In the present study, we explored the association between a potentially modifiable risk factor, serum uric acid levels and the development of either micro- or macroalbuminuria in a well-characterized cohort of patients with type 1 diabetes who had participated in the CACTI study over a 6-year follow-up period. Our results indicate that baseline serum uric acid levels are a strong predictor of the development of micro- or macroalbuminuria at 6 years, independent of HbA1c and of degree of pre-albuminuria, in patients with type 1 diabetes.
Few studies have explored the relationship between uric acid and diabetic kidney disease in patients with type 1 diabetes. A recent cross-sectional analysis by Rosolowsky et al.
in patients with type 1 diabetes demonstrated that high normal serum uric acid levels were independently associated with lower GFR as estimated from the serum concentration of cystatin C [11
]. In addition, a prospective observational study by Hovind et al.
found baseline serum uric acid levels to be predictive macroalbuminuria over an 18-year follow-up period in 263 patients with type 1 diabetes [12
]. Consistent with their results, our study demonstrates that serum uric acid levels are a powerful predictor of the future development of micro- or macroalbuminuria in patients with type 1 diabetes.
Controversy exists as to whether uric acid plays a pathological role in endothelial dysfunction and kidney disease in humans [21
]. Uric acid is a potent antioxidant and when administered acutely may actually improve endothelial function [22–24
]. Nevertheless, recent experimental evidence suggests that uric acid may induce oxidative stress once it enters cells, and as such it may be a mediator of disease. In animals, mild hyperuricemia induced by the administration of a uricase inhibitor results in endothelial dysfunction [8
] and hypertension [9,10
], both of which resolve once uric acid levels are lowered. In a recent study by Kosugi et al.
, allopurinol treatment of diabetic (db/db) mice significantly lowered uric acid levels, reduced albuminuria and ameliorated tubulointerstitial injury, suggesting a role for uric acid in diabetic nephropathy [25
]. Mild hyperuricemia was further shown to induce renal microvascular disease independent of blood pressure, as a consequence of activation of the renin–angiotensin–aldosterone system [26
], and by inhibition of intrarenal production of nitric oxide [27
Our study has several limitations. First, albuminuria was our primary outcome and a clinically more relevant endpoint would have been end-stage renal disease or cardiovascular events and mortality; however, we are limited in sample size and duration of follow-up, and hence are not able to assess either outcome. Second, in the absence of reliable markers of early decline in GFR [28
], we cannot exclude the possibility that the rise in serum uric acid is but a sensitive marker of early kidney disease. Nevertheless, this does not preclude it from being a potentially modifiable risk factor for cardiovascular and renal complications of diabetes. Finally, the higher baseline levels of serum uric acid in the patients who developed micro- or macroalbuminuria may have identified a group of individuals at greater risk of developing DN due to other manifestations of metabolic syndrome. Although examination of baseline characteristics showed no significant differences between both groups with regard to blood pressure and body weight, the CACTI study is an observational epidemiologic study and not an interventional one, so recommendations with regard to therapies aimed at actually lowering serum uric acid levels cannot be made based on these results.
In conclusion, our results indicate that serum uric acid levels are a strong predictor of micro- or macroalbuminuria in patients with type 1 diabetes. Measuring serum uric acid levels routinely may help identify a group of patients at higher risk of developing diabetic complications. Further studies are needed to confirm these findings and to examine the impact of lowering serum uric acid levels on diabetic complications in patients with type 1 diabetes.