Individualized anemia management enhanced by ferric pyrophosphate citrate protocol.

The optimal use of erythropoiesis-stimulating agents (ESAs) and parenteral iron in managing anemia in end-stage renal disease (ESRD) remains controversial. One-size-fits-all rule-based algorithms dominate dosing protocols for ESA and parenteral iron. However, the Food & Drug Administration (FDA) guidelines for using ESAs in chronic kidney disease recommend individualized therapy for the patient. This prospective quality assurance project was at a single hemodialysis (HD) center comprising three 6-month phases (A, B, C) separated by 3-month washout periods. Standard bi-weekly ESA dose titration and intravenous (IV) iron sucrose protocols were used in baseline Phase A, and ferric pyrophosphate citrate (FPC) augmented iron in Phase B. In Phase C, an FPC protocol and weekly, individualized ESA management were used. We examined clinic-level mean differences in hemoglobin (Hb) and ESRD-related outcomes by phase with repeated ANOVA. To examine the Hb at the patient level, we used multi-level mixed-effect regression adjusting for phase, month, and other relevant confounders at each month over time to derive the mean marginal effects of phase. There were 54, 78, and 66 patients in phases A, B, and C, respectively, with raw mean Hb values of 9.9, 10.2, and 10.3 g/dL. The percentage of Hb values < 9 g/dL declined from 14.3% in Phase A to 7.6% in Phase C (p = 0.007). The multivariable mixed-effect regression results showed mean marginal Hb was higher by 0.3 mg/dL and 0.4 mg/dL in Phases B and C, respectively, compared to Phase A. We also observed reduced ferritin (p = 0.003) and transferrin saturation (TSAT) (p = 0.008) levels from Phase A to Phase C with the repeated ANOVA analysis. Ferric pyrophosphate citrate (FPC) appears to support more efficient ESA-stimulated erythropoiesis. Moreover, individualized ESA management combined with FPC (Phase C) was associated with further improvement in efficiency as we observed the fewest patients with Hb values < 9 g/dL concurrent with greater decreases in ferritin levels and reduced ESA doses. However, future prospective studies to confirm these findings on a larger, more diverse cohort of ESRD patients are warranted.

Assessing accuracy of estimated dry weight in dialysis patients post transplantation: the kidney knows best.

INTRODUCTION: Estimated dry weight is used to guide fluid removal during outpatient hemodialysis sessions. Errors in estimated dry weight can result in intradialytic hypotension and interdialytic fluid overload. The goal of this study was to assess the accuracy of estimated dry weight by comparing it to the 2-week post-transplant weight in two cohorts of hemodialysis patients. METHODS: This observational, multi-center, retrospective cohort study included maintenance hemodialysis patients who underwent kidney transplantation at two medical centers in Massachusetts. The relationship between estimated dry weight pre-transplant and weight at week 2 post-transplant in patients with good allograft function (serum creatinine ≤ 1.5 mg/dL) was analyzed. Estimated dry weight was considered accurate if it was within ± 2% of the week 2 post-transplant weight. RESULTS: Fifty seven patients with good allograft function were identified: mean age 54 ± 14 years, 32 (58%) from deceased donors, 22 (38.6%) females. 38 were Caucasian (66.7%), 11 Hispanic (19.3%), 3 black (5.3%), and 5 others (8.8%). 2-week mean post transplantation serum creatinine was 1.2 ± 0.2 mg/dL. Mean (SD) estimated dry weight was 71.4 ± 15.9. Before transplantation, only 14 (24.6%) patients were within ± 2% of the 2-week post-transplant weight; 23 (40.3%) were above and 20 (35.1%) were below. CONCLUSIONS: Our point of view, based on the assumption that the weight of patients with good allograft function at 2 weeks post-transplant approaches their accurate dry weight, is that a majority of maintenance hemodialysis patients (75.4%) are hypervolemic or hypovolemic prior to renal transplantation. This highlights the importance of finding novel tools to achieve euvolemia in patients undertaking dialysis. Timely feedback regarding achieved weight 2 weeks post-transplant to treating nephrologists and dialysis centers may be a starting point for assessing accuracy of dry weight.

The Role of Feedback Control Design in Developing Anemia Management Protocols.

The optimal use of erythropoiesis stimulating agents to treat anemia of end-stage renal disease remains difficult due to reported associations with adverse events. A patient's hemoglobin response to these agents cannot be accurately described using population-level models due to many individual factors including chronic inflammation, red blood cell lifespan, and acute blood loss. As a consequence, it is generally understood that current one-size-fits-all anemia management protocols result in suboptimal outcomes. In this paper, we report on our collaboration with the medical community in designing anemia management protocols. In clinical implementation, these new dosing protocols have led to improved outcomes due to their use of control-relevant modelling, model parameter identification, and principles of feedback control. This is an example of medical professionals and control engineers working together to positively affect the performance of anemia management protocols in end-stage renal disease.

Individualization of Ultrafiltration in Hemodialysis.

OBJECTIVES: There are approximately 660 000 end-stage renal disease patients in the USA, with hemodialysis (HD) the primary form of treatment. High ultrafiltration rates (UFRs) are associated with intradialytic hypotension, a complication associated with adverse clinical outcomes including mortality. Individualized UFR profiles could reduce the incidence of intradialytic hypotension. METHODS: The patient's fluid dynamics during HD is described by a nonlinear model comprising intravascular and interstitial pools, whose parameters are given by the patient's estimated nominal parameter values with uncertainty ranges; the output measurement is hematocrit. We design UFR profiles that minimize the maximal UFR needed to remove a prescribed volume of fluid within a set time, with hematocrit not exceeding a specified time-varying critical profile. RESULTS: We present a novel approach to design individualized UFR profiles, and give theoretical results guaranteeing that the system remains within a predefined physiologically plausible region and does not exceed a specified time-invariant critical hematocrit level for all parameters in the uncertainty ranges. We test the performance of our design using a real patient data example. The designed UFR maintains the system below a time-varying critical hematocrit profile in the example. CONCLUSION: Theoretical results and simulations show that our designed UFR profiles can remove the target amount of fluid in a given time period while keeping the hematocrit below a specified critical profile. SIGNIFICANCE: Individualization of UFR profiles is now feasible using current HD technology and may reduce the incidence of intradialytic hypotension.

Comparison of stroke volume measurements during hemodialysis using bioimpedance cardiography and echocardiography.

BACKGROUND: Fluid management remains a major challenge of hemodialysis (HD) care, with serious implications for morbidity and mortality. Intradialytic fluid management is typically guided by blood pressure, an indirect resultant of hemodynamics status. Direct measurements of hemodynamic parameters may improve cardiovascular outcomes by providing rational bases for intervention. We compare stroke volume (SV) measurements using a noninvasive, regional biompedance cardiography device (NiCaS) with Doppler echocardiography (Echo) in HD setting. METHODS: Stroke volumes were simultaneously measured using the devices in 17 patients receiving maintenance HD. Measurements were made during 2 weekly HD treatments, and twice within each HD treatment during the first and last hour of each treatment, for a total of 64 SV measurements. Agreement between devices was assessed using linear regression, a Pearson's correlation coefficient, and a Bland-Altman plot all adjusted for repeated measures within patients. RESULTS: Echo and NiCaS SV mean and 95% CIs were 58.0 (50.1, 65.8) and 56.7 (49.4, 64.0) mL, respectively. NiCaS SV correlated strongly with Echo SV during the first and last hours of treatments (r = 0.93, P < 0.001 and r = 0.92, P < 0.001, respectively). Linear regression of NiCaS on Echo showed a slope of 0.97, 95% CI (0.91, 1.02) which did not differ from 1, P = 0.20. A Bland-Altman plot and 4-Quadrant plot confirmed that the 2 methods produced comparable measurements. CONCLUSION: NiCaS SV measurements are similar to and strongly correlated with Echo SV measurements. This suggests that noninvasive NiCaS technology may be a practical method for measuring SV during HD.

Variable-Volume Kinetic Model to Estimate Absolute Blood Volume in Patients on Dialysis Using Dialysate Dilution.

Long- and short-term adverse outcomes in hemodialysis (HD) have been associated with intradialytic hypotension, a common HD complication and significant cause of morbidity. It has been suggested that knowledge of absolute blood volume (ABV) could be used to significantly improve treatment outcomes. Different dilution-based protocols have been proposed for estimating ABV, all relying on the classic mono-exponential back-extrapolation algorithm (BEXP). In this paper, we introduce a dialysate dilution protocol and an estimation algorithm based on a variable-volume, two-compartment, intravascular blood water content kinetic model (VVKM). We compare ABV estimates derived using the two algorithms in a dialysate dilution study including three arterio-venous (AV) and three central-venous (CV) access patients, and multiple bolus injection tests (3-5) within each of several (2-6) HD treatments. The distribution of differences between ABV estimated from the two methods showed negligible systematic difference between the mean values of ABVs estimated from the BEXP and VVKM algorithms, however, the VVKM estimates were 53% and 42% more precise for the CV and AV patients, respectively. Good agreement was observed between measured and VVKM-estimated blood water concentration with the root-mean-square error (RMSE) less than 0.02 kg/kg (2%) and 0.03 kg/kg (3%) for AV and CV patients, respectively. The dilution protocol and the new VVKM-based estimation algorithm offer a noninvasive, inexpensive, safe, and practical approach for ABV estimation in routine HD settings.

Models for the red blood cell lifespan.

The lifespan of red blood cells (RBCs) plays an important role in the study and interpretation of various clinical conditions. Yet, confusion about the meanings of fundamental terms related to cell survival and their quantification still exists in the literature. To address these issues, we started from a compartmental model of RBC populations based on an arbitrary full lifespan distribution, carefully defined the residual lifespan, current age, and excess lifespan of the RBC population, and then derived the distributions of these parameters. For a set of residual survival data from biotin-labeled RBCs, we fit models based on Weibull, gamma, and lognormal distributions, using nonlinear mixed effects modeling and parametric bootstrapping. From the estimated Weibull, gamma, and lognormal parameters we computed the respective population mean full lifespans (95 % confidence interval): 115.60 (109.17-121.66), 116.71 (110.81-122.51), and 116.79 (111.23-122.75) days together with the standard deviations of the full lifespans: 24.77 (20.82-28.81), 24.30 (20.53-28.33), and 24.19 (20.43-27.73). We then estimated the 95th percentiles of the lifespan distributions (a surrogate for the maximum lifespan): 153.95 (150.02-158.36), 159.51 (155.09-164.00), and 160.40 (156.00-165.58) days, the mean current ages (or the mean residual lifespans): 60.45 (58.18-62.85), 60.82 (58.77-63.33), and 57.26 (54.33-60.61) days, and the residual half-lives: 57.97 (54.96-60.90), 58.36 (55.45-61.26), and 58.40 (55.62-61.37) days, for the Weibull, gamma, and lognormal models respectively. Corresponding estimates were obtained for the individual subjects. The three models provide equally excellent goodness-of-fit, reliable estimation, and physiologically plausible values of the directly interpretable RBC survival parameters.

The greatly misunderstood erythropoietin resistance index and the case for a new responsiveness measure.

Introduction The optimal use of erythropoiesis stimulating agents (ESAs) to treat anemia in end stage renal disease remains controversial due to reported associations with adverse events. In analyzing these associations, studies often utilize ESA resistance indices (ERIs), to characterize a patient's response to ESA. In this study, we examine whether ERI is an adequate measure of ESA resistance. Methods We used retrospective data from a nonconcurrent cohort study of incident hemodialysis patients in the United States (n = 9386). ERI is defined as average weekly erythropoietin (EPO) dose per kg body weight (wt) per average hemoglobin (Hgb), over a 3-month period (ERI = (EPO/wt)/Hgb). Linear regression was used to demonstrate the relationship between ERI and weight-adjusted EPO. The coefficient of variation was used to compare the variability of Hgb with that of weight-adjusted EPO to explain this relationship. This analysis was done for each quarter during the first year of dialysis. Findings ERI is strongly linearly related with weight-adjusted EPO dose in each of the four quarters by the equation ERI = 0.0899*(EPO/wt) (range of R(2) = 0.97-0.98) and weakly linearly related to 1/Hgb (range of R(2) = 0.06-0.16). These correlations hold independent of age, sex, hgb level, ERI level, and epo-naïve stratifications. Discussion ERI is strongly linearly related to weight-adjusted (and nonweight-adjusted) EPO dose by a "universal," not patient-specific formula, and thus is a surrogate of EPO dose. Therefore, associations between ERI and clinical outcomes are associations between a confounded EPO dose and those outcomes.

Concordance of absolute and relative plasma volume changes and stability of Fcells in routine hemodialysis.

Central hematocrit (H) measurements are currently used to track the degree of ultrafiltration-induced hemoconcentration with the aim to detect and prevent excessive intravascular fluid depletion during hemodialysis (HD). Failure to maintain hemodynamic stability is commonly attributed to the misinterpretation of H caused by an unaccountable increase in Fcells , the ratio of whole-body hematocrit to H. It was the aim to examine Fcells under everyday conditions in a group of stable HD patients. Absolute plasma volume (Vp ) and H were concomitantly measured during routine HD in the extracorporeal system in hourly intervals by noninvasive and continuous technology (CritLine-Instrument-III) and indocyanine green dye dilution to derive relative plasma volumes from Vp and H (RPVp , RPVH ), respectively, and to calculate Fcells . Thirteen patients were studied during two midweek treatments (n = 26). Both absolute Vp (P < 0.05) and relative plasma volumes RPVH (P < 0.001) decreased during HD. Vp at any time point was positively correlated to RPVH (r = 0.52). Moreover, relative plasma volumes RPVH and RPVp determined by independent techniques were identical and showed negligible bias (-0.2%) but considerable limits of agreement (-15.6% to +15.3%). Fcells was stable and in the range of 0.9 ± 0.05 throughout HD and not different from the value assumed at the beginning of HD. Although Fcells remains constant in patients on routine dialysis and relative plasma volumes (RPVH and RPVp ) determined by independent techniques are therefore comparable, the variability of experimental conditions during dialysis and the limited accuracy of absolute volume measurements using available technology continues to complicate the ultrafiltration control problem.

Iron dosing in kidney disease: inconsistency of evidence and clinical practice.

The management of anemia in patients with chronic kidney disease (CKD) is difficult. The availability of erythropoiesis-stimulating agents (ESAs) has increased treatment options for previously transfusion-requiring patients, but the recent evidence of ESA side effects has prompted the search for complementary or alternative approaches. Next to ESA, parenteral iron supplementation is the second main form of anemia treatment. However, as of now, no systematic approach has been proposed to balance the concurrent administration of both agents according to individual patient's needs. Furthermore, the potential risks of excessive iron dosing remain a topic of controversy. How, when and whether to monitor CKD patients for potential iron overload remain to be elucidated. This review addresses the question of risk and benefit of iron administration in CKD, highlights the evidence supporting current practice, provides an overview of standard and potential new markers of iron status and outlines a new pharmacometric approach to physiologically compatible individualized dosing of ESA and iron in CKD patients.

Control-relevant erythropoiesis modeling in end-stage renal disease.

Anemia is prevalent in end-stage renal disease (ESRD). The discovery of recombinant human erythropoietin (rHuEPO) over 30 years ago has shifted the treatment of anemia for patients on dialysis from blood transfusions to rHuEPO therapy. Many anemia management protocols (AMPs) used by clinicians comprise a set of experience-based rules for weekly-to-monthly titration of rHuEPO doses based on hemoglobin (Hb) measurements. In order to facilitate the design of an AMP using model-based feedback control theory, we present a physiologically relevant erythropoiesis model and demonstrate its applicability using clinical data.

A mathematical model of parathyroid hormone response to acute changes in plasma ionized calcium concentration in humans.

A complex bio-mechanism, commonly referred to as calcium homeostasis, regulates plasma ionized calcium (Ca(2+)) concentration in the human body within a narrow range which is crucial for maintaining normal physiology and metabolism. Taking a step towards creating a complete mathematical model of calcium homeostasis, we focus on the short-term dynamics of calcium homeostasis and consider the response of the parathyroid glands to acute changes in plasma Ca(2+) concentration. We review available models, discuss their limitations, then present a two-pool, linear, time-varying model to describe the dynamics of this calcium homeostasis subsystem, the Ca-PTH axis. We propose that plasma PTH concentration and plasma Ca(2+) concentration bear an asymmetric reverse sigmoid relation. The parameters of our model are successfully estimated based on clinical data corresponding to three healthy subjects that have undergone induced hypocalcemic clamp tests. In the first validation of this kind, with parameters estimated separately for each subject we test the model's ability to predict the same subject's induced hypercalcemic clamp test responses. Our results demonstrate that a two-pool, linear, time-varying model with an asymmetric reverse sigmoid relation characterizes the short-term dynamics of the Ca-PTH axis.

A computational model of the human thyroid.

The thyroid, the largest gland in the endocrine system, secretes hormones that help promote bodily growth and development. This gland regulates hormonal secretion rate in spite of changes in dietary iodine which is a key ingredient in the hormone's biosynthesis. The thyroid relies on several feedback mechanisms for this regulation, and in this paper we use recent molecular-level and clinical observations to engineer a computational thyroid model. We use simulation and analysis to show that this models captures known aspects of thyroid physiology. We identify features in the model that are responsible for hormonal regulation, and use the model to identify and evaluate competing hypotheses associated with Wolff-Chaikoff escape.