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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.

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.MethodsHuman 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.ResultsStone 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.ConclusionsThe 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.

ObjectivesBasic calcium phosphate (BCP) crystal and interleukin 6 (IL-6) have been implicated in osteoarthritis (OA). We hypothesise that these two factors may be linked in a reciprocal amplification loop which leads to OA.MethodsPrimary murine chondrocytes and human cartilage explants were incubated with hydroxyapatite (HA) crystals, a form of BCP, and the modulation of cytokines and matrix-degrading enzymes assayed. The ability of IL-6 to stimulate chondrocyte calcification was assessed in vitro. The mechanisms underlying the effects of HA on chondrocytes were investigated using chemical inhibitors, and the pathways mediating IL-6-induced calcification characterised by quantifying the expression of genes involved in chondrocyte mineralisation. The role of calcification in vivo was studied in the meniscectomy model of murine OA (MNX), and the link between IL-6 and cartilage degradation investigated by histology.ResultsIn chondrocytes, BCP crystals stimulated IL-6 secretion, further amplified in an autocrine loop, through signalling pathways involving Syk and PI3 kinases, Jak2 and Stat3 molecules. Exogenous IL-6 promoted calcium-containing crystal formation and upregulation of genes involved in calcification: the pyrophosphate channel Ank, the calcium channel Annexin5 and the sodium/phosphate cotransporter Pit-1. Treatment of chondrocytes with IL-6 inhibitors significantly inhibited IL-6-induced crystal formation. In meniscectomised mice, increasing deposits of BCP crystals were observed around the joint and correlated with cartilage degradation and IL-6 expression. Finally, BCP crystals induced proteoglycan loss and IL-6 expression in human cartilage explants, which were reduced by an IL-6 inhibitor.ConclusionsBCP crystals and IL-6 form a positive feedback loop leading to OA. Targeting calcium-containing crystal formation and/or IL-6 are promising therapeutic strategies in OA.

PurposeTo propose a size-related definition of stone dust produced by lithotripsy of urinary stones.MethodsStone 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.ResultsAll 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.ConclusionA 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.

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.

Pseudoxanthoma elasticum is a rare disease mainly due to ABCC6 gene mutations and characterized by ectopic biomineralization and fragmentation of elastic fibers resulting in skin, cardiovascular and retinal calcifications. It has been recently described that pyrophosphate (a calcification inhibitor) deficiency could be the main cause of ectopic calcifications in this disease and in other genetic disorders associated to mutations of ENPP1 or CD73. Patients affected by Pseudoxanthoma Elasticum seem also prone to develop kidney stones originating from papillary calcifications named Randall’s plaque, and to a lesser extent may be affected by nephrocalcinosis. In this narrative review, we summarize some recent discoveries relative to the pathophysiology of this mendelian disease responsible for both cardiovascular and renal papillary calcifications, and we discuss the potential implications of pyrophosphate deficiency as a promoter of vascular calcifications in kidney stone formers and in patients affected by chronic kidney disease.

IntroductionHolmium:yttrium–aluminium–garnet (Ho:YAG) is currently the gold standard for lithotripsy for the treatment of all known urinary stone types. Stone composition and volume are major determinants of the lithotripsy. This in vitro study evaluated the required energy to ablate 1 mm3 of various stone types with different laser settings using Ho:YAG.Methods272 µm core-diameter laser fibers (Boston Scientific©) were connected to a 30 Watt MH1 Ho:YAG generator (Rocamed®). An experimental setup consisting of immerged human stones of calcium oxalate monohydrate (COM), uric acid (UA) or cystine (Cys) was used with a single pulse lasing emission (0.6/0.8/1 J), in contact mode. Stones were dried out before three-dimensional scanning to measure ablation volume per pulse (AVP) and required energy to treat 1 mm3 (RE).ResultsAll settings considered, ablation volumes per pulse (AVP) for COM were significantly lower than those for UA and Cys (p = 0.002 and p = 0.03, respectively), whereas AVP for Cys was significantly lower than those for UA (p = 0.03). The mean REs at 0.6 J pulse energy (PE) for COM, Cys and UA were 34, 8.5 and 3.2 J, respectively The mean REs at 1 J PE for COM, Cys and UA were 14.7, 6.4 and 2 J, respectively. At 0.6 J PE, RE for COM was more than tenfold and fivefold higher than those for UA and Cys, respectively.ConclusionThis in vitro study shows for the first time a volumetric evaluation of Ho:YAG efficiency by the ablation volume per pulse on human stone samples, according to various pulse energies. The REs for COM, UA and Cys should be considered in clinical practice.

Cotrimoxazole (Trimethoprim/Sulfamethoxazole-SMX) is frequently used in critically ill and immunocompromised patients. SMX is converted to N -acetyl-sulfamethoxazole (NASM) and excreted by the kidneys. NASM may form crystals in urine, especially in acid urine, that may induce a crystalline nephropathy. However, the imputability of crystals in acute kidney injury (AKI) has not been proven. We aimed to assess whether NASM crystals may promote AKI and to investigate risk factors associated with NASM crystalline nephropathy. Patients from Ile-de-France, France who developed AKI under SMX treatment introduced during hospitalization and had a crystalluria positive for NASM crystals were selected. Patients with excessive preanalytical delay for crystalluria or missing data regarding SMX treatment were excluded. We used the Naranjo score to assess the causal relationship between SMX and the development of AKI in patients with positive NASM crystalluria. Fourteen patients were included. SMX was the probable cause of AKI for 11 patients and a possible cause for 3 patients according to Naranjo score. Patients were exposed to high doses of SMX (but within recommended ranges), and most of them had a preexisting chronic kidney disease and were hypoalbuminemic. Urine pH was mildly acid (median 5.9). AKI occured more rapidly than expected after introduction of SMX (median 4 days) and recovered rapidly after drug discontinuation in most, but not all, cases. SMX is a probable cause of crystalline nephropathy. Monitoring of crystalluria in patients exposed to SMX may be of interest to prevent the development of crystalline nephropathy. Approval number of the study: BPD-2018-DIAG-008.

IntroductionTo assess the use of the 2016 proposed classification of the renal papillary abnormalities during flexible ureteroscopy that aims to standardize their description.Patients and methodsWe 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.ResultsMean 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.ConclusionsThe 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.

ObjectiveTo explore the risk of encrustation and biofilm formation for silicone ureteral stents compared to percuflex polymer stents, through a randomized multicenter study.Patients and methodsDesign, 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.Results119 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.ConclusionsThis 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.