Nephrolithiasis, or renal colic, is a substantial public health concern, impacting approximately 12% of the global population.¹ Uric acid nephrolithiasis is common, constituting approximately 10% of all forms of renal colic.² Diabetes, metabolic syndrome, obesity, and a high-purine diet are all associated with uric acid nephrolithiasis.²

In accordance with the AUA2019 kidney stone medical management guidelines, allopurinol can play a role in the medical treatment of calcium oxalate and uric acid stones.³ This is also recommended by the 2022 Canadian Urological Association kidney stone medical management guidelines.⁴ Patients with recurrent calcium oxalate stones and hyperuricosuria with normal urinary calcium levels may benefit from allopurinol to reduce recurrence risk.³ Moreover, in accordance with the Canadian Urological Association 2016 guidelines, allopurinol can be considered as a treatment option for calcium oxalate stones if hyperuricosuria and normocalcemia are present in patients (recommended dosage between 200 and 300 mg as a single dose once daily or in separated doses).⁵ Additionally, allopurinol remains an option for the treatment of uric acid stones following the trial of other first-line options, such as potassium citrate.³ It has been shown to help dissolve existing uric acid stones as well as help prevent future formation.

Allopurinol’s mechanism of action involves the inhibition of xanthine oxidase, which functions as an enzyme within the purine catabolism pathway.⁶ Xanthine oxidase converts hypoxanthine to xanthine and then to uric acid.⁶ Side effects associated with allopurinol include transaminitis and gastrointestinal disturbance.⁴ Less frequent but more severe reaction associated with allopurinol is allopurinol hypersensitivity syndrome, which can manifest as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic syndrome.^7-10

In a study evaluating 379 patients who had severe SJS or TEN, allopurinol was found to be the drug most frequently associated with SJS or TEN, with 66 patients (17.4%) within the SJS/TEN cohort reporting allopurinol exposure.⁷ SJS and TEN can result in a potentially life-threatening condition that involves exfoliation of the epidermis and mucous membranes.⁹ SJS is associated with a mortality rate of up to 5%, and TEN is associated with a mortality rate of up to 30%.⁹ The incidence of allopurinol hypersensitivity syndrome has shown to be higher in patients who have the HLA-B5801 allele as well as those with renal impairment.¹⁰

The pharmacodynamics between the human leukocyte antigen HLA-B*5801 gene and SJS/TEN syndrome are complex and not precisely understood. However, it is thought to be based on auto-reactivating CD8+ cytotoxic T lymphocytes releasing various cytotoxic proteins, such as granzyme B and perforin, that affect immune synapses and lead to sloughing of epithelial cells.¹¹ This may further result in a pathogenic reaction between cytotoxic T cells and the HLA-B*5801 allele at the genetic loci region of human chromosome 6p21.3.¹² In addition, several cytotoxic proteins and cytokines such as interleukin-15, interferon-γ, and tumor necrosis factor-α act as mediators for pathogenesis.^11-13 Given the role of allopurinol in the treatment of certain forms of nephrolithiasis, one way to possibly reduce the risk of SJS and TEN is for urologists to determine a patient’s HLA-B*5801 status prior to prescribing allopurinol.

Other medical societies have conditionally recommended screening of this gene. For example, the American College of Rheumatology recommends HLA-B*5801 testing of all high-risk populations—specifically those of Korean descent with stage 3 or worse chronic kidney disease, Han Chinese, Thai, and African American patients regardless of their level of renal function—prior to allopurinol initiation.¹⁴ Genotype screening for HLA-B*5801 is obtained through routine serum testing. If a patient tests positive, other therapeutic options for nephrolithiasis should be considered, such as thiazide diuretics.

A recent systematic review and meta-analysis found that HLA-B*5801 screening for detecting allopurinol-associated SJS or TEN is effective and may help reduce the risk of allopurinol-associated SJS or TEN.¹⁵ Specifically, this review found allopurinol associated with TEN and SJS related to Korean, Thai, Sardinian Italian, Han Chinese, Japanese, and other European populations. It is important to acknowledge that while there was an association of allopurinol associated with TEN and SJS in Japanese and other European populations, the sensitivity was much lower with a pooled sensitivity of 56%, compared to a pooled sensitivity of 97% for the other populations. The reported rates of adverse reaction due to use of allopurinol were 7.4% for Asian, 4% for Black, and 1% for Caucasian and Hispanic patients. In conclusion, the risk of SJS/TEN was reportedly higher in Asian and Black populations compared to other populations.¹⁶

While discussions around cost-effectiveness should be contextualized to specific geographic regions, data from Thailand highlight that HLA-B*5801 genotype screening prior to allopurinol prescriptions was highly cost-effective.¹⁷ In the United States, it was found that HLA-B*5801 genome screening was not found to be cost-effective for all races but could be an effective implementation for the high-risk African American and Asian ethnic populations.⁸

A limitation associated with HLA-B*5801 screening is that the time required for screening may delay treatment. For example, in the Canadian province of British Columbia, it takes approximately 2 to 3 weeks for testing results to return. While this may be a concern, urologists can consider other treatment options until they receive testing results. For example, in patients with calcium stones and hyperuricosuria, urologists may first prescribe thiazide diuretics and alkali citrates.⁴ In patients with uric acid stones, patients may be prescribed alkalinization therapy until screening is complete. Further, there have been innovations that have aimed to reduce the time needed for screening; for example, there is now rapid screening through polymerase chain reaction devices with a unit cost of only $3.80.¹⁸ Moreover, evaluation of this rapid screening tool shows 100% sensitivity and specificity in testing.¹⁸

Based on guidelines from the American College of Rheumatology, patients with planned allopurinol treatment from at-risk populations (Southeast Asian or African American ethnicity) may benefit from HLA-B*5801 screening to reduce the chance of SJS and TEN. This type of screening commonly occurs in rheumatologic practice, and urologists who provide allopurinol prescriptions for kidney stone prevention may consider this as part of their routine workflow. This has previously been shown to be a cost-effective strategy and importantly can reduce the chance of a severe, albeit rare, adverse event.