Correspondence

Indinavir Nephropathy

N Engl J Med 1997; 336:138-140January 9, 1997

Article

To the Editor:

The human immunodeficiency virus (HIV) encodes a protease needed for the production of infectious virions. Current therapeutic strategies employ new types of inhibitors of this protease.1 Their side effects are relatively minor, and the drugs have not been considered directly nephrotoxic. Indinavir differs from the other protease inhibitors in that a serious adverse effect, the occurrence of kidney stones, has been noted.2 We describe a patient in whom direct nephrotoxic effects of indinavir appeared to develop.

The patient was a 30-year-old white woman known to be HIV-positive for six years, who was infected heterosexually. Her CD4 count in June 1995 was 130 cells per cubic millimeter (12 percent of all lymphocytes), and she enrolled in a clinical trial in which she received indinavir (800 mg orally every eight hours) as the only antiviral drug. Her CD4 count rose to 428 cells per cubic millimeter by week 4 and remained at that level for 48 weeks. At week 24, she took a seven-day course of amoxicillin for bronchitis. Between week 28 and week 40, her serum creatinine level rose progressively from 1.0 to 1.7 mg per deciliter. Urinalysis revealed persistent pyuria, with 165 mg of protein per deciliter in a 24-hour collection. Her blood pressure was 170/100 mm Hg at week 28 and 150/90 mm Hg at week 32, and she reported back pain and fatigue. She started treatment with enalapril (2.5 mg per day). Workup revealed normal-sized kidneys, an unremarkable intravenous pyelogram, 4 percent eosinophils in the urine, and negative urinary cultures. A renal biopsy showed unremarkable glomeruli, prominent interstitial fibrosis, and tubular atrophy accompanied by chronic inflammation. Multiple collecting ducts contained crystals associated with histiocytes and giant cells (Figure 1AFigure 1Photomicrographs of Renal Tissue in an HIV-Positive Woman Treated with Indinavir., Figure 1B, and Figure 1C). The crystals appeared similar to those in the capsule preparation of indinavir. Immunofluorescence studies were negative. Four weeks after the patient discontinued treatment with indinavir, the serum creatinine level fell to 1.4 mg per deciliter. Her blood pressure became normal without enalapril, and the urinary leukocytes disappeared.

Indinavir is excreted largely as the parent molecule,3 and its solubility in water is pH-dependent, greater than 100 mg per milliliter at a pH below 3.5 and 0.03 mg per milliliter at pH 6.4 Indeed, in laboratory animals its oral absorption is facilitated by measures that increase gastric acidification and decreased by those that diminish it.4 Four percent of patients taking indinavir have symptoms of clinical nephrolithiasis.2 Thus, given the solubility of this drug, it is not surprising that intratubular crystal formation might occur and cause renal parenchymal injury. In our patient, we cannot be sure that amoxicillin did not play a part in the nephrotoxicity, although that possibility seems unlikely in view of the temporal relation with the use of indinavir. It may be that oral hydration could prevent this injury, but this remains to be determined.

Karen T. Tashima, M.D.
Brown University, Providence, RI 02906

Jeffrey D. Horowitz, M.D.
Truesdale Clinic, Fall River, MA 02720

Seymour Rosen, M.D.
Beth Israel Hospital, Boston, MA 02215

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