-
Pediatric Nephrology (Berlin, Germany) May 2005There is some controversy about the value of mutation analysis in the management of primary hyperoxaluria type 1 (PH1). About 50 different mutations of the AGXT gene... (Review)
Review
There is some controversy about the value of mutation analysis in the management of primary hyperoxaluria type 1 (PH1). About 50 different mutations of the AGXT gene encoding the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT) are currently known. The three most common mutations in the Western population account for less than half of the mutant alleles, and no simple screening test is available. Does the genotype help in diagnosis, prognosis and therapy? Definitive diagnosis is indispensable if liver transplantation is considered and can under certain circumstances be established by mutation analysis, but a liver biopsy is still necessary to determine AGT activity in a number of cases. Prognosis is difficult to assess due to a large clinical variation, despite identical mutations. Although the homozygous 508G>A (Gly170Arg) mutation appears to be associated with a better (and 33insC with a worse) prognosis, there are too many exceptions for precise prediction. Pyridoxine responsiveness can be anticipated in some genotypes (508G>A (Gly170Arg) and 454T>A (Phe153Ile)), but it should still be tested for in all patients. Genetic testing is thus clinically helpful but has clear limitations.
Topics: Child; Genetic Testing; Genotype; Humans; Hyperoxaluria, Primary; Prognosis
PubMed: 15772831
DOI: 10.1007/s00467-005-1813-0 -
Nephrologie & Therapeutique Jul 2011Primary hyperoxalurias are rare recessive inherited inborn errors of glyoxylate metabolism. They are responsible for progressive renal involvement, which further lead to...
Primary hyperoxalurias are rare recessive inherited inborn errors of glyoxylate metabolism. They are responsible for progressive renal involvement, which further lead to systemic oxalate deposition, which can even occur in infants. Primary hyperoxaluria type 1 is the most common form in Europe and is due to alanine-glyoxylate aminostransferase deficiency, a hepatic peroxisomal pyridoxin-dependent enzyme. Therefore primary hyperoxaluria type 1 is responsible for hyperoxaluria leading to aggressive stone formation and nephrocalcinosis. As glomerular filtration rate decreases, systemic oxalate storage occurs throughout all the body, and mainly in the skeleton. The diagnosis is first based on urine oxalate measurement, then on genotyping, which may also allow prenatal diagnosis to be proposed. Conservative measures - including hydration, crystallization inhibitors and pyridoxine - are safe and may allow long lasting renal survival, provided it is given as soon as the diagnosis has been even suspected. No dialysis procedure can remove enough oxalate to compensate oxalate overproduction from the sick liver, therefore a combined liver and kidney transplantation should be planned before advanced renal disease has occurred, in order to limit/avoid systemic oxalate deposition. In the future, primary hyperoxaluria type 1 may benefit from hepatocyte transplantation, chaperone molecules, etc.
Topics: Alanine Transaminase; Disease Progression; Genotype; Humans; Hyperoxaluria; Hyperoxaluria, Primary; Kidney Transplantation; Liver Transplantation; Mutation; Peritoneal Dialysis; Pyridoxine; Treatment Outcome; Vitamin B Complex
PubMed: 21636340
DOI: 10.1016/j.nephro.2011.03.004 -
Urologiia (Moscow, Russia : 1999) Dec 2019Primary hyperoxaluria is a group of inherited metabolic diseases characterized by increased formation of calcium-oxalate stones in kidneys with development of... (Review)
Review
Primary hyperoxaluria is a group of inherited metabolic diseases characterized by increased formation of calcium-oxalate stones in kidneys with development of nephrolithiasis and chronic kidney disease. The article summarizes the modern information on the diagnostics and treatment of the disorder depending on genotype of the patient (AGXT, GRHPR, HOGA1 genes). The evaluation of the molecular genetic aetiology of the kidney stone disease contributes to the personalized treatment and prevention of the pathology in the patients and their relatives.
Topics: Genetic Predisposition to Disease; Genotype; Humans; Hyperoxaluria, Primary; Kidney; Kidney Calculi; Molecular Biology; Phenotype
PubMed: 31808650
DOI: No ID Found -
BMC Nephrology Jun 2019Primary hyperoxaluria (PH) is a rare inborn disorder of the metabolism of glyoxylate, which causes the hallmark production oxalate and forms insoluble calcium oxalate... (Review)
Review
BACKGROUND
Primary hyperoxaluria (PH) is a rare inborn disorder of the metabolism of glyoxylate, which causes the hallmark production oxalate and forms insoluble calcium oxalate crystals that accumulate in the kidney and other organs. Since the manifestation of PH varies from recurrent nephrolithiasis, nephrocalcinosis, and end-stage renal disease with age at onset of symptoms ranging from infancy to the sixth decade, the disease remains undiagnosed until after kidney transplantation in some cases.
CASE PRESENTATION
Herein, we report 3 cases of PH diagnosed after kidney transplantation failure, providing the comprehensive clinical course, the ultrasonic image of renal graft and pathologic image of the biopsy, highlighting the relevance of biopsy findings and the results of molecular genetic testing. We also focus on the treatment and the unfavorable outcome of the patients. Meanwhile, we review the literature and show the additional 10 reported cases of PH diagnosed after kidney transplantation. Additionally, we discuss the progressive molecular understanding of the mechanisms involved in PH and molecular therapy.
CONCLUSIONS
Overall, the necessity of preoperative screening of PH in all patients even with a minor history of nephrolithiasis and the importance of proper treatment are the lessons we learn from the 3 cases, which prompt us to avoid tragedies.
Topics: Adult; Humans; Hyperoxaluria, Primary; Kidney Transplantation; Male; Postoperative Complications; Treatment Failure
PubMed: 31215412
DOI: 10.1186/s12882-019-1402-2 -
International Urology and Nephrology Jul 2022
Topics: Humans; Hyperoxaluria; Hyperoxaluria, Primary
PubMed: 34796413
DOI: 10.1007/s11255-021-03067-3 -
Pediatric Nephrology (Berlin, Germany) Jan 2016Deposition 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... (Review)
Review
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.
Topics: Animals; Biopsy; Bone Density; Bone Diseases, Metabolic; Bone Remodeling; Bone and Bones; Calcium Oxalate; Crystallization; Diagnostic Imaging; Humans; Hyperoxaluria, Primary; Predictive Value of Tests; Prognosis; Risk Factors; Stomatognathic Diseases
PubMed: 25631241
DOI: 10.1007/s00467-015-3048-z -
Pediatric Nephrology (Berlin, Germany) Dec 2013Primary hyperoxaluria type 1 (PH1) is a rare inborn error of glyoxylate metabolism of autosomal recessive inheritance, leading to progressive systemic oxalate storage... (Review)
Review
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.
Topics: Delayed Diagnosis; Developing Countries; Early Diagnosis; Guideline Adherence; Health Services Accessibility; Humans; Hyperoxaluria, Primary; Nephrology; Patient Selection; Practice Guidelines as Topic; Practice Patterns, Physicians'; Predictive Value of Tests; Prognosis
PubMed: 23494551
DOI: 10.1007/s00467-013-2444-5 -
British Journal of Clinical Pharmacology Jun 2022RNA interference (RNAi) is a natural biological pathway that inhibits gene expression by targeted degradation or translational inhibition of cytoplasmic mRNA by the RNA... (Review)
Review
RNA interference (RNAi) is a natural biological pathway that inhibits gene expression by targeted degradation or translational inhibition of cytoplasmic mRNA by the RNA induced silencing complex. RNAi has long been exploited in laboratory research to study the biological consequences of the reduced expression of a gene of interest. More recently RNAi has been demonstrated as a therapeutic avenue for rare metabolic diseases. This review presents an overview of the cellular RNAi machinery as well as therapeutic RNAi design and delivery. As a clinical example we present primary hyperoxaluria, an ultrarare inherited disease of increased hepatic oxalate production which leads to recurrent calcium oxalate kidney stones. In the most common form of the disease (Type 1), end-stage kidney disease occurs in childhood or young adulthood, often necessitating combined kidney and liver transplantation. In this context we discuss nedosiran (Dicerna Pharmaceuticals, Inc.) and lumasiran (Alnylam Pharmaceuticals), which are both novel RNAi therapies for primary hyperoxaluria that selectively reduce hepatic expression of lactate dehydrogenase and glycolate oxidase respectively, reducing hepatic oxalate production and urinary oxalate levels. Finally, we consider future optimizations advances in RNAi therapies.
Topics: Adult; Female; Humans; Hyperoxaluria, Primary; Male; Oxalates; RNA Interference; RNA, Small Interfering; Young Adult
PubMed: 34022071
DOI: 10.1111/bcp.14925 -
Pediatric Nephrology (Berlin, Germany) Aug 2023Primary hyperoxaluria (PH) results from genetic mutations in different genes of glyoxylate metabolism, which cause significant increases in production of oxalate by the... (Observational Study)
Observational Study
BACKGROUND
Primary hyperoxaluria (PH) results from genetic mutations in different genes of glyoxylate metabolism, which cause significant increases in production of oxalate by the liver. This study aimed to report clinical and laboratory manifestations and outcome of PH type 1 in children in our center.
METHODS
A single-center observational cohort study was conducted at Children's University Hospital in Damascus, and included all patients admitted from 2018 to 2020, with a diagnosis of hyperoxaluria (urinary oxalate excretion > 45 mg/1.73 m/day, or > 0.5 mmol/1.73 m/day). PH type 1 (PH1) diagnosis was established by identification of biallelic pathogenic variants (compound heterozygous or homozygous mutations) in AGXT gene on molecular genetic testing.
RESULTS
The study included 100 patients with hyperoxaluria, with slight male dominance (57%), and median age 1.75 years (range, 1 month-14 years). Initial complaint was urolithiasis or nephrocalcinosis in 47%, kidney failure manifestations in 29%, and recurrent urinary tract infection in 24%. AGXT mutations were detected in 40 patients, and 72.5% of PH1 patients had kidney failure at presentation. Neither gender, age nor urinary oxalate excretion in 24 h had statistical significance in distinguishing PH1 from other forms of hyperoxaluria (P-Value > 0.05). Parental consanguinity, family history of kidney stones, bilateral nephrocalcinosis, presence of oxalate crystals in random urine sample, kidney failure and mortality were statistically significantly higher in PH1 (P-values < 0.05). Mortality was 32.5% among PH1 patients, with 4 PH1 patients (10%) on hemodialysis awaiting combined liver-kidney transplantation.
CONCLUSION
PH1 is still a grave disease with wide variety of clinical presentations which frequent results in delays in diagnosis, thus kidney failure is still a common presentation. In Syria, we face many challenges in diagnosis of PH, especially PH2 and PH3, and in management, with hopes that diagnosis tools and modern therapies will become available in our country. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information.
Topics: Child; Humans; Male; Infant; Nephrocalcinosis; Hyperoxaluria, Primary; Oxalates; Hyperoxaluria; Kidney Calculi; Renal Insufficiency
PubMed: 36917293
DOI: 10.1007/s00467-023-05917-x -
Saudi Journal of Kidney Diseases and... May 2016The infantile form of primary hyperoxaluria type-1 (PH-1) is characterized by a rapid progression to the end-stage renal disease (ESRD) due to both increased oxalate...
The infantile form of primary hyperoxaluria type-1 (PH-1) is characterized by a rapid progression to the end-stage renal disease (ESRD) due to both increased oxalate load and reduced glomerular filtration rate. In the literature, data on this form are limited. The purpose of this study is to analyze retrospectively the clinical, biological, and radiological features of children who were diagnosed with PH-1 during the 1(st) year of life. We reviewed the records of all children with PH-1 diagnosed and followed-up at our department between January 1995 and December 2013. Among them, only infants younger than 12 months of age were retrospectively enrolled in the study. Fourteen infants with the median age of two months were enrolled in the study. At diagnosis, 11 patients had ESRD. All patients had nephrocalcinosis and two of them had calculi. The diagnosis was established in nine patients on the basis of the positive family history of PH-1, bilateral nephrocalcinosis, and quantitative crystalluria. In four patients, the diagnosis was made with molecular analysis of DNA. Kidney biopsy contributed to the diagnosis in one patient. During follow-up, two patients were pyridoxine sensitive and preserved renal function. Seven among 11 patients who had ESRD died, four patients are currently undergoing peritoneal dialysis. Children with infantile PH and ESRD are at high risk of early death. Peritoneal dialysis is not a treatment of choice. Combined liver-kidney transplantation is mandatory.
Topics: Female; Humans; Hyperoxaluria, Primary; Infant; Kidney; Male; Radiography; Retrospective Studies
PubMed: 27215245
DOI: 10.4103/1319-2442.182389