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Heart and kidney have a closely interrelated pathophysiology. Acute kidney injury (AKI) is associated with significantly increased rates of cardiovascular events, a relationship defined as cardiorenal syndrome type 3 (CRS3). The underlying mechanisms that trigger heart disease remain, however, unknown, particularly concerning the clinical impact of AKI on cardiac outcomes and overall mortality. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) are independently involved in the pathogenesis of both heart and kidney failure, and recent studies have proposed TWEAK as a possible therapeutic target; however, its specific role in cardiac damage associated with CRS3 remains to be clarified. Firstly, we demonstrated in a retrospective longitudinal clinical study that soluble TWEAK plasma levels were a predictive biomarker of mortality in patients with AKI. Furthermore, the exogenous application of TWEAK to native ventricular cardiomyocytes induced relevant calcium (Ca 2+ ) handling alterations. Next, we investigated the role of the TWEAK-Fn14 axis in cardiomyocyte function following renal ischaemia-reperfusion (I/R) injury in mice. We observed that TWEAK-Fn14 signalling was activated in the hearts of AKI mice. Mice also showed significantly altered intra-cardiomyocyte Ca 2+ handling and arrhythmogenic Ca 2+ events through an impairment in sarcoplasmic reticulum Ca 2+ -adenosine triphosphatase 2a pump (SERCA 2a ) and ryanodine receptor (RyR 2 ) function. Administration of anti-TWEAK antibody after reperfusion significantly improved alterations in Ca 2+ cycling and arrhythmogenic events and prevented SERCA 2a and RyR 2 modifications. In conclusion, this study establishes the relevance of the TWEAK-Fn14 pathway in cardiac dysfunction linked to CRS3, both as a predictor of mortality in patients with AKI and as a Ca 2+ mishandling inducer in cardiomyocytes, and highlights the cardioprotective benefits of TWEAK targeting in CRS3. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Background: Up to 50-60% of patients with diabetes have non-diabetic kidney disease (NDKD) on kidney biopsy. Diabetic retinopathy (DR) is a microvascular complication of diabetes frequently associated with diabetic nephropathy (DN). The objective of the current study was to investigate the kidney outcomes and survival in patients with biopsy diagnoses of DN and NDKD according to the presence of DR., Methods: We conducted an observational, multicentre and retrospective study of the pathological findings of renal biopsies from 832 consecutive patients with diabetes from 2002 to 2014 from 18 nephrology departments. The association of DR with kidney replacement therapy (KRT) or survival was assessed by Kaplan-Meier and Cox regression analyses., Results: Of 832 patients with diabetes and renal biopsy, 768 had a retinal examination and 221/768 (22.6%) had DR. During a follow-up of 10 years, 288/760 (37.9%) patients with follow-up data needed KRT and 157/760 (20.7%) died. The incidence of KRT was higher among patients with DN (alone or with NDKD) and DR [103/175 (58.9%)] than among patients without DR [88/216 (40.7%), P  < .0001]. The incidence of KRT was also higher among patients with only NDKD and DR than among those without DR [18/46 (39.1%) versus 79/331 (23.9%), P  < .0001]. In multivariate analysis, DR or DN were independent risk factors for KRT {hazard ratio [HR] 2.48 [confidence interval (CI) 1.85-3.31], P  < .001}. DN (with or without DR) was also identified as an independent risk factor for mortality [HR 1.81 (CI 1.26-2.62), P  = .001]., Conclusions: DR is associated with a higher risk of progression to kidney failure in patients with histological DN and in patients with NDKD., Competing Interests: S.B. reports honorarium for conferences, consulting fees and advisory boards from AstraZeneca, Boehringer, Bayer and Mundipharma. M.J.S. reports personal fees from Novo Nordisk, Jansen, Mundipharma, AstraZeneca, Esteve, Fresenius, Ingelheim Lilly, Vifor, ICU, Pfizer, Bayer, Travere Therapeutics and GE Healthcare and grants and personal fees from Boehringer Ingelheim, outside the current study. N.M. reports honoraria from Alexion and GSK. N.G.-F. paticipates on scientific advisory virtual of Mundipharma, honoraria for lectures of Astellas and medical Statistics Consulting and payment for expert testimony of Baxter, Viforpharma and Fresenius. B.F.-F. has received grants from Esteve and Astrazeneca and have worked for Cátedra UAM-mundipharma. B.F.-F. has received consultancy or speaker fees or travel support from Astrazeneca, Bayer, Menarini, Novo-Nordisk BoeringerInheilm and Mundipharma. B.F.F is Editor for Nefroplus. B.F.-F. has received travel support from Astrazeneca, Bayer, Menarini, Novo-Nordisk BoeringerInheilm and Mundipharma. B.F.-F. has been advisor for Astrazeneca, Bayer, Menarini, Novo-Nordisk Boeringer Inheilm and Mundipharma. M.P. reports consulting fees and payment for honoraria from Alexion, Novartis, Otsuka, Vifor, GSK, Travere. M.J.S. is Editor Emeritus of CKJ. The rest of authors have no conflicts of interest to declare., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Objective: We aimed to test the non-inferiority of oral versus intravenous hydration in the incidence of contrast-associated acute kidney injury (CA-AKI) in elderly outpatients undergoing a contrast-enhanced computed tomography (CE-CT) scan., Methods: PNIC-Na (NCT03476460) is a phase-2, single-center, randomized, open-label, non-inferiority trial. We included outpatients undergoing a CE-CT scan, >65 years having at least one risk factor for CA-AKI, such as diabetes, heart failure, or an estimated glomerular filtration rate (eGFR) of 30-59 mL/min/1.73 m². Participants were randomized (1:1) to oral sodium-chloride capsules or intravenous hydration. The primary outcome was an increase in serum creatinine >0.3 mg/dL or a reduction in eGFR >25% within 48 h. The non-inferiority margin was set at 5%., Results: A total of 271 subjects (mean age 74 years, 66% male) were randomized, and 252 were considered for the main analysis (per-protocol). A total of 123 received oral hydration and 129 intravenous. CA-AKI occurred in 9 (3.6%) of 252 patients and 5/123 (4.1%) in the oral-hydration group vs. 4/129 (3.1%) in the intravenous-hydration group. The absolute difference between the groups was 1.0% (95% CI -4.8% to 7.0%), and the upper limit of the 95% CI exceeded the pre-established non-inferiority margin. No major safety concerns were observed., Conclusion: The incidence of CA-AKI was lower than expected. Although both regimens showed similar incidences of CA-AKI, the non-inferiority was not shown.

Biomarkers of mineral bone disorders (MBD) including phosphorus, fibroblast growth factor (FGF)-23 and Klotho are strongly altered in patients with acute kidney injury (AKI) who have high cardiac outcomes and mortality rates. However, the crosslink between MBD and cardiac damage after an AKI episode still remains unclear. We tested MBD and cardiac biomarkers in an experimental AKI model after 24 or 72 hours of folic acid injection and we analyzed structural cardiac remodeling, intracellular calcium (Ca 2+ ) dynamics in cardiomyocytes and cardiac rhythm. AKI mice presented high levels of FGF-23, phosphorus and cardiac troponin T and exhibited a cardiac hypertrophy phenotype accompanied by an increase in systolic Ca 2+ release 24 hours after AKI. Ca 2+ transients and contractile dysfunction were reduced 72 hours after AKI while diastolic sarcoplasmic reticulum Ca 2+ leak, pro-arrhythmogenic Ca 2+ events and ventricular arrhythmias were increased. These cardiac events were linked to the activation of the calcium/calmodulin-dependent kinase II pathway through the increased phosphorylation of ryanodine receptors and phospholamban specific sites after AKI. Cardiac hypertrophy and the altered intracellular Ca 2+ dynamics were prevented in transgenic mice overexpressing Klotho after AKI induction. In a translational retrospective longitudinal clinical study, we determined that combining FGF-23 and phosphorus with cardiac troponin T levels achieved a better prediction of mortality in AKI patients at hospital admission. Thus, monitoring MBD and cardiac damage biomarkers could be crucial to prevent mortality in AKI patients. In this setting, Klotho might be considered as a new cardioprotective therapeutic tool to prevent deleterious cardiac events in AKI conditions., (Copyright © 2022 Elsevier Inc. All rights reserved.)