The burden of kidney transplant evaluation — an older adults’ perspective
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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.
Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia
X-linked hypophosphataemia (XLH) is a rare metabolic bone disorder caused by pathogenic variants in the PHEX gene, which is predominantly expressed in osteoblasts, osteocytes and odontoblasts. XLH is characterized by increased synthesis of the bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23), which results in renal phosphate wasting with consecutive hypophosphataemia, rickets, osteomalacia, disproportionate short stature, oral manifestations, pseudofractures, craniosynostosis, enthesopathies and osteoarthritis. Patients with XLH should be provided with multidisciplinary care organized by a metabolic bone expert. Historically, these patients were treated with frequent doses of oral phosphate supplements and active vitamin D, which was of limited efficiency and associated with adverse effects. However, the management of XLH has evolved in the past few years owing to the availability of burosumab, a fully humanized monoclonal antibody that neutralizes circulating FGF23. Here, we provide updated clinical practice recommendations for the diagnosis and management of XLH to improve outcomes and quality of life in these patients.
Group arts interventions for depression and anxiety among older adults: a systematic review and meta-analysis
In this systematic review and meta-analysis, we assessed the efficacy of group arts interventions, where individuals engage together in a shared artistic experience (for example, dance or painting), for reducing depression and anxiety among older adults (> 55 yr without dementia). Fifty controlled studies were identified via electronic databases searched to February 2024 (randomised: 42, non-randomised: 8). Thirty-nine studies were included. Thirty-six studies investigated the impact of group arts interventions on depression (n = 3,360) and ten studies investigated anxiety (n = 949). Subgroup analyses assessed whether participant, contextual, intervention and study characteristics moderated the intervention–outcome relationship. Risk of bias was assessed with appropriate tools (RoB-2, ROBINS-1). Group arts interventions were associated with a moderate reduction in depression (Cohen’s d = 0.70, 95% confidence interval (CI) = 0.54–0.87, P < 0.001) and a moderate reduction in anxiety (d = 0.76, 95% CI = 0.37–1.52, P < 0.001), although there was publication bias in the depression studies. After a trim and fill adjustment, the effect for depression remained (d = 0.42; CI = 0.35–0.50; P < 0.001). Context moderated this effect: There was a greater reduction in depression when group arts interventions were delivered in care homes (d = 1.07, 95% CI = 0.72–1.42, P < 0.001) relative to the community (d = 0.51, 95% CI = 0.32–0.70, P < 0.001). Findings indicate that group arts are an effective intervention for addressing depression and anxiety among older adults.
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