Sodium-glucose cotransporter 2 inhibition: towards an indication to treat diabetic kidney disease.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have clearly demonstrated their beneficial effect in diabetic kidney disease (DKD) on top of the standard of care [blood glucose control, renin-angiotensin system blockade, smoking cessation and blood pressure (BP) control], even in patients with overt DKD. However, the indication of this drug class is still blood glucose lowering in type 2 diabetic patients with estimated glomerular filtration rate >45 mL/min/1.73 m2. Based on the new evidence, several scientific societies have emphasized the preferential prescription of SGLT2i for patients at risk of heart failure or kidney disease, but still within the limits set by health authorities. A rapid positioning of both the European Medicines Agency and the US Food and Drug Administration will allow patients with overt DKD to benefit from SGLT2i. Clinical experience suggests that SGLT2i safety management may in part mirror renin-angiotensin blockade safety management in patients with overt DKD. This review focuses on the rationale for an indication of SGTL2i in DKD. We further propose clinical steps for maximizing the safety of SGLT2i in DKD patients on other antidiabetic, BP or diuretic medication.

Effects of Pentoxifylline on Soluble Klotho Concentrations and Renal Tubular Cell Expression in Diabetic Kidney Disease.

OBJECTIVE: The effect of pentoxifylline on Klotho levels in patients with type 2 diabetes mellitus with chronic kidney disease (CKD) was assessed in a post hoc analysis of the Pentoxifylline for Renoprotection in Diabetic Nephropathy (PREDIAN) trial. RESEARCH DESIGN AND METHODS: Circulating and urinary tumor necrosis factor-α (TNF-α) and Klotho were measured before and after 1 year of pentoxifylline. The effect on Klotho expression was assessed in cultured renal tubular cells. RESULTS: Pentoxifylline administration resulted in decreased serum and urinary TNF-α, whereas serum and urinary Klotho increased significantly. Changes in urinary Klotho, urinary TNF-α, and phosphorus were associated with changes in serum Klotho; changes in estimated glomerular filtration rate, urinary TNF-α, and albuminuria were related to urinary Klotho variation. In renal tubular cells, pentoxifylline prevented the decrease in Klotho expression induced by inflammatory cytokines or albumin. CONCLUSIONS: Pentoxifylline increased Klotho levels in patients with diabetes with stage 3-4 CKD and prevented reduced Klotho expression in vitro. This beneficial effect may be related to anti-inflammatory and antialbuminuric activity.

Mineral metabolism disorders, vertebral fractures and aortic calcifications in stable kidney transplant recipients: The role of gender (EMITRAL study).

BACKGROUND AND OBJECTIVES: The relationship between mineral metabolism disorders, bone fractures and vascular calcifications in kidney transplant recipients has not been established. METHOD: We performed a cross-sectional study in 727 stable recipients from 28 Spanish transplant clinics. Mineral metabolism parameters, the semi-quantification of vertebral fractures and abdominal aortic calcifications were determined centrally. RESULTS: Vitamin D deficiency (25OHD3<15ng/ml) was more common in female recipients at CKD-T stages I-III (29.6% vs 44.4%; p=0.003). The inverse and significant correlation between 25OHD3 and PTH was gender-specific and women exhibited a steeper slope than men (p=0.01). Vertebral fractures (VFx) with deformity grade ≥2 were observed in 15% of recipients. Factors related to VFx differed by gender; in males, age (OR 1.04; 95% CI 1.01-1.06) and CsA treatment (OR: 3.2; 95% CI: 1.6-6.3); in females, age (OR 1.07; 95% CI: 1.03-1.12) and PTH levels (OR per 100pg/ml increase: 1.27; 95% CI: 1.043-1.542). Abdominal aortic calcifications were common (67.2%) and related to classical risk factors but not to mineral metabolism parameters. CONCLUSIONS: Vitamin D deficiency is more common among female kidney transplant recipients at earlier CKD-T stages, and it contributes to secondary hyperparathyroidism. Prevalent vertebral fractures are only related to high serum PTH levels in female recipients.

Clinical impact of the ERBP Working Group 2010 Recommendations for the anemia management in chronic kidney disease not on dialysis: ACERCA study.

BACKGROUND AND OBJECTIVE: The Anemia Working Group of ERBP in 2010 recommended a target hemoglobin (Hb) level in the range of 11-12 g/dL, without intentionally exceeding 13 g/dL during the treatment with erythropoiesis stimulating agents (ESAs). This study evaluated if there was a clinical impact of this statement in the anemia management of chronic kidney disease (CKD) patients treated with ESAs not on dialysis in routine clinical practice in Spain. METHODS: This was an observational and cross-sectional study carried out in CKD patients not on dialysis in Spain who initiated ESA treatment (naïve), or were shifted from a previous ESA to another ESAs (converted) since January 2011. RESULTS: Of 441 patients evaluated, 67.6% were naïve and 32.4% were converted. At the study visit, 42.5% of naïve patients achieved the Hb target of 11-12 g/dL, with a mean Hb of 11.3±1.3 g/dL (vs 10.1±0.9 g/dL at the start of ESA therapy). Only 35.3% of converted patients maintained Hb levels within the recommended target at the study visit. Yet, 8.2% of naïve patients and 7.9% of those converted had Hb levels >13 g/dL. Hb levels were similar across subgroups of patients, regardless of the presence of significant comorbidities. CONCLUSIONS: Anemia management in CKD patients treated with ESAs by Spanish nephrologists seems to be aimed at preventing Hb levels <11 g/dL, while <50% of patients were within the narrow recommended Hb target range. This, together with the lack of individualization in Hb targets according to patients' comorbidities show that there is still room for improvement in renal anemia management in the clinical setting.

Vascular calcification in patients with nondialysis CKD over 3 years.

BACKGROUND AND OBJECTIVES: Vascular calcification (VC) is common in CKD, but little is known about its prognostic effect on patients with nondialysis CKD. The prevalence of VC and its ability to predict death, time to hospitalization, and renal progression were assessed. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Study of Mineral and Bone Disorders in CKD in Spain is a prospective, observational, 3-year follow-up study of 742 patients with nondialysis CKD stages 3-5 from 39 centers in Spain from April to May 2009. VC was assessed using Adragao (AS; x-ray pelvis and hands) and Kauppila (KS; x-ray lateral lumbar spine) scores from 572 and 568 patients, respectively. The primary end point was death. Secondary outcomes were hospital admissions and appearance of a combined renal end point (beginning of dialysis or drop >30% in eGFR). Factors related to VC were assessed by logistic regression analysis. Survival analysis was assessed by Cox proportional models. RESULTS: VC was present in 79% of patients and prominent in 47% (AS≥3 or KS>6). Age (odds ratio [OR], 1.05; 95% confidence interval [95% CI], 1.02 to 1.07; P<0.001), phosphorous (OR, 1.68; 95% CI, 1.28 to 2.20; P<0.001), and diabetes (OR, 2.11; 95% CI, 1.32 to 3.35; P=0.002) were independently related to AS≥3. After a median follow-up of 35 months (interquartile range=17-36), there were 70 deaths (10%). After multivariate adjustment for age, smoking, diabetes, comorbidity, renal function, and level of phosphorous, AS≥3 but not KS>6 was independently associated with all-cause (hazard ratio [HR], 2.07; 95% CI, 1.07 to 4.01; P=0.03) and cardiovascular (HR, 3.46; 95% CI, 1.27 to 9.45; P=0.02) mortality as well as a shorter hospitalization event-free period (HR, 1.14; 95% CI, 1.06 to 1.22; P<0.001). VC did not predict renal progression. CONCLUSIONS: VC is highly prevalent in patients with CKD. VC assessment using AS independently predicts death and time to hospitalization. Therefore, it could be a useful index to identify patients with CKD at high risk of death and morbidity as previously reported in patients on dialysis.

Consensus document on the management of renal disease in HIV-infected patients.

OBJECTIVE: To update the 2010 recommendations on the evaluation and management of renal disease in HIV-infected patients. METHODS: This document was approved by a panel of experts from the AIDS Working Group (GESIDA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), the Spanish Society of Nephrology (S.E.N.), and the Spanish Society of Clinical Chemistry and Molecular Pathology (SEQC). The quality of evidence and the level of recommendation were evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: The basic renal work-up should include measurements of serum creatinine, estimated glomerular filtration rate by CKD-EPI, Urine protein-to-creatinine ratio, and urinary sediment. Tubular function tests should include determination of serum phosphate levels and urine dipstick for glucosuria. In the absence of abnormal values, renal screening should be performed annually. In patients treated with tenofovir or with risk factors for chronic kidney disease (CKD), more frequent renal screening is recommended. In order to prevent disease progression, potentially nephrotoxic antiretroviral drugs are not recommended in patients with CKD or risk factors for CKD. The document advises on the optimal time for referral of a patient to the nephrologist and provides indications for renal biopsy. The indications for and evaluation and management of dialysis and renal transplantation are also addressed. CONCLUSIONS: Renal function should be monitored in all HIV-infected patients. The information provided in this document should enable clinicians to optimize the evaluation and management of HIV-infected patients with renal disease.

Executive summary of the consensus document on the management of renal disease in HIV-infected patients.

The aim of this article is to update the 2010 recommendations on the evaluation and management of renal disease in HIV-infected patients. Renal function should be monitored in all HIV-infected patients. The basic renal work-up should include measurements of serum creatinine, estimated glomerular filtration rate by CKD-EPI, urine protein-to-creatinine ratio, and urinary sediment. Tubular function tests should include determination of serum phosphate levels and urine dipstick for glucosuria. In the absence of abnormal values, renal screening should be performed annually. In patients treated with tenofovir or with risk factors for chronic kidney disease (CKD), more frequent renal screening is recommended. In order to prevent disease progression, potentially nephrotoxic antiretroviral drugs are not recommended in patients with CKD or risk factors for CKD. The document provides indications for renal biopsy and advises on the optimal time for referral of a patient to the nephrologist. The indications for and evaluation and management of dialysis and renal transplantation are also addressed.

[Executive summary of the recommendations on the evaluation and management of renal disease in human immunodeficiency virus-infected patients]. / Resumen ejecutivo del documento de consenso sobre el manejo de la patología renal en pacientes con infección por el virus de la inmunodeficiencia humana.

The aim of this article is to update the 2010 recommendations on the evaluation and management of renal disease in human immunodeficiency virus (HIV)-infected patients. Renal function should be monitored in all HIV-infected patients. The basic renal work-up should include measurements of serum creatinine, estimated glomerular filtration rate by CKD-EPI, urine protein-to-creatinine ratio, and urinary sediment. Tubular function tests should include determination of serum phosphate levels and urine dipstick for glycosuria. In the absence of abnormal values, renal screening should be performed annually. In patients treated with tenofovir, or with risk factors for chronic kidney disease (CKD), more frequent renal screening is recommended. In order to prevent disease progression, potentially nephrotoxic antiretroviral drugs are not recommended in patients with CKD or risk factors for CKD. The document provides indications for renal biopsy and advises on the optimal time for referral of a patient to the nephrologist. The indications for and evaluation and management of dialysis and renal transplantation are also addressed.

[Consensus document for the detection and management of chronic kidney disease]. / Documento de consenso para la detección y manejo de la enfermedad renal crónica.

Chronic kidney disease (CKD) is an important global health problem, involving to 10% of the Spanish population, promoting high morbidity and mortality for the patient and an elevate consumption of the total health resources for the National Health System. This is a summary of an executive consensus document of ten scientific societies involved in the care of the renal patient, that actualizes the consensus document published in 2007. The central extended document can be consulted in the web page of each society. The aspects included in the document are: Concept, epidemiology and risk factors for CKD. Diagnostic criteria, evaluation and stages of CKD, albuminuria and glomerular filtration rate estimation. Progression factors for renal damage. Patient remission criteria. Follow-up and objectives of each speciality control. Nephrotoxicity prevention. Cardio-vascular damage detection. Diet, life-style and treatment attitudes: hypertension, dyslipidaemia, hyperglycemia, smoking, obesity, hyperuricemia, anemia, mineral and bone disorders. Multidisciplinary management for Primary Care, other specialities and Nephrology. Integrated management of CKD patient in haemodialysis, peritoneal dialysis and renal transplant patients. Management of the uremic patient in palliative care. We hope that this document may be of help for the multidisciplinary management of CKD patients by summarizing the most updated recommendations.

[Consensus document for the detection and management of chronic kidney disease]. / Documento de consenso para la detección y manejo de la enfermedad renal crónica.

Chronic kidney disease (CKD) is an important global health problem, involving to 10% of the Spanish population, promoting high morbidity and mortality for the patient and an elevate consumption of the total health resources for the National Health System. This is a summary of an executive consensus document of ten scientific societies involved in the care of the renal patient, that actualizes the consensus document published in 2007. The central extended document can be consulted in the web page of each society. The aspects included in the document are: Concept, epidemiology and risk factors for CKD. Diagnostic criteria, evaluation and stages of CKD, albuminuria and glomerular filtration rate estimation. Progression factors for renal damage. Patient remission criteria. Follow-up and objectives of each speciality control. Nephrotoxicity prevention. Cardio-vascular damage detection. Diet, life-style and treatment attitudes: hypertension, dyslipidaemia, hyperglycemia, smoking, obesity, hyperuricemia, anemia, mineral and bone disorders. Multidisciplinary management for Primary Care, other specialities and Nephrology. Integrated management of CKD patient in haemodialysis, peritoneal dialysis and renal transplant patients. Management of the uremic patient in palliative care. We hope that this document may be of help for the multidisciplinary management of CKD patients by summarizing the most updated recommendations.

[Consensus document for the detection and management of chronic kidney disease]. / Documento de consenso para la detección y manejo de la enfermedad renal crónica.

Chronic kidney disease (CKD) is an important global health problem, involving to 10% of the Spanish population, promoting high morbidity and mortality for the patient and an elevate consumption of the total health resources for the National Health System. This is a summary of an executive consensus document of ten scientific societies involved in the care of the renal patient, that actualizes the consensus document published in 2007. The central extended document can be consulted in the web page of each society. The aspects included in the document are: Concept, epidemiology and risk factors for CKD. Diagnostic criteria, evaluation and stages of CKD, albuminuria and glomerular filtration rate estimation. Progression factors for renal damage. Patient remission criteria. Follow-up and objectives of each speciality control. Nephrotoxicity prevention. Cardio-vascular damage detection. Diet, life-style and treatment attitudes: hypertension, dyslipidaemia, hyperglycemia, smoking, obesity, hyperuricemia, anemia, mineral and bone disorders. Multidisciplinary management for Primary Care, other specialities and Nephrology. Integrated management of CKD patient in haemodialysis, peritoneal dialysis and renal transplant patients. Management of the uremic patient in palliative care. We hope that this document may be of help for the multidisciplinary management of CKD patients by summarizing the most updated recommendations.

Diabetic kidney disease: from physiology to therapeutics.

Diabetic kidney disease (DKD) defines the functional, structural and clinical abnormalities of the kidneys that are caused by diabetes. This complication has become the single most frequent cause of end-stage renal disease. The pathophysiology of DKD comprises the interaction of both genetic and environmental determinants that trigger a complex network of pathophysiological events, which leads to the damage of the glomerular filtration barrier, a highly specialized structure formed by the fenestrated endothelium, the glomerular basement membrane and the epithelial podocytes, that permits a highly selective ultrafiltration of the blood plasma. DKD evolves gradually over years through five progressive stages. Briefly they are: reversible glomerular hyperfiltration, normal glomerular filtration and normoalbuminuria, normal glomerular filtration and microalbuminuria, macroalbuminuria, and renal failure. Approximately 20-40% of diabetic patients develop microalbuminuria within 10-15 years of the diagnosis of diabetes, and about 80-90% of those with microalbuminuria progress to more advanced stages. Thus, after 15-20 years, macroalbuminuria occurs approximately in 20-40% of patients, and around half of them will present renal insufficiency within 5 years. The screening and early diagnosis of DKD is based on the measurement of urinary albumin excretion and the detection of microalbuminuria, the first clinical sign of DKD. The management of DKD is based on the general recommendations in the treatment of patients with diabetes, including optimal glycaemic and blood pressure control, adequate lipid management and abolishing smoking, in addition to the lowering of albuminuria.

Consensus document for the detection and management of chronic kidney disease.

Chronic kidney disease (CKD) is a major public health problem that, in its different stages, may affect up to 10% of the Spanish population and results in high morbidity and mortality, as well as high consumption of National Health System resources. Ten scientific societies involved in the management of kidney patients agreed to update the 2007 CKD consensus document. The current version is an abridged edition of the detailed general document, which can be consulted on the webpages of each signatory society. It includes the following aspects: CKD definition, epidemiology and risk factors and criteria on diagnosis, assessment and staging of CKD, albuminuria and glomerular filtration estimation. Progression factors and concept. Criteria for referral to Nephrology. Patient follow-up, attitudes and objectives by specialty. Prevention of nephrotoxicity. Detection of cardiovascular damage. Attitudes, lifestyle and treatment: management of high blood pressure, dyslipidaemia, hyperglycaemia, smoking, obesity, hyperuricaemia, anaemia and mineral and bone metabolism disorders. Coordinated follow-up by Primary Care – other specialties – Nephrology. Management of renal replacement therapy, haemodialysis, peritoneal dialysis and renal transplantation patients. Palliative treatment of terminal uraemia. We hope that this document will be very useful in the multidisciplinary management of CKD patients, in view of the updated recommendations.

Prospective assessment of antidonor cellular alloreactivity is a tool for guidance of immunosuppression in kidney transplantation.

Current characterization of the immune risk in renal transplant patients is only focused on the assessment of preformed circulating alloantibodies; however, alloreactive memory T cells are key players in mediating allograft rejection. Immune monitoring of antidonor alloreactive memory/effector T cells using an IFN-γ Elispot has been shown to distinguish patients at risk for immune-mediated graft dysfunction, suggesting a potential tool for immunosuppression individualization. In this nonrandomized study, we prospectively assessed donor and nondonor T-cell alloreactivity in 60 highly alloreactive patients receiving calcineurin inhibitor-based immunosuppression and in non-T-cell alloreactive transplant recipients treated with a calcineurin inhibitor-free regimen. The impact was evaluated using 1-year allograft outcome. We found a strong association between ongoing antidonor T-cell alloreactivity and histological lesions of acute T cell-mediated rejection in 6-month protocol biopsies, distinguishing those patients with better 1-year graft function, regardless of immunosuppression regimen. Interestingly, evidence for enhanced immune regulation, driven by circulating Foxp3-demethylated regulatory T cells, was only observed among patients achieving antidonor T-cell hyporesponsiveness. Thus, prospective evaluation of donor-specific T-cell sensitization may add crucial information on the alloimmune state of transplanted patients to be used in daily clinical practice.

Use of methoxy polyethylene glycol-epoetin beta in stage 3, 4 or 5 non-dialysis chronic kidney disease.

BACKGROUND: Methoxy polyethylene glycol-epoetin beta (PEG-EPO) is indicated for the treatment of anaemia due to chronic kidney disease. Its long half-life allows it to be administered once per month in maintenance therapy. OBJECTIVE: To evaluate the use, effectiveness and cost of PEG-EPO in a group of pre-dialysis chronic renal failure patients. METHOD: Retrospective observational study in pre-dialysis patients who began treatment with PEG-EPO between May 2008 and February 2009. The following data were gathered: age, sex, haemoglobin levels (Hb) and erythropoiesis-stimulating agent (ESA) dose and frequency. The follow-up period was 12 months. RESULTS: We included 198 patients. Mean Hb upon starting PEG-EPO in patients who had received no prior treatment was 10.8g/l, and 11.6g/l at 90 days (P<.0001). In patients previously treated with ESA, mean Hb before starting PEG-EPO treatment was 11.2g/l, and 11.4g/l at 12 months (P=.846). Hb values were higher than 12g/l (P<.0001) after 12 months of treatment in 25% of patients; of these, 45% had values above 13g/l. We observed doses 39% lower than those indicated on the drug leaflet, resulting in a reduction in the originally expected theoretical costs. CONCLUSIONS: The doses of PEG-EPO administered to patients with a prior history of ESA treatment were lower than those indicated by the drug leaflet, and Hb remained stable after 12 months of treatment. A large portion of the patients had levels above the 13g/l threshold.

Monocyte subpopulations and cardiovascular risk in chronic kidney disease.

Chronic microinflammation and its cellular hallmark, monocyte activation, contribute substantially to the tremendous burden of cardiovascular disease (CVD) in patients with chronic kidney diseases (CKD). Monocyte heterogeneity is widely acknowledged. Cell-surface expression of CD14 and CD16 defines three functionally and phenotypically distinct subsets of monocytes: classical (CD14(++)CD16(-)) monocytes, intermediate (CD14(++)CD16(+)) monocytes, and nonclassical (CD14(+)CD16(++)) monocytes. A growing body of circumstantial evidence suggests that intermediate monocytes, in particular, contribute to the development of atherosclerosis in the general population as well as in patients with CKD. Intermediate monocytes express a unique pattern of chemokine receptors that have been implicated in atherogenesis. Moreover, this subset of monocytes is predisposed to secrete proinflammatory cytokines. Findings from epidemiological studies indicate that numbers of intermediate monocytes increase with worsening renal function, and that high cell counts predict adverse outcomes in patients undergoing dialysis as well as in patients at early stages of CKD. Based on laboratory and clinical data, intermediate monocytes are a promising therapeutic target for CVD in patients with CKD.

C.E.R.A. once every 4 weeks in patients with chronic kidney disease not on dialysis: The ARCTOS extension study.

C.E.R.A., a continuous erythropoietin receptor activator is approved for the treatment of anemia in patients with chronic kidney disease (CKD). The ARCTOS (administration of C.E.R.A. in CKD patients to treat anemia with a twice-monthly schedule) phase 3 study demonstrated the efficacy and safety of C.E.R.A. in correcting anemia when administered once every 2 weeks (Q2W) subcutaneously in patients with CKD not on dialysis. We assessed the feasibility and long-term safety of converting patients who responded to treatment with C.E.R.A. Q2W to C.E.R.A. once every 4 weeks (Q4W) during a 24-week extension period. After the core ARCTOS study period (28 weeks), 296 patients entered the 24-week extension period. At week 29, patients who responded to C.E.R.A. Q2W during the core period were rerandomized to receive subcutaneous C.E.R.A. Q2W or Q4W. Patients in the comparator arm could receive darbepoetin alfa once weekly or Q2W. Dosage was adjusted to maintain hemoglobin (Hb) between 11 and 13 g/dL. Mean Hb levels remained stable in all groups, and were comparable at the end of the extension period (mean [standard deviation], C.E.R.A. Q2W, 11.92 [0.90] g/dL; C.E.R.A. Q4W, 11.70 [0.86] g/dL; darbepoetin alfa, 11.89 [0.98] g/dL). Mean within-patient standard deviation values for Hb were also comparable in all groups (0.66, 0.62, and 0.65 g/dL for C.E.R.A. Q2W, C.E.R.A. Q4W and darbepoetin alfa, respectively). All treatments were well tolerated. Subcutaneous C.E.R.A. Q4W is safe and effective in maintaining stable Hb levels in patients with CKD not on dialysis following correction with subcutaneous C.E.R.A. Q2W.

Maintenance of target hemoglobin level in stable hemodialysis patients constitutes a theoretical task: a historical prospective study.

Maintenance of target hemoglobin (Hb) values in hemodialysis patients treated with erythropoiesis-stimulating agents (ESAs) remains difficult. We examined Hb variability in the clinical setting in hemodialysis patients. Hemodialysis patients treated with ESAs who maintained the recommended Hb range of 11-13 g per 100 ml over 3 months and were not admitted to hospital, did not require transfusion, and did not experience any major clinical event during this period were followed prospectively for 1 year. Anemia events, Hb variation events (any value out of +/-1.5 g per 100 ml of the median Hb level in the total follow-up period for the individual patient), risk factors for anemia, and Hb variation events were assessed. We studied 420 patients (63% males, mean age 61 years), 222 received short-acting erythropoietin (EPO) and 198 long-acting darbepoetin. A total of 4654 blood samples (mean 11.1 per patient-year) were analyzed. Only 3.8% of patients were maintained within the target Hb levels (11-13 g per 100 ml) during 1 year. Hb variation events occurred in 20.8% of laboratory values and anemia events in 14.7%, with a median time to the first event of 3 months. Treatment with short-acting EPO (vs long-acting darbepoetin), change of ESA dose in the previous visit, resistance index, and hospitalization were significant risk factors for both anemia events and Hb variation events. Our results show that Hb values are rarely maintained within the recommended guidelines even in more stable hemodialysis patients. Hb variability is frequently associated with clinical events or ESA dose changes. Long-acting darbepoetin achieved better Hb stability than short-acting EPO.