- Email: [email protected]
The association between gout and nephrolithiasis: The National Health and Nutrition Examination Survey III, 1988-1994
The Association Between Gout and Nephrolithiasis: The National Health and Nutrition Examination Survey III, 1988-1994 Holly Mattix Kramer, MD, MPH, and Gary Curhan, MD, ScD ● Background: Gout, an inflammatory arthritis, reportedly afflicts more than 2 million men and women in the United States. Previous reports have suggested an association between gout and kidney stone disease; however, these studies did not adjust for such important potential confounders as obesity and the presence of hypertension. To our knowledge, no published study has examined the independent association between gout and kidney stone disease. Methods: We used a national probability sample of the US population to determine the independent association between reported gout and history of kidney stone disease. Results: Among men and women 20 years and older, 5.6% (10 million) reported the previous passage of a kidney stone and 2.7% (5.1 million) reported a diagnosis of gout by a physician. Moreover, 8.6% of individuals who reported the passage of a kidney stone on two or more occasions had a history of gout. Conversely, the prevalence of previous kidney stones in subjects with reported gout was 13.9%. In the age-adjusted model, gout was associated with an increased odds ratio (OR) for previous kidney stones (OR, 1.97; 95% confidence interval [CI], 1.37 to 2.83). After further adjustment for sex, race, body mass index, and presence of hypertension, the OR for previous kidney stones in individuals with gout decreased to 1.49 (95% CI, 1.04 to 2.14). Conclusion: Showing an independent association between kidney stone disease and gout strongly suggests that they share common underlying pathophysiological mechanisms. Identification of these mechanisms may lead to improved preventive strategies for both conditions. © 2002 by the National Kidney Foundation, Inc. INDEX WORDS: Kidney stones; Third National Health and Nutrition Examination Survey (NHANES III); gout; epidemiology.
M
ORE THAN 500,000 Americans experience kidney stones every year, and the economic impact in the United States caused by time lost from work and the cost of treatment exceeds $2 billion.1-3 Gout, an inflammatory arthritis induced by the deposition of monosodium urate monohydrate crystals in tissues,4 reportedly afflicts more than 2 million men and women in the United States.5,6 Although gout has been purportedly linked with kidney stone disease as early as the 16th century,7 few studies have examined the association between established gout and kidney stone disease. In 1967, Yu and Gutman8 reported a 15% to 22% prevalence of kidney stones among individuals with gout, greater than the 12% lifetime risk reported in the general population.1,2 A smaller study of 168 patients found that 15% with documented primary gout reported a history of kidney stones.9 It is important to note that these studies did not assess the independent association between gout and kidney stone disease by controlling for potential confounders. Multiple subsequent studies have shown that several factors may influence the development of both gout and kidney stones, such as body mass index (BMI) and hypertension.10-15 It is possible that gout may not truly influence the development of kidney stones, but may simply reflect the presence of other factors that increase the risk for kidney stone formation,
such as obesity or hypertension. To our knowledge, no published studies have examined the independent association between gout and kidney stone disease in a nationally representative sample of subjects. The primary objective of this cross-sectional study is to investigate the prevalence of gout and kidney stones in the US population and determine the independent association between gout and kidney stone disease in men and women. METHODS
Study Population We used data from the Third National Health and Nutrition Examination Survey (NHANES III). The NHANES III was designed to be a probability sample of the total civilian
From the Renal Unit and General Medicine Unit, Department of Medicine, Massachusetts General Hospital; and the Channing Laboratory, Brigham and Women’s Hospital, Boston, MA. Received January 14, 2002; accepted in revised form March 19, 2002. Supported in part by grant no. DK59583 from the National Institute of Health (G.C.). H.M.K. is an American Kidney Fund Clinical Scientist in Nephrology Fellow. Address reprint requests to Gary Curhan, MD, ScD, Channing Laboratory, 181 Longwood Ave, Boston, MA 02115. E-mail: [email protected] © 2002 by the National Kidney Foundation, Inc. 0272-6386/02/4001-0006$35.00/0 doi:10.1053/ajkd.2002.33911
American Journal of Kidney Diseases, Vol 40, No 1 (July), 2002: pp 37-42
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noninstitutionalized population aged 2 months or older in the United States and collected health and nutritional data on 33,994 men, women, and children from 1988 to 1994. Certain subgroups were oversampled, such as young children, older persons, non-Hispanic blacks, and Mexican Americans. Details of the survey design may be found in the NHANES III operation manual.16 There were 17,030 men and women 20 years and older who completed both the interview and physical examination. Of these, we excluded 11 subjects with missing data for previous kidney stones and 2 subjects with missing data for history of gout. Overall, 17,017 persons 20 years and older at the time of the interview were eligible for the analysis.
Gout During the home interview, all subjects were asked, “Has a doctor ever told you that you had gout?” Interviewers were instructed to emphasize the word doctor. If the respondent stated that it was another health professional who gave this diagnosis of gout to him or her, then the answer was coded as no. If the response was yes, then the subject was asked, “How old were you when you were first told you had gout?”
Kidney Stone Disease During the standardized home interview, subjects were asked, “Have you ever had a kidney stone?” and interviewers were advised to stress the word ever when asking this question. Previous kidney stones were defined as the subject responding yes to this question. Subjects who responded yes also were asked the number of different occasions they passed a kidney stone and whether they ever were administered medications or underwent lithotripsy or surgery to treat their kidney stone disease. Age at the time of the passage of the first kidney stone was not ascertained.
Covariates Medical history and medication use were collected during a standardized home interview, and a detailed physical examination was completed. Age was defined as age at the time of the interview, and race/ethnicity was self-reported as non-Hispanic white, non-Hispanic black, and Mexican American. Other race/ethnicities were grouped into “other.” BMI (in kilograms per square meter) was calculated from the weight and height measured during the physical examination. Subjects also were asked whether a doctor had ever told them that they had high blood pressure. A history of hypertension was defined as the subject stating a physician had diagnosed hypertension or they were currently administered medication, losing weight, or restricting their salt intake because of high blood pressure.
Statistical Analysis All statistical analyses were computed using SAS-callable SUDAAN (Research Triangle Institute, Research Triangle Park, NC) to incorporate sample weights, adjust for clusters and strata of the complex sample design, and provide prevalence estimates, which reflect the entire US population. NHANES III data are weighted to account for the probability of selection and adjust for nonresponse to the interview
KRAMER AND CURHAN
and physical examination. Categorical variables were compared using the Wald chi-square test, and mean values of continuous variables were compared between groups using a t-test. Logistic regression was used to calculate the odds ratio (OR) for kidney stone disease after controlling for multiple covariates simultaneously. The following covariates were included in the logistic model: age, sex, race/ ethnicity, history of hypertension, and BMI. Age was categorized into decades. Race/ethnicity was categorized as nonHispanic white, non-Hispanic black, Mexican American, and other. The sample size of other was too small to be used analytically, and results from this group are not shown. A history of hypertension was dichotomized as yes or no. BMI was divided into four categories based on the International Obesity Task Force17: less than 18.5, 18.5 to 24.9, 25 to 30, and greater than 30 kg/m2.
RESULTS
The age range in the population was 20 to 90 years, 52.4% were women, and 47.6% were men. The diagnosis of gout by a physician was reported by 3.8% of men and 1.6% of women (2.7% of the total population). Overall, 5.6% reported the previous passage of a kidney stone (6.9% of men, 4.3% of women), and 26.3% of these subjects had passed a kidney stone on two or more occasions. Characteristics of the US population by history of kidney stones are listed in Table 1. Subjects with previous kidney stones were older (53.7 versus 44.2 years; P ⬍ 0.0001), more likely to be men (58.9% versus 47.0%; P ⬍ 0.0001) and non-Hispanic white (87.7% versus 75.6%; P ⬍ 0.0001), and had a greater BMI (27.9 versus 26.4 kg/m2; P ⬍ 0.0001). In addition, the prevalence of gout (6.7% versus 2.4%; Table 1.
Characteristics of the US Population by History of Kidney Stone Disease Kidney Stones
No Kidney Stones
Age (y) 53.7 ⫾ 0.7 44.2 ⫾ 0.4 27.9 ⫾ 0.3 26.4 ⫾ 0.1 BMI (kg/m2) Men (%) 58.9 47.0 Race (%) Non-Hispanic white 87.7 75.6 Non-Hispanic black 3.7 11.4 Mexican American 2.5 5.2 History of gout (%) 6.7 2.4 History of hypertension (%) 38.2 23.0 Current HCTZ use 2.9 1.2 Current allopurinol use 2.7 0.6
P
⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001 0.02 0.007
NOTE. Values expressed as means ⫾ SE or percent. Abbreviation: HCTZ, hydrochlorothiazide.
GOUT AND NEPHROLITHIASIS
39
P ⬍ 0.0001) and previously diagnosed hypertension (38.2% versus 23.0%; P ⬍ 0.0001) were significantly greater in subjects with previous kidney stones. Use of hydrochlorothiazide (P ⫽ 0.02) and allopurinol (P ⫽ 0.007) also was greater in subjects with previous kidney stones. Among individuals who reported the passage of a kidney stone on two or more occasions, 8.6% had a history of gout. Conversely, the prevalence of previous kidney stones in subjects with reported gout was 13.9%. Estimated numbers of men and women in the United States with previous kidney stones by age categories are listed in Table 2. The prevalence of previous kidney stones in the population aged 20 to 29 years was 1.2% (0.4 million) and increased to 7.9% (1.6 million) in those aged 60 to 69 years. A history of kidney stone disease in men increased from 1.2% in subjects aged 20 to 29 years to 15.2% in those 80 years or older. Likewise, a history of kidney stone disease in women increased from 1.3% in subjects aged 20 to 29 years to 6.5% in those 80 years and older. The estimated total number of men and women in the United States with previous kidney stones was 10.0 million. The estimated number of men and women in the United States with reported gout is listed in Table 3. The prevalence of gout was lowest (0.4%) in subjects aged 20 to 29 years and highest (7.3%) in those aged 70 to 79 years. Table 2.
Sex
Men
Total Women
Total
Population Estimate With History of Kidney Stone Disease by Age Categories
Age Category (y)
20-29 30-39 40-49 50-59 60-69 70-79 ⱖ80 20-29 30-39 40-49 50-59 60-69 70-79 ⱖ80
Population Estimate (in millions)
0.2 0.8 1.5 1.1 0.9 1.0 0.4 5.9 0.2 0.8 0.7 0.8 0.7 0.6 0.3 4.1
Population (%)
1.2 3.6 8.9 10.0 10.1 15.3 15.2 1.3 3.6 4.2 6.9 6.1 6.5 6.5
Table 3.
Sex
Men
Total Women
Total
Population Estimate With Gout by Age Categories
Age Category (y)
20-29 30-39 40-49 50-59 60-69 70-79 ⱖ80 20-29 30-39 40-49 50-59 60-69 70-79 ⱖ80
Population Estimate (in millions)
0.3 0.4 0.4 0.6 0.8 0.7 0.2 3.4 0.1 0.1 0.1 0.3 0.4 0.4 0.3 1.7
Population (%)
0.2 2.1 2.2 5.7 9.1 10.8 8.6 0.6 0.1 0.6 2.3 3.5 4.6 5.6
Among men, the prevalence of gout increased from 0.2% (0.3 million) in subjects aged 20 to 29 years to 10.8% (0.7 million) in those aged 70 to 79 years. The prevalence of gout in women was less than 1% in all age categories younger than 50 years and increased to 2.3% (0.3 million) in women aged 50 to 59 years and 5.6% (0.3 million) in women 80 years and older. The estimated total number of men and women with reported gout in the United States was 5.1 million. The overlap between kidney stone disease and gout in the US population is shown in Fig 1. Approximately 0.7 million individuals in the United States are estimated to have both gout and kidney stone disease. Age- and multivariate-adjusted ORs for previous kidney stones by history of gout are listed in Table 4. In the age-adjusted model, gout was
Fig 1. Estimated prevalence of kidney stone disease and gout in the US population, NHANES III, 1988 to 1994.
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KRAMER AND CURHAN
Table 4. Age- and Multivariate-Adjusted ORs for Previous Symptomatic Kidney Stones by History of Gout in NHANES III
Total population No gout Gout Men No gout Gout Women No gout Gout
Age Adjusted
Multivariate Adjusted
1.00 (reference) 1.97 (1.37-2.83)
1.00 (reference) 1.49 (1.04-2.14)
1.00 (reference) 1.61 (1.05-2.48)
1.00 (reference) 1.46 (0.94-2.27)
1.00 (reference) 2.08 (1.15-3.78)
1.00 (reference) 1.65 (0.92-2.95)
NOTE. Values expressed as OR (95% CI).
significantly associated with previous kidney stones in the total population (OR, 1.97; 95% confidence interval [CI], 1.37 to 2.83), in men (OR, 1.61; 95% CI, 1.05 to 2.48), and in women (OR, 2.08; 95% CI, 1.15 to 3.78). After adjusting for race, sex, BMI, and history of hypertension, the OR for the population was 1.49 (95% CI, 1.04 to 2.14). The only covariates that individually attenuated the age-adjusted OR by at least 10% were sex and the presence of hypertension. However, sex-specific results were not statistically significant, and no substantial differences were noted between men (OR, 1.46; 95% CI, 0.94 to 2.27) and women (OR, 1.65; 95% CI, 0.92 to 2.95). DISCUSSION
In this nationally representative sample of men and women, the frequency of kidney stone disease in subjects with gout was almost threefold greater than that in the general US population. After adjusting for potential confounders, including age, sex, and BMI, we found that a history of gout was associated with a 49% increase in risk for previous kidney stones. In 1967, Yu and Gutman8 reported a history of kidney stones in 22% of 1,258 patients with primary gout. This is approximately 50% greater than the frequency of kidney stone disease we found among men and women in the US population with a history of gout. In a smaller study of 168 patients with documented previous gout, 15% reported a history of kidney stones.9 Subjects in these investigations included few women and were not as racially diverse as the US popu-
lation. Thus, the greater frequency of kidney stone disease among individuals with gout in previous studies possibly was caused by the homogeneity of the study populations. Individuals with gout may have greater urinary excretion of uric acid and/or persistently acidic urine,18 which may predispose to the formation of both uric acid– and calcium oxalate– containing kidney stones. Greater uric acid excretion may promote calcium stone formation by forming a nidus.19 In addition, uric acid is less soluble in acidic urine and more likely to precipitate,19 thus increasing the risk for uric acid stones. Determining the temporal relationship between gout and kidney stones is problematic because both diseases may not be diagnosed until an individual becomes symptomatic. Thus, in some individuals, kidney stone formation may be influenced by the presence of gout, which has not yet become symptomatic and/or diagnosed. Moreover, studies have found that approximately 50% of individuals with both gout and kidney stones experience the onset of gout after the passage of the first stone.8,9 In this study, we could not determine whether individuals with gout and prevalent kidney stones were diagnosed with gout before the passage of the first kidney stone because the age the first kidney stone was passed was not ascertained in NHANES III. Many researchers have used the term gouty diathesis to describe individuals who may have latent gout and are at greater risk for kidney stone formation.8,20-22 Individuals with gouty diathesis are characterized as having persistently acidic urine and a history of uric acid– or calciumcontaining kidney stones, but do not necessarily have a history of gout.20 Khatchadourian et al20 compared 24-hour urine measurements of various urinary factors in 95 subjects with gouty diathesis with those of 99 healthy controls with no history of kidney stones. Individuals with gouty diathesis not only had persistently acidic urine, increasing the risk for uric acid precipitation, but also had lower urinary citrate excretion (461 versus 677 mg/d; P ⬍ 0.05),20 an important inhibitor of calcium oxalate crystal formation.23 No difference in urinary calcium excretion was noted between the two groups, and urinary uric acid excretion was lower in subjects with gouty diathesis compared with controls.20 Moreover, only 21% with uric acid– and 12% with calcium-
GOUT AND NEPHROLITHIASIS
containing stones among subjects with gouty diathesis reported a history of primary gout.20 In a study of 56 patients with uric acid stones, urine pH and fractional excretion of uric acid were significantly lower compared with agematched controls with non–uric acid stones.22 The investigators of that study suggested that the low urine pH and low fractional excretion of uric acid in the uric acid–stone formers were markers of latent gout or gouty diathesis. However, a history of gout was not ascertained from these subjects. These important studies20-22 provided insight into the possible relationship between gouty diathesis and urinary risk factors for kidney stone formation, but they did not delineate the association between an actual history of gout and kidney stone formation. Prospective studies are needed to determine whether the presence of gout is an independent predictor of the formation of future kidney stones and whether the presence of kidney stones predicts the future development of symptomatic gout. This study was performed in a nationally representative sample of men and women and race/ ethnicity groups; thus, the findings are generalizable to the US population. However, the analysis was limited by its cross-sectional design, and we could not adjust for dietary factors or medication use, which may have been modified after the onset of gout or kidney stones. Prospective studies investigating the association between gout and kidney stone disease should adjust for such dietary factors as protein, sodium, potassium, calcium (both dietary and supplemental calcium), sucrose, and fluid intake and use of such medications as hydrochlorothiazide and allopurinol. We also were unable to determine the temporal relationship between the onset of gout and passage of the first kidney stone because the age at the passage of the first kidney stone was not ascertained. Other limitations include the possible misclassification of prevalent but asymptomatic kidney stones because an individual may not be aware of the presence of a kidney stone until it becomes symptomatic. The self-reported diagnosis of gout by a physician also was not validated in this study. Nonetheless, a subject’s report of kidney stone disease or gout was unlikely to be
41
related to the previous diagnosis of the other. Thus, any misclassification of kidney stone disease or gout likely would have been nondifferential and would not explain the positive association between gout and kidney stone disease found in this study. Results of this study also suggest no substantial sex differences in the association between gout and kidney stone disease. In summary, the prevalence of gout was greater in individuals with previous kidney stones. Even after adjusting for potential confounders, individuals with a history of gout were 49% more likely to have a history of kidney stones. Because kidney stone disease and gout are so common, showing they are associated strongly suggests common underlying pathophysiological mechanisms. Identification of these mechanisms may lead to improved preventive strategies for both conditions. REFERENCES 1. Pak CYC: Etiology and treatment of urolithiasis. Am J Kidney Dis 18:624-637, 1991 2. Johnson CM, Wilson DM, O’Fallon WM, Malek RS, Kurland LT: Renal stone epidemiology: A 25-year study in Rochester, Minnesota. Kidney Int 16:624-631, 1979 3. Parks JH, Coe FL: The financial effects of kidney stone prevention. Kidney Int 50:1706-1712, 1996 4. Hershfield MS: Gout and uric acid metabolism, in Bennett JC, Plum F (eds): Cecil’s Textbook of Medicine (ed 20). Philadelphia, PA, Saunders, 1996, pp 1508-1515 5. Agudelo CA, Wise CM: Gout: Diagnosis, pathogenesis and clinical manifestations. Curr Opin Rheumatol 13:234239, 2001 6. Lawrence RC, Helmick CG, Arnett FC, et al: Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the US. Arthritis Rheum 41:778-799, 1998 7. Eknoyan G: Michaelangelo: Art, anatomy, and the kidney. Kidney Int 57:1190-1201, 2000 8. Yu T, Gutman AB: Uric acid nephrolithiasis in gout: Predisposing factors. Ann Intern Med 67:1133-1148, 1967 9. Fessel WJ: Renal outcomes of gout and hyperuricemia. Am J Med 67:74-82, 1979 10. Roubenoff R, Klag MJ, Mead LA, Liang KY, Seidler AJ, Hochberg MC: Incidence and risk factors for gout in white men. JAMA 266:3004-3007, 1991 11. Hall AP, Barry PE, Dawber TR, McNamara PM: Epidemiology of gout and hyperuricemia. Am J Med 42:2737, 1967 12. Hochberg MC, Thomas J, Johniene TD, Mead L, Levine DM, Klag MJ: Racial differences in the incidence of gout: The role of hypertension. Arthritis Rheum 38:628-632, 1995 13. Abbott RD, Brand FN, Kannel WB, Castelli WP: Gout and coronary disease: The Framingham Study. J Clin Epidemiol 41:237-242, 1988
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14. Curhan GC, Willett WC, Rimm EB, Speizer FE, Stampfer MJ: Body size and risk of kidney stones. J Am Soc Nephrol 9:1645-1652, 1998 15. Madore F, Stampfer MJ, Willett WC, Speizer FE, Curhan GC: Nephrolithiasis and risk of hypertension in women. Am J Kidney Dis 32:802-807, 1998 16. National Center for Health Statistics: Survey Design of the Third National Health and Nutrition Examination Survey, 1988-1994. Hyattsville, MD, Centers for Disease Control and Prevention, 1996 17. World Health Organization: Obesity: Preventing and Managing the Global Epidemic: Report of a WHO Consultation on Obesity. Geneva, June 3-5, 1997. Geneva, Switzerland, WHO, 1998 18. Gutman AB, Yu T: Urinary ammonium excretion in primary gout. J Clin Invest 44:1474-1481, 1965
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19. Coe FL, Parks JH, Asplin JR: Nephrolithiasis: Pathogenesis and treatment of kidney stones. N Engl J Med 327:1141-1152, 1992 20. Khatchadourian J, Preminger GM, Whitson PA, Adams-Huet B, Pak CYC: Clinical and biochemical presentation of gout diathesis: Comparison of uric acid versus pure calcium stone formation. J Urol 154:1665-1669, 1995 21. Pak CYC, Sakhaee K, Fuller C: Successful management of uric acid nephrolithiasis with potassium citrate. Kidney Int 30:422-428, 1986 22. Pak CYC, Sakhaee K, Peterson RD, Poindexter JR, Frawley WH: Biochemical profile of idiopathic uric acid nephrolithiasis. Kidney Int 60:757-761, 2001 23. Kok DJ, Papoulos SE, Bijvoet OL: Crystal agglomeration is a major element in calcium oxalate urinary stone formation. Kidney Int 37:51-59, 1990
M
ORE THAN 500,000 Americans experience kidney stones every year, and the economic impact in the United States caused by time lost from work and the cost of treatment exceeds $2 billion.1-3 Gout, an inflammatory arthritis induced by the deposition of monosodium urate monohydrate crystals in tissues,4 reportedly afflicts more than 2 million men and women in the United States.5,6 Although gout has been purportedly linked with kidney stone disease as early as the 16th century,7 few studies have examined the association between established gout and kidney stone disease. In 1967, Yu and Gutman8 reported a 15% to 22% prevalence of kidney stones among individuals with gout, greater than the 12% lifetime risk reported in the general population.1,2 A smaller study of 168 patients found that 15% with documented primary gout reported a history of kidney stones.9 It is important to note that these studies did not assess the independent association between gout and kidney stone disease by controlling for potential confounders. Multiple subsequent studies have shown that several factors may influence the development of both gout and kidney stones, such as body mass index (BMI) and hypertension.10-15 It is possible that gout may not truly influence the development of kidney stones, but may simply reflect the presence of other factors that increase the risk for kidney stone formation,
such as obesity or hypertension. To our knowledge, no published studies have examined the independent association between gout and kidney stone disease in a nationally representative sample of subjects. The primary objective of this cross-sectional study is to investigate the prevalence of gout and kidney stones in the US population and determine the independent association between gout and kidney stone disease in men and women. METHODS
Study Population We used data from the Third National Health and Nutrition Examination Survey (NHANES III). The NHANES III was designed to be a probability sample of the total civilian
From the Renal Unit and General Medicine Unit, Department of Medicine, Massachusetts General Hospital; and the Channing Laboratory, Brigham and Women’s Hospital, Boston, MA. Received January 14, 2002; accepted in revised form March 19, 2002. Supported in part by grant no. DK59583 from the National Institute of Health (G.C.). H.M.K. is an American Kidney Fund Clinical Scientist in Nephrology Fellow. Address reprint requests to Gary Curhan, MD, ScD, Channing Laboratory, 181 Longwood Ave, Boston, MA 02115. E-mail: [email protected] © 2002 by the National Kidney Foundation, Inc. 0272-6386/02/4001-0006$35.00/0 doi:10.1053/ajkd.2002.33911
American Journal of Kidney Diseases, Vol 40, No 1 (July), 2002: pp 37-42
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38
noninstitutionalized population aged 2 months or older in the United States and collected health and nutritional data on 33,994 men, women, and children from 1988 to 1994. Certain subgroups were oversampled, such as young children, older persons, non-Hispanic blacks, and Mexican Americans. Details of the survey design may be found in the NHANES III operation manual.16 There were 17,030 men and women 20 years and older who completed both the interview and physical examination. Of these, we excluded 11 subjects with missing data for previous kidney stones and 2 subjects with missing data for history of gout. Overall, 17,017 persons 20 years and older at the time of the interview were eligible for the analysis.
Gout During the home interview, all subjects were asked, “Has a doctor ever told you that you had gout?” Interviewers were instructed to emphasize the word doctor. If the respondent stated that it was another health professional who gave this diagnosis of gout to him or her, then the answer was coded as no. If the response was yes, then the subject was asked, “How old were you when you were first told you had gout?”
Kidney Stone Disease During the standardized home interview, subjects were asked, “Have you ever had a kidney stone?” and interviewers were advised to stress the word ever when asking this question. Previous kidney stones were defined as the subject responding yes to this question. Subjects who responded yes also were asked the number of different occasions they passed a kidney stone and whether they ever were administered medications or underwent lithotripsy or surgery to treat their kidney stone disease. Age at the time of the passage of the first kidney stone was not ascertained.
Covariates Medical history and medication use were collected during a standardized home interview, and a detailed physical examination was completed. Age was defined as age at the time of the interview, and race/ethnicity was self-reported as non-Hispanic white, non-Hispanic black, and Mexican American. Other race/ethnicities were grouped into “other.” BMI (in kilograms per square meter) was calculated from the weight and height measured during the physical examination. Subjects also were asked whether a doctor had ever told them that they had high blood pressure. A history of hypertension was defined as the subject stating a physician had diagnosed hypertension or they were currently administered medication, losing weight, or restricting their salt intake because of high blood pressure.
Statistical Analysis All statistical analyses were computed using SAS-callable SUDAAN (Research Triangle Institute, Research Triangle Park, NC) to incorporate sample weights, adjust for clusters and strata of the complex sample design, and provide prevalence estimates, which reflect the entire US population. NHANES III data are weighted to account for the probability of selection and adjust for nonresponse to the interview
KRAMER AND CURHAN
and physical examination. Categorical variables were compared using the Wald chi-square test, and mean values of continuous variables were compared between groups using a t-test. Logistic regression was used to calculate the odds ratio (OR) for kidney stone disease after controlling for multiple covariates simultaneously. The following covariates were included in the logistic model: age, sex, race/ ethnicity, history of hypertension, and BMI. Age was categorized into decades. Race/ethnicity was categorized as nonHispanic white, non-Hispanic black, Mexican American, and other. The sample size of other was too small to be used analytically, and results from this group are not shown. A history of hypertension was dichotomized as yes or no. BMI was divided into four categories based on the International Obesity Task Force17: less than 18.5, 18.5 to 24.9, 25 to 30, and greater than 30 kg/m2.
RESULTS
The age range in the population was 20 to 90 years, 52.4% were women, and 47.6% were men. The diagnosis of gout by a physician was reported by 3.8% of men and 1.6% of women (2.7% of the total population). Overall, 5.6% reported the previous passage of a kidney stone (6.9% of men, 4.3% of women), and 26.3% of these subjects had passed a kidney stone on two or more occasions. Characteristics of the US population by history of kidney stones are listed in Table 1. Subjects with previous kidney stones were older (53.7 versus 44.2 years; P ⬍ 0.0001), more likely to be men (58.9% versus 47.0%; P ⬍ 0.0001) and non-Hispanic white (87.7% versus 75.6%; P ⬍ 0.0001), and had a greater BMI (27.9 versus 26.4 kg/m2; P ⬍ 0.0001). In addition, the prevalence of gout (6.7% versus 2.4%; Table 1.
Characteristics of the US Population by History of Kidney Stone Disease Kidney Stones
No Kidney Stones
Age (y) 53.7 ⫾ 0.7 44.2 ⫾ 0.4 27.9 ⫾ 0.3 26.4 ⫾ 0.1 BMI (kg/m2) Men (%) 58.9 47.0 Race (%) Non-Hispanic white 87.7 75.6 Non-Hispanic black 3.7 11.4 Mexican American 2.5 5.2 History of gout (%) 6.7 2.4 History of hypertension (%) 38.2 23.0 Current HCTZ use 2.9 1.2 Current allopurinol use 2.7 0.6
P
⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001 0.02 0.007
NOTE. Values expressed as means ⫾ SE or percent. Abbreviation: HCTZ, hydrochlorothiazide.
GOUT AND NEPHROLITHIASIS
39
P ⬍ 0.0001) and previously diagnosed hypertension (38.2% versus 23.0%; P ⬍ 0.0001) were significantly greater in subjects with previous kidney stones. Use of hydrochlorothiazide (P ⫽ 0.02) and allopurinol (P ⫽ 0.007) also was greater in subjects with previous kidney stones. Among individuals who reported the passage of a kidney stone on two or more occasions, 8.6% had a history of gout. Conversely, the prevalence of previous kidney stones in subjects with reported gout was 13.9%. Estimated numbers of men and women in the United States with previous kidney stones by age categories are listed in Table 2. The prevalence of previous kidney stones in the population aged 20 to 29 years was 1.2% (0.4 million) and increased to 7.9% (1.6 million) in those aged 60 to 69 years. A history of kidney stone disease in men increased from 1.2% in subjects aged 20 to 29 years to 15.2% in those 80 years or older. Likewise, a history of kidney stone disease in women increased from 1.3% in subjects aged 20 to 29 years to 6.5% in those 80 years and older. The estimated total number of men and women in the United States with previous kidney stones was 10.0 million. The estimated number of men and women in the United States with reported gout is listed in Table 3. The prevalence of gout was lowest (0.4%) in subjects aged 20 to 29 years and highest (7.3%) in those aged 70 to 79 years. Table 2.
Sex
Men
Total Women
Total
Population Estimate With History of Kidney Stone Disease by Age Categories
Age Category (y)
20-29 30-39 40-49 50-59 60-69 70-79 ⱖ80 20-29 30-39 40-49 50-59 60-69 70-79 ⱖ80
Population Estimate (in millions)
0.2 0.8 1.5 1.1 0.9 1.0 0.4 5.9 0.2 0.8 0.7 0.8 0.7 0.6 0.3 4.1
Population (%)
1.2 3.6 8.9 10.0 10.1 15.3 15.2 1.3 3.6 4.2 6.9 6.1 6.5 6.5
Table 3.
Sex
Men
Total Women
Total
Population Estimate With Gout by Age Categories
Age Category (y)
20-29 30-39 40-49 50-59 60-69 70-79 ⱖ80 20-29 30-39 40-49 50-59 60-69 70-79 ⱖ80
Population Estimate (in millions)
0.3 0.4 0.4 0.6 0.8 0.7 0.2 3.4 0.1 0.1 0.1 0.3 0.4 0.4 0.3 1.7
Population (%)
0.2 2.1 2.2 5.7 9.1 10.8 8.6 0.6 0.1 0.6 2.3 3.5 4.6 5.6
Among men, the prevalence of gout increased from 0.2% (0.3 million) in subjects aged 20 to 29 years to 10.8% (0.7 million) in those aged 70 to 79 years. The prevalence of gout in women was less than 1% in all age categories younger than 50 years and increased to 2.3% (0.3 million) in women aged 50 to 59 years and 5.6% (0.3 million) in women 80 years and older. The estimated total number of men and women with reported gout in the United States was 5.1 million. The overlap between kidney stone disease and gout in the US population is shown in Fig 1. Approximately 0.7 million individuals in the United States are estimated to have both gout and kidney stone disease. Age- and multivariate-adjusted ORs for previous kidney stones by history of gout are listed in Table 4. In the age-adjusted model, gout was
Fig 1. Estimated prevalence of kidney stone disease and gout in the US population, NHANES III, 1988 to 1994.
40
KRAMER AND CURHAN
Table 4. Age- and Multivariate-Adjusted ORs for Previous Symptomatic Kidney Stones by History of Gout in NHANES III
Total population No gout Gout Men No gout Gout Women No gout Gout
Age Adjusted
Multivariate Adjusted
1.00 (reference) 1.97 (1.37-2.83)
1.00 (reference) 1.49 (1.04-2.14)
1.00 (reference) 1.61 (1.05-2.48)
1.00 (reference) 1.46 (0.94-2.27)
1.00 (reference) 2.08 (1.15-3.78)
1.00 (reference) 1.65 (0.92-2.95)
NOTE. Values expressed as OR (95% CI).
significantly associated with previous kidney stones in the total population (OR, 1.97; 95% confidence interval [CI], 1.37 to 2.83), in men (OR, 1.61; 95% CI, 1.05 to 2.48), and in women (OR, 2.08; 95% CI, 1.15 to 3.78). After adjusting for race, sex, BMI, and history of hypertension, the OR for the population was 1.49 (95% CI, 1.04 to 2.14). The only covariates that individually attenuated the age-adjusted OR by at least 10% were sex and the presence of hypertension. However, sex-specific results were not statistically significant, and no substantial differences were noted between men (OR, 1.46; 95% CI, 0.94 to 2.27) and women (OR, 1.65; 95% CI, 0.92 to 2.95). DISCUSSION
In this nationally representative sample of men and women, the frequency of kidney stone disease in subjects with gout was almost threefold greater than that in the general US population. After adjusting for potential confounders, including age, sex, and BMI, we found that a history of gout was associated with a 49% increase in risk for previous kidney stones. In 1967, Yu and Gutman8 reported a history of kidney stones in 22% of 1,258 patients with primary gout. This is approximately 50% greater than the frequency of kidney stone disease we found among men and women in the US population with a history of gout. In a smaller study of 168 patients with documented previous gout, 15% reported a history of kidney stones.9 Subjects in these investigations included few women and were not as racially diverse as the US popu-
lation. Thus, the greater frequency of kidney stone disease among individuals with gout in previous studies possibly was caused by the homogeneity of the study populations. Individuals with gout may have greater urinary excretion of uric acid and/or persistently acidic urine,18 which may predispose to the formation of both uric acid– and calcium oxalate– containing kidney stones. Greater uric acid excretion may promote calcium stone formation by forming a nidus.19 In addition, uric acid is less soluble in acidic urine and more likely to precipitate,19 thus increasing the risk for uric acid stones. Determining the temporal relationship between gout and kidney stones is problematic because both diseases may not be diagnosed until an individual becomes symptomatic. Thus, in some individuals, kidney stone formation may be influenced by the presence of gout, which has not yet become symptomatic and/or diagnosed. Moreover, studies have found that approximately 50% of individuals with both gout and kidney stones experience the onset of gout after the passage of the first stone.8,9 In this study, we could not determine whether individuals with gout and prevalent kidney stones were diagnosed with gout before the passage of the first kidney stone because the age the first kidney stone was passed was not ascertained in NHANES III. Many researchers have used the term gouty diathesis to describe individuals who may have latent gout and are at greater risk for kidney stone formation.8,20-22 Individuals with gouty diathesis are characterized as having persistently acidic urine and a history of uric acid– or calciumcontaining kidney stones, but do not necessarily have a history of gout.20 Khatchadourian et al20 compared 24-hour urine measurements of various urinary factors in 95 subjects with gouty diathesis with those of 99 healthy controls with no history of kidney stones. Individuals with gouty diathesis not only had persistently acidic urine, increasing the risk for uric acid precipitation, but also had lower urinary citrate excretion (461 versus 677 mg/d; P ⬍ 0.05),20 an important inhibitor of calcium oxalate crystal formation.23 No difference in urinary calcium excretion was noted between the two groups, and urinary uric acid excretion was lower in subjects with gouty diathesis compared with controls.20 Moreover, only 21% with uric acid– and 12% with calcium-
GOUT AND NEPHROLITHIASIS
containing stones among subjects with gouty diathesis reported a history of primary gout.20 In a study of 56 patients with uric acid stones, urine pH and fractional excretion of uric acid were significantly lower compared with agematched controls with non–uric acid stones.22 The investigators of that study suggested that the low urine pH and low fractional excretion of uric acid in the uric acid–stone formers were markers of latent gout or gouty diathesis. However, a history of gout was not ascertained from these subjects. These important studies20-22 provided insight into the possible relationship between gouty diathesis and urinary risk factors for kidney stone formation, but they did not delineate the association between an actual history of gout and kidney stone formation. Prospective studies are needed to determine whether the presence of gout is an independent predictor of the formation of future kidney stones and whether the presence of kidney stones predicts the future development of symptomatic gout. This study was performed in a nationally representative sample of men and women and race/ ethnicity groups; thus, the findings are generalizable to the US population. However, the analysis was limited by its cross-sectional design, and we could not adjust for dietary factors or medication use, which may have been modified after the onset of gout or kidney stones. Prospective studies investigating the association between gout and kidney stone disease should adjust for such dietary factors as protein, sodium, potassium, calcium (both dietary and supplemental calcium), sucrose, and fluid intake and use of such medications as hydrochlorothiazide and allopurinol. We also were unable to determine the temporal relationship between the onset of gout and passage of the first kidney stone because the age at the passage of the first kidney stone was not ascertained. Other limitations include the possible misclassification of prevalent but asymptomatic kidney stones because an individual may not be aware of the presence of a kidney stone until it becomes symptomatic. The self-reported diagnosis of gout by a physician also was not validated in this study. Nonetheless, a subject’s report of kidney stone disease or gout was unlikely to be
41
related to the previous diagnosis of the other. Thus, any misclassification of kidney stone disease or gout likely would have been nondifferential and would not explain the positive association between gout and kidney stone disease found in this study. Results of this study also suggest no substantial sex differences in the association between gout and kidney stone disease. In summary, the prevalence of gout was greater in individuals with previous kidney stones. Even after adjusting for potential confounders, individuals with a history of gout were 49% more likely to have a history of kidney stones. Because kidney stone disease and gout are so common, showing they are associated strongly suggests common underlying pathophysiological mechanisms. Identification of these mechanisms may lead to improved preventive strategies for both conditions. REFERENCES 1. Pak CYC: Etiology and treatment of urolithiasis. Am J Kidney Dis 18:624-637, 1991 2. Johnson CM, Wilson DM, O’Fallon WM, Malek RS, Kurland LT: Renal stone epidemiology: A 25-year study in Rochester, Minnesota. Kidney Int 16:624-631, 1979 3. Parks JH, Coe FL: The financial effects of kidney stone prevention. Kidney Int 50:1706-1712, 1996 4. Hershfield MS: Gout and uric acid metabolism, in Bennett JC, Plum F (eds): Cecil’s Textbook of Medicine (ed 20). Philadelphia, PA, Saunders, 1996, pp 1508-1515 5. Agudelo CA, Wise CM: Gout: Diagnosis, pathogenesis and clinical manifestations. Curr Opin Rheumatol 13:234239, 2001 6. Lawrence RC, Helmick CG, Arnett FC, et al: Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the US. Arthritis Rheum 41:778-799, 1998 7. Eknoyan G: Michaelangelo: Art, anatomy, and the kidney. Kidney Int 57:1190-1201, 2000 8. Yu T, Gutman AB: Uric acid nephrolithiasis in gout: Predisposing factors. Ann Intern Med 67:1133-1148, 1967 9. Fessel WJ: Renal outcomes of gout and hyperuricemia. Am J Med 67:74-82, 1979 10. Roubenoff R, Klag MJ, Mead LA, Liang KY, Seidler AJ, Hochberg MC: Incidence and risk factors for gout in white men. JAMA 266:3004-3007, 1991 11. Hall AP, Barry PE, Dawber TR, McNamara PM: Epidemiology of gout and hyperuricemia. Am J Med 42:2737, 1967 12. Hochberg MC, Thomas J, Johniene TD, Mead L, Levine DM, Klag MJ: Racial differences in the incidence of gout: The role of hypertension. Arthritis Rheum 38:628-632, 1995 13. Abbott RD, Brand FN, Kannel WB, Castelli WP: Gout and coronary disease: The Framingham Study. J Clin Epidemiol 41:237-242, 1988
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14. Curhan GC, Willett WC, Rimm EB, Speizer FE, Stampfer MJ: Body size and risk of kidney stones. J Am Soc Nephrol 9:1645-1652, 1998 15. Madore F, Stampfer MJ, Willett WC, Speizer FE, Curhan GC: Nephrolithiasis and risk of hypertension in women. Am J Kidney Dis 32:802-807, 1998 16. National Center for Health Statistics: Survey Design of the Third National Health and Nutrition Examination Survey, 1988-1994. Hyattsville, MD, Centers for Disease Control and Prevention, 1996 17. World Health Organization: Obesity: Preventing and Managing the Global Epidemic: Report of a WHO Consultation on Obesity. Geneva, June 3-5, 1997. Geneva, Switzerland, WHO, 1998 18. Gutman AB, Yu T: Urinary ammonium excretion in primary gout. J Clin Invest 44:1474-1481, 1965
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19. Coe FL, Parks JH, Asplin JR: Nephrolithiasis: Pathogenesis and treatment of kidney stones. N Engl J Med 327:1141-1152, 1992 20. Khatchadourian J, Preminger GM, Whitson PA, Adams-Huet B, Pak CYC: Clinical and biochemical presentation of gout diathesis: Comparison of uric acid versus pure calcium stone formation. J Urol 154:1665-1669, 1995 21. Pak CYC, Sakhaee K, Fuller C: Successful management of uric acid nephrolithiasis with potassium citrate. Kidney Int 30:422-428, 1986 22. Pak CYC, Sakhaee K, Peterson RD, Poindexter JR, Frawley WH: Biochemical profile of idiopathic uric acid nephrolithiasis. Kidney Int 60:757-761, 2001 23. Kok DJ, Papoulos SE, Bijvoet OL: Crystal agglomeration is a major element in calcium oxalate urinary stone formation. Kidney Int 37:51-59, 1990