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Local and systemic side-effects of glucose remain major limitations of peritoneal dialysis (PD). Glucose transport during PD is thought to occur via inter-endothelial pathways, but recent data indicated that some glucose is transferred via facilitative glucose channels. Here we used BAY-876, a potent and highly selective blocker of facilitative glucose channel 1 (GLUT1), in an experimental rat model of PD using either 1.5% or 2.3% glucose fluid in a 1-h dwell. We also sought to elucidate whether diffusion of radiolabeled [18F]-deoxyglucose in the opposite direction (plasma → dialysate) is also lowered by selective/non-selective GLUT inhibition. Results show that selective GLUT1 inhibition markedly improved UF and enhanced the sodium dip, but no alterations in glucose transport or [18F]-deoxyglucose diffusion could be detected. Non-selective GLUT-inhibition using phloretin showed similar improvements on water and sodium transport, but also markedly decreased diffusion capacity for [18F]-deoxyglucose. We conclude that selective GLUT1 inhibition improved the UF efficiency in terms of mL of water removed per gram glucose absorbed by almost 70% for 1.5% glucose, implicating a role for GLUT1 in glucose mediated osmotic water transport in PD. Selective inhibitors of facilitative glucose transporter 1 may be promising agents to improve UF efficacy in patients treated with PD.Translational StatementPeritoneal dialysis (PD) is limited by systemic and local glucose toxicity. Here we used a highly selective inhibitor of facilitative glucose channel 1 (GLUT1) in a rat model of PD, and show marked, direct improvements in osmotic water removal (UF) per gram glucose absorbed. Inhibitors of GLUT1 may provide marked improvements in UF in patients on PD.

Background: The continuous global rise of end-stage kidney disease creates a growing demand of economically beneficial home-based kidney replacement therapies such as peritoneal dialysis (PD). However, undesirable absorption and exposure of peritoneal tissues to glucose remain major limitations of PD. Methods: We compared a reference (standard) automated PD regimen 6 × 2 L 1.36% glucose (76 mmol/L) over 9 h with a novel, theoretically glucose sparing (optimised) prescription consisting of ‘ultrafiltration cycles’ with high glucose strength (126 mmol/L) and ‘clearance cycles’ with ultra-low, physiological glucose (5 mmol/L) for approximately 40% of the treatment time. Twenty-one prevalent PD patients underwent the optimised regimen (7 × 2 L 2.27% glucose + 5 × 2 L 0.1% glucose over 8 h) and the standard regimen in a crossover fashion. Six patients were excluded from data analysis. Results: Median glucose absorption was 43 g (IQR 41–54) and 44 g (40–55) for the standard and optimised intervention, respectively ( p = 1). Ultrafiltration volume, weekly Kt/V creatinine and urea were significantly improved during optimised interventions, while no difference in sodium removal was detected. Post hoc analysis showed significantly improved ultrafiltration efficiency (ml ultrafiltration per gram absorbed glucose) during optimised regimens. No adverse events were observed except one incidence of drain pain. Conclusion: Optimised treatments were feasible and well tolerated in this small pilot study. Despite no difference in absorbed glucose, results indicate possible improvements of ultrafiltration efficiency and small solute clearances by optimised regimens. Use of optimised prescriptions as glucose sparing strategy should be evaluated in larger study populations.

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.

Lay summary Peritoneal dialysis (PD) uses the peritoneal membrane for dialysis. The peritoneal membrane is a thin layer of tissue that lines the abdomen. The lining is used as a filter to help remove extra fluid and poisonous waste from the blood. Everybody is unique. What is normal for one person’s membrane may be very different from another person’s. The kidney care team wants to provide each person with the best dialysis prescription for them and to do this they must evaluate the person’s peritoneal lining. Sometimes dialysis treatment itself can cause the membrane to change after some years. This means more assessments (evaluations) will be needed to determine whether the person’s peritoneal membrane has changed. Changes in the membrane may require changes to the dialysis prescription. This is needed to achieve the best dialysis outcomes. A key tool for these assessments is the peritoneal equilibration test (PET). It is a simple, standardized and reproducible tool. This tool is used to measure the peritoneal function soon after the start of dialysis. The goal is to understand how well the peritoneal membrane works at the start of dialysis. Later on in treatment, the PET helps to monitor changes in peritoneal function. If there are changes between assessments causing problems, the PET data may explain the cause of the dysfunction. This may be used to change the dialysis prescription to achieve the best outcomes. The most common problem with the peritoneal membrane occurs when fluid is not removed as well as it should be. This happens when toxins (poisons) in the blood cross the membrane more quickly than they should. This is referred to as a fast peritoneal solute transfer rate (PSTR). Since more efficient fluid removal is associated with better outcomes, developing a personal PD prescription based on the person’s PSTR is critically important. A less common problem happens when the membrane fails to work properly (also called membrane dysfunction) because the peritoneal membrane is less efficient, either at the start of treatment or developing after some years. If membrane dysfunction gets worse over time, then this is associated with progressive damage, scarring and thickening of the membrane. This problem can be identified through another change of the PET. It is called reduced ‘sodium dip’. Membrane dysfunction of this type is more difficult to treat and has many implications for the individual. If the damage is major, the person may need to stop PD. They would need to begin haemodialysis treatment (also spelled hemodialysis). This is a very important and emotional decision for individuals with kidney failure. Any decision that involves stopping PD therapy or transitioning to haemodialysis therapy should be made jointly between the clinical team, the person on dialysis and a caregiver, if requested. Although evidence is lacking about how often tests should be performed to determine peritoneal function, it seems reasonable to repeat them whenever there is difficulty in removing the amount of fluid necessary for maintaining the health and well-being of the individual. Whether routine evaluation of membrane function is associated with better outcomes has not been studied. Further research is needed to answer this important question as national policies in many parts of the world and the COVID-19 has placed a greater emphasis and new incentives encouraging the greater adoption of home dialysis therapies, especially PD. For Chinese and Spanish Translation of the Lay Summary, see Online Supplement Appendix 1. Key recommendations Guideline 1: A pathophysiological taxonomy: A pathophysiological classification of membrane dysfunction, which provides mechanistic links to functional characteristics, should be used when prescribing individualized dialysis or when planning modality transfer (e.g. to automated peritoneal dialysis (PD) or haemodialysis) in the context of shared and informed decision-making with the person on PD, taking individual circumstances and treatment goals into account. (practice point) Guideline 2a: Identification of fast peritoneal solute transfer rate (PSTR): It is recommended that the PSTR is determined from a 4-h peritoneal equilibration test (PET), using either 2.5%/2.27% or 4.25%/3.86% dextrose/glucose concentration and creatinine as the index solute. (practice point) This should be done early in the course dialysis treatment (between 6 weeks and 12 weeks) (GRADE 1A) and subsequently when clinically indicated. (practice point) Guideline 2b: Clinical implications and mitigation of fast solute transfer: A faster PSTR is associated with lower survival on PD. (GRADE 1A) This risk is in part due to the lower ultrafiltration (UF) and increased net fluid reabsorption that occurs when the PSTR is above the average value. The resulting lower net UF can be avoided by shortening glucose-based exchanges, using a polyglucose solution (icodextrin), and/or prescribing higher glucose concentrations. (GRADE 1A) Compared to glucose, use of icodextrin can translate into improved fluid status and fewer episodes of fluid overload. (GRADE 1A) Use of automated PD and icodextrin may mitigate the mortality risk associated with fast PSTR. (practice point) Guideline 3: Recognizing low UF capacity: This is easy to measure and a valuable screening test. Insufficient UF should be suspected when either (a) the net UF from a 4-h PET is Guideline 4a: Diagnosing intrinsic membrane dysfunction (manifesting as low osmotic conductance to glucose) as a cause of UF insufficiency: When insufficient UF is suspected, the 4-h PET should be supplemented by measurement of the sodium dip at 1 h using a 3.86% glucose/4.25% dextrose exchange for diagnostic purposes. A sodium dip ≤5 mmol/L and/or a sodium sieving ratio ≤0.03 at 1 h indicates UF insufficiency. (GRADE 2B) Guideline 4b: Clinical implications of intrinsic membrane dysfunction (de novo or acquired): in the absence of residual kidney function, this is likely to necessitate the use of hypertonic glucose exchanges and possible transfer to haemodialysis. Acquired membrane injury, especially in the context of prolonged time on treatment, should prompt discussions about the risk of encapsulating peritoneal sclerosis. (practice point) Guideline 5: Additional membrane function tests: measures of peritoneal protein loss, intraperitoneal pressure and more complex tests that estimate osmotic conductance and ‘lymphatic’ reabsorption are not recommended for routine clinical practice but remain valuable research methods. (practice point) Guideline 6: Socioeconomic considerations: When resource constraints prevent the use of routine tests, consideration of membrane function should still be part of the clinical management and may be inferred from the daily UF in response to the prescription. (practice point)

Background It has been estimated that automated peritoneal dialysis (APD) is currently the fastest growing renal replacement therapy in the world. However, in light of the growing number of diabetic patients on peritoneal dialysis (PD), the unwanted glucose absorption during APD remains problematic. Recent results, using an extended 3-pore model of APD, indicated that large reductions in glucose absorption are possible by using optimized bi-modal treatment regimens, having “UF cycles” using a higher glucose concentration, and “Clearance cycles” using a low concentration or, preferentially, no glucose. The present study is designed to test the theoretical prediction of a lower glucose absorption using these novel regimes. Methods This study is a randomized single-center, open-label, prospective study. Prevalent PD patients between 18 and 75 years old without known catheter problems or recent peritonitis are eligible for inclusion. Patients are allocated to a first treatment session of either standard APD (6 × 2 L 1.36% over 9 h) or optimized APD (7 × 2 L 2.27% + 5 × 2 L 0.1% over 8 h). A second treatment session using the other treatment will be performed in a crossover fashion. Samples of the dialysis fluid will be taken before and after the treatment, and the volume of the dialysate before and after the treatment will be carefully assessed. The primary endpoint is difference in glucose absorption between the optimized and standard treatment. Secondary endpoints are ultrafiltration, sodium removal, Kt/V urea, and Kt/V Creatinine. The study will be closed when a total of 20 patients have successfully completed the interventions or terminated according to interim analysis. A Monte Carlo power analysis shows that the study has 80% power to detect a difference of 10 g (in line with that of theoretical results) in glucose absorption between the two treatments in 10 patients. Discussion The present study is the first clinical investigation of optimized bi-modal treatments proposed by recent theoretical studies. Trial registration ClinicalTrials.gov identifier: NCT04017572. Registration date: July 12, 2019, retrospectively registered.

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/ D 0) 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.

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.

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease and renal replacement therapy worldwide. A pathophysiological hallmark of DKD is glomeru- lar basal membrane (GBM) thickening, whereas this feature is absent in minimal change disease (MCD). According to fundamental transport physiological principles, a thicker GBM will impede the diffusion of middle-molecules such as cystatin C, potentially leading to a lower estimated GFR (eGFR) from cystatin C compared to that of creatinine. Here we test the hypothesis that thickening of the glomerular filter leads to an increased diffusion length, and lower clearance, of cystatin C. Twenty- nine patients with a kidney biopsy diagnosis of either DKD (n = 17) or MCD (n = 12) were retrospectively included in the study. GBM thickness was measured at 20 sepa- rate locations in the biopsy specimen and plasma levels of cystatin C and creatinine were retrieved from health records. A modified two-pore model was used to simulate the effects of a thicker GBM on glomerular water and solute transport. The mean age of the patients was 52 years, and 38% were women. The mean eGFRcystatin C/ eGFRcreatinine-ratio was 74% in DKD compared to 98% in MCD (p < 0.001). Average GBM thickness was strongly inversely correlated to the eGFRcystatin C/eGFRcreatinine- ratio (Pearson's r = −0.61, p < 0.01). Two-pore modeling predicted a eGFRcystatin C/ eGFRcreatinine-ratio of 78% in DKD. We provide clinical and theoretical evidence sug- gesting that thickening of the glomerular filter, increasing the diffusion length of cys- tatin C, lowers the eGFRcystatin C/eGFRcreatinine-ratio in DKD. (Less)

Background Optimal infusion rate of colloids in patients with suspected hypovolemia is unknown, and the primary objective of the present study was to test if plasma volume expansion by 5% albumin is greater if fluid is administered slowly rather than rapidly. Methods Patients with signs of hypoperfusion after major abdominal surgery were randomized to intravenous infusion of 5% albumin at a dose of 10 ml/kg (ideal body weight) either rapidly (30 min) or slowly (180 min). Plasma volume was measured using radiolabeled albumin at baseline, at 30 min, and at 180 min after the start of infusion. Primary outcome was change in plasma volume from the start of infusion to 180 min after the start of infusion. Secondary outcomes included the change in the area under the plasma volume curve and transcapillary escape rate (TER) for albumin from 180 to 240 min after the start of albumin infusion. Results A total of 33 and 31 patients were included in the analysis in the slow and rapid groups, respectively. The change in plasma volume from the start of infusion to 180 min did not differ between the slow and rapid infusion groups (7.4 ± 2.6 vs. 6.5 ± 4.1 ml/kg; absolute difference, 0.9 ml/kg [95%CI, − 0.8 to 2.6], P = 0.301). Change in the area under the plasma volume curve was smaller in the slow than in the rapid infusion group and was 866 ± 341 and 1226 ± 419 min ml/kg, respectively, P

Angiotensin II (Ang II) induces marked, dynamic increases in the permeability of the glomerular filtration barrier (GFB) in rats. After binding to its receptor, Ang II elicits Ca2+ influx into cells, mediated by TRPC5 and TRPC6 (transient receptor potential canonical type 5 and 6). Clemizole and La3+ salts have been shown to block TRPC channels in vitro, and we therefore tested their potential effect on Ang II‐induced glomerular hyperpermeability. Anesthetized male Sprague‐Dawley rats were infused with Ang II (80 ng kg–1 min–1) alone, or together with clemizole or low‐dose La3+ (activates TRPC5, blocks TRPC6) or high‐dose La3+ (blocks both TRPC5 and TRPC6). Plasma and urine samples were taken during baseline and at 5 min after the start of the infusions and analyzed by high‐performance size‐exclusion chromatography for determination of glomerular sieving coefficients for Ficoll 10–80 Å (1–8 nm). Ang II infusion evoked glomerular hyperpermeability to large Ficolls (50–80 Å), which was ameliorated by clemizole, having no significant effect on glomerular filtration rate (GFR) or Ang II‐mediated increase in mean arterial pressure (ΔMAP). In contrast, high‐ and low‐dose La3+ significantly lowered ΔMAP and reduced Ang II‐induced hyperpermeability. Combined, clemizole and low‐dose La3+ were less effective at ameliorating Ang II‐induced glomerular hyperpermeability than low‐dose La3+ alone. In conclusion, our data show that both clemizole and La3+ are effective against Ang II‐induced glomerular hyperpermeability, with differential effects on blood pressure. Further research using more specific blockers of TRPC5 and TRPC6 should be performed to reveal the underlying mechanisms.

Introduction: Unwanted glucose absorption during peritoneal dialysis (PD) remains a clinical challenge, especially in diabetic patients. Recent experimental data indicated that inhibitors of the sodium and glucose co-transporter (SGLT)-2 could act to reduce glucose uptake during PD, which raises the question of whether glucose absorption may also occur via intracellular or trans-cellular pathways. Methods: We performed PD in anesthetized Sprague-Dawley rats using a fill volume of 20 mL with either 1.5% glucose fluid or 4.25% glucose fluid for 120 min dwell time to evaluate the effects of SGLT2 inhibition by empagliflozin on peritoneal water and solute transport. To assess the diffusion capacity of glucose, we developed a modified equation to measure small solute diffusion capacity, taking convective- and free water transport into account. Results: SGLT2 inhibition markedly increased the urinary excretion of glucose and lowered plasma glucose after PD compared to sham groups. Glucose absorption for 1.5% glucose was 165 mg 95% CI (145–178) in sham animals and 157 mg 95% CI (137–172) for empagliflozin-treated animals. For 4.25% glucose, absorption of glucose was 474 mg 95% CI (425–494) and 472 mg 95% CI (420–506) for sham and empagliflozin groups, respectively. No significant changes in the transport of sodium or water across the peritoneal barrier could be detected. Conclusion: We could not confirm recent findings that SGLT2 inhibition reduced glucose absorption and increased osmotic water transport during experimental PD.

Angiotensin II (Ang II) induces marked, dynamic increases in the permeability of the glomerular filtration barrier (GFB) in rats. After binding to its receptor, Ang II elicits Ca2+ influx into cells, mediated by TRPC5 and TRPC6 (transient receptor potential canonical type 5 and 6). Clemizole and La3+ salts have been shown to block TRPC channels in vitro, and we therefore tested their potential effect on Ang II‐induced glomerular hyperpermeability. Anesthetized male Sprague‐Dawley rats were infused with Ang II (80 ng kg–1 min–1) alone, or together with clemizole or low‐dose La3+ (activates TRPC5, blocks TRPC6) or high‐dose La3+ (blocks both TRPC5 and TRPC6). Plasma and urine samples were taken during baseline and at 5 min after the start of the infusions and analyzed by high‐performance size‐exclusion chromatography for determination of glomerular sieving coefficients for Ficoll 10–80 Å (1–8 nm). Ang II infusion evoked glomerular hyperpermeability to large Ficolls (50–80 Å), which was ameliorated by clemizole, having no significant effect on glomerular filtration rate (GFR) or Ang II‐mediated increase in mean arterial pressure (ΔMAP). In contrast, high‐ and low‐dose La3+ significantly lowered ΔMAP and reduced Ang II‐induced hyperpermeability. Combined, clemizole and low‐dose La3+ were less effective at ameliorating Ang II‐induced glomerular hyperpermeability than low‐dose La3+ alone. In conclusion, our data show that both clemizole and La3+ are effective against Ang II‐induced glomerular hyperpermeability, with differential effects on blood pressure. Further research using more specific blockers of TRPC5 and TRPC6 should be performed to reveal the underlying mechanisms., Angiotensin II (Ang II) elicits Ca2+ influx into cells, mediated by TRPC5 and TRPC6 (transient receptor potential canonical type 5 and 6). Clemizole and La3+ salts have been shown to block TRPC5 and TRPC6 in vitro, and we therefore tested their potential effect on Ang II‐induced glomerular hyperpermeability in anesthetized Sprague‐Dawley rats. Clemizole and La3+ effectively reduced Ang II‐induced glomerular hyper permeability, with differential effects on blood pressure.

BackgroundDiabetic nephropathy (DN) is a leading cause of end stage renal disease and renal replacement therapy worldwide. A pathophysiological hallmark of DN is glomerular basal membrane (GBM) thickening, whereas this feature is absent in minimal change disease. Theoretically, a thicker GBM will impede the diffusion of middle-molecules such as cystatin C, potentially leading to a lower estimated GFR (eGFR) from cystatin C compared to that of creatinine. Here we test the hypothesis that thickening of the glomerular filter leads to an increased diffusion length, and lower clearance, of cystatin C.MethodsTwenty-nine patients with a kidney biopsy diagnosis of either DN (n=17) or minimal change disease (MCD) (n=12) were retrospectively included in the study. GBM thickness was measured at 20 separate locations in the biopsy specimen and plasma levels of cystatin C and creatinine were retrieved from health records. A modified two-pore model was used to simulate the effects of a thicker GBM on glomerular water and solute transport.ResultsThe mean age of the patients was 52 years, and 38% were women. The mean eGFRcystatin C/eGFRcreatinine-ratio was 74% in DKD compared to 98% in MCD (P < 0.001). Average GBM thickness was strongly inversely correlated to the eGFRcystatin C/eGFRcreatinine-ratio (Pearson’s r=-0.61, P < 0.01). Two-pore modeling predicted a eGFRcystatin C/eGFRcreatinine-ratio of 78% in DN.ConclusionsWe provide clinical and theoretical evidence suggesting that thickening of the glomerular filter, increasing the diffusion length of cystatin C, lowers the eGFRcystatin C/eGFRcreatinine-ratio in DN.Significance statementIncreased thickness of the glomerular basement membrane (GBM) is an early structural abnormality in diabetes, and has been identified as an independent risk factor for progression to diabetic nephropathy (DN). Increased GBM thickness will increase the diffusion length of mid-sized molecules like cystatin C across the renal filter, potentially leading to increased plasma concentrations and lower estimated GFR from cystatin C. The authors show theoretically that estimated GFR from cystatin C (eGFRcystatin C) is lower than that of creatinine (eGFRcreatinine) in DN to a degree directly depending on GBM thickness. In line with theory, they provide clinical data showing a lower eGFRcystatin Cin diabetic patients with the eGFRcystatin C/eGFRcreatinine-ratio being inversely correlated to GBM thickness assessed from electron micrographs.

Introduction The osmotic conductance to glucose (OCG) is a crucial determinant of ultrafiltration (UF) in peritoneal dialysis (PD) patients and can be used to monitor membrane integrity in patients on long-term PD. It has been proposed that OCG can be assessed based on drained volumes in 2 consecutive 1-hour glucose dwells, usually 1.5% and 4.25% glucose, in a so-called double mini-peritoneal equilibration test (dm-PET). However, recent data indicated that the dm-PET provides a poor estimate of OCG unless the residual volume (RV) is taken into account. We introduce an easy, robust, and accurate method to measure OCG and compare it with conventional methods. Methods In a prospective cohort of 21 PD patients, a modified version of the dm-PET was performed, along with the determination of RV before, between, and after dwells. Based on computer simulations derived from the 3-pore model (TPM) for membrane permeability, we developed and validated a novel single-dwell method to estimate OCG. We next validated the equation in an independent cohort consisting of 32 PD patients. Results Single-dwell OCG correlated more closely with actual UF (r = 0.94 vs. r = 0.07 for conventional dm-PET), sodium sieving, and free water transport (FWT) compared with other methods. These findings were replicated in the validation cohort in which OCG calculated using the single-dwell method closely correlated with parameters of osmotic water transport, even when RV was not taken into account, using only drained volumes. Conclusion We propose a novel, easy, and robust single-dwell method to determine OCG in individual patients and to monitor membrane integrity over time on PD., Graphical abstract

It is well known that proteinuria following urinary tract obstruction is mainly of a tubular nature. However, it is unknown whether there are also changes in glomerular permeability. In this study, we compared glomerular sieving coefficients (θ) of polydisperse fluorescein isothiocyanate (FITC)-Ficoll 70/400 following a 120- or 180-min unilateral ureteral obstruction (UUO) in anesthetized Sprague-Dawley rats. Samples were collected from the obstructed kidney at 5, 15, and 30 min postrelease and analyzed by means of high-pressure size-exclusion chromatography. After 120-min UUO, mean θ for Ficoll70Åwas increased ( P < 0.01) from 2.2 ± 0.5 × 10−5(baseline) to 10.6 ± 10 × 10−515 min postrelease (highest value). After 180-min UUO, mean θ for Ficoll70Åwas further increased ( P < 0.001) from 1.4 ± 0.5 × 10−5(baseline) to 40 ± 10 × 10−5at 5 min postrelease (highest value). Administration of a reactive oxygen species (ROS) scavenger (Tempol; 1 mg·kg−1·min−1) partly abrogated the permeability effects following 120-min UUO but not after 180 min. Moreover, administration of the RhoA kinase inhibitor Y-27632, the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester, or Rac-1 inhibition did not ameliorate glomerular hyperpermeability following 180-min UUO. We show, for the first time, that acute UUO results in marked elevations in glomerular permeability. In addition, our data suggest a time-dependent pathophysiology of UUO-induced hyperpermeability, where reactive oxygen species generation may play an important role in the early stages.

One of the many unresolved questions regarding the permeability of the glomerular filtration barrier is the reason behind the marked difference in permeability between albumin and polysaccharide probe molecules such as Ficoll and dextran of the same molecular size. Although the differences in permeability have been mainly attributed to charge effects, we have previously shown that this would require a highly charged filtration barrier, having a charge density that is ~10 times more than that on the albumin molecule. In this article, the classic two-pore model was extended by introducing size distributions on the solute molecules, making them conformationally flexible. Experimental sieving data for Ficoll from the rat glomerulus and from precision-made silicon nanopore membranes were analyzed using the model. For the rat glomerulus a small-pore radius of 36.2 Å and a geometric standard deviation (gSD) for the Ficoll size-distribution of 1.16 were obtained. For the nanopore membranes, a gSD of 1.24 and a small-pore radius of 43 Å were found. Interestingly, a variation of only ~16% in the size of the polysaccharide molecule is sufficient to explain the difference in permeability between albumin and Ficoll. Also, in line with previous data, the effects of applying a size distribution on the solute molecule are only evident when the molecular size is close to the pore size. Surely there is at least some variation in the pore radii, and, likely, the gSD obtained in the current study is an overestimation of the “true” variation in the size of the Ficoll molecule.

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 < 0.6), fast (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.

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 × 10−5 ± 0.7 × 10−5 ( P = 0.024) and 4.5 × 10−5 ± 0.8 × 10−5 ( P = 0.007), respectively, compared with baseline (2.2 × 10−5 ± 0.4 ×10−5). 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.

Background:Correction of acute metabolic acidosis using sodium bicarbonate is effective, but has been hypothesized to exacerbate intra-cellular acidosis causing cellular dysfunction. The effects of acidemia and bicarbonate therapy on the cellular components of the glomerular filtration barrier, crucial for the integrity of the renal filter, are as yet unknown. Controversy persists regarding the most appropriate method to assess acid-base status: the “Stewart approach” or the “Siggaard-Andersen approach” using the standard base excess (SBE).Methods:Here we performed physiological studies in anesthetized Sprague-Dawley rats during severe metabolic acidosis (HCl iv 6 mmol kg-1) and following bicarbonate (2.5 mmol kg-1) administration. We assessed glomerular permeability using sieving coefficients of polydisperse fluorescein isothiocyanate (FITC)-Ficoll 70/400. Acid-base status was evaluated using SBE, standard bicarbonate, total CO2, the Stewart-Fencl strong ion difference (ΔSID = Na – Cl – 38) and a theoretical model of plasma and erythrocyte strong ion difference.Results:Our data show that neither acidosis nor its correction with NaHCO3altered glomerular permeability. We identified ΔSID as a strong estimator of plasma base excess (as assessed using the Van Slyke equation).In silicomodeling indicates that changes in the strong ion difference in erythrocytes would explain their buffering effect by means of a shift of anions from the extracellular fluid.Conclusion:These data demonstrate a remarkable tolerance of the glomerular filter to severe acute acidosis and bicarbonate therapy. Our results also cast light on the buffer mechanism in erythrocytes and the ability of different acid-base parameters to evaluate the extent of an acid-base disorder.IMPORTANCE STATEMENTMetabolic acidosis is a frequent complication of acute kidney injury in critically ill patients and is associated with a high risk of mortality. Correction of acidosis using sodium bicarbonate is simple and effective, but could possibly induce intracellular acidosis causing cellular dysfunction. The effects of acidemia and subsequent bicarbonate treatment on the cellular components of the glomerular filtration barrier, crucial for the integrity of the renal filter, are unknown. We show that neither severe acidemia nor bicarbonate therapy appear to have negative effects on glomerular permeability. Our analysis also highlights the buffering effects of erythrocytes, which appear to be mediated by a shift of strong anions into the red cells, increasing the strong ion difference in the extracellular fluid.

BackgroundContinuous 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.MethodA 9-h CFPD session was simulated for: slow (dialysate to plasma creatinine [D/P crea] < 0.6), fast (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.ResultsIncreasing 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.ConclusionWhile 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.

Background Osmosis drives transcapillary ultrafiltration and water removal in patients treated with peritoneal dialysis. Crystalloid osmosis, typically induced by glucose, relies on dialysate tonicity and occurs through endothelial aquaporin-1 water channels and interendothelial clefts. In contrast, the mechanisms mediating water flow driven by colloidal agents, such as icodextrin, and combinations of osmotic agents have not been evaluated. Methods We used experimental models of peritoneal dialysis in mouse and biophysical studies combined with mathematical modeling to evaluate the mechanisms of colloid versus crystalloid osmosis across the peritoneal membrane and to investigate the pathways mediating water flow generated by the glucose polymer icodextrin. Results In silico modeling and in vivo studies showed that deletion of aquaporin-1 did not influence osmotic water transport induced by icodextrin but did affect that induced by crystalloid agents. Water flow induced by icodextrin was dependent upon the presence of large, colloidal fractions, with a reflection coefficient close to unity, a low diffusion capacity, and a minimal effect on dialysate osmolality. Combining crystalloid and colloid osmotic agents in the same dialysis solution strikingly enhanced water and sodium transport across the peritoneal membrane, improving ultrafiltration efficiency over that obtained with either type of agent alone. Conclusions These data cast light on the molecular mechanisms involved in colloid versus crystalloid osmosis and characterize novel osmotic agents. Dialysis solutions combining crystalloid and colloid particles may help restore fluid balance in patients treated with peritoneal dialysis.

At present, there is no comprehensive psycholinguistic database containing Swedish words with ratings of word properties such as e.g. imageability, although researchers carrying out psycholinguistic studies in Swedish face the need to be able to control for and systematically vary such properties. The present study addressed this issue by investigating the possibility of transferring English word ratings to Swedish.Imageability,familiarityandage of acquisition(AoA) ratings were obtained for a sample of Swedish words (N = 99). These ratings were then compared with the corresponding English ratings from the Medical Research Council (MRC) Psycholinguistic Database (Coltheart 1981) using Spearman correlation. Swedish and English word ratings were found to be highly correlated for imageability and AoA, and moderately correlated for familiarity. Following these results, we suggest that, in general, ratings of these variables can be reliably transferred between the two languages, although some caution should be taken, since for some individual words, some ratings might differ substantially for their Swedish and English translations.

Following reversal of short periods of ureteral obstruction (UO), glomerular and tubular renal dysfunction recovers with time. Diabetes mellitus (DM) affects glomerular function; thus, the ability of diabetic kidneys to recover from UO may be impaired. This study investigated the effects of long-term DM on the recovery of glomerular and tubular function, as well as permeability of the glomerular filtration barrier (GFB), after unilateral UO (UUO) reversal.Diabetes mellitus was induced in Wistar rats by intraperitoneal streptozotocin. All diabetic and age-matched control rats underwent reversible 24-hour left UUO. The renal function of both kidneys was measured using clearance techniques 3 hours and 7 and 30 days after UUO reversal. Glomerular permeability was assessed by measuring the glomerular sieving coefficients for fluorescein isothiocyanate-conjugated Ficoll (molecular radius: 20-90 Å).Unilateral UO induced transient changes in the size selectivity of GFB small pores. However, the size selectivity function of large pores had not returned to baseline even 30 days after UUO reversal. Diabetes mellitus caused exaggerated early alterations in glomerular hemodynamic and tubular function, as well as size selectivity dysfunction of both small and large pores. At 30 days after UUO reversal, despite glomerular hemodynamic and tubular function and the size selectivity of small pores returning to normal in both diabetic and non-diabetic rats, the residual size selectivity dysfunction of large pores was more severe in diabetic rats.Unilateral UO caused long-term dysfunction in the size selectivity of large pores of the GFB. In addition, DM significantly exaggerated this dysfunction, indicating a more ominous outcome in diabetic kidneys following UUO.背景: 在短期输尿管梗阻(ureteral obstruction，UO)得到治愈后，肾小球与肾小管功能障碍会随着时间的推移而逐渐恢复。糖尿病(DM)可以影响肾小球功能；因此，糖尿病肾脏从UO中恢复的能力可能会受损。这项研究在单侧UO(unilateral UO，UUO)得到治愈后，探究了长期DM对肾小球与肾小管功能恢复、以及肾小球滤过屏障(glomerular filtration barrier，GFB)通透性的影响。 方法: Wistar大鼠腹腔注射链脲佐菌素后诱发糖尿病。所有的糖尿病大鼠以及年龄匹配的对照组大鼠都要进行可逆性的24小时左侧UUO手术。在UUO逆转后的第3小时、7天以及30天，通过测定清除率的方法，测量双侧肾脏的肾功能。通过测定荧光素-异硫氰酸盐-共轭聚蔗糖(分子半径:20-90Å)的肾小球滤过系数评估肾小球通透性。 结果: 单侧UO可以导致GFB小孔的尺寸选择性出现短暂的变化。然而，即使UUO逆转30天后大孔的尺寸选择性功能仍然没有能够恢复到基线水平。糖尿病可加剧肾小球血流动力学以及肾小管功能的早期改变，除此之外还会导致大孔和小孔的尺寸选择性功能都出现障碍。UUO逆转后第30天，尽管在糖尿病大鼠与非糖尿病大鼠中肾小球血流动力学与肾小管功能以及小孔的尺寸选择性功能都恢复正常，但是在糖尿病大鼠中，大孔的尺寸选择性功能仍然有较严重的障碍。 结论: 单侧UO可导致GFB大孔的尺寸选择性出现长期功能障碍。另外，DM可导致这种功能障碍显著加重，这表明UUO后糖尿病肾脏的预后更差。.

An increased kidney oxygen consumption causing tissue hypoxia has been suggested to be a common pathway toward chronic kidney disease. The mammalian target of rapamycin (mTOR) regulates cell proliferation and mitochondrial function. mTOR inhibitors (e.g., rapamycin) are used clinically to prevent graft rejection. mTOR has been identified as a key player in diabetes, which has stimulated the use of mTOR inhibitors to counter diabetic nephropathy. However, the effect of mTOR inhibition on kidney oxygen consumption is unknown. Therefore, we investigated the effects of mTOR inhibition on in vivo kidney function, oxygen homeostasis, and glomerular permeability. Control and streptozotocin-induced diabetic rats were chronically treated with rapamycin, and the functional consequences were studied 14 days thereafter. In both groups, mTOR inhibition induced mitochondrial uncoupling, resulting in increased total kidney oxygen consumption and decreased intrarenal oxygen availability. Concomitantly, mTOR inhibition induced tubular injury, as estimated from urinary excretion of kidney injury molecule-1 (KIM-1) and reduced urinary protein excretion. The latter corresponded to reduced sieving coefficient for large molecules. In conclusion, mTOR inhibition induces mitochondrial dysfunction leading to decreased oxygen availability in normal and diabetic kidneys, which translates into increased KIM-1 in the urine. Reduced proteinuria after mTOR inhibition is an effect of reduced glomerular permeability for large molecules. Since hypoxia has been suggested as a common pathway in the development of chronic kidney disease, mTOR inhibition to patients with preexisting nephropathy should be used with caution, since it may accelerate the progression of the disease.

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.

There is increasing evidence that the permeability of the glomerular filtration barrier (GFB) is partly regulated by a balance between the bioavailability of nitric oxide (NO) and that of reactive oxygen species (ROS). It has been postulated that normal or moderately elevated NO levels protect the GFB from permeability increases, whereas ROS, through reducing the bioavailability of NO, have the opposite effect. We tested the tentative antagonism between NO and ROS on glomerular permeability in anaesthetized Wistar rats, in which the left ureter was cannulated for urine collection while simultaneously blood access was achieved. Rats were systemically infused with either l-NAME or l-NAME together with the superoxide scavenger Tempol, or together with l-arginine or the NO-donor DEA-NONOate, or the cGMP agonist 8-bromo-cGMP. To measure glomerular sieving coefficients (theta, θ) to Ficoll, rats were infused with FITC-Ficoll 70/400 (mol/radius 10–80 Å). Plasma and urine samples were analyzed by high-performance size-exclusion chromatography (HPSEC) for determination of θ for Ficoll repeatedly during up to 2 h. l-NAME increased θ for Ficoll70Åfrom 2.27 ± 1.30 × 10−5to 8.46 ± 2.06 × 10−5( n = 6, P < 0.001) in 15 min. Tempol abrogated these increases in glomerular permeability and an inhibition was also observed with l-arginine and with 8-bromo-cGMP. In conclusion, acute NO synthase inhibition in vivo by l-NAME caused rapid increases in glomerular permeability, which could be reversed by either an ROS antagonist or by activating the guanylyl cyclase-cGMP pathway. The data strongly suggest a protective effect of NO in maintaining normal glomerular permeability in vivo.

BackgroundA modified version of automated peritoneal dialysis (APD) using not only variable dwell times but also variable fill volumes has been tested against conventional APD (cAPD) with fixed dwell volumes in a randomized controlled clinical study. The results have indicated that the modified schedule for APD, denoted adapted APD (aAPD), can lead to improved small solute clearances, and, above all, a markedly increased sodium removal (NaR). To theoretically test these results, we have modeled aAPD vs cAPD in computer simulations using the 3-pore model (TPM).MethodsThe TPM, modified by including a transient, initial inflation of small solute mass transfer area coefficients (PS values), was employed. For simulations of osmotic ultrafiltration (UF), the TPM uses a constantly inflated value for PS for glucose and also a reduced value for PS for Na+, setting the peritoneal lymphatic reabsorption term at 0.3 mL/min. The simulations were performed by assuming that increases in intraperitoneal hydrostatic pressure (IPP) are transmitted to the capillary level ( via vein compression) and therefore do not significantly affect the Starling balance. Furthermore, the effective peritoneal surface area (A) was set to be variable as a function of intraperitoneal volume (IPV).ResultsThe simulations demonstrated a minor improvement of small solute clearances (∼0.7 – 1.6%) and a very small improvement of UF and NaR in aAPD compared to cAPD.ConclusionsDue mainly to the increased fill volumes in 3 out of 5 dwells in aAPD, this modality caused minor increases in small solute clearances and marginal effects on UF and NaR. The computer simulations point to a need for accurate sodium determinations in aAPD, considering all the methodological problems and pitfalls relevant to determining dialysate Na+ concentrations and peritoneal sodium mass balance.

Microalbuminuria is an early manifestation of diabetic nephropathy. Potential contributors to this condition are reduced glomerular filtration barrier (GFB) size- and charge selectivity, and impaired tubular reabsorption of filtered proteins. However, it was recently reported that no significant alterations in charge selectivity of the GFB occur in early experimental diabetic nephropathy. We here aimed at investigating the functional changes in the GFB in long-term type-1 diabetes in rats, applying a novel distributed two-pore model. We examined glomerular permeability in 15 male Wistar rats with at least 3 months of streptozotocin (STZ)-induced diabetes (blood glucose ∼20 mmol/L) and in age-matched control rats. The changes in glomerular permeability were assessed by determining the glomerular sieving coefficients (θ) for FITC-Ficoll (molecular radius 20-90 Å) using size exclusion HPLC. The values of θ for FITC-Ficoll of radius >50 Å were significantly increased in STZ-diabetic rats compared to age-matched controls (θ for 50-69 Å = 0.001 vs. 0.0002, and θ for 70-90 Å = 0.0007 vs. 0.00006, P < 0.001), while θ for FITC-Ficoll

to the editor: The purpose of this Letter to the Editor is to address a number of issues in the study by Vuchkova et al. ([29][1]) that may warrant correction or further clarification. In their study, plasma elimination of a bolus dose of albumin and IgG is used as an indirect measure of renal