Background. There is a lack of robust evidence regarding immunosuppressive therapy in children and adolescents after kidney transplantation (KTx), and as such, international practice is highly variable. Recent clinical practice recommendations advocating individualized immunosuppressive strategies that incorporate newer agents are often not implemented. This can potentially contribute to reduced patient and renal allograft survival. Methods. The guideline was developed between January 1, 2024, and December 12, 2025, according to the Guidance Manual of the German Association of Scientific Medical Societies by the German Societies for Pediatric Nephrology, Nephrology, Transplantation, and Pediatrics, the German Kidney Association, the International Pediatric Transplant Association, the European Society for Pediatric Nephrology and the Members of the Cooperative European Pediatric Renal Transplant Initiative. Results. This evidence- and consensus-based guideline provides up-to-date, state-of-the-art recommendations for immunosuppressive therapy after KTx in pediatric kidney transplant recipients. It is based on the best available evidence and the consensus of the relevant German Medical Societies, Members of the Cooperative European Paediatric Renal Transplant Initiative, and the working group on transplantation of the European Society for Paediatric Nephrology, and the International Pediatric Transplant Association. Conclusions. The formal consensus reached is particularly significant in cases of weak or inconclusive evidence and where recommendations are based solely on expert opinion.

Kidney fibrosis is characterized by excessive deposition of extracellular matrix, which is ultimately disrupting normal renal architecture. Despite its clinical relevance, no targeted antifibrotic therapies are currently available. Myofibroblasts, primarily derived from pericytes and resident fibroblasts, are key effectors of fibrosis due to their high extracellular matrix production. Here, we tested the hypothesis that ferroptosis induction would enable the targeted elimination of activated kidney fibroblasts. We found that kidney fibroblasts exhibit marked sensitivity to ferroptotic cell death upon exposure to the ferroptosis inducer RAS-selective lethal 3 (RSL3), an effect further amplified by transforming growth factor-β stimulation. In tissue slice cultures of murine fibrotic kidneys, RSL3 eliminated myofibroblasts without causing overt damage to other cell types. Extending these findings in vivo, we applied a postischemia/reperfusion model of kidney fibrosis and demonstrated that repeated low-dose systemic administration of RSL3 significantly reduced the activated fibroblast population without inducing appreciable injury to parenchymal cells. These results provide proof-of-principle that the ferroptosis susceptibility of activated fibroblasts may offer a potential strategy for the selective depletion of profibrotic effector cells in kidney fibrosis.NEW & NOTEWORTHY This study reveals ferroptosis, a pharmacologically inducible form of cell death, as a novel mechanism to eliminate activated fibroblasts, the main drivers of kidney fibrosis. Due to their high ferroptosis sensitivity, these cells are selectively depleted by RSL3 in vitro, in kidney tissue slice cultures, and in fibrotic kidneys in vivo. These findings highlight ferroptosis induction as a promising antifibrotic strategy in kidney disease.

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.

[This corrects the article DOI: 10.1016/j.jhlto.2025.100466.].

BACKGROUND:Urinary albumin-to-creatinine ratio (UACR) and protein-to-creatinine ratio (UPCR) are established markers for risk stratification in pediatric chronic kidney disease (CKD), yet their relative strength of association with CKD progression remains unclear. We compared a head-to-head evaluation of UACR and UPCR associations with estimated glomerular filtration rate (eGFR) decline and kidney survival in a large pediatric CKD cohort. METHODS:We analyzed 596 children aged 6-17 years with CKD stages 3-4 from the 4C cohort. Baseline UACR and UPCR were log-transformed and z-standardized. CKD progression was evaluated by annual eGFR slope and a composite kidney outcome (50% eGFR loss, eGFR <10 mL/min/1.73 m² or kidney replacement therapy). Associations per 1-SD increase were estimated using adjusted linear mixed-effect and Cox models. Differences in effect sizes were assessed using bootstrap-based bias-corrected and accelerated 95% confidence intervals (CI). RESULTS:Mean (SD) age was 12.4 (3.3) years; 70% had congenital anomalies of the kidneys and urinary tract (CAKUT). Median (interquartile range) eGFR was 28 (14) mL/min/1.73 m². Over a median follow-up of 2.5 (3.8) years, 334 events occurred. A 1-SD increase in log-UACR and log-UPCR was associated a 2.17-fold (95% CI 1.84 to 2.55) and 1.70-fold (95% CI 1.52 to 1.90) higher risk of the composite outcome, respectively; UACR showed a 28% stronger association (HRUACR/HRUPCR = 1.28; 95% CI 1.12 to 1.53). No relative difference was found in overall eGFR slope change (slope ∆UACR - slope ∆UPCR = -0.05; 95% CI -0.50 to 0.24), but UACR showed stronger associations in children with advanced CKD and severe proteinuria. CONCLUSION:Both UACR and UPCR were independently associated with CKD progression in this pediatirc cohort. In direct comparison, UACR demonstrated stronger associations with adverse kidney outcomes, suggesting a comparatively greater prognostic signal and supporting current guideline emphasis on albuminuria for risk stratification and intervention outcome monitoring.

The composition of the gut microbiota (GM) is altered in solid organ transplantation (SOT) recipients, where the degree of dysbiosis is associated with long-term survival and is believed to be influenced by immunosuppression therapy. At the interface stands secretory (S)IgA, however, little is known about its role in governing dysbiosis in the context of SOT. We performed quantitative metagenomic analyses of the GM accompanied by SIgA sequencing in 48 pediatric SOT recipients (age = 10.6 ± 4.7 y) receiving either heart (n = 11), kidney (n = 10) or liver transplantation (n = 27), and compared the results to age-matched healthy controls (HC, n = 16). We confirmed compositional and functional dysbiosis in SOT recipients, with the degree of dysbiosis being associated with tacrolimus (TAC) levels. Overall, SOT recipients exhibited higher SIgA levels than HC, along with an increased percentage of bacteria targeted and altered target spectra. Furthermore, altered SIgA responses were associated with the degree of dysbiosis. A mechanistic model connecting immunosuppression, GM composition and SIgA-targeting is proposed, suggesting that GM dysbiosis in SOT recipients is mediated by the immune system through the SIgA response; direct drug-mediated effects on fecal communities were not observed in in vitro experiments. Our study provides new insights into factors that contribute to persisting dysbiosis in SOT recipients.

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.

Background:Prior studies assessing the association between donor sex and liver transplant outcomes showed conflicting results. We hypothesized that donor age, recipient sex, and time posttransplant modify the relationship between donor sex and mortality. Methods:First deceased donor liver transplant recipients 13 y or older recorded in the Scientific Registry of Transplant Recipients and the Collaborative Transplant Study (n = 198 856; 1988-2019) were studied. We used multivariable Cox models to estimate the association between donor sex and mortality, accounting for the modifying effects of recipient sex, donor age (13-44, 45-59, ≥60 y), and time posttransplant (<3 versus ≥3 mo). Results from cohort-specific Cox models were combined using a 2-stage individual-patient data meta-analysis. Results:Among male recipients, early posttransplant mortality was higher with female than male donors (only statistically significant with donors aged 13-44 y); subsequently, mortality was higher with female than male donors aged 13-44 y but lower with female than male donors aged 45 y or older. Among female recipients, early posttransplant mortality was lower with female than male donors (only statistically significant with donors aged 45-59 y); subsequently, there were no significant differences in mortality by donor sex. Donor sex-related differences in mortality appeared to be driven by differences in graft survival. In the first 3 mo posttransplant, absolute mortality rates were higher in the Collaborative Transplant Study compared with the Scientific Registry of Transplant Recipients. Conclusions:Donor age modifies the association between donor sex and mortality. Among male recipients, young female donors were associated with higher mortality than young male donors, but female donors older than 45 y may offer superior long-term patient survival than same-aged male donors.

Background: Mineralocorticoid receptor antagonists (MRAs) are the guideline-recommended fourth-line therapy for resistant hypertension. However, 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 in randomized trials, with modest reductions in blood pressure. Whether GLP-1RAs provide benefit as an alternative fourth-line 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 therapy in this population. Methods: In this retrospective multicenter cohort study using the TriNetX US Collaborative Network, adults with overweight or obesity and resistant hypertension (uncontrolled blood pressure despite ACE-inhibitors/angiotensin receptor blockers, calcium antagonists and diuretics) initiating fourth-line therapy between June 2017 and March 2025 were identified. 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). 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, 4,153 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 vs −6.3 (95%CI -4.7 to -8.0) mmHg). Interpretation: Among overweight or obese adults with resistant hypertension, GLP-1RA initiation was associated with lower cardiovascular and kidney risk compared with MRAs despite similar blood pressure reductions. Randomized trials are needed to determine whether GLP-1RAs should be incorporated into treatment strategies for resistant hypertension in patients with obesity.

Smoking, a risk factor for periodontitis and peri-implantitis, is associated with shifts in the oral microbiome (OM) composition. Although smoking habits are almost always established before adulthood, data on effects of smoking on the OM in adolescents is rare. The aim of this study was to investigate the early impact of smoking on the OM composition in pupils. The adolescent cohort, aged 14–20, comprised 98 smokers and 98 non-smokers matched for several physiological co-variates. Buccal swabs were analysed for OM composition using high-throughput sequencing of the full-length 16 S rRNA gene targeting species-level resolution. Parameters of bacterial diversity and abundance of individual bacterial taxa were related to information on smoking. The microbiome dataset contained 733 species-level taxa. Streptococcus, Rothia, and Haemophilus dominated both groups, smokers and non-smokers. Smoking exerted a discernible influence on the overall microbial composition as measured by weighted UniFrac distances. The number of species-level bacterial taxa was significantly higher in individual smokers compared to non-smokers. Furthermore, several taxa, including known pathogens, exhibited significant differences in abundance between the two groups. The genera Veillonella, and Actinomyces, as well as and multiple Actinomyces species, Dialister invisus, Atopobium parvulum, Streptococcus mutans and Prevotella melaninogenica were significantly more abundant in smokers. Our findings indicated an early onset of smoking-related changes already in the oral microbiome of adolescents.

Background: SGLT2 inhibitors (SGLT2i) have been shown to reduce cardiovascular and renal outcomes including mortality in diabetes mellitus type 2, chronic kidney disease and heart failure. However, evidence on heart failure patients ≥80 years remains scarce despite the particularly increased cardiovascular risk in this population. Methods: We conducted a retrospective cohort study utilizing the TriNetX database investigating SGLT2i treatment in heart failure patients aged 80 years or older. The primary outcome was all-cause mortality. Secondary outcomes included major adverse cardiovascular events (MACE) and major adverse kidney events (MAKE). Findings: 66,127 SGLT2i-users were compared to 66,127 non-users after propensity-score matching including comorbidities and frailty-related factors. Use of SGLT2i was associated with significantly reduced all-cause mortality (adjusted hazard ratio: 0.735; 95% CI: 0.717-0.754), MACE (aHR: 0.883; 95% CI: 0.866-0.899) and MAKE (aHR: 0.743; 95% CI: 0.726-0.761) after two years of follow-up. These effects were consistent across subgroups while exhibiting only few adverse events. Interpretation: Even the oldest patients with heart failure benefit from the use of SGLT2i and showed a decreased risk of mortality, MACE, and MAKE. Advanced age is no reason to withhold this treatment from patients.

Cardiac complications are among the most common causes of death in patients after pediatric kidney transplantation (KTx), but defined diagnostic procedures identifying young patients at risk are not established. Cardiovascular magnetic resonance (CMR) imaging with native T1 mapping allows detection of diffuse myocardial alterations but is not routinely available for cardiovascular screening. Whether abnormalities detected by echocardiography reflect underlying myocardial structural changes remains unclear. Pediatric KTx recipients underwent comprehensive transthoracic echocardiography and CMR imaging with native T1 mapping. Associations between echocardiographic measures and T1 values were analyzed using multivariable linear regressions. Receiver operating characteristics analyses assessed the ability of septal E/e′ to identify elevated T1 values, with area under the curve (AUC) and optimal cut-offs determined using positive likelihood ratios (LR +). Forty-six pediatric KTx recipients (16 ± 3.5 years old; time since KTx 7.9 ± 5.3 years) were included. Diastolic echocardiographic abnormalities were common, with 87

Aging kidneys exhibit accumulation of senescent cells together with sterile low-grade inflammation. However, the spatial organization of senescence-associated immune cell accumulation in the aging kidney remains poorly defined. We systematically analyzed kidneys from young, middle-aged, and aged mice, focusing on the spatial relationship between senescent tubular cells and distinct immune cell populations. Senescent tubular cells showed significant local enrichment of immune cells, with macrophages representing the most prominent associated immune cell population. This spatial association was more closely linked to p16Ink4a burden as an indicator of biological aging than to chronological age alone, as kidneys with higher p16Ink4a levels displayed enhanced inflammatory and SASP-associated transcriptional signatures. Complementary spatial transcriptomic analyses identified a cortex-restricted senescence-associated neighborhood enriched for inflammatory, macrophage-related, and failed-repair tubular transcriptional programs, supporting the presence of localized senescence-associated inflammatory niches at the transcriptomic level. Both, genetic and pharmacological senolytic interventions reduced senescent-cell burden and decreased immune cell accumulation in aged kidneys. However, macrophages remained preferentially localized near residual senescent tubular structures after senolysis, consistent with persistent local immune senescent cell interactions. Our findings provide quantitative spatial evidence that senescence-associated inflammatory niches emerge in the aging kidney cortex and can be modulated by senolytic intervention. Together, these results establish a spatial framework for renal inflammaging and highlight senescence-associated inflammatory microenvironments as potential therapeutic targets in kidney aging.

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.