Atazanavir and Nephrolithiasis
Yes, atazanavir (300 mg daily with ritonavir) causes nephrolithiasis, and the risk is substantially higher than with other protease inhibitors—you must ensure adequate hydration (≥1.5 liters daily), monitor renal function regularly, and strongly consider switching to an alternative antiretroviral if stones develop. 1
Evidence of Nephrolithiasis Risk
The FDA drug label explicitly warns that nephrolithiasis has been reported with atazanavir use and recommends considering temporary interruption or discontinuation when stones occur 1. This is not a theoretical concern—the clinical evidence demonstrates a dramatically elevated risk:
- Ritonavir-boosted atazanavir causes nephrolithiasis at a rate of 20.2-23.7 cases per 1000 person-years, compared to only 0.86-2.2 cases per 1000 person-years with other protease inhibitors 2, 3
- The adjusted hazard ratio for stone formation with atazanavir/ritonavir is 10.44-21.47 times higher than alternative regimens 2, 3
- Atazanavir crystals are found in urine in approximately 8.9% of asymptomatic patients receiving the drug, indicating subclinical crystalluria is common 4
The mechanism is straightforward: atazanavir reaches extremely high urinary concentrations (median 22.3 mg/L), far exceeding plasma levels, and has pH-dependent solubility that promotes crystalline precipitation in the urinary tract 5, 4.
Clinical Presentation and Timing
Most atazanavir-related nephrolithiasis occurs within the first 24-28 months of therapy, though risk continues throughout treatment 3. Unlike typical calcium-based stones, atazanavir stones are completely radiolucent on CT scan and plain radiographs, which can lead to missed diagnoses 6. You must maintain high clinical suspicion in patients with:
- Flank or back pain with negative imaging studies 6
- Unexplained acute kidney injury despite adequate hydration 6
- Crystalluria, hematuria, or persistent pyuria 5
Risk Mitigation Strategy
Mandatory Baseline and Ongoing Monitoring
The FDA label requires renal laboratory testing before starting atazanavir and continued monitoring during treatment 1. Specifically:
- Measure serum creatinine and calculate creatinine clearance at baseline 1
- Monitor renal function every 3-6 months in all patients on atazanavir 1
- Check urinalysis for crystalluria, hematuria, and pyuria periodically 5
Essential Hydration Protocol
Patients must drink at least 1.5 liters of water daily to prevent stone formation by maintaining adequate urine flow and dilution 7. This is the single most important preventive measure and should be emphasized at every visit.
High-Risk Populations to Avoid
The FDA label and clinical guidelines identify patients who should receive alternative antiretrovirals instead of atazanavir 1:
- Patients with preexisting chronic kidney disease (consider alternatives) 1
- Patients at high risk for renal disease (consider alternatives) 1
- Patients with history of nephrolithiasis (use alternative regimens) 5
Longer cumulative exposure to atazanavir is the primary risk factor for crystalluria development 4.
Management When Stones Develop
Immediate Actions
If nephrolithiasis is diagnosed, discontinue atazanavir immediately and switch to an alternative antiretroviral regimen 3. The evidence is unequivocal:
- Patients who continue atazanavir after stone diagnosis have a 33.3% recurrence rate 3
- No patients who discontinued atazanavir experienced stone recurrence during follow-up 3
- Most acute kidney injury from atazanavir resolves with drug discontinuation 7
Alternative Antiretroviral Selection
When switching from atazanavir due to nephrolithiasis, consider 7:
- Darunavir/ritonavir: Substantially lower nephrolithiasis risk (0.86 vs 20.2 per 1000 person-years) 2
- Dolutegravir: No renal toxicity, no drug interactions with most agents 7
- Raltegravir: Compatible with most regimens, no nephrotoxicity 7
Additional Renal Complications
Beyond nephrolithiasis, atazanavir causes other forms of kidney injury 1, 5:
- Chronic tubulointerstitial nephritis with progressive CKD developing over years, characterized by granulomas and intrarenal atazanavir crystal deposition 5
- Acute tubulointerstitial nephritis developing rapidly (within weeks) after initiation 5
- Chronic kidney disease reported in post-marketing surveillance, requiring consideration of discontinuation in patients with progressive renal dysfunction 1
Critical Pitfall to Avoid
Do not assume normal CT imaging excludes atazanavir stones—these stones are radiolucent and invisible on standard imaging 6. In patients with unexplained flank pain, acute kidney injury, or obstructive symptoms despite negative CT, perform ureteroscopy or consider empiric discontinuation of atazanavir and observe for clinical improvement 6.