Is allopurinol (hypoxanthine guanine phosphoribosyltransferase inhibitor) nephrotoxic, causing impaired renal function?

From the Guidelines

Allopurinol is not inherently nephrotoxic, but it can cause acute kidney injury in certain situations, particularly when patients develop allopurinol hypersensitivity syndrome, a rare but serious adverse reaction. According to the 2017 updated EULAR evidence-based recommendations for the management of gout 1, the greatest concern with the use of allopurinol in patients with renal failure is the development of severe cutaneous adverse reactions (SCARs), which includes drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis.

Key Considerations

• Patients with pre-existing kidney disease require dose adjustment of allopurinol, typically starting at a lower dose (50-100 mg daily) and gradually increasing as needed while monitoring kidney function 1.
• The medication works by inhibiting xanthine oxidase, reducing uric acid production and preventing crystal formation in the kidneys.
• When initiating allopurinol, it's essential to start at a low dose, especially in those with renal impairment, monitor for hypersensitivity reactions, ensure adequate hydration, and regularly assess kidney function.
• Paradoxically, allopurinol can actually be renoprotective in the long term by preventing uric acid nephropathy and reducing the risk of kidney stones.

Dose Adjustment and Monitoring

• The dose of allopurinol can be raised above 300 mg daily, even with renal impairment, as long as this is accompanied by adequate patient education and monitoring for drug toxicity 1.
• Prior to initiation, consider HLA-B*5801 in selected patients, specifically in higher risk sub-populations for severe allopurinol hypersensitivity reaction 1.
• Regular monitoring of kidney function and adjustment of the dose as needed is crucial to minimize the risk of adverse reactions.

Alternative Therapies

• Febuxostat has been found more effective in patients with CKD than allopurinol given at doses adjusted to creatinine clearance and therefore can be used in these patients 1.
• Benzbromarone is not recommended for use in patients with eGFR <30 mL/min, but can be used in patients with moderate renal impairment because it is predominately metabolised by the liver 1.

From the FDA Drug Label

Some patients with pre-existing renal disease or poor urate clearance have shown a rise in BUN during administration of allopurinol tablets Although the mechanism responsible for this has not been established, patients with impaired renal function should be carefully observed during the early stages of administration of allopurinol tablets and the dosage decreased or the drug withdrawn if increased abnormalities in renal function appear and persist Renal failure in association with administration of allopurinol tablets has been observed among patients with hyperuricemia secondary to neoplastic diseases. Patients with decreased renal function require lower doses of allopurinol tablets than those with normal renal function. Allopurinol may be associated with nephrotoxicity, as evidenced by renal failure and rise in BUN in some patients, particularly those with pre-existing renal disease or poor urate clearance 2, 2, 2.

• Key points:
  • Patients with impaired renal function should be closely monitored during the early stages of allopurinol administration.
  • Dosage reduction or drug withdrawal may be necessary if renal function abnormalities persist.
  • Patients with decreased renal function require lower doses of allopurinol.

From the Research

Allopurinol Nephrotoxicity

• Allopurinol is not directly stated to be nephrotoxic in the provided studies, but its use in patients with renal impairment requires careful consideration 3, 4.
• The risk of allopurinol hypersensitivity syndrome (AHS) is increased in renal impairment, and AHS may occur even at low doses of allopurinol 3.
• Studies suggest that allopurinol dose reduction according to creatinine clearance in patients with renal impairment may lead to under-treatment of hyperuricemia 3, 4.
• Allopurinol treatment has been shown to slow down renal disease progression and reduce cardiovascular risk in patients with chronic kidney disease 5.

Comparison with Febuxostat

• Febuxostat, a novel xanthine oxidase inhibitor, has been shown to be effective in reducing serum uric acid concentrations and may suppress the progressive decline in renal function in patients with chronic kidney disease 6, 7.
• A comparison of long-term efficacy and renal safety of febuxostat and allopurinol in patients with chronic kidney diseases found that febuxostat may exert a protective effect on the kidneys 7.
• Febuxostat was found to be more effective than allopurinol in reducing serum uric acid levels, and its long-term use was associated with a positive eGFR slope, whereas allopurinol was associated with a negative eGFR slope 7.