Asymptomatic hyperuricaemia in chronic kidney disease: mechanisms and clinical implications

Abstract

Asymptomatic hyperuricaemia (HU) is considered a pathogenic factor in multiple disease contexts, but a causative role is only proven for the crystalline form of uric acid in gouty arthritis and urate nephropathy. Epidemiological studies document a robust association of HU with hypertension, cardiovascular disease (CVD) and CKD progression, but CKD-related impaired uric acid (UA) clearance and the use of diuretics that further impair UA clearance likely accounts for these associations. Interpreting the available trial evidence is further complicated by referring to xanthine oxidase inhibitors as urate-lowering treatment, although these drugs inhibit other substrates, so attributing their effects only to HU is problematic. In this review we provide new mechanistic insights into the biological effects of soluble and crystalline UA and discuss clinical evidence on the role of asymptomatic HU in CKD, CVD and sterile inflammation. We identify research areas with gaps in experimental and clinical evidence, specifically on infectious complications that represent the second common cause of death in CKD patients, referred to as secondary immunodeficiency related to kidney disease. In addition, we address potential therapeutic approaches on how and when to treat asymptomatic HU in patients with kidney disease and where further interventional studies are required.

Keywords: asymptomatic hyperuricemia; cardiovascular disease; chronic kidney disease; gout; infection; uric acid.

Graphical Abstract

Figure 1:

The differential effects of soluble versus crystalline UA on innate immune cells and tubular epithelial cells. Crystalline UA (known as MSU crystals in gouty arthritis) triggers activation of the NLRP3 inflammasome complex following phagocytosis in macrophages, which results in the production of IL-1β, leading to an inflammatory cascade. Crystalline UA can also directly activate macrophages, likely through a signaling pathway that involves the Syk and JNK kinases, leading to cytokine production and metabolic reprogramming. UA crystals can also interact with receptors such as CLEC12a and SIRL-1 on the cell surface of immune cells and trigger the release of ROS and NETs via a RIPK3–MLKL-mediated cell death pathway (necroptosis), but also macrophage extracellular traps. In contrast, soluble UA suppresses these pro-inflammatory responses in activated cells. For example, soluble UA inhibits the pro-inflammatory function of human CD14⁺ blood monocytes through SLC2A9-mediated intracellular uptake of soluble UA. In macrophages, soluble UA reduces the production of ROS, and the release of IL-1β and IL-6 under hypoxic/inflammatory conditions, while enhancing fatty acid oxidation and mitochondrial dynamics, similar to that observed in tubular epithelial cells. In neutrophils, soluble UA impairs the β2 integrin activity and internalization/recycling by regulating intracellular pH and cytoskeletal dynamics that alter the migratory and phagocytic capacity of neutrophils. Soluble UA is known to scavenge ROS under hydrophilic conditions, thereby inhibiting lipid peroxidation as well as Akt phosphorylation in endothelial cells and modulating the activity of extracellular superoxide dismutase in atherosclerotic vessels. Akt, protein kinase B (PKB); CLEC12a, C-type lectin domain family 12 member A; ERK, extracellular signal-regulated kinase; IL-1β, interleukin-1β; JNK, c-Jun N-terminal kinase; METs, macrophage extracellular traps; MLKL, mixed lineage kinase domain-like protein; NETs, neutrophil extracellular traps; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; RIPK3, receptor interacting serine/threonine kinase-3; ROS, reactive oxygen species; Syk, spleen tyrosine kinase; SLC2A9, glucose transporter 9; SIRL-1, signal inhibitory receptor on leukocytes-1; WASP, Wiskott–Aldrich syndrome protein.

Figure 2:

The clinical implications of asymptomatic versus symptomatic HU. Experimental and clinical evidence implies that HU has a causative role in gouty arthritis, urolithiasis and kidney stones as well as in acute and chronic UA nephropathy. All diseases are caused by crystalline UA, which triggers pro-inflammatory responses in the kidney and joints, referred to symptomatic HU. In contrast, soluble UA/asymptomatic HU has now been shown to not cause kidney injury and contribute to the progression of CKD unless UA crystallizes in the kidney. Confirmation comes from large multicentre RCTs with ULT that have disproven a causal relationship of asymptomatic HU with CKD progression. Currently the role of asymptomatic HU in CKD-related CVD and the contribution to the acquired or secondary immunodeficiency (increased risk for infection) in patients with CKD is not well understood. Some recent findings indicate that soluble UA impairs the phagocytic capacity of human neutrophils and that HU patients with kidney disease are at a higher infection risk. Further studies are needed to clarify this. More recent experimental and clinical evidence indicates that soluble UA/asymptomatic HU suppresses sterile forms of inflammation by impairing immune cell functions, e.g. in the context of gouty arthritis in advanced CKD.

Figure 3:

The schematic illustrates how to manage asymptomatic and symptomatic HU in patients with CKD according to the current clinical evidence. In CKD patients with asymptomatic HU, ULT is not beneficial and therefore not recommended to slow down CKD progression. This accounts also for CKD and ESKD patients with cardiovascular complications; due to the lack of RCTs with ULT in these patients, causality has not been proven. Data on asymptomatic HU and infectious complication are sparse because experimental and clinical evidence are needed to identify the physiological effects of UA and to test whether ULT improves host defence in CKD/ESKD patients. In CKD patients with symptomatic HU, patients with gout flares and for gout prophylaxis should be treated with corticosteroids or IL-1 inhibitors (e.g. anakinra, canakinumab) as well as with ULT (e.g. allopurinol, febuxostat, benzbromarone). This also applies to ESKD patients with gouty arthritis. Caution should be exercised when giving colchicine and ULT due to potential side effects (e.g. allopurinol hypersensitivity syndrome, recurrence of acute gout attacks). Patients with CKD/ESKD should be examined for the presence of UA crystals in the urine and the urine pH measured to identify patients with chronic UA nephropathy. Treatment with ULT in these patients is currently not recommended due to the lack of RCTs.