Personalized Intervention in Monogenic Stone Formers

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.

Empiric therapy for kidney stones

“…I hope and expect that these advances will continue to progress and that I will be a part of such progress. The concept of "precision medicine" is a most attractive one, as my colleague Dr. Sayer opines about in this issue of Urolithiasis, and we have promoted elsewhere [16]. As of this writing, however, it is not yet a practical concept, but that assertion may seem badly outdated in the coming few years.…”

The current status of preventive measures for urinary calculi in children

“…Fourteen single genes cause 15% of renal calculi or renal calcium syndrome cases. 71 Although single gene detection technology is still developing, early diagnosis of single gene calculi is still difficult. It is worth noting that recent studies have found that the diagnosis of the etiology of hereditary renal stones is significantly delayed.…”

Oxidative Stress in Urolithiasis

“…It mainly affects adults. Monogenic stone condition, such as cystinuria (found approximately at 1% of all stones and 7% of stones in children) and primary hyperoxaluria, is a relatively rare condition that is often found in children, so-called childhood UL [147,148]. Cystinuria is an autosomal recessive trait caused by mutations in SLC3A1 or SLC7A9 gene resulting in an inborn error in transport of urinary cystine, ornithine, lysine and arginine (commonly known as COLA) that subsequently initiate cystine stone formation.…”

“…Stone formation without any identifiable clinical causes is labeled "idiopathic," which is commonly observed in the CaOx formers [149]. However, it has been suggested that genetic screening should be performed in the previously classified idiopathic calcium UL in order to certainly rule out an underlying genetic susceptibility [148].…”