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An umbrella concept addressing the relationship between chronic kidney disease (CKD) and mineral and bone disorders has been developed in recent years. Given the high prevalence of osteoporosis-related fractures in postmenopausal women with CKD, especially those undergoing chronic hemodialysis, the strategy used in the prevention and management of CKD and its associated osteoporosis in these postmenopausal women has become a topic of substantial debate. This controversy has ongoing relevance because osteoporosis results in a significant economic burden secondary to increased morbidity and mortality. The perfect goal of treatment and prevention includes both bone protection and renal protection, or at least protection of one disease without compromising the other disease. Both CKD and osteoporosis are frequently observed in the same patients, and often have parallel progression in postmenopausal women. Estrogen, the main female hormone during reproductive age, has been reported to have a protective effect on kidney fibrosis in several animal models, and is also considered one of the most effective drugs in the management of postmenopausal women with osteoporosis and prevention of osteoporosis. However, due to the many adverse events associated with the use of estrogen with and without progestin, some of which have contributed to significant morbidity and mortality, drug modification, which has had fewer reported incidences of adverse events without compromising the protective effect on both the kidney and bone, may have an easier road to acceptance. Therapeutic alternatives, such as the selective estrogen receptor modulators (SERMs), have shown the benefits of estrogen on bone, serum lipid levels, and renal protection, without any adverse effects on the breast and endometrium. The Multiple Outcomes of Raloxifene Evaluation trial (MORE) and its extension—Continuing Outcomes Relevant to Evista (CORE), a double-blind, randomized clinical trial encompassing postmenopausal women with osteoporosis, showed promising results in both bone and renal studies. Raloxifene increased bone mineral density (BMD) in the spine and femoral neck and reduced the risk of vertebral fracture. In addition, raloxifene slowed the increase in the rate of serum creatinine and also significantly slowed the decrease in the estimated glomerular filtration rate; of most importance, raloxifene use was associated with significantly fewer kidney-related adverse events. Hemodialyzed women on raloxifene treatment demonstrated increased trabecular BMD, a decrease in bone resorption markers, and a decrease in the low-density lipoprotein-cholesterol value. Thus, raloxifene and, most likely, other SERMs could be better in place of estrogen in the management of postmenopausal women with CKD and its associated osteoporosis, although much evidence should be provided in the advanced-stage CKD, especially in the Stage 5 CKD patients on dialysis.

Background: Secondary hyperparathyroidism is associated with vascular calcification and arterial stiffness in patients with end-stage renal disease. The aim of this study was to analyze the frequency of intradialytic hypotension (IDH) and cardiovascular function before and after parathyroidectomy (PTX) in maintenance hemodialysis patients. Methods: We compared predialytic and intradialytic blood pressure, left and right ventricular ejection fraction (LVEF and RVEF), and cardiothoracic ratio 1 month before PTX, and 6 and 12 months after PTX. IDH was defined as a decrease in systolic blood pressure ≥ 20 mmHg or a decrease in mean arterial pressure ≥ 10 mmHg. Results: At the time of PTX, the mean age of the patients was 57.4 ± 12.0 years, and the mean dialysis vintage was 12.2 ± 5.8 years. At baseline, 6 months, and 12 months after PTX, the average numbers of sessions disturbed by IDH during 13 dialysis sessions (1 month) were 6.4, 3.9 (p < 0.016 vs. baseline), and 4.0 sessions (p < 0.037 vs. baseline, p = 0.801 vs. 6 months), respectively. LVEF and RVEF were improved significantly after PTX. Furthermore, volume status was also improved, as evidenced by the significantly greater ultrafiltration volume and reduced cardiothoracic ratio. Conclusions: Hemodialysis patients with severe secondary hyperparathyroidism are more likely to achieve normotensive and euvolemic status after PTX, probably through improved heart function and reduced IDH episodes.

Background Peritoneal dialysis (PD)-related peritonitis is a serious complication that typically leads to hospitalization, catheter loss, and even mortality. Previous studies of the risk factors for peritonitis are discordant. To date, no biomarker associated with PD-related peritonitis has been investigated. However, it has been shown that serum decoy receptor 3 (DcR3) is a valuable marker in predicting the outcome of several inflammatory diseases. The aim of this study was to investigate whether serum DcR3 is a predictor of peritonitis in chronic PD patients. Methods We conducted a prospective cohort study of PD patients in the PD unit of a tertiary referral center from March 1 to November 30, 2007, and followed up until December 31, 2009. Clinical and laboratory parameters were recorded and serum DcR3 was measured to assess risk factors for developing PD-related peritonitis. Results A total of 77 patients (38 men and 39 women; mean age 58 ± 13 years) were enrolled in this study. The average time on PD was 24.5 months and 46 patients (60%) were diabetic. The mean follow-up duration was 499 ± 17 days. The rate of peritonitis incidence was 0.17 episodes per patient-year. Baseline serum DcR3 in 77 patients was 1.94 ± 1.23 ng/mL. Kaplan–Meier survival analysis showed that patients with serum DcR3 > 1.8 ng/mL had a higher risk of peritonitis than those with serum DcR3 p = 0.016). The Cox proportional hazard model further showed that high serum DcR3 (>1.8 ng/mL) was an independent risk factor for subsequent peritonitis (hazard ratio 3.61, 95% CI 1.17–11.08; p = 0.03). Conclusion Serum DcR3 was associated with increased risk of PD-related peritonitis.

Background Spironolactone has been shown to reduce cardiovascular death in patients with mild-to-moderate chronic kidney disease (CKD), but its risks and benefits in advanced CKD remain unsettled. We aimed to assess whether spironolactone reduces cardiovascular mortality and morbidity in pre-dialysis stage 5 CKD patients. Methods Using Taiwan's National Health Insurance Research Database from January 2000 to June 2009, we enrolled 27,213 pre-dialysis stage 5 CKD adult patients, in whom 1363 patients were treated with spironolactone (user) and 25,850 were not (nonuser). Outcomes were all-cause mortality, hospitalization for heart failure (HHF) and major adverse cardiac event (MACE, the composite of acute myocardial infarction and ischemic stroke). Patients were followed up till December 31, 2009. Results Over 85,758 person-years of follow-up, spironolactone users had higher incidence for all-cause mortality (24.7/100 person-years vs. 10.6/100 person-years), infection-related death (4.4/100 person-years vs. 1.7/100 person-years) and HHF (4.0/100 person-years vs. 1.4/100 person-years). Multivariable Cox hazards model showed that spironolactone users were associated with higher risks of all-cause mortality (adjusted hazard ratio [aHR] 1.35, 95% confidence interval [CI] 1.24–1.46), infection-related death (aHR 1.42, CI 1.16–1.73) and HHF (aHR 1.35, CI 1.08–1.67) as compared to nonusers. The risks for cardiovascular mortality, MACE and hyperkalemia-associated hospitalization were similar between two groups. After matching users and nonusers (1:3 ratio) by propensity scores, the results were consistent in matched cohort and across subgroups. Conclusions Spironolactone may be associated with higher risks for all-cause and infection-related mortality and HHF in pre-dialysis stage 5 CKD patients. Spironolactone should be used with caution in advanced CKD patients.

Cognitive dysfunction is closely related to aging and chronic kidney disease (CKD). However, the association between renal function changes and the risk of developing cognitive impairment has not been elucidated. This longitudinal cohort study was to determine the influence of annual percentage change in estimated glomerular filtration rate (eGFR) on subsequent cognitive deterioration or death of the elderly within the community. A total of 33,654 elders with eGFR measurements were extracted from the Taipei City Elderly Health Examination Database. The Short Portable Mental Status Questionnaire was used to assess their cognitive progression at least twice during follow-up visits. Multivariable Cox regression models were used to estimate the hazard ratio (HR) for cognitive deterioration or all-cause mortality with the percentage change in eGFR. During a median follow-up of 5.4 years, the participants with severe decline in eGFR (>20% per year) had an increased risk of cognitive deterioration (HR, 1.33; 95% confidence interval [CI], 1.08–1.72) and the composite outcome (HR, 1.17; 95% CI, 1.03–1.35) when compared with those who had stable eGFR. Severe eGFR decline could be a possible predictor for cognitive deterioration or death among the elderly. Early detection of severe eGFR decline is a critical issue and needs clinical attentions.

Background Traumatic brain injury (TBI) is an important cause of death and disability worldwide. The relationship between TBI and kidney diseases is largely unknown. Methods We aimed to determine whether TBI is associated with long-term adverse renal outcomes. We performed a nationwide, population-based, propensity score-matched cohort study of 32,152 TBI patients and 128,608 propensity score-matched controls. Data were collected by the National Health Insurance Research Database of Taiwan from 2000 to 2012. Our clinical outcomes were chronic kidney disease (CKD), end-stage renal disease (ESRD) and the composite endpoint of ESRD or all-cause mortality. Results The incidence rate of CKD was higher in the TBI than in the control cohort (8.99 vs. 7.4 per 1000 person-years). The TBI patients also showed higher risks of CKD (adjusted hazard ratio [aHR] 1.14, 95% confidence interval [CI] 1.08–1.20; P < 0.001) and composite endpoints (aHR 1.08, 95% CI 1.01–1.15; P = 0.022) than the control groups, but the ESRD was not significantly different between the groups. In subgroup analyses, the risks of incident CKD and composite endpoints were significantly raised in TBI patients aged < 65 years and/or without comorbidities. However, the risks of both CKD and composite outcome were little affected by the severity of TBI. Conclusions TBI has a modest but significant effect on incident CKD and composite endpoint, but not on ESRD alone. TBI patients under 65 are at greater risk of CKD and composite outcome than their older counterparts.

The role of aldosterone has expanded from its genomic effects that involve renal sodium transport to nongenomic effects such as cardiac and renal fibrosis. Elevated aldosterone levels are associated with increased mortality in the general population. However, the association is reversed in patients with end-stage renal disease on maintenance hemodialysis. We have shown that the inverse association between aldosterone and mortality in hemodialysis patients is due to the confounding effect of volume overload. Volume overload, which is prevalent in patients with chronic kidney disease, is associated with both lower aldosterone concentrations and higher mortality. Our findings support salt and water restriction and treatment of hyperaldosteronemia in hemodialysis patients who have achieved strict volume control.

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)-β1 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-β1 expression was significantly suppressed in kidney tissues of UUO-JCKD group as well as in UUO-A+V group. Second, TGF-β1 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-β1 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-β1 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-β1 expression and the amelioration of renal fibrosis.

Before the introduction of erythropoiesis-stimulating agents (ESAs) in 1989, repeated transfusions given to patients with end-stage renal disease caused iron overload, and the need for supplemental iron was rare. However, with the widespread introduction of ESAs, it was recognized that supplemental iron was necessary to optimize hemoglobin response and allow reduction of the ESA dose for economic reasons and recent concerns about ESA safety. Iron supplementation was also found to be more efficacious via intravenous compared to oral administration, and the use of intravenous iron has escalated in recent years. The safety of various iron compounds has been of theoretical concern due to their potential to induce iron overload, oxidative stress, hypersensitivity reactions, and a permissive environment for infectious processes. Therefore, an expert group was convened to assess the benefits and risks of parenteral iron, and to provide strategies for its optimal use while mitigating the risk for acute reactions and other adverse effects. Fil: Macdougall, Iain C.. King's College Hospital Nhs Foundation Trust; Reino Unido Fil: Bircher, Andreas J.. Universitatsspital Basel; Suiza Fil: Eckardt, Kai Uwe. Universitat Erlangen-nuremberg; Alemania Fil: Obrador, Gregorio T.. Universidad Panamericana; México Fil: Pollock, Carol A.. The University Of Sydney; Australia. Royal North Shore Hospital; Australia Fil: Stenvinkel, Peter. Karolinska University Hospital; Suecia Fil: Swinkels, Dorine W.. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Wanner, Christoph. Universitatsklinikum Wurzburg; Alemania Fil: Weiss, Günter. Medizinische Universitat Innsbruck; Austria Fil: Chertow, Glenn M.. University Of Stanford; Estados Unidos Fil: Toblli, Jorge Eduardo. Hospital Alemán. Laboratorio de Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Genetic variations may affect posttransplantation metabolic syndrome and diabetes mellitus (PTDM), which is associated with greater morbidity and progressive impairment of both patient and graft survivals. The aim of this study was to evaluate several candidate gene polymorphisms for their association with the risk of developing PTDM.In April 1999, we enrolled 278 renal transplant participants, including 251 subjects free of diabetes and 27 with PTDM. We studied several candidate gene polymorphisms associated with diabetes: 4G/5G polymorphism of plasminogen activator inhibitor 1 (PAI-1) at -675; C/T polymorphism of interleukin-1beta (IL-1β) at -511; G/C polymorphism of IL-6 at 174; polymorphic XbaI of Glucose transporter 1 (GLUT1); and C/T polymorphism of methylenetetrahydrofolate redutase (MTHFR) at 677.The PTDM group had an older mean age (47.6 ± 9.8 years), greater predominance of men (77.8%), higher number of chronic diseases (CDN ≥2, 96.3%), and more patients using tacrolimus-based immunosuppression (44.4%; P.05). Using model A, a simple logistic regression, we observed that patients with the IL-6 G/G genotype experienced a lower risk of developing PTDM (odds ratio [OR], 0.08; 95% confidence interval [CI] 0.01-0.86), and multiple logistic regression models B and C, after adjusting for different variables, confirmed this observation (model B: OR, 0.05; 95% CI, 0.00-0.66). The IL-6 G/G genotype showed a borderline effect in model C (OR, 0.02; 95% CI, 0.00-1.16). There were no significant differences between the 2 groups in genotype variations of PAI-1, IL-1β, GLUT-1, and MTHFR.The G/G genotype of IL-6 may play an important role to lower the risk for PTDM development.

OBJECTIVE The current study aimed to investigate whether microalbuminuria or moderately decreased glomerular filtration rate (GFR) is a better predictor for the development and progression of retinopathy in type 2 diabetic patients. RESEARCH DESIGN AND METHODS Type 2 diabetic patients without cardiovascular diseases, malignancy, pregnancy, and acute intercurrent illness were enrolled between 1 August 2001 and 31 December 2002. All participants provided their detailed medical history and underwent an eye fundus examination. They were followed up in outpatient clinics, and serum creatinine, urinary albumin-to-creatinine ratio (UACR), and retinal photographs were followed up annually until 31 December 2009. The primary outcomes were development and progression of diabetic retinopathy and nephropathy. The secondary outcomes were cardiovascular events and all-cause mortality. RESULTS Among 487 participants, 81 subjects had normoalbuminuria and moderate renal impairment (baseline eGFR 30–59.9 mL/min/1.73 m2), and 106 subjects had microalbuminuria and baseline eGFR ≥60 mL/min/1.73 m2. Patients with microalbuminuria and eGFR ≥60 mL/min/1.73 m2 had a significantly greater risk for development and progression of diabetic retinopathy (HR 3.34 [95% CI 1.04–10.70]) compared with those with moderate renal impairment and normoalbuminuria after multivariate adjustment. Risks for renal outcome, cardiovascular events, and all-cause mortality were not significantly different between the two groups. CONCLUSIONS Microalbuminuria has a greater impact on predicting the development and progression of diabetic retinopathy compared with moderate decline in GFR among type 2 diabetic patients.

A combination therapy of pentoxifylline with an angiotensin converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) decreased proteinuria or glomerular filtration rate decline in early chronic kidney disease (CKD). Whether adding pentoxifylline to ACEI/ARB provides additional benefits on outcome is unclear in CKD stage 5 patients who have not yet received dialysis (CKD 5 ND). A prospective cohort study was conducted based on the Taiwan National Health Insurance Research Database. From January 1, 2000 to June 30, 2009, we enrolled 14,117 CKD 5 ND with serum creatinine levels >6 mg/dL and hematocrit levels

Summary Background and objectives Bilirubin is a protective factor with antioxidant and anti-inflammatory properties, but its association with clinical outcomes of hemodialysis patients is unknown. Bilirubin degradation is mainly determined by the activity of hepatic bilirubin uridine diphosphate-glucuronosyltransferase (UGT1A1), which is significantly influenced by a TA-repeat polymorphism in the gene’s promoter, an allele designated UGT1A1*28. The study aimed to clarify the association between serum bilirubin and UGT1A1*28 polymorphism and their respective effect on outcomes of chronic hemodialysis patients. Design, setting, participants, & measurements The cohort study comprised 661 chronic hemodialysis patients who were prospectively followed for 12 years. The endpoints were cardiovascular events (CVEs) and allcause mortality. Results After adjustment for traditional and dialysis-related risk factors, individuals with bilirubin in the upper tertile had an adjusted hazard ratio of 0.32 for CVEs and 0.48 for all-cause mortality compared with those in the lower tertile. Individuals homozygous for UGT1A1*28 (genotype 7/7) had significantly higher bilirubin levels than those with 6/6 and 7/6 genotypes. In the same multivariable-adjusted model, individuals with 7/7 had approximately one tenth the risk for CVEs and one fourth the risk for all-cause mortality as compared with carriers of the 6 allele. Conclusions A graded, reverse association was noted between serum bilirubin and adverse outcomes among chronic hemodialysis patients. Moreover, the UGT1A1*28 polymorphism had strong effects on bilirubin levels and the 7/7 genotype might have an important effect on reducing CVEs and death. Clin J Am Soc Nephrol 6: 567–574, 2011. doi: 10.2215/CJN.06130710

Elevated levels of serum pancreatic enzymes are frequently observed in hemodialysis (HD) patients. The complex hemodynamic, biochemical, and physiological alterations in uremia were speculated to cause excessive release of pancreatic enzymes beyond decreased renal clearance. However, hemodynamic factors are seldom explored in this aspect. We performed the study to evaluate the association between intradialytic hemodynamic change and elevated serum pancreatic amylase (SPA). Eighty-three prevalent HD patients without any clinical evidence of acute pancreatitis underwent pre-HD and post-HD blood sampling for serum pancreatic enzyme levels. Demographic, biochemical, and hematological data were collected from patient record review. Hemodialysis information including intradialytic blood pressure changes and ultrafiltration (UF) amount were collected and averaged for 1 month before the blood sampling day. Patients with elevated SPA during the HD session had greater mean systolic blood pressure and mean arterial pressure reduction, greater UF volume, greater pre-HD blood urea nitrogen and serum creatinine, higher serum phosphorus, lower pre-HD serum total CO2, and lower left ventricle ejection fraction (LVEF). Using multivariate linear and logistic regression analysis, the independent predictors of elevated SPA were determined to be mean arterial pressure reduction during HD, mean UF amount, pre-HD serum total CO2, and LVEF. Greater blood pressure reduction during HD, greater UF volume, lower pre-HD serum total CO2, and lower LVEF were significantly associated with elevated SPA during HD. This suggests that hemodynamic factors contribute to elevated serum pancreatic enzymes in HD patients.

Dual renin angiotensin system (RAS) blockade using angiotensin-receptor blockers (ARBs) in combination with angiotensin converting enzyme inhibitors (ACEIs) is reported to improve proteinuria in both diabetic and non-diabetic patients. However, its renoprotective effect and safety remain uncertain in patients with advanced chronic kidney disease (CKD). From January 1, 2000 through June 30, 2009, we enrolled 14,117 pre-dialytic stage 5 CKD patients with serum creatinine >6mg/dL and hematocrit

High-performance liquid chromatography with tandem mass spectrometry (HPLC/MS/MS) was used to determine melamine oral bioavailability (BA) and urinary excretion. Organ distribution after a 14-day consecutive oral melamine administration (100 mg/kg/day, once a day) was also evaluated. A noncompartmental model was utilized to obtain pharmacokinetic parameters. According to the results, the BA of melamine was estimated to be 98.1%. Approximately 63% of administered melamine was recovered in urine within 96 h after a single oral administration (100 mg/kg). The bladder had the highest melamine concentration of all the organs after a 14-day consecutive oral administration of melamine, and almost no melamine was found in the rat brain. This result indicated that the oral absorption of melamine was almost complete and urinary excretion was the major route for its elimination. Repeated exposure to high-dose melamine may result in only slight accumulation in organs.

In this study, we describe a method for the analysis of melamine in rat plasma, liver, kidney, spleen, bladder, and brain using trichloroacetic acid precipitation with mixed-mode cation-exchange solid-phase extraction and hydrophilic interaction chromatography coupled to tandem mass spectrometry detection. Method validation was investigated completely, including linearity, precision, accuracy, matrix effect, extraction recovery, and carryover for the determination of melamine. The method exhibited a good linear range covering 20–500 ng/mL, and the overall precision ranged from 1.6 to 16.3%, with the accuracy varying from −7.9 to 15.1%. The mean matrix effects of melamine in rat plasma, liver, kidney, spleen, bladder, and brain ranged from 66.2 ± 6.7 to 95.5 ± 13.2%, and the mean recoveries for melamine varied from 79.8 ± 8.2 to 113.0 ± 9.6%. Rat kidney showed the highest level among the organs (192.5% of the plasma melamine level), and the average concentration of melamine in the brain was only 7.5% of the plasma melamine concentration. This work has pointed out that even with the application of two popular preparation procedures (acid precipitation and solid-phase extraction) of melamine, the matrix effect in analyzing biological samples still exists in certain kinds of matrices.

Hemorrhagic acalculous cholecystitis is a rare but potentially fatal disease. An increased bleeding tendency is present in both acute and chronic renal failure with impaired platelet function. We herein present a case of hemorrhagic acalculous cholecystitis in a hemodialysis patient who suffered from acute abdomen and upper gastrointestinal bleeding. The pathogenesis may have been associated with ischemia and reperfusion injury, eventually leading to necrosis of the gall-bladder wall. Abdominal ultrasound can aid in diagnosis. Biliary colic, jaundice, and melena are the typical symptoms of hemorrhagic cholecystitis, particularly in a patient with unexplained gastrointestinal bleeding.

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 HOMAIR. 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 HOMAIR (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. Am J Clin Nutr 2009;90:64‐9.

Patients undergoing maintenance hemodialysis have elevated markers of oxidative stress, but the reasons for this are not fully understood. Intravenous administration of iron, which many of these patients receive, may provoke the generation of bioactive iron, which enhances oxidative stress and lipid peroxidation. In this study, 110 hemodialysis patients were randomly assigned to five groups that were administered single intravenous doses of iron sucrose, ranging from 20 to 500 mg. A time- and dosage-dependent rise in lymphocyte 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in lymphocyte DNA, a marker of oxidative DNA damage, with a significant increase at 2 h after intravenous iron ofor = 200 mg (P0.05). Four weeks later, patients were randomly assigned to weekly iron sucrose (100 mg of elemental iron) or saline for 12 wk, and 89 patients completed the study. Mean lymphocyte 8-OHdG content was significantly higher in patients receiving intravenous iron compared with control subjects (P0.05), especially in those with ferritin levels500 microg/L. In addition, flow cytometric techniques revealed increased production of reactive oxygen species in lymphocytes among those treated with intravenous iron. Treatment with intravenous iron but not saline was also associated with decreased plasma ascorbate and alpha-tocopherol levels and increased oxidized glutathione/reduced glutathione ratio (P0.05). In summary, intravenous iron sucrose provokes oxidative damage to peripheral blood lymphocyte DNA in hemodialysis patients, especially among those with high levels of ferritin.

Anemia is a frequently encountered problem of chronic kidney disease (CKD) and deteriorates as renal function declines. Anemia increases the risk of death in CKD patients with diabetes and hypertension, which are the 2 leading causes of CKD. Recent studies suggest that correction of anemia improves patient quality of life and may delay the progression to end-stage renal disease. Anemia is often only treated in the late stages of CKD or after the initiation of renal replacement therapy. Thus, anemia of CKD is often unnoticed and lacks appropriate treatment. To practically manage high-risk patients with CKD and its associated cardiovascular diseases, it is mandatory to diagnose and appropriately treat anemia of CKD earlier. The optimal level of hemoglobin for greatest clinical benefit is unclear, but at present, it is recommended to remainor = 11 g/dL. This paper provides recommendations for the diagnosis and management of anemia associated with CKD based on international practice guidelines.

To the editor: Dysregulation in platelet production and abnormal platelet counts have been well known as a predictor of adverse outcomes in patients with infection, cancer, and end-stage renal disease.[1][1][⇓][2]-[3][3] The prevalence rates of thrombocytopenia and thrombocytosis among people

Decoy receptor 3 (DcR3) expression in kidneys has been shown to predict progression of chronic kidney disease. We prospectively investigated a cohort comprising 96 renal transplant recipients (RTRs) undergoing graft kidney biopsies. Computer-assisted quantitative immunohistochemical staining value of DcR3 in renal tubular epithelial cells (RTECs) was used to determine the predictive role of DcR3 in kidney disease progression. The primary end point was doubling of serum creatinine and/or graft failure. A multivariate Cox proportional hazards model was used to assess the risk of DcR3 expression in rejected kidney grafts toward the renal end point. In total, RTRs with kidney allograft rejection were evaluated and the median follow-up was 30.9 months. The greater expression of DcR3 immunoreactivity in RTECs was correlated with a higher rate of the histopathological concordance of acute T cell-mediated rejection. Compared with 65 non-progressors, 31 progressors had higher DcR3 expression (HDE) regardless of the traditional risk factors. Cox regression analysis showed HDE was significantly associated with the risk of renal end point with a hazard ratio of 3.19 (95% confidence interval, 1.40 to 7.27; P = 0.006) after adjusting for other variables. In repetitive biopsies, HDE in tissue showed rapid kidney disease progression due to persistent inflammation.

Nonalcoholic fatty liver disease (NAFLD) is an important risk factor for the development of type 2 diabetes mellitus. Interferon gamma-induced protein 10 (IP-10), a proinflammatory chemokine, plays a crucial role in inflammatory diseases. This cross-sectional pilot study investigated whether circulating IP-10 is associated with the progression of liver disease and prediabetes in patients with NAFLD. A total of 90 patients with NAFLD alone (n = 48) or NAFLD with incident diabetes (n = 42) and 43 controls participated in this study. Fasting plasma was used to assess metabolic parameters, inflammatory factors, endotoxin levels and malondialdehyde (MDA) concentrations. Insulin resistance was estimated using homeostatic model assessment (HOMA-IR). IP-10 levels were significantly higher in patients with NAFLD alone (median (interquartile range): 369.44 (309.30–418.97) pg/mL) and in those with incident diabetes (418.99 (330.73–526.04) pg/mL) than in controls (293.37 (214.10–331.57) pg/mL) (P

Background Volume overload is frequently encountered and is associated with cardiovascular risk factors in patients with chronic kidney disease ( CKD) . However, the relationship between volume overload and adverse outcomes in CKD is not fully understood. Methods and Results A prospective cohort of 338 patients with stage 3 to 5 CKD was followed for a median of 2.1 years. The study participants were stratified by the presence or absence of volume overload, defined as an overhydration index assessed by bioimpedance spectroscopy exceeding 7%, the 90th percentile for the healthy population. The primary outcome was the composite of estimated glomerular filtration rate decline ≥50% or end‐stage renal disease. The secondary outcome included a composite of morbidity and mortality from cardiovascular causes. Animal models were used to simulate fluid retention observed in human CKD . We found that patients with volume overload were at a higher risk of the primary and secondary end points in the adjusted Cox models. Furthermore, overhydration appears to be more important than hypertension in predicting an elevated risk. In rats subjected to unilateral nephrectomy and a high‐salt diet, the extracellular water significantly increased. This fluid retention was associated with an increase in blood pressure, proteinuria, renal inflammation with macrophage infiltration and tumor necrosis factor‐α overexpression, glomerular sclerosis, and cardiac fibrosis. Diuretic treatment with indapamide attenuated these changes, suggesting that fluid retention might play a role in the development of adverse outcomes. Conclusions Volume overload contributes to CKD progression and cardiovascular diseases. Further research is warranted to clarify whether the correction of volume overload would improve outcomes for CKD patients.

Metformin is recommended as a first-line treatment for patients with type 2 diabetes. However, use of this drug has been contraindicated in individuals with impaired kidney function because of the perceived risk of lactic acidosis. Evidence now supports cautious use of metformin in people with mild-to-moderate chronic kidney disease. However, studies examining the use of metformin in patients with advanced chronic kidney disease are lacking. We aimed to assess the safety of metformin in patients with type 2 diabetes and advanced (approximately stage 5) chronic kidney disease.We did a retrospective, observational, cohort study of patients with type 2 diabetes who were enrolled prospectively in Taiwan's national health insurance research database between Jan 1, 2000, and June 30, 2009, and had follow-up data until Dec 31, 2009. We included individuals with a serum creatinine concentration greater than 530 μmol/L, which is approximately equivalent to stage 5 chronic kidney disease. From a consecutive sample of 12 350 patients with type 2 diabetes and chronic kidney disease, 1005 used metformin and 11 345 were non-users. We matched users and non-users of metformin by propensity score in a 1:3 ratio. Our primary outcome was all-cause mortality.813 metformin users were matched by propensity score to 2439 non-users. The two groups of patients did not differ significantly by 30 baseline clinical and socioeconomic variables. Median follow-up in the matched cohort was 2·1 years (range 0·3-9·8). All-cause mortality was reported in 434 (53%) of 813 metformin users and in 1012 (41%) of 2439 non-users. After multivariate adjustment, metformin use was an independent risk factor for mortality (adjusted hazard ratio 1·35, 95% CI 1·20-1·51; p0·0001). The increased mortality risk was dose-dependent and was consistent across all subgroup analyses. However, metformin use compared with no use was associated with a higher but non-significant risk of metabolic acidosis (1·6 vs 1·3 events per 100 patient-years; adjusted hazard ratio 1·30, 95% CI 0·88-1·93; p=0·19).Use of metformin in people with type 2 diabetes and a serum creatinine concentration greater than 530 μmol/L is associated with a significantly increased risk of all-cause mortality compared with non-users. Metformin use should not be encouraged in this patient group.Taipei Tzu Chi Hospital, Taipei Veterans General Hospital, Foundation for Poison Control, National Health Research Institutes, Ministry of Science and Technology of Taiwan.

Patients with chronic kidney disease have an increased prevalence of peripheral arterial disease. Endothelial progenitor cells (EPC) are pivotal in neovascularization, but their role in mediating peripheral arterial disease in chronic kidney disease is not fully known. Here we studied the impact of indoxyl sulfate, a protein-bound uremic toxin, on EPC function in response to tissue ischemia or cell hypoxia in mice that underwent subtotal nephrectomy or sham operation. At 16 weeks, unilateral hindlimb ischemia was induced in all. Four weeks later, subtotal nephrectomy mice had significantly increased plasma levels of indoxyl sulfate, reduced reperfusion, decreased EPC mobilization, and impaired neovascularization in ischemic hindlimbs compared with control mice. Treatment with AST-120, an oral adsorbent of uremic toxins, reversed these changes. Ischemia-induced protein expression including phospho-eNOS, phospho-STAT3, interleukin-10, and VEGF were significantly decreased in ischemic hindlimbs of subtotal nephrectomy mice versus control mice; all effects were reversed by AST-120. Subtotal nephrectomy mice fed a diet with indole for 12 weeks resulted in impaired neovascularization in ischemic hindlimbs; also reversed by AST-120. In cultured human EPCs, VEGF expression was increased in hypoxia through HIF-1α and interleukin-10/STAT3 signaling; effects suppressed by pretreatment with indoxyl sulfate. Moreover, indoxyl sulfate markedly attenuated hypoxia-induced EPC migration and tube formation. Thus, indoxyl sulfate may be a therapeutic target for EPC-rescue of impaired neovascularization in patients with chronic kidney disease and peripheral arterial disease.

Hemodialysis vascular accesses are prone to recurrent stenosis and thrombosis after endovascular interventions. In vitro data suggest that indoxyl sulfate, a protein-bound uremic toxin, may induce vascular dysfunction and thrombosis. However, there is no clinical evidence regarding the role of indoxyl sulfate in hemodialysis vascular access. From January 2010 to June 2013, we prospectively enrolled patients undergoing angioplasty for dialysis access dysfunction. Patients were stratified into tertiles by baseline serum indoxyl sulfate levels. Study participants received clinical follow-up at 6-month intervals until June 2014. Primary end points were restenosis, thrombosis, and failure of vascular access. Median follow-up duration was 32 months. Of the 306 patients enrolled, 262 (86%) had symptomatic restenosis, 153 (50%) had access thrombosis, and 25 (8%) had access failure. In patients with graft access, free indoxyl sulfate tertiles showed a negative association with thrombosis-free patency (thrombosis-free patency rates of 54%, 38%, and 26% for low, middle, and high tertiles, respectively; P=0.001). Patients with graft thrombosis had higher free and total indoxyl sulfate levels. Using multivariate Cox regression analysis, graft thrombosis was independently predicted by absolute levels of free indoxyl sulfate (hazard ratio=1.14; P=0.01) and free indoxyl sulfate tertiles (high versus low, hazard ratio=2.41; P=0.001). Results of this study provide translational evidence that serum indoxyl sulfate is a novel risk factor for dialysis graft thrombosis after endovascular interventions.

Thiazolidinediones (TZDs) reduce urinary albumin excretion and proteinuria in diabetic nephropathy. The effect of TZDs on hard renal outcome in diabetic patients with chronic kidney disease (CKD) is unknown. We investigate the association of TZDs and risk of long-term dialysis or death in diabetic patients with advanced CKD. The nationwide population-based cohort study was conducted using Taiwan’s National Health Insurance Research Database. From January 2000 to June 2009, 12350 diabetic patients with advanced CKD (serum creatinine levels greater than 6 mg/dL but not yet receiving renal replacement therapy) were selected for the study. We used multivariable Cox regression models and a propensity score-based matching technique to estimate hazard ratios (HRs) for development of long-term dialysis and the composite outcome of long-term dialysis or death for TZD users (n=1224) as compared to nonusers (n=11126). During a median follow-up of 6 months, 8270 (67.0%) patients required long-term dialysis and 2593 (21.0%) patients died before starting long-term dialysis. Using propensity score matched analysis, we found TZD users were associated with a lower risk for long-term dialysis (HR, 0.80; 95% confidence interval [CI], 0.74-0.86) and the composite outcome of long-term dialysis or death (HR, 0.85; 95% CI, 0.80-0.91). The results were consistent across most patient subgroups. Use of TZDs among diabetic patients with advanced CKD was associated with lower risk for progression to end-stage renal disease necessitating long-term dialysis or death. Further randomized controlled studies are required to validate this association.

Soluble epoxide hydrolase (sEH) is abundantly expressed in kidney and plays a potent role in regulating inflammatory response in inflammatory diseases. However, the role of sEH in progression of chronic kidney diseases such as obstructive nephropathy is still elusive. In current study, wild-type (WT) andsEHdeficient (sEH−/−) mice were subjected to the unilateral ureteral obstruction (UUO) surgery and the kidney injury was evaluated by histological examination, western blotting, and ELISA. The protein level of sEH in kidney was increased in UUO-treated mice group compared to nonobstructed group. Additionally, UUO-induced hydronephrosis, renal tubular injury, inflammation, and fibrosis were ameliorated insEH−/−mice with the exception of glomerulosclerosis. Moreover,sEH−/−mice with UUO showed lower levels of inflammation-related and fibrosis-related protein such as monocyte chemoattractant protein-1, macrophage inflammatory protein-2, interleukin-1β(IL-1β), IL-6, inducible nitric oxide synthase, collagen 1A1, andα-actin. The levels of superoxide anion radical and hydrogen peroxide as well as NADPH oxidase activity were also decreased in UUO kidneys ofsEH−/−mice compared to that observed in WT mice. Collectively, our findings suggest that sEH plays an important role in the pathogenesis of experimental obstructive nephropathy and may be a therapeutic target for the treatment of obstructive nephropathy-related diseases.

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.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.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 (ferritin100 microg/L and/or TSAT20%). 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 (P0.05) and TSAT (P0.001).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.

Background Previous studies have demonstrated that high estimated glomerular filtration rate (eGFR) is paradoxically associated with an increased risk of mortality, and the association becomes more predominant in older people. However, the role of malnutrition–inflammation–cachexia syndrome (MICS) in the association between eGFR and mortality has never been explored. Methods We conducted a community‐based cohort study using data from the Taipei City Elderly Health Examination Database, collected during the period 2001–10. All participants aged ≥65 years were included and stratified by the absence or presence of MICS, which is defined as the presence of at least one of the following markers: body mass index

Background Endotoxemia is exaggerated and contributes to systemic inflammation and atherosclerosis in patients requiring continuous ambulatory peritoneal dialysis (CAPD). The risk of mortality is substantially increased in patients requiring CAPD for >2 years. However, little is known about the effects of long-term CAPD on circulating endotoxin and cytokine levels. Therefore, the present study evaluated the associations between plasma endotoxin levels, cytokine levels, and clinical parameters with the effects of a short-dwell exchange on endotoxemia and cytokine levels in patients on long-term CAPD. Methods A total of 26 patients were enrolled and divided into two groups (short-term or long-term CAPD) according to the 2-year duration of CAPD. Plasma endotoxin and cytokine levels were measured before and after a short-dwell exchange (4-h dwell) during a peritoneal equilibration test (a standardized method to evaluate the solute transport function of peritoneal membrane). These data were analyzed to determine the relationship of circulating endotoxemia, cytokines and clinical characteristics between the two groups. Results Plasma endotoxin and monocyte chemotactic protein-1 (MCP-1) levels were significantly elevated in the long-term group. PD duration was significantly correlated with plasma endotoxin (r = 0.479, P = 0.016) and MCP-1 (r = 0.486, P = 0.012). PD duration was also independently associated with plasma MCP-1 levels in multivariate regression. Plasma MCP-1 levels tended to decrease (13.3% reduction, P = 0.077) though endotoxin levels did not decrease in the long-term PD group after the 4-h short-dwell exchange. Conclusion Long-term PD may result in exaggerated endotoxemia and elevated plasma MCP-1 levels. The duration of PD was significantly correlated with circulating endotoxin and MCP-1 levels, and was an independent predictor of plasma MCP-1 levels. Short-dwell exchange seemed to have favorable effects on circulating MCP-1 levels in patients on long-term PD.

● Background: Dalysis 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. Am J Kidney Dis 45:1073-1083. © 2005 by the National Kidney Foundation, Inc.

Protective effect of vitamin C on 8-hydroxy-2′-deoxyguanosine level in peripheral blood lymphocytes of chronic hemodialysis patients.BackgroundThis study focused on the effect of vitamin C on the 8-hydroxy-2′-deoxyguanosine (8-OHdG) level of cellular DNA, as well as 8-oxoguanine-DNA glycosylase 1 (hOGG1) and human MutT homologue (hMTH1) gene expression in peripheral blood lymphocytes of chronic hemodialysis patients.MethodsSixty chronic hemodialysis patients (35 men and 25 women) were recruited to participate in a randomized, placebo-controlled study. Treatment order is block-randomized with intravenous sodium ascorbate (vitamin C, 300 mg) or placebo (0.9% saline), administered postdialysis three times a week. We evaluated 8-OHdG level, intracellular reactive oxygen species (ROS) production, and gene expression of hOGG1 and hMTH1 in peripheral blood lymphocytes byusing high-performance liquid chromatography (HPLC) electrochemical detection method, flow cytometric analysis, andreverse transcription-polymerase chain reaction (RT-PCR),respectively.ResultsA total of 51 patients completed the study (26 in placebo group and 25 in vitamin C group). Mean 8-OHdG levels significantly decreased in total subjects following 8 weeks of vitamin C supplementation (22.9 vs. 18.8/106 dG, P < 0.01). The decrease in 8-OHdG levels after vitamin C supplementation was also noted in the patients with ferritin

Renal anemia is mainly caused by inadequate synthesis of erythropoietin from diseased kidneys. At the present time, recombinant human erythropoietin (rHuEPO) is used to correct anemia successfully in most patients with end-stage renal diseases. Nevertheless, poor response to rHuEPO still exists in some hemodialysis patients and its mechanism in some cases remains obscure. Herein, we describe a rare case of rHuEPO hyporesponsiveness due to mechanical hemolysis induced by a traumatic carotid-jugular arteriovenous fistula (AVF) in the presence of subclinical aluminum intoxication. Following surgical resection of the traumatic AVF and 8 months of desferrioxamine treatment, the responsiveness to rHuEPO was restored and the rHuEPO dose requirements reduced.

Background. Optimal response to recombinant human erythropoietin (rHuEpo) in haemodialysis (HD) patients requires provision of sufficient available iron. However, a balance between iron requirements and supplements remains a challenge in clinical practice. Reticulocyte parameters, i.e. reticulocyte haemoglobin content (CHr) and reticulocytes in a high-fluorescence intensity region (HFR), have been shown to be accurate predictors of iron-deficient erythropoiesis as compared with traditional markers. Therefore, the aim of this study was to appraise the diagnostic power of these two parameters in the early prediction of response to intravenous iron (IVFE) medications in HD patients receiving rHuEpo. Methods. Sixty-five HD patients with a serum ferritin level of -500 mgul and on rHuEpo therapy for )6 months were enrolled for IVFE supplementation (100 mg iron saccharate three times a week for 4 weeks, then 100 mg every 2 weeks for 5 months). Haemoglobin, haematocrit, serum ferritin, transferrin saturation, reticulocyte count, percentage of hypochromic red cells, CHr and HFR were measured before and following iron supplementation. Response was defined as a rise in haematocrit of )3% anduor a reduction in rHuEpo dose of )30% over the baseline values at the end of the study. Results. Forty-two patients had a dramatic response to IVFE therapy with a 13.5% increase in mean haematocrit and a 38% reduction in rHuEpo dose at the end of the study (P-0.001). This paralleled a statistically significant rise in CHr and HFR (P0.001). Univariate analyses showed that ferritin (P-0.010) and CHr (P-0.001) at baseline, changes in CHr (DCHr2W, P-0.001) and HFR (DHFR2W, P-0.010) at 2 weeks, as well as changes in CHr (DCHr4W, P-0.001) and HFR (DHFR4W, P-0.001) at 4 weeks, strongly correlated with response to IVFE supplementation. Stepwise discriminant analysis disclosed that DCHr4W in conjunction with DHFR4W exhibited an r 2 value of 0.531 (P-0.001) to predict response to IVFE therapy. Analyses by receiver operating characteristic curves and logistic regression further revealed that DCHr4W at a cut-off value of )1.2 pg and DHFR4W of )500uml were more specific to the status of iron-deficient erythropoiesis following IVFE medications. Combined use of the two cut-off values allowed for the highest accuracy in the early prediction of the response toIVFE therapy,with a sensitivity of 96% and a specificity of 100%. Conclusions. Our study shows that changes in CHr and HFR at either 2 or 4 weeks are superior to the conventional erythrocyte and iron metabolism indices and may serve as reliable parameters to detect irondeficient erythropoiesis in HD patients undergoing rHuEpo therapy. During aggressive IVFE treatment, early identification of non-responsiveness and subsequent discontinuation of treatment can avoid the inadvertent iron-related toxicity due to over-treatment.

Background. The aim of this study was to identify the factors determining the circulating soluble transferrin receptor (sTf R) concentrations in haemodialysis (HD) patients on maintenance recombinant human erythropoietin (rHuEpo) treatment. Methods. In a prospective cross-sectional study, 91 chronic HD patients and 18 anaemic controls with normal renal function were recruited. For each subject, blood samples were measured for complete blood count, reticulocyte count, percentage of hypochromic red cells (% HRC), serum ferritin, serum iron, transferrin saturation (TS), serum erythropoietin (sEpo), C-reactive protein (CRP), and sTf R. HD patients received constant rHuEpo doses and basal sEpo was measured P86 h after the last injection. The age, gender, dialysis vintage, and the above-mentioned parameters were used as independent variables and logarithmic sTfR (log10 sTfR) as a dependent variable in the forward stepwise multiple regression model. Results. HD patients were similar to controls regarding haematocrit, serum ferritin, TS, and % HRC, but had significantly lower sTf R, sEpo, and reticulocyte index. Univariate analyses showed that the sTf R level strongly correlated with sEpo (rs0.60, P-0.001) and % HRC (rs0.60, P-0.001), and significantly with serum ferritin (rs0.29, P-0.01), TS (rs0.27, P-0.05), and dose of rHuEpo administered (rs0.27, P-0.05) in HD patients. sTf R also had a positive correlation with haematocrit (rs0.26, P-0.05), red blood cell (RBC) count (rs0.23, P-0.05), and reticulocyte count (rs0.24, P-0.05), but not with CRP (rs0.16, P)0.05). Multivariate regression analysis disclosed that sEpo, HRC, and serum ferritin were the independent predictors of sTf R level. Overall, the model explained 58.8% of the variability in sTfR (R 2 s0.588, P-0.001). Conclusions. Circulating sTf R is a good index of marrow erythropoietic activity in HD patients during rHuEpo treatment. Its level is also independently up-regulated by functional iron deficiency in the process of enhanced erythropoiesis. Our study showed that sTf R levels quantitatively reflect the integrated effects of iron availability, iron reserves, and erythropoietic stimulation.

Aims Several studies reported treatment benefits of tolvaptan in patients with congestive heart failure (CHF). However, the optimal dosage remains unclear. We aimed to compare different dosage of tolvaptan to determine the optimal dosage in terms of the efficacy and safety. Methods We searched MEDLINE, PubMed, EMBASE, Cochrane CENTRAL and ClinicalTrials.gov through Aug 31, 2016. Randomized controlled trials (RCTs) comparing tolvaptan of different dosages or to placebo in patients with CHF were included. We used network meta-analysis to look for the optimal dosage in terms of effectiveness and safety. Urine output, body weight change and change in serum sodium were the main outcomes of efficacy. Adverse effects were the secondary outcomes. Quality was assessed by Cochrane risk-of-bias tool. Results Twelve RCTs reporting 14 articles with 5793 patients (mean age, 65.7 ± 11.9 years; 73.7% man) were included. Compared with placebo, the tolvaptan 30 mg had similar effects to tolvaptan 45–90 mg in terms of urine output (mean difference [MD] 2.03 liter; 95% confidence interval [CI] 1.3 to 2.71), body weight change (MD -1.12 kg; 95% CI -1.37 to -0.88) and change in serum sodium (MD 3.06 meq/L; 95% CI 2.43 to 3.68). Compared with placebo, tolvaptan of different dosage showed a non-significant higher risk of adverse effects. Conclusions These findings suggest that tolvaptan 30 mg and 45 mg may be the optimum dosage for CHF patients, because of its ability to provide favourable clinical results without greater adverse effects. However, tolvaptan is not beneficial for reducing all-cause mortality in CHF patients.