In general, 50% of patients experience recurrent urinary stones within 5 years without prophylactic intervention.
Appropriate education and preventive measures are best instituted with a motivated patient after spontaneous stone passage or surgical stone removal. Risk factors as described previously should be identified and modified, if possible.
Irrespective of the final metabolic evaluation and stone analysis, the patient’s fluid intake should be about 1.6 L/ 24 h. Fluids should be encouraged during mealtime. Additionally, liquids should be increased approximately 2 hours after meals. Water produced as a metabolic by-product reaches its nadir at this time, and thus the body is relatively dehydrated. Fluid ingestion also should be encouraged to force a nighttime diuresis adequate to awaken the patient to void. Awakening and ambulating to void limit urinary stasis and offer an opportunity to ingest additional fluids.
These lifestyle changes are difficult to maintain and should be encouraged during subsequent office visits. Motivated patients who regularly return to a urinary stone clinic have a reduced stone recurrence rate that is probably due to increased compliance.
A. METABOLIC EVALUATION
A systematic metabolic evaluation should be instituted after a patient has recovered from urinary stone intervention or spontaneous stone passage. Stone analysis should be obtained to help direct the workup. An outpatient urine collection during typical activities and fluid intake helps unmask significant abnormalities. An initial 24-hour urine collection for calcium stone formers should include tests for calcium, uric acid, oxalate, citrate, sodium, volume, and pH. An open dialog with local laboratories helps to standardize collection routines and determine whether an outside laboratory is preferred. Baseline serum levels for blood urea nitrogen, creatinine, calcium, phosphorous, and uric acid are appropriate.
Hypercalciuria is the most common abnormality. To differentiate among hypercalciuria types I, II, and III, a patient should be placed on a sodium- and calcium-restricted diet for a few days to a week. This is easily achieved (100 mEq/day) by eliminating table salt and reducing obviously salty foods. Calcium is restricted (400–500 mg) by excluding dairy products. A repeat 24-hour urine collection is evaluated for calcium. A urinary calcium level <250 mg/day confirms a diagnosis of dietary-dependent hypercalciuria type II. Type I and type III hypercalciuria must be differentiated in patients with urinary calcium levels >250 mg/day. A calcium binder such as cellulose phosphate is prescribed (5 g three times daily with meals) for a few days. This is followed by a repeat 24-hour urine calcium level and parathyroid hormone blood value. Patients who have type I absorptive hypercalciuria have at least a 50% drop in urinary calcium levels and normal parathyroid hormone levels.
Hyperuricosuria, hyperoxaluria, and hypocitraturia calcium stone formers can be treated appropriately and followed with repeat 24-hour urine collections. Many calcium stone formers have multiple defects; although one treatment may reverse one defect, it may exacerbate others.
Subsequent 24-hour urine collections are critical for effective long-term follow-up and stone prevention. Treatment of cystinuria should be titrated with repeat 24-hour cystine levels. Repeat urine cultures should be obtained in patients with infectious calculi.
B. ORAL MEDICATIONS
1. Alkalinizing pH agents–
Potassium citrate is an oral agent that elevates urinary pH effectively by 0.7–0.8 pH units. Typical dosing is 60 mEq in 3 or 4 divided doses daily. It is available in wax-matrix 10-mEq tablets, liquid preparations, and crystals that must be mixed with fluids. The effect is maintained over many years.
Care should be taken in patients susceptible to hyperkalemia, those with renal failure, and those taking potassium-sparing diuretics. Although the medication is usually well tolerated, some patients may complain of abdominal discomfort, especially with tablet preparations. It is indicated in those with calcium oxalate calculi secondary to hypocitraturia (<320 mg/day), including those with renal tubular acidosis. Potassium citrate also may be used effectively to treat uric acid lithiasis and nonsevere forms of hyperuricosuric calcium nephrolithiasis.
Sodium and potassium bicarbonate, orange juice, and lemonade are alternative alkalinizing agents. There are no effective long-term urinary acidifying agents.
2. Gastrointestinal absorption inhibitor–
Cellulose phosphate binds calcium in the gut and thereby inhibits calcium absorption and urinary excretion. It is a popular drug in the treatment of absorptive hypercalciuria type I with recurrent calcium nephrolithiasis, although it only prevents new stone formation. Patients should have normal parathyroid hormone values, normal serum calcium and phosphate values, no evidence of bone disease, and evidence of increased intestinal calcium absorption. The drug decreases the urinary saturation of calcium phosphate and calcium oxalate.
It may increase urinary oxalate and urinary phosphate levels. A typical starting dosage is 5 g three times daily with meals; the dosage may be titrated by following 24-hour urinary calcium levels. Urinary magnesium, calcium, oxalate, and sodium levels and serum parathyroid hormone should be monitored one to two times yearly. Magnesium supplements are frequently required and should be taken at least 1 hour before or after cellulose phosphate is taken. Cellulose phosphate is associated with a sodium load and should be used with caution in those with congestive heart failure. Gastrointestinal side effects are infrequent; they include dyspepsia and loose bowel movements.
Cellulose phosphate may be suboptimal treatment for postmenopausal women who are at risk for bone disease.
An alternative treatment for such patients would be hydrochlorothiazides supplemented with potassium citrate to offset the potential hypokalemia and hypocitraturia.
3. Phosphate supplementation–
Renal phosphate leak is best treated by replacing phosphate. Phosphate absorption may be inhibited in the presence of aluminum-, magnesium-, or calcium-containing antacids. This treatment should be used with caution in digitalized patients and in those with severe renal failure, Addison disease, or severe hepatic dysfunction. It is generally well tolerated. Dosing can begin with 250 mg three to four times daily and may be doubled depending on follow-up serum electrolyte, calcium, and phosphorus levels.
Thiazides can correct the renal calcium leak associated with renal hypercalciuria. This prevents a secondary hyperparathyroid state and its associated elevated vitamin D synthesis and intestinal calcium absorption. A rapid decrease in urinary calcium excretion is appreciated and is sustained long-term (>10 years). A starting dose of 25 mg may be titrated based on urinary calcium levels. Side effects are usually well tolerated. Potassium levels should be monitored. Hypokalemia induces a hypocitraturic state; potassium replacement corrects the hypokalemia and its associated hypocitraturia.
Thiazides result in a transient decrease in urinary calcium excretion in absorptive hypercalciurics. Urinary calcium excretion rebounds to pretreatment values in 50% of such patients after 4–5 years of therapy. Dietary changes are not believed to be responsible for this phenomenon. Thiazides do not restore normal intestinal absorption of calcium.
5. Calcium supplementation–
Enteric hyperoxaluric calcium nephrolithiasis is effectively treated with calcium supplements. Calcium gluconate and calcium citrate are better absorbed and are more effective in increasing serum calcium availability than are other forms of calcium.
Calcium carbonate, calcium phosphate, and oyster shell are forms of calcium that are less efficiently absorbed; they remain in the intestinal lumen, available to bind oxalate, thus reducing its absorption. These less efficiently absorbed forms of calcium are optimal to treat enteric hyperoxaluric calcium nephrolithiasis and must be given with meals to be effective.
6. Uric acid-lowering medications–
Allopurinol is used to treat hyperuricosuric calcium nephrolithiasis with or without hyperuricemia. Unlike uricosuric agents that reduce serum uric acid levels by increasing urinary uric acid excretion, allopurinol is a xanthine-oxidase inhibitor and reduces both serum and urinary levels of uric acid. It has no impact on the biosynthesis of purines; rather, it acts exclusively on purine catabolism. Elevated levels of xanthine and hypoxanthine in the urine secondary to allopurinol have not been associated with nephrolithiasis.
Allopurinol is a potentially dangerous drug and should be discontinued at the first appearance of a skin rash, which infrequently may be fatal. Therapy can start at 300 mg/day. It is tolerated best when taken after meals.
Acetohydroxamic acid reversibly inhibits bacterial urease, decreasing urinary ammonia levels, and will subsequently acidify urine.
It is best used as prophylaxis after removal of struvite stones. It also may be used after unsuccessful attempts at curative surgical removal of calculi or culture-specific antibiotic therapy. Patients with serum creatinine >2.5 mg/dL are unable to achieve therapeutic urinary levels. Acetohydroxamic acid is not effective with non-urease-producing bacteria. Long-term data (>7 years) are unavailable. A significant number of patients complain of side effects, including headaches that are usually shortlived and responsive to aspirin compounds. Other frequent complaints include nausea, vomiting, anorexia, nervousness, and depression. A typical dosing regimen is 1 250 mg tablet three or four times daily (total dosage: 10– 15 mg/kg/day).
8. Prevention of cystine calculi –
Conservative measures, including massive fluid intake and urinary alkalinization, are frequently inadequate to control cystine stone formation. Penicillamine, the same drug that is used to chelate excess copper in the treatment of Wilson disease, undergoes a thiol-disulfide exchange with cystine.
This reduces the amount of urinary cystine that is relatively insoluble. Cystine solubility is pH-dependent (pH 5: 150–300 mg/L; pH 7: 200–400 mg/L; pH 7.5: 220–500 mg/L). D-Penicillamine is associated with numerous and frequent side effects, including rashes and hematologic, renal, and hepatic abnormalities. An initial dosage of 250 mg daily in 3–4 divided doses may help reduce severe side effects. It may be increased gradually to 2 g/day. Dosage should be titrated with quantitative urinary cystine values. Penicillamine increases the requirement of pyridoxine (vitamin B6), which should be supplemented with 25–50 mg/day.
Mercaptopropionylglycine (Thiola) is better tolerated by patients than is penicillamine. Mercaptopropionylglycine, a reducing agent, binds to the sulfide portion of cystine, forming a mixed disulfide (Thiola-cysteine) water-soluble compound. It may retard the rate of new stone formation.
The dosage should be titrated with repeat 24-hour urinary cystine values. An initial dosage may be 200–300 mg three times daily, either 1 hour before or 2 hours after each meal. Side effects are not infrequent and may include drug fever; nausea, vomiting, and gastrointestinal upset; rash, wrinkling, or friable skin; lupuslike symptoms, decreased taste perception; and a variety of hematologic disorders.
Marshall L. Stoller, MD
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