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The donor, i.e. adult or paediatric, might influence the outcome of the graft function.The glomerular filtration rate (GFR) of 120 transplanted children (47 girls) aged 10.4+/-4.6 years (0.7-17.2) was prospectively assessed over a 5-year period. The patients were divided into two groups according to the age of donor: adult (donor age18 years; n=33) and paediatric (donor age18 years; n=87). GFR was assessed by inulin clearance at 3, 6 and 12 months and yearly thereafter.The average GFR was stable in the range of 70 ml/min/1.73 m2 for the whole follow-up period. The adjusted GFR in adult graft recipients was significantly higher at 3 months post-transplantation: 80.6+/-36.9 vs 65.1+/-22.0, P=0.02. However, from the second year post-transplantation, the adjusted GFR in paediatric graft recipients became significantly higher than that of adult graft recipients. Such results could be due to an improvement in the absolute GFR (ml/min) of paediatric graft recipients with time (P=0.0001) whereas that of the adult graft recipients remained stable despite the children's growth.The adjusted GFR of adult graft recipients was significantly higher than that of paediatric graft recipients in the early post-transplant period. In the long-term, a progressive decrease in adjusted GFR was noted in adult graft recipients. On the one hand, this may be due to a functional adaptation and/or inadequate compensatory growth of the graft. On the other hand, the absolute GFR of paediatric graft recipients increased, suggesting an ongoing capacity for growth and/or compensatory hypertrophy after child-to-child renal transplantation.

Changes in spectral analysis of the variability in systolic blood pressure (SBP) and heart rate (HR) were investigated in 12 normotensive volunteers during a well-standardized stress test. BP was measured indirectly from the finger by a noninvasive device (Finapres). The stress test was a computerized version of the Stroop color word conflict test (CWT). The influences of acute (single dose) beta 1-selective blockade by bisoprolol or angiotensin-converting enzyme (ACE) inhibition by lisinopril were analyzed by a double-blind placebo-controlled trial. During the placebo phase, the efficiency of the stress test was confirmed by a significant increase in SBP (25 +/- 11%), HR (36 +/- 23%), and plasma concentrations of epinephrine (Epi, 54 +/- 37%) and norepinephrine (NE, 27 +/- 35%). Stress induced a significant increase in the amplitude of SBP and HR oscillations in the medium-frequency band (MF, 70- to 140-mHz range), which corresponds to the Mayer waves (27 +/- 32 and 42 +/- 43%, respectively for SBP-MF and HR-MF). The stress-induced increase in NE correlated significantly with the increase in HR (r = 0.68, p < 0.05). The stress-induced increase in SBP-MF correlated significantly with the increase in Epi (r = 0.69, p < 0.05) and in HR-MF (r = 0.69, p < 0.05). A significant decrease in SBP-MF at rest was observed with a single oral (p.o.) dose of bisoprolol, but not of lisinopril. As a noninvasive method, spectral analysis of the variability in SBP and HR may be of benefit in stress-induced modifications of the autonomic nervous system.

The pharmacokinetics of Chlormezanone (CM) has been determined after a single oral dose of 400 mg CM in 5 young volunteers (28 y) and in 8 elderly patients (79 y). In the young subjects, CM was rapidly absorbed and distributed, and was slowly eliminated with a half-life of 38 h major metabolites were not detected in plasma or urine. Only 3% of CM was excreted unchanged in urine. In elderly patients absorption was delayed but not reduced; the Cmax and AUC did not differ from those in younger subjects, the elimination rate was reduced compared to the younger subjects (mean 54 h). The increase was in part related to the reduction in renal function and metabolism observed in aging. However, the change in pharmacokinetics was moderate and no adjustment in dosage seems necessary for treatments of limited duration in elderly patients.

Renal transplantation using living donors still remains of interest, given the shortage of cadaveric donors. Using reference methods for measuring kidney function, we studied the adaptation to nephrectomy in 99 living donors. The glomerular filtration rate and renal plasma flow showed long lasting increase (by 40 and 33% respectively). Age and the glomerular filtration rate at surgery had a clear-cut effect on these changes. The spontaneous changes in protein intake further influence the value of post-nephrectomy glomerular filtration rate. The analysis of serial changes in serum creatinine or creatinine clearance would falsely have suggested a late increase in renal function. Microalbuminuria increased in few patients, pointing to the need for careful long term follow-up of such donors.

Since renal transplantation is known to be the best choice for the growing child with end-stage renal failure, we prospectively evaluated early and late graft function in transplanted children.The study included 78 children (32 girls, 46 boys) 10.4 +/- 0.6 years at the time of transplantation. Renal investigations were performed at 3, 6 and 12 months post-transplantation and yearly thereafter. Inulin clearance was used to evaluate the glomerular filtration rate (GFR), and the reabsorption rates of Na, P and Ca were measured concomitantly.The overall adjusted GFR was approximately 70 mL/min/1.73 m2 and remained unchanged during the first 5 years post-transplantation. In the mean time the absolute GFR increased significantly, suggesting a remaining capacity for compensatory hypertrophy of the transplanted kidney. Renal function was significantly influenced by the number of rejection episodes during the first 2 years post-transplantation but no correlation was found between GFR and the number of HLA mismatches or the use of preemptive transplantation.

Moxonidine is an imidazoline I1-receptor agonist that centrally acts by reducing the sympathetic tone. Furthermore, proximal tubular I1-receptors have been isolated in human kidneys, but their natriuretic effects have never been demonstrated. Because stress tests elicited a sympathetically mediated increase in blood pressure and in sodium reabsorption, the aim of this study was to assess the effects of moxonidine (0.4 mg/day; 1 month) on stress-induced cardiovascular response and renal sodium handling in hypertensives, in a double-blind, crossover, placebo-controlled study. The stress test used is an efficient and reproducible computerized version of Stroop's stress test. During the experimental sessions, both rest and stress renal functional parameters were determined: glomerular filtration rate (inulin clearance), renal plasma flow (para-aminohippurate clearance), filtration fraction, sodium excretion, and segmental sodium tubular reabsorption (lithium clearance). During the placebo phase, stress induced a significant increase in systolic blood pressure (deltaSBP; 15.8+/-10.7 mm Hg) and diastolic blood pressure (deltaDBP; 8.2+/-6.1 mm Hg). During stress, glomerular filtration rate tended to decrease, whereas renal plasma flow significantly decreased, resulting in a significant increase in filtration fraction. Despite the increase in BP, stress induced a decrease in sodium excretion that was mainly due to a nonsignificant increase in sodium reabsorption in the proximal parts of the tubules. Moxonidine significantly reduced rest and stress BP, but the stress cardiovascular reactivity was not altered. At rest, renal function was well preserved by the treatment. Stress-induced modifications in renal function and sodium handling were not altered by the treatment. In conclusion, moxonidine reduced rest and stress-induced peak BP and preserved basal renal function. The study failed to demonstrate any effect of moxonidine either on basal renal sodium handling or on stress-induced increase in sodium reabsorption.

We examined the renal hemodynamic modifications induced by a selective angiotensin II (AII) AT1 receptor antagonist, losartan, in 10 patients with essential hypertension. In this single-blind study, renal hemodynamic parameters were determined twice (patients were their own controls) first after a 15-day single-blind placebo run-in period and again after a 1-month losartan period. The dosage of losartan was 50 mg/day. Glomerular filtration rate (GFR, inulin clearance), renal plasma flow [RPF; para-aminohippurate (PAH) clearance], microalbuminuria, sodium excretion, proximal sodium tubular reabsorption (lithium clearance), and acid uric metabolism were measured. After 1-month losartan treatment, systolic and diastolic BP (SBP, DBP) decreased significantly throughout the 210-min recording whereas heart rate (HR) was unchanged. GFR (100 +/- 19 vs. 96 +/- 17 ml/min/1.73 m2) and RPF (471 +/- 118 vs. 468 +/- 108 ml/ min/1.73 m2) were not altered by losartan. Rather than occurrence of any modification in filtration fraction (FF), a significant decrease in microalbuminuria was evident (57 +/- 77 vs. 40 +/- 59 mg/24 h, p < 0.05). Urinary sodium excretion was not modified, but an almost significant (p = 0.07) decrease in proximal sodium reabsorption was observed (72.9 +/- 7.7 vs. 68.1 +/- 6.4% of filtered sodium). The increase in renal uric clearance accounted for the significant decrease in serum uric acid (195 +/- 49 vs. 183 +/- 43 microM; p < 0.05). After 1-month losartan treatment, renal function was well preserved; the decrease in uric acid may be of clinical interest when adjuvent diuretic therapy is required.

The 1-month reproducibility of haemodynamic and sympatho-adrenal responses to a standardized mental stress test was studied in ten normotensive and ten hypertensive individuals. The stress test was a computerized adaptation of the Stroop test and sympathetic activity was evaluated by measuring urinary catecholamine excretion. Three-way analysis of variance (stress, session, blood pressure) revealed significant increases in systolic and diastolic blood pressures and in heart rate during the stress test. Test-retest correlation coefficients for basal stress levels, and stress-induced variations were significant (r from 0.59 to 0.88). The stress test induced a significant increase in urinary noradrenaline excretion with large intra- and interindividual variability. The significant test-retest correlations and the lack of period effect for haemodynamic parameters indicated good temporal stability. However, a slight decrease in stress-induced reactivity was observed. This standardized mental stress test may be useful in epidemiological and therapeutic trials to measure blood pressure and heart rate responses, but measurement of urinary catecholamine excretion does not provide any additional information.

This study aimed at comparing estimations of spontaneous cardiac baroreflex sensitivity (BRS) obtained with 3 different methods from continuous non-invasive blood pressure recordings in humans. A new method, allowing the quantification of the statistical dependence between values of 2 parameters (Z coefficient), was applied to beat-to-beat systolic blood pressure (SBP) and heart period (HP) values. SBP and HP values with positive Z coefficient and corresponding to baroreflex activity (SBP and HP values both lower or higher than the modal values) were submitted to a linear regression and the regression coefficient (Zgain) was taken as an index of BRS. Second, cross-spectral analysis of SBP and HP gave a BRS value (Csgain) computed as the average value of transfer function moduli for frequencies between 0.07 and 0.14 Hz, with coherence between SBP and HP greater than 0.5. The third method relies on the analysis of linear sequences (r0.97) containing at least 3 values of SBP and HP varying in the same direction. The average regression coefficient obtained from all selected SBP and HP sequences is the index of BRS (Seqgain). SBP and HR were recorded during 1 hour with a Finapres in 10 healthy male volunteers (NT), 23 to 32 year-old (SBP: 123 +/- 2 mmHg) and 10 recent and untreated hypertensive subjects (HT) (SBP: 152 +/- 6 mmHg). [table: see text] These results show that, in both groups, Zgain and Seqgain correlated with Csgain. No correlation was found between Zgain and Seqgain in healthy volunteers whereas the correlation was strong in hypertensives probably due to more heterogeneous SBP levels and BRS values in these subjects. This suggests that these methods are sensitive to different ways of response of the baroreflex.

A stress test was performed before (S1) and after a 1-month treatment period (S2) in patients with essential hypertension, randomly allocated to receive either an angiotensin-converting enzyme inhibitor (ACEI), lisinopril (n = 10), or placebo (n = 10). The two groups were similar with regard to systolic and diastolic blood pressure (SBP, DBP), body weight, renal function, and 24-h sodium excretion. At S1, stress induced a significant increase in SBP of 18 +/- 9 mm Hg and in DBP of 10 +/- 6 mm Hg and a significant reduction in sodium excretion from 258 +/- 105 to 204 +/- 72 mumol/min. Stress-induced sympathetic stimulation was assessed by a significant increase in urinary norepinephrine (NE) excretion from 21 +/- 10 to 26 +/- 10 micrograms/g creatinine. One-month treatment by placebo did not change stress-induced BP reactivity, sodium retention, or urinary NE excretion. In the lisinopril group, rest and stress BP were significantly reduced by the treatment. Stress-induced sodium retention was higher after 1-month placebo treatment (72 +/- 78 vs 48 +/- 67 mumol/min), whereas this retention was significantly reduced by lisinopril (13 +/- 27 vs 69 +/- 60 mumol/min).

We performed a nutritional trial to assess the variations of circulating insulin-like growth factor-I (IGF-I) in chronic renal failure (CRF). Eight patients suffering from mild renal failure (SCr = 374 +/- 52 mumol/l) were prescribed a standard diet for 1 month followed by 1 month of protein restriction. Mean protein intake was 0.77 and 0.46 g/kg BW/day, mean caloric intake 25 and 24.7 kcal/kg BW/day for the first and the second month, respectively. After each period of diet, nitrogen balances were negative (-1.2 +/- 1.6 and -1.6 +/- 0.9 g/N/day). Despite these low-caloric conditions, mean serum IGF-I level was at the upper level of normal (358 +/- 136 ng/ml) after 1 month of standard protein intake, and statistically reduced (289 +/- 122 ng/ml, p0.002) by the low-protein diet. No correlation was observed between serum IGF-I levels and protein, caloric intake, and nitrogen balances for the two periods. Estimation of the IGF-I binding by the ratio of extracted to nonextracted IGF-I value suggested abnormal binding in CRF. This binding was modified by reduced protein intake. In conclusion, larger studies are needed in CRF to assess the significance of IGF-I variations and the IGF-I binding proteins which modulate the bioactivity of this growth factor.

Summary The hardness and frequent recurrence of cystine stones present a special challenge to the urologist. In this study, 15 cystinuric patients (11 males, 4 females; mean age 36 years, range 17–54) were treated and followed up over a period of 30 months (range 2–40). Most patients had a previous history of open surgery. The diagnosis of cystinuria was confirmed by metabolic studies and infrared spectrometry of stones. Over the follow-up period recurrence was observed in 23 instances in 11 patients, leading to 38 “stone treatments” on 74 cystine stones. The percutaneous approach was used alone in 9 cases and in association with extracorporeal shock wave lithotripsy (ESWL) in 9 cases. ESWL was used alone in 18 cases. Medical treatment included high fluid intake, alkalinisation and Thiola (tiopronin, N-(2-mercaptopropionyl)glycine) in 6 patients. The overall stone-free rate assessed 3 months after treatment was 44.7%, which compares poorly with the rate for non-cystine stones. The recurrence rate is very high and instrumental treatment should not therefore be used excessively; it is indicated only for stones that are symptomatic or refractory to intensive medical therapy.

In this study, the measurement of blood pressure values, glomerular filtration rate (GFR, inulin clearance), renal plasma flow (RPF, PAH clearance), the filtration fraction (GFR/RPF), natiuresis and proximal sodium resorption (measured by lithium clearance), was performed at rest and during a computerised psychological stress test (Stroop word color conflict test) in 12 normotensive and 10 hypertensive subjects. The stress induced in the normotensives induced a significant increase of the filtration fraction and proximal tubule sodium resorption. The hypertensive kidney, submitted to a basal vasoconstriction greater than that of the normotensive kidney, does not react to stress. In the hypertensives, proximal sodium resorption occurs but is not significantly greater than at rest. In the long-term, the increased sodium resorption during stress could contribute to the development and the persistence of essential hypertension.

The hardness and frequent recurrence of cystine stones represent a special challenge for the urologist. Fifteen cystinuric patients were treated in our department and followed over a mean period of 30 months. Most patients had a previous history of open surgery (1.5 pyelolithotomy/patient). Diagnosis of cystinuria was confirmed by metabolic studies and stone analysis. Over the follow-up period recurrence was observed in 23 instances in 11 patients thus leading to 38 stone treatments on 74 cystine stones. Stone size was less than 10 mm: 35 (47%); 10-20 mm: 21 (28%); 20-30 mm: 14 (19%); 30 mm: 4 (staghorn stones). A percutaneous approach was used in 9 cases as monotherapy (55% success) and in association with ESWL in 10 cases (50% success). ESWL was employed 18 times as monotherapy (39% success). Medical treatment included high fluid intake, alkalinisation and thiola in 6 patients. In conclusion, results obtained are poor in terms of stone clearance when compared to non-cystine stones. Recurrence rate is very high. Instrumental treatment should not be used excessively and is only indicated in symptomatic stones or refractory to intensive medical therapy.

The pharmacokinetics of oxiracetam in patients with renal impairment were investigated after administration of a 800 mg single oral dose of oxiracetam. The renal insufficiency was estimated on the basis of the creatinine clearance (CLcr) which ranged from 9 to 95 ml/min among the 20 patients. In plasma, the terminal elimination half-life (T1/2) ranged from 10.6 to 68.1 h, the highest T1/2 corresponding to the patients with a high degree of renal impairment. In urine, the amounts of oxiracetam excreted during the 48 h postdosing represented 8.3 to 82.6% of the dose. They were lower in patients with a high degree of renal impairment. The correlations between the total clearance of oxiracetam, the renal clearance, the terminal apparent elimination rate constant in plasma, and CLcr were estimated by linear regression analysis. The correlation coefficients were 0.916, 0.985 and 0.803 respectively. The apparent volume of distribution of the central compartment V(1) and the total volume of distribution at the steady-state V(SS) were not dependent on the degree of renal impairment. The mean values±SD were 25.9±13.0 litres and 48.3±21.5 litres respectively. Oxiracetam concentrations in plasma of patients were estimated for repeated administration of 800 mg of oxiracetam. The estimations showed that the steady-state concentrations would be obtained after 6–10 days of repeated administration for patients whose CLcr is 9–15 ml/min and 3–5 days for patients with CLcr between 15 and 40 ml/min. The dosage of oxiracetam in renal insufficient patients was evaluated in order to reach a mean steady-state concentration level of oxiracetam in plasma close to that in patients with normal renal function. For patients with CLcr between 40 and 60 ml/min, the adjusted daily dose would be 50% of the dose given to a patient with normal renal function. For patients with CLcr between 15 and 40 ml/min, the adjusted daily dose would be 25% of the dose given to a patient with normal renal function. For patients whose CLcr was below 40 ml/min, one daily administration in agreement with the dosage reduction, could be given.

The orthosympathetic nervous system is involved in the pathogenesis of essential hypertension. In this study, we carried out tests of sympathetic stimulation using successfully an isometric exercise and a psychological stress. The efficacy of the two tests in 10 normotensive patients (NTs) was assessed by a significant increase in blood pressure and heart rate and a significant increase in metanephrine urinary excretion. These tests, repeated 2 months later, were perfectly reproducible in NTs. The cardiovascular response during exercise and stress was significantly higher in 10 hypertensive patients (HTs) than in NTs. At rest, urinary norepinephrine excretion was significantly higher in HTs. In contrast to NTs, stress in HTs significantly increased urinary excretion of epinephrine and norepinephrine, whereas exercise failed to increase urinary catecholamine excretion in both groups. In HTs, both tests induced an increase in microalbuminuria. Among functional renal parameters, only proximal sodium reabsorption (measured by lithium clearance) was significantly lower in HTs than in NTs, compensated by a higher distal reabsorption. In HTs, 2 months of treatment with bisoprolol reduced rest and peak heart rate and blood pressure, but failed to reduce blood pressure reactivity to the orthosympathetic stimulation. Proximal sodium reabsorption at rest was normalized by the treatment. Bisoprolol was also able to reduce microalbuminuria during the 24 h and in the rest period preceding the test, but the same percent increase was observed during tests.

Etude chez des vieillards des fonctions renales. Comparaison du volume urinaire, de l'excretion urinaire et de la clairance de la creatinine, ainsi que de la creatinine plasmatique (CP) avec les valeurs obtenues avec de jeunes insuffisants renaux. Etude des correlations entre les clairances de la creatine mesurees, calculees, la CP et la vitesse de filtration glomerulaire

1 The acute effects of a high dose of piretanide, a new potent diuretic were studied in eight patients with severely impaired renal function (GFR between 0.09 and 0.17 ml s-1 1.73 m-2). 2 After hydration and following two control periods, a single dose of 48 mg piretanide was ingested. Thereafter, urine was collected every 30 min for 2 h and every hour for the next 4 h. Urinary fluid losses were replaced orally (100 ml of water ever hour) and intravenously (isotonic saline + glucose infusion). 3 The following measurements were made: urine flow rate, clearances of inulin, PAH, urea, creatinine, uric acid, osmolar and free water clearances, excretion rates of sodium, chloride, potassium, calcium, phosphate, bicarbonate, ammonium, titratable acidity and urine pH. 4 Piretanide (48 mg) appeared to be effective in advanced renal insufficiency, producing a significant increase in urine flow rate, in sodium, chloride, potassium and calcium excretion and in Cosm. 5 There was no significant change in GFR, as measured by inulin clearance, or in the other measured parameters.

The acute effects of a single dose of diltiazem (Tildiem®), a calcium antagonist, were studied in 9 patients with severely impaired renal function (GFR between 0.03 and 0.87 ml/s/1.73 m2). Control measurements were made of inulin and PAH clearance, creatinine, blood pressure, heart rate and ECG. Following administration of diltiazem 120 mg, 7 blood samples were collected in the first 12 h and after 24 h, 32 h, 48 h; urine was collected for the first 12 h, 12–24 h and 24–48 h, and blood pressure, heart rate and ECG were recorded after 6 h. Diltiazem and its main metabolite, desacetyldiltiazem, had a pharmacokinetic profile similar to that in patients with normal renal function (peak plasma concentration, half-life and urinary excretion). Diltiazem is normally eliminated in the urine to a small extent, because it is metabolized, and this also applies to desacetyldiltiazem, which is probably further metabolized.

1. The kinetics of a single oral dose (300 mg) of cicletanine a new antihypertensive drug with diuretic properties, and its effects on the urinary excretion of electrolytes and of the major stable metabolites of prostacyclin and thromboxane A2 were studied in patients with normal renal function (n = 6), mild (n = 9) and severe (n = 10) renal insufficiency. 2. In normotensive subjects with normal renal function, cicletanine was rapidly and regularly absorbed, its apparent elimination half-life established around 7 h, and both its renal clearance (0.4 ml min-1) and its cumulative renal excretion (0.85% of the administered dose), were low. Mild renal insufficiency did not significantly alter these parameters, while severe renal impairment reduced the renal clearance and the cumulative urinary excretion of cicletanine and increased its apparent elimination half-life (31 h). However the area under the plasma curve was not changed due to reduced plasma concentrations in these patients. 3. Cicletanine induced a rapid and marked (four fold as a mean) increase in the urinary excretion of water, sodium and potassium which lasted for 6 to 10 h, in subjects with normal renal function. Renal insufficiency did not alter the slope of the calculated plasma concentration-effects curves but reduced the maximum effect observed for water, sodium and potassium. 4. A single oral dose of cicletanine did not change the urinary excretion of 6-keto-prostaglandin F1 alpha and thromboxane B2 in the three groups of patients studied, the basal values of which being found to be closely related to the creatinine clearance.(ABSTRACT TRUNCATED AT 250 WORDS)

The association of thrombocytopenia, macrothrombocytopathia, nephritis and deafness is rare. Reported here is a new case of this triple association. The clinical course, the nephropathologic findings and the bilateral neurologic hearing loss were similar to those already reported, with a slowly progressive impairment of renal function accompanied by a persistent proteinuria. The platelet diameters were increased. These macroplatelets contained granules of normal structure but with an irregular distribution in the cytoplasm. In other areas the cytoplasm was rich in surface connected system. The survival of these platelets and their contraction were normal. Their aggregation and excretion in response to collagen, adenosine diphosphate and thrombin, and the values of platelet factor 3 activity were all decreased. The degranulation defect, also present, was observed in the absence of a decrease in intracellular cyclic adenosine 5′-monophosphate (AMP) suggesting a relationship between these two findings.

By using a highly specific chromatographic technique, the effect of renal failure on the pharmacokinetics of the six main components of teicoplanin, taken individually or as a whole, was assessed for over 120 h after administration of a 3-mg/kg intravenous dose to healthy volunteers (group 1, n = 6) and to noninfected patients with moderate (group 2, n = 6) or severe (group 3, n = 7) renal failure. In subjects with normal renal function, total teicoplanin was mainly excreted in urine and its concentrations in plasma could be adequately fitted to a three-compartment model. Renal failure did not affect the model or the distribution of teicoplanin but strongly decreased its renal clearance (9.3, 3.2, and 0.6 ml/h per kg, respectively, for the three groups of subjects), in close relationship with the creatinine clearance (r = 0.973, n = 18, P less than 0.001). The cumulative urinary excretion of unchanged total teicoplanin was decreased (50, 21, and 5% of the given dose for groups 1 to 3) and the terminal half-life was enhanced (62, 96, and 111 h for groups 1 to 3) by renal impairment. The relative behavior of the six major components was only slightly affected by renal failure. Consequently, the dosage regimen adjustment could be based on the total teicoplanin concentration, and simulations with the mean estimated pharmacokinetic parameters suggest that the 6-mg/kg daily dose, known to be effective in patients with normal renal function, could be given every 2 and 3 days in patients with moderate and severe renal insufficiency, respectively.

Tubular maximal transport of glucose (TmG), plasma glucose threshold ( PGT ) and fractional maximal tubular reabsorption (TmG/GFR) were measured in fourteen kidney-grafted patients. Seven patients showed decreased PGT and normal or decreased TmG/GFR (type A or B renal glycosuria (RG) ), whereas seven other patients showed normal values. No difference was found between the two groups with respect to parameters of renal function and to clinical parameters characterizing kidney transplantation. The only difference observed between the two groups was the rate of decrease of plasma creatinine levels during the 1st week after transplantation: it was faster in the group without renal glycosuria. No difference was seen between the two groups of patients with respect to the number of rejection episodes occurred over the first 12 months.

In calcium stone formers, the ratio of urinary magnesium concentration to urinary calcium concentration (Mg/Ca) is used to express the already reported low Mg excretion relatively to Ca excretion. However the Mg/Ca value depends on the Ca excretion rate, decreases after oral Ca load and is not directly related to Mg excretion. Therefore when studying patients with different Ca excretion rates, or when performing an oral Ca load, Mg/Ca is not directly useful to express a relative hypomagnesuria. We established a new parameter from the normal relationship between urinary Mg and Ca excretion rates. Its value is above - .065 in 97.5% of 99 control urinary samples. It is stable for any studied Ca excretion rate, including post Ca load excretion rates, and is highly correlated with Mg excretion rate. This parameter allows for the accurate diagnosis of relative hypomagnesuria in stone formers.

1 A pharmacokinetic study of nalidixic acid (NA) and metabolites was carried out in 23 patients with differing renal function so as to determine the influence of renal insufficiency on the excretion and biotransformation rate of this antibacterial agent. Plasma and urine concentration of NA and of its 7-hydroxy (HNA) and 7-carboxy (CNA) derivatives were measured after a single oral administration. 2 Renal insufficiency did not markedly affect the renal clearance of NA while it significantly decreased the elimination rate of HNA, a compound which largely excreted into the urine. 3 Interestingly, CNA which could never be detected in the plasma of patients with normal renal function appeared in that of patients with renal insufficiency. Plasma concentrations of CNA and creatinine were positively related, and the amount of urinary CNA increased with the renal impairment. 4 These results suggest that HNA can still be biotransformed into CNA by the impaired kidney. Since CNA cannot be easily excreted in the urine of patients with renal insufficiency it is hypothesized that this compound back diffuses into the plasma. 5 Finally, the study of the urinary concentrations of NA and metabolites shows that a standard NA dosage can be used, at least in patients with mild renal insufficiency.

The pharmacokinetics of penbutolol, its 4-hydroxylated metabolite and of their conjugates was studied in hypertensive patients with various degrees of renal impairment. A single oral dose of penbutolol 40 mg, was rapidly absorbed after a lag-time of 0.34 h. Its plasma concentration reached a maximum after 0.84 h and then declined bi-exponentially, with an apparent elimination half-life of 21.8 h. The hydroxylation of penbutolol was negligible and conjugation was of major importance for its elimination. Consequently, the kinetics of unchanged penbutolol were not altered by renal impairment. The 48 h-urinary excretion of penbutolol and its metabolites reached 13-14% of the administered dose, which is consistent with extensive metabolism of the drug. After treatment for 30 days with penbutolol 40 mg/d there was no accumulation of the parent drug but the concentration of its conjugates was increased. It is concluded that the dose of penbutolol need not be changed in patients with mild renal insufficiency, 4-hydroxypenbutolol is unlikely to participate in the anti-hypertensive effect of the drug, due to its low concentrations, and biotransformation of penbutolol may be enhanced during chronic treatment.

The influence of hemodialysis on the pharmacokinetics of ceftriaxone was studied in 5 patients with chronic renal failure, with a glomerular filtration rate of less than 5 ml/min, and treated by regular hemodialysis. A single dose of 2 g ceftriaxone was administered IV at the end of a hemodialysis, and venous samples were drawn 12 and 24 h thereafter. Two hemodialysis were performed at the 44th (HD1) and the 92nd (HD2) hour, and blood samples were drawn simultaneously on arterial and venous sides of the dialyzer at the onset of HD1 and at the end of HD2. Plasma ceftriaxone concentrations were measured on each sample by both microbiological and chromatographic (HPLC) methods. In these patients, ceftriaxone kinetics are considerably longer than in normal subjects, with an elimination half-life of 16 h, an apparent distribution volume of 800 ml/kg, but without decrease of plasma clearance, except in one patient who had hepatic cytolysis at the time of injection. Plasma concentrations on both sides of dialyzers, or before and after hemodialysis, are not significantly different, and the mean hemodialysis clearance ranges between 26 and 30 ml/min/m2 dialyzer area. According to these data, the dose-interval between successive administrations of ceftriaxone 2 g IV should be 48 h in patients with chronic renal failure, and supplemental doses do not appear necessary after hemodialysis.

Labetalol, a blocker of alpha- and beta-adrenoreceptors, was tried on 45 patients with severe (29 cases) or mild to moderate (16 cases) hypertension. After an initial period of dosage adjustment and a 2 months treatment in effective doses, there was a significant fall in supine blood pressure from mean values of 207/132 to 170/106 mmHg. In 23 patients hypertension was controlled by labetalol alone in doses of 400 and 1800 mg per day. True failures were rare (16%). Digestive disorders and postural hypotension were the most frequently encountered side-effects; they obliged to discontinue treatment in 4 cases, but were compatible with it in 11 cases. In 22 patients the fall in BP was accompanied by a significant (p less than 0,001) decrease in plasma renin activity from 123 to 44 ng/l/min supine and from 144 to 83 ng/l/min standing. Studies of the renal function showed no changes during oral therapy. Following intravenous injection of 50 mg labetalol to 20 subjects, inulin and PAH clearances remained unaltered, and there was a significant, though transient (1 hour), decrease in chloride, sodium and phosphorus excretion. Effective in lowering blood pressure be used and well tolerated by the kidneys, labetalol can safely be used for the treatment of severe hypertension with organic renal involvement.

The kinetics of zimeldine (Z) and its demethylated metabolite, norzimelidine (NZ), were determined after administration of a single 200 mg oral dose of Z to 6 healthy volunteers (Group I), and to patients with mild (Group II) and severe renal failure (Group III). Z and NZ concentrations were assayed by HPLC in serial plasma and urine samples over 6 days following the dose. In Group I Z was rapidly absorbed and metabolized into NZ, and then the plasma concentrations declined with apparent elimination half-lives of 8.4 h and 24.9 h for Z and NZ respectively, whilst the renal clearance of both compounds was low, Z 15.7 ml/min and NZ 33.0 ml/min. The plasma level of Z differed little between Groups I and III, but the area under the curve was significantly higher in Group III than in Group I subjects (AUC0-144 = 17.3 and 6.8 mumol X l-1 X h, respectively). Severe renal failure did not affect the peak plasma concentration of NZ but it did significantly increase peak time, apparent elimination half-life, and the area under the plasma concentration curve. A significant inverse relationship was found between renal clearance of NZ and plasma creatinine. Since NZ is as pharmacologically potent as Z, the results suggest that the dose of Z should be reduced in patients with severe renal insufficiency.

The effects on magnesium excretion of 4 short-term diuretic treatments (methyclothiazide 2 mg either alone or associated with increasing doses of triamterene) were evaluated in 8 normal volunteers and compared to spontaneous variations during placebo administration. The thiazide exerted a small but significant magnesuric effect, which was prevented only by the lowest dose (25 mg) of triamterene. Larger doses had no protective effect on thiazide-induced magnesuria. Independently of their absolute effects on magnesium excretion, all diuretics impaired the normal ability of the kidneys to compensate fully for the expected changes in magnesium reabsorption induced by extracellular volume contraction.

1. The kinetics of the hypolipidaemic drug, ciprofibrate, were studied after a single oral dose (100 mg) in subjects with normal renal function (n = 6), patients with mild (n = 6) and severe (n = 6) renal insufficiency as well as in haemodialysed patients (n = 5). 2. Under fasting conditions, ciprofibrate, was absorbed rapidly in subjects with normal renal function, and its apparent elimination half-life was approximately 81 h. Both renal clearance (0.15 ml min-1) and cumulative renal excretion (less than 7% of the administered dose) were low. 3. Mild renal insufficiency did not alter the pharmacokinetics of ciprofibrate, but severe renal impairment significantly reduced both its renal clearance and cumulative urinary excretion and increased the apparent elimination half-life. 4. A 5 h haemodialysis session did not lower the plasma concentrations of ciprofibrate. 5. It is concluded that, from a pharmacokinetic point of view, a reduction in the dosage of ciprofibrate should be considered in patients with a glomerular filtration rate below 30 ml min-1/1.73 m2.

A study was carried out, of the changes of renal functional value and of urinary electrolytes excretion after rapid intravenous injection of acebutolol in twelve subjects with various glomerular filtration. Renal functional value was estimated by measuring inuline. P.A.H., urea and creatinin clearances during a control period of thirty minutes and during the four hours following administration of acebutolol. The variations in the excretion of electrolytes: chloride, sodium, potassium, calcium and phosphorus were measured during the same periods. The following results were obtained: in subjects with normal renal functional value, administration of acetubolol brings about: a variation which is under 20 p.cent of glomerular filtration and P.A.H. clearance; a 50 p.cent average decrease of natriuresis. in cases of renal insufficiency: clearances of inuline and P.A.H. are unchanged. There is a 20 p.cent average decrease of natriuresis. There is a decrease of urinary output (35-45 p.cent) and of urea clearance (20-50 p.cent).

The glomerular filtration rate (GFR, inulin clearance) and renal plasma flow (RPF, PAH clearance) were measured in 35 hypertensive patients during chronic administration of an alpha-beta-blocker, labetalol. No significant changes in GFR occurred but RPF increased significantly. The increase in RPF was positively correlated with the decrease in mean arterial blood pressure. Patients with renal failure showed changes similar to patients with normal renal function. Thus chronic treatment with labetalol, unlike most beta-blockers, can increase RPF, an effect which could be related to the alpha-blocking activity of the drug.

A retrospective study of 166 cases of renovascular hypertension was performed. Before 1979, 114 patients were treated for renovascular hypertension. Forty underwent surgery. In this group, therapy resulted in cure or improvement in 45% of the patients. Seventy-four patients underwent medical therapy: 88% of these patients had improvement of blood pressure when beta-blockers were used, but only 41% when they were not. More recently (from 1979 to 1983), 52 patients were treated for renovascular hypertension, of which 31 patients have been operated for fibromuscular renal artery stenosis (62%) or atherosclerotic renal artery stenosis (32%). In this group, 90% of the patients were considered to be cured or improved with a mean follow-up of 36 months. Eighteen of thirty-one patients underwent autotransplantation with satisfactory results on blood pressure control. Twenty-one patients were treated by antihypertensive drugs: 86% of the patients were improved or cured (71.5% of the patients had atherosclerotic lesions) with a mean follow-up of 46.8 months.

The spontaneous changes in renal handling of uric acid, the consequences of methyclothiazide (M) and of a combination of M with three doses of triamterene (25, 50, 75 mg) were assessed in eight normal men, in a ten-week placebo controlled, double-blind study. In untreated subjects, significant correlations were found between blood uric acid (bUA) and UAV, between bUA and FeUA, between FeUA and plasma renin activity (PRA) and between bUA and PRA. Spontaneous variations in bUA and UAV were shown to be predominantly dependent on changes in sodium status. All diuretics significantly increased bUA and decreased FeUA. Under diuretics, bUA kept correlations with FeUA and PRA similar to that observed in untreated subjects indicating that the changes were dependent only on variations in renal transport induced by changes in sodium status. Addition of triamterene to methyclothiazide significantly lessened the thiazide induced abnormalities in UA.

The effects of a single oral dose and of an 8 week treatment with labetalol--an alpha 1- and beta 1-2-adrenoceptor blocking agent--and with atenolol--a beta 1-adrenoceptor blocking agent--were compared in 52 hypertensives. A single oral dose of atenolol induced a marked bradycardia without decrease in blood pressure. On the contrary labetalol lowered blood pressure but not resting heart rate. After an 8 week treatment both drugs exhibited a similar antihypertensive effect. However labetalol did not decrease heart rate and plasma renin activity as markedly as atenolol did. It was concluded that the alpha 1 blocking properties of labetalol were of importance in the development of the antihypertensive properties that this drug exhibits after a single or multiple administrations.

The kinetics of nalidixic acid (NA) and its two metabolites, 7-hydroxynalidixic acid (HNA) and 7-carboxynalidixic acid (CNA) were studied after a single oral dose and after two doses a day for 7 days. Total unconjugated NA, HNA, and CNA concentrations in plasma and urine samples were assayed by a new high-pressure liquid chromatographic (HPLC) technique. NA was rapidly absorbed and hydroxylated to HNA. Both were rapidly excreted in urine with an apparent elimination half-life (t1/2) of 6 to 7 hr. CNA was never detected in the plasma, although it accounted for about 25% of total urinary NA and metabolites. No major sex-related differences in the kinetics and the metabolic pattern were observed. During the 7-day treatment there was no significant cumulation of NA and HNA. The study demonstrated that the concentration of the active compounds, unconjugated NA and HNA, was more than five times the minimum bacteria inhibiting concentration for 8 hr after drug and slightly above this concentration during the next 4 hr.

Renal insufficiency is the most frequent complication of malignant hypertension (MHT). The initiation of effective hypotensive treatment is generally followed by a rapid improvement of renal functions, but the long-term evolution has been only rarely studied. A group of 30 patients was retrospectively selected on the following criteria: Malignant hypertension: mean DBP 138 +/- 20 mmHg, hypertensive retinopathy stage III-IV; Early renal insufficiency: mean Inulin clearance (CIN) 66 +/- 26 ml/min, mean PAH clearance (CPAH) 364 +/- 161 ml/min; Clinical and functional follow-up ranging from 5 to 18 years. Among these patients, two groups were defined according to the quality of BP control: good or fair responders (GR) with a DBP always less than 110 mmHg, poor responders (PR) with a DBP occasionally greater than or equal to 110 mmHg. The results show in the two groups an improvement of CIN at 3 years, followed by a stabilization then a decrease after the 6th year. However the early improvement is significantly lower in PR. Despite similar initial values (GR = 54.7 +/- 31.3; PR = 51.4 +/- 13.2), CIN remains always lower in PR (at 9 years = GR 72.4 +/- 30.6; PR 56.0 +/- 19.8). During the first 3 years, CPAH increases in GR, whereas it decreases in PR, resulting in significantly different values at 3 years. At 9 years, CPAH remains improved in GR (329.1 +/- 109.3 vs 281.7 +/- 173.8 initially) but decreased in PR (256.0 +/- 166.9 vs 307.3 +/- 119.5 initially). The parallel improvement of CIN and CPAH in GR confirms a favorable effect of BP control on early vascular lesions.(ABSTRACT TRUNCATED AT 250 WORDS)