Clinical Guidance

Primary hyperoxaluria type 1 (PH1) is caused by deficiency of the liver peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine. When AGT activity is reduced or absent, glyoxylate is converted to oxalate, which cannot be metabolized and must be excreted by the kidneys. Insoluble calcium oxalate crystals form due to high urinary oxalate concentration. Crystal deposition leads to nephrolithiasis (i.e., calcium oxalate kidney stones) in the renal pelvis/ urinary tract and often in kidney parenchyma (nephrocalcinosis). The natural history of untreated PH1 is (1) progressive decline in kidney function because of complications of nephrolithiasis (e.g., urinary obstruction, infection) and nephrocalcinosis, and (2) other organ and tissue damage from calcium oxalate deposition (i.e., "oxalosis"). In the absence of treatment oxalosis progresses leading to death from kidney failure and/or other organ involvement . Table 4. Primary Hyperoxaluria Type 1: Clinical Presentations

Diagnostic Criteria

Consensus guidelines for the diagnostic approach to individuals with a suspicion of primary hyperoxaluria and management of all types of primary hyperoxaluria have been published . See for a diagnostic algorithm. Suggestive Findings Primary hyperoxaluria type 1 (PH1) should be suspected in a proband of any age with recurrent calcium oxalate stones or nephrocalcinosis, especially if associated with progressive chronic kidney disease (CKD) or a family history of stones and CKD . Typical clinical findings vary by age at presentation. Clinical Findings Infancy (age 12 months) • Impaired kidney function or poor weight gain and/or poor linear growth of undetermined etiology • Nephrocalcinosis. Renal ultrasound examination most commonly reveals diffuse nephrocalcinosis with few if any observable discrete stones. • First kidney stone Childhood/adolescence (ages 1-17 years) • First kidney stone • Multiple or recurring calcium-containing kidney stones • Impairment of kidney function associated with stones or nephrocalcinosis. Nephrocalcinosis has been observed at the time of the first imaging study in 30% of individuals with preserved kidney function . Adulthood (age ≥18 years) • Recurrent nephrolithiasis in which kidney imaging reveals multiple bilateral radiopaque calculi known or suspected to be calcium oxalate, especially if urinary testing is available and confirms hyperoxaluria • Nephrocalcinosis • Reduced kidney function or end-stage kidney disease (ESKD) with a history of kidney stones or nephrocalcinosis Post kidney transplantation. In approximately 10% of individuals with PH1 the diagnosis is made following kidney transplantation when calcium oxalate crystals are found on allograft biopsy performed for early non-function of the transplanted kidney and/or a subsequent increase in serum creatinine concentration . Supportive Laboratory Findings Hyperoxaluria resulting from increased hepatic production of oxalate is the central laboratory feature of PH1 . Preferred testing for assessment of oxalate excretion is based on kidney function . • CKD stages 1 to 3b (i.e., kidney function is preserved). Because most excess oxalate is excreted in the urine and plasma oxalate concentrations are normal to mildly elevated, measurement of urine oxalate is important. • CKD stages 4 and 5 (advanced CKD or the individual is on dialysis). Because less oxalate than expected is excreted in the urine and plasma oxalate concentration is markedly increased, assessment of plasma oxalate concentration is preferred. Table 1. Primary Hyperoxaluria Type 1: Supportive Laboratory Findings

Management Guidelines

Clinical practice recommendations for management of primary hyperoxaluria (PH) have been published . The following recommendations are also based on the authors' experience and participation in the Rare Kidney Stone Consortium PH Registry.

Evaluations Following Initial Diagnosis

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

Surveillance Guidelines

Individuals with PH1 require lifelong care, the frequency of which is related to kidney function . CKD stages 1 and 2 (measured GFR or estimated GFR [eGFR] 60 mL/min/1.73 m2). The following are required to evaluate/ensure treatment efficacy:

• Regular monitoring of kidney function. Serum creatinine and/or cystatin C for determination of eGFR should be performed at least annually and more frequently in children and adolescents and in individuals with changing kidney function or clinically active stone disease.