How much energy do we need to ablate 1 cubic millimeter of stone during Thulium Fiber Laser lithotripsy? An in vitro study.

INTRODUCTION: Both Holmium:yttrium-aluminium-garnet (Ho:YAG) laser and Thulium Fiber Laser (TFL) can effectively treat all urinary stone types. This in vitro study evaluated the ablation volume per pulse (AVP) and required energy needed to ablate 1mm3 (RE, J/mm3) of various stone types at different laser settings with TFL. METHODS: 272-µm core-diameter laser fibers (Boston Scientific©) were connected to a 50 Watts TFL generator (IPG®). An experimental setup immerged human stones of calcium oxalate monohydrate (COM), uric acid (UA), and cystine (CYS) with a single pulse lasing emission (0.5/0.8/1 J), in contact mode. Stones were dried out before three-dimensional scanning to measure AVP and deduce from the pulse energy (PE) and AVP the RE. A direct comparison with known Ho:YAG's AVP and RE was then carried out. RESULTS: AVP for COM stones was significantly greater than those for CYS stones and similar to UA stones (p = 0.02 and p = 0.06, respectively). If AVP increased with PE against COM and UA stones, AVP decreased against CYS stones. 1 J PE resulted in a threefold lower RE compared with other PE for COM stones. On the contrary, RE for CYS increased with PE, whereas PE did not had influence on RE for UA. TFL was associated with greater AVP for COM, but lower for UA and CYS stones compared to Ho:YAG laser. CONCLUSION: This in vitro study firstly describes the ablation volume per pulse and required energy to treat a cubic millimeter of three frequent human stone types, and suggest TFL could not be suited for cystine. Therefore, stone composition could be considered when choosing the laser source for lithotripsy.

Ureteroscopic management in cystinuric patients: long-term results from a tertiary care referral center.

OBJECTIVE: To evaluate long-term surgical and functional outcomes of cystinuric patients exclusively treated with Ureteroscopy (URS). METHODS: Data from patients treated for cystine stones at a single academic center were retrospectively analyzed. The management protocol consisted of (i) treating symptomatic or > 7 mm stones, (ii) multi-staged URS for voluminous stones, (iii) referring patients to a dedicated nephrological clinic. The eGFR was calculated according to the MDRD formula. CKD category was assessed according to the NKF classification. Relevant CKD was defined as CKD category ≥ 3a. Descriptive statistics were used to analyze the cohort data. RESULTS: Data from 46 cystinuric patients treated with 332 URS were available. Median age at diagnosis and at first URS in our center were 18 and 32 years, respectively. Median follow-up was 101 months. Median number of URS and recurrences per patient were 6 and 2, respectively. The median interval between the first and the last available creatinine level was 64 months. Median first and last eGFR were 72 and 74 mL/min, respectively. Overall, 83% of patients had stable or improved renal function within the study period. Ureteral stricture occurred in 3 (6.5%) patients. CONCLUSIONS: Cystinuria requires intensive endoscopic management. Most patients treated with URS have stable or improved renal function within a long-term follow-up. CKD is a not neglectable event that potentially occurs at an early stage of life. Current findings should be considered for the surgical management of cystinuric patients.

Pulsed thulium:YAG laser-ready to dust all urinary stone composition types? Results from a PEARLS analysis.

PURPOSE: To evaluate whether stone dust can be obtained from all prevailing stone composition types using the novel pulsed thulium:YAG (p-Tm:YAG), including analysis of stone particle size after lithotripsy. METHODS: Human urinary stones of 7 different compositions were subjected to in vitro lithotripsy using a p-Tm:YAG laser with 270 µm silica core fibers (Thulio®, Dornier MedTech GmbH®, Wessling, Germany). A cumulative energy of 1000 J was applied to each stone using one of three laser settings: 0.1 J × 100 Hz, 0.4 J × 25 Hz and 2.0 J × 5 Hz (average power 10 W). After lithotripsy, larger remnant fragments were separated from stone dust using a previously described method depending on the floating ability of dust particles. Fragments and dust samples were then passed through laboratory sieves to evaluate stone particle count according to a semiquantitative analysis relying on a previous definition of stone dust (i.e., stone particles ≤ 250 µm). RESULTS: The p-Tm:YAG laser was able to produce stone dust from lithotripsy up to measured smallest mesh size of 63 µm in all seven stone composition types. Notably, all dust samples from all seven stone types and with all three laser settings had high counts of particles in the size range agreeing with the definition stone dust, i.e., ≤ 250 µm. CONCLUSION: This is the first study in the literature proving the p-Tm:YAG laser capable of dusting all prevailing human urinary stone compositions, with production of dust particles ≤ 250 µm. These findings are pivotal for the broader future implementation of the p-Tm:YAG in clinical routine.

Pulsed Thulium:YAG laser - What is the lithotripsy ablation efficiency for stone dust from human urinary stones? Results from an in vitro PEARLS study.

BACKGROUND: The novel pulsed thulium:yttrium-aluminum-garnet (p-Tm:YAG) laser was recently introduced. Current studies present promising p-Tm:YAG ablation efficiency, although all are based on non-human stone models or with unknown stone composition. The present study aimed to evaluate p-Tm:YAG ablation efficiency for stone dust from human urinary stones of known compositions. METHODS: Calcium oxalate monohydrate (COM) and uric acid (UA) stones were subjected to lithotripsy in vitro using a p-Tm:YAG laser generator (Thulio®, Dornier MedTech GmbH, Germany). 200 J was applied at 0.1 J × 100 Hz, 0.4 J × 25 Hz or 2.0 J × 5 Hz (average 10W). Ablated stone dust mass was calculated from weight difference between pre-lithotripsy stone and post-lithotripsy fragments > 250 µm. Estimated ablated volume was calculated using prior known stone densities (COM: 2.04 mg/mm3, UA: 1.55 mg/mm3). RESULTS: Mean ablation mass efficiency was 0.04, 0.06, 0.07 mg/J (COM) and 0.04, 0.05, 0.06 mg/J (UA) for each laser setting, respectively. This translated to 0.021, 0.029, 0.034 mm3/J (COM) and 0.026, 0.030, 0.039 mm3/J (UA). Mean energy consumption was 26, 18, 17 J/mg (COM) and 32, 23, 17 J/mg (UA). This translated to 53, 37, 34 J/mm3 (COM) and 50, 36, 26 J/mm3 (UA). There were no statistically significant differences for laser settings or stone types (all p > 0.05). CONCLUSION: To our knowledge, this is the first study showing ablation efficiency of the p-Tm:YAG laser for stone dust from human urinary stones of known compositions. The p-Tm:YAG seems to ablate COM and UA equally well, with no statistically significant differences between differing laser settings.

Detection and localization of calcium oxalate in kidney using synchrotron deep ultraviolet fluorescence microscopy.

Renal oxalosis is a rare cause of renal failure whose diagnosis can be challenging. Synchrotron deep ultraviolet (UV) fluorescence was assayed to improve oxalosis detection on kidney biopsies spatial resolution and sensitivity compared with the Fourier transform infrared microspectroscopy gold standard. The fluorescence spectrum of synthetic mono-, di- and tri-hydrated calcium oxalate was investigated using a microspectrometer coupled to the synchrotron UV beamline DISCO, Synchrotron SOLEIL, France. The obtained spectra were used to detect oxalocalcic crystals in a case control study of 42 human kidney biopsies including 19 renal oxalosis due to primary (PHO, n = 11) and secondary hyperoxaluria (SHO, n = 8), seven samples from PHO patients who received combined kidney and liver transplants, and 16 controls. For all oxalocalcic hydrates samples, a fluorescence signal is detected at 420 nm. These spectra were used to identify standard oxalocalcic crystals in patients with PHO or SHO. They also revealed micrometric crystallites as well as non-aggregated oxalate accumulation in tubular cells. A nine-points histological score was established for the diagnosis of renal oxalosis with 100% specificity (76-100) and a 73% sensitivity (43-90). Oxalate tubular accumulation and higher histological score were correlated to lower estimated glomerular filtration rate and higher urinary oxalate over creatinine ratio.

Crystalline structures of L-cysteine and L-cystine: a combined theoretical and experimental characterization.

It is assumed that genetic diseases affecting the metabolism of cysteine and the kidney function lead to two different kinds of pathologies, namely cystinuria and cystinosis whereby generate L-cystine crystals. Recently, the presence of L-cysteine crystal has been underlined in the case of cystinosis. Interestingly, it can be strikingly seen that cystine ([-S-CH2-CH-(NH2)-COOH]2) consists of two cysteine (C3H7NO2S) molecules connected by a disulfide (S-S) bond. Therefore, the study of cystine and cysteine is important for providing a better understanding of cystinuria and cystinosis. In this paper, we elucidate the discrepancy between L-cystine and L-cysteine by investigating the theoretical and experimental infrared spectra (IR), X-ray diffraction (XRD) as well as Raman spectra aiming to obtain a better characterization of abnormal deposits related to these two genetic pathologies.

Evaluation and understanding of automated urinary stone recognition methods.

OBJECTIVE: To assess the potential of automated machine-learning methods for recognizing urinary stones in endoscopy. MATERIALS AND METHODS: Surface and section images of 123 urinary calculi (109 ex vivo and 14 in vivo stones) were acquired using ureteroscopes. The stones were more than 85% 'pure'. Six classes of urolithiasis were represented: Groups I (calcium oxalate monohydrate, whewellite), II (calcium oxalate dihydrate, weddellite), III (uric acid), IV (brushite and struvite stones), and V (cystine). The automated stone recognition methods that were developed for this study followed two types of approach: shallow classification methods and deep-learning-based methods. Their sensitivity, specificity and positive predictive value (PPV) were evaluated by simultaneously using stone surface and section images to classify them into one of the main morphological groups (subgroups were not considered in this study). RESULTS: Using shallow methods (based on texture and colour criteria), relatively high sensitivity, specificity and PPV for the six classes were attained: 91%, 90% and 89%, respectively, for whewellite; 99%, 98% and 99% for weddellite; 88%, 89% and 88% for uric acid; 91%, 89% and 90% for struvite; 99%, 99% and 99% for cystine; and 94%, 98% and 99% for brushite. Using deep-learning methods, the sensitivity, specificity and PPV for each of the classes were as follows: 99%, 98% and 97% for whewellite; 98%, 98% and 98% for weddellite; 97%, 98% and 98% for uric acid; 97%, 97% and 96% for struvite; 99%, 99% and 99% for cystine; and 94%, 97% and 98% for brushite. CONCLUSION: Endoscopic stone recognition is challenging, and few urologists have sufficient expertise to achieve a diagnosis performance comparable to morpho-constitutional analysis. This work is a proof of concept that artificial intelligence could be a solution, with promising results achieved for pure stones. Further studies on a larger panel of stones (pure and mixed) are needed to further develop these methods.

Towards automatic recognition of pure and mixed stones using intra-operative endoscopic digital images.

OBJECTIVE: To assess automatic computer-aided in situ recognition of the morphological features of pure and mixed urinary stones using intra-operative digital endoscopic images acquired in a clinical setting. MATERIALS AND METHODS: In this single-centre study, a urologist with 20 years' experience intra-operatively and prospectively examined the surface and section of all kidney stones encountered. Calcium oxalate monohydrate (COM) or Ia, calcium oxalate dihydrate (COD) or IIb, and uric acid (UA) or IIIb morphological criteria were collected and classified to generate annotated datasets. A deep convolutional neural network (CNN) was trained to predict the composition of both pure and mixed stones. To explain the predictions of the deep neural network model, coarse localization heat-maps were plotted to pinpoint key areas identified by the network. RESULTS: This study included 347 and 236 observations of stone surface and stone section, respectively; approximately 80% of all stones exhibited only one morphological type and approximately 20% displayed two. A highest sensitivity of 98% was obtained for the type 'pure IIIb/UA' using surface images. The most frequently encountered morphology was that of the type 'pure Ia/COM'; it was correctly predicted in 91% and 94% of cases using surface and section images, respectively. Of the mixed type 'Ia/COM + IIb/COD', Ia/COM was predicted in 84% of cases using surface images, IIb/COD in 70% of cases, and both in 65% of cases. With regard to mixed Ia/COM + IIIb/UA stones, Ia/COM was predicted in 91% of cases using section images, IIIb/UA in 69% of cases, and both in 74% of cases. CONCLUSIONS: This preliminary study demonstrates that deep CNNs are a promising method by which to identify kidney stone composition from endoscopic images acquired intra-operatively. Both pure and mixed stone composition could be discriminated. Collected in a clinical setting, surface and section images analysed by a deep CNN provide valuable information about stone morphology for computer-aided diagnosis.

Vitamin D and Calcium Supplementation Accelerate Vascular Calcification in a Model of Pseudoxanthoma Elasticum.

Arterial calcification is a common feature of pseudoxanthoma elasticum (PXE), a disease characterized by ABCC6 mutations, inducing a deficiency in pyrophosphate, a key inhibitor of calcium phosphate crystallization in arteries. METHODS: we analyzed whether long-term exposure of Abcc6-/- mice (a murine model of PXE) to a mild vitamin D supplementation, with or without calcium, would impact the development of vascular calcification. Eight groups of mice (including Abcc6-/- and wild-type) received vitamin D supplementation every 2 weeks, a calcium-enriched diet alone (calcium in drinking water), both vitamin D supplementation and calcium-enriched diet, or a standard diet (controls) for 6 months. Aorta and kidney artery calcification was assessed by 3D-micro-computed tomography, Optical PhotoThermal IR (OPTIR) spectroscopy, scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy (SEM-EDS) and Yasue staining. RESULTS: at 6 months, although vitamin D and/or calcium did not significantly increase serum calcium levels, vitamin D and calcium supplementation significantly worsened aorta and renal artery calcification in Abcc6-/- mice. CONCLUSIONS: vitamin D and/or calcium supplementation accelerate vascular calcification in a murine model of PXE. These results sound a warning regarding the use of these supplementations in PXE patients and, to a larger extent, patients with low systemic pyrophosphate levels.

Cystinuria: clinical practice recommendation.

Cystinuria (OMIM 220100) is an autosomal recessive hereditary disorder in which high urinary cystine excretion leads to the formation of cystine stones because of the low solubility of cystine at normal urinary pH. We developed clinical practice recommendation for diagnosis, surgical and medical treatment, and follow-up of patients with cystinuria. Elaboration of these clinical practice recommendations spanned from June 2018 to December 2019 with a consensus conference in January 2019. Selected topic areas were chosen by the co-chairs of the conference. Working groups focusing on specific topics were formed. Group members performed systematic literature review using MEDLINE, drafted the statements, and discussed them. They included geneticists, medical biochemists, pediatric and adult nephrologists, pediatric and adult urologists experts in cystinuria, and the Metabolic Nephropathy Joint Working Group of the European Reference Network for Rare Kidney Diseases (ERKNet) and eUROGEN members. Overall 20 statements were produced to provide guidance on diagnosis, genetic analysis, imaging techniques, surgical treatment (indication and modalities), conservative treatment (hydration, dietetic, alkalinization, and cystine-binding drugs), follow-up, self-monitoring, complications (renal failure and hypertension), and impact on quality of life. Because of the rarity of the disease and the poor level of evidence in the literature, these statements could not be graded. This clinical practice recommendation provides guidance on all aspects of the management of both adults and children with cystinuria, including diagnosis, surgery, and medical treatment.

Toward improved endoscopic examination of urinary stones: a concordance study between endoscopic digital pictures vs microscopy.

OBJECTIVE: To improve endoscopic recognition of the most frequently encountered urinary stone morphologies for a better aetiological approach in lithiasis by urologists. MATERIALS AND METHODS: An expert urologist intraoperatively and prospectively (between June 2015 and June 2018) examined the surface, the section, and the nucleus of all encountered kidney stones. Fragmented stones were subsequently analysed by a biologist based on both microscopic morphological (i.e. binocular magnifying glass) and infrared (i.e. Fourier transform-infrared spectroscopy) examinations (microscopists were blinded to the endoscopic data). Morphological criteria were collected and classified for the endoscopic and microscopic studies. The Wilcoxon-Mann-Whitney test was used to detect differences between the endoscopic and microscopic diagnoses. A diagnosis for a given urinary stone was considered 'confirmed' for a non-statistically significant difference. RESULTS: A total of 399 urinary stones were included in this study: 51.4% of the stones had only one morphological type, while 48.6% were mixed stones (41% had at least two morphologies and 7.6% had three morphologies). The overall matching rate was 81.6%. Diagnostics were confirmed for the following morphologies: whewellite (Ia or Ib), weddellite (IIa or IIb), uric acid (IIIa or IIIb), carbapatite-struvite association (IVb), and brushite (IVd). CONCLUSIONS: Our preliminary study demonstrates the feasibility of using endoscopic morphology for the most frequently encountered urinary stones and didactic boards of confirmed endoscopic images are provided. The present study constitutes the first step toward endoscopic stone recognition, which is essential in lithiasis. We provide didactic boards of confirmed endoscopic images that pave the way for automatic computer-aided in situ recognition.

Thulium fiber laser: ready to dust all urinary stone composition types?

PURPOSE: To evaluate whether stone dust can be obtained from all prevailing stone composition types using the thulium fiber laser (TFL) for lithotripsy. Where applicable, stone dust was further characterized by morpho-constitutional analysis. METHODS: Human urinary stones were submitted to in vitro lithotripsy using a FiberLase U2 TFL generator with 150 µm silica core fibers (IPG Photonics®, IPG Medical™, Marlborough, MA, USA). Laser settings were 0.05 J, 320 Hz and 200 µs. A total of 2400 J were delivered to each stone composition type. All evaluated stones had a > 90% degree of purity (calcium oxalate monohydrate, calcium oxalate dihydrate, uric acid, carbapatite, struvite, brushite and cystine). Spontaneously floating stone particles were considered as stone dust and collected for analysis by scanning electron microscopy and Fourier transform infrared spectroscopy. RESULTS: Stone dust could be retrieved from all evaluated urinary stones after TFL lithotripsy. Most stone dust samples revealed changes in crystalline organization, except for calcium oxalate monohydrate and carbapatite, which conserved their initial characteristics. Mean maximal width of stone dust particles did not exceed 254 µm. CONCLUSIONS: The TFL is capable to produce stone dust from all prevailing stone types. Morpho-constitutional changes found in stone dust suggest a photothermal interaction of laser energy with the stone matrix during TFL lithotripsy.

What is the exact definition of stone dust? An in vitro evaluation.

PURPOSE: To propose a size-related definition of stone dust produced by lithotripsy of urinary stones. METHODS: Stone dust was defined as particles small enough to adhere to the following criteria: (1) spontaneous floating under 40 cm H2O irrigation pressure; (2) mean sedimentation time of > 2 s through 10 cm saline solution; (3) fully suitable for aspiration through a 3.6 F working channel. Irrigation, sedimentation, and aspiration tests were set up to evaluate each criterion. Primary outcome was particle size limit agreeing with all three criteria. Stone particles with a given size limit (≤ 2 mm, ≤ 1 mm, ≤ 500 µm, ≤ 250 µm, ≤ 125 µm and ≤ 63 µm) were obtained from laser lithotripsy, including samples from prevailing stone types: calcium oxalate monohydrate, calcium oxalate dihydrate, uric acid, carbapatite, struvite, brushite, and cystine. RESULTS: All particles ≤ 250 µm from all stone types were in agreement with all three criteria defining stone dust, except for struvite where size limit for a positive irrigation and sedimentation test was ≤ 125 µm. CONCLUSION: A size limit of ≤ 250 µm seems to generally adhere to our definition of stone dust, which is based on floating and sedimentation proprieties of stone particles, as well as on the ability to be fully aspirated through the working channel of a flexible ureteroscope.

Classification of the renal papillary abnormalities by flexible ureteroscopy: evaluation of the 2016 version and update.

INTRODUCTION: To assess the use of the 2016 proposed classification of the renal papillary abnormalities during flexible ureteroscopy that aims to standardize their description. PATIENTS AND METHODS: We performed a prospective monocentric single operator collection of the data using this classification during 88 consecutive flexible ureteroscopies required for renal stones treatment. Outcome measurements and statistical analysis: data of stones analysis (microscopy and infrared spectrophotometry) and of serum and urines biochemical samples have been compared with the results of the classified endoscopic descriptions. RESULTS: Mean duration of description was 81.4 s. We reported that 83% of the patients had Randall plaques (RP), as only 4.5% of the patients had no abnormality. Concerning the papillary stones and anchored stones were observed in 30.7% and aspect of intraductal crystallization (Sc) in 15.9%. Erosions were present in 55.7% and extrophic papillae in 8%. Sa1 and Pa2 were significantly correlated to RP, anchored stones (Sa) to papillary erosions and calcium phosphate stones to intraductal crystallization. Hypercalciuria was significantly higher in Sa2 than Sa1 stones. CONCLUSIONS: The different descriptions in the 2016 classification were confirmed by the results of this study. Papillary abnormalities are consequences of stones development. Their descriptions could also improve the follow-up and the diagnosis of a metabolic lithogenesis. We recommend their systematic description during ureteroscopy. Some improvements are proposed to update this classification.

Silicone-hydrocoated ureteral stents encrustation and biofilm formation after 3-week dwell time: results of a prospective randomized multicenter clinical study.

OBJECTIVE: To explore the risk of encrustation and biofilm formation for silicone ureteral stents compared to percuflex polymer stents, through a randomized multicenter study. PATIENTS AND METHODS: Design, setting and participants: A Multicenter, prospective, randomized, single blind, comparative study of hydrocoated silicone stent (Coloplast Imajin® hydro) versus Percuflex™ Plus stent (Boston Scientific), in 141 patients treated by flexible URS for a kidney stone. The study had ethical committee approval in the respective hospitals. Outcome measurements and statistical analysis: Endpoints related to encrustation were biofilm formation and mineral encrustation after a period of 3-week indwelling time. They were evaluated at removal through a scoring scale of ureteral stents encrustation, infrared spectroscopy and optical microscopy of inner and outer surfaces of tips, angles and along the stent's body. Comparison was performed using ANOVA. RESULTS: 119 stents were available after removal for analysis, 56 in the silicone and 63 in the Percuflex TM Plus group. Mean dwelling duration was 21.8 days for silicone, 22.1 days for PercuflexTM Plus. There was significantly more biofilm on Percuflex™ Plus compared to silicone (1.24 ± 0.08 vs 0.93 ± 0.09, p = 0.0021), and more mineral encrustation (1.22 ± 0.10 vs 0.78 ± 0.11, p = 0.0048), respectively. CONCLUSIONS: This multicenter randomized study shows that silicone-hydrocoated stents are less prone to encrustation than PercuflexTM Plus after a 3-week dwelling period and confirms the low encrustation potential of silicone.

Using micro computed tomographic imaging for analyzing kidney stones.

Stone analysis is a critical part of the clinical characterization of urolithiasis. This article reviews the strengths and limitations of micro CT in the analysis of stones. Using micro CT alone in a series of 757 stone specimens, micro CT identified the 458 majority calcium oxalate specimens with a sensitivity of 99.6% and specificity of 95.3%. Micro CT alone was also successful in identifying majority apatite, brushite, uric acid, and struvite stones. For some minor minerals-such as apatite in calcium oxalate or calcium salts in uric acid stones-micro CT enables the detection of minute quantities well below 1%. The addition of a standard for calibrating X-ray attenuation values improves the ability of micro CT to identify common stone minerals. The three-dimensional nature of micro CT also allows for the visualization of surface features in stones, which is valuable for the study of stone formation.

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

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.

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

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.

Stiripentol identifies a therapeutic target to reduce oxaluria.

PURPOSE OF REVIEW: Oxalate is a metabolic end-product promoting the formation of calcium oxalate crystals in urine. Massive urine oxalate excretion occurs in genetic diseases, mainly primary hyperoxaluria type I and II, threatening renal function. Ethylene glycol poisoning may induce the precipitation of calcium oxalate crystals in renal tubules, leading to acute renal failure. In both cases, oxalate results from glyoxylate transformation to oxalate in the liver, by lactate dehydrogenase (LDH) enzymes, especially the LDH-5 isoenzyme. The purpose of the review is to highlight LDH as a potential therapeutic target according to recent publications. RECENT FINDINGS: Genetic therapy targeting LDH metabolism decreases urine oxalate excretion in rodents. Stiripentol is an antiepileptic drug that has been shown recently to inhibit neuronal LDH-5 isoenzyme. Stiripentol was hypothesized to reduce hepatic oxalate production and urine oxalate excretion. In vitro, stiripentol decreases oxalate synthesis by hepatocytes. In vivo, stiripentol oral administration decreases urine oxalate excretion in rats and protects renal function and renal tissue against ethylene glycol intoxication and chronic calcium oxalate crystalline nephropathy. SUMMARY: The use of stiripentol in-vitro and in-vivo highlights that targeting hepatic LDH by pharmacological or genetic tools may decrease oxalate synthesis, deserving clinical studies.