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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.

The accuracy of methods for measurement of creatinine in plasma, urine and dialysate is of great importance in continuous ambulatory peritoneal dialysis (CAPD) patients, to assess the adequacy of CAPD (creatinine clearance) and to monitor the nutritional status (creatinine kinetic lean body mass). The methods most widely employed for creatinine determination are Jaffe's reaction and the enzymatic method, however these techniques may suffer from glucose interference, particularly for dialysate. We compared creatinine values obtained by Jaffe's reaction, the enzymatic method and high pressure liquid chromatography (HPLC) for three creatinine calibration curves prepared in three dialysis solutions with various concentrations of glucose and for plasma, urine and dialysate of 40 CAPD patients. High values of intercept of creatinine calibration curves were observed only with Jaffe's reaction and the enzymatic method in dialysis solutions. In plasma, urine and dialysate, creatinine values obtained by HPLC were always found to be lower than those measured by the other two methods. Concerning creatinine measurement in plasma and urine, Jaffe's reaction and the enzymatic method appeared equivalent. However it must be noted that, in dialysates, the enzymatic method may have glucose interference, and the use of a correcting factor for glucose with Jaffe's reaction is convenient. Nevertheless HPLC remains a method of reference. It is concluded that, for the CAPD patient, follow-up by creatinine kinetic lean body mass or creatinine clearance is possible provided that the same creatinine assay method is used in all biological fluids.

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.

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).

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.

1. Ten healthy subjects received two treatments: a single 1 g oral dose of nalidixic acid (NA) followed 1 h later by either an infinitesimal dilution of the drug (NA 7CH) or by succussed water which served as placebo. The study was repeated 18 months later in 10 different subjects. 2. A further 10 healthy subjects received three treatments: a single 100 mg oral dose of atenolol (AT) followed 3 h later by either placebo or a dilution of AT (AT 7CH) or of bisoprolol (BI 7CH). The homoeopathic preparations were administered by the sublingual route. 3. In the first NA experiment NA 7CH significantly shortened the elimination half-life of NA from 8.6 +/- 2.2 (placebo) to 6.4 +/- 1.6 h (NA 7CH). In the second NA experiment none of the pharmacokinetic parameters was modified significantly by the administration of NA 7CH. Neither AT 7CH nor BI 7CH modified the pharmacokinetics of AT.

EXTRACELLULAR types (high-Na) of cold-storage solution (CSS) have been shown to be more effective in preserving kidneys than intracellular CSS (high-K). 1,2 We have previously demonstrated with the isolated perfused rat kidney model (IPK) that a high-Na version of University of Wisconsin (UW) Belzer's CSS (Na-UW) seemed to be less injurious to recovery function than the original high-K UW Belzer's solution (K-UW). 3 On the other hand, a number of clinical investigations have suggested that calcium entry blockers (CEB) may improve graft function when administered after and/or prior to transplantation. 4,5 The ischemia reperfusion syndrome involves, in part, an alteration in intracellular calcium metabolism that induces an increase in renal vascular resistances (RVR) and other cellular dysfunction, and high-K CSS per se are vasoconstrictive. 6 Since maneuvers that would prevent vasoconstriction may favour the intraorgan diffusion of the cold-storage solution and ameliorate preservation, we evaluated with the IPK model, the actual benefit of the vasodilator nifedipine on kidneys preserved in K-UW and Na-UW.

The pharmacokinetics of piroximone (PI) were determined in patients with renal failure (inulin clearance less than 50 ml min-1 per 1.73 m2) using two protocols: (a) 10 patients received a single i.v. infusion of 0.5 mg kg-1 PI and the data were compared with those from seven healthy subjects receiving the same regimen; (b), a single oral dose of either 25 or 50 mg PI was given to 20 patients. PI concentrations were assayed by h.p.l.c. in plasma and urine over 48 h. After i.v. administration to healthy subjects PI was distributed rapidly and eliminated with a mean half-life of 1.3 +/- 0.2 h. The urinary recovery of unchanged PI was 64% of the dose. In the patients the extent of renal elimination of PI was decreased (-78%) in relation to the degree of renal insufficiency as assessed by inulin clearance (r = 0.97, P < 0.0001). Mean Cmax, AUC and t1/2,z values after i.v. infusion were increased by 47%, 127% and 77%, respectively, in comparison with healthy subjects. Similar results were obtained after oral administration. Until chronic dosing studies are undertaken, PI dosage should be adapted in relation to renal function.

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.

Late graft dysfunction remains the main cause of graft loss in renal transplantation in spite of improvements in shortterm renal allograft survival and advances in immunosuppressive therapy [1]. Chronic rejection is often an unpredictable outcome in renal transplantation, although many previous publications have tried to identify risk factors [2, 3]. However, most publications have focused on variables in univariate statistical analysis without taking into account potential confounding factors. Both immune and nonimmune mechanisms have been implicated in the pathogenesis of chronic rejection [4], Among the nonimmunological mechanisms, hyperfiltration could be a cause of chronic graft failure [5], although clear human functional data in renal transplantation are lacking.

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.

The isolated perfused rat kidney (IPK) model was used to assess initial renal function after 24 h preservation in 3 different cold storage solutions : EuroCollins (EC), a solution prepared according to the formulation of Belzer's solution (High-K + UW) and a high Na + -low K + Belzer UW solution (High-Na + UW). GFR and FR Na were measured after 24h cold storage in each of the solutions during 60 min, and were compared to values obtained in a control group in which renal function was measured immediately after the kidneys had been harvested. ATP and CP were measured in fresh renal tissue, in kidneys preserved for 24 h in each solution, in control IPK, and in reperfused IPK after they had been preserved for 24 h. Main results showed that preservation in either solution caused a dramatic decrease in GFR and in FR Na within the first 60 min following reperfusion of cold-stored kidneys. However FR Na was significantly higher in the High-Na + UW group. ATP and CP content were decreased to 10% of basal values in all experimental groups after cold-storage. Normothermic reperfusion of IPK after cold-storage induced a restoration of ATP levels, but CP content decreased further. There was no significant difference in ATP and CP content between cold-storage solutions, nor any correlation between metabolic and functional parameters.

The isolated perfused rat kidney (IPK) model was used to assess initial renal function after 24h preservation in 3 different cold storage solutions: EuroCollins (EC), a solution prepared according to the formulation of Belzer’s solution (High-K+ UW) and a high Na+ - low K+ Belzer UW solution (High-Na+ UW).

The isolated perfused rat kidney (IPK) model was used to assess initial renal function after 24 h preservation in 3 different cold storage solutions: EuroCollins (EC), a solution prepared according to the formulation of Belzer's solution (High-K+ UW) and a high Na(+)-low K+ Belzer UW solution (High-Na+ UW). GFR and FRNa were measured after 24 h cold storage in each of the solutions during 60 min, and were compared to values obtained in a control group in which renal function was measured immediately after the kidneys had been harvested. ATP and CP were measured in fresh renal tissue, in kidneys preserved for 24 h in each solution, in control IPK, and in reperfused IPK after they had been preserved for 24 h. Main results showed that preservation in either solution caused a dramatic decrease in GFR and in FRNa within the first 60 min following reperfusion of cold-stored kidneys. However FRNa was significantly higher in the High-Na+ UW group. ATP and CP content were decreased to approximately 10% of basal values in all experimental groups after cold-storage. Normothermic reperfusion of IPK after cold-storage induced a restoration of ATP levels, but CP content decreased further. There was no significant difference in ATP and CP content between cold-storage solutions, nor any correlation between metabolic and functional parameters.

Assessment of renal function in children raises several difficulties concerning technical and analytical aspects. Renal function parameters are influenced by both age and renal failure. Inulin clearance is the standard method to measure glomerular filtration rate, but it cannot be routinely used. Among other methods, plasma creatinine determination is not reliable to evaluate the level of renal function or to follow the course of renal diseases. Creatinine clearance estimated from calculations such as Schwartz formula does not provide an accurate estimation of the glomerular filtration rate. More precise estimate can be obtained from endogenous creatinine clearance, providing that the measurement is performed accurately. In this paper the authors review these factors and report personal data obtained from 500 children who underwent renal function investigation.

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.

Accurate methods of measuring glomerular filtration rate are usually considered as expansive and time consuming. Therefore, alternative methods (creatinine clearance, either calculated or measured, reciprocal plasma creatinine, slopes of creatinine vs time) have frequently been used to assess the rate of progression of renal failure and predict the time of dialysis. The present review underlines the limitations of such techniques frequently underestimated in recent trials intending to evaluate the potential benefit of protein restriction. It delimitates the restrictive conditions in which such methods could be used for clinical but not research purposes.

Phase I studies cannot predict the therapeutic efficacy of a new drug. However, they can lead to important information concerning: i), the undersirable effects and their mechanisms of occurrence; and ii), the pharmacokinetics and the metabolism of the drug as well as their possible alterations in renal or hepatic diseases. When considering the therapeutic effects, 3 cases have to be considered which are, in order of decreasing predictive value: i), when a direct relationship is expected between the drug concentration in the body and its therapeutic effects (eg, antibiotics); ii), when the drug has a known molecular or cellular target which is directly involved in the pathophysiology of the disease (eg, renin inhibitors); and iii), when the drug does not have a known target or is directed toward a precise target which is not directly involved in the disease. In all these cases, a phase I study in healthy volunteers should be able to describe, at least qualitatively, the pharmacodynamic effects of the drug which are relevant to its therapeutic goal.

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

Background: Comparison between inulin clearance (glomerular filtration rate, ml/min/1.73m2) with (GFRu) and without (GFRp) urinary collection measured by constant infusion technique.

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.

1 The pharmacological actions of piretanide, a new high efficiency diuretic, were studied in sixteen patients with GFR (inulin clearance) varying from 0.1--2.5 ml/s. 2 After hydration and following two control periods, a single dose of 6 mg piretanide was ingested. Thereafter, urine was collected every 30 min for 2 h and every hour for the next 4 h. Fluid losses were replaced. 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 Main results showed piretanide was efficient in the group with normal GFR (inulin clearance greater than 1.5 ml/s) and in the group with slightly decreased GFR (1.0 less than inulin clearance less than 1.4 ml/s), in terms of diuresis, natriuresis, kaliuresis and calciuresis. It was inefficient in the group with severe renal insufficiency (inulin clearance less than 0.3 ml/s). 5 Free water clearance showed preservation of diluting ability to a large extent. 6 In the three groups, no significant change in inulin clearance and PAH clearance occurred.