Key points

Introduction

Urolithiasis has been a documented medical affliction since at least ancient Egyptian civilization, and continues to be responsible for an increasing number of practitioner visits worldwide. Furthermore, the recurrence rates of symptomatic stones are high at more than 50% within 5 years of a first episode, suggesting that identifiable high-risk cohorts may experience common pathways in the pathogenesis of stone formation that can be targeted for prevention efforts. This exciting field of research continues to grow. The goal of this article is to discuss new frontiers of understanding regarding the pathophysiology of urinary stone disease.

Introduction

Urolithiasis has been a documented medical affliction since at least ancient Egyptian civilization, and continues to be responsible for an increasing number of practitioner visits worldwide. Furthermore, the recurrence rates of symptomatic stones are high at more than 50% within 5 years of a first episode, suggesting that identifiable high-risk cohorts may experience common pathways in the pathogenesis of stone formation that can be targeted for prevention efforts. This exciting field of research continues to grow. The goal of this article is to discuss new frontiers of understanding regarding the pathophysiology of urinary stone disease.

Physiochemical aspects of urinary stone formation

At the root of the pathophysiology of urolithiasis is the physiochemical formation of urinary stones. As the glomerular filtrate passes through the nephron, the urine becomes concentrated with stone-forming salts which, when supersaturated, can precipitate out of solution into crystals that can either be expulsed with voided urine or grow and aggregate under the relative influences of various stone-promoting or stone-inhibiting agents, resulting in stone formation. Given an estimated transit time through the nephron of 5 to 7 minutes, traditional thought was that this did not allow sufficient time for free particles to aggregate enough to increase in size to occlude a tubular lumen and serve as a site of stone formation. This theory suggested that some adhesion to tubular epithelial cells as fixed particles would be required to allow for crystal growth and subsequent stone formation. Although recalculation of nephron dimensions in the context of crystal conglomeration during acute increases in supersaturation have concluded that a free-particle theory of stone formation is a potential mechanism of disease, research into the fixed particle mechanism has gained some favorable results. In particular, the theory has been evaluated that intraluminal deposits, mostly within the distal nephron, could serve as sites of stone formation.

Histopathologic evidence of plugs of mineral deposits has been noted in several stone-forming groups of patients, such as those with brushite stones, hyperparathyroidism, cystinuria, and distal renal tubular acidosis, and those with a history of intestinal surgery, including bypass surgery for obesity, small bowel resection, and ileostomy creation. This theory is supported by observations of stone material growing from the ends of these plugs; however, whether these intraluminal deposits lead to stone formation remains unknown. Much research must be performed to elucidate this question, and most likely this is one of multiple pathways in the pathogenesis of urinary stone disease.

Randall plaques

Associations with Urinary Stone Disease

In contrast to the free and fixed particle theories of stone pathogenesis is the Randall plaque hypothesis. The theory evolved during a search for an initiating lesion for renal stones, which Alexander Randall thought originated in the renal papilla. Strong evidence was gained for this hypothesis during human autopsy studies in which calcium deposits were found in nearly 20% of renal papillae, with nearly one-third of these patients having a primary renal stone at the site. These deposits were coined “Randall plaques” and histologic analysis showed that the lesions were in the interstitial tissues of the papilla near segments of the nephron, rather than within the nephron lumen itself. Randall hypothesized the exposed plaque material served as a nidus for stone formation. This hypothesis has regained popularity over the past decade, particularly in regard to the pathogenesis of idiopathic calcium oxalate stones, the most commonly encountered stone in clinical practice. Published observations by Miller and colleagues during endoscopy confirmed that most stones in their study population of patients with idiopathic calcium oxalate stones, which were visually noted to be attached to and primarily originating from these Randall plaques ( Fig. 1 ). Further evaluation from this group lent more credence to this observation. The group decided to also analyze free-floating stones encountered during ureteroscopy. More than half of these stones had mucus-covered, concavely cupped regions on one side of the stone that were found to contain apatite on micro-CT analysis of internal structure. This evidence supported the idea that these stones had also grown from a papillary plaque and then subsequently fallen off. Internal structure analysis of the remainder of the stones showed similar evidence of previous attachment to a Randall plaque at one end indicated by the presence of apatite. This finding also provided strong evidence that calcium oxalate stones arise from Randall plaques.

A Randall plaque forming at a renal papilla, as visualized on endoscopy. No stone is currently attached.

Vascular disease associations with urolithiasis

To explore new frontiers in the pathogenesis of urinary stone disease, it is helpful to explore associations between urolithiasis and other phenomena, such as vascular disease. The link between urolithiasis and vascular disease is well documented in the literature. Nephrolithiasis has been associated with a 31% increased risk of myocardial infarction (MI), as documented by Rule and colleagues in a study of more than 4500 stone formers compared with nearly 11,000 control patients with 9 years of follow-up. The risk was noted to be independent of kidney disease or other common risk factors for MI. Data from a large cohort of nearly 10,000 women participating in the Study of Osteoporotic Fractures has similarly revealed that patients with a history of nephrolithiasis have an increased relative risk (RR) of MI (RR, 1.78) and angina (RR, 1.63).

Although the precise mechanisms underlying these associations remain to be elucidated, one speculation is that the disease processes may have shared risk factors that have not been fully identified. One potential risk factor could be atherosclerosis, as supported by the vascular theory of Randall plaque formation. The association between nephrolithiasis and subclinical atherosclerosis was recently investigated within the Coronary Adult Risk Development in Young Adults (CARDIA) cohort, which identified a significant association between kidney stones and carotid artery atherosclerosis (odds ratio [OR], 1.6), even after adjusting for known major atherosclerotic risk factors. This study provided further support for possible common systemic pathophysiology that may be shared between vascular and urinary stone disease.

Perhaps most well studied is the association between urinary stone disease and hypertension, which was recognized as early as the 1760s when Morgagni described a patient with clinical and anatomic findings suggestive of both diseases. More recent studies have confirmed these observations. In their prospective analysis of 503 men, Cappuccio and colleagues noted an RR of 1.96 for the development of kidney stones in hypertensive men compared with normotensive men at 8 years. Similarly, in another prospective analysis, Borghi and colleagues noted an OR of 5.5 linking a baseline history of hypertension to the formation of a kidney stone at 5 years of follow-up. This risk seemed particularly pronounced for individuals who were overweight. The link between hypertension and urinary stone disease seems to be potentially bidirectional, as supported by studies that have demonstrated stone formation to predate the onset of hypertension. In their prospective study of a cohort of more than 50,000 men, Madore and colleagues noted an association between nephrolithiasis and risk of hypertension (OR, 1.31), and reported that in men who had both disorders, 79.5% experienced the occurrence of nephrolithiasis before or concomitant to their diagnosis of hypertension. A similar association was seen in women, with an RR of 1.36 for developing a new diagnosis of hypertension in those with a history of nephrolithiasis, as demonstrated from data secured from the Nurses’ Heath study, a cohort with nearly 90,000 women.

Although an association seems to exist between hypertension and urinary stone disease, the pathophysiology responsible for this link remains unclear. Multiple theories have been proposed, some highlighting the contribution of urinary composition to the mechanism of disease. Strazzullo and colleagues in a case-controlled study of 110 patients, evaluated calcium metabolism in cohorts with and without essential hypertension, noting higher urinary calcium excretion rates in hypertensive individuals despite similar total and ionized serum calcium levels. The response to intravenous calcium infusion was also investigated, showing that hypertensive patients excreted more calcium at all serum calcium concentrations, suggesting that a form of urinary leak of calcium could be occurring within hypertensive patients. Cappuccio and colleagues similarly recorded abnormalities of calcium metabolism in hypertensive patients, specifically highlighting increased parathyroid gland activity, urinary cyclic AMP, and intestinal calcium absorption. Increased levels of urinary uric acid and decreased levels of urinary citrate have also been seen in studies of hypertensive individuals. These risk factors for the development of urinary stones are well established. Differences in urinary composition of magnesium and oxalate may also contribute to the link between hypertension and urinary stone disease. Diet has also been implicated as a potential link between hypertension and a predisposition for urolithiasis. In particular, the known effects of increased dietary sodium, known to promote urolithiasis via hypercalciuria and also promote hypertension, has led to its consideration as a potential parsimonious factor.

Animal models have also demonstrated this association between hypertension and urinary stone disease. Although otherwise rare in animals, Wexler and McMurtry showed that strains of spontaneously hypertensive rats that were born normotensive and developed hypertension with maturation were prone to the development of urinary stone disease. The substrain most prone to urolithiasis also became obese with maturity and stereotypically formed microscopic stones within the kidney. These stones began in a subepithelial location before detaching and serving as a nidus for further stone growth, a mechanism reminiscent of current Randall plaque theories of stone formation. This finding also implicates other metabolic associations with urinary stone disease, such as obesity.

Obesity, diabetes, and urinary stone disease

Several studies have found significant associations between weight and body mass index (BMI) and urinary stones. Taylor and colleagues, in an analysis of 3 large prospective cohorts of nearly 250,000 individuals, showed that the RR of incident kidney stone formation for people weighing more than 100 kg, compared with those weighing less than 68.2 kg, was 1.44 in men, 1.89 in older women, and 1.92 in younger women. Using a BMI cutoff of 30, the RRs were 1.33, 1.90, and 2.09, respectively. Similarly, in a study of more than 800 renal stone formers, Del Valle and colleagues showed that most patients (nearly 60%) were either overweight or obese. In 2006, Taylor and Curhan investigated the relationship of BMI as a continuous variable to stone formation, and noted that even in nonobese patients (BMI <30), an increasing BMI lent itself to a higher risk of urolithiasis. The effect was most significant in women, wherein those with a BMI of 23 to 24.9 had a 25% increased incidence of stones compared with those with a BMI of 21 to 22.9. Those with a BMI of 27.5 to 29.9 had a 65% to 75% increased incidence. Similar results were seen in men, wherein those with a BMI of 25 to 29.9 had a 15% to 25% increase in stone incidence compared with those with a BMI of 21 to 22.9. These findings support the idea that increasing weight and BMI are directly correlated to susceptibility to urinary stone formation.

Multiple groups have investigated urine chemistries to better characterize the links between BMI and urinary stone disease. Ekeruo and colleagues, for example, noted that obese (BMI >30) urinary stone formers most commonly had evidence of hypocitraturia (54%) and hyperuricosuria (43%) compared with nonobese stone formers. Taylor and Curhan and Powell and colleagues similarly investigated urine chemistries, showing increased urinary excretion of oxalate, uric acid, phosphate, sodium, sulfate, and cysteine in obese versus nonobese patients. Urinary composition in the obese population seems to contain higher levels of substances known to precipitate urinary stones compared with the nonobese population.

The close association between obesity and diabetes, another known risk factor for urolithiasis, may compound the influence of obesity on the development of urinary stones. Obesity has been shown to carry with it a well-established increased risk for diabetes mellitus. In several large-scale studies, patients with diabetes have been closely linked to increased risk of formation of all types of urinary calculi and increased risk of uric acid stone formation in particular. Several pathophysiologic mechanisms have been suggested to explain these observations. One explanation offered by Canda and Isgoren stems from their observation of decreased function of interstitial cells and neural tissue within the urothelial tissue of diabetic rabbits. They suggested that these perturbations of function could affect ureteral peristalsis and promote urinary stone formation by virtue of urinary stasis. Other authors, however, suggest that the insulin resistance seen in diabetics is the underlying mechanism through which stones form. Insulin resistance has been noted to impair renal ammoniagenesis, resulting in acidic urine. It also promotes reabsorption of uric acid in the proximal tubule, resulting in hyperuricemia. Both of these factors could contribute to an increased propensity for uric acid urolithiasis. Hyperglycemia has also been associated with increased urinary calcium and oxalate excretion. Taken together, these metabolic changes may explain the consistent association seen between diabetes and urinary stone disease.

Dyslipidemia and urinary stone disease

The links between dyslipidemia and urinary stone disease have also been investigated. Kadlec and colleagues, in their retrospective review of nearly 600 endourologic stone procedures for which stone composition data were available, noted that more than 30% of their cohort was characterized as dyslipidemic (defined by the use of a cholesterol-lowering medication). Of these patients with dyslipidemia, nearly 70% had calcium oxalate stones and 15% had uric acid stones. A recent study by Inci and colleagues similarly found that total cholesterol levels were significantly higher in stone formers compared with patients who do not form stones, with the association noted to be particularly prominent for calcium oxalate and uric acid stone formers.

To evaluate the potential pathophysiologic mechanisms linking dyslipidemia with urinary stone disease, related research on atorvastatin may be useful to consider. Atorvastatin is a commonly prescribed drug used to decrease serum cholesterol levels. Tsujihata and colleagues reported that the administration of atorvastatin to stone-forming rats significantly lowered crystalline deposits on quantitative light microscopy analysis of excised kidney specimens. They hypothesized that anti-inflammatory and antioxidative effects of the drug were responsible, through preventing renal tubular cell injury from oxalate and subsequently inhibiting renal crystal retention. In their experimental model, they found that urinary levels of biomarkers for renal tubular cell injury ( N -acetyl glucosamidase) and oxidative stress (8-OHdG) were decreased significantly by atorvastatin treatment. Furthermore, atorvastatin treatment decreased the apoptosis of renal tubular cells. These results suggest that common pathophysiology shared between dyslipidemia and urinary stone formation may be related to inflammation and subsequent cellular injury of renal tubular cells.

The metabolic syndrome and unification of the metabolic links to urinary stone disease

Metabolic syndrome is the term given to a combination of risk factors that may include impaired fasting glucose, elevated blood pressure, central obesity, and dyslipidemia in the form of high serum triglycerides or low high-density lipoprotein cholesterol levels. The presence of at least 3 of these traits establishes a diagnosis. This syndrome has been strongly associated with various disease states, most notably diabetes and cardiovascular disease, with a documented relative risk of 3 for diabetes, and 1.78 for cardiovascular disease and death.

More recently, metabolic syndrome has become the subject of increased urologic research because of continued observations that it is associated with an increased risk of urinary stone disease. West and colleagues examined the association between the number of metabolic syndrome traits and risk of nephrolithiasis using a national sample of patients in the United States. Prevalence of kidney stones increased with the number of traits, from 3% with 0 traits to 9.8% with 5 traits. The presence of 2 or more traits significantly increased the odds of stone disease, and the presence of 4 or more traits was associated with an approximate 2-fold increase. In a study of Italian adults, Rendina and colleagues similarly found an approximate 2-fold increase in the risk of stone disease for patients with metabolic syndrome. In an analysis of the individual components of the syndrome, they found that the only syndrome trait independently associated with increased stone risk on its own was hypertension. The risk of nephrolithiasis with hypertension was reported with an OR of 2.1 for men and 4.9 for women. The presence of hypertension with any other trait of metabolic syndrome further increased the risk of urolithiasis, with an OR of 2.2 compared with those individuals with hypertension alone. Jeong and colleagues confirmed a similar pattern in an American population, finding metabolic syndrome and the trait of hypertension as independent risk factors for the presence of urinary stones. The other components of metabolic syndrome did not independently carry a risk for kidney stone disease. Patients with metabolic syndrome had an OR of 1.25 for stone disease, and those with hypertension had an OR of 1.47. These studies suggest that synergistic effects of the components of the syndrome lead to an increased risk of urolithiasis. Therefore, the pathophysiology explaining increased urinary stone risk related to metabolic syndrome likely goes beyond simple cumulative effects on urine chemistry by the individual components of the syndrome. Underlying shared systemic influences are likely at play. The vascular theory of stone development is one hypothesis that attempts to link the components of the metabolic syndrome with urinary stone disease by considering a possible common systemic malfunction of inflammation and tissue damage as an underlying mechanism. However, further research is needed to investigate this hypothesis further, and to consider other possible unifying mechanisms of disease. This research will likely need to go beyond epidemiologic and urine composition studies to tease out the mechanisms behind the individual disease states themselves.