Optimization of bimodal automated peritoneal dialysis prescription using the three-pore model

Background: Previous studies suggested that automated peritoneal dialysis (APD) could be improved in terms of shorter treatment times and lower glucose absorption using bimodal treatment regimens, having ‘ultrafiltration (UF) cycles’ using a high glucose concentration and ‘clearance cycles’ using low or no glucose. The purpose of this study is to explore such regimes further using mathematical optimization techniques based on the three-pore model. Methods: A linear model with constraints is applied to find the shortest possible treatment time given a set of clinical treatment goals. For bimodal regimes, an exact analytical solution often exists which is herein used to construct optimal regimes giving the same Kt/V urea and/or weekly creatinine clearance and UF as a 6 × 2 L 1.36% glucose regime and an ‘adapted’ (2 × 1.5 L 1.36% + 3 × 3 L 1.36%) regime. Results: Compared to the non-optimized (standard and adapted regimes), the optimized regimens demonstrated marked reductions (>40%) in glucose absorption while having an identical weekly creatinine clearance (35 L) and UF (0.5 L). Larger fill volumes of 1200 mL/m2 (UF cycles) and 1400 mL/m2 (clearance cycles) can be used to shorten the total treatment time. Conclusion: These theoretical results imply substantial improvements in glucose absorption using optimized APD regimens while achieving similar water and solute removal as non-optimized APD regimens. While the current results are based on a well-established theoretical model for peritoneal dialysis, experimental and clinical studies need to be performed to validate the current findings

High versus low ultrafiltration rates during experimental peritoneal dialysis in rats : Acute effects on plasma volume and systemic haemodynamics

Introduction: Intradialytic hypotension is a common complication of haemodialysis, but uncommon in peritoneal dialysis (PD). This may be due to lower ultrafiltration rates in PD compared to haemodialysis, allowing for sufficient refilling of the blood plasma compartment from the interstitial volume, but the underlying mechanisms are unknown. Here we assessed plasma volume and hemodynamic alterations during experimental PD with high versus low ultrafiltration rates. Methods: Experiments were conducted in two groups of healthy Sprague-Dawley rats: one group with a high ultrafiltration rate (N = 7) induced by 8.5% glucose and a low UF group (N = 6; 1.5% glucose), with an initial assessment of the extracellular fluid volume, followed by 30 min PD with plasma volume measurements at baseline, 5, 10, 15 and 30 min. Mean arterial pressure, central venous pressure and heart rate were continuously monitored during the experiment. Results: No significant changes over time in plasma volume, mean arterial pressure or central venous pressure were detected during the course of the experiments, despite an ultrafiltration (UF) rate of 56 mL/h/kg in the high UF group. In the high UF group, a decrease in extracellular fluid volume of −7 mL (−10.7% (95% confidence interval: −13.8% to −7.6%)) was observed, in line with the average UF volume of 8.0 mL (standard deviation: 0.5 mL). Conclusion: Despite high UF rates, we found that plasma volumes were remarkably preserved in the present experiments, indicating effective refilling of the plasma compartment from interstitial tissues. Further studies should clarify which mechanisms preserve the plasma volume during high UF rates in PD

Optimizing Automated Peritoneal Dialysis Using an Extended 3-Pore Model

Introduction In the current study, an extended 3-pore model (TPM) is presented and applied to the problem of optimizing automated peritoneal dialysis (APD) with regard to osmotic water transport (UF), small/middle-molecule clearance, and glucose absorption. Methods Simulations were performed for either intermittent APD (IPD) or tidal APD (TPD). IPD was simulated for fill and drain volumes of 2 L, whereas TPD was simulated using a tidal volume of 0.5 L, 1 L, or 1.5 L with full drains and subsequent fills (2 L) occurring after every fifth dwell. A total of 25 cycles for a large number of different dialysate flow rates (DFR) were simulated using 3 different glucose concentrations (1.36%, 2.27%, and 3.86%) and 3 different peritoneal transport types: slow (peritoneal equilibrium test D/Pcrea 0.8), and average. Solute clearance and UF were simulated to occur during the entire dwell, including both fill and drain periods. Results It is demonstrated that DFRs exceeding ∼ 3 L/h are of little benefit both for UF and small-solute transport, whereas middle-molecule clearance is enhanced at higher DFRs. The simulations predict that large reductions (> 20%) in glucose absorption are possible by using moderately higher DFRs than a standard 6 × 2 L prescription and by using shorter optimized “bi-modal” APD regimens that alternate between a glucose-free solution and a glucose-containing solution. Discussion Reductions in glucose absorption appear to be significant with the proposed regimens for APD; however, further research is needed to assess the feasibility and safety of these regimens

Computer Simulations of Continuous Flow Peritoneal Dialysis Using the 3-Pore Model-A First Experience

Background:Continuous flow peritoneal dialysis (CFPD) is performed using a continuous flux of dialysis fluid via double or dual-lumen PD catheters, allowing a higher dialysate flow rate (DFR) than conventional treatments. While small clinical studies have revealed greatly improved clearances using CFPD, the inability to predict ultrafiltration (UF) may confer a risk of potentially harmful overfill. Here we performed physiological studies of CFPD in silico using the extended 3-pore model.Method:A 9-h CFPD session was simulated for: slow (dialysate to plasma creatinine [D/P crea] 0.8) and average (0.6 ≤ D/P crea ≤ 0.8) transporters using 1.36%, 2.27%, or 3.86% glucose solutions. To avoid overfill, we applied a practical equation, based on the principle of mass-balance, to predict the UF rate during CFPD treatment.Results:Increasing DFR > 100 mL/min evoked substantial increments in small- and middle-molecule clearances, being 2 - 5 times higher compared with a 4-h continuous ambulatory PD (CAPD) exchange, with improvements typically being smaller for average and slow transporters. Improved UF rates, exceeding 10 mL/min, were achieved for all transport types. The β2-microglobulin clearance was strongly dependent on the UF rate and increased between 60% and 130% as a function of DFR. Lastly, we tested novel intermittent-continuous regimes as an alternative strategy to prevent overfill, being effective for 1.36% and 2.27%, but not for 3.86% glucose.Conclusion:While we find substantial increments in solute and water clearance with CFPD, previous studies have shown similar improvements using high-volume tidal automated PD (APD). Lastly, the current in silico results need confirmation by studies in vivo

Albumin Turnover in Peritoneal and Hemodialysis

The turnover of albumin is increased in both peritoneal dialysis (PD) and hemodialysis (HD) due to increased external losses, normally leading to compensatory increases in the hepatic albumin synthesis. The normal rate of albumin synthesis is on the order of 12 g/day corresponding to an equally large albumin fractional catabolic rate of ~4% daily. Most albumin catabolism is assumed to occur in the endothelium, but there is also renal and hepatic catabolism and leakage into the gastrointestinal tract. In PD the daily losses are on the order of 5 g/day. There are also external albumin losses in HD, particularly when high-performance membranes are used, the losses per session ranging between 1 and 8 g (or more). The dialytic albumin losses cannot be detected by assessing the transcapillary escape rate of albumin from the plasma compartment to the interstitium. In PD, tracer albumin that has been injected into the peritoneal fluid is absorbed to the tissues surrounding the peritoneal cavity without much edema formation, due to the process of "volume recirculation". A small fraction of the dialysate albumin tracer (0.2-0.3 ml/minute) is directly reabsorbed to the plasma via the lymphatics. A significant portion of dialysis patients are affected by chronic inflammation, such as in the malnutrition inflammation and atherosclerosis syndrome, which is also associated with cardiovascular mortality and fluid overload. These patients usually have a reduced ability to compensate for external losses of albumin, which may result in hypoalbuminemia. Reduced plasma albumin levels in dialysis patients may thus be regarded as a sign of chronic inflammation rather than reflecting malnutrition

Phloretin Improves Ultrafiltration and Reduces Glucose Absorption during Peritoneal Dialysis in Rats

Background: Harmful glucose exposure and absorption remain major limitations of peritoneal dialysis. We previously showed that inhibition of sodium glucose cotransporter 2 did not affect glucose transport during peritoneal dialysis in rats. However, more recently we found that phlorizin, a dual blocker of sodium glucose co-transporter 1 and 2, reduces glucose diffusion in peritoneal dialysis. Therefore, either inhibiting sodium glucose co-transporter 1 or blocking facilitative glucose channels by phlorizin metabolite phloretin would reduce glucose transport in peritoneal dialysis. Methods: We tested a selective blocker of sodium glucose co-transporter 1, mizagliflozin, as well as phloretin, a non-selective blocker of facilitative glucose channels, in an anesthetized Sprague-Dawley rat model of peritoneal dialysis. Results: Intraperitoneal phloretin treatment reduced glucose absorption by more than 30% and resulted in a more than 50% higher ultrafiltration rate compared to control animals. Sodium removal and sodium clearances were similarly improved, whereas the amount of ultrafiltration per mmol sodium removed did not differ. Mizagliflozin did not influence glucose transport or osmotic water transport. Conclusions: Taken together, our present and previous results indicate that blockers of facilitative glucose channels may be a promising target for reducing glucose absorption and improving ultrafiltration efficiency in peritoneal dialysis

Sustained, delayed, and small increments in glomerular permeability to macromolecules during systemic ET-1 infusion mediated via the ETa receptor

Dolinina J, Rippe A, Öberg CM. Sustained, delayed, and small increments in glomerular permeability to macromolecules during systemic ET-1 infusion mediated via the ETA receptor. Am J Physiol Renal Physiol 316: F1173–F1179, 2019. First published March 13, 2019; doi:10.1152/ajprenal.00040.2019.—Emerging evidence indicates that endogenous production of endothelin (ET)-1, a 21-amino acid peptide vasoconstrictor, plays an important role in proteinuric kidney disease. Previous studies in rats have shown that chronic administration of ET-1 leads to increased glomerular albumin leakage. The underlying mechanisms are, however, currently not known. Here, we used size-exclusion chromatography to measure glomerular sieving coefficients for neutral FITC-Ficoll (molecular Stokes-Einstein radius: 15–80 Å, molecular weight: 70 kDa/400 kDa) in anesthetized male Sprague-Dawley rats (n = 12) at baseline and at 5, 15, 30, and 60 min after intravenous administration of ET-1. In separate experiments, ET-1 was given together with the selective ET type A (ETA) or ET type B (ETB) receptor antagonists JKC-301 and BQ-788, respectively. At both 15 and 30 min postadministration, the glomerular sieving coefficient for macromolecular Ficoll (70 Å) was significantly increased to 4.4 x 10-5 0.7 x 10-5 (P = 0.024) and 4.5 x 10-5 0.8 x 10-5 (P = 0.007), respectively, compared with baseline (2.2 x 10-5 0.4 x10-5). Decreased urine production after ET-1 prevented the use of higher doses of ET-1. Data analysis using the two-pore model indicated changes in large-pore permeability after ET-1, with no changes in the small-pore pathway. Administration of ETA blocker abrogated the permeability changes induced by ET-1 at 30 min, whereas blockade of ETB receptors was ineffective. Mean arterial pressure was only significantly increased at 60 min, being 123 4 mmHg compared with 111 2 mmHg at baseline (P = 0.02). We conclude that ET-1 evoked small, delayed, and sustained increases in glomerular permeability, mediated via the ETA receptor

Dual SGLT1/SGLT2 inhibitor phlorizin reduces glucose transport in experimental peritoneal dialysis

Introduction: Glucose absorption during peritoneal dialysis (PD) is commonly assumed to occur via paracellular pathways. We recently showed that SGLT2 inhibition did not reduce glucose absorption in experimental PD, but the potential role of glucose transport into cells is still unclear. Here we sought to elucidate the effects of phlorizin, a non-selective competitive inhibitor of sodium glucose co-transporters 1 and 2 (SGLT1 and SGLT2), in an experimental rat model of PD. Methods: A 120-min PD dwell was performed in 12 anesthetised Sprague-Dawley rats using 1.5% glucose fluid with a fill volume of 20 mL with (n = 6) or without (n = 6) intraperitoneal phlorizin (50 mg/L). Several parameters for peritoneal water and solute transport were monitored during the treatment. Results: Phlorizin markedly increased the urinary excretion of glucose, lowered plasma glucose and increased plasma creatinine after PD. Median glucose diffusion capacity at 60 min was significantly lower (p < 0.05) being 196 µL/min (IQR 178–213) for phlorizin-treated animals compared to 238 µL/min (IQR 233–268) in controls. Median fractional dialysate glucose concentration at 60 min (D/D0) was significantly higher (p < 0.05) in phlorizin-treated animals being 0.65 (IQR 0.63–0.67) compared to 0.61 (IQR 0.60–0.62) in controls. At 120 min, there was no difference in solute or water transport across the peritoneal membrane. Conclusion: Our findings indicate that a part of glucose absorption during the initial part of the dwell occurs via transport into peritoneal cells