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Kidney International Reports Feb 2022
PubMed: 35155853
DOI: 10.1016/j.ekir.2021.12.032 -
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 -
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 -
ACS Pharmacology & Translational Science Nov 2022Due to the lack of treatment options for the genetic disease primary hyperoxaluria (PH), including three subtypes PH1, PH2, and PH3, caused by accumulation of oxalate... (Review)
Review
Due to the lack of treatment options for the genetic disease primary hyperoxaluria (PH), including three subtypes PH1, PH2, and PH3, caused by accumulation of oxalate forming kidney stones, there is an urgent need for the development of a drug therapy aside from siRNA drug lumasiran for patients with PH1. After the recent success of drug therapies based on small interfering RNA (siRNA), nedosiran is currently being developed for the treatment of three types of PH as a siRNA-based modality. Through specific inhibition of lactate dehydrogenase enzyme, the key enzyme in biosynthesis of oxalate in liver, phase 1, 2, and 3 clinical trials of nedosiran have achieved the desired primary end point of reduction of urinary oxalate levels in patients with PH1. More PH2 and PH3 patients need to be tested for efficacy. It has also produced a favorable secondary end point on safety and toxicity in PH patients. In addition to common injection site reactions that resolved spontaneously, no severe nedosiran treatment-associated adverse events were reported. Based on the positive results in the clinical studies, nedosiran is a candidate siRNA drug to treat PH patients.
PubMed: 36407951
DOI: 10.1021/acsptsci.2c00110 -
International Journal of Surgery... Dec 2016Renal stones are common and are usually secondary to risk factors affecting the solubility of substances in the urinary tract. Primary, that is genetic, causes are rare... (Review)
Review
Renal stones are common and are usually secondary to risk factors affecting the solubility of substances in the urinary tract. Primary, that is genetic, causes are rare but nevertheless are important to recognise so that appropriate treatments can be instigated and the risks to other family members acknowledged. A brief overview of the investigation of renal stones from a biochemical point of view is presented with emphasis on the problems that can arise. The genetic basis of renal stone disease caused by (i) derangement of a metabolic pathway, (ii) diversion to an insoluble product, (iii) failure of transport and (iv) renal tubular acidosis is described by reference to the disorders of adenine phosphoribosyl transferase (APRT) deficiency, primary hyperoxaluria, cystinuria and autosomal dominant distal renal tubular acidosis.
Topics: Acidosis, Renal Tubular; Adenine Phosphoribosyltransferase; Adult; Genetic Predisposition to Disease; Humans; Hyperoxaluria, Primary; Kidney Calculi; Metabolism, Inborn Errors; Urolithiasis
PubMed: 27838384
DOI: 10.1016/j.ijsu.2016.11.015 -
Clinical Kidney Journal May 2022Primary hyperoxaluria type 1 (PH1) is a rare and severe autosomal recessive disease of oxalate metabolism, resulting from a mutation in the gene that encodes the... (Review)
Review
Primary hyperoxaluria type 1 (PH1) is a rare and severe autosomal recessive disease of oxalate metabolism, resulting from a mutation in the gene that encodes the hepatic peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT). Until recently, treatment of PH1 was supportive, consisting of intensive hyperhydration, use of crystallization inhibitors (citrate and neutral phosphorus), in a subset of responsive PH1 patients' pharmacologic doses of vitamin B6 (pyridoxine), and kidney and liver transplantation when patients progressed to kidney failure. Treatment approaches have been similar for PH2 caused by mutations in hepatic glyoxylate reductase/hydroxypyruvate reductase (), although pyridoxine does not have any benefit in this group. PH3 is caused by mutations of mitochondrial 4-hydroxy-2-oxoglutarate aldolase () and was the most recently described. Kidney failure appears less common in PH3, although kidney stones occur as frequently as in PH1 and PH2. Oxalate metabolism in the liver is complex. Novel therapies based on RNA interference (RNAi) have recently emerged to modulate these pathways, designed to deplete substrate for enzymes upstream and decrease/avoid oxalate production. Two hepatic enzymes have been targeted to date in PH: glycolate oxidase (GO) with lumasiran and lactate dehydrogenase A (LDH-A) with nedosiran. Lumasiran was approved for the treatment of PH1 in 2020 by both the European Medicines Agency and the Food and Drug Administration, whilst clinical trials with nedosiran are ongoing. Results with the two RNAi therapies demonstrate a significant reduction of urinary oxalate excretion in PH1 patients, but long-term data on efficacy (preservation of kidney function, decreased stone events) and safety remain to be established. Nevertheless, the hepatically targeted RNAi approach represents a potential 'game changer' in the field of PH1, bringing hope to families and patients that they may be able to avoid liver and/or kidney transplantation in the future and suffer fewer stone events, perhaps with less strict therapeutic regimens. Pharmacological compounds directly inhibiting GO or LDH are also under development and could be of special interest in developing countries where RNAi therapies may not be readily available in the near future. Approaches to manipulate the intestinal microbiome with a goal to increase oxalate degradation or to stimulate secretion of oxalate into the intestine from plasma are also under development. Overall, we appear to be entering a new phase of PH treatment, with an array of promising approaches emerging that will need optimization and evaluation to establish long-term efficacy and safety.
PubMed: 35592618
DOI: 10.1093/ckj/sfab245 -
Current Rheumatology Reports Jul 2013Oxalate arthropathy is a rare cause of arthritis characterized by deposition of calcium oxalate crystals within synovial fluid. This condition typically occurs in... (Review)
Review
Oxalate arthropathy is a rare cause of arthritis characterized by deposition of calcium oxalate crystals within synovial fluid. This condition typically occurs in patients with underlying primary or secondary hyperoxaluria. Primary hyperoxaluria constitutes a group of genetic disorders resulting in endogenous overproduction of oxalate, whereas secondary hyperoxaluria results from gastrointestinal disorders associated with fat malabsorption and increased absorption of dietary oxalate. In both conditions, oxalate crystals can deposit in the kidney leading to renal failure. Since oxalate is primarily renally eliminated, it accumulates throughout the body in renal failure, a state termed oxalosis. Affected organs can include bones, joints, heart, eyes, and skin. Since patients can present with renal failure and oxalosis before the underlying diagnosis of hyperoxaluria has been made, it is important to consider hyperoxaluria in patients who present with unexplained soft tissue crystal deposition. The best treatment of oxalosis is prevention. If patients present with advanced disease, treatment of oxalate arthritis consists of symptom management and control of the underlying disease process.
Topics: Arthritis; Calcium Oxalate; Humans; Hyperoxaluria; Synovial Fluid
PubMed: 23666469
DOI: 10.1007/s11926-013-0340-4 -
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 -
Frontiers in Medicine 2021Primary hyperoxaluria type 1 (PH1) is a rare genetic disease that can result in irreversible damage to the kidneys and, eventually, extrarenal organs. While kidney...
Primary hyperoxaluria type 1 (PH1) is a rare genetic disease that can result in irreversible damage to the kidneys and, eventually, extrarenal organs. While kidney failure is a known consequence of PH1, few studies to date have characterized clinical consequences of PH1 prior to kidney failure, and data on healthcare resource use outcomes across different stages of disease severity in PH1 are also limited. To help fill this knowledge gap, this study characterized the clinical and healthcare resource use (HRU) burden in patients with PH1 with varying stages of kidney disease. Nephrologists in the United States, Canada, United Kingdom, France, Germany, and Italy abstracted chart data from patients with PH1 under their care via an online questionnaire. Eligible patients had confirmed PH1 and ≥2 office visits from 2016 to 2019. A total of 120 patients were analyzed (median age at diagnosis, 17.4 years old, median age at index 19.5 years old, median eGFR at index 45 ml/min/1.73 m; median follow-up 1.7 years). During follow-up, the most common PH1 manifestations were kidney stones and urinary tract infections (UTIs, both 56.8%), and the most common symptoms were fatigue/weakness (71.7%) and pain (64.6%). With regard to HRU during follow-up, 37.4% required lithotripsy, 31.3% required ureteroscopy, and 9.6% required nephrolithotomy. PH1-related hospitalizations and emergency/urgent care visits were noted for 84.0 and 81.6% of patients, respectively. The current study demonstrated that patients with PH1 across various stages of kidney disease exhibited a substantial clinical burden, including kidney stones, UTIs, fatigue/weakness, and pain, and required frequent HRU, including kidney stone procedures, hospitalizations, and emergency visits. These findings highlight the significant morbidity and HRU burden in patients with PH1.
PubMed: 34616753
DOI: 10.3389/fmed.2021.703305 -
Clinics and Research in Hepatology and... May 2024Enteric hyperoxaluria is a metabolic disorder resulting from conditions associated with fatty acid malabsorption and characterized by an increased urinary output of... (Review)
Review
Enteric hyperoxaluria is a metabolic disorder resulting from conditions associated with fatty acid malabsorption and characterized by an increased urinary output of oxalate. Oxalate is excessively absorbed in the gut and then excreted in urine where it forms calcium oxalate crystals, inducing kidney stones formation and crystalline nephropathies. Enteric hyperoxaluria is probably underdiagnosed and may silently damage kidney function of patients affected by bowel diseases. Moreover, the prevalence of enteric hyperoxaluria has increased because of the development of bariatric surgical procedures. Therapeutic options are based on the treatment of the underlying disease, limitation of oxalate intakes, increase in calcium salts intakes but also increase in urine volume and correction of hypocitraturia. There are few data regarding the natural evolution of kidney stone events and chronic kidney disease in these patients, and there is a need for new treatments limiting kidney injury by calcium oxalate crystallization.
Topics: Humans; Hyperoxaluria; Oxalates; Calcium Oxalate; Malabsorption Syndromes
PubMed: 38503362
DOI: 10.1016/j.clinre.2024.102322