Immunologically Mediated Chronic Tubulo-lnterstitial Nephritis Caused by Valproate Therapy

Yutaka Fukuda, MD, PhD, Department of Pediatrics, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113 (Japan) Dear Sir, Valproic acid (VPA) is a highly effective drug for seizure disorders. It is well known that the side reactions of VPA are gastrointestinal upset, liver damage and thrombocy-topenia, but only rarely are side effects seen in the kidney. Valproate therapy has been implicated as a cause of Fanconi syndrome in only two [1,2] and as a cause of acute tubulo-interstitial nephritis (TIN) in only one [3] previously reported cases. We encountered a patient with chronic TIN associated with valproate therapy, which was thought to be a seizure disorder for 18 months. A 10-year-old boy with chronic TIN had apparently been well except for episodes of bronchial asthma and febrile convulsions, until the age of 10 years. He had an abnormal EEG at the age of 4 years and had been treated with VPA (300 mg/day; Kyowa Hak-ko Kogyo Co., Ltd. Tokyo) from the age of 8 years. Eighteen months after starting VPA therapy, glucosuria was noted on routine uri-nalysis. The patient was referred to another university hospital to examine glucosuria on February 5, 1989. Blood studies revealed a hemoglobin of 9.1 g/dl, a WBC count of 7,300/mm3, and a platelet count of 125,000/ mm3. Liver function test results were within the normal range. Serum BUN, creatinine, and ß2-microglobulin (ß2-MG) were elevated to 30 (normal 8-17) mg/dl, 1.7 (0.6-1.2) mg/ dl, and 6.6 (0.8-2.4) mg/l, respectively. Blood gas analysis showed metabolic acido-sis with pH 7.25 and HCO319.3 mEq/1. His urine had a pH of 5.7 with glucosuria(+), proteinuria(+) and generalized hyperami-noaciduria with normal concentrations of plasma amino acids, but no cells or casts were present. Tubular functions were re-markedly deranged, as evidenced by the ß2MG index of 18.6 μg/mg·Cr ( < 0.4), N-ace-tyl-ß-Dglucosaminidase index of 29.6 U/ g·Cr (1.5-11.3), lysozyme of 9.4μg/ml (0), PSP test of 35% (120 min; 63-80), %TRP of 66% (85-98), FEHCO3of 10.1 % ( < 3), and Fishberg test of 1.017 ( > 1.024). His glomer-ular function was also decreased, as evidenced by a creatinine clearance of 38 ml/ min/1.73 m2 (120-140). From these results, he was diagnosed as having Fanconi syndrome and renal failure. On September 3, 1989, he was admitted to our department for further examination of the Fanconi syndrome and renal failure. On physical examination, his vital signs were stable and his growth was appropriate for age. He appeared slightly pale and his palpebral conjunctiva was anemic. The lungs were clear. A grade-1 systolic murmur was heard on the precor-dium. Abdominal examination was negative. No edema was found. Pigment degeneration