Nephrolithiasis

Background

The overall lifetime rate of kidney stones in the general population is approximately 12% for men and 4% for women. Having a family member with a history of stones doubles these rates. Approximately 30 million people are at risk in the United States. Peak incidence occurs in people aged 35-45 years, but the disease can affect anyone at any age. Initial stones in elderly people and in children are relatively uncommon; however, consider kidney stones whenever acute back or flank pain is encountered, regardless of patient age. When stones occur in persons in these uncommon age groups, a metabolic workup consisting of a 24-hour urine collection and appropriate serum laboratory testing is recommended

Urinary tract stone disease has been a part of the human condition for millennia; in fact, bladder and kidney stones have even been found in Egyptian mummies. Some of the earliest recorded medical texts and figures depict the treatment of urinary tract stone disease.

patophysiology
Urinary tract stone disease is likely caused by 2 basic phenomena. The first is supersaturation of the urine by stone-forming constituents, including calcium, oxalate, and uric acid. Crystals or foreign bodies can act as nidi, upon which ions from the supersaturated urine form microscopic crystalline structures. The overwhelming majority of renal calculi contain calcium. Uric acid calculi and crystals of uric acid, with or without other contaminating ions, comprise the bulk of the remaining minority. Other, less frequent stone types include cystine, ammonium acid urate, xanthine, dihydroxyadenine, and a variety of rare stones related to precipitation of medications in the urinary tract.

About 75% of all stones are calcium-based, consisting of calcium oxalate, calcium phosphate, or a mixture of oxalate and phosphate. Mixed stones have more than one component, such as a uric acid nidus with aggregation of calcium. Another 10% of renal stones are uric acid-based, 1% are cystine-based, and the remainder are primarily struvite. In susceptible patients, stone formation begins when urine is supersaturated with calcium, cystine, uric acid, struvite, or oxalate.

The first is supersaturation of the urine by stone-forming constituents, including calcium, oxalate, and uric acid. Crystals or foreign bodies can act as nidi, upon which ions from the supersaturated urine form microscopic crystalline structures. The overwhelming majority of renal calculi contain calcium. Uric acid calculi and crystals of uric acid, with or without other contaminating ions, comprise the bulk of the remaining minority. Other, less frequent stone types include cystine, ammonium acid urate, xanthine, dihydroxyadenine, and a variety of rare stones related to precipitation of medications in the urinary tract.

With the nucleation process, sodium hydrogen urate, uric acid, and hydroxyapatite crystals form a nucleus. Calcium and oxalate ions then adhere to the nucleus to form a mixed stone. This is known as heterogeneous nucleation.

Absorptive hypercalciuria. With this autosomal dominant disorder, absorption of calcium is increased in the intestine. The resulting transient hypercalcemia inhibits secretion of parathyroid hormone, which decreases renal reabsorption and increases urinary excretion of calcium. This, in turn, normalizes the serum calcium level.

Absorptive hypercalciuria type I (AH-I) is a severe form of disease that occurs with normal and high dietary intake of calcium. Absorptive hypercalciuria type II (AH-II) is a milder form occurring only with high intake of calcium.

Renal hypercalciuria. The initiating event here is impaired renal tubular reabsorption of calcium. This results in a decrease in serum calcium concentration, which stimulates release of parathyroid hormone. Under the influence of secondary hyperparathyroidism, there is increased mobilization of calcium from bone, increased renal synthesis of vitamin D3, and increased intestinal absorption of calcium. All these factors exacerbate hypercalciuria.

Reabsorptive hypercalciuria. This results from excessive bone reabsorption caused by primary hyperparathyroidism. It is also associated with increased intestinal calcium absorption secondary to greater than normal synthesis of vitamin D. Hypercalcemia is a consistent diagnostic feature. Increased filtered load of calcium leads to hypercalciuria.

Unclassified hypercalciuria. This category includes (1) renal phosphate leak with hypophosphatemia and hypercalciuria and (2) fasting hypercalciuria with normal parathyroid hormone, serum calcium, and serum phosphate levels.

Hyperuricosuria-With this entity, encountered in about 35% of patients with renal calculi, urinary uric acid excretion greater than 750 mg/day leads to heterogeneous nucleation and formation of calcium oxalate stones. Hyperuricosuria occurs after eating purine-rich foods or because of uric acid overproduction (3).

Hyperoxaluria-There are three types of hyperoxaluria-enteric, primary, and dietary. Enteric hyperoxaluria is seen with increased absorption of oxalate in patients with ileal disorders, such as inflammatory bowel disease or gastric or small-bowel resection.

Primary hyperoxaluria is a hereditary metabolic disorder of amino acid metabolism that leads to increased production and excretion of oxalate (> 40 mg/day) even on oxalate-restricted diets. It is characterized by recurrent nephrolithiasis leading to renal failure (4).

Dietary hyperoxaluria usually is associated with an oxalate-rich diet and resolves when oxalate is restricted. Foods high in oxalate include berries, nuts, draft beer, tomatoes, beans, beets, radishes, greens, and chocolate.

Hypocitraturia--Citrate inhibits stone formation by lowering urinary saturation of calcium salts and forming soluble complexes with calcium. Citrate also directly inhibits crystallization of calcium salts. Several conditions, such as distal renal tubular acidosis, enteric hyperoxaluria, hypokalemia, strenuous physical exercise, and diets high in animal protein, lead to hypocitraturia. This results in increased stone formation. Hypocitraturia may be the only cause of renal stones in 5% to 10% of patients.

Gouty diathesis--Uric acid or calcium oxalate stones may form in patients with primary gout with or without gouty arthritis and hyperuricemia. Patients may have a urinary pH of less than 5.5, when uric acid is much less soluble. Uric acid may precipitate to form a radiolucent uric acid stone, or it may act as a nidus for calcium oxalate or phosphate aggregate deposits.

Cystinuria--This inborn error of metabolism leads to increased excretion of cystine in the urine. It should be suspected in young patients with recurrent stones and a strong family history of renal calculi. Hexagonal crystals are seen in urine.

Struvite infection--When urine is infected with urea-splitting organisms, the urea is broken down by bacterial urease to ammonia. Increased ammonia then hydrolyzes to ammonium and hydroxide. It is the latter that contributes to the alkaline pH of the urine. As urinary pH goes up, triple phosphates are formed, eventually leading to formation of struvite stones.

Other disorders--In addition to gouty diathesis, conditions that may be conducive to uric acid stones include myeloproliferative disorders, malignancy, and glycogen storage disorders. Stones may also develop in diarrheal states and with jejunoileal bypass because of net alkali deficit, dehydration, and precipitation of uric acid. Other factors potentiating stone formation include low urine volume, metabolic acidosis, and hypomagnesuria.

Diagnostic evaluation

Patients with a first kidney stone should be assessed to find the cause, identify those at high risk for recurrence, and institute measures to prevent future stone formation. Table 2 lists the risk factors that should be looked for in the initial evaluation. In addition to patients with known risk factors, all children and white men with a family history of nephrolithiasis should be considered high-risk. Physical examination generally does not contribute to diagnosis, except for band keratopathy with primary hyperparathyroidism.

Lab Studies:

Urinalysis

• Evaluate the urine for evidence of hematuria and infection. Approximately 85% of patients with urinary calculi exhibit hematuria.
• Absence of hematuria does not preclude presence of urinary calculi; in fact, approximately 15% of patients with urinary stones do not exhibit hematuria.
• Offer strongly motivated patients a metabolic 24-hour urinalysis.

CBC count

• In the context of nephrolithiasis, an elevated white blood cell count suggests renal or systemic infection.
• A depressed red blood cell count suggests a chronic disease state or severe ongoing hematuria.

Serum electrolytes, creatinine, calcium, uric acid, and phosphorus studies

• These are needed to assess a patient's current renal-function status and to begin the assessment of metabolic risk for future stone formation.
• A high serum uric acid finding may indicate gouty diathesis or hyperuricosuria, while hypercalcemia suggests either renal-leak hypercalciuria or hyperparathyroidism.

Calcium, oxalate, and uric acid

In acute renal colic, abdominal films can identify radiopaque stones in 80% to 90% of patients. Intravenous pyelography is the "gold standard" for identifying filling defects and obstruction from radiolucent stones and urinary tract abnormalities. When contrast media are contraindicated, ultrasound is a valuable alternative (5). If a stone is retrieved, x-ray diffraction or polarizing microscopy identifies the composition. In patients with recurrent stones, further tests may be warranted.

Creatinine

• Creatinine is the control that allows verification of a true 24-hour sample. Most individuals excrete 1-1.5 g of creatinine daily.
• Values at either extreme that are not explained by estimates of lean body weight should prompt consideration that the sample is inaccurate.
• Consider the sample inaccurate if values at either extreme are not explained by estimates of lean body weight.

Total volume

• Patients in whom stones form should strive to achieve a urine output of more than 2 L daily in order to reduce the risk of stone formation.
• Patients with cystine stones or those with resistant cases may need a daily urinary output of 3 L for adequate prophylaxis.

Twenty-four–hour urinalysis (calcium, oxalate, uric acid, sodium, phosphorus, citrate, magnesium, creatinine, total volume)

Normal fasting urinary calcium is less than 0.11 mg per deciliter of glomerular filtrate. Normal postload urinary calcium is less than 0.2 mg per milligram of creatinine. Interpretation of the test is given in table 4.

Management Of Nephrolithiasis

Increased hydration is the mainstay of most medical therapies for nephrolithiasis. As a general measure, all patients with kidney stones should be encouraged to increase fluid intake and keep urine volumes high. Water is probably the safest fluid, but its salt and calcium content should be checked.

Patients should be advised to drink two glasses of water at bedtime and an additional glass every time they awaken at night. During the day, patients should drink fluids at 1- to 2-hour intervals to prevent supersaturation. Urine output of more than 2 L/day is recommended to reduce the possibility of subsequent stone formation

If a patient older than 40 years has formed a single stone that passed spontaneously or was easily treated, follow-up care for recurrent stones may not be necessary. This patient is at a reasonably low risk for recurrence if adequate fluid intake is maintained.

In other patients, whether or not they have elected directed metabolic therapy, routine follow-up care consists of plain abdominal radiographs (or renal sonograms in the case of radiolucent stones) every 6-12 months.

If medical therapy is instituted, a 24-hour urinalysis 3 months after starting any new therapy should be performed to assess the degree of patient compliance and the adequacy of the metabolic response. Checking all possible metabolic parameters—not just the previously abnormal ones—is necessary because of the possibility of new problems arising as a result of the new therapy.

Once a stable regimen has been established, annual 24-hour urinalyses are adequate

Oxalate-containing foods should be restricted and salt and purine intake limited. High-sodium diets can lead to hypercalciuria and hypocitraturia, while low-sodium diets decrease hypercalciuria. Low calcium diets are not advised, except in AH-I, because of risks of osteoporosis and increased oxalate availability in the intestine.

Thiazides (eg, hydrochlorothiazide [Esidrix, HydroDIURIL, Oretic], 12.5 to 25 mg/day) are used to decrease hypercalciuria because they enhance calcium reabsorption in distal tubules and create a state of alkalosis, which increases citrate excretion.

Diet:

For almost all patients in whom stones form, an increase in fluid intake and, therefore, an increase in urine output is recommended. This is likely the single most important aspect of stone prophylaxis.

The only other general dietary guidelines are to avoid excessive salt and protein intake.

Dietary calcium should not be altered unless specifically indicated by 24-hour urinalysis findings. Urinary calcium levels are normal in many patients with calcium stones. Reducing dietary calcium in these patients may actually worsen their stone disease, because more oxalate is absorbed from the gastrointestinal tract in the absence of sufficient intestinal calcium to bind with it. This results in a net increase in oxalate absorption and hyperoxaluria, which tends to increase new kidney stone formation in patients with calcium oxalate calculi.

As a general rule, dietary calcium should be restricted to 600-800 mg per day in patients with diet-responsive hypercalciuria who form calcium stones. This is roughly equivalent to a single high-calcium or dairy meal per day.

Drug treatment Table 5 lists various drugs used for nephrolithiasis, their actions, indications, and drawbacks.

Drug	Biochemical effects	Indications	Drawbacks
Thiazide diuretics	Decrease urinary calcium	AH-I, renal hypercalciuria	Side effects, limited long-term effect
Potassium citrate	Increases urinary citrate, treats hypokalemia, corrects metabolic acidosis	AH-I, AH-II, hypocitraturia, hyperuricosuria, cystinuria, enteric hyperoxaluria
Cellulose sodium phosphate (Calcibind)	Binds calcium in gut, decreases calcium absorption	AH-I	Hypomagnesemia, hypomagnesuria, hyperoxaluria
Allopurinol (Zyloprim)	Decreases uric acid secretion	Hyperuricemia, hyperuricosuria	Dermatitis, liver necrosis
Penicillamine (Cuprimine, Depen) or alpha-mercaptopropionyl-glycine	Decreases urinary cystine	Cystinuria	Pancytopenia, dysgeusia, nephrotic syndrome
Captopril (Capoten)	Binds cystine	Cystinuria
Orthophosphates	Reduce serum vitamin D and urinary calcium	Renal phosphate leak, reabsorptive hypercalcemia	Contraindicated with urinary tract infections
Acetohydroxamic acid (Lithostat) with antibiotics	Inhibits urease and prevents breakdown of urea into ammonia	Struvite stones	Hemolytic anemia in about 3% of patients
AH-I, absorptive hypercalciuria type I; AH-II, absorptive hypercalciuria type II.

AH-I--No drug is effective in correcting the underlying increased calcium absorption. However, cellulose sodium phosphate (Calcibind), 5 g three times daily taken with meals, binds with calcium and inhibits its absorption. Adverse effects associated with this therapy include negative calcium balance and parathyroid hormone stimulation in patients with renal or reabsorptive calciuria or with normal calcium absorption; hypomagnesemia because of binding of magnesium in the gut; and secondary hyperoxaluria due to binding of calcium and magnesium ions, which reduces oxalate binding to calcium and provides more free oxalate in the gut for absorption.

Thus, in documented cases of AH-I, cellulose sodium phosphate is used along with moderate restriction of dietary oxalate and magnesium supplementation. This treatment reduces urinary calcium and maintains bone density. However, cellulose sodium phosphate is costly and often inconvenient.

An alternative treatment is a thiazide diuretic, which does not decrease intestinal calcium absorption (8). However, thiazides do decrease calcium excretion in urine. Use of a potassium-sparing diuretic (eg, triamterene [Dyrenium], 50 mg/day; spironolactone [Aldactone], 25 mg/day; amiloride hydrochloride [Midamor], 5 mg/day) or potassium supplement is advisable. Potassium citrate has the advantage of increasing citrate excretion in urine.

Metabolic side effects of thiazides, such as hypercalcemia, hypokalemia, and alkalosis, need to be watched. Thiazides are not effective in the long run. After prolonged use, the hypocalciuric effect is lost. If this occurs, thiazide treatment can be stopped for 6 to 12 months and cellulose sodium phosphate tried (6).

AH-II--No specific treatment is necessary for this disease, because the defect is mild. A decrease in calcium intake, together with an increase in fluids, usually prevents recurrence.

Renal phosphate leak--Orthophosphates, as neutral or alkaline soluble salts of sodium or potassium or both, 0.5 g three to four times per day, may restore normal levels of vitamin D3 and correct calcium absorption. However, they are contraindicated in patients with urinary tract infections.

Renal hypercalciuria--Thiazide with potassium citrate or thiazide with potassium-sparing diuretic is the treatment of choice to decrease renal excretion of calcium.

Enteric hyperoxaluria--Restriction of oxalate in the diet is essential. Potassium citrate, 60 to 120 mEq/day, should be used if hypokalemia and metabolic acidosis are present. Calcium citrate (Citracal), 200 to 400 mg three or four times a day, prevents calcium deficiency and binds oxalate in gut. Associated hypercalciuria is treated with thiazides.

Hyperuricosuria--Allopurinol (Zyloprim), 300 mg/day, is the treatment of choice for urinary uric acid greater than 800 mg/day or for hyperuricemia. In mild hyperuricosuria or associated hypocitraturia, use of low-dose potassium citrate (30 to 60 mEq/day) may be effective. Oral sodium bicarbonate may be used but requires frequent dosing because of its rapid excretion. The dose for citrate or bicarbonate should be adjusted to maintain a urinary pH of 6.5 to 7.

Hypocitraturia-In distal renal tubular acidosis and diarrheal syndromes, acidosis and hypokalemia are encountered. Urinary citrate excretion is decreased under such conditions. Potassium citrate therapy improves citrate excretion and corrects acidosis and hypokalemia (9). Potassium citrate therapy also inhibits urinary supersaturation and crystallization of calcium salts. This dramatically decreases the risk for recurrence of nephrolithiasis.

Gouty diathesis--Potassium citrate, 15 mEq twice daily, can raise urinary pH to 7 and inhibit precipitation of uric acid. This prevents formation of calcium stones by increasing urinary citrate levels. If associated hyperuricemia or hyperuricosuria is present, allopurinol is indicated.

Cystinuria--Around-the-clock increase in fluid intake (to keep urinary cystine concentration less than 300 mg/L at all times) is effective for preventing stones in 70% of patients. Alkalinization of urine with citrate, lactate, or bicarbonate, which increases solubility of cystine (pH, > 7.5), is another option. Patients not responding to these measures need penicillamine (Cuprimine, Depen), 1 to 2 g/day, or alpha-mercaptopropionyl-glycine (alpha-MPG) therapy. These agents reduce cystine excretion and allow a more soluble cystine compound to be excreted. The limiting factor is side effects. Penicillamine causes severe hematologic and nephritic complications in a high percentage of patients. Pancytopenia, nephrotic proteinuria, immune complex glomerulonephritis, and rash have been described.

Alpha-MPG (1,200 mg/day) is better tolerated, but patients previously treated with penicillamine may develop rash, fever, proteinuria, and pemphigus when treated with alpha-MPG. A relatively recent therapeutic choice is captopril (Capoten). This angiotensin-converting enzyme inhibitor binds to cystine and decreases urinary cystine excretion (10).

Struvite stones--Prevention of struvite stone formation may be attempted by effective control of infection with antibiotics. However, this is difficult, and surgery may be needed. After stone removal, urine cultures should be done monthly for 6 to 8 months and every 2 months thereafter for up to 2 years. Aggressive treatment of infections with urea-splitting organisms should be undertaken.

In patients for whom surgery is not possible, acetohydroxamic acid (Lithostat), 250 mg three or four times per day, is used in conjunction with antibiotics. This drug inhibits the enzyme urease and prevents breakdown of urea into ammonia, leading to lower urinary pH and decreased precipitation of phosphates. Severe hemolytic anemia has been described in 3% of patients.

Lithotripsy and surgical management of nephrolithiasis
Medical therapy can reduce the risk of recurrence of stones in 80% to 90% of patients but may not successfully remove existing stones. Extracorporeal shock wave lithotripsy has been widely used to treat renal stone disease. The shock waves break stones into tiny fragments that can be easily passed. Complications and morbidity are much lower with this procedure than with other invasive therapies. Success rates are highest in patients with single stones, small stones (<>

Infected or large stones may require percutaneous nephrolithotomy or open surgery. Lower ureteral stones are treated with ureteroscopic procedures. Since these surgical techniques do not treat the underlying risk factors, continued medical supervision and therapy for preventing stone recurrence are mandatory in patients who have undergone extracorporeal shock wave lithotripsy or other surgical procedures

Complications:

• Serious complications of urinary tract stone disease

• Abscess formation

• Serious infection of the kidney that diminishes renal function

• Urinary fistula formation

• Ureteral scarring and stenosis

• Ureteral perforation

• Extravasation

• Urosepsis

• Renal loss due to long-standing obstruction

Prognosis:

As the minimally invasive modalities for stone removal are generally successful in removing calculi, the primary consideration in managing stones is not whether the stone can be removed but whether it can be removed in an uncomplicated manner with minimum morbidity.

The usually quoted recurrence rate for urinary calculi is 50% within 5 years and 70% or higher within 10 years, although a large, prospective study published in 1999 suggested that the recurrence rate may be somewhat lower at 25-30% over a 7.5-year period. Metabolic evaluation and treatment are indicated for patients at greater risk for recurrence, including those who present with multiple stones, those who have a history of previous stone formation, and those who present with stones at a younger age

Summary
Nephrolithiasis is caused by several biochemical mechanisms, identification of which allows specific therapy that may prevent recurrences. In patients with their first kidney stone, careful evaluation is needed to identify those at highest risk for recurrence. Extensive evaluation of this subgroup should lead to proper diagnosis and management of nephrolithiasis, resulting in lower morbidity for these patients.