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Dawn S Milliner - One of the best experts on this subject based on the ideXlab platform.
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plasma oxalate as a predictor of kidney function decline in a Primary Hyperoxaluria cohort
International Journal of Molecular Sciences, 2020Co-Authors: Ronak Jagdeep Shah, Dawn S Milliner, Felicity Enders, Lisa E Vaughan, John C LieskeAbstract:This retrospective analysis investigated plasma oxalate (POx) as a potential predictor of end-stage kidney disease (ESKD) among Primary Hyperoxaluria (PH) patients. PH patients with type 1, 2, and 3, age 2 or older, were identified in the Rare Kidney Stone Consortium (RKSC) PH Registry. Since POx increased with falling estimated glomerular filtration rate (eGFR), patients were stratified by chronic kidney disease (CKD) subgroups (stages 1, 2, 3a, and 3b). POx values were categorized into quartiles for analysis. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for risk of ESKD were estimated using the Cox proportional hazards model with a time-dependent covariate. There were 118 patients in the CKD1 group (nine ESKD events during follow-up), 135 in the CKD 2 (29 events), 72 in CKD3a (34 events), and 45 patients in CKD 3b (31 events). During follow-up, POx Q4 was a significant predictor of ESKD compared to Q1 across CKD2 (HR 14.2, 95% CI 1.8–115), 3a (HR 13.7, 95% CI 3.0–62), and 3b stages (HR 5.2, 95% CI 1.1–25), p < 0.05 for all. Within each POx quartile, the ESKD rate was higher in Q4 compared to Q1–Q3. In conclusion, among patients with PH, higher POx concentration was a risk factor for ESKD, particularly in advanced CKD stages.
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clinical features of genetically confirmed patients with Primary Hyperoxaluria identified by clinical indication versus familial screening
Kidney International, 2020Co-Authors: David J Sas, Dawn S Milliner, Xiaojing Tang, Ramila A Mehta, Felicity Enders, Fang Zhao, Barbara M Seide, John C LieskeAbstract:Primary Hyperoxaluria is a rare monogenic disorder characterized by excessive hepatic production of oxalate leading to recurrent nephrolithiasis, nephrocalcinosis, and progressive kidney damage. Most patients with Primary Hyperoxaluria are diagnosed after clinical suspicion based on symptoms. Since some patients are detected by family screening following detection of an affected family member, we compared the clinical phenotype of these two groups. Patients with Primary Hyperoxaluria types 1, 2, and 3 enrolled in the Rare Kidney Stone Consortium Primary Hyperoxaluria Registry were retrospectively analyzed following capture of clinical and laboratory results in the Registry. Among 495 patients with Primary Hyperoxaluria, 47 were detected by family screening. After excluding 150 patients with end stage kidney disease at diagnosis, 300 clinical suspicion and 45 family screening individuals remained. Compared to patients with clinical suspicion, those identified by family screening had significantly fewer stones at diagnosis (mean 1.2 vs. 3.6), although initial symptoms occurred at a similar age (median age 6.1 vs. 7.6 years). Urinary oxalate did not differ between these groups. The estimated glomerular filtration rate at diagnosis and its decline over time were similar for the two groups. Altogether, five of 45 in family screening and 67 of 300 of clinical suspicion individuals developed end stage kidney disease at last follow-up. Thus, patients with Primary Hyperoxaluria identified through family screening have significant disease despite no outward clinical suspicion at diagnosis. Since promising novel treatments are emerging, genetic screening of family members is warranted because they are at significant risk for disease progression.
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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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hydroxyproline metabolism and oxalate synthesis in Primary Hyperoxaluria
Journal of The American Society of Nephrology, 2018Co-Authors: Sonia Fargue, Dawn S Milliner, John Knight, Julie B Olson, Todd W Lowther, Ross P HolmesAbstract:Background Endogenous oxalate synthesis contributes to calcium oxalate stone disease and is markedly increased in the inherited Primary Hyperoxaluria (PH) disorders. The incomplete knowledge regarding oxalate synthesis complicates discovery of new treatments. Hydroxyproline (Hyp) metabolism results in the formation of oxalate and glycolate. However, the relative contribution of Hyp metabolism to endogenous oxalate and glycolate synthesis is not known.Methods To define this contribution, we performed primed, continuous, intravenous infusions of the stable isotope [15N,13C5]-Hyp in nine healthy subjects and 19 individuals with PH and quantified the levels of urinary 13C2-oxalate and 13C2-glycolate formed using ion chromatography coupled to mass detection.Results The total urinary oxalate-to-creatinine ratio during the infusion was 73.1, 70.8, 47.0, and 10.6 mg oxalate/g creatinine in subjects with PH1, PH2, and PH3 and controls, respectively. Hyp metabolism accounted for 12.8, 32.9, and 14.8 mg oxalate/g creatinine in subjects with PH1, PH2, and PH3, respectively, compared with 1.6 mg oxalate/g creatinine in controls. The contribution of Hyp to urinary oxalate was 15% in controls and 18%, 47%, and 33% in subjects with PH1, PH2, and PH3, respectively. The contribution of Hyp to urinary glycolate was 57% in controls, 30% in subjects with PH1, and <13% in subjects with PH2 or PH3.Conclusions Hyp metabolism differs among PH types and is a major source of oxalate synthesis in individuals with PH2 and PH3. In patients with PH1, who have the highest urinary excretion of oxalate, the major sources of oxalate remain to be identified.
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combined liver kidney transplantation for Primary Hyperoxaluria type 2 a case report
American Journal of Transplantation, 2018Co-Authors: Tsering Dhondup, Dawn S Milliner, Elizabeth C Lorenz, John C LieskeAbstract:Combined liver/kidney transplant is the preferred transplant option for most patients with Primary Hyperoxaluria type 1 (PH1) since orthotopic liver transplantation replaces the deficient liver-specific AGT enzyme, thus restoring normal metabolic oxalate production. However, Primary Hyperoxaluria type 2 (PH2) is caused by deficient glyoxylate reductase / hydroxypyruvate reductase (GRHPR), and this enzyme is widely distributed throughout the body. Though the relative abundance and activity of GRHPR in various tissues is not clear, some evidence suggests that the majority of enzyme activity may indeed reside within the liver. Thus the effectiveness of liver transplantation in correcting this metabolic disorder has not been demonstrated. Here we report a case of 44-year old man with PH2, frequent stone events, and end-stage renal disease who received a combined liver/ kidney transplant. Although requiring confirmation in additional cases, the normalization of plasma oxalate, urine oxalate and urine glycerate levels observed in this patient within a month of the transplant that remain reduced at the most recent follow-up at 13 months suggests correction of the GRHPR deficiency in PH2 can be achieved by liver transplantation. This article is protected by copyright. All rights reserved.
Bernd Hoppe - One of the best experts on this subject based on the ideXlab platform.
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novel therapeutic approaches in Primary Hyperoxaluria
Expert Opinion on Emerging Drugs, 2018Co-Authors: Alexander Weigert, Christina Martinhigueras, Bernd HoppeAbstract:Introduction: Currently, three types of Primary Hyperoxaluria (PH I-III) are known, all based on different gene-mutations affecting the glyoxylate metabolism in the liver. Disease hallmark is an increased endogenous oxalate production and thus massively elevated urinary excretion of oxalate and other type-specific metabolites. Hyperoxaluria induces the formation of calcium-oxalate kidney stones and/or nephrocalcinosis. In addition to that, a chronic inflammasome activation by Hyperoxaluria per se, often leads to an early deterioration of kidney function, regularly resulting in end-stage renal disease (ESRD) at least in patients with type I PH. Except for vitamin B6 treatment in PH I, therapeutic regimen nowadays consists only of supportive measures, like significantly increased fluid intake and medication increasing the urinary solubility like alkaline citrate. Areas covered: Disease burden can be severe, and both clinicians and scientist are eager in finding new therapeutic approaches. The currently ongoing clinical studies and promising research in this field are reported in this paper. To present a complete overview, we searched electronic databases, like Clinical trial gov, National Center for Biotechnology Information PubMed, congress reports, press releases and personal information acquired at congresses and conventions. Searches were conducted using the following medical headings: (Primary) Hyperoxaluria, PH, therapy, treatment and research. Expert opinion: There is light on the horizon that new treatment options will be available in due time, as there are several promising therapeutic agents currently under investigation, some being at the first levels of drug development, but some already in ongoing clinical trials (phase I-III).
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Metabolic profile and impact of diet in patients with Primary Hyperoxaluria
International Urology and Nephrology, 2018Co-Authors: Roswitha Siener, Bernd Hoppe, Patricia Löhr, Stefan C. Müller, Stefan LatzAbstract:Purpose The Primary goal of this pilot study was to evaluate metabolic characteristics and to examine the impact of diet in patients with Primary Hyperoxaluria (PH) under controlled, standardized conditions. Methods Four patients with genetically confirmed PH collected 24 h urines on their habitual, self-selected diets and on day 1, 6, 7, 8, and 11 under controlled, standardized conditions. The [^13C_2]oxalate absorption, calcium, and ammonium chloride loading tests were performed. Results While none of the patients had abnormal findings from the calcium loading test, incomplete distal renal tubular acidosis (RTA) was diagnosed in each of the four patients. Dietary intervention resulted in a significant decrease in urinary oxalate expressed as molar creatinine ratio (mmol/mol) between 30 and 40% in two of four patients. The evaluation of dietary records revealed a high daily intake of oxalate-rich foods as well as gelatin-containing sweets and meat products, rich sources of hydroxyproline, under the habitual, self-selected diets of the two responders. Intestinal oxalate hyperabsorption of 12.4% in one of the two patients may have additionally contributed to the increased urinary oxalate excretion under the individual diet. Conclusions Our pilot data indicate that patients with PH may benefit from a restriction of dietary oxalate and hydroxyproline intake. Further research is needed to define the role of distal RTA in PH and to evaluate the hypothesis of an acquired acidification defect.
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systematic assessment of urinary hydroxy oxo glutarate for diagnosis and follow up of Primary Hyperoxaluria type iii
Pediatric Nephrology, 2017Co-Authors: Ada Ventzke, Bodo B. Beck, Markus Feldkötter, Andrew Zusern Wei, Jutta Becker, Bernd HoppeAbstract:Background There are currently three distinct autosomal recessive inherited types of Primary Hyperoxaluria (PH: PHI, PHII, and PHIII), all characterized by the endogenous overproduction of oxalate. The PH type is difficult to differentiate by clinical features alone. In addition to universal general characteristics to all Hyperoxaluria subtypes, specific urinary metabolites can be detected: glycolate in PHI, L-glyceric acid in PHII, and hydroxy-oxo-glutarate (HOG) in PHIII. PHIII is considered to be the most benign form and is characterized by severe recurrent urolithiasis in early life, followed by clinical remission in many, but not all patients. We examined urinary HOG (UHOG) excretion as a diagnostic marker and its correlation to progression of the clinical course of PHIII.
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kidney stones in Primary Hyperoxaluria new lessons learnt
PLOS ONE, 2013Co-Authors: Dorrit E. Jacob, Bodo B. Beck, Bernd Grohe, Michaela Gesner, Bernd HoppeAbstract:To investigate potential differences in stone composition with regard to the type of Primary Hyperoxaluria (PH), and in relation to the patient’s medical therapy (treatment naive patients versus those on preventive medication) we examined twelve kidney stones from ten PH I and six stones from four PH III patients. Unfortunately, no PH II stones were available for analysis. The study on this set of stones indicates a more diverse composition of PH stones than previously reported and a potential dynamic response of morphology and composition of calculi to treatment with crystallization inhibitors (citrate, magnesium) in PH I. Stones formed by PH I patients under treatment are more compact and consist predominantly of calcium-oxalate monohydrate (COM, whewellite), while calcium-oxalate dihydrate (COD, weddellite) is only rarely present. In contrast, the single stone available from a treatment naive PH I patient as well as stones from PH III patients prior to and under treatment with alkali citrate contained a wide size range of aggregated COD crystals. No significant effects of the treatment were noted in PH III stones. In disagreement with findings from previous studies, stones from patients with Primary Hyperoxaluria did not exclusively consist of COM. Progressive replacement of COD by small COM crystals could be caused by prolonged stone growth and residence times in the urinary tract, eventually resulting in complete replacement of calcium-oxalate dihydrate by the monohydrate form. The noted difference to the naive PH I stone may reflect a reduced growth rate in response to treatment. This pilot study highlights the importance of detailed stone diagnostics and could be of therapeutic relevance in calcium-oxalates urolithiasis, provided that the effects of treatment can be reproduced in subsequent larger studies.
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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.
Gill Rumsby - One of the best experts on this subject based on the ideXlab platform.
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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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patients with Primary Hyperoxaluria type 2 have significant morbidity and require careful follow up
Kidney International, 2019Co-Authors: Sander F Garrelfs, Bodo B. Beck, Gill Rumsby, Hessel Peterssengers, Florian Erger, Jaap W Groothoff, Michiel J S Oosterveld, Alessandra Pelle, Thomas J Neuhaus, Brigitte AdamsAbstract:Primary Hyperoxaluria type 2 is a rare inherited disorder of glyoxylate metabolism causing nephrocalcinosis, renal stone formation and ultimately kidney failure. Previously, Primary Hyperoxaluria type 2 was considered to have a more favorable prognosis than Primary Hyperoxaluria type 1, but earlier reports are limited by low patient numbers and short follow up periods. Here we report on the clinical, genetic, and biochemical findings from the largest cohort of patients with Primary Hyperoxaluria type 2, obtained by a retrospective record review of genetically confirmed cases in the OxalEurope registry, a dataset containing 101 patients from eleven countries. Median follow up was 12.4 years. Median ages at first symptom and diagnosis for index cases were 3.2 years and 8.0 years, respectively. Urolithiasis was the most common presenting feature (82.8% of patients). Genetic analysis revealed 18 novel mutations in the GRHPR gene. Of 238 spot-urine analyses, 23 (9.7%) were within the normal range for oxalate as compared to less than 4% of 24-hour urine collections. Median intra-individual variation of 24-hour oxalate excretion was substantial (34.1%). At time of review, 12 patients were lost to follow-up; 45 of the remaining 89 patients experienced chronic kidney disease stage 2 or greater and 22 patients had reached stage 5. Median renal survival was 43.3 years, including 15 kidney transplantations in 11 patients (1 combined with liver transplantation). Renal outcome did not correlate with genotype, biochemical parameters or initially present nephrocalcinosis. Thus, Primary Hyperoxaluria type 2 is a disease with significant morbidity. Accurate diagnosis by 24-hour urine analysis and genetic testing are required with careful follow-up.
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urine oxalate biological variation in patients with Primary Hyperoxaluria
Urological Research, 2016Co-Authors: Oliver Cliffordmobley, Anna Sjogren, Elisabeth Lindner, Gill RumsbyAbstract:Hyperoxaluria is a well-recognised risk factor for urolithiasis and patients with Primary Hyperoxaluria (PH) gradually build up calcium oxalate deposits leading to chronic kidney disease. Efforts to improve treatment for PH have focused on reducing urine oxalate excretion and thus decreasing lithogenesis. To determine the efficacy of treatments designed to alter a biochemical parameter it is necessary to know the biological and analytical variation of that parameter. In this study, we estimated the intra-individual biological variation of urine oxalate excretion in patients with PH, and from this determined what would constitute a significant change in the form of a reference change value (RCV). Each patient collected four 24-h urines on consecutive weeks. The intra-individual biological variation of oxalate excretion calculated from these samples ranged from 0 to 36 % with a mean of 14 %. The corresponding RCVs were 4-84 % with a mean of 32 %. This result implies that, on average, a reduction of almost one-third in urine oxalate excretion is required to prove an effect from treatment. The wide range of biological variation between individuals may reflect other, as yet unknown, determinants of oxaluria in PH, as well as inaccuracies in urine collection. The data suggest that it is more appropriate to use individual RCVs established prior to treatment to determine its efficacy: a relatively small fall in urine oxalate excretion may be outside the biological variation of some patients but not of others.
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data from a large european study indicate that the outcome of Primary Hyperoxaluria type 1 correlates with the agxt mutation type
Kidney International, 2014Co-Authors: Giorgia Mandrile, Bodo B. Beck, Christiaan S Van Woerden, Sallyanne Hulton, Paola Berchialla, Cecile Acquaviva Bourdain, Gill RumsbyAbstract:Primary Hyperoxaluria type 1 displays a heterogeneous phenotype, likely to be affected by genetic and non-genetic factors, including timeliness of diagnosis and quality of care. As previous genotype-phenotype studies were hampered by limited patient numbers the European OxalEurope Consortium was constituted. This preliminary retrospective report is based on 526 patients of which 410 have the AGXT genotype defined. We grouped mutations by the predicted effect as null, missense leading to mistargeting (G170R), and other missense, and analyzed their phenotypic correlations. Median age of end-stage renal disease increased from 9.9 for 88 homozygous null patients, 11.5 for 42 heterozygous null/missense, 16.9 for 116 homozygous missense patients, 25.1 for 61 G170R/null patients, 31.2 for 32 G170R/missense patients, and 33.9 years for 71 homozygous G170R patients. The outcome of some recurrent missense mutations (p.I244T, p.F152I, p.M195R, p.D201E, p.S81L, p.R36C) and an unprecedented number of G170R homozygotes is described in detail. Diagnosis is still delayed and actions aimed at increasing awareness of Primary Hyperoxaluria type 1 are recommended. Thus, in addition to G170R, other causative mutations are associated with later onset of end-stage renal disease. The OxalEurope registry will provide necessary tools for characterizing those genetic and non-genetic factors through a combination of genetic, functional, and biostatistical approaches.
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multiple mechanisms of action of pyridoxine in Primary Hyperoxaluria type 1
Biochimica et Biophysica Acta, 2013Co-Authors: Sonia Fargue, Gill Rumsby, Christopher J DanpureAbstract:Primary Hyperoxaluria type 1 (PH1) is a rare hereditary calcium oxalate kidney stone disease caused by a deficiency of the liver-specific pyridoxal-phosphate-dependent peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). About one third of patients are responsive to pharmacological doses of pyridoxine (vitamin B6), but its mechanism of action is unknown. Using stably transformed Chinese Hamster Ovary (CHO) cells expressing various normal and mutant forms of AGT, we have shown that pyridoxine increases the net expression, catalytic activity and peroxisomal import of the most common mistargeted mutant form of AGT (i.e. Gly170Arg on the background of the polymorphic minor allele). These multiple effects explain for the first time the action of pyridoxine in the most common group of responsive patients. Partial effects of pyridoxine were also observed for two other common AGT mutants on the minor allele (i.e. Phe152Ile and Ile244Thr) but not for the minor allele mutant AGT containing a Gly41Arg replacement. These findings demonstrate that pyridoxine, which is metabolised to pyridoxal phosphate, the essential cofactor of AGT, achieves its effects both as a prosthetic group (increasing enzyme catalytic activity) and a chemical chaperone (increasing peroxisome targeting and net expression). This new understanding should aid the development of pharmacological treatments that attempt to enhance efficacy of pyridoxine in PH1, as well as encouraging a re-evaluation of the extent of pyridoxine responsiveness in PH1, as more patients than previously thought might benefit from such treatment.
Jaap W Groothoff - One of the best experts on this subject based on the ideXlab platform.
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patients with Primary Hyperoxaluria type 2 have significant morbidity and require careful follow up
Kidney International, 2019Co-Authors: Sander F Garrelfs, Bodo B. Beck, Gill Rumsby, Hessel Peterssengers, Florian Erger, Jaap W Groothoff, Michiel J S Oosterveld, Alessandra Pelle, Thomas J Neuhaus, Brigitte AdamsAbstract:Primary Hyperoxaluria type 2 is a rare inherited disorder of glyoxylate metabolism causing nephrocalcinosis, renal stone formation and ultimately kidney failure. Previously, Primary Hyperoxaluria type 2 was considered to have a more favorable prognosis than Primary Hyperoxaluria type 1, but earlier reports are limited by low patient numbers and short follow up periods. Here we report on the clinical, genetic, and biochemical findings from the largest cohort of patients with Primary Hyperoxaluria type 2, obtained by a retrospective record review of genetically confirmed cases in the OxalEurope registry, a dataset containing 101 patients from eleven countries. Median follow up was 12.4 years. Median ages at first symptom and diagnosis for index cases were 3.2 years and 8.0 years, respectively. Urolithiasis was the most common presenting feature (82.8% of patients). Genetic analysis revealed 18 novel mutations in the GRHPR gene. Of 238 spot-urine analyses, 23 (9.7%) were within the normal range for oxalate as compared to less than 4% of 24-hour urine collections. Median intra-individual variation of 24-hour oxalate excretion was substantial (34.1%). At time of review, 12 patients were lost to follow-up; 45 of the remaining 89 patients experienced chronic kidney disease stage 2 or greater and 22 patients had reached stage 5. Median renal survival was 43.3 years, including 15 kidney transplantations in 11 patients (1 combined with liver transplantation). Renal outcome did not correlate with genotype, biochemical parameters or initially present nephrocalcinosis. Thus, Primary Hyperoxaluria type 2 is a disease with significant morbidity. Accurate diagnosis by 24-hour urine analysis and genetic testing are required with careful follow-up.
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Primary Hyperoxaluria type 1 practical and ethical issues
Pediatric Nephrology, 2013Co-Authors: Pierre Cochat, Jaap W GroothoffAbstract:Primary Hyperoxaluria type 1 (PH1) is a rare inborn error of glyoxylate metabolism of autosomal recessive inheritance, leading to progressive systemic oxalate storage (named ‘oxalosis’) with a high rate of morbidity and mortality, as well as an unacceptable quality of life for most patients. The adverse outcome, however, is partly due to issues that can be overcome. First, the diagnosis of PH is often delayed due to a general lack of knowledge of the disease among physicians. This accounts specifically for patients with pyridoxine sensitive PH, a group that is paradoxically most easy to treat. Second, lack of adherence to a strict conduction of conservative treatment and optimal urological management may enhance an adverse outcome of the disease. Third, specific techniques to establish PH1 and specific therapies are currently often not available in several low-resources countries with a high prevalence of PH. The management of patients with advanced disease is extremely difficult and warrants a tailor-made approach in most cases. Comprehensive programs for education of local physicians, installation of national centers of expertise, European support of low-resources countries for the management of PH patients and intensified international collaboration on the management of current patients, as well as on conduction of clinical studies, may further improve outcome of PH.
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Primary Hyperoxaluria type 1 a too often missed diagnosis and potentially treatable cause of end stage renal disease in adults results of the dutch cohort
Nephrology Dialysis Transplantation, 2012Co-Authors: S M Van Der Hoeven, C S Van Woerden, Jaap W GroothoffAbstract:Background. Primary Hyperoxaluria Type 1, an inherited disorder with increased endogenous oxalate production, leads to the development of urolithiasis, nephrocalcinosis and end-stage renal disease (ESRD). Contrary to the general belief that patients diagnosed during adulthood experience a relatively mild course of disease, we were confronted with several cases of ESRD caused by previously undiagnosed Primary Hyperoxaluria. Methods. To study renal and patient survival in relation with genotype, age at onset of disease and therapeutic delay, we performed a nationwide search among all Dutch nephrologists and paediatric nephrologists. Results. Of the 79 included patients, 38% was diagnosed at an adult age. ESRD was present at the time of diagnosis in 26% of paediatric diagnosed patients versus 52% of adult-diagnosed patients (P = 0.021). Homozygosity for the pyridoxine-responsive p.Gly170Arg or p.Phe152Ile genotype was found in 26% of paediatric diagnosed patients versus 68% of adult-diagnosed patients (P < 0.001). Of homozygous p.Gly170Arg or p.Phe152Ile patients, 48% developed ESRD at a median age of 37 years, compared with 48% in those with other mutations at a median age of 0.5 years (P < 0.001). Of the 16 patients found through family screening, 81% had a preserved renal function. Conclusions. The high prevalence of pyridoxine-responsive genotypes and favourabl prognosis of timely treatment warrant early diagnostic screening for Primary Hyperoxaluria Type 1 in patients with recurrent urolithiasis. This will preserve kidney function and prevent diagnosis of adult diagnosed patients in ESRD.
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Primary Hyperoxaluria type 1 indications for screening and guidance for diagnosis and treatment
Nephrology Dialysis Transplantation, 2012Co-Authors: Pierre Cochat, Michel Daudon, Sonia Fargue, Jerome Harambat, Jaap W Groothoff, Christopher J Danpure, Sallyanne Hulton, Cecile Acquaviva, Mario De Marchi, Bernd HoppeAbstract:Primary Hyperoxaluria Type 1 is a rare autosomal recessive inborn error of glyoxylate metabolism, caused by a deficiency of the liver-specific enzyme alanine:glyoxylate aminotransferase. The disorder results in overproduction and excessive urinary excretion of oxalate, causing recurrent urolithiasis and nephrocalcinosis. As glomerular filtration rate declines due to progressive renal involvement, oxalate accumulates leading to systemic oxalosis. The diagnosis is based on clinical and sonographic findings, urine oxalate assessment, enzymology and/or DNA analysis. Early initiation of conservative treatment (high fluid intake, pyridoxine, inhibitors of calcium oxalate crystallization) aims at maintaining renal function. In chronic kidney disease Stages 4 and 5, the best outcomes to date were achieved with combined liver–kidney transplantation.
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efficacy and safety of oxalobacter formigenes to reduce urinary oxalate in Primary Hyperoxaluria
Nephrology Dialysis Transplantation, 2011Co-Authors: Bernd Hoppe, Markus J Kemper, Pierre Cochat, Jaap W Groothoff, Sally A Hulton, Patrick Niaudet, George Deschenes, Robert J Unwin, Dawn S MillinerAbstract:Background. Primary Hyperoxaluria (PH) is a rare genetic disease, in which high urinary oxalate (Uox) cause recurrent kidney stones and/or progressive nephrocalcinosis, often followed by early end-stage renal disease, as well as extremely high plasma oxalate, systemic oxalosis and premature death. Oxalobacter formigenes, an anaerobic oxalate degrading bacterium, naturally colonizes the colon of most humans. Orally administered O. formigenes (Oxabact) was found to significantly reduce urine and plasma oxalate. We aimed to evaluate its effect and safety in a randomized, double-blind, placebo-controlled multicenter study.Methods. Oral Oxabact was given to PH patients (> 5 years old, Uox > 1.0 mmol/1.73m(2)/day, glomerular filtration rate (GFR) > 50 mL/min) at nine PH referral sites worldwide. Primary endpoint was the change from baseline in Uox (mmol/1.73m(2)/day) after 24 weeks of treatment (> 20% reduction).Results. Of the 43 subjects randomized, 42 patients received either placebo (23 subjects) or Oxabact (19 subjects). The change in Uox was 160 mmol/mol, Oxabact -28%, placebo -6%; P < 0.082). No serious adverse events were reported.Conclusion. Oxabact was safe and well tolerated. However, as no significant change in Uox was seen, further studies to evaluate the efficacy of Oxabact treatment are needed.
Pierre Cochat - One of the best experts on this subject based on the ideXlab platform.
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Bone impairment in Primary Hyperoxaluria: a review
Pediatric Nephrology, 2016Co-Authors: Justine Bacchetta, Georges Boivin, Pierre CochatAbstract:Deposition of calcium oxalate crystals in the kidney and bone is a hallmark of Primary Hyperoxaluria (PH). Since the bone compartment can store massive amounts of oxalate, patients present with recurrent low-trauma fractures, bone deformations, severe bone pains, and specific oxalate osteopathy on X-ray. Bone biopsy from the iliac crest displays specific features such as oxalate crystals surrounded by a granulomatous reaction corresponding to an invasion of bone surface by macrophages. The objective of this manuscript is therefore to provide an overview of bone impairment in PH, by reviewing the current literature on bone and dental symptoms as well as imaging techniques used for assessing bone disease.
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recurrence of crystalline nephropathy after kidney transplantation in aprt deficiency and Primary Hyperoxaluria
Canadian journal of kidney health and disease, 2015Co-Authors: Guillaume Bollee, Pierre Cochat, Michel DaudonAbstract:Purpose of review To provide transplant physicians with a summary of the pathogenesis and diagnosis of adenine phosphoribosyl transferase (APRT) deficiency and Primary Hyperoxaluria and, focussed on kidney transplantation, and to discuss interventions aimed at preventing and treating the recurrence of crystalline nephropathy in renal transplant recipients.
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renal function can be impaired in children with Primary Hyperoxaluria type 3
Pediatric Nephrology, 2015Co-Authors: Lise Allard, Pierre Cochat, Annelaure Leclerc, Francois Cachat, Christine Fichtner, Vandrea De Souza, Clotilde Druck Garcia, Mariechristine Camoinschweitzer, Mariealice MacherAbstract:Background Primary Hyperoxaluria type 3 (PH3) is characterized by mutations in the 4-hydroxy-2-oxoglutarate aldolase (HOGA1) gene. PH3 patients are believed to present with a less severe phenotype than those with PH1 and PH2, but the clinical characteristics of PH3 patients have yet to be defined in sufficient detail. The aim of this study was to report our experience with PH3.
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Primary Hyperoxaluria type 1 practical and ethical issues
Pediatric Nephrology, 2013Co-Authors: Pierre Cochat, Jaap W GroothoffAbstract:Primary Hyperoxaluria type 1 (PH1) is a rare inborn error of glyoxylate metabolism of autosomal recessive inheritance, leading to progressive systemic oxalate storage (named ‘oxalosis’) with a high rate of morbidity and mortality, as well as an unacceptable quality of life for most patients. The adverse outcome, however, is partly due to issues that can be overcome. First, the diagnosis of PH is often delayed due to a general lack of knowledge of the disease among physicians. This accounts specifically for patients with pyridoxine sensitive PH, a group that is paradoxically most easy to treat. Second, lack of adherence to a strict conduction of conservative treatment and optimal urological management may enhance an adverse outcome of the disease. Third, specific techniques to establish PH1 and specific therapies are currently often not available in several low-resources countries with a high prevalence of PH. The management of patients with advanced disease is extremely difficult and warrants a tailor-made approach in most cases. Comprehensive programs for education of local physicians, installation of national centers of expertise, European support of low-resources countries for the management of PH patients and intensified international collaboration on the management of current patients, as well as on conduction of clinical studies, may further improve outcome of PH.
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Primary Hyperoxaluria type 1 indications for screening and guidance for diagnosis and treatment
Nephrology Dialysis Transplantation, 2012Co-Authors: Pierre Cochat, Michel Daudon, Sonia Fargue, Jerome Harambat, Jaap W Groothoff, Christopher J Danpure, Sallyanne Hulton, Cecile Acquaviva, Mario De Marchi, Bernd HoppeAbstract:Primary Hyperoxaluria Type 1 is a rare autosomal recessive inborn error of glyoxylate metabolism, caused by a deficiency of the liver-specific enzyme alanine:glyoxylate aminotransferase. The disorder results in overproduction and excessive urinary excretion of oxalate, causing recurrent urolithiasis and nephrocalcinosis. As glomerular filtration rate declines due to progressive renal involvement, oxalate accumulates leading to systemic oxalosis. The diagnosis is based on clinical and sonographic findings, urine oxalate assessment, enzymology and/or DNA analysis. Early initiation of conservative treatment (high fluid intake, pyridoxine, inhibitors of calcium oxalate crystallization) aims at maintaining renal function. In chronic kidney disease Stages 4 and 5, the best outcomes to date were achieved with combined liver–kidney transplantation.
