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Journal of the American Society of... Oct 2015Primary hyperoxaluria (PH) is a rare autosomal recessive disease characterized by oxalate accumulation in the kidneys and other organs. Three loci have been identified:...
Primary hyperoxaluria (PH) is a rare autosomal recessive disease characterized by oxalate accumulation in the kidneys and other organs. Three loci have been identified: AGXT (PH1), GRHPR (PH2), and HOGA1 (PH3). Here, we compared genotype to phenotype in 355 patients in the Rare Kidney Stone Consortium PH registry and calculated prevalence using publicly available whole-exome data. PH1 (68.4% of families) was the most severe PH type, whereas PH3 (11.0% of families) showed the slowest decline in renal function but the earliest symptoms. A group of patients with disease progression similar to that of PH3, but for whom no mutation was detected (11.3% of families), suggested further genetic heterogeneity. We confirmed that the AGXT p.G170R mistargeting allele resulted in a milder PH1 phenotype; however, other potential AGXT mistargeting alleles caused more severe (fully penetrant) disease. We identified the first PH3 patient with ESRD; a homozygote for two linked, novel missense mutations. Population analysis suggested that PH is an order of magnitude more common than determined from clinical cohorts (prevalence, approximately 1:58,000; carrier frequency, approximately 1:70). We estimated PH to be approximately three times less prevalent among African Americans than among European Americans because of a limited number of common European origin alleles. PH3 was predicted to be as prevalent as PH1 and twice as common as PH2, indicating that PH3 (and PH2) cases are underdiagnosed and/or incompletely penetrant. These results highlight a role for molecular analyses in PH diagnostics and prognostics and suggest that wider analysis of the idiopathic stone-forming population may be beneficial.
Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Genetic Association Studies; Heterozygote; Humans; Hyperoxaluria, Primary; Infant; Middle Aged; Young Adult
PubMed: 25644115
DOI: 10.1681/ASN.2014070698 -
Clinical Journal of the American... Jul 2020
Topics: Adolescent; Adult; Anxiety; Caregivers; Child; Humans; Hyperoxaluria; Hyperoxaluria, Primary; Kidney Calculi; Kidney Failure, Chronic; Kidney Transplantation; Quality of Life; Surveys and Questionnaires; Young Adult
PubMed: 32165441
DOI: 10.2215/CJN.13831119 -
American Journal of Kidney Diseases :... Feb 2023Lumasiran reduces urinary and plasma oxalate (POx) in patients with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function. ILLUMINATE-C evaluates...
RATIONALE & OBJECTIVE
Lumasiran reduces urinary and plasma oxalate (POx) in patients with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function. ILLUMINATE-C evaluates the efficacy, safety, pharmacokinetics, and pharmacodynamics of lumasiran in patients with PH1 and advanced kidney disease.
STUDY DESIGN
Phase 3, open-label, single-arm trial.
SETTING & PARTICIPANTS
Multinational study; enrolled patients with PH1 of all ages, estimated glomerular filtration rate ≤45 mL/min/1.73 m (if age ≥12 months) or increased serum creatinine level (if age <12 months), and POx ≥20 μmol/L at screening, including patients with or without systemic oxalosis.
INTERVENTION
Lumasiran administered subcutaneously; 3 monthly doses followed by monthly or quarterly weight-based dosing.
OUTCOME
Primary end point: percent change in POx from baseline to month 6 (cohort A; not receiving hemodialysis at enrollment) and percent change in predialysis POx from baseline to month 6 (cohort B; receiving hemodialysis at enrollment). Pharmacodynamic secondary end points: percent change in POx area under the curve between dialysis sessions (cohort B only); absolute change in POx; percent and absolute change in spot urinary oxalate-creatinine ratio; and 24-hour urinary oxalate adjusted for body surface area.
RESULTS
All patients (N = 21; 43% female; 76% White) completed the 6-month primary analysis period. Median age at consent was 8 (range, 0-59) years. For the primary end point, least-squares mean reductions in POx were 33.3% (95% CI, -15.2% to 81.8%) in cohort A (n = 6) and 42.4% (95% CI, 34.2%-50.7%) in cohort B (n = 15). Improvements were also observed in all pharmacodynamic secondary end points. Most adverse events were mild or moderate. No patient discontinued treatment or withdrew from the study. The most commonly reported lumasiran-related adverse events were injection-site reactions, all of which were mild and transient.
LIMITATIONS
Single-arm study without placebo control.
CONCLUSIONS
Lumasiran resulted in substantial reductions in POx with acceptable safety in patients with PH1 who have advanced kidney disease, supporting its efficacy and safety in this patient population.
FUNDING
Alnylam Pharmaceuticals.
TRIAL REGISTRATION
Registered at ClinicalTrials.gov with study number NCT04152200 and at EudraCT with study number 2019-001346-17.
PLAIN-LANGUAGE SUMMARY
Primary hyperoxaluria type 1 (PH1) is a rare genetic disease characterized by excessive hepatic oxalate production that frequently causes kidney failure. Lumasiran is an RNA interference therapeutic that is administered subcutaneously for the treatment of PH1. Lumasiran has been shown to reduce oxalate levels in the urine and plasma of patients with PH1 who have relatively preserved kidney function. In the ILLUMINATE-C study, the efficacy and safety of lumasiran were evaluated in patients with PH1 and advanced kidney disease, including a cohort of patients undergoing hemodialysis. During the 6-month primary analysis period, lumasiran resulted in substantial reductions in plasma oxalate with acceptable safety in patients with PH1 complicated by advanced kidney disease.
Topics: Adolescent; Adult; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Male; Middle Aged; Young Adult; Hyperoxaluria; Hyperoxaluria, Primary; Kidney Diseases; Oxalates
PubMed: 35843439
DOI: 10.1053/j.ajkd.2022.05.012 -
Drugs Dec 2023Nedosiran (RIVFLOZA™), a once-monthly subcutaneous small interfering RNA (siRNA) therapy, is being developed by Dicerna Pharmaceuticals, a Novo Nordisk company, for... (Review)
Review
Nedosiran (RIVFLOZA™), a once-monthly subcutaneous small interfering RNA (siRNA) therapy, is being developed by Dicerna Pharmaceuticals, a Novo Nordisk company, for the treatment of primary hyperoxaluria (PH). It reduces oxalate overproduction by inhibiting the expression of the hepatic lactate dehydrogenase (LDH) enzyme. Nedosiran received its first approval on 29 September 2023 in the USA to lower urinary oxalate levels in children aged ≥ 9 years and adults with PH type 1 (PH1) and relatively preserved kidney function [e.g. estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m]. This article summarizes the milestones in the development of nedosiran leading to this first approval for PH1.
Topics: Child; Adult; Humans; Hyperoxaluria, Primary; Oxalates; Lactate Dehydrogenases; RNA, Small Interfering
PubMed: 38060091
DOI: 10.1007/s40265-023-01976-4 -
Clinical Kidney Journal May 2022Primary hyperoxaluria type 1 (PH1) is a rare genetic form of calcium oxalate kidney stone disease. It is caused by a deficiency in the liver-specific enzyme,... (Review)
Review
Primary hyperoxaluria type 1 (PH1) is a rare genetic form of calcium oxalate kidney stone disease. It is caused by a deficiency in the liver-specific enzyme, alanine:glyoxylate aminotransferase (AGT), a pyridoxal-5'-phosphate (PLP)-dependent enzyme involved in the metabolism of glyoxylate. The excessive endogenous synthesis of oxalate that ensues leads to hyperoxaluria, and the crystallization of the poorly soluble calcium salt of oxalate is responsible for a severe kidney stone disease, which can progress to end-stage renal disease, systemic deposition of oxalate and death. Knowledge about metabolic precursors of glyoxylate and oxalate, molecular pathology of AGT and analytical methods for diagnosis and clinical assessment have allowed a better understanding of the mechanisms underlying PH1 and opened the door to new therapeutic strategies.
PubMed: 35592619
DOI: 10.1093/ckj/sfab217 -
Nefrologia : Publicacion Oficial de La... May 2014Primary hyperoxaluria (PH) occurs due to an autosomal recessive hereditary disorder of the metabolism of glyoxylate, which causes excessive oxalate production. The most... (Review)
Review
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.
Topics: Humans; Hyperoxaluria, Primary
PubMed: 24798559
DOI: 10.3265/Nefrologia.pre2014.Jan.12335 -
La Tunisie Medicale Jul 2023There are three types of primary hyperoxaluria, with type 1 considered the most severe.
INTRODUCTION
There are three types of primary hyperoxaluria, with type 1 considered the most severe.
AIM
To analyze the clinical, genetic, and evolutionary characteristics of type 1 primary hyperoxaluria with pediatric onset.
METHODS
This was a retrospective, descriptive study that included Tunisian children under the age of 18 at the time of diagnosis over a period of 25 years (January 1, 1996, to December 31, 2022).
RESULTS
Thirty-five patients were included, with a mean age of 4.1 years. The most common presenting circumstances of the disease were nephrolithiasis and end-stage renal failure. The average serum creatinine level was 225.42 µmol/l. Five mutations were identified, with the p.Ile244Thr mutation being the most prevalent. Nephrocalcinosis, surgical intervention, and a creatinine level ≥57 µmol/l were predictive of progression to end-stage renal failure. The infantile form was predictive of mortality.
CONCLUSIONS
Screening for the disease would improve the prognosis of this condition.
Topics: Child; Humans; Child, Preschool; Adult; Hyperoxaluria, Primary; Retrospective Studies; Kidney Failure, Chronic; Mutation
PubMed: 38445424
DOI: No ID Found -
World Journal of Nephrology May 2015Hyperoxaluria is characterized by an increased urinary excretion of oxalate. Primary and secondary hyperoxaluria are two distinct clinical expressions of hyperoxaluria.... (Review)
Review
Hyperoxaluria is characterized by an increased urinary excretion of oxalate. Primary and secondary hyperoxaluria are two distinct clinical expressions of hyperoxaluria. Primary hyperoxaluria is an inherited error of metabolism due to defective enzyme activity. In contrast, secondary hyperoxaluria is caused by increased dietary ingestion of oxalate, precursors of oxalate or alteration in intestinal microflora. The disease spectrum extends from recurrent kidney stones, nephrocalcinosis and urinary tract infections to chronic kidney disease and end stage renal disease. When calcium oxalate burden exceeds the renal excretory ability, calcium oxalate starts to deposit in various organ systems in a process called systemic oxalosis. Increased urinary oxalate levels help to make the diagnosis while plasma oxalate levels are likely to be more accurate when patients develop chronic kidney disease. Definitive diagnosis of primary hyperoxaluria is achieved by genetic studies and if genetic studies prove inconclusive, liver biopsy is undertaken to establish diagnosis. Diagnostic clues pointing towards secondary hyperoxaluria are a supportive dietary history and tests to detect increased intestinal absorption of oxalate. Conservative treatment for both types of hyperoxaluria includes vigorous hydration and crystallization inhibitors to decrease calcium oxalate precipitation. Pyridoxine is also found to be helpful in approximately 30% patients with primary hyperoxaluria type 1. Liver-kidney and isolated kidney transplantation are the treatment of choice in primary hyperoxaluria type 1 and type 2 respectively. Data is scarce on role of transplantation in primary hyperoxaluria type 3 where there are no reports of end stage renal disease so far. There are ongoing investigations into newer modalities of diagnosis and treatment of hyperoxaluria. Clinical differentiation between primary and secondary hyperoxaluria and further between the types of primary hyperoxaluria is very important because of implications in treatment and diagnosis. Hyperoxaluria continues to be a challenging disease and a high index of clinical suspicion is often the first step on the path to accurate diagnosis and management.
PubMed: 25949937
DOI: 10.5527/wjn.v4.i2.235 -
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