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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]

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: 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]

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]

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]

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]

Identifying a functional molecular therapeutic target of vascular calcification (VC) that will not affect normal osteogenic differentiation is a challenge. To address this aim, we screened the differentially expressed genes (DEGs) in different VC conditions, including endothelial‐osteogenic transition (EOT) (GSE167962), chronic kidney disease (CKD), and atherosclerosis (AS) (GSE159832). KEGG pathways, protein–protein interactions, and hub genes were also analyzed. The intersecting DEGs among the EOT, CKD, and AS groups were verified by quantitative reverse transcription polymerase chain reaction and immunohistochemistry in a DOCA‐salt hypertension mouse model. The phosphoinositide 3‐kinase–protein kinase B signaling pathway, ECM‐receptor interaction, chemokine signaling pathway, and focal adhesion were enriched in EOT and AS‐induced VC. ECM‐receptor interaction, PPAR signaling pathway, apelin signaling pathway, AMPK signaling pathway, adipocytokine signaling pathway, and cholesterol metabolism were enriched in CKD and AS‐induced VC. C4b, Cebpa, Lyz2, and Spp1 were also upregulated in EOT, CKD, AS, and hypertension. This study identified promising molecular targets for VC therapy. Significance statement: This research has pinpointed four crucial genes (C4b, Cebpa, Lyz2, and Spp1) linked to vascular calcification in various cardiovascular conditions such as chronic kidney disease, hypertension, atherosclerosis, and endothelial‐osteogenic transition. [ABSTRACT FROM AUTHOR]

Nephrocalcinosis is a widespread challenge in intensive production of salmon smolt. There is however no consensus on its aetiology, which makes it problematic to implement proper measures to limit its development. We performed a survey of nephrocalcinosis prevalence and environmental factors in 11 different hatcheries in Mid‐Norway as well as a 6‐month monitoring in one of the hatcheries. A multivariate analysis indicated that the most influencing factor for the prevalence of nephrocalcinosis was the supplementation of sea water during smolt production. In the 6‐month monitoring, the hatchery introduced salinity in the production water prior to the change in day length. Mismatch in those environmental signals may increase the risk for developing nephrocalcinosis. Salinity fluctuations prior to smoltification can cause osmotic stress and result in unbalanced levels of ions in fish blood. This was clearly illustrated in our study, as the fish experienced chronic hypercalcaemia and hypermagnesaemia. Both magnesium and calcium are excreted over the kidneys and it is possible that their prolonged, elevated levels in plasma resulted in an oversaturation of the urine when finally excreted. This again could have led to the aggregation of calcium deposits within the kidney. This study indicates a relationship between osmotic stress induced by salinity changes in juvenile Atlantic salmon and the development of nephrocalcinosis. Other factors that may affect the severity of nephrocalcinosis are currently subjects for discussion. [ABSTRACT FROM AUTHOR]

In an adult male goldfish (Carassius auratus, Linnaeus), an unusual combination of diseases was detected. The owner noted a bilateral, asymmetrical distention of the abdomen, multiple cutaneous masses and an altered swimming behaviour over the course of time; diagnostic work‐up was not requested and euthanasia elected. Grossly, the cutaneous masses were whitish, discrete, extremely friable. Histologically, the dermis was multifocally expanded by moderately cellular, unencapsulated neoplastic tissue, composed of dermal spindle cells. The celomic cavity opening revealed a gelatinous multicystic mass, corresponding to the kidney, which replicated several cysts compressing the residual parenchyma. Histologically, sparse, late‐stage granulomas, basophilic intratubular deposits and crystals were also detected. No mycobacterial DNA was detected in tissue with granulomas. No parasites were detected in the histological sections examined. Diagnoses of cutaneous nerve sheath tumours, polycystic kidney disease, renal late‐stage granulomas, nephrocalcinosis and crystals were formulated. The authors had proposed to recapitulate each single condition. [ABSTRACT FROM AUTHOR]

The kidney is critical for mineral homeostasis. Calcium and magnesium reabsorption in the renal thick ascending limb (TAL) involves claudin‐16 (CLDN16) and claudin‐19 (CLDN19) and pathogenic variants in either gene lead to familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) with severe calcium and magnesium wasting. While both CLDN16 and CLDN19 localize to the TAL, varying expression patterns in the renal tubule have been reported using different antibodies. We, therefore, studied the localization of CLDN19 in the kidneys of wild‐type and Cldn19‐deleted mice using three anti‐CLDN19 antibodies and examined the role of Cldn19 deletion on CLDN16 and CLDN10 localization. We find that CLDN19 localizes to basolateral membrane domains of the medullary and cortical TAL but only to the tight junction of TALs in the outer stripe of outer medulla and cortex, where it colocalizes with CLDN16. Furthermore, in TALs from Cldn19‐deleted mice, CLDN16 is expressed in basolateral membrane domains but not at the tight junction. In contrast, Cldn19 ablation does not change CLDN10 localization. These findings directly implicate CLDN19 in regulating permeability in the TAL by allowing junctional insertion of CLDN16 and may explain the shared renal phenotypic characteristics in FHHNC patients. [ABSTRACT FROM AUTHOR]

Aim: Perturbed calcium homeostasis limits life expectancy in familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC). This rare disease occurs by loss‐of‐function mutations in CLDN16 or CLDN19 genes, causing impaired paracellular reabsorption of divalent cations along the cortical thick ascending limb (cTAL). Only partial compensation takes place in the ensuing late distal convoluted tubule, connecting tubule, and collecting duct, where the luminal transient receptor potential channel V5 (TRPV5), as well as basolateral plasma membrane calcium ATPase (PMCA) and sodium‐potassium exchanger (NCX1) mediate transcellular Ca2+ reabsorption. The loop diuretic furosemide induces compensatory activation in these distal segments. Normally, furosemide enhances urinary calcium excretion via inhibition of the aforementioned cTAL. As Ca2+ reabsorption in the cTAL is already severely impaired in FHHNC patients, furosemide may alleviate hypercalciuria in this disease by activation of the distal transcellular Ca2+ transport proteins. Methods: Cldn16‐deficient mice (Cldn16−/−) served as a FHHNC model. Wild‐type (WT) and Cldn16−/− mice were treated with furosemide (7 days of 40 mg/kg bw) or vehicle. We assessed renal electrolyte handling (metabolic cages) and key divalent transport proteins. Results: Cldn16−/− mice show higher Ca2+ excretion than WT and compensatory stimulation of Cldn2, TRPV5, and NCX1 at baseline. Furosemide reduced hypercalciuria in Cldn16−/− mice and enhanced TRPV5 and PMCA levels in Cldn16−/− but not in WT mice. Conclusions: Furosemide significantly reduces hypercalciuria, likely via upregulation of luminal and basolateral Ca2+ transport systems in the distal nephron and collecting duct in this model for FHHNC. [ABSTRACT FROM AUTHOR]

A study published in Clinical Cardiology by Dong et al. explores the relationship between blood pressure variability (BPV) and mortality risk in individuals with end-stage kidney disease (ESKD) undergoing hemodialysis. The study found that increasing home BPV was associated with a higher risk of all-cause mortality in this population. The authors suggest that comorbid cardiovascular diseases, diabetes, systemic inflammation, and higher vascular stiffness may contribute to this association. They propose that a more comprehensive understanding of vascular integrity impairment, specifically vascular frailty, could help explain the relationship between BPV and mortality risk. The authors recommend incorporating additional features of vascular frailty, such as measurements of vascular calcification severity and evidence of autonomic dysfunction, in future assessments of ESKD patients to gain a better understanding of the underlying mechanisms. [Extracted from the article]

Chronic kidney disease–mineral and bone disorders (CKD‐MBD) is a common complication of CKD Stages 3–5. Hyperphosphatemia is one of the major metabolic components of CKD‐MBD, frequently resulting in vascular calcification (VC) in advanced‐stage patients. Also, a long duration of renal replacement therapy can cause the worsening of VC, leading to increased cardiovascular morbidity and mortality. Vascular smooth muscle cells play an important role in the development of VC through osteochondrogenic transformation and the apoptotic process. It has been shown that mitochondrial dysfunction is involved with CKD progression, and excessive oxidative stress can aggravate osteoblastic transformation and VC. Currently, novel interventions targeting mitochondrial function and dynamics, in addition to mitochondrial antioxidants, have been studied with the aim of attenuating VC. This review aims to comprehensively summarize and discuss the experimental and clinical reports concerning mitochondrial studies, along with the purpose of interventions that can improve the outcomes of VC among CKD patients. [ABSTRACT FROM AUTHOR]

Background: Although nephrolithiasis (NL) and nephrocalcinosis (NC) are very common features of primary hyperoxaluria type 1 (PH1), the long‐term prognosis of NL and NC after preemptive liver transplantation (PLT) has not been elucidated. Material and Methods: We describe the cases of two chronic kidney disease (CKD) stage three patients with different clinical courses after PLT for PH1. Results: The first patient underwent PLT at 7 years of age with an estimated glomerular filtration rate (eGFR) of 47.8 ml/min/1.73 m2. Two years later, she experienced several episodes of obstructive pyelonephritis due to urolithiasis, and developed septic shock in one of these episodes. At the same time as these episodes, preexisting NL and NC progressively improved, with disappearance on X‐ray disappeared at 8 years after transplantation. Her renal function has been maintained with an eGFR of 58.7 ml/min/1.73 m2. The second patient received PLT at 10 years of age with an eGFR of 58.9 ml/min/1.73 m2. Her renal function has been maintained with an eGFR of 65.9 ml/min/1.73 m2. She had repeated urolithiasis which started to appear at 3 years after LT. The radiological findings still show bilateral NL and NC, but the stones in the renal pelvis have shown mild improvement. Conclusions: Regardless of the regression in NC seen on X‐ray, long‐term maintenance of the renal function in patients with PH1 with CKD stage 3 can be achieved with PLT. In patients with NL, there is a risk of serious complications due to posttransplant immunosuppressive therapy when obstructive pyelonephritis occurs after LT. [ABSTRACT FROM AUTHOR]

Keywords: Atlantic salmon; nephrocalcinosis; radiology EN Atlantic salmon nephrocalcinosis radiology 1883 1888 6 11/11/22 20221201 NES 221201 INTRODUCTION Nephrocalcinosis is a common disorder in nurseries in Norway (Klykken, Reed, et al., 2022) and was reported as one of the main welfare challenges in farmed salmon by The Norwegian Fish Health Report of 2019 (Sommerset et al., 2020). Nephrocalcinosis in Atlantic salmon is mainly identified as amorphous carbonate apatite, a calcium-dominated mineral (Klykken, Reed, et al., 2022), and it has previously been demonstrated that this mineral composition is suitable for x-ray detection (Smith & Lehr, 1966). In conclusion, we are confident that radiology is a suitable diagnostic tool for assessing mineral deposits (amount and distributions) associated with nephrocalcinosis in farmed Atlantic salmon, with minimal risk to the operator when appropriate measures are taken. Regarding the future use of radiology to assess nephrocalcinosis, one should be aware of the limitations of the method, since soft tissue changes not including mineralization cannot be seen on radiographs. [Extracted from the article]

Summary: Extracellular vesicles (EVs) are critical in the initiation and progression of cardiovascular calcification, and immune cell infiltration and inflammation have a central role in this process. EVs egress from various cardiovascular cell types, which when acquiring specific properties, become calcifying. These calcifying EVs form nidi for microcalcification, which can progress to the macrocalcification lesions that are visualized clinically. We make the distinction between inflammatory‐driven and mineral dysregulation‐driven calcification, which both share EVs as a central initiator. In inflammation‐mediated calcification, inflammation precedes microcalcification and results from EV release from macrophages. Local cellular crosstalk mediated by EVs as well as circulating EVs and other inflammatory nanoparticles, such as calciprotein particles and lipoproteins, are also critical in the progression of cardiovascular calcification. It is imperative that future work links the already established and to be discovered roles of inflammation and innate immunity in cardiovascular calcification to these key signaling and functional roles of these nanoparticles. It remains an understudied area with high potential to unravel mechanistic roles and has important implications in drug target research. [ABSTRACT FROM AUTHOR]

Nephrocalcinosis is a common disorder in farmed Atlantic salmon, but the consequences for the fish physiology are not well understood. We performed a transcriptome study in kidneys of Atlantic salmon (Salmo salar) smolts without and with severe chronic nephrocalcinosis (NC). The study revealed that numerous genes are differentially expressed in fish with NC compared with healthy salmon. The most evident changes in gene expression patterns in the NC group were a massive downregulation of metabolism and energy production, upregulation of signalling pathways important for tissue repair and function maintenance and upregulation of inflammatory responses. Overall, the extensive tissue damage and the gene regulation responses that affect salmon with severe nephrocalcinosis are highly likely to have dramatic consequences on fish survival. [ABSTRACT FROM AUTHOR]

Introduction: Arterial calcification is an integral component of active atherosclerosis and is an independent risk factor for cardiovascular disease. Atherosclerosis is a systemic, life‐threating disease that may occur at different sites and in various clinical presentations. Intracranial and valvular calcifications are common among dialysis patients and have been associated with poor cardiovascular outcomes. The aim of this study was to assess the clinical impact of valvular and intracranial arterial calcifications on mortality among chronic hemodialysis patients. Methods: A blinded neuroradiologist graded intracranial calcifications (ICC) of all hemodialysis patients who underwent brain computerized tomography (CT) from 2015 to 2017 in our institution. Valvular calcifications were assessed by echocardiography. Only hemodialysis patients with available echocardiography and brain CT were included. Findings: This study included 119 patients (mean age 70.6 ± 12.6 years, 57.1% men, and mean dialysis vintage 25.8 ± 42.6 months). Among the cohort, 19 (16%) had no cardiac or brain calcifications and 65 (54.6%) had both valvular and intracranial calcifications. Considering the patients with no calcification as the reference group yielded adjusted odds ratios for all‐cause mortality of 3.68 (95%CI 1.55–8.75) among patients with any brain calcifications, p = 0.002. While valvular calcifications alone did not increase the 1‐year mortality rate, ICC was the most important predictor of all‐cause 1‐year mortality in the study cohort. Discussion: We found an independent association between ICC and the risk of death among hemodialysis patients. Assessing ICC may contribute to the risk stratification of hemodialysis patients. These calcifications are no less important than valvular calcifications. [ABSTRACT FROM AUTHOR]

Metastatic pulmonary calcification (MPC) is characterized by deposition of calcium in the normal lung parenchyma secondary to elevation of serum calcium. Most patients are asymptomatic and routine chest radiograph is not sensitive to make the diagnosis. Further imaging is needed such as computed tomography (CT) which typically shows small centrilobular nodules in the upper lobes. We report a case of a 30‐year‐old woman with end stage kidney disease who was diagnosed with pulmonary tuberculosis which was then revised to metastatic pulmonary calcification. The CT thorax feature for this patient was atypical for metastatic pulmonary calcification where it demonstrated tree‐in‐bud nodules suggestive of infection. The final diagnosis was made based on bronchoalveolar lavage which was culture‐negative for Mycobacterium and transbronchial lung biopsy demonstrating calcium deposition in the interstitium. [ABSTRACT FROM AUTHOR]

Background: Progression of vascular calcification causes cardiovascular disease, which is the most common cause of death in chronic kidney failure and after kidney transplantation (KT). The prognostic impact of the extent of medial vascular calcification at KT is unknown. Methods: In this prospective cohort study, we investigated the impact of medial calcification compared to a mix of intimal and medial calcification represented by coronary artery calcification (CAC score) and aortic valve calcification in 342 patients starting on kidney failure replacement therapy. The primary outcomes were cardiovascular events (CVE) and death. The median follow‐up time was 6.4 years (interquartile range 3.7–9.6 years). Exposure was CAC score and arteria epigastrica medial calcification scored as none, mild, moderate, or severe by a pathologist at time of KT (n = 200). We divided the patients according to kidney failure replacement therapy during follow‐up, that is, living donor KT, deceased donor KT, or dialysis. Results: Moderate to severe medial calcification in the arteria epigastrica was associated with higher mortality (p = 0.001), and the hazard ratio for CVE was 3.1 (95% confidence interval [CI] 1.12–9.02, p < 0.05) compared to no or mild medial calcification. The hazard ratio for 10‐year mortality in the dialysis group was 33.6 (95% CI, 10.0–113.0, p < 0.001) compared to living donor recipients, independent of Framingham risk score and prevalent CAC. Conclusion: Scoring of medial calcification in the arteria epigastrica identified living donor recipients as having 3.1 times higher risk of CVE, independent of traditional risk factors. The medial calcification score could be a reliable method to identify patients with high and low risk of CVE and mortality following KT. [ABSTRACT FROM AUTHOR]

Background: Although the primary cause of death in COVID‐19 infection is respiratory failure, there is evidence that cardiac manifestations may contribute to overall mortality and can even be the primary cause of death. More importantly, it is recognized that COVID‐19 is associated with a high incidence of thrombotic complications. Hypothesis: Evaluate if the coronary artery calcium (CAC) score was useful to predict in‐hospital (in‐H) mortality in patients with COVID‐19. Secondary end‐points were needed for mechanical ventilation and intensive care unit admission. Methods: Two‐hundred eighty‐four patients (63, 25 years, 67% male) with proven severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection who had a noncontrast chest computed tomography were analyzed for CAC score. Clinical and radiological data were retrieved. Results: Patients with CAC had a higher inflammatory burden at admission (d‐dimer, p =.002; C‐reactive protein, p =.002; procalcitonin, p =.016) and a higher high‐sensitive cardiac troponin I (HScTnI, p = <.001) at admission and at peak. While there was no association with presence of lung consolidation and ground‐glass opacities, patients with CAC had higher incidence of bilateral infiltration (p =.043) and higher in‐H mortality (p =.048). On the other side, peak HScTnI >200 ng/dl was a better determinant of all outcomes in both univariate (p = <.001) and multivariate analysis (p = <.001). Conclusion: The main finding of our research is that CAC was positively related to in‐H mortality, but it did not completely identify all the population at risk of events in the setting of COVID‐19 patients. This raises the possibility that other factors, including the presence of soft, unstable plaques, may have a role in adverse outcomes in SARS‐CoV‐2 infection. [ABSTRACT FROM AUTHOR]

Pseudoxanthoma elasticum (PXE; OMIM 264800) is a rare heritable multisystem disorder, characterized by ectopic mineralization affecting elastic fibres in the skin, eyes and the cardiovascular system. Skin findings often lead to early diagnosis of PXE, but currently, no specific treatment exists to counteract the progression of symptoms. PXE belongs to a group of Mendelian calcification disorders linked to pyrophosphate metabolism, which also includes generalized arterial calcification of infancy (GACI) and arterial calcification due to CD73 deficiency (ACDC). Inactivating mutations in ABCC6, ENPP1 and NT5E are the genetic cause of these diseases, respectively, and all of them result in reduced inorganic pyrophosphate (PPi) concentration in the circulation. Although PPi is a strong inhibitor of ectopic calcification, oral supplementation therapy was initially not considered because of its low bioavailability. Our earlier work however demonstrated that orally administered pyrophosphate inhibits ectopic calcification in the animal models of PXE and GACI, and that orally given Na4P2O7 is absorbed in humans. Here, we report that gelatin‐encapsulated Na2H2P2O7 has similar absorption properties in healthy volunteers and people affected by PXE. The sodium‐free K2H2P2O7 form resulted in similar uptake in healthy volunteers and inhibited calcification in Abcc6−/− mice as effectively as its sodium counterpart. Novel pyrophosphate compounds showing higher bioavailability in mice were also identified. Our results provide an important step towards testing oral PPi in clinical trials in PXE, or potentially any condition accompanied by ectopic calcification including diabetes, chronic kidney disease or ageing. [ABSTRACT FROM AUTHOR]

Warfarin produced a similar proportional increase in progression in ESRD patients, but because of the underlying propensity towards arterial calcification in ESRD, the rate of progression in ESRD patients treated with warfarin was almost 20-fold greater than in women without ESRD not treated with warfarin. One could argue that it could be used in patients with excellent control of their mineral metabolism but our data show that warfarin increases arterial calcification in patients with normal renal function and presumably normal mineral metabolism. Patients with end-stage renal disease (ESRD) often have indications for long-term anticoagulation such as atrial fibrillation, thrombosis of arteriovenous fistulas and grafts, metallic heart valves, and hypercoagulable states. [Extracted from the article]

Background: Nephrocalcinosis is a pathological feature of chronic kidney disease (CKD). Its pathophysiological implications for cats with CKD are unexplored. Objectives: Identify nephrocalcinosis risk factors and evaluate its influence on CKD progression and all‐cause mortality. Animals: Fifty‐one euthyroid client‐owned cats with International Renal Interest Society (IRIS) stages 2‐3 azotemic CKD. Methods: Retrospective cohort study. Histopathological kidney sections were assessed for nephrocalcinosis (von Kossa stain). Nephrocalcinosis severity was determined by image analysis (ImageJ). Ordinal logistic regressions were performed to identify nephrocalcinosis risk factors. The influence of nephrocalcinosis on CKD progression and mortality risk were assessed using linear mixed model and Cox regression, respectively. Cats were categorized by their owner‐reported time‐averaged phosphate‐restricted diet (PRD) intake, where PRD comprised ≥50%, 10‐50%, or none of food intake. Results: Nephrocalcinosis was rated as mild‐to‐severe in 78.4% and absent‐to‐minimal in 21.6% of cases. Higher baseline plasma total calcium concentration (tCa; odds ratio [OR] = 3.07 per 1 mg/dL; P =.02) and eating a PRD (10%‐50%: OR = 8.35; P =.01; ≥50%: OR = 5.47; P =.01) were independent nephrocalcinosis risk factors. Cats with absent‐to‐minimal nephrocalcinosis had increasing plasma creatinine (0.250 ± 0.074 mg/dL/month; P =.002), urea (5.06 ± 1.82 mg/dL/month; P =.01), and phosphate (0.233 ± 0.115 mg/dL/month; P =.05) concentrations over a 1‐year period, and had shorter median survival times than cats with mild‐to‐severe nephrocalcinosis. Conclusion and Clinical Importance: Higher plasma tCa at CKD diagnosis and PRD intake are independently associated with nephrocalcinosis. However, nephrocalcinosis is not associated with rapid CKD progression in cats. [ABSTRACT FROM AUTHOR]

Deregulations in gut microbiota may play a role in vascular and bone disease in chronic kidney disease (CKD). As glomerular filtration rate declines, the colon becomes more important as a site of excretion of urea and uric acid, and an increased bacterial proteolytic fermentation alters the gut microbial balance. A diet with limited amounts of fibre, as well as certain medications (eg phosphate binders, iron supplementation, antibiotics) further contribute to changes in gut microbiota composition among CKD patients. At the same time, both vascular calcification and bone disease are common in patients with advanced kidney disease. This narrative review describes emerging evidence on gut dysbiosis, vascular calcification, bone demineralization and their interrelationship termed the 'gut‐bone‐vascular axis' in progressive CKD. The role of diet, gut microbial metabolites (ie indoxyl sulphate, p‐cresyl sulphate, trimethylamine N‐oxide (TMAO) and short‐chain fatty acids (SCFA)), vitamin K deficiency, inflammatory cytokines and their impact on both bone health and vascular calcification are discussed. This framework may open up novel preventive and therapeutic approaches targeting the microbiome in an attempt to improve cardiovascular and bone health in CKD. [ABSTRACT FROM AUTHOR]

Deletions of the NaPi2a gene and mutations in the SLC34A gene should be considered in patients with atypical presentation, without phosphaturia, with mild hypo to normal phosphatemia, and nephrocalcinosis. [ABSTRACT FROM AUTHOR]

Objective: Hypercalciuria, impaired kidney function and renal calcifications are common in chronic hypoparathyroidism (HypoPT). We aimed to study associations between indices of known importance to the kidney in HypoPT by hypothesizing adverse effects of hypercalciuria on renal outcomes. Design: We used cross‐sectional design. Patients: We identified all patients followed for chronic HypoPT at our department and who had been examined by a 24‐h urine collection for measurement of renal calcium excretion (24 h U‐Ca). Measurements: By chart review, we identified additional biochemistry measured in close connection with the collection of urine, as well as demographic, treatments and anthropometrics. Results: The 166 included patients (79.5% females) had a high prevalence of hypercalciuria (65.7%). In multiple adjusted analyses, hypercalciuria was in an independent manner inversely associated with (residual) levels of plasma PTH and positively associated with levels of 1,25‐dihydroxyvitamin D and ionized calcium as well as 24 h U‐phosphate, gender, and etiology (surgical vs. non‐surgical). Overall, this model explained 54% (p <.001) of the variation in the presence of hypercalciuria. Chronic kidney disease stage three or above was present in 18.3% of the patients, and 42.6% of the 54 patients examined by renal imaging had renal calcifications. However, neither renal function nor renal calcifications were associated with 24 h U‐Ca. Conclusions: Hypercalciuria, impaired renal function and renal calcifications are common in hypoparathyroidism. Hypercalciuria is to a large extent explained by indices of known physiological importance to 24 h U‐Ca. However, in the present study, a high renal calcium excretion did not explain renal impairment or kidney calcifications. [ABSTRACT FROM AUTHOR]

Vascular calcification is a common pathologic condition in patients with chronic kidney disease (CKD) and aging individuals. It has been established that vascular calcification is a gene‐regulated biological process resembling osteogenesis involving osteogenic differentiation. However, there is no efficient treatment available for vascular calcification so far. The natural polyamine spermidine has been demonstrated to increase life span and protect against cardiovascular disease. It is unclear whether spermidine supplementation inhibits vascular calcification in CKD. Alizarin red staining and quantification of calcium content showed that spermidine treatment markedly reduced mineral deposition in both rat and human vascular smooth muscle cells (VSMCs) under osteogenic conditions. Additionally, western blot analysis revealed that spermidine treatment inhibited osteogenic differentiation of rat and human VSMCs. Moreover, spermidine treatment remarkably attenuated calcification of rat and human arterial rings ex vivo and aortic calcification in rats with CKD. Furthermore, treatment with spermidine induced the upregulation of Sirtuin 1 (SIRT1) in VSMCs and resulted in the downregulation of endoplasmic reticulum (ER) stress signaling components, such as activating transcription factor 4 (ATF4) and CCAAT/enhancer‐binding protein homologous protein (CHOP). Both pharmacological inhibition of SIRT1 by SIRT1 inhibitor EX527 and knockdown of SIRT1 by siRNA markedly blocked the inhibitory effect of spermidine on VSMC calcification. Consistently, EX527 abrogated the inhibitory effect of spermidine on aortic calcification in CKD rats. We for the first time demonstrate that spermidine alleviates vascular calcification in CKD by upregulating SIRT1 and inhibiting ER stress, and this may develop a promising therapeutic treatment to ameliorate vascular calcification in CKD. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is a severe health problem worldwide, and vascular calcification (VC) contributes substantially to the cardiovascular morbidity and high mortality of CKD. CKD is often accompanied by a variety of pathophysiological states, such as inflammation, oxidative stress, hyperglycaemia, hyperparathyroidism and haemodynamic derangement, that can cause injuries to smooth muscle cells (SMCs) and endothelial cells (ECs) to promote VC. Similar to SMCs, whose role has been widely explored in VC, ECs may contribute to VC via osteochondral transdifferentiation, apoptosis, etc. In addition, given their location in the innermost layer of the blood vessel lumen and preferential reception of various pro‐calcification stimuli, ECs can pass messages to vascular wall cells and communicate with them. Crosstalk between ECs and SMCs via cytokines through a paracrine mechanism, extracellular vesicles, miRNAs and myoendothelial gap junctions also plays a role in VC. In this review, we emphasize the role of intercellular crosstalk between ECs and SMCs in VC associated with CKD. [ABSTRACT FROM AUTHOR]

Aim: Vascular calcification has played a vital role in increasing the prevalence of cardiovascular disease (CVD) and mortality in maintenance haemodialysis (MHD) patients. This study is aimed at exploring the prognostic value of abdominal aortic calcification (AAC) estimated by plain lateral abdominal radiography in MHD patients. Methods: Lateral abdominal radiography was used to determine the abdominal aortic calcification score (AACS). The serum level of fibroblast growth factor‐23 was tested by enzyme‐linked immunosorbent assay. Patients were divided into two groups: no or minor calcification group (AACS < 5) and moderate to severe calcification group (AACS ≥ 5). All patients were followed up to death or the end of the study (30 November 2016). Results: A total of 114 patients were enrolled in this study, including 64 males (56.1%), and the mean age was 57.42 ± 13.48 years. Seventy‐six patients (66.7%) exhibited AAC. Independent predictors for moderate to severe calcification were older age (odds ratio (OR) 1.06 (1.02–1.10), P = 0.003), longer dialysis vintage (OR 1.01 (1.00–1.02), P = 0.039), presence of smoking (OR 3.01 (1.18–7.70), P = 0.021) and higher Log fibroblast growth factor‐23 serum levels (OR 2.83 (1.01–7.94), P = 0.048). During a median follow‐up of 6.0 (5.6, 6.1) years, 22 patients (19.3%) died of all‐cause death, and 17 cases (14.9%) died of CVD. Kaplan–Meier survival curves showed that patients in the moderate to severe calcification group had significantly higher all‐cause (28.3 vs 11.5%, P = 0.028) and CVD mortality (22.6 vs 8.2%, P = 0.035) than that in the no or minor calcification group. A multivariate Cox regression showed that AACS (hazard ratio 1.08 (1.01–1.15), P = 0.022) was an independent predictor of CVD mortality. Compared with the no or minor calcification group, the risk of CVD mortality was increased by a factor of 3.14 in patients in the moderate to severe calcification group (hazard ratio 3.14 (1.04–9.44), P = 0.042). Conclusion: Our data suggest that AAC is prevalent in MHD patients and could provide potential predictive information for CVD mortality. Plain lateral abdominal radiography, which is simple and cheap and involves lower radiation, might represent an appropriate screening method for evaluating vascular calcification in daily clinical practice. SUMMARY AT A GLANCE: This single‐centre study found that older age, dialysis vintage, smoking and fibroblast growth factor‐23 were predictors of abdominal aortic calcification on lateral abdominal radiography in a cohort of 114 prevalent dialysis patients. The study also identified abdominal aortic calcification as an independent predictor of cardiovascular mortality. The findings show that radiography as a non‐invasive and simple tool could add to the identification of more vulnerable dialysis patients. [ABSTRACT FROM AUTHOR]

Aim: To investigate the possible associations between intrarenal arteriolosclerosis as determine by renal biopsy and endothelial function as well as arterial stiffness measured by peripheral arterial tonometry (EndoPAT). Methods: This was a cross‐sectional study. Patients who underwent both renal biopsy and EndoPAT were recruited, and intrarenal arteriolosclerosis was graded according to the pathological slice. Endothelial function and arterial stiffness were both measured by EndoPAT and were expressed by the reactive hyperemia index (RHI) and augmentation index (AIx), respectively. AIx@75, representing the AIx standardized to a heart rate of 75 bpm was also determined. Results: In total, 113 patients were assessed, the mean age was 51 ± 13, and 68.1% were men. The natural logarithm RHI (LnRHI), AIx and AIx@75 were significantly different among different grades of intrarenal arteriolosclerosis (P =.030, P <.001, P <.001, respectively). In the multivariable adjusted model, for every SD increase in the AIx and AIx@75, the odds of having more severe arteriolosclerosis were 2.506 times (95% confidence interval [CI] 1.464‐4.288, P =.001] and 3.191 times (95% CI 1.780‐5.719, P <.001) higher, respectively, and the association between the LnRHI and intrarenal arteriolosclerosis was nullified (P =.059). The positive values of the AIx and AIx@75 for the diagnosis of severe intrarenal arteriolosclerosis were 0.80 (95% CI 0.73‐0.88, P <.001) and 0.78 (95% CI 0.70‐0.87, P <.001), respectively. Conclusion: Subjects with more severe intrarenal arteriolosclerosis have greater peripheral vascular stiffness; AIx and AIx@75 reflected peripheral vascular stiffness could be used to identify patients with severe intrarenal arteriolosclerosis. SUMMARY AT A GLANCE: In this single centre cross‐sectional study, the relationship between clinical and pathological measures of vascular disease was assessed using kidney biopsies and peripheral arterial tonometry, respectively. Patients more severe biopsy‐proven arteriolosclerosis had greater vascular stiffness after multivariable adjustment. Peripheral arterial tonometry may be useful as a noninvasive measure of intrarenal arteriolosclerosis. [ABSTRACT FROM AUTHOR]

Background: Renal calcified lesions are known as one of the complications during adrenocorticotropic hormone (ACTH) therapy for intractable epilepsy. However, laboratory changes during the therapy or laboratory features of high‐risk cases with renal calcified lesions are yet to be clarified. Methods: In this study, 43 patients with West syndrome aged ≤2 years were included. We retrospectively reviewed age and body mass index at the beginning of ACTH therapy, as well as the amount of fluid intake, daily urinary volume, and laboratory data during therapy. In addition, we studied the urinary sediment of the cases with renal calcified lesions diagnosed by computed tomography. Results: After initiating ACTH treatment, urinary calcium (Ca)/creatinine ratio and urinary pH increased within 2 weeks. Urinary crystals and renal tubular epithelial cells (RTECs) in urinary sediment were frequently found in most cases. Urinary Ca levels, proteinuria or frequency of urinary crystals, and number of RTECs in the urinary sediment were significantly higher in patients with epithelial casts (ECs) or hematuria than in patients without these findings. Among the seven patients who underwent abdominal CT, ECs or hematuria were found only in those with renal calcified lesions. These findings suggested that patients with ECs or hematuria were more likely to have calcified lesions. Conclusions: The risk of renal calcified lesions increased after 2 weeks of ACTH treatment. Abnormal findings in urinary sediments might be an early sign of renal calcification during ACTH therapy. [ABSTRACT FROM AUTHOR]

Calcium oxalate (CaOx) crystal‐induced nephropathies comprise a range of kidney disorders, for which there are no efficient pharmacological treatments. Although CaOx crystallization inhibitors have been suggested as a therapeutic modality already decades ago, limited progress has been made in the discovery of potent molecules with efficacy in animal disease models. Herein, an image‐based machine learning approach to systematically screen chemically modified myo‐inositol hexakisphosphate (IP6) analogues is utilized, which enables the identification of a highly active divalent inositol phosphate molecule. To date, this is the first molecule shown to completely inhibit the crystallization process in the nanomolar range, reduce crystal–cell interactions, thereby preventing CaOx‐induced transcriptomic changes, and decrease renal CaOx deposition and kidney injury in a mouse model of hyperoxaluria. In conclusion, IP6 analogues based on such a scaffold may represent a new treatment option for CaOx nephropathies. [ABSTRACT FROM AUTHOR]

Background: Patients with chronic kidney disease stage 5 (CKD5) are predisposed to vascular calcification (VC), but the combined effect of factors associated with VC was sparsely investigated. We applied the relaxed linear separability (RLS) feature selection model to identify features that concomitantly associate with VC in CKD5 patients.Methods: Epigastric arteries collected during surgery from living donor kidney transplant recipients were examined to score the histological extent of medial VC. Sixty-two phenotypic features in 152 patients were entered into RLS model to differentiate between no-minimal VC (n = 93; score 0-1) and moderate-extensive VC (n = 59; score 2-3). The subset of features associated with VC was selected on the basis of cross-validation procedure. The strength of association of the selected features with VC was expressed by the absolute value of 'RLS factor'.Results: Among 62 features, a subset of 17 features provided optimal prediction of VC with 89% of patients correctly classified into their groups. The 17 features included traditional risk factors (diabetes, age, cholesterol, BMI and male sex) and markers of bone metabolism, endothelial function, metabolites, serum antibodies and mitochondrial-derived peptide. Positive RLS factors range from 1.26 to 4.05 indicating features associated with increased risk of VC, and negative RLS factors range from -0.95 to -1.83 indicating features associated with reduced risk of VC.Conclusion: The RLS model identified 17 features including novel biomarkers and traditional risk factors that together concomitantly associated with medial VC. These results may inform further investigations of factors promoting VC in CKD5 patients. [ABSTRACT FROM AUTHOR]

Background: Although the levels of intact parathyroid hormone (iPTH) are well-controlled following the Kidney Disease Outcomes Quality Initiative guideline, the incidence of osteoporosis and fracture are still high in haemodialysis (HD) patients. This study was conducted to investigate the correlation between bone turnover markers, bone mineral density (BMD), and bone histomorphometry in HD patients. Methods: Twenty-two chronic HD patients were enrolled. Serum levels of bone turnover markers were measured. Double tetracycline-labelled iliac crest bone specimens were evaluated using specialized a computer program (Osteomeasure). The types of bone histomorphometry were classified based on turnover, mineralization and volume. BMD and coronary artery calcification were also determined. Results: Bone histomorphometry revealed osteitis fibrosa (50%), adynamic bone disease (45%) and mixed uremic osteodystrophy (5%). Serum iPTH level predicted high bone turnover with area under the receiver operating characteristic (ROC) of 0.833 (95% CI = 0.665-1.000, P = 0.008). Serum TRAP- 5b also had ROC of 0.733 (95% CI = 0.517-0.950, P = 0.065). In addition, when using serum iPTH (cut-off 484.50 ng/mL) or serum TRAP-5b (cut-off 1.91 pg./mL) to predict high turnover, the sensitivity was 0.917. On the other hand, when both iPTH and TRAP-5B were above these cut-off, the specificity was 1.000. Low BMD and severe vascular calcification were commonly identified. However, there were no significant correlations between bone biomarkers and BMD or severe vascular calcification. Conclusion: Although iPTH levels were close to the target of Kidney Disease Outcomes Quality Initiative guideline, abnormal bone histomorphometry, BMD, and severe vascular calcification are still common. Bone biopsy is still crucially required as an accurate diagnostic tool in providing optimal guide for the treatment. © 2019 Asian Pacific Society of Nephrology. [ABSTRACT FROM AUTHOR]

Vascular calcification is prevalent in patients with chronic kidney disease (CKD) and a major risk factor of cardiovascular disease. Vascular calcification is now recognised as a biological process similar to bone formation involving osteogenic differentiation of vascular smooth muscle cells (VSMCs). Cell division cycle 42 (CDC42), a Rac1 family member GTPase, is essential for cartilage development during endochondral bone formation. However, whether CDC42 affects osteogenic differentiation of VSMCs and vascular calcification remains unknown. In the present study, we observed a significant increase in the expression of CDC42 both in rat VSMCs and in calcified arteries during vascular calcification. Alizarin red staining and calcium content assay revealed that adenovirus‐mediated CDC42 overexpression led to an apparent VSMC calcification in the presence of calcifying medium, accompanied with up‐regulation of bone‐related molecules including RUNX2 and BMP2. By contrast, inhibition of CDC42 by ML141 significantly blocked calcification of VSMCs in vitro and aortic rings ex vivo. Moreover, ML141 markedly attenuated vascular calcification in rats with CKD. Furthermore, pharmacological inhibition of AKT signal was shown to block CDC42‐induced VSMC calcification. These findings demonstrate for the first time that CDC42 contributes to vascular calcification through a mechanism involving AKT signalling; this uncovered a new function of CDC42 in regulating vascular calcification. This may provide a potential therapeutic target for the treatment of vascular calcification in the context of CKD. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background and objective: Biallelic loss‐of‐function mutations of human FAM20A have been known to cause enamel‐renal syndrome (ERS), featured by agenesis of dental enamel, nephrocalcinosis, and other orodental abnormalities, including gingival hyperplasia. However, while the histopathology of this gingival anomaly has been analyzed, its underlying molecular mechanism remains largely unknown. This study aimed to unravel the pathogenesis of gingival hyperplasia in ERS. Methods: Whole‐exome sequencing was conducted for an ERS case. Transcriptome analyses, using RNA sequencing, of the patient's gingiva were performed to unravel dysregulated molecules and aberrant biological processes underlying the gingival pathology of ERS, which was further confirmed by histology and immunohistochemistry. Results: Two novel frameshift FAM20A mutations in Exon 1 (g.5417delG; c.129delG; p.Cys44Alafs*101) and Exon 5 (g.62248_62249delAG; c.734_735delAG; p.Glu245Glyfs*11) were identified. Transcriptional profiling of patient's gingival tissue revealed a total of 1683 genes whose expression had increased (1129 genes) or decreased (554 genes) at least 2‐fold compared to control gingival tissues. There were 951 gene ontology (GO) terms of biological process being significantly over‐represented or under‐represented. While GOs involved in extracellular matrix organization, angiogenesis, biomineralization, and epithelial cell proliferation appeared to be activated in ERS gingiva, genes related to keratinocyte differentiation, epithelial development, and keratinization were of decreased expression. FAM20A immunohistochemistry revealed a strong reactivity at the suprabasal layers of epithelium in control gingiva but showed a significantly diminished and scattered signal in ERS tissues. For genes showing significant over‐expression in the transcriptome analyses, namely ALPL, SPARC, and ACTA2, an increased immunoreactivity was observed. Conclusion: Our results unraveled a potential role for FAM20A in homeostasis of both gingival epithelium and connective tissues. [ABSTRACT FROM AUTHOR]

Patients with chronic kidney disease (CKD) have a predisposition to develop vascular calcification due to dysregulated homeostatic mechanisms, which lead to an imbalance in the circulatory promoters and inhibitors of vascular calcification, leading to a net calcification stress. These factors promote ectopic calcification and induce vascular smooth muscle cells to undergo osteogenic differentiation and actively calcify the vascular media. The article summarizes clinically relevant pathogenic mechanisms of vascular calcification in patients with CKD and in dialysis patients and summarizes novel therapeutic interventions. In addition to the management of traditional cardiovascular risk factors, patients with CKD-mineral and bone disorder need close attention in the management of the mineral metabolism to prevent adverse effects on the bone and vascular compartments. This article reviews current evidence and therapeutic guidelines in the management of mineral metabolism in CKD and dialysis. [ABSTRACT FROM AUTHOR]

TCM/S-associated AKI increased from 0.13% (8 patients) to 0.30% (37 patients)( I P i = 0.021). Thirty patients were followed up for 1 year, and patients in the AKI group had persistently higher SeCr, I P i = 0.005. Studies found that approximately 13%-50% patients with rhabdomyolysis develop acute kidney injury (AKI). ( I P i = 0.029) Patients using RAS blockers had a higher risk of AKI than patients who did not use RAS blockers (OR 2.53, I P i = 0.004). Patients with CKD had significantly more ICU treatment (11.5%, 1.5%, I P i < 0.001) than patients with normal renal function and had a higher mortality rate during hospitalization (11.1%, 1.0% I P i < 0.001). [Extracted from the article]

The article describes the case of a 23-year-old Malaysian woman with fever and left loin pain on a background of established distal renal tubular acidosis (dRTA) of unknown aetiology. Highlights include bilateral nephrocalcinosis and left-sided dilated renal calyces according to computed tomography imaging, erythrocytes with transverse bands of pallor known as stomatocytes according to blood film, and management of dRTA on maintaining urine calcium and serum bicarbonate in normal range.

Aims: to describe a case in which dental changes were observed and investigation proceeded to consider Enamel-Renal-Syndrome (ERS), a rare disorder that associates amelogenesis imperfecta with nephrocalcinosis.Case Report: an 11-year-old male patient upon intraoral examination revealed generalized gingival hyperplasia, a few teeth were absent clinically and the remaining ones were yellowish-brown in color. The enamel alterations were suggesting of amelogenesis imperfecta. Unerupted teeth with increased pericoronal spaces, suggesting hyperplasic follicles or dentigerous cysts and an enamel with lower thickness and density were observed in the panoramic radiography. The patient was referred for an assay to investigate mucopolysaccharidosis; however, it was negative. A renal ultrasound showed bilateral nephrocalcinosis and laboratory exams, including calcium, phosphate, and creatinine levels were below the average. An incisional gingival biopsy showed numerous round to ovoid basophilic calcifications in the connective tissue. The final diagnosis was ERS.Conclusion: Dentists should refer patients with similar clinical presentation for renal ultrasound evaluation in order to rule out the possible diagnosis of ERS. [ABSTRACT FROM AUTHOR]

Renal tubular transport mechanisms are optimized to be energy efficient and tailored to local gradients and transport rates. The combined transcellular action of ion channels, transporters, and pumps, together with the paracellular pathway, enables kidney function. Monogenetic diseases and mouse models indicate that both trans- and paracellular proteins can become disease-causing candidates and may be targets for future therapeutic approaches. Recent advances in tight junction research have provided new insights into their structure, function, and regulation. The thick ascending limb (TAL) is a nephron segment with specific requirements for the paracellular pathway. It has to fuel the generation of the corticomedullary concentration gradient, to be watertight, and to provide a highly selective permeability for Na+ and divalent cations. Tight junction composition and function in the TAL is organized along the corticomedullary axis. Even on the level of a seemingly homogeneous tubular epithelium like the TAL, there is a separation of tight junction protein expression in the strands between the respective tricellular nexus of the junctional network. Here, we highlight some new insights from our recent work and that of others in this context. In addition, we provide some perspectives for the further study of paracellular transport mechanisms. [ABSTRACT FROM AUTHOR]

The article reports on the study conducted to determine the types of disorders caused due to abnormal mineralization of soft tissues in elasmobranchs. Topics discussed include several types of soft tissue mineralization including nephrocalcinosis, calcinosis circumscripta and metastatic mineralization; causes of Nephrocalcinosis including increased levels of carbon dioxide and magnesium deficient diet, and disturbance in calcium and phosphorus metabolism leading to metastatic mineralization.

We report a rare case of nephrocalcinosis caused by hereditary renal hypouricaemia 3 months after kidney transplantation. A 41-year-old man who underwent living-related kidney transplantation from his father was admitted to our hospital for a protocol biopsy; he had a serum creatinine (S-Cr) of 1.37 mg/dL and no proteinuria. Histologically, there was no evidence of rejection or calcineurin inhibitor toxicity, although scattered nephrocalcinosis was observed in the distal tubules. Perioperatively, the patient had a serum uric acid (S-UA) of 1.9 mg/dL with a fractional excretion of uric acid (FEUA) of 29% (normal, <10%) and UA clearance of 26.8 mL/min (normal, 7.3-14.7 mL/min) 3 days after kidney transplantation. The donor also had a relatively low S-UA of 2.4 mg/dL and high FEUA of 10.3%. Subsequent DNA direct sequencing followed by restriction fragment length polymorphism revealed that both the recipient's and donor's urate transporter 1 ( URAT1) gene had a heterozygous nonsense mutation in exon 5 (C889T). Further, the immunoreactivity of antibodies for the C terminus of URAT1 revealed a partial deletion. De Galantha and von Kossa staining revealed that the nephrocalcinosis was due to urate crystals and calcium stones. Therefore, we diagnosed hereditary renal hypouricaemia. We directed the patient to avoid hard exercise, drink plenty of water, and alkalize the urine. The 1-year follow-up allograft biopsy showed no evidence of nephrocalcinosis in the distal tubules. This is the first report of nephrocalcinosis in the distal tubules as a diagnostic clue to hereditary renal hypouricaemia. We also review the related literature. [ABSTRACT FROM AUTHOR]

Aim Ceftriaxone is a commonly used antibiotic among the paediatric population. Various reports have associated high doses of Ceftriaxone with the development of nephrolithiasis; our aim was to test this association with a 5 day course of treatment. Methods Our study group consisted of 120 patients divided into two groups. The first group included 60 patients who underwent treatment with Ceftriaxone therapy that was started empirically and continued for 5 days at the dose of 80 mg/kg per day. The second group (60 patients) who received treatment with other antibiotics (other than Ceftriaxone), as recommended by hospital protocols. Patients with urinary tract infections (UTI) were excluded as UTI may be a predisposing cause for nephrolithiasis. Baseline and follow up after 5 days were done with; abdominal ultrasound, serum urea, creatinine, serum calcium, 24 h urinary calcium and urinary calcium/ creatinine ratio. Extended metabolic tests were done for cases that developed nephrolithiasis. Results Five cases out of the 60 patients treated with Ceftriaxone developed calculi; that were small and were eliminated spontaneously in four cases at mean duration of 3 weeks. In these cases renal ultrasonography examinations were normal prior to treatment; and none of them had metabolic disturbances or risk factors leading to stone formation. By multiple regression analysis, only age was related to nephrolithiasis formation being higher in the group that has developed stones. Conclusion Only patients who underwent Ceftriaxone therapy have developed renal stones, even with a short course of therapy (5 days), and in the absence of a known predisposing cause for nephrolithiasis. We have thus concluded that Ceftriaxone by itself maybe a predisposing factor for nephrolithiasis [ABSTRACT FROM AUTHOR]