The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne



IDNEY stones have a lifetime incidence of up to 13 percent in North America.1 In the United States, this disorder was responsible for an estimated 1.32 million visits to physicians in 1995 and for $1.83 billion in health care costs in 1993.2 In at least 70 percent of cases, the stones consist of calcium oxalate crystals, often with calcium phosphate or sodium urate.3,4 Kidney stones generally form only in urine that is markedly supersaturated with respect to a solid phase.5 Heterogeneous nucleation, in which the initial ion complex is attached to a foreign surface, occurs more often and at a lower level of supersaturation than homogeneous nucleation, which occurs when stones form independently of a nucleating surface. The rapid transit of urine through the tubule does not allow sufficient time for suspended crystals to aggregate into lumen-obstructing calculi. In vitro data suggest that calcium oxalate crystals attach to tubular epithelial cells6; in vivo, crystals adhere to papillary-duct cells. The attachment of crystals to urothelium may allow sufficient time for growth into clinically significant stones. Once a kidney stone forms, there is approximately a 50 percent probability that a second stone will form within five to seven years in the absence of treatment.3 Understanding, and then altering, the factors that lead to stone formation should help prevent recurrences. Standard therapy is based on a reduction of urinary supersaturation, since we cannot yet biochemically modulate promoters or inhibitors of stone formation. Hypercalciuria (more than 4 mg of urinary calcium [0.1 mmol] per kilogram of body weight per day), leading to increased supersaturation, is the most common metabolic abnormality in patients with calcium-containing kidney stones.3 Hypercalciuria may be due to known disorders such as primary hyperparathyroidism; in most cases, however, no specific cause can be identified and the disorder is therefore classified as idiopathic. Studies of an animal model of hypercalciuria, the genetic hypercalciuria stone-forming rat, suggest that excess vitamin D receptors in the intestine, kidney, and bone may cause systemic dysregulation of calcium transport.7 Thirty to 50 percent of patients with kidney stones have idiopathic hypercalciuria: they absorb, and excrete, a greater proportion of dietary calcium than do normal persons.8 A reduction of dietary calcium has been considered a logical way to prevent recurrent stones, on the as-

sumption that a diet low in calcium would reduce urinary calcium, lower the relative supersaturation with respect to calcium oxalate, and help prevent recurrent stones. However, the prescription of an indiscriminate reduction in calcium intake has raised some questions.3,4,9,10 A reduction of dietary calcium not only reduces urinary calcium but also increases urinary oxalate,11 and this may result in increased supersaturation with respect to the calcium oxalate solid phase. If so, is stone formation more rather than less likely to recur with a low-calcium diet? Moreover, patients with idiopathic hypercalciuria frequently have decreased bone mineral density.8 If the reduction in intestinal calcium absorption induced by a low-calcium diet is not at least matched by a similar reduction in urinary calcium excretion, then total body calcium will decrease. Since approximately 98 percent of body calcium is located in bone, does a low-calcium diet lead to a further reduction in bone mineral density? Strong support for the hypothesis that a low-calcium diet actually increases the risk of nephrolithiasis comes from a prospective epidemiologic study of the relation between reported dietary calcium intake and the risk of an initial symptomatic kidney stone.12 Kidney stones were significantly more likely to develop in subjects with the lowest reported calcium intake (a mean of 516 mg [12.9 mmol] per day) than in those with the highest reported calcium intake (1326 mg [33.1 mmol] per day), after adjustment for age and energy intake. An editorial accompanying the report concluded, “There is no benefit to the time-honored advice to eat a diet low in calcium.”9 Because of the concern about possible adverse effects of a low-calcium diet, clinicians adopted alternative approaches to the care of patients with idiopathic hypercalciuria and nephrolithiasis.3,4 Patients were advised to consume age- and sex-appropriate amounts of calcium. Dietary calcium should bind intestinal oxalate and prevent its absorption and subsequent urinary excretion.11 Urinary calcium excretion and supersaturation with respect to calcium oxalate are reduced when the intake of animal protein and sodium is restricted. A reduction in animal protein reduces the production of metabolic acids, resulting in a lower level of acid-induced urinary calcium excretion, and increases the excretion of citrate, which forms a soluble complex with calcium and thus reduces supersaturation with respect to calcium oxalate. A reduction of animal protein should also limit the excretion of urate, crystals of which are a potential surface for heterogeneous nucleation. Since dietary, and thus urinary, sodium is directly correlated with urinary calcium excretion, a reduction in sodium intake should reduce calcium excretion. Until now, there have been no data from long-

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term, controlled clinical studies to support either approach to treatment. In this issue of the Journal, Borghi et al.13 provide a clear answer to the question of the relative effectiveness of these alternative approaches. The investigators tested the two approaches in men with idiopathic hypercalciuria and recurrent calcium oxalate stones. The men were randomly assigned either to a low-calcium diet (400 mg [10 mmol] per day) or to a diet with normal calcium (1200 mg [30 mmol] per day), low animal protein (52 g per day), and low salt (2900 mg [50 mmol] of sodium chloride per day); both groups were told to consume 2 or 3 liters of water per day, depending on the season. The men were followed for five years, and data were obtained on urinary ion excretion, the relative supersaturation with respect to calcium oxalate, and stone formation. The relative risk of recurrent stones was significantly lower in the group assigned to the diet with normal calcium, low animal protein, and low salt than in the group assigned to the low-calcium diet. Urinary calcium levels fell with both diets, as did the relative supersaturation with respect to calcium oxalate. However, the reduction in relative supersaturation was greater with the normalcalcium diet because of a marked difference in urinary oxalate. Oxalate excretion fell with the normal-calcium diet and rose with the low-calcium diet. The difference in the rate of stone formation was greatest in the latter part of the study, perhaps because some patients had nascent stones at the time of enrollment that subsequently developed into overt disease14 and these patients were withdrawn from further analysis. The comparison of a low-calcium diet with a diet that contained a normal amount of calcium and identical amounts of animal protein and salt would have directly tested the influence of dietary calcium on stone formation. Future studies should address the independent role of each of the three dietary components — calcium, animal protein, and salt — in the recurrence of kidney stones. Measurement of bone mineral density might have addressed the question of whether the low-calcium diet was detrimental to total body calcium stores. In addition, it is not known whether the findings are valid for women, in whom a reduction of mineral density induced by a low-calcium diet is likely to be of greater consequence than it is in men. However, we now know that, at least for men with idiopathic hypercalciuria, a diet with a normal amount of calcium and reduced amounts of animal protein and salt is superior to a low-calcium diet in preventing recurrent stones. For patients with hypercalciuria in whom the relative supersaturation with respect to calcium oxalate is not reduced through diet alone, the calcium-conserving thiazide diuretics have been shown to reduce the risk of recurrent disease.15 Although all patients should be advised to

consume adequate amounts of fluid to ensure excretion of at least 2 liters of urine each day, an increase in fluid intake alone is insufficient to prevent recurrent nephrolithiasis in patients with hypercalciuria.16 Many experts on stone disease have argued that the use of a low-calcium diet is not warranted on theoretical and epidemiologic grounds.3,4,9,10,12 With the data from the carefully controlled study by Borghi et al., we can now assure men with idiopathic hypercalciuria that a diet containing an ample amount of calcium (1200 mg per day), in conjunction with a reduced amount of animal protein and salt, is superior to a low-calcium diet for the prevention of recurrent calcium oxalate stones.13 Physicians should no longer prescribe a low-calcium diet to prevent recurrent nephrolithiasis in patients with idiopathic hypercalciuria.
University of Rochester School of Medicine and Dentistry Rochester, NY 14642

1. Ramello A, Vitale C, Marangella M. Epidemiology of nephrolithiasis. J Nephrol 2000;13:Suppl 3:S45-S50. 2. Kidney and urologic diseases statistics for the United States. Bethesda, Md.: National Institute of Diabetes & Digestive & Kidney Diseases, 2001. (Accessed December 18, 2001, at kidney/pubs/kustats/kustats.htm.) 3. Asplin JR, Favus MJ, Coe FL. Nephrolithiasis. In: Brenner BM, ed. Brenner & Rector’s the kidney. 6th ed. Vol. 2. Philadelphia: W.B. Saunders, 2000:1774-819. 4. Bushinsky DA. Nephrolithiasis. J Am Soc Nephrol 1998;9:917-24. 5. Bushinsky DA, Parker WR, Asplin JR. Calcium phosphate supersaturation regulates stone formation in genetic hypercalciuric stone-forming rats. Kidney Int 2000;57:550-60. 6. Lieske JC, Toback FG. Renal cell-urinary crystal interactions. Curr Opin Nephrol Hypertens 2000;9:349-55. 7. Bushinsky DA. Genetic hypercalciuric stone-forming rats. Curr Opin Nephrol Hypertens 1999;8:479-88. 8. Monk RD, Bushinsky DA. Pathogenesis of idiopathic hypercalciuria. In: Coe FL, Favus MJ, Pak CYC, Parks JH, Preminger GM, eds. Kidney stones: medical and surgical management. Philadelphia: Lippincott-Raven, 1996:759-72. 9. Lemann J Jr. Composition of the diet and calcium kidney stones. N Engl J Med 1993;328:880-2. 10. Bushinsky DA. Renal lithiasis. In: Humes HD, DuPont HL, Gardner LB, et al., eds. Kelly’s textbook of internal medicine. 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2000:1243-8. 11. Lemann J Jr, Pleuss JA, Worcester EM, Hornick L, Schrab D, Hoffman RG. Urinary oxalate excretion increases with body size and decreases with increasing dietary calcium intake among healthy adults. Kidney Int 1996;49:200-8. [Erratum, Kidney Int 1996;50:341.] 12. Curhan GC, Willett WC, Rimm EB, Stampfer MJ. A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. N Engl J Med 1993;328:833-8. 13. Borghi L, Schianchi T, Meschi T, et al. Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med 2002;346:77-84. 14. Parks JH, Coe FL. An increasing number of calcium oxalate stone events worsens treatment outcome. Kidney Int 1994;45:1722-30. 15. Pearle MS, Roehrborn CG, Pak CY. Meta-analysis of randomized trials for medical prevention of calcium oxalate nephrolithiasis. J Endourol 1999; 13:679-85. 16. Borghi L, Meschi T, Amato F, Briganti A, Novarini A, Giannini A. Urinary volume, water and recurrences in idiopathic calcium nephrolithiasis: a 5-year randomized prospective study. J Urol 1996;155:839-43. Copyright © 2002 Massachusetts Medical Society.

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