Elucidating the causal nexus and immune mediation between frailty and chronic kidney disease: integrative multi-omics analysis. Renal failure BACKGROUND:Empirical research has consistently documented the concurrent manifestation of frailty and chronic kidney disease (CKD). However, the existence of a reverse causal association or the influence of confounding variables on these correlations remains ambiguous. METHODS:Our analysis of 7,078 participants from National Health and Nutrition Examination Survey(NHANES) (1999-2018) applied weighted logistic regression and Mendelian Randomization (MR) to investigate the correlation between the frailty index (FI) and renal function. The multivariate MR analysis was specifically adjusted for type 2 diabetes and hypertension. Further analysis explored 3282 plasma proteins to link FI to CKD. A two-step network MR highlighted immune cells' mediating roles in the FI-CKD relationship. RESULT:Genetically inferred FI and various renal function markers are significantly correlated, as supported by NHANES analyses. Multivariate MR analysis revealed a direct causal association between the FI and CKD. Additionally, our investigation into plasma proteins identified Tmprss11D and MICB correlated with FI and CKD, respectively. A two-step network MR to reveal 15 immune cell types, notably Central Memory CD4+ T cells and Lymphocytes, as crucial mediators between FI and CKD. CONCLUSION:Our work establishes a causal connection between frailty and CKD, mediated by specific immune cell profiles. These findings highlight the importance of immune mechanisms in the frailty-CKD interplay and suggest that targeting shared risk factors and immune pathways could improve management strategies for these conditions. Our research contributes to a more nuanced understanding of frailty and CKD, offering new avenues for intervention and patient care in an aging population. 10.1080/0886022X.2024.2367028

Impairment of Renal and Hematopoietic Stem/Progenitor Cell Compartments in Frailty Syndrome: Link With Oxidative Stress, Plasma Cytokine Profiles, and Nuclear DNA Damage. The journals of gerontology. Series A, Biological sciences and medical sciences Frailty is an age-related syndrome that drives multiple physiological system impairments in some older adults, and its pathophysiological mechanisms remain unclear. We evaluated whether frailty-related biological processes could impair stem cell compartments, specifically the renal stem compartment, given that kidney dysfunctions are frequent in frailty. A well-characterized in vitro nephrosphere model of human adult renal stem/progenitor cells has been instrumental to and was appropriate for verifying this hypothesis in our current research. Evaluating the effects of plasma from older individuals with frailty (frail plasma) on allogeneic renal stem/progenitor cells, we showed significant functional impairment and nuclear DNA damage in the treated cells of the renal stem compartment. The analysis of the frail plasma revealed mitochondrial functional impairment associated with the activation of oxidative stress and a unique inflammatory mediator profile in frail individuals. In addition, the plasma of frail subjects also contained the highest percentage of DNA-damaged autologous circulating hematopoietic progenitor/stem cells. The integration of both molecular and functional data obtained allowed us to discern patterns associated with frailty status, irrespective of the comorbidities present in the frail individuals. The data obtained converged toward biological conditions that in frailty caused renal and hematopoietic impairment of stem cells, highlighting the possibility of concomitant exhaustion of several stem compartments. 10.1093/gerona/glae188

Frailty and chronic diseases: A bi-directional relationship. Aging medicine (Milton (N.S.W)) Frailty is a multidimensional syndrome associated with a decline in reserve capacity across multiple organ systems involving physical, psychological, and social aspects. Weakness is the earliest indicator of the frailty process. Multi-morbidity is the state of presence of two or more chronic diseases. Frailty and chronic diseases are interlinked as frail individuals are more prone to develop chronic diseases and multi-morbid individuals may present with frailty. They share common risk factors, pathogenesis, progression, and outcomes. Significant risk factors include obesity, smoking, aging, sedentary, and stressful lifestyle. Pathophysiological mechanisms involve high levels of circulating inflammatory cytokines as seen in individuals with frailty and chronic diseases such as hypertension, cardiovascular diseases, type 2 diabetes mellitus, chronic kidney disease, and anemia. Hence, frailty and chronic diseases go hand in hand and it is of utmost importance to identify them and intervene during early stages. Screening frailty and treating multi-morbidity incorporate both pharmacological and majorly non- pharmacological measures, such as physical activities, nutrition, pro-active care, minimizing polypharmacy and addressing reversible medical conditions. The purpose of this mini-review is to highlight the interrelation of frailty and chronic diseases through the discussion of their predictors and outcomes and how timely interventions are essential to prevent the progression of one to the other. 10.1002/agm2.12349