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Crystalluria and Urinary Tract Abnormalities Associated with Indinavir

Jeffrey B. Kopp, MD; Kirk D. Miller, MD; Jo Ann M. Mican, MD; Irwin M. Feuerstein, MD; Ellen Vaughan, RN, MSN; Chandra Baker, BS; Lewis K. Pannell, PhD; and Judith Falloon, MD
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From the National Institute of Diabetes and Digestive and Kidney Diseases. Warren Grant Magnuson Clinical Center, and the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland. Note in Proof: Since our study of indinavir-associated urinary tract abnormalities ended in December 1996, 8 additional patients from the group of 240 described here developed urinary tract symptoms and crystalluria while receiving indinavir: Two of these 8 patients had nephrolithiasis, 5 had back or flank pain, and 1 had dysuria. Three other patients who began receiving indinavir also developed symptoms: One had nephrolithiasis, 1 had back or flank pain, and 1 had dysuria. Acknowledgments: The authors thank the physicians and nurses of the National Institute of Allergy and Infectious Disease/Critical Care Medicine Department HIV Research Clinic and the National Institute of Allergy and Infectious Disease HIV Primary Care Clinic for their care of the patients described in this report. They also thank Mr. Daniel Hogan of Leica, Inc., for assistance with polarized microscopy and Ms. Lisa Miller and Ms. Shuying Liu for logistical support. Grant Support: Merck & Co. provided the indinavir used in the in vitro studies. Requests for Reprints: Jeffrey B. Kopp, MD, Building 10, Room 3N116, National Institutes of Health, Bethesda, MD 20892. Current Author Addresses: Drs. Kopp, Miller, Mican, Feuerstein, Pannell, and Falloon and Ms. Vaughan and Ms. Baker: Building 10, National Institutes of Health, Bethesda, MD 20892.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1997;127(2):119-125. doi:10.7326/0003-4819-127-2-199707150-00004
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Background: Indinavir, a protease inhibitor widely used to treat patients with HIV infection, has been associated with nephrolithiasis. Distinctive urinary crystals and a spectrum of urologic disorders were noted in patients receiving indinavir.

Objective: To determine the composition of urinary crystals and the frequency of asymptomatic crystalluria and urinary tract symptoms in patients receiving indinavir.

Patients: Patients with HIV infection who were enrolled in studies conducted at the National Institutes of Health.

Measurements: Microscopic urinalysis, high-performance liquid chromatography (HPLC) and mass spectrometry of urinary crystals and stones, and clinical evaluation of patients with urologic symptoms.

Results: Of 240 patients receiving indinavir, 142 provided urine specimens for analysis. Twenty-nine (20%) had crystals consisting of plate-like rectangles and fan-shaped or starburst forms. Mass spectrometry and HPLC confirmed that these crystals were composed of indinavir. Of 40 patients who were not receiving indinavir, none had similar crystals (P < 0.001). Nineteen of the 240 patients receiving indinavir (8%) developed urologic symptoms. Of these, 7 (3%) had nephrolithiasis and the other 12 (5%) had previously undescribed syndromes: crystalluria associated with dysuria and crystalluria associated with back or flank pain. Four of the patients with the latter syndrome had radiographic evidence of intrarenal sludging.

Conclusions: Indinavir forms characteristic crystals in the urine. This crystalluria may be associated with dysuria and urinary frequency, with flank or back pain associated with intrarenal sludging, and with the classic syndrome of renal colic.


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Figure 1.
Contrast-enhanced computed tomographic scan of the kidneys (top) and abdominal radiograph of patient with nephrolithiasis (patient 1) (bottom).Top.Bottom.

Scan obtained during acute renal colic. The left renal pelvis and calyces are dilated, and the excretion of contrast is impaired. Radiograph taken immediately after computed tomography shows left hydronephrosis with a delayed nephrogram. The arrow indicates the likely location of obstruction.

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Figure 2.
Contrast-enhanced computed tomographic scans showing intrarenal defects (patient 8).Top.Bottom.

A scan obtained at the time of flank pa n shows bilateral defects in the excretion of intravenous contrast that appear as pyramidal lucencies extending from the medulla to the cortex. A scan obtained 1 week after indinavir was withheld and symptoms had resolved. Substantal resolution of the renal parenchymal defects is shown.

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Figure 3.
Urine from a patient with dysuria (patient 16).Left.leftrightRight.

Urine in a glass tube. Opalescent particles ( ) spontaneously form a yellow sediment ( ). The microscopic appearance of this sediment viewed under polarized light (x40) can be seen. A modified Sternheimer-Malbin stain gives these crystals their purple color.

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Figure 4.
Microscopic appearance of indinavir crystals.

Crossed polarizing filters and a λ wave plate produce variation in the color of the crystals and background as one filter is rotateo. A. Irregular plate forms (x40) in urine from an asymptomatic patient. B. Starburst forms (x80) in urine from an asymptomatic patient. C. Aggregated crystals, predominantly starburst forms, in a patient with dysuria and grossly apparent crystalluria (x40). D. Indinavir crystals prepared in vitro (x40).

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