Single-cell RNA sequencing reveals transdifferentiation of parathyroid chief cells into oxyphil cells in patients with uremic secondary hyperparathyroidism.

The parathyroid gland is one of the main organs that regulate calcium and phosphorus metabolism. It is mainly composed of chief cells and oxyphil cells. Oxyphil cell counts are low in the parathyroid glands of healthy adults but are dramatically increased in patients with uremia and secondary hyperparathyroidism (SHPT). Increased oxyphil cell counts are related to drug treatment resistance, but the origin of oxyphil cells and the mechanism of proliferation remain unknown. Herein, three types of parathyroid nodules (chief cell nodules, oxyphil cell nodules and mixed nodules, respectively) excised from parathyroid glands of uremic SHPT patients were used for single-cell RNA sequencing (scRNA-seq), other molecular biology studies, and transplantation into nude mice. Through scRNA-seq of parathyroid mixed nodules from three patients with uremic SHPT, we established the first transcriptomic map of the human parathyroid and found a chief-to-oxyphil cell transdifferentiation characterized by gradual mitochondrial enrichment associated with the uremic milieu. Notably, the mitochondrial enrichment and cellular proliferation of chief cell and oxyphil cell nodules decreased significantly after leaving the uremic milieu via transplantation into nude mice. Remarkably, the phenotype of oxyphil cell nodules improved significantly in the nude mice as characterized by decreased mitochondrial content and the proportion of oxyphil cells to chief cells. Thus, our study provides a comprehensive single-cell transcriptome atlas of the human parathyroid and elucidates the origin of parathyroid oxyphil cells and their underlying transdifferentiating mechanism. These findings enhance our understanding of parathyroid disease and may open new treatment perspectives for patients with chronic kidney disease.

Microglial purinergic signaling in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease. The prevalent features of AD pathogenesis are the appearance of ß-amyloid (Aß) plaques and neurofibrillary tangles, which cause microglial activation, synaptic deficiency, and neuronal loss. Microglia accompanies AD pathological processes and is also linked to cognitive deficits. Purinergic signaling has been shown to play a complex and tight interplay with the chemotaxis, phagocytosis, and production of pro-inflammatory factors in microglia, which is an important mechanism for regulating microglia activation. Here, we review recent evidence for interactions between AD, microglia, and purinergic signaling and find that the purinergic P2 receptors pertinently expressed on microglia are the ionotropic receptors P2X4 and P2X7, and the subtypes of P2YRs expressed by microglia are metabotropic receptors P2Y2, P2Y6, P2Y12, and P2Y13. The adenosine P1 receptors expressed in microglia include A1R, A2AR, and A2BR. Among them, the activation of P2X4, P2X7, and adenosine A1, A2A receptors expressed in microglia can aggravate the pathological process of AD, whereas P2Y2, P2Y6, P2Y12, and P2Y13 receptors expressed by microglia can induce neuroprotective effects. However, A1R activation also has a strong neuroprotective effect and has a significant anti-inflammatory effect in chronic neuroinflammation. These receptors regulate a variety of pathophysiological processes in AD, including APP processing, Aß production, tau phosphorylation, neuroinflammation, synaptic dysfunction, and mitochondrial dysfunction. This review also provides key pharmacological advances in purinergic signaling receptors.

Inactivation of common airborne antigens by perfluoroalkyl chemicals modulates early life allergic asthma.

Allergic asthma, driven by T helper 2 cell-mediated immune responses to common environmental antigens, remains the most common respiratory disease in children. Perfluorinated chemicals (PFCs) are environmental contaminants of great concern, because of their wide application, persistence in the environment, and bioaccumulation. PFCs associate with immunological disorders including asthma and attenuate immune responses to vaccines. The influence of PFCs on the immunological response to allergens during childhood is unknown. We report here that a major PFC, perfluorooctane sulfonate (PFOS), inactivates house dust mite (HDM) to dampen 5-wk-old, early weaned mice from developing HDM-induced allergic asthma. PFOS further attenuates the asthma protective effect of the microbial product lipopolysaccharide (LPS). We demonstrate that PFOS prevents desensitization of lung epithelia by LPS, thus abolishing the latter's protective effect. A close mechanistic study reveals that PFOS specifically binds the major HDM allergen Der p1 with high affinity as well as the lipid A moiety of LPS, leading to the inactivation of both antigens. Moreover, PFOS at physiological human (nanomolar) concentrations inactivates Der p1 from HDM and LPS in vitro, although higher doses did not cause further inactivation because of possible formation of PFOS aggregates. This PFOS-induced neutralization of LPS has been further validated in primary human cell models and extended to an in vivo bacterial infection mouse model. This study demonstrates that early life exposure of mice to a PFC blunts airway antigen bioactivity to modulate pulmonary inflammatory responses, which may adversely affect early pulmonary health.

Two-Dimensional Violet Phosphorus P11: A Large Band Gap Phosphorus Allotrope.

The discovery of novel large band gap two-dimensional (2D) materials with good stability and high carrier mobility will innovate the next generation of electronics and optoelectronics. A new allotrope of 2D violet phosphorus P11 was synthesized via a salt flux method in the presence of bismuth. Millimeter-sized crystals of violet-P11 were collected after removing the salt flux with DI water. From single-crystal X-ray diffraction, the crystal structure of violet-P11 was determined to be in the monoclinic space group C2/c (no. 15) with unit cell parameters of a = 9.166(6) Å, b = 9.121(6) Å, c = 21.803(14)Å, ß = 97.638(17)°, and a unit cell volume of 1807(2) Å3. The structure differences between violet-P11, violet-P21, and fibrous-P21 are discussed. The violet-P11 crystals can be mechanically exfoliated down to a few layers (∼6 nm). Photoluminescence and Raman measurements reveal the thickness-dependent nature of violet-P11, and exfoliated violet-P11 flakes were stable in ambient air for at least 1 h, exhibiting moderate ambient stability. The bulk violet-P11 crystals exhibit excellent stability, being stable in ambient air for many days. The optical band gap of violet-P11 bulk crystals is 2.0(1) eV measured by UV-Vis and electron energy-loss spectroscopy measurements, in agreement with density functional theory calculations which predict that violet-P11 is a direct band gap semiconductor with band gaps of 1.8 and 1.9 eV for bulk and monolayer, respectively, and with a high carrier mobility. This band gap is the largest among the known single-element 2D layered bulk crystals and thus attractive for various optoelectronic devices.

Phosphorus balance calculator: an individualized tool for treatment of hyperphosphatemia in hemodialysis patients.

BACKGROUND AND HYPOTHESIS: Lack of evaluations of the dietary phosphorus and dialysis phosphorus removal in daily clinical practice are the common obstacle to assess phosphorus balance and control phosphorus in hemodialysis patients. We aimed to investigate whether the individualized therapy using phosphorus balance calculator improves phosphorus control. METHODS: A randomized, open-label, multicenter, 4-week clinical trial was conducted. 119 maintenance hemodialysis patients aged 18 to 85 years old and with serum phosphorus level higher than 1.45mmol/l from 3 university teaching hospitals in Shanghai were enrolled. Patients were randomized in a 1:1 ratio to individualized therapy (n=60), or conventional therapy (n=59). The primary outcome was the serum phosphorus concentration after 4-week treatment. Secondary outcomes included the serum calcium and parathyroid hormone (PTH) concentrations, changes in serum phosphorus, calcium and PTH concentrations, and the proportion of patients achieving target ranges of serum phosphorus, calcium and PTH after 4-week treatment. RESULTS: Among 119 randomized participants (mean age, 62 years; 68 male[57%]), 116 completed the trial. By using the phosphorus balance calculator, the individualized group achieved a better phosphorus balance state, significantly reduced the serum phosphorus (1.62±0.45mmol/l versus 1.85±0.45 mmol/l, P=0.006), increased the proportions of patients achieving target serum phosphorus range (41% versus 18%, P=0.006), and had greater adjusted mean difference in change in serum phosphorus over the 4 weeks (-0.47 versus -0.23mmol/l, P=0.010) when compared to conventional therapy. No significant changes were observed in serum calcium and PTH levels, the proportion of patients achieving target serum calcium or PTH levels, and adjusted mean difference of serum calcium and PTH levels over the treatment period. CONCLUSION: Phosphorus balance calculator was proved to improve serum phosphorus control in patients undergoing maintenance hemodialysis, offering a new tool for managing hyperphosphatemia.

Accumulation Kinetics and Gut Microenvironment Responses to Environmentally Relevant Doses of Micro/Nanoplastics by Zooplankton Daphnia Magna.

Microplastics are emerging pollutants that have been widely reported in aquatic ecosystems. Based on the analysis of environmentally relevant concentrations of microplastics in global freshwater systems, herein, we employed aggregated-induced emission (AIE) microplastic fluorogens and imaged and quantified the bioaccumulation of differentially charged micro- (20 µm)/nano- (200 nm) plastics (MNPs) in zooplankton Daphnia magna. We found that all particles of different sizes and charges were readily ingested, especially larger-sized and positively charged MNPs, with over 50% of the ingested particles accumulating in the gut. Bioaccumulation of MNPs reached 50% of steady-state condition within 1 h. The presence of algae inhibited the ingestion and depuration of MNPs. To further demonstrate the effects of such accumulation on gut health, we further applied the AIE probes for visualizing the pH and esterase in the digestive tract, as well as the gut inflammation. An accumulation of MNPs in D. magna significantly and rapidly induced the acidification of gut pH while inducing esterase activity. The NPs apparently induced gut inflammation in contrast to the MPs, demonstrating the size-dependent effects on oxidative stress. Our results highlighted that MNP exposure at environmentally relevant concentrations perturbed the microenvironments of zooplankton guts, which may significantly affect their digestion and assimilation of food materials as well as contaminant uptake.

Unveiling the Microfiber Release Footprint: Guiding Control Strategies in the Textile Production Industry.

Microplastic fibers from textiles have been known to significantly contribute to marine microplastic pollution. However, little is known about the microfiber formation and discharge during textile production. In this study, we have quantified microfiber emissions from one large and representative textile factory during different stages, spanning seven different materials, including cotton, polyester, and blended fabrics, to further guide control strategies. Wet-processing steps released up to 25 times more microfibers than home laundering, with dyeing contributing to 95.0% of the total emissions. Microfiber release could be reduced by using white coloring, a lower dyeing temperature, and a shorter dyeing duration. Thinner, denser yarns increased microfiber pollution, whereas using tightly twisted fibers mitigated release. Globally, wet textile processing potentially produced 6.4 kt of microfibers in 2020, with China, India, and the US as significant contributors. The study underlined the environmental impact of textile production and the need for mitigation strategies, particularly in dyeing processes and fiber choice. In addition, no significant difference was observed between the virgin polyesters and the used ones. Replacing virgin fibers with recycled fibers in polyester fabrics, due to their increasing consumption, might offer another potential solution. The findings highlighted the substantial impact of textile production on microfiber released into the environment, and optimization of material selection, knitting technologies, production processing, and recycled materials could be effective mitigation strategies.

Exposure to bisphenol A alternatives bisphenol AF and fluorene-9-bisphenol induces gonadal injuries in male zebrafish.

Bisphenol A (BPA), present in many household products, can damage the male reproductive system. Accordingly, we summarized urine samples from 6921 human in National Health and Nutrition Examination Survey and found urinary BPA levels were inversely linked with blood testosterone in the children group. Currently, BPA replacements, such as fluorene-9-bisphenol (BHPF) and Bisphenol AF (BPAF), have been introduced to produce "BPA-free" products. Here we demonstrated that BPAF and BHPF could induce delayed gonadal migration and reduce the number of progenitors of germ cell lineage in zebrafish larvae. A close receptor analysis study reveals that BHPF and BPAF can strongly bind to androgen receptors, leading to the downregulation of meiosis-related genes and the overexpression of inflammatory markers. Furthermore, BPAF and BPHF can induce activation of the gonadal axis via negative feedback, leading to the hypersecretion of some upstream hormones and an increase in the expression of upstream hormone receptors. Our findings call for further research on the toxicological effects of BHPF and BPAF on human health and recommend that BPA replacements be investigated for anti-estrogenic action.

Compact Super Electron-Donor to Monolayer MoS2.

The surface functionalization of two-dimensional (2D) materials with organic electron donors (OEDs) is a powerful tool to modulate the electronic properties of the material. Here we report a novel molecular dopant, Me-OED, that demonstrates record-breaking molecular doping to MoS2, achieving a carrier density of 1.10 ± 0.37 × 1014 cm-2 at optimal functionalization conditions; the achieved carrier density is much higher than those by other OEDs such as benzyl viologen and an OED based on 4,4'-bipyridine. This impressive doping power is attributed to the compact size of Me-OED, which leads to high surface coverage on MoS2. To confirm, we study tBu-OED, which has an identical reduction potential to Me-OED but is significantly larger. Using field-effect transistor measurements and spectroscopic characterization, we estimate the doping powers of Me- and tBu-OED are 0.22-0.44 and 0.11 electrons per molecule, respectively, in good agreement with calculations. Our results demonstrate that the small size of Me-OED is critical to maximizing the surface coverage and molecular interactions with MoS2, enabling us to achieve unprecedented doping of MoS2.

Integrated transcriptomic and proteomic analyses for the characterization of parathyroid oxyphil cells in uremic patients.

Chief cells are the predominant cells in parathyroid glands of healthy adults; however, parathyroid oxyphil cells, whose function is unknown, increase dramatically in patients with secondary hyperparathyroidism (SHPT). Calcitriol and calcimimetics are the most powerful treatments for SHPT, while the mechanisms leading to calcitriol or calcimimetic resistance in oxyphil cell-predominant SHPT are unknown. Here we used transcriptomic and proteomic techniques to characterize oxyphil cells by comparing the differences between chief and oxyphil cell nodules of parathyroid glands in uremic patients. Compared to chief cell nodules, the most marked expression increases in oxyphil cell nodules were for mitochondrion-associated proteins. The mitochondria number and mitochondrial DNA content were also significantly increased in oxyphil cell nodules. Moreover, oxyphil cell nodules expressed parathyroid-specific factors, and exhibited lower levels of proliferation-related proteins but higher synthesis and secretion level of parathyroid hormone (PTH). The protein expression of SHPT-regulating factors, including vitamin-D receptor, calcium-sensing receptor and Klotho, were significantly downregulated in oxyphil cell nodules. Therefore, oxyphil cells characterized by enrich mitochondria in uremic patients showed higher synthesis and secretion of PTH but lower expression of SHPT regulators than chief cells, which may contribute to the pathophysiology of SHPT and the treatment resistance to calcitriol and calcimimetics.

Connectome-based prediction of craving for gaming in internet gaming disorder.

BACKGROUND: Craving-related brain responses have been associated with the emergence and maintenance of addictions. However, little is known about brain network organizations underlying cravings in internet gaming disorder (IGD). METHODS: Sixty-six IGD subjects and 61 matched individuals with recreational game use (RGU) were scanned while performing a cue-craving task. A recently developed whole-brain analysis approach, connectome-based predictive modelling (CPM) with leave-one-out cross-validation was conducted to identify networks that predicted craving responses in IGD. Then, the craving network was tested in different brain states (cue-craving under deprivation) to investigate replicability. RESULTS: CPM identified an IGD craving network, as indicated by a significant correspondence between predicted and actual craving values (r = 0.49, p < 0.001), characterized by within-network default mode (DMN) connectivity and connectivity between canonical networks implicated in executive/cognitive control (frontoparietal, medial frontal, DMN) and reward responsiveness (subcortical, motor/sensory). Network strength in the cue-craving task during gaming deprivation also predicted IGD craving scores (r = 0.43, p = 0.017), indicating network replication across brain states. CONCLUSIONS: The CPM results demonstrate that individual differences in cognitive, attention, and control network function can predict craving intensities in IGD subjects. These networks may be targets for potential interventions using brain modulation.

Early Renal-Replacement Therapy May Reduce the All-Cause Mortality of Severe COVID-19: An Observational Cohort Study.

INTRODUCTION: The efficacy of renal-replacement treatment (RRT) remains to be validated in COVID-19. In this retrospective cohort study, we aimed to assess the efficacy of early initiation of RRT in intensive care unit (ICU) adults with severe COVID-19. METHODS: Fifty-eight adult patients in ICU with critically ill or severe COVID-19 with a tendency of critical illness were recruited from February 9, 2020, to March 30, 2020. Early RRT were determined by the ICU medical team based on boom in cytokines levels, increased organs injury/failure, and rapid aggravation of condition. All participants were followed up from the first day of ICU admission to March 30, 2020. The primary outcome was all-cause mortality in ICU. RESULTS: The mean age of the cohort was 68.4 ± 14.6 years, with 81.0% having at least one comorbidity before hospitalization. Twenty patients (34.5%) initiated early RRT after 24.1 ± 10.4 days from the onset and 6.4 ± 3.6 days from ICU admission. Thirty-four of 58 participants (58.6%) died during ICU follow-up. Univariate and multivariate Cox proportional-hazards model showed that early RRT was associated with a lower risk of all-cause mortality in ICU with an adjusted HR of 0.280 (95% CI: 0.106-0.738, p = 0.010). Sudden unexpected death (SUD) was remarkably reduced in the early RRT group, compared with the control group (0.2 vs. 2.9 per 100 person-day, p = 0.02). CONCLUSION: Early RRT can reduce the all-cause in-hospital mortality, especially SUD in patients with severe COVID-19, but not improve multi-organ impairment or increase the risk of AKI. Early initiation of RRT merits an optional strategy in critically ill patients with COVID-19 (ChiCTR2000030773).

Glomerular filtration rate by different measures and albuminuria are associated with risk of frailty: the Rugao Longitudinal Ageing Study.

BACKGROUND AND AIM: A decreased estimated glomerular filtration rate (eGFR) is associated with frailty, but the association between kidney function and frailty using multidimensional assessments has not been entirely examined. We aimed to investigate whether albuminuria and the eGFR using different biomarkers were associated with frailty. METHODS: A total of 1830 older adults were included. Kidney function was assessed by the eGFR (based on combined creatinine-cystatin C [eGFRcr-cys]) and ß2-microglobulin [eGFRB2M]) and urine albumin-creatinine ratio (UACR). Frailty was measured by the Fried phenotype (FP) and frailty index (FI). Logistic regression models were used to investigate cross-sectional and longitudinal associations of baseline kidney measures with prevalent and incident frailty. RESULTS: At baseline, kidney function was associated with prevalent frailty. During the 2-year follow-up, a decreased eGFR (per 10 units) was associated with an increased risk of incident frailty using the FP (eGFRcr-cys: OR 1.18, 95% CI 1.03-1.35; eGFRB2M: OR 1.14, 95% CI 1.02-1.29, respectively) and FI (eGFRB2M: OR 1.18, 95% CI 1.04-1.65). An increased logUACR was associated with a higher risk of incident frailty using the FP (OR 1.18, 95% CI 1.03-1.35). Additionally, individuals with chronic kidney disease (CKD) had a higher risk of incident frailty using the FP (eGFRcr-cys: OR 2.13, 95% CI 1.28-3.47; eGFRB2M: OR 1.58, 95% CI 1.10-2.29, respectively) and FI (eGFRcr-cys: OR 1.97, 95% CI 1.15-3.32; eGFRB2M: OR 1.51, 95% CI 1.03-2.24, respectively). CONCLUSION: Kidney function decline and CKD were associated with an increased risk of prevalent and incident frailty in older adults. Physicians should pay more attention to monitoring frailty status in older adults with CKD, even in those with kidney function decline.

Phosphate Overload Stimulates Inflammatory Reaction via PiT-1 and Induces Vascular Calcification in Uremia.

OBJECTIVE: Vascular calcification (VC) is an important risk factor for cardiovascular disease in maintenance hemodialysis (MHD) patients. Hyperphosphatemia and microinflammation statement are known major contributors to the development of VC; however, the mechanisms are unknown. The aims of this study were to explore the risk factors of VC in MHD patients and to explore whether high phosphate could increase the secretion of inflammatory cytokines via PiT-1 in monocytes. METHODS: A cross-sectional study was conducted on 65 MHD patients to assess the relevance of coronary artery calcification (CAC), inflammatory factors, serum phosphate, and sodium-dependent phosphate cotransporter (NPT) mRNA expression of peripheral blood mononuclear cells (PBMCs). Multivariate logistic regression analysis was used to analyze the predictors of CAC. The calcification effects of high phosphate (HP), TNF-α, and supernatants of healthy human monocytes treated with HP were further evaluated in cultured HASMCs. RESULTS: Diabetes, longer dialysis vintage, higher serum TNF-α levels, and PiT-1 mRNA expression of PBMCs) were independent risk factors of CAC in MHD patients. The mRNA levels of PiT-1 in PBMCs were positively correlated with serum phosphate, CAC scores, and Pit-2 mRNA levels of PBMCs. The expressions of TNF-α, IL-6, and PiT-1 in human monocytes were significantly increased in a dose-dependent manner after treatment with HP, which was subsequently inhibited by NPT antagonist phosphonoformic acid. Neither TNF-α alone nor supernatants of monocytes stimulated with HP promoted the expression of osteopontin and Runt-related transcription factor 2 (Runx2) or caused mineralization in human aortic smooth muscle cells, but combined with HP intervention, the calcification effects were markedly increased in human aortic smooth muscle cells and ameliorated by phosphonoformic acid treatment. CONCLUSION: Hyperphosphatemia directly increased the synthesis and secretion of TNF-α by monocytes may via PiT-1 pathway, resulting in elevated systemic inflammatory response, which may further aggravate VC induced by phosphate overload in MHD patients.

Metabolomics and In Silico Docking-Directed Discovery of Small-Molecule Enzyme Targets.

The identification of target proteins for small molecules is of great importance in drug discovery and for understanding the cellular mode of action (MOA) of toxicants. Herein, a "bottom-up" oriented target finding strategy is proposed based on the principle that the targeted enzymes can be inferred according to their phenotypic changes at the metabolome level. Meanwhile, computer-assisted in silico molecular docking analysis was performed to evaluate the binding affinities between the chemicals and the target enzymes to further rank the possible targets. In this study, triphenyl phosphate (TPhP) was used as an example to illustrate the workflow. After a comprehensive metabolome and lipidome analysis, 51 related metabolic enzymes were selected for ranking binding energies, wherein 25 proteins exhibited a higher affinity for TPhP than for their endogenous substrates. Two proteins, hydroxyacyl-coenzyme A dehydrogenase (HADH) and 3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10), were further confirmed by surface phasma resonance (SPR) and isothermal titration calorimetry (ITC) analysis, displayed Kd values at low micromolar levels for TPhP. Overall, the proposed strategy has provided a feasible means for discovering enzymatic targets for the large-scale small-molecule sets, with the advantages of closely associating with the phenotype change, reducing the cost of groping, and improving the accuracy of target prediction.

Frailty and the risk of kidney function decline in the elderly population: the Rugao Longevity and Ageing Study.

BACKGROUND: The diverse risk factors for kidney impairments suggest that kidney function decline is more likely to occur in individuals with a broadly constituted health deficit. Here we conducted a longitudinal cohort study to evaluate the association of baseline frailty status with the risk of estimated glomerular filtration rate (eGFR) decline. METHODS: Overall, 1269 participants aged 70-84 years from Rugao Longevity and Ageing cohort with 3-year follow-up were included. Frailty was measured using a modified Fried frailty assessment. GFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation. Associations between baseline frailty status and rapid eGFR decline were examined by multinomial logistic analysis. A linear mixed-effect model was used to determine eGFR decline in mL/min/1.73 m2 over the study period comparing those with frail or prefrail at baseline versus those with robust status. RESULTS: The mean (± standard deviation) age of participants was 75.1 ± 3.8 years. A total of 144 (11%) participants had rapid eGFR decline by at least 10% during the 3-year follow-up. Compared with robust status, baseline frail status was associated with a 2.48-fold [95% confidence interval (CI) 1.24-4.95] increased risk of rapid eGFR decline after multiple adjustments. In multivariate linear mixed model analysis, subjects with frail status but not prefrail status at baseline had a significant coefficient of -1.70 (95% CI -3.35 to -0.04) for the frail × visit term, which indicates an accelerated eGFR decline compared with robust subjects over the study period (P = 0.044). CONCLUSIONS: Frailty may serve as an independent biomarker to predict the decline of kidney function.

Modification and Validation of the Phosphate Removal Model: A Multicenter Study.

BACKGROUND: Our research group has previously reported a noninvasive model that estimates phosphate removal within a 4-h hemodialysis (HD) treatment. The aim of this study was to modify the original model and validate the accuracy of the new model of phosphate removal for HD and hemodiafiltration (HDF) treatment. METHODS: A total of 109 HD patients from 3 HD centers were enrolled. The actual phosphate removal amount was calculated using the area under the dialysate phosphate concentration time curve. Model modification was executed using second-order multivariable polynomial regression analysis to obtain a new parameter for dialyzer phosphate clearance. Bias, precision, and accuracy were measured in the internal and external validation to determine the performance of the modified model. RESULTS: Mean age of the enrolled patients was 63 ± 12 years, and 67 (61.5%) were male. Phosphate removal was 19.06 ± 8.12 mmol and 17.38 ± 6.75 mmol in 4-h HD and HDF treatments, respectively, with no significant difference. The modified phosphate removal model was expressed as Tpo4 = 80.3 × C45 - 0.024 × age + 0.07 × weight + ß × clearance - 8.14 (ß = 6.231 × 10-3 × clearance - 1.886 × 10-5 × clearance2 - 0.467), where C45 was the phosphate concentration in the spent dialysate measured at the 45th minute of HD and clearance was the phosphate clearance of the dialyzer. Internal validation indicated that the new model was superior to the original model with a significantly smaller bias and higher accuracy. External validation showed that R2, bias, and accuracy were not significantly different than those of internal validation. CONCLUSIONS: A new model was generated to quantify phosphate removal by 4-h HD and HDF with a dialyzer surface area of 1.3-1.8 m2. This modified model would contribute to the evaluation of phosphate balance and individualized therapy of hyperphosphatemia.

Higher one-year achievement rate of serum phosphate associated with lower cardiovascular mortality in hemodialysis patients.

BACKGROUND: Estimation of phosphate load in hemodialysis patients is always controversial in clinical practice. The aim of this study was to verify individual achievement rate of serum phosphate as the evaluation of phosphate load through investigating its impact on cardiovascular mortality in hemodialysis patients. METHODS: This was a single-center, retrospective cohort study. A total of 251 maintenance hemodialysis patients were enrolled. The individual achievement rate of serum phosphate was defined as the times of tests within the target range divided by total times of tests over a period of time. Cox regression model was used to examine the relationship between individual achievement rate of serum phosphate and cardiovascular mortality. RESULTS: The mean age of the study population was 61 ± 13 years old. A total of 44 (17.5%) patients died from cardiovascular disease (CVD) during a median follow-up of 65 months. Multivariable Cox analysis showed that one-year serum phosphate achievement rate of 0% (HR = 4.117, P = 0.016) and 25% (HR = 3.343, P = 0.023) increased the risk of cardiovascular mortality while the achievement rate of 50% (HR = 2.129, P = 0.162) and 75% (HR = 1.080, P = 0.902) did not, compared to the rate of 100%. Urea reduction ratio (URR) was positively, while serum intact parathyroid hormone (iPTH), alkaline phosphatase (ALP), normalized protein catabolic rate (nPCR), and total phosphate-binding capacity of drug were negatively associated with achievement in target of serum phosphate. CONCLUSIONS: Keeping one-year achievement rate of serum phosphate higher than 50% provides significant clinical benefits in reducing cardiovascular mortality.

Full-Scale Clinical Data and Reshaped Intestinal Microbiome on a Short-Term Low-Phosphorus Diet among Healthy Adults.

OBJECTIVES: During the past few decades, phosphorus intake has dramatically increased along with higher protein intake and overuse of inorganic phosphate additives worldwide. The detrimental effects of overconsumption of phosphorus are well recognized for patients with chronic kidney disease (CKD), and dietary phosphorus restriction was recommended for these patients. However, the effects of dietary phosphorus restriction in healthy people have not been fully studied. METHODS: In this open-label crossover study, healthy adult men (n = 12) consumed normal phosphorus diet (NPD, 1,500 mg/d) for five days. After a 10-day washout period, healthy adults took low phosphorus diet (LPD, 500 mg/d) for another five days. On the fifth day of each intervention, blood, urine and saliva samples were collected at ten time points, and fecal specimens were collected for bacterial taxa identification. RESULTS: We found that 24-h mean levels of serum phosphate (Pi), urinary Pi, serum parathyroid hormone and fibroblast growth factor 23 decreased, while serum calcium (Ca) and 1,25-dihydroxy vitamin D increased significantly under LPD compared with those under NPD. Dietary phosphorus intake did not change salivary Pi, urinary Ca, salivary Ca and magnesium (Mg) metabolism. Compared with NPD, LPD increased the relative abundance of beneficial microbes including Bacteroidetes, Ruminococcaceae and Lachnospiraceae, indicating that multiple bacterial metabolic pathways have been shifted. CONCLUSIONS: Full-scale data of dietary phosphorus restriction on Pi, Ca and Mg metabolism in healthy male adults are provided. More importantly, for the first time, dietary phosphorus restriction was found to reshape the intestinal microbiome, which provides information for benefits of dietary phosphorus restriction in healthy people, and potential clues for treating patients with CKD.

Dominant factors of the phosphorus regulatory network differ under various dietary phosphate loads in healthy individuals.

BACKGROUND: The purpose of this study was to explore the contribution of each factor of the phosphorus metabolism network following phosphorus diet intervention via Granger causality analysis. METHODS: In this study, a total of six healthy male volunteers were enrolled. All participants sequentially received regular, low-, and high-phosphorus diets. Consumption of each diet lasted for five days, with a 5-day washout period between different diets. Blood and urinary samples were collected on the fifth day of consumption of each diet at 9 time points (00:00, 04:00, 08:00, 10:00, 12:00, 14:00, 16:00, 20:00, 24:00) for measurements of serum levels of phosphate, calcium, PTH, FGF23, BALP, α-Klotho, and 1,25 D and urinary phosphorus excretion. Granger causality and the centrality of the above variables in the phosphorus network were analyzed by pairwise panel Granger causality analysis using the time-series data. RESULTS: The mean age of the participants was 28.5 ± 2.1 years. By using Granger causality analysis, we found that the α-Klotho level had the strongest connection with and played a key role in influencing the other variables. In addition, urinary phosphorus excretion was frequently regulated by other variables in the network of phosphorus metabolism following a regular phosphorus diet. After low-phosphorus diet intervention, serum phosphate affected the other factors the most, and the 1,25 D level was the main outcome factor, while urinary phosphorus excretion was the most strongly associated variable in the network of phosphorus metabolism. After high-phosphorus diet intervention, FGF23 and 1,25 D played a more critical role in active regulation and passive regulation in the Granger causality analysis. CONCLUSIONS: Variations in dietary phosphorus intake led to changes in the central factors involved in phosphorus metabolism.