Role of the diurnal variation of urinary pH and urinary calcium in urolithiasis: A study in outpatients

BACKGROUND: We previously reported that the urinary excretion of calcium and the diurnal variation of urinary pH were important for stone formation in hospitalized inpatients with hospital standard diet. Because almost all urinary stones are formed in outpatients with ambulatory free diet, it is essential to investigate these factors in outpatients. METHODS: We examined the urinary excretion of calcium, oxalate, uric acid, phosphate and magnesium in 96 male outpatients and 142 male inpatients. We also studied the relationship between the stone composition and the diurnal variation of urinary pH in 32 male outpatients (five uric acid stones (UA), 13 pure calcium oxalate stones (CaOX) and 14 mixed calcium oxalate and calcium phosphate stones (CaOX-CaP)) and 53 male inpatients (nine UA, 15 CaOX and 29 CaOX-CaP). RESULTS: There was a significant difference in the urinary excretion of calcium among outpatients with UA, CaOX and CaOX-CaP (133 +/- 96 vs 219 +/- 97 vs 268 +/- 102 mg per day, P < 0.05). In outpatients with UA, urinary pH was constantly low throughout the entire day. In contrast, outpatients with CaOX and those with CaOX-CaP had diurnal variation of urinary pH that was low in the early morning, followed by elevation in the daytime and was lowered in the night. The pHs in the early morning, afternoon and night were significantly higher in outpatients with CaOX-CaP than in those with CaOX. CONCLUSION: The diurnal variation of urinary pH and the urinary calcium are important for stone formation.     

Thiazides reduce brushite, but not calcium oxalate, supersaturation, and stone formation in genetic hypercalciuric stone-forming rats

Over 59 generations, a strain of rats has been inbred to maximize urine calcium excretion. The rats now excrete eight to 10 times as much calcium as controls. These rats uniformly form calcium phosphate (apatite) kidney stones and have been termed genetic hypercalciuric stone-forming (GHS) rats. The addition of a common amino acid and oxalate precursor, hydroxyproline, to the diet of the GHS rats leads to formation of calcium oxalate (CaOx) kidney stones. Hydroxyproline-supplemented GHS rats were used to test the hypothesis that the thiazide diuretic chlorthalidone would decrease urine calcium excretion, supersaturation, and perhaps stone formation. All GHS rats received a fixed amount of a standard 1.2% calcium diet with 5% trans-4-hydroxy-l-proline (hydroxyproline) so that the rats would exclusively form CaOx stones. Half of the rats had chlorthalidone (Thz; 4 to 5 mg/kg per d) added to their diets. Urine was collected weekly, and at the conclusion of the study, the kidneys, ureters, and bladders were radiographed for the presence of stones. Compared with control, the addition of Thz led to a significant reduction of urine calcium and phosphorus excretion, whereas urine oxalate excretion increased. Supersaturation with respect to the calcium hydrogen phosphate fell, whereas supersaturation with respect to CaOx was unchanged. Rats that were fed Thz had fewer stones. As calcium phosphate seems to be the preferred initial solid phase in patients with CaOx kidney stones, the reduction in supersaturation with respect to the calcium phosphate solid phase may be the mechanism by which thiazides reduce CaOx stone formation.     

Calcium carbonate crystals promote calcium oxalate crystallization by heterogeneous or epitaxial nucleation: Possible involvement in the control of urinary lithogenesis

A large proportion of urinary stones have calcium oxalate (CaOx) as the major mineral phase. In these stones, CaOx is generally associated with minor amounts of other calcium salts. Several reports showing the presence of calcium carbonate (C_aCO₃) and calcium phosphate in renal stones suggested that crystals of those salts might be present in the early steps of stone formation. Such crystals might therefore promote CaOx crystallization from supersaturated urine by providing an appropriate substrate for heterogeneous nucleation. That possibility was investigated by seeding a metastable solution of⁴⁵Ca oxalate with vaterite or calcite crystallites. Accretion of CaOx was monitored by⁴⁵Ca incorporation. We showed that (1) seeds of vaterite (the hexagonal polymorph of C_aCO₃) and calcite (the rhomboedric form) could initiate calcium oxalate crystal growth; (2) in the presence of lithostathine, an inhibitor of C_aCO₃ crystal growth, such accretion was not observed. In addition, scanning electron microscopy demonstrated that growth occurred by epitaxy onto calcite seeds whereas no special orientation was observed onto vaterite. It was concluded that calcium carbonate crystals promote crystallization of calcium oxalate and that inhibitors controlling calcium carbonate crystal formation in Henle’s loop might play an important role in the prevention of calcium oxalate stone formation.     

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 stone risk factors in the siblings of patients with calcium renal stones

PURPOSE: We determined which, if any, urinary stone risk factors accurately discriminate stone forming and nonstone forming siblings of patients with calcium renal stones. MATERIALS AND METHODS: A total of 252 siblings of stone formers provided 2, 24-hour urine samples, which were sent overnight and analyzed at a central laboratory. Standard stone risk factors were measured and the supersaturation of calcium oxalate, calcium phosphate and uric acid was calculated. RESULTS: Discriminant functions were derived for each gender by multivariate analysis. In stone forming sisters higher urinary calcium and pH discriminated with a success rate of 70%. In stone forming brothers higher urinary calcium, lower urinary potassium and older age discriminated with a success rate of 79%. CONCLUSIONS: Select urinary measurements as well as age classify siblings into those with and without stones with fair accuracy. Calcium excretion and urinary pH in females, and calcium excretion, urinary potassium and age in males are feasible identifiers of stone forming siblings. To determine whether these measurements can be used to predict new stone onset may require years of observation of our current cohort.     

Evaluation of urine composition and calcium salt crystallization properties in standardized volume-adjusted 12-h night urine from normal subjects and calcium oxalate stone formers

The volume of 12-h night urine from ten normal men (NM), ten normal women (NW) and 31 male calcium stone formers (SFM) was adjusted to 750 ml and analysed with respect to supersaturation with calcium oxalate (CaOx) and calcium phosphate (CaP), inhibition of CaOx crystal growth and aggregation, as well as the CaOx and CaP crystallization propensity. Concentrations of oxalate and glycosaminoglycans and AP(CaOx) index, an estimate of the CaOx ion-activity product, were higher and the concentration of citrate lower in NM than in NW. In SFM the directly assessed risk of CaOx crystallization was higher and the inhibition of CaOx crystal growth lower than in NM. There were no differences between the groups regarding inhibition of CaOx crystal growth by 74% dialysed urine or inhibition of CaOx crystal aggregation. SFM with mixed CaOxCaP stones had a higher concentration of phosphate and a higher AP(CaP) index at pH 7.0 than SFM with CaOx stones.     

Effect of etidronate disodium (EHDP) on calcium oxalate renal stones induced by synthetic 1 alpha(OH) vitamin D3 and ethylene glycol in rats

Combination of 1 alpha(OH) D3(vit D) and ethylene glycol induced renal or ureteral stones or both consisting of calcium oxalate in male Wistar rats. This study investigates the effect of EHDP on calcium oxalate stone using the rat model. EHDP reduced the frequency of renal stone and calcium content in the kidney, and reduced the size of the stones in the renal pelvis and ureter. EHDP biochemically ameliorated renal injury induced by vit D and ethylene glycol. EHDP suppressed urinary excretion of calcium even though serum calcium slightly increased. EHDP had a phosphaturic action. EHDP elevated urinary excretion of magnesium. However, the severity of hypermagnesuria decreased in the rat which was not given EHDP concomitantly. Although EHDP slightly elevated urinary excretion of oxalate in the control rat, it did not affect the high level of urinary oxalate in the vit D/ethylene glycol rat. EHDP did not produce any histological change in the kidney or femoral bone. These data indicate that EHDP can suppress renal stone formation in the vit D/ethylene glycol rat. It is speculated that firstly, EHDP may physicochemically inhibit stone formation in the process of nidus, aggregation and crystal growth of calcium oxalate, under the supersaturated condition of calcium oxalate in the urine, and secondly, EHDP may endocrinologically inhibit production of 1,25 (OH)2 vit D in the kidney or inhibit 1, 25 (OH)2 vit D-mediated intestinal calcium absorption. It is suggested that in order to prevent stone recurrence, EHDP may be clinically applied not only to calcium phosphate stones but also to calcium oxalate stones and hypercalciuria mediated by an active form of vitamin D.     

Risk factors of calcium stone formation in patients with primary Sjögren's syndrome

Distal renal tubular acidosis (dRTA), which occurs in patients with primary Sjögren's syndrome (SS), is a risk factor for the development of urolithiasis. Twenty-seven patients with SS were evaluated with respect to biochemical risk factors of calcium stone formation. Sixteen had no history of urolithiasis (group 1) whereas 11 had such a history (group 2). The stone composition was known for seven of the patients, and calcium phosphate was the major stone constituent in all of them. dRTA was present in all patients in group 2, and in 7 of the 16 patients in group 1. Hypocitraturia was common inboth groups, and the urinary excretion of citrate did not differ between the two groups. There was a higher urinary excretion of calcium and urate in group 2 and this group also had a higher urine volume. The risk of forming a urine supersaturated with calcium oxalate (CaOx) expressed in terms of AP(CaOx)index(s), which is an approximate estimate of the ion-activity product of CaOx calculated for a 24-h urine volume of 1500 ml, was higher in stone formers. A similarly derived estimate of the ion-activity product of calcium phosphate, AP(CaP)index(s), was calculated for a urine pH of 7. Although AP(CaP)index(s) was not significantly higher in group 2, there was a good correlation between AP(CaP)index(s) and AP(CaOx)index(s). We conclude that the urine composition in patients with SS, dRTA and urolithiasis is similar to that of other stone-forming patients with dRTA, and recurrence preventive therapy can be designed as for these patients.     

Urine pH in renal calcium stone formers who do and do not increase stone phosphate content with time

Background. Calcium phosphate (CaP) renal stones appear to beincreasing in prevalence, and are caused by high urine CaP supersaturation,which arises from genetic hypercalciuria and high urine pH.Renal damage from stones or procedures, or treatments for stonecould raise urine pH; alternatively pH may be intrinsicallyhigh in some people who are thereby predisposed to CaP stones. Methods. To distinguish these alternatives we sequenced changesin urine pH and stone CaP content asking which occurs firstin patients whose stones showed progressive increase in CaPover time. From 4767 patients we found 62 in whom we could documenttransformation from calcium oxalate (CaOx) to CaP stones, and134 CaOx controls who did not transform. Laboratory and clinicalfinding were contrasted between these groups. Results. Even when patients were forming relatively pure CaOxstones, those destined to increase stone CaP had higher urinepH than controls who never did so. Their higher pH was presentbefore and during treatments to prevent new stone formation.Shock wave lithotripsy was strongly associated with increasingstone CaP but urine pH bore no relationship to number of procedures. Conclusion. We conclude that high pH may not be acquired asa result of stones or their treatments but may precede transformationfrom CaOx to CaP stones and arise from diet or possibly heredity.     

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.     

Dual roles of brushite crystals in calcium oxalate crystallization provide physicochemical mechanisms underlying renal stone formation

Calcium oxalate monohydrate (COM) crystals are the major mineral component of most kidney stones, and thus have an important role in chronic human disease. However, the physicochemical mechanisms leading to calcium oxalate (CaOx) stone disease are only partially defined. As spontaneous precipitation of CaOx is rare under renal conditions, an alternative pathway for CaOx crystallization seems necessary to resolve this central issue. We performed kinetic studies using the dual constant composition method to simultaneously analyze the crystallization of COM and brushite, the form of calcium phosphate that is most readily formed in the typical slightly acidic urinary milieu. These studies were supported by parallel analysis by scanning electron and atomic force microscopy. In these studies, mineralization of a thermodynamically stable phase (COM) was induced by the presence of brushite, a more readily precipitated inorganic phase. Furthermore, once formed, the COM crystals grew at the expense of brushite crystals causing the dissolution of the brushite crystals. These studies show that brushite may play crucial roles in the formation of COM crystals. The definition of these two roles for brushite thereby provides physicochemical explanations for the initiation of COM crystallization and also for the relative paucity of calcium phosphate detected in the majority of CaOx renal stones.     

Spontaneous urinary calcium oxalate crystallization in hypercalciuric children

Idiopathic hypercalciuria is the most important predisposing risk factor for calcium oxalate (CaOx) renal stone formation. We assessed the associations between spontaneous CaOx crystallization based on the Bonn Risk Index (BRI), urinary pH, calciuria, oxaluria, and citraturia in 140 Caucasian patients with hypercalciuria, aged 4–17 years, and compared the findings with those in 210 normocalciuric controls. Of the 140 hypercalciuric patients, 58 had renal stones, and 82 had recurrent erythrocyturia, renal colic, or urinary obstructive symptoms—but without stones. Urinary ionized calcium ([Ca²⁺]) levels were measured using a selective electrode, while the onset of crystallization was determined using a photometer and titration with 40 mmol/L ammonium oxalate (Ox²⁻). The calculation of the BRI was based on the [Ca²⁺]:Ox²⁻ ratio. The BRI values were 12-fold higher in hypercalciuric children than in healthy controls, but no differences were found in the BRI between subjects with urinary stones and those with urolithiasis-like symptoms. An increased BRI suggested an association with hypercalciuria, lower urinary pH, hypocitraturia, and hypooxaluria. These data indicate that hypercalciuria is an important factor associated with increased urinary CaOx crystallization, although the causal pathways need further investigation. Determination of the BRI in children with hypercalciuria may improve the risk assessment of kidney stones.     

Gestational hypercalciuria causes pathological urine calcium oxalate supersaturations

Although normal pregnant women are more hypercalciuric than women with calcium oxalate nephrolithiasis (243 +/- 23 mg/day vs. 194 +/- 5 mg/day), pregnancy is not an established stone-forming state and pregnant women do not exhibit pathological crystalluria. One hypothesis to explain their lack of overt stone formation and pathological crystalluria is that pregnancy does not raise urine supersaturation with respect to stone forming salts such as calcium oxalate or calcium monohydrogen phosphate (brushite) to levels as high as in stone forming women. To test this hypothesis, we studied eleven normal women during each trimester of pregnancy, and between six and eight weeks post-partum. During pregnancy, hypercalciuria occurs with unchanged urine volume, citrate and magnesium excretions do not increase proportionally with calcium excretion, and urine pH increases. Supersaturations with respect to calcium oxalate (CaOx) and brushite (Br) are as high as those of women with calcium nephrolithiasis. The lack of pathological crystalluria and stones during pregnancy is not due to a failure of supersaturations to increase; urinary potential for crystallization is as high as in patients with established stone disease.     

Clinical and biochemical profile of patients with “pure” uric acid nephrolithiasis compared with “pure” calcium oxalate stone formers

The purpose of the present study was to compare the clinical characteristics of “pure” uric acid (UA) stone formers with that of “pure” calcium oxalate (CaOx) stone formers and to determine whether renal handling of UA, urinary pH, and urinary excretion of promoters and inhibitors of stone formation were different between the two groups. Study subjects comprised 59 patients identified by records of stone analysis: 30 of them had “pure” UA stones and 29 had “pure” CaOx nephrolithiasis. Both groups underwent full outpatient evaluation of stone risk analysis that included renal handling of UA and urinary pH. Compared to CaOx stone formers, UA stone formers were older (53.3 ± 11.8 years vs. 44.5 ± 10.0 years; P = 0.003); they had higher mean weight (88.6 ± 12.5 kg vs. 78.0 ± 11.0 kg; P = 0.001) and body mass index (29.5 ± 4.2 kg/m² vs. 26.3 ± 3.5 kg/m²; P = 0.002) with a greater proportion of obese subjects (43.3% vs. 16.1%; P = 0.01). Patients with “pure” UA lithiasis had significantly lower UA clearance, UA fractional excretion, and UA/creatinine ratio, with significantly higher serum UA. The mean urinary pH was significantly lower in UA stone formers compared to CaOx stone formers (5.17 ± 0.20 vs. 5.93 ± 0.42; P < 0.0001). Patients with CaOx stones were a decade younger, having higher 24-h urinary calcium excretion (218.5 ± 56.3 mg/24 h vs. 181.3 ± 57.1 mg/24 h; P = 0.01) and a higher activity product index for CaOx [AP (CaOx) index]. Overweight/obesity and older age associated with low urine pH were the principal characteristic of “pure” UA stone formers. Impairment in urate excretion associated with increased serum UA was also another characteristic of UA stone formers that resembles patients with primary gout. Patients with pure CaOx stones were younger; they had a low proportion of obese subjects, a higher urinary calcium excretion, and a higher AP index for CaOx.     

Presence of lipids in urine,crystals and stones: implications for the formation of kidney stones

BACKGROUND: Cell membranes and their lipids play critical roles in calcification. Specific membrane phospholipids promote the formation of calcium phosphate and become a part of the organic matrix of growing calcification. We propose that membrane lipids also promote the formation of calcium oxalate (CaOx) and calcium phosphate (CaP) containing kidney stones, and become a part of their stone matrix. METHODS: Human urine, crystals of CaOx and CaP produced in the urine of healthy individuals, and urinary stones containing struvite, uric acid, CaOx and CaP crystals for the presence of membrane lipids were analyzed. Crystallization of CaOx monohydrate at Langmuir monolayers of dipalmitoylphosphatidylglycerol (DPPG), dipalmitoylphosphatidylcholine (DPPC), dipalmitoylphosphatidylserine (DPPS), dioleoylphosphatidylglycerol (DOPG), palmitoyloleoylphosphatidylglycerol (POPG) and dimyristoylphosphatidylglycerol (DMPG) was investigated to directly demonstrate that phospholipid assemblies can catalyze CaOx nucleation. RESULTS: Urine as well as CaOx and CaP crystals made in the urine and various types of urinary stones investigated contained some lipids. Urine of both CaOx and uric acid stone formers contained significantly more cholesterol, cholesterol ester and triglycerides than urine of healthy subjects. However, urine of CaOx stone formers contained more acidic phospholipids. The organic matrix of calcific stones contained significantly more acidic and complexed phospholipids than uric acid and struvite stones. For each Langmuir monolayer precipitation was heterogeneous and selective with respect to the orientation and morphology of the CaOx crystals. Crystals were predominantly monohydrate, and most often grew singly with the calcium rich (10-1) face toward the monolayer. The number of crystals/mm2 decreased in the order DPPG> DPPC and was inversely proportional to surface pressure and mean molecular area/molecule. CONCLUSIONS: Stone forming conditions in the kidneys greatly impact their epithelial cells producing significant differences in the urinary lipids between healthy and stone forming individuals. Altered membrane lipids promote face selective nucleation and retention of calcium oxalate crystals, and in the process become a part of the growing crystals and stones.     

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.     

The relationship of 3' vitamin D receptor haplotypes to urinary supersaturation of calcium oxalate salts and to age at onset and familial prevalence of nephrolithiasis.

BACKGROUND: Idiopathic hypercalciuria (IHc) and idiopathic hypocitraturia are frequently associated with calcium nephrolithiasis. We investigated the relationship of vitamin D receptor (VDR) polymorphisms (BsmI, TaqI and FokI) to urinary supersaturation of calcium oxalate salts in recurrent calcium oxalate stone formers with IHc and the clinical relevance of this relationship. METHODS: The study included 110 Caucasian stone formers with IHc and 127 unrelated healthy controls without history of nephrolithiasis. Age at onset of nephrolithiasis, familial history score (FHS) and the ion activity product of calcium oxalate salts in urine (AP(CaOx)) were tabulated. BsmI, TaqI and FokI VDR polymorphisms were evaluated in all participants. RESULTS: Patients and controls were classified as homozygous (bbTT and BBtt) or heterozygous in relation to BsmI and TaqI polymorphisms. Compared with BBtt patients, bbTT homozygous stone formers showed lower citrate excretion (1.91+/-0.89 vs 3.46+/-1.39 mmol/24 h, P = 0.004) and higher AP(CaOx) (2.02+/-0.51 vs 1.53+/-0.53, P = 0.006). Among controls, there were similar differences in citrate excretion and AP(CaOx) between the two groups, but they were not statistically significant. Compared with BBtt, bbTT patients showed lower mean age at onset of nephrolithiasis (29.7+/-12.1 vs 38.1+/-12.7 years, P = 0.008) and higher values of FHS (2.45+/-1.9 vs 0.83+/-0.7, P = 0.006). Similar results were obtained for individual BsmI and TaqI alleles. The analysis of FokI alleles was not informative. CONCLUSIONS: Recurrent calcium oxalate stone formers with IHc and the bT VDR haplotype have more aggressive kidney stone diseases as indicated by a higher familial incidence and lower mean age at onset. This clinical severity is associated with the higher urinary supersaturation of calcium oxalate salts and abnormalities of renal citrate handling.     

Reactive oxygen species,inflammation and calcium oxalate nephrolithiasis

Calcium oxalate (CaOx) kidney stones are formed attached to Randall’s plaques (RPs) or Randall’s plugs. Mechanisms involved in the formation and growth are poorly understood. It is our hypothesis that stone formation is a form of pathological biomineralization or ectopic calcification. Pathological calcification and plaque formation in the body is triggered by reactive oxygen species (ROS) and the development of oxidative stress (OS). This review explores clinical and experimental data in support of ROS involvement in the formation of CaOx kidney stones. Under normal conditions the production of ROS is tightly controlled, increasing when and where needed. Results of clinical and experimental studies show that renal epithelial exposure to high oxalate and crystals of CaOx/calcium phosphate (CaP) generates excess ROS, causing injury and inflammation. Major markers of OS and inflammation are detectable in urine of stone patients as well as rats with experimentally induced CaOx nephrolithiasis. Antioxidant treatments reduce crystal and oxalate induced injury in tissue culture and animal models. Significantly lower serum levels of antioxidants, alpha-carotene, beta-carotene and beta-cryptoxanthine have been found in individuals with a history of kidney stones. A diet rich in antioxidants has been shown to reduce stone episodes. ROS regulate crystal formation, growth and retention through the timely production of crystallization modulators. In the presence of abnormal calcium, citrate, oxalate, and/or phosphate, however, there is an overproduction of ROS and a decrease in the antioxidant capacity resulting in OS, renal injury and inflammation. Cellular degradation products in the urine promote crystallization in the tubular lumen at a faster rate thus blocking the tubule and plugging the tubular openings at the papillary tips forming Randall’s plugs. Renal epithelial cells lining the loops of Henle/collecting ducts may become osteogenic, producing membrane vesicles at the basal side. In addition endothelial cells lining the blood vessels may also become osteogenic producing membrane vesicles. Calcification of the vesicles gives rise to RPs. The growth of the RP’s is sustained by mineralization of collagen laid down as result of inflammation and fibrosis.     

Estimated levels of supersaturation with calcium phosphate and calcium oxalate in the distal tubule

Approximate estimates of the ion-acitivity products of calcium phosphate and calcium oxalate in distal tubular urine were derived from the 16-h urinary excretion of calcium, oxalate, citrate, magnesium and phosphate. Urine variables were obtained from 96 normal subjects and 277 calcium stone formers and the calculations were carried out with iterative approximation using the EQUIL2 program. With respect to other ions of importance for the ion-activity products, the urine was assumed to have a fixed composition with pH 6.45. Significantly higher ion-activity products of both calcium phosphate and calcium oxalate were recorded in stone formers. It was concluded that diurnal variations in urine composition and pH might result in peaks of calcium phosphate supersaturation in distal tubular urine whereby a crystallization can occur. In association with abnormalities in terms of promotion and inhibition of calcium salt crystallization, such a precipitation can be of importance for the subsequent formation of calcium renal stones.     

Calcium phosphate: an important crystal phase in patients with recurrent calcium stone formation?

Summary Stone and urine composition were analysed in 75 men and 40 women with recurrent calcium oxalate stone disease (group R) and in 48 men and 19 women who had formed only one calcium-oxalate-containing stone (group S). Patients who had developed stones with a large fraction of calcium phosphate were significantly more frequent in group R than in group S. There was furthermore a higher excretion of calcium and higher calcium oxalate supersaturation levels in patients with stones containing more than 25% calcium phosphate. It was concluded from these observations that the calcium phosphate content of renal stones might be a useful factor in predicting the future course of the disease.