Recent Advances in the Pathophysiology of Nephrolithiasis


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.


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.[5-7] It is also associated with an increased risk of hypertension,[8-12] coronary artery disease,[13,14] the metabolic syndrome (MS),[15-20] and diabetes mellitus.[19-24] 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.

Ethiologic Mechanisms of Uric Acid Stone Formation

Three major factors for the development of uric acid (UA) stones are low urine volume, acidic urine pH, and hyperuricosuria. However, abnormally acidic urine is the principal determinate in UA crystallization. The etiologic mechanisms for UA stone formation are diverse, and include congenital, acquired, and idiopathic causes.[26] The most prevalent cause of UA nephrolithiasis is idiopathic. In its initial description, the term ‘gouty diathesis’ was coined.[27] The clinical and biochemical presentation of idiopathic UA nephrolithiasis (IUAN) cannot be attributed to an inborn error of metabolism [26,28,29] or secondary causes such as chronic diarrhea,[30] strenuous physical exercise,[31] and a high purine diet.[32]

Calcium Oxalate Nephrolithiasis

Although it affects both genders, calcium oxalate nephrolithiasis generally tends to occur in more men than women. In the calcium oxalate stone former, urinary oxalate and urinary calcium are equally conducive in raising urinary calcium oxalate supersaturation.[75] Hyperoxaluria is encountered in 8-50% of kidney stone formers.[76-78] The main etiologic causes of hyperoxaluria can be classified into three groups: (1) increased oxalate production as a result of an inborn error in metabolism of the oxalate synthetic pathway, (2) increased substrate provision from dietary oxalate-rich foods or other oxalate precursors, and (3) increased intestinal oxalate absorption.[1] With the study of Oxalobacter formigenes (OF)[79,80] and the role of putative anion transporter Slc26a6[81] as potential tools in the treatment of primary hyperoxaluria, our knowledge of the pathophysiologic mechanisms of oxalate metabolism has advanced significantly over the past decade.[82]

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