Iron Administration, Infection, and Anemia Management in CKD: Untangling the Effects of Intravenous Iron Therapy on Immunity and Infection Risk.

Patients with chronic kidney disease (CKD) are at increased risk for infection, attributable to immune dysfunction, increased exposure to infectious agents, loss of cutaneous barriers, comorbid conditions, and treatment-related factors (eg, hemodialysis and immunosuppressant therapy). Because iron plays a vital role in pathogen reproduction and host immunity, it is biologically plausible that intravenous iron therapy and/or iron deficiency influence infection risk in CKD. Available data from preclinical experiments, observational studies, and randomized controlled trials are summarized to explore the interplay between intravenous iron and infection risk among patients with CKD, particularly those receiving maintenance hemodialysis. The current evidence base, including data from a recent randomized controlled trial, suggests that proactive judicious use of intravenous iron (in a manner that minimizes the accumulation of non-transferrin-bound iron) beneficially replaces iron stores while avoiding a clinically relevant effect on infection risk. In the absence of an urgent clinical need, intravenous iron therapy should be avoided in patients with active infection. Although serum ferritin concentration and transferrin saturation can help guide clinical decision making about intravenous iron therapy, definition of an optimal iron status and its precise determination in individual patients remain clinically challenging in CKD and warrant additional study.

Personalized Anemia Management and Precision Medicine in ESA and Iron Pharmacology in End-Stage Kidney Disease.

Substantial progress has been made in the application of computer-driven methods to provide erythropoietic dosing information for patients with anemia resulting from chronic kidney disease. Initial solutions were simply computerized versions of traditional paper-based anemia management protocols. True personalization was achieved through the use of advanced modeling techniques such as artificial neural networks, physiologic models, and feedback control systems. The superiority of any one technique over another has not been determined, but all methods have shown an advantage in at least one area over the traditional paper expert system used by most dialysis facilities. Improvements in the percentage of hemoglobin measurements within target range, decreased within-subject hemoglobin variability, decreased erythropoiesis-stimulating agent dose, and decreased transfusion rates all have been shown.

Individualized anemia management in a dialysis facility - long-term utility as a single-center quality improvement experience
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BACKGROUND: Standard protocol-based approaches to erythropoiesis stimulating agent (ESA) dosing in anemia management of end-stage renal disease (ESRD) fail to address the inter-individual variability in patient's response to ESA. We conducted a single-center quality improvement project to investigate the long-term performance of a computer-designed dosing system. MATERIALS AND METHODS: The study was a retrospective case-control study with long-term follow-up. All hemodialysis patients who received treatment at University Kidney Center (Louisville, KY, USA) between September 1, 2009, and March 31, 2017, were included. We implemented an individualized ESA dosing algorithm into an electronic health records database software to provide patient-specific ESA dose recommendations to anemia managers at monthly intervals. The primary outcome was the percentage of hemoglobin (Hb) concentrations between 10 and 12 g/dL during the case-control study and 9 and 11 g/dL during follow-up. Secondary outcomes were intra- and inter-individual Hb variability. For the case-control study, we compared outcomes over 12 months before and after implementation of the algorithm. Subjects served as their own controls. We used the last Hb concentration of the month and ESA dose per week. Long-term follow-up examined trends in proportion within the target range, Hb, and ESA dose. RESULTS: Individualized ESA dosing in 56 subjects was associated with a moderate (6.6%) increase of mean Hb maintenance within target over the 12-month observation period (62.7% before vs. 69.3% after, p = 0.063). Intra-individual mean Hb variability decreased (1.1 g/dL before vs. 0.8 g/dL after, p < 0.001), so did inter-individual mean Hb variability (1.2 g/dL before vs. 1.0 g/dL after, p = 0.010). Long-term follow-up in 233 subjects for 42 months demonstrated stability of the achieved Hb despite an increasing ESA resistance in the patient population. CONCLUSION: Implementation of the individualized ESA dosing algorithm facilitates improvement in Hb maintenance within target, decreases Hb variability and reduces the dose of ESA required to achieve Hb target.
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Positive Iron Balance in Chronic Kidney Disease: How Much is Too Much and How to Tell?

BACKGROUND: Regulation of body iron occurs at cellular, tissue, and systemic levels. In healthy individuals, iron absorption and losses are minimal, creating a virtually closed system. In the setting of chronic kidney disease and hemodialysis (HD), increased iron losses, reduced iron absorption, and limited iron availability lead to iron deficiency. Intravenous (IV) iron therapy is frequently prescribed to replace lost iron, but determining an individual's iron balance and stores can be challenging and imprecise, contributing to uncertainty about the long-term safety of IV iron therapy. SUMMARY: Patients on HD receiving judicious doses of IV iron are likely to be in a state of positive iron balance, yet this does not appear to confer an overt risk for clinically relevant iron toxicity. The concomitant use of iron with erythropoiesis-stimulating agents, the use of maintenance iron dosing regimens, and the reticuloendothelial distribution of hepatic iron deposition likely minimize the potential for iron toxicity in patients on HD. Key Messages: Because no single diagnostic test can, at present, accurately assess iron status and risk for toxicity, clinicians need to take an integrative approach to avoid iron doses that impose excessive exposure while ensuring sufficient replenishment of iron stores capable of overcoming hepcidin blockade and allowing for effective erythropoiesis.

The effect of treatment time, dialysis frequency, and ultrafiltration rate on intradialytic hypotension.

Dialysis treatment time, the frequency of dialysis treatments, and the rate of fluid ultrafiltration-each impacts the incidence of intradialytic hypotension. These factors influence blood pressure independently and together. The strongest evidence supports that rapid ultrafiltration increases the likelihood of intradialytic hypotension and that combined strategies leading to a reduction in ultrafiltration rate have the greatest impact on reducing intradialytic hypotension. A practical approach to avoiding the effects of ultrafiltration on systemic hemodynamics would be to set a maximum ultrafiltration rate needed to achieve the desired fluid removal and vary the duration of the treatment to achieve that target volume. Randomized, controlled clinical trials of such strategies are warranted.

Pharmacokinetic assessment in patients receiving continuous RRT: perspectives from the Kidney Health Initiative.

The effect of AKI and modern continuous RRT (CRRT) methods on drug disposition (pharmacokinetics) and response has been poorly studied. Pharmaceutical manufacturers have little incentive to perform pharmacokinetic studies in patients undergoing CRRT because such studies are neither recommended in existing US Food and Drug Administration (FDA) guidance documents nor required for new drug approval. Action is urgently needed to address the knowledge deficit. The Kidney Health Initiative has assembled a work group composed of clinicians and scientists representing academia, the FDA, and the pharmaceutical and dialysis industries with expertise related to pharmacokinetics, AKI, and/or CRRT. The work group critically evaluated key considerations in the assessment of pharmacokinetics and drug dosing in CRRT, practical constraints related to conducting pharmacokinetic studies in critically ill patients, and the generalizability of observations made in the context of specific CRRT prescriptions and specific patient populations in order to identify efficient study designs capable of addressing the knowledge deficit without impeding drug development. Considerations for the standardized assessment of pharmacokinetics and development of corresponding drug dosing recommendations in critically ill patients with AKI receiving CRRT are proposed.

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.

The medical director in integrated clinical care models.

Integrated clinical care models, like Accountable Care Organizations and ESRD Seamless Care Organizations, present new opportunities for dialysis facility medical directors to affect changes in care that result in improved patient outcomes. Currently, there is little scholarly information on what role the medical director should play. In this opinion-based review, it is predicted that dialysis providers, the hospitals in which the medical director and staff physicians practice, and the payers with which they contract are going to insist that, as care becomes more integrated, dialysis facility medical directors participate in new ways to improve quality and decrease the costs of care. Six broad areas are proposed where dialysis unit medical directors can have the greatest effect on shifting the quality-care paradigm where integrated care models are used. The medical director will need to develop an awareness of the regional medical care delivery system, collect and analyze actionable data, determine patient outcomes to be targeted that are mutually agreed on by participating physicians and institutions, develop processes of care that result in improved patient outcomes, and lead and inform the medical staff. Three practical examples of patient-centered, quality-focused programs developed and implemented by dialysis unit medical directors and their practice partners that targeted dialysis access, modality choice, and fluid volume management are presented. Medical directors are encouraged to move beyond traditional roles and embrace responsibilities associated with integrated care.

Balancing ESA and iron therapy in a prospective payment environment.

Ever since the introduction of EPO, ESAs and iron dosing have been driven by financial incentives. When ESAs were a profit center for providers, large doses were used. With ESAs becoming a cost center, a new trend has appeared, gradually replacing their use with iron to achieve the same therapeutic effect at lower cost. This financially driven approach, treating ESAs and iron as alternatives, is not consistent with human physiology where these agents act in a complementary manner. It is likely that we are still giving unnecessarily large doses of ESAs and iron, relative to what our patients' true needs are. Although we have highlighted the economic drivers of this outcome, many other factors play a role. These include our lack of understanding of the complex interplay of the anemia of chronic disease, inflammation, poor nutrition, blood loss through dialysis, ESAs and iron deficiency. We propose that physiology-driven modeling may provide some insight into the interactions between erythropoiesis and ferrokinetics. This insight can then be used to derive new, physiologically compatible dosing guidelines for ESAs and iron.

Individualized anemia management reduces hemoglobin variability in hemodialysis patients.

One-size-fits-all protocol-based approaches to anemia management with erythropoiesis-stimulating agents (ESAs) may result in undesired patterns of hemoglobin variability. In this single-center, double-blind, randomized controlled trial, we tested the hypothesis that individualized dosing of ESA improves hemoglobin variability over a standard population-based approach. We enrolled 62 hemodialysis patients and followed them over a 12-month period. Patients were randomly assigned to receive ESA doses guided by the Smart Anemia Manager algorithm (treatment) or by a standard protocol (control). Dose recommendations, performed on a monthly basis, were validated by an expert physician anemia manager. The primary outcome was the percentage of hemoglobin concentrations between 10 and 12 g/dl over the follow-up period. A total of 258 of 356 (72.5%) hemoglobin concentrations were between 10 and 12 g/dl in the treatment group, compared with 208 of 336 (61.9%) in the control group; 42 (11.8%) hemoglobin concentrations were <10 g/dl in the treatment group compared with 88 (24.7%) in the control group; and 56 (15.7%) hemoglobin concentrations were >12 g/dl in the treatment group compared with 46 (13.4%) in the control group. The median ESA dosage per patient was 2000 IU/wk in both groups. Five participants received 6 transfusions (21 U) in the treatment group, compared with 8 participants and 13 transfusions (31 U) in the control group. These results suggest that individualized ESA dosing decreases total hemoglobin variability compared with a population protocol-based approach. As hemoglobin levels are declining in hemodialysis patients, decreasing hemoglobin variability may help reduce the risk of transfusions in this population.

Cocaine-induced acute interstitial nephritis: A case report and review of the literature.

BACKGROUND: Acute tubular necrosis and pigment induced kidney injury are well described consequences of cocaine abuse. However, acute interstitial nephritis associated with cocaine use has been previously reported in only three patients. CASE PRESENTATION: We present the case of a 49-year-old man who developed acute kidney injury from biopsy-proven interstitial nephritis after nasal insufflation of cocaine. Unlike prior reports, our patient remained non-oliguric and did not require renal replacement therapy. CONCLUSIONS: Interstitial nephritis should be considered as a potential cause of acute kidney injury associated with cocaine use. The approach to management of cocaine associated acute kidney injury (AKI) may be different in patients with interstitial nephritis than for those with tubular necrosis or pigment induced renal injury.

Phase IIa study of the immunogenicity and safety of the novel Staphylococcus aureus vaccine V710 in adults with end-stage renal disease receiving hemodialysis.

Bacteremia is the second leading cause of death in patients with end-stage renal disease who are on hemodialysis. A vaccine eliciting long-term immune responses against Staphylococcus aureus in patients on chronic hemodialysis may reduce the incidence of bacteremia and its complications in these patients. V710 is a vaccine containing iron surface determinant B (IsdB), a highly conserved S. aureus surface protein, which has been shown to be immunogenic in healthy subjects. In this blinded phase II immunogenicity study, 206 chronic hemodialysis patients between the ages of 18 and 80 years old were randomized to receive 60 µg V710 (with or without adjuvant), 90 µg V710 (with adjuvant), or a placebo in various combinations on days 1, 28, and 180. All 201 vaccinated patients were to be followed through day 360. The primary hypothesis was that at least 1 of the 3 groups receiving 2 V710 doses on days 1 and 28 would have a ≥2.5 geometric mean fold rise (GMFR) in anti-IsdB IgG titers over the baseline 28 days after the second vaccination (day 56). At day 56, all three groups receiving 2 doses of V710 achieved a ≥2.5 GMFR in anti-IsdB antibodies compared to the baseline (P values of <0.001 for all 3 groups), satisfying the primary immunogenicity hypothesis. None of the 33 reported serious adverse experiences were considered vaccine related by the investigators. V710 induced sustained antibody responses for at least 1 year postvaccination in patients on chronic hemodialysis.

Drug dosing consideration in patients with acute and chronic kidney disease-a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO).

Drug dosage adjustment for patients with acute or chronic kidney disease is an accepted standard of practice. The challenge is how to accurately estimate a patient's kidney function in both acute and chronic kidney disease and determine the influence of renal replacement therapies on drug disposition. Kidney Disease: Improving Global Outcomes (KDIGO) held a conference to investigate these issues and propose recommendations for practitioners, researchers, and those involved in the drug development and regulatory arenas. The conference attendees discussed the major challenges facing drug dosage adjustment for patients with kidney disease. In particular, although glomerular filtration rate is the metric used to guide dose adjustment, kidney disease does affect nonrenal clearances, and this is not adequately considered in most pharmacokinetic studies. There are also inadequate studies in patients receiving all forms of renal replacement therapy and in the pediatric population. The conference generated 37 recommendations for clinical practice, 32 recommendations for future research directions, and 24 recommendations for regulatory agencies (US Food and Drug Administration and European Medicines Agency) to enhance the quality of pharmacokinetic and pharmacodynamic information available to clinicians. The KDIGO Conference highlighted the gaps and focused on crafting paths to the future that will stimulate research and improve the global outcomes of patients with acute and chronic kidney disease.

Pharmacokinetics of dexrazoxane in subjects with impaired kidney function.

Dexrazoxane is approved as a cardioprotective agent for use in female patients with breast cancer who are receiving doxorubicin. The effect of renal insufficiency on elimination is not known. The pharmacokinetics of dexrazoxane 150 mg/m(2), given as a 15-minute constant-rate intravenous infusion, were assessed in 24 men and women with varying degrees of renal function in a single-dose, open-label, parallel-group study. Blood and urine samples were measured by a validated liquid chromatography/mass spectrometry assay. Dexrazoxane pharmacokinetic parameters were derived by standard noncompartmental methods. The effect of kidney function and effect of body surface area on the pharmacokinetics of dexrazoxane were analyzed using linear and nonlinear regression in the SPSS statistical program. Dexrazoxane clearance is decreased in subjects with kidney dysfunction. Compared with normal subjects (creatinine clearance [CL(CR)] >80 mL/min), mean area under the concentration curve from time 0 to infinity (AUC(0-inf)) was 2-fold greater in subjects with moderate (CL(CR) 30-50 mL/min) to severe (CL(CR) <30 mL/min) renal dysfunction. Modeling demonstrated that equivalent exposure (AUC(0-inf)) could be achieved if dosing were reduced by 50% in subjects with CL(CR) less than 40 mL/min compared with control subjects (CL(CR) >80 mL/min). Modeling study results suggested that equivalent exposure could be achieved if dosing was halved in subjects with CL(CR) less than 40 mL/min compared with controls.

Determining optimum hemoglobin sampling for anemia management from every-treatment data.

BACKGROUND AND OBJECTIVES: Anemia management protocols in ESRD call for hemoglobin (Hb) monitoring every 2 to 4 weeks. Short-term Hb variability affects the reliability of Hb measurement and may lead to incorrect dosing of erythropoiesis stimulating agents. We prospectively analyzed short-term Hb variability and quantified the relationship between frequency of Hb monitoring and error in Hb estimation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using the Crit-Line III TQA device, we prospectively observed Hb during each dialysis treatment in 49 ESRD patients and quantified long- and short-term Hb variability. We estimated Hb from data sampled at regular intervals; 8×, 4×, 2×, or 1× per month to establish how well we account for short-term variability at different monitoring intervals. We calculated the Hb estimation error (Hb(err)) as a root mean-squared difference between the observed and estimated Hb and compared it with the measurement error. RESULTS: The most accurate Hb estimation is achieved when monitoring 8× per month (Hb(err) = 0.23 ± 0.05 g/dl), but it exceeds the accuracy of the measurement device. The estimation error increases to 0.34 ± 0.07 g/dl when monitoring 4× per month, 0.39 ± 0.08 g/dl when monitoring 2× a month, and 0.45 ± 0.09 g/dl when monitoring 1× per month. Estimation error comparable to instrument error information is as follows: 8× per month, 15 patients; 4× per month, 22 patients; 2× per month, 6 patients; 1× per a month, 6 patients. CONCLUSIONS: Four times a month is the clinically optimal Hb monitoring frequency for anemia management.

Randomized trial of model predictive control for improved anemia management.

BACKGROUND AND OBJECTIVES: Variable hemoglobin (Hb) response to erythropoiesis stimulating agents may result in adverse outcomes. The utility of model predictive control for drug dosing was previously demonstrated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a double-blinded, randomized, controlled trial to test model predictive control for dosing erythropoietin in ESRD patients. The trial included 60 hemodialysis patients who were randomized into a treatment arm (30 subjects) that received erythropoietin doses on the basis of the computer recommendations or a control arm (30 subjects) that received erythropoietin doses on the basis of recommendations from a standard anemia management protocol (control). The subjects were followed for 8 months, and the proportions of measured Hb within the target of 11 to 12 g/dl and outside 9 to 13 g/dl were measured. Variability of the Hb level was measured by the absolute difference between the achieved Hb and the target Hb of 11.5 g/dl as well as the area under the Hb curve. RESULTS: Model predictive control resulted in 15 observations >13 or <9 g/dl (outliers), a mean absolute difference between achieved Hb and 11.5 g/dl of 0.98 +/- 0.08 g/dl, and an area under the Hb curve of 2.86 +/- 1.46. The control group algorithm resulted in 30 Hb outliers (P = 0.051), produced a mean absolute difference between achieved Hb and 11.5 g/dl of 1.18 +/- 0.18 g/dl (P < 0.001 difference in variance), and an area under the Hb curve of 3.38 +/- 2.69 (P = 0.025 difference in variance). CONCLUSIONS: Model predictive control of erythropoietin administration improves anemia management.