Spot urinary citrate-to-creatinine ratio is a marker for acid-base status in chronic kidney disease.

Due to multiple compensating mechanisms, the serum bicarbonate concentration is a relatively insensitive marker of acid-base status; especially in chronic kidney disease (CKD). This is a major drawback that impairs the ability to diagnose acid excess or monitor alkali therapy. We postulated that it is more logical to measure the compensatory defense mechanism(s) rather than the defended parameter, which remains normal if the compensation is successful. Therefore, a retrospective cross-sectional study was performed in 1733 stone formers along with a prospective cross-sectional study of 22 individuals with normal kidney function and 50 patients in different stages of CKD. While serum bicarbonate was flat and did not fall below the reference range until near CKD stage 5, citrate excretion (24-hour urinary citrate excretion rate; urinary citrate-to-creatinine ratio, in the retrospective analysis, and spot urinary citrate-to-creatinine ratio in the prospective study) progressively and significantly declined starting from CKD stage 2. Following an acute acid load in 25 participants with a wide range of estimated glomerular filtration rates, the urinary citrate-to-creatinine ratio inversely and significantly associated with acid accumulation, whereas serum bicarbonate did not. We compared changes in serum bicarbonate and urinary citrate-to-creatinine ratio in response to alkali therapy in patients with CKD stage 3 or 4 started on potassium citrate in our kidney stone database. With alkali therapy, there was no change in serum bicarbonate, but the urinary citrate-to-creatinine ratio rose consistently in all patients adherent to potassium citrate therapy. Thus, the urinary citrate-to-creatinine ratio (the defense mechanism) is a potential easily implementable, pragmatic, and a superior parameter to serum bicarbonate (the defended entity) to assess acid-base status, and monitor alkali therapy. Additional studies are needed before a clinical test can be devised.

Dietary effects on urinary physicochemistry in Navy bottlenose dolphins (Tursiops truncatus) for the prevention of ammonium urate kidney stones.

Bottlenose dolphins are susceptible to developing ammonium urate (NH4U) kidney stones. The current study was designed to test the hypothesis that diet influences the urinary physicochemistry risk factors associated with nephrolithiasis in dolphins. A comprehensive nutrient analysis was performed revealing that the baseline diet (BD) commonly fed to dolphins under professional care had a greater purine content and a more negative dietary cation-anion difference (DCAD) when compared with a model diet consumed by free-ranging dolphins. A modified diet (MD) was formulated to include free-ranging diet fish species and achieve a more positive DCAD. The BD had a more negative DCAD (-52 mEq/Mcal metabolizable energy) when compared with the MD (+51 mEq/Mcal ME), which more closely approximated the DCAD of the free-ranging model diet (+152 mEq/Mcal ME). Six dolphins (with stones) were fed the BD followed by the MD for a minimum of 4 wk. At the end of each feeding trial, a 6-h continuous urine collection was performed to compare urine parameters of dolphins fed the BD versus MD. Dolphins consuming the MD demonstrated a significant decrease in urinary ammonium, net acid excretion, saturation index of ammonium urate, and phosphorous, and a significant increase in urinary citrate and net gastrointestinal (GI) alkali absorption, as compared with urine parameters assessed when fed the BD. Increasing the proportion of free-ranging diet fish species and optimizing the DCAD positively influenced some of the risk factors believed to be associated with NH4U kidney stone development in bottlenose dolphins under professional care.

Increased production and reduced urinary buffering of acid in uric acid stone formers is ameliorated by pioglitazone.

Idiopathic uric acid nephrolithiasis is characterized by an overly acidic urine pH caused by the combination of increased acid production and inadequate buffering of urinary protons by ammonia. A large proportion of uric acid stone formers exhibit features of the metabolic syndrome. We previously demonstrated that thiazolidinediones improved the urinary biochemical profile in an animal model of the metabolic syndrome. In this proof-of-concept study, we examined whether the thiazolidinedione pioglitazone can also ameliorate the overly acidic urine in uric acid stone formers. Thirty-six adults with idiopathic uric acid nephrolithiasis were randomized to pioglitazone 30 mg/day or matching placebo for 24 weeks. At baseline and study end, participants underwent collection of blood and 24-hour urine in an inpatient research unit while consuming a fixed metabolic diet, followed by assessment of the ammoniagenic response to an acute oral acid load. Twenty-eight participants completed the study. Pioglitazone treatment improved features of the metabolic syndrome. Pioglitazone also reduced net acid excretion and increased urine pH (5.37 to 5.59), the proportion of net acid excreted as ammonium, and ammonium excretion in response to an acute acid load, whereas these parameters were unchanged with placebo. Treatment of patients with idiopathic uric acid nephrolithiasis with pioglitazone for 24 weeks led to a reduction in the acid load presented to the kidney and a more robust ammoniagenesis and ammonium excretion, resulting in significantly higher urine pH. Future studies should consider the impact of this targeted therapy on uric acid stone formation.

The Differential Effects of Human Immunodeficiency Virus and Hepatitis C Virus on Bone Microarchitecture and Fracture Risk.

Background: Human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected individuals have a significantly greater osteoporotic fracture risk than HIV-monoinfected persons, despite the fact that HIV/HCV coinfection has not been associated with lower bone mineral density (BMD) than HIV or HCV alone. To evaluate if changes in bone microarchitecture, measured by trabecular bone score (TBS), could explain these differences, we performed a prospective, cross-sectional cohort study of virologically suppressed HIV-infected subjects, untreated HCV-infected subjects, HIV/HCV-coinfected subjects, and uninfected controls. Methods: We enrolled 532 male subjects: 57 HIV/HCV coinfected, 174 HIV infected, 123 HCV infected, and 178 controls. We conducted analysis of covariance comparing BMD and TBS between groups, controlling for age, race, body mass index, and smoking. We used linear regression to evaluate predictors of BMD and TBS and evaluated the effects of severity of HCV infection and tenofovir disoproxil fumarate use. Results: Despite both infections being associated with decreased BMD, only HCV, but not HIV, was associated with lower TBS score. Also, HIV/HCV-coinfected subjects had lower TBS scores than HIV-monoinfected, HCV-monoinfected, and uninfected subjects. Neither the use of TDF or HCV viremia nor the severity of HCV liver disease was associated with lower TBS. Conclusions: HCV infection is associated with microarchitectural changes at the lumbar spine as assessed by the low TBS score, suggesting that microstructural abnormalities underlie some of the higher fracture risk in HCV infection. TBS might improve fracture risk prediction in HCV infection.

Comparison of potential dietary and urinary risk factors for ammonium urate nephrolithiasis in two bottlenose dolphin ( Tursiops truncatus) populations.

Dietary and urinary risk factors have been implicated in conditions favoring ammonium urate nephrolithiasis in managed dolphins compared with free-ranging dolphins. In this study, urine samples were collected from 16 dolphins (8 cases, 8 controls) from the U.S. Navy Marine Mammal Program for the purposes of assessing changes in urinary biomarkers after a large meal. Urinary biomarkers and nephrolithiasis presence were assessed opportunistically in 15 long-term resident free-ranging dolphins living in Sarasota Bay, Florida. Additionally, the total purine contents of fish commonly consumed by each dolphin population were measured to evaluate potential dietary risk factors. Populations were compared for total dietary purine composition, recently fed status, nephrolithiasis presence, and differences in urinary biochemical, acid-base, and physicochemical parameters via Wilcoxon rank sum analysis and least square means. Managed dolphins had higher urinary pH and ammonium ([Formula: see text]) in both pre- and postprandial conditions and higher urinary uric acid and saturation indices of NH4U in the postprandial condition compared with free-ranging dolphins ( P < 0.05). The purine content was greater ( P < 0.0001) in the diet consumed by managed dolphins [7 mmol/Mcal metabolizable energy (ME)] than in the free-ranging dolphin diet (4 mmol/Mcal ME). Free-ranging dolphins did not show evidence of nephrolithiasis. Observed differences in urinary biomarkers and dietary purine content in these two dolphin populations suggest a pathophysiologic basis for the role of fish types on the risk of NH4U stone formation. Future research should investigate fish type and feeding frequency, inhibitors and promoters, and alkalinizing therapy for reducing NH4U nephrolithiasis in dolphins.

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

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Relationship between Urinary Calcium and Bone Mineral Density in Patients with Calcium Nephrolithiasis.

PURPOSE: Calcium nephrolithiasis is associated with an increased risk of osteoporosis and fracture. Hypercalciuria has been assumed to be pathogenic for bone loss in kidney stone formers, although this association was shown in small cross-sectional studies. We explored the association of urine calcium with bone mineral density in kidney stone formers. MATERIALS AND METHODS: We retrospectively studied bone mineral density in kidney stone formers. Excluded were subjects with hypercalcemia, chronic bowel disease, primary hyperparathyroidism, distal renal tubular acidosis or endogenous creatinine clearance less than 40 ml per minute. We included 250 males and 182 females subdivided into 145 who were estrogen treated and postmenopausal, and 37 who were nonestrogen treated and postmenopausal. We assessed the association of lumbar spine and femoral neck bone mineral density with 24-hour urine calcium on random and restricted diets, and while fasting using univariable and multivariable models adjusting for body mass index, urine sodium and sulfate. RESULTS: On multivariable analysis no significant association was found between urine calcium on a random or a restricted diet, or during fasting conditions and femoral neck or lumbar spine bone mineral density in men and estrogen treated women. In estrogen untreated women lumbar spine bone mineral density inversely correlated with urine calcium on the restricted diet (r = -0.38, p = 0.04 and adjusted r = -0.45, p = 0.02) and in the fasting state (r = -0.42, p = 0.05). CONCLUSIONS: Unlike in previous small cross-sectional studies we found no significant relationship between urine calcium and bone mineral density in a large group of calcium kidney stone formers. However, a significant inverse relationship was found in estrogen untreated kidney stone formers only. This study suggests that mechanism(s) other than hypercalciuria explain the lower bone mineral density and the higher fracture risk in patients who are kidney stone formers. It also highlights the role of estrogen on bone integrity.

Temporal Changes in Kidney Stone Composition and in Risk Factors Predisposing to Stone Formation.

PURPOSE: The prevalence of kidney stones has increased globally in recent decades. However, studies investigating the association between temporal changes in the risk of stone formation and stone types are scarce. We investigated temporal changes in stone composition, and demographic, serum and urinary parameters of kidney stone formers from 1980 to 2015. MATERIALS AND METHODS: We retrospectively analyzed the records of 1,516 patients diagnosed with either calcium or uric acid stones at an initial visit to a university kidney stone clinic from 1980 to 2015. RESULTS: From 1980 to 2015, the proportion of uric acid stones in all stone formers increased from 7% to 14%. While age and body mass index increased with time in both uric acid and calcium stone formers, uric acid stone formers were consistently older and had a higher body mass index and lower urinary pH than calcium stone formers. The proportion of females with stones has increased over time but the increase in female gender was more prominent among calcium stone formers. Urinary pH, phosphorus, oxalate and sodium increased with time in calcium stone formers but remained unchanged in uric acid stone formers. After accounting for various parameters of stone risk, the strongest clinical discriminant of uric acid vs calcium stones was urinary pH. Limitations of this study include the retrospective single center design and the available number of patients with stone analysis. CONCLUSIONS: From 1980 to 2015, the proportion of uric acid stones increased significantly. With time, there were proportionately more female calcium stone formers but not uric acid stone formers. Urinary pH is the most prominent factor distinguishing uric acid from calcium stones.

The Vacuolar H+-ATPase B1 Subunit Polymorphism p.E161K Associates with Impaired Urinary Acidification in Recurrent Stone Formers.

Mutations in the vacuolar-type H(+)-ATPase B1 subunit gene ATP6V1B1 cause autosomal-recessive distal renal tubular acidosis (dRTA). We previously identified a single-nucleotide polymorphism (SNP) in the human B1 subunit (c.481G>A; p.E161K) that causes greatly diminished pump function in vitro To investigate the effect of this SNP on urinary acidification, we conducted a genotype-phenotype analysis of recurrent stone formers in the Dallas and Bern kidney stone registries. Of 555 patients examined, 32 (5.8%) were heterozygous for the p.E161K SNP, and the remaining 523 (94.2%) carried two wild-type alleles. After adjustment for sex, age, body mass index, and dietary acid and alkali intake, p.E161K SNP carriers had a nonsignificant tendency to higher urinary pH on a random diet (6.31 versus 6.09; P=0.09). Under an instructed low-Ca and low-Na diet, urinary pH was higher in p.E161K SNP carriers (6.56 versus 6.01; P<0.01). Kidney stones of p.E161K carriers were more likely to contain calcium phosphate than stones of wild-type patients. In acute NH4Cl loading, p.E161K carriers displayed a higher trough urinary pH (5.34 versus 4.89; P=0.01) than wild-type patients. Overall, 14.6% of wild-type patients and 52.4% of p.E161K carriers were unable to acidify their urine below pH 5.3 and thus, can be considered to have incomplete dRTA. In summary, our data indicate that recurrent stone formers with the vacuolar H(+)-ATPase B1 subunit p.E161K SNP exhibit a urinary acidification deficit with an increased prevalence of calcium phosphate-containing kidney stones. The burden of E161K heterozygosity may be a forme fruste of dRTA.

Assessment of Urinary Inhibitor or Promoter Activity in Uric Acid Nephrolithiasis.

PURPOSE: We assessed decreased inhibitor activity or increased promoter activity in the urine of idiopathic uric acid stone formers compared to nonstone formers independent of urinary pH. MATERIALS AND METHODS: A total of 30 idiopathic uric acid stone formers, and 9 obese and 12 lean nonstone formers collected 24-hour urine while on a metabolic diet. Three urine aliquots per subject were used to assess spontaneous nucleation (de novo crystal formation), crystal growth using a 0.1 mg/ml anhydrous uric acid seed and steady-state uric acid solubility (the maximum amount of uric acid dissolvable in urine) using a 5 mg/ml uric acid seed. All experiments were performed for 6 hours at a constant pH of 5.0. Uric acid concentration was measured in filtered aliquots at 0, 3 and 6 hours. RESULTS: At baseline 24-hour urinary pH was significantly lower and uric acid saturation was significantly higher in idiopathic uric acid stone formers. No significant spontaneous nucleation developed and similar uric acid steady-state solubility was reached in the 3 groups. Idiopathic uric acid stone formers and lean nonstone formers showed a similar decrease in uric acid concentration during crystal growth. Obese nonstone formers started with a higher uric acid concentration and consequently demonstrated a greater decrease in the uric acid concentration for crystal growth. CONCLUSIONS: This study suggests that there is no significant difference between idiopathic uric acid stone formers and nonstone formers in promoter or inhibitor activity in whole urine against uric acid stone formation when urine pH is maintained constant. The findings suggest that uric acid stone formation is dictated by high urinary saturation with respect to uric acid, which is driven primarily by low urine pH.

Pathophysiological and physicochemical basis of ammonium urate stone formation in dolphins.

PURPOSE: Nephrolithiasis is increasingly reported in bottle-nosed dolphins. All cases to date have been ammonium urate nephrolithiasis. MATERIALS AND METHODS: A case-control study was performed in dolphins with and without evidence of nephrolithiasis to identify biomarkers and risk factors associated with stone formation in a managed population. Dolphins were sampled in fasting and postprandial states to study the effect of dietary factors on serum and urinary biochemistry. Urine was continuously collected for 6 hours via catheter and divided into 3, 2-hour collections with a bolus fish meal given after completing the first collection. Blood was sampled at the beginning of the fasting period and the end of the postprandial period. RESULTS: There were no significant differences in serum and urine chemistry or acid-base profiles between dolphins with vs without stones at baseline or postprandially. This suggests that cases and controls represent a continuum of stone risk. On analysis combining cases and controls in a single cohort we noted significant postprandial increases in urinary uric acid, sulfate and net acid excretion accompanied by increased urinary ammonium excretion and a commensurate increase in urine pH. The supersaturation index of ammonium urate increased more than twofold postprandially. CONCLUSIONS: These findings suggest that dolphins are susceptible to ammonium urate nephrolithiasis at least in part because a high dietary load of acid and purines results in a transient but marked increase in the urinary supersaturation of the sparingly soluble ammonium urate salt.

Animal protein and the risk of kidney stones: a comparative metabolic study of animal protein sources.

PURPOSE: We compared the effect of 3 animal protein sources on urinary stone risk. MATERIALS AND METHODS: A total of 15 healthy subjects completed a 3-phase randomized, crossover metabolic study. During each 1-week phase subjects consumed a standard metabolic diet containing beef, chicken or fish. Serum chemistry and 24-hour urine samples collected at the end of each phase were compared using mixed model repeated measures analysis. RESULTS: Serum and urinary uric acid were increased for each phase. Beef was associated with lower serum uric acid than chicken or fish (6.5 vs 7.0 and 7.3 mg/dl, respectively, each p <0.05). Fish was associated with higher urinary uric acid than beef or chicken (741 vs 638 and 641 mg per day, p = 0.003 and 0.04, respectively). No significant difference among phases was noted in urinary pH, sulfate, calcium, citrate, oxalate or sodium. Mean saturation index for calcium oxalate was highest for beef (2.48), although the difference attained significance only compared to chicken (1.67, p = 0.02) but not to fish (1.79, p = 0.08). CONCLUSIONS: Consuming animal protein is associated with increased serum and urine uric acid in healthy individuals. The higher purine content of fish compared to beef or chicken is reflected in higher 24-hour urinary uric acid. However, as reflected in the saturation index, the stone forming propensity is marginally higher for beef compared to fish or chicken. Stone formers should be advised to limit the intake of all animal proteins, including fish.

The diurnal variation in urine acidification differs between normal individuals and uric acid stone formers.

Many biological functions follow circadian rhythms driven by internal and external cues that synchronize and coordinate organ physiology to diurnal changes in the environment and behavior. Urinary acid-base parameters follow diurnal patterns and it is thought these changes are due to periodic surges in gastric acid secretion. Abnormal urine pH is a risk factor for specific types of nephrolithiasis and uric acid stones result from excessively low urine pH. Here we placed 9 healthy volunteers and 10 uric acid stone formers on fixed metabolic diets to study the diurnal pattern of urinary acidification. All showed clear diurnal trends in urinary acidification, but none of the patterns were affected by inhibitors of the gastric proton pump. Uric acid stone formers had similar patterns of change throughout the day but their urine pH was always lower compared to healthy volunteers. Uric acid stone formers excreted more acid (normalized to acid ingestion), with the excess excreted primarily as titratable acid rather than ammonium. Urine base excretion was also lower in uric acid stone formers (normalized to base ingestion), along with lower plasma bicarbonate concentrations during part of the day. Thus, increased net acid presentation to the kidney and the preferential use of buffers, other than ammonium, result in much higher concentrations of undissociated uric acid throughout the day and consequently an increased risk of uric acid stones.

Metabolic syndrome and the risk of calcium stones.

BACKGROUND: The metabolic syndrome (MS) is associated with increased prevalence of kidney stones, yet the specific stone type remains largely unknown. This study was conducted to assess whether risk factors associated with calcium nephrolithiasis increase with individual characteristics of the MS. METHODS: A retrospective analysis was performed in 109 non-stone-forming subjects and 128 recurrent calcium stone formers from Dallas, Texas. A separate analysis was performed in 140 recurrent calcium stone formers from Bern, Switzerland. Demographic, anthropometric, serum and urinary profiles were measured. RESULTS: In non-stone formers from Dallas, urinary calcium (3.6 ± 1.8 to 6.0 ± 2.9 mmol/day, P = 0.0003 for trend, zero to four features) increased with increasing features of the MS. This change was attendant with a significant rise in supersaturation index (SI) of calcium oxalate (CaOx) (2.76 ± 1.21 to 4.45 ± 1.65, P < 0.0001; zero to four features). In calcium stone formers from Dallas, urinary calcium marginally increased (5.2 ± 2.3 to 7.0 ± 4.0 mmol/day, P = 0.09; zero to four features), while urinary oxalate (356 ± 141 to 504 ± 203 µmol/day, P = 0.001; zero to four features) and SI CaOx (4.46 ± 1.80 to 6.16 ± 3.71, P = 0.009; zero to four features) significantly increased with features of the MS. However, when adjusted for confounding variables such as total volume, age, gender, urine sodium and urine sulfate, urinary calcium and SI CaOx showed no significant changes in stone formers yet remained significant in non-stone formers. In a separate cohort from Bern, Switzerland urinary calcium (6.9 ± 3.6 versus 7.0 ± 3.2, P = 0.8) and SI CaOx (3.37 ± 1.98 versus 4.04 ± 2.78, P = 0.5) did not differ between subjects with and without the MS. CONCLUSIONS: In non-stone formers, the risk of CaOx stone formation increases with the number of features of the MS. However, in stone-forming subjects, the propensity for CaOx precipitation is much higher but is not independently associated with increasing features of the MS.

Androgen Deprivation Therapy Differentially Impacts Bone and Muscle in the Short Term in Physically Active Men With Prostate Cancer.

Androgen deprivation therapy (ADT) is a cornerstone of advanced prostate cancer (PCa) therapy. Its use is associated with a loss of bone mineral density (BMD) and a greater risk of falls and osteoporotic fractures. In this prospective cohort study, we examined the impact of ADT on muscle and bone strength in men initiating ADT for PCa. Participants were evaluated at three time points: immediately before (week 0), and 6 and 24 weeks after ADT initiation. Study measures included fasting blood levels (for markers of muscle and bone metabolic activity), MRI and QCT imaging (for muscle fat content, and bone density and architecture), and validated clinical tests of muscle strength and gait. Sixteen men completed all study visits. At baseline and throughout the study, participants exercised a median of four times/week, but still experienced weight gain (+2.0 kg at week 24 versus week 0, p = 0.004). Biochemically, all men sustained dramatic early and persistent reductions in sex hormones post-ADT, along with a progressive and significant increase in serum C-telopeptide of type I collagen (CTX, +84% at week 24 versus week 0). There was a trend for rise in serum sclerostin (p = 0.09) and interleukin 6 (IL-6) (p = 0.08), but no significant change in serum myostatin (p = 0.99). Volumetric BMD by QCT declined significantly at the femoral neck (-3.7% at week 24 versus week 0), particularly at the trabecular compartment. On MRI, there were no significant changes in thigh muscle fat fraction. On physical testing, men developed weaker grip strength, but experienced no worsening in lower extremity and lumbar spine muscle strength, or on functional tests of gait. In conclusion, in physically active men, ADT for 24 weeks results in a significant increase in bone resorption and reduction in BMD, but nonsignificant changes in thigh muscle quality (on imaging) or strength and gait (on functional testing). © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Defining hypercalciuria in nephrolithiasis.

The classic definition of hypercalciuria, an upper normal limit of 200 mg/day, is based on a constant diet restricted in calcium, sodium, and animal protein; however, random diet data challenge this. Here our retrospective study determined the validity of the classic definition of hypercalciuria by comparing data from 39 publications analyzing urinary calcium excretion on a constant restricted diet and testing whether hypercalciuria could be defined when extraneous dietary influences were controlled. These papers encompassed 300 non-stone-forming patients, 208 patients with absorptive hypercalciuria type I (presumed due to high intestinal calcium absorption), and 234 stone formers without absorptive hypercalciuria; all evaluated on a constant restricted diet. In non-stone formers, the mean urinary calcium was well below 200 mg/day, and the mean for all patients was 127±46 mg/day with an upper limit of 219 mg/day. In absorptive hypercalciuria type I, the mean urinary calcium significantly exceeded 200 mg/day in all studies with a combined mean of 259±55 mg/day. Receiver operating characteristic curve analysis showed the optimal cutoff point for urinary calcium excretion was 172 mg/day on a restricted diet, a value that approximates the traditional limit of 200 mg/day. Thus, on a restricted diet, a clear demarcation was seen between urinary calcium excretion of kidney stone formers with absorptive hypercalciuria type I and normal individuals. When dietary variables are controlled, the classic definition of hypercalciuria of nephrolithiasis appears valid.

Rising occurrence of hypocitraturia and hyperoxaluria associated with increasing prevalence of stone disease in calcium kidney stone formers.

OBJECTIVE: To evaluate metabolic risk factors in calcium kidney stone formers from two different decades, comparing changes in metabolic profiles over time. METHODS: A retrospective analysis was performed of calcium kidney stone formers who underwent metabolic evaluation of urolithiasis with 24-hour urine collections at a single institution. There were 309 patients evaluated from 1988 to 1994 (Group A), and 229 patients from 2007 to 2010 (Group B). A comparison between both groups was performed to assess changes in demographics and in metabolic stone profiles. RESULTS: Comparing Group A to Group B, the percentage of females increased from 43 to 56%, obese patients (BMI ≥ 30) increased from 22 to 35%, and patients ≥ 50 years increased from 29 to 47% (all p < 0.005). A greater percentage of patients had hypocitraturia in the recent cohort (46-60%, p = 0.001), with hypocitraturia significantly more frequent in obese patients (p = 0.005). Hyperoxaluria was also increased in Group B compared to Group A (23-30% p = 0.07), a finding that was significant in males (32-53%, p = 0.001). CONCLUSIONS: Urolithiasis has increased in females, obese, and older patients, consistent with population-based studies. We report a rising incidence of hypocitraturia and hyperoxaluria in the contemporary cohort, particularly in obese patients and in males, respectively. Further studies are needed to better characterize the metabolic changes corresponding to the increase in stone disease.

Comparison of semi-empirical and computer derived methods for estimating urinary saturation of calcium oxalate.

PURPOSE: Estimating calcium oxalate saturation in human urine is critical for nephrolithiasis clinical research and practice. The Joint Expert Speciation System (Mayhem Unit Trust and Council for Scientific and Industrial Research, Pretoria, South Africa) computer program has questioned the validity of the widely used EQUIL 2 program in estimating calcium oxalate urinary saturation. To attempt resolution the computer model based supersaturation index (by the Joint Expert Speciation System) and the relative saturation ratio (by EQUIL 2) were compared with the experimentally derived activity product ratio, that is the ratio of activity products before and after incubating urine with synthetic calcium oxalate. MATERIALS AND METHODS: To determine the experimental conditions required to attain calcium oxalate steady state solubility the filtrate concentration product of calcium and oxalate was determined after incubating 8 urine samples with 2 to 15 mg/ml calcium oxalate for various intervals. In 20 urine samples the activity product ratio of calcium oxalate was compared with the relative saturation ratio and the supersaturation index. RESULTS: Steady state solubility occurred after incubating 15 mg calcium oxalate per ml urine for 72 hours. The mean +/- SD supersaturation index of 4.92 +/- 2.57 in the original urine samples closely approximated the activity product ratio of 5.08 +/- 3.10 but the relative saturation ratio of 7.47 +/- 3.89 was significantly higher than the activity product ratio. The supersaturation index was recalculated after omitting soluble complexes recognized by the Joint Expert Speciation System but not by EQUIL 2, including Ca(2)H(2)(PO(4))(2) and (CaCitPO(4))(4-). The corrected supersaturation index was compared with the relative saturation ratio. After correction the supersaturation index increased to 7.28 +/- 3.81, which was not significantly different from the relative saturation ratio. CONCLUSIONS: The Joint Expert Speciation System is more accurate than EQUIL 2 to estimate calcium oxalate saturation, probably by accounting for Ca(2)H(2)(PO(4))(2), (CaCitPO(4))(4-), and other minor complexes of calcium and oxalate.

Comparison of semi-empirical and computer derived methods for estimating urinary saturation of brushite.

PURPOSE: The Equil 2 computer program has been questioned by the new Joint Expert Speciation System program (Mayhem Unit Trust and Council for Scientific and Industrial Research, Pretoria, South Africa) for estimating the urinary saturation of stone forming salts to gauge the propensity for stone formation. To attempt resolution the supersaturation index according to the Joint Expert Speciation System and the relative saturation ratio according to Equil 2 were compared with the semi-empirically derived concentration-to-product ratio. MATERIALS AND METHODS: Data were obtained from a recent article in The Journal of Urology(R), in which pH, calcium and citrate were varied over a wide range in 72 urine samples. We calculated the relative saturation ratio and the supersaturation index of brushite, and compared them with the available concentration-to-product ratio derived from the growth or dissolution of synthetic brushite. RESULTS: The mean concentration-to-product ratio did not differ from the supersaturation index but the concentration-to-product ratio and the supersaturation index were significantly lower than the relative saturation ratio (p <0.004). On the saturation value and urinary variable plot the relative saturation ratio could be readily distinguished from the concentration-to-product ratio because it was consistently and significantly higher. While the supersaturation index pattern was similar to the concentration-to-product ratio, the supersaturation index was slightly lower at high urinary pH and calcium, and slightly higher at lower urinary pH and calcium (p <0.001). When the Ca(2)H(2)(PO(4))(2) complex was deleted from the Joint Expert Speciation System, the corrected supersaturation index was not significantly different from the relative saturation ratio determined by Equil 2. CONCLUSIONS: The relative saturation ratio overestimates brushite saturation by about 80%. The supersaturation index yields a good approximation of brushite saturation at modest degrees of saturation but it overestimates saturation at low pH or calcium (low saturation) and underestimates it at high pH or calcium (high saturation).