Pharmacokinetics of rilmenidine in patients with chronic renal insufficiency and in hemodialysis patients.

The pharmacokinetics of rilmenidine (1 mg orally) was studied in 3 groups of patients with stable chronic renal insufficiency. This was an open, single-blind study following a single administration, and after 15 days of treatment. Group 1 included 11 patients with a creatinine clearance between 15 and 80 mL/min. Group 2 included 17 patients with a creatinine clearance < 15 mL/min. Group III included 10 hemodialysis patients. In patients with chronic renal failure, total plasma clearance and renal clearance of rilmenidine decreased; terminal half-life was 30-42 hours, which is clearly longer than previous values achieved in healthy volunteers. After repeated administration (1 mg daily in group 1, 1 mg every other day in group 2, 1 mg at the end of each dialysis session in group 3), the area under the curve was significantly increased, corresponding to drug accumulation. The steady state was reached after 6 days in patients in group 1 and after 8 days in patients in group 2. The pharmacokinetics of rilmenidine was linear since the terminal elimination half-life and renal clearance were not significantly different after single and repeated administration of rilmenidine. A positive correlation was found between rilmenidine total plasma clearance and creatinine clearance, and between rilmenidine renal clearance and creatinine clearance. Mean rilmenidine hemodialysance was 85 mL/min, that is, 26% of the rilmenidine renal clearance value achieved in healthy volunteers (330 mL/min). Thus, the following dosage schedule can be proposed. In patients whose creatinine clearance ranges between 15 and 80 mL/min, a 1 mg dose every day can be recommended.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium metabolism, plasma parathyroid hormone, and calcitriol in transient hypertension of pregnancy.

In order to know if abnormalities of calcium metabolism may be involved in the pathophysiology of pregnancy-induced hypertension (PIH), as it has been incriminated in essential hypertension, we measured plasma and urinary calcium and phosphate as well as plasma PTH and free calcitriol index (ratio of total calcitriol on the D binding protein) in normotensive pregnant women (n = 25), in women with PIH after the same duration of amenorrhea (> 28 wk, n = 21:preeclampsia and 20 transient hypertensions), and in age-matched nonpregnant women (n = 15). The severity of PIH was mild since blood uric acid was not increased and plasma volume, measured with the Evans blue technique, was found only moderately decreased (-10.5 +/- 3.1% of normal value). The results show that normotensive pregnant women showed the expected increase of the vitamin D parameters in comparison to nonpregnant controls. Hypertensive pregnant women were not different from the normotensive ones regarding plasma corrected calcium and phosphate and urinary excretion of calcium and phosphate, but had higher plasma PTH (13 +/- 1 v 8.8 +/- 1.6 pg/mL) and lower total and free calcitriol index (86 +/- 7 v 110 +/- 6 pg/mL and 1.72 +/- 0.10 v 2.25 +/- 0.13 x 10(-5)). Correlative studies showed PIH having a negative correlation between blood pressure and plasma corrected calcium (r = -0.43, P < .05), which is in agreement with epidemiological studies of essential hypertension. In conclusion, disturbances of calcium regulating hormones do exist in transient forms of pregnancy-induced hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial natriuretic factor in pregnancy-induced hypertension and preeclampsia: increased plasma concentrations possibly explaining these hypovolemic states with paradoxical hyporeninism.

Plasma immunoreactive atrial natriuretic factor 99-126 (ir ANF), plasma volume, plasma renin activity, and plasma aldosterone were measured during pregnancy in 14 normotensive nonpregnant women, 15 normotensive pregnant women, 35 patients with pregnancy-induced hypertension (PIH), and in ten patients with preeclampsia (PE). Repeated measurements were carried out 2 months after delivery in a subgroup of the same patients. The plasma levels of ANF were found to be higher in pregnant normotensive women than in nonpregnant normotensive women, but the decrease of plasma ANF 2 months after delivery was not significant on the basis of seven paired data, so that it cannot presently be stated with certainty that pregnancy per se stimulates ANF secretion. Still higher levels of ANF were found in PIH and, especially, in PE. A positive correlation was found in the pooled population of normotensive and hypertensive pregnant women between plasma ANF and mean arterial pressure. A greater decrease of plasma ANF was found after delivery in the hypertensive patients than in the normotensive controls. This excludes an absolute deficiency of ANF secretion in the pathogenesis of hypertension. These findings suggest a compensatory role of ANF in the prevention of blood pressure increase. Plasma renin activity (PRA) and plasma aldosterone concentrations were higher in normotensive pregnant women than in normotensive nonpregnant women. Compared to normal pregnancy, plasma volume was decreased in PIH (-17%) and in PE (-25%), whereas PRA was less increased in both groups and plasma aldosterone concentration was less increased only in the PE group. The simultaneous high levels of plasma ANF may explain this inappropriate hypostimulation of renin secretion by hypovolemia in these hypertensive states.

Improvement of severe secondary hyperparathyroidism in dialysis patients by intravenous 1 alpha(OH) vitamin D3, oral CaCO3 and low dialysate calcium.

Seventeen patients (9 men, 8 women; aged 27 to 75 years) who were on chronic hemodialysis for 1 to 14 years were included in the study because they had severe hyperparathyroidism diagnosed by elevated plasma alkaline phosphatase and on plasma intact PTH levels more than twice the upper limit of normal. They had been previously treated with various combinations of oral calcium and/or Al(OH)3 as phosphate binders, oral 1 alpha(OH) vitamin D3 metabolites and a dialysate calcium concentration (DCa) of 1.6 to 1.75 mmol/liter. When i.v. alpha calcidol was introduced DCa was reduced to 1.25 mmol/liter and CaCO3 taken with the meal was used as the sole phosphate binder. alpha calcidol was i.v. injected after the third dialysis of the week at a dose up to 4 micrograms per dialysis in order to obtain a predialysis plasma concentration of Ca at 2.5 +/- 0.2 and PO4 between 1.5 and 2 mmol/liter. All the other treatments were discontinued. During the six months of follow-up, the mean weekly dose of alpha calcidol was 6 micrograms and CaCO3 700 +/- 50 mmol. Plasma calcium (PCa) increased moderately from 2.35 to 2.47 mmol/liter (P < 0.05) whereas plasma PO4 (PPO4) did not significantly increase (1.56/1.64 mmol/liter). Total alkaline phosphatase and its bone isoenzyme activity decreased significantly to normal values [respectively from 186 to 83 IU (normal: 135) and from 102 to 32 IU (normal < 33)] whereas plasma intact PTH decreased from 485 to 125 pg/ml (normal < 55).(ABSTRACT TRUNCATED AT 250 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.

[Digoxin-like natriuretic factor, raised during normal pregnancy, is increased in pregnancy-induced hypertension and pre-eclampsia]. / Le facteur natriurétique digoxin-like, augmenté dans la grossesse normale, est majoré dans l'hypertension induite par la grossesse et la prééclampsie.

UNLABELLED: The increase of peripheral resistance in pregnancy induced hypertension (PIH) and in preeclampsia (PE) is not yet explained since previous studies have found that renin-angiotensin-aldosterone system is actually depressed, that adrenergic system is inconstantly stimulated and that vasodilating prostaglandins are inconstantly decreased. In order to get a better insight in the pathogenesis of PIH and PE, we have measured the 24 h urinary excretion of digoxin-like natriuretic factor (DLF) in 15 normotensive pregnant women (NP), in 29 women with PIH and in 6 women with PE under normal salt diet, without treatment. DLF have been measured by radio receptor binding assay. Normal values were established in 14 normotensive non pregnant (NNP). In NP, 24 h urinary excretion of DLF was significantly higher than in NNP (respectively 14.9 +/- 7.5 and 9.5 +/- 2.5 nmol/mmol of creatininuria, p less than 0.01). Comparatively to NP, 24 h urinary excretion of DLF was significantly higher in PIH (31.7 +/- 19 nmol/mmol of creatininuria) and in PE (40.7 +/- 16.3 nmol/mmol of creatininuria). In PIH and PE, there were simultaneously a decrease of plasma renin activity and plasma volume but no difference for plasma catecholamines. IN CONCLUSION: 1. the production of DLF is increased by normal pregnancy; 2. it is increased in PIH and PE in comparison with NP and may explain the increase of peripheral resistance.

[Increase of the pressor response to angiotensin II in normal pregnancy. A sign of increasing blood volume more than decreasing vascular reactivity]. / L'augmentation de la dose pressive d'angiotensine II au cours de la grossesse normale. Un reflet de l'augmentation de la volémie plutôt que la diminution de la réactivité vasculaire.

Plasma volume and the pressor dose of angiotensin II were estimated in 15 normotensive pregnant women during the second and third trimester and 2-3 months post-partum together. Plasma volume estimated by the Evans Blue technique increased during pregnancy significantly more than the body weight: its increase was 37 and 54% of the post-partum values whereas the body weight increase was only 6 and 12%. The pressor dose of angiotensin II was significantly increased during pregnancy only when it was related to body weight (14.2 +/- 4.3 and 14.9 +/- 5.2 at the 2nd and 3rd trimester versus 11.2 +/- 2.9 ng min-1 kg-1 BW post-partum) but not when it was related to plasma volume (0.25 +/- 07 and 0.26 +/- 0.09 versus 0.25 +/- 0.07 ng min-1 ml-1 PV). It is concluded that the increased pressor dose of angiotensin II (related to body weight) observed in normal pregnancy cannot be interpreted as an evidence for decreased vascular reactivity but that it could be a mere reflection of plasma volume increase.

[Pregnancy-induced hypertension and pre-eclampsia develop in spite of high circulating levels of cardionatrin]. / L'hypertension induite par la grossesse et la prééclampsie se développent malgré des taux circulants élevés de cardionatrine.

Plasma cardionatrine was measured during pregnancy in 14 normotensive non pregnant women, 15 normotensive pregnant women, 35 pregnancy induced hypertension (PIH) and 10 preeclampsia (PE) and again 2 months after delivery in respectively 7, 15 and 7 cases together with plasma volume, PRA and plasma aldosterone. The plasma levels of cardionatrine are higher in pregnant normotensive women than in non pregnant normotensive women suggesting that pregnancy per se stimulates cardionatrine secretion. The higher levels of cardionatrine in PIH and specially in PE during pregnancy and the greater decrease of plasma cardionatrine after delivery in the hypertensive patients than in the normotensive controls exclude a deficiency of cardionatrine secretion in the pathogenesis of hypertension. These data rather suggest a compensatory role of cardionatrine in the prevention of blood pressure increase. Plasma volume was decreased in PIH (-17 p. 100) and in preeclampsia (-25 p. 100). The simultaneous high levels of cardionatrin may explain the inappropriate stimulation of the renin and aldosterone secretion in these hypovolemic hypertensive states.

[Sequential study of the plasmatic atrial natriuretic factor and the urinary excretion of an ouabain displacing factor and of dopamine in normotensive pregnant women before and after labor]. / Etude séquentielle du facteur atrial natriurétique plasmatique et de l'excrétion urinaire d'un facteur déplaçant l'ouabaïne et de la dopamine chez la femme enceinte normotendue avant et après l'accouchement.

Estimation of urinary excretion of a ouabain displacing factor (ODF) and dopamine was carried out immediately before delivery, 7 days and 70-90 days after delivery in 12 normotensive pregnant women. Simultaneous estimation of plasma 99-126 atrial natriuretic factor (ANF), plasma renin activity (PRA) and plasma aldosterone were also undertaken. The data were compared with those obtained in a non pregnant normotensive group of women (n = 14) and a group of pregnant normotensive women in the early third trimester (n = 14). Urinary ODF and dopamine were significantly higher in the early third trimester when compared with non pregnant women but immediately before delivery, ODF excretion had fallen below non pregnant values and dopamine excretion had dropped to control values. Both remained low after delivery. Plasma ANF was higher in pregnant women when compared with non pregnant controls and remained high just before delivery and 7 and 70-90 days after delivery. PRA and plasma aldosterone were higher during pregnancy and had fallen to non pregnant values 7 days post-partum. It is concluded that there is considerable discrepancy in the evolution of natriuretic and antinatriuretic factors before and after delivery and that the drop of PRA and aldosterone by 7 days post-partum, contrasting with the unchanged high values of ANF, may contribute to negative sodium balance after delivery.

Randomised controlled trial of enalapril and beta blockers in non-diabetic chronic renal failure.

OBJECTIVE: To compare the ability of angiotensin converting enzyme inhibitors and beta blockers to slow the development of end stage renal failure in non-diabetic patients with chronic renal failure. DESIGN: Open randomised multicentre trial with three year follow up. SETTING: Outpatient departments of six French hospitals. PATIENTS: 100 hypertensive patients with chronic renal failure (initial serum creatinine 200-400 mumol/l. 52 randomised to enalapril and 48 to beta blockers (conventional treatment). INTERVENTIONS: Enalapril or beta blocker was combined with frusemide and, if necessary, a calcium blocker or centrally acting drug in patients whose diastolic pressure remained above 90 mm Hg. RESULTS: 17 patients receiving conventional treatment and 10 receiving enalapril developed end stage renal failure. The cumulative renal survival rate was significantly better in the enalapril group than in the conventional group (P < 0.05). The slope of the reciprocal serum creatinine concentration was steeper in the conventionally treated patients (-6.89 x 10(-5)l/mumol/month) than in the enalapril group (-4.17 x 10(-5)l/mumol/month; P < 0.05). No difference in blood pressure was found between groups. CONCLUSION: In hypertensive patients with chronic renal failure enalapril slows progression towards end stage renal failure compared with beta blockers. This effect was probably not mediated through controlling blood pressure.

[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 of idiopathic calcium lithiasis]. / Physiopathologie de la lithiase calcique idiopathique.

In this review article the various steps and local mechanisms of stone formations are summarized. Then the pathophysiology of the various risk factors namely urinary excretion of calcium, oxalate, uric acid, urine volume, urine pH and urinary inhibitors of stone formation is extensively discussed.

[Long-term development of Permacath Quinton catheters used as a vascular access route for extra-renal detoxification]. / Etude du devenir à long terme du cathéter Permcath Quinton utilisé comme voie d'abord vasculaire en épuration extra-rénale.

Between July 1984 and July 1991, we have inserted surgically 147 Permcath Quinton catheters in 126 uremic patients for the following reasons: group I: necessity of hemodialysis without vascular access for acute (group Ia: 44 patients) or chronic renal failure (group Ib: 11 patients); group II: difficulty of creation or loss of vascular access (group II: 45 patients); group III: hemodialysis for patients with short life expectation or contraindications for vascular access on their limbs (group III: 26 patients). The duration of use (+/- SD and range) were respectively for each group: 1.6 +/- 2 (0-10); 3.4 +/- 2.8 (1-11); 7.4 +/- 11 (0-50); 6.7 +/- 8.7 (0.1-34.5) months. Seventeen patients (group IV) coming from groups Ib and II preferred to go on with the use of their catheter for 10.5 +/- 13.5 (0.1-50) months rather than to use their arteriovenous fistula. The complications observed on whole population were: 11 septicemia responsible of 2 deaths, 9 cutaneous local infections, 28 total obstructions of the catheter, 17 partial obstructions with insufficient flow; 10 destructions of the catheter. In conclusion the Permcath Quinton catheter is an adequate long term vascular access for hemodialysis. It is well tolerated since it is preferred to the usual arteriovenous fistula by many patients who have both. The incidence of infection is low. However, obstruction (partial ou total) is frequent (29%), necessitating local fibrinolytic treatment.

[Hypertension and pregnancy. Diagnosis, physiopathology and treatment]. / Hypertension et grossesse. Diagnostic, physiopathologie et traitement.

This review on hypertension in pregnancy focuses mainly on the pathophysiology and prevention of pregnancy induced hypertension which, when associated with proteinuria, is usually called preeclampsia. Rather than a genuine hypertensive disease, preeclampsia is mainly a systemic endothelial disease causing activation of platelets and diffuse ischemic disorders whose most obvious clinical manifestations involve the kidney (hence the proteinuria, edema and hyperuricemia), the liver (hence the hemolytic elevated liver enzymes and low platelets, or HELLP syndrome), and the brain (hence eclamptic convulsions). Hypertension is explained by increased vascular reactivity rather than by an imbalance between vasoconstrictive and vasodilating circulating hormones. This increased reactivity is due to endothelial dysfunction with imbalance between prostacyclin and thromboxane A2 and possibly dysfunction of NO and endothelin synthesis. The aggressive substances for endothelium are thought to be of placentar origin and the cause of their release is explained by placentar ischemia related to a defect of trophoblastic invasion of the spiral arteries. The etiology of this latter defect is unknown but involves immunologic mechanisms with genetic predisposition. The only effective treatment for PIH is extraction of the baby with the whole placenta. The decision for extraction is often a very delicate obstetric problem. Antihypertensive drugs are mainly indicated in severe hypertension (> 160-100 mm Hg), with the aim of preventing cerebral hemorrhage in the mother, but have not been shown to improve fetal morbidity or mortality. Eclamptic seizures can be prevented and treated more effectively with magnesium sulfate than with diazepam or phenytoin. Prevention of preeclampsia remains the main challenge. Whereas antihypertensive drugs are ineffective, calcium supplementation and low dose aspirin have proven effective but mainly in selected populations with a relatively high incidence of preeclampsia (> 8-10%). In multiparas the selection of such a high risk population is relatively easy when at least 2 (or 1?) previous pregnancies were complicated with early preeclampsia and/or intrauterine growth retardation. In nulliparas the selection of the high-risk population is still a subject of research. The 2 most promising criteria are abnormal Doppler velocimetry of the uterine arteries at around 20 weeks of amenorrhea, and abnormally high plasma levels of beta HCG at 17 weeks of amenorrhea.