Hypercalciuria and Thiazides

Hypercalciuria is considered an idiopathic disease, with several abnormalities of calcium balance present, including increased intestinal absorption of calcium, reduced bone mineralization, and impaired renal tubular calcium reabsorption. Primary hyperparathyroidism causes resorptive hypercalcuria. Prevention of stone recurrence in patients with idiopathic hypercalciuria is commonly accomplished with thiazide or thiazide-like diuretics, whereas resorptive hypercalcuria is best treated with parathyroid surgery.

Thiazide diuretics enhance renal calcium absorption in the proximal and distal renal tubule, and thus have been the mainstay of treatment of hypercalciuric calcium nephrolithiasis. Multiple RCTs have demonstrated the benefits of thiazide and thiazide-like diuretics in the prevention of recurrent stone disease. Interestingly, only two of these trials limited their participants to those with hypercalciuria, whereas the remainder enrolled calcium stone formers not selected based on urinary calcium excretion. All studies that followed patients for a minimum of 2 years demonstrated a benefit of thiazide treatment. These trials all examined patients with calcium oxalate stones or unspecified calcium stones. Although there are no RCTs that studied calcium phosphate stones per se, thiazides are often used for patients with calcium phosphate stones who also demonstrate hypercalciuria. A Cochrane database review that analyzed five studies (316 patients) using thiazides or thiazide-like diuretics noted a 60% decrease in the number of new stone recurrences in patients treated with thiazides compared with placebo.

Potential side-effects of thiazides and thiazide-like diuretics include hypokalemia, glucose intolerance, dyslipidemia, and hyperuricemia. A review of the RCTs of thiazide therapy for nephrolithiasis noted that serum glucose and lipids were evaluated in two of the studies and were unchanged by therapy, serum uric acid was increased in each of the three studies that examined it, and three of four studies that measured serum potassium noted hypokalemia. Because of this latter potential side effect, potassium supplementation should usually accompany thiazide therapy to avert hypokalemia and resultant thiazide-induced hypocitraturia. Potassium is usually administered as the citrate salt but potassium chloride can also be effective. Amiloride or spironolactone are alternatives to reduce potassium loss, but the poorly soluble triamterene should be avoided.

For patients with idiopathic hypercalciuria, typical doses of these medications are as follows: hydrochlorothiazide, 50 mg daily or 25 mg twice daily; chlorthalidone, 25 to 50 mg daily; indapamide, 1.25 to 2.5 mg daily; amiloride, 5 mg daily; and amiloride/hydrochlorothiazide, 5/50 mg daily. There are several common strategies to avert thiazide-induced hypokalemia, which include the addition of potassium citrate or potassium chloride (10–20 mEq orally daily to twice daily, useful in patients who also have hypocitraturia) or the use of a combination thiazide/potassium-sparing diuretic, such as amiloride/hydrochlorothiazide in patients who do not require citrate repletion. Monitoring of urine pH is also critical because elevation of the urine pH greater than 6.5 can lead to supersaturation of calcium phosphate and possible change in stone recurrence composition.

Hyperoxaluria, Magnesium, Pyridoxine, and Oxalobacter

Hyperoxaluria has often been treated with dietary rather than pharmacologic intervention. Historically, patients have been advised to restrict dietary oxalate, and some have advised a calcium-rich diet in which ingested calcium binds oxalate in the stomach and gastrointestinal tract, limiting its availability for intestinal absorption and for urinary excretion. Two pharmacologic agents that may lower urinary oxalate are magnesium and pyridoxine. In both cases, however, the data are far less compelling than those that favor thiazides.

Magnesium, a cation, forms complexes with oxalate anions in the urine, reducing the oxalate available to bind calcium and form calcium oxalate calculi. Dietary magnesium may reduce intestinal oxalate absorption in a manner similar to dietary calcium, as described previously. There are several noncontrolled trials in the literature evaluating magnesium oxide and magnesium hydroxide preparations that reported decreases in stone recurrence rates on these medications. However, the single RCT that examined magnesium hydroxide versus placebo reported no difference between treatment and placebo arms in prevention of stone recurrence. Magnesium supplementation is most often used in patients with hypomagnesiuria, most of whom have bowel disease. Potential side effects of magnesium therapy include diarrhea and gastrointestinal discomfort. Although less well-studied than magnesium supplementation, calcium supplementation (calcium carbonate, calcium citrate) is another potential therapeutic target for hyperoxaluria that functions by the same mechanism, complexing with oxalate anions. Supplementation of calcium is a strategy commonly used to lower stone risk for patients with a history of Roux-en-Y gastric bypass surgery, in whom hyperoxaluria is the most common urine abnormality found on metabolic stone evaluation.

The rationale for use of vitamin B ₆ is that deficiencies may lead to excess urine oxalate. The literature is lacking in RCTs regarding this use of pyridoxine for prevention of recurrent stone disease, but uncontrolled studies have shown that vitamin B ₆ may decrease urine oxalate or stone recurrence in patients with calcium oxalate stones. Epidemiologic studies have failed to demonstrate a benefit of vitamin B ₆ supplementation in men, but did show that in women, high daily doses of vitamin B ₆ (>40 mg/day) may decrease risk of stone formation compared with those who ingest little or no vitamin B ₆ . A retrospective study of pyridoxine in addition to dietary counseling in patients with hyperoxaluria noted an approximately 30% decrease in urine oxalate on follow-up 24-hour urine studies.

Another potential therapy is the bacterium Oxalobacter formigenes , which colonizes the intestinal tract. Studies have shown that lack of colonization of this bacterium, the sole substrate of which is oxalate, may be associated with an increased incidence of calcium oxalate stone disease. Early evidence demonstrated that oral Oxalobacter formulations could decrease urine oxalate excretion. However, a recent RCT of orally administered Oxalobacter in patients with primary hyperoxaluria, a rare genetic calcium oxalate stone disease characterized by abnormal hepatic oxalate synthesis, failed to show differences in urine oxalate between the oral Oxalobacter group and placebo. This potential therapy might be more successful if targeted toward patients with enteric hyperoxaluria, related to excessive absorption in the setting of inflammatory bowel disease and other causes of short bowel syndrome.

Hypocitraturia, Alkali Citrate, and Fruit Juices

Citrate is a known endogenous inhibitor of calcium oxalate stone formation; it forms soluble complexes with calcium and reduces urinary supersaturation of calcium oxalate. In some cohort studies of stone formers, the incidence of hypocitraturia is in excess of 50%. Several RCTs have been performed, each using a different alkali-citrate preparation. Potassium citrate and potassium-magnesium citrate were both shown to significantly decrease recurrent stone formation in patients with hypocitraturia and unselected stone formers, respectively, whereas sodium-potassium citrate failed to show a benefit. Potassium citrate is commercially available in tablet, liquid, and powder forms (to be mixed with water), whereas potassium-magnesium-citrate remains an investigational drug. A typical starting dose of potassium citrate is 40 to 60 mEq daily in divided doses, increasing until the desired level of citraturia is reached. Many clinicians monitor serum potassium 7 to 10 days after starting or changing doses of this medication. A theoretical risk of hyperkalemia exists when using potassium-based preparations, and patients with decreased glomerular filtration rate should be monitored closely when administering this medication. In addition, some patients report gastrointestinal side effects when taking potassium citrate and it is contraindicated in patients with active peptic ulcer disease. For patients with renal insufficiency or others with increased risk of hyperkalemia, sodium citrate or sodium bicarbonate may be used to increase urine citrate; however, excess sodium is another driving force in stone formation, and sodium can lead to exacerbations of congestive heart failure, hypertension, and lower extremity edema or fluid retention.

Urine citrate may also be significantly increased by ingesting beverages that are high in citrate content. In 1996, a retrospective study reported significant increases in urine citrate seen in patients who are hypocitraturic treated with a “homemade lemonade” formula (7.5 cups of water mixed with 0.5 cup of concentrated lemon juice, sweetened to taste with artificial sweetener and consumed daily). Since then, several studies have tested various beverages, including other lemonade-based preparations, orange juice, pomegranate juice, lime juices, melon juice, diet sodas, and others, with equivocal results. In addition, a single retrospective study noted that patients on lemonade therapy demonstrated a decreased stone recurrence rate. Although the potential for beverage-based therapies remains of interest to patients who prefer nonpharmacologic interventions, lemonade-based therapies have been the most well-studied and some follow-up studies have produced similar results to the initial report.

Hyperuricosuria and Allopurinol

Urine uric acid is thought to promote the formation of calcium oxalate stones. Uric acid reduces the solubility of calcium, called “salting out,” and promotes the formation of calcium oxalate calculi. Thus, hyperuricosuric calcium oxalate nephrolithiasis has traditionally been treated with allopurinol, a xanthine oxidase inhibitor that reduces endogenous uric acid production and urinary uric acid excretion. A single RCT examined stone recurrence in patients who are hyperuricosuric treated with either allopurinol or placebo and noted that the allopurinol arm demonstrated a significant decrease in stone recurrence of more than 50%. This trial excluded patients with hypercalciuria and the effectiveness of xanthine oxidase inhibition in patients with hypercalciuria has not been established. Allopurinol is typically prescribed at a dose of 100 to 300 mg daily for treatment of hyperuricosuric calcium nephrolithiasis and is often used if dietary measures to reduce urine uric acid excretion (ie, dietary protein moderation) are not successful. Rare side effects of this medication include Stevens-Johnson syndrome and elevated liver enzymes. For this reason, liver function tests should be monitored several months after initiation of allopurinol therapy. An uncontrolled trial also demonstrated that potassium citrate is effective in decreasing stone recurrence in patients with hyperuricosuric calcium oxalate nephrolithaisis.

Interesting recent research in uric acid metabolism may lead to novel therapies for hyperuricosuric nephrolithiasis and uric acid nephrolithiasis (see later) in the future. Specifically, recent reports of a new xanthine oxidase inhibitor (febuxostat) and a recombinant form of the enzyme uricase (Rasburicase) have demonstrated superiority to allopurinol in lowering serum uric acid and may also be more potent at reducing the frequency of gouty attacks. These medications represent potential therapeutic agents for stone disease but have not been tested to date.