Estimation of the concentration of urinary ionic calcium and its clinical role in urolithiasis

The concentration of urinary ionic calcium was estimated using an ion-selective electrode and ion analyzer for healthy controls and patients with calcium urolithiasis. The following results were obtained: 1) After calculating the ionic strength and calibrating the standard solutions of ionic calcium in each urine, the urinary ionic calcium was estimated using an ion-selective electrode and ion analyzer. The reproducibility and accuracy of the value of urinary ionic calcium were satisfactory. 2) There was a significant correlation between the concentration of urinary ionic calcium and the total calcium excretion. Although the percentage of ionic calcium did not show any correlations among the total calcium, oxalate and urinary pH, it had an inverse relation to urinary citrate and phosphate. 3) In calcium stone formers, the excretion of ionic calcium was higher than in healthy controls significantly. 4) In hypercalciuric calcium stone formers, the concentrations and excretions of total and ionic calcium were significantly higher than in normocalciuric calcium stone formers. However, the percentage of ionic calcium was not different. 5) When the patients were treated with citrate orally, the excretion of urinary citrate was increased, and the excretion of ionic calcium and the percentage for total calcium were decreased significantly. There were significant reductions of ionic calcium in the urine after oral administration of rice-bran. 6) The estimation of urinary ionic calcium might be important to evaluate the urinary risk in recurrent calcium stone, and to estimate the effects of the preventive treatments for its recurrence.     

Familial aggregation of renal calcium stone disease

The question of a familial predisposition towards stone formation in primary nephrolithiasis has not been explored completely. In a sample of 214 calcium stone patients, and 428 age and sex-matched controls we observed a higher frequency of stones among the first degree relatives of stone patients compared to the relatives of controls. A family history of renal stones was more common among the female (45 per cent) than among the male patients (31 per cent). There was no relationship between family history of renal stones, and abnormal calcium and oxalate excretion rates. A significant association between a family history and a higher urinary pH was observed among the female calcium stone patients. A genetic defect in urinary acidification with variable expressivity might be associated with a high frequency of stone formation. Moreover, uric acid excretion was higher in male stone patients with a family history of stones. Finally, the parents and siblings of the renal stone patients were affected more by calculi than were the corresponding relatives of their spouses.     

Urinary excretion of glycosaminoglycans in normal and stone forming subjects

There is evidence suggesting that glycosaminoglycans (GAG) are potent inhibitors of growth and aggregation of calcium oxalate crystals in vitro. This finding raises the possibility that the urinary GAG could play an inhibitory role in the urolithiasis. To investigate this hypothesis, a study on the urinary excretion of GAG in normal and stone forming adults and children was undertaken. Different methods were compared, and the best results were obtained when the GAG were measured by densitometry after agarose gel electrophoresis. Although the GAG concentration was increased in the morning urine compared to the 24-hour urine samples, and in males compared to females, the GAG/creatinine ratio was independent of period of urine collection and of sex. So, it was advantageous to express the amounts of urinary GAG as mg/g of creatinine. Children excreted more GAG than adults, with a higher proportion of chondroitin sulfate. We have shown that the stone forming subjects, both adults and children, excreted lower levels of urinary GAG as compared to normal subjects, independently of the metabolic disorder. The proportions between chondroitin sulfate and heparan sulfate and the structures of these GAG were unaltered in the stone formers. These results indicate that there is a definite difference in terms of levels of GAG between normal and stone forming urines, and suggest a correlation between the urinary GAG concentration and urolithiasis.     

Influence of dietary animal protein on renal stone disease

The effect of dietary protein load on the incidence of nephrolithiasis was studied in rats and men. Three groups of adult male Wister rats were fed with a standard protein diet, a high protein diet, or a low protein diet for 4 weeks. In the high protein group, calcium excretion was significantly increased and citrate excretion was remarkably decreased. This group also exhibited low grade metabolic acidosis due to catabolism of excess amino acids, and increases in urinary cyclic AMP excretion and bone resorption. These findings indicate that protein-induced hypercalciuria is due to low grade metabolic acidosis, which directly affects renal handling of calcium. Long-term calcium loss in the urine may lead to negative calcium balance and hyperfunction of the parathyroid gland may induce bone resorption. The influence of 40 g animal protein load on urinary risk factors of calcium stone formation was investigated in 23 healthy males and 26 patients with nephrolithiasis. All subjects were given control diets each day containing 60 g protein for a week and during the next week each received an additional 40 g animal protein. In the controls, added dietary protein resulted in decreased urinary citrate and increased urinary uric acid, with no change in urinary calcium or cyclic AMP excretion. In contrast, the patients showed increased urinary calcium and cyclic AMP as well as decreased urinary citrate. Further examination of the patients revealed that the significant increases of calcium and cyclic AMP excretion occurred only in hypercalciuric patients, who seemed to be classified into renal hypercalciuria.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of renal function and metabolic abnormalities of cystine stone patients and calcium oxalate stone patients in China

Purpose

To compare renal function and metabolic abnormalities of cystine stone patients and calcium oxalate stone patients in China.

Methods

Between 2008 and 2011, thirty cystine stone patients were involved in our study, and an equal number of age- and gender pair-matched patients with calcium oxalate stones. Non-stone forming individuals were elected as controls. The evaluation included blood chemistry studies and 24-h urine collection in both groups of patients.

Results

The cystine stone patients had higher mean values of serum blood urea nitrogen, urate and creatinine levels than patients in other two groups. With respect to urine risk factors, cystine stone patients had higher urinary citrate and lower urinary oxalate and creatinine than calcium oxalate stone patients. When compared to non-stone forming individuals, cystine stone patients had higher urinary urate excretion and lower urinary creatinine excretion. Metabolic abnormalities could be demonstrated in 80 % of the cystine stone patients and in 100 % of the calcium oxalate stone patients. We also compared urine risk factors among cystine stone patients with different urine cystine excretion (<1 mmol/24 h, 1–2 mmol/24 h and >2 mmol/24 h). No significant difference was found in urine risk factors among three groups.

Conclusions

This study suggested that cystine stone patients were at greater risk for the loss of renal function than calcium oxalate stone patients, but the risk of the formation of calcium oxalate stones was lower. Our results also indicated that urinary cystine had little or no impact on the excretion of urine chemistries in cystine stone patients.     

Value of routine citrate analysis and calcium/citrate ratio in calcium urolithiasis

24-hour urinary citrate excretion was measured in 176 calcium oxalate stone formers and 100 normal controls. A statistically significant difference (p less than 0.03) could be found between the two groups. When stone formers were divided into a group of 69 patients with recurrent calcium urolithiasis (RCU) and a group of 106 patients with a single stone episode, the latter did not differ from the control group, while in RCU a significantly lower citrate excretion compared with controls (p less than 0.005) could be found. Thus, patients with RCU could benefit from alkali citrate prophylaxis. A female-male difference in citrate excretion could not be found in either the control group or stone formers. Recurrent stone formers presented a significantly higher calcium/citrate ratio compared with controls, which would indicate an increased risk for stone formation. The value of routine citrate analysis is limited, however, by the great, variability of citrate levels in stone formers and controls.     

Acute caffeine effects on urine composition and calcium kidney stone risk in calcium stone formers

PURPOSE: Caffeine increases urinary calcium (ca) excretion in nonstone formers. We designed a study to determine the effect of caffeine consumption on urinary composition in stone formers. MATERIALS AND METHODS: A total of 39 normocalcemic patients with calcium stones consumed caffeine (6 mg/kg lean body mass) after 14 hours of fasting. Urinary composition was compared 2 hours before and 2 hours after caffeine consumption. Control subjects included 9 nonstone formers studied contemporaneously with patients plus data from 39 nonstone formers from previous studies matched to each patient by level of fasting calcium/creatinine (Cr), gender and age. RESULTS: Caffeine increased urinary Ca/Cr, magnesium/Cr, citrate/Cr and sodium/Cr but not oxalate/Cr in stone formers and controls. The Tiselius stone risk index for calcium oxalate precipitation increased from 2.4 to 3.1 in stone formers and from 1.7 to 2.5 in nonstone formers. Of the 39 stone formers 32 had an increased Tiselius risk index after caffeine. Post-caffeine increases in Ca/Cr and Na/Cr were highly correlated. CONCLUSIONS: Caffeine consumption may modestly increase risk of calcium oxalate stone formation.     

The efficacy of dietary intervention on urinary risk factors for stone formation in recurrent calcium oxalate stone patients

PURPOSE: Nutrition is suggested to be the major environmental risk factor in idiopathic calcium oxalate stone disease. The study was designed to evaluate the effect of dietary intervention on urinary risk factors for recurrence in calcium oxalate stone formers. MATERIALS AND METHODS: A total of 76 men and 31 women with idiopathic calcium oxalate stone disease collected 24-hour urine on their habitual, self-selected diets and after 7 days on a balanced standardized diet according to the recommendations for calcium oxalate stone formers. RESULTS: On the usual diet, a urine volume of less than 2.0 l per 24 hours was present in 57.9%, hypercalciuria in 25.2%, hypomagnesuria in 18.7%, hyperoxaluria in 14.0%, hyperuricosuria in 41.3% and hypocitraturia in 57.0% of patients. The frequency of metabolic abnormalities and the risk of calcium oxalate stone formation decreased significantly on the ingestion of the balanced diet, due to the significant increase in urinary volume, pH and citrate excretion and the significant decrease in urinary calcium and uric acid excretion. No change occurred in urinary oxalate and magnesium excretion. CONCLUSIONS: The evaluation of urinary risk profiles of the patients on their usual dietary habits revealed a high risk for calcium oxalate stone formation. A low fluid intake and an increased intake of protein and alcohol were identified as the most important dietary risk factors. The shift to a nutritionally balanced diet according to the recommendations for calcium oxalate stone formers significantly reduced the stone forming potential.     

The influence of diet on urinary risk factors for stones in healthy subjects and idiopathic renal calcium stone formers

The daily intake of 103 recurrent idiopathic calcium stone formers and 146 controls was assessed by means of a computer-assisted 24-h dietary record. Timed 24-h urine samples were collected over the same period to assess the relationship between dietary intake of nutrients and urinary risk factors for calcium stones. After standardisation for sex, age and social status a total of 128 subjects underwent final statistical analysis; 64 renal stone formers and 64 controls. Significant increases in the consumption of animal and vegetable protein and purine were identified as the nutritional factors that distinguished renal stone formers from controls. As expected, the daily urinary excretion of calcium and oxalate was higher and the daily urinary excretion of citrate was lower in stone formers than in controls. No difference with respect to daily urinary uric acid excretion was recorded. Daily urinary excretion of calcium was correlated to dietary protein intake while daily urinary oxalate was correlated to dietary vitamin C intake. It was concluded that renal stone formers could be predisposed to stones because of their dietary patterns. A link between the protein content of the diet and urinary calcium was confirmed, but dietary animal protein had a minimal effect on oxalate excretion.     

Physicochemical metabolic characteristics for calcium oxalate stone formation in patients with gouty diathesis

PURPOSE: We determined why calcium oxalate stones instead of uric acid stones form in some patients with gouty diathesis. MATERIALS AND METHODS: Gouty diathesis was diagnosed from absence of secondary causes of uric acid stones or low urinary pH, and reduced fractional excretion of urate with discriminant score of the relationship between urinary pH and fractional excretion of urate less than 80. From the stone registry 163 patients with gouty diathesis were identified, including 62 with uric acid stones (GD + UA) and 101 patients with calcium oxalate stones (GD + Ca). Metabolic data and 24-hour urinary chemistry study were compared between the 2 groups. RESULTS: Compared with GD + UA, GD + Ca had significantly greater urinary calcium (196 +/- 96 mg per day vs 162 +/- 82 mg per day, p <0.05) and significantly lower urinary citrate (430 +/- 228 vs 519 +/- 288 mg per day, p <0.05), resulting in higher urinary saturation of calcium oxalate. Both groups had low urinary pH (less than 5.5) and high urinary undissociated uric acid (greater than 100 mg/dl). Urinary calcium post-oral calcium load was significantly higher in GD + Ca than in GD + UA (0.227 vs 0.168 mg/dl glomerular filtrate, p <0.001). CONCLUSIONS: Calcium oxalate stones may form in some patients with gouty diathesis due to increased urinary excretion of calcium and reduced excretion of citrate. Relative hypercalciuria in GD + Ca may be due to intestinal hyperabsorption of calcium.     

Acute acid load in recurrent oxalate stone formers

An acute acid load was used to evaluate potential chemical differences of urinary composition in recurrent oxalate stone formers and healthy controls. After intake of ammonium chloride, total calcium, ionized calcium and magnesium increased and citrate decreased significantly in both groups. Differences between stone formers and controls could be demonstrated from the excretion of total calcium, citrate, oxalate and uric acid only after acute acid load, whereas ionized calcium did not improve discrimination. These findings support the stone-promoting role of high acid food as well as the possibility of discriminating recurrent oxalate stone formers from controls by an acute acid-loading test.     

Urinary inhibitors of crystallization in hypercalciuric children with hematuria and nephrolithiasis

Urinary inhibitors are suggested to play a significant role in reducing crystallization in calcium (Ca) stone former and idiopathic hypercalciuria (IH). Urinary inhibitors such as magnesium (Mg), citrate, and glycosaminoglycans (GAGs) were evaluated, as well as urinary Ca and creatinine (Cr), in IH children with nephrolithiasis (LIT) or with hematuria plus IH (HEM) and were compared with a control group. The mean 24-h urinary excretion of Mg was similar in all groups. However, the urine Ca/Mg ratio was significantly increased (P <0.005) in LIT and HEM groups. A higher mean value for GAGs and citrate was found in the HEM group, but a very low level of GAGs (less than 60% of the normal value) and citrate (less than 30% of the normal value) was found in the LIT group. These data suggest that, despite a high urinary Ca excretion (3.6±0.1 mg/kg per day) in the HEM group, elevated urinary GAGs (32.0±1.0 mg/g Cr) and a normal urinary citrate (428.7±62.3 mg/24 h) excretion may prevent Ca crystallization and thus renal stones. In contrast, in the LIT group low urinary GAG (10.3±0.9 mg/g Cr) and citrate (235.2±52.3 mg/24 h) excretion may precipitate stone formation in the presence of a high urinary Ca excretion. Thus, it is reasonable to suggest that patients with hematuria and IH may not develop overt renal stone due to the presence of normal levels of renal stone inhibitors. Received October 30, 1995; accepted December 15, 1995     

Pathophysiology of incomplete renal tubular acidosis in recurrent renal stone formers: evidence of disturbed calcium,bone and citrate metabolism

Summary Urinary acidification, bone metabolism and urinary excretion of calcium and citrate were evaluated in 10 recurrent stone formers with incomplete renal tubular acidosis (RTA), 10 recurrent stone formers with normal urinary acidification (NUA) and 10 normal controls (NC). Patients with iRTA had lower plasma standard bicarbonate after fasting (P<0.01) and lower urinary excretion of titratable acid (P<0.05) and citrate (P<0.01) compared with NUA patients and NC, and higher urinary excretion of ammonia (P<0.05) compared with NC (P<0.05). Hypercalciuria was found in 6 of 10 patients with iRTA compared with 3 of 10 with NUA, and O of 10 NC. The citrate/calcium ratio in urine was significantly reduced in iRTA compared with the value in NUA (P<0.01), and in NUA compared with NC (P<0.05). Biochemical markers of bone formation (serum osteocalcin) and bone resorption (urinary hydroxyproline) were significantly increased in iRTA compared with NUA and NC (P<0.01), indicating increased bone turnover in stone formers with iRTA. Stone formers with iRTA thus presented with disturbed calcium, bone and citrate metabolism-the same metabolic abnormalities which characterize classic type 1 RTA. Mild non-carbonic acidosis during fasting may be a pathophysilogical factor of both nephrolithiasis and disturbed bone metabolism in stone formers with iRTA     

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.     

Inhibitors of stone formation in hypercalciuric children with and without stone disease.

The extretion of two inhibitors of urinary stone formation (citrate, magnesium) was evaluated in 71 hypercalciuric children and 50 controls. Patients were classified into two groups: 42 nonstone former (NSF), 22 boys and 20 girls, 3-14 years old, and 29 stone formers (SF), 18 boys and 11 girls, 2.5-18 years old. Our study was unable to show significant differences in magnesium and citrate urinary outputs between controls and patient groups. The Mg/Ca ratio was found significantly lower in hypercalcuric children than in controls (p less than 0.001), but not between NSF and SF patients. Our data demonstrated that both NSF and SF groups had a significantly lower citrate/Ca ratio than controls (p less than 0.001), also it was lower in SF than in NSF (p less than 0.05). We found no significant difference in citrate excretion between boys and girls neither in patients nor in controls.     

Juvenile renal stone disease: a study of urinary promoting and inhibiting factors

Urinary excretion of the most widely studied renal stone promoting (calcium, oxalate, uric acid and phosphate) and inhibiting (citrate, magnesium, pyrophosphate and glycosaminoglycans) factors, as well as the Tamm-Horsfall mucoprotein, was evaluated in 14 children with idiopathic calcium nephrolithiasis, 6 children with renal stone disease secondary to excretory malformations and 19 normal controls. No statistically significant differences in urinary excretion of promoting and inhibiting factors were found in children with idiopathic calcium nephrolithiasis but the relationship between promoting and inhibiting factors was changed as shown by an abnormal ratio of oxalate/citrate X glycosaminoglycans. This finding suggests that there is an imbalance between promoting and inhibiting factors in children with idiopathic calcium nephrolithiasis, and it is not detected by assay of each single substance.     

Role of the urinary calcium in the growth of calcium stone

We analyzed the relationship between the rate and clinical factors. The growth rate per year of the stone was measured by Nabeshima's method in 29 male patients with renal calcium stones including 7 pure calcium oxalate (CaOx) stones and 22 mixed calcium oxalate and calcium phosphate (CaOx-CaP) stones. The 24-hour urinary excretion of calcium, phosphate, uric acid and magnesium were assayed under an ambulatory free diet in 5 patients with CaOx stones and 15 with CaOx-CaP stones. The relationship between the growth rate and the urinary excretion of stone-forming parameters was examined. We found a significant positive correlation between the growth rate of calcium stones and the urinary excretion of calcium (p<0.02). In addition, the growth rate of CaOx-CaP stone was significantly higher than that of pure CaOx stone (p<0.05). In conclusion, urinary calcium is important for the growth of renal calcium stones.     

Urinary glycosaminoglycan excretion in normal and stone-forming subjects: significant disturbance in recurrent stone formers

The overnight (12 h) urinary excretion of glycosaminoglycans, citrate, magnesium, calcium and uric acid were measured in 82 normal subjects and 63 outpatients who had formed at least one urinary stone. No significant difference could be found between the two groups of unselected subjects with respect to any of the urinary parameters. Nonetheless, recurrent stone formers had significantly lower glycosaminoglycans and predictive risk index than normal controls.     

Prospective study on the efficacy of a selective treatment and risk factors for relapse in recurrent calcium oxalate stone patients

OBJECTIVE: The present study was performed to examine the efficacy of a selective treatment according to the guidelines for the prevention of recurrence in calcium oxalate stone patients and to assess risk factors for stone recurrence. METHODS: To investigate the effect of specific diagnostic and therapeutic measures, 134 recurrent calcium oxalate stone formers participated in a prospective study for two years with regular follow-ups of at least every six months. Depending on the results of analysis of 24-hour urine, nutrition record and metabolic situation, selective recommendations were given concerning diet and medication. RESULTS: Throughout the follow-up period, 57 (43%) of the patients experienced relapses. In recurrence-free patients, the significant increase in urinary volume, as well as urinary pH, potassium and citrate excretion, three indexes of compliance with alkalization, resulted in a significant decrease in the calculated risk of calcium oxalate stone formation. In patients with recurrences during follow-up, the relative supersaturation with calcium oxalate increased significantly, mainly due to the significant rise in urinary oxalate excretion exceeding the significant increases in urinary volume, pH, potassium and citrate excretion. Multiple logistic regression analysis revealed previous ESWL treatment and a history of multiple stones as independent predictors of the risk for recurrence. CONCLUSIONS: The results indicate that compliance with drinking advice and alkalization therapy was highest among both, patients with and without recurrences, compared with all other therapeutic measures. The increase in oxalate excretion is identified as the major urinary risk factor for relapse during follow-up in recurrent calcium oxalate stone disease.     

Role of inhibitor deficiency in urolithiasis. I. Rationale of urinary magnesium, citrate, pyrophosphate and glycosaminoglycan determinations.

Between October 1988 and March 1990, 173 urinary stone patients (average age 38.3 years) were evaluated metabolically, especially with regard to urinary magnesium, pyrophosphate (Ppi) citrate and glycosaminoglycans (GAG). 25 healthy subjects served as controls. Inhibitory deficiency was found to be the most frequent causal factor in our series, with an incidence of 48.7% in first-time stone formers and 51.08% in recurrent urolithiasis (p less than 0.1). Deficient citrate levels were present in 46.56%, hypomagnesiuria in 24.4%, hypopyrophosphaturia in 10.7% and deficient GAG in 2.7% of the patients. Deficient urinary Ppi was seen in only 2.7% of the stone formers as the only metabolic defect, while deficient GAG was never the only causal factor. All 4 inhibitors showed no correlation with age, sex, activity of stone disease, stone weight and burden. There were no statistically significant differences with controls. We think that routine metabolic evaluation must be performed both in recurrent patients and first-time stone formers and must include urinary citrate and Mg determinations in every case. Urinary Ppi should be determined in selected cases and GAG determinations are irrational.