Abstract
Purpose:
Treatment of a first-time renal stone consists of acute management followed by medical efforts to prevent stone recurrence. Although nephrolithiasis is roughly 50% heritable, the presence of a family history usually does not affect treatment since most stone disease is regarded as polygenic, ie not attributable to a single gene. Recent evidence has suggested that single mutations could be responsible for a larger proportion of renal stones than previously thought. This intriguing possibility holds the potential to change the management paradigm in stone prevention from metabolically directed therapy to more specific approaches informed by genetic screening and testing. This review synthesizes new findings concerning monogenic kidney stone disease, and provides a concise and clinically useful reference for monogenic causes. It is expected that increased awareness of these etiologies will lead to increased use of genetic testing in recurrent stone formers and further research into the prevalence of monogenic stone disease.
Materials and Methods:
We assembled a complete list of genes known to cause or influence nephrolithiasis based on recent reviews and commentaries. We then comprehensively searched PubMed® and Google Scholar™ for all research on each gene having a pertinent role in nephrolithiasis. We determined which genes could be considered monogenic causes of nephrolithiasis. One gene, ALPL, was excluded since nephrolithiasis is a relatively minor aspect of the disorder associated with the gene (hypophosphatasia). We summarized selected studies and assembled clinically relevant details.
Results:
A total of 27 genes were reviewed in terms of recent findings, mode of inheritance of stone disease, known or supposed prevalence of mutations in the general population of stone patients and specific therapies or considerations.
Conclusions:
There is a distinct opportunity for increased use of genetic testing to improve the lives of pediatric and adult stone patients. Several genes first reported in association with rare disease may be loci for novel mutations, heterozygous disease and forme frustes as causes of stones in the broader population. Cases of idiopathic nephrolithiasis should be considered as potentially having a monogenic basis.
References
- 1 : The role of the 24-hour urine collection in the prevention of kidney stone recurrence. J Urol2017; 197: 1084. Link, Google Scholar
- 2 : Progress in understanding the genetics of calcium-containing nephrolithiasis. J Am Soc Nephrol2017; 28: 748. Google Scholar
- 3 : The role of the microbiome in kidney stone formation. Int J Surg2016; 36: 607. Google Scholar
- 4 : Segregation of urine calcium excretion in families ascertained for nephrolithiasis: evidence for a major gene. Kidney Int2005; 68: 966. Google Scholar
- 5 : A twin study of genetic and dietary influences on nephrolithiasis: a report from the Vietnam Era Twin (VET) Registry. Kidney Int2005; 67: 1053. Google Scholar
- 6 : Fourteen monogenic genes account for 15% of nephrolithiasis/nephrocalcinosis. J Am Soc Nephrol2015; 26: 543. Google Scholar
- 7 : Prevalence of monogenic causes in pediatric patients with nephrolithiasis or nephrocalcinosis. Clin J Am Soc Nephrol2016; 11: 664. Google Scholar
- 8 : Tubular and genetic disorders associated with kidney stones. Urolithiasis2017; 45: 127. Google Scholar
- 9 : When to suspect a genetic disorder in a patient with renal stones, and why. Nephrol Dial Transplant2013; 28: 811. Google Scholar
- 10 : The need for genetic study to diagnose some cases of distal renal tubular acidosis. Nefrologia2016; 36: 552. Google Scholar
- 11 : Autosomal dominant distal renal tubular acidosis caused by a mutation in the anion exchanger 1 gene in a Japanese family. CEN Case Rep2015; 4: 218. Google Scholar
- 12 : Incomplete distal renal tubular acidosis from a heterozygous mutation of the V-ATPase B1 subunit. Am J Physiol Renal Physiol2014; 307: F1063. Google Scholar
- 13 : The vacuolar H+-ATPase B1 subunit polymorphism p.E161K associates with impaired urinary acidification in recurrent stone formers. J Am Soc Nephrol2016; 27: 1544. Google Scholar
- 14 : Metabolic diagnosis and medical prevention of calcium nephrolithiasis and its systemic manifestations: a consensus statement. J Nephrol2016; 29: 715. Google Scholar
- 15 : Calcium and bone homeostasis in heterozygous carriers of CYP24A1 mutations: a cross-sectional study. Bone2015; 81: 89. Google Scholar
- 16 : Hypercalcemia, hypercalciuria, and elevated calcitriol concentrations with autosomal dominant transmission due to CYP24A1 mutations: effects of ketoconazole therapy. J Clin Endocrinol Metab2012; 97: E423. Google Scholar
- 17 : Successful treatment of hypercalcaemia associated with a CYP24A1 mutation with fluconazole. Clin Kidney J2015; 8: 453. Google Scholar
- 18 : Clinical and biochemical phenotypes of adults with monoallelic and biallelic CYP24A1 mutations: evidence of gene dose effect. Osteoporos Int2016; 27: 3121. Google Scholar
- 19 : Take another CYP: confirming a novel mechanism for “idiopathic” hypercalcemia. J Clin Endocrinol Metab2012; 97: 768. Google Scholar
- 20 : Altered calcium and vitamin D homeostasis in first-time calcium kidney stone-formers. PLoS One2015; 10: e0137350. Google Scholar
- 21 : Deficient mineralization of intramembranous bone in vitamin D-24-hydroxylase-ablated mice is due to elevated 1,25-dihydroxyvitamin D and not to the absence of 24,25-dihydroxyvitamin D. Endocrinology2000; 141: 2658. Google Scholar
- 22 : Hereditary causes of kidney stones and chronic kidney disease. Pediatr Nephrol2013; 28: 1923. Google Scholar
- 23 : Heterozygous cystinuria and urinary lithiasis. Am J Med Genet1985; 22: 703. Google Scholar
- 24 : Cystinuria revisited: presentations with calcium-containing stones demands vigilance and screening in the stone clinic. Med Surg Urol2014; 3: 140. Google Scholar
- 25 : Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3/type IIc sodium-phosphate cotransporter: presentation as hypercalciuria and nephrolithiasis. J Clin Endocrinol Metab2009; 94: 4433. Google Scholar
- 26 : Mutations in SLC34A3/NPT2c are associated with kidney stones and nephrocalcinosis. J Am Soc Nephrol2014; 25: 2366. Google Scholar
- 27 : Late-onset hereditary hypophosphatemic rickets with hypercalciuria (HHRH) due to mutation of SLC34A3/NPT2c. Bone2016; 97: 15. Google Scholar
- 28 : Autosomal-recessive mutations in SLC34A1 encoding sodium-phosphate cotransporter 2A cause idiopathic infantile hypercalcemia. J Am Soc Nephrol2016; 27: 604. Google Scholar
- 29 : Common and rare variants associated with kidney stones and biochemical traits. Nat Commun2015; 6: 7975. Google Scholar
- 30 : Convergent signaling pathways regulate parathyroid hormone and fibroblast growth factor-23 action on NPT2A-mediated phosphate transport. J Biol Chem2016; 291: 18632. Google Scholar
- 31 : The primary hyperoxalurias: a practical approach to diagnosis and treatment. Int J Surg2016; 36: 649. Google Scholar
- 32 : Recurrent exercise-induced acute kidney injury by idiopathic renal hypouricemia with a novel mutation in the SLC2A9 gene and literature review. BMC Pediatr2014; 14: 73. Google Scholar
- 33 : Hereditary renal hypouricemia: a new role for allopurinol?. Am J Med2014; 127: e3. Google Scholar
- 34 : Xanthine urolithiasis. Urology2006; 67: 1084.e9. Google Scholar
- 35 : Classical xanthinuria: a rare cause of pediatric urolithiasis. Turk J Urol2013; 39: 274. Google Scholar
- 36 : Familial hypomagnesemia with hypercalciuria and nephrocalcinosis. Kidney Int1995; 47: 1419. Google Scholar
- 37 : Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis. J Am Soc Nephrol2001; 12: 1872. Google Scholar
- 38 : Claudins and mineral metabolism. Curr Opin Nephrol Hypertens2016; 25: 308. Google Scholar
- 39 : Sequence variants in the CLDN14 gene associate with kidney stones and bone mineral density. Nat Genet2009; 41: 926. Google Scholar
- 40 : Activating mutations in the calcium-sensing receptor: genetic and clinical spectrum in 25 patients with autosomal dominant hypocalcaemia—a German survey. Clin Endocrinol (Oxf)2011; 75: 760. Google Scholar
- 41 : Activating calcium-sensing receptor mutations: prospects for future treatment with calcilytics. Trends Endocrinol Metab2016; 27: 643. Google Scholar
- 42 : Calcium-sensing-related gene mutations in hypercalcaemic hypocalciuric patients as differential diagnosis from primary hyperparathyroidism: detection of two novel inactivating mutations in an Italian population. Nephrol Dial Transplant2014; 29: 1902. Google Scholar
- 43 : Proteinuria in Dent disease: a review of the literature. Pediatr Nephrol2016;
10.1007/s00467-016-3499-x . Crossref, Google Scholar - 44 : Bartter syndrome type 3: an unusual cause of nephrolithiasis. Nephrol Dial Transplant2002; 17: 521. Google Scholar
- 45 : Patients with biallelic mutations in the chloride channel gene CLCNKB: long-term management and outcome. Am J Kidney Dis2007; 49: 91. Google Scholar
- 46 : Phosphoribosylpyrophosphate synthetase superactivity. GeneReviews® 2015. Available at https://www.ncbi.nlm.nih.gov/books/NBK1973/. Accessed March 28, 2017. Google Scholar
- 47 : Mutations in SLC26A1 cause nephrolithiasis. Am J Hum Genet2016; 98: 1228. Google Scholar
- 48 : Urolithiasis and hepatotoxicity are linked to the anion transporter Sat1 in mice. J Clin Invest2010; 120: 706. Google Scholar
- 49 : Identification and characterization of a gene with base substitutions associated with the absorptive hypercalciuria phenotype and low spinal bone density. J Clin Endocrinol Metab2002; 87: 1476. Google Scholar
