Hyperuricemia as a potential risk factor for type 2 diabetes and diabetic nephropathy

Correspondência para: Richard J Johnson. University of Colorado Anschutz Medical. Campus, Aurora, CO, 80045, USA. E-mail: richard.johnson@ ucdenver.edu O ácido úrico sérico tem recentemente sido considerado um biomarcador em potencial, independentemente prevendo o desenvolvimento de hipertensão, diabetes mellitus e doença renal crônica.1-3 Também foi relatado que o ácido úrico sérico elevado prediz o desenvolvimento de nefropatia no diabetes tipo 1.4-7 No entanto, pouco se sabe sobre o papel do ácido úrico sérico na predição de nefropatia no diabetes tipo 2. Neste número da Brazilian Journal of Nephrology, Fouad et al.8 realizaram um estudo caso-controle em adultos egípcios, com e sem diabetes tipo 2, comparados por idade, gênero e índice de massa corporal (IMC). O estudo incluiu 986 participantes; 250 controles nãodiabéticos: 352 com diabetes tipo 2 por menos de 5 anos e 384 com diabetes tipo 2 por mais de 5 anos. Os participantes dos três grupos eram igualmente obesos, com IMC médio entre 30 e 32 kg/m2. A observação mais importante foi que o ácido úrico sérico apresentou um aumento gradual entre os grupos e, globalmente, 32% dos indivíduos com diabetes tipo 2 exibiram hiperuricemia (definida como ácido úrico sérico > 7,0 mg/dl). Além disso, o aumento do ácido úrico sérico correlacionou-se com piora da hipertensão, da albuminúria e da função renal. O artigo é interessante por várias razões. Em primeiro lugar, alguns estudos sobre diabetes mellitus relataram que o ácido úrico sérico é menor do que o observado em indivíduos não diabéticos, o que tem sido atribuído ao aumento da TFG (hiperfiltração) e ao baixo Hiperuricemia como potencial fator de risco para diabetes tipo 2 e nefropatia diabética

5][6][7] Less is known, however, about the role of serum uric acid in predicting nephropathy in type 2 diabetes.
In this issue of the Brazilian Journal of Nephrology, Fouad et al. 8 performed a case-control study in Egyptian adults with and without type 2 diabetes that were matched for age, sex and body mass index (BMI).The study included 986 participants; 250 non-diabetic controls, 352 with type 2 diabetes for less than 5-years and 384 with type 2 diabetes for more than 5-years.
The participants of the three groups were similarly obese with mean BMI between 30 and 32 kg/m 2 .The most important observation was that serum uric acid showed a stepwise increase between groups, and overall 32% of subjects with type 2 diabetes demonstrated hyperuricemia (defined as serum uric acid > 7.0 mg/dl).Furthermore, the increase in serum uric acid correlated with worsening hypertension, albuminuria and kidney function.
The paper is interesting for several reasons.First, some studies of diabetes mellitus have reported serum uric acid to be lower than what is observed in nondiabetic subjects, and this has been attributed to elevated GFR (hyperfiltration) and poor glycemic control (elevated HbA1c). 9,10Bo et al. 11 , however, noted that subjects with

Hyperuricemia as a potential risk factor for type 2 diabetes and diabetic nephropathy
Hiperuricemia como potencial fator de risco para diabetes tipo 2 e nefropatia diabética type 2 diabetes with kidney disease tended to have higher serum uric acid levels.
In the study by Fouad et al. 8 the serum uric acid was higher in subjects with type 2 diabetes, with the highest levels of serum uric acid observed in those with poor glycemic control.One potential explanation provided by the authors was that their subjects already had kidney disease with falling eGFR, for which reason hyperfiltration that is commonly seen early in the course of diabetic kidney disease was not observed.
This may relate to the fact that in type 2 diabetes subjects often have other comorbidities including hypertension and/or vascular disease that may lead to earlier development of kidney disease than is normally observed during the initial years of type 1 diabetes.It is also possible that other risk factors may be playing an important role in causing early kidney disease in this population.One recently proposed risk factor is heat stress and dehydration, that may be more common among individuals living in hot environments. 12here are some limitations of the study worth mentioning.First, it is unclear if the elevated serum uric acid in subjects with type 2 diabetes simply reflects worse renal function among this group.It would have been interesting to determine if serum uric acid was elevated independently of the eGFR in subjects with type 2 diabetes.
Second, the study was cross-sectional, and hence it is not possible to determine causality, i.e. if elevated serum uric acid mediated the the development of nephropathy.Nevertheless, the observation that hyperuricemia was common in subjects with type 2 diabetes compared to non-diabetic control subjects with similar levels of obesity is fascinating, as is the stepwise increase in serum uric acid with duration of diabetes.
We have much more to learn about the role of uric acid in diabetes mellitus and diabetic kidney disease.Some early pilot studies suggest lowering serum uric acid can improve insulin resistance in subjects with heart failure or metabolic syndrome. 13,14Other small studies suggest lowering serum uric acid may improve diabetic nephropathy. 15t is also interesting that the potential benefit of lowering serum uric acid may be primarily in subjects who are not taking agents that block the renin angiotensin system.For example, one Egyptian study reported marked exacerbation of nondiabetic kidney disease when serum uric acid lowering agents were withdrawn, but only in those not taking ACE inhibitors. 16Currently there is a large clinical trial ongoing in the North America to determine if lowering serum uric acid can halt or delay the development of nephropathy in subjects with type 1 diabetes. 17t would seem important to design a similar study in subjects with type 2 diabetes.In the meantime, given the potential toxicities of allopurinol, we do not recommend routine lowering of serum uric acid in patients with type 2 diabetes, but would reserve such treatment for those with gout, uric acid stones, or those with marked hyperuricemia (serum uric acid > 9.0 mg/dl).