BACKGROUND:Cognitive impairment is common among patients undergoing hemodialysis and worsens their quality of life and survival. The programmed cell death 1 (PD-1) pathway-comprising the receptor PD-1 and its ligand programmed cell death ligand 1 (PD-L1)-was initially recognized as a mechanism of tumor immune evasion that was also involved in chronic inflammation and immune aging. However, its role in cognitive impairment remains poorly understood. METHODS:In this cross-sectional study, patients aged ≥65 years undergoing hemodialysis were recruited from 7 centers. Global cognitive function was assessed by the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). Serum soluble PD-1 (sPD-1) and soluble PD-L1 (sPD-L1) were measured by enzyme-linked immunosorbent assay. Multivariable logistic regression was used to adjust for age, sex, dialysis vintage, C-reactive protein, and other confounders. RESULTS:Median age of the 384 patients was 74 years (interquartile range, 70-80), 67.5% were male, 61.2% scored below the MoCA score cutoff of 26, and 10.2% scored below the MMSE score cutoff of 24. Higher sPD-1 levels were associated with cognitive impairment as defined by both assessment tools; moreover, higher sPD-L1 levels were associated with MoCA-defined impairment (odds ratio, 2.53; 95% confidence interval, 1.26-5.06, P = .009). The association between sPD-1 and MMSE-defined impairment was stronger in patients without cancer history. CONCLUSION:These findings highlight the potential role of the PD-1 pathway in risk stratification and future interventions in cognitive impairment in patients undergoing hemodialysis.

Serum zinc levels decline with chronic kidney disease (CKD) progression, and zinc deficiency has been linked to impaired urinary sodium excretion and hypertension. However, its clinical impact on hypertension management in end-stage kidney disease remains unclear. This study investigated the association between serum zinc deficiency and antihypertensive treatment intensity in patients with stage 5 CKD initiating dialysis. In this single-center cross-sectional study, 175 adults initiating hemodialysis or peritoneal dialysis between November 2021 and December 2024 were included. Serum zinc levels were measured at dialysis initiation, and zinc deficiency was defined as < 60 μg/dL. Logistic and ordered logistic regression analyses adjusted for demographic and hypertension-related factors were conducted to evaluate factors associated with zinc deficiency and its relationship with the number of prescribed antihypertensive agents. Zinc deficiency was present in 59.4

Cognitive impairment is common in patients undergoing hemodialysis; however, evidence linking routinely measured bone turnover markers to cognition remains limited. In this exploratory cross-sectional study, we aimed to evaluate whether bone-specific alkaline phosphatase (BAP), total alkaline phosphatase (ALP), and tartrate-resistant acid phosphatase 5b (TRACP-5b) are related to global cognitive function in older patients undergoing hemodialysis. Adults aged ≥65 yr receiving maintenance hemodialysis were enrolled at seven centers in Tokyo and Chiba, Japan (November 2021-November 2022). Global cognition was assessed using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). Multivariable linear regression with robust SEs and facility fixed effects was used to examine associations with MoCA scores across sequentially adjusted models. Because of a ceiling effect, MMSE was analyzed using logistic regression with MMSE ≤23 as the outcome (unadjusted and age-/sex-adjusted). For statistical analyses, bone turnover markers were natural log-transformed. Among 380 participants (median age 74 yr; 67.6% male), higher BAP was consistently associated with lower MoCA scores (fully adjusted β -1.03; 95% CI, -1.90 to -0.16). Total ALP showed inverse associations in less-adjusted models; however, these associations attenuated after full adjustment (β -.88; 95% CI, -1.89 to 0.14). TRACP-5b was not clearly associated with MoCA scores. Higher BAP and total ALP were associated with higher odds of MMSE-defined cognitive dysfunction, whereas TRACP-5b was not. These findings suggest a potential association between bone formation-related markers and cognitive performance in older patients undergoing hemodialysis. Prospective and mechanistic studies are warranted to clarify causality and clinical utility.

Soluble Klotho is an anti-aging hormone implicated in vascular calcification. The calcification propensity score (T50) is a method used to evaluate the calcification propensity. However, no study has evaluated the association between soluble Klotho and T50. Therefore, this study aimed to investigate the association between soluble Klotho and T50 in patients undergoing hemodialysis. This cross-sectional study recruited patients undergoing hemodialysis. We measured T50 using the turbidimetric method and soluble Klotho using an enzyme-linked immunosorbent assay. Multiple regression analysis was used to examine the association between soluble Klotho and T50. In total, 199 patients were included in this study. Patients' mean age was 65.2 ± 10.2 years, and the median soluble Klotho concentration was 408 (321-525) pg/mL. The serum T50 value was 78 (63-104) minutes. The correlation coefficient between T50 and soluble Klotho was 0.39 (p < 0.001). Multivariate analysis revealed that the T50 value was significantly longer when comparing the group with the lowest and highest Klotho concentrations (β-coefficient = 21.3 [95% confidence interval: 4.5-38.2, p < 0.013]). The analysis of hemodialysis patients revealed for the first time that Klotho is associated with the T50 time. Soluble Klotho may be involved in vascular calcification.

KEY POINTS:Blood biomarkers related to amyloid β and neurofilament light chain are used to predict cognitive decline in the general population. Evidence for their usefulness is lacking in patients receiving hemodialysis despite their high risk of cognitive impairment. Neurofilament light chain levels were negatively associated with cognitive function, whereas the amyloid β ratio was not. BACKGROUND:Cognitive dysfunction is frequently observed in patients undergoing hemodialysis in clinical settings; however, its pathophysiology remains uncertain. In recent years, noninvasive blood biomarkers have garnered increasing attention in predicting Alzheimer's disease development. Within the general population, neurofilament light chain (NfL) levels have been used to prognosticate changes in cognitive function alongside the amyloid β (A β ) 1-42/1-40 ratio. Nevertheless, this has not been studied in patients with CKD, particularly those undergoing hemodialysis. METHODS:This exploratory cross-sectional study investigated the association of the serum A β 1-42/1-40 ratio and NfL levels with cognitive function assessed using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE), in patients undergoing hemodialysis. RESULTS:We included 384 patients with a median age of 74 (interquartile range [IQR], 70-80) years. The median (IQR) MoCA and MMSE scores were 25 (22-26) and 28 (26-29), respectively. The median (IQR) A β 1-42/1-40 ratio and NfL level were 0.04 (0.03-0.06) and 196.2 pg/ml (146.5-262.2), respectively. The multivariate linear regression analysis indicated a weak negative association between the log-transformed NfL levels and cognitive function, after adjusting for confounding factors including age ( β coefficient [95% confidence interval], -0.98 [-1.81 to -0.15]; P = 0.021 for MoCA and -0.66 [-1.32 to -0.01]; P = 0.046 for MMSE). However, the A β 1-42/1-40 ratio was not associated with cognitive function. CONCLUSIONS:Our exploratory analysis identified a weak negative association between serum NfL levels and cognitive function in patients undergoing hemodialysis.

Cognitive impairment is highly prevalent among older adults receiving maintenance hemodialysis; however, its pathophysiology is multifactorial and poorly understood. Evidence linking the lipid-profile components to cognitive function in patients undergoing hemodialysis remains limited. To address this evidence gap, we evaluated the associations between serum lipid-profile components and global cognitive function. We conducted an exploratory cross-sectional study of patients aged ≥ 65 years receiving maintenance hemodialysis at seven dialysis centers in Japan. Serum high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels were measured immediately before the first hemodialysis session of the week. Global cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE). Multivariate linear regression analyses were performed, adjusting for clinical comorbidities and markers of nutritional status, inflammation, and dialysis adequacy. Among 265 participants (median age, 74 years; 67.6

Ionized calcium (iCa) has physiological activity in the body; however, the direct measurement of iCa is technically limited. Although total serum calcium (tCa) and corrected serum calcium (cCa) using the Payne correction formula have been used to assess calcium levels, their limitations have been noted. We aimed to clarify the degree of correlation and dissociation among iCa, tCa, and cCa levels in patients undergoing hemodialysis. This cross-sectional study assessed the correlation between iCa, tCa, and cCa levels in patients undergoing hemodialysis. Factors involved in the correlation between iCa and tCa levels were evaluated using multiple regression analysis. Based on these results, we proposed a novel iCa prediction equation. Two hundred and thirteen patients were enrolled. The median patient age was 65 (standard deviation, 10.2) years, and 68.2

Background Cognitive dysfunction is frequently observed in patients undergoing hemodialysis in clinical settings; however, its pathophysiology remains uncertain. In recent years, noninvasive blood biomarkers have garnered increasing attention in predicting Alzheimer's disease development. Within the general population, neurofilament light chain (NfL) levels have been used to prognosticate changes in cognitive function alongside the amyloid beta (A beta) 1-42/1-40 ratio. Nevertheless, this has not been studied in patients with CKD, particularly those undergoing hemodialysis.Methods This exploratory cross-sectional study investigated the association of the serum A beta 1-42/1-40 ratio and NfL levels with cognitive function assessed using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE), in patients undergoing hemodialysis.Results We included 384 patients with a median age of 74 (interquartile range [IQR], 70-80) years. The median (IQR) MoCA and MMSE scores were 25 (22-26) and 28 (26-29), respectively. The median (IQR) A beta 1-42/1-40 ratio and NfL level were 0.04 (0.03-0.06) and 196.2 pg/ml (146.5-262.2), respectively. The multivariate linear regression analysis indicated a weak negative association between the log-transformed NfL levels and cognitive function, after adjusting for confounding factors including age (beta coefficient [95% confidence interval], -0.98 [-1.81 to -0.15]; P = 0.021 for MoCA and -0.66 [-1.32 to -0.01]; P = 0.046 for MMSE). However, the A beta 1-42/1-40 ratio was not associated with cognitive function.Conclusions Our exploratory analysis identified a weak negative association between serum NfL levels and cognitive function in patients undergoing hemodialysis.

Pain from arteriovenous fistula puncture significantly affects the quality of life of patients undergoing hemodialysis. AT-04 was designed to alleviate this pain using magnetic stimulation, which is anticipated to be beneficial for managing pain across different conditions. However, limited research exists on the effectiveness of AT-04 in diminishing the pain related to arteriovenous fistula puncture in hemodialysis patients. Between July and August 2024, we enrolled 14 outpatient maintenance hemodialysis patients at Tokyu Hospital who had given informed consent. AT-04 was administered before arteriovenous fistula puncture. We assessed the pain intensity of the puncture using the Visual Analog Scale (VAS) before the application of AT-04, as well as at one and four weeks afterward. We observed changes in puncture pain levels before and after the AT-04 application. The participants had an average age of 80 years (IQR, 74–85) and a mean dialysis duration of 5.8 years (IQR, 1.0–8.9). Lidocaine tape was utilized by 71.4

Background The role of parathyroid gland (PTG) ultrasonography in the management of secondary hyperparathyroidism after the introduction of calcimimetics remains unclear. Recent investigations have prompted renewed interest in the use of PTG ultrasonography for assessing treatment resistance to calcimimetics and determining the optimal timing for surgical intervention. This study aimed to explore the hypothesis that the PTG volume correlates with the calcimimetic dose. Methods We retrospectively observed outpatients undergoing haemodialysis at baseline and a 4-year follow-up. PTG volume was measured using ultrasonography between January and December 2017 and January and December 2021. We examined the association between baseline PTG volume and calcimimetic doses after 4 years. Results Of the 121 patients {median age 64 years [interquartile range (IQR) 54-72]}, 71 had PTG nodules on ultrasonography and the median total PTG volume was 34 mm3 (IQR 0-178). In the short dialysis vintage group, baseline parathyroid hormone levels tended to correlate with baseline calcimimetic doses; however, this trend was not observed in the extended dialysis vintage group. Baseline PTG volume correlated with the cinacalcet-equivalent calcimimetic dose (correlation coefficient 0.46; P < .001) after 4 years. The calcimimetic dose in the group with an estimated PTG volume >500 mm3 was approximate to 80 mg/day higher than that in the non-PTG nodule group after 4 years. In multivariate linear regression analysis, PTG volume >500 mm3 was associated with a high calcimimetic dose at 4 years in all analysis models. Conclusions Assessing PTG volume using ultrasonography may help predict high calcimimetic doses.

Introduction:Klotho, an aging-suppressor protein, has been shown to promote cardiovascular and bone health in animal models of chronic kidney disease (CKD). However, limited data exist on its role in clinical outcomes among patients undergoing hemodialysis. This study aimed to investigate the association between soluble Klotho (sKlotho) levels and cardiovascular disease (CVD) events, fractures, and all-cause mortality in this population. Methods:We enrolled 1241 patients on hemodialysis from multiple medical institutions, with a median follow-up of 39 months. The primary outcome was a composite of CVD events, fractures, and all-cause mortality. Results:The median sKlotho concentration was 325.6 pg/ml (interquartile range [IQR]: 248.9-434.4 pg/ml). During the follow-up, 436 CVD and 100 fracture events were recorded, along with 228 deaths. Patients in the lowest quartile of sKlotho had significantly higher risks of CVD events (hazard ratio [HR] = 1.76; 95% confidence interval [CI]: 1.20-2.60), fractures (HR = 1.99; 95% CI: 1.01-3.91) and mortality (HR = 1.74; 95% CI: 1.00-3.03) than those in the highest quartile. Conclusion:These findings suggest that low serum sKlotho levels are strongly associated with poor cardiovascular and skeletal outcomes and increased mortality in patients on hemodialysis. This study highlights the potential utility of sKlotho as a biomarker for risk stratification in this high-risk population.

The challenge of managing acute hypercalcemia in patients diagnosed with hypercalcemia of malignancy (HCM) merits further attention. Elevated levels of PTHrP may be a risk factor for treatment resistance in acute hypercalcemia; however, few studies have tested this hypothesis. This study aimed to investigate whether high PTHrP levels represent an independent risk factor that impedes the treatment of acute hypercalcemia. This retrospective cohort study recruited 159 patients aged 20-80 years with diagnosed malignancies who had been hospitalized for hypercalcemia with PTHrP levels above the reference value (1.1 pmol/L). The median (25%-75%) patient age was 69 (61-76) years, and the median PTHrP level was 6.3 (3.3-11.1) pmol/L. The corrected calcium levels decreased from 12.8 mg/dL (11.9-14.1 mg/dL) to 10.6 mg/dL (9.8-11.7 mg/dL) following treatments, such as bisphosphonates and saline solution. Multivariate linear regression analysis showed less significant decreases in the corrected calcium levels as natural logarithm-transformed PTHrP levels increased (β coefficient [95% CI]: 0.569 [0.225-0.914]; p = .001 for Model 3). Multivariate logistic regression analysis showed an association between high natural logarithm-transformed PTHrP levels and lack of treatment response, defined as a corrected calcium level of ≤10.4 mg/dL in the last blood test conducted within 2 wk of treatment initiation (odds ratio [95% CI]: 0.504 [0.312-0.814]; p = .005). Therefore, elevated PTHrP levels are a potential risk factor for treatment resistance in hypercalcemia in HCM patients, complicating management regardless of calcium levels.

BackgroundProgramed death-ligand 1 (PD-L1) is overexpressed on renal tubular and vascular epithelial cells in inflammatory kidney diseases as well as on aged kidney podocytes, contributing to chronic kidney disease (CKD) progression. The association of serum soluble programed death-ligand 1 (sPD-L1) levels and chronic kidney disease (CKD) progression is unknown.MethodsTo compare serum sPD-L1 levels among healthy individuals and patients with various CKD stages, including those undergoing dialysis, a secondary analysis was performed using clinical data and residual serum samples from four distinct cohorts, each prospectively collected for different research purposes: The Vaccine Cohort (2021–2022), the Cancer Cohort (2010–2018), the Dialysis Initiation Cohort (2023–2024), and the Dialysis Maintenance Cohort (2011–2015) included patients on stable maintenance dialysis.ResultsThe study analyzed serum sPD-L1 levels in 2,829 participants (mean age, 54.2 years; male, 54.2%) across the four cohorts. In the Vaccine and Cancer cohorts, sPD-L1 levels increased significantly with age (P < 0.001) and male sex (P < 0.001). In the Vaccine Cohort, elevated median sPD-L1 levels (pg/mL) were significantly associated with CKD stage progression (P < 0.001), showing exponentially higher levels with CKD progression. A similar association was observed and validated in the Cancer Cohort (P < 0.001). In the Dialysis Initiation Cohort (n = 15), sPD-L1 levels significantly increased three months after dialysis initiation compared to pre-dialysis levels (P = 0.03). In the Dialysis Maintenance Cohort, sPD-L1 levels increased with longer dialysis duration (P < 0.001).ConclusionSerum sPD-L1 levels might increase with CKD stage progression, dialysis initiation and longer dialysis duration. Further clinical investigation is required to confirm these results.

BACKGROUND:A 2021 meta-analysis of 37 randomised controlled trials (RCTs) of vitamin D supplementation for prevention of acute respiratory infections (ARIs) revealed a statistically significant protective effect of the intervention (odds ratio [OR] 0·92 [95% CI 0·86 to 0·99]). Since then, six eligible RCTs have been completed, including one large trial (n=15 804). We aimed to re-examine the link between vitamin D supplementation and prevention of ARIs. METHODS:Updated systematic review and meta-analysis of data from RCTs of vitamin D for ARI prevention using a random effects model. Subgroup analyses were done to determine whether effects of vitamin D on risk of ARI varied according to baseline 25-hydroxyvitamin D (25[OH]D) concentration, dosing regimen, or age. We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Web of Science, and the ClinicalTrials.gov between May 1, 2020 (end-date of search of our previous meta-analysis) and April 30, 2024. No language restrictions were imposed. Double-blind RCTs supplementing vitamin D for any duration, with placebo or lower-dose vitamin D control, were eligible if approved by a Research Ethics Committee and if ARI incidence was collected prospectively and pre-specified as an efficacy outcome. Aggregate data, stratified by baseline 25(OH)D concentration and age, were obtained from study authors. The study was registered with PROSPERO (no. CRD42024527191). FINDINGS:We identified six new RCTs (19 337 participants). Data were obtained for 16 085 (83·2%) participants in three new RCTs and combined with data from 48 488 participants in 43 RCTs identified in our previous meta-analysis. For the primary comparison of any vitamin D versus placebo, the intervention did not statistically significantly affect overall ARI risk (OR 0·94 [95% CI 0·88-1·00], p=0·057; 40 studies; 61 589 participants; I2=26·4%). Pre-specified subgroup analysis did not reveal evidence of effect modification by age, baseline vitamin D status, dosing frequency, or dose size. Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (OR 0·96 [95% CI 0·90-1·04]; 38 studies; I2=0·0%). A funnel plot showed left-sided asymmetry (p=0·0020, Egger's test). INTERPRETATION:This updated meta-analysis yielded a similar point estimate for the overall effect of vitamin D supplementation on ARI risk to that obtained previously, but the 95% CI for this effect estimate now includes 1·00, indicating no statistically significant protection. FUNDING:None.

[This corrects the article DOI: 10.1371/journal.pone.0309657.].

Key PointsIn the lower-parathyroid hormone (PTH) group, associations between serum alkaline phosphatase (ALP) and all-cause mortality were positive and linear.In the higher-PTH group, lower serum ALP tended to have higher risk than those with intermediate serum ALP.Serum ALP was independently and linearly associated with new hip fracture regardless of intact PTH level.BackgroundMonitoring of serum alkaline phosphatase (ALP) is recommended in the management of CKD-mineral bone disorder because of associations with poor outcomes among patients on dialysis. However, such associations may have changed with several advances in the management of CKD-mineral bone disorder over the past decade.MethodsBaseline data of 241,670 patients on dialysis (mean age, 69 +/- 12 years; male, 65.9%; median dialysis duration, 68 months) were extracted from a nationwide dialysis registry in Japan at the end of 2019. Outcomes, including all-cause and cardiovascular (CV) mortality and hip fracture, were evaluated using the registry at the end of 2020 and 2021. All-cause mortality was assessed using Cox regression analysis, whereas CV mortality and new hip fracture were assessed using competing-risks regression analysis. Multiple imputations for missing values were performed.ResultsWithin the 2-year study period, a total of 40,449 patients (16.7%) died, including 13,562 CV deaths (5.6%). Of the 168,836 patients with no history of hip fracture at the end of 2019, 4136 (2.4%) suffered hip fracture within 2 years. Higher serum ALP was independently associated with higher all-cause and CV mortality and new hip fracture, but the association with CV mortality was marginal (hazard ratio, 1.21; 95% confidence interval [CI], 1.18 to 1.24; subhazard ratio, 1.07; 95% CI, 1.03 to 1.12 and subhazard ratio, 1.28, 95% CI, 1.19 to 1.38, respectively). There is a linear association between serum ALP and all-cause mortality among the lower parathyroid hormone (PTH) group, whereas lower serum ALP tended to have higher all-cause mortality than intermediate serum ALP among patients in the higher PTH group.ConclusionsHigher serum ALP was independently and linearly associated with higher all-cause and CV mortality and new hip fracture in Japanese patients on dialysis. Higher serum ALP and higher intact PTH were synergistic in increasing all-cause and CV mortality but were not associated with new hip fracture.

In patients undergoing hemodialysis, serum blood urea nitrogen (BUN) and creatinine (Cr) levels are affected by factors such as diet and muscle mass. Few studies have examined the optimal range of serum BUN/Cr ratios in these patients. Therefore, this study examined the association between the BUN/Cr ratio and all-cause mortality. This retrospective cohort study evaluated pre-dialysis BUN/Cr ratios. Cox regression analysis was performed with all-cause mortality as the outcome and the BUN/Cr ratio as an explanatory factor. This study included 1321 patients undergoing hemodialysis (mean age: 63.5 ± 11.7 years; dialysis duration: 110 [17–203] months; 70.0