Kidney Stone Biology: insights from Genetics

ABSTRACT Kidney stone disease (KSD) affects >10% of the global population and has a high likelihood of recurrence. Its prevalence has risen significantly in recent decades, posing a substantial economic burden. Moreover, KSD is linked to several comorbidities, amplifying its impact on general health and well-being. Environmental factors play a critical role in KSD development, acting upon an underlying genetic substratum. These genetic factors affect the regulation of stone-forming elements and natural inhibitors of crystallization within the kidney. Understanding the interplay between genetic and environmental factors is essential for improving KSD management. Tailored dietary interventions and targeted therapies can address individual risk profiles, reducing the burden of this complex disease. We believe that the common form of KSD, which is the one observed in the general population, is indeed a heterogeneous condition characterized by significant variability in the influence of environmental and genetic factors among patients as well as distinct biological pathways involved in lithogenesis for each individual. The aim of this review is to describe the relevant biology of nephrolithiasis, leveraging ‘experiments of nature’, specifically the known genetic associations of KSD and the resulting biological and physiological derangements. We hypothesize that the carriers, molecular pathways and physiological processes identified in this manner play a major role in the biology of lithogenesis, not only in rare genetic nephrolithiasis, but also in ‘common’ KSD.