Early Recognition and Management of Rare Kidney Stone Disorders

Ross Goldstein, MD, MBA; David S. Goldfarb, MD


Urol Nurs. 2017;37(2):81-89. 

In This Article

Primary Hyperoxaluria

Primary hyperoxaluria (PH) is a very rare but serious autosomal recessive metabolic disease with an estimated prevalence of about 1 to 3 per million population (Ferrandino, 2012). Three types of PH have been described, and all are due to impairment of different enzymes in the oxalate metabolic pathways (Edvardsson et al., 2013). In Type 1 PH, which accounts for 80% of PH cases, the hepatic conversion of glyoxalate to glycine is impaired due to deficiency or dysfunction of alanine: glyoxylate aminotransferase (AGT) (see Figure 2) (Edvardsson et al., 2013). This defect leads to increased conversion to oxalate and subsequent calcium oxalate stone formation (van der Hoeven, van Woerden, & Groothoff, 2012). The formation of these insoluble crystals leads to interstitial scarring, fibrosis, and renal insufficiency. Renal insufficiency, in turn, prevents excretion of oxalate, resulting in systemic deposition of oxalate in tissues, including bone, skin, retina, myocardium, vascular walls, and the central nervous system (van der Hoeven et al., 2012). Some cases of Type 1 PH are not due to deficiency of AGT, but rather, to mistargeting of AGT to mitochondria (Edvardsson et al., 2013). Type 2 PH and Type 3 PH are due to impairment of glyoxylate reductase/hydroxyl pyruvate reductase (GRHPR) and 4-hydroxy-2-oxaloglutarate aldolase (HOGA1), respectively (Edvardsson et al., 2013).

Figure 2.

Impairment of AGT or GRHPR Leads to Primary Hyperoxaluria Type 1 and Type 2, Respectively
Notes: AGT = alanine:glyoxylate aminotransferase, GRHPR = glyoxylate reductase/hydroxyl pyruvate reductase, LDH = lactate dehydrogenase, PH = primary hyperoxaluria.

Clinical Presentation in Patients With Primary Hyperoxaluria

The majority of patients with Type 1 PH present with recurrent kidney stones and/or nephrocalcinosis, although onset of symptoms related to stone formation may occur at any age (Cochat et al., 2012; van der Hoeven et al., 2012). Presentation manifests as occasional stones in adulthood, or in severe cases, irreversible renal failure as early as the first year of life (van der Hoeven et al., 2012). In the classic case, onset of symptoms is before age 20 years, with a median age at onset of 5 to 6 years (Edvardsson et al., 2013; Lieske et al., 2005; van der Hoeven et al., 2012). Over time, progressive kidney damage leads to reduced kidney function.

In one study, more than one-third of patients had ESRD at the time of diagnosis, underscoring the need for early recognition of PH symptoms (van der Hoeven et al., 2012). Patients who are diagnosed only in adulthood (> 18 years) have a higher rate of ESRD and mortality compared with those diagnosed in childhood due to prolonged exposure of the kidney to elevated urinary oxalate levels (van der Hoeven et al., 2012), again emphasizing the importance of preventing diagnostic delays. In some cases, diagnosis has been made only after the patient develops ESRD or undergoes transplant (Lieske et al., 2005).

Diagnosis of Primary Hyperoxaluria

Diagnosis of PH should be suspected in any child with a first kidney stone, in adults with recurrent stone disease, any subject with nephrocalcinosis especially when associated with decreased GFR, and any subject with oxalate crystals in any biological fluid or tissue (Cochat et al., 2012). Stones are typically calcium oxalate monohydrate (COM), although they may be mixed COM and calcium oxalate dihydrate (Edvardsson et al., 2013).

Measurement of urinary oxalate excretion, glycolate, glycerate, and creatinine is essential to the metabolic workup (timed 12-hour or 24-hour urine collection) (Cochat et al., 2012; Edvardsson et al., 2013). Type 1 PH is characterized by markedly elevated urine oxalate excretion of greater than 0.5 mmol/1.73 m2 per day (Cochat et al., 2012). Oxalate excretion must be normalized to body surface area (BSA) for accurate interpretation in children (Edvardsson et al., 2013). If GFR is less than 60 mL/min/1.73m2, plasma oxalate should also be measured. Although plasma oxalate increases with renal failure due to any cause, levels greater than 100 μmol/L are more likely to be due to PH (Cochat et al., 2012). Urinary levels of glycolate are abnormal in Type 2 PH; in Type 3 PH, urinary levels of glycerate are abnormal.

Liver, kidney, or bone marrow biopsy is used to identify enzymatic deficiencies or tissue deposition of oxalate (i.e., oxalate crystals in any biological fluid or tissue). Measurement of AGT catalytic activity and immunoreactivity in a liver biopsy was the gold standard diagnostic test for Type 1 PH (Cochat et al., 2012). Currently, however, genotyping an individual for the relevant genes has supplanted measurement of tissue enzyme activity. The diagnosis is confirmed by DNA testing to identify specific mutations in AGTX in the case of Type 1 PH, or in GRHPR or HOGA1 in the case of Types 2 and 3 PH, respectively (Cochat et al., 2012; Edvardsson et al., 2013). The presence of oxalate crystals on renal biopsy supports the diagnosis of PH (Edvardsson et al., 2013).

Treatment of Primary Hyperoxaluria

The goal of treatment in PH is to minimize stone formation and preserve kidney function. As with cystinuria, conservative therapy is initiated as soon as a diagnosis is suggested (Cochat et al., 2012). Fluid intake is increased to at least 3 L/m2/day. In infants, achieving this level of hydration requires a nasogastric tube or a gastrostomy feeding tube (Cochat et al., 2012). Oral therapy with potassium citrate or phosphate is administered to help inhibit calcium oxalate crystallization (in this case, increasing urinary citrate is the goal, not alkalinization as in cystinuria). The recommended dose of potassium citrate is 0.10 to 0.15 g/kg body weight per day (0.3 to 0.5 mmol/kg), as long as GFR is preserved (Cochat et al., 2012). In patients with a confirmed diagnosis of Type 1 PH, vitamin B6 (pyridoxine therapy) is administered, with the goal of decreasing urine oxalate excretion by greater than 30%. The starting dose is 5 mg/kg per day; doses are increased stepwise by 5 mg/kg per day up to a maximum of 20 mg/kg per day. In some cases, pyridoxine responsiveness can be predicted by AGTX genotyping. Dietary limitation of oxalate intake is of limited use in the management of PH because the main source of oxalate is endogenous; however, it is prescribed nonetheless. Patients with PH should avoid excessive intake of vitamin C and D (Cochat et al., 2012).

Key point. Patients with PH present with calcium oxalate stones, which could lead to failure to recognize the underlying cause of stone presentation. Therefore, it is critical to consider that a higher volume of calcium oxalate stone disease in a pediatric patient may have a genetic cause, and the diagnosis of PH should not be missed.