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NEJM Evidence Jul 2022Hyperoxaluria is defined as urinary oxalate (U) excretion greater than 0.5 mmol per day. Hyperoxaluria can result from genetic causes, and these are known as primary...
Hyperoxaluria is defined as urinary oxalate (U) excretion greater than 0.5 mmol per day. Hyperoxaluria can result from genetic causes, and these are known as primary hyperoxalurias. Secondary hyperoxaluria results from high intake of oxalate-rich foods (e.g., chocolate, nuts, spinach), lack of calcium in the diet to bind oxalate in the gut, or oxalate malabsorption; these forms are termed enteric hyperoxaluria. Usually only primary and enteric hyperoxalurias lead to the complications of kidney stones, crystal nephropathy, chronic kidney disease (CKD), and systemic oxalosis..
PubMed: 38319262
DOI: 10.1056/EVIDe2200110 -
Drugs Feb 2021Lumasiran (Oxlumo™) is a subcutaneously administered small interfering RNA (siRNA) targeting the mRNA for hydroxyacid oxidase 1 gene (HAO1; encodes glycolate oxidase)... (Review)
Review
Lumasiran (Oxlumo™) is a subcutaneously administered small interfering RNA (siRNA) targeting the mRNA for hydroxyacid oxidase 1 gene (HAO1; encodes glycolate oxidase) and was developed by Alnylam Pharmaceuticals for the treatment of primary hyperoxaluria type 1 (PH1). By silencing the gene encoding glycolate oxidase, lumasiran depletes glycolate oxidase and thereby inhibits the synthesis of oxalate, which is the toxic metabolite that is directly associated with the clinical manifestations of PH1. On 19 November 2020, lumasiran received its first global approval in the EU for the treatment of PH1 in all age groups. On 23 November 2020, lumasiran was approved in the USA for the treatment of adult and paediatric patients with PH1. This article summarizes the milestones in the development of lumasiran leading to this first approval.
Topics: Adult; Alcohol Oxidoreductases; Child; Humans; Hyperoxaluria, Primary; Injections, Subcutaneous; RNA, Messenger; RNA, Small Interfering
PubMed: 33405070
DOI: 10.1007/s40265-020-01463-0 -
Frontiers in Pediatrics 2022Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive genetic disorder caused by mutations in the AGXT gene. The hepatic peroxisomal enzyme alanine glyoxylate... (Review)
Review
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive genetic disorder caused by mutations in the AGXT gene. The hepatic peroxisomal enzyme alanine glyoxylate aminotransferase (AGT) defects encoded by the AGXT gene increase oxalate production, resulting in nephrocalcinosis, nephrolithiasis, chronic kidney disease, and kidney failure. Traditional pharmacological treatments for PH1 are limited. At present, the treatment direction of PH1 is mainly targeted therapy which refer to a method that targeting the liver to block the pathway of the production of oxalate. Lumasiran (OxlumoTM, developed by Alnylam Pharmaceuticals), an investigational RNA interference (RNAi) therapeutic agent, is the first drug approved for the treatment of PH1, which was officially approved by the US Food and Drug Administration and the European Union in November 2020. It is also the only drug that has been shown to decrease harmful oxalate. Currently, there are 5 keys completed and ongoing clinical trials of lumasiran in PH1. Through the three phase III trials that completed the primary analysis period, lumasiran has been shown to be effective in reducing oxalate levels in urine and plasma in different age groups, such as children, adults, and patients with advanced kidney disease, including those on hemodialysis. In addition to clinical trials, cases of lumasiran treatment for PH1 have been reported in small infants, twin infants, and children diagnosed with PH1 after kidney transplantation. These reports confirm the effectiveness and safety of lumasiran. All adverse events were of mild to moderate severity, with the most common being mild, transient injection-site reactions. No deaths or severe adverse events were reported. This article reviews PH1 and lumasiran which is the only approved therapeutic drug, and provide new options and hope for the treatment of PH1.
PubMed: 36704142
DOI: 10.3389/fped.2022.1052625 -
Nephrologie & Therapeutique Feb 2021Nephrocalcinosis is defined by calcium phosphate or calcium oxalate deposits in the kidney parenchyma, particularly in tubular epithelial cells and interstitial tissue....
Nephrocalcinosis is defined by calcium phosphate or calcium oxalate deposits in the kidney parenchyma, particularly in tubular epithelial cells and interstitial tissue. It should be differentiated from urolithiasis where calcium salts deposits are located in the kidney and urinary tract. The epidemiology of nephrocalcinosis in children is unknown but the condition is not so rare, with an increased incidence in preterm infants. Often detected as an incidental finding, nephrocalcinosis may be classified according to the radiological type: medullary, cortical or diffuse. Nephrocalcinosis in children can be caused by a variety of etiology. The most common causes concern medullary nephrocalcinosis and include hereditary tubular disorders, in particular distal renal tubular acidosis and Dent disease, metabolic disorders such as idiopathic hypercalciuria and hyperoxaluria, and iatrogenic causes such as vitamin D intoxication. In the newborn, the main cause is hypercalciuria of the premature baby, whose multifactorial origin is largely iatrogenic. Primary hyperoxaluria which can lead to early onset nephrocalcinosis and usually to chronic kidney disease should always be considered and further investigated. In order to provide a specific diagnosis, it is essential to take into account the family history, the clinical context and complete laboratory data. Early initiation of an appropriate etiological treatment is recommended and may prevent or delay the progression to chronic kidney disease in some cases.
Topics: Calcium Oxalate; Child; Humans; Hyperoxaluria; Infant, Newborn; Infant, Premature; Kidney; Nephrocalcinosis
PubMed: 33461896
DOI: 10.1016/j.nephro.2020.12.001 -
World Journal of Hepatology Oct 2020Combined liver and kidney transplantation (CLKT) is indicated in patients with failure of both organs, or for the treatment of end-stage chronic kidney disease (ESKD)... (Review)
Review
Combined liver and kidney transplantation (CLKT) is indicated in patients with failure of both organs, or for the treatment of end-stage chronic kidney disease (ESKD) caused by a genetic defect in the liver. The aim of the present review is to provide the most up-to-date overview of the rare conditions as indications for CLKT. They are major indications for CLKT in children. However, in some of them ( atypical hemolytic uremic syndrome or primary hyperoxaluria), CLKT may be required in adults as well. Primary hyperoxaluria is divided into three types, of which type 1 and 2 lead to ESKD. CLKT has been proven effective in renal function replacement, at the same time preventing recurrence of the disease. Nephronophthisis is associated with liver fibrosis in 5% of cases and these patients are candidates for CLKT. In alpha 1-antitrypsin deficiency, hereditary C3 deficiency, lecithin cholesterol acyltransferase deficiency and glycogen storage diseases, glomerular or tubulointerstitial disease can lead to chronic kidney disease. Liver transplantation as a part of CLKT corrects underlying genetic and consequent metabolic abnormality. In atypical hemolytic uremic syndrome caused by mutations in the genes for factor H, successful CLKT has been reported in a small number of patients. However, for this indication, CLKT has been largely replaced by eculizumab, an anti-C5 antibody. CLKT has been well established to provide immune protection of the transplanted kidney against donor-specific antibodies against class I HLA, facilitating transplantation in a highly sensitized recipient.
PubMed: 33200012
DOI: 10.4254/wjh.v12.i10.722 -
Indian Journal of Pediatrics Sep 2020Although kidney stones are less common in children than in adults, incidence in children is rising. Kidney stones may lead to significant morbidity in addition to... (Review)
Review
Although kidney stones are less common in children than in adults, incidence in children is rising. Kidney stones may lead to significant morbidity in addition to escalating medical costs. Clinical presentation is variable. Bilateral kidney stones in a younger child should prompt work-up for primary hyperoxaluria. Metabolic abnormalities are more frequent in children and can result in frequent stone recurrence. Whole exome sequencing data shows genetic defects in about 30% of stone formers. 24 h urine collection should be conducted when patient receives his usual diet and fluid intake with normal activity. Infrared spectroscopy and X-ray diffraction are used for stone analysis. Urine studies should be delayed by 4-6 wk after stone fragmentation or treatment of any stone related complications. The goal of evaluation is to identify modifiable risk factors for which targeted therapy may be instituted. Primary indications for surgical intervention include pain, infection and obstruction. Extracorporeal shockwave lithotripsy (ESWL), ureteroscopy, and percutaneous nephrolithotomy (PCNL) are most commonly used, and selection is based on stone size, anatomy, composition and anatomy. Advances in technology have allowed a shift to minimally invasive surgeries. Comprehensive management requires multidisciplinary team. Children with kidney stones require long term follow-up with periodic assessment of stone forming activity and ascertaining stone burden. High index of suspicion should be there to diagnose diseases like primary hyperoxaluria, Dent's disease, renal tubular acidosis (RTA) etc. as these diseases have ramifications on kidney function and growth.
Topics: Adult; Child; Humans; Kidney Calculi; Lithotripsy; Recurrence; Risk Factors; Ureteroscopy
PubMed: 32794099
DOI: 10.1007/s12098-020-03424-7 -
Orphanet Journal of Rare Diseases Aug 2023Inborn metabolic diseases (IMD) are rare conditions that can be diagnosed during adulthood. Patients with IMD may have joint symptoms and the challenge is to establish... (Review)
Review
Inborn metabolic diseases (IMD) are rare conditions that can be diagnosed during adulthood. Patients with IMD may have joint symptoms and the challenge is to establish an early diagnosis in order to institute appropriate treatment and prevent irreversible damage. This review describes the joint manifestations of IMD that may be encountered in adults. The clinical settings considered were arthralgia and joint stiffness as well as arthritis. Unspecific arthralgias are often the first symptoms of hereditary hemochromatosis, chronic low back pain may reveal an intervertebral disc calcification in relation with alkaptonuria, and progressive joint stiffness may correspond to a mucopolysaccharidosis or mucolipidosis. Gaucher disease is initially revealed by painful acute attacks mimicking joint pain described as "bone crises". Some IMD may induce microcrystalline arthropathy. Beyond classical gout, there are also gouts in connection with purine metabolism disorders known as "enzymopathic gouts". Pyrophosphate arthropathy can also be part of the clinical spectrum of Gitelman syndrome or hypophosphatasia. Oxalate crystals arthritis can reveal a primary hyperoxaluria. Destructive arthritis may be indicative of Wilson's disease. Non-destructive arthritis may be seen in mevalonate kinase deficiency and familial hypercholesterolemia.
Topics: Humans; Adult; Chondrocalcinosis; Gout; Joint Diseases; Metabolism, Inborn Errors; Hepatolenticular Degeneration
PubMed: 37563694
DOI: 10.1186/s13023-023-02810-6 -
Clinical Kidney Journal May 2022While the surgical approaches available in primary hyperoxaluria (PH) are common to all patients requiring intervention for urolithiasis, the indications for treatment... (Review)
Review
While the surgical approaches available in primary hyperoxaluria (PH) are common to all patients requiring intervention for urolithiasis, the indications for treatment and their corresponding toxicities are unique. Being a rare disease, we are guided by case series. This review summarizes the available literature highlighting the important disease-specific considerations. Shockwave lithotripsy (SWL) is of particular interest. It is generally the first-line treatment for stones in children, but here the stones produced will be relatively resistant to fragmentation. In addition, there are concerning reports in children of sudden unilateral decline in function in the treated kidney as measured by nuclear renography. Percutaneous nephrostolithotomy might intuitively seem favorable given the shortest drain duration and the ability to treat larger stones efficiently but, similar to SWL, rapid chronic kidney disease (CKD) progression has been seen postoperatively. Ureteroscopy is therefore generally the safest option, but considerations regarding stent encrustation, the growth of residual fragments and the large volume of stone often faced may limit this approach. The surgeon must balance the above with consideration of the patient's CKD status when considering a plan of monitoring and treating stones in PH.
PubMed: 35592623
DOI: 10.1093/ckj/sfab187