Comparison of Packed Cell Volume Changes after Erythropoietin Administration and Blood Transfusion in Patients with Anemia of Chronic Kidney Disease on Hemodialysis

Introduction: Anemia of chronic kidney disease (CKD) can be managed by regular administration of erythropoiesis stimulating agents (ESAs) and/or blood transfusion. The response to these therapies can be monitored by serial packed cell volume (PCV). Objective: This study was done to compare the temporal changes in PCV after ESA therapy and blood transfusion in patients with recently diagnosed anemia in CKD stage 5 on hemodialysis (CKD 5 HD). Methods: Medical records of patients undergoing hemodialysis at the National Kidney Center, Balaju, Kathmandu from July to September 2013 were examined retrospectively. The data collected were analyzed using Minitab 16. Results: A total of 44 patients were on ESA therapy while 48 patients were on blood transfusion. The mean PCV at the start of blood transfusion was significantly lower than the mean PCV at the start of ESA therapy (p = 0.000) but at four weeks, the mean PCV in blood transfusion group was significantly greater than that in ESA therapy group (p = 0.008). At eight weeks and twelve weeks, the mean PCVs in both groups were not significantly different from each other (p = 0.949 and p = 0.747). Conclusions: Blood transfusion increases PCV immediately and in sustained manner while with ESA therapy, the response takes a longer time to manifest. A large number of non-responders to ESA therapy may have influenced the findings of this study. It is recommended that adequate dosing of ESA and attention to comorbid conditions be followed during ESA therapy. Keywords: Anemia; chronic renal insufficiency; blood transfusion; hematinics.

MO556TREATMENT OF ANAEMIA WITH ERYTHROPOIESIS STIMULATION AGENTS (ESAS) AND CONCOMITANT THERAPIES AMONG PATIENTS WITH NON-DIALYSIS DEPENDENT CHRONIC KIDNEY DISEASE (NDD-CKD) IN GERMANY, SPAIN AND THE UK: A RETROSPECTIVE CHART REVIEW

Background and Aims Among patients with CKD, prevalence of anaemia increases with CKD severity,1 and is accompanied by elevated risk of hospitalisation and mortality.2 Treatment options include iron therapy and ESAs; international guidelines recommend initiating ESA therapy when haemoglobin (Hb) declines <10 g/dL, and to monitor Hb and iron status every 3 months during ESA treatment.3 This study aimed to describe the routine clinical management of patients with NDD-CKD and anaemia following ESA initiation, in Germany, Spain and the UK. Method This was a non-interventional, retrospective cohort study of adults with NDD-CKD stages 3b–5 (as defined in KDIGO 2012 guidelines)1 diagnosed with anaemia (Hb <13.0 g/dL [males] or <12.0 g/dL [females]), who began ESA treatment 01 Jan 2015–31 Dec 2015 inclusive. Data for ≤24 months after ESA initiation were extracted from medical records: patient characteristics; anaemia diagnosis and treatment (including iron and ESA use); Hb, serum ferritin and transferrin saturation (TSAT) measurements; and CKD-related outcomes. Patients were excluded if they had been diagnosed with end-stage kidney disease at baseline, or previously received a kidney transplant or dialysis. Results In total, 848 patient records (Germany, 211; Spain, 430; UK, 207) were included. Average age was 66 years (Table). Most patients were white and almost half had >2 comorbidities. Prior to ESA initiation, at least half of all patients in each country received either oral or intravenous (IV) iron therapy. The average (mean ± SD) number of months between anaemia diagnosis and initiation of ESA therapy was 8.4 ± 19.2. Hb levels were recorded at ESA initiation for almost all (91.3%) patients and averaged 9.8 ± 1.0 g/dL for the total cohort; this initial Hb level was similar between countries (Table). Mean ± SD estimated glomerular filtration rate (eGFR) at ESA initiation was 28.0 ± 10.4 ml/min/1.73m2. Across countries, 72–88% of patients received ESAs at home. The mean ± SD duration of therapy (at the time of data collection) was 41.2 ± 18.2 months, and the median weekly dose of short-acting and long-acting ESAs was 3238 IU and 20 μg, respectively. During their initial course of therapy, three-quarters of patients had either an increase or decrease in ESA dose. Less than 10% of patients switched ESAs, while approximately one-third discontinued within 2 years of initiation. At 3 and 6 months post-ESA initiation, only 64.7% of the sample had a documented Hb measurement despite continuing ESA treatment; this proportion was further reduced to 60.0% by 12 months after initiation. The Hb target was maintained by 88.7%, 74.6% and 49.4% of patients at 3, 6 and 12 months, respectively. Mean ferritin levels were 167.3 ng/mL at initiation and 198.7 ng/mL at 12 months (among the 85% and 48% of the sample, respectively, with recorded data). Mean TSAT was 22.1% at initiation and 25.6% at 12 months (among the 67% and 38%, respectively, with recorded data). Approximately three-quarters of patients (77.3%) received iron therapy concomitantly with ESA treatment; in the UK, most of these received IV iron, while in Germany and Spain, a majority received oral iron (Table). Blood transfusions were more common in Spain (24.2%) than in Germany (5.1%) or the UK (8.4%). Approximately one-fifth of patients required dialysis. Conclusion Initiation of ESAs to treat anaemia among patients with NDD-CKD in Germany, Spain and the UK follows current guidelines. However, recommendations to regularly monitor Hb were not routinely followed or were poorly documented. As most patients with NDD-CKD anaemia were treated at home, oral therapies may be of benefit to these patients

Anaemia in chronic kidney disease – a review

The management of anaemia in chronic kidney disease (CKD) patients is a complex, multifaceted process reliant on the administration of exogenous erythropoiesis stimulating agents (ESAs) and iron supplements to ensure the adequate production of viable erythrocytes. Recommended best practice guidelines should be adhered to in order to ensure favourable treatment outcomes whilst minimising the risks often associated with ESA therapy. A paucity in readily available, accurate data makes quantifying the extent to which renal anaemia affects our population and how it is managed challenging, however it is expected to follow international trends. Novel preparations for treating renal anaemia are currently in the clinical trial phase, therefore the potential benefits and risks have yet to be confirmed.

P1379PLATELET/LYMPHOCYTE RATIO AS A MARKER OF ERYTHROPOIETIN RESPONSIVENESS IN END-STAGE RENAL DISEASE

Background and Aims Neutrophil/Lymphocyte Ratio (NLR) and Platelet/Lymphocyte Ratio (PLR) are closely associated with increased inflammation in end-stage renal disease, which often contributes to the severity of anemia in these patients. Erythropoiesis stimulating agents (ESA) have become a standard treatment of anemia in hemodialysis patients. Since some patients do not respond well to erythropoietin therapy (EPO) the aim of this study is to investigate if NLR and PLR as markers of increased inflammation, could be associated with resistance to EPO therapy. Method A total of 90 patients (36 females, 54 males; mean age 60,45 ±11,58) undergoing maintenance hemodialysis and who received recombinant human EPO therapy were examined. Patients' clinical characteristics, laboratory data, dialysis adequacy and the applied doses os EPO were examined in a period of 3 months. EPO hyporesponsiveness index (EHRI) was calculated as the weekly dose of EPO divided by kilograms of body weight divided by the hemoglobin level. Results Obtained results show a statistically significant correlation of moderate-intensity between EHRI and NLR ( r = 0.497, p < 0.01) as well as a negative correlation of moderate-intensity between EHRI and hemoglobin levels (Hgb) (r = -0.403, p < 0.01). When it comes to the connection of NLR and PLR with logarithmically converted EHRI values, the results show that there is no statistically significant correlation between NLR and EHRI. Comparison of PLR among 25th, 50th and 75th percentile of EHRI showed that PLR levels increased going from the 25th towards the 75th percentile (p < 0.01). Post hoc analysis indicated that there is also a statistically strong connection for the 25th i 50th percentile (<0 .05) and furthermore for the 50th and 75th percentile (< 0.05). Conclusion PLR was found to be superior to NLR in terms of evaluating ESA therapy resistance. PLR could be used as a predictor of ESA therapy response.

Soluble Fas affects erythropoiesis in vitro and acts as a potential predictor of erythropoiesis-stimulating agent therapy in patients with chronic kidney disease

Serum soluble Fas (sFas) levels are associated with erythropoietin (Epo) hyporesponsiveness in patients with chronic kidney disease (CKD). Whether sFas could predict the need for erythropoiesis-stimulating agent (ESA) usage and its influence in erythropoiesis remain unclear. We evaluated the relation between sFas and ESA therapy in patients with CKD with anemia and its effect on erythropoiesis in vitro. First, we performed a retrospective cohort study with 77 anemic patients with nondialysis CKD. We performed in vitro experiments to investigate whether sFas could interfere with the behavior of hematopoietic stem cells (HSCs). HSCs were isolated from umbilical cord blood and incubated with recombinant sFas protein in a dose-dependent manner. Serum sFas positively correlated with Epo levels ( r = 0.30, P = 0.001) but negatively with hemoglobin ( r = −0.55, P < 0.001) and glomerular filtration rate ( r = −0.58, P < 0.001) in patients with CKD at baseline. Elevated sFas serum levels (4,316 ± 897 vs. 2,776 ± 749, P < 0.001) with lower estimated glomerular filtration rate (26.2 ± 10.1 vs. 33.5 ± 14.3, P = 0.01) and reduced hemoglobin concentration (11.1 ± 0.9 vs. 12.5 ± 1.2, P < 0.001) were identified in patients who required ESA therapy compared with patients with non-ESA. Afterward, we detected that the sFas level was slight correlated with a necessity of ESA therapy in patients with nondialysis CKD and anemia. In vitro assays demonstrated that the erythroid progenitor cell frequency negatively correlated with sFas concentration ( r = −0.72, P < 0.001). There was decreased erythroid colony formation in vitro when CD34+ HSCs were incubated with a higher concentration of sFas protein (1.56 ± 0.29, 4.33 ± 0.53, P < 0.001). Our findings suggest that sFas is a potential predictor for ESA therapy in patients with nondialysis CKD and that elevated sFas could affect erythropoiesis in vitro.

Levocarnitine Injections Decrease the Need for Erythropoiesis-Stimulating Agents in Hemodialysis Patients with Renal Anemia

Aims: The aim of this study was to evaluate the efficacy of levocarnitine injection for renal anemia in hemodialysis patients. Methods: In this randomized controlled clinical trial, we randomly assigned patients on maintenance hemodialysis at our hospital to receive levocarnitine injections (n = 30) or no injection (n = 30) and monitored the patients during 12 months of treatment. In the treatment group, patients received an injection of levocarnitine 1,000 mg 3 times weekly after hemodialysis sessions. All patients received recombinant human erythropoietin as an erythropoiesis-stimulating agent (ESA). Response to ESA therapy was determined by calculating the erythropoietin responsiveness index (ERI; ESA dose·kg-1·g-1· dL-1·week-1). Results: (1) The target levels of hemoglobin and hematocrit were maintained during the study period in both the levocarnitine group and the control group. (2) The dose of ESAs required to maintain these levels decreased gradually in the levocarnitine group and was significantly lower at 6 and 12 months than at study initiation. Furthermore, the dose of ESAs was significantly lower than that in the control group at 12 months. (3) The ERI showed a significant decrease at 6 and 12 months in the levocarnitine group, with a significant difference between the 2 groups at 12 months. Conclusion: Our results suggest that levocarnitine administration can reduce the dose of ESAs required in patients with renal anemia on hemodialysis and improve the response to ESA therapy.

Evaluation of the Impact of a New Synthetic Vitamin E-Bonded Membrane on the Hypo-Responsiveness to the Erythropoietin Therapy in Hemodialysis Patients: A Multicenter Study

Background: Oxidative stress has been related to hypo-response to erythropoiesis-stimulating agents (ESAs) in hemodialysis (HD) patients. The aim of this study was to verify whether vitamin E (ViE) on a synthetic polysulfone dialyzer can improve ESA responsiveness. Methods: This controlled, multicenter study involved 93 HD patients on stable ESA therapy, who were randomized to either ViE-coated polysulfone dialyzer or to a low-flux synthetic dialyzer. The primary outcome measure was the change in ESA resistance index (ERI) from baseline. Results: Mean ERI decreased in the ViE group by 1.45 IU/kg*g/dl and increased in the control group by 0.53 IU/kg*g/dl, with a mean difference of 1.98 IU/kg*g/dl (p = 0.001 after adjusting for baseline ERI, as foreseen by the study protocol). Baseline ERI was inversely related to its changes during follow-up only in the control group (R2 = 0.29). Conclusions: The ViE dialyzer can improve ESA response in HD patients. Changes in ERI during follow-up are independent from baseline ERI only in the ViE group. Video Journal Club ‘Cappuccino with Claudio Ronco' at http://www.karger.com/?doi=453442.

Impact of Erythropoietic Stimulating Agents on Mutational Composition in Patients with Low-Risk Myelodysplastic Syndromes

Background:Chronic anemia is most often the presenting symptom and major issue for patients (pts) with low-risk myelodysplastic syndrome (LR-MDS). Erythropoietic stimulating agents (ESAs) are the initial therapy for many LR-MDS pts and can predictably yield benefit in pts with low transfusion burden and a low erythropoietin (EPO) level. (Hellstrom-Lindberg, 2013). However, only about 40-50% of pts respond to erythropoietin (ESAs). We posit that improvement of the predictive algorithm for response to ESA therapy might be optimized with inclusion of molecular mutation informatics. If validated, the model could inform those pts with risk of ESA treatment failure and thus favor alternative approaches such as hypomethylating therapy (Thus, sparing unnecessary pt exposure, cost and time to an ineffective agent, as well as delay to delivery of a possibly more effective therapy). Furthermore, the impact of EPO stimulation/treatment on the clonal dynamics of LR-MDS is not yet well understood nor described. Thus, we analyzed molecular profiles of LR-MDS pts in order to identify mutations associated with ESA failure and the subsequent clonal alterations post ESA exposure. Methods:Of 394 pts who had LR-MDS based on International Prognostic Scoring System (IPSS) criteria, and were treated at Cleveland Clinic from 2002-2015, we studied 49 primary cases with clinical and mutational data. Next generation targeted deep sequencing was performed for a panel of 60 genes that are known to be commonly mutated in myeloid malignancies. ESA response was assessed in the first 8 weeks of treatment according to International Working Group (IWG) criteria (Cheson, 2006). We further studied clonal alterations upon ESA treatment in a small subset of patients who had sequential samples during the course of treatment. Results: Median age of 50 pts was 76 yrs (range, 45-87) and 56% were male. 28% had MDS with single lineage dysplasia, 21% had MDS with ringed sideroblasts, 38% had MDS with multilineage dysplasia, 6% had isolated del(5q), and 7% had MDS-unclassifiable. 65% had normal cytogenetics at diagnosis and 44% had low EPO level at baseline. 43% of pts responded to ESA therapy. Mutations commonly found in our cohort included SF3B1 (25% in responders vs 22% in non-responders), U2AF1 and DNMT3A (15% in responders vs 11% in non-responders), ASXL1 (10% in responders vs 15% in non-responders), and TET2 (10% in responders vs 11% in non-responders). In 20 responders, 2 cases had CBL2 mutation, while 2 other cases harbored JAK2 mutation, which were not detected in non-responders. In 27 non-responders, NGS identified EZH2, ETV6, and RUNX1 mutations in 2 individual cases while one case harbored both ETV6 and RUNX1 mutations. None of these mutations were found in responders. Of interest, among 8 patients who had low baseline EPO level without response to ESA, 3 patients harbored RUNX1 mutation. Serial analysis of eight cases revealed genomic diversity that may give insight to prognostic models for EPO response. For example, we found in one case who had a U2AF1, CBL mutations prior to starting ESA, at the time of evolution to AML this pt had acquired additional mutations involving RUNX1, IDH1, and GPR98. Additional cases with high risk mutations at presentation including EZH2, ASXL1, DNMT3A, U2AF1did not respond and evolved to secondary acute myeloid leukemia (sAML). Conclusions: Evaluation of the mutational spectrum in LR-MDS patient, revealed insight into clonal dynamics that may be determinants of EPO responsiveness. We found in our cohort that LR-MDS individuals harboring RUNX1 and ETV6 mutations did not respond to ESA directed therapy and were noted to evolve to high risk MDS or sAML. Notably, pts with SF3B1 mutations can respond to ESA therapy but not all pts appear to reliably do so. These mutational data will inform a future algorithm to help predict ESA responsive patients in LR-MDS that will require prospective validation. Disclosures Carraway: Novartis: Membership on an entity's Board of Directors or advisory committees; Baxalta: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees.