Primary Hyperoxaluria and Oxalosis: New Methods for Diagnosis
Kidney stones are a major health problem in the United States, affecting approximately 1 in 11 people-an estimated overall prevalence of about 9%. Men are more likely (11%) than women (7%) to experience stone disease.1 Increased urinary oxalate frequently leads to kidney stone formation, and in some circumstances causes kidney injury that can result in kidney failure. Oxalate can cause disease primarily because its calcium salt is poorly soluble in water and, thus, in urine. Dietary intake of oxalate accounts for at least 30% of urinary excretion, with some studies suggesting as much as 60% of urinary oxalate may be derived from dietary sources.2 Oxalate is also produced by the liver as an end product of normal metabolism. Since humans possess no enzyme systems to degrade oxalate, it is primarily (>90%) excreted into the urine, where it can combine with calcium to form stones. A smaller amount is excreted into the gut.
Among stone formers, hyperoxaluria is found in approximately 20%. Dietary factors such as high oxalate and low calcium intake account for the hyperoxaluria in most such patients, though increased kidney excretion of oxalate in the absence of identifiable factors (so-called idiopathic hyperoxaluria) is also commonly encountered. The degree of hyperoxaluria observed in these circumstances is generally mild. Secondary hyperoxaluria may be due to any number of factors. Most patients with severe secondary hyperoxaluria have gastrointestinal diseases that cause fat malabsorption. Examples include patients with surgical resections of large portions of the small intestine, chronic pancreatitis, or following malabsorptive bariatric surgery for weight loss. In all of these examples, the malabsorbed fat travels to the colon where it binds calcium, thus freeing oxalate for absorption into the bloodstream. This can cause mild to severe hyperoxaluria and can result in kidney failure. In some patients without fat malabsorption, dietary factors such as a combination of high oxalate and low calcium intake can result in mild to moderate hyperoxaluria. Total parenteral nutrition in premature infants, ingestion of large amounts of oxalate or metabolic precursors of oxalate such as ascorbic acid or ethylene glycol, are all known to cause hyperoxaluria. Pyridoxine deficiency will also result in hyperoxaluria. Enteric hyperoxaluria, encountered in a small proportion of hyperoxaluric stone formers, is characterized by moderate to marked increases in urine oxalate and caused by enhanced absorption of oxalate from the intestinal tract.
The primary hyperoxalurias are rare, inherited disorders,3,4 characterized by marked increases in urine oxalate excretion of 2 to 6 times the upper limit of normal. Primary hyperoxaluria type 1, 2, and 3 (PH1, PH2, and PH3, respectively) are caused by increased production of oxalate by the liver. The degree of hyperoxaluria seen in both enteric and primary hyperoxaluria typically leads to active calcium oxalate stone disease and can cause kidney injury, resulting in compromised kidney function.
Primary hyperoxaluria also causes kidney failure and can cause severe systemic disease (oxalosis) and death if not adequately treated. Among patients with primary hyperoxaluria, kidney failure can occur at any age from infancy to middle or even late adulthood. Earlier literature showed that about 50% of patients developed kidney failure by 15 years of age, and about 80% developed kidney failure by age 30.5With improved diagnosis and management, recent studies suggest median age at kidney failure to be 33 years, a significant improvement in patient outcomes.6 Yet, due to lack of familiarity with the disease, delays of many years from onset of symptoms to diagnosis are common.6,7 Onset of calcium oxalate stone formation in childhood or adolescence, or calcium oxalate stones or nephrocalcinosis that are associated with kidney failure in patients of any age, are important clues to the diagnosis and warrant specific diagnostic testing for the disease.8 (Figure 1)
PH1 and PH2 are autosomal recessive disorders that result from inherited enzyme deficiencies in the liver. The degree of hyperoxaluria is marked, and stone formation typically begins in childhood.6 Recently, a third cause of primary hyperoxaluria—now referred to as primary hyperoxaluria type 3 (PH3)—has been described. Patients with PH3 often present with calcium oxalate stone disease early in life. Although autosomal recessive inheritance is suggested by family studies, there also appear to be variable and intermittent elevations of urine oxalate in some heterozygotes (ie, individuals with a mutation in only 1 allele a the specific chromosome gene locus).9-11
Urinary oxalate excretion rates, combined with clinical findings, are helpful in distinguishing primary hyperoxaluria from other forms of hyperoxaluria (Table 1), although the cutoffs are not absolute (eg, certain patients with enteric hyperoxaluria may excrete >1 mmol/1.73m2/24 hours, whereas PH patients occasionally excrete <1 mmol/1.73m2/24 hours).
Primary Hyperoxaluria Type 1
PH1 is a hereditary disorder of glyoxylate metabolism caused by deficiency of alanine:glyoxylate-aminotransferase (AGT), a hepatic enzyme that converts glyoxylate to glycine.12 (Figure 2) Absence of AGT activity results in conversion of glyoxylate to oxalate, which is not capable of being degraded. Therefore, excess oxalate is excreted in the urine, causing kidney stones, nephrocalcinosis, and kidney failure. As kidney function declines, blood levels of oxalate increase markedly, and oxalate combines with calcium to form calcium oxalate deposits in the kidneys, eyes, heart, bones, and other organs, resulting in systemic disease.13,14 (Figure 3)
Presenting symptoms of PH1 include kidney stones, crystal precipitates in kidney tissues, or end-stage kidney disease with or without a history of calcium oxalate calculi in the urinary system. Age of symptom onset is variable; however, most individuals present in childhood or adolescence with symptoms related to kidney stones. In some infants with a more severe phenotype, kidney failure may be the initial presenting feature. Less frequently, affected individuals present in adulthood with recurrent kidney stones or kidney failure. End-stage kidney failure is most often seen in the third decade of life, but can occur at any age. The exact prevalence and incidence of PH1 are not known, but prevalence rates of 1 to 3 per million population and incidences of 0.1 per million/year have been estimated from population surveys.15,16
Primary Hyperoxaluria Type 2
PH2 is a hereditary disorder of glyoxylate metabolism caused by deficiency of the hepatic enzyme glyoxylate reductase/hydroxypyruvate reductase (GRHPR).7 Absence of GRHPR activity results in excess oxalate and usually L-glycerate excreted in the urine leading to kidney stones and sometimes kidney failure. While the exact prevalence and incidence of PH2 are not known, it is less common than PH1.
Onset of PH2 is typically in childhood or adolescence with symptoms related to kidney stones. As seen in PH1, kidney failure may be the initial presenting feature. Renal manifestations of PH2 parallel those in PH1. However, a Mayo Clinic study found that patients with PH2 appear to have less active stone formation and better preservation of kidney function when compared to patients with PH1.17 End-stage kidney disease is also less common and of later onset than in PH1; however, once it happens, oxalate deposition in other organs such as bone, retina, and myocardium can occur.18
Primary Hyperoxaluria Type 3
PH3, caused by mutations in HOGA1 (formerly DHDPSL), was recently described.9,10,19 Patients with PH3 often experience calcium oxalate stone disease early in life, with 50% of them presenting with kidney stones before age 5. Data from the Rare Kidney Stone Consortium Primary Hyperoxaluria Registry suggest that PH3 accounts for approximately 10% of patients with PH of known type. Although autosomal recessive inheritance is suggested by family studies, there also appear to be variable and intermittent elevations of urine oxalate in some heterozygotes.11
Unclassified Forms of Hyperoxaluria
Some patients have marked hyperoxaluria and clinical manifestations indistinguishable from those of PH, but they have no demonstrable abnormalities of the enzymes or the genes implicated in PH types 1, 2, and 3. It is expected that additional PH types will be identified.
Symptoms and Diagnosis
Symptoms due to hyperoxaluria may appear anytime from birth to adulthood and presentation can vary from mild to severe. The first sign or symptom is usually blood in the urine, pain, passage of a stone, or urinary tract infection related to a kidney stone. However, a minority of patients present with kidney failure as the first sign and, in some cases, the disease may go unrecognized until age 30 to 50. The diagnosis is sometimes not recognized until a transplant has been performed and the disease recurs in the allograft. Depending upon the stage of disease, symptoms may vary. (Table 2)
Primary hyperoxaluria disorders have clinical and biochemical similarities that make differentiation difficult, and without careful testing patients may be misclassified. Since there are important differences in the treatment options for the various types of hyperoxaluria, definitive testing is essential. Testing for urinary glycolate and glycerate excretion rates can be helpful. In well-characterized patients, that is, those in whom secondary causes of hyperoxaluria have been excluded and the diagnosis is highly suspected based on clinical and biochemical grounds, a molecular-based diagnosis is feasible. Liver biopsy, which measures AGT and GRHPR enzyme activities, is definitive, and may be diagnostic in cases where the clinical, biochemical, or molecular parameters do not differentiate among the 3 subtypes.
Because of the difficulties in identifying primary hyperoxaluria among patients with other forms of hyperoxaluria, a consensus algorithm was developed as a product of the Oxalosis and Hyperoxaluria meeting sponsored by the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases and the Oxalosis and Hyperoxaluria Foundation (Annapolis, MD; Nov 2003), and has been recently updated.20 (Figure 4) This evidence-based algorithm can be used to improve the diagnosis of patients with primary hyperoxaluria, permitting earlier treatment intervention.
Urine testing for oxalate, glycolate, and glycerate (L-glyceric acid) can help distinguish primary from enteric and other forms of hyperoxaluria, and is also helpful to differentiate PH1 from PH2. Mayo Medical Laboratories offers HYOX/86213 Hyperoxaluria Panel, Urine, an assay performed by gas chromatography-mass spectrometry, that assesses glycolate, glycerate, oxalate, and glyoxalate levels on a single urine specimen. Increased urinary oxalate and glycolate indicate PH1. PH2 is indicated by an increase in urinary oxalate and glycerate.
Measurement of urine oxalate is best performed on a 24-hour urine specimen (OXU/8669 Oxalate, Urine). When timed urine collections are difficult in infants or other patients, random urine oxalate/creatinine ratios can be used. In patients with elevated values, confirmation with a second specimen is recommended. In addition to measurement of oxalate, the supersaturation profile (SSAT/82029 Supersaturation Profile, Urine) provides valuable information. The supersaturation profile includes the concentrations of 10 urinary ions (potassium, calcium, phosphorus, oxalate, uric acid, citrate, magnesium, sodium, chloride, sulfate) and may help identify specific additional risk factors for stone formation. It can also help establish the basis for treatment recommendations.
Caution is warranted in interpretation of urine oxalate excretion in patients with reduced kidney function, as urine oxalate concentrations may be lower due to reduced glomerular filtration rate (GFR).
Primary hyperoxaluria is typically diagnosed by measuring oxalate levels in urine. However, in patients with reduced kidney function, oxalate measurement in plasma may also be helpful. As kidney function decreases, the kidney excretion of oxalate also decreases. Once the GFR declines to less than 10 to 20 mL/min/1.73 m2, plasma oxalate levels in primary hyperoxaluria begin to increase rapidly and urine oxalate levels fall.13 In such situations, plasma oxalate levels (POXA/81408 Oxalate, Plasma) may be more informative than urine testing. In these patients, predialysis plasma oxalate concentrations are often >60 mcmol/L. This is in contrast to patients with kidney failure due to other causes, whose elevation in plasma oxalate concentration is more modest, with values generally <30 mcmol/L.
In addition to its value for diagnosis of primary hyperoxaluria and other hyperoxaluric states in patients with kidney failure, oxalate measurement is often used to monitor the efficiency of oxalate removal during dialysis and to monitor patients during critical periods, such as before and after kidney or liver transplantation. A steady decrease in plasma oxalate concentration is expected during dialysis. Oxalate levels in dialysate fluid can be used to monitor the adequacy of oxalate removal during hemodialysis (DOXA/61644 Oxalate Analysis in Hemodialysate).
Historically, the diagnosis of PH was confirmed by enzyme analysis performed on liver biopsy; however, this has been largely replaced by molecular testing, which forms the basis of confirmatory or carrier testing in most cases.21
PH1 is inherited as an autosomal recessive disorder caused by mutations in the AGXT gene, which encodes the enzyme AGT.22 Several common AGXT mutations have been identified including c.33dupC, p.Gly170Arg (c.508G->A), and p.IIe244Thr (c.731T->C). These mutations account for 1 of the 2 affected alleles in approximately 70% of individuals with PH1. Direct sequencing of the AGXT gene is predicted to identify 99% of alleles in individuals who are known by enzyme analysis to be affected with PH1.23 Mayo Medical Laboratories offers full gene analysis (AGXMS/89915 AGXT Gene, Full Gene Analysis) to evaluate individuals with a suspected diagnosis of PH1. Site-specific (known mutation) testing (AGXKM/89916 AGXT Gene, Known Mutation) for mutations that have already been identified in an affected patient is useful for confirming a suspected diagnosis in a family member. It is also useful for determining whether at-risk individuals are carriers of the disease and, subsequently, at risk for having a child with PH1 deficiency.
While age of onset and severity of disease are variable and not necessarily predictable by genotype, a correlation between pyridoxine responsiveness and the p.Gly170Arg mutation has been observed.24,25Pyridoxine (vitamin B6) is a known cofactor of AGT and is effective in reducing urine oxalate excretion in some PH1 patients treated with pharmacologic doses. Individuals with 2 copies of the p.Gly170Arg mutation have been shown to normalize their urine oxalate when treated with pharmacologic doses of pyridoxine, and those with a single copy of the mutation show reduction in urine oxalate.24,25 This is valuable because patients with most other mutations are not responsive to pyridoxine, and strategies are desirable that help to identify individuals most likely to benefit from such targeted therapies.
PH2 is inherited as an autosomal recessive disorder caused by mutations in the GRHPR gene, which encodes the hepatic enzyme GRHPR.26,27 The absence of GRHPR activity results in excess oxalate and usually L-glycerate excreted in the urine. Two common GRHPR gene mutations have been identified: c.103delG and c.403_404+2delAAGT. These mutations account for about one-third of the mutant alleles described in the Northern European Caucasian population and about 15% in the Asian population.26 Direct sequencing of the GRHPR gene will identify these 2 mutations as well as other less common or novel mutations associated with PH2. Mayo Medical Laboratories offers full gene analysis (GRHMS/50037 GRHPR Gene, Full Gene Analysis) to evaluate individuals with a suspected diagnosis of PH2, and site-specific (known mutation) testing (GRHKM/50038 GRHPR Gene, Known Mutation) for diagnostic confirmation of PH2 when familial mutations in the GRHPR gene have been previously identified. The known mutation assay is also useful for carrier testing of individuals with a family history of PH2 to determine if they are at risk for having a child with PH2 deficiency.
PH3 is an autosomal recessive disorder caused by mutations in the HOGA1 gene. Although HOGA1 gene mutation testing is not routinely available, it can be obtained on a research basis.
For those patients where a molecular diagnosis cannot be established, a liver biopsy for enzyme measurement may be necessary to provide a definitive diagnosis. Enzyme measurement on liver biopsy samples obtained percutaneously can be arranged by contacting Mayo Medical Laboratories.
Though kidney biopsy is usually not required for the diagnosis of primary hyperoxaluria, a patient who initially presents in kidney failure will frequently undergo biopsy to ascertain the cause. Characteristic histopathologic changes in kidney parenchyma are important in establishing a diagnosis of primary hyperoxaluria. Consultative review of kidney biopsy specimens is available and includes the following tests:
- 88501 Renal Pathology Consultation
- 8331 Renal Biopsy, Light Microscopy
- 8104 Renal Biopsy, Immunohistology
- 4993 Renal Biopsy, Electron Microscopy
Bone Marrow Biopsy
In patients who have kidney failure, a bone marrow biopsy can determine if the bones have oxalate deposits and if the patient has systemic oxalosis. A consultative review of bone marrow is available as 5434 Hematopathology Consultation.
Other tests useful for identification of systemic oxalosis include a retinal examination for oxalate crystals and an echocardiogram to detect oxalate cardiomyopathy.
Treatment for Hyperoxaluria
Treatment for hyperoxaluria depends on the specific type and may include any of the following treatment options:
Hyperoxaluria patients who do not have kidney failure need to increase the amount of water or other liquids they drink. The extra fluid is intended to increase urine volume to reduce the concentration of oxalate. Lower oxalate concentrations are less likely to injure kidney cells or lead to calcium oxalate crystal or stone formation.
Patients with absorptive, enteric, or idiopathic stone disease often benefit from dietary reduction of oxalate intake and maintenance of normal dietary calcium intake (ie, not reduced). In patients with enteric hyperoxaluria, calcium is often given with meals as an oxalate binder. By contrast, in patients with primary hyperoxaluria dietary modification is of limited benefit as the vast majority of the excess urinary oxalate is produced by hepatic cells.
Prescription-level doses of phosphates and citrate can be effective in reducing stone formation. Other medications, such as thiazide diuretics, also may be considered, depending on which other abnormalities are present in the urine.
In some patients with PH1, pharmacologic doses of pyridoxine (5-8 mg/kg/day) reduce urine oxalate to normal or near normal, while in others there is a reduction to 30% to 50% of baseline. Each patient’s response to pyridoxine should be evaluated with urine oxalate measurements before, and monthly for 3 months after, initiation of pyridoxine at full therapeutic dose. Because of pyridoxine’s substantial potential benefit, patients with the p.Gly170Arg mutation, those with other mutations who have demonstrated pyridoxine responsiveness, and any patient with PH1 whose pyridoxine response is unknown should be maintained on therapeutic doses of this agent.
Symptomatic Kidney Stone Management
Kidney stones are common in people with hyperoxaluria. Large kidney stones that cause pain or other symptoms or obstruct the flow of urine from the kidneys may require removal or fragmentation. Kidney stones that form in children and teenagers are likely to be caused by an underlying condition, such as hyperoxaluria. For this reason, all young people with kidney stones should have a thorough evaluation, including measurement of oxalate in the urine.
Kidney and Liver Transplant
Patients with hyperoxaluria, depending on severity of the disease, may eventually lose kidney function. In some cases, patients with primary hyperoxaluria will not be diagnosed until their kidneys stop functioning (end-stage kidney failure). For patients with kidney failure, individualized treatment entails 4 approaches, based on each patient’s disease characteristics and needs:
- Kidney dialysis is helpful but it does not cure hyperoxaluria and patients will continue to accumulate oxalate in other body tissues. This is a temporary solution until kidney transplant can be done. Often, aggressive dialysis regimens (hemodialysis 5-6 days per week) are needed to keep pace with oxalate production.
- Kidney-alone transplant may be effective for patients with PH1 who respond fully to pyridoxine treatment with normal or near normalization of urine oxalate, and in PH2 patients.
- Combined kidney-liver transplantation should be considered for PH1 patients who do not respond fully to pyridoxine. Replacement of the AGT enzyme by the transplanted liver reduces the likelihood of oxalate-induced damage to the transplanted kidney.
- No patients with end-stage kidney disease due to PH3 have yet been reported. Given uncertainties regarding the metabolic pathway involved, liver transplantation cannot at this time be recommended for patients with PH3.
Mayo Clinic Hyperoxaluria Center
The Mayo Clinic Hyperoxaluria Center, a member of the National Institutes of Health-funded Rare Kidney Stone Consortium, is a center of excellence for the diagnosis and care of the patient with hyperoxaluria, with an emphasis on primary hyperoxaluria. The center has established programs and resources for pediatric and adult patients at all stages of disease and integrates the many specialties needed to provide appropriate care and support for these patients. The staff is available to provide expert consultation for clinicians on interpretation of test results and questions regarding clinical management of patients with this disease.
The center houses a bank for urine, plasma, whole blood, and liver samples collected from primary hyperoxaluria patients to help facilitate investigation and collaborative research. The center also compiles statistics on patient outcomes and houses an international data registry, under the sponsorship of the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) and the National Center for Advancing Translational Sciences (NCATS).
The Mayo Clinic Hyperoxaluria Center was founded by the Oxalosis and Hyperoxaluria Foundation (OHF) in 2003, and is supported by the Rare Diseases Clinical Research Network of the National Institutes of Health. Hyperoxaluria is 1 of 4 diseases in the Rare Kidney Stone Consortium. The other 3 diseases are Dent disease, cystinuria, and adenine phosphoribosyltransferase (APRT) deficiency. For more information about the registry, investigational protocols, or the Oxalosis and Hyperoxaluria Foundation, see the Resources list.
The Mayo Clinic Hyperoxaluria Center staff provides expert consultation for clinicians on interpretation of test results and questions regarding clinical management of patients with this disease. For information about patient referrals or individual patient questions, please contact:
- Mayo Clinic Hyperoxaluria Center:
For additional information on the disease and the Hyperoxaluria Center:
- Website: www.mayoclinic.org/nephrology-rst/hyperoxaluriacenter.html
- Facebook page: Primary Hyperoxaluria Disease-Mayo Clinic: Contains information and tips about kidney stones, kidney stone prevention and management, and hyperoxaluria, and notifications about upcoming meetings and conferences.
- The Rare Kidney Stone Consortium: www.rarekidneystones.org
- The Oxalosis and Hyperoxaluria Foundation: www.ohf.org
For test-specific information, please contact Mayo Medical Laboratories at 1-800-533-1710.
Authored by Plumhoff EA, Masoner DE, Lieske, JC, Milliner DS
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