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Chronic kidney disease (CKD) is one of the fastest growing global causes of death, estimated to rank among the top five by 2040 (Foreman et al , 2018). This illustrates current pitfalls in diagnosis and management of CKD. Advanced CKD requires renal function replacement by dialysis or transplantation. However, earlier CKD stages, even when renal function is still normal, are already associated with an increased risk of premature death (Perez‐Gomez et al , 2019). Thus, novel approaches to diagnose and treat CKD are needed. The histopathological hallmark of CKD is kidney fibrosis, which is closely associated with local inflammation and loss of kidney parenchymal cells. Thus, kidney fibrosis is an attractive process to develop tests allowing an earlier diagnosis of CKD and represents a potential therapeutic target to slow CKD progression or promote regression. Graphical Abstract A. Ortiz shares his views on the new model of primary renal fibrosis, based on transgenic mice with specific PDGFR‐β activation in renal mesenchymal cells, developed by P. Boor and collaborators (in this issue of EMBO Molecular Medicine ).

We conduct a quantitative analysis contrasting human-written English news text with comparable large language model (LLM) output from six different LLMs that cover three different families and four sizes in total. Our analysis spans several measurable linguistic dimensions, including morphological, syntactic, psychometric, and sociolinguistic aspects. The results reveal various measurable differences between human and AI-generated texts. Human texts exhibit more scattered sentence length distributions, more variety of vocabulary, a distinct use of dependency and constituent types, shorter constituents, and more optimized dependency distances. Humans tend to exhibit stronger negative emotions (such as fear and disgust) and less joy compared to text generated by LLMs, with the toxicity of these models increasing as their size grows. LLM outputs use more numbers, symbols and auxiliaries (suggesting objective language) than human texts, as well as more pronouns. The sexist bias prevalent in human text is also expressed by LLMs, and even magnified in all of them but one. Differences between LLMs and humans are larger than between LLMs.

Chronic kidney disease (CKD) is a devastating condition that is reaching epidemic levels owing to the increasing prevalence of diabetes mellitus, hypertension and obesity, as well as ageing of the population. Regardless of the underlying aetiology, CKD is slowly progressive and leads to irreversible nephron loss, end-stage renal disease and/or premature death. Factors that contribute to CKD progression include parenchymal cell loss, chronic inflammation, fibrosis and reduced regenerative capacity of the kidney. Current therapies have limited effectiveness and only delay disease progression, underscoring the need to develop novel therapeutic approaches to either stop or reverse progression. Preclinical studies have identified several approaches that reduce fibrosis in experimental models, including targeting cytokines, transcription factors, developmental and signalling pathways and epigenetic modulators, particularly microRNAs. Some of these nephroprotective strategies are now being tested in clinical trials. Lessons learned from the failure of clinical studies of transforming growth factor β1 (TGFβ1) blockade underscore the need for alternative approaches to CKD therapy, as strategies that target a single pathogenic process may result in unexpected negative effects on simultaneously occurring processes. Additional promising avenues include preventing tubular cell injury and anti-fibrotic therapies that target activated myofibroblasts, the main collagen-producing cells.Here, the authors review drivers of fibrogenesis, including epithelial cell injury, inflammation, regeneration pathways and factors that promote the AKI-to-CKD transition. They discuss direct targeting of fibrotic pathways and therapeutic approaches that have reportedly decreased kidney fibrosis in preclinical and/or clinical studies.

Early detection is a key strategy to prevent kidney disease, its progression and related complications, but numerous studies show that awareness of kidney disease at the population level is low. Therefore, increasing knowledge and implementing sustainable solutions for early detection of kidney disease are public health priorities. Economic and epidemiological data underscore why kidney disease should be placed on the global public health agenda — kidney disease prevalence is increasing globally and it is now the seventh leading risk factor for mortality worldwide. Moreover, demographic trends, the obesity epidemic and the sequelae of climate change are all likely to increase kidney disease prevalence further, with serious implications for survival, quality of life and health care spending worldwide. Importantly, the burden of kidney disease is highest among historically disadvantaged populations that often have limited access to optimal kidney disease therapies, which greatly contributes to current socioeconomic disparities in health outcomes. This joint statement from the International Society of Nephrology, European Renal Association and American Society of Nephrology, supported by three other regional nephrology societies, advocates for the inclusion of kidney disease in the current WHO statement on major non-communicable disease drivers of premature mortality.Addressing the burden of non-communicable diseases is a global public health priority. In this joint Consensus Statement, the American Society of Nephrology, the European Renal Association and the International Society of Nephrology highlight the need to recognize kidney disease as a key driver of premature mortality, in addition to other non-communicable diseases already prioritized by the World Health Organization.

Patients with chronic kidney failure—defined as a glomerular filtration rate persistently below 15 mL/min per 1·73 m2—have an unacceptably high mortality rate. In developing countries, mortality results primarily from an absence of access to renal replacement therapy. Additionally, cardiovascular and non-cardiovascular mortality are several times higher in patients on dialysis or post-renal transplantation than in the general population. Mortality of patients on renal replacement therapy is affected by a combination of socioeconomic factors, pre-existing medical disorders, renal replacement treatment modalities, and kidney failure itself. Characterisation of the key pathophysiological contributors to increased mortality and cardiorenal risk staging systems are needed for the rational design of clinical trials aimed at decreasing mortality. Policy changes to improve access to renal replacement therapy should be combined with research into low-cost renal replacement therapy and optimum clinical care, which should include multifaceted approaches simultaneously targeting several of the putative contributors to increased mortality.

In the EMPA-KIDNEY (The Study of Heart and Kidney Protection With Empagliflozin) trial, empagliflozin reduced cardiorenal outcomes by 28% (hazard ratio 0.72; 95% confidence interval 0.64–0.82; P < .0001) in a diverse population of over 6000 chronic kidney disease (CKD) patients, of whom >50% were not diabetic. It expanded the spectrum of CKD that may benefit from sodium-glucose cotransporter 2 (SGLT2) inhibition to participants with urinary albumin: creatinine ratio <30 mg/g and estimated glomerular filtration rate (eGFR) >20 mL/min/1.73 m2 or even lower (254 participants had an eGFR 15–20 mL/min/1.73 m2). EMPA-KIDNEY was stopped prematurely because of efficacy, thus limiting the ability to confirm benefit on the primary outcome in every pre-specified subgroup, especially in those with more slowly progressive CKD. However, data on chronic eGFR slopes were consistent with benefit at any eGFR or urinary albumin:creatinine ratio level potentially delaying kidney replacement therapy by 2–27 years, depending on baseline eGFR. The representation of diverse causes of CKD (>1600 participants with glomerular disease, >1400 with hypertensive kidney disease, >450 with tubulointerstitial disease and >600 with unknown cause) was higher than in prior SGLT2 inhibitor trials, although polycystic kidney disease was excluded. Around 15% (almost 1000) of participants were not on renin–angiotensin system blockade. The clinical characteristics of the cohort differed from DAPA-CKD (A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease), as did the frequency of individual components of the primary outcome in the placebo arm. Thus, rather than compare EMPA-KIDNEY with DAPA-CKD, the results of both trials should be seen as complementary to those of other SGLT2 inhibitor trials. Overall, EMPA-KIDNEY, a recent meta-analysis and post hoc analyses of participants with type 2 diabetes mellitus (T2DM) but no baseline CKD in other trials, indicates that SGLT2 inhibitor treatment will benefit an expanded CKD population with diverse baseline albuminuria or eGFR values, presence of T2DM or cause of CKD, as well as providing primary prevention of CKD in at least the T2DM setting.

Intradialytic hypotension (IDH) is a frequent and serious complication of chronic haemodialysis, linked to adverse long-term outcomes including increased cardiovascular and all-cause mortality. IDH is the end result of the interaction between ultrafiltration rate (UFR), cardiac output and arteriolar tone. Thus excessive ultrafiltration may decrease the cardiac output, especially when compensatory mechanisms (heart rate, myocardial contractility, vascular tone and splanchnic flow shifts) fail to be optimally recruited. The repeated disruption of end-organ perfusion in IDH may lead to various adverse clinical outcomes affecting the heart, central nervous system, kidney and gastrointestinal system. Potential interventions to decrease the incidence or severity of IDH include optimization of the dialysis prescription (cool dialysate, UFR, sodium profiling and high-flux haemofiltration), interventions during the dialysis session (midodrine, mannitol, food intake, intradialytic exercise and intermittent pneumatic compression of the lower limbs) and interventions in the interdialysis period (lower interdialytic weight gain and blood pressure–lowering drugs). However, the evidence base for many of these interventions is thin and optimal prevention and management of IDH awaits further clinical investigation. Developing a consensus definition of IDH will facilitate clinical research. We review the most recent findings on risk factors, pathophysiology and management of IDH and, based on this, we call for a new consensus definition of IDH based on clinical outcomes and define a roadmap for IDH research.

Ultra-Wide-Band (UWB) positioning systems are now a real option to estimate the position of generic agents (e.g., robots) within indoor/GPS-denied environments. However, these environments can comprise metallic structures or other elements which can negatively affect the signal transmission and hence the accuracy of UWB-based position estimations. Regarding this fact, this paper proposes a novel method based on point-to-sphere ICP (Iterative Closest Point) to determine the 3D position of a UWB tag. In order to improve the results in noise-prone environments, our method first selects the anchors’ subset which provides the position estimate with least uncertainty (i.e., largest agreement) in our approach. Furthermore, we propose a previous stage to filter the anchor-tag distances used as input of the ICP stage. We also consider the addition of a final step based on non-linear Kalman Filtering to improve the position estimates. Performance results for several configurations of our approach are reported in the experimental results section, including a comparison with the performance of other position-estimation algorithms based on trilateration. The experimental evaluation under laboratory conditions and inside the cargo hold of a vessel (i.e., a noise-prone scenario) proves the good performance of the ICP-based algorithm, as well as the effects induced by the prior and posterior filtering stages.

Abstract The endothelium is the largest organ in the body and recent studies have shown that the endothelial glycocalyx (eGCX) plays a major role in health and disease states. The integrity of eGCX is vital for homoeostasis and disruption of its structure and function plays a major role in several pathologic conditions. An increased understanding of the numerous pathophysiological roles of eGCX may lead to the development of potential surrogate markers for endothelial injury or novel therapeutic targets. This review provides a state-of-the-art update on the structure and function of the eGCX, emphasizing the current understanding of interorgan crosstalk between the eGCX and other organs that might also contribute to the pathogenesis of kidney diseases.

Hoogsteen (HG) base pairing is characterized by a 180° rotation of the purine base with respect to the Watson-Crick-Franklin (WCF) motif. Recently, it has been found that both conformations coexist in a dynamical equilibrium and that several biological functions require HG pairs. This relevance has motivated experimental and computational investigations of the base-pairing transition. However, a systematic simulation of sequence variations has remained out of reach. Here, we employ advanced path-based methods to perform unprecedented free-energy calculations. Our methodology enables us to study the different mechanisms of purine rotation, either remaining inside or after flipping outside of the double helix. We study seven different sequences, which are neighbor variations of a well-studied A⋅T pair in A 6 -DNA. We observe the known effect of A⋅T steps favoring HG stability, and find evidence of triple-hydrogen-bonded neighbors hindering the inside transition. More importantly, we identify a dominant factor: the direction of the A rotation, with the 6-ring pointing either towards the longer or shorter segment of the chain, respectively relating to a lower or higher barrier. This highlights the role of DNA’s relative flexibility as a modulator of the WCF/HG dynamic equilibrium. Additionally, we provide a robust methodology for future HG proclivity studies.