Urinary stones are highly prevalent, affecting approximately 10% of adults worldwide with the incidence appearing to be on the rise. In general, stone formation is felt to result from an imbalance between promoters and inhibitors of crystallization. The underlying cause appears multifactorial and includes environmental, dietary, hormonal and genetic components.

The current availability of high throughput sequencing has enabled studies that suggest up to 30% of pediatric and 10% of adult stone formers might have an underlying monogenic cause, with up to 35 genes implicated to date.^1,2 In addition, genome-wide association studies suggest that these and other genes may also influence kidney stone risk amongst the general stone forming population.³ Genetic testing is increasingly available in the clinic, and indeed now similar in cost to many other tests that are frequently ordered for urinary stone management (eg sophisticated kidney imaging). The Table lists some of the more common monogenic causes of urinary stone disease. Increasingly among these diseases, treatments can be individualized based upon the precise diagnosis, and in some cases these treatments may have a dramatic impact on long-term patient outcome. For example, there is now a U.S. Food and Drug Administration-approved treatment for primary hyperoxaluria type 1, while clinical trials are ongoing for novel approaches to primary hyperoxaluria types 2 and 3.^4,5 In all cases, making a precise diagnosis will allow the assembly of cohorts of patients with a single diagnosis to allow better understanding of disease pathogenesis and natural history, and eventually test treatment approaches.

Certain features highlight that a monogenic cause of urinary stones might be present (see Figure). These include early onset of stone disease during childhood, multiple recurrent clinical stone events, the presence of nephrocalcinosis, the presence of pathological crystals in the urine (eg cystine, dihydroxyadenine) or other specific clinical features including visual and/or hearing defects. In some cases, a firm clinical diagnosis can be made on biochemical grounds alone (eg cystinuria) while in most cases genetic testing is required to provide a precise diagnosis, since the clinical presentation of patients with many of these monogenic causes of urinary stones can greatly overlap.⁶

Figure. Clinical and laboratory features that increase the likelihood of an underlying monogenic cause of urinary stone disease. GFR, glomerular filtration rate. APRT, adenine phosphoribosyltransferase. UA, uric acid. PH, primary hyperoxaluria. DHA, dihydroxyadenine.

Implementing genetic testing in a clinical setting presents definite challenges. The typical current approach in routine clinical practice employs a candidate gene panel that only includes known monogenic causes of stones (as opposed to speculative ones). This allows a more straightforward interpretation of the results and increases the likelihood that any genetic findings are clinically relevant. Such urinary stone disease genetic panels are currently offered by multiple clinical testing laboratories. However, ordering and interpreting these genetic panels requires careful planning and forethought. Ideally, the ordering provider should have access to multi-disciplinary colleagues to help with patient counseling and interpretation of the results. All patients should have pretest counseling so that they understand the reason for the testing, the possibility of a negative result and the implications of any positive results. Equally important is interpretation of the genetic results and clearly communicating that back to the patient. This is true whether a clearly pathogenic change in a specific gene is identified, or if one or more variants of uncertain significance is reported. In certain cases, followup studies including testing in family members may be helpful or indicated. Often, patients with a potential genetic cause of their urinary stone disease could benefit from referral to a tertiary center with clinical experience and/or ongoing research of that disease.

We have already entered the era where genetic testing can improve the care of a sizable subset of patients with urinary stone disease. Thus, it becomes imperative for providers caring for these patients to understand the role for genetic testing in the clinic, and develop appropriate workflows for obtaining it, interpreting it, and using it to improve patient care.