Effect of a Reduction in Uric Acid on Renal Outcomes During Losartan Treatment

Abstract

Abstract-Emerging data show that increased serum uric acid (SUA) concentration is an independent risk factor for end-stage renal disease. Treatment with the antihypertensive drug losartan lowers SUA. Whether reductions in SUA during losartan therapy are associated with renoprotection is unclear. We therefore tested this hypothesis. In a post hoc analysis of 1342 patients with type 2 diabetes mellitus and nephropathy participating in the Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan Trial, we determined the relationship between month 6 change in SUA and renal endpoints, defined as a doubling of serum creatinine or end-stage renal disease. Baseline SUA was 6.7 mg/dL in placebo and losartan-treated subjects. During the first 6 months, losartan lowered SUA by Ϫ0.16 mg/dL (95% CI: Ϫ0.30 to Ϫ0.01; Pϭ0.031) as compared with placebo. The risk of renal events was decreased by 6% (95% CI: 10% to 3%) per 0.5-mg/dL decrement in SUA during the first 6 months. This effect was independent of other risk markers, including estimate glomerular filtration rate and albuminuria. Adjustment of the overall treatment effects for SUA attenuated losartan's renoprotective effect from 22% (95% CI: 6% to 35%) to 17% (95% CI: 1% to 31%), suggesting that approximately one fifth of losartan's renoprotective effect could be attributed to its effect on SUA. Losartan lowers SUA levels compared with placebo treatment in patients with type 2 diabetes mellitus and nephropathy. The degree of reduction in SUA is subsequently associated with the degree in long-term renal risk reduction and explains part of losartan's renoprotective effect. These findings support the view that SUA may be a modifiable risk factor for renal disease. (Hypertension. 2011;58:2-7.)Key Words: serum uric acid Ⅲ angiotensin receptor blocker Ⅲ losartan Ⅲ diabetic nephropathy Ⅲ type 2 diabetes mellitus O ver the past decades, serum uric acid (SUA) has emerged as a cardiovascular risk marker. Increased SUA has been shown to predict the risk of hypertension, diabetes mellitus, and cardiovascular disease. [1][2][3] More recent data also point to SUA as a risk marker for progression of chronic kidney disease. 4,5 These observations raise the question as to whether interventions that lower uric acid could confer cardiovascular or renal protection. In this respect, the angiotensin receptor blocker losartan is of potential interest. The drug has been clearly demonstrated to be renoprotective in patients with diabetic nephropathy, with this effect largely attributed to its effects on blood pressure and/or proteinuria/albuminuria. 6 However, it is unclear whether other off-target effects of the drug could contribute to the ultimate improvement in renal outcome with this agent. Importantly, previous studies have shown that losartan lowers SUA. This hypouricemic effect does not occur with other angiotensin receptor blockers 7 and appears to be largely mediated through reductions in the level of human urate transporter 1 (URAT1) ...

Linking uric acid metabolism to diabetic complications

“…SUA is an independent risk factor for CKD, even without diabetes [57] . SUA is known to be associated with disease progression in the early stage of diabetic nephropathy [17,58] . We found that the progression of renal dysfunction in patients with type 2 diabetic overt nephropathy with an SUA concentration of ≥ 6.3 mg/dL carries a poor prognosis, even though their SUA range is considered high-normal [59] .…”

Endothelin-A Receptor Antagonism Modifies Cardiovascular Risk Factors in CKD

“…More recently, the angiotensin-receptor blocker losartan has been shown to decrease serum uric acid in a group of patients with type 2 diabetes and nephropathy, and this reduction was associated with a reduction in CKD progression. 23 ETreceptor antagonism offers a potentially novel approach to decreasing serum uric acid in patients with proteinuric CKD.…”

The effect of angiotensin II receptor blockers on hyperuricemia

“…Although beyond the scope of this review, other clinically meaningful results unrelated to gout manifestations have been reported. Losartan has demonstrated renoprotective effects directly related to the degree of serum uric acid lowering; however, these endpoints were not explored in the included studies that enrolled patients with baseline hyperuricemia or a gout diagnosis [Ito et al 2012;Miao et al 2011].…”