Catheter-related bloodstream infection (CRBSI) significantly increases the mortality rate among hemodialysis patients. This study aims to analyze the prevalence of CRBSI and its risk factors in hemodialysis patients, providing actionable recommendations using Gansu Province as a case study. A cross-sectional study was conducted involving 540 hemodialysis patients with central venous catheters, selected from 28 hospitals across seven cities in Gansu Province. Patients were divided into an infected group (90 cases) and a non-infected group (450 cases). Data collected included clinical characteristics, infection rates, pathogens, and their antibiotic sensitivity. Logistic regression analysis was performed to identify risk factors for CRBSI. The CRBSI incidence rate was 16.67%. Gram-positive bacteria predominated among isolated pathogens (59.02%), with Staphylococcus aureus (31.15%) being the most common. Logistic regression identified hospital level, diabetic nephropathy as the primary disease, anemia, hypoproteinemia, and elevated serum ferritin as significant risk factors. CRBSI incidence in Gansu’s hemodialysis patients is high, with Gram-positive bacteria as the dominant pathogens. Key risk factors include hospital level, diabetic nephropathy, anemia, hypoproteinemia, and elevated serum ferritin. Targeted interventions are necessary to reduce CRBSI occurrence.

Autosomal dominant tubulointerstitial kidney disease -UMOD is characterized by progressive renal interstitial inflammation and fibrosis. However, its underlying mechanisms remain unclear. Here, we identify a large ADTKD pedigree harboring a novel UMOD p.H36Y mutation. Using CRISPR/Cas9 technology, we generated a UmodH36Y/+ mouse model that recapitulates the key phenotypes observed in affected individuals, including renal dysfunction, cyst formation, and interstitial inflammation. Multi-omics analyses in kidneys from male UmodH36Y/+ mice revealed marked macrophage pyroptosis. Mechanistically, the Umod p.H36Y variant activated the amyloid precursor protein (App)-Cd74 axis which mediated the crosstalk between renal mutant tubular cells and macrophages. This axis sustains NF-κB pathway activation in macrophages, initiating pyroptosis and pro-inflammatory cytokine release. The same mechanism is recapitulated in the UMOD p.Trp31Cys cell model. Notably, Pharmacologic inhibition using ARN2966, a small-molecule App inhibitor, attenuated renal injury in male UmodH36Y/+ mice. Collectively, these findings uncover a targetable pathway in ADTKD-UMOD.

Fabry disease is a rare X-linked disorder caused by mutations in the GLA gene, leading to a deficiency in α-galactosidase A (α-Gal A) and lysosomal dysfunction. This results in the accumulation of lipid substances, such as globotriaosylceramide (GL-3) and globotriaosylsphingosine (Lyso-GL-3), in organs like the kidneys, heart, and nervous system, causing organ dysfunction. Renal involvement, including proteinuria and renal dysfunction, is a major contributor to disability and mortality. Early detection and treatment, such as enzyme replacement therapy (ERT), are critical; however, ERT is less effective in patients with severe proteinuria. Identifying novel biomarkers for early kidney damage is essential. Myeloid bodies, multilamellar myelin figures observed under electron microscopy, are a hallmark of Fabry disease and are crucial for diagnosis. First identified in urine sediment in 1977, their role in disease progression was confirmed in 2018. However, the prevalence of urinary myeloid bodies and their link to disease progression are not fully understood. This study aims to analyze urinary myeloid bodies in Fabry patients, assess their prevalence, and explore their potential as a non-invasive biomarker for monitoring ERT effectiveness and disease progression. This single-center, retrospective study included 25 patients with Fabry disease and 27 controls (2 healthy individuals and 25 patients with other renal diseases). We analyzed 24-hour urine samples for the presence of urinary myeloid bodies and evaluated clinical data, including serum creatinine, estimated glomerular filtration rate (eGFR), 24-hour urinary protein levels, α-Gal A, and Lyso-GL-3. Seven Fabry patients underwent analysis of urine samples before and after one year of ERT. Urinary myeloid bodies were detected in 21 Fabry patients (84%), while no myeloid bodies were observed in the control group (Table 1). The median age of the Fabry patient cohort was 43 years, with a male-to-female ratio of 44% to 56%. None of the Fabry patients had a history of cationic amphiphilic drug use. Urinary myeloid bodies were detected in 21 patients (84%) (Fig. 1A–F). Comparison between Fabry patients with and without urinary myeloid bodies revealed no statistically significant differences in age, gender, serum creatinine, eGFR, 24-hour urinary protein, α-Gal A, or Lyso-GL-3 (Table 1). Based on the presence of urinary myeloid bodies and proteinuria, patients were divided into four groups (Fig. 1G). Two patients exhibited neither condition, while fourteen patients presented with both. Seven additional patients showed urinary myeloid body excretion despite the absence of proteinuria. Among the Fabry patients with myeloid bodies, 48% had no proteinuria, and 52% were in CKD stage 1, G1 (Fig. 1H–K). Furthermore, urinary myeloid bodies were detected in four patients under the age of 20, despite the absence of or only minimal proteinuria, and these patients all exhibited a substantial number of myeloid bodies. After one year of ERT, significant reductions in both the count (P = 0.043) and area ratio (P = 0.028) of myeloid bodies were observed (Fig. 1L and M). Urinary myeloid bodies are specific to Fabry disease and are associated with early renal injury, even in the absence of proteinuria. These findings suggest that urinary myeloid bodies may serve as a non-invasive biomarker for the early diagnosis of Fabry disease and for monitoring the efficacy of ERT.

INTRODUCTION:The relationship between the triglyceride-glucose (TyG) index and mortality in hemodialysis patients remains uncertain. This study aimed to investigate the correlation between TyG index and all-cause mortality in initial hemodialysis patients in China. METHODS:783 patients participated in the study and were grouped into quintiles according to the TyG index. Multivariate Cox models and subgroup analyses were utilized. Nonlinear correlations were explored using restricted cubic splines, and a two-piecewise Cox proportional hazards model was developed around the inflection point. RESULTS:During a median follow-up of 44 months, 231 (29.50%) patients occurred mortality. Multivariate Cox regression confirmed that both lower and higher TyG indices independently predicted all-cause mortality (all p < 0.05). The predictive value of a high TyG index for all-cause mortality remained consistent across age, sex, BMI, and diabetes subgroups. A restricted cubic spline unveiled a J-shaped relationship between the two variables in initial hemodialysis patients. A TyG index exceeding 8.83 exhibited a positive correlation with all-cause mortality (hazard ratio, 1.78; 95% CI: 1.27-2.46, p < 0.001). CONCLUSIONS:A J-shaped relationship was identified between the TyG index and all-cause mortality in initial hemodialysis patients in China, with a threshold of 8.83 for all-cause mortality.

BACKGROUND:Recent findings have spotlighted sarcopenia as a critical factor exacerbating cardiovascular risk in dialysis patients. However, no studies have investigated the relationship of muscle characteristics with thoracic aortic calcification (TAC). We explored whether skeletal muscle radiodensity (SMD) and skeletal muscle index (SMI) are associated with TAC in dialysis patients. METHODS:In this study, 2517 dialysis patients (between January 2020 and June 2023) from four centres with chest computed tomography (CT) scans were analysed cross-sectionally. A cohort of 544 initial-dialysis patients (between January 2014 and December 2020) was followed for TAC progression. Chest CT images were used to assess SMD and SMI at the L1 level, as well as to measure the scores of TAC, including ascending TAC (ATAC), aortic arch calcification (AoAC) and descending TAC (DTAC). Multivariable linear regression models were employed to assess the effects of SMD and SMI on TAC and its progression. Restricted cubic spline was used to assess the potential non-linear relationships of SMD and SMI with TAC progression. RESULTS:The mean (SD) age for the cross-sectional study was 54.8 (14.0) years, with males accounting for 58.2%. Over a mean (SD) follow-up duration of 3.45 (1.82) years, 85.7% showed TAC progression. Comparing the highest quartile of SMD to the lowest quartile, a significant inverse association was observed with TAC (β, -1.08 [-1.42 to -0.75]; p < 0.001); similar trends were noted for SMI (β, -0.42 [-0.74 to -0.10]; p = 0.011). SMD and SMI as continuous variables were also both significantly negatively correlated with TAC. In the longitudinal study, multivariable linear regression models revealed that an increase of 1 SD in SMD resulted in a decrease of 0.10 SD (95% CI, -0.17 to -0.02; p = 0.011) in TAC progression, and an increase of 1 SD in SMI resulted in a decrease of 0.12 SD (95% CI, -0.20 to -0.04; p = 0.003) in TAC progression. Restricted cubic spline models excluded non-linear trends for the relationships of SMD and SMI with TAC progression. The associations of SMD and SMI with DTAC were consistent with those observed for TAC, but neither showed a significant association with ATAC. CONCLUSIONS:Higher SMD and higher SMI were significantly associated with lower TAC and its progression in dialysis patients. Improving SMD and SMI could be a new approach for reducing TAC.

To assess the effectiveness and safety of Sacubitril/Valsartan in reducing blood pressure in individuals with non-dialysis-dependent chronic kidney disease (NDD-CKD) Stage 3-5 complicated by hypertension. This study was a multicenter retrospective analysis conducted from March 1, 2022 to March 31, 2024, involving adult patients with NDD-CKD Stage 3-5 and hypertension, who received Sacubitril/Valsartan either as a monotherapy or in addition to current antihypertensive treatments that were insufficient. The main outcomes measured were blood pressure control, changes in blood pressure and laboratory parameters within 8 weeks post-treatment initiation, and incidence of adverse events. The study included a total of 459 individuals with NDD-CKD Stage 3-5 and hypertension. At the study endpoint, mean systolic blood pressure, diastolic blood pressure, and pulse pressure were markedly reduced compared to baseline (all p < 0.001). The average blood pressure reductions were 12.17 (4.66, 22.00), 6.00 (0.67, 12.66), and 6.67 (0.08, 14.00) mmHg, respectively. Throughout the study period, 96 patients (20.92%) with NDD-CKD Stage 3-5 developed worsening renal function, 15 patients (3.27%) developed hyperkalemia, and 49 patients (10.68%) experienced symptomatic hypotension. Overall, there were no significant differences in the changes in serum creatinine, estimated glomerular filtration rate, and serum potassium before and after treatment (p = 0.28, p = 0.91, p = 0.61, respectively). Sacubitril/Valsartan significantly lowers blood pressure in patients with NDD-CKD Stage 3-5 complicated by hypertension, with good safety profiles. Trial Registration: ClinicalTrials.gov identifier: ChiCTR2400086079

Background Vascular calcification is highly prevalent and associated with mortality in hemodialysis patients. However, extreme splanchnic arterial calcification in calciphylaxis with poor prognosis raises questions regarding the reliability of previous vascular calcification scoring methods. Therefore, this study aimed to examine the distribution characteristics of abdominal aortic branch calcification and identify a more reliable predictor of mortality in hemodialysis patients.Methods The cohort study included 237 hemodialysis patients. The distribution characteristics of abdominal aortic branch calcification were determined by quantifying the calcification volumes. The primary and secondary outcomes were all-cause mortality and new-onset cardiovascular events, respectively. We compared the prognostic values of abdominal aortic branch calcification and constructed a predictive nomogram model.Results The prevalence of abdominal vascular calcification in hemodialysis patients was 95.36%, with the highest prevalence in the abdominal aorta (88.61%) and internal iliac artery (85.65%). During a median follow-up period of 3.92 years, 137 patients died. Internal iliac artery and mesenteric artery calcification showed the greatest predictive values for mortality. Internal iliac artery calcification and serum albumin level were independently associated with mortality in hemodialysis patients (p < .001). The nomogram model constructed with internal iliac artery calcification, serum albumin level, age, and comorbid cardiovascular disease was well discriminative, calibrated, and clinically applicable for predicting 3-year survival.Conclusion Abdominal aortic branch calcification, particularly internal iliac artery calcification, is a preferable prognostic predictor than abdominal aorta or coronary artery calcification in hemodialysis patients.

Low muscle mass (LMM) and mild anemia (MA) are prevalent yet often overlooked conditions in middle-aged and older adults, each independently associated with adverse health outcomes. However, evidence regarding their combined effect on mortality remains limited. This study aimed to investigate the joint association of LMM and MA with all-cause, cardiovascular, and cancer mortality in a national sample of U.S. adults. We analyzed data from 10,313 participants aged 45 years and older from the National Health and Nutrition Examination Survey (NHANES) 1999–2006 and 2011–2018, with mortality follow-up through December 2019. LMM was defined using appendicular skeletal muscle mass index (ASM/BMI), and MA was classified based on hemoglobin levels according to WHO criteria. Multivariable Cox proportional hazards models were used to assess individual and joint associations, adjusting for sociodemographic, lifestyle, and clinical factors. Over a median follow-up of 15.3 years, individuals with both LMM and MA had significantly elevated risks of all-cause (HR = 2.43; 95

BACKGROUND & AIMS:A newly developed low-attenuation muscle index (LAMI) reflects the relationship of the degree of adipose tissue infiltration in low-attenuation muscle and the skeletal muscle quality on computed tomography (CT) images. We investigated the relationship between CT-derived LAMI and ratio of low-attenuation muscle area to skeletal muscle area (LAMA/SMA) at transverse process of the first lumbar vertebra (L1) and all-cause death in dialysis patients. METHODS:This retrospective cohort study of initial-dialysis patients enrolled from January 1, 2014, to June 30, 2020. The endpoint of all-cause death was recorded up to December 31, 2022. Patients were divided into low- (n = 408) and high- (n = 425) LAMI groups according to the sex-based LAMI cutoff value. Baseline clinical data, CT-derived parameters, survival rates and survival times were compared between the two groups. Restricted cubic spline was used to explore the relationships between LAMI and all-cause death separately for men and women. Multivariate Cox regression analysis and stepwise Cox regression analysis were used to analyze the association between LAMI and all-cause death. RESULTS:A total of 833 patients were eligible to analysis, and 536 (64.35 %) patients were male. The median follow-up time was 3.86 years (range, 0-9.11), and 225 (27.01 %) patients died during follow-up period. The low-LAMI group exhibited significantly lower low-attenuation muscle radiodensity [6.35(4.33,7.67)HU vs. 7.58(6.06,8.92)HU] and LAMA/SMA ratio [0.35(0.27,0.44) vs. 0.43(0.34, 0.51)], yet significantly greater skeletal muscle radiodensity (41.50 [7.09]HU vs. 29.60 [7.46]HU) compared to the high-LAMI group (all P < 0.001). Additionally, this group had a significantly lower incidence of all-cause death (20.3 % vs. 33.4 %) and significantly longer survival time (50.97[24.98]months vs. 44.90[23.92]months) (both P < 0.001). According to the sex-based restricted cubic spline models, linear relationships between LAMI and all-cause death were found for men and women (both nonlinear P > 0.05). Multivariate Cox regression analysis and stepwise Cox regression analysis revealed that a low LAMI and a low LAMA/SMA ratio were both independent protective factors of all-cause death in dialysis patients (all P < 0.01). CONCLUSIONS:Adipose tissue infiltration in skeletal muscle is not always a harmful phenotype for dialysis patients, when its area is relatively localized.

Secondary hyperparathyroidism (SHPT) is characterized by parathyroid hyperplasia, persistently elevated parathyroid hormone levels, and disturbances in mineral metabolism. Currently, a considerable amount of literature has consistently shown that thermal ablation is effective in maintaining parathyroid hormone levels within an appropriate range, normalizing calcium and phosphorus levels, improving clinical symptoms, and reducing the volume of parathyroid glands. However, there are currently no established guidelines regarding its utilization. The Asian consensus statement of experts on thermal ablation for SHPT in chronic kidney disease was jointly initiated by experts from China and Korea in the fields of nephrology, interventional ultrasound or radiology, thyroid surgery, ultrasound medicine, nuclear medicine, and diagnostic radiology-to formulate recommendations aimed at establishing standardized protocols for thermal ablation targeting the parathyroid glands. Based on the systematic review of literatures related to ultrasound-guided thermal ablation of parathyroid glands and the professional opinions of experts, the consensus statement covers the relevant content regarding thermal ablation treatment for SHPT, including indications, contraindications, pre-ablation evaluation, operational procedures, post-ablation follow-up, therapeutic effect evaluation, complications prevention and treatment. According to the Grading of Recommendations Assessment, Development and Evaluation, a total of 18 recommendations were given. This consensus statement will positively promote the standardization of ultrasound-guided thermal ablation of parathyroid glands.

This study aimed to assess the efficacy and safety of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in lowering lipid levels among chronic kidney disease (CKD) patients, including those with stages 4–5 CKD. CKD patients with atherosclerotic cardiovascular disease treated between January 2022 and December 2022 at Zhong Da Hospital affiliated with Southeast University were enrolled in this study. Patients received either evolocumab or alirocumab for three months, either in combination with statin therapy with or without ezetimibe. Efficacy and safety measures were compared among the different groups before and after treatment. A total of 496 CKD patients were included in the study, comprising 263 with stages 1–2 CKD, 170 with stage 3 CKD, and 63 with stages 4–5 CKD. Among them, 301 patients were classified into the atherosclerotic cardiovascular disease (ASCVD) group, whereas 195 were classified into the very-high-risk ASCVD group. LDL-C, total cholesterol (TC), and lipoprotein (a) (Lp(a)) levels decreased significantly in all groups, including stages 4–5 CKD patients, after treatment (P < 0.05). The serum creatinine (Scr) level and estimated glomerular filtration rate (eGFR) remained stable during treatment (P > 0.05). The incidence of adverse drug events did not differ significantly among the different kidney function groups (P ≥ 0.05). PCSK9 inhibitors can be effectively and safely utilized for lipid-lowering therapy in CKD patients, even those with stages 4–5 CKD. Not applicable.

Acute kidney injury (AKI) is a severe syndrome with rapid kidney function decline, increasing the risk of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Macrophages are involved in acute phase of AKI and contribute to AKI-CKD transition, however the mechanisms remain unclear. The triggering receptor expressed on myeloid cells 2 (TREM2), a significant regulator within macrophages, has diverse roles in diseases, such as modulating immune responses in neurodegenerative disorders and influencing tumor microenvironments in cancer. While studies have shown TREM2 knockout worsens kidney injury after obstruction or ischemia-reperfusion injury (IRI), macrophage-specific TREM2 knockout have protective effects in the late stage of hepatic ischemia/reperfusion, highlighting the complex role of TREM2 in disease pathogenesis. Thus, elucidating the function of TREM2 in macrophages is crucial for understanding the AKI - CKD transition and identifying potential therapeutic targets. In-vivo and in-vitro experiments were done to study how macrophage TREM2 deficiency affects kidney repair after IRI. In-vivo, macrophage-specific TREM2 knockout (LysM-Cre+ TREM2fl/fl, TREM2 MKO) and wild-type (LysM-Cre− TREM2fl/f, WT) mice were made using CRISPR/Cas9. A unilateral renal IRI mouse model was established. Ischemic kidneys were collected at 1, 3, 7 days after AKI for histopathology, qRT-PCR to analyze kidney injury molecules, and western blot for signaling pathways. In-vitro, Raw264.7 cells had TREM2 expression reduced with lentivirus vectors. Normal and TREM2-knockdown cells were treated with LPS, and qRT-PCR measured inflammatory cytokine levels. Proteomics and RNA sequencing were used to find the underlying molecular mechanisms. Upon LPS induction in Raw264.7 and TREM2-kd Raw264.7 cells, compared with the normal group, the mRNA level of the inflammatory factor IL-6 was significantly decreased in TREM2-kd Raw264.7 cells (P = 0.0292), and the expression of iNOS in pro-inflammatory M1 macrophages was downregulated (P = 0.0273). In in-vivo experiments, there was no significant difference in the degree of tubular damage shown by renal pathology between MKO and WT mice after 1 and 3 days of IRI, while the renal tubular damage score was significantly lower at 7 days after IRI compared with WT mice. Genes involved in kidney injury in the kidneys demonstrated a similar pattern. Gene expression analysis showed no significant difference in the expression of renal injury-related factors between the two groups after 1 and 3 days of IRI. However, the expression of NGAL (P = 0.0090) and PAI (P = 0.0484) mRNA was down-regulated in the TREM2 MKO group after 7 days of IRI. Examination of apoptosis-related proteins Bax and Bcl2 in the IRI 7-day kidneys of TREM2 MKO and WT groups showed no differences. Proteomics and RNA sequencing analyses are currently underway. TREM2 deficiency in macrophages promotes renal repair 7 days after renal IRI, which is inconsistent with the results of systemic TREM2 knockout. This discrepancy may be attributed to the differential effects of TREM2 in macrophages compared with other cell types. A comprehensive understanding of the role of macrophage TREM2 in the AKI-CKD transformation is essential. Currently, we are optimizing the IRI 14-day and 28-day models to further explore the role of macrophage TREM2 in this transformation. We anticipate that RNA sequencing and proteomics data will provide insights into how macrophage TREM2 exerts its renoprotective effects.

Introduction:The prevalence of urinary myeloid bodies in Fabry disease patients and their correlation with renal involvement remains unclear. Methods:This single-center, retrospective study included 25 patients with Fabry disease and 27 controls. We analyzed 24-h urine samples for the presence of urinary myeloid bodies and evaluated clinical data, including serum creatinine, estimated glomerular filtration rate (eGFR), 24-h urinary protein levels, α-Gal A, and Lyso-GL-3. Seven Fabry patients underwent analysis of urine samples before and after 1 year of enzyme replacement therapy (ERT). Results:Urinary myeloid bodies were detected in 84% of Fabry patients (21 out of 25), with no significant gender differences. None of the healthy controls or patients with other renal disease patients had urinary myeloid bodies. Among the Fabry patients with myeloid bodies, 48% had no proteinuria, and 52% were in CKD1 stage G1. Furthermore, urinary myeloid bodies were detected in 4 patients under the age of 20, despite the absence of or only minimal proteinuria, and these patients all exhibited a substantial number of myeloid bodies. After 1 year of ERT, significant reductions in both the count (p = 0.043) and area ratio (p = 0.028) of myeloid bodies were observed. Conclusion:Urinary myeloid bodies are specific to Fabry disease and are associated with early renal injury, even in the absence of proteinuria. These findings suggest that urinary myeloid bodies may serve as a noninvasive biomarker for the early diagnosis of Fabry disease and for monitoring the efficacy of ERT.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in GLA gene, which result in deficient α-galactosidase A activity, leading to intralysosomal accumulation of metabolic substrates and multi-organ injury. Due to the heterogeneity of clinical phenotypes and limitations of current diagnostic modalities, the diagnosis of FD remains challenging. Enzyme replacement therapy is the cornerstone of FD treatment. However, this therapy cannot fully reverse pre-existing organ damage, and patients will still face an unfavorable prognosis. The mechanisms of organ injury in FD cannot fully explain reduced enzyme activity alone and therefore warrant further elucidation. In recent years, omics, including transcriptomics, proteomics, and metabolomics, have demonstrated great potential for elucidating FD pathophysiology, identifying novel biomarkers, and uncovering therapeutic targets. This review presents the pathophysiological mechanisms of FD in its principal target organs and summarizes recent advances in omics applied to its primary target organs, chiefly the kidney and heart. Omics-based investigations hold promise for advancing precision medicine in FD, offering new avenues for early diagnosis and personalized therapy.

BACKGROUND:Calciphylaxis, also termed calcific uremic arteriolopathy (CUA), is a rare and potentially fatal vasculopathic disorder predominantly affecting patients with end-stage kidney disease (ESKD), particularly those undergoing dialysis or who have recently received kidney transplantation. The hallmark histopathological features of CUA encompass medial calcification of systemic arterioles, intimal fibrosis, and thrombosis. In contrast, Acquired Reactive Perforating Collagenosis (ARPC), a rare perforating dermatosis frequently associated with systemic diseases, is characterized by the transcutaneous elimination of degenerated dermal collagen fibers through the epidermis. Despite the clinical resemblance of cutaneous lesions between CUA and ARPC, their therapeutic approaches differ substantially. Misdiagnosis may result in delayed appropriate treatment and consequently poor prognosis. CASE PRESENTATION:This report describes three cases of ARPC that were initially misdiagnosed as CUA at external institutions. CONCLUSIONS:This report aims to provide clinicians with valuable insights to enhance the accurate diagnosis and optimal management of these two distinct conditions. CLINICAL TRIAL NUMBER:Not applicable.

The ATP6V0A4 gene encodes the a4 subunit of vacuolar H+-ATPase (V-ATPase), which mediates hydrogen ion transport across the membrane. Previous studies have suggested that mutations in ATP6V0A4 consistently result in a loss of function, impairing the hydrogen ion transport efficacy of V-ATPase and leading to distal renal tubular acidosis and sensorineural hearing loss. Here, we identified a 32-year-old male patient and his father, both of whom harbored a heterozygous ATP6V0A4 p.V512L mutation and exhibited hypochloremic metabolic alkalosis, acidic urine, and hypokalemia. Through a series of protein structural analyses and functional experiments, the V512L mutation was confirmed as a gain-of-function mutation in the ATP6V0A4 gene. V512-a4 increased a4 subunit expression abundance by enhancing V512L-a4 stability and reducing its degradation, which in turn potentiated the capacity of V-ATPase to acidify the tubular lumen, leading to acidic urine and metabolic alkalosis. Through mutant V512L-a4 subunit structure-based virtual and experimental screening, we identified F351 (C25H26FN3O2S), a small-molecule inhibitor specifically targeting the V512L-a4 mutant. In conclusion, we identified a gain-of-function mutation in the ATP6V0A4 gene, broadening its phenotypic and mutational spectrum, and we provide valuable insights into potential therapeutic approaches for diseases associated with ATP6V0A4 mutations.

BACKGROUND:Cardiac valve calcification (CVC) is common in dialysis patients and associated with increased cardiovascular risk. However, early screening has been limited by cost concerns. This study aimed to develop and validate a machine learning model to enhance early detection of CVC. METHODS:Data were collected at four centers between 2020 and 2023, including 852 dialysis patients in the development dataset and 661 in the external validation dataset. Predictive factors were selected using LASSO regression combined with univariate and multivariate analyses. Machine learning models including CatBoost, XGBoost, decision tree, support vector machine, random forest, and logistic regression were used to develop the CVC risk model. Model performance was evaluated in both validation sets. Risk thresholds were defined using the Youden index and validated in the external dataset. RESULTS:In the development dataset, 32.9% of patients were diagnosed with CVC. Age, dialysis duration, alkaline phosphatase, apolipoprotein A1, and intact parathyroid hormone were selected to construct the CVC risk prediction model. CatBoost exhibited the best performance in the training dataset. The logistic regression model demonstrated the best predictive performance in both internal and external validation sets, with AUROCs of 0.806 (95% CI 0.750-0.863) and 0.757 (95% CI 0.720-0.793), respectively. Calibration curves and decision curves confirmed its predictive accuracy and clinical applicability. The logistic regression model was selected as the optimal model and achieved excellent risk stratification in CVC risk prediction. CONCLUSION:The predictive model effectively identifies CVC risk in dialysis patients and offers a robust tool for early detection and improved management.