Pathophysiology and management of enteric hyperoxaluria.

Enteric hyperoxaluria is a metabolic disorder resulting from conditions associated with fatty acid malabsorption and characterized by an increased urinary output of oxalate. Oxalate is excessively absorbed in the gut and then excreted in urine where it forms calcium oxalate crystals, inducing kidney stones formation and crystalline nephropathies. Enteric hyperoxaluria is probably underdiagnosed and may silently damage kidney function of patients affected by bowel diseases. Moreover, the prevalence of enteric hyperoxaluria has increased because of the development of bariatric surgical procedures. Therapeutic options are based on the treatment of the underlying disease, limitation of oxalate intakes, increase in calcium salts intakes but also increase in urine volume and correction of hypocitraturia. There are few data regarding the natural evolution of kidney stone events and chronic kidney disease in these patients, and there is a need for new treatments limiting kidney injury by calcium oxalate crystallization.

Sulfamethoxazole-induced crystal nephropathy: characterization and prognosis in a case series.

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.

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.

Hydration for Adult Patients with Nephrolithiasis: Specificities and Current Recommendations.

Nephrolithiasis affects around 10% of the population and is frequently associated with impaired dietary factors. The first one is insufficient fluid intake inducing reduced urine volume, urine supersaturation, and subsequently urinary lithiasis. Kidneys regulate 24 h urine volume, which, under physiological conditions, approximately reflects daily fluid intake. The aim of this study is to synthesize and highlight the role of hydration in the treatment of nephrolithiasis. Increasing fluid intake has a preventive effect on the risk of developing a first kidney stone (primary prevention) and also decreases the risk of stone recurrence (secondary prevention). Current guidelines recommend increasing fluid intake to at least at 2.5 L/day to prevent stone formation, and even to 3.5-4 L in some severe forms of nephrolithiasis (primary or enteric hyperoxaluria or cystinuria). Fluid intake must also be balanced between day and night, to avoid urinary supersaturation during the night. Patients should be informed and supported in this difficult process of increasing urine dilution, with practical ways and daily routines to increase their fluid intake. The liquid of choice is water, which should be chosen depending on its composition (such as calcium, bicarbonate, or magnesium content). Finally, some additional advice has to be given to avoid certain beverages such as those containing fructose or phosphoric acid, which are susceptible to increase the risk of nephrolithiasis.

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.

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.

How to Monitor Hydration Status and Urine Dilution in Patients with Nephrolithiasis.

Maintenance of hydration status requires a tight balance between fluid input and output. An increase in water loss or a decrease in fluid intake is responsible for dehydration status, leading to kidney water reabsorption. Thus, urine volume decreases and concentration of the different solutes increases. Urine dilution is the main recommendation to prevent kidney stone recurrence. Monitoring hydration status and urine dilution is key to preventing stone recurrence. This monitoring could either be performed via spot urine or 24 h urine collection with corresponding interpretation criteria. In laboratory conditions, urine osmolality measurement is the best tool to evaluate urine dilution, with less interference than urine-specific gravity measurement. However, this evaluation is only available during time lab examination. To improve urine dilution in nephrolithiasis patients in daily life, such monitoring should also be available at home. Urine color is of poor interest, but reagent strips with urine-specific gravity estimation are currently the only available tool, even with well-known interferences. Finally, at home, fluid intake monitoring could be an alternative to urine dilution monitoring. Eventually, the use of a connected device seems to be the most promising solution.

How useful is an oral calcium load test for diagnosing recurrent calcium stone formers?

Hypercalciuria is the main risk factor for recurrent calcium urolithiasis. The goal of our study is to determinate how useful an oral calcium load test is for stone formers to classify different forms of hypercalciuria in pathogenetic categories defined as renal or absorptive according to the current knowledge. Between June 2013 and February 2016, a prospective study was carried out on 117 documented recurrent hypercalciuric stone formers undergoing an oral calcium load test modified from the original description by Pak. After 2 days of calcium-restricted diet, urine and blood were analyzed at baseline and 120 min after receiving orally 1 g of calcium. Total and ionized calcium, parathyroid hormone from serum and urine calcium and creatinine were assessed in order to divide patients in three groups as previously described: resorptive, absorptive, and renal hypercalciuria. This allowed the identification of 19, 39, 34 and 33 patients with normocalcemic primary hyperparathyroidism (NPHPT), renal hypercalciuria aka renal calcium leak (RCL), absorptive hypercalciuria (AH) and unidentified cause, respectively. Patients with NPHPT (who required parathyroidectomy) experienced a lower PTH decrease (41.41 ± 12.82 vs. 54.06 ± 13.84% p < 0.01), higher beta-crosslaps, as well as lower TmP/GFR and distal third radius bone mineral density. RCL resulted in increased fasting urine calcium-to-creatinine ratio (Uca/Cr), i.e., > 0.37 mmol/mmol), without hyperparathyroidism. AH was diagnosed by the presence of ΔUCa/Cr > 0.60 mmol/mmol between baseline and 120 min without any other anomaly. For all remaining patients, results were inconclusive due to the lack of sufficient increase in serum calcium or because the cause of lithogenesis could not be clearly identified. The oral calcium load test is useful in nearly 80% of patients by identifying the different forms of hypercalciuria causing urolithiasis and by guiding treatment, including parathyroid surgery.

Deep morphological recognition of kidney stones using intra-operative endoscopic digital videos.

Objective.To assess the performance and added value of processing complete digital endoscopic video sequences for the automatic recognition of stone morphological features during a standard-of-care intra-operative session.Approach.A computer-aided video classifier was developed to predictin-situthe morphology of stone using an intra-operative digital endoscopic video acquired in a clinical setting. Using dedicated artificial intelligence (AI) networks, the proposed pipeline selects adequate frames in steady sequences of the video, ensures the presence of (potentially fragmented) stones and predicts the stone morphologies on a frame-by-frame basis. The automatic endoscopic stone recognition (A-ESR) is subsequently carried out by mixing all collected morphological observations.Main results.The proposed technique was evaluated on pure (i.e. include one morphology) and mixed (i.e. include at least two morphologies) stones involving 'Ia/Calcium Oxalate Monohydrate' (COM), 'IIb/Calcium Oxalate Dihydrate' (COD) and 'IIIb/Uric Acid' (UA) morphologies. The gold standard ESR was provided by a trained endo-urologist and confirmed by microscopy and infra-red spectroscopy. For the AI-training, 585 static images were collected (349 and 236 observations of stone surface and section, respectively) and used. Using the proposed video classifier, 71 digital endoscopic videos were analyzed: 50 exhibited only one morphological type and 21 displayed two. Taken together, both pure and mixed stone types yielded a mean diagnostic performances as follows: balanced accuracy = [88 ± 6] (min = 81)%, sensitivity = [80 ± 13] (min = 69)%, specificity = [95 ± 2] (min = 92)%, precision = [78 ± 12] (min = 62)% and F1-score = [78 ± 7] (min = 69)%.Significance.These results demonstrate that AI applied on digital endoscopic video sequences is a promising tool for collecting morphological information during the time-course of the stone fragmentation process without resorting to any human intervention for stone delineation or the selection of adequate steady frames.

Thulium Fiber Laser's Dust for Stone Composition Analysis: Is It Enough? A Pilot Study.

Introduction: We aimed to evaluate if the biochemical composition of urinary stones can be determined by analyzing the stone dust only, and whether a photo taken during the surgery could be useful for completing the morpho-constitutional analysis. Materials and Methods: Twenty patients went through a retrograde intrarenal surgery for renal stone treatment with thulium fiber laser (Fiber Dust; Quanta, 2020) using 150 µm silica core laser fibers. After laser lithotripsy, residual fragments (RF) were removed with a basket (ZeroTip; Boston Scientific) and spontaneously floating stones particles were considered stone dust and were aspirated through the working channel. Pairs of RF and stone dust were labeled and sent to analysis by scanning electron microscopy and Fourier transform infrared spectroscopy. Photos of the stone (surface and section) were taken from videos recorded during the surgery. Results: A total of 20 patients were included in this study. Mean age was 49.8 years with metabolic and genetic disorders. Mean stone volume was 750 mm3 for ureteral stones and 2334 mm3 for renal stones. Mean stone density was 1187 HU. Positive urine culture was found in 25% patients. In 2/20 (10%), the biochemistry differed only in the relative proportions of each constituent, while in 5/20 (25%), only one component was missing. Laser crystalline conversion was found in 3/20 (15%). Whewellite and weddellite layers were found in photos, thus adding missing information from dust stone analysis. Conclusion: By analyzing aspirated dust through the ureteroscope's working channel with physical techniques, we can understand the lithogenic process of the urinary stone, without needing to analyze the stone fragment. Morphologic analysis, given by a proper stone picture, adds missing information in specific cases.

How Reliable Is Endoscopic Stone Recognition? A Comparison Between Visual Stone Identification and Formal Stone Analysis.

Objective: To assess the diagnostic accuracy and intra-observer agreement of endoscopic stone recognition (ESR) compared with formal stone analysis. Introduction: Stone analysis is a corner stone in the prevention of stone recurrence. Although X-ray diffraction (XRD) and infrared spectroscopy are the recommended techniques for reliable formal stone analysis, this is not always possible, and the process takes time and is costly. ESR could be an alternative, as it would give immediate information on stone composition. Materials and Methods: Fifteen endourologists predicted stone composition based on 100 videos from ureterorenoscopy. Diagnostic accuracy was evaluated by comparing the prediction from visual assessment with stone analysis by XRD. After 30 days, the videos were reviewed again in a random order to assess intra-observer agreement. Results: The median diagnostic accuracy for calcium oxalate monohydrate was 54% in questionnaire 1 (Q1) and 59% in questionnaire 2 (Q2), whereas calcium oxalate dihydrate had a median diagnostic accuracy of 75% in Q1 and 50% in Q2. The diagnostic accuracy for calcium hydroxyphosphate was 10% in Q1 and 13% in Q2. The median diagnostic accuracy for calcium hydrogen phosphate dihydrate and calcium magnesium phosphate was 0% in both questionnaires. The median diagnostic accuracy for magnesium ammonium phosphate was 20% in Q1 and 40% in Q2. The median diagnostic accuracy for uric acid was 22% in both questionnaires. Finally, there was a diagnostic accuracy of 60% in Q1 and 80% in Q2 for cystine. The intra-observer agreement ranged between 45% and 72%. Conclusion: Diagnostic accuracy of ESR is limited and intra-observer agreement is below the threshold of acceptable agreement.

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.

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.

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.

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.

Description of Stone Morphology and Crystalluria Improve Diagnosis and Care of Kidney Stone Formers.

Stone analysis by physical methods is critical to determine their chemical nature and to diagnose the underlying conditions affecting kidney stone formers. This analysis should be completed by a morphologic examination of stone surface and section, leading to the diagnosis of anatomical or metabolic disorders and of specific diseases. Crystalluria study, the analysis of urine crystals, provides complementary information and is extremely useful for both diagnosis and patient follow-up. This review describes briefly how these techniques may be used and in which conditions stone morphology and urine crystal description are particularly relevant for patients medical care.