Clinical characteristics.

Primary hyperoxaluria type 1 (PH1) is caused by deficiency of the liver peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine. When AGT activity is reduced or absent, glyoxylate is converted to oxalate, which cannot be metabolized and must be excreted by the kidneys. Insoluble calcium oxalate crystals form due to high urinary oxalate concentration. Urinary crystals aggregate, leading to nephrolithiasis (i.e., calcium oxalate kidney stones) in the renal pelvis / urinary tract; often the crystals deposit in kidney parenchyma (nephrocalcinosis). The age at presentation of PH1 ranges from infancy (age <12 months) in 10% of individuals, childhood/adolescence (age 1-17 years) in 70%, and adulthood (age ≥18 years) in 20%.

The natural history of untreated PH1 is (1) progressive decline in kidney function due to complications of nephrolithiasis (e.g., urinary obstruction, infection) and nephrocalcinosis, and (2) in persons with advanced chronic kidney disease (CKD), high plasma oxalate concentrations result in other organ and tissue damage from calcium oxalate deposition (i.e., "oxalosis"), most commonly in the bones, heart, and retina. In the absence of treatment, progression of oxalosis results in death from kidney failure and/or other organ involvement.

Diagnosis/testing.

The diagnosis of PH1 is established in a proband with supportive laboratory findings (excess excretion of oxalate in the urine and/or markedly increased plasma oxalate concentration) and biallelic pathogenic variants in AGXT identified by molecular genetic testing.

Management.

Targeted therapies: (1) Pyridoxine (vitamin B₆) to reduce liver oxalate production in individuals with missense AGXT variants known to be pyridoxine responsive; (2) RNA interference (RNAi) therapeutics (lumasiran and nedosiran) that target specific hepatic enzymes to reduce liver overproduction of oxalate; and (3) liver transplantation to restore normal hepatic AGT enzyme activity.

Supportive care: Goal is to reduce stone formation, reduce frequency of symptomatic stone events, and preserve kidney function. Advanced loss of kidney function may require dialysis and kidney transplantation. Kidney and liver transplantation can be performed simultaneously or sequentially.

Surveillance: Individuals with PH1 require lifelong care including regularly scheduled assessments of (1) kidney function and urinalysis; (2) urine volume and urine oxalate excretion; (3) kidney ultrasound examination; and (4) signs and symptoms of systemic oxalosis (most commonly involving bones, heart, and retina). The frequency of these assessments is based on the individual's kidney function.

Agents/circumstances to avoid: Intravascular volume depletion; high doses of nonsteroidal anti-inflammatory drugs or any pharmacologic agent that can compromise kidney function; intake of vitamin C exceeding the recommended daily allowance; loop diuretics; large intake of foods high in oxalate (e.g., chocolate, rhubarb, starfruit).

Evaluation of relatives at risk: Family screening for PH1, particularly sibs of the proband, is warranted given intrafamilial variability, significant disease risks even in asymptomatic family members, and availability of therapeutic agents highly effective in reducing urine oxalate.

Pregnancy management: Although pregnancy does not appear to be an important risk factor for developing end-stage kidney disease (ESKD) in most women with PH1, close monitoring is warranted by both an obstetrician and nephrologist during pregnancy and the postpartum period. Of note, the recently approved targeted therapies, lumasiran and nedosiran, have not been studied during human pregnancy. While preclinical animal studies have been reassuring, pending more clinical data the authors would advise women to discontinue use of either therapy prior to becoming pregnant and during pregnancy.

Genetic counseling.

PH1 is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an AGXT pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the AGXT pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

Primary hyperoxaluria type 1 (PH1) should be suspected in a proband of any age with recurrent calcium oxalate stones or nephrocalcinosis, especially if associated with progressive chronic kidney disease (CKD) or a family history of stones and CKD [Groothoff et al 2023, Michael et al 2024]. Typical clinical findings vary by age at presentation.

Establishing the Diagnosis

The diagnosis of PH1 is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in AGXT identified by molecular genetic testing (see Table 3).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic AGXT variants of uncertain significance (or of one known AGXT pathogenic variant and one AGXT variant of uncertain significance (VUS) does not establish or rule out the diagnosis. For information about evaluation of VUSs, see Molecular Genetics, AGXT-specific technical laboratory considerations.)

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1) whereas genomic testing does not (see Option 2).

Clinical Description

Primary hyperoxaluria type 1 (PH1) is caused by deficiency of the liver peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine. When AGT activity is reduced or absent, glyoxylate is converted to oxalate, which cannot be metabolized and must be excreted by the kidneys. Insoluble calcium oxalate crystals form due to high urinary oxalate concentration. Crystal deposition leads to nephrolithiasis (i.e., calcium oxalate kidney stones) in the renal pelvis / urinary tract and often in kidney parenchyma (nephrocalcinosis).

The natural history of untreated PH1 is (1) progressive decline in kidney function because of complications of nephrolithiasis (e.g., urinary obstruction, infection) and nephrocalcinosis, and (2) other organ and tissue damage from calcium oxalate deposition (i.e., "oxalosis"). In the absence of treatment oxalosis progresses leading to death from kidney failure and/or other organ involvement [van der Hoeven et al 2012, Cochat & Groothoff 2013, Metry et al 2023].

Genotype-Phenotype Correlations

Genotype-phenotype correlations reported with specific AGXT pathogenic variants (see Table 10) and classes of AGXT variants are summarized below.

Pyridoxine-responsive variants. Pyridoxine (vitamin B₆), a cofactor for AGT, acts as a chemical chaperone that promotes enzyme function. Individuals homozygous for three pathogenic variants (p.Phe152Ile, p.Gly170Arg, or p.Ile244Thr) who are treated with pharmacologic doses of pyridoxine have reduced oxalate production and thus significantly older age at time of first presentation, diagnosis, and onset of kidney failure compared to other genotypes (see Figure 1 in Metry et al [2023]) (full text).

Although individuals who are compound heterozygotes for p.Phe152Ile, p.Gly170Arg, or p.Ile244Thr and a non-pyridoxine-sensitive pathogenic variant developed kidney failure at a slightly younger age than those homozygous for either variant, it was not significantly different.

• p.Phe152Ile (mostly from Western European countries). The median age of symptom onset was 19.6 years (range: 0.4-57.9) and age at diagnosis was 30.9 years (range: 8.4-59.3), the oldest of all other genotypes.
• p.Gly170Arg (responsible for approximately 30% of all variants). When compared to all other pathogenic variants, the urine oxalate excretion rates are lower even in the absence of treatment, the decline in eGFR is slower, and the onset of ESKD is later [Mandrile et al 2014, Hopp et al 2015, Singh et al 2022a, Metry et al 2023, Sas et al 2024]. Mean age at symptom onset was 14.0 years (range: 0.2-63.4) and age at diagnosis was 28.1 years (range: 0.2-63.4) [Metry et al 2023].
• p.Ile244Thr (primarily found in individuals from the Canary Islands and North Africa). Although data are limited, median age of symptom onset was 3.0 years (range: 0-49.6) and age at diagnosis was 8.0 years (range: 0-52.2) [Metry et al 2023]. Homozygotes for this variant showed kidney survival like that of homozygotes for p.Gly170Arg [Metry et al 2023].
• p.Gly41Arg. Anecdotal evidence suggests that this variant may be pyridoxine responsive [Singh et al 2020].

Classes of variants (missense and null variants). For information on classes of AGXT pathogenic variants by age of onset of symptoms, age at diagnosis, and age at kidney failure, see Figure 1 in Metry et al [2023] (full text).

Prevalence

Population-based analysis of AGXT pathogenic variants identified in the National Heart, Lung, and Blood Institute Exome Sequencing Project suggested that the prevalence of PH1 is 1:149,000 in European Americans and 1:157,000 in African Americans [Hopp et al 2015].

Clinical estimates of prevalence of PH1, primarily from European studies, range from one to three in 1,000,000 and one in 120,000 live births [Cochat & Rumsby 2013].

It is estimated that PH1 accounts for 1%-2% of children with ESKD in Western Europe and North America [Harambat et al 2012] and 10%-17% in Middle Eastern countries [Soliman & Mabrouk 2022].

The increased prevalence of PH1 in the Canary Islands is attributed to the AGXT pathogenic variant p.Ile244Thr (see Table 10) [Santana et al 2003].

A higher prevalence of PH1 is reported in Tunisia, Syria, and Druze communities due to high rates of consanguinity and founder variants in these populations [Kalfon et al 2017, Mbarek et al 2017, Murad et al 2021]. PH1 is also reported to be more common in Kuwait and other North African and Middle Eastern countries for similar reasons [Soliman & Mabrouk 2022].

When considering the above data, it is important to remember that PH1 remains underdiagnosed because of wide variability in its age of onset (infancy to adulthood) and clinical presentation (ranging from severe disease in infancy to adults with recurrent stones to advanced disease present in 20%-50% at the time of diagnosis). Additional factors contributing to underdiagnosis are lack of familiarity with PH1 among many physicians and lack of laboratory resources to measure oxalate concentration and perform genetic testing, especially in developing countries.

Primary Hyperoxaluria

Primary hyperoxaluria (PH) should be included in the differential diagnosis of any condition that causes calcium oxalate kidney stone disease and/or nephrocalcinosis or is associated with hyperoxaluria. The three known types of PH are PH1 (due to biallelic AGXT pathogenic variants), PH2 (due to biallelic GRHPR pathogenic variants), and PH3 (due to biallelic HOGA1 pathogenic variants). Each gene encodes an enzyme for different metabolic pathways relevant for the metabolism of glyoxylate [Cochat & Rumsby 2013].

Of note, up to 10% of clinically suspected primary hyperoxaluria is genetically unresolved.

The clinical manifestations of the three known types of PH overlap considerably (see Table 5).

• Urinary organic acid metabolites reflect the metabolic pathways and can be useful in differentiating among PH types. Metabolites are typically measured in random urine specimens with correction for creatinine concentration. Urine glycolate is often elevated in PH1, glycerate is increased in PH2, and 4-hydroxy-2-oxoglutarate (HOG) and 2,4-dihydroxyglutarate (DHG) are increased in most individuals with PH3.
• One recent series of predominantly North American populations found urine oxalate to be lower in PH3 than in PH1 and PH2 [Singh et al 2022b], whereas a largely European series observed similar oxalate excretion rates among all three PH types [Martin-Higueras et al 2021].
• In both series urinary citrate and calcium excretion rates were normal in individuals with PH3 [Martin-Higueras et al 2021, Singh et al 2022b]. These observations in individuals with PH3 contrast to those in individuals with PH1, who often manifest lower urinary citrate and calcium excretion rates [Singh et al 2022b].

Phenotypic overlap of PH1 with other monogenic stone diseases can occur [Daga et al 2018, Cogal et al 2021], particularly among those with childhood onset of calcium-containing stones and/or nephrocalcinosis. These monogenic stone diseases can be differentiated from PH by the absence of marked hyperoxaluria and comprehensive genetic testing.

Calcium oxalate stone disease of unknown cause (also called idiopathic calcium oxalate stone disease) can be associated with mild hyperoxaluria. Among individuals who form idiopathic stones, urine oxalate excretion (1) is typically lower (<0.6 mmol/day) compared to individuals with a primary hyperoxaluria, (2) varies from one collection to the next, and (3) is frequently accompanied by hypercalciuria. Since idiopathic stone disease is very common and since calcium oxalate is found in approximately 80% of stones [Worcester & Coe 2010], a high index of clinical suspicion is necessary to identify the small proportion of individuals who form calcium oxalate stones due to a primary hyperoxaluria.

Secondary Hyperoxaluria

Secondary forms of hyperoxaluria – including excessive dietary intake of oxalate or oxalate precursors and enteric hyperoxaluria – should be considered in the differential diagnosis of all individuals who present with hyperoxaluria [Lumlertgul et al 2018].

Dietary or other sources of excessive oxalate or oxalate precursors include:

• Foods high in oxalate (e.g., spinach, beetroot, dark chocolate), especially if dietary calcium intake is low;
• Diets markedly deficient in calcium, which result in a greater proportion of free oxalate in the intestinal lumen, thus enhancing absorption of oxalate and resulting in hyperoxaluria;
• Very high doses of vitamin C [D'Costa et al 2019];
• Toxins, such as ethylene glycol, which can cause marked hyperoxaluria and associated acute kidney failure.

Enteric hyperoxaluria results from fat malabsorption in the small intestine. Undigested fat reaching the colon combines with calcium, thus decreasing the amount of calcium available to bind to oxalate, which is subsequently absorbed. Fatty acids not absorbed in the small intestine can damage the colonic mucosa, leading to further increase in oxalate absorption. Causes to consider include the following:

• Any gastrointestinal disease or surgery that impairs fat absorption [Witting et al 2021]. Note that hyperoxaluria resulting from short bowel syndrome can be quite marked and can overlap the range seen in any of the primary hyperoxalurias. Bariatric surgical procedures such as gastric bypass are a frequent cause of hyperoxaluria and stones.
• Medications that interfere with fat absorption from the gastrointestinal tract (e.g., orlistat)

Zellweger Spectrum Disorder

Generalized loss of peroxisomal function is observed in Zellweger spectrum disorder (ZSD) including cerebrohepatorenal syndrome, neonatal adrenoleukodystrophy, and Refsum disease. Among a Dutch cohort of 31 individuals with ZSD, 19/23 (83%) of those in whom urine testing was performed had hyperoxaluria, often with associated hyperglycolic aciduria [van Woerden et al 2006]. Five of the individuals with ZSD had renal involvement characterized by urolithiasis, three had nephrocalcinosis, and one had kidney failure. The presence of neurodevelopmental impairment, retinopathy, hearing loss, and hepatic dysfunction in ZSD [Braverman et al 2016] facilitates clinical differentiation from primary hyperoxaluria.

Nephrocalcinosis of Prematurity

Nephrocalcinosis of prematurity, which occurs in a significant proportion of infants born prior to 28 weeks' gestation, is also characterized by nephrolithiasis [Habbig et al 2011]. Contributing risk factors in premature infants are thought to include (1) urine oxalate that is higher than that observed in infants born at term [Schell-Feith et al 2010], (2) hypercalciuria, and (3) hypocitraturia.

Evaluations Following Initial Diagnosis

The following evaluations are recommended to establish the extent of disease and needs in an individual diagnosed with primary hyperoxaluria type 1 (PH1):

• Kidney imaging for assessment of number and location of stones and presence of nephrocalcinosis
• Baseline 24-hour urine collection with measurement of excretion rates of oxalate, calcium, and citrate, pH, urine volume, and other components of a supersaturation profile to identify specific risk factors for stones
  Note: Baseline measurement of 24-hour excretion rates is recommended in nearly all individuals, even those requiring catheter placement for accurate collection. In rare exceptions only a spot urine with concentrations corrected for creatinine content is used (see Table 1).
• Measurement of plasma oxalate concentration (see Table 1)
• Assessment of kidney function (estimated glomerular filtration rate [eGFR]) by serum creatinine concentration, blood urea nitrogen, and/or cystatin C concentration
• When chronic kidney disease (CKD) is stage 3b or higher, evaluate for systemic oxalate deposits (i.e., oxalosis) with:
  • Bone imaging for evidence of sclerosis and/or pathologic fractures due to oxalate osteodystrophy;
  • Ophthalmologic examination including visual acuity and retinal examination for retinal oxalate deposition;
  • Echocardiography for evidence of cardiomyopathy;
  • Electrocardiogram for conduction disturbances;
  • Complete blood count for evidence of anemia, with further studies as needed to determine if erythropoietin resistance is the cause.
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to obtain a pedigree and inform affected individuals and their families about the nature, mode of inheritance, and implications of PH1 to facilitate medical and personal decision making
• Assessment of need for family support and resources from patient advocacy groups such as Oxalosis and Hyperoxaluria Foundation and Parent to Parent

Treatment of Manifestations

Management options for PH1 include targeted therapies and supportive care [Groothoff et al 2023, Michael et al 2024].

Surveillance

Individuals with PH1 require lifelong care, the frequency of which is related to kidney function [Cochat & Rumsby 2013, Groothoff et al 2023, Michael et al 2024].

CKD stages 1 and 2 (measured GFR or estimated GFR [eGFR] >60 mL/min/1.73 m²). The following are required to evaluate/ensure treatment efficacy:

• Regular monitoring of kidney function. Serum creatinine and/or cystatin C for determination of eGFR should be performed at least annually and more frequently in children and adolescents and in individuals with changing kidney function or clinically active stone disease.
• Regular kidney ultrasound examinations at least annually, or more often as needed to monitor and manage stone-forming activity
• Urinalysis and measurements of urine oxalate excretion, urine volume, and calcium oxalate saturation (spot and 24-hour collections) at least annually, more often in individuals with active stones or changes in kidney function

CKD stages 3a and 3b (GFR <60 and >30 mL/min/1.73 m²). Monitor the following at least every six months or more often with any change in clinical status:

• Kidney function
• Kidney ultrasound for stones and incipient nephrocalcinosis
• Urine oxalate and plasma oxalate concentrations

CKD stages 4 and 5 (GFR <30 mL/min/1.73 m²) or a rapid deterioration in function. The following should be performed at regular intervals, including prior to initiation of dialysis and during ongoing dialysis care:

• History and physical examination at least every three months for signs and symptoms of systemic oxalosis with assessment of growth and development (in children), bone or joint involvement, evidence of cardiomyopathy, signs of arterial insufficiency or ischemia, and skin examination for livedo reticularis, subcutaneous oxalate deposits, and/or ischemic ulcers
• Serum creatinine and plasma oxalate concentrations, typically monthly or more often depending on clinical circumstances
• Radiographs of the long bones to evaluate for radiodense metaphyseal bands and diffuse demineralization. Obtain initially, then repeat for bone symptoms and/or pathologic fractures; more frequent bone evaluation is needed in infants and young children.
• Ophthalmologic examination for visual acuity testing, evidence of retinal oxalate deposits, and optical coherence tomography (OCT) if available. Retinal photographs can be valuable to monitor changes over time.
• Electrocardiogram to evaluate for associated atrioventricular block or other oxalate-related conduction abnormalities, repeated every six to 12 months
• Echocardiogram for evidence of oxalate cardiomyopathy, repeated every 6-12 months.
• Hemoglobin to evaluate for anemia associated with either renal dysfunction or marrow deposition of oxalate, repeated every three months
• Thyroid function testing once a year
• Regular dental examinations/care

Note: Evaluations should occur more often in newly diagnosed symptomatic individuals or in children younger than ages two to three years.

Agents/Circumstances to Avoid

Avoid the following:

• Intravascular volume depletion. The importance of maintaining dilute urine cannot be overemphasized.
• Intake of vitamin C that exceeds the recommended daily allowance
• Loop diuretics to maintain dilute urine, as they can lead to hypercalciuria and increase calcium oxalate stone production
• High doses of nonsteroidal anti-inflammatory drugs (NSAIDs) or any pharmacologic agent that can compromise kidney function
• Large intake of foods high in oxalate (e.g., chocolate, rhubarb, starfruit)

Evaluation of Relatives at Risk

For early diagnosis and treatment. Family screening for PH1, particularly of sibs of the proband, is warranted given intrafamilial variability, significant disease risks even in asymptomatic individuals, and availability of therapeutic agents highly effective in reducing urine oxalate (see Targeted Therapies) [Cochat et al 2012]. Asymptomatic individuals found to have biallelic AGXT pathogenic variants are at increased risk for kidney stones and kidney damage [Sas et al 2020] and thus require the same management as those who have manifestations of PH1.

For kidney or liver organ donation. Molecular genetic testing to clarify the genetic status is recommended for relatives who are potential donors to inform decisions regarding living donor selection. It is unclear if a parent or sib who is heterozygous for an AGXT pathogenic variant is an appropriate donor. Although heterozygotes can have reduced liver AGT enzyme activity, they typically have normal urine oxalate excretion and remain free of stones or oxalate-related CKD.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Of note, women with PH1 warrant close monitoring by both an obstetrician and nephrologist during pregnancy and the postpartum period.

Although pregnancy does not appear to be an important risk factor for the development of ESKD in most women with PH1 [Miao et al 2022], women have been reported whose kidney function has deteriorated during the pregnancy and has remained abnormal post delivery [Cimino et al 2005]. Maintenance of adequate fluid intake throughout pregnancy can be challenging, especially during the first trimester and in women with hyperemesis gravidarum, when intravenous fluid administration may be required. Recommendations include continuation of pyridoxine throughout pregnancy for women known to be pyridoxine responsive and monitoring kidney function and possible stone formation throughout pregnancy and the early postpartum period.

Women with PH1 have had successful pregnancies following kidney transplantation alone and combined liver and kidney transplantation [Miao et al 2022]. In one woman liver function was apparently preserved, but kidney graft function declined transiently after the birth of her first child and permanently after the birth of her second child [Pruvot et al 1997].

Lumasiran and nedosiran, recently approved for use in individuals with PH1 (see Targeted Therapies), have not been studied during human pregnancy. Although preclinical animal studies were reassuring, pending more clinical experience the authors would advise women taking lumasiran or nedosiran to discontinue it prior to becoming pregnant and to consult with their nephrologist throughout the pregnancy regarding supportive care.

To date, no information is available regarding lumasiran or nedosiran transmission in breast milk; thus, risk to breast-feeding infants cannot be ruled out.

Therapies Under Investigation

Several novel therapies are under investigation.

Gene modification. Now that effectiveness of RNAi therapeutic agents lumasiran and nedosiran, which reduce the activity of the hepatic enzymes glycolate oxidase and lactate dehydrogenase A (LDHA), has been confirmed in individuals with PH1, the use of CRISPR/Cas9 for gene editing holds promise of a durable effect following a single treatment [Zheng et al 2020, Martinez-Turrillas at al 2022]. While such agents could avoid the inconvenience and risk of non-adherence associated with repeated dosing required with RNAi therapeutics, there is limited clinical experience to date with this technology and investigations in its use in PH1 are at the preclinical stage.

Small molecule therapies. Chemical chaperones may have general stabilizing functions, or they may be designed to target proteins with specific pathogenic variants. Missense pathogenic variants that do not cause loss of protein stability are not suitable candidates for this pharmacogenetic approach; nor are insertions, deletions, nonsense variants, or splice junction changes, which usually do not produce a protein product.

Small molecule inhibitors of LDHA for treatment of PH1 are in early clinical studies. Stiripentol, administered orally, inhibits activity of LDHA and is approved by the FDA for clinical use as an anti-seizure medication in Dravet syndrome. A few case reports have suggested a possible urine oxalate-reducing effect of stiripentol in PH1. However, to date, anecdotal evidence has been scattered, with effects in one report indistinguishable from those of concomitantly administered pyridoxine, and in individuals with PH1 with CKD or kidney failure, neither plasma oxalate concentration nor urine oxalate declined significantly [Kempf et al 2020, Martin-Higueras et al 2021, Violier et al 2022]. A clinical trial is currently ongoing.

Oxalate-degrading bacteria. Oral administration of bacteria such as Oxalobacter formigenes (O formigenes) or lactic acid bacteria to degrade oxalate and reduce the amount of oxalate available for intestinal absorption [Ivanovski & Drüeke 2013] is being investigated. O formigenes is also thought to stimulate secretion of endogenous oxalate into the intestine [Arvans et al 2017]. A human strain of O formigenes (HC-1) has been shown to promote oxalate secretion into the intestine of a mouse model of primary hyperoxaluria [Hatch et al 2011] and in this model reduced the amount of oxalate excreted via the kidney. Despite these findings in animal studies, and promising early findings in pilot studies in individuals with PH [Hoppe et al 2006], four double-blind, placebo-controlled trials of O formigenes administered orally to individuals with PH with preserved kidney function have failed to show benefit [Hoppe et al 2011, Hoppe et al 2017, Milliner et al 2018, Ariceta et al 2023], and a study of individuals with PH1 on dialysis also failed end points for efficacy [Hoppe et al 2021].

Other efforts to insert oxalate-degrading enzymes into bacteria that inhabit normal intestinal flora [Lubkowicz et al 2022] and to bind intestinal oxalate with compounds such as lanthanum [Pozdzik et al 2021] are in early stages of development.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Primary hyperoxaluria type 1 (PH1) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are presumed to be heterozygous for an AGXT pathogenic variant.
• Targeted molecular genetic testing for the AGXT pathogenic variants identified in the proband is recommended for the parents of the proband to confirm that both parents are heterozygous for an AGXT pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
    One individual with PH1 caused by maternal chromosome 2 telomeric isodisomy has been reported. The affected individual was homozygous for the common p.Lys12GlnfsTer156 pathogenic variant. The mother was heterozygous for the variant; the variant was absent in the father [Chevalier-Porst et al 2005].
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an AGXT pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• The age at onset and clinical manifestations can vary widely among sibs with the same biallelic AGXT pathogenic variants. Affected sibs often demonstrate significantly discordant disease expression [Frishberg et al 2005, Cochat & Rumsby 2013, Ben-Shalom et al 2022, Deesker et al 2022], with differences of more than 20 years between timing of end-stage kidney disease onset among sibs in some families [Hopp et al 2015].
• Given the variability in clinical expression, significant disease risk in asymptomatic individuals [Sas et al 2020], and the availability of therapeutic agents highly effective in reducing urinary oxalate, family screening, particularly of sibs, is strongly recommended.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

• Unless an affected individual's reproductive partner also has PH1 or is a carrier of an AGXT pathogenic variant, offspring will be obligate heterozygotes (carriers) for an AGXT pathogenic variant.
• One family with pseudodominant inheritance (i.e., an autosomal recessive condition present in individuals in two or more generations) has been reported: offspring of an affected individual and a carrier were affected [Hoppe et al 1997].

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an AGXT pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the AGXT pathogenic variants in an affected family member.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the AGXT pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

AGXT encodes alanine-glyoxylate aminotransferase (AGT), a key enzyme in the detoxification of glyoxylate, which converts glyoxylate to glycine (see Figure 1a in Groothoff et al [2023]). AGT, synthesized mainly in the liver, is translated in the cytosol and then guided into peroxisomes by a C-terminal peroxisomal targeting signal. Pyridoxine (vitamin B₆) is an essential cofactor for AGT activity.

Mechanism of disease causation. Loss of AGT function results in accumulation of its substrate, glyoxylate, and the conversion of glyoxylate into oxalate, which forms insoluble calcium oxalate salts that the body cannot readily eliminate, resulting in nephrolithiasis and nephrocalcinosis. Loss of protein function is caused by typical mechanisms such as frameshifting variants and nonsense-mediated mRNA decay.

Abnormal AGT function can also result from:

• Misfolding of AGT, which affects binding of the essential cofactor, pyridoxine (vitamin B₆) [Fargue et al 2013, Fargue & Acquaviva Bourdain 2022].
• "Mistargeting" of AGT, whereby the genetic change affects the AGT peroxisomal targeting sequence, causing the enzyme to be mislocated to mitochondria, where it is unable to detoxify glyoxylate, which in turn is metabolized to oxalate. Note: The variant p.Pro11Leu (the so-called minor allele) creates a cryptic N-terminal mitochondrial targeting sequence with no functional effect on the protein and, therefore, does not cause PH1 by itself. However, when in cis with one of four other pathogenic variants, p.Pro11Leu mistargets the enzyme to mitochondria, where it is unable to detoxify glyoxylate, which is then metabolized to oxalate. The four mistargeting variants are c.121G>A (p.Gly41Arg), c.454T>A (p.Phe152Ile), c.508G>A (p.Gly170Arg), and c.731T>C (p.Ile244Thr) [Oppici et al 2015, Fargue & Acquaviva Bourdain 2022] (see Table 10).
• The "minor allele" variant differs from the major (wild type) allele by a c.32C>T (p.Pro11Leu) substitution, c.1020A>G (p.Ile340Met), and a 74-base pair insertion in intron 1 [Oppici et al 2015, Fargue & Acquaviva Bourdain 2022].

AGXT-specific laboratory technical considerations. For individuals who have clinical findings of PH1 but only one or no AGXT pathogenic variant identified by multigene panel testing or exome sequencing, genome sequencing may be considered to more thoroughly interrogate AGXT (e.g., to detect deep intronic variants or structural variants).

Evaluation of AGXT variants of uncertain significance (VUSs)

• Family segregation studies can sometimes be helpful to classify a VUS as pathogenic or benign.
• Enzyme analysis can be used to identify alanine-glyoxylate aminotransferase (AGT) enzyme deficiency. Note that such testing requires use of liver tissue obtained by liver biopsy.

Author Notes

The Oxalosis and Hyperoxaluria Foundation (OHF; gro.fho@ofni) and Rare Kidney Stone Consortium (RKSC; ude.oyam@senotsyendikerar) are actively involved in clinical research regarding individuals with primary hyperoxaluria type 1 (PH1). They would be happy to communicate with persons who have any questions regarding diagnosis of primary hyperoxaluria type 1 (PH1) or other considerations.

The OHF and RKSC are also interested in hearing from clinicians treating families affected by frequent kidney stones, nephrocalcinosis, and/or kidney failure in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Contact Dr Peter C Harris ([email protected]) to inquire about review of AGXT variants of uncertain significance.

Acknowledgments

The authors gratefully acknowledge research support from the NIDDK and NCATS (U54KD083908, and DK133171) and support from the OHF for the RKSC OHF Primary Hyperoxaluria Registry. We are indebted to the many referring physicians, patients, and families for their contributions to the PH Registry.

Author History

Ben H Chew, MD, MSc, FRCSC; University of British Columbia (2009-2017)
Andrea G Cogal (2017-present)
Marion B Coulter-Mackie, PhD; BC Children's Hospital and BC Women's Hospital & Health Centre (2002-2017)
Peter C Harris, PhD (2017-present)
R Morrison Hurley, MD, MSc, FRCPC; BC Children's Hospital (2002-2014)
Dirk Lange, PhD; University of British Columbia (2009-2017)
John C Lieske, MD (2017-present)
Dawn S Milliner, MD (2017-present)
David J Sas, DO (2022-present)
Colin T White, MD; BC Children's Hospital and BC Women's Hospital & Health Centre (2002-2017)

Revision History

• 15 August 2024 (bp) Comprehensive update posted live
• 30 November 2017 (sw) Comprehensive update posted live
• 17 July 2014 (me) Comprehensive update posted live
• 17 November 2011 (me) Comprehensive update posted live
• 11 August 2009 (me) Comprehensive update posted live
• 21 December 2006 (me) Comprehensive update posted live
• 25 June 2004 (me) Comprehensive update posted live
• 19 June 2002 (me) Review posted live
• 4 January 2002 (rmh) Original submission

Literature Cited

• Al-Abadi E, Hulton SA. Extracorporal shock wave lithotripsy in the management of stones in children with oxalosis--still the first choice? Pediatr Nephrol. 2013;28:1085–9. [PubMed: 23397522]
• Ariceta G, Barrios K, Brown BD, Hoppe B, Rosskamp R, Langman CB. Hepatic Lactate Dehydrogenase A: An RNA Interference Target for the Treatment of All Known Types of Primary Hyperoxaluria. Kidney Int Rep. 2021;6:1088-98. [PMC free article: PMC8071644] [PubMed: 33912759]
• Ariceta G, Collard L, Abroug S, Moochhala SH, Gould E, Boussetta A, Ben Hmida M, De S, Hunley TE, Jarraya F, Fraga G, Banos A, Lindner E, Dehmel B, Schalk G. ePHex: a phase 3, double-blind, placebo-controlled, randomized study to evaluate long-term efficacy and safety of Oxalobacter formigenes in patients with primary hyperoxaluria. Pediatr Nephrol. 2023;38:403-15. [PMC free article: PMC9763141] [PubMed: 35552824]
• Arvans D, Jung YC, Antonopoulos D, Koval J, Granja I, Bashir M, Karrar E, Roy-Chowdhury J, Musch M, Asplin J, Chang E, Hassan H. Oxalobacter formigenes-derived bioactive factors stimulate oxalate transport by intestinal epithelial cells. J Am Soc Nephrol. 2017;28:876–87. [PMC free article: PMC5328155] [PubMed: 27738124]
• Bacchetta J, Boivin G, Cochat P. Bone impairment in primary hyperoxaluria: a review. Pediatr Nephrol. 2016;31:1-6. [PubMed: 25631241]
• Bacchetta J, Clavé S, Perrin P, Lemoine S, Sellier-Leclerc AL, Deesker LJ. Lumasiran, Isolated Kidney Transplantation, and Continued Vigilance. N Engl J Med. 2024;390:1052-54. [PubMed: 38477995]
• Baum MA, Langman C, Cochat P, Lieske JC, Moochhala SH, Hamamoto S, Satoh H, Mourani C, Ariceta G, Torres A, Wolley M, Belostotsky V, Forbes TA, Groothoff J, Hayes W, Tönshoff B, Takayama T, Rosskamp R, Russell K, Zhou J, Amrite A, Hoppe B; PHYOX2 study investigators. PHYOX2: a pivotal randomized study of nedosiran in primary hyperoxaluria type 1 or 2. Kidney Int. 2023;103:207-17. [PubMed: 36007597]
• Ben-Shalom E, Cytter-Kuint R, Rinat C, Becker-Cohen R, Tzvi-Behr S, Goichberg J, Peles V, Frishberg Y. Long-term complications of systemic oxalosis in children-a retrospective single-center cohort study. Pediatr Nephrol. 2021;36:3123-32. [PubMed: 33651179]
• Ben-Shalom E, Garrelfs SF, Groothoff JW. Primary hyperoxaluria: the pediatric nephrologist's point of view. Clin Kidney J. 2022;15:i23-i28. [PMC free article: PMC9113416] [PubMed: 35592624]
• Bergstralh EJ, Monico CG, Lieske JC, Herges RM, Langman CB, Hoppe B, Milliner DS. IPHR Investigators. Transplantation outcomes in primary hyperoxaluria. Am J Transplant. 2010;10:2493–501. [PMC free article: PMC2965313] [PubMed: 20849551]
• Berini SE, Tracy JA, Engelstad JK, Lorenz EC, Milliner DS, Dyck PJ. Progressive polyradiculoneuropathy due to intraneural oxalate deposition in type 1 primary hyperoxaluria. Muscle Nerve. 2015;51:449–54. [PMC free article: PMC4577279] [PubMed: 25363903]
• Birtel J, Herrmann P, Garrelfs SF, Dulz S, Atiskova Y, Diederen RM, Gliem M, Brinkert F, Holz FG, Boon CJF, Hoppe B, Charbel Issa P. The ocular phenotype in primary hyperoxaluria type 1. Am J Ophthalmol. 2019;206:184-91. [PubMed: 31078535]
• Braverman NE, Raymond GV, Rizzo WB, Moser AB, Wilkinson ME, Stone EM, Steinberg SJ, Wangler MF, Rush ET, Hacia JG, Bose M. Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines. Mol Genet Metab. 2016;117:313-21. [PMC free article: PMC5214431] [PubMed: 26750748]
• Breeggemann MC, Gluck SL, Stoller ML, Lee MM. A case report of kidney-only transplantation in primary hyperoxaluria type 1: a novel approach with the use of nedosiran. Case Rep Nephrol Dial. 2023;13:63-9. [PMC free article: PMC10368091] [PubMed: 37497389]
• Carrasco A Jr, Granberg CF, Gettman MT, Milliner DS, Krambeck AE. Surgical management of stone disease in patients with primary hyperoxaluria. Urology. 2015;85:522–6. [PMC free article: PMC4559267] [PubMed: 25733260]
• Chevalier-Porst F, Rolland MO, Cochat P, Bozon D. Maternal isodisomy of the telomeric end of chromosome 2 is responsible for a case of primary hyperoxaluria type 1. Am J Med Genet A. 2005;132A:80–3. [PubMed: 15580638]
• Cimino S, Ranno S, Garozzo M, Reggio M, Battaglia G, Maugeri O, Ventimiglia B. Minerva Urol Nefrol. 2005;57:341–3. [Primary hyperoxaluria and pregnancy] [PubMed: 16247357]
• Cochat P, Groothoff J. Primary hyperoxaluria type 1: practical and ethical issues. Pediatr Nephrol. 2013;28:2273. [PubMed: 23494551]
• Cochat P, Hulton SA, Acquaviva C, Danpure CJ, Daudon M, De Marchi M, Fargue S, Groothoff J, Harambat J, Hoppe B, Jamieson NV, Kemper MJ, Mandrile G, Marangella M, Picca S, Rumsby G, Salido E, Straub M, van Woerden CS. Primary hyerpoxaluria type 1: indications for screening and guidance for diagnosis and treatment. Nephrol Dial Transplant. 2012;27:1729–36. [PubMed: 22547750]
• Cochat P, Rumsby G. Primary hyperoxaluria. New Engl J Med. 2013;369:649–58. [PubMed: 23944302]
• Cogal AG, Arroyo J, Shah RJ, Reese KJ, Walton BN, Reynolds LM, Kennedy GN, Seide BM, Senum SR, Baum M. erickson SB, Jagadeesh S, Soliman NA, Goldfarb DS, Beara-Lasic L, Edvardsson VO, Pallson R, Milliner DS, Sas DJ, Lieske JC, Harris PC. Comprehensive genetic analysis reveals complexity of monogenic urinary stone disease. Kidney Int Rep. 2021;6:2862–84. [PMC free article: PMC8589729] [PubMed: 34805638]
• Coulter-Mackie MB, Lian Q, Applegarth D, Toone J. The major allele of the alanine:glyoxylate aminotransferase gene: nine novel mutations and polymorphisms associated with primary hyperoxaluria type 1. Mol Genet Metab. 2005;86:172–8. [PubMed: 15963748]
• Coulter-Mackie MB, Rumsby G, Applegarth DA, Toone JR. Three novel deletions in the alanine:glyoxylate aminotransferase gene of three patients with type 1 hyperoxaluria. Mol Genet Metab. 2001;74:314–21. [PubMed: 11708860]
• Daga A, Majmundar AJ, Braun DA, Gee HY, Lawson JA, Shril S, Jobst-Schwan T, Vivante A, Schapiro D, Tan W, Warejko JK, Widmeier E, Nelson CP, Fathy HM, Gucev Z, Soliman NA, Hashmi S, Halbritter J, Halty M, Kari JA, El-Desoky S, Ferguson MA, Somers MJG, Traum AZ, Stein DR, Daouk GH, Rodig NM, Katz A, Hanna C, Schwaderer AL, Sayer JA, Wassner AJ, Mane S, Lifton RP, Milosevic D, Tasic V, Baum MA, Hildebrandt F. Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis. Kidney Int. 2018;93:204-13. [PMC free article: PMC5750088] [PubMed: 28893421]
• Danpure CJ, Purdue PE, Fryer P, Griffiths S, Allsop J, Lumb MJ, Guttridge KM, Jennings PR, Scheinman JI, Mauer SM, et al. Enzymological and mutational analysis of a complex primary hyperoxaluria type 1 phenotype involving alanine:glyoxylate aminotransferase peroxisome-to-mitochondrion mistargeting and intraperoxisomal aggregation. Am J Hum Genet. 1993;53:417-32. [PMC free article: PMC1682352] [PubMed: 8101040]
• Dasgupta D, Wee MJ, Reyes M, Li Y, Simm PJ, Sharma A, Schlingmann KP, Janner M, Biggin A, Lazier J, Gessner M, Chrysis D, Tuchman S, Baluarte HJ, Levine MA, Tiosano D, Insogna K, Hanley DA, Carpenter TO, Ichikawa S, Hoppe B, Konrad M, Sävendahl L, Munns CF, Lee H, Jüppner H, Bergwitz C. Mutations in SLC34A3/NPT2c are associated with kidney stones and nephrocalcinosis. J Am Soc Nephrol. 2014;25:2366-75. [PMC free article: PMC4178443] [PubMed: 24700880]
• D'Costa MR, Winkler NS, Milliner DS, Norby SM, Hickson LJ, Lieske JC. Oxalosis associated with high-dose vitamin C ingestion in a peritoneal dialysis patient. Am J Kidney Dis. 2019;74:417-20. [PMC free article: PMC6708738] [PubMed: 30910370]
• Deesker LJ, Garrelfs SF, Mandrile G, Oosterveld MJS, Cochat P, Deschênes G, Harambat J, Hulton SA, Gupta A, Hoppe B, Beck BB, Collard L, Topaloglu R, Prikhodina L, Salido E, Neuhaus T, Groothoff JW, Bacchetta J. Improved Outcome of Infantile Oxalosis Over Time in Europe: Data From the OxalEurope Registry. Kidney Int Rep. 2022;7:1608-18. [PMC free article: PMC9263236] [PubMed: 35812297]
• Demoulin N, Aydin S, Gillion V, Morelle J, Jadoul M. Pathophysiology and management of hyperoxaluria and oxalate nephropathy: a review. Am J Kidney Dis. 2022;79:717-27. [PubMed: 34508834]
• Devresse A, Cochat P, Godefroid N, Kanaan N. Transplantation for primary hyperoxaluria type 1: designing new strategies in the era of promising therapeutic perspectives. Kidney Int Rep. 2020;5:2136-45. [PMC free article: PMC7710835] [PubMed: 33305106]
• Edvardsson VO, Goldfarb DS, Lieske JC, Beara-Lasic L, Auglani F, Milliner DS, Palsson R. Hereditary causes of kidney stones and chronic kidney disease. Pediatr Nephrol. 2013;28:1923–42. [PMC free article: PMC4138059] [PubMed: 23334384]
• Edvardsson VO, Sas DJ. Urinary Stone Disease and Nephrocalcinosis. In: Emma F, Goldstein SL, Bagga A, Bates CM, Shroff R, editors. Pediatric Nephrology. Cham: Springer International Publishing; 2022. p. 1295-322.
• Fargue S, Acquaviva Bourdain C. Primary hyperoxaluria type 1: pathophysiology and genetics. Clin Kidney J. 2022;15(Suppl 1):i4-i8. [PMC free article: PMC9113437] [PubMed: 35592619]
• Fargue S, Rumsby G, Danpure CJ. Multiple mechanisms of action of pyridoxine in primary hyperoxaluria type 1. Biochim Biophys Acta. 2013;1832:1776–83. [PubMed: 23597595]
• Frishberg Y, Rinat C, Shalata A, Khatib I, Feinstein S, Becker-Cohen R, Weismann I, Wanders RJ, Rumsby G, Roels F, Mandel H. Intra-familial clinical heterogeneity: absence of genotype-phenotype correlation in primary hyperoxaluria type 1 in Israel. Am J Nephrol. 2005;25:269–75. [PubMed: 15961946]
• Gang X, Liu F, Mao J. Lumasiran for primary hyperoxaluria type 1: What we have learned? Front Pediatr. 2023;10:1052625. [PMC free article: PMC9871624] [PubMed: 36704142]
• Garrelfs SF, Frishberg Y, Hulton SA, Koren MJ, O'Riordan WD, Cochat P, Deschênes G, Shasha-Lavsky H, Saland JM, Van't Hoff WG, Fuster DG, Magen D, Moochhala SH, Schalk G, Simkova E, Groothoff JW, Sas DJ, Meliambro KA, Lu J, Sweetser MT, Garg PP, Vaishnaw AK, Gansner JM, McGregor TL, Lieske JC, et al. Lumasiran, an RNAi therapeutic for primary hyperoxaluria type 1. N Engl J Med. 2021a;384:1216–26. [PubMed: 33789010]
• Garrelfs SF, Metry EL, van Harskamp D, Vaz FM, van den Akker CHP, Schierbeek H, Groothoff JW, Oosterveld MJS. Glycolate oxidase inhibition by lumasiran varies between patients with primary hyperoxaluria type 1. Kidney Int. 2023;103:990-3. [PubMed: 36871948]
• Garrelfs SF, van Harskamp D, Peters-Sengers H, van den Akker CHP, Wanders RJA, Wijburg FA, van Goudoever JB, Groothoff JW, Schierbeek H, Oosterveld MJS. Endogenous oxalate production in primary hyperoxaluria type 1 patients. J Am Soc Nephrol. 2021b;32:3175-86. [PMC free article: PMC8638398] [PubMed: 34686543]
• Godron A, Harambat J, Boccio V, Mensire A, May A, Rigothier C, Couzi L, Barrou B, Godin M, Chauveau D, Faguer S, Vallet M, Cochat P, Eckart P, Guest G, Guigonis V, Houillier P, Blanchard A, Jeunemaitre X, Vargas-Poussou R. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: phenotype-genotype correlation and outcome in 32 patients with CLDN16 or CLDN19 mutations. Clin J Am Soc Nephrol. 2012;7:801-9. [PMC free article: PMC3338284] [PubMed: 22422540]
• Grateau G, Grünfeld JP, Beurton D, Hannedouche T, Crosnier J. Post-surgical deterioration of renal function in primary hyperoxaluria. Nephrol Dial Transplant. 1987;1:261-4. [PubMed: 3110687]
• Groothoff J, Sellier-Leclerc AL, Deesker L, Bacchetta J, Schalk G, Tönshoff B, Lipkin G, Lemoine S, Bowman T, Zhou J, Hoppe B. Nedosiran Safety and Efficacy in PH1: Interim Analysis of PHYOX3. Kidney Int Rep. 2024;9:1387-96. [PMC free article: PMC11068990] [PubMed: 38707801]
• Groothoff JW, Metry E, Deesker L, Garrelfs S, Acquaviva C, Almardini R, Beck BB, Boyer O, Cerkauskiene R, Ferraro PM, Groen LA, Gupta A, Knebelmann B, Mandrile G, Moochhala SS, Prytula A, Putnik J, Rumsby G, Soliman NA, Somani B, Bacchetta J. Clinical practice recommendations for primary hyperoxaluria: an expert consensus statement from ERKNet and OxalEurope. Nat Rev Nephrol. 2023;19:194-211. [PubMed: 36604599]
• Gupta A, Somers MJG, Baum MA. Treatment of primary hyperoxaluria type 1. Clin Kidney J. 2022;15:i9-i13. [PMC free article: PMC9113429] [PubMed: 35592620]
• Habbig S, Beck BB, Hoppe B. Nephrocalcinosis and urolithiasis in children. Kidney Int. 2011;80:1278–91. [PubMed: 21956187]
• Harambat J, van Stralen KJ, Espinosa L, Groothoff JQ, Hulton SA, Cerkausiene R, Schaefer F, Verrina E, Jager KJ, Cochat P. Characteristics and outcomes of children with primary oxalosis requiring renal replacement therapy. Clin J Am Soc Nephrol. 2012;7:458–65. [PMC free article: PMC3302673] [PubMed: 22223608]
• Hatch M, Gjymishka A, Salido EC, Allison MJ, Freel RW. Enteric oxalate elimination is induced and oxalate is normalized in a mouse model of primary hyperoxaluria following intestinal colonization with Oxalobacter. Am J Physiol Gastrointest Liver Physiol. 2011;300:G461-9. [PMC free article: PMC3064122] [PubMed: 21163900]
• Hopp K, Cogal AG, Bergstralh EJ, Seide BM, Olson JB, Meek AM, Lieske JC, Milliner DS, Harris PC., Rare Kidney Stone Consortium. Phenotype-genotype correlations and estimated carrier frequencies of primary hyperoxaluria. J Am Soc Nephrol. 2015;26:2559–70. [PMC free article: PMC4587693] [PubMed: 25644115]
• Hoppe B, Beck B, Gatter N, von Unruh G, Tischer A, Hesse A, Laube N, Kaul P, Sidhu H. Oxalobacter formingenes: a potential tool for the treatment of primary hyperoxaluria type 1. Kidney Int. 2006;70:1305–11. [PubMed: 16850020]
• Hoppe B, Danpure CJ, Rumsby G, Fryer P, Jennings PR, Blau N, Schubiger G, Neuhaus T, Leumann E. A vertical (pseudodominant) pattern of inheritance in the autosomal recessive disease primary hyperoxaluria type 1: lack of relationship between genotype, enzymic phenotype, and disease severity. Am J Kidney Dis. 1997;29:36–44. [PubMed: 9002528]
• Hoppe B, Groothoff JW, Hulton SA, Cochat P, Niaudet P, Kemper MJ, Deschenes G, Unwin R, Milliner D. Efficacy and safety of Oxalobacter formigenes to reduce urinary oxalate in primary hyperoxaluria. Nephrol Dial Transplant. 2011;26:3609–15. [PubMed: 21460356]
• Hoppe B, Niaudet P, Salomon R, Harambat J, Hulton SA, Van’t Hoff W, Moochhal SH, Deschênes G, Lindner E, Sjögren A, Cochat P. A randomised Phase I/II trial to evaluate the efficacy and safety of orally administered Oxalobacter formigenes to treat primary hyperoxaluria. Pediatr Nephrol. 2017;32:781–90. [PubMed: 27924398]
• Hoppe B, Pellikka PA, Dehmel B, Banos A, Lindner E, Herberg U. Effects of Oxalobacter formigenes in subjects with primary hyperoxaluria Type 1 and end-stage renal disease: a Phase II study. Nephrol Dial Transplant. 2021;36:1464-73. [PubMed: 32810261]
• Hoyer-Kuhn H, Kohbrok S, Volland R, Franklin J, Beck BB, Hoppe B. Vitamin B6 in primary hyperoxaluria 1: first prospective trial after 40 years of practice. Clin J Am Soc Nephrol. 2014;9:468–77. [PMC free article: PMC3944765] [PubMed: 24385516]
• Ivanovski O, Drüeke TB. A new era in the treatment of calcium oxalate stones? Kidney Int. 2013;83:998–1000. [PubMed: 23728004]
• Janiec A, Halat-Wolska P, Obrycki Ł, Ciara E, Wójcik M, Płudowski P, Wierzbicka A, Kowalska E, Książyk JB, Kułaga Z, Pronicka E, Litwin M. Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations. Nephrol Dial Transplant. 2021;36:1484-92. [PMC free article: PMC8311581] [PubMed: 33099630]
• Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519-22. [PubMed: 28959963]
• Kalfon L, Weissman I, Hershkovits M, Nasser Samra N, Edri N, Khayat M, Tanus M, Shihab S, Mandel H, Falik-Zaccai T. [Oxalate stones are prevalent among Druze and Muslim Arabs in the Galilee]. Harefuah. 2017;156:156-62. [PubMed: 28551940]
• Kempf C, Pfau A, Holle J, Müller-Schlüter K, Bufler P, Knauf F, Müller D. Stiripentol fails to lower plasma oxalate in a dialysis-dependent PH1 patient. Pediatr Nephrol. 2020;35:1787-9. [PMC free article: PMC7385015] [PubMed: 32418144]
• Kohli H, Kurtz MP. Primary hyperoxaluria type 1: urologic and therapeutic management. Clin Kidney J. 2022;15:i14-i16. [PMC free article: PMC9113488] [PubMed: 35592623]
• Lubkowicz D, Horvath NG, James MJ, Cantarella P, Renaud L, Bergeron CG, Shmueli RB, Anderson C, Gao JR, Kurtz CB, Perreault M, Charbonneau MR, Isabella VM, Hava DL. An engineered bacterial therapeutic lowers urinary oxalate in preclinical models and in silico simulations of enteric hyperoxaluria. Mol Syst Biol. 2022;18:e10539. [PMC free article: PMC8899768] [PubMed: 35253995]
• Lawrence JE, Wattenberg DJ. Primary Hyperoxaluria: The Patient and Caregiver Perspective. Clin J Am Soc Nephrol. 2020;15:909-11. [PMC free article: PMC7341774] [PubMed: 32165441]
• Lorenz EC, Lieske JC, Seide BM, Meek AM, Olson JB, Bergstralh EJ, Milliner DS. Sustained pyridoxine response in primary hyperoxaluria type 1 recipients of kidney alone transplant. Am J Transplant. 2014;14:1433-8. [PMC free article: PMC4543374] [PubMed: 24797341]
• Lorenz EC, Lieske JC, Seide BM, Olson JB, Mehta R, Milliner DS. Recovery From Dialysis in Patients With Primary Hyperoxaluria Type 1 Treated With Pyridoxine: A Report of 3 Cases. Am J Kidney Dis. 2021;77:816-9. [PMC free article: PMC7930154] [PubMed: 32891627]
• Lumlertgul N, Siribamrungwong M, Jaber BL, Susantitaphong P. Secondary oxalate nephropathy: a systematic review. Kidney Int Rep. 2018;3:1363–72. [PMC free article: PMC6224620] [PubMed: 30450463]
• Mandrile G, Beck B, Acquaviva C, Rumsby G, Deesker L, Garrelfs S, Gupta A, Bacchetta J, Groothoff J; OxalEurope Consortium/Erknet Guideline Workgroup On Hyperoxaluria. Genetic assessment in primary hyperoxaluria: why it matters. Pediatr Nephrol. 2023;38:625-34. [PMC free article: PMC9842587] [PubMed: 35695965]
• Mandrile G, van Woerden CS, Berchialla P, Beck BB, Acquaviva Bourdain C, Hulton SA, Rumsby G. OxalEurope Consortium. Data from a large European study indicate that the outcome of primary hyperoxaluria type 1 correlates with the AGXT mutation type. Kidney Int. 2014;86:1197–204. [PubMed: 24988064]
• Martin-Higueras C, Garrelfs SF, Groothoff JW, Jacob DE, Moochhala SH, Bacchetta J, Acquaviva C, Zaniew M, Sikora P, Beck BB, Hoppe B. A report from the European Hyperoxaluria Consortium (OxalEurope) Registry on a large cohort of patients with primary hyperoxaluria type 3. Kidney Int. 2021;100:621–35. [PubMed: 33865885]
• Martinez-Turrillas R, Martin-Mallo A, Rodriguez-Diaz S, Zapata-Linares N, Rodriguez-Marquez P, San Martin-Uriz P, Vilas-Zornoza A, Calleja-Cervantes ME, Salido E, Prosper F, Rodriguez-Madoz JR. In vivo CRISPR-Cas9 inhibition of hepatic LDH as treatment of primary hyperoxaluria. Mol Ther Methods Clin Dev. 2022;25:137-46. [PMC free article: PMC8971349] [PubMed: 35402636]
• Mbarek IB, Mdimeg S, Moussa A, Zellama D, Kaarout H, Abdelmoula J, Achour A, Abroug S, Omezzine A, Bouslama A. Unusual clinical outcome of primary hyperoxaluria type 1 in Tunisian patients carrying 33_34InsC mutation. BMC Nephrol. 2017;18:195. [PMC free article: PMC5472968] [PubMed: 28619084]
• Metry EL, Garrelfs SF, Deesker LJ, Acquaviva C, D'Ambrosio V, Bacchetta J, Beck BB, Cochat P, Collard L, Hogan J, Ferraro PM, Franssen CFM, Harambat J, Hulton SA, Lipkin GW, Mandrile G, Martin-Higueras C, Mohebbi N, Moochhala SH, Neuhaus TJ, Prikhodina L, Salido E, Topaloglu R, Oosterveld MJS, Groothoff JW, Peters-Sengers H. Determinants of Kidney Failure in Primary Hyperoxaluria Type 1: Findings of the European Hyperoxaluria Consortium. Kidney Int Rep. 2023;8:2029-42. [PMC free article: PMC10577369] [PubMed: 37849991]
• Metry EL, van Dijk LMM, Peters-Sengers H, Oosterveld MJS, Groothoff JW, Ploeg RJ, Stel VS, Garrelfs SF. Transplantation outcomes in patients with primary hyperoxaluria: a systematic review. Pediatr Nephrol. 2021;36:2217-26. [PMC free article: PMC8260423] [PubMed: 33830344]
• Miao J, Mehta RA, Norby S, Seide B, Milliner DS, Lieske J, Kattah A. Comparison of clinical features of pregnant and non-pregnant females with primary hyperoxaluria. J Nephrol. 2022;35:1771-4. [PMC free article: PMC9694097] [PubMed: 35041195]
• Michael M, Groothoff JW, Shasha-Lavsky H, Lieske JC, Frishberg Y, Simkova E, Sellier-Leclerc AL, Devresse A, Guebre-Egziabher F, Bakkaloglu SA, Mourani C, Saqan R, Singer R, Willey R, Habtemariam B, Gansner JM, Bhan I, McGregor T, Magen D. Lumasiran for Advanced Primary Hyperoxaluria Type 1: Phase 3 ILLUMINATE-C Trial. Am J Kidney Dis. 2023;81:145-55.e1. [PubMed: 35843439]
• Michael M, Harvey L, Milliner DS, Frishberg Y, Sas DJ, Calle J, Copelovitch L, Penniston K, Saland J, Somers MJG, Baum MA. Diagnosis and management of primary hyperoxaluria: best practices. Ped Neph. 2024. [PubMed: 38753085]
• Milliner D, Hoppe B, Groothoff J. A randomised Phase II/III study to evaluate the efficacy and safety of orally administered Oxalobacter formigenes to treat primary hyperoxaluria. Urolithiasis. 2018;46:313–23. [PMC free article: PMC6061479] [PubMed: 28718073]
• Milliner DS, McGregor TL, Thompson A, Dehmel B, Knight J, Rosskamp R, Blank M, Yang S, Fargue S, Rumsby G, Groothoff J, Allain M, West M, Hollander K, Lowther WT, Lieske JC. End Points for Clinical Trials in Primary Hyperoxaluria. Clin J Am Soc Nephrol. 2020;15:1056-65. [PMC free article: PMC7341772] [PubMed: 32165440]
• Mitsimponas KT, Wehrhan T, Falk S, Wehrhan R, Neukam FW, Schlegel KA. Oral findings associated with primary hyperoxaluria type 1. J Craniomaxillofac Surg. 2012;40:e301–6. [PubMed: 22417769]
• Monico CG, Olson JB, Milliner DS. Implications of genotype and enzyme phenotype in pyridoxine response of patients with type I primary hyperoxaluria. Am J Nephrol. 2005;25:183–8. [PubMed: 15849466]
• Monico CG, Rossetti S, Schwanz HA, Olson J, Lundquist P, Dawson D, Harris P, Milliner DS. Comprehensive mutation screening in 55 probands with type 1 primary hyperoxaluria shows feasibiity of a gene-based diagnosis. J Am Soc Nephrol. 2007;18:1905–14. [PubMed: 17460142]
• Murad H, Alhalabi MB, Dabboul A, Alfakseh N, Nweder MS, Zghib Y, Wannous H. Molecular analysis of the AGXT gene in Syrian patients suspected with primary hyperoxaluria type 1. BMC Med Genomics. 2021;14:146. [PMC free article: PMC8176596] [PubMed: 34082749]
• Nogueira PK, Vuong TS, Bouton O, Maillard A, Marchand M, Rolland MO, Cochat P, Bozon D. Partial deletion of the AGXT gene (EX1_EX7del): a new genotype in hyperoxaluria type 1. Hum Mutat. 2000;15:384–5. [PubMed: 10737993]
• Nwachukwu C, Singh G, Moore B, Strande NT, Bucaloiu ID, Chang AR. Risk of Nephrolithiasis in Adults Heterozygous for SLC34A3 Ser192Leu in an Unselected Health System Cohort. J Am Soc Nephrol. 2023;34:1819-21. [PMC free article: PMC10631595] [PubMed: 37639356]
• Oppici E, Montioli R, Cellini B. Liver peroxisomal alanine:glyoxylate aminotransferase and the effects of mutations associated with Primary Hyperoxaluria Type I: An overview. Biochim Biophys Acta. 2015;1854:1212-9. [PubMed: 25620715]
• Pais VM Jr, Assimos DG. Pitfalls in the management of patients with primary hyperoxaluria: a urologist's perspective. Urol Res. 2005;33:390-3. [PubMed: 16284885]
• Perinpam M, Enders FT, Mara KC, Vaughan LE, Mehta RA, Voskoboev N, Milliner DS, Lieske JC. Plasma oxalate in relation to eGFR in patients with primary hyperoxaluria, enteric hyperoxaluria and urinary stone disease. Clin Biochem. 2017;50:1014–9. [PMC free article: PMC5705406] [PubMed: 28764885]
• Pozdzik A, David C, Vekeman J, Tielens F, Daudon M. Lanthanum carbonate to control plasma and urinary oxalate level in type 1 primary hyperoxaluria? IJU Case Rep. 2021;4:235-8. [PMC free article: PMC8255283] [PubMed: 34258537]
• Pruvot FR, Noel C, Declerck N, Valat-Rigot AS, Roumilhac D, Hazzan M, Puech F, Lelievre G. Consecutive successful pregnancies in a combined liver and kidney transplant recipient with type 1 primary hyperoxaluria. Transplantation. 1997;63:615–6. [PubMed: 9047162]
• Pszczolinski R, Acquaviva C, Berrahal I, Biebuyck N, Burtey S, Clabault K, Dossier C, Guillet M, Hemery F, Letavernier E, Rousset-Rouvière C, Bacchetta J, Moulin B. Primary hyperoxaluria in adults and children: a nationwide cohort highlights a persistent diagnostic delay. Clin Kidney J. 2024;17:sfae099. [PMC free article: PMC11087826] [PubMed: 38737343]
• Rao NM, Yallapragada A, Winden KD, Saver J, Liebeskind DS. Stroke in primary hyperoxaluria type I. J Neuroimaging. 2014;24:411–3. [PMC free article: PMC4156598] [PubMed: 23551880]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Santana A, Salido E, Torres A, Shapiro LJ. Primary hyperoxaluria type 1 in the Canary Islands: a conformational disease due to I244T mutation in the P11L-containing alanine:glyoxylate aminotransferase. Proc Natl Acad Sci U S A. 2003;100:7277–82. [PMC free article: PMC165866] [PubMed: 12777626]
• Sas DJ, Enders FT, Gunderson TM, Mehta RA, Olson JB, Seide BM, Banks CJ, Dehmel B, Pellikka PA, Lieske JC, Milliner DS. Natural History of Clinical, Laboratory, and Echocardiographic Parameters of a Primary Hyperoxaluria Cohort on Long Term Hemodialysis. Front Med (Lausanne). 2021;8:592357. [PMC free article: PMC8062902] [PubMed: 33898474]
• Sas DJ, Enders FT, Mehta RA, Tang X, Zhao F, Seide BM, Milliner DS, Lieske JC. Clinical features of genetically confirmed patients with primary hyperoxaluria identified by clinical indication versus familial screening. Kidney Int. 2020;97:786-92. [PMC free article: PMC7175669] [PubMed: 32093915]
• Sas DJ, Magen D, Hayes W, Shasha-Lavsky H, Michael M, Schulte I, Sellier-Leclerc AL, Lu J, Seddighzadeh A, Habtemariam B, McGregor TL, Fujita KP, Frishberg Y; ILLUMINATE-B Workgroup. Phase 3 trial of lumasiran for primary hyperoxaluria type 1: a new RNAi therapeutic in infants and young children. Genet Med. 2022;24:654-62. [PubMed: 34906487]
• Sas DJ, Mara K, Mehta RA, Seide BM, Banks CJ, Danese DS, McGregor TL, Lieske JC, Milliner DS. Natural history of urine and plasma oxalate in children with primary hyperoxaluria type 1. Pediatr Nephrol. 2024;39:141-8. [PMC free article: PMC11044200] [PubMed: 37458799]
• Schell-Feith EA, Kist-van Holthe JE, van der Heijden AJ. Nephrocalcinosis in preterm neonates. Pediatr Nephrol. 2010;25:221-30. [PMC free article: PMC6941622] [PubMed: 18797936]
• Scott LJ, Keam SJ. Lumasiran: first approval. Drugs. 2021;81:277–82. [PubMed: 33405070]
• Sellier-Leclerc AL, Metry E, Clave S, Perrin P, Acquaviva-Bourdain C, Levi C, Crop M, Caillard S, Moulin B, Groothoff J, Bacchetta J. Isolated kidney transplantation under lumasiran therapy in primary hyperoxaluria type 1: a report of five cases. Nephrol Dial Transplant. 2023;38:517-21. [PubMed: 36307929]
• Singh P, Chebib FT, Cogal AG, Gavrilov DK, Harris PC, Lieske JC. Pyridoxine responsiveness in a type 1 primary hyperoxaluria patient with a rare (atypical) AGXT gene mutation. Kidney Int Rep. 2020;5:955-8. [PMC free article: PMC7270974] [PubMed: 32518881]
• Singh P, Vaughan LE, Schulte PJ, Sas DJ, Milliner DS, Lieske JC. Estimated GFR Slope Across CKD Stages in Primary Hyperoxaluria Type 1. Am J Kidney Dis. 2022a;80:373-82. [PMC free article: PMC9398980] [PubMed: 35306035]
• Singh P, Viehman JK, Mehta RA, Cogal AG, Hasadsri L, Oglesbee D, Olson JB, Seide BM, Sas DJ, Harris PC, Lieske JC, Milliner DS. Clinical characterization of primary hyperoxaluria type 3 in comparison with types 1 and 2. Nephrol Dial Transplant. 2022b;37:869–75. [PMC free article: PMC9214566] [PubMed: 33543760]
• Soliman NA, Mabrouk S. Primary hyperoxaluria type 1 in developing countries: novel challenges in a new therapeutic era. Clin Kidney J. 2022;15:i33-i36. [PMC free article: PMC9113489] [PubMed: 35592622]
• Soliman NA, Nabhan MM, Abdelrahman SM, Abdelaziz H, Helmy R, Ghanim K, Bazaraa HM, Badr AM, Tolba OA, Kotb MA, Eweeda KM, Fayez A. Clinical spectrum of primary hyperoxaluria type 1: Experience of a tertiary center. Nephrol Ther. 2017;13:176-82. [PMC free article: PMC5921832] [PubMed: 28161266]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD^®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]
• Stone HK, VandenHeuvel K, Bondoc A, Flores FX, Hooper DK, Varnell CD Jr. Primary hyperoxaluria diagnosed after kidney transplant: A review of the literature and case report of aggressive renal replacement therapy and lumasiran to prevent allograft loss. Am J Transplant. 2021;21:4061-7. [PMC free article: PMC8639665] [PubMed: 34254430]
• Tammachote R, Kingsuwannapong N, Tongkobpetch S, Srichomthong C, Yeetong P, Kingwatanakul P, Monico CG, Suphapeetiporn K, Shotelersuk V. Primary hyperoxaluria type 1 and brachydactyly mental retardation syndrome caused by a novel mutation in AGXT and a terminal deletion of chromosome 2. Am J Med Genet A. 2012;158A:2124–30. [PubMed: 22821680]
• Tang X, Bergstralh EJ, Mehta RA, Vrtiska TJ, Milliner DS, Lieske JC. Nephrocalcinosis is a risk factor for kidney failure in primary hyperoxaluria. Kidney Int. 2015;87:623-31. [PMC free article: PMC4344931] [PubMed: 25229337]
• Tang X, Voskoboev NV, Wannarka SL, Olson JB, Milliner DS, Lieske JC. Oxalate quantification in hemodialysate to assess dialysis adequacy for primary hyperoxaluria. Am J Nephrol. 2014;39:376–82. [PMC free article: PMC4485608] [PubMed: 24776840]
• Toussaint C. Pyridoxine-responsive PH1: treatment. J Nephrol. 1998;11 Suppl 1:49–50. [PubMed: 9604811]
• van der Hoeven SM, van Woerden CS, Groothoff JW. Primary hyperoxaluria type 1, a too often missed diagnosis and potentially treatable cause of end-stage renal disease in adults: results of the Dutch cohort. Nephrol Dial Transplant. 2012;27:3855–62. [PubMed: 22844106]
• van Woerden CS, Groothoff JW, Wijburg FA, Duran M, Wanders RJA, Barth PG, Poll-The BT. High incidence of hyperoxaluria in generalized peroxisomal disorders. Mol Genet Metab. 2006;88:346–50. [PubMed: 16621644]
• Violier P, Boyer O, Berthaud R, Dorval G. Treatment with stiripentol in a patient with primary hyperoxaluria type 1: lesson for the clinical nephrologist. J Nephrol. 2022;35:1049-51. [PubMed: 34283403]
• Williams EL, Acquaviva A, Chevalier F, Coulter-Mackie B, Monico C, Giachino D, Robbiano A, Salido E, Waterham H, Rumsby G. Primary hyperoxaluria type 1: Update and additional mutation analysis of the AGXT gene. Hum Mut. 2009;30:910–7. [PubMed: 19479957]
• Witting C, Langman CB, Assimos D, Baum MA, Kausz A, Milliner D, Tasian G, Worcester E, Allain M, West M, Knauf F, Lieske JC. Pathophysiology and treatment of enteric hyperoxaluria. Clin J Am Soc Nephrol. 2021;16:487–95. [PMC free article: PMC8011014] [PubMed: 32900691]
• Woodward G, Pryke R, Hoppe B, Rumsby G. Rapid liquid chromatography tandem mass-spectrometry screening method for urinary metabolites of primary hyperoxaluria. Ann Clin Biochem. 2019;56:232–9. [PubMed: 30373392]
• Worcester EM, Coe FL. Calcium kidney stones. N Engl J Med. 2010;363:954–63. [PMC free article: PMC3192488] [PubMed: 20818905]
• Zhao F, Bergstralh EJ, Mehta RA, Vaughan LE, Olson JB, Seide BM, Meek AM, Cogal AG, Lieske JC, Milliner DS., Investigators of Rare Kidney Stone Consortium. Predictors of incident ESRD among patients with primary hyperoxaluria presenting prior to kidney failure. Clin J Am Soc Nephrol. 2016;11:119–26. [PMC free article: PMC4702224] [PubMed: 26656319]
• Zhao Y, Li Y, Fang X, He L, Fan Y, Geng H, Wu J. Extended genetic analysis of exome sequencing for primary hyperoxaluria in pediatric urolithiasis patients with hyperoxaluria. Gene. 2022;815:146155. [PubMed: 34995728]
• Zheng R, Fang X, Chen X, Huang Y, Xu G, He L, Li Y, Niu X, Yang L, Wang L, Li D, Geng H. Knockdown of lactate dehydrogenase by adeno-associated virus-delivered CRISPR/Cas9 system alleviates primary hyperoxaluria type 1. Clin Transl Med. 2020;10:e261. [PMC free article: PMC7752156] [PubMed: 33377632]