Pathogenesis and Cost-Effectiveness of Preventing Kidney Stones
Lotan, Yair MD
Yair Lotan, MD, is a professor at the Department of Urology at the University of Texas (UT) Southwestern and is a Helen J. and Robert S. Strauss Professor in urology. His practice focuses on oncology and endourology. His research is focused on the areas of bladder cancer screening, biomarkers, decision analysis, and health economics. Dr Lotan has participated in multiple collaborative studies involving early detection of bladder cancer and has published over 250 peer reviewed articles and has been invited to write multiple book chapters, reviews, and editorials.
The author is a consultant for Danone.
Correspondence: Yair Lotan, MD, Department of Urology, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390 ( email@example.com).
Nephrolithiasis is a common problem that results in considerable cost and morbidity. Stone risk is associated with multiple risk factors such as diet and fluid intake, age, gender, ethnicity, geography, occupation, and comorbidities such as diabetes and obesity. There is evidence that high volume intake can reduce the risk of stone disease by 40% to 50%. While there are currently no recommendations to prevent kidney stones, a strategy to reduce risk of stone formation, such as increasing fluid intake, could reduce both morbidity and cost of stone disease. Using France as a model, increased intake of water (>2 L/d) results in considerable cost savings ranging from €273 million in a highly compliant population to €68 million in a population of low compliance (25%). Focusing prevention strategies on high-risk populations can significantly increase cost effectiveness. Future prospective studies will be necessary to demonstrate the potential benefits of primary prevention of nephrolithiasis.
WHY SHOULD WE PREVENT STONE DISEASE?
At this time, there are no recommendations for primary prevention to primarily kidney stones. Healthcare systems focus on treating new and recurrent stones when patients become symptomatic, and evaluation of causes of stone disease is inconsistent among healthcare practitioners. Contrary to the current approach to stone disease, considerable effort is made to prevent diseases such as cancer, cardiovascular disease, and infectious diseases. The rationale for preventing the above diseases is that they have a considerable morbidity and mortality and result in significant costs to society. Nephrolithiasis also fulfills these criteria. Nephrolithiasis is a common disorder, with an approximate incidence of 0.4% to 1% and a lifetime prevalence in the United States of approximately 10% to 12%.1 In fact, the rates of stone disease are increasing in part because of changes in diet and increases in diabetes and obesity.2 Furthermore, stone disease is a worldwide problem, with rates of 4% to 5% in Central and South America, 1% to 5% in Asia, 5% to 9% in Europe, and as high as 20% in the Middle East.3,4 Although in the past, nephrolithiasis was found much more commonly in adult men, more recent data have demonstrated a significant narrowing of the gender gap.1,2 The disease is still significantly more common in the adult population compared with in children.1,5
Nephrolithiasis has considerable morbidity with significant pain in the acute phase, resulting in loss of work and potential surgery as well as long-term complications including pyelonephritis and chronic kidney disease. Finally, there is a very high cost associated with managing stones as a result of diagnostic tests, acute management, surgery, and medications. In the United States, the direct cost of nephrolithiasis exceeded $2 billion in the year 2000.1
ETIOLOGY OF KIDNEY STONES
Calcium comprises the most common component of stones, occurring in nearly 75% of cases. Among the calcium-containing stones, calcium oxalate occurs most frequently (60% of all stones), followed by hydroxyapatite (20%) and brushite (2%). Uric acid and struvite (magnesium ammonium phosphate) each comprises approximately 7% of stones, followed by cystine in 1% to 3%.
For the most part, kidney stones form as a result of super saturation of crystals, resulting in the precipitation of crystals out of solution. Once formed, crystals may clear with the urine or fixate in the kidney at anchoring sites that promote growth and aggregation, ultimately leading to stone formation.5 Factors that contribute to stone formation are first and foremost low urine volume, which can contribute to all types of stone formation. Calcium stones may be associated with multiple metabolic abnormalities, including hypercalciuria, hyperoxaluria, hyperuricosuria, and hypocitraturia. On the other hand, uric acid, cystine, and struvite stones are associated primarily with a single metabolic abnormality; uric acid stones form only in an acid urine, cystine stones are caused by impaired renal reabsorption of cystine, and infection stones are caused by urease-producing bacteria as a consequence of alkaline urine.5–7
Inhibitors in urine can help prevent stone formation even with higher concentration of solutes. The main inhibitors are citrate, magnesium, and pyrophosphate along with polyanions, including glycosaminoglycans, acid mucopolysaccharides, and RNA. Two urinary glycoproteins, nephrocalcin and Tamm-Horsfall, are potent inhibitors of calcium oxalate monohydrate crystal aggregation. Further factors, such as gender, ethnicity, geography, fluid intake, diet, obesity, bowel disease, and other environmental and metabolic factors, contribute to the risk of stone disease in any given individual or population.8–10
Environmental factors may be among the most significant factors in stone formation. Low urine volume, an important environmental factor, reflects low fluid intake or excessive fluid loss and directly increases stone risk by increasing urinary saturation of stone-forming salts. Areas with higher mean annual temperature (MAT) have increased risk for stones because of the impact of temperature on fluid status and urine volume.11,12 Studies found that MAT is the primary independent risk factor for stone disease when controlling for age, gender, race, diuretic use, and sunlight index.12 Stone disease in the United States shows marked geographic variability, and the Southeast, which has a MAT approximately 8°C higher than the Northwest, also has a 50% higher prevalence of stone disease than the Northwest.1,2 Temperature changes can also cause transient variations in stone prevalence, such as seen with desert military deployments and seasonal cyclicity.13,14 Upon exposure to warmer MAT, stones can form as rapidly as 3 months in studies of military deployment in a hot, arid climate.15
Obesity and diabetes are associated with an increased risk for uric acid and calcium oxalate stone formation. Both of these conditions are characterized by insulin resistance, which is associated with excessively low urinary pH due to increased net acid excretion and impaired buffering from defects in renal ammonia synthesis.16,17 Acidic urine is the main risk factor for uric acid nephrolithiasis, and impaired renal acid excretion can lead to hypocitraturia, which is an important risk factor for calcium stone formation.18,19 Furthermore, the compensatory hyperinsulinemia that results from insulin resistance has been shown to increase the urinary excretion of calcium, further potentiating the risk for calcium stone formation.20
HOW DO WE PREVENT KIDNEY STONES?
Although there is not a current strategy of primary prevention of nephrolithiasis, there are known strategies to reduce the risk of formation and recurrence of stones.
Increased fluid intake is the best reported strategy. Two large observational studies comprising 45 619 male health professionals21 and 91 731 female nurses22 found that fluid intake was inversely related to the risk of kidney stone formation. Furthermore, a randomized trial of calcium stone-formers showed decreased stone recurrence rate with increased fluid intake and urine volume.23
In one of the only reported primary prevention efforts, Frank and colleagues24 educated settlers in the Israeli Judean desert on the importance of increased fluid intake in preventing stone disease. After 3 years, they found a 90% reduction in stone incidence compared with a comparable nearby settlement, where no educational effort was initiated. Other strategies include modifying the diet to limit intake of salt and animal protein along with a normal calcium intake or an overall healthful diet such as the Dietary Approaches to Stop Hypertension diet.25,26
Low salt intake reduced urinary calcium excretion, which can reduce the risk of stone formation.27 Addition of fruits and vegetables to the diet of hypocitraturic stone formers who previously had low consumption increased urinary citrate excretion without affecting oxalate excretion and decreased urinary saturation of calcium oxalate and uric acid.28 Furthermore, a 5-year randomized trial of hypercalciuric men (n = 120) with recurrent calcium oxalate stones found that a diet with “normal” amounts of calcium (30 mmol/d) but reduced animal protein (52 g/d) and salt (50 mmol of sodium chloride per day) reduced risk of recurrent stones by 49% compared with a low-calcium diet (10 mmol of calcium per day).29 Although these strategies showed efficacy in recurrent stone formers, these have not been studied prospectively for primary prevention.
WHAT ARE THE POTENTIAL COST IMPLICATIONS?
Because nephrolithiasis is a worldwide problem and any primary prevention strategy would need to be applied to large populations, the financial impact would be very important to assess before initiating changes in public policy. A cost effectiveness analysis was performed using a Markov model that took into consideration baseline risk of stone disease using France as a model and comparing low water intake (<2 L/d) with adequate water intake (≥2 L/d).4 The model was designed for a 25-year span, and for each year, a subject could be stone free, develop a new stone or stone recurrence, develop a complication such as pyelonephritis or chronic kidney disease, or die of other causes.
The annual incidence of nephrolithiasis in the general population of France was estimated at 21 000, leading to an annual incidence of 0.032% based on a French population of 65 million. The risk of stone recurrence in patients with previous stones was based on a French study that demonstrated a 14.4% annual recurrence rate.30 We assumed a 40% risk reduction based on a report by Curhan et al25 that found that the annual stone incidence was 0.23% in subjects without high water intake and 0.14% after increase of the water.
Costs were obtained from the French National Healthcare System and resource utilization was based on a modified Delphi panel. The base-case analysis found that the total cost of urolithiasis is €4267, with direct costs of €2767, including cost of treatment and complications. The annual budget impact for stone disease based on 65 million inhabitants is €590 million for the payer. Use of high water intake by 100% of the population results in annual cost savings of €273 million and 9265 fewer stones. Even if only 25% of the population is compliant, there is still a cost saving of €68 million and 2316 stones.
Nephrolithiasis is a common problem that results in considerable cost and morbidity. There is evidence that high fluid volume intake can reduce the risk of stone disease by 40% to 50%. Using France as a model, increased intake of water (>2 L/d) results in considerable cost savings ranging from €273 million in a highly compliant population to €68 million in a population of low compliance (25%). However, the distribution of stones is not equal for all groups in the population. It is higher in working-age adults and there are risk factors such as geography, occupation, obesity, gender, and ethnicity. Focusing on prevention strategies in high-risk populations can significantly increase cost effectiveness. Future prospective studies will be necessary to demonstrate the potential benefits of primary prevention of nephrolithiasis.
1. Pearle MS, Calhoun EA, Curhan GC. Urologic diseases in America project: urolithiasis. J Urol. 2005; 173:(3): 848–857.
2. Scales CD Jr, Smith AC, Hanley JM, Saigal CS.; Urologic Diseases in America Project. Prevalence of kidney stones in the United States. Eur Urol. 2012; 62:(1): 160–165.
3. Ramello A, Vitale C, Marangella M. Epidemiology of nephrolithiasis. J Nephrol. 2000; 13:(Suppl 3): S45–S50.
4. Lotan Y, Buendia Jiménez I, Lenoir-Wijnkoop I, et al. Primary prevention of nephrolithiasis is cost-effective for a national healthcare system [published online ahead of print June 11, 2012]. BJU Int. 2012;110(11 Pt C):E1060–E1067.
5. Pearle MS, Lotan Y. Urinary lithiasis: etiology, epidemiology and pathogenesis. In: Wein J, Kavoussi LR, Novick AW, et al. (eds) Campbell-Walsh Urology. 10th ed. Philadelphia, PA: Saunders; 2012; : 1257–1286.
6. Asplin JR. Uric acid stones. Semin Nephrol. 1996; 16: 412
7. Joly D, Rieu P, Mejean A, Gagnadoux MF, Daudon M, Jungers P. Treatment of cystinuria. Pediatr Nephrol. 1999; 13: 945
8. Pearle MS. Prevention of nephrolithiasis. Curr Opin Nephrol Hypertens. 2001; 10:(2): 203–209.
9. Taylor EN, Stampfer MJ, Curhan GC. Obesity, weight gain, and the risk of kidney stones. JAMA. 2005; 293:(4): 455–462.
10. 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:(12): 3225–3232.
11. Bateson EM. Renal tract calculi and climate. Med J Aust. 1973; 2: 111–113.
12. Soucie JM, Coates R, McClellan W, Austin H, Thun M. Relation between geographic variability in kidney stones prevalence and risk factors for stones. Am J Epidemiol. 1996; 143: 487–495.
13. Pierce LW, Bloom B. Observations on urolithiasis among American troops in a desert area. J Urol. 1945; 54: 466
14. Elliott JP Jr, Gordon JO, Evans JW, Platt L. A stone season. A 10-year retrospective study of 768 surgical stone cases with respect to seasonal variation. J Urol. 1975; 114: 574–577.
15. Evans K, Costabile RA. Time to development of symptomatic urinary calculi in a high risk environment. J Urol. 2005; 173: 858–861.
16. Mokdad AH, Bowman BA, Ford ES, et al. The continuing epidemics of obesity and diabetes in the United States. JAMA. 2001; 286:(10): 1195–1200.
17. Abate N, Chandalia M, Cabo-Chan AV Jr, et al. The metabolic syndrome and uric acid nephrolithiasis: novel features of renal manifestation of insulin resistance. Kidney Int. 2004; 65:(2): 386–392.
18. Asplin JR. Uric acid stones. Semin Nephrol. 1996; 16:(5): 412–424.
19. Cupisti A, Meola M, D’Alessandro C, et al. Insulin resistance and low urinary citrate excretion in calcium stone formers. Biomed Pharmacother. 2007; 61:(1): 86–90.
20. Cupisti A, Morelli E, Lupetti S, et al. Low urine citrate excretion as main risk factor for recurrent calcium oxalate nephrolithiasis in males. Nephron. 1992; 61:(1): 73–76.
21. 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:(12): 833–838.
22. Curhan GC, Willett WC, Speizer FE, Spiegelman D, Stampfer MJ. 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:(7): 497–504.
23. 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:(3): 839–843.
24. Frank M, Atsmon A, Sugar P, De Vries A. Epidemiological investigation of urolithiasis in the hot arid Southern region of Israel. Urol Int. 1963; 15: 65–76.
25. Curhan GC, Willett WC, Knight EL, Stampfer MJ. Dietary factors and the risk of incident kidney stones in younger women: Nurses’ Health Study II. Arch Intern Med. 2004; 164:(8): 885–891.
26. Taylor EN, Fung TT, Curhan GC. DASH-style diet associates with reduced risk for kidney stones. J Am Soc Nephrol. 2009; 20:(10): 2253–2259.
27. Nouvenne A, Meschi T, Prati B, et al. Effects of a low-salt diet on idiopathic hypercalciuria in calcium-oxalate stone formers: a 3-mo randomized controlled trial. Am J Clin Nutr. 2010; 91:(3): 565–570.
28. Meschi T, Maggiore U, Fiaccadori E, et al. The effect of fruits and vegetables on urinary stone risk factors. Kidney Int. 2004; 66:(6): 2402–2410.
29. 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:(2): 77–84.
30. Daudon M. Epidemiology of nephrolithiasis in France. Ann Urol (Paris). 2005; 39:(6): 209–231.
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