mean and the variability in BP reduction. No trials evaluating furosemide, spironolactone or cicletanine satisfied the inclusion criteria for this analysis. RESULTS: The average weighted reductions in SBP over 8-12 weeks were most marked with diuretics, and in particular indapamide SR 1.5 mg/day (mean change from baseline -22.2mm Hg), which reduced SBP to a greater extent than any of the other drugs evaluated (at any dosage considered). Average weighted reductions in DBP were generally similar with all classes of antihypertensives and ranged from -11.4mm Hg with the beta-adrenoceptor blocker atenolol and calcium channel antagonists to -10.3mm Hg with the angiotensin II type 1 receptor antagonists. CONCLUSION: This new analysis supports the results of the earlier investigation, in that indapamide SR 1.5 mg/day appeared to be the most effective drug for producing significant reductions in SBP within 8-12 weeks, which is an essential element in optimising cardiovascular prevention among hypertensive patients. The clinical application of these results should take into consideration all the limitations discussed in this analysis.

Long term outcome of patients with low level of cryoglobulin (<0.05g/L).

OBJECTIVES: To date, no studies have yet assessed the characteristics of non-HCV patients with low level of cryoglobulin (≤0.05 g/L). The aims of the current study were thus to: 1) determine the prevalence of cryoglobulin ≤0.05 g/L in patients with non-HCV cryoglobulin; and 2) compare clinical features and long term outcome, including organ complications and mortality rate, between non-HCV patients with cryoglobulin level ≤0.05 g/L and those exhibiting cryoglobulin level >0.05 g/L. METHODS: Among 6379 cryoglobulin testing, cryoglobulin was detected in 618 patients (9.69% of cases); of these 618 patients, 453 non-HCV patients were included in the study. The medical records of these patients were reviewed. RESULTS: Of the 453 non-HCV cryoglobulin-positive patients, 265 (58.6%) exhibited cryoglobulin level ≤0.05 g/L. We showed that patients with cryoglobulin level ≤0.05 g/L had: 1) less commonly: palpable purpura (p<0.001), digital ulcers (p=0.006), peripheral neurologic involvement (p=0.03) and renal impairment (p=0.03); and 2) lower median values of ESR (p<0.001) and C-reactive protein (p=0.001). The patients with cryoglobulin level ≤0.05 g/L less often experienced infections (p=0.04) and hematological malignancies (p=0.01); both groups did not differ regarding prevalence of connective tissue diseases and solid tumors. Mortality rate was as high as 13.6% in patients with cryoglobulin level ≤0.05 g/L; death was mainly due to: solid tumors (16.6%), cardiovascular complications (13.8%), hematological malignancies (11.1%), infections (8.3%), pulmonary/renal complications of cryoglobulin (8.3%) and connective tissue diseases (8.3%). CONCLUSION: Our study shows a high prevalence of cryoglobulin level ≤0.05 g/L in clinical practice. Our findings further underscore that non-HCV cryoglobulin level ≤0.05 g/L may be responsible for severe renal and neurological complications, leading to high morbidity and mortality in these patients. Thus, our data suggest that both appropriate therapy and close follow-up may be required to improve such patients' outcome.

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.

[Diagnostic value of myocardial thallium stress scintigraphy in the detection of coronary artery disease in patients undergoing chronic hemodialysis]. / Valeur diagnostique de la scintigraphie myocardique au thallium sous stimulation dans la détection de la maladie coronarienne chez l'hémodialysé chronique.

Atherosclerotic heart disease is the leading cause of death in patients with end stage renal disease, but its non invasive detection remains difficult because of a low efficacy of exercise testing. The aim of the study was to evaluate diagnostic accuracy of thallium myocardial imaging after dipyridamole combined with exercise. Forty two chronic dialysis patients (34 men, 8 women) aged 55 +/- 11 years (range: 36 to 75) without symptom of angina nor myocardial infarction were studied. In each patient, an echocardiography, a myocardial scintigraphy with dipyridamole combined with symptom-limited exercise, and coronarography were performed. A coronary heart disease was diagnosed by coronarography in 10 patients (4.5 and 1 respectively with 1, 2 and 3 vessels diseased). Echocardiography detected a left ventricular hypertrophy (LVH) in 26 patients and a regional asynergia in 14 patients. A positive scintigraphy was present in 11 patients. Three false-positive and 2 false-negative on scintigraphy were noted. Sensibility, specificity, positive predictive value and negative predictive value were respectively evaluated at 80, 73, 73 and 93%. All the five patients with either false-positive or false-negative scintigraphy exhibited a LVH. CONCLUSION. In chronic dialysis patients, coronary heart disease may be detected by thallium myocardial imaging after dipyridamole combined with exercise.

[Evaluation of hospital cost of six days of treatment of deep venous thrombosis. Comparison of subcutaneous nadroparin and intravenous heparin in 40 patients]. / Evaluation du coût hospitalier de six jours de traitement curatif d'une thrombose veineuse profonde. Comparaison nadroparine sous-cutanée et héparine intraveineuse chez 40 patients.

For curative treatment of deep vein thrombosis, all trials have shown that twice a day low molecular weight heparin were at least as efficacious as unfractionated heparin on clot reduction or stabilisation. Through the unit cost of low molecular weight heparin is higher, the real cost of treatment should take into account not only the cost of the drug, but also the cost of materials used and lab tests as well as the time necessary. We have therefore prospectively compared the operating and overall costs of nadroparin and intravenous heparin treatment of deep vein thrombosis in hospitalised patients (21 with unfractionated heparin and 19 with nadroparin). The results show that low molecular weight heparin is no more expensive than treatment with unfractionated heparin (336 +/- 74.9 F for unfractionated heparin and 344.9 +/- 44.05 F for nadroparin). In addition, using nadroparin rather than heparin saves approximately one hour per patient per week nursing time (42 +/- 7 minutes vs 104.0 +/- 10.7 minutes, p < 0.05). The methodology of this study should be repeated with other low molecular weight heparin and low molecular weight heparin compare not only to standard i.v. heparin, but also to standard SC heparin.

[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.

[Functional acute kidney failure]. / Insuffisances rénales aiguës fonctionnelles.

Prerenal acute renal failure is defined as a reduction in the glomerular filtration rate due to a primary disturbance in renal hemodynamics in the absence of any structural kidney damage. In case of moderate hypotension or hypovolemia, a number of adaptative systemic and intrarenal responses preserve renal perfusion and filtration rates, particularly by inducing a marked reduction in preglomerular arteriolar resistance and an increase in postglomerular resistance. However, these mechanisms are inherently limited. In the presence of advanced circulatory failure or iatrogenic pharmacologic interventions compromising these renal defense mechanisms, prerenal failure becomes evident. Therefore, prerenal failure may occur during acute hemodynamic disturbances due to hypovolemia or systemic vasodilatation, in severe cardiac failure, in cirrhosis with ascites, and in certain clinical situations following administration of nonsteroidal antiinflammatory agents or angiotensin converting enzyme inhibitors. The treatment depends on the underlying cause.

[Molecular basis of renal development]. / Bases moléculaires du développement rénal.

The first step of renal development is characterized by the invasion of a mesenchymal tissue, the metanephric blastema, by an epithelial structure, the ureter bud. Reciprocal inductive interactions between these two tissues, involving the sequential activation of genes that begin to be identified, are required for the successive stages of kidney morphogenesis. Recent technological advances such as gene targeting and improvement of organotypic culture have revealed the role of these genes and of several essential factors in kidney development. This review will focus on the genes which govern renal organogenesis, with special emphasis on those coding transcription and diffusible factors.

Do matrix metalloproteinases MMP-2 and MMP-9 (gelatinases) play a role in renal development, physiology and glomerular diseases?

Metalloproteinases MMP-2 and MMP-9 (also called gelatinases) are involved in cell invasion and in embryonic development and organogenesis. A growing number of reports suggest that MMP-2 and MMP-9 play some role in renal development, renal tubule physiology and glomerular pathophysiology. This editorial will focus on recent controversial data, especially those obtained from studies on MMP-9-deficient mice, which shed new light on the functions of gelatinases in normal and diseased kidneys.

The management of uraemia in the elderly: treatment choices.

The particularity of geriatric medicine and the lack of information due to the fact that geriatric nephrology dates back only 10 years explains why the management of chronic uraemia among the elderly presents itself as a succession of difficult dilemmas. (1) Should causes of chronic renal failure be systematically determined and treated? Risk-benefit assessments of the investigations and treatments involved in preventing or slowing down the evolution to end-stage renal disease (ESRD) are required to answer this question. (2) In cases of ESRD, should dialysis always be considered? The fact that life expectancy is limited for the aged does not justify depriving them of treatment. Nevertheless, in some borderline situations, conservative treatment may be preferable. (3) When should dialysis be started? Currently the mortality before the 90th day of dialysis is very high among elderly patients. To improve results it is probably necessary to determine appropriate criteria for starting treatment before complications occur. (4) What is the best method for the first treatment? There is much controversy about the respective advantages of haemodialysis and peritoneal dialysis. The choice depends on the individual's medical and social conditions. (5) Should dialysis treatment be stopped, and, if so, in this case, when? The large acceptance rate of elderly patients for dialysis implies that withdrawal of treatment must sometimes be considered. Fears linked to this dilemma probably explain why some physicians choose to exclude elderly patients from dialysis. It seems to us more ethical to treat this group of patients and assume responsibility for stopping treatment should it be necessary.

[Toxic effect of two antitumoral agents derived from platinum, the cisplatin and the oxaliplatin on primary cultures of proximal tubular cells of the kidney in rabbits]. / Action toxique de deux agents antitumoraux dérivés du platine, le cisplatine et l'oxaliplatine sur des cultures primaires de cellules tubulaires proximales de rein de lapin.

There is a large field of use for cisplatin and its derivatives in the treatment of human malignancies. The nephrotoxicity is their most important use-limiting factor. The aim of this work has been to study comparatively the cisplatin and a new molecule, the oxaliplatin on primary culture of proximal tubular cells of rabbit kidney. Several markers, functional, enzymatic and biochemical have been evaluated after exposure to platinum's derivatives. The results indicates that their toxic effects are exerted on DNA and proteins synthesis, and for the cisplatin on the glucose uptake. Oxalyplatin's effect on DNA synthesis seems to be more effective, but induced a more progressive cytotoxicity. The lipids peroxidation's role with abnormalities of glutathione dependent detoxication system of the cell is possible. In conclusion, oxaliplatin seems to have a pharmacological effect more powerful than cisplatin. Its low dose effect ratio seems to promise greater safety in its use.

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.

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.