Idiopathic Calcium Stone Research Articles

Insulin Resistance in Hypercalciuric Calcium Kidney Stone Patients

Rational and ObjectiveDiabetes and uric acid kidney stones are strongly associated. Patients with calcium kidney stones also have higher risk of developing diabetes compared to non-kidney stone patients yet this has not been further investigated. We aimed to characterize insulin resistance in calcium kidney stone patients. Study DesignObservational Setting & PopulationThis study was performed in the University of Chicago Clinical Research Center. Kidney stone patients (N=42) were selected for having idiopathic hypercalciuria and calcium stones with no other medical conditions and controls (N=27) were healthy. ExposuresAll participants presented to the Clinical Research Center in a fasting state and at least 2 timed fasting blood and urine were collected prior to a fixed breakfast. Six additional timed blood and urine collections were performed after breakfast. OutcomesWe compared fasting and fed indices of insulin resistance between the groups. Analytic ApproachWe used t-tests and multivariable linear regression models. A sensitivity analysis removing all patients who had ever been on a thiazide diuretic was also performed. ResultsIn separate multivariable linear models, kidney stone patients had higher fasting serum insulin (24 (3 to 46pmol/L), p=0.03) and higher homeostatic model of insulin resistance (HOMA-IR) (1.0 (0.2 to 1.8), p=0.02). In separate multivariable linear models, kidney stone patients had higher fed serum glucose (10 (2 to 18mg/dL), p=0.01). Results were similar in a sensitivity analysis removing all patients who had ever been on a thiazide diuretic. There were no differences in urine composition based on HOMA-IR levels. LimitationsSingle institution. Small sample size limited subanalyses by different calcium stone types. ConclusionsCalcium kidney stone patients without diabetes or other medical conditions demonstrated signs of insulin resistance compared to healthy matched controls.

The Vitamin D Metabolite Diagnostic Ratio Associates With Phenotypic Traits of Idiopathic Hypercalciuria

IntroductionUnderlying mechanisms for hypercalciuria remain unknown in most cases, hence the designation “idiopathic”. We hypothesized that the Vitamin D-inactivating enzyme CYP24A1 contributes to the pathogenesis of hypercalciuria in kidney stone formers. MethodsWe conducted association analyses between CYP24A1 activity, estimated by the Vitamin D metabolite diagnostic ratio (25(OH) Vitamin D3/total 24,25 (OH)2 Vitamin D ratio; VMDR), and the phenotype of participants in two observational cohorts of kidney stone formers, the Swiss Kidney Stone Cohort and the Bern Kidney Stone Registry. Circulating 25(OH)- and 24,25 (OH)2 Vitamin D were quantified using a validated LC-MS/MS assay. Results974 participants were included in the analysis. We found a positive association of VMDR (and hence negative association of CYP24A1 activity) with total (β 0.009 mmol/L; 95% CI 0.002, 0.016; p = 0.02) and ionized plasma calcium (β 0.005 mmol/L; 95% CI 0.002, 0.008; p < 0.01), absolute and fractional excretion of urinary calcium (β 0.054 mmol/24h; 95% CI 0.010, 0.097; p = 0.02 and β 0.046 %; 95% CI 0.018, 0.074; p < 0.01, respectively). Further, VMDR was associated with an increased likelihood of forming calcium oxalate dihydrate stones (Odds ratio 1.64; 95% CI 1.22, 2.35; p < 0.01) and reduced bone mineral density at the femoral neck (β -0.005 g/cm2; 95% CI -0.010, -0.001; p = 0.04). The described associations became stronger when the analysis was confined to idiopathic calcium stone formers. ConclusionOur study reveals that CYP24A1 activity, estimated by VMDR, is associated with clinical traits previously linked to idiopathic hypercalciuria.

Water Loading and Uromodulin Secretion in Healthy Individuals and Idiopathic Calcium Stone Formers.

Uromodulin is a protein made only by the kidney and released in urine, circulating in polymerizing and nonpolymerizing forms. This protein's multiple functions include inhibition of stone formation in the urine. The physiological determinants of uromodulin production are incompletely understood. We investigated changes in uromodulin levels and key factors governing its production and release in urine and serum. We performed an experiment to determine whether water loading, a common intervention to prevent stone formation, will alter the rate of uromodulin production. During a 2-day period, 17 stone forming participants and 14 control participants were subjected to water loading (day 1) and normal fluid intake (day 2). Uromodulin levels were measured on timed hourly collections in urine and plasma during the period of the study. Water loading increased urinary uromodulin secretion (33±4 versus 10±4 μ g/min at baseline, P < 0.0001) in stone formers and control participants. Despite high urine volumes, most participants maintained relatively stable urinary uromodulin concentrations. Native Western blots for polymerizing and nonpolymerizing uromodulin suggest that polymerizing uromodulin was the predominant form at higher urinary flow volumes. Urine flow rates and sodium excretion were significant correlates of urinary uromodulin production. Water loading did not affect serum uromodulin levels, which were also not associated with urinary uromodulin. Water loading increases the secretion of polymerizing urinary uromodulin. This increased secretion reduces the variability of urinary uromodulin concentrations despite high urine volumes. Serum uromodulin levels were not affected by this treatment.

Мочекаменная болезнь на фоне почечного канальцевого ацидоза.

Introduction. Distal renal tubular acidosis (dRTA) is a rare cause of stone formation in urolithiasis patients according to the conventional wisdom in the urological community. At the same time prevalence of the incomplete dRTA in patients with idiopathic calcium stones is 16.8% (13.6% in men and 25.5% in women) according to the recent studies. Previously, we published a review article, which describes the features of the dRTA etiology and pathogenesis, and presents diagnostic and treatment algorithms. We consider it interesting to present a clinical case in continuation of the previous publication. Clinical case. There are anamnesis data, results of laboratory and instrumental analysis of the patient Zh. with a urolithiasis and renal tubular acidosis are presented. The patient was prescribed a long course of conservative citrate and thiazide diuretics therapy. The patient managed to achieve normalization of the main parameters of blood and urine, stable remission of the disease against the background of ongoing therapy. Conclusions, patients with distal renal tubular acidosis and urolithiasis are quite common in the clinical practice of urologist. Timely diagnosis of the disease and the appointment of adequate therapy can improve the quality of patient's life and reduce the number of stone relapses.

Clinical Effectiveness of Calcium Oxalate Stone Treatments

Introduction: Lowering kidney stone risk and urine calcium oxalate supersaturation is a primary clinical focus for kidney stone prevention and can be achieved with multiple strategies. Common strategies include advice to increase fluid intake, restrict dietary sodium, or prescribing a thiazide-type diuretic. We investigated how physicians make these decisions in real-world practice and evaluate their efficacy based on 24-h urine collections. Methods: We reviewed medical charts for 203 kidney stone formers with idiopathic calcium stones from University of Chicago Kidney Stone Clinic between 2005 and 2020. Patients had three 24-h urines before an initial pre-treatment clinic visit and one follow-up 24-h urine. We analyzed changes in urine composition based on treatment advice using t tests and ANOVA. Results: Patients who received advice to increase fluid intake had lower urine volume at baseline (1.5 vs. 2.5 L/day, p < 0.001) and larger increase in urine volume at follow-up (0.6 vs. 0.1 L/day, p < 0.001) compared to those who did not receive the advice. Patients who were advised to restrict dietary sodium had a higher urine sodium at baseline (208 vs. 139 mEq/day, p < 0.001), a larger reduction in urine sodium (−28 vs. 13 mEq/day, p = 0.002), and larger reduction in urine calcium (−74 vs. −28 mg/day, p = 0.005) compared with those not advised to restrict dietary sodium. Patients started on a thiazide had a higher baseline urine calcium (281 vs. 213 mg/day) and larger reduction in urine calcium (−83 vs. −9 mg/day, p < 0.001) compared with patients not started on a thiazide. In combination, thiazide prescriptions with dietary sodium restriction reduced urine calcium by 99 mg/day and reduced calcium oxalate supersaturation from 8.0 to 5.5 and calcium phosphate supersaturation from 1.4 to 1.0. Conclusion: Providers use 24-h urine data to guide treatment strategy decisions. These strategies achieved the intended effects on urine composition and lowered kidney stone risk.

Prospective long-term evaluation of incomplete distal renal tubular acidosis in idiopathic calcium nephrolithiasis diagnosed by low-dose NH4CL loading – gender prevalences and impact of alkali treatment

PurposeProspective evaluation of the prevalence of incomplete distal renal tubular acidosis (idRTA) in idiopathic calcium stone formers (ICSF) diagnosed by half-dose ammonium chloride loading (NH4Cl, 0.05 g/kg body weight/day) and impact of alkali treatment of idRTA.MethodsEvaluation of 386 consecutive idiopathic calcium stone formers (ICSF) (280 males, 106 females) for idRTA. If screening fasting urine pH was > 5.80, 1-day NH4Cl loading was performed without severe adverse effects. Normally, urine pH falls below 5.45.ResultsSixty-four idiopathic calcium stone formers exhibited idRTA, one complete dRTA. Prevalence was higher in women (25.4%) than in men (13.6%). Thus, for more equilibrated comparisons, we formed pairs of 62 idiopathic calcium stone formers (ICSF) with and 62 without idRTA, matched for gender, age, BMI and serum creatinine. Idiopathic calcium stone formers with idRTA more often had hypercalciuria (p < 0.025) and urine citrate < 2 mmol/d (p < 0.05), formed calcium phosphate stones more frequently, exhibited higher numbers of stones/year (1.4 ± 1.5 vs. 0.9 ± 0.8, p = 0.034) and 2.5 times more intrarenal calcifications (4.6 ± 5.9 vs. 1.8 ± 3.6, p = 0.002). All idiopathic calcium stone formers with idRTA were recommended chronic alkali therapy. After 4–15 years of follow-up, stone events /years follow-up (stone passage or urologic intervention) were higher in patients non-adherent to alkali therapy (0.61 ± 0.92) than in patients adherent to treatment (0.11 ± 0.21, p = 0.006).Conclusion Incomplete distal renal tubular acidosis is 1.8-fold more prevalent among female idiopathic calcium stone formers, predicts more stone recurrences, predisposes to calcium phosphate stones and is associated with 2.5 times more intrarenal calcifications vs. non-idRTA patients. Chronic alkali treatment reduces clinical stone recurrences by 5.5 times.Graphical abstract

Recurrence prevention of kidney stones - pharmacologic and dietary measures

Recurrence prevention of kidney stones - pharmacologic and dietary measures Abstract. Kidney stone episodes are traumatic events for affected patients and the risk of recurrence is high. Both prevalence and incidence of kidney stone disease are rising globally, and associated cost are gigantic. Hence, effective, well-tolerated and cheap measures for recurrence prevention are of utmost importance. In this article, we summarize the possibilities for the prevention of idiopathic calcium stones and uric acid stones, which together are responsible for the bulk of kidney stone episodes. Formally, preventive measures can be divided into dietary and pharmacologic interventions. In daily practice, frequently both approaches have to be combined to achieve a successful long-term recurrence prevention. The biggest challenge in the recurrence prevention of kidney stones is to achieve a sustained adherence to preventive measures in the affected patients.

Dent disease: A window into calcium and phosphate transport.

This review examines calcium and phosphate transport in the kidney through the lens of the rare X‐linked genetic disorder Dent disease. Dent disease type 1 (DD1) is caused by mutations in the CLCN5 gene encoding ClC‐5, a Cl−/H+ antiporter localized to early endosomes of the proximal tubule (PT). Phenotypic features commonly include low molecular weight proteinuria (LMWP), hypercalciuria, focal global sclerosis and chronic kidney disease; calcium nephrolithiasis, nephrocalcinosis and hypophosphatemic rickets are less commonly observed. Although it is not surprising that abnormal endosomal function and recycling in the PT could result in LMWP, it is less clear how ClC‐5 dysfunction disturbs calcium and phosphate metabolism. It is known that the majority of calcium and phosphate transport occurs in PT cells, and PT endocytosis is essential for calcium and phosphorus reabsorption in this nephron segment. Evidence from ClC‐5 KO models suggests that ClC‐5 mediates parathormone endocytosis from tubular fluid. In addition, ClC‐5 dysfunction alters expression of the sodium/proton exchanger NHE3 on the PT apical surface thus altering transcellular sodium movement and hence paracellular calcium reabsorption. A potential role for NHE3 dysfunction in the DD1 phenotype has never been investigated, either in DD models or in patients with DD1, even though patients with DD1 exhibit renal sodium and potassium wasting, especially when exposed to even a low dose of thiazide diuretic. Thus, insights from the rare disease DD1 may inform possible underlying mechanisms for the phenotype of hypercalciuria and idiopathic calcium stones.

Nephrolithiasis secondary to inherited defects in the thick ascending loop of henle and connecting tubules.

Twin and genealogy studies suggest a strong genetic component of nephrolithiasis. Likewise, urinary traits associated with renal stone formation were found to be highly heritable, even after adjustment for demographic, anthropometric and dietary covariates. Recent high-throughput sequencing projects of phenotypically well-defined cohorts of stone formers and large genome-wide association studies led to the discovery of many new genes associated with kidney stones. The spectrum ranges from infrequent but highly penetrant variants (mutations) causing mendelian forms of nephrolithiasis (monogenic traits) to common but phenotypically mild variants associated with nephrolithiasis (polygenic traits). About two-thirds of the genes currently known to be associated with nephrolithiasis code for membrane proteins or enzymes involved in renal tubular transport. The thick ascending limb of Henle and connecting tubules are of paramount importance for renal water and electrolyte handling, urinary concentration and maintenance of acid-base homeostasis. In most instances, pathogenic variants in genes involved in thick ascending limb of Henle and connecting tubule function result in phenotypically severe disease, frequently accompanied by nephrocalcinosis with progressive CKD and to a variable degree by nephrolithiasis. The aim of this article is to review the current knowledge on kidney stone disease associated with inherited defects in the thick ascending loop of Henle and the connecting tubules. We also highlight recent advances in the field of kidney stone genetics that have implications beyond rare disease, offering new insights into the most common type of kidney stone disease, i.e., idiopathic calcium stone disease.

Changes in renal papillary density after hydration therapy in calcium stone formers

BackgroundPrevious studies have shown that, compared with non-stone formers, stone formers have a higher papillary density measured with computer tomography (CT) scan. The effect of increased hydration on such papillary density in idiopathic calcium stone formers is not known.MethodsPatients with recurrent calcium oxalate stones undergoing endourological procedures for renal stones at our Institution from June 2013 to June 2014 were considered eligible for enrolment. Enrolled patients underwent a baseline unenhanced CT scan before the urological procedure; after endoscopic removal of their stones, the patients were instructed to drink at least 2 L/day of a hypotonic, oligomineral water low in sodium and minerals (fixed residue at 180 °C < 200 mg/L) for at least 12 months. Finally, the patients underwent a follow-up unenhanced CT scan during hydration regimen.ResultsTwenty-five patients were prospectively enrolled and underwent baseline and follow-up CT scans. At baseline, mean papillary density was 43.2 ± 6.6 Hounsfield Units (HU) (43.2 ± 6.7 for the left kidney and 42.8 ± 7.1 HU for the right kidney). At follow-up and after at least 12 months of hydration regimen, mean papillary density was significantly reduced at 35.4 ± 4.2 HU (35.8 ± 5.0 for the left kidney and 35.1 ± 4.2 HU for the right kidney); the mean difference between baseline and follow-up was − 7.8 HU (95% confidence interval − 10.6 to − 5.1 HU, p < 0.001).ConclusionsIncreased fluid intake in patients with recurrent calcium oxalate stones was associated with a significant reduction in renal papillary density.Trial registrationNCT03343743, 15/11/2017 (Retrospectively registered).

Understanding the gut–kidney axis in nephrolithiasis: an analysis of the gut microbiota composition and functionality of stone formers

ObjectivesThe involvement of the gut microbiota in the pathogenesis of calcium nephrolithiasis has been hypothesised since the discovery of the oxalate-degrading activity of Oxalobacter formigenes, but never comprehensively studied with...

PD03-06 PLAQUE, PITTING, CONTOUR LOSS - A PATHOGENETIC SEQUENCE IN RENAL PAPILLAE OF IDIOPATHIC CALCIUM STONE FORMERS

You have accessJournal of UrologyStone Disease: Basic Research & Pathophysiology I1 Apr 2018PD03-06 PLAQUE, PITTING, CONTOUR LOSS - A PATHOGENETIC SEQUENCE IN RENAL PAPILLAE OF IDIOPATHIC CALCIUM STONE FORMERS Melanie Adamsky, Andrew Cohen, Christopher Riedinger, Glenn Gerber, Elaine Worcester, and Frederic Coe Melanie AdamskyMelanie Adamsky More articles by this author , Andrew CohenAndrew Cohen More articles by this author , Christopher RiedingerChristopher Riedinger More articles by this author , Glenn GerberGlenn Gerber More articles by this author , Elaine WorcesterElaine Worcester More articles by this author , and Frederic CoeFrederic Coe More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.272AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Renal papillary abnormalities are thought to have deeper roots in renal physiology and stone pathogenesis. A unifying hypothesis is that Randall′s plaque (RP) production is continuous, plaque loss gives rise to pitting, and this loss of tissue gives rise to changes in papillary contour (Figure 1). We have tested these predictions in a cohort of idiopathic calcium stone formers (ICSF). METHODS A previously described renal papillary grading system, which quantifies the degree of RP, pitting, plugging, and contour on each papillum, was applied to ICSF during ureteroscopy. We performed 2x2 table analysis of relationships between the scores for each papillary feature at the level of the papillum and the level of the kidney. Finally, we calculated mean scores for each feature by kidney and used Pearson correlation coefficients to measure relationships between features at the kidney level. RESULTS 85 patients were included with a total of 361 papillae graded. In table analysis of pitting scores by plaque scores, values deviated powerfully from chance (X2=63.997, p<0.00001). Increasing plaque scores were associated with decreasing percentage of pitting score zero. The presence of plaque without pitting is more often seen than pitting without plaque. A similar but less pronounced relationship was seen in the analysis of contour loss by pitting scores (X2= 35.9461, p=0.0029). Furthermore, contour loss and plaque scores showed a very strong relationship (X2 = 57.2033, p<0.00001). Results of the papillum-level analysis are summarized in Figure 2. At the level of the kidney, the strongest relationship exists between mean RP and mean contour scores (rp=0.4630, p=0.0003). CONCLUSIONS These data support our critical hypothesis that RP and attached calcium stone complex are shed from the papillum leaving behind a pitting defect on the papillary surface, which can then either heal over or, with repeated insult, progress to loss of papillary contour. We believe that understanding this sequence helps link renal physiology to a urologic endpoint. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e72-e73 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Melanie Adamsky More articles by this author Andrew Cohen More articles by this author Christopher Riedinger More articles by this author Glenn Gerber More articles by this author Elaine Worcester More articles by this author Frederic Coe More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Effectiveness of Treatment Modalities on Kidney Stone Recurrence.

Nephrolithiasis is highly prevalent across all demographic groups in the Western world and beyond, and its incidence rates are rising. In addition to the morbidity of the acute event, stone disease often becomes a lifelong problem that requires preventative therapy to diminish ongoing morbidity. Across the majority of stone types, increased fluid intake and targeted dietary modifications are mainstays of therapy. Specific dietary interventions associated with reduced calcium stone risk include adequate dietary calcium intake and restriction of sodium, protein, and oxalate intake, among others. Pharmaceutical therapy may be required if lifestyle changes are insufficient to minimize risk of stone recurrence, and must be targeted to the specific metabolic abnormalities portending risk for a given patient. Therapeutic options for idiopathic calcium stone disease include thiazides, citrate salts, and uric acid-lowering agents. Alkali salts are also the treatment of choice for uric acid stone disease. Management of struvite stone disease is largely surgical, but acetohydroxamic acid is a proven second line therapy. Cystinuria requires lifestyle modifications and may call for thiol-binding agents. Significant heterogeneity of the clinical population with stone disease has previously limited opportunities for large randomized controlled trials. However, as clinical phenotypes and genotypes are increasingly clarified, there are mounting opportunities for targeted randomized controlled trials in stone prevention. In the meantime, the currently available evidence for both lifestyle and pharmacologic interventions is reviewed herein.

MP90-04 A NOVEL USE OF STRUCTURED WATER FOR THE PREVENTION OF RECURRENT STONES IN IDIOPATHIC HYPERCALCIURIA.

You have accessJournal of UrologyStone Disease: Medical & Dietary Therapy1 Apr 2017MP90-04 A NOVEL USE OF STRUCTURED WATER FOR THE PREVENTION OF RECURRENT STONES IN IDIOPATHIC HYPERCALCIURIA. Ali Sami Ali SamiAli Sami More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2823AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The majority of stones (85%) contain primarily calcium oxalate. Most renal stones are idiopathic calcium stones, and the most common predisposing factor in these patients is hypercalciuria. Structured water is a new type of water that has been prepared using different types of energy fields and modulators to produce this structured water that has new and different characteristics from the ordinary water. In this study, we compared the efficacy of the structured water (Magnalife®) with hydrochlorothiazide and with ordinary bottled water in the prevention of recurrent renal stones in patients with idiopathic hypercalciuria. METHODS We conducted a three-year randomized trial comparing the effect of structured water with the effect of hydrochlorothiazide and ordinary bottled water in 300 patients with recurrent calcium oxalate stones and hypercalciuria. 100 men used structured water (Magnalife®). The other 100 men used 50 mg hydrochlorothiazide, and 100 men used ordinary bottled water. Urine analysis with renal ultrasonography and radiology were done at baseline and at yearly intervals and any time of recurrence and at the end of the 3 years (36th month). All patients were informed and signed a written informed consent form. RESULTS Of the 300 men included in this study, 95 had recurrent stones, 15 men (15%) in the group of structured water ,31 men (31%) in the hydrochlorothiazide group, and 49 men (49%) in the group of ordinary bottled water. The difference in the recurrence rate between the structured water group and the hydrochlorothiazide group is significant (P=0.007) Also the difference between the difference between the structured water group and the ordinary water group is significant (p<0.001), furthermore the hydrochlorothiazide group and the ordinary bottled water group recurrence rate is significantly different (P=0.009). CONCLUSIONS Structured water is a safe, effective, and affordable new way to prevent recurrent urinary stones without the need for medications that are expensive and have many side effects. Furthermore, it is more potent than some preventive measures and drugs as a prophylactic way against recurrent urinary stones. It is far more effective than ordinary bottled water in preventing recurrent stones. Further studies are recommended to explore its role in other fields of urology. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1211 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Ali Sami More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Idiopathic hypercalciuria and formation of calcium renal stones

The most common presentation of nephrolithiasis is idiopathic calcium stones in patients without systemic disease. Most stones are primarily composed of calcium oxalate and form on a base of interstitial apatite deposits, known as Randall's plaque. By contrast some stones are composed largely of calcium phosphate, as either hydroxyapatite or brushite (calcium monohydrogen phosphate), and are usually accompanied by deposits of calcium phosphate in the Bellini ducts. These deposits result in local tissue damage and might serve as a site of mineral overgrowth. Stone formation is driven by supersaturation of urine with calcium oxalate and brushite. The level of supersaturation is related to fluid intake as well as to the levels of urinary citrate and calcium. Risk of stone formation is increased when urine citrate excretion is <400 mg per day, and treatment with potassium citrate has been used to prevent stones. Urine calcium levels >200 mg per day also increase stone risk and often result in negative calcium balance. Reduced renal calcium reabsorption has a role in idiopathic hypercalciuria. Low sodium diets and thiazide-type diuretics lower urine calcium levels and potentially reduce the risk of stone recurrence and bone disease.

Dietary recommendations and treatment of patients with recurrent idiopathic calcium stone disease.

This review describes the various dietary regimens that have been used to advise patients on how to prevent the recurrence of their calcium-containing kidney stones. The conclusion is that although there is some general advice that may be useful to many patients, it is more efficacious to screen each patient individually to identify his/her main urinary, metabolic, nutritional, environmental, and lifestyle risk factors for stone-formation and then tailor specific advice for that particular patient based on the findings from these investigations. If the patient can be motivated to adhere strictly to this conservative approach to the prophylactic management of their stone problem over a long time period, then it is possible to prevent them from forming further stones. This approach to stone management is considerably less expensive than any of the procedures currently available for stone removal or disintegration. In the UK, for each new stone episode prevented by this conservative approach to prophylaxis it is calculated to save the Health Authority concerned around £2000 for every patient treated successfully. In the long term, this accumulates to a major saving within each hospital budget if most stone patients can be prevented from forming further stones and when the savings are totalled up country-wide saves the National Exchequer considerable sums in unclaimed Sick Pay and industry a significant number of manpower days which would otherwise be lost from work. It is also of immense relief and benefit to the patients not to have to suffer the discomfort and inconvenience of further stone episodes.

Biopsy proven medullary sponge kidney: clinical findings, histopathology, and role of osteogenesis in stone and plaque formation.

Medullary sponge kidney (MSK) is associated with recurrent stone formation, but the clinical phenotype is unclear because patients with other disorders may be incorrectly labeled MSK. We studied 12 patients with histologic findings pathognomonic of MSK. All patients had an endoscopically recognizable pattern of papillary malformation, which may be segmental or diffuse. Affected papillae are enlarged and billowy, due to markedly enlarged inner medullary collecting ducts (IMCD), which contain small, mobile ductal stones. Patients had frequent dilation of Bellini ducts, with occasional mineral plugs. Stones may form over white (Randall's) plaque, but most renal pelvic stones are not attached, and have a similar morphology as ductal stones, which are a mixture of calcium oxalate and apatite. Patients had no abnormalities of urinary acidification or acid excretion; the most frequent metabolic abnormality was idiopathic hypercalciuria. Although both Runx2 and Osterix are expressed in papillae of MSK patients, no mineral deposition was seen at the sites of gene expression, arguing against a role of these genes in this process. Similar studies in idiopathic calcium stone formers showed no expression of these genes at sites of Randall's plaque. The most likely mechanism for stone formation in MSK appears to be crystallization due to urinary stasis in dilated IMCD with subsequent passage of ductal stones into the renal pelvis where they may serve as nuclei for stone formation.

The relationship between calcium kidney stones, arterial stiffness and bone density: unraveling the stone-bone-vessel liaison.

Kidney stone disease is associated with a higher incidence of cardio-vascular (CV) events for still unclear reasons. Reduced bone density is also a frequent finding in calcium kidney stones. The association of reduced bone density with increased vascular stiffness and calcification has been discovered in a number of conditions. We investigated the hypothesis that patients with calcium kidney stones have increased arterial stiffness, which would be associated with reduced bone density and higher CV risk. We compared measures of arterial stiffness [carotid-radial pulse-wave velocity (CR-PWV), carotid-femoral pulse-wave velocity (CF-PWV) and augmentation index (AI)] and of bone density (T-scores determined at lumbar spine, neck and hip) among 42 idiopathic calcium stone formers compared with 42 age- and sex-matched healthy volunteers. Stone formers had higher values of CR-PWV, CF-PWV and AI, and lower values of all T-scores. Furthermore, the prevalence of abnormal arterial stiffness and reduced bone density was significantly higher among stone formers. Statistical adjustment for age, sex, body mass index and other covariates did not change the results. Our study confirms that stone formers have increased arterial stiffness and reduced bone density. Abnormal arterial stiffness appears to be independent of reduced bone density and may explain the higher CV risk observed in stone formers.

Unified theory on the pathogenesis of Randall's plaques and plugs.

Kidney stones develop attached to sub-epithelial plaques of calcium phosphate (CaP) crystals (termed Randall's plaque) and/or form as a result of occlusion of the openings of the Ducts of Bellini by stone-forming crystals (Randall's plugs). These plaques and plugs eventually extrude into the urinary space, acting as a nidus for crystal overgrowth and stone formation. To better understand these regulatory mechanisms and the pathophysiology of idiopathic calcium stone disease, this review provides in-depth descriptions of the morphology and potential origins of these plaques and plugs, summarizes existing animal models of renal papillary interstitial deposits, and describes factors that are believed to regulate plaque formation and calcium overgrowth. Based on evidence provided within this review and from the vascular calcification literature, we propose a "unified" theory of plaque formation-one similar to pathological biomineralization observed elsewhere in the body. Abnormal urinary conditions (hypercalciuria, hyperoxaluria, and hypocitraturia), renal stress or trauma, and perhaps even the normal aging process lead to transformation of renal epithelial cells into an osteoblastic phenotype. With this de-differentiation comes an increased production of bone-specific proteins (i.e., osteopontin), a reduction in crystallization inhibitors (such as fetuin and matrix Gla protein), and creation of matrix vesicles, which support nucleation of CaP crystals. These small deposits promote aggregation and calcification of surrounding collagen. Mineralization continues by calcification of membranous cellular degradation products and other fibers until the plaque reaches the papillary epithelium. Through the activity of matrix metalloproteinases or perhaps by brute physical force produced by the large sub-epithelial crystalline mass, the surface is breached and further stone growth occurs by organic matrix-associated nucleation of CaOx or by the transformation of the outer layer of CaP crystals into CaOx crystals. Should this theory hold true, developing an understanding of the cellular mechanisms involved in progression of a small, basic interstitial plaque to that of an expanding, penetrating plaque could assist in the development of new therapies for stone prevention.

Interstitial calcinosis in renal papillae of genetically engineered mouse models: relation to Randall's plaques.

Genetically engineered mouse models (GEMMs) have been highly instrumental in elucidating gene functions and molecular pathogenesis of human diseases, although their use in studying kidney stone formation or nephrolithiasis remains relatively limited. This review intends to provide an overview of several knockout mouse models that develop interstitial calcinosis in the renal papillae. Included herein are mice deficient for Tamm-Horsfall protein (THP; also named uromodulin), osteopontin (OPN), both THP and OPN, Na(+)-phosphate cotransporter Type II (Npt2a) and Na(+)/H(+) exchanger regulatory factor (NHERF-1). The baseline information of each protein is summarized, along with key morphological features of the interstitial calcium deposits in mice lacking these proteins. Attempts are made to correlate the papillary interstitial deposits found in GEMMs with Randall's plaques, the latter considered precursors of idiopathic calcium stones in patients. The pathophysiology that underlies the renal calcinosis in the knockout mice is also discussed wherever information is available. Not all the knockout models are allocated equal space because some are more extensively characterized than others. Despite the inroads already made, the exact physiological underpinning, origin, evolution and fate of the papillary interstitial calcinosis in the GEMMs remain incompletely defined. Greater investigative efforts are warranted to pin down the precise role of the papillary interstitial calcinosis in nephrolithiasis using the existing models. Additionally, more sophisticated, second-generation GEMMs that allow gene inactivation in a time-controlled manner and "compound mice" that bear several genetic alterations are urgently needed, in light of mounting evidence that nephrolithiasis is a multifactorial, multi-stage and polygenic disease.