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Kinetic modeling has direct implications for nephrology nurses delivering prescribed hemodialysis treatment. Studies indicate that patient outcome in morbidity and mortality are closely related to correct delivery of hemodialysis prescription. Correct nursing management of treatment time, dialyzer efficiency, blood flow rate, and problems of recirculation will contribute to successful delivery of intended dialytic therapy.
The kinetic model for K+, H+, Ca2+ concentrational self-oscillations in erythrocytes induced by A23187 and FCCP ionophores are considered. The model is based on the experimental data available and contains the minimal number of essential variables. The model was analysed by the method based on the graph representation of kinetic equations. The critical graph fragments provoking self-oscillatory trajectories in the system were revealed. It is shown that self-oscillatory behaviour is basically induced by conjugated processes produced by A23187. The parameter domain for self-oscillations is estimated including parameters of Ca2+-induced (through K+-channels) proton transport with FCCP participation. Numerical integration of kinetic equations was performed. The results obtained are in a good qualitative agreement with experimental data.
The kinetic model of carbohydrate metabolism has been expanded to include: (a) the accumulation of alpha and beta-cellulose, insoluble cell-wall glycogen and mucopolysaccharide; (b) the role of RNA turnover as a source of carbon for end-product synthesis and as a buffer regulating the level of uridine nucleotides in this metabolic network; and (c) the role of purine-nucleoside phosphorylase, 5'-AMP nucleotidase, nucleosidediphosphate kinase and polynucleotide phosphorylase. One of many predictions based on this model is that cells differentiating in the presence of glucose will produce sorocarps with an abnormally high trehalose to cellulose ratio. External perturbation of either the model or of developing cells by glucose increases the levels of sorocarp trehalose and glycogen, 5-fold and 6-fold respectively. Evaluation of the experimental data and the simulation analyses have allowed several predictions to be made concerning the compartmentation of metabolites and the permeability of cells to glucose during differentiation.
A kinetic model for axonemal motion based upon a four-state mechanochemical cycle of dynein with two active sites is described. Our model analysis determines the pseudo-steady-state concentrations of enzyme species for specified rate constants, most of which are experimentally determined, with given substrate and product concentrations. The proportion of enzyme species in which both active sites are detached from the microtubule (denoted as "both detached"), numerically calculated from the model, appears to be proportional to experimental observations of flagellar beat frequency. This correlation between beat frequency and the both-detached enzyme species is maintained over a wide range of substrate concentrations and exhibited an apparent positive cooperativity at low substrate concentrations, which we call "obligate cooperativity." The unusual obligate cooperativity exhibited by flagellar beat frequency parallels that seen in the calculated proportion of the both-detached enzyme species and is interpreted as a requirement for a molecule of substrate to bind to each active site in a multimeric dynein in order to produce oscillatory motion. Furthermore, the proportion of the both-detached enzyme species correlates with experimentally observed changes in beat frequency with a nucleotide analog and with product inhibition.
Urea kinetic modeling (UKM) was carried out to evaluate the water control in patients undergoing long-term hemodialysis. In 21 patients on chronic dialysis, the results of two different determinations of the total body water, i.e. by the deuterium oxide (D2O) method and by UKM, were compared. A correlation was observed with Y = 0.98X + 5.9 (P less than 0.01, r = 0.91) for males and Y = 0.97X + 6.2 (P less than 0.01, r = 0.90) for females, indicating that UKM is useful for determining the total body water. In addition, the 21 patients were classified into two groups based on their ECG findings, and UKM was performed in the two groups for comparison. The values of the total body water were 68.5 +/- 4.0% and 68.6 +/- 6.2% of body weight, respectively, with no significant difference between them. However, the CTR was 50.2 +/- 2.8% and 46.2 +/- 4.4%, respectively. Thus, not only X-ray examinations but also UKM should be carried out to determine the standard weight (SW-DW) in the presence of cardiac dysfunction. Instructions for water control were given when the total body water exceeded 73% during the UKM measurements over 5 years, which allowed an optimal total body water to be maintained thereafter. The possible influence of erythropoietin (EPO) was also examined by performing UKM in 8 cases receiving EPO and 7 cases without EPO. No noticeable difference was observed between the two groups. 17 patients using a polyacrylonitrile (PAN) membrane were further divided into those with and those without EPO to evaluate the possible influence of the PAN membrane-EPO combination. As a result, no significant difference was demonstrated, suggesting that UKM can be satisfactorily performed under such conditions. In 11 patients on chronic dialysis, the levels of alpha-human atrial natriuretic peptide (alpha-hANP) were measured pre- and post-dialysis to examine the relationship between the change in alpha-hANP and rate of weight loss (%). A significant correlation was observed with Y = 12.8X + 5.1 (P less than 0.05, r = 0.68). In conclusion, UKM was found to be useful for evaluating the water control and for assessing the optimal dialysis in patients receiving long-term hemodialysis.
Three urea kinetic analyses were applied to hemodialysis and their conformity assessed. Sixteen patients underwent 50 measurements of dialyzer clearance (K), protein catabolic rate (PCR), and dialysis quantification (Kt/V) using the urea kinetic model (UKM) of Gotch and Sargent, Malchesky's direct dialysis quantification (DDQ), and the graphic technique of urea reduction analysis (URA) devised by Keshaviah. Additionally, the equations proposed by Jindal (percent urea reduction), and Daugirdas were used to calculate Kt/V values for each study. Dialyzer performance determined by whole blood urea clearance consistently exceeded simultaneous dialysate urea removal and was 55% greater than the clearance calculated by DDQ. Despite these variations, dialysis adequacy (Kt/V) and normalized protein catabolic rate (nPCR) were remarkably constant when derived by fixed-volume single-pool analyses (ie, UKM, DDQ, and URA). Application of variable-volume corrections increased Kt/V and nPCR, but caused DDQ values to diverge from those of UKM and URA. During rapid high-efficiency dialysis (RHED), the UKM predicted urea removal in excess of that documented by DDQ. During this trial (low-level RHED with K = 2.98 mL.kg-1 per min), urea dysequilibrium across blood-cell interfaces was sufficient to cause UKM to overestimate protein catabolism by 5%. The basic assumption of single-pool kinetics may be inappropriate during RHED, and further increases in dialyzer clearance will increase the discrepancy between projected and actual urea removal. Future comparisons of RHED prescriptions should employ mass balance data, or redesigned kinetic analyses.
Using kinetic modelling for shaping profile dialysis, we present a promising approach to improve the cardiovascular stability of patients during dialysis treatment. In order to obtain an insight into the physiological mechanisms of increased stability, a model considering alterations of electrolytes and water distribution and of acid-base status was developed. This algorithm was used for the evaluation of 114 dialysis sessions, which were performed with highly individualised profiles. Each profile was developed for one patient by trying empirically to prevent episodes of hypotension as well as other clinical problems throughout dialysis. The main advantage of profile dialysis compared to standard bicarbonate dialysis, for example, is a reduced water influx into the cell during the treatment. According to our clinical and theoretical results a correlation between water influx into the cell and time of occurrence of hypotensive episodes in individuals can be assumed. Hypotension usually starts after 0.5 litres of water have entered the intracellular space, regardless of the time necessary for this fluid shift.
GENKI (Generative ENsemble KPI-Informed) is a variational autoencoder-based framework for large-scale kinetic modeling of metabolism. Developed for metabolic engineering applications, GENKI is designed to improve the recovery of kinetically feasible models that reproduce experimentally observed phenotypes under genetic and environmental perturbations. The framework is trained on feasible kinetic model ensembles and uses phenotype-based key performance indicators (KPIs), derived from multi-omics and bioprocess data, to label and enrich models according to their agreement with mutant and condition-specific observations. This enables targeted generation of biologically relevant parameter sets with improved predictive performance. Crucially, GENKI recovers kinetic parameter sets that jointly reproduce wild-type and multiple perturbed physiologies within a single model. We apply GENKI to large-scale kinetic models of Escherichia coli and Saccharomyces cerevisiae under enzyme perturbations and oxygen shifts. In both systems, GENKI enriches kinetic ensembles with models that more accurately reproduce experimentally observed physiologies across multiple perturbations and conditions. GENKI therefore provides a practical framework for perturbation-aware kinetic model refinement within iterative Design-Build-Test-Learn workflows.
The effects of tissue heterogeneity on the estimation of regional cerebral glucose utilization (rCMRglc) in normal humans with [18F]2-fluoro-2-deoxy-D-glucose ([18F]FDG) and positron emission tomography (PET) were compared with respect to the various kinetic models of the [18F]FDG method. The kinetic models were conventional homogeneous tissue models of the [18F]FDG method, with (4K Model) and without (3K Model) a rate constant to account for an apparent loss of [18F]2-fluoro-2-deoxy-D-glucose-6-phosphate ([18F]FDG-6-P), and a tissue heterogeneity model (TH Model). When either of the kinetic models designed for homogeneous tissues was applied to heterogeneous tissues, estimates of the rate constant for efflux of [18F]FDG from the tissue (k2*) and of the rate constant for phosphorylation of [18F]FDG (k3*) decreased as the duration of the experimental period was increased. When the 4K Model was used, estimates of the rate constant for the apparent dephosphorylation of [18F]FDG-6-P (k4*) were significantly greater than zero and fell with increasing duration of the experimental period. Although the TH Model included no term to describe an apparent dephosphorylation of [18F]FDG-6-P, the fit of the TH Model to the time course of total tissue radioactivity was at least as good as and often better than the fit of the 4K Model in the 120-min period following the pulse of [18F]FDG. Hence, the high estimates of k4* found in PET studies of less than or equal to 120 min can be explained as the consequence of measuring radioactivity in a heterogeneous tissue and applying a model designed for a homogeneous tissue; there remains no evidence of significant dephosphorylation of [18F]FDG-6-P in this time period. Furthermore, use of the 4K Model led to an overestimation of rCMRglc; whole-brain glucose utilization calculated with the 4K Model was greater than 20% higher than values usually obtained in normal humans by the model-independent Kety-Schmidt technique. rCMRglc was accurately estimated by the TH Model and, in experimental periods sufficiently long to minimize the effects of tissue heterogeneity, also by the original 3K Model of the deoxyglucose method.
A physiology-oriented compartmental kinetics model of alveolar retention of inhaled insoluble particulate matter in rat lungs was proposed in a recent paper, (W. Stöber, P.E. Morrow, and M.D. However, 1989, Fundam. App. Toxicol. 13, 823-843), and the retention patterns obtained with the model for a hypothetical set of input data appeared to simulate phenomena which were observed in inhalation studies with Fischer 344 rats. The present paper represents the results of applying the new model for simulations of the actual experimental retention data of five different inhalation studies with Fischer 344 rats exposed to three different materials. The experimental data showed that model adjustments had to be made in order to account for clearance effects that appeared to be influenced by the age of the animals. After these adjustments were made and an appropriate set of values for the model parameters describing the respective exposure conditions was used, the model was constrained to represent the empirical data of all of the studies by one unique set of parameter values. Changes in particular values of this set were considered to be acceptable only if they reflected changes of relevant properties of the inhaled particulate matter. The final simulations did not completely comply with this self-imposed criterion. However, the degree of compliance and the simulation quality achieved with a minimum of parameter variations seem to be unprecedented in retention modeling. The results of the study encourage attempts for further refining the present model.
A kinetic model involving intraerythrocytic and whole blood H+ concentrations during and after bicarbonate and acetate hemodialysis is proposed to account for experimental data. A two-compartment model appeared to be the simplest kinetic model to explain the decrease in proton concentration during bicarbonate hemodialysis and its increase between two dialysis sessions, whether acetate or bicarbonate. This model takes into account the hemoglobin buffer power and the cellular metabolic acidosis. During acetate hemodialysis, one must introduce a new compartment to explain the initial increase in H+ concentration in erythrocytes. This compartment, which generates protons, seems to correspond to the carbonic anhydrase cycle. The various parameters obtained show no significant variations between patients receiving bicarbonate hemodialysis. For acetate hemodialysis, the model describes equally well patients with a great initial increase in H+ concentration and those with a slight initial increase. The variations observed in the parameters are due mainly to the carbonic anhydrase compartment. It is suggested the magnitude of this initial increase and the degree of acetate intolerance are correlated.
The general use of first order kinetics to describe the disappearance of insulin from plasma in man contrasts the available evidence of saturation kinetics for insulin. In order to bridge this gap, we have put forward three alternative models of insulin kinetics. Model 1 considers the combined existence of first order and saturation (Michaëlis-Menten) kinetics. Model 2 considers saturation kinetics alone. Model 3 considers first order kinetics alone. The validity of the models was studied in normal and type I (insulin-dependent) diabetic subjects. Sequential constant intravenous infusions of insulin at different rates were used to achieve different levels of steady state plasma insulin concentrations, while the glycaemic level (usually normoglycaemia) was maintained by a glucose clamp. Appropriate validation procedures demonstrated that the model of saturation kinetics alone (model 2) was superior to the other models in normal subjects at physiological and supraphysiological plasma insulin concentrations, and in diabetic patients at supraphysiological concentrations. The minimal model at physiological insulin concentrations in type I diabetic patients was that of first order kinetics (model 3). The kinetics of insulin was independent of the species of insulin (human or porcine) in both study groups. The actual glycaemic clamp level (normoglycaemia and moderate hyperglycaemia) did not influence the insulin disappearance rate. Binding of insulin to its receptor is considered to be the initial step in insulin degradation. Saturation kinetics of insulin may therefore be influenced by the saturation of binding of insulin molecules to their receptors. We found values of Km (i.e. the concentration of plasma insulin at which the insulin disappearance rate is half maximal) in normal subjects comparable to values of Kd (i.e. the dissociation constant for insulin-receptor binding) from receptor studies in isolated cells. Changes in regional (hepatic and/or renal) blood flow at hyperinsulinaemia represent an alternative explanation to a model of saturation kinetics. Increases in Vmax (i.e. the maximal insulin disappearance rate) and Km with increasing insulin dose were observed in normal subjects. This finding suggests that insulin may disappear from plasma by more than one saturable pathway. Additional studies are needed to confirm this observation. The clearance rate of insulin at infinitesimal plasma insulin concentrations (Vmax/Km) was 28 +/- 8 ml.kg-1.min-1 in normal subjects. This value is higher than most clearance rates previously reported in studies using first order kinetics. The clearance rate of insulin in type I diabetic patients was 20 +/- 4 ml.kg-1.min-1, corresponding to a reduction in clearance of 30% compared to normal subjects.(ABSTRACT TRUNCATED AT 400 WORDS)
Three molecular (enzyme) kinetic models have been designed that exhibit the basic properties of associative learning (classical conditioning). The enzyme systems are acted upon by an 'unconditioned' and a 'conditioned' ligand: temporally paired application of the two ligands leads to covalent enzyme modification, which serves as 'memory trace'. The behaviour of the systems has been investigated by computer simulation. Although the models are hypothetic, they do not contain biochemically inconceivable steps. The models demonstrate that already fairly simple molecular events may produce the phenomenology of associative learning.
A six-compartment, nine-parameter kinetic model of 2-deoxyglucose (2DG) metabolism, which includes bidirectional tissue transport, phosphorylation, two-step dephosphorylation, phosphoisomerization, and conjugation to UDP and macromolecules, has been derived. Data for analysis were obtained from 540- and 1,000-microns-thick hippocampal and hypothalamic brain slices, which were incubated in buffer containing [14C]2DG, frozen, extracted with perchlorate, and separated on anion-exchange columns. Solutions of the equations of the model were fit to the data by means of nonlinear least-squares analysis. These studies suggest that dephosphorylation is adequately described by a single reaction so that the model reduces to eight parameters. The in vitro rate constants for transport, phosphorylation, and dephosphorylation are very similar to prior in vivo results. The phosphoisomerization rate constant is similar to dephosphorylation, so glycosylated macromolecules slowly accumulate and gradually assume larger relative importance as other compounds disappear more rapidly. Rate constants for 540-microns slices from hypothalamus and hippocampus are similar, while 1,000-microns slices have smaller tissue transport constants and larger phosphorylation constants. The rate equation for glucose utilization of this model is relatively insensitive to uncertainties regarding the rate constants. Including later metabolic components in kinetic models improves the calculations of glucose utilization with long isotope exposures.
The objective of this study was to analyze risk factors affecting mortality rates (MR) in hemodialysis patients undergoing shortened dialysis time who were regularly kinetically modeled. Over a 14-month period, 180 in-center hemodialysis patients, 54% male, 46% female, 57% Black, 39% Caucasian, and 4% Hispanic, treated with rapid high efficiency dialysis (RHED = 2-3 h, 3 times/week) and conventional dialysis (3-4 h, 3 times/week) were studied. Median patient age was 56.7 years (16-84 years) and dialysis care ranged from 6 months to 18 years (mean +/- SD = 4.0 +/- 4.2 years). The patients underwent monthly urea kinetic modeling. The dialysis prescription was based upon normalizing Kt/V between 0.8 and 1.2 and the protein catabolic rate (PCRn) between 0.9 and 1.1. Thirty-three percent of the patients received recombinant human erythropoietin (r-HuEPO). The effects of various covariates, including primary diagnosis, post/predialysis BUN ratios, creatinine, albumin, calcium, phosphate, cholesterol, hemoglobin, r-HuEPO, Kt/V, and PCRn were analyzed using analysis of variance, chi 2 and linear discriminant function (DF) statistical methods. Several significant factors emerged as influencing outcome. The DF analysis produced a highly statistically significant (p < 0.0001) model to predict mortality based upon certain laboratory and dialysis parameters. Further, the linear DF correctly predicted mortality rate in 86% of cases. The results of the analysis revealed an overall mortality rate of 15.6%; hospitalization rates (HR) were 1.4 +/- 1.8 times/year. Length of dialysis time, i.e., dialysis times between 2 and 4 h, when adjusted for Kt/V has no correlation with MR or HR. Variables associated with survival were higher post/predialysis BUN ratios, normal Kt/V (0.8-1.2), normal albumin levels (> 3.5 g/dl), higher postdialysis BUN, creatinine, and cholesterol levels, and use of r-HuEPO. The use of r-HuEPO when analyzed by DF significantly improved MR, 8.3% as opposed to 19.2%. It is concluded that urea kinetic modeling permits shortening dialysis times without affecting mortality or hospitalization rates, and that low postdialysis BUN, post/predialysis BUN ratios, creatinine, and albumin values are correlated with a lower chance of survival.
To test the accuracy of urea kinetic modeling (UKM), the classic fixed-volume model UKMf, two variable-volume models (UKMvb and UKMvd), direct dialysis quantification (DDQ) and a partial dialysate collection method (PDC) were evaluated in 15 stable, high-hematocrit patients. Urea generation rate (G) was also determined from a 1-week collection of total dialysate and urine (OWC). The results, except distribution volumes, were highly correlated. However, Kt/V, the normalized whole-body urea clearance, was about 8% higher with UKMvb and UKMvd. Two of three simple equations for Kt/V rendered grossly deviating, but highly correlating, results. The normalized protein catabolic rate was 8% higher with UKMvd. With OWC as reference, UKMvb and UKMvd overestimated G by 19 and 15%, respectively. All results of PDC closely followed those of DDQ. This method may be an alternative for exact quantification. Before using a new UKM method it should be compared to an established reference method.
Urea kinetic modeling (UKM) has been originally proposed by F. Gotch and J. Sargent as a guide to optimize and individualize the dialysis prescription in uremic patients. In a recent report, the US National Cooperative Dialysis Study group, showed the power of this approach compared to conventional methods. It was also concluded that dialysis adequacy could be predicted with a high success rate by determining three parameters; uremia represented by the Urea Time Averaged Concentration, dialysis dose defined as KT/V ratio, and dietary protein intake calculated from the urea generation rate. In spite of its potential usefulness, UKM has not gained clinical acceptance among nephrologists since it appeared always complicated due to its mathematical formulation or cumbersome to be used routinely in dialyzed patients. In this paper the authors will bring the reader from basic concepts to practical use of UKM to guide dialysis strategy. Limits of validity and difficulty in using this approach are also discussed. It is concluded that UKM by using very simple and basic parameters is a practical, and very powerful tool for assessing the dialysis adequacy and nutritional status of dialyzed patients. Direct quantification from dialysate (or ultrafiltrate) collection appeared a simple and precise method which should avoided multiple blood sampling.
A kinetic model is presented based on the simplest plausible mechanism for bacterial binding protein-dependent transport. The transport phenotypes of the 18 variant arabinose-binding proteins analyzed by Kehres and Hogg (1992, Protein Sci. 1, 1652-1660) (wild type and 17 mutants) are interpreted to mean that in wild-type arabinose uptake the forward transport rate (k(for)) greatly exceeds the dissociation rate (kund) of a binding protein docked with the AraG:AraH membrane complex, and that k(for) dominance is preserved in all of the binding protein surface mutants. The assumptions and predictions of the model are consistent with existing data from other periplasmic transport systems.