Background and objectives Intradialytic hypoxemia has been recognized for decades, but its associations with outcomes have not yet been assessed in a large patient cohort. Design, setting, participants, & measurements Our retrospective cohort study was conducted between January of 2012 and January of 2015. We recorded blood oxygen saturation every minute during hemodialysis in patients with arteriovenous access. A 6-month baseline period with at least 10 treatments with oxygen saturation measurements preceded a 12-month follow-up. Patients were stratified by the presence or absence of prolonged intradialytic hypoxemia defined as oxygen saturation <90% for at least one third of the treatment time. Demographic, laboratory, and treatment data and hospitalization and mortality rates were compared between the groups. Multivariate Cox regression analysis was used to assess baseline predictors of all-cause mortality during follow-up. Results In total, 100 (10%) of 983 patients had prolonged intradialytic hypoxemia. These patients were older (+3.6 years; 95% confidence interval, 0.8 to 6.3), had longer dialysis vintage (+1.2 years; 95% confidence interval, 0.3 to 2.1), and had higher prevalence of congestive heart failure (+10.8%; 95% confidence interval, 1.6 to 20.7) and chronic obstructive pulmonary disease (+13%; 95% confidence interval, 5 to 21.2). They also resembled an inflammatory phenotype, with lower serum albumin levels (−0.1 g/dl; 95% confidence interval, −0.2 to 0) and higher neutrophil-to-lymphocyte ratios (+1; 95% confidence interval, 0.5 to 1.6). They had lower hemoglobin levels (−0.2 g/dl; 95% confidence interval, −0.4 to 0) and required more erythropoietin (+1374 U per hemodialysis treatment; 95% confidence interval, 343 to 2405). During follow-up, all-cause hospitalization (1113 hospitalizations; univariate hazard ratio, 1.46; 95% confidence interval, 1.22 to 1.73) and mortality (89 deaths; adjusted hazard ratio, 1.98; 95% confidence interval, 1.14 to 3.43) were higher in patients with prolonged intradialytic hypoxemia. Conclusions Prolonged intradialytic hypoxemia was associated with laboratory indicators of inflammation, higher erythropoietin requirements, and higher all–cause hospitalization and mortality.

Protein-bound uremic toxins (PBUTs) are difficult to remove by conventional hemodialysis; a high degree of protein binding reduces the free fraction of toxins and decreases their diffusion across dialyzer membranes. Mechanistic understanding of PBUT kinetics can open new avenues to improve their dialytic removal. We developed a comprehensive model of PBUT kinetics that comprises: (1) a three-compartment patient model, (2) a dialyzer model. The model accounts for dynamic equilibrium between protein, toxin, and the protein-toxin complex. Calibrated and validated using clinical and experimental data from the literature, the model predicts key aspects of PBUT kinetics, including the free and bound concentration profiles for PBUTs and the effects of dialysate flow rate and dialyzer size on PBUT removal. Model simulations suggest that an increase in dialysate flow rate improves the reduction ratio (and removal) of strongly protein-bound toxins, namely, indoxyl sulfate and p-cresyl sulfate, while for weakly bound toxins, namely, indole-3-acetic acid and p-cresyl glucuronide, an increase in blood flow rate is advantageous. With improved dialyzer performance, removal of strongly bound PBUTs improves gradually, but marginally. The proposed model can be used for optimizing the dialysis regimen and for in silico testing of novel approaches to enhance removal of PBUTs.

Protein-bound uremic toxins (PBUTs) are poorly removed during hemodialysis (HD) due to their low free (dialyzable) plasma concentration. We compared PBUT removal between HD, hemodiafiltration (HDF), membrane adsorption, and PBUT displacement in HD. The latter involves infusing a binding competitor pre-dialyzer, which competes with PBUTs for their albumin binding sites and increases their free fraction. We used a mathematical model of PBUT/displacer kinetics in dialysis comprising a three-compartment patient model, an arterial/venous tube segment model, and a dialyzer model. Compared to HD, improvements in removal of prototypical PBUTs indoxyl sulfate (initial concentration 100 µM, 7% free) and p-cresyl sulfate (150 µM, 5% free) were: 5.5% and 6.4%, respectively, for pre-dilution HDF with 20 L replacement fluid; 8.1% and 9.1% for post-dilution HDF 20 L; 15.6% and 18.3% for pre-dilution HDF 60 L; 19.4% and 22.2% for complete membrane adsorption; 35.0% and 41.9% for displacement with tryptophan (2000 mg in 500 mL saline); 26.7% and 32.4% for displacement with ibuprofen (800 mg in 200 mL saline). Prolonged (one-month) use of tryptophan reduces the IS and pCS time-averaged concentration by 28.1% and 29.9%, respectively, compared to conventional HD. We conclude that competitive binding can be a pragmatic approach for improving PBUT removal.

Central venous oxygen saturation (ScvO₂) in the superior vena cava is predominantly determined by cardiac output, arterial oxygen content, and oxygen consumption by the upper body. While abnormal ScvO₂ levels are associated with morbidity and mortality in non-uremic populations, ScvO₂ has received little attention in hemodialysis patients. From 1/2012 to 8/2015, 232 chronic hemodialysis patients with central venous catheters as vascular access had their ScvO₂ monitored during a 6-month baseline period and followed for up to 36 months. Patients were stratified into upper and lower two tertiles by a ScvO₂ of 61.1%. Survival analysis employed Kaplan-Meier curves and adjusted Cox proportional hazards models. Patients in the lower tertiles of ScvO₂ were older, had longer hemodialysis vintage, lower systolic blood pressure, lower ultrafiltration rates, higher leukocyte counts and neutrophil-to-lymphocyte ratios. Kaplan-Meier analysis indicated a shorter survival time in the lower tertiles of ScvO₂ (P = 0.005, log-rank test). In adjusted Cox analysis, a 1 percent point decrease in mean ScvO₂ was associated with a 4% increase in mortality (HR 1.04 [95% CI 1.01–1.08], P = 0.044), indicating that low ScvO₂ is associated with poor outcomes. Research on the relative contributions of cardiac output and other factors is warranted to further elucidate the pathophysiology underlying this novel finding.