SOUTHERN MEDICAL JOURNAL, AUGUST 1975 – Vol 68, no. 8, pp 1001, 1003
CHELATION THERAPY IN LEAD NEPHROPATHY
Jean M. Morgan, MD†
Abstract: Although treatment has been well defined for childhood lead poisoning and for industrial lead exposure, the treatment of lead nephropathy has been poorly studied. The available chelating agents are reviewed and the results of treatment in 17 cases of lead nephropathy are shown. It is concluded that lead nephropathy should be recognized early and treated energetically, as this may stabilize or improve renal function. Since EDTA is excreted much like creatinine, the dosage must be reduced proportionately in response to elevated serum creatinine levels in the patient with renal failure.
The guidelines for management of childhood lead poisoning1 and industrial lead exposure2,3 have been well defined, but little has been published on the treatment of chronic lead nephropathy. It has been suggested that this form of renal disease produces an irreversible scarring of the kidney and that treatment may be of little value.4 Since the therapeutic agents available for use can cause renal toxicity, it is important to know whether treatment is indicated, as well as how it can be given safely in the patient with renal insufficiency. This paper is an attempt to review the chelation therapy available for treatment of lead poisoning, to define safe limits for use in renal failure, and to show the results of treatment in lead nephropathy. Fro
m this, conclusions and recommendations are drawn concerning the treatment of this disease.Therapeutic Agents
Three agents have been used in the treatment of lead poisoning: dimercaprol (2,3-dimecaptopropanol), known as British anti-lewisite (BAL; penicillamine; and edetate (EDTA) calcium disodium.1 The indications fro and use of each agent are defined below.
BAL (British anti-lewisite). BAL is an old agent, first made available during World War II. It is the chelating agent of choice for mercury, arsenic, and gold poisoning, but it also is known to chelate lead.1 It must be injected parenterally, after which high levels in the blood are maintained for two hours; the dose is excreted within 6 to 24 hours. Therefore, in acute poisoning, it is recommended that injections be repeated every four hours in doses of 3 to 5 mg/kg of body weight. Approximately half the injected dose is excreted through the biliary system. Hepatic injury does require reduction in BAL dosage, although the drug is well tolerated in the presence of renal failure. It has been shown that combination therapy, using both BAL and EDTA, results in greater salvage in severe childhood lead poisoning with encephalopathy than does EDTA therapy alone.1 combination BAL-EDTA therapy is recommended in all cases of severe acute intoxication, particularly when encephalopathy is present. BAL is also a good second-line drug which should be used in the patient who is sensitive to EDTA.
d-Penicillamine. This agent was first used in the treatment of Wilson’s disease in 1956 and is the recognized therapy for this disease and for cystinuria.4 It can be used orally over long periods of time. Penicillamine given parenterally has been shown to be nearly as effective as parenteral EDTA in promoting the urinary excretion of lead.5
* * * patient with chronic lead intoxication, in that there is more opportunity for the redistribution of lead in the tissues, which produce a greater recovery of lead per milligram of EDTA administered.3 In the patient with renal failure, it is of primary importance that the rate of administration does not exceed the rate of excretion since that would produce increasing and toxic levels in the blood. Thus widely spaced, small doses of EDTA are efficacious in treatment and quite safe even in advanced renal disease. When in doubt, one should always err on the side of less frequent doses.The intramuscular use of EDTA has been confined almost entirely to small children. It can be given in doses of 12.5mg/kg every four hours in cases of acute, severe poisoning.1 Excretion is nearly as rapid after intramuscular use as after intravenous administration.6
There has been much controversy about the oral administration of EDTA. Absorption from the intestinal tract is poor. Studies in the rat demonstrate that 80% to 95% of the dose remains in the feces.6 [Despite this fact, oral administration in the human has been shown to effectively promote lead excretion and has been used for treatment.10] This practice has been criticized by Rieders,3 since the gastrointestinal tract is the major route for lead excretion and the lead-EDTA complex is readily absorbed in the cat.11 Thus, oral administration of EDTA actually may increase lead absorption. In man, however, Bell et al12 and Shiels et al13 have demonstrated increased fecal lead content after oral EDTA therapy, suggesting that fecal as well as urinary excretion is promoted. It is quite clear that EDTA should never be given orally in the treatment of acute lead poisoning or during periods of excessive exposure when the lead concentration in the intestinal tract may be quite high. There may well be some place for oral therapy in the chronically or mildly poisoned individual who is not currently being exposed. When used orally, doses must be high (i.e., 2 to 4gm daily in divided doses) to effectively promote lead excretion. No adverse effects have been observed when orally administered EDTA has been used in this way.10,12,13
EDTA as a Diagnostic Agent
Lead nephropathy is a late consequence of lead exposure and usually does not become clinically apparent for 10 to 20 years.14 Since lead exposure may have ended years before the renal disease becomes apparent, the urinary lead excretion may be normal. However, anemia is always present in the untreated patient, and the erythrocyte delta-amino-levulinic acid dehydratase (ALA-D) activity is depressed. The level of lead in bone is characteristically high, and the abnormal tissue stores can be demonstrated by the administration of EDTA.14 In response to the test dose of 1gm given intravenously, the normal individual seldom excretes mort than 0.2mg.3 The patient with lead poisoning usually excretes more than 1mg in the first 24 hours.3 When renal insufficiency is advanced and lead exposure has been very remote, it may be necessary to collect urine for three days to demonstrate a significant increase over basal lead excretion.14,15 Orally administered EDTA also has been used for this purpose.16,17 In the absence of renal failure, most of a 2gm dose given orally at bedtime will be excreted in the overnight urine, which can be collected and analyzed for lead. Such a simplification of the test permits its use in clinic or office patients. The response is almost as good as for intravenous administration; an excretion of 0.5mg/literor more in the overnight urine should be considered significant.17
Results of Treatment in Lead NephropathySeventeen patients with lead nephropathy were reviewed to determine the effects of adequate treatment. Diagnosis was based on the demonstration of characteristic focal interstitial fibrosis with tubular degeneration and nephrosclerosis in the absence of urinary infection, obstruction, or other disease.18 In all cases lead poisoning had been prolonged and severe and was easily demonstrated. All subjects were anemic. In all subjects, the source of lead was illegal alcohol. Since these individuals frequently continue to use "moonshine" despite admonitions against it, it is almost impossible to adequately de-lead them. For this reason, patients are classified as "treated," or "intractable and/or inadequately treated" for comparative purposes.
____________________________________________
† From the Department of Medicine,
University of Alabama Medical Center, and the Surgical Nephrology Research
Laboratory, BA Hospital, Birmingham, Ala.
Reprint requests to Dr. Morgan, VA Hospital, 700 S 195h St, Birmingham, Ala
35233
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