Published: Sep 5, 2014
By Salynn Boyles, Contributing Writer, MedPage Today

Action Points

• In a meta-analysis of cohort studies, a history of kidney stones was associated with an increased adjusted risk estimate for CHD and stroke.
• The data suggest that the risk may be higher in women than men.

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Development of kidney stones was associated with an increased risk for coronary heart disease (CHD) and stroke, and the risk appeared to be greater for women than men in a meta-analysis of six cohort studies.

The studies included close to 50,000 patients with kidney stones and 3.56 million controls. Pooled results found kidney stone history to be associated with a 19% greater risk for CHD (hazard ratio 1.19, 95% CI 1.05-1.35, P=0.05, in six cohorts) and a 40% greater risk for stroke (HR 1.40, 95% CI 1.20-1.82, P<0.001, in three cohorts), researcher Xue Qin, MD, PhD, of Guangxi Medical University, Nanning, China, and colleagues wrote online in the American Journal of Kidney Disease.

In pooled results, women showed a statistically significant increased risk for myocardial infarction (HR 1.49, 95% CI 1.21-1.82, in four cohorts), while men did not (HR 1.15, 95% CI 0.89-1.50, in two cohorts).

Kidney Stones May Be Riskier for Women

The researchers noted that a paucity of studies separately evaluating for effect modification by sex, along with other limitations, could explain the risk difference among men and women.

But they added that several recent studies have shown a gender difference in kidney stone-related CHD and stroke risk.

One was reported in JAMA in July 2013 by Pietro Ferraro, MD, of Columbus-Gemelli Hospital, Rome, and colleagues.

The prospective study included 45,748 men and 196,357 women in the U.S. without a history of CHD at baseline, including 19,678 who reported a history of kidney stones. Two cohorts of women (Nurses Health Study I and II) and one of men (Health Professionals Follow-up Study) were followed for up to 24 years.

After adjusting for potential confounders, women with a history of kidney stones had about an 18% increased risk for CHD in one cohort (NHS-I) and a 48% increased risk in another (NHS-II) compared with women who had never had a kidney stone. No significant association was seen in men (HR 1.06, 95% CI 0.99-1.13) and results were similar when the researchers analyzed fatal and nonfatal MI and revascularization.

Canadian Study Also Showed Sex Difference

An even larger study from Alberta, Canada, reported in March of this year, showed similar differences in risk by gender.

The cohort study included close to 3.2 million people registered in Alberta’s universal healthcare system between 1997 and 2009 who were followed for a median of 11 years.

After adjustment for estimated CVD risk and other potential confounders, people who had at least one kidney stone had a 40% higher risk for acute MI (adjusted HR 1.40, 95% CI 1.30-1.51), a 63% higher risk for revascularization (adjusted HR 1.63, 95% CI 1.51-1.76), and a 26% higher risk for stroke (adjusted HR 1.26, 95% CI 1.12-1.42) compared with those with no kidney stone history. The magnitude of increased risk appeared more pronounced for women than men (P=0.01).

Both studies were included in the newly-published meta-analysis.

Gary C. Curhan, MD, who was a co-author on both, said the new data make a strong case for a real gender difference in cardiovascular disease risk associated with kidney stone history.

Curhan is a professor of medicine at Harvard Medical School and a renal disease specialist at Brigham and Women’s Hospital, Boston.

“The risk certainly seems to be higher in women than men, but I would not say the risk is zero in men,” he told MedPage Today. “These two studies give us more confidence that this association is real. The next step is to try and answer the question ‘Why is there a difference?'”

Kidney Stones Increased Stroke Risk, MI in Women

The six cohort studies included in the new meta-analysis were published between 2005 and 2014. All six included results for CHD (MI and coronary revascularization) and four reported results for stroke as well.

The median duration of follow-up was 8.9 years (range 5 to 13.7) and all studies adjusted for at least five of seven major potential confounders: age, sex, BMI, hypertension, diabetes, lipid levels, and smoking. The six studies were considered fair (score 4 to 6) or good (score 7 to 9) on the Newcastle-Ottawa rating scale.

Among the main findings:

• CHD incidence was increased in patients with kidney stones relative to those without kidney stones, with HR of 1.19 (95% CI 1.05-1.35), which reached statistical significance (P=0.005), but with significant evidence of heterogeneity (I2=84.2%, P<0.001).
• Sensitivity analyses performed by omitting one study at a time in a stepwise fashion and calculating the pooled HR for the rest of the studies, revealed similar HRs without much fluctuation, ranging from a low of 1.13 (95% CI 1.00-1.27) to a high of 1.26 (95% CI 1.09-1.44), respectively.
• Several studies reported HRs and 95% CIs for CHD subtypes (MI and coronary revascularization) separately. Compared with patients without kidney stones, kidney stone disease was associated with both an increased risk of MI (HR 1.29, 95% CI 1.10-1.52, in six cohorts) and coronary revascularization (HR 1.31, 95% CI 1.05-1.65, in four cohorts), with evidence of heterogeneity for both subgroups (I2=84.8% and I2=95.4%, respectively).
• Several cohorts provided estimates of hazard ratios for myocardial infarction in men and women with kidney stones separately, with the pooled female cohorts showing a statistically significant association (HR 1.49, 95% CI 1.21-1.82, in four cohorts), whereas no association was seen in men (HR 1.15, 95% CI 0.89-1.50, in two cohorts).
• Three studies were used to evaluate the impact of kidney stones on stroke (Alexander et al, 2014,Chung et al, 2012, Li et al, 2005). Overall, having kidney stones appeared to be significantly associated with stroke risk compared with controls (HR 1.40, 95% CI 1.20-1.64), with modest evidence of heterogeneity (I2=66.8%, P=0.05).

Metabolic Disturbance May Explain Link

“Our study suggests that kidney stones might be an important contributor to the risk of vascular events, the potential mechanisms for the findings may be related to metabolic disturbances,” the researchers wrote, adding that obesity, high blood sugar, high cholesterol, and hypertension may contribute to a higher risk of uric acid and calcium stone formation.

“Other metabolic abnormalities presenting mostly in stone formers, such as hypercalciuria, hyperuricemia, and hyperoxaluria, may proceed through the lack of effective calcification inhibitors, which were found to be deficient in blood and urine,” they added. “This mechanism may be the potential link between cardiovascular disease and kidney stones.”

Curhan noted that kidney stones may also trigger low-grade inflammation that could increase cardiovascular risk, and that unrecognized shared risk factors for kidney stones and cardiovascular disease may be relevant.

“There are many different potential explanations for the association, but we don’t know the answer,” he told MedPage Today.

The researchers concluded that research is needed to better understand the association between kidney stones and cardiovascular risk.

“There is a need for well-designed prospective studies to determine whether the association is sex specific and to explore pathophysiologic mechanisms underlying this association,” they wrote.