Recent Advances in the Pathophysiology of Nephrolithiasis

Khashayar Sakhaee

Disclosures

June 29, 2009

In This Article

Abstract and Introduction

Abstract

Over the past 10 years, major progress has been made in the pathogenesis of uric acid and calcium stones. These advances have led to our further understanding of a pathogenetic link between uric acid nephrolithiasis and the metabolic syndrome, the role of Oxalobacter formigenes in calcium oxalate stone formation, oxalate transport in Slc26a6-null mice, the potential pathogenetic role of Randall's plaque as a precursor for calcium oxalate nephrolithiasis, and the role of renal tubular crystal retention. With these advances, we may target the development of novel drugs including (1) insulin sensitizers; (2) probiotic therapy with O. formigenes, recombinant enzymes, or engineered bacteria; (3) treatments that involve the upregulation of intestinal luminal oxalate secretion by increasing anion transporter activity (Slc26a6), luminally active nonabsorbed agents, or oxalate binders; and (4) drugs that prevent the formation of Randall's plaque and/or renal tubular crystal adhesions.

Introduction

Calcium oxalate is the most prevalent type of kidney stone disease in the United States and has been shown to occur in 70-80% of the kidney stone population.[1] The prevalence of recurrent calcium oxalate stones has progressively increased in untreated subjects, approaching a 50% recurrence rate over 10 years.[2] The lifetime risk for kidney stone disease currently exceeds 6-12% in the general population.[3,4] In the final quarter of the twenty-first century, the prevalence of kidney stone disease increased in both gender and ethnicity.[4] Although kidney stone nephrolithiasis is perceived as an acute illness, there has been growing evidence that nephrolithiasis is a systemic disorder that leads to end-stage renal disease.[5,6,7] It is also associated with an increased risk of hypertension,[8,9,10,11,12] coronary artery disease,[13,14] the metabolic syndrome (MS),[15,16,17,18,19,20] and diabetes mellitus.[19,20,21,22,23,24] Nephrolithiasis without medical treatment is a recurrent illness with a prevalence of 50% over 10 years.[2] Nephrolithiasis has remained a prominent issue that imposes a significant burden on human health and is a considerable financial expenditure for the nation. In 2005, based on inpatient and outpatient claims, this condition was estimated to cost over $2.1 billion.[25] A novel strategy for the development of new drugs has been hampered largely by the complexity of this disease's pathogenetic mechanism and its molecular genetic basis. Our further understanding of these underlying pathophysiologic mechanisms will be the key step in developing more effective preventive and therapeutic measures.

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