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.

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.

[Epidemiology of severe chronic renal insufficiency in Burkina Faso]. / Epidémiologie de l'insuffisance rénale chronique sévère au Burkina Faso.

We identified 174 cases of chronic severe renal failure (blood creatinine > 650 mumol/l) and/or blood urea > 35 mmol/l) in a retrospective study of patients admitted to hospital between January 1989 and June 1996. Of these patients, 110 were men and 64 were women. The mean age was 36 +/- 15 years. Fifty three patients had a history of hypertension before admission, 3 patients had diabetes and 3 had gout. The most frequent clinical signs were dyspnea (55.2% of all patients), fatigue (78.2%), vomiting (63.2%) and edema (66.1%). The prevalence of hypertension was 64.9%. Glomerulonephritis was found in 42.5% of patients, chronic interstitial nephritis in 16.1%, polycystic kidney disease in 2 cases, congenital renal hypoplasia in 4 cases and unclassified kidney disease in 14.4% of cases. End-stage renal failure was complicated by heart failure in 40.2% of patients, pericarditis in 31.6%, hemorrhage of the gastrointestinal tract in 15% and infections in 22.4%. 47.7% of the patients died following admission.

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.

Effects of low-protein diet supplemented with ketoacids on plasma lipids in adult chronic renal failure.

We designed a short-term randomized controlled study in 12 adult patients with chronic renal failure to assess the metabolic effects of a low-protein diet (LPD) supplemented or not with ketoacids (Cetolog, Clintec Corp., France). Dietary survey included a monthly 3-day food record and a 24-hour urinary urea measurement. After a baseline period (1.11 g protein, 31.7 kcal/kg BW/day), patients reduced their protein intake (PI) to 0.71 g/kg BW/day. Energy intake (EI) was kept constant (31.4 kcal/kg BW/day) during the 3-month period. Baseline plasma lipids did not show overt hyperlipemia. After reducing PI, a significant increase in apolipoprotein AI and the Apo-AI/Apo-B ratio was observed. Plasma Lp(a) levels were elevated at baseline and did not change during the 3-month LPD period. There was no difference between groups receiving ketoacids or not. Thus, in adult chronic renal failure, under a sufficient EI, reducing PI by 40% had a beneficial effect on plasma lipid profile. This improvement in lipid profile might reduce the high cardiovascular risk in these patients.

[Recombinant human growth hormone (rhGH) administration in a patient with chronic renal insufficiency: renal and metabolic effects]. / Administration d'hormone de croissance recombinante humaine (rhGH) chez une patiente insuffisante rénale chronique: effets rénaux et métaboliques.

We report the renal and metabolic effects of a 40 day administration of recombinant human growth hormone in a 31 years old diabetic and GH-deficient patient who underwent a kidney and pancreas transplantation. The data show an increase in glomerular filtration rate, tubular reabsorption of phosphate, and plasma hemoglobin level. Anabolism is suggested from a decrease in serum urea nitrogen and an increase in muscle mass (increase in plasma creatinine). These positive effects might be partly explained by an overcome of endogenous growth hormone resistance when administering pharmacological doses of recombinant growth hormone.

Insulin-like growth factor-1 and its binding proteins during a low-protein diet in chronic renal failure.

The effects of a low-protein diet on the serum insulin-like growth factor (IGF)-1 and IGF binding proteins (IGFBP) were investigated during a 3-month controlled study in 12 adult chronic renal failure patients. Six patients were randomly supplemented with keto acids (Cetolog, Clintec, Velizy, France). Protein intake was prescribed so that both groups were isonitrogenous. Dietary survey included a monthly 3-day food record and a 24-h urinary urea measurement. After a 4- to 6-wk equilibrium period (1.11 g of protein, 32 kcal/kg body wt per day), patients reduced their protein intake to 0.71 g protein/kg body wt per day. Energy intake was kept constant (31 kcal/kg body wt per day) during the 3-month period. Serum IGF-1 levels were in normal range and, for 11 of the 12 patients, were correlated with the GFR (P = 0.01). These serum IGF-1 values did not decrease after reducing the protein intake. By Western ligand blotting, serum IGFBP1, IGFBP2, and IGFBP4 levels were significantly higher than normal adults, whereas the IGFBP3 level was not increased. IGFBP were not modified when protein intake was reduced. The IGFBP1 level was elevated despite a normal insulin level. IGFBP4 changes were inversely correlated with IGF-1 variations. There was no difference between groups receiving or not receiving the keto acids. Thus, in adult chronic renal failure, reducing protein intake by 40% did not modify the growth hormone/IGF-1/IGFBP axis.

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.

Evaluation of a high sodium-low potassium cold-storage solution by the isolated perfused rat kidney technique.

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.

Epidemiological profile of hypertensive disease and renal risk factors in black Africa.

OBJECTIVE: To describe the characteristics and renal function of hypertensive patients at their first hospital admission in Sub-Saharan Africa. DESIGN: Retrospective study of all hypertensive patients. SETTING: Department of Cardiology and Internal Medicine of Yalgado Ouedraogo National Hospital in Burkina Faso, a country in Sub-Saharan Africa. PATIENTS: Three hundred and seventeen consecutive hypertensive patients (systolic blood pressure > or = 160 mmHg or diastolic blood pressure > or = 90 mmHg, or both, or patients receiving antihypertensive treatment) referred between 1 November 1988 and 31 October 1990. RESULTS: The hypertensive patients accounted for 36.5% of admissions and included 198 males and 119 females (mean +/- SD age 49 +/- 14 years). Two-thirds of the patients belonged to the poorer socio-economic groups. Hospital admission was necessary because of the symptoms and complications of hypertension: 43% had diastolic blood pressure > 130 mmHg, 73.5% had at least one target organ affected and 38.2% had renal involvement in the form of chronic renal failure or as proteinuria > 1.5 g/24 h. Patients with renal involvement were younger and had blood pressure that responded less well to acute treatment. One-fifth of the patients died during their hospital stay, and most of these had impaired renal function.

Thrombospondin in human glomerulopathies. A marker of inflammation and early fibrosis.

Extensive damage is thought to occur to endothelial cells in renal vasculitis and other glomerulopathies. The state of inflammation of these endothelial cells was investigated through the use of a panel of monoclonal antibodies (MAb) directed against thrombospondin (TSP), von Willebrand factor (vWF), integrins (alpha IIb beta 3, alpha v beta 3), CD36, and classical markers of inflammation (P-selectin, E-selectin, ICAM-1, VCAM). Results show that the anti-TSP MAb (LYP10) stains large areas of interstitium in focal sclerosis, vasculitis, membranous glomerulonephritis (GN), and diabetic GN but does not in normal kidney. In contrast, very limited areas are stained by LYP10 in minimal change nephropathy and Berger's disease. On paraffin-embedded specimens these areas stained by LYP10 appear edematous and early fibrous. Up-regulation of vWF and ICAM-1 is matched by an increased binding of LYP10 to the interstitium. In addition, fibrous crescents in injured glomeruli are stained by LYP10. This study reports for the first time an increased TSP secretion in glomerulopathies. Such TSP secretion may be part of physiological adaptive changes associated with inflammation and early fibrosis.

[Renal insufficiency in arterial hypertension in black Africa]. / Insuffisance rénale au cours de l'hypertension artérielle en Afrique noire.

OBJECTIVES: The increased risk of renal disease due to high blood pressure observed in Black Americans would suggest ethnic factors are involved. We examined the clinical features of renal disease in patients hospitalized in Ouagadougou, Burkina Faso for high blood pressure to determine the risk factors in this black population. METHODS: From November 1988 to October 1990, 317 patients (mean age 49 +/- 14 years, 62.5% males) under treatment for high blood pressure or with a diastolic pressure > 90 mmHg without antihypertensive therapy were examined at their initial hospitalization. The patients were divided into socio-economic groups according to their professional occupation and level of education. Criteria of renal disease, including raised serum creatinine, proteinuria and blood urea nitrogen, together with factors related to hypertension, including obesity, diabetes mellitus, hypertensive retinopathy, heart failure, coronary artery disease, cerebral vascular events and hypertensive encephalopathy were analyzed. RESULTS: Severe hypertension, diastolic pressure > 130 mm Hg was observed in 43% of the patients. There was a significant inverse correlation between age and diastolic pressure (r = 0.23, p < 0.0001). Response to initial anti-hypertensive treatment was good in 88% and proportional to severity. Hospital mortality was 18.6% (59 patients) including 39 cases during the first two days. Mortality was not correlated with blood pressure, age, sex or socio-economic conditions. Renal disease was observed in 121 patients and chronic renal failure in 117 (44%). Effect of hypertension on at least one target organ was observed in 73.2% of the patients and on at least three target organs in 38.2%. Subjects with renal disease were younger (p < 0.02) and responded less well to treatment than those without renal disease. CONCLUSIONS: These clinical observations confirm the high prevalence of renal failure and the gravity of high blood pressure in Black Africans. In Burkina Faso, hospitalization for high blood pressure often leads to the discovery of terminal renal failure.

Effects of lisinopril on stress-induced peak blood pressure and sodium excretion: a double-blind controlled study.

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).

Papillary necrosis and medullary sponge kidney in a patient with hemoglobin SC.

A 22-year-old woman with hemoglobin SC who was hematologically asymptomatic, developed gross hematuria associated with urinary tract infection, without any urological antecedents. Investigations revealed a unilateral hematuria due to papillary necrosis on the left kidney. Medullary sponge kidney was also discovered by radiologic investigations. Papillary cysts could play a role in the occurrence of papillary necrosis.

Pharmacokinetics of ganciclovir in a patient undergoing chronic haemodialysis.

The pharmacokinetics of ganciclovir was evaluated in a 73-year old anuric, haemodialyzed patient given 1.25 mg.kg-1 at the end of each haemodialysis session, three times per week. A biexponential decrease in plasma ganciclovir was observed, with a peak concentration of 3.7 mg.l-1 followed by a steady state value of 2.6 mg.l-1 for almost 40 h. The total plasma clearance was 0.05 ml.min-1.kg-1, the volume of distribution at steady state was 0.6 l.kg-1, the elimination half life was 132 h, the area under curve was 372 micrograms.h.ml-1, the mean residence time was 190 h, and the percentage of ganciclovir cleared from plasma after a 5 h haemodialysis session was 52.1%. The simulated pharmacokinetics over one month, following the same scheme of administration, did not suggest marked accumulation of ganciclovir. These results were obtained after a reduction of 58% in the recommended dose in patients with impaired renal function.