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IgA nephropathy is the commonest pattern of primary glomerular disease in the world, with high rates of progression to kidney failure. As IgA nephropathy commonly causes kidney failure at a young age, kidney transplantation is commonly used to treat kidney failure. However, high rates of recurrent disease in the allograft remain a common management challenge. The prevalence of post-transplant recurrence approaches 15% at ten years post-transplant and is associated with poor allograft function and high rates of allograft loss. Post-transplant IgA nephropathy has also been described de novo in some case series. Treatment of recurrent IgA nephropathy has been challenging but with the rapid growth of new treatments for IgA nephropathy it is likely that many of these treatments will, over time, transition to the treatment of recurrent disease. In this narrative review, our aim is to evaluate post-transplant IgA nephropathy in terms of epidemiology, risk factors, underlying pathophysiology, diagnosis and management strategies., Competing Interests: Declarations. Conflict of interest: JB is a consultant to Calliditas Therapeutics AB and reports grants and consultancy and personal fees from Calliditas Therapeutics, Everest Medicines, and STADA Arzneimittel AG. Other authors have anything to disclose. Ethical approval: This article does not contain any studies with human participants or animals performed by any of the authors. Informed consent: Not applicable., (© 2024. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Background: Ambulatory blood pressure monitoring is essential for understanding blood pressure patterns beyond clinical visits, aiding in risk assessment, treatment evaluation, and managing hypertension. This retrospective cohort study aimed to identify risk factors for all-cause mortality and major cardiovascular events in patients who underwent ambulatory blood pressure monitoring., Methodology: Eligible participants aged 18 or older, with an estimated glomerular filtration rate (eGFR) > 60 ml/min/1.73 m 2 , who underwent ambulatory blood pressure monitoring for various reasons, were included in the study. Data were gathered through telephone interviews, electronic health records, and the national health record system. Descriptive analysis and classification and regression tree modeling were used to uncover significant risk factors related to all-cause mortality and cardiovascular events, and to assess the model's performance compared to traditional Cox survival analysis., Results: The study included 1291 patients, primarily male (51.8%) with a mean age of 61.1 ± 15.2 years. During a mean follow-up of 46.9 months, 76 (5.9%) patients died of any cause, and 195 (15.1%) had a cardiovascular event. The highest survival rates were observed in patients with a diastolic blood pressure (BP) dipping percentage between - 2% and 29%, nighttime systolic BP variability below 32 mmHg, and age below 72. Conversely, smokers with a diastolic BP dipping percentage below - 10% showed the lowest survival rates. The best cardiovascular outcomes were observed in patients with diastolic BP dipping above - 11%, nighttime mean systolic BP < 144 mmHg, no statin use, normotensive status, and daytime mean heart rate ≥ 60 bpm. Conversely, the worst outcomes were seen in patients with diastolic BP dipping below - 11% and a morning surge ≥ 14 mmHg. In all-cause mortality and cardiovascular event analysis, the combined model demonstrated excellent calibration and predictive power, like the classification and regression tree model and traditional analysis., Conclusion: These findings highlight the potential of a combined model for assessing mortality and cardiovascular event risk in patients who have undergone ambulatory blood pressure monitoring., (© 2024. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Anemia of chronic kidney disease is a multifactorial condition secondary to various etiologies, including nutritional deficiencies, chronic inflammation, erythropoietin deficiency or resistance, bone marrow suppression, iron deficiency and adverse drug effects. The major therapeutic intervention for anemia among chronic kidney disease patients is erythropoiesis-stimulating agents. However, a limitation of erythropoiesis-stimulating agents is the risk for thromboembolic events, hypertension, seizures, solid organ malignancies and hyporesponsiveness. A novel interleukin-6 monoclonal antibody, ziltivekimab, has been evaluated for managing anemia in chronic kidney disease patients in pilot clinical trials with promising outcomes, including an improvement in hemoglobin levels and reduction of inflammatory parameters. These trials have shown that ziltivekimab does not increase the risk for cytopenia or infectious complications as has been described for other interleukin-6-targeting monoclonal antibodies, like tocilizumab. Furthermore, potentially beneficial effects on serum lipid profile have been reported, leading to the hypothesis of a favorable impact of the drug on atherosclerotic complications. In addition, ziltivekimab has shown efficacy in improving anemia parameters, including hemoglobin levels and iron studies. Ziltivekimab deserves full scale clinical development, and to this aim, large-scale clinical trials are under way., (© 2024. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Background: Obesity is a growing epidemic affecting approximately 40% of the adult population in developed countries with major health consequences and comorbidities, including diabetes mellitus and insulin resistance, metabolically associated fatty liver disease, atherosclerotic cardiovascular and cerebrovascular diseases and chronic kidney disease. Pharmacotherapies targeting significant weight reduction may have beneficial effects on such comorbidities, though such therapeutic options are highly limited. In this narrative review, we aim to evaluate current knowledge regarding dual agonist therapies and potential implications for managing fatty kidney and chronic kidney disease., Results and Conclusion: Glucagon-like peptide-1 agonists and sodium-glucose cotransporter-2 inhibitors are two novel classes of glucose-lowering medications with potential implications and beneficiary effects on renal outcomes, including estimated glomerular filtration rate, albuminuria and chronic kidney disease progression. Recently, dual agonist therapies targeting glucagon-like peptide-1 and glucagon receptors, namely survodutide and cotadutide, have been evaluated in managing metabolically associated fatty liver disease, a well-established example of visceral obesity. Fatty kidney is another novel concept implicated in the pathophysiology of chronic kidney disease among patients with visceral obesity., (© 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Obesity poses a significant and growing risk factor for chronic kidney disease (CKD), requiring comprehensive evaluation and management strategies. This review explores the intricate relationship between obesity and CKD, emphasizing the diverse phenotypes of obesity, including sarcopenic obesity and metabolically healthy versus unhealthy obesity, and their differential impact on kidney function. We discuss the epidemiological evidence linking elevated body mass index (BMI) with CKD risk while also addressing the paradoxical survival benefits observed in obese CKD patients. Various measures of obesity, such as BMI, waist circumference, and visceral fat assessment, are evaluated in the context of CKD progression and outcomes. Mechanistic insights into how obesity promotes renal dysfunction through lipid metabolism, inflammation, and altered renal hemodynamics are elucidated, underscoring the role of adipokines and the renin-angiotensin-aldosterone system. Furthermore, the review examines current strategies for assessing kidney function in obese individuals, including the strengths and limitations of filtration markers and predictive equations. The management of obesity and associated comorbidities like arterial hypertension, type 2 diabetes mellitus, and non-alcoholic fatty liver disease in CKD patients is discussed. Finally, gaps in the current literature and future research directions aimed at optimizing the management of obesity-related CKD are highlighted, emphasizing the need for personalized therapeutic approaches to mitigate the growing burden of this intertwined epidemic.

Intrauterine development is crucial for life-long health; therefore, elucidation of its key regulators is of interest for their potential prognostic and therapeutic implications. Originally described as a membrane-bound anti-aging protein, Klotho has evolved as a regulator of numerous functions in different organ systems. Circulating Klotho is generated by alternative splicing or active shedding from cell membranes. Recently, Klotho was identified as a regulator of placental function, and while Klotho does not cross the placental barrier, increased levels of circulating α-Klotho have been identified in umbilical cord blood compared with maternal blood, indicating that Klotho may also play a role in intrauterine development. In this narrative review, we discuss novel insights into the specific functions of the Klotho proteins in the placenta and in intrauterine development, while summarizing up-to-date knowledge about their structures and functions. Klotho plays a role in stem cell functioning, organogenesis and haematopoiesis. Low circulating maternal and foetal levels of Klotho are associated with preeclampsia, intrauterine growth restriction, and an increased perinatal risk for newborns, indicating a potential use of Klotho as biomarker and therapeutic target. Experimental administration of Klotho protein indicates a neuro- and nephroprotective potential, suggesting a possible future role of Klotho as a therapeutic agent. However, the use of Klotho as intervention during pregnancy is as yet unproven. Here, we summarize novel evidence, suggesting Klotho as a key regulator for healthy pregnancies and intrauterine development with promising potential for clinical use., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Shared anatomical, histological and physiological pathways between the kidney and the eye are well documented, demonstrating that ocular manifestations serve as valuable prognostic indicators in chronic kidney disease (CKD), providing insights into disease severity and progression. Through non-invasive imaging modalities such as retinal fundus photography, early retinal microvascular alterations indicative of CKD progression can be detected, enabling timely intervention and risk stratification. However, the conclusions drawn from the review primarily demonstrate a strong or independent association between glaucoma or retinopathy and CKD., Results and Conclusion: Multiple shared pathophysiological events have been implicated in the pathogenesis in the alterations at eye and kidney including renin-angiotensin-aldosterone system. Patients with CKD are more likely to experience glaucoma, age-related macular degeneration, cataracts, uremic optic neuropathy and retinopathy. To establish the role of ocular manifestations in predicting CKD progression, it is crucial to address the limitations of correlation and explore the underlying causality with further research on common disease pathogenesis. Additionally, specific methods for risk stratification based on retinal changes, the effectiveness of timely interventions, and the development of predictive tools combining ocular and renal data are of utmost importance research topics to enlighten the bidirectional causality., (© 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

The Kidney Disease: Improving Global Outcomes (KDIGO) 2024 Guidelines for identification and management of chronic kidney disease (CKD) are a welcome development coming 12 years after the paradigm changing 2012 guidelines. We are living in an unprecedented era in nephrology with novel therapies, including sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists and non-steroidal mineralocorticoid receptor antagonists now being proven in multiple randomised controlled clinical trials to reduce both the progression of CKD and cardiovascular morbidity and mortality. The KDIGO 2024 CKD guideline is aimed at a broad audience looking after children and adults with CKD and provide practical and actionable steps to improve care. This commentary reviews the guideline sections pertaining to the evaluation and risk assessment of individuals with CKD from a European perspective. We feel that despite the last guideline being published 12 years ago, and that the assessment of CKD has been emphasized by many other national/international nephrology, cardiology and diabetology guidelines and societies, the diagnosis and treatment of CKD remains poor across Europe. As such the KDIGO 2024 CKD Guidelines should be seen as an urgent call to action to improve diagnosis and care of children and adults with CKD across Europe. We know what we need to do. We now need to get on and do it., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Sarcopenia, a condition marked by progressive muscle mass and function decline, presents significant challenges in aging populations and those with chronic illnesses. Current standard treatments such as dietary interventions and exercise programs are often unsustainable. There is increasing interest in pharmacological interventions like bimagrumab, a monoclonal antibody that promotes muscle hypertrophy by inhibiting muscle atrophy ligands. Bimagrumab has shown effectiveness in various conditions, including sarcopenia., Aim: The primary objective of this meta-analysis is to evaluate the impact of bimagrumab treatment on both physical performance and body composition among patients diagnosed with sarcopenia., Materials and Methods: This meta-analysis follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We systematically searched PubMed, Ovid/Medline, Web of Science, and the Cochrane Library databases up to June 2024 using appropriate Medical Subject Headings (MeSH) terms and keywords related to bimagrumab and sarcopenia. Eligible studies were randomized controlled trials (RCTs) that assessed the effects of bimagrumab on physical performance (e.g., muscle strength, gait speed, six-minute walk distance) and body composition (e.g., muscle volume, fat-free body mass, fat body mass) in patients with sarcopenia. Data extraction was independently performed by two reviewers using a standardized form, with discrepancies resolved through discussion or consultation with a third reviewer., Results: From an initial search yielding 46 records, we screened titles, abstracts, and full texts to include seven RCTs in our meta-analysis. Bimagrumab treatment significantly increased thigh muscle volume (mean difference [MD] 5.29%, 95% confidence interval [CI] 4.08% to 6.50%, P < 0.001; moderate heterogeneity χ2 = 6.41, I2 = 38%, P = 0.17) and fat-free body mass (MD 1.90 kg, 95% CI 1.57 kg to 2.23 kg, P < 0.001; moderate heterogeneity χ2 = 8.60, I2 = 30%, P = 0.20), while decreasing fat body mass compared to placebo (MD - 4.55 kg, 95% CI - 5.08 kg to - 4.01 kg, P < 0.001; substantial heterogeneity χ2 = 27.44, I2 = 89%, P < 0.001). However, no significant improvement was observed in muscle strength or physical performance measures such as gait speed and six-minute walk distance with bimagrumab treatment, except among participants with slower baseline walking speeds or distances., Discussion and Conclusion: This meta-analysis provides valuable insights into the effects of bimagrumab on sarcopenic patients, highlighting its significant improvements in body composition parameters but limited impact on functional outcomes. The observed heterogeneity in outcomes across studies underscores the need for cautious interpretation, considering variations in study populations, treatment durations, and outcome assessments. While bimagrumab shows promise as a safe pharmacological intervention for enhancing muscle mass and reducing fat mass in sarcopenia, its minimal effects on muscle strength and broader physical performance suggest potential limitations in translating body composition improvements into functional gains. Further research is needed to clarify its long-term efficacy, optimal dosing regimens, and potential benefits for specific subgroups of sarcopenic patients., (© 2024. The Author(s).)

Chronic kidney disease (CKD) is among the leading causes of morbidity and mortality as it affects more than 10% of the global adult population. Cognitive impairment has a positive correlation with the stage of CKD. It has been recorded in more than half of CKD patients undergoing kidney replacement therapy. The assessment of cognitive function in dialysis patients presents challenges due to various patient limitations. Such a common debilitating comorbidity of CKD has no approved treatment option, highlighting the importance of preventive measures and screening modalities. Erythropoietin therapy, exercise training, cognitive stimulation or behavioral therapies, alterations in dialysis frequency, dialysate cooling and kidney transplantation have been proposed as potential preventive and/or therapeutic options with variable efficiency at a clinical level. Regular screening, such as yearly, for cognitive impairment in maintenance dialysis patients is not only beneficial for timely and accurate diagnosis but also crucial for effective management and improved patient care. However, current practices face challenges, including the absence of validated tools specific for kidney failure and complications arising from patient conditions., (© 2024. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Obesity represents a prevalent global health concern with significant implications for various diseases, including chronic kidney disease (CKD). Within this landscape, the phenomenon of metabolically healthy obesity has emerged, challenging traditional notions about the health risks associated with excess weight. While traditional CKD risk factors involve obesity, metabolic syndrome, diabetes, and hypertension, the metabolically healthy obese (MHO) subgroup disrupts these assumptions. Our main objective in this study is to integrate existing literature on CKD in MHO individuals. In this endeavor, we delve into the pathophysiological foundations, the transition between obesity phenotypes and their impact on renal health, examine the implications of their metabolic resilience on mortality within a renal context, and explore potential management strategies specifically designed for MHO individuals. Offering a comprehensive overview of the pathophysiology, we cover various factors contributing to the risk of CKD in the metabolically healthy obese setting, including inflammation, cytokines, hemodynamics, and the renin-angiotensin-aldosterone system, gastrointestinal microbiota, diet, exercise, adipose distribution, and lipotoxicity. Through this synthesis, we aim to provide a comprehensive understanding of the risk of CKD in those classified as MHO.

Cardiovascular-kidney-metabolic (CKM) syndrome and chronic kidney disease (CKD) are two significant comorbidities affecting a large proportion of the general population with considerable crosstalk. In addition to substantial co-incidence of CKD and CKM syndrome in epidemiological studies, clinical and pre-clinical studies have identified similar pathophysiological pathways leading to both entities. Patients with CKM syndrome are more prone to develop acute kidney injury and CKD, while therapeutic alternatives and their success rates are considerably lower in such patient groups. Nevertheless, the association between CKM syndrome and CKD or ESKD is bidirectional rather than being a cause-effect relationship as patients with CKD are also prone to develop peripheral insulin resistance, high blood pressure, and dyslipidemia. Furthermore, such patients are less likely to receive kidney transplantation in addition to the higher allograft dysfunction risk. We hereby aim to evaluate the association in-between kidney diseases and CKM syndrome, including epidemiological data, pre-clinical studies with pathophysiological pathways, and potential therapeutic perspectives., Competing Interests: Declaration of competing interest All authors have no conflict of interest., (Copyright © 2024 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: Chronic kidney disease (CKD) and end-stage renal disease (ESKD) are significant global health challenges associated with progressive kidney dysfunction and numerous complications, including cardiovascular disease and mortality. This study aims to explore the potential association between plasma klotho levels and various prognostic outcomes in CKD and ESKD, including all-cause mortality, cardiovascular events, metabolic syndrome development and adverse renal events necessitating renal replacement therapies., Methods: A literature search was conducted through 3 June 2024 using the electronic databases Cochrane Library, Ovid MEDLINE, CINAHL, Web of Science, SCOPUS and PubMed. This systematic review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines., Results: Fourteen studies were included. For all-cause mortality, comparing CKD patients with low versus high klotho levels showed a significant association {odds ratio [OR] 1.81 [95% confidence interval (CI) 1.34-2.44], P  = .0001}, with substantial heterogeneity ( I 2  = 69%). Excluding one study reduced heterogeneity ( I 2  = 43%) while maintaining significance [OR 1.97 (95% CI 1.45-2.66), P  < .0001]. Cardiovascular mortality was higher in patients with low klotho levels [OR 2.11 (95% CI 1.61-2.76), P  < .00001], with low heterogeneity ( I 2  = 25%). Excluding one study eliminated heterogeneity ( I 2  = 0%) while maintaining significance [OR 2.39 (95% CI 1.83-3.12), P  < .00001]. Composite cardiovascular events did not differ significantly between low and high klotho groups [OR 1.51 (95% CI 0.82-2.77), P  = .18], but with high heterogeneity ( I 2  = 72%). Patients with low klotho levels had a higher risk of adverse renal events [OR 2.36 (95% CI 1.37-4.08), P  = .002], with moderate heterogeneity ( I 2  = 61%). Sensitivity analysis reduced heterogeneity ( I 2  = 0%) while maintaining significance [OR 3.08 (95% CI 1.96-4.85), P  < .00001]. Specifically, for ESKD or kidney replacement therapy risk, low klotho levels were associated with an increased risk [OR 2.30 (95% CI 1.26-4.21), P  = .007]. Similarly, CKD progression risk was higher in patients with lower klotho levels [OR 2.48 (95% CI 1.45-4.23), P  = .0009]., Conclusion: Lower serum klotho levels serve as a significant predictor of adverse outcomes, including increased risks of all-cause mortality, cardiovascular mortality and progression to end-stage kidney disease among CKD patients., Competing Interests: M.K. is a member of the CKJ Editorial Board. The other authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background and Aim: Post-transplant diabetes mellitus (PTDM) is a complex condition arising from various factors including immunosuppressive medications, insulin resistance, impaired insulin secretion, and inflammatory processes. Its impact on patient and graft survival is a significant concern in kidney transplant recipients. PTDM's impact on kidney transplant recipients, including patient and graft survival and cardiovascular mortality, is a significant concern, given conflicting findings in previous studies. This meta-analysis was imperative to not only incorporate emerging evidence but also to delve into cause-specific mortality considerations. We aimed to comprehensively evaluate the association between PTDM and clinical outcomes, including all-cause and cardiovascular mortality, sepsis-related mortality, malignancy-related mortality, and graft loss, in kidney transplant recipients., Materials and Methods: PubMed, Ovid/Medline, Web of Science, Scopus, and Cochrane Library databases were screened and studies evaluating the effect of PTDM on all-cause mortality, cardiovascular mortality, sepsis-related mortality, malignancy-related mortality, and overall graft loss in adult kidney transplant recipients were included., Results: 53 studies, encompassing a total of 138,917 patients, to evaluate the association between PTDM and clinical outcomes were included. Our analysis revealed a significant increase in all-cause mortality (RR 1.70, 95% CI 1.53 to 1.89, P<0.001) and cardiovascular mortality (RR 1.86, 95% CI 1.36 to 2.54, P<0.001) among individuals with PTDM. Moreover, PTDM was associated with a higher risk of sepsis-related mortality (RR 1.96, 95% CI 1.51 to 2.54, P<0.001) but showed no significant association with malignancy-related mortality (RR 1.20, 95% CI 0.76 to 1.88). Additionally, PTDM was linked to an increased risk of overall graft failure (RR 1.33, 95% CI 1.16 to 1.54, P<0.001)., Conclusion: These findings underscore the importance of comprehensive management strategies and the need for research targeting PTDM to improve outcomes in kidney transplant recipients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background and Aim: Sodium-glucose cotransporter (SGLT)-2 inhibitors are novel anti-diabetic medications with potential beneficial effects on cardiovascular and renal outcomes, metabolic parameters, and body weight. In addition to the beneficial effects on renal functions, including estimated glomerular filtration rate and reduction in proteinuria, recent studies have investigated the potential role of SGLT-2 inhibitor therapy on nephrolithiasis development. Nephrolithiasis, a condition affecting almost 10% of the general population at least once during a lifetime, is a common disorder with considerable risk for acute and chronic kidney injury and relatively few effective therapeutic options., Materials and Methods: We have performed a literature search through multiple databases, including PubMed, Ovid/Medline, Web of Science, Scopus, and Cochrane Library. We have followed the systematic review and meta-analysis guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses.We have included a total of 11 635 698 patients who experienced nephrolithiasis from six clinical trials to conduct this meta-analysis study. In the pooled analysis, nephrolithiasis occurred in 1,27% of patients from the SGLT2i group (n = 739 197), compared to 1,56% of patients (n = 10 896 501) from the control arm (active control, placebo or no therapy)., Results: We have included a total of 11 635 698 participants who experienced nephrolithiasis from a total of six clinical studies with nephrolithiasis rates of 1,27% in the SGLT2i group (n = 739 197), compared to 1,56% in the control arm (n = 10 896 501). SGLT-2 inhibitor therapy has been associated with a lower risk for nephrolithiasis compared to placebo (OR 0.61, 95% CI, 0.53-0.70, p < 0.00001) or active therapy such as glucagon-like peptide 1 and dipeptidyl peptidase-IV inhibitors (OR 0.66, 95% CI, 0.47-0.93, p = 0.02)., Conclusion: We have demonstrated a lower risk of nephrolithiasis risk with SGLT-2 inhibitor therapy compared to placebo or active control. Potential underlying mechanisms include osmotic diuresis leading to a reduction in the concentration of lithogenic substances, anti-inflammatory and anti-fibrotic effects, and an increase in urine pH. There is a clear need for future large-scale randomized clinical trials evaluating such associations for better understanding., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: The fundamental role of the renin-angiotensin-aldosterone system in the pathophysiology of chronic kidney disease, congestive heart failure, hypertension and proteinuria is well established in pre-clinical and clinical studies. Mineralocorticoid receptor antagonists are among the primary options for renin-angiotensin-aldosterone system blockage, along with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers., Methods: In this narrative review, we aim to evaluate the efficiency and safety of mineralocorticoid receptor antagonists in kidney transplant recipients, including the potential underlying pathophysiology., Results: The efficiency and safety of mineralocorticoid receptor antagonists in managing chronic kidney disease and proteinuria, either non-nephrotic or nephrotic range, have been demonstrated among nontransplanted patients, though studies investigating the role of mineralocorticoid receptor antagonists among kidney transplant recipients are scarce. Nevertheless, promising results have been reported in pre-clinical and clinical studies among kidney transplant recipients regarding the role of mineralocorticoid receptor antagonists in terms of ischaemia-reperfusion injury, proteinuria, or calcineurin inhibitor-mediated nephrotoxicity without considerable adverse events such as hypotension, hyperkalaemia or worsening renal functions., Conclusion: Even though initial results regarding the role of mineralocorticoid receptor antagonist therapy for kidney transplant recipients are promising, there is clear need for large-scale randomized clinical trials with long-term follow-up data., (© 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

The global burden of chronic kidney disease (CKD) is high and increasing. Early diagnosis and intervention are key to improve outcomes. Single-nephron glomerular hyperfiltration is an early pathophysiologic manifestation of CKD that may result in absolute glomerular hyperfiltration, i.e. a high glomerular filtration rate (GFR), or be associated with normal or low GFR because of nephron loss (relative glomerular hyperfiltration). Even though compensatory glomerular hyperfiltration may contribute to maintain kidney function after the loss of kidney mass, the associated increased glomerular capillary pressure and glomerular and podocyte size drive podocyte loss, albuminuria and proximal tubular overload, contributing to CKD progression. In this regard, all kidney protective drugs in clinical use so far, from renin-angiotensin system blockers to mineralocorticoid receptor blockers to sodium-glucose co-transporter 2 inhibitors to tolvaptan, induce an early dip in glomerular filtration that is thought to represent reversal of hyperfiltration. As glomerular hyperfiltration may be present early in the course of kidney disease, its recognition may provide an effective intervention window that may predate current criteria based on high albuminuria or loss of GFR. Nevertheless, there is no diagnostic method with high sensitivity and specificity to identify single-nephron glomerular hyperfiltration, except when it leads to obvious absolute glomerular hyperfiltration, as observed in the early stages of diabetic kidney disease when nephron mass is still preserved. We now review the concept of glomerular hyperfiltration as an indicator of CKD risk, including definitions, challenges in diagnosis and evaluation, underlying pathophysiological mechanisms, potential therapeutic approaches and unanswered questions., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Cardiovascular kidney metabolic (CKM) syndrome represents a complex interplay of cardiovascular disease (CVD), chronic kidney disease (CKD), and metabolic comorbidities, posing a significant public health challenge. Gender exerts a critical influence on CKM syndrome, affecting the disease severity and onset through intricate interactions involving sex hormones and key physiological pathways such as the renin-angiotensin system, oxidative stress, inflammation, vascular disease and insulin resistance. It is widely known that beyond the contribution of traditional risk factors, men and women exhibit significant differences in CKM syndrome and its components, with distinct patterns observed in premenopausal women and postmenopausal women compared to men. Despite women generally experiencing a lower incidence of CVD, their outcomes following cardiovascular events are often worse compared to men. The disparities also extend to the treatment approaches for kidney failure, with a higher prevalence of dialysis among men despite women exhibiting higher rates of CKD. The impact of endogenous sex hormones, the correlations between CKM and its components, as well as the long-term effects of treatment modalities using sex hormones, including hormone replacement therapies and gender-affirming therapies, have drawn attention to this topic. Current research on CKM syndrome is hindered by the scarcity of large-scale studies and insufficient integration of gender-specific considerations into treatment strategies. The underlying mechanisms driving the gender disparities in the pathogenesis of CKM syndrome, including the roles of estrogen, progesterone and testosterone derivatives, remain poorly understood, thus limiting their application in personalized therapeutic interventions. This review synthesizes existing knowledge to clarify the intricate relationship between sex hormones, gender disparities, and the progression of CVD within CKM syndrome. By addressing these knowledge gaps, this study aims to guide future research efforts and promote tailored approaches for effectively managing CKD syndrome.

Background and objectives Frailty and cognitive impairment significantly impact survival time and time to initiate dialysis in older adults with advanced chronic kidney disease (CKD). This study aims to evaluate the effects of frailty and cognitive impairment on these outcomes and determine the most effective assessment tool for predicting early dialysis initiation and short survival time. Materials and methods This prospective observational cohort study involved 240 patients aged ≥65 years with stage 4 or 5 CKD, recruited from a nephrology outpatient department (ambulatory care) between March 2020 and March 2021. Frailty was assessed using the Physical Frailty Phenotype (PFP), PRISMA-7, Clinical Frailty Scale (CFS), and FRAIL scale. Cognitive function was evaluated using the Montreal Cognitive Assessment (MoCA). The primary outcomes were time to initiate dialysis and survival time, with secondary outcomes including hospitalization rates, length of stay, and mortality after dialysis initiation. Results Frail patients only showed significantly shorter time to dialysis initiation when identified by the PFP and FRAIL scale (28.3 months for frail vs. 31.2 months for non-frail, p = 0.028; 26.9 months for frail vs. 30.9 months for non-frail, p = 0.038). The PFP, FRAIL, and CFS tools indicated significantly shorter survival times for frail patients compared to non-frail patients (26.8 months for frail vs. 30.6 months for non-frail, p = 0.003). Frailty is strongly correlated with severe cognitive impairment, as 45.5% of frail patients (according to the FRAIL scale) have dementia compared to 15.1% of non-frail patients (p<0.001). However, cognitive impairment did not significantly affect the time to dialysis initiation or survival time. Hospitalization rates and length of stay in the hospital were significantly higher only for frail patients identified by PRISMA-7, with a median hospital length of stay of 9.15 days for frail patients vs 6.37 days for non-frail patients (p = 0.044). Overall, 37.5% of the patients did not survive during the study follow-up, with frail patients having a higher mortality rate. Conclusion Frailty, mainly when assessed by PFP and FRAIL, is a significant predictor of early dialysis initiation and reduced survival time in older adults with advanced CKD. Cognitive impairment, while prevalent, did not independently predict these outcomes. Regular frailty screening should be incorporated into CKD management to tailor interventions and improve patient outcomes., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. The Ethical Committee of Dr. C.I. Parhon University Hospital issued approval 8044/18.10.2019. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Hussien et al.)

Autosomal dominant polycystic kidney disease (ADPKD), the most common hereditary kidney disease, accounts for approximately 10% of the patients on kidney transplantation waitlists. High rates of complications including hemorrhage, infections, nephrolithiasis and kidney size-related compressive complaints have been reported among ADPKD patients. Therefore, the need for routine native nephrectomy and timing of such procedure in ADPKD patients being prepared for transplantation are debated. Even though pre-transplant nephrectomy has the potential to provide fewer infectious complications due to lack of immunosuppressive medication use, such procedure has been associated with longer hospital stay, loss of residual kidney function and need for dialysis. Although simultaneous nephrectomy and transplantation could potentially lead to longer perioperative duration, perioperative complications and need for blood transfusions, this was not confirmed in cohort studies. Therefore, some institutions routinely perform simultaneous unilateral nephrectomy and kidney transplantation. In this narrative review, our aim is to evaluate the current evidence regarding the need and timing of nephrectomy in ADPKD patients in relation to kidney transplantation., (© 2024. The Author(s).)

Objective: Kidney transplantation is the gold standard therapeutic alternative for patients with end-stage renal disease; nevertheless, it is not without potential complications leading to considerable morbidity and mortality such as post-transplant diabetes mellitus (PTDM). This narrative review aims to comprehensively evaluate PTDM in terms of its diagnostic approach, underlying pathophysiological pathways, epidemiological data, and management strategies., Methods: Articles were retrieved from electronic databases using predefined search terms. Inclusion criteria encompassed studies investigating PTDM diagnosis, pathophysiology, epidemiology, and management strategies., Results: PTDM emerges as a significant complication following kidney transplantation, influenced by various pathophysiological factors including peripheral insulin resistance, immunosuppressive medications, infections, and proinflammatory pathways. Despite discrepancies in prevalence estimates, PTDM poses substantial challenges to transplant. Diagnostic approaches, including traditional criteria such as fasting plasma glucose (FPG) and HbA1c, are limited in their ability to capture early PTDM manifestations. Oral glucose tolerance test (OGTT) emerges as a valuable tool, particularly in the early post-transplant period. Management strategies for PTDM remain unclear, within sufficient evidence from large-scale randomized clinical trials to guide optimal interventions. Nevertheless, glucose-lowering agents and life style modifications constitute primary modalities for managing hyperglycemia in transplant recipients., Discussion: The complex interplay between PTDM and the transplant process necessitates individualized diagnostic and management approaches. While early recognition and intervention are paramount, modifications to maintenance immunosuppressive regimens based solely on PTDM risk are not warranted, given the potential adverse consequences such as increased rejection risk. Further research is essential to refine management strategies and enhance outcomes for transplant recipients., (© 2024 John Wiley & Sons Ltd.)

Increasing serum osmolality has recently been linked with acute stress responses, which over time can lead to increased risk for obesity, hypertension, and other chronic diseases. Salt and fructose are two major stimuli that can induce acute changes in serum osmolality. Here we investigate the early metabolic effects of sodium and fructose consumption and determine whether the effects of sodium or fructose loading can be mitigated by blocking the change in osmolality with hydration. Forty-four healthy subjects without disease and medication were recruited into four groups. After overnight fasting, subjects in Group 1 drank 500 mL of salty soup, while those in Group 2 drank 500 mL of soup without salt for 15 min. Subjects in Group 3 drank 500 mL of 100% apple juice in 5 min, while subjects in Group 4 drank 500 mL of 100% apple juice and 500 mL of water in 5 min. Blood pressure (BP), plasma sodium, and glucose levels were measured every 15 min in the first 2 h. Serum and urine osmolarity, serum uric acid, cortisol, fibroblast growth factor 21 (FGF21), aldosterone, adrenocorticotropic hormone (ACTH) level, and plasma renin activity (PRA) were measured at the baseline and 2 h. Both acute intake of salt or fructose increased serum osmolality (maximum ∼4 mOsm/L peaking at 75 min) associated with a rise in systolic and diastolic BP, PRA, aldosterone, ACTH, cortisol, plasma glucose, uric acid, and FGF21. Salt tended to cause greater activation of the renin-angiotensin-system (RAS), while fructose caused a greater rise in glucose and FGF21. In both cases, hydration could prevent the osmolality and largely block the acute stress response. Acute changes in serum osmolality can induce remarkable activation of the ACTH-cortisol, RAS, glucose metabolism, and uric acid axis that is responsive to hydration. In addition to classic dehydration, salt, and fructose-containing sugars can activate these responses. Staying well hydrated may provide benefits despite exposure to sugar and salt. More studies are needed to investigate whether hydration can block the chronic effects of sugar and salt on disease., (© 2024. The Author(s).)

The role of proximal tubules (PTs), a major component of the renal tubular structure in the renal cortex, has been examined extensively. Along with its physiological role in the reabsorption of various molecules, including electrolytes, amino acids and monosaccharides, transcellular transport of different hormones and regulation of homeostasis, pathological events affecting PTs may underlie multiple disease states. PT hypertrophy or a hyperfunctioning state, despite being a compensatory mechanism at first in response to various stimuli or alterations at tubular transport proteins, have been shown to be critical pathophysiological events leading to multiple disorders, including diabetes mellitus, obesity, metabolic syndrome and congestive heart failure. Moreover, pharmacotherapeutic agents have primarily targeted PTs, including sodium-glucose cotransporter 2, urate transporters and carbonic anhydrase enzymes. In this narrative review, we focus on the physiological role of PTs in healthy states and the current understanding of the PT pathologies leading to disease states and potential therapeutic targets., Competing Interests: M.K., C.Z. and F.M. are members of the CKJ editorial board. The remaining authors have no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Proteinuria poses a substantial risk for the progression of chronic kidney disease (CKD) and its related complications. Kidneys excrete hundreds of individual proteins, some with a potential impact on CKD progression or as a marker of the disease. However, the available data on specific urinary proteins and their relationship with CKD severity remain limited. Therefore, we aimed to investigate the urinary proteome and its association with kidney function in CKD patients and healthy controls. The proteomic analysis of urine samples showed CKD stage-specific differences in the number of detected proteins and the exponentially modified protein abundance index for total protein (p = 0.007). Notably, specific urinary proteins such as B2MG, FETUA, VTDB, and AMBP exhibited robust negative associations with kidney function in CKD patients compared to controls. Also, A1AG2, CD44, CD59, CERU, KNG1, LV39, OSTP, RNAS1, SH3L3, and UROM proteins showed positive associations with kidney function in the entire cohort, while LV39, A1BG, and CERU consistently displayed positive associations in patients compared to controls. This study suggests that specific urinary proteins, which were found to be negatively or positively associated with the kidney function of CKD patients, can serve as markers of dysfunctional or functional kidneys, respectively., (© 2024. The Author(s).)

'Elderly' is most commonly defined as an individual aged 65 years or older. However, this definition fails to account for the differences in genetics, lifestyle and overall health that contribute to significant heterogeneity among the elderly beyond chronological age. As the world population continues to age, the prevalence of chronic diseases, including chronic kidney disease (CKD), is increasing and CKD frequently progresses to kidney failure. Moreover, frailty represents a multidimensional clinical entity highly prevalent in this population, which needs to be adequately assessed to inform and support medical decisions. Selecting the optimal treatment pathway for the elderly and frail kidney failure population, be it haemodialysis, peritoneal dialysis or conservative kidney management, is complex because of the presence of comorbidities associated with low survival rates and impaired quality of life. Management of these patients should involve a multidisciplinary approach including doctors from various specialties, nurses, psychologists, dieticians and physiotherapists. Studies are mostly retrospective and observational, lacking adjustment for confounders or addressing selection and indication biases, making it difficult to use these data to guide treatment decisions. Throughout this review we discuss the difficulty of making a one-size-fits-all recommendation for the clinical needs of older patients with kidney failure. We advocate that a research agenda for optimization of the critical issues we present in this review be implemented. We recommend prospective studies that address these issues, and systematic reviews incorporating the complementary evidence of both observational and interventional studies. Furthermore, we strongly support a shared decision-making process matching evidence with patient preferences to ensure that individualized choices are made regarding dialysis vs conservative kidney management, dialysis modality and optimal vascular access., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Proteinuria is a well-established biomarker of chronic kidney disease (CKD) and a risk predictor of associated disease outcomes. Proteinuria is also a driver of CKD progression toward end-stage kidney disease. Toxic effects of filtered proteins on proximal tubular epithelial cells enhance tubular atrophy and interstitial fibrosis. The extent of protein toxicity and the underlying molecular mechanisms responsible for tubular injury during proteinuria remain unclear. Nevertheless, albumin elicits its toxic effects when degraded and reabsorbed by proximal tubular epithelial cells. Overall, healthy kidneys excrete over 1000 individual proteins, which may be potentially harmful to proximal tubular epithelial cells when filtered and/or reabsorbed in excess. Proteinuria can cause kidney damage, inflammation and fibrosis by increasing reactive oxygen species, autophagy dysfunction, lysosomal membrane permeabilization, endoplasmic reticulum stress and complement activation. Here we summarize toxic proteins reported in proteinuria and the current understanding of molecular mechanisms of toxicity of proteins on proximal tubular epithelial cells leading to CKD progression., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Background: Recent studies indicate that accumulation of adipose tissue in various organs such as liver and kidney may contribute to the pathophysiology of metabolic syndrome. We aim to investigate the association between kidney and liver adipose tissue accumulation, assessed by the magnetic resonance imaging (MRI) proton density fat fraction technique, along with its relation to clinical and biochemical parameters., Methods: We included 51 volunteers with phenotypical features of metabolic syndrome (mean age = 34 years, mean body-mass index = 26.4 kg/m 2 ) in our study in which liver and kidney adipose tissue accumulation was assessed via MRI-proton density fat fraction along with multiple other clinical and biochemical parameters such as estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio, serum lipid profile, liver function tests and body-mass index (BMI)., Results: Our results from the univariate linear regression analysis indicate that both the kidney and liver scores were positively correlated with markers such as BMI, urine albumin-to-creatinine ratio, triglycerides (p < 0.001) and negatively correlated with eGFR (p < 0.05). In multivariate analysis, urine albumin-to-creatinine ratio (p < 0.05), triglycerides (p < 0.01), eGFR (p < 0.05) and BMI (p < 0.001) were found to be independently associated with kidney and liver fat accumulation, respectively (R 2  = 0.64; R 2  = 0.89). There was also a positive correlation between kidney and liver fat accumulation., Conclusion: We have found a significant association between adipose tissue accumulation in liver and kidney and the parameters of metabolic syndrome. Moreover, the presence of a strong association between kidney and liver fat accumulation and kidney function parameters such as urine albumin-to-creatinine ratio and eGFR may be an indicator of the clinical significance of parenchymal fat accumulation., (© 2023. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Infectious diseases are among the most common cause of morbidity and mortality among hospitalized patients while systemic inflammatory response syndrome is primarily attributed to the imbalance between pro-inflammatory and anti-inflammatory cytokines. Despite the improvements in the antibiotherapy alternatives and diagnostic modalities, the morbidity and mortality rates of sepsis and septic shock are relatively high among patients admitted to the intensive care units. Extracorporeal cytokine hemadsorption therapies are therapeutic approaches for such patient group with promising early results that especially have grown during COVID-19 pandemic. In this narrative review, our aim is to evaluate the current pre-clinical and clinical knowledge regarding the use of cytokine filtration systems among patients with septic shock., (© 2023 Wiley Periodicals LLC.)

As the number of patients living with kidney failure grows, the need also grows for kidney transplantation, the gold standard kidney replacement therapy that provides a survival advantage. This may result in an increased rate of transplantation from HLA-mismatched donors that increases the rate of antibody-mediated rejection (AMR), which already is the leading cause of allograft failure. Plasmapheresis, intravenous immunoglobulin therapy, anti-CD20 therapies (i.e., rituximab), bortezomib and splenectomy have been used over the years to treat AMR as well as to prevent AMR in high-risk sensitized kidney transplant recipients. Eculizumab and ravulizumab are monoclonal antibodies targeting the C5 protein of the complement pathway and part of the expanding field of anticomplement therapies, which is not limited to kidney transplant recipients, and also includes complement-mediated microangiopathic hemolytic anemia, paroxysmal nocturnal hemoglobinuria, and ANCA-vasculitis. In this narrative review, we summarize the current knowledge concerning the pathophysiological background and use of anti-C5 strategies (eculizumab and ravulizumab) and C1-esterase inhibitor in AMR, either to prevent AMR in high-risk desensitized patients or to treat AMR as first-line or rescue therapy and also to treat de novo thrombotic microangiopathy in kidney transplant recipients., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)