Search Results (443)

Progression to fibrosis is a major complication of chronic kidney disease (CKD) in obesity, type 2 diabetes, hypertension, and metabolic syndrome, yet effective antifibrotic therapies remain limited. Here, we review how disordered renal energy metabolism—ectopic lipid accumulation, impaired fatty acid oxidation (FAO), and a compensatory shift toward glycolysis—drives tubulointerstitial fibrosis in fatty kidney disease. Lipid overload in tubular, glomerular, and vascular cells arises from increased uptake via scavenger and lipoprotein receptors, enhanced lipogenesis, and reduced lipid catabolism and clearance. Spatial lipidomic studies further reveal nephron-segment-specific lipid signatures and obesity-associated oxidized phospholipids linked to glomerular inflammation. Lipotoxicity, mitochondrial damage, and associated innate-immune signaling, ferroptosis, cellular senescence, and adipose-derived mediators (including leptin, adiponectin, and a locally active renin–angiotensin system) converge on myofibroblast activation from pericytes, fibroblasts, and other resident cells. We discuss established and emerging therapies targeting this metabolic axis—peroxisome proliferator-activated receptor-α (PPARα) modulators, sodium–glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and the mineralocorticoid receptor antagonist finerenone—and propose that restoring metabolic flexibility, by rescuing FAO while limiting maladaptive glycolysis, offers a promising disease-modifying strategy for fatty kidney disease. Full article

Cats with urethral obstruction may develop tubular damage before conventional indicators of renal dysfunction become abnormal, making early recognition challenging when relying solely on conventional renal biomarkers. This study evaluated urinary kidney injury molecule-1 (KIM-1) concentrations in non-azotemic cats with urethral obstruction and compared its expression with conventional renal biomarkers. Twenty-four male cats were prospectively enrolled and allocated into a control group (n = 12) and a urethral obstruction group (n = 12), all presenting serum creatinine concentrations within the reference interval. Urinary KIM-1 concentrations were quantified by enzyme-linked immunosorbent assay (ELISA) and normalized to urinary creatinine concentrations. Serum creatinine and blood urea nitrogen (BUN) did not differ significantly between groups. In contrast, urinary KIM-1 concentrations were significantly higher in cats with urethral obstruction compared with healthy controls (p < 0.001). These findings suggest that increased urinary KIM-1 expression may be associated with renal tubular injury in non-azotemic cats with urethral obstruction, even in the absence of alterations in conventional renal biomarkers. Therefore, urinary KIM-1 may represent a useful non-invasive marker of renal tubular injury associated with obstructive urinary disease. Further prospective studies incorporating additional renal biomarkers, histopathological evaluation, and longitudinal follow-up are warranted to better define its clinical applicability. Full article

Background and Clinical Significance: IgG4-related disease (IgG4-RD) is a chronic fibroinflammatory, immune-mediated multisystem disorder that can mimic neoplastic, infectious, or autoimmune conditions. Among its head-and-neck manifestations, IgG4-related dacryoadenitis and sialadenitis, historically referred to as Mikulicz disease, should be distinguished from the classical Mikulicz syndrome, which describes secondary lacrimal and salivary gland enlargement due to other systemic disorders. Renal involvement, most commonly in the form of IgG4-related tubulointerstitial nephritis (IgG4-TIN), is less frequent but carries major prognostic implications because delayed diagnosis may lead to irreversible kidney damage. Case Presentation: A 49-year-old man with no relevant past medical history presented with a 2-year history of intermittent polyuria and foamy urine. Laboratory testing revealed advanced kidney dysfunction, with serum creatinine of 4.2 mg/dL, estimated glomerular filtration rate of 16 mL/min/1.73 m², and proteinuria of 2874 mg/day. Physical examination showed bilateral parotid enlargement, upper eyelid edema, lacrimal gland enlargement, and sicca symptoms, raising suspicion for IgG4-related dacryoadenitis and sialadenitis (Mikulicz disease). Further work-up demonstrated marked eosinophilia, polyclonal hypergammaglobulinemia, and significantly elevated serum IgG4 levels (3180 mg/dL), while infectious serologies and autoimmune studies were negative. Kidney biopsy revealed plasma cell-rich tubulointerstitial nephritis with lymphoplasmacytic and eosinophilic infiltrates, interstitial fibrosis, tubular atrophy, and more than 40 IgG4-positive plasma cells per high-power field, supporting the diagnosis of IgG4-related tubulointerstitial nephritis in the setting of systemic IgG4-RD. Treatment with prednisone followed by mycophenolate mofetil led to improvement in glandular manifestations and a partial reduction in proteinuria, but renal recovery remained incomplete. The patient subsequently developed a severe pulmonary infection complicated by sepsis and oligoanuric acute kidney injury superimposed on chronic kidney disease, and ultimately progressed to end-stage kidney disease requiring chronic maintenance hemodialysis. Conclusions: This case highlights that a Mikulicz disease phenotype may represent the initial manifestation of systemic IgG4-RD and should prompt evaluation for extraglandular involvement, particularly renal disease. In patients with glandular enlargement, eosinophilia, hypergammaglobulinemia, and unexplained renal dysfunction, IgG4-RD should be actively considered. Kidney biopsy remains essential for diagnostic confirmation and prognostic assessment, as delayed recognition may result in irreversible renal damage and progression to end-stage kidney disease. Full article

Acute kidney injury (AKI) caused by ischemia–reperfusion injury (IRI) involves rapid activation of innate immune responses, in which myeloid-derived immune cells critically shape injury severity. Y-box binding protein 1 (YB-1) regulates pro-inflammatory gene expression intracellularly and can be secreted to function extracellularly, yet how these two compartments jointly influence early IRI pathology remains poorly understood. To dissect the roles of intracellular myeloid versus extracellular YB-1, we subjected myeloid-specific Ybx1 knockout, Ybx1^fl/fl × LysM^cre, mice and wild-type (WT) littermates to unilateral renal IRI following administration of either a neutralizing anti-YB-1 antibody or control IgG. Kidney injury, inflammation, immune cell recruitment, neutrophil extracellular trap (NET) formation, antibody localization, and Fcγ receptor expression were assessed by qRT-PCR, histology, immunostaining, Western blotting, and flow cytometry. Myeloid-specific knockout of Ybx1 markedly reduced renal inflammation, neutrophil infiltration, NET formation, and tubular injury. This protective phenotype was lost when extracellular YB-1 was simultaneously reduced: anti-YB-1 treatment in knockout mice restored pro-inflammatory cytokine expression, increased tubular damage markers such as NGAL and KIM-1, exacerbated neutrophil recruitment and NET formation, and led to luminar accumulation of YB-1/anti-YB-1 immune complexes in tubular cells. Mechanistically, Ybx1-deficient myeloid cells exhibited significantly reduced CD16 expression, pointing to impaired Fcγ receptor-mediated phagocytosis as the cause of defective immune complex clearance. In contrast, wild-type mice efficiently cleared extracellular YB-1 complexes and showed no injury aggravation upon antibody treatment. Our findings identify myeloid YB-1 as a central regulator of early inflammatory injury in renal IRI and reveal that its protective depletion becomes pathogenic when extracellular YB-1 is simultaneously neutralized, likely due to unmasked defects in immune complex clearance. Full article

Dengue remains a major public health problem in tropical and subtropical regions, particularly in Latin America. Acute kidney injury (AKI) is one of the severe complications associated with dengue and has been linked to worse clinical outcomes, including prolonged hospitalization, need for renal replacement therapy, and increased mortality. This review aimed to summarize the available evidence on the epidemiology, pathophysiology, clinical manifestations, diagnosis, management, and prognosis of dengue-associated AKI, while also providing an overview of the literature from Latin America. This manuscript was developed as a narrative review. For the Latin America-specific overview, a focused structured search was conducted in PubMed, ScienceDirect, Cochrane Library, LILACS, and Web of Science, including studies published up to December 2025. The available data suggest that AKI in dengue is multifactorial, involving plasma leakage, renal hypoperfusion, endothelial dysfunction, tubular injury, rhabdomyolysis, thrombotic microangiopathy, and inflammatory renal damage. Clinically, AKI has been associated with oliguria, proteinuria, elevated serum creatinine, renal replacement therapy, and higher mortality. Only four eligible indexed studies from Latin America were identified in our search, all from Brazil, with small sample sizes and incomplete reporting of renal outcomes; however, additional unpublished or non-indexed local data may exist. In summary, dengue-associated AKI is a relevant complication of severe dengue, but the evidence available from Latin America remains limited. These findings highlight the need for improved renal surveillance and standardized reporting in dengue-endemic settings across Latin America. Full article

Background/Objectives: Arsenic (ARS) exposure is a major cause of kidney injury, driven by oxidative stress, inflammation, fibrosis, and apoptosis. This study evaluated the renoprotective effects of morin (MOR) and morin-loaded PLGA nanoparticles (MOR–PGNPs) against ARS-induced nephrotoxicity in rats. Methods: Sixty male Sprague Dawley rats were randomly allocated into six groups (n = 10 per group). The control group received corn oil. The MOR group received MOR (100 mg/kg), and the MOR–PGNPs group received the same dose of MOR encapsulated in PLGA nanoparticles. ARS was administered at 10 mg/kg for 14 days. Co-treated groups received ARS together with either MOR or MOR–PGNPs, with a 28 min interval between administrations. Renal function markers (serum urea, creatinine, uric acid, renal KIM-1), oxidative stress and antioxidant parameters (Nrf2/HO-1, CAT, SOD, GPx, ROS, MDA), inflammatory mediators (TLR4/NF-κB, TNF-α, IL-6, IL-1β), fibrotic markers (TGF-β1, fibronectin), and apoptotic proteins (caspase-3, caspase-8, Bax, Bcl-2) were assessed, alongside histopathological and ultrastructural evaluations. Results: ARS exposure significantly impaired renal function, increased KIM-1, suppressed Nrf2/HO-1 signaling, reduced antioxidant enzyme activities, and elevated ROS and MDA levels. It also activated TLR4/NF-κB signaling, upregulated pro-inflammatory cytokines and fibrotic markers, and increased pro-apoptotic proteins while downregulating Bcl-2. MOR co-treatment partially ameliorated these alterations. MOR–PGNPs produced potentially enhanced protection, restoring kidney function markers, enhancing antioxidant defenses, and markedly attenuating inflammation, fibrosis, and apoptosis. Histopathological and ultrastructural analyses confirmed preservation of glomerular and tubular architecture, mitochondrial integrity, and minimal cytoplasmic vacuolization in the MOR–PGNPs group. Conclusions: MOR–PGNPs at 100 mg/kg effectively mitigated ARS-induced renal damage through antioxidant, anti-inflammatory, antifibrotic, and anti-apoptotic mechanisms, supporting PLGA-based morin nanoparticles as a promising and safe renoprotective strategy. Full article

Nuclear factor-κB (NF-κB) is a critical regulator of inflammation and stress response signaling in acute kidney injury (AKI). Increasing evidence demonstrates that NF-κB signaling is directly related to oxidative stress, autophagy, mitochondrial malfunction, and apoptosis in the process of AKI. Injury-related stimuli, including ischemia–reperfusion, sepsis, nephrotoxins, reactive oxygen species (ROS) and damage-associated molecular patterns (DAMPs), activate canonical and non-canonical NF-κB pathways, resulting in renal inflammation and tubular injury. Recent investigations have shown that TLR4/NF-κB signaling, NLRP3 inflammasome activation, defective autophagy, and mitochondrial dysfunction mediate inflammatory and pro-apoptotic responses in AKI. On the other hand, autophagy-associated proteins such as microtubule-associated protein 1 light chain 3 beta (LC3B) and Beclin-1 may play renoprotective roles through the regulation of NF-κB signaling. This review tries to cover the knowledge regarding NF-κB signaling in AKI and to emphasize the possible function of NF-κB signaling in the control of inflammation, autophagy, and apoptosis. It also seeks to provide some insight into future research directions that may guide the development of more effective therapies for AKI. Full article

Despite their reduced viability, kidneys from donors-after-circulatory-death (DCD) increase the pool of transplantable kidneys. Molecular hydrogen (H₂) is emerging as a gas with therapeutic potential against graft injury. We investigated the effect of H₂ in an ex vivo porcine model of DCD kidney transplantation. Renal arteries of male Yorkshire pigs (n = 6) were clamped in situ for 60 min to induce ischemia, and ureters and arteries were cannulated to mimic DCD kidney injury. Upon nephrectomy, kidneys were flushed with UW solution or H₂-saturated UW solution and then preserved by machine perfusion at 4 °C for 4 h followed by a 4-h reperfusion period with warm autologous blood. Urine and arterial blood samples were collected hourly. H₂ preserved renal architecture, evidenced by significantly reduced tubular necrosis and renal expression of damage markers, which corresponded with the downregulated renal expression of pro-inflammatory genes compared to the UW-only group (p < 0.05). H₂ also markedly reduced levels of serum creatinine, BUN and intrarenal resistance, while flow rate, creatinine clearance and urine output were significantly higher, which positively correlated with Trx-1 and HO-1 expression in comparison with UW only group (p < 0.05). Improvement in renal graft quality and function is associated with Trx-1/HO-1 activation, suggesting preliminary clinical trials in kidney transplantation. Full article

Background: Pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, is widely employed in oncological practice; however, its propensity to induce nephrotoxicity through immune-mediated oxidative and inflammatory mechanisms remains an insufficiently characterized clinical concern. The present study comparatively investigated the renoprotective effects of flunarizine, a voltage-dependent calcium channel antagonist, and carvacrol, a monoterpene, against pembrolizumab-induced renal injury in rats. Methods: Twenty-four male Wistar albino rats were assigned to four groups (n = 6): healthy control (HG), pembrolizumab alone (PZB), flunarizine+pembrolizumab (FLPZ), and carvacrol+pembrolizumab (CCPZ). Pembrolizumab was administered intraperitoneally at 5 mg/kg; flunarizine orally at 5 mg/kg and carvacrol intraperitoneally at 50 mg/kg, once daily for seven consecutive days. Renal oxidative status was assessed by measuring malondialdehyde (MDA) and total glutathione (tGSH) levels. Histopathological evaluation was performed using hematoxylin and eosin staining. Two double immunofluorescence panels were employed to assess 3,3′-dityrosine/Hepatitis A virus cellular receptor 1 (HAVCR1) and cyclooxygenase-1 (COX-1)/cyclooxygenase-2 (COX-2) expression, respectively. Results: Pembrolizumab caused pronounced oxidative stress and inflammatory responses in renal tissue, leading to a significant increase in renal MDA levels and a marked decrease in tGSH levels. These biochemical alterations were accompanied by severe tubular degeneration and increased expression of 3,3′-dityrosine, which is associated with oxidative damage, as well as HAVCR1, a marker of cellular injury, and COX-1 and COX-2, which reflect inflammatory activity. These findings indicate that pembrolizumab disrupts the renal redox balance and activates both oxidative and inflammatory pathways in kidney tissue. Flunarizine and carvacrol significantly reduced these pathological changes. Both agents attenuated oxidative stress markers and supported antioxidant defenses, thereby alleviating tissue damage. However, flunarizine demonstrated a more pronounced renoprotective effect across all evaluated parameters, restoring MDA and tGSH levels closer to physiological values and reducing tubular injury to a minimal level. Carvacrol showed a more limited but still statistically significant protective effect. Conclusions: Both agents confer significant renoprotection against pembrolizumab-induced oxidative injury; however, flunarizine exhibits a more robust protective profile, likely attributable to its capacity to attenuate calcium-mediated mitochondrial dysfunction and preserve cellular bioenergetic homeostasis. Full article

Cardiac surgery-associated acute kidney injury (CSA-AKI) is a frequent and severe complication of open-heart surgery. Although oxidative/inflammatory mechanisms are known to contribute to its pathophysiology, the circulating factors involved are poorly understood. In this preliminary investigation, we evaluated the effects of plasma from patients undergoing cardiac surgery on endothelial and renal tubular cells at anesthesia induction (T0) and 48 h after surgery (T1). Plasma levels of thiobarbituric acid-reactive substances (TBARSs), glutathione (GSH), and nitric oxide (NO) were measured in parallel. At T0, patient plasma showed increased TBARSs and reduced GSH and NO levels, consistent with oxidative imbalance, and induced cellular injury. In both cell types, plasma exposure reduced cell viability and mitochondrial membrane potential, while it increased oxidant release. Endothelial cells also showed decreased NO production, whereas renal tubular displayed increased apoptotic markers and reduced anti-aging factors. At T1, these alterations were further aggravated only in patients who developed CSA-AKI, whose plasma caused more severe endothelial and tubular damage. These findings support the presence of circulating injurious factors in cardiac surgery patient plasma that may contribute to CSA-AKI pathogenesis and help identify patients at risk before irreversible kidney damage develops. Full article

Background and Clinical Significance: Autosomal dominant tubulointerstitial kidney disease caused by a mutation in the uromodulin gene (ADTKD-UMOD) is a rare kidney disorder characterized by progressive tubulointerstitial damage and a slowly progressive loss of renal function. ADTKD is often under-recognized in the clinical setting. Diagnosis of ADTKD-UMOD can be challenging due to its nonspecific symptoms and is confirmed by genetic testing alone. Case presentation: We report the case of a 42-year-old male patient referred for evaluation of renal dysfunction, which was accidentally discovered during routine laboratory checks. He had no significant medical history and no known family history of kidney disease or gout. Physical examination was unremarkable. Renal dysfunction was confirmed, with serum creatinine at 1.44 mg/dL and eGFR at 59.5 mL/min/1.73 m². Urinalysis was within physiological limits, proteinuria being 75 mg/day. Uric acid was mildly elevated (7.5 mg/dL) without a history of gout. Other laboratory findings, including autoantibodies, were in the normal range. The patient underwent a kidney biopsy, though it was not diagnostic, showing mild focal tubular atrophy and interstitial fibrosis without glomerular involvement. Immunofluorescence staining was negative for complement and immunoglobulins. Given the above nonspecific findings, the patient was suspected of having possible ADTKD. Genetic investigation using a clinical exome next-generation sequencing approach identified a novel heterozygous missense variant in the UMOD gene (c.409T>C; p.Cysteine137Arginine (p.Cys137Arg)) that is likely pathogenic. The patient is under regular clinical-laboratory monitoring. After one year, his overall health is good, renal function is stable with no proteinuria, and uric acid is mildly increased without gout attacks. Conclusions: Increased clinical awareness is crucial for detecting ADTKD-UMOD. Genetic testing can help to resolve clinical diagnostic challenges in patients with unexplained decreased kidney function. Full article

Chronic kidney disease (CKD) affects nearly 10% of the global population, yet diagnosis and disease monitoring still rely primarily on plasma creatinine. Because creatinine levels are strongly influenced by non–renal factors, such as age, sex, muscle mass, and diet, its accuracy as a kidney function marker is limited. To identify plasma biomarkers that reflect kidney injury, we applied untargeted and targeted metabolomics in the adenine-induced CKD mouse model, a well-known tubular damage model, and validated the findings in plasma from patients with advanced CKD and healthy controls. We identified five metabolites that showed altered plasma levels in both experimental and human CKD, of which galactonic acid, pipecolic acid, and N-acetylneuraminic acid were significantly associated with measured glomerular filtration rate (GFR). As a proof-of-concept, we demonstrated that integrating these metabolites into a biomarker panel alongside creatinine could improve GFR estimation compared with creatinine alone. Our study introduces a promising metabolite-based biomarker panel that might enhance the accuracy of kidney function assessment and could potentially support diagnosis, risk stratification, and monitoring of disease progression; however, validation in a broader CKD cohort is needed. Full article

Hypoxia during the postnatal period represents a significant risk factor for renal injury in neonates, yet the molecular mechanisms linking oxygen deprivation to kidney damage remain unclear. In this study, we explored whether ferroptosis serves as a key mediator in hypoxia-induced acute kidney injury (AKI). Using a neonatal rat model, we demonstrated that hypoxic exposure disrupts iron homeostasis, leading to iron accumulation and excessive lipid peroxidation in renal tissues. These alterations were associated with marked tubular injury, glomerular damage, and progressive fibrotic remodeling. Importantly, reoxygenation attenuated ferroptosis-related signaling pathways and improved renal structural and functional outcomes, although incomplete recovery was observed in fibrotic changes. Our findings suggest that ferroptosis is not only involved in the initiation of hypoxia-induced renal injury but may also contribute to its progression toward chronic kidney pathology. Targeting ferroptosis and iron metabolism may therefore represent a promising strategy for preventing or treating neonatal hypoxia-related AKI. Full article

Iron overload significantly contributes to chronic kidney disease progression by triggering oxidative stress and mitochondrial impairment via the Fenton reaction. This study investigates the protective role of aldehyde dehydrogenase 1a3 (ALDH1a3), an enzyme that detoxifies reactive aldehydes, in renal iron overload. C57BL/6N mice were fed a 2.25% ferric citrate diet for 24 weeks to establish a chronic model, followed by treatment with the chelator Dimercaprol (DP). In vitro, TCMK−1 cells were subjected to iron intervention with ALDH1a3 overexpression or inhibition. Chronic iron overload induced significant renal iron deposition, lipid peroxidation (elevated MDA, depleted GSH), and mitochondrial structural damage. ALDH1a3 was endogenously upregulated in renal tubular epithelial cells under iron stress. Overexpressing ALDH1a3 significantly enhanced cell viability, suppressed reactive oxygen species and MDA levels, and preserved mitochondrial membrane potential, whereas its inhibition exacerbated cellular damage. Furthermore, DP treatment reduced iron deposition and was associated with increased ALDH1a3 expression. In conclusion, ALDH1a3 acts as a critical endogenous protective factor against iron−induced nephrotoxicity by mitigating oxidative damage and maintaining mitochondrial stability. These findings indicate that ALDH1a3 is a promising potential therapeutic target for the treatment of iron overload−related kidney diseases. Full article

In recent decades, there has been a worrying increase in the consumption of energy drinks, especially among the young population. These beverages have been linked to effects primarily on the nervous and cardiovascular systems; however, renal consequences remain poorly understood, particularly those associated with long-term consumption. The heterogeneity in consumption patterns, together with variability in consumer profiles, has limited the ability to obtain conclusive and consistent evidence on this issue. Therefore, it is essential to address this topic from a preclinical perspective under controlled experimental conditions. The aim of the present study was to evaluate the available preclinical evidence through a systematic review followed by a meta-analysis. Nineteen studies met the inclusion criteria, with rats being the most commonly used experimental model. Overall, the results show a significant association between energy drink consumption and impaired kidney function, as reflected in elevated levels of serum biomarkers such as creatinine, urea, and uric acid. Among these, serum creatinine (mean Hedges’ g = −1.40; 95% confidence interval: −2.55 to −0.25) and urea (Hedges’ g = −1.93; 95% confidence interval: −2.99 to −0.87) had the highest effect sizes and greater statistical robustness, suggesting a particularly significant impact on kidney function. Although fewer studies reported increased uric acid levels, this parameter may have pathophysiological relevance. Elevated uric acid has been associated with mechanisms such as inflammation, oxidative stress, and endothelial dysfunction, which may contribute to the progression of renal damage. Additionally, morphological alterations in glomerular and tubular structures were observed, particularly after prolonged exposure and at high doses. Despite the need for methodological improvements in future research, these findings highlight potential adverse renal effects that should be considered in the development of regulatory policies on energy drink consumption. Full article