Handbook of Solvents - George Wypych - ChemTech - Ventech!

20.4 Industrial solvents and kidney disease 1361
5. Statistical association in the majority of the studies.
These criteria fulfill the Bradford-Hill criteria, 52 and establish the basic criteria required
for causation.
20.4.6. MECHANISM
Immune-mediated mechanisms play a major role in the pathogenesis of glomerular disease,
in general. In the vast majority of the cases, antigen-antibody reaction and immune complexes
form in the kidney, mainly around the glomerular capillary wall and mesangium.
Cellular antigens, both endogenous such as DNA and tumor antigens, as well as exogenous
such as viral antigen hepatitis B and C, drugs, and bacteria have been shown to be causative
factors in human glomerular immune-mediated diseases. The most common pathological
process described in association with solvent exposure and chronic glomerular nephritis has
been that of IgA nephropathy, Good Pasture’s syndrome, and proliferative
glomerulonephritis.
Unlike acute renal failure caused by hydrocarbons, where the renal damage is secondary
to the nephrotoxins and mainly cause damage of the proximal tubule acute renal failure,
the glomerular chronic renal failure, appears to be immunologically mediated. Among others,
genetic factors may be involved in the pathogenesis of hydrocarbon induced
nephropathy. It has been suggested that the propensity to develop this autoimmune disease
depends on a combination of a genetic component and predilection, and environmental
component. 24 Individuals susceptible to glomerular or tubular injury by hydrocarbons may
develop chronic kidney disease through three possible mechanisms. The first mechanisms
is direct tubular toxicity which is commonly the cause of acute renal failure. While it is true
that the initial injury of acute renal failure is directed toward the tubule of the nephron,
glomerulonephritis may be the result of an autoimmune reaction to the tubulotoxins. 53,54 The
second mechanism mainly involves immunosuppression. Ravnskov, 53 in a review of the
pathogenesis of hydrocarbon associated glomerulonephritis, suggested that hydrocarbons
are immunosuppressives and this effect is noted in several locations in the immunological
cascade. This includes leukocyte mobility and phagocytosis suppression such as shown in
the benzene effects in mice. 55 This suppression of the normal immune response by hydrocarbons
may play a role in the pathogenesis of immune-mediated glomerular lesions. The
third mechanism involves alteration in membrane permeability. Good Pasture’s syndrome
is mediated by antibodies reactive with the glomerular basement membrane and alveolar
basement membranes. Antibodies in experimental models can usually bind to alveolar
basement membranes in vitro by indirect immunofluorescence. Experimental studies suggested
that hydrocarbons alter the permeability of pulmonary capillaries, thereby allowing
anti-glomerular basement membranes to bind to the alveolar basement membranes. 56 This
etiology is further supported by the observation that differential sensitivity to exposures due
to genetic factors since DR3 and DR4 antigens are more frequent in patients with toxic nephritis
than in the general population. 57,58 The study by Zimmerman et al. 40 have shown that
in 6 of 8 patients with Good Pasture’s syndrome had extensive occupational exposure to
solvents ranging from 4 months to 10 years. The results of this study suggested that interaction
between the inhaled hydrocarbons and the lung and kidney basement membranes could
induce autoantibodies to these membranes. Goyer 48 suggested an autoimmune mechanisms
responsible for glomerular lesions following chronic exposure to solvents. Based on case
studies and case reports, it is proposed that chronic exposure to low levels of solvents in susceptible
individuals induces an initial cell injury sufficient to damage cell membranes and to