Q J Med 2001; 94: 79-87
© 2001 Association of Physicians
Membranous nephropathy, hydrocarbon exposure and genetic variants of hydrocarbon detoxification
From the Regional Renal Unit, Royal Liverpool Hospital, Liverpool, and 1 Health and Safety Laboratory, Broad Lane, Sheffield, 2 Department of Renal Medicine, Salford Royal Hospitals NHS Trust, Salford, Manchester, UK
Received 9 March 2000 and in revised form 8 November 2000
 |
Summary |
|---|
 Top Summary IntroductionMethodsResultsDiscussionReferences |
|---|
Modulation of biotransformation by genetic traits may be important in determining environmentally-induced nephrotoxicity. We conducted a case-control study to investigate the role of occupational hydrocarbon exposure, along with polymorphisms of the genes coding for N-acetyltransferase 2 (NAT2) and glutathione S-transferase µ (GSTµ), in the development of idiopathic membranous glomerulonephritis (IMGN). Patients (n=36) with biopsy-proven IMGN were matched with healthy controls for age, gender, and geographical area. Lifetime hydrocarbon exposure was assessed by a validated questionnaire. The polymorphisms of the NAT2 and GSTµ genes (GSTM1) were defined by use of a polymerase chain reaction on white-cell DNA from peripheral blood. Exposure to hydrocarbons was significantly greater in patients with IMGN than in controls (mean±SEM hydrocarbon exposure score 11 003±2955.7 vs. 4352±1418, p<0.02). NAT2 acetylator status was identical in patients and controls with 23 (63.9%) fast and 13 (36.1%) slow acetylators in each group. GSTµ was present in 15 (41.7%) patients and 16 (44.4%) controls. While occupational exposure to hydrocarbons remains a likely factor in its pathogenesis, further work is required to identify the genetic polymorphisms that modulate the risk of IMGN.
|
Introduction |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
Man's interaction with his environment is highly complex. We learn to adapt to our surroundings and thereby to survive and flourish. Man clearly has a huge impact on his own environment: farming the land, the industrialization of the modern world and the use of other animal species to our own ends. It has become increasingly evident that our environment also has a significant impact on us. Exposure to sunlight can lead to skin cancer; chemicals, such as aniline dyes, and benzo(
)pyrene in cigarette smoke, can lead to bladder1,2 and lung cancer,3 respectively, and increased air pollution has been implicated in the recent progressive increase in the incidence of asthma.4,5 It remains to be explained why certain individuals appear to have an increased susceptibility to such environmental influences compared to others, who seem to escape unscathed. One possible explanation is that of genetic susceptibility. We now recognize that many human genes exist as different forms, a phenomenon known as polymorphism. The importance of such genetic polymorphisms is indicated by the numerous studies that have helped to clarify the role of these polymorphisms in different disease processes such as insulin resistance6 and Guillain-Barre syndrome.7 Workers in other fields are investigating the impact of genetic polymorphisms on various diseases, such as the renin-angiotensin system and diabetes8 and schizophrenia,9 but the specific parts that these polymorphisms may play have yet to be fully elucidated. Hydrocarbon exposure, to a greater or lesser degree, is an unavoidable consequence of life in a modern industrialized society: these chemicals are found in car exhaust fumes, cigarette smoke, volatile fuels such as petrol, and some aerosols, to name but a few sources. The association between organic solvent exposure, and the development of intrinsic renal disease was reviewed by Yaqoob and Bell in 1995.10 There is a growing body of evidence to suggest that occupational hydrocarbon exposure may not only be implicated in the aetiology of certain renal diseases (neoplastic and non-neoplastic), e.g. glomerulonephritis, tubulointerstitial disease and uroepithelial tumours,1,11–14 but also many extra-renal diseases, e.g. myocardial infarction,15 hepatic and neurological toxicity,16,17 and lung and other cancers.18–20 Because evidence for the toxic nature of these compounds continues to accumulate, many countries have taken measures to reduce overall hydrocarbon exposure, e.g. reducing car exhaust fumes and emissions from factories and power stations, as well as setting ‘safe’ levels of exposure at the workplace.
For the purposes of this study, the term ‘hydrocarbons’ refers to alicyclic and halogenated hydrocarbons (e.g. perchloroethylene, trichloroethylene, chloroform), glycols (e.g. ethylene glycol, diethylene glycol, and glycerol), and aromatic compounds (e.g. toluene, xylene); occupational and environmental exposure were both assessed.
Hydrocarbons gain access to the body via the lungs or by direct contact through the skin. Once absorbed, a small percentage is excreted unchanged in the urine (<1%) and some is exhaled unchanged via the lungs. The remainder of the hydrocarbons that gain access to the body are metabolized by various enzymes: in phase 1, by the cytochrome p450 system; and in phase 2, by conjugating enzymes such as the glutathione S-transferases. The breakdown products are thereafter excreted in the urine.13,17
Unlike exposure to hydrocarbons, the incidence of membranous glomerulonephritis is rare: the incidence of glomerulonephritis is approximately 25–30 per million per year.21 In our unit, covering a population of 2.5 million, the incidence of biopsy-proven idiopathic membranous glomerulonephritis is 3–5 patients per million population per year. Although the morbidity from this condition may be significant (fluid accumulation, thromboembolic disease, chronic renal disease and end-stage renalfailure) the long-term renal survival is >70%, and of the remainder who develop end-stage renal failure, many will survive for >5 years.22 Therefore, the number of prevalent patients accumulates over time, leading to a cohort of patients who require extensive monitoring and care. Risk factors for progression of membranous glomerulonephritis to renal failure, and subsequently dialysis, include renal impairment at presentation, significant and persistent proteinuria, male gender, and renal biopsy demonstrating marked tubulo-interstitial disease.23–29 However, it is still not possible to predict with any degree of accuracy those patients who will remain stable or improve, and those patients whose disease will progress.30
Membranous glomerulonephritis may be secondary to several recognized causes: drugs (e.g. gold, penicillamine, captopril), infections (hepatitis B, malaria), systemic disorders such as sarcoidosis and systemic lupus erythematosis, and tumour-related disease. However, over 50% of patients have no discernible cause for their disease and are labelled ‘idiopathic’ (IMGN).31–34 It is in this group that the link between IMGN and occupational hydrocarbon exposure was described by Harrison et al. in 1986.35
The discrepancy between the rare incidence of IMGN and the significant numbers of people exposed to high levels of hydrocarbons suggests that although hydrocarbon exposure may be important in the development of IMGN, it is not sufficient on its own to ensure it. Additional cofactors must be necessary to render individuals susceptible to hydrocarbon toxicity. Abnormalities in the pathways responsible for metabolizing hydrocarbons may provide an answer for this possible metabolic ‘missing link’.36
The metabolism of hydrocarbons involves two major steps (phase 1 and phase 2 detoxification processes). Within each of these two steps there are different pathways, involving different enzymes, which the metabolism of a specific hydrocarbon moiety may follow. We therefore hypothesized that if any one of these enzymes in any given metabolic pathway were to be over- or under-active, the resultant accumulation of intermediate metabolites might result in tissue injury, specifically nephrotoxicity.
Based on this hypothesis, we carried out work on patients with varying histological types of glomerulonephritis, including 11 patients with IMGN, to assess them for polymorphisms of several genes known to encode for enzymes involved in the metabolism of hydrocarbons.37 This work suggested a relationship between the polymorphisms of two of these genes, NAT2 and GSTM1 (encoding for N-acetyltransferase 2 and glutathione-S transferase µ, respectively), and the development of IMGN.37 Others have also suggested a role for GST in the toxicity of hydrocarbons.38 We therefore designed a study to investigate the role that the polymorphisms of GSTM1 and NAT2 may play in predisposing an individual to toxic insult from hydrocarbons and result in intrinsic renal disease, specifically IMGN.
|
Methods |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
This study was designed to answer a specific question: are hydrocarbon exposure and the polymorphisms of GSTµ and NAT2 implicated in the aetiology of idiopathic membranous glomerulonephritis? Prior to initiation of the study, statistical advice was sought regarding the necessary numbers of patients and controls required to achieve a power calculation of 95%. Using the ARCUS statistics package, a power calculation was made, based on work previously published from our unit.37 This calculation compared the proportions of gene polymorphisms found in that study to the expected proportions found in the general population.39–42 Thirty-two patients and 32 controls were required. This minimum number of subjects was exceeded, with the recruitment of 36 patients and 36 matched controls.
Following approval from the local ethics committees in Liverpool and Manchester, all patients with biopsy-proven IMGN in the Liverpool and West Manchester areas, from 1982 up to and including 1997, were approached to take part in this study.
In total, 30 patients from Liverpool were eligible for the study, of whom 27 participated (three refused or were not contactable). A further nine patients were recruited, by blinded selection, from Hope Hospital in Manchester (two others refused). All patients with secondary causes for membranous glomerulonephritis were excluded from the study.
Controls were recruited randomly from the Blood Transfusion Service in Liverpool and Manchester, and were matched for age, gender and geographical area (based on hospital catchment area). Three further healthy controls were recruited randomly from the surgical day case units in order to more accurately age match some of the older IMGN patients.
All subjects were assessed for lifetime hydrocarbon exposure score using a detailed, validated43 and established questionnaire.38,44–47 A nurse was recruited from a non-renal specialty to carry out the questionnaires over the telephone. She was given no indication as to the status of the individuals that she was questioning, i.e. patient or control, and none of the questions asked would have identified them in this way. None of the subjects had any prior knowledge of the contents of the questionnaire, and they were directed to simply answer the questions posed without embellishment. Lifetime hydrocarbon exposure was assessed up to the time of the biopsy proving IMGN in the patients, and the same time scale was adopted for each matched control subject.
Whole blood samples for white-cell DNA analysis were taken and stored at -70 °C until the time of analysis, and used to assess the specific polymorphisms of the genes coding for GSTµ and NAT2. Analysis was done in exactly the same way as performed by Pai et al.37
PCR sample preparation
Whole blood (0.1 ml) was mixed with 0.75 ml 10 mM Tris, pH 8.0, 1 mM EDTA, then centrifuged at 12000 g for 20 s. The supernatent was aspirated and the pellet washed twice with 0.5 ml Tris-EDTA as above. The final pellet was re-suspended in 0.1 ml 50 mM KCI, 2.5 mM MgCI2, 20 mM Tris, pH 8.3, 0.45% nonidet P-40 and 0.45% Tween-20 containing 0.2 mg/ml proteinase K. After incubation for 30 min at 55 °C, 0.1 ml water was added and the lysate was stored at -20 °C. We used 5 µl in each PCR.
GSTM1 analysis
The PCR assay uses three oligonucleotide primers P1 (5'-CGCCATCTTGTGCTACATTGCCCG-3'), P2 (5'-ATCTTCTCCTCTTCTGTCTC-3'), and P3 (5'-TTCTGGATTGTAGCAGATCA-3'). The P1 and P2 primers are homologous to sequences in both the GSTM1 and GSTM4 genes, and the sequence of P3 is unique to the GSTM1 gene. Using the three primers in a single amplification reaction under set conditions (i. 94 ° for 1 min 30 s then, ii. 30 cycles of 94 ° for 30 s followed by 52 ° for 1 min followed by 72 ° for 1 min then, iii. final extension for 3 min at 72 °) each, the P1/P2 primer pair will anneal to sequences in both the GSTM1 and GSTM4 genes, yielding fragments of 157 bp, while the P1/P3 primer pair will generate a product of 239 bp from the GSTM1 gene only. Amplification of DNA from individuals possessing two wild-type GSTM1 alleles yields PCR products of both 157 bp and 239 bp, while DNA from individuals homozygous for the GSTM1 gene deletion generates only the 157 bp product. The amplification of the GSTM4 gene, in addition to the GSTM1 gene, serves as an internal control for the reaction in DNA samples from individuals with GSTM1 deletion.
NAT2 analysis
For the PCR assay, two primers, P1 (5'-GCTGGGTCTGGAAGCTCCTC-3') and P2 (5'-TTGGGTGATACATACACAAGGG-3') were used. PCR conditions were 93 °C for 1.5 min followed by 35 cycles of 93 °C for 45 s, 58 °C for 45 s and 72 °C for 45 s, followed by one more cycle with a final extension step of 72 °C for 3 min. For restriction enzyme digestion, 20 µl PCR product was mixed with 2.5 µl 10xreaction buffer and 5 units of the appropriate restriction enzyme in a final volume of 25 µl. The four restriction enzymes used were Taq1, Kpn1, Dde1 and BamH1. Taq1 digests were incubated overnight at 65 °C, while Kpn1, Dde1 and BamH1 were incubated overnight at 37 °C. The digested samples were loaded on to 8% polyacrylamide gels and run at 150 V with 1xTBE as electrode buffer, and were visualized by staining with ethidium bromide under ultraviolet light. The acetylator status (phenotype) was determined by assessment of allele pair combinations for four of the six known NAT-2 alleles (F1, S1k, S1kd, S1d, S2 and S3) which together will predict the correct phenotype in around 98% of individuals.48
Statistical analysis
Conditional logistic regression analysis (on the SPSS system) was used to explore the relationship between total cumulative lifetime hydrocarbon exposure, IMGN and the gene polymorphisms in question. Mann–Whitney U test and Fisher's exact test were used to try to clarify the difference between ‘high’ and ‘low’ hydrocarbon exposure (as defined by the score on the questionnaire), and relate this to the gene polymorphisms assessed in the development of IMGN.
|
Results |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
Using conditional logistic regression analysis to relate the presence of IMGN to NAT status (fast or slow acetylator) and GSTM1 status (wild type, meaning GSTµ present, or null, meaning GSTµ absent), and cumulative hydrocarbon exposure, only the hydrocarbon exposure reached significance when comparing patients with IMGN to controls (IMGN patients mean±SEM 11003.4±2955.7 vs. controls 4351.7±1418.0. p<0.02).
In the patient group, the mean hydrocarbon exposure score appeared to be greater in those with GSTM1 wild type vs. GST null, although this did not reach significance (p=0.39, Mann–Whitney U test). This trend was also seen when comparing NAT slow vs. NAT fast acetylators, but again, the difference was not significant (p=0.14, Mann–Whitney U test) (Table 1
).
|
No work has looked specifically at a level of hydrocarbon exposure based on our validated questionnaire that could differentiate between high and low hydrocarbon exposure. Some work appears to put the level of hydrocarbon exposure that may have clinical significance as high as 10 000.47 We prospectively explored the relationship between GSTµ and NAT2 status and a hydrocarbon cut-off score of 10 000 in the patient group. A much greater proportion of the GSTµ null patients had a hydrocarbon score <10 000 compared to the wild-type group, although this trend did not reach significance (p=0.14, Fisher's exact test). There was no such trend when examining NAT status in this way (p=0.39).
The variations of the genotypic frequencies are shown in Table 2. The frequency of the various genotypic polymorphisms is in keeping with previous work looking at these variations in the general population.39–42
|
|
Discussion |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
The association between occupational hydrocarbon exposure and non-neoplastic renal disease is well described.10,11,13,17,36,44–47 Hydrocarbon exposure is also associated with early markers of renal damage in asymptomatic subjects with no detectable overt clinical disease process.49 Some of this work has linked hydrocarbon exposure to specific types of glomerulonephritis.35,37,43,50 Recent publications have further implicated hydrocarbon exposure in the progression of glomerulonephritis.51,52 The impact of hydrocarbon exposure on the progression of glomerulonephritis, and the subsequent development of end-stage renal failure, is supported by previous data.12,46
The mechanism by which hydrocarbons induce tissue injury, such as glomerulonephritis, or trigger the development of neoplasia is unclear. Various hypotheses have been postulated to describe the pathways involved.50 It is unlikely that hydrocarbons induce direct nephrotoxicity in view of the rarity of glomerulonephritis on the background of the ubiquitous nature of hydrocarbons. An autoimmune response triggered by low-grade, direct hydrocarbon damage to the renal tubules leading to the release of self-antigens has been suggested. A toxic immune factor may arise independently of hydrocarbon exposure, and the secondary insult of the hydrocarbons (or some other endogenous or exogenous factor) facilitates the development of disease.10 However, these hypotheses do not fully explain why some people develop overt disease following exposure to hydrocarbons, while others escape unscathed. The difference in inter-individual susceptibility may be explained by polymorphisms in the genes responsible for hydrocarbon metabolism, which in turn affects the production of toxic metabolites, such as arene oxides, which have been implicated in the pathway for chemical carcinogenesis.53
The enzyme systems involved in the metabolism of hydrocarbons are mainly located in the liver, but they are also known to exist in renal tubular cells and other organs.13 The metabolism of many chemicals, including hydrocarbons, occurs in two distinct phases. Phase 1 metabolism, catalysed predominantly by the P450 monooxygenases, involves the insertion of one molecule of oxygen into the lipophilic chemical that is undergoing metabolism, producing a molecule with an electrophilic centre. Phase 2 metabolism involves the conjugation of this molecule with another moiety, e.g. glutathione or glucuronic acid, by way of one of the phase 2 enzymes, e.g. glutathione S-transferases, N-acetyltransferases and UDP-glucuronyl transferases. The finer details of these chemical reactions have been reviewed by others.54,55 N-acetylation is a major route of biotransformation for xenobiotics containing an aromatic amine or a hydrazine group. These are converted to aromatic amides and hydrazides, respectively. Aromatic amines can be both activated and deactivated by this pathway: if the aromatic amine is converted directly to an amide by NAT, a molecule of low reactivity is produced that is unlikely to cause DNA damage. However, if the aromatic amine is first N-hydroxylated by cytochrome P450 before the reaction catalysed by NAT takes place, the resultant acetoxy esters can break down to form highly reactive nitrenium and carbonium ions that bind to DNA.
Conjugation with glutathione involves the glutathione thiolate anion (GS-) attacking an electrophilic carbon atom. Glutathione can also conjugate xenobiotics containing electrophilic heteroatoms (O, N and S). These reactions are catalysed by GST. This detoxification pathway allows the elimination of potentially toxic electrophile molecules that can bind to proteins and nucleic acids leading to damage at the cellular and genetic level. However, some molecules may be activated by glutathione by such mechanisms as the formation of glutathione conjugates of haloalkanes, vicinal dihaloalkanes, halogenated alkenes, quinones, quinoneimines and isothiocyanates. GSTs can be divided into three main groups based on their isoelectric point: neutral (µ and 
), acidic (–
) and basic (
). The neutral group is known to have higher catalytic activity against the mutagenic epoxides styrene and benzo()pyrene 4,5-oxide.56
The polymorphisms of GST and NAT have been implicated as risk modifiers. Lung cancer patients who are GSTM1-deficient have a 100-fold increase in certain polycyclic aromatic hydrocarbon-DNA adducts, which may indicate an increased susceptibility to lung cancer in these patients.57,58 Low GSTµ activity may also play a part in the development of primary liver cancer.39,41 The association between bladder cancer and certain hydrocarbons is well established, with slow N-acetylation predisposing to this disease.14 It was for this reason that Pai et al. first examined these particular polymorphisms.
The mechanism by which these genetic polymorphisms could increase an individual's susceptibility to damage from hydrocarbons has not been clearly defined. Increased production of an intermediate toxic metabolite may occur if a toxifying enzyme is more active in some individuals compared to others. For instance, where acetylation produces a reactive intermediate, the ‘fast acetylators’ may produce enough of this intermediate so quickly as to overwhelm the next step in the detoxification process. Up until the last few years, it has only been possible to ascertain an individual's acetylation status by observing the metabolism of certain pharmacological agents.59 However, genotypic variants of NAT2 are now so well described42,48,60,61 that it is possible to infer phenotype from genotype; assessment of four of the alleles of NAT2 will predict the phenotype in approximately 98% of the Caucasian population of the UK.14,48 Similarly, a toxic intermediate may accumulate if it is produced at a normal rate by a phase 1 detoxification process, but the subsequent step(s) in the detoxification process is/are not functioning adequately (e.g. absent GSTµ activity), leading to reduced clearance of the intermediate product. Variations of either of these two detoxification pathways will cause an accumulation of potentially reactive intermediate products, which may lead to tissue damage. It is possible that hydrocarbon nephrotoxicity requires a combination of enzyme polymorphisms to render an individual susceptible to disease.
This study was designed to investigate further the suggestion from previous investigations that hydrocarbon exposure and genetic polymorphisms of NAT2 (fast acetylation status) and GSTM1 (absent GSTµ activity) have a pivotal role in the aetiology of IMGN.37 This larger study does not support the association of either the absence of activity of GSTµ or the presence of fast acetylation status and the development of IMGN from a previous smaller group of patients. However, we have demonstrated a statistically significant association between cumulative lifetime hydrocarbon exposure and the development of IMGN, confirming the findings of Harrison et al.35 It is not known whether hydrocarbon exposure is pivotally important in the development of IMGN or it is merely one of several different trigger factors in the development of this disorder in genetically predisposed patients.
This information should alert nephrologists to an important additional occupational factor in the pathogenesis of IMGN, with obvious implications for prevention. It may be prudent to advise these patients to either avoid, or carefully protect themselves against further hydrocarbon exposure until it becomes clear whether or not hydrocarbon exposure can also affect the progression of IMGN.51,52
The gold standard to assess lifetime hydrocarbon exposure would be regular direct measurements of air samples and skin contact samples; this is clearly impractical over an individual's lifetime. We were interested to explore the possibility that a certain level of lifetime hydrocarbon exposure, as defined by a ‘cut-off’ on the hydrocarbon exposure questionnaire, may provide a useful indicator towards those individuals who are at risk of developing chronic toxicity. This would give a definition of ‘high’ vs. ‘low’ hydrocarbon exposure, based on the exposure score from our questionnaire. Previous work46 exploring factors involved in the progression of renal impairment has suggested that those patients with a higher hydrocarbon exposure score, as assessed with the same methods in our study, were more likely to progress to end-stage renal failure. It is evident that the group with the better prognosis had a mean hydrocarbon score of <10000, whilst those that were more likely to progress had a mean hydrocarbon score >30000.47 From our own results, the patients with IMGN have a mean hydrocarbon exposure score of >11000 (Table 1
), whilst the controls have a mean hydrocarbon score of <5000 (Table 1). Future work would need to look prospectively at this proposed ‘cut-off’ of 10 000 between high and low exposure, both in the development and progression of IMGN, in order to investigate this further.
The in vivo actions of environmental hydrocarbons are modified by their complex metabolism. Abnormalities of this metabolism (e.g. absent GSTµ activity) may predispose individuals to toxicity from lower levels of hydrocarbon exposure than would be expected. This suggestion may be supported by the fact that in our patients with IMGN, there was a much larger proportion of GSTµ null patients with a hydrocarbon score <10 000 compared to the GSTµ wild-type patients. However, this does not reach statistical significance (p=0.14).
Of further interest is the male-to-female ratio of patients with IMGN of 3:1 in our study. Others have noted a similarly greater prevalence of men than women in studies of diverse histopathological forms of glomerulonephritis, including membranous,25,26,28,35 proliferative,43 and other forms,12,45,62 but the cause for this difference remains unclear. Occupational exposure to hydrocarbons has been proposed as a risk factor for the development of various types of glomerulonephritis.12,35,62 The observation that hydrocarbon exposure is greater in patients with IMGN may help explain the gender differences recorded in our study. Occupations with significant hydrocarbon exposure, such as spray painting and industrial work, are predominantly filled by men. This case-control study examined the impact that hydrocarbons and genetic polymorphisms may have had on patients in developing IMGN. As such, it was not designed specifically to answer the apparent gender differences seen, and any bias that these gender differences may have on the results is balanced by the use of age- and sex-matched controls.
The safety levels of hydrocarbon exposure in the workplace, as presently defined, may be set too high. A high level of exposure over a short period of time is hazardous and is known to cause neurological damage.17 Even lower levels of exposure over a prolonged period of time, conferring a high lifetime exposure (as measured by our questionnaire) appear to increase the risk of non-neoplastic renal disease.37,45,46
Various treatments strategies for IMGN have been suggested, mainly centring on steroids and immunosuppressive agents (e.g. chlorambucil, cyclophosphamide, cyclosporin A).64–68 But even if we were able to predict accurately which patients with IMGN were likely to develop progressive renal failure, and targeted this population with chemotherapy, the treatments used are toxic, with well-recognized side-effects (immunosuppression, malignancy, osteoporosis, hypertension, etc.), and reports of successful induction of remission are variable.61,65 Hence, it may be more productive to concentrate our resources on preventing development of IMGN in the first place. To do this, we need to know the pathogenic mechanism leading to the development of IMGN before specific strategies can be developed. Workers whose employment involves hydrocarbon exposure should be adequately protected to maintain their exposure below the accepted ‘safety’ levels of the specific agent at the work site. It is also possible to carry out simple screening measures for early renal damage by measuring urinary markers in at risk, exposed subjects.38,47 Regular monitoring and appropriate reduction of specific hydrocarbon exposure remain the best available approach for renal protection.
We have demonstrated a relationship between lifetime hydrocarbon exposure and the development of IMGN. However, we have been unable to demonstrate a specific genetic polymorphism linking hydrocarbon exposure to nephrotoxicity. Whether polymorphisms of other recently described enzymes closely involved in the metabolism of hydrocarbons will help identify this link will require further study.
|
Acknowledgments |
|---|
We are grateful for the continued support of Drs Bone and Ahmad; we are also grateful for the cooperation of Drs P. Kalra and S. Waldek who allowed us to include their patients in this work, the help of Sarah Moore for statistical advice, and the help of the medical and nursing staff in the Blood Transfusion Service in Liverpool and Manchester. This project was funded jointly by The Health and Safety Executive and by Mersey Kidney Research.
|
Notes |
|---|
Address correspondence to Dr C. Gradden, Renal Unit, 6C Link, Royal Liverpool University Hospital Trust, Prescot Street, Liverpool L7 8XP. e-mail: farndon{at}freeuk.com
|
References |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
1. Cole P, Hoover R, Friedell GH. Occupation and cancer of the lower urinary tract. Cancer1972; 29:1250.[ISI][Medline]
2. Case RA, Hosker ME, McDonald DE, Pearson JT. Tumours of the urinary bladder in workmen engaged in the manufacture and use of certain dyestuff intermediates in the British chemical industry. Part I. The role of aniline, benzidine, alpha-naphthylamine, and beta-naphthylamine. 1954. Br J Ind Med1993; 50:389–411.[ISI][Medline]
3.
Denissenko ME, Pao A, Tang M, Pfeifer GP. Preferential formation of benzo()pyrene adducts at lung cancer mutational hotspots in p53. Science1996; 274:430–2.
4. Goldsmith CA, Kobzik L. Particulate air pollution and asthma: a review of epidemiological and biological studies. Rev Environ Health1999; 14:121–34.[Medline]
5. D'Amato G. Outdoor air pollution in urban areas and allergic respiratory diseases. Monaldi Arch Chest Dis1999; 54:470–4.[Medline]
6. Pizzuti A, Frittitta L, Argiolas A, Baratta R, Goldfine ID, Bozzali M, Ercolino T, Scarlato G, Iacoviello L, Vigneri R, Tassi V, Trischitta V. A polymorphism (K121Q) of the human glycoprotein PC-1 gene coding region is strongly associated with insulin resistance. Diabetes1999; 48:1881–4.[Abstract]
7.
van der Pol WL, van den Berg LH, Scheepers RH, van der Bom JG, van Doorn PA, van Koningsveld R, van den Broek MC, Wokke JH, van de Winkel JG. IgG receptor IIa alleles determine susceptibility and severity of Guillain-Barre syndrome. Neurology2000; 54:1661–5.
8.
van Ittersum FJ, de Man AM, Thijssen S, de Knijff P, Slagboom E, Smulders Y, Tarnow L, Donker AJ, Bilo HJ, Stehouwer CD. Genetic polymorphisms of the renin-angiotensin system and complications of insulin-dependent diabetes mellitus. Nephrol Dial Transplant2000; 15:1000–7.
9. Tan EC, Chong SA. Identification of genes for schizophrenia susceptibility. Ann Acad Med Singapore2000; 29:305–12.[Medline]
10. Yaqoob M, Bell GM. Organic solvents and renal disease. In: Holgate ST, ed. New Horizons in Medicine, 6th edn. Oxford, Blackwell Science, 1995:206–17.
11. Narvarte J, Saba SR, Ramirez G. Occupational exposure to organic solvents causing chronic tubulointerstitial nephritis. Arch Intern Med1989; 149:154–8.[Abstract]
12. Finn R, Fennerty AG, Ahmad R. Hydrocarbon exposure and renal failure. Clin Nephrol1980; 14:173–5.[ISI][Medline]
13. Roy AT, Brautbar N, Lee DBN. Hydrocarbons and renal failure. Nephron1991; 58:385–92.[ISI][Medline]
14.
Risch A, Wallace DMA, Bathers S, Sim E. Slow N-acetylation genotype is a susceptibility factor in occupational and smoking related bladder cancer. Hum Mol Genet1995; 4:231–6.
15. Carder JR, Fuerst RS. Myocardial infarction after toluene inhalation. Paediatr Emerg Care1997; 13:117–19.
16. Pyatt J, Gilmore I, Mullins PA. Abnormal liver function test following inadvertent inhalation of volatile hydrocarbons. Postgrad Med J1998; 74:747–8.[Abstract]
17. Andrews LS, Snyder R. Toxic effects of solvents and vapours. In: Klassen CD, ed. Casarett and Doull's Toxicology: The Basic Science of Poisons, 5th edn. New York, McGraw-Hill, 1995:737–71.
18. Boffetta P, Jourenkova N, Gustavsson P. Cancer risk from occupational and environmental exposure to polycyclic aromatic hydrocarbons. Cancer Causes Control1997; 8:444–72.[ISI][Medline]
19. Mastrangelo G, Fadda E, Marzia V. Polycyclic aromatic hydrocarbons and cancer in man. Environ Health Perspect1996; 104:1166–70.[ISI][Medline]
20. Nadon L, Siemiatycki J, Dewar R, Krewski D, Gerin M. Cancer risk due to occupational exposure to polycyclic aromatic hydrocarbons. Am J Int Med1995; 28:303–24.
21. Tufveson G, Geerlings W, Brunner FP, Brynger H, Dykes SR, Ehrich JHH, Fassbinder W, Rizzoni G, Selwood NH, Wing AJ. Combined report on regular dialysis and transplantation in Europe, XIX, 1988. Nephrol Dial Transplant1989; 4(Suppl. 4):5–29.
22. Remuzzi G, Bertani T, Schieppati A. Idiopathic membranous nephropathy. Report of a meeting of Physicians and Scientists. Lancet1993; 342:1277–80.[ISI][Medline]
23. Erwin DT, Donadio JV, Holley KE. The clinical course of idiopathic membranous nephropathy. Mayo Clin Proc1973; 48:697–712.[ISI][Medline]
24. Mallick NP, Short CD, Manos J. Clinical membranous nephropathy. Nephron1983; 34:209–19.[ISI][Medline]
25. Davison AM, Cameron JS, Kerr DNS, Ogg CS, Wilkinson RW. The natural history of renal function in untreated idiopathic membranous glomerulonephritis in adults. Clin Nephrol1984; 22:61–7.[ISI][Medline]
26. Donadio JV Jr, Torres VE, Velosa JA, Wagoner RD, Holley KE, Okamura M, Ilstrup DM, Chu C-P. Idiopathic membranous nephropathy: the natural history of untreated patients. Kidney Int1988; 33:708–15.[ISI][Medline]
27.
Schieppati A, Mosconi L, Perna A, Mecca G, Bertani T, Garattini S, Remuzzi G. Prognosis of untreated patients with idiopathic membranous nephropathy. N Engl J Med1993; 329:85–9.
28. Pei Y, Cattran D, Greenwood C. Predicting chronic renal insufficiency in idiopathic membranous glomerulonephritis. Kidney Int1992; 42:960–6.[ISI][Medline]
29. Cattran DC, Pei Y, Greenwood CM, Ponticelli C, Passerini P, Honakanen E. Validation of a predictive model of idiopathic membranous nephropathy: its clinical and research implications. Kidney Int1997; 51:901–7.[ISI][Medline]
30. Zucchelli P, Pasquali S. Membranous Nephropathy. In: Davison AM, Cameron JS, Grunfeld J-P, Kerr DNS, Ritz E, Winearls CG, eds. Oxford Textbook Nephrology, 2nd edn, Vol. 1. Oxford, Oxford University Press, 1998:571–90.
31. Ehrenreich T, Porush JG, Churg J, Garfinkel L, Glabman S, Goldstein MH, Grishman E, Yunis SL. Treatment of idiopathic membranous nephropathy. New Engl J Med1976; 295:741–6.[Abstract]
32. Zollinger HU, Mihatsch MJ, eds. Epimembranous glomerulonephritis. In: Renal Pathology in Biopsy. Berlin, Springer-Verlag, 1978:261–78.
33. Noel LH, Zanetti M, Droz D, Barbanel C. Long-term prognosis of idiopathic membranous glomerulonephritis. Am J Med1979; 66:82–90.[ISI][Medline]
34.
Abe S, Amagasaki Y, Konishi K, Kato E, lyori S, Sakaguchi H. Idiopathic membranous glomerulonephritis: aspects of geographical differences. J Clin Pathol1986; 39:1193–8.
35.
Harrison DJ, Thomson D, Macdonald MK. Membranous glomerulonephritis. J Clin Pathol1986; 39:167–71.
36. Zimmerman SW, Groehler K, Beirne GJ. Hydrocarbon exposure and chronic glomerulonephritis. Lancet1975; 2:199–201.[ISI][Medline]
37.
Pai P, Hindell P, Stevenson A, Mason H. Bell GM. Genetic variants of microsomal metabolism and susceptibility to hydrocarbon-associated glomerulonephritis. Q J Med1997; 90:693–8.
38. Lock EA. Mechanism of nephrotoxic action due to organohalogenated compounds. Toxicol Lett1989; 46:93–106.[ISI][Medline]
39.
Lui YH, Taylor J, Linko P, Lucier GW, Thompson CL. Glutathione S-transferase µ in human lymphocyte and liver: role in modulating formation of carcinogenic-derived DNA adducts. Carcinogenesis1991; 12:2269–75.
40. Hussey AJ, Hayes JD, Beckett GJ. The polymorphic expression of neutral glutathione S-transferase in human mononuclear leukocytes as measured by specific radioimmunoassay. Biochem Pharmacol1987; 36:4013–15.[ISI][Medline]
41.
Hayes PC, Bouchier IAD, Beckett GJ. Glutathione S-transferase in health and disease. Gut1991; 32:813–18.
42. Cascorbi I, Drakoulis N, Brockmöller J. Maurer A, Sperling K, Roots I. Arylamine N-acetyltransferase (NAT2) Mutations and Their Allelic Linkage in Unrelated Caucasian Individuals: Correlation with Phenotypic Activity. Am J Hum Genet1995; 57:581–92.[ISI][Medline]
43. Bell GM, Gordon ACH, Lee P, Doig A, MacDonald MK, Thomson D, Anderton JL, Robson JS. Proliferative glomerulonephritis and exposure to organic solvents. Nephron1985; 40:161–5.[ISI][Medline]
44. Hotz P, Pilliod J, Söderström D, Rey F, Boillat MA, Savolainen H. Relation between renal function tests and a retrospective organic solvent exposure score. Br J Ind Med1989; 46:815–19.[ISI][Medline]
45.
Yaqoob M, Bell GM, Percy DF, Finn R. Primary glomerulonephritis and hydrocarbon exposure: a case-control study and literature review. Q J Med1992; 83:409–18.
46.
Yaqoob M, Bell GM, Stevenson A, Mason H, Percy DF. Renal impairment with chronic hydrocarbon exposure. Q J Med1993; 86:165–74.
47. Yaqoob M, Stevenson A, Mason H, Bell GM. Hydrocarbon exposure and tubular damage: additional factors in the progression of renal failure in primary glomerulonephritis. Q J Med1993; 86:661–7.
48. Hickman D, Risch A, Camilleri JP, Sim E. Genotyping human polymorphic arylamine N-acetyltransferase: identification of new slow allotypic variants. Pharmacogenetics1992; 2:217–26.[ISI][Medline]
49. Stevenson A, Yaqoob M, Mason H, Pai P, Bell GM. Biochemical markers of basement membrane disturbances and occupational exposure to hydrocarbons and mixed solvents. Q J Med1995; 88:23–8.
50. Daniell WE, Couser WG, Rosenstock L. Occupational solvent exposure and glomerulonephritis, a case report and review of the literature. J Am Soc Nephrol1988; 259:2280–3.
51. Ravnskov U. Hydrocarbons May Worsen Renal Function in Glomerulonephritis: A Meta-Analysis of the Case-Control Studies. Am J Ind Med2000; 37:599–606.[ISI][Medline]
52.
Ravnskov U. Hydrocarbon exposure may cause glomerulonephritis and worsen renal function: evidence based on Hill's criteria for causality. Q J Med2000; 93:551–6.
53. Pelkonen O, Nebert DW. Metabolism of polycyclic aromatic hydrocarbons: etiologic role in chemical carcinogenesis. Pharmacol Rev1982; 34:189–222.[ISI][Medline]
54. Clayton GD, Clayton EE (eds). Patty's Industrial Hygiene and Toxicology. New York, Wiley, 1981 (Vol. 26) and 1982 (Vol. 2C).
55. Parkinson A. Biotransformation of Xenobiotics. In: Klassen CD, ed. Casarett and Doull's Toxicology: The Basic Science of Poisons, 5th edn. New York, McGraw-Hill, 1995:113–86.
56. Warholm M, Guthenberg C, Mannervik B. Molecular and catalytic properties of glutathione transferase µ from human liver: an enzyme efficiently conjugating epoxides. Biochemisty1983; 22:3610–17.[Medline]
57. Bartsch H, Rojas M, Alexandrov K, Risch A. Impact of adduct determination on the assessment of cancer susceptibility. Recent Results Cancer Res1998; 154:86–9.[Medline]
58.
Henderson CJ, Smith AG, Ure J, Brown K, Bacon EJ, Wolf CR. Increased tumorigenesis in mice lacking pi class glutathione S-transferase. Proc Natl Acad Sci USA1998; 95:5275–80.
59. Grant DM, Tang BK, Kalow W. A simple test of acetylator phenotype using caffeine. Br J Pharmacol1984; 17:459–64.
60. Grant DM. Molecular genetics of the N-acetyltransferases. Pharmacogenetics1993; 3:45–50.[ISI][Medline]
61. Lin HJ, Han C-Y, Lin BK, Hardy S. Slow acetylation mutations in the human polymorphic n-acetyltransferase gene in 786 Asians, Blacks, Hispanics, and Whites: application to metabolic epidemiology. Am J Hum Genet1993; 52:827–34.[ISI][Medline]
62. Ravnskov U, Forsberg B, Skerfving S. Glomerulonephritis and exposure to organic solvents. Acta Med Scand1979; 205:575–9.[ISI][Medline]
63. Ravnskov U, Lundström S, Norden A. Hydrocarbon exposure and glomerulonephritis: evidence from patients’ occupations. Lancet1983; 2:1214–16.[ISI][Medline]
64. Ponticelli C, Zucchelli P, Passerini P, Cesana B, Locatelli F, Pasquali S, Sasdelli M, Redaelli B, Grassi C, Pozzi C, Bizzari D, Banfi G. A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy. Kidney Int1995; 48:1600–4.[ISI][Medline]
65. Collaborative study of the adult idiopathic nephrotic syndrome. A controlled study of short-term prednisone treatment in adults with membranous nephropathy. N Engl J Med1979; 301:1301–6.[Abstract]
66. Jindal K, West M, Bear R, Goldstein M. Long-term benefits of therapy with cyclophosphamide and prednisone in patients with membranous glomerulonephritis and impaired renal function. Am J Kidney Dis1992; 19:61–7.[ISI][Medline]
67. Bruns FJ, Adler S, Fraley DS, Segel DP. Sustained remission of membranous glomerulonephritis after cyclophosphamide and prednisone. Ann Intern Med1991; 114:725–30.
68. Murphy BF, McDonald I, Fairley KF, Kincaid-Smith PS. Randomized controlled trial of cyclophosphamide, warfarin and dipyridamole in idiopathic membranous glomerulonephritis. Clin Nephrol1992; 37:229–34.[ISI][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||