![]() Thus, it appears that other than urinary supersaturation, crystal-cell attachment, crystal aggregation/growth, and tubular epithelial cell damage are highly important processes during stone formation. In addition, crystal uptake often damages cells and causes epithelial cell death, which releases cellular debris that forms a nidus of additional crystal growth, thereby promoting stone formation 36, 37. Some crystals are endocytosed by epithelial cells, and thereafter, dissolved within lysosomes, or re-emerge at the basolateral surface, again providing centers for stone growth in the renal interstitial area 32– 35. When the attached crystals are retained at the luminal side of tubular epithelial cells, they aggregate, grow, and develop into stones in the urinary tract (nephrolithiasis or urolithiasis) 25– 31. CaOx crystals attach to the surface of renal tubular epithelial cells by interacting with negatively charged membrane components such as phosphatidylserine, which is redistributed to the cell surface upon mechanical (by the crystals themselves) and/or chemical (by oxalate) cell injury 23, 24. The excessive supersaturation in urine results in crystal nucleation, the initial step in the transformation from a liquid to a solid phase within the urinary tract 19– 22. Globally, ~80% of kidney stones are composed of calcium oxalate (CaOx) mixed with calcium phosphate, 10% of struvite, 9% of uric acid, and the rest are composed of cystine or ammonium acid urate or are diagnosed as drug-related stones 17, 18. Conversely, stone formers are at risk of hypertension, acute kidney injury (AKI), and chronic kidney disease 6– 16. Metabolic syndrome associated with obesity, diabetes, and hypertension is considered a strong risk factor for stone formation. Kidney stone formation is highly prevalent and has been increasing with recurrence rate up to 50% within the first 5 years after the initial stone episode in both sexes over the past 50 years, owing to rapid changes in lifestyle and dietary habits as well as global warming 1– 6. ![]() Our results could be the basis for the development of a comprehensive therapy against kidney stone disease. We also found that tubular KIM-1 may remove developed stones. Furthermore, only AIM was effective in improving the physical complaints including bodyweight-loss through its DAMPs removal effect. Among various negatively charged substances, rAIM was most effective in stone prevention due to its high binding affinity to crystals. Expression of injury molecules and inflammatory cytokines in the kidney and overall renal dysfunction were abrogated by rAIM. Accordingly, when stones were induced by glyoxylate in mice, recombinant AIM (rAIM) injection dramatically reduced stone development. ![]() The N-terminal domain of AIM associates with calcium oxalate crystals via charge-based interaction to impede the development of stones, whereas the 2nd and C-terminal domains capture the inflammatory DAMPs to promote their phagocytic removal. Here, we show that AIM (also called CD5L) suppresses stone development and improves stone-associated physical damages. No treatments that prevent the occurrence/recurrence of stones have reached the clinic. The prevalence of kidney stones is increasing and its recurrence rate within the first 5 years is over 50%.
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