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American Journal of Kidney Diseases

Kidney Stones and the Risk of Coronary Heart Disease

      Commentary on Ferraro PM, Taylor EN, Eisner BH, et al. History of kidney stones and the risk of coronary heart disease. JAMA. 2013;310(4):408-415.
      Kidney stones, often considered a cause of transient—albeit severe, expensive, and time-consuming—discomfort, have recently been linked to many important comorbid conditions. Associations with diabetes, obesity, hypertension, gout, chronic kidney disease, and even the development of end-stage kidney disease have made stones look like something more worrisome than the average stone former may have been led to believe. Whether the association of kidney stones could be extended to coronary artery disease was considered in the article by Ferraro et al
      • Ferraro P.M.
      • Taylor E.N.
      • Eisner B.H.
      • et al.
      History of kidney stones and the risk of coronary heart disease.
      reviewed here.

      What Does This Important Study Show?

      This article showed that women, but not men, with a history of kidney stones had a higher rate of coronary heart disease (CHD; defined by fatal or nonfatal myocardial infarction or coronary revascularization) than comparable participants without a history of stones. Starting with participants with and without a history of kidney stones and without a history of CHD, a large number of people—more than 45,000 men from the Health Professionals Follow-up Study (HPFS) and more than 196,000 women from the Nurses' Health Study (NHS) I and II—were followed prospectively for a median of 9 years. With over 1.3 million person-years of follow-up, individuals with a history of stone disease in the older cohort of women (NHS I, mean age, 59 years) had a multivariable hazard ratio (HR) for development of total CHD of 1.18 (95% confidence interval [CI], 1.08-1.28) compared with women without stones; the younger cohort of women with stones (NHS II, mean age, 37.4 years), with 1.8 million person-years of follow-up, had a multivariable HR of 1.48 (95% CI, 1.23-1.78). Men with kidney stones drawn from the HPFS, where the mean age was 55.8 years, were no more likely to develop CHD than individuals who did not form stones, as seen in 0.8 million person-years of follow-up, with multivariable HR of 1.06 (95% CI, 0.99-1.13).
      Much of the knowledge gained in the last 20 years regarding the epidemiology of stones arises from these 3 cohorts, which have been followed by Curhan, Taylor, and co-investigators. There are many reasons these cohorts remain a reliable and continuous source of useful information about kidney stones. The cohorts are large, offering significant power to detect even weak associations of stones with other conditions. In other studies, participants with no prior history of stones could be followed to determine variables associated with the development of stones. For example, one seminal study of the HPFS over 20 years ago demonstrated that greater intake of dietary calcium was associated with fewer stones,
      • Curhan G.C.
      • Willett W.C.
      • Rimm E.B.
      • Stampfer M.J.
      A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones.
      while a second study, published nearly a decade ago, showed that the presence of obesity and weight gain increase the likelihood of stones.
      • Taylor E.N.
      • Stampfer M.J.
      • Curhan G.C.
      Obesity, weight gain, and the risk of kidney stones.
      These reports are all prospective observational studies, with both the strengths and limitations of that study design. Importantly, both the data regarding diagnoses, such as myocardial infarction, and variables, such as dietary intake, have been thoroughly validated. For instance, self-reported kidney stones were shown to be reported accurately in 97% of cases.
      • Curhan G.C.
      • Willett W.C.
      • Speizer F.E.
      • Spiegelman D.
      • Stampfer M.J.
      Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women.
      In the current study, myocardial infarction or coronary heart disease were carefully documented by state death certificates, National Death Index data, autopsy records, next of kin, and medical records, while self-reported revascularization was shown to be “virtually 100% specific,” likely in part reflecting that all participants are health care workers.
      • Rimm E.B.
      • Giovannucci E.L.
      • Willett W.C.
      • et al.
      Prospective study of alcohol consumption and risk of coronary disease in men.
      While the strengths are abundant, the weaknesses of these observational studies are inherent to the nature of the follow-up. These studies require multivariable adjustments that may fail to account for unanticipated or unknown confounders. In this case, perhaps some unknown variable or a known variable that was insufficiently accounted for is common to stone formers but not to non–stone formers and is responsible for the association between stone formation and increased development of coronary disease. The authors repeatedly caution that these cohorts are not representative of all populations in the United States or elsewhere, and that the participants, being motivated health professionals, may be composed of racial, socioeconomic, or geographic groupings that influence the findings. Finally, these observational studies reveal associations and not causal relationships; they must be viewed as hypothesis-generating investigations that could lead to interventional studies. Unfortunately, appropriate investigations have not always followed, though an important exception was the randomized trial showing that a diet higher in calcium intake (but lower in animal protein, oxalate, and sodium) reduced stone incidence in hypercalciuric Italian men.
      • Borghi L.
      • Schianchi T.
      • Meschi T.
      • et al.
      Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria.
      In this case, however, an intervention to explore the finding more fully is not easily designed.

      How Does This Study Compare With Prior Studies?

      Given associations with chronic kidney disease, obesity, weight gain, hypertension, diabetes, and metabolic syndrome, the finding that stone formers would have more coronary artery disease is not very surprising and has been shown before. These comorbid conditions were addressed in the multivariable analysis, but how well that adjustment dealt with possible known (and unknown) confounders cannot be determined. The authors meticulously detail previous related findings. Given the cohorts used and the longitudinal method, with substantial follow-up, this is probably the most rigorous paper on the subject yet published.
      That an association between kidney stones and CHD would be observed in women and not men is both surprising and currently inexplicable, although a cross-sectional study in Portugal showed an association of stones with myocardial infarction in women only.
      • Domingos F.
      • Serra A.
      Nephrolithiasis is associated with an increased prevalence of cardiovascular disease.
      A prior longitudinal study of all stone formers in Olmsted County, MN showed that the multivariable-adjusted HR for development of myocardial infarction in men and women stone formers compared with non–stone formers was 1.31 (95% CI, 1.02-1.69), but the study did not assess whether this association differed between men and women.
      • Rule A.D.
      • Roger V.L.
      • Melton 3rd, L.J.
      • et al.
      Kidney stones associate with increased risk for myocardial infarction.
      In a different study using these same NHS and HPFS cohorts, diabetes was associated with a higher prospective risk of stones in women but not in men.
      • Taylor E.N.
      • Stampfer M.J.
      • Curhan G.C.
      Diabetes mellitus and the risk of nephrolithiasis.
      We know little about why kidney stones affect more men than women: most recently, the prevalence of kidney stones in the US was 10.6% in men and 7.1% in women.
      • Scales C.D.
      • Smith A.C.
      • Hanley J.M.
      • Saigal C.S.
      Prevalence of kidney stones in the United States.
      Coronary heart disease also is more common in men than in women, although rates in older women do rise toward those in men. It is therefore surprising that even in the younger NHS II cohort, women stone formers were significantly more likely to develop CHD.
      Do differing associations among men and women with stones suggest different genetic etiologies? We previously showed that male monozygotic twins were about twice as likely as male dizygotic twins to be concordant for a history of stones, demonstrating a strong heritable contribution to stones in the general population.
      • Goldfarb D.S.
      • Fischer M.E.
      • Keich Y.
      • Goldberg J.
      A twin study of genetic and dietary influences on nephrolithiasis: a report from the Vietnam Era Twin (VET) Registry.
      We now have shown a very similar effect for monozygotic concordance to exceed that of dizygotic concordance in a population of women, which suggests that the strength of the genetic contribution to stones in women is similar to that in men.
      • Goldfarb D.S.
      • Noonan C.
      • Goldberg J.
      A twin study of genetic influences on nephrolithiasis in women and men.
      While this suggests that heritability of the kidney stone trait is similar in men and women, the responsible genotypes remain obscure.

      What Should Clinicians and Researchers Do?

      As an alternative to relating stones to CHD via shared, unidentified risk factors, the authors cite Stoller et al's “vascular etiology.”
      • Stoller M.L.
      • Meng M.V.
      • Abrahams H.M.
      • Kane J.P.
      The primary stone event: a new hypothesis involving a vascular etiology.
      This proposal suggests that kidney stones are initiated by a vascular injury. The result would implicate some disorder leading to calcification of both blood vessels and nephrons. A more speculative approach would be to relate the current finding to the well-known association of hypercalciuria and calcium stones with low bone mineral density. That association has led to the hypothesis that kidney stones are the result of osteoclast activation, which leads to a release of calcium and hypercalciuria, with the kidney injured as an innocent bystander.
      • Weisinger J.R.
      Bone loss in hypercalciuria: cause or consequence?.
      Since loss of bone mineral density recently has been related to vascular calcification, another distinctive mechanism of mutual vessel and nephron injury may be worth investigating.
      • Asci G.
      • Ok E.
      • Savas R.
      • et al.
      The link between bone and coronary calcifications in CKD-5 patients on haemodialysis.
      It would be interesting to note if the women with stones who developed CHD also had a different bone mineral density than women who did not develop CHD, and whether men with and without stones also are affected differently.
      Could an intervention prevent CHD in women with kidney stones? The outcomes of interest are relatively infrequent in women compared with men; accordingly, a large sample of women stone formers would be required. It is difficult to imagine an appropriate intervention: would one randomize half a group of women stone formers to statins, exercise, aspirin, smoking cessation, exercise, or dietary manipulation? Doing the same for men when the observational study does not support the association of stones with CHD would not be practical either.
      If an intervention arising from these observations seems unlikely, what could clinicians take away from this study? If the linkage of stones to a growing list of serious comorbid conditions suggests that stones be taken as a wake-up call, they may earn new respect. They may represent a sentinel event in the health of an individual. Rather than simply advising that the afflicted persons—whether men or women, young or old—simply “drink a lot,” we should advise patients to regard stones as a cardiac and metabolic risk factor. Stones apparently represent something unhealthy happening to endothelium, bone mineral density, insulin sensitivity, and kidney function. We may remain uncertain and even vague about the causal links between these conditions, but we do know how to promote better health in general and cardiovascular and kidney health in particular.
      If kidney stones are viewed as the first sign of metabolic dysregulation in otherwise healthy people, particularly in individuals lacking other established risk factors for CHD, stones can lead to earlier calls for weight loss, exercise, and sodium restriction. The motivation necessary to address these variables can arise from stones, which are tangible and memorable harbingers, and this could lead to a greater impact before the sequelae of hypertension, cardiovascular disease, and diabetes are evident. Taking a kidney stone as a clarion call may lead to abstinence from soda and fructose intake, with stones and other cardiovascular morbidities diminished.
      • Taylor E.N.
      • Curhan G.C.
      Fructose consumption and the risk of kidney stones.
      A modest increase in low fat dairy intake also may reduce stone recurrence
      • Curhan G.C.
      • Willett W.C.
      • Rimm E.B.
      • Stampfer M.J.
      A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones.
      while encouraging better bone mineral density, and, as part of the Dietary Approaches to Stop Hypertension diet, lower blood pressure.
      • Taylor E.N.
      • Fung T.T.
      • Curhan G.C.
      DASH-style diet associates with reduced risk for kidney stones.
      The effectiveness of regarding stones as a cardiac risk factor has not been and will not be tested in randomized controlled trials. Instead, such recommendations seem prudent, reasonable, and inexpensive, if brought to our patients and the public as part of a thoughtful approach to disease prevention.

      Acknowledgements

      Support: None.
      Financial Disclosure: The author declares that he has no relevant financial interests.

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