Chronic Kidney Disease and Urate

Effects of Elevated Urate and MSU Crystals in Chronic Kidney Disease

• Elevated urate levels in patients with CKD stages 3-5 are associated with endothelial dysfunction, vascular smooth muscle cell proliferation, increased IL-6 synthesis, elevated systolic blood pressure, and lower glomerular filtration rate.
• Serum urate levels > 7 mg/dL correlated with worsening renal function independent of age, gender, race, diabetes, hypertension, alcohol use, smoking, lipids, and baseline renal function.
• Retrospective study of 12,751 CKD patients showed that achieving a target serum urate of < 6 mg/dL in CKD stages 2 and 3 was associated with a 30% higher likelihood of eGFR improvement.
• In vitro, ex vivo, and some clinical studies have shown the effect of urate lowering on kidney function, but there is limited prospective evidence of intervention and slowing the progression of CKD.
• Randomized trial of febuxostat in asymptomatic hyperuricemia patients with stage 3 CKD found no significant difference in eGFR slope compared to placebo, but the placebo group only had a 1% decline in eGFR.
• Study comparing allopurinol and febuxostat versus standard of care in CKD stage 3 patients with hyperuricemia showed that the febuxostat group had significantly lower mean serum urate, higher mean eGFR, and longer renal survival time free from disease progression.
• MSU crystallization depends on urate concentration and other factors, such as increased concentration, decreased temperature, and local factors promoting nucleation and crystal growth.
• Only a fraction of hyperuricemic patients develop clinical gout, and some patients have normal serum urate levels during acute gout attacks, indicating a complex relationship between serum urate level and MSU crystallization.
• Urate levels decrease during an acute gout attack, possibly due to the uricosuric effects of inflammatory mediators and hormone production.
• MSU crystals activate an inflammatory cascade in leukocytes, leading to the production of IL-1 and IL-18, and cause the release of reactive oxygen and nitrogen species, resulting in necroinflammation.
• Crystal-induced inflammation involves the release of stimulatory molecules, fueling the recruitment of innate immune cells into the synovium and surrounding soft tissue, mediated by pattern-recognition receptors.
• MSU crystals, along with other crystal types, can cause direct cytotoxicity and inflammation-driven cytotoxicity, referred to as necroinflammation.

Urate Transport and its Clinical Relevance

• URAT1 is a crucial apical urate exchanger in the proximal tubule, playing a key role in urate homeostasis physiology.
• The URAT1 protein is encoded by the SLC22A12 gene, and GLUT9 (SLC2A9) is responsible for basolateral urate transport in the proximal tubule.
• ABCG2 is an ATP-binding cassette transporter involved in renal and gastrointestinal urate excretion, handling diverse compounds.
• Organic anion transporters (OAT) significantly impact urate retention and elimination from the kidney.
• Recent studies suggest a potential uricosuric effect of SGLT2 inhibitor, indicating urate transport across SGLT2.
• Gut eliminates 20-30% of urate daily in healthy individuals, yet the mechanism of extra-renal urate elimination remains unclear.
• ABCG2 contributes to intestinal urate excretion, emphasizing direct intestinal secretion as a factor in urate elimination.
• Hyperuricemia is defined as serum urate concentration >6.8 mg/dL, with gout prevalence rising with increases in serum urate.
• Higher serum urate levels are linked to increased risk of diabetes, metabolic syndrome, elevated BMI, hypercholesterolemia, hypertriglyceridemia, and insulin resistance.
• Elevated serum urate levels are associated with adverse cardiovascular effects, including hypertension, cardiovascular and cerebrovascular events, heart failure, and multiple mechanisms of cardiovascular disease.
• Lowering urate levels with allopurinol has been shown to decrease cardiovascular risk, slow the progression of renal disease, and reduce the risk for cardiovascular events.
• Elevated urate levels are associated with hypertension, and lowering serum urate with xanthine oxidase inhibitors and uricosurics has been shown to decrease blood pressure.