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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.

Influence of the early-life gut microbiota on the immune responses to an inhaled allergen

Antibiotics, among the most used medications in children, affect gut microbiome communities and metabolic functions. These changes in microbiota structure can impact host immunity. We hypothesized that early-life microbiome alterations would lead to increased susceptibility to allergy and asthma. To test this, mouse pups between postnatal days 5–9 were orally exposed to water (control) or to therapeutic doses of azithromycin or amoxicillin. Later in life, these mice were sensitized and challenged with a model allergen, house dust mite (HDM), or saline. Mice with early-life azithromycin exposure that were challenged with HDM had increased IgE and IL-13 production by CD4+ T cells compared to unexposed mice; early-life amoxicillin exposure led to fewer abnormalities. To test that the microbiota contained the immunological cues to alter IgE and cytokine production after HDM challenge, germ-free mice were gavaged with fecal samples of the antibiotic-perturbed microbiota. Gavage of adult germ-free mice did not result in altered HDM responses, however, their offspring, which acquired the antibiotic-perturbed microbiota at birth showed elevated IgE levels and CD4+ cytokines in response to HDM, and altered airway reactivity. These studies indicate that early-life microbiota composition can heighten allergen-driven Th2/Th17 immune pathways and airway responses in an age-dependent manner.

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.

Perturbations in the microbiota-gut-brain axis shaped by social status loss

Social status is closely linked to physiological and psychological states. Loss of social dominance can lead to brain disorders such as depression, but the underlying mechanisms remain unclear. The gut microbiota can sense stress and contribute to brain disorders via the microbiota-gut-brain axis (MGBA). Here, using a forced loss paradigm to demote dominant mice to subordinate ranks, we find that stress alters the composition and function of the gut microbiota, increasing Muribaculaceae abundance and enhancing butanoate metabolism, and gut microbial depletion resists forced loss-induced hierarchical demotion and behavioral alteration. Single-nucleus transcriptomic analysis of the prefrontal cortex (PFC) indicates that social status loss primarily affected interneurons, altering GABAergic synaptic transmission. Weighted gene co-expression network analysis (WGCNA) reveals modules linked to forced loss in the gut microbiota, colon, PFC, and PFC interneurons, suggesting changes in the PI3K-Akt signaling pathway and the glutamatergic synapse. Our findings provide evidence for MGBA perturbations induced by social status loss, offering potential intervention targets for related brain disorders.

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.

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