Pathogenesis Of Kidney Stones Research Articles

Genetic insights into kidney stone formation: a Mendelian randomization study of protein quantitative trait loci.

Kidney stones are a common urological condition caused by a complex interaction of genetic, metabolic, and environmental factors. Recent genomic research has shed light on the genetic basis of kidney stone susceptibility.This study aims to identify protein quantitative trait loci (pQTL) associated with kidney stone formation and explore their causal relationships using Mendelian randomization.We conducted two-sample Mendelian Randomization (MR) analyses utilizing Genome-Wide Association Study (GWAS) summary data to assess the causal impact of pQTL on kidney stone formation. Data sources included the UK Biobank dataset "ukb-b-8297" and an external validation dataset "ukb-b-13537". We employed inverse variance weighting (IVW) as the primary MR method, supplemented by sensitivity analyses such as MR-PRESSO, Leave-One-Out, and Cochran Q tests to validate the robustness of our findings.Our analyses identified significant associations between several pQTL and kidney stones. Key proteins such as CD27, CXCL9, and TNFRSF1A exhibited significant centrality in the protein-protein interaction (PPI) network, suggesting their critical roles in kidney stone pathogenesis. The KEGG pathway enrichment analysis revealed significant pathways, including cytokine-cytokine receptor interaction and osteoclast differentiation, highlighting the involvement of immune response and inflammatory processes in kidney stone formation.This study underscores the significance of pQTL in kidney stone research, identifying key proteins and pathways that may serve as biomarkers or therapeutic targets. The findings provide insights into the genetic and molecular mechanisms underlying kidney stone formation, offering potential avenues for future research and therapeutic interventions.

Gut Microbiota Comparison in Rectal Swabs Versus Stool Samples in Cats with Kidney Stones

To investigate the role of the intestinal bacterial microbiota in the pathogenesis of calcium oxalate nephrolithiasis in cats, a condition characterized by the formation of kidney stones, it is desirable to identify a sample collection method that accurately reflects the microbiota’s composition. The objective of this study was to evaluate the impact of fecal sample collection methods on the intestinal microbiota composition in two cat populations: healthy cats and kidney stone-diseased cats. The study included eighteen cats from the same colony, comprising nine healthy cats and nine cats with spontaneously occurring presumed calcium oxalate kidney stones. Three fecal collection methods were compared: rectal swabs, the collection of fresh stool, and the collection of stool exposed to ambient air for 24 h. The bacterial microbiota was analyzed through the high-resolution sequencing of the V3–V4 region of the 16S rRNA gene. For all cats, within the same individual, a one-way PERMANOVA analysis showed a significant difference between the rectal swabs and fresh stool (p = 0.0003), as well as between the rectal swabs and stool exposed to ambient air for 24 h (p = 0.0003), but no significant difference was identified between the fresh stool and non-fresh stool (p = 0.0651). When comparing the two populations of cats, this study provides seemingly conflicting results. (1) A principal component analysis (PCA) comparison revealed a significant difference in the bacterial composition between the healthy cats and the cats with kidney stones only when the sample was a fresh fecal sample (p = 0.0037). This finding suggests that the intestinal bacteria involved in the pathogenesis of kidney stones in cats are luminal and strictly anaerobic bacteria. Consequently, exposure to ambient air results in a loss of information, preventing the identification of dysbiosis. For clinical studies, non-fresh stool samples provided by owners does not appear suitable for studying the gut microbiota of cats with kidney stones; fresh stool should be favored. (2) Interestingly, the rectal swabs alone highlighted significant differences in the proportion of major phyla between the two populations. These findings highlight the critical importance of carefully selecting fecal collection methods when studying feline gut microbiota. Combining rectal swabs and fresh stool sampling provides complementary insights, offering the most accurate understanding of the gut microbiota composition in the context of feline kidney stone pathogenesis.

Selenium participates in the formation of kidney stones by alleviating endoplasmic reticulum stress and apoptosis of renal tubular epithelial cells

ABSTRACT Objectives: To investigate the role of selenium and selenium-containing proteins in the etiology and pathogenesis of kidney stones. Methods: The HK-2 cell line was subjected to supersaturation oxalate treatment to establish an in vitro model of calcium oxalate kidney stones, while SD rats were administered with ethylene glycol to establish an in vivo model of calcium oxalate kidney stones. qPCR analysis was employed to investigate the alterations in selenoproteins within the models, and subsequently, genes exhibiting significant changes were identified. Subsequently, based on the functions of these genes, their regulatory effects on endoplasmic reticulum stress (ERS) and apoptosis during the disease progression were examined both in HK-2 cells and rat kidneys. Finally, Selenomethionine (SeMet) supplementation was introduced to explore its therapeutic potential for kidney stone management. Results: The involvement of Selenoprotein K in the pathogenesis of calcium oxalate kidney stone disease has been confirmed, exhibiting significant alterations. Manipulation of its expression levels through overexpression and knockdown techniques resulted in a corresponding reduction or increase in oxidative stress, ERS, and apoptosis within renal tubular epithelial cells. SelK regulates ERS and apoptosis by controlling the IRE1-ASK1-JNK pathway. In addition, SeMet treatment, which contains selenium, effectively reduced the levels of oxidative stress, ERS, and apoptosis in vivo and in vitro models, thereby alleviating tubular epithelial cell damage and reducing the formation of kidney stones in experimental rats. Discussion: Selenium is involved in the occurrence and development of kidney stones by regulating oxidative damage to renal tubular epithelial cells. The results suggest that dietary selenium supplementation in daily life may be of great significance for the prevention and treatment of kidney stones.

The interactions of protein-calcium oxalate in crystallization process

Understanding the pathogenic crystallization of calcium oxalate (CaOx), a major constituent of kidney stones, is crucial in developing effective treatment strategies. In this work, the interactions between lysozyme and CaOx during crystallization have been investigated. Further investigations into the crystal morphology, size, quantity, and nucleation time of the lysozyme have been designed. The results reveal that CaCl2 could act as an effective precipitant for lysozyme crystallization. The formation process and structure of the distinctive composite CaOx-lysozyme crystal has been investigated. The addition of lysozyme promoted the formation of individual CaOx crystals by preventing the crystal aggregation in the solution. The presence of lysozyme induced a transformation in the CaOx crystals from calcium oxalate monohydrate to calcium oxalate dihydrate. These findings contribute to a better understanding of protein-CaOx interactions and their implications in kidney stone pathogenesis.

Quercetin inhibits calcium oxalate crystallization and growth but promotes crystal aggregation and invasion

Recent evidence has shown an association between kidney stone pathogenesis and oxidative stress. Many anti-oxidants have been studied with an aim for stone prevention. Quercetin, a natural flavonol, is one among those eminent anti-oxidants with satisfactory anti-inflammatory property to cope with renal tissue injury in kidney stone disease. Nevertheless, its direct effect (if any) on calcium oxalate (CaOx) crystals and the stone formation mechanism had not been previously explored. This study has addressed the ability of quercetin at various concentrations (2.5, 5, 10, 20, 40, 80 and 160 μM) to directly modulate CaOx crystallization, growth, aggregation, adhesion on kidney cells, and invasion through the matrix. The data have shown that quercetin significantly inhibits CaOx crystallization and crystal growth but promotes crystal aggregation in concentration-dependent manner. However, quercetin at all these concentrations do not affect CaOx adhesion on kidney cells. For the invasion, quercetin at all concentrations constantly promotes CaOx invasion through the matrix without concentration-dependent pattern. These discoveries have demonstrated for the first time that quercetin has direct but dual modulatory effects on CaOx crystals. While quercetin inhibits CaOx crystallization and growth, on the other hand, it promotes CaOx crystal aggregation and invasion through the matrix. These data highlight the role for quercetin in direct modulation of the CaOx crystals that may intervene the stone pathogenesis.

Association between oxidative balance score and kidney stone in United States adults: analysis from NHANES 2007-2018.

Purpose: To investigate the relationship between the Oxidative Balance Score (OBS) and kidney stone risk using NHANES 2007-2018 data, and to explore potential mechanisms and population-specific effects. Materials and methods: Data from the NHANES 2007-2018 were analyzed. OBS was calculated based on 16 dietary components and 4 lifestyle components. Multivariate logistic regression was employed to investigate the relationship between OBS and kidney stone. Further stratified analyses were conducted to examine the associations across different subgroups. Results: A total of 19,799 participants were included in the study. There was a consistent inverse association between OBS and the risk of kidney stones (OR = 0.97; 95% CI: 0.96-0.99). After dividing the participants into quartiles based on OBS, compared to the lowest quartile of OBS, the risk of kidney stones in the highest quartile of OBS was reduced by 33% (95% CI 0.50-0.89; p = 0.002). This association was consistent across both dietary and lifestyle OBS scores. The protective effect of OBS was notably pronounced among Non-Hispanic white and Other race groups, and among individuals with a higher level of education. However, the association was not significant among individuals with diabetes. Conclusion: A higher OBS, indicating a balance skewed towards antioxidants, is associated with a reduced risk of kidney stones, especially among specific population subgroups. These findings underscore the potential role of oxidative balance in kidney stone pathogenesis and highlight the importance of considering individual and population-specific factors in future research and preventive strategies.

Rare phylotypes in stone, stool, and urine microbiomes are associated with urinary stone disease.

Introduction: In complex microbial communities, the importance of microbial species at very low abundance levels and their prevalence for overall community structure and function is increasingly being recognized. Clinical microbiome studies on urinary stone disease (USD) have indicated that both the gut and urinary tract microbiota are associated with the onset of the disease and that kidney stones them-selves harbor a complex, yet consistent and viable, microbiome. However, how rare phylotypes contribute to this association remains unclear. Delineating the contribution of rare and common phylotypes to urinary stone disease is important for the development of bacteriotherapies to promote urologic health. Methods: The objectives of the current report were to conduct a metaanalysis of 16S rRNA datasets derived from the kidney stone, stool, and urine samples of participants with or without urinary stone disease. To delineate the impact of rare and common phylotypes, metaanalyses were conducted by first separating rare and common taxa determined by both the frequency and abundance of amplicon sequence variants. Results: Consistent with previous analyses, we found that gut, upper urinary, and lower urinary tract microbiomes were all unique. Rare phylotypes comprised the majority of species observed in all sample types, with kidney stones exhibiting the greatest bias toward rarity, followed by urine and stool. Both rare and common fractions contributed significantly to the differences observed between sample types and health disparity. Furthermore, the rare and common fractions were taxonomically unique across all sample types. A total of 222 and 320 unique rare phylotypes from urine and stool samples were found to be significantly associated with USD. A co-occurrence correlation analysis revealed that rare phylotypes are most important for microbiome structure in stones, followed by urine and stool. Discussion: Collectively, the results indicate that rare phylotypes may be important for the pathophysiology of USD, particularly in the kidney stone matrix, which is inherently a very low microbial biomass niche that can have implications for the diagnosis and treatment of kidney stones. Further studies are needed to investigate the functional significance of rare phylotypes in kidney stone pathogenesis.

Causal relationship between kidney stones and gut microbiota contributes to the gut-kidney axis: a two-sample Mendelian randomization study.

Gut microbiota, particularly Oxalobacter formigenes, has been previously reported to be associated with kidney stones. However, the conflicting results from both observational and intervention studies have created substantial uncertainty regarding the contribution of Oxalobacter formigenes to the formation of kidney stone. We employed a two-sample MR analysis to investigate the causal relationship between gut microbiota and kidney stones using GWASs summary statistics obtained from the MiBioGen and FinnGen consortia. Moreover, we conducted a reserve MR analysis to assess the direction of the causal associations between gut microbiota and kidney stones. The inverse variance weighted (IVW) approach represents the primary method of Mendelian Randomization (MR) analysis. Our analyses do not yield supportive evidence for a causal link between the genus Oxalobacter (OR = 0.99, 95% CI: 0.90-1.09, p = 0.811) and the formation of kidney stones. The order Actinomycetales (OR = 0.79, 95% CI: 0.65-0.96, p = 0.020), family Actinomycetaceae (OR = 0.79, 95% CI: 0.65-0.96, p = 0.019), family Clostridiaceae 1 (OR = 0.80, 95% CI: 0.67-0.96, p = 0.015), genus Clostridiumsensustricto 1 (OR = 0.81, 95% CI: 0.67-0.98, p = 0.030) and genus Hungatella (OR = 0.86, 95% CI: 0.74-0.99, p = 0.040) had protective effects on kidney stones, and the genus Haemophilus (OR = 1.16, 95% CI: 1.01-1.33, p = 0.032), genus Ruminococcaceae (UCG010) (OR = 1.38, 95% CI: 1.04-1.84, p = 0.028), genus Subdoligranulum (OR = 1.27, 95% CI: 1.06-1.52, p = 0.009) were risk factors for kidney stones. Differential abundance analysis provide no evidence of a association between Oxalobacter formigenes and kidney stones, and showed genus Subdoligranulum were risk factors for kidney stones. Reverse MR analysis did not indicate any causal association of kidney stones on gut microbiota. No considerable heterogeneity of instrumental variables or horizontal pleiotropy was observed. Our two-sample MR study did not find any causal relationship between genus Oxalobacter and kidney stones. The association between gut microbiota and kidney stones does not solely depend on the presence of genus Oxalobacter/Oxalobacter formigenes. A more integrated approach using multiple omics platforms is needed to better understand the pathogenesis of kidney stones in the context of complex gene-environment interactions over time.

A Mechanistic Insight into Beneficial Effects of Polyphenols in the Prevention and Treatment of Nephrolithiasis: Evidence from Recent In Vitro Studies

Nephrolithiasis is a pathological condition characterized by the formation of solid crystals in the kidneys or other parts of urinary tract. Kidney stones are a serious public health issue and financial burden for health care system, as well as a painful and uncomfortable condition for patients, resulting in renal tissue injury in severe cases. Dietary habits, low fluid and high salt intake predominantly, contribute to the development of kidney stones. Current research suggests that polyphenols have a protective effect in the pathogenesis of kidney stones. Polyphenols are a group of naturally occurring compounds found in plant-based foods such as fruits, vegetables, tea, and coffee. In this review, we explore mechanisms underlying the beneficial effects of polyphenols, such as oxidative stress reduction and modulation of inflammatory pathways, in various in vitro models of nephrolithiasis. Additionally, certain polyphenols, such as catechins found in green tea, have been shown to inhibit the formation and growth of kidney stones in animal studies. This review highlights the antioxidant and anti-inflammatory effects, as well as the inhibition of crystal formation, as results of polyphenol treatment in vitro. Further research is required to determine the specific effects of polyphenols on kidney stone formation in humans; however, current knowledge implicates that incorporating a variety of polyphenol-rich foods into the diet may be a beneficial strategy for individuals at risk of developing nephrolithiasis.

Nuclear Magnetic Resonance Metabolomic Profiling and Urine Chemistries in Incident Kidney Stone Formers Compared with Controls.

The urine metabolites and chemistries that contribute to kidney stone formation are not fully understood. This study examined differences between the urine metabolic and chemistries profiles of first-time stone formers and controls. High-resolution 1H-nuclear magnetic resonance (NMR) spectroscopy-based metabolomic analysis was performed in 24-hour urine samples from a prospective cohort of 418 first-time symptomatic kidney stone formers and 440 controls. In total, 48 NMR-quantified metabolites in addition to 12 standard urine chemistries were assayed. Analysis of covariance was used to determine the association of stone former status with urine metabolites or chemistries after adjusting for age and sex and correcting for the false discovery rate. Gradient-boosted machine methods with nested cross-validation were applied to predict stone former status. Among the standard urine chemistries, stone formers had lower urine oxalate and potassium and higher urine calcium, phosphate, and creatinine. Among NMR urine metabolites, stone formers had lower hippuric acid, trigonelline, 2-furoylglycine, imidazole, and citrate and higher creatine and alanine. A cross-validated model using urine chemistries, age, and sex yielded a mean AUC of 0.76 (95% CI, 0.73 to 0.79). A cross-validated model using urine chemistries, NMR-quantified metabolites, age, and sex did not meaningfully improve the discrimination (mean AUC, 0.78; 95% CI, 0.75 to 0.81). In this combined model, among the top ten discriminating features, four were urine chemistries and six NMR-quantified metabolites. Although NMR-quantified metabolites did not improve discrimination, several urine metabolic profiles were identified that may improve understanding of kidney stone pathogenesis.

Liesegang rings in the setting of end‐stage renal disease

Liesegang rings are acellular, lamellar, concentric rings of organic or inorganic material naturally formed in both biologic and environmental systems. Description in human tissue is scarce. Liesegang rings have exclusively been identified in association with pathologic disease processes and thus are not typically considered in differential diagnosis. They are usually described with cystic or inflammatory lesions. Histologically, Liesegang rings show features that are also seen in sections of parasitic ova, larvae, psammoma bodies, and by radiology as calcifications in cystic diseases of the breast and kidney. We noted at autopsy of a 59-year-old diabetic woman multiple black "stones" in the renal medulla. Microscopic examination demonstrated these to contain Liesegang rings. Liesegang rings formation should be considered in the differential diagnosis of atypical appearing deposits in the kidneys and other tissues. They may play a role in the pathogenesis of kidney stones.

Initial experience: ex-vivo perfused pig kidney to study urinary oxalate excretion.

Existing animal models of renal oxalate excretion utilize either gut or peritoneal cavity for oxalate absorption. Ex vivo renal perfusion is an established tool for graft preservation. We sought to repurpose this concept to study the early pathogenesis of urinary lithiasis. Juvenile female Yorkshire porcine kidneys were removed laparoscopically and placed on an ex vivo cardiopulmonary bypass circuit utilizing whole-blood based perfusate. Pre-defined goals were identified for each attempt (n = 5) with plans to increase physiologic model complexity. Tissue perfusion and oxygenation were monitored by serial perfusate iSTAT testing. Once steady urine production was achieved, aqueous oxalate was injected into the perfusate. Renal outcomes were assessed by histology and blood/urinary assays. After demonstrating proof-of-concept in early trials, normothermic (37°C) ex vivo whole-blood perfusion with Steen Solution™ was performed exceeding three hours at physiologic mean arterial pressures. Circuit parameters remained in the physiologic range for electrolytes, temperature, mean arterial pressure, lactate, and pH. Urine was produced in three experiments. Urinary filtrate demonstrated consistently higher urine creatinine compared to perfusate, and arterial perfusate oxalate boluses lead to urinary oxalate spikes followed by continuous oxalate clearance. Histopathologic analysis with H&E and Pizzolato's method staining demonstrated formation of calcium oxalate crystals. In light of these promising metabolite clearances, ex vivo porcine renal perfusion appears to be a feasible alternative to study oxalate excretion. Longer validation studies are necessary to establish this technique as a model for kidney stone pathogenesis.

Hyaluronic acid promotes calcium oxalate crystal growth, crystal-cell adhesion, and crystal invasion through extracellular matrix

Hyaluronic acid (HA), a macromolecule in glycosaminoglycans family, is normally excreted into the urine with a small amount, but with much greater level in the urine from stone patients (formers). However, its precise roles in kidney stone pathogenesis remained unclear. This study examined its roles in calcium oxalate (CaOx) kidney stone formation processes, including neocrystallization, crystal growth, adhesion, internalization, aggregation and invasion. The results showed that HA (1, 10, 100, 1000, or 10,000 ng/ml) did not affect CaOx neocrystallization, aggregation, and internalization into MDCK distal renal tubular cells. However, HA significantly promoted CaOx crystal growth (at 10–10,000 ng/ml), adhesion onto renal tubular cells (at 1000–10,000 ng/ml), and invasion through extracellular matrix (ECM) (at 1–10,000 ng/ml). Analysis of the plasminogen sequence revealed six sites with the HA-binding motif “B(X7)B" that explained the HA ability to trigger the plasminogen-plasmin system required for crystal invasion. In summary, our systematic analysis highlights the promoting effects of HA on CaOx crystal growth, crystal-cell adhesion and invasion through the ECM. These effects of HA may explain its high level in the stone patients' urine, thereby promoting the stone formation.

Construction and Analysis of Immune Infiltration-Related ceRNA Network for Kidney Stones.

Purpose: Kidney stones is a common medical issue that mediates kidney injury and even kidney function loss. However, the exact pathogenesis still remains unclear. This study aimed to explore the potential competing endogenous RNA (ceRNA)-related pathogenesis of kidney stones and identify the corresponding immune infiltration signature. Methods: One mRNA and one long non-coding RNA (lncRNA) microarray dataset was obtained from the GEO database. Subsequently, we compared differentially expressed mRNAs (DE-mRNAs) and lncRNAs between Randall’s plaques in patients with calcium oxalate (CaOx) stones and controls with normal papillary tissues. lncRNA-targeted miRNAs and miRNA–mRNA pairs were predicted using the online databases. lncRNA-related DE-mRNAs were identified using the Venn method, and GO and KEGG enrichment analyses were subsequently performed. The immune-related lncRNA–miRNA–mRNA ceRNA network was developed. The CIBERSORT algorithm was used to estimate the rate of immune cell infiltration in Randall’s plaques. The ceRNA network and immune infiltration were validated in the glyoxylate-induced hyperoxaluric mouse model and oxalate-treated HK-2 cells. Results: We identified 2,340 DE-mRNAs and 929 DE-lncRNAs between Randall’s plaques in patients with CaOx stones and controls with normal papillary tissues. lncRNA-related DE-mRNAs were significantly enriched in extracellular matrix organization and collagen-containing extracellular matrix, which were associated with kidney interstitial fibrosis. The immune-related ceRNA network included 10 lncRNAs, 23 miRNAs, and 20 mRNAs. Moreover, we found that M2 macrophages and resting mast cells were differentially expressed between Randall’s plaques and normal tissues. Throughout kidney stone development, kidney tubular injury, crystal deposition, collagen fiber deposition, TGF-β expression, infiltration of M1 macrophages, and activation of mast cells were more frequent in glyoxylate-induced hyperoxaluric mice compared with control mice. Nevertheless, M2 macrophage infiltration increased in early stages (day 6) and decreased as kidney stones progressed (day 12). Furthermore, treatment with 0.25 and 0.5 mM of oxalate for 48 h significantly upregulated NEAT1, PVT1, CCL7, and ROBO2 expression levels and downregulated hsa-miR-23b-3p, hsa-miR-429, and hsa-miR-139-5p expression levels in the HK-2 cell line in a dose-dependent manner. Conclusion: We found that significant expressions of ceRNAs (NEAT1, PVT1, hsa-miR-23b-3p, hsa-miR-429, hsa-miR-139-5p, CCL7, and ROBO2) and infiltrating immune cells (macrophages and mast cells) may be involved in kidney stone pathogenesis. These findings provide novel potential therapeutic targets for kidney stones.

MP07-20 INITIAL EXPERIENCE: EX-VIVO PERFUSED PIG KIDNEY TO STUDY URINARY OXALATE EXCRETION

You have accessJournal of UrologyStone Disease: Basic Research & Pathophysiology (MP07)1 Sep 2021MP07-20 INITIAL EXPERIENCE: EX-VIVO PERFUSED PIG KIDNEY TO STUDY URINARY OXALATE EXCRETION Jonathan Pavlinec, Mark Martin, William Donelan, Elizabeth Kwenda, Paul Dominguez-Gutierrez, Vincent Bird, and Benjamin Canales Jonathan PavlinecJonathan Pavlinec More articles by this author , Mark MartinMark Martin More articles by this author , William DonelanWilliam Donelan More articles by this author , Elizabeth KwendaElizabeth Kwenda More articles by this author , Paul Dominguez-GutierrezPaul Dominguez-Gutierrez More articles by this author , Vincent BirdVincent Bird More articles by this author , and Benjamin CanalesBenjamin Canales More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001980.20AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Existing animal models of renal oxalate excretion utilize either gut or peritoneal cavity for oxalate absorption. Ex vivo renal perfusion is an established tool for graft preservation. We sought to repurpose this concept in order to study the early pathogenesis of urinary lithiasis. METHODS: Juvenile female Yorkshire porcine kidneys were removed laparoscopically and placed on an ex vivo neonatal cardiopulmonary bypass circuit utilizing whole-blood based perfusate oxygenated with 95% carbogen. Pre-defined goals were identified for each attempt (n=5) with plans to increase physiologic model complexity. Tissue perfusion and oxygenation was monitored by serial perfusate iSTAT testing. Once steady urine production was achieved, aqueous oxalate was injected into the perfusate. Renal outcomes were assessed by histology and blood/urinary assays. RESULTS: After demonstrating proof-of-concept in early trials, normothermic (37C) ex vivo whole-blood perfusion with Steen SolutionTM was performed exceeding three hours at physiologic mean arterial pressures. Circuit parameters remained in the physiologic range for electrolytes, temperature, mean arterial pressure, lactate, and pH. Urine was produced in three experiments, with two additional attempts stopped early due to challenges related to hilar cannulation. Urinary filtrate demonstrated consistently higher urine creatinine compared to perfusate, and arterial perfusate oxalate boluses lead to urinary oxalate spikes followed by continuous oxalate clearance. Histopathologic analysis with H&E and Pizzolato’s method staining demonstrated formation of calcium oxalate crystals. CONCLUSIONS: In light of promising renal urinary oxalate and creatinine clearance, ex vivo porcine renal perfusion appears to be a feasible alternative to study oxalate excretion. Longer validation studies are necessary to establish this technique as a model for kidney stone pathogenesis. Source of Funding: No extra-instatutional funding was utilized for this project © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e147-e148 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jonathan Pavlinec More articles by this author Mark Martin More articles by this author William Donelan More articles by this author Elizabeth Kwenda More articles by this author Paul Dominguez-Gutierrez More articles by this author Vincent Bird More articles by this author Benjamin Canales More articles by this author Expand All Advertisement Loading ...

Low PTH Levels in Adolescents With Anorexia Nervosa.

Introduction: Patients with anorexia nervosa (AN) experience medical complications including impaired bone metabolism, increased fracture rate, kidney stones and chronic renal failure. However, the mechanisms of such complications are not fully understood. Healthy adolescents have been shown to have higher PTH levels when compared with pre-pubertal children and adults. Given the importance of central measures of calcium and vitamin D metabolism in bone and kidney health, 25-hydroxyvitamin D (25OHD) and parathyroid hormone (PTH) have been extensively investigated in patients with AN, however none of the previous studies accounted for age-specific reference ranges for PTH. The aim of this study was to investigate central measures of calcium and vitamin D metabolism in adolescents with newly diagnosed AN using age-specific reference ranges and to determine whether any significant abnormalities required further study.Methods: This was a cross-sectional study of 61 adolescents (mean age = aged 15.2 ± 1.56 years) with newly diagnosed AN, referred to a tertiary center over a period of 2 years. Demographic, auxiological, and nutrient (vitamin D and calcium) intake data was obtained. Central measures of calcium and vitamin D metabolism in blood and urine were investigated. PTH results were compared with age-specific reference ranges from the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER). Descriptive statistics and correlation analysis were performed.Results: Low PTH levels were observed in 35% of the cohort. Overall, serum calcium, phosphate and 25OHD were within the reference range. Using loess curves, PTH had a significant negative and non-linear correlation with 25OHD with an inflection point at a 25OHD level of 100 nmol/l, above which the association was no longer present. Correlation analysis did not show a significant association between PTH and total or corrected serum calcium, urine calcium/creatinine (Ca/Cr) ratio, total dietary calcium intake, magnesium or Tanner staging.Conclusion: PTH levels were reduced in approximately a third of adolescents with AN. This observation has not been reported given the universal usage of reference ranges that covers all ages. This finding may unmask a potential role for reduced PTH levels in the pathogenesis of kidney stones and bone phenotype in patients with AN.

Roles for Exosome in Various Kidney Diseases and Disorders.

Exosome is a nanoscale vesicle with a size range of 30–100 nm. It is secreted from cell to extracellular space by exocytosis after fusion of multivesicular body (MVB) (formed by endocytic vesicles) with plasma membrane. Exosome plays several important roles in cellular homeostasis and intercellular communications. During the last two decades, exosome has acquired a wide attention to explore its additional roles in various aspects of cell biology and function in several organ systems. For the kidney, several lines of evidence have demonstrated 1that exosome is involved in the renal physiology and pathogenic mechanisms of various kidney diseases/disorders. This article summarizes roles of the exosome as the potential source of biomarkers, pathogenic molecules, and therapeutic biologics that have been extensively investigated in many kidney diseases/disorders, including lupus nephritis (LN), other glomerular diseases, acute kidney injury (AKI), diabetic nephropathy (DN), as well as in the process of renal fibrosis and chronic kidney disease (CKD) progression, in addition to polycystic kidney disease (PKD), kidney transplantation, and renal cell carcinoma (RCC). Moreover, the most recent evidence has shown its emerging role in kidney stone disease (or nephrolithiasis), involving inflammasome activation and inflammatory cascade frequently found in kidney stone pathogenesis.

Urinary extracellular vesicle-associated MCP-1 and NGAL derived from specific nephron segments differ between calcium oxalate stone formers and controls.

Randall's plaque (RP; subepithelial calcification) appears to be an important precursor of kidney stone disease. However, RP cannot be noninvasively detected. The present study investigated candidate biomarkers associated with extracellular vesicles (EVs) in the urine of calcium stone formers (CSFs) with low (<5% papillary surface area) and high (≥5% papillary surface area) percentages of RP and a group of nonstone formers. RPs were quantitated via videotaping and image processing in consecutive CSFs undergoing percutaneous surgery for stone removal. Urinary EVs derived from cells of different nephron segments of CSFs (n = 64) and nonstone formers (n = 40) were quantified in biobanked cell-free urine by standardized and validated digital flow cytometer using fluorophore-conjugated antibodies. Overall, the number of EVs carrying surface monocyte chemoattractant protein (MCP)-1 and neutrophil gelatinase-associated lipocalin (NGAL) were significantly lower in CSFs compared with nonstone former controls (P < 0.05) but did not differ statistically between CSFs with low and high RPs. The number of EVs associated with osteopontin did not differ between any groups. Thus, EVs carrying MCP-1 and NGAL may directly or indirectly contribute to stone pathogenesis as evidenced by the lower of these populations of EVs in stone formers compared with nonstone formers. Validation of EV-associated MCP-1 and NGAL as noninvasive biomarkers of kidney stone pathogenesis in larger populations is warranted.

PD38-04 NEUTROPHIL INFILTRATION AND NETOSIS IN THE PATHOGENESIS OF HUMAN KIDNEY BRUSHITE STONES

INTRODUCTION AND OBJECTIVES:The pathogenesis of kidney stones in humans is poorly understood. There are multiple types of kidney stones, and the role of inflammation in promoting specific stone typ...

Modulatory effects of fibronectin on calcium oxalate crystallization, growth, aggregation, adhesion on renal tubular cells, and invasion through extracellular matrix

Fibronectin, an extracellular matrix (ECM) protein, has been thought to be involved in pathogenic mechanisms of kidney stone disease, especially calcium oxalate (CaOx) type. Nevertheless, its precise roles in modulation of CaOx crystal remained unclear. We thus performed a systematic evaluation of effects of fibronectin on CaOx monohydrate (COM) crystal (the major causative chemical crystal in kidney stone formation) in various stages of kidney stone pathogenesis, including crystallization, crystal growth, aggregation, adhesion onto renal tubular cells, and invasion through ECM in renal interstitium. The data showed that fibronectin significantly decreased crystallization, growth and adhesive capability of COM crystals in a dose‐dependent manner. In contrast, COM crystal aggregation and invasion through ECM migration chamber were significantly enhanced by fibronectin in a dose‐dependent fashion. Sequence analysis revealed two and six calcium‐binding and oxalate‐binding domains, respectively. Saturation of fibronectin with oxalate prior to crystal modulation assays could abolish all the effects of fibronectin, whereas saturation with calcium had minimal interference. These data strongly indicate the dual functions of fibronectin, which serves as an inhibitor for COM crystallization, crystal growth and adhesion onto renal tubular cells, but on the other hand, acts as a promoter for COM crystal aggregation and invasion through ECM. Moreover, its crystal modulatory activities are mainly due to oxalate‐binding capability.Support or Funding InformationThis study was supported by Mahidol University research grant and the Thailand Research Fund (IRN60W0004 and IRG5980006).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.