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Primary Hyperoxaluria Type 1

, PhD, , MD, , PhD, and , MD, MSc, FRCSC.

Author Information
, PhD
Pediatrics (Biochemical Diseases)
BC Children's Hospital and BC Women's Hospital & Health Centre
Vancouver, Canada
, MD
Pediatrics (Nephrology)
BC Children's Hospital and BC Women's Hospital & Health Centre
Vancouver, Canada
, PhD
Department of Urologic Sciences
University of British Columbia
Vancouver, Canada
, MD, MSc, FRCSC
Department of Urologic Sciences
University of British Columbia
Vancouver, Canada

Initial Posting: ; Last Update: July 17, 2014.

Summary

Clinical characteristics.

Primary hyperoxaluria type 1 (PH1) is caused by a deficiency of the liver peroxisomal enzyme alanine:glyoxylate-aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine. When AGT activity is absent, glyoxylate is converted to oxalate, which forms insoluble calcium salts that accumulate in the kidney and other organs. Individuals with PH1 are at risk for recurrent nephrolithiasis (deposition of calcium oxalate in the renal pelvis/urinary tract), nephrocalcinosis (deposition of calcium oxalate in the renal parenchyma), or end-stage renal disease (ESRD) with a history of renal stones or calcinosis. Age at onset of symptoms typically ranges from one to 25 years. Approximately 19% of affected individuals present before age four to six months with severe disease, often associated with failure to thrive, nephrocalcinosis, anemia, and metabolic acidosis. Approximately 54% of affected individuals present in late childhood or early adolescence, usually with symptomatic nephrolithiasis. The remainder of affected individuals present in adulthood with recurrent renal stones. The natural history of untreated PH1 is one of inexorable decline in renal function as a result of progressive nephrolithiasis/nephrocalcinosis, with eventual progression to oxalosis (widespread tissue deposition of calcium oxalate) and death from ESRD.

Diagnosis/testing.

The diagnosis of PH1 is suspected in an individual with an elevated oxalate to creatinine ratio in urine and an elevated plasma oxalate concentration. The diagnosis can be confirmed by detection of biallelic pathogenic variants in AGXT on molecular genetic testing. Failure to detect at least one common, known, or otherwise proven AGXT pathogenic variant requires consideration of liver biopsy to assay the activity of the enzyme alanine:glyoxylate-aminotransferase (AGT).

Management.

Treatment of manifestations: Reduction of calcium oxalate supersaturation and oxalate biosynthesis; organ transplantation as either preemptive liver transplantation or combined liver/kidney transplantation. For kidney stones: consider shockwave lithotripsy, percutaneous nephrolithotomy, or ureteroscopy.

Prevention of primary manifestations: Maintenance of high fluid intake; pyridoxine supplements for those who are pyridoxine responsive; use of potassium or sodium citrate, pyrophosphate-containing solutions, or thiazides to minimize stone formation.

Surveillance: Regular renal ultrasound and fundoscopic eye examinations; ongoing urinalysis; regular measurement of glomerular filtration rate (GFR). Additionally:

  • In those with reduced GFR: regular measurement of plasma oxalate.
  • In patients with greatly reduced GFR or rapid deterioration in function: multi-system testing prior to initiation of dialysis

Agents/circumstances to avoid: Dehydration; foods high in oxalate (e.g., chocolate, rhubarb, and starfruit); megadoses of vitamins C and D; loop diuretics.

Evaluation of relatives at risk: Early diagnosis of at-risk relatives enables early institution of treatment and preventive measures.

Genetic counseling.

PH1 is inherited in an autosomal recessive manner. At conception, each sib of a proband with PH1 has a 25% risk of being affected, a 50% risk of being an asymptomatic carrier, and a 25% risk of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if both pathogenic variants have been identified in a family. Assay of AGT enzymatic activity prenatally is not generally offered because it requires a fetal liver biopsy.

Diagnosis

Suggestive Findings

Primary hyperoxaluria type 1 (PH1) is suspected in a proband with any of the following [Milliner 2005, Bobrowski & Langman 2008, Cochat et al 2012]:

  • Frequent recurrent nephrolithiasis (deposition of calcium oxalate stones in the renal pelvis/urinary tract). Renal ultrasound examination often reveals bilateral and multiple radiopaque calculi [Jamieson et al 2000, Hoppe et al 2009].
    Note: (1) Computed tomography (CT) and kidney ureter bladder (KUB) x-ray may demonstrate similar findings. (2) CT scan is more sensitive than KUB in the detection of stones [Barrett & Danpure 1999]; however, one must consider the radiation risk associated with CT.
  • Stone composition of pure calcium oxalate monohydrate (whewellite). PH1 calculi also demonstrate peculiar morphologic characteristics including a whitish or pale yellow surface and a distinct crystalline structure, not found in stones formed as a result of other hyperoxaluric states [Daudon et al 2008].
  • Nephrocalcinosis (deposition of calcium oxalate in the renal parenchyma), in particular if associated with decreased glomerular filtration rate (GFR). In older children or adults, the strongest echoes are from the corticomedullary regions, whereas in infants the pattern is more likely to be that of diffuse nephrocalcinosis with few if any observable discrete stones.
    Note: Computed tomography (CT) and kidney ureter bladder (KUB) x-ray may demonstrate similar findings.
  • The finding of oxalate crystals in any biologic fluid or tissue [Cochat et al 2012].
  • A child with a first kidney stone [Cochat et al 2012].
  • A child younger than age six to 12 months with failure to thrive [Cochat & Rumsby 2013].
  • End-stage renal disease (ESRD) with a history of renal stones or calcinosis

Note: PH1 is often associated with nephrocalcinosis, anemia, and metabolic acidosis [Cochat et al 1999]. Most affected individuals are symptomatic before age ten years [Sikora et al 2008]. In rare cases, diagnosis may be complicated by co-occurrence of more common unrelated kidney disorders [Devriendt et al 2011]. See Testing Strategy for algorithms to aid in diagnosis and treatment.

Preliminary Testing

Urinary oxalate-to-creatinine molar ratio. Wherever possible, preliminary testing should include a 24-hour urine collection for oxalate and creatinine. Note: In the absence of a 24-hour sample, random urine samples are acceptable.

At any age urinary oxalate excretion persistently above 0.7 mmol/1.73 m2 per day or above the age-related reference range(s) (Table 1) warrants further diagnostic evaluation [Milliner 2005].

Note: (1) Those individuals who present in adulthood often have urinary oxalate excretion at the lower range of hyperoxaluria values [Watts 1998]. (2) Urinary excretion of creatinine on a per-kg basis differs between males and females and does not stabilize until ages 14 to 18 years [Remer et al 2002].

Concentration of glycolic acid (glycolate). Wherever possible, preliminary testing should include a 24-hour urine collection for glycolate. Measurement of glycolate in urine depends on either reversed phase high-pressure liquid chromatography or ion chromatography.

Normal ranges (Table 1) are defined for each separate assay [Petrarulo et al 1998]:

Thus, hyperglycolic aciduria suggests but does not confirm the diagnosis of PH1 in an individual with hyperoxaluria.

Table 1.

Normal Values for Urinary Oxalate, Glycolate, and L-Glycerate Excretion in 24-Hour Urine and Spot Urine Samples

ParameterAgeNormal Values 1
In 24-hour urine samples
Urinary oxalate excretion 2All ages<0.50 mmol (<45 mg)/1.73 m2/day
Urinary glycolate excretion<0.50 mmol (<45 mg)/1.73 m2/day
Urinary l-glyceric acid excretion<5 μmol/L
In spot urine samples
Spot urinary oxalate-to-creatinine molar ratio 20-6 mos 3<325-360 mmol/mol
7-24 mos 3<132-174 mmol/mol
2-5 yrs<98-101 mmol/mol
5-14 yrs<70-82 mmol/mol
>16 yrs<40 mmol/mol
Spot urinary glycolate-to-creatinine molar ratio0-6 mos 3<363-425 mmol/mol
7-24 mos 3<245-293 mmol/mol
2-5 yrs<191-229 mmol/mol
5-14 yrs<166-186 mmol/mol
>16 yrs<99-125 mmol/mol
Spot urinary l-glycerate-to-creatinine molar ratio0-6 mos 314-205 mmol/mol
7-24 mos 314-205 mmol/mol
2-5 yrs14-205 mmol/mol
5-14 yrs23-138 mmol/mol
>16 yrs<138 mmol/mol

Adapted from Hoppe [2012]

1.

Values are laboratory and method dependent.

2.

To prevent alkaline conversion of ascorbate to oxalate in urine, the sample must be strongly acidified to stabilize ascorbate and minimize formation of calcium crystals [Marangella & Petrarulo 1995].

3.

In children younger than age 1.5-2.0 years, rapidly changing glomerular filtration rates make the interpretation of oxalate to creatinine ratio of little practical value [Applegarth, personal communication]. Normal newborns and young infants/children can excrete ≥3-5 times the amount of oxalate excreted by adults; this amount slowly decreases into the normal adult range in the older child [Leumann et al 1990, von Schnakenburg et al 1994, Marangella & Petrarulo 1995].

Concentration of L-glycerate. Elevation of this urinary metabolite is often seen, but not pathognomonic for either PH1 [Cochat & Rumsby 2013] or primary hyperoxaluria type 2 (PH2) (see Differential Diagnosis) [Rumsby et al 2001].

Concentration of HOG (4-hydroxy-2-oxoglutarate). Increased levels of this urinary metabolite have been seen in conjunction with the presumed diagnosis of PH3 [Belostotsky et al 2012].

Urinary calcium. Individuals with PH1 and PH2 often have hypocalciuria; though those with PH3 often demonstrate significant hypercalciuria [Williams et al 2012].

Plasma concentration of oxalate. Plasma oxalate concentration exceeding the upper limit of the normal range when corrected for renal function is consistent with but not diagnostic of primary hyperoxaluria. Individuals with primary hyperoxaluria type 1 usually have plasma oxalate levels two to five times the upper limit of normal. Of note, in their recent review Cochat & Rumsby [2013] contend that plasma oxalate concentrations higher than 50 µmol/L regardless of renal function would be very suggestive of PH1.

When the GFR is known to be reduced (<60 mL/min/1.73 m2), plasma oxalate concentration should be measured and monitored regularly (at least annually).

Note: (1) Pediatric normal ranges are defined for the specific assay used [Petrarulo et al 1998] and are affected by the degree of renal dysfunction and/or need for dialysis (see Table 2). (2) Interpretation of results warrants caution: in affected individuals with adequate renal function, elevation of plasma oxalate concentration may be modest; in individuals with end-stage renal disease, absolute excretion of oxalate and glycolic acid is lower even with a very high plasma oxalate concentration [Hoppe et al 2009, Danpure 2014]. (3) In plasma, the spontaneous occurrence of oxalogenesis requires stringent handling of the sample, including handling in a cold environment, immediate deproteinization, and freezing until assayed.

Table 2.

Plasma Oxalate Concentrations in Individuals with PH1 by Renal Function

Individual with PH1 Stratified by Renal FunctionIndividual w/out PH1
GFR 20-30 mL/min/1.73 m2GFR <20 mL/min/1.73 m2 or ESRD 1Maintenance HD 2Maintenance HD 2
Plasma oxalate concentration 3>2 µmol/L>20 µmol/L50 - >100 µmol/L10-40 µmol/L

m2 = meters squared

GFR = glomerular filtration rate

HD = hemodialysis

1.

End-stage renal disease but not on dialysis

2.

Sample drawn pre-dialysis

3.

Individual without PH1 normal value <2.5 µmol/L based on oxalate oxidase assay

Confirming the Diagnosis

The diagnosis of PH1 can be confirmed by detection of biallelic pathogenic variants in AGXT on molecular genetic testing (Table 3). Of note, molecular genetic testing is indicated in all patients as genotype information helps predict treatment responses (see Genotype-Phenotype Correlations) [Harambat et al 2010].

If molecular genetic testing fails to detect at least one common, known, or otherwise proven AGXT pathogenic variant, liver biopsy for the purpose of assaying alanine:glyoxylate-aminotransferase (AGT) enzyme activity (see Assay of AGT catalytic activity below) needs to be considered.

Molecular Genetic Testing

One genetic testing strategy is testing of AGXT that may begin with EITHER sequence analysis [Monico et al 2007] OR targeted analysis for pathogenic variants or sequencing of selected exons.

If only one pathogenic variant is identified, follow with sequence analysis of exons and flanking intronic regions [Williams & Rumsby 2007, Coulter-Mackie et al 2008].

Deletion/duplication analysis may be useful if only one pathogenic variant has been identified or if hemizygosity is suspected. However, so far, only six of more than 170 known pathogenic variants are of the type that would be detectable by this approach.
Note: Typically, testing is included for the two common AGXT polymorphic variants defined most importantly by the presence of a proline or a leucine at amino acid residue. Although the p.Pro11Leu variant, referred to as the “minor allele,” does not cause PH1 by itself, it is known to exacerbate the deleterious effects of other pathogenic variants in cis configuration. See Molecular Genetics. The most common pathogenic variant c.508G>A (p.Gly170Arg) occurs in cis configuration with the “minor allele,” while the second most common pathogenic variant c.33dupC (p.Lys12GlnfsTer156) occurs in cis configuration with the “major allele” (see Table 3, footnote 2 and Molecular Genetics, “Major” and “minor” AGXT alleles).

An alternative genetic testing strategy is use of a multi-gene panel that includes AGXT (mutation of which causes PH1), GRHPR (mutation of which causes PH2) and HOGA1 (mutation of which causes PH3) (see Differential Diagnosis). Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

Table 3.

Summary of Molecular Genetic Testing Used in Primary Hyperoxaluria Type 1

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
AGXTTargeted analysis for pathogenic variants 2, 350%-70% 4
Sequence analysis 3, 5, 6100% 7
Deletion/duplication analysis 8<3% 9
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants.

2.

Targeted analysis for pathogenic variants refers to testing for specific common AGXT pathogenic variant(s). Pathogenic variants included in a panel may vary by laboratory but generally include the two most common pathogenic variants, c.508G>A (p.Gly170Arg) and c.33dupC (p.Lys12GlnfsTer156). At least 50% of uncharacterized European and North American individuals with PH1 have at least one p.Gly170Arg pathogenic allele [Rumsby et al 2004], which is specifically associated with mistargeting of AGT to the mitochondria. The c.33dupC pathogenic allele is the second most common variant [Pirulli et al 1999, Coulter-Mackie et al 2004]. The choice of less common pathogenic variants for targeted analysis for pathogenic variants may be influenced by the ethnic background of the affected individual [Coulter-Mackie 2005].

3.

Generally, analysis includes testing for the AGXT “minor” or “major allele” status. See Molecular Genetics, “Major” and “minor” AGXT alleles.

4.

Molecular genetic testing for the four most common pathogenic variants identifies both alleles in approximately 34% of individuals with PH1 and one allele in approximately 28% [Rumsby et al 2004]. A panel including the four common pathogenic variants plus an additional group of recurrent pathogenic variants detected at least one pathogenic variant in 83% of individuals with PH1 and both pathogenic variants in 51% [Coulter-Mackie et al 2008]. Sequencing of selected exons (1,4, and 7) detected at least one pathogenic variant in 70% and both in 50% [Williams & Rumsby 2007, Williams et al 2009].

5.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6.

Sequence analysis can detect the common and rare AGXT pathogenic variants included in the targeted analysis panels.

7.

In individuals with enzymatically confirmed PH1 or one common AGXT pathogenic variant already identified [Coulter-Mackie et al 2008]

8.

Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

9.

Out of more than 170 known AGXT pathogenic variants, six large deletions have been reported [Nogueira et al 2000, Coulter-Mackie et al 2001, Coulter-Mackie et al 2005, Monico et al 2007, Williams et al 2009, Tammachote et al 2012]. The sensitivity of this approach is expected to be low.

Biochemical Testing

Assay of alanine:glyoxylate-aminotransferase (AGT) enzyme (EC 2.6.1.44) catalytic activity requires at least 2 mg of liver taken by percutaneous needle biopsy or at autopsy. Several methods in use:

Note: (1) Approximately 50%-70% of affected individuals have undetectable levels of AGT catalytic activity, and approximately 30%-50% of affected individuals have substantial residual AGT catalytic activity (2%-48% of mean normal activity) [Danpure 2014]. In many human metabolic disorders, this level of residual activity is sufficient for normal function. Most individuals with classic PH1 who have residual AGT enzymatic activity have a unique protein-targeting (or trafficking) defect in which functional AGT enzyme is synthesized in adequate amounts but approximately 90% of the enzyme produced is mislocalized to mitochondria and only approximately 10% is properly localized in the peroxisomes (where it catalyzes the glyoxylate substrate). Individuals with such a protein-trafficking defect have classic PH1 despite the presence of residual AGT activity. (2) The detection of a mistargeting pathogenic variant (See Molecular Genetics, “Major” and “minor” AGXT alleles) clarifies the significance of high residual AGT enzyme activity (when the diagnosis of PH1 has been established by liver biopsy and AGT enzyme assay), helping to distinguish between mislocalized AGT enzyme (i.e., classic PH1) and true partial AGT enzyme activity (no known associated phenotype).

Testing Strategy

To confirm/establish the diagnosis in a proband. An evidence-based guideline for diagnosis that incorporates aspects of clinical and laboratory approaches to the diagnosis of primary hyperoxaluria has been developed [Harambat et al 2011] (see Figure 1). The intent of this algorithm is to facilitate recognition and diagnosis of affected individuals and to enable earlier treatment. The algorithm also assists the clinician in differentiating between PH types 1, 2, and 3 and provides guidance as to best-evidence conservative management of the conditions:

Figure 1.

Figure 1.

Proposed algorithm for the diagnosis and conservative treatment of primary hyperoxalurias

PH = primary hyperoxaluria
GFR = glomerular filtration rate
Uox = urinary oxalate
Pox = plasma oxalate
CaOx = calcium (more...)

  • Measurement of urinary and plasma metabolites is a screening test (see Preliminary Testing). Restrict plasma oxalate measurements to GFR <30-45 mL/min/1.73 m2 (chronic kidney disease [CKD] Category 3b or lower).
  • Finding of known biallelic (homozygous or compound heterozygous) AGXT pathogenic variants confirms the diagnosis of PH1. Finding of one AGXT pathogenic variant in a symptomatic individual strongly supports the diagnosis.

Prognostic testing for affected individuals. Testing for the presence of the specific pathogenic variants p.Gly170Arg and p.Phe152Ile, if not already determined through molecular genetic analysis, may have predictive value as these pathogenic variants are associated with a positive response to pyridoxine supplementation especially for homozygotes [van Woerden et al 2004, Monico et al 2005a, Monico et al 2005b]. Among the known pathogenic variants, p.Gly170Arg is associated with a better prognosis [Hoppe 2010]. See Genotype-Phenotype Correlations.

Clinical Characteristics

Clinical Description

In primary hyperoxaluria type 1 (PH1), supersaturation of the urine with oxalate leads to nephrolithiasis/nephrocalcinosis, renal tubular damage, and renal failure with eventual development of systemic manifestations (oxalosis) [Marangella et al 2001]. The presentation of PH1 is variable. Age at onset of symptoms ranges from birth to the sixth decade (median age: 5-6 years) [Lieske et al 2005b]; exceptions occur.

Approximately 19% of affected individuals present with a severe, very early-onset form of PH1 in the first few months of life. At the other end of the spectrum of clinical severity seen in PH1, some individuals remain apparently asymptomatic for more than 40-50 years [Danpure 2014].

Renal manifestations. Overall the renal manifestations of PH1 can be quite variable, with individuals generally falling into one of five groups [Cochat et al 2010]:

  • Early nephrocalcinosis and renal failure leading to a diagnosis in infancy or early childhood (infantile form)
  • Recurrent urolithiasis and progressive renal failure with diagnosis in childhood or adolescence
  • Late onset form with occasional stones diagnosed in adulthood
  • Diagnosis secondary to recurrence following renal transplantation
  • Diagnosis in a presymptomatic individual because of a positive family history

While the median age for end-stage renal disease (ESRD) in PH1 is 24 years [Bergstralh et al 2010], ESRD can appear as early as age six months and is present in 50% of children at the time of diagnosis [Cochat et al 1999]. In approximately 10%, the presentation/diagnosis of PH1 is made only following a renal transplant [Cochat & Rumsby 2013]; in 20%-50%, PH1 will be diagnosed at the time of their presentation in the late stages of chronic kidney disease (CKD) or even ESRD [Harambat et al 2012, van der Hoeven et al 2012].

No validated tools are available to predict the renal course in PH1; however, Diallo et al [2004] described two patterns on renal ultrasound examination in individuals known to have PH1 and determined that all five individuals with cortical nephrocalcinosis developed ESRD, in contrast to 2/8 with medullary nephrocalcinosis.

Also in evaluating the response of 12 individuals with PH1 to vitamin B6, Hoyer-Kuhn et al [2014] suggested that disease severity and long-term outcomes could depend on the presence of the c.508G>A (p.Gly170Arg) pathogenic variant, with worse outcomes expected in patients who did not have this pathogenic variant. See Reduction of Oxalate Biosynthesis.

From the authors’ experience 19% of affected individuals present before age four to six months with severe early-onset (infantile) disease. In this group, presenting signs and symptoms include: nephrocalcinosis (91%) with or without nephrolithiasis (21%), failure to thrive (22%), urinary tract infection (21%), and uremia (14%). Early death is common; 50% have ESRD at diagnosis and 80% develop ESRD by age three years [Cochat et al 1999, Millan et al 2003]. The severity of infantile-onset PH1 is illustrated in case reports [Mayordomo-Colunga et al 2011].

Some affected infants are pyridoxine sensitive and show improvement in renal function with high-dose vitamin B6 therapy [van Woerden et al 2003]. Case reports emphasize the importance of early diagnosis and prompt initiation of appropriate therapy [Patwardhan & Higgins 2005, Khoo et al 2006, Chand & Kaskel 2009, Fargue et al 2009, Orazi et al 2009].

Approximately 54% of individuals present in late childhood or early adolescence. Although hematuria, dysuria, and urinary tract infections occur, nephrolithiasis is the most common presentation. In contrast, the presenting finding in the younger child is more likely to be recurrent urinary tract infections or enuresis [Watts 1998, Milliner 2005].

The remainder of affected individuals present in adulthood with recurrent renal stones [Amoroso et al 2001]. For many of these adults, the diagnosis was either previously missed or delayed. Some individuals, mainly adults, may present with acute renal failure secondary to bilateral renal obstruction caused by oxalate stones. A higher prevalence of ESRD without a prior history of renal stones was observed in a national study from the Netherlands [van Woerden et al 2003].

The natural history of untreated PH1 is one of inexorable decline in renal function as a result of progressive nephrolithiasis/nephrocalcinosis, with eventual progression to oxalosis and certain death from ESRD and/or complications of oxalosis in the absence of treatment [Watts 1998, Cochat & Rolland 2003, Bobrowski & Langman 2008, Hoppe et al 2009].

In children with PH1, survival was only 76% following initiation of renal replacement therapy, the need for which occurred at a median age of only 1.5 years and carried an overall three times higher risk of death than ESRD due to any other cause [Harambat et al 2012].

Oxalosis. When the glomerular filtration rate (GFR) is less than 25 mL/min/1.73 m2, the daily production of oxalate far outstrips renal oxalate clearance, resulting in a rapid decline in residual renal function with a concurrent increase in body oxalate stores (oxalosis) [Watts 1998, Milliner 2005, Cochat et al 2006]. Oxalosis is the deposition of oxalate in a variety of tissues, including the kidneys, retina, myocardium, bone marrow, blood vessels, retina, heart, peripheral nerves, bone and bone marrow, subcutaneous tissue, and synovia [Watts 1998]. Table 4 outlines both the organ involved and associated symptoms as well as suggested diagnostic imaging or testing.

Bone is the largest repository for excess oxalate. Deposition of oxalate in bone, commonly identified as dense suprametaphyseal bands on x-ray, may lead to pain, erythropoietin-resistant anemia, and spontaneous fracture [Cochat et al 2006]. Bone mineral density measurements, as opposed to the gold standard of bone biopsy, allow for noninvasive assessment of oxalate burden [Behnke et al 2001].

Atherosclerotic oxalosis. A distinct form of cardiovascular involvement in oxalosis is the deposition of calcium oxalate crystals in atherosclerotic plaques of the coronary artery and other sites in the absence of renal insufficiency [Fishbein et al 2008].

Oral conditions associated with oxalosis. A number of oral or dental conditions have been described in PH1/oxalosis including dental pain due to oxalate deposition, root resorption, and rapidly appearing dental mobility [Mitsimponas et al 2012].

Neurologic oxalosis. Although it is extremely uncommon for PH1 to present with stroke/infarct, two case reports describe stroke/infarct with evidence for calcium oxalate in the cerebral vessels or one possibly with microemboli consisting of circulating oxalate in supersaturated form [Rao et al 2014].

Table 4.

Organ Involvement in Individuals with PH and Renal Failure

InvolvmentOrganSymptomsDiagnosis
AlwaysKidney
  • Stones
  • Medullary or diffuse nephrocalcinosis
  • Cortical nephrocalcinosis
US, CT (cortical nephrocalcinosis may be missed on US)
FrequentBone
  • Fractures
  • Bone pain
  • Growth retardation
X-ray
Eye
  • Disturbed vision
  • Specific brown colored retinal deposits
Fundoscopy
OftenArteries
  • Media calcifications
US, CT
Myocardium
  • Cardiac failure
  • Arrhythmia
  • Heart block
  • Left ventricular hypertrophy
  • Systolic and diastolic dysfunction
ECG, echocardiography, CT (calcifications)
Thyroid
  • Hypothyroidism
US, thyroid function tests
Less oftenSkin
  • (Painful) skin nodules
  • Skin necrosis
  • Gangrene
  • Calciphylaxis-like skin lesions
  • Pruritus
Skin biopsy
Nerves
  • Ischemic neuropathy
Clinical assessment
Muscle
  • Myopathy by CaOx deposition
Biopsy, CT
Bowel
  • Prolonged oxalosis (depositions of CaOx in the intestinal wall)
CT
Joints
  • Arthritis (late sign)
X-ray, CT

US = ultrasound

CT= computed tomography

Pregnancy. Pregnancy does not appear to be an important risk factor for the development of ESRD in the majority of women with PH1 [Norby & Milliner 2004]; however, women in whom renal function deteriorated during the pregnancy and remained abnormal post-delivery have been reported [Cimino et al 2005]. Following pregnancy women are at increased risk for stone formation.

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

Generally, the offspring of women with PH1 have done well [Norby & Milliner 2004].

Pathophysiology

The stone type that is most prevalent in individuals with PH1 is calcium oxalate monohydrate or whewellite [Daudon et al 2008]. These authors noted that stones from patients with PH differ in morphologic characteristics from idiopathic calcium oxalate stone formers: they appear white or pale-yellow on the surface and form a loose, unorganized section whereas idiopathic oxalate stone formers appear as a dark-brown surface with a well-organized radiating inner structure. These differences in morphology suggest a different mechanism of stone formation from idiopathic oxalate stones.

Genotype-Phenotype Correlations

Although other genetic and environmental factors play a role in determining the course of PH1 [Hoppe 2010], pathogenic variants that result in mistargeting of AGT enzyme activity (see Molecular Genetics, Abnormal gene product) are the most likely to be associated with B6 (pyridoxine) responsiveness [Monico et al 2005a, Danpure 2014] which is mediated by the effect of B6 on catalytic activity, perixosomal import, and protein stability [Fargue et al 2013a, Fargue et al 2013b].

  • Homozygotes for either c.508G>A (p.Gly170Arg) or c.454T>A (p.Phe152Ile) show B6 responsiveness and benefit from early treatement (see Management).
  • Response to B6 therapy is relative to the number of copies of the p.Gly170Arg pathogenic variant present [Monico et al 2005a, Monico et al 2005b].
  • Results of in vitro studies suggest that additional pathogenic variants may respond to B6, reinforcing the recommendation of testing all patients for B6 responsiveness [Fargue et al 2013a].

The presence of the p.Gly170Arg pathogenic variant could even predict disease severity and/or rate of progression [Hoyer-Kuhn et al 2014]. A large retrospective study of individuals with PH1 suggested that the p.Gly170Arg pathogenic variant is associated with longer preservation of renal function with conservative treatment compared to other pathogenic variants [Harambat et al 2010].

Although it may be possible to establish a relationship between the AGXT genotype and AGT enzyme activity in vitro, in most cases it is difficult to correlate enzyme activity with clinical severity [Pirulli et al 2003, Danpure & Rumsby 2004, van Woerden et al 2004, Danpure 2014].

Although the clinical course of PH1 in affected sibs is usually similar, families in which affected relatives with identical pathogenic variants had different disease manifestations have been described [Frishberg et al 2005, Beck & Hoppe 2006, Lorenzo et al 2006, Mandrile et al 2008, Alfadhel et al 2012]. Possible causes of this intrafamilial variation include differences in activity level of other enzymes important in oxalate synthesis, modifier genes, the quantity of oxalate precursors in the diet, renal oxalate handling, absorption of dietary oxalate, hydration status, infections, and urinary crystallization factors [Danpure 2014].

Other than potential delay in diagnosis due to the rarity of PH1, the reason for a poorer outcome in infants with the same pathogenic variants as older individuals is not clear. Possibilities include:

  • The low glomerular filtration rate (GFR) (both absolute and corrected) in children under age six to 12 months, which predisposes to earlier oxalate deposition [Quigley 2012]
  • High oxalate excretion in infants (Table 1)
  • Reduced number of nephrons present at birth, which may be associated with low birth weight as well as environmental and genetic factors [Luyckx & Brenner 2005, Puddu et al 2009, Luyckx & Brenner 2010]

Nomenclature

With the identification of oxalate in human urine in the 1800s, hyperoxaluria fell into a category referred to as "oxalate diathesis" – a catch-all term for a wide variety of ailments.

PH1 can be considered a peroxisomal disorder, as it results from deficiency of a single peroxisomal enzyme. PH1, however, is distinct from disorders of peroxisomal biogenesis (see Peroxisomal Biogenesis Disorders, Zellweger Type and Rhizomelic Chondrodysplasia Punctata Type 1) in that a normal number of relatively normal-looking peroxisomes are observed on liver biopsy.

Prevalence

PH1 is estimated to account for 1%-2% of children with end-stage renal disease (ESRD) [Harambat et al 2012].

When considering the following statistics, it is important to remember that PH1 remains underdiagnosed because of the wide variability in its clinical presentation and age of onset.

The prevalence of PH1 ranges from 1:1,000,000 to 3:1,000,000 depending on the population studied and the methods of ascertainment [van Woerden et al 2003, Hoppe et al 2005, Danpure 2014]; incidence ranges from 4:1,000,000 to 10:1,000,000 depending on the population [Applegarth et al 2000, Danpure 2014]. PH1 is estimated to occur in 1:120,000 live births in Europe [Cochat et al 2006].

An increased frequency of PH1 (≤10%) has been reported in Tunisia and Kuwait [Kamoun & Lakhoua 1996, Al-Eisa et al 2004, Cochat et al 2006], in Arabs and Druze families of Israel [Rinat et al 1999], and in Iran [Madani et al 2001] as a result of the high rate of consanguinity in these populations. No single pathogenic variant is present in these populations [Coulter-Mackie 2005] [Rinat et al 1999, Frishberg et al 2005]. Of note, in Tunisia an association was identified between specific pathogenic variants and geographic location within the country [Nagara et al 2013].

Differential Diagnosis

Primary hyperoxaluria type 2 (PH2) is caused by mutation of GRHPR, resulting in deficiency of the cytosolic enzyme glyoxylate reductase – hydroxypyruvate reductase (GRHPR), which catalyzes the reduction of glyoxylate and hydroxypyruvate to D-glycerate. While found in many tissues, GRHPR is mainly found in hepatocytes with some expression in mitochondria [Cregeen et al 2003, Belostotsky et al 2010]. In PH2, glyoxylate removal is impaired, resulting in the metabolism of glyoxylate by lactate dehydrogenase to oxalate and L-glycerate. The diagnosis of PH2 can be established by sequence analysis of GHPRH or assay of GRHPR enzymatic activity in liver. Inheritance is autosomal recessive.

PH2 is rarer than PH1.

From a small cohort of individuals with PH1 and PH2 from one center, PH1 as a group appears to differ from PH2 in the following respects:

  • PH2 is considered a less aggressive disease than PH1, even when onset is early.
  • PH1 has statistically higher urine oxalate excretions and more stone-forming activity and thus requires more frequent stone removal.
  • Individuals with PH1 have statistically lower urine osmolalities and lower urine concentration of calcium, citrate, and magnesium [Milliner et al 2001]. (For a single individual with hyperoxaluria, the differences observed cannot reliably distinguish PH1 from PH2.)
  • In PH1, urinary glycolate and oxalate are elevated.
  • In PH2, urinary L-glycerate and oxalate are elevated [Danpure 2014]; however, exceptions exist.

Primary hyperoxaluria type 3 (PH3) is caused by a defect in the hepatocyte-specific mitochondrial enzyme 4-hydroxy-2-oxoglutarate aldolase (HOGA) [Belostotsky et al 2010], which appears to lead to excess metabolism of hydroxyproline with the forward reaction product (HOG) itself being converted to pyruvate or glyoxalate [Riedel et al 2011, Pitt et al 2015] or perhaps actually inhibiting mitochondrial GRHPR (effectively causing ‘secondary’ PH2) [Belostotsky et al 2012, Riedel et al 2012]. Elevated levels of oxalate and glycolate have been seen in about 5% of affected individuals [Monico et al 2002, Hoppe et al 2009]. Mutation of HOGA1 encoding 2-keto-4-hydroxy-glutarate aldolase is causative [Belostotsky et al 2010, Monico et al 2011, Belostotsky et al 2012, Williams et al 2012]. Diagnosis is by exclusion of PH1 and PH2 with confirmation by DNA sequence analysis of HOGA1. Inheritance is autosomal recessive.

See Hyperoxaluria, primary: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.

Enteric hyperoxaluria. Diseases affecting the small bowel, including celiac disease [Ciacci et al 2008], Crohn's disease, pancreatitis, and short bowel syndrome can be associated with hyperoxaluria. The precipitation of enteric calcium by non-absorbed free fatty acids leads to loss of the normal inhibition in oxalate reabsorption from the gut, increasing plasma oxalate concentration by increasing paracellular and transcellular transport. Delivery of excess fatty acids and bile salts to the colon also injures the mucosa and increases oxalate absorption [Milliner 2005, Hoppe et al 2009]. Individuals with PH1 show low to normal levels of oxalate absorption [Sikora et al 2008]. Gastric bypass procedures used in the treatment of obesity have been associated with increased oxalate absorption, high levels of hyperoxaluria, and increased risk of kidney stone formation [Asplin & Coe 2007, Kleinman 2007, Duffey et al 2008, Lieske et al 2008]. Urinary risk factors for stones such as hyperoxaluria occur more commonly in individuals with Roux-en-Y gastric bypass than gastric banding [Semins et al 2010, Kumar et al 2011, Tasca 2011].

Dietary hyperoxaluria. Excess intake of foods high in oxalate including chocolate, cocoa, leafy greens (especially rhubarb and spinach), black tea, nuts, peanut butter, or starfruit [Holmes & Kennedy 2000, Monk & Bushinsky 2000] may lead to elevated plasma concentration of oxalate and hence increased urinary concentration of oxalate.

It was previously thought that dietary oxalate accounted for little of the urinary oxalate levels (<10%), but Holmes et al [2001] showed that between 24% and 53% of urinary oxalate is attributable to oxalate from the diet [Holmes & Assimos 2004]. Therapy consists of dietary oxalate restriction and use of calcium carbonate or calcium citrate at meal times to bind dietary oxalate [Penniston & Nakada 2009].

Idiopathic calcium oxalate urolithiasis is associated with "mild metabolic hyperoxaluria." Features that often differentiate this from PH1:

  • Lower urinary oxalate excretion (see Table 5)
  • Less severe stone disease
  • Less common development of ESRD
  • Tendency to hypercalciuria as opposed to hypocalciuria in PH1 (or PH2)
  • Day-to-day variability in the levels of urinary oxalate excretion in contrast to PH1, in which levels are persistently elevated in the urine [Milliner 2005]

Table 5.

Urinary Oxalate Excretion Rates in Disorders Considered in the Differential Diagnosis of PH1

Customary Urinary Oxalate Excretion Rates 1
NormalIn Individuals with:
PH1PH2 2Enteric hyperoxaluriaDietary hyperoxaluriaIdiopathic calcium oxalate urolithiasis
<0.45>1
(usually >2)
>0.46>1
(fluctuates with diet)
<0.6<0.7

Based on data from algorithm in Milliner [2005], with permission from S Karger AG, publisher

1.

Calculated as mmol/1.73 m2/day

2.

PH2 information based on Kemper et al [1997]

Dent disease. The clinical features of Dent disease may overlap those of PH1. Both are associated with nephrocalcinosis and urolithiasis in childhood and progress to renal failure (see Table 6) [Milliner 2006].

Table 6.

Clinical and Diagnostic Features of Dent Disease and Primary Hyperoxaluria Type 1

Dent DiseasePH1
Clinical FeaturesNephrocalcinosis3+2+
Urolithiasis3+4+
Osteodystrophy1+1+ 1
Renal failure2+2+
Differentiating FindingsHypercalciuria1+
Hyperoxaluria3+
Low-molecular-weight proteinuria1+

2

GeneCLCN-5AGXT
InheritanceX-linkedAutosomal recessive
1.

After renal failure established

2.

May be observed following renal damage but not an early or characteristic finding

Other hereditary causes of kidney stones. A number of common and rare forms of nephrocalcinosis or urolithiasis may be associated with kidney disease [Monico & Milliner 2012, Edvardsson et al 2013].

  • A condition that may present with findings of nephrolcalcinosis in addition to PH1 or Dent disease is familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) (OMIM 248250).
  • While not associated with nephrocalcinosis, children with adenine phosphoribosyltransferase (APRT) deficiency (OMIM 614723) can develop crystal nephropathy and chronic kidney disease, as do children with PH and FHHNC.

Other. Acute renal failure secondary to oxalate deposition in the kidneys has occurred in persons taking large doses ("megadoses") of ascorbic acid (vitamin C) [Petrarulo et al 1998, Mashour et al 2000] as well as in a number of persons who were “juicing” (extraction of juice from vegetables or fruit) with high oxalate-containing foods [Getting et al 2013].

Ingestion of ethylene glycol, an oxalate precursor, can lead to excess production and increased concentrations of oxalate in both the plasma and urine [Milliner 2005].

Hyperoxaluria in association with total parenteral nutrition (TPN) has been described in premature infants [Sikora et al 2003] and adults [Buchman et al 1995].

Hyperoxaluria has been documented in peroxisomal biogenesis disorders, Zellweger spectrum despite the apparent cytoplasmic stability of AGT [van Woerden et al 2006]. The presence of hyperoxaluria was statistically correlated with the degree of neurologic involvement.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with primary hyperoxaluria type 1 (PH1), the following evaluations are recommended based on the guidelines and suggestions of Hoppe & Langman [2003], two recent reviews by the European Hyperoxaluria Consortium, OxalEurope [Cochat et al 2012] (see Table 4), and a recent review by Hoppe [2012].

The following are recommended in all cases:

  • Molecular genetic testing to determine the AGXT genotype if not already performed
  • Medical genetics consultation

The further extent of the initial evaluation of patients with PH1 should depend on their baseline renal function at the time of diagnosis and the evaluations performed as part of the diagnostic work up.

  • For those with preserved renal function (i.e., measured or estimated GFR >60 mL/min/1.73 m2):
    • Renal ultrasound examination and fundoscopic eye examination to identify the presence/extent of oxalate deposition
    • Baseline urinalysis (spot and 24 hour collection)
  • For those with a GFR <60 mL/min/1.73 m2. In addition to the above evaluations: measurement of plasma oxalate
  • For those with a GFR <30 mL/min/1.73 m2 or in whom there is a rapid deterioration in function. In addition to the above evaluations:
    • Bone x-rays to evaluate for radiodense metaphyseal bands and diffuse demineralization, potentially bone marrow examination may also be required
    • Thyroid function testing
    • Electrocardiogram to evaluate for an associated atrioventricular block
    • Ultrasound and/or CT scan of the heart and viscera allows evaluation of calcification in such organs
    • Hemoglobin to evaluate for anemia associated with either renal dysfunction or marrow deposition of oxalate
    • History and physical examination to assess the risk of arterial insufficiency or ischemia based on vessel wall deposition

Treatment of Manifestations

Reduction of Calcium Oxalate Supersaturation

The general therapies for nephrolithiasis benefit all individuals with PH1. Early diagnosis and initiation of conservative therapy are critical in preserving adequate renal function for as long as possible [Fargue et al 2009].

The following recommendations are universally embraced, and those listed here can all be found in the following recent reviews [Cochat et al 2012, Hoppe 2012, Cochat & Rumsby 2013].

  • Drinking large volumes of fluid (2-3 L/m2/24 hours) at regular intervals over the entire day/night prevents calcium oxalate supersaturation and is effective for all genotypes. Note that small children may require gastrostomy or nasogastric tube insertion for both feeds and fluid supplementation. Extreme care should be taken during any illness that could lead to hypovolemia or decreased oral fluid intake; patients should be advised to seek early medical attention.
  • Alkalinzation of urine (pH 6.2-6.8) to inhibit calcium oxalate crystallization can be targeted using oral potassium citrate at a dose of 0.1-0.15 mg/kg or 0.3-0.5 mmol/kg per day in 3-4 divided doses so long as the GFR is preserved. When the GFR is reduced or concerns about potassium levels ensue, alkalinization can be achieved with sodium citrate.
  • Moderate doses of pyrophosphate-containing solutions may also inhibit crystal formation, and may be dosed as 20-30 mg/kg per day of phosphate.
  • Drugs such as thiazides can decrease urinary calcium excretion and may inhibit stone formation, in particular in patients with PH3.
  • Any significant intake of vitamin C or D is to be avoided as both may promote stone formation.
  • Supplementation of dietary calcium (300 mg) or provision of supplemental calcium (300-500 mg) at each meal significantly has been shown to decrease urinary calcium oxalate without altering calcium excretion [Penniston & Nakada 2009]. While promising, this strategy remains unproven in individuals with PH1.
  • Dietary restriction of oxalate as such is not supported as being an effective therapy for patients with PH1, although the principle of careful food choices (avoid high oxalate food and drink) would seem reasonable.

Treatment of Kidney Stones

The stone type most prevalent in PH1 is calcium oxalate monohydrate or whewellite [Daudon et al 2008].

Patients must be counseled regarding the different success rates among the following three surgical modalities:

  • Shockwave lithotripsy (SWL) is a viable first option, but only if patients are willing to accept a lower success rate and higher rate of subsequent endoscopic surgery.
  • For larger, bulky stone burdens (>15 mm), percutaneous nephrolithotomy should be considered as first-line therapy.
  • Ureteroscopy holds a very good record for success of stone clearance with minimal complication rates and may be supplanting SWL as first-line therapy at many centers.

SWL. While SWL is often the first choice for treatment of kidney stones given its minimally invasive nature and requirement for only sedative anesthesia, its value has been questioned as the first-line treatment for stones in children with PH1 and PH2 as calcium oxalate monohydrate stones are among the hardest stones, and are thus more likely to be resistant to extracorporeal shockwave lithotripsy (SWL) [Williams et al 2003].

A retrospective review of 36 individuals with PH who were treated with SWL between 1987 and 2009 in Birmingham, UK revealed that those who were treated with SWL required more subsequent treatments to render them stone free [Al-Abadi & Hulton 2013]. Whereas SWL was effective in 43%, repeat SWL was required in 61%. Stones in the lower pole of the kidney or parenchymal stones did not respond as well to SWL as stones in other locations. There is good evidence that any given stone(s) should not be treated with more than two SWL sessions, particularly if no change is observed with treatment [Pace et al 2000].

Ureteroscopy. Of note, in the endourology literature the trend is toward endoscopic treatment (ureteroscopy) over SWL for all stone types because of its higher success rate, but with the recognition of a potentially higher complication rate and longer hospital stay [Aboumarzouk et al 2012, Matlaga et al 2012].

Percutaneous nephrolithotomy and ureteroscopy. In the cohort of Al-Abadi & Hulton [2013], percutaneous nephrolithotomy or ureteroscopy both resulted in better stone-free rates and lower retreatment rates. While the two latter modalities are more effective at rendering the patient stone free, they have higher rates of potential complications than SWL. Percutaneous nephrolithotomy is still the best modality for large, bulky stone burdens.

Reduction of Oxalate Biosynthesis

AGT is a pyridoxal phosphate (PLP)-dependent enzyme. Approximately 10%-30% of individuals with PH1 respond to treatment with pyridoxine (vitamin B6, precursor to PLP as defined by a greater than 30% reduction in plasma oxalate concentration or normalization of urinary oxalate excretion after a minimum of three months of maximal therapy [Watts et al 1985, Leumann & Hoppe 2001]. Of this group, only 40% show normalization and the other 60% a partial reduction in the concentration of plasma and urine oxalate [Toussaint 1998].

Monico et al [2005b] showed that the presence of the p.Gly170Arg pathogenic variant was associated with pyridoxine responsiveness — homozygotes showing normalization (urine oxalate concentration <0.5-0.7 mmol/1.73 m2/day) and compound heterozygotes demonstrating a partial reduction in plasma oxalate concentration by at least 30% of prior documented levels. The same result was seen in patients with at least one p.Phe152Ile pathogenic allele.

At present, two different approaches are used to titrate the pyridoxine dose:

  • A stepwise increase from initial low levels (1-2 mg/kg/day) [Bobrowski & Langman 2008]
  • Initial high doses to maximize oxalate removal, with subsequent reduction to establish the minimal effective dose

With either approach, doses of pyridoxine in the range of 5 mg/kg/day appear adequate in the treatment of those likely to respond, with no additional benefit expected at doses higher than 10 mg/kg/day [Monico et al 2005b, Bobrowski & Langman 2008, Hoppe et al 2009]. In adults, a dose of 500 mg is felt to remain below the toxic range. Paresthesias, a known complication of large doses of pyridoxine [Toussaint 1998], have only developed in one individual on a dose of 2.1 mg/kg/day and resolved following discontinuation of the drug.

Pyridoxal phosphate levels may be followed in individuals to ensure that adequate absorption is occurring [Harambat et al 2011].

Individuals responsive to pyridoxine should continue this therapy to decrease the burden of oxalate on the kidney, even when on hemodialysis or following successful kidney transplantation.

Note: It is recommended that all patients with PH1, even those diagnosed in ESRD and on dialysis, receive a minimum three-month trial of pyridoxine at the time of initial diagnosis [Milliner 2005].

Dialysis

The issues related to the removal of oxalate and current modalities of dialysis are quite complex. Interested readers are directed to two papers outlining the specific details of extracorporeal removal of oxalate [Cochat et al 2012, Plumb et al 2013].

In brief, despite the small size of the oxalate molecule (90 daltons), the rate of oxalate production in persons with PH1-related ESRD (4-7 mmol/1.73 m2/day) vastly outstrips the ability to remove it via conventional dialysis in adults (1-2 mmol/1.73 m2/day) or children (3-4 mmol/1.73 m2/day). The sequestration of oxalate in tissue compartments outside the vascular space makes it difficult to effectively remove it from the body. Current guidelines suggest that the intent of dialysis is to reduce and maintain the plasma oxalate level as long as possible below 30-45 µmol/L (the calcium/oxalate supersaturation threshold at which tissue deposition occurs).

While more aggressive strategies using high flux dialyzers, daily hemodialysis (HD), combined HD and peritoneal dialysis (PD), hemodialfiltration, and even charcoal perfusion have all been reported [reviewed in detail by Plumb et al 2013], the end result is that while plasma removal rates of oxalate can be achieved in the range of greater than 60%, the total body store of oxalate rebounds (in general) to a level of 80% of the predialysis levels within 24 hours of the last HD run.

A case report of one patient treated with aggressive HD (8-10 hrs, 7 nights/wk) does suggest that this level of intense dialysis allows for maintenance of the pre-dialysis oxalate levels at or just below the tissue saturation point (30-45 µmol/L), but further studies are needed before these data can be confirmed [Plumb et al 2013].

Despite the limitations of dialysis, Cochat et al [2010] have suggested six situations in which dialysis may be indicated:

  • When PH1 is not yet diagnosed in an individual requiring dialysis for other reasons
  • In a small child/infant with oxalosis awaiting liver/kidney transplantation
  • As a strategy to deplete body oxalate burden preceding or after liver transplantation
  • As an adjunct therapy to decrease oxalate burden in the presence of delayed or poor renal function after liver/kidney transplantation
  • In older individuals if liver/kidney transplantation is not deemed an option
  • In countries with no access to organ transplantation [Cochat et al 2006]

Organ Transplantation

As neither maintenance hemodialysis (HD), peritoneal dialysis (PD), nor a combination of the two clears oxalate quickly enough to prevent systemic oxalosis in an individual with a glomerular filtration rate (GFR) lower than 25-30 mL/min/1.73 m2 [Thamilselvan & Khan 1998], organ transplantation is an acceptable option for disease therapy or perhaps cure [Marangella et al 2001]. Much discussion has occurred regarding the best transplantation strategy for an individual with PH1.

The following recommendations and suggested approaches to this issue are all well summarized in three current reviews of PH1 [Cochat et al 2012, Hoppe 2012, Cochat & Rumsby 2013]. Specific percentages and outcome numbers can be extracted from these papers.

The reader is strongly encouraged to review (and consider as current best practice level recommendations) the recently published suggestions on organ transplant of non-pyridoxine sensitive patients with PH1 from the European Hyperoxaluria Consortium (OxalEurope) [Cochat et al 2012]. These guidelines (see Table 7) also take into consideration the patient’s age (infantile form), residual GFR, and evidence of systemic oxalate deposition in extrarenal organs.

Table 7.

Suggested Transplantation Options for Individuals with Pyridoxine-Resistant PH1 Based on Residual GFR and Systemic Involvement

Transplantation (Tx) Options:Simultaneous liver - kidneySequential liver - kidneyIsolated kidneyIsolated liver
Hemodialysis (HD) Strategy:Perioperative ± postoperative based on POx & GFRStandard HD after liver Tx aiming at POx <20 µmol/LPreoperative & perioperativeSometimes perioperative
CKD Category / Residual GFRCKD Category 3 (30<GFR<59)NoNoNoOption in carefully selected patients
CKD Category 4 (15<GFR<29)YesOptionOnly if affected person is known to be B6 responsiveNo
CKD Category 5
(GFR <15)
YesYesOnly if affected person is known to be B6 responsiveNo
Infantile form (ESRD <2 yrs)YesYesNoNo

From Cochat et al [2012]; recommendations assume the availability of facilities.

POx= plasma oxalate

The three organ transplantation strategies that have been considered and implemented in the past are:

  • Isolated kidney transplantation (restores oxalate excretion to "normal");
  • "Preemptive" liver transplantation before end-stage renal disease (restores AGT enzyme activity, decreases ongoing oxalate synthesis); or
  • Combined liver-kidney transplantation, either concurrent or sequential (reduces oxalate synthesis and increases oxalate excretion).

In almost all other situations, the current recommendations are for dual liver/kidney transplant in patients with PH1. In the majority of these situations, the only three issues to be considered are:

  • Order of transplant (liver/kidney and sequential vs concurrent);
  • Timing of transplant (at what level of renal dysfunction to consider liver transplant); and
  • Use of deceased vs. living donors for either or both organs.

Certainly the overall survival numbers for any version of dual transplant greatly outstrip those seen from historic results for isolated kidney transplant: adult five-year survival numbers for kidney vs dual transplant are 45% vs 67% [Bergstralh et al 2010]; those for children are 14% vs 76% [Harambat et al 2012].

Isolated liver transplant as such may be a consideration with respect to a patient with significant residual renal function (e.g., GFR >60 mL/min/1.73 m2 or above), with the presumption that decline in renal function will be arrested and only a single organ transplant required. However, in such scenarios the concerns regarding risk of liver transplant morbidity and mortality in the face of an uncertain rate of decline in renal function often delay the decision to proceed to a point at which it is clear that dual transplantation will still be required.

In general it is believed that simultaneous liver/kidney transplant is the most logical for any patient, adult or child, with CKD Category 4 or below, given the need for renal function to excrete the body burden of oxalate. That decision, however, may be mitigated by concerns for patients with CKD Category 5 or on dialysis, as they often face severe oxalate burden that can overwhelm a new renal graft following transplant and lead to graft failure caused by oxalate stones/deposition. The choice in such patients, and often in small children/infants where anatomy may preclude a simultaneous approach, is to proceed with a sequential liver transplant followed at an indeterminate time later by a single kidney transplant.

Most of the published literature still reports the majority of organs used as being from deceased donors; however, living/living related donation of a split liver graft if the recipient is small enough and/or living donor kidney is certainly a viable alternative in some situations. Note: The appropriateness of using a parent or sib who is heterozygous for a AGXT pathogenic variant as a donor remains unclear in the literature.

Finally, the importance of establishing the diagnosis of PH1 before transplantation is illustrated by two recent reports of individuals with undiagnosed late-onset PH1 who received isolated kidney transplants and subsequently experienced unexpected rapid recurrence of stones and systemic oxalosis. In both cases a diagnosis of PH1 was made post transplant [Kim et al 2005, Madiwale et al 2008].

It is also important to note that in all forms of transplantation, in particular isolated kidney, the individual must:

  • Be monitored closely and even dialyzed following surgery to prevent further calcium oxalate deposition in the kidney graft from mobilization of the body burden of oxalate;
  • Continue pyridoxine supplementation to promote excretion of the total body store of oxalate if responsiveness has been documented prior to transplantation [Marangella 1999].

Prevention of Primary Manifestations

Recommendations can all be found in Treatment of Manifestations, specifically in the sub-sections on Reduction of Calcium Oxalate Supersaturation and Reduction of Oxalate Biosynthesis.

Prevention of Secondary Complications

Secondary complications may arise as a result of systemic oxalosis. Table 4 lists the broad range of tissues and organs that suffer consequences of oxalosis.

Regular dental care and ophthalmologic follow up should be part of patient management.

Surveillance

According to the European Hyperoxaluria Consortium (OxalEurope) [Cochat et al 2012] individuals with:

  • Preserved renal function (i.e., measured or estimated GFR >60 mL/min/1.73 m2) likely require only the following to evaluate/ensure treatment efficacy:
    • Regular renal ultrasound examinations and fundoscopic eye examinations to identify the extent of any oxalate deposition
    • Ongoing urinalysis (spot and 24-hour collections)
  • GFR <60 mL/min/1.73 m2 should have the above evaluations as well as regular (not defined) measurements of plasma oxalate.
  • GFR <30 mL/min/1.73 m2 or a rapid deterioration in function should have the above evaluations as well as the following testing (performed prior to initiation of dialysis if possible, and repeated as needed):
    • Bone x-rays to evaluate for radiodense metaphyseal bands and diffuse demineralization, potentially bone marrow examination may also be required
    • Thyroid function testing
    • Electrocardiogram to evaluate for an associated atrioventricular block
    • Ultrasound and/or CT scan of the heart and viscera for evaluation of calcification in such organs
    • Hemoglobin to evaluate for anemia associated with either renal dysfunction or marrow deposition of oxalate
    • History and physical examination to assess the risk of arterial insufficiency or ischemia based on vessel wall deposition

Further testing and surveillance of other organ involvement can be inferred from the list in Table 4 – noting that at GFR <30 mL/min/1.73 m2 the ongoing deposition of tissue oxalate (oxalosis) will, of course, predispose all patients to multi-organ involvement, and this will worsen/accelerate as the patient enters ESRD/ initiates dialysis.

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

Agents/Circumstances to Avoid

Avoid the following:

  • Intravascular volume depletion. The importance of maintaining dilute urine cannot be overemphasized.
  • Foods high in oxalate (chocolate, rhubarb, and starfruit in particular)
  • Any significant intake of vitamin C or D, as both may promote stone formation
  • Loop diuretics to maintain dilute urine, as they can lead to hypercalciuria and increase the production of calcium oxalate stones

One infant with PH1 developed hepatitis after exposure to the anesthetic sevoflurane; this was felt to be an idiosyncratic reaction [Reich et al 2004]

Evaluation of Relatives at Risk

Consideration should be given to testing asymptomatic at-risk family members in order to plan early treatment, monitoring, and preventive intervention [Cochat et al 2012]. If the AGXT pathogenic variants in the family are known, the affected/carrier status of at-risk family members can be confirmed by molecular genetic testing. The benefits of early initiation of conservative measures cannot be ignored [Chand & Kaskel 2009, Fargue et al 2009, Martin et al 2011].

Asymptomatic individuals:

  • Can be monitored periodically for renal function and urinary oxalate;
  • Should maintain adequate hydration and avoid high-oxalate foods.

In addition:

  • Potassium citrate administration may also be considered as an aid to reducing calcium oxalate excretion [Leumann & Hoppe 2001].
  • For those with the pathogenic variant p.Gly170Arg or p.Phe152Ile, pyridoxine should be supplemented.

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

Pregnancy Management

Pregnancy does not appear to be an important risk factor for the development of end-stage renal disease (ESRD) in the majority of women with PH1 [Norby & Milliner 2004]; however, women in whom renal function deteriorated during the pregnancy and remained abnormal post-delivery have been reported [Cimino et al 2005].

Of particular note, pregnant women with PH1 warrant close monitoring during pregnancy by both an obstetrician and nephrologist because of the increased risk of developing nephrolithiasis after delivery.

Therapies Under Investigation

Several novel therapies are under investigation.

Oxalate-degrading bacteria. Approaches involving oral administration of bacteria such as Oxalobacter formigenes (O. formigenes) or lactic acid bacteria to degrade oxalate [Sidhu et al 2001] and reduce the amount of oxalate available for intestinal absorption [Campieri et al 2001, Lieske et al 2005a, Azcarate-Peril et al 2006] are being investigated. Unfortunately this bacteria currently remains off the Qualified Presumption of Safety and Generally Recognized as Safe lists as maintained by the FDA, limiting the use in humans.

O. formigenes shows the most promise as a potential therapy for the hyperoxalurias. Although it is a normal component of the intestinal flora, many individuals do not maintain colonization. O. formigenes is also thought to stimulate secretion of endogenous oxalate into the intestine for its own metabolic use [Hatch et al 2006, Hatch & Freel 2008]. 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 & Freel 2013] in which there was more secretion of oxalate via the distal ileum, cecum, and distal colon into the luminal side and, thus, into the feces. Administration of the HC-1 strain reduced the amount of oxalate excreted via the kidney and has potential as a probiotic.

A controlled diet was compared to two probiotic preparations to evaluate urinary oxalate levels and calcium oxalate supersaturation in individuals with hyperoxaluria and calcium oxalate stones of unknown etiology [Lieske et al 2010]: (1) the probiotic Oxadrop contains Lactobacillus acidophilus, L. brevis, Streptococcus thermophilus, and Bifidobacterium infantis; (2) AKSB, a formulation designed by the Mayo Clinic, contains Enterococcus faecium, Saccharomyces cerevisiae subspecies boulardi, LEVUCELL SB (yeast), S. cerevisiae, and fructooligosaccharide. When administered to stone formers, neither formulation reduced the amount of urinary oxalate excreted by affected individuals or the urinary calcium-oxalate supersaturation levels. However, an oxalate-restricted diet alone for one week significantly reduced the calcium oxalate supersaturation and the urinary levels of oxalate.

A probiotic, VSL#3 (Sigma-Tau Pharmaceuticals, Inc., Gaithersburg, MD, USA), which contains freeze-dried live lactic acid bacteria made up of Streptococcus thermophilus, Bifidobacterium breve, B. longum, B. infantis, Lactobactillus acidophlus, L. plantarum, L. paracasei, and L. delbrueckii subspecies bulgaricus was administered to 13 healthy volunteers who were then challenged to an oral load of 80 mg oxalate [Okombo & Liebman 2010]. Four of the subjects who started with higher baseline oxalate levels showed the largest reduction in urinary oxalate levels compared to the other subjects. The authors suggest that individuals who are hyperabsorbers of oxalate may benefit most from the probiotic VSL#3. This study must be validated in individuals with PH1.

Similar studies have been performed in mice genetically altered to mimic PH1. AGXT-deficient mice were both hyperoxaluric and hyperoxalemic [Hatch et al 2011]. In AGXT-deficient mice colonized with O. formigenes, urinary and plasma levels of oxalate decreased by 50%.

Advances have been made to circumvent the colonization of O. formigenes by expressing bacterial oxalyl-CoA decarboxylase and formyl-CoA transferase in human embryo kidney (HEK) 293 cells [Ye et al 2007]. Further experiments have shown that the enzymes are expressed in the cytosol of cells and transfected cells were able to degrade oxalate to some degree. Although still in the experimental stages, the transfer of genes encoding oxalate-degrading enzymes may be a potential candidate for gene therapy of hyperoxalurias.

Other bacterial species. Giardina et al [2014] looked at a number of other bacteria with potential for oxalate degradation in the gut. These in vitro studies demonstrated (in addition to O. formigenes) four probiotic strains which appeared promising: Lactobacillus plantarum, L. acidophilus, Bifidobacgerium breve, and B. longum.

Finally, in a different approach, a crystalline-stabilized oxalate-degrading enzyme has been used successfully in a mouse model system and may avoid the colonization issue [Grujic et al 2009].

Hepatocyte transplantation. Repopulation of the liver of an individual with PH1 with normal or genetically corrected hepatocytes is less invasive than liver transplantation. However, host cells must be ablated as they would continue to produce oxalate and the donor hepatocytes would then require a growth advantage to achieve repopulation. The effectiveness of this approach has been demonstrated in a mouse model of PH1 [Guha et al 2005, Jiang et al 2008]. Koul et al [2005] transfected AGXT (genetically engineered for selective peroxisomal delivery) into cultured human hepatocytes by amplifying the cDNA and using liposomal transfection techniques. They demonstrated high efficiency of transfection and appropriate intracellular localization to peroxisomes [Koul et al 2005].

Recently, liver cell transplantation was performed ‘successfully’ in a 15-month old girl with PH1 as a bridge to an older age/larger size to allow for orthotopic liver transplant [Beck et al 2012]. The exact protocol is outlined in the paper; the child tolerated both the cellular infusions and the immunosuppression. Initially no significant change was seen in plasma oxalate levels post infusion; however, the plasma oxalate levels slowly decreased over the next two weeks from a mean of 105 to a lower mean of 70, and eventually fell to approximately 35 µmol/L at day 29. Long-term follow up (2-11 months) demonstrated persistently elevated (mean 80 µmol/L) – albeit improved over baseline – levels of plasma oxalate. Of note, clinically the patient improved from week two onward, despite the fact that donor chimerism was not demonstrated during the protocol biopsy at five months or at the time of liver harvest prior to the eventual orthotopic liver transplant.

Gene therapy. Salido et al [2011] have demonstrated successful replacement of AGT enzyme activity in the livers of a knockout mouse model of PH1 utilizing a somatic gene transfer via two adeno-associated viral vectors. That they were able to do so in the absence of either hepatic toxicity or immunogenicity for at least the first 50 days is very encouraging.

Pyridoxamine. This approach aims to reduce oxalate by targeting precursors in the metabolic pathway and preventing their eventual metabolism to oxalate. Pyridoxamine, a drug touted as therapy for human diabetic nephropathy, is used to trap glycoaldehyde and glyoxylate. Animal studies have shown 50% reduction of urinary oxalate excretion [Chetyrkin et al 2005, Scheinman et al 2005]; current evidence from preclinical and phase II trials in humans appears to demonstrate a favorable toxicity profile of pyridoxamine.

Chemical chaperones. These small molecules facilitate folding of new proteins offering protection from cellular quality-control degradative processes. Stabilization of missense AGT may permit the protein to achieve a folded state with some degree of enzymatic activity [Danpure 2005a, Danpure 2005b]. In PH1 specifically, this type of effect has been demonstrated in vitro for both mistargeting and aggregation/accelerated degradation polymorphism-pathogenic variant combinations [Lumb et al 2003, Coulter-Mackie & Lian 2008, Hopper et al 2008]. Chemical chaperones may have general stabilizing functions or they may be designed to target specific pathogenic variants. Pyridoxine, commonly used in treatment of PH1, has been shown in vitro to act as a chemical chaperone increasing expression and correcting peroxisomal targeting, particularly for the three common AGXT alleles encoding protein variants p.Gly170Arg, p.Phe152Ile,or p.Ile244Thr [Fargue et al 2013a, Fargue et al 2013b, Cellini et al 2014]. Pathogenic missense variants – in which the mode of action is not through loss of 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.

Manipulation of the metabolic pathway. The concept of substrate depletion is aimed at reducing the amount of available glyoxylate, the immediate precursor of oxalate, thereby reducing the oxalate concentration [Coulter-Mackie 2006]. An Agxt knockout mouse model has been developed to explore the effects of substrate depletion and to clarify the various adjustments in the metabolic pathway that result from absence of AGT [Hernandez-Fernaud & Salido 2010, Knight et al 2012]. A model system developed in CHO cells uses stable transfection with all combinations of recombinant genes that encode glycolate oxidase, glyoxylate reductase, and AGT, allowing investigation of the interaction of these enzymes and the effects of deficiencies of one or more [Behnam et al 2006]. Another study examined the effect on urinary oxalate of dietary hydroxyproline from collagen, which enters the pathway farther upstream. Results suggested that hydroxyproline metabolism may be a significant contributor to glyoxylate and oxalate [Knight et al 2006].

A study of eight recombinant cytosolic aminotransferases suggested that phosphoserine aminotransferase and alanine transaminase were able to transaminate glyoxylate to glycine efficiently. These reactions may compete with conversion of glyoxylate to oxalate [Donini et al 2009].

Severe dietary restriction of either oxalate [Hatch & Freel 1995] or glycine, a glyoxylate precursor, is of little utility in decreasing the accumulation of oxalate in individuals with PH1 [Danpure 2014].

Trapping glycine in the liver utilizing benzoate or inhibiting the conversion of glycine to glyoxylate is of little or no clinical utility [Danpure 2014].

Auxiliary liver transplant. A previously heretical approach to organ transplant, auxiliary liver transplant has been proposed and demonstrated to ‘be effective’ in two published cases [Onaca et al 2005, Elias et al 2013] and to potentially provide effective oxalate clearance for some patients with PH1. This approach is not universally accepted as such, however [Trotter & Milliner 2014], and the basic principle behind the need to remove the native liver in addition to ‘replacing liver mass with a transplanted organ’ (namely the ongoing and overwhelming production of oxalate from the abnormal liver cells) would seem to suggest that the addition of a small piece of normal liver and its normal AGT enzymatic function would not be enough to provide sufficient metabolic clearance of oxalate being produced by the remaining PH1 liver tissue.

Onaca et al [2005] and Elias et al [2013] have each reported at least one patient with PH1 in whom this approach appeared to protect against oxalosis – without necessitating a high-risk full liver transplant.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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 a child affected with PH1 are obligate heterozygotes (i.e., carriers of one AGXT pathogenic variant).
  • Heterozygotes are asymptomatic.

Sibs of a proband

  • At conception, each sib of a proband with PH1 has 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.
    Note: In a very rare exception to this generalization, one case of PH1 caused by maternal chromosome 2 telomeric isodisomy has been reported [Chevalier-Porst et al 2005]. The mother was a heterozygous carrier of the common c.33dupC pathogenic variant. This situation would alter the recurrence risk. Confirmation of carrier status of both parents is appropriate.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with PH1 are obligate heterozygotes (carriers) for a pathogenic variant in AGXT. Hoppe et al [1997] described a family with pseudo-dominant inheritance: offspring of an affected individual (p.[Gly170Arg]+[Ser187Phe]) and a carrier (p.Gly170Arg) were affected.

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

Carrier Detection

Carrier testing using molecular genetic testing is possible for at-risk family members if the AGXT pathogenic variants in the family are known. If the proband's pathogenic variants are not identified using currently available methods, linkage analysis may be considered (see Molecular Genetic Testing).

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, clarification of carrier status, and discussion of the availability of prenatal 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the AGXT pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Biochemical testing

  • Biochemical testing has been supplanted by molecular genetic testing.
  • Assay of AGT enzymatic activity prenatally is not generally offered because the enzyme is not expressed in amniocytes or chorionic villi and, thus, the assay of enzyme activity requires a fetal liver biopsy. AGT is not detectable in fetal liver until after 14 weeks’ gestation [Danpure et al 1989].

Requests for prenatal testing for conditions which (like PH1) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate. Side effects of renal and/or liver transplantation and scarcity of suitable organs for transplantation may be a consideration for parents who already have one affected child.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the AGXT pathogenic variants have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • Oxalosis & Hyperoxaluria Foundation (OHF)
    201 East 19th Street
    Suite 12E
    New York NY 10003
    Phone: 800-643-8699 (toll-free)
    Email: info@ohf.org
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    United Kingdom
    Phone: 0800-652-3181
    Email: info.svcs@climb.org.uk
  • Rare Kidney Stone Consortium Registry
    Phone: 800-270-4637 (toll-free)
    Email: hyperoxaluriacenter@mayo.edu

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Primary Hyperoxaluria Type 1: Genes and Databases

GeneChromosome LocusProteinLocus SpecificHGMD
AGXT2q37​.3Alanine-glyoxylate transaminaseAGXT mutation database
AGXT database
AGXT

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Primary Hyperoxaluria Type 1 (View All in OMIM)

259900HYPEROXALURIA, PRIMARY, TYPE I; HP1
604285ALANINE-GLYOXYLATE AMINOTRANSFERASE; AGXT

Molecular Genetic Pathogenesis

When alanine:glyoxylate aminotransferase (AGT) enzymatic activity is deficient, the substrate glyoxylate accumulates and is converted to oxalate by glycolate oxidase in peroxisomes or in the cytosol by lactate dehydrogenase [Holmes & Assimos 1998, Danpure 2014]. Oxalate forms insoluble calcium oxalate salts that the body cannot readily eliminate. In the most common pathogenic allele (c.508G>A (p.Gly170Arg), the AGT enzyme is mistargeted to the mitochondria rather than to the peroxisomes, where the substrate is localized. The mistargeted AGT enzyme retains substantial enzymatic activity but has no contact with its substrate, and thus the functional consequences are the same as for other pathogenic variants which result in no enzymatic activity. Mistargeting and high residual activity are seen in heterozygotes and homozygotes for the c.508G>A variant that causes mistargeting [Danpure 1998, Danpure 2014]. (See “Major” and “minor” AGXT alleles.)

Gene structure. AGXT (NM_000030.2) spans approximately 10 kb and comprises 11 exons. For a detailed summary of gene and protein information, see Table A, Gene.

Benign allelic variants. Three benign single-base substitution variants that do not result in amino acid substitutions are reported [Purdue et al 1990, von Schnakenburg & Rumsby 1997].

“Major” and “minor” AGXT alleles. Two common normal alleles of AGXT are known: the most frequent is commonly termed the “major allele” (80% frequency in individuals of European origin) and the less frequent the “minor allele” (20% frequency in individuals of European origin, 2% in Japanese, 3% in South African blacks) [Danpure et al 1994b, Coulter-Mackie et al 2003].

The “major allele” is the haplotype defined by NM_000030.2, while the “minor allele” haplotype has two single amino acid substitutions (p.Pro11Leu and p.Ile340Met among other genomic changes in strong disequilibrium [reviewed by Pey et al 2013].

In the “minor allele,” the only normal allelic variant of functional significance is p.Pro11Leu, which alters the amino acid sequence and creates a cryptic N-terminal mitochondrial targeting sequence [Purdue et al 1991, Fargue et al 2013b]. The mitochondrial targeting sequence of the minor allele is functionally ineffective due to protein conformation; about 5% of AGT encoded by the minor allele is found in the mitochondria [see Pey et al 2013 and references therein]. However, certain pathogenic variants on the minor allele disrupt AGT folding, thereby unmasking the mitochondrial targeting signal, resulting in efficient mislocalization of AGT. Therefore, when in cis configuration the minor allele acts synergistically with some pathogenic variants (see Pathogenic allelic variants).

Other AGXT allelic haplotypes have been reported [Danpure et al 1994a, Tarn et al 1997, Coulter-Mackie et al 2003]. These normal variants may be useful intragenic markers for linkage analysis [Tarn et al 1997] and for determination of phase of pathogenic variants.

Pathogenic allelic variants. More than 170 AGXT pathogenic variants have been documented [Williams et al 2009]. A database of AGXT pathogenic variants is available on Dr. Gill Rumsby’s Web site. Pathogenic missense variants make up approximately 50% of PH1-causing variants.

There are four common pathogenic variants and a few with ethnic associations. Most of the additional pathogenic variants are private (i.e., they have not been documented in more than one family).

The four common pathogenic variants p.Gly170Arg, p.Phe152Ile, and p.Ile244Thr (which occur on the “minor allele”) and c.33dupC (on the “major allele”) together account for more than 50% of PH1-causing alleles.

  • An AGT “minor allele” background may exacerbate at least one copy of the AGXT “minor allele” with one of the following common pathogenic variants in cis configuration.
    • p.Gly170Arg, the most common pathogenic variant, accounts for approximately 25%-40% of PH1-causing alleles. When in cis configuration with the p.Pro11Leu variant of the “minor allele,” p.Gly170Arg slows the rate of dimerization of AGT monomers, exposing the cryptic mitochondrial targeting signal resulting in efficient import of monomers to the mitochrondrion, rather than to the peroxisome [Lumb et al 1999, Lumb & Danpure 2000]. Denaturation studies support a destabilizing effect of p.Gly170Arg [Cellini et al 2010a]. Analysis of the crystal structure of AGT with p.Gly170Arg indicates significant local structural changes that may be associated with decreased protein stability [Djordjevic et al 2010].

      In individuals with the p.Gly170Arg variant, the therapeutic response to pyridoxine is likely attributable at least in part to enhancement of the dimerization process by increased pyridoxal phosphate (PLP) [Cellini et al 2011].
    • p.Phe152Ile. When in cis configuration with the p.Pro11Leu variant of the “minor allele,” p.Phe152Ile is also associated with mitochondrial mistargeting. In the absence of saturating PLP, p.Phe152Ile is thought to monomerize and be susceptible to mistargeting [Cellini et al 2009, Cellini et al 2011, Fargue et al 2013b].

      This is consistent with the positive response to pyridoxine in affected individuals with the p.Phe152Ile variant.
    • p.Ile244Thr appears to be the result of a founder effect within the Canary Islands population [Santana et al 2003]. AGT with the p.Ile244Thr pathogenic variant on the minor allele apparently has an altered conformation [Santana et al 2003]. This variant is also apparently associated with mistargeting [Fargue et al 2013b].
  • c.33dupC (p.Lys12GlnfsTer156), the fourth common pathogenic variant, occurs on the “major AGXT allele” and accounts for about 30% of PH1-causing alleles [Coulter-Mackie et al 2004]. This allele occurs in a variety of ethnic groups and results in a frameshift that predicts nonsense mediated decay and deficiency of AGT.

Pathogenic variants documented in more than one family include p.Gly82Glu and p.Gly156Arg on the major allele, p.Arg233Cys on the minor allele, and p.Gly41Arg on both the major and minor alleles.

Most missense variants have not had specific biochemical phenotypes associated with them other than degradation and loss of enzymatic activity [Coulter-Mackie & Lian 2006]. The pathogenic mechanism of a few of the rarer missense variants is known:

See Table 8.

In addition to the missense variants, splicing and nonsense variants and several small insertions and deletions are known [reviewed by Coulter-Mackie & Rumsby 2004, Williams et al 2009].

Large documented deletions include:

Table 8.

AGXT Allelic Variants Discussed in This GeneReview

Variant ClassificationDNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
Defines “minor AGXT allelec.32C>Tp.Pro11Leu 2NM_000030​.2
NP_000021​.1
c.1020A>Gp.Ile340Met 2
Pathogenicc.33dupC
(33_34insC)
p.Lys12GlnfsTer156
c.121G>Ap.Gly41Arg
c.245G>Ap.Gly82Glu
c.454T>Ap.Phe152Ile
c.466G>Ap.Gly156Arg
c.508G>Ap.Gly170Arg
c.560C>Tp.Ser187Phe
c.613T>Cp.Ser205Pro
c.697C>Tp.Arg233Cys
c.731T>Cp.Ile244Thr
c.738G>Ap.Trp246Ter

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

2.

Two of the variants that define the haplotype of the “minor AGXT allele

Normal gene product. The mRNA (NM_000030.2) encodes a 392-amino acid with a molecular mass of 43 kd. In humans, alanine:glyoxylate aminotransferase (AGT) is synthesized mainly in the liver and is normally located exclusively in the peroxisomes [Danpure 2014]. The enzyme is translated in the cytosol and transported into the peroxisomes. A C-terminal peroxisomal targeting signal is recognized by the peroxisomal receptor, Pex5p, allowing translocation into the peroxisome [Fodor et al 2012]. AGT is a key enzyme in the detoxification of glyoxylate, converting glyoxylate to glycine [Holmes & Assimos 1998, Danpure 2014]. In humans, glyoxylate is produced in the peroxisomes. PLP is an essential cofactor for AGT activity. The PLP site in AGT lies in a highly conserved amino acid sequence and is critical in the catalytic activity of the enzyme. The crystal structure of the normal AGT protein has been determined [Zhang et al 2003], allowing a delineation of the active site and the dimerization interface.

Note that AGXT encodes alanine:glyoxylate aminotransferase (AGT;EC 2.6.1.44), whose activity is largely confined to peroxisomes in the liver. This protein also shows serine:pyruvate aminotransferase activity (SPT;EC 2.6.1.51) (OMIM 604285). AGT and SPT are two separate enzymatic activities on the same protein coded by AGXT. AGT is the major activity; when it is deficient, PH1 results.

Abnormal gene product. Approximately 50% of all individuals with PH1 show no AGT enzymatic activity and produce no immunologically detectable AGT protein.

Mutation resulting in nonsense codons, frameshifts, or splice junction variants is usually predicted to result in little or no functional protein.

Approximately 30% of affected individuals display a high level of residual AGT activity. Most of these individuals exhibit the mistargeting defect in which an otherwise functional AGT enzyme is synthesized in adequate amounts but is mislocalized to mitochondria instead of peroxisomes, where it is normally found and where the substrate glycolate remains. These individuals have classic PH1 despite the residual AGT enzymatic activity.

Pathogenic variants that cause true partial enzymatic activity appear to be rare and may be associated with late-onset or mild disease.

With many genetic diseases, it is now clear that a common consequence of pathogenic missense variants is protein misfolding and subsequent elimination by intracellular quality-control processes [Waters 2001]. This biologic instability of protein carrying a missense change has been documented in p.Ser205Pro [Nishiyama et al 1993] and with a variety of other pathogenic missense variants in AGT [Coulter-Mackie & Lian 2006, Coulter-Mackie & Lian 2008, Hopper et al 2008]. Biochemical studies of a broad range of individual pathogenic variants has revealed a diversity of effects both structural and functional, such as altered PLP or substrate binding, thermostability changes, altered interactions with peroxisomal targeting components, and misfolding with subsequent aggregation or degradation [Cellini et al 2007, Cellini et al 2012, Fodor et al 2012, Oppici et al 2012, Mesa-Torres et al 2013, Pey et al 2013]. The findings may provide clues to potential therapeutic strategies as well as clues to the response to PLP. For instance, p.Gly82Glu has been demonstrated to have a reduced affinity for the pyridoxal phosphate cofactor [Cellini et al 2007].

It has been reported recently that the protein encoded by four pathogenic variants that occur on the minor allele (p.Gly170Arg, p.Ile244Arg, p.Phe152Ile, and p.Gly41Arg) undergo mistargeting [Fargue et al 2013b]. It is speculated that this is a common feature of variants occurring on the minor allele. Variant AGT proteins with p.Gly170Arg, p.Ile244Thr, p.Ile244Arg, and p.Phe162Ile are able to dimerize and are catalytically active although functionally ineffective if located in the mitochondria. The variant p.Gly41Arg tends to aggregate and is inactive.

The effect of a given pathogenic missense variant may be exacerbated if it occurs on the AGT “minor allele.” In vitro studies have shown increased stability and enzymatic activity for some pathogenic variants when expressed on a “major allele” haplotype compared to a “minor allele” [Williams & Rumsby 2007, Coulter-Mackie & Lian 2008, Williams et al 2009]. It has been speculated that some missense variants found on the “minor allele” in association with PH1 may not cause disease if they occurred on the major allele. However, some missense variants (e.g., p.Gly41Arg) found on both major and minor alleles cause disease in both instances.

The recent determination of a crystal structure for AGT [Zhang et al 2003] has permitted the rationalization of the functional consequences of selected missense pathogenic protein variants: p.Gly170Arg (mitochondrial mistargeting), p.Gly82Glu (prevention of cofactor binding), p.Gly41Arg (protein aggregation) [Danpure 2004, Danpure & Rumsby 2004, Danpure 2006], p.Gly47Arg (affects dimerization), and p.Ser81Leu (no effect on dimerization) [Robbiano et al 2010]. See Pathogenic allelic variants for additional descriptions of abnormal proteins.

References

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Suggested Reading

  1. Knight J, Holmes RP, Assimos DG. Intestinal and renal handling of oxalate loads in normal individuals and stone formers. Urol Res. 2007;35:111–7. [PMC free article: PMC2637801] [PubMed: 17431604]
  2. Kumar R, Ghoshal UC, Singh G, Mittal RD. Infrequency of colonization with Oxalobacter formigenes in inflammatory bowel disease: possible role in renal stone formation. J Gastroenterol Hepatol. 2004;19:1403–9. [PubMed: 15610315]
  3. Leumann E, Hoppe B. Primary hyperoxaluria type 1: is genotyping clinically helpful? Pediatr Nephrol. 2005;20:555–7. [PubMed: 15772831]
  4. Nouvenne A, Meschi T, Guerra A, Allegri F, Prati B, Fiaccadori E, Maggiore U, Borghi L. Diet to reduce mild hyperoxaluria in patients with idiopathic calcium oxalate stone formation: a pilot study. Urology. 2009;73:725–30. [PubMed: 19193409]
  5. Perera MT, Sharif K, Lloyd C, Foster K, Hulton SA, Mirza DF, McKiernan PJ. Pre-emptive liver transplantation for primary hyperoxaluria (PH-I) arrests long-term renal function deterioration. Nephrol Dial Transplant. 2011;26:354–9. [PubMed: 20573805]
  6. Trinchieri A, Lizzano R, Castelnuovo C, Zanetti G, Pisani E. Urinary patterns of patients with renal stones associated with chronic inflammatory bowel disease. Arch Ital Urol Androl. 2002;74:61–4. [PubMed: 12161938]

Chapter Notes

Author History

Ben H Chew, MD, MSc, FRCSC (2009-present)
Marion B Coulter-Mackie, PhD (2002-present)
R Morrison Hurley, MD, MSc, FRCPC; BC Children’s Hospital (2002-2014)
Dirk Lange, PhD (2009-present)
Colin T White, MD (2002-present)

Revision History

  • 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 to live Web site
  • 25 June 2004 (me) Comprehensive update posted to live Web site
  • 19 June 2002 (me) Review posted to live Web site
  • 4 January 2002 (rmh) Original submission
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