Search Results (265)

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

Inflammatory bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic relapsing–remitting condition characterized by systemic and intestinal inflammation and immune dysregulation. Up to 47% of IBD patients develop extraintestinal manifestations, yet kidney and urological involvement remain underrecognized. Accumulating evidence has linked IBD to nephrolithiasis, glomerular diseases, tubulointerstitial nephritis, acute kidney injury, chronic kidney disease, and, rarely, amyloid A amyloidosis. Population studies have consistently shown elevated risks for various important kidney disorders in IBD, with CD generally posing a greater risk than UC. The pathogenesis of kidney complications in IBD reflects complex gut–kidney interactions, including metabolic and absorptive abnormalities, shared genetic and immune pathways, intestinal dysbiosis with nephrotoxic microbial metabolites, systemic inflammation, and drug-related nephrotoxicity. Strategies for kidney protection in IBD include increased awareness, close monitoring of kidney function, urinary metabolic profiling in high-risk patients, and prompt nephrology referral for early detection and treatment. Management should include an effective and sustained control of intestinal inflammation, discontinuation of potential nephrotoxic drugs when indicated, and timely diagnosis and treatment of kidney manifestations, as well as integrating kidney complications into IBD guidelines to enhance awareness, ultimately optimizing both the kidney and overall outcomes for IBD patients. Future studies are needed to validate the potential predictive biomarkers for kidney complications and to develop targeted interventions to address shared gut–kidney pathogenic mechanisms in IBD. Full article

Background/Objectives: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, providing substantial survival benefits across a wide range of malignancies. However, ICI-associated renal toxicity encompasses a broad spectrum of clinical entities, ranging from nonspecific acute kidney injury to well-defined immune-mediated nephropathies with distinct pathophysiological mechanisms. Methods: We performed a large-scale pharmacovigilance study using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database to evaluate immune-mediated nephropathy associated with ICIs from January 2014 to March 2025. To improve specificity and minimize misclassification, the analysis was restricted to well-defined immune-mediated renal adverse events identified using MedDRA Preferred Terms, excluding nonspecific acute kidney injury. Disproportionality analysis was conducted using reporting odds ratios (RORs) with 95% confidence intervals (CIs) to assess associations between individual ICIs, treatment regimens, and nephropathy reporting. Results: Among 203,652 ICI-related adverse event reports (irAEs), 2361 (1.12%) involved immune-mediated nephropathy. Compared with other irAEs (non-nephropathy), immune-mediated nephropathy was more frequently reported in patients aged ≥ 65 years and in those with lung and genitourinary malignancies. Tubulointerstitial nephritis was the predominant subtype. Higher reporting signals were observed with cemiplimab and pembrolizumab, whereas durvalumab and atezolizumab demonstrated lower reporting signals. Combination regimens involving PD-1 and CTLA-4 inhibitors were associated with higher reporting frequencies compared with monotherapy. Conclusions: This real-world pharmacovigilance analysis identifies clinically relevant differences in immune-mediated nephropathy reporting across ICI classes and treatment strategies. PD-1 inhibitors and PD-1/CTLA-4 combination regimens were associated with higher reporting signals, suggesting potential variation in renal safety profiles. These findings should be interpreted cautiously, given the inherent limitations of spontaneous reporting systems, but they provide hypothesis-generating evidence to support future prospective studies with detailed clinical and histopathological correlation. Full article

Background: Obesity often affects kidney health. Irisin, a myokine released during exercise, may exert renoprotective effects. This study examined the effects of swimming-induced irisin on kidney health in obese rats. Materials and methods: Sixty male rats were divided into four groups: control non-trained, obese non-trained, control trained, and obese trained. Obesity was induced using a high-fat diet, and an 8-week swimming program was implemented. Measurements included body and kidney weights, renal function markers (serum urea, creatinine, and urinary albumin), lipid profile, fasting glucose, insulin, and HOMA-IR. Levels of skeletal muscle irisin and PGC-1α were measured by ELISA, and citrate synthase activity was assessed spectrophotometrically. Renal tissue analysis included phospho-AMPKα1 (measured by ELISA), Complex I activity, ATP, Malondialdehyde (MDA), superoxide dismutase (SOD) activity (measured spectrophotometrically), and PGC-1α mRNA expression (qRT-PCR). Renal tissues were examined under a light microscope for histopathological evaluation, followed by semi-quantitative scoring of glomerular and tubulointerstitial lesions, morphometric analysis of glomerular tuft area, and a composite score of cleaved caspase-3 immunoexpression. Results: Exercise increased skeletal muscle levels of irisin, PGC-1α, and citrate synthase activity. It also activated renal AMPK, improved mitochondrial function, increased PGC-1α mRNA levels, and reduced renal oxidative stress, as evidenced by decreased malondialdehyde (MDA) levels and restored superoxide dismutase (SOD) activity in obese rats. These changes were associated with improved renal function, reduced tubular injury and apoptosis in obese rats, partial restoration of the glomerular tuft area, lower lesion scores, and reduced cleaved caspase-3 immunoexpression. Conclusions: These findings suggest that irisin may mediate the renoprotective effects of exercise through the AMPK–PGC-1α pathway, highlighting swimming as a beneficial non-pharmacological intervention and supporting a potential adjunct role for irisin in managing obesity-related CKD. 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

Salmonella spp. is a major zoonotic pathogen. Although reptiles are mostly considered subclinical carriers, clinical disease may develop following immunosuppression. Clinical salmonellosis in reptiles has been extensively reported; however, the condition has been rarely described in bearded dragons (Pogona vitticeps). We retrospectively analyzed six cases of salmonellosis in bearded dragons and characterized the pathological, immunohistochemical, and bacteriological findings. Clinical signs and gross findings were mostly non-specific. Histological findings mainly consisted of fibrinonecrotizing enterocolitis (83.3%); necrotizing or granulomatous hepatitis (66.7%); pneumonia including bronchopneumonia or interstitial pneumonia in one case each (33.3%); tubulointerstitial nephritis with tubular necrosis (16.7%); and coelomitis (16.7%). Salmonella enterica subsp. houtenae was cultured in three cases (33.3%), whereas S. enterica subsp. enterica serovar Rissen, S. enterica subsp. enterica serovar Cotham, and S. enterica subsp. diarizonae were cultured in one case each. Intralesional bacteria were detected via immunohistochemistry in kidneys and colon in two cases (33.3%). The predominance of lesions in the intestines and liver likely reflects initial intestinal colonization followed by hematogenous dissemination to the liver. Hepatic lesions are thought to represent different stages along a continuum, progressing from acute necrosis to discrete granuloma formation. Renal and respiratory involvement was infrequent, as reported in other reptile species. Some of the isolated Salmonella subspecies (S. diarizonae and S. houtenae) are well-recognized causes of clinical disease in other reptile species but not previously identified in bearded dragons. This study provides a comprehensive pathological, immunohistochemical, and bacteriological characterization of salmonellosis in bearded dragons, thus raising awareness and assisting in the identification of this condition. Full article

A distinct form of chronic kidney disease of unknown etiology (CKDu) has emerged in tropical regions of Sri Lanka, predominantly affecting individuals aged 30–60 years in the North Central Province. Unlike conventional chronic kidney disease (CKD), CKDu occurs independently of diabetes or hypertension and is characterized by tubulointerstitial damage, including tubular atrophy, interstitial inflammation, and fibrosis. Epidemiological studies showed familial clustering, suggesting an underlying genetic predisposition. This study aimed to identify genetic variants associated with CKDu in Sri Lankan populations using whole-exome sequencing (WES). Eighty-six individuals (47 CKDu patients and 39 controls) were recruited from endemic and non-endemic regions. Physiological, biochemical, and geographic parameters were recorded. DNA extracted from blood was subjected to WES to identify variants associated with CKDu. Results: A total of 171 unique variants across 121 genes were identified. Among the most prevalent genes were ATXN3, LFNG, PNLDC1, LINC02456, and HLA-DRB1. In the case–control comparison, only LFNG showed statistically significant enrichment in affected individuals, whereas signals in ATXN3, PNLDC1, and LINC02456 were not statistically significant, but have an association with renal dysfunction, and thus are included as hypothesis-generating variant observations. HLA-DRB1 variants showed trends toward a protective haplotype. LFNG showed the greatest prevalence in affected individuals (71.7%), followed by PNLDC1 (63%), ATXN3 (56%), FIP1L1 (41%), and HLA-DRB1 (32%). Conclusion: Findings suggest genetic variants in combination with environmental factors may contribute to CKDu susceptibility in the Sri Lankan population. We underscore the multi-factorial nature of CKDu and highlight the need for integrative genomic and environmental research to elucidate disease mechanisms and inform targeted prevention strategies. Full article

Accurate segmentation of renal anatomical structures is essential for informed clinical decision-making in nephropathology, supporting precise diagnosis, treatment planning, and longitudinal monitoring of kidney diseases. In this work, we propose an Edge-Aware U-Net architecture with Boundary-Sensitive Optimization, specifically designed to address the challenges of fine anatomical boundary delineation in histopathological images. Comprehensive benchmarking against state-of-the-art models including U-Net, Attention U-Net, and ResUNet demonstrates robust quantitative performance alongside strong potential for clinical deployment. The proposed model achieves superior boundary preservation, reflected by a high structural similarity index (SSIM: 0.9473), while maintaining computational efficiency with an average inference time of 52 ms per image. It further outperforms existing methods across key image quality metrics, including PSNR (17.269 dB), MAE (0.0266), and RMSE (0.0321). Clinical validation indicates statistically significant improvements in glomerular detection (p < 0.01) and effective tubulointerstitial differentiation (F1-score: 0.891), with consistent performance observed across multiple staining protocols. Full article

Background: Hyperuricemia (HUA) is a metabolic disorder that severely threatens human health. Chronic uric acid (UA) overload promotes the progression of tubulointerstitial fibrosis (TIF), leading to impaired UA excretion. Our previous studies identified HIPK2 inhibitor XRF-1021, which exhibits robust anti-TIF activity and lowers UA levels in vivo. This study aimed to elucidate its UA-lowering mechanism and therapeutic potential for HUA. Methods: Uricase and xanthine oxidase (XOD) assays were performed to assess effects on UA degradation/production. HEK293T cells transiently expressing UA transporters and gene-knockdown rats were used to evaluate transporter inhibition, while HK-2 cells were analyzed by Western blot. Pharmacokinetics were characterized in rats. Efficacy was tested in potassium oxonate-induced acute HUA rats, diet/adenine-induced chronic HUA quails, and adenine-induced mice with HUA secondary to TIF. Maximum tolerated dose and long-term toxicity were assessed in rats. Results: XRF-1021 neither activated uricase nor inhibited XOD, indicating no direct effect on UA catabolism or synthesis. Instead, XRF-1021 inhibited URAT1 and GLUT9, reducing renal UA reabsorption, while sparing OAT3, OAT4, and ABCG2 activity and upregulating OAT3 and NPT4, suggesting minimal risk of disrupting drug or uremic toxin handling. XRF-1021 showed dose-dependent systemic exposure in rats, lowered serum UA, and provided renal protection in vivo. LD₅₀ values were 2345.4 mg/kg (male) and 1078.9 mg/kg (female), with no obvious toxicity after long-term dosing. Conclusions: XRF-1021 lowers UA by inhibiting URAT1 and GLUT9 to enhance renal UA excretion and provides kidney protection, supporting XRF-1021 as a promising candidate for HUA therapy. Full article

Background: In patients with diabetes or hypertension, if appropriate intervention is not initiated early in the course of kidney disease, not only does the risk of progressing to end-stage renal failure increase, but mortality associated with vascular complications also rises as the disease progresses; therefore, there is an urgent need to develop urinary biomarkers that enable early diagnosis and prediction of disease progression. Methods: This two-year prospective observational study involved 185 outpatients. Patients were classified into two groups based on their baseline urinary L-FABP levels relative to the reference value of 8.4 μg/g·Cr at the start of the study. The rate of eGFR decline during the observation period was evaluated. Results: The results showed an interaction (synergistic effect) between urinary L-FABP and time in patients with diabetes or hypertension who had an eGFR of at least 60 mL/min/1.732 m²/kg/1.732 m². Patients with high urinary L-FABP levels (>8.4 μg/g·Cr) exhibited a notably faster eGFR decline compared with those with low levels (≤8.4 μg/g·Cr). This finding suggests the potential of urinary L-FABP as a predictor of renal function decline; we evaluated this utility using the area under the ROC curve (AUC) and logistic regression analysis. The results indicate that urinary L-FABP holds potential as a predictor of renal function decline in diabetic or hypertensive patients with preserved eGFR. Conclusions: Among the analysis groups in which the validation was conducted, it was demonstrated that urinary L-FABP holds potential as a predictor of renal function decline in patients with diabetes or hypertension who have a maintained eGFR. Given that urinary L-FABP is thought to reflect tubulointerstitial damage associated with renal microcirculatory impairment, its future utility as a urinary biomarker for the early diagnosis and prognosis of chronic kidney disease (CKD) is anticipated. Full article

Background and Clinical Significance: Sarcoidosis is a systemic inflammatory disorder characterized by noncaseating granulomas. While pulmonary involvement is common, isolated renal involvement is rare and diagnostically challenging. We report a case emphasizing the utility of urinary tubular markers for early detection. Case Presentation: A 60-year-old woman with a history of suspected ocular sarcoidosis presented with progressive renal impairment and constitutional symptoms. Initial workup for systemic sarcoidosis was negative, leading to a misdiagnosis of chronic fatigue syndrome. Her rising serum creatinine was initially attributed to dehydration. However, a marked elevation in urinary β2-microglobulin (33,736 μg/L) prompted a renal biopsy, which revealed granulomatous tubulointerstitial nephritis. Following prednisolone therapy, her renal function improved, and her fatigue resolved completely. Conclusions: This case demonstrates that the kidney can be the primary site for histological diagnosis in the absence of pulmonary lesions. Incorporating urinary β2-microglobulin into routine monitoring may facilitate the early detection of renal sarcoidosis, preventing diagnostic delays. Full article

Chronic kidney disease (CKD) affects more than 10% of the population and is associated with a persistent, low-grade inflammatory state that accelerates tubulointerstitial fibrosis, worsens prognosis, and increases cardiovascular risk. This review aims to synthesize current knowledge on specialized pro-resolving mediators (SPMs) in the context of CKD pathophysiology, biomarkers, and therapeutic potential. We discuss key anti-inflammatory and pro-resolving mechanisms of SPMs that translate into nephroprotective and antifibrotic effects in experimental kidney models. The review summarizes data on EPA/DHA supplementation, including its impact on lipid profiles, inflammatory biomarkers (CRP, IL-6, TNF-α), and oxidative stress in patients with CKD. We also highlight contemporary analytical methods for biomarker assessment (LC-MS/MS, UHPLC-HRMS) and their potential for monitoring inflammatory activity across its phases (initiation, attenuation, resolution), CKD progression, and responses to ω-3/SPM-based interventions. Finally, we discuss the therapeutic potential of SPMs, as well as safety considerations and pharmacological interactions. In conclusion, SPMs and ω-3-derived mediators represent promising research and clinical targets as markers and modulators of inflammation in CKD, but require further validation in well-designed prospective studies. Full article

The increasing global burden of chronic kidney disease (CKD) magnifies an urgent need to find treatable targets. Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a chemokine secreted by kidney tubular epithelia in response to a variety of stimuli. To better understand the effects of tubular MCP-1 in response to kidney injury, we generated tubular epithelia-specific MCP-1 knockout mice (KO; Pax8-Mcp-1^fl/fl). We then exposed these mice and their control littermates to Adriamycin (Adr; 18 mg/kg, IV bolus). Thirty-two days after Adr injection, Mcp-1 transcript and protein levels were suppressed in the KO mice compared to their wild-type (WT) littermates. The KO mice exhibited no effect on survival, change in body weight, albuminuria, kidney function, glomerular or tubular injury, or tubulointerstitial fibrosis compared to WT. Overall, the results suggest that tubule-secreted MCP-1 is not necessary for progression of Adr-induced injury. These findings contribute to our understanding of the role of MCP-1 in kidney injury. Full article

One of the key pathological features of Diabetic Kidney Disease (DKD) progression is the accumulation of extracellular matrix (ECM) proteins in kidneys, leading to thickening of the glomerular and tubular basement membranes, subsequently resulting in mesangial expansion, sclerosis, and tubulointerstitial fibrosis. Given the high prevalence of DKD among both T2DM and T1DM patients, as well as the complexity of its underlying molecular mechanisms, this study provides a comparative analysis of published urinary proteomics datasets in DKD (n = 4). By integrating these data with published tissue proteomics (n = 2) and published transcriptomics datasets (n = 5), the study further aims to link urinary findings to tissue pathophysiology. Through integrative proteomic and transcriptomic analysis, DKD was associated with distinct alterations in the urinary proteome, particularly involving proteins related to ECM turnover. Using multiple validation datasets, several upregulated proteins with potential biological significance were identified, including annexins, collagens, cathepsins, and glycoproteins. Overall, our findings underscore the critical role of ECM remodeling in DKD progression and further validation could open new avenues for biomarker development and targeted therapy in early stages of DKD. Full article

Feline chronic kidney disease is a leading cause of mortality in geriatric cats, characterized by a progressive and irreversible loss of renal function. Despite its high prevalence, early diagnosis remains challenging due to nephron compensatory mechanisms and the limited sensitivity of traditional biomarkers, creating a diagnostic gap that necessitates the exploration of novel biomarkers for earlier detection. This review examines the complex pathophysiology of the disease, including renin–angiotensin–aldosterone system activation, tubulointerstitial fibrosis, and mineral metabolism disturbances. By analyzing recent scientific literature, this work evaluates current diagnostic landscape and clinical relevance of emerging biomarkers. Evidence indicates that symmetric dimethylarginine and fibroblast growth factor-23 improve detection of early metabolic and filtration changes, while urinary biomarkers like cystatin B and retinol-binding protein provide specific insights into tubular injury. Bridging the diagnostic gap requires a transition from a reactive, azotemia-based framework to a multi-parametric diagnostic approach that integrates novel biomarkers with serial clinical and laboratory monitoring. Although financial constraints and limited availability restrict widespread clinical implementation, incorporating these advances is essential for earlier prognostic stratification and timely therapeutic decision-making. This integrated strategy has the potential to slow disease progression and improve survival and quality of life in cats with chronic kidney disease. Full article