Cisplatin-induced acute kidney injury (AKI) is characterized by profound oxidative stress and mitochondrial dysfunction in proximal tubular cells. However, the upstream mechanisms governing this redox imbalance remain incompletely defined. Here, we identify mitochondrial calcium uptake 1 (MICU1) as a critical regulator of tubular redox homeostasis. Using integrated multi-omics approaches, we found that MICU1 is markedly downregulated in injured proximal tubular subpopulations across various kidney diseases. Mechanistically, MICU1 deficiency disrupts mitochondrial calcium homeostasis, resulting in calcium overload and excessive mitochondrial reactive oxygen species (mtROS) generation. These changes trigger intrinsic apoptotic pathways, whereas MICU1 restoration alleviates such damage. Furthermore, we demonstrate that the ARNT/HIF-1α axis transcriptionally regulates MICU1. Under cisplatin stress, this axis is suppressed, thereby promoting mitochondrial dysfunction. Crucially, we found that MICU1-mediated mtROS control contributes to the preservation of epidermal growth factor receptor (EGFR) signaling, whereas excessive mtROS accumulation is associated with EGFR signaling impairment. Importantly, pharmacological targeting of mitochondrial calcium uptake using the small-molecule modulator MCU-i4 attenuates calcium overload, suppresses mtROS accumulation, and mitigates renal injury in vitro and in vivo. Collectively, our findings support a transcriptional-mitochondrial axis linking calcium dysregulation to oxidative stress and identify MICU1 as a potential therapeutic target for redox-driven kidney injury.

Early apoptosis of grafted islets is one of the critical challenges that significantly impact the efficacy of islet transplantation. We employed Staurosporine to pre-induce apoptosis in bone marrow mesenchymal stem cells (BMSCs). The conditioned medium from apoptotic BMSCs was then used to pretreat β cells, which notably enhanced the suppression of β cell apoptosis. For in vivo experiments, co-transplantation of islets and apoptotic BMSCs under the renal capsule of diabetic rats inhibited islets apoptosis and resulted in better transplantation outcomes. Subsequently proteomic analysis revealed that the iron-loaded form of Lcn2 protein (holo-Lcn2) secreted by apoptotic BMSCs played a crucial role in exerting anti-apoptotic effects. Holo-Lcn2 binds to the Slc22a17 transporter on cell membrane, facilitating the transport of Fe3+ into cells. Inhibition of Fe3+ transport suppressed the anti-apoptotic effect of holo-Lcn2. Thus, we hypothesize that apoptotic BMSCs reduce grafted islets apoptosis through the holo-Lcn2/Slc22a17/Fe3+ axis. This study provides insights into the application of BMSCs-based acellular therapies in islet transplantation.

Decorin, a small leucine-rich proteoglycan, has emerged as a multifunctional signaling molecule with critical implications for pancreatic islet biology beyond its canonical role in extracellular matrix organization. Despite extensive characterization of decorin's functions in matrix architecture and growth factor sequestration across various tissues, its specific contributions to pancreatic islet development and homeostasis remain insufficiently explored. Current evidence demonstrates decorin's molecular structure and post-translational modifications enable modulation of signaling pathways through pan-receptor tyrosine kinase inhibition and transforming growth factor-beta sequestration, with regulatory activities that vary substantially across distinct cellular and pathological environments. Within the pancreatic islet microenvironment, decorin influences pancreatic islet morphogenesis and beta-cell differentiation through modulation of local matrix composition and growth factor bioavailability, while conferring protection against diabetic complications through anti-fibrotic properties that mitigate peri-islet extracellular matrix remodeling observed in progressive islet dysfunction. By synthesizing findings from developmental biology, matrix biochemistry, and diabetes research, we address this critical knowledge gap and position decorin as an underrecognized regulator of pancreatic islet biology whose multifaceted mechanisms warrant investigation to reveal therapeutic strategies for preserving beta-cell function and preventing diabetes-associated fibrotic pathology.

ObjectiveInfectious arteritis involving the iliac arteries is a rare but severe complication after kidney transplantation, frequently leading to graft loss and mortality. Direct repair within infected fields is often unsuccessful. We report outcomes of femoral-femoral artery artificial vascular bypass (Fem-Fem bypass) as a strategy to exclude infected arterial segments and preserve limb perfusion in five such cases.MethodRetrospective analysis of four kidney transplant recipients who developed infectious arteritis (external iliac artery) with rupture or aneurysm between January 2015 and January 2023. All underwent resection of the infected arterial segment with proximal/distal ligation and extra-anatomic Fem-Fem bypass using a synthetic graft.ResultsAmong the four patients, two were infected with carbapenem-resistant Pseudomonas aeruginosa (CRPA), one with carbapenem-resistant Enterobacteriaceae (CRE), and one with mucormycosis. All underwent Fem-Fem bypass following resection of the infected arterial segment. One patient with CRPA infection died 5 months postoperatively due to septicemia and multiorgan failure. The remaining three patients survived with functional grafts and patent bypasses at follow-up, without recurrence of infection or vascular complications.ConclusionsFem-Fem bypass effectively controls hemorrhage or aneurysm expansion and maintains limb perfusion by excluding the infected iliac arterial segment in kidney transplant recipients with infectious arteritis. It represents a viable salvage option when endovascular repair fails or is contraindicated. Long-term success depends on effective infection control, appropriate antimicrobial therapy, and patient-specific factors. Mortality remains significant in cases with systemic sepsis or highly resistant pathogens.

Background: Kidney transplantation (KT) is the most effective treatment for end-stage renal disease. Hypothermic machine perfusion (HMP) can improve renal energy metabolism and reduce ischemia-reper fusion injury compared with static cold storage. This study aimed to evaluate the association between HMP parameters and graft function in deceased donor kidney transplantation (DDKT) and to develop a predictive model for early risk stratification. Methods: A retrospective analysis was conducted on 2,041 DDKT recipients from 1 January 2015 to 30 June 2023. The primary outcome, delayed graft function (DGF), was defined as the need for at least one dialysis session within the first week after transplantation. Consensus clustering (CC) and restricted cubic spline (RCS) analysis were used to evaluate the associations between clinical data, HMP parameters, and graft function. Feature selection was performed using Lasso-penalized logistic regression (LR), and multivariable LR was used to construct the predictive model. The model's performance was assessed using the area under the curve (AUC), calibration curves, and decision curve analysis (DCA). Results: Among the DDKT recipients, 12.9% developed DGF. HMP parameters varied significantly between the two groups, with DGF recipients showing distinct patterns in perfusion resistance, flux, and pressure. CC identified two recipient clusters with distinct DGF risk profiles, graft function, and donor characteristics. Non-linear relationships were identified between HMP parameters and DGF risk, with thresholds for initial resistance, terminal resistance, and terminal flux. The predictive model integrating six variables achieved an AUC of 0.78 (95% CI: 0.76-0.82) in the test set. Calibration and DCA confirmed good reliability and net clinical benefit. Conclusion: Non-linear relationships between HMP parameters and DGF underscore graft perfusion complexity. The proposed model demonstrated robust internal performance and may support early post-transplant risk stratification. External validation in independent cohorts is warranted to confirm generalizability and clinical applicability.

Ischemia–reperfusion injury (IRI) limits graft function and long-term outcomes after kidney transplantation. Proximal tubular (PT) cells are highly mitochondria-rich and metabolically active, making them vulnerable to ischemic and oxidative stress. However, the molecular mechanisms linking mitochondrial dysfunction to graft function remain incompletely understood. We integrated single-nucleus RNA sequencing, bioinformatics analyses, and experimental validation to identify mitochondria-associated genes in PT cells related to graft injury and vulnerability in the transplant setting. Mitochondria-related differentially expressed genes (Mito-DEGs) were used to construct machine learning models for delayed graft function (DGF) risk stratification. The candidate gene HAO2 was further evaluated by immunohistochemistry (IHC) in kidney transplant biopsies, a murine IRI model, and H₂O₂-treated HK-2 cells. Human biopsy samples were obtained at or prior to reperfusion and may not fully capture the extent of post-transplant IRI. Both overexpression and siRNA-mediated knockdown were performed to assess its function. Cell viability, apoptosis, and mitochondrial function were assessed using standard assays. PT cells from acute kidney injury samples exhibited mitochondrial dysfunction and metabolic impairment. Donor kidney clustering suggested heterogeneity in DGF risk associated with mitochondrial bioenergetic capacity. An eight-gene Mito-DEG signature demonstrated moderate performance in stratifying DGF risk. IHC analysis demonstrated that HAO2 expression was reduced in DGF recipient biopsies. Consistently, HAO2 was downregulated in murine IRI kidneys and injured HK-2 cells. Functionally, HAO2 overexpression alleviated oxidative stress, apoptosis, and mitochondrial dysfunction, whereas HAO2 knockdown exerted opposite effects and further aggravated H₂O₂-induced injury. Regulatory analysis identified 14 miRNAs and four TFs potentially controlling HAO2, while downstream pathways linked HAO2 to amino acid and fatty acid metabolism, extracellular matrix organization, and immune responses. These findings suggest that HAO2 may serve as a functional indicator of mitochondrial metabolic capacity associated with graft vulnerability rather than being specific to IRI alone. Given the observational nature of the clinical data, further studies are required to determine whether HAO2 provides added value beyond established histopathological assessment and to clarify its potential role in guiding mitochondrial-targeted conditioning strategies, such as oxygenated machine perfusion, aimed at preserving graft function during transplantation. Not applicable.

The scarcity of functional transplantable pancreatic islets remains a central limitation for curative cell replacement therapies for diabetes. Although human pluripotent stem cells provide a theoretically unlimited source of β cells, intrinsic metabolic constraints that restrict efficient endocrine lineage commitment and functional maturation are poorly defined. We combined metabolic pathway interrogation with functional and in vivo analyses to examine how mitochondrial redox signaling influences endocrine specification during human pluripotent stem cell differentiation. Targeted modulation of mitochondrial reactive oxygen species–linked arachidonic acid and eicosanoid metabolism was used to assess its impact on β-cell differentiation, maturation, and therapeutic performance following transplantation. We identify a previously unrecognized mitochondrial reactive oxygen species–driven arachidonic acid/12-hydroxyeicosatetraenoic acid metabolic axis that functions as a metabolic checkpoint limiting endocrine lineage commitment. Disruption of this pathway markedly enhances the generation of stem cell–derived β cells and accelerates their functional maturation, resulting in improved glucose-responsive insulin secretion in vitro. Notably, β cells produced through this metabolic reprogramming strategy restore normoglycaemia more rapidly and robustly after transplantation into diabetic mice than cells generated using conventional differentiation protocols. These findings define a mechanistic link between mitochondrial redox signaling and eicosanoid metabolism in β-cell fate control and establish metabolic pathway engineering as a powerful strategy to improve the efficacy of stem cell–based islet replacement therapies for diabetes.

OBJECTIVES:Pneumocystis jirovecii pneumonia, a common pulmonary infection after kidney transplant, cannot be detected by conventional culture methods, and limitations have been shown with lung tissue biopsy, sputum collection, and sample smear staining. Early diagnosis is key as long-term survival is decreased in patients with Pneumocystis jirovecii pneumonia who are not treated in a timely and effective manner. MATERIALS AND METHODS:From January 2018 to January 2023, our study enrolled 110 patients with pulmonary infection seen at the First Affiliated Hospital of Xi'an Jiaotong University (China). Of these patients, 46 had confirmed Pneumocystis jirovecii pneumonia per metagenomic next-generation sequencing or conventional detection methods. We compared percentages of positive tests, other pathogen species, and other factors between the 2 test methods. Clinical characteristics of patients with (n = 46) and without (n = 64) Pneumocystis jirovecii were analyzed retrospectively. RESULTS:Overall incidence of PJP was 2.3% (46/1977). Among 46 patients diagnosed with Pneumocystis jirovecii pneumonia, average time of onset post-transplant was 7.21 ± 2.55 months; 42 patients were cured, and 4 patients died. Thirty-three patients had mixed pulmonary infections, with Pneumocystis jirovecii and human cytomegalovirus being the most common pathogen combination, and 13 patients had monotypic pulmonary infections. Sixteen patients were Pneumocystis jirovecii positive according to conventional pathogen detection, for a detection rate of 34.8% (16/46), with significant difference shown between detection methods (χ2 = 92.0, P < .01). Patients who were treated with tacrolimus had insufficient use of sulfamethoxazole-trimethoprim and previous cytomegalovirus infection, and patients with acute rejection were more likely to develop Pneumocystis jirovecii pneumonia (P < .05). CONCLUSIONS:Metagenomic next-generation sequencing showed more advantages in early diagnosis of Pneumocystis jirovecii pneumonia. Precision medicine can be adopted to reduce costs and improve cure rates based on results of metagenomic next-generation sequencing.