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Introduction Side effects of calcineurin inhibitors (CNI) comprise hypertension, diabetes and nephrotoxicity, and endothelial dysfunction (ED) has often been implicated. Belatacept, a co-stimulation blocker, may offer a more favourable vascular profile.Methods We investigated markers of endothelial function in blood samples from kidney transplant recipients (KTR) that were converted from CNI to belatacept. We assessed established markers of ED including soluble thrombomodulin, P-selectin and angiopoietin 1 and 2. In addition, we assessed expression levels of microRNAs (miRNAs), which have been identified as discriminative markers for ED, rejection and renal fibrosis in the setting of transplantation. Lastly, we used patient samples and CNI-dilution series in a validated model of ED in which changes in morphological characteristics of endothelial cells were evaluated.Results Unexpectedly, we found no differences in our assays between both groups. We did observe dose-related effects of CNI on endothelial cell (EC) morphology upon direct exposure of EC to tacrolimus and ciclosporin A, but a similar effect was not seen when plasma samples of KTR who were converted to belatacept were compared with samples from KTR on CNI's.Discussion These data suggest that CNI-side-effects bundled under the term "CNI-toxicity" are not derived from a significant clinical effect of CNI on endothelial function.

BACKGROUND: Renal dysfunction increases cardiovascular (CV) risk. We compared cystatin C-based estimated glomerular filtration rate (eGFRcys), creatinine-based eGFR (eGFRcr), and their ratio (eGFRcys/eGFRcr) in relation to major adverse cardiovascular events (MACE) and all-cause mortality in chronic coronary syndrome, assessing the added prognostic value of the eGFRratio.

METHODS: In this post hoc analysis of 14,513 Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy trial patients, we investigated associations between baseline eGFRcys, eGFRcr, their ratio, and MACE and all-cause death using Cox regression models, unadjusted and adjusted for eGFRcys, eGFRcr, and their combination. Discrimination was assessed using Harrell's C-index; added value by the fraction of new information (FNI).

RESULTS: Median age was 65 years; 82% were male. Median eGFRcys was 77 (interquartile range [IQR]: 61-94) and eGFRcr 79 (IQR: 65-91) mL/min/1.73 m². Over 3.7 years, 1449 MACE and 1063 deaths occurred. Lower eGFR values and eGFRratio were associated with increased MACE risk, primarily driven by CV death. For eGFRcys 60 versus 90, the hazard ratio (HR) for MACE adjusted for eGFRcr was 1.77 (95% CI: 1.49-2.09, FNI 54%). In contrast, eGFRcr adjusted for eGFRcys showed no positive association (HR 0.82, 95% CI: 0.68-0.97, FNI 3%). A lower eGFRratio was linked to higher MACE risk (HR 1.99, 95% CI: 1.80-2.21), which remained after eGFRcr adjustment (HR 1.89, 95% CI: 1.70-2.10, FNI 54%) but was attenuated after eGFRcys adjustment (HR 1.29, 95% CI: 1.13-1.46, FNI 5%).

CONCLUSION: In chronic coronary syndrome, lower eGFRcys, eGFRcr, and eGFRratio were associated with higher MACE and mortality risk. eGFRcys had the strongest association; eGFRcr and eGFRratio added limited incremental value.

Albuminuria and proteinuria are key biomarkers for diagnosing, staging, and monitoring of chronic kidney disease. Both are also strongly associated with renal and cardiovascular risk. Given their important diagnostic role, reliable measurement of urinary albumin and protein is essential for clinical practice and trials. However, variability in the methodology presently used to collect, store, and prepare urine samples may influence assay performance and contribute to inconsistent results. In response to a call for harmonization, the United States of America National Kidney Foundation organized a workshop in April 2025 to define optimal methods and practices for measuring albuminuria and proteinuria. As part of this initiative, the available evidence on pre-analytical factors affecting urinary albumin and protein measurements was discussed.

For this purpose, a narrative literature review was conducted to identify relevant studies focusing on urine collection strategies, including 24-h versus single-void samples, timing of sample collection, the need for repeated measurements, clinical conditions that may cause false-positive results, and the effects of sample storage and handling under various temperature conditions. Given heterogeneity in study designs and outcome measures, findings were synthesized qualitatively.

This consensus report summarizes the findings of this literature review and the resulting discussion. It highlights the importance of standardized urine collection and handling procedures to minimize biological and analytical variability. In addition, it provides practical recommendations.

Background: Patients with end-stage kidney disease (ESKD) undergoing haemodialysis (HD) have a high risk of cardiovascular (CV) events. This study evaluated troponin I (hs-cTnI) as a predictor of major adverse cardiac events (MACEs), CV death and all-cause death.

Methods: The AURORA trial, a multicentre, randomized, double-blind trial involved 2776 HD patients comparing rosuvastatin with placebo. No significant effect was found on the composite primary endpoint of CV death, non-fatal myocardial infarction or non-fatal stroke. In this post hoc analysis, we analysed the association between baseline hs-cTnI and outcomes using Cox regression analyses. We adjusted for multiple background factors and available biomarkers. Hs-cTnI was log2-transformed and modelled using a four-knot restricted cubic spline. Variables were ordered by their importance in the models using chi 2 value minus degrees of freedom.

Results: Baseline median hs-cTnI was 17.3 pg/mL. During follow-up, 734 MACEs, 598 CV deaths, and 1094 total deaths occurred. Patients in the upper quartile of hs-cTnI (>32.6 pg/mL) had significantly higher risk of MACEs [hazard ratio (HR) 1.92; 95% confidence interval (CI) 1.57-2.35], CV death (HR 2.12; 95% CI 1.69-2.66), all-cause death (HR 1.84; 95% CI 1.55-2.17) and non-CV death (HR 1.59; 95% CI 1.23-2.05) after full adjustment compared with those in the lowest quartile (<10.1 pg/mL). Hs-cTnI was identified as the strongest predictor for MACEs, CV death, and all-cause death, but not for non-CV death.

Conclusions: Baseline hs-cTnI is a strong and independent predictor for MACEs and death in patients with ESKD undergoing haemodialysis.

The aim of this study was to explore biological interaction and pathophysiology mechanisms in a new mouse model of cardiovascular-kidney-metabolic (CKM) syndrome, induced by chronic moderate renal failure in combination with consumption of a customized Western diet rich in carbohydrates, fat and salt. Male C57BL/6J mice were subjected to unilateral nephrectomy, fed a customized Western diet rich not only in sugar and fat but also in salt, and followed for 12 weeks or 20 weeks. Sham-operated mice on a standard chow served as healthy controls. Body composition, weight gain, glucose metabolism, fat distribution, blood pressure, cardiac function, vascular reactivity, renal function, inflammation and mitochondrial function were measured and combined with biochemical and histopathological analyses. The novel triple-hit model of CKM syndrome showed signs and symptoms of metabolic syndrome, disturbed glucose metabolism, impaired adipocyte physiology and fat redistribution, cardiovascular dysfunction, renal damage and dysfunction, systemic inflammation, elevated blood pressure and cardiac remodeling. The pathological changes were more pronounced in mice after prolonged exposure for 20 weeks, but no deaths occurred. In the present mouse model of CKM syndrome, profound and significant metabolic, cardiac, vascular and renal dysfunctions and injuries emerged by using a Western diet rich not only in fat and carbohydrates but also in salt. This multisystem disease model could be used for mechanistic studies and the evaluation of new therapeutic strategies. The authors describe a novel mouse model of cardiovascular-kidney-metabolic syndrome induced by unilateral nephrectomy and a Western diet rich in carbohydrates, fat and salt, which could be used to study human condition and identify therapies.

Background

Statins are widely used to reduce the risk of cardiovascular disease (CVD). Patients with end-stage renal disease (ESRD) on hemodialysis have significantly increased risk of developing CVD. Statin treatment in these patients however did not show a statistically significant benefit in large trials on a patient cohort level.

Methods

We generated gene expression profiles for statins to investigate the impact on cellular programs in human renal proximal tubular cells and mesangial cells in-vitro. We subsequently selected biomarkers from key statin-affected molecular pathways and assessed these biomarkers in plasma samples from the AURORA cohort, a double-blind, randomized, multi-center study of patients on hemodialysis or hemofiltration that have been treated with rosuvastatin. Patient clusters (phenotypes) were created based on the identified biomarkers using Latent Class Model clustering and the associations with outcome for the generated phenotypes were assessed using Cox proportional hazards regression models. The multivariable models were adjusted for clinical and biological covariates based on previously published data in AURORA.

Results

The impact of statin treatment on mesangial cells was larger as compared with tubular cells with a large overlap of differentially expressed genes identified for atorvastatin and rosuvastatin indicating a predominant drug class effect. Affected molecular pathways included TGFB-, TNF-, and MAPK-signaling and focal adhesion among others. Four patient clusters were identified based on the baseline plasma concentrations of the eight biomarkers. Phenotype 1 was characterized by low to medium levels of the hepatocyte growth factor (HGF) and high levels of interleukin 6 (IL6) or matrix metalloproteinase 2 (MMP2) and it was significantly associated with outcome showing increased risk of developing major adverse cardiovascular events (MACE) or cardiovascular death. Phenotype 2 had high HGF but low Fas cell surface death receptor (FAS) levels and it was associated with significantly better outcome at 1 year.

Conclusions

In this translational study, we identified patient subgroups based on mechanistic markers of statin therapy that are associated with disease outcome in patients on hemodialysis.

Inflammation mediated by interleukin-6 (IL-6) is strongly associated with cardiovascular risk. Here we evaluated clazakizumab, a monoclonal antibody targeting the IL-6 ligand, in a phase 2b dose-finding study. Adults with cardiovascular disease and/or diabetes receiving maintenance dialysis with high-sensitivity C-reactive protein (hs-CRP) >= 2 mg l(-1) at baseline were randomized to receive clazakizumab (2.5 mg, 5 mg or 10 mg, n = 32 per dose group) or placebo (n = 31) every 4 weeks. The primary endpoint was the change from baseline in hs-CRP to week 12, expressed as the geometric mean ratio. Clazakizumab treatment signficantly reduced serum hs-CRP concentrations at week 12 by 86%, 90% and 92% relative to placebo in patients randomized to 2.5 mg, 5 mg or 10 mg clazakizumab, respectively (all P < 0.0001), meeting the primary outcome. With regard to secondary endpoints, clazakizumab treatment reduced serum fibrinogen, amyloid A, secretory phospholipase A2, and lipoprotein(a) concentrations, as well as increased mean serum albumin concentrations at 12 weeks, relative to placebo. The proportion of patients who achieved hs-CRP < 2.0 mg l(-1) was 79%, 82% and 79% in the 2.5 mg, 5 mg and 10 mg clazakizumab groups, respectively, compared with 0% of placebo-treated patients. With regard to safety, no cases of sustained grade 3 or 4 thrombocytopenia or neutropenia were observed. Serious infections were seen with similar frequency in the placebo, clazakizumab 2.5 mg and clazakizumab 5 mg groups, but were numerically more frequent in the clazakizumab 10 mg group. The results of this trial indicate that in patients receiving maintenance dialysis, clazakizumab reduced inflammatory biomarkers associated with cardiovascular events.

Background/Objectives: The prevalence of cardiovascular-kidney-metabolic (CKM) syndrome is increasing rapidly, and cardiovascular complications pose significant risks in individuals with kidney disease and metabolic dysfunction. Understanding the mechanisms of CKM disorders is crucial, as is the discovery of novel preventive treatments. This study aimed to examine the therapeutic effects of a specially formulated nitric oxide-enhancing food additive in a mouse model of CKM syndrome induced by unilateral nephrectomy (UNX) in combination with chronic Western diet (WD) feeding.

Methods: C57BL/6J mice underwent UNX and were fed a WD high in salt, sugar, and fat for 12 weeks, compared to sham-operated mice on standard chow. One group of UNX+WD mice received Flexovital (FLX), a food additive containing extracts of Rhodiola rosea and beetroot, and the amino acids L-arginine and L-citrulline. CKM parameters were assessed both in vivo and ex vivo alongside histological and biochemical analyses.

Results: The UNX+WD mice showed an increase in body fat mass, the fat/lean mass ratio, and adipocyte area, of which most were significantly reduced by FLX. Elevated fasting glucose levels were also reduced by FLX, which tended towards improving glucose clearance. Elevated arterial blood pressure and endothelial dysfunction in UNX+WD mice were significantly reduced by FLX. FLX improved GFR and reduced glomerular and tubular injuries in UNX+WD mice. Additionally, FLX increased the P/O ratios of oxidative phosphorylation in the isolated renal mitochondria of UNX+WD mice.

Conclusions: In this model of CKM syndrome, FLX effectively prevented the onset and progression of CKM dysfunctions induced by UNX+WD, as well as the associated organ injuries. These promising results highlight the need for validation in upcoming human trials.