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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.

Idiopathic calcium nephrolithiasis (ICN) is a disease whose prevalence is rising. Our aim was to assess whether lifestyle indicators and habits of calcium stone formers in Italy have changed over the last 25 years, trying to establish a connection with the diffusion of Internet access. Therefore we examined the database of the Stone Clinic of Parma University Hospital and extracted 1952 (1192 M, 760 F) patients with ICN who underwent a full clinical and laboratory evaluation from 1986 to 2010. Laboratory evaluation included data on urinary 24-h volume, pH, sodium, potassium, chloride, calcium, phosphate, uric acid, magnesium, oxalate, and citrate. Patients were split in three groups on a chronological basis, according to official EUROSTAT-ISTAT data of Internet connection among families in Italy: Group 1, pre-Internet era (1986–1998, 853 patients); Group 2, narrow-band era (1999–2004, 467 patients); Group 3, broad-band era (2005–2010, 632 patients). Over the time we found a significant increase in water intake (1.37 vs. 1.78 L in men and 1.21 vs. 1.55 L in women, Group 1 vs. Group 3, p-trend

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.

An increased calcium excretion in 24-hour urine was found in 32 of 42 out-patients with recurrent calcium nephrolithiasis (calcium excretion > 300 mg in males, > 250 mg in females). Subsequent hospitalization of the 32 patients revealed the following diagnosis after a calcium tolerance test: absorptive hypercalciuria in 18, renal hypercalciuria in 4, primary hyperparathyroidism in 2 and dietary hypercalciuria in 7. Normocalciuria in 10 out-patients was confirmed in 6; in one instance there was, however, primary hyperparathyroidism, in 3 there was absorptive hypercalciuria. In one patient it was not possible to classify the hypercalciuria. Total as well as nephrogenic cAMP showed wide scatter and was unsuitable, therefore, in differential diagnosis. In 2 of 3 cases of hyperparathyroidism the serum level of parathormone was distinctly elevated.

While bone involvement is more evident in case of secondary calcium calculosis, such as hyperparathyroidism, medullary sponge disease, hypercalcemic systemic illness and chronic diarrhea syndrome, less known and more controversial is still the link between bone loss and idiopathic calcium nephrolithiasis. In this study 46 patients with idiopathic calcium nephrolithiasis were consecutively enrolled at their customer diet. Our data show that dietary habits, especially an high sodium and animal protein intake, could seem to influence bone loss of the lumbar spine and of the neck. Furthemore a negative correlation has been found between citrate urinary excretion and bone loss, that suggests a protective role of potassium citrate not only on prevention of recurrent calcium nephrolithiasis, but also on bone loss.

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.

Objective: The object of this study was to investigate the role for measurement of 24-h renal oxalate excretion in the evaluation of idiopathic calcium stone formers. Materials and Methods: Renal excretion rates of oxalate and creatinine were measured in 24-h urines in 46 consecutive male recurrent idiopathic calcium stone formers and 61 healthy males. Furthermore, day-to-day variation in renal oxalate excretion in 10 male recurrent stone formers and 10 healthy males were evaluated by measuring 24-h oxalate excretion on 5 different days in each individual. Concentrations of oxalate in urine were measured using an enzymatic method without ascorbate interference. Results: The cumulative frequency distribution curves of 24-h renal oxalate excretion rates of stone formers and controls were congruent, and there were no statistically significant differences in oxalate excretion rates between stone formers and controls. Mean 24-h oxalate excretion (95%-confidence intervals) was 0.22 (0.18-0.25) mmol and 0.21 (0....

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: 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.

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..

Background: The purpose of this trial was to evaluate the efficacy of a low-animal-protein diet (LAPD) or a high-fiber diet (HFD) for the prevention of calcium nephrolithiasis recurrence. Methods: We conducted a 4-year randomized trial comparing the effect of 2 diets in 175 idiopathic calcium stone formers. Fifty-five were assigned to a LAPD (25 g/day fiber) and 60 were placed on a normal diet (control group). The primary outcome measure was the time to the first recurrence of calcium nephrolithiasis. Daily urine compositions were analyzed at baseline, at month 4 (M4), M12, M24, M36 and M48. Results: Seventy-three patients completed the trial (23 in the LAPD group, 27 in the HFD group and 23 in the control group). Recurrence was 48% (11/23) in the LAPD group, 63% (17/27) in the HFD group and 48% (11/23) in the control group (p = not significant). During follow-up, urinary calcium levels and other urine parameters did not change significantly in the 3 groups, except for a significant decrease in 24-hour urinary sulfate in the LAPD group. Conclusions: In idiopathic calcium stone formers, neither a LAPD nor a HFD appeared to provide protection against recurrence.

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.

Purpose: Pharmacological treatment of hypocitraturic calcium nephrolithiasis requires as many as 12 tablets, or numerous crystal packages or liquid supplements taken throughout the day. In addition to added cost, this cumbersome regimen decreases patient compliance, which may increase stone recurrence rates. We evaluated the urinary biochemical effects of dietary citrate supplementation in hypocitraturic calcium stone formers in an attempt to decrease or eliminate the need for pharmacological therapy.Materials and Methods: A total of 12 patients who were either noncompliant with or intolerant of pharmacological citrate therapy supplemented their routine diet with citrate in the form of lemonade, consisting of 4 ounces of reconstituted lemon juice (5.9 gm. citric acid) mixed with tap water to a total volume of 2 1. and consumed at uniform intervals throughout the day. Urine specimens (24-hour) were obtained for biochemical analysis after 6 days of lemonade therapy and compared to pre-lemonade basel...

The pathogenesis of idiopathic calcium nephrolithiasis most likely involves an imbalance between factors promoting and inhibiting calcium crystal growth and aggregation in the urine. Among many factors able to cause this disorder, urine concentration induced by chronic dehydration seems to be an important condition that increases the risk of stone formation1. To verify the effect of drastic dehydration on lithogenic risk, we carried out this study.

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.

MOUNTING evidence indicates that two disorders, idiopathic hypercalciuria and hyperuricosuria, account for approximately 65 per cent of calcium stones in patients without a better known cause of nephrolithiasis. Of 230 patients studied during the past five years in the Michael Reese Hospital kidney-stone program, only 84 had a well established cause of stones (Table 1). The urine of the remaining 146 patients, who would usually be considered to have idiopathic recurrent stone formation,1 contained excessive amounts of calcium and uric acid. Because it has become clear that both hypercalciuria and hyperuricosuria can participate in the formation of calcium stones, it . . .

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.

Our particular interest concerns urine citrate in idiopathic calcium oxalate stone disease. Only 3 previous (1,2,6) studies have included both sexes; they disagree as to the level of urine citrate, and the reduction of citrate in patients compared to normal, although both find that patients excrete less citrate than normals. They used different citrate methods. In one of the two, the numbers of women were small: 7 patients and 15 normals. In four other studies, of only men, patients were found to excrete between 97 and 63 percent as much citrate as normals (3,4,5,6,7).

Low urinary citrate excretion is thought to be an important risk factor for calcium nephrolithiasis, and hypocitraturia is referred to as a common biochemical finding in this disease (1, 2).

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.

We studied 253 subjects, age 17–70 years, out of a total population of 540 patients affected by recurrent calcium nephrolithiasis who were, subsequently, referred to our clinic.

There is increasing evidence that intestinal absorption of stone-forming substances may be disturbed in many patients with calcium nephrolithiasis. This disturbance in intestinal absorption in such patients is usually metabolic in origin, although it may be modified by dietary aberrations. The resulting aberration in urinary composition may lead or contribute to stone formation.

Metolazone, a nonthiazide diuretic with the hypocalciuric effect of the thiazides, was evaluated in patients with idiopathic calcium nephrolithiasis. During the mean 3-yr treatment period, there was a 77% decrease in stone incidence in 38 male patients (from 2.10 to 0.49 stones/patient/year). Urine calcium decreased 51% (from 231 +/- 19 to 114 +/- 7 mg/24 hr after 13 mo therapy). The treatment response was the same when these patients were divided into normocalciuric (n = 23), borderline hypercalciuric (n = 10), and hypercalciuric groups (n = 5). In six other patients with high sodium intake there was no decrease in urine calcium on stone formers regardless of the initial level of urine calcium excretion. High sodium intake may blunt and low intake potentiate the hypocalciuric effect of metolazone.

The physico-chemical basis for the action of various drugs in calcium nephrolithiasis may be described in terms of changes produced in the urinary state of saturation (APR), limit of metastability (FPR), or in crystal growth. The validation of this scheme for drug action requires further correlation of objective responses to drug therapy, described in terms of urinary crystallisation, with the clinical response.

Urinary saturation with respect to calcium oxalate monohydrate was measured in 111 consecutive patients with calcium nephrolithiasis. Each patient also was evaluated by a detailed conventional metabolic protocol. Patients with idiopathic hypercalciuria produced abnormally oversaturated urine more frequently than normal subjects and normocalciuric patients, but normocalciuric patients had unexpectedly high levels of urine saturation. Measuring levels of calcium concentration, oxalate concentration, or the chemical concentration product of calcium and oxalate in urine did not predict oversaturation. During thiazide treatment, saturation level tended to fall if it was initially elevated, whether the patient was hypercalciuric or not. Patients whose urine was not remarkably oversaturated showed no tendency to elaborate even less saturated urine during thiazide treatment; instead, the average calcium oxalate saturation level remained constant. Direct urine saturation measurements can detect a small but significant number of normocalciuric patients who have marked oversaturation with respect to calcium oxalate and appear to benefit from treatment.

The efficacy of T in the treatment of idiopathic calcium nephrolithiasis has been recently questioned (1) both in randomized and non randomized clinical trials. Moreover, the positive effect in preventing Ca stone recurrences so far reported might be due at least in part to dietary advice and close clinical supervision (“stone clinic effect”)(2). The purpose of our study was to investigate the effects of T vs non medical treatment in idiopathic calcium stone formers (CSF).

A group of patients forming calcium oxalate stones are hyperuricosuric and it is thought that their excessive urate excretion contributes to calcium-stones formation1. The pathomechanisms invoked are dietary purine excess and endogenous uric acid overproduction, being defective tubular reabsorption of urate “unattractive” because uricemia was found to be normal in patients with recurrent calcium nephrolithiasis (RCN) and hyperuricosuria. Current studies were undertaken to define the incidence, role of diet, abnormalities of the renal handling of urate, and associated metabolic disturbances in patients with RCN and hyperuricosuria.

Renal stones is not one of the "in" topics of medical research. Historical importance it has aplenty, but glamour and excitement none. Research in the stone field has been ploddingly slow and carried out in relatively few laboratories. Nevertheless, genuine, valuable accor plishments have been made in the past decade leading to better understanding of pathogenetic mechanisms and rational therapy of stone disease. Witness the increased knowledge of factors affecting calcium excretion, the careful descriptions of cystinuria and the hyperoxaluric states, the successful treatment of uric acid stones with allopurinol and alkali, and the reduction of calcium stone formation with . . .