MINI REVIEW article
Front. Physiol.
Sec. Renal Physiology and Pathophysiology
Volume 16 - 2025 | doi: 10.3389/fphys.2025.1614438
This article is part of the Research TopicDivalent Cations in Kidney Physiology and DiseaseView all 3 articles
Targeting the NLRP3 Inflammasome for Calcium Oxalate Stones: Pathophysiology and Emerging Pharmacological Interventions
Provisionally accepted
Andrew M. Boldt
Francesca Di Sole*- Des Moines University, Des Moines, United States
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Kidney stone disease (nephrolithiasis) is a widespread condition affecting millions worldwide, with its prevalence rising due to dietary changes, obesity, and climate-related factors. The formation of kidney stones is driven by urinary solute supersaturation, metabolic abnormalities, and environmental influences. Calcium oxalate stones, the most common type, result from hypercalciuria, hyperoxaluria, and hypocitraturia, often exacerbated by high dietary protein intake and hormonal imbalances such as hyperparathyroidism. A significant complication of kidney stones is their association with chronic kidney disease (CKD). Recurrent stone formation contributes to renal scarring, urinary obstruction, and inflammation, ultimately leading to long-term kidney damage. This review explores the pivotal role of the NLRP3 inflammasome in kidney stone-related inflammation. Activated by calcium oxalate crystals and oxidative stress, NLRP3 triggers the release of pro-inflammatory cytokines (IL-1β and IL-18), exacerbating renal injury and fibrosis. Persistent NLRP3 activation is linked to CKD progression and an increased risk of end-stage renal disease. Emerging therapies targeting NLRP3 offer potential strategies to mitigate kidney stone-induced inflammation and CKD progression. Direct inhibitors such as MCC950 and CP-456,773 block inflammasome activation, reducing inflammatory cytokine release. Indirect approaches, including atorvastatin and phenylbutyric acid, address oxidative stress and mitochondrial dysfunction to lower stone formation risk. While these treatments show promise in preclinical studies, further research is needed to validate their clinical efficacy. Future studies should focus on optimizing NLRP3-targeted therapies, assessing their long-term effects on kidney stone prevention and CKD progression. Combining NLRP3 inhibitors with antioxidants may enhance renal protection, providing new avenues for therapeutic intervention.
Keywords: Calcium oxalate stones, Kidney stone disease, NLRP3 inflammasome, Chronic Kidney Disease, renal inflammation
Received: 18 Apr 2025; Accepted: 16 May 2025.
Copyright: © 2025 Boldt and Di Sole. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Francesca Di Sole, Des Moines University, Des Moines, United States
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