Dietary and medical management of recurrent nephrolithiasis

Reducing calcium excretion

Hypercalciuria has been traditionally defined as 24-hour urinary calcium excretion greater than 300 mg/day in men, greater than 250 mg in women, or greater than 4 mg/kg in men or women.¹⁷ It is a graded risk factor, and the cut points used in published research and clinical laboratories vary substantially. Some institutions use the same value for hypercalciuria in both sexes, eg, greater than 200 mg/day.¹⁸

Excessive sodium intake is the most common cause of hypercalciuria. Systemic conditions such as primary hyperparathyroidism, sarcoidosis, and renal tubular acidosis also cause hypercalciuria but are uncommon.¹⁹ Management depends on the underlying cause and includes dietary modifications and pharmacologic therapy.

Dietary modifications have a pivotal role in the management of recurrent stones that are due to hypercalciuria.

Dietary calcium should not be restricted, since calcium reduces the excretion of urinary oxalate by decreasing intestinal absorption of oxalate. Guidelines from the American Urological Association recommend a daily calcium intake of 1,000 to 1,200 mg.^11–20 Moreover, restriction of dietary calcium to less than 800 mg/day (the current recommended daily allowance for adults) can lead to negative calcium balance and bone loss.

Sodium intake also influences hypercalciuria. Calcium is reabsorbed passively in the proximal tubule due to the concentration gradient created by active reabsorption of sodium. A high sodium intake causes volume expansion, leading to a decrease in proximal sodium and calcium reabsorption and enhancing calcium excretion. A low-sodium diet (80–100 mmol/day, or 1,800–2,300 mg/day) is recommended. This enhances proximal sodium and passive calcium absorption and leads to a decrease in calcium excretion.²¹

Dietary protein increases the acid load by production of sulfuric acid and leads to hypercalciuria by its action on bone and kidney. Animal protein has a higher content of sulfur and generates a higher acid load compared with vegetable protein and has been associated with an increased incidence of stone formation, at least in men.^20,22 Borghi et al²³ reported that the combination of restricted intake of animal protein (52 g/day), restricted salt intake (50 mmol, or 2,900 mg/day of sodium chloride), and normal calcium intake (30 mmol/day, or 1,200 mg/day) was associated with a lower incidence of stone recurrence in men with hypercalciuria compared with traditional low-calcium intake (10 mmol, or 400 mg/day). Patients should therefore be advised to avoid excessive intake of animal protein.

Increasing the dietary intake of fruits and vegetables as in the Dietary Approach to Stop Hypertension (DASH) diet is beneficial and reduces the risk of stone recurrence, mainly by increasing citrate excretion.²⁴

Pharmacologic therapy in hypercalciuria. Thiazide diuretics are the mainstay of pharmacotherapy for preventing recurrent stones in patients with idiopathic hypercalciuria. They reduce the risk of stone recurrence by about 50%, as reported in a recent meta-analysis that looked at five trials comparing thiazide diuretics with placebo.²⁵ They lower calcium excretion by causing volume depletion, thereby increasing proximal sodium and passive calcium reabsorption.

Chlorthalidone and hydrochlorothiazide are the thiazides commonly used to treat hypercalciuria. The dosage is titrated to the urinary calcium excretion, and a common mistake is to use doses that are too low. They are usually started at 25 mg/day, but often require an increase to 50 to 100 mg/day for adequate lowering of urinary calcium.

Care should be taken to avoid hypokalemia. If it occurs, it can be corrected by adding the potassium-sparing diuretic amiloride (5–10 mg/day), which increases calcium reabsorption in collecting ducts or, in patients with hypocitraturia, potassium citrate-potassium bicarbonate. (Sodium salts should be avoided, since they increase renal calcium excretion.)²⁶

Management of hypercalciuria with metabolic causes, which include primary hyper­parathyroidism and chronic acidemia. Patients who have hypercalciuria from primary hyperparathyroidism are treated with parathyroidectomy.²⁷ Chronic metabolic acidosis causes hypercalciuria by loss of bone calcium and hypocitraturia by increasing active proximal absorption of citrate. Potassium citrate or potassium bicarbonate is used to prevent stones in such patients; sodium salts should be avoided.²⁸

Reducing oxalate excretion

Hyperoxaluria has traditionally been defined as urinary oxalate excretion of more than 45 mg/day. However, the optimal cutoff point for urinary oxalate excretion is unclear, as is the optimal cutoff for hypercalciuria. The risk of stone formation has been shown to increase with oxalate excretion even above 25 mg/day, which is within the normal limit.¹⁸

Idiopathic hyperoxaluria. High dietary oxalate intake, especially when associated with low calcium intake, leads to idiopathic hyperoxaluria. However, the contribution of abnormal endogenous oxalate metabolism is uncertain. Ingested calcium binds to oxalate in the intestinal tract and reduces both the absorption of intestinal oxalate absorption and the excretion of urinary oxalate.²⁹ High dietary oxalate intake has usually been regarded as a major risk factor for kidney stones.

Taylor and Curhan,³⁰ in a prospective study, reported a mild increase in the risk of stones in the highest quintile of dietary oxalate intake compared with the lowest quintile for men (relative risk [RR] 1.22, 95% confidence interval [CI] 1.03–1.45) and older women (RR 1.21, 95% CI 1.01–1.44). They also demonstrated that eating eight or more servings of spinach per month compared with fewer than one serving per month was associated with a similar increase of stone risk in men (RR 1.30, 95% CI 1.08–1.58) and older women (RR 1.34 95% CI 1.1–1.64). In contrast, spinach and dietary oxalate intake did not increase the risk of nephrolithiasis in young women. The authors concluded that the risk associated with oxalate intake was modest, and their data did not support the contention that dietary oxalate is a major risk factor for kidney stones.

Higher oxalate intake increases urinary oxalate excretion and presumably the risk of nephrolithiasis. Limiting dietary oxalate to prevent stones is recommended if habitually high dietary intake of oxalate is identified or follow-up urine measurements show a decrease in oxalate excretion.³¹ Foods rich in oxalate include spinach, rhubarb, nuts, legumes, cocoa, okra, and chocolate.

The DASH diet, which is high in fruits and vegetables, moderate in low-fat dairy products, and low in animal protein, is an effective dietary alternative and has been associated with a lower risk of calcium oxalate stones.²⁴ Consuming fruits and vegetables increases the excretion of urinary citrate, which is an inhibitor of stone formation. Also, it has been proposed that the DASH diet contains unknown factors that reduce stone risk.

Taylor et al³² prospectively examined the relationship between the DASH diet and the incidence of kidney stones and found that the diet significantly reduced the risk of kidney stones. The relative risks of occurrence of kidney stones in participants in the highest quintile of the DASH score (a measure of adherence to the DASH diet) compared with the lowest quintile were 0.55 (95% CI 0.46–0.65) for men, 0.58 (95% CI 0.49–0.68) for older women, and 0.60 (95% CI 0.52–0.70) for younger women, which the authors characterized as “a marked decrease in kidney stone risk.”

Vitamin C intake should be restricted to 90 mg/day in patients who have a history of calcium oxalate stones. Urivetzky et al³³ found that urinary oxalate excretion increased by 6 to 13 mg/day at doses of ascorbic acid greater than 500 mg.

Pyridoxine (vitamin B₆), a coenzyme of alanine-glyoxylate aminotransferase (AGT), increases the conversion of glyoxylate to glycine instead of oxalate and is used in the treatment of type 1 primary hyperoxaluria (see below).³⁴ However, its effect in preventing stones in idiopathic hyperoxaluria is not well known, and it has not been studied in a randomized controlled trial. In a prospective study, Curhan et al³⁵ reported that high intake of pyridoxine (> 40 mg/day) was associated with a lower risk of stone formation in women, but no such benefit was found in men.

Enteric hyperoxaluria. About 90% of dietary oxalate binds to calcium in the small intestine and is excreted in the stool. The remaining 10% is absorbed in the colon and is secreted in urine. Hyperoxaluria is frequently seen with fat malabsorption from inflammatory bowel disease, short gut syndrome, and gastric bypass surgery. In these conditions, excess fat binds to dietary calcium, leading to increased absorption of free oxalate in the colon.³⁶

Treatment is directed at decreasing intestinal oxalate absorption and should include high fluid intake and oral calcium supplements. Calcium carbonate or citrate causes precipitation of oxalate in the intestinal lumen and is prescribed as 1 to 4 g in three to four divided doses, always with meals. Calcium citrate is preferred over calcium carbonate in stone-formers because of the benefit of citrate and calcium citrate’s higher solubility and greater effectiveness in the presence of achlorhydria.³⁷ Patients should be advised to avoid foods high in oxalate and fat.

Primary hyperoxaluria is caused by inherited inborn errors of glyoxylate metabolism that cause overproduction of oxalate and urinary oxalate excretion above 135 to 270 mg/day.

Type 1 primary hyperoxaluria is the most common (accounting for 90% of cases) and is caused by reduced activity of hepatic peroxisomal AGT.

Type 2 is from a deficiency of glyoxylate reductase-hydroxypyruvate reductase (GRHPR).

Type 3 is from mutations in the HOGA1 gene, which codes for the liver-specific mitochondrial 4-hydroxy-2-oxoglutarate aldolase enzyme involved in degradation of hydroxyproline to pyruvate and glyoxalate.³⁸

High fluid intake to produce a urinary volume of 3 L/day reduces intratubular oxalate deposition and should be encouraged. Potassium citrate (0.15 mg/kg), oral phosphate supplements (30–40 mg/kg of orthophosphate), and magnesium oxide (500 mg/day/m²) inhibit precipitation of calcium oxalate in the urine.^39,40 Pyridoxine, a coenzyme of AGT, increases the conversion of glyoxylate to glycine instead of oxalate and is prescribed at a starting dose of 5 mg/kg (which can be titrated up to 20 mg/kg if there is no response) in patients with type 1 primary hyperoxaluria. About 50% of patients with type 1 respond successfully to pyridoxine, and a 3- to 6-month trial should be given in all patients in this category.³⁴ AGT is present only in hepatocytes, and GRHPR is found in multiple tissues; therefore, combined liver-kidney transplant is the treatment of choice in patients with type 1 primary hyperoxaluria, whereas isolated kidney transplant is recommended in patients with type 2.⁴¹

Reducing uric acid excretion

Hyperuricosuria is defined as uric acid excretion of greater than 800 mg/day in men and greater than 750 mg/day in women.

The association of hyperuricosuria with increased risk of calcium oxalate stone formation is controversial. Curhan and Taylor,¹⁸ in a cross-sectional study of 3,350 men and women, reported that there was no difference in mean 24-hour uric acid excretion in individuals with and without a history of stones.

The mechanism by which uric acid leads to calcium oxalate stones is not completely known and could be the “salting out” of calcium oxalate from the urine.⁴²

Dietary purine restriction, ie, limiting intake of nondairy animal protein to 0.8 to 1 g/kg/day, is the initial dietary intervention.¹¹ Allopurinol is the alternative approach if the patient is not compliant or if dietary restriction fails.⁴³

In a study by Ettinger et al,⁴⁴ 60 patients with hyperuricosuria and normocalciuria were randomized to receive allopurinol (100 mg three times daily) or a placebo. The allopurinol group had a rate of calculus events of 0.12 per patient per year, compared with 0.26 in the placebo group.