2022 Taiwan lipid guidelines for primary prevention.

Elevated circulating low-density lipoprotein cholesterol (LDL-C) is a major risk factor of atherosclerotic cardiovascular disease (ASCVD). Early control of LDL-C to prevent ASCVD later in life is important. The Taiwan Society of Lipids and Atherosclerosis in association with the other seven societies developed this new lipid guideline focusing on subjects without clinically significant ASCVD. In this guideline for primary prevention, the recommended LDL-C target is based on risk stratification. A healthy lifestyle with recommendations for foods, dietary supplements and alcohol drinking are described. The pharmacological therapies for LDL-C reduction are recommended. The aim of this guideline is to decrease the risk of ASCVD through adequate control of dyslipidemia in Taiwan.

TREM-2 mediates dendritic cell-induced NO to suppress Th17 activation and ameliorate chronic kidney diseases.

Chronic kidney disease (CKD) is a global public health issue. CKD is caused by the infiltration of various myeloid cell types into renal tissue, resulting in renal fibrosis and tubular atrophy. Unilateral ureteral obstruction (UUO) surgery in mice is a model of CKD and characterized by high expression of the anti-inflammatory receptor, Triggering receptor expressed on myeloid cells 2 (TREM-2), on myeloid cells in affected kidneys. Here, we show that iNOS expression and nitric oxide (NO) induction were decreased in Trem-2-/- bone marrow-derived DCs (BMDCs) and in Trem-2 knockdown DC2.4 cells stimulated in vitro with LPS. The nitration of RORγt was decreased in T cells co-cultured with LPS-stimulated Trem-2-/- BMDCs, enhancing IL-17 production. UUO-treated Trem-2-/- mice displayed aggravated renal pathogenesis accompanied by greater neutrophil infiltration and enhanced Th17 cells differentiation, phenotypes that could be rescued by the administration of L-arginine (a biological precursor of NO). Our data identify a key mechanism underlying TREM-2-mediated NO to modulate the cellular crosstalk between dendritic cells, Th17, and neutrophils. Furthermore, we also reveal TREM-2 as a potential novel target for the development of anti-inflammatory drugs in CKD treatment. KEY MESSAGES: The expression of TREM-2 is increased in nephritis TREM-2+ DCs maintain NO production to negatively regulate Th17 differentiation The severe pathologies of nephritis can be rescued by L-arginine supplementation.

Long-term safety and efficacy of ferric citrate in phosphate-lowering and iron-repletion effects among patients with on hemodialysis: A multicenter, open-label, Phase IV trial.

BACKGROUND: We explored the long-term safety and efficacy of ferric citrate in hemodialysis patients in Taiwan, and further evaluated the iron repletion effect and change of iron parameters by different baseline groups. METHODS: This was a 12-month, Phase IV, multicenter, open-label study. The initial dose of ferric citrate was administered by patients' clinical condition and further adjusted to maintain serum phosphorus at 3.5-5.5 mg/dL. The primary endpoint was to assess the safety profiles of ferric citrate. The secondary endpoints were to evaluate the efficacy by the time-course changes and the number of subjects who achieved the target range of serum phosphorus. RESULTS: A total of 202 patients were enrolled. No apparent or unexpected safety concerns were observed. The most common treatment-emergent adverse events were gastrointestinal-related with discolored feces (41.6%). Serum phosphorus was well controlled, with a mean dose of 3.35±1.49 g/day, ranging from 1.5 to 6.0 g/day. Iron parameters were significantly improved. The change from baseline of ferritin and TSAT were 227.17 ng/mL and 7.53%, respectively (p-trend<0.001), and the increase started to slow down after 3-6 months of treatment. In addition, the increase trend was found only in patients with lower baseline level of ferritin (≤500 ng/mL) and TSAT (<30%). CONCLUSIONS: Ferric citrate is an effective phosphate binder with favorable safety profile in ESRD patients. The iron-repletion by ferric citrate is effective, and the increase is limited in patients with a higher baseline. In addition to controlling hyperphosphatemia, ferric citrate also shows additional benefits in the treatment of renal anemia. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03256838; 12/04/2017.

Association of anemia and iron parameters with mortality among prevalent peritoneal dialysis patients in Taiwan: the AIM-PD study.

In 1996, the National Health Insurance Administration of Taiwan applied a restrictive reimbursement criteria for erythropoiesis-stimulating agents (ESAs) use in patients with chronic kidney disease. The maximal ESAs dosage allowed by insurance is capped at 20,000 U of epoetin per month. Nephrologists avoided the use of high ESA dosages to achieve a hemoglobin level of 10-11 g/dL using iron supplementation. We assessed the association of anemia and iron parameters with mortality among peritoneal dialysis (AIM-PD) patients. A retrospective cohort study was conducted based on the Taiwan Renal Registry Data System. From January 1, 2000 to December 31, 2008, we enrolled 4356 well-nourished PD patients who were older than 20 years and had been receiving PD for more than 12 months. All patients were divided into subgroups according to different hemoglobin, ferritin and transferrin saturation (TSAT) values. Patients were followed until death or December 31, 2008. In a median 2.9-year study period, 694 (15.9%) patients died. By multivariate adjustment, a hemoglobin level lower than 10 g/dL was significantly associated with a higher risk for all-cause and cardiovascular deaths. Moreover, a serum ferritin level higher than 800 ng/mL was associated with a higher risk for all-cause deaths, and a TSAT value between 20 and 50% was associated with the lowest all-cause mortality. In conclusions, we recommend avoiding a low hemoglobin level and a serum ferritin level of more than 800 ng/mL and maintaining a TSAT value between 20 and 50%, as these conditions were associated with lower risks of all-cause mortality in the AIM-PD study.

Early elimination of uremic toxin ameliorates AKI-to-CKD transition.

Acute kidney injury (AKI)-related fibrosis is emerging as a major driver of chronic kidney disease (CKD) development. Aberrant kidney recovery after AKI is multifactorial and still poorly understood. The accumulation of indoxyl sulfate (IS), a protein-bound uremic toxin, has been identified as a detrimental factor of renal fibrosis. However, the mechanisms underlying IS-related aberrant kidney recovery after AKI is still unknown. The present study aims to elucidate the effects of IS on tubular damage and its involvement in the pathogenesis of AKI-to-CKD transition. Our results showed that serum IS started to accumulate associated with the downregulation of tubular organic anion transporter but not observed in the small-molecule uremic toxins of the unilateral ischemia-reperfusion injury (UIRI) without a contralateral nephrectomy model. Serum IS is positively correlated with renal fibrosis and binding immunoglobulin protein (BiP) and CAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) expression induction in the UIRI with a contralateral nephrectomy model (UIRI+Nx). To evaluate the effects of IS in the AKI-to-CKD transition, we administered indole, a precursor of IS, at the early stage of UIRI. Our results demonstrated IS potentiates renal fibrosis, senescence-associated secretory phenotype (SASP), and activation of endoplasmic reticulum (ER) stress, which is attenuated by synergistic AST-120 administration. Furthermore, we clearly demonstrated that IS exposure potentiated hypoxia-reperfusion (H/R) induced G2/M cell cycle arrest, epithelial-mesenchymal transition (EMT) and aggravated ER stress induction in vitro. Finally, the ER chemical chaperon, 4-phenylbutyric acid (4-PBA), successfully reversed the above-mentioned AKI-to-CKD transition. Taken together, early IS elimination in the early stage of AKI is likely to be a useful strategy in the prevention and/or treatment of the AKI-to-CKD transition.

Iron Therapy in Chronic Kidney Disease: Days of Future Past.

Anemia affects millions of patients with chronic kidney disease (CKD) and prompt iron supplementation can lead to reductions in the required dose of erythropoiesis-stimulating agents, thereby reducing medical costs. Oral and intravenous (IV) traditional iron preparations are considered far from ideal, primarily due to gastrointestinal intolerability and the potential risk of infusion reactions, respectively. Fortunately, the emergence of novel iron replacement therapies has engendered a paradigm shift in the treatment of iron deficiency anemia in patients with CKD. For example, oral ferric citrate is an efficacious and safe phosphate binder that increases iron stores to maintain hemoglobin levels. Additional benefits include reductions in fibroblast growth factor 23 levels and the activation of 1,25 dihydroxyvitamin D. The new-generation IV iron preparations ferumoxytol, iron isomaltoside 1000, and ferric carboxymaltose are characterized by a reduced risk of infusion reactions and are clinically well tolerated as a rapid high-dose infusion. In patients undergoing hemodialysis (HD), ferric pyrophosphate citrate (FPC) administered through dialysate enables the replacement of ongoing uremic and HD-related iron loss. FPC transports iron directly to transferrin, bypassing the reticuloendothelial system and avoiding iron sequestration. Moreover, this paper summarizes recent advancements of hypoxia-inducible factor prolyl hydroxylase inhibitors and future perspectives in renal anemia management.

Association of Anemia and Iron Parameters With Mortality Among Patients Undergoing Prevalent Hemodialysis in Taiwan: The AIM - HD Study.

Background The Taiwan Health Insurance Bureau has conducted a bundled payment system for hemodialysis reimbursement since 1995. The maximum dose of erythropoiesis-stimulating agents allowed by insurance is capped at 20 000 U of epoetin or 100 µg of darbepoetin alfa per month. Nephrologists have avoided the use of high dosages of erythropoiesis-stimulating agents to achieve a hemoglobin level of 10 to 11 g/dL by iron supplementation. The clinical impact of these policies on patients' outcomes is unknown. The authors aimed to assess the AIM-HD (Association of Anemia, Iron parameters, and Mortality among the prevalent Hemodialysis patients) Study in Taiwan. Methods and Results The AIM-HD study was conducted based on the Taiwan Renal Registry Data System. From 2001 to 2008, the authors enrolled 42 230 patients undergoing hemodialysis who were older than 20 years and had received hemodialysis for more than 12 months. Patient follow-ups occurred until death or December 31, 2008. During a study period of 8 years, 12 653 (30.0%) patients died. After multivariate adjustment, the authors found that a hemoglobin level <10 g/dL was significantly associated with higher risk for all-cause and cardiovascular deaths. Moreover, a serum ferritin level between 300 and 800 ng/mL and transferrin saturation value between 30% and 50% were associated with the lowest all-cause mortality. Conclusions The authors recommend avoiding a low hemoglobin level and maintaining serum ferritin between 300 and 800 ng/mL and transferrin saturation between 30% and 50%, which were associated with lower risks of all-cause mortality among patients undergoing hemodialysis receiving the restricted erythropoiesis-stimulating agent doses but prompt intravenous iron supplementation in Taiwan.

Diet, gut microbiome and indoxyl sulphate in chronic kidney disease patients.

Emerging evidence suggests that intestinal dysbiosis plays an important role in host inflammation locally and systemically. Such pathological condition is even more prevailing in patients with chronic kidney disease (CKD). Of note, indoxyl sulphate (IS), a gut-derived uremic toxin, is notorious for its pro-inflammatory feature in CKD patients. IS accumulates in the body as the urinary excretion of uremic toxins is impaired, and further worsens the kidney function in a vicious cycle to CKD. Dietary restriction in vegetables, fruits and yogurt leads to the predominance of indole-producing intestinal microbial flora and further exaggerates the accumulation of IS in CKD patients. Recently, interventional studies have shown that circulating IS can be reduced by dietary prebiotic and/or probiotic supplements. However, further randomized controlled trials are warranted to examine whether such beneficial effect of dietary prebiotic/probiotic supplements could be extrapolated to better hard outcomes in CKD population. In this review, we would also like to emphasize the importance of achieving sufficient intake of dietary fibre by proper vegetable pre-treatment and accurate fruit selection, instead of directly avoiding these potassium-rich yet fibre-rich and base-producing foods.

Safety and efficacy of ferric citrate in phosphate reduction and iron supplementation in patients with chronic kidney disease.

Ferric citrate has been reported to have the potential to reduce phosphate and increase iron availability in patients with chronic kidney disease. In the present study, we evaluated its safety and efficacy in phosphate reduction and iron supplementation in chronic kidney disease stage 3-5 requiring dialysis patients. We systematically searched for clinical trials published in PubMed, Medline, and Cochrane databases. Only randomized controlled trials on the effects of ferric citrate in chronic kidney disease stage 3-5 requiring dialysis patients were selected. The primary outcomes were changes in serum phosphate, calcium, and anemia-related parameters. The secondary outcomes were the adverse effects of ferric citrate. Nine studies providing data on 1755 patients were included in the meta-analysis. Ferric citrate significantly reduced serum phosphate compared with placebo (mean difference, -1.39; 95% confidence interval, -2.12 to -0.66) and had a non-inferior effect compared with active treatment. Furthermore, ferric citrate significantly improved hemoglobin, transferrin saturation and ferritin. Adverse effects of constipation did not differ significantly between ferric citrate and placebo or active treatment. This review provides evidence that ferric citrate effectively alleviates hyperphosphatemia and iron deficiency in patients with chronic kidney disease stage 3-5 requiring dialysis patients. However, the included studies did not have cardiovascular complications or mortality information and could not assess whether ferric citrate affected the risk of all-cause death or cardiovascular complications in patients with chronic kidney disease. Further studies are required to assess whether the long-term use of ferric citrate can reduce the risk of cardiovascular events and all-cause mortality.

Renal Outcomes of Pioglitazone Compared with Acarbose in Diabetic Patients: A Randomized Controlled Study.

OBJECTIVE: To assess the effect of pioglitazone on renal outcome, including urinary albumin excretion and estimated glomerular filtration rate (eGFR), in diabetic patients. DESIGN: A prospective, randomized, open-labeled, controlled study. SETTING: Taipei Veterans General Hospital. PATIENTS: Sixty type 2 diabetic patients treated with sulfonylureas and metformin, whose glycated hemoglobin (HbA1c) levels were between 7% and 10% and eGFR was between 45 and 125 mL/min/1.73 m2. INTERVENTION: The patients were randomized to receive acarbose or pioglitazone and followed up for 6 months. Thirty patients were randomly assigned to receive acarbose, and 30 patients were assigned to receive pioglitazone. MEASUREMENTS: The primary study endpoint was the changes in the urinary albumin-to-creatinine ratio (UACR). The secondary endpoint was the changes in eGFR and other parameters. RESULTS: After 6 months of treatment, the mean changes in UACR were -18 ± 104 and 12 ± 85 (p = 0.25, between groups) for the acarbose and pioglitazone groups, respectively. The mean changes in eGFR were 0 ± 14 and -7 ± 16 mL/min/1.73 m2 (p = 0.09, between groups) for the acarbose and pioglitazone groups, respectively. The reductions in HbA1c were similar in both groups. Fasting blood glucose was lower in the pioglitazone group than in the acarbose group. Significant body weight gain was observed in the pioglitazone group as compared with the acarbose group (1.3 ± 2.8 vs. -0.6 ± 1.5 kg, p = 0.002). CONCLUSION: In type 2 diabetic patients who were treated with sulfonylureas and metformin and possessed HbA1c levels between 7% and 10%, additional acarbose or pioglitazone for 6 months provided similar glycemic control and eGFR and UACR changes. In the pioglitazone group, the patients exhibited significant body weight gain. TRIAL REGISTRATION: ClinicalTrials.gov NCT01175486.

Iron supplementation associates with low mortality in pre-dialyzed advanced chronic kidney disease patients receiving erythropoiesis-stimulating agents: a nationwide database analysis.

BACKGROUND: A risk/benefit analysis of iron supplementation in pre-dialysis advanced chronic kidney disease (CKD) patients has not been conducted. We aim to assess the effectiveness and the safety of iron supplementation in patients with CKD Stage 5 who have not yet received dialysis (CKD 5 ND). METHODS: A prospective cohort study was conducted based on the Taiwan National Health Insurance Research Database. From 1 January 2000 to 30 June 2009, we enrolled 31 971 adult patients who had a serum creatinine >6 mg/dL and a haematocrit <28% and who were treated with erythropoiesis-stimulating agents (ESAs). All patients were further divided into two groups with or without iron supplementation within 90 days after starting ESA therapy. Patient follow-up took place until dialysis, death before initiation of dialysis or 31 December 2009. The primary outcomes were death before initiating dialysis, hospitalization before death or long-term dialysis. RESULTS: After propensity score matching, the patients who received iron supplementation were associated with a lower risk of all-cause death [hazard ratio (HR), 0.85; 95% confidence interval (CI), 0.80-0.90] compared with non-users. The survival benefit of iron use was consistent across the majority of dosage groups, except for those who were treated with monthly IV iron >200 mg. Moreover, compared with the non-users, the iron users were associated with a lower risk of hospitalizations (HR, 0.97; 95% CI, 0.94-0.99) but with a higher risk of faster progression to end-stage renal disease (HR, 1.05; 95% CI, 1.01-1.08). CONCLUSIONS: Iron supplementation is associated with 15% risk reduction in death among CKD 5 ND patients who received ESA treatment. Randomized studies are needed to validate this association.

Attenuation of Tubular Injury and Renal Fibrosis by TI-HU-YIN via Reduction in Transforming Growth Factor-ß1 Expression in Unilateral Ureteral Obstruction Mice.

TI-HU-YIN (JCKD), a compound composed of many Chinese herbs, is hypothesized to attenuate renal tubular injury and interstitial fibrosis. Moreover, its renoprotective effects were assessed in animal and in vitro studies. First, male C57BL/6 mice were under sham operation or unilateral ureteral obstruction (UUO) surgery, and then treated with phosphate buffer solution (PBS), aliskirin and valsartan (A+V), and JCKD for 14 days. At 7 and 14 days, mice were sacrificed and the kidney tissues were assessed for histopathological changes and transforming growth factor (TGF)-ß1 expression. As compared to sham group, UUO-PBS group had more serious tubular dilatation and injury, α-smooth muscle actin-positive areas, F4/80-positive macrophages, and interstitial fibrosis. Impressively, these pathologic changes were significantly attenuated in UUO mice both treated with JCKD and A+V as compared to UUO-PBS group. At 14 days, TGF-ß1 expression was significantly suppressed in kidney tissues of UUO-JCKD group as well as in UUO-A+V group. Second, TGF-ß1 production was increased in macrophage J774 cells and NRK-52E proximal tubular cells stimulated by angiotensin (Ang)-II at 10 nM for 24 h and at 1 nM for 48 h, respectively. JCKD (≥ 400 µg/ml) inhibited the TGF-ß1 production at baseline and stimulated by Ang II in both cell lines. Our study showed that JCKD reduced renal injury, macrophage infiltration and interstitial fibrosis possibly through suppressing the TGF-ß1 expression in UUO mice. Accordingly, JCKD is potential to retard the progression of chronic kidney disease. Further studies are needed to validate its renoprotective effects in the inhibition of TGF-ß1 expression and the amelioration of renal fibrosis.

The impact of dialysis therapy on older patients with advanced chronic kidney disease: a nationwide population-based study.

BACKGROUND: Older patients with advanced chronic kidney disease (CKD) face the decision of whether to undergo dialysis. Currently available data on this issue are limited because they were generated by small, short-term studies with statistical drawbacks. Further research is urgently needed to provide objective information for dialysis decision making in older patients with advanced CKD. METHODS: This nationwide population-based cohort study was conducted using Taiwan's National Health Insurance Research Database. Data from 2000 to 2010 were extracted. A total of 8,341 patients≥70 years old with advanced CKD and serum creatinine levels>6 mg/dl, who had been treated with erythropoiesis-stimulating agents were included. Cox proportional hazard models in which initiation of chronic dialysis was defined as the time-dependent covariate were used to calculate adjusted hazard ratios for mortality. The endpoint was all-cause mortality. RESULTS: During a median follow-up period of 2.7 years, 6,292 (75.4%) older patients chose dialysis therapy and 2,049 (24.6%) received conservative care. Dialysis was initiated to treat kidney failure a median of 6.4 months after enrollment. Dialysis was associated with a 1.4-fold increased risk of mortality compared with conservative care (adjusted hazard ratio 1.39, 95% confidence interval 1.30 to 1.49). In subgroup analyses, the risk of mortality remained consistently increased, independent of age, sex and comorbidities. CONCLUSIONS: In older patients, dialysis may be associated with increased mortality risk and healthcare cost compared with conservative care. For patients who are ≥70 years old with advanced CKD, decision making about whether to undergo dialysis should be weighted by consideration of risks and benefits.

Anaemia management in patients with chronic kidney disease: Taiwan practice guidelines.

The introduction of erythropoiesis-stimulating agents (ESAs) markedly improved the lives of many anaemic patients with chronic kidney disease (CKD). In Taiwan, the strategy of management of anaemia in patients with CKD was different from many other parts of the world. In 1996, the National Health Insurance Administration of Taiwan applied a more restrictive reimbursement criteria for ESA use in patients with CKD. ESA is to be initiated when non-dialysis CKD patients have a serum creatinine >6 mg/dL and a hematocrit <28% to maintain a hematocrit level not exceeding 30%. The maximal dose of epoetin-α or ß was 20 000 U per month. The target haemoglobin range and dose limitation for ESAs were the same for dialysis CKD patients. Thus, long before randomized controlled trials showing an increased risk for cardiovascular events at nearly normal haemoglobin concentrations and higher ESA doses in CKD, nephrologists in Taiwan had avoided the use of disproportionately high dosages of ESAs to achieve a haemoglobin level of 10-11 g/dL. Moreover, intravenous iron supplementation was encouraged earlier in Taiwan in 1996, when we reached consensus on the diagnostic criteria for iron deficiency (serum ferritin <300 ng/mL and/or transferrin saturation <30%). The experience of CKD anaemia management in Taiwan demonstrated that a reasonable haemoglobin target can be achieved by using the lowest possible ESA dose and intravenous iron supplementation.

Iron sucrose accelerates early atherogenesis by increasing superoxide production and upregulating adhesion molecules in CKD.

High-dose intravenous iron supplementation is associated with adverse cardiovascular outcomes in patients with CKD, but the underlying mechanism is unknown. Our study investigated the causative role of iron sucrose in leukocyte-endothelium interactions, an index of early atherogenesis, and subsequent atherosclerosis in the mouse remnant kidney model. We found that expression levels of intracellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and adhesion of U937 cells increased in iron-treated human aortic endothelial cells through upregulated NADPH oxidase (NOx) and NF-κB signaling. We then measured mononuclear-endothelial adhesion and atherosclerotic lesions of the proximal aorta in male C57BL/6 mice with subtotal nephrectomy, male apolipoprotein E-deficient (ApoE(-/-)) mice with uninephrectomy, and sham-operated mice subjected to saline or parenteral iron loading. Iron sucrose significantly increased tissue superoxide production, expression of tissue cell adhesion molecules, and endothelial adhesiveness in mice with subtotal nephrectomy. Moreover, iron sucrose exacerbated atherosclerosis in the aorta of ApoE(-/-) mice with uninephrectomy. In patients with CKD, intravenous iron sucrose increased circulating mononuclear superoxide production, expression of soluble adhesion molecules, and mononuclear-endothelial adhesion compared with healthy subjects or untreated patients. In summary, iron sucrose aggravated endothelial dysfunction through NOx/NF-κB/CAM signaling, increased mononuclear-endothelial adhesion, and exacerbated atherosclerosis in mice with remnant kidneys. These results suggest a novel causative role for therapeutic iron in cardiovascular complications in patients with CKD.

Intravenous ferric chloride hexahydrate supplementation induced endothelial dysfunction and increased cardiovascular risk among hemodialysis patients.

BACKGROUND: The association between intravenous (IV) iron administration and outcomes in hemodialysis (HD) patients is still debated. Therefore, this study was aimed to assess the relationship between the IV administration of ferric chloride hexahydrate (Atofen®) and cardiovascular (CV) outcome and the interaction between iron-induced oxidative stress and endothelial dysfunction in chronic HD patients. METHODOLOGY/PRINCIPAL FINDINGS: A cohort of 1239 chronic HD patients was recruited. In a follow-up of 12 months, Kaplan-Meier survival curves showed that higher doses of IV Atofen associated with higher risks for CV events and deaths in HD patients. In multivariate Cox models, compared to no iron supplementation, IV Atofen administration was an independent predictor for CV events and overall mortality. However, the nature of the observational cohort study possibly bears selection bias. We further found that IV Atofen enhanced the superoxide production of mononuclear cells (MNCs), the levels of circulating soluble adhesion molecules, and the adhesion of MNCs to human aortic endothelial cells (HAECs). In vitro experiments showed that Atofen increased the expression of intracellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 in HAECs and aggravated the endothelial adhesiveness in a dose-dependent manner. These iron-induced changes were significantly attenuated by the co-treatment of HAECs with N-acetylcysteine and inhibitors of NADPH oxidase, nuclear factor κB, and activator protein-1. CONCLUSION: A cumulative dose of IV Atofen >800 mg within 6 months was associated with an adverse CV outcome and a higher mortality among chronic HD patients. The detrimental effects of IV iron supplementation were partly due to the increased oxidative stress and induction of MNC adhesion to endothelial cells, a pivotal index of early atherogenesis.

Adiposity and insulin resistance in nondiabetic hemodialysis patients: effects of high energy supplementation.

BACKGROUND: In contrast to the general population, a higher body mass index is associated with better survival among hemodialysis patients. Theoretically, high energy supplementation in these patients ought to lead to weight gain over time, but the benefits of this strategy are unclear. OBJECTIVE: The objective was to assess whether high energy supplementation in nondiabetic hemodialysis patients might adversely affect insulin resistance -- a known risk factor for cardiovascular disease. DESIGN: We first investigated the association between body fat mass and insulin resistance (homeostasis model assessment of insulin resistance; HOMA-IR) in nondiabetic hemodialysis patients in a cross-sectional analysis (study 1). Of the 106 individuals studied, 55 were randomly assigned to either high energy supplementation (an extra 475 kcal/d; n = 28) or not (n = 27) for 12 wk to assess prospective changes in body fat mass and insulin resistance (study 2). RESULTS: In study 1, body fat mass (P < 0.05) and C-reactive protein (CRP) (P < 0.05) each contributed independently to HOMA-IR. In study 2, 41 patients completed the study. The 20 patients who received high energy supplementation had a significantly greater increase in body fat mass (P < 0.05), CRP (P < 0.05), and HOMA-IR (P < 0.001) than did the 21 controls. CONCLUSIONS: Body fat mass and CRP are primary determinants of insulin resistance in nondiabetic hemodialysis patients. High energy supplementation, because it increases adiposity and inflammation, exacerbates insulin resistance. A long-term study is needed to clarify the metabolic effects of high energy supplementation on cardiovascular disease outcomes in hemodialysis patients.

Novel aspects of vitamin C in epoetin response.

Provision of sufficient available iron is a prerequisite to ensure the bodys optimal response to recombinant human erythropoietin (epoetin). Functional iron deficiency (a state when iron supply is reduced to meet the demands for increased erythropoiesis) is a common cause of poor response to epoetin in dialysis patients who have normal iron status, even when they are iron-overloaded. Iron supplementation is not justified for this hyporesponsiveness in patients with iron overload due to the potential hazards of iron overload aggravated by intravenous iron therapy. Furthermore, in vivo studies have indicated that the promising effect of intravenous iron medication to overcome iron-deficient erythropoiesis is not observed in iron-overloaded hemodialysis (HD) patients. Vitamin C, a water-soluble antioxidant as well as a reducing agent, has a number of associations with iron metabolism. Recent research highlights that vitamin C can potentiate the mobilization of iron from inert tissue stores and facilitates the incorporation of iron into protoporphyrin in HD patients being treated with epoetin. Interest has turned towards the use of vitamin C as an adjuvant therapy in this field. This review focuses on the improvement of epoetin response by administration of vitamin C and discusses its clinical implications and potential issues for internal medicine doctors.

Association between transferrin receptor-ferritin index and conventional measures of iron responsiveness in hemodialysis patients.

BACKGROUND: The diagnostic power of the transferrin receptor-ferritin (TfR-F) index for identification of iron responsiveness in long-term hemodialysis (HD) patients compared with the routine markers recommended by the current US and European guidelines was appraised. METHODS: Initially, 121 long-term HD patients with a serum ferritin level less than 800 microg/L and on recombinant erythropoietin (rHuEPO) therapy for longer than 6 months were enrolled for intravenous iron (IVFE) supplementation (100 mg of iron polymaltose 3 times/wk for 4 weeks, then 100 mg every 2 weeks for 5 months). Routine iron tests (ie, serum ferritin and transferrin saturation [TSAT]), TfR-F index calculated by the ratio of soluble TfR to log ferritin level, hematocrit, hemoglobin, red blood cell count, and serum high-sensitive C-reactive protein were examined at baseline. Hematocrit and hemoglobin were followed up every 2 weeks during the study period. RESULTS: One hundred patients (52 men, 48 women; mean age, 59 years) completed this study. Fifty-two patients were IVFE responders, defined as an increase in hematocrit greater than 3% and/or a decrease in rHuEPO dose greater than 30% of baseline values at the end of the study, and 48 nonresponders did not fulfill these criteria. Of 52 responders, only 14 patients (27%) could be recognized for iron deficiency by means of routine iron tests (ferritin < 100 microg/L and/or TSAT < 20%). Thirty-three responders (63%) could be further identified for iron deficiency by using TfR-F index (> 0.6), but 5 (10%) still could not by either method. Analyses by using receiver operating characteristic (ROC) curves showed that a cutoff value greater than 0.6 for TfR-F index had greater sensitivity (90%) for the detection of iron deficiency than ferritin level less than 100 microg/L (29%) and TSAT less than 20% (6%). TfR-F index showed a greater area under the ROC curve than ferritin level (P < 0.05) and TSAT (P < 0.001). CONCLUSION: TfR-F index is superior to routine tests for predicting response to IVFE supplementation in long-term HD patients. Our study indicates that TfR-F index is a new and surrogate marker to estimate body iron stores and guide IVFE therapy for long-term HD patients.

High-calorie supplementation increases serum leptin levels and improves response to rHuEPO in long-term hemodialysis patients.

BACKGROUND: Dialysis patients with a high body mass index are less likely to experience severe anemia. Leptin, a hormone secreted by adipocytes, may have a role in protecting against renal anemia. The aim of the present study is to determine the effect of an increase in serum leptin levels by increasing energy intake on recombinant human erythropoietin (rHuEPO) response in long-term hemodialysis (HD) patients. METHODS: We enrolled 65 long-term HD patients to explore the association between leptin level and rHuEPO response by classifying them as either high- or low-leptin individuals (phase 1). Thereafter, 39 patients with malnutrition by means of Subjective Global Assessment were randomly assigned to high-energy and high-protein (an extra 475 kcal and 16.6 g of protein daily; group A; n = 12) or standard-energy, but high-protein (an extra 67.2 kcal and 16.8 g of protein daily; group B; n = 27), supplementation for 12 weeks. Serial serum leptin levels, nutritional measures, and hematologic parameters were obtained. Age- and sex-matched well-nourished patients (group C; n = 16) not administered extra nutritional supplementation served as control subjects (phase 2). RESULTS: In phase 1, a significantly lower erythropoietin dose, greater hematocrit, and better nutritional measures were observed in the high-leptin group (P < 0.001). In phase 2, there was a significant increase in body fat mass (P = 0.001) and median serum leptin levels (P < 0.001) in response to 12 weeks of high-energy supplementation in group A, accompanied by markedly improved erythropoiesis (P < 0.05) compared with groups B and C. CONCLUSION: Hyperleptinemia reflects better nutritional status and rHuEPO response in long-term HD patients. Increasing energy intake improves erythropoiesis, which may be mediated in part by an increase in serum leptin levels.