Erythrocyte-stimulating Agents Research Articles

#2621 HEMOGLOBIN VARIABILITY IS ASSOCIATED WITH NUTRITIONAL STATUS IN HEMODIALYSIS PATIENTS UNDERGOING DARBEPOETIN-ALFA TREATMENT

Abstract Background and Aims Anemia is the most common finding in hemodialysis (HD) patients. A significant proportion of patients are taking erythropoietin (EPO) or other erythrocyte-stimulating agents (ESAs), yet the response to treatment is unsatisfactory, and EPO responsiveness is inconsistent in HD patients. Further, although the introduction of EPO has led to a dramatic reduction in blood transfusion requirements and is associated with improved quality of life, fluctuations in hemoglobin (Hb) levels, known as Hb variability, during EPO treatment is a well-documented phenomenon. Malnutrition is a well-known risk factor in the general population and in HD patients. However, few studies have evaluated the association between EPO responsiveness/Hb variability and nutritional status in HD patients. Therefore, our aim was to investigate whether EPO responsiveness and Hb variability can be associated with nutritional status in HD patients undergoing NESP® (darbepoetin-alfa; Kyowa Kirin Korea Co., Ltd.) treatment. Method In this prospective study, we included adult ninety-eight patients aged over 20 years who had been undergoing HD over 6 months. The target hemoglobin (Hb) level is 10–11 g/dL according to the Korean reimbursement guideline. Dose adjustments of NESP® were made according to the Hb level measured monthly in our facility. Every study population have more than 24 monthly Hb data points. We checked average darbepoetin-alfa dose weekly and the EPO resistance index (ERI) as a marker of EPO responsiveness was calculated by dividing the weekly average darbepoetin-alfa dose by the Hb level. In addition, we evaluated the more than 24 month Hb variability, which was expressed by Hb-Coefficient of Variation (Hb-CV). All of them were measured by BCM® (Fresenius Medical Care a Deutschland GmbH, Germany) to assess the nutritional status three times (Baseline, 12 Mos, 24 Mos). Nutritional parameters obtained by BCM® were body mass index (BMI), fat tissue index (FTI), lean tissue index (LTI), body cell mass index, phase angle (PhA). Clinical parameters and routine biochemical tests such as dose of erythropoietin, Kt/Vurea, iron and lipid profiles, C-reactive protein, albumin, calcium, phosphorus, intact-parathyroid hormone were also taken into account. Results In this study, the mean age of the patients was 64.0 ± 11.9 years, and 55.0% were male. Dialysis vintage was 54.9 ± 46.8 months. Follow-up duration was 79.3±47.9 months. Mean Hb was 10.7 ± 1.3 g/dL. We divided into tertiles (T) according to the ERI. The average ERI was 0.02 ± 0.01, 0.04 ± 0.01, and 0.07 ± 0.03 in ERI-T1, ERI-T2, and ERI-T3, respectively. The ERI-T3 group had the lower Hb level (p = 0.038) whereas administration dose of EPO were higher in ERI-T3 (p = 0.001). The ERI-T3 group had the lower PhA (p = 0.044), BMI (p = 0.001) and FTI (p = 0.046) values. We divided into tertiles (T) according to the Hb-CV. The average Hb-CV was 0.06 ± 0.01, 0.08 ± 0.05, and 0.12 ± 0.02 in Hb-CV-T1, Hb-CV-T2, and Hb-CV-T3, respectively. When comparing the three groups, the Hb-CV-T3 group had the lower BMI (p = 0.002) and lower FTI (p = 0.002). Age (r = 0.203, p = 0.036), female sex (r = 0.376, p = 0.001), presence of diabetes mellitus (r = 0.191, p = 0.049), total iron binding capacity (r = 0.205, p = 0.035) and triglyceride (r = 0.227, p = 0.018) were positively correlated with FTI. ERI (r = -0.193, p = 0.046) and Hb-CV (r = -0.268, p = 0.005) were negatively correlated with FTI. In multiple linear regression analysis, FTI was negatively associated with ERI (β = -0.218, p = 0.014), Hb-CV (β = -0.181, p = 0.039), whereas FTI was positively associated with age (β = 0.197, p = 0.017) and female sex (β = 0.386, p = 0.001). Conclusion In HD patients with higher ERI, PhA, BMI and FTI were significantly decreased. Furthermore, in patients with high Hb-CV, BMI and FTI were decreased. In addition, FTI was negatively associated with ERI and Hb-CV. Therefore, EPO responsiveness and Hb-variability is associated with nutritional status, especially fat tissue in hemodialysis patients undergoing darbepoetin-alfa treatment.

Considerations for Use of Hematopoietic Growth Factors in Patients With Cancer Related to the COVID-19 Pandemic.

Hematopoietic growth factors, including erythrocyte stimulating agents (ESAs), granulocyte colony-stimulating factors, and thrombopoietin mimetics, can mitigate anemia, neutropenia, and thrombocytopenia resulting from chemotherapy for the treatment of cancer. In the context of pandemic SARS-CoV-2 infection, patients with cancer have been identified as a group at high risk of morbidity and mortality from this infection. Our subcommittee of the NCCN Hematopoietic Growth Factors Panel convened a voluntary group to review the potential value of expanded use of such growth factors in the current high-risk environment. Although recommendations are available on the NCCN website in the COVID-19 Resources Section (https://www.nccn.org/covid-19/), these suggestions are provided without substantial context or reference. Herein we review the rationale and data underlying the suggested alterations to the use of hematopoietic growth factors for patients with cancer in the COVID-19 era.

A 19-year retrospective analysis of venous thromboembolism trends in chemotherapy-induced anemia: Red blood cell transfusion versus erythrocyte stimulating agent administration

Abstract Background Chemotherapy-induced anemia (CIA) contributes to poor patient outcomes and increased mortality. Prompt and effective treatment of CIA is essential to prevent fewer chemotherapy dose delays and reductions. Optimal therapy of CIA involves intravenous iron, red blood cell (RBC) transfusions, and erythrocyte stimulating agents (ESAs). Despite the baseline coagulopathies present in patients with malignancy, administration of both RBC transfusions and ESAs is independently associated with venous thromboembolism (VTE). It remains unknown whether the risk of VTE in patients with CIA is greater among patients who receive RBC transfusions or ESAs and whether or not this risk is consistent across gender and age. Methods A retrospective study analyzed 13,334 patients with various malignancies who developed CIA between 1998-2017. Using multivariate Cox regression, we determined adjusted hazard ratios (and corresponding 95% confidence intervals) of VTE development after controlling for RBC and ESA intervention (within 90 days after CIA diagnosis). Data was then stratified by gender and age ( Results Among the 13,334 patients with CIA, 2,620 (19.7%) developed a VTE. Despite stratification by gender, VTE risk following RBC transfusion was approximately four-fold the VTE risk following ESA administration (Table). Among patients with CIA who were Table: 106P . Treatment and outcomes within 90 days following CIA diagnosis No treatment RBC only ESA only RBC and ESA Patients with VTE (All Patients) 2028 (10,948) 538 (1,892) 42 (368) 12 (126) 18.5% 28.4% (HR = 2.18, 95% CI 1.98-2.39, p 11.4% (HR = 0.55, 95% CI 0.42-0.72, p 9.5% Men with VTE (All male patients) 970 (5428) 269 (917) 21 (182) 5 (61) 17.9% 29.3% (HR = 2.33, 95% CI (2.04-2.67, p 11.5% (HR = 0.55, 95% CI (0.37-0.81, p = 0.002) 8.3% Women with VTE (All female patients) 1058 (5519) 269 (975) 21 (186) 7 (65) 19.2% 27.6% (HR = 2.04, 95% CI (1.79-2.33), p 11.3% (HR = 0.56, 95% CI (0.38-0.81), p = 0.002) 10.8% Conclusions Among patients with CIA, there is an approximate four-fold increased risk of VTE development with RBC transfusion as compared with ESA administration. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Association Between Changes in CMS Reimbursement Policy and Drug Labels for Erythrocyte-Stimulating Agents With Outcomes for Older Patients Undergoing Hemodialysis Covered by Fee-for-Service Medicare

ImportanceIn 2011, the US Centers for Medicare & Medicaid Services (CMS) changed its reimbursement policy for hemodialysis to a bundled comprehensive payment system that included the cost of erythrocyte-stimulating agents (ESAs). Also in 2011, the US Food and Drug Administration revised the drug label for ESAs, recommending more conservative dosing in patients with chronic kidney disease. In response to concerns that these measures could have adverse effects on patient care and outcomes, the CMS and the FDA initiated a collaboration to assess the effect.ObjectiveTo assess the effects of the changes in reimbursement policy and the ESA drug label on patients who underwent incident hemodialysis.Design, Setting, and ParticipantsFor this retrospective cohort study, patients 66 years or older who had undergone incident hemodialysis, and were enrolled in Medicare parts A, B, or D for at least 12 months prior to hemodialysis initiation between January 1, 2008, and December 31, 2013, were recruited from hemodialysis centers across the United States. Patients were divided into 2 cohorts based on their date of hemodialysis initiation and followed: January 1, 2008, to December 31, 2009, for the prepolicy cohort and July 1, 2011, to June 30, 2013, for the postpolicy cohort, with the exclusion of January 1, 2010, to June 30, 2011, as a transition period.InterventionsChanges in CMS reimbursement policy for dialysis and the FDA label for ESAs.Main Outcomes and MeasuresMajor adverse cardiovascular events (MACEs), including acute myocardial infarction (AMI), stroke, and all-cause mortality; hospitalized congestive heart failure (H-CHF); venous thromboembolism; and red blood cell transfusions. Secondary outcomes included evaluating effects on black and other patient subgroups.ResultsBaseline characteristics of the 69 718 incident hemodialysis patients were similar between cohorts. Compared with the prepolicy period, the risk of MACE, death, H-CHF, and venous thromboembolism were similar in the postpolicy period, and the risk of stroke decreased (hazard ratio [HR], 0.77; 95% CI, 0.64-0.93; P = .01); the use of ESAs also decreased, and the rate of blood transfusions increased (HR, 1.09; 95% CI, 1.07-1.12; P < .001). In the post-postpolicy period, black patients had a significant reduction in risk of MACE (HR, 0.82; 95% CI, 0.73-0.92; P < .001) and all-cause mortality (HR, 0.82; 95% CI, 0.73-0.93; P = .002).Conclusions and RelevanceAfter the bundling policy and ESA labeling changes in 2011, the risks of MACE and death for patients 66 years or older and covered by fee-for-service Medicare who had undergone incident hemodialysis did not change; the risk of stroke was reduced, and the rate of blood transfusions modestly increased. Black patients had substantial reductions in the risks of MACE and death.

Management of Hyperglycemia in Diabetic Kidney Disease.

The growing incidence and prevalence of diabetes has made a significant impact on the development of diabetic kidney disease (DKD) (1). DKD is among the most frequent complications of diabetes; indeed, diabetes accounts for ∼50% of all cases of end-stage renal disease (ESRD) in developed countries (2). Patients often have comorbid diabetes and chronic kidney disease (CKD). Although intensive glycemic management has been shown to delay the onset and progression of increased urinary albumin excretion and reduced estimated glomerular filtration rate (eGFR) in diabetes patients (3), conservative dose selection and adjustment of antidiabetic medications is necessary to balance glycemic control with safety. A1C has limitations related to its precision and interpretation in the CKD population (4), with erythrocyte turnover being a major cause of A1C imprecision in this population. Red blood cell survival times become shorter as eGFR falls, resulting in a reduction in measured A1C. Treatment with erythrocyte-stimulating agents lowers A1C further, perhaps because of changes in hemoglobin concentrations (5,6). Observational data support the notion that higher A1C levels in nondialysis diabetes patients with CKD stages 3–5 (eGFR levels <60 mL/min/1.73 m2) are associated with worse outcomes, including progression of kidney disease (7). However, these patients are at higher risk for hypoglycemic events (8). Factors that may contribute to this increased risk can include slowed elimination of hypoglycemic agents, alcohol intake, chronic malnutrition, acute caloric deprivation, and decreased renal gluconeogenesis as kidney function declines (8–10). In the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study, when compared with patients with normal renal function, those with baseline serum creatinine of 1.3–1.5 mg/dL had a 66% increased risk of severe hypoglycemia (11). A U-shaped relationship between A1C and mortality has been demonstrated, suggesting that hypoglycemia may be one reason for higher mortality in those …

Nutritional vitamin D supplementation and health-related outcomes in hemodialysis patients: a protocol for a systematic review and meta-analysis.

BackgroundThe prevalence of vitamin D deficiency in hemodialysis patients is high. While most hemodialysis patients are treated with activated vitamin D (1,25[OH]2D) to prevent renal osteodystrophy, clinical practices of the screening and treatment of 25(OH)2D deficiency are highly variable. It is unclear if nutritional vitamin D supplementation with D2 or D3 provides an additional clinical benefit beyond that provided by activated vitamin D treatment in this population.Methods/designWe will conduct a systematic review of nutritional vitamin D (D2/D3) supplementation and health-related outcomes in hemodialysis patients according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The primary objective is to assess the impact of nutritional vitamin D supplementation on clinical outcomes relevant in hemodialysis patients, such as mortality, cardiovascular events, infections, and fractures. Secondary outcomes will include anemia, hyperparathyroidism, medication use (erythrocyte-stimulating agents, activated vitamin D), and quality of life. We will search MEDLINE, Scopus, Web of Science, and ClinicalTrials.gov for randomized, controlled trials of nutritional vitamin D supplementation (ergocalciferol/D2 or cholecalciferol/D3) in chronic hemodialysis patients. The Cochrane Risk Assessment Tool will be used to assess the quality of eligible studies. We will perform meta-analyses using standard techniques for the outcomes listed above if pooling is deemed appropriate/sufficient. The results of this systematic review may highlight gaps in our knowledge of the relevance of nutritional vitamin D in end-stage renal disease, allowing for the informed design of clinical trials assessing the impact of nutritional vitamin D therapy in the hemodialysis population in the future.Systematic review registrationPROSPERO CRD42014013931

Medication adherence and growth in children with CKD.

Poor growth is a consequence of CKD, but can often be partially or fully prevented or corrected with the use of a number of medications. The extent of nonadherence with medications used to treat or mitigate growth failure in CKD has not been examined prospectively in children with CKD. The prevalence of both prescription of and nonadherence to recombinant human growth hormone (rhGH), phosphate binders, alkali, active vitamin D, nutritional vitamin D, iron, and erythrocyte-stimulating agents was summarized over the first seven visits of the Chronic Kidney Disease in Children cohort study. The association between self-reported nonadherence to each medication group and the mean annual change in age- and sex-specific height z score was quantified using seven separate linear regression models with generalized estimating equations. Of 834 participants, 597 reported use of at least one of these medication groups and had adherence data available. Nonadherence ranged from 4% over all visits for erythrocyte-stimulating agents to 22% over all visits for nutritional vitamin D. Of the study participants, 451 contributed data to at least one of the analyses of adherence and changes in height z score. Children nonadherent to rhGH had no change in height z score, whereas those adherent to rhGH had a significant improvement of 0.16 SDs (95% confidence interval, 0.05 to 0.27); the effect size was slightly larger and remained significant after adjustment. Among participants with height≤3rd percentile and after adjustment, adherence to rhGH was associated with a 0.33 SD (95% confidence interval, 0.10 to 0.56) greater change in height z score. Nonadherence with other medication groups was not significantly associated with a change in height z score. Self-reported nonadherence to rhGH was associated with poorer growth velocity in children with CKD, suggesting an opportunity for intervention and improved patient outcome.

Benefits and risks of erythrocyte-stimulating agents

Benefits and risks of erythrocyte-stimulating agents

Erythropoietin and intravenous iron in PBM

The concept of patient blood management is such that if a patient with anemia can be identified in the pre-operative period, therapeutic modalities can be targeted to that patient who might benefit from such treatment. Management strategies include the optimization of preoperative hemoglobin by maximizing hemopoiesis and RBC mass. This can best be achieved with the use of iron supplementation, either oral or intravenous, with or without the use of erythrocyte stimulating agents (ESAs) such as erythropoietin. The use of i.v. iron and ESAs is reviewed. Different i.v. iron formulations available are discussed along with current indications and contraindications for the use of ESAs.

Oral Rigosertib (ON 01910.Na) Treatment Produces An Encouraging Rate Of Transfusion Independence In Lower Risk Myelodysplastic Syndromes (MDS) Patients; A Genomic Methylation Profile Is Associated With Responses

▪Rigosertib, a novel orally bioavailable small molecule inhibitor of PI3-Kinase and PLK1 pathways, was tested in a phase II study in lower risk (intermediate-1 or low risk per IPSS classification) transfusion-dependent MDS patients. This randomized, two-arm study administered rigosertib (560 mg bid) either intermittently (2 out of 3 weeks) or continuously to transfusion-dependent patients (4 units RBC transfusions over 8 weeks). Erythrocyte stimulating agents (ESAs) were allowed on study. Forty eight patients have been enrolled as of August 2nd, 2013 and another 12 patients will be enrolled. Continuous dosing was stopped after 9 patients due to a higher urinary toxicity resulting in 39 patients receiving intermittent dosing. Overall the drug was well tolerated, except for reversible grade 3 urinary toxicity (dysuria, hematuria, cystitis, and urinary urgency) in 6/48 (12%) patients while 17/48 (35%) experienced grade 2 urinary toxicity. Notably, no significant treatment emergent myelosuppression was evident in these patients. Dosing has been modified to a total daily dose of 840 mg (560 mg am/280 mg afternoon) to improve urinary tolerability. Other measures to manage urinary symptoms include hydration, sodium bicarbonate and dose reduction or interruption. Of 33 patients (3 with del5q) on intermittent dosing treated for at least 8 consecutive weeks, 15 (45%) achieved transfusion independence (TI or no RBC transfusion for at least 8 consecutive weeks) lasting 8 to 53+ weeks (median=17 weeks). Intent-to-treat analysis showed 17/48 (35%) patients achieved TI. Twelve of 15 responding patients were refractory to prior treatment with ESAs. Fourteen of 15 responding patients (11 out of 12 ESA refractory) received concomitant ESAs, suggesting an effect of rigosertib on ESA resistance or potential synergy with ESA. These effects are being explored in additional trials now in planning.There was no obvious correlation of response to karyotype or other classifications. We hypothesized that DNA methylation profiles could help explain the differences between responders and non-responders. Pre-therapy bone marrow mononuclear cells from 32 patients (including 4 from the prior Phase I study previously reported in ASH 2011) were analyzed using the Illumina 450K methylation array platform. Seven had complete response or CR (TI + increase in Hb >2Gm/dL), 10 had partial response or PR (TI without Hb increase) and 15 had no response or NR. Supervised hierarchical clustering by methylation intensity demonstrated a distinct profile associated with complete responders. Bisulfite sequencing (which allows quantification of multiple consecutive CpGs in an amplicon) of several differentially methylated loci confirmed the Illumina 450K data. In general, hypermethylation of a group of genes was associated with responders. Functional annotation of the hypo and hypermethylated genes which best distinguished CRs from NRs showed that the genes most affected by methylation were related to regulation of transcription followed by genes involved in cell-cell adhesion, inflammatory response, apoptosis and proliferation. Additional patient samples are being analyzed to confirm these results. In this interim analysis the observed correlation of hematological response to genomic methylation status suggests the possibility of preselecting patients likely to benefit from treatment with rigosertib. ConclusionsIntermittent dosing of oral rigosertib is well tolerated and active in producing transfusion independence in lower risk MDS patients. A genomic methylation signature, once confirmed in prospective studies, may allow pre-selection of responders. Disclosures:Raza:Onconova Therapeutics: Research Funding. Al-Kali:Onconova Therapeutics: Research Funding. Tibes:Onconova Therapeutics: Research Funding. Spitzer:Onconova Therapeutics: Research Funding. Wilhelm:Onconova Therapeutics: Employment, Equity Ownership. Mukherjee:Onconova Therapeutics: Research Funding.

Understanding Medical Care of Transplant Recipients through Integrated Registry and Pharmacy Claims Data

Background: Limited data exist on medication use aside from immunosuppression among large samples of kidney transplant recipients. Methods: We examined a novel database wherein Organ Procurement and Transplantation Network (OPTN) registry data were linked to records from a US pharmaceutical claims clearinghouse (2005-2010 claims) to examine pharmaceutical care at the first transplant anniversary (n = 16,157). We quantified the use of the following medication types within ±60 days of the first-year OPTN report according to estimated glomerular filtration rate (eGFR): antihypertensives, lipid-lowering, bone and mineral, and anemia treatments. Adjusted associations of medication use with eGFR and other clinical factors were quantified by multivariate logistic regression. Results: Requirements for multiple antihypertensive agents rose with lower eGFR, with β-blockers comprising the most commonly used antihypertensive agent. The adjusted likelihood of vitamin D (adjusted odds ratio (aOR) 2.07, 95% CI 1.19-3.59) and especially erythrocyte-stimulating agents (aOR 19.94, 95% CI 7.01-56.00) rose in a graded manner to peak with eGFR <15 versus >90, whereas statin use was most common with eGFR 30-59 ml/min/1.73 m². Black race was independently associated with increased use of all classes of antihypertensives and vitamin D, but lower adjusted statin use. Rapamycin-based immunosuppression was associated with increased use of statins and erythrocyte-stimulating agents. Conclusions: Integrated registry and pharmacy fill data provide a novel tool for pharmacoepidemiologic investigations of delivered post-transplant care. Transplant recipients with reduced renal function have increased requirements for pharmaceutical care of comorbidities. Causes of racial variation in medication fills warrant further investigation.

Phase II study of orally administered rigosertib (ON 01910.Na) in transfusion-dependent lower-risk myelodysplastic syndrome (MDS) patients.

7031 Background: Rigosertib, a novel small molecule inhibitor of PI3-Kinase and PLK pathways is currently evaluated (IV infusions) in a phase III trial in higher risk MDS patients who have failed hypomethylating agents. A previous phase I study found good bioavailability and activity of orally administered rigosertib in transfusion-dependent MDS patients (ASH 2011). Here we report preliminary results from an ongoing phase II study. Methods: This is a randomized, two-arm study of oral rigosertib (560 mg bid) administered either intermittently (2 out of 3 weeks) or continuously. Transfusion-dependent patients must have received at least 4 units RBC transfusions over 8 weeks before randomization, and can receive transfusions and erythrocyte stimulating agents (ESAs) while on study. Results: Twenty nine MDS patients (25 intermediate-1 and 4 low risk per IPSS classification) have been randomized as of December 17, 2012. Overall oral rigosertib was well tolerated except for a high incidence (5 of 9 patients) of grade 2+ urinary side effects (dysuria, hematuria, cystitis, and urinary urgency), in the continuous dosing arm. Accordingly, the protocol was amended to allow all patients to be treated with intermittent dosing, with option of dose interruption/reduction resulting in a much lower frequency of urinary side effects (4/20 patients with urinary grade 2+ toxicity). Fifteen patients (none of them with del5q cytogenetic) have been treated with intermittent dosing for at least 8 weeks. Seven (47%) patients achieved transfusion independence (no RBC transfusion for at least 8 consecutive weeks), which lasted 8 to 27 + weeks. Six of 7 responding patients were refractory to prior treatment with ESAs and 5 of these 7 patients received concomitant ESAs, suggesting an effect of rigosertib on ESA resistance. Conclusions: Preliminary results of this phase II study indicate that intermittent dosing of rigosertib administered orally is well tolerated and active in producing transfusion independence in approximately 50% transfusion dependent, lower risk MDS patients. The contributing role of rigosertib and ESAs in these transfusion responses is being investigated. Clinical trial information: NCT01584531.

ESAs in Transplant Anemia

ESAs in Transplant Anemia

Assessment and treatment of preoperative anemia: Continuing Professional Development

The purpose of this continuing professional development (CPD) module is to review the risk of anemia and transfusion in perioperative patients and to propose an approach for the diagnosis and treatment of preoperative anemia. Preoperative anemia has been associated with increased transfusion of red blood cells, organ injury, and mortality. Postoperative anemia has also been associated with impaired recovery from surgery. Transfusion also increases the risk of infection, organ injury, and mortality. Preoperatively, iron deficiency anemia can be corrected with oral or intravenous iron; certain types of patients might respond to administration of erythrocyte stimulating agents (ESAs). With ESAs, the increased risk of thrombosis should be balanced against the expected benefit. Preoperative diagnosis and treatment of anemia may reduce the risk of morbidity and mortality associated with both anemia and transfusion.

Vitamin D deficiency is an independent predictor of anemia in end-stage heart failure

Both, anemia and vitamin D deficiency are prevalent in patients with heart failure. According to recent evidence, vitamin D may stimulate erythropoiesis. We measured circulating 25-hydroxyvitamin D (25[OH]D), 1,25-dihydroxyvitamin D (1,25[OH](2)D) and hemoglobin (Hb) in a cross-sectional study in 364 end-stage heart failure patients awaiting cardiac transplantation, of whom 52.6% met the criteria for anemia (Hb < 13 g/dl in males and <12 g/dl in females). None of the patients were on erythrocyte-stimulating agents. Of the study cohort, 87.8% had 25(OH)D concentrations below 50 nmol/l. The mean Hb concentrations were significantly reduced in the lower tertiles of 25(OH)D and 1,25(OH)(2)D (P < 0.001). In multivariate-adjusted logistic regression analyses, the odds ratios for anemia of the lowest tertile of 25(OH)D (<18 nmol/l) and 1,25(OH)(2)D (<40 pmol/l) were 2.69 (1.46-5.00) and 4.08 (2.18-7.62) compared with their respective highest tertile (>32 nmol/l and >70 pmol/l). Patients with severe dual deficiency of 25(OH)D and 1,25(OH)(2)D had an odds ratio for anemia of 9.87 (95% CI 3.59-27.1) compared with patients in the highest tertile for both vitamin D metabolites. Circulating 1,25(OH)(2)D was directly related to circulating 25(OH)D levels and kidney function (P < 0.001), and inversely associated with C-reactive protein (P = 0.020). Our data demonstrate that vitamin D deficiency is independently associated with low Hb values and anemia in end-stage heart failure. Circulating 1,25(OH)(2)D is a better predictor of anemia than circulating 25(OH)D. Prospective randomized studies with administration of vitamin D (metabolites) will have to clarify if the association of vitamin D deficiency with anemia is causal.

Cardiovascular Risks of Anemia Correction with Erythrocyte Stimulating Agents: Should Blood Viscosity Be Monitored for Risk Assessment?

To date, all major clinical trials for anemia correction using erythrocyte stimulating agents (ESAs) failed to show improved outcomes for cardiovascular disease (CVD), stroke, and vascular thrombosis. Even moderate elevations in hemoglobin (e.g., to 13 g/dL) using erythropoietin have been associated with significantly increased risk of thrombotic cardiovascular events and heart failure. This review presents a biophysical rationale for increased risk of CVD among certain patients treated with ESAs and suggests a risk management approach based on blood viscosity. Whole blood viscosity is a key determinant of the work of the heart, and elevated blood viscosity appears to be both a strong predictor of cardiovascular disease and an important pathophysiological factor in the development of atherothrombosis. Blood donation has been shown to reduce viscosity. Reflecting these findings, studies in male blood donors and in women of premenopausal age with regular menstruation have shown reduced incidence of cardiovascular events such as myocardial infarction, angina, stroke, and the requirement for procedures such as percutaneous transluminal coronary angioplasty and coronary artery bypass graft compared with non-donors and postmenopausal women, respectively. We propose that blood viscosity monitoring should be considered as part of a cardiovascular risk assessment, whenever an increased cardiovascular risk is detected and particularly in the context of anemia correction.

A Dialysis Case Presentation and Discussion Edited by Roger A. Rodby: Bullous Skin Lesions in a Patient Undergoing Chronic Hemodialysis

Porphyria cutanea tarda (PCT) is a vesiculobullous skin disorder characterized by a defect in heme biosynthesis. Reduced activity of the hepatic enzyme uroporphyrinogen decarboxylase (URO-D) results in accumulation of photosensitive porphyrins; this ultimately leads to the skin fragility and blistering that is characteristic of this disease. The majority of cases of PCT are associated with acquired deficiencies of the enzyme URO-D, secondary to hepatic injury precipitated by medications or infections. Less commonly, PCT has been documented in patients with end-stage renal disease. The pathogenesis of PCT in long-term hemodialysis (HD) has been attributed to many factors, but the following mechanisms have been implicated: (i) decreased hepatic URO-D activity due to suppressive effects of iron and other hepatotoxins and (ii) poor porphyrin clearance by renal replacement therapies. We report a case of PCT that developed in a patient on maintenance HD for 4 years. He had a history of hepatitis C and evidence of iron overload. However, as the patient was anemic, therapeutic phlebotomy was problematic and therefore erythrocyte-stimulating agents were maximized to mobilize iron stores and allow phlebotomy. With this treatment, the patient's skin lesions improved in conjunction with decreasing ferritin levels.

Does TREAT Give the Boot to ESAs in the Treatment of CKD Anemia?

> “It was the best of times, it was the worst of times, it was the age of wisdom, it was the age of foolishness, it was the epoch of belief, it was the epoch of incredulity, it was the season of Light, it was the season of Darkness, it was the spring of hope, it was the winter of despair, we had everything before us, we had nothing before us, we were all going direct to Heaven, we were all going direct the other way.” > > Charles Dickens, A Tale of Two Cities , 18591 The recently published landmark study the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT)2 has turned the world of anemia management upside down. Patients who have chronic kidney disease (CKD) and anemia and literally could not get up in the morning will despair that insurance companies will put erythrocyte-stimulating agents (ESAs) beyond their reach. Insurance companies and Medicare may look at this as the “season of Light.” TREAT provides definitive evidence to justify making tough reimbursement decisions: Restricting the use of ESAs to symptomatic patients or those who are awaiting kidney transplantation. Some in the academy will view the era before the anemia trials as “the age of foolishness”: ESA treatment decisions and guidelines based on flawed data using hemoglobin (Hb) as a nonvalidated surrogate. Biotechnology companies looking to bring a new epoetin molecule to the market might view this as “the season of Darkness” because the market for their new drug has just vaporized; however, my guess is that most nephrologists will be confused, some perhaps incredulous. How should the results of the TREAT study and those of the major anemia trials preceding it be interpreted in terms of making decisions about treating individual patients? TREAT2 is a placebo-controlled, double-blind, randomized study that comprised 4038 patients and was neutral for its …

Patterns of Hypomethylating Agent and Transfusion Use in Myelodysplastic Syndrome: a Claims Database Study.

Abstract 2490Poster Board II-467 Introduction:Myelodysplastic syndrome (MDS) is characterized by ineffective hematopoiesis, multilineage dysplasia, peripheral cytopenias, and susceptibility to leukemic transformation. Supportive treatments include red blood cell (RBC) and platelet (PLT) transfusions as well as erythrocyte stimulating agents (ESAs) to correct disease-induced cytopenias. Active treatment with hypomethylating agents (HMAs) have been shown in clinical trials to reduce transfusion dependence and leukemic progression among patients with MDS. The purpose of this study is to describe the patterns of care among patients with MDS, and outcomes associated with HMA treatment options. Methods:Data were obtained from the MarketScan® database, which contains pharmacy, medical, hospital, and laboratory claims for several million members, from January 2002 through June 2008. Inclusion criteria included: age 18 or older; at least 2 claims with an ICD-9 diagnosis of MDS in 2006 or later; at least 6 months of pre-diagnosis health plan enrollment; at least 4 months of enrollment after initial HMA treatment; at least 1 complete cycle of decitabine (DAC; 5 treatments) or azacitidine (AZA, 7 treatments). Patients were excluded if they were treated with lenalidomide, had a prior cancer diagnosis, prior treatment with DAC or AZA, or had other isolated cytopenia or myeloproliferative diagnoses. Patients with a diagnosis of acute myelogenous leukemia within the first 28 days of treatment were also excluded. Descriptive statistics characterized patient demographics, including time between diagnosis and treatment, days per cycle, use of ESA, and number of treatment cycles. Logistic regression assessed predictors of HMA treatment using age at MDS diagnosis, gender, Charlson Comorbidity Index (CCI), and calendar year as predictors. Poisson regression compared the risk of RBC or PLT transfusion between DAC and AZA, controlling for age, gender, CCI, treatment cycles, time to initiating treatment, and follow-up duration. Results:2525 patients met full inclusion criteria (51% female), of whom 95.4% received no HMA treatment. Logistic regression revealed that females were less likely to receive HMA therapy (OR 0.486, p<0.001). There was no significant difference in follow-up duration between the DAC and AZA groups. Over 50% of HMA-treated patients received 4 or more treatment cycles, with no significant difference between DAC (n=37) and AZA (n=60). Mean (SD) days from MDS diagnosis to first treatment was 93.7 (101.4) for DAC vs. 50.8 (73.4) for AZA (p=0.03). Median treatment days per cycle were 4.86 for DAC and 5.00 for AZA (p>0.05). Mean (SD) days to discontinuation of RBC/PLT transfusion was 15.8 (48.3) for DAC and 70.1 (136.1) for AZA (p<0.05). The RBC/PLT transfusion rate was lower for DAC than for AZA (0.06 vs 0.17 per month, p<0.05). Poisson regression found a significantly lower likelihood of RBC/PLT transfusion in the DAC group (OR=0.206, p<0.05). Use of ESA did not differ between treatments (p>0.05). Discussion:Only a small portion of MDS patients receive HMA treatments, with females less likely to receive drug therapy. Initiation of decitabine occurs later than azacitadine after MDS diagnosis for unclear reasons. Decitabine is associated with lower rates of RBC/PLT transfusion and shorter time to discontinuation of transfusions, consistent with a prompt time to clinical response. Further research is needed to clarify optimal initiation timing for HMA treatment to maximize therapeutic benefits. Disclosures:Hatoum:Eisai Inc.: Research Funding. Lin:Eisai Inc.: Research Funding. Buchner:Eisai Inc.: Employment. Kim:Eisai Inc.: Employment.

Vitamin D deficiency and anemia: a cross-sectional study

Vitamin D has been suggested to have an effect on erythropoiesis. We sought to evaluate the prevalence of anemia in a population of individuals with vitamin D deficiency compared with those with normal levels in a population of a large integrated healthplan. A cross-sectional analysis in the period 1 January 2004 through 31 December 2006 of subjects with documented concurrent levels of 25-hydroxyvitamin D and hemoglobin were evaluated. Vitamin D deficiency was defined as <30 ng/mL and anemia was defined as a hemoglobin <11 g/dL. A total of 554 subjects were included in the analysis. Anemia was present in 49% of 25-hydroxyvitamin D-deficient subjects compared with 36% with normal 25-hydroxyvitamin D levels (p < 0.01). Odds ratio for anemia in subjects with 25-hydroxyvitamin D deficiency using logistic regressions and controlling for age, gender, and chronic kidney disease was 1.9 (95% CI 1.3–2.7). 25-hydroxyvitamin D-deficient subjects had a lower mean Hb (11.0 vs. 11.7; p = 0.12 ) and a higher prevalence of erythrocyte stimulating agent use (47% vs. 24%; p < 0.05). This study demonstrates an association of vitamin D deficiency and a greater risk of anemia, lower mean hemoglobin, and higher usage of erythrocyte-stimulating agents. Future randomized studies are warranted to examine whether vitamin D directly affects erythropoiesis.