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.

Keywords: Uric acid; cardiovascular disease (CVD); chronic kidney disease (CKD); diabetes; gout; hypertension; hyperuricemia; kidney function; review; serum urate; xanthine oxidoreductase.

Figure 1.

Transport pathways for urate in proximal tubule cells. (A) Urate reabsorption. Sodium-dependent anion transport by SMCT1 and SMCT2 increases intracellular concentrations of monovalent anions that exchange with luminal urate (URAT1/OAT10). OAT4 appears to exchange urate with divalent anions. GLUT9 is the exit pathway for urate at the basolateral membrane. (A) Urate secretion. Urate enters the cell at the basolateral membrane by exchange with α-ketoglutarate, mediated by OAT1 and OAT3. At the apical membrane, urate is secreted by MRP4, ABCG2, NPT1, and/or NPT4. Figure is copyright Annual Reviews and is reproduced from Mandal and Mount.

Figure 2.

Potential mechanisms by which urate may cause kidney disease. Urate may induce renal damage in its soluble (crystal-independent) or crystal form. After entering renal cells, soluble uric acid can activate various cascades and responses that lead to damaging inflammatory, proliferative, and maladaptive changes in glomeruli and the tubulointerstitium (TI). Crystalline uric acid seems to be confined to the TI, where it may elicit similar changes. Abbreviation: VSM, vascular smooth muscle.

Figure 3.

Mechanism of hyperuricemia-induced hypertension. Hyperuricemia-induced hypertension has been proposed to be a consequence of the effect of serum and/or intracellular urate to stimulate the renin-angiotensin-aldosterone system, lower endothelial nitric oxide, induce oxidative stress, and stimulate vascular smooth muscle cell proliferation, resulting in systemic and renal vasoconstriction and arteriolosclerosis leading to hypertension.