Abstract The renin–angiotensin–aldosterone system (RAAS) plays a central role in regulating renal hemodynamics, sodium and water balance, and cardiovascular homeostasis. Chronic RAAS activation contributes to hypertension, proteinuria, inflammation, fluid overload, and fibrosis, making RAAS blockade (RAASb) a cornerstone therapy across the kidney life cycle. Over the past decades, ACE inhibitors, angiotensin receptor blockers, direct renin inhibitors, and mineralocorticoid receptor antagonists have demonstrated substantial benefits in slowing chronic kidney disease (CKD) progression, reducing proteinuria, and lowering cardiovascular risk. However, the efficacy and safety of RAASb vary according to the kidney life cycle. Evidence supports its use in proteinuric CKD and even in advanced stages, whereas the benefit in non-proteinuric disease remains limited. Novel non-steroidal mineralocorticoid receptor antagonists such as finerenone further enhance renal and cardiovascular protection, particularly in persons with diabetes and CKD. In dialysis populations, RAASb may preserve residual kidney function improve cardiac structure/function, although the benefit of steroidal MRAs remains uncertain. In kidney transplantation, RAASb appears safe and may improve long-term graft and patient survival, particularly when initiated early. The emergence of SGLT2 inhibitors and GLP-1 receptor agonists has reshaped therapeutic strategies, with accumulating evidence supporting complementary rather than competing roles with RAASb. This review synthesizes current evidence on RAAS modulation across the kidney life cycle from primary prevention to advanced CKD, dialysis, and transplantation, highlighting both established benefits and areas of current clinical uncertainty.

Abstract Introduction Haemodialysis (HD) contributes vastly to greenhouse gas (GHG) emissions. Recognizing this, the German Society for Nephrology initiated a web-based Carbon Footprint assessment tool to benchmark emissions. Methods This study collected data from five pilot HD centers between 2015 and 2023. Emission categories appropriate for HD were defined, and included transportation, energy consumption, manufacturing/disposal, and other operational factors. Results All-center, all-period average was 3.72 ± 0.44 tons of CO2 equivalents per patient per year (t/p/y), with manufacturing/disposal, energy consumption and patient transportation as the largest contributions. Over the assessment period, a reduction of 9.1% was achieved, through changes in dialysate flow (-0.16 t/p/y), solar power system installation (-0.21 t/p/y) and transition to a planetary health-adapted diet (-0.10 t/p/y). A best-case scenario with modelled implementation of all ready-to-use measures including 40% of patients switching to automated peritoneal dialysis and 10% to incremental HD projected a reduction potential of 38.7% or 1.5 t/p/y, substantially less than what is needed to reach net zero. Conclusion Using available technology, HD-related GHG emission was reduced by 9% in the short range. Higher future reductions to meet the targets of a 50% reduction by 2030 and ‘net zero’ by 2045 might necessitate enhancing prevention and transplantation efforts, technological innovation, support chain adaptations and structural changes like increased use of peritoneal dialysis.

ABSTRACTIn 2025, the World Health Assembly of the World Health Organization (WHO) adopted a resolution on reducing the burden of noncommunicable diseases (NCDs) by promoting kidney health and strengthening the prevention and control of kidney disease. Following the WHO resolution, the United Nations (UN) included kidney health in its 2025 Political Declaration on NCDs. These measures are a clear response to the growing burden of kidney diseases. This achievement for kidney health was facilitated by years of effort by multiple stakeholders and decision-makers, including nephrology associations, particularly the International Society of Nephrology, the European Renal Association (ERA) and the American Society of Nephrology, gathering evidence on the growing burden of chronic kidney disease (CKD), raising awareness of this burden, advancing research and innovation, and adopting scientific and policy recommendations for the early detection, prevention and treatment of CKD. The WHO and UN measures add kidney disease to a list of major NCDs (e.g. cancer, cardiovascular diseases, diabetes, respiratory diseases) that should be prioritized by healthcare systems. The kidney health resolution is fully aligned with the ERA’s activities and recommendations, as well as with the 2025 KDIGO document on the prevention of CKD and maintenance of kidney health. This novel preventive approach has been tried and tested for other conditions, such as cardiovascular disease, the age-adjusted mortality of which is falling dramatically, compared with the equally dramatic increase in CKD mortality. The next step would be to define an actionable condition of very high risk of CKD, that may be termed pre-CKD. This should be complemented by programs for the early diagnosis and treatment of CKD, such as the one promoted by ERA’s ‘Protect Your Kidneys, Protect Your Future’ campaign which emphasizes the need to know and treat the ABCDE numbers (Albuminuria, Blood pressure, Cholesterol, Diabetes, Estimated glomerular filtration rate) to improve cardiovascular–kidney–metabolic health.

Abstract Background and Aims Dialysis can be a significant challenge for people already coping with the complexities of severe mental illness (SMI). Despite the increased prevalence of end-stage kidney disease (ESKD) in patients with SMI, there is a lack of detailed evaluation regarding its management in those who exhibit aggressive or oppositional behavior. Method This retrospective, national and multicenter cohort study included patients between January 1, 2015, and December 31, 2023, aged ≥18 years, with a diagnosis of SMI (schizophrenia, bipolar disorder or other inorganic or organic psychotic disorder) associated with ESKD and a history of anti-treatment behavior that impeded the delivery of dialysis care. Results Fifty-one patients with ESKD and SMI from 13 centers were included, with a mean follow-up of 5.5 years and an overall mortality rate of 49% (25 patients). Thirty-nine patients (76.5%) underwent hemodialysis, 7 patients (13.7%) received peritoneal dialysis, and 5 patients (9.8%) opted for conservative treatment. Forced hospitalization at the start of dialysis was necessary in 9 patients (17.6%). When comparing dialysis parameters at baseline and at the end of follow-up, the dialysis regimen was generally well maintained over time (number of scheduled or completed dialysis sessions, duration of dialysis sessions, interdialytic weight gain, Kt/V or blood flow rate). Hyperkalemia above 5.5 mmol/L was common (13.9%). Behavioral disorders worsened in dialysis patients: while verbal aggression towards nursing staff significantly decreased (from 33.3% to 3.9%, P < 0.01), the incidence of conflicts with other patients increased from 3.9% to 46.2% (P < 0.001). At the end of follow-up, emergency consultations were more frequent (17 patients vs 11, p=0.015). During the follow-up, 16 patients (31.3%) changed dialysis centers at least once. Conclusion Despite behavioral challenges, healthcare providers make effective dialysis management possible through their strong commitment and expertise. However, they need the right tools, training, and support to care for SMI patients with CKD.

Abstract Background and Aims Advances in clinical trials and guidelines have the potential to improve therapeutic strategies for IgAN. More up-to-date evidence on patient characteristics and treatment patterns, and their association with CKD progression based on multicenter data in China, is needed. This study aimed to evaluate treatment patterns of IgAN in the real-world clinical setting in China, using data from a regional electronic health record database, where healthcare information has been linked across hospitals in this region. Method A retrospective observational study of adult patients with biopsy-confirmed primary IgAN from Yinzhou District, Ningbo City, China, was conducted using data from 01/01/2015 to 06/30/2023. Patients with secondary IgAN, history of dialysis or eGFR <15 mL/min/1.73 m2 at renal biopsy, or a history of kidney transplantation, were excluded. Index date was the date of the initial biopsy which confirmed IgAN. IgAN-related treatment patterns after renal biopsy were described, including initial treatments within 30 days after renal biopsy and initial treatment durations, as well as overall treatments during the entire follow-up. Results A total of 978 patients were included (52.0% were women). At renal biopsy, the median age was 43 years, 55.0% had hypertension, 9.1% had diabetes, 40.0% had >1g/day proteinuria, and 70.1% were in CKD stage I or II. Around 85.9% of patients were assigned Grade III-V per Lee's grading system, which is indicative of severe IgAN. During follow-up, 31.8% had time-averaged proteinuria >1 g/day. Of 742 patients with initial treatment records after renal biopsy, 79.5% were treated with RAASi, 15.1% with corticosteroids, 6.1% with immunosuppressants, 3.4% with SGLT2i, and 0.1% with targeted therapies. RAASi combination therapies are most frequently used as first-line therapy (79.5%). Composite renal event (at least one of ESKD, 40% eGFR decline, doubling of serum creatinine or mortality) was experienced by 6.7% of patients with a median time to event of about 31.9 months. Conclusion Results suggested that adult patients with IgAN in this Chinese cohort were diagnosed relatively young and were at early CKD stages. While the average proteinuria level was lower than other sites in China, these patients had concomitant high-risk comorbid conditions, and a majority had higher grade (III-V) per Lee's grading indicating risk of progression. Findings indicated adherence to both Chinese and international guidelines for IgAN treatments, where administering RAASi as supportive care has been generally considered. Despite high levels of treatment with RAASi at initial biopsy, a substantial portion of patients have high proteinuria levels at follow-up, indicating an unmet need.

Abstract Background and Aims The choice between renal replacement therapy or conservative management of end-stage renal disease is complex in the elderly, due to the high prevalence of associated comorbidities, frailty, loss of quality of life and high mortality rate. This decision is especially relevant in particularly aged geographic areas. Several scores have been developed to help the decision of dialysis start among elderly patients, although they tend to lack generalizability as they are usually developed in widely different populations. In the present study we aim to compare two different prognostic scores in a sample of CKD stage 4 and 5 elderly patients from our area. Method We retrospectively identified all consecutive CKD stage 4 or 5 patients aged ≥70 years, reviewed at our outpatient clinic during a six-month period. Two different prognostic scores (1, 2) were applied at the first visit in which options for renal replacement therapy were discussed with the patient, including conservative management. Need for renal replacement therapy initiation and patient survival during the following 5 years after the visit were recorded. The scores are summarized in Table 1. Statistical analysis was performed using IBM SPSS Statistics 26. Results Demographic and clinical characteristics of the study sample are summarized in Table 2. When predicting 6-month mortality, both scores showed an area under the ROC curve of 0.705 (Fig. 1A). The area under the ROC curve decreased for both scores when predicting 5-year mortality (AUC: 0.688 and 0.679 for the Santos J and Wick JP scores, respectively) (Fig. 1B). No survival analysis was performed at the 6-month mark due to the low number of events. Moreover, in Kaplan-Meier analysis, both scores, analyzed as tertiles, were associated with 5-year patient survival (Santos J: Log-Rank: 11.511; P = 0.003; Wick JP: Log-Rank: 11.061; P = 0.004) (Fig. 2C and 2D). Conclusion Although a higher result was associated with lower 5-year survival in both scores, they showed poor discrimination of 6-month and 5-year mortality in our study sample to be considered as part of our daily clinical routine. These results highlight the current need to develop predictive models accurate enough to help both patients and physicians in the decision-making progress of when and if to start dialysis.

Abstract Background and Aims Crescentic glomerulonephritis (cGN) is a severe kidney pathology characterized by the aberrant proliferation of parietal epithelial cells leading to crescent formation within the Bowman's space. Despite its clinical relevance, the molecular pathways involved in crescent formation remain poorly understood. Given the mechanical stress experienced by podocytes, likely exacerbated in cGN, we hypothesized that an activation of the mechanosensor YAP, a key effector of the Hippo pathway, may contribute to the development of cGN. Method To investigate this hypothesis, we combined a classical experimental mouse model of cGN (nephrotoxic nephritis model), a transgenic mouse model (podocyte-specific overexpression of YAP5SA) with in vitro molecular studies, and the analysis of human cGN biopsies. Results Interestingly, we observed a strong podocyte-specific overactivation of YAP in the nephrotoxic nephritis model, a classical cGN model. This observation led us to investigate whether YAP activation in podocytes might drive cGN. To explore this hypothesis, we selectively overexpressed a constitutively active YAP variant (NLS-YAP5SA) within podocytes. Remarkably, targeted YAP hyperactivation per se induced cell autonomous hypertrophy of podocytes and aberrant non-cell autonomous activation and proliferation of parietal epithelial cells (PECs), leading to crescents. Transcriptomic profiling in a podocyte cell line expressing the same YAP5SA isoform revealed the reactivation of developmental programs within differentiated podocytes. Mechanistically, this analysis disclosed connective tissue growth factor (CTGF) and heparin-binding EGF-like growth factor (HBEGF) as potential mediators in the crosstalk between YAP-activated podocytes and PECs, driving PEC hyperplasia. Importantly, we confirmed abnormally high YAP activity in podocytes of cGN patients. Conclusion Collectively, these findings highlight the pivotal role of YAP in the pathogenesis of cGN and indicate that targeting YAP or its downstream mediators could be a promising therapeutic strategy for this severe kidney disease.

Abstract Background and Aims Kidney transplantation (KT) is the therapy of choice for patients with advanced chronic kidney disease; however, predicting graft outcomes and improving clinical results remain challenging. Early identification of reliable biomarkers could improve clinical care, which can be achieved through metabolomic analysis. This study employed a semi-targeted metabolomic approach, combining the advantages of targeted and untargeted strategies to identify specific metabolites and discover novel compounds. This study aimed to identify metabolomic biomarkers within the first week after KT that could predict renal function at six months and explore potential therapeutic targets. Method We conducted a prospective, observational, single-center study including 50 adult patients who received a deceased donor kidney transplant. Plasma samples were collected one week post-transplant and analyzed using Ultra-Performance Liquid Chromatography (UPLC) coupled to a Q-Exactive Plus mass spectrometer, following a semi-targeted metabolomic approach. Metabolomic data from 48 patients were statistically analyzed using Partial Least Squares-Discriminant Analysis (PLS-DA) to identify metabolic profiles associated with renal function at six months. Patients were categorized into two groups based on serum creatinine levels: ≥1.5 mg/dL and <1.5 mg/dL. Model performance was assessed using Variable Importance in Projection (VIP) scores, with the optimal number of latent variables determined through Leave-One-Out Cross-Validation (LOOCV). Additionally, permutation testing (1000 iterations) was performed. Results The study population had a mean age of 53.98 years, predominantly male (70%) and Caucasian (94%). Hypertension (82%), dyslipidemia (70%), and obesity (28%) were the most prevalent comorbidities. The majority of donors were from donation after brain death (DBD) (58%), while 42% were from donation after circulatory death (DCD), with a mean cold ischemia time of 17.30 hours. The semi-targeted metabolomic analysis identified 226 polar metabolites in plasma samples collected one week post-transplant. A PLS-DA model, optimized using VIP scores >1.5 demonstrated strong predictive performance (AUC: 0.958, accuracy: 87.5%, sensitivity: 86.4%, specificity: 88.5%). Twelve metabolites contributed the most to the differentiation between patients with serum creatinine levels ≥1.5 mg/dL and <1.5 mg/dL at six months post-transplant. Metabolites associated with better graft function (serum creatinine <1.5 mg/dL) included 3-methylindole (skatole), guaiacol, histidine, 3-indolepropionic acid, and α-lipoic acid. These compounds are known for their antioxidant, anti-inflammatory, and gut microbiota-modulating properties. Conversely, metabolites associated with impaired graft function (serum creatinine ≥1.5 mg/dL), suggesting a potential link to poorer outcomes, were homocarnosine, 5-methylcytosine, xanthosine, choline, phenylalanine, kynurenic acid, and L-kynurenine. Notably, xanthosine, kynurenic acid, L-kynurenine, and choline have been previously identified as prognostic markers for chronic kidney disease progression in several studies, further supporting their relevance in post-transplant renal dysfunction. Several metabolites from the tryptophan metabolic pathway were identified, underscoring the critical role of tryptophan metabolism in post-transplant renal function and its potential as a therapeutic target. Conclusion Early metabolomic profiling following kidney transplantation appears to be a valuable tool for predicting renal function. The identification of metabolites with potential protective antioxidant and anti-inflammatory effects, alongside others associated with poorer outcomes that could serve as therapeutic targets, highlights their clinical relevance. The observed association of several metabolites with the tryptophan metabolic pathway emphasizes the need for further investigation into its role in post-transplant outcomes. These biomarkers hold promise for improving patient monitoring and optimizing long-term graft survival.

Abstract Background and Aims There is limited evidence surrounding the long-term glycaemic benefits from continuous glucose monitoring (CGM) in people with diabetes (PwD) on dialysis. The aim of this study was to establish the potential benefits of CGM use on glycaemic control, guiding insulin therapy regimen, and improving clinical outcomes in PwD on dialysis. Method A retrospective, cross-sectional study was conducted across all dialysis units within University Hospitals Birmingham (UHB) NHS Foundation Trust, United Kingdom. Patients aged >18 years, with known diagnosis of diabetes receiving regular dialysis—including haemodialysis (HD), peritoneal dialysis (PD), and home haemodialysis (HHD)—who used CGM (FreeStyle Libre or Dexcom) for more than 3 months were included. Patients not sharing CGM data were excluded. Data was extracted by accessing electronic patient records and CGM (LibreView or Dexcom Clarity) Portals. The demographic characteristics, insulin treatment, and CGM metrics (time in range [TIR], time above range [TAR], time below range [TBR], glucose variability [GV], HbA1C levels and number of hypoglycaemia events) were recorded. Results A total of 55 adult patients were included. 76.4% (n = 42/55) of patients were on HD; 21.8% (n = 12/55) on PD; and 1.8% (n = 1/55) on HHD. The median number of months on CGM was 26 (IQR = 19.31). All patients were on insulin therapy. 29.1% (n = 16/55) patients had their insulin therapy regimen changed following CGM use. 63.6% (n = 35/55) patients were on basal-bolus regimen. 4.65% (n = 2/43) of HD and HHD patients had required different insulin doses between their dialysis and non-dialysis days. There was no difference between measured baseline and latest HbA1C following CGM introduction (68.22 ± 21.86 vs 63.38 ± 17.96 [mmol/mol], P = 0.757). Furthermore, there was also no difference between the mean glucose on CGM over the last 14-days and 90-days period (11.94 ± 3.31 vs 12.08 ± 3.26 [mmol/L], P = 0.586). The latest median TIR for our patients remained suboptimal at 38.0%. The hyperglycaemic burden was excessive, with a median TAR-very high of 26.0% and TAR-high of 28.0%. Of the 48 patients who were on FreeStyle Libre, 77.1% (n = 37/48) had at least one prolonged hypoglycaemia event of >15 minutes over the last-90-days. 29.7% (n = 11/37) did not have any further hypoglycaemia event over the last 14-days (P < 0.001). Conclusion While significant improvements in overall glycaemic control were not observed, our findings underscore the complexity of glycaemic management in this population and the need for tailored interventions. We strongly advocate for large-scale randomised controlled trials to explore how CGM technology can be further optimised to achieve meaningful improvements in glycaemic and clinical outcomes for this challenging patient group.

Abstract Background and Aims Uncomfortable complaints frequently observed in maintenance hemodialysis (HD) patients, such as pruritus, restless legs syndrome (RLS), burning feet, leg muscle cramps, and insomnia, contribute to a decline in the quality of life (QOL) for these patients. One of the effects of on-line hemodiafiltration (OHDF) is the improvement of uncomfortable complaints by increasing the removal rate of α1-microglobulin. The purpose of this study is to investigate whether changing from conventional HD to OHDF enhances the removal efficiency of small-middle molecular weight substances and large-middle molecular weight proteins, subsequently improving dialysis-related symptoms in dialysis patients. Method This study involved 24 HD patients (21 males and 4 females) with a mean age of 63 ± 12 years and an HD duration of 78.6 ± 74.3 months, including 11 patients with diabetes and 13 without diabetes. All participants were receiving pharmacological treatment, including Nalfurafine hydrochloride (2.5 µg/day), Clonazepam (0.5 mg/day), and Shakuyakukanzoto extract (6.0 g/day). During HD and at 0, 1, 2 and 3 months after transition to OHDF, the serum albumin and blood urea nitrogen concentrations, the removal rates of β2-microglobulin and α1-microglobulin were measured. The associations between these parameters and dialysis-related symptoms, including daytime itching, nighttime itching, restless legs and leg muscle cramps were investigated. The severity of the subjective symptoms was assessed using a Visual Analogue Scale (VAS), with 0 indicated no symptoms, 1 indicated mild symptoms, 2 indicated moderate symptoms, 3 indicated moderate to severe symptoms and 4 indicated severe symptoms. Results There were no significant differences in the BUN removal rate and KT/V between HD and HDF. The serum albumin concentration at 2 months after the transition from HD to HDF was lower than that during HD. The β2-microglobulin and α1-microglobulin removal rates at 0, 1, 2 and 3 months after the transition from HD to HDF were significantly higher than those during HD (Table 1). After the transition from HD to OHDF, all symptoms, including daytime itching, nighttime itching, restless legs, and leg muscle cramps, significantly improved (Table 2). Furthermore, 13 out of 24 patients were able to reduce or discontinue medications. Conclusion Transition from HD to OHDF resulted in a slight decrease in serum albumin concentrations; however, no significant decline in Kt/V was observed, and the marked reduction in the removal rates of small to middle-weight substances was not evident. The removal efficiencies of β2-microglobulin and α1-microglobulin significantly improved, consequently the overall patients experienced an improvement in dialysis-related symptoms. Therefore, HDF treatment has demonstrated the potential to enhance the QOL for dialysis patients suffering from uncomfortable dialysis-related symptoms.