Can hyperuricemia cause acute kidney injury?

Can Hyperuricemia Cause Acute Kidney Injury?

Yes, hyperuricemia can directly cause acute kidney injury through multiple mechanisms, including uric acid crystal deposition in renal tubules causing acute obstructive uropathy, as well as non-crystalline inflammatory and vasoactive effects that exacerbate kidney injury even at moderately elevated levels.

Mechanisms of Hyperuricemia-Induced AKI

Crystal-Mediated Injury (Acute Urate Nephropathy)

• Severe hyperuricemia causes uric acid crystallization in the collecting ducts and deep cortical and medullary vessels, leading to acute oliguric renal failure and anuria 1
• This mechanism is most commonly seen in tumor lysis syndrome, where massive cell lysis releases intracellular nucleic acids that are metabolized to uric acid 1
• Xanthine crystal deposition can also occur when allopurinol is used, as it increases serum levels of the purine precursors xanthine and hypoxanthine, which have lower solubility in urine and can cause acute obstructive uropathy 1

Non-Crystalline Injury Mechanisms

• Even mild-to-moderate hyperuricemia (levels that do not cause intrarenal crystal formation) can exacerbate acute kidney injury through proinflammatory pathways involving chemokine expression and leukocyte infiltration 2
• Experimental evidence demonstrates that hyperuricemia significantly increases tubular injury, macrophage infiltration, and monocyte chemoattractant protein-1 expression in cisplatin-induced AKI models, even without visible intrarenal crystals 2
• Uric acid has systemic effects on renal microvasculature and hemodynamics, as well as local crystalline and non-crystalline effects on renal tubules 3

Clinical Evidence Supporting the Association

Risk Prediction Studies

• Hyperuricemia independently predicts contrast-induced AKI with a pooled odds ratio of 2.03 (95% CI 1.48-2.78) in meta-analysis 4
• In patients with relatively normal baseline serum creatinine (<1.5 mg/dL) undergoing percutaneous coronary intervention, hyperuricemia was associated with a 5.38-fold increased risk of contrast-induced AKI (95% CI 1.99-14.58) 5
• The incidence of contrast-induced AKI was significantly higher in hyperuricemic patients (8.1% vs. 1.4%) 5

Chronic Kidney Disease Association

• An increased incidence of end-stage renal disease was found in patients with hyperuricemia, though gout itself was not an independent predictor 1
• A fourfold increase in mortality due to kidney disease has been reported in patients with gout compared with non-gouty patients 1

Clinical Contexts Where Hyperuricemia Causes AKI

Hyperuricemia is recognized as a potentially modifiable risk factor for AKI in multiple clinical scenarios 3:

• Tumor lysis syndrome (most common and severe presentation) 1
• Cardiovascular surgery 3
• Radiocontrast administration 3, 5, 4
• Rhabdomyolysis 3
• Heat stress and dehydration (may underlie Mesoamerican nephropathy) 3

Therapeutic Implications

Evidence for Uric Acid Lowering

• Two randomized controlled trials found that allopurinol with saline hydration significantly protected renal function compared with hydration alone (mean difference in serum creatinine: -0.52 mg/dL; 95% CI: -0.81 to -0.22) 4
• Lowering serum uric acid with saline hydration was significantly associated with reduced risk for AKI compared with saline hydration alone 4
• Treatment with rasburicase reversed inflammatory changes, lessened tubular injury, and improved renal function in experimental models 2

Management in Tumor Lysis Syndrome

• For patients with preexisting hyperuricemia (≥450 μmol/L or ≥7.5 mg/dL), treatment with rasburicase is preferred over allopurinol 1
• Oliguria due to acute uric acid nephropathy rapidly responds to hemodialysis, often restarting diuresis as plasma uric acid falls to 10 mg/dL 1
• Uric acid clearance during hemodialysis is approximately 70-100 mL/min, with plasma levels falling by about 50% per 6-hour treatment 1, 6

Important Clinical Caveats

• Allopurinol only prevents formation of new uric acid and does not reduce preexisting hyperuricemia, which is why rasburicase is preferred when rapid uric acid reduction is needed 1, 7
• The mechanism by which uric acid induces contrast-induced AKI is likely related to acute uricosuria 4
• Hyperuricemia should be considered a red flag for metabolic syndrome and cardiovascular diseases, prompting screening for renal disease 1