Reactive oxygen species as the molecular modulators of calcium oxalate kidney stone formation: Evidence from clinical and experimental investigations

Saeed R. Khan

Research output: Contribution to journalArticle

Abstract

Purpose: Idiopathic calcium oxalate kidney stones form while attached to Randall plaques, the subepithelial deposits on renal papillary surfaces. Plaque formation and growth mechanisms are poorly understood. Plaque formation elsewhere in the body is triggered by reactive oxygen species and oxidative stress. This review explores possible reactive oxygen species involvement in plaque formation and calcium oxalate nephrolithiasis. Materials and Methods: A search of various databases for the last 8 years identified literature on reactive oxygen species involvement in calcium oxalate nephrolithiasis. The literature was reviewed and results are discussed. Results: Under normal conditions reactive oxygen species production is controlled, increasing as needed and regulating crystallization modulator production. Reactive oxygen species overproduction or decreased antioxidants lead to oxidative stress, inflammation and injury, and are involved in stone comorbidity. All major chronic inflammation markers are detectable in stone patient urine. Patients also have increased urinary excretion of the IαI and the thrombin protein families. Results of a recent study of 17,695 participants in NHANES III (National Health and Nutrition Examination Survey) showed significantly lower antioxidants, carotene and β-cryptoxanthin in those with a kidney stone history. Animal model and tissue culture studies revealed that high oxalate, calcium oxalate and calcium phosphate crystals provoked renal cell reactive oxygen species mediated inflammatory responses. Calcium oxalate crystals induce renin up-regulation and angiotensin II generation. Nonphagocytic NADPH oxidase leads to reactive oxygen species production mediated by protein kinase C. The P-38 MAPK/JNK transduction pathway is turned on. Transcriptional and growth factors, and generated secondary mediators become involved. Chemoattractant and osteopontin production is increased and macrophages infiltrate the renal interstitium around the crystal. Phagocytic NADPH oxidase is probably activated, producing additional reactive oxygen species. Localized inflammation, extracellular matrix and fibrosis develop. Crystallization modulators have a significant role in inflammation and tissue repair. Conclusions: Based on available data, Randall plaque formation is similar to extracellular matrix mineralization at many body sites. Renal interstitial collagen becomes mineralized, assisting plaque growth through the interstitium until the mineralizing front reaches papillary surface epithelium. Plaque exposure to pelvic urine may also be a result of reactive oxygen species triggered epithelial sloughing.

Original languageEnglish (US)
Pages (from-to)803-811
Number of pages9
JournalJournal of Urology
Volume189
Issue number3
DOIs
StatePublished - Mar 2013
Externally publishedYes

Fingerprint

Calcium Oxalate
Kidney Calculi
Reactive Oxygen Species
Inflammation
Kidney
Nutrition Surveys
NADPH Oxidase
Crystallization
Extracellular Matrix
Oxidative Stress
Antioxidants
Urine
Osteopontin
Oxalates
MAP Kinase Signaling System
Chemotactic Factors
Carotenoids
Growth
Renin
Thrombin

Keywords

  • calcification, physiologic
  • calcium oxalate
  • kidney
  • nephrolithiasis
  • reactive oxygen species

ASJC Scopus subject areas

  • Urology

Cite this

Reactive oxygen species as the molecular modulators of calcium oxalate kidney stone formation : Evidence from clinical and experimental investigations. / Khan, Saeed R.

In: Journal of Urology, Vol. 189, No. 3, 03.2013, p. 803-811.

Research output: Contribution to journalArticle

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abstract = "Purpose: Idiopathic calcium oxalate kidney stones form while attached to Randall plaques, the subepithelial deposits on renal papillary surfaces. Plaque formation and growth mechanisms are poorly understood. Plaque formation elsewhere in the body is triggered by reactive oxygen species and oxidative stress. This review explores possible reactive oxygen species involvement in plaque formation and calcium oxalate nephrolithiasis. Materials and Methods: A search of various databases for the last 8 years identified literature on reactive oxygen species involvement in calcium oxalate nephrolithiasis. The literature was reviewed and results are discussed. Results: Under normal conditions reactive oxygen species production is controlled, increasing as needed and regulating crystallization modulator production. Reactive oxygen species overproduction or decreased antioxidants lead to oxidative stress, inflammation and injury, and are involved in stone comorbidity. All major chronic inflammation markers are detectable in stone patient urine. Patients also have increased urinary excretion of the IαI and the thrombin protein families. Results of a recent study of 17,695 participants in NHANES III (National Health and Nutrition Examination Survey) showed significantly lower antioxidants, carotene and β-cryptoxanthin in those with a kidney stone history. Animal model and tissue culture studies revealed that high oxalate, calcium oxalate and calcium phosphate crystals provoked renal cell reactive oxygen species mediated inflammatory responses. Calcium oxalate crystals induce renin up-regulation and angiotensin II generation. Nonphagocytic NADPH oxidase leads to reactive oxygen species production mediated by protein kinase C. The P-38 MAPK/JNK transduction pathway is turned on. Transcriptional and growth factors, and generated secondary mediators become involved. Chemoattractant and osteopontin production is increased and macrophages infiltrate the renal interstitium around the crystal. Phagocytic NADPH oxidase is probably activated, producing additional reactive oxygen species. Localized inflammation, extracellular matrix and fibrosis develop. Crystallization modulators have a significant role in inflammation and tissue repair. Conclusions: Based on available data, Randall plaque formation is similar to extracellular matrix mineralization at many body sites. Renal interstitial collagen becomes mineralized, assisting plaque growth through the interstitium until the mineralizing front reaches papillary surface epithelium. Plaque exposure to pelvic urine may also be a result of reactive oxygen species triggered epithelial sloughing.",
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