Willibald Estelberger

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.

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

Selective decrease in serum immunoglobulin G1: A tissue nonspecific tumor marker detecting early stages of gynecologic malignant disease with high efficiency

Malignant diseases of various tissue origin have previously been found to be associated with a characteristic shift in the serum pattern of IgG subclasses, i.e., a highly significant reduction of the percent of IgG1 and an increase of the percentage of IgG2 relative to the total IgG. In the present study we examined the diagnostic performance of this indirect tumor marker in patients with carcinomas of various sites within the female reproductive tract.

ΣS, a measure of reactive sulfur groups of immunoglobulin G, is a sensitive tumor marker discriminating different stages of breast cancer

ΣS is a measure of the disulfide bonds and free thiol groups of serum immunoglobulin (Ig) G, as determined by the reaction with dithionitrobenzoate. Significant decreases of 2S previously were detected in malignant compared with benign diseases of various organs. This study shows the application of ΣS for the diagnosis of breast cancer. The following results were obtained. First, 132 patients with benign breast diseases showed a ΣS of 1.48 ± 0.29 (standard deviation) per mole IgG; this was not different from 1.51 ± 0.36 found in 182 controls. In contrast, IgG from 198 patients with primary breast carcinoma of all four stages (tumor‐node‐metastasis system) gave a ΣS of 1.22 ± 0.29, a significant (P less than 0.0001) decrease of ΣS from benign to malignant breast disease. Second, ΣS values of single Stages I, II, III, and IV, were 1.27 (n = 59), 1.23 (n = 83), 1.19 (n = 35), and 1.10 (n = 21), respectively, each significantly different from ΣS in benign disease and showing a decreasing trend with increasing tumor progress. Differences were significant between Stages I and IV (P less than 0.025) and II and IV (P less than 0.05). Third, 63% of Stage I breast carcinoma patients had ΣS values below a critical threshold of 1.38. This serum positivity rose to 90% in Stage IV. These values exceeded those reported with other tumor markers. The overall power of ΣS to distinguish between benign and malignant breast disease had a specificity of 61% and a sensitivity of 78%. Early stages (I and II) of breast cancer could be distinguished from benign diseases with 64% specificity and 69% sensitivity. Advanced Stage IV could be discriminated from early Stages I and II with 55% specificity and 71% sensitivity. Thus, the analysis of ΣS may significantly contribute to the surveillance of patients with breast cancer.

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.

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.

Selective decrease of serum immunoglobulin G1 as a marker of malignant transformation in colorectal tissue.

Malignant diseases of various origins were previously shown to be associated with a characteristic and highly significant change in the serum pattern of immunoglobulin (Ig)G subclasses, comprised of a decrease in %IgG1 and an increase in %IgG2 relative to and independent of the absolute concentration of total IgG. The goal of the current study was to evaluate this phenomenon as an indirect marker in the primary diagnosis of colorectal carcinoma.

The conformational flexibility of 5,6,7,8-tetrahydrobiopterin and 5,6,7,8-tetrahydroneopterin: a molecular dynamical simulation.

5,6,7,8‐Tetrahydrobiopterin is an essential cofactor of diverse enzymes. Of the eight possible stereoisomers, only the 6R,1′R,2′S‐configuration is biologically active. Other stereoisomers, as well as other reduced pterins such as, e.g. 5,6,7,8‐tetrahydroneopterin, fail to exhibit significant cofactor activity. Different theoretical models (molecular mechanics, semi‐empirical quantum chemical calculations) investigating the stereostructure of tetrahydrobiopterin have yielded diverging answers. It has been claimed on the basis of semi‐empirical quantum chemical calculations that conformational properties, and thus particular features in overall shape, might be responsible for the unique biological properties of natural tetrahydrobiopterin in contrast, e.g. to 6R,1′S,2′R‐5,6,7,8‐tetrahydroneopterin. Molecular dynamical simulations of both molecules at realistic temperatures demonstrate, however, that they possess sufficient conformational flexibility as to render questionable any biological significance of mere conformational properties.

System identification of the low-dose kinetics of p-aminohippuric acid.

The renal clearance of p-aminohippuric acid, due to tubular secretion in addition to glomerular filtration, can only be determined by kinetic experiments. Maximal information can be gained from observed temporal marker concentration profiles by fitting dynamic mathematical models of the processes involved, such as absorption, distribution, and elimination, to the kinetic data. Thereby the values of the system constants, such as fractional elimination or fractional distribution rates, and their accuracy measures are determined by methods which are based firstly on measured time-dependent data elicited in an individual test object by perturbing inputs and secondly, on mathematical formulations of prior knowledge of the underlying physiological system. Such methods of model adaptation are called system identification. In this context a computer-based method of system identification and error estimation for the system constants of two-compartment models matched a dynamic concentration profiles of p-aminohippuric acid is presented. The method is used of single-injection experiments to demonstrate that such a technique is able to correctly estimate the clearance of p-aminohippuric acid if sufficiently long experimental protocols are chosen, and to ascertain the sufficient length of a protocol for an individual subject. The renal clearance of p-aminohippuric acid is known to exhibit concentration-dependence generally, but to achieve its maximal value when low doses are applied. The present study deals with the low-dose kinetics of p-aminohippuric acid.