Calcium Phosphate Supersaturation Research Articles

The Rise in Tubular pH during Hypercalciuria Exacerbates Calcium Stone Formation.

In calcium nephrolithiasis (CaNL), most calcium kidney stones are identified as calcium oxalate (CaOx) with variable amounts of calcium phosphate (CaP), where CaP is found as the core component. The nucleation of CaP could be the first step of CaP+CaOx (mixed) stone formation. High urinary supersaturation of CaP due to hypercalciuria and an elevated urine pH have been described as the two main factors in the nucleation of CaP crystals. Our previous in vivo findings (in mice) show that transient receptor potential canonical type 3 (TRPC3)-mediated Ca2+ entry triggers a transepithelial Ca2+ flux to regulate proximal tubular (PT) luminal [Ca2+], and TRPC3-knockout (KO; -/-) mice exhibited moderate hypercalciuria and microcrystal formation at the loop of Henle (LOH). Therefore, we utilized TRPC3 KO mice and exposed them to both hypercalciuric [2% calcium gluconate (CaG) treatment] and alkalineuric conditions [0.08% acetazolamide (ACZ) treatment] to generate a CaNL phenotype. Our results revealed a significant CaP and mixed crystal formation in those treated KO mice (KOT) compared to their WT counterparts (WTT). Importantly, prolonged exposure to CaG and ACZ resulted in a further increase in crystal size for both treated groups (WTT and KOT), but the KOT mice crystal sizes were markedly larger. Moreover, kidney tissue sections of the KOT mice displayed a greater CaP and mixed microcrystal formation than the kidney sections of the WTT group, specifically in the outer and inner medullary and calyceal region; thus, a higher degree of calcifications and mixed calcium lithiasis in the kidneys of the KOT group was displayed. In our effort to find the Ca2+ signaling pathophysiology of PT cells, we found that PT cells from both treated groups (WTT and KOT) elicited a larger Ca2+ entry compared to the WT counterparts because of significant inhibition by the store-operated Ca2+ entry (SOCE) inhibitor, Pyr6. In the presence of both SOCE (Pyr6) and ROCE (receptor-operated Ca2+ entry) inhibitors (Pyr10), Ca2+ entry by WTT cells was moderately inhibited, suggesting that the Ca2+ and pH levels exerted sensitivity changes in response to ROCE and SOCE. An assessment of the gene expression profiles in the PT cells of WTT and KOT mice revealed a safeguarding effect of TRPC3 against detrimental processes (calcification, fibrosis, inflammation, and apoptosis) in the presence of higher pH and hypercalciuric conditions in mice. Together, these findings show that compromise in both the ROCE and SOCE mechanisms in the absence of TRPC3 under hypercalciuric plus higher tubular pH conditions results in higher CaP and mixed crystal formation and that TRPC3 is protective against those adverse effects.

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.

MP10-02 DIETARY INTERVENTION IN ENTERIC HYPEROXALURIA

You have accessJournal of UrologyCME1 Apr 2023MP10-02 DIETARY INTERVENTION IN ENTERIC HYPEROXALURIA William DeFoor, Joonsue Lee, Nehus Edward, Marion Schulte, Sydney Huesman, Ashleigh Libs, and Prasad Devarajan William DeFoorWilliam DeFoor More articles by this author , Joonsue LeeJoonsue Lee More articles by this author , Nehus EdwardNehus Edward More articles by this author , Marion SchulteMarion Schulte More articles by this author , Sydney HuesmanSydney Huesman More articles by this author , Ashleigh LibsAshleigh Libs More articles by this author , and Prasad DevarajanPrasad Devarajan More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003225.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Medically complex, gastrostomy-fed children are particularly vulnerable to forming kidney stones. We have previously shown that there are elevated urinary oxalate levels in patients using enteral feeding formulas primarily based on soy protein, a known high oxalate food. Enteric hyperoxaluria may predispose patients to calcium oxalate stones. The objective of this study is assess if targeted dietary intervention decreases urinary oxalate excretion. METHODS: A retrospective cohort study was performed on medically complex children with cerebral palsy and severe developmental delay presenting to a high-volume Pediatric Stone Center with nephrolithiasis from 2015 to 2020. Inclusion criteria included those who underwent a dietary and urinary metabolic evaluation before and after the index visit. Diets were analyzed by a registered dietitian. Urinary metabolites including calcium, oxalate, and citrate as well as the supersaturations of calcium oxalate and calcium phosphate were analyzed via two 24-hour urine collections. Dietary oxalate load was determined by evaluating individual recipes for known high oxalate ingredients or soy-based formulas. Patients were stratified into those on a low versus high oxalate diet. Statistical analysis was performed using paired t-tests. RESULTS: A total of 13 medically complex stone-forming children met inclusion criteria. All patients were non-ambulatory. 11 of 13 (85%) were primarily fed via gastrostomy. Of the 13 patients, 4 were on a low oxalate diet and 9 were found to have a diet of high oxalate foods. The baseline urinary oxalate excretion (26 vs. 71 mg/m2/day, P = 0.001) and supersaturation of calcium oxalate (6.1 vs. 14.3, P=0.01) were lower in those with a low oxalate diet. Four patients on high oxalate diets were targeted for lowering the enteral oxalate load. A follow-up urinary metabolic evaluation was performed a mean of 6.5 months after the dietary intervention. The urinary oxalate level decreased from 71 to 33 mg/m2/day (P=0.049). Urinary excretion of calcium and citrate as well as the supersaturation of calcium phosphate were similar following dietary modifications. CONCLUSIONS: Urinary oxalate excretion and supersaturation of calcium oxalate were elevated in medically complex stone-forming children with high dietary oxalate content. Targeted dietary intervention to reduce the oxalate load in enteral formulas can lead to a substantial decrease in urinary oxalate excretion. Further investigation is required to determine if this leads to lower stone recurrence, hospitalizations, and the need for surgical interventions. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e114 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information William DeFoor More articles by this author Joonsue Lee More articles by this author Nehus Edward More articles by this author Marion Schulte More articles by this author Sydney Huesman More articles by this author Ashleigh Libs More articles by this author Prasad Devarajan More articles by this author Expand All Advertisement PDF downloadLoading ...

Association between obstructive sleep apnea and 24-h urine chemistry risk factors for urinary stone disease

The effect of obstructive sleep apnea (OSA) on 24-h urine parameters and resultant kidney stone risk is unknown. We sought to compare urinary lithogenic risk factors among patients with kidney stone disease with and without OSA. We performed a retrospective cohort study of adult patients with nephrolithiasis undergoing both polysomnography and 24-h urine analysis. Measures of acid load including gastrointestinal alkali absorption, urinary titratable acid, and net acid excretion were calculated from 24-h urine. We performed univariable comparisons of 24-h urine parameters between those with and without OSA and fit a multivariable linear regression model adjusting for age, sex, and BMI. Overall, there were 127 patients who underwent both polysomnography and a 24-h urine analysis from 2006 to 2018. There were 109 (86%) patients with OSA and 18 (14%) without. Patients with OSA were more commonly male, had greater BMI and had higher rates of hypertension. Patients with OSA had significantly higher levels of 24-h urinary oxalate, uric acid, sodium, potassium, phosphorous, chloride, and sulfate; higher supersaturation of uric acid; higher titratable acid, and net acid excretion; and lower urinary pH and supersaturation of calcium phosphate (p < 0.05). The difference in urinary pH and titratable acid, but not net acid excretion, remained significant when adjusting for BMI, age, and gender (both p = 0.02). OSA is associated with changes in urinary analytes that promote kidney stone formation, similar to those observed with obesity. After accounting for BMI, OSA is independently associated with lower urine pH and increased urinary titratable acid.

Biomimetic mineralized collagen scaffolds enhancing odontogenic differentiation of hDPSCs and dentin regeneration through modulating mechanical microenvironment

Dentin regeneration is a huge challenge because of its complicated structure and the shortage of odontoblasts. Unlike in vitro remineralization of dentin through supersaturation of calcium phosphate, the materials of mineralized collagen scaffolds could recruit the human dental pulp stem cells (hDPSCs) and induce their differentiation in vivo and achieve dentin repair. Inspired by the biomineralization of dentin, herein, mineralized collagen fibrils with various mineralization degrees and mechanical properties were prepared through biomolecule hyaluronic acid (HA) modification, and first time find the mechanical properties have a positive correlation with mineralization degree. When 1.2 mg/mL HA was used to modification, the mineralized HA-modified collagen scaffolds (HA-MCS) with similar modulus and stiffness to that of natural dentin could be obtained. Furthermore, testing ALP activity and alizarin red S staining experiments confirmed the HA-MCS with a biomimetic mechanical microenvironment could enhance the proliferation and differentiation of hDPSCs. Additionally, in vivo experiments performed on the beagle model further proved this point that HA-MCS with a biomimetic mechanical microenvironment could promote dentin regeneration. These results not only elucidate that the modulation of mechanical properties of biomaterials could enhance the proliferation and differentiation of stem cells, but also provide a strategy for hard tissue regeneration.

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.

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.

Kidney toxicity of phosphate: is that crystal clear yet?

Hyperphosphatemia is a well-known feature of advanced chronic kidney disease (CKD) and a major risk factor for cardiovascular events in patients with CKD, inducing calcium phosphate supersaturation and vascular calcifications.1 Although the serum phosphate level is not recognized as an independent risk factor for CKD progression, increased urinary phosphate excretion has been associated with CKD progression in small cohort studies.2,3 In experimental studies, exposure to a high-phosphate diet has been shown to accelerate kidney damage in rats with reduced nephron number induced by partial nephrectomy.

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 ...

Sex Differences of Kidney Stone Urine Risk Factors after Roux-en-Y Gastric Bypass

Introduction: Roux-en-Y gastric bypass (RYGB) is a bariatric surgical procedure that is associated with higher risk of kidney stones after surgery. We examined urine composition in 18 men and women before and after RYGB to examine differences in kidney stone risk. Methods: Three 24-h urine collections were performed before and 1 year after RYGB. We analyzed mean urinary values for pre- and post-RYGB collections and compared men and women. Results: Seven men and eleven women completed pre- and post-RYGB urine collections. Pre-RYGB, men had higher calcium oxalate supersaturation (CaOx SS) (7.0 vs. 5.0, p = 0.04) compared with women. Post-RYGB, women had higher urine CaOx SS (13.1 vs. 4.6, p = 0.002), calcium phosphate supersaturation (1.04 vs. 0.59, p = 0.05), and lower urine volumes (1.7 vs. 2.7L, p < 0.001) compared with men. Discussion/Conclusion: There are important differences in urine composition by sex that may contribute to higher kidney stone risk in women after RYGB compared with men.

Evaluation of fasting impact during Ramadan month on patients with a history of kidney stones in a military hospital

Introduction: One of the cornerstones and common causes of kidney stone formation is the volume of fluid consumed during a 24- hour that influences on forming that by several mechanisms. Since fluid intake decreases during Ramadan, one of the common questions posed is whether Ramadan fasting is associated with the precipitating of stone formation. The present study was aimed to investigate the effect of Ramadan fasting on precipitating and Inhibitors of stone formation in patients with a history of renal kidney disease. Methods: The study population included all of the patients with kidney stone diseases who were seen at the Clinic of Urology and Nephrology affiliated with Baqiyatallah hospital during the month of Ramadan in 2014 and 2015. The number of 66 patients was chosen and included in the study through randomized simple sampling. All subjects underwent blood tests like serum uric acid, serum phosphate, serum calcium, and serum sodium. Samples were tested in terms of volume, magnesium, uric acid, Calcium, Phosphate, Sodium, citrate, oxalate, Calcium oxalate supersaturation, Calcium Phosphate supersaturation, Uric acid supersaturation. Results: Sixty-six eligible patients were included that the mean age was 48.35±12.10 years. Fourteen men and 52 women were included. There were no significant differences in the mean pH of urine, urinary sodium, urinary oxalate, supersaturated levels of calcium oxalate in the urine, urinary phosphate levels, and super-saturated levels of urinary calcium phosphate between the two groups (P&gt;0.05). The average volume of urine, urinary magnesium, urinary calcium, urinary citrate, the uric acid level in the non-fasting group was higher than the fasting group (P&lt;0.05). There were no differences in the average blood calcium levels, blood sodium, blood phosphate levels, blood acidic levels between the two groups (P&gt;0.05). There was no difference in the mean super-saturated level of uric acid between the two groups (P=0.035). Conclusion: There was controversial evidence on the effect of Ramadan fasting on kidney stone formation and there is not enough evidence in the present study that Ramadan fasting precipitates risk factors associated with calculus formation.

In support of hydroxycitrate being clinically investigated as a potential therapy of calcium nephrolithiasis: Theoretical modelling and in vitro investigation of thermodynamic effects

Hydroxycitrate (HCA), has been mooted as a potentially equivalent, if not superior therapy to citrate for calcium urolithiasis. However, past studies were mainly mechanistic while thermodynamic experiments were limited. We determined stability constants for HCA protonation and metal ion complexation, and measured HCA speciation by potentiometric titration. We modelled the effect of HCA, citrate and pH on calcium oxalate (CaOx) and calcium phosphate (CaP) supersaturation (SS) using the program JESS to which we had added our determined thermodynamic constants. Finally, we measured the effects of HCA on CaOx metastable limit (MSL) in artificial urine using turbidimetry. Our experiments showed that fully dissociated HCA is the dominant species at urinary pH 6. Modelling predicted that HCA decreases SS CaOx and CaP to a greater extent than citrate. In vitro experiments showed increases in the MSLs of CaOx and CaP thereby confirming favorable thermodynamic effects of HCA on SS. Clinical trials are warranted to investigate the promise of HCA for reducing this important risk factor for calcium nephrolithiasis.

Association of Chronic Kidney Disease Stage with 24-Hour Urine Values Among Patients with Nephrolithiasis.

Introduction: Nephrolithiasis is a known risk factor for chronic kidney disease (CKD); however, it is unknown how CKD affects urinary parameters related to stone risk. The purpose of this study was to assess the relationship of diminishing glomerular filtration rate (GFR) and kidney stone-related 24-hour urine (24H urine) composition. Materials and Methods: A single-institution retrospective review of patients (n = 2057) who underwent 24H urine analysis was performed. The serum creatinine within 1 year of the first 24H urine was used to determine estimated GFR and stratify patients by CKD stage. We performed analysis of variance and multivariable linear regression to assess the relationship of GFR and urinary analytes. Results: Among all patients, there were 184 (8.9%), 1537 (74.7%), 245 (11.9%), 70 (3.4%), 17 (0.8%), and 4 (0.2%) in CKD stage I, II, IIIa, IIIb, IV, and V groups, respectively. On analysis of 24H urine composition, as CKD increased, changes in urinary parameters protective against crystallization included decreased calcium and uric acid (UA) (P < 0.001). In addition, parameters favoring crystallization included decreased citrate and magnesium (P = 0.002 and P < 0.001, respectively). The net effect with increasing GFR was decreasing supersaturation of calcium oxalate and phosphate. On linear regression, urinary excretion of calcium, oxalate, citrate, UA, phosphate, and ammonia all decreased with decreasing GFR (all P < 0.05). Conclusions: Higher CKD stage was associated with changes in urinary analytes that both promoted and inhibited stone formation, with the net effect of decreasing calcium oxalate and phosphate supersaturation. These patients may benefit from medical therapy that targets improving urinary citrate instead of lowering calcium or UA.

PD04-01 ANTIBIOTICS AFFECT THE GUT MICROBIOME AND ALTER KIDNEY STONE FORMATION IN GENETIC HYPERCALCIURIC STONE-FORMING RATS

You have accessJournal of UrologyStone Disease: Basic Research & Pathophysiology I (PD04)1 Apr 2020PD04-01 ANTIBIOTICS AFFECT THE GUT MICROBIOME AND ALTER KIDNEY STONE FORMATION IN GENETIC HYPERCALCIURIC STONE-FORMING RATS Joshua Stern*, John Asplin, Nancy Krieger, Sylvia Suadicani, Luojing Chen, Jennifer Becker, Michaela Chan, Justin Lee, Yi Wang, and David Bushinsky Joshua Stern*Joshua Stern* More articles by this author , John AsplinJohn Asplin More articles by this author , Nancy KriegerNancy Krieger More articles by this author , Sylvia SuadicaniSylvia Suadicani More articles by this author , Luojing ChenLuojing Chen More articles by this author , Jennifer BeckerJennifer Becker More articles by this author , Michaela ChanMichaela Chan More articles by this author , Justin LeeJustin Lee More articles by this author , Yi WangYi Wang More articles by this author , and David BushinskyDavid Bushinsky More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000824.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Recent evidence suggests both antibiotic exposure and the gut microbiome (GMB) are associated with stone disease. Antibiotics can cause rapid alterations in the GMB. We utilized genetic hypercalciuric stone-forming (GHS) rats that form calcium phosphate (CaP) stones, to determine the effect of antibiotics on the gut microbiome, urine ion excretion and stone formation. METHODS: 116th generation GHS rats were fed a fixed amount of a normal Ca (1.2%) and P (0.65%) diet, housed in metabolic cages and divided into 3 groups (n=10): control (CTL) diet, or supplemented with ciprofloxacin (Cipro, 5 mg/d) or Bactrim (250 mg/d). Urine and fecal pellets were collected at 6, 12 and 18 wks for analyses. DNA from fecal pellets were amplified on the 16S rRNA V4 region using primers on an Illumina platform. QIIME was used for analysis. At 18 wks kidney stone formation was determined by Faxitron analysis and assessed by 3 blinded reviewers. RESULTS: After 18 wks, urine Ca decreased with Bactrim (CTL=13.7± 0.4, Bactrim=12.1±0.4 mg/d, p<0.05) as did urine oxalate (CTL=1.2±0.04, Bactrim=0.8±0.02 mg/d, p<0.05). CaP supersaturation increased with Bactrim (CTL=6.8±0.4, Bactrim=8.4±0.5, p<0.05) while CaOx supersaturation fell (CTL=16.2± 0.6, Bactrim=12.0±0.4, p<0.05). Calcification was increased with Bactrim (CTL=1.0±0.2, Bactrim=2.98±0.3, p<0.05). Cipro was not different from CTL for any parameter. Principal component analysis of the GMB showed the Bactrim group and controls clustered separately (p=0.001). Microbial diversity negatively correlated with urinary oxalate in all animals (R=-0.46, p=0.006) and positively correlated with urinary pH in the Bactrim group (R=0.76, p=0.01). CONCLUSIONS: Bactrim altered the GMB of GHS rats, decreased urine Ca, increased CaP supersaturation and increased calcification, while Cipro had no effects. Whether the alteration in the GMB is mechanistically related to the changes in urine ion excretion and calcification remains to be determined. Source of Funding: NIDDK © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e78-e78 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Joshua Stern* More articles by this author John Asplin More articles by this author Nancy Krieger More articles by this author Sylvia Suadicani More articles by this author Luojing Chen More articles by this author Jennifer Becker More articles by this author Michaela Chan More articles by this author Justin Lee More articles by this author Yi Wang More articles by this author David Bushinsky More articles by this author Expand All Advertisement PDF downloadLoading ...

Effect of the membrane exclusion mechanism on phosphate scaling during synthetic effluent desalination

Calcium phosphate scaling is one of the main limitations in effluent desalination using membranes. This may be overcome by tailoring membranes with lower rejection of the scalant ions.In this study, we systematically examined the use of negatively and positively charged membranes, rejecting ions mainly based on Donnan exclusion, as a low-scaling alternative to dielectric-exclusion-dominated polyamide NF membranes for effluent desalination.The two charged membranes exhibited a lower calcium and especially phosphate rejection than the polyamide membrane. Consequently, the calcium phosphate supersaturation and then the propensity to scaling of the charged membranes were much lower than the polyamide membrane. This also allowed filtering at a much higher recovery ratio with the charged membranes. It was also found that, despite the fact that the charged membranes had an opposite fixed charge, their scaling behavior was similar. Apparently, although these membranes showed opposite selectivity towards scalant ions (phosphate and calcium) in single salt solutions, the rejection pattern in mixed salt solutions resulted in similar saturation indices, much lower than for polyamide membrane.The scale formed on all three membranes was identified as amorphous calcium phosphate (ACP), although its saturation index was lower than its solubility factor. This was explained by concentration polarization which increases the saturation index in the solution adjacent to the membrane surface.Tests in absence of permeate flux showed a much slower precipitation that took a few days compared with filtration conditions (few hours). In addition, under these conditions, the effect of the scaling on the membrane permeability was generally reduced and the scale contained crystalline calcium phosphate products, different from ACP.The results indicate that the ion rejection and resulting polarization next to the membrane surface plays a crucial role in scaling. Thus, tuning ion selectivity of NF membranes towards scalant ions presents a promising alternative for scaling mitigation during effluent desalination.

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.

MP08-05 IMPACT OF DEMOGRAPHIC FACTORS AND SYSTEMIC DISEASE ON URINARY STONE RISK PARAMETERS AMONGST STONE FORMERS

This article examines via multivariate analysis the associations between demographic factors and systemic diseases on stone risk parameters in a stone-forming population. A retrospective chart review of adult stone formers who completed 24-hour urine collections from April 2004 through August 2015 was performed. Data was collected on age, sex, race, body mass index (BMI), and diagnoses of diabetes and hypertension. CT imaging and renal/abdominal ultrasonography (within ± 66 mo) were reviewed for diagnosis of fatty liver disease. Statistical analysis included Pearson and Spearman correlation analysis, and linear and logistic regression analyses, both univariate and multivariate. Five hundred eighty-nine patients were included. Numerous urinary parameters were significant in association with demographic factors or systemic diseases in a multivariate analysis. Older age was associated with decreased calcium (Ca) excretion (P = 0.0214), supersaturation of calcium oxalate (SSCaOx; P = 0.0262), supersaturation of calcium phosphate (SSCaP; P < 0.0001), and urinary pH (P = 0.0201). Men excreted more Ca (P = 0.0015) and oxalate (Ox; P = 0.0010), had lower urine pH (P = 0.0269), and higher supersaturation of uric acid (SSUA; P < 0.0001) than women. Blacks had lower urine volume (P = 0.0023), less Ca excretion (P = 0.0142), less Ox excretion (P = 0.0074), and higher SSUA (P = 0.0049). Diabetes was associated with more Ox excretion (P < 0.0001), lower SSCaP (P = 0.0068), and lower urinary pH (P = 0.0153). There were positive correlations between BMI and Ca excretion (P = 0.0386), BMI and Ox excretion (P = 0.0177), and BMI and SSUA (P = 0.0045). These results demonstrate that demographic factors and systemic disease are independently associated with numerous risk factors for kidney stones. The mechanisms responsible for these associations and disparities (racial differences) need to be further elucidated.

The Effect of Lemonade and Diet Lemonade Upon Urinary Parameters Affecting Calcium Urinary Stone Formation.

To determine the effects of regular and diet lemonade upon urinary parameters affecting kidney stone formation. In this prospective blinded crossover study, 12 healthy participants consumed either 2 L of regular or diet lemonade daily while on a standardized low sodium moderate calcium diet. Twenty four-hour urine collections were obtained at baseline on the controlled diet only and on days 4 and 5 of each treatment phase. There was a 1-week washout period between regular and diet lemonade treatments. Primary outcomes were urine citrate, pH, and volume determined by 24-hour urine collections. Secondary outcomes included the supersaturation of calcium oxalate, calcium phosphate, and uric acid. Urine volume was significantly higher with both regular and diet lemonade consumption compared with baseline values. Urinary citrate significantly increased from baseline with diet lemonade only. Urine pH was unchanged with both beverages. The supersaturation of calcium oxalate significantly decreased with diet lemonade only, whereas supersaturation of calcium phosphate decreased with both beverages. Daily consumption of 2 L of regular and diet lemonade resulted in an intake of 168.4 and 170.2 mEq of citrate but a total alkali intake of 12.2 and 16.0 mEq, respectively. Compared with diet lemonade, regular lemonade provided subjects with 805 additional calories and 225 g of sugar per day. Diet lemonade may provide a low-calorie sugar-free cost-effective option for decreasing the risk of recurrent calcium nephrolithiasis through a significant increase in urine volume, increase in urinary citrate, and reduction in supersaturation of calcium oxalate and calcium phosphate.

Short-Term Changes in Urinary Relative Supersaturation Predict Recurrence of Kidney Stones: A Tool to Guide Preventive Measures in Urolithiasis

Kidney stone disease is characterized by a relatively high rate of recurrence. In our study we analyzed the association between relative supersaturation and the risk of stone recurrence. Additionally, we examined the association between the risk of recurrence and changes in relative supersaturation and urinary composition after 1 week of medical treatment. We performed a post hoc analysis of data from a previously published randomized controlled trial comparing the effect of 2 diets in 120 men with recurrent calcium oxalate stones and hypercalciuria. Baseline and followup 24-hour urine parameters were used to calculate the relative supersaturation of calcium oxalate, calcium phosphate and uric acid using the EQUIL2, JESS and LithoRisk computer programs. Cox models were used to calculate the estimated association between each baseline relative supersaturation, and 1-week changes and the risk of recurrence during followup. During a 5-year followup 35 patients (34%) experienced recurrence. A reduction in calcium oxalate relative supersaturation at 1 week was significantly associated with a lower risk of recurrence using the EQUIL2 calculation (for every 10% reduction from baseline HR 0.92, 95% CI 0.86-1.00, p = 0.044). However, there was no association for relative supersaturation calculated by other methods or for the relative supersaturation of other salts. Changes in the 24-hour urine excretion of citrate, potassium and magnesium were significantly associated with a risk of recurrence. In recurrent stone formers with hypercalciuria baseline values and changes in the relative supersaturation of calcium oxalate may be associated with the risk of recurrence. Changes in urinary citrate, potassium and magnesium following dietary intervention may also be predictive.

Influence of BMI in nephrolithiasis in an Appalachian pediatric population: A single-center experience

The prevalence of pediatric nephrolithiasis has increased significantly in the past 20 years. Metabolic abnormalities predisposing adults to nephrolithiasis in obese patients include increased urinary sodium and uric acid excretion as well as low urine pH; however, limited data are available in the pediatric population. The aim was to investigate whether obese pediatric patients presenting with nephrolithiasis have a unique metabolic profile similar to reported findings in obese adults with nephrolithiasis. A retrospective chart review was performed in children aged 1-18 years seen at Kentucky Children's Hospital between 2010 and 2016. Inclusion criteria included all patients with documented stones confirmed by ultrasonography or computed tomography. A total of 111 patient charts were reviewed in the study with a mean age of 11.8±4.2 years. Seventy patients (63%) had a normal BMI and 41 patients (37%) were considered overweight/obese. There was no statistically significant relationship between BMI and stone recurrence. Obese patients had significantly decreased levels of urinary citrate, oxalate, magnesium, and potassium with significant elevations of urinary urea nitrogen, ammonia, and low urine pH compared with normal weight patients (Summary Figure). Several groups have reported on metabolic findings within obese and non-obese pediatric patients. A Turkish study reported increased oxalate excretion and hypocitraturia in obese patients while a Korean study also reported increased rates of hypocitraturia in recurrent stone formers. Similar to these studies, we did find significant differences in citrate within our study population; however, we found significantly lower levels of urinary oxalate in obese patients. The majority of these studies do not report an association with BMI and urine pH although this has been reported in the adult population and our findings support an inverse relationship between body mass index (BMI) and pH. Our group found a higher level of calcium phosphate stones, supporting of Eisner's findings that high BMI is associated with increased supersaturation of calcium phosphate. Limitations of our study include being a single center and retrospective in nature. Our study demonstrates differences in types of stones and urinary metabolites in an obese pediatric population suggestive of different metabolic profiles contributing to stone disease. We report similar association between BMI and urine pH, urinary potassium, and citrate. This study confirmed our primary hypothesis that obese pediatric patients would have a different urinary mineral profile as evidenced by lower levels of citrate and potassium and low urine pH; however, obese patients did not exhibit significantly elevated urinary sodium and uric acid when normalized to weight, as described in the adult population. Our study did not confirm our secondary hypothesis that stone composition would be associated with BMI status or stone recurrence.