Clinical description.

Primary hyperoxaluria type 3 (PH3) is characterized by recurring calcium oxalate stones beginning in childhood or adolescence and, on occasion, nephrocalcinosis or reduced kidney function. In 50%-65% of individuals with PH3 stone formation begins prior to age five years. Although the frequency and severity of stone activity often seem to abate by adolescence and adulthood, stone formation can occur throughout life and some adults have many stones. To date systemic oxalosis has not been reported in PH3.

Diagnosis/testing.

The diagnosis of PH3 is established in a proband with calcium oxalate kidney stone(s) and/or nephrocalcinosis, urine oxalate >0.7 mmol/1.73 m²/24 hours (in those with preserved kidney function), increased concentration of plasma oxalate (particularly in those with reduced kidney function), and biallelic (homozygous or compound heterozygous) pathogenic variants in HOGA1.

Management.

Treatment of manifestations: Reduction of urine supersaturation of calcium oxalate by maintaining high oral fluid intake at all times and use of an inhibitor of calcium oxalate crystallization such as potassium or sodium citrate; prevention of stone complications by prompt relief of urinary tract obstruction and treatment of urinary tract infections; and avoidance of marked dietary oxalate excess.

Prevention of primary manifestations: Same as Treatment of manifestations.

Surveillance: For those who are stable, annual clinical assessment of: stone-related symptoms (pain), frequency of passage of urinary stones and/or gravel, urinary tract infection; adherence to high fluid intake and medication schedule; annual: assessment of kidney function by serum creatinine, measurement of plasma oxalate concentration in those with impaired renal function, 24-hour urine oxalate and supersaturation study, and renal ultrasound examination or other imaging to monitor for stone formation.

Agents/circumstances to avoid: Intravascular volume contraction, delays in treatment of acute stone episodes, marked dietary oxalate excess, high-dose ascorbic acid, and nephrotoxic agents.

Evaluation of relatives at risk: Presymptomatic diagnosis and treatment is warranted in relatives at risk to reduce stone formation and the risk of nephrocalcinosis and chronic kidney disease.

Pregnancy management: Adequate fluid intake throughout the pregnancy.

Genetic counseling.

PH3 is inherited in an autosomal recessive manner. At conception, each sib of an affected individual 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. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible if the HOGA1 pathogenic variants in the family are known.

Suggestive Findings

Primary hyperoxaluria type 3 (PH3) should be considered in any individual with the following:

• Recurring calcium oxalate stones
• Onset of stone disease in childhood or adolescence
• Nephrocalcinosis
• Reduced kidney function in the presence of calcium stones or nephrocalcinosis
• Family history of chronic kidney disease and/or recurring calcium oxalate stones consistent with autosomal recessive inheritance

Note: Since idiopathic stone disease is very common [Worcester & Coe 2010] and since calcium oxalate is found in approximately 80% of stones [Worcester & Coe 2010], a high index of clinical suspicion is necessary to identify the small proportion of individuals who form calcium oxalate stones as a result of PH3.

Establishing the Diagnosis

Algorithms for the diagnosis of the primary hyperoxalurias have recently been published [Harambat et al 2011, Edvardsson et al 2013] (see Figure 1).

Figure 1.

Algorithm for the diagnostic evaluation of primary hyperoxaluria in an affected individual 1. Chronic kidney disease is defined as a glomerular filtration rate <50 mL/min/1.73 m², or serum creatinine ≥2x normal for age.

The diagnosis of PH3 is established in a proband with the clinical findings of calcium oxalate kidney stone(s) and/or (on occasion) nephrocalcinosis and the following biochemical and molecular genetic findings.

Clinical Description

Individuals with primary hyperoxaluria type 3 (PH3) most often present in childhood with signs or symptoms related to kidney stones including hematuria, frequent urination, dysuria, blood visible in the urine, or pain associated with a stone.

Although the stones are likely to be discovered due to symptoms, they may be detected incidentally on imaging studies performed for other purposes.

Approximately 50%-65% of individuals with PH3 present with a stone prior to age five years [Monico et al 2011, Matsumoto & Milliner 2015]. Although the frequency and severity of stone activity appear to abate in adolescence and adulthood [Hoppe 2012], stone formation can occur throughout life, and some adults have many stones.

Nephrocalcinosis has been reported to date only occasionally in individuals with PH3 [Williams et al 2012, Tang et al 2015].

Over time, kidney function may become compromised from frequent stones and/or nephrocalcinosis, resulting in chronic kidney disease (CKD). However, kidney function appears to remain better preserved among individuals with PH3 compared to those with PH1 or PH2 [Hopp et al 2015].

To date, only one individual with PH3 has been reported to progress to end-stage renal disease. In this eight-year-old patient, stone removal procedures and urinary tract obstruction may have contributed to the loss of kidney function [Hopp et al 2015].

Systemic oxalosis. The plasma concentration of oxalate increases significantly in individuals with PH and advanced CKD. When the plasma oxalate concentration reaches super-saturation, calcium oxalate crystals are deposited in many body tissues. Crystal-induced injury can include cutaneous ulcers, vascular disease, cardiomyopathy, cardiac conduction disturbances, non-healing fractures, erythropoietin-resistant anemia, and retinal deposits [Hoppe 2012]. Although systemic oxalosis is well recognized in PH1 and seen occasionally in PH2, it has not been reported to date in PH3, an observation consistent with the infrequency of end-stage renal disease (ESRD) in PH3.

Heterozygotes. Although some heterozygotes (carriers) have had elevations of urinary oxalate [Monico et al 2011], this may be coincidental as it is not seen in the majority. As more families are studied, additional information is expected to provide a better understanding of the risk to heterozygotes.

Genotype-Phenotype Correlations

Although no differences in phenotypic manifestations were noted among individuals with the two most common HOGA1 pathogenic variants [Hopp et al 2015], the relatively recent discovery of mutation of HOGA1 as the cause of PH3 and the rarity of PH3 (<100 affected individuals described to date) have limited this type of analysis.

Families of Ashkenazi Jewish heritage with PH3 have developed hypercalciuria in addition to hyperoxaluria [Monico et al 2011, Hoppe 2012]; however, to date no specific genotype-phenotype correlation has been established [Belostotsky et al 2010].

Prevalence

Surveys of clinicians in central Europe led to estimates of the prevalence of primary hyperoxaluria (of all causes) of 1-3 per million population [Hoppe et al 2009].

Among individuals with primary hyperoxaluria approximately 70% have PH1, 10% have PH2, 10% have PH3, and 10% have no as-yet identified genetic cause [Cochat & Rumsby 2013, Hopp et al 2015].

Registry data of the Rare Kidney Stone Consortium and OxalEurope suggest a prevalence of PH3 that is similar to PH2 and approximately one sixth that of PH1.

By contrast, estimates from publicly available population data (NHLBI ESP) showed a PH3 carrier frequency of 1:185 [Hopp et al 2015], which was similar to the rate observed for PH1, suggesting certain individuals with PH3 either remain undiagnosed or do not have clinical manifestations. Prevalence of PH3 from the genomic data is currently estimated at 1:136,000 [Hopp et al 2015].

PH3 has been observed more commonly among individuals of Ashkenazi Jewish descent [Belostotsky et al 2010]; however, the true prevalence in this population is unknown.

Primary Hyperoxalurias

The three known types of primary hyperoxaluria (PH) are PH1 (due to mutation of AGXT), PH2 (mutation of GRHPR), and PH3 (mutation of HOGA1). Each gene encodes an enzyme for different metabolic pathways relevant for the metabolism of glyoxylate [Cochat & Rumsby 2013]. Oxalate accumulates as an end product in all forms of PH; however, the specific pathways that lead to its accumulation in PH3 require further clarification [Monico et al 2011, Riedel et al 2012, Williams et al 2012].

Of the primary hyperoxalurias, approximately 70% are PH1, 10% are PH2, 10% PH3, and 10% do not have an identified genetic cause [Hopp et al 2015]. The clinical manifestations of the three known types of PH overlap considerably.

In some individuals with PH3, significant stone manifestations have been observed in infancy and early childhood; these appear to have abated by later childhood or adolescence [Hoppe 2012, Hopp et al 2015].

Urine oxalate excretion rates tend to be lower in individuals with PH3 than in those with PH1 or PH2 [Monico et al 2011, Hopp et al 2015]. In PH3 urine oxalate excretion appears to be more variable over time. However, because of the overlap of urinary oxalate excretion in all three types, the type of PH (and thus the diagnosis of PH3) cannot be confirmed on this basis alone [Hopp et al 2015].

Hypercalciuria, observed in a subset of individuals with PH3, is not usually observed in PH1 and PH2 [Monico et al 2011, Williams et al 2012].

Hyperoxaluria of the degree observed in individuals with primary hyperoxaluria causes deposition of calcium oxalate crystals in the kidney (nephrocalcinosis) associated with inflammation, kidney damage, and often chronic kidney disease and/or end-stage renal disease (ESRD). ESRD appears to be unusual in PH3, having been reported in just one individual to date [Hopp et al 2015]; however, modest renal impairment has been described in other cohorts [Allard et al 2015].

Systemic calcium oxalate deposition (systemic oxalosis) may develop due to high levels of plasma oxalate in patients with PH who have advanced CKD. Systemic oxalosis results in varying degrees of organ dysfunction including infiltrative cardiomyopathy, arrhythmias due to involvement of the cardiac conduction system, erythropoietin-resistant anemia due to extensive crystal deposition in the bone marrow, pathologic fractures, and/or retinal oxalate deposition [Hoppe et al 2009]. Systemic oxalosis has not yet been reported in any individual with PH3, an observation consistent with the infrequency of end-stage renal disease (ESRD) in PH3.

Differences in urinary metabolites other than oxalate can provide clues regarding the most likely type of PH.

• 4-hydroxy-2-oxoglutarate (HOG). In PH3 urinary levels of HOG are often high, whereas in PH1 and PH2 urinary HOG is undetectable [Riedel et al 2012]. The diagnostic sensitivity and specificity of this finding remain to be determined [Belostotsky et al 2012, Riedel et al 2012].
• Urinary glycolate may be elevated in PH1 or occasionally in PH3 [Williams et al 2012].
• Urine glycerate is increased in most individuals with PH2; however, exceptions (perhaps related to the sensitivity of the testing process) occur [Rumsby et al 2001].

See OMIM Primary Hyperoxaluria Phenotypic Series to view genes associated with this phenotype in OMIM.

Idiopathic calcium oxalate stone disease can be associated with mild hyperoxaluria. The hyperoxaluria is typically of a lesser degree (<0.6 mmol/day) than that observed in the primary hyperoxalurias, is variable from one collection to the next, and is frequently associated with mild hypercalciuria.

Secondary Hyperoxalurias

Secondary forms of hyperoxaluria are not uncommon and should be systematically considered.

Dietary or other sources of excessive oxalate or oxalate precursors should be considered in the differential diagnosis. Very high doses of vitamin C are a potential cause. Exposure to toxins such as ethylene glycol can cause marked hyperoxaluria and associated acute renal failure.

Enteric hyperoxaluria results from any cause of fat malabsorption in the small intestine. In the colon, this undigested fat combines with calcium and decreases the amount of calcium available to bind to oxalate. This free oxalate is absorbed. In addition, fatty acids that are not absorbed in the small intestine can damage the colonic mucosa, leading to further increase in oxalate absorption. Thus, any gastrointestinal disease or surgery that impairs fat absorption is a potential cause of enteric hyperoxaluria [Kumar et al 2011]. Hyperoxaluria resulting from short bowel syndrome and following malabsorptive types of gastric bypass surgery can be quite marked, overlapping the range seen in inherited PH of all types.

Medications that interfere with fat absorption from the GI tract (e.g., orlistat) can be associated with hyperoxaluria.

Marked deficiency of dietary calcium, leaving a greater proportion of oxalate free in the intestinal lumen, can result in increased absorption of oxalate resulting in hyperoxaluria.

Nephrocalcinosis of prematurity occurs in a significant proportion of infants born prior to 28 weeks' gestation and is characterized by both nephrocalcinosis and nephrolithiasis [Habbig et al 2011]. Risk factors among premature infants thought to contribute to this disease include urine oxalate that is higher than that observed in infants born at term [Schell-Feith et al 2010] as well as hypercalciuria and hypocitric aciduria. Calcium oxalate crystals have been detected in the renal parenchyma [Schell-Feith et al 2010]. Since individuals with PH3 can develop stones in infancy or during early childhood [Hoppe 2012, Matsumoto & Milliner 2015], there may be confusion with stones or nephrocalcinosis related to prematurity.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with primary hyperoxaluria type 3 (PH3), the following evaluations are recommended:

• Kidney imaging for assessment of number and location of stones and presence of nephrocalcinosis
• Measurement of plasma oxalate concentration to assess the degree of oxalate overproduction
• Baseline 24-hour collection with measurement of oxalate, calcium, citrate, pH, urine volume, and other components of a supersaturation profile to identify specific risk factors for stones – information that is valuable in guiding treatment
• Assessment of kidney function by serum creatinine and eGFR
• If chronic kidney disease (CKD) is present, evaluation for signs of systemic oxalosis by physical examination (livedo reticularis or non-healing ulcers of the skin), echocardiography (oxalate cardiomyopathy), electrocardiogram (conduction disturbances), complete blood count (erythropoietin-resistant anemia), bone films (sclerosis, pathologic fractures due to oxalate osteodystrophy), and retinal examination (retinal oxalate deposits)
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Reduction of urine supersaturation of calcium oxalate in order to reduce stone formation and formation of calcium oxalate crystals that can be injurious to the kidney:

• Maintainance of high oral fluid intake (>2.5 L/m² BSA)
• Oral administration of an inhibitor of calcium oxalate crystallization. Most patients are treated with one of these agents, which include potassium and sodium citrate [Leumann & Hoppe 2001], orthophosphate [Milliner et al 1994], or magnesium [Watts 1994]. Note: Simultaneous administration of citrate and phosphate should be done with caution due to the potential for increasing calcium phosphate supersaturation.

Avoidance of supersaturation of calcium oxalate in the blood. Although there is little experience with chronic kidney disease in PH3, a decline in GFR to less than approximately 40 mL/min/1.73m² would be expected to result in increased plasma oxalate and the potential for systemic oxalosis (as in other forms of PH). If plasma oxalate exceeds 35-50 μmol/L dialysis or transplantation is needed to reduce the risk of multiorgan complications of calcium oxalate deposition.

Prevention of stone complications through regular monitoring (see Surveillance) and prompt attention to the following, any of which can damage kidney function:

• Alleviate obstruction of the urinary tract by a stone promptly through stent placement and/or stone removal.
• Maintain continuous fluid intake and urine flow before, during, and for several days after stone removal procedures.
• Treat urinary tract infections promptly and thoroughly, as bacteria may cause pyelonephritis or infect stones and complicate management.

Avoidance of acute kidney injury by avoiding intravascular volume contraction at all times. This may necessitate intravenous fluids during severe gastroenteritis or other circumstances in which oral fluid intake cannot be maintained.

Avoidance of marked dietary oxalate excess. Since the source of the excess oxalate in PH3 is metabolic overproduction, little is gained by strict low-oxalate diets, which in young children may compromise nutrition. Simple avoidance of marked dietary oxalate excess is recommended.

Prevention of Primary Manifestations

See Treatment of Manifestations.

Surveillance

Attention to ongoing care, including adherence to high fluid intake and medication schedule, is essential to good outcomes.

For patients who are stable and doing well (see Note) the following are recommended annually:

• Clinical assessment of stone-related symptoms including pain, frequency of passage of stones or gravel in the urine, and urinary tract infection
• Assessment of kidney function (serum creatinine and eGFR) and electrolytes
• Measurement of plasma oxalate concentration, particularly in those with any impairment of glomerular filtration rate (GFR)
• 24-hour urine oxalate and supersaturation study. During follow up, changes in the urine supersaturation can be used to monitor the effectiveness of therapy by confirming that the crystallization potential has decreased.
• Renal ultrasound examination or other imaging to monitor for stone formation

Note: Very young patients, those with complex stone problems, and those with reduced kidney function need closer management with more frequent assessments.

Agents/Circumstances to Avoid

The following should be avoided:

• Intravascular volume contraction (Note: Liberal use of intravenous fluids is indicated whenever oral fluid intake is inadequate.)
• Delays in treatment of acute stone episodes
• Nephrotoxic agents
• Marked dietary oxalate excess
• High-dose ascorbic acid

Evaluation of Relatives at Risk

Using molecular genetic testing for the HOGA1 pathogenic variants found in the proband, it is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from early treatment and preventive measures.

• Urine oxalate should be measured in all sibs who are affected (i.e., have biallelic HOGA1 pathogenic variants) or who are carriers (i.e., heterozygous for one HOGA1 pathogenic variant)
• Any sib with elevated urine oxalate/creatinine ratio or elevated oxalate excretion rate corrected for 1.73 m² BSA should undergo kidney ultrasound examination, measurement of plasma oxalate concentration, a baseline 24-hour urine collection with a supersaturation profile, and measurement of serum creatinine concentration (see Evaluations Following Initial Diagnosis).

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

Pregnancy Management

There have been no studies of pregnancy in women with PH3. However, most women with PH1 or PH2 who had good kidney function during pregnancy have done well and have delivered healthy infants [Norby & Milliner 2004].

Adequate fluid intake should be maintained throughout the pregnancy. Circumstances that compromise fluid intake, such as hyperemesis gravidarum, should prompt early initiation of IV fluid to maintain adequate hydration.

Stones that become symptomatic during pregnancy may require routine (but specialized) techniques for management.

In patients with stones, urinary tract infections should be treated promptly and thoroughly due to the potential for bacteria to cause pyelonephritis or infect stones and complicate management.

Therapies Under Investigation

Humans cannot degrade oxalate; however, certain bacteria use oxalate as an energy source. Preliminary studies suggest that oral administration of O formigenes could reduce oxalate excretion in individuals with PH. Two previous double-blind studies were inconclusive [Hoppe et al 2006]. A third clinical trial is under way in Europe, with results expected in 2015.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Primary hyperoxaluria type 3 (PH3) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one HOGA1 pathogenic variant).
• Heterozygotes (carriers) are usually asymptomatic; however, exceptions may occur (see Clinical Description, Heterozygotes).

Sibs of a proband

• At conception, each sib of an affected individual 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.
• Heterozygotes (carriers) are usually asymptomatic; however, exceptions may occur (see Clinical Description, Heterozygotes).

Offspring of a proband. The offspring of an individual with PH3 are obligate heterozygotes (carriers) for a HOGA1 pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier (i.e., heterozygous) for a HOGA1 pathogenic variant.

Heterozygote Detection

Carrier testing for at-risk relatives requires prior identification of the HOGA1 pathogenic variants in the family.

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

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the HOGA1 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

While there is interest in prenatal testing in PH, especially in families with early renal failure, the interest in prenatal testing for PH3 is low given that the phenotype is usually relatively mild and renal failure is rare. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Author Notes

The Rare Kidney Stone Consortium, funded by the NIDDK and CCATS, is a member of the Rare Disease Clinical Research Network of the National Institutes of Health. The Consortium maintains registries for patients with primary hyperoxaluria, enteric hyperoxaluria, cystinuria, Dent disease, and APRT deficiency. A biobank, protocols for genetic testing, and a number of other protocols are open to enrollment for patients with these diseases.

Revision History

• 24 September 2015 (me) Review posted live
• 13 February 2015 (dsm) Original submission

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