The majority of calcium-containing stones contain calcium oxalate; hypercalciuric and hyperoxaluric states promote stone formation. In some instances, hyperuricemia also contributes to calcium stone formation.

Hypercalciuric states can be categorized into three groups according to cause: increased gut absorption of dietary calcium, increased resorption of calcium from bone, and the presence of a renal calcium leak. Combinations of these factors are at play in certain clinical settings. About 50% of patients with calcium stones are found to be hypercalciuric; genetic factors that increase renal calcium excretion are believed to play a major role (as manifested by at 50% risk of stone disease in persons with a positive family history), though the responsible gene mutations have yet to be identified.

Hyperoxaluria is less common than is hypercalciuria, but recent studies indicate that up to 30% of patients with calcium oxalate stones are hyperoxaluric. Hyperoxaluria may result from increased absorption of dietary oxalate, as occurs in patients with inflammatory bowel disease, short-bowel syndrome (seen after bariatric surgery), or diets low in calcium (less gut precipitation of calcium oxalate, greater absorption); from increased endogenous production of oxalate, as occurs in patients with deficiency of pyridoxine (an important cofactor in glyoxylate metabolism) or genetic defect in enzymes of the glyoxylate pathway; or, less commonly, from markedly increased ingestion of oxalate or one of its precursors. Of concern is the potential contribution from use of broad-spectrum antibiotics, resulting in reduction of gut Oxalobacter formigenes, a component of normal gut bacterial flora, which metabolizes oxalate and prevents its absorption.

Hyperuricosuria can contribute. It is believed that adsorption of glutamic acid onto a uric acid nidus allows for the growth of calcium oxalate crystals. However, a significant number of patients with calcium stones have no discernible metabolic derangement, making rational drug therapy more difficult.

Low urinary citrate is found in some patients with calciumcontaining stones. Citrate is a potent inhibitor of stone formation, and low urinary citrate would predispose a patient to calcium stone formation.

Struvite formation occurs in an alkaline environment and is almost invariably associated with urinary tract bacterial infection involving urea-splitting Proteus species.

Most patients with uric acid stones have persistently acid urine, which decreases the solubility of uric acid. Some patients may be hyperuricosuric. Hyperuricosuric states are seen in patients with a high dietary intake of protein and with primary and secondary gout. In patients who have myeloproliferative disorders or are undergoing chemotherapy, significant hyperuricosuria can occur, and uric acid stones can form if adequate urine flow and alkalinization are not maintained.

Cystine stones are found exclusively in patients with cystinuria. These patients have an inherited disorder in which renal and gastrointestinal transport of cystine, ornithine, lysine, and arginine are abnormal.

In patients on treatment for HIV with indinavir, rare instances of crystallization of indinavir with resultant stones have been reported.

These occur in the setting of xanthinuria, an extremely rare genetic disorder of purine metabolism associated with a deficiency of xanthine oxidase. Rarely, xanthine stones may be seen in patients taking xanthine oxidase inhibitors for the treatment of uric acid disorders.

Physicochemical factors that have been identified as important in stone formation include changes in urinary pH and urinary concentrations of potential inhibitors of stone formation, such as magnesium, citrate, sulfate, organic matrix, and pyrophosphate. As noted earlier, an alkaline pH facilitates struvite formation, and an acidic pH facilitates the formation of uric acid and xanthine stones. Magnesium, citrate, pyrophosphate, and certain anions in high urinary concentrations are potent inhibitors of stone formation. Deficiencies in one or more of the inhibitors have been identified in some patients with recurrent stones.

Three major theories have been advanced to explain stone formation and growth. The matrix nucleation theory suggests that some matrix substances (e.g., uric acid) form an initial nucleus for subsequent stone growth by precipitation. The precipitation-crystallization theory suggests that when the urinary crystalloids are present in a supersaturated state, precipitation and subsequent growth occur. The inhibitor absence theory postulates that the deficiency of one or more of numerous agents known to retard stone formation leads to nephrolithiasis. Evidence for and against each of these theories has been advanced; multiple factors may be involved in any patient.

Clinical presentations range from asymptomatic disease to acute pain. Asymptomatic stones are typically incidental findings detected on imaging studies done for other reasons or for evaluation of hematuria. Renal colic occurs in the context of ureteral obstruction, presenting as abrupt onset of persistent pain that waxes and wanes, localized to one flank when the stone sits wedged at the ureteropelvic junction and radiating into the groin and genitalia when the offending stone lodges in the lower portion of the ureter, usually at the ureterovesical junction. When lodged in the bladder neck, the pain is suprapubic, and anuria may ensue. Nausea and vomiting may be prominent (mimicking a gastrointestinal source), but fever is absent unless there is concurrent pyelonephritis. The presentation may be mistaken for pyelonephritis or for an abdominal or pelvic process due to the pain radiation. Gross or microscopic hematuria may be noted, either in the context of pain or in an otherwise asymptomatic patient. Presence of fever and pyuria (>5 WBC/HPF) suggests superimposed pyelonephritis behind the obstruction, predisposing to bacteremia and urosepsis.

Clinical course depends in part on size and location of the stone. For stones less than 5 mm in diameter, any obstruction that occurs is, in over 98% of instances, transient and of no lasting significance. Larger stones have a greater risk of causing a more prolonged obstruction. The 10% to 30% that do not pass may cause continuing pain, infection, or obstruction. Stones lying more proximally are less likely to pass than those more distal in location. Calculi extending from one renal calix to another (“staghorn” calculi) can result in significant renal parenchymal damage, particularly in association with infection, but often do not cause ureteral obstruction.

Natural history of stone formation is a matter of some controversy. The likelihood of recurrence of calcium stones with time was examined prospectively in one study of patients in whom single stones formed. An exceedingly high incidence of recurrence was found, with a mean time to recurrence of 6.78 years. With time, the incidence of cumulative recurrence approached 100%. Recurrence appeared early in half of the patients but took up to 20 years in others. Other studies have found a more benign course. In one, a group of 101 patients was followed for an extended period (mean, 7 years); additional stone formation was observed in only one third of the patients. These differences in recurrence rates undoubtedly reflect heterogeneity among patients in the respective referral groups. In any case, the incidence of recurrence is high enough to justify evaluation and consideration of preventive treatment.

In the setting of suspected nephrolithiasis (e.g., acute flank pain or hematuria), the diagnostic test of choice is low-dose, noncontrast computed tomography (CT) scan with stone protocol, which has test characteristics for stone detection that approximate those of standard helical CT (sensitivity 98%, specificity 95%, negative predictive value 95%). Advantages include lower radiation dose compared to conventional CT, better sensitivity and specificity compared to intravenous pyelography, and no need for infusion of iodinated contrast. Moreover, it is capable of detecting other pathology that might be responsible for symptoms. However, cumulative dose of ionizing radiation can become an issue in patients with stone disease who are likely to have recurrent symptomatic episodes and undergo multiple studies over many years. Alternatives include plain film of the abdomen (reasonable sensitivity for larger [>5 mm] radiopaque stones [which includes most stones other than urate]) and renal ultrasound, which is useful for detection hydronephrosis due to ureteral obstruction but of low sensitivity for detection of small stones. Magnetic resonance imaging is inadequate for stone detection. Other tests indicated in the evaluation of acute renal colic are CBC, urinalysis, electrolytes, BUN, and creatinine for detection of infection and renal injury.