Publications by authors named "Dominique Bazin"

55 Publications

Advances in the identification of calcium carbonate urinary crystals.

Clin Chim Acta 2021 Apr 31;515:1-4. Epub 2020 Dec 31.

Sorbonne Universités, UPMC Université Paris-6, UMR S 1155, Paris, France; INSERM, UMR S 1155, Paris, France; AP-HP, Hôpital Tenon, Service d'explorations fonctionnelles multidisciplinaires, Paris-6, France.

The examination of the urinary sediment of a 64-year-old woman showed the presence of three different types of crystals, all with unusual morphology, which could not be identified with bright field microscopy, polarized light, and the knowledge of urine pH (7.5). The use of microscopic infrared spectroscopy, Raman spectroscopy and energy dispersive X-ray spectroscopy led to the identification of the three types of crystals as calcite, vaterite and aragonite, which are all variants of calcium carbonate crystals. This paper confirms the complex morphology and nature that urinary crystals may at times have and the utility of advanced infrared spectroscopy techniques for their identification.
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http://dx.doi.org/10.1016/j.cca.2020.12.024DOI Listing
April 2021

Calcium Pyrophosphate Dihydrate Crystal Deposition in Gouty Tophi.

Arthritis Rheumatol 2021 02 5;73(2):324-329. Epub 2020 Dec 5.

Université de Paris, INSERM UMR 1132, Hôpital Lariboisière, AP-HP, Paris, France, and Vien Gut Medical Center and French-Vietnamese research center on gout and chronic diseases, Ho Chi Minh City, Vietnam.

Objective: The coexistence of calcium pyrophosphate dihydrate (CPPD) and monosodium urate monohydrate crystals in gouty tophi has rarely been reported. We undertook this study to investigate CPPD crystal deposits in a series of surgically removed gouty tophi and to identify factors associated with these deposits.

Methods: Twenty-five tophi from 22 gout patients were analyzed using polarized light microscopy, field emission scanning electron microscopy (FESEM), and μ Fourier transform infrared (μFTIR) spectroscopy.

Results: Tophi consisted of multiple lobules separated by fibrous septa and surrounded by a foreign-body giant cell reaction. CPPD crystal aggregates were identified in 9 of 25 tophi from 6 patients. CPPD crystals were dispersed or highly compacted, localized at the edge or inside the tophus lobules, with some lobules completely filled with crystals. Both monoclinic and triclinic CPPD crystal phases were identified using FESEM and μFTIR. Compared to patients without CPPD, those with CPPD-containing tophi were older (mean 60.5 years versus 47.2 years; P = 0.009), and had longer-term gout duration (mean 17.0 years versus mean 9.0 years; P < 0.05) and tophi duration (mean 10.0 years versus mean 4.6 years; P < 0.01). None of the patients had radiographic chondrocalcinosis of the knee or wrist.

Conclusion: CPPD crystal formation seems to be a late and frequent event of tophus maturation, occurring more frequently with aging, and could contribute to the speed of tophus dissolution and the apparent persistence of tophus sometimes observed even after effective, long-lasting urate-lowering therapy.
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http://dx.doi.org/10.1002/art.41515DOI Listing
February 2021

[Crystalline pathologies in the human body: first steps of pathogenesis].

Ann Biol Clin (Paris) 2020 08;78(4):349-362

Inserm, UMRS 1155, UPMC, Hôpital Tenon, Paris, France, Service d'explorations fonctionnelles, Hôpital Tenon, AP-HP, France.

The prevalence of crystalline pathologies including urolithiasis, gallstones, vascular calcifications and crystalline arthritis, is very high in the general population beyond 60 years old. Characterization of microcrystals in tissue at the micrometer and at the nanometer scale through physico-chemical techniques constitutes a new opportunity for the physician to decipher the early stage of the pathogenesis of these biological entities. In this review, such description indicates a wide variety of the chemical process associated to the nucleation process directly from supersaturated solution or from organic support such as DNA or elastin. We will also discuss the case of vesicles which play a major role in the case of ectopic calcification situated in kidney tissue, namely the Randall's plaque. All this research focused on the very first steps of the genesis of pathological calcifications constitute a major step to develop specific therapy able to avoid the formation of these abnormal deposits in tissues. As already underlined, crystals may be the consequence of various pathologies, but they are also involved in the dysfunction of the tissues.
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http://dx.doi.org/10.1684/abc.2020.1557DOI Listing
August 2020

The Case | Fluctuating serum creatinine and crystals in urine.

Kidney Int 2020 06;97(6):1307-1308

Sorbonne Université, Institut national de la santé et de la recherche médicale (INSERM) Unité mixte de recherche (UMR) S 1155, Assistance Publique des Hôpitaux de Paris (AP-HP) Service des Explorations Fonctionnelles Multidisciplinaires, Hôpital Tenon, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2019.11.028DOI Listing
June 2020

Nanometric Chemical Speciation of Abnormal Deposits in Kidney Biopsy: Infrared-Nanospectroscopy Reveals Heterogeneities within Vancomycin Casts.

Anal Chem 2020 06 20;92(11):7388-7392. Epub 2020 May 20.

Université Paris-Saclay, CNRS, Institut de Chimie Physique, UMR 8000, 91405 Orsay, France.

Infrared (IR) spectromicroscopy allows chemical mapping of a kidney biopsy. It is particularly interesting for chemical speciation of abnormal tubular deposits and calcification. In 2017, using IR spectromicroscopy, we described a new entity called vancomycin cast nephropathy. However, despite recent progresses, the IR microspectrometer spatial resolution is intrinsically limited by diffraction (a few micrometers). Combining atomic force microscopy and IR lasers (AFMIR) allows acquisition of infrared absorption spectra with a resolution and sensitivity in between 10 and 100 nm. Here we show that AFMIR can be used on standard paraffin embedded kidney biopsies. Vancomycin cast could be identified in a damaged tubule. Interestingly unlike standard IR spectromicroscopy, AFMIR revealed heterogeneity of the deposits and established that vancomycin coprecipitated with phosphate containing molecules. These findings highlight the high potential of this approach with nanometric spatial resolution which opens new perspectives for studies on drug-induced nephritis, nanocrystals, and local lipid or carbohydrates alterations.
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http://dx.doi.org/10.1021/acs.analchem.0c00290DOI Listing
June 2020

1-Methyluric Acid Nephropathy.

Kidney Int Rep 2020 May 22;5(5):737-741. Epub 2020 Feb 22.

Sorbonne Université, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche-S 1155, Assistance Publique des Hôpitaux de Paris Service des Explorations Fonctionnelles Multidisciplinaires, Hôpital Tenon, Paris, France.

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http://dx.doi.org/10.1016/j.ekir.2020.02.1026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210604PMC
May 2020

Nanoscale Analysis of Randall's Plaques by Electron Energy Loss Spectromicroscopy: Insight in Early Biomineral Formation in Human Kidney.

ACS Nano 2020 02 27;14(2):1823-1836. Epub 2020 Jan 27.

Laboratoire de Physique des Solides, CNRS UMR 8502 , Université de Paris-Saclay , F-91405 , Orsay , France.

Idiopathic kidney stones originate mainly from calcium phosphate deposits at the tip of renal papillae, known as Randall's plaques (RPs), also detected in most human kidneys without stones. However, little is known about the mechanisms involved in RP formation. The localization and characterization of such nanosized objects in the kidney remain a real challenge, making their study arduous. This study provides a nanoscale analysis of the chemical composition and morphology of incipient RPs, characterizing in particular the interface between the mineral and the surrounding organic compounds. Relying on data gathered from a calculi collection, the morphology and chemical composition of incipient calcifications in renal tissue were determined using spatially resolved electron energy-loss spectroscopy. We detected microcalcifications and individual nanocalcifications found at some distance from the larger ones. Strikingly, concerning the smaller ones, we show that two types of nanocalcifications coexist: calcified organic vesicles and nanometric mineral granules mainly composed of calcium phosphate with carbonate in their core. Interestingly, some of these nanocalcifications present similarities with those reported in physiological bone or pathological cardiovascular biominerals, suggesting possible common formation mechanisms. However, the high diversity of these nanocalcifications suggests that several mechanisms may be involved (nucleation on a carbonate core or on organic compounds). In addition, incipient RPs also appear to present specific features at larger scales, revealing secondary calcified structures embedded in a fibrillar organic material. Our study proves that analogies exist between physiological and pathological biominerals and provides information to understand the physicochemical processes involved in pathological calcification formation.
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http://dx.doi.org/10.1021/acsnano.9b07664DOI Listing
February 2020

Localization and characterization of thyroid microcalcifications: A histopathological study.

PLoS One 2019 24;14(10):e0224138. Epub 2019 Oct 24.

Sorbonne Université, INSERM, UMR_S 1155, AP-HP, Hôpital Tenon, Paris, France.

Thyroid calcification is frequent in thyroid nodules. The aim of our study was to evaluate the prevalence of calcifications in thyroid tissue samples of patients with various thyroid diseases, and to identify their composition according to their localization. Among 50 thyroid samples included, 56% were malignant (papillary carcinoma) and 44% were benign (adenoma, multinodular goiter, Graves' disease, sarcoidosis). Calcifications were found in 95% of samples using polarised light microscopy, whereas only 12% were described in initial pathological reports. Three types were individualised and analyzed by infrared spectrometry (μFTIR): colloid calcifications composed of calcium oxalate, capsular calcifications and psammoma bodies, both composed of calcium phosphate. Of notice, psammoma bodies characterized by FE-SEM were composed of concentric structure suggesting a slow process for crystal deposition. Calcium phosphates were found only in malignant samples whereas calcium oxalate was not associated with a define pathology. Proliferation assessed by KI67 staining was high (33% of positive follicles), and RUNX2, OPN, and CD44 positive staining were detected in thyrocytes with a broad variation between samples. However, thyrocyte proliferation and differentiation markers were not associated with the number of crystals. TRPV5 and CaSR expression was also detected in thyrocytes. mRNA transcripts expression was confirmed in a subgroup of 10 patients, altogether with other calcium transporters such as PMCA1 or Cav1.3. Interestingly, TRPV5 mRNA expression was significantly associated with number of colloid calcifications (rho = -0.72; p = 0.02). The high prevalence of calcium oxalate crystals within colloid gel raises intriguing issues upon follicle physiology for calcium and oxalate transport.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224138PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812851PMC
March 2020

Vitamin D and Calcium Supplementation Accelerates Randall's Plaque Formation in a Murine Model.

Am J Pathol 2019 11 23;189(11):2171-2180. Epub 2019 Aug 23.

Sorbonne Universités, Université Pierre et Marie Curie Univ Paris 06, Paris, France; INSERM, Unité Mixte de Recherche S 1155, Paris, France; Physiology Unit, Assistance Publique des Hôpitaux de Paris, Hôpital Tenon, Paris, France. Electronic address:

Most kidney stones are made of calcium oxalate crystals. Randall's plaque, an apatite deposit at the tip of the renal papilla, is considered to at the origin of these stones. Hypercalciuria may promote Randall's plaque formation and growth. We analyzed whether long-term exposure of Abcc6 mice (a murine model of Randall's plaque) to vitamin D supplementation, with or without a calcium-rich diet, would accelerate the formation of Randall's plaque. Eight groups of mice (including Abcc6 and wild type) received vitamin D alone (100,000 UI/kg every 2 weeks), a calcium-enriched diet alone (calcium gluconate 2 g/L in drinking water), both vitamin D supplementation and a calcium-rich diet, or a standard diet (controls) for 6 months. Kidney calcifications were assessed by 3-dimensional microcomputed tomography, μ-Fourier transform infrared spectroscopy, field emission-scanning electron microscopy, transmission electron microscopy, and Yasue staining. At 6 months, Abcc6 mice exposed to vitamin D and calcium supplementation developed massive Randall's plaque when compared with control Abcc6 mice (P < 0.01). Wild-type animals did not develop significant calcifications when exposed to vitamin D. Combined administration of vitamin D and calcium significantly accelerates Randall's plaque formation in a murine model. This original model raises concerns about the cumulative risk of vitamin D supplementation and calcium intakes in Randall's plaque formation.
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http://dx.doi.org/10.1016/j.ajpath.2019.07.013DOI Listing
November 2019

Localization, Morphologic Features, and Chemical Composition of Calciphylaxis-Related Skin Deposits in Patients With Calcific Uremic Arteriolopathy.

JAMA Dermatol 2019 07;155(7):789-796

Service de Dermatologie, Sorbonne Université, Hôpital Tenon, Paris, France.

Importance: Calcific uremic arteriolopathy (CUA), a rare, potentially fatal, disease with calcium deposits in skin, mostly affects patients with end-stage renal disease who are receiving dialysis. Chemical composition and structure of CUA calcifications have been poorly described.

Objectives: To describe the localization and morphologic features and determine the precise chemical composition of CUA-related calcium deposits in skin, and identify any mortality-associated factors.

Design, Setting, And Participants: A retrospective, multicenter cohort study was conducted at 7 French hospitals including consecutive adults diagnosed with CUA between January 1, 2006, and January 1, 2017, confirmed according to Hayashi clinical and histologic criteria. Patients with normal renal function were excluded. For comparison, 5 skin samples from patients with arteriolosclerosis and 5 others from the negative margins of skin-carcinoma resection specimens were also analyzed.

Main Outcomes And Measures: Localization and morphologic features of the CUA-related cutaneous calcium deposits were assessed with optical microscopy and field-emission-scanning electron microscopy, and the chemical compositions of those deposits were evaluated with μ Fourier transform infrared spectroscopy, Raman spectroscopy, and energy dispersive radiographs.

Results: Thirty-six patients (median [range] age, 64 [33-89] years; 26 [72%] female) were included, and 29 cutaneous biopsies were analyzed. Calcific uremic arteriolopathy and arteriolosclerosis skin calcifications were composed of pure calcium-phosphate apatite. Calcific uremic arteriolopathy vascular calcifications were always circumferential, found in small to medium-sized vessels, with interstitial deposits in 22 (76%) of the samples. A thrombosis, most often in noncalcified capillary lumens in the superficial dermis, was seen in 5 samples from patients with CUA. Except for calcium deposits, the vessel structure of patients with CUA appeared normal, unlike thickened arteriolosclerotic vessel walls. Twelve (33%) patients died of CUA.

Conclusions And Relevance: Calcific uremic arteriolopathy-related skin calcifications were exclusively composed of pure calcium-phosphate apatite, localized circumferentially in small to medium-sized vessels and often associated with interstitial deposits, suggesting its pathogenesis differs from that of arteriolosclerosis. Although the chemical compositions of CUA and arteriolosclerosis calcifications were similar, the vessels' appearances and deposit localizations differed, suggesting different pathogenetic mechanisms.
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http://dx.doi.org/10.1001/jamadermatol.2019.0381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624803PMC
July 2019

Daily Green Tea Infusions in Hypercalciuric Renal Stone Patients: No Evidence for Increased Stone Risk Factors or Oxalate-Dependent Stones.

Nutrients 2019 Jan 24;11(2). Epub 2019 Jan 24.

Sorbonne Université, Service d'Explorations Fonctionnelles Multidisciplinaires, AP-HP, Hôpital Tenon, 75020 Paris, France.

Green tea is widely used as a ''healthy'' beverage due to its high level of antioxidant polyphenol compounds. However tea is also known to contain significant amount of oxalate. The objective was to determine, in a cross-sectional observational study among a population of 273 hypercalciuric stone-formers referred to our center for metabolic evaluation, whether daily green tea drinkers ( = 41) experienced increased stone risk factors (especially for oxalate) compared to non-drinkers. Stone risk factors and stone composition were analyzed according to green tea status and sex. In 24-h urine collection, the comparison between green tea drinkers and non-drinkers showed no difference for stone risk factors such as urine oxalate, calcium, urate, citrate, and pH. In females, the prevalence of calcium oxalate dihydrate (COD) and calcium phosphate stones, assessed by infrared analysis (IRS) was similar between green tea drinkers and non-drinkers, whereas prevalence of calcium oxalate monohydrate (COM) stones was strikingly decreased in green tea drinkers (0% vs. 42%, = 0.04), with data in accordance with a decreased oxalate supersaturation index. In males, stone composition and supersaturation indexes were similar between the two groups. Our data show no evidence for increased stone risk factors or oxalate-dependent stones in daily green tea drinkers.
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http://dx.doi.org/10.3390/nu11020256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412450PMC
January 2019

Urothelium proliferation is a trigger for renal crystal deposits in a murine lithogenesis model.

Sci Rep 2018 11 5;8(1):16319. Epub 2018 Nov 5.

Sorbonne Université, INSERM, UMR_S 1155, AP-HP, Hôpital Tenon, 4 rue de la Chine, 75020, Paris, France.

Most mouse kidney stone models induce nephrocalcinosis rather than urolithiasis. The aim of our study was to find an accelerated experimental model in order to study the early events of stone formation, that is, at the time of crystal binding to intrarenal urothelium. C57B6 mice exposed to vitamin D supplements and water containing hydroxyl-L-proline, ammonium chloride and calcium chloride were studied for 42 days. A group receiving urothelial cell mitogen Fibroblast Growth Factor 7 (FGF7) was compared to control group receiving saline. Calcium oxalate monohydrate (COM) crystals were detected in urines by day 2 and within urinary spaces in specialized fornix areas in both groups as soon as day 14 with enhanced deposits in FGF7 group compared to controls at day 21. Urothelial cells proliferation, uroplakin III downregulation and de novo expression of osteopontin receptor CD44 detected in FGF7 group, were delayed in the control group (day 42). Crystal aggregates within specialized fornix areas by day 42 were located in urinary spaces but also within and under a multilayered metaplastic urothelium, simultaneous to macrophages influx. Point of note, administration of a normal diet by day 21 was responsible for a spontaneous crystal clearance. Our data show that under supersaturation conditions, urothelial cell proliferation and calcium oxalate crystal retention occur within specialized fornix areas. Enhanced crystal deposits following FGF7 administration suggest that urothelium proliferation would be a relevant trigger for renal stone formation.
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http://dx.doi.org/10.1038/s41598-018-34734-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218513PMC
November 2018

Fragments and dust after Holmium laser lithotripsy with or without "Moses technology": How are they different?

J Biophotonics 2019 04 13;12(4):e201800227. Epub 2018 Dec 13.

Service d'Urologie, Sorbonne Université, Service d'Urologie, AP-HP, Hôpital Tenon, Paris, France.

Urinary stones can be readily disintegrated by Holmium:YAG laser (Holmium laser lithotripsy), resulting in a mixture of small stone dust particles, which will spontaneously evacuate with urine and larger residual fragments (RF) requiring mechanical retrieval. Differences between fragments and dust have not been well characterized. Also, it remains unknown how the recently introduced "Moses technology" may alter stone disintegration products. Three complementary analytical techniques have been used in this study to offer an in-depth characterization of disintegration products after in vitro Holmium laser lithotripsy: stereoscopic microscopy, scanning electron microscopy and Fourier-transform infrared spectroscopy. Dust was separated from fragments based on its floating ability in saline irrigation. Depending on initial crystalline constituents, stone dust either conserved attributes found in larger RFs or showed changes in crystalline organization. These included conversion of calcium oxalate dihydrate towards calcium oxalate monohydrate, changes in carbapatite spectra towards an amorphous phase, changes of magnesium ammonium phosphate towards a differing amorphous and crystalline phase and the appearance of hydroxyapatite on brushite fragments. Comparatively, "Moses technology" produced more pronounced changes. These findings provide new insights suggesting a photothermal effect occurring in Holmium laser lithotripsy. Figure: Appearance of hydroxyapatite hexagons on stone dust collected after Holmium laser lithotripsy of a brushite stone using "Moses technology."
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http://dx.doi.org/10.1002/jbio.201800227DOI Listing
April 2019

ABCC6 Deficiency Promotes Development of Randall Plaque.

J Am Soc Nephrol 2018 09 10;29(9):2337-2347. Epub 2018 Jul 10.

Institut des maladies mitochondriales, du coeur et des vaisseaux-MITOVASC, Centre National de la Recherche Scientifique 6015, Institut National de la Santé et de la Recherche Médicale U1083, Angers University, Angers, France.

Background: Pseudoxanthoma elasticum (PXE) is a genetic disease caused by mutations in the gene that result in low pyrophosphate levels and subsequent progressive soft tissue calcifications. PXE mainly affects the skin, retina, and arteries. However, many patients with PXE experience kidney stones. We determined the prevalence of this pathology in patients with PXE and examined the possible underlying mechanisms in murine models.

Methods: We conducted a retrospective study in a large cohort of patients with PXE and analyzed urine samples and kidneys from mice at various ages. We used Yasue staining, scanning electron microscopy, electron microscopy coupled to electron energy loss spectroscopy, and Fourier transform infrared microspectroscopy to characterize kidney calcifications.

Results: Among 113 patients with PXE, 45 (40%) had a past medical history of kidney stones. Five of six computed tomography scans performed showed evidence of massive papillary calcifications (Randall plaques). mice spontaneously developed kidney interstitial apatite calcifications with aging. These calcifications appeared specifically at the tip of the papilla and formed Randall plaques similar to those observed in human kidneys. Compared with controls, mice had low urinary excretion of pyrophosphate.

Conclusions: The frequency of kidney stones and probably, Randall plaque is extremely high in patients with PXE, and mice provide a new and useful model in which to study Randall plaque formation. Our findings also suggest that pyrophosphate administration should be evaluated for the prevention of Randall plaque and kidney stones.
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http://dx.doi.org/10.1681/ASN.2017101148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115671PMC
September 2018

New techniques on uropaleopathology.

Urolithiasis 2019 10 5;47(5):487-488. Epub 2018 Jun 5.

Section of Medical and Forensic Anthropology (UVSQ/EA 4569 Paris Descartes University), UFR of Health Sciences, 2 Avenue de la Source de la Bièvre, 78180, Montigny-Le-Bretonneux, France.

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http://dx.doi.org/10.1007/s00240-018-1062-xDOI Listing
October 2019

Two-photon optical imaging, spectral and fluorescence lifetime analysis to discriminate urothelial carcinoma grades.

J Biophotonics 2018 11 16;11(11):e201800065. Epub 2018 Jul 16.

IMNC Laboratory, UMR 8165-CNRS/IN2P3, Paris-Saclay University, Orsay, France.

In the framework of urologic oncology, mini-invasive procedures have increased in the last few decades particularly for urothelial carcinoma. One of the essential elements in the management of this disease is still the diagnosis, which strongly influences the choice of treatment. The histopathologic evaluation of the tumor grade is a keystone of diagnosis, and tumor characterization is not possible with just a macroscopic evaluation. Even today intraoperative evaluation remains difficult despite the emergence of new technologies which use exogenous fluorophore. This study assessed an optical multimodal technique based on endogenous fluorescence, combining qualitative and quantitative analysis, for the diagnostic of urothelial carcinoma. It was found that the combination of two-photon fluorescence, second harmonic generation microscopy, spectral analysis and fluorescence lifetime imaging were all able to discriminate tumor from healthy tissue, and to determine the grade of tumors. Spectral analysis of fluorescence intensity and the redox ratio used as quantitative evaluations showed statistical differences between low-grade and high-grade tumors. These results showed that multimodal optical analysis is a promising technology for the development of an optical fiber setup designed for an intraoperative diagnosis of urothelial carcinoma in the area of endo-urology.
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http://dx.doi.org/10.1002/jbio.201800065DOI Listing
November 2018

Delayed ileal perforation from sodium polystyrene sulfonate.

Kidney Int 2018 05;93(5):1251-1252

Department of Nephrology and Internal Medicine, Centre Hospitalier Sud Francilien, Corbeil, France.

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http://dx.doi.org/10.1016/j.kint.2017.10.014DOI Listing
May 2018

Recurrence rates of urinary calculi according to stone composition and morphology.

Urolithiasis 2018 Oct 1;46(5):459-470. Epub 2018 Feb 1.

Department of Anatomy and Cell Biology, Indiana University, Indianapolis, IN, USA.

Few studies have examined the relative risk of recurrence of different stone types. The object of the present study was to evaluate the tendency for stone recurrence as a function of major mineral composition of the stones and morphological characteristics of the stones. This study was carried out using 38,274 stones for which we had data available to specify if the stone was from the first or a subsequent urinary stone episode. Stones were analyzed for morphology by stereomicroscope and for composition by infrared spectroscopy. Overall, 42.7% of stones were from patients who had had a previous stone event, with these being more frequent in men (44.4%) than in women (38.9%, p < 0.0001). Age of first stone occurrence was lowest for dihydroxyadenine (15.7 ± 16.6 years) and highest for anhydrous uric acid (62.5 ± 14.9 years), with the average age of first stones of calcium oxalate falling in the middle (40.7 ± 14.6 years for calcium oxalate dihydrate, and 48.4 ± 15.1 years for calcium oxalate monohydrate, COM). By composition alone, COM was among the least recurrent of stones, with only 38.0% of COM stones coming from patients who had had a previous episode; however, when the different morphological types of COM were considered, type Ic-which displays a light color, budding surface and unorganized section-had a significantly greater rate of recurrence, at 82.4% (p < 0.0001), than did other morphologies of COM. Similarly, for stones composed of apatite, morphological type IVa2-a unique form with cracks visible beneath a glossy surface-had a higher rate of recurrence than other apatite morphologies (78.8 vs. 39-42%, p < 0.0001). Stone mineral type alone is insufficient for identifying the potential of recurrence of the stones. Instead, the addition of stone morphology may allow the diagnosis of highly recurrent stones, even among common mineral types (e.g., COM) that in general are less recurrent.
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http://dx.doi.org/10.1007/s00240-018-1043-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711148PMC
October 2018

Drug-Induced Kidney Stones and Crystalline Nephropathy: Pathophysiology, Prevention and Treatment.

Drugs 2018 Feb;78(2):163-201

Department of Nephrology, Necker Hospital, AP-HP, Paris, France.

Drug-induced calculi represent 1-2% of all renal calculi. The drugs reported to produce calculi may be divided into two groups. The first one includes poorly soluble drugs with high urine excretion that favour crystallisation in the urine. Among them, drugs used for the treatment of patients with human immunodeficiency, namely atazanavir and other protease inhibitors, and sulphadiazine used for the treatment of cerebral toxoplasmosis, are the most frequent causes. Besides these drugs, about 20 other molecules may induce nephrolithiasis, such as ceftriaxone or ephedrine-containing preparations in subjects receiving high doses or long-term treatment. Calculi analysis by physical methods including infrared spectroscopy or X-ray diffraction is needed to demonstrate the presence of the drug or its metabolites within the calculi. Some drugs may also provoke heavy intra-tubular crystal precipitation causing acute renal failure. Here, the identification of crystalluria or crystals within the kidney tissue in the case of renal biopsy is of major diagnostic value. The second group includes drugs that provoke the formation of urinary calculi as a consequence of their metabolic effects on urinary pH and/or the excretion of calcium, phosphate, oxalate, citrate, uric acid or other purines. Among such metabolically induced calculi are those formed in patients taking uncontrolled calcium/vitamin D supplements, or being treated with carbonic anhydrase inhibitors such as acetazolamide or topiramate. Here, diagnosis relies on a careful clinical inquiry to differentiate between common calculi and metabolically induced calculi, of which the incidence is probably underestimated. Specific patient-dependent risk factors also exist in relation to urine pH, volume of diuresis and other factors, thus providing a basis for preventive or curative measures against stone formation.
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http://dx.doi.org/10.1007/s40265-017-0853-7DOI Listing
February 2018

High frequency and wide range of human kidney papillary crystalline plugs.

Urolithiasis 2018 Aug 12;46(4):333-341. Epub 2017 Dec 12.

Sorbonne Universités, UPMC Univ Paris 06, UMR S 1155, 75020, Paris, France.

Most of kidney stones are supposed to originate from Randall's plaque at the tip of the papilla or from papillary tubular plugs. Nevertheless, the frequency and the composition of crystalline plugs remain only partly described. The objective was to assess the frequency, the composition and the topography of papillary plugs in human kidneys. A total of 76 papillae from 25 kidneys removed for cancer and without stones were analysed by immunohistochemistry combined with Yasue staining, field emission-scanning electron microscopy and Fourier transformed infrared micro-spectroscopy. Papillary tubular plugs have been observed by Yasue staining in 23/25 patients (92%) and 52/76 papillae (68%). Most of these plugs were made of calcium phosphate, mainly carbonated apatite and amorphous calcium phosphate, and rarely octacalcium phosphate pentahydrate. Calcium and magnesium phosphate (whitlockite) have also been observed. Based upon immunostaining coupled to Yasue coloration, most of calcium phosphate plugs were located in the deepest part of the loop of Henle. Calcium oxalate monohydrate and dihydrate tubular plugs were less frequent and stood in collecting ducts. At last, we observed calcium phosphate plugs deforming and sometimes breaking adjacent collecting ducts. Papillary tubular plugging, which may be considered as a potential first step toward kidney stone formation, is a very frequent setting, even in kidneys of non-stone formers. The variety in their composition and the distal precipitation of calcium oxalate suggest that plugs may occur in various conditions of urine supersaturation. Plugs were sometimes associated with collecting duct deformation.
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http://dx.doi.org/10.1007/s00240-017-1031-9DOI Listing
August 2018

Flyscan opportunities in medicine: the case of quantum rattle based on gold quantum dots.

J Synchrotron Radiat 2017 Sep 7;24(Pt 5):991-999. Epub 2017 Aug 7.

Laboratoire Chimie de la Matière Condensée de Paris, UMR UPMC College de France - CNRS 7574, Université Pierre et Marie Curie (Paris 6), 4 Place Jussieu, 75252 Paris, France.

The new rapid scan method, Flyscan mode, implemented on the DiffAbs beamline at Synchrotron SOLEIL, allows fast micro-X-ray fluorescence data acquisition. It paves the way for applications in the biomedical field where a large amount of data is needed to generate meaningful information for the clinician. This study presents a complete set of data acquired after injection of gold-cluster-enriched mesoporous silica nanospheres, used as potential theranostic vectors, into rats. While classical X-ray fluorescence investigations (using step-by-step acquisitions) are based on a limited number of samples (approximately one per day at the DiffAbs beamline), the Flyscan mode has enabled gathering information on the interaction of nanometer-scale vectors in different organs such as liver, spleen and kidney at the micrometer scale, for five rats, in only a single five-day synchrotron shift. Moreover, numerous X-ray absorption near-edge structure spectra, which are beam-time-consuming taking into account the low concentration of these theranostic vectors, were collected.
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http://dx.doi.org/10.1107/S1600577517009572DOI Listing
September 2017

Free DNA precipitates calcium phosphate apatite crystals in the arterial wall in vivo.

Atherosclerosis 2017 04 4;259:60-67. Epub 2017 Mar 4.

UMR 1148, Inserm-Paris7, Denis Diderot University, Xavier Bichat Hospital, 75018 Paris, France.

Background And Aims: The arterial wall calcium score and circulating free DNA levels are now used in clinical practice as biomarkers of cardiovascular risk. Calcium phosphate apatite retention in the arterial wall necessitates precipitation on an anionic platform. Here, we explore the role of tissue-free DNA as such a platform.

Methods: The first step consisted of histological observation of samples from human and rat calcified arteries. Various stains were used to evaluate colocalization of free DNA with calcified tissue (alizarin red, fluorescent Hoechst, DNA immunostaining and TUNEL assay). Sections were treated by EDTA to reveal calcification background. Secondly, a rat model of vascular calcifications induced by intra-aortic infusions of free DNA and elastase + free DNA was developed. Rat aortas underwent a micro-CT for calcium score calculation at 3 weeks. Rat and human calcifications were qualitatively characterized using μFourier Transform Infrared Spectroscopy (μFTIR) and Field Emission-Scanning Electron Microscopy (FE-SEM).

Results: Our histological study shows colocalization of calcified arterial plaques with free DNA. In the intra-aortic infusion model, free DNA was able to penetrate into the arterial wall and induce calcifications whereas no microscopic calcification was seen in control aortas. The calcification score in the elastase + free DNA group was significantly higher than in the control groups. Qualitative evaluation with μFTIR and FE-SEM demonstrated typical calcium phosphate retention in human and rat arterial specimens.

Conclusions: This translational study demonstrates that free DNA could be involved in arterial calcification formation by precipitating calcium phosphate apatite crystals in the vessel wall.
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http://dx.doi.org/10.1016/j.atherosclerosis.2017.03.005DOI Listing
April 2017

Vancomycin-Associated Cast Nephropathy.

J Am Soc Nephrol 2017 Jun 12;28(6):1723-1728. Epub 2017 Jan 12.

Urgences Néphrologiques et Transplantation rénale, Hôpital Tenon, Assistance Publique - Hôpitaux de Paris, Paris, France;

Vancomycin is a widely prescribed antibiotic, but the exact nature of vancomycin-associated nephrotoxicity is unclear, in particular when considering the frequent coadministration of aminoglycosides. We describe here the initial case of a 56-year-old woman with normal renal function developing unexplained ARF without hypovolemia after administration of vancomycin without coadministration of aminoglycosides. Studying the patient's renal biopsy specimen, we ascertained that obstructive tubular casts composed of noncrystal nanospheric vancomycin aggregates entangled with uromodulin explained the vancomycin-associated ARF. We developed in parallel a new immunohistologic staining technique to detect vancomycin in renal tissue and confirmed retrospectively that deleterious vancomycin-associated casts existed in eight additional patients with acute tubular necrosis in the absence of hypovolemia. Concomitant high vancomycin trough plasma levels had been observed in each patient. We also reproduced experimentally the toxic and obstructive nature of vancomycin-associated cast nephropathy in mice, which we detected using different imaging techniques. In conclusion, the interaction of uromodulin with nanospheric vancomycin aggregates represents a new mode of tubular cast formation, revealing the hitherto unsuspected mechanism of vancomycin-associated renal injury.
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http://dx.doi.org/10.1681/ASN.2016080867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461798PMC
June 2017

Topography, Composition and Structure of Incipient Randall Plaque at the Nanoscale Level.

J Urol 2016 11 6;196(5):1566-1574. Epub 2016 May 6.

Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S 1155, Paris, France; Physiology Unit, Assistance Publique Hôpitaux de Paris, Hôpital Tenon, Paris, France. Electronic address:

Purpose: Randall identified calcium phosphate plaques in renal papillae as the origin of kidney stones. However, little is known about the early steps of Randall plaque formation preceding the onset of urolithiasis. Our objective was to characterize the composition and the initial formation site of incipient Randall plaque in nonstone forming, living patients.

Materials And Methods: Median patient age was 67.7 years. A total of 54 healthy papillae from kidneys removed for cancer and without stones were analyzed by immunohistochemistry and von Kossa staining, field emission-scanning electron microscopy with energy dispersive x-ray analysis, μ-Fourier transform infrared spectroscopy, cryo-transmission electron microscopy coupled to selected area electron diffraction and electron energy loss spectroscopy.

Results: Incipient Randall plaque was observed in 72.7% of kidneys. As expected, carbonated apatite was the main component of microcalcifications but amorphous calcium phosphate and whitlockite were identified in 80% and 40% of papillae, respectively. Incipient plaques were noted in the deepest part of the papillae around the loop of Henle tip as well as around the vasa recta, representing 62.4% and 37.2% of microcalcifications, respectively. Plaques were rarely close to collecting ducts. At the nanoscale level incipient calcifications were often composed of several nanocrystals in organic material that looked like microvesicles.

Conclusions: Incipient Randall plaque is frequent. It appears not only at the extreme tip of the renal papillae around the hairpin structure of the loop of Henle but also around the vasa recta. Nanoscale analyses suggest a local nucleation process promoting nanocrystal growth in a supersaturated milieu. In addition, plaques contain various calcium and magnesium phosphates, and not only carbonated apatite.
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http://dx.doi.org/10.1016/j.juro.2016.04.086DOI Listing
November 2016

Rapid and reliable diagnosis of Wilson disease using X-ray fluorescence.

J Pathol Clin Res 2016 Jul 6;2(3):175-86. Epub 2016 Jun 6.

INSERMUnité 1193, Villejuif, F-94800France; Univ Paris-SudUMR-S 1193, Villejuif, F-94800France; DHU HepatinovVillejuif, F-94800France.

Wilson's disease (WD) is a rare autosomal recessive disease due to mutations of the gene encoding the copper-transporter ATP7B. The diagnosis is hampered by the variability of symptoms induced by copper accumulation, the inconstancy of the pathognomonic signs and the absence of a reliable diagnostic test. We investigated the diagnostic potential of X-ray fluorescence (XRF) that allows quantitative analysis of multiple elements. Studies were performed on animal models using Wistar rats (n = 10) and Long Evans Cinnamon (LEC) rats (n = 11), and on human samples including normal livers (n = 10), alcohol cirrhosis (n = 8), haemochromatosis (n = 10), cholestasis (n = 6) and WD (n = 22). XRF experiments were first performed using synchrotron radiation to address the elemental composition at the cellular level. High-resolution mapping of tissue sections allowed measurement of the intensity and the distribution of copper, iron and zinc while preserving the morphology. Investigations were further conducted using a laboratory X-ray source for irradiating whole pieces of tissue. The sensitivity of XRF was highlighted by the discrimination of LEC rats from wild type even under a regimen using copper deficient food. XRF on whole formalin-fixed paraffin embedded needle biopsies allowed profiling of the elements in a few minutes. The intensity of copper related to iron and zinc significantly discriminated WD from other genetic or chronic liver diseases with 97.6% specificity and 100% sensitivity. This study established a definite diagnosis of Wilson's disease based on XRF. This rapid and versatile method can be easily implemented in a clinical setting.
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http://dx.doi.org/10.1002/cjp2.48DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958738PMC
July 2016

Calcium and vitamin D have a synergistic role in a rat model of kidney stone disease.

Kidney Int 2016 10 27;90(4):809-17. Epub 2016 Jul 27.

Sorbonne Universités, UPMC Univ Paris 6, UMR S 1155, Paris, France; INSERM, UMR S 1155, Paris, France; Physiology Unit, AP-HP, Hôpital Tenon, Paris, France.

Vitamin D supplementation in humans should be accompanied by calcium administration to avoid bone demineralization through vitamin D receptor signaling. Here we analyzed whether long-term exposure of rats to vitamin D supplementation, with or without a calcium-rich diet, would promote kidney stone formation. Four groups of rats received vitamin D alone (100,000 UI/kg/3 weeks), a calcium-enriched diet alone, both vitamin D supplementation and calcium-enriched diet, or a standard diet (controls) for 6 months. Serum and urine parameters and crystalluria were monitored. Kidney stones were assessed by 3-dimensional micro-computed tomography, infrared spectroscopy, von Kossa/Yasue staining, and field emission scanning electron microscopy. Although serum calcium levels were similar in the 4 groups, rats receiving vitamin D had a progressive increase in urinary calcium excretion over time, especially those receiving both calcium and vitamin D. However, oral calcium supplementation alone did not increase urinary calcium excretion. At 6 months, rats exposed to both calcium and vitamin D, but not rats exposed to calcium or vitamin D alone, developed significant apatite kidney calcifications (mean volume, 0.121 mm(3)). Thus, coadministration of vitamin D and increased calcium intake had a synergistic role in tubular calcifications or kidney stone formation in this rat model. Hence, one should be cautious about the cumulative risk of kidney stone formation in humans when exposed to both vitamin D supplementation and high calcium intake.
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http://dx.doi.org/10.1016/j.kint.2016.05.027DOI Listing
October 2016

Reply.

Urology 2015 Dec;86(6):1096

APHP, Service des Explorations Fonctionnelles, Hôpital Tenon, Paris, France; INSERM, UMR S 1155, Hôpital Tenon, Paris, France.

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http://dx.doi.org/10.1016/j.urology.2015.06.070DOI Listing
December 2015

Some advances in the field of physico-chemical characterization of pathological microcrystals.

Ann Biol Clin (Paris) 2015 Sep-Oct;73(5):517-34

Service d'explorations fonctionnelles multidisciplinaires, AP-HP, Hôpital Tenon, Paris, France, Inserm, UMR S 1155, Hôpital Tenon, Paris, France.

Recent advances in the characterization of microcrystals in tissue samples based on physico-chemical techniques are reviewed. It is a new opportunity for the physician to access early a diagnosis of rare but severe pathologies and to start a specific therapy able to delay or to stop an irreversible alteration of the organ, for example to avoid dialysis and transplantation when kidney is mainly affected. To date, more than 400 biopsies of kidneys containing crystals were performed and characterized using such techniques. The data collected on crystals, tissue alteration, clinical and biological investigations are of prime importance to help a better understanding of biochemical process involved in crystal formation. Such techniques may be applied to microcrystalline pathologies affecting other organs than kidney, namely prostate, pancreas, thyroid, breast… Multicentric and international collaborations were developed, thus offering new opportunities in studying pathophysiology of deposited microcrystals and their consequences. In fact, crystals may be the consequence of various pathologies, but they are also involved in the dysfunction of the tissue where they accumulate. Two techniques are mainly applied to such diagnosis: scanning electron microscopy and Fourier transform infrared spectroscopy, including synchrotron radiation infrared microspectroscopy.
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http://dx.doi.org/10.1684/abc.2015.1070DOI Listing
August 2016

High Prevalence of Opaline Silica in Urinary Stones From Burkina Faso.

Urology 2015 Dec 1;86(6):1090-5. Epub 2015 Oct 1.

APHP, Service des Explorations Fonctionnelles, Hôpital Tenon, Paris, France; INSERM, UMR S 1155, Hôpital Tenon, Paris, France.

Objective: To underline peculiar composition of kidney stones and to propose an epidemiologic study of urinary stones in West African countries, where epidemiologic studies are scarce. Only few data are available regarding stone composition in sub-Saharan countries. Recently, a set of 100 stones consecutively removed by surgery in the Department of Urology of the University Hospital of Ouagadougou in Burkina Faso were collected for physical analysis, which provided the opportunity to obtain an epidemiologic profile of stone composition in this country.

Materials And Methods: A total of 100 stones from 64 men, 22 women, 10 boys, and four girls were analyzed by morphologic examination, infrared spectroscopy, and electron microscopy in our laboratory. The results were considered by sex and separately for adults and children.

Results: Sixty-five percent of the 100 stones contained calcium oxalate as the main component. Interestingly, the second main component was opaline silica (18%). Furthermore, opaline silica was identified in any proportion in 48% of the stones. The prevalence was sex and age dependent. Opaline silica was detected as the main component in 42% of the nuclei, which underlines its role as one of the main components involved in the initiation of calculi in this country.

Conclusion: For the first time, a dramatically high occurrence of a "scarce" urinary stone component, namely opaline silica, was reported in a series of consecutive calculi from a single country. We propose that a regular consumption of clay could be the origin of this phenomenon in these populations.
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http://dx.doi.org/10.1016/j.urology.2015.06.068DOI Listing
December 2015

Claudin-16 Deficiency Impairs Tight Junction Function in Ameloblasts, Leading to Abnormal Enamel Formation.

J Bone Miner Res 2016 Mar 20;31(3):498-513. Epub 2015 Oct 20.

EA 2496, Laboratory Orofacial Pathologies, Imaging and Biotherapies, Dental School Paris Descartes University, Sorbonne Paris Cité, France.

Claudin-16 protein (CLDN16) is a component of tight junctions (TJ) with a restrictive distribution so far demonstrated mainly in the kidney. Here, we demonstrate the expression of CLDN16 also in the tooth germ and show that claudin-16 gene (CLDN16) mutations result in amelogenesis imperfecta (AI) in the 5 studied patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). To investigate the role of CLDN16 in tooth formation, we studied a murine model of FHHNC and showed that CLDN16 deficiency led to altered secretory ameloblast TJ structure, lowering of extracellular pH in the forming enamel matrix, and abnormal enamel matrix protein processing, resulting in an enamel phenotype closely resembling human AI. This study unravels an association of FHHNC owing to CLDN16 mutations with AI, which is directly related to the loss of function of CLDN16 during amelogenesis. Overall, this study indicates for the first time the importance of a TJ protein in tooth formation and underlines the need to establish a specific dental follow-up for these patients.
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http://dx.doi.org/10.1002/jbmr.2726DOI Listing
March 2016