Sabine Zitta

Effect of hemodialysis on the antioxidative properties of serum.

In patients with chronic renal failure undergoing regular hemodialysis (HD), oxidative stress is involved in the development of dialysis-related pathologies. The aim of the study was to measure the effect of HD treatment on the general antioxidative status of serum with special consideration of the specific oxidizability of lipids and proteins. Indicators for the oxidative/antioxidative status of plasma were monitored at the beginning and at the end of a dialysis session on the arterial and venous side of the dialyzer. A decrease in the antioxidant status was accompanied by an increased oxidizability of proteins as well as lipids during HD treatment. During the first passage of the dialyzer, the lag time of lipid oxidation decreased from 114.0+/-19.8 to 81.5+/-18.9 min, the lag time of protein oxidation decreased from 105.0+/-24.6 to 72.9+/-21.3 min and the total antioxidative status decreased from 518+/-24 to 252+/-124 microM trolox equivalents. The carbonyl content of serum proteins was high in patients with end stage renal disease (ESRD) (3.9+/-1.1 vs. 0.9+/-0.1 nmol/mg in controls) but did not change significantly during dialysis procedure. Our data demonstrate that the susceptibility of serum lipids and proteins to oxidative modification is severely increased by HD treatment.

Determination of the glomerular filtration rate by identification of sinistrin kinetics.

A computer-based method of system identification and estimation of parameter variance for two-compartment models matched to dynamic sinistrin concentration profiles for the determination of glomerular filtration rate is described. Thereby a procedure for the judgment of the optimal sampling time horizon is presented. Since single-injection techniques are suspected of yielding systematic overestimation of the glomerular filtration rate, a method is demonstrated confirming that such a technique employing sinistrin kinetics can be used to correctly determine the glomerular filtration rate. The validation of the system parameters gained by the single-injection method is made through prediction of the concentration contour under a constant infusion regimen in the same subject on a different occasion. This was performed in healthy controls and in patients with various degrees of renal insufficiency. Upon consideration of the dependence of the clearance estimates and their variances on the protocol duration in test subjects examined from four to ten hours, an adaptive design of the protocol length is developed.

The assessment of GFR after orthotopic liver transplantation using cystatin C and creatinine‐based equations

The measurement of kidney function after orthotopic liver transplantation (OLT) is still a clinical challenge. Cystatin C (CysC) has been proposed as a more accurate marker of renal function than serum creatinine (sCr). The aim of this study was to evaluate sCr‐ and CysC‐based equations including the Chronic kidney disease (CKD)‐EPI to determine renal function in liver transplant recipients. CysC and sCr were measured in 49 patients 24 months after OLT. The glomerular filtration rate (GFR) was calculated using the MDRD 4, the Cockroft‐Gault, Hoek, Larsson, and the CKD‐EPI equations based on sCr and/or CysC. As reference method, inulin clearance (IC) was estimated. Bias, precision, and accuracy of each equation were assessed and compared with respect to IC. Forty‐five percent had a GFR < 60 ml/min/1.73 m2 according to the IC. The Larsson, the Hoek and the CKD‐EPI‐CysC formula identified the highest percentage of patients with CKD correctly (88%, 88%, and 84%, respectively). The sCr‐based equations showed less bias than CysC‐based formulas with a similar precision. All CysC‐based equations were superior as compared with sCr‐based equations in the assessment of renal function in patients with an IC < 60 ml/min/1.73 m2.

Relationship between generation and plasma concentration of anorganic phosphorus. In vivo studies on dialysis patients and in vitro studies on erythrocytes.

The plasma concentration of inorganic phosphorus (Pi) was determined before, during and after hemodialysis in 28 patients with chronic renal failure. Pi plasma concentration decreased rapidly when hemodialysis was started but did not fall below normal levels during continued dialysis. These changes of Pi concentration were fitted to a model of Pi kinetics in which Pi delivery to plasma is a nonlinear function of the extracellular Pi concentration. In separate in vitro studies, erythrocytes from six subjects with normal renal function and from 14 patients with chronic renal failure were incubated in homologous plasma with various amounts of Pi added. All other factors known to affect the Pi shift between intra - and extracellular fluid compartments (pH, calcium concentration) were kept constant. The relation between Pi concentration in plasma used for incubation and in red cells after 1h incubation suggested a mechanism in which a high plasma concentration results in movement of Pi into red cells where Pi is stored most probably in glucose esters. At low Pi plasma concentration Pi is delivered to plasma at a rate which cannot be explained solely by passive movement of intracellular Pi to plasma but requires additional generation from intracellular storage forms. The generation and delivery of Pi in patients and in their erythrocytes indicate a simple cell-mediated Pi homeostasis counter-acting abnormal fluctuations of plasma Pi.

Glomerular Filtration Rate (GFR) determination via individual kinetics of the inulin-like polyfructosan sinistrin versus creatinine-based population-derived regression formulae

BackgroundIn renal patients estimation of GFR is routinely done by means of population-based formulae using serum creatinine levels. For GFR determination in the creatinine-blind regions or in cases of reno-hepatic syndrome as well as in critical cases of live kidney donors individualized measurements of GFR (mGFR) employing the kinetics of exogenous filtration markers such as the inulin-like polyfructosan sinistrin are necessary. The goal of this study is to compare mGFR values with the eGFR values gained by the Modification of Diet in Renal Disease (MDRD4) and Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) formulae.MethodsIn 170 subjects comprising persons with normal renal function or with various stages of kidney diseases (CKD 1-4) GFR was measured by application of intravenous bolus of sinistrin and assessment of temporal plasma concentration profiles by means of pharmacokinetic methods (mGFR). Comparisons of mGFR with MDRD4- and CKD-EPI-derived eGFR values were performed by means of linear regression and Bland-Altman analyses.ResultsReasonable agreement of mGFR and eGFR values was observed in patients with poor renal function [GFR below 60 (ml/min)/1.73 m2]. In cases of normal or mildly impaired renal function, GFR determination by MDRD4 or CKD-EPI tends to underestimate GFR. Notably, there is practically no difference between the two eGFR methods.ConclusionsFor routine purposes or for epidemiological studies in cases of poor renal function eGFR methods are generally reliable. But in creatinine-blind ranges [GFR above 60 (ml/min)/1.73 m2] eGFR values are unreliable and should be replaced by clinically and physiologically suitable methods for mGFR determination.Consorthttp://www.consort-statement.org/index.aspx?o=1190

Unpredicted lack of effect of exercise on plasma concentrations of carvedilol.

In vitro studies have shown that &bgr;-blockers are taken up into and released from adrenergic cells together with epinephrine and norepinephrine. Consequently, studies in humans revealed an increase in plasma concentrations of propranolol and atenolol during physical exercise. However, carvedilol has not been investigated in a similar fashion. Eleven hypertensive patients on long-term treatment (4 months) with carvedilol followed an exercise regimen. Plasma concentrations of carvedilol were determined at rest (9.7 ± 3.4 ng/ml), during exercise (9.0 ± 3.2 ng/ml), and after 15 min of recovery (9.1 ± 2.7 ng/ml). Contrary to predictions, exercise had no effect on plasma concentrations of carvedilol, a finding that is in contrast to other &bgr;-blockers. We conclude that carvedilol is not taken up into and released from adrenergic nerves during exercise, a feature that clearly distinguishes carvedilol from all other &bgr;-adrenergic antagonists so far investigated.

Cystatin C Does Not Detect Acute Changes in Glomerular Filtration Rate in Early Diabetic Nephropathy

Background. The measurement of renal functional reserve (acute change in glomerular filtration rate [GFR] after protein load) allows the detection of sub-clinical renal dysfunction and has prognostic implications in diabetes. Our aim was to test cystatin C as an index of GFR and renal functional reserve. Methods. GFR was measured by CSinistrin at baseline and after protein load in 28 diabetic patients with serum creatinine <1.2 mg/dL. The CSinistrin was compared with cystatin C, serum creatinine, creatinine clearance, and Cockcroft-Gault formula. Results. Baseline CSinistrin ranged from 67–172 mL/min. Regression analysis showed an overall low relationship between CSinistrin and the indirect markers of GFR. The highest correlation with CSinistrin was obtained for cystatin C clearance (R2 = 0.58, r = 0.76, p < 0.001), the 1/serum cystatin C (R2 = 0.58, r = 0.76, p < 0.001), and serum cystatin C (R2 = 0.52, r = 0.72, p < 0.001). Renal functional reserve was preserved in 6 of 28 patients. There was no significant change in cystatin C in response to protein load. Conclusion. Wide variation in baseline GFR emphasizes the need for the early detection of renal dysfunction. Cystatin C correlated best with CSinistrin at baseline, but did not detect renal functional reserve.

Exercise does not Affect Plasma Concentrations of (R)- and (S)-Carvedilol

AbstractPurpose: In vitro studies have shown that beta-blockers are taken up into and released from adrenergic cells. As a consequence, plasma concentrations of beta-blockers increase during exercise together with those of epinephrine and norepinephrine. However, effects of exercise on plasma concentrations of (R)- and (S)-carvedilol are unknown. Methods: Twelve healthy males received oral single doses of 12.5 mg (R)-carvedilol, 12.5 mg (S)-carvedilol and 25 mg (R,S)-carvedilol in a cross-over fashion; 11 patients with essential arterial hypertension were given 25 mg (R,S)-carvedilol. Exercise was performed 3 hours following drug intake, and blood samples were taken at rest, at the end of exercise, and after 15 min of recovery. Plasma concentrations of (R)- and (S)-carvedilol were determined by HPLC. Results: Plasma concentrations of (R)-carvedilol were 2- to 3-fold higher than those of (S)-carvedilol (p < 0.05 in all cases). Plasma concentrations of both (R)- and (S)-carvedilol remained unaffected during exercise and recovery. Conclusions: Contrary to all other beta-blockers so far investigated, exercise had no effect on plasma concentrations of (R)- and (S)-carvedilol. We conclude that neither (R)- nor (S)-carvedilol is released from adrenergic cells during exercise, a feature that clearly distinguishes carvedilol from other beta-blockers. Thus, the human organism appears to handle (R)- and (S)-carvedilol differently than other beta-adrenoceptor antagonists. This finding deserves further investigation on a molecular and cellular level in order to clarify these differences between the pharmacokinetics of carvedilol and other beta-blockers.

Renal functional reserve in patients with Type 1 diabetes mellitus

SummaryAimDecreased renal functional reserve might precede incipient diabetic nephropathy in patients with Type1 diabetes. The aim of this study was to assess the relationship between renal functional reserve and easily assessable estimates of systemic endothelial dysfunction in normoalbuminuric patients with Type 1 diabetes and diabetic retinopathy.MethodsRenal functional reserve was calculated as the relative change in glomerular filtration rate after protein ingestion. Glomerular filtration rate was measured using pharmacokinetic compartmental analysis of single-shot plasma sinistrin clearance. We measured the activity of von Willebrand factor and concentrations of C-reactive protein and apolipoprotein B, as easily assessable estimates of systemic endothelial dysfunction.ResultsTwenty-two patients were studied. Renal functional reserve was inversely associated with activity of von Willebrand factor (R=−0.431,p=0.045) and, in a multivariate model, with concentration of C-reactive protein (R=0.652,p=0.031).ConclusionRenal functional reserve is inversely associated with concentration of C-reactive protein in normoalbuminuric patients with Type 1 diabetes and diabetic retinopathy. This finding provides evidence that decreased renal functional reserve might reflect endothelial dysfunction. We speculate that decreased renal functional reserve might possibly show as an early marker of diabetic nephropathy.

Determination of Renal Reserve Capacity by Identification of Kinetic Systems

A method of adapting two-compartment models to dynamic marker concentration profiles for the determination of renal clearance and of its acute changes due to protein ingestion in patients with essential hypertension is described. In 9 healthy controls glomerular filtration rates (GFR) and effective renal plasma flows (ERPF) (ml/min/1.73 m2; means +/- sd) rose significantly tested pairwise from 118.2 +/- 13.9 to 139.5 +/- 30.9, p = 0.023 and from 503.2 +/- 75.6 to 558.3 +/- 96.2, p = 0.013, respectively. Four patients with mild hypertension and mean arterial pressure (MAP) of 106 +/- 3 mmHg (duration = 13.8 +/- 10.3 years) showed rises in GFR (73.9 +/- 14.7 to 83.6 +/- 17.4, p = 0.034) after stimulation, whereas 6 patients with a MAP of 119 +/- 3 mmHg (duration = 17.5 +/- 13.7 years) exhibited ‘paradoxical’ decreases in GFR (113.3 +/- 18.7 to 103.0 +/- 14.3, p = 0.037). The ERPFs showed nonsignificant changes in the first group of patients (277.8 +/- 52.6 to 323.9 +/- 42.8), whereas the second group revealed increases in ERPF (430.7 +/- 134.5 to 502.3 +/- 113.1, p = 0.013). All patients had normal serum creatinine levels. The study demonstrates that modern system identification of kinetic experiments, but not traditional techniques relying on steady-state data, allow one to detect such dynamic alterations as measures of renal functional reserve.