Table 2.

Analysis of the association between hyperuricemia and cardiovascular disease using Hill's considerations

Consideration	Comment in view of current evidence
Strength	Associations with hypertension and cardiovascular mortality are not found to be particularly strong (relative risks and hazard ratios usually do not duplicate baseline risks) [10]. An exception is the strong association being recently described with chronic kidney disease [47].
Consistency	Limited evidence. Most associations have been described in North American and European Caucasian populations. Some large epidemiological studies are not in favor of the association.
Specificity	Not applicable for the most part. Cardiovascular diseases are complex and have multiple sufficient causative models, of which hyperuricemia could be considered an additional component cause. On the other hand, hyperuricemia is considered causative of other disease processes, like gout. The question of hyperuricemia being a causative factor for cardiovascular disease at all, or just a well-hidden confounder, has not been conclusively answered.
Temporality	Evidence from prospective studies has established a temporal relation between hyperuricemia and hypertension, stroke, cardiovascular mortality, and chronic kidney disease.
Biologic gradient	Large epidemiological studies in mortality of cardiovascular diseases and development of chronic kidney disease have established compelling dose-dependent relationships with population concentrations of serum urate [36-38,47].
Plausibility	In view of information provided by basic and animal models, plausibility is good.
Coherence	Remaining questions about its role in cardiovascular disease given its antioxidant properties [50]. Oxidative stress is considered a factor in atherosclerosis and cardiovascular disease, so can serum urate be a detrimental factor?
Experimental evidence	Experiments in animal models have added urate-lowering agents to revert renal vascular disease caused by hyperuricemia [15,51]. Initial experiences in treating hypertension, ischemic heart disease, and progression of chronic kidney disease have been published [23,24,34,48].
Analogy	Additional explanations, mainly that the relation between serum urate and cardiovascular diseases is not independent, have been progressive addressed. However, more evidence is needed.