BACKGROUND: Creatinine is an important clinical laboratory parameter for the evaluation of kidney function. It is essential to determine its concentration in serum of patients suffering from renal insufficiency. During hemodialysis treatment, the measurement of creatinine in the effluent dialysate or ultrafiltrate may give additional information on the efficiency of the extracorporal procedure. Therefore, enzyme sensors with co-immobilized creatinine amidohydrolase, creatine amidinohydrolase and sarcosine oxidase have been used to determine creatinine. METHODS: Enzymatically generated hydrogen peroxide has amperometrically been detected at a platinum-working electrode. To exclude electroactive compounds of the sample matrix, which might interfere with the electrochemical measurement, the sensors have additionally been modified by a Nafion membrane. RESULTS: Such sensors showed a linear detection range of 0.06-1.7 mg/dl for creatinine. Diluting the sample with measuring buffer, it has also been possible to measure pathological creatinine concentrations up to 11 mg/dl. A good correlation between creatinine concentrations in serum, dialysate and ultrafiltrate determined by the presented enzyme sensors and those obtained by both, conventional colorimetric Jaffé and enzymatic measurements have been achieved. CONCLUSION: Further developments will aim at the integration of this measuring principle into the concept to low-cost disposable planar sensors.

Biosensing Techniques↗

PubMed2001

Alterations in calcium and magnesium content of red cell membranes in patients with primary hypertension.

A cellular calcium-magnesium antagonism seems to be involved in the pathogenesis of primary hypertension. Total plasma, intracellular, and membranous calcium (Ca) and magnesium (Mg) contents were determined in 39 untreated patients with essential hypertension (EH) and 40 normotensive healthy subjects (NT). Membranous and intracellular measurements were performed in erythrocytes. Ca and Mg contents were measured by atomic absorption spectroscopy and membrane protein was determined according to Bradford's method as a membranous reference. There was no significant difference in plasma Ca (NT: 2.60 +/- 0.15 v EH: 2.64 +/- 0.17 mmol/L) and Mg concentrations (NT: 0.83 +/- 0.12 v EH: 0.87 +/- 0.14 mmol/L) in the studied groups. Intracellular Mg (NT: 1.72 +/- 0.15 mmol/L v EH: 1.64 +/- 0.19 mmol/L) and Ca (NT: 2.06 +/- 0.20 mmol/L v EH: 2.10 +/- 0.24 mmol/L) contents were also not significantly different between groups. Membrane Ca content was significantly increased in the EH group (2.23 +/- 0.32 micromol/g membranous protein) compared to controls (1.05 +/- 0.30 micromol/g membranous protein, P < .01). On the contrary, membranous Mg content was significantly decreased compared to controls (0.31 +/- 0.09 v 0.50 +/- 0.10 mmol/g membranous protein content, P < .01). The Ca/Mg ratio in membranes was significantly increased in EH as compared to healthy subjects (P < .01) and correlated to mean arterial blood pressure values (r = 0.47, P < .01). We conclude that the membranous alterations of Ca and Mg metabolism, shown by increased Ca/Mg ratio in red cell membranes of hypertensive subjects, may play a role in the pathogenesis of primary hypertension.

Calcium↗

PubMed2001

A randomized, controlled parallel-group trial on efficacy and safety of iron sucrose (Venofer) vs iron gluconate (Ferrlecit) in haemodialysis patients treated with rHuEpo.

BACKGROUND: The objectives of the present trial were to compare the efficacy and safety of two i.v. iron preparations with respect to haemoglobin levels, iron status and recombinant human erythropoetin (rHuEpo) dosage requirements in stable, rHuEpo-treated haemodialysis patients (maintenance phase of iron treatment) over 6 months. METHODS: A total of 59 patients were randomized and assigned to one of two treatment groups and 55 patients were analysed (iron sucrose n=27; iron gluconate n=28). Iron sucrose was administered in a dose of 250 mg iron diluted in 100 ml normal saline given over 60 min once per month, while 62.5 mg iron as iron gluconate was given once per week in a slow push injection (5 min). RESULTS: --Efficacy parameters: Haemoglobin levels could be maintained from baseline to endpoint in both groups. There were, however, more patients in the iron sucrose group than in the iron gluconate group for whom treatment was discontinued because their haemoglobin values exceeded 12.5 g/dl or ferritin values exceeded 1000 ng/ml (five vs two and three vs one patient, respectively). Transferrin saturation and serum ferritin increased significantly in both groups (+255.7 ng/ml with iron sucrose and +278.5 ng/ml with iron gluconate), while rHuEpo dosage did not change significantly throughout the study. --Safety parameters: There were a total of 174 infusions of iron sucrose and 720 injections of iron gluconate during the trial; all of them were well tolerated. In particular, we did not observe anaphylactoid reactions or any events suggestive of iron toxicity such as hypotension, dizziness, or nausea. CONCLUSIONS: High doses of iron sucrose (Venofer((R)) at a dose of 250 mg/month) was equally effective in maintaining haemoglobin and equally well tolerated as low doses of iron gluconate (Ferrlecit((R)) at a dose of 62.5 mg once per week) in stable, rHuEpo treated haemodialysis patients.

Drug Administration Schedule↗

PubMed2001

Acute effects of haemodialysis on endothelial function and large artery elasticity.

BACKGROUND: Disturbances of functional properties of large arteries contribute to increased cardiovascular morbidity and mortality in patients with end-stage renal disease. However, it is not clear whether haemodialysis per se acutely affects mechanical vessel wall properties or endothelial function. METHODS: Twenty-five chronic haemodialysis patients (mean+/-standard error of the mean (SEM): age 52+/-5 years; time on dialysis 63+/-7 months; blood pressure 132+/-4/72+/-2 mmHg) were studied before and immediately after a haemodialysis (HD) session using a polysulphone dialyser (ultrafiltration 1460+/-54 ml), as well as on the following day. Blood pressure was measured with an automatic sphygmomanometer and applanation tonometry. End-diastolic diameter and distension of the brachial and carotid arteries were measured by Doppler frequency analysis of vessel wall movements in M-mode using a multigate pulsed Doppler system and aortic pulse wave velocity (PWV) by an automatic device (Complior). Endothelial function was determined as brachial artery flow-mediated dilation (FMD) and compared with endothelium-independent nitroglycerine-induced dilation (NMD). RESULTS: FMD was 7.9+/-1.8% in patients before HD and did not change significantly after HD or in the dialysis-free intervall (6.7+/-2.1 and 7.1+/-2.0%, respectively; NS). The same was true for NMD and PWV (12.6+/-0.8 m/s before HD, 12.8+/-0.8 m/s after HD, and 11.9+/-0.7 m/s on the HD-free day). Carotid distensibility coefficients decreased significantly during HD (from 18.1+/-1.9 x 10(-3)/kPa to 16.7+/-2.2 x 10(-3)/kPa, P<0.05) and increased again on the HD-free day (19.8+/-2.4 x 10(-3)/kPa). However, when corrected for blood pressure by tonometry, isobaric carotid distensibility did not change significantly. Brachial artery distensibility also did not show significant acute changes. CONCLUSIONS: Haemodialysis per se did not have a significant effect on endothelial function or large artery mechanical vessel wall properties in patients on maintenance dialysis therapy.

Arteries↗

PubMed2000

Effects of bicarbonate- and lactate-buffered replacement fluids on cardiovascular outcome in CVVH patients.

BACKGROUND: Bicarbonate-buffered replacement fluid (RF-bic) in continuous venovenous hemofiltration (CVVH) may be superior to lactate-buffered replacement fluid (RF-lac) in acute renal failure. In an open, randomized, multicenter study, we investigated the effects of RF-bic and RF-lac on cardiovascular outcome in patients requiring CVVH following acute renal failure. METHODS: One hundred seventeen patients between the age of 18 and 80 years were randomized to CVVH either with RF-bic (N = 61) or RF-lac (N = 56). Patients were treated with CVVH for five days or until either renal function was restored or the patient was removed from the study. Data were analyzed on day 5 or according to the "last observation carried forward" (LOCF) option. Adverse events were classified according to the WHO-Adverse Reaction Terminology system. RESULTS: Blood lactate levels were significantly lower and blood bicarbonate levels were significantly higher in patients treated with RF-bic than in those treated with RF-lac (lactate, 17.4 +/- 8.5 vs. 28.7 +/- 10.4 mg/dL, P < 0.05; bicarbonate, 23.7 +/- 0.4 vs. 21.8 +/- 0.5 mmol/L, P < 0. 01). The number of hypotensive crises was lower in RF-bic-treated patients than in RF-lac-treated patients (RF-bic 14 out of 61 patients, RF-lac in 29 out of 56 patients; 0.26 +/- 0.09 vs. 0.60 +/- 0.31 episodes per 24 h, P < 0.05). Nine out of 61 patients (15%) treated with RF-bic and 21 out of 56 patients (38%) treated with RF-lac developed cardiovascular events during CVVH therapy (P < 0. 01). A multiple regression analysis showed that the occurrence of cardiovascular events was dependent on replacement fluid and previous cardiovascular disease and not on age or blood pressure. Patients with cardiac failure died less frequently in the group treated with RF-bic (7 out of 24, 29%) than in the group treated with RF-lac (12 out of 21, 57%, P = 0.058). In patients with septic shock, lethality was comparable in both groups (RF-bic, 10 out of 27, 37%; RF-lac, 7 out of 20, 35%, P = NS). CONCLUSIONS: The results show that the administration of RF-bic solution was superior in normalizing acidosis of patients without the risk of alkalosis. The data also suggest that the use of RF-bic during CVVH reduces cardiovascular events in critically ill patients with acute renal failure, particularly those with previous cardiovascular disease or heart failure.

APACHE↗

PubMed2000

Focal sclerosis with tip lesions secondary to polycythaemia vera.

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Glomerulosclerosis, Focal Segmental↗

PubMed2000

Measurement of skeletal status after renal transplantation by quantitative ultrasound.

BACKGROUND: Osteoporosis remains a major problem following kidney transplantation. Radiographic measures of bone mass are of limited predictive value after transplantation and are complicated by preexisting renal osteopathy. Quantitative ultrasound (QUS) is a new and non-invasive method to assess skeletal status, however, no data exist on ultrasonic bone parameter after kidney transplantation. We evaluated the potential use of this novel method in renal allograft recipients and studied the accuracy compared to normal controls. METHOD: Thirty patients (NTP, age 47.5 +/- 13.0 years) were studied 4.8 +/- 3.2 years after transplantation. Twenty-five healthy control persons (CON) were matched for age and sex. The left and right os calcis were studied by QUS and speed of sound (SOS) and broadband ultrasound attenuation (BUA) were measured. Bone stiffness (BS) was calculated from these parameters and corrected for age (CBS). Differences between right and left os calcis were compared to CON to assess the side variability. RESULTS: Mean +/- SD BS was 75 +/- 22% compared to young adults, age-corrected CBS was decreased in NTP with 86 +/- 25% of normal, indicating a two-fold increased risk of fracture. SOS was 1525 +/- 47.7 m/s, BUA 105 +/- 22 dB/MHz. Mean difference between right and left os calcis was significantly higher in NTP than in CON (7.2 +/- 7.1% vs. 2.1 +/- 2.1%, p < 0.01). Limits of agreement of the measurements (MW of differences +/- 2 SD) according to a Bland-Altmann-type statistic were -16.9% and 20.7%. There was no correlation between CBS and age, cumulative steroid dose, parathyroid hormone concentrations or time after transplantation. CONCLUSION: Our data show altered bone structure expressed by low bone stiffness values measured by quantitative ultrasound in kidney transplant patients. However, because of relatively high inter-feet variance of QUS results we suggest measurement of both ossa calcis to minimize measurement error after transplantation.

Biomechanical Phenomena↗

PubMed1999

Effects of moxonidine and clonidine on potassium excretion in Sprague-Dawley rats.

Recently we demonstrated that clonidine and moxonidine exert specific action on fractional fluid and Na+ excretion in anaesthetised Sprague-Dawley rats. Classically, most of the diuretics used induce an increased K+ excretion, at least in part due to Na+ load in the distal tubule and exchange of Na+ by K+. Therefore, we studied the effects of moxonidine and clonidine on K+ excretion in anaesthetised Sprague-Dawley rats. Moxonidine (0.25 and 0.5 mg kg-1 body wt. i.v.) increased transiently K+ (1.0 +/- 0.3 -1.9 +/- 0.4 and 0.9 +/- 0.2 -2.9 +0.7 micromol min-1 100 g body wt.) and Na+ (1.4 +/- 1.0 -6. 9 +/- 3.1 and 0.8 +/- 0.36 -6.6 +/- 1.5 micromol min-1100 g body wt.) excretion. Clonidine (0.25 mg kg-1) caused a more pronounced increase in K+ (1.0 +/- 0.1 -2.7 +/- 0.4 micromol min-1 100 g body wt.) and Na+ (0.6 +/- 0.3 -9.5 +/- 0.4 micromol min-1 100 g body wt.) excretion, whereas the higher dose of 0.5 mg kg-1 body wt. had less effect as compared to moxonidine (K+: 0.8 +/- 0.1 -1.7 +/- 0.2 micromol min-1 100 g body wt., Na+: 0.3 +/- 0.1 -3.4 +/- 1.0 micromol min-1 100 g body wt.). The increased electrolyte excretion returned (similar to moxonidine) to baseline levels within 20 min after injection of the drugs. Antagonists such as idazoxan and yohimbine did not change K+ and Na+ excretion by their own. Both, the non-selective imidazoline/alpha2-adrenoceptor antagonist idazoxan and the pure alpha2-adrenoceptor antagonist yohimbine attenuated the moxonidin-induced effects on K+ and Na+ excretion. This could be also observed with clonidine and simultaneous injection of these two antagonists. Our results demonstrate that moxonidine and clonidine also increase renal K+ excretion in this animal model. K+and Na+ excretion show a parallel behaviour, indicating that the increased K+ excretion is mainly due to Na+ load in the tubular system.

Adrenergic alpha-2 Receptor Agonists↗

PubMed1997

Differential regulation of glomerular gelatinase B (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in obese Zucker rats.

The obese Zucker rat represents a model of obesity combined with insulin resistance and hyperlipidaemia, which over a period of several months develops spontaneous glomerulosclerosis. The present study addressed the question as to whether glomerular sclerosis was associated with alterations in the degradation of matrix components. In the early phase (up to 6 months) glomeruli from obese rats displayed increased total collagen content (+64%) and decreased gelatinolytic activity (-34%) as compared to lean control animals. This decline in glomerular gelatinolytic activity was due to a reduction in gelatinase B [matrix metalloproteinase (MMP)-9]. Glomerular MMP-9 mRNA was reduced 4.6 +/- 0.6-fold (n = 3; p < 0.05), MMP-9 protein was not detectable by Western blotting and MMP-9 activity was considerably suppressed in gelatin zymograms. MMP-2, in terms of mRNA expression and activity, was unchanged. Tissue inhibitor of metalloproteinases (TIMP)-1 mRNA expression, TIMP-1 protein (immunohistochemistry) and TIMP-1 activity (reverse zymography) were enhanced in glomeruli from obese rats, while TIMP-2 mRNA remained unchanged. Moreover, mRNA for the alpha 1 IV collagen chain was 2.1 +/- 0.8-fold higher in glomeruli isolated from obese animals (n = 3; p < 0.05). These findings indicate that matrix expansion in glomeruli from obese Zucker rats is due to both enhanced synthesis of matrix components as well as reduced degradation by matrix metalloproteinases. Apparently the latter effect is based on a reduction in MMP-9 and up-regulation of its inhibitor TIMP-1.

Albuminuria↗

PubMed1996

Tubular gelatinase A (MMP-2) and its tissue inhibitors in polycystic kidney disease in the Han:SPRD rat.

Thickening of the tubular basement membrane is one of the hallmarks of the polycystic kidney disease (PKD). The present study was conducted to investigate the potential role of the matrix metalloproteinase-2 (MMP-2) and its specific tissue inhibitors (TIMP-1 and TIMP-2) in the accumulation of matrix components in PKD. As a model of PKD, two-month-old heterozygous Han:SPRD rats, which are at an early stage of cystogenesis, were used. MMP-2, but not MMP-9 (gelatinase B) nor MMP-3 (stromelysin) could be detected in proximal tubules of the normal rat kidney. The presence of the inhibitors TIMP-1 and TIMP-2 was confirmed on the mRNA level. In tubules from PKD rats MMP-2 activity was lower (31 +/- 8 vs. 58 +/- 7 U/prep., N = 9, P < 0.05), mRNA of MMP-2 was reduced 4.2 +/- 0.6-fold (N = 4, P < 0.05) and enzyme protein was depressed 3.8 +/- 0.8-fold (N = 4, P < 0.05). By contrast, TIMP-1 mRNA was 9.0 +/- 1.1-fold and TIMP-2 mRNA 3.8 +/- 0.7-fold (N = 4, P < 0.05) elevated over controls. Cyst fluid from homozygous rats contained MMP-2 protein and activity. These findings indicate that tubular MMP-2 activity is reduced in PKD, due to down-regulation of MMP-2, up-regulation of TIMP-1 and TIMP-2, and luminal secretion of the enzyme. It is conceivable that these alterations relate to the enhanced matrix accumulation observed in the evolution of PKD.

Animals↗

PubMed1992

[Long lasting normalization of uric acid after combination therapy with 300 mg allopurinol and 60 mg benzbromarone in patients with gout and hyperuricemia].

Lasting normalisation of uric acid levels after treatment of patients with gout and hyperuricaemia with a combination of 300 mg allopurinol and 60 mg benzbromarone A total of 210 patients (163 men, 47 women) with gout and hyperuricaemia was treated for three months with daily doses of 300 mg allopurinol and 60 mg benzbromarone. During the course of treatment, the uric acid levels decreased to 4.3 +/- 1.3 mg/dl in male, and 4.4 +/- 1.3 mg/dl in female patients. Both of these levels differ significantly from the initial levels (p less than 0.001). Three months after discontinuation of treatment, uric acid levels were 5.7 +/- 1.2 mg/dl in women, and 5.9 +/- 1.4 mg/dl in men, levels that again differed significantly from the initial levels (p less than 0.001); both levels were, however, within the therapeutic range of below 6.4 mg/dl.

Allopurinol↗

PubMed1992

Ultrasound studies of the effect of trospium chloride on gall-bladder kinetics.

In a randomized double-blind study the effects of increasing doses of trospium chloride (Spasmo-lyt, CAS 10405-02-4), 0.2, 0.5, 1.0, and 1.5 mg i.v., on gall-bladder contractility were compared among themselves and against placebo and n-butylscopolamine bromide (20 mg i.v.) by an intraindividual 5-fold crossover technique. Gall-bladder volumes after drug-induced contraction (fat stimulus with sodium iopodate) were measured by ultrasound scanning conducted by a single examiner. Serial measurements, carried out in 6 female subjects without any evidence of gall-bladder disease, demonstrated a dose-dependent trend of inhibition of gall-bladder motility produced by trospium chloride. In the maximal doses employed (1.0 and 1.5 mg i.v.) trospium chloride effected almost total inhibition of motility. The response to n-butylscopolamine bromide tested in a nonblind comparison, showed a dose-effect ratio of roughly 40:1 between trospium chloride and n-butylscopolamine bromide given intravenously. This work confirms that ultrasound measurement of gall-bladder volume is a suitable pharmacodynamic model for testing the dose-effect relationships of antispasmodic agents.

Benzilates↗

PubMed1990

[Maltose-dextran--a new combination solution for the induction of diuresis in man].

40 healthy men received an infusion solution of low molecular dextran with either 0%, 5%, 10% or 20% Maltose over a 60 min period. The combination of LMWD with 10% maltose solution showed a significant increase of urine excretion from 132 ml/h to 315 ml/h at the end of the infusion. The overall excretion rate in 3 h was 683 ml, 185 ml more than infused. The increase in urine excretion from 53.0 ml/h to 173.5 ml/h after the application of 5% maltose/dextran 40 solution was only due to a water diuresis. The maltose concentration was not high enough to induce a visible osmotic diuresis. The application of 20% maltose/dextran 40 solution showed a clear osmotic effect. Nevertheless, there was no significant increase in the urinary excretion rate compared to the LMWD solution without any maltose. The high oncotic and osmotic pressure of this combination activated mechanisms, which were opposed to the induced osmotic diuresis.

Adolescent↗