Hyperuricemia in Kidney Disease: A Major Risk Factor for Cardiovascular Events, Vascular Calcification, and Renal Damage

Abstract

Kidney disease, especially when it is associated with a reduction in estimated glomerular filtration rate, can be associated with an increase in serum urate (uric acid), suggesting that hyperuricemia in subjects with kidney disease may be a strictly secondary phenomenon. Mendelian randomization studies that evaluate genetic scores regulating serum urate also generally have not found evidence that serum urate is a causal risk factor in chronic kidney disease. Nevertheless, this is countered by a large number of epidemiologic, experimental, and clinical studies that have suggested a potentially important role for uric acid in kidney disease and cardiovascular disease. Here, we review the topic in detail. Overall, the studies strongly suggest that hyperuricemia does have an important pathogenic role that likely is driven by intracellular urate levels. An exception may be the role of extracellular uric acid in atherosclerosis and vascular calcification. One of the more striking findings on reviewing the literature is that the primary benefit of lowering serum urate in subjects with CKD is not by slowing the progression of renal disease, but rather by reducing the incidence of cardiovascular events and mortality. We recommend large-scale clinical trials to determine if there is a benefit in lowering serum urate in hyperuricemic subjects in acute and chronic kidney disease and in the reduction of cardiovascular morbidity and mortality in subjects with end-stage chronic kidney disease.

Keywords: Hyperuricemia; acute kidney injury; allopurinol; cardiovascular mortality; chronic kidney disease.

Figure 1.. Mechanisms of Hyperuricemia in the Subject with CKD.

A decline in kidney function is associated with a reduction in urinary urate excretion. This may be compounded by diuretic use, and an elevated body mass index (BMI), especially when accompanied by hyperinsulinemia, can be associated with decrease uric acid excretion. Hypertension (HTN) may also reduce urate excretion, possibly related to renal vasoconstriction. While fractional excretion of renal urate excretion incrases, as well as increased compensatory excretion by the gut, these mechanisms cannot fully correct the uric acid (UA) imbalance. As a result, approximately half of subjects with CKD have hyperuricemia at the time of initiation of dialysis.

Figure 2.. Proposed mechanism of uric acid-induced acute kidney injury.

Hyperuricemia may increase the risk for AKI via both crystal-independent and crystal-dependent pathways. Hyperuricemia appears to affect renal hemodynamics, causing renal vasoconstriction, impaired autoregulation and increased glomerular pressure, while it can also affect tubular function, leading to inflammatory responses, oxidative stress, epithelial mesenchymal transition, and apoptosis. Crystalluria may also contribute to tubular injury. Key: RBF: renal blood flow; RAS: renin-angiotensin-aldosterone system; NO: nitric oxide; VSMC: vascular smooth muscle cell; VEC: vascular endothelial cell; GFR: glomerular filtration rate; MCP-1: monocyte chemoattractant protein-1; ICAM: intercellular adhesion molecule; PTC: proximal tubular cell; TLR: Toll-like receptor.

Figure 3.. Potential Mechanisms for Uric acid Involvement in Atherosclerosis, Vascular Calcification, and Cardiovascular Disease.

Uric acid may be generated in endothelial cells, causing local vascular smooth muscle cell proliferation and migration via the release of PDGF, and inflammation by the release of MCP-1, with facilitation of oxidation of LDL. Urate may then be deposited in plaque, in which crystals may act as a nidus for calcium deposition and vascular calcification potentially resulting in accelerated atherosclerosis. Urate deposits may also serve as a nidus for local intravascular inflammation that may stimulate atherogenesis and/or lead to adjacent inflammatory plaque