Pathophysiology of kidney stones and strategies for treatment.
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Calcium Oxalate↗
Biomedical subjects
F L Coe
Publications and source records attributed to F L Coe.
Chlorthalidone promotes mineral retention in patients with idiopathic hypercalciuria.
In seven patients with severe idiopathic hypercalciuria and recurrent calcium oxalate nephrolithiasis, we have determined the effects on mineral balance of chronic treatment with chlorthalidone or trichlormethiazide, drugs that are widely used to lower urine calcium losses and reduce stone recurrence. Each person excreted above 350 mg of calcium daily while untreated, and was studied twice, before and after three to six months of treatment. Compared to pretreatment, the drugs reduced intestinal calcium absorption; but they reduced urine calcium loss even more, so calcium retention increased. Phosphate retention also increased. Serum levels of calcitriol, parathyroid hormone, calcium, phosphate, and magnesium were unchanged. At least in patients of this type, chlorthalidone and trichlormethiazide seem ideal treatments, that lower urine calcium yet increase calcium and phosphate retention. Whether patients with less severe hypercalciuria respond this way is unknown.
Adult↗
Crystal adsorption and growth slowing by nephrocalcin, albumin, and Tamm-Horsfall protein.
Urine inhibition of calcium oxalate monohydrate (COM) crystal growth (CG) seems due to a glycoprotein that contains gamma-carboxyglutamic acid and has been named nephrocalcin (NC); however, Tamm-Horsfall protein (THP) and albumin resemble NC and make its measurement and role uncertain. NC in urine is aggregated to molecular mass 64 kDa and higher, similar to albumin (64 kDa) and THP (87 kDa). Albumin and THP are calcium binding, albumin adsorbs to COM crystals, and THP has been described as an inhibitor of COM growth. Antisera to NC have cross-reacted with THP even though the NC was isolated from cultured renal cells. Here we have compared highly purified NC, THP, and albumin adsorption with COM crystals and CG inhibition; also we compared their patterns of cross-reactivities with a new antiserum against NC and a monoclonal antibody to THP. NC adsorbs to COM crystals, THP does not. Albumin and THP do not inhibit CG. Cross-reactivity of albumin and THP to the antiserum is slight by direct enzyme-linked immunosorbent assay and nonexistent by competitive ELISA; reaction of NC to the anti-THP monoclonal antibody is absent.
Adsorption↗
Nephrolithiasis in pregnancy.
Despite anatomic and physiologic changes that predispose to stone formation, nephrolithiasis in pregnancy remains an uncommon occurrence. Stones occur more frequently in multiparas, during the later stages of gestation, and without a difference in laterality. Correct diagnosis can be confusing. Ultrasound has become a primary diagnostic tool and limited excretory urograms are only recommended for complicated cases. Conservative management can result in spontaneous passage of most stones. When necessary, cystoscopy or surgery can be done safely. Preexisting stone disease is associated with an increased incidence of urinary tract infections in pregnancy. Renal colic often precipitates premature labor. Most drugs used to treat stone disease are contraindicated in gestation. Increased quantities of known inhibitors of stone formation are present in gestation and may explain why the incidence of stones is not increased in this hypercalciuric state.
Colic↗
Nephrolithiasis and gestation.
Although both anatomical and physiological changes in pregnancy may predispose to kidney stone formation, it still remains an uncommon occurrence. Correct diagnosis is often difficult. Ultrasound has become the primary diagnostic tool, and a limited study excretory urogram is only necessary for complicated cases. Nephrolithiasis during pregnancy occurs more frequently during the later stages of gestation in multiparas, and without a difference in laterality. Conservative management with bed rest, hydration and analgesia can result in spontaneous passage of the majority of stones in gravidas. Past experience indicates that cystoscopy and/or surgery can usually be done safely when absolutely necessary. Pre-existing stone disease can increase the incidence of maternal urinary tract infections by 10-20%. The most common obstetric complication of stones during gestation is the precipitation of premature labour by renal colic. Unfortunately, most drugs used to treat stone disease are contraindicated in gestation. Experimental evidence suggests that known inhibitors of stone formation are present in gestation, and may help to explain why the incidence of stones is not increased in this particularly hypercalciuric state.
Female↗
Reduced glomerular filtration rate and hypercalciuria in primary struvite nephrolithiasis.
Struvite nephrolithiasis is caused by infection with bacteria that possess the enzyme urease, and convert urea to ammonia that raises urine pH and crystallizes with magnesium and trivalent phosphate ion. Of the 75 of our 1431 stone patients with struvite stones 52 were women. Struvite stones occurred almost exclusively in women; a minority of women and most men had mixed stones of struvite and calcium oxalate. Increased serum creatinine levels and reduced creatinine clearance were common in patients with struvite stones, not in those with mixed stones; both were rare in calcium stone disease. Men and women with mixed struvite, calcium oxalate stones were hypercalciuric, but women with struvite stones were not. Patients with mixed stones usually had initial symptoms of stone passage, and were less likely to need surgery, including nephrectomy, or to form contralateral stones. Patients with struvite stones usually presented with infection or no symptom, not passage. We conclude that struvite stones occur in two forms. The struvite stone is a disease of women, presumably occurring de novo from infection. The mixed stones occur in both sexes, presumably from secondary infection in hypercalciuric patients who begin with calcium-oxalate stone disease.
Blood Pressure↗
Isolation from human calcium oxalate renal stones of nephrocalcin, a glycoprotein inhibitor of calcium oxalate crystal growth. Evidence that nephrocalcin from patients with calcium oxalate nephrolithiasis is deficient in gamma-carboxyglutamic acid.
We have determined that the organic matrix of calcium oxalate kidney stones contains a glycoprotein inhibitor of calcium oxalate crystal growth (nephrocalcin) that resembles nephrocalcin present in the urine of patients with calcium oxalate stones and differs from nephrocalcin from the urine of normal people. Pulverized calcium oxalate renal stones were extracted with 0.05 M EDTA, pH 8.0; nephrocalcin eluted in five peaks using DEAE-cellulose column chromatography, and each peak was further resolved by Sephacryl S-200 column chromatography. Four of the five DEAE peaks corresponded to those usually found in nephrocalcin from urine; the fifth eluted at a lower ionic strength than any found in urine. Amino acid compositions and surface properties of nephrocalcins isolated from kidney stones closely resembled those of nephrocalcins isolated from urine of stone-forming patients: they differed from normal in lacking gamma-carboxyglutamic acid residues, and in forming air-water interfacial films that were less stable than those formed by nephrocalcin from normal urine.
1-Carboxyglutamic Acid↗
Glycoprotein calcium oxalate crystal growth inhibitor in urine.
Urine is normally supersaturated with respect to calcium oxalate. Inhibitors of the growth and aggregation of calcium oxalate crystals are present in urine and probably protect against calcium stone formation. These inhibitors are deficient in stone formers. The major inhibitor of calcium oxalate crystal growth is a non-dialyzable, anionic macromolecule. An acidic glycoprotein has been isolated from urine and human kidney tissue culture medium which inhibits calcium oxalate crystal growth in vitro. This glycoprotein crystallization inhibitor has a molecular weight of 14,000 daltons and contains 2-3 residues of gamma-carboxyglutamic acid. The dissociation constant for the calcium oxalate crystal-inhibitor complex is about 10(-7) M. The glycoprotein isolated from the urine of calcium stone formers has a decreased affinity for crystal surface, and a proportionally weaker inhibitory activity; it also lacks gamma-carboxyglutamic acid.
Calcium Oxalate↗
Is estrogen preferable to surgery for postmenopausal women with primary hyperparathyroidism?
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Estrogens↗
Recurrent renal calculi. Causes and prevention.
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Adolescent↗
Urine citrate and calcium in calcium nephrolithiasis.
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Calcium↗
A urinary calcium-citrate index for the evaluation of nephrolithiasis.
We have performed a multivariate analysis of urine abnormalities in patients with calcium oxalate nephrolithiasis, in which effects of gender were also considered. The characteristic of patients that most clearly sets them apart from normal people is a high level of urine calcium for any given level of urine citrate. Other urine measurements cannot improve upon the separation between patients and normals provided by urine calcium and citrate, and their abnormal relationship to each other. Normal women have higher urine citrate and lower urine calcium than normal men or patients of either sex; normal men differ from stone forming men only moderately. Direct measurements of supersaturation are not helpful in distinguishing between patients and normals, once calcium and citrate have been considered. From our analysis, we have derived a new index for evaluating the significance of urine calcium and citrate levels that seems to offer a better basis for clinical diagnosis than criteria presently in use.
Calcium↗
Immunochemistry of urinary calcium oxalate crystal growth inhibitor (CGI).
Calcium oxalate crystal growth inhibitor (CGI) was isolated from human urine in monomeric form (14,000 daltons). Antibody was elicited and purified to monospecificity by affinity chromatography. Tamm-Horsfall protein was isolated from human urine and an antibody to Tamm-Horsfall protein compared to anti-CGI. The anti-CGI reacted with its antigen on immunodiffusion, by ELISA and by Western Blotting of polyacrylamide gel electrophoresis-separated antigen. Immunofluorescent localization of CGI was found in distal renal tubules. This was precisely the localization of Tamm-Horsfall protein. Isolated Tamm-Horsfall protein was found to bind CGI which could only be partially removed with EDTA. While anti-CGI is suitable to assay CGI in human urine by ELISA techniques, it will also detect CGI that is complexed to THP. While the CGI found in human urine possesses 90% of the urinary macromolecular crystal growth inhibitor activity, THP is without effect on crystal growth, in spite of bound CGI. The balance between free CGI and that bound to Tamm-Horsfall protein may be important in the overall balance of urinary macromolecules that affect calcium oxalate nephrolithiasis.
Calcium Oxalate↗
Effects of medium pH on duodenal and ileal calcium active transport in the rat.
To study the effect of pH on Ca active transport in vitro pH was varied from 7.1 to 7.7, and bidirectional transmural Ca fluxes were measured under short-circuited conditions across duodenum or ileum from rats fed either normal chow (NCD, 1.2% Ca) or low Ca (LCD, 0.002% Ca). Duodenum and ileum from rats fed LCD actively absorbed calcium at medium pH 7.4. Reduction in mucosal and serosal medium bicarbonate from 25 to 10 mM (pH 7.4 to 7.1) decreased duodenal net Ca absorption (Jnet) from 121 +/- 32 to 39 +/- 9 nmol X cm-2 X h-1 (P less than 0.02) and ileal Jnet from 74 +/- 13 to 22 +/- 6 (P less than 0.01). The decline in duodenal and ileal Ca Jnet was due to a decrease in the mucosal-to-serosal flux (Jm----s). Raising medium pH from 7.4 to 7.7 by increasing bicarbonate from 25 to 50 mM did not alter Ca Jm----s, serosal-to-mucosal flux (Js----m), or Jnet X Ca fluxes across ileum from rats fed NCD demonstrated net secretion. LCD ileal Jm----s was unaltered when pH was reduced from 7.4 to 7.1 by increasing the PCO2 content of the buffer from 30 to 81 mmHg while maintaining bicarbonate at 24 mM. The results indicate that in vitro conditions that simulate metabolic acidosis (low bicarbonate and pH, normal PCO2) inhibit 1,25D-mediate calcium Jm----s, whereas conditions that simulate respiratory acidosis have no effect on Ca fluxes. The present studies suggest that decreases in calcium Jm----s is by a primary alteration in transport of other ions rather than direct effect on Ca transport.
Animals↗
Effect of atrial natriuretic factor in rat pregnancy.
Protocols were designed to 1) identify atrial natriuretic factor (ANF) bioactivity in pregnant rats, 2) compare ANF activity in atria from gravid and virgin Sprague-Dawley animals, and 3) assess renal and vascular responsiveness to ANF during gestation. Similar quantities of ANF were extracted from atria of term gravid and age-matched controls (assayed as the natriuretic response in awake virgins). We then purified by high-performance liquid chromatography a peptide identical to the synthetic 23 amino acid atriopeptin II (AP II). With equimolar injections of ANF, gravid rats had a blunted natriuretic response (P less than 0.05). However, when dose was based on estimated extracellular volume, awake virgin and pregnant animals displayed similar highly significant dose-response curves to infused AP II (R's 0.8). When hydropenic rats were assayed, both gravid and virgins required 10 times more ANF to initiate a diuresis; dose-response curves again being similar and highly significant. Decrements in blood pressure were also similar in pregnant and nongravid animals. Thus, despite an increased intravascular volume of 70% during gestation, cardiac content of ANF and the renal and vascular responsiveness to this peptide are similar to those in virgin rats, suggesting resetting of ANF-volume relationships during pregnancy.
Animals↗
Ion microprobe determination of bone surface elements: effects of reduced medium pH.
When neonatal mouse calvariae are cultured in a medium having a low pH they release calcium (Ca) while buffering protons (H). However, for 1 neq Ca released, 16-21 neq H enter the calvariae, arguing strongly against simple dissolution of bone mineral as the mechanism of H buffering. To determine if H for sodium (Na) exchange could explain the lack of stoichiometry between H and Ca, we cultured calvariae for 3 h in control (pH = 7.40 +/- 0.01) or reduced-pH (pH = 7.21 +/- 0.01) medium and then examined the surface Na, K, and Ca using a high-resolution scanning ion microprobe. The calvarial surface was rich in Na and K relative to Ca (Na/Ca, 52 +/- 17; K/Ca, 61 +/- 17; all values are the ratios of counts per second of detected secondary ions, means +/- SE). Compared with the surface the calvarial cross section contained far less Na and K relative to Ca (Na/Ca, 2 +/- 1; K/Ca, 1 +/- 1; both P less than 0.01 vs. surface). Compared with the control surface, culture in a reduced-pH medium reduced the surface Na and K relative to Ca (Na/Ca, 5 +/- 1; K/Ca, 7 +/- 1; both P less than 0.025 vs. surface) to values still greater than the cross section (P less than 0.05 for both). Neonatal mouse calvariae have a surface that is rich in Na and K relative to Ca. Reduced medium pH depletes surface Na and K of cultured calvariae with respect to Ca.
Acidosis↗
Mechanism of chronic hypercalciuria with furosemide: increased calcium absorption.
Furosemide produces chronic hypercalciuria. The source of the additional urinary calcium is not known but must be either bone mineral or calcium absorbed by the intestine. Without bone calcium dissolution or increased absorption the filtered load of calcium would fall and urinary calcium excretion would return to pretreatment levels. To determine whether furosemide alters intestinal calcium absorption, we fed furosemide (75 mg . kg body-1 wt . day-1) to 11 rats eating 15 g/day of a 0.60% calcium diet. Compared with 11 control rats, furosemide increased urine calcium (15.6 +/- 0.8 mg/5 days vs. 4.1 +/- 0.3, P less than 0.001). Fecal calcium excretion fell (194 +/- 7 mg/5 days vs. 223 +/- 12, P less than 0.05), indicating an increase in intestinal calcium absorption sufficient to sustain the hypercalciuria. The increase in absorption occurred without an increase in the level of serum 1,25-dihydroxycholecalciferol (180 +/- 20 pg/ml vs. 220 +/- 16, furosemide vs. control, respectively, P = NS). To determine whether the intestinal effect of furosemide persists after the initial sodium diuresis abates, we analyzed only the last 3 days of balance. Again, rats fed furosemide had increased urine excretion and intestinal absorption of calcium, so that net calcium balance was not different from that of controls. Twelve additional rats were fed a 0.02% calcium diet to which 35 mg . kg body wt-1 . day-1 of furosemide was added. Compared with eleven controls, urine calcium increased and fecal calcium excretion again fell, but balance was not different. Chronic administration of furosemide increases intestinal calcium absorption enough to permit urine calcium excretion to remain elevated without the necessity for bone dissolution.
Animals↗
Ca and P regulation of 1,25(OH)2D3 synthesis by vitamin D-replete rat tubules during acidosis.
Elevated blood ionized Ca concentration appears to be necessary for suppression by chronic metabolic acidosis (CMA) of serum 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels in vitamin D-replete rats eating a low-Ca diet (LCD). The present study asks whether in vitro 1,25(OH)2D3 production by proximal tubule cells from such rats is suppressed and whether suppression can be reversed in vitro by an altered ionic milieu. Young rats were fed LCD and given 1.5% NH4Cl in their drinking water for 10 days to produce CMA. Compared with controls, CMA rats had low serum 1,25(OH)2D3 levels. Tubules prepared from CMA rats produced 1,25(OH)2D3 at a low rate compared with control; variation of medium Ca and pH from 7.2 to 7.4 did not increase 1,25(OH)2D3 production. Reducing medium phosphorus concentration ([P]) increased 1,25(OH)2D3 production by tubules from control but not CMA rats. Increasing medium [P] increased 1,25(OH)2D3 production by tubules from CMA but not control rats. CMA appears to alter proximal tubule cell response to medium [P] so that 1,25(OH)2D3 production rises when medium [P] is increased but not when it is reduced. Medium pH and Ca concentration do not appear to be important regulators of renal 1,25(OH)2D3 production in short-term incubations.
Acidosis↗