Evaluation of recombinant human erythropoietin responsiveness by measuring erythrocyte creatine content in haemodialysis patients

Background One of the main causes of anaemia in patients with end-stage renal disease is relative deficiency in erythropoietin production. Eythropoiesis stimulating agent (ESA), a potent haematopoietic growth factor, is used to treat anaemia in haemodialysis patients. The effect of ESA is usually assessed by haematological indices such as red blood cell count, haemoglobin concentration and haematocrit, but erythrocyte indices do not provide information of the rapid change in erythropoietic activity. As erythrocyte creatine directly assess erythropoiesis, the aim of this study was to evaluate the effect of ESA in haemodialysis patients by measuring the erythrocyte creatine content. Methods ESA dose was fixed 3 months prior to the enrollment and was maintained throughout the entire study period. Erythrocyte creatine was measured with haematologic indices in 83 haemodialysis patients. Haemoglobin was also measured 3 months after. Results ESA dose (152.4 ± 62.9 vs. 82.2 ± 45.5 units/kg/week, P = 0.0001) and erythrocyte creatine (2.07 ± 0.73 vs. 1.60 ± 0.41 μmol/gHb, p = 0.0003) were significantly higher in 27 patients with haemoglobin <10 g/dL compared to 56 patients with haemoglobin ≥10 g/dL. There was a fair correlation between ESA dose and the concentration of creatine in the erythrocytes (r = 0.55, P < 0.0001). Increase in haemoglobin (>0.1 g/dL) was observed in 37 patients, whereas haemoglobin did not increase in 46 patients. Erythrocyte creatine levels were significantly higher in those patients with an increase in haemoglobin compared to those without (2.04 ± 0.64 vs. 1.52 ± 0.39 μmol/gHb, p < 0.0001). When 8 variables (ESA dose, erythropoietin resistance index, C-reactive protein, intact parathyroid hormone, iron supplementation, presence of anaemia, erythrocyte creatine and reticulocyte) were used in the multivariate logistic analysis, erythrocyte creatine levels emerged as the most important variable associated with increase in haemoglobin (Chi-square = 6.19, P = 0.01). Conclusion Erythrocyte creatine, a useful marker of erythropoietic capacity, is a reliable marker to estimate ameliorative effectiveness of ESA in haemodialysis patients.

Evaluation of Recombinant Human Erythropoietin Responsiveness by Erythrocyte Creatine in Haemodialysis Patients

Background: One of the main causes of anaemia in patients with end-stage renal disease is relative deficiency in erythropoietin production. Recombinant human erythropoietin (rHuEpo), a potent haematopoietic growth factor, is used to treat anaemia in haemodialysis patients. The effect of rHuEpo is usually assessed by haematological indices such as red blood cell count, haemoglobin concentration and haematocrit, but erythrocyte indices do not provide information of the rapid change in erythropoietic activity. As erythrocyte creatine directly assess erythropoiesis, the aim of this study was to evaluate the effect of rHuEpo in haemodialysis patients by measuring erythrocyte creatine. Methods: rHuEpo dose was fixed 3 months prior to the enrollment and was maintained throughout the entire study period. Eerythrocyte creatine was measured with haematologic indices in 83 haemodialysis patients. Haemoglobin was also measured 3 months after. Results: rHuEpo dose (152.4±62.9 vs. 82.2±45.5 units/kg/week, P=0.0001) and erythrocyte creatine (2.07±0.73 vs. 1.60±0.41 µmol/gHb, p=0.0003) were significantly higher in 27 patients with haemoglobin <10g/dL compared to 56 patients with haemoglobin ≥10g/dL. There was a fair correlation between rHuEpo dose and erythrocyte creatine (r=0.55, P <0.0001). Increase in haemoglobin (>0.1g/dL) was observed in 37 patients, whereas haemoglobin did not increase in 46 patients. Erythrocyte creatine was significantly higher in patients with increase in haemoglobin compared to those without (2.04±0.64 vs. 1.52±0.39 µmol/gHb, p <0.0001). When 8 variables (rHuEpo dose, erythropoietin resistance index, C-reactive protein, intact parathyroid hormone, incidence of iron deficiency, presence of anaemia, erythrocyte creatine and reticulocyte) were used in the multivariate logistic analysis, erythrocyte creatine emerged as the most important variable associated with increase in haemoglobin (Chi-square=6.19, P=0.01). Conclusion: Erythrocyte creatine, a useful marker of erythropoietic capacity, is a reliable marker to estimate ameliorative effectiveness of rHuEpo in haemodialysis patients.

Relationships among the Dosage of Erythropoiesis-Stimulating Agents, Erythropoietin Resistance Index, and Mortality in Maintenance Hemodialysis Patients

<b><i>Background:</i></b> Erythropoiesis-stimulating agents (ESAs) constitute an important treatment option for anemia in hemodialysis (HD) patients. We investigated the relationships among the dosage of ESA, erythropoietin resistance index (ERI) scores, and mortality in Chinese MHD patients. <b><i>Methods:</i></b> This multicenter observational retrospective study included MHD patients from 16 blood purification centers (<i>n</i> = 824) who underwent HD in 2011–2015 and were followed up until December 31, 2016. We collected demographic variables, HD parameters, laboratory values, and ESA dosages. Patients were grouped into quartiles according to ESA dosage to study the effect of ESA dosage on all-cause mortality. The ERI was calculated as follows: ESA (IU/week)/weight (kg)/hemoglobin levels (g/dL). We also compared outcomes among the patients stratified into quartiles according to ERI scores. We used the Cox proportional hazards model to measure the relationships between the ESA dosage, ERI scores, and all-cause mortality. Using propensity score matching, we compared mortality between groups according to ERI scores, classified as either &#x3e; or ≤12.80. <b><i>Results:</i></b> In total, 824 patients were enrolled in the study; 200 (24.3%) all-cause deaths occurred within the observation period. Kaplan-Meier analyses showed that patients administered high dosages of ESAs had significantly worse survival than those administered low dosages of ESAs. A multivariate Cox regression identified that high dosages of ESAs could significantly predict mortality (ESA dosage &#x3e;10,000.0 IU/week, HR = 1.59, 95% confidence intervals (CIs) (1.04, 2.42), and <i>p</i> = 0.031). Our analysis also indicated a significant increase in the risk of mortality in patients with high ERI scores. Propensity score matching-analyses confirmed that ERI &#x3e; 12.80 could significantly predict mortality (HR = 1.56, 95% CI [1.11, 2.18], and <i>p</i> = 0.010). <b><i>Conclusions:</i></b> Our data suggested that ESA dosages &#x3e;10,000.0 IU/week in the first 3 months constitute an independent predictor of all-cause mortality among Chinese MHD patients. A higher degree of resistance to ESA was related to a higher risk of all-cause mortality.

MO901ASSOCIATION OF MALNUTRITION AND INFLAMMATION WITH ERYTHROPOIETIN RESISTANCE INDEX

Background and Aims Erythropoietin Resistance Index (EPORI) has been previously associated with higher risk of mortality and morbidity in hemodialysis (HD) patients (pts). The objectives of this study were to identify which factors, such as the risk of malnutrition, are associated with EPORI and to assess its association with mortality and hospitalization risk. Method Historical cohort study in a group of high-flux HD pts from 25 outpatient HD clinics, starting from a baseline group of 2975 pts. We evaluated EPORI, interdialytic weigh gain (IDWG), Malnutrition Inflammation Score (MIS) and the other parameters at the study baseline. For a better understanding of weight gain patterns, we calculated the average of the IDWG at the day of monthly blood sample collection of the previous 3 months, values &gt;4% were considered high. A MIS&gt;5 indicated nutritional risk. Results We analyzed 2044 pts, 1148 (56%) males, 642 (31%) diabetic, with a mean age 68.4±14.12 years, a mean HD vintage 105±74 months and mean EPORI 7.23±7.51 (U/week/kg)/(g/dL). During a follow-up of 48 months, 719 pts (35%) died and 1291 pts (63%) were hospitalized at least once after baseline assessment, 531 pts and 400 pts were excluded because follow up was not possible and EPORI data was not available, respectively. ROC curve analysis identified different cut-off values for EPORI in relation with all-cause mortality and hospitalizations. Univariable analysis An EPORI&gt;5 was associated with higher MIS (7.06±3.9, vs 6.02±3.48, p&lt;0.001), higher IDWG (3.15±1.23 vs 1.26±1.09, p&lt;0.001), lower Hematocrit (Htc) (33.26±3.17 vs 33.69±2.61, p&lt;0.001), higher C-Reactive Protein (CRP) 14.94±24.45 vs 10.4±18.9, p&lt;0.001), female gender (57% vs 48%, p&lt;0.001), death (58% vs 49%, p&lt;0.001) and hospitalization (55% vs 47%, p&lt;0.001). When analyzing with Kaplan-Meier estimator using log-rank test to compare survival curves, mortality and hospitalizations were increased in all sub-groups with higher values for EPORI (cut-offs of 5 to 8) when compared, respectively, with lower EPORI values. Multivariable analysis The predictors of EPORI were MIS&gt;5 (OR 1.564, p&lt;0.001), IDWG (OR 1.234, p&lt; 0.001), CRP (OR 1.010, p&lt;0.001) and Htc (OR 0.948, p&lt;0.001). In similar models, adjusting for MIS&gt;5 (p&lt;0.001), gender (p&lt;0.001), age (p&lt;0.001), CRP (p&lt;0.001) and dialysis vintage (p&lt;0.001), different EPORI cut-off values were associated with higher risk of mortality and hospitalizations. Conclusion In the modern hemodialysis era, higher EPORI cut-off values were associated with a progressive higher risk of mortality and of hospitalization. The modification of the EPORI predictors that are susceptible to improvement, such as the nutritional and inflammation status, may contribute for a better prognosis in this population.

Erythropoietin Resistance Index and the Affecting Factors in Children with Peritoneal Dialysis

<b><i>Background:</i></b> Erythropoiesis-stimulating agents (ESAs) are used to treat anemia in CKD. Erythropoietin resistance index (ERI) is a useful tool used to evaluate the response to ESAs. In this study, we aimed to evaluate the causes of high ERI in children undergoing peritoneal dialysis (PD). <b><i>Method:</i></b> Patients who had been on PD for at least 1 year were included in this retrospective study. Demographic characteristics, residual kidney function (RKF), adequacy of dialysis, peritoneal glucose exposure, the number and reason for hospitalization, and medications were recorded. Anemia and laboratory parameters that may affect anemia were noted by taking the average of laboratory values in the last follow-up year (time-averaged). The weekly ESA dose was proportioned to the annual average hemoglobin value and body weight to calculate the ERI in terms of U/kg/week/g/dL. <b><i>Results:</i></b> A total of 100 patients were included in the study. The mean ESA dose and ERI value were 119.8 ± 66.22 U/kg/week and 13.01 ± 7.52 U/kg/week/g/dL, respectively. It was determined that the patients &#x3c;5 years of age have very high ERI value, and these patients need 2 times more ESA than those &#x3e;10 years of age. Absence of RKF, large number of hospitalization, and ACEI use were also found to affect the ERI value negatively. <b><i>Conclusion:</i></b> We demonstrate that the most important factor affecting ERI value is young age. We also reveal that absence of RKF, large number of hospitalization, and ACEI use are also important variables affecting the ERI value.

Using a generic definition of cachexia in patients with kidney disease receiving haemodialysis: a longitudinal (pilot) study

Background Research indicates that cachexia is common among persons with chronic illnesses and is associated with increased morbidity and mortality. However, there continues to be an absence of a uniformed disease-specific definition for cachexia in chronic kidney disease (CKD) patient populations. Objective The primary objective was to identify cachexia in patients receiving haemodialysis (HD) using a generic definition and then follow up on these patients for 12 months. Method This was a longitudinal study of adult chronic HD patients attending two hospital HD units in the UK. Multiple measures relevant to cachexia, including body mass index (BMI), muscle mass [mid-upper arm muscle circumference (MUAMC)], handgrip strength (HGS), fatigue [Functional Assessment of Chronic Illness Therapy (FACIT)], appetite [Functional Assessment of Anorexia/Cachexia Therapy (FAACT)] and biomarkers [C-reactive protein (CRP), serum albumin, haemoglobin and erythropoietin resistance index (ERI)] were recorded. Baseline analysis included group differences analysed using an independent t-test, dichotomized values using the χ2 test and prevalence were reported using the Statistical Package for the Social Sciences 24 (IBM, Armonk, NY, USA). Longitudinal analysis was conducted using repeated measures analysis. Results A total of 106 patients (30 females and 76 males) were recruited with a mean age of 67.2 years [standard deviation (SD) 13.18] and dialysis vintage of 4.92 years (SD 6.12). At baseline, 17 patients were identified as cachectic, having had reported weight loss (e.g. &gt;5% for &gt;6 months) or BMI &lt;20 kg/m2 and three or more clinical characteristics of cachexia. Seventy patients were available for analysis at 12 months (11 cachectic versus 59 not cachectic). The FAACT and urea reduction ratio statistically distinguished cachectic patients (P = 0.001). However, measures of weight, BMI, MUAMC, HGS, CRP, ERI and FACIT tended to worsen in cachectic patients. Conclusion Globally, cachexia is a severe but frequently underrecognized problem. This is the first study to apply the defined characteristics of cachexia to a representative sample of patients receiving HD. Further, more extensive studies are required to establish a phenotype of cachexia in advanced CKD.

Impact of gender, C-reactive protein and body mass index on erythropoietin resistance index in maintenance hemodialysis patients

Introduction: Anemia is caused by a variety of mechanisms in chronic kidney disease (CKD), including erythropoietin (EPO) deficiency, resistance to erythropoiesis-stimulating agents (ESAs), impaired iron metabolism and its clinical management remains challenging. Objectives: The aim of the current study was to evaluate the impact of CRP, BMI, gender and duration of hemodialysis. Patients and Methods: A total of 94 maintenance HD patients participated in this study. Laboratory investigation included CBC, renal function test and qualitatively C-reactive protein was performed. Erythropoietin resistance index (ERI) was calculated as weekly EPO dose/ body weight in kg/hemoglobin level. Results: Female gender had significantly higher ERI (11.36 ± 1.52) compared to male HD patients (10.68 ± 1.56) (P ˃ 0.05). Patients with low BMI had significant higher ERI (12.08 ± 1.09) compared to HD patients with overweight (10.62 ± 0.79) and obese (9.62 ± 1.68) (P ˃ 0.05). The highest ERI were found in the positive CPR group (P ˃ 0.05) compared to negative CRP group. There is no significant difference between duration of hemodialysis. Conclusion: Our data exposed that female gender; low BMI and inflammation (positive CRP) contributed to EPO hyporesponsiveness. In addition, there is no significant difference between lengths on hemodialysis.

P1373ERYTHROPOETIN RESISTANCE IN PRE-DIALYSIS PERIOD AND ITS RELATION TO PROGNOSIS IN JAPANESE INCIDENT DIALYSIS PATIENTS

Background and Aims Erythropoiesis stimulating agents (ESA) are essential for better quality of life and longer life expectancy in end-stage kidney disease patients (ESKD). Resistance to ESA leads to worse prognosis in hemodialysis and peritoneal dialysis patients. Resistance to ESA exists in pre-dialysis period. We studied the clinical significance of pre-dialysis resistance to ESA by investigating the erythropoietin resistance index (ERI) in patients with ESKD prior to dialysis induction and its association with mortality and cause of death in three-year follow-up after dialysis initiation. Method Subjects included 1,420 patients in 17 centers participating in Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis (AICOPP) from Oct. 2011 to Sep. 2013. ESA responsiveness was estimated by using erythropoietin resistance index (ERI) (U/kg/week/g/dL), which was calculated as weekly weight-adjusted epoetin dose divided by the hemoglobin (Hb) concentration before starting dialysis. We excluded 302 patients because ERI was not available. Thus, 1,118 subjects were enrolled. Subjects were divided into four categories of ERI; ERI &lt; 5, 5≤ ERI &lt;10, 10≤ ERI &lt;15 and 15≤ ERI. Cumulative survival rates from all-cause, cardiovascular disease (CVD), infection and malignancy were compared by Kaplan-Meier method according to ERI categories. Three-year mortality was analyzed by logistic regression analysis adjusted by age, gender, Charlson comorbidity index (CCI), and ERI categories. Results During three-year follow-up period, 191 (17.1%) patients died. Age and female gender share were higher in proportion to ERI. Diabetes, coronary artery disease (CAD), and values of albumin (Alb) and brain natriuretic peptide (BNP) were not correlated with ERI (Table 1). Kaplan-Meier survival curve showed that patients with the highest ERI (15≤ ERI) had a higher all-cause mortality (Log rank test p=0.002, Figure 1). Concerning the cause of death, mortality from infection (p=0.023, Figure 2) and malignancy (p=0.031) were high in the highest ERI category, however there was no significant difference in each ERI category regarding CVD mortality (p=0.33). According to multivariate analysis analyses by logistic regression model, all-cause (odd ratio [OD]: 1.65, 95% confidence interval [CI]: 1.14-2.38, p=0.008) and infection-related mortality (OR: 2.13, 95% CI: 1.08-4.11, p=0.029) were significantly correlated with the highest ERI category, but unexpectedly CVD mortality was not (OR: 1.04, 95% CI: 0.59-1.75, p=0.90). Mortality from malignancy did not reach the significant level (OR: 1.92, 95% CI: 0.96-3.73, p=0.063) and may require longer observation period for analysis. Conclusion Pre-dialysis ERI is a prognostic marker in Japanese dialysis patients and predicts the susceptibility to infection.

P1385BOLUS FERRIC CARBOXYMALTOSE ADMINISTRATION COULD BE A GOOD OPTION FOR IRON MAINTENANCE THERAPY IN HD FACILITIES WITHOUT REGULAR MEDICAL ASSISTANCE

Background and Aims In 2013, the European Medicines Agency (EMA) claimed that iron preparations should be exclusively given in an environment where resuscitation facilities are available and, therefore, the iron administration was highly discouraged without the presence of a doctor. What this means is that in dialysis centres without regular medical presence the dose of iron administered might be inadequate. Ferric carboxyimaltose (FCM) allows to administer high single doses of iron with an excellent safety profile. Method We compare the effect of a maintenance iron therapy in two groups of prevalent and clinical stable hemodialysis patients; the former (A; n=19pts) was treated with iron gluconate (FG) in low refracted doses (i.e. 60 mg one or two times a week) while the latter (B;n=20 pts) was treated with FCM in high doses (i.e. 200 mg once or twice a month). The groups have been followed up for one year. All treated patients in the two groups had similar and “adequate” basal iron parameters according to European Clinical Guideline (Serum Ferritin(SF) ≥200 mic/l and transferrin saturation(TS) ≥20%) (see Table 1). The therapy was administered in order to maintain SF between 200-500 mic/l and TS between 20-40%. Erythropoietin dose (Epo) was evaluated considering the erythropoietin resistance index (ERI =EPO/weight/Hb). Results Table 1 show the results at the start and end follow up. The mean monthly iron dose was similar between the two groups at the end of follow up (144±100 mg group A vs 157±81 mg group B). In group A there was a more significant increase in the TS with a non-significant trend to an increase in SF. Six pts of group A had an overshooting of SF (1164±360mc/L) vs 3 pts in group B (SF 830±30 mc/L). No significant differences in pre and post therapy ERI could be recorded. Conclusion A therapy with a high single doses of FCM could be a positive solution to treat patients in dialysis centres without regular medical presence.