Calcium Phosphate Stone Formation Research Articles

#1430 Acid excretion is disturbed in calcium oxalate and calcium phosphate stone formers in the Swiss kidney stone cohort

Abstract Background and Aims Kidney stone is a highly prevalent disease worldwide that causes high morbidity and may increase the risk for chronic kidney disease. Urine pH influences the crystallization of some types of kidney stones, such as calcium phosphate and uric acid. This study aimed to identify whether other acid-base parameters are associated with stone formation in the Swiss kidney stone cohort. Method Urinary, serum, clinical, and anthropomorphic baseline data were obtained from the Swiss Kidney Stone Cohort, a prospective, longitudinal, and multi-centric observational study. We included 200 non-stone formers (NSF, determined by CT scan), and 265 calcium oxalate (CaOx) and 113 calcium phosphate (CaP) stone formers with complete data for urine pH (collected under oil). Titratable acids were calculated based on urine phosphate and creatinine levels and urine bicarbonate based on urine pH. Net acid excretion (NAE) was calculated and NAE capacity (NAEC), the NAE for a given urine pH, which reveals the ability of kidneys to excrete acids, was calculated from the residuals of the relation between urine pH and NAE. Logistic regression analyses were used to estimate the potential contributions of various acid-base variables to the occurrence of CaOx or CaP kidney stones. Odds ratio (OR) are reported as “OR [95% confidence interval]” Results CaOx stone formers were slightly older than NSF individuals and CaP stone formers (NSF = 42.9 ± 13.6 y.o., CaOx = 47.3 ± 14.3 y.o., CaP = 43.3 ± 12.9 y.o.), slightly more overweight (NSF = 25.0 ± 4.15, CaOx = 27.1 ± 4.72, CaP = 25.9 ± 4.55), and had a higher prevalence of males (NSF = 56.0%, CaOx= 72.1%, CaP = 59.3%), but had similar baseline estimated glomerular filtration rate (NSF = 97.1 ± 16.5, CaOx = 96.3 ± 18.3, CaP = 99.5 ± 18.0 ml/min/1.73 m2). Hypertension, type 2 diabetes, pyelonephritis, and nephrocalcinosis were more prevalent among people with either type of kidney stones in comparison with NSFs, while inflammatory bowel disease was more common among CaOx stone formers in comparison with NSF individuals. CaOx and CaP stone formers showed disturbed capacity of excreting acids in relation to NSF (NAEC NSF = 1.81 ± 8.21 µmol/min; CaOx = −1.35 ± 8.45, P < .001; CaP = −0.89 ± 7.66, P = .016) and lower 24 h urine excretion of ammonium (NSF = 19.8 ± 8.70 µmol/min; CaOx = 17.4 ± 8.54, P = .012; CaP = 16.5 ± 8.23, P = .005), but also of citrate, oxalate, and potassium (Table 1). In addition, CaOx exhibited a lower urine volume. In contrast, both CaOx and CaP excreted more calcium (NSF = 3.12 ± 1.85 µmol/min; CaOx = 3.82 ± 1.91 p <0.001; CaP = 4.63 ± 2.27, p <0.001). Urine pH was more acidic in CaOx (p < 0.001) in comparison with NSFs and CaP (P = .004), NSF = 6.05 ± 0.51; CaOx = 5.86 ± 0.53; CaP = 6.16 ± 0.62. The correlations between urine pH and both urine calcium and ammonium were disturbed in CaOx stone formers and shifted in CaP stone formers (Fig. 1). Logistic models including urine ammonium, pH, citrate, phosphate, potassium, calcium, magnesium, oxalate, protein, and volume showed that ammonium is negatively associated with both CaOx and CaP stone formation (unadjusted model OR 0.41[0.26-0.57], p< 0.001 for CaOx and OR 0.42[0.26–0.67], P < .001 for CaP) and urine calcium is positively associated with kidney stones (OR 2.37 [1.72-3.43], P < .001 for CaOx and OR 5.82 [3.6–10.1], P < .001 for CaP). Similar results were obtained after adjustment for age, sex, and BMI. Removing urine ammonium, pH, and phosphate from our logistic model and adding NAEC rendered comparable goodness of fit and model complexity. Holding all other independent variables constant, the odds of CaOx associated with NAEC were 0.45 [0.33–0.61], P < .001 and with calcium of 2.6 [1.91–3.64], P < .001. For CaP, NAEC was still associated with it, but urine magnesium showed a lower odds ratio value (0.44 [0.27–0.72], P = .001 vs 0.54 [0.36–0.80], P = .003). Urine citrate was only associated with CaOx stones. Conclusion Baseline urine ammonium and net acid excretion capacity are strongly associated with the occurrence of CaOx and CaP kidney stones. Reduced NAEC indicates that poor control of ammonium excretion is a hallmark of both types of kidney stones, although more strongly apparent in CaOx.

Contrasting Response of Urine Stone Risk to Medical Treatment in Calcium Oxalate versus Calcium Phosphate Stone Formers.

Randomized controlled trials have shown that both thiazide diuretics and potassium citrate (K-Cit) can prevent calcium stone recurrence, but most participants formed calcium oxalate stones (CaOx). While thiazides are expected to lower stone risk for calcium phosphate (CaP) stones, the effect of K-Cit on risk for CaP stones is unclear. To study the impact of common calcium stones treatments, we analyzed the 24-hour urines of CaOx and CaP stone formers (SF) by 4 treatment types: Lifestyle, K-Cit, Thiazide, or Both medications. Patients treated with thiazides reduced urine calcium in both CaOx (M = -74.4, SD = 94.6 mg/day) and CaP SF (M = -102, SD = 99.7 mg/day), while those on K-Cit had no change in urine calcium. Among CaOx SF, urine citrate rose in patients administered K-Cit with or without thiazide, but citrate did not rise significantly in CaP SF. Urine pH rose in all CaOx SF, but among CaP SF only rose in patients receiving K-Cit. CaOx supersaturation (SS) decreased in all patients who received Thiazide, and decreased among CaOx SF treated with K-Cit. CaP SS decreased in both CaOx SF (M = -0.46, SD = 0.86) and CaP SF (M = -0.76, SD = 0.85) treated with Thiazide except CaOx SF who received Both. Patients treated with K-Cit alone increased CaP SS in CaOx SF (M = 0.25, SD = 0.79). Patients treated with Thiazide lowered urine calcium and SS in both stone groups. Patients treated with K-Cit had no significant changes in urine calcium and had a decrease in CaOx SS in CaOx SF. The study raises questions about the best preventive treatment for patients with CaP stones and suggests that K-Cit may not confer the same benefits on CaP SF as it does on CaOx SF.

Urine pH and Citrate as Predictors of Calcium Phosphate Stone Formation.

Urinary parameters including urine pH and citrate are recognized as critical in the pathophysiology of calcium-based stones. The factors contributing to variation in these parameters between calcium oxalate and calcium phosphate stone formers are however not well understood. In this study using readily available laboratory data, we explore these differences to delineate the odds of forming calcium phosphate (CaP) versus calcium oxalate (CaOx) stones. In this single-center retrospective study, we compared serum and urinary parameters between adult CaP stone formers (SF), CaOx SF, and non-stone formers (NSF). Urine pH was higher and urine citrate lower in CaP SF compared to same-sex CaOx SF and NSF. In CaP SF, higher urine pH and lower citrate were independent of markers of dietary acid intake and gastrointestinal alkali absorption, suggesting abnormal renal citrate handling and urinary alkali excretion. In a multivariable model, urine pH and urine citrate were most discriminatory between CaP SF and CaOx SF (Receiver Operating Characteristic Area Under the Curve of 0.73 and 0.65 respectively). An increase in urine pH by 0.35, a decrease in urine citrate by 220 mg/day, a doubling of urine calcium, and female sex all independently doubled the risk of CaP compared to CaOx. High urine pH and hypocitraturia are two clinical parameters that distinguish the urine phenotype of CaP SF from CaOx SF. The alkalinuria is due to intrinsic differences in the kidney independent of intestinal alkali absorption and is accentuated in the female sex.

Urinary Metabolic Disturbances During Topiramate Use and their Reversibility Following Drug Cessation

ObjectiveTo understand the metabolic disturbances of stone formers currently taking topiramate and to examine the reversibility of these disturbances with cessation of the medication. Materials and MethodsAll progress notes written by 5 endourologists from a single academic center were retrospectively reviewed from January 2010 to July 2020 containing the words “topiramate” or “topamax.” Inclusion criteria were age >18 and presence of either a 24-hour urine sample or stone analysis while on topiramate. In addition, a subgroup of 18 patients with 24-hour urine samples before and after stopping topiramate were identified. ResultsA total of 93 patients were identified and included for final analysis. Twenty-four hour urine samples were available in 67 patients and showed mean citrate excretion of 331 ± 322 mg/d, mean pH of 6.6 ± 0.5, and mean calcium phosphate supersaturation of 1.9 ± 1.1. In the subgroup analysis urinary citrate excretion increased from 225 mg/d to 614 mg/d (P <.01) and pH decreased from 6.59 ± 0.54 to 6.33 ± 0.47 (P = .06) after stopping topiramate. In addition, 114 stone events occurred in 73 distinct patients, with 50% of stones either pure or majority (≥50%) calcium phosphate by composition. ConclusionHypocitraturia and elevated pH is seen during topiramate use with resultant higher rate of calcium phosphate stone formation compared to the general population. Stopping topiramate leads to significant increase in citrate excretion and normalization of pH. These metabolic disturbances appear to be reversible with medication cessation.

Bisphosphonate Use May Reduce the Risk of Urolithiasis in Astronauts on Long-Term Spaceflights.

ABSTRACTLong‐duration spaceflight is associated with an increased risk of urolithiasis, and the pain caused by urinary calculi could result in loss of human performance and mission objectives. The present study investigated the risk of urolithiasis in astronauts during 6 months on the International Space Station, and evaluated whether the suppression of bone resorption by the bisphosphonate, alendronate (ALN), can reduce the risk. A total of 17 astronauts were included into the analysis: exercise using the advanced resistive exercise device (ARED) plus weekly oral 70 mg alendronate (ARED+ALN group, n = 7) was compared to resistive exercise alone (ARED group, n = 10). Urine volume decreased in both groups during spaceflight but recovered after return. The ARED group showed increased urinary calcium excretion from the 15th to 30th day of spaceflight, whereas urinary calcium was slightly decreased in the ARED+ALN group. Urinary N‐terminal telopeptide (NTX) and helical peptide (HP) of type I collagen, as bone resorption markers, were elevated in the ARED group during and until 0 days after spaceflight, while there was no elevation in these parameters in the ARED+ALN group. Urinary oxalate and uric acid excretion tended to be higher in the ARED group than in the ARED+ALN group during spaceflight. These results demonstrate that astronauts on long‐duration spaceflights may be at high risk for the formation of urinary calcium oxalate and calcium phosphate stones through increased urinary excretion of oxalate and uric acid, from degraded type I collagen, as well as of calcium from enhanced bone resorption. Our findings suggest that increased bone resorption during spaceflight, as a risk factor for urinary calculus formation, could be effectively prevented by an inhibitor of bone resorption. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

MP54-13 METABOLIC DISTURBANCES DURING TOPIRAMATE USE AND THEIR REVERSIBILITY FOLLOWING DRUG CESSATION

You have accessJournal of UrologyStone Disease: Epidemiology & Evaluation II (MP54)1 Sep 2021MP54-13 METABOLIC DISTURBANCES DURING TOPIRAMATE USE AND THEIR REVERSIBILITY FOLLOWING DRUG CESSATION Daniel Pelzman, Eman Kazi, and Michelle Semins Daniel PelzmanDaniel Pelzman More articles by this author , Eman KaziEman Kazi More articles by this author , and Michelle SeminsMichelle Semins More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002084.13AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Topiramate is a commonly used medication which inhibits carbonic anhydrase, causing renal tubular acidosis and hypocitraturia, thereby increasing the risk for kidney stone formation. Despite the strong association between topiramate use and kidney stone formation, few studies have examined the characteristics of stone formers taking topiramate. Additionally, the reversibility of the metabolic disturbances with cessation of the medication has not been previously studied. To fill this knowledge gap, we investigated the stone composition and 24-hour urine samples of a large cohort of stone formers taking topiramate. METHODS: All progress notes written by 5 endourologists from a single academic center were retrospectively reviewed from January 2010 to July 2020 containing the words “topiramate” or “topamax.” Inclusion criteria were age >18 and presence of either a 24-hour urine sample or stone analysis while on topiramate. In addition, a subgroup of 17 patients with 24-hour urine samples before and after stopping topiramate were identified. RESULTS: A total of 93 patients were identified and included for final analysis. Twenty-four hour urine samples were available in 65 patients and showed mean citrate excretion of 333 mg/day (95% confidence interval (CI) [254-412]), mean pH of 6.54 (95% CI [6.41-6.68]), and mean calcium phosphate supersaturation of 1.8 (95% CI [1.6-2.1]). In the subgroup analysis, mean urinary citrate excretion increased from 233 mg/day (95% CI [135-330]) to 633 mg/day (95% CI [471-796], p<0.01), and pH decreased from 6.61 (95% CI [6.34-6.89]) to 6.34 (95% CI [6.12-6.56], p=0.06) after stopping topiramate (Figure 1). 114 stone events occurred in 73 distinct patients with 50% either pure or majority (≥50%) calcium phosphate by composition. CONCLUSIONS: Hypocitraturia and elevated pH is seen during topiramate use with resultant higher rate of calcium phosphate stone formation compared to the general population. Stopping topiramate leads to significant increase in citrate excretion and normalization of pH. Patients and providers should be aware of this risk when starting topiramate therapy. These metabolic disturbances appear to be reversible with medication cessation. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e954-e954 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Daniel Pelzman More articles by this author Eman Kazi More articles by this author Michelle Semins More articles by this author Expand All Advertisement Loading ...

MO119COMPUTER-DERIVED SOFTWARE IN CLINICAL PRACTICE: RESULTS FROM A SHORT-TERM FOLLOW-UP ACCORDING TO KIDNEY STONE COMPOSITION IN KIDNEY STONE FORMERS

Abstract Background and Aims Urinary supersaturation (SS) contributes to stone formation, and its assessment in stone formers may be helpful in clinical practice. Several computer programs are available for SS calculation, including EQUIL2, JESS and Lithorisk1. The aim of this study was to evaluate changes in SS in 24-hour urine in patients with known stone composition before and after about three months of regular treatment. Method Patients who submitted their stone/s for composition analysis and had provided an adequate 24-hour urine collection (creatinine 15-20 mg/kg/24-hour) before and around 90 days under regular treatment were included. Stone composition was defined using morphoconstitutional and infrared spectroscopy. The treatment was initiated in accordance with specific guidelines, and included dietary advices and medications2. SS for calcium oxalate (CaOx), calcium phosphate (CaP) and uric acid (UA) using EQUIL2, JESS and Lithorisk were calculated at baseline and after about 90 days on treatment. Continuous variables were reported as means (SD) while categorical variables were reported as frequencies and percentages. Baseline and follow-up SS urine values were compared using the Wilcoxon signed-rank test. 3D graphs were plotted using mean SS values of CaOx, CaP and UA obtained from each program before and after treatment, dividing the stones into 4 groups1: calcium oxalate monohydrate (COM), calcium oxalate dihydrate (COD), calcium phosphate (CaP), and uric acid (UA). Ethical Committee approval was obtained. Results 105 patients (61 men, 58%) were followed and provided 24h urine collection. Of these, 101 (96%) were recurrent patients. The mean (SD) follow-up was 94 (14) days. 48 (46%) of all calculi were made of CaOx, either COM or COD, 36 (34%) of UA, and 21 (20%) of CaP. A significant reduction in SS values during treatment was observed in patients with COM (p&amp;lt;0.05) , COD (p&amp;lt;0.001), and UA stones (p&amp;lt;0.001) with all programs. The reduction in SS values over time in patients with CaP stones was not significant (Table 1). Figure 1 shows 3D plots with SS before and after treatment into 4 groups of stone formers. Conclusion EQUIL2, JESS and Lithorisk are suitable software currently used for clinical and research purposes. SS values calculated by EQUIL2, JESS and Lithorisk during follow-up showed a significant reduction among COM, COD and UA stone formers. CaP stone formers did not show significant changes in SS over time.

The calcium sensing receptor modulates H+-ATPase activity in intercalated cells.

Previous studies found that calcium sensing receptor (CaSR) it's expressed in intercalated cells of the collecting duct and that its activation by calcium in the luminal membrane promotes acidification of urine. Therefore, the aim of the study was to analyze the effects of CaSR stimulus on the biochemical activity of the vacuolar H+-ATPase in a cellular model of intercalated cells, MDCK-C11 cells. Biochemical activity of H+-ATPase was performed using cell homogenates and the inorganic phosphate released was determined by a colorimetric method. Changes in cytosolic ionized calcium ([Ca2+]i) were also determined using Fluo-4. A significant increase of vacuolar H+-ATPase activity was observed when the CaSR was stimulated with agonists such as Gd3+ (300 μM), neomycin (200 μM) and by the calcimimetic R-568 (1 μM). This activity was also stimulated in a dose-dependent fashion by changes in extracellular Ca2+ concentration ([Ca2+]o) between 10-2 and 2 mM. The calciolytic NPS 2143 (150 nM) significantly reduced the vacuolar H+-ATPase activity observed with 2 mM [Ca2+]o. Inhibition of phospholipase C (PLC) activity with U73122 (5 x 10-7 M) reversed the increase in pump activity observed in the presence of Gd3+. Activation of CaSR by the specific CaSR agonist R-568 produced a sustained rise of [Ca2+]i, an effect that disappears when extracellular calcium was removed in the presence of thapsigargin. In summary, CaSR stimulation induces an increase in the vacuolar H+-ATPase activity of MDCK-C11 cells, an effect that involves an increase in [Ca2+]i and require PLC activity. The consequent decrease in intratubular pH could lead to increase ionization of luminal calcium, potentially reducing the formation of calcium phosphate stones.

Re: Urinary Lithogenic Risk Profile in ADPKD Patients Treated with Tolvaptan.

No AccessJournal of UrologyUrological Survey1 Nov 2020Re: Urinary Lithogenic Risk Profile in ADPKD Patients Treated with Tolvaptan Dean G. AssimosMD Dean G. AssimosDean G. Assimos More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001258.01AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "Re: Urinary Lithogenic Risk Profile in ADPKD Patients Treated with Tolvaptan." The Journal of Urology, 204(5), pp. 1090–1091 Suggested Reading : Impact of potassium citrate vs citric acid on urinary stone risk in calcium phosphate stone formers. J Urol 2018; 200: 1278. Link, Google Scholar : Profile of the brushite stone former. J Urol 2010; 184: 1367. Link, Google Scholar : Short-term tolvaptan increases water intake and effectively decreases urinary calcium oxalate, calcium phosphate and uric acid supersaturations. J Urol 2016; 195: 1476. Link, Google Scholar : Nephrolithiasis associated with autosomal dominant polycystic kidney disease: contemporary urological management. J Urol 2000; 163: 726. Link, Google Scholar : Percutaneous nephrolithotomy for large or multiple upper tract calculi and autosomal dominant polycystic kidney disease. J Urol 2010; 183: 183. Link, Google Scholar © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 204Issue 5November 2020Page: 1090-1091 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Dean G. Assimos More articles by this author Expand All Advertisement PDF DownloadLoading ...

A New Discovery of Calcium Phosphate Urinary Stones Formation Induced by Melamine: Nanocrystalline Assembly Mechanism

Summary of main observation and conclusionMelamine (Mel), a contaminant that has received much attention in recent years, has been adulterated into milk powder, causing a large number of infants suffering from kidney stone disease. To study the process and mechanism of calcium phosphate (CaP) stone formation induced by Mel, we simulated the formation process of CaP stones and studied the effect of Mel on crystallization in aqueous and synthetic urine systems, respectively. Ion selective electrode method was used to study the thermodynamic parameters and reaction rate of the crystallization process. It was firstly discovered that Mel could induce the formation of CaP crystals significantly under weak acidic urine conditions in which CaP cannot be stably present, so it may cause people to produce CaP stones. Thermodynamic parameter and reaction rate analysis indicated that Mel could increase the reaction tendency and accelerate the formation of CaP crystals, which was achieved by two process of electrostatic adsorption and release of calcium ions. This research is expected to provide scientific guidance for the prevention and treatment of Mel‐related stones.

Chlorthalidone Is Superior to Potassium Citrate in Reducing Calcium Phosphate Stones and Increasing Bone Quality in Hypercalciuric Stone-Forming Rats.

The pathophysiology of genetic hypercalciuric stone-forming rats parallels that of human idiopathic hypercalciuria. In this model, all animals form calcium phosphate stones. We previously found that chlorthalidone, but not potassium citrate, decreased stone formation in these rats. To test whether chlorthalidone and potassium citrate combined would reduce calcium phosphate stone formation more than either medication alone, four groups of rats were fed a fixed amount of a normal calcium and phosphorus diet, supplemented with potassium chloride (as control), potassium citrate, chlorthalidone (with potassium chloride to equalize potassium intake), or potassium citrate plus chlorthalidone. We measured urine every 6 weeks and assessed stone formation and bone quality at 18 weeks. Potassium citrate reduced urine calcium compared with controls, chlorthalidone reduced it further, and potassium citrate plus chlorthalidone reduced it even more. Chlorthalidone increased urine citrate and potassium citrate increased it even more; the combination did not increase it further. Potassium citrate, alone or with chlorthalidone, increased urine calcium phosphate supersaturation, but chlorthalidone did not. All control rats formed stones. Potassium citrate did not alter stone formation. No stones formed with chlorthalidone, and rats given potassium citrate plus chlorthalidone had some stones but fewer than controls. Rats given chlorthalidone with or without potassium citrate had higher bone mineral density and better mechanical properties than controls, whereas those given potassium citrate did not. In genetic hypercalciuric stone-forming rats, chlorthalidone is superior to potassium citrate alone or combined with chlorthalidone in reducing calcium phosphate stone formation and improving bone quality.

The observation of the effect of sodium potassium citrate on prolonging the retention time of double J tube in vivo

Objective To explore the effect and mechanism of the extension of double-J tube in vivo retention time with sodium potassium citrate. Methods From March 2015 to July 2017, a total of 86 cases who underwent postoperative indwelling double-J tube for long time were selected. All patients were randomly divided into experimental and control groups, the experimental group with oral sodium potassium citrate postoperatively and the control group without special treatment. The differences of urinary scale and calculus of double-J tube were observed in 2, 4 and 6 months after catheterization, and the difficulty of tube extraction was determined. Results Indwelling double-J tube for 2 months, the double-J tube incidence rate of pulling out hard in the experimental group was 2.5%, the incidence rate in the control group was 2.2%, there was no statistical significant difference (P>0.05). Indwelling tube for 4 months, the incidence rate was 5.0% in the experimental group, and 9.1% for the control group.Indwelling tubes for six months, the incidence rate was 10.0% in the experimental group and 15.9% for the control group.The difference had statistical significance (P<0.01). The incidence rate of double-J tube wall stones was 80% in the experimental group, and 89.1% in the control group. The difference was statistically significant. Calcium oxalate and phosphate stones were the main components of the wall stones. Conclusions The difficulty to pull out of the double-J tube is positively correlated with the retention time in the body. Potassium sodium hydrogen citrate can significantly reduce the formation of calcium oxalate and phosphate stones in double-J tube wall, thus prolonging the retention time of double-J tube in vivo and reducing the difficulty of extubation. Key words: Catheters, Indwelling; Sildenafil Citrate

Helper T-cell signaling and inflammatory pathway lead to formation of calcium phosphate but not calcium oxalate stones on Randall's plaques.

To elucidate the difference in the lithogenesis of calcium oxalate and calcium phosphate stones. Renal papillary tissues were obtained from 23 idiopathic calcium oxalate and seven calcium phosphate stone patients who had undergone endoscopic lithotripsy. Samples were individually collected from two different regions in each patient: the papillary mucosa containing Randall's plaque and mucosa not containing Randall's plaque. A microarray analysis was carried out on those tissues to compare their gene expression patterns. Furthermore, a causal pathway analysis comparing their differences was carried out. Cluster analysis showed that gene expression profiles of calcium phosphate stone patients markedly differed from those of calcium oxalate stone patients. Disease and function analysis showed that Randall's plaque-containing tissues of calcium phosphate stone-forming patients had significantly higher movement and migration of mononuclear leukocytes, and lower tendency toward infection and lymph node formation than Randall's plaque-containing tissues of calcium oxalate stone formers. Additional pathway analysis showed increased immune cell signaling in calcium phosphate formers, such as the helper Tcell 1 and 2 pathways, which was confirmed by their messenger ribonucleic acid expression. The present results show the upregulation of helper T-cell signaling pathways in Randall's plaque-containing papillae in calcium phosphate, but not in calcium oxalate stone formers. Thus, helper T-cell immune responses and the related inflammatory processes seem to lead to the formation of calcium phosphate stones on Randall's plaques.

Impact of Potassium Citrate vs Citric Acid on Urinary Stone Risk in Calcium Phosphate Stone Formers

To our knowledge no medication has been shown to be effective for preventing recurrent calcium phosphate urinary stones. Potassium citrate may protect against calcium phosphate stones by enhancing urine citrate excretion and lowering urine calcium but it raises urine pH, which increases calcium phosphate saturation and may negate the beneficial effects. Citric acid can potentially raise urine citrate but not pH and, thus, it may be a useful countermeasure against calcium phosphate stones. We assessed whether these 2 agents could significantly alter urine composition and reduce calcium phosphate saturation. In a crossover metabolic study 13 recurrent calcium phosphate stone formers without hypercalciuria were evaluated at the end of 3, 1-week study phases during which they consumed a fixed metabolic diet and received assigned study medications, including citric acid 30 mEq twice daily, potassium citrate 20 mEq twice daily or matching placebo. We collected 24-hour urine specimens to perform urine chemistry studies and calculate calcium phosphate saturation indexes. Urine parameters did not significantly differ between the citric acid and placebo phases. Potassium citrate significantly increased urine pH, potassium and citrate compared to citric acid and placebo (p <0.01) with a trend toward lower urine calcium (p = 0.062). Brushite saturation was increased by potassium citrate when calculated by the relative supersaturation ratio but not by the saturation index. Citric acid at a dose of 60 mEq per day did not significantly alter urine composition in calcium phosphate stone formers. The long-term impact of potassium citrate on calcium phosphate stone recurrence needs to be studied further.

Calcium-sensing receptor (CaSR) modulates vacuolar H+-ATPase activity in a cell model of proximal tubule.

The calcium-sensing receptor (CaSR) is localized in the apical membrane of proximal tubules in close proximity to the transporters responsible for proton secretion. Therefore, the aim of the present study was to analyze the effects of CaSR stimulation on the biochemical activity of the vacuolar H+-ATPase in a cellular model of proximal tubule cells, OKP cells. Biochemical activity of H+-ATPase was performed using cell homogenates, and the inorganic phosphate released was determined by a colorimetric method. Changes in cytosolic ionized calcium [Ca2+]i were also determined using Fluo-4. A significant increase of vacuolar H+-ATPase activity was observed when the CaSR was stimulated with agonists such as Gd3+ (300µM) and neomycin (200µM). This activity was also stimulated in a dose-dependent fashion by changes in extracellular Ca2+ (Ca2+o) between 10-4 and 2mM. Gd3+ and neomycin produced a sustained rise of [Ca2+]i, an effect that disappears when extracellular calcium was removed in the presence of 0.1µM thapsigargin. Inhibition of phospholipase C (PLC) activity with U73122 (5 × 10-8M) reduced the increase in [Ca2+]i induced by neomycin. CaSR stimulation induces an increase in the vacuolar H+-ATPase activity of OKP cells, an effect that involves an increase in [Ca2+]i and require phospholipase C activity. The consequent decrease in intratubular pH could lead to increase ionization of luminal calcium, potentially enhancing its reabsorption in distal tubule segments and reducing the formation of calcium phosphate stones.

Solubility of calcium oxalate and calcium phosphate crystallization in the presence of crude extract and fractions from Kelussia odoratissima Mozaff

Background and Aim: Urinary tract stones are the third common urinary tract disease that may lead to renal failure. Kelussia odoratissima is traditionally used in the treatment of kidney stones in Chaharmahal va Bakhtiari region. This study was designed to investigate in vitro effect of crude extract and fractions of K. odoratissima on kidney stones (calcium oxalate and calcium phosphate). Materials and Methods: A total of 70% ethanolic extract of K. odoratissima was prepared by maceration method followed by liquid–liquid extraction with hexane, chloroform, ethyl acetate, and saturated n-butanol to get four fractions. Calcium oxalate and calcium phosphate were synthesized and then were treated with hydroalcoholic extract and fractions. Their effects on the dissolution of generated stone were assayed by calcium kit. The stones were synthesized and confirmed by fourier-transform infrared technique. Results: Results showed that total extract and its fractions had significant potency to dissolve calcium oxalate and calcium phosphate crystals. The results indicate the higher potency of fractions containing nonpolar compounds to dissolve calcium phosphate and calcium oxalate stones compared to the fractions containing polar compounds. n-butanolic fraction had the least effect and hexane fraction had the greatest effect on the calcium phosphate stones. Furthermore, the total extract has less dissolution ability, compared to the fractions. Conclusion: The obtained results of this study exhibited that the use of K. odoratissima extract and its fractions could help to dissolve urinary stones. Therefore, it can be effective in prevention and treatment of kidney stones on people who are prone to the formation of calcium oxalate and phosphate stones. Abbreviations Used: Caox: Calcium Oxalate, Caph: Calcium Phosphate, K. odoratissima: Kelussia odoratissima Mozaff

Effect of L-Methionine on the Risk of Phosphate Stone Formation

To determine the physiological effects following administration of the sulfur-containing amino acid L-methionine on urinary risk factors for calcium oxalate and phosphate stone formation under controlled, standardized conditions. Twelve healthy subjects were studied while consuming a standardized diet for 6 days. Day 5 was considered as control day. On day 6 (test day), participants received 1500 mg L-methionine at 9 AM. On the control and test days, 24-hour fractional urine collections were obtained. After single-dose administration of L-methionine, 24-hour fractional urinary pH decreased to values between 5.98 and 6.32. Urinary sulfate excretion, a direct marker for the metabolism of L-methionine, and ammonium excretion, which reflects the increase in net acid production, increased significantly after L-methionine administration. Urinary calcium excretion did not differ between control and test day (5.55 vs 5.45 mmol/24 hours; P = .754). The relative supersaturation of brushite and struvite decreased significantly by 25% (P = .010) and 34% (P = .049), respectively, whereas the risk of calcium oxalate stone formation was not affected by application of L-methionine (P = .477). The present findings show that L-methionine effectively decreases urinary pH and the risk of struvite and calcium phosphate stone formation in healthy subjects. Hypercalciuria is not expected to occur at physiological doses of L-methionine.

MP58-01 DISCOVERY OF RANDALL’S PLAQUE GENE EXPRESSION PROFILING IN CALCIUM OXALATE STONE FORMERS BY IMMUNOHISTOCHEMICAL GENOME-WIDE ANALYSIS

You have accessJournal of UrologyStone Disease: Basic Research & Pathophysiology I1 Apr 2016MP58-01 DISCOVERY OF RANDALL’S PLAQUE GENE EXPRESSION PROFILING IN CALCIUM OXALATE STONE FORMERS BY IMMUNOHISTOCHEMICAL GENOME-WIDE ANALYSIS Kazumi Taguchi, Shuzo Hamamoto, Atsushi Okada, Rei Unno, Hideyuki Kamisawa, Taku Naiki, Ryosuke Ando, Keiichi Tozawa, Kenjiro Kohri, and Takahiro Yasui Kazumi TaguchiKazumi Taguchi More articles by this author , Shuzo HamamotoShuzo Hamamoto More articles by this author , Atsushi OkadaAtsushi Okada More articles by this author , Rei UnnoRei Unno More articles by this author , Hideyuki KamisawaHideyuki Kamisawa More articles by this author , Taku NaikiTaku Naiki More articles by this author , Ryosuke AndoRyosuke Ando More articles by this author , Keiichi TozawaKeiichi Tozawa More articles by this author , Kenjiro KohriKenjiro Kohri More articles by this author , and Takahiro YasuiTakahiro Yasui More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.799AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Randall's plaque (RP) is the origin of renal calcification on which idiopathic calcium oxalate (CaOx) kidney stones develop; however, its exact role in CaOx crystal formation remains unknown. We previously reported the potential therapeutic roles of osteopontin and macrophage (Mϕ) for CaOx kidney stone formation using transgenic mouse and genome-wide analysis. To establish the genomic pathogenesis of RP, we performed a microarray as well as immunohistochemical analysis for comparing the gene expressions among renal papillary RP and normal tissue of 23 CaOx, six calcium phosphate (CaP) stone formers, and normal papillary tissue of seven control patients. METHODS We obtained the papillary tissue samples by cold cup biopsy during retrograde intrarenal surgery or ureteroscopy. Comparisons were made between: 1) RP of CaOx and CaP stone formers; 2) RP and normal tissue of CaOx stone formers and normal tissue of control patients; and 3) between RP and normal tissue of CaOx stone formers. The analyses were performed using GeneSpring13.1® and IPA® software. We then validated the results using reverse transcription-polymerase chain reaction and immunohistochemistry. RESULTS Genes that expressed more than two-fold higher levels in CaP than in CaOx stone formers included fibrinogen, collagens, P38 mitogen-activated protein kinase (MAPK), nuclear factor κB, and chemokines but decreased expressions of immune-related molecules, such as immunoglobulin, interferon-α, and T-cell receptor. Papillary tissue both from RP and normal lesions of CaOx stone-forming patients expressed activated cellular hyperpolarization, reproductive development, and molecular transport. Compared to normal papillary tissue, RP tissue contained upregulated lipocalin 2, interleukin 11, prostaglandin-endoperoxide synthase 1, glutathione peroxidase 3, and monocyte to Mϕ differentiation but downregulation of solute carrier family 12 member 1 and sodium leak channel non-selective (either > 2.0- or 0.5-fold, p < 0.01). Network and toxicity analyses showed that these genes were associated with activated MAPK, the Akt/phosphatidylinositol 3-kinase pathway, and pro-inflammatory cytokines, which caused renal injury and oxidative stress. CONCLUSIONS Our results are the first to establish that genes related to renal dysfunction, pro-inflammation, oxidative stress, and ion transport induce the development of RP in CaOx stone formers. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e775 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Kazumi Taguchi More articles by this author Shuzo Hamamoto More articles by this author Atsushi Okada More articles by this author Rei Unno More articles by this author Hideyuki Kamisawa More articles by this author Taku Naiki More articles by this author Ryosuke Ando More articles by this author Keiichi Tozawa More articles by this author Kenjiro Kohri More articles by this author Takahiro Yasui More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

MP58-06 PREDICTORS OF PROGRESSIVE STONE DISEASE IN CALCIUM PHOSPHATE STONE FORMERS

You have accessJournal of UrologyStone Disease: Basic Research & Pathophysiology I1 Apr 2016MP58-06 PREDICTORS OF PROGRESSIVE STONE DISEASE IN CALCIUM PHOSPHATE STONE FORMERS Steeve Doizi, Margaret Pearle, John Poindexter, Beverley Huet, Khashayar Sakhaee, and Naim Maalouf Steeve DoiziSteeve Doizi More articles by this author , Margaret PearleMargaret Pearle More articles by this author , John PoindexterJohn Poindexter More articles by this author , Beverley HuetBeverley Huet More articles by this author , Khashayar SakhaeeKhashayar Sakhaee More articles by this author , and Naim MaaloufNaim Maalouf More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.804AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES To assess the predictive factors of progressive stone disease in calcium phosphate (CaP) stone formers (SF). METHODS This retrospective single center study included patients with history of CaP stone containing at least 50% of hydroxyapatite or brushite who completed at least two 24 hour urine collections and had annual radiographic follow-up evaluation. Exclusion criteria were: presence of any struvite in stone composition, pregnant women, hyperparathyroidism, distal renal tubular acidosis, neurogenic bladder, eGFR<70mL/min, use of: diuretics, topiramate and calcium. CaP SF included were classified as non-progressors (NP) or progressors (P), defined by new stone formation (new stone of any size detected on imaging, or stone passage if patient was previously stone free) or enlargement of pre-existing stone(s) by at least 2mm in any axis between two identical imaging modalities (kidney-ureter-bladder + ultrasound or CT-scan). We compared 24-hr urinary biochemical parameters at different times: T1 was the first analysis before any medical intervention or dietary instructions, T2 was the first analysis after start of any therapy (diet alone, diet+potassium citrate, diet+potassium citrate+thiazide (hydrochlorothiazide or indapamide)), T3: last analysis available for patients without progression or urine chemistry at time of progression. Saturation (RSR, calculated by EQUIL2) and Supersaturation Index (SI, calculated by JESS) were calculated with respect to brushite (Br). RESULTS 40 patients were included, 19 P and 21 NP. The two groups were comparable for age, gender, BMI, number of previous stone events. Among the different parameters evaluated, total volume, urinary calcium in mg/day, RSR Br and SI Br adjusted by fixed urine volume (2 liters) were significantly higher in P than NP at T1 (Table). Following initial evaluation at T1, more P patients were started on thiazide diuretics. At T2, no biochemical difference between the groups was observed. At T3, pH, RSR Br and SI Br were significantly higher in P compared with NP. In multivariate analysis assessing baseline clinical and biochemical parameters, SI Br/2 liters was the single best predictor of progression with an area under the curve on ROC analysis of 0.78. CONCLUSIONS Brushite supersaturation appears to be the best predictor of progression in calcium phosphate stone formers. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e777-e778 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Steeve Doizi More articles by this author Margaret Pearle More articles by this author John Poindexter More articles by this author Beverley Huet More articles by this author Khashayar Sakhaee More articles by this author Naim Maalouf More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Effect of Potassium Citrate on Calcium Phosphate Stones in a Model of Hypercalciuria.

Potassium citrate is prescribed to decrease stone recurrence in patients with calcium nephrolithiasis. Citrate binds intestinal and urine calcium and increases urine pH. Citrate, metabolized to bicarbonate, should decrease calcium excretion by reducing bone resorption and increasing renal calcium reabsorption. However, citrate binding to intestinal calcium may increase absorption and renal excretion of both phosphate and oxalate. Thus, the effect of potassium citrate on urine calcium oxalate and calcium phosphate supersaturation and stone formation is complex and difficult to predict. To study the effects of potassium citrate on urine supersaturation and stone formation, we utilized 95th-generation inbred genetic hypercalciuric stone-forming rats. Rats were fed a fixed amount of a normal calcium (1.2%) diet supplemented with potassium citrate or potassium chloride (each 4 mmol/d) for 18 weeks. Urine was collected at 6, 12, and 18 weeks. At 18 weeks, stone formation was visualized by radiography. Urine citrate, phosphate, oxalate, and pH levels were higher and urine calcium level was lower in rats fed potassium citrate. Furthermore, calcium oxalate and calcium phosphate supersaturation were higher with potassium citrate; however, uric acid supersaturation was lower. Both groups had similar numbers of exclusively calcium phosphate stones. Thus, potassium citrate effectively raises urine citrate levels and lowers urine calcium levels; however, the increases in urine pH, oxalate, and phosphate levels lead to increased calcium oxalate and calcium phosphate supersaturation. Potassium citrate induces complex changes in urine chemistries and resultant supersaturation, which may not be beneficial in preventing calcium phosphate stone formation.