Is oxidative stress, a link between nephrolithiasis and obesity, hypertension, diabetes, chronic kidney disease, metabolic syndrome?

Abstract

Epidemiological studies have provided the evidence for association between nephrolithiasis and a number of cardiovascular diseases including hypertension, diabetes, chronic kidney disease, metabolic syndrome. Many of the co-morbidities may not only lead to stone disease but also be triggered by it. Nephrolithiasis is a risk factor for development of hypertension and have higher prevalence of diabetes mellitus and some hypertensive and diabetic patients are at greater risk for stone formation. An analysis of the association between stone disease and other simultaneously appearing disorders, as well as factors involved in their pathogenesis, may provide an insight into stone formation and improved therapies for stone recurrence and prevention. It is our hypothesis that association between stone formation and development of co-morbidities is a result of certain common pathological features. Review of the recent literature indicates that production of reactive oxygen species (ROS) and development of oxidative stress (OS) may be such a common pathway. OS is a common feature of all cardiovascular diseases (CVD) including hypertension, diabetes mellitus, atherosclerosis and myocardial infarct. There is increasing evidence that ROS are also produced during idiopathic calcium oxalate (CaOx) nephrolithiasis. Both tissue culture and animal model studies demonstrate that ROS are produced during interaction between CaOx/calcium phosphate (CaP) crystals and renal epithelial cells. Clinical studies have also provided evidence for the development of oxidative stress in the kidneys of stone forming patients. Renal disorders which lead to OS appear to be a continuum. Stress produced by one disorder may trigger the other under the right circumstances.

Fig. 1

Diagrammatic presentation of associations between nephrolithiasis and co-morbidities based upon epidemiological data. Dashed arrows indicate that links have been seen in specific stone types or relationships are weak

Fig. 2

Signalling pathways associated with nephrolithiasis as determined by animal model and tissue culture studies

Fig. 3

Nephrolithiasis and its co-morbidities lead to the development of oxidative stress which is considered a major cause of inflammation. It is our hypothesis that oxidative stress and inflammation produced by one disorder may under certain conditions lead to the development of the co-morbidity. For example, mildly high calcium or phosphate may promote deposition of calcium phosphate crystals in the renal interstitium with localized inflammation and deposition of collagen leading to the development of Randall’s plaque. Or mildly high calcium and phosphate or oxalate and low citrate or magnesium in the urine may lead to crystallization in the collecting ducts of kidney which is oxidatively stressed and injured