Epoetin Beta and C-Terminal Fibroblast Growth Factor 23 in Patients With Chronic Heart Failure and Chronic Kidney Disease.

Background In patients with chronic heart failure and chronic kidney disease, correction of anemia with erythropoietin-stimulating agents targeting normal hemoglobin levels is associated with an increased risk of cardiovascular morbidity and mortality. Emerging data suggest a direct effect of erythropoietin on fibroblast growth factor 23 (FGF23), elevated levels of which have been associated with adverse outcomes. We investigate effects of erythropoietin-stimulating agents in patients with both chronic heart failure and chronic kidney disease focusing on FGF23. Methods and Results In the EPOCARES (Erythropoietin in CardioRenal Syndrome) study, we randomized 56 anemic patients (median age 74 [interquartile range 69-80] years, 66% male) with both chronic heart failure and chronic kidney disease into 3 groups, of which 2 received epoetin beta 50 IU/kg per week for 50 weeks, and the third group served as control. Measurements were performed at baseline and after 2, 26, and 50 weeks. Data were analyzed using linear mixed-model analysis. After 50 weeks of erythropoietin-stimulating agent treatment, hematocrit and hemoglobin levels increased. Similarly, C-terminal FGF23 levels, in contrast to intact FGF23 levels, rose significantly due to erythropoietin-stimulating agents as compared with the controls. During median follow-up for 5.7 (2.0-5.7) years, baseline C-terminal FGF23 levels were independently associated with increased risk of mortality (hazard ratio 2.20; 95% CI, 1.35-3.59; P=0.002). Conclusions Exogenous erythropoietin increases C-terminal FGF23 levels markedly over a period of 50 weeks, elevated levels of which, even at baseline, are significantly associated with an increased risk of mortality. The current results, in a randomized trial setting, underline the strong relationship between erythropoietin and FGF23 physiology in patients with chronic heart failure and chronic kidney disease. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00356733.

Improvement of radiocephalic fistula maturation: rationale and design of the Liposomal Prednisolone to Improve Hemodialysis Fistula Maturation (LIPMAT) study - a randomized controlled trial.

BACKGROUND: Non-maturation is a frequent complication of radiocephalic arteriovenous fistulas (RCAVF). In an animal model, liposomal prednisolone improved maturation of experimental fistulas. The Liposomal Prednisolone to Improve Hemodialysis Fistula Maturation (LIPMAT) study investigates if liposomal prednisolone improves RCAVF maturation. METHODS AND RESULTS: The LIPMAT study is an investigator-initiated, multicenter, double-blinded, placebo-controlled randomized controlled trial with 1:1 randomization to liposomal prednisolone or placebo. Eighty patients receiving an RCAVF will be included. The primary outcome is the cephalic vein diameter six weeks after surgery, measured by ultrasound. The LIPMAT study started in May 2016. Enrollment is expected to be completed by the end of 2017. CONCLUSIONS: The LIPMAT study is the first to evaluate the efficacy of liposomal prednisolone to enhance RCAVF maturation.

Relation between Red Cell Distribution Width and Fibroblast Growth Factor 23 Cleaving in Patients with Chronic Kidney Disease and Heart Failure.

OBJECTIVE: In chronic kidney disease (CKD), both anemia and deregulated phosphate metabolism are common and predictive of adverse outcome. Previous studies suggest that iron status influences phosphate metabolism by modulating proteolytic cleavage of FGF23 into C-terminal fragments. Red cell distribution width (RDW) was recently identified as a strong prognostic determinant for cardiovascular morbidity and mortality, independently of iron status. We assessed whether RDW is associated with FGF23 cleaving in CKD patients with heart failure. MATERIALS AND METHODS: The associations between RDW and either intact FGF23 (iFGF23), C-terminal FGF23 (cFGF23, reflecting iFGF23 and C-terminal fragments together) and the iFGF23/cFGF23 ratio were analyzed in 52 patients with CKD (eGFR 34,9 ± 13.9 ml/min/1.73m2) and chronic heart failure (CHF). Associations between RDW and FGF23 forms were studied by linear regression analysis adjusted for parameters of renal function, iron metabolism, phosphate metabolism and inflammation. RESULTS: Median cFGF23 levels were 197.5 [110-408.5] RU/ml, median iFGF23 levels were 107.3 [65.1-162.2] pg/ml and median FGF23 ratio was 0.80 [0.37-0.86]. Mean RDW was 14.1 ± 1.2%. cFGF23 and RDW were associated (ß = 1.63 x 10(-3), P < 0.001), whereas iFGF23 and RDW were not (ß = -1.38 x 10(-3), P = 0.336). The iFGF23/cFGF23 ratio was inversely associated with RDW. The difference between cFGF23 and iFGF23 (cFGF23- iFGF23) was positively associated with RDW (ß = 1.74 x 10(-3), P < 0.001). The association between cFGF23 and RDW persisted upon multivariable linear regression analysis, adjusted for parameters of renal function, phosphate metabolism, iron metabolism and inflammation (ß = 0.97 x 10(-3), P = 0.047). CONCLUSION: RDW is associated with cFGF23 but not with iFGF23 levels in patients with CKD and CHF. This suggests a connection between RDW and FGF23 catabolism, independent of iron status and inflammation. Future studies are needed to unravel underlying mechanisms and whether these pertain to the link between RDW and outcome.

Neutrophil gelatinase-associated lipocalin (NGAL) in chronic cardiorenal failure is correlated with endogenous erythropoietin levels and decreases in response to low-dose erythropoietin treatment.

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.

Short-term erythropoietin treatment does not substantially modulate monocyte transcriptomes of patients with combined heart and renal failure.

BACKGROUND: Combined heart and renal failure is associated with high cardiovascular morbidity and mortality. Anti-oxidant and anti-inflammatory, non-hematopoietic effects of erythropoietin (EPO) treatment have been proposed. Monocytes may act as biosensors of the systemic environment. We hypothesized that monocyte transcriptomes of patients with cardiorenal syndrome (CRS) reflect the pathophysiology of the CRS and respond to short-term EPO treatment at a recommended dose for treatment of renal anemia. METHODS: Patients with CRS and anemia (n = 18) included in the EPOCARES trial were matched to healthy controls (n = 12). Patients were randomized to receive 50 IU/kg/week EPO or not. RNA from CD14(+)-monocytes was subjected to genome wide expression analysis (Illumina) at baseline and 18 days (3 EPO injections) after enrolment. Transcriptomes from patients were compared to healthy controls and effect of EPO treatment was evaluated within patients. RESULTS: In CRS patients, expression of 471 genes, including inflammation and oxidative stress related genes was different from healthy controls. Cluster analysis did not separate patients from healthy controls. The 6 patients with the highest hsCRP levels had more differentially expressed genes than the 6 patients with the lowest hsCRP levels. Analysis of the variation in log(2) ratios of all individual 18 patients indicated that 4 of the 18 patients were different from the controls, whereas the other 14 were quite similar. After short-term EPO treatment, every patient clustered to his or her own baseline transcriptome. Two week EPO administration only marginally affected expression profiles on average, however, individual gene responses were variable. CONCLUSIONS: In stable, treated CRS patients with mild anemia, monocyte transcriptomes were modestly altered, and indicated imprints of inflammation and oxidative stress. EPO treatment with a fixed dose has hematopoietic effects, had no appreciable beneficial actions on monocyte transcription profiles, however, could also not be associated with undesirable transcriptional responses.

Atherosclerotic renal artery stenosis is prevalent in cardiorenal patients but not associated with left ventricular function and myocardial fibrosis as assessed by cardiac magnetic resonance imaging.

BACKGROUND: Atherosclerotic renal artery stenosis (ARAS) is common in cardiovascular diseases and associated with hypertension, renal dysfunction and/or heart failure. There is a paucity of data about the prevalence and the role of ARAS in the pathophysiology of combined chronic heart failure (CHF) and chronic kidney disease (CKD). We investigated the prevalence in patients with combined CHF/CKD and its association with renal function, cardiac dysfunction and the presence and extent of myocardial fibrosis. METHODS: The EPOCARES study (ClinTrialsNCT00356733) investigates the role of erythropoietin in anaemic patients with combined CHF/CKD. Eligible subjects underwent combined cardiac magnetic resonance imaging (cMRI), including late gadolinium enhancement, with magnetic resonance angiography of the renal arteries (MRA). RESULTS: MR study was performed in 37 patients (median age 74 years, eGFR 37.4 ± 15.6 ml/min, left ventricular ejection fraction (LVEF) 43.3 ± 11.2%), of which 21 (56.8%) had ARAS (defined as stenosis >50%). Of these 21 subjects, 8 (21.6%) had more severe ARAS >70% and 8 (21.6%) had a bilateral ARAS >50% (or previous bilateral PTA). There were no differences in age, NT-proBNP levels and medication profile between patients with ARAS versus those without. Renal function declined with the severity of ARAS (p = 0.03), although this was not significantly different between patients with ARAS versus those without. Diabetes mellitus was more prevalent in patients without ARAS (56.3%) against those with ARAS (23.8%) (p = 0.04). The presence and extent of late gadolinium enhancement, depicting myocardial fibrosis, did not differ (p = 0.80), nor did end diastolic volume (p = 0.60), left ventricular mass index (p = 0.11) or LVEF (p = 0.15). Neither was there a difference in the presence of an ischemic pattern of late enhancement in patients with ARAS versus those without. CONCLUSIONS: ARAS is prevalent in combined CHF/CKD and its severity is associated with a decline in renal function. However, its presence does not correlate with a worse LVEF, a higher left ventricular mass or with the presence and extent of myocardial fibrosis. Further research is required for the role of ARAS in the pathophysiology of combined chronic heart and renal failure.

The role of melatonin treatment in chronic kidney disease.

The pineal hormone melatonin plays a major role in circadian sleep-wake rhythm. Patients with Chronic Kidney Disease (CKD), especially those who are on hemodialysis, frequently suffer from sleep disturbances. In this review an overview is given of the classification of stages of chronic kidney disease, followed by a presentation of the circadian rhythm disorders in renal disease involving sleep disturbances in relation to melatonin deficiency. The therapeutic benefit of melatonin treatment in sleep disorders related to chronic kidney disease including the controlled trials solving this topic, is described. Furthermore, the beneficial effect of melatonin on blood pressure alterations in CKD states and the protection of melatonin in oxidative stress and inflammation in renal disorders are explored. Finally a hypothetic model is described for the relation between circadian rhythm disorders and CKD.

Determinants of red cell distribution width (RDW) in cardiorenal patients: RDW is not related to erythropoietin resistance.

BACKGROUND: Studies have shown that red cell distribution width (RDW) is related to outcome in chronic heart failure (CHF). The pathophysiological process is unknown. We studied the relationship between RDW and erythropoietin (EPO) resistance, and related factors such as erythropoietic activity, functional iron availability and hepcidin. METHODS AND RESULTS: In the Mechanisms of Erythropoietin Action in the Cardiorenal Syndrome (EPOCARES) study, which investigates the role of EPO in 54 iron-supplemented anemic patients with CHF and chronic kidney disease (CKD) (n = 35 treated with 50 IU/kg/wk Epopoetin beta, n = 19 control), RDW was not associated with EPO resistance. We defined EPO resistance by EPO levels (r = 0.12, P = .42), the observed/predicted log EPO ratio (r = 0.12, P = .42), the increase in reticulocytes after 2 weeks of EPO treatment (r = -0.18, P = .31), and the increase of hemoglobin after 6 months of EPO treatment (r = 0.26, P = .35). However, RDW was negatively correlated with functional iron availability (reticulocyte hemoglobin content, r = -0.48, P < .001, and transferrin saturation, r = -0.39, P = .005) and positively with erythropoietic activity (soluble transferrin receptor, r = 0.48, P < .001, immature reticulocyte fraction, r = 0.36, P = .01) and positively with interleukin-6 (r = 0.48, P < .001). No correlation existed between hepcidin-25 and RDW. CONCLUSIONS: EPO resistance was not associated with RDW. RDW was associated with functional iron availability, erythropoietic activity, and interleukin-6 in anemic patients with CHF and CKD.

The role of renal function loss on circadian misalignment of cytokines EPO, IGF-1, IL-6 and TNF-alfa in chronic renal disease.

OBJECTIVE: Chronic inflammation plays a pivotal role in the development of renal disease. Circadian sleep-wake rhythm is disturbed in renal disease. Awareness of other disturbed rhythms, such as inflammation processes, can affect the treatment of patients with renal disease. Knowledge of possibly related circadian misalignment of the cytokines erythropoietin (EPO), Insulin Growth Factor-1 (IGF-1) and interleukins (IL) however is limited. We therefore performed an observational study. The objective of this study was to characterize levels of EPO, IGF-1 and inflammation markers IL-6 and TNF-α, related to renal function. METHODS: The study population consisted of patients with various degrees of renal function, admitted to our hospital. During 24 hours, blood of 28 subjects with various degrees of renal function was collected every 2 hours. The patients were stable, not acutely ill and they were waiting for a procedure, such as elective surgery. Circadian parameters of EPO, IGF-1, IL-6 and TNF-α were measured in serum and were correlated with glomerular filtration rate (GFR) and Hb, using Pearson correlations. RESULTS: Although diurnal variations in EPO level were found in 15 out of 28 patients, the curves did not show a consistent phase. The presence of an EPO rhythm was not related to GFR. No diurnal rhythm could be detected for IGF-1, IL-6 and TNF-α. Mean levels of IGF-1 were correlated inversely to mean levels of EPO (p=0.03). When divided based on GFR and Hb subjects with GFR 10-30 ml/min and lower Hb had the highest IGF-1 levels (p=0.02). A relationship between Il-6, TNF-α and EPO or GFR was not found. CONCLUSION: The existence of a circadian (mis)alignment of EPO, IGF-1, IL-6 and TNF-α was not found. The association between high IGF-1 and low Hb suggests that EPO and IGF-1 have an alternating role, dependent on GFR, in stimulating erythropoiesis. These results could have consequences for the treatment of anemia.

Short- and long-term effects of erythropoietin treatment on endothelial progenitor cell levels in patients with cardiorenal syndrome.

OBJECTIVE: Patients with cardiorenal syndrome (CRS) have high cardiovascular morbidity. Endothelial progenitor cells (EPC) constitute an endogenous vascular repairsystem, protecting against atherosclerosis development. Erythropoietin (EPO) treatment may have beneficial effects by mobilizing EPC from the bonemarrow. Our objective is to determine EPC levels and effects of EPO therapy on EPC levels in CRS patients. DESIGN: Open-label randomized trial. SETTING: Part of the EPOCARES-trial, conducted in Utrecht (Netherlands). PATIENTS: Patients with CRS and anaemia and healthy controls were included. Interventions Patients were randomized to receive EPO therapy (50 IU/kg/wk) for 52 weeks or no EPO therapy. MAIN OUTCOME MEASURES: CD34(+)KDR(+)-EPC, cultured EPC outgrowth and function at baseline, after 18 days and after 52 weeks. RESULTS: Patients showed lower CD34(+)KDR(+)-cell numbers compared to controls (6(12) vs. 19(19) cells/10(5) granulocytes; p = 0.010), despite increased levels of stromal cell-derived factor-1α; (3.1(0.8) vs 2.6(0.3) ng/ml; p = 0.001). EPC outgrowth and function were not different between patients and controls. EPC levels did not change after 18 days with or without EPO treatment. CD34(+)KDR(+)-cells significantly declined after 52 weeks in the non-treated group (p = 0.028). Long-term EPO therapy did not significantly affect this reduction in CD34(+)KDR(+)-EPC levels. CONCLUSIONS: CRS patients showed reduced CD34(+)KDR(+)-EPC levels compared to controls, consistent with a reduced vascular regenerative potential and despite upregulated SDF-1α levels. Over a one-year follow-up period a marked 68% further reduction in EPC levels was observed in the patient group without EPO treatment. In spite of promising experimental studies, our longitudinal, randomized study did not show significant influence of either short- or long-term EPO therapy on reduced EPC levels in CRS patients.

Hepcidin-25 is a marker of the response rather than resistance to exogenous erythropoietin in chronic kidney disease/chronic heart failure patients.

AIMS: Erythropoietin (EPO) resistance, an important cause of anaemia in patients with heart and renal failure, is associated with increased mortality. The hypothesis of the present study was that exogenous EPO decreases hepcidin levels and that the decrease in hepcidin levels upon EPO treatment is related to the bone marrow response. METHODS AND RESULTS: In the EPOCARES trial, patients with renal failure (glomerular filtration rate 20-70 mL/min), heart failure, and anaemia were randomized to receive 50 IU/kg/week EPO (n = 20) or not (n = 13). Haemoglobin (Hb), hepcidin-25, ferritin, reticulocytes, serum transferrin receptor (sTfR), IL-6, and high-sensitivity C-reactive protein were measured at baseline and during treatment. Hepcidin-25 was measured by weak cation exchange chromatography/matrix assisted laser desorption ionization time-of-flight mass spectrometry. Baseline hepcidin levels were increased compared with a healthy reference population and were inversely correlated with Hb (r(2) = 0.18, P = 0.02), and positively with ferritin (r(2) = 0.51, P < 0.001), but not with renal function, high-sensitivity C-reactive protein or IL-6. Erythropoietin treatment increased reticulocytes (P < 0.001) and sTfR (P < 0.001), and decreased hepcidin (P < 0.001). Baseline hepcidin levels and the magnitude of the decrease in hepcidin correlated with the increase in reticulocytes (r(2) = 0.23, P = 0.03) and sTfR (r(2) = 0.23, P = 0.03) and also with the Hb response after 6 months (r(2) = 0.49, P = 0.001). CONCLUSION: In this group of patients with combined heart and renal failure and anaemia, increased hepcidin levels were associated with markers of iron load and not with markers of inflammation. The (change in) hepcidin levels predicted early and long-term bone marrow response to exogenous EPO. In our group hepcidin seems to reflect iron load and response to EPO rather than inflammation and EPO resistance.

High cumulative incidence of cancer in patients with cardio-renal-anaemia syndrome.

AIMS: The combination of chronic kidney disease (CKD), chronic heart failure (HF), and anaemia, the so-called cardio-renal-anaemia syndrome (CRA) is associated with dysregulation of erythropoietin levels and inflammation. Both have been associated with the development of cancer. This study aimed to determine the cumulative incidence of cancer in patients with CRA, as compared with anaemic CKD and control patients. METHODS AND RESULTS: Patients aged <80 years who attended the nephrology or cardiology outpatient clinics between March 2006 and November 2007 were eligible for inclusion in this retrospective case-control study if haemoglobin <8.1 mmol/L (13 g/dL) and serum creatinine >80 mmol/L (0.90 mg/dL). Medical records dating back to 1996 were reviewed. The relationship between cancer and CRA, chronic HF, CKD, and anaemia was analysed using logistic regression analysis. Data from 1087 patients were reviewed. We identified 348 patients with both CKD and anaemia, of whom 132(38.3%) had CRA. The control group included 264 patients attending the hypertension outpatient clinic. Patients with CRA had a 19% cumulative incidence of cancer compared with 11% for patients with anaemia, CKD and no chronic HF, and 11% in the control group. The odds ratio (OR) for cancer was 1.8(95% CI 1.0-3.2) for the CRA group compared with the control group. Chronic HF was an independent risk factor for cancer after correction for age and gender (adjusted OR 2.0; 95% CI 1.2-3.3, P = 0.007). CONCLUSION: The cumulative incidence of cancer among patients with CRA is high compared with controls and to anaemic CKD patients without chronic HF. Chronic HF was an independent risk factor for cancer. These results stress the importance of clarifying the mechanisms involved in the development of cancer in CRA.

Erythropoietin treatment in patients with combined heart and renal failure: objectives and design of the EPOCARES study.

BACKGROUND: Anemia is common in patients with the combination of chronic heart failure and chronic kidney disease and is associated with increased mortality. Recent clinical studies suggest that recombinant human erythropoietin (EPO) treatment has desirable as well as undesirable effects, related to its hematopoietic or nonhematopoietic effects. Therefore a translational study is needed to elucidate mechanistic aspects of EPO treatment. METHODS: In this open-label randomized 12-month trial (the Mechanisms of Erythropoietin Action in the Cardiorenal Syndrome [EPOCARES]), patients with the combination of chronic heart failure and chronic kidney disease (glomerular filtration rate 20-70 ml/min) and mild anemia (hemoglobin 10.3-12.6 g/dL in men, and 10.3-11.9 g/dL in women) are being randomized into 3 groups: 1 group (n=25) receives a fixed dose of 50 IU/kg per week EPO to increase hemoglobin level to a maximum of 13.7 g/dL for men and 13.4 g/dL for women; another group (n=25) is treated with 50 IU/kg per week EPO maintaining baseline hemoglobin levels for the first 6 months by phlebotomy. The control group (n=25) receives standard care without EPO. RESULTS: Cardiac and renal function as well as a panel of biomarkers and iron parameters are being assessed. Furthermore, the effects of EPO on monocyte gene expression profiles and on endothelial progenitor cells are being evaluated. CONCLUSION: This translational study is designed primarily to discern hematopoietic from nonhematopoietic effects of EPO in cardiorenal patients. The study will add insights into the mechanisms that could explain the fragile balance between desirable and undesirable effects of EPO (Trial registration: ClinicalTrials.gov identifier NCT00356733).

Impairment of endogenous melatonin rhythm is related to the degree of chronic kidney disease (CREAM study).

BACKGROUND: The nocturnal endogenous melatonin rise, which is associated with the onset of sleep propensity, is absent in haemodialysis patients. Information on melatonin rhythms in chronic kidney disease (CKD) is limited. Clear relationships exist between melatonin, core body temperature and cortisol in healthy subjects. In CKD, no data are available on these relationships. The objective of the study was to characterize the rhythms of melatonin, cortisol and temperature in relation to renal function in patients with CKD. METHODS: From 28 patients (mean age 71 years) with various degrees of renal function, over a 24-h period, blood samples were collected every 2 h. An intestinal telemetric sensor was used to measure core temperature. The presence of diurnal rhythms was examined for melatonin, temperature and cortisol. Correlation analysis was performed between Cockcroft-Gault GFR (GFR), melatonin, cortisol and temperature parameters. RESULTS: The mean GFR was 57 +/- 30 ml/min. The subjects exhibited melatonin (n = 24) and cortisol (n = 22) rhythms. GFR was significantly correlated to melatonin amplitude (r = 0.59, P = 0.003) and total melatonin production (r = 0.51, P = 0.01), but not to temperature or cortisol rhythms. Interestingly, no associations were found between the rhythms of temperature, melatonin and cortisol. CONCLUSIONS: As melatonin amplitude and melatonin rhythm decreased with advancing renal dysfunction, follow-up research into circadian rhythms in patients with CKD is warranted.

Hemoglobin variability in patients with chronic kidney disease in the Netherlands.

PURPOSE: Hemoglobin cycling has been reported in hemodialysis patients treated with erythropoiesis-stimulating agents (ESA) and is associated with increased mortality. Information on hemoglobin cycling in Europe is limited. We investigated hemoglobin variability in the Netherlands. Hemodialysis and peritoneal dialysis patients were studied and pre-dialysis patients were enrolled. METHODS: This observational retrospective study was executed in a Dutch dialysis center. We studied 157 patients from 2005 to 2007: 56 hemodialysis, 12 peritoneal dialysis and 29 pre-dialysis patients, all treated with ESA; and 60 pre-dialysis patients without ESA. Patients were divided on the basis of their pattern of hemoglobin fluctuation around a range of 11-12 g/dL. In dialysis patients, the amount of time that hemoglobin remained within that range was calculated. For all patients, the magnitude of hemoglobin fluctuations was assessed (i.e. the difference between hemoglobin maximum and minimum) and data on ESA dose changes and hospitalizations were collected. RESULTS: None of the ESA treated patients had hemoglobin levels stable within the target range over a one-year period. Pre-dialysis patients without ESA also showed variable hemoglobin levels. A stepwise decrease in the magnitudes of hemoglobin fluctuation was observed in the hemodialysis patients, peritoneal dialysis patients, pre-dialysis patients using ESA, and the pre-dialysis patients without ESA, respectively. CONCLUSION: In the Netherlands, hemoglobin variability is common in hemodialysis and peritoneal dialysis patients, but also in pre-dialysis patients. The results of this study warrant further research into the relationship between hemoglobin variability and clinical outcomes.

Mechanisms of Disease: erythropoietin resistance in patients with both heart and kidney failure.

Anemia is common in patients who have both heart failure and chronic kidney disease, and there is an association between anemia and progression of both diseases. The main causes of anemia are deficient production of erythropoietin (EPO), iron deficiency, and chronic disease with endogenous EPO resistance. EPO has been successfully used for over a decade to treat anemia in patients with chronic kidney disease. Less obvious are the safety and efficacy of EPO treatment in patients with both heart failure and renal disease. Up to 10% of patients receiving EPO are hyporesponsive to therapy and require large doses of the agent. Several mechanisms could explain resistance to endogenous and exogenous EPO. Proinflammatory cytokines antagonize the action of EPO by exerting an inhibitory effect on erythroid progenitor cells and by disrupting iron metabolism (a process in which hepcidin has a central role). EPO resistance might also be caused by inflammation, which has a negative effect on EPO receptors. Furthermore, neocytolysis could have a role. As resistance to exogenous EPO is associated with an increased risk of death, it is important to understand how cardiorenal failure affects EPO production and function.

Erythropoietin and the cardiorenal syndrome: cellular mechanisms on the cardiorenal connectors.

We have recently proposed severe cardiorenal syndrome (SCRS), in which cardiac and renal failure mutually amplify progressive failure of both organs. This frequent pathophysiological condition has an extremely poor prognosis. Interactions between inflammation, the renin-angiotensin system, the balance between the nitric oxide and reactive oxygen species and the sympathetic nervous system form the cardiorenal connectors and are cornerstones in the pathophysiology of SCRS. An absolute deficit of erythropoietin (Epo) and decreased sensitivity to Epo in this syndrome both contribute to the development of anemia, which is more pronounced than renal anemia in the absence of heart failure. Besides expression on erythroid progenitor cells, Epo receptors are present in the heart, kidney, and vascular system, in which activation results in antiapoptosis, proliferation, and possibly antioxidation and anti-inflammation. Interestingly, Epo can improve cardiac and renal function. We have therefore reviewed the literature with respect to Epo and the cardiorenal connectors. Indeed, there are indications that Epo can diminish inflammation, reduce renin-angiotensin system activity, and shift the nitric oxide and reactive oxygen species balance toward nitric oxide. Information about Epo and the sympathetic nervous system is scarce. This analysis underscores the relevance of a further understanding of clinical and cellular mechanisms underlying protective effects of Epo, because this will support better treatment of SCRS.