What are indinavir (Human Immunodeficiency Virus (HIV) antiretroviral medication) stones in a patient with a history of HIV infection?

What Are Indinavir Stones?

Indinavir stones are radiolucent kidney stones composed of crystallized indinavir (an HIV protease inhibitor) that form in the urinary tract due to the drug's poor solubility in urine, occurring in approximately 10-20% of patients taking this medication. 1, 2, 3

Composition and Radiographic Characteristics

• Indinavir stones are unique because they are completely radiolucent on plain X-rays and CT scans, distinguishing them from virtually all other types of kidney stones which are typically visible on CT imaging. 1, 4

• The crystals have distinctive microscopic appearances: plate-like rectangles and fan-shaped or starburst forms when examined under microscopy. 3

• Mass spectrometry and high-performance liquid chromatography confirm these crystals are composed purely of indinavir. 3

Clinical Presentations

Indinavir can cause three distinct urological syndromes beyond classic nephrolithiasis: 1, 3

1. Classic Nephrolithiasis (3% of patients)

• Presents with acute unilateral renal colic, flank pain, nausea, and vomiting. 2, 3
• May cause severe azotemia and obstructive uropathy. 2

2. Crystalluria with Back/Flank Pain (Novel Syndrome)

• Back or flank pain with renal parenchymal filling defects on CT scan but without visible stones. 1
• Four patients in one series showed radiographic evidence of intrarenal sludging. 3

3. Crystalluria with Lower Urinary Tract Symptoms

• Dysuria, urgent urination, and urinary frequency. 1, 3
• Asymptomatic crystalluria occurs in 20-67% of indinavir-treated patients. 1, 5

Associated Urinary Findings

• Persistent pyuria (sterile leukocyturia) is common and has been associated with gradual loss of renal function unrelated to obstructive symptoms. 1

• Hematuria is frequently present in symptomatic patients. 4

• Urine typically shows low pH (≤5.5 in 72% of urinalyses) and high specific gravity (≥1.025 in 66% of urinalyses). 5

• Proteinuria and casts may be observed in 39% of patients. 5

Risk Factors for Stone Formation

The highest incidence of urologic symptoms occurs during the first 6 months of indinavir treatment, though symptoms continue at a slower rate thereafter. 1

Patient-Specific Risk Factors:

• Low lean body mass. 1
• Coinfection with hepatitis B or C. 1

Medication-Related Risk Factors:

• Indinavir regimens of 1000 mg twice daily (higher doses). 1
• Ritonavir-boosted indinavir regimens significantly increase risk, with higher indinavir peak concentrations associated with urologic symptoms. 1
• Concomitant use of trimethoprim-sulfamethoxazole. 1

Environmental Factors:

• Temperature, atmospheric pressure, and humidity affect nephrolithiasis risk. 1

Pathophysiology

• Although indinavir is 80% metabolized in the liver, its pH-based solubility in urine makes renal excretion critical. 1

• The low solubility of indinavir crystals in urine is the critical factor for stone formation. 6

• Elevated urinary pH with reduced citric acid excretion contributes to low urinary solubility. 6

• Dehydration and pharmacokinetic interactions leading to elevated plasma indinavir concentrations increase stone formation risk. 6

Diagnostic Approach

When indinavir nephrotoxicity is suspected, urine should be inspected for the presence of crystals and pyuria. 1

• HIV-positive patients presenting with renal colic or renal insufficiency and absence of radio-opaque stones on imaging should prompt consideration of indinavir urolithiasis. 2

• Plain abdominal X-rays and CT scans will not visualize indinavir stones. 2, 4

• Excretory urography identifies stones in only 1 of 13 cases, and renal ultrasound in only 4 of 11 cases in one series. 4

• Microscopic urinalysis is essential for identifying characteristic indinavir crystals. 3

Management and Prevention

Acute Management:

• Most cases of acute renal failure secondary to indinavir resolve with discontinuation of the drug. 1

• Acute episodes are treated with intravenous fluids, NSAIDs (such as diclofenac), and antibiotics if infection is suspected. 6

• Emergency drainage may be required for severe obstruction. 6

• It is reasonable to restart indinavir therapy once rehydration is achieved in patients who develop indinavir nephrolithiasis. 1

Prevention Strategies:

Patients receiving indinavir should drink at least 1.5 liters of water daily to prevent stone formation. 1, 2

• Increase oral fluid intake especially during the first 2 hours after indinavir intake and during the night. 2

• Target urine production of 2 liters per day or more. 2

• Urinary acidification with L-methionine (urine pH 5.3-5.8) may be beneficial. 2

Monitoring Recommendations:

Periodic monitoring of renal function and pyuria should be performed during the first 6 months of indinavir therapy and biannually thereafter. 1

• Routine screening for crystalluria is not warranted unless there is suspicion of nephrolithiasis. 1

• Among high-risk patients, biannual monitoring for renal function and urinary abnormalities is warranted. 1

Important Clinical Caveats

• Indinavir need not be withheld from patients with reduced renal function, though dose adjustments are recommended for creatinine clearance <40 mL/min. 1

• Reducing indinavir dosage carries the risk of viral mutations with development of resistance. 6

• Patients who develop indinavir-induced hypertension, pyuria, rhabdomyolysis, or renal insufficiency (acute or chronic) should discontinue the medication. 1

• Long-term complications include renal atrophy, interstitial nephritis, and development of renal failure. 1

• Indinavir is now rarely used in modern HIV treatment regimens, having been largely replaced by newer antiretrovirals with better safety profiles.