Hyperuricemia, Acute and Chronic Kidney Disease, Hypertension, and Cardiovascular Disease: Report of a Scientific Workshop Organized by the National Kidney Foundation

Abstract

Urate is a cause of gout, kidney stones, and acute kidney injury from tumor lysis syndrome, but its relationship to kidney disease, cardiovascular disease, and diabetes remains controversial. A scientific workshop organized by the National Kidney Foundation was held in September 2016 to review current evidence. Cell culture studies and animal models suggest that elevated serum urate concentrations can contribute to kidney disease, hypertension, and metabolic syndrome. Epidemiologic evidence also supports elevated serum urate concentrations as a risk factor for the development of kidney disease, hypertension, and diabetes, but differences in methodologies and inpacts on serum urate concentrations by even subtle changes in kidney function render conclusions uncertain. Mendelian randomization studies generally do not support a causal role of serum urate in kidney disease, hypertension, or diabetes, although interpretation is complicated by nonhomogeneous populations, a failure to consider environmental interactions, and a lack of understanding of how the genetic polymorphisms affect biological mechanisms related to urate. Although several small clinical trials suggest benefits of urate-lowering therapies on kidney function, blood pressure, and insulin resistance, others have been negative, with many trials having design limitations and insufficient power. Thus, whether uric acid has a causal role in kidney and cardiovascular diseases requires further study.

Involvement of Arterial Stiffness and Inflammation in Hyperuricemia-Related Development of Hypertension

“…5,6 However, arterial stiffness, renal dysfunction, and inflammation have also been reported to be associated with AN indicates annual examination; baPWV, brachial-ankle pulse wave velocity; CRP, C-reactive protein; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; start, start of the study period; SBP, systolic blood pressure; total, all study subjects included in the analysis; and UA, uric acid.…”

“…Renal dysfunction elevates the BP via several mechanisms such as sodium retention, sympathetic activation, etc. 6,20 Inflammation is also a risk factor for the development of hypertension via several mechanisms. 21 Conventional observational studies, in which the relevant assessments are conducted at 2 observational points, have the limitation that they exclude the effects of time-varying confounders on the association of the explained variables with the outcome variables.…”

“…In addition, experimental studies have demonstrated that hyperuricemia contributes to the development of hypertension via activation of the renin-angiotensin system, increased oxidative stress, loss of nitric oxide synthase activity, renal microvascular changes, etc. 6,22,23 However, the mechanisms underlying the risk of hypertension associated with hyperuricemia in clinical settings still remain unclear. Gaffo et al 24 proposed the existence of a causal association of hyperuricemia with cardiovascular disease, both independent and that mediated by other risk factors for cardiovascular disease.…”

“…5 Thus, we attempted to verify the possibility of involvement of these risk factors in the risk of development of hypertension associated with hyperuricemia. 6 Although an observational study would be needed for such an objective, conventional observational studies, in which the relevant assessments are conducted at 2 observational points, have the limitation that they exclude the effects of timevarying confounding variables.7 However, analysis of repeated measures data by mixed model linear (MML) regression analysis and general estimated equation (GEE) analysis may be useful to minimize the effects of time-varying confounders. In the present prospective observational study conducted in Japanese men without hypertension at the study baseline, we analyzed repeated measures data by MML regression analysis and GEE analysis to clarify the longitudinal associations of hyperuricemia with the above-mentioned risk factors for the development of hypertension, and then to examine the longitudinal associations of these risk factors with the development of hypertension.…”

“…5 Thus, we attempted to verify the possibility of involvement of these risk factors in the risk of development of hypertension associated with hyperuricemia. 6 Although an observational study would be needed for such an objective, conventional observational studies, in which the relevant assessments are conducted at 2 observational points, have the limitation that they exclude the effects of timevarying confounding variables. 7 However, analysis of repeated measures data by mixed model linear (MML) regression analysis and general estimated equation (GEE) analysis may be useful to minimize the effects of time-varying confounders.…”