INTRODUCTION:Cardio-renal syndrome type 4 (CRS4) is defined as heart failure driven by chronic kidney disease (CKD). Cardiovascular mortality is the leading cause of death in patients with advanced CKD with current medical treatments exhibiting limited efficacy. Short leukocyte telomere lengths in such patients are correlated with increased mortality, particularly cardiovascular mortality. Here, we examined telomere shortening in mouse and human cardiomyocyte models of CRS4 and its potential protective role by overexpression of telomerase reverse transcriptase. METHODS:We engineered an adeno-associated virus 9 (AAV9) gene therapy JV101, which overexpressed catalytically inactive and nuclear localized human telomerase reverse transcriptase (modhTERT) under cardiac troponin T promoter control. Both in vivo and in vitro models were utilized to conduct a comprehensive evaluation of the therapeutic effects of modhTERT on CRS4. RESULTS:Overexpression of modhTERT recapped myocardial telomeres and reversed cardiac dysfunction, hypertrophy and fibrosis, and mitochondrial dysfunction in two CRS4 mouse models: 5/6 nephrectomy and Angiotensin II - high salt - uninephrectomy. The reversal of cardiac dysfunction by modhTERT was both long-term and persistent. In contrast, beta-blocker administration merely delayed the progression of heart failure in these models, without achieving functional reversal. Surprisingly, JV101 ameliorated kidney function as measured by blood urea nitrogen levels in CKD murine models. Experiments in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) demonstrated that modhTERT bound to myocardial telomeric ends. Transcriptomic analysis of isolated mouse cardiomyocytes revealed that modhTERT reversed differentially repressed genes that were highly enriched in mitochondrial metabolism. Coculture of hiPSC-CMs with serum from hemodialysis patients or indoxyl sulfate toxin induced myocardial contractile dysfunction. Overexpression of modhTERT also blocked further telomere shortening and reversed contractile dysfunction in hiPSC-CMs. CONCLUSIONS:Our results provide proof-of-concept evidence for treating CRS4 by telomere recapping gene therapy.

Cardiovascular-kidney-metabolic (CKM) syndrome significantly impacts a large segment of the general population. The risk factors associated with progression of CKM syndrome as well as all-cause mortality warrant further investigations. In this study, we aimed to assess whether nephrolithiasis history would help to identify the high-risk populations among CKM patients. We conducted a multi-center study involving patients with CKM syndrome at stages 2-3 from 28 urban centers across China. We employed multivariable Cox proportional hazards regression analysis to estimate hazard ratios (HRs) along with their corresponding 95% confidence intervals (CIs) for the associations with a history of nephrolithiasis. Subgroup analyses and sensitivity analyses were performed to enhance the robustness of our findings. A total of 344,220 CKM patients at stages 2-3 were included in this study. Among the participants, 28,451 had a history of nephrolithiasis. When compared to individuals without nephrolithiasis history, those with the history demonstrated an increased risk of progression to CKM stage 4 (HR 1.52, 95% CI [1.48-1.56]) and all-cause mortality (HR 1.08, 95% CI [1.03-1.14]). Similar results were obtained in the participants with asymptomatic nephrolithiasis. Consistent findings were observed through subgroup analyses and sensitivity analyses as well. The history of nephrolithiasis is associated with an elevated risk of incident cardiovascular disease and increased all-cause mortality among CKM patients. These findings highlight the significant role of nephrolithiasis in identifying high-risk populations within CKM patients.

Teaching renal pathology, characterized by complex spatial relationships and dynamic pathological processes, poses significant challenges. Traditional methods such as static slides often fail to convey these concepts effectively. This study evaluated the efficacy of custom-developed renal pathology three-dimensional (3D) animations in enhancing learning outcomes and satisfaction during students’ internal medicine clerkships in nephrology. A randomized controlled trial was conducted. 93 students undertaking nephrology clerkships were randomly assigned 1:1 to either a conventional teaching group or a 3D animation group (intervention group). The intervention group utilized specifically developed 3D animations depicting renal microstructure and the dynamic progression of common pathologies. Teaching effectiveness was assessed via pre- and post-teaching written examinations. Student and faculty satisfaction with the 3D animations was evaluated using 5-point scale questionnaires. Baseline knowledge scores were comparable between groups. Post-teaching scores were significantly higher in the 3D animation group, representing a greater score improvement (34.5 ± 34.8 vs. 19.1 ± 32.4, p = 0.03). Over 95

Obesity is a well-established risk factor for acute kidney injury (AKI), but the underlying mechanisms remain unclear. Here, using murine AKI models, we demonstrate that high-fat diet (HFD)-induced obesity exacerbates renal damage. Multimorbidity analysis identified chemerin (encoded by Rarres2) as a key adipokine linking obesity to renal injury, and Rarres2–/– mice exhibited attenuated renal inflammation and injury. Mechanistically, we revealed that chemokine-like receptor 1 (CMKLR1), the receptor for chemerin, was predominantly expressed on renal macrophages. Single-cell RNA sequencing uncovered distinct Cmklr1hi subsets of mononuclear phagocytes with enhanced chemotactic and proinflammatory signatures. Through in vitro transwell assays and in vivo adoptive transfer experiments, we proved that chemerin–CMKLR1 signaling directly drove macrophage recruitment. The subsequent sustained cytokine secretion dominated immune reprogramming and amplified kidney damage, as evidenced by TNF-α supplementation reversing renal protection in Rarres2–/– mice. This pathological axis was exacerbated in obesity: HFD-fed AKI mice and obese AKI patients showed elevated renal chemerin levels and amplified immune dysfunction. Rarres2–/– mice were protected from HFD-aggravated cisplatin-induced AKI, and this protection was abolished by exogenous TNF-α administration. Collectively, we identified chemerin as a specific inflammatory and metabolic target, mechanistically rooted in immune reprogramming through CMKLR1-dependent macrophage chemotaxis and subsequent TNF-α-mediated inflammation. This pathological process was amplified by HFD-induced elevation of chemerin. Our study indicates that targeting the chemerin–CMKLR1 axis may represent a promising therapeutic strategy for patients with cisplatin-induced AKI, particularly those who also suffer from metabolic syndrome.

INTRODUCTION:Sepsis-associated acute kidney injury (SA-AKI) is frequently complicated by immune paralysis and kidney infection. Despite the spleen's critical immunological role, the neural mechanisms regulating the splenic immune responses during SA-AKI remain unclear. METHODS:To examine this, we used splenic denervation, continuous intrasplenic infusion, single-cell sequencing and neutrophil-specific β2-adrenergic receptor Adrb2 knockout mice to define the role of the splenic norepinephrine-β2-adrenergic receptor (NE/β2-AR) axis in SA-AKI. RESULTS:Our findings indicate that pre-emptive splenic denervation in mice mitigates sepsis-induced kidney injury, whereas local intrasplenic norepinephrine infusion exacerbates kidney damage in a cecal ligation/puncture (CLP) mouse model. Targeted blockade of splenic β2-adrenergic receptor (β2-AR) signaling enhances survival and attenuates kidney damage in CLP mice. Local splenic depletion of neutrophil and neutrophil-specific conditional knockout of Adrb2 demonstrate that NE/β2-AR signaling influences splenic neutrophils, thereby driving the progression of acute sepsis. Mechanistic investigations reveal that splenic NE/β2-AR signaling enhances neutrophil prostaglandin E2 synthesis via the cAMP-response element binding protein pathway, thereby suppressing T helper 1 cell activation, increasing local bacterial infections, and aggravating SA-AKI. CONCLUSIONS:These findings clarify the role of splenic NE/β2-AR signaling in modulating neutrophil-mediated immunosuppression, thereby driving sepsis progression and aggravating kidney damage.

Background: Magnesium is essential for mitochondrial function and muscle regeneration, potentially protecting against low muscle mass (LMM). We examined the association of dietary magnesium intake with LMM risk and skeletal muscle index (SMI), and whether inflammatory indicators mediate this relationship. Methods: A total of 5793 participants aged 20–59 years were included in this study from the National Health and Nutrition Examination Survey (NHANES) conducted from 2011 to 2018. To investigate the association of dietary magnesium intake with LMM and SMI, we applied weighted logistic regression model, linear regression model, restricted cubic spline analysis, subgroup analysis and sensitivity analysis. Inflammatory indicators were assessed using mediation analysis, including the C-reactive protein–albumin–lymphocyte (CALLY) index, neutrophil–platelet score (NP), platelet-to-albumin ratio (PAR) and red blood cell distribution width-to-albumin ratio (RAR) mediation. Results: In the fully adjusted model, participants in the highest magnesium quartile had a reduced risk of LMM, with OR of 0.33 (95% CI: 0.18, 0.60), and increased levels of SMI, with β values of 0.05 (95% CI: 0.04, 0.07). Mediation analysis showed that NP, PAR, and RAR mediated 18%, 13%, and 21% of the association between magnesium and LMM, respectively, and also acted as mediators of the relationship between magnesium and SMI, with mediation ratios of 32%, 24%, and 25%, respectively. Conclusion: Higher dietary magnesium intake was associated with lower LMM risk and higher SMI, partly mediated through inflammatory indicators involving NP, PAR, and RAR. This finding may provide a new perspective on the prevention and management of LMM.

This prospective cohort study investigated the kidney clearance of protein-bound uremic toxins (PBUTs)—specifically, indole sulfate (IS), p-cresol sulfate (pCS), and indole-3-acetic acid (IAA)—across various stages of chronic kidney disease (CKD) stages and their associations with adverse clinical outcomes. From July 2018 to December 2020, 186 non-dialysis CKD patients were enrolled and followed until June 2025. Serum and 24-hour (24 h) urine PBUT levels were measured, and kidney clearances were analyzed. The findings indicated a decrease in the 24 h kidney clearances of IS (Cis), pCS (Cpcs), and IAA (Ciaa) corresponding with a reduction in glomerular filtration rate (GFR) across the CKD stages. For instance, the clearance of indoxyl sulfate was observed to decline from 26.7 mL/min in stage 1 to 2.2 mL/min in stage 5. PBUT clearances and fractional clearances were generally unaffected by 24 h urinary protein levels, with the exception of fractional clearance of IAA. Elevated levels of Cis and Ciaa were independently correlated with decreased risks of renal outcomes (IS: HR 0.964; IAA: HR 0.941) and hospitalization (IS: HR 0.984; IAA: HR 0.961). The study concluded that the 24 h kidney clearances of IS and IAA are independently associated with renal adverse outcomes and hospitalization, with minimal influence from urinary protein excretion.

ObjectiveTo investigate the association between hypothyroidism and incident chronic kidney disease and identify potential mediators.MethodsThis study included a retrospective cohort and Mendelian randomization analysis. Data were obtained from the UK Biobank and FinnGen via the Integrative Epidemiology Unit Open Genome-Wide Association Studies Project. After exclusions, 439,381 participants were included. The risk of incident chronic kidney disease was the primary outcome. Associations were assessed using Fine and Gray models as well as stratified and sensitivity analyses, and the cumulative risk was presented using Kaplan-Meier curves. For Mendelian randomization analyses, causal effects were estimated using the inverse-variance weighted method. Mendelian randomization-Egger regression, Mendelian randomization-pleiotropy residual sum and outlier test, weighted median method, and weighted mode method were used to assess the robustness of the causal estimates. Mediation analysis was conducted to explore the effects of body mass index, inflammatory factors, and senescence-associated secretory phenotype proteins.ResultsHypothyroidism was associated with a higher risk of incident chronic kidney disease (hazard ratio: 1.35, 95% confidence interval: 1.19-1.53). Mendelian randomization analysis supported a causal effect (odds ratio: 8.23, 95% confidence interval: 3.22-21.00). Absolute risk differences increased over time (5 years, 1.10; 8 years, 1.80; 10 years, 2.40; and 12 years, 3.13). Body mass index and obesity partially mediated this effect. Senescence-associated secretory phenotype proteins were also identified as important mediators, including transforming growth factor-alpha, transforming growth factor-beta, transforming growth factor-beta receptors 2 and 3, growth differentiation factor 15, C-X-C motif chemokine-10, matrix metalloproteinase 1, and matrix metalloproteinase 9.ConclusionsHypothyroidism was associated with incident chronic kidney disease. Obesity and senescence-associated secretory phenotype proteins may mediate this relationship.

BACKGROUND:This study aimed to compare uremic toxin removal with expanded hemodialysis against post-dilution online haemodiafiltration therapy in Chinese patients with chronic kidney failure in a single treatment. METHODS:This randomized, controlled, open-label, parallel, multicenter trial enrolled prevalent patients on hemodialysis. The study endpoints were to establish the non-inferiority of expanded hemodialysis versus haemodiafiltration in removing beta-2-microglobulin (β2M) and lambda-free light chains (λFLC) and to evaluate the reduction ratios of urea, alpha-1-microglobulin (α1M), myoglobin, complement factor D, kappa-free light chains (κFLC) and Chitinase-3-like protein 1 (YKL-40) during a mid-week dialysis session. The 95% confidence intervals of the difference in λFLC and β2M reduction ratios with expanded hemodialysis were compared against pre-defined non-inferiority margins (-3.783 and -7.848, respectively). Non-inferior reduction ratios were tested for superiority using hierarchical testing. RESULTS:Overall, 274 adult patients were randomized to expanded hemodialysis (n = 138) or haemodiafiltration (n = 136). No differences in demographics, baseline characteristics, and treatment parameters were observed between the arms. The reduction ratio of λFLC with expanded hemodialysis was superior to haemodiafiltration; reduction ratio difference of 17.0% [95% confidence interval: 14.8%, 19.2%]. The reduction ratio of β2M with expanded hemodialysis was non-inferior to haemodiafiltration; reduction ratio difference of -1.2% [95% confidence interval: -2.5%, 0.2%]. Expanded hemodialysis showed significantly higher removal of α1M, YKL-40, complement factor D, myoglobin, and κFLC than haemodiafiltration therapy. There were no significant differences in Kt/Vurea, urea reduction ratio, and the rate of complications between the arms. CONCLUSION:Our study demonstrates the effectiveness of expanded hemodialysis therapy in removing multiple middle molecules compared to haemodiafiltration therapy, with no observed differences in the overall safety of Chinese patients.

Hemodialysis as the primary renal replacement therapy for patients afflicted by end-stage renal disease, necessitates monitoring of electrolyte cations in the dialysate to ensure the safety and efficacy of the treatment. Concerned elements include calcium, potassium, and sodium. Currently, prevailing detection methods fall short in providing in situ and real-time detection capabilities, highlighting the need of innovation. Elemental analysis of bulk liquids with laser-induced breakdown spectroscopy (LIBS) presents an interesting potential for dialysate monitoring. Methodological research should further aim to achieve simultaneous multi-element determinations in dialysates with high accuracy and precision, using an arrangement compatible with a flowing dialysate and ready for deployment in a clinical environment. In this work, we developed an experimental arrangement tailored for dialysate analysis, integrating an optimized LIBS setup into a circulating dialysate system, which simulated the clinical operation. Such an arrangement allowed generating a stable and hot plasma within a flowing dialysate. The emission lines from calcium, potassium, and sodium were subsequently captured by a detection system optimized for a simultaneous detection of the three elements with concentrations corresponding to those of a real dialysate. Due to self-absorption of the lines, notably self-reversal of the sodium D-lines, univariate regression, usually efficient for processing LIBS spectra of electrolyte cations in a liquid, was revealed insufficient to provide an analytical performance satisfying the requirements of the clinical practice. Data processing based on multivariate regression was thus developed in this work to substantially improve the model prediction performances. More specifically, back-propagation neural networks (BPNN) coupled with feature selection demonstrated the effectiveness to harness the complexity of the spectrum heavily deformed by selfabsorption and self-reversal of the characteristic lines. The resulted models exhibit a limit of detection (LOD) of 0.302, 0.571, and 4.25 mmol/L, respectively for Ca, K, and Na. The prediction performances of the trained models were assessed using independent test samples, yielding root mean square errors of prediction (RMSEP) of 0.106, 0.137, and 0.646 mmol/L for Ca, K, and Na, respectively. Such performances satisfy the clinical requirements for monitoring of electrolyte cations in a dialysate.

Journal Article Accepted manuscript Real-time monitoring of postfilter calcium in regional citrate anticoagulation for continuous kidney replacement therapy Get access Zhang Qi, Zhang Qi Department of Nephrology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Search for other works by this author on: Oxford Academic PubMed Google Scholar Zhang Beiyi, Zhang Beiyi School of Physics and Astronomy, Shanghai Jiao Tong University, Shanghai, China Search for other works by this author on: Oxford Academic PubMed Google Scholar Yue Zengqi, Yue Zengqi School of Physics and Astronomy, Shanghai Jiao Tong University, Shanghai, China Search for other works by this author on: Oxford Academic PubMed Google Scholar Sun Chen, Sun Chen School of Physics and Astronomy, Shanghai Jiao Tong University, Shanghai, China Search for other works by this author on: Oxford Academic PubMed Google Scholar Yu Jin, Yu Jin School of Physics and Astronomy, Shanghai Jiao Tong University, Shanghai, China Correspondence to: Yu Jin; E-mail: [email protected] Search for other works by this author on: Oxford Academic PubMed Google Scholar Ding Feng Ding Feng Department of Nephrology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Correspondence to: Ding Feng; E-mail: [email protected] Search for other works by this author on: Oxford Academic PubMed Google Scholar Nephrology Dialysis Transplantation, gfaf006, https://doi.org/10.1093/ndt/gfaf006 Published: 13 January 2025

Background : Sarcopenia, an age-related syndrome characterized by progressive loss of muscle mass, strength, and function, presents a significant global health burden with limited therapeutic interventions. This study integrates genomic causality, multi-tissue omics, and cellular mediation analyses to identify and prioritize mechanistically grounded therapeutic targets. Methods : A multi-tiered analytical framework was applied, beginning with two-sample Mendelian randomization (MR) to infer causal relationships between 4,907 plasma proteins (cis-pQTLs from 35,559 individuals) and sarcopenia traits in Pan-UK Biobank participants. Bayesian colocalization and transcriptomic validation in human sarcopenia muscle biopsies were employed to prioritize targets. Cellular mediation analysis quantified contributions of immune and stromal cell subtypes to protein-trait pathways using transcriptomic deconvolution. Results : MR identified 1,237 plasma proteins causally associated with sarcopenia traits, with six targets (HGFAC, GATM, HMOX2, F2, LMAN2L, HPGDS) validated through colocalization, transcriptomic expression, and sarcopenia-related dysregulation. Cellular mediation revealed immune mechanisms underlying HGFAC’s effects, with CD4+ regulatory T cells mediating 3.49% of its impact on sarcopenia traits. Prothrombin exhibited muscle-protective effects independent of coagulation. Conclusion : This study establishes a causal map linking plasma proteins to sarcopenia through immune-stromal interactions. The integration of MR, multi-omics validation, and cellular mediation prioritizes six proteins as actionable targets, supporting repurposing of thrombin inhibitors and development of immunometabolic therapies. The framework bridges genomic causality with cellular pathophysiology, advancing precision strategies for age-related muscle decline.

Background:Cardiovascular-kidney-metabolic (CKM) syndrome affects a significant portion of the general population. Urinary albumin-to-creatinine ratio (UACR) is an important indicator of kidney injury. While some studies have indicated associations between UACR within the normal range and mortality outcomes, it remains uncertain whether traditionally normal UACR could help to distinguish the prognosis of CKM patients. Methods:This cohort study included patients with CKM syndrome at stages 2 and 3 and traditionally normal UACR from the China Renal Data System (CRDS) and UK Biobank (UKB) databases. UACR was treated as a continuous variable and categorized into low-normal and high-normal. The associations were initially assessed in the CRDS database and subsequently validated in the UKB database. Multivariable Cox proportional hazards regression was employed to estimate the associations with UACR. Additionally, subgroup analyses and sensitivity analyses were conducted to enhance the robustness of the results. Results:The study encompassed a total of 14 602 patients from the CRDS database and 82 694 patients from the UKB database. Near-linear associations were identified between continuous UACR levels and progression to CKM stage 4, as well as all-cause mortality. When compared with the low-normal UACR group, individuals with high-normal UACR exhibited an elevated risk of progression to CKM stage 4 (HR 1.133, 95% CI 1.026-1.250) and increased all-cause mortality (HR 2.321, 95% CI 1.679-3.208) within the CRDS database. These associations were further corroborated in the UKB database. Consistent findings were also observed through subgroup analyses and sensitivity analyses. Conclusions:The findings indicate that elevated UACR levels within the normal range are significantly associated with poor prognosis among CKM patients at stages 2 and 3. These results underscore the critical role of UACR in identifying high-risk populations, particularly among individuals with metabolic disorders. This information may prove valuable for monitoring and implementing risk intervention strategies for CKM patients.

Objective·To evaluate the clearance and pharmacokinetics/pharmacodynamics (PK/PD) of antibiotics from the perspective of protein binding rates in critically ill patients undergoing intermittent hemodialysis (IHD), in order to explore the association between protein binding rate and dialysis clearance of antibiotics, and to provide theoretical basis for developing antibiotic dosing regimens during hemodialysis.Methods·Nineteen patients undergone low-flux hemodialysis and received antibiotic therapy at the Department of Nephrology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, were enrolled and divided into the meropenem group (n=7), the vancomycin group (n=5) and the ceftriaxone group (n=7) according to the type of antibiotics. A liquid chromatography with tandem mass spectrometry (LC-MS/MS) method was established to detect meropenem, vancomycin, and ceftriaxone in human plasma/serum and dialysate. A two-compartment pharmacokinetic model was established using MATLAB. Instantaneous and total dialysis clearance rates were calculated, and PK/PD parameters were analyzed.Results·No significant differences were found in the clinical characteristics of subjects among the three groups. The dialysis clearance rates were as follows: meropenem group (5.14‒5.97 L/h) > vancomycin group (2.87‒3.77 L/h)> ceftriaxone group (1.21‒1.90 L/h), with statistically significant differences (P<0.001). All three antibiotics showed good fit in the two-compartment pharmacokinetic model with a dialysate chamber (fval%<2), and the calculated PK/PD parameters were consistent with previous literature. For meropenem, the fraction of time that the free drug concentration remained above the minimal inhibitory concentration (%fT>MIC) values were 95.2%, 60.8% and 32.4% at minimal inhibitory concentration (MIC) values of 2, 8 and 16 μg/mL, respectively. For ceftriaxone (free concentration), the %fT>MIC values were all above 45.0% at MICs of 0.25, 4 and 16 μg/mL. For vancomycin, only 14.0% of the trough concentrations reached the target range of 15‒20 mg/L.Conclusion·The three antibiotics are well described by the two-compartment model. The plasma protein binding rate has a significant effect on the dialysis clearance of antibiotics in low-flux IHD, with higher protein binding associated with lower clearance. The regimens of meropenem (0.5 g/d) and ceftriaxone (2.0 g/d) are generally effective among patients undergoing low-flux IHD, while the vancomycin regimen with a loading dose of 1.0 g and a maintenance dose of 0.5 g/2 d carries a risk of treatment failure.

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent monogenic polycystic kidney disorder, but ADPKD presented as Glomerulocystic kidney (GCK) in adults is uncommon. Thin basement membrane nephropathy (TBMN) seems to account for major causes of familial hematuria and can coexist with other glomerular diseases. Here, we report a case of atypical manifestation of ADPKD presenting as GCK superimposed with TBMN in an adult man. A 40-year-old male presented with moderate proteinuria, microhematuria and renal insufficiency. He has no family history of kidney disease. Ultrasound revealed slightly enlarged kidneys with echogenic cortex. 2 to 3 visible small cortical cysts on both kidneys, and no anatomical abnormalities were detected by CT scan. Renal biopsy demonstrated that 33.3