Risk factors and outcomes in patients who switched from peritoneal dialysis to physician-oriented or patient-oriented kidney replacement therapy.

BACKGROUND: We aimed to compare the cardiovascular events and mortality in patients who underwent either physician-oriented or patient-oriented kidney replacement therapy (KRT) conversion due to discontinuation of peritoneal dialysis (PD). METHODS: Patients with end-stage kidney disease who were receiving PD and required a switch to an alternative KRT were included. They were divided into physician-oriented group or patient-oriented group based on the decision-making process. Logistic regression analysis was used to explore the influencing factors related to KRT conversion in PD patients. The association of physician-oriented or patient-oriented KRT conversion with outcomes after the conversion was assessed by using Cox proportional hazards models. RESULTS: A total of 257 PD patients were included in the study. The median age at catheterization was 35 years. 69.6% of the participants were male. The median duration of PD was 20 months. 162 participants had patient-oriented KRT conversion, while 95 had physician-oriented KRT conversion. Younger patients, those with higher education levels, higher income, and no diabetes were more likely to have patient-oriented KRT conversion. Over a median follow-up of 39 months, 40 patients experienced cardiovascular events and 16 patients died. Physician-oriented KRT conversion increased nearly 3.8-fold and 4.0-fold risk of cardiovascular events and death, respectively. After adjusting for confounders, physician-oriented KRT conversion remained about a 3-fold risk of cardiovascular events. CONCLUSION: Compared to patient-oriented KRT conversion, PD patients who underwent physician-oriented conversion had higher risks of cardiovascular events and all-cause mortality. Factors included age at catheterization, education level, annual household income, and history of diabetes mellitus.

Cobaltosic oxide-polyethylene glycol-triphenylphosphine nanoparticles ameliorate the acute-to-chronic kidney disease transition by inducing BNIP3-mediated mitophagy.

Accumulating evidence highlights mitochondrial dysfunction as a crucial factor in the pathogenesis of acute kidney injury (AKI); thus, novel therapeutic strategies maintaining mitochondrial homeostasis are highly anticipated. Recent studies have shown that cobaltosic oxide has peroxidase-like catalytic activities, although its role and mechanism remain elusive in AKI. In the present study, we synthesized and identified cobaltosic oxide-polyethylene glycol-triphenylphosphine (COPT) nanoparticles by conjugating cobaltosic oxide with polyethylene glycol and triphenylphosphine, to improve its biocompatibility and mitochondria-targeting property. We found that COPT preferentially accumulated in the kidney proximal tubule cells, and significantly alleviated ischemic AKI in mouse models and gentamicin induced-AKI in the zebrafish model. COPT also inhibited the transition from AKI to chronic kidney disease (CKD), with few side effects. Further studies demonstrated that COPT localized in the mitochondria, and ameliorated hypoxia-reoxygenation-mediated mitochondrial damage through enhancing mitophagy in vitro and in vivo. Mechanistically, COPT dose-dependently induced the expression of Bcl-2/adenovirus E1B 19-kDa interacting protein (BNIP3), while knockdown of BNIP3 attenuated COPT-induced mitophagic flux and mitochondrial protection. Thus, our findings suggest that COPT nanoparticles ameliorate AKI and its progression to CKD through inducing BNIP3-mediated mitophagy, indicating that COPT may serve as a promising mitochondria-targeting therapeutic agent against AKI.

Imbalanced lipid homeostasis caused by membrane αKlotho deficiency contributes to the acute kidney injury to chronic kidney disease transition.

After acute kidney injury (AKI), renal tubular epithelial cells (RTECs) are pathologically characterized by intracellular lipid droplet (LD) accumulation, which are involved in RTEC injury and kidney fibrosis. However, its pathogenesis remains incompletely understood. The protein, αKlotho, primarily expressed in RTECs, is well known as an anti-aging hormone wielding versatile functions, and its membrane form predominantly acts as a co-receptor for fibroblast growth factor 23. Here, we discovered a connection between membrane αKlotho and intracellular LDs in RTECs. Fluorescent fatty acid (FA) pulse-chase assays showed that membrane αKlotho deficiency in RTECs, as seen in αKlotho homozygous mutated (kl/kl) mice or in mice with ischemia-reperfusion injury (IRI)-induced AKI, inhibited FA mobilization from LDs by impairing adipose triglyceride lipase (ATGL)-mediated lipolysis and lipophagy. This resulted in LD accumulation and FA underutilization. IRI-induced alterations were more striking in αKlotho deficiency. Mechanistically, membrane αKlotho deficiency promoted E3 ligase peroxin2 binding to ubiquitin-conjugating enzyme E2 D2, resulting in ubiquitin-mediated degradation of ATGL which is a common molecular basis for lipolysis and lipophagy. Overexpression of αKlotho rescued FA mobilization by preventing ATGL ubiquitination, thereby lessening LD accumulation and fibrosis after AKI. This suggests that membrane αKlotho is indispensable for the maintenance of lipid homeostasis in RTECs. Thus, our study identified αKlotho as a critical regulator of lipid turnover and homeostasis in AKI, providing a viable strategy for preventing tubular injury and the AKI-to-chronic kidney disease transition.

Geriatric Nutritional Risk Index and Risk of Mortality in Critically Ill Patients With Acute Kidney Injury: A Multicenter Cohort Study.

OBJECTIVES: Malnutrition is associated with adverse outcomes in acute or chronic diseases. However, the prediction value of the Geriatric Nutritional Risk Index (GNRI) in critically ill patients with acute kidney injury (AKI) has not been well studied. METHODS: Data was extracted from the Medical Information Mart for Intensive Care III (MIMIC-III) and the electronic intensive care unit database. We used two nutritional indicators, the GNRI and the modified Nutrition Risk in Critically ill (NUTRIC) score, to evaluate the relationship between the nutritional status of patients with AKI and prognosis. The outcome is in-hospital mortality and 90-day mortality. The prediction accuracy of GNRI was compared with the NUTRIC score. RESULTS: A total of 4,575 participants with AKI were enrolled in this study. The median age of 68 (interquartile range, 56-79) years, and 1,142 (25.0%) patients experienced in-hospital mortality, and 1,238 (27.1%) patients experienced 90-day mortality. Kaplan-Meier survival analysis indicated that lower GNRI levels and high NUTRIC score are associated with lower in-hospital and 90-day survival of patients with AKI (P < .001 by log-rank test). After multivariate adjustment, Cox regression analysis demonstrated a 2-fold increased risk of in-hospital (hazard ratio = 2.019, 95% confidence interval: 1.699-2.400, P < .001) and 90-day (hazard ratio = 2.023, 95% confidence interval: 1.715-2.387, P < .001) mortality in the low GNRI group. Moreover, the multivariate-adjusted Cox model containing GNRI had higher prediction accuracy for the prognosis of patients with AKI than that with NUTRIC score (AUCGNRI model vs. AUCNUTRIC model for in-hospital mortality = 0.738 vs. 0.726, AUCGNRI model vs. AUCNUTRIC model for 90-day mortality = 0.748 vs. 0.726). In addition, the prediction value of GNRI was validated by the electronic intensive care unit database (7,881 patients with AKI) with satisfying performance (AUCGNRI model = 0.680). CONCLUSIONS: Our results demonstrated that GNRI is strongly associated with survival in patients in the intensive care unit coexisting with AKI, and the GNRI has a superior predictive value than the NUTRIC score.

Visit-to-visit ultrafiltration volume variability predicts all-cause mortality in patients receiving hemodialysis.

PURPOSE: Little is known about the effect of visit-to-visit ultrafiltration volume (UV) variability on the outcome. In this study, we investigated the association between visit-to-visit UV variability and all-cause mortality in patients receiving hemodialysis (HD). METHODS: We consecutively enrolled patients who received maintenance HD in our center from March 2015 to March 2021. UV variability was defined using standard deviation (UVSD) and coefficient of variation (UVCV) (standard deviation divided by the mean). The relationship between UV variability and all-cause mortality was assessed using univariate and multivariate Cox proportional hazard regression models. Receiver operating characteristic curves were used to evaluate the predictive abilities of UVSD and UVCV for short-term and long-term survival rates. RESULTS: A total of 283 HD patients were included. The mean age was 57.54 years, and 53% were males. Follow-up was done for a median of 3.38 years (IQR 1.83-4.78). During the follow-up period, 73 patients died. Cox proportional hazards models indicated that UVSD and UVCV (higher versus lower) were positively associated with all-cause mortality (p=.003 and p<.001, respectively), while in multivariable-adjusted models, only higher UVCV remained significantly associated with all-cause mortality in patients receiving HD (HR 2.55 (95% CI 1.397-4.654), p=.002). Moreover, subgroup analyses showed that the predictive performance of UVCV was more accurate among older patients, males and patients with comorbidities. CONCLUSIONS: Visit-to-visit UV variability, especially UVCV, is a helpful indicator for predicting all-cause mortality in patients receiving HD, especially for older patients, males and those with comorbidities.

Daily Walking Dose and Health-related Quality of Life in Patients With Chronic Kidney Disease.

OBJECTIVE: Exercise, like daily walking, may improve overall health and impede progression of chronic kidney disease (CKD); however, no specific walking dose has been recommended for patients with CKD. We aimed to investigate the association between daily walking steps and health-related quality of life (HRQOL) in adults with CKD. DESIGN AND METHODS: The walking steps of patients with CKD were extracted from the We Run mobile application. Their average daily walking steps were calculated and subdivided into the low-, middle-, and high-level groups. HRQOL was assessed using the physical component summary (PCS) and mental component summary (MCS) of the MOS 36 Short Form Health Survey (SF-36). RESULTS: A total of 558 adults (50.5%, men) with an average age of 40.2 (±13.8) years were enrolled. The median daily step count was 7,404 steps. The daily walking step count demonstrated an inverse U-shaped relationship with the SF-36 and subscale scores. Participants with daily walking steps between 7,000 and 12,000 have the highest PCS (68.1 ± 12.2) and MCS scores (70.0 ± 19.5). The multiple linear regression model showed that compared with patients with a daily step count of 7,000 to 12,000, patients with a daily step count >12,000 had a significantly lower MCS score (P < .001), while patients with a daily step count <7,000 had significantly lower PCS (P < .001) and MCS scores (P = .034). Moreover, the multivariable logistic regression model showed that patients with a daily step count >12,000 had significantly lower mental health-related quality (odds ratio [OR], 2.188; 95% confidence interval [CI], 1.079-1.439 for low MCS), while those with a daily step count <7,000 had a significantly lower HRQOL than the 7,000 to 12,000 daily step count group (OR, 2.113; 95% CI, 1.203-3.711 for low PCS; OR, 2.099; 95% CI, 1.210-3.643 for low MCS). CONCLUSIONS: These findings suggest that daily walking steps between 7,000 and 12,000 are associated with high HRQOL in adults with CKD.

Arteriolar hyalinosis and renal outcomes in patients with immunoglobulin A nephropathy.

BACKGROUND: The relationship between arteriolar hyalinosis and renal progression in immunoglobulin A nephropathy (IgAN) is not fully understood. We aimed to investigate the clinicopathological features and outcomes of IgAN with or without arteriolar hyalinosis. METHODS: A total of 762 diagnosed with IgAN patients were retrospectively analyzed. We classified IgAN patients into two groups with or without arteriolar hyalinosis. Then, the clinicopathological characteristics of the two groups were compared. We used Kaplan-Meier survival analysis to compare the composite kidney outcome of the two groups and applied multivariate Cox regression analyses to test the association between arteriolar hyalinosis and composite kidney outcome. RESULTS: Overall, 412 (54.1%) patients had arteriolar hyalinosis, including 173 patients diagnosed with hypertension. IgAN patients with arteriolar hyalinosis were older and had higher proteinuria, urea, uric acid, and blood pressure, while lower eGFR than those without arteriolar hyalinosis. Subgroup analysis showed similar results in IgAN patients with hypertension. Kaplan-Meier survival analysis showed that IgAN patients with arteriolar hyalinosis had worse composite kidney outcome than those without arteriolar hyalinosis. In addition, subgroup analysis revealed that patients with hypertension have worse composite kidney outcome than those without hypertension. Multivariate Cox regression analyses confirm that arteriolar hyalinosis (HR 2.57; 95% CI 1.41-4.69; p = 0.002) is an independent risk factor for renal prognosis in IgAN patients. CONCLUSIONS: Our study demonstrated that arteriolar hyalinosis is a common vascular lesion in IgAN patients. Arteriolar hyalinosis connects closely with hypertension, and arteriolar hyalinosis is an independent risk factor for renal prognosis in patients with IgAN.

IRF-1 promotes renal fibrosis by downregulation of Klotho.

Although the key role of renal fibrosis in the progression of chronic kidney disease (CKD) is well known, the causes of renal fibrosis are not fully clarified. In this study, interferon regulatory factor 1 (IRF-1), a mammalian transcription factor, was highly expressed in fibrotic kidney of CKD patients. Concordantly, the expression level of IRF-1 was significantly elevated in the kidney of unilateral ureteral obstruction (UUO) and Adriamycin nephropathy (ADR) mice. In tubular epithelial cells, overexpression of IRF-1 could induce profibrotic markers expression, which accompanied by dramatic downregulation of Klotho, an important inhibitor of renal fibrosis. Luciferase reporter analysis and ChIP assay revealed that IRF-1 repressed Klotho expression by downregulation of C/EBP-ß, which regulates Klotho gene transcription via directly binding to its promoter. Further investigation showed that tumor necrosis factor-alpha may be an important inducement for the increase of IRF-1 in tubular epithelial cells after UUO and genetic deletion of IRF-1 attenuated renal fibrosis in UUO mice. Hence, these findings demonstrate that IRF-1 contributes to the pathogenesis of renal fibrosis by downregulation of Klotho, and suppresses IRF-1 may be a potential therapeutic target for CKD.

MicroRNA-34a Promotes Renal Fibrosis by Downregulation of Klotho in Tubular Epithelial Cells.

Renal fibrosis is the main pathological characteristic of chronic kidney disease (CKD), whereas the underlying mechanisms of renal fibrosis are not clear yet. Herein, we found an increased expression of microRNA-34a (miR-34a) in renal tubular epithelial cells of patients with renal fibrosis and mice undergoing unilateral ureteral obstruction (UUO). In miR-34a-/- mice, miR-34a deficiency attenuated the progression of renal fibrosis following UUO surgery. The miR-34a overexpression promoted epithelial-to-mesenchymal transition (EMT) in cultured human renal tubular epithelial HK-2 cells, which was accompanied by sharp downregulation of Klotho, an endogenous inhibitor of renal fibrosis. Luciferase reporter assay revealed that miR-34a downregulated Klotho expression though direct binding with the 3' UTR of Klotho. Conversely, overexpression of Klotho prevented miR-34a-induced EMT in HK-2 cells. Furthermore, results showed that miR-34a was induced by transforming growth factor ß1 (TGF-ß1) through p53 activation, whereas dihydromyricetin could inhibit TGF-ß1-induced miR-34a overexpression. Accordingly, dihydromyricetin administration dramatically restored the aberrant upregulation of miR-34a and Klotho reduction in obstructed kidney, and markedly ameliorated renal fibrosis in the Adriamycin nephropathy and UUO model mice. These findings suggested that miR-34a plays an important role in the progression of renal fibrosis, which provides new insights into the pathogenesis and treatment of CKD.

The clinical characteristic and outcome of skin and soft tissue infection in immunosuppressive patients with nephrotic syndrome.

OBJECTIVE: Skin and soft tissue infection (SSTI) is the most common of infectious diseases with high morbidity and mortality. However, the clinical characteristics of SSTI in patients with nephrotic syndrome (NS), especially in those patients who received immunosuppressive therapy, are still lacking. The present study was conducted to investigate the clinical characteristics and outcomes of SSTI in patients with NS. METHODS: A retrospective study was carried out among the patients diagnosed with NS and SSTI, who have priorly received or currently have been receiving immunosuppressive therapy between April 2011 and January 2019; the clinical profile included patient's baseline characteristics, clinical presentation, microbiological findings, treatment, and prognosis. RESULTS: A total of 70 patients were analyzed. Results showed that more than half of the patients were under 35 years old, and moderate infection was the most common type of SSTI. Leg and cellulitis were the most common site of lesion and the typical clinical manifestation of SSTI, respectively. Patients in the severe infection group have a higher level of procalcitonin (PCT) and C-reactive protein (CRP), while a lower level of albumin, CD4+ T and CD8+ T cell count. Moreover, the gram-negative bacteria were the primary pathogens of SSTI in patients with NS, and Klebsiella pneumoniae were the most frequent strains isolated from those patients. Besides, patients in the mild and moderate infection groups experienced a better outcome. CONCLUSIONS: Patients with NS and SSTI usually showed a satisfying outcome with proper anti-infection treatment, but severe SSTI can be life-threatening.

High phosphate-induced downregulation of PPARγ contributes to CKD-associated vascular calcification.

Medial arterial calcification associated with hyperphosphatemia is a main cause of cardiovascular mortality in patients with chronic kidney disease (CKD), but the mechanisms underlying high phosphate-induced vascular calcification remain largely unknown. Here, we observed a significant decrease in the expression of peroxisome proliferator-activated receptor-gamma (PPARγ) in calcified arteries both in CKD patients and in a mouse model of CKD with hyperphosphatemia. In vitro, high phosphate treatment led to a decreased expression of PPARγ in mouse vascular smooth muscle cells (VMSCs), accompanied by apparent osteogenic differentiation and calcification. Pretreatment with PPARγ agonist rosiglitazone significantly reversed high phosphate-induced VSMCs calcification. Further investigation showed that methyl-CpG binding protein 2 (Mecp2)-mediated epigenetic repression was involved in high phosphate-induced PPARγ downregulation. Moreover, the expression of Klotho that has the ability to inhibit vascular calcification by regulating phosphate uptake decreased with the PPARγ reduction in VSMCs after high phosphate treatment, and rosiglitazone failed to inhibit high phosphate-induced calcification in VSMCs with knockdown of Klotho or in aortic rings from Klotho-deficient (kl/kl) mice. Finally, an in vivo study demonstrated that oral administration of rosiglitazone could increase Klotho expression and protect against high phosphate-induced vascular calcification in CKD mice. These findings suggest that the inhibition of PPARγ expression may contribute to the pathogenesis of high phosphate-induced vascular calcification, which may provide a new therapeutic target for vascular calcification in CKD patients.

Association of Geriatric Nutritional Risk Index with Mortality in Hemodialysis Patients: A Meta-Analysis of Cohort Studies.

BACKGROUND/AIMS: Geriatric nutritional risk index (GNRI) was developed as a "nutrition-related" risk index and was reported in different populations as associated with the risk of all-cause and cardiovascular morbidity and mortality. Therefore, GNRI can be used to classify patients according to a risk of complications in relation to conditions associated with protein-energy wasting (PEW). However, not all reports pointed to the prognostic ability of the GNRI. The purpose of this study was to assess the associations of GNRI with mortality in chronic hemodialysis patients. METHODS: We electronically searched original articles published in peer-reviewed journals from their inception to September 2018 in The PubMed, Embase, and the Cochrane Library databases. The primary outcome was all-cause and cardiovascular mortality. We pooled unadjusted and adjusted odds ratios (ORs) with 95% confidence intervals (95% CIs) using Review Manager 5.3 software. RESULTS: A total of 10,739 patients from 19 cohort studies published from 2010 to 2018 were included. A significant negative association was found between the GNRI and all-cause mortality in patients with chronic hemodialysis (OR, 0.90; 95% CI, 0.84-0.97, p=0.004) (per unit increase) and (OR, 2.15; 95% CI, 1.88-2.46, p＜0.00001) (low vs. high GNRI). Moreover, there was also a significant negative association between the GNRI (per unit increase) and cardiovascular events (OR, 0.98; 95% CI, 0.97-1.00, p=0.01), as well as cardiovascular mortality (OR, 0.89; 95% CI, 0.80-0.99, p=0.03). CONCLUSION: Our findings supported the hypothesis that the low GNRI is associated with an increased risk of all-cause and cardiovascular mortality in chronic hemodialysis patients. Based on our literature review, GNRI has been found to be an effective tool for identifying patients with nutrition-related risk of all-cause and cardiovascular disease.

High Uric Acid-Induced Epithelial-Mesenchymal Transition of Renal Tubular Epithelial Cells via the TLR4/NF-kB Signaling Pathway.

BACKGROUND: Hyperuricemia is an independent risk factor for causing chronic kidney disease and contributes to kidney fibrosis. After urate crystals get deposited in the kidney, they can cause hyperuricemia nephropathy, leading to glomerular hypertrophy and renal tubular interstitial fibrosis. Recent data showed that uric acid (UA) could induce epithelial mesenchymal transition (EMT) of renal tubular cells, in which NRLP3 inflammatory pathway was involved. However, whether TLR4/NF-κB signaling pathway is also involved in EMT of renal tubular cells induced by UA is not clear. METHODS: Human renal tubular epithelial cells (HK-2) were directly treated with UA and the phenotypic transition was detected by morphological changes and the molecular markers of EMT. The activation of the TLR4/NF-κB signaling pathway induced by UA was measured by Western blot and its involvement was further confirmed by the inhibition of NF-κB activation or knockdown of toll like receptor 4 (TLR4) expression. RESULTS: UA induced obvious morphological changes of HK-2 cell, accompanied with altered molecular markers of EMT including fibronectin, α-SMA and E-cadherin. In addition, UA significantly upregulated the gene expression of interleukin-1ß and tumor necrosis factor-α in a time- and dose-dependent manner. Furthermore, UA significantly activated the TLR4/NF-κB signaling pathway in HK-2 cells, while the inhibition of the TLR4 expression by siRNA and NF-κB activation by PDTC significantly attenuated EMT induced by UA in HK-2 cells. CONCLUSIONS: UA can induce EMT in renal tubular epithelial cells by the activation of the TLR4/NF-κB signaling pathway, and the targeted intervention of the TLR4/NF-κB signaling pathway might effectively inhibit UA-induced renal interstitial fibrosis mediated by EMT.

High Phosphate-Induced Calcification of Vascular Smooth Muscle Cells is Associated with the TLR4/NF-κb Signaling Pathway.

BACKGROUND/AIMS: Hyperphosphatemia is one of the most notable features of chronic kidney disease (CKD). Numerous epidemiological and clinical studies have found that high serum phosphate concentrations are associated with calcification in the coronary arteries. However, the mechanisms underlying the vascular calcification induced by high phosphate have not been understood fully. METHODS: Vascular smooth muscle cells (VSMCs) were cultured in high-phosphate media to induce vascular calcification, which was detected by Alizarin red S staining. Gene expression and protein levels of differentiation markers were determined by real-time RT-PCR and western blotting, respectively. Protein levels of phosphorylated NF-κB and TLR4 were detected by western blotting, and the role of NF-κB/TLR4 was further confirmed by using an NF-κB inhibitor or TLR4 siRNA. RESULTS: Our results showed that high-phosphate media induced obvious calcification of VSMCs. Simultaneously, VSMC differentiation was confirmed by the increased expression of bone morphogenetic protein-2 and Runt-related transcription factor 2 and decreased expression of the VSMC-specific marker SM22α, which was accompanied by the increased expression of inflammatory cytokines. Moreover, a significant upregulation of TLR4 and phosphorylated NF-κB was also detected in VSMCs with high-phosphate media. In contrast, VSMC calcification and the increased expression of inflammatory cytokines were markedly attenuated by pretreatment with TLR4 siRNA and pyrrolidine dithiocarbamic acid, an NF-κB inhibitor. CONCLUSION: These data suggest that high-phosphate conditions directly induce vascular calcification via the activation of TLR4/NF-κB signaling in VSMCs. Moreover, inhibition of the TLR4/NF-κB signaling pathway might be a key intervention to prevent vascular calcification in patients with CKD.

Pyroptosis: The Determinator of Cell Death and Fate in Acute Kidney Injury.

Background: Acute kidney injury (AKI) is kidney damage that leads to a rapid decline in function. AKI primarily occurs when the tubular epithelium is damaged, causing swelling, loss of brush margin, and eventual apoptosis. Research has shown that tubular epithelial cell damage in AKI is linked to cell cycle arrest, autophagy, and regulation of cell death. Summary: Pyroptosis, a type of programmed cell death triggered by inflammation, is believed to play a role in the pathophysiology of AKI. Cumulative evidence has shown that pyroptosis is the main cause of tubular cell death in AKI. Thus, targeted intervention of pyroptosis may be a promising therapeutic approach for AKI. This review delves deep into the cutting-edge research surrounding pyroptosis in the context of AKI, shedding light on its intricate mechanisms and potential implications for clinical practice. Additionally, we explore the exciting realm of potential preclinical treatment options for AKI, aiming to pave the way for future therapeutic advancements. Key Messages: Pyroptosis, a highly regulated form of cell death, plays a crucial role in determining the fate of cells during the development of AKI. This intricate process involves the activation of inflammasomes, which are multi-protein complexes that initiate pyroptotic cell death. By understanding the mechanisms underlying pyroptosis, researchers aim to gain insights into the pathogenesis of AKI and potentially identify new therapeutic targets for this condition.

Immunosuppressant Agents as Add-On Therapy Failed to Improve the Outcome of Immunoglobulin A Nephropathy with Crescent Score C1.

INTRODUCTION: The renoprotective benefits of adding immunosuppressant therapy to corticosteroid (CS) treatment for immunoglobulin A nephropathy (IgAN) patients with less than 25% crescent formation (C1) remain uncertain, warranting further research. METHODS: A retrospective study was conducted on IgAN patients with crescent C1 lesions confirmed by renal biopsy at Xinqiao Hospital between May 1, 2017, and May 1, 2020. Patients were stratified into either the CS treatment group or the CS combined with an additional immunosuppressant therapy group. Follow-up assessments were conducted within 24 months. Propensity score analysis was used to match patients receiving CS and CS + immunosuppressant drug treatment in a 1:1 ratio. Primary outcomes included changes in estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR). Subgroup analyses were performed to evaluate the benefits of different populations. Composite endpoint outcomes comprised a 30% eGFR decrease, end-stage kidney disease (ESKD) necessitating dialysis or transplant, or kidney disease-related mortality. Adverse events were also compared between the two groups. RESULTS: 296 IgAN patients with C1 lesions were included in the analysis. Baseline characteristics indicated that IgAN patients in the CS + immunosuppressant group exhibited poorer renal function and higher UACR levels. Propensity score analysis effectively minimized the influence of baseline clinical characteristics, including age, serum creatinine, initial eGFR, UACR, and 24-h proteinuria. Both treatment groups demonstrated continuous eGFR improvement and significant UACR reduction during follow-up, especially at 6 months. However, no significant differences in eGFR and UACR reduction rates were observed between the two groups throughout the entire follow-up period, both before and after matching. Subgroup analysis revealed improved eGFR in both treatment groups, notably among patients with an initial eGFR below 90 mL/min/1.73 m2. Conversely, IgAN patients with C1 lesions and a cellular crescent ratio exceeding 50% treated with CS and immunosuppressant therapy experienced a significant improvement in renal function and a decline in urinary protein creatinine ratio. Composite endpoint outcomes did not significantly differ between the two groups, while the incidence of adverse events was comparable. CONCLUSION: Our findings suggest that the addition of immunosuppressant therapy to corticosteroid monotherapy did not confer significant therapeutic advantages in patients with C1 lesions compared to CS monotherapy, although some specific patient populations appeared to derive modest benefits from this combined approach.

Comparative analysis of four nutritional scores in predicting adverse outcomes in biopsy-confirmed diabetic kidney Disease.

Malnutrition is associated with adverse outcomes in patients with diabetic kidney disease (DKD). However, it is uncertain which nutritional assessment tools are most effective in predicting the adverse outcomes of DKD. This retrospective study was conducted at a single center and included 367 patients diagnosed with DKD based on biopsy results between August 2009 and December 2018. Four nutritional assessment indices, namely the Prognostic Nutritional Index (PNI), Geriatric Nutritional Risk Index (GNRI), Triglycerides (TG) × Total Cholesterol (TC) × Body Weight (BW) Index (TCBI), and Controlling Nutritional Status (CONUT) score, were selected and calculated. We aimed to assess the association between these nutritional scores and adverse outcomes, including progression to end-stage kidney disease (ESKD), cardiovascular diseases events (CVD), and all-cause mortality. Univariate and multivariate Cox regression analyses, Kaplan-Meier analysis, along with Restricted cubic spline analysis were used to examine the relationship between nutritional scores and adverse outcomes. Furthermore, the area under the curve (AUC) was calculated using time-dependent receiver operating characteristics to determine the predictive value of the four nutritional scores alone and some combinations. Lastly, ordered logistic regression analysis was conducted to explore the correlation between the four nutritional scores and different renal histologic changes. The incidence of ESKD, CVD, and all-cause mortality was significantly higher in patients with DKD who had a lower PNI, lower GNRI, and higher CONUT score. Additionally, The TCBI performed the worst in terms of grading and risk assessment. The PNI offer the highest predictive value for adverse outcomes and a stronger correlation with renal histologic changes compared to other nutritional scores. Patients diagnosed with DKD who have a worse nutritional status are more likely to experience higher rates of adverse outcomes. The PNI might offer more valuable predictive values and a stronger correlation with different renal histologic changes compared to other nutritional scores.

Association between the Triglyceride Glucose Index and All-Cause Mortality in Critically Ill Patients with Acute Kidney Injury.

Introduction: The triglyceride glucose (TyG) index is a reliable alternative biomarker of insulin resistance, but the association between the TyG index and acute kidney injury (AKI) in critically ill patients remains unclear. Methods: The data for the study were extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Cox regression and restricted cubic spline (RCS) analysis were performed to analyze the association between the TyG index and all-cause mortality. Besides, Cox regression was carried out in subgroups of age, gender, BMI, diabetes history, and dialysis status. Results: A total of 7,508 critically ill participants with AKI from the MIMIC-IV database were included in this study, with 3,688 (49.12%) participants failed to survive. In Cox regression, after confounder adjustment, patients with a higher TyG index had a higher risk of all-cause mortality (HR = 1.845, 95% CI = 1.49-2.285, p < 0.001). In RCS, after confounder adjustment, the risk of death was positively correlated with the increased value of the TyG index when TyG index surpassed 10.014. This relationship was validated in age, gender, BMI, diabetes subgroups but not in the dialysis subgroup. Interestingly, RCS analysis demonstrated that, in patients undertaking dialysis, there is a "U"-shaped curve for the value of TyG index and risk of all-cause mortality. When TyG index is less than 10.460, the risk of all-cause mortality would decrease with the increased value of TyG index, while when TyG index is higher than 11.180, the risk of all-cause mortality would increase firmly with the increased value of TyG index. Conclusion: Overall, a higher TyG index is associated with a higher risk of all-cause mortality in critically ill AKI. Interestingly, the relationship in the dialysis subgroup follows a "U"-shaped curve, indicating the importance of proper clinical blood glucose and lipid management in this particular population.

A Klotho-Based Machine Learning Model for Prediction of both Kidney and Cardiovascular Outcomes in Chronic Kidney Disease.

Introduction: This study aimed to develop and validate machine learning (ML) models based on serum Klotho for predicting end-stage kidney disease (ESKD) and cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Methods: Five different ML models were trained to predict the risk of ESKD and CVD at three different time points (3, 5, and 8 years) using a cohort of 400 non-dialysis CKD patients. The dataset was divided into a training set (70%) and an internal validation set (30%). These models were informed by data comprising 47 clinical features, including serum Klotho. The best-performing model was selected and used to identify risk factors for each outcome. Model performance was assessed using various metrics. Results: The findings showed that the least absolute shrinkage and selection operator regression model had the highest accuracy (C-index = 0.71) in predicting ESKD. The features mainly included in this model were estimated glomerular filtration rate, 24-h urinary microalbumin, serum albumin, phosphate, parathyroid hormone, and serum Klotho, which achieved the highest area under the curve (AUC) of 0.930 (95% CI: 0.897-0.962). In addition, for the CVD risk prediction, the random survival forest model with the highest accuracy (C-index = 0.66) was selected and achieved the highest AUC of 0.782 (95% CI: 0.633-0.930). The features mainly included in this model were age, history of primary hypertension, calcium, tumor necrosis factor-alpha, and serum Klotho. Conclusion: We successfully developed and validated Klotho-based ML risk prediction models for CVD and ESKD in CKD patients with good performance, indicating their high clinical utility.

[Genetic and clinical study of three Chinese pedigrees with Fabry disease].

OBJECTIVE: Fabry disease is a rare lysosome storage disease featuring X-linked recessive inheritance. The study was to explore potential mutations of alpha-galactosidase A (GLA) gene and their correlation with clinic manifestations in three Chinese pedigrees with Fabry disease. METHODS: All exons and flanking sequences of GLA gene were amplified with PCR. Potential mutations were detected with bidirectional DNA sequencing. Correlation between particular mutations and clinic features were analyzed. RESULTS: A unreported missense mutation, c.797A>C (D266A) in GLA exon 5 was identified in pedigree 1. Also in exon 5, a missense mutation c.644A>G (N215S) was found in pedigree 2. In pedigree 3, a nonsense mutation c.355C>T (Q119X) was found in exon 2. The c.797A>C mutation was not detected in 200 unrelated male controls. The probands of pedigrees 1 and 3 had presented mainly with skin damage and chronic renal insufficiency, whilst the proband of pedigree 2 had presented with hypertrophic cardiomyopathy. CONCLUSION: The unreported c.797A>C (D266A) mutation is the sixth missense type mutation of the 266th codon of GLA gene, and all other 5 missense mutations reported previously had been confirmed to be responsible for Fabry disease. The c.797A>C mutation, not found in 200 unrelated male controls, may be the causative mutation in pedigree 1. The c.644A>G and c.355C>T mutations were first detected in Chinese patients. Variable phenotypes of Fabry disease may be in part attributed to the natures of particular mutations of GLA gene.