Calcium Oxalate Nephrolithiasis Research Articles

Comprehensive analysis and validation of TP73 as a biomarker for calcium oxalate nephrolithiasis using machine learning and in vivo and in vitro experiments.

Calcium oxalate (CaOx) nephrolithiasis constitutes approximately 75% of nephrolithiasis cases, resulting from the supersaturation and deposition of CaOx crystals in renal tissues. Despite their prevalence, precise biomarkers for CaOx nephrolithiasis are lacking. With advances in high-throughput sequencing, we aimed to identify biomarkers of CaOx nephrolithiasis by combining twoCaOx nephrolithiasis datasets (GSE73680 and GSE117518). Utilizing weighted gene co-expression network analysis (WGCNA) and four machine learning, we identified six hub genes (DLK2, BHLHA15, C12orf5, ICMT, LOXHD1, and TP73) as potential biomarkers. Additionally, CIBERSORT immune infiltration analysis suggested that these core genes may influence immune cell recruitment and infiltration in CaOx nephrolithiasis. Then, TP73 emerged as a significant hub gene in CaOx nephrolithiasis via receiver operating characteristic (ROC) analysis (AUC = 0.885). Furthermore, the role of TP73 was validated in CaOx nephrolithiasis rat models induced by 1% ethylene glycol, as well as clinical samples and renal tubular epithelial cell models treated with 1mM oxalate. Immunohistochemistry, RNA-Sequencing, and RT-qPCR experiments demonstrated an increased expression of TP73 in CaOx nephrolithiasis rat models and clinical samples. After transfection with TP73 lentivirus, CCK-8 assays suggested that TP73 could inhibit the proliferation of HK-2 and NRK-52E cells. In oxalate-induced cell models, dihydroethidium staining and flow cytometry apoptosis assays indicated that TP73 could enhance ROS levels and cell apoptosis. In summary, our study preliminarily identified TP73 as a diagnostic biomarker and elucidated the promoting role of TP73 in CaOx nephrolithiasis, providing a deeper understanding of the clinical diagnosis and pathogenesis.

Kukoamine A alleviates nephrolithiasis by inhibiting endogenous oxalate synthesis via the IL-6/JAK/STAT3/DAO signaling pathway

BackgroundThe recurrent nature and socioeconomic burden of nephrolithiasis demand effective treatments. Delineating the crosstalk between inflammatory processes and the endogenous oxalate metabolism pathway, which underpins nephrolithiasis pathogenesis, is essential for advancing treatment strategies. PurposeWe aim to screen therapeutic Chinese herbal remedies and their bioactive constituents for kidney stone treatment using a fruit fly model, followed by efficacy and mechanism validation in a rodent nephrolithiasis model as well as in vitro human cell culture model. Study design and methodsWe developed a fruit fly model to screen for efficient traditional Chinese medicine herbs and their active compounds for kidney stone treatment. Candidate active compounds from efficient herbs were separated and identified by solid-phase chromatography coupled with LC-MS analysis. Fruit fly genetic tools were employed to manipulate the expression of related genes to explore the therapeutic mechanisms of the Lycii Cortex and kukoamine A (KuA). To confirm the therapeutic effects and mechanisms of KuA for mammalian nephrolithiasis, mouse model of glyoxylate-induced kidney stone and human renal tubular cells were used. The therapeutic role of kukoamine A in nephrolithiasis was evaluated by assessing tubular injury, crystal deposition, and adhesion. The level of expression and phosphorylation in cells and mice was assessed using RT-qPCR and western blot. ResultsOur findings indicate that Lycii Cortex potently inhibits calcium oxalate stone formation via activation of the JNK/Upd3/JAK/STAT signaling cascade, resulting in diminished endogenous oxalate synthesis by downregulating D-amino acid oxidase (DAO) gene expression, predominantly in fruit fly Malpighian tube stellate cells. KuA was identified as the principal bioactive constituent mediating these effects. Both mouse models and human cell assays confirmed KuA's efficacy in preventing calcium oxalate nephrolithiasis in mammals, through hepatic JAK/STAT3 pathway activation and upregulation of IL-6, culminating in reduced urinary crystal deposition. ConclusionOur research underscores the potential of kukoamine A as a lead compound in treating nephrolithiasis and reveals the interplay between the IL-6/JAK/STAT3 inflammatory pathway and endogenous oxalate metabolism in nephrolithiasis pathogenesis. Additionally, it highlights the utility of the fruit fly model as a powerful tool for deciphering the therapeutic mechanisms of traditional Chinese herbs.

Prophylactic and curative activity of Withania somnifera on experimentally induced calcium oxalate nephrolithiasis

Withania somnifera an ayurvedic herb was utilized to assess the antilithic properties of calcium oxalate (CaOx) Nephrolithiasis in rats fed ethylene glycol (EG) in an experimental setting. There were 5 groups of animals (n = 6). The control group was given normal saline, Lithiatic control was given ethylene glycol 1% (v/v) with ammonium chloride 1% (w/v) for 4 days (received stone inducing treatment till 28th day ), follow by 1% ethylene glycol alone in water, Standard group received antiurolithiatic drug (Cystone) (500 mg/Kg) from 15th day till 28th day, treatment group received Withania somnifera methanolic extract (200 mg/Kg) from 15th day till 28th day (Curative regimen) and received Withania somnifera methanolic extract (WS-200 mg/Kg) from 1st day till 28th day (prophylactic regimen) in wistar rats. Blood and kidney tissue were collected after the 28th day of urine. Ca2-, Mg2+, K+ and PO4- levels were estimated in urine, creatinine and urea level were estimated in serum whereas all oxidative stress was measured in kidney tissue. Additionally, Urinary microscopy and kidney histopathology were estimated. Lithiatic control group showed significant elevation (P<0.0001 vs. control) in serum creatinine, blood urea and antioxidants levels. Due to crystal deposits, the histopathology of Lithiatic group showed tubule dilatation with interstitial inflammatory infiltrate, whereas the therapy group showed less tubule dilatation with interstitial inflammatory infiltrate. It can be concluded that at 200 mg/kg the herbal drug possessed significant potential in the management of nephrolithiasis.

Identification and validation of the biomarkers related to ferroptosis in calcium oxalate nephrolithiasis.

Ferroptosis is a specific type of programmed cell death characterized by iron-dependent lipid peroxidation. Understanding the involvement of ferroptosis in calcium oxalate (CaOx) stone formation may reveal potential targets for this condition. The publicly available dataset GSE73680 was used to identify 61 differentially expressed ferroptosis-related genes (DEFERGs) between normal kidney tissues and Randall's plaques (RPs) from patients with nephrolithiasis through employing weighted gene co-expression network analysis (WGCNA). The findings were validated through in vitro and in vivo experiments using CaOx nephrolithiasis rat models induced by 1% ethylene glycol administration and HK-2 cell models treated with 1 mM oxalate. Through WGCNA and the machine learning algorithm, we identified LAMP2 and MDM4 as the hub DEFERGs. Subsequently, nephrolithiasis samples were classified into cluster 1 and cluster 2 based on the expression of the hub DEFERGs. Validation experiments demonstrated decreased expression of LAMP2 and MDM4 in CaOx nephrolithiasis animal models and cells. Treatment with ferrostatin-1 (Fer-1), a ferroptosis inhibitor, partially reversed oxidative stress and lipid peroxidation in CaOx nephrolithiasis models. Moreover, Fer-1 also reversed the expression changes of LAMP2 and MDM4 in CaOx nephrolithiasis models. Our findings suggest that ferroptosis may be involved in the formation of CaOx kidney stones through the regulation of LAMP2 and MDM4.

Urinary oxalate excretion is increased in calcium oxalate nephrolithiasis patients and associated with increased urinary capacity of calcium oxalate crystallization

Urinary oxalate excretion is increased in calcium oxalate nephrolithiasis patients and associated with increased urinary capacity of calcium oxalate crystallization

Inhibitory effect of Incarvillea diffusa Royle extract in the formation of calcium oxalate nephrolithiasis by regulating ROS-induced Nrf2/HO-1 pathway in rats

Ethnopharmacological relevanceCalcium oxalate (CaOx) kidney stones are widely acknowledged as the most prevalent type of urinary stones, with high incidence and recurrence rates. Incarvillea diffusa Royle (ID) is a traditionally used medicinal herb in the Miao Minzu of Guizhou province, China, for treating urolithiasis. However, the active components and the underlying mechanism of its pharmacodynamic effects remain unclear. Aim of the studyThis study aimed to investigate the potential inhibitory effect of the active component of ID on the formation of CaOx nephrolithiasis and elucidate the underlying mechanism. Materials and methodsIn vivo, a CaOx kidney stone model was induced in Sprague-Dawley (SD) rats using an ethylene glycol and ammonium chloride protocol for four weeks. Forty-eight male SD rats were randomly assigned to 6 groups (n = 8): blank group, model group, apocynin group, and low, medium, and high dose of ID's active component (IDW) groups. After three weeks of administration, rat urine, serum, and kidney tissues were collected. Renal tissue damage and crystallization, Ox, BUN, Ca2+, CRE, GSH, MDA, SOD contents, and levels of IL-1β, IL-18, MCP-1, caspase-1, IL-6, and TNF-α in urine, serum, and kidney tissue were assessed using HE staining and relevant assay kits, respectively. Protein expression of Nrf2, HO-1, p38, p65, and Toll-4 in kidney tissues was quantified via Western blot. The antioxidant capacities of major compounds were evaluated through DPPH, O2·-, and ·OH radical scavenging assays, along with their effects on intracellular ROS production in CaOx-induced HK-2 cells. ResultsWe found that IDW could significantly reduce the levels of CRE, GSH, MDA, Ox, and BUN, and enhancing SOD activity. Moreover, it could inhibit the secretion of TNF-α, IL-1β, IL-18, MCP-1, caspase-1, and decreased protein expression of Nrf2, HO-1, p38, p65, and Toll-4 in renal tissue. Three major compounds isolated from IDW exhibited promising antioxidant activities and inhibited intracellular ROS production in CaOx-induced HK-2 cells. ConclusionsIDW facilitated the excretion of supersaturated Ca2+ and decreased the production of Ox, BUN in SD rat urine, and mitigated renal tissue damage by regulating Nrf2/HO-1 signaling pathway. Importantly, the three major compounds identified as active components of IDW contributed to the inhibition of CaOx nephrolithiasis formation. Overall, IDW holds significant potential for treating CaOx nephrolithiasis.

PPARγ agonist alleviates calcium oxalate nephrolithiasis by regulating mitochondrial dynamics in renal tubular epithelial cell.

Kidney stone formation is a common disease that causes a significant threat to human health. The crystallization mechanism of calcium oxalate, the most common type of kidney stone, has been extensively researched, yet the damaging effects and mechanisms of calcium oxalate crystals on renal tubular epithelial cells remain incompletely elucidated. Regulated mitochondrial dynamics is essential for eukaryotic cells, but its role in the occurrence and progression of calcium oxalate (CaOx) nephrolithiasis is not yet understood. An animal model of calcium oxalate-related nephrolithiasis was established in adult male Sprague‒Dawley (SD) rats by continuously administering drinking water containing 1% ethylene glycol for 28 days. The impact of calcium oxalate crystals on mitochondrial dynamics and apoptosis in renal tubular epithelial cells was investigated using HK2 cells in vitro. Blood samples and bilateral kidney tissues were collected for histopathological evaluation and processed for tissue injury, inflammation, fibrosis, oxidative stress detection, and mitochondrial dynamics parameter analysis. Calcium oxalate crystals caused higher levels of mitochondrial fission and apoptosis in renal tubular epithelial cells both in vivo and in vitro. Administration of a PPARγ agonist significantly alleviated mitochondrial fission and apoptosis in renal tubular epithelial cells, and improved renal function, accompanied by reduced levels of oxidative stress, increased antioxidant enzyme expression, alleviation of inflammation, and reduced fibrosis in vivo. Our results indicated that increased mitochondrial fission in renal tubular epithelial cells is a critical component of kidney injury caused by calcium oxalate stones, leading to the accumulation of reactive oxygen species within the tissue and the subsequent initiation of apoptosis. Regulating mitochondrial dynamics represents a promising approach for calcium oxalate nephrolithiasis.

Lycopene from tomatoes and tomato products exerts renoprotective effects by ameliorating oxidative stress, apoptosis, pyroptosis, fibrosis, and inflammatory injury in calcium oxalate nephrolithiasis: the underlying mechanisms.

Several mechanisms underlying nephrolithiasis, one of the most common urological diseases, involve calcium oxalate formation, including oxidative stress, inflammatory reactions, fibrosis, pyroptosis, and apoptosis. Although lycopene has strong antioxidant activity, its protective effects against CaOx-induced injury have not yet been reported. This study aimed to systematically investigate the protective effects of lycopene and explore its mechanisms and molecular targets. Crystal deposition, renal function, oxidative stress, inflammatory response, fibrosis, pyroptosis, and apoptosis were assessed to evaluate the renoprotective effects of lycopene against crystal formation in a CaOx rat model and oxalate-stimulated NRK-52E and HK-2 cells. Lycopene markedly ameliorated crystal deposition, restored renal function, and suppressed kidney injury by reducing oxidative stress, apoptosis, inflammation, fibrosis, and pyroptosis in the rats. In cell models, lycopene pretreatment reversed reactive oxygen species increase, apoptotic damage, intracellular lactate dehydrogenase release, cytotoxicity, pyroptosis, and extracellular matrix deposition. Network pharmacology and proteomic analyses were performed to identify lycopene target proteins under CaOx-exposed conditions, and the results showed that Trappc4 might be a pivotal target gene for lycopene, as identified by cellular thermal shift assay and surface plasmon resonance analyses. Based on molecular docking, molecular dynamics simulations, alanine scanning mutagenesis, and saturation mutagenesis, we observed that lycopene directly interacts with Trappc4 via hydrophobic bonds, which may be attributed to the PHE4 and PHE142 residues, preventing ERK1/2 or elevating AMPK signaling pathway phosphorylation events. In conclusion, lycopene might ameliorate oxalate-induced renal tubular epithelial cell injury via the Trappc4/ERK1/2/AMPK pathway, indicating its potential for the treatment of nephrolithiasis.

Melatonin alleviates intrarenal CaOx crystals deposition through inhibiting LPS-induced non-canonical inflammasome-mediated renal tubular epithelial cells pyroptosis

Urinary tract infection has long been considered a complication rather than etiology of calcium oxalate (CaOx) nephrolithiasis. This study aimed to explore the role of lipopolysaccharide (LPS), an important component of Gram-negative bacteria, on CaOx nephrolithiasis formation and antagonistic effect of melatonin. Male C57BL/6 mice were intraperitoneally injected with glyoxylate acid (80 mg/kg) daily for 7 days to construct CaOx nephrolithiasis model. A single dose of LPS (2.0 mg/kg) was given 2 h before the second glyoxylate acid treatment in the presence or absence of melatonin (25 mg/kg). Our results found that LPS promoted adhesion of CaOx crystals to renal tubular epithelial cells (RTECs) and intrarenal CaOx crystals deposition. Protein levels of cleaved Caspase-11, N-terminal of cleaved GSDMD (GSDMD-N), NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and cleaved Caspase-1, several markers of non-classical inflammasome activation were upregulated in LPS-treated mouse kidneys and HK-2 cells. Moreover, the number of GSDMD pores was increased in LPS-treated HK-2 cell membrane. Melatonin inhibited Caspase-11 cleavage and antagonized the subsequent LPS-mediated upregulation of GSDMD-N, NLRP3 and cleaved Caspase-1 in kidney tissues and HK-2 cells. In addition, melatonin reduced membrane localization of GSDMD-N and the number of GSDMD pores in LPS-treated HK-2 cells. Accordingly, melatonin inhibited LPS-induced IL-1β and IL-18 in mouse serum and HK-2 culture supernatant. Importantly, melatonin alleviated LPS-induced crystal-cell interactions and intrarenal CaOx crystals deposition. We provide experimental evidence that LPS promoted CaOx nephrolithiasis formation by inducing non-canonical inflammasome-mediated RTECs pyroptosis. Melatonin alleviated CaOx nephrolithiasis formation through inhibiting LPS-induced non-canonical inflammasome-mediated RTECs pyroptosis.

Butyric acid inhibits oxidative stress and inflammation injury in calcium oxalate nephrolithiasis by targeting CYP2C9.

This study investigates the mechanism by which butyric acid can protect against calcium oxalate (CaOx) nephrolithiasis. To do so, a rat model was used with 0.75% ethylene glycol administration to induce CaOx crystal formation. Histological and von Kossa staining revealed calcium deposits and renal injury, while dihydroethidium fluorescence staining was used to detect reactive oxygen species (ROS) levels. Flow cytometry and TUNEL assays were used to assess apoptosis, respectively. Treatment with sodium butyrate (NaB) was found to partially reverse the oxidative stress, inflammation, and apoptosis associated with CaOx crystallization in the kidney. In addition, in HK-2cells, NaB reversed the decreased cell viability, increased ROS levels and apoptosis damage caused by oxalate exposure. Network pharmacology was employed to predict the target genes of butyric acid, CYP2C9. Subsequently, NaB was found to significantly reduce CYP2C9 levels in vivo and in vitro, and inhibition of CYP2C9 by Sulfaphenazole (a specific CYP2C9 inhibitor), was able to reduce ROS levels, inflammation injury, and apoptosis in oxalate-induced HK-2cells. Collectively, these findings suggest that butyric acid may inhibit oxidative stress and reduce inflammation injury in CaOx nephrolithiasis by suppressing CYP2C9.

Dynamic change and preventive role of stress response via Keap1-Nrf2 during renal crystal formation

Oxidative stress is a major risk factor for calcium oxalate nephrolithiasis. Reports suggest that oxidative stress response is induced in animals and humans with kidney stones. Keap1, Nrf2, and HO-1 are known as oxidative stress mediators. However, the association between oxidative stress response and stone formation is unclear. In this study, we analyzed oxidative stress response from the acute to the crystal formation phase when crystal formation was applied to renal crystal mice model and bioimaging mice and investigated the effect on crystal formation. In renal tissues, after glyoxylate administration, HO-1 increased for up to 6 h and returned to baseline at 24 h. This was observed following each daily dose until five days after the crystallization phase; however, the range of increase was attenuated. The possibility that Nrf2 activity influenced the number of crystals was considered in the experiment. Crystal formation increased in Nrf2-deficient mice and could be reduced by Nrf2 activators. In conclusion, the oxidative stress response via the Keap1-Nrf2 pathway may contribute to crystal formation. Particularly, this pathway may be a prospective target for drug development to prevent and cure nephrolithiasis.

Diagnostic policies on nephrolithiasis/nephrocalcinosis of possible genetic origin by Italian nephrologists: a survey by the Italian Society of Nephrology with an emphasis on primary hyperoxaluria

BackgroundPrimary hyperoxaluria is a genetic disorder of the metabolism of glyoxylate, the precursor of oxalate. It is characterized by high endogenous production and excessive urinary excretion of oxalate, resulting in the development of calcium oxalate nephrolithiasis, nephrocalcinosis, and, in severe cases, end-stage kidney disease and systemic oxalosis. Three different forms of primary hyperoxaluria are currently known, each characterized by a specific enzymatic defect: type 1 (PH1), type 2 (PH2), and type 3 (PH3). According to currently available epidemiological data, PH1 is by far the most common form (about 80% of cases), and is caused by a deficiency of the hepatic enzyme alanine:glyoxylate aminotransferase.MethodsA survey on rare forms of nephrolithiasis and nephrocalcinosis with a focus on primary hyperoxaluria in the setting of Italian Nephrology and Dialysis Centers, using an online questionnaire, was recently conducted by the Project Group “Rare Forms of Nephrolithiasis and Nephrocalcinosis” of the Italian Society of Nephrology, with the aim of assessing the impact and management of this disorder in clinical practice in Italy.ResultsForty-five public and private Italian Centers participated in the survey, and responses to the questionnaire were provided by 54 medical professionals. The survey results indicate that 21 out of the 45 participating Centers are managing or have managed primary hyperoxaluria patients, most of whom are on dialysis, or are recipients of kidney transplants.ConclusionsThe data of this survey indicate the need to implement genetic testing in suspected cases of primary hyperoxaluria, not only in the setting of dialysis or transplantation, but also with the aim of encouraging early diagnosis of PH1, which is the only type of primary hyperoxaluria for which specific drug therapy is currently available.Graphical abstract

Risk factors and predictors of urogenous sepsis after percutaneous nephrolithotomy for idiopathic calcium oxalate nephrolithiasis.

The aim of this study was to use bioinformatics approaches to screen and identify the key genes of idiopathic calcium oxalate nephrolithiasis, and explore its potential molecular mechanism. The GSE73680 kidney stone data set was downloaded from the Gene Expression Omnibus (GEO). R software (The R Foundation for Statistical Computing) was used to screen differentially expressed genes. GeneMANIA and Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) databases were used to analyze related genes interacting with crucial genes, and a protein-protein interaction (PPI) network was constructed. The differential genes were then subjected to the Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) database. The clinical data of 156 patients who received percutaneous nephrolithotomy (PCNL) therapy at our facility between January 2013 and December 2017 were retrospectively analyzed. The various parameters associated with postoperative urogenous sepsis were identified using multivariable logistic regression analysis. The study discovered one differentially expressed gene was nucleotide-binding oligomerization domain-containing protein 2 (NOD2). GO and KEGG analysis showed that NOD2 might affect the occurrence of idiopathic calcium oxalate kidney stones by affecting inflammation, receptor expression, immune environment, necrosis, apoptosis, and other pathways. The clinical parameter of patients who participated in the study, including preoperative urinary white blood cell (WBC) count, preoperative urinary nitrite, stone diameter, operation time, WBC count, and WBC D values, were statistically different between the systemic inflammatory response syndrome (SIRS) group and the urosepsis group. According to multivariate logistic regression analysis, the preoperative urine nitrite, calculus diameter, blood WBC, and NOD2 expression 3 hours after surgery were all independently associated with the urosepsis development. Preoperative urinary nitrite positive status, postoperative WBC count ≥2.98×109/L 3 hours after operation, stone diameter >6 cm, and low expression of NOD2 in renal papillary tissue are more likely to cause the urinary source of idiopathic calcium oxalate nephrolithiasis after PCNL urogenous sepsis. These parameters also offer a viable treatment paradigm for the perioperative management of PCNL in treating idiopathic calcium oxalate kidney stones.

Untargeted and targeted metabolomics reveal bile acid profile changes in rats with ethylene glycol-induced calcium oxalate nephrolithiasis

Calcium oxalate (CaOx) nephrolithiasis is a prevalent disorder linked to metabolism. Examining metabolic alterations could potentially give an initial understanding of the origins of CaOx nephrolithiasis. This study aims to determine gut metabolic biomarkers differentiating CaOx nephrolithiasis utilizing untargeted and targeted metabolomics. CaOx nephrolithiasis model rats were built by 1% ethylene glycol administration. Histologic staining and renal function measurement revealed the presence of crystals in the lumen of the renal tubules, the renal injury and interstitial fibrosis in CaOx rats, demonstrating that the models of CaOx were established successfully. Hematoxylin & eosin (H&E) staining showed that CaOx group had inflammation and damage in the ileal tissue. Immunofluorescence and PCR results displayed that the tight junction proteins, ZO-1 and Occludin levels were decreased in the ileal tissues of the CaOx group. The untargeted metabolomic analysis revealed that 269 gut metabolites were differentially expressed between the CaOx group and the control group. Meanwhile, bile secretion, the main metabolic pathway in CaOx nephrolithiasis, was identified. Following, five significant bile acid metabolites were selected utilizing the targeted bile acid metabolomics, including Hyodeoxycholic acid (HDCA), Glycohyodeoxycholic acid (GHDCA), Nor-Deoxycholic Acid, omega-muricholic acid, and Taurolithocholic acid. Among these metabolites, HDCA and GHDCA presented the highest predictive accuracy with AUC = 1 to distinguish the CaOx group from the control group. As a result of network pharmacology, target genes of HDCA and GHDCA in CaOx nephrolithiasis were enriched in oxidative stress and apoptosis pathways. Conclusively, our study provides insight into bile acids metabolic changes related to CaOx nephrolithiasis. Although alterations in biochemical pathways indicate a complex pathology in CaOx rats, bile acid changes may serve as biomarkers of CaOx nephrolithiasis.

Increased renal uptake and urine excretion of oxidized LDL is possibly associated with formation of large calcium oxalate nephrolithiasis: a preliminary study

Growing evidence have suggested an association between nephrolithiasis and cardiovascular disease (CVD)with unclear mechanism. Oxidized low-density lipoproteins (oxLDL) induces atherosclerosis and was found to be the possible link between these two diseases. Our study aimed to examine the serum, urine and kidney expression of oxLDL in relation to large calcium oxalate (CaOx) renal stone disease. A total of 67 large CaOx dominant renal stone patients and 31 stone-free controls were enrolled in the prospective case-control study. All participants were without known CVD history. Serum, urine, and kidney biopsy were collected before and during percutaneous nephrolithotomy, respectively. Enzyme-linked immunosorbent assays were used to assess serum and urine oxLDL, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), and high-sensitivity C-reactive protein (hsCRP). There was no significantly difference in circulating oxLDL, but serum hsCRP was significantly near two-fold higher in nephrolithiasis patients. Serum hsCRP was also correlated with stone maximal length. Urine oxLDL was significantly higher in the nephrolithiasis group and correlated with serum hsCRP and stone maximal length. Increased oxLDL uptake in kidney was found in nephrolithiasis patients, whereas no significantly renal expression of oxLDL was observed in controls. The renal uptake of oxLDL with increased oxLDL excretion from large CaOxrenal stone formers, independent of increased circulating oxLDL, is a novel pathological finding in kidney stone disease and brings attention to the possible involvement of renal steatosis in the process of urolithiasis formation.

Increased renal uptake and urine excretion of oxidized LDL is possibly associated with formation of large calcium oxalate nephrolithiasis

Increased renal uptake and urine excretion of oxidized LDL is possibly associated with formation of large calcium oxalate nephrolithiasis

Лечение пациентов с хроническим калькулезным пиелонефритом.

Introduction. Frequent complications of kidney stone disease (KSD) are infectious and inflammatory processes in the organs of the genitourinary system, the most important of which is pyelonephritis. Adhering to a restrained tactic with small caliceal calculi, we observe a significant number of patients with chronic calculous non-obstructive pyelonephritis. Conservative treatment of these patients presents great practical difficulties, as it involves the mandatory parallel treatment of two diseases – pyelonephritis and KSD. The aim of this prospective study was to investigate the effectiveness of conservative therapy in patients with chronic calculous pyelonephritis. Materials and methods. The study included 100 patients with a verified diagnosis of chronic calculous pyelonephritis against the background of existing small caliceal calculi (up to 10 mm). Patients were divided into 2 groups, comparable in terms of the main evaluated criteria. Patients of the first (control) group (40 people) received etiotropic antibiotic course therapy in combination with antispasmodics and immunomodulators. Patients of the second (main) group (60 people) additionally for 3 months took the phytocomplex Onpelvicit 1 capsule 3 times a day under the control of urine pH. Results. At the control examination after 3 months in the group of patients treated with Onpelvicit the frequency of exacerbations of chronic pyelonephritis was significantly lower than in the control group of patients. In the main group, 50% of patients showed a decrease in the size of the calculus, in 15% of cases – complete litholysis. The noted positive effect in relation to chronic pyelonephritis is obviously associated with the phytocomponents of the drug. The effect on the size of the stones is largely due to the presence of sodium and potassium citrates in the complex. Citrate is one of the main inhibitors of crystallization. This effect is realized in both calcium oxalate and urate nephrolithiasis, although the mechanisms differ. Stabilization of the colloidal state of urine, normalization of the acidity index prevents the crystallization of salts and the growth of calculi. Conclusion. Chronic calculous pyelonephritis, which occurs against the background of small calyx calculi of the kidney, is a variant of a combined pathology that is widely encountered in urological practice. The dominant concept of management of this group of patients is to conduct conservative treatment. A pronounced acid reaction of urine in combination with crystalluria of one kind or another is a significant factor in the progression or recurrence of stone formation and the severe course of the inflammatory process. The present study shows that the correction of these disorders has a positive effect on the course of both diseases.

OXGR1 is a candidate disease gene for human calcium oxalate nephrolithiasis

Nephrolithiasis (NL) affects 1 in 11 individuals worldwide, leading to significant patient morbidity. NL is associated with nephrocalcinosis (NC), a risk factor for chronic kidney disease. Causative genetic variants are detected in 11% to 28% of NL and/or NC, suggesting that additional NL/NC-associated genetic loci await discovery. Therefore, we employed genomic approaches to discover novel genetic forms of NL/NC. Exome sequencing and directed sequencing of the OXGR1 locus were performed in a worldwide NL/NC cohort. Putatively deleterious, rare OXGR1 variants were functionally characterized. Exome sequencing revealed a heterozygous OXGR1 missense variant (c.371T>G, p.L124R) cosegregating with calcium oxalate NL and/or NC disease in an autosomal dominant inheritance pattern within a multigenerational family with 5 affected individuals. OXGR1 encodes 2-oxoglutarate (α-ketoglutarate [AKG]) receptor 1 in the distal nephron. In response to its ligand AKG, OXGR1 stimulates the chloride-bicarbonate exchanger, pendrin, which also regulates transepithelial calcium transport in cortical connecting tubules. Strong amino acid conservation in orthologs and paralogs, severe in silico prediction scores, and extreme rarity in exome population databases suggested that the variant was deleterious. Interrogation of the OXGR1 locus in 1107 additional NL/NC families identified 5 additional deleterious dominant variants in 5 families with calcium oxalate NL/NC. Rare, potentially deleterious OXGR1 variants were enriched in patients with NL/NC compared with Exome Aggregation Consortium controls (χ2= 7.117, P= .0076). Wild-type OXGR1-expressing Xenopus oocytes exhibited AKG-responsive Ca2+ uptake. Of 5 NL/NC-associated missense variants, 5 revealed impaired AKG-dependent Ca2+ uptake, demonstrating loss of function. Rare, dominant loss-of-function OXGR1 variants are associated with recurrent calcium oxalate NL/NC disease.

Editorial Comment

In 1985, potassium citrate was approved by the FDA for kidney stone prevention in distal renal tubular acidosis with calcium stones, hypocitraturic calcium oxalate nephrolithiasis of any etiology and uric acid lithiasis with or without calcium stones. Potassium citrate is now widely used either alone or in combination with thiazide or thiazide analogue diuretics for the treatment of calcium nephrolithiasis.

A pilot dynamic analysis of formative factors of nephrolithiasis related to metabolic syndrome: evidence in a rat model

Introduction and objective To examine the dynamic changes in the formative factors of nephrolithiasis and the final micromorphological changes in an obesity-initiated metabolic syndrome (MS) rat model. Methods Forty five-week-old male Sprague–Dawley (SD) rats were randomly divided into four groups: the regular diet group (RD), high-fat diet group (HFD), regular diet with drug (ethylene glycol and ammonium chloride) group (RDD), and high-fat diet with drug group (HFDD). A dynamic assessment of MS components (body weight (BW), body length (BL), Lee’s index (LI), blood glucose (BG), total cholesterol (TC), and triglycerides (TGs)) and stone-forming factors (urinary pH, urinary calcium, and urinary oxalate acid) was carried out. In addition, the levels of oxidative stress (OS) markers (CAT, SOD, TAC, GSH-PX, and MDA) were measured, and histological analysis was carried out at the end of 16 weeks. Results MS-related parameters, such as BW, LI, BG, TC, and TG, were significantly higher in HFD-fed rats than in RD-fed rats (p < 0.001). In the HFDD group, significantly lower urinary pH, hyperoxaluria, and hypocalciuria were noted in the dynamic assessment of stone-forming factors (p < 0.001). CAT, TAC, and MDA were notably changed in the HFD-fed groups, particularly the HFDD rats. Histological analysis showed that the renal tubules of HFDD rats had the highest scores for both inflammation and renal crystallization deposition (p < 0.05). Conclusions Our results suggest that male SD rats with MS are prone to developing nephrolithiasis. Validation in an in vivo model may lead to an understanding of the underlying pathophysiological mechanisms of action of MS-related nephrolithiasis in humans. Key messages Male SD rats with metabolic syndrome are more prone to developing calcium oxalate nephrolithiasis after treatment with ethylene glycol and ammonium chloride compared to control lean rats. MS-related nephrolithiasis in rats induced by ethylene glycol and ammonium chloride is mainly related to increased hyperoxaluria and inflammation and decreased antioxidant levels. High-fat diet-fed SD rats treated with ethylene glycol and ammonium chloride are a stable and valid in vivo model for understanding the potential mechanism of action of MS-related nephrolithiasis.