[Primary hyperoxaluria: A review]. / Hyperoxalurie primitive : une revue de la littérature.

Primary hyperoxalurias (PH) are inborn errors in the metabolism of glyoxalate and oxalate with recessive autosomal transmission. As a result, an increased endogenous production of oxalate leads to exessive urinary oxalate excretion. PH type 1, the most common form, is due to a deficiency of the peroxisomal enzyme alanine: Glyoxylate aminotransferase (AGT) in the liver. PH type 2 is due to the deficiency of the glyoxylate reductase/hydroxypyruvate réductase, present in the cytosol of hepatocytes and leucocytes. PH type 3 is linked to the gene HOGA1, encoding a mitochondrial enzyme, the 4-hydroxy-2-oxo-glutarate aldolase. Recurrent urolithiaisis and nephrocalcinosis are the markers of the disease. As a result, a progressive dysfunction of the kidneys is commonly observed. At the stage of severe chronic kidney disease, plasma oxalate increase leads to a systemic oxalosis. Diagnostic is often delayed and it based on stone analysis, cristalluria, oxaluria determination and DNA analysis. Early initiation of conservative treatment including high fluid intake and long-term co-administration of inhibitors of calcium oxalate crystallization and pyridoxine, could efficiently prevent end stage renal disease. In end stage renal failure, a combined liver-kidney transplantation corrects the enzyme defect.

[Oxalate: a poorly soluble organic waste with consequences]. / L'oxalate: un déchet organique peu soluble, avec conséquences.

Oxalate is a highly insoluble metabolic waste excreted by the kidneys. Disturbances of oxalate metabolism are encountered in enteric hyperoxaluria (secondary to malabsorption, gastric bypass or in case of insufficient Oxalobacter colonization), in hereditary hyperoxaluria and in intoxication (ethylene glycol, vitamin C). Hyperoxaluria causes a large spectrum of diseases, from isolated hyperoxaluria to kidney stones and nephrocalcinosis formation, eventually leading to kidney failure and systemic oxalosis with life-threatening deposits in vital organs. New causes of hyperoxaluria are arising recently, in particular after gastric bypass surgery, which requires regular and preemptive monitoring. The treatment of hyperoxaluria involves reduction in oxalate intake and increase in calcium intake. Optimal urine dilution and supplementation with inhibitors of kidney stone formation (citrate) are required. Some conditions may need vitamin B6 supplementation, and the addition of probiotics might be useful in the future. Primary care physicians should identify cases of recurrent calcium oxalate stones and severe hyperoxaluria. Further management of hyperoxaluria requires specialized care.

L'oxalate est un déchet métabolique peu soluble excrété par les reins, et les hyperoxaluries peuvent être distinguées en hyperoxaluries entériques, hyperoxaluries héréditaires et les intoxications (éthylène glycol, vitamine C). L'hyperoxalurie induit un large spectre de maladies allant de l'hyperoxalurie isolée, formation de calculs rénaux, voire d'une néphrocalcinose, à l'insuffisance rénale et l'oxalose systémique avec des dépôts s'accumulant dans de nombreux organes. De nouvelles causes d'hyperoxalurie sont apparues ces dernières années, en particulier les hyperoxaluries survenant à la suite d'un bypass gastrique. Le traitement des hyperoxaluries fait intervenir, d'une part, une diminution contrôlée des apports en oxalate et une augmentation des apports en calcium et, d'autre part, une dilution des urines et l'ajout d'inhibiteurs de la lithogenèse (citrate). Dans certaines conditions particulières, une supplémentation en vitamine B6 ou l'utilisation de probiotiques peuvent être envisagées. Le praticien doit rester attentif aux cas de calculs d'oxalate de calcium récidivants ou d'hyperoxalurie sévère et les adresser pour une prise en charge spécialisée et multidisciplinaire.

Primary hyperoxaluria.

Primary hyperoxaluria (PH) occurs due to an autosomal recessive hereditary disorder of the metabolism of glyoxylate, which causes excessive oxalate production. The most frequent and serious disorder is due to enzyme deficit of alanine-glyoxylate aminotransferase (PH type I) specific to hepatic peroxisome. As oxalate is not metabolised in humans and is excreted through the kidneys, the kidney is the first organ affected, causing recurrent lithiasis, nephrocalcinosis and early renal failure. With advance of renal failure, particularly in patients on haemodialysis (HD), calcium oxalate is massively deposited in tissues, which is known as oxalosis. Diagnosis is based on family history, the presence of urolithiasis and/or nephrocalcinosis, hyperoxaluria, oxalate deposits in tissue forming granulomas, molecular analysis of DNA and enzyme analysis if applicable. High diagnostic suspicion is required; therefore, unfortunately, in many cases it is diagnosed after its recurrence following kidney transplantation. Conservative management of this disease (high liquid intake, pyridoxine and crystallisation inhibitors) needs to be adopted early in order to delay kidney damage. Treatment by dialysis is ineffective in treating excess oxalate. After the kidney transplant, we normally observe a rapid appearance of oxalate deposits in the graft and the results of this technique are discouraging, with very few exceptions. Pre-emptive liver transplantation, or simultaneous liver and kidney transplants when there is already irreversible damage to the kidney, is the treatment of choice to treat the underlying disease and suppress oxalate overproduction. Given its condition as a rare disease and its genetic and clinical heterogeneity, it is not possible to gain evidence through randomised clinical trials. As a result, the recommendations are established by groups of experts based on publications of renowned scientific rigour. In this regard, a group of European experts (OxalEurope) has drawn up recommendations for diagnosis and treatment, which were published in 2012.

An update on primary hyperoxaluria.

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 <0.5 mmol/1.73 m(2) body surface area per day), which results in recurrent urolithiasis and/or progressive nephrocalcinosis. All entities can induce kidney damage, which is followed by reduced oxalate elimination and consequent systemic deposition of calcium oxalate crystals. Systemic oxalosis should be prevented, but diagnosis is all too often missed or delayed until end-stage renal disease (ESRD) occurs; this outcome occurs in >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.

The enzyme 4-hydroxy-2-oxoglutarate aldolase is deficient in primary hyperoxaluria type 3.

BACKGROUND: Mutations in the 4-hydroxy-2-oxoglutarate aldolase (HOGA1) gene have been recently identified in patients with atypical primary hyperoxaluria (PH). However, it was not clearly established whether these mutations caused disease via loss of function or activation of the gene product. METHODS: Whole-gene sequencing of HOGA1 was conducted in 28 unrelated patients with a high clinical suspicion of PH and in whom Types 1 and 2 had been excluded. RESULTS: Fifteen patients were homozygous or compound heterozygous for mutations in HOGA1. In total, seven different mutations were identified including three novel changes: a missense mutation, c.107C > T (p.Ala36Val), and two nonsense mutations c.117C > A (p.Tyr39X) and c.208C > T (p.Arg70X) as well as the previously documented c.860G > T (p.Gly297Val), c.907C > T (p.Arg303Cys) and in-frame c.944_946delAGG (p.Glu315del) mutations. The recurrent c.700 + 5G > T splice site mutation in intron 5 was most common with a frequency of 67%. Expression studies on hepatic messenger RNA demonstrated the pathogenicity of this mutation. CONCLUSIONS: The detection of a patient with two novel nonsense mutations within exon 1 of the gene, c.117C > A (p.Tyr39X) and c.208C > T (p.Arg70X), provides definitive proof that PH Type 3 is due to deficiency of the 4-hydroxy-2-oxoglutarate aldolase enzyme.

Early renal failure after domino liver transplantation using organs from donors with primary hyperoxaluria type 1.

BACKGROUND: Organ shortage is responsible for high mortality rates of patients awaiting liver transplantation (LT). Domino transplantation has had reported success in patients with metabolic disorders. Primary hyperoxaluria type 1 (PH1) is a rare metabolic disorder. There are a few case reports that suggest that PH1 livers originating from donors that have undergone combined liver-kidney transplantation can be successfully used for domino transplantation. METHODS: In the last decade, five patients received a domino liver transplant from patients with PH1 in the EUROTRANSPLANT region. In this study, we report the clinical course and outcome of these five patients who were received a domino graft transplant. RESULTS: All patients, with the exception of one, suffered from multifocal hepatocellular carcinoma and underwent domino LT from patients undergoing combined liver-kidney transplantation for PH1. Within the first 4 weeks, all the domino recipients developed dialysis-dependent kidney failure despite good liver function. Four of the five patients died. The only survivor underwent retransplantation due to hepatic artery thrombosis. Twenty months after transplantation, this patient is doing well and has had no recurrence of hepatocellular carcinoma. CONCLUSION: Domino LT using donors with PH1 results in early renal failure and cannot be recommended for transplantation unless preventive strategies have been identified.

Clearance and removal of oxalate in children on intensified dialysis for primary hyperoxaluria type 1.

Patients with end-stage renal failure owing to primary hyperoxaluria type 1 (PH1) receive dialysis while waiting for transplantation. So far, dialysis has not been shown to overcome the problem of ongoing oxalate production and deposition at extrarenal sites. We report on six children with PH1 who had to be dialyzed for a median period of 2.5 years while awaiting liver transplantation. Aiming at preventing oxalate tissue accretion, oxalate mass transfer was studied and dialysis intensified accordingly. Mean plasma oxalate concentration was between 51 and 137 micromol/l. In three of the six patients with a urinary output between 630 and 3140 ml, urinary removal of oxalate was between 5.6 and 12.4 mmol/week/1.73 m2. Hemodialysis (HD) in five of the six patients demonstrated a mean oxalate dialysance between 158 and 444 l/week/1.73 m2. Peritoneal dialysis (PD) in two of the six patients showed mean oxalate clearances of 66 and 103 l/week/1.73 m2. One patient received HD and PD. By adding all modes of elimination, a mean total oxalate mass between 10.1 and 24.1 mmol/week/1.73 m2 was removed. Dialysis is still necessary as a temporary therapy for a number of patients with PH1. Dialysis should be instituted pre-emptively and maximally exploited by intensified HD/PD treatment protocols, without, however, cutting back urinary output.

Oxalobacter formigenes: a potential tool for the treatment of primary hyperoxaluria type 1.

Primary hyperoxaluria is characterized by severe urolithiasis, nephrocalcinosis, and early renal failure. As treatment options are scarce, we aimed for a new therapeutic tool using colonic degradation of endogenous oxalate by Oxalobactor formigenes. Oxalobacter was orally administered for 4 weeks as frozen paste (IxOC-2) or as enteric-coated capsules (IxOC-3). Nine patients (five with normal renal function, one after liver-kidney transplantation, and three with renal failure) completed the IxOC-2 study. Seven patients (six with normal renal function and one after liver-kidney transplantation) completed the IxOC-3 study. Urinary oxalate or plasma oxalate in renal failure was determined at baseline, weekly during treatment and for a 2-week follow-up. The patients who showed >20% reduction both at the end of weeks 3 and 4 were considered as responders. Under IxOC-2, three out of five patients with normal renal function showed a 22-48% reduction of urinary oxalate. In addition, two renal failure patients experienced a significant reduction in plasma oxalate and amelioration of clinical symptoms. Under IxOC-3 treatment, four out of six patients with normal renal function responded with a reduction of urinary oxalate ranging from 38.5 to 92%. Although all subjects under IxOC-2 and 4 patients under IxOC-3 showed detectable levels of O. formigenes in stool during treatment, fecal recovery dropped directly at follow up, indicating only transient gastrointestinal-tract colonization. The preliminary data indicate that O. formigenes is safe, leads to a significant reduction of either urinary or plasma oxalate, and is a potential new treatment option for primary hyperoxaluria.

Primary hyperoxaluria type 1: still challenging!

Primary hyperoxaluria type 1, the most common form of primary hyperoxaluria, is an autosomal recessive disorder caused by a deficiency of the liver-specific enzyme alanine: glyoxylate aminotransferase (AGT). This results in increased synthesis and subsequent urinary excretion of the metabolic end product oxalate and the deposition of insoluble calcium oxalate in the kidney and urinary tract. As glomerular filtration rate (GFR) decreases due to progressive renal involvement, oxalate accumulates and results in systemic oxalosis. Diagnosis is still often delayed. It may be established on the basis of clinical and sonographic findings, urinary oxalate +/- glycolate assessment, DNA analysis and, sometimes, direct AGT activity measurement in liver biopsy tissue. The initiation of conservative measures, based on hydration, citrate and/or phosphate, and pyridoxine, in responsive cases at an early stage to minimize oxalate crystal formation will help to maintain renal function in compliant subjects. Patients with established urolithiasis may benefit from extracorporeal shock-wave lithotripsy and/or JJ stent insertion. Correction of the enzyme defect by liver transplantation should be planned, before systemic oxalosis develops, to optimize outcomes and may be either sequential (biochemical benefit) or simultaneous (immunological benefit) liver-kidney transplantation, depending on facilities and access to cadaveric or living donors. Aggressive dialysis therapies are required to avoid progressive oxalate deposition in established end-stage renal disease (ESRD), and minimization of the time on dialysis will improve both the patient's quality of life and survival.

Glyoxylate reductase activity in blood mononuclear cells and the diagnosis of primary hyperoxaluria type 2.

BACKGROUND: Primary hyperoxaluria type 2 (PH2) is a rare monogenic disorder characterized by an elevated urinary excretion of oxalate. Increased oxalate excretion in PH2 patients can cause nephrolithiasis and nephrocalcinosis, and can, in some cases, result in renal failure and systemic oxalate deposition. The disease is due to a deficiency of glyoxylate reductase/hydroxypyruvate reductase (GRHPR) activity. A definitive diagnosis of PH2 is currently made by the analysis of GR activity in a liver biopsy. GRHPR is expressed in virtually every tissue in the body, suggesting that utilization of more readily available cells could be used to determine GRHPR deficiency. In this study, we have evaluated the potential of determining GR and d-glycerate dehydrogenase (DGDH) activity in blood mononuclear cells (BMC) as a diagnostic indicator of PH2. METHODS: Blood samples were obtained from 10 male and 10 female normal subjects, median age 31, range 21-63, at the Wake Forest University Medical Center and from primary hyperoxaluria patients at the Mayo Clinic. The BMC were isolated and GR and DGDH activities measured in cell lysates. RESULTS: An assay of 20 normal individuals indicated that BMC contained a DGDH and GR activity of 0.97+/-0.20 (range 0.62-1.45), and 10.6+/-3.3 (range 8.3-16.6) nmol/min/mg protein, respectively. The intra-assay coefficient of variation for DGDH and GR activity was 8.2 and 11.5%, respectively. The BMC lysates from normal adult subjects and patients with PH1 showed similar GR and DGDH activities. This was confirmed by the presence of immunoreactive GRHPR protein by western blot analysis. In contrast, PH2 BMC lysates did not exhibit DGDH or GR activity, and showed no immunoreactive GRHPR by western blot analysis. CONCLUSION: These results suggest that the assay of DGDH or GR activity in BMC could be used as a minimally invasive diagnostic test for PH2.

[Sequential combined liver-kidney transplantation for a one-year-old boy with infantile primary hyperoxaluria type 1].

We present the case of a one-year-old male patient with infantile primary hyperoxaluria type 1 (PH1). The patient visited hospital because of growth delay and poor feeding when he was six months old, and was diagnosed as PH1 with chronic renal failure. He underwent peritoneal dialysis until receiving a living-related liver transplantation when he was seventeen months old, and after the operation, underwent hemodialysis or hemodiafiltration four times per week. Six months after the liver transplantation, his serum oxalate level decreased to around 20 micromol/l and a living-related kidney transplantation was successfully performed. Nine months have passed since the kidney transplantation, and the patient's liver and kidney functions have been good and his growth and development much better than before the sequential liver and kidney transplantation. However, his serum and urine oxalate levels remained high and he has required high dose hydration to prevent deposition of calcium oxalate crystals in his grafted kidney. The key-points for treating infantile PHI patients are summarized as follows; 1) make a precise diagnosis as soon as possible, 2) perform a combined liver-kidney transplantation successfully, 3) conduct careful monitoring of the serum and urine oxalate levels and continue adequate hydration after kidney transplantation until the serum and urine oxalate levels normalize. Furthermore, cooperation between the medical staff and the patient's family seems to be essential.

Primary hyperoxaluria type 1 in the Canary Islands: a conformational disease due to I244T mutation in the P11L-containing alanine:glyoxylate aminotransferase.

Primary hyperoxaluria type 1 (PH1) is an inborn error of metabolism resulting from a deficiency of alanine:glyoxylate aminotransferase (AGXT; EC 2.6.1.44). Most of the PH1 alleles detected in the Canary Islands carry the Ile-244 --> Thr (I244T) mutation in the AGXT gene, with 14 of 16 patients homozygous for this mutation. Four polymorphisms within AGXT and regional microsatellites also were shared in their haplotypes (AGXT*LTM), consistent with a founder effect. The consequences of these amino acid changes were investigated. Although I244T alone did not affect AGXT activity or subcellular localization, when present in the same protein molecule as Leu-11 --> Pro (L11P), it resulted in loss of enzymatic activity in soluble cell extracts. Like its normal counterpart, the AGXT*LTM protein was present in the peroxisomes but it was insoluble in detergent-free buffers. The polymorphism L11P behaved as an intragenic modifier of the I244T mutation, with the resulting protein undergoing stable interaction with molecular chaperones and aggregation. This aggregation was temperature-sensitive. AGXT*LTM expressed in Escherichia coli, as a GST-fusion protein, and in insect cells could be purified and retained enzymatic activity. Among various chemical chaperones tested in cell culture, betaine substantially improved the solubility of the mutant protein and the enzymatic activity in cell lysates. In summary, I244T, the second most common mutation responsible for PH1, is a protein conformational disease that may benefit from new therapies with pharmacological chaperones or small molecules to minimize protein aggregation.

Primary hyperoxaluria type 1 in The Netherlands: prevalence and outcome.

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is a phenotypically heterogeneous disease. To date the relationship between biochemical parameters and outcome is unclear. We therefore undertook a national cohort study on biochemical and clinical parameters and outcome in PH1. METHODS: Review of medical charts of all Dutch PH1 patients, who were identified by sending questionnaires to all Dutch nephrologists for children and adults. RESULTS: Fifty-seven patients were identified. The prevalence and incidence rates were 2.9/10(6) and 0.15/10(6)/year, respectively. Median age at diagnosis was 7.3 years (range 0-57). Seventeen (30%) patients were older than 18 years at time of diagnosis, of whom 10 (59%) presented with end-stage renal disease (ESRD), in contrast to only nine (23%) of those aged under 18 years. Median age at initial symptoms was 6.0 years (range 0-50). In four of nine patients with infantile PH1, normal renal function was preserved after a median follow-up of 7.7 years (range 0.1-16). Progression to renal insufficiency was associated with the presence of nephrocalcinosis, as assessed by ultrasound (relative risk=1.8; 95% CI, 1.0-3.4) and with pyridoxine-unresponsiveness (relative risk=2.2; 95% CI, 1.1-4.2) but not with age at presentation, the extent of hyperoxaluria, or AGT activity. No apparent nephrocalcinosis was found in five of the 19 patients who presented with ESRD. CONCLUSIONS: Although more than one-half of the PH1 patients have symptoms under the age of 10 years, PH1 can present at any age. In adults, PH1 presents predominantly with ESRD, which may be due to misinterpretation of early symptoms. Although nephrocalcinosis is correlated with development of renal insufficiency, the latter can occur even in the absence of nephrocalcinosis. Pyridoxine sensitivity is associated with better outcome in PH1.

Crystalluria: a clinically useful investigation in children with primary hyperoxaluria post-transplantation.

Primary hyperoxaluria type I (PH I) is a congenital error of metabolism that can be manifested by an increased oxalate production, and ultimately result in kidney failure. After a combined liver/kidney transplantation, children with PH I have persistent excretion of oxalate that causes crystal formation in the urinary tract, and could result in systemic oxalosis and eventual graft failure. We speculated that crystalluria may be predictive of this nephrolithogenic tendency and thus investigated the effect of an intensive therapeutic strategy to prevent crystal formation in 13 children at our hospital. Oxalate crystal volume (OCV) measurements were performed at regular intervals for 36 months, and compared with urine supersaturation measurements. We found that crystalluria with the OCV measurement is non-invasive, easily performed, and gives feedback on the efficacy of PH I therapy within one hour. Further study is needed to determine whether this method is a better predictor of nephrocalcinosis than is supersaturation alone.

Primary hyperoxaluria type 1: a cluster of new mutations in exon 7 of the AGXT gene.

Primary hyperoxaluria type 1 (PH1) is a severe autosomal recessive inborn error of glyoxylate metabolism caused by deficiency of the hepatic peroxisomal enzyme alanine:glyoxylate aminotransferase. This enzyme is encoded by the AGXT gene on chromosome 2q37.3. DNA samples from 79 PH1 patients were studied using single strand conformation polymorphism analysis to detect sequence variants, which were then characterised by direct sequencing and confirmed by restriction enzyme digestion. Four novel mutations were identified in exon 7 of AGXT: a point mutation T853C, which leads to a predicted Ile244Thr amino acid substitution, occurred in nine patients. Two other mutations in adjacent nucleotides, C819T and G820A, mutated the same codon at residue 233 from arginine to cysteine and histidine, respectively. The fourth mutation, G860A, introduced a stop codon at amino acid residue 246. Enzyme studies in these patients showed that AGT catalytic activity was either very low or absent and that little or no immunoreactive protein was present. Together with a new polymorphism in exon 11 (C1342A) these findings underline the genetic heterogeneity of the AGXT gene. The novel mutation T853C is the second most common mutation found to date with an allelic frequency of 9% and will therefore be of clinical importance for the diagnosis of PH1.