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.     

The pathogenesis of calyceal diverticular calculi

Controversy exists over whether metabolic factors or urinary stasis predominate in the pathogenesis of calyceal diverticular calculi. We performed a study to better define the effects urinary stasis and metabolic abnormalities have in the pathogenesis of calyceal diverticular stones. Twenty-nine patients who underwent percutaneous treatment of calyceal diverticular calculi were studied. All patients underwent 24 h urine collection to evaluate metabolic risk factors. In three patients, urine was sampled directly from the diverticulum for metabolic studies. The urinary stone risk parameters of the patients with calyceal diverticular stones (Tic SF) were similar to those of a well-characterized cohort of calcium oxalate stone formers (CaOx SF). When compared to a group of normal people, the Tic SF and CaOx SF were significantly more hypercalciuric and their urine was significantly more supersaturated with calcium oxalate. Urine aspirated directly from the diverticulum had the lowest SSCaOx when compared to ipsilateral and contralateral renal pelves. The urinary risk profiles of patients with diverticular calculi are similar to those of CaOx SF, suggesting a metabolic etiology of diverticular stones. However, the SS CaOx of urine aspirated directly from the diverticula is significantly lower than that of the renal pelves; these data support the hypothesis that urinary stasis significantly contributes to the pathogenesis of calyceal diverticular calculi. Taken together, it seems likely that calyceal diverticular calculi arise from a combination of metabolic abnormalities and urinary stasis.     

Vinegar reduced renal calcium oxalate stones by regulating acetate metabolism in gut microbiota and crystal adhesion in rats

Purpose

Urolithiasis is a common urologic disease. Higher consumption of vinegar was associated with a lower risk of urolithiasis. Recent studies reported that disorder of gut microbiota and injury of the tight junction of renal tubular epithelial cells were associated with the formation of renal calcium oxalate (CaOx) stones. We aimed to explore the mechanism of vinegar reduced renal CaOx stone formation by regulating gut microbiota and the tight junction of renal tubular epithelial cells.

Methods

Thirty Sprague–Dawley rats were randomly allocated to control group, model group and vinegar group. Rats in control group got 2 ml/kg of sterile water by gavage. Model group rats were additionally supplied with drinking water with 1% (v/v) ethylene glycol (EG) every day. Rats in vinegar group had 1% (v/v) EG in drinking water and were gavaged with 2 ml/kg of vinegar (5% acetate) every day.

Results

Vinegar reduced renal CaOx crystals and urinary oxalate. Vinegar increased the relative abundances of Ruminococcus gauvreauii, Ruminococcus torques, Ruminococcus-2, Moryella, Enterococcus, Alistipes, and Parabacteroides in the gut microbiota. Blood acetate increased in vinegar group. The renal tight junction occludin protein decreased in the model group and increased in the vinegar group. Studies in vitro verified that acetate could reverse the decline in occludin expression induced by CaOx crystals and inhibit CaOx crystal adhesion to cells.

Conclusion

Vinegar reduced renal CaOx stones by regulating gut microbiota and increasing blood acetate to restore renal tight junction and reduce CaOx crystal adhesion.

     

In idiopathic calcium oxalate stone‐formers,unattached stones show evidence of having originated as attached stones on Randall’s plaque

Study Type – Diagnostic (exploratory cohort)
Level of Evidence 2b

OBJECTIVE

To analyse the structure and composition of unattached stones in idiopathic calcium oxalate (CaOx) stone‐formers (ICSF) and compare them to attached stones from the same cohort, to investigate whether there is more than one pathogenic mechanism for stone formation in ICSF.

PATIENTS AND METHODS

ICSF undergoing percutaneous nephrolithotomy or ureteroscopy for the treatment of nephrolithiasis gave consent to participate in this study. All accessible renal papillae were endoscopically imaged using a digital endoscope. All stones were removed and determined by the operating surgeon to be attached or unattached to the underlying papilla. Micro‐computed tomography (micro‐CT), which provides three‐dimensional analysis of entire stones, was used to compare the structure and composition of attached and unattached stones.

RESULTS

Of 115 stones collected from nine patients (12 renal units), only 25 stones were found not to be attached to renal papillae. Of these 25 stones, four were lost and 12 showed definite morphological evidence of having been attached to tissue, probably having been displaced from papillae during access. For the remaining nine stones, micro‐CT analysis showed at least one internal region of calcium phosphate within each of these unattached CaOx stones, i.e. the internal structure of the unattached stones is consistent with their having originated attached to Randall’s plaque, and then having become detached but retained in the kidney, with new layers of CaOx eventually covering the original attachment site.

CONCLUSIONS

Micro‐CT analysis supports the hypothesis that in ICSF, both attached and unattached stones occur as a result of a common pathogenic mechanism, i.e. in this type of stone former, CaOx stones, even those not showing morphology that betrays attachment, all originate attached to interstitial plaque on the renal papilla.     

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.     

Inhibitory effect of an aqueous extract of Radix Paeoniae Alba on calcium oxalate nephrolithiasis in a rat model

Objective: To examine the effect of an aqueous extract of Radix Paeoniae Alba (RPA) on the formation of calcium oxalate (CaOx) stones and the potential mechanism underlying the effect.

Materials and methods: An in vitro assay was used to determine whether the RPA extract prevents the formation of CaOx or promotes CaOx dissolution. We also investigated the efficacy of the extract in vivo as a preventive and therapeutic agent for experimentally induced CaOx nephrolithiasis in rats. Various biochemical, molecular, and histological parameters were assessed in kidney tissue and urine at the end of the in vivo experiment.

Results: Significant dissolution of formed crystals (8.99?±?1.43) and inhibition of crystal formation (2.55?±?0.21) were observed in vitro after treatment with 64?mg/mL of the RPA extract compared with a control treatment (55.10?±?4.98 and 54.57?±?5.84, respectively) (p?Conclusions: RPA is a useful agent that prevents the formation of CaOx kidney stones.     

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.     

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.     

A formal test of the hypothesis that idiopathic calcium oxalate stones grow on Randall’s plaque

OBJECTIVE

To confirm that more than half of all idiopathic calcium oxalate (CaOx) stones grow on interstitial plaque, as CaOx stones can grow attached to interstitial apatite plaque but whether this is the usual mechanism of stone formation is uncertain.

PATIENTS AND METHODS

In nine idiopathic CaOx stone formers (ICSF) undergoing percutaneous nephrolithotomy or ureteroscopy all accessible renal papillae were endoscopically imaged using a digital endoscope. All stones were removed intact, and recorded by the operating surgeon as being attached or unattached; for all attached stones the surgeon determined if the site of attachment was to plaque. This determination was further verified by reviewing the intraoperative video record, and only instances where plaque was reliably seen on video were used for analysis. Surgical observations were further validated by a combination of microcomputed tomographic analysis and papillary biopsy. The results were analysed statistically using fixed‐sample testing and group sequential sampling.

RESULTS

The nine patients had a total of 115 stones, primarily CaOx; 90 stones were attached. Of these, 81 were attached to plaque; surgeons could not visualize the site of attachment with sufficient clarity to judge in the other nine cases. Based on these data, the final point estimate for the number of stones attached to plaque was 0.754 (95% confidence interval 0.575–0.933; P = 0.013).

CONCLUSIONS

In ICSF most stones grow attached to papillae, on plaque, so growth on plaque is the main mechanism for stone formation in this very common group of patients.     

Effect of preoperative metabolic profiling to reduce the risk of kidney stones after bariatric surgery in patients with a history of stone formation

BackgroundRoux-en-Y gastric bypass (RYGB) is associated with an increased risk of kidney stone formation. This is not observed after sleeve gastrectomy (SG).ObjectivesAim of this study was to assess whether preoperative metabolic profiling is helpful in selecting the most optimal bariatric procedure for patients with a kidney stone history.SettingGeneral hospital, the Netherlands.MethodsPatients with a kidney stone history and in the run up to bariatric surgery were screened with non-contrast abdominal computed tomography (CT), serum profiling, and 24-hour urine analysis. Those with stones on radiologic imaging and/or high preoperative urinary oxalate were advised to undergo SG instead of RYGB. Pre- and postoperative urine and serum profile differences between both groups were evaluated retrospectively.ResultsPostoperatively, RYGB (N = 28, M:F = 8:20) was associated with a 23.5% reduction in urinary volume, a 85% increase in urinary oxalate excretion with a 230% increase in calcium oxalate (CaOx) supersaturation and a 62% decrease in urinary citrate. Although SG (N = 30, M:F = 12:18) was also associated with a reduction in urinary volume, it had no adverse effects on urinary oxalate and citrate excretion, nor on calcium oxalate supersaturation (CaOx-SS). Both RYGB and SG showed favorable effects on postoperative sodium, calcium, uric acid, and phosphate excretion.ConclusionsThis study indicates that preoperative metabolic profiling is important to select the optimal bariatric procedure in patients with an a priori increased risk of kidney stone development. These patients should be strongly encouraged to undergo SG instead of RYGB to prevent progressive or recurrent kidney stone disease.     

The hole truth: intracrystalline proteins and calcium oxalate kidney stones

The ultimate aim of our research is to understand the role of macromolecules in the formation of human kidney stones, particularly their interactions with calcium oxalate (CaOx) crystals. The invariable association of stones with proteins raises the possibility that proteins play a role in their formation, similar to the role of proteins in healthy biomineralization. Do these proteins induce mineralization? Are they merely a response to the disease process? Or are they protective molecules that were overwhelmed by mineral supersaturation? A protein of particular interest is fragment 1 (F1) of prothrombin. We have shown that mRNA for prothrombin is present in the kidney. Because the F1 fragment of prothrombin present in urine is slightly different from that found in the blood, we refer to this protein as "urinary prothrombin fragment 1" (UPTF1). Available evidence suggests that the kidney manufactures the protein for protection against stone disease and that the protein has a directive role in stone formation. We now have evidence that proteins are interred within CaOx crystals precipitated from human urine, where it is distributed in continuous channels. These proteins could facilitate crystal deconstruction and removal after attachment to the renal epithelium and endocytosis. We suspect that the formation of CaOx crystals in the urine is a normal process designed to permit harmless disposal of an excess of calcium, oxalate, or both. The incorporation of proteins provides a second line of defense against stone formation by enabling the destruction and removal of retained crystals. Understanding the basic molecular strategies by which plants produce protein-containing CaOx crystals may provide insight into human CaOx stone formation.     

Hyperoxaluria: a gut-kidney axis?

Hyperoxaluria leads to urinary calcium oxalate (CaOx) supersaturation, resulting in the formation and retention of CaOx crystals in renal tissue. CaOx crystals may contribute to the formation of diffuse renal calcifications (nephrocalcinosis) or stones (nephrolithiasis). When the innate renal defense mechanisms are suppressed, injury and progressive inflammation caused by these CaOx crystals, together with secondary complications such as tubular obstruction, may lead to decreased renal function and in severe cases to end-stage renal failure. For decades, research on nephrocalcinosis and nephrolithiasis mainly focused on both the physicochemistry of crystal formation and the cell biology of crystal retention. Although both have been characterized quite well, the mechanisms involved in establishing urinary supersaturation in vivo are insufficiently understood, particularly with respect to oxalate. Therefore, current therapeutic strategies often fail in their compliance or effectiveness, and CaOx stone recurrence is still common. As the etiology of hyperoxaluria is diverse, a good understanding of how oxalate is absorbed and transported throughout the body, together with a better insight in the regulatory mechanisms, is crucial in the setting of future treatment strategies of this disorder. In this review, the currently known mechanisms of oxalate handling in relevant organs will be discussed in relation to the different etiologies of hyperoxaluria. Furthermore, future directions in the treatment of hyperoxaluria will be covered.     

Calcium oxalate crystal interaction with renal tubular epithelium,mechanism of crystal adhesion and its impact on stone development

The interaction between renal epithelial cells and calcium oxalate (CaOx) crystals and/or oxalate ions plays a critical role in the formation of urinary stones. Epithelial cells respond to hyperoxaluria and the presence of CaOx crystals in the kidneys by increased enzymuria and internalization of the crystals. Crystal cell interaction results in movement of crystals from the luminal to the basolateral side between the cells and the basement membrane. Once beneath the epithelium, crystals adhere to the basement membrane and become anchored inside the kidneys. Crystals anchored to basement membrane of the peripheral collecting duct aggregate with other crystals and move through an eroding epithelium to the papillary surface, furnishing an encrustation platform or a nidus for future development of a kidney stone. Thus interaction between renal epithelial cells and CaOx crystals and/or oxalate ions is an essential element in the development of urinary stone disease.     

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.     

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.     

Comparison of fibronectin content in urinary macromolecules between normal subjects and recurrent stone formers.

OBJECTIVES: Fibronectin (FN: 230 kD) is a multifunctional alpha(2)-glycoprotein distributed throughout the extracellular matrix and body fluids. Recent studies have shown that a variety of molecules, including FN, inhibit the endocytosis of calcium oxalate (CaOx) crystals in vitro. We recently reported that FN was oversecreted from the renal tubular cells as a result of the stimulation of CaOx crystals, and inhibited the aggregation of CaOx crystals and the adhesion of CaOx crystals to the renal tubular cells. In the present study, we investigated the difference of FN content in urinary macromolecules (UMMs) between normal subjects and recurrent stone formers. MATERIALS AND METHODS: Urinary parameters in relation to urolithiasis of normal subjects and recurrent stone formers were measured. Proteins in extracted UMMs from urine of normal subjects and recurrent stone formers were measured with a BioRad protein assay, GAGs in each UMMs with a modified DMB assay and the FN content with the ELISA method. RESULTS: In urinary parameters, citrate was significantly higher in urine from normal subjects (female) than normal subjects (male) or recurrent stone formers, and the other parameters showed no differences between each group. The protein concentrations in UMMs showed no differences between each group. Normal subjects (male and female) showed a significantly higher concentration of GAGs than recurrent stone formers (with and without silent stone). Compared with normal subjects and recurrent stone formers without silent stones, higher FN levels were found in recurrent stone formers with silent stones. Normal subjects showed a significantly higher concentration of FN than recurrent stone formers without silent stones. No difference in FN level was shown between normal subjects (male) and normal subjects (female). CONCLUSION: Recurrent stone formers with silent stones showed a significantly higher concentration of FN in UMMs than normal subjects. This finding suggests that FN might be oversecreted from the renal tubular cells as a result of the stimulation of CaOx stones in vivo. Recurrent stone formers without silent stones showed a significantly lower concentration of FN in UMMs than normal subjects. From this finding it is suggested that FN might play a role as a potent inhibitor of CaOx urolithiasis in a clinical setting.     

Calcium phosphate crystal-associated proteins: α-2-HS-glycoprotein, prothrombin fragment 1 and osteopontin

To study the inhibitory effects of calcium phosphate-associated proteins on calcium oxalate crystallization and urinary concentrations of proteins in people who form stones and healthy controls. From 60 L of urine from healthy men, calcium phosphate-associated proteins (alpha-2-HS-glycoprotein, prothrombin fragment 1 and osteopontin) were obtained. The effects of the proteins on calcium oxalate (CaOx) crystallization were studied with a mixed suspension mixed product removal system. To examine urinary concentrations of the proteins, urine samples were collected from 17 healthy subjects and 15 stone formers and analyzed using anion-exchange chromatography and an enzyme immunoassay. Prothrombin fragment 1 (PTF1) and osteopontin (OPN) had strong inhibitory effects on CaOx crystallization, while alpha-2-HS-glycoprotein had a mild inhibitory effect. Urinary concentrations of PTF1 and OPN were lower in stone formers than in healthy controls. Low urinary concentrations of PTF1 and OPN might be one of the reasons 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.     

Stressbedingte Alteration der Harnzusammensetzungen

Background

Increased emotional stress in everyday life influences the way of living and metabolism of people living in developed countries. Contemporaneously, the incidence and prevalence of urolithiasis rises. Does a pathogenetically relevant relationship exist between chronic stress burden and permanently altered urinary composition?

Patients and methods

The influence of chronic stress burden on urine composition and risk of urinary calcium oxalate (CaOx) stone formation was, for the first time, comprehensively investigated in 29 healthy controls (CG), 29 idiopathic CaOx stone formers (SF) and 28 patients suffering from chronic inflammatory bowel disease (CIBD). After 4?days with standardized nutrition, 24-h urine was collected. Extensive urinalysis was performed and APCaOx index calculated. Evaluation of subjective stress level was carried out by using the standardized and well-established questionnaire Trierer Inventar zur Beurteilung von chronischem Stress (TICS). The concentration values of the urinary parameters as well as the APCaOx values were linearly correlated with the stress scores obtained from the different items of the TICS. A significance level p??0.05 was considered to indicate statistical significance.

Results

The mean APCaOx indices amounted to 0.8±0.3 in CG, 1.2±0.7 in SF and 1.9±1.2 in CIBD. The increased APCaOx in SF mainly results from relatively increased Ca and oxalate excretions, whereas in CIBD this also results from reduced urinary excretions of citrate and Mg as well as reduced 24-h urinary volumes. The calculation of linear correlation coefficients between a TICS stress dimension and a concentration value of a urinary parameter or APCaOx results in r values not exceeding 0.600. However, some of these correlations are statistically highly significant. In SF only one combination with Ca was observed, while in CIBD in contrast a number of combinations, in particular including Na, was obtained. In CG direct statistical relationships between stress burden and citrate as well as Mg exist. In this group, increased stress burden is associated with increased inhibitory potential to prevent CaOx stone formation.

Conclusion

In the investigated study groups, differently complex relationships between amount of stress burden and risk of CaOx stone formation were observed, however, without obvious physicochemical principle(s). In some individuals, stress can be associated with a significantly stress-related alteration of urinary composition towards increased CaOx stone formation risk. The results obtained from the CIBD group allow for the first time a conclusive link between emotional stress and inflammatory activity on the one hand and inflammatory activity and metabolic risk constellation of CaOx stone formation on the other hand.