Indinavir is primarily metabolized by the liver with 20% eliminated through urine, approximately half of which is unchanged [1
]. Indinavir crystallization occurs at a urine concentration of 100 mg/l which corresponds to a plasma concentration of 6.4 mg/l [2
]. The peak plasma concentration of indinavir in patients at the recommended dose of 400–800 mg is already 8–10 mg/l [3
]. Within 3 h after a typical indinavir dosage of 800 mg orally in a patient averaging 1.5 l urine output daily, the urine concentration already exceeds the limits of solubility at 200–300 mg/l making crystal formation likely common [3
]. Current recommendations to prevent nephrolithiasis include hydration with at least 1.5 l of fluids daily to increase the clearance of indinavir [2
In the clinical setting, many factors may increase the risk of indinavir crystallization in urine with the most important being volume depletion leading to higher urine drug concentration. Other cited risk factors include variations in individual pharmacokinetics of indinavir, hepatic insufficiency leading to greater dependence on renal clearance, differences in plasma protein binding of indinavir, low urinary pH decreasing indinavir solubility, renal insufficiency, renal tubular cell injury as a predisposition for crystal adherence and agglomeration, and low lean body mass [3
]. It is important to note that the effect of renal insufficiency on the pharmacokinetics of indinavir has not been studied well.
In the patient presented, a kidney biopsy demonstrated crystal-induced tubular injury with rupture and electron microscopy revealed granulomatous giant cell reaction with crystals within the lumen. Even though the patient had discontinued indinavir for 1.5 years by the time of renal biopsy, the crystals remained in the renal tubules. One hypothesis of stone formation long after discontinuation of indinavir is that the soft, gelatinous nature of indinavir crystals allows it to gradually collect and build up within the renal tubules with time and when a critical mass of indinavir crystals develops, it precipitates into an obstructing stone [5
A second hypothesis for stone formation centers on low lean body mass that results in a low distribution volume of indinavir and hence a higher plasma concentration of indinavir [4
]. Since dosing of indinavir is independent of body mass, plasma concentrations of indinavir may vary greatly among patients on the same dose. The higher plasma concentration leads to a higher urinary concentration of indinavir that increases the risk of crystal and stone formation.
The detection of indinavir itself poses another challenge as no single imaging modality proves superior in definitively diagnosing indinavir stones. One study found that no abdominal imaging study is diagnostic, intravenous pyelogram detects less than 8% of indinavir stones, renal ultrasounds demonstrated obstruction in 82% of cases, and CT imaging revealed obstruction with no stones in over 50% of the cases [4
]. Stones that were visible on CT were more likely of mixed composition, containing indinavir with radioopaque substances such as calcium or uric acid [4
]. Accurate diagnosis is important as conservative management is often effective, but some cases may require ureteral stenting to relieve obstruction [6