Calcium Oxalate Nephrocalcinosis Research Articles

Sulforaphane elicts dual therapeutic effects on Renal Inflammatory Injury and crystal deposition in Calcium Oxalate Nephrocalcinosis: Erratum

[This corrects the article DOI: 10.7150/thno.44054.].

P0229 - Sulforaphane elicts a dual therapeutic effects on renal inflammatory injury and crystal deposition in calcium oxalate nephrocalcinosis

P0229 - Sulforaphane elicts a dual therapeutic effects on renal inflammatory injury and crystal deposition in calcium oxalate nephrocalcinosis

P0223 - Metformin elicits dual therapeutic effects on renal inflammatory and oxidative injury in calcium oxalate nephrocalcinosis

P0223 - Metformin elicits dual therapeutic effects on renal inflammatory and oxidative injury in calcium oxalate nephrocalcinosis

XIST Promote Calcium Oxalate Nephrocalcinosis Induced Renal Inflammatory and Oxidative Injury Via miR-223-NLRP3 Pathway

Background: The function of lncRNA X‐inactive specific transcript (XIST) in many diseases, including cancers and inflammatory sickness, has been elucidated in previous papers. But for renal calculus, it remains poorly understood. In this study, we revealed the potential effects of XIST on kidney stones via inflammatory response and oxidative stress. Method: We established a glyoxylate-induced calcium oxalate (CaOx) stone mouse model and exposed HK-2 cells to calcium oxalate monohydrate (COM). The interactions among XIST, miR-223 and NOD‐like receptor protein 3 (NLRP3) and respective effect were studied via the analysis of RNAs and protein expressions, luciferase activity, and immunohistochemistry (IHC). Necrosis and reactive oxygen species (ROS) generation were detected after XIST silence, miR-223 activation and inhibition or both of XIST knock-down and miR-223 activation in vitro and in vivo. Finding: The levels of XIST, NLRP3, Caspase-1 and IL-1β were notably increased in the kidney samples from the glyoxylate-induced CaOx stone mouse model. XIST knockdown significantly suppressed the inflammatory damage and ROS production, and further attenuated kidney stones formation. MiRNA-223 mimics also exerted the same effects. Moreover, we verified the interactions among XIST, miRNA-223 and NLRP3 and the subsequent effects. Interpretation: Our results suggested that lncRNA XIST participated in the formation and progression of renal calculus via interplaying with miR-223 and the NLRP3/Caspase-1/IL-1β pathway to mediate inflammatory response and ROS production. Funding: This study was supported by National Natural Science Foundation of China (8167031233). Declaration of Interest: The authors declare that they have no competing conflicts of interest. Ethical Approval: The animal study was approved by the Ethics Committee of Tongji Hospital.

Sulforaphane elicts dual therapeutic effects on Renal Inflammatory Injury and crystal deposition in Calcium Oxalate Nephrocalcinosis.

Intrarenal calcium oxalate (CaOx) crystals induce renal tubular epithelial cells (TECs) injury and inflammation, which involve Toll-like receptor 4 (TLR4)/interferon regulatory factor 1 (IRF1) signaling. Additionally, infiltrating macrophages (Mϕs) might influence intrarenal CaOx crystals and CaOx-induced renal injury. Although the roles of nuclear factor erythroid 2-related factor 2 (Nrf2) in regulating inflammation and macrophage polarization are well characterized, its potential mechanisms in regulating CaOx nephrocalcinosis remain undefined.Methods: We used a Gene Expression Omnibus dataset to analyze gene-expression profiles. Luciferase reporter, western blot, quantitative polymerase chain reaction, immunofluorescence staining, fluorescence in situ hybridization, positron emission tomography computed tomography imaging, flow cytometry, and chromatin immunoprecipitation assays were employed to study the mechanism of miR-93-TLR4/IRF1 regulation by Nrf2. Anti-inflammatory activity and regulation of macrophage polarization by Nrf2 were investigated in vitro and in vivo.Results: We found that stone-mediated kidney inflammation significantly affected stone growth, and that sulforaphane attenuated CaOx nephrocalcinosis-induced kidney injury and renal CaOx crystals deposition. Additionally, Nrf2 levels significantly increased and negatively correlated with TLR4 and IRF1 levels in a mouse model of CaOx nephrocalcinosis following sulforaphane treatment. Moreover, Nrf2 suppressed TLR4 and IRF1 levels and decreased M1-macrophage polarization which induced by supernatants from COM-stimulated TECs in vitro. In terms of mechanism, transcription factor analyses, microRNA microarray, and chromatin immunoprecipitation assays showed that Nrf2 exhibited positive transcriptional activation of miR-93-5p. In addition, Luciferase reporter, qRT-PCR, and western blot validated that miR-93-5p targets TLR4 and IRF1 mRNA. Furthermore, suppressed miR-93-5p expression partially reversed Nrf2-dependent TLR4/IRF1 downregulation.Conclusions: The results suggested that sulforaphane might promote M2Mϕ polarization and inhibit CaOx nephrocalcinosis-induced inflammatory injury to renal tubular epithelial cells via the Nrf2-miR-93-TLR4/IRF1 pathway in vitro and in vivo.

AhR activation attenuates calcium oxalate nephrocalcinosis by diminishing M1 macrophage polarization and promoting M2 macrophage polarization.

Calcium oxalate (CaOx) crystal can trigger kidney injury, which contributes to the pathogenesis of nephrocalcinosis. The phenotypes of infiltrating macrophage may impact CaOx-mediated kidney inflammatory injury as well as crystal deposition. How aryl hydrocarbon receptor (AhR) regulates inflammation and macrophage polarization is well understood; however, how it modulates CaOx nephrocalcinosis remains unclear.Methods: Mice were intraperitoneally injected with glyoxylate to establish CaOx nephrocalcinosis model with or without the treatment of AhR activator 6-formylindolo(3,2-b)carbazole (FICZ). Positron emission tomography computed tomography (PET-CT) imaging, Periodic acid-Schiff (PAS) staining, and polarized light optical microscopy were used to evaluate kidney injury and crystal deposition in mice kidney. Western blotting, immunofluorescence, chromatin immunoprecipitation, microRNA-fluorescence in situ hybridization, and luciferase reporter assays were applied to analyze polarization state and regulation mechanism of macrophage.Results: AhR expression was significantly upregulated and negatively correlated with interferon-regulatory factor 1 (IRF1) and hypoxia inducible factor 1-alpha (HIF-1α) levels in a murine CaOx nephrocalcinosis model following administration of FICZ. Moreover, AhR activation suppressed IRF1 and HIF-1α levels and decreased M1 macrophage polarization in vitro. In terms of the mechanism, bioinformatics analysis and chromatin immunoprecipitation assay confirmed that AhR could bind to miR-142a promoter to transcriptionally activate miR-142a. In addition, luciferase reporter assays validated that miR-142a inhibited IRF1 and HIF-1α expression by directly targeting their 3'-untranslated regions.Conclusions: Our results indicated that AhR activation could diminish M1 macrophage polarization and promote M2 macrophage polarization to suppress CaOx nephrocalcinosis via the AhR-miR-142a-IRF1/HIF-1α pathway.

Hyperoxaluria Is Reduced and Nephrocalcinosis Prevented with an Oxalate-Degrading Enzyme in Mice with Hyperoxaluria

Background/Aims: Hyperoxaluria is a major risk factor for recurrent urolithiasis and nephrocalcinosis. We tested an oral therapy with a crystalline, cross-linked formulation of oxalate-decarboxylase (OxDc-CLEC®) on the reduction of urinary oxalate and decrease in the severity of kidney injury in two models: AGT1 knockout mice (AGT1KO) in which hyperoxaluria is the result of an Agxt gene deficiency, and in AGT1KO mice challenged with ethylene glycol (EG). Methods: Four different doses of OxDc-CLEC mixed with the food, or placebo were given to AGT1KO mice (200 mg/day, n = 7) for 16 days and to EG-AGT1KO mice (5, 25, and 80 mg, n = 11) for 32 days. Results: Oral therapy with 200 mg OxDc-CLEC reduced both urinary (44%) and fecal oxalate (72%) in AGT1KO mice when compared to controls. Similarly, in EG-AGT1KO mice, each of the three doses of OxDc-CLEC produced a 30–50% reduction in hyperoxaluria. A sustained urinary oxalate reduction of 40% or more in the 80 mg group led to 100% animal survival and complete prevention of nephrocalcinosis and urolithiasis. Conclusion: These data suggest that oral therapy with OxDc-CLEC may reduce hyperoxaluria, prevent calcium oxalate nephrocalcinosis and urolithiasis, and can represent a realistic option for the treatment of human hyperoxaluria, independent of cause.

Tubular and Interstitial Nephrocalcinosis

We determined whether nephrocalcinosis is common and whether its detection is influenced by renal tissue processing. Renal cortical and papillary tissue was obtained from the unaffected parts of 15 kidneys removed due to an oncological indication. The effect of tissue processing on the loss of crystals was studied in a kidney with nephrocalcinosis due to chronic pyelonephritis. Immediately frozen and formaldehyde fixed sections were analyzed by polarized light and Raman spectroscopy, and stained for calcium (Yasue) and hyaluronan. Although 13 of 15 snap-frozen sections from tumor kidneys contained birefringent particles (mean +/- SD 3.2 +/- 2.9 particles per cm(2)) in the renal tubules, this was not considered nephrocalcinosis because the crystals were not attached to the epithelial lining. Interstitial nephrocalcinosis was found on Yasue stain in 3 of 15 kidneys with tumor (20%). Calcium deposits were found in the papillary interstitium only, always together with hyaluronan. Formaldehyde fixed sections from the pyelonephritis kidney contained fewer renal tubular cell associated birefringent particles than immediately frozen sections (9.4 +/- 1.9 vs 41.6 +/- 1.2 per cm(2)). Particles were composed of calcium oxalate monohydrate (Yasue and Raman). There are 2 distinct forms of nephrocalcinosis, including tubular nephrocalcinosis, which seems to be reserved for specific conditions such as chronic pyelonephritis, and interstitial nephrocalcinosis. The incidence of tubular calcium oxalate nephrocalcinosis could be underestimated due to the loss of crystals during tissue processing for routine histology. The crystal binding molecule hyaluronan may have a role in the 2 forms of nephrocalcinosis.

1046: Continuous Infusion of Oxalate (OX) Increases Intrarenal Concentrations of Calcium at Doses and in Regions not Associated with Calcium Oxalate Nephrocalcinosis (CAOX-NEPHCAL)

You have accessJournal of UrologyPodium, Tuesday, May 23, 2006, 8:00 - 10:00 am1 Apr 20061046: Continuous Infusion of Oxalate (OX) Increases Intrarenal Concentrations of Calcium at Doses and in Regions not Associated with Calcium Oxalate Nephrocalcinosis (CAOX-NEPHCAL) Susan R. Marengo, Martin I. Resnick, and Andrea M. Romani Susan R. MarengoSusan R. Marengo More articles by this author , Martin I. ResnickMartin I. Resnick More articles by this author , and Andrea M. RomaniAndrea M. Romani More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(18)33271-3AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "1046: Continuous Infusion of Oxalate (OX) Increases Intrarenal Concentrations of Calcium at Doses and in Regions not Associated with Calcium Oxalate Nephrocalcinosis (CAOX-NEPHCAL)." The Journal of Urology, 175(4S), p. 336 © 2016 by American Urological AssociationFiguresReferencesRelatedDetails Volume 175Issue 4SApril 2006Page: 336 Advertisement Copyright & Permissions© 2016 by American Urological AssociationMetricsAuthor Information Susan R. Marengo More articles by this author Martin I. Resnick More articles by this author Andrea M. Romani More articles by this author Expand All Advertisement PDF downloadLoading ...

Continuous infusion of oxalate by minipumps induces calcium oxalate nephrocalcinosis

It is hypothesized that oxalate plays an active role in calcium oxalate (CaOx) nephrocalcinosis and oxalate driven nephrolithiasis by interacting with the kidney. We developed an adjustable, nonprecursor, continuous infusion model of hyperoxaluria and CaOx nephrocalcinosis to investigate this hypothesis. Minipumps containing PBS or KOx (60-360 micromol/day; n = 5-7/dose) were implanted subcutaneously in male Sprague-Dawley rats on D0 and D6. Rats were killed on D13. Oxalate excretion and CaOx crystalluria were monitored by 20+4 h urine collections. Localization and content of intrarenal crystals were determined on frozen sections using polarization and microFTIR. Oxalate excretion was significantly elevated in all KOx rats (P < or = 0.005). CaOx crystalluria was most persistent in the 240-360 micromol/day KOx rats, but even 60 micromol/day KOx rats showed sporadic crystalluria. One hundred percent of KOx rats had CaOx nephrocalcinosis as confirmed by microFTIR. Most crystals were localized to the lumens of the corticomedullary collecting ducts. A few crystals are localized just under the papillar urothelium. The minipump model is the first model of hyperoxaluria to provide continuous infusion of oxalate. It permits control of the levels of hyperoxaluria, crystalluria and CaOx nephrocalcinosis. The level of sustained hyperoxaluria and CaOx nephrocalcinosis induced by treatment with 360 micromol/day KOx for 13D models the conditions frequently observed in jejunoileal bypass patients. Adjustments in the length of treatment and level of hyperoxaluria may allow this model to also be used to study the oxalate driven CaOx-nephrolithiasis common in patients with hyperoxaluria due to other causes.

Combined hepatic and renal transplantation in primary hyperoxaluria type I: Clinical report of nine cases

The purpose of this article is to report the experience of three centers with combined hepatic and renal transplantation for pyridoxine-resistant primary hyperoxaluria type I (alanine:glyoxylate aminotransferase [EC 2.6.1.44] deficiency), with particular emphasis on the selection criteria and timing of the operation. Nine patients with this inherited disease were treated by combined hepatic and renal transplantation. The former replaces the enzyme-deficient organ while the latter replaces the functionally affected organ. One patient with gross systemic oxalosis died in the immediate postoperative period and another died 8 weeks postoperatively of a generalized cytomegalovirus infection, having shown evidence of biochemical correction. One patient with particularly severe osteodystrophy at the time of the operation died 14 months postoperatively from renal failure due to progressive calcium oxalate nephrocalcinosis involving the transplanted kidney, plus thromboembolic disease. He also had very extensive systemic oxalosis. An additional patient with severe osteodystrophy died 9 months postoperatively. One patient developed hyper-rejection of the kidney and died later of gastrointestinal hemorrhage. The four long-term survivors (22 to 38 months) have remained asymptomatic from the standpoint of their renal disease, with resolution of any manifestations of systemic oxalosis that they may have had. They are either employed or continuing their education. A prolonged period of end-stage renal failure treated by dialysis regimens that are suitable for non-hyperoxaluric renal failure and extensive systemic oxalosis, particularly oxalotic osteodystrophy, are poor prognostic features. We propose that hepatic transplantation should be considered as definitive treatment before end-stage renal failure develops. This should be supplemented by renal transplantation with vigorous pre- and perioperative hemodialysis to deplete the body stores of oxalate. Although some authorities would reserve hepatic transplantation for patients in whom renal transplantation has failed, we suggest that combined liver and kidney transplantation is appropriate in patients who have never had a renal graft. Furthermore, the time has come to consider hepatic transplantation before any irreversible renal damage has occurred in these patients.

Combined hepatic and renal transplantation in primary hyperoxaluria type I: clinical report of nine cases

purpose and patients and methods: The purpose of this article is to report the experience of three centers with combined hepatic and renal transplantation for pyridoxine-resistant primary hyperoxaluria type I (alanine:glyoxylate aminotransferase [EC 2.6.1.44] deficiency), with particular emphasis on the selection criteria and timing of the operation. Nine patients with this inherited disease were treated by combined hepatic and renal transplantation. The former replaces the enzyme-deficient organ while the latter replaces the functionally affected organ. results: One patient with gross systemic oxalosis died in the immediate postoperative period and another died 8 weeks postoperatively of a generalized cytomegalovirus infection, having shown evidence of biochemical correction. One patient with particularly severe osteodystrophy at the time of the operation died 14 months postoperatively from renal failure due to progressive calcium oxalate nephrocalcinosis involving the transplanted kidney, plus thromboembolic disease. He also had very extensive systemic oxalosis. An additional patient with severe osteodystrophy died 9 months postoperatively. One patient developed hyper-rejection of the kidney and died later of gastrointestinal hemorrhage. The four long-term survivors (22 to 38 months) have remained asymptomatic from the standpoint of their renal disease, with resolution of any manifestations of systemic oxalosis that they may have had. They are either employed or continuing their education. conclusions: A prolonged period of end-stage renal failure treated by dialysis regimens that are suitable for non-hyperoxaluric renal failure and extensive systemic oxalosis, particularly oxalotic osteodystrophy, are poor prognostic features. We propose that hepatic transplantation should be considered as definitive treatment before end-stage renal failure develops. This should be supplemented by renal transplantation with vigorous pre- and perioperative hemodialysis to deplete the body stores of oxalate. Although some authorities would reserve hepatic transplantation for patients in whom renal transplantation has failed, we suggest that combined liver and kidney transplantation is appropriate in patients who have never had a renal graft. Furthermore, the time has come to consider hepatic transplantation before any irreversible renal damage has occurred in these patients.

A case of oxalate nephrocalcinosis and primary hyperoxaluria.

SUMMARY A case of primary hyperoxaluria with calcium oxalate nephrocalcinosis in a man aged 32 is described. The anatomical and histological features, the nature of the metabolic defect, and the probable natural history of the condition are discussed.