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Representative SEM images and energy dispersive spectroscopy (EDS) spectra (insets) obtained from stones overgrown on implants—regular water group. a, b BRP-PA group: in a, large calcium phosphate crystals are randomly organized amongst a fibrous segment of BRP tissue (thin arrow). In b, multiple BRP tissue fibers are visible (thin arrows) amidst magnesium phosphate (arrow head) and granular precipitates (thick arrow). c, d BRP-OPN group: in c, a high density of magnesium phosphate (struvite type) crystals. In d, a crust of poorly defined, granular agglomerates of calcium phosphate and magnesium phosphate crystals or amorphous mineral. Scale bars are as follows: a 100 µm, b 50 µm, c 40 µm, d 30 µm
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Idiopathic stone formers often form calcium oxalate (CaOx) stones that are attached to calcium phosphate (CaP) deposits in the renal tissue, known as Randall’s plaques (RP). Plaques are suggested to originate in the renal tubular basement membrane and spread into the interstitial regions where collagen fibrils and vesicles become mineralized; if th...
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Background: The evaluation of 24 h urinary oxalate excretion is the gold standard for diagnosing hyperoxaluria in
patients with recurrent urolithiasis. However, 24 h urine sample collection is cumbersome. Therefore we aim to
see if oxalate to creatinine ratio in random urine sample can be used as an alternative.
Materials and methods: A cross-secti...
Citations
... Renal tubulointerstitial injury can trigger fibrotic process that activates extracellular matrix (ECM) secretion and accumulation in the renal tissue (Peerapen and Thongboonkerd, 2020;Shin et al., 2022;Yoodee et al., 2021). These matters together with calcium phosphate accumulation then induce Randall's plaque formation and ultimately the stone development (Evan et al., 2018;Khan et al., 2021;O'Kell et al., 2019). ...
Recent evidence has shown an association between kidney stone pathogenesis and oxidative stress. Many anti-oxidants have been studied with an aim for stone prevention. Quercetin, a natural flavonol, is one among those eminent anti-oxidants with satisfactory anti-inflammatory property to cope with renal tissue injury in kidney stone disease. Nevertheless, its direct effect (if any) on calcium oxalate (CaOx) crystals and the stone formation mechanism had not been previously explored. This study has addressed the ability of quercetin at various concentrations (2.5, 5, 10, 20, 40, 80 and 160 μM) to directly modulate CaOx crystallization, growth, aggregation, adhesion on kidney cells, and invasion through the matrix. The data have shown that quercetin significantly inhibits CaOx crystallization and crystal growth but promotes crystal aggregation in concentration-dependent manner. However, quercetin at all these concentrations do not affect CaOx adhesion on kidney cells. For the invasion, quercetin at all concentrations constantly promotes CaOx invasion through the matrix without concentration-dependent pattern. These discoveries have demonstrated for the first time that quercetin has direct but dual modulatory effects on CaOx crystals. While quercetin inhibits CaOx crystallization and growth, on the other hand, it promotes CaOx crystal aggregation and invasion through the matrix. These data highlight the role for quercetin in direct modulation of the CaOx crystals that may intervene the stone pathogenesis.
... Moreover, the damaged mitochondria can trigger inflammatory cascade at renal interstitial area [117,145] by recruiting numerous inflammatory cells into this area, leading to accumulation of various proinflammatory cytokines and tissue inflammation [116,129]. Together with supersaturation of calcium phosphate, which is common in the renal interstitium, Randall's plaque starts to form [126,146,147]. After erosion into the urinary space, where CaOx is frequently supersaturated, this plaque then serves as the nidus for CaOx stone to grow [25]. ...
... When the MQC system is overwhelmed by extremely severe oxidative stress, mitochondrial dysfunction occurs, leading to ROS overproduction, mitochondrial degradation, inflammation, cell death, and renal tubulointerstitial injury. All these detrimental derangements lead to CaOx crystal deposition, growth, aggregation, nidus formation, Randall's plaque development and, finally, kidney stone formation [25,129,146,147] (Fig. 2). ...
Recent evidence has shown significant roles of mitochondria-derived vesicles (MDVs) in mitochondrial quality control (MQC) system. Under mild stress condition, MDVs are formed to carry the malfunctioned mitochondrial components, such as mitochondrial DNA (mtDNA), peptides, proteins and lipids, to be eliminated to restore normal mitochondrial structure and functions. Under severe oxidative stress condition, mitochondrial dynamics (fission/fusion) and mitophagy are predominantly activated to rescue mitochondrial structure and functions. Additionally, MDVs generation can be also triggered as the major MQC machinery to cope with unhealthy mitochondria when mitophagy is unsuccessful for eliminating the damaged mitochondria or mitochondrial fission/fusion fail to recover the mitochondrial structure and functions. This review summarizes the current knowledge on MDVs and discuss their roles in physiologic and pathophysiologic conditions. In addition, the potential clinical relevance of MDVs in therapeutics and diagnostics of kidney stone disease (KSD) are emphasized.
... They added poly-L-aspartic acid to the CP solution, and observed multi-laminated CP spherules formed through the PILP pathway by SEM. These spherules were striking resemble kidney stones, which give some clues that PILP could be a necessary process of kidney stone formation (Chidambaram et al., 2015;Lovett et al., 2019;O'Kell et al., 2019). ...
Biomineralization is a typical interdisciplinary subject attracting biologists, chemists, and geologists to figure out its potential mechanism. A mounting number of studies have revealed that the classical nucleation theory is not suitable for all nucleation process of biominerals, and phase-separated structures such as polymer-induced liquid precursors (PILPs) play essential roles in the non-classical nucleation processes. These structures are able to play diverse roles biologically or pathologically, and could also give inspiring clues to bionic applications. However, a lot of confusion and dispute occurred due to the intricacy and interdisciplinary nature of liquid precursors. Researchers in different fields may have different opinions because the terminology and current state of understanding is not common knowledge. As a result, our team reviewed the most recent articles focusing on the nucleation processes of various biominerals to clarify the state-of-the-art understanding of some essential concepts and guide the newcomers to enter this intricate but charming field.
... The further characterization of the regions of blue AF in Randall's plaque will require a concerted assessment of metabolites and protein constituents with orthogonal approaches like regional proteomics and small-molecule mass spectrometry [28], but the unique fluorescence signature of Randall's plaque will make this process much easier to accomplish. Up to now, attempts to model Randall's plaque have relied on educated guesses for matching the molecular environment of these interstitial apatite deposits [29,30], but the work reported here is a step toward elucidating the organic composition of Randall's plaque. The discovery of a unique fluorescence of Randall's plaque will also benefit studies of biopsies from stone patients, enabling localization of plaque in tissue without the need for staining. ...
Kidney stones frequently develop as an overgrowth on Randall's plaque (RP) which is formed in the papillary interstitium. The organic composition of RP is distinct from stone matrix in that RP contains fibrillar collagen; RP in tissue has also been shown to have two proteins that are also found in stones, but otherwise the molecular constituents of RP are unstudied. We hypothesized that RP contains unique organic molecules that can be differentiated from the stone overgrowth by fluorescence. To test this, we used micro-CT-guided polishing to expose the interior of kidney stones for multimodal imaging with multiphoton, confocal and infrared microscopy. We detected a blue autofluorescence signature unique to RP, the specificity of which was also confirmed in papillary tissue from patients with stone disease. High-resolution mineral mapping of the stone also showed a transition from the apatite within RP to the calcium oxalate in the overgrowth, demonstrating the molecular and spatial transition from the tissue to the urine. This work provides a systematic and practical approach to uncover specific fluorescence signatures which correlate with mineral type, verifies previous observations regarding mineral overgrowth onto RP and identifies a novel autofluorescence signature of RP demonstrating RP's unique molecular composition.
... The polymer used in the PILP process, referred to as the process directing agent, was usually polyaspartate but similar anionic polyelectrolytes were also used [242,243]. Model systems were devised for biomimetic mineralization of collagen sponges [241,244,245] and models of bone [42,241,242,246], tendon [247], dentin [248] and soft tissues [249][250][251][252]. ...
... Biomimetic studies of collagen mineralization were also been made with OPN [41,159,[250][251][252][253][254] and interpreted as due to the PILP mechanism. A comparative study showed that collagen mineralization using solutions containing OPN was more homogeneous, rapid and reproducible than with polyaspartate [159]. ...
... The solution used to mineralize collagen in the work of Rodriguez et al. [41] was designed [112] so that the OPNmix was largely in the form of the equilibrium CaP nanocluster complexes described in Section 4.2. The same OPNmix sample, in a closely similar solution with some minor changes in buffering, was used in subsequent work [159,[251][252][253][254]. Almost certainly these studies were also made with the equilibrium CaP nanocluster complexes. ...
Biofluids that contain stable calcium phosphate nanoclusters sequestered by phosphopeptides make it possible for soft and hard tissues to co-exist in the same organism with relative ease. The stability diagram of a solution of nanocluster complexes shows how the minimum concentration of phosphopeptide needed for stability increases with pH. In the stable region, amorphous calcium phosphate cannot precipitate. Nevertheless, if the solution is brought into contact with hydroxyapatite, the crystalline phase will grow at the expense of the nanocluster complexes. The physico-chemical principles governing the formation, composition, size, structure, and stability of the complexes are described. Examples are given of complexes formed by casein, osteopontin, and recombinant phosphopeptides. Application of these principles and properties to blood serum, milk, urine, and resting saliva is described to show that under physiological conditions they are in the stable region of their stability diagram and so cannot cause soft tissue calcification. Stimulated saliva, however, is in the metastable region, consistent with its role in tooth remineralization. Destabilization of biofluids, with consequential ill-effects, can occur when there is a failure of homeostasis, such as an increase in pH without a balancing increase in the concentration of sequestering phosphopeptides.
... In many cases, [8][9][10] these stones originate from mineral deposits at the tip of renal papillae known as Randall's plaques (RPs). [11][12][13] Interestingly, they are not only detected as an anchored site for stone formation in renal-stoneforming patients but also in incipient forms in more than two thirds of people without kidney stone. 14 The molecular mechanisms involved in the pathogenesis of RPs are still not known and many questions still remain on the formation of such pathological calcifications. ...
Idiopathic kidney stones originate mainly from calcium phosphate deposits at the tip of renal papillae, known as Randall’s plaques (RPs), also detected in most human kidneys without stones. However, little is known about the mechanisms involved in RP formation. The localization and characterization of such nano-sized objects in the kidney remains a real challenge making their study arduous. This study provides a nanoscale analysis of the chemical composition and morphology of incipient RPs, characterizing in particular the interface between the mineral and the surrounding organic compounds. Relying on data gathered from a calculi collection, the morphology and chemical composition of incipient calcifications in renal tissue was determined using spatially resolved electron energy-loss spectroscopy (EELS). We detected micro-calcifications and individual nano-calcifications found at some distance from the larger ones. Strikingly, concerning the smaller ones, we show that two types of nano-calcifications coexist: calcified organic vesicles and nanometric mineral granules mainly composed of calcium phosphate with carbonate in their core. Interestingly, some of these nano-calcifications present similarities with those reported in physiological bone or pathological cardiovascular biominerals, suggesting possible common formation mechanisms. However the high diversity of these nano-calcifications suggests that several mechanisms may be involved (nucleation on a carbonate core or on organic compounds). In addition, incipient RPs also appear to present specific features at larger scales revealing secondary calcified structures embedded in a fibrillar organic material. Our study proves that analogies exist between physiological and pathological biominerals and provides information to understand the physico-chemical processes involved in pathological calcification formation.
Kidney stone, one of the oldest known diseases, has plagued humans for centuries, consistently imposing a heavy burden on patients and healthcare systems worldwide due to their high incidence and recurrence rates. Advancements in endoscopy, imaging, genetics, molecular biology and bioinformatics have led to a deeper and more comprehensive understanding of the mechanism behind nephrolithiasis. Kidney stone formation is a complex, multi‐step and long‐term process involving the transformation of stone‐forming salts from free ions into asymptomatic or symptomatic stones influenced by physical, chemical and biological factors. Among the various types of kidney stones observed in clinical practice, calcareous nephrolithiasis is currently the most common and exhibits the most intricate formation mechanism. Extensive research suggests that calcareous nephrolithiasis primarily originates from interstitial subepithelial calcified plaques and/or calcified blockages in the openings of collecting ducts. These calcified plaques and blockages eventually come into contact with urine in the renal pelvis, serving as a nidus for crystal formation and subsequent stone growth. Both pathways of stone formation share similar mechanisms, such as the drive of abnormal urine composition, involvement of oxidative stress and inflammation, and an imbalance of stone inhibitors and promoters. However, they also possess unique characteristics. Hence, this review aims to provide detailed description and present recent discoveries regarding the formation processes of calcareous nephrolithiasis from two distinct birthplaces: renal interstitium and tubule lumen.
Effective prevention of recurrent kidney stone’s diseases requires the understanding of their mechanisms of formation. Numerous in vivo observations have demonstrated that a large number of pathological calcium oxalate kidney...
