AST-120 improved uremic pruritus by lowering indoxyl sulfate and inflammatory cytokines in hemodialysis patients.

BACKGROUND AND HYPOTHESIS: Pruritus is a common and distressing symptom that affects patients with chronic kidney disease. The concentration of protein bounded uremic toxin was associated with the uremic pruritus. The aim is to assess the efficacy of AST-120 for uremic pruritus in hemodialysis patients. MATERIALS AND METHODS: The participants were enrolled and then divided into the AST-120 treatment group and control group with a ratio of 2:1. All participants underwent pre-observation screenings two weeks before the study with three visits. In the treatment phase (week 1 to week 4), the treatment group added 6g/day of AST-120 along with routine anti-pruritic treatment. Visual analog scale (VAS) and biochemical parameters were measured. RESULTS: The VAS score began to be lower in the AST-120 treatment group after the 5th visiting (p < 0.05). The reduction in indoxyl sulfate (IS) at 5th week along with TNF-alpha. The reduction ratio of indoxyl sulfate correlated with reduction of parathyroid hormone. CONCLUSION: This study has demonstrated that the four-week treatment of AST-120 decreased the severity of uremic pruritus in patients with ESRD. The concentration of IS and TNF-alpha decreased in the AST-120 treatment group. The reduction of iPTH correlated with the reduction of IS in the AST-120 treatment.

Intravitreal ranibizumab injection is associated with an increased risk of chronic kidney disease: a population-based study in Taiwan.

Systemic vascular endothelial growth factor (VEGF) blockade has been the top adjunctive chemotherapy since 1990. Anti-VEGF therapy has also been associated with worsened renal function in some patients. However, the association between patient outcomes and use of intravitreal VEGF inhibitors remains controversial. Thus, it is necessary to determine the action mechanism and long-term renal effects of ranibizumab. The National Health Insurance Research Database (NHIRD) is one of the largest global databases that are extensively used for epidemiological research. NHIRD contains the medical information of all insureds, such as inpatient, outpatient, emergency, and traditional Chinese medicine records. We selected subjects aged ≥ 20 years who recently administered ranibizumab for the ranibizumab cohort. Non-ranibizumab cohort consisted of subjects who did not receive ranibizumab, and the index date was a random date between 2008 and 2018. We excluded subjects with missing sex and age records and those in which the date of primary outcome was before the index date. The two cohorts were matched via 1:1 propensity score matching based on sex, age, index year, hypertension, diabetes mellitus, hyperlipidemia, stroke, coronary artery disease, alcoholism, chronic obstructive pulmonary disease, and age-related macular degeneration, retinal vein occlusion, and diabetic macular edema. Medical confounders were angiotensin I-converting enzyme inhibitors, statins, corticosteroids, VEGF inhibitors including bevacizumab and aflibercept, lithium, amphotericin B, adefovir, NSAIDS, cisplatin, and calcineurin inhibitors. Among 48,248 participants aged ≥ 20 years, 24,136 (50%) received ranibizumab (13,565 male [56.20%] and 10,571 female [43.80%]). Moreover, 24,136 participants who did not receive ranibizumab were matched by age, sex, comorbidities, and medications. Subjects who received ranibizumab exhibited a significantly higher risk of CKD than those who did not receive ranibizumab (adjusted hazard ratio = 1.88, 95% CI = 1.79-1.96). Our findings revealed that exposure to intravitreal ranibizumab is an independent risk factor for CKD. Therefore, physicians and ophthalmologists should make the patients aware of such a correlation to increase patient safety and decrease the CKD burden.

Serum lipopolysaccharide-binding protein levels and cardiovascular events in hemodialysis patients: A prospective cohort study.

INTRODUCTION: Patients with end-stage kidney disease (ESKD) exhibit an elevated cardiovascular risk. Chronic inflammation is one of the main mechanisms of cardiovascular disease (CVD). Lipopolysaccharide has been proposed as a link between systemic inflammation and CVD. Herein, we evaluated whether lipopolysaccharide-binding protein (LBP), a surrogate marker of lipopolysaccharide and consequent inflammation, is associated with cardiovascular events in ESKD. METHODS: We performed a prospective cohort study of maintenance haemodialysis patients. Baseline serum LBP levels were categorized into tertiles and also modelled continuously for analyses. Cox regression methods were used to evaluate the association of serum LBP levels with cardiovascular events. RESULTS: A total of 360 haemodialysis patients were included in this analysis. During a median follow-up of 3.1 years, 90 (25.0%) patients had cardiovascular events. Patients in the upper tertile of serum LBP levels had a significantly greater risk of cardiovascular events [hazard ratio (HR) 4.87; 95% confidence intervals (CI), 2.12-11.15] than those in the lower tertile, independent of age, sex, hypertension, diabetes, CVD, dialysis vintage, body mass index, non-high-density lipoprotein cholesterol, albumin, phosphorus, high-sensitivity C-reactive protein, and interleukin-6. The association was consistent regardless of whether competing risk of death was accounted for (subdistribution HR 4.87; 95% CI, 1.96-12.11 for upper versus lower tertiles) or serum LBP was analysed as a continuous variable (HR 1.30; 95% CI, 1.02-1.66 per 1 SD increment). CONCLUSIONS: Serum LBP levels were independently associated with cardiovascular events in heomodialysis patients. LBP might serve as a novel biomarker for CVD in ESKD.

Association between atrial fibrillation and risk of end-stage renal disease among adults with diabetes mellitus.

Diabetes mellitus (DM) is an important risk factor in patients with end-stage renal disease (ESRD). DM is associated with the development of cardiovascular diseases, such as atrial fibrillation (AF), due to poor glycemic control. However, few studies have focused on the risk of developing ESRD among DM patients with and without AF. This study evaluated ESRD risk among DM patients with and without AF in Taiwan. Data were retrieved from one million patients randomly sampled from Taiwan's National Health Insurance Research Database, including 6,105 DM patients with AF propensity score-matched with 6,105 DM patients without AF. Both groups were followed until death, any dialysis treatment, or December 31, 2013, whichever occurred first. AF was diagnosed by a qualified physician according to the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM), using the diagnostic code 427.31. Patients aged <20 years or diagnosed with ESRD before the index date were excluded. A Cox proportional hazard regression model was used to calculate the relative ESRD risk. Among DM patients, those with AF have more comorbidities than those without AF. We also found a 1.18-fold (95% confidence interval [CI]: 1.01-1.46) increase in ESRD risk among patients with AF compared with those without AF. In addition, DM patients with hypertension, chronic kidney disease (CKD), or higher Charlson Comorbidity Index scores also have significantly increased ESRD risks than those without these complications. A 1.39-fold (95% CI: 1.04-1.86) increase in risk was observed for patients with AF among the non-CKD group. Our findings suggest that patients with DM should be closely monitored for irregular or rapid heart rates.

The association between EKG abnormalities and the development of microalbuminuria in type 2 diabetes.

ABSTRACT: Microalbuminuria is associated with both with chronic kidney disease and various cardiovascular abnormalities. Given the common use of electrocardiograms (EKGs) in diagnosing cardiovascular dysfunction, this study is analyzing the relationship between EKG abnormalities and diabetic nephropathy in type 2 diabetes mellitus (DM) patients. The enrollments of this study were from the 10-year follow-up data (2003-2012) of the Diabetes Management through an Integrated Delivery System project. All study subjects underwent at least 1 EKG measurement. The urinary microalbuminuria was recorded annually. The logistic regression model was used to evaluate the association between EKG abnormalities and the occurrence of diabetic nephropathy in type 2 DM patients. The total of 1189 patients with type 2 DM are included in this study and a total of 552 patients had microalbuminuria during a 10-year follow-up. A significantly higher odds ratio of microalbuminuria occurrence (4.85) was found in the patients with premature supraventricular contraction or tachycardia compared to those without EKG abnormalities. The odds ratios of microalbuminuria occurrence were 1.00, 2.43, 2.64, and 2.98, respectively, for patients with insulin resistance in the Q (quartile) 1(as the reference), Q2, Q3, and Q4, respectively. Our findings can serve as a reference for the association between EKG abnormalities and the development of microalbuminuria in type 2 diabetes.

Worldwide Epidemiology of Diabetes-Related End-Stage Renal Disease, 2000-2015.

OBJECTIVE: The annual risk among patients with diabetes of reaching end-stage renal disease (ESRD) is largely unknown worldwide. This study aimed to compare the incidence of diabetes-related ESRD by creating a global atlas during 2000-2015. RESEARCH DESIGN AND METHODS: The annual incidence of ESRD among patients with diabetes was calculated as the quotient of the number of incident ESRD patients with diabetes divided by the total number of patients with diabetes after subtraction of the number with existing ESRD. The estimated ESRD prevalence and annual incidence were validated with use of the data provided by Fresenius Medical Care, Germany, and previously reported data, respectively. RESULTS: Data were obtained from 142 countries, covering 97.3% of the world population. The global percentage of the prevalent ESRD patients with diabetes increased from 19.0% in 2000 to 29.7% in 2015 worldwide, while the percentage of incident ESRD patients due to diabetes increased from 22.1% to 31.3%. The global annual incidence of ESRD among patients with diabetes increased from 375.8 to 1,016.0/million with diabetes during 2000-2015. The highest average rates were observed in the Western Pacific Region. Comparatively, the rates of incident ESRD among European patients with diabetes ranged from one-half (309.2 vs. 544.6) to one-third (419.4 vs. 1,245.2) of the rates of the Western Pacific population during 2000-2015. CONCLUSIONS: Great and nonrandom geographic variation in the annual rates among patients with diabetes of reaching ESRD suggests that distinct health care, environmental, and/or genetic factors contribute to the progression of diabetic kidney disease. Measures to prevent and treat diabetes-related ESRD require better patient susceptibility stratification.

The Efficacy of Lactobacillus-Containing Probiotic Supplementation in Hemodialysis Patients: A Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVES: This study was performed to determine the effects of probiotic supplementation on cholesterol-triglyceride ratio, an indirect marker of insulin resistance, protein-bound uremic toxins, biomarkers of inflammation, and microbial translocation in end-stage renal disease patients on hemodialysis. METHODS: Fifty-six patients aged 39-75 years were assigned into two groups to receive either probiotic sachets (n = 28) or a placebo (n = 28) in a randomized double-blinded placebo-controlled clinical trial. The patients in the probiotic group received twice daily sachets that contained a mixture of three viable and freeze-dried strains: Lactococcus lactis subsp. Lactis LL358, Lactobaccillus salivarius LS159, and Lactobaccillus pentosus LPE588 at high dose (100 billion; 1 × 1011 cfu/day) for 6 months. RESULTS: A total of 50 patients were available for final analysis. Probiotic supplementation did not have a significant influence on cholesterol-triglyceride ratio. Probiotic supplementation for 6 months caused a significant decrease in serum levels of indoxyl sulfate. Compared with the placebo, probiotic supplementation did not result in significant changes in hemoglobin levels, blood urea nitrogen, blood glucose, serum p-cresyl sulfate, inflammatory, and microbial translocation markers. No clinically significant changes in body composition were observed between the two groups during the study period. The probiotic supplementation was well tolerated by all subjects with minimal adverse effects during the 6-month-long study. CONCLUSION: Our results suggest that high-dose multistrain lactobaccillus probiotic supplementation over 6 months as a monotherapy did not significantly decrease markers of insulin resistance, cholesterol-triglyceride ratio, and most of the studied markers, with the exception of levels of indoxyl sulfate in patients on HD.

Choices in hemodialysis therapies: variants, personalized therapy and application of evidence-based medicine.

The extent of removal of the uremic toxins in hemodialysis (HD) therapies depends primarily on the dialysis membrane characteristics and the solute transport mechanisms involved. While designation of 'flux' of membranes as well toxicity of compounds that need to be targeted for removal remain unresolved issues, the relative role, efficiency and utilization of solute removal principles to optimize HD treatment are better delineated. Through the combination and intensity of diffusive and convective removal forces, levels of concentrations of a broad spectrum of uremic toxins can be lowered significantly and successfully. Extended clinical experience as well as data from several clinical trials attest to the benefits of convection-based HD treatment modalities. However, the mode of delivery of HD can further enhance the effectiveness of therapies. Other than treatment time, frequency and location that offer clinical benefits and increase patient well-being, treatment- and patient-specific criteria may be tailored for the therapy delivered: electrolytic composition, dialysate buffer and concentration and choice of anticoagulating agent are crucial for dialysis tolerance and efficacy. Evidence-based medicine (EBM) relies on three tenets, i.e. clinical expertise (i.e. doctor), patient-centered values (i.e. patient) and relevant scientific evidence (i.e. science), that have deviated from their initial aim and summarized to scientific evidence, leading to tyranny of randomized controlled trials. One must recognize that practice patterns as shown by Dialysis Outcomes and Practice Patterns Study and personalization of HD care are the main driving force for improving outcomes. Based on a combination of the three pillars of EBM, and particularly on bedside patient-clinician interaction, we summarize what we have learned over the last 6 decades in terms of best practices to improve outcomes in HD patients. Management of initiation of dialysis, vascular access, preservation of kidney function, selection of biocompatible dialysers and use of dialysis fluids of high microbiological purity to restrict inflammation are just some of the approaches where clinical experience is vital in the absence of definitive scientific evidence. Further, HD adequacy needs to be considered as a broad and multitarget approach covering not just the dose of dialysis provided, but meeting individual patient needs (e.g. fluid volume, acid-base, blood pressure, bone disease metabolism control) through regular assessment-and adjustment-of a series of indicators of treatment efficiency. Finally, in whichever way new technologies (i.e. artificial intelligence, connected health) are embraced in the future to improve the delivery of dialysis, the human dimension of the patient-doctor interaction is irreplaceable. Kidney medicine should remain 'an art' and will never be just 'a science'.

Development and validation of a multifrequency bioimpedance spectroscopy equation to predict appendicular skeletal muscle mass in hemodialysis patients.

BACKGROUND & AIMS: The Body Composition Monitor (BCM), a multifrequency bioimpedance spectroscopy device, has been widely used to assess body composition in hemodialysis patients because its measurement is not affected by overhydration commonly seen in chronic kidney disease. We aimed to develop and validate an equation for obtaining appendicular skeletal muscle mass (ASM) from BCM taking dual-energy X-ray absorptiometry (DXA) as the reference among hemodialysis patients. METHODS: A total of 322 consecutive body composition measurements with BCM and DXA in 263 hemodialysis patients were randomly divided at a ratio of 2:1 into development and validation groups. Stepwise multiple regression modeling was applied to develop the ASM prediction equation. We evaluated the model as a diagnostic tool for sarcopenia using cutoffs of ASM defined by the Asian Working Group for Sarcopenia (AWGS). We further explored the association between ASM predicted by the BCM equation and all-cause mortality in two independent cohorts: one with 326 stage 3-5 CKD patients and one with 629 hemodialysis patients. RESULTS: BCM yielded the following equation: ASM (kg) = -1.838 + 0.395 × total body water (L) + 0.105 × body weight (kg) + 1.231 × male sex - 0.026 × age (years) (R2 = 0.914, standard error of estimate = 1.35 kg). In the validation group, Bland-Altman reliability analysis showed no significant bias of 0.098 kg and limits of agreement ±2.440 kg. Using the AWGS criteria, the model was found to have a sensitivity of 94.1%, a specificity of 98.8%, a positive predictive value of 84.2%, and a negative predictive value of 99.6% for the diagnosis of sarcopenia. Low ASM predicted by the BCM equation was associated with significantly worse overall survival among CKD patients but not hemodialysis patients. CONCLUSIONS: The new BCM equation provides a feasible and valid option for assessing ASM in hemodialysis patients.

Resveratrol Rescue Indoxyl Sulfate-Induced Deterioration of Osteoblastogenesis via the Aryl Hydrocarbon Receptor /MAPK Pathway.

Indoxyl sulfate (IS), a uremic toxin derived from dietary tryptophan metabolism by the gut microbiota, is an endogenous aryl hydrocarbon receptor (AhR) agonist and a key player in bone remodeling. Resveratrol (RSV), an AhR antagonist, plays a protective role in shielding against AhR ligands. Our study explored the impact of IS on osteoblast differentiation and examined the possible mechanism of IS in controlling the expression of osteoblastogenesis markers through an in-depth investigation of AhR signaling. In vivo, we found histological architectural disruption of the femoral bones in 5/6 nephrectomies of young adult IS exposed mice, including reduced Runx2 antigen expression. RSV improved the diaphysis architecture, Runx2 expression, and trabecular quality. In vitro data suggest that IS at 500 and 1000 µM disturbed osteoblastogenesis through suppression of the ERK and p38 mitogen-activated protein kinase (MAPK) pathways, which were found to be downstream of AhR. RSV proved to ameliorate the anti-osteoblastogenic effects of IS through the inhibition of AhR and downstream signaling. Taken together, we demonstrated that the IS/AhR/MAPK signaling pathway plays a crucial role in the inhibition of osteoblastogenesis, and RSV has a potential therapeutic role in reversing the IS-induced decline in osteoblast development and suppressing abnormal bone turnover in chronic kidney disease patients.

Concentration and Duration of Indoxyl Sulfate Exposure Affects Osteoclastogenesis by Regulating NFATc1 via Aryl Hydrocarbon Receptor.

Indoxyl sulfate (IS) is a chronic kidney disease (CKD)-specific renal osteodystrophy metabolite that affects the nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a transcription factor promoting osteoclastogenesis. However, the mechanisms underlying the regulation of NFATc1 by IS remain unknown. It is intriguing that the Aryl hydrocarbon receptor (AhR) plays a key role in osteoclastogenesis, since IS is an endogenous AhR agonist. This study investigates the relationship between IS concentration and osteoclast differentiation in Raw 264.7 cells, and examines the effects of different IS concentrations on NFATc1 expression through AhR signaling. Our data suggest that both osteoclastogenesis and NFATc1 are affected by IS through AhR signaling in both dose- and time-dependent manners. Osteoclast differentiation increases with short-term, low-dose IS exposure and decreases with long-term, high-dose IS exposure. Different IS levels switch the role of AhR from that of a ligand-activated transcription factor to that of an E3 ubiquitin ligase. We found that the AhR nuclear translocator may play an important role in the regulation of these dual functions of AhR under IS treatment. Altogether, this study demonstrates that the IS/AhR/NFATc1 signaling axis plays a critical role in osteoclastogenesis, indicating a potential role of AhR in the pathology and abnormality of bone turnover in CKD patients.

Central obesity and incident atherosclerotic cardiovascular disease events in hemodialysis patients.

BACKGROUND AND AIMS: Waist circumference and waist-hip ratio have been shown to predict atherosclerotic cardiovascular disease (ASCVD) in the general population, but the association is less clear in patients with CKD. Both anthropometric measures of central obesity are surrogates for underlying fat and are prone to measurement error. The aim of this study was to investigate the association between central obesity determined by dual-energy X-ray -absorptiometry (DXA) and ASCVD among patients undergoing maintenance hemodialysis. METHODS AND RESULTS: We prospectively analyzed a cohort of 166 prevalent hemodialysis patients (60 ± 12 years of age). Total adiposity (total fat mass) and central adiposity (android and gynoid fat mass) were assessed by using DXA. Central obesity was defined as a sex-specific android to gynoid fat mass ratio (A/G ratio) above the median. The main outcome measure was incident ASCVD events. Patients with central obesity had significantly higher BMI, total fat mass, high-sensitivity C-reactive protein, and triglycerides but significantly lower high-density lipoprotein cholesterol than patients without central obesity. During a median follow-up of 4.3 years, 40 patients had an incident ASCVD event. Patients with central obesity did not display a significantly higher risk of ASCVD in multivariate Cox regression analysis (hazard ratio 1.03, 95% confidence interval 0.54-1.97). A/G ratio, when examined as a continuous variable, was not an independent predictor of ASCVD in either sex. CONCLUSIONS: Hemodialysis patients with central obesity, as measured by the A/G ratio, had less favorable plasma lipid profiles and higher levels of inflammation but not an increased risk of ASCVD.

Serum Lipopolysaccharide-Binding Protein is Associated with Chronic Inflammation and Metabolic Syndrome in Hemodialysis Patients.

BACKGROUND: In hemodialysis (HD) patients, impaired gut barrier and alteration in microbiota in the gut is thought to increase the risk of bacterial translocation and chronic inflammation. Lipopolysaccharide-binding protein (LBP) is an acute-phase reactant that mediates immune responses triggered by microbial products. Our aim is to investigate the relationship between circulating levels of LBP, and various metabolic and inflammatory markers in HD patients. Besides, we also aim to determine its relationship among -patients with different body mass index. PATIENTS AND METHODS: A total of 123 HD patients were stratified into three -tertiles, according to serum LBP level. The LBP and inflammatory markers were determined using immunoassay methods. A bioimpedance spectroscopy device was used for body composition measurement. RESULTS: The serum levels of the two proinflammatory markers, high-sensitivity C-reactive protein (hsCRP) and interleukin (IL)-6, were significantly higher in patients in the upper tertile when compared with the rest of the tertiles. In HD patients, a significant positive correlation was found between serum LBP levels and CRP, IL-6, soluble CD14 (sCD14), and fasting blood glucose levels. Patients with metabolic syndrome and pre-existing cardiovascular disease had higher LBP levels than those without metabolic syndrome. Besides, obese patients were also associated with higher serum LBP levels. Multivariate regression analyses showed that IL-6 level was the strongest correlate of LBP level, followed by hsCRP level and sCD14. CONCLUSIONS: Our study suggested that elevated plasma LBP was associated with metabolic syndrome and obesity. In addition, increased LBP level was correlated positively to markers of inflammation, and sCD14 levels.

Effect of uremic toxin-indoxyl sulfate on the skeletal system.

Chronic kidney disease-mineral bone disorders (CKD-MBD) exhibit abnormalities in the circulating mineral levels, vitamin D metabolism, and parathyroid function that contribute to the formation of a bone lesion. The uremic toxin, indoxyl sulfate (IS), accumulates in the blood in cases of renal failure and leads to bone loss. The bone and renal responses to the action of the parathyroid hormone (PTH) are progressively decreased in CKD in spite of increasing PTH levels, a condition commonly called PTH resistance. There is a high prevalence of low bone turnover or adynamic bone disease in the early stages of CKD. This could be due to the inhibition of bone turnover, such as in PTH resistance, reduced active vitamin D levels, diabetes, aluminum, and, increased IS. With an increase in IS, there is a decrease in the osteoblast Wnt/b-catenin signaling and increase in the expression of Wnt signaling inhibitors, such as sclerostin and Dickkopf-1 (DKK1). Thus, a majority of early CKD patients exhibit deterioration of bone quality owing to the action of IS, this scenario could be termed uremic osteoporosis. However, this mechanism is complicated and not fully understood. With progressive deterioration in the renal function, IS accumulates along with persistent PTH secretion, potentially leading to high-turnover bone disease because high serum PTH levels have the ability of overriding peripheral PTH resistance and other inhibitory factors of bone formation. Finally, it leads to deterioration in bone quantity with prominent bone resorption in end stage renal disease. Uremic toxins adsorbents may decelerate oxidative stress and improve bone health in CKD patients. This review article focuses on IS and bone loss in CKD patients.

Impact of Misclassification of Obesity by Body Mass Index on Mortality in Patients With CKD.

INTRODUCTION: Unlike the general population, a higher body mass index (BMI) is associated with greater survival among patients with chronic kidney disease (CKD). This "obesity paradox" may be due to limitations of BMI as a measure of adiposity in CKD. Both BMI and body fat percentage (BF%) are used to classify obesity, but outcomes may vary. Therefore, we investigated the 2 different cutoffs for diagnosing obesity (BMI ≥28 kg/m2 or BF% >25% for men and >35% for women) and the impact on all-cause mortality in CKD. METHODS: A total of 326 patients with non-dialysis-dependent CKD were prospectively followed for a median of 4.9 years (range 2.9-5.3). BF% and lean body mass were determined using the Body Composition Monitor, a novel multifrequency bioimpedance spectroscopy device. Covariates included age, gender, diabetes, cardiovascular disease, estimated glomerular filtration rate, proteinuria, and high-sensitivity C-reactive protein. RESULTS: Per the BMI definition, 27.9% of patients were obese. However, 48.8% of patients were obese according to the BF% definition. A BMI ≥28 kg/m2 had a moderately high specificity of 83.2% but a low sensitivity of 39.6% for detecting BF%-defined obesity. In the fully adjusted models containing both BMI and BF%, obesity defined by BMI was associated with a significantly lower risk of death (hazard ratio [HR]: 0.23; 95% CI: 0.07-0.71; P = 0.011), whereas the result was reversed when obesity was defined by BF% (HR: 2.75; 95% CI: 1.28-5.89; P = 0.009). When patients were classified into 4 distinct groups based on both the BMI and BF% cutoffs for obesity, a considerable proportion of patients (29.4%) had excess body fat in the context of a normal BMI. These patients were more likely to have lower lean body mass (i.e., sarcopenic obesity) and had higher mortality compared with patients with obesity defined by both BMI and BF% (HR: 5.11; 95% CI: 1.43-18.26; P = 0.012). CONCLUSION: Diagnostic discordance between BMI and BF% may partly explain the obesity paradox. Proper diagnosis of obesity in patients with CKD is required for both risk prediction and treatment.

Normal-weight obesity and clinical outcomes in nondiabetic chronic kidney disease patients: a cohort study.

Background: Normal-weight obesity (NWO), defined by a normal body mass index (BMI) and high body fat percentage, has been shown to be associated with cardiometabolic dysfunction and an increased risk of cardiovascular disease and mortality in the general population. However, little is known about the clinical implications of NWO among patients with chronic kidney disease (CKD). Objective: The aim of this study was to assess the characteristics and outcomes of nondiabetic CKD patients with NWO. Design: A total of 178 nondiabetic patients with stages 3-5 CKD were prospectively followed for a median of 4.9 y. The patients were classified into 3 different adiposity phenotypes: nonobese [BMI (in kg/m2) <25 and fat mass percentage (FM%) ≤25% for men or ≤35% for women], NWO (BMI <25 and FM% >25% for men or >35% for women), and preobese-obese (BMI ≥25). FM% was determined using the Body Composition Monitor, a multifrequency bioimpedance spectroscopy device. The outcome was a composite of cardiovascular events or all-cause mortality. Results: The prevalence of NWO was 28.1% among nondiabetic CKD patients with a normal BMI. NWO patients were older, had lower lean body mass, and had higher plasma interleukin-6 concentrations than nonobese patients. However, homeostatic model assessment for insulin resistance levels did not differ between the 2 groups. NWO patients showed a significant 3-fold higher risk of the composite outcome (HR 2.96, 95% CI: 1.13, 7.77; P < 0.05) than did nonobese patients in the fully adjusted model. Preobese-obese patients were not at increased risk compared to nonobese patients. Conclusions: NWO was associated with the worst prognosis among the 3 different adiposity phenotypes in nondiabetic CKD patients. Our findings suggest the importance of using direct measures of adiposity for risk assessment in CKD patients who are normal-weight. This trial was registered at clinicaltrials.gov as NCT03285074.

Impaired Gut Epithelial Tight Junction Expression in Hemodialysis Patients Complicated with Intradialytic Hypotension.

BACKGROUND: There is accumulating evidence pointing to uremia-induced impairment of the intestinal epithelial barrier structure in advanced chronic kidney disease (CKD) and hemodialysis (HD) patients. In this study, the impact of intradialytic hypotension on intestinal barrier integrity is being explored. METHODS: Immunohistochemical staining was used to detect the expression of 4 types of tight junction (TJ) proteins such as occludin, zonula occludens-1 (ZO-1), claudin-1, and claudin-4, in colonic samples of a group of patients receiving segmental colectomy. Five patients with nondialysis CKD (group 2), 5 HD patients with intradialytic hypotension (group 3), and 5 non-CKD subjects (group 1) were examined. RESULTS: Both patients' groups 2 and 3 demonstrated significantly reduced expression of occludin as compared to group 1 (p < 0.05 and p < 0.01, resp.). Except for claudin-4, expression of all markers of TJ proteins was significantly reduced in patients' group 3 as compared to control (p < 0.01). In addition, decreased expressions of claudin-1 and ZO-1 were also more pronounced in group 3 when compared to group 2. CONCLUSIONS: This study extends the earlier finding by demonstrating that dialysis-related hypotension caused even marked depletion of the key protein constituents of the epithelial TJ.

Precise Quantitative Assessment of the Clinical Performances of Two High-Flux Polysulfone Hemodialyzers in Hemodialysis: Validation of a Blood-Based Simple Kinetic Model Versus Direct Dialysis Quantification.

Highly permeable dialysis membranes with better design filters have contributed to improved solute removal and dialysis efficacy. However, solute membrane permeability needs to be well controlled to avoid increased loss of albumin that is considered to be detrimental for dialysis patients. A novel high-flux dialyzer type (FX CorDiax; Fresenius Medical Care) incorporating an advanced polysulfone membrane modified with nano-controlled spinning technology to enhance the elimination of a broader spectrum of uremic toxins has been released. The aim of this study was to compare in the clinical setting two dialyzer types having the same surface area, the current (FX dialyzer) and the new dialyzer generation (FX CorDiax), with respect to solute removal capacity over a broad spectrum of markers, including assessment of albumin loss based on a direct dialysis quantification method. We performed a crossover study following an A1-B-A2 design involving 10 patients. Phase A1 was 1 week of thrice-weekly bicarbonate hemodialysis with the FX dialyzer, 4 h per treatment; phase B was performed with a similar treatment regimen but with a new FX CorDiax dialyzer and finally the phase A2 was repeated with FX dialyzer as the former phase. Solute removal markers of interest were assessed from blood samples taken before and after treatment and from total spent dialysate collection (direct dialysis quantification) permitting a mass transfer calculation (mg/session into total spent dialysate/ultrafiltrate). On the blood side, there were no significant differences in the solute percent reduction between FX CorDiax 80 and FX 80. On the dialysate side, no difference was observed regarding eliminated mass of different solutes including ß2 -microglobulin (143.1 ± 33.6 vs. 138.3 ± 41.9 mg, P = 0.8), while the solute mass removal of total protein (1.65 ± 0.51 vs. 2.14 ± 0.75 g, P = 0.04), and albumin (0.41 ± 0.21 vs. 1.22 ± 0.51 g, P < 0.001) were significantly less for FX CorDiax 80 compared to the FX 80 dialyzer. The results of this cross-over study indicate that the new FX CorDiax dialyzer has highly effective removal of middle molecules, without any concomitant increase in total protein and albumin loss. The clinical relevance and potential benefit of this finding needs to be determined.

Proportions of Proinflammatory Monocytes Are Important Predictors of Mortality Risk in Hemodialysis Patients.

Despite the continuous progression in dialysis medicine, mortality and the burden of cardiovascular disease (CVD) among hemodialysis patients are still substantial. Substantial evidence suggests that proinflammatory (CD16+) monocytes contribute to the development of atherosclerosis. A cohort of 136 stable hemodialysis patients (follow-up: 6.25 year) was assessed to investigate the association between the proportion of CD16+ monocytes for all-cause and CVD mortalities. The CD16+ monocytes were associated with both mortalities after adjusting for a preexisting CVD history. Compared to the reference group (CD16+ monocytes within [15.6-18.6], the first and second quartile), patients with CD16+ monocytes above the highest quartile level (>21.5) had an adjusted hazard ratio (HR) of 30.85 (95% confidence interval [CI]: 7.12-133.8) for CVD mortality and 5.28 (2.07-13.49) for all-cause mortality, and those with CD16+ monocytes below the lowest quartile ≤15.6), had significantly elevated death risks after 3.5-year follow-up (HR [95% CI]: 10.9 [2.42-48.96] and 4.38 [1.45-13.24] for CV and all-cause mortalities, respectively). The hemodialysis patients with CD16+ monocyte level in a low but mostly covering normal range also portended a poor prognosis. The findings shed some light for nephrologists on future prospects of early recognizing immune dysfunction and improving early intervention outcomes.

A Practical Standardized Composite Nutrition Score Based on Lean Tissue Index: Application in Nutrition Screening and Prediction of Outcome in Hemodialysis Population.

OBJECTIVE: Rapid screening and monitoring of nutritional status is mandatory in hemodialysis population because of the increasingly encountered nutritional problems. Considering the limitations of previous composite nutrition scores applied in this population, we tried to develop a standardized composite nutrition score (SCNS) using low lean tissue index as a marker of protein wasting to facilitate clinical screening and monitoring and to predict outcome. DESIGN AND METHODS: This retrospective cohort used 2 databases of dialysis populations from Taiwan between 2011 and 2014. First database consisting of data from 629 maintenance hemodialysis patients was used to develop the SCNS and the second database containing data from 297 maintenance hemodialysis patients was used to validate this developed score. RESULTS: SCNS containing albumin, creatinine, potassium, and body mass index was developed from the first database using low lean tissue index as a marker of protein wasting. When applying this score in the original database, significantly higher risk of developing protein wasting was found for patients with lower SCNS (odds ratio 1.38 [middle tertile vs highest tertile, P < .0001] and 2.40 [lowest tertile vs middle tertile, P < .0001]). The risk of death was also shown to be higher for patients with lower SCNS (hazard ratio 4.45 [below median level vs above median level, P < .0001]). These results were validated in the second database. CONCLUSION: We developed an SCNS consisting of 4 easily available biochemical parameters. This kind of scoring system can be easily applied in different dialysis facilities for screening and monitoring of protein wasting. The wide application of body composition monitor in dialysis population will also facilitate the development of specific nutrition scoring model for individual facility.