Background Calcineurin Inhibitors (CNI) and mammalian target of rapamycin inhibitors (mTORi) have been traditionally used as immunosuppressants to prevent rejection in kidney transplant recipients, but they are often associated with undesirable renal and metabolic adverse effects. Belatacept, a selective T-cell co-stimulation blocker, does not have undesirable effects. However, there is no data on using belatacept in combination with low dose calcineurin inhibitors (CNIs)/sirolimus. At our institution, patients are switched to this combination regimen if they have slow or delayed graft function, complications related to CNIs or graft rejection while on CNIs or sirolimus. Methods We conducted a retrospective study evaluating all patients >18 years of age at Indiana University Hospital who had a kidney transplant and were switched from tacrolimus, sirolimus or cyclosporine to a combination of belatacept and lower dose CNI/sirolimus. A response to the addition of belatacept was defined as >10% change in the eGFR per year from baseline (pre-belatacept values) over 2 years. Logistic regression models were performed. Results Seventy-nine subjects were included in the study with a mean age of 52.3 ± 14.7 years and followed up to 2.01 years (Median [IQR] = 1.02 [0.93, 1.99] years) post belatacept use. Response was observed in 54% of patients with improved eGFR by 6 months (p = 0.003) and sustained improvement at 2 years with an eGFR of 49.1 ± 19.5 vs. 35.3 ± 11.4 (p = 0.04; n = 13 each) in non-responders. The final multiple logistic regression model found having a retransplant (OR=5.81; 95% CI: 1.67–20.22; p = 0.006), log of higher level of proteinuria (OR=1.74; 95% CI: 1.08–2.78; p = 0.022), longer dialysis vintage before transplantation (OR=1.01; 95% CI: 1.00–1.03; p = 0.048) and history of graft rejection prior to the conversion to this regimen(OR=11.36;95% CI:1.84–70.07;p = 0.009) were all significantly associated with non-response. Conclusion Belatacept in combination with low dose conventional immunosuppression appears to be a favorable option in patients with slow/delayed graft function or intolerance to conventional drugs at their usual therapeutic levels.

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.

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.

ABSTRACT Renal ischemia‐reperfusion injury (IRI) is a major cause of acute kidney injury (AKI), with high mortality and a significant risk of progression to chronic kidney disease (CKD). To address the lack of targeted therapies, we developed NKN‐LNP, a cascade‐targeting drug delivery system that enables spatiotemporally controlled delivery to injured tubules. This system first targets neutrophils via a surface polypeptide, hijacking their inflammatory migration to traverse the glomerular barrier and reach the injury site. Microenvironmental matrix metalloproteinase 2/9 (MMP‐2/9) then triggers nanoparticle release, exposing a second peptide that selectively binds to upregulated kidney injury molecule‐1 (KIM1) on tubular cells. Loaded with the NAD+ precursor β‐nicotinamide mononucleotide (NMN), the accumulated NKN‐LNP potently activates the NAD+‐SIRT3 signaling axis, restoring mitochondrial function and ameliorating renal damage in AKI mice. Importantly, this targeted strategy also exerts potent antifibrotic effects, thereby mitigating the AKI‐to‐CKD transition. This neutrophil‐mediated dual‐targeting platform offers a promising nanotherapeutic strategy for precise treatment of renal IRI and its chronic progression.

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.

Background Thymoglobulin is used in kidney transplantation as an induction therapy to prevent acute rejections; however, studies and data to support thymoglobulin induction therapy in Chinese patients undergoing kidney transplant with donation after cardiac death (DCD) kidneys remain unclear. Therefore, we investigated the clinical outcomes of thymoglobulin induction therapy in recipients of DCD kidney transplant in real-world clinical practice. Methods This pooled analysis from the T-DCD and START-DCD studies was conducted to investigate acute rejection (AR), biopsy-proven AR (BPAR), delayed graft function (DGF), and graft and patient survival at 6 months in patients undergoing DCD kidney transplantation in the pooled population, in subgroups receiving thymoglobulin doses of <4 mg/kg and ≥4 mg/kg, and in subgroups receiving thymoglobulin doses of <1.5 mg/kg, 1.5 mg/kg to 4 mg/kg, and ≥4 mg/kg. Possible risk factors for AR, BPAR, DGF, graft survival, and patient survival were investigated as well. Results A total of 458 patients were included in this study. The incidence of AR within 6 months was 8% (n = 10) in patients receiving <4 mg/kg of thymoglobulin and 10.5% (n = 35) in those receiving ≥4 mg/kg. The dose-dependent incidence of BPAR was 3.1% in patients receiving a thymoglobulin dose <1.5 mg/kg, 2.3% in those receiving 1.5 to 4 mg/kg, and 1.6% in those receiving ≥4 mg/kg. In these 3 subgroups, a statistically significant reduction in DGF incidence (P = .023) was observed in 21.9%, 15.9%, and 7.2% of patients, respectively. The overall graft survival and patient survival rates at 6 months were 98% and 99.56%, respectively. The possible risk factors for AR were donor or recipient age, those for DGF were baseline creatinine and dosage, and those for graft survival were donor body mass index, warm ischemia time, thymoglobulin dosage, and donor history of cardiopulmonary resuscitation. Conclusion Based on a pooled analysis of the T-DCD and START-DCD data in Chinese patients, treatment with thymoglobulin as an induction therapy has shown greater dose-dependent protection against DGF within 6 months after kidney transplantation. The higher thymoglobulin dose did not prolong the duration or reduce the incidence of AR and BPAR and showed no significant effect on graft survival or patient survival within 6 months of transplantation.

Ischemic heart disease (IHD) remains a major global health challenge due to its persistently high incidence and mortality rates. Although early thrombolytic or interventional therapy reduces infarct size, myocardial ischemia–reperfusion injury (MIRI) often occurs when restoring blood flow to ischemic myocardium, paradoxically causing cardiomyocyte death. Unlike conventional cardioprotective agents, bioengineered nanomaterials enable targeted drug delivery to ischemic cardiomyocytes through tunable physicochemical properties. This improves therapeutic efficacy while reducing systemic exposure, providing innovative strategies for MIRI treatment. This review summarizes recent advances in nanomaterial-based MIRI therapies and critically evaluates their clinical translation potential, highlighting both opportunities and challenges.

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.

Islet transplantation offers a promising therapeutic strategy for type 1 diabetes patients with inadequate glycemic control or severe complications. Islet encapsulation using biocompatible materials presents a potential solution to reduce immune rejection. This study fabricated and characterized Schiff base hydrogels (CMOCs) composed of varying ratios of carboxymethyl chitosan (CMCS) and oxidized carboxymethyl starch (OCMS). CMOCs exhibited desirable mechanical properties, injectability, self-healing properties, antibacterial properties, biocompatibility, and controlled-release capabilities. CMOC3, with the highest CMCS content, was selected for loading Fasudil and further islet encapsulation experiments. In vitro studies demonstrated that CMOC3 and CMOC3-Fasudil hydrogel (CMOC3-Fas) not only supported islet survival and insulin secretion but also increased insulin bioavailability through chelating the zinc ions from the insulin hexamers. CMOC3-Fas exhibited pro-angiogenic and anti-inflammatory properties, and effectively reduced islet cell death under hypoxic conditions. Finally, transplantation of islets encapsulated within CMOC3-Fas achieved prolonged normoglycemia and increased body weight in diabetic mice. This study demonstrates the synergistic protective effect of Schiff-base hydrogel co-delivering fasudil for islet encapsulation, potentially paving the way for improved islet transplantation therapy in type 1 diabetes.

Objectives:To examine whether habitual whole-grain intake is associated with lower patient-reported systemic inflammatory distress among ambulatory survivors of esophageal squamous-cell carcinoma (ESCC). Methods:We conducted a cross-sectional questionnaire study (May 2023-July 2025) at four tertiary hospitals in Shanxi Province among adults with stage I-IIIA ESCC (n = 392). A validated semi-quantitative food frequency questionnaire quantified five whole-grain categories. Exposures were modeled as grams/day-¹ (sex-specific quartiles; continuous per 10 g), an energy-adjusted density metric (g/1,000 kcal), and a diversity score (0-5 categories consumed ≥ once/week). Systemic inflammatory symptoms were measured with the seven-item Inflammation Distress Index (IDI). Multivariable logistic models estimated adjusted odds ratios (aORs) for elevated IDI (≥ 10); γ-log generalized linear models analyzed continuous IDI; restricted cubic splines assessed dose-response. Models adjusted for sociodemographic, clinical, and behavioral covariates, with total energy included when grams were exposed. Results:Median whole-grain intake was 35.4 g/day-¹ (IQR 22.1-58.7); 28.1% had elevated IDI. Prevalence declined across quartiles (39.8%, 34.7%, 25.5%, 12.2%). Fully adjusted aORs (vs. Q1) were 0.95 (0.62-1.47), 0.49 (0.31-0.76), and 0.19 (0.11-0.33) for Q2-Q4 (p-trend < 0.001). Each 10 g/day-¹ increment corresponded to a 6% lower mean IDI (mean ratio 0.94; 0.92-0.96). Splines showed a steep inverse slope up to ~60 g/day-¹ with a plateau (p-nonlinearity = 0.031). Findings were consistent by stage (interaction p = 0.59) and smoking status (p = 0.67), robust in sensitivity analyses, and supported by density (Q4 vs. Q1 aOR 0.21; per +5 g/1,000 kcal-¹ aOR 0.93) and diversity (per +1 category aOR 0.86; ≥ 3 vs. 0-1 aOR 0.48) metrics. Conclusion:In Shanxi ESCC survivorship care, higher whole-grain intake-particularly ~50 g/day-¹ and with greater variety-aligns with substantially lower systemic inflammatory distress, supporting grain-centered dietary counseling.

BackgroundThe onset and progression of chronic kidney disease (CKD) has been linked to metabolic syndrome (MetS), with the results of recent observational studies supporting a potential link between renal failure and MetS. The causal nature of this relationship, however, remains uncertain. This study thus leveraged a Mendelian Randomization (MR) approach to probe the causal link of MetS with renal failure.MethodsA genetic database was initially used to identify SNPs associated with MetS and components thereof, after which causality was evaluated through the inverse variance weighted (IVW), MR-Egger regression, and weighted media techniques. Results were subsequently validated through sensitivity analyses.ResultsIVW (OR = 1.48, 95% CI = 1.21–1.82, P =1.60E−04) and weighted median (OR = 1.58, 95% CI =1.15–2.17, P = 4.64E-03) analyses revealed that MetS was linked to an elevated risk of renal failure. When evaluating the specific components of MetS, waist circumference was found to be causally related to renal failure using the IVW (OR= 1.58, 95% CI = 1.39–1.81, P = 1.74e-11), MR-Egger (OR= 1.54, 95% CI = 1.03–2.29, P = 0.036), and weighted median (OR= 1.82, 95% CI = 1.48–2.24, P = 1.17e-8). The IVW method also revealed a causal association of hypertension with renal failure (OR= 1.95, 95% CI = 1.34–2.86, P = 5.42e-04), while renal failure was not causally related to fasting blood glucose, triglyceride levels, or HDL-C levels.ConclusionThese data offer further support for the existence of a causal association of MetS with kidney failure. It is thus vital that MetS be effectively managed in patients with CKD in clinical settings, particularly for patients with hypertension or a high waist circumference who are obese. Adequate interventions in these patient populations have the potential to prevent or delay the development of renal failure.