Doris Fuertinger

Intradialytic Hypoxemia and Clinical Outcomes in Patients on Hemodialysis

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.

A model of erythropoiesis in adults with sufficient iron availability

In this paper we present a model for erythropoiesis under the basic assumption that sufficient iron availability is guaranteed. An extension of the model including a sub-model for the iron dynamics in the body is topic of present research efforts. The model gives excellent results for a number of important situations: recovery of the red blood cell mass after blood donation, adaptation of the number of red blood cells to changes in the altitude of residence and, most important, the reaction of the body to different administration regimens of erythropoiesis stimulating agents, as for instance in the case of pre-surgical administration of Epoetin-α. The simulation results concerning the last item show that choosing an appropriate administration regimen can reduce the total amount of the administered drug considerably. The core of the model consists of structured population equations for the different cell populations which are considered. A key feature of the model is the incorporation of neocytolysis.

A physiologically based model of vascular refilling during ultrafiltration in hemodialysis

An assessment of fluid status can be obtained by monitoring relative blood volume (RBV) during hemodialysis (HD) treatment. The dynamics of RBV is determined by fluid removal from the intravascular compartment by ultrafiltration (UF) and vascular refill from the interstitium. To characterize this dynamics, a two-compartment model describing the short-term dynamics of vascular refilling and UF is developed. Fluid movement between the compartments is governed by lymphatic and microvascular fluid shifts. Further, protein flux is described by convection, diffusion and the lymphatic protein flux. Patient specific parameters are identified based on hematocrit (Hct) measurements by the Crit-Line monitor (CLM). Different measurement frequencies and UF profiles are compared to determine data fidelity and influence on the quality of parameter estimates. This relevant information can be used to assess the (patho)physiological status of hemodialysis patients and could aid in individualizing therapy.

Association between intradialytic central venous oxygen saturation and ultrafiltration volume in chronic hemodialysis patients

Abstract Background Cardiac disease is highly prevalent in hemodialysis (HD) patients. Decreased tissue perfusion, including cardiac, due to high ultrafiltration volumes (UFVs) is considered to be one of the drivers of cardiac dysfunction. While central venous oxygen saturation (ScvO2) is frequently used as an indicator of cardiac output in non-uremic populations, the relationship of ScvO2 and UFV in HD patients remains unclear. Our aim was to determine how intradialytic ScvO2 changes associate with UFV. Methods We conducted a 6-month retrospective cohort study in maintenance HD patients with central venous catheters as vascular access. Intradialytic ScvO2 was measured with the Critline monitor. We computed treatment-level slopes of intradialytic ScvO2 over time (ScvO2 trend) and applied linear mixed effects models to assess the association between patient-level ScvO2 trends and UFV corrected for body weight (cUFV). Results We studied 6042 dialysis sessions in 232 patients. In about 62.4% of treatments, ScvO2 decreased. We observed in nearly 80% of patients an inverse relationship between cUFV and ScvO2 trend, indicating that higher cUFV is associated with steeper decline in ScvO2 during dialysis. Conclusions In most patients, higher cUFV volumes are associated with steeper intradialytic ScvO2 drops. We hypothesize that in a majority of patients the intradialytic cardiac function is fluid dependent, so that in the face of high ultrafiltration rates or volume, cardiac pre-load and consequently cardiac output decreases. Direct measurements of cardiac hemodynamics are warranted to further test this hypothesis.

A Numerical Method for Structured Population Equations Modeling Control of Erythropoiesis

Abstract Population equations with more than one structuring attribute play an essential role in modeling cell populations important for the process of erythropoiesis. Attributes in this case are cell age, iron content of cells and number of transferrin receptors on the cell membrane. The system is controlled via a feedback control using the oxygen carrying capacity of blood (which is determined by the number of red blood cells) as input for the controller and erythropoietin secreted by the kidneys as control for the system. The numerical algorithm is based on Trotter-Kato type approximations of the system state by system states of high order ordinary differential equations on finite dimensional subspaces of the state space of the system. These finite dimensional subspaces are generated by Legendre polynomials.

A novel mathematical model of protein-bound uremic toxin kinetics during hemodialysis

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.

Prediction of hemoglobin levels in individual hemodialysis patients by means of a mathematical model of erythropoiesis

Anemia commonly occurs in people with chronic kidney disease (CKD) and is associated with poor clinical outcomes. The management of patients with anemia in CKD is challenging, due to its severity, frequent hypo-responsiveness to treatment with erythropoiesis stimulating agents (ESA) and common hemoglobin cycling. Nonlinear dose-response curves and long delays in the effect of treatment on red blood cell population size complicate predictions of hemoglobin (Hgb) levels in individual patients. A comprehensive physiology based mathematical model for erythropoiesis was adapted individually to 60 hemodialysis patients treated with ESAs by identifying physiologically meaningful key model parameters from temporal Hgb data. Crit-Line® III monitors provided non-invasive Hgb measurements for every hemodialysis treatment. We used Hgb data during a 150-day baseline period together to estimate a patient’s individual red blood cell lifespan, effects of the ESA on proliferation of red cell progenitor cells, endogenous erythropoietin production and ESA half-life. Estimated patient specific parameters showed excellent alignment with previously conducted clinical studies in hemodialysis patients. Further, the model qualitatively and quantitatively reflected empirical hemoglobin dynamics in demographically, anthropometrically and clinically diverse patients and accurately predicted the Hgb response to ESA therapy in individual patients for up to 21 weeks. The findings suggest that estimated model parameters can be used as a proxy for parameters that are clinically very difficult to quantify. The presented method has the potential to provide new insights into the individual pathophysiology of renal anemia and its association with clinical outcomes and can potentially be used to guide personalized anemia treatment.