Intradialytic kinetics of middle molecules during hemodialysis and hemodiafiltration.

BACKGROUND: The kinetics of ß2-microglobulin during hemodialysis and hemodiafiltration is well described by a two-compartment model where clearance by the dialyzer is from a central compartment volume that approximates plasma volume and a total distribution volume that approximates extracellular fluid volume. The kinetics of middle molecules with molecular weights larger than ß2-microglobulin have not been extensively studied. METHODS: Intradialytic plasma concentrations and overall dialyzer clearances of ß2-microglobulin (11.8 kD), myoglobin (16.7 kD) and complement factor D (24.4 kD) were used to estimate three kinetic parameters from a two-compartment model, namely intercompartmental clearance, central compartment volume and total distribution volume, in hemodialysis patients; these data were collected during two clinical trials of medium cut-off dialyzers (with extended middle molecule removal) during hemodialysis and high-flux dialyzers during hemodialysis and hemodiafiltration. In the current exploratory analyses, the kinetic parameters from all dialyzers were combined. Overall dialyzer clearance was evaluated by total mass removed in the dialysate. RESULTS: In total, 345 sets of kinetic parameters from 35 patients were determined. Intercompartmental clearance and central compartment volume for myoglobin and complement factor D were smaller (P < 0.001) than those for ß2-microglobulin. Independent of middle molecule, intercompartmental clearance and central compartment volume were associated with overall dialyzer clearance (P < 0.001), but total distribution volume was not (P = 0.083). CONCLUSIONS: A two-compartment kinetic model can only describe intradialytic kinetics of middle molecules with molecular weights larger than ß2-microglobulin if the central compartment is small and dependent on overall dialyzer clearance.

Single Daily Icodextrin Exchange as Initial and Solitary Therapy.

BACKGROUND: Incremental dialysis utilizes gradually increasing dialysis doses in response to declines in residual kidney function, and it is the preferred renal replacement therapy for patients who have just transitioned to end-stage renal disease (ESRD). Incremental peritoneal dialysis (PD) may impose fewer restrictions on patients' lifestyle, help attenuate lifetime peritoneal and systemic exposure to glucose and its degradation products, and minimize connections that could compromise the sterile fluid path. In this study, we utilized a 3-pore kinetic model to assess fluid and solute removal during single daily icodextrin treatments for patients with varying glomerular filtration rates (GFR). METHODS: Single icodextrin exchanges of 8 to 16 hours using 2- and 2.5-L bag volumes were simulated for different patient transport types (i.e., high to low) to predict daily peritoneal ultrafiltration (UF), daily peritoneal sodium removal, and weekly total (peritoneal + residual kidney) Kt/V (Kt/VTotal) for patients with residual renal GFRs ranging from 0 to 15 mL/min/1.73 m2. RESULTS: Daily peritoneal UF varied from 359 to 607 mL, and daily peritoneal Na removal varied from 52 to 87 mEq depending on length of icodextrin exchange and bag volume. Both were effectively independent of patient transport type. All but very large patients (total body water [TBW] > 60 L) were predicted to achieve adequate dialysis (Kt/VTotal ≥ 1.7) with a GFR of 10 mL/min/1.73 m2, and small patients (TBW: 30 L) were predicted to achieve adequate dialysis with a GFR of 6 mL/min/1.73 m2. CONCLUSIONS: A single daily icodextrin exchange can be tailored to augment urea, UF, and Na removal in patients with sufficient residual kidney function (RKF). A solitary icodextrin exchange may therefore be reasonable initial therapy for some incident ESRD patients.

A Pseudo-One Compartment Model of Phosphorus Kinetics During Hemodialysis: Further Supporting Evidence.

A pseudo-one compartment model has been proposed to describe phosphorus kinetics during hemodialysis and the immediate post-dialysis period. This model assumes that phosphorus mobilization from tissues is proportional to the difference between the pre-dialysis serum concentration (a constant) and the instantaneous serum concentration. The current study is exploratory and evaluated the ability of a pseudo-one compartment model to describe the kinetics of phosphorus during two short hemodialysis treatments separated by a 60-min inter-treatment period without dialysis; the latter is the post-dialysis rebound period for the first short hemodialysis treatment. Serum was collected frequently during both hemodialysis treatments and the inter-treatment period to assess phosphorus kinetics in 21 chronic hemodialysis patients. Phosphorus mobilization clearance and pre-dialysis central distribution volume were previously estimated for each patient during the first hemodialysis treatment and the inter-treatment period. Assuming those kinetic parameters remained constant for each patient, serum phosphorus concentrations during the second treatment were used to estimate the driving force concentration (Cdf ) for phosphorus mobilization from tissues during the second treatment. Treatment time (117 ± 14 [mean ± standard deviation] vs. 117 ± 14 min), dialyzer phosphorus clearance (151 ± 25 vs. 140 ± 32 mL/min), and net fluid removal (1.44 ± 0.74 vs. 1.47 ± 0.76 L) were similar during both short hemodialysis treatments. Measured phosphorus concentration at the start of the second hemodialysis treatment (3.3 ± 0.9 mg/dL) was lower (P < 0.001) than at the start of the first treatment or Cpre (5.4 ± 1.9 mg/dL). Calculated Cdf was 4.9 ± 2.0 mg/dL, not significantly different from Cpre (P = 0.12). Cdf and Cpre were correlated (R = 0.72, P < 0.001). The results from this study demonstrate that the driving force concentration for phosphorus mobilization during hemodialysis is constant and not different from that pre-dialysis, providing further evidence supporting a fundamental assumption of the pseudo-one compartment model.

Prescriptions of dialysate potassium concentration during short daily or long nocturnal (high dose) hemodialysis.

The prescription of dialysate potassium concentration during short daily and long nocturnal (high dose) hemodialysis (HD) is challenging due to limited clinical experience with such modalities. The aim here is to propose a quantitative approach for prescribing dialysate potassium concentrations during high-dose HD. Potassium kinetic parameters based on a pseudo one-compartment model from 547 patients participating in the HEMO Study were used for prediction purposes in this study. Patients were categorized based on the prescribed dialysate potassium concentration during thrice weekly HD as 1K (mean of 1.02 mEq/L, N = 60), 2K (2.01 mEq/L, N = 437), or 3K (3.01 mEq/L, N = 50). Dialysate potassium concentrations were then predicted for each patient during short daily and long nocturnal HD based on a pseudo one-compartment model to maintain the identical weekly dialytic potassium removal and predialysis serum potassium concentration as during thrice weekly HD. Predicted prescribed dialysate potassium concentrations for short daily HD were 0.18-0.45 mEq/L higher than during thrice weekly HD but were approximately 4 (3.72-4.26) mEq/L for all patients during long nocturnal HD. The intradialytic decrease in serum potassium concentration was predicted to be reduced by more than one-half during short daily HD and by approximately three-quarters during long nocturnal HD of that during thrice weekly HD. Prescribed dialysate potassium concentration during high-dose HD modalities can be quantitatively predicted using a pseudo one-compartment kinetic model. High-dose HD modalities may improve clinical outcomes by reducing intradialytic decreases in serum potassium.

Potassium kinetics during hemodialysis.

Hyperkalemia in hemodialysis patients is associated with high mortality, but prescription of low dialysate potassium concentrations to decrease serum potassium levels is associated with a high incidence of sudden cardiac arrest or sudden death. Improved clinical outcomes for these patients may be possible if rapid and substantial intradialysis decreases in serum potassium concentration can be avoided while maintaining adequate potassium removal. Data from kinetic modeling sessions during the HEMO Study of the dependence of serum potassium concentration on time during hemodialysis treatments and 30 minutes postdialysis were evaluated using a pseudo one-compartment model. Kinetic estimates of potassium mobilization clearance (K(M)) and predialysis central distribution volume (V(pre)) were determined in 551 hemodialysis patients. The studied patients were 58.8 ± 14.4 years of age with predialysis body weight of 72.1 ± 15.1 kg; 306 (55.4%) of the patients were female and 337 (61.2%) were black. K(M) and V(pre) for all patients were non-normally distributed with values of 158 (111, 235) (median [interquartile range]) mL/min and 15.6 (11.4, 22.8) L, respectively. K(M) was independent of dialysate potassium concentration (P > 0.2), but V(pre) was lower at higher dialysate potassium concentration (R = -0.188, P < 0.001). For patients with dialysate potassium concentration between 1.6 and 2.5 mEq/L (N = 437), multiple linear regression of K(M) and V(pre) demonstrated positive association with predialysis body weight and negative association with predialysis serum potassium concentration. Potassium kinetics during hemodialysis can be described using a pseudo one-compartment model.

Simplified phosphorus kinetic modeling: predicting changes in predialysis serum phosphorus concentration after altering the hemodialysis prescription.

BACKGROUND: The KDIGO work group recommends increasing dialytic phosphorus removal in Stage 5D chronic kidney disease patients with persistent hyperphosphatemia; however, optimal prescriptions to enhance phosphorus removal by hemodialysis (HD) therapies have not yet been established. This study evaluated whether phosphorus kinetic modeling based on a pseudo one-compartment model could provide practical clinical guidance for predicting changes in predialysis serum phosphorus concentration after altering the HD prescription. METHODS: Patient-specific phosphorus kinetic parameters determined from thrice weekly HD treatments on 774 patients in the HEMO Study were used to predict changes in predialysis serum phosphorus concentration after altering the HD prescription from thrice weekly to short daily and long nocturnal HD therapies. The effect of changes in the oral phosphorus binder prescription on predicted changes in the predialysis serum phosphorus concentration was also illustrated using the concept of equivalent phosphorus binder dose. RESULTS: Decreases in predialysis serum phosphorus concentration from thrice weekly HD to short daily and long nocturnal HD prescriptions demonstrated strong associations with the predialysis serum phosphorus concentration during thrice weekly HD that were relatively independent of patient-specific phosphorus kinetic parameters. Thus, the percent decrease in predialysis serum phosphorus concentration was approximately the same among patients for a given alteration in the HD prescription. Both increased weekly treatment time and frequency resulted in a reduction in the predialysis serum phosphorus concentration; however, the effect of treatment time was more influential. Simultaneous reduction in the effective phosphorus binder dose blunted the decrease in the predialysis serum phosphorus concentration. CONCLUSIONS: This study demonstrated that a simplified form of phosphorus kinetic modeling based on a pseudo one-compartment model can provide practical clinical guidance for predicting changes in predialysis serum phosphorus concentration after altering the HD prescription. Prospective validation of this approach in future studies is warranted.

Determinants of phosphorus mobilization during hemodialysis.

Our recent work proposed a pseudo one-compartment model for describing intradialysis and postdialysis rebound kinetics of phosphorus. In this model, phosphorus is removed directly from a central distribution volume with the rate of phosphorus mobilization from a second, very large compartment proportional to the phosphorus mobilization clearance. Here, we evaluated factors of phosphorus mobilization clearance and postdialysis central distribution volume from 774 patients in the HEMO Study. Phosphorus mobilization clearance and postdialysis central distribution volume were 87 (65, 116) ml/min, median (interquartile range), and 9.4 (7.2, 12.0) liter, respectively. The phosphorus mobilization clearance was significantly higher for male patients than for female patients. Both the phosphorus mobilization clearance and the postdialysis central distribution volume were significantly associated with postdialysis body weight but negatively with the predialysis serum phosphorus concentration. The postdialysis central distribution volume was also significantly associated with age. Overall, the postdialysis central distribution volume was 13.6% of the postdialysis body weight. Thus, the phosphorus mobilization clearance during hemodialysis is higher when predialysis serum phosphorus concentration is low and higher in male patients than in female patients. The central distribution volume of phosphorus is a space approximating the extracellular fluid volume.

Phosphorus kinetics during hemodiafiltration: analysis using a pseudo-one-compartment model.

BACKGROUND/AIMS: On-line hemodiafiltration (HDF) has been previously shown to result in modest reductions in predialysis serum phosphorus concentration compared with conventional hemodialysis (HD); however, understanding of phosphorus kinetics during these therapies remains limited. METHODS: Previously published phosphorus kinetic data during HDF and HD were analyzed using a pseudo-one-compartment kinetic model. Phosphorus mobilization clearance (KM) and dialyzer phosphorus clearance (Kd) were simultaneously estimated from measured predialysis and postdialysis serum phosphorus concentrations and total removed phosphorus during each treatment. RESULTS: KM varied among patients between 53 and 173 ml/min. Values of KM during HDF (105 ± 34, mean ± standard deviation, ml/min) and HD (112 ± 44 ml/min) were not different (p = 0.5); however, Kd during HDF (175 ± 23 ml/min) was higher (p = 0.01) than during HD (160 ± 14 ml/min). CONCLUSION: A pseudo-one-compartment kinetic model is useful for the analysis of phosphorus kinetic data during HDF. Lower predialysis serum phosphorus concentrations during HDF are likely due to increased extracorporeal phosphorus clearance.

Physiologic volume of phosphorus during hemodialysis: predictions from a pseudo one-compartment model.

The kinetics of plasma phosphorus concentrations during hemodialysis (HD) are complex and cannot be described by conventional one- or two-compartment kinetic models. It has recently been shown by others that the physiologic (or apparent distribution) volume for phosphorus (Vr-P) increases with increasing treatment time and shows a large variation among patients treated by thrice weekly and daily HD. Here, we describe the dependence of Vr-P on treatment time and predialysis plasma phosphorus concentration as predicted by a novel pseudo one-compartment model. The kinetics of plasma phosphorus during conventional and six times per week daily HD were simulated as a function of treatment time per session for various dialyzer phosphate clearances and patient-specific phosphorus mobilization clearances (K(M)). Vr-P normalized to extracellular volume from these simulations were reported and compared with previously published empirical findings. Simulated results were relatively independent of dialyzer phosphate clearance and treatment frequency. In contrast, Vr-P was strongly dependent on treatment time per session; the increase in Vr-P with treatment time was larger for higher values of K(M). Vr-P was inversely dependent on predialysis plasma phosphorus concentration. There was significant variation among predicted Vr-P values, depending largely on the value of K(M). We conclude that a pseudo one-compartment model can describe the empirical dependence of the physiologic volume of phosphorus on treatment time and predialysis plasma phosphorus concentration. Further, the variation in physiologic volume of phosphorus among HD patients is largely due to differences in patient-specific phosphorus mobilization clearance.

Steady state phosphorus mass balance model during hemodialysis based on a pseudo one-compartment kinetic model.

PURPOSE: Mathematical models of phosphorus kinetics and mass balance during hemodialysis are in early development. We describe a theoretical phosphorus steady state mass balance model during hemodialysis based on a novel pseudo one-compartment kinetic model. METHODS: The steady state mass balance model accounted for net intestinal absorption of phosphorus and phosphorus removal by both dialysis and residual kidney function. Analytical mathematical solutions were derived to describe time-dependent intradialytic and interdialytic serum phosphorus concentrations assuming hemodialysis treatments were performed symmetrically throughout a week. RESULTS: Results from the steady state phosphorus mass balance model are described for thrice weekly hemodialysis treatment prescriptions only. The analysis predicts 1) a minimal impact of dialyzer phosphorus clearance on predialysis serum phosphorus concentration using modern, conventional hemodialysis technology, 2) variability in the postdialysis-to-predialysis phosphorus concentration ratio due to differences in patient-specific phosphorus mobilization, and 3) the importance of treatment time in determining the predialysis serum phosphorus concentration. CONCLUSIONS: We conclude that a steady state phosphorus mass balance model can be developed based on a pseudo one-compartment kinetic model and that predictions from this model are consistent with previous clinical observations. The predictions from this mass balance model are theoretical and hypothesis-generating only; additional prospective clinical studies will be required for model confirmation.

Patient-specific phosphorus mobilization clearance during nocturnal and short daily hemodialysis.

The kinetics of plasma phosphorus during different hemodialysis (HD) modalities are incompletely understood. We recently demonstrated that a pseudo one-compartment kinetic model including phosphorus mobilization from various body compartments into extracellular fluids can describe intradialytic and postdialytic rebound kinetics of plasma phosphorus during conventional and short 2-hour HD treatments. In this model, individual patient differences in phosphorus kinetics were characterized by a single parameter, the phosphorus mobilization clearance (K(M)). In this report we determined K(M) in patients treated by in-center nocturnal HD (ICNHD) and short daily HD (SDHD) with low dialyzer phosphate clearance. In the ICNHD study, eight patients underwent 8-hour HD treatments where intradialytic and postdialytic plasma samples were collected; K(M) values were determined by nonlinear regression of plasma concentration as a function of time. In the SDHD study, five patients were studied during 28 treatments for approximately 3 hours. Here, K(M) was calculated using only predialytic and postdialytic plasma phosphorus concentrations. Dialyzer phosphate clearances were 134 ± 20 (mean ± SD) and 95 ± 16 mL/min during ICNHD and SDHD, respectively. K(M) values for the respective therapies were 124 ± 83 and 103 ± 33 mL/min, comparable to those determined previously during conventional and short HD treatments of 98 ± 44 mL/min. When results from ICNHD, SDHD, and previous HD modalities were combined, K(M) was directly correlated with postdialytic body weight (r = 0.38, P = 0.025) and inversely correlated with predialytic phosphorus concentration (r = -0.47, P = 0.005). These findings suggest that phosphorus kinetics during various HD modalities can be described by a pseudo one-compartment model.

A simple method to estimate phosphorus mobilization in hemodialysis using only predialytic and postdialytic blood samples.

We have recently developed a pseudo one-compartment model to describe intradialytic and postdialytic rebound kinetics of plasma phosphorus. In this model, individual patient differences in phosphorus kinetics were characterized by a single parameter; the phosphorus mobilization clearance (K(M) ). In this work, we propose a simple method to estimate K(M) from predialytic and postdialytic plasma phosphorus concentrations. Clinical data were collected from 22 chronic hemodialysis patients that underwent a 4-hour treatment session. A simple algebraic equation was derived from the pseudo one-compartment model to determine K(M) from predialytic and postdialytic plasma phosphorus concentrations. K(M) values computed using this equation were compared with values obtained from nonlinear regression of the full kinetic model to frequent intradialytic and postdialytic measurements of plasma phosphorus concentrations. There was good agreement between K(M) values (concordance correlation coefficient of 0.94) obtained from the simple method (105 ± 52 mL/min, mean ± SD) and from the full model (99 ± 47 mL/min). The 95% confidence interval for the difference between estimated K(M) values was -26 to 36 mL/min. The proposed simple method requires the use of only predialytic and postdialytic blood samples to estimate patient specific K(M) ; this approach may allow easy clinical evaluation of phosphorus kinetics in hemodialysis patients.

Kinetic model of phosphorus mobilization during and after short and conventional hemodialysis.

BACKGROUND AND OBJECTIVES: The kinetics of plasma phosphorus (inorganic phosphorus or phosphate) during hemodialysis treatments cannot be explained by conventional one- or two-compartment models; previous approaches have been limited by assuming that the distribution of phosphorus is confined to classical intracellular and extracellular fluid compartments. In this study a novel pseudo one-compartment model, including phosphorus mobilization from a large second compartment, was proposed and evaluated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Clinical data were obtained during a crossover study where 22 chronic hemodialysis patients underwent both short (2-hour) and conventional (4-hour) hemodialysis sessions. The model estimated two patient-specific parameters, phosphorus mobilization clearance and phosphorus central distribution volume, by fitting frequent intradialytic and postdialytic plasma phosphorus concentrations using nonlinear regression. RESULTS: Phosphorus mobilization clearances varied among patients (45 to 208 ml/min), but estimates during short (98 ± 44 ml/min, mean ± SD) and conventional (99 ± 47 ml/min) sessions were not different (P = 0.74) and correlated with each other (concordance correlation coefficient ρ(c) of 0.85). Phosphorus central distribution volumes for each patient (short: 11.0 ± 4.2 L and conventional: 11.9 ± 3.8 L) were also correlated (ρ(c) of 0.45). CONCLUSIONS: The reproducibility of patient-specific parameters during short and conventional hemodialysis treatments suggests that a pseudo one-compartment model is robust and can describe plasma phosphorus kinetics under conditions of clinical interest.