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High-dose vitamin D supplementation is common in the general population, but unsupervised high-dose supplementation in vitamin D-replete individuals poses a risk of severe toxicity. Susceptibility to vitamin D toxicity shows a significant inter-individual variability that may in part be explained by genetic predispositions (i.e., CYP24A1 polymorphism). The classic manifestation of vitamin D toxicity is hypercalcemia, which may be refractory to conventional therapy. Its causes include the endogenous overaction of 1α-hydroxylase, monogenic alterations affecting vitamin D metabolizing enzymes and exogenous vitamin D intoxication. In this manuscript, we include a literature review of potential pharmacological interventions targeting calcitriol metabolism to treat vitamin D intoxication and present a case of severe, exogenous vitamin D intoxication responding to systemic corticosteroids after the failure of conventional therapy. Systemic glucocorticoids alleviate acute hypercalcemia by inhibiting enteric calcium absorption and increasing the degradation of vitamin D metabolites but may cause adverse effects. Inhibitors of 1α-hydroxylase (keto/fluconazole) and inducers of CYP3A4 (rifampicin) may be considered steroid-sparing alternatives for the treatment of vitamin D intoxication.

Spermidine, a naturally occurring polyamine, extends the lifespan of mice and is cardioprotective in both aged mice and hypertensive rats. In humans, high dietary spermidine intake is associated with reduced blood pressure and a lower incidence of cardiovascular disease. Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes in vivo , coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that were fed a high-salt diet, a model for hypertension-induced congestive heart failure, spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. In humans, high levels of dietary spermidine, as assessed from food questionnaires, correlated with reduced blood pressure and a lower incidence of cardiovascular disease. Our results suggest a new and feasible strategy for protection against cardiovascular disease.

Kidney transplantation (KT) is the current treatment of choice in patients with end-stage kidney disease. Immunosuppression is required to prevent acute rejection but is associated with a high incidence of adverse events. The immunosuppressive burden substantially differs between individuals, necessitating new immune monitoring strategies to achieve personalization of immunosuppression. To compare the evolution of T cell profiles in correlation with immunosuppression and clinical outcomes, 87 kidney transplant recipients were followed for 12 months after KT. Flow cytometry along with assessment of T cell activation markers and clinical data was performed before KT and during study visits 10 days, 2 months and 12 months after KT. Longitudinal T cell phenotyping revealed a significant decrease of T cell activation markers HLA-DR, FCRL3, and CD147 in CD4 + effector T cells after KT. The most pronounced reduction (75%) was found for the activation-proliferation marker HLA-DR, which persisted throughout the observational period. The decrease in HLA-DR expression reflected immunosuppressive burden through strong associations with tacrolimus trough-level exposure (coeff = −0.39, p < 0.01) and BK viremia incidence (coeff = −0.40, p < 0.01) in multivariable regression analysis. T cell activation marker HLA-DR emerges as a potential biomarker for tacrolimus-related immunosuppressive burden in association with BK viremia risk following KT.

Chronic kidney disease and diabetes mellitus are associated with extensive media calcification, which leads to increased cardiovascular morbidity and mortality. Here, we investigated the role of autophagy in the pathogenesis of uremic vascular media calcification. DBA/2 mice were fed with high-phosphate diet (HPD) in order to cause vascular calcification. DBA/2 mice on standard chow diet were used as control. In parallel, autophagy and its response to rapamycin, 3-methyladenine (3-MA), and bafilomycin were studied in an model using mouse vascular smooth muscle cells (MOVAS). DBA/2 mice on HPD developed severe vascular media calcification, which is mirrored by culturing MOVAS under calcifying conditions. Both, and , autophagy significantly increased in MOVAS under calcifying conditions and in aortas of HPD mice, respectively. Histologically, autophagy was located to the aortic , but also vascular endothelial cells, and was found to continuously increase during HPD treatment. 3-MA as well as bafilomycin blocked autophagy in MOVAS and increased calcification. , rapamycin treatment further increased autophagy and resulted in a significant decrease of vascular calcification and . Rapamycin reduced transcription levels in aortas and MOVAS to control levels, whereas it increased α-smooth muscle actin and transcription in MOVAS to control levels. Furthermore, rapamycin-treated HPD mice survived significantly longer compared to HPD controls. These findings indicate that autophagy is an endogenous response of vascular smooth muscle cells (VSMC) to protect from calcification in uremia. Induction of autophagy by rapamycin protects cells and mice from uremic media calcification possibly by inhibiting osteogenic transdifferentiation of VSMC.

Cytomegalovirus (CMV) infection detrimentally influences graft survival in kidney transplant recipients, with the risk primarily determined by recipient and donor serostatus. However, recipient CD8 + T cells play a crucial role in CMV control. The optimal preventive strategy (prophylaxis vs. pre-emptive treatment), particularly for seropositive (intermediate risk) recipients, remains uncertain. We investigated CD8 + T cell subpopulation dynamics and CMV occurrence (DNAemia ≥ 100 IU/mL) in 65 kidney transplant recipients, collecting peripheral blood mononuclear cells before (T1) and 1 year after transplantation (T2). Comparing the two timepoints, we found an increase in granulocyte, monocyte and CD3 + CD8 + T cells numbers, while FoxP3 + CD25 + , LAG-3 + and PD-1 + frequencies were reduced at T2. CMV DNAemia occurred in 33 recipients (55.8%) during the first year. Intermediate risk patients were disproportionally affected by posttransplant CMV ( N = 29/45, 64.4%). Intermediate risk recipients developing CMV after transplantation exhibited lower leukocyte, monocyte, and granulocyte counts and higher FoxP3 + CD25 + frequencies in CD3 + CD8 + T cells pre-transplantation compared to patients staying CMV negative. Pre-transplant FoxP3 + CD25 + in CD3 + CD8 + T cells had the best discriminatory potential for CMV infection prediction within the first year after transplantation (AUC: 0.746). The FoxP3 + CD25 + CD3 + CD8 + T cell subset may aid in selecting intermediate risk kidney transplant recipients for CMV prophylaxis.

Acute kidney injury (AKI) is a common complication after coronary artery bypass grafting (CABG), associated with adverse short- and long-term outcomes. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been shown to reduce occurrence of AKI in several populations, yet their perioperative effects in patients undergoing CABG are unknown. We conducted a retrospective study at the Department of Cardiac Surgery, Medical University of Graz (2020–2024) to evaluate the impact of preoperative SGLT2i use on cardiac surgery–associated AKI in adults undergoing urgent or emergent isolated coronary artery bypass grafting in patients with an indication for SGLT2i therapy (type 2 diabetes mellitus, heart failure with reduced ejection fraction, or chronic kidney disease). Patients with preoperative dialysis, sepsis, reoperation, mechanical circulatory support or missing laboratory data were excluded. Exposure was defined as SGLT2i use within two weeks before surgery, and the primary outcome was cardiac surgery-associated AKI (CSA-AKI) according to KDIGO criteria. Secondary outcomes included kidney replacement therapy, ICU length of stay, 30-day mortality and postoperative diabetic ketoacidosis. Causal effects were estimated using entropy balancing. Results were reported as weighted risk differences, risk ratios, and adjusted mean differences, with time-to-event outcomes analyzed via weighted Cox models and Kaplan–Meier estimates. Among 484 patients, 135 were on SGLT2i. CSA-AKI occurred in 23.0 % of SGLT2i users vs. 28.1 % of non-users (risk ratio of 0.63 [95 % CI 0.44–0.91; p = 0.014]). The association was pronounced in patients with heart failure with reduced ejection fraction and those with high EuroSCORE II. No differences were observed in other secondary endpoints and no cases of postoperative diabetic ketoacidosis occurred. Preoperative SGLT2i use was associated with a significantly lower risk of CSA-AKI in patients undergoing urgent or emergent CABG. These findings need to be confirmed in prospective multicenter trials but underline the favorable safety profile of this medication. •Preoperative SGLT2i linked to reduced CSA-AKI in urgent/emergency CABG.•Causal inference framework applied to emulate randomized trial conditions.•Protective effect most evident in HFrEF and high EuroSCORE II patients.•No increase in postoperative DKA or adverse safety signals observed.•Supports continuation of SGLT2i in high-risk cardiac surgery patients.

Lipocalin-2 (Lcn-2) is involved in divergent processes such as acute kidney injury or bacterial host defence. Our study was designed to evaluate the functional role of Lcn-2 in nephrotoxic serum nephritis (NTS). Since Lcn-2 is expressed in tubular epithelial cells as well as in cells of innate immunity such as macrophages and polymorphonuclear neutrophils (PMN), we induced NTS in wild-type (WT), Lcn-2 knock-out (KO) mice and WT/Lcn-2 KO chimeras. Mice lacking Lcn-2 exhibited more glomerular damage with increased proteinuria and interstitial leukocyte accumulation compared to WT mice. Chimeras able to express Lcn-2 in macrophages and PMN but not in epithelial cells were found to develop NTS comparable to wild-type controls. In contrast, chimeras expressing Lcn-2 in tubular epithelial cells with no expression in innate immune cells developed increased NTS due to decreased concerted apoptosis but increased necrosis and formation of damage-associated molecular patterns (DAMPs) such as high-mobility group box 1 (HMGB-1) in the kidney. In vivo blockade of HMGB-1, a toll-like receptor (TLR)-2 agonist, significantly reduced inflammation and NTS in Lcn-2 knock-out mice. In parallel, TLR-2 signalling was found to drive Lcn-2 transcription in vitro. Taken together, Lcn-2 expressed in innate immune cells is protective in NTS by inducing concerted apoptosis and inhibiting the formation of HMGB-1 thereby limiting cytokine production via TLR-2 signalling. In parallel, TLR-2 dependent transcription of Lcn-2 is an endogenous inhibitor of inflammation in NTS.

Video Abstract 10.1093/ckj/sfae410 Video Abstract  Watch the video abstract of this contribution sfae410Media1 6368028933112