Calcium nephrolithiasis, metabolic syndrome and the cardiovascular risk.

Sakhaee et al. [1] in this issue have investigated whether the risk of the common calcium nephrolithiasis is associated with the metabolic syndrome (MS). This question is interesting since it deals with a more general problem on whether calcium nephrolithiasis is a ‘systemic disorder’ [2, 3] and entails a cardiovascular (CV) risk. The concept of nephrolithiasis as a systemic disease was first addressed by Baggio and Gambaro [4] after the finding that idiopathic calcium oxalate stone formers have a lower plasma concentration of gamma-linolenic acid and a higher concentration of arachidonic acid (AA) than healthy controls and that supplementation with fish oil lowers urinary calcium and oxalate [5]. It was suggested that stone formers have a systemic imbalance between the essential fatty acid (EFA) omega-3 and the omega-6 pathways which causes higher phospholipid AA level responsible for hypercalciuria and hyperoxaluria. Although a subsequent study could not confirm these results since reduced levels of AA were found in stone formers’ red blood cell membranes, it was observed that these levels were relatively higher in hyperoxaluric stone formers compared to normo-oxaluric patients [6]. In a subsequent study, higher plasma AA was again observed in stone formers, as well as higher serum PGE2, 25-vitamin D and 1,25 vitamin D [7]. Elevated urinary levels of bone turnover markers were also found in the stone formers [7]. Supplementation with fish oil in the same study induced a reduction in AA, 1,25 vitamin D and hydroxyproline suggesting that phospholipid AA levels influence an array of calcium disturbance mechanisms, including bone loss and kidney stone formation. However, although stimulating the omega-3 cascade can induce a urinary milieu which is less supportive of lithogenesis, the same favourable outcome was also achieved by stimulating the omega-6 pathway [8] suggesting that the relationship between EFA and renal stones could be more complex, possibly explaining why, in large prospective cohorts, no relationship between renal stone episodes and omega-6 and omega-3 EFA intake was demonstrated [9]. One should also expect that a systemic disorder in AA metabolism could also lead to alterations in the CV system, namely to atherosclerosis, but this was not investigated. In addition to the AA metabolism disorder, it has been reported that patients with kidney stones suffer from other non-renal manifestations like metabolic bone disease, MS and CV disease. They will be discussed separately. With respect to metabolic bone disease, it is evident that stone patients have a larger risk of being exposed to this disorder [10], although the pathogenetic link is still controversial [11]. Several papers have suggested an association between nephrolithiasis and MS [12], but which stones are passed by patients affected by MS is not clear. They certainly have a significant risk to form uric acid stones since a reasonable pathophysiological link with MS and allied conditions has been discovered [13]: in fact, some of the MS features (high blood glucose—type 2 diabetes, obesity), possibly because of the insulin-resistance, have an abnormally low urine pH which favours uric acid crystallization. However, whether they also pass an increased number of calcium stones is unknown. The article by Sakhaee et al. [1] leaves this question largely unanswered. The authors have indirectly addressed this issue by investigating the urinary calcium stone risk in patients with MS, with and without previous renal stones. Their data could suggest that calcium oxalate stones are also very common in MS patients. However, the finding that, in the nonstone-forming group, an association exists between urinary stone risk factors and number of features of MS, while this is lost in stone formers, may indicate that actually the calcium stone-driving mechanisms are not triggered by MS. On the other hand, the ‘clinical’ relevance of the association between urinary calcium stone risk factors with the MS in non-stone formers is questionable; indeed, these subjects have not (yet?) formed stones. Thus, the study of Sakhaee et al. [1] may support the idea that the association between MS and nephrolithiasis is largely driven by uric acid stones rather than by an increased propensity of patients with MS to form calcium stones. Two recent papers have described the relationship between renal stones and CV disease. Rule et al. [14], in