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Low Sodium Diet Decreases Stone Formation in Genetic Hypercalciuric Stone-Forming Rats
Abstract
Background:
Urine (u) calcium (Ca) excretion is directly dependent on dietary sodium (Na) intake leading to the recommendation for Na restriction in hypercalciuric kidney stone formers. However, there is no direct evidence that limiting Na intake will reduce recurrent stone formation.
Materials and methods:
We used genetic hypercalciuric stone-forming (GHS) rats, which universally form Ca phosphate (P) kidney stones, fed either a low Na (LNa, 0.05%) or normal Na (NNa, 0.4%) Na diet (D) for 18 weeks. Urine was collected at 6-week intervals. Radiographic analysis for stone formation and bone analyses were done at the conclusion of the study.
Results:
Mean uCa was lower with LNaD than NNaD as was uP and LNaD decreased mean uNa and uChloride. There were no differences in urine supersaturation (SS) with respect to calcium phosphate (CaP) or Ca oxalate (CaOx). However, stone formation was markedly decreased with LNaD by radiographic analysis. The LNaD group had significantly lower femoral anterior-posterior diameter and volumetric bone mineral density (vBMD), but no change in vertebral trabecular vBMD. There were no differences in the bone formation rate or osteoclastic bone resorption between groups. The LNaD group had significantly lower femoral stiffness; however, the ultimate load and energy to fail was not different.
Conclusion:
Thus, a low Na diet reduced uCa and stone formation in GHS rats, even though SS with respect to CaP and CaOx was unchanged and effects on bone were modest. These data, if confirmed in humans, support dietary Na restriction to prevent recurrent Ca nephrolithiasis.
... Stone formation is a consequence of an imbalance between promoters and inhibitors in the kidney [18]. The major components of kidney stones are inorganic materials, with a small percentage of organic material; 90% of the inorganic components are CaOx [19]. Magnesium is one of the inhibitors of crystallization, as encountered in ethylene glycolinduced stone formation, and it decreases the supersaturation of CaOx, reducing crystal growth [20]. ...
Background/aims:
Hypercalciuria is the most common identifiable risk factor predisposing to CaOx stone formation. Increased oral magnesium intake may lead to decreased CaOx stone formation by binding intestinal Ox leading to decreased absorption and/or binding urinary Ox to decrease urinary supersaturation. This study assessed the effect of oral magnesium on 24-hour urine ion excretion, supersaturation, and kidney stone formation in a genetic hypercalciuric stone-forming (GHS) rat model of human idiopathic hypercalciuria.
Methods:
When fed the oxalate precursor, hydroxyproline, every GHS rat develops CaOx stones. The GHS rats were fed a normal calcium and phosphorus diet with hydroxyproline to induce CaOx , were divided into three groups of ten rats per group: control diet with 4.0 g/kg MgO, low MgO diet (0.5 g/kg), and high MgO diet (8 g/kg). At 6 weeks, twenty-four-hour urines were collected, and urine chemistry and supersaturation were determined. Stone formation was quantified.
Results:
The GHS rats fed the low and high Mg diets had a significant reduction and increase, respectively, in urinary Mg compared to those fed the control diet. Dietary Mg did not alter urine Ca excretion while the low Mg diet led to a significant fall in urinary Ox. Urine supersaturation with respect to CaOx was significantly increased with low Mg, whereas urine supersaturation was significantly decreased with high Mg. There was no effect of dietary Mg on stone formation within 6 weeks of treatment.
Conclusion:
Dietary magnesium decreases urine supersaturation but not CaOx stone formation in GHS rats.
Kidney stone disease (KSD) (alternatively nephrolithiasis or urolithiasis) is a global healthcare problem that affects almost all of developed and developing countries. Its prevalence has been continuously increasing with a high recurrence rate after stone removal. Although effective therapeutic modalities are available, preventive strategies for both new and recurrent stones are required to reduce physical and financial burdens of KSD. To prevent kidney stone formation, its etiology and risk factors should be firstly considered. Low urine output and dehydration are the common risks for all stone types, whereas hypercalciuria, hyperoxaluria and hypocitraturia are the major risks of calcium stone. In this article, up-to-date knowledge on strategies (nutrition-based mainly) to prevent KSD is provided. Important roles of fluid intake (2.5-3.0 L/day), diuresis (>2.0-2.5 L/day), lifestyle and habit modifications (e.g., maintain normal body mass index, fluid compensation for working in high-temperature environment, and avoid cigarette smoking), and dietary management (e.g., sufficient calcium at 1,000-1,200 mg/day, limit sodium at 2 g/day or 3-5 g/day of NaCl, limit oxalate-rich foods, avoid vitamin C and vitamin D supplements, limit animal proteins to 0.8-1.0 g/kg body weight/day but increase plant proteins in calcium and uric acid stone patients and those with hyperuricosuria, increase proportion of citrus fruits, and consider lime powder supplementation) are summarized. Moreover, uses of natural bioactive products (e.g., caffeine, epigallocatechin gallate, and diosmin), medications (e.g., thiazides, alkaline citrate, other alkalinizing agents, and allopurinol), bacterial eradication, and probiotics are also discussed.
Table salt is one of the most common household chemicals and is an important source of human nutrition
What is table Salt? What does salt taste like? What are the sources of salt? What are the health effects of salt? What are bath salts? Are there any adverse effects to bath salts?
Biblical verses dealing with these issues are studied from a contemporary viewpoint.
Potassium citrate is prescribed to decrease stone recurrence in patients with calcium nephrolithiasis. Citrate binds intestinal and urine calcium and increases urine pH. Citrate, metabolized to bicarbonate, should decrease calcium excretion by reducing bone resorption and increasing renal calcium reabsorption. However, citrate binding to intestinal calcium may increase absorption and renal excretion of both phosphate and oxalate. Thus, the effect of potassium citrate on urine calcium oxalate and calcium phosphate supersaturation and stone formation is complex and difficult to predict. To study the effects of potassium citrate on urine supersaturation and stone formation, we utilized 95th-generation inbred genetic hypercalciuric stone-forming rats. Rats were fed a fixed amount of a normal calcium (1.2%) diet supplemented with potassium citrate or potassium chloride (each 4 mmol/d) for 18 weeks. Urine was collected at 6, 12, and 18 weeks. At 18 weeks, stone formation was visualized by radiography. Urine citrate, phosphate, oxalate, and pH levels were higher and urine calcium level was lower in rats fed potassium citrate. Furthermore, calcium oxalate and calcium phosphate supersaturation were higher with potassium citrate; however, uric acid supersaturation was lower. Both groups had similar numbers of exclusively calcium phosphate stones. Thus, potassium citrate effectively raises urine citrate levels and lowers urine calcium levels; however, the increases in urine pH, oxalate, and phosphate levels lead to increased calcium oxalate and calcium phosphate supersaturation. Potassium citrate induces complex changes in urine chemistries and resultant supersaturation, which may not be beneficial in preventing calcium phosphate stone formation.
Copyright © 2015 by the American Society of Nephrology.
Dietary sodium chloride intake is nowadays globally known as one of the major threats for cardiovascular health. However,
there is also important evidence that it may influence idiopathic calcium nephrolithiasis onset and recurrence. Higher salt
intake has been associated with hypercalciuria and hypocitraturia, which are major risk factors for calcium stone formation.
Dietary salt restriction can be an effective means for secondary prevention of nephrolithiasis as well. Thus in this paper,
we review the complex relationship between salt and nephrolithiasis, pointing out the difference between dietary sodium and
salt intake and the best methods to assess them, highlighting the main findings of epidemiologic, laboratory and intervention
studies and focusing on open issues such as the role of dietary salt in secondary causes of nephrolithiasis.
Purpose:
The purpose of this guideline is to provide a clinical framework for the diagnosis, prevention and follow-up of adult patients with kidney stones based on the best available published literature.
Materials and methods:
The primary source of evidence for this guideline was the systematic review conducted by the Agency for Healthcare Research and Quality on recurrent nephrolithiasis in adults. To augment and broaden the body of evidence in the AHRQ report, the AUA conducted supplementary searches for articles published from 2007 through 2012 that were systematically reviewed using a methodology developed a priori. In total, these sources yielded 46 studies that were used to form evidence-based guideline statements. In the absence of sufficient evidence, additional statements were developed as Clinical Principles and Expert Opinions.
Results:
Guideline statements were created to inform clinicians regarding the use of a screening evaluation for first-time and recurrent stone formers, the appropriate initiation of a metabolic evaluation in select patients and recommendations for the initiation and follow-up of medication and/or dietary measures in specific patients.
Conclusions:
A variety of medications and dietary measures have been evaluated with greater or less rigor for their efficacy in reducing recurrence rates in stone formers. The guideline statements offered in this document provide a simple, evidence-based approach to identify high-risk or interested stone-forming patients for whom medical and dietary therapy based on metabolic testing and close follow-up is likely to be effective in reducing stone recurrence.
We summarize the data regarding the associations of individual dietary components with kidney stones and the effects on 24-hour urinary profiles. The therapeutic recommendations for stone prevention that result from these studies are applied where possible to stones of specific composition. Idiopathic calcium oxalate stone-formers are advised to reduce ingestion of animal protein, oxalate, and sodium while maintaining intake of 800 to 1200 mg of calcium and increasing consumption of citrate and potassium. There are few data regarding dietary therapy of calcium phosphate stones. Whether the inhibitory effect of citrate sufficiently counteracts increasing urine pH to justify more intake of potassium and citrate is not clear. Reduction of sodium intake to decrease urinary calcium excretion would also be expected to decrease calcium phosphate stone recurrence. Conversely, the most important urine variable in the causation of uric acid stones is low urine pH, linked to insulin resistance as a component of obesity and the metabolic syndrome. The mainstay of therapy is weight loss and urinary alkalinization provided by a more vegetarian diet. Reduction in animal protein intake will reduce purine ingestion and uric acid excretion. For cystine stones, restriction of animal protein is associated with reduction in intake of the cystine precursor methionine as well as cystine. Reduction of urine sodium results in less urine cystine. Ingestion of vegetables high in organic anion content, such as citrate and malate, should be associated with higher urine pH and fewer stones because the amino acid cystine is soluble in more alkaline urine. Because of their infectious origin, diet has no definitive role for struvite stones except for avoiding urinary alkalinization, which may worsen their development.
Genetic hypercalciuric stone-forming (GHS) rats, bred to maximize urine (U) calcium (Ca) excretion, have increased intestinal Ca absorption and bone Ca resorption and reduced renal Ca reabsorption, leading to increased UCa compared to the Sprague-Dawley (SD) rats. GHS rats have increased vitamin D receptors (VDR) at each of these sites, with normal levels of 1,25(OH)(2)D(3) (1,25D), indicating that their VDR is undersaturated with 1,25D. We tested the hypothesis that 1,25D would induce a greater increase in UCa in GHS rats by feeding both strains ample Ca and injecting 1,25D (25 ng/100 g body wt/d) or vehicle for 16d. With 1,25D, UCa in SD increased from 1.7±0.3 mg/d to 24.4±1.2 (Δ=22.4±1.5) and increased more in GHS from 10.5±0.7 to 41.9±0.7 (Δ=29.8±1.8, p=0.003). To determine the mechanism of the greater increase in UCa in GHS rats, we measured kidney RNA expression of components of renal Ca transport. Expression of TRPV5 and calbindin D(28K) were increased similarly in SD+1,25D and GHS+1,25D. NCX1 was increased in GHS+1,25D. Klotho was decreased in SD+1,25D and GHS+1,25D. TRPV6 was increased in SD+1,25D and increased further in GHS+1,25D. Claudin 14, 16 and 19, NKCC2 and ROMK did not differ between SD+1,25D and GHS+1,25D. Increased UCa with 1,25D in GHS exceeded that of SD, indicating that the increased VDR in GHS induces a greater biological response. This increase in UCa, which must come from the intestine and/or bone, must exceed any effect of 1,25D on TRPV6 or NCX1 mediated renal Ca reabsorption.
Urolithiasis is a worldwide problem with significant health and economic burdens. Medical therapy that alters the course of stone disease has enormous medical and financial impact. Urolithiasis is a final manifestation of a broad range of etiologies and pathogenesis. The modest progress in understanding the pathophysiology has hampered successful development of targeted therapy. Current regimens are based mostly on rational alteration of urinary biochemistry and physical chemistry to lower the risk of precipitation. In terms of pharmacotherapy, there are drugs to successfully improve hypercalciuria, hypocitraturia, aciduria, hyperuricosuria, and hypercystinuria. These agents have been proven to be effective in randomized controlled trials in improving urinary biochemical and physicochemical risk factors, as well as clinical outcomes. Although our current regimens have clearly improved the management and lives of stone formers, there are still clearly identifiable immense voids in the knowledge of pathophysiology of stone disease that can be filled with combined basic science and clinical studies.
We have established a colony of genetic hypercalciuric (IH) rats as a model of idiopathic hypercalciuria in humans. To test the hypothesis that hypercalciuria can cause crystallization in kidneys through increased supersaturation, in the absence of confounding effects of diet and whatever complex inhibitor disorders underlay stone disease, we fed males and females of the 21st generation of IH rats 13 g per day of a low calcium (LCD, 0.02% Ca), followed by a normal calcium (NCD, 0.6% Ca) and then a high calcium (HCD, 1.2% Ca) diet, each for seven days. During the last 24 hours of each period complete urine collections were obtained and analyzed for all substances known to affect urinary calcium oxalate (CaOx) and brushite (CaHPO4) supersaturation. Relative supersaturation with respect to the solid phases of CaOx and CaHPO4 were then calculated. Compared to same gender controls (Ctl) urine calcium excretion was higher in the female IH rats on all diets and in the male IH rats on NCD and HCD. The female and male IH rats on NCD and HCD were supersaturated with respect to CaOx; however, the male and female Ctl were supersaturated with respect CaOx only on HCD. The female IH rats on NCD and HCD and the male IH rats on NCD were supersaturated with respect to CaHPO4; however, neither the male nor female Ctl rats were supersaturated with respect to CaHPO4 on any diet. On NCD and HCD urine supersaturation with respect to CaHPO4 by females exceeded that of males.(ABSTRACT TRUNCATED AT 250 WORDS)
A fundamental mechanism for hypercalciuria in genetic hypercalciuric rats appears due to a primary increase in intestinal calcium absorption. However previous studies could not exclude additional mechanisms to account for the hypercalciuria. To determine if enhanced bone mineral dissolution either as a primary abnormality or secondary to a defect in renal tubule calcium reabsorption is responsible for a component of the augmented calcium excretion we studied rats continually inbred for hypercalciuria. Nineteenth generation adult female idiopathic hypercalciuric (IH) and non-inbred control (Ctl) rats were fed 13 g/day of a normal calcium diet (0.6% calcium, NCD) for 10 days. Urine calcium excretion over the last seven days was greater in IH (34 +/- 2 mg/7 day) than in Ctl (2.9 +/- 0.3, P < 0.01) rats. Some rats in each group were continued on the same diet while others were fed a low calcium diet (0.02% calcium, LCD) for an additional 10 days; balance measurements were made over the final seven days. With LCD, urine calcium excretion was approximately 8-fold higher in IH compared to Ctl (13 +/- 2 mg/7 day vs. 1.6 +/- 0.1, IH vs. Ctl, respectively, P < 0.01). In IH rats percent calcium absorption was greater (59 +/- 3% vs. 45 +/- 3, IH vs. Ctl, P < 0.01), however calcium retention was negative (-1.9 +/- 2.0 mg/7 day vs. 6.5 +/- 0.5, IH vs. Ctl, P < 0.01) compared to Ctl rats. The fall in urine calcium excretion when IH rats are fed LCD indicates that enhanced intestinal calcium absorption is a primary mechanism of the hypercalciuria.(ABSTRACT TRUNCATED AT 250 WORDS)
Our genetic hypercalciuric (GH) rats have been selected and inbred for 29 generations to maximize urine calcium (UCa) excretion compared to identical gender controls (Ctl). To determine the effect of the increased UCa on urinary supersaturation and stone formation, we pair fed 15 GH and 15 Ctl rats a standard 1.2% calcium diet for 18 weeks, measured urine supersaturation every two weeks, and examined the urinary tract of 1/3 of the rats for the presence of stones every six weeks. Any stones formed were studied by SEM, X-ray and electron diffraction and X-ray microanalysis. Over the entire study UCa was increased in the GH compared to Ctl, resulting in greater supersaturation with respect to calcium hydrogen phosphate (CaHPO4) at all times and calcium oxalate (CaOx) at most times. There was a progressive increase in the incidence of stone formation in GH rats with one of five rats having stones at six weeks, three of five with stones at 12 weeks and five of five with stones at 18 weeks. There were no stones formed in Ctl rats. SEM reveals discrete stones and not nephrocalcinosis. X-ray and electron diffraction and X-ray microanalysis reveal the stones to be poorly crystalline apatite which is a solid phase of calcium and phosphate. Compared to Ctl, in the GH rats the saturation ratio for CaHPO4 increased proportionally more than that for CaOx, perhaps explaining why the rats formed apatite and not oxalate stones. This is the first description of an animal model of spontaneous nephrolithiasis.
As a model of human hypercalciuria, we have selectively inbred genetic hypercalciuric stone-forming (GHS) Sprague-Dawley rats whose mean urine calcium excretion is eight to nine times greater than that of controls. A large component of this excess urine calcium excretion is secondary to increased intestinal calcium absorption, which is not due to an elevation in serum 1,25(OH)2D3, but appears to result from an increased number of intestinal 1,25(OH)2D3 receptors (VDR). When GHS rats are fed a low-calcium diet, the hypercalciuria is only partially decreased and urine calcium excretion exceeds intake, suggesting that an additional mechanism contributing to the hypercalciuria is enhanced bone demineralization. To determine if GHS rat bones are more sensitive to exogenous 1,25(OH)2D3, we cultured calvariae from neonatal (2- to 3-day-old) GHS and control rats with or without 1,25(OH)2D3 or parathyroid hormone (PTH) for 48 h at 37 degrees C. There was significant stimulation of calcium efflux from GHS calvariae at 1 and 10 nM 1,25(OH)2D3, whereas control calvariae showed no significant response to 1,25(OH)2D3 at any concentration tested. In contrast, PTH induced similar bone resorption in control and GHS calvariae. Immunoblot analysis demonstrated a fourfold increase in the level of VDR in GHS calvariae compared with control calvariae, similar to the increased intestinal receptors described previously. There was no comparable change in VDR RNA levels as measured by slot blot analysis, suggesting the altered regulation of the VDR occurs posttranscriptionally. That both bone and intestine display an increased amount of VDR suggests that this may be a systemic disorder in the GHS rat and that enhanced bone resorption may be responsible, in part, for the hypercalciuria in the GHS rat.
Idiopathic hypercalciuria is a frequent cause of calcium (Ca) containing kidney stones. We have previously shown that there is increased intestinal Ca absorption in selectively inbred genetic hypercalciuric stone forming (GHS) rats; however, excess Ca excretion persists when the rats are fed a low Ca diet indicating a defect in renal Ca reabsorption and/or increased bone resorption. To determine if GHS rats have a defect in renal Ca reabsorption we performed 14C-inulin clearance studies on parathyroidectomized female GHS and control (Ctl) rats. After three baseline collections, chlorothiazide (CTZ) or furosemide (FUR) was infused and three more collections were obtained. Both GFR and filtered load of Ca did not differ among the groups; however, fractional and absolute excretion (UcaV) of Ca was three times higher in GHS rats. The increased Ca excretion was not diminished by a low Ca diet. Urine flow rate nearly tripled in all rats after either FUR or CTZ. After CTZ, UcaV was decreased to a greater extent in GHS compared to Ctl rats. After FUR, UcaV was increased to a greater extent in Ctl rats compared to GHS rats. These data indicate that GHS rats have a defect in renal Ca reabsorption, in addition to increased intestinal Ca absorption. The effect of CTZ was greater, and that of FUR was smaller, in GHS compared with Ctl rats, suggesting that the defect in renal Ca handling might be at the level of the thick ascending limb.
The mechanism of excess urine calcium excretion in human idiopathic hypercalciuria (IH) has not been determined but may be secondary to enhanced intestinal calcium absorption, decreased renal calcium reabsorption, and/or enhanced bone demineralization. We have developed a strain of genetic hypercalciuric stone-forming (GHS) rats as an animal model of human IH. When these GHS rats are placed on a low-calcium diet (LCD), urinary calcium (UCa) excretion exceeds dietary calcium intake, suggesting that bone may contribute to the excess UCa excretion. We used the GHS rats to test the hypothesis that bone contributes to the persistent IH when they are fed an LCD by determining if alendronate (Aln), which inhibits bone resorption, would decrease UCa excretion.
GHS rats (N = 16) and the parent strain (Ctl, N = 16) were fed 13 g/day of a normal (1.2%) calcium diet (NCD) for seven days and were then switched to a LCD (0. 02%) for seven days. Ctl and GHS rats in each group were then continued on LCD for an additional seven days, with or without injection of Aln (50 micrograms/kg/24 hrs). UCa excretion was measured daily during the last five days of each seven-day period. To determine the effects of Aln on urine supersaturation, the experiment was repeated. All relevant ions were measured, and supersaturation with respect to calcium oxalate and calcium hydrogen phosphate was determined at the end of each period.
UCa was greater in GHS than in Ctl on NCD (7.4 +/- 0.5 mg/24 hrs vs. 1.2 +/- 0.1, GHS vs. Ctl, P < 0.01) and on LCD (3.9 +/- 0.2 mg/24 hrs vs. 0. 7 +/- 0.1, GHS vs. Ctl, P < 0.01). LCD provides 2.6 mg of calcium/24 hrs, indicating that GHS rats are excreting more calcium than they are consuming. On LCD, Aln caused a significant decrease in UCa in GHS rats and brought GHS UCa well below calcium intake. Aln caused a marked decrease in calcium oxalate and calcium hydrogen phosphate supersaturation.
Thus, on a LCD, there is a significant contribution of bone calcium to the increased UCa in this model of IH. Aln is effective in decreasing both UCa and supersaturation. The Aln-induced decrease in urine supersaturation should be beneficial in preventing stone formation in humans, if these results, observed in a short-term study using the hypercalciuric stone-forming rat can be confirmed in longer term human studies.
Human calcium oxalate (CaOx) nephrolithiasis may occur if urine is supersaturated with respect to the solid-phase CaOx. In these patients, dietary oxalate is often restricted to reduce its absorption and subsequent excretion in an effort to lower supersaturation and to decrease stone formation. However, dietary oxalate also binds intestinal calcium which lowers calcium absorption and excretion. The effect of increasing dietary oxalate on urinary CaOx supersaturation is difficult to predict.
To determine the effect of dietary oxalate intake on urinary supersaturation with respect to CaOx and brushite (CaHPO4), we fed 36th and 37th generation genetic hypercalciuric rats a normal Ca diet (1.2% Ca) alone or with sodium oxalate added at 0.5%, 1.0%, or 2.0% for a total of 18 weeks. We measured urinary ion excretion and calculated supersaturation with respect to the CaOx and CaHPO4 solid phases and determined the type of stones formed.
Increasing dietary oxalate from 0% to 2.0% significantly increased urinary oxalate and decreased urinary calcium excretion, the latter presumably due to increased dietary oxalate-binding intestinal calcium. Increasing dietary oxalate from 0% to 2.0% decreased CaOx supersaturation due to the decrease in urinary calcium offsetting the increase in urinary oxalate and the decreased CaHPO4 supersaturation. Each rat in each group formed stones. Scanning electron microscopy revealed discrete stones and not nephrocalcinosis. X-ray and electron diffraction and x-ray microanalysis revealed that the stones were composed of calcium and phosphate; there were no CaOx stones.
Thus, increasing dietary oxalate led to a decrease in CaOx and CaHPO4 supersaturation and did not alter the universal stone formation found in these rats, nor the type of stones formed. These results suggest the necessity for human studies aimed at determining the role, if any, of limiting oxalate intake to prevent recurrence of CaOx nephrolithiasis.
Hypercalciuria is the most common metabolic abnormality observed in patients with nephrolithiasis. Hypercalciuria raises urine supersaturation with respect to the solid phases of calcium oxalate and calcium phosphate, leading to an enhanced probability for nucleation and growth of crystals into clinically significant stones. However, there is little direct proof that supersaturation itself regulates stone formation. Through successive inbreeding of the most hypercalciuric progeny of hypercalciuric Sprague-Dawley rats, we have established a strain of rats, each of which excrete abnormally large amounts of urinary calcium and each of which forms calcium phosphate kidney stones. We used these hypercalciuric (GHS) rats to test the hypothesis that an isolated reduction in urine supersaturation, achieved by decreasing urine phosphorus excretion, would decrease stone formation in these rats.
Thirty 44th-generation female GHS rats were randomly divided into three groups. Ten rats received a high-phosphorus diet (0.565% phosphorus), 10 a medium-phosphorus diet (0.395% phosphorus), and 10 a low-phosphorus diet (0.225% phosphorus) for a total of 18 weeks. The lowered dietary phosphorus would be expected to result in a decrease in urine phosphorus excretion and a decrease in urinary supersaturation with respect to the calcium phosphate solid phase. Every two weeks, 24-hour urine collections were obtained. All relevant ions were measured, and supersaturation with respect to calcium oxalate and calcium hydrogen phosphate were determined. At the conclusion of the experiment, each rat was killed, and the kidneys, ureters, and bladder were dissected en block and x-rayed to determine whether any stones formed. A decrease in stone formation with a reduction in urinary supersaturation would support the hypothesis that supersaturation alone can regulate stone formation.
Decreasing the dietary phosphorus intake led to a progressive decrease in urine phosphorus excretion and an increase in urine calcium excretion, the latter presumably caused by decreased intestinal calcium phosphate binding and increased calcium absorption. With decreasing dietary phosphorus intake, there was a progressive decrease in saturation with respect to the calcium phosphate solid phase. Fifteen of the 20 kidneys from the 10 rats fed the high-phosphorus diet had radiographic evidence of kidney stone formation, whereas no kidneys from the rats fed either the medium- or low-phosphorus diet developed kidney stones.
A decrease in urine phosphorus excretion not only led to a decrease in urine supersaturation with respect to the calcium phosphate solid phase but to an elimination of renal stone formation. The results of this study support the hypothesis that variation in supersaturation alone can regulate renal stone formation. Whether a reduction of dietary phosphorus will alter stone formation in humans with calcium phosphate nephrolithiasis remains to be determined.
The pathogenesis of nephrolithiasis, based on the anomalies of the urinary environment, demands metabolic and physicochemical assessment for the medical management of patients. Standard metabolic protocols include the measurement of pertinent urine chemistry values and the calculation of the extent of saturation in stone-forming salts. However, patients are often given fragmentary and hard-to-consult reports and so this weakens the strength of the therapeutic recommendations. This paper introduces LithoRisk, a dedicated software which graphically represents risk profiles of stone formation, including the extent of saturation.
LithoRisk uses the results of 24-h urine chemistry values widely available in hospital laboratories, i.e., sodium, potassium, calcium, magnesium, ammonia, phosphate, sulphate, citrate, oxalate, chloride, pH and urine volume. Uric acid and cystine are optional. The relative supersaturation (beta), estimated according to our own ab initio calculation, is given in a scale whereby beta=1 is saturation, beta < 1 under - and beta > 1 oversaturation. LithoRisk is available as a CD-ROM and can be loaded on Windows 95/98/Millenium/XP. Colour or laser printers are suitable for printed records.
LithoRisk is easily loaded on any PC by following video instructions. Once the loading of the program is completed a grey icon LithoRisk appears on the Desktop. The program can be opened by clicking twice on the icon. The patients data page first appears on the screen and is followed by the evaluation page for the input of variables. This generates the graph representing the diagnostic lithorisk profile, which is drawn as a line connecting different values, according to a specific scale and related to an arbitrary normal point. Normal values are shown as green lines, whereas abnormal ones are red. The beta values for calcium oxalate and phosphate, uric acid and cystine are instantaneously calculated and reported on the graph.
LithoRisk produces a complete, unique and easy to understand report that includes all relevant parameters, it therefore expresses the overall risk of stone formation. It requires the results of chemistry tests done on the same 24-h urine collection, and carried out using suitable preservatives. If the tests for unusual parameters, i.e. sulphate and ammonia, are unavailable, one can use default values with minimal alterations on beta calculation. In spite of being arbitrary, the normal thresholds values are based on widely accepted literature data. The risk profile recognises the most relevant abnormalities and enables the establishment of individual targets aimed at reducing the propensity towards stone formation.
The therapeutic action of citrate in the management of calcium oxalate urolithiasis has been attributed to the depletion of free calcium ions by complexation of the latter by citrate itself. However, little attention has been given to the nature of such complexes and the chemical conditions which control their formation because it is very difficult to measure them in solution. We therefore modelled the theoretical formation of these complexes in urine following administration of a citrate-containing preparation, using a powerful speciation program, JESS (Joint Expert Speciation System), which has been widely used to model metal-ligand equilibria in biological systems but which has hitherto not been applied in urolithiasis research. This program has an extensive database of thermodynamic constants and is able to calculate mixed ligand speciation.
Urine data obtained before and after citrate administration in four groups of subjects (male and female normals and stone formers) were used as input for JESS to calculate the speciation of calcium, citrate and oxalate. The program was also used to examine the effects of varying different urinary components on the nature and concentration of the various species.
The speciation predicted the formation of a key calcium-citrate-phosphate species (previously unreported in urolithiasis research), which accounts for a significant percentage of the complexation of the free calcium. Moreover, the formation of this complex was found to be dependent on an increase in urinary pH rather than on an increase in urinary citrate concentration per se.
The therapeutic action of citrate in the management of calcium oxalate urolithiasis is due to the formation of a pH dependent calcium-citrate-phosphate complex which reduces the concentration of the free calcium ion species, thereby reducing the risk of stone formation.
Purpose:
Kidney stone disease is characterized by a relatively high rate of recurrence. In our study, we analyzed the association between RSS and the risk of stone recurrence. Additionally, we examined the association between changes in RSS and of urinary composition after 1 week of medical treatment and the risk of recurrence.
Materials and methods:
We performed a post-hoc analysis of data from a previously published randomized controlled trial comparing the effect of two diets in 120 men with recurrent calcium oxalate stones and hypercalciuria. Baseline and follow-up 24h urine parameters were used to calculate RSS for calcium oxalate, calcium phosphate and uric acid using different computer programs EQUIL-2, JESS and Lithorisk. Cox models were used to compute estimates of association between each baseline RSS and 1-week changes and risk of recurrence during follow-up.
Results:
During a 5-year follow-up, 35 patients (34%) experienced recurrence. Reduction in RSS for calcium oxalate at 1 week was significantly associated with lower risk of recurrence when using the EQUIL-2 calculation (for every 10% reduction from baseline HR 0.92, 95% CI 0.86, 1.00, p=0.044), whereas there was no association for RSS calculated with other methods nor for RSS of other salts. Changes in 24h urine excretions of citrate, potassium and magnesium were significantly associated with risk of recurrence.
Conclusions:
In recurrent stone formers with hypercalciuria, baseline values and changes in RSS for calcium oxalate may be associated with risk of recurrence. Changes in urinary citrate, potassium and magnesium following dietary intervention may also be predictive.
Kidney stones are prevalent, and cause considerable morbidity though little mortality. The most common metabolic abnormality in patients with kidney stones is hypercalciuria, which is a complex metabolic trait that is dependent on the amount of dietary calcium absorbed, any calcium released from net bone resorption in excess of formation and the extent to which filtered calcium is reabsorbed in the renal tubule. Each of these calcium fluxes is under the control of a number of factors and hormones including parathyroid hormone and 1,25 dihydroxyvitamin D. Whether a patient forms a kidney stone is dependent not only on the magnitude of the hypercalciuria but on urinary volume and excretion of other ions including oxalate and phosphate. Hypercalciuria, and resultant stone formation, is an inherited trait. Given the many determinants of not only urine calcium excretion, but also the other factors that determine whether a patient will form a kidney stone, it is clear that multiple genetic loci are involved. In this chapter, we will describe the progress that has been made in understanding the genetic basis for hypercalciuria and stone formation in both experimental models and in humans.
In this review, we discuss how the genetic hypercalciuric stone-forming (GHS) rats, which closely model idiopathic hypercalciuria and stone formation in humans, provide insights into the pathophysiology and consequences of clinical hypercalciuria.
Hypercalciuria in the GHS rats is due to a systemic dysregulation of calcium transport, as manifest by increased intestinal calcium absorption, increased bone resorption and decreased renal tubule calcium reabsorption. Increased levels of vitamin D receptor in intestine, bone and kidney appear to mediate these changes. The excess receptors are biologically active and increase tissue sensitivity to exogenous vitamin D. Bones of GHS rats have decreased bone mineral density (BMD) as compared with Sprague-Dawley rats, and exogenous 1,25(OH)2D3 exacerbates the loss of BMD. Thiazide diuretics improve the BMD in GHS rats.
Studying GHS rats allows direct investigation of the effects of alterations in diet and utilization of pharmacologic therapy on hypercalciuria, urine supersaturation, stone formation and bone quality in ways that are not possible in humans.
Animal protein intake may cause an acid load that predisposes individuals to stones by influencing calcium and citrate excretion. These associations were not confirmed in recent studies. Therefore the present study was aimed to compare acid load of diet in stone formers and controls.
Participants to the study were 157 consecutive calcium stone formers and 144 controls. Diet was analyzed in these subjects using a software that evaluated nutrient intake from a three-day food intake diary. This software also estimated the potential renal acid load (PRAL, mEq/day). Twenty-four-hour urine excretion of ions and citrate was measured in stone formers. Stone former diet had lower intake of glucose, fructose, potassium and fiber and higher PRAL in comparison with controls. The multinomial logistic regression analysis showed that stone risk decreased in association with the middle and the highest tertiles of fiber intake and increased in association with the highest tertile of PRAL. The linear multiple regression analysis showed that calcium excretion was associated with the sodium excretion and that citrate excretion was associated with the PRAL and animal protein intake in stone formers.
Our findings suggest that stone formers may undergo a greater dietary acid load sustained by a low vegetable intake and base provision. Dietary acid load does not appear as the main determinant of calcium excretion, but may promote stone risk by decreasing citrate excretion. Sodium intake may predispose to stones by stimulating calcium excretion.
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Idiopathic hypercalciuria is an inherited metabolic abnormality that is characterised by excessive amounts of calcium excreted in the urine by people whose calcium serum levels are normal. Morbidity associated with idiopathic hypercalciuria is chiefly related to kidney stone disease and bone demineralisation leading to osteopenia and osteoporosis. Idiopathic hypercalciuria contributes to kidney stone disease at all life stages; people with the condition are prone to developing oxalate and calcium phosphate kidney stones. In some cases, crystallised calcium can be deposited in the renal interstitium, causing increased calcium levels in the kidneys. In children, idiopathic hypercalciuria can cause a range of comorbidities including recurrent macroscopic or microscopic haematuria, frequency dysuria syndrome, urinary tract infections and abdominal and lumbar pain. Various dietary interventions have been described that aim to decrease urinary calcium levels or urinary crystallisation.
Our objectives were to assess the efficacy, effectiveness and safety of dietary interventions for preventing complications in idiopathic hypercalciuria (urolithiasis and osteopenia) in adults and children, and to assess the benefits of dietary interventions in decreasing urological symptomatology in children with idiopathic hypercalciuria.
We searched the Cochrane Renal Group's Specialised Register (23 April 2013) through contact with the Trials' Search Co-ordinator using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE and EMBASE.
We included all randomised controlled trials (RCTs) and quasi-RCTs that investigated dietary interventions aimed at preventing complications of idiopathic hypercalciuria, compared with placebo, no intervention, or other dietary interventions regardless of route of administration, dose or amount.
Studies were assessed for inclusion and data extracted using a standardised data extraction form. We calculated risk ratios (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, both with 95% confidence intervals (CI).
We included five studies (379 adult participants) that investigated a range of interventions. Lack of similarity among interventions investigated meant that data could not be pooled. Overall, study methodology was not adequately reported in any of the included studies. There was a high risk of bias associated with blinding (although it seems unlikely that outcomes measures were unduly influenced by lack of intervention blinding), random sequence generation and allocation methodologies were unclear in most studies, but selective reporting bias was assessed as low.One study (120 participants) compared a low calcium diet with a normal calcium, low protein, low salt diet for five years. There was a significant decrease in numbers of new stone recurrences in those treated with the normal calcium, low protein, low salt diet (RR 0.77, 95% CI 0.61 to 0.98). This diet also led to a significant decrease in oxaluria (MD 78.00 µmol/d, 95% CI 26.48 to 129.52) and the calcium oxalate relative supersaturation index (MD 1.20 95% CI 0.21 to 2.19).One study (210 participants) compared a low salt, normal calcium diet with a broad diet for three months. The low salt, normal calcium diet decreased urinary calcium (MD -45.00 mg/d, 95% CI -74.83 to -15.17) and oxalate excretion (MD -4.00 mg/d, 95% CI -6.44 to -1.56).A small study (17 participants) compared the effect of dietary fibre as part of a low calcium, low oxalate diet over three weeks, and found that although calciuria levels decreased, oxaluria increased. Phyllanthus niruri plant substrate intake was investigated in a small subgroup with hypercalciuria (20 participants); there was no significant effect on calciuria levels occurred after three months of treatment.A small cross-over study (12 participants) evaluating the changes in urinary supersaturation indices among patients who consumed calcium-fortified orange juice or milk for one month found no benefits for participants.None of the studies reported any significant adverse effects associated with the interventions.
Long-term adherence (five years) to diets that feature normal levels of calcium, low protein and low salt may reduce numbers of stone recurrences, decrease oxaluria and calcium oxalate relative supersaturation indexes in people with idiopathic hypercalciuria who experience recurrent kidney stones. Adherence to a low salt, normal calcium level diet for some months can reduce calciuria and oxaluria. However, the other dietary interventions examined did not demonstrate evidence of significant beneficial effects.No studies were found investigating the effect of dietary recommendations on other clinical complications or asymptomatic idiopathic hypercalciuria.
To assess (i) the extent to which urinary supersaturation (SS) has successfully discriminated between stone formers (SF) and healthy individuals (N), (ii) whether absolute SS has diagnostic worth and (iii) whether high SS is the fundamental cause of stone formation per se.
Google Scholar was used to identify studies in which urinary compositional data had been determined. In those cases where SS values were not given, or where other risk indices had been reported, they were (re-)calculated. Collected data were termed "global" but were then "filtered" according to stone type and protocols used for SS calculations. SS distribution plots for calcium oxalate, brushite and uric acid were constructed. Data were statistically analysed using the unpaired t and Mann-Whitney tests.
A total of 47 studies yielded 123 SS values for N and 122 values for SF. Mean and median SS values were significantly greater in SF compared to N in all but one of the comparisons. Wide variations in SS occurred for N and SF. The two groups could not be separated.
Absolute SS has no diagnostic worth. It is impossible to quantify the meaning of a "high" SS value. Urines cannot be identified as originating from N or SF based on their SS. Supersaturation should be determined in clinical and research settings for relative comparisons during the assessment of treatment efficacies. This study provides a compelling argument for SS being a casual factor rather than a causal one.
Calcium is an important participant in many physiologic processes including coagulation, cell membrane transfer, hormone release, neuromuscular activation, and myocardial contraction. The body cooperates in a sophisticated web of hormonally mediated interactions to maintain stable extracellular calcium levels. Calcium is vital for skeletal mineralization, and perturbations in extracellular calcium may be corrected at the expense of bone strength and integrity. The aim of this review is to delineate our current understanding of idiopathic hypercalciuria in the context of bone health, specifically its definition, etiology, epidemiology, laboratory evaluation, and potential therapeutic management.
Urolithiasis affects approximately 10% of individuals in Western societies by the seventh decade of life. The most common form, idiopathic calcium oxalate urolithiasis, results from the interaction of multiple genes and their interplay with dietary and environmental factors. To date, considerable progress has been made in identifying the metabolic risk factors that predispose to this complex trait, among which hypercalciuria predominates. The specific genetic and epigenetic factors involved in urolithiasis have remained less clear, partly owing to the candidate gene and linkage methods that have been available until now, being inherently low in their power of resolution and in assessing modest effects in complex traits. However, together with investigations of rare, Mendelian forms of urolithiasis associated with various metabolic risk factors, these methods have afforded insights into biological pathways that seem to underlie the development of stones in the urinary tract. Monogenic diseases account for a greater proportion of stone formers in children and adolescents than in adults. Early diagnosis of monogenic forms of urolithiasis is of importance owing to associated renal injury and other potentially treatable disease manifestations, but diagnosis is often delayed because of a lack of familiarity with these rare disorders. In this Review, we will discuss advances in the understanding of the genetics underlying polygenic and monogenic forms of urolithiasis.
Idiopathic calcium oxalate (CaOx) stone-formers (ICSFs) differ from patients who make idiopathic calcium phosphate (CaP) stones (IPSFs). ICSFs, but not IPSFs, form their stones as overgrowths on interstitial apatite plaque; the amount of plaque covering papillary surface is positively correlated with urine calcium excretion and inversely with urine volume. The amount of plaque predicts the number of recurrent stones. The initial crystal overgrowth on plaque is CaP, although the stone is mainly composed of CaOx, meaning that lowering supersaturation (SS) for CaOx and CaP is important for CaOx stone prevention. IPSFs, unlike ICSFs, have apatite crystal deposits in inner medullary collecting ducts, which are associated with interstitial scarring. ICSFs and IPSFs have idiopathic hypercalciuria, which is due to decreased tubule calcium reabsorption, but sites of abnormal reabsorption may differ. Decreased reabsorption in proximal tubules (PTs) delivers more calcium to the thick ascending limb (TAL), where increased calcium reabsorption can load the interstitium, leading to plaque formation. The site of abnormal reabsorption in IPSFs may be the TAL, where an associated defect in bicarbonate reabsorption could produce the higher urine pH characteristic of IPSFs. Preventive treatment with fluid intake, protein and sodium restriction, and thiazide will be effective in ICSFs and IPSFs by decreasing urine calcium concentration and CaOx and CaP SS and may also decrease plaque formation by increased PT calcium reabsorption. Citrate may be detrimental for IPSFs if urine pH rises greatly, increasing CaP SS. Future trials should examine the question of appropriate treatment for IPSFs.
We have bred a strain of rats to maximize urine (u) calcium (Ca) excretion and model hypercalciuric nephrolithiasis. These genetic hypercalciuric stone-forming (GHS) rats excrete more uCa than control Sprague-Dawley rats, uniformly form kidney stones, and similar to patients, demonstrate lower bone mineral density. Clinically, thiazide diuretics reduce uCa and prevent stone formation; however, whether they benefit bone is not clear. We used GHS rats to test the hypothesis that the thiazide diuretic chlorthalidone (CTD) would have a favorable effect on bone density and quality. Twenty GHS rats received a fixed amount of a 1.2% Ca diet, and half also were fed CTD (4 to 5 mg/kg/d). Rats fed CTD had a marked reduction in uCa. The axial and appendicular skeletons were studied. An increase in trabecular mineralization was observed with CTD compared with controls. CTD also improved the architecture of trabecular bone. Using micro-computed tomography (µCT), trabecular bone volume (BV/TV), trabecular thickness, and trabecular number were increased with CTD. A significant increase in trabecular thickness with CTD was confirmed by static histomorphometry. CTD also improved the connectivity of trabecular bone. Significant improvements in vertebral strength and stiffness were measured by vertebral compression. Conversely, a slight loss of bending strength was detected in the femoral diaphysis with CTD. Thus results obtained in hypercalciuric rats suggest that CTD can favorably influence vertebral fracture risk. CTD did not alter formation parameters, suggesting that the improved vertebral bone strength was due to decreased bone resorption and retention of bone structure.
Sodium restriction is widely recommended to prevent urinary stone recurrence. However, the effect of urinary sodium excretion has not been fully evaluated. We investigated the relationship between urinary sodium, urinary metabolite excretion and the risk of recurrence in urinary stone formers.
Selected for study were 798 stone formers with no evidence of metabolic disorders as the cause of abnormal urinary solutes. We analyzed the relationship between urinary sodium and other metabolic parameters by gender. Values were adjusted by covariates according to correlation status. Patients were divided into stone formers with hypernatriuresis or normal natriuresis (less than 220 mEq daily) and urinary parameters were compared. Kaplan-Meier analysis was done to determine the cumulative incidence of recurrent stones by urinary sodium. Patients were considered recurrence-free at a minimum followup of 3 years without incidence.
In the 492 men and 306 women mean ± SD age was 40.0 ± 11.4 and 45.4 ± 12.7 years, and mean body mass index was 23.9 ± 3.1 and 23.0 ± 3.0 kg/m(2), respectively. Using covariate adjusted partial correlation coefficients urinary sodium was noted to influence volume, pH, calcium, uric acid, oxalate and citrate in men, and volume, pH, calcium, uric acid and citrate in women (each p <0.05). At a median followup of 56.1 months 46 of 98 stone formers (46.9%) with normal natriuresis experienced stone recurrence vs 60 of 93 (64.5%) with hypernatriuresis. Patients with hypernatriuresis also had significantly decreased time to recurrence than those with normal natriuresis (log rank test p = 0.043).
Results show that urinary sodium is an important determinant of other stone forming parameters and of the risk of recurrent stones. These findings suggest that a sodium restricted diet should be the initial step when treating stone formers.
The impact of the Dietary Approaches to Stop Hypertension (DASH) diet on kidney stone formation is unknown. We prospectively examined the relation between a DASH-style diet and incident kidney stones in the Health Professionals Follow-up Study (n = 45,821 men; 18 yr of follow-up), Nurses' Health Study I (n = 94,108 older women; 18 yr of follow-up), and Nurses' Health Study II (n = 101,837 younger women; 14 yr of follow-up). We constructed a DASH score based on eight components: high intake of fruits, vegetables, nuts and legumes, low-fat dairy products, and whole grains and low intake of sodium, sweetened beverages, and red and processed meats. We used Cox hazards regression to adjust for factors that included age, BMI, and fluid intake. Over a combined 50 yr of follow-up, we documented 5645 incident kidney stones. Participants with higher DASH scores had higher intakes of calcium, potassium, magnesium, oxalate, and vitamin C and had lower intakes of sodium. For participants in the highest compared with the lowest quintile of DASH score, the multivariate relative risks for kidney stones were 0.55 (95% CI, 0.46 to 0.65) for men, 0.58 (95% CI, 0.49 to 0.68) for older women, and 0.60 (95% CI, 0.52 to 0.70) for younger women. Higher DASH scores were associated with reduced risk even in participants with lower calcium intake. Exclusion of participants with hypertension did not change the results. In conclusion, consumption of a DASH-style diet is associated with a marked decrease in kidney stone risk.
An uncontrolled trial reported that sodium thiosulfate reduces formation of calcium kidney stones in humans, but this has not been established in a controlled human study or animal model. Using the genetic hypercalciuric rat, an animal model of calcium phosphate stone formation, we studied the effect of sodium thiosulfate on urine chemistries and stone formation. We fed genetic hypercalciuric rats normal food with or without sodium thiosulfate for 18 wk and measured urine chemistries, supersaturation, and the upper limit of metastability of urine. Eleven of 12 untreated rats formed stones compared with only three of 12 thiosulfate-treated rats (P < 0.002). Urine calcium and phosphorus were higher and urine citrate and volume were lower in the thiosulfate-treated rats, changes that would increase calcium phosphate supersaturation. Thiosulfate treatment lowered urine pH, which would lower calcium phosphate supersaturation. Overall, there were no statistically significant differences in calcium phosphate supersaturation or upper limit of metastability between thiosulfate-treated and control rats. In vitro, thiosulfate only minimally affected ionized calcium, suggesting a mechanism of action other than calcium chelation. In summary, sodium thiosulfate reduces calcium phosphate stone formation in the genetic hypercalciuric rat. Controlled trials testing the efficacy and safety of sodium thiosulfate for recurrent kidney stones in humans are needed.
Kidney stone patients often have a decrease in BMD. It is unclear if reduced BMD is caused by a primary disorder of bone or dietary factors. To study the independent effects of hypercalciuria on bone, we used genetic hypercalciuric stone-forming (GHS) rats. GHS and control (Ctl) rats were fed a low Ca (0.02% Ca, LCD) or a high Ca (1.2% Ca, HCD) diet for 6 wk in metabolic cages. All comparisons are to Ctl rats. Urine Ca was greater in the GHS rats on both diets. GHS fed HCD had reduced cortical (humerus) and trabecular (L(1)-L(5) vertebrae) BMD, whereas GHS rats fed LCD had a reduction in BMD similar to Ctl. GHS rats fed HCD had a decrease in trabecular volume and thickness, whereas LCD led to a approximately 20-fold increase in both osteoid surface and volume. GHS rats fed HCD had no change in vertebral strength (failure stress), ductibility (failure strain), stiffness (modulus), or toughness, whereas in the humerus, there was reduced ductibility and toughness and an increase in modulus, indicating that the defect in mechanical properties is mainly manifested in cortical, rather than trabecular, bone. GHS rat cortical bone is more mineralized than trabecular bone and LCD led to a decrease in the mineralization profile. Thus, the GHS rats, fed an ample Ca diet, have reduced BMD with reduced trabecular volume, mineralized volume, and thickness, and their bones are more brittle and fracture prone, indicating that GHS rats have an intrinsic disorder of bone that is not secondary to diet.
Cardiovascular disease (CVD) is the leading cause of death and disability worldwide. Raised blood pressure (BP), cholesterol and smoking, are the major risk factors. Among these, raised BP is the most important cause, accounting for 62% of strokes and 49% of coronary heart disease. Importantly, the risk is throughout the range of BP, starting at systolic 115 mm Hg. There is strong evidence that our current consumption of salt is the major factor increasing BP and thereby CVD. Furthermore, a high salt diet may have direct harmful effects independent of its effect on BP, for example, increasing the risk of stroke, left ventricular hypertrophy and renal disease. Increasing evidence also suggests that salt intake is related to obesity through soft drink consumption, associated with renal stones and osteoporosis and is probably a major cause of stomach cancer. In most developed countries, a reduction in salt intake can be achieved by a gradual and sustained reduction in the amount of salt added to food by the food industry. In other countries where most of the salt consumed comes from salt added during cooking or from sauces, a public health campaign is needed to encourage consumers to use less salt. Several countries have already reduced salt intake, for example, Japan (1960-1970), Finland (1975 onwards) and now the United Kingdom. The challenge is to spread this out to all other countries. A modest reduction in population salt intake worldwide will result in a major improvement in public health.
Excessive urine calcium excretion in patients with idiopathic hypercalciuria may involve a primary increase in intestinal calcium absorption, overproduction of 1,25-dihydroxyvitamin D3 or a defect in renal tubular calcium reabsorption. To determine the mechanism of hypercalciuria in an animal model, hypercalciuria was selected for in rats and the most hypercalciuric animals inbred. Animals from the fourth generation were utilized to study mineral balance and intestinal transport in relation to levels of serum 1,25(OH)2D3. Both urine calcium excretion and net intestinal calcium absorption were greater in hypercalciuric males (HM) than in normocalciuric males (NM) and in hypercalciuric females (HF) than in normocalciuric females (NF). However, serum 1,25(OH)2D3 was lower in HM than in NM and not different in HF than in NF. Net calcium balance was more positive in HM than in NM and in HF than in NF. In vitro duodenal calcium net flux was correlated with serum 1,25(OH)2D3 in HM and HF and in NM and NF. However, with increasing serum 1,25(OH)2D3 there was greater calcium net flux in hypercalciuric rats than in normocalciuric controls. Hypercalciuria in this colony of hypercalciuric rats is due to a primary intestinal overabsorption of dietary calcium and not an overproduction of 1,25(OH)2D3 or a defect in the renal tubular reabsorption of calcium.
A BASIC computer program for the calculation of urinary supersaturation with respect to the common kidney stone components is described. In vitro and in vivo tests show that the program described accurately calculates supersaturation. The application of this computer program to urolithiasis research is discussed.
Effects of potassium citrate therapy (60 mEq/day) on urinary chemistries and crystallization were compared to those of sodium citrate treatment in five patients with uric acid lithiasis. Both alkali treatments significantly increased urinary pH (P less than 0.001), from 5.35 +/- 0.18 SD to 6.68 +/- 0.14 for potassium citrate and 6.73 +/- 0.20 for sodium citrate. During potassium citrate therapy, urinary calcium significantly declined from 154 +/- 47 mg/day to 99 +/- 23 mg/day (P less than 0.01) and urinary citrate rose from 398 +/- 119 mg/day to 856 +/- 103 mg/day (P less than 0.001). The urinary saturation (activity product ratio) of calcium oxalate decreased from 3.21-fold to 1.69-fold saturation (P less than 0.01), and the inhibitor activity against calcium oxalate precipitation (formation product ratio) significantly increased. However, sodium citrate therapy did not significantly decrease urinary calcium (to 139 +/- 24 mg/day), although it increased urinary citrate substantially (to 799 +/- 89 mg/day, P less than 0.01). Urinary environment became supersaturated with respect to brushite (calcium phosphate) and monosodium urate. The inhibitor activity against calcium oxalate precipitation was not significantly altered for the whole group; in two patients, it decreased by more than 30%. The results indicate that (1) both alkali therapies are equally effective in preventing uric acid stone formation because of their ability to increase urinary pH, and (2) potassium citrate may prevent the complication of calcium nephrolithiasis in patients with uric acid stones, whereas sodium citrate may not.
The effect of high sodium intake on bone mineral content of rats fed a normal (0.6% Ca) or a low (0.02% Ca) calcium diet was studied. Rats on a normal calcium diet given 1.8% sodium chloride to drink showed persistent and significant hypercalciuria and subnormal bone mineral content. Total calcium content of femur was significantly lower after 4 months (p < 0.02) and 12 months (p < 0.001). In rats maintained on a low calcium diet (0.02% Ca), a high sodium diet for 8 weeks caused a significant loss of calcium in bone similar to that seen in animals fed a normal calcium diet for 4 months. We conclude that high sodium intake reduces bone mineral content, especially if the diet is low in calcium.
In humans, familial or idiopathic hypercalciuria (IH) is a common cause of hypercalciuria and predisposes to calcium oxalate nephrolithiasis. Intestinal calcium hyperabsorption is a constant feature of IH and may be due to either a vitamin D-independent process in the intestine, a primary overproduction of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], or a defect in renal tubular calcium reabsorption. Selective breeding of spontaneously hypercalciuric male and female Sprague-Dawley rats resulted in offspring with hypercalciuria, increased intestinal calcium absorption, and normal serum 1,25(OH)2D3 levels. The role of the vitamin D receptor (VDR) in the regulation of intestinal calcium absorption was explored in 10th generation male genetic IH rats and normocalciuric controls. Urine calcium excretion was greater in IH rats than controls (2.9 +/- 0.3 vs. 0.7 +/- 0.2 mg/24 h, P < 0.001). IH rat intestine contained twice the abundance of VDR compared with normocalciuric controls (536 +/- 73 vs. 243 +/- 42 nmol/mg protein, P < 0.001), with no difference in the affinity of the receptor for its ligand. Comparable migration of IH and normal intestinal VDR on Western blots and of intestinal VDR mRNA by Northern analysis suggests that the VDR in IH rat intestine is not due to large deletion or addition mutations of the wild-type VDR. IH rat intestine contained greater concentrations of vitamin D-dependent calbindin 9-kD protein. The present studies strongly suggest that increased intestinal VDR number and normal levels of circulating 1,25(OH)2D3 result in increased functional VDR-1,25(OH)2D3 complexes, which exert biological actions in enterocytes to increase intestinal calcium transport. Intestinal calcium hyperabsorption in the IH rat may be the first example of a genetic disorder resulting from a pathologic increase in VDR.
Calcium oxalate (CaOx) and calcium phosphate (CaP) crystals do not precipitate in large amounts in normal urine despite considerable supersaturation (SS), partly because urine inhibits crystal nucleation, aggregation, and growth. In normal rats and rats bred for hypercalciuria (GHS), we varied SS by varying calcium intake to test the hypothesis that increased SS might deplete inhibitors and reduce inhibition of crystal formation. In normal rats when compared to a low calcium diet (0.02% Ca), a high calcium diet (1.2% Ca) raised the SS of CaOx from 0.8 to 8.2. The high calcium diet also raised the upper limit of metastability (ULM) of CaOx (the SS at which crystals form in urine) from 11.8 to 36. In GHS rats, diet change altered CaOx SS from 1.5 to 12, and ULM from 17 to 50 (all differences, P < 0.001). Because ULM rose with SS, the increased SS had little potential to increase CaOx stone risk. For CaP, however, SS rose from 0.6 to 2.4 and 1.1 to 8 in normal and GHS rats (P < 0.001 for both), respectively, whereas ULM for CaP did not increase significantly (8 vs. 7 and 7 vs. 11; P = NS, both changes). Therefore, CaP SS rose close to the ULM, posing a high stone risk. The stones formed by these rats are composed of CaP. Increasing CaOx SS by diet raises ULM for CaOx thereby offsetting the risk of CaOx stones in rats.
Calcium intake is believed to play an important role in the formation of kidney stones, but data on the risk factors for stone formation in women are limited.
To examine the association between intake of dietary and supplemental calcium and the risk for kidney stones in women.
Prospective cohort study with 12-year follow-up.
Several U.S. states.
91,731 women participating in the Nurses' Health Study I who were 34 to 59 years of age in 1980 and had no history of kidney stones.
Self-administered food-frequency questionnaires were used to assess diet in 1980, 1984, 1986, and 1990. The main outcome measure was incident symptomatic kidney stones.
During 903,849 person-years of follow-up, 864 cases of kidney stones were documented. After adjustment for potential risk factors, intake of dietary calcium was inversely associated with risk for kidney stones and intake of supplemental calcium was positively associated with risk. The relative risk for stone formation in women in the highest quintile of dietary calcium intake compared with women in the lowest quintile was 0.65 (95% CI, 0.50 to 0.83). The relative risk in women who took supplemental calcium compared with women who did not was 1.20 (CI, 1.02 to 1.41). In 67% of women who took supplemental calcium, the calcium either was not consumed with a meal or was consumed with meals whose oxalate content was probably low. Other dietary factors showed the following relative risks among women in the highest quintile of intake compared with those in the lowest quintile: sucrose, 1.52 (CI, 1.18 to 1.96); sodium, 1.30 (CI, 1.05 to 1.62); fluid, 0.61 (CI, 0.48 to 0.78); and potassium, 0.65 (CI, 0.51 to 0.84).
High intake of dietary calcium appears to decrease risk for symptomatic kidney stones, whereas intake of supplemental calcium may increase risk. Because dietary calcium reduces the absorption of oxalate, the apparently different effects caused by the type of calcium may be associated with the timing of calcium ingestion relative to the amount of oxalate consumed. However, other factors present in dairy products (the major source of dietary calcium) could be responsible for the decreased risk seen with dietary calcium.
Calcium and sodium absorption by the kidney normally proceed in parallel. However, a number of physiological, pharmacological, pathological, and genetic conditions dissociate this relation. In each instance, the dissociation can be traced to the distal convoluted tubule, where calcium and sodium transport are inversely related. Based on the identification of the relevant sodium transporters in these cells and on analysis of the mechanism of calcium transport, an explanation for this inverse relation can be developed. Apical membrane calcium entry is mediated by voltage-sensitive calcium channels that are activated upon membrane hyperpolarization. Basolateral calcium efflux is effected primarily by Na+/Ca2+ exchange. According to the model, inhibition of sodium entry through either the Na-Cl cotransporter or the Na+ channel hyperpolarizes the cell, as does parathyroid hormone, thereby activating the calcium entry channel and increasing the driving force for diffusional entry. Membrane hyperpolarization also increases the driving force of calcium efflux through the Na+/Ca2+ exchanger. Thus sodium-dependent changes of calcium transport are indirect and occur secondarily through effects on membrane voltage.
Hypercalciuria in genetic hypercalciuric stone-forming (GHS) rats is accompanied by intestinal Ca hyperabsorption with normal serum 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels, elevation of intestinal, kidney, and bone vitamin D receptor (VDR) content, and greater 1,25(OH)2D3-induced bone resorption in vitro. To test the hypothesis that hyperresponsiveness of VDR gene expression to 1,25(OH)2D3 may mediate these observations, male GHS and wild-type Sprague- Dawley normocalciuric control rats were fed a normal Ca diet (0.6% Ca) and received a single intraperitoneal injection of either 1,25(OH)2D3 (10-200 ng/100 g body wt) or vehicle. Total RNAs were isolated from both duodenum and kidney cortex, and the VDR and calbindin mRNA levels were determined by Northern blot hybridization using specific cDNA probes. Under basal conditions, VDR mRNA levels in GHS rats were lower in duodenum and higher in kidney compared with wild-type controls. Administration of 1,25(OH)2D3 increased VDR gene expression significantly in GHS but not normocalciuric animals, in a time- and dose-dependent manner. In vivo half-life of VDR mRNA was similar in GHS and control rats in both duodenum and kidney, and was prolonged significantly (from 4-5 to > 8 h) by 1,25(OH)2D3 administration. Neither inhibition of gene transcription by actinomycin D nor inhibition of de novo protein synthesis with cycloheximide blocked the upregulation of VDR gene expression stimulated by 1,25(OH)2D3 administration. No alteration or mutation was detected in the sequence of duodenal VDR mRNA from GHS rats compared with wild-type animals. Furthermore, 1,25(OH)2D3 administration also led to an increase in duodenal and renal calbindin mRNA levels in GHS rats, whereas they were either suppressed or unchanged in wild-type animals. The results suggest that GHS rats hyperrespond to minimal doses of 1,25(OH)2D3 by an upregulation of VDR gene expression. This hyperresponsiveness of GHS rats to 1,25(OH)2D3 (a) occurs through an increase in VDR mRNA stability without involving alteration in gene transcription, de novo protein synthesis, or mRNA sequence; and (b) is likely of functional significance, and affects VDR-responsive genes in 1, 25(OH)2D3 target tissues. This unique characteristic suggests that GHS rats may be susceptible to minimal fluctuations in serum 1, 25(OH)2D3, resulting in increased VDR and VDR-responsive events, which in turn may pathologically amplify the actions of 1,25(OH)2D3 on Ca metabolism that thus contribute to the hypercalciuria and stone formation.
Chronic metabolic acidosis increases urine calcium excretion without altering intestinal calcium absorption, suggesting that bone mineral is the source of the additional urinary calcium. During metabolic acidosis there appears to be an influx of protons into bone mineral, lessening the magnitude of the decrement in pH. Although in vitro studies strongly support a marked effect of metabolic acidosis on the ion composition of bone, there are few in vivo observations. We utilized a high-resolution scanning ion microprobe with secondary ion mass spectroscopy to determine whether in vivo metabolic acidosis would alter bone mineral in a manner consistent with its purported role in buffering the increased proton concentration. Postweanling mice were provided distilled drinking water with or without 1.5% NH(4)Cl for 7 days; arterial blood gas was then determined. The addition of NH(4)Cl led to a fall in blood pH and HCO(-)(3) concentration. The animals were killed on day 7, and the femurs were dissected and split longitudinally. The bulk cortical ratios Na/Ca, K/Ca, total phosphate/carbon-nitrogen bonds [(PO(2) + PO(3))/CN], and HCO(-)(3)/CN each fell after 1 wk of metabolic acidosis. Because metabolic acidosis induces bone Ca loss, the fall in Na/Ca and K/Ca indicates a greater efflux of bone Na and K than Ca, suggesting H substitution for Na and K on the mineral. The fall in (PO(2) + PO(3))/CN indicates release of mineral phosphates, and the fall in HCO(-)(3)/CN indicates release of mineral HCO(-)(3). Each of these mechanisms would result in buffering of the excess protons and returning the systemic pH toward normal.
Although renal stone disease has been associated with reduced bone mass, the impact of nutrient intake on bone loss is unknown.
The present study was undertaken to investigate the influence of nutrient intake on bone density of 85 calcium stone-forming (CSF) patients (47 male and 38 premenopausal females) aged 41+/-11 years (X+/-SD). Bone mineral density (BMD) was measured using dual energy X-ray absorptiometry at the lumbar spine (L2-L4) and femoral neck sites, and low BMD was defined as a T score < -1 (WHO criteria). A 4-day dietary record and a 24-hour urine sample were obtained from each patient for the assessment of nutrient intake and urinary calcium (U(Ca)), sodium (U(Na)), phosphate and creatinine excretion.
Forty-eight patients (56%) presented normal BMD and 37 (44%) low BMD. There were no statistical differences regarding age, weight, height, body mass index, protein, calcium and phosphorus intakes between both groups. The mean U(Ca), phosphorus and nitrogen appearance also did not differ between groups. However, there was a higher percentage of hypercalciuria among low vs normal BMD patients (62 vs 33%, p < 0.05). Low BMD patients presented a higher mean sodium chloride (NaCl) intake and excretion (UNa) than normal BMD (14+/-5 vs 12+/-4 g/day and 246+/-85 vs 204+/-68 mEq/day, respectively p < 0.05). The percentage of patients presenting NaCl intake > or = 16 g/day was also higher among low vs normal BMD patients (35 vs 12%, p < 0.05). After adjustment for calcium and protein intakes, age, weight, body mass index, urinary calcium, citrate and uric acid excretion, and duration of stone disease, multiple-regression analysis showed that a high NaCl intake (> or = 16 g/day) was the single variable that was predictive of risk of low bone density in CSF patients (odds ratio = 3.8).
These data suggest that reducing salt intake should be recommended for CSF patients presenting hypercalciuria and osteopenia.
We have successively inbred over 45 generations a strain of rats to maximize urine calcium excretion. The rats now consistently excrete 8 to 10 times as much calcium as controls and uniformly form poorly crystalline calcium phosphate kidney stones. In humans with calcium nephrolithiasis, consumption of a diet high in acid precursors is often cited as a risk factor for the development of calcium-based kidney stones; however, the effect of this diet on urinary supersaturation with respect to the common solid phases found in kidney stones has not been determined.
To determine the effect of the addition of an acid precursor on urine ion excretion, supersaturation, and stone formation, we fed these genetic hypercalciuric stone-forming (GHS) rats 13 g/day of a 1.2% calcium diet with 0.0, 0.5, 1.0, or 1.5% NH4Cl in the drinking water for 14 weeks (N = 8 for each). Urine was collected and analyzed every two weeks.
As expected, the addition of dietary NH4Cl led to a progressive fall in urine pH and urine citrate, while urine ammonium increased. Urine calcium and phosphorus increased, while urine oxalate fell. Increasing dietary NH4Cl led to a fall in supersaturation with respect to CaHPO4 (brushite) and CaOx and a rise in supersaturation with respect to uric acid. In spite of differences in supersaturation, most rats in each group formed stones that contained calcium phosphate and not calcium oxalate.
Thus, while the provision of additional dietary acids alters urinary ion excretion and lowers supersaturation with respect to CaHPO4 and CaOx, it does not change the character or rate of stone formation in the GHS rats.
A low-calcium diet is recommended to prevent recurrent stones in patients with idiopathic hypercalciuria, yet long-term data on the efficacy of a low-calcium diet are lacking. Recently, the efficacy of a low-calcium diet has been questioned, and greater emphasis has been placed on reducing the intake of animal protein and salt, but again, long-term data are unavailable.
We conducted a five-year randomized trial comparing the effect of two diets in 120 men with recurrent calcium oxalate stones and hypercalciuria. Sixty men were assigned to a diet containing a normal amount of calcium (30 mmol per day) but reduced amounts of animal protein (52 g per day) and salt (50 mmol of sodium chloride per day); the other 60 men were assigned to the traditional low-calcium diet, which contained 10 mmol of calcium per day.
At five years, 12 of the 60 men on the normal-calcium, low-animal-protein, low-salt diet and 23 of the 60 men on the low-calcium diet had had relapses. The unadjusted relative risk of a recurrence for the group on the first diet, as compared with the group on the second diet, was 0.49 (95 percent confidence interval, 0.24 to 0.98; P=0.04). During follow-up, urinary calcium levels dropped significantly in both groups by approximately 170 mg per day (4.2 mmol per day). However, urinary oxalate excretion increased in the men on the low-calcium diet (by an average of 5.4 mg per day [60 micromol per day]) but decreased in those on the normal-calcium, low-animal-protein, low-salt diet (by an average of 7.2 mg per day [80 micromol per day]).
In men with recurrent calcium oxalate stones and hypercalciuria, restricted intake of animal protein and salt, combined with a normal calcium intake, provides greater protection than the traditional low-calcium diet.
Over 54 generations, we have successfully bred a strain of rats that maximizes urinary calcium excretion. The rats now consistently excrete 8 to 10 times as much calcium as controls, uniformly form poorly crystalline calcium phosphate kidney stones, and are termed genetic hypercalciuric stone-forming (GHS) rats. These rats were used to test the hypothesis that increasing urinary oxalate excretion would not only increase the supersaturation with respect to the calcium oxalate solid phase, but also would increase the ratio of calcium oxalate-to-calcium phosphate supersaturation and result in calcium oxalate stone formation.
To increase urine oxalate excretion an oxalate precursor, hydroxyproline, was added to the diet of male GHS rats. The GHS rats were fed a standard 1.2% calcium diet alone or with 1%, 3% or 5% trans-4-hydroxy-l-proline (hydroxyproline).
The addition of 1% hydroxyproline to the diet of GHS rats led to an increase in urinary oxalate excretion, which did not increase further with the provision of additional hydroxyproline. The addition of 1% and 3% hydroxyproline did not alter calcium excretion while the provision of 5% hydroxyproline led to a decrease in urine calcium excretion. The addition of 1% hydroxyproline led to an increase in urinary calcium oxalate supersaturation, which did not further increase with additional hydroxyproline. The addition of 1% and 3% hydroxyproline did not alter urinary supersaturation with respect to calcium hydrogen phosphate while the addition of 5% hydroxyproline tended to lower this supersaturation. Compared to rats fed the control and the 3% hydroxyproline diet the addition of 5% hydroxyproline increased the ratio of calcium oxalate supersaturation to calcium phosphate supersaturation. Virtually all rats formed stones. In the control and 1% hydroxyproline group, all of the stones were composed of calcium and phosphate (apatite), in the 3% hydroxyproline group the stones were a mixture of apatite and calcium oxalate, while in the 5% hydroxyproline group all of the stones were calcium oxalate.
The provision of additional dietary hydroxyproline to GHS rats increases urinary oxalate excretion, calcium oxalate supersaturation and the ratio of calcium oxalate-to-calcium phosphate supersaturation, resulting in the formation of calcium oxalate kidney stones. Thus, with the addition of a common amino acid, the GHS rats now not only model the most common metabolic abnormality found in patients with nephrolithiasis, hypercalciuria, but form the most common type of kidney stone, calcium oxalate.
During diuresis induced in dogs by water, sodium chloride, sodium bicarbonate, mannitol, glucose, or sucrose, the plasma calcium clearance is, on the average, half the sodium clearance. Free calcium ion clearance therefore equals sodium clearance. This relationship is not altered by reducing calcium or sodium intake, by varying urinary flow or urinary ionic strength, or by varying chloride excretion, independently of sodium excretion. It is only slightly affected by urinary pH, and is not distinctly altered by potassium infusion. Sodium and calcium ions are thus reabsorbed in the proportions in which they are present in plasma. However, previous observations made during sulfate diuresis, when approximately half of the urinary calcium is complexed by sulfate, suggest that the tubular cells tend to maintain a constant ratio of sodium to free calcium ions in the tubular fluid, rather than to reabsorb proportionate quantities of each. It is speculated that this may reflect competitive binding of calcium and sodium at the cell membrane.
The inbred genetic hypercalciuric stone-forming (GHS) rats develop calcium phosphate (apatite) stones when fed a normal 1.2% calcium diet. The addition of 1% hydroxyproline to this diet does not alter the type of stone formed, while rats fed this diet with 3% hydroxyproline form mixed apatite and calcium oxalate stones and those with 5% hydroxyproline added form only calcium oxalate stones. The present study was designed to determine the localization of stone formation and if this solid phase resulted in pathologic changes to the kidneys.
GHS rats were fed 15 g of the standard diet or the diet supplemented with 1%, 3%, or 5% hydroxyproline for 18 weeks. A separate group of Sprague-Dawley rats (the parental strain of the GHS rats), fed the standard diet for a similar duration, served as an additional control. At 18 weeks, all kidneys were perfusion-fixed for structural analysis, detection of crystal deposits using the Yasue silver substitution method, and osteopontin immunostaining.
There were no crystal deposits found in the kidneys of Sprague-Dawley rats. Crystal deposits were found in the kidneys of all GHS rats and this Yasue-stained material was detected only in the urinary space. No crystal deposits were noted within the cortical or medullary segments of the nephron and there was no evidence for tubular damage in any group. The only pathologic changes occurred in 3% and 5% hydroxyproline groups with the 5% group showing the most severe changes. In these rats, which form only calcium oxalate stones, focal sites along the urothelial lining of the papilla and fornix of the urinary space demonstrated a proliferative response characterized by increased density of urothelial cells that surrounded the crystal deposits. At the fornix, some crystals were lodged within the interstitium, deep to the proliferative urothelium. There was increased osteopontin immunostaining in the proliferating urothelium.
Thus in the GHS rat, the initial stone formation occurred solely in the urinary space. Tubular damage was not observed with either apatite or calcium oxalate stones. The apatite stones do not appear to cause any pathological change while those rats forming calcium oxalate stones have a proliferative response of the urothelium, with increased osteopontin immunostaining, around the crystal deposits in the fornix.
A variety of dietary and metabolic factors may contribute or cause stone formation in idiopathic calcium oxalate nephrolithiasis. Dietary factors include a high intake of animal proteins, oxalate and sodium, and a low intake of fluids and potassium-containing citrus products. Some of the metabolic causes of stones are hypercalciuria, hypocitraturia, gouty diathesis, hyperoxaluria, and hyperuricosuria. Dietary modification, to be applied in all patients with stones includes a high fluid intake, restriction of oxalate and sodium, and balanced diet with animal proteins complemented by adequate intake of fruits and vegetables. When dietary modification is ineffective in controlling stone formation or in the presence of severe metabolic derangements, a pharmacologic intervention may be necessary. In a simple approach, thiazide or indapamide with potassium citrate is recommended for patients with hypercalciuria, and potassium citrate alone for the remaining normocalciuric subjects.
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.
We quantified the burden of urolithiasis in the United States by identifying trends in the use of health care resources and estimating the economic impact of the disease.
The analytical methods used to generate these results have been described previously.
The rate of national inpatient hospitalizations for a diagnosis of urolithiasis decreased by 15% and hospital length of stay decreased from 2.6 to 2.2 days between 1994 and 2000. Rates of hospitalization were 2.5 to 3-fold higher for Medicare beneficiaries with little change between 1992 and 1998. Almost 2 million outpatient visits for a primary diagnosis of urolithiasis were recorded in 2000. Hospital outpatient visits increased by 40% between 1994 and 2000 and physician office visits increased by 43% between 1992 and 2000. In the Medicare population hospital outpatient and office visits increased by 29% and 41%, respectively, between 1992 and 1998. The distribution of surgical procedures remained relatively stable through the 1990s. Shock wave lithotripsy was the most commonly performed procedure, followed closely by ureteroscopy. Overall the total estimated annual expenditure for individuals with claims for a diagnosis of urolithiasis was almost $2.1 billion in 2000, representing a 50% increase since 1994.
The cost of urolithiasis is estimated at almost $2 billion annually and it appears to be increasing with time despite a shift in inpatient to outpatient treatment and the emergence of minimally invasive treatment modalities, perhaps because the prevalence of stone disease is increasing.