Urinary Citrate Excretion Research Articles

P0077A NEW MUTATION OF DNAJB11 AS A CAUSE OF CYSTIC KYDNEY DISEASE: THE FOURTH GENE OF ADPKD

Abstract Background and Aims Monogenic inherited diseases are an underestimated but important cause of chronic kidney disease (CKD). Despite the increasing knowledge about their inheritance, they are identified in fewer than 10% of CKD patients. Among monogenic causes of CKD, polycystic kidney diseases (PKD) represent a group of disorders with a clinical and genetic heterogeneity and a variable phenotype (from early manifestations during pregnancy or childhood to the absence of clinical manifestations until adulthood). We here present a PKD family with 5 members displaying the disease (Figure 1). Method We revised patients clinical history, laboratory data and imaging exams. An accurate family history was recovered. Blood samples were collected from living patients to perform an exome analysis using next generation sequencing to analyze all possible genes involved in PKD. Results Each patient presented a clinical history of nephrolithiasis, a variable degree of CKD (from normal kidney function to renal transplant), urinary and blood parameters compatible with distal renal tubular acidosis (hypercalciuria, low urinary citrate excretion and hypokalemia). Imaging exams showed several renal cysts in the medulla or at the cortico-medullary junction with intracystic calcifications (Figure 2). Some patients displayed also large cortical renal cysts and also hepatic and pancreatic cysts. The genetic analysis performed using next generation sequencing in four patients showed a new mutation on the gene DNAJB11; the mutation introduced a stop codon and was identified as pathogenic by prediction programs. It was present in heterozygosity in all subjects and had an autosomal dominant pattern of inheritance. Conclusion DNAJB11 mutations were reported as a cause of PKD for the first time in 2018 by Cornec-Le-Gall and colleagues. The nephropathy derived from these mutations need to be differentiated from ADPKD (autosomal dominant polycystic kidney disease), from ADTKD (autosomal dominant tubulointerstitial kidney disease) and from medullary sponge kidney. DNAJB11 encodes a co-chaperone of the endoplasmic reticulum (ER) also called ERdj3. It is part of the HSP40 protein family and plays a central role in both intracellular and extracellular proteomic homeostasis (proteostasis). In the intracellular compartment it acts as a co-chaperone in the pathway of the unfolded protein response (UPR) in which it binds misfolded proteins which have to be secreted and activates BiP an HSP70 of ER whose function is to correct the misfolding. In the kidney it is mainly expressed in the thick ascending limb of Henle’s loop, in the distal tubule and in the collecting duct justifying the clinical presentation of nephropathy and differentiating the disease from ADPKD (Figure 3).

SO014CHANGES IN CHARACTERISTICS OF CRYSTALLURIA IN PATIENTS WITH RECURRENT NEPHROLITHIASIS

Abstract Background and Aims The study of crystals in the urinary sediment finds application in the diagnosis of hereditary or metabolic nephrolithiasis and in the identification of crystals from drugs. Method We conducted a thorough microscopic urine examination, focused on the determination of crystalluria, associated with the metabolic study at baseline and about 6 months after the start of a metaphylactic therapy, in 21 patients with recurrent nephrolithiasis, followed at the Metabolic Stone Clinic of our Institution. The analysis of the crystals was performed in parallel and blind through direct microscopic examination (MD) and automated instrumentation (SA) (SediMax analyzer - Menarini Diagnostics) of our institution. We used a semi-quantitative approach for both methods. Results We examined 42 sediments (21 at baseline and 21 after an average follow-up of 196±88 days) from 21 patients (8 females, 13 males), all of them showing calcium oxalate crystalluria. The analysis on baseline evaluation and follow-up on both Crystalluria MD and crystalluria SA through spaghetti plots showed a tendency to reduction of severity for the first one only. This trend is consistent with the data obtained from the metabolic studies: urinary oxalate and calcium excretions, the main drivers of calcium oxalate crystallization, which showed decreasing levels. The same examination for urinary citrate excretion showed a rising trend, again in accordance with the on-going changes in urine lithogenic profile. Conclusion The study of crystals in the urinary sediment, repeated over time, may represent a further indicator of the effectiveness of metaphylactic therapy and an indicator of patient adherence to the prescription in metabolic calcium oxalate nephrolithiasis.

Association of Impaired Renal Function With Changes in Urinary Mineral Excretion and Stone Composition

ObjectiveTo investigate the effect of kidney function on stone composition and urinary mineral excretion in patients undergoing surgical intervention for nephrolithiasis. MethodsUsing our institutional kidney stone database, we performed a retrospective review of stone patients who underwent surgical intervention between 2004 and 2015. Patients’ demographic information, 24-hour urinary mineral excretion, and stone characteristics were reported. The patients’ estimated glomerular filtration rates (eGFR) were compared with their stone compositions and 24-hour urine mineral excretions. ResultsA statistically significant difference was noted between the groups, with uric acid stones being associated with lower eGFR and calcium phosphate stones associated with higher eGFR. No relationship could be demonstrated between eGFR and calcium oxalate or struvite stones. Patients with lower eGFR also demonstrated a statistically significant association with lower urinary pH as well as lower urinary excretion of calcium and citrate. ConclusionWhile various factors have been found to play significant roles in kidney stone formation and composition, our findings demonstrate a definite relationship between these and renal function. This paper highlights the fact that renal function evaluation should be considered an important component in the evaluation, counseling, and management of patients with nephrolithiasis.

MP43-06 BAKING SODA EXERTS A SIGNIFICANT ALKALINIZING EFFECT IN PATIENTS WITH UROLITHIASIS WITHOUT INCREASING URINARY CALCIUM EXCRETION

You have accessJournal of UrologyStone Disease: Medical & Dietary Therapy (MP43)1 Apr 2020MP43-06 BAKING SODA EXERTS A SIGNIFICANT ALKALINIZING EFFECT IN PATIENTS WITH UROLITHIASIS WITHOUT INCREASING URINARY CALCIUM EXCRETION Kristina Penniston*, Scott Quarrier, Shuang Li, and R. Allan Jhagroo Kristina Penniston*Kristina Penniston* More articles by this author , Scott QuarrierScott Quarrier More articles by this author , Shuang LiShuang Li More articles by this author , and R. Allan JhagrooR. Allan Jhagroo More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000898.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Baking soda (sodium bicarbonate, NaHCO3) has been used for decades as an alkalinizing agent. When taken orally, NaHCO3 increases urine pH and citrate. Despite rising prices of prescriptive urinary alkalinizing agents, urologists may be reluctant to recommend NaHCO3 due to fear of Na-induced hypercalciuria. To assess this potential adverse event, we reviewed our recent clinical experience with baking soda as alkali treatment. METHODS: A convenience sample of patients from our metabolic stone prevention clinic who used baking soda within the past year was assembled from an IRB-approved prospectively maintained database. In addition to taking 1/4 tsp baking soda BID (dissolved in water or other liquid), providing approximately 25 mEq alkali, most patients were counseled to increase intake of bicarbonate precursors from fruits and vegetables. Results from patients’ 24-h urine collections before and during treatment were retrospectively reviewed. The primary outcome was change in urinary calcium (UCa) excretion. Patients were excluded for urine creatinine variation >40% and/or no follow-up urine collection. In order to assess only patients compliant with treatment, those with no increases in either urine citrate or pH and/or 24-h urine Na:Cl ratio <0.9 while on treatment were excluded. RESULTS: Patients (n=21) were mostly male (71%) and were 60±10 y. Urine collections were 9.1±2.1 months apart. Overall, significant increases were observed in urinary citrate excretion (523 to 822 mg/d), pH (5.83 to 6.26), and 24-h urine Na:Cl ratio (1.03 to 1.17); p≤0.003 for all comparisons (paired t-tests). The increase in urinary Na excretion (40±102 mEq) was >3-fold higher than change in Cl excretion, confirming higher Na intake from NaHCO3 vs. dietary salt (NaCl). UCa excretion was not different before and during treatment (191 mg and 217 mg respectively; p=0.18, paired t-test). Before treatment, 4 patients had UCa>250 mg; 2 of these resolved on treatment. Of 5 patients with new-onset hypercalciuria, higher dietary NaCl intake, suggested by higher post-treatment Cl excretion (delta >200 mEq), was deemed to have explained the rise in UCa in a subset of these. CONCLUSIONS: Treatment with baking soda providing 25 mEq alkali daily in patients who achieved increases in urinary citrate excretion and/or urine pH was not associated with higher UCa. Moreover, treatment with baking soda did not exacerbate hypercalciuria in patients with high pre-treatment urine calcium. A prospective trial to confirm these results is currently underway. Source of Funding: none © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e649-e649 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kristina Penniston* More articles by this author Scott Quarrier More articles by this author Shuang Li More articles by this author R. Allan Jhagroo More articles by this author Expand All Advertisement PDF downloadLoading ...

Exploring the Potential Relationship Between Phytate Ingestion, Urinary Phytate Excretion, and Renal Stone Risk in a Unique Human Model: No Hard Evidence in Support of Phytate as a Stone Inhibitor

Dietary phytate (IP6) enjoys a reputation as an inhibitor of calcium renal stone formation, although there are very few human studies to support this notion. In South Africa, urolithiasis occurs in the white (W) but is rare in the black (B) population. We undertook this unique human model to further investigate the IP6 theory. Healthy W and B males completed baseline food-frequency recall questionnaires. Dietary intake of IP6 was restricted for 18 days. An IP6 dietary supplement was ingested on days 15-18. Twenty-four-hour urinary phytate and other urinary components were determined. Relative supersaturations of calcium salts were calculated. The urinary metastable limit (MSL) of calcium oxalate (CaOx) and its crystallisation kinetics were determined experimentally. Habitual dietary intake of IP6 and its urinary excretion were significantly higher in B than in W (1650 ± 202 vs. 640 ± 134 mg/d, P = .0002 and 1.13 ± 0.12 vs. 0.75 ± 0.13 μM, P <.05, respectively). In B, urinary phytate decreased significantly after 15 days of IP6 restriction, but in W, its excretion remained constant. After supplementation, urinary IP6 increased significantly in both groups reaching levels commensurate with the baseline value in B. No significant differences occurred in B in any of the routine urinary risk factors throughout the trial. However, in W, urinary citrate excretion increased on day 18 relative to day 0. There were no significant intragroup or intergroup changes in relative supersaturation, metastable limit, or crystallization kinetics. Despite notable differences in the renal handling of ingested IP6, there were no changes in any of the well-established urinary risk factors for calcium renal stone formation in either of our uniquely different test groups. We conclude that, in the absence of hard evidence, claims that IP6 is a stone inhibitor remain unproven.

Cortisol and 11 beta-hydroxysteroid dehydrogenase type 2 as potential determinants of renal citrate excretion in healthy children.

In patients with Cushing disease, renal citrate excretion is reduced. A low urinary citrate concentration is a risk factor for nephrolithiasis. Since higher acid loading is one major determinant of reduced citrate excretion, we aimed to examine whether glucocorticoids still within the physiological range may already impact on urinary citrate excretion independently of acid-base status. Overall, 132 healthy prepubertal participants of the DOrtmund Nutritional and Anthropometric Longitudinally Designed (DONALD) Study who had collected two successive 24-h urine samples (at 1 and 2 years) before the start of their pubertal growth spurt were included in the study. Net acid excretion capacity (NAEC), urinary potential renal acid load (PRAL), creatinine, calcium, and various cortisol metabolites were measured in all samples. Glucocorticoid quantification was done by GC-MS and radioimmunoassay. In regression models multivariable-adjusted for 24-h urinary PRAL, NAEC, creatinine and calcium, urinary free cortisol (UFF), 6β-hydroxycortisol, and 20α-dihydrocortisol showed significant inverse relationships (P ≤ 0.02) with 24-h renal citrate output. By contrast, the estimate of renal 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), i.e., the ratio of urinary free cortisone/UFF, associated positively with urinary citrate (P = 0.04). In line with studies in hypercortisolic state, even moderately high cortisol levels in healthy children, still within the physiological range, may negatively impact on the kidney's citrate excretion. Besides, a higher 11β-HSD2 activity, favoring cortisol inactivation, is paralleled by an increased citrate excretion.

Crystal deposition triggers tubule dilation that accelerates cystogenesis in polycystic kidney disease.

The rate of disease progression in autosomal-dominant (AD) polycystic kidney disease (PKD) exhibits high intra-familial variability suggesting that environmental factors may play a role. We hypothesized that a prevalent form of renal insult may accelerate cystic progression and investigated tubular crystal deposition. We report that calcium oxalate (CaOx) crystal deposition led to rapid tubule dilation, activation of PKD-associated signaling pathways, and hypertrophy in tubule segments along the affected nephrons. Blocking mTOR signaling blunted this response and inhibited efficient excretion of lodged crystals. This mechanism of "flushing out" crystals by purposefully dilating renal tubules has not previously been recognized. Challenging PKD rat models with CaOx crystal deposition, or inducing calcium phosphate deposition by increasing dietary phosphorous intake, led to increased cystogenesis and disease progression. In a cohort of ADPKD patients, lower levels of urinary excretion of citrate, an endogenous inhibitor of calcium crystal formation, correlated with increased disease severity. These results suggest that PKD progression may be accelerated by commonly occurring renal crystal deposition which could be therapeutically controlled by relatively simple measures.

Impact of potassium citrate on urinary risk profile, glucose and lipid metabolism of kidney stone formers in Switzerland.

BackgroundHypocitraturia and hypercalciuria are the most prevalent risk factors in kidney stone formers (KSFs). Citrate supplementation has been introduced for metaphylaxis in KSFs. However, beyond its effects on urinary parameters and stone recurrence, only a few studies have investigated the impact of citrate on other metabolic pathways such as glucose or lipid metabolism.MethodsWe performed an observational study using data from the Swiss Kidney Stone Cohort. Patients were subdivided into two groups based on treatment with potassium citrate or not. The outcomes were changes of urinary risk parameters, haemoglobin A1c (HbA1c), fasting glucose, cholesterol and body mass index (BMI).ResultsHypocitraturia was present in 19.3% of 428 KSFs and potassium citrate was administered to 43 patients (10.0%) at a mean dosage of 3819 ± 1796 mg/day (corresponding to 12.5 ± 5.9 mmol/ day). Treatment with potassium citrate was associated with a significantly higher mean change in urinary citrate (P = 0.010) and urinary magnesium (P = 0.020) compared with no potassium citrate treatment. Exogenous citrate administration had no effect on cholesterol, fasting glucose, HbA1c and BMI. Multiple linear regression analysis demonstrated no significant association of 1,25-dihydroxyvitamin D3 [1,25(OH)2 D3] levels with urinary citrate excretion.ConclusionPotassium citrate supplementation in KSFs in Switzerland resulted in a beneficial change of the urinary risk profile by particularly increasing anti-lithogenic factors. Fasting glucose, HbA1c, cholesterol levels and BMI were unaffected by potassium citrate therapy after 3 months, suggesting that potassium citrate is safe and not associated with unfavourable metabolic side effects. Lastly, 1,25(OH)2 D3 levels were not associated with urinary citrate excretion.

Urine citrate excretion identifies changes in acid retention as eGFR declines in patients with chronic kidney disease.

Previous studies have shown that acid (H+) retention in patients with chronic kidney disease (CKD) but without metabolic acidosis increases as the estimated glomerular filtration rate (eGFR) decreases over time. The present study examined whether changes in urine excretion of the pH-sensitive metabolite citrate predicted changes in H+ retention over time in similar patients with CKD that were followed for 10 yr. We randomized 120 CKD2 nondiabetic, hypertension-associated nephropathy patients with plasma total CO2 of >24 mM to receive 0.5 meq·kg body wt-1·day-1 NaHCO3 ([Formula: see text]; n = 40), 0.5 meq·kg body wt-1·day-1 NaCl (NaCl; n = 40), or usual care (UC; n = 40). We assessed eGFR (CKD-EPI) and H+ retention by comparing the observed with expected plasma total CO2 increase 2 h after an oral NaHCO3 bolus (0.5 meq/kg body wt). Although 10 yr versus baseline eGFR was lower for each group, 10-yr eGFR was higher (P < 0.01) in [Formula: see text] (59.6 ± 4.8 ml·min-1·1.73 m-2) than NaCl and UC (52.1 ± 5.9 and 52.3 ± 4.1 ml·min-1·1.73 m-2, respectively) groups. Less eGFR preservation was associated with higher 10-yr versus baseline H+ retention in the NaCl group (26.5 ± 13.1 vs. 18.2 ± 15.3 mmol, P < 0.01) and UC group (24.8 ± 11.3 vs. 17.7 ± 10.9 mmol, P < 0.01) and with lower 10-yr versus baseline 8-h urine citrate excretion (UcitrateV) for the NaCl group (162 ± 47 vs. 196 ± 52 mg, respectively, P < 0.01) and UC group (153 ± 41 vs. 186 ± 42 mg, respectively, P < 0.01). Conversely, better eGFR preservation in the [Formula: see text] group was associated with no differences in 10-yr versus baseline H+ retention (14.2 ±13.5 vs. 16.1 ± 15.1 mmol, P = 1.00) or UcitrateV (212 ± 45 vs. 203 ± 49 mg, respectively, P = 0.74). An overall generalized linear model for repeated measures showed that UcitrateV predicted H+ retention (P < 0.01). Less eGFR preservation in patients with CKD2 without metabolic acidosis was associated with increased H+ retention that was predicted by decreased UcitrateV.

Dietary vinegar prevents kidney stone recurrence via epigenetic regulations.

BackgroundEpidemiological evidence of over 9000 people suggests that daily intake of vinegar whose principal bioactive component is acetic acid is associated with a reduced risk of nephrolithiasis. The underlying mechanism, however, remains largely unknown.MethodsWe examined the in vitro and in vivo anti-nephrolithiasis effects of vinegar and acetate. A randomized study was performed to confirm the effects of vinegar in humans.FindingsWe found individuals with daily consumption of vinegar compared to those without have a higher citrate and a lower calcium excretion in urine, two critical molecules for calcium oxalate (CaOx) kidney stone in humans. We observed that oral administration of vinegar or 5% acetate increased citrate and reduced calcium in urinary excretion, and finally suppressed renal CaOx crystal formation in a rat model. Mechanism dissection suggested that acetate enhanced acetylation of Histone H3 in renal tubular cells and promoted expression of microRNAs-130a-3p, −148b-3p and -374b-5p by increasing H3K9, H3K27 acetylation at their promoter regions. These miRNAs can suppress the expression of Nadc1 and Cldn14, thus enhancing urinary citrate excretion and reducing urinary calcium excretion. Significantly these mechanistic findings were confirmed in human kidney tissues, suggesting similar mechanistic relationships exist in humans. Results from a pilot clinical study indicated that daily intake of vinegar reduced stone recurrence, increased citrate and reduced calcium in urinary excretion in CaOx stone formers without adverse side effects.InterpretationVinegar prevents renal CaOx crystal formation through influencing urinary citrate and calcium excretion via epigenetic regulations. Vinegar consumption is a promising strategy to prevent CaOx nephrolithiasis occurrence and recurrence.FundNational Natural Science Foundations of China and National Natural Science Foundation of Guangdong Province.

Hydroxycitrate: a potential new therapy for calcium urolithiasis.

Alkali supplements are used to treat calcium kidney stones owing to their ability to increase urine citrate excretion which lowers stone risk by inhibiting crystallization and complexing calcium. However, alkali increases urine pH, which may reduce effectiveness for patients with calcium phosphate stones and alkaline urine. Hydroxycitrate is a structural analog of citrate, widely available as an over-the-counter supplement for weight reduction. In vitro studies show hydroxycitrate has the capacity to complex calcium equivalent to that of citrate and that it is an effective inhibitor of calcium oxalate monohydrate crystallization. In fact, hydroxycitrate was shown to dissolve calcium oxalate crystals in supersaturated solution in vitro. Hydroxycitrate is not known to be metabolized by humans, so it would not be expected to alter urine pH, as opposed to citrate therapy. Preliminary studies have shown orally ingested hydroxycitrate is excreted in urine, making it an excellent candidate as a stone therapeutic. In this article, we detail the crystal inhibition activity of hydroxycitrate, review the current knowledge of hydroxycitrate use in humans, and identify gaps in knowledge that require appropriate research studies before hydroxycitrate can be recommended as a therapy for kidney stones.

Urine citrate excretion as a marker of acid retention in patients with chronic kidney disease without overt metabolic acidosis

Acid (H+) retention appears to contribute to progressive decline in glomerular filtration rate (GFR) in patients with chronic kidney disease (CKD), including some patients without metabolic acidosis. Identification of patients with H+ retention but without metabolic acidosis could facilitate targeted alkali therapy; however, current methods to assess H+ retention are invasive and have little clinical utility. We tested the hypothesis that urine excretion of the pH-sensitive metabolite citrate can identify H+ retention in patients with reduced GFR but without overt metabolic acidosis. H+ retention was assessed based on the difference between observed and expected plasma total CO2 after an oral sodium bicarbonate load. The association between H+ retention and urine citrate excretion was evaluated in albuminuric CKD patients with eGFR 60-89 ml/min/1.73m2 (CKD 2, n=40) or >90 ml/min/1.73m2 (CKD 1, n= 26) before and after 30 days of base-producing fruits and vegetables. Baseline H+ retention was higher in CKD 2, while baseline urine citrate excretion was lower in CKD 2 compared to CKD 1. Base-producing fruits and vegetables decreased H+ retention in CKD 2 and increased urine citrate excretion in both groups. Thus, H+ retention is associated with lower urine citrate excretion, and reduction of H+ retention with a base-producing diet is associated with increased urine citrate excretion. These results support further exploration of the utility of urine citrate excretion to identify H+ retention in CKD patients with reduced eGFR but without metabolic acidosis, to determine their candidacy for kidney protection with dietary H+ reduction or alkali therapy.

Heritable traits that contribute to nephrolithiasis.

Urinary stones tend to cluster in families. Of the known risk factors, evidence is strongest for heritability of urinary calcium excretion. Recent studies suggest that other stone risk factors may have heritable components including urinary pH, citrate and magnesium excretion, and circulating vitamin D concentration. Several risk factors assumed purely environmental may also have heritable components, including dietary intake and thirst. Thus, future studies may reveal that genetics plays an even stronger role in urinary stone pathogenesis than previously known.

Impact of dyslipidemia on 24-h urine composition in adults without urolithiasis

PurposesTo evaluate the influence of dyslipidemia on 24-h urine composition in adults who were non-stone formers (NF).MethodsSamples for 24-h urine composition were analyzed from 584 NF adults without urolithiasis in a national six-city-based epidemiologic study. The samples were divided into groups based on total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL). The groups were compared based on demographic data and each component of 24-h urinalysis.ResultsThe numbers of participants in high TG, high TC, high LDL, and low HDL were 106, 175, 147, and 59, respectively. The high TG group had increased urinary excretions of oxalate [mean difference (MD) = 0.032 mmol, 95% confidence interval (CI): 0.000–0.065] and potassium (MD = 4.298 mmol, 95%CI: 0.182–8.414). Increased urinary excretion of calcium (MD = 0.531 mmol, 95%CI: 0.061–1.001), sodium (MD = 41.561 mmol, 95%CI: 9.179–73.942), and chloride (MD = 45.209 mmol, 95%CI: 12.118–78.299) were found in the high TC group. Interestingly, the high LDL group had a decreased urinary excretion of calcium (MD = − 0.573 mmol, 95%CI: -1.048 to − 0.097), oxalate (MD = − 0.038 mmol, 95%CI: -0.07 to − 0.006), sodium (MD = − 53.285 mmol, 95%CI: -85.823 to − 20.748), and chloride (MD = − 55.809 mmol, 95%CI: -89.035 to − 22.583). Increased urinary excretions of citrate (MD = 0.455 mmol, 95%CI: 0.076–0.835) and magnesium (MD = 0.697 mmol, 95%CI: 0.244–1.149) were found in the low HDL group.ConclusionsThe present study first investigated the effects of dyslipidemia on 24-h urinalysis in NF adults. Of note, high LDL and low HDL were found to be adversely related to kidney stone formation. However, people with high TG and high TC should be cautious of getting kidney stones.

Renal expression and urinary excretion of Na+/dicarboxylate cotransporter 1 (NaDC1) in obstructive nephropathy: a candidate biomarker for this pathology.

Obstructive nephropathy is characterized by alterations in renal function that depends on the degree and type of obstruction. To increase the knowledge about the physiopathological mechanisms involved in the renal damage associated with bilateral ureteral obstruction (BUO), we studied the renal expression and function (as urinary citrate excretion) of sodium-dependent dicarboxylate cotransporter (NaDC1) in rats. In addition, we evaluated the urinary excretion of NaDC1 as a candidate biomarker forthis pathology. Male Wistar rats underwent bilateral ureteral obstruction for 1 (BUO1), 2 (BUO2), 5 (BUO5), and 24 (BUO24) h or sham operation. After 24h of ureteral releasing, traditional parameters of renal function and citrate levels were determined, and NaDC1 levels were evaluated in total renal homogenates, apical plasma membranes, and urine by electrophoresis and Western blotting. Traditional parameters of renal function were only modified in BUO5 and BUO24. The renal expression of NaDC1 was decreased in BUO5 and BUO24, with a concomitant increase in urinary excretion of citrate. Moreover, the urinary excretion of NaDC1 increased after short times of ureteral obstruction (BUO1 and BUO2) and was positively correlated with the time elapsed after obstruction. The results obtained from the renal expression of NaDC1 could explain an adaptive mechanism to prevent the formation of kidney stones by increasing the levels of citrate, a calcium chelator. The urinary excretion of NaDC1 could be postulated as an early biomarker of obstructive nephropathy that also gives information about the duration of the obstruction.

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.

PD17-04 MAGNESIUM SUPPLEMENTATION IMPROVES URINARY CITRATE EXCRETION IN THE METABOLIC STONE CLINIC SETTING

You have accessJournal of UrologyStone Disease: Medical & Dietary Therapy I1 Apr 2018PD17-04 MAGNESIUM SUPPLEMENTATION IMPROVES URINARY CITRATE EXCRETION IN THE METABOLIC STONE CLINIC SETTING Natasza Posielski, Roy A. Jhagroo, Stephen Y. Nakada, and Kristina L. Penniston Natasza PosielskiNatasza Posielski More articles by this author , Roy A. JhagrooRoy A. Jhagroo More articles by this author , Stephen Y. NakadaStephen Y. Nakada More articles by this author , and Kristina L. PennistonKristina L. Penniston More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.966AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Urinary citrate (UCit) excretion is a well-described target of medical management of calcium stones. Urinary magnesium (UMg) excretion has been linked with UCit excretion, but this relationship has received little attention, especially in the context of medical management for hypocitraturia. We hypothesized that Mg supplementation could increase UMg in patients with lower excretion and that lower UCit excretion would be more favorably addressed with higher UMg excretion. METHODS With IRB approval, patients with low UMg (defined as ≤70mg/day) in their first urine collection were identified from patients seen between 2009-2016 in our multidisciplinary stone clinic. Those without two 24-hour urine collections, with >40% difference in urinary creatinine excretion, or >2 years between collections were excluded. Patients were separated into two groups based on those to whom over-the-counter Mg supplementation (300-500 mg/d) was recommended at baseline. Primary outcome measures included changes in UMg and UCit excretion. RESULTS Of 117 patients (age 57±16 y; M:F 48:69) meeting inclusion criteria, 40 (34%) were recommended Mg supplementation (Mg+) while 77 (66%) were not (no-Mg), although increased dietary Mg may have been suggested in some cases. The prevalence of patients with a history of calcium-containing stones was not different between groups (83 vs 100% for Mg+ and no-Mg groups, p=0.16). There was no difference in alkali prescription prevalence (50 and 53% for Mg+ and no-Mg groups) nor in baseline UCit excretion (352 vs 415 mg/d for Mg+ and no-Mg groups; p=0.26). A rise in UMg was observed (54 to 72 and 46 to 67 mg/d within Mg+ and no-Mg groups; p<0.001 for both, paired t-tests). Yet UCit increased only in the supplemented group (figure, A). Change in UCit differed by baseline UMg status and treatment group (figure, B). Among only patients with hypocitraturia (defined as <340 mg/d, prevalence 48% for both groups), UCit increased only in the Mg+ group (140 to 243, p=0.003; vs 176 to 209 mg/d for no-Mg). CONCLUSIONS Low UMg excretion was effectively increased with Mg supplementation. Moreover, lower UCit excretion increased significantly in patients on Mg supplementation vs. those not. Our results suggest that certain patients may require correction of low UMg as part of medical management for hypocitraturia. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e385 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Natasza Posielski More articles by this author Roy A. Jhagroo More articles by this author Stephen Y. Nakada More articles by this author Kristina L. Penniston More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

MP31-05 POTASSIUM CITRATE FOR URIC ACID STONE RISK: DOES DIABETES MATTER?

You have accessJournal of UrologyStone Disease: Medical & Dietary Therapy II1 Apr 2018MP31-05 POTASSIUM CITRATE FOR URIC ACID STONE RISK: DOES DIABETES MATTER? Kimberly A Maciolek, Kristina L Penniston, and Sara L Best Kimberly A MaciolekKimberly A Maciolek More articles by this author , Kristina L PennistonKristina L Penniston More articles by this author , and Sara L BestSara L Best More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.1034AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Potassium citrate (KCit) is recommended in the pharmacologic management of patients with hypocitraturia with or without acidic urine. It is indicated for the prevention of both calcium and uric acid stones. Diabetes mellitus (DM) is associated with acidic urine and increased risk for uric acid stones. While KCit is used in this patient population, its effectiveness has not been adequately assessed. We retrospectively evaluated 24-h urinary risk factors and changes in 24-h urine parameters associated with KCit therapy in cohorts of patients with and without DM. METHODS With IRB approval, we identified 161 stone formers (SFs) from clinical records, 32 of whom had DM. Patients were included if they underwent 24-h urine testing within 3 years before and after initiating KCit. Pre- and post-KCit urine parameters were compared between non-DM and DM SFs using univariate and multivariate analyses. Correcting for multiple statistical comparisons, a p-value of ≤0.003125 was required for significance. RESULTS Patients with DM were older (DM: 61 vs non-DM: 54, p=0.003) and had a higher BMI (34 vs 29, p<0.001). At baseline, SFs with DM had significantly lower urine pH (5.4 vs 6.1, p=0.002) and brushite RS (0.29 vs 1.2, p<0.0001). Similar baseline urine citrate (311 vs 251 mg/d, p=0.23) was observed. In both patients with and without DM, urinary potassium excretion increased (+24 mEq/d, p=0.0001; and +24 mEq/d, p<0.0001), suggesting KCit compliance. Patients in both groups achieved significant increases in urine citrate (DM, 311 to 606 mg/d, p<0.0001; non-DM, 251 to 449 mg/d, p<0.0001) and pH (DM, 5.4 to 6.4, p<0.0001; non-DM, 6.1 to 6.5, p<0.0001) and decreases in uric acid RS (DM, 2.3 to 0.51, p=0.0004; non-DM, 1.1 to 0.36, p<0.0001). SFs with DM but not those without DM exhibited a statistically significant increase in brushite RS (0.29 to 0.98, p=0.0003), likely due to higher urine pH, but nonetheless remained well below the risk cutoff of 2.0. CONCLUSIONS KCit therapy was associated with increased urine pH and citrate excretion in patients with DM, equivalent in patients without DM. While statistically equivalent, the increase in urinary citrate excretion was greater in patients with DM than in those without. Neither patients with nor without DM had clinically relevant increases in brushite RS while on KCit therapy. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e412-e413 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Kimberly A Maciolek More articles by this author Kristina L Penniston More articles by this author Sara L Best More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Cuantificación del riesgo de formación de cálculos cálcicos en la orina correspondiente a 2 momentos del día en un grupo de niños estudiados para descartar prelitiasis

BackgroundVarious genetic and environmental factors are involved in urolithiasis. The 2 most common metabolic abnormalities are the increase in urinary calcium and low urinary citrate excretion. The ratio calculated between the concentrations of both substances is a good risk marker for the formation of calcium stones. ObjectivesTo determine whether the risk of urinary calcium stone formation changes throughout the day in the same patient. MethodsWe studied 56 children (23V, 33M) to check if they had prelithiasis. Calcium, citrate, and creatinine concentrations were determined in two urine samples collected one before dinner and the other in the morning. It was collected if they had ultrasound stones and if there was a history of urolithiasis in first and/or second degree relatives. ResultsIn 25 patients (44.6%), renal ultrasound was positive for lithiasis (stones [n=9] and microlithiasis [n=16]). Forty of the 56 families (71.4%) had a history of urolithiasis. The percentage of abnormal urinary calcium (28.6%) concentrations and an abnormal calcium/citrate ratio (69.6%) was higher in the first urine of the day. The calcium/citrate ratio was the only studied parameter that was related to a family history of urolithiasis. There were no differences in urinary parameters between patients with and without ultrasound-confirmed kidney stones. ConclusionsUrinary concentrations of calcium and the calcium/citrate ratio vary throughout the day. Urine produced at night has a higher risk of urinary calcium stone formation.

Quantification of the risk of urinary calcium stone formation in the urine collected at 2 times of the day in a group of children studied to rule out prelithiasis

BackgroundVarious genetic and environmental factors are involved in urolithiasis. The 2 most common metabolic abnormalities are the increase in urinary calcium and low urinary citrate excretion. The ratio calculated between the concentrations of both substances is a good risk marker for the formation of calcium stones. ObjectivesTo determine whether the risk of urinary calcium stone formation changes throughout the day in the same patient. MethodsWe studied 56 children (23 V, 33 M) to check if they had prelithiasis. Calcium, citrate, and creatinine concentrations were determined in two urine samples collected one before dinner and the other in the morning. It was collected if they had ultrasound stones and if there was a history of urolithiasis in first and/or second degree relatives. ResultsIn 25 patients (44.6%), renal ultrasound was positive for lithiasis (stones [n=9] and microlithiasis [n=16]). Forty of the 56 families (71.4%) had a history of urolithiasis. The percentage of abnormal urinary calcium (28.6%) concentrations and an abnormal calcium/citrate ratio (69.6%) was higher in the first urine of the day. The calcium/citrate ratio was the only studied parameter that was related to a family history of urolithiasis. There were no differences in urinary parameters between patients with and without ultrasound-confirmed kidney stones. ConclusionsUrinary concentrations of calcium and the calcium/citrate ratio vary throughout the day. Urine produced at night has a higher risk of urinary calcium stone formation.