An exploratory study of the relationship between systemic microcirculatory function and small solute transport in incident peritoneal dialysis patients

Background: The peritoneal capillary endothelium is widely considered to be the most influential structure in dictating the rate of small solute transport (SST) during peritoneal dialysis (PD). PD patients are at significant risk of systemic microcirculatory dysfunction. The relationship between peritoneal and systemic microcirculations in patients new to PD has not been well studied. We hypothesised that for patients on PD for less than 6 months, dysfunction in the systemic microcirculation would be reflected in the rate of SST. Methods: We recruited 29 patients to a cross-sectional, observational study. Rate of SST was measured using a standard peritoneal equilibration test. Laser Doppler Flowmetry was used to measure response to physical and pharmacological challenge (post-occlusive hyperaemic response and iontophoretic application of vasodilators) in the cutaneous microcirculation. Sidestream Darkfield imaging was used to assess sublingual microvascular density, flow and endothelial barrier properties. Results: We found no moderate or strong correlations between any of the measures of systemic microcirculatory function and rate of SST or albumin clearance. There was however a significant correlation between dialysate interleukin-6 concentrations and both SST ( rs = 0.758 p ≤ 0.0001) and albumin clearance ( rs = 0.53, p = 0.01). Conclusions: In this study, systemic microvascular dysfunction did not significantly influence the rate of SST even early in patients PD careers. In conclusion, this study demonstrates that intraperitoneal factors particularly inflammation have a far greater impact on rate of SST than systemic factors.

Hydration enthalpies of amorphous sucrose, trehalose and maltodextrins and their relations to heat capacities

The mechanisms of the glass transition and the behavior of small solute molecules in the glassy matrix is one of most important topics of modern thermodynamics. Water plays an important...

The impact of intradialytic cycling on the removal of protein-bound uraemic toxins: A randomised cross-over study

The evidence on impact of intradialytic exercise on the removal of urea, is conflictive. Impact of exercise on kinetics of serum levels of protein-bound uraemic toxins, known to exert toxicity and to have kinetics dissimilar of those of urea, has so far not been explored. Furthermore, if any effect, the most optimal intensity, time point and/or required duration of intradialytic exercise to maximise removal remain obscure. We therefore studied the impact of different intradialytic cycling schedules on the removal of protein-bound uraemic toxins during haemodialysis (HD). This randomised cross-over study included seven stable patients who were dialysed with an FX800 dialyser during three consecutive midweek HD sessions of 240 min: (A) without cycling; (B) cycling for 60 min between 60th and 120th minutes of dialysis; and (C) cycling for 60 min between 150th and 210th minutes, with the same cycling load as in session B. Blood and dialysate flows were respectively 300 and 500 mL/min. Blood was sampled from the blood inlet at different time points, and dialysate was partially collected (300 mL/h). Small water soluble solutes and protein-bound toxins were quantified and intradialytic reduction ratios (RR) and overall removal were calculated per solute. Total solute removal and reduction ratios were not different between the three test sessions, except for the reduction ratios RR60–120 and RR150–210 for potassium. In conclusion, we add evidence to the existing literature that, regardless of the timing within the dialysis session, intradialytic exercise has no impact on small solute clearance, and demonstrated also a lack of impact for protein-bound solutes.

Alanyl-Glutamine Restores Tight Junction Organization after Disruption by a Conventional Peritoneal Dialysis Fluid

Understanding and targeting the molecular basis of peritoneal solute and protein transport is essential to improve peritoneal dialysis (PD) efficacy and patient outcome. Supplementation of PD fluids (PDF) with alanyl-glutamine (AlaGln) increased small solute transport and reduced peritoneal protein loss in a recent clinical trial. Transepithelial resistance and 10 kDa and 70 kDa dextran transport were measured in primary human endothelial cells (HUVEC) exposed to conventional acidic, glucose degradation products (GDP) containing PDF (CPDF) and to low GDP containing PDF (LPDF) with and without AlaGln. Zonula occludens-1 (ZO-1) and claudin-5 were quantified by Western blot and immunofluorescence and in mice exposed to saline and CPDF for 7 weeks by digital imaging analyses. Spatial clustering of ZO-1 molecules was assessed by single molecule localization microscopy. AlaGln increased transepithelial resistance, and in CPDF exposed HUVEC decreased dextran transport rates and preserved claudin-5 and ZO-1 abundance. Endothelial clustering of membrane bound ZO-1 was higher in CPDF supplemented with AlaGln. In mice, arteriolar endothelial claudin-5 was reduced in CPDF, but restored with AlaGln, while mesothelial claudin-5 abundance was unchanged. AlaGln supplementation seals the peritoneal endothelial barrier, and when supplemented to conventional PD fluid increases claudin-5 and ZO-1 abundance and clustering of ZO-1 in the endothelial cell membrane.

Flexibility in peritoneal dialysis prescription: Impact on technique survival

Background: Patient burnout is a major cause of technique failure on peritoneal dialysis (PD). Reducing the PD prescription on an individual basis, dependent upon residual kidney function (RKF), may have a role in prolonging time on PD by reducing dialysis burden. This retrospective study aimed to determine the safety and impact of flexible PD prescribing on technique and patient survival. Methods: All patients (186) from our centre starting PD from 1st January 2012 to 31st December 2016 were included. Data on dialysis prescription were collected for each patient from the time they had started PD, and dialysis adequacy measured regularly (3–6 monthly) using PD Adequest. Results: Median age at start of dialysis was 61 years. Only 49% started on PD 7 days a week and this dropped to 27% at 3 months following the first clearance test. Over 90% achieved creatinine clearance > 50 L/week/1.73 m2 up to 2 years of follow-up, with 87% achieving this standard at 3 years. Patient and technique survival at 1, 2 and 3 years were 91%, 81%, and 72%, and 89%, 87% and 78% respectively. Factors on univariate analysis affecting technique survival included increasing age (HR 0.98, p = 0.04, 95% CI (0.96–0.999)), two or more episodes of PD-associated peritonitis (HR 4.52, p = 0.00, 95% CI (1.87–10.91)) and increasing PD intensity (HR 3.30, p = 0.02, 95% CI (1.22–8.93)). After multivariate adjustment which included baseline kidney function, low PD intensity continued to be associated with better technique survival (HR 0.17, p = 0.03, 95% CI (0.03–0.85)). Conclusion: Tailoring the PD prescription to RKF enables days off dialysis while still maintaining recommended levels of small solute clearance. This approach reduces dialysis burden and is associated with higher technique survival.

Prescribing peritoneal dialysis for high-quality care in children

Background: Peritoneal dialysis (PD) remains the most widely used modality for chronic dialysis in children, particularly in younger children and in lower and middle income countries (LMICs). We present guidelines for dialysis initiation, modality selection, small solute clearance, and fluid removal in children on PD. A review of the literature and key studies that support these statements are presented. Methods: An extensive Medline search for all publications on PD in children was performed using predefined search criteria. Results: High-quality randomized trials in children are scarce and current clinical practice largely relies on data extrapolated from adult studies or drawn from observational cohort studies in children. The evidence and strength of the recommendation is GRADE-ed, but in the absence of high-quality evidence, the opinion of the authors is provided and must be carefully considered by the treating physician, and adapted to local expertise and individual patient needs as appropriate. We discuss the timing of dialysis initiation, factors to be considered when selecting a dialysis modality, the assessment and management of volume status on PD, achieving optimal small solute clearance, and the importance of preserving residual kidney function. While optimal dialysis must remain the goal for every patient, a careful discussion with fully informed patients and caregivers is important to understand the patient and family’s expectations of dialysis and reasonable adjustments to the dialysis program may be considered in accordance with a philosophy of shared decision-making. Conclusions: There continues to be very poor evidence in the field of chronic PD in children and these recommendations can at best serve to guide clinical decision-making. In LMICs, every effort should be made to conform to the framework of these statements, taking into account resource limitations.

2005 Guidelines on targets for solute and fluid removal in adults being treated with chronic peritoneal dialysis: 2019 Update of the literature and revision of recommendations

Background: The International Society for Peritoneal Dialysis guidelines for small solute clearance and fluid removal in peritoneal dialysis (PD) were published in 2005. The aim of this article is to update those guidelines by reviewing the literature that supported those guidelines and examining publications since then. Methods: An extensive search of publications was performed through electronic databases and a hand search through reference lists from the existing guideline and selected articles. Results: There have been no prospective intervention trials to inform the area of small solute clearance in PD since the publication of the original guideline in 2005. The trials to date are largely limited to a few prospective cohort studies and retrospective studies. These have, however, consistently demonstrated that residual renal function (RRF) is more often associated with patient outcome than peritoneal clearance. One of the few randomised controlled trials performed in this area does suggest that a weekly Kt/ V of 2.27 ± 0.02 provides no statistically significant survival advantage over a weekly Kt/ V of 1.80 ± 0.02. The lower limit of Kt/ V is unknown but there is weak evidence to suggest that anuric people doing PD should have a weekly Kt/ V of at least 1.7. Conclusions: There continues to be very poor evidence in the area of small solute clearance and fluid removal in PD. The evidence that exists suggests that RRF is more important than peritoneal clearance and that there appears to be no survival advantage in aiming for a weekly Kt/ V >1.70.

Haemodialysis

Maintenance haemodialysis (HD) is a highly successful treatment for patients with established renal failure and is the default therapy when other renal replacement therapy options are not available. HD uses the countercurrent flow of blood and dialysate through a hollow fibre dialyser to maximize the concentration gradient for diffusive transport of solutes. A hydrostatic gradient across the dialyser membrane induces ultrafiltration (UF) of water and convective transport of solutes by solvent drag. High-flux membranes are standard in most HD centres and are needed to achieve significant removal of middle molecules, of which β‎2-microglobulin (the cause of dialysis-related amyloid) is the prime example. The technique of haemodiafiltration contributes additional convective removal of fluid and better clearance of middle molecules. The need to secure and maintain reliable vascular access is fundamental to achieving adequate dialysis and maintaining health. An arteriovenous fistula is the preferred option, with fewer complications and longer survival than other access options. For historical and pragmatic reasons, HD is normally provided three times per week. Working definitions of adequacy are based on small-solute—typically urea—removal. The optimal dialysis dose has not been well defined, but minimum targets of delivered dose measured by urea reduction ratio and normalized urea clearance (Kt/V) have been established. The main acute complication of HD is intradialytic hypotension, resulting from an imbalance between the UF rate and the rate of vascular refill. Underlying cardiovascular disease, antihypertensive drugs, autonomic dysfunction, shortened dialysis times, large interdialytic fluid gains, and inaccurate dry-weight assessment all predispose. In the longer term, dialysis-related amyloidosis is a disabling, progressive condition caused by the polymerization of β‎2-microglobulin within tendons, synovium, and other tissues.

Estimating total small solute clearance in patients treated with continuous ambulatory peritoneal dialysis without urine and dialysate collection

Background: International Society for Peritoneal Dialysis guidelines recommend to routinely monitor the total measured clearance (mCl) of small solutes such as creatinine; however, collection of 24-h urine and peritoneal dialysis (PD) fluid is burdensome to patients and prone to errors. We hypothesized that equations could be developed to estimate mCl (estimated clearance (eCl)) using endogenous filtration markers. Methods: In the Guangzhou PD Study ( n = 980), we developed eCl equations using linear regression in two-third and validated them in the remaining one-third. Reference tests were mCl for urea nitrogen (UN) (mClUN, ml/min) and average mCl for UN and creatinine (mClUN-cr, ml/min/1.73 m2). Index tests were various eCl equations using UN, creatinine, low-molecular-weight proteins (LMWPs) (beta-trace protein (BTP), beta-2 microglobulin (B2M), and cystatin C), demographic variables, and body size. After reexpression of the equations in the combined data set, we analyzed accuracy (eCl within ± 2.0 units of mCl) and the predictive value of eCl to detect a weekly total standard Kt/V (weekly mClUN indexed for total body water) > 1.7 using receiver operating characteristic curve. Results: Mean age of the cohort was 50 ± 15 years, 53% were male; mClUN was 6.9 ± 1.8 and mClUN-cr was 7.5 ± 2.8. Creatinine but not UN contributed to eCl for both mCl. LMWP did not improve accuracy for mClUN (range 88–89%). BTP and B2M improved the accuracy for mClUN-cr (82% vs. 80%); however, differences were small. The area under the curve for predicting a weekly Kt/V > 1.7 was similar for all equations (range 0.79–0.80). Conclusions: Total small solute clearance can be estimated moderately well in continuous ambulatory PD patients using serum creatinine and demographic variables without urine and dialysate collection.