[Compensatory hyperfunction in living kidney donors]. / Hyperfonction compensatrice chez les donneurs vivants de rein.

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.

Screening early renal failure: cut-off values for serum creatinine as an indicator of renal impairment.

BACKGROUND: The aim of this study was to define cut-off values for serum creatinine as an indicator of several levels of renal impairment. METHODS: To identify the suitable values, receiver operating characteristic curves were constructed based on the data of 984 laboratory assessments of renal function. The glomerular filtration rate was measured with inulin clearance. Three levels of renal impairment were analyzed. An index that gave the same weight to false positive and false negative results was used to determine the thresholds. Robustness of the results was tested using a "bootstrap" technique. RESULTS: Considering an inulin clearance of less than 80 ml/min/1.73 m2, the cut-off value for serum creatinine was 11.5 mumol/liter for men and 90 mumol/liter for women. The cut-off value for a clearance of less than 60 ml/min/1.73 m2 was 137 mumol/liter for men and 104 mumol/liter for women. For a clearance of less than 30 ml/min/1.73 m2, the cut-off value was 177 mumol/liter for men and 146 mumol/liter for women. CONCLUSION: This method is useful to determine a cut-off value for serum creatinine in epidemiological studies concerning early chronic renal failure screening. The value of the glomerular filtration rate of reference and the weight of false positive and false negative results have to be adapted to the aim of the individual study design.

[Graft function following renal transplantation in children]. / Evolution de la fonction du greffon après transplantation rénale chez l'enfant.

BACKGROUND: 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. POPULATION AND METHODS: 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. RESULTS: 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.

Pharmacokinetics of milnacipran in renal impairment.

The pharmacokinetics of a single 50 mg dose of milnacipran, a new non tricyclic antidepressant drug, were compared in 8 chronic renal failure subjects (Clc(reat) between 9 to 84.5 ml.min(-1)) and in 6 healthy volunteers. Concentrations of unchanged (F2207 racemate and F2695 and F2696, enantiomers) and glucuroconjugated drug (main metabolite) were measured using HPLC and GC-MS. As for drugs mainly eliminated via renal route, the pharmacokinetics of milnacipran were markedly affected by impaired renal function with the elimination half-life of severely impaired subject being approximately three times that of the control group. Milnacipran apparent total clearance and renal clearance were positively correlated with glomerular filtration rate, while non-renal clearance and apparent volume of distribution were unaffected by renal impairment. Plasma concentrations of the glucuroconjugate were gradually increased in plasma, while its total urine excretion remained unchanged. As for the racemate, pharmacokinetics of each enantiomer were modified by renal failure, although, as predictable from its higher renal clearance value, it was more marked for F2696 than for F2695. Considering that modifications were shown to be proportional to the degree of renal impairment and that milnacipran presents low variability, the necessary dose adjustment is therefore easy to predict.

Effects of moxonidine on stress-induced peak blood pressure and renal function: a randomized, double-blind, placebo-controlled crossover study.

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.

Role of the donor in post-transplant renal function.

BACKGROUND: The donor, i.e. adult or paediatric, might influence the outcome of the graft function. METHODS: 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 age > 18 years; n=33) and paediatric (donor age < 18 years; n=87). GFR was assessed by inulin clearance at 3, 6 and 12 months and yearly thereafter. RESULTS: 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. CONCLUSIONS: 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.

Nifedipine improves recovery function of kidneys preserved in a high-sodium, low-potassium cold-storage solution: study with the isolated perfused rat kidney technique.

BACKGROUND: Extracellular types (high-Na) of cold-storage solution (CSS) have been shown to be more effective in preserving kidneys than intracellular CSS (high-K). On the other hand, calcium entry blockers (CEB) have been demonstrated to improve graft function when administered after and/or prior to transplantation. The ischaemia 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. Since CEB act via a modification in intracellular calcium metabolism on vascular smooth muscle, glomerular, and tubular cells, we evaluated the actual benefit on CEB on kidneys preserved in Belzer's CSS (K-UW) and a high-Na version of Belzer's CSS (Na-UW). METHOD: The isolated perfused rat kidney (IPK) was used, first as a vascular bed to test the effects of CSS on RVR, and the influence of nifedipine. Second, the recovery function of the IPK was assessed by GFR and tubular Na reabsorption, after 24 h preservation in K-UW and Na-UW, with or without nifedipine. Results were compared with a control group in which renal function was measured without prior cold-storage. RESULTS: K-UW but not Na-UW induced an increase in RVR when flushed into the kidney. This vasoconstriction is prevented by nifedipine. K-UW CSS was more deleterious to renal function than Na-UW. Addition of nifedipine to the flush, the CSS for 24 h, and to the normothermic reperfusate further improved recovery function of the IPK cold stored in Na-UW but not in K-UW, without any modification of RVR. CONCLUSION: Nifedipine may be of potential effect in attenuating ischaemic injury by a mechanism which does not involve its vasodilatory properties.

Creatinine determination in peritoneal dialysis: what method should be used?

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.

Reproducibility of the cardiovascular reactivity to a computerized version of the Stroop stress test in normotensive and hypertensive subjects.

The 1-month reproducibility of haemodynamic and sympathoadrenal 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.

Effects of losartan on renal function in patients with essential hypertension.

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.

[Comparison of three methods for the estimation of spontaneous cardiac baroreflex sensitivity in normotensive and hypertensive subjects]. / Comparaison de trois méthodes d'estimation de la sensibilité du baroréflexe cardiaque spontané chez l'homme normotendu et hypertendu.

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 (r > 0.97) 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 new non-invasive statistical method to assess the spontaneous cardiac baroreflex in humans.

1. A new method was developed to evaluate cardiac baroreflex sensitivity. The association of a high systolic blood pressure with a low heart rate or the converse is considered to be under the influence of cardiac baroreflex activity. This method is based on the determination of the statistical dependence between systolic blood pressure and heart rate values obtained non-invasively by a Finapres device. Our computerized analysis selects the associations with the highest statistical dependence. A 'Z-coefficient' quantifies the strength of the statistical dependence. The slope of the linear regression, computed on these selected associations, is used to estimate baroreflex sensitivity. 2. The present study was carried out in 11 healthy resting male subjects. The results obtained by the 'Z-coefficient' method were compared with those obtained by cross-spectrum analysis, which has already been validated in humans. Furthermore, the reproducibility of both methods was checked after 1 week. 3. The results obtained by the two methods were significantly correlated (r = 0.78 for the first and r = 0.76 for the second experiment, P < 0.01). When repeated after 1 week, the average results were not significantly different. Considering individual results, test-retest correlation coefficients were higher with the Z-analysis (r = 0.79, P < 0.01) than with the cross-spectrum analysis (r = 0.61, P < 0.05). 4. In conclusion, as the Z-method gives results similar to but more reproducible than the cross-spectrum method, it might be a powerful and reliable tool to assess baroreflex sensitivity in humans.

Spectral analysis of stress-induced change in blood pressure and heart rate in normotensive subjects.

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.

Pharmacokinetics of piroximone after oral and intravenous administration to patients with renal insufficiency.

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.