Is there a risk of cardiovascular disease in renal stone formers? Giovanni Gambaro, Rome, Italy

Chairs: Pascal Houillier, Paris, France Piergiorgio Messa, Milan, Italy

Prof. Giovanni GambaroNephrology Division

Department of Internal Medicine and Medical SpecialtiesColumbus-Gemelli University Hospital

Rome, Italy

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Chairman and dear colleagues.

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The question I was thinking of before knowing that the first presentation was not going to bepresented, I was thinking about saying that after this presentation, certainly there's noproblem to understand that there is a cardiovascular disease risk in renal stone formers.

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Anyway, renal stone disease is a quite frequent condition.

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According to the NHANES study, the prevalence has grown from 4% to 9% in 20 years. Now,the prevalence in the United States is around 9%. A very similar prevalence has been foundrecently in Italy in an urban population in Florence.

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So this condition is very frequent, although it is generally considered benign, a trivial disorderin terms of comorbidities and mortalities. On the other hand, the disease is frequentlyassociated to a number of systemic conditions which can increase the cardiovascular risk perse.

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It is associated to obesity, to high blood pressure,

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to nephrolithiasis, to diabetes and to CKD. So it is a working hypothesis that perhapsnephrolithiasis is also linked to cardiovascular disease

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because it is associated to conditions at cardiovascular risk factors. However, there are veryfew data supporting this idea.

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The first data started almost 40 years ago in Sweden and they were a bit contradictory. Arecent paper from a cross-sectional study in a Portuguese population has strengthened

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the topic showing that females have an increased prevalence of myocardial infarction if theyare stone formers with an odds ratio of 57% more than the control females. This study wasadjusted for a number of covariates in particular the traditional cardiovascular risk factors.

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In a study published in an abstract form in the Journal of Urology in 2009 in a female cohort atrisk of osteoporosis they looked for cardiovascular outcomes.

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They found that the risk was higher in stone forming females in reference to myocardialinfarction, angina and congestive heart failure. The follow-up was quite long.

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But a more interesting study is this one from the Olmsted County cohort which is a cohort ofalmost 5.000 people with 10.000 controls followed up for 9 years and they found that

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the stone formers had an increased risk of cardiovascular outcomes, 30% more compared tocontrols.

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Generally speaking, these kinds of studies have some caveats in reference to the low numberof cardiovascular events. The populations are generally not sufficiently powered todemonstrate a strong association with cardiovascular outcomes. Furthermore, most of themhave not been adjusted for the nutritional intakes and drug treatments.

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So to overcome these problems, a study has been performed merging 3 cohorts from GaryCurhan's laboratory in Boston, the Health Professional follow-up study including male medicaldoctors more than 50.000 male medical doctors and 2 huge cohorts of nurses from theNurses Health Studies 1 and 2. These two cohorts differ for the date of enrolment and alsofor the age of enrolment being this cohort younger than the first cohort.

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The endpoints, which were looked for, were the composite of myocardial infarction and needsfor coronary artery revascularisation

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and the analysis was adjusted for demographic factors. I call your attention to menopausalconditions, to the comorbidities in particular, the cardiovascular comorbidities, the drug use inparticular I call your attention to thiazide diuretics and oestrogen replacement therapy.Finally, to the daily intake of nutrients in particular calcium, vitamin D and the kind of diet wasalso evaluated in a general way using the DASH-score.

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So the final population was of 250.000 people with a cumulative follow-up of 60 years andalmost 17.000 incident cardiovascular events. So the final population and the number ofevents were very strong and sufficiently robust to demonstrate an association, if anassociation exists.

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The finding that there was no different risk in stone formers and non-stone formers in males.These are the data from the composite and the secondary cardiovascular outcomes in theHealth Professional follow-up study, so male doctors.

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However, when we looked at the female cohort, there was a strong association, especially inthe second cohorts for all the outcomes. I remind you that this is the younger age cohort.These are younger females than in the first cohort and these data are essentially consistentwith those that should have been presented by the missing presentation

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from Todd Alexander from the Alberta cohort. The Alberta cohort is a huge cohort of over 3million people, indeed almost 4 million with a median follow-up of 11 years. They found thatindeed the female stone formers had a higher risk of developing cardiovascular outcomescompared to males. A younger age, which means less than 50 years, is associated with astronger risk of developing cardiovascular outcomes. I mean that if the stone is formed before50 years of age, the risk of developing also a cardiovascular outcome is higher. So, this is aresult which is very consistent with what we found.

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So the preliminary conclusion from these studies is that the prospective studies on the largecohorts demonstrated an association between nephrolithiasis and cardiovascular morbidities

in females. However, such an association does not depend on the cardiovascular risk factors.

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So I'll show you that hypertension, obesity, diabetes and CKD are associated tonephrolithiasis and this association could explain the increased cardiovascular risk.

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However, the adjustment that we did in the 3 Boston cohorts demonstrated that theassociation between nephrolithiasis and the cardiovascular risk is independent from the othertraditional cardiovascular risk factors. So, there is some missing factors that we do notmeasure, we do not recognise which link nephrolithiasis with the cardiovascular system.

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We wonder whether the metabolic bone disease could be this missing phenomenon and thereason for this, the rationale was that the reduced mineral bone density is quite a frequentobservation in stone formers, particularly in calcium stone formers. Furthermore, there is aninverse relationship between the bone mineral density and the arterial stiffness andfurthermore, the arterial stiffness is a strong proxy of cardiovascular morbidity and mortality.

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We looked for the pulse wave velocity, so the stiffness of the aorta and other arteries inidiopathic calcium stone formers and we found that the pulse wave velocity was increased instone formers as well as the augmentation index suggesting that these patients, the stoneformers, the calcium idiopathic stone formers have more rigid arteries. There was anassociation also with the bone mineral density in these stone formers.

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Another poster presented in this congress from Guy's Hospital in London has shown datawhich is consistent with our findings because in a small population of renal stone formersthey evaluated a score of abdominal aortic calcification, and they found that the idiopathiccalcium stone formers had a higher score of calcification in comparison with secondary stoneformers.

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So the hypothesis that I'm proposing to you, just a working hypothesis is that the missing linkbetween nephrolithiasis and the cardiovascular morbidity

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is through metabolic bone disease and vascular stiffness and calcification which can be thecommon link between the cardiovascular system and renal stone disease. Thank you for yourattention.

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Chairman: Thank you. Thank you Giovanni for this very, very clear hypothesis that is veryintriguing to connect again the bone also to nephrolithiasis. It's an old hypothesis but this isrenewed by this new point of view. Are there any questions on these points or on someothers of course from the audience? Giovanni, I would like to go back to these three bigstudies the Nurse and the Health Professional, which are completely in female and malepatients. Do you think that the missing information on calcium supplementation, for examplein the female patients which could be much more induced to consume calcium for theprevention of osteoporotic disease at least in the second study where older patients in thecohorts might be at some extent influence or affect this relationship to some extent?

Prof. Gambaro: Actually, we corrected for the calcium supplements. So I don't think this is thereason. It is difficult to explain why the females have a higher risk in comparison to males. Onthe other hand, it is not astonishing because there are many other data, many other reportssuggesting that female gender can influence differently the outcome. In the Alberta cohort,the risk of ESRD is higher in females than in male stone formers. The risk of diabetes isincreased in female stone formers and not in male stone formers. The risk of obesity andmetabolic bone disease is higher in female stone formers and not in male stones formers. Sothis is not astonishing, it is difficult to understand why. I guess that probably just to link theyoung age and the female gender, I guess that probably and this is just speculation, there isa stronger genetic background in females. I mean generally in females stone disease is lessprevalent. So I imagine that being a female stone former, it needs to have a stronger geneticbackground. Furthermore, to develop renal stones earlier, it means I have a stronger geneticbackground. If such genetic background for stone formation is also associated in some way tothe cardiovascular disease risk, then we may explain, it could be possible to explain why theyounger females have such a strong association.

Chairman: Are females much more environmental with a much more genetic background?

Prof. Gambaro: Yes, I think so.

Chairman: Any more questions?

Question: What's the evidence that metabolic bone disease is the primary event in calciumstone disease? You suggested that metabolic bone disease could be the primary event inboth stone disease and cardiovascular risk. What's the evidence that metabolic bone diseaseis the primary event?

Prof. Gambaro: In some diseases other than renal stone disease, an inverse relationship hasbeen established between bone disease and the rigidity of the pulse wave velocity ofarteries. This is the case of osteoporotic females. Also in CKD there is an inverse relationship.This was the reason why we went to speculate that something like this was also happeningin stone formers. So, I don't know why there is such an inverse relationship. Perhaps thebone can be viewed as a buffer for calcium. If this buffer does not work correctly, then thevessels can be another buffer. But this is just speculation and I imagine that there is muchmore elegant molecular biological explanation of such a relationship. But the epidemiology is

that there is an inverse relationship in a number of clinical conditions.

Chairman: Ok, if there are no more questions… there is another one. Could you please go tothe microphone in order for us to hear better?

Question: Is there any relation between the type of stone and the cardiovascular risk?

Prof. Gambaro: We don't know because these studies involved epidemiological cohorts so weonly have the information of being renal stone formers. We tried to develop this conceptbecause this is a very important question. Admitting that the excess of cardiovascular risk isdue to gout. Let us consider that it is only the hyperuricemic stone formers. Then if we alsoconsider this, we cannot explain all the increased risk. This is the reason why I think that thecalcium idiopathic stone formers are possibly one of the involved populations in explaining theincreased cardiovascular risk. It is not easy to investigate further this issue. We are trying tomerge data from a big laboratory that performed a good quality analysis of stones because itis not sufficient to say calcium oxalate, calcium phosphate, it is necessary to go deeper in thecharacterization of the stone composition. But we are trying to do it. Thank you. - Well, thankyou we now have two free communications.