Platelets are abundant, small, anucleate circulating cells, serving many emerging pathophysiological roles beyond hemostasis; including active critical roles in thrombosis, injury response, and immunoregulation. In the absence of genomic DNA transcriptional regulation (no nucleus), platelets require strategic prepackaging of all the needed RNA and organelles from megakaryocytes, to sense stress (e.g., hyperglycemia), to protect themselves from stress (e.g., mitophagy), and to communicate a stress response to other cells (e.g., granule and microparticle release). Distinct from avian thrombocytes that have a nucleus, the absence of a nucleus allows the mammalian platelet to maintain its small size, permits morphological flexibility, and may improve speed and efficiency of protein expression in response to stress. In the absence of a nucleus, platelet lifespan of 7–10 days, is largely determined by the mitochondria. The packaging of 5–8 mitochondria is critical in aerobic respiration and yielding metabolic substrates needed for function and survival. Mitochondria damage or dysfunction, as observed with several disease processes, results in greatly attenuated platelet survival and increased risk for thrombovascular events. Here we provide insights into the emerging roles of platelets despite the lack of a nucleus, and the key role played by mitochondria in platelet function and survival both in health and disease.

Background and objectivesUromodulin, produced exclusively in the kidney’s thick ascending limb, is a biomarker of kidney tubular health. However, the relationship between urine uromodulin and histologic changes in the kidney tubulointerstitium has not been characterized. In this study, we test the association of urine uromodulin with kidney histologic findings in humans and mice.Design, setting, participants, & measurementsWe investigated the independent association of urine uromodulin measured at the time of kidney biopsy with histologic features in 364 participants at two academic medical centers from 2015 to 2018 using multivariable linear regression models. This relationship was further examined by comparison of uromodulin staining in murine models of kidney fibrosis and repair.ResultsWe found urine uromodulin to be correlated with serum creatinine (rho=−0.43; P<0.001), bicarbonate (0.20; P<0.001), and hemoglobin (0.11; P=0.03) at the time of biopsy but not with urine albumin (−0.07; P=0.34). Multivariable models controlling for prebiopsy GFR, serum creatinine at biopsy, and urine albumin showed higher uromodulin to be associated with lower severity of interstitial fibrosis/tubular atrophy and glomerulosclerosis (interstitial fibrosis/tubular atrophy: −3.5% [95% confidence intervals, −5.7% to −1.2%] and glomerulosclerosis: −3.3% [95% confidence intervals, −5.9% to −0.6%] per two-fold difference in uromodulin). However, when both interstitial fibrosis/tubular atrophy and glomerulosclerosis were included in multivariable analysis, only interstitial fibrosis/tubular atrophy was independently associated with uromodulin (interstitial fibrosis/tubular atrophy: −2.5% [95% confidence intervals, −4.6% to −0.4%] and glomerulosclerosis: −0.9% [95% confidence intervals, −3.4% to 1.5%] per two-fold difference in uromodulin). In mouse kidneys, uromodulin staining was found to be lower in the fibrotic model than in normal or repaired models.ConclusionsHigher urine uromodulin is independently associated with lower tubulointerstitial fibrosis in both human kidney biopsies and a mouse model of fibrosis.PodcastThis article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_08_10_CJN04360422.mp3.

any studies in the past decade have elaborated the emerging functions of platelets beyond hemostasis and thrombosis. Molecular and functional studies have shown diverse roles of platelets in vascular integrity and remodeling, immunoregulation and tissue regeneration (Fig. 1). Although the function of platelets in the development and progression of cardiovascular diseases is well established, platelets were also demonstrated to be critical players in the pathophysiology of cancer, inflammatory diseases and infections such as that with severe acute respiratory syndrome coronavirus (SARS-CoV)-2, giving rise to COVID-19. Investigations of platelets and their heterogeneous states, platelet releasates and other target cells in various diseases have provided important mechanistic insights for diagnosis, prognosis and therapeutics. In this Review, we discuss the pathophysiological role of platelets and the latest developments in basic and clinical platelet methodologies. We also provide new insights into the development of guidelines for platelet investigation in which knowledge of underlying mechanisms might be important for diagnosis.

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