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Aim: To conduct a systematic review with meta‐analysis to provide a comprehensive synthesis of randomized controlled trials (RCTs) and prospective cohort studies investigating the effects of currently available bolus advisors on glycaemic parameters in adults with diabetes. Materials and Methods: An electronic search of PubMed, Embase, CINAHL, Cochrane Library and ClinicalTrials.gov was conducted in December 2022. The risk of bias was assessed using the revised Cochrane Risk of Bias tool. (Standardized) mean difference (MD) was selected to determine the difference in continuous outcomes between the groups. A random‐effects model meta‐analysis and meta‐regression were performed. This systematic review was registered on PROSPERO (CRD42022374588). Results: A total of 18 RCTs involving 1645 adults (50% females) with a median glycated haemoglobin (HbA1c) concentration of 8.45% (7.95%–9.30%) were included. The majority of participants had type 1 diabetes (N = 1510, 92%) and were on multiple daily injections (N = 1173, 71%). Twelve of the 18 trials had low risk of bias. The meta‐analysis of 10 studies with available data on HbA1c showed that the use of a bolus advisor modestly reduced HbA1c compared to standard treatment (MD −011%, 95% confidence interval −0.22 to −0.01; I2 = 0%). This effect was accompanied by small improvements in low blood glucose index and treatment satisfaction, but not with reductions in hypoglycaemic events or changes in other secondary outcomes. Conclusion: Use of a bolus advisor is associated with slightly better glucose control and treatment satisfaction in people with diabetes on intensive insulin treatment. Future studies should investigate whether personalizing bolus advisors using artificial intelligence technology can enhance these effects. [ABSTRACT FROM AUTHOR]

Background: Proactive screening for cognitive dysfunction (CD) and peripheral neuropathy (PNP) in elderly patients with diabetes mellitus is essential for early intervention, yet clinical examination is time-consuming and prone to bias. Objective: We aimed to investigate PNP and CD in a diabetes cohort and explore the possibility of identifying key features linked with the respective conditions by machine learning algorithms applied to data sets obtained in playful games controlled by sensor-equipped insoles. Methods: In a cohort of patients diagnosed with diabetes (n=261) aged over 50 years PNP and CD were diagnosed based on complete physical examination (neuropathy symptom and disability scores, and Montreal Cognitive Assessment). In an observational and proof-of-concept study patients performed a 15 min lasting gaming session encompassing tutorials and four video games with 5,244 predefined features. The steering of video games was solely achieved by modulating plantar pressure values, which were measured by sensor-equipped insoles in real-time. Data sets were used to identify key features indicating game performance with correlation regarding CD and PNP findings. Thereby, machine learning models (e.g. gradient boosting and lasso and elastic-net regularized generalized linear models) were set up to distinguish patients in the different groups. Results: PNP was diagnosed in 59% (n=153), CD in 34% (n=89) of participants, and 23% (n=61) suffered from both conditions. Multivariable regression analyses suggested that PNP was positively associated with CD in patients with diabetes (adjusted odds ratio = 1.95; 95% confidence interval: 1.03-3.76; P=0.04). Predictive game features were identified that significantly correlated with CD (n=59), PNP (n=40), or both (n=59). These features allowed to set up classification models that were enriched by individual risk profiles (i.e. gender, age, weight, BMI, diabetes type, and diabetes duration). The obtained models yielded good predictive performance with the area under the receiveroperating-characteristic curves reaching 0.95 for CD without PNP, 0.83 for PNP without CD, and 0.84 for CD and PNP combined. Conclusions: The video game-based assessment was able to categorize patients with CD and/or PNP with high accuracy. Future studies with larger cohorts are needed to validate these results and potentially enhance the discriminative power of video games. [ABSTRACT FROM AUTHOR]

Aims: Inflammation and angiogenesis play an important role in the development of early diabetic kidney disease. We investigated the association of soluble Tumour Necrosis Factor Receptor 1 (sTNF‐R1), sTNF‐R2 and endostatin with new onset microalbuminuria in normoalbuminuric patients with diabetes mellitus type 2. Methods: We conducted a case control study to assess serum levels of sTNF‐R1, sTNF‐R2 and endostatin in 169 patients with new onset microalbuminuria and in 188 matched normoalbuminuric, diabetic controls. Baseline serum samples from participants of the ROADMAP (Randomized Olmesartan and Diabetes Microalbuminuria Prevention) and observational follow‐up (ROADMAP‐OFU) studies were used. Results: Endostatin and sTNF‐R1 but not sTNF‐R2 were increased at baseline in patients with future microalbuminuria. In the multivariate analysis, each log2 increment in endostatin levels was associated with an increase of only 6% in the risk of development of microalbuminuria (adjusted HR (95% CI) 1.006 (1.001–1011). sTNF‐R1 and sTNF‐R2 levels were conversely associated with microalbuminuria, but the results did not reach statistical significance. The respective adjusted HRs (95% CI) were 1.305 (0.928–1.774) and 0.874 (0.711–1.074). Conclusions: sTNF‐R1 and sTNF‐R2 failed to predict the occurrence of microalbuminuria in normoalbuminuric patients with type 2 diabetes. Likewise, the utility of endostatin in predicting new onset proteinuria is limited. [ABSTRACT FROM AUTHOR]

Background: Fibrosis is characterized by excessive extracellular matrix formation in solid organs, disrupting tissue architecture and function. The Y-box binding protein-1 (YB-1) regulates fibrosis-related genes (e.g., Col1a1, Mmp2, and Tgfβ1) and contributes significantly to disease progression. This study aims to identify fibrogenic signatures and the underlying signaling pathways modulated by YB-1. Methods: Transcriptomic changes associated with matrix gene patterns in human chronic kidney diseases and murine acute injury models were analyzed with a focus on known YB-1 targets. Ybx1-knockout mouse strains (Ybx1ΔRosaERT+TX and Ybx1ΔLysM) were subjected to various kidney injury models. Fibrosis patterns were characterized by histopathological staining, transcriptome analysis, qRT-PCR, methylation analysis, zymography, and Western blotting. Results: Integrative transcriptomic analyses revealed that YB-1 is involved in several fibrogenic signatures related to the matrisome, the WNT, YAP/TAZ, and TGFß pathways, and regulates Klotho expression. Changes in the methylation status of the Klotho promoter by specific methyltransferases (DNMT) are linked to YB-1 expression, extending to other fibrogenic genes. Notably, kidney-resident cells play a significant role in YB-1-modulated fibrogenic signaling, whereas infiltrating myeloid immune cells have a minimal impact. Conclusions: YB-1 emerges as a master regulator of fibrogenesis, guiding DNMT1 to fibrosis-related genes. This highlights YB-1 as a potential target for epigenetic therapies interfering in this process. [ABSTRACT FROM AUTHOR]

Summary: The prevalence of kidney disease is increasing rapidly worldwide, reflecting rising rates of obesity, diabetes, and associated metabolic syndrome (MetS). Chronic kidney disease and related comorbidities such as obesity, diabetes, and hypertension place a significant financial burden on healthcare systems. Despite the widespread use of RAAS inhibitors, intensive blood pressure and glycemic control, and newer therapeutic options consisting of sodium/glucose cotransporter‐2 (SGLT‐2) inhibitors or glucagon‐like peptide‐1 (GLP‐1) receptor agonists, a significant risk of progression to end‐stage renal disease remains in the high‐risk obese and diabetic population. The MetS is a cluster of cardiovascular risk factors that adversely affect the development and progression of chronic kidney failure. According to the criteria of the World Health Organization, it is defined by visceral adiposity, impaired glucose tolerance or insulin resistance, atherogenic dyslipidemia, raised blood pressure, and microalbuminuria with a albumin‐to‐creatinine ratio ≥30 mg/g. At molecular level MetS is marked by a proinflammatory state and increased oxidative stress leading to various pathophysiological changes causing endothelial dysfunction and a hypercoagulable state. Because the kidney is a highly vascularized organ, it is especially susceptible for those microvascular changes. Therefore, the MetS and its individual components are associated with the premature development, acceleration, and progression of chronic kidney disease. Therefore, it is becoming increasingly important to elucidate the underlying mechanisms of MetS‐associated chronic kidney disease in order to develop new strategies for preventing and slowing the progression of renal disease. In this review, we will elucidate (i) the renal structural, hemodynamic, and metabolic changes that occur in obesity and obesity‐related kidney injury; (ii) the clinicopathological characteristics of obesity‐related kidney injury, primarily focusing on obesity‐associated glomerulopathy; (iii) the potential additional factors or predisposing factors that may turn patients more susceptible to renal structural or functional compensatory failure and subsequent injury. [ABSTRACT FROM AUTHOR]

The interleukin-1 gene cluster encodes cytokines, which modulate mesangial cell proliferation and matrix expansion, both constituting central factors in the development and progression of immunoglobulin A nephropathy (IgAN). A candidate-gene study was performed to examine the association of polymorphisms of the interleukin-1 gene cluster with the risk of progressive IgAN. To gain deeper insights into the involvement of interleukin genes in IgAN, a meta-analysis of genetic association studies (GAS) that examine the association between interleukin variants and IgAN was conducted. Association study: The case-control study consisted of 121 unrelated Caucasians with sporadic, histologically diagnosed IgAN and of 246 age- and sex-matched healthy controls. Persistent proteinuria (>2 g/24 h) and/or impaired kidney function (serum creatinine > 1.5 mg/dL) defined progressive (n = 67) vs. non-progressive (n = 54) IgAN cases. Genotypes were assessed for two promoter-region single-nucleotide polymorphisms, C-899T (rs1800587) in IL1A and C-511T (rs16944) in IL1B, and for one penta-allelic variable-length tandem repeat polymorphism (VNTR 86 bp intron 2) in IL1RN. The association of these variants with the susceptibility of IgAN and the development of progressive IgAN (healthy status, IgAN, progressive IgAN) was tested using the generalized odds ratio (ORG) metric. Linkage disequilibrium and haplotype analysis were also performed. Meta-analysis: We included in the meta-analysis 15 studies investigating association between 14 interleukin variants harbored in eight different genes and IgAN. The ORG was used to evaluate the association between interleukin variants and IgAN using random effects models. The present case-control study revealed association of IL1B C-511T (rs16944) with the progression of IgAN (p = 0.041; ORG = 2.11 (1.09–4.07)). On haplotype analysis, significant results were derived for the haplotypes C-C-1 (p = 0.005; OR = 0.456 (0.261~0.797)) and C-T-2 (p = 0.003; OR = 4.208 (1.545–11.50)). Regarding association and meta-analysis results, variants in IL1B (rs1143627 and rs16944), IL1RN (rs928940, rs439154, and rs315951) and IL10 (rs1800871) were associated with IgAN based on either genotype or allele counts. Genetic variants and haplotypes in the IL1B, IL1RN, and IL10 genes might contribute to an increased risk for development and progression of IgAN. [ABSTRACT FROM AUTHOR]

In aging kidneys, a decline of function resulting from extracellular matrix (ECM) deposition and organ fibrosis is regarded as "physiological." Whether a direct link between high salt intake and fibrosis in aging kidney exists autonomously from arterial hypertension is unclear. This study explores kidney intrinsic changes (inflammation, ECM derangement) induced by a high-salt diet (HSD) in a murine model lacking arterial hypertension. The contribution of cold shock Y-box binding protein (YB-1) as a key orchestrator of organ fibrosis to the observed differences is determined by comparison with a knockout strain (Ybx1DRosaERT + TX). Comparisons of tissue from mice fed with normal-salt diet (NSD, standard chow) or high-salt diet (HSD, 4% NaCl in chow; 1% NaCl in water) for up to 16 mo revealed that with HSD tubular cell numbers decrease and tubulointerstitial scarring [periodic acid-Schiff (PAS), Masson's trichrome, Sirius red staining] prevails. In Ybx1DRosaERT + TX animals tubular cell damage, a loss of cell contacts with profound tubulointerstitial alterations, and tubular cell senescence was seen. A distinct tubulointerstitial distribution of fibrinogen, collagen type VI, and tenascin-C was detected under HSD, transcriptome analyses determined patterns of matrisome regulation. Temporal increase of immune cell infiltration was seen under HSD of wild type, but not Ybx1DRosaERT + TX animals. In vitro Ybx1DRosaERT + TX bone marrow-derived macrophages exhibited a defect in polarization (IL-4/IL-13) and abrogated response to sodium chloride. Taken together, HSD promotes progressive kidney fibrosis with premature cell aging, ECM deposition, and immune cell recruitment that is exacerbated in Ybx1DRosaERT + TX animals. NEW & NOTEWORTHY Short-term experimental studies link excessive sodium ingestion with extracellular matrix accumulation and inflammatory cell recruitment, yet long-term data are scarce. Our findings with a high-salt diet over 16 mo in aging mice pinpoints to a decisive tipping point after 12 mo with tubular stress response, skewed matrisome transcriptome, and immune cell infiltration. Cell senescence was aggravated in knockout animals for cold shock Y-box binding protein (YB-1), suggesting a novel protective protein function. [ABSTRACT FROM AUTHOR]

Antineutrophil cytoplasm antibody (ANCA)–associated vasculitis (AAV) comprises a group of multisystem disorders with alternating periods of relapse and remission. Beyond that, a smouldering progress during apparently clinically silent phases often develops. AAVs are subgrouped in microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA) and renal limited vasculitis (RLV). ANCA are hallmark of this disease entity, although they are not always present. Despite the simplification of treatment, fundamental aspects concerning assessment of its efficacy and its adaptation to encountered complications or to the relapsing/remitting/subclinical disease course remain still unknown. Through the advances in pathogenesis and pathophysiology of AAV a reliable biomarker‐based monitoring and treatment algorithm has not been established and disease management follows not infrequently a "trial and error" approach. Here, we overviewed the most interesting biomarkers reported so far. [ABSTRACT FROM AUTHOR]

DNA-binding protein A (DbpA) belongs to the Y-box family of cold shock domain proteins that exert transcriptional and translational activities in the cell via their ability to bind and regulate mRNA. To investigate the role of DbpA in kidney disease, we utilized the murine unilateral ureter obstruction (UUO) model, which recapitulates many features of obstructive nephropathy seen in humans. We observed that DbpA protein expression is induced within the renal interstitium following disease induction. Compared with wild-type animals, obstructed kidneys from Ybx3-deficient mice are protected from tissue injury, with a significant reduction in the number of infiltrating immune cells as well as in extracellular matrix deposition. RNAseq data from UUO kidneys show that Ybx3 is expressed by activated fibroblasts, which reside within the renal interstitium. Our data support a role for DbpA in orchestrating renal fibrosis and suggest that strategies targeting DbpA may be a therapeutic option to slow disease progression. [ABSTRACT FROM AUTHOR]

Aim: To validate a recently proposed risk prediction model for chronic kidney disease (CKD) in type 2 diabetes (T2D). Materials and Methods: Subjects from the German/Austrian Diabetes Prospective Follow‐up (DPV) registry with T2D, normoalbuminuria, an estimated glomerular filtration rate of 60 ml/min/1.73m2 or higher and aged 39‐75 years were included. Prognostic factors included age, body mass index (BMI), smoking status and HbA1c. Subjects were categorized into low, moderate, high and very high‐risk groups. Outcome was CKD occurrence. Results: Subjects (n = 10 922) had a mean age of 61 years, diabetes duration of 6 years, BMI of 31.7 kg/m2, HbA1c of 6.9% (52 mmol/mol); 9.1% had diabetic retinopathy and 16.3% were smokers. After the follow‐up (~59 months), 37.4% subjects developed CKD. The area under the curve (AUC; unadjusted base model) was 0.58 (95% CI 0.57‐0.59). After adjustment for diabetes and follow‐up duration, the AUC was 0.69 (95% CI 0.68‐0.70), indicating improved discrimination. After follow‐up, 15.0%, 20.1%, 27.7% and 40.2% patients in the low, moderate, high and very high‐risk groups, respectively, had developed CKD. Increasing risk score correlated with increasing cumulative risk of incident CKD over a median of 4.5 years of follow‐up (P <.0001). Conclusions: The predictive model achieved moderate discrimination but good calibration in a German/Austrian T2D population, suggesting that the model may be relevant for determining CKD risk. [ABSTRACT FROM AUTHOR]

Necrotizing fasciitis (NF) is an uncommon soft tissue infection. Multifocal‐extremity NF is a rarity with high mortality rates. Herein we report a case of bilateral non‐contiguous NF of the lower extremities due to Escherichia coli with a fatal outcome, stressing the necessity of rapid and aggressive intervention in suspected cases. [ABSTRACT FROM AUTHOR]

Introduction: Predicting outcome after transplantation of marginal kidneys is a challenging task. Donor creatinine or estimated glomerular filtration rate (eGFR) are integral components of the respective risk scores. However, there is uncertainty on which of their values obtained successively during procurement is the most suitable. Material and methods: This is a retrospective study of 221 adult brain death donors with marginal kidneys, transplanted in 223 recipients. We applied logistic regression analysis to investigate the association between initial (at hospital admission), nadir (lowest), zenith (highest) and terminal (at recovery) donor eGFR with primary non‐function (PNF), delayed graft function (DGF), 3‐ and 12‐month graft function and 1‐ and 3‐year patient‐ and death‐censored graft survival. Results: In the multivariate analysis, admission, terminal, and the lowest donor eGFR could most accurately predict DGF. The respective ORs [95% CI] were: 0.875 [0.771–0.993], 0.818 [95% CI: 0.726–0.922] and 0.793 [0.689–0.900]. Although not being significant for DGF (OR 0.931 [95% CI: 0.817–1.106]), the highest eGFR was the best predictor of 3‐month graft function (adjusted b coefficient 1.161 [95% CI: 0.355–1.968]). Analysis of primary nonfunction showed that determination of initial and the highest eGFR proved to be the best predictors. The respective ORs [95% CI] were: 0.804 [0.667–0.968] and 0.750 [0.611–0.919]. There were no differences in the risk associations of each of the four eGFR recordings with patient‐ and graft survival. Conclusion: The various eGFR recordings determined during the procurement process of marginal donors can predict PNF, DGF and 3‐ and 12‐month graft function. Regarding short‐term patient‐ and graft survival, there appears to be impacted by recipient factors rather than donor kidney function. Summary at a glance: Predicting outcomes after transplantation of marginal kidneys is a difficult task. The successive donor creatinine recordings obtained from admission to the hospital until organ recovery associate differently with clinically relevant short‐term endpoints, such as primary non‐function, delayed graft function and graft function up to 1 year. However, one‐ and three‐ year patient‐ and graft survival depend more on recipient‐related factors and less on the donor's kidney function. [ABSTRACT FROM AUTHOR]

Highlights: A HIF-1α biosensor was generated to facilitate studies on the role of different agents in normoxic HIF-1α stabilization. Micromilieu factors (MFs) induce normoxic HIF-1α stabilization with two different kinetics in HCAECs. There is an unknown indirect regulation of normoxic HIF-1α stabilization by NF-κB. Normoxic endothelial HIF-1α stabilization plays an important role in the inflammatory response of ECs to MFs, which could play a crucial role in the progression of atherosclerosis. Knowledge about normoxic hypoxia-inducible factor (HIF)-1α stabilization is limited. We investigated normoxic HIF-1α stabilization and its consequences using live cell imaging, immunoblotting, Bio-Plex multiplex immunoassay, immunofluorescence staining, and barrier integrity assays. We demonstrate for the first time that IL-8 and M-CSF caused HIF-1α stabilization and translocation into the nucleus under normoxic conditions in both human coronary endothelial cells (HCAECs) and HIF-1α-mKate2-expressing HEK-293 cells. In line with the current literature, our data show significant normoxic HIF-1α stabilization caused by TNF-α, INF-γ, IL-1β, and IGF-I in both cell lines, as well. Treatment with a cocktail consisting of TNF-α, INF-γ, and IL-1β caused significantly stronger HIF-1α stabilization in comparison to single treatments. Interestingly, this cumulative effect was not observed during simultaneous treatment with IL-8, M-CSF, and IGF-I. Furthermore, we identified two different kinetics of HIF-1α stabilization under normoxic conditions. Our data demonstrate elevated protein levels of HIF-1α-related genes known to be involved in the development of atherosclerosis. Moreover, we demonstrate an endothelial barrier dysfunction in HCAECs upon our treatments and during normoxic HIF-1α stabilization comparable to that under hypoxia. This study expands the knowledge of normoxic HIF-1α stabilization and activation and its consequences on the endothelial secretome and barrier function. Our data imply an active role of HIF-1α in vivo in the vasculature in the absence of hypoxia. [ABSTRACT FROM AUTHOR]