Abstract Background and Aims Vicadrostat (BI 690517) is a highly selective aldosterone synthase inhibitor (ASi) in clinical development for CKD treatment. Coadministration of vicadrostat with a sodium-glucose cotransporter-2 inhibitor may provide additive efficacy and mitigate risk of hyperkalemia. This phase II trial (NCT05182840) investigated the efficacy and safety of vicadrostat, given alone or in combination with empagliflozin, in participants with CKD and with or without type 2 diabetes [1, 2]. The aim of the present analyses was to assess effects of vicadrostat on albuminuria by body mass index (BMI) at baseline. Method Adults with CKD (eGFR 30–<90 ml/min/1.73 m², UACR 200-<5000 mg/g) receiving a maximally tolerated dose of a renin-angiotensin system inhibitor were randomized (R1) 1:1 to receive background empagliflozin 10 mg or matching placebo (PBOEMPA) during an 8-week run-in. They were then re-randomized (R2) 1:1:1:1 to receive vicadrostat (3 mg, 10 mg, or 20 mg) or matching placebo (PBOVICA) for 14 weeks, in addition to their assigned empagliflozin or PBOEMPA. The primary outcome was the change from R2 baseline in urine albumin:creatinine ratio (UACR) at Week 14. Secondary outcomes included UACR response (≥30% reduction from R2 baseline in UACR at Week 14), changes in systolic blood pressure (SBP) and estimated glomerular filtration rate (eGFR) from R2 baseline to Week 14. Data for empagliflozin and PBOEMPA were pooled and the effects of vicadrostat, adjusted for the presence or absence of background empagliflozin use, were assessed by BMI subgroups (≥30 vs <30 kg/m2). Results Of 583 participants in the present analyses, 249 (42.7%) had BMI ≥30 kg/m2 and 334 (57.3%) had BMI <30 kg/m2. Baseline demographics and clinical characteristics are shown in Table 1. Vicadrostat consistently reduced UACR in participants with BMI ≥30 and <30 kg/m2 (vicadrostat 10 mg: PBO-adjusted percent change from baseline of −37.5% [95% CI −50.9, −20.5] with BMI <30 kg/m2 and −39.1% [95% CI m53.1, −20.9; Pinteraction = 0.13] with a BMI ≥30 kg/m2), with the largest reductions seen in the 10 mg and 20 mg dose groups (Fig. 1). UACR response rates (≥30% reduction) were achieved in more than half of people in the vicadrostat 10 mg and 20 mg dose groups (with BMI ≥30 kg/m2: 10-mg vicadrostat 61.5%, placebo 18.4%; BMI <30 kg/m2: 10-mg vicadrostat 50.7%, placebo 26.2%). Vicadrostat consistently reduced SBP in both BMI groups (PBO-adjusted difference with vicadrostat 10 mg: BMI ≥30 kg/m2 −10.59 mmHg [95% CI −16.64, −4.54]; BMI <30 kg/m2 −6.98 mmHg [95% CI −15.60, 1.63]). Conclusion Vicadrostat with or without empagliflozin reduced albuminuria irrespective of baseline BMI dichotomized at 30 kg/m2 in participants with CKD and with or without type 2 diabetes. Vicadrostat given in combination with empagliflozin shows promise as a potential treatment option for patients with CKD that will undergo further testing in a phase 3 trial program (EASi-KIDNEYTM, NCT06531824).

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.

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 Heart failure with preserved ejection fraction (HFpEF) and chronic kidney disease (CKD) constitute a high-risk phenotype with significant morbidity and mortality and poor prognosis. Multiple proinflammatory comorbid conditions influence the pathogenesis of HFpEF and CKD. The understanding of the molecular mechanisms underpinning kidney damage cardio-renal interactions in HFpEF remains poorly understood. Unveiling new molecular targets could pave the way for new mechanism-based interventions to prevent HFpEF and CKD progression. Method A mouse model of HFpEF, characterized by the combination of high-fat diet (60 kcal% fat,) and L-NAME in the drinking water (0.5 g/L) for 15 weeks was employed. Control mice received a control diet (10 kcal% fat,) and vehicle in the drinking water (Fig. 1A). Deep renal phenotyping in control and HFpEF mice was performed by: i) renal biomarker profiling; ii) histological analysis; iii) RNA sequencing; iv) proteomics; v) CUT&RUN assay to investigate chromatin accessibility (Fig. 1B). Results HFpEF mice displayed renal dysfunction as assessed by increased creatinine, cystatin C and galectin-3 levels (Fig. 1C) as well as alterations of tissue architecture as shown by Collagen 1A1 and Periodic acid-Schiff (PAS) staining (Fig. 1D). Bulk RNA-seq and proteomic analyses unveiled three top-ranking signals in HFpEF vs control kidneys, namely Kynureninase (KYNU), Receptor Accessory Protein 6 (REEP6), and Retinol Dehydrogenase 16 family member 2 (RDH16F2) (Fig. 1E). Analysis of the chromatin landscape by CUT&RUN assays identified increased accessible loci in HFpEF vs control kidneys, with a prominent role of epigenetic readers (BET proteins) in regulating the transcription of target genes. Of interest, enhanced BET protein enrichment was associated with kidney inflammation and fibrosis in HFpEF mice. Conclusion HFpEF is associated with relevant epigenetic and transcriptional alterations in the kidney, eventually promoting organ dysfunction and structural remodeling. Our study sheds light on epigenome-environment interactions and new molecular targets potentially implicated in the progression of cardio-renal damage in HFpEF.

Abstract Background and Aims Diabetic kidney disease (DKD) affects over half a billion people globally, leading to severe outcomes such as chronic kidney disease (CKD) and cardiovascular events. Current diagnostic tools are imprecise, while renal biopsy is invasive and costly. Multiparametric MRI (mpMRI) offers a non-invasive alternative to assess renal microstructure. Matrix metalloproteinase-10 (MMP-10) and its inhibitor TIMP-1 disbalance has been implicated in DKD. Neutrophil gelatinase-associated lipocalin (NGAL) serves as a reliable indicator of DKD progression. This study evaluates the utility of mpMRI in the assessment of renal microstructural perfusion, fibrosis and inflammation, and its correlation with circulating serum biomarkers, in patients with DKD. We hypothesise that albuminuria may have an impact on renal microvasculature and fibrosis from the early stages of DKD, and these changes may be quantified by mpMRI. Method An observational study was conducted including 47 adults with type 2 diabetes (T2D) and DKD (CKD Stage 3 of KDIGO classification), categorized according to macroalbuminuria and non-macroalbuminuria. Nineteen healthy controls were included. Participants underwent serum and imaging biomarker assessments, including MMP10, TIMP1, NGAL, and mpMRI (renal blood flow -RBF-, T1 mapping and apparent diffusion coefficient -ADC-). Statistical analyses evaluated the impact of albuminuria on the associations between diverse biomarkers. Results Reduced RBF (in cortex and medulla), ADC and T1 cortico-medullary differentiation (CMD) was found in DKD subjects compared to controls. Analyzing patients without (<300 mg/g) and with (≥300 mg/g) macroalbuminuria we noted lower RBF and T1 CMD values in the macroalbuminuric group. An interaction was observed between biomarkers (TIMP, MMP10/TIMP and NGAL) and mpMRI parameters. Conclusion Our study suggests that renal mpMRI could be a valuable tool for a more precise evaluation of DKD. Renal mpMRI is able to detect the impact of albuminuria, on renal microperfusion and fibrosis in DKD even among patients with similar grade of 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 Intradialytic hypotension (IDH) is a common complication of hemodialysis that negatively affects patients’ quality of life and increases mortality risk. One strategy to mitigate IDH involves lowering the ultrafiltration rate (UFR) to reduce dialysis strain; however, this often requires longer treatment times and may not benefit all patients. We developed an artificial intelligence (AI) model to predict IDH risk [1] and performed an in-silico simulation to characterize which patients are sensitive versus insensitive to changes in UFR. Our aim was to identify patient subgroups that could benefit from tailored UFR adjustments to reduce IDH events. Method We included 4,966 adult patients who underwent 1,187,298 hemodialysis sessions between 2021 and 2023 in Fresenius Medical Care Clinics in Czech Republic, Portugal, Spain, and Singapore (machine data available for these countries). Mean age was 68.9 ± 13.9 years, dialysis vintage 5.58 ± 5.73 years, and median UFR 7.0 [5.1–9.0] ml/hr/kg. The AI model used demographic, biochemical, and clinical treatment data. The final model demonstrated good discrimination (AUC = 0.75). Using model-based predictions, we then simulated the dose–response relationship between UFR and IDH risk per patient. We defined patients as “UFR-insensitive” when a substantial decrease in UFR (e.g., from the 85th to the 15th percentile) produced a small reduction in IDH risk (threshold 2.2%, i.e. IDH risk reduction median value) in more than 75% of their treatments. On the contrary, we defined patients as “UFR-sensitive” when a substantial decrease in UFR produced a substantial reduction in IDH risk (threshold 2.2%) in more than 75% of their treatments. We compared characteristics and observed IDH rates between UFR-insensitive and UFR-sensitive patients. Results Of the 4,966 patients analyzed, 1,177 were classified as UFR-insensitive and 1,394 as UFR-sensitive. Despite similar level of hydration status as judged by body composition monitoring, UFR-insensitive patients had fewer hypotensive events. Notably, they showed a negative change in systolic pressure from pre- to post-dialysis (versus a positive change in UFR-sensitive patients) and had lower pre-dialysis systolic pressures. UFR-insensitive patients also tended to have higher blood flow and blood volume during treatment, higher UFRs, greater small solute clearance, lower recirculation rates, and were less likely to have diabetes. Figure 1 illustrates simulated IDH risk curves at varying UFR values for a representative UFR-sensitive and UFR-insensitive patient. Conclusion Identifying patients whose IDH risk responds favorably to UFR adjustments is essential for optimizing dialysis treatment. Our findings suggest that UFR-sensitive patients experience more hypotensive events overall, highlighting the potential benefit of precisely targeted UFR modifications to reduce IDH. This approach could help improve dialysis outcomes and patient quality of life by tailoring treatment to individual risk profiles.

Abstract Background and Aims Pathogenic variants of the polycystic kidney and hepatic disease 1 (PKHD1) gene alter epithelial water and ion transport, and lead to renal collecting duct dilatations and to liver cysts formation, hallmarks of autosomal recessive polycystic kidney disease (ARPKD). In the context of epithelial models using ARPKD genetics, loss of fibrocystin/polyductin (FPC) protein function results in a change from absorptive to secretory epithelial phenotype, thus reflecting one major pathophysiological mechanism for cyst growth. Our aim is to understand the molecular aspects of defective epithelial homeostasis by identifying channels that mediate aberrant electrolyte transport and promote cystic fluid accumulation. Here we employ a monolayered, three-dimensional (3D) epithelial model, allowing us to control cystogenic signals, determine channel distribution and test therapeutic targets. Method To model ARPKD conditions, Pkhd1 knockout clones were established using CRISPR/Cas9 in a principle-like Madin-Darby canine kidney (pl-MDCK) cell line. Single cells seeded into matrigel were allowed to form polarized spheroids with a lumen and stimulated by forskolin to enhance cAMP levels inducing secretory cystic epithelia. Measurement of cyst pressure and determination of the proportional lumen (i.e. ratio of lumen to spheroid area) confirmed enhanced water and ion transport across the epithelial barrier, as observed in ARPKD. The involvement of chloride channels in ARPKD disease progression was addressed by pharmacological inhibition, and subcellular distribution of water and ion channels was tested. Impact of FPC function was determined expressing functional domain constructs. Results Besides significantly enhanced cyst pressure, which is represented also by increased proportional lumina of pl-MDCK spheroids, FPC deficiency results in a prominent re-localization of the ion channels ENaC and CFTR from the apical to the basolateral membrane domain. In wild type cells, enhanced cAMP-levels mimic this phenotype and correlate with increased pressure values, whereas tight junctions (ZO-1) and the water channel aquaporin-2 remain apical in control and disease conditions. Both, treatment with selective chloride channel- inhibitors as well as controlled expression of the FPC cytoplasmic domain allowed us to suppressed cAMP-induced cyst formation in Pkhd1-KO cell lines, and controls. Conclusion A secretory phenotype of cyst-lining epithelia in disease conditions, as represented by enhanced cAMP-signals, mimics disturbed epithelial homeostasis in ARPKD and associates with altered ion channel distribution. Targeting of mis-localized ion channels represents a strategy to test for therapeutic options. Reconstitution of a functional c-terminal domain of FPC was sufficient to correct aberrant ion flux in our 3D in vitro model, suggesting that the cytoplasmic tail may function as a natural inhibitor of cyst growth and disease progression.

Abstract Background and Aims Timing of preemptive kidney transplantation (PKT) and the role of eGFR change in outcome prediction remain a subject of debate. This study aims to assess potential factors, with special attention to uremic burden, which may be associated with 5-year outcomes. In our retrospective observational cohort study, first PKT adults registered in CRISTAL between 2013–2019 were analyzed to elucidate the role of eGFR and other associating factors with death and graftloss. Method Recipient, donor and transplantation related features were analyzed by using multivariable logistic regression analysis. Conditional inference tree was applied for risk stratification. Results 2327 first PKT (52.8 (IQR 43–64) years; 38% females) were included. Mean percentage of PKT over time was 14%. Primary kidney disease (congenital anomalies, glomerulonephritis and other causes versus ADPKD), donor age and number of DR mismatches associated with combined 5-year outcomes (OR 2.64 (CI 95% 1.42–4.93); 1.94 (1.1–4.93); 1.76 (1.06–2.92); 1.03 (1.02–1.05); 1.67 (1.1–2.53) P < 0.05), whereas donor type was not associated with the outcomes. By supervised decision-tree analysis, more than 30% risk of failure in PKT was attributed to high recipient risk, higher donor age, uremic burden index (UBI)—a novel parameter defined by the product of eGFR change and the logarithmic time on waiting list—and 2 DR mismatches. Conclusion In conclusion, eGFR and donor type were not associated with death or graft failure in PKT. UBI can potentially be a novel parameter of uremic burden and contribute to predict 5-year risk of failure. Clinical decision based on objective risk estimations might be crucial to approach the “PKT in due course” concept.

Abstract Background and Aims Haemodialysis (HD) is associated with a decline in physical capacity, quality of life (QoL), and the emotional well-being of the patient. Evidence suggests that physical exercise provides benefits to lifestyle, prevents muscle loss, enhances mood, and alleviates symptoms associated with renal disease. Given these benefits, assessing the impact of an intradialytic exercise programme on emotional well-being, health-related QoL, and HD-related symptoms is essential. This study aimed to investigate the effects of such a programme on physical fitness, emotional response, health-related QoL in patients undergoing HD and symptoms associated with renal disease. Method Clinical trial with convenience sampling. The patients included in the study participated in an individualised intradialytic exercise programme, which lasted for 5 months with a frequency of 2 days per week, supervised by exercise professionals. Pre- and post-intervention assessments included the Hospital Anxiety and Depression Scale (HADS), the 12-Item Short-Form Health Survey (SF-12) for health-related QoL, and the Edmonton Symptom Assessment System (ESAS). IBM SPSS Statistics for Windows, Version 29.0.2.0 (Armonk, NY: IBM Corp), was used to analyse the collected data. The significance level was set at P < 0.05. Results A total of 71 patients undergoing HD participated in the individualised intradialytic exercise programme. Of these, 37 patients (52.1%) were under 65 years old (mean age 65.6 ± 15.5 years), 43 patients (60.6%) were male, and 25 patients (35.2%) were immigrants. The mean duration of time on HD was 4.9 ± 4.4 years. Regarding the Charlson Comorbidity Index, 40 patients (56.3%) had a score of less than 8, with an overall mean score of 7.1 ± 2.8. The results of the HADS scale showed improvements in anxiety scores pre- and post-intervention (from 4.5 to 4.0; P = 0.013) and also in depression scores (from 8.6 to 7.6; P = 0.006) (HADS, Table 1). The physical and mental components of health-related QoL, as measured by the SF-12, also showed a significant improvement (P < 0.001) (SF-12, Table 1). Regarding the symptoms measured by the ESAS questionnaire, pain, depression, drowsiness, appetite, and sleep improved following participation in the exercise programme (ESAS, Table 1). No significant differences were observed in symptoms related to fatigue, nausea, anxiety, well-being, and shortness of breath. Conclusion Participation in intradialytic exercise leads to improvements in both physical symptoms related to renal disease, as well as enhancing mental health and overall health-related QoL. Incorporating intradialytic exercise programmes should be considered an important component of comprehensive care for patients undergoing HD.