The Role of Genetic Testing for Kidney Stone Disease
By: Connor M. Forbes, MD, FRCPSC; Ryan S. Hsi, MD, FACS | Posted on: 01 Apr 2021
Heritability of Kidney Stones
Kidney stones occur as a result of a complex interplay of genetic and environmental factors. In clinical practice, environmental factors are the main focus in the preventive management of kidney stone disease. These factors include fluid intake, diet and insensible fluid losses because they are modifiable and appropriate interventions can impact kidney stone recurrence risk. However, genetic factors are known to play a significant role in kidney stone formation. The contribution of heritability to kidney stone disease based on twin studies is estimated at 57% for men and 46% for women.1 As the knowledge base of the role of genetics in kidney stones increases, the question arises as to the role of genetic testing for urinary stone disease. We present a brief review of the genetics of kidney stone disease and implications for testing in the clinical setting.
Monogenic and Polygenic Causes of Kidney Stone Disease
Genetic causes of kidney stone disease can be classified as monogenic or polygenic. Monogenic causes arise from mutations in a single gene. These can have autosomal dominant, autosomal recessive or X-linked recessive inheritance patterns. At least 30 genes have been identified as monogenic causes of kidney stone disease, but they still contribute toward the minority of kidney stone cases overall.2 In a cohort of pediatric and adult patients without known secondary cause of kidney stones, 14 genes accounted for 15% of all kidney stone disease.2 The most common monogenic cause of kidney stone disease is cystine nephrolithiasis. Other causes include familial hypercalciuria, hyperoxaluria, Dent disease, Bartter syndrome and several others. Mutations for these syndromes occur in genes with a broad spectrum of functions. Interested readers can find detailed information on monogenic causes of kidney stones in a review by Howles and Thakker.3
Polygenic causes of kidney stone disease result from interactions between multiple gene mutations. Polygenic causes contribute to more than 45% of kidney stone disease cases.3 The subtle changes associated with each individual mutation make identifying genes in polygenic stone formers difficult. Nevertheless, researchers have successfully identified genes through genome-wide association studies. While individual genes and gene networks have plausible pathophysiology for contribution to stone formation and many have associations with an increased odds ratio of stone formation,4 at this time more study is needed to determine the causative impact of mutations in these candidate genes on overall recurrence risk.
In addition, certain aspects of diet, often thought of as purely environmental factors, also have hereditary influences. Selection of diet and portion size, for example intake of protein and oxalate, appears to be hereditary.5 Metabolic syndrome and the severity of metabolic syndrome are heritable in patients of both White and Black descent,6 thus linking genetic and environmental factors that contribute to stone risk.
Rationale for Testing and Current Indications
Current North American guidelines do not specifically require genetic testing for kidney stone formers. Instead, heritable causes of kidney stone disease are diagnosed by inference, with confirmatory genetic testing depending on local practices. Patients with cystine nephrolithiasis are diagnosed by stone composition or presence of hexagonal crystals in the urine.7 A U.S. based consensus paper does not recommend testing for cystine nephrolithiasis mutations, as the clinical course does not appear to be different between mutations.7 However, European consensus recommendations include genetic testing in cystine nephropathy patients for specific clinical scenarios, such as a diagnosis of hyperechogenic colon prenatally, and for genetic counseling/classification.8 Primary hyperoxaluria may be suspected based on clinical features, stone analysis, family history and high output of oxalate on 24-hour urine testing. Referral to a specialized center and confirmatory genetic testing of the patient are indicated as the disease prognosis differs between mutations.9 Testing and counseling for relatives should also be considered.
There is emerging evidence that genetic testing can have clinical utility in personalizing kidney stone disease management. In a study of 65 patients from 51 families with kidney stones, without a known monogenic cause of kidney stones and aged <25 years, whole exome genetic sequencing was performed.10 This revealed a monogenic mutation causing kidney stones from individuals in 15 of the 51 families (29.4%). Importantly, the diagnosis had clinical implications in 60% of the detected cases. This included addition of phosphorous supplementation, treatment with cysteamine and ophthalmological/audiological screening. At this time, whole exome sequencing is expensive and is not indicated except under extremely specific scenarios for stone formers, but this study helps to illustrate the potential benefits of genetic screening, especially in high risk groups.
There are several testing options available for patients in whom there is a high degree of suspicion for genetic causes of stone disease. For those with a family history of primary hyperoxaluria or a high degree of clinical suspicion, a free genetic test for primary hyperoxaluria is available (https://www.invitae.com/en/alnylam-act-hyperoxaluria-type-1/). Renasight™ is one of several commercially available genetic panels for kidney stone formers. The Mayo Clinic has an actively recruiting clinical trial that assesses 90 genes related to monogenic kidney stone formation, and the test is free for patients who meet inclusion criteria (https://www.mayo.edu/research/clinical-trials/cls-20357366). A nonexhaustive list of laboratories that offer genetic testing specifically for kidney stones or include kidney stones as part of a panel can be found in the Appendix.
Appendix. Laboratories currently offering genetic testing that includes nephrolithiasis in United States
|Test Name||Lab Location||Method||Type||Cost||Turnaround Time||Website|
|Nephrolithiasis testing (may include cystinuria/primary hyperoxaluria)|
|RENALZOOM||Johns Hopkins||Next generation sequencing||Panel||$2,915||6–8 weeks||https://www.hopkinsmedicine.org/dnadiagnostic/tests/tests/renalzoom|
|Nephrolithiasis and related disorders next generation sequencing panel||CTGT Genetic Testing||Next generation sequencing & duplication/deletion||Panel||$990–$1,500||2–4 weeks||http://www.ctgt.net/panel/nephrolithiasis-and-related-disorders-ngs-panel|
|Nephrolithiasis and Nephrocalcinosis Panel||Prevention Genetics||Exome sequencing||Panel||$890||18 days||https://www.preventiongenetics.com/testInfo?val=Nephrolithiasis+and+Nephrocalcinosis+Panel|
|KidneySeq Version 4 Nephrolithiasis and Nephrocalcinosis Panel||Iowa Institute of Human Genetics||Next generation sequencing||Panel||$2,000||45 days||https://medicine.uiowa.edu/humangenetics/kidneyseq|
|Nephrolithiasis and Nephrocalcinosis Panel||GeneDX||Next generation sequencing||Panel||Unknown||4 weeks||https://www.genedx.com/test-catalog/disorders/cystinuria/|
|Monogenic Kidney Stone Panel||Mayo Clinic||Unknown||Panel||Unknown (free for qualifying patients)||Unknown||https://www.mayo.edu/research/clinical-trials/cls-20357366|
|Renasight||Natera||Next generation sequencing||Panel||Unknown||3 weeks||https://www.natera.com/organ-health/renasight-genetic-testing/|
|Cystinuria Panel||Fulgent||Next generation sequencing||Three gene panel||Unknown||3–5 weeks||https://fulgentgenetics.com/Cystinuria|
|Cystinuria Panel||Invitae||Next generation sequencing & deletion/ duplication||Three gene panel||Unknown||10–21 days||https://www.invitae.com/en/physician/tests/06142/|
|Cystinuria Panel||Blueprint Genetics||Next generation sequencing||Two gene panel||$1,400||4 weeks||https://blueprintgenetics.com/tests/panels/metabolic-disorders/cystinuria-panel/|
|Cystinuria Panel||Prevention Genetics||Exome sequencing||Two gene panel||$890||18 days||https://www.preventiongenetics.com/testInfo?val=Cystinuria+Panel|
|Primary Hyperoxaluria||Invitae||Next generation sequencing & deletion/ duplication||Three gene panel||Unknown (free for qualifying patients)||10–21 days||https://www.invitae.com/en/physician/tests/06227/
|Primary Hyperoxaluria||Prevention Genetics||Next generation sequencing & duplication/deletion||Three gene panel||$640||18 days||https://www.preventiongenetics.com/testInfo?val=Primary+Hyperoxaluria+Panel|
|Modified from Katherine Steigelman (Travere).|
Prior to embarking on such testing, clinicians must discuss the possible findings and implications of these findings with the patient. Having a confirmatory diagnosis may not change clinical care or provide actionable interventions, and finding variants of uncertain significance can lead to extensive and costly workups without satisfactory answers. Some patients will find this knowledge motivating, and others will find it discouraging. Those who choose to proceed should test wisely and be prepared for additional testing and treatment, which may include genetic counseling.
The future promise of personalized medicine for kidney stone disease rests on defining the role of genetic testing to improve patient outcomes. However, much work remains, particularly in determining the best patient populations for testing and the impact of testing on clinical care, as well as improving the cost efficiency of genetic testing.
- Goldfarb DS, Avery AR, Beara-Lasic L et al: A twin study of genetic influences on nephrolithiasis in women and men. Kidney Int Rep 2019; 4: 535.
- Halbritter J, Baum M, Hynes AM et al: Fourteen monogenic genes account for 15% of nephrolithiasis/nephrocalcinosis. J Am Soc Nephrol 2015; 26: 543.
- Howles SA and Thakker RV: Genetics of kidney stone disease. Nat Rev Urol 2020; 17: 407.
- Taguchi K, Yasui T, Milliner DS et al: Genetic risk factors for idiopathic urolithiasis: a systematic review of the literature and causal network analysis. Eur Urol Focus 2017; 3: 72.
- Lieske JC, Turner ST, Edeh SN et al: Heritability of dietary traits that contribute to nephrolithiasis in a cohort of adult sibships. J Nephrol 2016; 29: 45.
- Musani SK, Martin LJ, Woo JG et al: Heritability of the severity of the metabolic syndrome in whites and blacks in 3 large cohorts. Circ Cardiovasc Genet 2017; 10: e001621.
- Eisner BH, Goldfarb DS, Baum MA et al: Evaluation and medical management of patients with cystine nephrolithiasis: a consensus statement. J Endourol 2020; 34: 1103.
- Servais A, Thomas K, Dello Strologo L et al: Cystinuria: clinical practice recommendation. Kidney Int 2021; 99: 48.
- Hoppe B: An update on primary hyperoxaluria. Nat Rev Nephrol 2012; 8: 467.
- Daga A, Majmundar AJ, Braun DA et al: Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis. Kidney Int 2018; 93: 204.