Background for Occupational Kidney Disease
"In the vast majority of cases,
acute tubular necrosis is the renal lesion that develops. Hours to days after
the exposure, the acute tubular necrosis is manifested by decreased urine
output, usually in the oliguric range of less than 500 ml/d. The urinalysis
typically is diagnostic of acute tubular necrosis, with renal tubular cells,
muddy brown granular casts, and little or no protein. Red blood cells, white
blood cells, or casts of either cell type are not typically seen with acute
tubular necrosis and suggest the presence of glomerulonephritis." [LaDou,
"Because most of the transport
systems are localized in the proximal tubule, that part of the nephron is the
most frequent target of nephrotoxic chemicals. . . According to some authors, up
to 20% of the cases of acute renal failure might be ascribed to toxic injury,
mostly by drugs." [Sullivan, p. 281]
tubular necrosis (ATN) is characterized by an abrupt decrease in the GFR due to
proximal tubular dysfunction caused by ischemia (50% of cases) and nephrotoxins
(35% of cases). Although this type of renal injury has long been designated ATN,
in many cases little true necrosis of tubular cells is present on histologic
examination. . . . The presence of tubular dysfunction, rather than necrosis,
may explain the abrupt recovery of renal function that is seen in some patients
with ATN." [Schrier, p. 153-4]
parenchymal ARF [acute renal failure] is rare. . . . Poor renal blood flow,
however, is the most common cause of ATN, typically occurring in patients
with markedly low blood pressure from major bleeding, surgery, or
severe infections. Fluid loss from excessive sweating, gastrointestinal
disorders with diarrhea and vomiting, and overuse of diuretic drugs may also
cause prerenal ATN. . . . Isolated ATN, without severe interstitial or
glomerular damage or inflammation, is reversible and has a good
prognosis." [APHA, p. 439-40]
high molecular weight (HMW) proteins such as albumin (about 65,000 daltons) and
low molecular weight (LMW) proteins such as B-2 microglobulin (<40,000
daltons) are able to cross the glomerulus to varying degrees. . . . Against this
background, changes in the level o f excretion of HMW and LMW plasma proteins
can serve as approximate markers of glomerular and tubular dysfunction,
respectively. . . . In the absence of acute illness or unusually intense
activity, protein excretion in excess of 150 mg per day is a reliable indicator
of kidney damage. . . . At the earliest stages of renal damage, the specific
proteins present may localize the site of damage to either the glomerulus or the
tubule. When more advanced disease is present, however, multiple classes of
proteins may be present, reflecting more widespread damage." [Rosenstock, p. 567]
". . . in general, glomerular
lesions after occupational or environmental exposures are very uncommon. . . .
Most chronic kidney diseases associated with exposure to agents such as lead or
cadmium present with chronic interstitial nephritis characterized by tubular
proteinuria (usually less than 2 g/24 h) and a urinary sediment usually lacking
any cellular elements." [LaDou, p. 363]
renal failure is long-standing, progressive deterioration of renal function.
Symptoms develop slowly and include anorexia, nausea, vomiting, stomatitis,
dysgeusia, nocturia, lassitude, fatigue, pruritus, decreased mental acuity,
muscle twitches and cramps, water retention, malnutrition, GI ulceration and
bleeding, peripheral neuropathies, and seizures. Diagnosis is based on
laboratory testing of renal function, sometimes followed by renal biopsy."
[Merck Manual, p. 1985]
"Membranous nephropathy is
deposition of immune complexes on the GBM [glomerular basement membrane] with GBM thickening. Cause is usually
unknown, although secondary causes include drugs, infections, autoimmune
diseases, and cancer. Symptoms and signs include insidious onset of edema, heavy
proteinuria, benign urinary sediment, normal renal function, and normal or
elevated BP. Diagnosis is by renal biopsy." [Merck Manual, p.
Concerning the relative
prevalence of chronic kidney disease caused by metals, both occupational and
nonoccupational, cadmium and lead are common causes of chronic interstitial
nephritis and tubular dysfunction, while mercury is an uncommon cause of
nephrotic syndrome, and silicon is an uncommon cause of glomerulonephritis.
[Goldfrank, Table 27-7]
"Historic cohort mortality
studies of cadmium-exposed working populations have yielded mixed results in
studying end-stage renal disease as a cause of death." [Rosenstock, p.
"In two recent
case-control studies, where exposure to organic solvents has been assessed
in great detail, no significant risk for either renal disease in general or
glomerulonephritis was found." [APHA, p.
"Evidence from chronic
lead nephropathy is not consistent. In some reports, workers with previous
heavy and long-term lead exposure display little, if any, evidence of
adverse renal effects." [APHA, p. 437]
reproducibility in selected genetically susceptible experimental
animals, it appears that the mercury-induced proteinuric syndrome occurs
rarely in humans. Recent cross-sectional studies of exposed workers have
found no increase in urinary albumin, anti-GMB antbodies or other
autoantibodies." [Rosenstock, p. 581]
"Mercury accumulates in
kidney tissues. Several investigations have found renal changes in workers
chronically exposed to mercury vapor; generally these changes are small, but
they may be indicative of glomerular or tubular damage." [Rom, p. 995]
Mortality studies have not
detected any excess of end-stage renal disease in populations exposed to
cadmium compounds. [Rom, p. 1002]
Big Picture of Chronic Renal Disease and End-Stage Renal Disease (ESRD)
Chapter in Maxcy-Rosenau-Last Public Health & Preventive Medicine, 15th
Ed., 2008 on "Renal and Urinary Tract Disease"
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."
Dominant Polycystic Kidney Disease
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."
Disease and Illicit Drugs
Disease and the Human Immunodeficiency Virus
Uremic Syndrome (HUS)
causes of renal disease were not mentioned in this chapter.
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).
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."
is "A clinical syndrome reflecting dysfunction of all organ systems due
to untreated or undertreated acute or chronic renal failure."
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.
Facts About Chronic Kidney Disease (CKD) from the National Kidney Foundation
Acute Toxic Effects on the Kidneys
Renal Principles in Goldfrank's Toxicologic Emergencies, 8th
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."
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
5. Olson's Poisoning & Drug Overdose, p. 38-9.
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."
failure is characterized by a progressive rise in the serum creatinine and
blood urea nitrogen levels, usually accompanied by oliguria or anuria."
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.
Occupational Kidney Disease
Renal Toxicology by Rodriquez and Hernandez in LaDou, Occupational &
Environmental Medicine, 2007)
two forms of renal disease resulting from mercury exposure are acute tubular
necrosis and nephrotic syndrome."
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."
is unclear whether uranium is responsible for significant occupationally
related renal disease in humans."
possible association of silica and glomerulonephritis is suggested by animal
studies, case-control studies, and multiple case reports."
by Organic Solvents
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."
by Carbon Disulfide
number of renal disorders are reported, along with accelerated
Clinical Renal Toxicology by Bernard in Sullivan, Clinical Environmental
Health and Toxic Exposures, 2001
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."
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."
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."
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."
number of solvents used in industry or home products (e.g., halogenated
hydrocarbons, ethylene glycol, petroleum distillates, and toluene) are direct
Renal and Bladder Disorders by Rhoads and Daniell in Rosenstock, Clinical
Occupational & Environmental Medicine, 2005
acute renal injury and renal failure
and other elements
Lead, Mercury, Beryllium
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
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."
weight of evidence favors any effect of solvents being non-specific and not
limited to specific solvent compounds. Immune mechanisms are probably
exposure to carbon disulfide may accelerate atherosclerosis, and epidemiologic
studies of chronically exposed workers have demonstrated significantly
increased risks for cardiovascular disease."
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."
What about Silica?
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]
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]
silica in International Chemical Safety Cards: EFFECTS
OF LONG-TERM OR REPEATED EXPOSURE: The substance may have effects on the lungs
, resulting in fibrosis (silicosis). This substance is carcinogenic to humans.
"The results do
not clearly show that patients with silicosis have an excess of end-stage
renal disease, . . ." [See PubMed #1 below]
". . .
risks of neither end-stage renal disease nor renal cancer were related to
cumulative exposure." [See PubMed #3 below]
Abstracts on Silica and Kidney Disease:
and end-stage renal disease.
stage renal disease among ceramic workers exposed to silica.
from lung and kidney disease in a cohort of North American industrial sand
workers: an update.
Effects of Occupational Exposure to Respirable Crystalline Silica
Occupational Sentinel Health Events
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:
lead (battery makers, plumbers, solders);
(electrolytic processes, arsenical ore smelting);
mercury (battery makers, jewelers, dentists);
tetrachloride (fluorocarbon formulators, fire extinguisher makers);
glycol (antifreeze manufacture);
lead (chromate pigment production workers);
main reference was Schreiner GE, Maher JF (1965): Toxic nephropathy. Am J Med
Table of Toxic Effects to Kidneys
Renal Failure (CFR)
METALS: Ag, As (N), Au= (N), Bi (N), Cd, Cr (N), Hg salts (N), Li
(N), Pb, Pl= (N), Sb= (N), Tl (N), Ur; CCl4, other chlorinated solvents,
glycols (N), petroleum distillates (case reports), toluene (N), paraquat,
Si, organic solvents
salts (N), phenylmercury (N), Cr(VI), As (N)
(10 yr latency), Hg0, Hg salts, Hg=, As (N), Pb, Toluene (N);
salts (N), Cd, Cr (N), Hg (N), Vd (N), CCl4, other chlorinated solvents,
dioxane, toluene (N), alkyl derive ethylene glycol, phenol, PCP, DNP
Cd, Be, CS2 (atherosclerosis)
Si, organic solvents;
Stibine, Cd, Pb, Hg salts
(N), Pb, Cr salts (N), Ge (N), Hg salts, Hg=, halogenated hydrocarbons,
ethylene glycol, petroleum distillates, toluene (N), Ur
Cd, Chromates (markers), Ur (markers)
salts (N),methylHg (no)
(nephropathy rare), Hg salts (N), methylHg (no)
diuretics, methoxyethylHg, ethylHg, phenylHg
IV salts (oral or skin burns)
Hg proteinuria abates when exp. stops
arsenic, bismuth, cadmium, Hg0, lead, chloroform, uranium
hexafluoride, dioxane; p. 440
cadmium; p. 436-7
(N); Organic gold (Au=); Organic mercury (Hg=); Elemental Hg (Hg0);
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.
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
(any agent that causes hemolysis, eg, Arsine and Stibine)
(any agent that causes rhabdomyolysis, eg, acute poisoning from
Pentachlorophenol, Dinitrophenol, and Dinitro-o-cresol)
ischemia (any agent that causes poor renal blood flow secondary to
cardiovascular collapse or liver failure)
Chronic renal failure (CRF, chronic renal insufficiency; chronic kidney disease,
unspecified) ICD-9 585.9
Past history of occupational acute
tubular necrosis without full recovery
tubulointerstitial nephropathy, ICD-9 583.89
Lead poisoning, chronic
Chronic berylium disease
syndrome with unspecified pathological lesion in kidney, ICD-9 581.9
Mercury poisoning, chronic
of renal dysfunction in workers previously exposed to mercury vapour at a
results may suggest that microalbuminuria and enzymuria reported in subjects
with ongoing exposure to Hg vapour are reversible in most instances."
adverse effects of lead on renal function in lead-exposed workers.
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."
absorption and renal dysfunction in a South African battery factory.
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."
effects in long term exposed lead smelter workers.
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."
of microproteinuria in cadmium workers with incipient tubular dysfunction after
reduction of exposure.
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."
of cadmium exposure in workers in a cadmium pigment factory after changes in the
of urinary low molecular weight protein was observed in the workers over the
High-Risks Job Tasks for Occupational CRF with High, Sustained Exposures to Cd,
Pb, and Hg
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,
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]
Working in chloralkali plant, Manufacturing instruments (thermometers,
barometers, etc.), Fur preserving, and Gold extracting; [APHA, p. 209]
Revised: March 14, 2013