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PubMed2000

Mice lacking renal chloride channel, CLC-5, are a model for Dent's disease, a nephrolithiasis disorder associated with defective receptor-mediated endocytosis.

Nephrolithiasis (kidney stones) affects 5-10% of adults and is most commonly associated with hypercalciuria, which may be due to monogenic renal tubular disorders. One such hypercalciuric disorder is Dent's disease, which is characterized by renal proximal tubular defects that include low molecular weight proteinuria, aminoaciduria and glycosuria, together with rickets in some patients. Dent's disease is due to inactivating mutations of the renal-specific voltage-gated chloride channel, CLC-5, which is expressed in the proximal tubule, thick ascending limb and collecting duct. The subcellular localization of CLC-5 to the proximal tubular endosomes has suggested a role in endocytosis, and to facilitate in vivo investigations of CLC-5 in Dent's disease we generated mice lacking CLC-5 by targeted gene disruption. CLC-5-deficient mice developed renal tubular defects which included low molecular weight (<70 kDa) proteinuria, generalized aminoaciduria that was more pronounced for neutral and polar amino acids, and glycosuria. They also developed hypercalciuria and renal calcium deposits and some had deformities of the spine. Furthermore, endocytosis as assessed by horseradish peroxidase uptake in the proximal tubule was severely impaired in CLC-5-deficient mice, thereby demonstrating a role for CLC-5 in endosomal uptake of low molecular weight proteins. Thus, CLC-5-deficient mice provide a model for Dent's disease and this will help in elucidating the function of this chloride channel in endocytosis and renal calcium homeostasis.

Animals↗
PubMed2003

Endoscopic renal papillary biopsies: a tissue retrieval technique for histological studies in patients with nephrolithiasis.

PURPOSE: The mechanisms behind calcium nephrolithiasis remain unclear. Previous research has relied on animal models or cell lines, yielding limited insight into the pathophysiology of human calcium stone disease. To determine changes occurring in the human kidney during active stone disease we used an endoscopic renal papillary biopsy protocol in calcium stone formers undergoing percutaneous nephrolithotomy. MATERIALS AND METHODS: Following stone burden clearance via percutaneous nephrolithotomy 15 idiopathic calcium oxalate and 4 ileal bypass stone formers underwent flexible and rigid nephroscopy. Biopsies from select papillae in the peripheral and interpolar regions were obtained with 5Fr flexible cup biopsy forceps. A papilla adjacent to the accessed calix was biopsied with 10Fr cup biopsy forceps. Cortical biopsies along the access tract were also obtained with the 10Fr forceps. RESULTS: All patients had successful biopsy completion. No complications were attributable to the biopsy process and no blood transfusions were required. Of the 19 patients 12 were contacted for followup at a mean of 21.7 +/- 9.0 months with none experiencing adverse sequelae such as bleeding or significant pain. A total of 14 patients had followup serum creatinine available showing that the difference in mean preoperative and postoperative values was not clinically significant (1.00 +/- 0.27 and 1.11 +/- 0.27 mg/dl, respectively). The quality of biopsied tissue permitted accurate immunohistochemical staining of crystal deposits and mineral analysis. CONCLUSIONS: Endoscopic papillary biopsies were performed safely in a small patient population. Tissue obtained using this protocol can be used for detailed histological and analytical studies, which may lead to significant advances in our understanding of stone formation mechanisms.

Biopsy↗
PubMed2005

Ethnic background has minimal impact on the etiology of nephrolithiasis.

PURPOSE: Nephrolithiasis disproportionately affects white patients. However, recent studies propose an increase in the incidence of stone disease in nonwhite populations. We compared the metabolic risk factors of ethnically disparate stone formers from the same geographic region. MATERIALS AND METHODS: A retrospective review of 1,141 patients identified 98 (9%) nonwhite stone formers. Of these individuals 60 underwent a comprehensive metabolic evaluation, comprising 44 black, 8 Asian and 8 Hispanic patients. A similar sex and age matched group of 66 white stone forming patients were also identified for comparative analysis. Stone analyses were recorded when available. Urinary metabolic abnormalities were defined as low urine volume-urine volume less than 2,000 cc, gouty diathesis-pH 5.5 or less (normal level 5.5 to 6.5), hypercalciuria-calcium greater than 200 mg, hyperoxaluria-oxalate greater than 45 mg, hyperuricosuria-uric acid greater than 600 mg, hypocitraturia-citrate less than 600 mg and purine gluttony-sulfate greater than 20 mg. RESULTS: The incidence of metabolic abnormalities was surprisingly similar between the white and nonwhite stone formers. Whites have a higher prevalence of hypercalciuria compared with nonwhites (67% vs 25%, respectively, p <0.01). This comparison persisted when the white group was compared with individual ethnic groups (25% in each group). Whites also displayed a higher mean urinary calcium level (233 mg) than their nonwhite counterparts overall (146 mg), specifically with respect to blacks (146 mg, p <0.01). Asians had higher urine volumes with respect to whites and blacks (p <0.01) and, therefore, a decreased prevalence of low urine volumes (37.5% vs 74.2% and 79.5%, respectively). Hypocitraturia, hyperuricosuria, hyperoxaluria, gouty diathesis and high sulfate levels were equally represented among all ethnic groups. CONCLUSIONS: Although there appears to be a predominance of stone disease among whites, all racial groups demonstrated a remarkable similarity in the incidence of underlying metabolic abnormalities. These results suggest that dietary and environmental factors may be as important as ethnicity in the etiology of stone disease.

Adult↗
PubMed2005

Management of gestational nephrolithiasis in the presence of a bicornuate uterus and pelvic kidney.

A 39-year-old para 0(+1) woman with known nephrolithiasis within a left-sided pelvic kidney presented with left-sided renal colic at 7 weeks gestation. She had a previous miscarriage due to a bicornuate uterus. Ultrasound and magnetic resonance urography confirmed an incomplete obstruction of the left upper renal tract which was relieved by percutaneous nephrostomy. She presented again at 14 weeks with renal colic and minimal output. An ultrasound confirmed recurrent hydronephrosis and a nephrostogram showed that the catheter had retracted almost completely from the collecting system. This was considered to be due to the upward pressure of the enlarging uterus on the catheter, which had been fixed externally to the skin. This problem was obviated by not securing the replacement nephrostomy tube to the skin. She developed pre-eclamptic toxaemia and gave birth at 35 weeks gestation by caesarean section. The calculus was later dissolved using extra-corporeal shockwave lithotripsy.

Adult↗
PubMed2005

Segregation of urine calcium excretion in families ascertained for nephrolithiasis: evidence for a major gene.

BACKGROUND: The quantitative genetics of urine calcium excretion has not been established. It is a trait of interest because hypercalciuria is commonly found in subjects with nephrolithiasis. The aim of this study was to model the segregation of this trait in a sample of French-Canadian families ascertained through a stone former. METHODS: Major gene, polygenic, and mixed models were fit to 24-hour urine calcium excretion from 567 individuals in 221 nuclear families, while simultaneously taking into account gender, age at examination, body mass index (BMI), and the use of thiazide drugs. The nuclear families were extracted from 154 pedigrees, some of which were four generations, with at least two siblings with a history of calcium stones. RESULTS: All the proposed genetic models fit the data significantly better than the null model. The most parsimonious model was the mixed codominant/polygenic model but it was statistically indistinguishable from the single-gene codominant model. In both of these models the heritability attributable to the major gene was estimated to be 0.58. CONCLUSION: Our results suggest that a major gene with a relatively large effect on variation in urine calcium excretion is segregating in French-Canadian families with stone formers. This implies that the power of quantitative trait segregation analysis of urine calcium excretion may be increased in these families, and results indicate that it should be feasible to genetically map the quantitative trait locus.

Adult↗
PubMed1997

Bilateral xanthine nephrolithiasis in a dog.

Xanthinuria is an uncommon metabolic disorder clinically manifested as urolithiasis. There are two forms of the disease, congenital and iatrogenic. The former was diagnosed in a four-year-old dachshund bitch. The patient was presented with signs of terminal chronic renal failure. Urine was bacteriologically sterile with massive amorphous crystalluria. Bilateral nephrolithiasis was diagnosed at necropsy. The kidneys were shrunken with marked atrophy of the renal cortex and medulla. Infrared spectrometry revealed that the stones comprised 100 per cent xanthine. Later, two of the patient's siblings were examined for urine xanthine content; both showed higher concentrations of xanthine than a control dog. The described case is compared with seven known published cases of congenital xanthinuria.

Animals↗
PubMed2004

Left perinephric abscess associated with nephrolithiasis and bladder calculi in a bitch.

An eight-year-old, entire female Pekingese cross, weighing 3.8 kg, had been inappetent with fever, depression, abdominal pain, vomiting and diarrhoea for seven days. The radiographic and ultrasonographic findings were consistent with glomerulonephritis, nephrolithiasis in both kidneys, bladder calculi and an accumulation of fluid in the left perinephric space. The clinical signs, together with the results of the diagnostic imaging, suggested that this fluid could be pus. A definitive diagnosis of a subcapsular abscess in the left kidney was established when this kidney was removed surgically. A histopathological examination of the kidney revealed a diffuse suppurative interstitial nephritis, membranous glomerulonephritis and an abscess invading the perinephric adipose tissue from the renal cortex. Twelve months after surgery the dog remains clinically stable, but owing to the disease of its remaining kidney its long-term prognosis is poor.

Abscess↗
PubMed2003

Helical CT for nephrolithiasis and ureterolithiasis: comparison of conventional and reduced radiation-dose techniques.

PURPOSE: To determine the accuracy of unenhanced helical computed tomography (CT) performed at reduced milliampere-second, and therefore at a reduced patient radiation dose, by using conventional unenhanced helical CT as the standard. MATERIALS AND METHODS: Fifty patients with acute flank pain who weighed less than 200 lb (90 kg) were prospectively recruited for this study. Conventional helical CT scans were obtained with patients in the prone position by using 5-mm-thick sections, 140 kVp, 135-208 mAs (mean, 160 mAs), and a pitch of 1.5 (single-detector row CT) or 0.75 (multi-detector row CT, 4 x 5-mm detector configuration). Conventional CT was immediately followed by low-dose scanning, whereby the tube current was reduced to 100 mA (mean, 76 mAs). All other technical parameters and anatomic coverage remained constant. Three independent readers who were blinded to patient identity interpreted the scans in random order. The observers noted the location, size, and number of calculi; secondary signs of obstruction; and other clinically relevant findings. High- and low-dose scans were compared by using paired t tests and the signed rank test. RESULTS: Calculi were found in 33 (66%) patients; 25 (50%) had renal calculi and 19 (38%) had an obstructing ureteral calculus. The accuracy rates (averaged over the three readers) for determining the various findings on the low-dose scan compared with the high-dose scan were as follows: nephrolithiasis, 91%; ureterolithiasis, 94%; obstruction, 91%; and normal findings, 92%. When interpretations between readers were compared, agreement rates were 90%-95% for standard-dose scans and 90%-92% for reduced-dose scans (P >.5). Uncomplicated mild diverticulitis was found in three patients. No other clinically important abnormality was identified. A reduction in the tube current to 100 mA resulted in a dose reduction of 25% for multi-detector row CT and 42% for single-detector row CT. CONCLUSION: In patients who weighed less than 200 lb, unenhanced helical CT performed at a reduced tube current of 100 mA, and therefore at a reduced patient dose, resulted in scans of high accuracy.

Adolescent↗
PubMed1985

Nephrolithiasis in premature infants.

The clinical records of ten premature infants with nephrolithiasis were reviewed. The probable mechanism of stone formation was hypercalciuria due to furosemide therapy (nine patients) and congenital hyperparathyroidism (one patient). The relatively high rates of urinary excretion of calcium from immature kidneys predisposed these neonates to the development of calcium stones. Renal calculi in neonates are complications of distinct, treatable conditions, and premature babies receiving furosemide treatment should be screened by ultrasonography for renal calcifications.

Female↗
PubMed1991

Molecular abnormality of Tamm-Horsfall glycoprotein in calcium oxalate nephrolithiasis.

Tamm-Horsfall glycoprotein (THP) inhibits self-aggregation of calcium oxalate monohydrate (COM) crystals and may therefore be part of the natural defenses against deposition of COM in the kidney in the form of stones or nephrocalcinosis. We have studied THP from six patients with severe nephrolithiasis and have found that their THP inhibits COM self-aggregation less than normal THP under conditions of NaCl and THP concentration and pH similar to those of human urine. The reason for the reduced inhibition of COM crystal aggregation seems to be an enhanced self-aggregation of patient THP, which removes it from effective interactions with the COM crystals. In one family, the father and the oldest son both excreted THP that behaved abnormally and in similar ways, whereas THP from the other son and from the wife behaved normally.

Adult↗
PubMed2004

Epidemiology of nephrolithiasis today.

The epidemiology of nephrolithiasis differs according to geographical area and socio-economic conditions. In Italy the prevalence of the disease in 1993 was 17.2/1,000 inhabitants, most patients are men and elderly. The relative risk increased in subjects with family history for calculosis, with the tendency to eat protein-rich food and with overweight and body mass index (MBI) >32 kg/m2. Calcium oxalate and/or phosphate stones account for almost 70% of all renal stones observed in economically developed countries.

Adult↗
PubMed2004

Crystallization inhibitors in the pathophysiology and treatment of nephrolithiasis.

It is currently agreed that stone formation in the urinary tract requires supersaturation with respect to a given solid phase. However, this principle fully applies only to stones other than calcium-containing stones, in which case compounds acting as inhibitors are postulated to naturally occur in urine. Stone formation would therefore ensue from an imbalance between promoters and inhibitors. The saturation state can be estimated by means of computer model systems based on ab initio calculations, which account for the main soluble complexes formed in urine between relevant cations and anions. This estimates the overall promoting potential of urine. However, in the case of calcium nephrolithiasis, supersaturation does not make a clear-cut separation between normal subjects and patients. Several studies in the last two decades have identified many inhibitors of calcium oxalate and calcium phosphate crystallization, which are classified into the ionic and macromolecular. They have been shown to act on kinetics by interfering with nucleation, growth and aggregation of crystals. Unfortunately, except for citrate, none of the newly discovered substances has been definitely characterized in its molecular composition and structure, type and potency of inhibition, differences in concentration and structure between stone-forming and non stone-forming subjects. Citrate exhibits a dual action in urine, opposing crystal formation by both thermodynamic and kinetic mechanisms. At present it is the only natural inhibitor which can be measured in urine, quantitated as to inhibitory activity and used in medical treatment.

Calcium Oxalate↗
PubMed2004

Hypophosphatemia and calcium nephrolithiasis.

Our knowledge of phosphate balance under physiological and pathological situations has increased substantially during the last decade thanks to the molecular identification of three dissimilar families of sodium-phosphate cotransport systems, two of them almost exclusively expressed in epithelia whereas the third one has a ubiquitous expression. Intracellular proteins such as NHERF1 (sodium-proton exchanger regulatory factor 1) can interact with phosphate transporters through PDZ domains thus regulating the expression of the transporters at the membrane. Moreover, newly acknowledged paracrine/endocrine peptides, such as fibroblast growth factor 23 (FGF23), also affect the activity of phosphate transporters. Renal phosphate leak, related to invalidation (in the mouse) or to mutations (in humans) of the renal phosphate transporter NPT2a, leads to hypophosphatemia on the one hand, and to nephrolithiasis or bone demineralization on the other hand. Similar features are observed during invalidation of NHERF or in case of overproduction of FGF23. These observations highlight the importance of phosphate homeostasis in common diseases such as renal stones or bone loss.

Animals↗
PubMed2005

Fatty acids and idiopathic calcium nephrolithiasis.

Clinical and experimental investigations seem to underline the important role of fatty acids in the pathogenesis of hypercalciuria, a well-known risk factor for lithogenesis. To evaluate the relationships between the previously reported increase in plasma phospholipid arachidonic acid level and the factors responsible for calcium metabolism in idiopathic calcium nephrolithiasis, a best-fit model was constructed. This new statistical application shows a causal relationship between plasma phospholipid arachidonic acid content, intestinal calcium absorption, biochemical markers of bone turnover, urinary calcium excretion and bone mineral density at the lumbar spine. This model suggests that a defect in the phospholipid fatty acid composition could represent the primary event responsible for the mosaic of metabolic and clinical alterations that are distinctive features of renal stone formers, such as kidney, intestine, and bone calcium metabolism, and several forms of idiopathic hypercalciuria.

Animals↗
PubMed1995

Nephrolithiasis and nephrocalcinosis in cerebrotendinous xanthomatosis: report of three siblings.

We report the existence of nephrocalcinosis (NC) and/or nephrolithiasis (NL) in three siblings with cerebrotendinous xanthomatosis (CTX). Incomplete renal tubular acidosis (RTA) type 1 is also found in these three siblings after the evaluation of renal acidification function. Although the association of RTA with NC and/or NL is well known, they are rarely reported in CTX patients.

Acid-Base Equilibrium↗
PubMed1988

Acute effect of indapamide on urine calcium excretion in nephrolithiasis and human essential hypertension.

The effects of indapamide (2.5 mg once a day) on urinary composition are reported in 20 patients (10 with recurrent calcium nephrolithiasis and 10 with essential hypertension) compared with 20 controls. Indapamide was well absorbed in every patient (mean plasma level at the steady state was 111 +/- 41 ng/ml) and its antihypertensive action was more pronounced in hypertensive than in normotensive patients. It lowered calcium excretion in 18/20 patients (mean fall on the 7th day of treatment: 53%) and raised the Mg/Ca ratio in 20/20 patients (mean increase on the 7th day: 167%). The effect on Ca2+ and Mg2+ excretion was not associated with a strong diuretic effect. During intravenous calcium loading (0.375 mmol/kg body weight) 6 normal subjects after a single oral dose of indapamide excreted less calcium, suggesting a direct renal hypocalciuric action by the drug. Indapamide could represent an alternative drug to thiazide diuretics in diseases with dangerous renal calcium losses, but long-term studies are needed.

Adult↗
PubMed1993

Physicochemical background for ambiguity of clinical recommendations in treating phosphate nephrolithiasis.

Efficiency of clinical recommendations for curing and prevention of phosphate nephrolithiasis founded on physicochemical investigations is unexpectedly low and apparently did not exceed 50%. We tried to consider possible physicochemical causes of this fact. For this purpose the influence of changes of urine pH and of calcium, phosphate and complexon concentrations on the probability of different precipitation phases of solid calcium phosphate has been reviewed. The importance of tendencies of changing the urine dynamic physicochemical parameters such as the precipitation induction period and the amplitude of urine pH variations in time has been shown. It was established that the probability of the existence of Ca3(PO4)2, Ca8H2(PO4)6.5H2O, CaHPO4.2 H2O and MgNH4PO4.6 H2O in urine depends on the time of its transition from the supersoluble state and is determined in the final analysis by the relationship of formation rates and solid phase dissolution rates. This was verified by experiments and by data obtained in the clinical laboratory.

Humans↗