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.

Test your knowledge on the effects of elevated urate and MSU crystals in chronic kidney disease with this quiz. Explore the association between urate levels and endothelial dysfunction, vascular smooth muscle cell proliferation, and inflammatory processes. Delve into the impact of urate-lowering interventions and the complex relationship between serum urate levels and MSU crystallization.