Hickson, LaTonya J

ABSTRACT Cellular senescence in the kidney plays a crucial role in the progression of acute kidney injury and chronic kidney disease. Therapeutic approaches targeting senescent cells, such as small molecule senolytic and senomorphic drugs, display efficacy in preclinical models. However, such drugs pose a risk of adverse effects and only partially mitigate disease progression, highlighting the need for new therapeutic approaches that more comprehensively and safely address disease pathways in aging kidney disease. This review discusses the potential of extracellular vesicles and longevity proteins, such as α‐klotho and silencing information regulator 2‐related enzyme 1 (SIRT1), in regulating cellular senescence and alleviating kidney fibrosis. Particularly, combination therapy that simultaneously targets inflammation, tissue damage, and senescence is promising for kidney disease, given the potential to synergistically overcome the limitations of current unimodular treatment modalities and pave the way for more effective management of kidney disease. This review highlights the mechanisms of cellular senescence in kidney disease, particularly in diabetic kidney disease, the latest knowledge on senotherapy, and the potential and challenges of new therapeutic strategies, including combining extracellular vesicles and longevity proteins.

Key Points BeWell360-PKD shows that integrating certified health and wellness coaches and augmenting patients' personal capacity as part of autosomal dominant polycystic kidney disease care is feasible and acceptable. Embedding BeWell360 coaches reduced care burden, improved caregiver self-efficacy, and enhanced care engagement by patients with autosomal dominant polycystic kidney disease and by their informal caregivers. This aligns with evolving care standards and guidelines promoting sustainable healthy lifestyle changes through tailored, integrative behavior-change centered interventions. Background Autosomal dominant polycystic kidney disease (ADPKD) imposes substantial care burden on patients and their informal caregivers (CGs), often contributing to nonadherence and impaired quality of life. Existing care models insufficiently address the behavioral and psychosocial dimensions of this burden. To evaluate the feasibility and effect of BeWell360-PKD , a person-centered intervention integrating Health and Wellness Coaching and capacity-workload support into ADPKD care, on care burden, adherence, self-efficacy, activation, and resilience. Methods In this 6-month, single-arm, mixed-methods pilot study, seven patient-CG dyads were enrolled from tertiary care polycystic kidney disease clinic. Board-certified Health and Wellness Coachings delivered individualized coaching within routine nephrology care, emphasizing capacity-building, goal setting, and care enactment support. Primary outcomes included changes in treatment burden (treatment burden questionnaire, ADPKD impact scale) and CG burden (burden scale for family CGs short version). Secondary outcomes included patient activation and resilience and CG self-efficacy. Semistructured interviews explored participant experiences. Results Patients experienced reduced treatment burden (treatment burden questionnaire mean change −9.3) and modest, domain-specific improvements in physical and fatigue-related ADPKD symptom burden. CG self-efficacy improved (+2.4), while CG burden increased (+14.8), and patient activation declined (−6.6). Qualitative themes reflected disease burden, emotional adaptation, and the perceived value of coaching in promoting behavior change and relational support. Conclusions BeWell360-PKD was feasible to implement and demonstrated early signals of benefit in reducing patient burden and improving CG self-efficacy. Increased CG burden and declining activation highlight the complexity of dyadic adaptation in ADPKD and the need for larger, controlled studies to refine and tailor coaching interventions.

Endothelial progenitor cells (EPCs) constitute a promising focus for research in regenerative medicine. These cells originate from the bone marrow and other circulating hematopoietic cells and regulate tissue regeneration and vascular integrity. EPC mobilization serves for neovascularization and re-endothelialization after injury in multiple organ systems, including the renal and cardiovascular systems. Both their number and function may vary in disease states such as CKD, depending on severity, comorbid conditions, and other factors. Therefore, circulating EPC count and function have been proposed as markers for vascular health, and their mobilization or replenishment may offer a potential therapy. Delivery of EPCs has shown success in repairing injured kidneys in animal models of both chronic and AKIs. This approach may be limited by EPC heterogeneity and incomplete characterization that may be addressed by standardization, engineering, or combination with other therapies. The aim of this article was to review the current state and recent advances in our understanding of the role of EPCs in homeostasis and conditions that may lead to their dysregulation in kidney diseases.

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.

ABSTRACT Background The optimal duration of antifrailty interventions and how best to deliver them to patients with chronic kidney disease (CKD) is unknown. The aim of this study was to examine the safety, feasibility and preliminary efficacy of a 4-week supervised exercise intervention on frailty in patients with CKD. Methods We conducted a prospective feasibility study involving patients with ≥stage 3 CKD (1 patient with stage 3 CKD, 7 patients with stage 4 CKD and 17 patients with stage 5 CKD) who were either frail or prefrail according to the physical frailty phenotype and/or had a Short Physical Performance Battery (SPPB) score ≤10. The exercise intervention consisted of two supervised outpatient sessions per week for 4 weeks (eight total sessions). Frailty and other study measures were assessed at baseline and after 4 weeks of exercise. Results Of the 34 participants who completed the baseline assessment and were included in the analyses, 25 (73.5%) completed the 4-week assessment. Overall, 64.0% of patients were on dialysis and 64.0% had diabetes mellitus. After 4 weeks of exercise, frailty prevalence, total SPPB scores and energy/fatigue scores improved. No adverse study-related outcomes were reported. Conclusions The 4 weeks of supervised exercise was safe, was associated with an excellent completion rate and improved frailty parameters in CKD patients with CKD. This study provides important preliminary data for a future larger prospective randomized study. Clinical Trial.gov registration: NCT03535584

Background In participants with concomitant chronic coronary disease and advanced chronic kidney disease (CKD), the effect of treatment strategies on the timing of dialysis initiation is not well characterized. Methods and Results In ISCHEMIA‐CKD (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches–Chronic Kidney Disease), 777 participants with advanced CKD and moderate or severe ischemia were randomized to either an initial invasive or conservative management strategy. Herein, we compare the proportion of randomized participants with non–dialysis‐requiring CKD at baseline (n=362) who initiated dialysis and compare the time to dialysis initiation between invasive versus conservative management arms. Using multivariable Cox regression analysis, we also sought to identify the effect of invasive versus conservative chronic coronary disease management strategies on dialysis initiation. At a median follow‐up of 23 months (25th–75th interquartile range, 14–32 months), dialysis was initiated in 18.9% of participants (36/190) in the invasive strategy and 16.9% of participants (29/172) in the conservative strategy (P= 0.22). The median time to dialysis initiation was 6.0 months (interquartile range, 3.0–16.0 months) in the invasive group and 18.2 months (interquartile range, 12.2–25.0 months) in the conservative group (P= 0.004), with no difference in procedural acute kidney injury rates between the groups (7.8% versus 5.4%; P =0.26). Baseline clinical factors associated with earlier dialysis initiation were lower baseline estimated glomerular filtration rate (hazard ratio [HR] associated with 5‐unit decrease, 2.08 [95% CI, 1.72–2.56]; P <0.001), diabetes (HR, 2.30 [95% CI, 1.28–4.13]; P =0.005), hypertension (HR, 7.97 [95% CI, 1.09–58.21]; P =0.041), and Hispanic ethnicity (HR, 2.34 [95% CI, 1.22–4.47]; P =0.010). Conclusions In participants with non–dialysis‐requiring CKD in ISCHEMIA‐CKD, randomization to an invasive chronic coronary disease management strategy (relative to a conservative chronic coronary disease management strategy) is associated with an accelerated time to initiation of maintenance dialysis for kidney failure. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01985360.

Significance Statement Renal artery stenosis (RAS) engenders stenotic-kidney ischemia, dysfunction, and injury, but whether these are mediated by cellular senescence has not been elucidated. INK-ATTAC transgenic mice, high-resolution imaging, and unbiased single-cell RNA sequencing of murine kidneys demonstrated cellular senescence as an important mechanism of progressive injury to epithelial/stromal cells within poststenotic kidneys. Both p16-specific and broad quercetin/dasatinib interventions to blunt senescence improved renal function and structure, underscoring the central role of senescence in the pathogenesis. Furthermore, this mechanism was conserved in human subjects with RAS. These observations reveal new mechanisms that contribute to the pathogenesis of chronic ischemic renal injury, and support the development of senolytic therapy to reduce senescent cell burden and delay renal injury. Background Peripheral vascular diseases may induce chronic ischemia and cellular injury distal to the arterial obstruction. Cellular senescence involves proliferation arrest in response to stress, which can damage neighboring cells. Renal artery stenosis (RAS) induces stenotic-kidney dysfunction and injury, but whether these arise from cellular senescenceand their temporal pattern remain unknown. Methods Chronic renal ischemia was induced in transgenic INK-ATTAC and wild type C57BL/6 mice by unilateral RAS, and kidney function ( in vivo micro-MRI) and tissue damage were assessed. Mouse healthy and stenotic kidneys were analyzed using unbiased single-cell RNA-sequencing. To demonstrate translational relevance, cellular senescence was studied in human stenotic kidneys. Results Using intraperitoneal AP20187 injections starting 1, 2, or 4 weeks after RAS, selective clearance of cells highly expressing p16 Ink4a attenuated cellular senescence and improved stenotic-kidney function; however, starting treatment immediately after RAS induction was unsuccessful. Broader clearance of senescent cells, using the oral senolytic combination dasatinib and quercetin, in C57BL/6 RAS mice was more effective in clearing cells positive for p21 ( Cdkn1a ) and alleviating renal dysfunction and damage. Unbiased, single-cell RNA sequencing in freshly dissociated cells from healthy and stenotic mouse kidneys identified stenotic-kidney epithelial cells undergoing both mesenchymal transition and senescence. As in mice, injured human stenotic kidneys exhibited cellular senescence, suggesting this process is conserved. Conclusions Maladaptive tubular cell senescence, involving upregulated p16 ( Cdkn2a ), p19 ( Cdkn2d ), and p21 ( Cdkn1a ) expression, is associated with renal dysfunction and injury in chronic ischemia. These findings support development of senolytic strategies to delay chronic ischemic renal injury.

Hospitalized patients with COVID-19 show increased serum concentrations of neurofilament light chain that correlate with worse clinical outcomes.