Clinical studies of the recurrence of urolithiasis (4). Crystal formation in urine and stone recurrence

Relationship between stone formation and crystal formation in urine was studied. Crystals in the sediments of early morning urine in 238 stone formers and the same numbers of non-stone formers were examined by light microscopy. Almost all crystals found in the early morning urine were composed of calcium oxalate both in stone formers and in non-stone formers. The frequency of calcium oxalate crystal formation was slightly higher in stone formers than in non-stone formers, but, no significant difference was noted. On the other hand, the urine containing calcium oxalate crystals of the stone formers had significantly lower specific gravity than that of the non-stone formers. Calcium oxalate crystals in the urine were formed significantly more frequently in the recurrent or bilateral male stone formers than in male unilateral stone formers without previous stone history. Frequency of calcium oxalate crystal formation was not influenced by urinary excretion of calcium, oxalate, uric acid, phosphate and magnesium. These finding led us to the conclusion that it was clinically useful to measure urinary specific gravity in which calcium oxalate crystals were formed in predicting the risk of stone formation.     

A study on the cause of urolithiasis of the upper urinary tract--clinical study of risk factors in the formation of stones in the upper urinary tract

Various risk factors and inhibitors of the stone formation of the upper urinary tract have been pointed out in urine. We examined the amount of daily excretion of several important risk factors (calcium, phosphorus, urate and oxalate) and inhibitors (magnesium and citrate) in the urine of 21 healthy males, 13 male single stone formeks and recurrent and/or multiple stone formers before and after taking the regular diet which contains 500 mg of calcium and 1,000 mg of phosphorus a day. The daily excretion of calcium, phosphorus and magnesium indicated no significant differences among the 3 groups. The excretion of oxalate in urine for 24 hours was significantly decreased in the stone formers after taking the regular diet. The urinary excretion of the urate per body surface area in the stone formers was significantly higher than that in the healthy control. The amount of the excretion of the citrate in urine in the recurrent and/or multiple stone formers was significantly lower than that in the other 2 groups. Many patients of the recurrent and/or multiple urinary stones had more than two abnormal values of above-mentioned risk factors and inhibitors. These results suggest that the causes of the formation of the upper urinary stone were not single but multiple and that the dietary advice to these patients was important against the recurrence of the urolithiasis.     

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.     

Oxalate loading test for outpatients with calcium oxalate stones

A spinach loading experiment was performed on 9 normal subjects, 25 outpatients who were single calcium oxalate stone formers and 25 recurrent calcium oxalate stone formers. The experimental diet contained 445 mg of total oxalate, 163 mg of soluble oxalate and 115 mg of calcium. Urinary oxalate excretion was observed 2 hrs before and 6 hrs after the experimental diet was consumed. There was no significant difference in urinary oxalate excretion in preloading urine of normal subjects and stone formers. However, urinary oxalate excretion in postloading urine was significantly elevated in stone formers. This loading test is recommended as a simple and valuable screening method of hyperabsorption of oxalate on outpatients with calcium oxalate stones.     

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.     

Effect of dietary intake on urinary oxalate excretion in calcium oxalate stone formers in their forties

PURPOSE: To examine the influence of dietary intake on urinary oxalate excretion in calcium oxalate stone formers in their forties. PATIENTS AND METHODS: Dietary intake was recorded by using the dietary-record method in 58 idiopathic stone formers in their forties. The patients collected their urine for 24 h at home and their urinary oxalate excretion was measured. The relationship between the dietary intake of various nutrients and urinary oxalate excretion was examined by mono- and multivariate analysis. RESULTS: The intake of animal fat was correlated with urinary oxalate excretion by monovariate analysis, but that of total protein, animal protein, calcium and carbohydrate were not. By multivariate analysis, the intake of animal fat was correlated with urinary oxalate excretion and the intake of calcium was inversely correlated with urinary oxalate excretion. CONCLUSION: The intake of animal fat was positively and the intake of calcium was negatively correlated with the urinary oxalate excretion in stone formers in their forties. It was shown that animal fat plays an important role in urinary oxalate excretion.     

Comparative study of 24-hour urinary excretion of glycosaminoglycans by renal stone formers and healthy adults

In order to find out the possible aetiological factors for urolithiasis in North-Western India, an endemic region for urinary calculi, we studied the 24-hour urinary excretion of glycosaminoglycans (GAGs), inhibitors of calcium oxalate crystallisation and/or crystal aggregation, in 58 healthy adults and in 100 stone formers. GAGs were colorimetrically estimated in urine in terms of glucuronic acid content after precipitation of GAGs by cetyl pyridinium chloride. The 24-hour urinary excretion of GAGs was significantly less in stone formers as compared to healthy adults (15.32 +/- 6.94 vs. 22.44 +/- 5.54 mumol/day; p less than 0.001). There was no significant difference in the 24-hour urinary excretion of GAGs between male and female stone formers, or between male and female healthy adults. There was no correlation between age and 24-hour urinary excretion of GAGs in any of the groups. In conclusion, 24-hour urinary excretion of GAGs is significantly less both in male and in female stone formers. The 24-hour urinary excretion of GAGs is not related to age or sex in both healthy adults as well as in stone formers.     

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.     

Clinical studies on the recurrence of urolithiasis: (1). Influence of diet on urinary excretion of the stone forming constituents

Twenty-four hour urinary excretion of the stone forming constituents, calcium, oxalate, uric acid, phosphate and magnesium were assayed either under the restricted diet (190 stone formers and 52 non-stone formers) or under the ambulatory free diet (93 stone formers and 14 non-stone formers). Under the ambulatory free diet, urinary excretion of calcium, uric acid and magnesium in the male stone formers, and urinary excretion of calcium and magnesium in the female stone formers was significantly higher than that under the restricted diet. Under the restricted diet, no difference in urinary excretion of calcium, oxalate, uric acid or phosphate was noted between the stone formers and non-stone formers. However, urinary magnesium excretion of the stone formers under the restricted diet was significantly lower than that of the non-stone formers. Under the free diet, no difference in urinary excretion of calcium, oxalate, uric acid, phosphate or magnesium was observed between the stone formers and non-stone formers. Also, there was no significant difference in urinary excretion of calcium, oxalate, uric acid, phosphate or magnesium between the unilateral urolithiasis patients without previous stone history and that of the bilateral or recurrent stone formers. We conclude that urinary excretion of calcium, oxalate, uric acid, phosphate and magnesium have no major role in the stone producing mechanism. However, reduction of urinary excretion of calcium, oxalate, uric acid and phosphate and augmentation of urinary excretion of magnesium are mandatory in preventing stone recurrence until a better understanding of the cause of urolithiasis is obtained.     

Frequency of renal phosphate leak among patients with calcium nephrolithiasis.

BACKGROUND: Nephrolithiasis is a frequent disorder affecting 10 to 15% of the population in Europe and the United States. More than 80% of renal stones are made of calcium oxalate and calcium phosphate. The main identified risks for calcium renal stone formation are hypercalciuria and urinary saturation. A urine phosphate (Pi) loss is often associated with hypercalciuria; furthermore, hyperphosphaturia increases urinary saturation. METHODS: To determine whether urinary phosphate loss is associated with calcium urolithiasis, we measured renal Pi threshold (TmPi) in 207 stone formers with normal parathyroid hormone (PTH) serum concentration and in 105 control subjects. RESULTS: The TmPi followed a normal distribution in both groups. The mean TmPi was significantly lower in stone formers versus controls (0.72 +/- 0.13 vs. 0.87 +/- 0.18 mmol/L, P < 0.0001) because of a shift to the left of the TmPi distribution curve in the stone former population, with no evidence for bimodal distribution. Five percent of the controls had a TmPi <0.63 versus 19% of the stone formers. Daily urinary calcium excretion was significantly higher in stone formers than in controls. Calcium excretion was also significantly higher in stone formers with TmPi <0.63 mmol/L compared with those with TmPi > or =0.63. Serum PTH and ionized calcium concentrations were not different in stone formers and in control subjects, whatever the TmPi value. CONCLUSIONS:: A low TmPi is more frequently encountered in stone formers with a normal PTH concentration than in control subjects and is associated with a high urinary Ca excretion. The hypophosphatemia induced by a renal phosphate leak may predispose the subject to calcium stone formation by increasing the serum calcitriol level, calcium excretion, and urinary saturation.     

The Relation Between Bone and Stone Formation

Hypercalciuria is the most common metabolic abnormality found in patients with calcium-containing kidney stones. Patients with hypercalciuria often excrete more calcium than they absorb, indicating a net loss of total-body calcium. The source of this additional urinary calcium is almost certainly the skeleton, the largest repository of calcium in the body. Hypercalciuric stone formers exhibit decreased bone mineral density (BMD), which is correlated with the increase in urine calcium excretion. The decreased BMD also correlates with an increase in markers of bone turnover as well as increased fractures. In humans, it is difficult to determine the cause of the decreased BMD in hypercalciuric stone formers. To study the effect of hypercalciuria on bone, we utilized our genetic hypercalciuric stone-forming (GHS) rats, which were developed through successive inbreeding of the most hypercalciuric Sprague-Dawley rats. GHS rats excrete significantly more urinary calcium than similarly fed controls, and all the GHS rats form kidney stones while control rats do not. The hypercalciuria is due to a systemic dysregulation of calcium homeostasis, with increased intestinal calcium absorption, enhanced bone mineral resorption, and decreased renal tubule calcium reabsorption associated with an increase in vitamin D receptors in all these target tissues. We recently found that GHS rats fed an ample calcium diet have reduced BMD and that their bones are more fracture-prone, indicating an intrinsic disorder of bone not secondary to diet. Using this model, we should better understand the pathogenesis of hypercalciuria and stone formation in humans to ultimately improve the bone health of patients with kidney stones.     

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     

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.     

Prevalence of hyperoxaluria in idiopathic calcium oxalate kidney stone disease

Urinary excretion of oxalate, calcium and urate has been investigated in 88 patients affected by idiopathic calcium oxalate stone disease and in 20 normal subjects. Of these ions, only oxalate was found significantly higher in stone formers. Defining hyperoxaluria as urinary oxalate excretion greater than 2 SD above normal, 50% of stone-forming people were found to be hyperoxaluric. When stone formers were classified in normo- and hyperoxaluric, the prevalence of hypercalciuria, hyperuricuria, family history of stone disease and recurrencies in stone formation was the same in both groups. It is concluded that hyperoxaluria is a frequent finding in finding in idiopathic calcium oxalate renal stone disease.     

The loss of circadian rhythmicity of urinary solute excretion in idiopathic stone formers

Circadian rhythmicity in urinary volume and excretion of creatinine, calcium, oxalate, uric acid and phosphate was studied in 15 idiopathic stone formers and in 17 control subjects who were age-matched, related adult males, living in the same house and engaged in similar occupations to those of the stone patients, but who had no clinically obvious stone disease. Three-hourly urine samples were collected and creatinine, calcium, oxalate, uric acid and inorganic phosphate were estimated. The time series of data were analysed by cosinor rhythmometry. Circadian rhythmicity has been described in urinary volume and urinary excretion of creatinine, calcium, oxalate, uric acid and inorganic phosphate in normal subjects, but it was not detected in the stone formers. The control subjects exhibited a circadian rhythmicity only in urinary volume and creatinine excretion. Thus they occupied a position midway between healthy adults, who exhibit circadian rhythmicity in all of the above parameters, and the stone formers, who appear to have lost it altogether.     

Urinary excretion of citrate, glycosaminoglycans, magnesium and zinc in relation to age and sex in normal subjects and in patients who form calcium stones.

One hundred and ninety-seven healthy subjects and 104 patients with idiopathic calcium stone disease had their urinary excretion of citrate, glycosaminoglycans, magnesium, and zinc measured and the results correlated with sex and age. In normal subjects the daily excretion of citrate, magnesium, and zinc increased with age to a maximum during the fifth decade and remained relatively constant until the eighth decade when they decreased. The daily excretion of magnesium and zinc were higher in men than in women, which was attributed to the higher body weights of the men. The urinary excretion of citrate, magnesium, and zinc related to creatinine remained relatively constant with age in adult life; analyses of magnesium and zinc excretion rates divided by urine creatinine did not distinguish men from women. There was no significant difference between men and women for citrate excretion in 24 hour urine, but the citrate:creatinine ratio was significantly higher in women than men. The higher citrate excretion in women may explain the lower incidence of calcium stones in women. The highest glycosaminoglycan excretion rates were seen during the first two decades which is why children and teenagers are less prone to develop calcium stones in spite of high urinary calcium concentrations. Urinary citrate and magnesium excretion were lower, and glycosaminoglycan and zinc excretion were higher, in stone formers than in controls. It seems that a decreased excretion of citrate and magnesium together with an increased excretion of calcium, may contribute to the formation of calcium stones. The role of urinary glycosaminoglycans and zinc in the formation of calcium stones remains uncertain.     

草酸钙结石患者尿中蛋白结合型γ-羧基谷氨酸的检测意义

目的　探讨含γ 羧基谷氨酸 (Gla)蛋白质及其Gla残基在尿石形成中的作用。　方法　采用过饱和结晶法从新鲜尿液中提取草酸钙晶体基质 ,高效液相色谱法 (HPLC)测定 2 5例草酸钙结石患者尿液和提取的晶体基质中蛋白结合型Gla含量。　结果　草酸钙结石患者尿蛋白结合型Gla浓度为 (1.32± 0 .2 4)nmol/ml,2 4h尿含量为 (2 .0 4± 0 .6 5 ) μmol,显著低于正常人 ;草酸钙结石患者尿液提取的晶体基质中蛋白结合型Gla含量亦显著低于正常人。　结论　草酸钙结石患者尿液中蛋白结合型Gla含量较少 ,尿液含Gla蛋白质的羧基化程度低下可能是结石形成的重要原因之一。     

The urinary response to an oral oxalate load in recurrent calcium stone formers

PURPOSE: Dietary oxalate may contribute up to 50% to 80% of the oxalate excreted in urine. We studied the urinary response to an oral oxalate load in male and female idiopathic recurrent calcium oxalate stone formers with and without mild hyperoxaluria to evaluate the potential pathophysiological significance of dietary oxalate. MATERIALS AND METHODS: A total of 60 recurrent calcium stone formers underwent an oral oxalate load test. Urine samples were obtained after an overnight fast. Each patient then received an oral oxalate load (5 mM. sodium oxalate dissolved in 250 ml. distilled water) and 3, 2-hour urine samples were obtained 2, 4 and 6 hours after the oxalate load. We compared the response to the oxalate load in patients with and without mild hyperoxaluria, and in male and female patients without hyperoxaluria. RESULTS: The peak urinary response occurred 4 hours after the oral oxalate load in all patients. Those with mild hyperoxaluria had a mean fasting urinary oxalate-to-creatinine ratio +/- SE of 0.027 +/- 0.003 and a mean peak urinary oxalate-to-creatinine ratio of 0.071 +/- 0.006. In comparison, patients with normal oxalate excretion had a fasting and peak urinary oxalate-to-creatinine ratio of 0.018 +/- 0.001 and 0.056 +/- 0.004, respectively (p <0.05). The mean 6-hour increment for urinary oxalate excretion after the oxalate load for patients with hyperoxaluria versus those with normal urinary oxalate excretion was 17.2 +/- 1.9 versus 12.1 +/- 0.98 mg. (p <0.05). In the subset of patients with normal urinary oxalate excretion mean 6-hour cumulative urinary oxalate excretion was 16.8 +/- 1.3 and 13.3 +/- 1.4 mg. in males and females, respectively (p not significant). CONCLUSIONS: Recurrent calcium stone formers with mild hyperoxaluria have higher fasting urinary oxalate and an exaggerated urinary response to an oral oxalate load compared with recurrent calcium stone formers with normal urinary oxalate excretion. Men and women stone formers without hyperoxaluria excrete similar fractions of an oral oxalate load. Increased gastrointestinal absorption and renal excretion of dietary oxalate may be a significant pathophysiological mechanism of stone formation in patients with mild hyperoxaluria.     

Fasting urine excretion of magnesium,calcium, and sodium in patients with renal calcium stones

Urine excretion of magnesium (Mg), calcium (Ca) and sodium(Na) was studied in patients with renal Ca stones having normal kidney function (n= 60), and in matched controls (n= 60), on a free diet following an overnight fasting period. In some formers, Mg was lower than in normals, whereas Ca was unusually high resulting in a significantly higher molar Ca/Mg ratio (p less than 0.001). 2. In 3 out of 4 stone groups Na excretion was significantly elevated because of reduced tubular reabsorption. In normals, fractional Na excretion varied between 0.44 and 0.54% of endogenous creatinine clearance, whereas it exceeded 1% in the stone patients. Conversely, the molar ratio Na/Ca was equal in all groups. 3. Fasting urinary cyclic AMP was comparable in both populations supporting the assumption that in the majority of patients Ca- or Mg- wasting via urine may not be responsible for secondary hyperparathyroidism. In small selected groups, losses of divalent cations may act in concert, leading to stimulation of the parathyroid glands. 4. Correlations between minerals and Na reveal a close relationship between Na, Ca and Mg in terms of clearance and excretion rate in patients and controls. Fractional Na and Ca excretion are correlated in patients but not in normals. This suggests that in the absence of phosphaturia, factors other than extracellular volume expansion and/or hyperparathyroidism are operative in stone disease. 5. The origin of fasting natriuresis and relative hypercalciuria may be ascribed to a change, as yet not causally identified, in distal tubular Na reabsorption.