Search Results (160)

Background and Objectives: Coronavirus Disease 2019 (COVID-19) may cause extensive multi-organ pathology, particularly in the lungs, heart, kidneys, and liver. While hypercoagulability—often signaled by elevated D-dimer—has been thoroughly investigated, the concurrent pathological findings across organs and their interrelation with distinct D-dimer levels remain incompletely characterized. This study aimed to evaluate the pathological changes observed in autopsied or deceased COVID-19 patients, focusing on the prevalence of organ-specific lesions, and to perform subgroup analyses based on three D-dimer categories. Methods: We conducted a retrospective review of 69 COVID-19 patients from a Romanian-language dataset, translating all clinical and pathological descriptions into English. Pathological findings (pulmonary microthrombi, bronchopneumonia, myocardial fibrosis, hepatic steatosis, and renal tubular necrosis) were cataloged. Patients were grouped into three categories by admission D-dimer: <500 ng/mL, 500–2000 ng/mL, and ≥2000 ng/mL. Laboratory parameters (C-reactive protein, fibrinogen, and erythrocyte sedimentation rate) and clinical outcomes (intensive care unit [ICU] admission, mechanical ventilation, and mortality) were also recorded. Intergroup comparisons were performed with chi-square tests for categorical data and one-way ANOVA or the Kruskal–Wallis test for continuous data. Results: Marked organ pathology was significantly more frequent in the highest D-dimer group (≥2000 ng/mL). Pulmonary microthrombi and bronchopneumonia increased stepwise across ascending D-dimer strata (p < 0.05). Myocardial and renal lesions similarly showed higher prevalence in patients with elevated D-dimer. Correlation analysis revealed that severe lung and heart pathologies were strongly associated with high inflammatory markers and a greater risk of ICU admission and mortality. Conclusions: Our findings underscore that COVID-19-related organ damage is magnified in patients with significantly elevated D-dimer. By integrating pathology reports with clinical and laboratory data, we highlight the prognostic role of hypercoagulability and systemic inflammation in the pathogenesis of multi-organ complications. Stratifying patients by D-dimer may inform more tailored management strategies, particularly in those at highest risk of severe pathology and adverse clinical outcomes. Full article

Renal function refers to the combined actions of the glomerulus and tubular system to achieve homeostasis in bodily fluids. While the glomerulus is essential in the first step of urine formation through a coordinated filtration mechanism, the tubular system carries out active mechanisms of secretion and reabsorption of solutes and proteins using specific transporters in the epithelial cells. The assessment of renal function usually focuses on glomerular function, so the tubular function is often underestimated as a fundamental part of daily clinical practice. Therefore, it is essential to properly understand the tubular physiological mechanisms and their clinical association with prevalent human pathologies. This review discusses the primary solutes handled by the kidneys, including glucose, amino acids, sodium, potassium, calcium, phosphate, citrate, magnesium and uric acid. Additionally, it emphasizes the significance of physicochemical characteristics of urine, such as pH and osmolarity. The use of a concise methodology for the comprehensive assessment of urine should be strengthened in the basic training of nephrologists when dealing with problems such as water and electrolyte balance disorders, acid-base disorders, and harmful effects of commonly used drugs such as chemotherapy, antibiotics, or diuretics to avoid isolated replacement of the solute without carrying out comprehensive approaches, which can lead to potentially severe complications. Full article

Metabolic syndrome (MetS), characterized by obesity, insulin resistance, and dyslipidemia, is a major risk factor for renal injury. Oxidative stress (OxS) plays a pivotal role in its progression; however, the underlying molecular mechanisms are not fully understood. In this study, we established a rat model of MetS using a high-fat diet combined with a single-dose streptozotocin injection in male Wistar rats. MetS rats exhibited systemic OxS, evidenced by elevated circulating levels of free oxygen radicals and decreased antioxidant defense capacity, as well as hypertension, renal lipid peroxidation, glomerular hyperfiltration, and renal tubular injury. Transcriptomic profiling of renal tissue revealed significant downregulation of six OxS-related genes: C-C motif chemokine ligand 5 (CCL5), glutamate-cysteine ligase catalytic subunit, glutathione peroxidase 6, recombination activating gene 2, NAD(P)H: quinone oxidoreductase 1, and selenoprotein P-1. Among these downregulated genes, CCL5 was further confirmed to be repressed at both mRNA and protein levels across intrarenal and systemic compartments. Given its documented functions in immune signaling and redox homeostasis, CCL5 downregulation may contribute to enhanced oxidative damage in MetS-associated renal injury. These findings highlight the role of redox gene dysregulation in the pathogenesis of MetS-related kidney disease and support the potential of CCL5 as a biomarker for oxidative renal injury. Full article

Mitochondrial dysfunction is a pivotal driver in the pathogenesis of acute kidney injury (AKI), chronic kidney disease (CKD), and congenital anomalies of the kidney and urinary tract (CAKUT). The kidneys, second only to the heart in mitochondrial density, rely on oxidative phosphorylation to meet the high ATP demands of solute reabsorption and filtration. Disrupted mitochondrial dynamics, such as excessive fission mediated by Drp1, exacerbate tubular apoptosis and inflammation in AKI models like ischemia–reperfusion injury. In CKD, persistent mitochondrial dysfunction drives oxidative stress, fibrosis, and metabolic reprogramming, with epigenetic mechanisms (DNA methylation, histone modifications, non-coding RNAs) regulating genes critical for mitochondrial homeostasis, such as PMPCB and TFAM. Epigenetic dysregulation also impacts mitochondrial–ER crosstalk, influencing calcium signaling and autophagy in renal pathology. Mitophagy, the selective clearance of damaged mitochondria, plays a dual role in kidney disease. While PINK1/Parkin-mediated mitophagy protects against cisplatin-induced AKI by preventing mitochondrial fragmentation and apoptosis, its dysregulation contributes to fibrosis and CKD progression. For instance, macrophage-specific loss of mitophagy regulators like MFN2 amplifies ROS production and fibrotic responses. Conversely, BNIP3/NIX-dependent mitophagy attenuates contrast-induced AKI by suppressing NLRP3 inflammasome activation. In diabetic nephropathy, impaired mitophagy correlates with declining eGFR and interstitial fibrosis, highlighting its diagnostic and therapeutic potential. Emerging therapeutic strategies target mitochondrial dysfunction through antioxidants (e.g., MitoQ, SS-31), mitophagy inducers (e.g., COPT nanoparticles), and mitochondrial transplantation, which mitigates AKI by restoring bioenergetics and modulating inflammatory pathways. Nanotechnology-enhanced drug delivery systems, such as curcumin-loaded nanoparticles, improve renal targeting and reduce oxidative stress. Epigenetic interventions, including PPAR-α agonists and KLF4 modulators, show promise in reversing metabolic reprogramming and fibrosis. These advances underscore mitochondria as central hubs in renal pathophysiology. Tailored interventions—ranging from Drp1 inhibition to mitochondrial transplantation—hold transformative potential to mitigate kidney injury and improve clinical outcomes. Additionally, dietary interventions and novel regulators such as adenogens are emerging as promising strategies to modulate mitochondrial function and attenuate kidney disease progression. Future research should address the gaps in understanding the role of mitophagy in CAKUT and optimize targeted delivery systems for precision therapies. Full article

Sepsis-associated acute kidney injury (S-AKI) is a severe complication in critically ill patients, marked by inflammation, oxidative stress, and renal dysfunction. This study aimed to evaluate the renoprotective effects of Fasudil (Fas), a Rho-associated kinase inhibitor, in a rat model of S-AKI induced by cecal ligation and puncture (CLP). Thirty-six Wistar albino rats were divided into control, CLP with saline, and Fas (100 mg/kg/day intraperitoneally) groups. Biochemical, histopathological, and molecular analyses were conducted to assess kidney function, oxidative stress, and inflammation. Fas treatment significantly decreased plasma malondialdehyde and TNF-α levels, reducing oxidative stress and systemic inflammation. Kidney function markers, including BUN and creatinine, showed marked improvement. Furthermore, Fas suppressed the expression of STAT-3 and NLRP-3 in renal tissues, highlighting its role in modulating key inflammatory pathways. Histological evaluation revealed alleviated renal damage, with less tubular necrosis and interstitial inflammation in the Fas-treated group. In conclusion, Fas demonstrates significant anti-inflammatory, antioxidant, and nephroprotective effects in S-AKI, primarily by inhibiting STAT-3 and NLRP-3 signaling. These results support its potential as a therapeutic agent in sepsis-induced kidney injury and suggest the need for further clinical evaluation. Full article

The renin–angiotensin system helps regulate the endocrine system in modulating blood pressure, fluid volume, and body fluid electrolyte levels. The disruption of the renin–angiotensin system can lead to kidney disease onset and progression. However, the mechanism by which kidney angiotensinogen expression and secretion induce the onset and progression of diabetic nephropathy remains unclear. In this study, we used renal proximal tubular epithelial cells, which express high levels of angiotensinogen, to examine food components that regulate angiotensinogen secretion. The renal proximal tubular epithelial cells were first treated with catalase (antioxidant), daidzein, equol (an isoflavone), a MAP kinase inhibitor, ERK, p38, or JNK and then stimulated with hydrogen peroxide. After 24 h, we collected a culture medium to perform an enzyme-linked immunosorbent assay test for angiotensinogen and cells in order to perform real-time PCR to detect angiotensinogen. We found that angiotensinogen secretion increased as the hydrogen peroxide concentration increased. Catalase, daidzein, and equol decreased angiotensinogen expression and secretion. To investigate the cell signaling mechanism involved in these effects, we assessed the contribution of the MAP kinase cascade. Our data suggest the contribution of p38 and JNK. Our study shows that, in proximal tubular epithelial cells, hydrogen peroxide stimulates angiotensinogen secretion. Isoflavones and p38 inhibited angiotensinogen secretion. Full article

Heat stress triggers systemic oxidative stress that compromises physiological homeostasis. This study evaluated methionine’s effects on hepatic and renal antioxidant capacity in heat-stressed Rex rabbits. Rabbits were divided into five groups (30 replicates/group): control (20–25 °C, basal diet), heat stress (HS, 30–34 °C, basal diet), and HS +0.15%, 0.3%, or 0.45% methionine-supplemented groups. After 21 days, serum, skin, liver, and kidney samples were analyzed for biochemical parameters, oxidative stress markers, and gene expression. Results showed that 0.15–0.3% methionine supplementation under heat stress increased methionine apparent digestibility and suppressed amino acid catabolism; decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels; reduced skin malondialdehyde (MDA) and elevated (MSRA) activity; attenuated hepatic central venous congestion and renal tubular vacuolization; enhanced hepatic superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities (0.3% group); and modulated antioxidant gene expression via Nrf2/HO-1 and Nrf2/NQO1 pathways. Pathological analysis confirmed reduced fibrosis and cellular damage in liver/kidney tissues. Optimal methionine supplementation (0.3%) effectively mitigated heat-induced oxidative organ damage by enhancing endogenous antioxidant defenses and regulating redox-sensitive signaling pathways. These findings provide a nutritional strategy for alleviating heat stress-related metabolic disorders in rabbits. Full article

The BCS1L gene encodes a mitochondrial chaperone which inserts the Fe₂S₂ iron–sulfur Rieske protein into the nascent electron transfer complex III. Variants in the BCS1L gene are associated with a spectrum of mitochondrial disorders, ranging from mild to severe phenotypes. Björnstad syndrome, a milder condition, is characterized by sensorineural hearing loss (SNHL) and pili torti. More severe disorders include Complex III Deficiency, which leads to neuromuscular and metabolic dysfunctions with multi-systemic issues and Growth Retardation, Aminoaciduria, Cholestasis, Iron Overload, and Lactic Acidosis syndrome (GRACILE). The severity of these conditions varies depending on the specific BCS1L mutation and its impact on mitochondrial function. This study describes a 27-month-old child with SNHL, proximal renal tubular acidosis, woolly hypopigmented hair, developmental delay, and metabolic alterations. Genetic analysis revealed a homozygous BCS1L variant (c.38A>G, p.Asn13Ser), previously reported in a patient with a more severe phenotype that, however, was not functionally characterized. In this work, functional studies in a yeast model and patient-derived fibroblasts demonstrated that the variant impairs mitochondrial respiration, complex III activity (CIII), and also alters mitochondrial morphology in affected fibroblasts. Interestingly, we unveil a new possible mechanism of pathogenicity for BCS1L mutant protein. Since the interaction between BCS1L and CIII is increased, this suggests the formation of a BCS1L-containing nonfunctional preCIII unable to load RISP protein and complete CIII assembly. These findings support the pathogenicity of the BCS1L c.38A>G variant, suggesting altered interaction between the mutant BCS1L and CIII. Full article

Acute kidney injury (AKI) remains a significant challenge in critical care medicine, affecting up to 50% of intensive care unit patients with substantial mortality rates. While traditional approaches to AKI assessment rely on static measurements like serum creatinine and urine output, the furosemide stress test (FST) has emerged as a dynamic functional tool for evaluating renal tubular function and predicting AKI progression. This comprehensive review examines the historical development, physiological basis, technical aspects, and clinical applications of FST in various patient populations. Originally developed and validated in 2013, FST has demonstrated superior predictive capabilities for AKI progression and the need for renal replacement therapy compared to conventional biomarkers. The test’s mechanism relies on assessing the kidney’s response to a standardized furosemide challenge, providing insights into both the structural integrity and functional reserve of the renal tubular system. Standardized protocols have been established for different clinical scenarios, though implementation challenges remain, including timing considerations, patient selection, and resource requirements. FST has shown utility in critical care, post-cardiac surgery, sepsis-associated AKI, and heart failure settings. Recent developments include integration with artificial intelligence, personalized medicine approaches, and combination with novel biomarkers. While limitations exist, including contraindications and technical challenges, ongoing research continues to refine protocols and expand applications. This review highlights FST’s role as a valuable prognostic tool in modern AKI management and discusses future directions, including automated monitoring systems, protocol standardization efforts, and potential applications in different patient populations. Full article

The use of adenosine triphosphate (ATP) has shown promising effects in alleviating ischemic damage across various tissues. However, the penetration of ATP into kidney tubular cells presents a challenge due to their unique anatomical and physiological properties. In this study, we introduce a novel bioinspired drug delivery system utilizing extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) and engineered to carry ATP. ATP-loaded liposomes (ATP-LPs) and ATP-loaded EVs (ATP-EVs) were prepared using microfluidic technology, followed by characterization of their morphology (DLS, NTA, SEM, TEM), ATP content, and release rate at 37 °C (pH 7.4). Additionally, the delivery efficacy of ATP-LPs and ATP-EVs was evaluated in vitro on renal cells (HK2 cells) under chemically induced ischemia. The results indicated successful ATP enrichment in EVs, with ATP-EVs showing no significant changes in morphology or size compared to naïve EVs. Notably, ATP-EVs demonstrated superior ATP retention compared to ATP-LPs, protecting the ATP from degradation in the extracellular environment. In an ATP-depleted HK2 cell model, only ATP-EVs effectively restored ATP levels, preserving cell viability and reducing apoptotic gene expression (BCL2-BAX). This study is the first to successfully demonstrate the direct delivery of ATP into renal tubular cells in vitro using EVs as carriers. Full article

Kidney disorders significantly contribute to morbidity and mortality in sickle cell disease (SCD). Acute kidney injury (AKI), a major risk factor for chronic kidney disease (CKD), often arises from intravascular hemolysis, where plasma cell-free heme drives AKI through inflammatory and oxidative stress mechanisms. Hydroxyurea (HU), a well-established SCD-modifying therapy, improves clinical outcomes, but its effects on systemic heme and inflammatory mediators of kidney injury remain underexplored. This study evaluated HU’s impact on plasma heme, pro-inflammatory mediators, kidney injury, and renal histopathology in a sickle cell mouse model. Townes humanized sickle cell mice (HbSS) and non-sickle (HbAA) controls were treated with HU or vehicle for two weeks. HU significantly reduced total plasma heme, lactate dehydrogenase, and pro-inflammatory cytokines (CXCL10, VEGF-A, IFN-γ) in HbSS mice. HU reduced renal injury biomarkers (cystatin C, NGAL) and improved renal histopathology, evidenced by reduced vascular congestion, glomerulosclerosis, and tubular damage. Interestingly, HU did not alter the levels of kidney repair biomarkers (clusterin and EGF). These findings suggest that HU mitigates kidney injury by reducing the deleterious effects of circulating heme and inflammation, supporting its potential to slow or prevent progressive kidney injury in SCD. Full article

Background: Microscopic polyangiitis (MPA) is a type of necrotizing vasculitis that primarily affects small vessels and belongs to the spectrum of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs). While previous studies have identified potential prognostic biomarkers, further research is needed to validate a reliable marker for risk stratification in clinical practice. Kidney injury molecule-1 (Kim-1), a transmembrane protein expressed on proximal tubular epithelial cells, has been implicated in tubular damage. This study investigated the potential of Kim-1 as a biomarker in MPA. Methods: Kidney biopsy tissues, along with urine and blood samples, were retrospectively analyzed from 52 MPA patients and compared to urine samples from 7 healthy controls. Global disease activity was assessed using the Birmingham vasculitis activity score (BVAS) and vasculitis damage index, while renal disease activity was evaluated using renal BVAS (BVAS-R). Results: Urinary Kim-1 levels were significantly elevated in MPA patients compared to healthy controls. Urinary Kim-1 was positively correlated with the Mayo Clinic Chronicity Score (MCCS) but not with the ANCA Kidney Risk Score (AKRiS), whereas tubular Kim-1 was associated with AKRiS but not with MCCS, indicating their distinct pathological significance. Higher tubular Kim-1 expression was observed in patients with elevated BVAS-R. Urinary Kim-1 levels correlated with proteinuria and were associated with the Mayo Clinic Chronicity Score (MCCS) and ANCA Kidney Risk Score (AKRiS) but not with glomerular lesion severity. Unlike C-reactive protein (CRP), neither urinary nor tubular Kim-1 predicted MPA recurrence. Conclusions: Urinary Kim-1 reflects histopathologic findings and renal impairment but does not predict systemic disease activity or recurrence in MPA, demonstrating its potential clinical utility as a biomarker for assessing chronic renal damage. Full article

Background: Cardiac arrest (CA) is a leading cause of mortality and morbidity, with survivors often developing post-cardiac arrest syndrome (PCAS), characterized by systemic inflammation, ischemia–reperfusion injury (IRI), and multiorgan dysfunction. Acute kidney injury (AKI), a frequent complication, is associated with increased mortality and prolonged intensive care unit (ICU) stays. This study evaluates AKI incidence and progression in cardiac arrest patients managed with different temperature protocols and explores urinary biomarkers’ predictive value for AKI risk. Methods: A prospective, single-center observational study was conducted, including patients with Return of Spontaneous Circulation (ROSC) post-cardiac arrest. Patients were stratified into three groups: therapeutic hypothermia (TH) at 33 °C, Targeted Temperature Management (TTM) at 35 °C, and no temperature management (No TTM). AKI was defined using KDIGO criteria, with serum creatinine and urinary biomarkers (TIMP-2 and IGFBP7) measured at regular intervals during ICU stay. Results: AKI incidence at 72 h was 31%, varying across protocols. It was higher in the No TTM group at 24 h and in the TH and TTM groups during rewarming. Persistent serum creatinine elevation and fluid imbalance were notable in the TH group. Biomarkers indicated moderate tubular stress in the TTM and No TTM groups. Conclusions: AKI is a frequent complication post-cardiac arrest, with the rewarming phase identified as critical for renal vulnerability. Tailored renal monitoring, biomarker-guided risk assessment, and precise temperature protocols are essential to improve outcomes. Full article

Background: Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare autoimmune disorder, characterized by acute tubulointerstitial nephritis and uveitis. It poses diagnostic challenges due to the mostly asynchronous onset of renal and ocular manifestations, as well as the variety of differential diagnoses. This review provides an overview of the epidemiology, pathogenesis, clinical features, diagnostic criteria, and management strategies. Methods: A comprehensive review of the peer-reviewed literature, including studies and case reports, was conducted. Results: The etiology of TINU syndrome involves an autoimmune reaction to renal and ocular antigens, leading to interstitial inflammation and tubular damage in the kidneys, and anterior uveitis with acute onset of flares. Diagnostic criteria based on ocular examination, laboratory parameters, and renal biopsy emphasize the need to exclude other systemic diseases. TINU syndrome accounts for approximately 2% of all uveitis cases. Primary treatment consists of corticosteroids, while immunomodulatory therapies (methotrexate, azathioprine, mycophenolate mofetil, or biologic agents) are reserved for refractory cases. Recurrence of uveitis appears to be more common than that of nephritis. Conclusions: TINU syndrome is rare and requires clinical suspicion for accurate diagnosis. Early diagnosis and initiation of treatment are crucial for achieving favorable outcomes. Advances in the understanding of its pathogenesis and treatment have improved patient outcomes. Further research is needed to investigate the underlying triggers and mechanisms in order to develop targeted therapies. Full article

The complement system plays a crucial role in regulating the inflammatory responses in kidney transplantation, potentially contributing to early decline in kidney function. Ischemia–reperfusion injury (IRI) is among the factors affecting graft outcomes and a primary contributor to delayed graft function. Complement activation, particularly the alternative pathway, participates in the pathogenesis of IRI, involving all kidney compartments. In particular, tubular epithelial cells often acquire a dysfunctional phenotype that can exacerbate complement activation and kidney damage. Currently, complement-modulating drugs are under investigation for the treatment of kidney diseases. Many of these drugs have shown potential therapeutic benefits, but no effective clinical treatments for renal IRI have been identified yet. In this review, we will explore drugs that target complement factors, complement receptors, and regulatory proteins, aiming to highlight their potential value in improving the management of renal IRI. Full article