New Frontiers in Stone Disease: Immune Cells

Abstract

APPROXIMATELY 5% to 10% of the general population will have a kidney stone in their lifetime with recurrence within 5 years of the first stone event in up to 50%. 1 Furthermore the incidence of stone disease appears to be increasing with global warming, migration to urban areas, obesity and dietary patterns, including high sodium and high fructose corn syrup intake, which have been implicated as possible causes. 2,3 The cost of treating stone disease is also rising. It has been reported that the total expenditure of treating kidney stones in the United States is in the range of $10 billion annually. 4 Despite the high incidence and associated high cost of treatment there remains a research gap. While surgical management has evolved, such as increased use of flexible ureteroscopy, medical management of stone disease has evolved little in the last 20 years. This may be multifactorial but a lack of in-depth understanding of the mechanisms of stone formation is surely a factor. Of stones in North America 80% contain calcium oxalate (CaOx) as pure CaOx or in combination with calcium phosphate. Randall suggested that a plaque in the renal interstitium functions as the site of future growth of a calculus. 5e7 Extensive study has shown that in idiopathic calcium oxalate stone formers the Randall plaques are indeed interstitial and not located in the renal tubules. 8,9 On microcomputerized tomography stones forming in these patients were directly visualized attached to papillae via a Randall plaque or they were freely floating and found to have structural evidence of a Randall plaque origin. 10 However, much is still not known as to the genesis of Randall plaque and it remains one of the gaps in knowledge of understanding stone formation. While several hypotheses exist, none has been definitely defined by confirmatory evidence. Kusmartsev et al (page 1143) describe a possible instrumental role of human macrophages in the pathogenesis of CaOx stone formation. 11 Their work demonstrates that macrophages differentiated with macrophage colony-stimulating factor were able to effectively phagocytose CaOx crystals less than 200 mm. The finding suggests that macrophages may serve an instrumental role in clearing these crystals and preventing future crystal growth and stone formation. This remarkable study may open new doors in terms of understanding the pathogenesis of CaOx stone disease. It is possible that differences in immune function among individuals could directly relate to stone formation. Perhaps these differences account for why Randall plaques form in some individuals and not in others. These remain early discoveries. Better understanding of the role of these macrophages and apatite deposits is also needed, and yet this is undeniably a significant advance. This work is hypothesis generating. 11 How are these immune responses mediated in different individuals with and without a history of CaOx stone formation? What are the implications for patients who are immunocompromised? Will immunotherapy ultimately be an effective tool for preventing CaOx stone formation? It seems that we may be on the cusp of a new era in stone disease. Numerous well established experts continue to push the field forward but importantly there are now new young investigators who have made stone disease their focus. Investigating the relationship of the immune system and stone disease is novel, and may lead to better understanding of the pathogenesis of the disease. With such efforts the new information gleaned could conceivably lead to translational breakthroughs in stone disease treatment and prevention.