Calcium intake and urinary stone disease

Introduction

As 80-90% of kidney stones are composed of calcium in the form of either calcium oxalate or calcium phosphate (1), excess calcium excretion in the urine has been a primary focus in preventing stone recurrence (2). Calcium metabolism and calcium homeostasis are complex processes that involve multiple organ systems. A thorough understanding of the interaction between the various players in calcium homeostasis is critical to understanding the abnormalities and dysregulation that can arise when calcium is not managed appropriately by the intestines, vitamin D and parathyroid hormones, bones, and the kidneys. Calcium intake is perhaps one of the most misunderstood factors related to urinary stone formation and there is controversy as to whether there are differences in the effect of dietary and supplemental calcium on kidney stone formation.

Intestinal calcium absorption

The ingestion of calcium is the only route by which humans can acquire this important element (3). About 30-40% of dietary calcium is absorbed from the gastrointestinal tract with the majority occurring in the small intestine (4). The amount of calcium absorbed in the intestine depends on habitual calcium intake. When calcium intake is low, calcium is actively transported in the duodenum and a larger portion of calcium is absorbed by an active process leading to a greater fractional absorption of calcium (5,6). The active, transcellular process of calcium absorption is regulated by calcitriol [1,25-(OH)₂-vitamin D₃] (7,8). When calcium intake is high, passive calcium absorption is the primary absorptive process occurring in the jejunum and ileum leading to a lower fractional absorption of calcium (4-6,9). Thus the process of adaptation of the intestines allows the fractional absorption of calcium to vary widely between individuals, ranging from 10-70% (10-12).

Many factors influence calcium absorption including age, gender, race, pregnancy/lactation/menopausal status, obesity, the timing and amount of calcium taken, vitamin D and parathyroid hormone levels, and the other nutritional factors consumed with the calcium (3). Calcium is absorbed in the ionic state and thus intake of calcium with compounds that complex calcium such as oxalate, phosphate, sulfate, citrate, fiber, and fats reduce the bioavailability of calcium for potential absorption (3,13).

Vitamin D is the major regulator of intestinal calcium absorption and is obtained from either the diet or exposure to sunlight (14). Vitamin D₂ and D₃ are ultimately converted to the physiologically active calcitriol [1,25-(OH)₂-vitamin D₃] which is the most potent stimulator of intestinal absorption of calcium. Calcitriol also acts on the bone, along with parathyroid hormone, to promote bone demineralization by stimulating osteoclasts (13). Parathyroid hormone does not directly affect intestinal calcium absorption, but it stimulates synthesis of calcitriol, which leads to enhanced intestinal calcium absorption.

Intestinal calcium absorption likely plays a role in kidney stone formation. Patients with excess calcium losses in the urine tend to have higher intestinal calcium absorption (15,16). Radioactive calcium isotopes have been used to evaluate the relationship between intestinal fractional calcium absorption and elevated urinary calcium levels (17-19). Recently, we evaluated data from the prospective multicenter study of osteoporotic fractures where more than 5,400 women underwent oral radioactive calcium assay to evaluate intestinal calcium absorption (20). In this study, fractional calcium absorption was independently associated with nephrolithiasis. Women with a history of kidney stones tended to have higher fractional calcium absorption at each level of dietary and supplemental calcium intake. Also, increasing calcium intake was associated with lower fractional calcium absorption, with no difference between dietary or supplemental calcium sources.

It is therefore likely that calcium absorption differs between stone formers and non-stone formers. This may be due to primary difference in baseline intestinal absorption of calcium, leading to greater calcium absorption and then greater urinary excretion and subsequent stone formation. On the other hand, differences in intestinal calcium absorption are very closely related to calcium intake, and thus it is possible that the differences in calcium absorption between stone formers and non-stone formers are secondary to differences in past calcium intake.

Hypercalciuria

Hypercalciuria is the most common abnormality in calcium stone formers, occurring in 35-65% of subjects, and may lead to supersaturation of urinary calcium salts (21-24). Several mechanisms can lead to hypercalciuria, as calcium homeostasis is primarily regulated through a complex interrelated interaction between the intestines, kidney, and bones (25,26). Historically, research from Pak et al. in 1974 classified the type of hypercalciuria based on the organ system responsible including intestinal absorptive, renal leak, or parathyroid resorptive hypercalciuria (27). Hypercalciuria not explained by the classification scheme was determined to be idiopathic, a category which represents at least 50% of stone formers (25). Idiopathic hypercalciuric stone forming patients likely have a more generalized systemic abnormality with some degree of dysregulation of calcium homeostasis in the intestine, kidney, and bone.

The dysregulation of calcium balance is complicated. One might expect that patients with primary hyperparathyroidism might be the most straightforward. Nephrolithiasis formation in these patients is largely attributed to hypercalciuria (21,28-30). Elevated serum parathyroid hormone levels increase serum calcium levels due to increased intestinal absorption, bone resorption, and renal reabsorption of calcium (31). Despite the increased parathyroid hormone mediated renal reabsorption of calcium in the distal nephron, the excess serum calcium load overwhelms the ability of the kidney to reclaim calcium. Thus, one would expect to find hypercalciuria in all patients with primary hyperparathyroidism, increasing the risk of nephrolithiasis. However, only 20% of patients with primary hyperparathyroidism form stones (29), and up to 35% of stone forming patients with primary hyperparathyroidism do not have hypercalciuria (32). Though urinary calcium levels do decrease significantly after parathyroidectomy, there are no apparent differences in the magnitude of the decrease in stone formers and non-stone formers (32).

This example serves to demonstrate that our understanding of calcium homeostasis remains somewhat limited. While Pak’s classification system potentially simplifies the causes of excess urinary calcium loses, it has not dramatically changed the understanding of the mechanisms of nephrolithiasis formation or changed the management of stone disease. It also has not lead to more effective prevention of stones, and thus, use of the classification system is not recommended in clinical practice (20,33,34).

Dietary calcium

For many years patients were advised to decrease their calcium intake in an attempt to limit the diet-dependent intestinal absorptive hypercalciuria, as dietary calcium restriction was one of the mainstays of therapy for prevention of stone recurrence (35,36). Large, prospective observational studies were the first to demonstrate the potential risks of a low calcium intake. Using data from more than 45,000 men in the Health Professionals Follow-up Study, Curhan et al. were the first to demonstrate in their 1993 article that low dietary calcium intake potentially increased the risk of stones by more than 51% compared to men with the highest dietary calcium intake after adjusting for multiple potential confounders (37). These findings were later confirmed with a similar effect in both younger and older women in the Nurses Health Studies II and I respectively (38,39), and more recently in the women in the observational arm of the Women’s Health Initiative (40). Dietary calcium intake is likely a protective factor against stone formation and this is likely the case whether dietary calcium comes from dairy or non-dairy sources (41).

The inverse relationship between low dietary calcium intake and an increase in stone formation is likely due to a secondary increase in urinary oxalate. Oxalate absorption occurs throughout the intestinal tract (42). When calcium and oxalate are consumed at the same meal, a calcium-oxalate complex forms within the intestinal tract limiting the intestinal absorption and subsequent urinary excretion of free oxalate (36,43). However, with dietary calcium restriction, free oxalate becomes increasingly available for intestinal absorption, leading to greater urinary excretion of oxalate (43-47).

This was ultimately tested in a randomized control trial in 2002 of men with hypercalciuria and a history of recurrent stones, where men were prescribed a low salt, low animal protein, moderate calcium (1,200 mg daily) diet and were compared to men prescribed a low calcium diet (400 mg daily) (48). Both groups were advised to decrease dietary oxalate intake and after 5 years of follow up the risk of stone recurrence was more than 50% lower in men on the normal calcium diet. While urinary calcium levels decreased in both groups, urinary oxalate levels increased in men on the low calcium diet and decreased in men on the normal calcium diet. Though it is suggestive, this study did not directly assess the independent effect of dietary calcium on urinary oxalate and stone recurrence as multiple dietary changes were made in both groups.

In addition, dietary calcium restriction may lead to bone demineralization. Patients with a history of kidney stones have an increased risk of bone mineral density problems and osteoporotic fractures, and these risks are likely compounded in patients with low dietary calcium intake (49,50). A population-based cohort study demonstrated that patients with a history of kidney stones had nearly a 4-fold increased risk of vertebral osteoporotic fractures (51). Cross-sectional data has demonstrated an association between dietary calcium restriction and decreased bone mineral density in stone formers (52).

As a result of the increased risk of stone formation and bone demineralization, dietary calcium restriction is now no longer recommended for patients with hypercalciuria (53). Almost 25 years later, the end result of such a focus on intestinal absorptive hypercalciura as a potential source for kidney stone formation, still leads many patients to intentionally decreasing their dietary calcium intake. As the prevalence of stone disease increases, continued efforts are needed to educate patients that modest dietary calcium intake between 800-1,200 mg daily is recommended for stone formers.

Calcium supplementation

The effect of calcium supplements on stone risk is currently controversial. As a part of the Women’s Health Initiative Calcium and vitamin D randomized control trial, more than 36,000 postemenopausal women were randomized to receive placebo or 500 mg of calcium carbonate plus 200 units of vitamin D₃ twice daily (54). The mean total calcium intake for the women receiving calcium and vitamin D was 2,100 mg of daily calcium consisting of an average of 1,100 mg daily from dietary calcium plus the additional 1,000 mg of supplemental calcium. After 7 years of follow up, there was a 17% increased risk of stone formation in the women randomized to calcium and vitamin D. The lower end of the 95% confidence intervals approached the null hypothesis but was statistically significant (HR 1.02-1.34). Interestingly, when only the women with greater than 80% compliance were analyzed, the risk was similar in magnitude, but no longer statistically significant (55). The risk of stone formation was similarly increased (20%) among women in the Nurse’s Health Study I observational study who reported taking supplemental calcium (39). In this observational cohort, 67% of the women taking calcium supplements took them separate from a meal or with a low-oxalate meal. Given the increased risk of stone formation, this may indicate that the relationship between calcium supplementation and a meal may be important.

In a separate study, postmenopausal women with a total calcium intake of over 2,400 mg daily, 800 mg/day from diet and 1,600 mg daily from calcium supplementation, had significantly higher rates of hypercalciuria compared to subjects receiving placebo during this 1-year study, though no stone events occurred during the study (56). Thus, calcium intake at high amounts may increase urinary calcium levels.

In contrast to the studies above, prospective observational studies such as the Nurse’s Health Study II, and the Health Professionals Follow Up Study demonstrated no increased risk of nephrolithiasis with calcium supplementation (37,38,57).

The timing of calcium supplementation is likely critically important. Whether obtained from dietary or supplemental sources, calcium present in the intestinal tract will bind oxalate leading to decreased oxalate absorption and subsequent urinary excretion. As calcium is always in relative excess in the urine, urinary oxalate is likely more important than even large increases in urinary calcium (43,58). To further evaluate the effect of timing of calcium intake, Domrongkitchaiporn et al. performed a randomized, crossover, diet controlled study in young, healthy, male navy privates where subjects received either 1,000 mg of calcium carbonate with three meals daily (3,000 mg total), or 3,000 mg of calcium carbonate at bedtime (59). Urinary calcium levels increased similarly between the two groups, but the urinary oxalate levels were significantly decreased when the calcium supplementation was taken with a meal. Despite the increase in urinary calcium, the protective effect on urinary oxalate prevented the supersaturation of calcium oxalate from increasing. The authors concluded that calcium supplements should be taken with meals in order to avoid increasing the risk of calcium oxalate nephrolithiasis.

These data suggest that calcium supplements, especially if medically necessary for the prevention or treatment of osteopenia and/or osteoporosis, should be taken with a meal, rather than between meals or at bedtime. Patients with a history of kidney stones, who are taking calcium supplements, should have their urine monitored when they begin this therapy and if the activity of their stone disease increases. Patients should be encouraged to use dietary calcium sources whenever possible, and if hypercalciuria does occur then the timing, type and dosage of calcium supplementation should be evaluated and the hypercalciuria treated if it is felt to be a contributing factor to stone formation.

Summary

Calcium is a very important mineral for cellular function. Calcium homeostasis is a complicated process which we do not completely understand. Dysregulation of calcium homeostasis is also complex and may lead to primary or secondary changes in intestinal calcium absorption. Alternatively, patients with a history of kidney stone formation may have abnormal intestinal calcium absorption either due to an inherent predisposition, or due to differences in calcium intake.

There is level 1 evidence that dietary calcium intake is a protective factor against stone formation. We no longer recommend dietary calcium restriction as it may lead to increased stone formation potentially through increased oxalate absorption, and may cause bone demineralization. Further efforts are needed to educate patients not to restrict calcium intake. The data on supplemental calcium intake is currently controversial. In cases where calcium supplementation is medically necessary, patients should be encouraged to take their calcium supplements with a meal and should be monitored for changes in the activity of their stone disease.

Acknowledgements

None.

Footnote

Conflicts of Interest: The author has no conflicts of interest to declare.

References

1. Gault MH, Chafe L. Relationship of frequency, age, sex, stone weight and composition in 15,624 stones: comparison of resutls for 1980 to 1983 and 1995 to 1998. J Urol 2000;164:302-7. [PubMed]
2. Pearle MS, Roehrborn CG, Pak CY. Meta-analysis of randomized trials for medical prevention of calcium oxalate nephrolithiasis. J Endourol 1999;13:679-85. [PubMed]
3. Emkey RD, Emkey GR. Calcium metabolism and correcting calcium deficiencies. Endocrinol Metab Clin North Am 2012;41:527-56. [PubMed]
4. Bronner F, Pansu D. Nutritional aspects of calcium absorption. J Nutr 1999;129:9-12. [PubMed]
5. Heaney RP, Saville PD, Recker RR. Calcium absorption as a function of calcium intake. J Lab Clin Med 1975;85:881-90. [PubMed]
6. Ireland P, Fordtran JS. Effect of dietary calcium and age on jejunal calcium absorption in humans studied by intestinal perfusion. J Clin Invest 1973;52:2672-81. [PubMed]
7. Christakos S, Gabrielides C, Rhoten WB. Vitamin D-dependent calcium binding proteins: chemistry, distribution, functional considerations, and molecular biology. Endocr Rev 1989;10:3-26. [PubMed]
8. Glenney JR Jr, Glenney P. Comparison of Ca++-regulated events in the intestinal brush border. J Cell Biol 1985;100:754-63. [PubMed]
9. Heaney RP, Recker RR, Stegman MR, et al. Calcium absorption in women: relationships to calcium intake, estrogen status, and age. J Bone Miner Res 1989;4:469-75. [PubMed]
10. Alevizaki CC, Ikkos DG, Singhelakis P. Progressive decrease of true intestinal calcium absorption with age in normal man. J Nucl Med 1973;14:760-2. [PubMed]
11. Bullamore JR, Wilkinson R, Gallagher JC, et al. Effect of age on calcium absorption. Lancet 1970;2:535-7. [PubMed]
12. Heaney RP, Recker RR. Distribution of calcium absorption in middle-aged women. Am J Clin Nutr 1986;43:299-305. [PubMed]
13. Allen LH. Calcium bioavailability and absorption: a review. Am J Clin Nutr 1982;35:783-808. [PubMed]
14. DeLuca HF. Recent advances in the metabolism of vitamin D. Annu Rev Physiol 1981;43:199-209. [PubMed]
15. Pak CY, East DA, Sanzenbacher LJ, et al. Gastrointestinal calcium absorption in nephrolithiasis. J Clin Endocrinol Metab 1972;35:261-70. [PubMed]
16. Worcester EM, Coe FL. New insights into the pathogenesis of idiopathic hypercalciuria. Semin Nephrol 2008;28:120-32. [PubMed]
17. Brannan PG, Morawski S, Pak CY, et al. Selective jejunal hyperabsorption of calcium in absorptive hypercalciuria. Am J Med 1979;66:425-8. [PubMed]
18. Liberman UA, Sperling O, Atsmon A, et al. Metabolic and calcium kinetic studies in idiopathic hypercalciuria. J Clin Invest 1968;47:2580-90. [PubMed]
19. Zerwekh JE, Sakhaee K, Pak CY. Utility and limitation of calciuric response to oral calcium load as a measure of intestinal calcium absorption: comparison with isotopic fractional calcium absorption. Invest Urol 1981;19:161-4. [PubMed]
20. Sorensen MD, Eisner BH, Stone KL, et al. Impact of calcium intake and intestinal calcium absorption on kidney stones in older women: the study of osteoporotic fractures. J Urol 2012;187:1287-92. [PubMed]
21. Coe FL, Parks JH, Asplin JR. The pathogenesis and treatment of kidney stones. N Engl J Med 1992;327:1141-52. [PubMed]
22. Pak CY. Should patients with single renal stone occurrence undergo diagnostic evaluation? J Urol 1982;127:855-8. [PubMed]
23. Coe FL, Kavalach AG. Hypercalciuria and hyperuricosuria in patients with calcium nephrolithiasis. N Engl J Med 1974;291:1344-50. [PubMed]
24. Pak CY, Holt K. Nucleation and growth of brushite and calcium oxalate in urine of stone-formers. Metabolism 1976;25:665-73. [PubMed]
25. Levy FL, Adams-Huet B, Pak CY. Ambulatory evaluation of nephrolithiasis: an update of a 1980 protocol. Am J Med 1995;98:50-9. [PubMed]
26. Pak CY, Britton F, Peterson R, et al. Ambulatory evaluation of nephrolithiasis. Classification, clinical presentation and diagnostic criteria. Am J Med 1980;69:19-30. [PubMed]
27. Pak CY, Oata M, Lawrence EC, et al. The hypercalciurias. Causes, parathyroid functions, and diagnostic criteria. J Clin Invest 1974;54:387-400. [PubMed]
28. Bilezikian JP, Marcus R, Levine MA. eds. The parathyroids: basic and clinical concepts. 2nd ed. San Diego, CA: Academic Press, 2001.
29. Rodman JS, Mahler RJ. Kidney stones as a manifestation of hypercalcemic disorders. Hyperparathyroidism and sarcoidosis. Urol Clin North Am 2000;27:275-85. viii. [PubMed]
30. Sorensen MD, Duh QY, Grogan RH, et al. Urinary parameters as predictors of primary hyperparathyroidism in patients with nephrolithiasis. J Urol 2012;187:516-21. [PubMed]
31. Silverberg SJ, Shane E, Jacobs TP, et al. Nephrolithiasis and bone involvement in primary hyperparathyroidism. Am J Med 1990;89:327-34. [PubMed]
32. Sorensen MD, Duh QY, Grogan RH, et al. Differences in metabolic urinary abnormalities in stone forming and nonstone forming patients with primary hyperparathyroidism. Surgery 2012;151:477-83. [PubMed]
33. Sakhaee K, Maalouf NM, Sinnott B. Clinical review. Kidney stones 2012: pathogenesis, diagnosis, and management. J Clin Endocrinol Metab 2012;97:1847-60. [PubMed]
34. Worcester EM, Coe FL. Clinical practice. Calcium kidney stones. N Engl J Med 2010;363:954-63. [PubMed]
35. Goldfarb S. The role of diet in the pathogenesis and therapy of nephrolithiasis. Endocrinol Metab Clin North Am 1990;19:805-20. [PubMed]
36. Liebman M, Chai W. Effect of dietary calcium on urinary oxalate excretion after oxalate loads. Am J Clin Nutr 1997;65:1453-9. [PubMed]
37. Curhan GC, Willett WC, Rimm EB, et al. A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. N Engl J Med 1993;328:833-8. [PubMed]
38. Curhan GC, Willett WC, Knight EL, et al. Dietary factors and the risk of incident kidney stones in younger women: Nurses’ Health Study II. Arch Intern Med 2004;164:885-91. [PubMed]
39. Curhan GC, Willett WC, Speizer FE, et al. Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women. Ann Intern Med 1997;126:497-504. [PubMed]
40. Sorensen MD, Kahn AJ, Reiner AP, et al. Impact of nutritional factors on incident kidney stone formation: a report from the WHI OS. J Urol 2012;187:1645-9. [PubMed]
41. Taylor EN, Curhan GC. Dietary calcium from dairy and nondairy sources, and risk of symptomatic kidney stones. J Urol 2013;190:1255-9. [PubMed]
42. Holmes RP, Goodman HO, Assimos DG. Dietary oxalate and its intestinal absorption. Scanning Microsc 1995;9:1109-18. [PubMed]
43. Hess B, Jost C, Zipperle L, et al. High-calcium intake abolishes hyperoxaluria and reduces urinary crystallization during a 20-fold normal oxalate load in humans. Nephrol Dial Transplant 1998;13:2241-7. [PubMed]
44. Bataille P, Charransol G, Gregoire I, et al. Effect of calcium restriction on renal excretion of oxalate and the probability of stones in the various pathophysiological groups with calcium stones. J Urol 1983;130:218-23. [PubMed]
45. Marshall RW, Cochran M, Hodgkinson A. Relationships between calcium and oxalic acid intake in the diet and their excretion in the urine of normal and renal-stone-forming subjects. Clin Sci 1972;43:91-9. [PubMed]
46. Lemann J Jr, Pleuss JA, Worcester EM, et al. Urinary oxalate excretion increases with body size and decreases with increasing dietary calcium intake among healthy adults. Kidney Int 1996;49:200-8. [PubMed]
47. Zarembski PM, Hodgkinson A. Some factors influencing the urinary excretion of oxalic acid in man. Clin Chim Acta 1969;25:1-10. [PubMed]
48. 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. [PubMed]
49. Jaeger P, Lippuner K, Casez JP, et al. Low bone mass in idiopathic renal stone formers: magnitude and significance. J Bone Miner Res 1994;9:1525-32. [PubMed]
50. Jaeger P, Hess B, Takkinen R, et al. Nutritional determinants of nephrolithiasis. Adv Nephrol Necker Hosp 1995;24:217-25. [PubMed]
51. Melton LJ 3rd, Crowson CS, Khosla S, et al. Fracture risk among patients with urolithiasis: a population-based cohort study. Kidney Int 1998;53:459-64. [PubMed]
52. Lauderdale DS, Thisted RA, Wen M, et al. Bone mineral density and fracture among prevalent kidney stone cases in the Third National Health and Nutrition Examination Survey. J Bone Miner Res 2001;16:1893-8. [PubMed]
53. Martini LA, Heilberg IP. Stop dietary calcium restriction in kidney stone-forming patients. Nutr Rev 2002;60:212-4. [PubMed]
54. Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006;354:669-83. [PubMed]
55. Wallace RB, Wactawski-Wende J, O’Sullivan MJ, et al. Urinary tract stone occurrence in the Women’s Health Initiative (WHI) randomized clinical trial of calcium and vitamin D supplements. Am J Clin Nutr 2011;94:270-7. [PubMed]
56. Riggs BL, O’Fallon WM, Muhs J, et al. Long-term effects of calcium supplementation on serum parathyroid hormone level, bone turnover, and bone loss in elderly women. J Bone Miner Res 1998;13:168-74. [PubMed]
57. Taylor EN, Stampfer MJ, Curhan GC. Dietary factors and the risk of incident kidney stones in men: new insights after 14 years of follow-up. J Am Soc Nephrol 2004;15:3225-32. [PubMed]
58. Robertson WG, Peacock M. Stone disease of the urinary tract. Practitioner 1981;225:961-9. [PubMed]
59. Domrongkitchaiporn S, Sopassathit W, Stitchantrakul W, et al. Schedule of taking calcium supplement and the risk of nephrolithiasis. Kidney Int 2004;65:1835-41. [PubMed]