Real-World Effectiveness of Preventive Pharmacological Therapy in Patients With Urolithiasis: A Retrospective Cohort Study.

RATIONALE & OBJECTIVE: Data supporting the efficacy of preventive pharmacological therapy (PPT) to reduce urolithiasis recurrence are based on clinical trials with composite outcomes that incorporate imaging findings and which have uncertain clinical significance. This study sought to evaluate if the use of PPT leads to fewer symptomatic stone events. STUDY DESIGN: Retrospective cohort study. SETTING: & Participants: Medicare enrollees with urolithiasis who completed 24-hour urine collections that revealed hypercalciuria, hypocitraturia, low urine pH, or hyperuricosuria. EXPOSURE: PPT (thiazide diuretics for hypercalciuria, alkali for hypocitraturia or low urine pH, or uric acid lowering drugs for hyperuricosuria) categorized as, 1) adherent to guideline-concordant PPT, 2) nonadherent to guideline-concordant PPT, or 3) untreated. OUTCOME: Symptomatic stone event occurrence (emergency department [ED] visit or hospitalization for urolithiasis or stone-directed surgery). ANALYTICAL APPROACH: Cox proportional hazards regression. RESULTS: Among 13,942 patients, 31.0% were prescribed PPT. Compared to no treatment, concordant/adherent PPT use was associated with a significantly lower hazard of symptomatic stone events for patients with hypercalciuria (hazard ratio [HR], 0.736 [95% confidence interval (CI), 0.593 to 0.915]) and low urine pH (HR, 0.804 [CI, 0.650 to 0.996]) but not for patients with hypocitraturia or hyperuricosuria. These associations were largely driven by significantly lower rates of ED visits after initiating PPT among the concordant/adherent group versus untreated patients. Patients with hypercalciuria had adjusted two-year predicted probabilities of a visit of 3.8% [95% CI, 2.5% to 5.2%%] and 6.9% [95% CI, 6.0% to 7.7%] for the concordant/adherent PPT and no-treatment groups, respectively. Among patients with low urine pH, these probabilities were 4.3% [95% CI, 2.9% to 5.7%] and 7.3% [95% CI, 6.5% to 8.0%] for the concordant/adherent PPT and no-treatment groups, respectively. LIMITATIONS: Potential bias from the possibility that patients prescribed PPT had more severe disease than untreated patients. CONCLUSION: Patients with urolithiasis and hypercalciuria who were adherent to treatment with thiazide diuretics as well as those with low urine pH adherent to prescribed alkali therapy had fewer symptomatic stone events than untreated patients.

Understanding the Barriers to Preventive Pharmacological Therapy Use in Older Patients With Urinary Stone Disease.

INTRODUCTION: Despite compelling clinical trial evidence and professional society guideline recommendations, prescription rates of preventative pharmacological therapy (PPT) for urinary stone disease are low. We sought to understand how patient- and clinician-level factors contribute to the decision to prescribe PPT after an index stone event. METHODS: We identified Medicare beneficiaries with urinary stone disease who had a 24-hour urine collection processed by a central laboratory. Among the subset with a urine chemistry abnormality (ie, hypercalciuria, hypocitraturia, hyperuricosuria, or low urine pH), we determined whether PPT was prescribed within 6 months of their collection. After assigning patients to the clinicians who ordered their collection, we fit multilevel models to determine how much of the variation in PPT prescription was attributable to patient vs clinician factors. RESULTS: Of the 11,563 patients meeting inclusion criteria, 33.6% were prescribed PPT. There was nearly sevenfold variation between the treating clinician with the lowest prescription rate (11%) and the one with the highest (75%). Nineteen percent of this variation was attributable to clinician factors. After accounting for measured patient differences and clinician volume, patients had twice the odds of being prescribed PPT if they were treated by a nephrologist (odds ratio [OR], 2.15; 95% CI, 1.79-2.57) or a primary care physician (OR, 1.78; 95% CI, 1.22-2.58) compared to being treated by a urologist. CONCLUSIONS: These findings suggest that the type of clinician whom a patient sees for his stone care determines, to a large extent, whether PPT will be prescribed.

First Reported Case of a Pyrophosphate Kidney Stone in a Human.

Urolithiasis composed of pyrophosphate salts has only been reported in animals, in the form of potassium magnesium pyrophosphate. However, there have been no reports of pyrophosphate stones in humans. Hypophosphatasia is an inherited disease characterized by low alkaline phosphatase activity and elevated levels of pyrophosphate in blood and urine. Urolithiasis is a part of the hypophosphatasia phenotype. The role of elevated urine pyrophosphate levels in the formation of stones in hypophosphatasia is unknown. Here, we report a case of a 60-year-old man with recurrent urolithiasis. The patient's most recent presentation was gross hematuria and his computed tomography scan showed bilateral kidney stones. Stones were removed via retrograde intrarenal surgery. Stone analysis revealed a composition of potassium magnesium pyrophosphate. The patient also has a long history of fracturing bone disease which led to the consideration of hypophosphatasia as the cause of both his bone disease and pyrophosphate stones. Hypophosphatasia was confirmed by genetic analysis. Pyrophosphate has been of interest in the fields of mineral metabolism because of its action as a crystallization inhibitor. However, pyrophosphate at elevated concentrations in the presence of divalent cations can exceed its solubility. Nephrocalcinosis and stone disease have been described in hypophosphatasia; stones have been assumed to be calcium phosphate but no compositional analysis has been reported. This is the first report of human stones composed of pyrophosphate salts, which led to the subsequent diagnosis of hypophosphatasia in this patient.

Effect of a high-citrate beverage on urine chemistry in patients with calcium kidney stones.

A well-accepted strategy to prevent kidney stones is to increase urine volume by increasing oral intake of fluids, especially water, to lower supersaturation of the relevant, relatively insoluble salts, and thereby lower the risk of precipitation. Randomized controlled trials have shown that this strategy works. It is inexpensive, safe, and intuitively attractive to patients. However, although any beverage can increase urine volume, and citrus juices can increase urine citrate content and pH, no beverage other than water has been clearly shown by randomized controlled trial to prevent kidney stones. We designed an innovative, palatable, low-calorie, high alkali citrate beverage to prevent kidney stones, called Moonstone. One packet of Moonstone powder, mixed in 500 ml of water, contains 24.5 meq of alkali citrate. We administered one packet twice a day to ten calcium stone formers. Moonstone resulted in an increase in mean 24-h urine citrate and urine pH, and a decrease in supersaturation of calcium oxalate in calcium stone formers compared to an equal volume of water. These changes, comparable to those seen in a prior study of a similar amount of (potassium-magnesium) citrate, will likely be associated with a clinically meaningful reduction in kidney stone burden in patients with calcium stones. The effect to increase urine pH would also be expected to benefit patients with uric acid and cystine stones, groups that we hope to study in a subsequent study. The study preparation was well tolerated and was selected as a preferred preventative strategy by about half the participants. Moonstone is an alternative, over-the-counter therapy for kidney stone prevention.

Associations between Net Gastrointestinal Alkali Absorption, 24-Hour Urine Lithogenic Factors, and Kidney Stones.

BACKGROUND: It is not clear whether kidney stone formers have an abnormal handling of alkali and acid precursors in the gut, which might affect urine composition and ultimately stone formation. In this study, we aimed to investigate the determinants of net gastrointestinal alkali absorption and its associations with key urinary parameters in a large group of stone formers and non-stone formers. METHODS: Data were collected from three independent cohorts with at least one 24-hour urine collection. We explored potential determinants of net gastrointestinal alkali absorption and the association between net gastrointestinal alkali absorption, urinary parameters, and stone former status. Finally, we estimated the proportion of the association between urine parameters and stone former status explained by differences in net gastrointestinal alkali absorption. RESULTS: The analysis included 6067 participants (1102 men and 4965 women; 698 and 1804 of whom were stone formers, respectively). Average net gastrointestinal alkali absorption values were consistently lower in stone formers across the three cohorts (from -15.0 to -4.9 mEq/d). Age was directly associated with net gastrointestinal alkali absorption, whereas body mass index and net endogenous acid production were inversely associated. Net gastrointestinal alkali absorption was inversely associated with supersaturation for calcium oxalate, uric acid, and renal net acid excretion and directly associated with supersaturation for calcium phosphate, urine pH, and citrate. The odds of being a stone former was 15% (13%-17%) lower per 10 mEq/24 hours higher net gastrointestinal alkali absorption. Differences in net gastrointestinal alkali absorption explained a modest amount of the differences between stone formers and non-stone formers for supersaturation for calcium oxalate (6.3%) and a sizable amount for supersaturation for uric acid (15.2%), urine pH (38.3%), citrate (26.2%), and renal net acid excretion (63.4%). CONCLUSIONS: Kidney stone formers have lower net gastrointestinal alkali absorption, and this explains differences in urine composition and the likelihood of stone formation.

Potential for Urolithiasis-related Research Using the Novel Medicare-Litholink Database.

INTRODUCTION: To overcome the data availability hurdle of observational studies on urolithiasis, we linked claims data with 24-hour urine results from a large cohort of adults with urolithiasis. This database contains the sample size, clinical granularity, and long-term follow-up needed to study urolithiasis on a broad level. METHODS: We identified adults enrolled in Medicare with urolithiasis who had a 24-hour urine collection processed by Litholink (2011 to 2016). We created a linkage of their collections results and paid Medicare claims. We characterized them across a variety of sociodemographic and clinical factors. We measured frequencies of prescription fills for medications used to prevent stone recurrence, as well as frequencies of symptomatic stone events, among these patients. RESULTS: In total, there were 11,460 patients who performed 18,922 urine collections in the Medicare-Litholink cohort. The majority were male (57%), White (93.2%), and lived in a metropolitan county (51.5%). Results from their initial urine collections revealed abnormal pH to be the most common abnormality (77.2%), followed by low volume (63.8%), hypocitraturia (45.6%), hyperoxaluria (31.1%), hypercalciuria (28.4%), and hyperuricosuria (11.8%). Seventeen percent had prescription fills for alkali monotherapy, and 7.6% had prescription fills for thiazide diuretic monotherapy. Symptomatic stone events occurred in 23.1% at 2 years of follow-up. CONCLUSIONS: We successfully linked Medicare claims with results from 24-hour urine collections performed by adults that were processed by Litholink. The resulting database is a unique resource for future studies on the clinical effectiveness of stone prevention strategies and urolithiasis more broadly.

Beyond the Urine Anion Gap: In Support of the Direct Measurement of Urinary Ammonium.

Ammonium is a major urinary buffer that is necessary for the normal excretion of the daily acid load. Its urinary rate of excretion (UNH4) may be increased several fold in the presence of extrarenal metabolic acidosis. Therefore, measurement of UNH4 can provide important clues about causes of metabolic acidosis. Because UNH4 is not commonly measured in clinical laboratories, the urinary anion gap (UAG) was proposed as its surrogate about 4 decades ago, and it is still frequently used for that purpose. Several published studies strongly suggest that UAG is not a good index of UNH4 and support the concept that direct measurement of UNH4 is an important parameter to define in clinical nephrology. Low UNH4 levels have recently been found to be associated with a higher risk of metabolic acidosis, loss of kidney function, and death in persons with chronic kidney disease, while surrogates like the UAG do not recapitulate this risk. In order to advance the field it is necessary for the medical community to become more familiar with UNH4 levels in a variety of clinical settings. Herein, we review the literature, searching for available data on UNH4 under normal and various pathological conditions, in an attempt to establish reference values to interpret UNH4 results if and when UNH4 measurements become available as a routine clinical test. In addition, we present original data in 2 large populations that provide further evidence that the UAG is not a good predictor of UNH4. Measurement of urine NH4 holds promise to aid clinicians in the care of patients, and we encourage further research to determine its best diagnostic usage.

Association of Urine Findings with Metabolic Syndrome Traits in a Population of Patients with Nephrolithiasis.

Background: The odds of nephrolithiasis increase with more metabolic syndrome (MetS) traits. We evaluated associations of metabolic and dietary factors from urine studies and stone composition with MetS traits in a large cohort of stone-forming patients. Methods: Patients >18 years old who were evaluated for stones with 24-hour urine collections between July 2009 and December 2018 had their records reviewed retrospectively. Patient factors, laboratory values, and diagnoses were identified within 6 months of urine collection and stone composition within 1 year. Four groups with none, one, two, and three or four MetS traits (hypertension, obesity, dyslipidemia, and diabetes) were evaluated. Trends across groups were tested using linear contrasts in analysis of variance and analysis of covariance. Results: A total of 1473 patients met the inclusion criteria (835 with stone composition). MetS groups were 684 with no traits, 425 with one trait, 211 with two traits, and 153 with three or four traits. There were no differences among groups for urine volume, calcium, or ammonium excretion. There was a significant trend (P<0.001) for more MetS traits being associated with decreasing urine pH, increasing age, calculated dietary protein, urine uric acid (UA), oxalate, citrate, titratable acid phosphate, net acid excretion, and UA supersaturation. The ratio of ammonium to net acid excretion did not differ among the groups. After adjustment for protein intake, the fall in urine pH remained strong, while the upward trend in acid excretion was lost. Calcium oxalate stones were most common, but there was a trend for more UA (P<0.001) and fewer calcium phosphate (P=0.09) and calcium oxalate stones (P=0.01) with more MetS traits. Conclusions: Stone-forming patients with MetS have a defined pattern of metabolic and dietary risk factors that contribute to an increased risk of stone formation, including higher acid excretion, largely the result of greater protein intake, and lower urine pH.

Neglected analytes in the 24-h urine: ammonium and sulfate.

PURPOSE OF REVIEW: Evaluation of the kidney stone patient includes measurement of 24 h urine chemistries. This review summarizes the application of physiologic principles to the interpretation of urine chemistries, using sulfate and ammonium to estimate diet acid load, and the renal response. RECENT FINDINGS: There has been increased recognition of the need to measure urine ammonium excretion in the clinical setting in order to understand renal acid excretion. Some 24 h urine kidney stone panels include ammonium measurements, providing an opportunity to apply this measurement to clinical practice. In order to better interpret ammonium excretion, one needs an estimate of dietary acid load to understand the driving forces for ammonium excretion. Sulfate is also included in some kidney stone panels and functions as an estimate of diet acid load. Combining these analytes with urine pH, the clinician can quickly estimate dietary stone risk as well as potential bowel disease, acidification disorders, and the presence of urease producing bacteria; all of which can affect stone risk. SUMMARY: Measurement of ammonium and sulfate excretion along with urine pH provide important insights into the acid/alkali content of diet, presence and severity of bowel disease, presence of renal acidification disorders, and urinary infection.

Effect of antibiotic treatment on Oxalobacter formigenes colonization of the gut microbiome and urinary oxalate excretion.

The incidence of kidney stones is increasing in the US population. Oxalate, a major factor for stone formation, is degraded by gut bacteria reducing its intestinal absorption. Intestinal O. formigenes colonization has been associated with a lower risk for recurrent kidney stones in humans. In the current study, we used a clinical trial of the eradication of Helicobacter pylori to assess the effects of an antibiotic course on O. formigenes colonization, urine electrolytes, and the composition of the intestinal microbiome. Of 69 healthy adult subjects recruited, 19 received antibiotics for H. pylori eradication, while 46 were followed as controls. Serial fecal samples were examined for O. formigenes presence and microbiota characteristics. Urine, collected serially fasting and following a standard meal, was tested for oxalate and electrolyte concentrations. O. formigenes prevalence was 50%. Colonization was significantly and persistently suppressed in antibiotic-exposed subjects but remained stable in controls. Urinary pH increased after antibiotics, but urinary oxalate did not differ between the control and treatment groups. In subjects not on antibiotics, the O. formigenes-positive samples had higher alpha-diversity and significantly differed in Beta-diversity from the O. formigenes-negative samples. Specific taxa varied in abundance in relation to urinary oxalate levels. These studies identified significant antibiotic effects on O. formigenes colonization and urinary electrolytes and showed that overall microbiome structure differed in subjects according to O. formigenes presence. Identifying a consortium of bacterial taxa associated with urinary oxalate may provide clues for the primary prevention of kidney stones in healthy adults.

Evidence for abnormal linkage between urine oxalate and citrate excretion in human kidney stone formers.

BACKGROUND: Animal models have demonstrated an interactive relationship between the epithelial anion exchanger SLC26A6 and transporter NaDC-1 that regulates citrate and oxalate homeostasis. This relationship is a potential mechanism to protect against kidney stones as higher urine oxalate is accompanied by higher urine citrate but it has not been explored in humans. METHODS: We examined 24-h urine data on 13,155 kidney stone forming patients (SF) from separate datasets at the University of Chicago and Litholink, a national laboratory, and 143 non-kidney stone forming participants (NSF) to examine this relationship in humans. We used multivariate linear regression models to examine the association between oxalate and citrate in all study participants and separately in SF and NSF. RESULTS: Higher urinary oxalate was associated with higher urinary citrate in both SF and NSF. In NSF, the multivariate adjusted urine citrate excretion was 3.0 (1.5-4.6) (mmol)/creatinine (mmol) per oxalate (mmol)/creatinine (mmol). In SF, the multivariate adjusted urine citrate excretion was 0.3 (0.2-0.4) (mmol)/creatinine (mmol) per oxalate (mmol)/creatinine (mmol). CONCLUSIONS: Higher urinary oxalate excretion was associated with higher urinary citrate excretion and this effect was larger in non-kidney stone forming participants compared with those who form kidney stones.

Complementary and Alternative Medicine Use in First-time and Recurrent Kidney Stone Formers.

OBJECTIVE: To describe the patterns of complementary and alternative medicine (CAM) among patients with kidney stones and analyze the alkali content of commonly used CAM therapies. METHODS: We prospectively conducted structured interviews with patients who presented to a specialty stone clinic for the management of kidney stones. Open-ended questions were used to elicit information regarding CAM knowledge, formulation/dosing, and patterns of use. Several common CAM therapies were then analyzed for their alkali, organic anion, and sugar content. RESULTS: Of 103 subjects, 82 (80%) patients reported knowledge of CAM and 52 (50%) reported using CAM. Patients with recurrent kidney stones were more likely to report using CAM than patients with first-time episodes (56% vs 26%, P = 0.04). Some respondents reported their condition decreased in severity or frequency since starting CAM therapy (17%) and improvements in pain (12%). Total alkali content per serving of the tested supplements was 0 mEq (Stonebreaker), 1.5 mEq (Ocean Spray Cranberry Juice Cocktail), 4.7 mEq (Lakewood Pure Cranberry Juice), 0.6 mEq (Braggs Apple Cider Vinegar), 11.9 mEq (LithoBalance), 9.5 mEq (Simply Grapefruit Juice), 19.8 mEq (KSP-Key Lime), and 20.2 mEq (KSP-Very Berry). CONCLUSION: Patients with kidney stones may use CAM to alleviate symptoms or prevent recurrence. Commercially available CAM therapies may contain comparable alkali content to commonly prescribed citrate therapy. These data suggest that providers should be prepared to discuss the role of CAM with their patients.

Effect of Bicarbonate on Net Acid Excretion, Blood Pressure, and Metabolism in Patients With and Without CKD: The Acid Base Compensation in CKD Study.

RATIONALE & OBJECTIVE: Patients with CKD are at elevated risk of metabolic acidosis due to impaired net acid excretion (NAE). Identifying early markers of acidosis may guide prevention in chronic kidney disease (CKD). This study compared NAE in participants with and without CKD, as well as the NAE, blood pressure (BP), and metabolomic response to bicarbonate supplementation. STUDY DESIGN: Randomized order, cross-over study with controlled feeding. SETTING & PARTICIPANTS: Participants consisted of 8 patients with CKD (estimated glomerular filtration rate 30-59mL/min/1.73m2 or 60-70mL/min/1.73m2 with albuminuria) and 6 patients without CKD. All participants had baseline serum bicarbonate concentrations between 20 and 28 mEq/L; they did not have diabetes mellitus and did not use alkali supplements at baseline. INTERVENTION: Participants were fed a fixed-acid-load diet with bicarbonate supplementation (7 days) and with sodium chloride control (7 days) in a randomized order, cross-over fashion. OUTCOMES: Urine NAE, 24-hour ambulatory BP, and 24-hour urine and plasma metabolomic profiles were measured after each period. RESULTS: During the control period, mean NAE was 28.3±10.2 mEq/d overall without differences across groups (P=0.5). Urine pH, ammonium, and citrate were significantly lower in CKD than in non-CKD (P<0.05 for each). Bicarbonate supplementation reduced NAE and urine ammonium in the CKD group, increased urine pH in both groups (but more in patients with CKD than in those without), and increased; urine citrate in the CKD group (P< 0.2 for interaction for each). Metabolomic analysis revealed several urine organic anions were increased with bicarbonate in CKD, including 3-indoleacetate, citrate/isocitrate, and glutarate. BP was not significantly changed. LIMITATIONS: Small sample size and short feeding duration. CONCLUSIONS: Compared to patients without CKD, those with CKD had lower acid excretion in the form of ammonium but also lower base excretion such as citrate and other organic anions, a potential compensation to preserve acid-base homeostasis. In CKD, acid excretion decreased further, but base excretion (eg, citrate) increased in response to alkali. Urine citrate should be evaluated as an early and responsive marker of impaired acid-base homeostasis. FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases and the Duke O'Brien Center for Kidney Research. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT02427594.

Microbial genetic and transcriptional contributions to oxalate degradation by the gut microbiota in health and disease.

Over-accumulation of oxalate in humans may lead to nephrolithiasis and nephrocalcinosis. Humans lack endogenous oxalate degradation pathways (ODP), but intestinal microbes can degrade oxalate using multiple ODPs and protect against its absorption. The exact oxalate-degrading taxa in the human microbiota and their ODP have not been described. We leverage multi-omics data (>3000 samples from >1000 subjects) to show that the human microbiota primarily uses the type II ODP, rather than type I. Furthermore, among the diverse ODP-encoding microbes, an oxalate autotroph, Oxalobacter formigenes, dominates this function transcriptionally. Patients with inflammatory bowel disease (IBD) frequently suffer from disrupted oxalate homeostasis and calcium oxalate nephrolithiasis. We show that the enteric oxalate level is elevated in IBD patients, with highest levels in Crohn's disease (CD) patients with both ileal and colonic involvement consistent with known nephrolithiasis risk. We show that the microbiota ODP expression is reduced in IBD patients, which may contribute to the disrupted oxalate homeostasis. The specific changes in ODP expression by several important taxa suggest that they play distinct roles in IBD-induced nephrolithiasis risk. Lastly, we colonize mice that are maintained in the gnotobiotic facility with O. formigenes, using either a laboratory isolate or an isolate we cultured from human stools, and observed a significant reduction in host fecal and urine oxalate levels, supporting our in silico prediction of the importance of the microbiome, particularly O. formigenes in host oxalate homeostasis.

Nephrolithiasis and Elevated Urinary Ammonium: A Matched Comparative Study.

OBJECTIVE: To describe the associations between elevated urinary ammonium and clinical characteristics of kidney stone formers. A 24-hour urine test is recommended in high-risk patients to identify urinary abnormalities and select interventions to reduce the recurrence risk. While elevations in urine ammonium may be seen in acidosis, diarrhea, high protein diets or due to pathogenic bacteria, the clinical characteristics of these patients have not been previously described. METHODS: We retrospectively identified adult patients with kidney stone disease who completed a 24-hour urine at our institution between 2006 and 2017. Patients with elevated urinary ammonium were identified (n = 121) and matched 1:1 by age and sex to controls for an overall cohort of n = 242. Differences in medical and surgical history, 24-hour urine analytes and stone composition were compared. RESULTS: Among 3625 24-hour urine studies screened, 7.1% of patients showed high urinary ammonium. In our study cohort, patients with elevated urinary ammonium also showed higher urine volume, oxalate, calcium, uric acid, sodium, chloride, and sulfate. Clinically, these patients had higher body mass index, and more often had a history of recurrent urinary tract infections, diabetes, gout, bowel resection, and urinary reconstruction history. Struvite stones tended to be more common in the elevated ammonium group vs control (n = 7 vs 1, P = .07). CONCLUSION: Elevated urinary ammonium among kidney stone patients is relatively uncommon. However, these patients have higher rates of comorbid metabolic conditions, urinary tract infections, and bowel surgery. This finding should prompt further review of the patient's history and may help direct prevention strategies.

Using Low-Calorie Orange Juice as a Dietary Alternative to Alkali Therapy.

Purpose: The pursuit of a dietary source to increase urine pH and citrate in stone formers has been ongoing for >30 years. Early evidence showed that orange juice (OJ) contains alkali and citrate, but high sugar and ascorbic acid content limited the use of OJ as a viable daily source of alkali. Recently, novel low-calorie OJs have emerged and could potentially be a better option. Methods: Beverages with high concentrations of alkali citrate and malate were identified using ion chromatography. Two low-calorie OJ beverages, in addition to crystal light lemonade beverage (CLLB), were chosen. Healthy volunteers (5 men, 5 women) drank 1 L of OJ or CLLB with 1 L water daily for 7 days, and then completed a 24-hour urinalysis. A washout week was instituted between trial weeks. The study design is a prospective randomized crossover control trial. A paired analysis using comparison of means was used to evaluate low-calorie OJ and CLLB. Volunteers had no prior history of kidney stones and maintained a journal with beverage compliance, side effect (SE), and dietary consumption data. Results: Tropicana 50 (TRP50), Kroger low-calorie OJ (KLCO), and CLLB were found to have a total alkali content of 56.60, 47.9, and 17.3 mEq/L, respectively, based on ion chromatography. Consumption of all three beverages raised urinary citrate (116.6 [-118 to 373, 177.9 [-3 to 359], 155.6 [-4 to 237] ▵mg/day 95% confidence interval) and urinary pH (0.25 [0.08-0.53], 0.74 [0.41-1.07 p < 0.05], 0.25 [0.25-0.64]), respectively, compared with water phase. Based on journal entries by volunteers, TRP50 had the most SEs (90% participants) felt to be a result of the artificial sweetener (Stevia®). Conclusion: Low-calorie OJs, and to a lesser extent CLLB, have alkali and citrate based on ion chromatography. Daily consumption by healthy volunteers of KLCO can raise urinary pH.

Assessment of conservative dietary management as a method for normalization of 24-h urine pH in stone formers.

Low urine pH is a metabolic risk factor for stone formation. While medical therapy is typically prescribed (as urinary alkalinization), patients typically prefer dietary modifications. We aimed to assess capacity to alter urine pH with dietary management alone. We analyzed a retrospective cohort of stone formers seen between 2000 and 2015 with multiple 24-h urine collections (24hUC). Patients ≥ 18 years old with low urine pH (< 6.0) were included; those prescribed alkalinizing agents or thiazides were excluded. Demographic data, 24hUC parameters, and medications were abstracted. 24hUC was utilized to calculate gastrointestinal alkali absorption (GIAA). The primary outcome was urine pH ≥ 6.0 on second 24hUC. Predictors were selected utilizing multivariable logistic regression. The database consisted of 2197 stone formers; 224 of these met inclusion criteria. On second 24hUC, 124 (55.4%) achieved a favorable pH ≥ 6.0. On univariable analysis, a second pH ≥ 6.0 was associated with high initial pH, low initial sulfate, younger age, increase in citrate/GIAA/urine volume, and decrease in ammonium (P < 0.02). On multivariable analysis, high initial pH (OR = 23.64, P < 0.001), high initial GIAA (OR = 1.03, P = 0.001), lower initial sulfate (OR = 0.95, P < 0.001), increase in urine volume (OR = 2.19, P = 0.001), increase in GIAA (OR = 8.6, P < 0.001), increase in citrate (OR = 2.7, P = 0.014), decrease in ammonium (OR = 0.18, P < 0.001), and younger age (OR = 0.97, P = 0.025) were associated with a second pH ≥ 6.0. The analysis demonstrated a corrected AUC of 0.853. These data suggest that certain dietary recommendations (increases in urine volume, citrate, GIAA, and decreased acid load) may normalize urine pH in a select group of patients. This may allow urologists to counsel patients with low urine pH on possibility of success with dietary modification alone.

A laboratory-based algorithm to predict future kidney function decline in older adults with reduced estimated glomerular filtration rate
.

BACKGROUND: Reduced estimated glomerular filtration rate (eGFR) in older adults is common and may reflect normal aging or significant kidney disease. Our objective was to develop a predictive model to better triage these individuals using routine laboratory data. MATERIALS AND METHODS: Using a large US laboratory data set, we calculated individual eGFR regression slopes for 43,523 individuals aged 60 - 75 years with baseline eGFRs between 30 and 59 mL/min/1.73m2. We developed general linear models to predict the eGFR regression slope using urine protein measurements and other routinely available laboratory data as dependent variables. We validated these models on a similar data set comprised of 11,979 individuals. RESULTS: In a model utilizing log10 urine albumin/creatinine (UACR), the variables that significantly predicted the eGFR regression slope were log10 UACR, initial eGFR, serum albumin, chloride, glucose, and aspartate aminotransferase (AST). In an otherwise identical model substituting log10 urine protein/creatinine (UPCR) for UACR, results were similar except that serum calcium was significant and AST was not. We analyzed the correspondence between actual eGFR regression slopes and those predicted by our models using receiver operator characteristic (ROC) statistics to calculate areas under the curves (AUC) for four eGFR slope cut points: -2, -3, -4, and -5 mL/min/year. AUCs using the UACR and UPCR models ranged from 0.716 to 0.900 and 0.751 to 0.868, respectively, for the training data set. Results were nearly identical for the validation data set. CONCLUSION: Use of a laboratory-based predictive model of eGFR decline for older adults with eGFR 30 - 59 mL/min/1.73m2 may help distinguish between individuals with and without risk for further decline in kidney function.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.