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P Varalakshmi - One of the best experts on this subject based on the ideXlab platform.
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beneficial role of sulfated polysaccharides from edible seaweed fucus vesiculosus in experimental Hyperoxaluria
Food Chemistry, 2007Co-Authors: Coothan Kandaswamy Veena, Anthony Josephine, Sreenivasan P Preetha, P VaralakshmiAbstract:Abstract Sulfated polysaccharides from marine algae are known to possess numerous properties of pharmacological importance. The present study is an attempt to evaluate the efficacy of the sulfated polysaccharides from edible seaweed, Fucus vesiculosus in ameliorating the abnormal biochemical changes in experimental Hyperoxaluria. Two groups of male albino rats of Wistar strain (140 ± 20 g) received 0.75% ethylene glycol for 28 days to induce Hyperoxaluria, and one of them received sulfated polysaccharides (fucoidan from F. vesiculosus , 5 mg/kg b.wt., s.c.) treatment, commencing from the 8th day of the experimental period. One group was maintained as a control group and another group served as a drug control, which received only sulfated polysaccharides. Incongruity in the renal tissue enzymes (ALP, β-Glu and γ-GT) were observed during Hyperoxaluria along with an increased activity of oxalate metabolizing enzymes like LDH, GAO and XO. These changes were reverted to near normalcy with sulfated polysaccharide administration. Alterations were observed in the activities/levels of tissue enzymic (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione S-transferase and glucose-6-phosphate dehydrogenase) and non-enzymic (reduced glutathione, ascorbate and α-tocopherol) antioxidants, along with high malondialdehyde levels in the hyperoxaluric group. However, normalized lipid peroxidation status and antioxidant defences were noticed with sulfated polysaccharide administration. Biochemical discrepancies observed in Hyperoxaluria disrupt membrane integrity, favouring a milieu for crystal retention. Advocation of sulfated polysaccharides enhanced the antioxidant status, thereby preventing membrane injury and alleviating the microenvironment favourable for stone formation.
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oral l arginine supplementation ameliorates urinary risk factors and kinetic modulation of tamm horsfall glycoprotein in experimental hyperoxaluric rats
Clinica Chimica Acta, 2005Co-Authors: Viswanathan Pragasam, Periandavan Kalaiselvi, Kamalanathan Sumitra, Shanmugarajan Srinivasan, P VaralakshmiAbstract:Abstract Background Oral supplementation of l -arginine ( l -arg) is found to be beneficial in many kidney disorders. We determined whether l -arg supplementation safeguards the renal epithelial cell damage induced by Hyperoxaluria with excretion of urinary marker enzymes and lithogenic salts with special reference to Tamm–Horsfall glycoprotein (THP). Methods Hyperoxaluria was induced by 0.75% ethylene glycol (EG) in drinking water. l -Arg was co-supplemented at the dose of 1.25 g/kg b.w. orally for 28 days. At the end of experimental period, 24-h urine samples were collected in all the experimental groups. Isolation and purification of THP was carried in rat urine and were subjected to spectrophotometric crystallization assay and calcium– 14 C-oxalate binding studies. Determination of the lithogenic risk factors like calcium, oxalate, phosphorus, citrate, and marker enzymes such as lactate dehydrogenase (LDH) and γ-glutamyltransferase (γ-GT) were carried out in the collected urine sample. Results Urinary excretion of calcium and oxalate was significantly increased in EG-treated rats. In l -arg supplemented hyperoxaluric rats, these concentrations were significantly ( p l -arg supplemented EG-treated rats. Citrate excretion was enhanced in the l -arg co-supplemented hyperoxaluric rats. In spectrophotometric crystallization assay system, l -arg supplemented rat THP showed inhibition in nucleation and aggregation phases, whereas EG-treated rat THP showed promotion of both calcium oxalate nucleation and aggregation phases. In calcium– 14 C-oxalate binding assay, THP derived from hyperoxaluric rats exhibited 2-fold increase ( p l -arg supplemented animals. Conclusions l -Arg could act as a potent antilithic agent, by increasing the level of citrate in the Hyperoxaluria-induced rats and decreasing calcium oxalate binding to the THP. l -Arg also effectively prevents the deposition of calcium oxalate crystals by curtailing the renal epithelial damage and protein oxidation as evidenced by the normal activities of urinary marker enzymes in l -arg supplemented hyperoxaluric rats.
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beneficial effect of vitamin e supplementation on the biochemical and kinetic properties of tamm horsfall glycoprotein in hypertensive and hyperoxaluric patients
Nephrology Dialysis Transplantation, 2005Co-Authors: Kamalanathan Sumitra, Viswanathan Pragasam, Periandavan Kalaiselvi, Ramasamy Sakthivel, P VaralakshmiAbstract:Background. This study aimed to assess the therapeutic efficacy of oral vitamin E supplementation on the biochemical and kinetic properties of Tamm–Horsfall glycoprotein (THP) in hypertensive and hyperoxaluric patients. Methods. Newly detected hypertensives (n ¼ 200) and stone formers (n ¼ 200) were each subdivided into two groups. One group (n ¼ 100) was administered the antioxidant vitamin E at 400 mg/day given as an oral supplement along with standard therapeutic drugs for hypertension and Hyperoxaluria and the patients were followed for a period of 9 months. The other group (n ¼ 100) did not receive vitamin E (placebo controls). Age and sex-matched controls (n ¼ 100) were monitored simultaneously. THP was isolated from 24 h urine samples before and at the end of every third month during a period of 9 months from the vitamin Etreated hypertensive and hyperoxaluric groups. THP samples were also collected from control subjects, and at the end of the ninth month from placebo controls. The isolated protein was assessed for purity by SDS–PAGE. The purity-checked proteins were subjected to spectrophotometric crystallization assay, calcium oxalate (CaOx) crystal interaction studies, and biochemical analysis of sialic acid, thiol and carbonyl content. Plasma superoxide, hydroxyl radical, hydrogen peroxide and vitamin E levels as well as superoxide dismutase and catalase activities were also monitored. Results. The THP from the hypertensive and hyperoxaluric subjects exhibited a significant promoting effect on the nucleation and aggregation phases and caused a concomitant increase in CaOx crystal interaction. The altered kinetic properties of THP in these subjects were strongly associated with increased carbonyl content and with decreased thiol and sialic acid contents. Oral administration of vitamin E to these patients caused near normalization of these biochemical alterations and satisfactorily restored the kinetic properties of THP to near normal activity. At the end of 9 months, THP isolated from placebo controls (hypertensive and hyperoxaluric) showed highly aggregated calcium oxalate monohydrate crystals as observed by light microscopy. In contrast, vitamin E-supplemented patients showed CaOx dihydrate crystals that were similar to control THP. There was an imbalance in the oxidant and antioxidant levels. For the oxidants, superoxide, hydrogen peroxide and hydroxyl radical levels were increased, and for the antioxidants, there was loss of antioxidant enzyme activities and a decline in plasma vitamin E level in both hypertensive and hyperoxaluric patients. Supplementary antioxidant (vitamin E) corrected this imbalance to near normal conditions. Conclusion. We hypothesize that the loss of THP inhibitory activity in the hypertensive and hyperoxaluric patients in a crystallizing medium is mediated primarily by oxidative damage to this protein. The possible occurrence of renal stones in essential hypertensive subjects, and the risk of recurrence in hyperoxaluric subjects, may be explained by oxidative damage to renal tissues that remained unchecked by standard drug therapies. The normalization of the kinetic properties of THP following vitamin E supplementation is in support of our hypothesis.
Bernd Hoppe - One of the best experts on this subject based on the ideXlab platform.
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Plasma oxalate levels in primary Hyperoxaluria type I show significant intra-individual variation and do not correlate with kidney function
Pediatric Nephrology, 2020Co-Authors: Philip Hillebrand, Bernd HoppeAbstract:Background Primary Hyperoxalurias are rare diseases with endogenous overproduction of oxalate, thus leading to Hyperoxaluria, hyperoxalemia, urolithiasis, and/or nephrocalcinosis and eventually early kidney failure. Plasma oxalate (POx) is an important diagnostic parameter in clinical studies on primary Hyperoxaluria (PH). This is especially the case in kidney failure, where urinary parameters are no longer suitable. We aimed to evaluate whether POx would be an adequate endpoint for clinical studies in PH patients with stable kidney function. In addition, the correlation of POx to serum creatinine (SCr) and calculated glomerular filtration rate (eGFR) was examined. Methods We retrospectively analyzed follow-up of individual POx values over time, as well as POx correlation to SCr, eGFR, and vitamin B6 (VB6), a common therapeutic in PH1. Results from 187 blood samples taken between 2009 and 2017, during routine laboratory evaluations from 41 patients with PH1 who had neither undergone dialysis nor transplantation, were evaluated. Results Negligibly low correlation coefficients (CCs) between POx vs. SCr (CC = -0.0950), POx vs. eGFR (CC = −0.1237), and POx vs. VB6 (CC = 0.1879) were found, with the exception of CKD stage 3a patients, who showed a positive correlation (CC of − 0.7329, POx vs eGFR). The intra-individual analysis of POx over time showed a high fluctuation of POx values. Conclusion We conclude that POx has a limited validity as a primary endpoint for clinical studies in PH1 patients with stable kidney function. In addition, it does not correlate to SCr and eGFR in this group of patients.
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an update on primary Hyperoxaluria
Nature Reviews Nephrology, 2012Co-Authors: Bernd HoppeAbstract:The autosomal recessive inherited primary Hyperoxalurias types I, II and III are caused by defects in glyoxylate metabolism that lead to the endogenous overproduction of oxalate. Type III primary Hyperoxaluria was first described in 2010 and further types are likely to exist. In all forms, urinary excretion of oxalate is strongly elevated (>1 mmol/1.73 m(2) body surface area per day; normal 30% of patients with primary Hyperoxaluria type I. The fact that such a large proportion of patients have such poor outcomes is particularly unfortunate as ESRD can be delayed or even prevented by early intervention. Treatment options for primary Hyperoxaluria include alkaline citrate, orthophosphate, or magnesium. In addition, pyridoxine treatment can be used to normalize or reduce oxalate excretion in about 30% of patients with primary Hyperoxaluria type I. Time on dialysis should be short to avoid overt systemic oxalosis. Transplantation methods depend on the type of primary Hyperoxaluria and on the particular patient, but combined liver and kidney transplantation is the method of choice in patients with primary Hyperoxaluria type I and isolated kidney transplantation is the preferred method in those with primary Hyperoxaluria type II. To the best of our knowledge, progression to ESRD has not yet been reported in any patient with primary Hyperoxaluria type III.
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The primary Hyperoxalurias.
Kidney international, 2009Co-Authors: Bernd Hoppe, Bodo B. Beck, Dawn S MillinerAbstract:The primary Hyperoxalurias (PHs) are rare disorders of glyoxylate metabolism in which specific hepatic enzyme deficiencies result in overproduction of oxalate. Due to the resulting severe Hyperoxaluria, recurrent urolithiasis or progressive nephrocalcinosis are principal manifestations. End stage renal failure frequently occurs and is followed by systemic oxalate deposition along with its devastating effects. Due to the lack of familiarity with PHs and their heterogeneous clinical expressions, the diagnosis is often delayed until there is advanced disease. In recent years, improvements in medical management have been associated with better patient outcomes. Although there are several therapeutic options that can help prevent early kidney failure, the only curative treatment to date is combined liver–kidney transplantation in patients with type I PH. Promising areas of investigation are being identified. Knowledge of the spectrum of disease expression, early diagnosis, and initiation of treatment before renal failure are essential to realize a benefit for patients.
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[13C2]oxalate absorption in children with idiopathic calcium oxalate urolithiasis or primary Hyperoxaluria
Kidney International, 2008Co-Authors: Przemyslaw Sikora, G.e. Von Unruh, Bodo B. Beck, Markus Feldkötter, M. Zajączkowska, A. Hesse, Bernd HoppeAbstract:Intestinal oxalate absorption is an important part of oxalate metabolism influencing its urinary excretion and its measurement can be a valuable diagnostic tool in hyperoxaluric disorders. In this study, we use [ 13 C 2 ]oxalate absorption under standardized dietary conditions to assess intestinal oxalate absorption and its impact on urinary oxalate excretion. Tests were conducted in age-matched pediatric patients that included 60 with idiopathic calcium oxalate urolithiasis, 13 with primary Hyperoxaluria, and 35 healthy children. In the idiopathic stone formers, median oxalate absorption was significantly higher than that in the controls or in patients with primary disease. From standardized values obtained in control patients, oxalate hyperabsorption was detected in 23 patients with idiopathic disease but not in any patients with primary Hyperoxaluria; therefore, a significant correlation between intestinal absorption and urinary excretion was found only in those with the idiopathic disease. We have shown that increased intestinal oxalate absorption is an important risk factor of idiopathic calcium oxalate urolithiasis. In contrast, low intestinal oxalate absorption in patients with primary Hyperoxaluria indicates that only foods with excessive oxalate content be restricted from their diet.
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Diagnostic and therapeutic approaches in patients with secondary Hyperoxaluria.
Frontiers in bioscience : a journal and virtual library, 2003Co-Authors: Bernd Hoppe, G.e. Von Unruh, Ernst Leumann, Norbert Laube, Albrecht HesseAbstract:Secondary Hyperoxaluria is due either to increased intestinal oxalate absorption or to excessive dietary oxalate intake. Certain intestinal diseases like short bowel syndrome, chronic inflammatory bowel disease or cystic fibrosis and other malabsorption syndromes are known to increase the risk of secondary Hyperoxaluria. Although the urinary oxalate excretion is usually lower than in primary Hyperoxaluria, it may still lead to significant morbidity by recurrent urolithiasis or progressive nephrocalcinosis. A clear distinction between primary and secondary Hyperoxalurias is important. As correct classification may be difficult, appropriate diagnostic tools are needed to delineate the metabolic background as a basis for optimal treatment. We developed an individual approach for the evaluation of patients with suspected secondary Hyperoxaluria. First, 24 h urines are examined repeatedly for lithogenic (e.g. calcium, oxalate, uric acid) and stone-inhibitory (e.g. citrate, magnesium) substances, and the patients are asked to fill in a dietary survey form. Urinary saturation is calculated using the computer based program EQUIL2, and the BONN-Risk-index is determined. The measurement of plasma oxalate and of urinary glycolate helps to distinguish between primary and secondary Hyperoxalurias. If secondary Hyperoxaluria is suspected, the stool is examined for Oxalobacter formigenes, an intestinal oxalate degrading bacterium, as lack or absence may lead to increased intestinal oxalate absorption. The last diagnostic step is to study the intestinal oxalate absorption using [13C2]oxalate. Depending on the results, various therapeutic options are available: 1) a diet low in oxalate, but normal or high in calcium, 2) a high fluid intake (>1.5 L/m2/d), 3) medications to increase the urinary solubility, 4) specific therapeutic measures in patients with malabsorption syndromes, depending on the underlying pathology, and 5) intestinal recolonization of Oxalobacter formigenes or the treatment with other oxalate degrading bacteria.
M. Marangella - One of the best experts on this subject based on the ideXlab platform.
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End-Stage Renal Failure in Primary Hyperoxaluria Type 2
The New England journal of medicine, 1994Co-Authors: M. Marangella, M Petrarulo, D CossedduAbstract:To the Editor: Primary Hyperoxaluria with l-glyceric aciduria (primary Hyperoxaluria type 2) is caused by a deficiency of d-glycerate dehydrogenase,1 which catalyzes the conversion of hydroxypyruva...
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Plasma and Urine Glycolate Assays for Differentiating the Hyperoxaluria Syndromes
The Journal of Urology, 1992Co-Authors: M. Marangella, M Petrarulo, D Cosseddu, C Vitale, F LinariAbstract:AbstractTo differentiate Hyperoxaluria syndromes we measured plasma and urine glycolate by a novel high performance liquid chromatographic procedure. Mean glycolate level was 7.9 ± 2.4μmol./l. in plasma and 422 ± 137μmol./24 hours in urine from 19 control subjects. Renal clearance was about 50% the glomerular filtration rate irrespective of the underlying disease. There was close correlation between glycolate and oxalate in plasma. Plasma glycolate was normal in all but 8 patients who had primary Hyperoxaluria 1. Plasma assay detected the disease more efficiently than urine assay. Pyridoxine decreased oxalate biosynthesis in 2 of the 4 patients treated with it and glycolate assay confirmed this behavior. Glycolate excretion was significantly high in 3 of 8 parents of primary Hyperoxaluria 1 patients. Idiopathic stone formers had mild increases in glycolate excretion but this was not related with oxalate excretion. Glycolate levels were normal in 5 patients with enteric Hyperoxaluria. We conclude that glyc...
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Plasma and urine glycolate assays for differentiating the Hyperoxaluria syndromes.
The Journal of urology, 1992Co-Authors: M. Marangella, M Petrarulo, D Cosseddu, C Vitale, F LinariAbstract:To differentiate Hyperoxaluria syndromes we measured plasma and urine glycolate by a novel high performance liquid chromatographic procedure. Mean glycolate level was 7.9 +/- 2.4 mumol./l. in plasma and 422 +/- 137 mumol./24 hours in urine from 19 control subjects. Renal clearance was about 50% the glomerular filtration rate irrespective of the underlying disease. There was close correlation between glycolate and oxalate in plasma. Plasma glycolate was normal in all but 8 patients who had primary Hyperoxaluria 1. Plasma assay detected the disease more efficiently than urine assay. Pyridoxine decreased oxalate biosynthesis in 2 of the 4 patients treated with it and glycolate assay confirmed this behavior. Glycolate excretion was significantly high in 3 of 8 patients of primary Hyperoxaluria 1 patients. Idiopathic stone formers had mild increases in glycolate excretion but this was not related with oxalate excretion. Glycolate levels were normal in 5 patients with enteric Hyperoxaluria. We conclude that glycolate assay is essential for identifying patients with primary Hyperoxaluria 1 and may represent a valuable tool for differentiating Hyperoxaluria.
F Linari - One of the best experts on this subject based on the ideXlab platform.
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Plasma and Urine Glycolate Assays for Differentiating the Hyperoxaluria Syndromes
The Journal of Urology, 1992Co-Authors: M. Marangella, M Petrarulo, D Cosseddu, C Vitale, F LinariAbstract:AbstractTo differentiate Hyperoxaluria syndromes we measured plasma and urine glycolate by a novel high performance liquid chromatographic procedure. Mean glycolate level was 7.9 ± 2.4μmol./l. in plasma and 422 ± 137μmol./24 hours in urine from 19 control subjects. Renal clearance was about 50% the glomerular filtration rate irrespective of the underlying disease. There was close correlation between glycolate and oxalate in plasma. Plasma glycolate was normal in all but 8 patients who had primary Hyperoxaluria 1. Plasma assay detected the disease more efficiently than urine assay. Pyridoxine decreased oxalate biosynthesis in 2 of the 4 patients treated with it and glycolate assay confirmed this behavior. Glycolate excretion was significantly high in 3 of 8 parents of primary Hyperoxaluria 1 patients. Idiopathic stone formers had mild increases in glycolate excretion but this was not related with oxalate excretion. Glycolate levels were normal in 5 patients with enteric Hyperoxaluria. We conclude that glyc...
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Plasma and urine glycolate assays for differentiating the Hyperoxaluria syndromes.
The Journal of urology, 1992Co-Authors: M. Marangella, M Petrarulo, D Cosseddu, C Vitale, F LinariAbstract:To differentiate Hyperoxaluria syndromes we measured plasma and urine glycolate by a novel high performance liquid chromatographic procedure. Mean glycolate level was 7.9 +/- 2.4 mumol./l. in plasma and 422 +/- 137 mumol./24 hours in urine from 19 control subjects. Renal clearance was about 50% the glomerular filtration rate irrespective of the underlying disease. There was close correlation between glycolate and oxalate in plasma. Plasma glycolate was normal in all but 8 patients who had primary Hyperoxaluria 1. Plasma assay detected the disease more efficiently than urine assay. Pyridoxine decreased oxalate biosynthesis in 2 of the 4 patients treated with it and glycolate assay confirmed this behavior. Glycolate excretion was significantly high in 3 of 8 patients of primary Hyperoxaluria 1 patients. Idiopathic stone formers had mild increases in glycolate excretion but this was not related with oxalate excretion. Glycolate levels were normal in 5 patients with enteric Hyperoxaluria. We conclude that glycolate assay is essential for identifying patients with primary Hyperoxaluria 1 and may represent a valuable tool for differentiating Hyperoxaluria.
Dawn S Milliner - One of the best experts on this subject based on the ideXlab platform.
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Pathophysiology and Treatment of Enteric Hyperoxaluria
Clinical journal of the American Society of Nephrology : CJASN, 2020Co-Authors: Celeste Witting, Dawn S Milliner, Craig B. Langman, Dean G. Assimos, Michelle A. Baum, Annamaria Kausz, Greg Tasian, Elaine M. Worcester, Meaghan Allain, Melissa WestAbstract:Enteric Hyperoxaluria is a distinct entity that can occur as a result of a diverse set of gastrointestinal disorders that promote fat malabsorption. This, in turn, leads to excess absorption of dietary oxalate and increased urinary oxalate excretion. Hyperoxaluria increases the risk of kidney stones and, in more severe cases, CKD and even kidney failure. The prevalence of enteric Hyperoxaluria has increased over recent decades, largely because of the increased use of malabsorptive bariatric surgical procedures for medically complicated obesity. This systematic review of enteric Hyperoxaluria was completed as part of a Kidney Health Initiative-sponsored project to describe enteric Hyperoxaluria pathophysiology, causes, outcomes, and therapies. Current therapeutic options are limited to correcting the underlying gastrointestinal disorder, intensive dietary modifications, and use of calcium salts to bind oxalate in the gut. Evidence for the effect of these treatments on clinically significant outcomes, including kidney stone events or CKD, is currently lacking. Thus, further research is needed to better define the precise factors that influence risk of adverse outcomes, the long-term efficacy of available treatment strategies, and to develop new therapeutic approaches.
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end points for clinical trials in primary Hyperoxaluria
Clinical Journal of The American Society of Nephrology, 2020Co-Authors: Dawn S Milliner, Tracy L Mcgregor, Aliza Thompson, Bastian Dehmel, John Knight, Ralf Rosskamp, Melanie Blank, Sixun Yang, Sonia Fargue, Gill RumsbyAbstract:Patients with primary Hyperoxaluria experience kidney stones from a young age and can develop progressive oxalate nephropathy. Progression to kidney failure often develops over a number of years, and is associated with systemic oxalosis, intensive dialysis, and often combined kidney and liver transplantation. There are no therapies approved by the Food and Drug Association. Thus, the Kidney Health Initiative, in partnership with the Oxalosis and Hyperoxaluria Foundation, initiated a project to identify end points for clinical trials. A workgroup of physicians, scientists, patients with primary Hyperoxaluria, industry, and United States regulators critically examined the published literature for clinical outcomes and potential surrogate end points that could be used to evaluate new treatments. Kidney stones, change in eGFR, urine oxalate, and plasma oxalate were the strongest candidate end points. Kidney stones affect how patients with primary Hyperoxaluria feel and function, but standards for measurement and monitoring are lacking. Primary Hyperoxaluria registry data suggest that eGFR decline in most patients is gradual, but can be unpredictable. Epidemiologic data show a strong relationship between urine oxalate and long-term kidney function loss. Urine oxalate is reasonably likely to predict clinical benefit, due to its causal role in stone formation and kidney damage in CKD stages 1-3a, and plasma oxalate is likely associated with risk of systemic oxalosis in CKD 3b-5. Change in slope of eGFR could be considered the equivalent of a clinically meaningful end point in support of traditional approval. A substantial change in urine oxalate as a surrogate end point could support traditional approval in patients with primary Hyperoxaluria type 1 and CKD stages 1-3a. A substantial change in markedly elevated plasma oxalate could support accelerated approval in patients with primary Hyperoxaluria and CKD stages 3b-5. Primary Hyperoxaluria type 1 accounts for the preponderance of available data, thus heavily influences the conclusions. Addressing gaps in data will further facilitate testing of promising new treatments, accelerating improved outcomes for patients with primary Hyperoxaluria.
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Update on Oxalate Crystal Disease
Current Rheumatology Reports, 2013Co-Authors: Elizabeth C. Lorenz, Dawn S Milliner, Clement J. Michet, John C. LieskeAbstract:Oxalate arthropathy is a rare cause of arthritis characterized by deposition of calcium oxalate crystals within synovial fluid. This condition typically occurs in patients with underlying primary or secondary Hyperoxaluria. Primary Hyperoxaluria constitutes a group of genetic disorders resulting in endogenous overproduction of oxalate, whereas secondary Hyperoxaluria results from gastrointestinal disorders associated with fat malabsorption and increased absorption of dietary oxalate. In both conditions, oxalate crystals can deposit in the kidney leading to renal failure. Since oxalate is primarily renally eliminated, it accumulates throughout the body in renal failure, a state termed oxalosis. Affected organs can include bones, joints, heart, eyes, and skin. Since patients can present with renal failure and oxalosis before the underlying diagnosis of Hyperoxaluria has been made, it is important to consider Hyperoxaluria in patients who present with unexplained soft tissue crystal deposition. The best treatment of oxalosis is prevention. If patients present with advanced disease, treatment of oxalate arthritis consists of symptom management and control of the underlying disease process.
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The primary Hyperoxalurias.
Kidney international, 2009Co-Authors: Bernd Hoppe, Bodo B. Beck, Dawn S MillinerAbstract:The primary Hyperoxalurias (PHs) are rare disorders of glyoxylate metabolism in which specific hepatic enzyme deficiencies result in overproduction of oxalate. Due to the resulting severe Hyperoxaluria, recurrent urolithiasis or progressive nephrocalcinosis are principal manifestations. End stage renal failure frequently occurs and is followed by systemic oxalate deposition along with its devastating effects. Due to the lack of familiarity with PHs and their heterogeneous clinical expressions, the diagnosis is often delayed until there is advanced disease. In recent years, improvements in medical management have been associated with better patient outcomes. Although there are several therapeutic options that can help prevent early kidney failure, the only curative treatment to date is combined liver–kidney transplantation in patients with type I PH. Promising areas of investigation are being identified. Knowledge of the spectrum of disease expression, early diagnosis, and initiation of treatment before renal failure are essential to realize a benefit for patients.
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phenotypic and functional analysis of human slc26a6 variants in patients with familial Hyperoxaluria and calcium oxalate nephrolithiasis
American Journal of Kidney Diseases, 2008Co-Authors: Carla G Monico, Dawn S Milliner, Julie B Olson, Andrea G Cogal, Adam B Weinstein, Zhirong Jiang, Audrey L Rohlinger, Beth B Bjornson, Eric J Bergstralh, Peter S AronsonAbstract:Background Urinary oxalate is a major risk factor for calcium oxalate stones. Marked Hyperoxaluria arises from mutations in 2 separate loci, AGXT and GRHPR , the causes of primary Hyperoxaluria (PH) types 1 (PH1) and 2 (PH2), respectively. Studies of null Slc26a6 −/− mice have shown a phenotype of Hyperoxaluria, hyperoxalemia, and calcium oxalate urolithiasis, leading to the hypothesis that SLC26A6 mutations may cause or modify Hyperoxaluria in humans. Study Design Cross-sectional case-control. Setting & Participants Cases were recruited from the International Primary Hyperoxaluria Registry. Control DNA samples were from a pool of adult subjects who identified themselves as being in good health. Predictor PH1, PH2, and non-PH1/PH2 genotypes in cases. Outcomes & Measures Homozygosity or compound heterozygosity for SLC26A6 variants. Functional expression of oxalate transport in Xenopus laevis oocytes. Results 80 PH1, 6 PH2, 8 non-PH1/PH2, and 96 control samples were available for SLC26A6 screening. A rare variant, c.487C→T (p.Pro163Ser), was detected solely in 1 non-PH1/PH2 pedigree, but this variant failed to segregate with Hyperoxaluria, and functional studies of oxalate transport in Xenopus oocytes showed no transport defect. No other rare variant was identified specifically in non-PH1/PH2. Six additional missense variants were detected in controls and cases. Of these, c.616G→A (p.Val206Met) was most common (11%) and showed a 30% reduction in oxalate transport. To test p.Val206Met as a potential modifier of Hyperoxaluria, we extended screening to PH1 and PH2. Heterozygosity for this variant did not affect plasma or urine oxalate levels in this population. Limitations We did not have a sufficient number of cases to determine whether homozygosity for p.Val206Met might significantly affect urine oxalate. Conclusions SLC26A6 was effectively ruled out as the disease gene in this non-PH1/PH2 cohort. Taken together, our studies are the first to identify and characterize SLC26A6 variants in patients with Hyperoxaluria. Phenotypic and functional analysis excluded a significant effect of identified variants on oxalate excretion.
