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David S. Goldfarb - One of the best experts on this subject based on the ideXlab platform.
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Treatment of calcium nephrolithiasis in the patient with Hyperuricosuria
Journal of Nephrology, 2014Co-Authors: Omotayo Arowojolu, David S. GoldfarbAbstract:Nearly one-third of patients with calcium stones have Hyperuricosuria. In vitro studies and clinical trials have investigated the relationship between uric acid and calcium stones, but the association between Hyperuricosuria and calcium stone formation in patients is still being debated. Uric acid appears to cause salting out of calcium oxalate in human urine. However, the importance of this in vitro phenomenon to the proposed association is not supported in cross-sectional observational studies. A small placebo-controlled randomized clinical trial showed that allopurinol decreased the rate of recurrent calcium oxalate calculi in patients with Hyperuricosuria and normocalciuria. An assessment of the effect of combination therapy of allopurinol with indapamide showed no additive effect. Allopurinol may have antioxidant effects that are responsible for its reducing calcium stone formation, which are independent of xanthine oxidase inhibition. In addition, a newer xanthine oxidoreductase inhibitor, febuxostat, may also be effective in the prevention of calcium stones, as it reduces urinary uric acid excretion.
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uric acid stones and Hyperuricosuria
Advances in Chronic Kidney Disease, 2012Co-Authors: Tapan H Mehta, David S. GoldfarbAbstract:Recent work has highlighted the strong relationships among obesity, diabetes, and the metabolic syndrome as causes of low urinary pH. Low urinary pH in turn is the major urinary risk factor for uric acid stones. Unlike calcium stones, uric acid stones can be dissolved and easily prevented with adequate urinary alkalinization. Recognizing the relevant risk factors should lead to increased identification of these radiolucent stones. The cornerstone of therapy is raising urinary pH; xanthine dehydrogenase inhibitors should be used only when urinary alkalinization cannot be achieved.
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potential pharmacologic treatments for cystinuria and for calcium stones associated with Hyperuricosuria
Clinical Journal of The American Society of Nephrology, 2011Co-Authors: David S. GoldfarbAbstract:Summary Two new potential pharmacologic therapies for recurrent stone disease are described. The role of Hyperuricosuria in promoting calcium stones is controversial with only some but not all epidemiologic studies demonstrating associations between increasing urinary uric acid excretion and calcium stone disease. The relationship is supported by the ability of uric acid to “salt out” (or reduce the solubility of) calcium oxalate in vitro. A randomized, controlled trial of allopurinol in patients with Hyperuricosuria and normocalciuria was also effective in preventing recurrent stones. Febuxostat, a nonpurine inhibitor of xanthine oxidase (also known as xanthine dehydrogenase or xanthine oxidoreductase) may have advantages over allopurinol and is being tested in a similar protocol, with the eventual goal of determining whether urate-lowering therapy prevents recurrent calcium stones. Treatments for cystinuria have advanced little in the past 30 years. Atomic force microscopy has been used recently to demonstrate that effective inhibition of cystine crystal growth is accomplished at low concentrations of L-cystine methyl ester and L-cystine dimethyl ester, structural analogs of cystine that provide steric inhibition of crystal growth. In vitro, L-cystine dimethyl ester had a significant inhibitory effect on crystal growth. The drug’s safety and effectiveness will be tested in an Slc3a1 knockout mouse that serves as an animal model of cystinuria. Clin J Am Soc Nephrol 6: 2093–2097, 2011. doi: 10.2215/CJN.00320111
Villis R. Marshall - One of the best experts on this subject based on the ideXlab platform.
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Dissolved urate salts out calcium oxalate in undiluted human urine in vitro: implications for calcium oxalate stone genesis.
Chemistry & Biology, 2003Co-Authors: Phulwinder K. Grover, Villis R. Marshall, Rosemary L. RyallAbstract:Abstract Hyperuricosuria has long been documented as a predisposing factor to calcium oxalate (CaOx) stone pathogenesis. However, its mechanism is still without sound scientific foundation. Previously, we showed that Hyperuricosuria, simulated by the addition of dissolved sodium urate, promotes the crystallization of CaOx. In the present study, we demonstrate that the urate's effect on the crystallization is attributable to its salting out CaOx from solution. Furthermore, analysis of urines revealed that their metastable limit decreased with increases in the product of the prevailing concentrations of calcium and urate: this has implications for CaOx stone genesis. We also outline anti-salting out strategies for future research for the prevention and/or treatment of CaOx calculi.
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effect of urate on calcium oxalate crystallization in human urine evidence for a promotory role of Hyperuricosuria in urolithiasis
Clinical Science, 1990Co-Authors: Phulwinder K. Grover, Rosemary L. Ryall, Villis R. MarshallAbstract:: 1. The effect of Hyperuricosuria, simulated by increasing the concentration of dissolved urate, on the crystallization of calcium oxalate in human urine was examined. 2. Twenty urine samples were studied. Ten of these, designated type A, spontaneously precipitated calcium oxalate dihydrate crystals upon the addition of a solution of sodium urate solution which raised the median urate concentration from 3.1 to 7.0 mmol/l. 3. Adding dissolved urate to the remaining type B samples raised the median urate concentration from 2.2 to 6.2 mmol/l, but did not cause the precipitation of calcium oxalate. This was induced in these samples by the addition of a standard load of oxalate above an empirically determined metastable limit. 4. In the type B urine samples, the addition of urate decreased the median metastable limit from 125 to 66 mumol of oxalate, trebled the median volume of crystalline calcium oxalate deposited from 35,000 to 105,000 microns3/microliters and significantly increased the overall size of the particles precipitated. Calcium oxalate monohydrate was exclusively precipitated, and the individual crystals deposited in the presence of urate were markedly smaller, more numerous, and more highly aggregated than those produced in its absence. 5. These results constitute the most convincing evidence yet obtained that Hyperuricosuria may be a powerful promoter of calcium oxalate stone formation.
Danika L Bannasch - One of the best experts on this subject based on the ideXlab platform.
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estimated frequency of the canine Hyperuricosuria mutation in different dog breeds
Journal of Veterinary Internal Medicine, 2010Co-Authors: Nili Karmi, Emily A Brown, S S Hughes, B Mclaughlin, Cathryn S Mellersh, V Biourge, Danika L BannaschAbstract:Background: Hyperuricosuria is a condition that predisposes dogs to urate urolithiasis. A mutation that causes canine Hyperuricosuria was previously identified in 3 unrelated dog breeds. The occurrence of the mutation in additional breeds was not determined. Hypothesis/Objectives: Identify additional breeds that have the Hyperuricosuria mutation and estimate the mutant allele frequency in those breeds. Animals: Three thousand five hundred and thirty dogs from 127 different breeds were screened for the Hyperuricosuria mutation. Methods: DNA samples were genotyped by pyrosequencing and allele-specific polymerase chain reaction methods. Results: Mutant allele frequencies that range from 0.001 to 0.15 were identified in the American Staffordshire Terrier, Australian Shepherd, German Shepherd Dog, Giant Schnauzer, Parson (Jack) Russell Terrier, Labrador Retriever, Large Munsterlander, Pomeranian, South African Boerboel, and Weimaraner breeds. Conclusions and Clinical Importance: The Hyperuricosuria mutation has been identified in several unrelated dog breeds. The mutant allele frequencies vary among breeds and can be used to determine an appropriate breeding plan for each breed. A DNA test is available and may be used by breeders to decrease the mutant allele frequency in breeds that carry the mutation. In addition, veterinarians may use the test as a diagnostic tool to identify the cause of urate urolithiasis.
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validation of a urine test and characterization of the putative genetic mutation for Hyperuricosuria in bulldogs and black russian terriers
American Journal of Veterinary Research, 2010Co-Authors: Nili Karmi, Noa Safra, Amy E Young, Danika L BannaschAbstract:Objective—To determine whether Hyperuricosuria was a predisposing factor for urate urolithiasis in Bulldogs and Black Russian Terriers (BRTs) and to estimate the allele frequency of the Cys181Phe genetic mutation in urate transporter SLC2A9 in these breeds. Animals—192 Bulldogs, 101 BRTs, 10 Dalmatians, and 9 dogs of other breeds. Procedures—Uric acid (UA) and creatinine (Cr) concentrations were quantified in urine samples collected from all dogs via midstream catch during natural voiding. Buccal swab or blood samples were also obtained, and DNA was extracted and used to genotype SLC2A9 sequence variants by use of pyrosequencing assays. A urine test for Hyperuricosuria was validated in adult dogs by comparing urinary UA:Cr ratios between known hyperuricosuric and nonhyperuricosuric dogs. Results—Significantly higher UA:Cr ratios were found in some Bulldogs and BRTs, compared with ratios in other dogs from these breeds. These dogs were also homozygous for the SLC2A9 Cys181Phe mutation. The allele frequency...
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mutations in the slc2a9 gene cause Hyperuricosuria and hyperuricemia in the dog
PLOS Genetics, 2008Co-Authors: Danika L Bannasch, Nili Karmi, Noa Safra, Amy E Young, R S Schaible, G V LingAbstract:Allantoin is the end product of purine catabolism in all mammals except humans, great apes, and one breed of dog, the Dalmatian. Humans and Dalmatian dogs produce uric acid during purine degradation, which leads to elevated levels of uric acid in blood and urine and can result in significant diseases in both species. The defect in Dalmatians results from inefficient transport of uric acid in both the liver and renal proximal tubules. Hyperuricosuria and hyperuricemia (huu) is a simple autosomal recessive trait for which all Dalmatian dogs are homozygous. Therefore, in order to map the locus, an interbreed backcross was used. Linkage mapping localized the huu trait to CFA03, which excluded the obvious urate transporter 1 gene, SLC22A12. Positional cloning placed the locus in a minimal interval of 2.5 Mb with a LOD score of 17.45. A critical interval of 333 kb containing only four genes was homozygous in all Dalmatians. Sequence and expression analyses of the SLC2A9 gene indicated three possible mutations, a missense mutation (G616T;C188F) and two promoter mutations that together appear to reduce the expression levels of one of the isoforms. The missense mutation is associated with Hyperuricosuria in the Dalmatian, while the promoter SNPs occur in other unaffected breeds of dog. Verification of the causative nature of these changes was obtained when hyperuricosuric dogs from several other breeds were found to possess the same combination of mutations as found in the Dalmatian. The Dalmatian dog model of Hyperuricosuria and hyperuricemia underscores the importance of SLC2A9 for uric acid transport in mammals.
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linkage analysis with an interbreed backcross maps dalmatian Hyperuricosuria to cfa03
Mammalian Genome, 2006Co-Authors: Noa Safra, Robert H Schaible, Danika L BannaschAbstract:Dalmatians, like humans, excrete uric acid in their urine. All other dogs and most mammals excrete allantoin, a water-soluble compound that is further along the purine degradation pathway. Excretion of uric acid at high concentrations (Hyperuricosuria) predisposes Dalmatians to the formation of urinary urate calculi. Hyperuricosuria (huu) is found in all Dalmatians tested and is inherited as an autosomal recessive trait. A genome scan and linkage analysis performed on a Dalmatian × Pointer interbreed backcross detected a single linked marker, REN153P03, located on CFA03. Haplotype analysis of the region around this marker defined a 3.3-Mb interval flanked by single recombination events. This interval, which contains the huu mutation, is estimated to include 24 genes.
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exclusion of urate oxidase as a candidate gene for Hyperuricosuria in the dalmatian dog using an interbreed backcross
Journal of Heredity, 2005Co-Authors: Noa Safra, G V Ling, R H Schaible, Danika L BannaschAbstract:Hyperuricosuria, an autosomal recessive disorder, is characterized by high levels of uric acid in the urine of Dalmatian dogs. Whereas high levels of uric acid are known to be caused by the silencing of the urate oxidase (uox) gene in humans and higher primates, the molecular basis for the Dalmatian defect is unknown. Transplantation studies show that the organ responsible for the Dalmatian phenotype is the liver, which is where urate oxidase is exclusively expressed and uric acid is converted into allantoin. We cloned and sequenced the canine uox cDNA and compared the sequence between a Dalmatian and non-Dalmatian dog. No change in cDNA sequence was identified. A Dalmatian 3 pointer backcross family was used to track the segregation of microsatellite markers surrounding the urate oxidase locus. The uox gene was excluded for Dalmatian Hyperuricosuria based on the cDNA sequence identity and negative LOD scores.
Cesare Polito - One of the best experts on this subject based on the ideXlab platform.
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differing urinary urea excretion among children with idiopathic hypercalciuria and or Hyperuricosuria
Journal of Pediatric Urology, 2008Co-Authors: Cesare Polito, Angela La Manna, Giuseppe Signoriello, Giuliana LamaAbstract:Abstract Objective To estimate dietary protein intake in children with idiopathic hypercalciuria (HC) and/or Hyperuricosuria (HU). Patients and methods We compared the 24-h urinary excretion of urea, as a reflection of protein intake, in four age- and sex-matched groups, each comprising 56 consecutive children: (1) HC, (2) HU, (3) HC + HU and (4) control. Results Urinary urea excretion was significantly higher in HC, HU and HC + HU than in controls. HC and HU children had similar urea excretion. HC + HU children had urinary urea significantly higher than HC and HU, but urinary calcium similar to HC and urinary uric acid excretion similar to HU subjects. Urinary calcium was significantly (R2 = 0.21) correlated with urea excretion in HC children only, whereas urinary uric acid was significantly (R2 = 0.21) correlated with urinary urea in HU children only. No significant correlation between urinary urea and calcium or uric acid excretion was found in HC + HU patients although they had the highest urinary urea. A significant (p = 0.004) interaction between urinary urea and sodium in increasing urinary calcium excretion resulted only in the HC group. Conclusion The association of dietary protein excess with HC and/or HU is conditioned by an individual (genetic?) predisposition and may be produced by different mechanisms.
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Differing urinary urea excretion among children with idiopathic hypercalciuria and/or Hyperuricosuria
Journal of Pediatric Urology, 2007Co-Authors: Cesare Polito, Angela La Manna, Giuseppe Signoriello, Giuliana LamaAbstract:Abstract Objective To estimate dietary protein intake in children with idiopathic hypercalciuria (HC) and/or Hyperuricosuria (HU). Patients and methods We compared the 24-h urinary excretion of urea, as a reflection of protein intake, in four age- and sex-matched groups, each comprising 56 consecutive children: (1) HC, (2) HU, (3) HC + HU and (4) control. Results Urinary urea excretion was significantly higher in HC, HU and HC + HU than in controls. HC and HU children had similar urea excretion. HC + HU children had urinary urea significantly higher than HC and HU, but urinary calcium similar to HC and urinary uric acid excretion similar to HU subjects. Urinary calcium was significantly (R2 = 0.21) correlated with urea excretion in HC children only, whereas urinary uric acid was significantly (R2 = 0.21) correlated with urinary urea in HU children only. No significant correlation between urinary urea and calcium or uric acid excretion was found in HC + HU patients although they had the highest urinary urea. A significant (p = 0.004) interaction between urinary urea and sodium in increasing urinary calcium excretion resulted only in the HC group. Conclusion The association of dietary protein excess with HC and/or HU is conditioned by an individual (genetic?) predisposition and may be produced by different mechanisms.
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appendectomy in children with hypercalciuria Hyperuricosuria
Journal of Pediatric Urology, 2005Co-Authors: Cesare Polito, Antonio Marte, Angela La MannaAbstract:Abstract Recurrent abdominal pains (RAPs) represent a common problem in children sometimes leading to unnecessary and invasive procedures. The rates of appendectomy were evaluated consecutively in 180 children with idiopathic hypercalciuria (HC) and/or Hyperuricosuria (HU) and RAPs, and in 270 control subjects. Of the HC/HU patients 10% and of controls 1.5% underwent appendectomy (p The inconstant association of dysuria and hematuria with RAPs in children with HC/HU may lead to the urological origin of pain being overlooked, and may explain the high rate of appendectomy among these children. The possibility of HC/HU therefore should be taken into account in children with RAPs even when dysuria and hematuria are not present.
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Appendectomy in children with hypercalciuria/Hyperuricosuria.
Journal of Pediatric Urology, 2005Co-Authors: Cesare Polito, Antonio Marte, Angela La MannaAbstract:Abstract Recurrent abdominal pains (RAPs) represent a common problem in children sometimes leading to unnecessary and invasive procedures. The rates of appendectomy were evaluated consecutively in 180 children with idiopathic hypercalciuria (HC) and/or Hyperuricosuria (HU) and RAPs, and in 270 control subjects. Of the HC/HU patients 10% and of controls 1.5% underwent appendectomy (p The inconstant association of dysuria and hematuria with RAPs in children with HC/HU may lead to the urological origin of pain being overlooked, and may explain the high rate of appendectomy among these children. The possibility of HC/HU therefore should be taken into account in children with RAPs even when dysuria and hematuria are not present.
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Growth and bone mineral density in long-lasting idiopathic hypercalciuria.
Pediatric Nephrology, 2003Co-Authors: Cesare Polito, Giovanni Iolascon, Barbara Nappi, Saverio Andreoli, Angela La MannaAbstract:Growth retardation and osteopenia have been reported in some children with idiopathic hypercalciuria (IHC), particularly in those with nephrocalcinosis. The duration of hypercalciuria might be a risk factor for osteopenia. A retrospective longitudinal analysis of statural growth and a cross-sectional evaluation of bone mineral density (BMD) was carried out in 26 IHC children followed for 4–13 years. None of the patients had nephrocalcinosis. Growth, including pubertal growth spurt, was normal in all subjects. BMD Z score less than −1 was recorded in 3 subjects with Hyperuricosuria. BMD Z score averaged −0.68±0.99 in the 9 subjects with associated Hyperuricosuria and 0.21±0.64 in the 17 with occasional or no Hyperuricosuria (P=0.018). Our analysis shows that children with long-lasting IHC without nephrocalcinosis have normal growth, but those with associated Hyperuricosuria may be at risk for osteopenia.
A Andres - One of the best experts on this subject based on the ideXlab platform.
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familial microscopic hematuria caused by hypercalciuria and Hyperuricosuria
American Journal of Kidney Diseases, 2000Co-Authors: Manuel Praga, Raquel Alegre, Eduardo Hernandez, Enrique Morales, Beatriz Dominguezgil, A Carreno, A AndresAbstract:Abstract We report 12 patients belonging to five different families in whom persistent isolated microhematuria was associated with hypercalciuria and/or Hyperuricosuria. Four patients had episodes of gross hematuria, three patients had passed renal stones, and a history of nephrolithiasis was obtained in four of the families (80%). Calcium oxalate and uric acid crystals were commonly observed in the urine sediments. Urinary erythrocytes had a normal appearance on phase-microscopic examination. Reduction of calciuria and uricosuria by thiazide diuretics, allopurinol, forced fluid intake, and dietetic measures led to a persistent normalization of urine sediment with complete disappearance of hematuria. Determination of calcium and uric acid urinary excretions should be included in the study of familial hematuria.
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association of thin basement membrane nephropathy with hypercalciuria Hyperuricosuria and nephrolithiasis
Kidney International, 1998Co-Authors: Manuel Praga, A Andres, Raquel Alegre, Enrique Morales, Miguel Angel Martinez, Julia Vara, J C Herrero, Olga Novo, J L RodicioAbstract:Association of thin basement membrane nephropathy with hyper- calciuria, Hyperuricosuria and nephrolithiasis. Background. Familial persistent microhematuria with normal renal function is the most common presentation of thin basement membrane nephropathy (TBMN). Gross hematuria episodes and loin pain attacks are other manifestations of the disease. On the other hand, it has been shown that hypercalciuria (HC) and Hyperuricosuria (HU) can produce both gross or microscopic non-glomerular hematuria, in addition to their role in renal stone formation. Methods. We studied the prevalence of HC, HU and nephroli- thiasis in a group of 27 biopsy-proven TBMN as well as in 19 non-biopsied first-degree relatives with persistent microhematuria and 25 first-degree relatives without microhematuria. A group of 27 patients with IgA nephropathy (IgAN) and persistent micro- hematuria, and another group of 20 healthy subjects without known renal diseases were selected as control groups. Results. Ten (37%) patients with TBMN and 8 (42%) relatives with microhematuria showed HC and/or HU at presentation; relatives without microhematuria, IgAN patients and normal controls showed a significantly lower prevalence of HC and HU. The prevalence of previous nephrolithiasis among TBMN patients (25%) was significantly higher than in IgAN patients (3%; P , 0.05). Family history of nephrolithiasis was recorded in 14 (51%) of the 27 TBMN families, in contrast with 2 of 27 (7%) with IgAN and 1 of 20 (5%) in normal controls (P , 0.05). The prevalence of nephrolithiasis, gross hematuria bouts and loin pain episodes among TBMN patients and microhematuric relatives showing HC and/or HU at presentation (44%, 44% and 27%, respectively) were significantly higher than those of TBMN patients and microhematuric relatives with normal calcium and uric acid urinary excretions (10%, 7% and 3%, respectively; P , 0.05). At the end of follow-up (8.8 6 4.1 years in TBMN patients and 9.1 6 4.2 years in relatives with microhematuria), all the cases main- tained normal renal function. Conclusions. We found a high prevalence of HC, HU, and nephrolithiasis among TBMN patients and relatives with micro- hematuria. Our study also shows a significant relationship be- tween the presence of HC and/or HU and the prevalence of nephrolithiasis, gross hematuria bouts and loin pain episodes. Hypercalciuria (HC) and Hyperuricosuria (HU) are im- portant lithogenic factors (1). In addition, several studies have showed that both metabolic disturbances can be associated with persistent microscopic hematuria in the absence of radiographically detectable calculi (2-11). When urinary calcium and uric acid are reduced by hydrochlo- rothiazide or allopurinol, respectively, hematuria resolves in most cases. We have observed several patients with persistent micro- hematuria associated with HC and/or HU in whom micro- hematuria persisted in spite of the treatment of these metabolic abnormalities. A later renal biopsy established the diagnosis of thin basement membrane nephropathy (TBMN) in most of them. These observations prompted us to review the history of all those patients diagnosed of TBMN at the Hospital Universitario 12 de Octubre. Our study shows a high prevalence of HC, HU and nephrolithi- asis among patients with TBMN and their families. Our findings also suggest that some clinical manifestations of the disease, such as episodes of gross hematuria and loin pain attacks, could be related to the presence of HC and/or HU.
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hypercalciuria and Hyperuricosuria causing hematuria in the absence of nephrolithiasis
Actas Urologicas Espanolas, 1990Co-Authors: Rodriguez Antolin A, F J Calahorra, Maria Jose Castro, A Andres, Cecilia Montoyo, Manuel PragaAbstract:: A prospective study was made of 38 adult patients (15 male and 23 female, age 30.5 +/- 10.8 years) with isolated hematuria of unknown etiology in which presence of hypercalciuria and/or Hyperuricosuria without lithiasis was observed. Eighteen patients also referred episodes of macroscopic hematuria. Twenty-six patients had hypercalciuria (5.1 +/- 1.4 mg/kg/day), 29 Hyperuricosuria (1053 +/- 198 mg/day) and 17 presented both alterations. A four months treatment was instituted with thiazides in patients with hypercalciuria and allopurinol in those with Hyperuricosuria. From the first months and throughout the whole therapy, urinary excretion of calcium an uric acid became normalized in all cases. In 22 patients (57.8%) (Group I: Respondents) hematuria disappeared coinciding with normalization of calcium and uric acid values in urine and was maintained during the follow-up months. In the remaining 16 patients (Group II: Non-Respondents) the hematuria condition persisted in spite of such normalization, in most cases other causes for hematuria becoming clear later. No differences with regard to age, relationship male/female nor basal calciuria and uricosuria values were seen between both Groups. Group I had a greater incidence of macroscopic hematuria episodes (64% vs 12% in Group II, p less than 0.01) and of family nephrolithiasis (64 vs 25% in Group II, p less than 0.05). We conclude that hypercalciuria and hyperuticosuria are potentially reversible causes of hematuria in adults. Therefore, urinary determination of calcium and uric acid should be included in urinary evaluation of patients with hematuria even though they do not present renal lithiasis.