Pathogenesis of solvent-dependent glomerulonephritis

From data on bioactivation (see chapter 3.1) as well as case reports in humans (see chapter 5), it seems that the renal tubuli are the main target of toxic effects of chemi-cals in the kidney. On the other hand, in case-control studies (see chapter 6.2) glo-merulonephritides seem to be associated with solvent exposures. Several hypo-theses have been developed that try to offer possible explanations for the generation of solvent-related glomerulonephritides. These hypothesis have been summarized in several publications (NELSON et al., 1990; HOTZ, 1994; ROY et al., 1991; YAQOOB et al., 1992; RAVNSKOV, 1998).

According to these hypotheses, two main ways of action are conceivable: the immunological and the toxicological. Both ways do not exclude each other, but could be active concurrently or sequentially (HOTZ, 1994).

One of the first hypotheses of an immunological mechanism suggests that solvents could damage the capillary basement membrane of the alveoles (ABM) in the lung and/or the glomeruli (GBM) in the kidney, inducing an antigen-antibody reaction that leads to glomerulonephritis. This idea is based on case reports that Goodpasture´s syndrome (see Tab. 2.1 and chapter 5), a disease which involves the development of anti-ABM and anti-GBM antibodies, has been described following exposure to organic solvents (NELSON et al., 1990). Since the antigen is cryptic (concealed within the type IV collagen of the basal membrane), it has been proposed that

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damaging agents which injure the basement membrane may expose the antigen, facilitating the binding of anti-GBM antibodies (BOMBASSEI and KAPLAN, 1992). In an experimental animal study, it was observed that when anti-GBM antibodies were injected into rabbits, these antibodies became bound to alveolar basement mem-brane after intratracheal gasoline instillation, but not after saline installation. While this supports the idea that prior damage to alveolar structures may be a prerequisite for anti-GBM antigen deposition in the alveoles, this study did not analyse de-novo synthesis of antibodies following hydrocarbon exposure (BOMBASSEI and KAPLAN, 1992). Moreover, lung damage following gasoline instillation is due to the specific physical properties of the liquid and bears no analogy to inhalation of hydrocarbon vapors.

Goodpasture´s syndrome is a very rare disease (Tab. 2.1) which typically evolves rapidly, while most cases of glomerulonephritis which have been supposed to be re-lated to solvent exposure in epidemiological studies are classified as other, more common types of chronic glomerulonephritides. Therefore, other mechanisms must play a role.

As another immunological mechanism, it has been hypothesized that glomerular damage may result from an indirect immunological process mediated by tubular anti-genic material. In membranous nephropathy, renal tubular epithelial antigen, immu-noglobulins, and complement have been found in glomerular capillaries (EHREN-REICH, 1977). One may speculate that constant low grade tubular damage in susceptible individuals due to chronic solvent exposure may provoke local autoimmu-nity by releasing either sequestered or altered tubular antigens (YAQOOB et al., 1993a). Some support for this hypothesis comes from the observation that gold and mercury, two substances that may cause glomerulonephritis in humans, may also damage the renal tubuli (Cahen et al., 1989; DEKANT and VAMVAKAS, 1993). Fur-thermore, experimental studies of gold-induced nephropathy in rats have shown that gold was present in the tubular epithelium, where it may induce an immunogenic re-sponse, but was not found in the glomeruli were lesions were observed (EHREN-REICH, 1977). However, experimental evidence of a similar action of solvents is lacking.

Toxic damage to the tubuli as the primary lesion is in the foreground of a further hypothesis. The idea is based on observations from experimental exposure of animals to hydrocarbons. These studies have sporadically produced glomerular lesions, but this has generally been accompanied by tubular or tubulointerstitial damage (MUTTI, 1996). Therefore, the primary event may be a toxic tubulointerstitial reaction, the deposition of glomerular immune complexes being secondary (RAVNSKOV, 1989, 1992, 1998). In this context, it has been suggested that repeated peak exposures might induce tubular damage (HOTZ, 1994).

The hypothesis of a primary toxic effect at the tubules seems to be supported by the observation that in chronic kidney diseases morphometric studies of the kidney tissue reveal a striking correlation between the extent of renal dysfunction and the magni-tude of tubulointerstitial disease (NATH, 1992). The main morphological expression of several disease processes is in the tubulointerstitium and interstitial damage has a

central role in loss of renal function (FINE et al., 1993; JACOBSON, 1991). However, it remains to be proven whether tubulointerstitial abnormalities found in primary glo-merular diseases are a secondary event due to ischaemic tubular injury from disrup-tion of the peritubular blood supply following glomerular distrucdisrup-tion, or whether there is a destructive process that attacks both the interstitium and the glomerulus (JACOBSON, 1991).

The aforementioned hypotheses are based on the assumption that solvents are a primary cause of glomerulonephritis. However, it has also been suggested that sol-vents may have a secondary effect on glomerular damage which has been initiated by other toxic substances, immune reactions or systemic diseases, for example dia-betes or hypertension. In this case, solvent exposure could lead to a progression of different types of glomerulonephritides. As will be shown in chapter 6.2, solvent exposure has indeed been associated in case-control studies with several types of glomerulonephritis, and additionally, there is some evidence from these studies that solvent exposure is related to the progression of renal failure in glomerulonephritis.

Preliminary data from a recently published animal study indicate that adriamycin-induced nephropathy is more severe in rats which are also exposed to styrene (MUTTI et al., 1999). However, the doses of adriamycin used to induce renal damage were very high (about acute LD50), and additional data are necessary to more explicitly draw out this hypothesis.

Individual susceptibility is generally assumed to play a role in glomerulonephritis, because this disease is rare, whereas exposure to organic solvents is very common.

There is some evidence that several forms of glomerulonephritides, including Good-pasture´s syndrome, membranous nephropathy, and IgA nephropathy, have human leukocyte antigen (HLA) associations (BOMBASSEI and KAPLAN, 1992; NELSON et al., 1990; IBELS and GYÖRY, 1994). Interindividual variations in xenobiotic-metabolizing enzymes may influence biotransformation of solvents and could play a role in individual susceptibility. In one study on a group of patients with primary glomerulonephritis and an elevated hydrocarbon exposure, an increased frequency of genes encoding for certain variants of glutathione transferases and N-acetyl transferases was found in a subgroup with membranous glomerulonephritis, but not for the whole group (PAI et al., 1997). Further studies are necessary before a rela-tionship between solvent exposure, biotransformation, and individual susceptibility to develop certain types of glomerulonephritides may be hypothesized.

In conclusion, several mechanisms have been suggested how exposure to solvents could be related to the development of glomerulonephritis, all of which are largely hypothetical. This does not argue against a role of solvents, but indicates the necessity of additional data. It must be remembered that the causative agents in most forms of human glomerulonephritis are unknown, and that, besides some infec-tious agents, other stimuli must be involved in the development of this complex disease (COUSER, 1999).

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