- Email: [email protected]
Gender Equivalence in the Prevalence of Nephrolithiasis among Adults Younger than 50 Years in the United States
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Gender Equivalence in the Prevalence of Nephrolithiasis among Adults Younger than 50 Years Old in the United States Gina Tundo, Sari Khaleel and Vernon M. Pais Jr. From the Section of Urology, Department of Surgery, Dartmouth Hitchcock Medical Center (GT), Lebanon and Dartmouth Institute for Health Policy and Clinical Practice, Hanover, New Hampshire (VMP), and Department of Urology, University of Minnesota (SK), Minneapolis, Minnesota
Purpose: Although urolithiasis affects each gender, conventional teaching proposes that men are 3 times more likely to have stones. However, clinical practice refutes such a disparity, particularly among working age adults. Small studies have suggested an erosion of this gender gap. Therefore, we examined the relationship between gender and stone prevalence among American adults younger than 50 years. Materials and Methods: We analyzed the NHANES (National Health and Nutrition Examination Survey) 2007 to 2012 cohort. Weighted proportions and multivariate logistic regression of the cohort and pertinent subgroups were assessed to determine the prevalence and the odds of nephrolithiasis. Results: The cohort of 17,658 subjects, which was weighted to represent the American population of 218,828,951 adults, was 48.1% male. In our cohort of 8,888 adults weighted to represent 123,976,786 subjects younger than 50 years, which was 49.3% male and 50.7% female, there was no difference in stone prevalence (6.3% in males and 6.4% in females, p ¼ 0.85). On unadjusted logistic regression of those younger than 50 years men were no more likely to report a stone history (OR 0.98, p ¼ 0.85). Multivariate logistic regression adjusting for diabetes, obesity, ethnicity, age, and water, sodium and protein intake confirmed no difference in stone prevalence between the genders (OR 1.1, p ¼ 0.51). Conclusions: Among adults of working and child rearing ages in the United States the much touted gender disparity in nephrolithiasis is not present. Prior assessments of gender based stone prevalence may have failed to specifically assess this economically critical demographic or there may in fact be an ongoing epidemiological change. Recognition that women are as likely as men to form stones in this cohort suggests the need to better elucidate the pathophysiology of stones in women.
Abbreviations and Acronyms BMI ¼ body mass index NCHS ¼ National Center for Health Statistics NHANES ¼ National Health and Nutrition Examination Survey Accepted for publication July 22, 2018. No direct or indirect commercial incentive associated with publishing this article. The corresponding author certifies that, when applicable, a statement(s) has been included in the manuscript documenting institutional review board, ethics committee or ethical review board study approval; principles of Helsinki Declaration were followed in lieu of formal ethics committee approval; institutional animal care and use committee approval; all human subjects provided written informed consent with guarantees of confidentiality; IRB approved protocol number; animal approved project number.
Key Words: nephrolithiasis, women’s health, nutrition surveys, health status disparities, age factors KIDNEY stones affect approximately 1/11 Americans.1 Nephrolithiasis has a significant negative impact on quality of life and it also poses a significant financial burden on society. The annual cost has been estimated at $2 billion, which appears to be increasing despite the emergence of minimally invasive treatment modalities as well
as a shift of care from the inpatient to the outpatient setting.2 Saigal et al reported that approximately a third of employees treated for nephrolithiasis in 2000 missed work due to the condition with an average work loss in the entire treated population of 19 hours per person.3 If an individual also received treatment,
0022-5347/18/2006-0001/0 THE JOURNAL OF UROLOGY® Ó 2018 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
Dochead: Adult Urology
https://doi.org/10.1016/j.juro.2018.07.048 Vol. 200, 1-5, December 2018 Printed in U.S.A.
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the incremental costs were $3,494 per person in 2000. Historically men have been identified as being significantly more likely than women to have kidney stones.2 However, our recent clinical observations suggest that this may be changing and females are increasingly impacted by nephrolithiasis. This is particularly true among younger women. Several smaller scale, single center studies have supported this finding. A retrospective review of all renal and ureteral stones submitted to a single laboratory in Massachusetts in 1990 vs 2010 revealed that the percent of stones submitted by women increased from 29.8% to 39.1%.4 Tasian et al similarly identified an increasing incidence of nephrolithiasis between 1997 and 2012 among women in South Carolina.5 Real world implications are suggested by another study showing a 52% increase in stone related health care utilization among women compared with a 22% increase in men between 1998 and 2004 in Florida.6 A review of the demographic subsets of a 2012 national assessment of stone prevalence also suggests a similar stone prevalence among younger participants.1 However, when focusing on the adult cohort as a whole, the investigators concluded that the stone prevalence was higher in men than in women. Among younger adults an increased incidence of stones in women may be more pronounced. An analysis of all stones submitted to the Mayo Clinic laboratory in 2010 revealed that men accounted for 58% of all stone submissions.7 However, when looking specifically at those younger than 30 years, women actually submitted more stones than men. When looking at individuals between ages 10 and 19, and 20 and 29 years, women accounted for 63% and 62% of submissions, respectively. Other regional studies have similarly demonstrated marked increases in the stone incidence in women of working and reproductive ages.8 An additional study by Masterson et al to determine the incidence of nephrolithiasis in Navy pilots corroborated the suggestion that younger women may have a higher incidence of nephrolithiasis than men.9 In this retrospective review of all Navy service members with a median age of 28 years from 2002 to 2011 they found that women had 17% higher odds of nephrolithiasis than men (OR 1.17, p <0.0001). More recent data suggest that there may be a particular import to health care events in the younger adult cohort, specifically those younger than 50 years, since they may face unique health challenges related to child rearing and economic responsibilities. Even in the setting of recommended radiation therapy of breast cancer after breast conserving surgery women younger than 50 years Dochead: Adult Urology
were less likely to pursue this guideline concordant care.10 The study investigators observed that this demographic drove the significant association between having young children and failing to undergo radiation therapy. They hypothesized that health care decisions were influenced by the competing demands on the time of those younger than 50 years, including providing child care. Despite the mentioned regional assessments to our knowledge there has been no recent national analysis of gender differences in stone prevalence among younger, working age adults. We specifically assessed adults younger than 50 years, given the unique health challenges that they face. We hypothesized that there is no gender disparity in this specific cohort. If working age females are equally as likely as their male counterparts to have urolithiasis, this may have implications to focus prevention efforts and highlight the need for continued efforts to elucidate the pathophysiology of stones in women.
METHODS Study Design The CDC (Centers for Disease Control and Prevention) and the NCHS developed and administered the NHANES to assess the health and nutritional status of the United States noninstitutionalized civilian population. NHANES is composed of a series of population based demographic, socioeconomic, dietary, health and disease related surveys as well as select physical examinations to obtain crosssectional, person level data on a nationally representative sample. The program was approved by the NCHS Ethics Review Board and all participants provided informed consent. Our data set was collected from 3 consecutive NHANES 2-year cycles, including 2007 to 2008, 2009 to 2010 and 2011 to 2012, as these cycles specifically inquired about history of kidney stones. Our population consisted of all adults older than 18 years with a documented stone history to examine stone prevalence in the entire adult population. We restricted our cohort to adults younger than 50 years. We included general demographic data and data on known and suspected risk factors for stone disease, including ethnicity, obesity and diabetes status.
Variables Self-reported gender was our primary exposure, which is treated as a dichotomous variable in the NHANES demographic data file. A history of nephrolithiasis was our primary outcome. This was obtained from the selfreported survey question, “Have you ever had a kidney stone?” in the kidney conditions data file of the questionnaire. Covariates obtained from the demographics file included age at the time of the survey and ethnicity. Age was used as a continuous variable but ethnicity was categorical, divided into Mexican American, other Hispanic,
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Caucasian, African American and other/multicultural. 229 Total daily plain water intake, sodium intake and protein 230 intake were recorded as continuous variables. 231 Obesity was classified as BMI greater than 30 kg/m2 232 and calculated from self-reported weight and height at the 233 time of screening. Diabetes history was obtained from the 234 diabetes section of the questionnaire, where respondents 235 were asked the question, “Other than during pregnancy, 236 have you ever been told by a doctor or health professional 237 that you have diabetes?” 238 Interview sampling weight, sampling unit and strata 239 variables for each participant were also obtained from the demographic files. 240 241 Statistical Analysis 242 Statistical analyses were performed using StataÒ, version 243 15.1 with survey command sets. Given the complex, 244 weighted survey design, we used the NCHS determined 245 and provided sample weights, sampling units and strata 246 for analyses. Mean estimates were determined using survey mean commands and differences in means were 247 assessed for statistical significance by survey weighted 248 regression. Weighted medians and IQRs were also calcu249 lated. Differences in the distribution of categorical vari250 ables were assessed by weighted survey commands, which 251 produced Rao-Scott corrected chi-square tests allowing for 252 the NHANES complex survey design. To account for our a 253 priori covariates logistic regression was done to assess the 254 effect of gender on the odds of our dichotomous outcome, 255 which was a history of nephrolithiasis. 256 257 258 RESULTS 259 The entire unselected cohort of 17,658 subjects, 260 which was weighted to represent the nationwide 261 American population of 218,828,951 adults, was 262 48.1% male and 51.9% female. As also previously 263 reported1 of all adults men had a significantly 264 higher stone prevalence of 9.8% vs 7.7% in women 265 (p ¼ 0.002). On multivariate logistic regression 266 adjusted for diabetes, obesity, ethnicity and age in 267 the entire cohort men were 37% more likely than 268 women to have ever had stones (OR 1.37, p <0.001). 269 However, our cohort of interest was those 270 younger than 50 years, who included 123,976,786 271 subjects, of whom 49.3% were male and 50.7% were 272 ½T1 female. The table lists the baseline characteristics of 273 this cohort. There was no significant difference in 274 median age or the percent with obesity or a diabetes 275 diagnosis in this cohort. The ethnic distribution 276 differed (see table). We also compared 3 dietary 277 trends known to correlate with stone risk, including 278 water, sodium and protein intake, in the female and 279 male cohorts. In our study population men had 280 higher mean sodium and protein intake, and 281 slightly higher water intake than women (see table). 282 When restricted to the weighted sample of those 283 younger than 50 years, there was no difference in 284 the stone prevalence between males and females 285 (6.3% vs 6.4%, p ¼ 0.85). There remained no Dochead: Adult Urology
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Baseline characteristics of men and women younger than 50 years in 2007 to 2012 NHANES cohort Men No. pts Mean age/median (IQR) Mean kg/m2 body mass index/median (IQR) % Obese % Ethnicity: Mexican American Other Hispanic Caucasian African American Other/multicultural % Diabetes Daily intake: Sodium (mg) Water (ml) Protein (gm) % Age at nephrolithiasis: Less than 50 20e29 30e39 40e49
Women
4,305 4,583 34.6/35 (20e49) 34.8/35 (20e49) 27.9/27.0 (16e60) 27.5/25.8 (15e72) 29.7
31.5
12.0 6.7 62.3 11.3 7.6 3.2
10.0 6.9 61.7 13.6 7.9 3.3
4,483 1,218 105 6.3 3.1 6.2 9.4
3,155 1,132 71 6.4 4.1 6.6 8.3
p Value e 0.41 0.018 0.146 <0.001
0.99 <0.001 0.021 <0.001 0.85 0.21 0.60 0.43
difference when restricted to subpopulations stratified by decade of age (see table). Among those younger than 50 years there was no significant difference in the unadjusted odds of a stone history in men compared to women (OR 0.98, p ¼ 0.85). On multivariate logistic regression adjusted for age, ethnicity, diabetes, obesity, and the intake of water, sodium and protein there remained no difference in the likelihood of stones between the genders (OR 1.1, p ¼ 0.51).
DISCUSSION Although classic epidemiological understanding has identified men as being significantly more likely than women to have urolithiasis, recent data suggest that this gender gap may be narrowing. We report that there was no appreciable gender difference in stone prevalence in this younger cohort of working and child rearing age using a large, nationally representative population based survey. To our knowledge it remains unknown whether this represents a true change in epidemiology or a previously present but unreported phenomenon. The evolving role of women in the workplace may contribute to increased lithogenicity. For instance, more time spent in the workplace may translate into dietary changes conducive to stone formation. While women indeed demonstrated lower mean fluid intake than men, other dietary factors remained higher in men, including mean protein and sodium intake. Gender based differential changes in dietary factors and the relative effect on lithogenicity may be an avenue for further investigation. Another factor postulated to contribute to an increasing stone prevalence in women is a
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disproportionate increase in the prevalence of obesity with time in females vs males. Obesity is a well recognized risk factor for stone formation. The pathophysiology behind this association is clearly multifactorial but it has been postulated to be due to lower urinary pH and increased urinary uric acid, sodium and calcium. Most studies to date have shown a significantly increased proportion of uric acid stone formation in the overweight and obese populations but no increase in calcium oxalate stone formation.11 Unfortunately the NHANES crosssectional survey data do not capture stone composition. A report showing a significant increase in the percent of stones submitted from females in 1990 vs 2010 also revealed a significant increase in stones that were greater than 50% uric acid in women.4 This could support the hypothesis that obesity may have a large role in the narrowing gender gap in the prevalence of nephrolithiasis. Previous NHANES data showed little change in the obesity prevalence in male and female adults from 1960 through 1980 but then there was an increase in obesity in both genders between 1980 and 2000.12 Interestingly between 2005 and 2014 there was a significant linear increase in the overall obesity prevalence in women but no significant trend in men. Moreover, in women the highest prevalence of obesity is in the 40 to 59-year age range. However, in our cohort of adults younger than 50 years we did not identify any increased likelihood of obesity in women compared to men. Furthermore, prior studies of the obesity prevalence using NHANES data have shown similar obesity rates through age categories spanning 20 years old through older than 60 years.12 Additionally, several studies have suggested that obesity confers a differentially greater risk of nephrolithiasis in women than in men. Taylor et al used data from 3 large cohort studies, including the HPFS (Health Professionals Follow-Up Study), and the NHS (Nurses’ Health Study) I and II, to examine the association of kidney stone formation with weight, weight gain, BMI and waist circumference.13 They found a RR of 1.44 for stone formation in men between ages 40 and 75 years who weighed more than 220 vs less than 150 pounds. In older women 34 to 59 years old and younger women 27 to 44 years old the RR of these weight categories was 1.89 and 1.92, respectively. The RR in men who had gained more than 35 pounds since age 21 years vs those whose weight did not change was 1.39. The corresponding RR of older and younger women in the same weight gain categories was 1.7 and 1.82, respectively. Finally, the RR in men with a BMI of 30 kg/m2 or greater vs those with a BMI of 21 to 22.9 kg/m2 was 1.33. The RR of the same BMI categories Dochead: Adult Urology
in older and younger women was 1.9 and 2.09, respectively. Nowfar et al corroborated these findings using data from the NIS (Nationwide Inpatient Sample) to calculate the prevalence of a primary diagnosis of renal or ureteral calculi from 1998 through 2003.14 The database also enabled them to collect information on obesity and other common comorbidities. Multivariate analysis revealed a statistically significant relationship between obesity and urolithiasis (overall OR 1.22). However, when stratified by gender, there was a stronger association in females than in males (OR 1.35 vs 1.04). Although we adjusted for obesity in our multivariate regression model, additional unaccounted for confounders may have obscured present but unseen differential risks. The relation between diet and stone risk is well documented along with noted differences in dietary habits between men and women. This was reflected in our cohort with higher mean sodium, protein and water intake in men than in women. However, adjusting for this factor along with patient characteristics, including obesity, did not significantly alter the gender specific stone risk. Another potential contributor to the nephrolithiasis risk in reproductive age women is the recently reported association between pregnancy history and stones. There are several lithogenic urinary changes during pregnancy, including hypercalciuria, hyperuricosuria and elevated pH.15 Reinstatler et al compared the odds of stone formation in women who had ever been pregnant to the odds in women who had never been pregnant and found that those with a pregnancy history had more than twice the odds of reporting kidney stone than their never pregnant counterparts.16 What can be concluded from these data is that working age women, of whom many have been pregnant, may face increased lifetime lithogenicity. This is a risk to which men are not exposed. To our knowledge it remains unknown whether this eroded gender gap is indeed particular to this age group or whether there has been an evolution in stone risk such that the gender equality in stone prevalence may persist as this cohort ages. The strengths of our study include those inherent to NHANES data, which represent a large, comprehensive sample appropriately weighted to represent the full nationwide adult population. It uses thorough, validated questionnaires to obtain reliable, comprehensive data on each individual participant. The limitations of this and any cross-sectional survey based study include the inability to follow the cohort longitudinally and to determine causality, the potential response bias and the potential for unidentified confounding variables.
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CONCLUSIONS Our findings suggest that there is indeed no gender disparity in the prevalence of kidney stones in the American population younger than 50 years. The results highlight the need for continued efforts to elucidate the pathophysiology of stones in women. A
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better understanding of the pathophysiology and the epidemiology of stone disease in young adults will ultimately allow for more focused preventive efforts and a reduction in health care costs and missed work productivity in this economically vital demographic.
REFERENCES 1. Scales CD Jr, Smith AC, Hanley JM et al: Prevalence of kidney stones in the United States. Eur Urol 2012; 62: 160.
6. Strope SA, Wolf JS and Hollenbeck BK: Changes in gender distribution of urinary stone disease. Urology 2010; 75: 543.
2. Pearle MS, Calhoun EA and Curhan GC: Urologic Diseases in America project: urolithiasis. J Urol 2005; 173: 848.
7. Kittanamongkolchai W, Vaughan LE, Enders FT et al: The changing incidence and presentation of urinary stones over 3 decades. Mayo Clin Pro 2018; 93: 291.
3. Saigal CS, Joyce G and Timilsina AR: Direct and indirect cost of nephrolithiasis in an employed population: opportunity for disease management? Kidney Int 2005; 68: 1808. 4. Moses RA, Pais VM, Ursiny M et al: Changes in stone composition over two decades: evaluation of over 10,000 stone analyses. Urolithiasis 2015; 43: 135. 5. Tasian GE, Ross ME, Song L et al: Annual incidence of nephrolithiasis among children and adults in South Carolina form 1997 to 2012. Clin J Am Soc Nephrol 2016; 11: 1.
8. Lieske JC, Rule AD, Krambeck AE et al: Stone composition as a function of age and sex. Clin J Am Soc Nephrol 2014; 9: 2141. 9. Masterson JH, Phillipa CJ, Crum-Cianfone NF et al: A 10-year retrospective review of nephrolithiasis in the Navy and Navy pilots. J Urol 2017; 198: 394. 10. Pan IW, Smith BD and Shih YT: Factors contributing to underuse of radiation among younger women with breast cancer. J Natl Cancer Inst 2014; 106: 1. 11. Shavit L, Ferraro PM, Johri N et al: Effect of being overweight on urinary metabolic risk
factors for kidney stone formation. Nephrol Dial Transplant 2015; 30: 607. 12. Flegal KM, Kruszon-Moran D, Carroll MD et al: Trends in obesity among adults in the United States, 2005 to 2014. JAMA 2016; 315: 2284. 13. Taylor EN, Stampfer MJ and Curran JC: Obesity, weight gain, and the risk of kidney stones. J Am Med Assoc 2005; 293: 455. 14. Nowfar S, Palazzi-Churas K, Chang DC et al: The relationship of obesity and gender prevalence changes in United States inpatient nephrolithiasis. J Urol 2011; 78: 1029. 15. Smith CL, Kristensen C, Davis M et al: An evaluation of the physicochemical risk for renal stone disease during pregnancy. Clin Nephrol 2001; 55: 205. 16. Reinstatler L, Khaleel S and Pais VM: Association of pregnancy with stone formation among women in the United States: a NHANES analysis 2007 to 2012. J Urol 2017; 198: 389.
EDITORIAL COMMENT Urinary stone disease is a growing and important public health problem in the United States. Tundo et al report the results of a cross-sectional analysis of data from the 2007 to 2012 NHANES, the gold standard for nationally representative health estimates. Focusing on younger adults, the authors compared the prevalence of self-reported stone disease by gender, finding an equal prevalence of stones (approximately 1/16) among men and women. These findings persisted after controlling for important potential confounders. This study represents an important contribution to our understanding of the epidemiology of urinary stone disease. Nationally representative data (reference 1 in article) as well as state and local data (references 5 and 7 in article) demonstrate the rapid growth of stone disease among historically lower risk groups, including women, African American
Dochead: Adult Urology
individuals and children. Two key questions pertain, including why and whether factors such as obesity impose differential risk in certain groups. As outlined by the authors, tantalizing associations and plausible mechanisms exist for a relationship between metabolic syndrome and stone disease and yet our understanding remains limited, particularly regarding a differential impact in individuals historically at lower risk. Ultimately turning the tide on urinary stone disease will require laser sharp focus on prevention and improving the health of the population.
Charles D. Scales, Jr. Department of Urology Duke University School of Medicine Durham, North Carolina
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Gender Equivalence in the Prevalence of Nephrolithiasis among Adults Younger than 50 Years Old in the United States Gina Tundo, Sari Khaleel and Vernon M. Pais Jr. From the Section of Urology, Department of Surgery, Dartmouth Hitchcock Medical Center (GT), Lebanon and Dartmouth Institute for Health Policy and Clinical Practice, Hanover, New Hampshire (VMP), and Department of Urology, University of Minnesota (SK), Minneapolis, Minnesota
Purpose: Although urolithiasis affects each gender, conventional teaching proposes that men are 3 times more likely to have stones. However, clinical practice refutes such a disparity, particularly among working age adults. Small studies have suggested an erosion of this gender gap. Therefore, we examined the relationship between gender and stone prevalence among American adults younger than 50 years. Materials and Methods: We analyzed the NHANES (National Health and Nutrition Examination Survey) 2007 to 2012 cohort. Weighted proportions and multivariate logistic regression of the cohort and pertinent subgroups were assessed to determine the prevalence and the odds of nephrolithiasis. Results: The cohort of 17,658 subjects, which was weighted to represent the American population of 218,828,951 adults, was 48.1% male. In our cohort of 8,888 adults weighted to represent 123,976,786 subjects younger than 50 years, which was 49.3% male and 50.7% female, there was no difference in stone prevalence (6.3% in males and 6.4% in females, p ¼ 0.85). On unadjusted logistic regression of those younger than 50 years men were no more likely to report a stone history (OR 0.98, p ¼ 0.85). Multivariate logistic regression adjusting for diabetes, obesity, ethnicity, age, and water, sodium and protein intake confirmed no difference in stone prevalence between the genders (OR 1.1, p ¼ 0.51). Conclusions: Among adults of working and child rearing ages in the United States the much touted gender disparity in nephrolithiasis is not present. Prior assessments of gender based stone prevalence may have failed to specifically assess this economically critical demographic or there may in fact be an ongoing epidemiological change. Recognition that women are as likely as men to form stones in this cohort suggests the need to better elucidate the pathophysiology of stones in women.
Abbreviations and Acronyms BMI ¼ body mass index NCHS ¼ National Center for Health Statistics NHANES ¼ National Health and Nutrition Examination Survey Accepted for publication July 22, 2018. No direct or indirect commercial incentive associated with publishing this article. The corresponding author certifies that, when applicable, a statement(s) has been included in the manuscript documenting institutional review board, ethics committee or ethical review board study approval; principles of Helsinki Declaration were followed in lieu of formal ethics committee approval; institutional animal care and use committee approval; all human subjects provided written informed consent with guarantees of confidentiality; IRB approved protocol number; animal approved project number.
Key Words: nephrolithiasis, women’s health, nutrition surveys, health status disparities, age factors KIDNEY stones affect approximately 1/11 Americans.1 Nephrolithiasis has a significant negative impact on quality of life and it also poses a significant financial burden on society. The annual cost has been estimated at $2 billion, which appears to be increasing despite the emergence of minimally invasive treatment modalities as well
as a shift of care from the inpatient to the outpatient setting.2 Saigal et al reported that approximately a third of employees treated for nephrolithiasis in 2000 missed work due to the condition with an average work loss in the entire treated population of 19 hours per person.3 If an individual also received treatment,
0022-5347/18/2006-0001/0 THE JOURNAL OF UROLOGY® Ó 2018 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
Dochead: Adult Urology
https://doi.org/10.1016/j.juro.2018.07.048 Vol. 200, 1-5, December 2018 Printed in U.S.A.
www.jurology.com
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the incremental costs were $3,494 per person in 2000. Historically men have been identified as being significantly more likely than women to have kidney stones.2 However, our recent clinical observations suggest that this may be changing and females are increasingly impacted by nephrolithiasis. This is particularly true among younger women. Several smaller scale, single center studies have supported this finding. A retrospective review of all renal and ureteral stones submitted to a single laboratory in Massachusetts in 1990 vs 2010 revealed that the percent of stones submitted by women increased from 29.8% to 39.1%.4 Tasian et al similarly identified an increasing incidence of nephrolithiasis between 1997 and 2012 among women in South Carolina.5 Real world implications are suggested by another study showing a 52% increase in stone related health care utilization among women compared with a 22% increase in men between 1998 and 2004 in Florida.6 A review of the demographic subsets of a 2012 national assessment of stone prevalence also suggests a similar stone prevalence among younger participants.1 However, when focusing on the adult cohort as a whole, the investigators concluded that the stone prevalence was higher in men than in women. Among younger adults an increased incidence of stones in women may be more pronounced. An analysis of all stones submitted to the Mayo Clinic laboratory in 2010 revealed that men accounted for 58% of all stone submissions.7 However, when looking specifically at those younger than 30 years, women actually submitted more stones than men. When looking at individuals between ages 10 and 19, and 20 and 29 years, women accounted for 63% and 62% of submissions, respectively. Other regional studies have similarly demonstrated marked increases in the stone incidence in women of working and reproductive ages.8 An additional study by Masterson et al to determine the incidence of nephrolithiasis in Navy pilots corroborated the suggestion that younger women may have a higher incidence of nephrolithiasis than men.9 In this retrospective review of all Navy service members with a median age of 28 years from 2002 to 2011 they found that women had 17% higher odds of nephrolithiasis than men (OR 1.17, p <0.0001). More recent data suggest that there may be a particular import to health care events in the younger adult cohort, specifically those younger than 50 years, since they may face unique health challenges related to child rearing and economic responsibilities. Even in the setting of recommended radiation therapy of breast cancer after breast conserving surgery women younger than 50 years Dochead: Adult Urology
were less likely to pursue this guideline concordant care.10 The study investigators observed that this demographic drove the significant association between having young children and failing to undergo radiation therapy. They hypothesized that health care decisions were influenced by the competing demands on the time of those younger than 50 years, including providing child care. Despite the mentioned regional assessments to our knowledge there has been no recent national analysis of gender differences in stone prevalence among younger, working age adults. We specifically assessed adults younger than 50 years, given the unique health challenges that they face. We hypothesized that there is no gender disparity in this specific cohort. If working age females are equally as likely as their male counterparts to have urolithiasis, this may have implications to focus prevention efforts and highlight the need for continued efforts to elucidate the pathophysiology of stones in women.
METHODS Study Design The CDC (Centers for Disease Control and Prevention) and the NCHS developed and administered the NHANES to assess the health and nutritional status of the United States noninstitutionalized civilian population. NHANES is composed of a series of population based demographic, socioeconomic, dietary, health and disease related surveys as well as select physical examinations to obtain crosssectional, person level data on a nationally representative sample. The program was approved by the NCHS Ethics Review Board and all participants provided informed consent. Our data set was collected from 3 consecutive NHANES 2-year cycles, including 2007 to 2008, 2009 to 2010 and 2011 to 2012, as these cycles specifically inquired about history of kidney stones. Our population consisted of all adults older than 18 years with a documented stone history to examine stone prevalence in the entire adult population. We restricted our cohort to adults younger than 50 years. We included general demographic data and data on known and suspected risk factors for stone disease, including ethnicity, obesity and diabetes status.
Variables Self-reported gender was our primary exposure, which is treated as a dichotomous variable in the NHANES demographic data file. A history of nephrolithiasis was our primary outcome. This was obtained from the selfreported survey question, “Have you ever had a kidney stone?” in the kidney conditions data file of the questionnaire. Covariates obtained from the demographics file included age at the time of the survey and ethnicity. Age was used as a continuous variable but ethnicity was categorical, divided into Mexican American, other Hispanic,
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Caucasian, African American and other/multicultural. 229 Total daily plain water intake, sodium intake and protein 230 intake were recorded as continuous variables. 231 Obesity was classified as BMI greater than 30 kg/m2 232 and calculated from self-reported weight and height at the 233 time of screening. Diabetes history was obtained from the 234 diabetes section of the questionnaire, where respondents 235 were asked the question, “Other than during pregnancy, 236 have you ever been told by a doctor or health professional 237 that you have diabetes?” 238 Interview sampling weight, sampling unit and strata 239 variables for each participant were also obtained from the demographic files. 240 241 Statistical Analysis 242 Statistical analyses were performed using StataÒ, version 243 15.1 with survey command sets. Given the complex, 244 weighted survey design, we used the NCHS determined 245 and provided sample weights, sampling units and strata 246 for analyses. Mean estimates were determined using survey mean commands and differences in means were 247 assessed for statistical significance by survey weighted 248 regression. Weighted medians and IQRs were also calcu249 lated. Differences in the distribution of categorical vari250 ables were assessed by weighted survey commands, which 251 produced Rao-Scott corrected chi-square tests allowing for 252 the NHANES complex survey design. To account for our a 253 priori covariates logistic regression was done to assess the 254 effect of gender on the odds of our dichotomous outcome, 255 which was a history of nephrolithiasis. 256 257 258 RESULTS 259 The entire unselected cohort of 17,658 subjects, 260 which was weighted to represent the nationwide 261 American population of 218,828,951 adults, was 262 48.1% male and 51.9% female. As also previously 263 reported1 of all adults men had a significantly 264 higher stone prevalence of 9.8% vs 7.7% in women 265 (p ¼ 0.002). On multivariate logistic regression 266 adjusted for diabetes, obesity, ethnicity and age in 267 the entire cohort men were 37% more likely than 268 women to have ever had stones (OR 1.37, p <0.001). 269 However, our cohort of interest was those 270 younger than 50 years, who included 123,976,786 271 subjects, of whom 49.3% were male and 50.7% were 272 ½T1 female. The table lists the baseline characteristics of 273 this cohort. There was no significant difference in 274 median age or the percent with obesity or a diabetes 275 diagnosis in this cohort. The ethnic distribution 276 differed (see table). We also compared 3 dietary 277 trends known to correlate with stone risk, including 278 water, sodium and protein intake, in the female and 279 male cohorts. In our study population men had 280 higher mean sodium and protein intake, and 281 slightly higher water intake than women (see table). 282 When restricted to the weighted sample of those 283 younger than 50 years, there was no difference in 284 the stone prevalence between males and females 285 (6.3% vs 6.4%, p ¼ 0.85). There remained no Dochead: Adult Urology
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Baseline characteristics of men and women younger than 50 years in 2007 to 2012 NHANES cohort Men No. pts Mean age/median (IQR) Mean kg/m2 body mass index/median (IQR) % Obese % Ethnicity: Mexican American Other Hispanic Caucasian African American Other/multicultural % Diabetes Daily intake: Sodium (mg) Water (ml) Protein (gm) % Age at nephrolithiasis: Less than 50 20e29 30e39 40e49
Women
4,305 4,583 34.6/35 (20e49) 34.8/35 (20e49) 27.9/27.0 (16e60) 27.5/25.8 (15e72) 29.7
31.5
12.0 6.7 62.3 11.3 7.6 3.2
10.0 6.9 61.7 13.6 7.9 3.3
4,483 1,218 105 6.3 3.1 6.2 9.4
3,155 1,132 71 6.4 4.1 6.6 8.3
p Value e 0.41 0.018 0.146 <0.001
0.99 <0.001 0.021 <0.001 0.85 0.21 0.60 0.43
difference when restricted to subpopulations stratified by decade of age (see table). Among those younger than 50 years there was no significant difference in the unadjusted odds of a stone history in men compared to women (OR 0.98, p ¼ 0.85). On multivariate logistic regression adjusted for age, ethnicity, diabetes, obesity, and the intake of water, sodium and protein there remained no difference in the likelihood of stones between the genders (OR 1.1, p ¼ 0.51).
DISCUSSION Although classic epidemiological understanding has identified men as being significantly more likely than women to have urolithiasis, recent data suggest that this gender gap may be narrowing. We report that there was no appreciable gender difference in stone prevalence in this younger cohort of working and child rearing age using a large, nationally representative population based survey. To our knowledge it remains unknown whether this represents a true change in epidemiology or a previously present but unreported phenomenon. The evolving role of women in the workplace may contribute to increased lithogenicity. For instance, more time spent in the workplace may translate into dietary changes conducive to stone formation. While women indeed demonstrated lower mean fluid intake than men, other dietary factors remained higher in men, including mean protein and sodium intake. Gender based differential changes in dietary factors and the relative effect on lithogenicity may be an avenue for further investigation. Another factor postulated to contribute to an increasing stone prevalence in women is a
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disproportionate increase in the prevalence of obesity with time in females vs males. Obesity is a well recognized risk factor for stone formation. The pathophysiology behind this association is clearly multifactorial but it has been postulated to be due to lower urinary pH and increased urinary uric acid, sodium and calcium. Most studies to date have shown a significantly increased proportion of uric acid stone formation in the overweight and obese populations but no increase in calcium oxalate stone formation.11 Unfortunately the NHANES crosssectional survey data do not capture stone composition. A report showing a significant increase in the percent of stones submitted from females in 1990 vs 2010 also revealed a significant increase in stones that were greater than 50% uric acid in women.4 This could support the hypothesis that obesity may have a large role in the narrowing gender gap in the prevalence of nephrolithiasis. Previous NHANES data showed little change in the obesity prevalence in male and female adults from 1960 through 1980 but then there was an increase in obesity in both genders between 1980 and 2000.12 Interestingly between 2005 and 2014 there was a significant linear increase in the overall obesity prevalence in women but no significant trend in men. Moreover, in women the highest prevalence of obesity is in the 40 to 59-year age range. However, in our cohort of adults younger than 50 years we did not identify any increased likelihood of obesity in women compared to men. Furthermore, prior studies of the obesity prevalence using NHANES data have shown similar obesity rates through age categories spanning 20 years old through older than 60 years.12 Additionally, several studies have suggested that obesity confers a differentially greater risk of nephrolithiasis in women than in men. Taylor et al used data from 3 large cohort studies, including the HPFS (Health Professionals Follow-Up Study), and the NHS (Nurses’ Health Study) I and II, to examine the association of kidney stone formation with weight, weight gain, BMI and waist circumference.13 They found a RR of 1.44 for stone formation in men between ages 40 and 75 years who weighed more than 220 vs less than 150 pounds. In older women 34 to 59 years old and younger women 27 to 44 years old the RR of these weight categories was 1.89 and 1.92, respectively. The RR in men who had gained more than 35 pounds since age 21 years vs those whose weight did not change was 1.39. The corresponding RR of older and younger women in the same weight gain categories was 1.7 and 1.82, respectively. Finally, the RR in men with a BMI of 30 kg/m2 or greater vs those with a BMI of 21 to 22.9 kg/m2 was 1.33. The RR of the same BMI categories Dochead: Adult Urology
in older and younger women was 1.9 and 2.09, respectively. Nowfar et al corroborated these findings using data from the NIS (Nationwide Inpatient Sample) to calculate the prevalence of a primary diagnosis of renal or ureteral calculi from 1998 through 2003.14 The database also enabled them to collect information on obesity and other common comorbidities. Multivariate analysis revealed a statistically significant relationship between obesity and urolithiasis (overall OR 1.22). However, when stratified by gender, there was a stronger association in females than in males (OR 1.35 vs 1.04). Although we adjusted for obesity in our multivariate regression model, additional unaccounted for confounders may have obscured present but unseen differential risks. The relation between diet and stone risk is well documented along with noted differences in dietary habits between men and women. This was reflected in our cohort with higher mean sodium, protein and water intake in men than in women. However, adjusting for this factor along with patient characteristics, including obesity, did not significantly alter the gender specific stone risk. Another potential contributor to the nephrolithiasis risk in reproductive age women is the recently reported association between pregnancy history and stones. There are several lithogenic urinary changes during pregnancy, including hypercalciuria, hyperuricosuria and elevated pH.15 Reinstatler et al compared the odds of stone formation in women who had ever been pregnant to the odds in women who had never been pregnant and found that those with a pregnancy history had more than twice the odds of reporting kidney stone than their never pregnant counterparts.16 What can be concluded from these data is that working age women, of whom many have been pregnant, may face increased lifetime lithogenicity. This is a risk to which men are not exposed. To our knowledge it remains unknown whether this eroded gender gap is indeed particular to this age group or whether there has been an evolution in stone risk such that the gender equality in stone prevalence may persist as this cohort ages. The strengths of our study include those inherent to NHANES data, which represent a large, comprehensive sample appropriately weighted to represent the full nationwide adult population. It uses thorough, validated questionnaires to obtain reliable, comprehensive data on each individual participant. The limitations of this and any cross-sectional survey based study include the inability to follow the cohort longitudinally and to determine causality, the potential response bias and the potential for unidentified confounding variables.
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CONCLUSIONS Our findings suggest that there is indeed no gender disparity in the prevalence of kidney stones in the American population younger than 50 years. The results highlight the need for continued efforts to elucidate the pathophysiology of stones in women. A
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better understanding of the pathophysiology and the epidemiology of stone disease in young adults will ultimately allow for more focused preventive efforts and a reduction in health care costs and missed work productivity in this economically vital demographic.
REFERENCES 1. Scales CD Jr, Smith AC, Hanley JM et al: Prevalence of kidney stones in the United States. Eur Urol 2012; 62: 160.
6. Strope SA, Wolf JS and Hollenbeck BK: Changes in gender distribution of urinary stone disease. Urology 2010; 75: 543.
2. Pearle MS, Calhoun EA and Curhan GC: Urologic Diseases in America project: urolithiasis. J Urol 2005; 173: 848.
7. Kittanamongkolchai W, Vaughan LE, Enders FT et al: The changing incidence and presentation of urinary stones over 3 decades. Mayo Clin Pro 2018; 93: 291.
3. Saigal CS, Joyce G and Timilsina AR: Direct and indirect cost of nephrolithiasis in an employed population: opportunity for disease management? Kidney Int 2005; 68: 1808. 4. Moses RA, Pais VM, Ursiny M et al: Changes in stone composition over two decades: evaluation of over 10,000 stone analyses. Urolithiasis 2015; 43: 135. 5. Tasian GE, Ross ME, Song L et al: Annual incidence of nephrolithiasis among children and adults in South Carolina form 1997 to 2012. Clin J Am Soc Nephrol 2016; 11: 1.
8. Lieske JC, Rule AD, Krambeck AE et al: Stone composition as a function of age and sex. Clin J Am Soc Nephrol 2014; 9: 2141. 9. Masterson JH, Phillipa CJ, Crum-Cianfone NF et al: A 10-year retrospective review of nephrolithiasis in the Navy and Navy pilots. J Urol 2017; 198: 394. 10. Pan IW, Smith BD and Shih YT: Factors contributing to underuse of radiation among younger women with breast cancer. J Natl Cancer Inst 2014; 106: 1. 11. Shavit L, Ferraro PM, Johri N et al: Effect of being overweight on urinary metabolic risk
factors for kidney stone formation. Nephrol Dial Transplant 2015; 30: 607. 12. Flegal KM, Kruszon-Moran D, Carroll MD et al: Trends in obesity among adults in the United States, 2005 to 2014. JAMA 2016; 315: 2284. 13. Taylor EN, Stampfer MJ and Curran JC: Obesity, weight gain, and the risk of kidney stones. J Am Med Assoc 2005; 293: 455. 14. Nowfar S, Palazzi-Churas K, Chang DC et al: The relationship of obesity and gender prevalence changes in United States inpatient nephrolithiasis. J Urol 2011; 78: 1029. 15. Smith CL, Kristensen C, Davis M et al: An evaluation of the physicochemical risk for renal stone disease during pregnancy. Clin Nephrol 2001; 55: 205. 16. Reinstatler L, Khaleel S and Pais VM: Association of pregnancy with stone formation among women in the United States: a NHANES analysis 2007 to 2012. J Urol 2017; 198: 389.
EDITORIAL COMMENT Urinary stone disease is a growing and important public health problem in the United States. Tundo et al report the results of a cross-sectional analysis of data from the 2007 to 2012 NHANES, the gold standard for nationally representative health estimates. Focusing on younger adults, the authors compared the prevalence of self-reported stone disease by gender, finding an equal prevalence of stones (approximately 1/16) among men and women. These findings persisted after controlling for important potential confounders. This study represents an important contribution to our understanding of the epidemiology of urinary stone disease. Nationally representative data (reference 1 in article) as well as state and local data (references 5 and 7 in article) demonstrate the rapid growth of stone disease among historically lower risk groups, including women, African American
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individuals and children. Two key questions pertain, including why and whether factors such as obesity impose differential risk in certain groups. As outlined by the authors, tantalizing associations and plausible mechanisms exist for a relationship between metabolic syndrome and stone disease and yet our understanding remains limited, particularly regarding a differential impact in individuals historically at lower risk. Ultimately turning the tide on urinary stone disease will require laser sharp focus on prevention and improving the health of the population.
Charles D. Scales, Jr. Department of Urology Duke University School of Medicine Durham, North Carolina
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