Clinical Guidance

No genotype-phenotype correlations for HOGA1 have been identified .

Source: GeneReviews — "Primary Hyperoxaluria Type 3"

Diagnostic Criteria

For recently published algorithms for the diagnosis of the primary hyperoxalurias (PH), see . Suggestive Findings Primary hyperoxaluria type 3 (PH3) should be considered in a proband with the following clinical, radiographic, and/or laboratory findings and family history. Clinical and radiographic findings • Calcium oxalate stones, especially when in both kidneys • Recurring calcium oxalate stones • Onset of stone disease in childhood or adolescence • Reduced kidney function in the presence of calcium stones or nephrocalcinosis (crystal deposition in renal parenchyma) • Nephrocalcinosis Laboratory findings • Urine oxalate. 0.7 mmol per 1.73 m2 per 24 hours in individuals with preserved kidney function (glomerular filtration rate [GFR] 40 mL/min per 1.7 m2). Note: Hyperoxaluria, which tends to be more variable in PH3 than in PH1 and PH2, may intermittently be in the range of 0.4-0.7 mmol per 1.73 m2 per 24 hrs. Note: (1) Normal urine oxalate is 0.46 mmol per 1.73 m2 per 24 hours. Values higher than the normal range should be repeated to detect persistent hyperoxaluria that may intermittently increase to a level indicative of PH. (2) Urine oxalate may be lower in individuals with advanced chronic kidney disease (CKD). (3) In children, the oxalate excretion rate must be corrected for 1.73 m2 body surface area. (4) The individual should not be receiving pyridoxine or vitamin supplements when urine and plasma oxalate levels are used for the purpose of diagnosis. (5) Urine oxalate should preferably be measured in a 24-hour urine sample; however, when timed urine collections cannot be obtained, a random urine oxalate-to-creatinine ratio can be used. (6) Since normal ranges for the oxalate-to-creatinine ratio vary during childhood by age, age-related normal values should be consulted for accurate interpretation . • Plasma oxalate. Mild elevation of plasma oxalate (1.6-20 mol/L) is often seen in individuals with PH3 with CKD stages 1-3A . Plasma oxalate may be higher in individuals with advanced CKD (GFR 45 mL/min per 1.73 m2). Note: (1) Normal plasma oxalate concentration varies depending on methods of sample preparation and measurement . (2) The individual being tested should not be receiving pyridoxine, high doses of ascorbic acid, or other vitamin supplements when urine and plasma oxalate are obtained for the purpose of diagnosis. • Urine 4-hydroxy-2-oxoglutarate (HOG) or 2,4-dihydroxyglutarate (DHG), measured in a random (spot) urine sample, are increased in most individuals with PH3 and appear to be sensitive diagnostic markers . Urine HOG-to-creatinine and DHG-to-creatinine ratios vary by age. Laboratory-specific normal values by age should be consulted. Table 1. Random Urine Oxalate-to-Creatinine Ratio in Children by Age Age | Upper Limit of Normal2 (mmol/mmol) | (mg/mg)

Source: GeneReviews — "Primary Hyperoxaluria Type 3"

Differential Diagnosis

Primary Hyperoxalurias Primary hyperoxaluria (PH) should be included in the differential diagnosis of any condition that causes calcium oxalate kidney stone disease or nephrocalcinosis and is associated with hyperoxaluria. The three known types of PH are PH1 (due to biallelic AGXT pathogenic variants), PH2 (due to biallelic GRHPR pathogenic variants), and PH3 (due to biallelic HOGA1 pathogenic variants). Each gene encodes an enzyme for different metabolic pathways relevant for the metabolism of glyoxylate . Although oxalate is believed to accumulate as an end product in all forms of PH, in PH3 the biochemical mechanism whereby deficiency of 4-hydroxy-2-oxoglutarate aldolase (HOGA) results in increased oxalate production is unclear . Of the primary hyperoxalurias, PH1 accounts for approximately 70%, PH2 for 10%, PH3 for 10%, and 10% do not have an identified genetic cause to date . The clinical manifestations of the three known types of PH overlap considerably . One recent series found urine oxalate to be lower in PH3 than PH1 and PH2 in a predominantly North American PH population , whereas a largely European case series observed similar oxalate excretion rates among all three PH types . In both series urine citrate and calcium excretion were normal in individuals with PH3. These observations in individuals with PH3 contrast with individuals with PH1, who often manifest lower urine citrate and calcium excretion rates . Although increased urinary excretion of the following specific organic acids are suggestive of PH type , definitive diagnosis requires genetic testing: • PH1: increased glycolate • PH2: increased glycerate • PH3: increased 4-hydroxy-2-oxoglutarate (HOG) and 2,4-dihydroxyglutarate (DHG) Table 3. Comparison of Primary Hyperoxaluria Types 1, 2, and 3

Management Guidelines

No clinical practice guidelines specific to primary hyperoxaluria type 3 (PH3) have been published, though general recommendations for individuals with all forms of PH are relevant . The following recommendations are also based on the authors' experience and participation in the Rare Kidney Stone Consortium PH Registry, the Oxalosis and Hyperoxaluria Foundation working group on practice guidelines, and the recommendations provided by .

Evaluations Following Initial Diagnosis

The following evaluations are recommended to establish the extent of disease and therapeutic needs in an individual diagnosed with PH3:

Source: GeneReviews — "Primary Hyperoxaluria Type 3"

Clinical Guidance

Individuals with PH3 should avoid the following:

• Intravascular volume contraction

Note: Liberal use of intravenous fluids is indicated whenever oral fluid intake is inadequate or there is loss of body fluids due to diarrhea or other causes.

• Delays in treatment of acute stone episodes

• Nephrotoxic agents

• High-dose ascorbic acid (more than 250 mg daily)

• Marked dietary oxalate excess by moderation of intake of high-oxalate foods

Source: GeneReviews — "Primary Hyperoxaluria Type 3"

Therapies Under Investigation

Evidence suggests that inhibition of the hepatic isoform of lactate dehydrogenase, LDHa, could reduce oxalate generation in PH1, PH2, and PH3.

• The siRNA therapeutic nedosiran, which targets hepatic LDHa, has been shown to reduce urinary oxalate excretion in individuals with PH1 . Studies with individuals with PH3 are ongoing .

• Preclinical studies have also demonstrated the potential for hepatically directed gene editing of the LDHa enzyme .

Source: GeneReviews — "Primary Hyperoxaluria Type 3"

Surveillance Guidelines

Attention to lifelong ongoing care, including adherence to high fluid intake and medication schedule, is essential to favorable outcomes. Individuals with PH3 should be counseled to promptly report stone-related symptoms to their health care provider. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations in those who are stable and doing well (except very young individuals; 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 infections

• Renal ultrasound examination or other imaging to monitor for stone formation

Note: Given the need for lifelong repeated kidney imaging, care should be taken to minimize radiation exposure.

• Assessment of kidney function (serum creatinine and eGFR) and electrolytes

• Measurement of plasma oxalate concentration, particularly in individuals with any impairment of 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.

Note: In young children or other individuals unable to complete an accurate 24-hour urine collection, random urine specimens may be used for comparative measurements.

Note: Individuals who need more frequent assessments are:

Source: GeneReviews — "Primary Hyperoxaluria Type 3"