Best Practices & Benign Disease
Introduction & Objective :
Recent evidence suggests that single mutations could be responsible for a larger proportion of kidney stones than previously thought. Diagnosis of a monogenic stone disorder brings patients the benefit of personalized therapies for stone prevention. To ensure cost-effective use of gene sequencing, it would be ideal to first identify candidates via metabolic testing. We hypothesized that some patients in a general stone clinic would possess metabolic phenotypes corresponding to known monogenic causes of stones, a first step in demonstrating the feasibility of triggered genetic testing.
375 patients at our institution billed for stones between 2010-2016 were reviewed retrospectively. 72 patients were excluded due to absent lab data or presence of a disease affecting stone formation. Lab values needed to identify metabolic phenotypes corresponding to specific mutations were extracted, being excluded if a patient was acutely ill, or if discordant with other time points.
16% of patients had lab values potentially consistent with a monogenic cause. The prevalence of the signature of distal renal tubular acidosis (dRTA), metabolic acidosis with inappropriately alkaline urine, was 7% (21/317) (ATP6V1B1, ATP6V0A4, SLC4A1 or CA2 mutations). Among those with a stone analysis available, 3% (3/114) had a predominantly calcium phosphate stone along with the signature of dRTA. Removing the requirement for metabolic acidosis added four more patients, which could include individuals with incomplete dRTA. Among patients with phosphate measured, 14% (18/133) had hypophosphatemia (evidence of SLC34A3 or SLC34A1 mutation). Among patients with 24h urine oxalate measured, 9% (1/11) had urine oxalate >70 mg (evidence of AGXT, GRHPR or HOGA1 mutation). Among those with uric acid recorded, 2% (1/47) had hypouricemia (evidence of SLC22A12 or SLC2A9 mutation). Among those with PTH measured, 10% (4/42) had hypocalcemia with normal PTH (evidence of CASR activating mutation), and, 9% (3/35) had hypercalcemia with normal-to-high PTH (evidence of a CASR inactivating mutation). Among 4 patients with urine cystine quantitated, 1 had cystinuria.
This pilot study provides evidence that in our patient population, triggered genetic testing has the potential to yield results for several genes, enabling personalized medicine for stone formers. Future research should sequence patients with these metabolic phenotypes to validate the net diagnostic yield and cost-effectiveness of this approach. Providers should obtain proper labs in all stone formers to exclude heritable disorders.