Kidney stone disease affects 12% of the global population with a prevalence that continues to increase. It is recurrent in up to 50% of patients within 5 years and is associated with major health concerns including coronary artery disease and chronic kidney disease. Thus, kidney stones pose a substantial health and economic burden. However, despite kidney stone disease being one of the oldest known and most common diseases worldwide, our understanding of the mechanisms underlying stone formation is lacking. Moreover, recent data have raised questions about the efficacy of currently used therapeutic options for calcium oxalate stones, which account for 75% of all kidney stones. Development of new therapeutics for the successful prevention and management of this disease will require improved understanding of the causes of kidney stones. Recent advancements have shed light on the nuanced contribution of diet, environment and genetics as well as the more fundamental roles of calcium oxalate crystallization, Randall’s plaque formation, inflammation and even a possible contribution of the recently discovered urinary microbiome. This review provides a comprehensive overview of our current understanding of kidney stone pathogenesis and identifies new frontiers and remaining gaps in our knowledge of this disease.

Calcium oxalate stones comprise greater than 70% of all kidney stones. In the current conceptual framework, the initial stone nidus is thought to include the aggregation of inorganic crystallites, the formation of which is favored by elevated concentrations of dissolved constituents. Here, we show that this highly prevalent stone type comprises a form of organic–inorganic polycrystalline biocomposite with integrated bacterial biofilms. Evidence from electron microscopy and fluorescence microscopy reveal the unanticipated internal structure of kidney stones from human patients, where bacterial biofilms are intercalated between polycrystalline mineral layers, even in stones identified as “noninfectious” clinically, including those in patients without underlying urinary tract infections. We observe similar bacterial biofilm architectures on the surfaces of stone fragments obtained due to lithotripsy, suggesting that bacteria are intrinsic to the process of nephrolithiasis. Crystallites proximal to biofilm layers exhibit significantly smaller grain sizes, which indicate a larger local concentration of nucleation sites. Staining reveals that biofilm areas of these stones are enriched with bacterial DNA. That bacteria are now observed so broadly in kidney stones (including even in less prevalent struvite stones) may be conceptually salient: Based on the evidence adduced here, we propose a model in which the urine-rich environment of the kidney can impinge on bacterial calcium homeostasis and amplify bacterial production of nucleation templates such as extracellular DNA. The resultant counterion condensation intrinsic to polyelectrolytes charged beyond the Manning criterion (such as DNA) drastically enhances the probability of heterogeneous nucleation, thereby amplifying calcium oxalate stone formation.

Deterministic formation of membrane scission necks by protein machinery with multiplexed functions is critical in biology. A microbial example is the M2 viroporin, a proton pump from the influenza A virus which is multiplexed with membrane remodeling activity to induce budding and scission in the host membrane during viral maturation. In comparison, the dynamin family constitutes a class of eukaryotic proteins implicated in mitochondrial fission, as well as various budding and endocytosis pathways. In the case of Dnm1, the mitochondrial fission protein in yeast, the membrane remodeling activity is multiplexed with mechanoenzyme activity to create fission necks. It is not clear why these functions are combined in these scission processes, which occur in drastically different compositions and solution conditions. In general, direct experimental access to changing neck sizes induced by individual proteins or peptide fragments is challenging due to the nanoscale dimensions and influence of thermal fluctuations. Here, we use a mechanical model to estimate the size of scission necks by leveraging Small-Angle X-ray Scattering (SAXS) structural data of protein-lipid systems under different conditions. The influence of interfacial tension, lipid composition, and membrane budding morphology on the size of the induced scission necks is systematically investigated using our data and molecular dynamic simulations. We find that the M2 budding protein from the influenza A virus has robust pH-dependent membrane activity that induces nanoscopic necks within the range of spontaneous hemi-fission for a broad range of lipid compositions. In contrast, the sizes of scission necks generated by mitochondrial fission proteins strongly depend on lipid composition, which suggests a role for mechanical constriction.

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