Search

Rationale & objective High anion gap acidosis frequently develops in patients with advanced chronic kidney disease (CKD) and might be involved in kidney injury. Its impact on kidney outcomes, however, has not been well studied. We sought to examine the association between time-updated anion gap and the risk of kidney failure with replacement therapy (KFRT) among patients with advanced CKD. Study design Retrospective cohort study. Setting & participants 1,168 patients with CKD glomerular filtration rate categories 3b-5 (G3b-G5) who had available data on anion gap. Exposure High time-updated anion gap defined as values ≥ 9.2 (top 25th percentile). Outcome KFRT and death. Analytical approach Marginal structural models were fit to characterize the association between anion gap and study outcomes while accounting for potential time-dependent confounding. Results The mean baseline estimated glomerular filtration rate (eGFR) of the study participants was 28 mL/min/1.73 m2. Over a median follow-up period of 3.1 years, 317 patients progressed to KFRT (7.5 per 100 patient-years), and 146 died (3.5 per 100 patient-years). In the marginal structural models, a high anion gap was associated with a higher rate of KFRT (HR, 3.04 [95% CI, 1.94-4.75]; P Limitations Observational study design and selection bias due clinical indications for measuring anion gap. Conclusions Among patients with advanced CKD, high anion gap was associated with an increased risk of progression to KFRT and death.

Background Studies examining associations between metabolic acidosis and cardiovascular events in chronic kidney disease (CKD) have shown conflicting results and have not differentiated between normal anion gap (hyperchloremic) acidosis and high anion gap acidosis. We aimed to examine the impact of normal and high anion gap acidosis, separately, on the risk of cardiovascular events among patients with CKD. Methods This retrospective cohort study included 1168 patients with an estimated glomerular filtration rate (eGFR) of 10–60 mL/min/1.73 m2 and available data on anion gap. We analyzed the association of time-updated high anion gap (anion gap ≥9.2) with the rate of cardiovascular events using marginal structural models (MSMs) to account for time-dependent confounding. We also analyzed the association between time-updated normal anion gap acidosis (anion-gap-adjusted bicarbonate level ≤22.8 mEq/L) and cardiovascular events. Results The mean baseline eGFR of the cohort was 28 mL/min/1.73 m2. The prevalence rates of high anion gap in CKD stages G3a, G3b, G4 and G5 were 20%, 16%, 27% and 46%, respectively. During a median follow-up period of 2.9 years, 132 patients developed cardiovascular events (3.3/100 patient-years). In MSMs, high anion gap was associated with a higher rate of cardiovascular events [hazard ratio (HR) 1.87; 95% confidence interval (95% CI) 1.13‒3.09; P = 0.02] and the composite of cardiovascular events or all-cause death (HR 3.28; 95% CI 2.19‒4.91; P Conclusions Among patients with advanced CKD, high anion gap was associated with an increased risk of cardiovascular events.

Hemoglobin levels usually decline before dialysis initiation. The influence of overhydration on anemia progression and iron sequestration is poorly documented. Furthermore, clinical implications of anemia at dialysis initiation remain to be elucidated. This multicenter retrospective cohort study enrolled incident dialysis patients. The patients were stratified by tertiles of overhydration rate (OH-R) defined by (BW − DW)/DW*100 (BW: body weight just before dialysis initiation, DW: dry weight). Time courses (6 months before, to 1 month after, dialysis initiation) of hemoglobin, C-reactive protein (CRP), and iron sequestration index (ISI) were examined using mixed effects models. We used Cox models to identify anemia parameters predicting subsequent cardiovascular disease (CVD). Among the 905 enrolled patients, hemoglobin levels gradually decreased before dialysis initiation and rapidly increased thereafter. An inverse V-shaped time course was observed for CRP and ISI with an increase during dialysis initiation. Patients with a higher OH-R showed lower hemoglobin levels along with higher CRP and ISI levels before dialysis initiation. Mean corpuscular hemoglobin concentration (MCHC) was more stable before dialysis initiation than were mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH). Low MCHC (

Intradialytic hypotension is related to patient-reported outcomes such as post-dialysis fatigue, but its impact on physical activity has not been fully studied. We aimed to examine the relationship between intradialytic blood pressure (BP) and objectively measured physical activity.In this cross-sectional study, 192 hemodialysis patients underwent 4 weeks of physical activity measurement using triaxial accelerometers to measure step counts and moderate-to-vigorous physical activity (MVPA). Intradialytic BP parameters (pre-dialysis BP, post-dialysis BP, nadir BP, and fall in BP) were measured during all dialysis sessions. Mixed-effects linear regression models were used to analyze associations between intradialytic BP parameters and physical activity (1) after dialysis sessions on dialysis days and (2) on the following non-dialysis days.The mean age of the patients was 71 years, and 47% had diabetes mellitus. Valid physical activity data were obtained in a total of 1938 dialysis days and 2629 non dialysis days. Lower nadir diastolic BP was significantly associated with lower step counts and shorter moderate-to-vigorous physical activity not only on dialysis days but also on the following non-dialysis days. Nadir diastolic BP showed a higher discrimination capacity for physical inactivity, defined as a step count 4000 on non-dialysis days, than the other BP parameters. The optimal cutoff point of nadir diastolic BP for discriminating physical inactivity was 68 mmHg; its sensitivity and specificity were 66% and 67%, respectively.Lower nadir diastolic BP was strongly associated with lower physical activity on both dialysis and non-dialysis days. Nadir diastolic BP may be a predictor for physical inactivity.

Autoantibodies against thrombospondin type 1 domain-containing 7A (THSD7A) cause membranous nephropathy (MN); however, the mechanisms involved in THSD7A expression and immunization are uncertain. We present 2 cases of THSD7A-associated MN accompanied by angiolymphoid hyperplasia with eosinophilia (ALHE), a benign tumor characterized by proliferation of plump endothelial cells. Prednisolone therapy, but not surgical resection of ALHE tumors, successfully suppressed eosinophilia and proteinuria in both cases. Because ALHE is characterized by the proliferation of plump endothelial cells, we focused on the roles of vascular endothelial growth factor A (VEGF-A) in MN pathogenesis. We found that plump endothelial cells in ALHE modestly expressed THSD7A in both cases. We also found that eosinophils in ALHE expressed VEGF-A, which upregulated THSD7A expression, especially under T-helper type 2-prone conditions in cultured endothelial cells. Furthermore, double-positive cells for THSD7A and CD83 surrounded the proliferated small vessels. Our results suggest that VEGF-A-induced THSD7A expression outside the kidney may be important for MN pathogenesis.

Background Developing strategies for managing coronary artery calcification (CAC) in patients with CKD is an important clinical challenge. Experimental studies have demonstrated that magnesium inhibits vascular calcification, whereas the uremic toxin indoxyl sulfate aggravates it. Methods To assess the efficacy of magnesium oxide (MgO) and/or the oral carbon adsorbent AST-120 for slowing CAC progression in CKD, we conducted a 2-year, open-label, randomized, controlled trial, enrolling patients with stage 3−4 CKD with risk factors for CAC (diabetes mellitus, history of cardiovascular disease, high LDL cholesterol, or smoking). Using a two-by-two factorial design, we randomly assigned patients to an MgO group or a control group, and to an AST-120 group or a control group. The primary outcome was percentage change in CAC score. Results We terminated the study prematurely after an interim analysis with the first 125 enrolled patients (of whom 96 completed the study) showed that the median change in CAC score was significantly smaller for MgO versus control (11.3% versus 39.5%). The proportion of patients with an annualized percentage change in CAC score of ≥15% was also significantly lower for MgO compared with control (23.9% versus 62.0%). However, MgO did not suppress the progression of thoracic aorta calcification. The MgO group’s dropout rate was higher than that of the control group (27% versus 17%), primarily due to diarrhea. The percentage change in CAC score did not differ significantly between the AST-120 and control groups. Conclusions MgO, but not AST-120, appears to be effective in slowing CAC progression. Larger-scale trials are warranted to confirm these findings.

Separate assessment of mineral bone disorder (MBD) parameters including calcium, phosphate, parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D (1,25D) predict renal outcomes in kidney transplant recipients (KTRs), with conflicting results. To date, data simultaneously evaluating these parameters and interwoven relations on renal outcomes are scarce. We conducted a prospective long-term follow-up cohort study included 263 KTRs with grafts functioning at least 1 year after transplantation. The outcome was a composite of estimated GFR halving and graft loss. Cox regression analyses were employed to evaluate associations between a panel of six MBD parameters and renal outcomes. The outcome occurred in 98 KTRs during a median follow-up of 10.7 years. In a multivariate Cox analysis, intact PTH (iPTH), phosphate, and 1,25D levels were associated with the outcome (hazard ratio, 1.60 per log scale; 95% confidence interval, 1.19–2.14, 1.60 per mg/dL; 1.14–2.23 and 0.82 per 10 pg/mL; 0.68–0.99, respectively). Competing risk analysis with death as a competing event yielded a similar result. After stratification into four groups by iPTH and phosphate medians, high risks associated with high iPTH was not observed in KTRs with low phosphate levels (P-interaction

Lower corrected calcium (cCa) levels are associated with a better prognosis among incident dialysis patients. However, cCa frequently overestimates ionized calcium (iCa) levels. The prognostic importance of the true calcium status defined by iCa remains to be revealed. We conducted a retrospective cohort study of incident hemodialysis patients. We collected data of iCa levels immediately before the first dialysis. We divided patients into three categories: apparent hypocalcemia (low iCa

Several experimental studies have shown that fibroblast growth factor 23 (FGF23) induces left ventricular hypertrophy (LVH). However, the opposite directional relationship, namely a potential effect of LVH on FGF23, remains uncertain. Here we evaluated the effects of LVH on FGF23 using cardiomyocyte-specific calcineurin A transgenic mice. At six weeks, these mice showed severe LVH, with elevated levels of serum intact FGF23. FGF23 levels were elevated in cardiomyocytes, but not osteocytes, of the transgenic animals. Moreover, transverse aortic constriction also upregulated myocardial FGF23 expression in wild type mice. The promoter region of the FGF23 gene contains two putative nuclear factors of activated T cells (NFAT)-binding sites, with NFAT1 activating the promoter in a proximal NFAT-binding site dependent manner. Neither serum, urinary, or fractional excretion values of calcium and phosphate nor serum levels of 1,25(OH)2 vitamin D were different between wild type and transgenic mice. Moreover, the renal expression of FGF receptors and α-Klotho was comparable. However, plasma levels of antidiuretic hormone were significantly increased in the transgenic mice, and aquaporin-2 immunohistochemical staining was mainly positive in the apical membrane of the collecting duct, compared to a primarily cytoplasmic staining in wild type mice. Real-time PCR analyses of kidney CYP27B1 and CYP24A1 expression in wild type mice showed that exogenous antidiuretic hormone blocked FGF23's actions on these vitamin D activating or inactivating enzymes. Finally, the renal resistance of transgenic mice to FGF23 was partly overcome by tolvaptan. Thus, LVH in transgenic mice is associated with an increase in myocardial and serum intact FGF23, with the kidneys being protected against FGF23 excess by elevated antidiuretic hormone levels.

Background and objectives Circulating levels of anions that bind to magnesium and calcium are often altered in patients with CKD. However, it is unknown how these alterations affect the ionized fraction of magnesium and calcium. Design, setting, participants, & measurements This cross-sectional study involved patients on maintenance hemodialysis and patients not on dialysis who visited the outpatient department of nephrology. We collected whole-blood samples to measure ionized magnesium and calcium concentrations. Adjusted anion gap was calculated as an integrative index of unmeasured anions. Results A total of 118 patients on hemodialysis and 112 patients not on dialysis were included. Although the prevalence of hypermagnesemia defined by total magnesium was much higher in patients on hemodialysis than in patients not on dialysis (69% versus 12%; P Conclusions Anions that accumulate in patients on hemodialysis contribute to the lower ionized fraction of magnesium and calcium. Equations that incorporate the anion gap provide better predictions of ionized magnesium and calcium in patients on hemodialysis.

Phosphate/calcium homeostasis is crucial for health maintenance. Lithocholic acid, a bile acid produced by intestinal bacteria, is an agonist of vitamin D receptor. However, its effects on phosphate/calcium homeostasis remain unclear. Here, we demonstrated that lithocholic acid increases intestinal phosphate/calcium absorption in an enterocyte vitamin D receptor-dependent manner. Lithocholic acid was found to increase serum phosphate/calcium levels and thus to exacerbate vascular calcification in animals with chronic kidney disease. Lithocholic acid did not affect levels of intestinal sodium-dependent phosphate transport protein 2b, Pi transporter-1, -2, or transient receptor potential vanilloid subfamily member 6. Everted gut sac analyses demonstrated that lithocholic acid increased phosphate/calcium absorption in a transcellular pathway-independent manner. Lithocholic acid suppressed intestinal mucosal claudin 3 and occludin in wild-type mice, but not in vitamin D receptor knockout mice. Everted gut sacs of claudin 3 knockout mice showed an increased permeability for phosphate, but not calcium. In patients with chronic kidney disease, serum 1,25(OH)2 vitamin D levels are decreased, probably as an intrinsic adjustment to reduce phosphate/calcium burden. In contrast, serum and fecal lithocholic acid levels and fecal levels of bile acid 7α-dehydratase, a rate-limiting enzyme involved in lithocholic acid production, were not downregulated. The effects of lithocholic acid were eliminated by bile acid adsorptive resin in mice. Thus, lithocholic acid and claudin 3 may represent novel therapeutic targets for reducing phosphate burden.

Background Serum chloride (Cl) levels confer better prognostic value than serum sodium (Na) levels among patients with heart failure. Little is known about the relationship between serum Cl levels and clinical outcomes among patients with chronic kidney disease (CKD). Methods This was a retrospective cohort study enrolling patients with Stages G3–G5 CKD who visited the nephrology outpatient department of Osaka University Hospital from April 2005 to December 2014. The main exposure was time-varying serum Cl levels categorized as quartiles. The study outcome was a composite of all-cause death and cardiovascular events. Results A total of 2661 patients with CKD were included in the analysis. During a median follow-up of 4.0 years, 284 deaths and 416 cardiovascular events occurred. Compared with patients in the third Cl quartile, those in the first Cl quartile showed a significantly higher risk of the outcome after adjustment for demographics and clinical factors including time-varying serum Na, serum albumin and bicarbonate levels, and use of diuretics and sodium bicarbonate [hazard ratio (HR) 2.13; 95% confidence interval (CI) 1.20–3.81; P = 0.01] and, additionally, anion gap (HR 2.13; 95% CI 1.26–3.57; P = 0.004). Adding serum Cl levels, but not serum Na levels, to the multivariable model significantly improved net reclassification index (0.335; P Conclusions Lower serum Cl levels are an independent predictor of death and cardiovascular events. The incremental prognostic value of Cl was superior to that of Na in patients with CKD.

BackgroundHypomagnesemia (Hypo-Mg) predicts mortality and chronic kidney disease (CKD) progression. However, in CKD, its prevalence, kidney-intrinsic risk factors, and the effectiveness of oral magnesium (Mg) therapy on serum Mg levels is uncertain.MethodsIn a cross-sectional study enrolling pre-dialysis outpatients with CKD, the prevalence of electrolyte abnormalities (Mg, sodium, potassium, calcium and phosphorus) was compared. In an open-label randomized controlled trial (RCT), we randomly assigned CKD patients to either the magnesium oxide (MgO) or control arm. The outcome was serum Mg levels at 1 year.ResultsIn 5126 patients, Hypo-Mg was the most common electrolyte abnormality (14.7%) with similar prevalence across stages of CKD. Positive proteinuria was a risk factor of Hypo-Mg (odds ratio 2.2; 95% confidence interval 1.2–4.0). However, stratifying the analyses by diabetes mellitus (DM), it was not significant in DM (Pinteraction = 0.04). We enrolled 114 patients in the RCT. Baseline analyses showed that higher proteinuria was associated with higher fractional excretion of Mg. This relationship between proteinuria and renal Mg wasting was mediated by urinary tubular markers in mediation analyses. In the MgO arm, higher proteinuria or tubular markers predicted a significantly lower 1-year increase in serum Mg. In patients with a urinary protein-to-creatinine ratio (uPCR) ConclusionsProteinuria leads to renal Mg wasting through tubular injuries, which explains the high prevalence of Hypo-Mg in CKD.

Protein carbamylation is a posttranslational modification that can occur non-enzymatically in the presence of high concentrations of urea. Although carbamylation is recognized as a prognostic biomarker, the contribution of protein carbamylation to organ dysfunction remains uncertain. Because vascular calcification is common under carbamylation-prone situations, we investigated the effects of carbamylation on this pathologic condition. Protein carbamylation exacerbated the calcification of human vascular smooth muscle cells (hVSMCs) by suppressing the expression of ectonucleotide pyrophosphate/phosphodiesterase 1 (ENPP1), a key enzyme in the generation of pyrophosphate, which is a potent inhibitor of ectopic calcification. Several mitochondrial proteins were carbamylated, although ENPP1 itself was not identified as a carbamylated protein. Rather, protein carbamylation reduced mitochondrial membrane potential and exaggerated mitochondria-derived oxidative stress, which down-regulated ENPP1. The effects of carbamylation on ectopic calcification were abolished in hVSMCs by ENPP1 knockdown, in mitochondrial-DNA-depleted hVSMCs, and in hVSMCs treated with a mitochondria-targeted superoxide scavenger. We also evaluated the carbamylation effects using ex vivo and in vivo models. The tunica media of a patient with end-stage renal disease was carbamylated. Thus, our findings have uncovered a previously unrecognized aspect of uremia-related vascular pathology.

Background The Agatston score, commonly used to quantify coronary artery calcification (CAC), is determined by the plaque area and density. Despite an excellent predictability of the Agatston score for cardiovascular events, the density of CAC has never been studied in patients with pre-dialysis chronic kidney disease (CKD). This study aimed to analyze the CAC density and its association with serum mineral levels in CKD. Methods We enrolled patients with pre-dialysis CKD who had diabetes mellitus, prior cardiovascular disease history, elevated low-density lipoprotein cholesterol levels, or smoking history. The average CAC density was calculated by dividing the Agatston score by the total area of CAC. Results The mean estimated glomerular filtration rate (eGFR) of 109 enrolled patients was 35.7 mL/min/1.73 m2. The correlation of the Agatston score with density was much weaker than that with the total area (R2 = 0.19, P < 0.001; and R2 = 0.99, P < 0.001, respectively). Multivariate analyses showed that serum magnesium level was inversely associated with the density, but not with the total area, after adjustment for demographics and clinical factors related to malnutrition-inflammation-atherosclerosis syndrome and mineral and bone disorders including fibroblast growth factor 23 (P = 0.006). This inverse association was pronounced among patients with higher serum phosphate levels (P for interaction = 0.02). Conclusion CAC density was inversely associated with serum magnesium levels, particularly in patients with higher serum phosphate levels.