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Introduction: Anemia is a risk factor for all-cause mortality in older adults. Iron deficiency may also be associated with adverse outcomes, independent of its role in causing anemia. This study tested the hypotheses that anemia, and low ferritin among non-anemic participants, were associated with all-cause and cause-specific mortality in a community-based cohort of older adults., Methods: Fasting blood was obtained from 5,070 ARIC participants (median age: 75 years) in 2011-2013. Anemia was defined by hemoglobin concentrations <12 g/dL in women and <13 g/dL in men. We classified 4,020 non-anemic participants by quartiles of plasma ferritin, measured by the SomaScan proteomics platform. Cox proportional hazards regression was used. Mortality was ascertained via phone calls with proxies as part of twice-yearly cohort follow-up, surveillance of local hospital discharge indexes, state death records, and linkage to the National Death Index., Results: Of the total participants, 21% had anemia at baseline. Over a median of 7.5 years, there were 1,147 deaths, including 357 due to cardiovascular disease (CVD), 302 to cancer, and 132 to respiratory disease. Compared to those with normal hemoglobin, participants with anemia had a higher risk of all-cause mortality (hazard ratio 1.81 [95% CI: 1.60-2.06]), and mortality due to CVD (1.77 [1.41-2.22]), cancer (1.81 [1.41-2.33]), and respiratory disease (1.72 [1.18-2.52]) in demographics-adjusted models. In fully adjusted models, associations with all-cause mortality (1.37 [1.19-1.58]) and cause-specific mortality were attenuated. In non-anemic participants, lower ferritin levels were not associated with all-cause or cause-specific mortality, though associations were observed among participants with lesser evidence of inflammation (CRP below the median level of 1.9 mg/L) and for cancer mortality in men only., Conclusion: Anemia is common among older adults and is associated with all-cause mortality, as well as mortality due to CVD, cancer, and respiratory disease. Our results do not provide evidence that iron deficiency, independent of anemia, is associated with mortality in this population., (© 2024 S. Karger AG, Basel.)

Introduction: Ferric citrate (FC) is an FDA-approved iron-based phosphate binder for adults with dialysis-dependent chronic kidney disease. This study investigated the impact of FC as the primary phosphate-lowering therapy on utilization of erythropoiesis-stimulating agents (ESAs) and intravenous (IV) iron., Methods: In this randomized, open-label, active-controlled, multicenter study (NCT04922645), patients on dialysis and receiving ESAs were randomized to receive FC or remain on standard of care (SOC) phosphate-lowering therapy for up to 6 months. Primary endpoints were the difference in change from baseline to efficacy evaluation period (EEP) in mean monthly ESA and IV iron doses. Secondary endpoints included treatment differences in hemoglobin, phosphate, TSAT, and ferritin levels., Results: Two hundred nine patients were randomized to FC and had a day 1 dosing visit (n = 103) or SOC (n = 106). The two groups had similar baseline laboratory characteristics; however, atherosclerotic CV disease, peripheral vascular disease, and congestive heart failure were more common in the SOC group. The mean treatment difference in ESA monthly dose was -30.8 μg (FC vs. SOC; p = 0.02). An absolute though non-statistically significant change in mean monthly IV iron dose of -37.2 mg (p = 0.17) was observed with FC. Mean hemoglobin, TSAT, and ferritin all increased from baseline to the EEP with FC versus SOC. Serious adverse events occurred in 28% of patients receiving FC versus 37% in those receiving SOC., Conclusions: In patients receiving dialysis, treatment with FC as compared to remaining on SOC phosphate binders resulted in reductions in mean monthly ESA and IV iron dose., (© 2024 S. Karger AG, Basel.)

Background: This study aimed to investigate the efficacy of enteral supplementation of vitamin B12 for vitamin B12 deficiency in patients who underwent total gastrectomy for gastric cancer., Methods: The study enrolled 133 patients who underwent total gastrectomy for gastric cancer at Kochi Medical School. Clinical data were obtained to investigate associations between vitamin B12 supplementation and vitamin B12 levels. Vitamin B12 deficiency was defined as serum vitamin B12 less than 200 pg/mL. Baseline characteristics and changes in hematological variables, including vitamin B12 levels, were examined., Results: Vitamin B12 deficiency was present in 71.4% of the 133 patients. Vitamin B12 levels at 3, 6, and 12 months after enteral supplementation were 306 pg/mL, 294 pg/mL, and 367 pg/mL, respectively, which were all significantly higher than those before supplementation (p < 0.001 for all comparisons). The median red blood cell count at 3, 6, and 12 months after enteral supplementation were 380 × 104/mm3, 394 × 104/mm3, and 395 × 104/mm3, respectively, which were all significantly higher than those before supplementation (p = 0.020, p = 0.001, and p = 0.003, respectively). Vitamin B12 levels at 3, 6, and 12 months after supplementation were significantly higher in patients supplemented enterally than those supplemented parenterally (p < 0.001 for all comparisons)., Conclusions: Vitamin B12 deficiency was found in 71.4% of postoperative patients who underwent total gastrectomy for gastric cancer, and enteral vitamin B12 supplements might be effective to improve anemia in these patients., (© 2021 S. Karger AG, Basel.)

Background and Purpose: Anemia predicts poor clinical outcome of ischemic stroke in the general stroke population. We studied whether this applies to those treated with mechanical thrombectomy for proximal anterior circulation occlusion in the setting of differing collateral circulation., Methods: We collected the data of 347 consecutive anterior circulation stroke patients who underwent mechanical thrombectomy after multimodal CT imaging in a single tertiary stroke care center. Patients with occlusion of the internal carotid artery and/or the first segment of the middle cerebral artery were included. We recorded baseline clinical, laboratory, procedural, and imaging variables, and the technical, imaging, and clinical outcomes. Differences between anemic and nonanemic patients were studied with appropriate statistical tests and binary logistic regression analysis., Results: Ninety-four out of the 285 patients eligible for analysis had anemia, and 243 had fair or good collateral circulation (collateral score, CS, >0). Fifty-four percent of the patients experienced good 3-month clinical outcome (modified Rankin Scale ≤2). In pooled analyses of the CS 1-4 and 2-4 ranges, nonanemic patients had good clinical outcome significantly more often (p < 0.001 for both). This effect was not seen in patients with poor collateral circulation (CS = 0). Nonanemic patients had significantly better odds of good clinical outcome (OR = 2.6, 95% CI 1.377-5.030, p = 0.004) in a binary regression model. A 0.1 g/dL increase in hemoglobin improved the odds of good clinical outcome by 2% (OR = 1.02, 95% CI 1.002-1.044, p = 0.03)., Conclusions: Low hemoglobin on admission predicts poor clinical outcome in mechanical thrombectomy patients with fair or good collateral circulation., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Introduction: It is established that anemia leads to adaptive changes in cardiac geometry including left ventricular hypertrophy (LVH). However, published data are still scarce regarding the association of LVH with normal-range hemoglobin levels., Objective: To evaluate the association between hemoglobin level and LVH in subjects with or without anemia., Methods: The study included 48,034 Korean men and women who received echocardiography during their medical health checkup. They were divided into 4 groups according to their hemoglobin concentration (g/dL) in men (<14, 14-14.9, 15-15.9, and ≥16) and women (<12, 12-12.9, 13-13.9, and ≥15). Multivariate logistic regression analysis was used to calculate adjusted ORs and 95% CI for LVH in each group compared with the group with the lowest hemoglobin. Subgroup analysis was conducted for subjects within normal hemoglobin levels., Results: There was an inverse relationship between hemoglobin levels and LVH, where unadjusted and adjusted ORs and 95% CI for LVH decreased with increasing hemoglobin levels in both men and women. In subgroup analysis, this inverse relationship was also observed in subjects with hemoglobin in the nonanemic range., Conclusion: The decrease in hemoglobin was significantly associated with the increased probability of LVH, and this association was found even in nonanemic subjects., (© 2020 S. Karger AG, Basel.)

Background: Anaemia is a common finding in diabetes, particularly in those patients with albuminuria or renal dysfunction and is associated with impaired erythropoietin (EPO) secretion. This review focuses on mechanisms involved in the regulation of erythropoiesis in diabetic patients in an effort to elucidate the competing effects of the renin angiotensin system (RAS) blockade and sodium-glucose cotransporter-2 (SGLT2) inhibitors on haemoglobin concentration and hematocrit values., Summary: The RAS shows significant activation in diabetic subjects. Angiotensin II, its active octapeptide, causes renal tubulointerstitial hypoxia, which stimulates hypoxia-inducible factors (HIF) and increases EPO secretion and erythropoiesis. As expected, drugs that inactivate RAS, such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARB) are associated with a significant hematocrit-lowering effect and/or anaemia in various clinical conditions, including diabetes. Dual blockade by a combination of ACEi and ARB in diabetic patients achieves a better RAS inhibition, but at the same time a worse drop of haemoglobin concentration. Increased glucose reabsorption by SGLTs in diabetic subjects generates a high-glucose environment in renal tubulointerstitium, which may impair HIF-1, damage renal erythropoietin-producing cells (REPs) and decrease EPO secretion and erythropoiesis. SGLT2 inhibitors, which inhibit glucose reabsorption, may attenuate glucotoxicity in renal tubulointerstitium, allowing REPs to resume their function and increase EPO secretion. Indeed, EPO levels increase within a few weeks after initiation of therapy with all known SGLT2 inhibitors, followed by increased reticulocyte count and a gradual elevation of haemoglobin concentration and hematocrit level, which reach zenith values after 2-3 months. Key Messages: The competing effects of RAS blockade and SGLT2 inhibitors on erythropoiesis may have important clinical implications. The rise of hematocrit values by SGLT2 inhibitors given on top of RAS blockade in recent outcome trials may significantly contribute to the cardiorenal protection attained. The relative contribution of each system to erythropoiesis and outcome remains to be revealed in future studies., (© 2020 S. Karger AG, Basel.)

Aim: To investigate the relationship between hemoglobin levels and the progression of IgA nephropathy (IgAN)., Methods: In a two-center cohort of 1,828 cases with biopsy-proven IgAN, we examined the association of hemoglobin levels with the primary outcome of a composite of all-cause mortality or kidney failure defined as a 40% decline in eGFR, or ESKD (defined as eGFR <15 mL/min/1.73 m2 or need for kidney replacement therapy including hemodialysis, peritoneal dialysis, or kidney transplantation), or the outcome of kidney failure, assessed using Cox and logistic regression models, respectively, with adjustment for confounders., Results: At baseline, mean age, eGFR, and hemoglobin levels were 33.75 ± 11.03 years, 99.70 ± 30.40 mL/min/1.73 m2, and 123.47 ± 18.36 g/L, respectively. During a median of approximately 7-year follow-up, 183 cases reached the composite outcome. After adjustment for demographic and IgAN-specific covariates and treatments, a lower quartile of hemoglobin was nonlinearly associated with an increased risk of the primary outcome or kidney failure in the Cox proportional hazards models (primary outcome: HR for quartile 3 vs. 4, 1.37; 95% CI, 0.83-2.25; HR for quartile 2 vs. 4, 1.18; 95% CI, 0.68-2.07; HR for quartile 1 vs. 4, 1.91; 95% CI, 1.15-3.17; kidney failure: HR for quartile 3 vs. 4, 1.39; 95% CI, 0.84-2.31; HR for quartile 2 vs. 4, 1.20; 95% CI, 0.68-2.11; HR for quartile 1 vs. 4, 1.83; 95% CI, 1.09-3.07) in the fully adjusted model. Then, hemoglobin levels were transformed to a binary variable for fitting the model according to the criteria for anemia of 110 g/L in the women and 120 g/L in men in China. The participants in the anemia group had an increased risk of developing outcomes compared with the nonanemia group in both genders (primary outcome: male: HR, 1.64; 95% CI, 1.01-2.68; female: HR, 1.68; 95% CI, 1.02-2.76; kidney failure: male: HR, 1.60; 95% CI, 0.97-2.64; female: HR, 1.58; 95% CI, 0.95-2.61) in the fully adjusted model., Conclusions: A low level of hemoglobin was nonlinearly associated with IgAN progression. The anemic IgAN patients presented a higher risk of developing poor outcomes compared with the nonanemic patients., (© 2020 S. Karger AG, Basel.)

Objectives: Different forms of anemia are considered as the most frequent complication of the gestational period. By its etiology, pathogenesis, and clinical hematology, it is not a single disease. Among all forms of anemia occurring during pregnancy, iron deficiency anemia (IDA) is the most common, accounting for 80-95% of all cases., Design: The article describes a theoretical basis for the diagnosis of the anemic syndrome among pregnant women, the determining factors of its development, and the diagnostic methods at different gestational periods. Participants/Materials, Setting, and Methods: Diagnostic and prognostic values of iron balance indicators in the body were established for IDA during pregnancy to improve the outcome of childbirth. A total of 140 anemic patients were examined. The control group consisted of 50 pregnant women without anemia and other significant health problems, 48 IDA pregnant women, and 42 pregnant women with anemia caused by various chronic diseases, including rheumatoid arthritis. All patients of the main and control groups were registered on clinical records at the Family Planning Center in Aktobe city, Kazakhstan., Results: Ferrokinetic indicators were suggested for diagnosing IDA and anemia of chronic diseases. It was established that IDA is characterized by low ferritin levels during gestation, while increased ferritin and C-reactive protein are typical for anemia of chronic diseases., Limitations: Differential diagnostics was applied for pregnant women with IDA and anemia of chronic diseases to observe the dynamics of serum ferritin and C-reactive protein (CRP) levels at different gestational periods. The article presents the results of a study on ferrokinetics in pregnant women with IDA and anemia caused by inflammation or chronic diseases. Other causes of anemia leading to a decrease in hemoglobin (Hb) levels to <90 g/L include hemoglobinopathies, which were not considered in this study., Conclusions: Determination of iron deficiency in pregnant women at different gestational periods will allow for identifying the risk group of anemic patients and deciding on the treatment. IDA (Hb <100 g/L) can be effectively measured by ferritin level <15 ng/mL, iron level of <11.5 μmol/L, and transferrin level >2.6 mg/L at p < 0.001. Anemia due to chronic diseases (Hb <100 g/L) can be effectively diagnosed with ferritin above 15 μg/L and CRP above 10 mg/L at p < 0.001., (© 2020 S. Karger AG, Basel.)

Background: Enarodustat (JTZ-951) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that mimics adaptive responses to hypoxic conditions and may provide a new therapeutic approach for managing anemia in patients with chronic kidney disease (CKD). We evaluated the efficacy, safety, and maintenance dose of enarodustat in anemic patients with CKD not on dialysis., Methods: Erythropoiesis-stimulating agent (ESA) naïve patients (correction group) and patients on a stable dose of ESA (conversion group) were randomized to receive 2, 4, or 6 mg of enarodustat or placebo once daily for 6 weeks in a double-blind manner (Period 1) followed by 24 weeks of open enarodustat treatment to maintain their hemoglobin (Hb) levels within a target range of 10.0-12.0 g/dL in reference to a dose adjustment algorithm (Period 2)., Results: In the correction group, Hb level increase rate per week increased in a dose-response manner. The proportion of subjects in the conversion group who maintained Hb levels within ± 1.0 g/dL of baseline did not differ between each enarodustat arm and placebo arm during Period 1. Over 70% of subjects in both groups maintained Hb levels within the target range at the end of treatment in Period 2. The mean prescribed doses were 3.58 and 3.74 mg/day in the correction group and the conversion group, respectively. Enarodustat was associated with decreases in hepcidin and ferritin and increased total iron-binding capacity and was generally well tolerated., Conclusions: Enarodustat corrects and maintains Hb levels in anemic patients with CKD not on dialysis., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

Background: Enarodustat (JTZ-951) is an orally available hypoxia-inducible factor prolyl hydroxylase inhibitor that increases endogenous erythropoietin levels in the treatment of anemia associated with chronic kidney disease (CKD)., Objective: A phase 2b study of enarodustat to assess the hemoglobin (Hb) response, safety, and maintenance dosage was conducted in Japanese anemic patients with hemodialysis-dependent CKD., Methods: Subjects receiving a stable dose of an erythropoiesis-stimulating agent were randomized to receive once-daily enarodustat at a dose of 2, 4, or 6 mg or placebo in a double-blind manner for 6 weeks (Period 1) followed by 24-week open treatment with enarodustat, adjusted in the range of 2-8 mg to maintain Hb within a target range (10.0-12.0 g/dL; Period 2)., Results: Change in Hb from baseline increased with enarodustat dose in Period 1. In Period 2, the proportion of subjects who maintained their Hb level within the target range at the end of treatment was 65.1%. To maintain Hb levels within the target range over the course of Period 2, approximately 80% of subjects required 2 dose adjustments or fewer. Enarodustat decreased hepcidin and ferritin levels, increased total iron-binding capacity, and was generally well tolerated., Conclusions: Enarodustat corrected and maintained Hb levels in anemic patients with hemodialysis-dependent CKD. Phase 3 studies of enarodustat are currently ongoing., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

Background: Molidustat, a novel hypoxia-inducible factor-prolyl hydroxylase inhibitor, is being investigated for the treatment of anemia associated with chronic kidney disease (CKD). The efficacy and safety of molidustat were recently evaluated in three 16-week phase 2b studies. Here, we report the results of two long-term extension studies of molidustat., Methods: Both studies were parallel-group, open-label, multicenter studies of ≤36 months' duration, in patients with anemia due to CKD, and included an erythropoiesis-stimulating agent as active control. One study enrolled patients not receiving dialysis (n = 164), and the other enrolled patients receiving hemodialysis (n = 88). The primary efficacy variable for both studies was change in blood hemoglobin (Hb) level from baseline to each post-baseline visit, and safety outcomes included adverse events (AEs)., Results: In patients not on dialysis, the mean ± SD Hb concentrations at baseline were 11.28 ± 0.55 g/dL for molidustat and 11.08 ± 0.51 g/dL for darbepoetin. The mean ± SD blood Hb concentrations throughout the study (defined as mean of each patient's overall study Hb levels) were 11.10 ± 0.508 and 10.98 ± 0.571 g/dL in patients treated with molidustat and darbepoetin, respectively. Similar proportions of patients reported at least one AE in the molidustat (85.6%) and darbepoetin (85.7%) groups. In patients on dialysis, mean ± SD Hb levels at baseline were 10.40 ± 0.70 and 10.52 ± 0.53 g/dL in the molidustat and epoetin groups, respectively. The mean ± SD blood Hb concentrations during the study were 10.37 ± 0.56 g/dL in the molidustat group and 10.52 ± 0.47 g/dL in the epoetin group. Proportions of patients who reported at least one AE were 91.2% in the molidustat group and 93.3% in the epoetin group., Conclusions: Molidustat was well tolerated for up to 36 months and appears to be an effective alternative to darbepoetin and epoetin in the long-term management of anemia associated with CKD., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

Background/aims: As shown in the China Health and Nutrition Survey, serum magnesium is associated with anemia. However, the roles of magnesium in anemia and erythropoietin (EPO) responsiveness remain unclear in maintenance hemodialysis (MHD) patients. This study aims to investigate the level of serum magnesium and its relationship with EPO responsiveness in MHD patients., Methods: A total of 307 MHD patients were recruited for this survey. Laboratory data and anthropometrics were collected. EPO responsiveness was evaluated by the erythropoietin resistance index (ERI). The subjects were divided into 3 groups according to serum magnesium concentrations (group A, the lowest tertile; group B, the middle tertiles; and group C, the highest tertile). Multivariate logistic regressions were conducted to evaluate the factors that may be associated with EPO responsiveness., Results: The mean serum magnesium level was significantly higher than normal levels in MHD patients, while no hypomagnesemia was observed. A multivariate logistic regression model revealed that high-sensitivity C-reactive protein, intact parathyroid hormone, serum albumin, and magnesium levels were correlated with a high ERI. The OR of a high ERI was found to be 2.57 (95% CI 1.330-4.975, p = 0.005) for group A and 1.66 (95% CI 0.878--3.140, p > 0.05) for group B compared with the OR for group C., Conclusion: Serum magnesium levels were higher than normal levels in MHD patients. A high serum magnesium level was correlated with good EPO responsiveness and was therefore suggested to be a protective factor for EPO hyporesponsiveness., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

Background/aims: The current treatment for anemia associated with chronic kidney disease (CKD) includes the administration of erythropoiesis stimulating agents (ESAs) combined with iron supplementation. Molidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, has potential to treat anemia associated with CKD through increased erythropoietin production and improved iron availability. Here, we report the effect of molidustat on iron metabolism., Method: Parameters of iron metabolism were monitored in three 16-week, randomized, controlled, phase 2 studies assessing the safety and efficacy of molidustat in the treatment of anemia associated with CKD in different populations: treatment-naïve and previously ESA-treated patients not on dialysis, and previously ESA-treated patients on hemodialysis. Iron supplementation was left at the discretion of the investigator., Results: In treatment-naïve patients not on dialysis, transferrin saturation (TSAT), hepcidin, ferritin, and iron concentrations decreased with molidustat, whereas total iron binding capacity (TIBC) increased. Similar results were observed in previously ESA-treated patients not on dialysis, although changes in those parameters were larger in treatment-naïve than in previously ESA-treated patients. In previously ESA-treated patients receiving hemodialysis, hepcidin concentration and TIBC remained stable with molidustat, whereas TSAT and ferritin and iron concentrations increased. Generally, similar trends were observed in secondary analyses of subgroups of patients not receiving iron supplementation., Conclusions: Molidustat is a potential alternative to standard treatment of anemia associated with CKD, with a different mechanism of action. In patients not receiving dialysis, molidustat increases iron availability. In patients receiving hemodialysis, further investigation is required to understand fully the mechanisms underlying iron mobilization associated with molidustat., (© 2019 The Author(s). Published by S. Karger AG, Basel.)

Background: Desidustat (ZYAN1) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that stimulates erythropoiesis. Stabilizing HIF via PHI is developing as a new therapeutic approach to treat anemia secondary to chronic kidney disease (CKD). This trial evaluated the safety, tolerability, and efficacy of Desidustat in adult CKD patients with anemia, who were not on dialysis., Methods: This was a Phase 2, randomized, double-blind, 6-week, placebo-controlled, dose-ranging, safety and efficacy study. A total of 117 eligible patients were randomized to 4 arms: 100, 150, 200 mg, or placebo. The investigational product was administered every alternate day for 6 weeks in fasting conditions. The primary endpoint was change in hemoglobin (Hb) from baseline to week 6., Results: Baseline demographics were well balanced among all the treatment arms. In the modified intent-to-treat (mITT) population, a mean Hb increase of 1.57, 2.22, and 2.92 g/dL in Desidustat 100, 150, and 200 mg arms, respectively, was observed post 6 weeks treatment. The responder rate (≥1 g/dL increase) was 66% in 100 mg, 75% in 150 mg, and 83% in 200 mg treatment arms, in the mITT population. Eighteen patients had at least one treatment emergent adverse event (TEAE), and 5 patients reported at least one drug-related mild TEAE. No death or serious adverse event was reported during the trial., Conclusion: There was dose-related increase in Hb across all doses compared to placebo in mITT and per-protocol populations. Desidustat also increased pharmacokinetic parameters Cmax and AUC in dose-related manner. There was no significant change in vital signs, electrocardiographic parameters, or safety laboratory values. Clinical Trial Registration Number CTRI/2017/05/008534 (registered on May 11, 2017)., (© 2019 S. Karger AG, Basel.)

Background: Incident hemodialysis patients have a high mortality risk within the first months after dialysis initiation. Pre-end-stage renal disease (ESRD) factors like anemia management may impact early post-ESRD outcomes. Therefore, we evaluated the impact of pre-ESRD hemoglobin (Hgb) and pre-ESRD Hgb slope on post-ESRD mortality and hospitalization outcomes., Methods: The study included 31,472 veterans transitioning to ESRD. Using Cox and negative binomial regression models, we evaluated the association of pre-ESRD Hgb and Hgb slope with 12-month post-ESRD all-cause and cardiovascular mortality and hospitalization rates using 4 levels of hierarchical multivariable adjustment, including erythropoietin use and kidney decline in slope models., Results: The cohort was 2% female, 30% African-American, and on average 68 ± 11 years old. Compared to Hgb 10-< 11 g/dL, both low (< 10 g/dL) and high (≥12 g/dL) levels were associated with higher all-cause mortality after full adjustment (HR 1.25 [95% CI 1.15-1.35] and 1.09 [95% CI 1.02-1.18], respectively). Similarly, Hgb exhibited a U-shaped association with CV mortality, while only lower Hgb was associated with a higher hospitalization rate. Neither an annual pre-ESRD decline in Hgb nor increase was associated with higher post-ESRD mortality risk after adjustment for kidney decline. However, we observed a modest J-shaped association between pre-ESRD Hgb slope and post-ESRD hospitalization rate., Conclusions: Lower and higher pre-ESRD Hgb levels are associated with a higher risk of early post-ESRD mortality, while there was no association between the pre-ESRD slope and mortality. An increase in pre-ESRD Hgb slope was associated with higher risk of post-ESRD hospitalization. Additional studies aimed at anemia management prior to ESRD transition are warranted., (© 2018 S. Karger AG, Basel.)

Background: For patients with anemia undergoing hemodialysis, erythropoiesis-stimulating agents (ESAs) are typically dosed via precise algorithms. Using one such algorithm, we assessed the maintenance of hemoglobin levels in patients switched from epoetin alfa reference product (Epogen®) to epoetin alfa-epbx (RetacritTM; a biosimilar to US-licensed Epogen®/Procrit®)., Methods: This randomized, open-label, non-inferiority study was conducted at Fresenius Medical Care North America (FMCNA) hemodialysis centers. Patients with anemia and chronic kidney disease undergoing maintenance hemodialysis and receiving routine intravenous (IV) Epogen® were randomized 1: 1 to switch to IV RetacritTM or continue standard-of-care (Epogen®) for 24 weeks, using analogous versions of the FMCNA ESA-dosing algorithm. The primary endpoint was the proportion of time patients' hemoglobin was 9-11 g/dL during weeks 17-24., Results: Of 432 randomized patients, 418 received treatment (RetacritTM, n = 212; standard-of-care, n = 206) and comprised the full analysis set. A similar proportion of patients discontinued from each arm. The proportion of time patients' hemoglobin was within the target range was 61.9% (95% CI 57.5-66.2) in the RetacritTM arm and 63.3% (95% CI 58.7-67.7) in the standard-of-care arm. The difference in proportions between treatment arms was -1.4% (95% CI -7.6 to 4.9), and the lower bound of the confidence interval was within the pre-specified non-inferiority margin of -12.5%. There was no statistically significant difference between arms in the mean change from baseline in the weekly mean ESA dose during weeks 17-24, and no clinically relevant differences in safety outcomes., Conclusions: Switching to RetacritTM was non-inferior to continuing -Epogen® in maintaining hemoglobin levels in patients receiving hemodialysis, when both ESAs were dosed using a specified algorithm (ClinicalTrials.gov, NCT02504294)., (© 2018 The Author(s) Published by S. Karger AG, Basel.)

Background: TP0463518 is a novel hypoxia-inducible factor prolyl hydroxylase inhibitor developed to aid in the treatment of anemia associated with chronic kidney disease (CKD) and is expected to increase erythropoietin (EPO) derived from liver. Two phase I studies were conducted in healthy volunteers (HV) and CKD patients undergoing hemodialysis (i.e., HD patients) or those not undergoing dialysis (i.e., ND patients)., Methods: Pharmacokinetics, pharmacodynamics, and safety profiles of TP0463518 were assessed. Forty HV received single oral doses of TP0463518 at 3, 6, 11, 20, and 36 mg or placebo. Twenty ND patients received single doses of TP0463518 at 1, 6, and 11 mg and 9 HD patients received TP0463518 at 1 and 11 mg doses. To identify the source organ of EPO, glycosylation patterns were determined using percentage migrated isoform (PMI) values., Results: Declining renal function slowed elimination of TP0463518 and increased the mean AUC0-∞. ∆Emax of serum EPO in 11-mg groups of HV, ND patients, and HD patients were 24.37 ± 11.37, 201.57 ± 130.34, and 1,324.76 ± 1,189.24 mIU/mL respectively. A strong correlation was -observed between logarithm conversions of ∆Emax and AUC0-∞ with correlation coefficients of 0.945. PMI values of blood after TP0463518 administration were elevated to similar or higher levels in comparison with those of umbilical cord blood, which mainly contains liver-derived EPO., Conclusions: TP0463518 induced dose-dependent EPO production, mainly derived from the liver in HV and CKD patients. These results suggest that TP0463518 is a new strategy for treating anemia in CKD, which can be used regardless of renal functions., (The Author(s). Published by S. Karger AG, Basel.)

Background: Anemia is one of the most prevalent complications in patients with chronic kidney disease, which is believed to be caused by the insufficient synthesis of erythropoietin by the kidney. This phase III study aimed to compare the efficacy and safety of CinnaPoietin® (epoetin beta, CinnaGen) with Eprex® (epoetin alfa, Janssen Cilag) in the treatment of anemia in ESRD hemodialysis patients., Methods: In this randomized, active-controlled, double-blind, parallel, and non-inferiority trial, patients were randomized to receive either CinnaPoietin® or Eprex® for a 26-week period. The primary endpoints of this study were to assess the mean hemoglobin (Hb) change during the last 4 weeks of treatment from baseline along with the evaluation of the mean weekly epoetin dosage per kilogram of body weight that was necessary to maintain the Hb level within 10-12 g/dL during the last 4 weeks of treatment. As the secondary objective, safety was assessed along with other efficacy endpoints., Results: A total of 156 patients were included in this clinical trial. There was no statistically significant difference between treatment groups regarding the mean Hb change (p = 0.21). In addition, the mean weekly epoetin dosage per kg of body weight for maintaining the Hb level within 10-12 g/dL showed no statistically significant difference between treatment arms (p = 0.63). Moreover, both products had comparable safety profiles. However, the incidence of Hb levels above 13 g/dL was significantly lower in the CinnaPoietin® group., Conclusion: CinnaPoietin® was proved to be non-inferior to Eprex® in the treatment of anemia in ESRD hemodialysis patients. The trial was registered in Clinicaltrials.gov (NCT03408639)., (© 2018 S. Karger AG, Basel.)

Kidney transplantation represents a renal replacement therapy for end-stage renal failure, with outcomes improving from year to year. With the improved survival prognosis, treatment of complications of chronic kidney disease after transplantation is becoming increasingly important. In particular, posttransplantation anemia (PTA) is often protracted, which could be related to a variety of factors, including the renal function status, graft rejection episodes, and infectious causes. PTA occurs in about 30-40% of transplant recipients, and is known to affect the function of the transplanted kidney as well as patient survival. Early PTA is associated with a risk of death and cardiovascular disorders, however, during this phase, priority is given to the appropriate maintenance of immunosuppression rather than to the treatment of anemia. Maintenance-phase PTA exerts a strong influence on the survival, prognosis of the transplanted kidney, quality of life, etc. Unlike the disease state and treatment of usual renal anemia, it has been suggested that PTA may possibly reflect the functional state of the transplanted kidney. Therefore, it has been suggested that proper renal function may be maintained by ensuring a normal hemoglobin level in kidney transplant recipients. Proper management of PTA could be expected to be associated with an improved prognosis of the transplanted kidney and improved patient survival in kidney transplant recipients. It is advisable to provide appropriate treatment by setting target levels in accordance with the dialysis vintage, primary disease, cardiovascular complications, and kidney transplant function and delineation of the transplant recipient characteristics., (© 2018 S. Karger AG, Basel.)

Background/aims: Different biochemical abnormalities of metabolic bone disease have been associated with anemia of chronic kidney disease (CKD), mainly in hemodialysis patients. However, all of these abnormalities are closely inter-related and their individual effect on the development of anemia is uncertain. This study was aimed to assess the relationship between anemia and a set of metabolic bone disease biomarkers in a cohort of adult patients with advanced non-dialysis-dependent CKD., Methods: The sample consisted of 382 patients submitted to a Nephrology Unit for evaluation of advanced CKD in a tertiary hospital from Gran Canaria during 3 years. Associations between anemia and serum levels of calcium (albumin-corrected), phosphorus, PTH, 25-hydroxivitamin D (25(OH)D3) and alkaline phosphatase were analyzed by using logistic regression models with adjustment for other demographic, clinical and biochemical covariates potentially related to anemia and to bone mineral metabolism., Results: Serum levels of calcium and 25(OH)D3 (negatively) and phosphorus (positively) were significantly associated with anemia in an unadjusted logistic regression model. In a fully adjusted multivariable model, the OR for anemia was 0.29 (95% CI 0.16-0.49; p < 0.0001) for every 1 mg/dl increase in serum calcium and 2.19 (95% CI 1.55-3.15; p < 0.001) for every 1 mg/dl increase in serum phosphorus. Female sex and lower serum albumin levels were also independently associated with anemia. The inclusion of albumin in the adjusted model displaced the significance of 25(OH)D3., Conclusions: Circulating levels of calcium and phosphorus are strongly linked to anemia in patients with advanced non-dialysis CKD., (© 2016 S. Karger AG, Basel.)

Background: The pathogenesis of chronic kidney disease associated anemia is multifactorial and includes decreased production of erythropoietin (EPO), iron deficiency, inflammation, and EPO resistance. To better understand the trajectory of these parameters, we described temporal trends in hemoglobin (Hb), ferritin, transferrin saturation, C-reactive protein (CRP), and darbepoetin dosing in the Trial to Reduce cardiovascular Events with Aranesp Therapy (TREAT)., Methods: We performed a post hoc analysis of 4,038 participants in TREAT. Mixed effects linear regression models were used to determine the trajectory of parameters of interest prior to end-stage renal disease (ESRD). Likelihood ratio tests were used to determine the overall differences in biomarker values and differences in trajectories between those who did and did not develop ESRD., Results: Hb declined precipitously in the year prior to the development of ESRD (irrespective of treatment assignment), and was on average 1.15 g/dL (95% CI -1.26 to -1.04) lower in those who developed ESRD versus those who did not, at the time of ESRD/end of follow-up. Simultaneously, the mean darbepoetin dose and CRP concentration increased, while serum ferritin and transferrin saturations were >140 μg/L and 20%, respectively., Conclusions: Our analyses provide descriptive insights regarding the temporal changes of Hb, darbepoetin dose, and related parameters as ESRD approaches in participants of TREAT. Hb declined as much as 1-2 years prior to the development of ESRD, without biochemical evidence of iron deficiency. The most precipitous decline occurred in the months immediately prior to ESRD, despite administration of escalating doses of darbepoetin and in parallel with an increase in CRP., (© 2017 S. Karger AG, Basel.)

Background/aims: No studies have examined the association among serum hepcidin, iron indices, or anemia status based on the kidney function of non-dialysis chronic kidney disease (CKD) patients., Methods: We reviewed data of 2238 patients from a large-scale multicenter prospective Korean study (2011-2016) and excluded 198 patients with missing data regarding serum hepcidin, hemoglobin, transferrin saturation (TSAT), ferritin, and usage of erythropoiesis-stimulating agents (ESA) or supplemental iron and 363 patients using ESA or supplemental iron. Finally, 1677 patients were included., Results: The mean patient age was 53.5 years, and 65.4% were men. TSAT and serum hepcidin were significantly associated with anemia status, whereas serum ferritin was not, regardless of anemia severity. For patients with an estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2, a 10% increase of TSAT was associated with hemoglobin <13 g/dL (odds ratio [OR], 0.628; 95% confidence interval [CI], 0.515-0.765; P<0.001) and hemoglobin <11.5 g/dL (OR, 0.672; 95% CI, 0.476-0.950; P=0.024), whereas a 10-ng/mL increase of serum hepcidin was associated with hemoglobin <11.5 g/dL (OR, 1.379; 95% CI, 1.173-1.620; P<0.001) and hemoglobin <10.0 g/dL (OR, 1.360; 95% CI, 1.115-1.659; P=0.002) for patients with eGFR <45 mL/min/1.73 m2 according to multivariate logistic analysis., Conclusions: TSAT was associated with less severe anemia in early CKD patients. Serum hepcidin was associated with more severe anemia in advanced CKD patients., (© 2017 The Author(s). Published by S. Karger AG, Basel.)

Background/aims: The renal prognosis of post-renal acute kidney injury (PoR-AKI) has not been verified so far. The objective of this study was to assess the association of baseline anemia with long-term renal prognosis in patients with PoR-AKI., Methods: We performed a multicenter retrospective cohort study. Consecutive adult patients from December 2006 to February 2010, who met the requirements as mentioned in the definition of PoR-AKI, were included. Patients without data on baseline renal function and at 6 months after PoR-AKI were excluded. We set baseline hemoglobin (Hb) level (g/dl) as the main exposure to be tested. The main outcome measure was long-term renal prognosis as determined by the difference between proximate estimated glomerular filtration rate (eGFR) at 6 months after diagnosis of PoR-AKI and baseline eGFR prior to the occurrence of the present PoR-AKI (ΔeGFR after 6 months) using the general linear model., Results: We included 136 patients with PoR-AKI. The most frequent cause of PoR-AKI was malignancy, accounting for 39.0% (n = 53) of cases. Multivariate analysis adjusted for possible confounders showed that ΔeGFR after 6 months significantly changed by -4.28 ml/min/1.73 m2 for every 1 g/dl lower Hb at diagnosis (95% CI 1.86-6.69, p < 0.01). An additional multivariate analysis that was stratified by the presence or absence of malignancy as the cause of PoR-AKI yielded the same significant result only in the stratum of the nonmalignant cause of PoR-AKI., Conclusion: Patients with a nonmalignant cause of PoR-AKI who have baseline anemia may have poor long-term renal prognosis. In these cases, close observation of renal function after renal recovery may be required., (© 2016 S. Karger AG, Basel.)

Background: HX575 (biosimilar epoetin alfa) was approved in Europe in 2007 for the treatment of chronic kidney disease (CKD)-related anemia. This study assessed the clinical equivalence of HX575 with the US-licensed reference epoetin alfa (Epogen®/Procrit®, Amgen/Janssen) following subcutaneous (SC) administration in dialysis patients with CKD-related anemia., Methods: This randomized, double-blind, parallel-group, multicenter study (NCT01693029) was conducted at 49 US clinical sites. Eligible patients were aged ≥18 years, had end-stage renal disease, were on hemodialysis or peritoneal dialysis for ≥6 months (or ≥12 months in the case of a failed kidney transplant), and were receiving treatment with stable SC doses of epoetin alfa. Eligible patients also had mean hemoglobin (Hb) concentration between 9.0 and 11.5 g/dL during the screening period. The primary endpoint was the mean absolute change in Hb concentration between the screening/baseline period (week-4 to week-1) and the evaluation period (weeks 21 to 28)., Results: Hb values at the end of the evaluation period and the Hb change from baseline to evaluation period were similar between treatment groups. The estimated difference between groups in mean absolute change in Hb concentration was -0.093 g/dL, with 90% CI (-0.23 to 0.04) entirely within the pre-specified equivalence limits (-0.5 to 0.5 g/dL). The safety profile of each medicine was similar and as expected in dialysis patients, and neither method of treatment led to the development of neutralizing, clinically relevant antibodies., Conclusions: SC HX575 in dialysis patients with renal anemia was therapeutically equivalent to the reference medicine in terms of maintaining stable Hb levels and safety., (© 2017 S. Karger AG, Basel.)

Background: Hypothesizing that statins may be useful as adjuvant treatment for renal anemia, we examined the association between statin prescription (Rx) and erythropoiesis-stimulating agent (ESA) hyporesponsiveness in Japanese hemodialysis (HD) patients prescribed ESAs., Methods: We examined 3,602 patients in 60 HD facilities dialyzed 3 times/week for ≥4 months from the Japan Dialysis Outcomes and Practice Patterns Study phases 3-5 (2005-2015). Statin Rx was reported at the end of a 4-month interval (baseline) for each patient. ESA hyporesponsiveness in the subsequent 4 months was then defined as a binary indicator (mean hemoglobin [Hgb] level <10 g/dL and mean ESA dose >6,000 units/week) and separately as the ESA resistance index (ERI; mean ESA dose/[dry weight × mean Hgb]). We used adjusted logistic and linear regressions to evaluate the associations between statin Rx and ESA hyporesponsiveness., Results: At baseline, 16.2% of patients reported statin Rx; 12.8% were classified as having ESA hyporesponsiveness during 4 months of follow-up. Compared to patients without statin Rx, patients with statin Rx had lower odds of ESA hyporesponsiveness (OR 0.87; 95% CI 0.66-1.15). Similarly, the ERI was lower for those with statin Rx than without (ratio of means, 0.94; 95% CI 0.89-0.99) after adjustment for possible confounders., Conclusions: Our results suggest that statins may slightly reduce ESA hyporesponsiveness in HD patients. However, any causal inference is limited by the observational study design and unmeasured compliance with statin Rx., (© 2017 S. Karger AG, Basel.)

Background: Therapeutic options for the treatment of anemia secondary to chronic kidney disease (CKD) remain limited. Vadadustat (AKB-6548) is an oral hypoxia-inducible factor prolyl-hydroxylase domain (HIF-PHD) inhibitor that is being investigated for the treatment of anemia secondary to CKD., Methods: A phase 2a, multicenter, randomized, double-blind, placebo-controlled, dose-ranging trial (NCT01381094) was undertaken in adults with anemia secondary to CKD stage 3 or 4. Eligible subjects were evenly randomized to 5 groups: 240, 370, 500, or 630 mg of once-daily oral vadadustat or placebo for 6 weeks. All subjects received low-dose supplemental oral iron (50 mg daily). The primary endpoint was the mean absolute change in hemoglobin (Hb) from baseline to the end of treatment. Secondary endpoints included iron indices, safety, and tolerability., Results: Ninety-three subjects were randomized. Compared with placebo, vadadustat significantly increased Hb after 6 weeks in a dose-dependent manner (analysis of variance; p < 0.0001). Vadadustat increased the total iron-binding capacity and decreased concentrations of ferritin and hepcidin. The proportion of subjects with at least 1 treatment-emergent adverse event was similar between vadadustat- and placebo-treated groups. No significant changes in blood pressure, vascular endothelial growth factor, C-reactive protein, or total cholesterol were observed. Limitations of this study included its small sample size and short treatment duration., Conclusions: Vadadustat increased Hb levels and improved biomarkers of iron mobilization and utilization in patients with anemia secondary to stage 3 or 4 CKD. Global multicenter, randomized phase 3 trials are ongoing in non-dialysis-dependent and dialysis-dependent patients., (© 2017 The Author(s) Published by S. Karger AG, Basel.)

Iron is needed for oxygen transport, muscle activity, mitochondrial function, DNA synthesis, and sensing of hypoxia. The hierarchical master determinant of dietary iron absorption and iron distribution within the body is the peptide hormone hepcidin. Hepcidin itself is regulated by a combination of signals derived from iron stores, inflammation, and erythropoietic expansion. Iron deficiency and iron deficiency anemia are common and important conditions that can be treated with iron preparations. However, other factors besides iron deficiency can cause anemia, especially inflammation, which responds poorly to iron treatment, and inherited disorders of red blood cells, which are associated with accumulation of excess pathogenic iron. Assessment of iron status is challenging, and indices such as serum ferritin, soluble transferrin receptor, and zinc protoporphyrin have specific weaknesses. Moreover, a diagnosis of iron deficiency or iron deficiency anemia is most useful if the diagnosis also leads to effective treatment. Low levels of hepcidin allow iron absorption and effective iron incorporation into red blood cells. The best 'biomarker' to guide treatment may therefore be the physiological 'determinant' of iron utilization. Iron is also important in transplantation medicine and influences clinical outcome of arterial pulmonary hypertension; here too, biomarkers including hepcidin may be useful to actively and beneficially manage iron status., (© 2016 Nestec Ltd., Vevey/S. Karger AG, Basel.)

Chronic hepatitis C is one of the most important causes of liver disease, leading to cirrhosis, hepatic decompensation and hepatocellular carcinoma. Recently some important advances in therapy have been achieved with the introduction of first wave, first generation direct acting antiviral agents (DAAs) such as boceprevir (BOC), in combination with pegylated interferon (Peg-IFN) and ribavirin (RBV). The superior rate of sustained virological response with this treatment is accompanied by an elevated frequency of anaemia. Several studies have evidenced the importance of single nucleotide polymorphisms (SNPs) in inosine triphosphatase (ITPA) and solute carrier family 29, member 1 (SLC29A1) genes in the development of this adverse event. Here, we investigated haemoglobin levels and the best-known functional SNPs in ITPA and SLC29A1 genes in 22 patients treated with triple therapy with BOC/Peg-IFN/RBV. The identification of ITPA protective and SLC29A1 risk genotypes still appears to be a current methodology in RBV dosing during hepatitis C virus therapy with DAAs., (© 2015 S. Karger AG, Basel.)

In 2013, Nangalia et al. and Klampfl et al. found a recurrent and abundant mutation in the calreticulin gene (CALR), mutually exclusive with JAK2 and MPL alterations. At present, the data concerning the new mutation, i.e. its prevalence, allele burden and clinical significance, are scarce. We report the incidence and molecular characteristics of CALR mutations in a group of 184 Polish patients with myeloproliferative neoplasms (MPNs). Clinical data analysis revealed significant differences between JAK2 V617F-mutated and CALR-mutated groups. In essential thrombocythemia patients, hemoglobin levels and leukocyte counts were significantly higher in JAK2-positive than in CALR-positive patients (p = 0.023 and p = 0.017, respectively), but the CALR-positive patients had significantly higher platelet counts (p = 0.022). Patients harboring CALR mutations were also younger at the time of diagnosis (p = 0.039). In primary myelofibrosis patients, the degree of anemia was less severe in those who were CALR exon 9 mutation-positive than in those who were JAK2 V617F-positive (p = 0.048)., (© 2014 S. Karger AG, Basel.)

Background: Hemodialysis (HD) patients occasionally experience minor asymptomatic elevation in C-reactive protein (CRP) levels, which may be associated with difficulty in managing renal anemia using erythropoiesis-stimulating agents (ESAs). Here, we assessed whether elevation of CRP predicts future incidences of ESA hyporesponsiveness., Methods: A total of 2,956 HD patients lacking ESA hyporesponsiveness and infectious diseases were enrolled, and the association between CRP levels and incidence of ESA hyporesponsiveness was assessed. CRP levels were divided into 4 categories (normal [<1.0 mg/l], mild [1.0 ≤ CRP <3.0 mg/l], moderate [3.0 ≤ CRP <10.0 mg/l] and high [≥ 10.0 mg/l]). The primary outcome was the cumulative incidence of ESA hyporesponsiveness, defined as a failure to achieve hemoglobin level ≥ 10 g/dl despite receiving high doses of ESAs (≥ 9,000 U/week recombinant human epoetin [rHuEPO]-α or rHuEPO-β and ≥ 60 μg/week darbepoetin-α) during 12 months of follow-up., Results: The cumulative incidence of ESA hyporesponsiveness was 134 (4.8%) occurrences over 4 months and 300 (12.4%) over 12 months. The elevated CRP groups had significantly higher incidence of ESA hyporesponsiveness over 4 months of follow-up than the normal reference group (adjusted relative risk [RR] 1.6, 95% CI 1.0-2.6 for moderate; adjusted RR 2.5, 95% CI 1.5-4.1 for high). Furthermore, the association remained consistent even over 12 months (adjusted RR 1.4, 95% CI 1.0-1.8 for moderate; adjusted RR 1.6, 95% CI 1.1-2.4 for high)., Conclusions: Elevated CRP levels were associated with future incidence of ESA hyporesponsiveness from low-grade inflammation (3.0 ≤ CRP <10.0 mg/l)., (© 2015 S. Karger AG, Basel.)

Renal anemia is caused by the deficiency of endogenous erythropoietin (Epo) due to renal dysfunction. We think that it is possible to slow the progression of chronic kidney disease (CKD) in case we initiate Epo early in pre-dialysis patients, especially in the non-diabetic population. Erythropoiesis stimulating agent (ESA) treatments targeting mild anemia (10-12 g/dl) can decrease the risk of occurrence of cardiovascular disease (CVD) in patients with hypertension, diabetes mellitus and congestive heart failure. As the large randomized controlled trials such as Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta, Correction of Hemoglobin and Outcomes in Renal Insufficiency and Trial to Reduce Cardiovascular Events with Aranesp Thearpy in the Western countries suggested, we do not recommend high doses of ESA to achieve the target hemoglobin (Hb) level. The target Hb of >13 g/dl might lead to increase in the risk of CVD although maintaining a high Hb of >12 g/dl without ESA is not harmful for CKD patients. It is desirable to determine the target Hb in dialysis patients depending on their ages. Renal anemia should be monitored constantly to start ESA and iron replacement therapy at an appropriate time, while avoiding their excess in order to minimize the occurrence of CVD and other complications. Taken all the international guidelines and our clinical experiences together, we should consider administration of ESA when the Hb level becomes <11 g/dl in pre-dialysis patients and <10 g/dl in dialysis patients., (© 2015 S. Karger AG, Basel.)

Background: The effect of anemia correction on kidney function in chronic kidney disease (CKD) patients remains unclear. As 19-40% of patients with CKD receive an erythropoiesis-stimulating agent (ESA), this is a potentially important consideration., Summary: We conducted a systematic review and meta-analysis of randomized trials to January 1, 2014 in adult patients with CKD stages 1 to 4., Selection Criteria for Studies: randomized controlled trials of at least 2 months duration. Patients were allocated to ESA versus placebo, no treatment, or different ESA doses with the purpose of achieving a higher versus a lower hemoglobin target. The analyzed outcomes were the need for renal replacement therapy, doubling of serum creatinine, change in GFR (ml/min), mortality and withdrawal of treatment due to adverse events. A total of 19 trials (n = 8,129 participants with CKD stage 1-4) were reviewed. There was no difference in the risk of end-stage kidney disease (RR, 0.97 [CI 0.83-1.20], 17 trials, 8,104 participants), change in GFR (Mean Difference [MD] -0.45 [-2.21, 1.31], 9 trials, 1,848 participants) or withdrawal of treatment due to adverse events (RR, 1.18 [CI 0.77-1.81], 10 trials, n = 1,958 participants) for patients at higher hemoglobin (Hb) targets. Furthermore, no statistically significant differences in mortality (Risk Ratio [RR] 1.10 [CI 0.90-1.35], 16 trials, n = 8,082 participants) were observed. Key Messages: There is no evidence that ESA treatment affects renal function in patients with CKD. Use of these agents should not therefore be influenced by considerations about influencing CKD progression.

Background: The optimal level of serum ferritin (s-ft) for anemia control and good survival in hemodialysis (HD) patients remains unclear. A 10-year survey was performed to clarify the appropriate quantities of s-ft and investigate the relationships among s-ft, transferrin saturation (TSAT), and mortality in HD patients., Methods: HD outpatients (n = 125) treated with erythropoiesis-stimulating agents (ESA) were followed for 10 years. The ESA and low-dose iron supplement dosages were adjusted to maintain the hemoglobin (Hb) at 10-11 g/dl, according to Japanese guidelines. The Kaplan-Meier method, log-rank tests, and the Cox proportional hazards model were used for performing the statistical analyses. The interactions among the Hb, s-ft, and TSAT were analyzed using a multiple linear regression model. Patients with TSAT ≥20% were classified according to the s-ft cutoff values: group 1 (s-ft <30 ng/ml); group 2 (s-ft 30-80 ng/ml); group 3 (s-ft >80 ng/ml); TSAT <20% was a predictor of poor outcome., Results: The survival rate in group 2 was significantly higher than that in other groups (p = 0.013), and the Cox proportional hazards model analysis showed a good effect of low levels of s-ft on patients' survival. The multiple linear regression model showed a strong effect of s-ft on the Hb (log [s-ft], β-coefficient -0.45: 95% confidence interval -0.65 to -0.26, p < 0.001)., Conclusion: This study revealed that low levels of s-ft have a beneficial effect on the outcome of HD patients receiving ESA. Thus, the optimal s-ft level might be lower than that established previously for these patients., (© 2015 S. Karger AG, Basel)

Objectives: Our study aims to determine the role of serum adiponectin in chronic heart failure (CHF) and cardiac cachexia (CC)., Methods: Ninety consecutive patients were included in the study. Patients were divided into three groups: 30 CHF patients with CC, 30 CHF patients without CC, and 30 healthy individuals. Adiponectin levels were measured through human ELISA kits., Results: Levels of serum adiponectin were significantly higher in the CHF patients with cachexia in comparison with the other groups (CHF with CC: 58.4 ± 15.5 ng/ml vs. CHF without CC: 24 ± 6.7 ng/ml and controls: 7.7 ± 3.4 ng/ml; p = 0.001). Serum adiponectin was negatively correlated with BMI, high-sensitivity C-reactive protein, and hemoglobin (r = -0.37, p = 0.02; r = -0.29, p = 0.02; r = -0.18, p = 0.03, respectively) in the CHF patients with cachexia. Additionally, serum adiponectin levels were positively correlated with B-type natriuretic protein levels, left ventricle end-diastolic and end-systolic diameters (r = 0.36, p = 0.02; r = 0.46, p = 0.01; r = 0.49, p = 0.006, respectively) in the CHF patients with cachexia., Conclusion: Our findings suggest that adiponectin may play a critical role in the pathogenesis of cardiac remodeling and anemia in CC., (Copyright © 2013 S. Karger AG, Basel.)

Introduction: Anaemia treatment in chronic kidney disease (CKD) patients has changed dramatically since the implementation of erythropoietin stimulating agents (ESAs) and has shifted the emphasis from treating severe anaemia in dialysis patients to preventing anaemia. The aim of this chapter is to determine the extent to which the UK Renal Association (RA) and National Institute for Health and Care Excellence (NICE) guidelines for anaemia management are met in the UK., Methods: Quarterly data were obtained for haemoglobin (Hb) and factors that influence Hb from UK renal centres for the incident and prevalent renal replacement therapy (RRT) cohorts for 2012., Results: In the UK, in 2012, 51% of patients commenced dialysis therapy with Hb 100 g/L (median Hb 100 g/L). Of patients in the early presentation group, 54% started dialysis with Hb 100 g/L whilst 34% of patients presenting late started dialysis with Hb 100 g/L. The UK median Hb of haemodialysis (HD) patients was 112 g/L, with 82% of patients having Hb 100 g/L. The median Hb of peritoneal dialysis (PD) patients in the UK was 114 g/L, with 85% of patients having Hb 100 g/L. The median ferritin in HD patients in the UK was 431 µg/L and 95% of HD patients had a ferritin 100 µg/L. In EW&NI the median ferritin in PD patients was 285 µg/L (IQR 164-466) with 88% of PD patients having a ferritin 100 µg/L. In EW&NI the median ESA dose was higher for HD than PD patients (7,248 vs. 4,250 IU/week). The percentage of patients treated with an ESA and having Hb >120 g/L ranged between centres from 7-39% for HD and from 0-33% for PD., Conclusions: There was poor correlation between median Hb achieved and median ferritin and ESA usage across the EW&NI centres. There was also a significant variation between centres in the percentages of patients treated with an ESA and having Hb >120 g/L. © 2014 S. Karger AG, Basel.

Background: During acellular replacement of an acute blood loss, hyperoxic ventilation (HV) increases the amount of O2 physically dissolved in the plasma and thereby improves O2 supply to the tissues. While this effect could be demonstrated for HV with inspiratory O2 fraction (FiO2) 0.6, it was unclear whether HV with pure oxygen (FiO2 1.0) would have an additional effect on the physiological limit of acute normovolemic anemia., Methods: Seven anesthetized domestic pigs were ventilated with FiO2 1.0 and subjected to an isovolemic hemodilution protocol. Blood was drawn and replaced by a 6% hydroxyethyl starch (HES) solution (130/0.4) until a sudden decrease of total body O2 consumption (VO2) indicated the onset of O2 supply dependency (primary endpoint). The corresponding hemoglobin (Hb) concentration was defined as 'critical Hb' (Hbcrit). Secondary endpoints were parameters of myocardial function, central hemodynamics, O2 transport and tissue oxygenation., Results: HV with FiO2 1.0 enabled a large blood-for-HES exchange (156 ± 28% of the circulating blood volume) until Hbcrit was met at 1.3 ± 0.3 g/dl. After termination of the hemodilution protocol, the contribution of O2 physically dissolved in the plasma to O2 delivery and VO2 had significantly increased from 11.7 ± 2 to 44.2 ± 9.7% and from 29.1 ± 4.2 to 66.2 ± 11.7%, respectively. However, at Hbcrit, cardiovascular performance was found to have severely deteriorated., Conclusion: HV with FiO2 1.0 maintains O2 supply to tissues during extensive blood-for-HES exchange. In acute situations, where profound anemia must be tolerated (e.g. bridging an acute blood loss until red blood cells become available for transfusion), O2 physically dissolved in the plasma becomes an essential source of oxygen. However, compromised cardiovascular performance might require additional treatment.

Unlabelled: Anemia is more prevalent in renal transplant recipients than in GFR-matched chronic kidney disease patients. Hepcidin is a small defensin-like peptide whose production by hepatocytes is modulated in response to anemia, hypoxia or inflammation. Growth differentiation factor 15 (GDF15) was recently identified as a hepcidin-suppression factor that is expressed at high levels in patients with ineffective erythropoiesis. The aim of the study was to assess GDF15 levels with relation to iron parameters in 62 stable kidney allograft recipients maintained on triple immunosuppressive therapy., Methods: Complete blood count, urea, creatinine, and iron status were assessed by standard methods. We measured GDF15, hepcidin, hemojuvelin, IL-6 and NGAL with commercially available assays., Results: Mean levels of GDF15, NGAL, hepcidin and hemojuvelin were significantly higher in kidney allograft recipients when compared to the control group (p < 0.001 for all). GDF15 was significantly higher in patients with anemia according to the WHO definition when compared to their nonanemic counterparts (p < 0.05). GDF15 levels were not dependent on the type of immunosuppressive therapy. In univariate analysis GDF15 was related to kidney function (creatinine r = 0.39, p < 0.01, eGFR by MDRD r = -0.37, p < 0.01), urea (r = 0.39, p < 0.01), uric acid (r = 0.42, p < 0.01), hepcidin (r = -0.32, p < 0.01), IL-6 (r = 0.28, p < 0.05), hemoglobin (r = -0.32, p < 0.05), and NGAL (r = -0.35, p < 0.01). GDF15 was not related to serum iron, or ferritin. In multivariate analysis, hepcidin was found to be a predictor of GDF15. In conclusion, our preliminary data may suggest possible mutual relations between GDF15 and hepcidin in patients with kidney disease and that GDF15 might be involved in the pathogenesis of anemia in kidney allograft recipients. However, the role of inflammation should be also elucidated., (Copyright © 2013 S. Karger AG, Basel.)

Background: Neutrophil-gelatinase associated lipocalin (NGAL), a tubular injury marker, is associated with iron metabolism in hemodialysis patients. We investigated whether serum NGAL levels reflect iron metabolism in combined chronic heart failure and chronic kidney disease (CHF/CKD) and whether treatment with low-dose erythropoietin stimulating agent (ESA) modulates NGAL levels., Methods: In the EPOCARES trial (ClinTrialsNCT00356733) serum NGAL, hepcidin-25, transferrin saturation (TSAT), reticulocyte hemoglobin content (Ret-He) and endogenous erythropoietin (EPO) levels were measured., Results: Baseline serum NGAL levels correlated with cystatin C (r=0.767, p<0.001) and baseline EPO levels (r=-0.395, p=0.003). There was no correlation with baseline TSAT, Ret-He, and hepcidin-25 levels. After two weeks, NGAL levels decreased in the ESA-group (p=0.02), while there was no change in the no-ESA group (p=0.62). The magnitude in NGAL decrease in the ESA-group correlated with baseline EPO levels (r=0.431, p=0.01)., Conclusions: In contrast to in HD patients, in combined CKD/ CHF, serum NGAL levels did not correlate with iron metabolism, hence NGAL might reflect tubular damage in these patients. NGAL levels inversely correlated with baseline EPO levels and decreased in response to short-term ESA treatment, which might reflect an effect of ESA on tubular damage. These findings need to be confirmed and alternative explanations should be evaluated., (Copyright © 2012 S. Karger AG, Basel.)

Background: The British Association for Paediatric Nephrology Registry was established to analyse data related to renal replacement therapy (RRT) for children. The registry receives data from the 13 paediatric nephrology centres in the UK., Aim: To provide centre specific data so that individual centres can reflect on the contribution that their data makes to the national picture and to determine the extent to which their patient parameters meet nationally agreed audit standards for the management of children with established renal failure., Method: Data returns have been a mixture of electronic and paper returns. Data were analysed to calculate summary statistics and where applicable the percentage achieving an audit standard. The standards used were those set out by the Renal Association and the National Institute for Health and Clinical Excellence., Results: Anthropometric data confirmed that children receiving RRT are short compared to healthy peers. Amongst patients with a height z-score of <2SD between 2000 and 2010, 27% were receiving growth hormone if they were on dialysis compared to 10% if they had a functioning transplant. Blood pressure was higher in children receiving RRT than in healthy children with wide inter-centre variation. The percentage of patients achieving the treatment standards for haemoglobin and ferritin has gradually increased over the last decade, more noticeably in dialysis patients. Analysis by age showed that the proportion of children with a haemoglobin below the standard was greatest for the under 5 years age group irrespective of RRT modality. The control of renal bone disease remained challenging., Conclusions: Optimizing growth in children on RRT remains challenging and the control of bone biochemistry in children on dialysis is imperfect. However there is some room for optimism as this year's data shows an improving trend in the control of anaemia and systolic blood pressure., (Copyright © 2012 S. Karger AG, Basel.)

Objectives: The dataset from the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial provides a rare opportunity to evaluate the whole spectrum of associations of hemoglobin (HB) and hematocrit (HCT) in heart failure (HF). In that trial, subjective and objective data were recorded at multiple time points when HB and HCT were also measured. We investigated the relationship between anemia and ventricular systolic function., Methods: A limited access dataset from the ESCAPE trial, provided by the National Heart, Lung and Blood Institute, was analyzed. Linear regression analysis, correlation coefficients and Student's t test were utilized., Results: Besides the known association of anemia with poor prognosis, more severe symptoms, decreased functional capacity and impaired kidney function, we found a significant and very consistent inverse correlation between HB and HCT and ventricular contractility. Both left ventricular ejection fraction and right ventricular fractional area change improved with a decrease in HB and vice versa. We hypothesize that this effect can result from a change in viscosity, which decreases with a decrease in HCT, and may facilitate adaptation of the heart to a volume overload state accompanied by hemodilution., Conclusions: In HF, anemia is associated with poor prognosis and functional impairment, but also with mildly improved systolic function. It may represent an adaptive reaction to congestion., (Copyright © 2012 S. Karger AG, Basel.)

Background: The UK Renal Association (RA) and National Institute for Health and Clinical Excellence (NICE) have published clinical practice guidelines which include recommendations for management of anaemia in established renal failure., Aim: To determine the extent to which the guidelines for anaemia management are met in the UK., Methods: Quarterly data were obtained regarding haemoglobin (Hb) and factors that influence Hb from renal centres in England, Wales, Northern Ireland (EWNI) and the Scottish Renal Registry for the incident and prevalent renal replacement therapy (RRT) cohorts for 2010., Results: In the UK, in 2010 53.6% of patients commenced dialysis therapy with Hb ≥ 10.0 g/dl (median Hb 10.1 g/dl). The median Hb of haemodialysis (HD) patients was 11.5 g/dl with an interquartile range (IQR) of 10.5-12.3 g/dl. Of HD patients 84.6% had Hb ≥ 10.0 g/dl. The median Hb of peritoneal dialysis (PD) patients in the UK was 11.6 g/dl (IQR 10.6-12.5 g/dl). Of UK PD patients, 87.2% had Hb ≥ 10.0 g/dl. The median ferritin in HD patients in EWNI was 444 µg/L (IQR 299-635) and 96% of HD patients had a ferritin ≥ 100 µg/L. The median ferritin in PD patients was 264 µg/L (IQR 148-426) with 86% of PD patients having a ferritin ≥ 100 µg/L. In EWNI the mean Erythropoietin Stimulating Agent (ESA) dose was higher for HD than PD patients (9,020 vs. 6,202 IU/week)., Conclusions: Of prevalent HD patients, 52.7% had Hb ≥ 10 and ≤ 12 g/dl. Of prevalent PD patients, 54.3% had Hb 10.5-12.5 g/dl., (Copyright © 2012 S. Karger AG, Basel.)

Anemia secondary to chronic kidney disease is a complex syndrome. Adequate dialysis can contribute to its correction by removing small and possibly medium/large molecules that may inhibit erythropoiesis. A clear relationship among hemoglobin, erythropoiesis stimulating agent (ESA) dose and increase in dialysis dose has been pointed out by a number of prospective and retrospective studies. Increasing attention has also been paid to the relationship between dialysis, increased inflammatory stimulus and ESA response, as dialysate contamination and low compatible treatments may increase cytokine production and consequently inhibit erythropoiesis. As medium/large molecular weight inhibitors can be removed only by more permeable membranes, convective treatment sand, particularly, online treatments, could theoretically improve anemia correction by two mechanisms: higher removal of medium and large solutes (possibly containing bone marrow inhibitors) and reduced microbiological and pyrogenic contamination of the dialysate. Unfortunately, available results are conflicting. Large, prospective, randomized studies on this topic are still needed., (Copyright © 2011 S. Karger AG, Basel.)

Background: Anemia may be present in patients with chronic obstructive pulmonary disease (COPD) and further impair their functional capacity., Objectives: This study investigated the prevalence of anemia of chronic disease (ACD) in COPD patients and its impact on dyspnea and exercise capacity, utilizing cardiopulmonary exercise testing (CPET)., Methods: ACD prevalence was assessed in 283 consecutive patients with stable COPD (263 males, 60 females; age 60.31 ± 5.34 years; percent forced expiratory volume in 1 s 46.94 ± 6.12). ACD diagnosis was based on a combination of clinical and laboratory parameters [hemoglobin (Hb) <13 g/dl for males, <12 g/dl for females; ferritin >30 ng/ml; total iron-binding capacity <250 μg/dl, and transferrin saturation rate between 15 and 50%]. Twenty-seven patients who were identified with ACD (cases) and 27 matched nonanemic patients (controls) completed maximal CPET, and data were compared between the groups., Results: ACD was diagnosed in 29 patients, which represents a prevalence of 10.24%; the severity of anemia was generally mild (mean Hb: 12.19 ± 0.66 g/dl). Patients with ACD had a higher Medical Research Council dyspnea score compared to controls (2.78 ± 0.44 vs. 2.07 ± 0.55; p <0.001) and lower peak O(2) uptake (VO(2)) (59.54 ± 17.17 vs. 71.26 ± 11.85% predicted; p <0.05), peak work rate (54.94 ± 21.42 vs. 68.72 ± 20.81% predicted; p <0.05) and peak VO(2)/heart rate (69.07 ± 17.26 vs. 82.04 ± 18.22% predicted; p <0.05). There was also a trend for a lower anaerobic threshold (48.48 ± 15.16 vs. 55.42 ± 9.99% predicted; p = 0.062). No exercise parameter indicative of respiratory limitation differed between the groups., Conclusions: ACD occurs in approximately 10% of stable COPD patients and has a negative impact on dyspnea and circulatory efficiency during exercise., (Copyright © 2011 S. Karger AG, Basel.)

Background: The effect of acute kidney injury (AKI) on anemia has been well-documented. However, the effect of 'preexisting' anemia on AKI has been less addressed. The aims of the present study were to investigate (1) the association between anemia at hospital admission and AKI occurrence, and (2) the effect of 'preexisting' anemia on the clinical outcomes of AKI., Methods: A retrospective cohort study was undertaken among patients aged > or =17 years who were admitted to our hospital during the year 2006 (n = 34,802). Anemia at hospital admission and AKI occurrences were determined using the WHO definition and the RIFLE criteria, respectively. A subgroup of patients with an estimated glomerular filtration rate > or =60 ml/min/1.73 m(2) was analyzed separately to control for the effect of chronic kidney disease on anemia., Results: The cumulative incidence of AKI was 11.2% in anemic patients at hospital admission, compared to 5.5% in nonanemic subjects. The association between anemia at admission and AKI occurrence remained statistically significant after controlling for potential confounders (odds ratio 1.5, 95% CI 1.4-1.6). In addition, an association between anemia at hospital admission and clinical outcomes of AKI was observed., Conclusion: Anemia at hospital admission should be recognized as a potential risk factor for in-hospital AKI occurrence., (Copyright 2010 S. Karger AG, Basel.)

International clinical practice guidelines have recently recognized for the first time the concrete difficulty of keeping chronic kidney disease (CKD) patients within the narrow haemoglobin (Hb) target recommended of 11-12 g/dl (110-120 g/l) because of the variability of individual patient Hb levels. This emerging clinical problem has been the topic of several editorials that, however, exclusively focused on haemodialysis patients. Recently, 3 retrospective studies have been published on Hb variability in non-dialysis CKD. The studies which overall included more than 6,000 patients showed that Hb variability in non-dialysis CKD is greatly prevalent and is associated with a worse cardiorenal outcome. This minireview summarizes the results and limits of these studies and discusses the potential implications for clinical practice., (Copyright 2010 S. Karger AG, Basel.)

Background: The UK Renal Association (RA) and National Institute for Health and Clinical Excellence (NICE) have published Clinical Practice Guidelines which include recommendations for management of anaemia in established renal failure., Aims: To determine the extent to which the guidelines for anaemia management are met in the UK., Methods: Quarterly data (haemoglobin (Hb) and factors that influence Hb) extracts from renal centres in England, Wales, Northern Ireland (EWNI), and annual data from the Scottish Renal Registry for incident and prevalent renal replacement therapy (RRT) cohorts for 2008 were analysed by the UK Renal Registry (UKRR)., Results: In the UK, in 2008 57% of patients commenced dialysis therapy with Hb >or= 10.0 g/dl (median Hb 10.2 g/dl). For incident patients the Hb at 3 and 6 months of dialysis treatment was 11.4 and 11.7 g/dl respectively. The median Hb of haemodialysis (HD) patients was 11.6 g/dl with an interquartile range (IQR) of 10.6-12.5 g/dl. Of HD patients 85% had a Hb >or= 10.0 g/dl. The median Hb of peritoneal dialysis (PD) patients in the UK was 11.7 g/dl (IQR 10.8-12.6 g/dl). Of UK PD patients 89% had a Hb >or= 10.0 g/dl. The median ferritin in HD patients in EWNI was 436 mg/L (IQR 289-622) and 95% of HD patients had a ferritin >or= 100 mg/L. The median ferritin in PD patients was 246 mg/L (IQR 141-399) with 84% of PD patients having a ferritin >or= 100 mg/L. In EWNI the mean ESA dose was higher for HD than PD patients (9,166 vs. 6,302 IU/week)., Conclusions: Last year for the first time a small fall (from 85.9% in 2006 to 85.6% in 2007) in the % of HD patients with a Hb of >or= 10 g/dl which was thought to be related to the implementation of the new Hb Standard which has a target range of 10.5-12.5 g/dl was seen. This year attainment of Hb >or= 10 g/dl in HD patients fell again slightly to 85.3%. In HD patients, 54% of patients had a Hb >or= 10.5 and

Background: The aim of this study was to compare the efficacy, safety and achievement of the target hemoglobin level (Hb >or=10 g/dl) in patients with preoperative anemia due to menorrhagia who received intravenous iron sucrose compared with oral iron protein succinylate for anemia management., Methods: Seventy-six patients with Hb levels <9.0 g/dl who were scheduled to undergo surgical treatment were randomized to receive either intravenous iron sucrose (based on the calculated total iron deficit divided into 2 ampoule infusions intravenously 3 times a week, beginning 3 weeks before surgery) or oral iron (80 mg/day of oral iron protein succinylate daily)., Results: The intravenous iron group had higher increases in Hb (3.0 vs. 0.8 g/dl; p < 0.0001) and ferritin levels (170.1 vs. 4.1 microg/l; p < 0.0001) than the oral iron group. Achieving the target Hb was also higher in the intravenous iron group than in the oral iron group (76.7 vs. 11.5%; p < 0.0001). There were tolerable adverse events in both groups., Conclusion: Preoperative intravenous iron sucrose administration is more effective than oral iron and is as safe as oral iron therapy in the correction of preoperative anemia due to menorrhagia., ((c) 2009 S. Karger AG, Basel.)