Search

The 2019 Kidney Disease Outcome Quality Initiative (K/DOQI) guideline recommended evaluating arteriovenous fistula (AVF) malfunction risks primarily based on clinical monitoring, which can be assisted with the value of vascular access flow (Qa). Nevertheless, Qa thresholds recommended by different guidelines vary, ranging from 300 to 500 ml/min. This study investigated the optimal Qa threshold to predict future functional patency in AVFs with Qa 500 ml/min.Both the clinical indicators of access dysfunction and the Qa value were monitored in patients receiving hemodialysis by the radiocephalic AVF. Routine access flow surveillance was performed by the ultrasound dilution method (HD03, Transonic Inc.). The development of clinically significant indicators of access dysfunction, which necessitated percutaneous transluminal angiography (PTA) to maintain functional patency, was analyzed in this cohort.Among the enrolled 302 patients, Qa of 52 patients was under 500 ml/min. These 52 patients received 2 Qa measurements during the follow-up period. Of these 52 patients, serial Qa of 17 patients varied trivially and their AVF remained functional. Multivariable logistic regression analysis revealed that a low Qa per ideal body weight (IBW) is an independent predictor of AVF functional loss. Receiver operating characteristic curve analysis of Qa/IBW in predicting future AVF functional loss revealed that the best cutoff value of Qa is 7.1 times the IBW.For radiocephalic AVFs with Qa 500 ml/min, the minimally required Qa to maintain access function is associated with individual IBW. The IBW-based Qa threshold assessment would allow more flexibility in the treatment of patients and reduce unnecessary invasive measures.

End-stage kidney disease (ESKD) is a global burden that reflects each country's unique condition. We used the National Health Insurance Research Database (NHIRD) of Taiwan to decipher changes in the mortality and international survival rates and to determine the effectiveness of the pre-end-stage renal disease care program (pre-ESRD care program) to guide future health policies for ESKD.We conducted a retrospective cohort analysis of the NHIRD data along with records from the catastrophic illness certificate program of ESKD patients from 2010 to 2018.From 2010 to 2018, the annual dialysis-related mortality rate in Taiwan increased from 10.6 to 11.8 deaths per hundred patient-years. The mortality rate for patients below 40 years appears to be decreasing, reflecting the improved quality of care for ESKD patients. Patients above 75 years showed increasing mortality, indicating the prolonged survival and aging of the ESKD population. Patients undergoing dialysis who participated in the pre-ESRD care program had a higher post-dialysis initiation life expectancy than those who did not participate. Among the program enrollees, the post-dialysis initiation life expectancy was higher in patients who had participated for more than one year. Taiwan has one of the highest ESKD patient survival rates globally.From 2010 to 2018, the reduced mortality in young patients and aging of the ESKD population might indicate that the quality of care in Taiwan for ESKD has improved. Furthermore, a better survival rate after dialysis initiation was observed in the pre-ESRD care program participants.

Background A discordant biological clock could potentially induce sudden cardiac death (SCD). We aimed to evaluate the circadian change of heart rate variability (HRV) and its relationship to the risks of ventricular arrhythmia (VA) and near syncope in patients with chronic kidney disease (CKD). Methods In this retrospective study, non-CKD and CKD patients were enrolled and underwent a 24-hour Holter examination for linear and nonlinear HRV analyses. The multiscale entropy (MSE) method was selected for nonlinear HRV analyses. The documented VAs or episodes of near syncope were classified as high-risk SCD group (n = 8) and others as low-risk SCD group (n = 21). Results In linear analyses, time and frequency domains revealed no significant difference between groups. In nonlinear analyses with MSE, MSE5, MSE6–20, and MSEslope 5 were significantly lower (p = 0.002, p Conclusions Nonlinear analysis with MSE demonstrated the loss of circadian change in CKD patients and was associated with a higher risk for VAs and near syncope. The MSE method demonstrated the diurnal change of rhythm dynamics which identifies potential autonomic dysfunction leading to poor prognosis.

An inverse relationship between body mass index (BMI) and mortality (the obesity paradox) has been found in patients with non-dialysis-dependent chronic kidney disease (CKD). However, it is unclear whether increased muscle mass or body fat confers the survival advantage. To resolve this we investigated the impact of body makeup on a composite outcome of death or cardiovascular events in a prospective cohort of 326 patients with stage 3-5 CKD not yet on dialysis. Lean mass and body fat were determined using the Body Composition Monitor, a multifrequency bioimpedance spectroscopy device, and were expressed as the lean tissue or fat tissue index, respectively. Patients were stratified as High (above median) or Low (below median) BMI, High or Low lean tissue index, or as High or Low fat tissue index. During a median follow-up of 4.6 years, there were 40 deaths and 68 cardiovascular events. In Cox proportional hazards models, a High lean tissue index, but not High BMI or High fat tissue index, predicted a lower risk of both the composite or its component outcomes (reference: below median). When patients were further stratified into four distinct body composition groups based on both the lean and fat tissue index, only the High lean/fat tissue index group had a significantly lower risk of the composite outcome (hazard ratio 0.36, 95% confidence interval 0.14-0.87; reference: Low lean/fat tissue index group). Thus, the lean tissue index can provide better risk prediction than the BMI alone in non-dialysis-dependent patients with CKD. The High lean/fat tissue index appears to be associated with best outcomes. An optimal body composition for improving the prognosis of CKD needs to be determined.

Cytomegalovirus (CMV) infection is a common infectious complication in immunocompromised patients. The colon is the most common site of CMV infection in the gastrointestinal tract. Rarely, however, invasion of the upper gastrointestinal tract, such as the esophagus or stomach, has been reported. Herein, we describe the first reported case of CMV gastritis in a patient with end-stage renal disease and uremic symptoms (including nausea, vomiting, and poor appetite) who had begun hemodialysis therapy. This patient was not a transplant recipient and was not receiving immunosuppressant treatment. As CMV gastritis is easily over looked in patients with end-stage renal disease, physicians should maintain a high index of suspicion and establish the diagnosis as early as possible using an upper GI endoscopic biopsy and adequate staining.

The 2014 Eighth Joint National Committee guidelines for hypertension management emphasize the upper limit of blood pressure (BP) as the target for treatment in the elderly population. Given the uncertainty regarding optimal BP range, we aimed to investigate the association between observed BP and subsequent mortality in older people.We extracted data from 128,765 participants ≥65 years of age who underwent annual health examinations in a retrospective, observational community-based study from 2001 to 2010. Seated BP was measured using an oscillometric device. The outcomes were all-cause and cardiovascular mortality.As compared to participants with systolic BP at 130 to 139 mm Hg, the risk of all-cause mortality was significantly higher among those with110 (adjusted hazard ratios [aHRs], 1.12; 95% confidence interval [CI], 1.05-1.20), 140 to 149 (aHR, 1.08; 95% CI, 1.03-1.14), 150 to 159 (aHR, 1.07; 95% CI, 1.01-1.17), 160 to 169 (aHR, 1.11; 95% CI, 1.04-1.19), and ≥170 mm Hg (aHR, 1.25; 95% CI, 1.17-1.33), whereas the differences were not significant for those with 110 to119 (aHR, 1.06; 95% CI, 1.00-1.12) and 120 to 129 mm Hg (aHR, 1.03; 95% CI, 0.97-1.08). Similarly, diastolic BP at 40 to 79 mm Hg was associated with the lowest risk of all-cause mortality. The J-shaped curve relationship between BP and cardiovascular mortality was also observed.Observed systolic and diastolic BP other than 110 to 139 and 40 to 79 mm Hg, respectively, were associated with a worse outcome. Our large cohort study supports the J-shaped mortality with observed BP in older people.

Studies revealed that the use of renin-angiotensin-aldosterone system antagonism is not associated with a statistically significant reduction in the risk of cardiovascular events in patients with chronic kidney disease (CKD) compared with that in the general population. We tested the hypothesis that indoxyl sulfate (IS) can interfere with the protective effect of valsartan-mediated on endothelial function in vitro and neovascularization in mice underwent subtotal nephrectomy. In human aortic endothelial cells, we first demonstrated that IS impaired the valsartan-mediated phosphorylation of eNOSThr495, nitric oxide production and tube formation via NADPH oxidase (NOX) and protein kinase C (PKC) phosphorylation, but this effect was suppressed by cotreatment with apocynin and calphostin C. In vivo, IS attenuated valsartan-induced angiogenesis in Matrigel plugs in mice. Moreover, in subtotal nephrectomy mice who underwent hindlimb ischemic surgery, valsartan significantly increased the mobilization of endothelial progenitor cells in circulation as well as the reperfusion of blood flow and density of CD31+ capillaries in ischemic limbs. However, IS attenuated the protective effect of valsartan-induced neovascularization and increased the expression of p-PKCαSer657 and p-eNOSThr497 in ischemic limbs. Cotreatment of apocynin and calphostin C reversed the IS impaired-neovascularization and decreased the expression of p-PKCαSer657 and p-eNOSThr497 in ischemic limbs. Our study suggests that the NOX/PKC/eNOS signaling pathway plays a pivotal role in the IS-mediated inhibition of valsartan-conferred beneficial effects on endothelial function in vitro and neovascularization in subtotal nephrectomy mice. We proposed a novel causative role for IS in cardiovascular complications in CKD patients., Highlights • The use of renin-angiotensin-aldosterone system antagonism fails to reduce in the risk cardiovascular events in patients with CKD. • Indoxyl sulfate interferes with the protective effect of angiotensin II receptor blocker-mediated neovascularization in CKD mice. • Indoxyl sulfate interferes with the beneficial effect of of valsartan on endothelial function by activating the NOX/PKC signaling pathway. • This article proposed a novel causative role for indoxyl sulfate in cardiovascular complications in CKD patients.

Background The association between periodontal disease and chronic kidney disease in older people is controversial, and evidence for a causal link between kidney function decline and subsequent mortality risk is limited. Study Design Longitudinal, observational, community-based cohort study. Setting & Participants Participants were citizens 65 years or older who received the Taipei City Government–sponsored Annual Elderly Health Examination Program during 2005 to 2010, including dental status assessment and biochemical examinations. Predictors Participants with periodontal disease defined by the World Health Organization Community Periodontal Index of Treatment Need criteria. Outcomes All-cause and cardiovascular mortality and estimated glomerular filtration rate (eGFR) decline ≥ 30% over 2 years. Results Of 100,263 study participants, 13,749 (13.7%) had periodontal disease. In a mean follow-up of 3.8 years, all-cause and cardiovascular mortality rates in those with periodontal disease (11.5% and 2.6%, respectively) were higher compared with those without periodontal disease (6.7% and 1.6%, respectively). After adjustment for demographic characteristics, comorbid conditions, and biochemistry data, adjusted HRs for all-cause and cardiovascular mortality were 1.34 (95% CI, 1.26-1.42) and 1.25 (95% CI, 1.13-1.41), respectively. The frequency of eGFR decline ≥ 30% over 1-, 2-, and 3-years' follow-up in those with periodontal disease was 1.8%, 3.7%, and 4.0%, respectively. In a logistic regression model, adjusted ORs of the detrimental effect of periodontal disease on 30% eGFR decline in participants over 1-, 2-, or 3-years' follow-up were 1.03 (95% CI, 0.85-1.25), 1.62 (95% CI, 1.41-1.87), and 1.59 (95% CI, 1.37-1.86), respectively. In subgroup analyses according to age, sex, and comorbid conditions, risks for eGFR decline and mortality remained consistent. Limitations Results may not be generalizable to other non-Asian ethnic populations. Conclusions The results indicate that periodontal disease is a risk factor for all-cause and cardiovascular mortality and eGFR decline ≥ 30% over 2 to 3 years in older people.

Chronic kidney disease (CKD) is an emerging worldwide public health problem. Inflammatory cell infiltration and activation during the early stages in injured kidneys is a common pathologic feature of CKD. Here, we determined whether an important inflammatory regulator, triggering receptor expressed on myeloid cells (TREM)-1, is upregulated in renal tissues collected from mouse ureteral obstruction–induced nephritis. TREM-1 is crucial for modulating macrophage polarization, and has a pivotal role in mediating tubular injury and interstitial collagen deposition in obstructive nephritis. Lysates from nephritic kidneys triggered a TREM-1-dependent M1 polarization ex vivo , consistent with the observation that granulocyte-macrophage colony-stimulating factor (GM-CSF)-derived M1 macrophages express higher levels of TREM-1 in comparison with M-CSF-derived cells. Moreover, agonistic TREM-1 cross-link significantly strengthens the inductions of iNOS and GM-CSF in M1 cells. These observations are validated by a strong clinical correlation between infiltrating TREM-1-expressing/iNOS-positive macrophages and renal injury in human obstructive nephropathy. Thus, TREM-1 may be a potential diagnostic and therapeutic target in human kidney disease.

Summary Objective The potential association between healthcare workers (HCWs) and the risk of clinically active tuberculosis (TB) in countries with intermediate TB burdens remains unclear. Methods A nationwide, population-based cohort study was performed by using Taiwan National Health Insurance Database during 2000–2010. We included HCWs and non-HCWs without history of tuberculosis matched at a 1:1 ratio according to age, sex, monthly income, underlying comorbidities, and concomitant medications. All subjects were followed from the date of enrollment until TB occurrence, death, or 31 December 2010. Results The study population comprised 11,811 healthcare workers and 11,811 matched subjects. 62 HCWs and 38 control subjects developed TB during a median follow-up period of 9.4 years. The incidence of TB was higher among HCWs than among matched subjects (61.08 vs . 37.81 per 100,000 person-years). The risk of TB was also greater among HCWs (adjusted hazard ratio [aHR], 1.62; 95% confidence interval [CI], 1.08–2.43), particularly for pulmonary TB in comparison with extrapulmonary TB (aHR, 1.56; 95% CI, 1.02–2.39). Among different job categories of HCWs, we found that only nurses had a significantly increased risk of developing TB (aHR, 2.55; 95% CI, 1.37–4.72) compared to the matched cohort. Conclusions HCWs are associated independently with a higher risk of developing TB in this intermediate-burden country. Therefore, the importance of TB surveillance among HCWs should be emphasized.

Diabetic nephropathy is characterized by excessive deposition of extracellular matrix protein and disruption of the glomerular filtration barrier. Matrix metalloproteinases (MMPs) affect the breakdown and turnover of extracellular matrix protein, suggesting that altered expression of MMPs may contribute to diabetic nephropathy. Here we used an MMP-9 gene knockout mouse model, with in vitro experiments and clinical samples, to determine the possible role of MMP-9 in diabetic nephropathy. After 6 months of streptozotocin-induced diabetes, mice developed markedly increased albuminuria, glomerular and kidney hypertrophy, and thickening of the glomerular basement membrane. Gelatin zymographic analysis and western blotting showed that there was enhanced MMP-9 protein production and activity in the glomeruli. However, MMP-9 knockout in diabetic mice significantly attenuated these nephropathy changes. In cultured podocytes, various cytokines related to diabetic nephropathy including TGF-β1, TNF-α, and VEGF stimulated MMP-9 secretion. Overexpression of endogenous MMP-9 induced podocyte dedifferentiation. MMP-9 also interrupted podocyte cell integrity, promoted podocyte monolayer permeability to albumin, and extracellular matrix protein synthesis. In diabetic patients, the upregulation of urinary MMP-9 concentrations occurred earlier than the onset of microalbuminuria. Thus, MMP-9 seems to play a role in the development of diabetic nephropathy.Kidney International advance online publication, 26 March 2014; doi:10.1038/ki.2014.67.

Background. Hyperuricemia is associated with the development of new cardiovascular events and chronic allograft nephropathy in patients with decreased allograft function. This study investigates whether hyperuricemia in kidney transplant recipients should be considered as an independent predictor of kidney disease progression after acute allograft dysfunction. Methods. Between September 1, 2010, and December 31, 2012, 124 patients who underwent kidney graft biopsy for acute allograft dysfunction were enrolled. Participants were divided into 2 groups: A hyperuricemic group (n ¼ 57) and a normouricemic group (n ¼ 67). The mean serum uric acid (UA) level was obtained by averaging all measurements, once per month for 3 months, before the study began. Clinical and laboratory data were collected. We investigated the role of hyperuricemia on the composite end point (CEP) of doubling of serum creatinine and graft failure by using Cox regression and Kaplan-Meier plots. Results. Over a mean follow-up of 14.27 months, the hyperuricemic group had a poor cumulative survival and easily reached the CEP of doubling of serum creatinine and graft failure (P ¼ .025) with a first-year cumulative incidence of 29.84% and a secondyear cumulative incidence of 35.09%. Cox regression models revealed that age at biopsy (unadjusted hazard ratio [HR], 1.03; 95% CI, 1.00e1.06), hyperuricemia (HR, 2.24; 95% CI, 1.13e4.46), and interstitial fibrosis and tubular atrophy (IF/TA), including

Hyperuricemia may be associated with the development of new cardiovascular events and graft loss in renal transplant recipients. This study was conducted to clarify whether hyperuricemia is a persistently independent predictor of long-term graft survival and patient outcome.Renal allograft recipients (n = 880) who underwent transplantation from December 1999 to March 2013 were included. Participants were divided into 2 groups: a hyperuricemic group (n = 389) and a normouricemic group (n = 491). The mean serum uric acid (UA) level was obtained by averaging all measurements, once per month for 3 months, before the study began. Clinical and laboratory data were collected. We investigated the role of hyperuricemia in the primary endpoint of graft failure by using time-varying analysis and Kaplan-Meier plots. All-cause mortality in renal transplant recipients was also surveyed.During a mean follow-up of 43.3 ± 26.3 months, the major predisposing factors in the 389 patients with hyperuricemia were male predominance (62.98%), high entry serum UA (7.70; range 6.70-8.80 mg/dL), more hypertension (92.29%), previous hemodialysis mode (29.56%), hepatitis C infection (24.42%), more frequent use of UA-lowering agents (43.44%), and use of more drugs for inducing high serum UA (17.74%). After 12 months, the hyperuricemic group had persistently high serum UA (7.66 ± 2.00 vs 6.17 ± 1.60 mg/dL, P.001) and poor renal function (serum creatinine 2.96 ± 3.20 vs 1.61 ± 1.96 mg/dL, P.001) compared with the normouricemic group. Survival analysis showed the hyperuricemic group had poorer graft survival (60.47%) than the normouricemic group (75.82%, P = .0069) after 13-year follow-up. However, there was no difference in all-cause mortality between the 2 groups.Persistently high serum UA seems to be implicated in elevation of serum creatinine, which could increase the risk for allograft dysfunction.

Optimal treatment algorithms for erythropoiesis-stimulating agent (ESA) and iron therapy in anemic CKD patients are lacking. Kuragano et al. evaluated hemodialysis patients over two years and report increased mortality risk and/or adverse events in those with high serum ferritin levels and high ferritin fluctuations, and an increase in adverse events in iron users. Clinical practice should avoid disproportionately high ESA or iron doses to achieve hemoglobin targets, particularly in those with significant comorbidity or ESA resistance.

TNFRSF6B overexpression in tumors is a novel predictor for poor prognosis in various cancers; however, whether TNFRSF6B could be expressed in kidney tissues of patients with chronic kidney disease is unknown. Current established risk factors cannot fully predict the progression of chronic kidney disease, and, therefore, it is mandatory to develop a newer marker for predicting disease progression. We conducted a prospective cohort study comprised 167 patients with chronic kidney disease undergoing renal biopsy at a tertiary hospital with median follow-up of 30.5 months. Computer-assisted quantitative immunohistochemical staining analysis of TNFRSF6B in kidney tissues, the expression of α-smooth muscle actin and percentage of fibrosis in renal interstitium, estimated glomerular filtration rate, and urinary protein excretion rate were investigated. Study endpoint was a doubling of serum creatinine and/or end-stage renal failure requiring renal replacement therapy. We found that TNFRSF6B was predominantly expressed in the tubular epithelial cells of renal cortex. The higher the expression of TNFRSF6B, the more the expression of α-smooth muscle actin and fibrosis in interstitium (P

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.

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.

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.

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.

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.

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: 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

Patients with end-stage renal disease undergoing regular dialysis are prone to encephalopathy, but the cause is often unclear. Dialysis patients are at risk for thiamine deficiency, which may mimic many uremic complications, including encephalopathy. To determine whether unexplained encephalopathy in regular dialysis patients is associated with thiamine deficiency, we conducted a prospective study that enrolled 30 consecutive dialysis patients with altered mental status admitted to a referred hospital during a 1-year period. A complete history, physical and neurological examinations, laboratory investigations, and computed tomographic scans or magnetic resonance imaging of the brain were obtained for each subject. In 10 of the 30 patients, diagnoses remained obscure after the initial workup. Manifestations included confusion, chorea, acute visual loss, rapidly progressive dementia, myoclonus, convulsions, and coma. Intravenous thiamine was administered to these 10 patients. All 10 patients had thiamine deficiency confirmed by a marked response to thiamine supplementation and/or a low serum thiamine concentration (35.3 +/- 6.0 nmol/L; normal, >50 nmol/L). Nine patients recovered, but one patient failed to respond because of delayed treatment. We conclude that in regular dialysis patients, unexplained encephalopathy can be mainly attributed to thiamine deficiency. This condition is fatal if unrecognized and can be successfully treated with prompt thiamine replacement.

Krüppel-like factor 4 (KLF4) exerts tumor suppressive or oncogenic functions in a cell-type-dependent manner, but its prognostic role in urothelial carcinoma of bladder (UCB) remains unclear. We aimed to determine how KLF4 regulates epithelial-mesenchymal transition (EMT) and predicts patient survival in UCB.The roles of KLF4 and other EMT regulators in cancer progression were studied in UCB specimens of 398 patients, UCB cell lines. The results were validated by open-access The Cancer Genome Atlas dataset.Over a median follow-up of 46.5 months, tissue microarray demonstrated that strong KLF4 expression was associated with higher risk toward metastasis and death (P0.001). KLF4 expression positively correlated with TWIST1 and vimentin, and inversely correlated with E-cadherin expression. Metastasis-free survival was poorest in KLF4/TWIST1 coexpression group, followed by KLF4 or TWIST1 expression-alone group, and no-expression group (P0.001). Multivariate analysis substantiated that KLF4/TWIST1 coexpression independently predicted overall mortality and metastasis risk with hazard ratios of 2.43 (95% CI: 1.65-3.64) and 7.54 (CI: 4.03-12.10). The Cancer Genome Atlas dataset of bladder cancer also revealed a trend toward decreased overall survival in the high KLF4 expression group as compared to the low KLF4 group. In vitro, KLF4 is accompanied with decreased E-cadherin and β-catenin expressions, increased vimentin and fibronectin expressions, and enhanced migration/invasion. KLF4 knockdown suppressed TWIST1 expression and inhibited EMT, migration and invasion, whereas enforced KLF4 overexpression activated TWIST1 expression and restored EMT and metastatic phenotype. Furthermore, TWIST1 knockdown abolished KLF4-faciliated EMT and metastatic feature without affecting KLF4 expression.KLF4 promotes TWIST1-mediated EMT and may represent a novel prognostic predictor in UCB.

Effect of vitamin E-bonded membrane on the 8-hydroxy 2′-deoxyguanosine level in leukocyte DNA of hemodialysis patients.Background8-Hydroxy 2′-deoxyguanosine (8-OHdG) of leukocyte DNA has been identified as a surrogate marker of oxidative stress in chronic hemodialysis (HD) patients. In this study, we focused on the determinants of the 8-OHdG level in leukocyte DNA of HD patients. We further investigated the influence of vitamin E-modified, regenerated cellulose (CL-E) membrane on the oxidative DNA damage, intracellular reactive oxygen species (ROS) production of granulocytes, and plasma α-tocopherol concentration.Methods8-OHdG content in cellular DNA of leukocytes was measured by a high-performance liquid chromatography-electrochemical detection (HPLC-ECD) method. Intracellular production of ROS, H2O2 and O2-· were analyzed by flow cytometry in leukocytes with and without phorbol-12-myristate-13-acetate (PMA) stimulation before dialysis, as well as at 15 and 30 minutes of dialysis. Plasma α-tocopherol concentration was measured by a HPLC method, and the value of α-tocopherol was corrected by total blood lipid concentration.ResultsIn the prospective cross sectional study, the mean 8-OHdG level in leukocyte DNA was equally lower in the patients of the CL-E, polymethylmethacrylate (PMMA), and polysulfone (PS) groups as compared with the cellulosic group (ANOVA, P < 0.001). The leukocyte 8-OHdG level correlated negatively with plasma α-tocopherol and blood lipid-adjusted plasma α-tocopherol, but correlated positively with serum iron and percentage of transferrin saturation. Forward stepwise multiple regression showed that dialysis membrane type, serum iron, and blood lipid-adjusted plasma α-tocopherol were the independent determinants of the leukocyte 8-OHdG level in HD patients. Like synthetic membranes, granulocyte ROS production was less augmented during dialysis with the CL-E membrane as compared with the cellulose membrane. Exposure to cellulose membrane impaired intracellular ROS production of granulocytes in response to PMA challenge, whereas the CL-E and synthetic membranes improved the granulocyte responsiveness to PMA. In the longitudinal cross-over study, the 8-OHdG level significantly decreased, and blood lipid-adjusted plasma α-tocopherol increased after switching the cellulose membrane to CL-E or synthetic membrane for eight weeks. In contrast, the 8-OHdG level dramatically rose, and blood lipid-adjusted plasma α-tocopherol declined after shift of CL-E or synthetic membrane to the cellulose membrane.ConclusionsCL-E membrane exhibited biocompatible and bioactive characteristics. Like synthetic membranes, treatment with a CL-E dialyzer effectively reduced the 8-OHdG content in leukocyte DNA, suppressed intracellular ROS production of granulocytes, and preserved the plasma level of vitamin E. It could further improve granulocyte responsiveness to a PMA challenge. Reduced DNA damage and improved immune function of leukocytes may reduce the cancer and infection risks in chronic HD patients.

Intravenous ascorbic acid as an adjuvant therapy for recombinant erythropoietin in hemodialysis patients with hyperferritinemia.BackgroundInadequate iron mobilization and defective iron utilization may cause recombinant erythropoietin (rEPO) hyporesponsiveness in hemodialysis (HD) patients with iron overload. We have demonstrated that intravenous ascorbic acid (IVAA), but not intravenous iron medication, can effectively circumvent the functional iron-deficient erythropoiesis associated with iron overload in HD patients. However, it is uncertain whether all HD patients with hyperferritinemia will consistently respond to IVAA and which index may indicate functional iron deficiency in the special entity. Therefore, a prospective study was conducted to establish the guidelines for IVAA adjuvant therapy.MethodsSixty-five HD patients with serum ferritin levels of more than 500 μg/liter were recruited and divided into the control (N = 19) and IVAA (N = 46) groups. IVAA patients with a hematocrit (Hct) of less than 30% received 300mg of ascorbic acid three times per week for eight weeks. Controls had a Hct of more than 30% and did not receive the adjuvant therapy. Red blood cell and reticulocyte counts, iron metabolism indices, erythrocyte zinc protoporphyrin (E-ZPP), and the concentrations of plasma ascorbate and oxalate were examined before and following the therapy.ResultsThirteen patients (four controls and nine IVAA patients) withdrew by the end of the study. Eighteen patients had a dramatic response to IVAA with a significant increase in their hemoglobin and reticulocyte index and a concomitant 24% reduction in rEPO dose after eight weeks. This paralleled a significant rise in serum iron and transferrin saturation (TS) and a fall in E-ZPP and serum ferritin (baselines vs. 8weeks, serum iron 68 ± 37 vs. 124 ± 64 μg/dl, TS 27 ± 10 vs. 48 ± 19%, E-ZPP 123 ± 44 vs. 70 ± 13 μmol/mol heme, and serum ferritin 816 ± 435 vs. 587 ± 323 μg/liter, P < 0.05). Compared with responders, mean values of hemoglobin, rEPO dose, iron metabolism parameters, and E-ZPP showed no significant changes in controls (N = 15) and in non-responders (N = 19). Thirty-seven patients (18 responders and 19 non-responders) were further analyzed by receiver operating characteristic curves to seek the criteria for prediction of a response to IVAA treatment. The results showed that E-ZPP at a cut-off level of more than 105 μmol/mol heme and TS at a level of less than 25% were more specific to confirm the status of functional iron deficiency in iron-overloaded patients. The two criterion values had the highest accuracy to predict a response to treatment.ConclusionsFunctional iron-deficient erythropoiesis plays a role in rEPO-hyporesponsive anemia in HD patients with hyperferritinemia. IVAA may be an adjuvant therapy for rEPO in these patients, and E-ZPP of more than 105 μmol/mol heme and TS of less than 25% should be used to guide the IVAA treatment.

Erythropoietin hyporesponsiveness: From iron deficiency to iron overload. Iron deficiency is the most frequently encountered cause of suboptimal response to recombinant human erythropoietin (rHuEPO). Carefully assessing iron status is of paramount importance in chronic renal failure patients prior to or during rHuEPO therapy. Because there is great need for iron in the EPO-stimulated erythroid progenitors, it is essential that serum ferritin and transferrin saturation levels should be maintained over 300 μg/liter and 30%, respectively. Investigators have shown that oral iron is unlikely to keep pace with the iron demand for an optimal rHuEPO response in uremics. Therefore, patients with iron deficiency will always require intravenous iron therapy. The early and prompt iron supplementation can lead to reductions in rHuEPO dose and hence cost. After the iron deficiency has been corrected or excluded, we must remember all of the possible causes of hyporespon-siveness in every rHuEPO-treated patient. As dose requirements vary, it is not clear which dose of rHuEPO causes this hyporesponsiveness. However, if the patient with iron repletion does not respond well after the induction period, the major causes blunting the response to rHuEPO should be investigated. Most factors are reversible and remediable, except resistant anemia associated with hemoglobinopathy or bone marrow fibrosis, which requires a further increase in the rHuEPO dose. By means of early detection and correction of the possible causes, the goal of increasing therapeutic efficacy can be achieved. Iron overload may lead to an enhanced risk for infection, cardiovascular complication, and cancer. Over-treatment with iron should be avoided in dialysis patients, despite the fact that the safe upper limit of serum ferritin to avoid iron overload is not clearly defined. On the other hand, functional iron deficiency may develop even when serum ferritin levels are increased. Controversy remains as to whether intravenous iron therapy can overcome this form of hyporesponsiveness in iron-overloaded patients. Moreover, a treatment option of iron supplementation is not warranted in these patients, as the potential hazards of iron overload will be worsened. We demonstrated that the mean hematocrit significantly increased from 25.1 ± 0.9% to 31 ± 1.2% after eight weeks of intravenous ascorbate therapy (300 mg three times a week) in 12 hemodialysis patients with serum ferritin levels of more than 500 μg/liter. The enhanced erythropoiesis paralleled with a rise in transferrin saturation (27.8 ± 2.5% vs. 44.8 ± 9.5%, P < 0.05) and reductions in erythrocyte zinc protoporphyrin (130 ± 32 vs. 72 ± 19 mmol/mol heme, P < 0.05) and monthly rHuEPO dose (24.2 ± 4.5 vs. 16.8 ± 3.4 3 103units, P < 0.05) at the end of study. It is speculated that ascorbate supplementation not only facilitates the iron release from storage sites and its delivery to hematopoietic tissues, but also increases iron utilization in ery-throid cells. Our study provides a more complete understanding of the pathogenesis of iron overload-related anemia and the development of an adjuvant therapy, intravenous ascorbic acid, to the existing treatments.

Jugular venous cannulation is generally safer than subclavian cannulation. The traumatic complications associated with jugular vein hemodialysis catheters are rare. A jugular vein, therefore, has become the preferred site for hemodialysis catheter insertion. We describe the first case of brachial plexus compression attributable to delayed recognition of a right subclavian pseudoaneurysm as a complication of jugular venous cannulation of hemodialysis catheter. We advocate that any neck swelling, new bruit, and the symptoms of brachial plexopathy after jugular venous cannulation warrant an intensive investigation to exclude arterial injury. Because delayed diagnosis may lead to a worsened prognosis in patients with brachial plexus palsy, physicians should exercise vigilance to detect and manage early the potentially serious and fatal complications of subclavian artery pseudoaneurysm and brachial nerve injury.

Taiwan had the highest prevalence of end-stage renal disease (ESRD) for more than a decade, and the incidence, although ranked first prior to 2009, has fallen behind that of the USA recently. Older people constitute about half of incident dialysis patients in Taiwan. A large Taiwanese cohort study showed that the prevalence of chronic kidney disease (CKD) is high (11.9%) in adults, and the prevalence is even higher (37.2%) among the elderly. Using the health insurance dataset, old age has been proved to be a significant risk factor of developing CKD, especially in rural areas where there is a larger proportion of older people and have a higher incidence of ESRD in Taiwan. It is known that glomerular filtration rate (GFR) decreases in parallel with age, accompanied by both structural and physiological changes, including a loss of renal mass, reduced renal blood flow, and impairment of autoregulation, sodium and potassium handling, as well as diluting and concentrating ability. The diminished renal reserve in the elderly results in the vulnerability of the kidney to various insults. Delayed diagnosis of kidney disease in the elderly potentially inflicts further damage and

bacteremia. Aft er removal of the permanent catheter and 6 weeks of vancomycin treatment, a polytetrafl uoroeth-ylene arteriovenous graft from the distal brachial artery just proximal to the antecubital fossa to the axillary vein over the right upper arm was placed (Figure 1a). However, during the week following surgery, she complained of an increasingly pain-ful, cold, and discolored right hand. On examination, a good bruit in the graft was noted, but the hand was cold and cyanotic with absent radial and ulnar pulses. Th e involved area extended from the right index fi nger to the thumb with dry gangrene over the index fi nger (Figure 1b). Brachial artery steal related to the graft was suspected and confi rmed by Doppler ultrasonogra-phy, which demonstrated decreased blood fl ow with a reversal during early diastole (Figure 2a) at the brachial artery distal to the arterial anastomosis, and a prominent increase in antegrade peak fl ow during systole aft er the graft was externally compressed (Figure 2b). In addition, segmental stenoses of the right radial and ulnar arteries were found. Because of worsening ischemic injury, the patient underwent surgical amputation of her right forearm below the elbow. Th e graft was preserved without liga-tion on account of generalized poor vascular condition for crea-tion of any new access. Vascular steal related to arteriovenous bridge graft in this case was probably due to peripheral vascular disease from diabetes, a large bridge graft , and inadequate col-lateral fl ow to maintain distal tissue perfusion.

Hypercalcemia occurs frequently after renal transplantation. Preexisting hyperparathyroidism is the most common cause of post-transplantation hypercalcemia. We describe a renal transplant recipient infected with Pneumocystis carinii pneumonia (PCP) who developed hypercalcemia, elevated 1,25-dihydroxyvitamin D, and suppressed parathyroid hormone levels. This phenomenon mimics the extrarenal production of 1,25-dihydroxyvitamin D by activated alveolar macrophages in granulomatous diseases with hypercalcemia. To the best of our knowledge, this is the first report of 1,25-dihydroxyvitamin D-mediated hypercalcemia caused by PCP in a renal transplant recipient. This entity should be included in the differential diagnosis for renal transplant recipients with hypercalcemia, especially in patients who develop lung infections.