Hickson, LaTonya J.

Objectives/Goals: In January 2023, Mayo Clinic set a goal to have 10% of studies open for six months or more without accrual. At that time, Mayo Clinic Florida had 19% non-accruing studies and 18% non-accruing clinical trials. Research administration implemented strategies to improve accrual outcomes. Methods/Study Population: Two strategies were developed to address non-accruing trials: a clean-up approach and a proactive approach. The clean-up approach involves escalating studies that haven’t been enrolled in over 6 months, identifying barriers, and escalating communication with the principal investigator (PI) and research administration alongside a physician partner. The proactive approach targets studies at the 3-month mark to address issues before reaching 6 months without accrual. Both strategies aim to reduce the cost and effort of non-accruing studies by either creating an enrollment plan or closing the study. Results/Anticipated Results: Since implementation, Mayo Clinic Florida’s non-accruing study portfolio decreased by 10%, and its clinical trials non-accruing portfolio decreased by 7% as of October 2024. Research Administration tracks key metrics (reasons for no enrollment, justifications, and actions) to identify trends and mitigate future accrual risks. A REDCap electronic data capture tool hosted at Mayo Clinic (supported by CCaTS grant UL1TR002377)1 notifies principal investigators when their studies are non-accruing. Future plans include establishing an API with Mayo Clinic’s portfolio management system to streamline the process while maintaining awareness and collaboration. Discussion/Significance of Impact: Through increased monitoring, enhanced communication, and deeper collaboration, Mayo Clinic Florida effectively reduced non-accruing studies in its research portfolio. This approach minimizes effort and costs associated with under-enrolled studies while tracking key metrics to inform future study development.

Cognitive impairment involves alterations to one's cognitive status that affects everyday life. Individuals with CKD, and particularly kidney failure, experience higher rates of cognitive impairment (20%–70%) compared with the general population. The highest prevalence is described in kidney failure such that dialysis-dependent patients have twice the prevalence of age-matched controls. In the past 5 years, the number of investigations examining the “kidney-brain axis,” mechanisms of CKD-related cognitive impairment, and potential therapeutics have exponentially increased. This review article summarizes recent literature on direct and indirect effects of CKD-associated cognitive impairment with emphasis on uremic toxins; brain injury mechanisms; overlap between CKD-associated cognitive impairment, Alzheimer's disease, and other neurodegenerative diseases. Reviewed therapeutic interventions include AST-120 (indoxyl sulfate absorbent), CH-223191 (aryl hydrocarbon receptor antagonist), triarylmethane-34 (Kca3.1-specific inhibitor), anakinra (IL-1R inhibitor), marimastat, exercise, supplements, and kidney transplantation. Special focus is placed on translational studies examining uremic toxin–associated pathogenic processes, including brain oxidative stress, neuroinflammation, and blood-brain barrier dysfunction through in vitro and in vivo models of CKD-associated brain injury. Finally, future research directions are suggested, including targeting of cellular senescence abundance with senotherapeutics and capitalizing on anti-inflammatory effects of regenerative, cell-based therapeutics ( e.g ., mesenchymal stem cells and extracellular vesicles), and use of aged murine models. Collectively, CKD-associated cognitive impairment represents a prevalent condition for which remaining knowledge gaps exist, and scientific advancements are needed to preserve cognitive function and improve the lives of individuals with CKD.

ABSTRACTCellular senescence is a biological mechanism of aging and age‐related diseases. The aim of this study was to examine whether senescence biomarkers are associated with frailty and physical function trajectories in patients undergoing kidney transplantation (KT). We also discussed the relationship between senescence biomarkers and KT function. In this multicenter study, we prospectively assessed plasma levels of senescence biomarkers, frailty as measured by the Physical Frailty Phenotype, and physical function as measured by the Short Physical Performance Battery prior to KT. Frailty, physical function, and KT function were also measured 1 year after KT. Variable associations were assessed using Cox and relaxed least absolute shrinkage and selection operation regression. The cohort consisted of 197 participants (mean age 53 ± 13 years, 61.4% male, and 80.2% White race). Higher pre‐KT levels of macrophage‐derived chemokine (MDC/CCL22) and growth differentiation factor‐15 (GDF‐15) were independently associated with less improvement in frailty and/or physical function during the first year after KT. Higher pre‐KT levels tumor necrosis factor receptor superfamily member 6 (FAS) and MMP‐9 levels were independently associated with lower KT function one year after KT. Pre‐KT cellular senescence may contribute to frailty, physical function, and kidney function trajectories during the first year after KT.

Background. Chronic systemic inflammation is associated with mortality in patients with chronic kidney disease, cardiovascular disease, and diabetes. The goal of this study was to examine the relationship between pretransplant inflammatory biomarkers (growth differentiation factor-15 [GDF-15], interleukin-6 [IL-6], soluble tumor necrosis factor receptor-1, monokine induced by gamma interferon/chemokine [C-X-C motif] ligand 9 [MIG/CXCL9], monocyte chemoattractant protein-1, soluble FAS, tumor necrosis factor-α, interleukin-15, and interleukin-1β) and death with function (DWF) after kidney transplantation (KT). Methods. We retrospectively measured inflammatory biomarker levels in serum collected up to 1 y before KT (time from blood draw to KT was 130 ± 110 d) in recipients transplanted between January 2006 and December 2018. Kaplan-Meier estimation, Cox regression, and Gradient Boosting Machine modeling were used to examine the relationship between inflammatory biomarkers and DWF. Results. Our cohort consisted of 1595 KT recipients, of whom 62.9% were male and 83.2% were non-Hispanic White. Over a mean follow-up of 7.4 ± 3.9 y, 21.2% of patients (n = 338) experienced DWF. Patients with the highest quartile levels of GDF-15 (>4766 pg/mL), IL-6 (>6.11 pg/mL), and MIG/CXCL9 (> 5835 pg/mL) had increased rates of DWF, and each predicted mortality independently of the others. When adjusted for clinical factors (age, diabetes, etc), the highest quartile levels of GDF-15 and IL-6 remained independently associated with DWF. Adding inflammatory markers to a clinical Cox model improved the C-statistic for DWF from 0.727 to 0.762 using a Gradient Boosting Machine modeling approach. Conclusions. These findings suggest that pre-KT serum concentrations of GDF-15, IL-6, and MIG/CXCL9 may help to risk stratify and manage patients undergoing KT and suggests that chronic inflammation may play a role in mortality in KT recipients.

Diabetic kidney disease (DKD) is the worldwide leader in end-stage kidney failure and has limited treatment options. Cellular senescence abundance and inflammation contribute to DKD pathogenesis. We previously demonstrated that activin A, an inflammatory mediator of pro-fibrotic kidney injury and cellular senescence, is increased in DKD and correlates with DKD injury and kidney function. We hypothesized that activin A contributes to DKD injury causing pro-fibrotic, pro-inflammatory, and cellular senescence effects in vitro, and that antagonism of activin A is achieved with follistatin. An in vitro model of DKD injury was applied with high-glucose (HG) and transforming growth factor-β (TGFβ) exposure for 24 hours in U-937-derived macrophages and renal epithelial (HK2) cells. Prior to exposure, U-937 cells were converted to M0 macrophages with phorbol myristate acetate (PMA). To examine the potential of reducing activin A release by DKD injured cells, follistatin, an activin A antagonist, was added to the media of cells at the time of injury for 24 hours. Additionally, an activin A neutralizing antibody was added to the collected supernatant of DKD injured cells. Activin A, senescence (p16), pro-fibrotic (collagen I), and pro-inflammatory (monocyte chemoattractant protein [MCP]-1, tumor necrosis factor [TNF]-alpha, interleukin [IL]-6) markers were measured through qPCR, ELISA (activin A), and immunofluorescence staining (activin A). DKD injury in renal epithelial cells increased protein expression of activin A, increased gene expression of activin A, p16, and collagen I, but did not significantly increase MCP-1 expression at 24 hour exposure (Figure 1). Furthermore, DKD injury led to increased activin A release in conditioned medium vs. control renal epithelial cells. Administration of follistatin reduced activin A release by renal epithelial cells. Application of neutralizing antibody reduced activin A levels in collected medium after cell injury. After DKD injury in U-937 derived macrophages, activin A gene expression was increased. Injured macrophages had increased gene expression of TNF-alpha and IL-6, demonstrating a pro-inflammatory phenotype. In conclusion, diabetic kidney injury increases activin A release, inflammation markers, and senescence markers in kidney cells and macrophages, therein contributing to downstream effects that further propagate disease. As shown, follistatin antagonism reduces activin A release by injured cells. Additional studies are needed to explore activin A as a promising therapeutic target and follistatin as a possible treatment in DKD. NIH 5TL1TR002380-07, AG076537, DK123492, DK109134. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.