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(f) High magnification of panel (e) circled area, showing many spherical calcifications within the papillary dermis. gl To investigate the origin of these cutaneous calcifications, osteogenic markers, assessed by immunohistochemistry were performed in three patients. The patients in this study have given written informed consent to publication of their case details. Mucocutaneous healing usually lasts 2-3 weeks.1 Calcinosis cutis is reported in various skin diseases, with dystrophic calcification following tissue damage being its most common cause.2 We describe four patients who presented TEN and atypical healing retardation due to calcinosis cutis. [Extracted from the article]

La cystinurie est une maladie monogénique induisant une perte de fonction d'un transporteur d'acides aminés dibasiques impliqué dans la réabsorption de cystine au niveau des tubules rénaux proximaux. L'excrétion urinaire de cystine chez ces patients est augmentée d'un rapport 10 à 60 par rapport au sujet sain, responsable d'une sursaturation avec précipitation de cristaux de cystine dans les reins et de calculs dans les cavités excrétrices. La physiopathologie de la cystinurie est particulière : la concentration plasmatique de cystine est souvent normale alors que l'absorption intestinale est diminuée. Ce paradoxe est expliqué par une absorption intestinale préservée de cystéine et de méthionine qui sont deux acides aminés soufrés métabolisés notamment en cystine. Le principe du traitement consiste à empêcher la formation de cristaux de cystine dans les reins afin de prévenir la survenue d'une maladie lithiasique, mais aussi d'une authentique néphropathie cristalline responsable d'une insuffisance rénale chez plus de la moitié des patients. Le traitement médical des patients cystinuriques repose (1) sur une diminution de l'excrétion urinaire quotidienne de cystine qui est le reflet de l'absorption intestinale et donc des apports en méthionine ; (2) sur une augmentation du seuil de solubilité urinaire de la cystine afin de prévenir une précipitation cristalline intratubulaire et intracavitaire par une dilution et une alcalinisation des urines avec des valeurs cibles de 3 L et un pH urinaire aux alentour de 7,5. Le traitement par sulfhydryle dont le but est de dissocier les ponts disulfures des molécules de cystine avec un effet modeste sur la dissolution des calculs de cystine constitués ne devrait en toute logique être utilisé en dernier recours une fois les mesures diététiques et la cible de pH urinaire obtenue. Cystinuria is a dibasic amino acid transporter molecular defect preventing cystine reabsorption within renal proximal tubules. A 10 to 60 fold increase of urine cystine concentration compared to healthy subjects is responsible for pure cystine crystal onset within tubules and stones in the urinary tract leading to chronic renal failure in half cases. Plasma cystine concentration is usually reported in the normal range despite a decreased cystine intestinal absorption. This discrepancy is explained by a preserved intestinal absorption of cysteine and methionine, two sulphur amino acids which are partly metabolized into cystine. Monitoring and treatment is based on a pathophysiological approach aiming at decreasing both urine cystine excretion and concentration but also increasing urine cystine solubility (i.e. raising urine pH). Guidelines are thus based upon a methionine restricted diet, a water intake target of 3 liters/day and a urine pH target of 7.5. Sulfhydryl treatment (mainly tiopronin), frequently used in France in order to dissociate cystine disulfur bonds has a moderate effect on cystine stones solubilization and thus should be consider, to our view, only after diet and urine goal targets are reached. [ABSTRACT FROM AUTHOR]

Background: Sarcoidosis, characterized by epithelioid granulomas, is considered to be caused by a complex interplay between genetics and environmental agents. It has been hypothesized that exogenous inorganic particles as crystalline silica could be a causal or adjuvant agent in sarcoidosis onset. Objectives: To investigate the location, frequency and physicochemical characteristics of foreign materials and mineral tissue deposits in the granulomatous area of cutaneous sarcoidosis. Methods: Skin biopsies (n = 14) from patients diagnosed with cutaneous sarcoidosis (mean age 43 years; 11 patients with extracutaneous involvement) were investigated using polarized light examination (PLE), μFourier Transform Infra‐Red (μFT‐IR) spectroscopy and Field Emission Scanning Electron Microscopy coupled with Energy Dispersive X‐ray Spectroscopy (FE‐SEM/EDX). Results: Combined PLE, μFT‐IR, FE‐SEM/EDX analysis allowed to characterize mineral deposits in 7/14 biopsies (50%). It identified crystalline silica (SiO2) inside granulomas in three biopsies and calcite (CaCO3) at their periphery in 4. Conclusion: This study emphasizes the need of using combined methods for assessment of mineral deposits in granulomatous diseases. According to the location and characteristics of deposits, we can hypothesize that SiO2 particles contribute to the granuloma formation, whereas CaCO3 deposits are related to the granuloma biology. However, the significance of the association between SiO2 deposits and sarcoidosis is still disputed. [ABSTRACT FROM AUTHOR]

The effect of mixing calcium and oxalate precursors by diffusion at miscible liquid interfaces on calcium oxalate crystalline phases, and in physiological conditions (concentrations and flow rates), is studied using a microfluidic channel. This channel has similar dimensions as the collection duct in human kidneys and serves as a biomimetic model in order to understand the formation of pathological microcalcifications. [ABSTRACT FROM AUTHOR]

Context: Primary hyperparathyroidism (PHPT) is commonly diagnosed in the setting of hypercalcemia, whereas normocalcemic primary hyperparathyroidism (NHPT) may be misdiagnosed., Objective: Our objective was to compare patients with hypercalcemic hyperparathyroidism (HPHPT) vs patients with NHPT hypercalciuric renal stones., Methods: We took advantage of a routine calcium load test performed in patients with hypercalciuric renal stones to assess retrospectively among patients with PHPT the prevalence and characteristics of NHPT and HPHPT under a calcium-restricted diet., Results: Among 1671 patients with hypercalciuria, 91 patients had a final diagnosis of PHPT (postload ionized calcium [iCa] > 1.31 mmol/L and parathyroid hormone [PTH] > 30 pg/mL). Prevalence of NHPT is 40% of all PHPT; however, according to total serum calcium, 4/35 NHPT and 7/56 HPHPT cases would have been misclassified in the other group. Eighteen of 35 NHPT and 40/56 HPHPT cases underwent parathyroidectomy. No significant characteristics relating to parathyroid weight, stone composition, or bone remodeling biomarkers were detected between groups. Although iCa is higher in HPHPT in the fasting state and after calcium load, we found no difference for calcium diet, 24-hour calciuria, or calcitriol. Renal calcium excretion postload increased by 303% in NHPT but only 176% in HPHPT (P = .01) likely explained by a lesser PTH decrease (P = .02). However, a strong negative association (P < .0001) detected between pooled preload and postload iCa and PTH only in the NHPT group suggests a persistent efficient PTH-CaSR control within the parathyroid glands in this group., Conclusion: Our data show the relevance of dynamic tests to unmask NHPT in patients with hypercalciuric renal stones., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Classical potassium binders are used in the treatment of hyperkalemia and are widely associated with gastrointestinal side effects, with crystal colonic injury being rare but potentially fatal. In this report, we describe the case of an 82-year-old male with hyperkalemia and calcium polystyrene sulfonate crystal-associated colonic necrosis. Traditionally, this diagnosis has relied on the examination of crystal morphology and polarization through microscopy. Our study enhances crystal identification by incorporating an analysis of the physical characteristics of the crystals using infrared spectroscopy. This is the first description, to our knowledge, of the calcium polystyrene sulfonate infrared spectrum., Competing Interests: No conflict of interest needs to be declared by the authors., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

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., (© 2024. The Author(s).)

The urine concentration impairment responsible for hyposthenuria in sickle cell nephropathy is currently thought to be a consequence of renal medulla lesions, which lead to nephrogenic diabetes insipidus. The objective of the present study was to investigate the mechanism of hyposthenuria in patients with sickle cell anemia. We performed an observational study of patients with homozygous SS sickle cell anemia and data available on the fasting plasma antidiuretic hormone (ADH) concentration. A total of 55 patients were analyzed. The fasting plasma ADH values ranged from 1.2 to 15.4 pg/mL, and 82% of the patients had elevated ADH values and low fasting urine osmolality (<505 mosmol/kgH 2 O). Plasma ADH was positively associated with plasma tonicity and natremia ( P < 0.001). None of the patients experienced polyuria and fasting free water clearance was negative in all cases, thus, ruling out nephrogenic diabetes insipidus. The tertile groups did not differ with regard to fasting urine osmolality, plasma renin level, mGFR, or several hemolysis biomarkers. The negative fasting free water clearance in all cases and the strong association between 24-h osmolal clearance and 24-h diuresis favors the diagnosis of osmotic diuresis due to an impaired medullary gradient, rather than lesions to collecting tubule. NEW & NOTEWORTHY The urine concentration impairment in sickle cell anemia is an osmotic diuresis related to an impaired renal medullary gradient leading to an ADH plateau effect. The fasting plasma ADH was high in the context of a basic state of close-to-maximal urine concentration probably driven by short nephrons maintaining a cortex-outer medullary gradient (about 400 milliosmoles). The patients had a low daily osmoles intake without evidence of thirst dysregulation so no one experienced polyuria.

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-CH 2 -CH-(NH 2 )-COOH] 2 ) consists of two cysteine (C 3 H 7 NO 2 S) 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., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Objective: Gitelman syndrome (GS) is the most frequent salt-wasting genetic tubulopathy and a source of hypokalaemia and hypomagnesemia. Chondrocalcinosis (CC) is a frequent feature of GS. The aim of our study was to determine the prevalence, distribution patterns, clinical phenotypes and risk factors for CC in GS., Methods: This prospective study of a cohort of 57 patients with GS included a systematic screening for CC by peripheral joint radiography, cervical spine CT and joint US. The prevalence of cervical C1-C2 CC by CT was compared between 33 GS patients and sex- and age-matched controls. Clinical and biochemical features were analysed to identify factors associated with CC., Results: Mean (s.d.) age of patients was 46.5 (12.4) years, 66.7% were women and 93.0% carried SLC12A3 mutations. Mean serum magnesium level was 0.60 (0.30) mmol/l. CC was observed in 79% of patients, with the highest prevalence at the cervical spine (81.8%) followed by the knee (52.6%), wrist (50.9%), ankle (38.6%), TM joint (36.4%), shoulder (33.3%), hip (22.8%), elbow (14.0%) and sclerochoroid (12.1%). Prevalence of CC at the C1-C2 level was higher in the GS cohort than control group (72.7% vs 9.1%) (adjusted odds ratio 21.0, 95% CI 2.8, 156.1, P = 0.003). Independent factors associated with CC were low serum magnesium level and age., Conclusion: GS was associated with widespread CC, favoured by aging and hypomagnesemia. The C1-C2 level was the most affected site. Follow-up of this unique cohort will help understanding the clinical consequences of CC, especially the precise characterization of pyrophosphate arthropathy., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Chronic wounds, including leg ulcers, constitute an important medical problem among older patients. Dystrophic calcifications (DC) are associated with a variety of disorders, including leg ulcers. The aim of this study was to report the clinical and biological characteristics of older patients with DC in leg ulcers and to determine the morphology and chemical composition of these calcifications. We conducted a prospective monocentric study in our Geriatric-Wound and Healing ward, Rothschild Hospital, Paris, from January 2018 to December 2019. Patients with leg ulcers were screened for DC by palpation. Patients' clinical, biological, and radiological findings were collected. DC morphology was analyzed using field-emission scanning electron microscopy and chemical composition was analyzed using µFourier transform infra-red spectroscopy and X-ray Fluorescence. Ten (7%) of the 143 patients hospitalized for leg ulcers presented DC. Older patients with DC were more likely to have leg ulcers with venous insufficiency (p = .015), colonized by Pseudomonas aeruginosa (p = .026), with a longer healing evolution (p = .0072) and hypercalcemia (p = .041). Five DC were extracted from ulcers: 2 presented 500 nm lacunar spheres and intermingled fibrils of about 10 nm in diameter, consistent with bacterial and biofilm imprints. DC were always composed of calcium-phosphate apatite and associated to the presence of zinc. Our analyses were consistent with the involvement of microorganisms and inflammatory process in DC formation. Early management of venous insufficiency, treatment of chronic bacterial colonization and use of calcium-solubilizing drugs seem to be rational strategies for calcified leg ulcer management in older patients., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Primary hyperparathyroidism (pHPT) has been reported to have a higher prevalence in sickle cell disease (SCD) patients, including a high rate of recurrence following surgery. However, most patients are asymptomatic at the time of diagnosis, with surprisingly infrequent hypercalciuria, raising the issue of renal calcium handling in SCD patients. We conducted a retrospective study including (1) 64 hypercalcemic pHPT non-SCD patients; (2) 177 SCD patients, divided into two groups of 12 hypercalcemic pHPT and 165 non-pHPT; (3) eight patients with a diagnosis of familial hypocalciuric hypercalcemia (FHH). Demographic and biological parameters at the time of diagnosis were collected and compared between the different groups. Determinants of fasting fractional excretion of calcium (FeCa 2+ ) were also analyzed in non-pHPT SCD patients. Compared to non-SCD pHPT patients, our data show a similar ionized calcium and PTH concentration, with a lower plasmatic calcitriol concentration and a lower daily urinary calcium excretion in pHPT SCD patients ( p < 0.0001 in both cases). Fasting FeCa 2+ is also surprisingly low in pHPT SCD patients, and thus inadequate to be considered hypercalcemia, recalling the FHH phenotype. FeCa 2+ is also low in the non-pHPT SCD control group, and negatively associated with PTH and hemolytic biomarkers such as LDH and low hemoglobin. Our data suggest that the pHPT biochemical phenotype in SCD patients resembles the FHH phenotype, and the fasting FeCa 2+ association with chronic hemolysis biomarkers strengthens the view of a potential pharmacological link between hemolytic by-products and calcium reabsorption, potentially through a decreased calcium-sensing receptor (CaSR) activity.

Glomerular hyperfiltration alone or associated with albuminuria is a well-known feature of sickle cell associated nephropathy. Though, glomerular hyperfiltration is currently considered to be related to a high renal plasma flow and chronic hemolysis, cardiac output influence on measured glomerular filtration rate (mGFR) have not been investigated so far. Thirty seven homozygous sickle cell patients (SCA) from the RAND study investigated before and under angiotensin converting enzyme inhibitor (ACEI) were included. Both mGFR and cardiac index (CI) were high (> 110 ml/min/1.73 m 2 and > 3.5 l/m 2 in 81% and 97% of cases) with low systemic vascular resistance (SVR) (< 700 dynes/s/cm -5 ) in 38% of cases. mGFR association with CI and SVR were significant at baseline (respectively ρ: 0.44, p = 0.008 and ρ: - 0.37, p = 0.02) and under ACEI (p = 0.007 and 0.01 respectively), in accordance with previous data showing that hyperfiltration was linked to an increased glomerular perfusion and a glomerulomegaly rather than increased capillary hydrostatic pressure. Of notice, after adjustment on CI, mGFR remained associated with reticulocyte count and albuminuria under ACEI (p = 0.006 and 0.02 respectively). Our results suggest that hyperfiltration is tightly linked to an increased cardiac output which may account for an increased renal blood flow. Chronic hemolysis could be a relevant factor accounting for hyperfiltration potentially acting on glomerular enlargement which appears as a key factor. Our data suggest that cardiac output assessment is a relevant tool in the routine management and monitoring of SCA nephropathy.

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (© 2020, American College of Rheumatology.)