Lead and Heavy Metals and the Kidney

Objectives

This chapter will:

1.
Discuss the mechanisms of the renal toxicity related to heavy metals exposure.
2.
Describe the clinical features of poisoning by heavy metals.
3.
Analyze the therapeutic approaches to heavy metal intoxication.

Heavy metals are chemical elements with a specific gravity that is five times the specific gravity of water (1°–4°C). Specific gravity is a measure of density of a given amount of a solid substance when compared with an equal amount of water. The toxic metals arsenic, cadmium, iron, lead, and mercury are defined heavy metals according to this definition. Heavy metals typically are used in agriculture and industrial activities, but natural phenomena such as earthquakes and volcanic eruptions also have been reported to significantly contribute to environment pollution. Heavy metals are used in industrial applications such as production of pesticides, batteries, alloys, and textile dyes. Excessive exposure may lead to specific disorders. The use of cisplatinum for cancer therapy and that of barium during radiologic examinations also can produce unexpected forms of toxicity resulting from heavy metals.

There are more than 30 metals that can cause renal damage through occupational, therapeutic, or accidental exposure. The more common substances involved in renal damage are arsenic, barium, cadmium, cobalt, copper, lead, lithium, mercury, and platinum. Small amounts of these elements are important factors and cofactors in many biochemical reactions.

Heavy metals availability and toxicity are determined by physical factors (phase association, temperature, adsorption), chemical factors (lipid solubility, kinetics), and biochemical factors such as human trophism.

Heavy metals may enter into the human body through food, water, or air; acute poisoning can occur as the result of accidental contamination, suicide attempt, or an inappropriate use of some therapeutic measures.

Mechanism of Heavy Metals Toxicity

The kidney is a target organ in heavy metal toxicity because of its ability to reabsorb and concentrate divalent metals. The extent of renal damage depends on the nature, the dose, and the time of exposure. In general, acute damage differs from chronic damage in its mechanism of toxicity. As a consequence, the clinical features and therapeutic approach are also different.

Heavy metals in plasma exist in nondiffusible (protein-bound) and diffusible (complexed and ionized) forms. The luminal fluid in the early proximal tubule can contain the bound form and the free form. The ionized form is toxic and produces direct cellular toxicity; the mechanism consists of membrane rupture and uncoupling of mitochondrial respiration, with the release of numerous death signals such as reactive oxygen species and cytokines.

Metals are cleared quickly from the blood and are sequestered in many tissues. In acute intoxication, the main site of reabsorption is the apical membrane of the first zone of the proximal tubule, but the loop of Henle and the terminal segments can participate in reabsorption of heavy metals. During chronic intoxication, on the other hand, the bound, inert form is conjugated with metallothionein and glutathione, which then are released into the blood by the liver and the kidney. These compounds subsequently are reabsorbed through an endocytotic process in segment S1 of the proximal tubule.

Therapeutic Approach

Treatment regimens include chelation therapy, decontamination procedures (e.g., charcoal, cathartics, emesis, gastric lavage), supportive care (e.g., intravenous fluids, cardiac stabilization, mechanical ventilation, exchange transfusion), and extracorporeal therapy. The choice of treatment depends on clinical parameters such as age; preexisting pathologies of the liver and kidney (affecting endogenous clearance); cardiovascular disease; toxicologic parameters such as total body, liver, and renal clearances; elimination half-life; molecular weight; toxic dose; protein binding; and the apparent distribution volume.

Considerations for some of the most common metals are reported in the following sections ( Table 222.1 ).

TABLE 222.1

Therapy in Acute Heavy Metal Toxicity

METAL	HD	PD	CVVH	CVVHDF	TPE	HP	CHELATORS
Aluminum	No	No	?	?	No	Yes	DFO
Arsenic	HD + DMSA or HD + BAL	PD + DMSA or PD + BAL	?	?	?	?	BAL, DMSA, D-penicillamine
Barium	Yes	Yes	?	Yes	?	?	—
Bismuth	Yes	Yes	?	?	?	?	BAL, DMSA, DMPS
Cadmium	No	No	No	No	No	No	Calcium-EDTA
Chrome	No	No	No	No	No	No	—
Copper	HD + D-penicillamine	?	?	CVVHDF + D-penicillamine	No	Yes	D-penicillamine, BAL
Lead	No	No	No	No	?	No	Calcium-sodium-EDTA, BAL, DMSA
Lithium	Yes	Yes	Yes	Yes	No	No	No
Mercury	No	No	No	CVVHDF + DMPS	?	No	BAL, DMSA, DMPS (inorganic only)
Platin	Yes	Yes	?	?	Yes	No	No
Thallium	HD + Prussian blue	?	?	?	No	No	Prussian blue

BAL, Dimercaprol; CVVH, continuous venovenous hemofiltration; CVVHDF, continuous venovenous hemodiafiltration; DFO, desferrioxamine; DMPS, dimercapo-1-propane sulfonate; DMSA, dimercaptosuccinic acid; EDTA, ethylenediamine tetra-acetic acid; HD, hemodialysis; HP, hemoperfusion; PD, peritoneal dialysis; TPE, therapeutic plasma exchange.

Lead

Lead (Pb) is one of the oldest occupational toxins, and evidence of lead poisoning can be found dating back to Roman times. Lead is the most ubiquitous of the nephrotoxic metals, and humans are exposed to this agent in air, food, and water.

Source of Exposure

Lead exists in three different forms: metallic lead, inorganic lead (water-soluble lead salts), and organic lead such as tetramethyl lead, which is more toxic than the inorganic form.

Acute Exposure

Acute intoxication is extremely rare and occurs after accidental or intentional ingestion of water-soluble inorganic lead salts or inhalation of tetramethyl lead.

Chronic Exposure

Lead paint, drinking water, lead-glazed ceramics, and herbal remedies from Asia are potential sources of lead exposure. Workers in certain occupations are exposed to high levels of lead, including manufacture of ammunition, batteries, sheet lead, bronze plumbing, radiation shields, and intravenous pumps. Lead also contaminates emissions from motor cars with antiknock additives (tetramethyl lead).

Mechanism of Kidney Damage

Acute Exposure

Acute lead poisoning disrupts the proximal tubular architecture, with histologic changes featuring eosinophilic intranuclear inclusions in tubular cells consisting of lead-protein complexes as well as mitochondrial swelling.

Chronic Exposure

The damage extends to the proximal tubule and to the distal tubule with increased urate secretion, vasoconstriction, and glomerulosclerosis with hypertension and interstitial fibrosis.

Clinical and Laboratory Features

Acute Exposure

Lead poisoning produces a metallic taste in the mouth, nausea, vomiting, diffuse abdominal pain, paresthesias, muscle weakness, and severe anemia with acute hemolytic crisis. Renal impairment may manifest as acute tubular necrosis with hematuria, casts, and aminoaciduria and may be so severe as to progress to frank acute renal failure. This damage occurs in 1 or 2 days. Severe toxicity, with a blood lead level of 50 µg/dL or more, also affects the central and peripheral nervous systems, with frank paralysis, tremors, decreased nerve conduction velocity, and papilledema.

Chronic Exposure

Patients present with myalgias, fatigue, dyspnea, nonspecific abdominal pain, and anorexia. Renal damage includes glycosuria, aminoaciduria, and phosphaturia (Fanconi-like syndrome).

Laboratory Tests

Normochromic or hypochromic anemia with basophilic stippling; elevated reticulocyte count; elevation of blood urea nitrogen (BUN), creatinine, and serum uric acid; with amino acids, glucose, and ALA in the urine (proximal tubule damage) are common laboratory features.

The lead level in the whole blood is an indicator of recent exposure; the selected diagnosis to evaluate the lead level is the ethylenediamine tetra-acetic acid (EDTA) lead mobilization test.

Treatment of Acute Lead Intoxication

Supportive Measures

Gastric lavage and decontamination with activated charcoal are indicated if lead salts have been ingested. Fluid-electrolyte balance must be maintained. Diuretic therapy is indicated, not to eliminate lead but to remove the chelators.

Chelating Agents

In an inorganic lead intoxication, there is an indication to use EDTA, dimercaprol (BAL), dimercaptosuccinic acid (DMSA), and D-penicillamine.

Extracorporeal Therapies

Extracorporeal detoxification measures are ineffective because 95% of lead is stored in the erythrocytes; however, chelators, which are nephrotoxic, can be removed effectively by hemodialysis. The half-life of lead in blood is 9 hours during combined hemodialysis and EDTA and 96 hours when EDTA is given alone. Peritoneal dialysis, hemoperfusion, continuous renal replacement therapies (CRRTs), and therapeutic plasma exchange are generally ineffective.

Mercury

Mercury (Hg) is a silvery white liquid that is volatile at room temperature because of its high vapor pressure. Mercury exists in three forms: elemental, inorganic, and organic.

Source of Exposure

The general population is exposed primarily to this metal from dental amalgam and the diet; amalgam fillings are the most important source of inorganic mercury, and fish are the most important source of the organic one. Occupational exposure occurs in dentistry, in thermometer factories, and in the alloys and chloralkali industries.

Mechanism of Kidney Damage

Mercury accumulates in the kidney and induces epithelial injury and necrosis in the pars recta of the proximal tubule. After acute exposure to mercury, acute tubular necrosis appears, usually accompanied by oligoanuria.

Clinical and Laboratory Features

Acute Exposure

Elemental mercury in vapors produces symptoms after a few hours such as chills, vomiting, diarrhea, acute dyspnea with the occasional fatal form of interstitial pneumonitis, and neurologic symptoms with hypotension and profuse salivation.

Chronic Exposure

Organic mercury gives skin manifestations and neurologic disturbances such as ataxia, paresthesias, and deafness. Mercury now is recognized as causing different types of kidney damage, such as nephrotic syndrome with membranous nephropathy pattern and tubular dysfunction with elevated urinary excretion of albumin, transferrin, retinol binding protein, and β-galactosidase.

Laboratory Tests

A mercury concentration greater than 45 mg/dL in blood suggests acute poisoning.

Treatment of Acute Mercury Exposure

Supportive Measures

Immediate elimination of the metal by gastrointestinal decontamination and rapid administration of chelators, followed by intensive monitoring of hemodynamics and breathing, is necessary.

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