Occupational renal diseases are important because they are entirely preventable. In addition, renal disease produced by heavy exposure to industrial toxins by relatively few workers provides a clinical basis for understanding the consequences of low-dose exposure to the general population from environmental pollution. The known toxins that produce kidney disease in the workplace are limited to the heavy metals plus silica and certain organic compounds, particularly halogenated hydrocarbons, employed as industrial solvents. The absence of information on the adverse renal effects of other industrial pollutants does not prove that no such effects occur, but rather that epidemiologic studies are lacking. It is probable that as the genetic basis of individual susceptibility unfolds, the contribution of toxins to renal disease in the general population will become clearer.
The renal diseases due to heavy metals are listed in the Table. Lead, cadmium, mercury arsenic, chromium, and uranium are widely recognized as nephrotoxins in humans. Given appropriate chemical forms, dosage, and route of administration, acute tubular necrosis (ATN) is consistently produced by these metals. ATN occurs because of the selective accumulation of metals in the proximal tubule. When the appropriate oxidative form is present in sufficient quantity, the metals induce irreversible cellular injury. Following intense occupational exposure, and in animal experiments, the cause of ATN is obvious. When recovery is incomplete, chronic tubular-interstitial nephritis (TIN) may persist as a residual. On the other hand, the role of heavy metals in the induction of immunologically mediated glomerular disease is by no means obvious.
The cause of chronic renal disease due to heavy metals in the absence of known prior ATN may not be obvious. Controversy arises because the inciting causes of most renal diseases are unknown. Many contributing factors are often present simultaneously and there may be a long latent period before renal disease is recognized, obscuring the contribution of a specific nephrotoxins. Like the heavy metals, some halogenated organic compounds can produce ATN following massive absorption. More commonly, solvent exposure in the workplace has been associated with glomerular disease. Immune complex as well as anti-glomerular basement membrane antibody disease has been described under the rubric "solvent nephropathy." The role of solvents in the induction of occasional glomerular disease with heavy albuminuria should not be confused with the histologic abnormalities and the minute protein excretion (tubular proteinuria) induced regularly by solvents and other petroleum products.
In addition to recognizing the similarities among the occupational renal diseases, it is important to note the differences. Heavy exposure to lead (blood lead > 150 μg/dL) regularly produces a reversible Fanconi syndrome in humans and experimental animals in association with characteristic acid-fast intranuclear inclusion bodies in proximal tubule cells. The acute appearance of aminoaciduria, glycosuria, phosphaturia, and tubular proteinuria is of little importance in the face of the potentially fatal lead encephalopathy. Lead-induced Fanconi syndrome has been described in children exhibiting pica as well as in experimental animals. In contrast to the Fanconi syndrome, peripheral neuropathy, colic, encephalopathy and anemia of acute lead poisoning, long-term occupational exposure (> 3 years) causes hypertension, gout, and interstitial nephritis. Lead appears to be an independent risk factor for elevated blood pressure even in the absence of overt renal failure. In the past, the lead etiology of interstitial nephritis was identified by the chelation challenge test that reflected cumulative exposure and excessive bone stores of lead. However, diagnostic criteria for chelatable lead have become unclear because of evidence that even low-level lead exposure (blood leads approximating 10 μg/dL) causes hypertension and renal damage. While prevalence of renal disease from lead may be less at lower levels of exposure, no threshold has been identified. Chelation therapy with either Ca Na2EDTA or succimer is rarely appropriate in the absence of symptomatic intoxication since comparable negative lead balance can be achieved over the long term by preventing further exposure. Over the last 30 years average blood leads in the United States have fallen from about 13 μg/dL to < 2 μg/dL but the contribution of lead to hypertension and renal disease has not been eliminated.
Cadmium can also produce interstitial nephritis. Unlike lead nephropathy, it is not associated with hypertension or gout. Cadmium is initially accumulated in the liver and then transferred to the kidney bound to the carrier protein, metallothionein. It is accumulated in lysosomes by endocytosis in proximal tubule cells. Release of lysosomal enzymes is believed to be responsible for the tubular damage. Chronic interstitial nephritis caused by cadmium is characterized by the Fanconi syndrome accompanied by clinically important proximal tubule reabsorptive defects for calcium and phosphorous. Hypercalciuria is responsible for osteoporosis, osteomalacia and kidney stones. A syndrome caused by cadmium contamination of rice called "itia-itia byo" (ouch ouch disease) has been described in Japan that produced painful bone disease most evident in chronically undernourished, multiparous women. Some reports indicate that the diffuse tubular proteinuria and enzymuria caused by cadmium predicts the future development of chronic renal failure. But following low-level absorption, the tubular damage may be reversible.
Inorganic mercury is accumulated in the proximal tubule with a half-life of about two months. Mercuric chloride (HgCl2, sublimate) is highly nephrotoxic and reproducibly produces acute tubular necrosis at doses > 1.0 mg/kg body weight. Elemental mercury (Hg0) and mercurous chloride (Hg2Cl2) do not cause ATN. Some organomercurials, although concentrated in proximal tubule, have no toxic effect. Others produce a diuresis and were widely used clinically prior to the development of furosemide. Still other organomercurials found as environmental contaminants in the food chain (e.g., methyl mercury) induce tubular proteinuria and neurologic disease, but chronic progressive kidney disease has not been found in humans. In minute doses, all forms of mercury may cause tubular proteinuria that does not predict the future development of renal failure. In genetically selected rodents, however, minute doses of mercury induce transient immune complex and antiglomerular antibody deposition in glomeruli that provides a model of the idiosyncratic immunologically mediated glomerular disease seen rarely in humans. Experimental mercury-induced glomerular disease may also provide a model for understanding silica- and solvent-induced glomerular nephritis (GN). Heightened autoimmune responses have been found after exposure to gold, silver, cadmium, and solvents but immune glomerular disease has not been identified as a result of occupational exposure to these metals. Iatrogenic gold-induced glomerular disease, and drug-induced lupus-like reactions raise the possibility that exposures to industrial toxins may be more important for the development of glomerular disease in humans than has been recognized. The contribution of environmental toxin exposure to the development of lupus erythematosus and glomerular diseases remains to be determined.
Although specific valance states of arsenic, chromium and uranium reproducibly produce acute tubular necrosis in experimental animals, chronic renal disease resulting from accidental exposure has rarely been identified. Silica, while not a heavy metal, is often considered a metal. It has long been associated with pulmonary fibrosis following inhalation in the workplace. A severe form of silicosis associated with a magnified immune response (silicoproteinosis) may be accompanied by immunologically mediated GN. Glomerular disease without pulmonary disease has also been described in association with silica in ANCA-positive rapidly progressive GN, vasculitis, and Wegener’s granulomatosis. Silica appears to act as an adjuvant stimulating the immune response.
