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D Fliser

Publications and source records attributed to D Fliser.

At least 37 records · Page 2Linked to original sources
PubMed1999

Renal handling of drugs in the healthy elderly. Creatinine clearance underestimates renal function and pharmacokinetics remain virtually unchanged.

OBJECTIVE: It is commonly assumed that renal function, and in parallel the excretion of drugs, is considerably reduced in the elderly. Endogenous creatinine clearance or indirect estimates of this parameter are generally recommended for adapting drug dosage. The present study evaluates the validity of both assumptions. METHODS: We compared pharmacokinetics (and pharmacodynamics) of 50 mg atenolol, 800 mg piracetam and 25 mg hydrochlorothiazide plus 50 mg triamterene in ten healthy young [25 (2) years] and 11 healthy elderly subjects [68 (5) years]. Inulin (Cin) and para-aminohippurate [PAH (CPAH)] clearance (infusion clearance technique), endogenous (C(Cr)) and calculated (Cockroft-Gault) creatinine clearance, analysis of drugs and their metabolites (HPLC), were performed. Renal haemodynamics and the pharmacokinetics of beta-adrenergic blocking agent, diuretics and the nootropic agent piracetam, respectively, were measured on separate days. RESULTS: Cin was significantly (P < 0.01) lower in the healthy elderly subjects [104 (12) vs 120 (14) ml x min(-2) x 1.73 m(-2) in the young], but remained within the normal range (> 90 ml x min(-2) x 1.73 m(-2)). In contrast, C(Cr) was even lower in healthy elderly subjects [95 (24) vs 121 (20) ml x min(-1) in the young], and the Cockroft-Gault clearance underestimated true glomerular filtration rate (GFR) even more seriously [74 (17) vs 122 (16) ml min(-1)]. For atenolol the mean area under the curve (AUC) was similar in both groups [3.16 (0.48) microg x h(-1) x ml(-1) in the elderly vs 3.01 (0.30) in the young], as was the mean maximal plasma concentration [0.42 (0.07) vs 0.44 (0.06) microg x ml(-1)], but the proportion of the drug excreted in urine was marginally (P < 0.025) lower in the elderly. Similar results were obtained for hydrochlorothiazide, whereas no marked differences between the groups were found for triamterene and its metabolite. Furthermore, the pharmacodynamic action of diuretics was not significantly altered in the elderly. CONCLUSIONS: The true GFR of the healthy elderly remains within the normal range and is underestimated by creatinine clearance and more so by its surrogate (Cockroft-Gault clearance). In parallel, pharmacokinetics of renally excreted drugs are not affected in the healthy elderly to a clinically significant extent. For drugs with a narrow therapeutic window, indirect estimates of GFR appear to be an unreliable means for calculating correct dosage in the elderly.

Adrenergic beta-Antagonists↗
PubMed1999

Coadministration of albumin and furosemide in patients with the nephrotic syndrome.

BACKGROUND: In patients with nephrotic syndrome, the natriuretic effect of furosemide (FU) is diminished. The effect of coadministration of FU and human albumin (HA) has remained controversial. METHODS: In a double-blind, placebo-controlled study, nine nephrotic patients (six males, 48 +/- 4 years) on standardized sodium chloride intake, in random order on three separate days, received by intravenous administration for 60 minutes either (a) 60 mg FU plus a sham infusion, (b) 60 mg FU plus 200 ml of a 20% solution of HA, or (c) sham infusion plus 200 ml of a 20% solution of HA. Urinary volume, sodium, albumin and FU excretion, renal hemodynamics, and plasma atrial natriuretic factor concentration were assessed. RESULTS: Administration of FU alone significantly (P < 0.01) increased mean cumulative urinary sodium (259 +/- 30 mmol) and volume excretion (2684 +/- 167 ml) in the first eight hours as compared with the HA infusion alone (118 +/- 12 mmol, 1827 +/- 141 ml). The coadministration of FU and HA caused an even more marked increase (P < 0.01 vs. HA alone) of urinary sodium (312 +/- 28 mmol) and volume excretion (3230 +/- 201 ml); the difference to FU administration alone was significant (P < 0.05). Plasma atrial natriuretic factor, serum albumin concentration, and urinary albumin excretion increased significantly on both HA infusion days, whereas urinary excretion of FU remained unchanged with HA coadministration. Glomerular filtration rate (CIn) was not significantly affected by any of the infusion protocols, but effective renal plasma flow (CPAH) increased significantly on both HA infusion days. CONCLUSIONS: Coadministration of HA potentiates the action of FU in patients with the nephrotic syndrome, but only modestly. This effect is mediated by changes in renal hemodynamics.

Adult↗
PubMed1999

How can we improve prognosis in diabetic patients with end-stage renal disease?

Diabetes has become the single most important cause of end-stage renal failure, but survival of diabetic patients with renal replacement therapy continues to be poor. The major causes of death are cardiovascular complications. Most cardiovascular complications, particularly coronary atheroma, accumulate before patients enter renal replacement programs. This observation points to the need for improved patient care in pre-end-stage renal failure. In the diabetic patient, dialysis should be started earlier than in the nondiabetic patient, and prophylactic vascular access should be established when the glomerular filtration rate is approximately 20 ml/min. Proposals to improve prognosis of the diabetic patient with renal failure include interdisciplinary care for the patients with renal disease, strict normotension, administration of ACE inhibitors, administration of lipid-lowering agents, near-normalization of anemia using recombinant human erythropoietin, and improvement of diabetic foot care in the patient on renal replacement therapy.

Diabetic Nephropathies↗
PubMed1998

Insulin resistance and hyperinsulinemia are already present in patients with incipient renal disease.

In uremic patients resistance to the action of insulin has been documented, but it is not known at what stage of renal disease it appears. We therefore examined 29 patients with IgA glomerulonephritis (IgAGN) and 21 patients with adult polycystic kidney disease (ADPKD) in different stages of renal failure, and in addition, healthy age-matched subjects. Insulin sensitivity and other variables of glucose metabolism were assessed using a frequent sampling intravenous glucose tolerance test (minimal-model technique). Glomerular filtration rate (GFR) was assessed in renal patients using the inulin-clearance technique. Mean insulin sensitivity index (SI), that is, insulin sensitivity, was significantly lower (P < 0.001) in all patients combined than in matched healthy subjects (N = 16; 14 males, mean age 42 +/- 3 years; mean SI 8.6 +/- 0.8 min-1 uU/ml). The mean SI was not significantly different in patients with renal disease of immune (IgAGN) or non-immune (ADPKD) origin, and it was not correlated with GFR (r = 0.01, P < 0.52), intact PTH (r = -0.23, P < 0.11) or calcitriol concentration (r = -0.03, P < 0.82). Consequently, the mean SI was similar in renal patients with GFR within the normal range (N = 19; 17 males, mean age 41 +/- 2 years; mean GFR 119 +/- 5 ml/min/1.73 m2; 5.1 +/- 0.7 min-1 uU/ml), in patients with mild to moderate renal failure (N = 16; 15 males, 46 +/- 3 years; 67 +/- 4 ml/min/1.73 m2; 5.1 +/- 0.7 min-1 microU/ml) and in patients with advanced renal failure (N = 15; 13 males, 46 +/- 3 years; 25 +/- 2 ml/min/1.73 m2; 4.7 +/- 0.6 min-1 uU/ml). Mean fasted plasma insulin concentration, the area under the curve for plasma insulin concentration (AUC) and total insulin delivery (TID) during the glucose tolerance test were significantly higher in patients than in healthy subjects, reflecting hyperinsulinemia in renal patients. Further, fasted plasma insulin concentration (r = -0.32, P < 0.009), AUC (r = -0.62, P < 0.0001) and TID (r = -0.34, P < 0.004) in patients were significantly correlated with insulin sensitivity (SI). The present data document that insulin resistance and concomitant hyperinsulinemia are present early in the course of renal disease, that is, even in patients with GFR within the normal range, irrespective of the type of renal disease. This observation may have potential implications with respect to the high cardiovascular morbidity and mortality in patients with renal disease.

Adult↗
PubMed1998

The sympathetic nervous system and the kidney: its importance in renal diseases.

There is a two-way relation between the sympathetic nerve system and the kidney. On the one hand the sympathetic nerve system affects renal function, i.e. renal hemodynamics, renin secretion and tubular sodium transport. On the other hand the kidney is the source of activating afferent signals, presumably via stimulation of chemoreceptors and baroreceptors. This concept is supported by clinical observations in endstage and pre-endstage renal disease, where sympathetic overactivity is present. It has been shown to depend on the presence of the diseased kidney and is abolished by bilateral nephrectomy. Experimentally, interruption of afferent nerve traffic by dorsal rhizotomy partially prevents hypertension in renal damage models. Imidazoline-preferring binding sites are found in the kidney. In the rat, natriuresis is elicited by injection of moxonidine into the renal artery. In humans, there is no definite evidence for a natriuretic effect, but some observations point in this direction. In renal disease, the issue arises whether sympathetic overactivity contributes to progression of renal failure. Indirect evidence in this direction could be the marked acceleration of progression by smoking, a state of known sympathetic overactivity. In experimental models of renal damage, treatment with moxonidine in antihypertensive doses markedly attenuated development of glomerulosclerosis. Preliminary observations show that even non-antihypertensive doses of moxonidine interfere with the development of glomerulosclerosis. Sympathicolytic agents are obviously rational in the antihypertensive therapy of the renal patient, because uraemia is a state of sympathetic overactivity and because blood pressure-independent effects of sympathetic activation on progression are likely.

Animals↗
PubMed1998

Relationship between hypertension and renal function and its therapeutic implications in the elderly.

The kidney is an important target of hypertension-induced organ damage. Recent long-term observation studies have documented that in individuals, without primary chronic renal disease, a very significant relationship exists between hypertension and impaired renal function, elderly hypertensives having a particularly worse prognosis. The hallmark of hypertensive renal injury is thought to be a progressive increase in intrarenal vascular resistance. The alterations in renal hemodynamics are accentuated in elderly patients with essential hypertension, pointing to a greater vulnerability of the senescent kidney to superimposed injury such as high blood pressure. Treatment of elevated blood pressure in the elderly therefore not only reduces cardiovascular morbidity and mortality, but also reduces the incidence of renal failure as a consequence of hypertension-induced damage.

Aging↗
PubMed1998

Effects of acute ACE inhibition on pulsatile renin and aldosterone secretion and their synchrony.

Pulsatile (burstlike) secretion of renin and aldosterone is positively coupled with a short time lag of about 10 to 20 minutes. We investigated how acute interruption of the renin-angiotensin-aldosterone axis, ie, acute angiotensin-converting enzyme (ACE) inhibition, alters the pattern of renin and aldosterone secretion. Eight healthy men (mean age, 22+/-1 years) were studied while on standardized salt intake. They were allocated on 2 occasions in random order to injection of placebo or 1.25 mg of the ACE inhibitor enalaprilat. Blood samples were obtained every 10 minutes for 24 hours for measurement of plasma renin and aldosterone concentrations. The hormone concentration profiles were analyzed using a multiparameter deconvolution technique; basal (tonic) and pulsatile hormone secretion was assessed. The regularity of pulsatile hormone secretion was analyzed using approximate entropy (ApEn). Cross-correlation and cross-ApEn analysis of renin and aldosterone secretion were performed to assess synchrony. Acute ACE inhibition caused an immediate burst of renin release and, in addition, significantly (P<0.01) increased 24-hour pulsatile and total renin secretion. It did not affect basal (nonpulsatile) renin secretion. The amplitude of renin bursts and the mass of hormone secreted per burst were significantly (P<0.01) increased, whereas the burst frequency (ie, number of secretory events) was unchanged. ApEn analysis revealed significantly (P<0.05) more regular renin secretion after ACE inhibition. In contrast, neither basal nor pulsatile aldosterone secretion was affected by administration of enalaprilat. Cross-ApEn analysis documented not only a maintained pattern of reproducibility (ie, synchrony) but also greater conditional regularity between pulsatile renin and aldosterone secretions with acute ACE inhibition. However, the quantitative strength of hormone coupling (assessed by cross-correlation analysis) was markedly diminished by enalaprilat treatment. The present findings suggest that the renin-angiotensin-aldosterone axis may not be completely uncoupled by acute ACE inhibition or that pulsatile renin and aldosterone secretion is driven by a common signal generator that is unaffected by ACE inhibition. In addition, a background basal and pulsatile aldosterone secretion not regulated by the renin-angiotensin axis may exist.

Adult↗
PubMed1998

Does essential hypertension cause progressive renal disease?

In the distant past, terminal renal failure occurred mainly as a result of malignant hypertension. The introduction of effective antihypertensive therapy has made malignant hypertension rare, and researchers have stopped focusing on the kidney's role in their hypertension research. However, recent long-term observational studies have documented an impressive relationship between hypertension and impaired renal function in patients without primary chronic renal disease; elderly and African American individuals with hypertension have the worst prognoses. The hallmark of hypertensive renal injury is thought to be a progressive increase in intrarenal vascular resistance, which may precede changes in renal structure. Because we lack evidence from renal biopsy studies, it is unclear whether an increase in albumin (protein) excretion correlates with these disturbances of renal function and structure. Nevertheless, because urinary excretion of albumin in patients with essential hypertension is related to the risk of cardiovascular complications, its measurement provides important clinical information.

Albuminuria↗
PubMed1997

Renal function in the elderly: impact of hypertension and cardiac function.

In senescence renal function is thought to decline markedly even in the absence of renal disease. It has also been proposed that the changes in renal function with age are not uniform and that confounding factors such as hypertension or atherosclerosis may play a role. We performed a comprehensive study to compare several aspects of renal function in four groups: (i) young healthy normotensive subjects (N = 24; 13 males; mean age 26 +/- 3 years); (ii) elderly healthy normotensive subjects (elderly NT; N = 29; 13 males; 68 +/- 7 years); (iii) elderly treated and untreated hypertensive patients (elderly HT; N = 25; 13 males; 70 +/- 6 years); and (iv) elderly patients with compensated mild to moderate heart failure (elderly HF; N = 14; 6 males; 69 +/- 6 years). Compared to young subjects mean GFR (C(In)) and ERPF (C(PAH)) were significantly lower in the elderly, despite similar mean plasma creatinine levels (young, 121 +/- 11, 650 +/- 85 ml/min/1.73 m2; elderly NT, 103 +/- 11, 486 +/- 102; elderly HT, 103 +/- 13, 427 +/- 55; elderly HF, 92 +/- 14, 377 +/- 103). Nevertheless, GFR was within the normal range in the majority of elderly NT and HT, but not in elderly HF. ERPF was significantly lower in elderly HT as compared with elderly NT, and still lower in elderly HF. Mean renovascular resistance and filtration fraction were significantly higher in the elderly, particularly in elderly HT and HF as compared with the young. Mean fractional excretion of Na+ was similar in all groups studied, but the lithium clearance was significantly lower in the elderly, suggesting a greater proximal and less distal sodium reabsorption in senescence. In the elderly, mean PTH concentration and urinary excretion of pyridoline cross-links were significantly higher and mean 25-(OH)D3, calcitriol and phosphate concentrations significantly lower; the correlation between PTH and GFR was significant (r = -0.432, P < 0.001). The results document that the decrease in renal hemodynamics with senescence is less marked than suggested by some studies using less stringent methodology and inclusion criteria. Comorbid conditions confound renal function in the elderly. Age-associated changes in renal hemodynamics are accompanied by significant alterations of renal hormones and of renal sodium handling.

Adult↗
PubMed1997

No effect of calcitriol on insulin-mediated glucose uptake in healthy subjects.

Administration of active vitamin D (calcitriol) improves insulin sensitivity in uraemic patients. These patients have subnormal plasma calcitriol concentrations in parallel with increased intact parathyroid hormone (PTH) concentrations. It is therefore unclear whether the improvement in insulin sensitivity results from a direct effect of calcitriol or from amelioration of secondary hyperparathyroidism. So far, no evidence has been presented that insulin sensitivity is specifically affected by calcitriol in healthy subjects. We investigated the effect of (supra)therapeutic doses of calcitriol on insulin sensitivity in healthy volunteers. In a double-blind parallel group design, 18 healthy male subjects received in random order either placebo or 1.5 micrograms of calcitriol per day by mouth for 7 days. Insulin-mediated glucose uptake, i.e. insulin sensitivity, was assessed using the euglycaemic clamp technique. Mean glucose disposal rate, i.e. M-value, was not significantly affected by placebo or calcitriol treatment (placebo: 7.1 +/- 1.3 mg kg-1 min-1 before and 7.2 +/- 1.5 mg kg-1 min-1 after treatment; calcitriol 7.0 +/- 1.4 mg kg-1 min-1 and 7.2 +/- 1.4 mg kg-1 min-1). There were no significant changes in mean plasma glucose, insulin, phosphate, bicarbonate and ionized calcium concentrations after administration of placebo or calcitriol. Furthermore, platelet intracellular calcium concentration (assessed by fluorescence spectroscopy) and mean arterial blood pressure (24 h ambulatory measurement) did not change with placebo and calcitriol treatment. On the other hand, mean intact PTH concentration decreased significantly (P < 0.01) with calcitriol treatment, but not with placebo. In addition, mean 24 h urinary calcium excretion increased significantly (P < 0.05) with calcitriol administration but was unchanged with placebo. Administration of (supra)physiological doses of calcitriol has no effect on insulin sensitivity in healthy subjects, despite a significant decrease in PTH concentrations. These observations are compatible with the notion that the effect of calcitriol on insulin sensitivity is present only in uraemic calcitriol-depleted patients.

Administration, Oral↗
PubMed1997

Subacute infusion of physiological doses of parathyroid hormone raises blood pressure in humans.

BACKGROUND: Acute administration of parathyroid hormone (PTH) causes vasodilation and blood pressure decrease in experimental animals. This effect contrasts with the putative role of secondary hyperparathyroidism in the pathogenesis of hypertension of patients with renal failure. Uraemia is characterized by insulin resistance and hyperinsulinaemia. We therefore investigated whether subacute administration of physiological doses of human 1,34-PTH affects blood pressure under conditions of controlled insulin levels (euglycaemic clamp technique) in humans. METHODS: In a double-blind cross-over design 10 healthy male subjects received, on two occasions, in random order, for 2 h, either a sham infusion or an infusion of 200 units of 1,34-PTH. RESULTS: Mean ionized calcium concentration increased significantly (P < 0.01) within the normal range during euglycaemic hyperinsulinaemia, both with sham infusion (from 1.25 +/- 0.04 to 1.29 +/- 0.02 mmol/l) and with infusion of 1,34-PTH, but the increase was more marked with 1,34-PTH administration (from 1.26 +/- 0.05 to 1.33 +/- 0.07). In addition, mean platelet intracellular calcium concentration (by fluorescence spectroscopy) was unchanged with sham infusion (49.9 +/- 4.1 versus 50.3 +/- 5.0 nmol), but increased significantly (P < 0.05; paired t-test) after 1,34-PTH infusion (from 49.8 +/- 5.0 to 52.8 +/- 5.8). The infusion of 1,34-PTH resulted in a significant (P < 0.01) increase in mean MAP (from 84 +/- 5 to 88 +/- 5 mmHg) as compared with sham infusion (85 +/- 4 versus 86 +/- 4). The intra-individual changes in intracellular calcium concentration (delta[Ca2+]i) were significantly correlated to the changes in mean MAP (delta MAP) (r = 0.87, P < 0.001). In contrast to blood pressure, insulin sensitivity was not affected by 1,34-PTH infusion (M-value: 7.2 +/- 1.6 mg/kg per min) as compared with sham infusion (7.3 +/- 1.4). CONCLUSION: Subacute administration of physiological doses of parathyroid hormone under hyperinsulinaemic conditions significantly affects intracellular calcium and blood pressure in healthy subjects, but does not affect the action of insulin.

Adult↗
PubMed1997

Altered action of angiotensin II in patients with type 2 diabetes mellitus of recent onset.

OBJECTIVE: Angiotensin II (Ang II) increases insulin sensitivity in healthy volunteers. This effect is thought to be mediated, at least in part, by an increase in skeletal muscle blood flow. In the past it had been documented that some biological actions of Ang II are altered in diabetes. We addressed the issue of whether this is also true for its action on insulin sensitivity. DESIGN AND METHODS: Twelve healthy volunteers (aged 43+/-9 years) and 15 patients with type 2 diabetes mellitus (NIDDM) of recent onset (aged 45+/-9 years) were allocated in random order in a double-blind placebo-controlled design to be administered a sham infusion or an infusion of 2 ng Ang II/kg per min. Insulin-stimulated glucose uptake (the M value) was measured with the euglycaemic clamp technique, leg muscle blood flow (MBF) with plethysmography, blood pressure with a Dinamap device, and glomerular filtration rate and effective renal plasma flow with the steady-state inulin (Cin) and p-aminohippurate (CPAH) clearance methods, respectively. RESULTS: In volunteers the mean M-value after Ang II infusion (10.1+/-1.5 mg/kg per min) was significantly higher (P < 0.01) than that after sham infusion (8.2+/-0.9 mg/kg per min). In contrast, in diabetic patients it was not significantly different with Ang II (6.1+/-1.3 mg/kg per min) and sham infusion (5.5+/-1.2 mg/kg per min). The difference in the mean absolute increase in the M value (deltaM) between groups was significant (P< 0.02). The Ang II-induced increase in MBF under euglycaemic conditions was attenuated in diabetic patients (from 15.0+/-3.5 to 15.5+/-3.9 ml/100 ml per min, NS) compared with volunteers (from 16.8+/-3.3 to 19.1+/-3.7 ml/100 ml per min, P< 0.01). Again, the difference between the mean absolute increases in MBF (deltaMBF) in the groups was significant (P < 0.01). A significant correlation was found between deltaMBF and deltaM (r= 0.62, P<0.01). The absolute acute increase in mean arterial blood pressure with Ang II was similar in diabetic patients and volunteers. Mean Cin, CPAH and fractional sodium excretion values were significantly lower and renal vascular resistances and filtration fractions higher during the Ang II than they were during the placebo clamp period. This was observed in patients as well as in healthy subjects, but the effects of Ang II on renal haemodynamics and sodium handling were more pronounced in diabetic patients. CONCLUSIONS: In patients with NIDDM of recent onset the stimulatory effect of Ang II on insulin sensitivity and on skeletal muscle blood flow is attenuated. In contrast, the effects of Ang II on renal perfusion and sodium handling are more pronounced in patients with NIDDM than they are in healthy subjects.

Adult↗
PubMed1997

Angiotensin II affects basal, pulsatile, and glucose-stimulated insulin secretion in humans.

Angiotensin II (Ang II) modulates the tissue response to insulin (insulin sensitivity), but the effect of Ang II on the secretion of insulin has not been investigated thus far. Nineteen healthy volunteers (17 male; mean age, 26+/-1 years) were studied. In a double-blind, randomized, placebo-controlled study, seven volunteers were allocated on three occasions in random order after an overnight fast to three interventions: (1) solvent (placebo) infusion; (2) infusion of 1.0 ng Ang II x kg(-1) x min(-1) (subpressor dose); and (3) infusion of 5.0 ng Ang II x kg(-1) x min(-1) (pressor dose). Frequent blood samples (each minute) were obtained for estimation of plasma insulin concentrations over a period of 120 minutes to assess basal and pulsatile insulin secretion. In an ancillary study, plasma glucose and insulin levels were measured after an oral glucose tolerance test while solvent (placebo) or Ang II was infused in 12 fasting healthy volunteers. Plasma insulin concentrations were measured immunoenzymatically (enzyme-linked immunosorbent assay). Insulin secretion pulses were analyzed with the deconvolution technique, and the regularity of insulin secretion was analyzed with the approximate entropy technique. Plasma insulin half-life was assessed using the hyperinsulinemic euglycemic clamp method. The pressor dose of Ang II reduced total, basal, and pulsatile insulin secretion, and this effect was highly significant (P<.01). The subpressor dose tended to suppress insulin secretion. The burst frequency (number of peaks) and the regularity of insulin secretion were not affected by administration of Ang II. After the oral glucose load, the insulinemic response was significantly lower and plasma glucose concentrations were significantly higher with infusion of Ang II compared with placebo. Ang II affects both the basal (nonpulsatile) and the pulsatile component of spontaneous insulin secretion and the glucose-stimulated insulin secretion in humans. This observation is of potential interest with respect to the interaction of Ang II and insulin, eg, in the genesis of hyperinsulinemia and hypertension.

Adult↗