Indinavir Human Immunodeficiency Virus Type 1-Infected Children Treated With Persistent Sterile Leukocyturia Is Associated With Impaired Renal Function in

Background. Prolonged administration of indinavir is associated with the occurrence of a variety of renal complications in adults. These well-documented side effects have restricted the use of this potent protease inhibitor in children. Design. A prospective study to monitor indinavir-related nephrotoxicity in a cohort of 30 human immunodeficiency virus type 1–infected children treated with indinavir. Methods. Urinary pH, albumin, creatinine, the presence of erythrocytes, leukocytes, bacteria and crystals, and culture were analyzed every 3 months for 96 weeks. Serum creatinine levels were routinely determined at the same time points. Steady-state pharmacokinetics of indinavir were done at week 4 after the initiation of indinavir. Results. The cumulative incidence of persistent sterile leukocyturia (>75 cells/ L in at least 2 consecutive visits) after 96 weeks was 53%. Persistent sterile leukocyturia was frequently associated with a mild increase in the urine albumin/creatinine ratio and by microscopic hematuria. The cumulative incidence of serum creatinine levels >50% above normal was 33% after 96 weeks. Children with persistent sterile leukocyturia more frequently had serum creatinine levels of 50% above normal than those children without persistent sterile leukocyturia. In children younger than 5.6 years, persistent sterile leukocyturia was significantly more frequent than in older children. A higher cumulative incidence of persistent leukocyturia was found in children with an area under the curve >19 mg/L*h or a peak serum level of indinavir >12 mg/L. In 4 children, indinavir was discontinued because of nephrotoxicity. Subsequently, the serum creatinine levels decreased, the urine albumin/creatinine ratios returned to zero, and the leukocyturia disappeared within 3 months. Conclusions. Children treated with indinavir have a high cumulative incidence of persistent sterile leukocyturia. Children with persistent sterile leukocyturia more frequently had an increase in serum creatinine levels of >50% above normal. Younger children have an additional risk for renal complications. The impairment of the renal function in these children occurred in the absence of clinical symptoms of nephrolithiasis. Indinavirassociated nephrotoxicity must be monitored closely, especially in children with risk factors such as persistent sterile leukocyturia, age <5.6 years, an area under the curve of indinavir >19 mg/L*h, and a Cmax >12 mg/L. Pediatrics 2002;110(2). URL: http://www.pediatrics. org/ cgi/content/full/110/2/e19; human immunodeficiency virus, children, indinavir, nephrotoxicity. ABBREVIATIONS. HIV, human immunodeficiency virus; AUC, area under plasma-concentration curve; IQR, interquartile range. Indinavir is a potent human immunodeficiency virus (HIV)-protease inhibitor that has been used successfully in adults in combination with nucleoside reverse transcriptase inhibitors to suppress infections by HIV-1. Discontinuation of the antiretroviral therapy rapidly results in virologic rebound, decreased immune function, and the redevelopment of acquired immune deficiency syndrome-defining illness. Thus, antiretroviral drugs such as indinavir need to be continued for many years. This necessitates a careful surveillance for long-term toxicity of the medication. The experience with the administration of indinavir to HIV-1–infected children has been limited because of the absence of a pediatric formulation and the well-documented side-effects of the drug on the upper and lower urinary tract in adults. Indinavir is metabolized by the liver, but 20% of a single oral dose is excreted unchanged in the urine.1 pH-dependent crystallization of indinavir in renal tubuli may cause renal symptoms such as kidney stones, flank pain (even without evident stone formation), interstitial nephritis, elevation of the serum creatinine, dysuria, and asymptomatic urine abnormalities such as hematuria, leukocyturia, and crystalluria. Indinavir crystals may illicit an inflammatory response in the tubules, leading to sterile leukocyturia and renal insufficiency.2–7 To minimize renal side effects of indinavir, an increased fluid intake is advised.8 The incidence of indinavir-associated nephrolithiasis in adults varies from 4% to 43%. 2,9 Renal complications (including nephrolithiasis) from indinavir From the *Department of Pediatrics, Sophia Children’s Hospital/Erasmus University Medical Centre Rotterdam, Rotterdam, the Netherlands; ‡Department of Internal Medicine, Erasmus University Medical Centre Rotterdam, Rotterdam, the Netherlands; §Department of Clinical Pharmacy, University Medical Centre Nijmegen, Nijmegen, the Netherlands; and Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Centre Rotterdam, Rotterdam, the Netherlands. Received for publication Nov 2, 2001; accepted Apr 8, 2002. Address correspondence to Ronald de Groot, MD, PhD, Sophia Children’s Hospital, Dr. Molewaterplein 60, 3015 GJ Rotterdam, the Netherlands. E-mail: rdegroot@alkg.azr. nl PEDIATRICS (ISSN 0031 4005). Copyright © 2002 by the American Acad-