Commentary: Special care considerations in older adults hospitalized with COVID-19

http://deepblue.lib.umich.edu/bitstream/2027.42/175336/2/Commentary Special care considerations in older adults hospitalized with COVID-19.pdfPublished versio

NFκB Promotes Inflammation, Coagulation, and Fibrosis in the Aging Glomerulus

The peak prevalence of ESRD from glomerulosclerosis occurs at 70 to 79 years. To understand why old glomeruli are prone to failure, we analyzed the Fischer 344 rat model of aging under ad libitum-fed (rapid aging) and calorie-restricted (slowed aging) conditions. All glomerular cells contained genes whose expression changed “linearly” during adult life from 2 to 24 months: mesangial cells (e.g., MMP9), endothelial cells (e.g., ICAM and VCAM), parietal epithelial cells (e.g., ceruloplasmin), and podocytes (e.g., nephrin and prepronociceptin). Patterns of aging glomerular gene expression closely resembled atherosclerosis, including activation of endothelial cells, epithelial cells, and macrophages, as well as proinflammatory pathways related to cell adhesion, chemotaxis, blood coagulation, oxidoreductases, matrix metalloproteinases, and TGF-β activation. We used a nonbiased data-mining approach to identify NFκB as the likely transcriptional regulator of these events. We confirmed NFκB activation by two independent methods: translocation of NFκB p50 to glomerular nuclei and ChIP assays demonstrating NFκB p50 binding to the κB motif of target genes in old versus young glomeruli. These data suggest that old glomeruli exhibit NFκB-associated up-regulation of a proinflammatory, procoagulable, and profibrotic phenotype compared with young glomeruli; these distinctions could explain their enhanced susceptibility to failure. Furthermore, these results provide a potential mechanistic explanation for the close relationship between ESRD and atherosclerotic organ failure as two parallel arms of age-associated NFκB-driven processes

Urine Podocyte mRNAs Mark Progression of Renal Disease

Because loss of podocytes associates with glomerulosclerosis, monitoring podocyte loss by measuring podocyte products in urine may be clinically useful. To determine whether a single episode of podocyte injury would cause persistent podocyte loss, we induced limited podocyte depletion using a diphtheria toxin receptor (hDTR) transgenic rat. We monitored podocyte loss by detecting nephrin and podocin mRNA in urine particulates with quantitative reverse transcriptase–PCR. Aquaporin 2 mRNA served as a kidney reference gene to account for variable kidney contribution to RNA amount and quality. We found that a single injection of diphtheria toxin resulted in an initial peak of proteinuria and podocyte mRNAs (podocin and nephrin) followed 8 d later by a second peak of proteinuria and podocyte mRNAs that were podocin positive but nephrin negative. Proteinuria that persisted for months correlated with podocin-positive, nephrin-negative mRNAs in urine. Animals with persistent podocyte mRNA in urine progressed to ESRD with global podocyte depletion and interstitial scarring. Podocytes in ectatic tubules expressed podocalyxin and podocin proteins but not nephrin, compatible with detached podocytes’ having an altered phenotype. Parallel human studies showed that biopsy-proven glomerular injury associated with increased urinary podocin:aquaporin 2 and nephrin:aquaporin 2 molar ratios. We conclude that a single episode of podocyte injury can trigger glomerular destabilization, resulting in persistent podocyte loss and an altered phenotype of podocytes recovered from urine. Podocyte mRNAs in urine may be a useful clinical tool for the diagnosis and monitoring of glomerular diseases

Aging, the Medical Subspecialties, and Career Development: Where We Were, Where We Are Going.

Historically, the medical subspecialties have not focused on the needs of older adults. This has changed with the implementation of initiatives to integrate geriatrics and aging research into the medical and surgical subspecialties and with the establishment of a home for internal medicine specialists within the annual American Geriatrics Society (AGS) meeting. With the support of AGS, other professional societies, philanthropies, and federal agencies, efforts to integrate geriatrics into the medical and surgical subspecialties have focused largely on training the next generation of physicians and researchers. They have engaged several subspecialties, which have followed parallel paths in integrating geriatrics and aging research. As a result of these combined efforts, there has been enormous progress in the integration of geriatrics and aging research into the medical and surgical subspecialties, and topics once considered to be geriatric concerns are becoming mainstream in medicine, but this integration remains a work in progress and will need to adapt to changes associated with healthcare reform