Case 3: Discussion

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Crystallization of the HIV protease inhibitor indinavir (Crixivan) within the renal tubules is associated with a range of urinary tract manifestations, including nephrolithiasis, flank pain without stone formation, interstitial nephritis, increased serum creatinine levels, dysuria, and asymptomatic urine abnormalities such as crystalluria, sterile pyuria, and hematuria (Figure 1).

Incidence of Indinavir-Related Renal Disease

In early clinical trials that involved treatment with indinavir, nephrolithiasis occurred in roughly 4% of patients [1]. More recent studies, however, have reported an incidence of nephrolithiasis of 12-33%, and this higher incidence may reflect a broader case definition used in some studies that included symptomatic hematuria and flank pain as evidence of stone formation [2-5]. Attempts to more clearly delineate the symptomatic urologic syndromes associated with indinavir have found a 3-4% incidence of nephrolithiasis and a 5-8% incidence of crystalluria associated with either dysuria or renal colic [6,7]. Asymptomatic crystalluria occurs in roughly 20% of indinavir-treated patients [6]. Indinavir-induced crystal nephropathy, characterized by elevated serum creatinine, loss of concentrating ability by the kidney, sterile pyuria, and renal parenchymal imaging abnormalities, has been reported in 9-19% of individuals receiving indinavir [7]. The onset of urologic symptoms after initiating therapy with indinavir has ranged from 1 day to longer than 100 weeks. There appears to be a relationship between plasma indinavir concentration and the development of urologic symptoms [8]. Ritonavir boosting has been associated with an increased incidence of nephrolithiasis depending on the dosing regimen. The twice-daily combination of 800 mg indinavir with 100 or 200 mg of ritonavir seems to confer a greater risk than dosing each at 400 mg twice daily [9,10]. Increased indinavir concentrations caused by decreased hepatic metabolism in patients with underlying liver disease, such as hepatitis B or C virus infection, may also lead to an increased risk of nephrolithiasis [11]. Concentrated urine due to excessive diaphoresis is thought to explain the relationship between the increased incidence of indinavir-related nephrolithiasis in the setting of increased environmental temperature [12].

Pathophysiology

Approximately 11% of the administered indinavir dose is excreted unmetabolized in the urine. This results in a drug concentration at the limit of its solubility (0.2 to 0.3 mg/ml), favoring precipitation in the collecting ducts [5]. Acidification of the urine in vitro below a pH of 4.5 increases crystal solubility, but normal or high urine pH favors precipitation [6,13]. The increased solubility at lower urinary pH is independent of urine specific gravity [13]. The urinary crystals tend to be either flat rectangular plates, fan-shaped, or starburst in appearance (Figure 2) [6]. The gelatinous stones that develop have been confirmed to be composed of indinavir sulfate by mass spectrometry analysis [14]. Renal biopsy reveals unremarkable glomeruli, prominent interstitial fibrosis, and tubular atrophy accompanied by chronic inflammation. Collecting ducts tend to contain crystals associated with histiocytes and giant cells [15].

Clinical Manifestations

Crystallization of indinavir within the renal tubules may be asymptomatic or associated with urologic symptoms with or without alteration in renal function. Symptomatic urinary tract disease associated with indinavir includes a range of clinical manifestations that depends on whether stone formation has occurred. Those patients with indinavir-related nephrolithiasis typically have acute onset of severe flank pain and hematuria. Kidney stones formed by indinavir are radiolucent unless calcium oxalate has been incorporated and thus may be missed on a non-contrast computed tomography (CT) scan. Patients with crystalluria in the absence of stone formation generally have intermittent dysuria or flank pain. This crystalluria-dysuria syndrome may mimic infectious cystitis and lead to unnecessary antimicrobial treatment, as was seen in the patient in this case presented here. Indinavir-induced crystal nephropathy generally does not cause symptoms, but this disorder should be suspected if the patient develops an increased serum creatinine level or sterile pyuria; computed tomographic scans show renal parenchymal imaging abnormalities, including cortical atrophy [7]. Persistent sterile pyuria appears to be an early indicator in the development of renal insufficiency and corresponds histologically to interstitial nephritis [16,17]. Unlike HIV nephropathy, proteinuria does not appear to be a significant component of indinavir-related nephropathy.

Prevention and Management

In order to prevent the formation of indinavir crystals within the urine, it is recommended that all patients on indinavir maintain a fluid intake of at least 1.5 liters per day (roughly 8 glasses of fluid per day). Routine urinalysis and monitoring of renal function should be incorporated into the care of patients on indinavir. Since asymptomatic crystalluria is relatively common and is not a predictor of subsequent complications, it is not an indication for the withdrawal of indinavir therapy. This finding may, however, suggest the need for increased fluid intake. The presence of sterile pyuria is more concerning as it seems to represent early tubular inflammation and identifies individuals with renal insufficiency as well as those at risk for developing renal insufficiency [18]. In most patients, the indinavir-induced renal insufficiency reverses with discontinuation of indinavir and increased hydration. Most indinavir stones are passed through the urine with conservative management consisting of vigorous hydration, adequate analgesics, and discontinuation of indinavir for 1-3 days. Attempts to treat indinavir nephrolithiasis with urinary acidification have been unsuccessful. For larger stones, or stones that fail to respond to conservative management, ureteral stenting and ureteroscopic removal may be necessary to remove the obstruction. Due to the gelatinous nature of these stones, lithotripsy is not effective [19].

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