Human hypertension caused by mutations in WNK kinases.

Hypertension is a major public health problem of largely unknown cause. Here, we identify two genes causing pseudohypoaldosteronism type II, a Mendelian trait featuring hypertension, increased renal salt reabsorption, and impaired K+ and H+ excretion. Both genes encode members of the WNK family of serine-threonine kinases. Disease-causing mutations in WNK1 are large intronic deletions that increase WNK1 expression. The mutations in WNK4 are missense, which cluster in a short, highly conserved segment of the encoded protein. Both proteins localize to the distal nephron, a kidney segment involved in salt, K+, and pH homeostasis. WNK1 is cytoplasmic, whereas WNK4 localizes to tight junctions. The WNK kinases and their associated signaling pathway(s) may offer new targets for the development of antihypertensive drugs.

Cerebroprotective effect of angiotensin IV in experimental ischemic stroke in the rat mediated by AT(4) receptors.

Recent studies have reported potential roles of angiotensins in an adaptative physiological mechanism of protection against cerebral ischemia-induced neurological damages. In the present study, we examined the protective role of angiotensin IV (AngIV) in a rat model of embolic stroke induced by intracarotid injection of calibrated microspheres (50 microm). Internal carotid infusions of increasing doses of AngIV (0.01, 0.1 and 1 nmol/0.1 mL saline) dose dependently decreased mortality, neurological deficit and cerebral infarct size at 24 hours. With the highest dose of AngIV, mortality was reduced from 55 % in saline infused controls to 10 % (p=0.003), neurological deficit was reduced from 3.8 +/- 0.3 to 1.4 +/- 0.3 , (p<0.0001) and cerebral infarct size at 24 hours was decreased from 432 +/- 26 mm(3) to 185 +/- 19, (p=0.0001). The AT(4) antagonist divalinal-AngIV (10(-9) mol/0.1 mL), or pretreatment with L-NAME (10(-7) mol/0.1 mL), both completely abolished the protective effect of AngIV (1 nmol). The AT(2) antagonist PD123319 (10(-7) mol/0.1 mL) partially prevented the protective effect of AngIV on the neurological score. Sequential cerebral arteriographies revealed that AngIV induced a redistribution of blood flow to the ischemic areas within minutes. These results suggest that pharmacological doses of AngIV are protective against acute cerebral ischemia by triggering an AT(4)-mediated, NO-dependent intracerebral hemodynamic mechanism.

Pancreatitis related to severe acute hypertriglyceridemia during pregnancy: treatment with lipoprotein apheresis.

We report a clinical observation of acute pancreatitis due to severe hypertriglyceridemia in a pregnant woman. In order to decrease the serum triglyceride level rapidly, two lipaphereses were undertaken using the double-filtration technique. This lipoprotein apheresis technique is briefly described and the efficacy in reducing rapidly hypertriglyceridemia is outlined. Like in 3 previously published reports, the patient had a rapid recovery, confirming that lipoprotein apheresis should be an adequate and a well-tolerated treatment in such a condition.

Use of alkaline calcium salts as phosphate binder in uremic patients.

In order to prevent aluminum toxicity induced by the association of aluminum phosphate binder with 1 alpha(OH) vitamin D3 derivatives and the use of deferoxamine with its own hazards to diagnose and treat this toxicity, we have shown in 1982 that it was possible to replace the iatrogenic association of aluminum phosphate binder with 1 alpha OH vitamin D derivatives by oral calcium carbonate taken with the meals in order to bind phosphate and correct the negative calcium balance. This led to the disappearance of the crippling aluminic osteomalacia and adynamic bone diseases in our center. The effectiveness of CaCO3 without 1 alpha(OH)D3 derivatives in the control of hyperparathyroidism in dialysis patients has been proven by the appearance in four patients of our dialysis population of an histological idiopathic adynamic bone disease associated with relative hypoparathyroidism, and by the finding that more than 50% of our dialysis population treated by this sole treatment have plasma concentration of intact PTH below twice the upper limit of normal (that is, the threshold above which only significant histological osteitis fibrosa is observed). Besides the compliance problem, the limit of CaCO3 is the occurrence of hypercalcemia which occurs in about 8% of the measurements. Since calcium acetate binds twice as much phosphate for the same dose of elemental calcium as CaCO3, its use has been recommended. However, clinical experience has shown that in spite of the fact that half the dose of calcium element given as acetate does actually control predialysis plasma phosphate as well as CaCO3, the incidence of hypercalcemia is not decreased, probably because calcium availability at the alkaline pH of the intestine is much greater with Ca acetate. When hypercalcemia is frequent (and not explained by autonomized hyperparathyroidism, adynamic bone disease, overtreatment with vitamin D, granulomatosis or neoplasia) it is necessary either to decrease the dose of calcium and complete the necessary binding of phosphate by adding small doses of Mg(OH)2 or Mg carbonate, provided the dialysate Mg is decreased to 0.2 to 0.35 mmol/liter to prevent hypermagnesemia or to decrease the dialysate calcium (DCa) concentration. The decrease of DCa can be made either just when hypercalcemia occurs or on a systemic basis according to the amount of CaCO3 used and to the necessity of associating 1 alpha(OH) vitamin D3 derivatives.(ABSTRACT TRUNCATED AT 400 WORDS)

Risk factors of renal failure progression two years prior to dialysis.

AIM: The respective contribution of sex, type of nephropathy, degree of proteinuria, blood pressure, protein and sodium daily intakes, blood lipid profile, protidemia, hemoglobinemia, acidosis and CaPO4 product on the rate of renal failure progression is debated. PATIENTS AND METHODS: The link between these parameters and the decrease of creatinine clearance, deltaCcr (according to Cockroft) was assessed in uni- and multivariate analysis in a population of 49 patients (26 women; age 60+/-15 years, weight 79+/-15 kg) selected out of 173 presently treated hemodialysis patients on the basis of availability of a quarterly follow-up for 2 years before starting dialysis. The patients were advised a moderate protein and salt restriction which could be retrospectively assessed (on urinary excretion of urea and sodium) at, respectively, 0.82 g/kg/day and 6.5 g/day. RESULTS: The 2-year deltaCcr was 14+/-14 ml/min. It was not different in men and women. This decrease in Ccr was neither significantly different in gomerular disease (17+/-8, n = 14), diabetic nephropathy (12+/-6, n = 7), nephroangiosclerosis (15+/-8, n = 5), interstitial nephritis (12+/-10, n = 14), and PKD (11 +/-12, n = 9). Patients with antihypertensive drugs (n = 42) had a faster progression than those without drugs (n = 7): deltaCcr = 15+/-14 vs 7+/-7 ml/min (p < 0.05) in spite of comparable blood pressure but with higher proteinuria. Linear regression of deltaCcr with the initial and 2-year averaged values of the quantitative parameters showed a significant positive link for both values with cholesterol, hemoglobine and proteinuria and a negative one with protidemia. A positive link was observed with the initial value of bicarbonate and the 2-year mean of diastolic and mean blood pressures. No link at all was observed with urea and Na excretion, CaPO4 product and triglycerides. Multiple regression disclosed a significant link only for protidemia (negative with both initial and 2-year averaged value), diastolic BP (only for the 2-year averaged value and hemoglobinemia (for the initial value). When the patients were classified according to a threshold value of their protidemia, DBP, hemoglobinemia, and cholesterolemia those with the combination of 2 risk factors of progression (protidemia > or = 66 g/l, DBP > or = 90 mmHg, hemoglobinemia > 11 g/dl, proteinuria > or = 3 g/d, CT > 5 mmol/l) had a significantly greater decrease of Ccr than those with the 3 other combinations at the exception of the association of low protidemia with DBP. CONCLUSION: Diastolic hypertension and low protidemia are the 2 most important factors predicting progression of renal failure. A predictive synergy was furthermore pointed out between low protidemia or diastolic hypertension with proteinuria and cholesterol. On the contrary anemia attenuates progression linked to low protidemia, diastolic hypertension, proteinuria and high cholesterol.

Non-AT(1)-receptor-mediated protective effect of angiotensin against acute ischaemic stroke in the gerbil.

Previous studies have shown that angiotensin II (Ang II), by mediating rapid recruitment of collateral circulation, has a protective effect in the setting of acute ischaemia. In an experimental model of acute cerebral ischaemia in the gerbil, Fernandez et al. have reported that the mechanism of the protective effect of Ang 11 is blood pressure (BP)-independent, and that the AT1-receptor antagonist, losartan, but not the ACE inhibitor (ACE-I),enalapril, decreases mortality following unilateral carotid artery ligation. The aim of this study was to examine there producibility of the respective effects of losartan and enalapril, and to verify that these differential effects are drug class-related. Acute cerebral ischaemia was induced in anaesthetised gerbils bv unilateral carotid ligation. The effect of pretreatment with two different ACE-I(enalapril and lisinopril), and two different AT1-receptor antagonists (losartan and candesartan), administered orally or intravenously, on mortality were compared. Kaplan-Meier survival curves at day three were analysed bv a log-rank test. Pretreatment with both enalapril and lisinopril significantly decreased survival at day three compared with controls, while the AT1-receptor antagonists losartan and candesartan, despite similarly lowering BP, did not increase mortality. Coadministration of losartan and enalapril increased mortality to the same extent as enalapril alone. This study confirms that Ang II contributes to protective mechanisms against acute cerebral ischaemia through non AT1-receptor-mediated, BP-independent effects.

[Could angiotensin II type I receptor antagonists have a superior beneficial effect than that of angiotensin II converting enzyme inhibitors with respect to the risk of cerebrovascular accident?]. / Les antagonistes des récepteurs de type 1 de l'angiotensine II peuvent-ils avoir un effet bénéfique supérieur à celui des inhibiteurs de l'enzyme de conversion vis-à-vis du risque d'accident vasculaire cérébral?

In contrast with the expected results, the Captopril Prevention Project study has found that the relative risk of stroke was greater by 25% in patients treated with ACEI than in patients receiving the conventional diuretics +/- betablockers regimen (Hanson et al. ISH Amsterdam, June 98). This difference persisted after adjustment for the initial differences of blood pressure levels between the groups after randomisation. This does not mean that ACEI would worsen the risk of stroke when compared to a placebo, since a potent protective effect of diuretics and betablockers on the relative risk of stroke has long been demonstrated. Nonetheless, these results suggest that for a similar blood pressure lowering effect, conventional therapy is more effective than ACEI to prevent stroke. This finding, in discrepancy with the current prevailing opinion that ACEI have emerged as the most effective preventive treatment to reduce cardiovascular morbidity, is regarded as surprising by the investigators. However, a number of animal experimental data may help to envisage the complete inhibition of angiotensin II formation as a two-edged sword, because of the multiplicity of its receptors mediating different, and even opposite effects. In a series of experimental studies in mammals, the group of Fernandez has provided a bundle of observations suggesting that angiotensin II contributes to early reperfusion following acute ischemia by enabling the recruitment of pre-existing collateral vascularisation, an effect mediated via the stimulation of non-AT1 receptors (possibly AT2). Indeed, the worsening of stroke in the gerbil after incomplete ligation of the carotid by pre-treatment with ACEI had been demonstrated by these authors (J Cerebral Blood Flow Metab, 1988; 24:937), and they further show that pre-administration of losartan significantly reduced the ischemic brain damage and the mortality induced by the abrupt ligation of one carotid, but that this preventive effect of losartan was abolished if enalapril was co-administrated (J Cardiovasc Pharmacol 1994; 24:937). The first available clinical data on stroke risk with ACEI reported in the CPP study, showing a less effective prevention of stroke with ACEI than diuretics supports the hypothesis that similar mechanism may also prevail in humans, and lead us to propose to discuss the rationale for a large multicentric trial aiming to compare the protective effect of ARAT1 and ACEI on the risk of recurrence of stroke.

[Evaluation of patient compliance among hypertensive patients treated by specialists]. / Evaluation de l'observance par l'interrogatoire au cours du suivi des hypertendus dans des consultations spécialisées.

OBJECTIVES: To evaluate compliance with antihypertensive therapy by a self-report in patients referred to hypertension specialists. METHODS: We studied 484 treated hypertensive subjects referred to several hypertension clinics and who were treated since at least one year. Patients were asked to fill in the Compliance Evaluation Test (CET), a questionnaire with 6 questions previously validated to assess factors that could affect medication compliance. We defined patients as "good compliant" when "No" was answered to the 6 items, as "minor noncompliant" when 1 or 2 "Yes" were answered, and as "noncompliant" when 3 or more "Yes" were answered. A good agreement was demonstrated between CET score and compliance evaluated by the number of pills missed during the previous month according to patient interview. RESULTS: We observed 8% of "noncompliant", 53% of "minor noncompliant" and 39% of "good compliant". [table: see text] Logistic regression analysis including age, sex, education level, blood pressure level and the number of antihypertensive tablets confirm the statistical differences observed. CONCLUSIONS: In clinical practice, a method of assessing medication compliance is to ask the patient for a self-report interview. We demonstrated that the compliance evaluation test is able to detect factors usually associated with poor compliance (young age, elevated blood pressure, number of tablets per day). The use of the compliance evaluation test may help physicians to face the problem of nonadherence among their hypertensive patients.

[Renal and hypertensive complications of extracorporeal lithotripsy]. / Complications rénales et hypertensives de la lithotritie extracorporelle: les patients à risque.

HISTOLOGICAL AND FUNCTIONAL CONSEQUENCES OF ESWL: Extracorporeal shock wave litotripsy is now used for the treatment of about 90% of stones. Because of the nonpunctual delivery of energy into the stone, a small volume of renal parenchyma is injured, giving rise to a fibrous scar which can be visualized by morphological techniques such as magnetic nuclear resonance. Isotopic techniques point out a 15% reduction of renal plasma flow on the side of the litotripsy. For a majority of patients, this alteration is transient. HYPERTENSION: In a few cases, abrupt onset of transient hypertension has been reported in clear relation with a compressive perirenal hematoma. The causal effect of ESWL on late occurrence of permanent hypertension is however still uncertain, probably because of the difficulty to show that this occurrence is not related to the older age of the patient alone. The FDA sponsored multicentric study begun in 1993 should solve this issue in the future. PATIENTS AT RISK: Recent articles suggest that altered renal function prior to ESWL would predict late occurrence of hypertension and worsening of renal failure. Furthermore, age and the resistance index of arcuate or interlobular renal arteries (measured by Doppler) could help to screen the patients at risk of developing hypertension. Practical attitude: In practice, renal function and blood pressure should be carefully monitored in patients aged over 60 and/or who have a serum creatinine > 300 mumol/l.

[Physiopathology, exploration and treatment of calcium lithiasis]. / Physiopathologie, exploration et traitement de la lithiase calcique.

The main risk factors for calcium urolithiasis that are clinically detectable are low diuresis, hypercalciuria, hyperruricuria, alkaline urinary pH, hyperoxaluria, hypomagnesuria, hypocitraturia. They should be evaluated, all the more precisely that the disease is active, under both the urological and metabolic points of view, using 24 hour urine collection made at home on a free diet with a dietary record. In the majority of the cases the calcic urolithiasis is idiopathic, i.e. not related to a cause of secondary hypercalciuria like primary hyperparathyroidism, or to a hyperroxaluria either primary or of digestive or toxic origin. Its treatment if mainly dietary with high fluid intake (diuresis greater than 2 1/24 h), normoclacic diet (800-1000h mh/24 h) with meat but not dairy product restriction, oxalate salts, carbohydrate and alcohol restriction. These dietary recommendations should be controlled by measuring the above cited parameters in the 24 hour urine samples and by measuring urea excretion which should not exceed 0.33 g/kg of body weight. When diet fails, drugs may be added mainly allopurinol, thiazides and potassium citrate.