Drug-Induced Acute Renal Failure:
The Haitian Experience
Bernard G. Jaar, MD

Acute Renal Failure is an uncommon occurrence outside the hospital in the absence of natural disasters. Between November 1995 and June 1996, there was an Acute Renal Failure outbreak in Haiti. In June 1996, a joint investigation was initiated by the Ministry of Health of Haiti, the State University General Hospital in Port-au-Prince, the Pan American Health Organization, the Caribbean Epidemiologic Center, and the Center for Disease Control and the Johns Hopkins Medical Institutions. It demonstrated that this epidemic of Acute Renal Failure was associated with diethylene glycol – contaminated glycerin used to manufacture paracetamol syrup in Haiti.

The investigation identified 86 cases and at least 79% of the cases had consumed one of two locally manufactured contaminated paracetamol syrup (1). On June 22, the Ministry of Health of Haiti issued an alert to parents not to administer these products and prohibited their sale. The manufacturing company announced a recall of these and other syrup products. Following the recall and public information campaign, the number of new cases decreased sharply. The last reported case was admitted to a hospital in June 29, 1996.

Eighty-six children, aged 3 months to 13 years, with a median age of them 5 years, presented with a non specific febrile prodomal illness followed within two weeks by anuric acute renal failure, pancreatitis, hepatitis, and neurologic dysfunction progressing to coma.

The nonspecific prodomal illness was characterized by a history of 8-15 days of fever in all cases, nausea and vomiting, diarrhea, cough and abdominal pain. Prior to admission, most of the children (79%) received an antipyretic medication and some received a course of antibiotherapy (ampicillin, axoxicillin. Trimethoprim-sulfamthoxale). The physical examination on admission revealed edema of the face or lower extremity, high blood pressure, hepatomegaly, and neurologic signs (irritability, coma)

During the first week of June 1996, three kidney blocks from three different patients, were examined by a renal pathologist at the Johns Hopkins medical institutions. The most striking finding in the slides were extensive tubular injury with tubular epethilial cell loss, degeneration, exfoliation, vacuolization and extensive tubular cell regeneration with mitotic figures. Immunohistochemical stains for cytomelagovirus, herpes simplex viruses I and II, andenovirus were negative. The blood vessels were unremarkable, and there was little instertitial nephritis. There were no distinctive crystals or casts. The extensive active tubular necrosis in this clinical setting was felt to be the most likely due to a toxin.

Despite symptomatic treatment, the disease was characterized by a very high mortality rate (> 87.2%). Ten Children were transferred to the U.S. for intensive care and dialysis. Of nine survivors eight recovered renal functions. However, one child maintained on peritoneal dialysis died after a few months, Of the 76 children who remained in Haiti, only 1 survived..

The toxic product diethylene glycol (DEG) is a colorless and almost odorless chemical. It is an extremely toxic industrial solvent, particularly well known as nephrotoxin and hepatotoxin. The mechanism of toxicity is unknown but is probably different from oxalate toxicity associated with ethylene glycol poisoning. Management of patients with DEG toxicity relies on early diagnosis, supportive and symptomatic care for multiorgan failure, Survival with DEG toxicity has been reported(2).

The outbreak in Haiti represents the fifth large acute renal failure associated with DEG. In 1937, 105 patients died in the US. When 72% used DEG as diluent in elixir sulfanilamide antibiotic preparation (3,4). As a result of this disaster, the 1938 Federal Food, Drug and Cosmetic Act was passed, requiring drug companies to demonstrated safety before marketing new pharmaceuticals(5).

In 1969, an epidemic of fatal renal failure occurred among 7 children in Capetown, South Africa. Anti-pyretics and sedatives formulated with DEG instead of propylene glycol were implicated (6). In 1986 a cluster of 14 unexpected deaths from renal failure occurred in Bombay, India, among patients in one hospital. This epidemic was traced to indigestion of DEG(7). At a Nigerian hospital in 1990, 47 children also died unexpectedly from renal failure. All had received Paracetamol syrup for the symptomatic treatment of their fever (8). More recently, in Bangladesh between January 1990 and December 1992, 236 children died of ARF after ingestion of DEG-contaminated paracetamol syrup (2).

Glycerin in used as a sweetner in formulations of many pharmaceutical syrups. Distrubution of the raw material involves many handlers. This emphasizes the need for manufactures to adequately identify raw materials and end products. In the Haiti Case, Infrared Spectrotropy tests required by the US pharmacopeia (UPS) would not have detected this DEG-contaminated glycerin syrup. A gas Chromatogrophy method capable of separating and detecting glycerin, ethylene glycol and DEG can be used to determining the glycerin is free of these contaminants..

Information regarding this outbreak was disseminated internationally in June 1996 and resulted in a major assistance (by the international society of Nephrology Commission on ARF Disaster of Nephrology Commission on ARF Disaster Relief Task Force ( DRTF) and the U.S army). Peritoneal dialysis solutions and catheters were donated by Fresenus USA and Baxter Healthcare corporation for use in Haiti. Despite this joint endeavor, the outcome of children treated in Haiti was poor. This experience highlights the difficulties in early recognition and management of ARF in Haiti and provides a unique opportunity to understand the need for a permanent dialysis program in Haiti Also this outbreak emphasizes the need for the pharmaceutical industry to be aware of possibly contamination of raw materials and to use appropriate quality-control measures to identify and prevent this tragedy,

In August 2, 1996, the FDA released an Import Alert (#55-02): Increased surveillance of glycerin due to the presence of diethylene glycol., indicating that China was the primary was the primary source of contaminated glycerine shipped from Germany to Haiti.