Control of metabolic predisposition to cardiovascular complications of chronic kidney disease by effervescent calcium magnesium citrate: a feasibility study.

AIMS: Cardiovascular (CV) complications are common in chronic kidney disease (CKD). Numerous metabolic disturbances including hyperphosphatemia, high circulating calciprotein particles (CPP), hyperparathyroidism, metabolic acidosis, and magnesium deficiency are associated with, and likely pathogenic for CV complications in CKD. The goal of this feasibility study was to determine whether effervescent calcium magnesium citrate (EffCaMgCit) ameliorates the aforementioned pathogenic intermediates. METHODS: Nine patients with Stage 3 and nine patients with Stage 5D CKD underwent a randomized crossover study, where they took EffCaMgCit three times daily for 7 days in one phase, and a conventional phosphorus binder calcium acetate (CaAc) three times daily for 7 days in the other phase. Two-hour postprandial blood samples were obtained on the day before and on the 7th day of treatment. RESULTS: In Stage 5D CKD, EffCaMgCit significantly increased T50 (half time for conversion of primary to secondary CPP) from baseline by 63% (P = 0.013), coincident with statistically non-significant declines in serum phosphorus by 25% and in saturation of octacalcium phosphate by 35%; CaAc did not change T50. In Stage 3 CKD, neither EffCaMgCit nor CaAc altered T50. With EffCaMgCit, a significant increase in plasma citrate was accompanied by statistically non-significant increase in serum Mg and phosphate. CaAc was without effect in any of these parameters in Stage 3 CKD. In both Stages 3 and 5D, both drugs significantly reduced serum parathyroid hormone. Only EffCaMgCit significantly increased serum bicarbonate by 3 mM (P = 0.015) in Stage 5D. CONCLUSIONS: In Stage 5D, EffCaMgCit inhibited formation of CPP, suppressed PTH, and conferred magnesium and alkali loads. These effects were unique, since they were not observed with CaAc. In Stage 3 CKD, neither of the regimens have any effect. These metabolic changes suggest that EffCaMgCit might be useful in protecting against cardiovascular complications of CKD by ameliorating pathobiologic intermediates.

Effects of Potassium Magnesium Citrate Supplementation on 24-Hour Ambulatory Blood Pressure and Oxidative Stress Marker in Prehypertensive and Hypertensive Subjects.

Diet rich in fruits, vegetables, and dairy products, known as the Dietary Approaches to Stop Hypertension (DASH) diet, is known to reduce blood pressure (BP) in hypertensive patients. More recently, the DASH diet was shown to reduce oxidative stress in hypertensive and nonhypertensive humans. However, the main nutritional components responsible for these beneficial effects of the DASH diet remain unknown. Because the DASH diet is rich in potassium (K), magnesium (Mg), and alkali, we performed a randomized, double-blinded, placebo-controlled study to compare effects of potassium magnesium citrate (KMgCit), potassium chloride (KCl), and potassium citrate (KCit) to allow dissociation of the three components of K, Mg, and citrate on 24-hour ambulatory BP and urinary 8-isoprostane in hypertensive and prehypertensive subjects, using a randomized crossover design. We found that KCl supplementation for 4 weeks induced a significant reduction in nighttime SBP compared with placebo (116 ± 12 vs 121 ± 15 mm Hg, respectively, p <0.01 vs placebo), whereas KMgCit and KCit had no significant effect in the same subjects (118 ± 11 and 119 ± 13 mm Hg, respectively, p >0.1 vs placebo). In contrast, urinary 8-isoprostane was significantly reduced with KMgCit powder compared with placebo (13.5 ± 5.7 vs 21.1 ± 10.5 ng/mgCr, respectively, p <0.001), whereas KCl and KCit had no effect (21.4 ± 9.1 and 18.3 ± 8.4, respectively, p >0.1 vs placebo). In conclusion, our study demonstrated differential effects of KCl and KMgCit supplementation on BP and the oxidative stress marker in prehypertensive and hypertensive subjects. Clinical significance of the antioxidative effect of KMgCit remains to be determined in future studies.

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.

Biochemical control of bone loss and stone-forming propensity by potassium-calcium citrate after bariatric surgery.

BACKGROUND: Patients undergoing Roux-en-Y gastric bypass (RYGB) surgery are prone to developing bone loss and kidney stones. The goal of the present study was to test the hypothesis that an effervescent formulation of potassium calcium citrate (PCC) would avert metabolic complications by providing bioavailable calcium and alkali. METHODS: A total of 24 patients with RYGB underwent a 2-phase crossover randomized trial comparing PCC and placebo. During the last 2 days of each 2-week phase, the serum and 24-hour urine samples were analyzed for calcium and bone turnover markers, acid base status, and urinary stone risk factors. RESULTS: Compared with placebo, PCC marginally reduced the serum parathyroid hormone level and significantly decreased urinary deoxypyridinoline by 12% (P <.001) and serum type 1 collagen C-telopeptide by 22% (P <.01). PCC significantly increased the net gastrointestinal alkali absorption, citrate, and pH and significantly lowered the urinary net acid excretion (P <.001). The urinary saturation of uric acid decreased significantly (P <.001). The supersaturation of calcium oxalate and brushite did not change despite an increase in calcium and pH. In untreated urine samples with citrate concentrations altered to mimic those of placebo and PCC, calcium oxalate agglomeration was significantly inhibited by PCC. CONCLUSION: In RYGB patients, PCC supplementation inhibited bone resorption by providing bioavailable calcium, reduced the urinary saturation of uric acid, and increased the inhibitor activity against calcium oxalate agglomeration by providing alkali that increased urinary pH and citrate.

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.

Fasting versus 24-h urine pH in the evaluation of nephrolithiasis.

An abnormal urinary pH (UpH) represents an important risk factor for nephrolithiasis. In some stone formers, a fasting urine specimen is obtained instead of a 24-h urine collection for stone risk evaluation. We examined the relationship between 24-h and fasting UpH in non-stone forming individuals and stone formers with various etiologies and a wide range of urine pH to test the validity of fasting UpH. Data from 159 subjects was examined in this retrospective study. We included non-stone forming subjects and stone formers with hypercalciuria, distal renal tubular acidosis, idiopathic uric acid nephrolithiasis, or chronic diarrhea. Participants collected a 24-h urine followed by a 2-h fasting urine. For the entire cohort, a significant correlation was seen between fasting and 24-h UpH (r (2) = 0.49, p < 0.001). Fasting pH was significantly higher than 24-h UpH for the entire cohort (6.02 ± 0.63 vs. 5.89 ± 0.51; p < 0.001), and in the subgroups of non-stone formers and stone formers with hypercalciuria or distal renal tubular acidosis. Fasting UpH was >0.2 pH units different from 24-h UpH in 58% of participants. The difference between fasting and 24-h UpH did not correlate with net gastrointestinal alkali absorption or urine sulfate, suggesting that dietary factors alone cannot explain this difference in UpH. Fasting urine pH correlates moderately with 24-h urine pH in a large cohort of individuals. Significant variability between these two parameters is seen in individual patients, emphasizing the cardinal role of 24-h urine collection for evaluating UpH in nephrolithiasis.

Detection of absorptive hypercalciuria type I without the oral calcium load test.

PURPOSE: We retrospectively analyzed the validity of a simple method of detecting absorptive hypercalciuria type I, a common stone forming condition with hypercalciuria that is believed to be due to high intestinal calcium absorption. The method is based on urinary calcium derived from 24-hour urine collections while on random and restricted diets rather than on a calciuric response to an oral calcium load. MATERIALS AND METHODS: A group of 916 well characterized patients with idiopathic calcium oxalate urolithiasis comprised the study group. We also analyzed a subgroup of 695 patients, excluding 221 with dietary abuse, defined as urinary sodium greater than 150 mEq daily and/or sulfate greater than 35 mmol daily, to eliminate potential confounding dietary factors affecting the diagnosis. In each group absorptive hypercalciuria type I was detected by the old criteria, requiring an exaggerated calciuric response to an oral calcium load test, and by the new criteria, based on 24-hour urinary calcium 200 mg or greater daily while on random and restricted diets. RESULTS: Using the old criteria as the gold standard the positive and negative predictive values, sensitivity and specificity of the new criteria were 80.1%, 95.9%, 90.8% and 90.5%, respectively. When excluding patients with dietary abuse the values were 85.9%, 97.2%, 92.4% and 94.5%, respectively. CONCLUSIONS: Absorptive hypercalciuria type I may be reliably detected by a simple method based on high 24-hour urinary calcium while on random and restricted diets, especially when excluding patients with evidence of dietary abuse during the restricted diet.

Evidence for metabolic origin of absorptive hypercalciuria Type II.

The objective of this retrospective data analysis was to test the hypothesis that absorptive hypercalciuria Type II (AH-II) is a less severe variant of absorptive hypercalciuria Type I (AH-I), a common cause of calcareous stones. 24-h urinary calcium obtained on constant metabolic diets was retrieved from several data sources, including those of the authors and another group. On a low calcium diet (10 mmol calcium), 35 patients with AH-II were compared with 70 non-stone formers (NSF) and 76 patients with AH-I. On a high calcium diet (25 mmol calcium/day), 10 patients with AH-II were compared with 35 NSF and 32 with AH-I. On a low calcium diet for all participants, 24-h urinary calcium in AH-II (4.13 ± 0.63 mmol/day) was significantly higher than in NSF (3.06 ± 1.17 mmol/day), but significantly lower than in AH-I (6.11 ± 1.14 mmol/day) (p < 0.001). In a smaller subset, fractional intestinal calcium absorption in AH-II (65.0 ± 11.1%) was intermediate between NSF (50.0 ± 6.4%) and AH-I (71.0 ± 6.7%) (p < 0.001 between AH-II and other groups). On a high calcium diet, the rise in urinary calcium in AH-II was significantly higher than in NSF, but not as marked as in AH-I. Estimated calcium balance in AH-II was similar to NSF, but significantly more positive than AH-I. In conclusion, AH-II shares with AH-I the same metabolic disturbance(s) stimulating intestinal absorption and renal excretion of calcium but to a lesser degree. Bone might be spared in AH-II.

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.

Biochemical and histological assessment of alkali therapy during high animal protein intake in the rat.

The Westernized diet is acidogenic due to the high content of sulfur-containing amino acids and relative deficiency of potassium organic anions. Chronic acid loads result in hypercalciuria and negative calcium balance often associated with loss of bone mineral. Alkali therapy tends to reverse the hypercalciuria but little is known regarding its effect on bone as assessed by bone histomorphometry. The present study utilized dynamic bone histomorphometry to evaluate the effects of alkali therapy on acid-induced changes in bone turnover. Serum and urine analyses and bone histomorphometry were assessed in adult rats after 2 months of either a low casein (LC) or high casein (HC) diet supplemented with either potassium chloride (KCl) or potassium citrate (KCit). Compared to animals on LC-KCl diet, HC-KCl diet delivered a substantial acid load as shown by significant increases in urinary sulfate, ammonium, and net acid excretion, and a lower urinary pH and citrate excretion without detectable changes in serum parameters. The acid load also resulted in hypercalciuria. Dynamic and static bone histomorphometry disclosed a significant reduction in cancellous bone volume and trabecular number associated with a 2.5-fold increase in eroded and a 3.5-fold increase in osteoclastic surfaces. There was also a near 2-fold increase in bone formation rate in rats on the HC-KCl diet. When animals on the HC diet were given KCit instead of KCl, all of the aforementioned changes in urine biochemistry and bone turnover were significantly attenuated or entirely prevented. These findings underscore the deleterious effects of high animal protein intake in promoting hypercalciuria and increasing bone turnover. Co-administration of potassium alkali attenuates or prevents these changes. In this animal model of high dietary animal protein intake, the major skeletal effect of alkali therapy is to reduce bone resorption, with little or no effect on bone formation.

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).

New methods of assessing crystal growth and saturation of brushite in whole urine: effect of pH, calcium and citrate.

PURPOSE: Brushite crystallization might be important in stone formation and prevention. To explore this question new methods for the saturation and crystal growth of brushite were devised that are applicable to whole urine without any computer program. MATERIALS AND METHODS: The saturation value (concentration-to-product ratio) was determined by dividing the molar concentration product of Ca ([Ca]) and phosphate ([P]), that is [Ca] x [P], of original urine by the steady state solubility obtained after incubating with an excess of brushite (10 mg/ml) for 5 hours. Crystal growth was measured from the depletion of filtrate ([Ca] x [P]) 3 hours after seeding with brushite (0.25 mg/ml). To test the effect of pH, Ca and citrate the saturation value and crystal growth were determined in 24-hour urine samples from 4 normal volunteers and 2 stone formers, and modified artificially to produce 4 ranges of pH, Ca and citrate by adding acid, base, Ca or citrate. RESULTS: The saturation value and crystal growth of brushite increased with an increase in pH or the Ca concentration but they decreased when the citrate concentration increased. The saturation value correlated strongly with crystal growth. CONCLUSIONS: The new methods of brushite saturation value and crystal growth should help discern how abnormalities in urinary pH, Ca and citrate interact to influence the formation of Ca stones in cases of distal renal tubular acidosis and alkali therapy.

Medical stone management: 35 years of advances.

PURPOSE: The urological community has had a vital role in the author's 35 years of research on the medical management of urolithiasis. The goal of this article is to review the progress made from the perspective of collaborating urologists and urological journals in which the findings were reported. MATERIALS AND METHODS: The author's work appeared in 94 articles in urological journals, including 63 in The Journal of Urology, and in 28 other journals with collaborating urologists. Progress on various aspects of medical management of stone disease was reviewed based on these articles. RESULTS: Pathophysiological exploration was performed by elucidating metabolic-dietary etiologies of hypocitraturia, separating hypercalciuria into 3 types, and linking gouty diathesis (uric acid stones) with obesity and insulin resistance. Physicochemical consequences of hypocitraturia were delineated and semi-empirical methods were developed to assess calcium salt saturation. Potassium-rich fruit juices differed from potassium-poor fruit juices and excessive salt intake increased the stone forming risk. Vital to diagnostic separation was a comprehensive analysis of urine for stone risk factors. As an example of selective treatment, potassium citrate was shown to be useful for controlling uric acid stones by urinary alkalinization as well as calcareous stones by hypercitraturia. CONCLUSIONS: During the last 35 years much progress has been made on the pathophysiology of stone formation, crystallization of stone forming salts, diagnostic separation and prevention of stone recurrence. The author's contribution in this effort would not have been possible without the active participation and support of the urological community.

Intestinal hyperabsorption of calcium and low bone turnover in hypercalciuric postmenopausal osteoporosis.

Hypercalciuria of intestinal origin has been linked with bone loss in calcium nephrolithiasis and idiopathic osteoporosis. This retrospective data analysis was performed to explore potential pathogenetic link between intestinal hyperabsorption of calcium and postmenopausal osteoporosis. Data were retrieved from postmenopausal women who were evaluated for osteoporosis or osteopenia at the Mineral Metabolism Clinic of UT Southwestern Medical Center. A total of 319 patients underwent the test of calciuric response to oral calcium load to obtain an indirect measure of intestinal calcium absorption. Serum and urinary biochemistry and L2-L4 bone mineral density (BMD) were compared between five quintiles of calciuric response. There was a statistically significant trend toward a rise in 24-h urinary calcium and a decrease in urinary deoxypyridinoline (DPD) and BMD, with increasing order of quintiles. The presentation of those in the 1st quintile was consistent with vitamin D insufficiency or deficiency, with impaired calcium absorption, secondary hyperparathyroidism, and stimulated bone turnover (high normal urinary DPD). In contrast, patients in the 5th quintile displayed a picture of absorptive hypercalciuria of stone disease, with intestinal hyperabsorption of calcium, high or high normal urinary calcium and suppressed bone turnover (low or low normal urinary DPD). Thus, the assessment of intestinal calcium absorption in a seemingly homogeneous group of postmenopausal women with osteoporosis or osteopenia revealed a spectrum of calciuric response whose extremes may represent two physiologically distinct subtypes that have important diagnostic and therapeutic implications.

Pharmacotherapy of kidney stones.

BACKGROUND: Kidney stones are associated with various biochemical disturbances in urine. Various drugs and dietary changes have been recommended to halt stone recurrence. OBJECTIVE: To determine whether a correction of urinary abnormalities by appropriate pharmacological agents and dietary modification may ameliorate stone disease. METHODS: A review of the literature was conducted on the role of diet, metabolic disorders and drugs for stone prevention. RESULTS/CONCLUSION: Metabolic risk factors are hypercalciuria, hypocitraturia, hyperoxaluria, hyperuricosuria, and abnormally low urinary pH. Dietary-environmental risk factors include high urinary sodium and low urine volume. Rare or less commonly encountered risk factors are high urinary cystine, and alkaline urine from an infection with urea-splitting organisms. To ameliorate or correct the above disturbances, all patients should be offered dietary modification, including restricted intake of sodium, oxalate and animal proteins. Useful drugs include thiazide or indapamide to control hypercalciuria, potassium citrate to correct hypocitraturia and undue urinary acidity, and allopurinol for co-existing hyperuricemia or marked hyperuricosuria.

Mechanism of urinary calcium regulation by urinary magnesium and pH.

Urinary magnesium and pH are known to modulate urinary calcium excretion, but the mechanisms underlying these relationships are unknown. In this study, the data from 17 clinical trials in which urinary magnesium and pH were pharmacologically manipulated were analyzed, and it was found that the change in urinary calcium excretion is directly proportional to the change in magnesium excretion and inversely proportional to the change in urine pH; a regression equation was generated to relate these variables (R(2) = 0.58). For further exploration of these relationships, intravenous calcium chloride, magnesium chloride, or vehicle was administered to rats. Magnesium infusion significantly increased urinary calcium excretion (normalized to urinary creatinine), but calcium infusion did not affect magnesium excretion. Parathyroidectomy did not prevent this magnesium-induced hypercalciuria. The effect of magnesium loading on calciuria was still observed after treatment with furosemide, which disrupts calcium and magnesium absorption in the thick ascending limb, suggesting that the effect may be mediated by the distal nephron. The calcium channel TRPV5, normally present in the distal tubule, was expressed in Xenopus oocytes. Calcium uptake by TRPV5 was directly inhibited by magnesium and low pH. In summary, these data are compatible with the hypothesis that urinary magnesium directly inhibits renal calcium absorption, which can be negated by high luminal pH, and that this regulation likely takes place in the distal tubule.

Urinary reference values for stone risk factors in children.

PURPOSE: Reference values for stone risk factors in 24-hour urine samples for nonstone forming children are limited. We measured urinary stone risk factors in healthy children 3 to 18 years old, and sought to determine whether the risk factors are affected by age. MATERIALS AND METHODS: A total of 48 healthy subjects with no history of stone disease, endocrine abnormalities or urological surgery were recruited from the Naval Medical Center in San Diego. Subjects were then further divided into 4 age groups, each separated by 5 years. A single outpatient 24-hour urine sample was obtained and analyzed. Urine chemistries were adjusted for urinary creatinine and body weight. RESULTS: After excluding under collected samples 46 urine samples were analyzed. Urinary pH and volume decreased with increasing age, although the difference in pH did not reach statistical significance. Unadjusted urinary parameters failed to show statistical difference among the age groups. When adjusted for urinary creatinine and body weight all urinary parameters (calcium, oxalate, uric acid, citrate, magnesium, sodium, phosphorus and potassium) decreased with increasing age (statistically significant except for calcium). CONCLUSIONS: Stone risk factors in 24-hour urine samples decrease with increasing age in healthy, nonstone forming children. Normative data, derived by adjustment with urinary creatinine or body weight and stratified according to quintiles of age, should be useful in defining abnormal stone risk factors in children with stones.

Aromatase deficiency causes altered expression of molecules critical for calcium reabsorption in the kidneys of female mice *.

UNLABELLED: Kidney stones increase after menopause, suggesting a role for estrogen deficiency. ArKO mice have hypercalciuria and lower levels of calcium transport proteins, whereas levels of the klotho protein are elevated. Thus, estrogen deficiency is sufficient to cause altered renal calcium handling. INTRODUCTION: The incidence of renal stones increases in women after menopause, implicating a possible role for estrogen deficiency. We used the aromatase deficient (ArKO) mouse, a model of estrogen deficiency, to test the hypothesis that estrogen deficiency would increase urinary calcium excretion and alter the expression of molecular regulators of renal calcium reabsorption. MATERIALS AND METHODS: Adult female wildtype (WT), ArKO, and estradiol-treated ArKO mice (n = 5-12/group) were used to measure urinary calcium in the fed and fasting states, relative expression level of some genes involved in calcium reabsorption in the distal convoluted tubule by real-time PCR, and protein expression by Western blotting or immunohistochemistry. Plasma membrane calcium ATPase (PMCA) activity was measured in kidney membrane preparations. ANOVA was used to test for differences between groups followed by posthoc analysis with Dunnett's test. RESULTS: Compared with WT, urinary Ca:Cr ratios were elevated in ArKO mice, renal mRNA levels of transient receptor potential cation channel vallinoid subfamily member 5 (TRPV5), TRPV6, calbindin-D28k, the Na+/Ca+ exchanger (NCX1), and the PMCA1b were significantly decreased, and klotho mRNA and protein levels were elevated. Estradiol treatment of ArKO mice normalized urinary calcium excretion, renal mRNA levels of TRPV5, calbindin-D(28k), PMCA1b, and klotho, as well as protein levels of calbindin-D28k and Klotho. ArKO mice treated with estradiol had significantly greater PMCA activity than either untreated ArKO mice or WT mice. CONCLUSIONS: Estrogen deficiency caused by aromatase inactivation is sufficient for renal calcium loss. Changes in estradiol levels are associated with coordinated changes in expression of many proteins involved in distal tubule calcium reabsorption. Estradiol seems to act at the genomic level by increasing or decreasing (klotho) protein expression and nongenomically by increasing PMCA activity. PMCA, not NCX1, is likely responsible for extruding calcium in response to in vivo estradiol hormonal challenge. These data provide potential mechanisms for regulation of renal calcium handling in response to changes in serum estrogen levels.

Reduction of renal stone risk by potassium-magnesium citrate during 5 weeks of bed rest.

PURPOSE: Exposure to the microgravity environment of space increases the risk of kidney stone formation, particularly for calcium oxalate and uric acid stones. This study was performed to evaluate the efficacy of potassium alkali as potassium-magnesium citrate in reducing renal stone risk and bone turnover. MATERIALS AND METHODS: This study was performed as a double-blind, placebo controlled trial. We studied 20 normocalciuric subjects randomized to either placebo or potassium-magnesium citrate (42 mEq potassium, 21 mEq magnesium, 63 mEq citrate per day) before and during 5 weeks of strict bed rest. The study was performed in the General Clinical Research Center and under a controlled dietary regimen composed of 100 mEq of sodium, 800 mg of calcium, 0.8 gm/kg animal protein and 2,200 kcal per day. Two 24-hour urine collections were obtained under oil each week for assessment of stone risk parameters and relative saturation of calcium oxalate, brushite and undissociated uric acid. Blood was also collected for determination of serum immunoreactive parathyroid hormone and vitamin D metabolites. RESULTS: Bed rest promoted a rapid increase in urinary calcium excretion of approximately 50 mg per day in both groups. Despite this increase subjects treated with potassium-magnesium citrate demonstrated significant decreases in the relative saturation of calcium oxalate and in the concentration of undissociated uric acid compared to placebo. Immunoreactive parathyroid hormone, serum 1,25-dihydroxyvitamin D and intestinal calcium absorption all decreased in both groups with no difference in response between the 2 treatment arms. CONCLUSIONS: Provision of alkali as potassium-magnesium citrate is an effective countermeasure for the increased risk of renal stone disease associated with immobilization. Despite an increase in urine calcium concentration, the relative saturation of calcium oxalate decreased due to citrate chelation of calcium and the concentration of undissociated uric acid decreased due to the significant increase in urine pH.