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Objective: Older patients with nonvalvular atrial fibrillation (AF) are at high risk for frailty and geriatric syndromes (GSs), which modulate their individual prognosis and are therefore relevant for further management. Because few studies have evaluated the geriatric profile of older AF patients, this secondary analysis aims to further characterize the patterns of GSs and geriatric resources (GRs) in AF patients and their association with anticoagulation use. Methods: Data from 362 hospitalized patients aged 65 years and older with AF (n = 181, 77.8 ± 5.8 years, 38% female) and without AF (non-AF [NAF]; n = 181, 77.5 ± 5.9 years, 40% female) admitted to an internal medicine and nephrology ward of a large university hospital in Germany were included. All patients underwent usual care plus a comprehensive geriatric assessment (CGA) including calculation of the Multidimensional Prognostic Index (MPI) and collection of 17 GSs and 10 GRs. Patients were followed up by telephone 6 and 12 months after discharge to collect data on their health status. Results: The mean MPI score of 0.47 indicated an average risk of poor outcome, and patients with AF had a significantly higher MPI than those without AF (p = 0.040). After adjustment for chronological age, biological sex, Cumulative Illness Rating Scale (CIRS) for relevant chronic diagnoses and MPI as a proxy for biological age, AF patients had significantly more mnestic resources (63.5% vs. 33.1%, p < 0.001), a tendency for less age-appropriate living conditions (56.4% vs. 72.9%, p = 0.051) and more sensory impairment (78.5% vs. 52.5%, p < 0.001) than NAF patients. They also had a higher number of GSs (p = 0.046). AF patients on oral anticoagulants (OACs, n = 91) had less age-appropriate living conditions (48.4% vs. 64.4%, p < 0.05) and mnestic resources (36.3% vs. 54.4%, p < 0.01), but more emotional resources (80.2% vs. 65.6%, p < 0.05) and chronic pain (56% vs. 40%, p < 0.05) than patients without OACs (n = 90). Overall, mortality at 1 year was increased in patients with a higher MPI (p < 0.009, adjusted for age, sex and CIRS), with a diagnosis of AF (p = 0.007, adjusted for age, sex, CIRS and MPI), with of male sex (p = 0.008, adjusted for age, CIRS and MPI) and those with AF and treated with hemodialysis (p = 0.022, compared to AF patients without dialysis treatment). Conclusions: Patients with AF and patients with AF and OACs show differences in their multidimensional frailty degree as well as GR and GS profiles compared to patients without AF or with AF not treated with OACs. Mortality after 1 year is increased in AF patients with a higher MPI and dialysis, independently from OAC use and overall burden of chronic disease as assessed per CIRS. GRs and GSs, especially age-appropriate living conditions, emotional resources, sensory impairment and chronic pain, can be considered as factors that may modify the individual impact of frailty, underscoring the relevance of these parameters in the management of older patients.

Background: Sarcopenia is associated with adverse health outcomes. Understanding the association between sarcopenia, multidimensional frailty, and prognosis is essential for improving patient care. The aim of this study was to assess the prevalence and prognostic signature of sarcopenia in an acute hospital setting co-led by internists and geriatricians. Methods: Sarcopenia was assessed by applying the European Working Group on Sarcopenia in Older People (EWGSOP2) algorithm, including the SARC-F score, handgrip strength, bioelectrical impedance analysis (BIA), and Timed Up and Go (TUG) test, to 97 older multimorbid inpatients (76.5 ± 6.8 years, 55% women). The patients underwent a Comprehensive Geriatric Assessment (CGA) including an evaluation of Geriatric Syndromes (GSs) and Resources (GR) and prognosis calculation using the CGA-based Multidimensional Prognostic Index (MPI), European Quality of life—5 Dimensions (EQ-5D-5L) scale, Rosenberg Self-Esteem Scale (RSES), and Geriatric Depression Scale (GDS). Information on survival and rehospitalizations was collected 1, 3, and 6 months after discharge. Results: Sarcopenia was present in 63% (95% CI: 54–72%) of patients and categorized as probable (31%), confirmed (13%), and severe sarcopenia (18%). Sarcopenic patients showed significantly higher median MPI-values (p < 0.001), more GSs (p = 0.033), fewer GR (p = 0.003), lower EQ-5D-5L scores (p < 0.001), and lower RSES scores (p = 0.025) than non-sarcopenic patients. Six months after discharge, being sarcopenic at baseline was predictive of falls (p = 0.027) and quality of life (p = 0.043), independent of age, gender, and MPI. Conclusions: Sarcopenia is highly prevalent in older hospitalized multimorbid patients and is associated with poorer prognosis, mood, and quality of life up to 6 months after discharge, independent of age, sex, and MPI as surrogate markers of biological age.

Reactive oxygen species (ROS), which excessively arise in diabetes and systemic inflammatory diseases, modify cellular lipids and cellular lipid composition leading to altered biophysical properties of cellular membranes. The impact of lipid peroxidation on transmembrane signaling routes is not yet well studied. The canonical transient receptor potential channel 6 (TRPC6) is implicated in the pathogenesis of several forms of glomerular diseases. TRPC6 is sensitive to membrane stretch and relies on a distinct lipid environment. This study investigates the effect of oxidative alterations to plasma membrane lipids on TRPC6 activity and the function of the glomerular filter. Knockout of the anti-oxidative, lipid modifying enzyme paraoxonase 2 (PON2) leads to altered biophysical properties of glomerular epithelial cells, which are called podocytes. Cortical stiffness, quantified by atomic force microscopy, was largely increased in PON2-deficient cultured podocytes. PON2 deficiency markedly enhanced TRPC6 channel currents and channel recovery. Treatment with the amphiphilic substance capsazepine in micromolar doses reduced cortical stiffness and abrogated TRPC6 conductance. In in vivo studies, capsazepine reduced the glomerular phenotype in the model of adriamycin-induced nephropathy in PON2 knockout mice and wildtype littermates. In diabetic AKITA mice, the progression of albuminuria and diabetic kidney disease was delayed. In summary, we provide evidence that the modification of membrane characteristics affects TRPC6 signaling. These results could spur future research to investigate modification of the direct lipid environment of TRPC6 as a future therapeutic strategy in glomerular disease.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is a serious hazard for hemodialysis (HD) patients and kidney transplant (KTX) recipients as they suffer from an impaired immune response to SARS-CoV-2 vaccination. In addition, a definition of SARS-CoV-2 IgG titer that indicates a sufficient immune response, especially against new omicron variants, is urgently needed. In the present study, the immune response to either a third or a fourth dose of a mRNA vaccine was investigated in 309 dialysis and 36 KTX patients. SARS-CoV-2 IgG titer thresholds indicating neutralizing activity against wild type (WT) and the omicron variant BA.1 were quantified. After four vaccine doses, a high-neutralizing activity against WT was evidenced in HD patients, whereas the neutralizing rate against BA.1 was significant lower. Concerning KTX recipients, humoral and cellular immune responses after a third vaccination were still highly impaired. This calls for modified omicron-targeting vaccines.

Diabetes and inflammatory diseases are associated with an altered cellular lipid composition due to lipid peroxidation. The pathogenic potential of these lipid alterations in glomerular kidney diseases remains largely obscure as suitable cell culture and animal models are lacking. In glomerular disease, a loss of terminally differentiated glomerular epithelial cells called podocytes refers to irreversible damage. Podocytes are characterized by a complex ramified cellular architecture and highly active transmembrane signaling. Alterations in lipid composition in states of disease have been described in podocytes but the pathophysiologic mechanisms mediating podocyte damage are unclear. In this study, we employ a genetic deletion of the anti-oxidative, lipid-modifying paraoxonase 2 enzyme (PON2) as a model to study altered cellular lipid composition and its effects on cellular signaling in glomerular disease. PON2 deficiency reproduces features of an altered lipid composition of glomerular disease, characterized by an increase in ceramides and cholesterol. PON2 knockout mice are more susceptible to glomerular damage in models of aggravated oxidative stress such as adriamycin-induced nephropathy. Voltage clamp experiments in cultured podocytes reveal a largely increased TRPC6 conductance after a membrane stretch in PON2 deficiency. Correspondingly, a concomitant knockout of TRPC6 and PON2 partially rescues the aggravated glomerular phenotype of a PON2 knockout in the adriamycin model. This study establishes PON2 deficiency as a model to investigate the pathophysiologic mechanisms of podocyte dysfunction related to alterations in the lipid composition, as seen in diabetic and inflammatory glomerular disease. Expanding the knowledge on these routes and options of intervention could lead to novel treatment strategies for glomerular disease.

The negative impact of chronic kidney disease (CKD) on health status and quality of life in older patients has been well documented. However, data on frailty trajectories and long-term outcomes of older CKD patients undergoing structured Comprehensive Geriatric Assessment (CGA) with multidimensional frailty evaluation are sparse. Here, we analysed records from 375 CKD patients admitted to our university hospital (mean age 77.5 (SD 6.1) years, 36% female) who had undergone a CGA-based calculation of the frailty score with the multidimensional prognostic index (MPI) as well as follow-up evaluations at 3, 6 and 12 months after discharge. Based on the MPI score at admission, 21% of the patients were frail and 56% were prefrail. MPI values were significantly associated with KDIGO CKD stages (p = 0.003) and rehospitalisation after 6 months (p = 0.027) and mortality at 3, 6 and 12 months (p = 0.001), independent of chronological age. Kidney transplant recipients (KTR) showed a significantly lower frailty compared to patients with renal replacement therapy (RRT, p = 0.028). The association between frailty and mortality after 12 months appeared particularly strong for KTR (mean MPI 0.43 KTR vs. 0.52 RRT, p < 0.001) and for patients with hypoalbuminemia (p < 0.001). Interestingly, RRT was per se not significantly associated with mortality during follow up. However, compared to patients on RRT those with KTR had a significantly lower grade of care (p = 0.031) and lower rehospitalisation rates at 12 months (p = 0.010). The present analysis shows that the large majority of older CKD inpatients are prefrail or frail and that the risk for CKD-related adverse outcomes on the long term can be accurately stratified by CGA-based instruments. Further studies are needed to explore the prognostic and frailty-related signature of laboratory biomarkers in CKD.

Dialysis patients and kidney transplant (KTX) recipients suffer from an impaired immune system and show a decreased response to the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) vaccination. We performed a retrospective analysis of 1505 serological SARS-CoV-2 measurements obtained from 887 dialysis patients and 86 KTX recipients. The results were separated by patient subgroups (dialysis/KTX) as well as SARS-CoV-2 status. The latter criterion included SARS-CoV-2-naïve patients with or without COVID-19 vaccination and convalescent patients receiving a booster shot. Serologies of 27 vaccinated healthy individuals served as the reference group. Vaccine-induced cellular immune response was quantified by an interferon-γ release assay in 32 KTX recipients. We determined seroconversion rates of 92.6%, 93.4%, and 71.4% in dialysis patients vaccinated with either BNT162b2, mRNA-1273, or AZD1222, respectively. Vaccination-induced anti-SARS-CoV-2 antibody titers were lower in dialysis patients compared to healthy individuals, and vaccination with mRNA-1273 induced higher titers than BNT162b2. The initial seroconversion rate was 39.5% in KTX recipients vaccinated with BNT162b2. A linear regression model identified medication with mycophenolate-mofetil/mycophenolic acid as an independent risk factor for missing seroconversion. Within a cohort of 32 KTX recipients, cellular and humoral immune reactivity to SARS-CoV-2 was detectable in three patients only. Conclusively, vaccine-induced seroconversion rates were similar in dialysis patients compared to healthy individuals but were strongly impaired in KTX recipients. Anti-SARS-CoV-2 IgG titers elicited by double active immunization were significantly lower in both cohorts compared to healthy individuals, and immune responses to vaccination vanished quickly.

Cyclin-dependent kinase 5 (Cdk5) is expressed in terminally differentiated cells, where it drives development, morphogenesis, and survival. Temporal and spatial kinase activity is regulated by specific activators of Cdk5, dependent on the cell type and environmental factors. In the kidney, Cdk5 is exclusively expressed in terminally differentiated glomerular epithelial cells called podocytes. In glomerular disease, signaling mechanisms via Cdk5 have been addressed by single or combined conventional knockout of known specific activators of Cdk5. A protective, anti-apoptotic role has been ascribed to Cdk5 but not a developmental phenotype, as in terminally differentiated neurons. The effector kinase itself has never been addressed in animal models of glomerular disease. In the present study, conditional and inducible knockout models of Cdk5 were analyzed to investigate the role of Cdk5 in podocyte development and glomerular disease. While mice with podocyte-specific knockout of Cdk5 had no developmental defects and regular lifespan, loss of Cdk5 in podocytes increased susceptibility to glomerular damage in the nephrotoxic nephritis model. Glomerular damage was associated with reduced anti-apoptotic signals in Cdk5-deficient mice. In summary, Cdk5 acts primarily as master regulator of podocyte survival during glomerular disease and—in contrast to neurons—does not impact on glomerular development or maintenance.

Acute kidney injury (AKI) is a frequent and critical complication in the clinical setting. In rodents, AKI can be effectively prevented through caloric restriction (CR), which has also been shown to increase lifespan in many species. In Caenorhabditis elegans (C. elegans), longevity studies revealed that a marked CR-induced reduction of endocannabinoids may be a key mechanism. Thus, we hypothesized that regulation of endocannabinoids, particularly arachidonoyl ethanolamide (AEA), might also play a role in CR-mediated protection from renal ischemia-reperfusion injury (IRI) in mammals including humans. In male C57Bl6J mice, CR significantly reduced renal IRI and led to a significant decrease of AEA. Supplementation of AEA to near-normal serum concentrations by repetitive intraperitoneal administration in CR mice, however, did not abrogate the protective effect of CR. We also analyzed serum samples taken before and after CR from patients of three different pilot trials of dietary interventions. In contrast to mice and C. elegans, we detected an increase of AEA. We conclude that endocannabinoid levels in mice are modulated by CR, but CR-mediated renal protection does not depend on this effect. Moreover, our results indicate that modulation of endocannabinoids by CR in humans may differ fundamentally from the effects in animal models.

Diseases of the renal filtration unit—the glomerulus—are the most common cause of chronic kidney disease. Podocytes are the pivotal cell type for the function of this filter and focal-segmental glomerulosclerosis (FSGS) is a classic example of a podocytopathy leading to proteinuria and glomerular scarring. Currently, no targeted treatment of FSGS is available. This lack of therapeutic strategies is explained by a limited understanding of the defects in podocyte cell biology leading to FSGS. To date, most studies in the field have focused on protein-coding genes and their gene products. However, more than 80% of all transcripts produced by mammalian cells are actually non-coding. Here, long non-coding RNAs (lncRNAs) are a relatively novel class of transcripts and have not been systematically studied in FSGS to date. The appropriate tools to facilitate lncRNA research for the renal scientific community are urgently required due to a row of challenges compared to classical analysis pipelines optimized for coding RNA expression analysis. Here, we present the bioinformatic pipeline CALINCA as a solution for this problem. CALINCA automatically analyzes datasets from murine FSGS models and quantifies both annotated and de novo assembled lncRNAs. In addition, the tool provides in-depth information on podocyte specificity of these lncRNAs, as well as evolutionary conservation and expression in human datasets making this pipeline a crucial basis to lncRNA studies in FSGS.