Risk-directed management of chronic kidney disease
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A first-in-human study of quantitative ultrasound to assess transplant kidney fibrosis
Kidney transplantation is the optimal treatment for renal failure. In the United States, a biopsy at the time of organ procurement is often used to assess kidney quality to decide whether it should be used for transplant. This assessment is focused on renal fibrotic burden, because fibrosis is an important measure of irreversible kidney injury. Unfortunately, biopsy at the time of transplant is plagued by problems, including bleeding risk, inaccuracies introduced by sampling bias and rapid sample preparation, and the need for round-the-clock pathology expertise. We developed a quantitative algorithm, called renal H-scan, that can be added to standard ultrasound workflows to quickly and noninvasively measure renal fibrotic burden in preclinical animal models and human transplant kidneys. Furthermore, we provide evidence that biopsy-based fibrosis estimates, because of their highly localized nature, are inaccurate measures of whole-kidney fibrotic burden and do not associate with kidney function post-transplant. In contrast, we show that whole-kidney H-scan fibrosis estimates associate closely with post-transplant renal function. Taken together, our data suggest that the addition of H-scan to standard ultrasound workflows could provide a safe, rapid and easy-to-perform method for accurate quantification of transplant kidney fibrotic burden, and thus better prediction of post-transplant renal outcomes.
Evolving adeno-associated viruses for gene transfer to the kidney via cross-species cycling of capsid libraries
The difficulty of delivering genes to the kidney has limited the translation of genetic medicines, particularly for the more than 10% of the global population with chronic kidney disease. Here we show that new variants of adeno-associated viruses (AAVs) displaying robust and widespread transduction in the kidneys of mice, pigs and non-human-primates can be obtained by evolving capsid libraries via cross-species cycling in different kidney models. Specifically, the new variants, AAV.k13 and AAV.k20, were enriched from the libraries following sequential intravenous cycling through mouse and pig kidneys, ex vivo cycling in human organoid cultures, and ex vivo machine perfusion in isolated kidneys from rhesus macaques. The two variants transduced murine kidneys following intravenous administration, with selective tropism for proximal tubules, and led to markedly higher transgene expression than parental AAV9 vectors in proximal tubule epithelial cells within human organoid cultures and in autotransplanted pig kidneys. Following ureteral delivery, AAV.k20 efficiently transduced kidneys in pigs and macaques. The AAV.k13 and AAV.k20 variants are promising vectors for therapeutic gene-transfer applications in kidney diseases and transplantation.
ACOT12, a novel factor in the pathogenesis of kidney fibrosis, modulates ACBD5
Lipid metabolism, particularly fatty acid oxidation dysfunction, is a major driver of renal fibrosis. However, the detailed regulatory mechanisms underlying this process remain unclear. Here we demonstrated that acyl-CoA thioesterase 12 (Acot12), an enzyme involved in the hydrolysis of acyl-CoA thioesters into free fatty acids and CoA, is a key regulator of lipid metabolism in fibrotic kidneys. A significantly decreased level of ACOT12 was observed in kidney samples from human patients with chronic kidney disease as well as in samples from mice with kidney injuries. Acot12 deficiency induces lipid accumulation and fibrosis in mice subjected to unilateral ureteral obstruction (UUO). Fenofibrate administration does not reduce renal fibrosis in Acot12−/− mice with UUO. Moreover, the restoration of peroxisome proliferator-activated receptor α (PPARα) in Acot12−/−Pparα−/− kidneys with UUO exacerbated lipid accumulation and renal fibrosis, whereas the restoration of Acot12 in Acot12−/− Pparα−/− kidneys with UUO significantly reduced lipid accumulation and renal fibrosis, suggesting that, mechanistically, Acot12 deficiency exacerbates renal fibrosis independently of PPARα. In Acot12−/− kidneys with UUO, a reduction in the selective autophagic degradation of peroxisomes and pexophagy with a decreased level of ACBD5 was observed. In conclusion, our study demonstrates the functional role and mechanistic details of Acot12 in the progression of renal fibrosis, provides a preclinical rationale for regulating Acot12 expression and presents a novel means of preventing renal fibrosis.
How digital technologies have been applied for architectural heritage risk management: a systemic literature review from 2014 to 2024
This systematic literature review critically examines the application of digital technologies in architectural heritage risk management from 2014 to 2024, focusing exclusively on English-language publications. As the significance of architectural heritage continues to be recognized globally, there is an increasing shift towards integrating digital solutions to ensure its preservation and management. This paper explores the evolution and application of digital technologies such as Building Information Modeling (BIM), Geographic Information Systems (GIS), and advanced imaging techniques within the field. It highlights how these technologies have facilitated the non-destructive evaluation of heritage sites and enhanced accessibility and interaction through virtual and augmented reality applications. By synthesizing data from various case studies and scholarly articles, the review identifies current trends and the expanding scope of digital interventions in heritage conservation. It discusses the interplay between traditional conservation approaches and modern technological solutions, providing insights into their complementary roles. The analysis also addresses the challenges and limitations encountered in the digital preservation of architectural heritage, such as data integration, the compatibility of different technologies, and the need for more comprehensive frameworks to guide the implementation of digital tools in heritage conservation practices. Ultimately, this review underscores the transformative impact of digital technology in managing architectural heritage risks, suggesting directions for future research and the potential for innovative applications in the field.
Sustainable supply chain management practices and performance: The moderating effect of stakeholder pressure
Currently, sustainable supply chain management practices have become an important strategy for firms to improve performance and gain competitive advantage. However, there is a current debate over the performance outcomes of sustainable supply chain management practices. Additionally, the role of stakeholder pressure is frequently overlooked. Drawing on Natural Resources-Based View and Stakeholder Theory, this study aims to elucidate the ambiguous connection between sustainable supply management, sustainable process management, stakeholder pressure and performance, and investigate the mediation role of sustainable process management and the moderation effect of stakeholder pressure. Our analysis, based on data collected from 235 Chinese manufacturing firms, reveals significant insights. First, stakeholder pressure positively moderates the relationship between sustainable process management and performance, while negatively moderates the relationship between sustainable supply management and performance. Second, sustainable process management has a complete mediation effect on the relationship between sustainable supply management and performance. The conclusion not only explains the inconsistent relationship between sustainable supply chain management practice and performance, but also reveals clearly the relationship between sustainable supply management and sustainable process management. Besides, it also highlights the difference in performance outcomes of sustainable supply management and sustainable process management under stakeholder pressures, and has valuable guidance to the practice of sustainable supply chain management in Chinese manufacturing firms.
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