Ambient temperature as a contributor to kidney stone formation: implications of global warming
Authors: Robert J. Fakheri, David S. Goldfarb
Journal: Kidney International (2011)

Nephrolithiasis is a common disease across the world that is becoming more prevalent. Although the underlying cause for most stones is not known, a body of literature suggests a role of heat and climate as significant risk factors for lithogenesis. Recently, estimates from computer models predicted up to a 10% increase in the prevalence rate in the next half century secondary to the effects of global warming, with a coinciding 25% increase in health-care expenditures. Our aim here is to critically review the medical literature relating stones to ambient temperature. We have categorized the body of evidence by methodology, consisting of comparisons between geographic regions, comparisons over time, and comparisons between people in specialized environments. Although most studies are confounded by other factors like sunlight exposure and regional variation in diet that share some contribution, it appears that heat does play a role in pathogenesis in certain populations. Notably, the role of heat is much greater in men than in women. We also hypothesize that the role of a significant human migration (from rural areas to warmer, urban locales beginning in the last century and projected to continue) may have a greater impact than global warming on the observed worldwide increasing prevalence rate of nephrolithiasis. At this time the limited data available cannot substantiate this proposed mechanism but further studies to investigate this effect are warranted. Nephrolithiasis is a common disease across the world that is becoming more prevalent. Although the underlying cause for most stones is not known, a body of literature suggests a role of heat and climate as significant risk factors for lithogenesis. Recently, estimates from computer models predicted up to a 10% increase in the prevalence rate in the next half century secondary to the effects of global warming, with a coinciding 25% increase in health-care expenditures. Our aim here is to critically review the medical literature relating stones to ambient temperature. We have categorized the body of evidence by methodology, consisting of comparisons between geographic regions, comparisons over time, and comparisons between people in specialized environments. Although most studies are confounded by other factors like sunlight exposure and regional variation in diet that share some contribution, it appears that heat does play a role in pathogenesis in certain populations. Notably, the role of heat is much greater in men than in women. We also hypothesize that the role of a significant human migration (from rural areas to warmer, urban locales beginning in the last century and projected to continue) may have a greater impact than global warming on the observed worldwide increasing prevalence rate of nephrolithiasis. At this time the limited data available cannot substantiate this proposed mechanism but further studies to investigate this effect are warranted. With the continued threat of global warming in the news, physicians have lately given much attention to the impact of climate change on human health and health care.1.Wilson J.F. Facing an uncertain climate.Ann Intern Med. 2007; 146: 153-156Crossref PubMed Scopus (3) Google Scholar The hypothesis that global warming might also increase the rate of renal calculi dates at least as far back as 1989.2.Curtin J. Sampson M. Greenhouse effect and renal calculi.Lancet. 1989; 2: 1110Abstract PubMed Scopus (6) Google Scholar More recently, an article in the Proceedings of the National Academy of Sciences projected the effect of climate change on the incidence of nephrolithiasis (Figure 1).3.Brikowski T.H. Lotan Y. Pearle M.S. Climate-related increase in the prevalence of urolithiasis in the United States.Proc Natl Acad Sci USA. 2008; 105: 9841-9846Crossref PubMed Scopus (231) Google Scholar Although the authors claim a 'well established dependence of nephrolithiasis on mean annual temperature,' the link between the two has never been proven unequivocally; in their paper, the authors later concede that 'the precise relationship between ambient temperature and stone risk remains unknown.' Our objective here is to review the medical literature regarding the relationship between temperature and stone formation. Ambient temperature has been a putative risk factor for nephrolithiasis for quite some time, but distinguishing its effects from other complex factors has been impossible in individual epidemiologic studies. When comparing two different geographic locations, there are many possible confounding explanations for differences in stone incidence or prevalence such as humidity, exposure to sunlight, diet, and genetics. Each of these potential causes for nephrolithiasis can invoke a physiologically plausible effect. The mechanism for higher temperatures causing stone disease is attributed to heat-induced sweating. Loss of extracellular fluid leads to an increase in serum osmolality that in turn causes increased secretion of vasopressin (antidiuretic hormone) by the posterior pituitary, leading to increased urinary concentration and reduced urinary volume. As urinary concentration increases, the concentration of relatively insoluble salts, such as calcium oxalate, increases. When the concentration of these salts increases such that their activity exceeds their upper limit of solubility, the salts precipitate out of solution and form solid crystals that develop into stones. The mechanism for humidity contributing to stone formation is similar: when humidity is low and the air is dry, more water is lost through the skin and, again, urinary volume falls and urinary concentration increases. Whether these mechanisms cause stone formation regardless of where stones originate (renal interstitium or urinary space) is unknown.4.Evan A.P. Lingeman J.E. Coe F.L. et al.Randall's plaque of patients with nephrolithiasis begins in basement membranes of thin loops of Henle.J Clin Invest. 2003; 111: 607-616Crossref PubMed Scopus (493) Google Scholar, 5.Coe F.L. Evan A.P. Worcester E.M. et al.Three pathways for human kidney stone formation.Urol Res. 2010; 38: 147-160Crossref PubMed Scopus (156) Google Scholar Exposure to sunlight is hypothesized to be an alternative explanation for the apparent relationship of ambient temperature to stone prevalence. We will explore whether data support this mechanism in the section on alternative hypotheses. The pertinent data that relate to the link between temperature and stone formation can be organized into three categories: (1) comparisons of stone incidence or prevalence in different regions of a single, contiguous geographic area; (2) comparisons of stone incidence over time in a single area—both by comparing seasons in a single year and comparing year after year changes; and (3) comparisons of specialized, thermally different environments to the normal environment of a given population. In the United States, Soucie et al.6.Soucie J.M. Thun M.J. Coates R.J. et al.Demographic and geographic variability of kidney stones in the United States.Kidney Int. 1994; 46: 893-899Abstract Full Text PDF PubMed Scopus (230) Google Scholar looked at data from nationwide surveys to map out the prevalence of kidney stones. The primary findings of the study were in stone prevalence based on geography. They found trends that stone prevalence increased from North to South and West to East. The North-to-South trend correlates well with temperature variation, but the role of climate in the West-to-East trend is much more ambiguous. In fact, the hottest states like Texas, Florida, and Louisiana had lower prevalence than cooler states like North Carolina and South Carolina. Differences in stone prevalence among different races were noted but whether they were accounted for by geographic, genetic, or dietary variation was not elucidated. In a follow-up analysis by Soucie et al.7.Soucie J.M. Coates R.J. McClellan W. et al.Relation between geographic variability in kidney stones prevalence and risk factors for stones.Am J Epidemiol. 1996; 143: 487-495Crossref PubMed Scopus (171) Google Scholar, the relation between stone prevalence and specific risk factors such as mean temperature, sunlight index, and beverage consumption was examined. For males, sunlight exposure explained more of the regional variation than mean annual temperature or beverage consumption. For women, beverage consumption, average temperature, and sunlight index each explained regional variation more or less equally, but even after adjustment for differences in all three risk factors, the regional variation in the odds of stones was still largely unexplained, unlike in males. It was speculated that some of the unexplained variation in the Southeast was because of an enriched gene pool that was prone to lithogenesis. We reanalyzed the data and plotted the prevalence rates for each state against ambient temperature data corresponding to the time the data were collected (Figure 2).8.Fakheri R.J. Goldfarb D.S. Association of nephrolithiasis prevalence rates with ambient temperature in the United States: a re-analysis.Kidney Int. 2009; 76: 798Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar There is clearly a correlation between temperature and stone prevalence rates for men, but a limited and questionable correlation, although a statistically significant one, for women. We suggested that men had a much steeper effect of increasing ambient temperature on stone prevalence than women because men work outdoors more frequently than women; data supporting this conjecture are not available.8.Fakheri R.J. Goldfarb D.S. Association of nephrolithiasis prevalence rates with ambient temperature in the United States: a re-analysis.Kidney Int. 2009; 76: 798Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar Changes in the proportion of women working outdoors may have increased since 1982 and changed the slope of the relationship between ambient temperature and stone prevalence. These data are consistent with a study of stone-formers that showed that men, but not women, had lower urine volumes in summer, with higher calcium oxalate supersaturation.9.Parks J.H. Barsky R. Coe F.L. Gender differences in seasonal variation of urine stone risk factors.J Urol. 2003; 170: 384-388Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Urine pH fell in men, but not in women, contributing to a difference in the risk of uric acid stones as well. No explanation to account for these differences was offered. The authors noted that men and women probably sweat to a similar degree as evidenced by their reduced urine sodium excretion, but women are better at replenishing losses. Perhaps, if men work outside more commonly than women, the mechanism, instead of relating to volume depletion from increased perspiration, could be from the limited access to water when working outdoors. Another possible explanation for the different gender response to temperature is the different stone composition in men versus women. Although struvite stones are only ∼10% of all stones, women suffer from them proportionally more often than men: ∼3:1 female-to-male ratio.10.Kristensen C. Parks J.H. Lindheimer M. et al.Reduced glomerular filtration rate and hypercalciuria in primary struvite nephrolithiasis.Kidney Int. 1987; 32: 749-753Abstract Full Text PDF PubMed Scopus (40) Google Scholar As struvite stones are related to infection, rather than to the urinary supersaturation of calcium salts, one would not expect them to be associated with environmental factors. This may partially explain the gender difference in relation to changes in stone prevalence rates with respect to temperature. As struvite is a relatively infrequent component of stones even among women, the relative flatness of the relationship remains otherwise unexplained. Few data regarding any purported effects of ambient temperature on stone composition are available. One study from Australia showed a trend for both calcium oxalate and uric acid stones to increase in the summer, with only the latter reaching statistical significance.11.Baker P.W. Coyle P. Bais R. et al.Influence of season, age, and sex on renal stone formation in South Australia.Med J Aust. 1993; 159: 390-392PubMed Google Scholar In Iran, a positive correlation between stone prevalence and both temperature and sunlight index was found for both men and women.12.Safarinejad M.R. Adult urolithiasis in a population-based study in Iran: prevalence, incidence, and associated risk factors.Urol Res. 2007; 35: 73-82Crossref PubMed Scopus (88) Google Scholar As in the United States, however, a stronger effect of temperature for men than for women was noted. The odds ratio for stones was almost twice as high in the hottest, most sunny parts of the country than in the coldest, least sunny parts. Other countries have conducted similar epidemiological studies. Most are smaller in area than the United States and span fewer latitudes. Therefore, there may be some uncertainty as to whether the range of ambient temperatures is sufficient to detect changes in stone prevalence. In Taiwan, there are regional differences in stone prevalence rates but no correlation between stone prevalence and mean temperature.13.Lee Y.H. Huang W.C. Tsai J.Y. et al.Epidemiological studies on the prevalence of upper urinary calculi in Taiwan.Urol Int. 2002; 68: 172-177Crossref PubMed Scopus (92) Google Scholar In Turkey, a national study showed higher prevalence of stone formation in the hottest geographic areas, South and Southeast, but the differences in prevalence rates were not quantitated.14.Akinci M. Esen T. Tellaloglu S. Urinary stone disease in Turkey: an updated epidemiological study.Eur Urol. 1991; 20: 200-203PubMed Google Scholar In the United Kingdom, an analysis of hospital discharge rates found a trend toward higher incidence of stones in the southern regions of England.15.Barker D.J. Donnan S.P. Regional variations in the incidence of upper urinary tract stones in England and Wales.Br Med J. 1978; 1: 67-70Crossref PubMed Scopus (31) Google Scholar But when this was further analyzed, no correlation was found. Regional variation was probably explained by patients of higher socioeconomic status in the south being admitted more frequently.16.Power C. Barker D.J. Blacklock N.J. Incidence of renal stones in 18 British towns. A collaborative study.Br J Urol. 1987; 59: 105-110Crossref PubMed Scopus (23) Google Scholar Whereas higher socioeconomic status could lead to stone formation via changes in diet (for example, higher intake of animal protein), an analysis of dietary variation in the United Kingdom found that consumption of fat, protein, and meat products was in fact inversely correlated with admission rates for stone disease.17.Barker D.J. Morris J.A. Margetts B.M. Diet and renal stones in 72 areas in England and Wales.Br J Urol. 1988; 62: 315-318Crossref PubMed Scopus (12) Google Scholar Similarly to the British study, in Sudan it was noted that urolithiasis is common in the northern region, farther from the Equator, but relatively rare in the southern region.18.Kambal A. Wahab E.M. Khattab A.H. Urolithiasis in Sudan. Geographical distribution and the influence of climate.Trop Geogr Med. 1979; 31: 75-79PubMed Google Scholar Statistical analysis did not demonstrate any correlation between mean annual temperature or relative humidity and incidence of calculi. The observed variation may have been because of sampling bias as the data were collected from surgical operations for urolithiasis. In Israel, the regional variation of urolithiasis was studied in the 1950s.19.Frank M. De Vries A. Atsmon A. et al.Epidemiological investigation of urolithiasis in Israel.J Urol. 1959; 81: 497-505Abstract Full Text PDF PubMed Scopus (40) Google Scholar There was no simple association with climate. Interestingly enough, the country of origin of the inhabitants of the settlements seemed to play an important role. A later study in Israel of the hot, arid Negev region found similar results in terms of association with climate and country of origin.20.Frank M. Atsmon A. Sugar P. et al.Epidemiological investigation of urolithiasis in the hot arid Southern region of Israel.Urol Int. 1963; 15: 65-76Crossref PubMed Scopus (18) Google Scholar Moreover, the average incidence rate of 2.4% was twice that of the previous study of northern and central Israel that has a milder climate. Other evidence supporting the role of temperature in the pathogenesis of stone disease has been seasonal variation with higher incidence rates during the warmer summer months than the colder winter months. These studies cannot clearly separate effects of ambient temperature from those of sunlight exposure. One of the first studies to analyze the relation between seasonal variation in temperature and stone incidence was done in Leeds, Great Britain.21.Robertson W.G. Peacock M. Marshall R.W. et al.Seasonal variations in the composition of urine in relation to calcium stone-formation.Clin Sci Mol Med. 1975; 49: 597-602PubMed Google Scholar The investigators analyzed 24-h urine samples from 246 male stone-formers. The data demonstrated statistically significant changes from the minimum value for both calcium and oxalate, with maximum values in the summer. No changes were observed in pH or volume. Rates of stone passage were also increased in the summer. The variation correlated with changes in both ambient temperature and hours of sunlight. A similar, but smaller, study was conducted in Finland.22.Elomaa I. Karonen S.L. Kairento A.L. et al.Seasonal variation of urinary calcium and oxalate excretion, serum 25(OH)D3 and albumin level in relation to renal stone formation.Scand J Urol Nephrol. 1982; 16: 155-161Crossref PubMed Scopus (21) Google Scholar Over the course of a year, the authors studied 11 normocalciuric stone-formers, 11 hypercalciuric stone-formers, 10 healthy subjects, and 14 long-stay hospital patients. The results showed that serum levels of 25-hydroxyvitamin D, urinary calcium, and urinary oxalate were all elevated in the summer for all groups except the hospitalized patients who showed no changes. Moreover, the levels of 25-hydroxyvitamin D were higher throughout the year in hypercalciuric stone-formers than normocalciuric stone-formers. These changes correlated temporally with increases in sunlight measured by units of ultraviolet light. Serum calcium was unchanged in all four groups. The limitations to this study include the small sample size and demographic differences between groups (for example, the long-stay hospital patients were mostly females, whereas the other groups were mostly or all males). Seasonal variation was also evaluated in Kuwait.23.Salem S.N. bu Elezz L.Z. The incidence of renal colic and calculi in Kuwait. An epidemiological study.J Med Liban. 1969; 22: 747-755PubMed Google Scholar By looking at emergency room visits for renal colic, the authors found 980 cases of colic in the summer versus only 524 cases in the winter. These totals respectively corresponded to 7.0 and 3.8% of emergency room visits. Statistical analysis was not presented. When comparing the incidence of stones in a given month to the mean temperature of the previous month, an Iraqi study found that temperature and stone incidence were correlated with threefold as many cases in the peak summer months compared with the trough winter months.24.Al-Dabbagh T.Q. Fahadi K. Seasonal variations in the incidence of ureteric colic.Br J Urol. 1977; 49: 269-275Crossref PubMed Scopus (28) Google Scholar For comparison with other studies, the 200% increase corresponded to a difference of ∼25 °C in mean monthly temperature. Conspicuously, females were excluded from this study. Likewise, in Saudi Arabia, in a 3-year study of emergency room visits, regression analysis found a statistically significant correlation between the mean monthly temperature and the number of males presenting with urinary colic (R=0.67).25.al-Hadramy M.S. Seasonal variations of urinary stone colic in Arabia.J Pak Med Assoc. 1997; 47: 281-284PubMed Google Scholar The difference between the peak and troughs was ∼100% change in incidence, corresponding to ∼12 °C, which is roughly consistent with the data from Iraq. Notably, this Saudi analysis failed to show any correlation with relative humidity, the fasting month of Ramadan or the pilgrimage festival. Again, females were not included in this study. In Varmin, Iran, the incidence of hospital admission for renal colic in the summer months was higher than in the winter with statistical significance; regression analysis was not presented.26.Basiri A. Moghaddam S.M. Khoddam R. et al.Monthly variations of urinary stone colic in Iran and its relationship to the fasting month of Ramadan.J Pak Med Assoc. 2004; 54: 6-8PubMed Google Scholar As in the Saudi Arabian study, the fasting month of Ramadan did not demonstrate a higher incidence of renal colic. Studies in Japan found higher incidence rates in the summer months and lower incidence rates in the winter months in both Tokyo and in a rural area; however, quantitative statistical analysis was not performed.27.Fujita K. Epidemiology of urinary stone colic.Eur Urol. 1979; 5: 26-28PubMed Google Scholar, 28.Fujita K. Weather and the incidence of urinary stone colic.J Urol. 1979; 121: 318-319PubMed Google Scholar, 29.Fujita K. Weather and the incidence of urinary stone colic in Tokyo.Int J Biometeorol. 1987; 31: 141-146Crossref PubMed Scopus (6) Google Scholar In Taiwan, there were similar findings with a cyclical pattern of urinary calculi attack rates.30.Chen Y.K. Lin H.C. Chen C.S. et al.Seasonal variations in urinary calculi attacks and their association with climate: a population based study.J Urol. 2008; 179: 564-569Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar As in most other studies, the male attack rate was significantly higher than that for females. Moreover, in the summer months, the attack rate went up on average ∼100% for men whereas only up 30% for women even from the much lower winter baseline. The seasonal variation in the Taiwanese study correlated primarily with ambient temperature and additionally with hours of sunshine. When a similar study of seasonal variation was performed in the United States, the change was not quite as dramatic.31.Chauhan V. Eskin B. Allegra J.R. et al.Effect of season, age, and gender on renal colic incidence.Am J Emerg Med. 2004; 22: 560-563Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar The authors measured the percentage of renal colic visits out of total emergency department visits from 15 hospitals in New Jersey over a period of 7 years. The proportion of visits was 14% higher in the summer compared with the winter, which corresponded to approximately a 20 °C difference. With regard to gender, the ratio of visits in warmer versus colder months was significantly higher for males. Although these data are in line with previous reports, using percentage of emergency department visits may have confounded their results because of an increase in the number of emergency department visits in the winter for other reasons such as respiratory infections. More recently, this question of seasonal variation was approached in Italy with more sophisticated computational methods.32.Boscolo-Berto R. Dal M.F. Abate A. et al.Do weather conditions influence the onset of renal colic? A novel approach to analysis.Urol Int. 2008; 80: 19-25Crossref PubMed Scopus (39) Google Scholar The authors attempted to overcome the limitations of previous studies that either (1) compared stone incidence with month but did not correlate with temperature or (2) compared the incidence in a given month with only the average temperature of the month. Thus, this study took each individual subject and looked at the temperature of the preceding 15, 30, 45, and 60 days to better estimate the temperature exposure of each individual. The correlation with renal colic was statistically significant with a stronger correlation in the shorter time frames. Humidity was also studied by a similar computational analysis and this had an inverse correlation with renal colic. Given the trend of stronger correlation with shorter time periods, it is unclear if a time period <15 days would have had an even stronger correlation with colic. Although all the above authors found some association between urolithiasis and seasonal variation, some other investigators found no appreciable association in their studied population. Most of these reports have come from studies of Scandinavian populations (for example, Sweden33.Almby B. Meirik O. Schonebeck J. Incidence, morbidity and complications of renal and ureteral calculi in a well defined geographical area.Scand J Urol Nephrol. 1975; 9: 249-253Crossref PubMed Scopus (28) Google Scholar, 34.Ahlstrand C. Tiselius H.G. Renal stone disease in a Swedish district during one year.Scand J Urol Nephrol. 1981; 15: 143-146Crossref PubMed Scopus (43) Google Scholar and Finland35.Juuti M. Heinonen O.P. Incidence of urolithiasis leading to hospitalization in Finland.Acta Med Scand. 1979; 206: 397-403Crossref PubMed Scopus (14) Google Scholar). In general, they lack rigorous statistical analysis and temperature data, and hence their value is limited. In Norway, it was reported that renal colic presented more commonly in the winter months than in the summer months.36.Laerum E. Urolithiasis in general practice. An epidemiological study from a Norwegian district.Scand J Urol Nephrol. 1983; 17: 313-319Crossref PubMed Scopus (20) Google Scholar In Mumbai, perhaps because of a range of mean temperature of only ∼10 °F between summer and winter, no seasonal variation was evident.37.Hussain F. Billimoria F.R. Singh P.P. Urolithiasis in northeast Bombay: seasonal prevalence and chemical composition of stones.Int Urol Nephrol. 1990; 22: 119-124Crossref PubMed Scopus (14) Google Scholar Another curious study was from Calgary, Alberta, Canada, that found a bimodal seasonal variation with peaks in September and January, but troughs in March and July (statistical analyses not presented).38.Levinson A.A. Mandin H. Seasonal variations in the incidence of kidney stones in Calgary, Alberta, Canada.Clin Nephrol. 1985; 24: 50-51PubMed Google Scholar In addition to the seasonal variation in the incidence of stone disease, some authors have looked at changes in prevalence rates over many years. Although these increases in incidence may reflect hotter climates from global warming, changes in diet and other behaviors confound the role of temperature. A report from the United Kingdom observed that in the summer months of 1989, there were more cases of renal calculi than in 1988 (58 vs 39).2.Curtin J. Sampson M. Greenhouse effect and renal calculi.Lancet. 1989; 2: 1110Abstract PubMed Scopus (6) Google Scholar They also reported that the average daily temperature and total hours of sunlight were increased in the latter year, 18.2 versus 16.1 °C and 1117 versus 726 h, respectively. Thus, a 53% increase in the hours of sunlight and a 2.1 °C increase in temperature were associated with a 48% increase in the incidence rate of kidney stones. In the United States, an increasing prevalence of stones in the period of 1988–1994 compared with the period of 1976–1980 was observed.39.Stamatelou K.K. Francis M.E. Jones C.A. et al.Time trends in reported prevalence of kidney stones in the United States: 1976-1994.Kidney Int. 2003; 63: 1817-1823Abstract Full Text Full Text PDF PubMed Scopus (1142) Google Scholar In males, the increase was from 4.9 to 6.3%, a relative increase of 29%, with a similar increase in females from 2.8 to 4.1%, a relative increase of 46%. From the earlier to the later surveyed period, mean annual temperature in the United States rose 0.5 °C.3.Brikowski T.H. Lotan Y. Pearle M.S. Climate-related increase in the prevalence of urolithiasis in the United States.Proc Natl Acad Sci USA. 2008; 105: 9841-9846Crossref PubMed Scopus (231) Google Scholar Although this increase in ambient temperature might contribute to increasing stone prevalence, the relatively greater increase in female stone prevalence is not most consistent with a temperature-related change based on the evidence presented above. Studies in Italy, Japan, and Germany also show increases in stone prevalence over similar intervals, measured over the last 20–30 years.40.Serio A. Fraioli A. Epidemiology of nephrolithiasis.Nephron. 1999; 81: 26-30Crossref PubMed Scopus (103) Google Scholar, 41.Trinchieri A. Coppi F. 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[Statistical observation of urolithiasis at the Hokkaido University Hospital (1959–1975) (author's transl)].Hokkaido Igaku Zasshi. 1978; 53: 322-327PubMed Google Scholar These worldwide increases in stone prevalence are variously ascribed to improved detection rates and changes in diet such as 'Westernization' and increasing prevalence of diabetes, hypertension, and obesity, all associated with greater risk for stones.45.Obligado S.H. Goldfarb D.S. The association of nephrolithiasis with hypertension and obesity: a review.Am J Hypertens. 2008; 21: 257-264Crossref PubMed Scopus (139) Google Scholar Any contribution to incre