Idiopathic Calcium Oxalate Stone Formers Research Articles

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.

Effect of a low-calorie diet on 24-hour urinary parameters of obese adults with idiopathic calcium oxalate kidney stones.

ABSTRACTPurpose:to evaluate the effect of low-calorie diet on 24-hour urinary metabolic parameters of obese adults with idiopathic calcium oxalate kidney stones.Materials and Methods:Adult idiopathic calcium oxalate stone formers, with body mass index (BMI) ≥30kg/m2 and a known lithogenic metabolic abnormality, were submitted to low-calorie diet for twelve weeks. After enrolment, anthropometric measures, serum exams, 24-hour urinary metabolic parameters and body impedance were collected one month prior to dietary intervention and at the end of twelve weeks. Correlations between weight loss, waist circumference loss, fat loss and variation in 24-hour urinary lithogenic parameters and calcium oxalate urinary supersaturation (CaOx SS) as per Tiselius equation were analysed.Results:From January 2017 to January 2018, 39 patients were enrolled to participate in this study. Median (range) prescribed diet was 1300 (1100-2100) Kcal/day. Mean age was 51.7±11.0 (29-68) years old and 69.2% were female. 30.8% of the participants shifted from obesity to BMI <30kg/m2 and none to BMI <25kg/m2. A significant correlation was found between baseline 24-hour urinary oxalate and weight (p=0.018) and BMI (p=0.026). No correlation was found between variation of weight, waist circumference, fat mass and 24-h urinary stone risk factors or CaOx SS.Conclusions:Short-term modest weight loss induced by twelve weeks of low-calorie diet is not associated with a decrease of 24-hour urinary lithogenic parameters in idiopathic calcium oxalate stone formers. Calcium oxalate urinary stone formation is probably multifactorial and driven by other factors than weight.

Increased Urinary Leukocyte Esterase Distinguishes Patients With Brushite Kidney Stones

Patients with brushite kidney stones have more severe renal papillary pathology than idiopathic calcium oxalate (CaOx) stone formers (SFs).1 We have shown that papillary tissue from brushite but not CaOx SFs demonstrates abundant neutrophil activation including neutrophil extracellular trap formation, a neutrophil response to bacteria and other perceived pathogens.2 This neutrophil infiltration may explain the increased scarring and inflammation observed in the papillae of brushite SFs.

Re: Simple Dietary Advice Targeting Five Urinary Parameters Reduces Urinary Supersaturation in Idiopathic Calcium Oxalate Stone Formers.

Re: Simple Dietary Advice Targeting Five Urinary Parameters Reduces Urinary Supersaturation in Idiopathic Calcium Oxalate Stone Formers.

Association Between Randall's Plaque Stone Anchors and Renal Papillary Pits.

Renal papillary pits are commonly encountered during ureteroscopy. The mechanism by which such pits arise is unclear. One hypothesis is that pits represent sites where stones overgrowing Randall's plaque (RP) were dislodged. We sought to examine this theory by using digital ureteroscopy and stone μCT. Patients undergoing endoscopic stone removal had procedures recorded and stones analyzed by using μCT. Stones with evidence of Randall's plaque anchors (RPAs) were identified in a blinded fashion. Surgical videos were reviewed independently by two urologists. Twenty-eight patients had μCT-confirmed stones with RPA. Among them, 93% were recurrent stone formers and 75% had had prior stone procedures. Metabolic abnormalities were present in 87%, with 79% classified as idiopathic calcium oxalate stone formers. A mean of 7.6 stones with RPA were identified per procedure. In each case, papillary pits were visualized before any stone manipulation and in several cases the active dislodgement of an attached stone led to immediate identification of an underlying pit. Such stones routinely demonstrated an RPA on μCT. The average depth of RPA was 302 ± 172 μm, consistent with the corresponding shallow pits visualized on the papillary surface. Stones overgrowing RP are capable of pulling away a piece of papilla when dislodged, resulting in a visible papillary pit. This process manifests as an RPA on the undersurface of the stone and a papillary pit on the corresponding area of attachment. Identification of pits may help identify patients who form stones primarily by the RP mechanism.

Development of a two-stage in vitro model system to investigate the mineralization mechanisms involved in idiopathic stone formation: stage 1-biomimetic Randall's plaque using decellularized porcine kidneys.

Idiopathic calcium oxalate (CaOx) stone formers form stones that are commonly 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, where they exhibit a morphology of concentrically laminated apatitic spherules, while in the interstitial regions, the collagen fibrils and vesicles become mineralized. We hypothesize that these minerals might form by non-classical crystallization mechanisms, such as via amorphous precursors, some of which might originate from a polymer-induced liquid-precursor (PILP) process. Thus, our goal is to identify mineralogical 'signatures' of various stone formation mechanisms. To do this for idiopathic CaOx stones, we are developing a two-stage model system of CaP-CaOx composite stones, consisting of stage (1) CaP mineralized plaque, followed by stage (2) CaOx overgrowth into a stone. For the studies presented here, decellularized porcine kidneys were mineralized with CaP using polyaspartic acid or the protein osteopontin (OPN) to induce the PILP process and create biomimetic RP. Analysis of the PILP-mineralized tissues shows features that resemble the native plaques, including mineral spherules and collagen with intrafibrillar mineral. In contrast, the classical crystallization produced large apatitic spherulites, which is a very different morphology, but one which is also found in some stones. An alternative hypothesis regarding Randall's plaque, and if or when it becomes pathological, is discussed.

Sensitivity of Noncontrast Computed Tomography for Small Renal Calculi With Endoscopy as the Gold Standard

To compare the sensitivity of noncontrast computed tomography (CT) with endoscopy for detection of renal calculi. Imaging modalities for detection of nephrolithiasis have centered on abdominal x-ray, ultrasound, and noncontrast CT. Sensitivities of 58%-62% (abdominal x-ray), 45% (ultrasound), and 95%-100% (CT) have been previously reported. However, these results have never been correlated with endoscopic findings. Idiopathic calcium oxalate stone formers with symptomatic calculi requiring ureteroscopy were studied. At the time of surgery, the number and the location of all calculi within the kidney were recorded followed by basket retrieval. Each calculus was measured and sent for micro-CT and infrared spectrophotometry. All CT scans were reviewed by the same genitourinary radiologist who was blinded to the endoscopic findings. The radiologist reported on the number, location, and size of each calculus. Eighteen renal units were studied in 11 patients. Average time from CT scan to ureteroscopy was 28.6 days. The mean number of calculi identified per kidney was 9.2 ± 6.1 for endoscopy and 5.9 ± 4.1 for CT (P <.004). The mean size of total renal calculi (sum of the longest stone diameters) per kidney was 22.4 ± 17.1 mm and 18.2 ± 13.2 mm for endoscopy and CT, respectively (P = .06). CT scan underreports the number of renal calculi, probably missing some small stones and being unable to distinguish those lying in close proximity to one another. However, the total stone burden seen by CT is, on average, accurate when compared with that found on endoscopic examination.

Papillary Ductal Plugging is a Mechanism for Early Stone Retention in Brushite Stone Disease.

Mechanisms of early stone retention in the kidney are under studied and poorly understood. To date attachment via Randall's plaque is the only widely accepted theory in this regard, which is best described in idiopathic calcium oxalate stone formers. Brushite stone formers are known to have distinct papillary morphology relative to calcium oxalate stone formers. As such we sought to determine whether stone attachment mechanisms in such patients may be similarly unique. Patients undergoing percutaneous and or ureteroscopic procedures for stone removal consented to endoscopic renal papillary examination and individual stone collection. Each removed stone was processed using micro computerized tomography to assess the 3-dimensional microstructure and the minerals contained, and search for common structural features indicative of novel mechanisms of early growth and attachment to renal tissue. A total of 25 intact brushite stones were removed from 8 patients and analyzed. Video confirmed attachment of 13 of the 25 stones with the remainder believed to have been accidently dislodged during the procedure. Microscopic examination by light and computerized tomography failed to show evidence of Randall's plaque associated with any stone containing brushite. Conversely each brushite stone demonstrated microstructural evidence of having grown attached to a ductal plug formed of apatite. Three-dimensional analysis of small brushite stones suggests overgrowth on ductal apatite plugs as a mechanism of early stone growth and retention. Such findings represent what is to our knowledge the initial supporting evidence for a novel mechanism of stone formation which has previously been hypothesized but never verified.

MP19-19 PATIENTS WITH CALCIUM STONES AND RANDALL’S PLAQUE EXCRETE DISTINCT POPULATIONS OF MICRO RNA-CONTAINING URINARY EXTRACELLULAR VESICLES

You have accessJournal of UrologyStone Disease: Basic Research & Pathophysiology II1 Apr 2017MP19-19 PATIENTS WITH CALCIUM STONES AND RANDALL’S PLAQUE EXCRETE DISTINCT POPULATIONS OF MICRO RNA-CONTAINING URINARY EXTRACELLULAR VESICLES John Lieske, Xiangling Wang, Robin Chirackal, John Knoedler, Amy Krambeck, Felicity Enders, Andrew Rule, Pritha Chanana, and Muthuvel Jayachandran John LieskeJohn Lieske More articles by this author , Xiangling WangXiangling Wang More articles by this author , Robin ChirackalRobin Chirackal More articles by this author , John KnoedlerJohn Knoedler More articles by this author , Amy KrambeckAmy Krambeck More articles by this author , Felicity EndersFelicity Enders More articles by this author , Andrew RuleAndrew Rule More articles by this author , Pritha ChananaPritha Chanana More articles by this author , and Muthuvel JayachandranMuthuvel Jayachandran More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.3261AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Randall’s plaques (RP) appear to be an important precursor of urinary stone disease. However, RP cannot be noninvasively detected. Furthermore, the biologic processes that mediate growth of RP remain unclear. This study was designed to identify specific micro RNA (miRNAs) changes within urinary extracellular vesicles (EVs) based on stone forming status, and the amount of intrarenal RP. METHODS A total of 40 subjects were included in this study. First time (incident) stone formers and population controls were recruited from the community (n=10 each). RP were assessed via endoscopic digital imaging with quantitative analysis in consecutive idiopathic calcium oxalate stone formers undergoing percutaneous surgery for stone removal. Subjects with high amounts of RP (HP; > 5% papillary surface area coverage; n=10) were age (+/- 5 yrs) and sex matched to a group with low amounts of RP (LP; < 5% papillary surface area coverage; n=10). Small non-coding miRNAs within urinary EVs were quantitated by XRNA Exosome RNA-Seq Library Kit (System Biosciences, Palo Alto, CA). Differentially expressed miRNAs with a p-value of 0.05 or lower were chosen for pathway analysis and miRNA target prediction comparing LP versus HP, and population controls versus stone formers. RESULTS When controls were compared to stone formers, a total of 10 miRNA were increased (6 to 10-fold), while 5 miRNA were decreased (2 to 5-fold). When LP were compared to HP stone formers, 3 miRNA were increased (6.5 to 10-fold) while 7 miRNA were decreased (6-9 fold). The upregulated miRNAs contribute in calcification, cell proliferation, acute kidney injury, renal fibrosis, pro-apoptotic and pro-inflammatory pathways whereas down-regulated miRNAs contribute anti-apoptotic and anti-inflammatory processes, prevent renal fibrosis, ischemic injury, and progression of chronic kidney disease. CONCLUSIONS Stone formers and those with high amounts of RP excrete distinct populations of miRNAs within urinary EVs. These miRNAs may serve as novel biomarkers to indicate the presence of RP. These miRNAs may also provide new insights into early renal cellular processes in the progression of stone pathogenesis and RP and new tools for the screening, diagnosis, risk stratification and monitoring of pharmacological therapy for persons with idiopathic stone disease. Further studies to validate and extend these observations are needed. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e238 Advertisement Copyright & Permissions© 2017MetricsAuthor Information John Lieske More articles by this author Xiangling Wang More articles by this author Robin Chirackal More articles by this author John Knoedler More articles by this author Amy Krambeck More articles by this author Felicity Enders More articles by this author Andrew Rule More articles by this author Pritha Chanana More articles by this author Muthuvel Jayachandran More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Risk of Chronic Kidney Disease in Brushite Stone Formers Compared With Idiopathic Calcium Oxalate Stone Formers

To study brushite stone formers (BSFs) change in renal function and overall risk of progression to chronic kidney disease (CKD) over time. A retrospective review of all patients with urolithiasis on stone analysis was performed from 1995 to 2003. Stones were classified as brushite if they had at least 10% brushite composition on analysis. Patients with a minimum of 6 years of clinical follow-up were included in the study. BSFs were matched 1:3 to idiopathic calcium oxalate stone formers (CaOx SF) over the same time period. Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease equation. CKD was classified according to the National Kidney Foundation definition, with grade 3 defined as <60 mL/min/1.73 m2. We identified 20 BSFs who met the inclusion criteria and matched to 60 CaOx SFs. Pure brushite stones were identified in 13 (65%) patients and 17 (85%) had >50% brushite composition. The median patient age (48 vs 47 years, P = .82) and baseline eGFR were not different between BSF and CaOx SF (74 vs 69 mL/min/1.73 m2, P = .68). No patients had stage IV or higher CKD in either group. At median follow-up of 13.6 years, both eGFR (78 vs 74 mL/min/1.73 m2, P = .61) and change in eGFR (0.31 vs 3.2 mL/min/1.73 m2, P = .92) were similar between groups despite the BSF having a higher stone recurrence rate (80% vs 42%, P = .003). No brushite patients experienced a change in CKD stage. BSFs were not shown to be at increased clinical risk of CKD compared with CaOx SFs at long-term follow-up despite more frequent stone recurrence.

Characterization of Inner Medullary Collecting Duct Plug Formation Among Idiopathic Calcium Oxalate Stone Formers

To study the prevalence of, risk factors for, and renal functional consequences of ductal plug formation in idiopathic calcium oxalate (iCaOx) stone formers (SF). Accessible renal papillae were videotaped to determine the percent surface area (SA) occupied by plaque and ductal plug in a consecutive cohort of iCaOx SF undergoing percutaneous nephrolithotomy for stone removal. Between 2009 and 2014, iCaOx SF comprised 96 of 240 enrolled patients. Of these, 41 (43%) had ductal plugs. Mean plaque SA did not differ between the low and high % plug groups (2.1% vs 3.4%, respectively). The amounts of mean % SA plaque and ductal plug were not strongly correlated (Spearman's ρ = 0.12, P = .3). Patients with >1% mean SA plug had a higher urinary pH (median 6.5 vs 6.0, P = .02) and elevated urinary hydroxyapatite supersaturation (median 5.4 vs 3.7 delta G; P = .04). Those with >1% plugging had more extensive ductal dilation (P = .002) compared to those with ≤1%. However, estimated glomerular filtration rate was the same (median 75.4 mL/min/1.73 m(2) vs 74.7 mL/min/1.73 m(2)). Number of prior stone events was associated with mean and maximum papillary SA occupied by plug (P < .05 for both), but not plaque (P = .3 and p = .5, respectively). Within a cohort of iCaOx SF, macroscopic plaque and ductal plugs often coexist. Intraluminal features known to favor calcium phosphate crystallization appear to play a role in plug formation. The pathogenic significance of these plugs remains to be established, although their extent appears to correlate with stone burden.

Alexander Randall may have had it right after all.

Several theories exist regarding the pathogenesis of urinary calculi, and the early incipient events leading to calculus formation remain the most controversial. The authors detail a theory by which microscopic Randall plaques (RP) lead to calcium oxalate calculi in idiopathic calcium oxalate stone formers (1). Outlined is a process by which RP form in the basement membrane of the loops of Henle and spread through the interstitium through mineral deposition in an organic matrix, eventually eroding through the urothelium. Once exposed to the urinary milieu, precipitation of minerals and organic substances occurs based on urinary constituents. The process leading to RP formation is not yet fully defined, but one must consider an alternative theory based on a more vascular process. In short, formation may be RP due to a process similar to how atherosclerotic lesions form in arteries as the vasa recta that surround the tubules have turbulent flow, relative hypoxia, and hyperosmolarity which is an ideal environment for vascular injury and a calcifying process. The early events leading to RP and calcium oxalate stone formation has yet to be determined, but is likely multifactorial and represents an area of research fit for collaboration beyond our fellow urologic colleagues.

Biomimetic Randall’s plaque as an in vitro model system for studying the role of acidic biopolymers in idiopathic stone formation

Randall's plaque (RP) deposits seem to be consistent among the most common type of kidney stone formers, idiopathic calcium oxalate stone formers. This group forms calcium oxalate renal stones without any systemic symptoms, which contributes to the difficulty of understanding and treating this painful and recurring disease. Thus, the development of an in vitro model system to study idiopathic nephrolithiasis, beginning with RP pathogenesis, can help in identifying how plaques and subsequently stones form. One main theory of RP formation is that calcium phosphate deposits initially form in the basement membrane of the thin loops of Henle, which then fuse and spread into the interstitial tissue, and ultimately make their way across the urothelium, where upon exposure to the urine, the mineralized tissue serves as a nidus for overgrowth with calcium oxalate into a stone. Our group has found that many of the unusual morphologies found in RP and stones, such as concentrically laminated spherulites and mineralized collagenous tissue, can be reproduced in vitro using a polymer-induced liquid precursor (PILP) process, in which acidic polypeptides induce a liquid phase amorphous precursor to the mineral, yielding non-equilibrium crystal morphologies. Given that there are many acidic proteins and polysaccharides present in the renal tissue and urine, we have put forth the hypothesis that the PILP system may be involved in urolithiasis. Therefore, our goal is to develop an in vitro model system of these two stages of composite stone formation to study the role that various acidic macromolecules may play. In our initial experiments presented here, the development of "biomimetic" RP was investigated, which will then serve as a nidus for calcium oxalate overgrowth studies. To mimic the tissue environment, MatriStem(®) (ACell, Inc.), a decellularized porcine urinary bladder matrix was used, because it has both an intact epithelial basement membrane surface and a tunica propria layer, thus providing the two types of matrix constituents found associated with mineral in the early stages of RP formation. We found that when using the PILP process to mineralize this tissue matrix, the two sides led to dramatically different mineral textures, and they bore a striking resemblance to native RP, which was not seen in the tissue mineralized via the classical crystal nucleation and growth process. The interstitium side predominantly consisted of collagen-associated mineral, while the luminal side had much less mineral, which appeared to be tiny spherules embedded within the basement membrane. Although these studies are only preliminary, they support our hypothesis that kidney stones may involve non-classical crystallization pathways induced by the large variety of macromolecular species in the urinary environment. We believe that mineralization of native tissue scaffolds is useful for developing a model system of stone formation, with the ultimate goal of developing strategies to avoid RP and its detrimental consequences in stone formation, or developing therapeutic treatments to prevent or cure the disease. Supported by NIDDK grant RO1DK092311.

The role of Randall plaques on kidney stone formation.

Randall’s plaque is microscopically a plaque of calcium deposited in the interstitial tissue of the renal papilla. These plaques are thought to serve as a nidus for urinary stone formation. Large amounts of Randall’s plaque are unique to idiopathic calcium oxalate stone formers. Although Randall’s plaques can be found in other stone formers, only in idiopathic calcium oxalate stone formers, the detailed mechanism of stone overgrow on plaque was thoroughly studied. Calcification is invariably located in the basement membrane of the loops of Henle and from there plaques spread through the interstitium toward urothelium. Within the basement membrane, mineral deposits are individual laminated particles in which zones of crystal and organic matrix overlay each other. In the interstitium, the particles appear to fuse on the collagen bundles to form a syncytium of crystal islands in an organic sea. By loss of integrity of urothelium, regions of plaque are exposed to urine. The exposed surface will touch and be covered by molecules of urine origin, including osteopontin, Tamm Horsfall protein, and crystals formed under urine supersaturations, resulting in a ribbon of alternating matrix and crystal. Eventually crystallization escapes from matrix modulation and crystals extend outward into the space of urine and begin to form a calcium oxalate stone proper. Randall’s plaque plays an important role and is prerequisite of kidney stone formation in idiopathic calcium oxalate stone formers.

Contrasting Histopathology and Crystal Deposits in Kidneys of Idiopathic Stone Formers Who Produce Hydroxy Apatite, Brushite, or Calcium Oxalate Stones

Our previous work has shown that stone formers who form calcium phosphate (CaP) stones that contain any brushite (BRSF) have a distinctive renal histopathology and surgical anatomy when compared with idiopathic calcium oxalate stone formers (ICSF). Here we report on another group of idiopathic CaP stone formers, those forming stone containing primarily hydroxyapatite, in order to clarify in what ways their pathology differs from BRSF and ICSF. Eleven hydroxyapatite stone formers (HASF) (2 males, 9 females) were studied using intra-operative digital photography and biopsy of papillary and cortical regions to measure tissue changes associated with stone formation. Our main finding is that HASF and BRSF differ significantly from each other and that both differ greatly from ICSF. Both BRSF and ICSF patients have significant levels of Randall's plaque compared with HASF. Intra-tubular deposit number is greater in HASF than BRSF and nonexistent in ICSF while deposit size is smaller in HASF than BRSF. Cortical pathology is distinctly greater in BRSF than HASF. Four attached stones were observed in HASF, three in 25 BRSF and 5-10 per ICSF patient. HASF and BRSF differ clinically in that both have higher average urine pH, supersaturation of CaP, and calcium excretion than ICSF. Our work suggests that HASF and BRSF are two distinct and separate diseases and both differ greatly from ICSF.

Primary Hyperoxaluria Type III Gene HOGA1 (Formerly DHDPSL) as a Possible Risk Factor for Idiopathic Calcium Oxalate Urolithiasis

Primary hyperoxaluria types I and II (PHI and PHII) are rare monogenic causes of hyperoxaluria and calcium oxalate urolithiasis. Recently, we described type III, due to mutations in HOGA1 (formerly DHDPSL), hypothesized to cause a gain of mitochondrial 4-hydroxy-2-oxoglutarate aldolase activity, resulting in excess oxalate. To further explore the pathophysiology of HOGA1, we screened additional non-PHI-PHII patients and performed reverse transcription PCR analysis. Postulating that HOGA1 may influence urine oxalate, we also screened 100 idiopathic calcium oxalate stone formers. Of 28 unrelated hyperoxaluric patients with marked hyperoxaluria not due to PHI, PHII, or any identifiable secondary cause, we identified 10 (36%) with two HOGA1 mutations (four novel, including a nonsense variant). Reverse transcription PCR of the stop codon and two common mutations showed stable expression. From the new and our previously described PHIII cohort, 25 patients were identified for study. Urine oxalate was lower and urine calcium and uric acid were higher when compared with PHI and PHII. After 7.2 years median follow-up, mean eGFR was 116 ml/min per 1.73 m(2). HOGA1 heterozygosity was found in two patients with mild hyperoxaluria and in three of 100 idiopathic calcium oxalate stone formers. No HOGA1 variants were detected in 166 controls. These findings, in the context of autosomal recessive inheritance for PHIII, support a loss-of-function mechanism for HOGA1, with potential for a dominant-negative effect. Detection of HOGA1 variants in idiopathic calcium oxalate urolithiasis also suggests HOGA1 may be a predisposing factor for this condition.

Oxalate and Sucralose Absorption in Idiopathic Calcium Oxalate Stone Formers

To better understand intestinal oxalate transport by correlating oxalate and sucralose absorption in idiopathic calcium oxalate stone formers. Oxalate has been hypothesized to undergo absorption in the large and small intestine by both paracellular and transepithelial transport. Sucralose is a chlorinated sugar that is absorbed by paracellular mechanisms. Idiopathic calcium oxalate stone formers were recruited to provide urine specimens on both a self-selected diet and after a meal containing 90 mg of (13)C(2-)oxalate and 5 g of sucralose, and a stool sample for determination of Oxalobacter formigenes colonization. The 24-hour urine collections were fractionated into the first 6 hours and the subsequent 18 hours. Sucralose and oxalate excretion were measured during these periods and used to estimate absorption. Thirty-eight subjects were evaluated. The majority of both the (13)C(2-)oxalate and sucralose absorption occurred within the 0-6-hour collection. The (13)C(2-)oxalate and sucralose absorptions were significantly correlated at the 0-6 hour, the 6-24 hour, and the total 24-hour time periods (P <.04). All 5 oxalate hyperabsorbers(>15% absorption) also absorbed significantly more sucralose during the 0-6 hour and whole 24-hour time points (P <.04). Oxalobacter formigenes colonization did not significantly alter oxalate absorption. The results suggest that most oxalate is absorbed in the proximal portion of the gastrointestinal tract and that paracellular transport is involved. Augmented paracellular transport, as evidenced by increased sucralose absorption, may also influence oxalate absorption.

Comparison of the pathology of interstitial plaque in human ICSF stone patients to NHERF-1 and THP-null mice

Extensive evidence now supports the role of papillary interstitial deposits-Randall's plaques-in the formation of stones in the idiopathic, calcium oxalate stone former. These plaques begin as deposits of apatite in the basement membranes of the thin limbs of Henle's loop, but can grow to become extensive deposits beneath the epithelium covering the papillary surface. Erosion of this covering epithelium allows deposition of calcium oxalate onto this plaque material, and the transition of mineral type and organic material from plaque to stone has been investigated. The fraction of the papilla surface that is covered with Randall's plaque correlates with stone number in these patients, as well as with urine calcium excretion, and plaque coverage also correlates inversely with urine volume and pH. Two animal models--the NHERF-1 and THP-null mice--have been shown to develop sites of interstitial apatite plaque in the renal papilla. In these animal models, the sites of interstitial plaque in the inner medulla are similar to that found in human idiopathic calcium oxalate stone formers, except that the deposits in the mouse models are not localized solely to the basement membrane of the thin limbs of Henle's loop, as in humans. This may be due to the different morphology of the human versus mouse papillary region. Both mouse models appear to be important to characterize further in order to determine how well they mimic human kidney stone disease.

Renal histopathology and crystal deposits in patients with small bowel resection and calcium oxalate stone disease

We present here the anatomy and histopathology of kidneys from 11 patients with renal stones following small bowel resection, including 10 with Crohn's disease and 1 resection in infancy for unknown cause. They presented predominantly with calcium oxalate stones. Risks of formation included hyperoxaluria (urine oxalate excretion greater than 45 mg per day) in half of the cases, and acidic urine of reduced volume. As was found with ileostomy and obesity bypass, inner medullary collecting ducts (IMCDs) contained crystal deposits associated with cell injury, interstitial inflammation, and papillary deformity. Cortical changes included modest glomerular sclerosis, tubular atrophy, and interstitial fibrosis. Randall's plaque (interstitial papillary apatite) was abundant, with calcium oxalate stone overgrowth similar to that seen in ileostomy, idiopathic calcium oxalate stone formers, and primary hyperparathyroidism. Abundant plaque was compatible with the low urine volume and pH. The IMCD deposits all contained apatite, with calcium oxalate present in three cases, similar to findings in patients with obesity bypass but not an ileostomy. The mechanisms for calcium oxalate stone formation in IMCDs include elevated urine and presumably tubule fluid calcium oxalate supersaturation, but a low calcium to oxalate ratio. However, the mechanisms for the presence of IMCD apatite remain unknown.

Introduction to special issue on the Proceedings of the 3rd International Urolithiasis Research Symposium held in Indianapolis

The 3rd International Urolithiasis Research Symposium, organized by the International Kidney Stone Institute, was held in Indianapolis, IN, USA, on 3–4 December 2009. The Symposium included special sessions on Nephrocalcinosis, Pediatric Stone Disease, Hypercalciuria and Plaque, and Stone Analysis. There were additionally two sessions on Shock Wave Lithotripsy, looking at renal injury and the mechanisms underlying tissue damage by shock waves. The Symposium also included two live stone surgeries that allowed participants to see two distinctly different pathologies on live video, with added commentary by experts in the auditorium showing biopsy results from similar patients. A main theme running throughout the Symposium was that we have much to learn about the pathologies underlying the different forms of stone disease. For too long these pathologies have been lumped together, but it is quite clear from recent studies in patients that trying to study ‘stone disease’ in a ‘calcium stone’ patient group that includes, for example, both idiopathic calcium oxalate stone formers and patients who form calcium oxalate stones as a consequence of bowel disease is very much a study of ‘‘apples and oranges.’’ Such confusion has clouded work in the past. In contrast, new clarity in this field promises to allow an acceleration of study of the diseases that result in urinary calculi. Included in this second installment of papers from the Symposium is a series comparing renal tissue calcifications between human disease and animal models. Miller et al. show how endoscopic viewing of the calyceal system can allow one to know with certainty which radiologic calcifications are nephrocalcinosis and which are urinary stones, while Khan reviews various animal models of renal calcification. Then Evan et al. relate the pathologic findings of two new mouse models to those found in humans with idiopathic calcium oxalate stone disease. Matlaga et al. give us a review of pediatric stone diseases, and Daudon et al. lead off a series of papers on stone analysis with a comprehensive review of phosphate stones and what is known of their etiology. We end with four papers on the general topic of lithotripsy, highlighted by the study of Shah et al. reporting a novel method to non-invasively displace small stones or stone fragments from the calyceal system to the ureteropelvic junction using pulsed ultrasound. The next International Urolithiasis Research Symposium is scheduled for 16–17 June 2011, again in Indianapolis. We look forward to seeing you there.