Nephrolithiasis

Published
December 22, 2003

Department of
Nephrology

The formation of crystal aggregates in the urinary tract results in kidney stones, the clinical condition referred to as nephrolithiasis. Kidney stones may 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: (1) calcium, (2) uric acid, (3) magnesium ammonium phosphates (or struvite), or (4) cystine.¹ Occasionally, calcium salts and uric acid will be present in the same stone. Some very rare types of kidney stones include xanthine and triamterene stones, which are seen in individuals taking xanthine oxidase inhibitors and triamterene-containing diuretics, respectively. Indinavir stones have been reported in HIV patients treated with this retroviral therapy.²

In this chapter, I will discuss the prevalence, pathophysiology, clinical presentation, and therapy of each of the four major types of stones.

Among American adults, the prevalence of nephrolithiasis is 1 in a 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 not known.

GENERAL PATHOPHYSIOLOGY

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 drive to remove this excess by crystal formation. This drive can be manipulated in two ways: (1) by changing the amount or concentration of compound available for crystallization, or (2) by changing the solubility of the compound. An example of the former would be to reduce the quantity of calcium or cystine in the urine of a patient with hypercalciuric or cystinuric stone disease or by reducing the concentration of the calcium or cystine by high fluid intake. An example of the latter would be to increase the solubility by increasing the pH of the urine in patients with uric acid or cystine stone disease or by increasing the urinary excretion of naturally occurring inhibitors of crystal formation, eg, citrate.

CALCIUM STONE DISEASE

PREVALENCE

Calcium stone disease is the most common form of nephrolithiasis and represents about 70% of all stone-forming disease. It occurs most often in the third to fifth decade of life, more often in men than women.

PATHOPHYSIOLOGY

In 60-70% of patients, hypercalciuria will be 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 and in the absence of any systemic diseases, and is called idiopathic hypercalciuria.⁴

Most patients with idiopathic hypercalciuria exhibit excessive gastrointestinal absorption of calcium (absorptive hypercalciuria). In many such cases, 1,25-vitamin D levels are slightly elevated and serum phosphorous is slightly low but parathyroid hormone 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-vitamin D. In these patients, thiazide diuretics reduce urinary calcium excretion, correct the secondary hyperparathyroidism, and return the 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 both men and women.^5,6 Further, a study in 120 Italian hypercalciuric calcium oxalate stone-formers demonstrated that a diet with normal calcium, low sodium, and low animal protein resulted in reduced frequency of calcium stones compared with a low-calcium diet.⁷ In this study, both diets were associated with a reduction in urinary calcium; 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 individuals on a normal calcium diet was attributed to the intestinal binding of dietary oxalate by dietary calcium, thus lessening 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 formers, 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 due to ingestion of foods or liquids containing large quantities of oxalate. Some of these foods and liquids include baked beans, collards, 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 glyoxalate to glycine is deficient. As a result, there is increased production of oxalate from glyoxalate.

Other risk factors for calcium stones include (1) chronic low urine output, (2) hyperuricosuria, and (3) 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 frequently composed of calcium phosphate, present as multiple stones on radiography (nephrocalcinosis), and occur in the presence of a persistently alkaline urine (pH >5.5) despite metabolic acidosis.

SIGNS AND SYMPTOMS

Patients often present with episodes of flank pain that radiates to the anterior abdomen or even to the genitalia. The pain is often 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 since calcium oxalate crystals may be seen in the urine of non-stone-forming patients. In some patients the renal stones are completely asymptomatic or may produce painless hematuria.

DIAGNOSIS

Stone analysis is the surest way to diagnose 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 will detect all types of renal stones if the stone is larger than 3 to 5 mm and the ultrasound is technically satisfactory.

At the present time, 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 will be demonstrated with this technology. Further, in a patient with azotemia, there is no risk from contrast administration. In addition, the anatomic status of the urinary tract will be clarified and other possible non-stone 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.

THERAPY AND OUTCOME

In recurrent hypercalciuric stone formers, treatment should consist of high fluid intake, dietary sodium restriction, and thiazide diuretics. Thiazide diuretics (not loop diuretics) reduce urinary calcium excretion by (1) inducing extracellular volume depletion, which in turn causes increased renal sodium and calcium reabsorption, and (2) 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 gastrointestinal absorption of oxalate and increased oxaluria. This increase in urinary oxalate can significantly raise the supersaturation of the urine for calcium oxalate. This in turn increases the stone formation rate. In hypercalcemic hypercalciuric stone forming individuals, 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

PREVALENCE

Uric acid stone disease is found in about 5% to 10% of stone formers.¹² It is more common in patients with chronic diarrheal disorders and in those with hyperuricosuria. Most uric acid stone formers do not have gout or 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 et al,¹³ about 30% of normouricosuric stone formers have diabetes and another 23% have abnormal glucose tolerance.

PATHOPHYSIOLOGY

Uric acid stones occur especially in patients with very low urine pH (below pH 5.0) and in those with hyperuricosuria.¹³ 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 ion and lower urine pH. Sakhaee et al¹³ suggested that the very low urine pH is in some way related to the insulin resistance.

Uric acid is very insoluble (15 mg/dL) in urine at pH 5.0, but becomes significantly more soluble in urine at pH 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) make one at risk for uric acid stone disease. There are rare congenital disorders of purine metabolism, ie, Lesch-Nyhan syndrome, which are associated with uric acid stones and hyperuricosuria and hyperuricemia.

Urate stones are radiolucent, but are visualized by both ultrasonography and noncontrast helical computed tomography. If the uric acid is mixed with calcium oxalate, the stone will be radiopaque.

SIGNS AND SYMPTOMS

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 often severe and comes in waves. Often there is microscopic or gross hematuria.

DIAGNOSIS

Uric acid stone disease should be suspected in any patient with typical symptoms of renal colic in whom the plain radiographs do not show a calcified stone. Urate crystals may be present in the urine, but occur in patients without stones as well. The urine pH will usually be less than 5.5. Stone analysis will provide sure diagnosis.

THERAPY AND OUTCOME

Since the solubility of uric acid is greatly increased when urine pH is raised, treatment should consist of alkalinization of urine to pH >6.5 with potassium citrate solution, 30 to 90 mEq per day in divided doses, and by 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, may also result in dissolution of the stones. When hyperuricosuria is also present, allopurinol can 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 and increase the tendency to form calcium oxalate stones.

STRUVITE STONE DISEASE

PREVALENCE

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 tracts.

PATHOPHYSIOLOGY

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, some Escherichia coli, and 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 very short periods of time. Treatment requires eradication of infection with antibiotics and the removal of the bacteria-laden stones by some interventional technique.

SIGNS AND SYMPTOMS

These stones may cause the typical symptoms of renal colic, but often they are discovered in the course of investigating a patient with recurrent urinary infections or in a patient with asymptomatic bacteriuria. Since these stones can grow to significant size, they are often found in the renal pelvis and infundibula of the kidneys.

DIAGNOSIS

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 will confirm the diagnosis.

THERAPY AND OUTCOME

Therapy must eradicate the urinary infection. Since the stones themselves are frequently infected with bacteria, the urinary infection cannot be eradicated without removing the stones as well. Thus, surgical removal of the stones accompanied by appropriate antibiotic therapy is necessary. Acetohydroxamic acid is a urease inhibitor. It has been used to prevent recurrence. Its effectiveness depends upon 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

PREVALENCE

Cystine stone disease occurs in less than 1% of all adult stone formers and in about 6% to 8% of children with nephrolithiasis.¹⁶

PATHOPHYSIOLOGY

Cystine stone disease occurs in individuals who have inherited an autosomally 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.

SIGNS AND SYMPTOMS

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 (ie, siblings may have the disorder).

DIAGNOSIS

Normal urine contains less than 20-30 mg/d (<100mg/gm creatinine) of cystine. Urinary cystine excretion of greater 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 will often reveal 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.

THERAPY AND OUTCOME

Treatment is directed at reducing urinary cystine concentration in the urine or by 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 (restriction of red meat, fish, poultry, and dairy products) in the diet and by dietary sodium restriction. 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 frequently ineffective at inhibiting recurrent stones.

Thiol derivatives are chelating agents. They contain sulfhydryl groups that can bind with the cystine and render it more soluble. Therefore, these agents may also help to dissolve cystine stones as well as prevent their formation. D-Penicillamine and alpha mercaptopropionylglycine are examples of such thiol chelating agents. Alpha mercaptopropionylglycine is slightly more effective and produces fewer side effects. Captopril, which also has sulfhydryl groups, has been used in limited studies with success.¹⁷

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