Published: August 2010
The formation of crystal aggregates in the urinary tract results in kidney stones, the clinical condition referred to as nephrolithiasis. Kidney stones might produce no symptoms or may be associated with one or several of the following: flank pain, gross or microscopic hematuria, obstruction of one or both kidneys, and urinary infections. The stones are usually formed by one of four substances: calcium, uric acid, magnesium ammonium phosphates (or struvite), or cystine. 1 Occasionally, calcium salts and uric acid are present in the same stone. Some rare types of kidney stones include xanthine and triamterene stones, which are seen in patients taking xanthine oxidase inhibitors and triamterene-containing diuretics, respectively. Indinavir stones have been reported in HIV-positive patients treated with this retroviral therapy. 2 In this chapter, I discuss the prevalence, pathophysiology, clinical presentation, and treatment of each of the four major types of stones.
Among American adults, the prevalence of nephrolithiasis is 1 in 1000, with men being almost twice as likely as women to have stones. Among the pediatric population, kidney stones are much less common, but the exact prevalence is unknown.
Kidney stones result from the growth of crystals into stones.3 Crystals form in urine that is supersaturated with particular salts such as calcium oxalate, sodium urate, magnesium ammonium phosphate, or cystine. There is a maximum to the amount of a compound that can be kept in stable solution, which is defined by its solubility or equilibrium concentration product. Supersaturation results when the amount of a compound in solution exceeds the solubility; at that point, there is a process that begins to remove this excess by crystal formation. This can be manipulated in two ways: by changing the amount or concentration of compound available for crystallization or by changing the solubility of the compound. An example of the former is reducing the quantity of calcium or cystine in the urine of a patient with hypercalciuric or cystinuric stone disease, or reducing the concentration of the calcium or cystine by high fluid intake (dilution of the urine). An example of the latter is increasing the solubility by increasing the urinary pH in patients with uric acid or cystine stone disease or by increasing the urinary excretion of naturally occurring inhibitors of crystal formation, such as citrate.
Calcium stone disease is the most common form of nephrolithiasis and represents about 70% of all cases of stone-forming disease. It occurs most often in the third to fifth decades of life and more often in men than women.
In 60% to 70% of patients, hypercalciuria is present (defined by 24-hour urinary calcium excretion of >300 mg in males, >250 mg in females, or >4 mg/kg in males or females). In less than 5%, the hypercalciuria may be associated with hyperparathyroidism or sarcoidosis, with or without hypercalcemia. More often, the hypercalciuria occurs with a normal serum calcium level and in the absence of any systemic diseases; this is called idiopathic hypercalciuria.4
Most patients with idiopathic hypercalciuria exhibit excessive gastrointestinal absorption of calcium (absorptive hypercalciuria). In many such cases, the 1,25-hydroxyvitamin D level is slightly elevated and the serum phosphorus level is slightly low, but parathyroid hormone (PTH) levels are normal. The mechanisms for these derangements are not known. These patients also have inappropriately high levels of urinary calcium excretion, even when on a calcium-restricted diet, which is why a calcium-restricted diet is not advised for these patients.
A minority of hypercalciuric patients have a renal leak of calcium (renal hypercalciuria). These patients have fasting hypercalciuria and slightly elevated levels of PTH and 1,25-hydroxyvitamin D. In these patients, thiazide diuretics reduce urinary calcium excretion, correct the secondary hyperparathyroidism, and return vitamin D levels to normal.
In both forms of hypercalciuria, the degree of hypercalciuria is worsened by high dietary sodium intake, high animal protein intake, and loop diuretics; it is reduced by distally acting thiazide diuretics and amiloride, as well as dietary restriction of sodium and protein. Several studies have shown that a higher dietary calcium intake has been associated with fewer calcium stone events in men and women. 5,6 A study of 120 Italian hypercalciuric calcium oxalate stone patients has demonstrated that a diet with normal calcium, low sodium, and low animal protein resulted in reduced incidence of calcium stones compared with those on a low-calcium diet. 7 In this study, both diets were associated with a reduction in urinary calcium level; however, urinary oxalate excretion rose in the low-calcium diet group and fell in the high-calcium diet group. The reduction in urinary oxalate excretion in persons on a normal calcium diet was attributed to the intestinal binding of dietary oxalate by dietary calcium, thus decreasing the amount of free oxalate available for absorption. Although both groups had reduced calcium oxalate saturation of their urine, the normal-calcium diet group had a more significant reduction. Compared with the patients on a low-calcium diet, the patients on the normal calcium, low-sodium, low-protein diet had a 50% reduction in stone risk at 5 years.
In some calcium stone patients, the mechanism for the increased rate of calcium oxalate stones is the presence of hyperoxaluria. 8 The hyperoxaluria is usually secondary to high dietary oxalate intake caused by ingestion of foods or liquids containing large quantities of oxalate. Some of these foods and liquids include baked beans, collard greens, green beans, rhubarb, tea, cocoa, peanut butter, and vegetable soup. In other cases, the hyperoxaluria occurs in the setting of gastrointestinal malabsorption, seen in patients with inflammatory bowel disease. When patients malabsorb fat, dietary calcium binds to the fat rather than to dietary oxalate, which is the norm. This results in a larger amount of unbound intestinal oxalate that passes into the colon, from which it is absorbed. In patients with ileostomies (colon excluded), this enhanced oxalate absorption does not occur. A rare cause of hyperoxaluria is the inherited condition known as primary hyperoxaluria.9 In this condition, the hepatic enzyme that converts glyoxylate to glycine is deficient. As a result, there is increased production of oxalate from glyoxylate.
Other risk factors for calcium stones include chronic low urine output, hyperuricosuria, and low urine citrate, which occurs most often in patients with inflammatory bowel disease, chronic metabolic acidosis, and renal tubular acidosis (RTA). Renal stones occur in the distal form of RTA, are often composed of calcium phosphate, manifest as multiple stones on radiography (nephrocalcinosis), and occur in the presence of a persistently alkaline urine (pH >5.5) despite metabolic acidosis.
Patients often present with episodes of flank pain that radiates to the anterior abdomen or even to the genitalia. The pain is typically severe and comes in waves. Often, there is microscopic or gross hematuria. Calcium oxalate crystals may be seen with urine microscopy, but this finding is not diagnostic because calcium oxalate crystals may be seen in the urine of non–stone-forming patients. In some patients, the renal stones are completely asymptomatic or produce painless hematuria.
Stone analysis is the best method for diagnosing calcium oxalate or calcium phosphate stones. Calcium-containing stones are radiopaque on routine radiography but show up as bright objects on computed helical tomography without contrast. Ultrasonography detects all types of renal stones if the stone is larger than 3 mm and the ultrasound procedure is technically satisfactory.
At present, helical computed tomography without contrast is the procedure of choice for the initial radiographic investigation. All types of stones located anywhere in the kidneys, ureters, or bladder are demonstrated with this technology. In a patient with azotemia, there is no risk from contrast administration. The anatomic status of the urinary tract will be clarified, and other possible nonstone causes for the patient's symptoms or signs may be identified.10
Of the conditions associated with calcium stones, only pyelotubular ectasia—medullary sponge kidney—is better demonstrated by intravenous urography.
In recurrent hypercalciuric stone patients, treatment should consist of high fluid intake, dietary sodium restriction, and thiazide diuretics. Thiazide diuretics (not loop diuretics) reduce urinary calcium excretion by inducing extracellular volume depletion, which in turn causes increased renal sodium and calcium reabsorption, and by directly increasing distal calcium reabsorption. An additional benefit of thiazide diuretics is that their chronic use is associated with preservation of bone mineral density.11 Dietary calcium restriction is not advised because of the potential for negative calcium balance and because a low-calcium diet increases the gastrointestinal absorption of oxalate and increased oxaluria. This increase in urinary oxalate can significantly raise the supersaturation of the urine for calcium oxalate, which in turn increases the stone formation rate. In hypercalcemic hypercalciuric stone-forming patients, the cause of the hypercalcemia should be sought and corrected. Correcting the metabolic acidosis in RTA and inflammatory bowel disease increases the urinary citrate excretion, an inhibitor of crystallization, and lessens the urinary calcium excretion.
Uric acid stone disease is found in about 5% to 10% of stone patients.12 It is more common in patients with chronic diarrheal disorders and in those with hyperuricosuria. Most uric acid stone patients do not have gout. About 30% to 40% of patients have hyperuricosuria. Uric acid stones may also be partially composed of calcium oxalate, and some patients have both uric acid and calcium oxalate stones. In a study by Sakhaee and colleagues,13 about 30% of normouricosuric stone patients have diabetes and another 23% have abnormal glucose tolerance.
Uric acid stones occur especially in patients with a very low urine pH (<5.0) and in those with hyperuricosuria. In some patients, this very low urine pH is caused by a defect in renal ammonia secretion that results in less buffering of secreted hydrogen ions and lower urine pH. Sakhaee and associates13 have suggested that the very low urine pH is in some way related to the insulin resistance.
Uric acid is rather insoluble (15 mg/dL) in urine at a pH of 5.0, but becomes significantly more soluble in urine at a pH of 7.0 (150 mg/dL). Any combination of low urine pH, concentrated urine (as seen in chronic diarrheal states), and increased urinary uric acid excretion (as seen in patients with gout, chronic probenecid therapy, or high purine intake) increases the risk for uric acid stone disease. Rare congenital disorders of purine metabolism, such as Lesch-Nyhan syndrome, are associated with uric acid stones, hyperuricosuria, and hyperuricemia.
Urate stones are radiolucent and can be visualized by ultrasonography and noncontrast helical computed tomography. If the uric acid is mixed with calcium oxalate, the stone will be radiopaque.
Patients often present with episodes of flank pain that radiates to the anterior abdomen or even to the genitalia, as in calcium stone disease. The pain is frequently severe and comes in waves. Often there is microscopic or gross hematuria.
Uric acid stone disease should be suspected in any patient with typical symptoms of renal colic in whom plain radiographs do not show a calcified stone. Urate crystals may be present in the urine, but they occur in patients without stones as well. The urine pH is usually lower than 5.5. Stone analysis provides a definitive diagnosis.
Because the solubility of uric acid is greatly increased when the urine pH is raised, treatment should consist of alkalinization of urine to a pH higher than 6.5 with potassium citrate solution, 30 to 90 mEq/day in divided doses, and hydration. This treatment has been shown to reduce uric acid stones by 90%. Such treatment, given to a patient with small stones in the kidneys, can also result in dissolution of the stones. When hyperuricosuria is also present, allopurinol may be used to reduce the serum uric acid level and thus reduce the renal excretion of uric acid. Restriction of animal protein is also recommended for patients with hyperuricosuria. Alkalinization of the urine with sodium bicarbonate or sodium citrate is not recommended because the sodium salts will increase calcium excretion, which increases the tendency to form calcium oxalate stones.
Infection stones, also known as struvite or magnesium ammonium phosphate stones, occur in about 10% to 12% of patients, more often in women. They occur more often also in patients with spinal cord injury, neurogenic bladder, vesicoureteral reflux, chronic indwelling Foley catheters, and recurrent urinary infections, and in those with chronic obstruction of the upper urinary tract.
Struvite stones occur only in the presence of urine persistently infected with urease-producing bacteria that split urea and cause persistently alkaline urine.14 Urea-splitting bacteria include Proteus (most commonly), Pseudomonas, Klebsiella, Escherichia coli, and some Staphylococcus species. Struvite stones are often branched (staghorn-shaped) and large. Because the stones contain ammonium, they have a tendency to adhere to the uroepithelium, which tends to accelerate the growth of these stones in a very short time. Treatment requires eradication of infection with antibiotics and the removal of the bacteria-laden stones by some interventional technique.
These stones can cause the typical symptoms of renal colic, but often they are discovered during the course of investigating a patient with recurrent urinary infections or in a patient with asymptomatic bacteriuria. Because these stones can grow to significant size, they are often found in the renal pelvis and infundibula of the kidneys.
The diagnosis of struvite stones is suspected by finding large or branched stones in the kidneys of a patient with persistently infected urine. Stone analysis confirms the diagnosis.
Treatment must eradicate the urinary infection. Because the stones themselves are often infected with bacteria, the urinary infection cannot be eradicated without also removing the stones. Thus, surgical removal of the stones accompanied by appropriate antibiotic therapy is necessary. Acetohydroxamic acid is a urease inhibitor and has been used to prevent recurrence. Its effectiveness depends on its presence in the urine; hence, it has limited effectiveness in patients with azotemia. The use of this drug is further compromised because it has potentially serious side effects that include gastrointestinal upset, neurologic deficits, and thrombophlebitis. 15
Cystine stone disease occurs in less than 1% of all adult stone patients and in about 6% to 8% of children with nephrolithiasis. 16
Cystine stone disease occurs in persons who have inherited an autosomal recessive gastrointestinal and renal tubular transport disorder of four amino acids: cystine, ornithine, arginine, and lysine. Of these, cystine is the most insoluble in normally acid urine and thus precipitates into stones.
The patient presents with symptoms of nephrolithiasis, often at a younger age than a person with calcium stone disease. The stones are radiopaque (ground-glass appearance) and amber. Family history is often helpful (i.e., siblings might have the disorder).
Normal urine contains less than 20 to 30 mg/day (<100 mg/g creatinine) of cystine. Urinary cystine excretion of more than 250 mg/g creatinine in adults is clearly abnormal and is the usual amount found in patients with cystinuria. The examination of a concentrated acidic urine specimen often reveals the presence of the cystine crystals, which are transparent and hexagonal. Cystine can be detected qualitatively by adding sodium nitroprusside to the urine and observing a purple-red color. Stone analysis is diagnostic.
Treatment is directed at reducing urinary cystine concentration in the urine or increasing urinary cystine solubility in the urine. The concentration of cystine in the urine is significantly helped by high fluid intake. There is a modest reduction of cystine excretion by reducing methionine in the diet by restricting red meat, fish, poultry, dairy products, and sodium. Alkalinization of the urine with potassium citrate to a pH of 6.5 to 7 is recommended. Sodium bicarbonate may be used for alkalinization, but the high sodium load increases cystine excretion. However, hydration and alkalinization alone are often ineffective at inhibiting recurrent stones.
Cystine is made up of two cysteine molecules connected by a disulfide bond. Thiol derivatives are chelating agents. They contain sulfhydryl groups that can bind with the cysteine molecules, reduce the formation of cystine, and render it more soluble. Therefore, these agents can also help dissolve cystine stones and prevent their formation.