I. Background for Occupational Kidney Disease

 Acute Renal Dysfunction

Chronic Renal Insufficiency

II. The Big Picture of Chronic Renal Disease and End-Stage Renal Disease (ESRD)

1. Chapter in Maxcy-Rosenau-Last Public Health & Preventive Medicine, 15^th Ed., 2008 on "Renal and Urinary Tract Disease"

Specific Renal Diseases:

Diabetic Renal Disease

Hypertensive Renal Disease

Glomerulonephritis

"Most forms of GN are probably immunologically mediated, and genetic predispositions to some are suggested by family clusters and by associations with certain HLA types. Associations with specific infections are well established, especially in the developing world, but few precursors or etiologic factors are recognized in the common forms of GN that persist in westernized countries. . . .Idiopathic GN may be associated with infections such as hepatitis B or C or malignancies."

Autosomal Dominant Polycystic Kidney Disease

Analgesic Nephropathy

Acute Renal Failure

"Most cases of community-acquired ARF have a single, treatable cause of renal failure that is either prerenal (secondary to vomiting, poor intake, diarrhea, glycosuria, gastrointestinal bleeding and diuretics) or postrenal (secondary to prostate enlargement from hyperplasia or carcinoma). It is not very common and the prognosis is usually good."

Renal Disease and Illicit Drugs

Renal Disease and the Human Immunodeficiency Virus

Hemolytic Uremic Syndrome (HUS)

Occupational causes of renal disease were not mentioned in this chapter.

2. Harrison's Practice

1. Chronic Renal Disease is "A pathophysiologic process with multiple causes that lasts > 3 months and results in progressive attrition of the number and function of nephrons." It frequently leads to end-stage renal disease (ESRD). 

2. ESRD is "A clinical state in which irreversible loss of endogenous renal function has occurred. Patients are permanently dependent on renal replacement therapy (dialysis or transplantation) to avoid life-threatening uremia."

3. Uremia is "A clinical syndrome reflecting dysfunction of all organ systems due to untreated or undertreated acute or chronic renal failure."

4. In the USA, 6% of adults have mild chronic renal disease (GFR 60-90 ml/min per 1.73 m2) and 4.5% have moderate to severe disease (GFR < 60 ml/min per 1.73 m2). Incidence of ESRD in the U.S. is about 95,000 new cases each year. Primary causes are Diabetes (44%), Hypertension (27%), Glomerulonephritis (8%), Cystic kidney (2%), and Other (18%). Seen at all ages, but incidence increases with age. Similar incidence in men and women. The risk factors are Diabetes, Hypertension, Family history of heritable renal disease, Older age, Autoimmune disease, and Past episode of acute renal failure.

3. The Facts About Chronic Kidney Disease (CKD) from the National Kidney Foundation

III. Acute Toxic Effects on the Kidneys

4. Renal Principles in Goldfrank's Toxicologic Emergencies, 8^th Ed., 2006.

Acute Renal Failure

Acute prerenal failure

"One important cause of prerenal failure is the extreme renal hypoperfusion caused by liver failure: the hepatorenal syndrome. This syndrome is characterized by impaired renal function and marked constriction of the renal arteries associated with severe chronic or acute hepatic failure."

Acute urinary obstruction

Acute tubular necrosis

"Acute tubular necrosis, the most common nephrotoxic event, is characterized pathologically by patchy necrosis of tubules, usually the proximal segments. This lesion is associated with three different processes: direct toxic injury, ischemic injury from renal hypoperfusion and pigmenturia. Direct toxicity accounts for approximately 35% of all cases of acute tubular necrosis."  Included in the list of "Xenobiotics that Cause Acute Tubular Necrosis" are ethylene glycol, diethylene glycol, halogenated hydrocarbons, arsenic, bismuth, chromium, mercury, mushroom toxins, myoglobin, hemoglobin, and radiocontrast agents.

Acute interstitial nephritis

Acute vasculitis

5. Olson's Poisoning & Drug Overdose, p. 38-9.

"Renal failure may be caused by a direct nephrotoxic action of the poison or acute massive tubular precipitation of myoglobin (rhabdomyolysis), hemoglobin (hemolysis), or calcium oxalate crystals (ethylene glycol), or it may be secondary to shock caused by blood fluid loss or cardiovascular collapse."

"Renal failure is characterized by a progressive rise in the serum creatinine and blood urea nitrogen levels, usually accompanied by oliguria or anuria."

Direct nephrotoxins include acetaminophen, acyclovir, mushroom toxins, analgesics (acetaminophen,  ibuprofen, and phenacetin), aminoglycosides, chlorates, chlorinated hydrocarbons, cyclosporin, EDTA, ethylene glycol, and heavy metal salts. Hemolytic agents include arsine, naphthalene, and oxidizing agents (esp. with G6PD deficiency). Agents causing rhabdomyolysis include amphetamines, cocaine, prolonged immobility in a coma, hyperthermia, phencyclidine, status epilepticus, and strychnine.

IV. Occupational Kidney Disease

6. Renal Toxicology by Rodriquez and Hernandez in LaDou, Occupational & Environmental Medicine, 2007)

Caused by Lead

Caused by Cadmium

Caused by Mercury

"The two forms of renal disease resulting from mercury exposure are acute tubular necrosis and nephrotic syndrome."

Caused by Beryllium

"Kidney damage occurs not as an isolated finding but only in conjunction with other forms of toxicity. In the kidneys, Berylliosis can produce granulomas and interstitial fibrosis. Beryllium nephropathy is associated with hypercalcuria and urinary tract stones."

Caused by Uranium

"It is unclear whether uranium is responsible for significant occupationally related renal disease in humans."

Caused by Silicosis

"The possible association of silica and glomerulonephritis is suggested by animal studies, case-control studies, and multiple case reports."

Caused by Organic Solvents

"There have been a number of intriguing case reports over the last 20 years of anti-glomerular basement membrane antibody-mediated glomerulonephritis occurring after solvent exposure. However, it remains unclear whether the solvent exposure is truly causal in these cases."

Caused by Carbon Disulfide

"A number of renal disorders are reported, along with accelerated atherosclerosis."

7. Clinical Renal Toxicology by Bernard in Sullivan, Clinical Environmental Health and Toxic Exposures, 2001

Nephrotoxins

"Chemicals can affect the renal function or structures through a direct toxic action or through various systemic effects, such as intravascular hemolysis, rhabdomyolysis, or cardiac failure. Only those chemicals producing specific effects on the kidney are considered here."

Lead

Cadmium

Mercury

Silica

"An association between exposure to silica and silicon-containing compounds and chronic nephropathy has been suspected for many years. Several cases of rapidly progressive glomerulonephritis without significant immune deposits have been reported in workers exposed to silica."

Chromium

"The acute tubular toxicity of chromate and dichromate salts in animals is well documented, and cases of renal tubular necrosis have been described in humans after acute poisoning."

Other Inorganic Compounds

"Uranium salts can produce acute tubular injury and tubular necrosis in animals and humans. Chronic effects, except a slight elevation of B2-microglobulin excretion in uranium mill workers, have not been reported."

Organic Chemicals

"A number of solvents used in industry or home products (e.g., halogenated hydrocarbons, ethylene glycol, petroleum distillates, and toluene) are direct tubular toxins."

8. Renal and Bladder Disorders by Rhoads and Daniell in Rosenstock, Clinical Occupational & Environmental Medicine, 2005

Acute renal disorders

Pigment Nephropathy

Acute Interstitial Nephritis

Nephrotoxic acute renal injury and renal failure

Metals and other elements

Halogenated hydrocarbons

Glycols

Petroleum distillates

Bipyridyl herbicides

Chronic renal disorders

Chronic tubulointerstitial nephropathy

Cadmium, Lead, Mercury, Beryllium

Chrome platers and long-term exposure to uranium dust:  ". . . no links have been established between chronic exposure to either of these agents and development of clinically significant renal dysfunction."

Chronic glomerulonephropathy

"Numerous case reports have described biopsy proven proliferative glomerulonephtitis in persons exposed to silica (either with silicosis or without any pulmonary disease), and two recent studies document an increased risk for end-stage renal disease (particularly due to glomerulonephritis) in silica-exposed workers. . . . The mechanism for this putative nephrotoxicity is not well understood and may involve both a direct nephrotoxic effect as well as an immune-mediated mechanism of injury."

"The weight of evidence favors any effect of solvents being non-specific and not limited to specific solvent compounds. Immune mechanisms are probably involved."

Vascular nephropathy

"Chronic exposure to carbon disulfide may accelerate atherosclerosis, and epidemiologic studies of chronically exposed workers have demonstrated significantly increased risks for cardiovascular disease."

Radiation nephritis

Hypertension

"Most authorities now question the existence, or at least the clinical significance, of any inherent hypertensive effect of lead beyond that secondarily attributable to lead-associated chronic renal insufficiency."

V. What about Silica?

1. "Epidemiological studies have revealed an excess prevalence of scleroderma (progressive systemic sclerosis) among workers exposed to silica in mining and stone-cutting trades. The features of scleroderma appear to be the same as those seen in a non-occupational setting. The association with scleroderma appears to be convincing for substantial silica exposure as well as overt silicosis." [Hendrick, p. 113]

2. "Scleroderma, a systemic connective tissue disorder, causes thickening of the arterial wall and narrowing of the arterial lumen of various arteries. In about 1/2 of patients, scleroderma affects the kidneys, causing glomerular disruption and intimal proliferation, medial thinning, and increased collagen deposition in the adventitial layer of small interlobular renal arteries. Secondary changes (eg, fibrin thrombi, fibrinoid necrosis, immune reactions, increased vasomotor tone) contribute to renal dysfunction." [Merck Manual, p. 2035]

3. See "Does Silica Cause Kidney Disease?"

VI. Occupational Sentinel Health Events

An occupational sentinel health event is "a disease, disability, or untimely death which is occupationally related and whose occurrence may: 1) provide the impetus for epidemiologic or industrial hygiene studies; or 2) serve as warning signal that materials substitution, engineering control, personal protection, or medical care may be required." [Mullan] According to the authors of this 1991 paper "Acute or chronic renal failure" is linked to the following agents: 

1. Inorganic lead (battery makers, plumbers, solders);

2. Arsine (electrolytic processes, arsenical ore smelting);

3. Inorganic mercury (battery makers, jewelers, dentists);

4. Carbon tetrachloride (fluorocarbon formulators, fire extinguisher makers);

5. Ethylene glycol (antifreeze manufacture);

6. Inorganic lead (chromate pigment production workers); 

The main reference was Schreiner GE, Maher JF (1965): Toxic nephropathy. Am J Med 38:409-449.

 

VII. Table of Toxic Effects to Kidneys

VIII. Haz-Map Kidney Diseases and Associated Chemicals

Nephrotoxin as defined in Haz-Map: The chemical is potentially toxic to the kidney in the occupational setting.

In order to be linked to a disease in Haz-Map, the chemical must be known to be an occupational cause of the disease. Thus, ethylene glycol causes acute tubular necrosis after ingestion, but because of irritating effects, the maximum concentration tolerated by workers is too low to cause acute renal failure [ACGIH]  

1. Acute tubular necrosis ICD-9 584.5

Hemoglobin (any agent that causes hemolysis, eg, Arsine and Stibine)

Myoglobin (any agent that causes rhabdomyolysis, eg, acute poisoning from Pentachlorophenol, Dinitrophenol, and Dinitro-o-cresol)

Renal ischemia (any agent that causes poor renal blood flow secondary to cardiovascular collapse or liver failure)

Carbon tetrachloride

Dioxane

Lead

Cadmium and compounds

Chromium and compounds

Uranium and compounds

Paraquat

Diquat

2. Chronic renal failure (CRF, chronic renal insufficiency; chronic kidney disease, unspecified) ICD-9 585.9

1. Past history of occupational acute tubular necrosis without full recovery

2. Chronic tubulointerstitial nephropathy, ICD-9 583.89

       Lead poisoning, chronic

       Cadmium poisoning, chronic

       Chronic berylium disease

3. Nephrotic syndrome with unspecified pathological lesion in kidney, ICD-9 581.9

       Mercury poisoning, chronic

IX. PubMed Abstracts

Assessment of renal dysfunction in workers previously exposed to mercury vapour at a chloralkali plant.

"The results may suggest that microalbuminuria and enzymuria reported in subjects with ongoing exposure to Hg vapour are reversible in most instances."

No adverse effects of lead on renal function in lead-exposed workers.

"These results suggest that long-term less severe exposure to lead up to 70 micrograms/dl of Pb-B may not cause adverse effects on renal glomerular function and proximal tubular function."

Lead absorption and renal dysfunction in a South African battery factory.

"The most plausible explanation for the discrepancy between this study and the negative studies cited is the presence of a higher cumulative body burden of Pb in this workforce. It is probable that average past exposure in this workforce was heavy, as control regulation for occupational Pb was introduced into South African industry only in 1991, setting the medical standard at 80 ug/dl blood Pb."

Kidney effects in long term exposed lead smelter workers.

"Despite many years of moderate to heavy exposure to lead, particularly for the retired lead workers, no signs of adverse effects on the kidney such as early tubular or glomerular malfunction were found. Reversible changes in kidney function during the 1950s and 1960s could not be excluded, however, due to a greater exposure to lead during that time."

Reversibility of microproteinuria in cadmium workers with incipient tubular dysfunction after reduction of exposure.

"When the microproteinuria was mild (beta 2 MG-U > 300 and < or = 1,500 micrograms/g creatinine) at the time exposure was reduced, and the historical Cd-U values had never exceeded 20 micrograms Cd/g creatinine, there was indication of a reversible tubulotoxic effect of Cd."

Markers of cadmium exposure in workers in a cadmium pigment factory after changes in the exposure conditions.

"Reversibility of urinary low molecular weight protein was observed in the workers over the four years."

X. High-Risks Job Tasks for Occupational CRF with High, Sustained Exposures to Cd, Pb, and Hg

Cadmium: Brazing, Nickel-cadmium battery manufacturing, Primary and secondary smelting, Scrap metal recovery, Electroplating, and Pigment manufacturing; [APHA, p. 435] Cadmium fumes may be produced during brazing of stainless steel, low-alloy steel, and nickel alloys. Brazers who are employed for the production of refrigerators, electronics, jewelry, and aerospace components may be at risk for cadmium induced kidney disease. [Burgess, p. 189]

Lead: Lead battery manufacturing, Soldering, Radiator repair, Primary smelting, Glass and ceramic manufacturing, and Paint stripping; [APHA, 436] Simple lead-tin soldering does not generate significant lead fume. [Burgess, p. 381]

Mercury: Working in chloralkali plant, Manufacturing instruments (thermometers, barometers, etc.), Fur preserving, and Gold extracting; [APHA, p. 209]

Revised: May 30, 2018

brownjay@haz-map.com