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Proximal tubule (PT) transports most of the renal Ca2+, which was usually described as paracellular (passive). We found a regulated Ca2+ entry pathway in PT cells via the apical transient receptor potential canonical 3 (TRPC3) channel, which initiates transcellular Ca2+ transport. Although TRPC3 knockout (−/−) mice were mildly hypercalciuric and displayed luminal calcium phosphate (CaP) crystals at Loop of Henle (LOH), no CaP + calcium oxalate (CaOx) mixed urine crystals were spotted, which are mostly found in calcium nephrolithiasis (CaNL). Thus, we used oral calcium gluconate (CaG; 2%) to raise the PT luminal [Ca2+]o further in TRPC3−/− mice for developing such mixed stones to understand the mechanistic role of PT-Ca2+ signaling in CaNL. Expectedly, CaG-treated mice urine samples presented with numerous mixed crystals with remains of PT cells, which were pronounced in TRPC3−/− mice, indicating PT cell damage. Notably, PT cells from CaG-treated groups switched their mode of Ca2+ entry from receptor-operated to store-operated pathway with a sustained rise in intracellular [Ca2+] ([Ca2+]i), indicating the stagnation in PT Ca2+ transport. Moreover, those PT cells from CaG-treated groups demonstrated an upregulation of calcification, inflammation, fibrotic, oxidative stress, and apoptotic genes; effects of which were more robust in TRPC3 ablated condition. Furthermore, kidneys from CaG-treated groups exhibited fibrosis, tubular injury and calcifications with significant reactive oxygen species generation in the urine, thus, indicating in vivo CaNL. Taken together, excess PT luminal Ca2+ due to escalation of hypercalciuria in TRPC3 ablated mice induced surplus CaP crystal formation and caused stagnation of PT [Ca2+]i, invoking PT cell injury, hence mixed stone formation.

Proximal tubular (PT) acidosis, which alkalinizes the urinary filtrate, together with Ca2+ supersaturation in PT can induce luminal calcium phosphate (CaP) crystal formation. While such CaP crystals are known to act as a nidus for CaP/calcium oxalate (CaOx) mixed stone formation, the regulation of PT luminal Ca2+ concentration ([Ca2+]) under elevated pH and/or high [Ca2+] conditions are unknown. Since we found that transient receptor potential canonical 3 (TRPC3) knockout (KO, /-) mice could produce mild hypercalciuria with CaP urine crystals, we alkalinized the tubular pH in TRPC3-/- mice by oral acetazolamide (0.08%) to develop mixed urinary crystals akin to clinical signs of calcium nephrolithiasis (CaNL). Our ratiometric (λ340/380) intracellular [Ca2+] measurements reveal that such alkalization not only upsurges Ca2+ influx into PT cells, but the mode of Ca2+ entry switches from receptor-operated to store-operated pathway. Electrophysiological experiments show enhanced bicarbonate related current activity in treated PT cells which may determine the stone-forming phenotypes (CaP or CaP/CaOx). Moreover, such alkalization promotes reactive oxygen species generation, and upregulation of calcification, inflammation, fibrosis, and apoptosis in PT cells, which were exacerbated in absence of TRPC3. Altogether, the pH-induced alteration of the Ca2+ signaling signature in PT cells from TRPC3 ablated mice exacerbated the pathophysiology of mixed urinary stone formation, which may aid in uncovering the downstream mechanism of CaNL.

Calcium-based renal calculi demonstrated significant heterogeneity in the structure, density, mineral composition, and material hardness not elucidated by routine clinical testing. Mineral density distributions within calcium oxalate stones revealed differential areas of low (590±80 mg/cc), medium (840±140 mg/cc), and high (1100±200 mg/cc) densities. Apatite stones also contained regions of low (700±200 mg/cc), medium (1100±200 mg/cc), and high (1400±140 mg/cc) densities within layers extending from single or multiple nucleation sites. Despite having lower average mineral density, calcium oxalate (CaOx) stones demonstrated higher material hardness compared to apatite stones, suggesting other chemical components might be involved in determining stone hardness properties. Carbon concentrated sites were identified between morphologic layers in CaOx stones and in stratified layers of apatite stones. Elemental analyses revealed numerous additional trace elements in both stone types. Despite the widespread assumption that stone mineral density is an indicator of susceptibility to lithotripsy, calcium stone mineral density estimates do not directly correlate with actual ex vivo stone hardness. Underlying stone heterogeneity in both structure and mineral density could explain why historical approaches have failed in accurately predicting response of stones to lithotripsy.

Citrate is critical for acid-base homeostasis and to prevent calcium nephrolithiasis. Both metabolic acidosis and hypokalemia decrease citrate excretion and increase expression of Na+-dicarboxylate cotransporter 1 (NaDC1; SLC13A2), the primary protein involved in citrate reabsorption. However, the mechanisms transducing extracellular signals and mediating these responses are incompletely understood. The purpose of the present study was to determine the role of the Na+-coupled electrogenic bicarbonate cotransporter (NBCe1) A variant (NBCe1-A) in citrate metabolism under basal conditions and in response to acid loading and hypokalemia. NBCe1-A deletion increased citrate excretion and decreased NaDC1 expression in the proximal convoluted tubules (PCT) and proximal straight tubules (PST) in the medullary ray (PST-MR) but not in the PST in the outer medulla (PST-OM). Acid loading wild-type (WT) mice decreased citrate excretion. NaDC1 expression increased only in the PCT and PST-MR and not in the PST-MR. In NBCe1-A knockout (KO) mice, the acid loading change in citrate excretion was unaffected, changes in PCT NaDC1 expression were blocked, and there was an adaptive increase in PST-MR. Hypokalemia in WT mice decreased citrate excretion; NaDC1 expression increased only in the PCT and PST-MR. NBCe1-A KO blocked both the citrate and NaDC1 changes. We conclude that 1) adaptive changes in NaDC1 expression in response to metabolic acidosis and hypokalemia occur specifically in the PCT and PST-MR, i.e., in cortical proximal tubule segments; 2) NBCe1-A is necessary for normal basal, metabolic acidosis and hypokalemia-stimulated citrate metabolism and does so by regulating NaDC1 expression in cortical proximal tubule segments; and 3) adaptive increases in PST-OM NaDC1 expression occur in NBCe1-A KO mice in response to acid loading that do not occur in WT mice.

BACKGROUND Vitamin D deficiency is a worldwide health concern. It prevails in epidemic proportions all over the Indian subcontinent with a prevalence of 70%-100% in the general population. Vitamin D is important in maintaining calcium and phosphorus homeostasis, but its role in kidney stone disease and its effect on stone formation are still not clear. AIMS AND OBJECTIVES In the present study, association between levels of Vitamin D and nephrolithiasis were studied. MATERIALS AND METHODS 50 patients with nephrolithiasis were selected and were compared with 50 controls matched in terms of age and sex. 25-OH Vitamin D levels were measured in both groups. RESULTS 25-OH Vitamin D levels were low in patients with nephrolithiasis when compared to controls.

Calcium has many important roles in physiology and pathology, such as in ensuring bone integrity, in maintaining haemostasis, and as a cofactor for metabolic enzymes. The kidney is the major organ ...

Hypercalciuria is a major risk factor for nephrolithiasis. We previously reported that Uromodulin (UMOD) protects against nephrolithiasis by upregulating the renal calcium channel TRPV5. This channel is crucial for calcium reabsorption in the distal convoluted tubule (DCT). Recently, mutations in the gene encoding Mucin-1 (MUC1) were found to cause autosomal dominant tubulointerstitial kidney disease, the same disease caused by UMOD mutations. Because of the similarities between UMOD and MUC1 regarding associated disease phenotype, protein structure, and function as a cellular barrier, we examined whether urinary MUC1 also enhances TRPV5 channel activity and protects against nephrolithiasis. We established a semiquantitative assay for detecting MUC1 in human urine and found that, compared with controls (n=12), patients (n=12) with hypercalciuric nephrolithiasis had significantly decreased levels of urinary MUC1. Immunofluorescence showed MUC1 in the thick ascending limb, DCT, and collecting duct. Applying whole–cell patch-clamp recording of HEK cells, we found that wild-type but not disease mutant MUC1 increased TRPV5 activity by impairing dynamin-2– and caveolin-1–mediated endocytosis of TRPV5. Coimmunoprecipitation confirmed a physical interaction between TRPV5 and MUC1. However, MUC1 did not increase the activity of N-glycan–deficient TRPV5. MUC1 is characterized by variable number tandem repeats (VNTRs) that bind the lectin galectin-3; galectin-3 siRNA but not galectin-1 siRNA prevented MUC1-induced upregulation of TRPV5 activity. Additionally, MUC1 lacking VNTRs did not increase TRPV5 activity. Our results suggest that MUC1 forms a lattice with the N-glycan of TRPV5 via galectin-3, which impairs TRPV5 endocytosis and increases urinary calcium reabsorption.

BACKGROUND: Recently published guidelines on the medical management of renal stone disease did not address relevant topics in the field of idiopathic calcium nephrolithiasis which are important also for clinical research. DESIGN: A steering committee identified 27 questions which were proposed to a faculty of 44 experts in nephrolithiasis and allied fields. A systematic review of the literature was conducted and 5216 potentially relevant articles were selected; from these 407 articles were deemed to provide useful scientific information. The Faculty divided into working groups analysed the relevant literature. Preliminary statements developed by each group were exhaustively discussed in plenary sessions and approved. RESULTS: Statements were developed to inform clinicians on the identification of secondary forms of calcium nephrolithiasis and systemic complications; on the definition of idiopathic calcium nephrolithiasis; on the use of urinary tests of crystallization and of surgical observations during stone treatment in the management of these patients; on the identification of patients warranting preventive measures; on the role of fluid and nutritional measures and of drugs to prevent recurrent episodes of stones; and finally on the cooperation between the urologist and nephrologist in the renal stone patients. CONCLUSIONS: This document has addressed idiopathic calcium nephrolithiasis from the perspective of a disease that can associate with systemic disorders emphasizing the interplay needed between urologists and nephrologists. It is complementary to the American Urological Association and European Association of Urology guidelines. Future areas for research are identified.

Regulated dicarboxylate transport is critical for acid-base homeostasis, prevention of calcium nephrolithiasis, regulation of collecting duct sodium chloride transport, and the regulation of blood pressure. Although luminal dicarboxylate reabsorption via NaDC1 (SLC13A2) is believed to be the primary mechanism regulating renal dicarboxylate transport, the specific localization of NaDC1 in the human kidney is currently unknown. This study’s purpose was to determine NaDC1's expression in normal and neoplastic human kidneys. Immunoblot analysis demonstrated NaDC1 expression with an apparent molecular weight of ~61 kDa. Immunohistochemistry showed apical NaDC1 immunolabel in the proximal tubule of normal human kidney tissue; well-preserved proximal tubule brush border was clearly labeled. Apical NaDC1 expression was evident throughout the entire proximal tubule, including the initial proximal convoluted tubule, as identified by origination from the glomerular tuft, and extending through the terminal of the proximal tubule, the proximal straight tubule in the outer medulla. We confirmed proximal tubule localization by colocalization with the proximal tubule specific protein, NBCe1. NaDC1 immunolabel was not detected other than in the proximal tubule. In addition, NaDC1 immunolabel was not detected in tumors of presumed proximal tubule origin, clear cell and papillary renal cell carcinoma, or in tumors of nonproximal tubule origin, oncocytoma and chromophobe carcinoma. In summary, 1) in the human kidney, apical NaDC1 immunolabel is present throughout the entire proximal tubule, and is not detectable in other renal cells; and 2) NaDC1 immunolabel is not present in renal tumors. These studies provide important information regarding NaDC1’s role in human dicarboxylate metabolism.

Background Our purpose is to show the effect of alendronate on patients with recurrent calcium lithiasis and loss of bone mass, and to observe their progress with analytical and densitometric markers.

Idiopathic calcium nephrolithiasis is a multifactorial disease with a pathogenesis that involves a complex interaction of environmental and individual factors. This review discusses what is known, about monogenic renal calcium stone-related disorders, provides an update on genetic research in calcium nephrolithlasis and such intermediate phenotypes as idiopathic hypercalciuria, discusses the problems that these conditions pose to clinicians and geneticists interested in their pathogenesis, and proposes some method tools potentially useful in this research frame of reference.

Growing evidence has assigned to oxalate a pivotal role in calcium nephrolithiasis pathophysiology. A better understanding of the mechanisms behind intestinal absorption and renal excretion has led to the identification of new treatments. Among these, diet and probiotics appear promising in terms of safety and rationale. However, the discrepancy between in vitro and in vivo results requires further studies to identify the right patient target, the correct dosage, and the real modification of natural and clinical history of nephrolithiasis.

IntroductionThe genetics underlying the idiopath-ic hypercalciuria leading to calcium-containing renal stones remains elus-ive. The discovery of rare monogenic tubulopathies, often leading to hype-rcalciuria, has increased our underst-anding of tubular physiology and pat-ho-physiology. However, insights int-o idiopathic calcium stone formation have not been gained from these dis-orders. The aim of this study is to ex-amine CYP24A1 mutations in cohorts of patients with calcium nephrolithi-asis.Materials and MethodsWe examined two cohorts of stone-forming patients for mutations in CYP24A1, which encodes the vitamin D24-hydroxylase enzyme. The first cohort had a biochemical phenotype of suppressed parathyroid hormone and high normal serum calcium, whilst the second cohort had a hypercalciuria phenotype. We did not identify bi-allelic sequence variants in CYP24A1 in our cohorts.ResultsIn cohort 1, we identified 9 known s-equence variants. In cohort 2 we ide-ntified 7 known sequence variants.ConclusionCYP24A1 mutations remain a rare cause of calcium nephrolithiasis and hypercalciuria.

Background Because the causes of stones are uncertain, interventions to prevent recurrence have an insecure foundation. Progress depends on careful evaluation of stone formers. Methods A descriptive retrospective database study of 1983 men and 816 women from the Southampton stones clinic from 1990 to March 2007. Anonymized data from the first attendance were analysed using non-parametric statistical tests. Results Sex ratio (2.43:1), age (median 49 y, 2.5th-97.5th percentiles, 23-77 y men, 20-79 y women), recurrent stone formers (30%) and type of stone were similar to other centres. Women more often had a positive family history (24% versus 19% men), previous urinary infection (31% versus 5%) and structural urinary tract abnormality (14% versus 7%); more men had gout (5% versus 1%) and bladder outlet obstruction (3% versus 4/GFR) < 0.70 mmol/L); 6% men and 1.6% women also had low plasma phosphate. Many variables correlated significantly but often weakly with age. Creatinine clearance, pH and (men) TmPO4/GFR decreased from 50 y, urine creatinine, calcium and citrate from 60 y. Conclusions Risk factors for stones differ between men and women, change with ageing and in some may have a genetic basis. The role of phosphaturia merits further exploration.

BACKGROUND: CaSR gene is a candidate for calcium nephrolithiasis. Single-nucleotide polymorphisms (SNPs) encompassing its regulatory region were associated with calcium nephrolithiasis. AIMS: We tested SNPs in the CaSR gene regulatory region associated with calcium nephrolithiasis and their effects in kidney. SUBJECTS AND METHODS: One hundred sixty-seven idiopathic calcium stone formers and 214 healthy controls were genotyped for four CaSR gene SNPs identified by bioinformatics analysis as modifying transcription factor binding sites. Strontium excretion after an oral load was tested in 55 stone formers. Transcriptional activity induced by variant alleles at CaSR gene promoters was compared by luciferase reporter gene assay in HEK-293 and HKC-8 cells. CaSR and claudin-14 mRNA levels were measured by real-time PCR in 107 normal kidney medulla samples and compared in patients with different CaSR genotype. RESULTS: Only rs6776158 (A>G), located in the promoter 1, was associated with nephrolithiasis. Its minor G allele was more frequent in stone formers than controls (37.8% vs 26.4%, P = .001). A reduced strontium excretion was observed in GG homozygous stone formers. Luciferase fluorescent activity was lower in cells transfected with the promoter 1 including G allele at rs6776158 than cells transfected with the A allele. CaSR mRNA levels were lower in kidney medulla samples from homozygous carriers for the G allele at rs6776158 than carriers for the A allele. Claudin-14 mRNA levels were also lower in GG homozygous subjects. CONCLUSIONS: Minor allele at rs6776158 may predispose to calcium stones by decreasing transcriptional activity of the CaSR gene promoter 1 and CaSR expression in kidney tubules.

Nephrolithiasis is a common disorder, with a rising prevalence in the general population. Its pathogenesis is still unclear, but a role for genetics has long been recognized, especially in cases of the more common calcium nephrolithiasis. Although relatively rare, monogenic causes of hypercalciuria and nephrolithiasis do exist and their timely recognition is important from a prognostic and therapeutic viewpoint. This article reviews the clinical and laboratory findings characterizing inherited causes of nephrolithiasis with a view to helping clinicians to recognize and manage these rare conditions.

Sakhaee et al in this issue have investigated whether the risk of the common calcium nephrolithiasis is associated with the metabolic syndrome (MS). This question is interesting since it deals with a more general problem on whether calcium nephrolithiasis is a ‘systemic disorder’ and entails a cardiovascular risk..

尿路結石形成と食事との関係を明らかにする目的で尿路結石患者の食事調査を行った.36例(男24例, 女12例)のカルシウム結石患者の栄養摂取量を調べ, 日本人の栄養所要量と比べ, つぎのごとき結果をえた.結石患者は男女別でも, また全体でも栄養所要量に比べて, 総蛋白質, 動物性蛋白質, 動物蛋白比すべて有意に高かった.食塩摂取量は男および全体で結石患者に有意に高く, 女でもその傾向がみられた.カルシウムおよび炭水化物は男および全体で結石患者の摂取量が所要量より有意に低く, また女でもその傾向がみられた, To clarify the relationship between renal stone formation and the diet, the consumption of various nutrients of calcium stone formers was investigated. The study included 24 male and 12 female stone formers, between 20 and 78 years old (mean 42 years). The daily consumption of nutrients was compared to the daily nutritive requirement for the Japanese. The amounts of total and animal protein ingested by all the patients were significantly larger than the daily nutritive requirements. The animal protein ratio was also significantly higher. Concerning the total protein, animal protein and animal protein ratio, male and female patients showed similar results. Salt consumption was significantly larger for all the patients and the male patients than the daily nutritive requirement for the Japanese. Female stone formers also showed this tendency. Consumption of calcium and carbohydrate by all the patients and the male patients was significantly smaller than the daily nutritive requirement. This tendency was observed for the female patients.

To the Editor: In their interesting review on Randall's plaque, Evan et al.1 go through a number of rodent models where hypercalciuria with/without stones or nephrocalcinosis have been observed, but do not form Randall's plaque-like structures. The list is incomplete, as they themselves pointed out. In our opinion, the Nuf rat model should be added:2 this rat has an activating mutation of the calcium-sensing receptor, which leads to calcifications at various renal levels and – of particular interest – in papillary ducts in up to 63% of heterozygous animals. Whether Randall's plaques exist in such a model is not known and cannot be ascertained from published pictures. Calcification interestingly occurs with no associated hypercalciuria. This model is attractive in relation to human idiopathic calcium stone disease (idiopathic calcium nephrolithiasis). Quite recently, Soldati et al.3 showed that an activating polymorphism of the calcium-sensing receptor is associated with hypercalciuria in idiopathic calcium nephrolithiasis, and Terranegra et al.4 have reported that calcium-sensing receptor SNPs form a haplotype block associated with idiopathic calcium nephrolithiasis and increase the risk of stones by as much as 3.36 times. Looking for the occurrence of Randall's plaques in the Nuf rat might therefore be highly rewarding.

Idiopathic calcium nephrolithiasis and hypercalciuria are multifactorial disease conditions, the pathogenesis of which involves the interaction of environmental and individual factors. Data support a strong role of genes in the pathogenesis of these two conditions. Findings obtained in monogenic disorders characterized by renal calcium stones, and/or hypercalciuria, and/or nephrocalcinosis have proposed a number of genes as candidate genes in the pathogenesis of the common idiopathic calcium nephrolithiasis and hypercalciuria. The physiological role of these genes, and findings in monogenic disorders and idiopathic, multifactorial disorders will be presented.

In two earlier publications we reported excellent therapeutic results in patients with recurrent calcium nephrolithiasis, using oral or intravenous i.v. sodium thiosulfate on the one hand, and on treatment of tumorus-soft periarticular tissues calcifications on the other. Thus, we considered useful to measure endogenous thiosulfaturia, using a specific HPLC method, in 25 healthy adult males and 25 patients with recurrent calcium nephrolithiasis. Healthy adult males excreted between 11 and 16 μ M/24 hour of endogenous thiosulfate, while patients with recurrent calcium nephrolithiasis excreted significantly lower amounts of 6 and 10 μ M/24 hour, except one patient, who did not excrete endogenous thiosulfate, reflecting probably a genetic abnormality. Thiosulfate is a unique agent for treatment of recurrent calcium nephrolithiasis as well as some other abnormal calcium depositions. Two doses of 5 mM sodium thiosulfate daily are therapeutically sufficient. © 2004 Kluwer Academic Publishers.

Nephrolithiasis seems to be the result of crystal formation, aggregation and retention in the kidney during crystalluria. These processes have to occur within the short urinary transit time through the kidney being in the order of few minutes. Recently much work was done on rather qualitative aspects of nephrolithiasis like genetics, metabolism and morphology. In this review we try to provide some quantitative information on urinary supersaturation with respect to stone minerals, especially Ca oxalate (CaOx), on the formation and aggregation of CaOx crystals and on crystal retention in the kidney. The paper is centered on idiopathic Ca nephrolithiasis being the most frequent stone disease with only partially known pathogenesis. New aspects of the role of urinary macromolecules in stone formation and of the mechanism of crystal aggregation are provided.

Many studies indicate that up-regulated production of 1,25(OH)2-vitamin D3 (calcitriol) with increased intestinal absorption of calcium is the primary event causing idiopathic hypercalciuria. Thus, a low calcium diet appears to be a straightforward strategy in calcium stone formers with hypercalciuria (HCSF). However, the efficacy of such a regimen has never been established, and lowering calcium intake from 1000 to 400 mg/day further enhances calcitriol production. On a diet chronically restricted in calcium, many stone formers increase their intake of animal flesh protein. The latter is known to increase renal mass, and calcitriol levels indeed are positively correlated with renal mass in animals as well as in HCSF. Thus, low calcium and high animal flesh protein consumption are independent stimuli for further up-regulation of calcitriol production. The rise in calcitriol suppresses parathyroid hormone synthesis thereby diminishing renal tubular calcium reabsorption, and increasing urinary calcium losses. Since calcitriol up-regulation also increases bone resorption, the combination of low calcium and high protein intake is particularly likely to induce negative calcium balance and thus osteopenia. Finally, low calcium intake carries the risk of insufficient intestinal binding of oxalate with subsequent increases in intestinal absorption and urinary excretion of oxalate. Indeed, most recent studies suggest that high amounts of calcium, when ingested simultaneously with oxalate-containing meals, are able to prevent hyperoxaluria during severe oral oxalate loading.

To clarify the relationship between renal stone formation and the diet, the consumption of various nutrients of calcium stone formers was investigated. The study included 24 male and 12 female stone formers, between 20 and 78 years old (mean 42 years). The daily consumption of nutrients was compared to the daily nutritive requirement for the Japanese. The amounts of total and animal protein ingested by all the patients were significantly larger than the daily nutritive requirements. The animal protein ratio was also significantly higher. Concerning the total protein, animal protein and animal protein ratio, male and female patients showed similar results. Salt consumption was significantly larger for all the patients and the male patients than the daily nutritive requirement for the Japanese. Female stone formers also showed this tendency. Consumption of calcium and carbohydrate by all the patients and the male patients was significantly smaller than the daily nutritive requirement. This tendency was observed for the female patients.

Partial biochemical and physicochemical characterization of organic macromolecules in urine from patients with renal stones and control subjects. From the urine of patients with calcium nephrolithiasis, and of control subjects, we isolated organic substances according to molecular size and tested them for effects on calcium oxalate precipitation. Nine subgroup materials of varying sizes were prepared by ultrafiltration and Sephadex G-200 column chromatography from 10 stone-formers, as well as from 10 control subjects. Uromucoid was found in large materials of both groups, whereas glycosaminoglycans were detected in large- and medium-sized materials of both groups. The small materials were devoid of uromucoid and glycosaminoglycans, but contained protein and uronic acid, a finding suggesting that they may be glycoproteins. The daily excretion of the uromucoid-rich material was greater, but that of the small glycoproteins was lower in stone-formers than in control subjects. The largest-sized material from stone-formers was devoid of any activity on calcium oxalate precipitation. All of the remaining materials (at a concentration of 5 mg/dl) exerted inhibition on calcium oxalate precipitation. The inhibition rose progressively with the decreasing size of organic materials. The calculated total inhibitor activity for the stone-forming group was 36% lower than that obtained in the control group. Caracterisation partielle biochimique et physico-chimique de macromolecules organiques dans l'urine de malades atteints de lithiase renale et dans l'urine de sujets controles. Des substances organiques ont ete isolees de l'urine de malades atteints de lithiase renale calcique et de l'urine de sujets controles. L'isolement a ete fonction de la taille moleculaire. Ces substances ont ete etudiees pour leur effet sur la precipitation de l'oxalate de calcium. Neuf sous-groupes de differentes tailles moleculairesont ete prepares par ultrafiltration et chromatographie sur colonne de Sephadex G-200 a partir de l'urine de 10 sujets lithiasiques et de 10 sujets controles. L'uromucoide a ete mis en evidence dans les sous-groupes de taille moleculaire elevee dans les deux categories de sujets, alors que les glycosaminoglycans ont ete detectes dans les sous-groupes de grande et moyenne taille moleculaire dans les deux groupes de sujets. Les sous-groupes de petite taille moleculaire etaient depourvus d'uromucoide et de glycosaminoglycans mais contenait des proteines et de l'acide uronique, constatation qui suggere qu'il puisse d'agir de glycoproteines. L'excretion quotidienne de materiel riche en uromucoide etait plus grande chez les lithiasiques chez les sujets controles, mais celle des petites glycoproteines etait inferieure chez les sujets lithiasiques. Le materiel de grande taille moleculaire provenant des sujets lithiasiques etait depourvu d'activite sur la precipitation de l'oxalate de calcium. Tous les autres materiels (a une concentration de 5 mg/dl) exercaient une inhibition sur la precipitation de l'oxalate de calcium. L'inhibition augmentait progressivement avec la diminution de la taille des substances organiques. L'activite inhibitrice totale calculee pour le groupe lithiasique etait de 36% inferieure a celle observee dans le groupe controle.

Uric acid saturation in calcium nephrolithiasis. Hyperuricosuria appears to cause calcium oxalate nephrolithiasis by promoting the formation of monosodium urate or uric acid crystals, which either act as seed crystals for calcium oxalate or adsorb normally occurring macromolecular inhibitors of calcium oxalate crystallization. Both mechanisms require that hyperuricosuria cause excessive supersaturation of the urine, but this has not yet been studied under conditions of normal lifestyle. We have measured the saturation with respect to sodium hydrogen urate and the concentration of undissociated uric acid in the urine samples of 67 patients with calcium nephrolithiasis, who had idiopathic hypercalciuria, hyperuricosuria, both, or neither disorder. Patients with hyperuncosuria excreted urine that was supersaturated with respect to monosodium urate or undissociated uric acid more frequently than did other stone formers or normal subjects, and are therefore at a greater risk of forming a solid phase of monosodium urate or uric acid. Treatment measures that lowered uric acid excretion also lowered urine saturation, and this may be the reason that such treatment tends to prevent calcium stone recurrence. Solution saluree d'acide urique dans la lithiase calcique. L'hyperuricosurie senible determiner des lithiases d'oxalate de calcium en favorisant la formation de cristaux d'urate monosodique et d'acide urique qui agissent comme germe de cristallisation pour l'oxalate de calcium ou bien adsorbent les inhibiteurs macromoleculaires physiologiques de la cristallisation de l'oxalate de calcium. Les deux mecanismes exigent une sursaturation des urines en ce qui concerne l'acide urique, mais cela n'a pas encore ete etudie dans de conditions de vie normale. Nous avons mesure la saturation en ce qui concerne l'urate acide de sodium et les concentrations d'acide urique non dissocie dans les urines de 67 malades atteints de lithiase calcique qui avaient une hypercalciurie idiopathique, une hyperuricosurie, les deux desordres, ou encore aucun de ces desordres. Les patients atteints d'hyperuricosurie elaborent une urine qui est plus souvent sursaturee, en ce qui concerne l'urate monosodique ou l'acide urique non dissocie, que celle des autres individus lithiasiques ou normaux. Les malades sont donc exposes a un plus grand risque de formation d'une phase solide d'urate monosodique ou d'acide urique. Les mesures therapeutiques qui abaissent l'excretion d'acide urique diminuent aussi la sursaturation de l'urine, et ceci peut etre la raison pour laquelle de tels traitements tendent a empecher la recidive de la lithiase calcique.

We measured the rate of oxalate flux across the red-cell membrane in the steady state in 114 patients with a history of calcium oxalate kidney stones and in 25 controls. Of the patients, 98 had recurrent, "idiopathic" kidney stones, 8 had primary hyperparathyroidism, 7 had renal or urinary tract malformations, and 1 had primary hyperoxaluria. Oxalate exchange was significantly higher in the 98 patients with idiopathic stone formation than in the controls (-1.10 +/- 0.95 [SD] X 10(-2) min-1 vs. -0.31 +/- 0.12 X 10(-2); P less than 0.001); it was above the upper limits of normal in 78 of these patients. All 8 patients with hyperparathyroidism and the patient with primary hyperoxaluria had values in the normal range; 2 of the patients with renal or urinary tract malformation had values at the upper normal limit. A study of five families indicated that the abnormality is an autosomal monogenic dominant trait with complete penetrance and variable expressivity. Oxalate-tolerance tests were carried out in five pairs of brothers. One brother in each pair had the abnormality in oxalate flux, and had a significantly higher percentage of oxalate excretion at two hours after oxalate loading (18.09 +/- 3.07 [SD] vs. 10.37 +/- 3.08 percent; t = 3.97; P less than 0.005) and four hours (14.87 +/- 2.91 vs. 9.89 +/- 2.93 percent; t = 2.70; P less than 0.05). Treatment with oral hydrochlorothiazide (50 mg per day) or amiloride (5 mg per day) or both restored normal or nearly normal red-cell oxalate exchange in all of 33 patients who initially had increased rates. We conclude that an inherited cellular defect in oxalate transport may be a factor in "primary" calcium oxalate stone formation and that this defect may be corrected with diuretics.

The frequency of renal tubular acidosis was evaluated in 28 adult patients with recurrent calcium nephrolithiasis (19 with 'renal' hypercalciuria, 9 with normocalciuria and no metabolic abnormality) and no evidence of obstruction or infection of the urinary tract. Eight patients with hypercalciuria (42%) had a defective renal reabsorption of bicarbonate, based on a fractional excretion of bicarbonate higher than 7% and a TmHCO3/GFR lower than 2.2 mEq/dl; 2 of them had an associated distal defect of acidification, as judged by a U-B pCO2 lower than 18 mm Hg in maximally alkaline urine. One patient with hypercalciuria had distal tubular acidosis, based on a urine pH higher than 5.3 during acidosis. Only 1 patient with normocalciuria had associated proximal and distal acidification defects. The remaining 8 patients displayed a normal renal acidifying capacity. The bicarbonate wastage was independent of serum PTH levels, vitamin D status and hypercalciuria and was associated with a defective tubular reabsorption of phosphate, increased random urinary pH and more active nephrolithiasis, with a prevalence of mixed calcium oxalate and phosphate stones. Our study shows a high incidence of defective tubular reabsorption of bicarbonate in patients with calcium nephrolithiasis and 'renal' hypercalciuria and suggests that the proximal acidification defect plays a pathogenetic role in promoting calcium nephrolithiasis.

One hundred patients with recurrent calcium nephrolithiasis were submitted to the Pak test. At fasting state hypercalciuria was found in 27 cases, while a group of 16 further patients became hypercalciuric after oral calcium load. Only measurement of urinary cAMP excretion in both conditions made it possible to diagnose renal hypercalciuria in 9 out of 27 patients in the former group; according to test results 4 patients were expected to have primary hyperparathyroidism, but afterwards the disease was identified in only one case.