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The Journal of Urology Oct 2022We evaluated the utility of diagnostic codes to screen for patients with primary hyperoxaluria (PH) and evaluate their positive predictive value (PPV) in identifying... (Review)
Review
PURPOSE
We evaluated the utility of diagnostic codes to screen for patients with primary hyperoxaluria (PH) and evaluate their positive predictive value (PPV) in identifying children with this rare condition in PEDSnet, a clinical research network of pediatric health systems that shares electronic health records data.
MATERIALS AND METHODS
We conducted a cross-sectional study of children who received care at 7 PEDSnet institutions from January 2009 through January 2021. We developed and applied screening criteria using diagnostic codes that generated 3 categories of the hypothesized probability of PH. Tier 1 had specific diagnostic codes for PH; tier 2 had codes for hyperoxaluria, oxalate nephropathy, or oxalosis; and tier 3 had a combination of ≥2 codes for disorder of carbohydrate metabolism and ≥1 code for kidney stones. We reviewed the electronic health records of patients with possible PH to confirm PH diagnosis and evaluate the accuracy and timing of diagnostic codes. The PPV of the codes was compared across tiers, time, PH type, and site.
RESULTS
We identified 341 patients in the screen; 33 had confirmed PH (9.7%). Tier 1 had the highest proportion of PH; however, the PPV was only 20%. The degree to which an institution accurately represented point of care diagnoses in the data extraction process was predictive of higher PPV. The PPV of diagnostic codes was highest for PH3 (100%) and lowest for PH1 (22.8%).
CONCLUSIONS
Diagnostic codes for PH have poor PPV. Findings suggest that one should be careful in research using large databases in which source validation is not possible.
Topics: Child; Cross-Sectional Studies; Databases, Factual; Electronic Health Records; Humans; Hyperoxaluria, Primary; Predictive Value of Tests
PubMed: 35930731
DOI: 10.1097/JU.0000000000002863 -
BMC Nephrology Nov 2021Primary hyperoxaluria (PH) is a rare inherited autosomal recessive disease caused by disturbed glyoxylate metabolism. The disease is characterized by calcium oxalate... (Review)
Review
BACKGROUND
Primary hyperoxaluria (PH) is a rare inherited autosomal recessive disease caused by disturbed glyoxylate metabolism. The disease is characterized by calcium oxalate crystal deposition in various organs, especially in the kidney. Due to the lack of current understanding of PH, nearly all patients are only initially diagnosed with PH when recurrent lithiasis and progressive end-stage renal disease occur. Many cases are not diagnosed in patients until renal allograft insufficiency occurs after renal transplantation. This case report and literature review aim to emphasize the need for careful pre-transplant PH screening of patients with bilateral nephrocalcinosis or nephrolithiasis.
CASE PRESENTATION
Renal allograft insufficiency was diagnosed as PH after kidney transplantation. Here, we detail the complete clinical course, including computed tomography images of the original kidney and renal graft, histopathological images of a biopsy of the transplanted kidney, the results of laboratory and molecular genetic tests, and the treatment. In addition, we reviewed the literature from 2000 to 2021 and analyzed 19 reported cases of PH diagnosed after kidney transplantation, and provide a summary of the characteristics, complications, treatment, and prognosis of these cases.
CONCLUSIONS
By reviewing and analyzing these cases, we concluded that patients with a history of nephrocalcinosis or nephrolithiasis in both kidneys need preoperative screening for PH and appropriate treatment before kidney transplantation. Delayed graft function caused by PH is easily misdiagnosed as acute rejection, and needle biopsy should be performed at an early stage.
Topics: Humans; Hyperoxaluria, Primary; Kidney Transplantation; Postoperative Period
PubMed: 34837989
DOI: 10.1186/s12882-021-02546-0 -
Biochimica Et Biophysica Acta.... Jan 2021The Primary Hyperoxalurias (PH) are rare disorders of metabolism leading to excessive endogenous synthesis of oxalate and recurring calcium oxalate kidney stones....
The Primary Hyperoxalurias (PH) are rare disorders of metabolism leading to excessive endogenous synthesis of oxalate and recurring calcium oxalate kidney stones. Alanine glyoxylate aminotransferase (AGT), deficient in PH type 1, is a key enzyme in limiting glyoxylate oxidation to oxalate. The affinity of AGT for its co-substrate, alanine, is low suggesting that its metabolic activity could be sub-optimal in vivo. To test this hypothesis, we examined the effect of L-alanine supplementation on oxalate synthesis in cell culture and in mouse models of Primary Hyperoxaluria Type 1 (Agxt KO), Type 2 (Grhpr KO) and in wild-type mice. Our results demonstrated that increasing L-alanine in cells decreased synthesis of oxalate and increased viability of cells expressing GO and AGT when incubated with glycolate. In both wild type and Grhpr KO male and female mice, supplementation with 10% dietary L-alanine significantly decreased urinary oxalate excretion ~30% compared to baseline levels. This study demonstrates that increasing the availability of L-alanine can increase the metabolic efficiency of AGT and reduce oxalate synthesis.
Topics: Alanine; Alcohol Oxidoreductases; Animals; CHO Cells; Cricetulus; Hyperoxaluria, Primary; Mice; Mice, Knockout; Oxalates; Transaminases
PubMed: 33002578
DOI: 10.1016/j.bbadis.2020.165981 -
International Journal of Nephrology and... 2022Primary hyperoxaluria (PH) is a rare genetic disease caused by excessive hepatic production and elevated urinary excretion of oxalate that leads to recurrent... (Review)
Review
Primary hyperoxaluria (PH) is a rare genetic disease caused by excessive hepatic production and elevated urinary excretion of oxalate that leads to recurrent nephrolithiasis, nephrocalcinosis and, eventually, kidney failure. As glomerular filtration rate declines, oxalate accumulates leading to systemic oxalosis, a debilitating condition with high morbidity and mortality. Although PH is usually diagnosed during infancy, it can present at any age with different phenotypes, ranging from mild symptoms to extremely debilitating manifestations. PH is an autosomal recessive disorder and, to date, three types have been identified: PH1, PH2 and PH3. PH1 is the most common and most aggressive type, accounting for almost 80% of primary hyperoxaluria diagnoses. Until 2020, general treatment for PH1 consisted mainly in high fluid intake, urine alkalization, surgical management of recurrent nephrolithiasis and eventually, if and when kidney failure occurred, intensive dialysis regimens and transplantation strategies (simultaneous or sequential liver-kidney transplant or isolated liver/kidney transplant in carefully selected patients). Specific treatment did and still consists in administration of pyridoxine hydrochloride, although it is only effective in a subset of PH1 patients. Lumasiran, a novel biological drug based on mRNA interference that has been recently approved in the US and European Union, showed promising results and is set to be a turning point in the management of PH1. This literature review aims to summarize the available evidence on PH1 treatment with lumasiran, in order to provide both pediatric and adult nephrologists and clinicians with the knowledge for the identification and management of PH1 patients suitable for treatment.
PubMed: 35747094
DOI: 10.2147/IJNRD.S293682 -
The American Journal of Dermatopathology Dec 2022A 19-year-old girl presented to the emergency department with a progressively painful purpuric lesion on the left dorsal foot, which had initially appeared 2 days prior....
A 19-year-old girl presented to the emergency department with a progressively painful purpuric lesion on the left dorsal foot, which had initially appeared 2 days prior. Three months earlier, she had been diagnosed with end-stage renal disease. Her medical history also included recurrent urolithiasis for the past 5 years and liver failure. Biopsy revealed oxalate crystals occluding vessels with secondary epidermal and dermal ischemia. Oxalate crystals were also visualized in the vessel walls and free in the subcutis. Genetic testing confirmed the diagnosis of primary hyperoxaluria type 1. She was treated with sodium thiosulfate, apixaban, pentoxifylline, wound care, and palliative care. At 4-month follow-up, the cutaneous manifestations of oxalosis were confined to only her feet, and she was undergoing evaluation for combined liver and kidney transplant. Cutaneous oxalosis because of primary hyperoxaluria should be considered in young patients presenting with purpuric lesions, recurrent urolithiasis, and early-onset renal failure.
Topics: Humans; Female; Young Adult; Adult; Hyperoxaluria, Primary; Hyperoxaluria; Kidney Failure, Chronic; Urolithiasis; Oxalates
PubMed: 36395453
DOI: 10.1097/DAD.0000000000002307 -
Urolithiasis Feb 2021The aim of our study is to explore the relationship between genotype and phenotype in Chinese PH1 patients and determine the putative mutation hotspot regions. This was... (Observational Study)
Observational Study
The aim of our study is to explore the relationship between genotype and phenotype in Chinese PH1 patients and determine the putative mutation hotspot regions. This was a retrospective study regarding 13 Chinese PH1 patients. And all sporadic published researches of Chinese PH1 populations were searched and enrolled based on the inclusive standard. All patients presented with multiple urolithiasis or nephrolithiasis. Urinary oxalate values demonstrated an obvious and extensive variability, ranging from 1.01 to 3.85 mmol/1.73 m. Molecular diagnosis showed that 13 mutant types were detected. Infantile form patient (pt.) 10 and five patients (pts. 5, 7, 8, 9, 12) carrying c.815_816insGA or c.33_34insC demonstrated a worse prognosis, of whom pt. 5 progressed into ESRD 4 years later and died of chronic kidney failure. Based on the integrated Chinese mutation data, two variants (c.815_816insGA and c.33_34insC) were determined as the most common mutations. Besides, c.1049G>A was initially identified in a Chinese patient. Conclusions: heterogeneity between genotype and phenotype was observed and described in Chinese PH1 patients. c.815_816insGA and c.33_34insC which were recognized as AGXT mutation hotspot regions in China implied a poor prognosis. And c.1049G>A was not determined as the race-specific mutation of Pakistani.
Topics: Adolescent; Age of Onset; Asian People; Calcium Oxalate; Child; Child, Preschool; China; Disease Progression; Female; Follow-Up Studies; Genotype; Humans; Hyperoxaluria, Primary; Infant; Kidney Failure, Chronic; Male; Mutation; Prognosis; Retrospective Studies; Transaminases; Urolithiasis
PubMed: 32556641
DOI: 10.1007/s00240-020-01201-x -
BioDrugs : Clinical Immunotherapeutics,... Jul 2022Over the last few years, US Food and Drug Administration-approved drugs using RNA interference have come to the market. Many have treated liver-specific diseases...
Over the last few years, US Food and Drug Administration-approved drugs using RNA interference have come to the market. Many have treated liver-specific diseases utilizing N-acetyl galactosamine conjugation because of its effective delivery and limited off-target effects. The autosomal recessive disorder primary hyperoxaluria, specifically type 1, has benefited from these developments. Primary hyperoxaluria arises from mutations in the enzymes involved in endogenous oxalate synthesis. The severity of disease varies but can result in kidney failure and systemic oxalosis. Until recently, the treatment options were limited and focused primarily on supportive treatments, pyridoxine use in a subset of patients with primary hyperoxaluria type 1, and liver-kidney transplants in those who progressed to kidney failure. Two genes have been targeted with RNA interference; lumasiran targets glycolate oxidase and nedosiran targets lactate dehydrogenase A. Lumasiran was recently approved in the treatment of primary hyperoxaluria type 1 and nedosiran is in the approval process. Unfortunately, despite initial hopes that nedosiran may also be a treatment option for primary hyperoxaluria types 2 and 3, initial data suggest otherwise. The use of RNA interference liver-specific targeting for the treatment of primary hyperoxaluria type 1 will likely transform the natural history of the disease.
Topics: Humans; Hyperoxaluria, Primary; RNA Interference; RNA, Small Interfering; Renal Insufficiency; United States
PubMed: 35731461
DOI: 10.1007/s40259-022-00539-5 -
Advances in Protein Chemistry and... 2019To carry out their biological function in cells, proteins must be folded and targeted to the appropriate subcellular location. These processes are controlled by a vast... (Review)
Review
To carry out their biological function in cells, proteins must be folded and targeted to the appropriate subcellular location. These processes are controlled by a vast collection of interacting proteins collectively known as the protein homeostasis network, in which molecular chaperones play a prominent role. Protein homeostasis can be impaired by inherited mutations leading to genetic diseases. In this chapter, we focus on a particular disease, primary hyperoxaluria type 1 (PH1), in which disease-associated mutations exacerbate protein aggregation in the cell and mistarget the peroxisomal alanine:glyoxylate aminotransferase (AGT) protein to mitochondria, in part due to native state destabilization and enhanced interaction with Hsp60, 70 and 90 chaperone systems. After a general introduction of molecular chaperones and PH1, we review our current knowledge on the structural and energetic features of PH1-causing mutants that lead to these particular pathogenic mechanisms. From this perspective, and in the context of the key role of molecular chaperones in PH1 pathogenesis, we present and discuss current and future perspectives for pharmacological treatments for this disease.
Topics: Animals; Homeostasis; Humans; Hyperoxaluria, Primary; Mitochondria; Molecular Chaperones; Phenotype; Protein Aggregates; Proteins
PubMed: 30635080
DOI: 10.1016/bs.apcsb.2018.09.003 -
Cureus Mar 2022Nephrolithiasis (NL) and urolithiasis (UL) are usual reasons for hospitalization and presentation in pediatric outpatient departments and their incidence continues to...
Nephrolithiasis (NL) and urolithiasis (UL) are usual reasons for hospitalization and presentation in pediatric outpatient departments and their incidence continues to rise worldwide. In Morocco, a previous epidemiological study done in the Fez region between January 2003 and November 2013 reported a prevalence of 0.83% of childhood UL. In two studies, heritability accounted for almost half of all NL or nephrocalcinosis (NC) prevalence. Genetic factors must be considered in the etiological diagnosis of urinary lithiasis in Morocco since the frequency of consanguineous marriages is high. Hereditary tubular disorders, especially distal renal tubular acidosis (dRTA) and Dent disease, and metabolic disorders like idiopathic hypercalciuria and hyperoxaluria are the most common causes of medullary NC. Primary hyperoxaluria type 1 (PH1), which can generate an early onset of NC, and often chronic kidney disease (CKD) should always be considered and thoroughly diagnosed. The aim of this work was to establish a molecular diagnosis of PH1 and dRTA and, thus, to predict and explain the disease phenotype in a cohort of 44 Moroccan patients with NL and/or NC by analyzing the and genes that cause NL and/or NC when mutated. Disease phenotype was molecularly explained and solved in six of 44 individuals with NL and/or NC (13.6%). In the pediatric subgroup of individuals, a causative mutation in 16.2% was identified, whereas in the adult cohort no pathogenic mutation was detected. In our patients, PH1 was objectified in 67% of cases followed by dRTA in 33% of cases. We suggest that prompt detection and prophylactic treatment of UL are necessary to limit the risk of everlasting renal damage and thus prevent or delay the progression to CKD.
PubMed: 35505724
DOI: 10.7759/cureus.23616 -
Molecular Biology Reports Apr 2021Primary hyperoxaluria type-III is a disorder of glyoxylate metabolism, caused by pathogenic variants in the HOGA1 gene. To date more than 50 disease-associated... (Review)
Review
Primary hyperoxaluria type-III is a disorder of glyoxylate metabolism, caused by pathogenic variants in the HOGA1 gene. To date more than 50 disease-associated pathogenic sequence variants are identified in the gene. A few of the variants are population specific and are considered to have a founder effect in respective populations. The most prevalent variant, c.700+5G>T, identified frequently in Caucasian (allele frequency 0.63) and European (0.35) populations. Two variants, c.860G>T (p.Gly287Val) and c.944_946delAGG (p.Glu315del), account for 95% of the allele count in patients of Ashkenazi Jews ancestry. A possible mutational hot-spot at c.834 position is frequently found mutated in Chinese patients. This observed ethnic associations of HOGA1 alleles span a spectrum ranging from recurrence limited to an ethnic group to a possible founder-effect.
Topics: Ethnicity; Founder Effect; Gene Frequency; Humans; Hyperoxaluria, Primary; Oxo-Acid-Lyases; Polymorphism, Genetic
PubMed: 33948853
DOI: 10.1007/s11033-021-06380-3