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Background and Aims: Cognitive impairment is a risk factor for death in dialysis patients and the general population. We sought to determine if cognitive impairment is associated with death in people with non-dialysis-dependent chronic kidney disease (CKD), and if so, whether this relationship is greater in the CKD population compared to the general population. Methods: National Health and Nutrition Examination Survey-III participants older than 60 years were asked to subtract 3 from 20 five times and to perform immediate and delayed recall of three items. A cognitive score of 0-11 was assigned based on the number of correct responses. Participants were categorized according to cognitive score (11, 9-10, 6-9, and 0-5) and CKD status. Survival analyses were conducted using Cox models. Results: Within the CKD subpopulation, those in the lowest cognitive score group had a twofold increased hazard of death compared to those with maximum score. Within the non-CKD subpopulation, those in the lowest cognitive score group had a 46% increased hazard of death compared to those with maximum score. However, the difference in the hazards of death in the CKD and non-CKD subpopulations with the lowest cognitive score was not significant (p = 0.99). Conclusions: Low cognitive score is associated with an increased risk of death in elderly individuals with and without CKD; however, there was no interaction of CKD and low cognitive score in this analysis. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Collecting duct (CD) adenylyl cyclase VI (AC6) has been implicated in arginine vasopressin (AVP)- stimulated renal water reabsorption. To evaluate the role of CDderived AC6 in regulating water homeostasis, mice were generated with CD-specific knockout (KO) of AC6 using the Cre/loxP system. CD AC6 KO and controls were studied under normal water intake, chronically water loaded, or water deprived; all of these conditions were repeated in the presence of continuous administration of 1-desamino- 8-D-arginine vasopressin (DDAVP). During normal water intake or after water deprivation, urine osmolality (Uosm) was reduced in CD AC6 KO animals vs. controls. Similarly, Uosm was decreased in CD AC6 KO mice vs. controls after water deprivation+DDAVP administration. Pair-fed (with controls) CD AC6 KO mice also had lower urine osmolality vs. controls. There were no detectable differences between KO and control animals in fluid intake or urine volume under any conditions. CD AC6 KO mice did not have altered plasma AVP levels vs. controls. AVP-stimulated cAMP accumulation was reduced in acutely isolated inner medullary CD (IMCD) from CD A6 KO vs. controls. Medullary aquaporin-2 (AQP2) protein expression was lower in CD AC6 KO mice vs. controls. There were no differences in urinary urea excretion or IMCD UT-A1 expression; however, IMCD UT-A3 expression was reduced in CD AC6 KO mice vs. controls. In summary, AC6 in the CD regulates renal water excretion, most likely through control of AVP-stimulated cAMP accumulation and AQP2. [ABSTRACT FROM AUTHOR]

Chronic kidney disease is considered an inflammatory state and a high fiber intake is associated with decreased inflammation in the general population. Here, we determined whether fiber intake is associated with decreased inflammation and mortality in chronic kidney disease, and whether kidney disease modifies the associations of fiber intake with inflammation and mortality. To do this, we analyzed data from 14,543 participants in the National Health and Nutrition Examination Survey III. The prevalence of chronic kidney disease (estimated glomerular filtration rate less than 60 ml/min per 1.73 m2) was 5.8%. For each 10-g/day increase in total fiber intake, the odds of elevated serum C-reactive protein levels were decreased by 11% and 38% in those without and with kidney disease, respectively. Dietary total fiber intake was not significantly associated with mortality in those without but was inversely related to mortality in those with kidney disease. The relationship of total fiber with inflammation and mortality differed significantly in those with and without kidney disease. Thus, high dietary total fiber intake is associated with lower risk of inflammation and mortality in kidney disease and these associations are stronger in magnitude in those with kidney disease. Interventional trials are needed to establish the effects of fiber intake on inflammation and mortality in kidney disease. [ABSTRACT FROM AUTHOR]

Although there is extensive information about sperm nuclear basic proteins (SNBP) in vertebrates, there is, by comparison, very little information in Arthropoda. This study aims to contribute to filling this gap by analyzing these proteins in the sperm of the noble false widow spider Steatoda nobilis (order Araneae, family Theridiidae). To this end, we have developed a protein extraction method that allows the extraction of both cysteine-containing and non-cysteine-containing protamines that is suitable for the preparation and analysis of SNBPs from samples in which the amount of starting tissue material is limited. We carried out top-down mass spectrometry sequencing and molecular phylogenetic analyses to characterize the protamines of S. nobilis and other spiders. We also used electron microscopy to analyze the chromatin organization of the Steatoda sperm and we found it to exhibit liquid-liquid phase spinodal decomposition during the late stages of spermiogenesis. These experiments further our knowledge on the distribution of SNBPs within the animal kingdom and provide additional support for a proposed evolutionary origin of many protamines from a histone H1 (H5) replication-independent precursor., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Mutations in methyl-CpG binding protein 2 (MeCP2), such as the T158M, P152R, R294X, and R306C mutations, are responsible for most Rett syndrome (RTT) cases. These mutations often result in altered protein expression that appears to correlate with changes in the nuclear size; however, the molecular details of these observations are poorly understood. Using a C2C12 cellular system expressing human MeCP2-E1 isoform as well as mouse models expressing these mutations, we show that T158M and P152R result in a decrease in MeCP2 protein, whereas R306C has a milder variation, and R294X resulted in an overall 2.5 to 3 fold increase. We also explored the potential involvement of the MeCP2 PEST domains in the proteasome-mediated regulation of MeCP2. Finally, we used the R294X mutant to gain further insight into the controversial competition between MeCP2 and histone H1 in the chromatin context. Interestingly, in R294X, MeCP2 E1 and E2 isoforms were differently affected, where the E1 isoform contributes to much of the overall protein increase observed, while E2 decreases by half. The modes of MeCP2 regulation, thus, appear to be differently regulated in the two isoforms., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Consuming excess animal meat may exacerbate kidney disorders, such as urinary stone disease and CKD. Plant-based meat alternatives imitate animal meat and replace animal with vegetable protein, but it is unclear whether eating plant-meat confers similar health benefits as eating whole vegetables. We hypothesized that eating plant-meat when compared with animal meat decreases dietary acid load but increases dietary phosphorus and nitrogen., Methods: The Study With Appetizing Plantfood—Meat Eating Alternatives Trial was a randomized 8-week, crossover trial (NCT03718988) of participants consuming ≥2 servings/d of either plant-meat or animal meat for each 8-week phase. We measured urine sulfate, ammonium, pH, phosphorus, urea nitrogen (UUN), citrate, and creatinine concentrations and serum creatinine and bicarbonate concentrations from stored participant samples from each phase., Results: At a single site, we enrolled 36 generally healthy participants (mean±SD age 50.2±13.8 years, 67% women, and 69% White). Eating the plant-meat diet versus eating the animal meat diet was associated with lower mean concentration of urine sulfate (−6.7 mEq/L; 95% confidence interval [CI], −11.0 to −2.4), urine ammonium (−4.2 mmol/L; 95% CI, −8.2 to −0.1), urine phosphorus (−9.0 mg/dl; 95% CI, −17.5 to −0.5), and UUN (−124.8 mg/dl; 95% CI, −226.9 to −22.6). Eating plant-meat compared with eating animal meat was associated with higher mean urine pH (+0.3 units; 95% CI, 0.2 to 0.5) and mean urine citrate/creatinine ratio (+111.65; 95% CI, 52.69 to 170.60). After participants consumed a plant-meat diet compared with when they consumed an animal meat diet, mean serum creatinine concentration was lower (−0.07 mg/dl, 95% CI, −0.10 to −0.04), whereas mean serum bicarbonate concentration was not different., Conclusions: Eating plant-based meat products, compared with eating animal meat, was associated with lower urinary excretion of sulfate, ammonium, phosphorus, and UUN and higher urinary excretion of citrate. Our findings provide rationale for examining whether plant-based meat will benefit patients with kidney disease., (Copyright © 2024 by the American Society of Nephrology.)

Individuals of Pacific ancestry suffer some of the highest rates of health disparities yet remain vastly underrepresented in genomic research, including currently available linear and pangenome references. To begin addressing this, we developed the first Pacific ancestry pangenome reference using 23 individuals with diverse Pacific ancestry. We assembled 46 haploid genomes from these 23 individuals, resulting in highly accurate and contiguous genome assemblies with an average quality value of 55.0 and an average N50 of 40.7 Mb, marking the first de novo assembly of highly accurate Pacific ancestry genomes. We combined these assemblies to create a pangenome reference, which added 30.6 Mb of novel sequence missing from the Human Pangenome Reference Consortium (HPRC) reference. Mapping short reads to this pangenome reduced variant call errors and yielded more true-positive variants compared to the HPRC and T2T-CHM13 references. This Pacific ancestry pangenome reference serves as a resource to enhance genetic analyses for this underserved population.

While there is extensive information about sperm nuclear basic proteins (SNBP) in vertebrates, there is very little information about Arthropoda by comparison. This paper aims to contribute to filling this gap by analyzing these proteins in the sperm of the noble false widow spider Steatoda nobilis (Order Araneae, Family Theridiidae). To this end, we have developed a protein extraction method that allows the extraction of cysteine-containing protamines suitable for the preparation and analysis of SNBPs from samples where the amount of starting tissue material is limited. We carried out top-down mass spectrometry sequencing and molecular phylogenetic analyses to characterize the protamines of S. nobilis and other spiders. We also used electron microscopy to analyze the chromatin organization of the sperm, and we found it to exhibit liquid-liquid phase spinodal decomposition during the late stages of spermiogenesis. These studies further our knowledge of the distribution of SNBPs within the animal kingdom and provide additional support for a proposed evolutionary origin of many protamines from a histone H1 (H5) replication-independent precursor., Competing Interests: Declaration of Interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported.

MeCP2 is a general regulator of transcription involved in the repression/activation of genes depending on the local epigenetic context. It acts as a chromatin regulator and binds with exquisite specificity to gene promoters. The set of epigenetic marks recognized by MeCP2 has been already established (mainly, cytosine modifications in CpG and CpA), as well as many of the constituents of its interactome. We unveil a new set of interactions for MeCP2 with the four canonical nucleosomal histones. MeCP2 interacts with high affinity with H2A, H2B, H3 and H4. In addition, Rett syndrome associated mutations in MeCP2 and histone epigenetic marks modulate these interactions. Given the abundance and the structural/functional relevance of histones and their involvement in epigenetic regulation, this new set of interactions and its modulating elements provide a new addition to the 'alphabet' for this epigenetic reader., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Introduction: Disruption of gut microbiota underpins some of the metabolic alterations observed in chronic kidney disease (CKD)., Methods: In a nonrandomized, open-label, 3-phase pilot trial, with repeated measures within each phase, we examined the efficacy of oligofructose-enriched inulin (p-inulin) in changing the gut microbiome and their metabolic products in 15 patients with CKD. The stability of microbiome and metabolome was studied during the pretreatment phase (8 weeks), a p-inulin treatment phase (12 weeks), and a post treatment phase (8 weeks) of the study., Results: Study participants completed 373 of the 420 expected study visits (88.8%). Adherence to p-inulin was 83.4%. 16S rRNA sequencing was performed in 368 stool samples. A total of 1085 stool, urine, and plasma samples were subjected to untargeted metabolomic studies. p-inulin administration altered the composition of the gut microbiota significantly, with an increase in abundance of Bifidobacterium and Anaerostipes . Intersubject variations in microbiome and metabolome were larger than intrasubject variation, indicating the stability of the gut microbiome within each phase of the study. Overall metabolite compositions assessed by beta diversity in urine and stool metabolic profiles were significantly different across study phases. Several specific metabolites in stool, urine, and plasma were significant at false discovery rate (FDR) ≤ 0.1 over phase. Specifically, there was significant enrichment in microbial metabolites derived from saccharolysis., Conclusion: Results from our study highlight the stability of the gut microbiome and the expansive effect of p-inulin on microbiome and host cometabolism in patients with CKD. Findings from this study will enable rigorous design of microbiome-based intervention trials., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)

MeCP2 (Methyl CpG binding protein 2) is an intrinsically disordered protein that binds to methylated genome regions. The protein is a critical transcriptional regulator of the brain, and its mutations account for 95% of Rett syndrome (RTT) cases. Early studies of this neurodevelopmental disorder revealed a close connection with dysregulations of the ubiquitin system (UbS), notably as related to UBE3A, a ubiquitin ligase involved in the proteasome-mediated degradation of proteins. MeCP2 undergoes numerous post-translational modifications (PTMs), including ubiquitination and sumoylation, which, in addition to the potential functional outcomes of their monomeric forms in gene regulation and synaptic plasticity, in their polymeric organization, these modifications play a critical role in proteasomal degradation. UbS-mediated proteasomal degradation is crucial in maintaining MeCP2 homeostasis for proper function and is involved in decreasing MeCP2 in some RTT-causing mutations. However, regardless of all these connections to UbS, the molecular details involved in the signaling of MeCP2 for its targeting by the ubiquitin-proteasome system (UPS) and the functional roles of monomeric MeCP2 ubiquitination and sumoylation remain largely unexplored and are the focus of this review., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Individuals with CKD have a high burden of cardiovascular disease (CVD). Abnormalities in cardiac structure and function represent subclinical CVD and can be assessed by cardiac magnetic resonance imaging (cMRI)., Methods: We investigated differences in cMRI parameters in 140 individuals with CKD stages 3b-4 who participated in the CKD Optimal Management with BInders and NicotinamidE (COMBINE) trial and in 24 age- and sex-matched healthy volunteers. Among COMBINE participants, we examined the associations of eGFR, urine albumin-creatinine ratio (UACR), phosphate, fibroblast growth factor 23 (FGF23), and parathyroid hormone (PTH) with baseline ( N =140) and 12-month change ( N =112) in cMRI parameters., Results: Mean (SD) ages of the COMBINE participants and healthy volunteers were 64.9 (11.9) and 60.4 (7.3) years, respectively. The mean (SD) baseline eGFR values in COMBINE participants were 32.1 (8.0) and 85.9 (16.0) ml/min per 1.73 m 2 in healthy volunteers. The median (interquartile range [IQR]) UACR in COMBINE participants was 154 (20.3-540.0) mg/g. Individuals with CKD had lower mitral valve E/A ratio compared with healthy volunteers (for CKD versus non-CKD, β estimate, -0.13; 95% CI, -0.24 to -0.012). Among COMBINE participants, multivariable linear regression analyses showed that higher UACR was significantly associated with lower mitral valve E/A ratio ( β estimate per 1 unit increase in natural-log UACR, -0.06; 95% CI, -0.09 to -0.03). This finding was preserved among individuals without baseline CVD. UACR was not associated with 12-month change in any cMRI parameter. eGFR, phosphate, FGF23, and PTH were not associated with any cMRI parameter in cross-sectional or change analyses., Conclusions: Individuals with CKD stages 3b-4 have evidence of cMRI abnormalities. Albuminuria was independently associated with diastolic dysfunction, as assessed by mitral valve E/A ratio, in individuals with CKD with and without clinical CVD. Albuminuria was not associated with change in any cMRI parameter., Competing Interests: G.A. Block reports receiving research funding from Akebia, Ardelyx, and GlaxoSmithKline; having consultancy agreements with Akebia, Keryx, Kirin, and Reata; receiving honoraria from Amgen and Kirin; serving as a scientific advisor for or member of Ardelyx, CJASN, Kirin, and Reata; having ownership interest in Ardelyx and Reata; and having other interests in/relationships with DaVita (previously medical director), Kidney Disease Improving Global Outcomes (previously on Executive Commitee), and Reata (previous employment). J. Carr reports serving on a speakers bureau for Bayer; receiving honoraria from Bayer, Bracco, and Guerbet; having consultancy agreements with Bayer, Bracco, and Siemens; receiving research funding from Bayer, Guerbet, and Siemens; and serving as a scientific advisor for or member of the Society for Cardiovascular MRI. A.K. Cheung reports having consultancy agreements with, and receiving honoraria from, Boehringer Ingelheim, Calliditas, and UptoDate; serving as a scientific advisor for or member of Hong Kong Journal of Nephrology, JASN, and Kidney Diseases; having other interests in/relationships with KDIGO; and having ownership interest in Merck. M. Chonchol reports having consultancy agreements with Amgen, Corvidia, Otsuka, Reata, Tricidia, and Vifor; receiving honoraria from Amgen, Corvidia, Reata, Tricidia, and Vifor; serving as a scientific advisor for or member of the CJASN editorial board; and receiving research funding from the Corvidia, National Institutes of Health (NIH), Otsuka, Reata, and Sanofi. L.F. Fried reports having consultancy agreements with Bayer, and serving on data safety monitoring boards for CSL Behring and Novo Nordisk. J.J. Gassman reports having consultancy agreements with, and receiving honoraria from, the Baim Institute (Harvard Clinical Research Institute). T. Isakova reports having consultancy agreements with, and receiving honoraria from, Akebia Therapeutics Inc.; and serving as an associate editor of American Journal of Kidney Diseases. J.H. Ix reports serving as a scientific advisor for or member of AlphaYoung; having consultancy agreements with Ardelyx, AstraZeneca, Bayer, Jnana, and Sanifit; and receiving research funding from Baxter International. R. Mehta reports having ownership interest in AbbVie Inc.; having consultancy agreements with, and receiving honoraria from, Akebia/Otsuka and AstraZeneca; and serving on the editorial board of the Journal of Cardiac Failure. J.P. Middleton reports serving on the editorial board for Advances in Chronic Kidney Disease and on a data safety monitoring board for the NIDDK; having consultancy agreements with AstraZeneca and Vifor/Relypsa; receiving research funding from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and Vifor/Relypsa; having other interests in/relationships with Raleigh Radiology (via spouse); and receiving honoraria from Relypsa/Vifor. D.S. Raj reports having other interests in/relationships with the American Association of Kidney Patients; serving as a scientific advisor for or member of the National Heart, Lung, and Blood Institute (NHLBI), NIDDK, and Novo Nordisk; receiving research funding from NIH; and having consultancy agreements with, and receiving honoraria from, Novo Nordisk. K.L. Raphael reports having consultancy agreements with AstraZeneca. S.M. Sprague reports serving as a scientific advisor for or member of the American Association of Endocrine Surgeons American Journal of Nephrology, International Federation of Clinical Chemistry and Laboratory Medicine Work Group for Parathyroid Hormone, and National Kidney Foundation of Illinois; having consultancy agreements with Amgen, Ardelyx, Fresenius, Horizon, Litholink Corp., OPKO, Shire, and Vifor; receiving research funding from Amgen, Ardelyx, OPKO, and Reata; receiving honoraria from Amgen, Ardelyx, Fresenius, Horizon, OPKO, and Vifor; serving on speakers bureaus for Amgen, Fresenius, Horizon, and OPKO; and having ownership interest via individually owned stocks in Apple, Bristol Myers, Coca Cola, First Australia Fund, IBM, Paycheck, US Concrete, and Walgreens. A. Srivastava reports serving on a speaker’s bureau for AstraZeneca; receiving honoraria from AstraZeneca, Bayer, and Horizon Therapeutics PLC; and having consultancy agreements with CVS Caremark and Tate & Latham (medicolegal consulting). M. Wolf reports having consultancy agreements with, and receiving honoraria from, Akebia, Amgen, Ardelyx, AstraZeneca, Bayer, Pharmacosmos, Unicycive, and Walden; and having ownership interest in, and serving as a scientific advisor for or member of, Akebia, Unicycive, and Walden. All remaining authors have nothing to disclose.All remaining authors have nothing to disclose., (Copyright © 2022 by the American Society of Nephrology.)

Competing Interests: Nothing to disclose.

Background and Objectives: In early-phase studies of individuals with hypertensive CKD and normal serum total CO 2 , sodium bicarbonate reduced urinary TGF- β 1 levels and preserved kidney function. The effect of sodium bicarbonate on kidney fibrosis and injury markers in individuals with diabetic kidney disease and normal serum total CO 2 is unknown., Design, Setting, Participants, & Measurements: We conducted a randomized, double-blinded, placebo-controlled study in 74 United States veterans with type 1 or 2 diabetes mellitus, eGFR of 15-89 ml/min per 1.73 m 2 , urinary albumin-to-creatinine ratio (UACR) ≥30 mg/g, and serum total CO 2 of 22-28 meq/L. Participants received oral sodium bicarbonate (0.5 meq/kg lean body wt per day; n =35) or placebo ( n =39) for 6 months. The primary outcome was change in urinary TGF- β 1-to-creatinine from baseline to months 3 and 6. Secondary outcomes included changes in urinary kidney injury molecule-1 (KIM-1)-to-creatinine, fibronectin-to-creatinine, neutrophil gelatinase-associated lipocalin (NGAL)-to-creatinine, and UACR from baseline to months 3 and 6., Results: Key baseline characteristics were age 72±8 years, eGFR of 51±18 ml/min per 1.73 m 2 , and serum total CO 2 of 24±2 meq/L. Sodium bicarbonate treatment increased mean total CO 2 by 1.2 (95% confidence interval [95% CI], 0.3 to 2.1) meq/L, increased urinary pH by 0.6 (95% CI, 0.5 to 0.8), and decreased urinary ammonium excretion by 5 (95% CI, 0 to 11) meq/d and urinary titratable acid excretion by 11 (95% CI, 5 to 18) meq/d. Sodium bicarbonate did not significantly change urinary TGF- β 1/creatinine (difference in change, 13%, 95% CI, -10% to 40%; change within the sodium bicarbonate group, 8%, 95% CI, -10% to 28%; change within the placebo group, -4%, 95% CI, -19% to 13%). Similarly, no significant effect on KIM-1-to-creatinine (difference in change, -10%, 95% CI, -38% to 31%), fibronectin-to-creatinine (8%, 95% CI, -15% to 37%), NGAL-to-creatinine (-33%, 95% CI, -56% to 4%), or UACR (1%, 95% CI, -25% to 36%) was observed., Conclusions: In nonacidotic diabetic kidney disease, sodium bicarbonate did not significantly reduce urinary TGF- β 1, KIM-1, fibronectin, NGAL, or UACR over 6 months., (Copyright © 2020 by the American Society of Nephrology.)

Background: Oral sodium bicarbonate (NaHCO 3 ) may preserve kidney function in CKD, even if initiated when serum bicarbonate concentration is normal. Adequately powered trials testing this hypothesis have not been conducted, partly because the best dose for testing is unknown., Methods: This multicenter pilot trial assessed the safety, tolerability, adherence, and pharmacodynamics of two doses of NaHCO 3 over 28 weeks in adults with eGFR 20-44 or 45-59 ml/min per 1.73 m 2 with urinary albumin/creatinine (ACR) ≥50 mg/g and serum bicarbonate 20-28 meq/L. We randomly assigned 194 participants from ten clinical sites to receive higher-dose (HD-NaHCO 3 ; 0.8 meq/kg of lean body wt per day; n =90) or lower-dose (LD-NaHCO 3 ; 0.5 meq/kg of lean body wt per day; n =52) NaHCO 3 or matching placebo ( n =52). The dose was adjusted depending on side effects. The prescribed dose at week 28 was the primary outcome; a dose was considered acceptable for a full-scale trial if ≥67% of participants were on full-dose and ≥80% were on ≥25% of the per-protocol dose., Results: Mean±SD baseline eGFR was 36±9 ml/min per 1.73 m 2 , serum bicarbonate was 24±2 meq/L, and median (IQR) ACR was 181 (25-745) mg/g. Both doses were well tolerated without significant changes in BP, weight, or serum potassium. The proportions of adverse events and hospitalizations were similar across the groups. Consequently, 87% in HD-NaHCO 3 , 96% in LD-NaHCO 3 , and 87% in placebo were on full dose at week 28; and 91% in HD-NaHCO 3 , 98% in LD-NaHCO 3 , and 92% in placebo were on ≥25% of the per-protocol dose. Mean urinary ammonium excretion was 25% lower and serum bicarbonate concentration was 1.3 meq/L higher in HD-NaHCO 3 compared with LD-NaHCO 3 at week 28. However, mean ACR increased by 12% in the lower-dose group and 30% in the higher-dose group., Conclusions: Both NaHCO 3 doses were well tolerated over 28 weeks with no significant difference in adverse events or hospitalization compared with placebo. The higher dose lowered urinary ammonium excretion and increased serum bicarbonate more than the lower dose but was associated with a greater increase in ACR. The higher 0.8 meq/kg of lean body wt per day dose of NaHCO 3 may be a reasonable choice for future trials., (Copyright © 2020 by the American Society of Nephrology.)

Introduction: Triage is the process of determining the priority of patients' treatments based on the severity of their conditions. The aim of the present study was to survey the effect of triage video podcasting on the knowledge and performance of pre-hospital students., Methods: Sixty pre-hospital students were randomly divided into two groups of a 30-subject control group and a 30-subject intervention group. A pre-test was administered among all students. Afterwards, for the first group, triage education was offered through lectures using PowerPoint, while for the second group, audio and video podcasts tailored for this training program were employed. Right after the training as well as one month later, post-tests were run for both groups, and the results were analysed using an independent t -test and covariance., Results: No significant difference was observed between the effects of both types of education on knowledge and performance, either immediately, or one month after training., Discussion: We suggest that video podcasts are ready to replace traditional teaching methods in triage.

Background and Objectives: The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that intensive BP lowering reduced the risk of cardiovascular disease, but increased eGFR decline. Serum parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23) concentrations are elevated in CKD and are associated with cardiovascular disease. We evaluated whether intact PTH or intact FGF23 concentrations modify the effects of intensive BP control on cardiovascular events, heart failure, and all-cause mortality in SPRINT participants with CKD., Design, Setting, Participants, & Measurements: We measured PTH and FGF23 in 2486 SPRINT participants with eGFR<60 ml/min per 1.73 m 2 at baseline. Cox models were used to evaluate whether serum PTH and FGF23 concentrations were associated with cardiovascular events, heart failure, and all-cause mortality, and whether PTH and FGF23 modified the effects of intensive BP control., Results: The mean age of this subcohort was 73 years, 60% were men, and mean eGFR was 46±11 ml/min per 1.73 m 2 . Median PTH was 48 (interquartile range [IQR], 35-67) pg/ml and FGF23 was 66 (IQR, 52-88) pg/ml. There were 261 composite cardiovascular events, 102 heart failure events, and 179 deaths within the subcohort. The adjusted hazard ratio (HR) per doubling of PTH concentration for cardiovascular events, heart failure, and all-cause mortality were 1.29 (95% confidence interval [95% CI], 1.06 to 1.57), 1.32 (95% CI, 0.96 to 1.83), and 1.04 (95% CI, 0.82 to 1.31), respectively. There were significant interactions between PTH and BP arm for both the cardiovascular ( P -interaction=0.01) and heart failure ( P -interaction=0.004) end points. Participants with a PTH above the median experienced attenuated benefits of intensive BP control on cardiovascular events (adjusted HR, 1.02; 95% CI, 0.72 to 1.42) compared with participants with a PTH below the median (adjusted HR, 0.67; 95% CI, 0.45 to 1.00). FGF23 was not independently associated with any outcome and did not modify the effects of the intervention., Conclusions: SPRINT participants with CKD and a high serum PTH received less cardiovascular protection from intensive BP therapy than participants with a lower serum PTH., (Copyright © 2018 by the American Society of Nephrology.)

Background and Objectives: Cognitive function worsens as kidney function declines, but mechanisms contributing to this association are not completely understood. Metabolic acidosis, a common complication of CKD, leads to neural networks overexcitation and is involved in cerebral autoregulation. We aimed to evaluate the association between serum bicarbonate concentration as a measure of metabolic acidosis, and cognitive function in hypertensive adults with and without CKD., Design, Setting, Participants, & Measurements: Five cognitive summary scores were measured (global cognitive function, executive function, memory, attention/concentration, and language) in 2853 participants in the Systolic BP Intervention Trial (SPRINT). Multivariable linear regression models adjusted for demographics, comorbidities, systolic BP, medications, eGFR and albuminuria evaluated the cross-sectional association between bicarbonate and cognition at SPRINT baseline. In a subset ( n =681) who underwent brain magnetic resonance imaging, the models were adjusted for white matter hyperintensity volume, vascular reactivity, and cerebral blood flow., Results: The mean age (SD) was 68 (8.5) years. Global cognitive and executive functions were positively associated with serum bicarbonate (estimate [SEM]: 0.014 [0.006]; P =0.01, and 0.018 [0.006]; P =0.003, respectively). Each 1 mEq/L lower bicarbonate level had a similar association with global cognitive and executive function as being 4.3 and 5.4 months older, respectively. The association with global cognition persisted after magnetic resonance imaging findings adjustment (estimate [SEM]: 0.03 [0.01]; P =0.01). There was no association between serum bicarbonate level and memory, attention/concentration, and language., Conclusions: In a large cohort of hypertensive adults, higher serum bicarbonate levels were independently associated with better global cognitive and executive performance. (ClinicalTrials.gov: NCT01206062)., (Copyright © 2018 by the American Society of Nephrology.)

Background and Objectives: Low urine ammonium excretion is associated with ESRD in CKD. Few laboratories measure urine ammonium, limiting clinical application. We determined correlations between urine ammonium, the standard urine anion gap, and a modified urine anion gap that includes sulfate and phosphate and compared risks of ESRD or death between these ammonium estimates and directly measured ammonium., Design, Setting, Participants, & Measurements: We measured ammonium, sodium, potassium, chloride, phosphate, and sulfate from baseline 24-hour urine collections in 1044 African-American Study of Kidney Disease and Hypertension participants. We evaluated the cross-sectional correlations between urine ammonium, the standard urine anion gap (sodium + potassium - chloride), and a modified urine anion gap that includes urine phosphate and sulfate in the calculation. Multivariable-adjusted Cox models determined the associations of the standard urine anion gap and the modified urine anion gap with the composite end point of death or ESRD; these results were compared with results using urine ammonium as the predictor of interest., Results: The standard urine anion gap had a weak and direct correlation with urine ammonium ( r =0.18), whereas the modified urine anion gap had a modest inverse relationship with urine ammonium ( r =-0.58). Compared with the highest tertile of urine ammonium, those in the lowest urine ammonium tertile had higher risk of ESRD or death (hazard ratio, 1.46; 95% confidence interval, 1.13 to 1.87) after adjusting for demographics, GFR, proteinuria, and other confounders. In comparison, participants in the corresponding standard urine anion gap tertile did not have higher risk of ESRD or death (hazard ratio, 0.82; 95% confidence interval, 0.64 to 1.07), whereas the risk for those in the corresponding modified urine anion gap tertile (hazard ratio, 1.32; 95% confidence interval, 1.03 to 1.68) approximated that of directly measured urine ammonium., Conclusions: Urine anion gap is a poor surrogate of urine ammonium in CKD unless phosphate and sulfate are included in the calculation. Because the modified urine anion gap merely estimates urine ammonium and requires five measurements, direct measurements of urine ammonium are preferable in CKD., (Copyright © 2018 by the American Society of Nephrology.)

Background and Objectives: Urinary ammonium excretion increases in response to nonvolatile acids to maintain normal systemic bicarbonate and pH. However, enhanced ammonia production promotes tubulointerstitial fibrosis in animal models. Therefore, a subset of individuals with CKD and normal bicarbonate may have acid-mediated kidney fibrosis that might be better linked with ammonium excretion than bicarbonate. We hypothesized that urine TGF- β 1, as an indicator of kidney fibrosis, would be more tightly linked with urine ammonium excretion than serum bicarbonate and other acid-base indicators . DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We measured serum bicarbonate and urinary ammonium, titratable acids, pH, and TGF- β 1/creatinine in 144 persons with CKD. Multivariable-adjusted linear regression models determined the cross-sectional association between TGF- β 1/creatinine and serum bicarbonate, urine ammonium excretion, urine titratable acids excretion, and urine pH., Results: Mean eGFR was 42 ml/min per 1.73 m 2 , mean age was 65 years old, 78% were men, and 62% had diabetes. Mean urinary TGF- β 1/creatinine was 102 (49) ng/g, mean ammonium excretion was 1.27 (0.72) mEq/h, mean titratable acids excretion was 1.14 (0.65) mEq/h, mean urine pH was 5.6 (0.5), and mean serum bicarbonate was 23 (3) mEq/L. After adjusting for eGFR, proteinuria, and other potential confounders, each SD increase of urine ammonium and urine pH was associated with a statistically significant 1.22-fold (95% confidence interval, 1.11 to 1.35) or 1.11-fold (95% confidence interval, 1.02 to 1.21) higher geometric mean urine TGF- β 1/creatinine, respectively. Each SD increase of serum bicarbonate and urine titratable acids was associated with a nonsignificant 1.06-fold (95% confidence interval, 0.97 to 1.16) or 1.03-fold (95% confidence interval, 0.92 to 1.14) higher geometric mean urine TGF- β 1/creatinine, respectively., Conclusions: Urinary ammonium excretion but not serum bicarbonate is associated with higher urine TGF- β 1/creatinine., (Copyright © 2018 by the American Society of Nephrology.)

Metabolic acidosis is not uncommon in CKD and is linked with bone demineralization, muscle catabolism, and higher risks of CKD progression and mortality. Clinical practice guidelines recommend maintaining serum total CO 2 at ≥22 mEq/L to help prevent these complications. Although a definitive trial testing whether correcting metabolic acidosis improves clinical outcomes has not been conducted, results from small, single-center studies support this notion. Furthermore, biologic plausibility supports the notion that a subset of patients with CKD have acid-mediated organ injury despite having a normal serum total CO 2 and might benefit from oral alkali before overt acidosis develops. Identifying these individuals with subclinical metabolic acidosis is challenging, but recent results suggest that urinary acid excretion measurements may be helpful. The dose of alkali to provide in this setting is unknown as well. The review discusses these topics and the prevalence and risk factors of metabolic acidosis, mechanisms of acid-mediated organ injury, results from interventional studies, and potential harms of alkali therapy in CKD., (Copyright © 2018 by the American Society of Nephrology.)

Introduction: It is unknown whether the criteria used to define Protein-energy wasting (PEW) syndrome in dialysis patients reflect protein or energy wasting in the general and moderate CKD populations., Methods: In 11,834 participants in the 1999-2004 National Health and Nutrition Examination Survey, individual PEW syndrome criteria and the number of PEW syndrome categories were related to lean body and fat masses (measured by dual-energy absorptiometry) using linear regression in the entire cohort and CKD sub-population., Results: Serum chemistry, body mass and muscle mass PEW criteria tended to be associated with lower lean body and fat masses, but the low dietary protein and energy intake criteria were associated with significantly higher protein and energy stores. When the number of PEW syndrome categories was defined by non-dietary categories alone, there was a monotonic inverse relationship with lean body and fat masses and strong positive relationship with mortality. In contrast, when dietary category alone was present, mean BMI was in the obesity range; additional presence of two non-dietary categories was associated with lower BMI and lower lean body and fat masses. Thus, the association of dietary category plus two additional non-dietary categories with lower protein or energy stores was driven by the presence of the two non-dietary categories. Results were similar in CKD subgroup., Conclusion: Hence, a definition of PEW syndrome without dietary variables has face validity and reflects protein or energy wasting.

Background: Fatigue is considered as a major problem in hemodialysis patients and can impair their quality of life. The purpose of this study was to investigate the effectiveness of acupressure on fatigue in hemodialysis patients., Materials and Methods: This is a clinical trial study in which 96 hemodialysis patients participated. Patients were randomly assigned into acupressure, placebo, and control groups (32 subjects fulfilling the inclusion criteria assigned to each group). The measures included the form of demographic characteristics, visual analog scale of fatigue, and Piper Fatigue Scale. Patients in the acupressure and placebo groups received acupressure intervention during the early 2 h of dialysis on six acupoints with massage for 20 min/day, 3 days per week for 4 weeks. In the placebo group, acupressure intervention was performed as mentioned above with a distance of 1 cm away from the actual intervention site. Patients in the control group received routine unit care only. Chi- quare test, Kruskal-Wallis, paired t-test, one-way analysis of variance (ANOVA), and Duncan test were used for data analysis., Results: One-way ANOVA tests showed significant differences in the total mean score of fatigue and fatigue mean scores in the behavioral, emotional, sensory, and cognitive dimensions in the acupressure, placebo, and control groups., Conclusion: The results of this study showed that acupressure may reduce fatigue in hemodialysis patients, and use of this non-pharmacologic technique for hemodialysis nurses is suggested.

Background and Objectives: Higher serum total alkaline phosphatase (AP) levels are associated with increased serum C-reactive protein (CRP) levels and mortality in the general and CKD populations. It is unclear to what extent these associations are related to bone disease., Design, Setting, Participants, & Measurements: In a nationally representative sample of 10,707 adult participants from the 1999-2004 National Health and Nutrition Examination Survey, serum nonskeletal AP levels were estimated from the measured serum skeletal and total AP levels. The associations of serum skeletal AP and nonskeletal AP levels with elevated serum CRP concentrations (>3 mg/L) and mortality were examined in multivariable models., Results: Skeletal AP was not associated with elevated CRP (for each doubling in non-CKD: odds ratio [OR], 1.00; 95% confidence interval [95% CI], 0.90-1.11; in CKD: OR, 1.19; 95% CI, 0.83-1.70) or mortality (for each doubling in non-CKD: hazard ratio [HR], 1.10; 95% CI, 0.94-1.29; in CKD: HR, 0.98; 95% CI, 0.75-1.28). In contrast, nonskeletal AP was associated with elevated CRP (for each doubling in non-CKD: OR, 4.51; 95% CI, 3.80-5.35; in CKD: OR, 5.98; 95% CI, 3.40-10.51). Nonskeletal AP was associated with mortality in non-CKD (for each doubling: HR, 1.96; 95% CI, 1.37-2.80) but not in CKD (for each doubling: HR, 0.92; 95% CI, 0.51-1.67) (interaction P=0.03)., Conclusions: Bone disease is unlikely to account for the known associations of serum total AP with increased inflammation and mortality.