High Osmol Gap Hyponatremia Caused by Icodextrin: A Case Series Report.

Recently, hyperosmolar hyponatremia following excessive off-label use of two exchanges of 2 L icodextrin daily during peritoneal dialysis (PD) was reported. We encountered a cluster of 3 cases of PD patients who developed hyperosmolar hyponatremia during on-label use of icodextrin. This appeared to be due to absorption of icodextrin since after stopping icodextrin, the serum sodium level and osmol gap returned to normal, while a rechallenge again resulted in hyperosmolar hyponatremia. We excluded higher than usual concentrations of specific fractions of dextrins in fresh icodextrin dialysis fluid (lot numbers of used batches were checked by manufacturer). We speculate that in our patients, either an exaggerated degradation of polysaccharide chains by α-amylase activity in dialysate, lymph, and interstitium and/or rapid hydrolysis of the absorbed larger degradation products in the circulation may have contributed to the hyperosmolality observed, with the concentration of oligosaccharides exceeding the capacity of intracellular enzymes (in particular maltase) to metabolize these products to glucose. Both hyponatremia and hyperosmolality are risk factors for poor outcomes in PD patients. Less conventional PD prescriptions such as off-label use of two exchanges of 2 L icodextrin might raise the risk of this threatening side effect. This brief report is intended to create awareness of a rare complication of on-label icodextrin use in a subset of PD patients and/or PD prescriptions.

Monitoring relative blood volume changes during hemodialysis: Impact of the priming procedure.

The monitoring of relative blood volume (RBV) changes during hemodialysis is increasingly used to evaluate the effect of dialyzer ultrafiltration on intravascular volume to guide the removal of excess fluid in a manner that maintains hemodynamic stability of the patient. RBV monitoring is typically based on an optical or acoustic sensor placed in the arterial blood line that measures a marker of hemoconcentration, such as hematocrit, hemoglobin, or total blood protein. However, the accuracy of RBV monitors and the impact of their clinical use remain the subject of ongoing debate. Here, we show that, depending on the procedure of filling the extracorporeal circuit with the patient's blood at the beginning of the dialysis session, the indications of an RBV monitor may be misleading as to the actual changes of the intravascular volume. When the blood is first pumped into the dialyzer, the priming fluid (saline) that fills the circuit may be either infused into the patient or disposed of to a drain bag. In the latter case, the intravascular volume is suddenly reduced, which is not accounted for by RBV monitors that track only the subsequent reductions in blood volume due to dialyzer ultrafiltration. We analyzed this general aspect of RBV monitoring using model-based simulations and showed quantitatively how RBV changes calculated using hematocrit differ depending on the priming procedure.

Association between Biomarkers of Mineral and Bone Metabolism and Removal of Calcium and Phosphate in Hemodialysis.

BACKGROUND: A significant drop of serum phosphate and calcium removal or loading during hemodialysis induce reactions in mineral and bone remodeling that may inversely affect phosphate and calcium removal during dialysis. OBJECTIVES: We aimed to analyze the interdependencies between biomarkers of mineral and bone metabolism and removal of phosphate and calcium during hemodialysis, as this complex relationship is not fully understood. METHODS: Three subsequent hemodialysis sessions during a 1-week treatment cycle with interdialytic periods of 2-2-3 days were monitored in 25 anuric patients. Calcium and phosphate concentrations were measured in serum before, at 1, 2, and 3 h, at the end, and 45 min after each session and in the outlet dialysate every 30 min. Biomarkers associated with mineral and bone metabolism: parathyroid hormone (PTH 1-34 and PTH 1-84), calcitonin, 25(OH)-vitamin D, fetuin-A, osteopontin, osteocalcin 1-43/49, and intact osteocalcin were assayed once in each patient before the midweek hemodialysis session. RESULTS: Post-dialytic and intra-dialytic serum phosphate of midweek hemodialysis session and phosphate mass removed within 1 week correlated positively with serum PTH (0.40 < rho <0.46, p value <0.05). Higher concentration of serum PTH was associated with an increased level of osteocalcin. Pre-dialytic, post-dialytic, average for treatment time and average weekly concentrations of ionized calcium in serum correlated positively with serum osteocalcin. Serum osteocalcin and osteopontin levels were associated with the masses of total and ionized calcium, respectively, removed during 3 hemodialysis sessions. CONCLUSIONS: During hemodialysis, phosphate removal was associated with serum PTH, whereas calcium kinetics was influenced by serum osteocalcin and osteopontin. These results demonstrate that active processes involving biomarkers of mineral and bone metabolism are affected by the phosphate and calcium kinetics already within 4 h hemodialysis sessions.

Transcapillary Refilling Rate and Its Determinants during Haemodialysis with Standard and High Ultrafiltration Rates.

BACKGROUND: Achieving euvolaemia using ultrafiltration (UF) during haemodialysis (HD) without inducing haemodynamic instability presents a major clinical challenge. Transcapillary refill is a key factor in sustaining the circulating blood volume (BV) during UF, which is in turn predicted by the rate of refilling. However, absolute plasma refilling rate (PRR), its determinants and variability with UF rate (UFR), have not been reported in the literature. METHOD: We studied paired HD sessions (n = 48) in 24 patients over 2 consecutive mid-week HD treatments. Plasma refilling was measured using real-time, minute-by-minute relative BV changes obtained from the integrated BV monitoring device during UF. A fixed bolus dilution approach at the start of HD was used to calculate absolute BV. The first control HD session was undertaken with a standard UFR required to achieve the prescribed target weight, while during the second study session, a fixed (high) UFR (1 L/h) was applied, either in the first (n = 12 patients) or in the final hour (n = 12 patients) of the HD session. Participants' had their hydration status measured pre- and post-HD using multifrequency bioimpedance (BIS). Blood pressure was measured at 15-min intervals and blood samples were collected at 7 intervals during HD sessions. RESULTS: The mean PRR during a standard 4-hr HD session was 4.3 ± 2.0 mL/kg/h and varied between 2 and 6 mL/kg/h. There was a mean time delay of 22 min (range 13.3-35.0 min) for onset of plasma refilling after the application of UF irrespective of standard or high UFRs. The maximum refilling occurred during the second hour of HD (mean max PRR 6.8 mL/kg/h). UFR (beta = 0.60, p < 0.01) and BIS derived pre-HD overhydration index (beta = 0.44, p = 0.01) were consistent, independent predictors of the mean PRR (R2 = 0.49) in all HD sessions. At high UFRs, PRR exceeded 10 mL/kg/h. The total overall plasma refill contribution to UF volume was not significantly different between standard and high UF. During interventions no significant haemodynamic instability was observed in the study. CONCLUSION: We describe absolute transcapillary refilling rate and its profile during HD with UF. The findings provide the basis for the development of UF strategies to match varying PRRs during HD. An approach to fluid removal, which is tailored to patients' refilling rates and capacity, provides an opportunity for more precision in the practice of UF.

Alterations of peritoneal transport characteristics in dialysis patients with ultrafiltration failure: tissue and capillary components.

BACKGROUND: Ultrafiltration failure (UFF) in peritoneal dialysis (PD) patients is due to altered peritoneal transport properties leading to reduced capacity to remove excess water. Here, with the aim to establish the role of local alterations of the two major transport barriers, peritoneal tissue and capillary wall, we investigate changes in overall peritoneal transport characteristics in UFF patients in relation to corresponding local alterations of peritoneal tissue and capillary wall transport properties. METHODS: Six-hour dwell studies using 3.86% glucose solutions and radioisotopically labelled serum albumin added to dialysate as a volume marker were analysed in 31 continuous ambulatory PD patients, 20 with normal ultrafiltration (NUF) and 11 with UFF. For each patient, the physiologically based parameters were evaluated for both transport barriers using the spatially distributed approach based on the individual intraperitoneal profiles of volume and concentrations of glucose, sodium, urea and creatinine. RESULTS: UFF patients as compared with NUF patients had increased solute diffusivity in both barriers, peritoneal tissue and capillary wall, decreased tissue hydraulic conductivity and increased local lymphatic absorption and functional decrease in the fraction of the ultra-small pores. This resulted in altered distribution of fluid and solutes in the peritoneal tissue, and decreased penetration depths of fluid and solutes into the tissue in UFF patients. CONCLUSIONS: Mathematical modelling using a spatially distributed approach for the description of clinical data suggests that alterations both in the capillary wall and in the tissue barrier contribute to UFF through their effect on transport and distribution of solutes and fluid within the tissue.

Patient-specific pulse wave propagation model identifies cardiovascular risk characteristics in hemodialysis patients.

Risk of cardiovascular associated death in dialysis patients is the highest among all other co-morbidities. Improving the identification of patients with the highest cardiovascular risk to design an adequate treatment is, therefore, of utmost importance. There are several non-invasive cardiovascular state biomarkers based on the pulse (pressure) wave propagation properties, but their major determinants are not fully understood. In the current study we aimed to provide a framework to precisely dissect the information available in non-invasively recorded pulse wave in hemodialysis patients. Radial pressure wave profiles were recorded before, during and after two independent hemodialysis sessions in 35 anuric prevalent hemodialysis patients and once in a group of 32 healthy volunteers. Each recording was used to estimate six subject-specific parameters of pulse wave propagation model. Pressure profiles were also analyzed using SphygmoCor software (AtCor Medical, Australia) to derive values of already established biomarkers, i.e. augmentation index and sub-endocardial viability ratio (SEVR). Data preprocessing using propensity score matching allowed to compare hemodialysis and healthy groups. Augmentation index remained on average stable at 142 ± 28% during dialysis and had similar values in both considered groups. SEVR, whose pre-dialytic value was on average lower by 12% compared to healthy participants, was improved by hemodialysis, with post-dialytic values indistinguishable from those in healthy population (p-value > 0.2). The model, however, identified that the patients on hemodialysis had significantly increased stiffness of both large and small arteries compared to healthy counterparts (> 60% before dialysis with p-value < 0.05 or borderline) and that it was only transiently decreased during hemodialysis session. Additionally, correlation-based clustering revealed that augmentation index reflects the shape of heart ejection profile and SEVR is associated with stiffness of larger arteries. Patient-specific pulse wave propagation modeling coupled with radial pressure profile recording correctly identified increased arterial stiffness in hemodialysis patients, while regular pulse wave analysis based biomarkers failed to show significant differences. Further model testing in larger populations and investigating other biomarkers are needed to confirm these findings.

Modeling Pathological Hemodynamic Responses to the Valsalva Maneuver.

The Valsalva maneuver (VM) consisting in a forced expiration against closed airways is one of the most popular clinical tests of the autonomic nervous system function. When properly performed by a healthy subject, it features four characteristic phases of arterial blood pressure (BP) and heart rate (HR) variations, based on the magnitude of which the autonomic function may be assessed qualitatively and quantitatively. In patients with some disorders or in healthy patients subject to specific conditions, the pattern of BP and HR changes during the execution of the Valsalva maneuver may, however, differ from the typical sinusoidal-like pattern. Several types of such abnormal responses are well known and correspond to specific physiological conditions. In this paper, we use our earlier mathematical model of the cardiovascular response to the Valsalva maneuver to show that such pathological responses may be simulated by changing individual model parameters with a clear physiological meaning. The simulation results confirm the adaptability of our model and its usefulness for diagnostic or educational purposes.

Concomitant bidirectional transport during peritoneal dialysis can be explained by a structured interstitium.

Clinical and animal studies suggest that peritoneal absorption of fluid and protein from dialysate to peritoneal tissue, and to blood and lymph circulation, occurs concomitantly with opposite flows of fluid and protein, i.e., from blood to dialysate. However, until now a theoretical explanation of this phenomenon has been lacking. A two-phase distributed model is proposed to explain the bidirectional, concomitant transport of fluid, albumin and glucose through the peritoneal transport system (PTS) during peritoneal dialysis. The interstitium of this tissue is described as an expandable two-phase structure with phase F (water-rich, colloid-poor region) and phase C (water-poor, colloid-rich region) with fluid and solute exchange between them. A low fraction of phase F is assumed in the intact tissue, which can be significantly increased under the influence of hydrostatic pressure and tissue hydration. The capillary wall is described using the three-pore model, and the conditions in the peritoneal cavity are assumed commencing 3 min after the infusion of glucose 3.86% dialysis fluid. Computer simulations demonstrate that peritoneal absorption of fluid into the tissue, which occurs via phase F at the rate of 1.8 ml/min, increases substantially the interstitial pressure and tissue hydration in both phases close to the peritoneal cavity, whereas the glucose-induced ultrafiltration from blood occurs via phase C at the rate of 15 ml/min. The proposed model delineating the phenomenon of concomitant bidirectional transport through PTS is based on a two-phase structure of the interstitium and provides results in agreement with clinical and experimental data.

Genotypic and phenotypic predictors of inflammation in patients with chronic kidney disease.

BACKGROUND: In complex diseases such as chronic kidney disease (CKD), the risk of clinical complications is determined by interactions between phenotypic and genotypic factors. However, clinical epidemiological studies rarely attempt to analyse the combined effect of large numbers of phenotype and genotype features. We have recently shown that the relaxed linear separability (RLS) model of feature selection can address such complex issues. Here, it is applied to identify risk factors for inflammation in CKD. METHODS: The RLS model was applied in 225 CKD stage 5 patients sampled in conjunction with dialysis initiation. Fifty-seven anthropometric or biochemical measurements and 79 genetic polymorphisms were entered into the model. The model was asked to identify phenotypes and genotypes that, when combined, could separate inflamed from non-inflamed patients. Inflammation was defined as a high-sensitivity C-reactive protein concentration above the median (5 mg/L). RESULTS: Among the 60 genotypic and phenotypic features predicting inflammation, 31 were genetic. Among the 10 strongest predictors of inflammation, 8 were single nucleotide polymorphisms located in the NAMPT, CIITA, BMP2 and PIK3CB genes, whereas fibrinogen and bone mineral density were the only phenotypic biomarkers. CONCLUSION: These results indicate a larger involvement of hereditary factors in inflammation than might have been expected and suggest that inclusion of genotype features in risk assessment studies is critical. The RLS model demonstrates that inflammation in CKD is determined by an extensive panel of factors and may prove to be a suitable tool that could enable a much-needed multifactorial approach as opposed to the commonly utilized single-factor analysis.

Phosphate, urea and creatinine clearances: haemodialysis adequacy assessed by weekly monitoring.

BACKGROUND: The specific distribution of phosphate and the control mechanisms for its plasma level makes phosphate kinetics during haemodialysis (HD) considerably different from those of urea and creatinine and makes the quantitative evaluation of adequacy of phosphate removal difficult. We propose the application of equivalent continuous clearance (ECC) as a phosphate adequacy parameter and compare it with ECC for creatinine and urea. METHODS: Three consecutive dialysis sessions were evaluated for 25 patients on maintenance HD. Concentrations of phosphate, urea and creatinine in plasma were measured every 1h during the treatment and 45 min after, and every 30 min in dialysate. ECC was calculated using the removed solute mass assessed in dialysate and weekly solute profile in plasma. Similar calculations were performed also for the midweek dialysis session only. Different versions of the reference concentration for ECC were applied. RESULTS: ECC with peak average reference concentration was 5.4 ± 1.0 for phosphate, 7.0 ± 1.0 for urea and 4.7 ± 1.0 mL/min for creatinine. ECC for urea and creatinine were well correlated in contrast to the correlations of ECC for phosphate versus urea and creatinine. Midweek ECC were higher than weekly ECC, but they were well correlated for urea and creatinine, but only weakly for phosphate. CONCLUSIONS: HD adequacy monitoring for phosphate may be performed using ECC, but it is less predictable than similar indices for urea and creatinine. The values of ECC for phosphate are within the range expected for its molecular size compared with those for urea and creatinine.

Effect of time-dependent dialysate bicarbonate concentrations on acid-base and uremic solute kinetics during hemodialysis treatments.

Recent studies have suggested benefits for time-dependent dialysate bicarbonate concentrations (Dbic) during hemodialysis (HD). In this clinical trial, we compared for the first time in the same HD patients the effects of time-dependent changes with constant Dbic on acid-base and uremic solute kinetics. Blood acid-base and uremic solute concentration were measured in twenty chronic HD patients during 4-h treatments with A) constant Dbic of 35 mmol/L; B) Dbic of 35 mmol/L then 30 mmol/L; and C) Dbic of 30 mmol/L then 35 mmol/L (change of Dbic after two hours during Treatments B and C). Arterial blood samples were obtained predialysis, every hour during HD and one hour after HD, during second and third treatments of the week with each Dbic concentration profile. Blood bicarbonate concentration (blood [HCO3]) during Treatment C was lower only during the first three HD hours than in Treatment A. Overall blood [HCO3] was reduced during Treatment B in comparison to Treatment A at each time points. We conclude that a single change Dbic in the middle of HD can alter the rate of change in blood [HCO3] and pH during HD; time-dependent Dbic had no influence on uremic solute kinetics.

Sequential peritoneal equilibration test: a new method for assessment and modelling of peritoneal transport.

BACKGROUND: In spite of many peritoneal tests proposed, there is still a need for a simple and reliable new approach for deriving detailed information about peritoneal membrane characteristics, especially those related to fluid transport. METHODS: The sequential peritoneal equilibration test (sPET) that includes PET (glucose 2.27%, 4 h) followed by miniPET (glucose 3.86%, 1 h) was performed in 27 stable continuous ambulatory peritoneal dialysis patients. Ultrafiltration volumes, glucose absorption, ratio of concentration in dialysis fluid to concentration in plasma (D/P), sodium dip (Dip D/P Sodium), free water fraction (FWF60) and the ultrafiltration passing through small pores at 60 min (UFSP60), were calculated using clinical data. Peritoneal transport parameters were estimated using the three-pore model (3p model) and clinical data. Osmotic conductance for glucose was calculated from the parameters of the model. RESULTS: D/P creatinine correlated with diffusive mass transport parameters for all considered solutes, but not with fluid transport characteristics. Hydraulic permeability (L(p)S) correlated with net ultrafiltration from miniPET, UFSP60, FWF60 and sodium dip. The fraction of ultrasmall pores correlated with FWF60 and sodium dip. CONCLUSIONS: The sequential PET described and interpreted mechanisms of ultrafiltration and solute transport. Fluid transport parameters from the 3p model were independent of the PET D/P creatinine, but correlated with fluid transport characteristics from PET and miniPET.

Osmotic and Gibbs-Donnan equilibrium for ions and neutral solutes.

The general set of equations for the equilibrium of two solutions with a mixture of non-permeating and permeating ions and neutral solutes at each side of a permselective membrane is formulated using the principles of electroneutrality and mass conservation law for each solution, and equilibrium conditions: equality of electrochemical potentials at both sides of the membrane for each permeating solution component. There is at least one permeating neutral chemical species (solvent) in the system. The theory is in general valid for non-ideal solutions. The generalized Gibbs-Donnan (G-D) equilibrium coefficients depend on activities/fractions of all species at one side of the membrane, and charges of ions and partial molar volumes of all species. The equilibrium osmotic pressure across the membrane is also provided by the theory and can be calculated using the ratio of activities (or equivalently the G-D factor) of any permeating neutral solute (including solvent) or the ratios of activities (or equivalently the G-D factors) of any two permeating ions.

Mathematical modelling of bicarbonate supplementation and acid-base chemistry in kidney failure patients on hemodialysis.

Acid-base regulation by the kidneys is largely missing in end-stage renal disease patients undergoing hemodialysis (HD). Bicarbonate is added to the dialysis fluid during HD to replenish the buffers in the body and neutralize interdialytic acid accumulation. Predicting HD outcomes with mathematical models can help select the optimal patient-specific dialysate composition, but the kinetics of bicarbonate are difficult to quantify, because of the many factors involved in the regulation of the bicarbonate buffer in bodily fluids. We implemented a mathematical model of dissolved CO2 and bicarbonate transport that describes the changes in acid-base equilibrium induced by HD to assess the kinetics of bicarbonate, dissolved CO2, and other buffers not only in plasma but also in erythrocytes, interstitial fluid, and tissue cells; the model also includes respiratory control over the partial pressures of CO2 and oxygen. Clinical data were used to fit the model and identify missing parameters used in theoretical simulations. Our results demonstrate the feasibility of the model in describing the changes to acid-base homeostasis typical of HD, and highlight the importance of respiratory regulation during HD.

Validity of the hydrogen ion mobilisation model during haemodialysis with time-dependent dialysate bicarbonate concentrations.

BACKGROUND: The hydrogen ion (H+) mobilisation model has been previously shown to accurately describe blood bicarbonate (HCO3) kinetics during haemodialysis (HD) when the dialysate bicarbonate concentration ([HCO3]) is constant throughout the treatment. This study evaluated the ability of the H+ mobilization model to describe blood HCO3 kinetics during HD treatments with a time-dependent dialysate [HCO3]. METHODS: Data from a recent clinical study where blood [HCO3] was measured at the beginning of and every hour during 4-h treatments in 20 chronic, thrice-weekly HD patients with a constant (Treatment A), decreasing (Treatment B) and increasing (Treatment C) dialysate [HCO3] were evaluated. The H+ mobilization model was used to determine the model parameter (Hm) that provided the best fit of the model to the clinical data using nonlinear regression. A total of 114 HD treatments provided individual estimates of Hm. RESULTS: Mean ± standard deviation estimates of Hm during Treatments A, B and C were 0.153 ± 0.069, 0.180 ± 0.109 and 0.205 ± 0.141 L/min (medians [interquartile ranges] were 0.145 [0.118,0.191], 0.159 [0.112,0.209], 0.169 [0.115,0.236] L/min), respectively; these estimates were not different from each other (p = 0.26). The sum of squared differences between the measured blood [HCO3] and that predicted by the model were not different during Treatments A, B and C (p = 0.50), suggesting a similar degree of model fit to the data. CONCLUSIONS: This study supports the validity of the H+ mobilization model to describe intradialysis blood HCO3 kinetics during HD with a constant Hm value when using a time-dependent dialysate [HCO3].

Modelling of icodextrin hydrolysis and kinetics during peritoneal dialysis.

In peritoneal dialysis, ultrafiltration is achieved by adding an osmotic agent into the dialysis fluid. During an exchange with icodextrin-based solution, polysaccharide chains are degraded by α-amylase activity in dialysate, influencing its osmotic properties. We modelled water and solute removal taking into account degradation by α-amylase and absorption of icodextrin from the peritoneal cavity. Data from 16 h dwells with icodextrin-based solution in 11 patients (3 icodextrin-exposed, 8 icodextrin-naïve at the start of the study) on dialysate volume, dialysate concentrations of glucose, urea, creatinine and α-amylase, and dialysate and blood concentrations of seven molecular weight fractions of icodextrin were analysed. The three-pore model was extended to describe hydrolysis of icodextrin by α-amylase. The extended model accurately predicted kinetics of ultrafiltration, small solutes and icodextrin fractions in dialysate, indicating differences in degradation kinetics between icodextrin-naïve and icodextrin-exposed patients. In addition, the model provided information on the patterns of icodextrin degradation caused by α-amylase. Modelling of icodextrin kinetics using an extended three-pore model that takes into account absorption of icodextrin and changes in α-amylase activity in the dialysate provided accurate description of peritoneal transport and information on patterns of icodextrin hydrolysis during long icodextrin dwells.

Computer simulations of osmotic ultrafiltration and small-solute transport in peritoneal dialysis: a spatially distributed approach.

The aim of this study was to simulate clinically observed intraperitoneal kinetics of dialysis fluid volume and solute concentrations during peritoneal dialysis. We were also interested in analyzing relationships between processes in the peritoneal cavity and processes occurring in the peritoneal tissue and microcirculation. A spatially distributed model was formulated for the combined description of volume and solute mass balances in the peritoneal cavity and flows across the interstitium and the capillary wall. Tissue local parameters were assumed dependent on the interstitial hydration and vasodilatation induced by glucose. The model was fitted to the average volume and solute concentration profiles from dwell studies in 40 clinically stable patients on chronic ambulatory peritoneal dialysis using a 3.86% glucose dialysis solution. The model was able to describe the clinical data with high accuracy. An increase in the local interstitial pressure and tissue hydration within the distance of 2.5 mm from the peritoneal surface of the tissue was observed. The penetration of glucose into the tissue and removal of urea, creatinine, and sodium from the tissue were restricted to a layer located within 2 mm from the peritoneal surface. The initial decline of sodium concentration (sodium dip) was observed not only in intraperitoneal fluid but also in the tissue. The distributed model can provide a precise description of the relationship between changes in the peritoneal tissue and intraperitoneal dialysate volume and solute concentration kinetics. Computer simulations suggest that only a thin layer of the tissue within 2-3 mm from the peritoneal surface participates in the exchange of fluid and small solutes between the intraperitoneal dialysate and blood.

Membrane transport of several ions during peritoneal dialysis: mathematical modeling.

Peritoneal dialysis utilizes a complex mass exchange device created by natural permselective membranes of the visceral and abdominal muscle tissues. In mathematical modeling of solute transport during peritoneal dialysis, each solute is typically considered as a neutral, independent particle. However, such mathematical models cannot predict transport parameters for small ions. Therefore, the impact of the electrostatic interactions between ions on the estimated transport parameters needs to be investigated. In this study, transport of sodium, chloride, and a third ion through a permselective membrane with characteristics of the peritoneal transport barrier was described using two models: a model with the Nernst-Planck (NP) equations for a set of interacting ions and a model with combined diffusive and convective transport of each ion separately (DC). Transport parameters for the NP model were calculated using the pore theory, while the parameters for the DC model were estimated by fitting the model to the predictions from the NP model. Solute concentration profiles in the membrane obtained by computer simulations based on these two models were similar, whereas the transport parameters (diffusive mass transport parameters and sieving coefficients) were generally different. The presence of the third ion could substantially modify the values of diffusive mass parameter for sodium and chloride ions estimated using the DC model compared with those predicted by NP. The extent of this modification depended on the molecular mass and concentration of the third ion, and the rate of volumetric flow. Closed formulas for the transport parameters of the DC model in terms of the NP model parameters, ion concentration profiles in the membrane, and volumetric flow across the membrane were derived. Their reliable approximations, which include only boundary ion concentrations instead of spatial intramembrane concentration profiles, were formulated. The precision of this approximation was demonstrated by numerical simulations of the investigated three-ion system. Our modeling demonstrated that the fitted transport parameters depend not only on ion molecular weight but also on the characteristics and concentration of all other ions in the fluid as well as on the fluid flow rate through the membrane. Therefore, theoretical predictions of ion transport parameters need to take into account multi-ionic character of dialysis and body fluids. The transport parameters estimated using the DC model for one ion may vary with the ionic composition, ion concentrations in the fluids, and volumetric flow and may not reflect the theoretical description of diffusive and convective characteristics of single ion.

Vascular refilling coefficient is not a good marker of whole-body capillary hydraulic conductivity in hemodialysis patients: insights from a simulation study.

Refilling of the vascular space through absorption of interstitial fluid by micro vessels is a crucial mechanism for maintaining hemodynamic stability during hemodialysis (HD) and allowing excess fluid to be removed from body tissues. The rate of vascular refilling depends on the imbalance between the Starling forces acting across the capillary walls as well as on their hydraulic conductivity and total surface area. Various approaches have been proposed to assess the vascular refilling process during HD, including the so-called refilling coefficient (Kr) that describes the rate of vascular refilling per changes in plasma oncotic pressure, assuming that other Starling forces and the flow of lymph remain constant during HD. Several studies have shown that Kr decreases exponentially during HD, which was attributed to a dialysis-induced decrease in the whole-body capillary hydraulic conductivity (LpS). Here, we employ a lumped-parameter mathematical model of the cardiovascular system and water and solute transport between the main body fluid compartments to assess the impact of all Starling forces and the flow of lymph on vascular refilling during HD in order to explain the reasons behind the observed intradialytic decrease in Kr. We simulated several HD sessions in a virtual patient with different blood priming procedures, ultrafiltration rates, session durations, and constant or variable levels of LpS. We show that the intradialytic decrease in Kr is not associated with a possible reduction of LpS but results from the inherent assumption that plasma oncotic pressure is the only variable Starling force during HD, whereas in fact other Starling forces, in particular the oncotic pressure of the interstitial fluid, have an important impact on the transcapillary fluid exchange during HD. We conclude that Kr is not a good marker of LpS and should not be used to guide fluid removal during HD or to assess the fluid status of dialysis patients.

Urine volume as an estimator of residual renal clearance and urinary removal of solutes in patients undergoing peritoneal dialysis.

In non-anuric patients undergoing peritoneal dialysis (PD), residual kidney function (RKF) is a main contributor to fluid and solute removal and an independent predictor of survival. We investigated if urine volume could be used to estimate renal clearances and removal of urea, creatinine, and phosphorus in PD patients. The observational, cross-sectional study included 93 non-anuric prevalent PD patients undergoing continuous ambulatory PD (CAPD; n = 34) or automated PD (APD; n = 59). Concentrations of urea, creatinine and phosphorus in serum and in 24-h collections of urine volume were measured to calculate weekly residual renal clearance (L/week) and removed solute mass (g/week). Median [interquartile range], 24-h urine output was 560 [330-950] mL and measured GFR (the mean of creatinine and urea clearances) was 3.24 [1.47-5.67] mL/min. For urea, creatinine and phosphorus, residual renal clearance was 20.60 [11.49-35.79], 43.02 [19.13-75.48] and 17.50 [8.34-33.58] L/week, respectively, with no significant differences between CAPD and APD. Urine volume correlated positively with removed solute masses (rho = 0.82, 0.67 and 0.74) and with weekly residual renal clearances (rho = 0.77, 0.62 and 0.72 for urea, creatinine, and phosphorus, respectively, all p < 0.001). Residual renal clearances and urinary mass removal rates for urea, creatinine, and phosphorus correlate strongly with 24-h urine volume suggesting that urine volume could serve as an estimator of typical values of residual solute removal indices in PD patients.