ABSTRACT Importance The prevalence of chronic kidney disease (CKD) is increasing, with aging being a major contributor. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are well established therapies for CKD; however, adults aged 80 years or older have been underrepresented in previous large-scale trials. Consequently, evidence regarding effects of SGLT2i therapy in this cohort remains limited. Objective To evaluate the association of SGLT2i initiation with mortality, kidney outcomes and cardiovascular outcomes among patients over 80 years of age and CKD. Design, Setting, Participants This retrospective cohort study used data from TriNetX Research Network, a multicenter electronic health record database. To ensure comparable standard of care and SGLT2i eligibility, the period for the occurrence of the index event was restricted to January 1, 2021, until January 1, 2025. Propensity score matching was performed to balance comorbidities, laboratory parameters, concomitant medications, and frailty-associated factors between groups. Exposures Initiation of SGLT2i therapy vs. non-use Main Outcomes and Measures Outcome analysis focused on all-cause mortality, major adverse kidney events (MAKE) and major adverse cardiovascular events (MACE). Cox proportional hazards models were used to estimate hazard ratios with 95% confidence intervals; following propensity score matching, results were considered as adjusted hazard ratios (aHR). Results After propensity score matching, 5,038 patients were included in each group. During two years of follow-up, SGLT2i initiation was associated with lower all-cause mortality (aHR 0.818; 95% CI 0.746 – 0.896, p<0.0001) and fewer MAKE events (aHR 0.779; 95% CI 0.0.715 - 0.850, p<0.0001). No significant difference in MACE was observed (aHR 1.007; 95%CI 0.938 - 1.082, p=0.84). Results were generally consistent across subgroups. Risk of acute kidney injury was higher in the SGLT2i group, while incident dialysis and end-stage renal disease were significantly reduced. Acute myocardial infarction and acute heart failure were increased in the SGLT2i group. Conclusion and Relevance Regarding survival and kidney endpoints, even the oldest CKD patients seem to benefit from SGLT2i treatment, which was associated with reduced mortality as well as improved long-term renal outcomes. MACE showed no significant differences, while specific cardiac events were increased, reflecting possible safety concerns requiring further investigation in this specific age group. Key points Question Is sodium-glucose cotransporter 2 inhibitor (SGLT2i) initiation associated with clinical outcomes in adults aged 80 years or older with chronic kidney disease? Findings In this retrospective cohort study of 10,076 propensity-score matched adults aged 80 years or older with chronic kidney disease, SGLT2i initiation was associated with lower all-cause mortality and fewer major adverse kidney events over 2 years. Meanings These findings support the consideration of SGLT2i treatment in very old adults with chronic kidney disease, a population underrepresented in clinical trials.

BACKGROUND AND HYPOTHESIS:Diabetes mellitus type 2 (T2DM) is the primary driver of chronic kidney disease (CKD). Renin-angiotensin-aldosterone system inhibitors (RAASi) represent basic therapy for CKD in T2DM. Recent studies demonstrated renal benefits of sodium glucose cotransporter 2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA), but data on direct comparisons and potential additive effects of their combination remain unclear. METHODS:Using data from the US Collaborative Network in TriNetX, we analyzed patients with T2DM, CKD, and eGFR between 20-60 mL/min. A target-trial emulation with propensity score matching evaluated different drug combinations in first-user design versus RAASi monotherapy. Primary endpoint was all-cause mortality. Secondary outcomes included a composite endpoint of all-cause mortality and major adverse kidney events (MAKE), and MAKE as a distinct endpoint. MAKE was defined as CKD stage 5, end-stage renal disease, eGFR <15 mL/min, or need for renal replacement therapy. Kaplan-Meier analysis was used for survival analysis. RESULTS:We identified n= 19,139 patients with T2DM, an eGFR between 20-60mL/min and already established RAASi treatment. RAASi combined with SGLT-2i (aHR 0.602, 95% CI 0.528-0.686) or GLP1-RA (aHR 0.597, 95% CI 0.507-0.702) reduced mortality compared to RAASi monotherapy. Triple therapy showed the greatest mortality reduction (aHR 0.317, 95% CI 0.234-0.429). Secondary endpoints favored dual therapy over RAASi monotherapy, with triple therapy providing the strongest risk reduction for both composite endpoint (aHR 0.414, 95% CI 0.328-0.524) and MAKE (aHR 0.509, 95% CI 0.374-0.693). CONCLUSION:SGLT-2i and GLP1-RA independently improve outcomes in T2DM patients on RAASi treatment. Triple therapy was associated with lower risk for mortality and renal outcomes.

BACKGROUND AND HYPOTHESIS:Women exhibit a lower cardiovascular risk and longer life expectancy compared with men in the general population. However, this advantage is diminished in dialysis and transplant patients, suggesting greater excess risk, i.e. risk above the general population, in women with kidney failure. Yet, data on excess risk in chronic kidney disease (CKD) populations, using those without CKD as the reference, are lacking. METHODS:In this retrospective cohort study, we analyzed de-identified, patient-level data from electronic medical records within the TriNetX database. Adults aged 18-90 years with an eGFR ≥15 mL/min/1.73 m2 without maintenance dialysis or kidney transplantation were included. Primary outcomes were all-cause mortality and cardiovascular composite outcome. Analyses were adjusted for age, sociodemographic factors, cardiovascular risk factors, laboratory measurements, medications and history of CVD, using multivariable Cox proportional hazards models. RESULTS:Of 328 431 eligible individuals, 43 830 were women with CKD, 45 173 men with CKD, 127 383 women without CKD and 112 045 men without CKD. In individuals without CKD, women displayed a reduced risk of all-cause mortality [hazard ratio (HR) 0.53; 95% confidence interval (CI) 0.49-0.58] and cardiovascular events (HR 0.70; 95% CI 0.68-0.71) compared with men. However, this risk reduction in women compared with men was significantly attenuated in individuals with CKD both for all-cause mortality (HR 0.73; 95% CI 0.69-0.77) and for cardiovascular events (HR 0.80; 95% 0.78-0.82). Consequently, CKD conferred significantly greater excess risk of mortality and cardiovascular events in women compared with men, consistent across different levels of kidney function, age and systolic blood pressure. CONCLUSIONS:The cardiovascular and survival advantage observed in women compared with men in the general population is significantly reduced in individuals with CKD, confining an increased excess risk in women with CKD.

Die Immunadsorption (IA) stellt ein wichtiges Verfahren der therapeutischen Apherese dar, mit dem Immunglobuline und Immunkomplexe selektiv aus dem Plasma entfernt werden, ohne dass eine Plasmasubstitution erforderlich ist. Sie stellt ein etabliertes Instrument zur Behandlung zahlreicher Autoimmunerkrankungen in Neurologie und Innerer Medizin dar, insbesondere bei schweren, therapierefraktären Verläufen und als Eskalationstherapie. Zu den zentralen neurologischen Indikationen zählen akute demyelinisierende Schübe bei multipler Sklerose und NMOSD („neuromyelitis optica spectrum disorder“), myasthene Krisen sowie Autoimmunenzephalitiden. Internistisch wird die IA v. a. bei der Anti-GBM(glomeruläre Basalmembran)-Antikörper-vermittelten Glomerulonephritis, bei systemischen Autoimmunerkrankungen und in der Transplantationsmedizin eingesetzt, wobei die Evidenzlage je nach Indikation unterschiedlich stark ist. Die ABO-Apherese als spezielle Form der IA spielt eine zentrale Rolle in der Vorbereitung ABO-inkompatibler Transplantationen.

Background:Mineralocorticoid receptor antagonists (MRAs) are the guideline-recommended therapy for resistant hypertension. Resistant hypertension is particularly common in individuals with overweight or obesity. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) induce substantial weight loss and reduce cardiovascular and renal events, with modest reductions in blood pressure. Whether GLP-1RAs provide benefit as an alternative therapeutic strategy in patients with resistant hypertension and overweight or obesity is unknown. We compared the effectiveness of GLP-1RAs and MRAs as fourth-line pharmacologic therapy in this population. Methods:In this retrospective multicenter cohort study using the TriNetX US Collaborative Network including 67 healthcare organizations, female and male adults with overweight or obesity and resistant hypertension (uncontrolled blood pressure despite ACE-inhibitors/angiotensin receptor blockers, calcium antagonists and diuretics) initiating a fourth-line pharmacological therapy between 01 June 2017 and 31 March 2025 were identified and included. Patients initiating GLP-1RAs (semaglutide or tirzepatide) were compared with those initiating MRAs (spironolactone or eplerenone). The primary outcome was major adverse cardiovascular events (MACE) during 2-year follow-up. Secondary outcomes included all-cause mortality, cardiovascular events, kidney outcomes, and blood pressure changes. Propensity score matching balanced baseline characteristics. Outcomes were analyzed using Kaplan-Meier estimates and Cox proportional hazards models. Findings:Among 213,309 eligible patients, 22,694 initiated GLP-1RAs and 5673 initiated MRAs. After propensity score matching, 4153 patients remained in each group. During a median follow-up of 1.4 years, GLP-1RA therapy was associated with lower risks of MACE (HR 0.63, 95% CI 0.52-0.78), all-cause mortality (HR 0.34, 95% CI 0.21-0.55), cardiovascular events (HR 0.74, 95% CI 0.59-0.92), major adverse kidney events (HR 0.64, 95% CI 0.46-0.88), and acute kidney injury (HR 0.62, 95% CI 0.46-0.83) compared with MRAs. Systolic blood pressure reductions at 12 weeks were similar (-5.7 [95% CI -4.0 to -7.4] mmHg versus -6.3 [95% CI -4.7 to -8.0] mmHg). Interpretation:In our retrospective study, among adults with resistant hypertension and overweight or obesity, GLP-1RA was associated with lower cardiovascular and kidney risk compared with MRAs despite smaller blood pressure reductions. GLP-1RAs may represent a potential alternative or complementary therapeutic option in this population. Prospective studies are needed to determine whether GLP-1RAs should be incorporated into treatment strategies for resistant hypertension in patients with overweight or obesity. Funding:None.

BACKGROUND:Baroreflex activation therapy (BAT) has emerged as a device-based therapy for resistant hypertension. Comparative evidence between first-generation (Rheos®) and second-generation (Barostim Neo™) BAT systems remains limited. METHODS:We retrospectively analysed all patients who underwent BAT implantation between 2006 and 2015 (n = 54) at our centre. The primary outcome was the change in 24h ambulatory blood pressure monitoring (ABPM) between device generations. Secondary outcomes included adverse events, major adverse cardiovascular events (MACE), kidney function, and device-related complications. Office blood pressure, 24h ABPM, and heart rate (HR) were assessed at baseline and during follow-up. Patients with insufficient 24h ABPM follow-up data were excluded from the primary endpoint analysis. RESULTS:In patients with ABPM data (n = 33), BAT significantly reduced 24h diastolic blood pressure (DBP), 24h systolic blood pressure (SBP), and HR (all p < 0.05). Daytime SBP, DBP, and HR decreased significantly. At night, SBP declined from 165 to 151 mmHg (p = 0.004) and DBP from 98 to 88 mmHg (p = 0.003), while HR remained unchanged. Rheos® was associated with significant reductions in 24h and night-time SBP; daytime SBP decreased numerically but did not reach statistical significance. Barostim Neo™ (n = 14) reduced 24h and daytime HR (p = 0.006 and p = 0.009) but showed no statistically significant BP reduction. No significant differences were observed between devices in complication rates, kidney function, or MACE. CONCLUSION:Baroreflex activation was safe and associated with reductions in 24h blood pressure and heart rate in patients with resistant hypertension. The first-generation Rheos® system demonstrated more pronounced blood pressure-lowering effects, whereas the second-generation Neo™ system was associated primarily with heart rate reduction without a significant effect on blood pressure. Although Rheos® is no longer commercially available, these findings highlight the importance of electrode design, implantation strategy, and patient selection in optimising the efficacy of contemporary BAT.

Abstract Background and hypothesis Sodium-glucose cotransporter-2 inhibitors (SGLT2-inhibitors) slow chronic kidney disease progression, but evidence in non-diabetic kidney transplant recipients is limited. We evaluated associations between SGLT2-inhibitor use and major adverse kidney events (MAKE), major adverse cardiovascular events (MACE), and all-cause mortality. Methods In this retrospective cohort study using the TriNetX federated research network, adult non-diabetic kidney transplant recipients transplanted between January 2015 and January 2022 were identified. SGLT2-inhibitor users initiating therapy ≥1000 days post-transplant were compared with non-users after 1:1 propensity score matching. The primary outcome was MAKE, defined as dialysis initiation or death. Secondary outcomes included all-cause mortality and MACE. Results Propensity score matching yielded 867 pairs of SGLT2-inhibitor users and non-users. SGLT2-inhibitor use was associated with lower risks of MAKE (adjusted hazard ratio [aHR] 0.64, 95% CI 0.45-0.91) and all-cause mortality (aHR 0.55, 95% CI 0.36-0.85). No significant association was observed for MACE (aHR 0.86, 95% CI 0.64-1.17). No increased risk of urinary tract infections was observed among SGLT2-inhibitor users. Conclusion SGLT2-inhibitor use was associated with lower risks of MAKE and all-cause mortality in non-diabetic kidney transplant recipients.

Cardiovascular disease is a major morbidity in children after kidney transplantation, limiting life expectancy and impairing graft function. Arterial hypertension is the dominant cardiovascular risk factor and highly abundant in this patient group. Arterial hypertension can cause left ventricular hypertrophy, which is predictive of cardiovascular death. Left ventricular hypertrophy can be non-invasively assessed by measuring left ventricular mass. Observational data indicated that intensified blood pressure control was associated with a significant reduction of left ventricular mass. Based on evidence from the randomized controlled ESCAPE trial, intensified blood pressure control is recommended in children with chronic kidney disease prior to kidney replacement therapy. However, current treatment recommendations for pediatric kidney transplant patients follow the recommendations for otherwise healthy children and adolescents with arterial hypertension, i.e., suggesting a blood pressure target < 90th percentile. In the proposed multicenter, randomized, parallel group trial with blinded endpoint evaluation, we aim to include 170 pediatric patients who underwent a kidney transplantation more than 12 months ago. Patients will be randomly assigned 1:1 to an intensified blood pressure management group (blood pressure target ≤ 60th percentile) and a standard blood pressure management group (blood pressure target < 90th percentile). The primary endpoint is left ventricular mass after 24 months. Secondary endpoints are pulse wave velocity, intima media thickness, estimated glomerular filtration rate, and albuminuria. Achievement of blood pressure targets will be facilitated through blood pressure telemonitoring. Blood pressure values will be transmitted in real time to the treating physician and the trial’s centralized study office allowing timely responses in case blood pressure values lie outside target range. The proposed study will result in an evidence-based definition of blood pressure targets and will therefore have direct implications for the care of children after kidney transplantation. In case intensified blood pressure targets are effective, this should eventually lead to lower cardiovascular morbidity and subsequently lower cardiovascular mortality of pediatric kidney transplant recipients. ClinicalTrials.gov NCT06589947. Registered on September 6, 2024.

High-dose melphalan followed by autologous stem cell transplantation (ASCT) remains the standard of care for fit patients with multiple myeloma (MM). However, individuals who are dependent on hemodialysis are frequently excluded from ASCT. Recommendations on chemotherapy dosing and hemodialysis scheduling vary in literature and definite conclusions are impeded by the heterogeneity of cohorts.We aimed to evaluate the safety and efficacy of ASCT in patients with MM and end-stage renal disease and to examine the pharmacokinetics of melphalan on a fixed schedule of melphalan infusion and hemodialysis.The outcome of 13 patients undergoing ASCT while being on hemodialysis between 2000 and 2022 was retrospectively analysed and compared to matched hemodialysis-independent patients. Melphalan plasma concentrations were measured in 4 hemodialysis-dependent and 5 independent patients.Plasma concentrations of hemodialysis-dependent patients were comparable to hemodialysis-independent patients with a 6-hour interval between melphalan infusion and hemodialysis (p = 0.9). The rate of immediate side effects of high-dose melphalan was significantly higher in 13 dialysis-dependent patients compared to 47 matched controls despite not having prolonged neutropenia (p = 0.9). Overall survival both from d0 of ASCT and diagnosis was comparable (p = 0.33 and p = 0.17, respectively).Thus, adopting the proposed schedule and management of immediate side effects make ASCT a safe option for myeloma patients with end-stage renal disease.

Sepsis and septic shock, defined by a profound immune dysregulation, are among the leading causes of death in the intensive care unit (ICU). Despite advances in understanding the underlying pathophysiology, evidence for specific immunomodulatory treatment does not exist to date. Therapeutic plasma exchange (TPE) represents an adjunctive treatment approach to rebalance immune homeostasis. In the EXCHANGE-1 trial, we recently demonstrated a rapid hemodynamic improvement, possibly caused by the removal of harmful mediators and the replacement of protective plasma proteins. The aim of this secondary analysis is to further characterize the underlying immunomodulatory effects and to identify biomarkers that may predict treatment response. This secondary analysis included patients in early septic shock (< 24 h duration) and a norepinephrine (NE) dose of ≥ 0.4 μg/kg/min. Patients were randomized 1:1 to receive standard of care (SOC) or SOC + one single TPE and plasma samples were collected before and after TPE. Within-group and between group effects of circulating levels of acute-phase proteins [CRP and Pentraxin3 (PTX3)], inflammatory mediators (IL-4, IL-6, IL-8, IL-10, TNF-α, IL-2Rα/CD25) and damage-associated molecular pattern (DAMP) [cell-free DNA (cfDNA)] were analyzed via paired t test or Wilcoxon signed-rank test and a mixed-effects model. Multivariate mixed‐effects modeling of NE and lactate reduction was performed to investigate if cfDNA could be associated with treatment response to TPE. TPE led to a significant reduction in circulating acute-phase protein levels (CRP p = 0.00976, PTX3 p = 0.0001). Pro-inflammatory cytokines, such as circulating TNF-α-, IL-6- und IL-8-levels, were significantly reduced in both groups with no significant difference between treatment groups except for IL-2Rα/CD25 (p ≤ 0.0001). In a multivariate mixed-effects model, rising cfDNA levels over the first 6 h indicated refractoriness to SOC treatment regarding NE (p = 0.004) and lactate (p = 0.001), whereas those receiving TPE demonstrated sustained reductions in both parameters. In this secondary analysis of the EXCHANGE-1 trial adjunctive TPE is associated with the reduction of acute-phase proteins and IL-2Rα/CD25, however not with the reduction of pro-inflammatory cytokines. This phenomenon could contribute to the observed enhancement in hemodynamics among patients with septic shock. Furthermore, TPE may be particularly beneficial for patients with septic shock who exhibit rising levels of cfDNA.

Rationale & Objectives:The cardiovascular-kidney-metabolic (CKM) syndrome is defined as the intricate interplay among metabolic risks, chronic kidney disease (CKD) and the cardiovascular system. The deteriorating CKM syndrome contributes to untimely morbidity and mortality. We aim to characterize gender- and age-related disparities in the prevalence of CKM syndrome over the last 2 decades. Study Design:A cross-sectional population-based survey. Setting & Participants:A total of 32,848 US adults participating in the NHANES survey from 1999 to 2020. Exposures:Gender, age (18-44, 45-64, and ≥65), and period (1999-2002, 2003-3008, 2009-2014, and 2015-2020). Outcomes:Prevalence of CKM stages. Analytical approach:Sample weights and Taylor series linearization method were applied to estimate prevalence and standard errors representative of the noninstitutionalized US adult population. For trend analysis across cycles, survey-weighted logistic regression was employed. Results:Young women aged < 45 years were classified more often, but with decreasing prevalence, in stages without CKM defining factors (22.7% of women vs 13.5% of men) and more often in stages with cardiovascular organ damage (13.4% of women vs 6.5% of men). Elderly women were increasingly classified in stages with cardiovascular organ damage over the last 20 years, reaching the same prevalence as men in the most recent period (25.3 % [95% CI, 20.0 %-30.6 %] of women vs 30.5 [95% CI, 25.7-35.3%] of men aged > 65 years). Limitations:NHANES data allow for assessing CKM stages with cardiovascular organ damage mainly based on self-reporting during interviews. Conclusions:We demonstrate an increasing proportion of women in advanced CKM stages over the last 20 years. Whereas the overrepresentation of younger women in the low-risk stages almost disappeared, elderly women in the last period showed almost the same risk of being in stages with cardiovascular organ damage as elderly men. Our analysis highlights an urgent need of preventive measures especially tailored to women.

Cardiovascular-kidney-metabolic (CKM) syndrome is staged to reflect increasing cardiometabolic risk. Substantial heterogeneity exists within stage 2, which includes individuals with metabolic risk factors or chronic kidney disease (CKD) without established cardiovascular disease and affect nearly half of US adults. This study aimed to develop and validate a sex-specific, clinically pragmatic model to subdivide CKM stage 2 into lower-risk (stage 2a) and higher-risk (stage 2b) subgroups We analyzed participants aged ≥18 years with CKM syndrome stage 2 from the 1999-2018 NHANES cycles linked to the US National Death Index. Participants were assigned to development and validation cohorts comprising five survey cycles each. Predictor variables were selected using modified LASSO-regression and Cox-regression model, with cardiovascular mortality as the primary outcome. Model performance was assessed using time-dependent area under the receiver operating characteristic curve (AUC) and the C-statistics. TriNetX database with patient-level data from medical records was analyzed to provide clinical validation using major adverse cardiovascular events (MACE) as the outcome. Stage 2b in women was defined by the presence of at least two of the following: age ≥66 years, CKD, diabetes, or hypertension (AUC 0.79; C-index 0.78). In men stage 2b required at least two of the following: age ≥61 years, CKD, diabetes, or current smoking (AUC 0.73; C-index 0.72). Discrimination was preserved in external validation (women: AUC 0.70, C-index 0.69; men: AUC 0.75, C-index 0.68) with significantly distinct 10-year absolute risk difference of cardiovascular death (women: 4.9% [95% CI 2.2-7.5]; men: 8.5% [95% CI 5.0-12.0]). In TriNetX database, 10-year MACE risk increased from 11.3% to 24.6% in women and from 13.1% to 30.8% in men from stage 2a to stage 2b. Subdividing CKM stage 2 into stages 2a and 2b identifies clinically meaningful differences in cardiovascular risk and may support targeted preventive strategies.