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Background: The prevalence of vascular calcification (VC) in chronic kidney disease (CKD) patients remains substantial, but currently, there are no effective pharmaceutical therapies available. BRCA1/BRCA2-containing complex subunit 36 (BRCC36) has been implicated in osteoblast osteogenic conversion; however, its specific role in VC remains to be fully elucidated. The aim of this study was to investigate the role and underlying mechanisms of BRCC36 in VC. Methods: The association between BRCC36 expression and VC was examined in radial arteries from patients with CKD, high-adenine-induced CKD mice, and vascular smooth muscle cells (VSMCs). Western blotting, real-time polymerase chain reaction, immunofluorescence, and immunohistochemistry were used to analyse gene expression. Gain- and loss-of-function experiments were performed to comprehensively investigate the effects of BRCC36 on VC. Coimmunoprecipitation and TOPFlash luciferase assays were utilized to further investigate the regulatory effects of BRCC36 on the Wnt/β-catenin pathway. Results: BRCC36 expression was downregulated in human calcified radial arteries, calcified aortas from CKD mice, and calcified VSMCs. VSMC-specific BRCC36 overexpression alleviated calcium deposition in the vasculature, whereas BRCC36 depletion aggravated VC progression. Furthermore, BRCC36 inhibited the osteogenic differentiation of VSMCs in vitro. Rescue experiments revealed that BRCC36 exerts the protective effects on VC partly by regulating the Wnt/β-catenin signalling pathway. Mechanistically, BRCC36 inhibited the Wnt/β-catenin pathway by decreasing the K63-linked ubiquitination of β-catenin. Additionally, pioglitazone attenuated VC partly through upregulating BRCC36 expression. Conclusions: Our research results emphasize the critical role of the BRCC36-β-catenin axis in VC, suggesting that BRCC36 or β-catenin may be promising therapeutic targets to prevent the progression of VC in CKD patients. [ABSTRACT FROM AUTHOR]

Background: Nephrocalcinosis (NC) is characterized by an excessive accumulation of calcium deposits in the kidneys. In children, it is often incidentally discovered with an uncertain prognosis. Case-diagnosis/treatment: A 3-month-old girl suspected to have a milk protein allergy underwent an ultrasound that revealed increased echogenicity in the kidney pyramids suggestive of medullary NC. At the age of 18 months, imaging findings revealed not only hyperechogenicity in the medulla but also in the cortex. Over the course of a long follow-up, her kidneys maintained size within the upper limits but showed an increase by age 7. Genetic analysis identified PKHD1 variants, which required structural predictive tools to guide clinical diagnosis. Until the age of 7, her kidney function has remained intact; however, her prognosis is uncertain. Conclusions: NC in newborns is a rare condition, but its incidence is rising. Recurrent urinary infections or kidney stones may lead to kidney failure. A proactive approach in sporadic NC enables an early diagnosis to orientate clinical supervision and facilitates counseling to support family planning decisions. [ABSTRACT FROM AUTHOR]

Vascular calcification is a crucial risk factor that affects the incidence and mortality of cardiovascular disease in chronic kidney disease patients. Modern medicine relies on calcium-phosphorus binding agents, calcium mimetics, active vitamin D, and hemodialysis to prevent and treat vascular calcification, however, their efficacy is unsatisfactory and adverse reactions often occur. Medical plant therapy can act as an integrative regulator in patients with chronic kidney disease-associated vascular calcification, which can significantly improve patients' symptoms, but its specific mechanism has not been fully elucidated yet. In this paper, we reviewed the domestic and international theoretical studies on the pathogenesis mechanism of chronic kidney disease-associated vascular calcification in recent years, summarized eight active ingredients of medicinal plants as well as four compound formulas for improving chronic kidney disease-associated vascular calcification, and explored the mechanism of action of herbal medicine, which will provide a new strategy for promoting the prevention and treatment of vascular calcification. [ABSTRACT FROM AUTHOR]

Randall's plaques (RP) serve as anchoring sites for calcium oxalate (CaOx) stones, but the underlying mechanism remains unclear. Renal interstitium with a high-calcium environment is identified as pathogenesis of RP formation where the role of human renal interstitial fibroblasts (hRIFs) was highlighted. Our study aims to elucidate the potential mechanism by which a high-calcium environment drives ectopic calcification of hRIFs to participate in RP formation. Alizarin Red staining demonstrated calcium nodules in hRIFs treated with high-calcium medium. Utilizing transcriptome sequencing, tissue factor pathway inhibitor-2 (TFPI-2) was found to be upregulated in high-calcium-induced hRIFs and RP tissues, and TFPI-2 promoted high-calcium-induced calcification of hRIFs. Subsequently, the downstream regulator of TFPI2 was screened by transcriptome sequencing analysis of hRIFs with TFPI-2 knockdown or overexpressed. Dachsous Cadherin Related 1 (DCHS1) knockdown was identified to suppress the calcification of hRIFs enhanced by TFPI-2. Further investigation revealed that TFPI-2/DCHS1 axis promoted high-calcium-induced calcification of hRIFs via disturbing the balance of ENPP1/ALP activities, but without effect on the canonical osteogenic markers, such as osteopontin (OPN), osteogenic factors runt-related transcription factor 2 (RUNX2), bone morphogenetic protein 2 (BMP2). In summary, our study mimicked the high-calcium environment observed in CaOx stone patients with hypercalciuria, and discovered that the high-calcium drove ectopic calcification of hRIFs via a novel TFPI-2-DCHS1-ALP/ENPP1 pathway rather than adaption of osteogenic phenotypes to participate in RP formation. [ABSTRACT FROM AUTHOR]

Introduction: Vascular calcification is accelerated in patients with chronic kidney disease (CKD) and increases the risk of cardiovascular events. CKD is frequently associated with anemia. Daprodustat (DPD) is a prolyl hydroxylase inhibitor for the treatment of CKD-associated anemia that enhances erythropoiesis through the activation of the hypoxia-inducible factor 1 (HIF-1) pathway. Studies showed that DPD promotes osteogenic differentiation of human aortic smooth muscle cells (HAoSMCs) and increases aorta calcification in mice with CKD. HIF-1 activation has been linked with endoplasmic reticulum (ER) stress; therefore, here we investigated the potential contribution of ER stress, particularly activating transcription factor 4 (ATF4), to the pro-calcification effect of DPD. Methods: Here, we used an adenine-induced CKD mouse model and HAoSMCs as an in vitro vascular calcification model to study the effect of DPD. Results: DPD treatment (15 mg/kg/day) corrects anemia but increases the expression of hypoxia (Glut1, VEGFA), ER stress (ATF4, CHOP, and GRP78), and osteo-/chondrogenic (Runx2, Sox9, BMP2, and Msx2) markers and accelerates aorta and kidney calcification in CKD mice. DPD activates the PERK/eIF2α/ATF4/CHOP pathway and promotes high phosphate-induced osteo-/chondrogenic differentiation of HAoSMCs. Inhibition of ER stress with 4-PBA or silencing of ATF4 attenuates HAoSMC calcification. DPD-induced ATF4 expression is abolished in the absence of HIF-1α; however, knockdown of ATF4 does not affect HIF-1α expression. Conclusion: We concluded that DPD induces ER stress in vitro and in vivo, in which ATF4 serves as a downstream effector of HIF-1 activation. Targeting ATF4 could be a potential therapeutic approach to attenuate the pro-calcific effect of DPD. [ABSTRACT FROM AUTHOR]

Simple Summary: This study explores kidney disease in young dogs, focusing on early diagnosis, management, and the importance of staging for effective treatment. Highlighting mineral metabolism imbalances and complications like nephrocalcinosis, the study presents a case of severe renal failure with uremic syndrome and bilateral nephrocalcinosis in a 50-day-old puppy. Despite intensive care, the puppy's condition worsened rapidly, leading to euthanasia. The study underscores the challenges in diagnosing and managing canine nephrocalcinosis in young animals. It emphasizes the need for further research to improve the understanding and treatment outcomes in such cases, enhancing the quality of life for animals suffering from this rare condition. This study explores kidney disease in young dogs, focusing on early diagnosis, management, and the importance of staging for effective treatment. Highlighting mineral metabolism imbalances and complications such as nephrocalcinosis, the study presents a case of severe renal failure with uremic syndrome and bilateral nephrocalcinosis in a 50-day-old puppy. Despite intensive care, the puppy's condition deteriorated rapidly, leading to euthanasia. The study underscores the challenges in diagnosing and managing canine nephrocalcinosis in young animals. It emphasizes the need for further research to improve the understanding and treatment outcomes in such cases, ultimately enhancing the quality of life for animals suffering from this rare condition. [ABSTRACT FROM AUTHOR]

Primary familial brain calcification (PFBC), also known as Fahr's disease, is a central nervous system calcium deposition disorder with symmetrical basal ganglia calcification. Most PFBC cases are caused by SLC20A2 gene variant. We report a Chinese female patient with PFBC and dopamine-responsive parkinsonism who had motor fluctuations and dyskinesia and recovered effectively after symptomatic medication adjustment. A novel heterozygous missense variant was found by whole-exome sequencing and proven harmful by family validation and genetic analysis. This example expands the phenotype of SLC20A2-associated PFBC patients and shows the clinical efficacy of dopaminergic replacement treatment. [ABSTRACT FROM AUTHOR]

Background: Ultrasound-guided kidney biopsy is an essential diagnostics method that can increase the accuracy of the differential diagnosis between acute and chronic nephropathies. In addition, it will help clinicians perform an etiologic diagnosis, issue a prognosis, and orient therapy for the majority of parenchymal nephropathies. Due to the relative invasiveness and potential adverse effects, the use of kidney biopsies is limited among practitioners. Results: Twenty-eight dogs, of mixed breed and variable ages, of which 11 (39, 29%) were males and 17 (60, 71%) were females, were examined and underwent an ultrasound-guided kidney biopsy to establish a definitive diagnosis. The patients were presented with a variety of diffuse nephropathies, such as kidney lymphoma: 1 (3.57%), glomerulonephritis: 13 (46.43%), tubulointerstitial nephritis: 11 (39.29%), and nephrocalcinosis. A total of 3 (10.71%) of 18 (64.29%) were in acute kidney injury, and 10 (35.71%) were CKD patients. The type and the severity of the kidney lesions were correlated with changes in the urinary n-acetyl-beta-d-glucosaminidase index (iNAG. To quantify the side effects of percutaneous kidney biopsy, the magnitude of post-biopsy hematuria and changes in urinary iNAG activity were evaluated. The results indicate a significant post-biopsy increase in the urinary iNAG activity in all the patients that underwent this procedure (100.08 ± 34.45 U/g), with a pre-biopsy iNAG vs. 147.65 ± 33.26 U/g post-biopsy iNAG (p < 0.001), suggesting an intensification in the kidney tubular damage that comes consecutives to kidney puncture and sampling. Transitory macro- or microhematuria were constant findings in all the dogs that underwent ultrasound-guided kidney biopsy, but the magnitude and extent could not be associated with the platelet count (PLT 109/L), aPTT (s), and PT (s) levels in our patients, and they were also resolved after 12–24 h without therapeutic interventions. Conclusions: Ultrasound-guided renal biopsy was shown to be a minimally invasive diagnostic procedure that causes transient and limited effects on kidney structures. Although these effects were minor and resolved without intervention, we feel that the benefit of obtaining higher-quality biopsied tissue outweighs the higher risks associated with this procedure. [ABSTRACT FROM AUTHOR]

Background: Lumasiran is the first RNA interference (RNAi) therapy of primary hyperoxaluria type 1 (PH1). Here, we report on the rapid improvement and even disappearance of nephrocalcinosis after early lumasiran therapy. Case-diagnosis/treatment: In patient 1, PH1 was suspected due to incidental discovery of nephrocalcinosis stage 3 in a 4-month-old boy. Bilateral nephrocalcinosis stage 3 was diagnosed in patient 2 at 22 months concomitantly to acute pyelonephritis. Urinary oxalate (UOx) and glycolate (UGly) were increased in both patients allowing to start lumasiran therapy before genetic confirmation. Nephrocalcinosis started to improve and disappeared after 27 months and 1 year of treatment in patients 1 and 2, respectively. Conclusion: These cases illustrate the efficacy of early lumasiran therapy in infants to improve and even normalize nephrocalcinosis. As proposed in the 2023 European guidelines, the interest of starting treatment quickly without waiting for genetic confirmation may have an impact on long-term outcomes. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) has emerged as one of the leading noncommunicable diseases affecting >10% of the population worldwide. Bone and mineral disorders are a common complication among patients with CKD resulting in a poor life quality, high fracture risk, increased morbidity and cardiovascular mortality. According to Kidney Disease: Improving Global Outcomes, renal osteodystrophy refers to changes in bone morphology found in bone biopsy, whereas CKD‐mineral and bone disorder (CKD‐MBD) defines a complex of disturbances including biochemical and hormonal alterations, disorders of bone and mineral metabolism and extraskeletal calcification. As a result, the management of CKD‐MBD should focus on the aforementioned parameters, including the treatment of hyperphosphatemia, hypocalcemia, abnormal PTH and vitamin D levels. Regarding the bone fragility fractures, osteoporosis and renal osteodystrophy, which constitute the bone component of CKD‐MBD, anti‐osteoporotic agents constitute the mainstay of treatment. However, a thorough elucidation of the CKD‐MBD pathogenesis is crucial for the ideal personalized treatment approach. In this paper, we review the pathology and management of CKD‐MBD based on the current literature with special attention to recent advances. [ABSTRACT FROM AUTHOR]

An increased prevalence of vascular calcification (VC) has been reported in kidney stone formers (KSFs), along with an elevated cardiovascular risk. The aim of the current study is to assess whether VC in these patients develops at a younger age and is influenced by stone composition. This single-center, matched case-control study included KSFs with uric acid or calcium oxalate stones (diagnosed based on stone analysis) and age- and sex-matched controls without a history of nephrolithiasis. The prevalence and severity of abdominal aortic calcification (AAC) and bone mineral density (BMD) were compared between KSFs and non-KSFs. In total, 335 patients were investigated: 134 with calcium oxalate stones, 67 with uric acid stones, and 134 controls. Overall, the prevalence of AAC was significantly higher among calcium stone formers than among the controls (67.9% vs. 47%, p = 0.002). In patients under 60 years of age, those with calcium oxalate stones exhibited both a significantly elevated AAC prevalence (61.9% vs. 31.3%, p = 0.016) and severity (94.8 ± 15.4 vs. 30.3 ± 15.95, p = 0.001) compared to the controls. Within the age group of 40–49, osteoporosis was identified only in the KSFs. Multivariate analysis identified age, smoking, and the presence of calcium stones as independent predictors of AAC. This study highlights that VC and osteoporosis occur in KSFs at a younger age than in non-stone-formers, suggesting potential premature VC. Its pathogenesis is intriguing and needs to be elucidated. Early evaluation and intervention may be crucial for mitigating the cardiovascular risk in this population. [ABSTRACT FROM AUTHOR]

Kidney stones are becoming increasingly common, affecting up to 10% of adults. A small percentage are of monogenic origin, such as Dent's disease (DD). DD is a syndrome that causes low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, and nephrocalcinosis. It is X-linked, and most patients have mutations in the CLCN5 gene. We performed a review of the literature and evaluated the case series (n = 6) of a single center in Spain, reviewing the natural evolution of kidney stones, clinical implications, laboratory analyses, radiological development, and treatment. All patients had a genetically confirmed diagnosis, with the CLCN5 mutation being the most frequent (66%). All patients had proteinuria and albuminuria, while only two and three presented hypercalciuria and phosphate abnormalities, respectively. Only one patient did not develop lithiasis, with most (60%) requiring extracorporeal shock wave lithotripsy or surgery during follow-up. Most of the patients are under nephrological follow-up, and two have either received a renal transplant or are awaiting one. The management of these patients is similar to that with lithiasis of non-monogenic origin, with the difference that early genetic diagnosis can help avoid unnecessary treatments, genetic counseling can be provided, and some monogenic kidney stones may benefit from targeted treatments. [ABSTRACT FROM AUTHOR]

Calcium‐sensing receptors (CaSRs) are G protein‐coupled receptors that help maintain Ca2+ concentrations, modulating calciotropic hormone release (parathyroid hormone (PTH), calcitonin and 1,25‐dihydroxyvitamin D) by direct actions in the kidneys, gastrointestinal tract and bone. Variability in population calcium levels has been attributed to single nucleotide polymorphisms in CaSR genes, and several conditions affecting calcium and phosphate homeostasis have been attributed to gain‐ or loss‐of‐function mutations. An example is autosomal dominant hypercalciuric hypocalcaemia, because of a missense mutation at codon 128 of chromosome 3, as reported in our specific case and her family. As a consequence of treating symptomatic hypocalcaemia as a child, this female subject slowly developed progressive end‐stage kidney failure because of nephrocalcinosis and nephrolithiasis. After kidney transplantation, she remains asymptomatic, with decreased vitamin D and elemental calcium requirements, stable fluid and electrolyte homeostasis during intercurrent illnesses and has normalised urinary calcium and phosphate excretion, reducing the likelihood of hypercalciuria‐induced graft impairment. We review the actions of the CaSR, its role in regulating renal Ca2+ homeostasis along with the impact of a proven gain‐of‐function mutation in the CaSR gene resulting in autosomal dominant hypercalciuric hypocalcaemia before and after kidney transplantation. [ABSTRACT FROM AUTHOR]

BACKGROUND: Vascular calcification, which is characterized by calcium deposition in arterial walls and the osteochondrogenic differentiation of vascular smooth muscle cells, is an actively regulated process that involves complex mechanisms. Vascular calcification is associated with increased cardiovascular adverse events. The role of 4-hydroxynonenal (4-HNE), which is the most abundant stable product of lipid peroxidation, in vascular calcification has been poorly investigated. METHODS: Serum was collected from patients with chronic kidney disease and controls, and the levels of 4-HNE and 8-isoprostaglandin F2α were measured. Sections of coronary atherosclerotic plaques from donors were immunostained to analyze calcium deposition and 4-HNE. A total of 658 patients with coronary artery disease who received coronary computed tomography angiography were recruited to analyze the relationship between coronary calcification and the rs671 mutation in aldehyde dehydrogenase 2 (ALDH2). ALDH2 knockout (ALDH2-/-) mice, smooth muscle cell--specific ALDH2 knockout mice, ALDH2 transgenic mice, and their controls were used to establish vascular calcification models. Primary mouse aortic smooth muscle cells and human aortic smooth muscle cells were exposed to medium containing β-glycerophosphate and CaCl2 to investigate cell calcification and the underlying molecular mechanisms. RESULTS: Elevated 4-HNE levels were observed in the serum of patients with chronic kidney disease and model mice and were detected in calcified artery sections by immunostaining. ALDH2 knockout or smooth muscle cell--specific ALDH2 knockout accelerated the development of vascular calcification in model mice, whereas overexpression or activation prevented mouse vascular calcification and the osteochondrogenic differentiation of vascular smooth muscle cells. In patients with coronary artery disease, patients with ALDH2 rs671 gene mutation developed more severe coronary calcification. 4-HNE promoted calcification of both mouse aortic smooth muscle cells and human aortic smooth muscle cells and their osteochondrogenic differentiation in vitro. 4-HNE increased the level of Runx2 (runt-related transcription factor-2), and the effect of 4-HNE on promoting vascular smooth muscle cell calcification was ablated when Runx2 was knocked down. Mutation of Runx2 at lysine 176 reduced its carbonylation and eliminated the 4-HNE--induced upregulation of Runx2. CONCLUSIONS: Our results suggest that 4-HNE increases Runx2 stabilization by directly carbonylating its K176 site and promotes vascular calcification. ALDH2 might be a potential target for the treatment of vascular calcification. [ABSTRACT FROM AUTHOR]

Background: Microscopic nephrocalcinosis is a common pathological feature of chronic kidney disease (CKD) in cats. Detection of macroscopic nephrocalcinosis using ultrasonography and its implications remain unexplored. Objectives: Identify risk factors associated with ultrasound‐diagnosed nephrocalcinosis and evaluate the influence of nephrocalcinosis on CKD progression. Animals: Thirty‐six euthyroid client‐owned cats with CKD. Methods: Prospective cohort study. Cats with CKD with and without ionized hypercalcemia were enrolled for renal ultrasonography. Cats were categorized according to the presence or absence of ultrasound‐diagnosed nephrocalcinosis. Binary logistic regression was performed to identify nephrocalcinosis risk factors. The influence of nephrocalcinosis on CKD progression was assessed using linear mixed models. Results: Ultrasound‐diagnosed nephrocalcinosis was evident in 61% of CKD cats overall, with increased prevalence (81%) in those with hypercalcemia. At enrollment, higher blood ionized calcium concentration (odds ratio [OR], 1.27 per 0.1 mg/dL; P =.01), plasma phosphate concentration (OR, 1.16 per 0.1 mg/dL; P =.05), plasma creatinine concentration (OR, 1.29 per 0.1 mg/dL; P =.02) and alanine aminotransferase activity (OR, 2.08 per 10 U/L; P =.04) were independent nephrocalcinosis risk factors. The rate of change in log‐transformed fibroblast growth factor‐23 differed significantly between groups (P =.04). Cats with CKD and nephrocalcinosis had increasing plasma creatinine concentrations (.03 ±.01 mg/dL/month; P =.04) and phosphate concentrations (.06 ±.02 mg/dL/month; P <.001) and decreasing body weight (.02 ±.01 kg/month; P <.001) over time. Conclusions and Clinical Importance: Nephrocalcinosis is prevalent in cats with CKD, especially in those with hypercalcemia. This pathological feature appears to be associated with CKD progression in cats. [ABSTRACT FROM AUTHOR]

Background: Identification of nephrocalcinosis in cats with chronic kidney disease (CKD) is of clinical interest but the ability of ultrasonography to detect nephrocalcinosis is uncertain. Objectives: To compare ultrasonography, micro‐computed tomography (μCT) and histopathology for identification of nephrocalcinosis. Animals: Twelve kidneys from 7 euthyroid client‐owned cats with CKD. Methods: Descriptive study. Renal ultrasonography was performed ante‐mortem for nephrocalcinosis detection. Kidneys were grouped based on nephrocalcinosis: present, suspected, or absent. When cats died, necropsy was performed. Renal tissue was evaluated using μCT for macroscopic nephrocalcinosis, and nephrocalcinosis volume‐to‐kidney tissue ratio (macro‐VN:KT) and sagittal nephrocalcinosis area‐to‐kidney tissue ratio (macro‐AN:KT) were calculated. Each kidney subsequently was bisected longitudinally, formalin‐fixed, and paraffin‐embedded for microscopic nephrocalcinosis assessment using von Kossa and Alizarin red staining with AN:KT (VK‐micro‐AN:KT and AR‐micro‐AN:KT) quantified using ImageJ. Data are presented as median (range). Relationships between macroscopic and microscopic AN:KT were assessed using Spearman's correlation. Results: Nephrocalcinosis by ultrasonography was considered to be absent in 3, suspected in 3, and present in 5 kidneys; 1 kidney had nephrolithiasis with nephrocalcinosis. The macro‐VN:KT was 0.001%, 0.001%, and 0.019%, and the macro‐AN:KT was 0.08%, 0.30%, and 1.47%, respectively. Histologically, VK‐micro‐AN:KT was 0.21%, 2.85%, and 4.56%, and AR‐micro‐AN:KT was 1.73%, 5.82%, and 8.90% for kidneys where ultrasonographic macro‐nephrocalcinosis was absent, suspected, or present, respectively. A strong correlation was identified between macroscopic (macro‐AN:KT) and microscopic (VK‐micro‐AN:KT) nephrocalcinosis (rs = 0.76; P =.01). Conclusions and Clinical Importance: Ultrasonographically diagnosed nephrocalcinosis correlates well with macroscopic and microscopic nephrocalcinosis at necropsy despite their separation in time. [ABSTRACT FROM AUTHOR]

Background: Enamel renal syndrome is a rare genetic disorder transmitted through an autosomal recessive mode. It is featured by a hypoplastic amelogenesis imperfecta, delayed tooth eruption, gingival fibromatosis, and nephrocalcinosis. The aim of this study was to describe clinically, radiologically, and histologically the main features of enamel renal syndrome and to point out the role of dentists in early diagnosing this genetic disease. Materials and methods: Our case of enamel renal syndrome was initially described by clinical, radiographic, and genealogic data, then complemented by ultrasound examination of the kidneys and microscopic observation of gingivae. Results: The study showed the presence of amelogenesis imperfecta (AI), several teeth impaction, gingival hyperplasia, bilateral nephrocalcinosis, and multiple calcifications in pulp, gingiva, dental follicle, and kidneys. Conclusion: The patient was followed for a full mouth rehabilitation and also referred to a nephrology for global medical checkup. The dentist plays a key role in diagnosing genetic diseases and in referring patients for medical comprehensive care. [ABSTRACT FROM AUTHOR]

This retrospective study aimed to compare risk factors for vascular calcification (VC) between pre-hemodialysis (HD) and prevalent HD adult patients while investigating associations with calcification biomarkers. Baseline data from 30 pre-HD and 85 HD patients were analyzed, including iPTH, vitamin D, FGF 23, fetuin-A, sclerostin, and VC scores (Adragao method). Prevalence of VC was similar in both groups, but HD patients had more frequent VC scores ≥ 6. Pre-HD patients were older, with higher prevalence of hypertension and less frequent use of calcium phosphate binders. Both groups showed similar patterns of hyperphosphatemia, low vitamin D, and iPTH. Fetuin-A and sclerostin levels were higher in pre-HD, while FGF 23 was elevated in HD patients. Higher VC risk in pre-HD patients was associated with male gender, older age, lower fetuin-A and higher sclerostin, lower ferritin, and no vitamin D treatment, while in HD patients with higher sclerostin, FGF 23 and urea, and lower iPTH. Conclusion: Biomarkers could be measurable indicators of biological processes underlying VC in CKD patients that may serve as a potential guide for considering personalized therapeutic approaches. Further studies are needed to elucidate the underlying pathways. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is a major threat to women's health globally. Early detection of breast cancer is crucial for saving lives. One important early sign is the appearance of breast calcification in mammograms. Accurate segmentation and analysis of calcification can improve diagnosis and prognosis. However, small size and diffuse distribution make calcification prone to oversight. Purpose: This study aims to develop an efficient approach for segmenting and quantitatively analyzing breast calcification from mammograms. The goal is to assist radiologists in discerning benign versus malignant lesions to guide patient management. Methods: This study develops a framework for breast calcification segmentation and analysis using mammograms. A Pro_UNeXt algorithm is proposed to accurately segment calcification lesions by enhancing the UNeXt architecture with a microcalcification detection block, fused-MBConv modules, multipleloss-function training, and data augmentation. Quantitative features are then extracted from the segmented calcification, including morphology, size, density, and spatial distribution. These features are used to train machine learning classifiers to categorize lesions as malignant or benign. Results: The proposed Pro_UNeXt algorithm achieved superior segmentation performance versus UNet and UNeXt models on both public and private mammogram datasets. It attained a Dice score of 0.823 for microcalcification detection on the public dataset, demonstrating its accuracy for small lesions. For quantitative analysis, the extracted calcification features enabled high malignant/benign classification, with AdaBoost reaching an AUC of 0.97 on the private dataset. The consistent results across datasets validate the representative and discerning capabilities of the proposed features. Conclusion: This study develops an efficient framework integrating customized segmentation and quantitative analysis of breast calcification. Pro_UNeXt offers precise localization of calcification lesions. Subsequent feature quantification and machine learning classification provide comprehensive malignant/benign assessment. This end-to-end solution can assist clinicians in early diagnosis, treatment planning, and follow-up for breast cancer patients. [ABSTRACT FROM AUTHOR]

Nephrolithiasis (NL) is a common condition worldwide. The incidence of NL and nephrocalcinosis (NC) has been increasing, along with their associated morbidity and economic burden. The etiology of NL and NC is multifactorial and includes both environmental components and genetic components, with multiple studies showing high heritability. Causative gene variants have been detected in up to 32% of children with NL and NC. Children with NL and NC are genotypically heterogenous, but often phenotypically relatively homogenous, and there are subsequently little data on the predictors of genetic childhood NL and NC. Most genetic diseases associated with NL and NC are secondary to hypercalciuria, including those secondary to hypercalcemia, renal phosphate wasting, renal magnesium wasting, distal renal tubular acidosis (RTA), proximal tubulopathies, mixed or variable tubulopathies, Bartter syndrome, hyperaldosteronism and pseudohyperaldosteronism, and hyperparathyroidism and hypoparathyroidism. The remaining minority of genetic diseases associated with NL and NC are secondary to hyperoxaluria, cystinuria, hyperuricosuria, xanthinuria, other metabolic disorders, and multifactorial etiologies. Genome-wide association studies (GWAS) in adults have identified multiple polygenic traits associated with NL and NC, often involving genes that are involved in calcium, phosphorus, magnesium, and vitamin D homeostasis. Compared to adults, there is a relative paucity of studies in children with NL and NC. This review aims to focus on the genetic component of NL and NC in children. [ABSTRACT FROM AUTHOR]

Background Fetuin-A is implicated in the pathogenesis of vascular calcification in chronic kidney disease (CKD); however, the relationship between fetuin-A, histopathologic lesions and long-term kidney outcomes in patients with various types of kidney disease remains unclear. Methods We measured urinary fetuin-A levels in 335 individuals undergoing clinically indicated native kidney biopsy. The expressions of fetuin-A mRNA and protein in the kidney were assessed using RNA sequencing and immunohistochemistry. The association of urinary fetuin-A with histopathologic lesions and major adverse kidney events (MAKE), defined as a decline in estimated glomerular filtration rate (eGFR) of at least 40%, kidney failure or death, was analyzed. Results Urinary fetuin-A levels showed a positive correlation with albuminuria (rs = 0.67, P  < .001) and a negative correlation with eGFR (rs = –0.46, P  < .001). After multivariate adjustment, higher urinary fetuin-A levels were associated with glomerular inflammation, mesangial expansion, interstitial fibrosis and tubular atrophy, and arteriolar sclerosis. Using a 1 transcript per million gene expression cutoff, we found kidney fetuin-A mRNA levels below the threshold in both individuals with normal kidney function and those with CKD. Additionally, immunohistochemistry revealed reduced fetuin-A staining in tubular cells of CKD patients compared with normal controls. During a median 21-month follow-up, 115 patients experienced MAKE, and Cox regression analysis confirmed a significant association between elevated urinary fetuin-A and MAKE. This association remained significant after adjusting for potential confounding factors. Conclusion Urinary fetuin-A is associated with chronic histological damage and adverse clinical outcomes across a spectrum of biopsy-proven kidney diseases. [ABSTRACT FROM AUTHOR]

Polycystic kidney disease (PKD) is a leading cause of end-stage renal disease. PKD arises from mutations in proteins, one a Ca2+ -conducting channel, expressed in the primary cilia of renal epithelial cells. A common hypothesis is that Ca2+ entering through ciliary ion channels may reduce cystogenesis. The cilia have at least two Ca2+ -conducting channels: polycystin-2 (PC2) and TRPV4 (transient receptor potential (TRP) cation channel, subfamily V, member 4), but how substantially they can increase intraciliary Ca2+ is unknown. By recording channel activities in isolated cilia, conditions are identified under which the channels can increase free Ca2+ within the cilium by at least 500-fold through regenerative (positive-feedback) signaling. Ca2+ that has entered through a channel can activate the channel internally, which increases the Ca2+ influx, and so on. Regenerative signaling is favored when the concentration of the Ca2+ buffer is reduced or when a slower buffer is used. Under such conditions, the Ca2+ that enters the cilium through a single PC2 channel is sufficient to almost fully activate that same channel. Regenerative signaling is not detectable with reduced external Ca2+ . Reduced buffering also allows regenerative signaling through TRPV4 channels, but not through TRPM4 (TRP subfamily M, member 4) channels, which are activated by Ca2+ but do not conduct it. On a larger scale, Ca2+ that enters through TRPV4 channels can cause secondary activation of PC2 channels. I discuss the likelihood of regenerative ciliary Ca2+ signaling in vivo, a possible mechanism for its activation, and how it might relate to cystogenesis. [ABSTRACT FROM AUTHOR]

This document is a letter published in the journal Blood Purification. The authors describe two additional cases of patients with metformin accumulation who were treated with continuous renal replacement therapy (CRRT) and regional citrate anticoagulation (RCA). The patients were successfully treated with diluted citrate during CRRT, and no signs of citrate accumulation were observed. The authors conclude that these findings support the safety of using diluted citrate in patients with metformin accumulation during CRRT, but emphasize the importance of close monitoring for signs of citrate accumulation. [Extracted from the article]

Five hundred and eighty-six kidney samples were screened to establish the diversity of renal disorders in pigs irrespective of age, sex and breed at organised and unorganised farms of Bikaner, Jaipur and Alwar districts of Rajasthan. Out of 586 specimens, a total of 154 kidneys revealed macroscopic lesions. In five(3.25 per cent) cases of nephrocalcinosis without stone and 2(1.30 per cent) cases with stone, kidneys without stone and with stone on medullary and cortical region were processed for further histopathological examination at the Department of Veterinary Pathology, Bikaner. The gross lesion showed white streaks in colour on the medullar and cortical surface of kidney and nephrolithiasis. The surface appeared whitish in colour, shiny in appearance and hard in consistency. Histopathological examination revealed calcification of tubular epithelium and some glomeruli. Severe expansion of the interstitium by inflammatory cells, consisting predominantly of lymphocytes and fibrosis of tissue were also observed. [ABSTRACT FROM AUTHOR]

Objective: The present study compared the clinical features of patients with primary Sjögren's syndrome (pSS) with and without nephrolithiasis and/or nephrocalcinosis to determine factors related to renal dysfunction. Methods: The clinical features of 68 patients with anti-Sjogren's syndrome antigen A (SSA)/Ro-antibody–positive pSS with and without nephrolithiasis and/or nephrocalcinosis who underwent abdominal computed tomography and/or ultrasonography were retrospectively analysed. Results: Of the 68 patients with anti-SSA-antibody–positive pSS, 23 (33%) had renal nephrolithiasis and/or nephrocalcinosis, whereas 45 (67%) did not. Fourteen (20%) patients had renal dysfunction at diagnostic imaging. Among five patients who underwent renal biopsy, four patients with renal nephrolithiasis and/or nephrocalcinosis were diagnosed with tubulointerstitial nephritis, and one without nephrolithiasis and/or nephrocalcinosis was diagnosed with minimal change nephrotic syndrome. Estimated glomerular filtration rate at diagnostic imaging was significantly lower in patients with than without nephrolithiasis and/or nephrocalcinosis group (P = 0.010). In addition to nephrolithiasis and/or nephrocalcinosis (odds ratio [OR], 3.467; P = 0.045), the gap between serum sodium and chloride concentrations (OR, 10.400; P = 0.012) and increased urinary β2-microglobulin (OR, 5.444; P = 0.033) were associated with renal dysfunction at the time of diagnostic imaging. Conclusion: Nephrolithiasis and/or nephrocalcinosis, normal anion gap metabolic acidosis, and tubulointerstitial damage are associated with renal dysfunction in patients with pSS. [ABSTRACT FROM AUTHOR]

Approximately 1% of all patients with Sjögren's syndrome (SS) are children. Unlike the adult form, in which sicca syndrome is the main presentation, in children, the most common clinical finding is recurrent enlargement of the salivary glands. In pediatric SS, extraglandular manifestations represent a significant feature and, among these, kidney manifestations are relevant. Kidney involvement is observed in 5–20.5% of children with SS, most frequently tubulointerstitial nephritis. This injury can lead to serious phenotypes, including distal kidney tubular acidosis with the development of severe hypokalemia, which can lead to ECG abnormalities, weakness, and hypokalemic periodic paralysis. Kidney implications in pediatric SS also include nephrolithiasis, nephrocalcinosis, and various types of glomerular damage, which often require immunosuppressive therapies. Laboratory findings are usually comparable to adults, including hyperglobulinemia and high rates of antinuclear antibodies (ANA, 63.6–96.2%), and anti-Ro/SSA (36.4–84.6%). The current classification criteria for SS are inaccurate for the pediatric population, and more specific criteria are needed to improve the diagnostic rate. Due to the rarity of the disease, strong recommendations for treatment are lacking, and several therapeutic strategies have been reported, mostly based on glucocorticoids and disease-modifying antirheumatic drugs, with different outcomes. The aim of this paper is to provide an overview of the kidney implications of pediatric SS based on the latest evidence of the medical literature. [ABSTRACT FROM AUTHOR]

Objectives: To identify etiologic variants and perform deep dental phenotyping in patients with amelogenesis imperfecta (AI). Methods: Three patients of two unrelated families were evaluated. Genetic variants were investigated by exome and Sanger sequencing. An unerupted permanent third molar (AI1) from Patient1 and a deciduous first molar (AI2) from Patient2, along with three tooth‐type matched controls for each were characterized. Results: All three patients harbored biallelic pathogenic variants in FAM20A, indicating AI1G. Of the four identified variants, one, c.1231C > T p.(Arg411Trp), was novel. Patient1 possessed the largest deletion, 7531 bp, ever identified in FAM20A. In addition to hypoplastic enamel, multiple impacted teeth, intrapulpal calcification, pericoronal radiolucencies, malocclusion, and periodontal infections were found in all three patients, gingival hyperplasia in Patient1 and Patient2, and alveolar bone exostosis in Patient3. Surface roughness was increased in AI1 but decreased in AI2. Decreased enamel mineral density, hardness, and elastic modulus were observed in AI1 enamel and dentin and AI2 dentin, along with decreased phosphorus, increased carbon, and increased calcium/phosphorus and carbon/oxygen ratios. Severely collapsed enamel rods and disorganized dentin–enamel junction were observed. Conclusions: We report a novel FAM20A variant and, for the first time, the defective mineral composition and physical/mechanical properties of AI1G teeth. [ABSTRACT FROM AUTHOR]

In patients with severe aorto-iliac calcifications, vascular reconstructions can be performed in order to allow kidney transplantation. The aim of this study was to analyze the outcomes of kidney transplant candidates who underwent an aortobifemoral bypass (ABFB) for aorto-iliac calcifications. A retrospective study including all kidney transplant candidates who underwent an ABFB between 2012 and 2022 was performed. Primary outcome was 30-day morbidity-mortality after ABFB. Secondary outcome was accessibility to kidney transplant waiting list. Twenty-two ABFBs were performed: 10 ABFBs in asymptomatic patients presenting severe aorto-iliac circumferential calcifications without hemodynamic consequences, and 12 ABFBs in symptomatic patients in whom aorto-iliac calcifications were responsible for claudication or critical limb threatening ischemia. Overall 30-day mortality was 0%. Overall 30-day morbidity was 22.7%: 1 femoral hematoma and 1 retroperitoneal hematoma requiring surgical drainage in the asymptomatic group, and 2 digestive ischemia requiring bowel resection and 1 femoral hematoma requiring surgical drainage in the symptomatic group. Among the 22 patients, 20 patients could access to kidney waiting list and 8 patients underwent a kidney transplantation, including 3 living-donor transplantations. Aorto-iliac revascularization can be an option to overcome severe calcifications contraindicating kidney transplantation. [ABSTRACT FROM AUTHOR]

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHNNC) is a rare autosomal recessive renal tubulopathy disorder characterized by excessive urinary loss of calcium and magnesium, polyuria, polydipsia, bilateral nephrocalcinosis, progressive chronic kidney disease, and renal failure. Also, sometimes amelogenesis imperfecta and severe ocular abnormalities are involved. The CLDN-16 and CLDN-19 genes encode the tight junction proteins claudin-16 and claudin-19, respectively, in the thick ascending loop of Henle in the kidney, epithelial cells of the retina, dental enamel, etc. Loss of function of the CLDN-16 and/or CLDN-19 genes leads to FHHNC. We present a case of FHHNC type 1, which was first confused with autosomal dominant hypocalcaemia (ADH) due to the presence of a very low serum parathyroid hormone (PTH) concentration and other similar clinical features before the genetic investigations. After the exome sequencing, FHHNC type 1 was confirmed by uncovering a novel homozygous missense mutation in the CLDN-16 gene (Exon 2, c.374 T > C) which causes, altered protein structure with F55S. Associated clinical, biochemical, and imaging findings also corroborate final diagnosis. Our findings expand the spectrum of the CLDN-16 mutation, which will further help in the genetic diagnosis and management of FHNNC. [ABSTRACT FROM AUTHOR]

Lumasiran (Oxlumo®), a first-in-class synthetic, double-stranded, ribonucleic acid (RNA) interference molecule targeting glycolate oxidase through silencing HAO1 mRNA, is approved in several countries for patients of any age and stage of kidney function with primary hyperoxaluria type 1 (PH1). Approval was based on results from the phase III ILLUMINATE trials. In the double-blind, placebo-controlled, ILLUMINATE-A trial, subcutaneous lumasiran was significantly more effective than placebo in reducing 24-h urinary oxalate excretion in patients aged ≥ 6 years with PH1; this effect was sustained for ≥ 36 months in ongoing longer-term analyses. In the single-arm ILLUMINATE-B trial, lumasiran reduced urinary oxalate:creatinine ratios and plasma oxalate levels in patients aged < 6 years with PH1. In the single-arm ILLUMINATE-C trial, lumasiran reduced plasma oxalate levels in patients with PH1 receiving dialysis as well as those not receiving dialysis. In secondary and exploratory analyses of these trials, nephrocalcinosis grade, kidney stone event rates and estimated glomerular filtration rates were either stable or improved with lumasiran. Lumasiran had an acceptable tolerability profile that remained consistent in longer-term analyses; the most common adverse events were mild and transient injection-site reactions. Thus, lumasiran is an effective treatment option, with an acceptable tolerability profile, in patients with PH1. Plain Language Summary: Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder that leads to excess oxalate in urine or plasma requiring removal by the kidneys. This overproduction is damaging and can lead to kidney failure. Management of PH1 is typically not curative, eventually ending in kidney and/or liver transplantation. Lumasiran (Oxlumo®) is the first medicine to be approved in several countries for use in patients with PH1, regardless of their age or level of kidney function. It reduces liver oxalate production, lessening damage to the kidneys and potentially reducing the need for organ transplantation. In clinical trials, lumasiran was effective in reducing oxalate levels (in urine and/or plasma) in patients of all ages with PH1, and irrespective of whether they were receiving dialysis or not. Lumasiran either improved or stabilized the severity of calcium deposition in the kidneys, number of kidney stone events and kidney function. Lumasiran had an acceptable tolerability profile; the most common side effects were mild injection-site reactions that resolved quickly. Thus, lumasiran is an effective treatment option, with an acceptable tolerability profile, in patients with PH1. [ABSTRACT FROM AUTHOR]

Patients with mutations in Cldn16 suffer from familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) which can lead to renal insufficiency. Mice lacking claudin-16 show hypomagnesemia and hypercalciuria, but no nephrocalcinosis. Calcium oxalate and calcium phosphate are the most common insoluble calcium salts that accumulate in the kidney in the case of nephrocalcinosis, however, the formation of these salts is less favored in acidic conditions. Therefore, urine acidification has been suggested to limit the formation of calcium deposits in the kidney. Assuming that urine acidification is causative for the absence of nephrocalcinosis in the claudin-16-deficient mouse model, we aimed to alkalinize the urine of these mice by the ablation of the subunit B1 of the vesicular ATPase in addition to claudin-16. In spite of an increased urinary pH in mice lacking claudin-16 and the B1 subunit, nephrocalcinosis did not develop. Thus, urinary acidification is not the only factor preventing nephrocalcinosis in claudin-16 deficient mice. [ABSTRACT FROM AUTHOR]

Vascular calcification (VC) has emerged as a key predictor of cardiovascular events in patients with chronic kidney disease (CKD). In recent years, an expanding body of research has put forth the concept of accelerated vascular aging among CKD patients, highlighting the significance of vascular cells senescence in the process of VC. Within the milieu of uremia, senescent vascular endothelial cells (VECs) release extracellular microvesicles (MV) that promote vascular smooth muscle cells (VSMCs) senescence, thereby triggering the subsequent osteogenic phenotypic switch and ultimately contributing to the VC process. In addition, senescent vascular progenitor or stem cells with diminished ability to differentiate into VECs and VSMCS, compromise the repair of vascular integrity, on the other hand, release a cascade of molecules associated with senescence, collectively known as the senescence-associated secretory phenotype (SASP), perpetuating the senescence phenomenon. Furthermore, SASP triggers the recruitment of monocytes and macrophages, as well as adjacent VECs and VSMCs into a pro-adhesive and pro-inflammatory senescent state. This pro-inflammatory microenvironment niche not only impacts the functionality of immune cells but also influences the differentiation of myeloid immune cells, thereby amplifying the reduced ability to effectively clear senescent cells of senescent macrophages, promoted calcification of VSMCs. The objective of this paper is to provide a comprehensive review of the contribution of vascular cell senescence to the emergence and advancement of VC. Gaining a comprehensive understanding of the involvement of cellular senescence within the vessel wall is pivotal, especially when it comes to its intersection with VC. This knowledge is essential for advancing groundbreaking anti-aging therapies, aiming to effectively mitigate cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Nephrocalcinosis is a common problem faced in both paediatrics and neonates, which may need referral on to paediatric nephrology. This 15 min consultation aims to look at children of different age groups (neonates, children 1-5 years old and older children) looking particularly at history, examination, causes, initial investigations and management. [ABSTRACT FROM AUTHOR]

Background: Severe coronary artery calcification is associated with low success rate of interventional operation, perioperative adverse cardiac events, and poor prognosis, which is a major problem faced by operators. The existing therapy methods all have inherent limitations, such as unsatisfactory balloon crossability, inadequate balloon dilation, and so on. The emergence of intravascular lithotripsy (IVL) has brought the dawn of the treatment of calcified lesions by using unfocused acoustic pressure waves to fracture calcification in situ. And IVL is the only technology capable of targeting deep calcification. Hypothesis: IVL may have great clinical application values and potential prospects. Method: Based on the existing clinical evidence of IVL and traditional treatment ways, this review discusses the safety and efficacy of IVL. Combined with clinical practice, the precautions and coping strategies of IVL are analyzed. And the review improves the management algorithm of coronary calcification. Results: IVL has extremely high safety and effectiveness for severe coronary calcification compared with other ways, and structural improvements of IVL will further expand its value. Conclusions: The emergence of IVL could set off a revolution in the treatment of coronary artery calcification. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease (CVD) is the primary cause of mortality in chronic kidney disease (CKD) patients, with metabolic disorders exacerbating this risk. Compared with body mass index, waist circumference (WC) has been proposed as a more effective indicator of abnormal visceral fat. However, the associations among CKD, abnormal WC, and CVD remain understudied. Material and Methods: A cross-sectional study in Taiwan (July 2006 to May 2016) involved 10,342 participants undergoing self-paid health checkups at a single medical center. Physical examinations and blood samples were taken to assess metabolic parameters, and renal function was evaluated using the Chronic Kidney Disease Epidemiology Collaboration formula. Coronary artery calcification (CAC) scores were determined through coronary 256-slice multidetector computed tomography angiography, with a CAC score of > 0 Agatston unit (AU) and ≥ 400 AU denoting positive CAC and severe CAC, respectively. Results: Sex-based comparisons were conducted between individuals with CKD and those without CKD. In the CKD group, both sexes exhibited significantly elevated levels for systolic blood pressure, serum fasting blood glucose (FBG), and hemoglobin A1c (HbA1c) as well as reduced serum high-density lipoprotein cholesterol. Examination of the associations of abnormal WC revealed that for both sexes, individuals with abdominal obesity (AO) were significantly older and had higher systolic/diastolic blood pressure, serum FBG, HbA1c, and lipid profiles compared with those without AO. Multiple logistic regression analysis revealed that CKD patients exhibited a more pronounced association with severe CAC scores compared with AO patients (odds ratios [ORs]: 2.7 and 1.4, respectively). Furthermore, the combined effects of AO and CKD (AO[+]/CKD[+]) resulted in increased risks of positive CAC (OR: 2.4, 95% confidence interval [CI]: 1.6– 3.5) and severe CAC (OR: 4.4, 95% CI: 1.4– 14.2). Conclusion: Abdominal obesity significantly raised the odds of CAC and was associated to a 4.4-fold increased risk of severe CAC in CKD patients. [ABSTRACT FROM AUTHOR]

Magnesium (Mg) plays crucial roles in multiple essential biological processes. As the kidneys are the primary organ responsible for maintaining the blood concentration of Mg, people with chronic kidney disease (CKD) may develop disturbances in Mg. While both hyper- and hypomagnesemia may lead to adverse effects, the consequences associated with hypomagnesemia are often more severe and lasting. Importantly, observational studies have shown that CKD patients with hypomagnesemia have greater vascular calcification. Vascular calcification is accelerated and contributes to a high mortality rate in the CKD population. Both in vitro and animal studies have demonstrated that Mg protects against vascular calcification via several potential mechanisms, such as inhibiting the formation of both hydroxyapatite and pathogenic calciprotein particles as well as limiting osteogenic differentiation, a process in which vascular smooth muscle cells in the media layer of the arteries transform into bone-like cells. These preclinical findings have led to several important clinical trials that have investigated the effects of Mg supplementation on vascular calcification in people with CKD. Interestingly, two major clinical studies produced contradictory findings, resulting in a state of equipoise. This narrative review provides an overview of our current knowledge in the renal handling of Mg in health and CKD and the underlying mechanisms by which Mg may protect against vascular calcification. Lastly, we evaluate the strength of evidence from clinical studies on the efficacy of Mg supplementation and discuss future research directions. [ABSTRACT FROM AUTHOR]

Background: Chronic kidney disease (CKD) is now globally recognized as a critical public health concern. Vascular calcification (VC) represents a significant risk factor for cardiovascular events in individuals with CKD. It is the accessible and precise diagnostic biomarkers for monitoring the progression of CKD and the concurrent VC are urgently needed. Methods: The adenine diet-induced CKD rat model was utilized to investigate chronic kidney injury, calcification in the kidney and thoracic aorta, and dysregulation of biochemical indices. Enzyme-linked immune sandwich assays were employed to analyze changes in calcification-related proteins. 16S rRNA sequencing was performed to delineate the microbiota characteristics in the gut and blood of CKD-afflicted rats. Additionally, transcriptome sequencing of kidney tissue was conducted to explore the relationship between CKD-associated microbiota features and alterations in kidney function. Results: The adenine diet-induced CKD inhibited body weight gain, and led to kidney injury, and pronounced calcification in kidney and thoracic aorta. The microbiota both in the gut and blood of these affected rats exhibited significantly lower alpha diversity and distinctive beta diversity than those in their healthy counterparts. CKD resulted in dysregulation of several biochemical indices (including elevated levels of creatinine, low-density lipoprotein-cholesterol, sodium, phosphorous, total cholesterol, and urea and decreased levels of albumin, calcium, lactate dehydrogenase, and total bilirubin). Moreover, it upregulated calcification-related factors (bone sialoprotein [BSP], Klotho, fibroblast growth factor [FGF]-23, and sclerostin [SOST]) and lipopolysaccharide (LPS). Notably, the increased Acinetobacter in the blood was positively associated with calcifications in the kidney and thoracic aorta, in addition to the positive correlation with gut microbiota. The enrichment of Acinetobacter was concurrent with increases in calcification factors (BSP, FGF- 23, and SOST), LPS, and phosphorous. Furthermore, transcriptome sequencing revealed that the enrichment of Acinetobacter was positively correlated with the majority of upregulated genes and negatively correlated with downregulated genes involved in the mineral absorption pathway. Conclusion: Our findings, for the first time, underscore that dysbiosis of symbiotic microbiota, both in the gut and blood, is involved in the progression of CKD. Particularly, the enrichment of Acinetobacter in blood emerges as a potential risk factor for CKD and its accompanying VC. [ABSTRACT FROM AUTHOR]

Background: Primary hyperoxaluria type 1 (PH1) is a rare, severe genetic disease causing increased hepatic oxalate production resulting in urinary stone disease, nephrocalcinosis, and often progressive chronic kidney disease. Little is known about the natural history of urine and plasma oxalate values over time in children with PH1. Methods: For this retrospective observational study, we analyzed data from genetically confirmed PH1 patients enrolled in the Rare Kidney Stone Consortium PH Registry between 2003 and 2018 who had at least 2 measurements before age 18 years of urine oxalate-to-creatinine ratio (Uox:cr), 24-h urine oxalate excretion normalized to body surface area (24-h Uox), or plasma oxalate concentration (Pox). We compared values among 3 groups: homozygous G170R, heterozygous G170R, and non-G170R AGXT variants both before and after initiating pyridoxine (B6). Results: Of 403 patients with PH1 in the registry, 83 met the inclusion criteria. Uox:cr decreased rapidly over the first 5 years of life. Both before and after B6 initiation, patients with non-G170R had the highest Uox:cr, 24-h Uox, and Pox. Patients with heterozygous G170R had similar Uox:cr to homozygous G170R prior to B6. Patients with homozygous G170R had the lowest 24-h Uox and Uox:cr after B6. Urinary oxalate excretion and Pox tend to decrease over time during childhood. eGFR over time was not different among groups. Conclusions: Children with PH1 under 5 years old have relatively higher urinary oxalate excretion which may put them at greater risk for nephrocalcinosis and kidney failure than older PH1 patients. Those with homozygous G170R variants may have milder disease. [ABSTRACT FROM AUTHOR]

Introduction: This study was designed to determine the mineral composition of calculi in nephrocalcinosis with nephrolithiasis, diagnose the underlying disease, and monitor the course of renal function in patients with nephrocalcinosis-nephrolithiasis. Methods: Renal calculi extruded in a series of 8 patients with nephrocalcinosis were analysed using Fourier transmission infrared spectrometry. In 4 patients, next-generation sequencing using a nephrocalcinosis-nephrolithiasis panel was performed to determine the nature of the underlying disease. In addition, longitudinal analysis of renal function was performed in all patients. Results: Seven patients revealed carbonate apatite as the sole constituent of renal calculi. One patient showed a mixed composition of dicalcium phosphate dihydrate/carbonate apatite at first analysis yet in subsequent episodes also had calculi composed of pure carbonate apatite. Further molecular analysis displayed distal renal tubular acidosis in 2 of 4 patients who consented to sequencing. No known genetic defect could be found in the other two cases. In line with prior reports, decline of renal function was dependent on underlying disease. Distal renal tubular acidosis revealed a progressive course of renal failure, whereas other causes showed stable renal function in long term analysis. Conclusion: Nephrocalcinosis with nephrolithiasis is a rare condition with heterogeneous aetiology. Yet mineral composition of renal calculi predominantly consisted of pure carbonate apatite. This uniform finding is similar to subcutaneous calcifications of various origins and might propose a general principle of tissue calcification. Progressive decline of renal function was found in distal renal tubular acidosis, whereas other conditions remained stable over time. Plain Language Summary: Renal stones may occur in conditions that involve calcification of the kidney itself. In this case series, we chemically analysed these stones. In some cases, we also performed genetic tests. Interestingly, we found a similar composition in most stones, irrespective of the underlying disorder. This suggests a common mechanism of calcification. [ABSTRACT FROM AUTHOR]

Enamel renal gingival syndrome is a rare clinical condition characterized by the presence of amelogenesis imperfecta hypoplastic type, gingival fibromatosis and delayed tooth eruption, in addition to nephrocalcinosis with normal blood calcium levels. It is inherited as an autosomal recessive trait caused by mutations in the FAM20A gene located on chromosome 17q24.2. The purpose of this report is to describe a case of enamel renal gingival syndrome and discuss its distinct features and management. [ABSTRACT FROM AUTHOR]

Introduction: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare genetic disorder. There are few descriptions of phenotype and genotype in pediatric patients, especially from Asia. Methods: We retrospectively reviewed the records of 11 patients who were diagnosed with FHHNC due to a common homozygous mutation in CLDN19, the gene encoding claudin 19, in the state of Sarawak, Malaysia. Results: Eleven patients from eight families, predominantly of Iban descent, were diagnosed with FHHNC at a median age of 7 years. These patients had an identical novel homozygous pathogenic variant in CLDN19, c427del. Seven patients (63.7%) had ocular abnormalities. All patients had nephrocalcinosis; hypomagnesemia and hypocalcemia were seen in 10 and 6 cases, respectively. One patient was asymptomatic at diagnosis. Progression to kidney failure was seen in two patients, at 7 and 15 years of age. Conclusions: The finding of a common novel mutation in non consanguineous families from the Iban population across different regions in the Sarawak state suggests a founder effect, underscoring the importance of genetic screening in children from this region presenting with unexplained ocular symptoms or electrolyte abnormalities associated with nephrocalcinosis, to facilitate early diagnosis and management of FHHNC. [ABSTRACT FROM AUTHOR]

Background: Furosemide is a drug widely used for several medical conditions and could be used without medical prescription. Furosemide-related nephrocalcinosis can occur regardless of age, although the risk is higher in premature infants. The defining characteristic of nephrocalcinosis is generalized calcium deposition in the kidney. The most useful imaging studies for evaluation are ultrasonography and computed tomography (more effective in detecting calcification). Case Presentation: A 32-year-old woman with a history of depressive syndrome was admitted for evaluation of fortuitously discovered nephrocalcinosis and hypokalemia. The studies performed revealed the presence of a metabolic alkalosis with discrete hyperreninism/hyperaldosteronism but normal ratio, normotension and urinary study showed elevated sodium, chloride, potassium and calcium fluctuating in different determinations. Surreptitious diuretic intake was suspected and urine analysis revealed doses equivalent to 80-120 mg. The patient was advised to discontinue all diuretic treatment; she was adequately supplemented with potassium and she was followed-up in outpatient clinics. During the follow-up, clinical and analytical improvement was noted, which led to the discontinuation of supplementation. Conclusion: Surreptitious diuretic intake is a clinical condition to rule out in patients with chronic hypokalemia, metabolic alkalosis with elevated urinary sodium and chloride. The relation between surreptitious diuretic intake and nephrocalcinosis has not been fully elucidated in adults. [ABSTRACT FROM AUTHOR]

Background: Nephrocalcinosis (NC) is a serious condition among neonates that needs proper management. The study aimed to detect the prevalence of nephrocalcinosis among preterm babies in Fallujah city, west of Iraq, and measure its association with a variety of risk factors. Methods: Thirty preterm cases were recruited from September to December of 2019. A pediatric radiologist performed an ultrasound on babies in the sample to detect nephrocalcinosis. Results: There were 30 neonate babies; 7 (23%) cases had nephrocalcinosis. The mean gestation weight was 1.6±0.4 Kg. About 6% of the neonates did not need an oxygen supply, 10% required steroids, 33% needed theophylline, 20% received vancomycin, 3% received diuretics, and 70% received gentamycin. There was a statistically non-significant association between gender and using oxygen, theophylline, steroids, vancomycin, and diuretics with the occurrence of nephrocalcinosis. Conclusion: Nephrocalcinosis among premature babies is a common disease and should be considered for screening. Treatment is mandatory to prevent its dangerous consequences. [ABSTRACT FROM AUTHOR]

Lowe syndrome (oculocerebrorenal syndrome of Lowe -- LS) is an ultra-rare, recessive X-linked, multisystem disorder that primarily occurs in males and affects the eyes, nervous system, and kidneys. It is a consequence of mutation of the OCRL gene on chromosome Xq25-26, which encodes phosphatidylinositol 4,5-bisphosphate 5 phosphatase, a protein present in the Golgi complex, lysosomes, and endosomes. The most common symptoms of LS involve congenital cataracts, neurological retardation, and incomplete Fanconi syndrome, ultimately leading to end-stage renal disease between the second and fourth decade of life. The authors present a boy with the intoxication of vitamin D3 and suspicion of congenital cytomegaly eventually diagnosed with LS at the age of 16 months. [ABSTRACT FROM AUTHOR]

Infantile hypercalcemia (IH) is a rare genetic disorder characterized by hypercalcemia, hypercalciuria, low parathyroid hormone, and nephrocalcinosis during the first months of life. Biallelic variants in the genes CYP24A1 and SCL34A1 cause IH1 and 2, respectively. We present the case of a newborn with an antenatal diagnosis of IH2 due to the identification of echogenic, yet normal-sized kidneys at 23 weeks gestation. Trio whole-exome sequencing initially identified only a heterozygous pathogenic variant in SLC34A1. Re-analysis of the exome data because of the clinical suspicion of IH2 revealed a 21-basepair deletion in trans that had initially been filtered out because of its high allele frequency. The diagnosis of IH2 enabled postnatal screening for hypercalcemia, present already at week 1, resulting in early treatment with phosphate supplementation and vitamin D avoidance. In the subsequent course, biochemical parameters were normalized, and the patient showed no obvious clinical complications of IH2, apart from the nephrocalcinosis. [ABSTRACT FROM AUTHOR]

This article explores the molecular mechanisms of loop diuretics and their effects on renal calcium and magnesium transport. Loop diuretics are commonly used to treat fluid retention in patients with heart failure, kidney disease, and cirrhosis. They primarily act on the thick ascending limb of the loop of Henle by inhibiting the NKCC2 cotransporter, resulting in increased urine volume and salt wasting. Loop diuretics also affect the reabsorption of calcium and magnesium in the kidney, leading to their loss in urine. The article discusses the role of various transporters and channels involved in calcium and magnesium reabsorption in the renal tubules. It also highlights the differential effects of loop diuretics on calcium and magnesium handling in Bartter syndrome, a genetic disorder affecting renal salt and mineral transport. Additionally, the article presents new findings suggesting that furosemide, a commonly used loop diuretic, may have beneficial effects on calcium excretion in patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). Further research is needed to explore the therapeutic potential of furosemide in these patients. [Extracted from the article]

Background: Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with chronic kidney disease (CKD) and could be related to oxidative stress. Vascular calcification (VC) has been established as a critical risk factor for accelerated CVD. In CKD, phosphorus (Pi), iron (Fe) and Nrf2 are modulators of VC and important agonists and antagonists of oxidative stress. The aim of this study was to determine whether Fe administration, which is commonly used to treat renal anemia, affects aortic Fe overload and VC, and whether Nrf2 and its related genes, ferritin H and HIF-1α, are involved in the development of VC. Methods: A CKD model was created in rats by administering adenine and simultaneously feeding a high-Pi diet. In addition to control and CKD rats without Fe administration (No-Fe group), Fe was administered orally (PO-Fe group) or intraperitoneally (IP-Fe group) to CKD animals to clarify the effects of Fe administration on the aortic Fe and calcium (Ca) contents and the involvement of Nrf2 and its induced antioxidative proteins, ferritin H and HIF-1α, in VC. Results: The aortic Fe content increased significantly in the IP-Fe group, which was closely correlated with liver HAMP (hepcidin) expression in all animals. Fe administration had no significant effect on the aortic Ca and Pi contents regardless of the route of Fe administration. The aortic mRNA level of Nrf2 was significantly increased in the IP-Fe group and correlated with serum Pi levels and aortic Fe contents, which could respond to oxidative stress. Notably, the mRNA level of Nrf2 was also significantly correlated with the mRNA levels of ferritin H and HIF-1α. Since we could not measure Nrf2 protein levels in this study, we confirmed the upregulation of HMOX1 and NQO1 mRNA expression in parallel with Nrf2 mRNA. Conclusion: Parenteral Fe administration increased aortic Fe in parallel with the liver HAMP mRNA level but did not affect VC. Aortic Nrf2 mRNA levels correlated significantly with aortic Fe and serum Pi levels and with aortic mRNA levels of ferritin H and HIF-1α as well as HMOX1 and NQO1. [ABSTRACT FROM AUTHOR]

Ectopic calcification (EC) involves multiple organ systems in chronic kidney disease (CKD). Previous CKD-animal models primarily focused on a certain histological abnormality but did not show the correlation with calcified development among various tissues. This study compared calcified deposition in various tissues during CKD progression in mice. Male 8-week-old C57BL/6J mice were randomly allocated to the seven groups: a basic, adenine, high-phosphorus, or adenine and high-phosphorus diet for 12–16 weeks (Ctl16, A12, P16, or AP16, respectively); an adenine diet for 4–6 weeks; and a high-phosphorus or adenine and high-phosphorus diet for 10–12 weeks (A6 + P10, A4 + P12, or A4 + AP12, respectively). Compared to the Ctl16 mice, the P16 mice only displayed a slight abnormality in serum calcium and phosphorus; the A12 mice had the most serious kidney impairment; the A4 + P12 and A6 + P10 mice had similar conditions of CKD, mineral abnormalities, and mild calcification in the kidney and aortic valves; the A4 + AP12 and AP16 groups had severe kidney impairment, mineral abnormalities and calcification in the kidneys, aortic valves and aortas. Furthermore, calcium-phosphate particles were deposited not only in the tubulointerstitial compartment but in the glomerular and tubular basement membrane. The elemental composition of EC in various tissues matched the calcification of human cardiovascular tissue as determined by energy dispersive spectroscopy. The severity of CKD was unparalleled with the progression of mineral metabolism disorder and EC. Calcification was closely related in different tissues and observed in the glomerular and tubular basement membranes. Previous CKD-animal models primarily focused on a certain histological abnormality but lacked investigations of the interplay of EC in various tissues. This study compared calcified deposition in several tissues during CKD progression in mice, which was closely related. The severity of CKD was unparalleled with the development of ectopic calcification. Glomerular and tubular basement membrane calcification was detected in CKD mice, which has been considered extremely rare in clinical. [ABSTRACT FROM AUTHOR]

The association between vascular calcification (VC) and kidney stone is still inconclusive. Therefore, we conducted a meta-analysis to estimate the risk of kidney stone disease in subjects with VC. To identify publications from related clinical studies, we performed a search on PubMed, Web of Science, Embase, and Cochrane Library databases from their inceptions until 1 September 2022. According to obvious heterogeneity, a random-effects model was used to calculate the odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Subgroup analysis was conducted trying to dissect the effects of VC in different segments and population regions in predicting kidney stone risk. Seven articles were included with a total number of 69,135 patients, of which 10,052 have vascular calcifications and 4728 have kidney stones. There was a significantly higher risk of kidney stone disease in participants with VC versus control (OR = 1.54, 95% CI: 1.13–2.10). Sensitivity analysis confirmed the stability of the results. VC can be separated into abdominal, coronary, carotid, and splenic aortic calcification while pooled analysis of abdominal aorta calcification did not indicate a significant higher kidney stone risk. An obvious higher risk of kidney stone was observed in Asian VC patients (OR = 1.68, 95% CI: 1.07–2.61). Combined evidence of observational studies suggested patients with VC may be associated with an increased risk of kidney stone disease. Despite the predictive value was relatively low, it is still worth noting that patients with VC are under the threat of kidney stone disease. [ABSTRACT FROM AUTHOR]