Search Results (228)

Primary hyperoxalurias (PHs) are rare autosomal recessive disorders characterized by overproduction of oxalate, a metabolic end product that readily forms calcium oxalate crystals. Excess hepatic oxalate leads to recurrent kidney stones, nephrocalcinosis, and progressive renal injury, often culminating in end-stage kidney disease (ESKD). Once renal clearance declines, systemic oxalate accumulation can cause multisystem deposition. PH encompasses three types—PH1, PH2, and PH3—caused by deficiencies in the hepatic enzymes AGT, GRHPR, and HOGA1, respectively, resulting in accumulation of glyoxylate and subsequent oxalate overproduction. Clinical presentation varies from infantile oxalosis to adult-onset recurrent nephrolithiasis, with PH1 generally being the most severe. Diagnosis relies on urinary oxalate measurements, plasma oxalate in advanced chronic kidney disease, urinary metabolite profiling, imaging, and genetic testing. Management includes hyperhydration, citrate supplementation, pyridoxine for responsive PH1 patients, dialysis and transplantation when required, while RNA interference therapies targeting glycolate oxidase or LDHA have demonstrated substantial biochemical efficacy in PH1 and represent promising emerging therapeutic options, although long-term clinical outcome data remain limited and broader applicability to other PH types is still under investigation. Future strategies focus on modulating intestinal oxalate absorption, gut microbiome therapies, oxalate-degrading enzymes, and novel gene-editing approaches. Early diagnosis and individualized management are critical to prevent kidney injury and systemic oxalosis. In this review, we summarize the genetic, biochemical, and clinical features of PH and discuss current and emerging therapeutic strategies. Full article

Calcium deposition within soft tissues is a significant pathological process, bearing significant implications for animal and human health. It is classified into four categories, including dystrophic, metastatic, idiopathic, and iatrogenic. It involves multiple molecular mechanisms. Vascular calcification includes medial artery mineralization, siderocalcinosis in equine cerebral arteries, and vitamin D-induced arterial mineralization in multiple species. Renal and urinary mineralization occurs with kidney disease, uremic gastropathy, and ethylene glycol toxicity. Calcinosis cutis is associated with renal insufficiency and systemic fungal infections and is commonly observed in dogs with hyperadrenocorticism, while calcinosis circumscripta occurs at pressure points secondarily to trauma. Multiple pathogens are responsible for soft tissue calcification; they can be zoonotic and include Mycobacterium spp., Brucella spp., Toxoplasma gondii, and Echinococcus granulosus, underscoring the translational role of veterinary medicine surveillance from a public health standpoint. In addition, the placental chorioallantois is frequently affected by idiopathic or infection-induced calcification, highlighting the convergence of metabolic dysregulation and infectious mechanisms. Tissue calcifications provide valuable insights into disease mechanisms and diagnostic challenges, with comparative pathology serving as a powerful tool to enhance our understanding of these processes from a One Health standpoint. Full article

Phosphate is emerging as an active mediator of oxidative stress and vascular injury in chronic kidney disease (CKD). This emerging pathophysiological framework, referred to as “Phosphatopathy”, describes the systemic syndrome driven by chronic phosphate overload and characterized by oxidative stress, inflammation, endothelial dysfunction, vascular calcification, cellular senescence, and metabolic imbalance. Beyond being a biochemical marker, phosphate overload triggers NOX-derived reactive oxygen species (ROS), activates Wnt/β-catenin and TGF-β signaling, and disrupts the FGF23–Klotho axis, promoting endothelial dysfunction, vascular calcification, and left ventricular hypertrophy (LVH). These pathways converge with systemic inflammation and energy imbalance, contributing to the malnutrition–inflammation–atherosclerosis (MIA) syndrome. Experimental and clinical data reveal that the phosphate/urinary urea nitrogen (P/UUN) ratio is a sensitive biomarker of inorganic phosphate load, while emerging regulators such as microRNA-125b and calciprotein particles integrate phosphate-driven oxidative and inflammatory responses. Therapeutic strategies targeting phosphate burden—rather than serum phosphate alone—include dietary restriction of inorganic phosphate, non-calcium binders, magnesium and zinc supplementation, and activation of important pathways related to the activation of antioxidant defense such as AMP-activated protein kinase (AMPK) and SIRT1. This integrative framework redefines phosphate as a modifiable upstream trigger of oxidative and metabolic stress in CKD. Controlling phosphate load and redox imbalance emerges as a convergent strategy to prevent vascular calcification, improve arterial stiffness, and reduce cardiovascular risk through personalized, mechanism-based interventions. Full article

Background: Cardiometabolic disorders such as hypertension and diabetes are major contributors to chronic kidney disease and often coexist, amplifying dysfunction and metabolic imbalance that favor renal injury and nephrolithiasis. Although pharmacological therapies exist for blood pressure and glycemic control, few target these mechanisms simultaneously. Rosmarinic acid (RA), a polyphenolic compound, exhibits antioxidant, anti-inflammatory, and nephroprotective effects, but its role in combined models of hypertension, diabetes, and nephrolithiasis remains unexplored. Objectives: This study investigated the therapeutic potential of RA in an experimental model combining hypertension, diabetes mellitus, and nephrolithiasis. Methods: Male Wistar spontaneously hypertensive (SHR) and normotensive rats were assigned to eight groups, including controls, comorbid groups, and treatments with RA (10 mg/kg) or hydrochlorothiazide (HCTZ; 5 mg/kg). Diabetes was induced by streptozotocin and nephrolithiasis by ethylene glycol plus ammonium chloride. Hemodynamic, biochemical, oxidative stress, and histological parameters were assessed. Results: SHR exhibited sustained hypertension, further aggravated by diabetes and nephrolithiasis. RA stabilized arterial pressure progression, whereas HCTZ significantly reduced blood pressure. RA and HCTZ treatments decreased urinary calcium oxalate crystal formation by 47.34 and 58.99%, respectively, and partially restored renal morphology. RA restored superoxide dismutase activity, preserved nitrite levels, and reduced lipid peroxidation, indicating antioxidant and endothelial protection. Neither treatment normalized glycemia or fully recovered renal function. Histological analysis showed attenuation of tubular and glomerular alterations in treated groups, particularly with RA. Conclusions: Overall, RA exerted antioxidant, nephroprotective, and antilithogenic effects in this complex comorbidity model, supporting its potential as a complementary therapeutic agent in chronic metabolic and renal disorders. Full article

(1) Background: this study aimed to determine whether a serum parathyroid hormone (PTH) threshold of 40 pg/mL represents a clinically relevant risk factor for vitamin D (VitD) deficiency and reduced bone mineral density (BMD). It also investigated potential genetic interactions influencing PTH regulation and skeletal health in patients with periodontitis. (2) Methods: a cross-sectional analysis was conducted on 1038 periodontitis patients (35–75 years). Serum PTH, VitD, calcium (Ca), phosphate (P), and urinary parameters were assessed. Dual-energy X-ray absorptiometry (DXA) was used to evaluate BMD in 261 subjects. Vitamin D Receptor (VDR) and estrogen receptor alpha (ERα) polymorphisms were genotyped, and composite genetic risk scores were calculated. Statistical analyses included correlation tests, subgroup comparisons, and regression models. (3) Results: sixty-two percent of individuals had PTH > 40 pg/mL, which was associated with significantly lower 25(OH)D and Ca levels and reduced T-scores (p < 0.05). PTH levels negatively correlated with BMD (Pearson’s r = –0.159, p = 0.0105). Patients with higher ERα polymorphism scores showed increased PTH values (p < 0.05), while VDR variants demonstrated a positive but no significant trend. (4) Conclusions: a PTH threshold of 40 pg/mL identifies individuals at higher risk of VitD deficiency and skeletal fragility, even without overt hypercalcemia. Genetic factors, particularly ERα variants, may contribute to elevated PTH levels, suggesting value in integrating biochemical, densitometric, and genetic screening for early bone health risk stratification. Full article

Background/Objectives: We evaluated serum and urinary biomarkers of bone and energy metabolism in an ovine osteoporosis model (Control, OVX, OVXD, OVXDS) at 0/3/8 months (M). Methods: Morning sampling; DXA (ROI ‘abdominal width’) and linear mixed models for repeated measures. Results: Only OVXDS showed severe DXA loss (Z-scores −3.29 at 3 M; −4.86 at 8 M), with ≈20% and ≈30% BMD reductions at 3 M and 8 M versus controls. OVX and OVXD remained within age-expected Z-score ranges at 8 M. At 3 M, OVXDS had hypocalcemia, markedly elevated UFEP, near-zero 25-OH-vitamin-D, and suppressed osteocalcin/NTX (depressed turnover). By 8 M, osteocalcin rose in OVXDS while NTX stayed low, consistent with altered coupling under chronic glucocorticoids and vitamin D deficiency. OVXD showed milder, later changes. Fructosamine and insulin were transiently higher in OVXDS at 3 M; IGF-1 was stable across groups/time. Conclusions: Combined ovariectomy, calcium/vitamin-D-deficient diet, and glucocorticoids produce the clearest biomarker signature and DXA loss. Assay cross-reactivity limited PTH/DKK-1/cathepsin-K measurement in sheep; we summarize DXA outcomes and expand assay limitations and future validation plans. Full article

Background/Objectives: To compare postoperative infectious complication rates after ureteroscopy (URS) in patients with anatomical anomalies of the urinary tract and neurogenic bladder to those in patients without these conditions, and to analyze associated risk factors, urine culture profiles, and stone composition in these special populations. Methods: This retrospective cohort study included patients undergoing URS at a single tertiary referral center. Patients were stratified into three groups: anatomical anomalies of the urinary tract (n = 23), neurogenic bladder (n = 30), and controls (n = 297). Demographic data, perioperative details, preoperative urine culture results, stone composition, and postoperative complications were collected and compared. Univariable analyses and chi-square or Kruskal–Wallis tests were used as appropriate. Results: Patients with anatomical anomalies of the urinary tract and neurogenic bladder had significantly higher rates of postoperative infectious complications compared to controls (30.4% and 33.3% vs. 4.0%; p < 0.001). Preoperative urine cultures were more frequently positive in these groups, with Escherichia coli, Enterococcus faecalis, and Pseudomonas aeruginosa being the most common pathogens. Stone analysis revealed a higher proportion of struvite and mixed calcium phosphate stones in the anatomical anomalies of the urinary tract and neurogenic bladder groups compared to controls, who predominantly formed calcium oxalate stones (75%). Conclusions: Patients with anatomical anomalies of the urinary tract or neurogenic bladder are at higher risk of postoperative infectious complications following URS, likely due to more frequent colonization and anatomical or functional urinary tract abnormalities. These findings underscore the importance of tailored perioperative management, including targeted antimicrobial strategies and careful surgical planning, to mitigate risks in these high-risk populations. Full article

Bladder dysfunction, particularly overactive bladder (OAB), is increasingly recognized as a clinical concern in patients with sickle cell disease (SCD), yet its pathophysiological mechanisms remain poorly understood. This study investigated the relationship between oxidative stress, inflammation, and bladder dysfunction in the Townes transgenic SCD mouse model. Cystometric analysis revealed that SCD mice exhibit an OAB phenotype, characterized by increased frequencies of voiding and non-voiding contractions and reduced bladder compliance. In vitro functional assays demonstrated detrusor hypocontractility in SCD mice, associated with a significant reduction in carbachol- and EFS-induced contractions and downregulation of muscarinic M3 receptor expression. Purinergic signaling and calcium-dependent contractility remained preserved. Molecular analyses showed increased mRNA expression of NOX-2 and IL-1β, and elevated protein levels of 3-nitrotyrosine and myeloperoxidase (MPO) activity, indicating redox imbalance and chronic inflammation in bladder tissue. Together, these changes suggest that oxidative and nitrosative stress, combined with inflammation, contribute to bladder remodeling and dysfunction in SCD. This is the first study to characterize bladder alterations in Townes SCD mice, establishing this model as a valuable tool for investigating lower urinary tract complications in SCD. Our findings provide mechanistic insight into the genitourinary manifestations of SCD and identify redox and inflammatory pathways as potential therapeutic targets for bladder dysfunction in affected individuals. Full article

Urinary tract infections (UTIs) are among the most prevalent infections in the human population. Uropathogenic Escherichia coli, the primary causative agent of UTIs, may also contribute to the development of metabolic kidney stones, particularly those composed of calcium oxalate. Kidney stone disease (KSD), known as nephrolithiasis or urolithiasis, is one of the most common disorders of the urinary system. This review explores the significant clinical association between UTIs and kidney stones, focusing on the mechanisms by which UPEC may promote stone formation, including oxidative stress, inflammation, and altered citrate metabolism. It also examines the role of immune responses, particularly macrophage activity, in the progression of KSD. Recent evidence suggests that the composition of the gut microbiota and metabolic imbalances have an additional impact on stone development. In light of these findings, current prevention and treatment strategies, including microbiota-targeted therapies, probiotics, and immune modulation, are also reviewed. Understanding the complex links between UTI, immunity, and metabolism provide new insights into the pathogenesis of KSD and allows for the development of more effective treatments for this disease. Full article

Primary hyperparathyroidism is nowadays a common endocrine disorder. Over time, the clinical manifestation has shifted from symptomatic cases to mostly asymptomatic diagnoses. Despite this, nephrolithiasis remains significant, often presenting as bilateral and recurrent, with the literature reporting prevalence rates of up to 40%. The nephrolithiasis pathogenesis in PHPT is multifactorial and not fully understood. While elevated PTH increases urinary calcium load, additional urinary abnormalities and demographic factors, including age and sex, influence the risk. Vitamin D status has also been explored as a possible contributor to stone formation both in the general population and in PHPT patients. The relationship between serum 25OHD levels and nephrolithiasis remains unclear, and the impact of vitamin D supplementation on stone risk in PHPT is still under investigation. The relationship between vitamin D status, supplementation and renal stones in PHPT is explored in the present review. Full article

Benign prostate hyperplasia (BPH) is characterized by prostate enlargement and dynamic alterations contributing to development of lower tract urinary symptoms (LUTS). Prostate hypercontractility has been proposed to contribute to BPH-related LUTS. The aim was to evaluate the effects of inhibiting stromal interaction molecule (STIM)/Orai calcium entry system on adrenergic and neurogenic contractions in prostate (HP) and bladder neck (HB) strips from BPH patients. Effects of STIM/Orai inhibition on adrenergic and neurogenic contractions of HP from organ donors (ODs) without BPH were also evaluated. HP and HB strips were obtained from 20 patients with BPH undergoing radical prostatectomy and from six OD at the time of organ collection for transplantation. Tissues were functionally evaluated for isometric tension recording. STIM-1, Orai1, and Orai3 protein expressions were determined in prostate tissues. STIM-1 was also localized by immunofluorescence in prostate sections. Norepinephrine-induced and neurogenic contractions were significantly reduced by STIM/Orai inhibition with YM-58483 (20 µM) in HP from BPH patients but not in tissues from ODs. STIM/Orai inhibition failed to significantly modify contraction of HB from BPH patients. Protein expression of STIM-1 was significantly elevated in HP from BPH patients. Functional contribution of STIM/Orai system to contractile tone is relevant in prostate when BPH is present, probably related to increased expression of STIM-1. Inhibition of STIM/Orai could have therapeutic implications for the management of BPH patients by alleviating prostatic hypercontraction. Full article

Background/Objectives: Menopause leads to estrogen deficiency, which negatively affects bone density, skin integrity, and hair health in women. This study aimed to evaluate the effects of fish-derived collagen peptides, calcium, and vitamin D3 supplementation on body composition, bone turnover markers, skin condition, and hair loss in menopausal women. Methods: Participants were randomized into four groups: placebo (G01), 1000 mg calcium + 400 IU vitamin D3 (G02), 5 g collagen (G03), and 1000 mg calcium + 400 IU vitamin D3 + 5 g collagen (G04). Participants received daily supplementation for six months. Body composition, biochemical bone markers (P1NP, BAP, osteocalcin), skin hydration, elasticity, transepidermal water loss (TEWL), and hair loss were assessed at baseline and follow-ups. Results: No significant changes were observed in body composition or bone biomarkers including P1NP, BAP, and osteocalcin across groups. Serum creatinine, ALT, and AST levels remained within normal ranges. Serum calcium levels remained stable, and urinary calcium excretion slightly increased in calcium-supplemented groups, indicating no adverse effects on kidney or liver function. G02 and G04 exhibited slightly decreased serum calcium levels compared to G01 and G03. However, G04 showed significantly improved skin hydration by 23% and skin elasticity by 8.52% compared to baseline after six months, whereas the placebo group showed negligible changes. G03 also showed notable improvement in elasticity by 12.23%, indicating collagen’s dominant role. The G02, G03, and G04 also significantly retarded hair shedding compared to the placebo (G01) group. TEWL did not significantly change in any group. Conclusions: These findings suggest that six-month supplementation with collagen peptides, particularly when combined with calcium and vitamin D, improves skin hydration and elasticity in menopausal women. Full article

Background: Cadmium (Cd) exposure is linked to cognitive decline in middle-aged and older adults, but the modifying role of essential minerals is unclear. This study aimed to identify key protective minerals and quantify their joint antagonistic effect against Cd neurotoxicity. Methods: Baseline serum minerals and urinary Cd were measured in 6795 adults (≥40 years) from the 2015 China Health and Nutrition Survey. Cognitive function (MMSE) was assessed after 3 years. Associations were analyzed using multiple linear regression and Quantile g-computation (QGC) for joint effects. Combined exposure groups and interaction terms were assessed. Restricted cubic spline (RCS) models explored potential nonlinear dose–response relationships. Results: Participants in the highest urinary Cd quartile had significantly lower MMSE score (β = −0.09, 95% CI: −0.15, −0.02) than the lowest quartile. Serum calcium (Ca), ferrum (Fe), magnesium (Mg), selenium (Se), and phosphorus (P) were positively associated with MMSE. QGC revealed that the joint effect of Cd and the 5-mineral mixture (β = 0.10, 95% CI: 0.05, 0.14) was weaker than the protective effect of the 5-mineral mixture. Any high-mineral group had significantly higher MMSE score compared to the high-Cd/low-mineral group. Conclusions: Essential minerals Ca, Fe, Mg, Se, and P effectively antagonize Cd-associated cognitive decline. Their combined exposure demonstrates significant protective effects, providing key evidence for precision nutrition and environmental health risk management in Cd-exposed populations. Full article

Hydrogen sulfide (H₂S) exerts regulatory functions in kidney diseases. However, its protective role against kidney stone formation remains unclear. Here, we demonstrate that hyperoxaluria or oxalate exposure impairs H₂S formation, leading to tubular injury and calcium oxalate (CaOx) crystal deposition in both in vivo and in vitro models. In male rats fed 5% hydroxy-L-proline (HP), time-dependent increases in urinary supersaturation, tubular damage, and renal CaOx deposition were observed compared to controls. These changes were associated with the decreased expression of H₂S-producing enzymes and elevated urinary secretion of osteopontin (OPN) and Tamm–Horsfall protein (THP). Notably, the protein level and activity of specificity protein 1 (Sp1), a transcription factor regulating these enzymes, were markedly decreased in HP-treated kidneys. Chronic supplementation with the H₂S donor GYY4137 (GYY) significantly attenuated HP-induced tubular injury and CaOx deposition by reducing OPN and THP secretion. Consistent with in vivo results, H₂S donors mitigated oxalate-induced tubular cell damage and CaOx formation in MDCK cells. Mechanistically, oxalate activated cyclic AMP/protein kinase A (PKA) signaling, which promoted OPN and THP secretion; these effects were eradicated by the PKA inhibitor H89 or GYY. These findings indicate that hyperoxaluria impairs Sp1 transcriptional activity, resulting in H₂S deficiency and compromised anticrystallization defense in oxalate-induced tubulopathy. Full article

Background and Objective: Information about the type of kidney stones is important for informed therapeutic decisions and the prevention of urolithiasis. Urinary stones are heterogeneous, and their elemental composition and crystal structure vary between patients. The formation of urinary stone deposits depends, among other things, on physiological conditions, the concentration of promoters and inhibitors of crystallization, and proteins found in the urine. The aim of this study was to determine differences in urine osteopontin (OPN) levels between groups of different stone-formers. Methods: Urinary stone specimens (n = 44) were acquired during elective endoscopic procedures. Specimens were divided into subgroups by k-means cluster analysis depending on calcium and phosphorus concentrations. The concentration of urine OPN was determined and compared for each subgroup and the control group. Results: Cluster analysis divided the deposits into three clusters. Cluster 1 contained mainly calcium oxalate deposits; Cluster 2 contained uric acid deposits; Cluster 3 contained deposits with a high content of calcium phosphate. Urine OPN concentration in CaP stone-formers (5.77 ng/mL) differed significantly from those of controls (17.05 ng/mL, p = 0.013) and CaOx stone-formers (15.31 ng/mL, p = 0.048). Conclusions: The concentration of urine OPN varies depending on the elemental composition of renal calculi. The lowest concentration of OPN was determined in the group of patients with a high content of calcium phosphate in the deposits. Full article