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Endocrine Practice : Official Journal... Dec 2017Primary hyperoxaluria type 1 (PH1) is a rare metabolic disorder of oxalate overproduction. It is associated with urolithiasis and nephrocalcinosis, which progress to... (Review)
Review
OBJECTIVE
Primary hyperoxaluria type 1 (PH1) is a rare metabolic disorder of oxalate overproduction. It is associated with urolithiasis and nephrocalcinosis, which progress to end-stage renal disease and systemic oxalosis. As oxalate deposits in tissues, non-parathyroid hormone (nonPTH)-mediated hypercalcemia, oxalate osteopathy, primary hypothyroidism, and primary hypogonadism develop. In this review, we will present a case of PH1 and provide an overview of this clinical entity and its endocrine manifestations.
METHODS
We conducted a PubMed search for articles related to PH1. The terms "primary hyperoxaluria," "nonPTH mediated hypercalcemia," "hypothyroidism," and "hypogonadism" were used to identify pertinent literature.
RESULTS
Given the rarity of PH1, there is scant literature regarding the incidence and clinical significance of endocrine manifestations of this disorder. There are rare reports of hypercalcemia secondary to osteoclast-stimulating activity of macrophages in bone granulomas, which occur in response to oxalate deposits. We report that hypercalcemia may also be mediated by 1,25-dihydroxyvitamin D and PTH-related protein (PTHrP). Primary hypothyroidism and primary hypogonadism are thought to be due partly to calcium oxalate deposition in thyroid and testicular tissue. The presented case is the first to report PTHrP-mediated hypercalcemia and primary hypogonadism in a patient with PH1.
CONCLUSION
PH1 is a metabolic disease with significant morbidity and mortality. Owing to its rarity, it is not widely recognized in the field of endocrinology, despite presenting with several endocrinopathies. Recognition of endocrine disturbances can result in early and successful treatment, limiting morbidity and improving quality of life in these challenging patients.
ABBREVIATIONS
1,25(OH)D= 1,25-dihydoxyvitamin D AGT = alanine:glyoxylate aminotransferase ESRD = end-stage renal disease GRHPR = glyoxylate reductase-hydroxypyruvate reductase nonPTH = non-parathyroid hormone PH = primary hyperoxaluria pQCT = peripheral quantitative computed tomography PTH = parathyroid hormone PTHrP = parathyroid hormone-related protein T4 = thyroxine TSH = thyroid-stimulating hormone.
Topics: Adult; Bone Marrow; Erectile Dysfunction; Humans; Hyperoxaluria, Primary; Kidney Failure, Chronic; Male; Nephrocalcinosis; Testis
PubMed: 29144803
DOI: 10.4158/EP-2017-0029 -
Journal of Managed Care & Specialty... Mar 2022Primary hyperoxaluria (PH) is a family of rare, life-threatening genetic liver disorders characterized by elevated production and excretion of oxalate. To date, the...
Primary hyperoxaluria (PH) is a family of rare, life-threatening genetic liver disorders characterized by elevated production and excretion of oxalate. To date, the clinical and economic burden associated with PH has not been well characterized due to the rarity of the disease and previous challenges with diagnostic coding that prevented proper identification of patients with PH in claims data. To characterize the clinical and economic costs, as well as health care resource utilization (HCRU), associated with PH relative to a matched cohort of patients without PH. Data from the IQVIA PharMetrics Plus Database were used to conduct a retrospective matched-cohort study to compare differences in clinical characteristics, HCRU, and pharmacy and medical costs in patients with PH compared with a matched cohort of patients without PH from January 2014 to December 2019. Overall, 324 patients were included in the PH cohort and 1,620 patients were in the non-PH cohort. The mean age of PH patients was 48.1 years, and approximately 58% of the sample were male. Significantly more patients in the PH cohort than the non-PH cohort were diagnosed with stage 2 chronic kidney disease (CKD; 3.1% vs 0.4%, respectively; < 0.001), stage 3 CKD (4.6% vs 0.5%; < 0.001), stage 4 CKD (2.5% vs 0.1%; < 0.001), and stage 5 CKD or end-stage renal disease (ESRD; 2.2% vs 0.1%; < 0.001). PH patients had a significantly higher mean Charlson Comorbidity Index composite score than patients in the non-PH cohort (0.79 vs 0.37; < 0.001). HCRU was significantly higher in patients with PH. The PH cohort had a significantly higher proportion of patients with at least 1 visit to clinicians specializing in nephrology (19% vs 0.4%, respectively; < 0.001), cardiology (22% vs 12%; < 0.001), ophthalmology (16% vs 7%; < 0.001), general surgery (9% vs 6%; = 0.011), and urology (65% vs 6%; < 0.001) compared with patients without PH. Mean total annual health care costs in the PH cohort were 65% higher than in the non-PH cohort ($22,549 vs $7,852, respectively; < 0.001). Similar results were found for total prescription drug costs ($4,125 vs $2,464; = 0.012). Despite the rarity of PH, patients with this disease incur substantial clinical and economic burden and may cause financial strain on the health care system. Additional research is warranted to understand the economic and clinical burden of PH stratified by the 3 subtypes of the disease. Funding for this research was provided by Dicerna Pharmaceuticals. Mucha and Hoppe are employed by Dicerna Pharmaceuticals. Silber Miyasoto, Skaar, and Wang are employed by Trinity Life Sciences, which was contracted by Dicerna Pharmaceuticals to conduct the study analysis. Langman is consultant to Dicerna Pharmaceuticals. This study was presented as a poster at the AMCP Nexus 2020 (virtual), October 19-23, 2020, and American Society of Nephrology 2020 (virtual), October 19-25, 2020.
Topics: Cohort Studies; Health Care Costs; Humans; Hyperoxaluria, Primary; Insurance Claim Review; Male; Middle Aged; Patient Acceptance of Health Care; Retrospective Studies; United States
PubMed: 35199581
DOI: 10.18553/jmcp.2022.28.3.316 -
EMBO Molecular Medicine Jan 2024The therapeutic use of adeno-associated viral vector (AAV)-mediated gene disruption using CRISPR-Cas9 is limited by potential off-target modifications and the risk of...
The therapeutic use of adeno-associated viral vector (AAV)-mediated gene disruption using CRISPR-Cas9 is limited by potential off-target modifications and the risk of uncontrolled integration of vector genomes into CRISPR-mediated double-strand breaks. To address these concerns, we explored the use of AAV-delivered paired Staphylococcus aureus nickases (D10ASaCas9) to target the Hao1 gene for the treatment of primary hyperoxaluria type 1 (PH1). Our study demonstrated effective Hao1 gene disruption, a significant decrease in glycolate oxidase expression, and a therapeutic effect in PH1 mice. The assessment of undesired genetic modifications through CIRCLE-seq and CAST-Seq analyses revealed neither off-target activity nor chromosomal translocations. Importantly, the use of paired-D10ASaCas9 resulted in a significant reduction in AAV integration at the target site compared to SaCas9 nuclease. In addition, our study highlights the limitations of current analytical tools in characterizing modifications introduced by paired D10ASaCas9, necessitating the development of a custom pipeline for more accurate characterization. These results describe a positive advance towards a safe and effective potential long-term treatment for PH1 patients.
Topics: Humans; Animals; Mice; CRISPR-Cas Systems; Deoxyribonuclease I; Gene Editing; Hyperoxaluria, Primary
PubMed: 38182795
DOI: 10.1038/s44321-023-00008-8 -
Scientific Reports Sep 2022Primary hyperoxaluria (PH) is an autosomal recessive disorder of oxalate metabolism caused by pathogenic variants in either of three genes (AGXT, GRHPR or HOGA1). The...
Primary hyperoxaluria (PH) is an autosomal recessive disorder of oxalate metabolism caused by pathogenic variants in either of three genes (AGXT, GRHPR or HOGA1). The study aimed at characterizing the clinical phenotypes as well as the genotypic spectrum of PH in Egypt. We screened 25 Egyptian patients suspected of PH for the three responsible genes by Sanger sequencing. We diagnosed 20 patients from 18 unrelated families, in which the natural history, family history, clinical features and genotypes were evaluated. PH patients were 15 males and 5 females ranging in age from 4 months to 31 years (median 8 years). Fifteen families were consanguineous (83%) and familial clustering was reported in six families (33%). Pathogenic variants in all 40 alleles were in AGXT, with none detected in GRHPR or HOGA1. We detected two novel pathogenic variants c.166-1_172dupGATCATGG (p.Asp58Glyfs*65) and c.766delC (p.Gln256fs*16) and seven previously reported variants in our cohort. This is the first study reporting the genotype of a considerable number of PH1 patients from Egypt. Our detected variants in the AGXT gene could form the basis for future genetic counseling and prenatal diagnosis in Egypt and surrounding populations.
Topics: Adolescent; Adult; Child; Child, Preschool; Egypt; Female; Humans; Hyperoxaluria, Primary; Infant; Male; Mutation; Oxalates; Phenotype; Transaminases; Young Adult
PubMed: 36151119
DOI: 10.1038/s41598-022-17980-9 -
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 -
Urolithiasis Apr 2023Nedosiran is an N-acetyl-D-galactosamine (GalNAc)-conjugated RNA interference agent targeting hepatic lactate dehydrogenase (encoded by the LDHA gene), the putative...
Nedosiran is an N-acetyl-D-galactosamine (GalNAc)-conjugated RNA interference agent targeting hepatic lactate dehydrogenase (encoded by the LDHA gene), the putative enzyme mediating the final step of oxalate production in all three genetic subtypes of primary hyperoxaluria (PH). This phase I study assessed the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of subcutaneous nedosiran in patients with PH subtype 3 (PH3) and an estimated glomerular filtration rate ≥ 30 mL/min/1.73 m. Single-dose nedosiran 3 mg/kg or placebo was administered in a randomized (2:1), double-blinded manner. Safety/tolerability, 24-h urinary oxalate (Uox) concentrations, and plasma nedosiran concentrations were assessed. The main PD endpoint was the proportion of participants achieving a > 30% decrease from baseline in 24-h Uox at two consecutive visits. Six participants enrolled in and completed the study (nedosiran, n = 4; placebo, n = 2). Nedosiran was well-tolerated and lacked safety concerns. Although the PD response was not met, 24-h Uox excretion declined 24.5% in the nedosiran group and increased 10.5% in the placebo group at Day 85. Three of four nedosiran recipients had a > 30% reduction in 24-h Uox excretion during at least one visit, and one attained near-normal (i.e., ≥ 0.46 to < 0.60 mmol/24 h; ≥ 1.0 to < 1.3 × upper limit of the normal reference range) 24-h Uox excretion from Day 29 to Day 85. Nedosiran displayed predictable plasma PK. The acceptable safety and trend toward Uox-lowering after single-dose nedosiran treatment enables further clinical development of nedosiran in patients with PH3 who currently have no viable therapeutic options. A plain language summary is available in the supplementary information.
Topics: Humans; Hyperoxaluria, Primary; Hyperoxaluria; Oxalates; Glomerular Filtration Rate
PubMed: 37118061
DOI: 10.1007/s00240-023-01453-3 -
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 -
American Journal of Kidney Diseases :... Feb 2023
Topics: Humans; Hyperoxaluria, Primary; Hyperoxaluria; Oxalates
PubMed: 36184293
DOI: 10.1053/j.ajkd.2022.08.005 -
Clinical Journal of the American... Jul 2021In the rare disease primary hyperoxaluria type 1, overproduction of oxalate by the liver causes kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVES
In the rare disease primary hyperoxaluria type 1, overproduction of oxalate by the liver causes kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an RNA interference therapeutic, suppresses glycolate oxidase, reducing hepatic oxalate production. The objective of this first-in-human, randomized, placebo-controlled trial was to evaluate the safety, pharmacokinetic, and pharmacodynamic profiles of lumasiran in healthy participants and patients with primary hyperoxaluria type 1.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
This phase 1/2 study was conducted in two parts. In part A, healthy adults randomized 3:1 received a single subcutaneous dose of lumasiran or placebo in ascending dose groups (0.3-6 mg/kg). In part B, patients with primary hyperoxaluria type 1 randomized 3:1 received up to three doses of lumasiran or placebo in cohorts of 1 or 3 mg/kg monthly or 3 mg/kg quarterly. Patients initially assigned to placebo crossed over to lumasiran on day 85. The primary outcome was incidence of adverse events. Secondary outcomes included pharmacokinetic and pharmacodynamic parameters, including measures of oxalate in patients with primary hyperoxaluria type 1. Data were analyzed using descriptive statistics.
RESULTS
Thirty-two healthy participants and 20 adult and pediatric patients with primary hyperoxaluria type 1 were enrolled. Lumasiran had an acceptable safety profile, with no serious adverse events or study discontinuations attributed to treatment. In part A, increases in mean plasma glycolate concentration, a measure of target engagement, were observed in healthy participants. In part B, patients with primary hyperoxaluria type 1 had a mean maximal reduction from baseline of 75% across dosing cohorts in 24-hour urinary oxalate excretion. All patients achieved urinary oxalate levels ≤1.5 times the upper limit of normal.
CONCLUSIONS
Lumasiran had an acceptable safety profile and reduced urinary oxalate excretion in all patients with primary hyperoxaluria type 1 to near-normal levels.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER
Study of Lumasiran in Healthy Adults and Patients with Primary Hyperoxaluria Type 1, NCT02706886.
Topics: Adolescent; Adult; Child; Female; Glycolates; Humans; Hyperoxaluria, Primary; Male; Oxalates; RNA, Small Interfering; Renal Agents; Single-Blind Method; Young Adult
PubMed: 33985991
DOI: 10.2215/CJN.14730920 -
Drugs Feb 2024Lumasiran (Oxlumo), a first-in-class synthetic, double-stranded, ribonucleic acid (RNA) interference molecule targeting glycolate oxidase through silencing HAO1 mRNA, is... (Review)
Review
Lumasiran (Oxlumo), a first-in-class synthetic, double-stranded, ribonucleic acid (RNA) interference molecule targeting glycolate oxidase through silencing HAO1 mRNA, is approved in several countries for patients of any age and stage of kidney function with primary hyperoxaluria type 1 (PH1). Approval was based on results from the phase III ILLUMINATE trials. In the double-blind, placebo-controlled, ILLUMINATE-A trial, subcutaneous lumasiran was significantly more effective than placebo in reducing 24-h urinary oxalate excretion in patients aged ≥ 6 years with PH1; this effect was sustained for ≥ 36 months in ongoing longer-term analyses. In the single-arm ILLUMINATE-B trial, lumasiran reduced urinary oxalate:creatinine ratios and plasma oxalate levels in patients aged < 6 years with PH1. In the single-arm ILLUMINATE-C trial, lumasiran reduced plasma oxalate levels in patients with PH1 receiving dialysis as well as those not receiving dialysis. In secondary and exploratory analyses of these trials, nephrocalcinosis grade, kidney stone event rates and estimated glomerular filtration rates were either stable or improved with lumasiran. Lumasiran had an acceptable tolerability profile that remained consistent in longer-term analyses; the most common adverse events were mild and transient injection-site reactions. Thus, lumasiran is an effective treatment option, with an acceptable tolerability profile, in patients with PH1.
Topics: Humans; Hyperoxaluria, Primary; Oxalates; RNA, Small Interfering; Randomized Controlled Trials as Topic
PubMed: 38252335
DOI: 10.1007/s40265-023-01987-1