Randall's Plaque Research Articles

Two distinct phenotypes of calcium oxalate stone formers could imply different long-term risks for renal function.

Endoscopic and biopsy findings have identified two distinct phenotypes among individuals with calcium oxalate (CaOx) kidney stones. The first type has normal renal papillae but shows interstitial mineral deposition, known as Randall's plaque. The other phenotype presents with collecting duct plugging and a higher incidence of loss of papilla tissue mass. With Randall's plaque, renal papilla injury involves the loss of small patches of calcified tissue (Randall's plaque detaching with the stone), which likely results in damage to only a few nephrons. In contrast, collecting duct mineral plugs are very large, causing obstruction to tubular flow. Since each terminal collecting duct drains thousands of nephrons, ductal plugs could lead to the degeneration of many nephrons and a significant loss of renal glomeruli. New visualization techniques for immune cells in papillary biopsies have revealed that the Randall's plaque phenotype is marked by the accumulation of macrophages around the plaque regions. In contrast, preliminary data on the plugging phenotype shows collecting duct damage with mineral plugsand increased T-lymphocytes throughout the papilla. These regions also show tubulitis, i.e., T-cell infiltration into nearby collecting duct epithelium. This suggests that while some CaOx stone formers may have some papillary inflammation but with minimal damage to nephrons, others suffer from obstruction to flow for many nephrons that may also include destructive inflammation in the renal tissue. We propose that CaOx stone formers with the plugging phenotype will have a higher long-term risk for loss of renal function.

Osteogenic-Like Microenvironment of Renal Interstitium Induced by Osteomodulin Contributes to Randall's Plaque Formation.

Calcium oxalate (CaOx) kidney stones are common and recurrent, lacking pharmacological prevention. Randall's plaques (RPs), calcium deposits in renal papillae, serve as niduses for some CaOx stones. This study exploresthe role of osteogenic-like cells in RP formation resembling ossification. CaP crystals deposit around renal tubules, interstitium, and blood vessels in RP tissues. Human renal interstitial fibroblasts (hRIFs) exhibit the highest osteogenic-like differentiation potential compared to chloride voltage-gated channel Ka positive tubular epithelial cells, aquaporin 2 positive collecting duct cells, and vascular endothelial cells, echoing the upregulated osteogenic markers primarily in hRIFs within RP tissues. Utilizing RNA-seq, osteomodulin (OMD) is found to be upregulated in hRIFs within RP tissues and hRIFs following osteogenic induction. Furthermore, OMD colocalizes with CaP crystals and calcium vesicles within RP tissues. OMD can enhance osteogenic-like differentiation of hRIFs in vitro and in vivo. Additionally, crystal deposits are attenuated in mice with Omd deletion in renal interstitial fibroblasts following CaOx nephrocalcinosis induction. Mechanically, a positive feedback loop of OMD/BMP2/BMPR1A/RUNX2/OMD drives hRIFs to adopt osteogenic-like fates, by which OMD induces osteogenic-like microenvironment of renal interstitium to participate in RP formation. Weidentify OMD upregulation as a pathological feature of RP, paving the way for preventing CaOx stones.

Two distinct phenotypes of calcium oxalate stone formers could imply different long-term risks for renal function.

Endoscopic and biopsy findings have identified two distinct phenotypes among individuals with calcium oxalate (CaOx) kidney stones. One phenotype exhibits normal renal papillae but shows interstitial mineral deposition, known as Randall's plaque. The other phenotype presents with collecting duct plugging and a higher incidence of loss of papilla tissue mass. With Randall's plaque, renal papilla injury involves the loss of small patches of calcified tissue (Randall's plaque detaching with the stone), which likely results in damage to only a few nephrons. In contrast, collecting duct mineral plugs are very large, causing obstruction to tubular flow. Since each terminal collecting duct drains thousands of nephrons, ductal plugs could lead to the degeneration of many nephrons and a significant loss of renal glomeruli. New visualization techniques for immune cells in papillary biopsies have revealed that the Randall's plaque phenotype is marked by the accumulation of macrophages around the plaque regions. In contrast, preliminary data on the plugging phenotype shows collecting duct damage with mineral plugs, increased T-lymphocytes throughout the papilla, and tubulitis, characterized by T-cell infiltration into nearby collecting duct epithelium. This suggests that while some CaOx stone formers may have some papillary inflammation but with minimal damage to nephrons, others suffer from obstruction to flow for many nephrons that may also include destructive inflammation in the renal tissue. We propose that the long-term risks for loss of renal function will be greater for CaOx stone formers with the plugging phenotype.

A high-calcium environment induced ectopic calcification ofrenal interstitial fibroblasts via TFPI-2-DCHS1-ALP/ENPP1 axis to participate inRandall's plaque formation.

Randall's plaques (RP) serve as anchoring sites for calcium oxalate (CaOx) stones, but the underlying mechanism remains unclear. Renal interstitium with a high-calcium environment is identified as pathogenesis of RP formation where the role of human renal interstitial fibroblasts (hRIFs) was highlighted. Our study aims to elucidate the potential mechanism by which a high-calcium environment drives ectopic calcification of hRIFs to participate in RP formation. Alizarin Red staining demonstrated calcium nodules in hRIFs treated with high-calcium medium. Utilizing transcriptome sequencing, tissue factor pathway inhibitor-2 (TFPI-2) was found to be upregulated in high-calcium-induced hRIFs and RP tissues, and TFPI-2 promoted high-calcium-induced calcification of hRIFs. Subsequently, the downstream regulator of TFPI2 was screened by transcriptome sequencing analysis of hRIFs with TFPI-2 knockdown or overexpressed. Dachsous Cadherin Related 1 (DCHS1) knockdown was identified to suppress the calcification of hRIFs enhanced by TFPI-2. Further investigation revealed that TFPI-2/DCHS1 axis promoted high-calcium-induced calcification of hRIFs via disturbing the balance of ENPP1/ALP activities, but without effect on the canonical osteogenic markers, such as osteopontin (OPN), osteogenic factors runt-related transcription factor 2 (RUNX2), bone morphogenetic protein 2 (BMP2). In summary, our study mimicked the high-calcium environment observed in CaOx stone patients with hypercalciuria, and discovered that the high-calcium drove ectopic calcification of hRIFs via a novel TFPI-2-DCHS1-ALP/ENPP1 pathway rather than adaption of osteogenic phenotypes to participate in RP formation.

The Role of Biochemistry in Understanding Kidney Stone Formation andUrinary Health

Renal illness caused by stones is the term for a solid substance concretion that usually develops inside the kidneys. A rising urological condition influences the well-being of people and affects about 12% of the world's population. An increased chance of ending stage of renal failure and they are closely related. There are several types of kidney stones. The CaC2O4 kidney calculi are the most common type. It appears at Randall plaque's renal papillary surfaces. (1) Several physicochemical mechanisms, such as supersaturating, urinary stone nucleation, growth, aggregation, and retention components found in tubular cells, which aid in the complex process of formation of stones. An inequity between the elements that promote or inhibit the crystallization of urine influences these phases. Moreover, Scientists have noticed that renal injury of cells promotes particle retention reticular body. (2)

Renal papillary tip biopsy in stone formers: a review of clinical safety and insights.

Alexander Randall first published renal papillary tip findings from stone formers in 1937, paving the way for endoscopic assessment to study stone pathogenesis. We performed a literature search to evaluate the safety of papillary tip biopsy and clinical insights gained from modern renal papillary investigations. A search on the topic of renal papillary biopsy provided an overview of Randall's plaques (RP), classification systems for renal papillary grading, and a summary of procedure type, complications, and outcomes. Within 26 identified manuscripts, 660 individuals underwent papillary tip biopsy percutaneously (n = 562), endoscopically (n = 37), or unspecified (n = 23). Post-operative hemoglobin changes were similar to controls.One individual (0.2%) reported fever > 38°, and long-term mean serum creatinine post-biopsy (n = 32) was unchanged. Biopsies during ureteroscopy or PCNL added ~20-30min of procedure time. Compared to controls, papillary plaque-containing tissue had upregulation in pro-inflammatory genes, immune cells, and cellular apoptosis. Urinary calcium and papillary plaque coverage were found to differ between RP and non-RP stone formers, suggesting differing underlying pathophysiology for these groups. Two renal papillary scoring systems have been externally validated and are used to classify stone formers. Overall, this review shows that renal papillary biopsies have a low complication profile with high potential for further research. Systematic adaption of a papillary grading scale, newer tissue analysis techniques, and the development of animal models of Randall's plaque may allow further exploration of plaque pathogenesis and identify targets for prevention therapies in patients with nephrolithiasis.

Calcium phosphate controls nucleation and growth of calcium oxalate crystal phases in kidney stones.

Kidney stone disease is a serious disease due to the severe pain it causes, high morbidity, and high recurrence rate. Notably, calcium oxalate stones are the most common type of kidney stone. Calcium oxalate appears in two forms in kidney stones: the stable phase, monohydrate (COM), and the metastable phase, dihydrate (COD). Particularly, COM stones with concentric structures are hard and difficult to treat. However, the factor determining the growth of either COM or COD crystals in the urine, which is supersaturated for both phases, remains unclear. This study shows that calcium phosphate ingredients preferentially induce COM crystal nucleation and growth, by observing and analyzing kidney stones containing both COM and COD crystals. The forms of calcium phosphate are not limited to Randall's plaques (1-2 mm size aggregates, which contain calcium phosphate nanoparticles and proteins, and form in the renal papilla). For example, aggregates of strip-shaped calcium phosphate crystals and fields of dispersed calcium phosphate microcrystals (nano to micrometer order) also promote the growth of concentric COM structures. This suggests that patients who excrete urine with a higher quantity of calcium phosphate crystals may be more prone to forming hard and troublesome COM stones.

Identification and validation of the biomarkers related to ferroptosis in calcium oxalate nephrolithiasis.

Ferroptosis is a specific type of programmed cell death characterized by iron-dependent lipid peroxidation. Understanding the involvement of ferroptosis in calcium oxalate (CaOx) stone formation may reveal potential targets for this condition. The publicly available dataset GSE73680 was used to identify 61 differentially expressed ferroptosis-related genes (DEFERGs) between normal kidney tissues and Randall's plaques (RPs) from patients with nephrolithiasis through employing weighted gene co-expression network analysis (WGCNA). The findings were validated through in vitro and in vivo experiments using CaOx nephrolithiasis rat models induced by 1% ethylene glycol administration and HK-2 cell models treated with 1 mM oxalate. Through WGCNA and the machine learning algorithm, we identified LAMP2 and MDM4 as the hub DEFERGs. Subsequently, nephrolithiasis samples were classified into cluster 1 and cluster 2 based on the expression of the hub DEFERGs. Validation experiments demonstrated decreased expression of LAMP2 and MDM4 in CaOx nephrolithiasis animal models and cells. Treatment with ferrostatin-1 (Fer-1), a ferroptosis inhibitor, partially reversed oxidative stress and lipid peroxidation in CaOx nephrolithiasis models. Moreover, Fer-1 also reversed the expression changes of LAMP2 and MDM4 in CaOx nephrolithiasis models. Our findings suggest that ferroptosis may be involved in the formation of CaOx kidney stones through the regulation of LAMP2 and MDM4.

Pathophysiology and Main Molecular Mechanisms of Urinary Stone Formation and Recurrence.

Kidney stone disease (KSD) is one of the most common urological diseases. The incidence of kidney stones has increased dramatically in the last few decades. Kidney stones are mineral deposits in the calyces or the pelvis, free or attached to the renal papillae. They contain crystals and organic components, and they are made when urine is supersaturated with minerals. Calcium-containing stones are the most common, with calcium oxalate as the main component of most stones. However, many of these form on a calcium phosphate matrix called Randall's plaque, which is found on the surface of the kidney papilla. The etiology is multifactorial, and the recurrence rate is as high as 50% within 5 years after the first stone onset. There is a great need for recurrence prevention that requires a better understanding of the mechanisms involved in stone formation to facilitate the development of more effective drugs. This review aims to understand the pathophysiology and the main molecular mechanisms known to date to prevent recurrences, which requires behavioral and nutritional interventions, as well as pharmacological treatments that are specific to the type of stone.

The Most Common Type of Kidney Stone and High Incidence in Males or Female

In the renal calyces and pelvis, mineral deposits known as kidney stones can be found either loosely or firmly attached to the renal papillae. They comprise both crystalline and organic molecules and are produced when the urine is very saturated with a specific mineral. The majority of stones are mostly formed of calcium oxalate, and a lot of these stones form on Randall's plaques on the renal papillary floor, which are made of calcium phosphate. In the first five years after the initial stone episode, charges of up to 50% may recur. There are charges of up to 14.8% and increasing for stone creation. Risk factors for kidney stone development include obesity, diabetes, high blood pressure, and metabolic syndrome. Kidney stones can then lead to hypertension, chronic kidney disease, and end-stage renal disease. Less invasive endourological techniques have replaced open surgical lithotomy for the treatment of symptomatic kidney stones, reducing patient morbidity, increasing stone-free rates, and improving quality of life. Prevention of recurrence requires behavioral and nutritional adjustments in addition to drugs according to the kind of stone. The creation of stronger capsules and the pressing need for recurrence prevention necessitate a greater comprehension of the mechanisms behind stone formation.

Micro-CT Analysis of Renal Papillae Shows That Randall's Plaque Formation Occurs Independently of Ductal Plugging

Micro-CT Analysis of Renal Papillae Shows That Randall's Plaque Formation Occurs Independently of Ductal Plugging

An overview of global research landscape in etiology of urolithiasis based on bibliometric analysis.

The high incidence, recurrence and treatment costs of urolithiasis have a serious impact on patients and society. For a long time, countless scholars have been working tirelessly on studies related to the etiology of urolithiasis. A comprehensive understanding of the current status will be beneficial to the development of this field. We collected all literature about the etiology of urolithiasis from 1990 to 2022 using the Web of Science (WoS) database. VOSviewer, Bibliometrix and CiteSpace software were used to quantitatively analyze and visualize the data as well. The query identified 3177 articles for final analysis, of which related to the etiology of urolithiasis. The annual number of publications related to urolithiasis research has steadily increased during the latest decade. United States (1106) and China (449) contributed the most publications. University of Chicago (92) and Indiana University (86) have the highest number of publications. Urolithiasis and Journal of Urology have published the most articles in the field. Coe FL is the most productive author (63 articles), whose articles have obtained the most citations in all (4141 times). The keyword, such as hypercalciuria, hyperoxaluria, citrate, oxidative stress, inflammation, Randall's plaque, are the most attractive targets for the researchers. Our review provides a global landscape of studies related to the etiology of urolithiasis, which can serve as a reference for future studies in this field.

MP05-03 DIFFERENCES IN PAPILLARY MORPHOLOGY BETWEEN BLACK AND WHITE STONE FORMERS

You have accessJournal of UrologyCME1 Apr 2023MP05-03 DIFFERENCES IN PAPILLARY MORPHOLOGY BETWEEN BLACK AND WHITE STONE FORMERS Luke Reynolds, Clark Judge, Julia Margason, India Skinner, Elaine Worcester, Frederick Coe, and Anna Zisman Luke ReynoldsLuke Reynolds More articles by this author , Clark JudgeClark Judge More articles by this author , Julia MargasonJulia Margason More articles by this author , India SkinnerIndia Skinner More articles by this author , Elaine WorcesterElaine Worcester More articles by this author , Frederick CoeFrederick Coe More articles by this author , and Anna ZismanAnna Zisman More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003216.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Nephrolithiasis is common and incidence is increasing faster among Blacks (B) compared to Whites (W). Recent evidence suggests that many stone formers (SF) form calcium oxalate stones on the base of a Randall plaque (RP), but this has only been studied in W SF. We sought to compare the renal papillary anatomy of B and W to improve our understanding of stone pathogenesis in the two groups. METHODS: SF undergoing ureteroscopy for the treatment of symptomatic and asymptomatic stone disease were prospectively enrolled. Patients with a systemic or anatomic cause for stone disease were excluded. Race was self-identified. Two blinded independent reviewers who had undergone standardized training on papillary grading used digital videos from ureteroscopy to assign scores of 0, 1, or 2 for plugging, plaque, pitting, and loss of contour. Scores were averaged across all papillae graded per kidney for each category, as well as the combined total score, and compared using Mann-Whitney U test. ANCOVA models were used to evaluate differences in these scores with adjustments for sex, age, BMI, and recurrence status (RS). RESULTS: Thirty-three B and 47 W patients were enrolled. Age was similar between groups but B had higher BMI (Table 1). The majority of patients were recurrent SF (66% W/83% B). B had significantly lower scores for plugging and plaque, as well as lower total scores (Table 1, Figure 1). In multivariate models, race was the only significant factor contributing to RP score, while race, age, and RS were significant for plugging. For total score, race and RS were significant contributors, and there was no interaction between race and RS. CONCLUSIONS: This study is the first to describe the papillary anatomy of B SF. Compared to W SF, B have significantly less RP and tubular plugging, suggesting potentially different mechanisms for stone formation. Source of Funding: P01 DK056788 (Worcester, Coe, Zisman) © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e44 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Luke Reynolds More articles by this author Clark Judge More articles by this author Julia Margason More articles by this author India Skinner More articles by this author Elaine Worcester More articles by this author Frederick Coe More articles by this author Anna Zisman More articles by this author Expand All Advertisement PDF downloadLoading ...

Mineralogy, geochemistry, and micromorphology of human kidney stones (urolithiasis) from Mersin, the southern Turkey.

This study describes the primary characteristics of the selected kidney stones surgically removed from the patients at the Mersin University Hospital in the southern Turkey and interprets their formation via petrographic, geochemical, XRD, SEM-EDX, and ICP-MS/OES analyses. The analytical results revealed that the kidney stones are composed of the minerals whewellite, struvite, hydroxyapatite, and uric acid alone or in different combinations. The samples occur in staghorn, bean-shaped composite, and individual rounded particle shapes, which are controlled by the shape of the nucleus and the site of stone formation. The cross-section of the samples shows concentric growth layers due to variations in saturation, characterizing the metastable phase. Kidney stone formation includes two main stages: (i) nucleation and (ii) aggregation and/or growth. Nucleation was either Randall plaque of hydroxyapatite in tissue on the surface of the papilla or a coating of whewellite on the plaque, or crystallization as free particles in the urine. Subsequently, aggregation or growth occurs by precipitation of stone-forming materials around the plaque or coating carried into the urine, or around the nucleus formed in situ in the urine. Urinary supersaturation is the main driving force of crystallization processes; and is controlled by many factors including bacterially induced supersaturation.

Homeopathy as a saviour for urolithiasis: A narrative review shading light on pathophysiology of renal stones and homeopathy drugs

Kidney stone disease is a crystal concretion formed generally within the kidneys. It is an accumulative urological disorder of human health, affecting about 12% of the world population. Higher risk of kidney failure which has been associated with end stage renal failure. Calcium oxalate, which forms at Randall's plaque on the renal papillary surfaces, is the most common type of kidney stone. Stone formation is highly prevalent, with rates of up to 14.8% and increasing, and a recurrence rate of up to 50% within the first 5 years of the initial stone incident. The formation of the stone is a complex process which results from numerous physiochemical events such as, super saturation, nucleation, growth, aggregation, and retention of urinary stone constituents within tubular cells. Several therapies are being performed for kidney stone treatment, including thiazide diuretics, allopurinol, painkillers, dietary changes, shock-wave treatment, ureterenooscopic and percutaneous nephrolithotomy, and ureterenooscopic and percutaneous nephrolithotomy in severe cases. However, the side effects that these treatments possess and reoccurrence of the disease have motivated researchers to search for better and safer options. Homeopathic drugs as well as several medicinal plants display antiurolithiatic activity and thus perform an important role in treatment of kidney stone disease. Therefore, the present review thereby wants to bring to the attention the wonderful results that homeopathy is offering in cases of urolithiasis in a very non-invasive and economical way which is not yet popularized.

Active metabolic lithiasis: A condition that requires proper evaluation and monitoring.

Kidney stone evolution is different among patients, with some exhibiting kidney stones once in a lifetime and others experiencing multiple recurrences, with some even presenting with them at short intervals of time. The present study analyzed the risk of recurrence in order to organize a personalized prophylaxis and follow-up for the patients at risk. Prior to the analysis, the patients completed the liquids, antecedents, medication, associated pathologies and aliments questionnaire. A total of 350 patients with kidney stones were consecutively enrolled between April 2019 and April 2022. The spectroscopic analysis of stone samples was performed with the Bruker Alpha II spectrometer, while the stone morphology was assessed using the Olympus SZ61TR stereomicroscope. Intact stones were sectioned and their cores were analyzed separately. Patients with metabolically active lithiasis had stones made of cystine (CYS), uric acid (UA), brushite or calcium oxalate dihydrate. Among patients aged 18-30 years, two morphological factors defining the metabolically active lithiasis were identified: Randall's plaques [odds ratio (OR), 8.8] and poor stone organization (OR, 12.0). In patients aged 31-40 years, one criterion for the diagnosis of metabolically active lithiasis was the identification of pale stone color (OR, 12.0). Among the 149 patients aged >50 years, 24.8% (n=37) had UA lithiasis. Furthermore, the association of the defining elements of the metabolic syndrome significantly increased the likelihood of the lithiasis recurrence (P=0.03; OR, 4.3). The presence of kidney stones in the family history was significantly associated with the type of stone (P=0.004). Among the 7 patients with CYS stones, 71.4% of them had family history of lithiasis. The study findings suggest that the identification of Randall plaques, a light stone color or a low degree of stone organization is associated with increased odds of lithiasis recurrence.

Stone Morphology Distinguishes Two Pathways of Idiopathic Calcium Oxalate Stone Pathogenesis.

Introduction: About 1 in 11 Americans will experience a kidney stone, but underlying causes remain obscure. The objective of the present study was to separate idiopathic calcium oxalate stone formers by whether or not they showed positive evidence of forming a stone on Randall's plaque (RP). Materials and Methods: In patients undergoing either percutaneous or ureteroscopic procedures for kidney stone removal, all stone material was extracted and analyzed using micro-CT imaging to identify those attached to RP. Twenty-four-hour urine samples were collected weeks after the stone removal procedure and patients were off of medications that would affect urine composition. The endoscopic video was analyzed for papillary pathology (RP, pitting, plugging, dilated ducts, and loss of papillary shape) by an observer blinded to the data on stone type. The percent papillary area occupied by RP and ductal plugging was quantified using image analysis software. Results: Patients having even one stone on RP (N = 36) did not differ from non-RP patients (N = 37) in age, sex, BMI, or other clinical characteristics. Compared with the non-RP group, RP stone formers had more numerous, but smaller, stones, more abundant papillary RP formation, and fewer ductal plugs, both by quantitative measurement of surface area (on average, three times more plaque area, but only 41% as much plug area as in non-RP patients) and by semiquantitative visual grading. Serum and blood values did not differ between RP and non-RP stone formers by any measure. Conclusions: Growth of many small stones on plaque seems the pathogenetic scheme for the RP stone-forming phenotype, whereas the non-RP phenotype stone pathogenesis pathway is less obvious. Higher papillary plugging in non-RP patients suggests that plugs play a role in stone formation and that these patients have a greater degree of papillary damage. Underlying mechanisms that create these distinctive phenotypes are presently unknown.

Collagen fibrils and cell nuclei are entrapped within Randall's plaques but not in CaOx matrix overgrowth: A microscopic inquiry into Randall's plaque stone pathogenesis.

Calcium oxalate (CaOx) stones can grow attached to the renal papillary calcification known as Randall's plaque. Although stone growth on Randall's plaque is a common phenomenon, this mechanism of stone formation is still poorly understood. The objective of this study was to investigate the microenvironment of mature Randall's plaque, explore its molecular composition and differentiate plaque from CaOx overgrowth using multimodal imaging on demineralized stone sections. Fluorescence imaging showed consistent differences in autofluorescence patterns between Randall's plaque and calcium oxalate overgrowth regions. Second harmonic generation imaging established the presence of collagen only in regions of decalcified Randall's plaque but not in regions of CaOx overgrowth matrix. Surprisingly, in these stone sections we observed cell nuclei with preserved morphology within regions of mature Randall's plaque. These conserved cells had variable expression of vimentin and CD45. The presence of nuclei in mature plaque indicates that mineralization is not necessarily associated with cell death. The markers identified suggest that some of the entrapped cells may be undergoing dedifferentiation or could emanate from a mesenchymal or immune origin. We propose that entrapped cells may play an important role in the growth and maintenance of Randall's plaque. Further characterization of these cells and thorough analyses of the mineralized stone forming renal papilla will be fundamental in understanding the pathogenesis of Randall's plaque and CaOx stone formation.

α-Klotho released from HK-2 cells inhibits osteogenic differentiation of renal interstitial fibroblasts by inactivating the Wnt-β-catenin pathway.

Randall's plaques (RP) are well established as precursor lesions of idiopathic calcium oxalate (CaOx) stones, and the process of biomineralization driven by osteogenic-like cells has been highlighted in RP formation, but the mechanism is poorly understood. Given the inhibitory role of α-Klotho (KL), an aging suppressor protein with high expression in kidneys, in ectopic calcification and the close association between KL gene polymorphisms and urolithiasis susceptibility, we determined the potential role of KL in RP formation. This study found that both soluble KL (s-KL) and transmembrane KL (m-KL) were downregulated, and that s-KL but not m-KL was inversely correlated with upregulation of osteogenic markers in RP tissues. Additionally, s-KL expression was markedly suppressed in human renal interstitial fibroblasts (hRIFs) and slightly suppressed in HK-2 cells after osteogenic induction, intriguingly, which was echoed to the greater osteogenic capability of hRIFs than HK-2 cells. Further investigations showed the inhibitory effect of s-KL on hRIF osteogenic differentiation in vitro and in vivo. Moreover, coculture with recombinant human KL (r-KL) or HK-2 cells suppressed osteogenic differentiation of hRIFs, and this effect was abolished by coculture with KL-silenced HK-2 cells or the β-catenin agonist SKL2001. Mechanistically, s-KL inactivated the Wnt-β-catenin pathway by directly binding to Wnt2 and upregulating SFRP1. Further investigations identified activation of the Wnt-β-catenin pathway and downregulation of SFRP1 and DKK1 in RP tissues. In summary, this study identified s-KL deficiency as a pathological feature of RP and revealed that s-KL released from HK-2 cells inhibited osteogenic differentiation of hRIFs by inactivating the Wnt-β-catenin pathway, not only providing in-depth insight into the role of s-KL in renal interstitial biomineralization but also shedding new light on the interaction of renal tubular epithelial cells with interstitial cells to clarify RP formation.

MP07-15 CALCIUM OXALATE STONE FORMERS WHO MAKE EVEN ONE STONE ON RANDALL'S PLAQUE HAVE SMALLER STONE BURDENS AND DISTINCTIVE PAPILLARY MINERAL PATHOLOGY

You have accessJournal of UrologyStone Disease: Basic Research & Pathophysiology (MP07)1 Sep 2021MP07-15 CALCIUM OXALATE STONE FORMERS WHO MAKE EVEN ONE STONE ON RANDALL'S PLAQUE HAVE SMALLER STONE BURDENS AND DISTINCTIVE PAPILLARY MINERAL PATHOLOGY James Williams, Haider Al-Awadi, Manognya Muthenini, Sharon Bledsoe, Tarek El-Achkar, Andrew Evan, Fredric Coe, Elaine Worcester, and James Lingeman James WilliamsJames Williams More articles by this author , Haider Al-AwadiHaider Al-Awadi More articles by this author , Manognya MutheniniManognya Muthenini More articles by this author , Sharon BledsoeSharon Bledsoe More articles by this author , Tarek El-AchkarTarek El-Achkar More articles by this author , Andrew EvanAndrew Evan More articles by this author , Fredric CoeFredric Coe More articles by this author , Elaine WorcesterElaine Worcester More articles by this author , and James LingemanJames Lingeman More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001980.15AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The purpose of this study was to compare idiopathic calcium oxalate stone formers with (RP) and without (Non-RP) positive evidence for formation of stones on Randall’s (interstitial) plaque. METHODS: Patients undergoing stone removal by percutaneous (PNL) or ureteroscopic (URS) endoscopy were consented for study. Included patients had stone analysis of >50% calcium oxalate, with no brushite, medullary sponge, bariatric surgery, primary hyperoxaluria or hyperparathyroidism. all stone material was imaged by micro CT and stones growing on Randall’s plaque were identified by adherent regions of apatite that showed characteristics of calcified tissue (including lumens of vessels/tubules in 76% of the cases). Endoscopic papillary appearance was graded and measured on endoscopic video by an investigator blinded to the patient classification. RESULTS: 32 RP patients had on average 5±6 stones on Randall’s plaque, with none in the 42 Non-RP patients. The RP group was younger (48±17 v 56±14, p=0.04), had more stones (8±8 v 5±4 stones/kidney, p=0.02), less total stone removed (80±120 v 480±1200 cubic mm/kidney), and smaller stones (160±230 v 560±1200 cubic mm per stone, p=0.01) than did Non-RP patients, and RP were more likely to have undergone URS. RP had on average 240% more Randall's plaque area (5.2±4.3 v 1.5±1.7 as percent of papilla area, p <0.0001) and 77% less ductal plugging area (0.17±0.38 v 0.73±0.77, p <0.0001). In semi-quantitative scores, RP had more plaque and pitting, less plugging/dilated ducts, and less loss of papillary contour (figure 1). 24-hour urine values did not differ between RP and Non-RP on any measure. CONCLUSIONS: Calcium oxalate stone formers who showed positive evidence of having even a single stone on plaque had small stone burdens and were more likely to have undergone URS. Their renal papillae showed much more plaque and much less ductal plugging than the Non-RP group. These data support RP as a distinct phenotype among calcium oxalate stone formers. Source of Funding: NIH P01 DK056788; NIH R01 DK124776 © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e145-e145 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information James Williams More articles by this author Haider Al-Awadi More articles by this author Manognya Muthenini More articles by this author Sharon Bledsoe More articles by this author Tarek El-Achkar More articles by this author Andrew Evan More articles by this author Fredric Coe More articles by this author Elaine Worcester More articles by this author James Lingeman More articles by this author Expand All Advertisement Loading ...