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At least 19 recordsLinked to original sources
PubMed2002

Potential mechanisms of marked hyperoxaluria not due to primary hyperoxaluria I or II.

BACKGROUND: Hyperoxaluria may be idiopathic, secondary, or due to primary hyperoxaluria (PH). Hepatic alanine:glyoxylate aminotransferase (AGT) or glyoxylate/hydroxypyruvate reductase (GR/HPR) deficiency causes PHI or PHII, respectively. Hepatic glycolate oxidase (GO) is a candidate enzyme for a third form of inherited hyperoxaluria. METHODS: Six children were identified with marked hyperoxaluria, urolithiasis, and normal hepatic AGT (N = 5) and GR/HPR (N = 4). HPR was below normal and GR not measured in one. Of an affected sibling pair, only one underwent biopsy. GO mutation screening was performed, and dietary oxalate (Diet(ox)), enteric oxalate absorption (EOA) measured using [13C2] oxalate, renal clearance (GFR), fractional oxalate excretion (FE(ox)) in the children, and urine oxalate in first-degree relatives (FDR) to understand the etiology of the hyperoxaluria. RESULTS: Mean presenting age was 19.2 months and urine oxalate 1.3 +/- 0.5 mmol/1.73 m2/24 h (mean +/- SD). Two GO sequence changes (T754C, IVS3 - 49 C>G) were detected which were not linked to the hyperoxaluria. Diet(ox) was 42 +/- 31 mg/day. EOA was 9.4 +/- 3.6%, compared with 7.6 +/- 1.2% in age-matched controls (P = 0.33). GFR was 90 +/- 19 mL/min/1.73 m2 and FE(ox) 4.2 +/- 1.4. Aside from the two brothers, hyperoxaluria was not found in FDR. CONCLUSIONS: These patients illustrate a novel form of hyperoxaluria and urolithiasis, without excess Diet(ox), enteric hyper-absorption, or hepatic AGT, GR/HPR deficiency. Alterations in pathways of oxalate synthesis, in liver or kidney, or in renal tubular oxalate handling are possible explanations. The affected sibling pair suggests an inherited basis.

Alcohol Oxidoreductases↗
PubMed1996

Hyperoxaluria with hyperglycoluria not due to alanine:glyoxylate aminotransferase defect: a novel type of primary hyperoxaluria.

Considering the clinical heterogeneity of primary hyperoxaluria type I (PH1) and the fact that in many instances this diagnosis was made without enzymatic and immunohistochemical investigation, other disturbances of oxalate metabolism than those presently known can be expected in PH1. Using a gaschromatographic/mass spectrometric method that allows quantification of these acids, hyperoxaluria and hyperglycoluria was found repeatedly in two unrelated patients. The hyperoxaluria was unresponsive to pyridoxine. There was no nephrocalcinosis or urolithiasis. In the liver biopsy normal AGT activity and normal localization of this enzyme in the peroxisome was found. In one patient abnormal Km and maximal activity and mozaicism of AGT were excluded. Hyperoxaluria and hyperglycoluria were also found in other family members, suggesting autosomal dominant transmission. Although the underlying defect leading to hyperoxaluria and hyperglycoluria could not be identified in these patients, it is probable that they represent a separate type of primary hyperoxaluria.

Alanine Transaminase↗
PubMed1991

Metabolism of pyridoxine in mild metabolic hyperoxaluria and primary hyperoxaluria (type 1).

Plasma pyridoxine metabolites in plasma and 4-pyridoxic acid excretions in urine were measured in normal subjects, in 7 patients with type-1 hyperoxaluria and in 8 patients with mild metabolic hyperoxaluria, while receiving various doses of pyridoxine. Compliance with ingestion of pyridoxine was verified by measuring urinary 4-pyridoxic acid. In the normal subjects the maximum level of pyridoxal phosphate was obtained after only 10 mg/day of pyridoxine. The patients were divided into nonresponders, good responders and poor responders to pyridoxine according to the fall in urinary oxalate and glycollate excretions. In patients taking pyridoxine, the plasma pyridoxal phosphate levels were as for normal subjects in primary hyperoxaluria, lower than for normal subjects in mild metabolic hyperoxaluria (p less than 0.01), and in the latter group lower in partial responders than in good responders (p = 0.04). Hence in mild metabolic hyperoxaluria there may be difficulty in converting pyridoxine to pyridoxal phosphate.

Chromatography, High Pressure Liquid↗
PubMed2005

Pyridoxamine lowers kidney crystals in experimental hyperoxaluria: a potential therapy for primary hyperoxaluria.

BACKGROUND: Primary hyperoxaluria is a rare genetic disorder of glyoxylate metabolism that results in overproduction of oxalate. The disease is characterized by severe calcium oxalate nephrolithiasis and nephrocalcinosis, resulting in end-stage renal disease (ESRD) early in life. Most patients eventually require dialysis and kidney transplantation, usually in combination with the replacement of the liver. Reduction of urinary oxalate levels can efficiently decrease calcium oxalate depositions; yet, no treatment is available that targets oxalate biosynthesis. In previous in vitro studies, we demonstrated that pyridoxamine can trap reactive carbonyl compounds, including intermediates of oxalate biosynthesis. METHODS: The effect of PM on urinary oxalate excretion and kidney crystal formation was determined using the ethylene glycol rat model of hyperoxaluria. Animals were given 0.75% to 0.8% ethylene glycol in drinking water to establish and maintain hyperoxaluria. After 2 weeks, pyridoxamine treatment (180 mg/day/kg body weight) started and continued for an additional 2 weeks. Urinary creatinine, glycolate, oxalate, and calcium were measured along with the microscopic analysis of kidney tissues for the presence of calcium oxalate crystals. RESULTS: Pyridoxamine treatment resulted in significantly lower (by approximately 50%) levels of urinary glycolate and oxalate excretion compared to untreated hyperoxaluric animals. This was accompanied by a significant reduction in calcium oxalate crystal formation in papillary and medullary areas of the kidney. CONCLUSION: These results, coupled with favorable toxicity profiles of pyridoxamine in humans, show promise for therapeutic use of pyridoxamine in primary hyperoxaluria and other kidney stone diseases.

Animals↗
PubMed2005

Pyridoxamine lowers oxalate excretion and kidney crystals in experimental hyperoxaluria: a potential therapy for primary hyperoxaluria.

In order to prevent kidney stones and nephrolithiasis in hyperoxaluria, a new treatment that specifically reduces oxalate production and therefore urinary oxalate excretion would be extremely valuable. Pyridoxamine(PM) could react with the carbonyl intermediates of oxalate biosynthesis, glycolaldehyde and glyoxylate, and prevent their metabolism to oxalate. In PM treated rats, endogenous urinary oxalate levels were consistently lower and became statistically different from controls after 12 days of experiment. In ethylene glycol-induced hyperoxaluria, PM treatment resulted in significantly lower (by ~50%) levels of urinary glycolate and oxalate excretion compared to untreated hyperoxaluric animals, as well as in a significant reduction in calcium oxalate crystal formation in papillary and medullary areas of the kidney. These results, coupled with favorable toxicity profiles of PM in humans, show promise for the therapeutic use of PM in primary hyperoxaluria and other kidney stone diseases.

Animals↗
PubMed1990

Plasma oxalate and creatinine and oxalate/creatinine clearance ratios in normal subjects and in primary hyperoxaluria. Evidence for renal hyperoxaluria.

Plasma oxalate and creatinine were measured repeatedly in healthy individuals and in 12 patients with type 1 primary hyperoxaluria unresponsive to pyridoxine. The mean ratios were 0.025 (SD 0.006) and 0.120 (SD 0.048), respectively. One patient repeatedly had normal plasma oxalate despite markedly raised urinary oxalate and it seems unlikely that this excess oxalate could have come from the liver. Oxalate/creatinine clearance ratios in the normal group had an overall mean of 0.59 (SD 0.27) in 24 h urine collections and 0.741 (SD 0.297) in repeated short clearance periods. Both renal tubular absorption and secretion of oxalate apparently occurred on different days, but this did not depend upon urinary flow rate. Oxalate/creatinine clearance ratios in type 1 primary hyperoxaluria had a mean of 2.88 (SD 3.11). The raised oxalate/creatinine clearance ratios in the patients were not correlated with either plasma oxalate or creatinine. A few patients showed much higher clearance ratios and in some were sufficiently high to indicate that oxalate was generated and secreted in the kidneys.

Creatinine↗
PubMed1995

The European Primary Hyperoxaluria Type 1 Transplant Registry report on the results of combined liver/kidney transplantation for primary hyperoxaluria 1984-1994. European PH1 Transplantation Study Group.

This paper reports on a total of 61 patients receiving 64 liver grafts for primary hyperoxaluria type 1 (PH1) at 25 centres throughout Europe between 1984 and 1994 recorded in a central registry. Fifty-seven patients received simultaneous kidney grafts and one patient a delayed kidney graft, two patients received isolated liver grafts and a further three patients underwent retransplantation of the liver, a final patient receiving a liver alone dying intra-operatively before a planned kidney graft was performed. Results of such liver grafts are excellent, reversing the metabolic defect of PH1. Thirteen grafts have been lost and 10 patients have died, with actuarial graft and patient survival rates of 88% at 1 year and patient survival of 80% at 5 years. Early combined liver and kidney grafting appears to represent the optimal treatment for patients with PH1, avoiding the adverse effects of a prolonged period of dialysis and the development of the complications of systemic oxalosis. The registry will continue to collect and collate data on patients undergoing hepatic transplantation for PH1.

Adolescent↗
PubMed1991

Combined liver-kidney and isolated liver transplantations for primary hyperoxaluria type 1: the European experience. The European Study Group on Transplantation in Hyperoxaluria Type 1.

The data provided by 14 European centres concerning 22 combined liver-kidney and two isolated liver grafts performed in primary hyperoxaluria type 1 (PH1) were discussed at a workshop which drew the following main conclusions: 1. In end-stage renal failure due to PH1 1-year kidney graft survival rate is far better after combined liver-kidney transplantation than after kidney transplantation alone. This may be due to enhanced renal graft tolerance induced by the simultaneously grafted liver, in addition to the reduced risk of oxalate-induced damage to the kidney graft because the oxalate overproduction has been corrected. 2. Prolonged dialysis using conventional regimes gives rise to extensive systemic oxalosis, especially oxalate osteopathy, which leads to long-lasting excretion of large amounts of oxalate even after oxalate synthesis has been normalised by liver-kidney transplantation, with the risk of jeopardising the success of the kidney graft. In addition, oxalate arteriopathy may endanger the recipient's life. 3. Patients whose GFR is in the range of 25-60 ml/min per 1.73 m2 should be followed up closely, with sequential assessments based on the rate of loss of overall renal function and the plasma and urine oxalate values. An isolated liver transplantation should be considered once the disease has been shown to be following an aggressive course. If this strategy is not followed, planning for an elective liver-kidney graft should begin when GFR decreases to about 25 ml/min per 1.73 m2 and the operation should be as soon as possible. 4. As orthotopic liver transplantation involves the removal of the recipient's biochemically defective but otherwise normal liver, the diagnosis of PH1 should be unequivocally established in every case by the measurement of alanine: glyoxylate aminotransferase enzyme activity in a preoperative liver biopsy.

Adolescent↗
PubMed1991

Hyperoxaluria in patients with recurrent calcium oxalate calculi: dietary and other risk factors.

The presence of mild hyperoxaluria in recurrent calcium oxalate stone formers is controversial. The aim of this study was to identify recurrent stone formers with mild hyperoxaluria and to classify them further by assessing their response to a low oxalate diet. In addition, the prevalence of other risk factors for stone formation in this group of patients was investigated. A total of 207 consecutive patients with recurrent renal calculi were screened and 40 (19%) were found to have mild hyperoxaluria. Of these, 18 (45%) responded to dietary oxalate restriction by normalising their urinary oxalate. The remaining 22 patients were classified as having idiopathic hyperoxaluria and were subdivided into those in whom urinary oxalate excretion was consistently elevated in all specimens measured and those in whom the elevation was intermittent in nature. Dietary oxalate restriction had a partially beneficial effect in lowering oxalate excretion in the patients with persistent hyperoxaluria. No difference in urinary oxalate excretion was found after dietary restriction in the patients with intermittent hyperoxaluria. Other risk factors, including dietary, absorptive and renal hypercalciuria and hypocitraturia, were documented, the prevalence of which (65%) was not significantly different from that (62.5%) found in 40 age- and sex-matched calcium stone formers without hyperoxaluria. The prevalence of hyperuricosuria was significantly greater in patients with hyperoxaluria when compared with stone controls. Further studies are required to elucidate the underlying mechanisms of hyperoxaluria in recurrent stone formers.

Calcium↗
PubMed1986

The determination of oxalate in haemodialysate and plasma: a means to detect and study 'hyperoxaluria' in haemodialysed patients.

In order to find out whether hyperoxaluria can be demonstrated in patients on chronic (twice a week) haemodialysis, a group of 13 patients was investigated. These included one patient with proven primary hyperoxaluria, one suspected of having this disease and 11 patients in whom no information was available as to their oxalate metabolism. Oxalate concentrations in haemodialysate fractions and blood samples, taken before and after dialysis, were determined. The patient with primary hyperoxaluria had a plasma oxalate concentration before dialysis above 100 mumol/l and after dialysis above 25 mumol/l, while the oxalate concentration in haemodialysate at the start of dialysis was above 25 mumol/l and at the end above 10 mumol/l. The patient suspected of hyperoxaluria had similar values. Of the remaining 11 patients, one was shown to exhibit a transient hyperoxaluria, but the others showed a normal oxalate metabolism. A plasma oxalate/creatinine concentration ratio exceeding 0.1, and the calculated total quantity of oxalate removed by dialysis exceeding 2 mmol, also enabled a diagnosis of hyperoxaluria to be made. Hyperoxaluria can still be demonstrated in patients, who because of renal failure are subjected to haemodialysis. Measurements of oxalate in haemodialysate and plasma are valuable in cases where kidney transplantations are considered, especially when the particular patient exhibits hyperoxaluria.

Adolescent↗
PubMed2006

High incidence of hyperoxaluria in generalized peroxisomal disorders.

The Zellweger spectrum disorders (ZSDs) are characterized by a generalized loss of peroxisomal functions caused by deficient peroxisomal assembly. Clinical presentation and survival are heterogeneous. Although most peroxisomal enzymes are unstable in the cytosol of peroxisome-deficient cells of ZSD patients, a few enzymes remain stable among which alanine:glyoxylate aminotransferase (AGT). Its deficiency causes primary hyperoxaluria type 1 (PH1, MIM 259900), an inborn error of glyoxylate metabolism characterized by hyperoxaluria, nephrocalcinosis, and renal insufficiency. Despite the normal level of AGT activity in ZSD patients, hyperoxaluria has been reported in several ZSD patients. We observed the unexpected occurrence of renal stones in a cohort of ZSD patients. This led us to perform a study in this cohort to determine the prevalence of hyperoxaluria in ZSDs and to find clinically relevant clues that correlate with the urinary oxalate load. We reviewed medical charts of 31 Dutch ZSD patients with prolonged survival (>1 year). Urinary oxalate excretion was assessed in 23 and glycolate in 22 patients. Hyperoxaluria was present in 19 (83%), and hyperglycolic aciduria in 14 (64%). Pyridoxine treatment in six patients did not reduce the oxalate excretion as in some PH1 patients. Renal involvement with urolithiasis and nephrocalcinosis was present in five of which one developed end-stage renal disease. The presence of hyperoxaluria, potentially leading to severe renal involvement, was statistically significant correlated with the severity of neurological dysfunction. ZSD patients should be screened by urinalysis for hyperoxaluria and renal ultrasound for nephrocalcinosis in order to take timely measures to prevent renal insufficiency.

Adolescent↗
PubMed2003

Dietary risk factors for hyperoxaluria in calcium oxalate stone formers.

BACKGROUND: Hyperoxaluria is a major predisposing factor in calcium oxalate urolithiasis. The aim of the present study was to clarify the role of dietary oxalate in urinary oxalate excretion and to assess dietary risk factors for hyperoxaluria in calcium oxalate stone patients. METHODS: Dietary intakes of 186 calcium oxalate stone formers, 93 with hyperoxaluria (>or=0.5 mmol/day) and 93 with normal oxalate excretion (<0.4 mmol/day), were assessed by a 24-hour weighed dietary record. Each subject collected 24-hour urine during the completion of the food record. Oxalate content of foods was measured by a recently developed analytical method. RESULTS: The mean daily intakes of energy, total protein, fat and carbohydrates were similar in both groups. The diets of the patients with hyperoxaluria were estimated to contain 130 mg/day oxalate and 812 mg/day calcium as compared to 101 mg/day oxalate and 845 mg/day calcium among patients without hyperoxaluria. These differences were not significant. The mean daily intakes of water (in food and beverages), magnesium, potassium, dietary fiber and ascorbic acid were greater in patients with hyperoxaluria than in stone formers with normal oxalate excretion. Multiple logistic regression analysis revealed that urinary oxalate excretion was significantly associated with dietary ascorbate and fluid intake, and inversely related to calcium intake. Differences of estimated diet composition of both groups corresponded to differences in urinary parameters. CONCLUSIONS: These findings suggest that hyperoxaluria predominantly results from increased endogenous production and from intestinal hyperabsorption of oxalate, partly caused by an insufficient supply or low availability of calcium for complexation with oxalate in the intestinal lumen.

Adult↗
PubMed2003

Diagnostic and therapeutic approaches in patients with secondary hyperoxaluria.

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.

Humans↗
PubMed1987

Oxalate dynamics in chronic renal failure. Comparison with normal subjects and patients with primary hyperoxaluria.

In order to separate the effect of oxalate retention in primary hyperoxaluria with renal failure from that of excessive oxalate synthesis and to determine the optimum time for renal transplantation in primary hyperoxaluria, we have studied a series of patients with different degrees of renal failure due to other causes. The results were compared with those obtained in studies on 8 patients with primary hyperoxaluria at different levels of residual overall renal function. In the patients with renal failure unrelated to primary hyperoxaluria, oxalate retention increases rapidly when the glomerular filtration rate (GFR) decreases below about 20 ml X min-1. These results suggest that the reduced renal excretory contribution to oxalate accumulation in primary hyperoxaluria would be expected to be particularly important in this range of GFR. In primary hyperoxaluria, oxalate retention occurs when GFR is only a little below the reference range and measures to remove oxalate from the body should be considered when the GFR falls below 40 ml X min-1 X 1.73 m-2, with a view to their introduction when the GFR is in the range 20-25 ml X min-1 X 1.73 m-2.

Carbon Radioisotopes↗
PubMed1989

Perspectives in the assessment and management of patients with primary hyperoxaluria type I.

In normal adults the urinary excretion of oxalate rarely exceeds 0.5 mmol/24 hours-1 despite dietary and seasonal fluctuations of intake and absorption. Hyperoxaluria may be encountered in a number of disease states because of increased absorption of dietary oxalate or derangements of metabolism (Table 1). More unusually, hyperoxaluria may arise from one of three inborn errors of metabolism, i.e., the primary hyperoxalurias. The most common, primary hyperoxaluria type I (PHI), is recessively inherited; it will be discussed in detail in this paper. Primary hyperoxaluria type II, caused by a deficiency of D-glycerate dehydrogenase (EC 1.1.1.29), has a similar clinical pattern of disease, but has been described in only a very few families. More recently, another idiopathic form of hyperoxaluria has been defined (type III). It is likely that this form results from a primary defect in oxalate absorption in the absence of any morphologically or functionally definable intestinal disease; a satisfactory response to dietary restriction of oxalate, along with the use of thiazide diuretics, has been described.

Humans↗
PubMed2004

Limitation of apoptotic changes in renal tubular cell injury induced by hyperoxaluria.

Renal tubular epithelium is the major target for oxalate induced injury, and sustained hyperoxaluria together with CaOx crystal formation/deposition may induce renal tubular cell damage and/or dysfunction. This may express itself in cell apoptosis. To evaluate the possible protective effects of certain agents (vitamin E, potassium citrate, allopurinol, verapamil and MgOH) on the presence and the severity of apoptotic changes caused by hyperoxaluria on renal tubular epithelium, an experimental study in rabbits was performed. Seventy rabbits were divided into seven different groups (each group n = 10): in group I severe hyperoxaluria was induced by continuous ethylene glycol (0.75%) administration started on day 0 and completed on day 14. Histologic alterations including crystal formation together with apoptotic changes (by using the TUNEL method) were evaluated on days 21 and 42, respectively. In the remaining experimental groups (groups II-VI), animals received some agents in addition to the induction of hyperoxaluria in an attempt to limit apoptotic changes. Group VII) animals constituted the controls. Kidneys were examined histopathologically under light microscopy for the presence and degree of crystal deposition in the tubular lumen. The percentage of apoptotic nuclei in the control group was significantly different from the other group animals (2.9-2.4%) in all study phases (P < 0.05). Apart from potassium citrate and allopurinol, the other medications seemed to prevent or limit the formation of apoptotic changes in renal tubular epithelium during the early period (day 21). The percentage of positively stained nuclei in animals undergoing potassium citrate medication ranged from 24.3% to 28.6%, with an average of 27.1%. This was 18.4% in animals receiving allopurinol. On the other hand, animals receiving magnesium hydroxide (MgOH), verapamil and vitamin E demonstrated limited apoptotic changes (11.2, 9.7, 8.7%, respectively) during this phase(P < 0.05). In the long-term (day 42), the animals receiving allopurinol and vitamin E showed a decrease in the percentage of the positively stained nuclei (13.5% and 8.3%, respectively). Animals in the other groups showed an increase in the number and percentage of apoptotic cells. Although, there was a significant decrease in the mean values of apoptosis in animals receiving vitamin E (8.7%-8.3%) and allopurinol (18.4%-13.5%) (P < 0.05), animals on verapamil, MgOH and potassium citrate medication had an increase in these values or the change was not found to be significant. In the light of our findings and results from the literature, it is clear that that both hyperoxaluria and CaOx crystals may be injurious to renal epithelial cells. Apoptotic changes observed in renal tubular epithelial cells induced by massive hyperoxaluria might result in cell degradation and may play a role in the pathologic course of urolithiasis. Again, as demonstrated in our study, the limitation of both crystal deposition and apoptotic changes might be instituted by some antioxidant agents as well as urinary inhibitors. Clinical application of such agents in the prophylaxis of stone disease might limit the formation of urinary calculi, especially in recurrent stone formers.

Allopurinol↗