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Nine pigs were fed crystalline ochratoxin A in amounts corresponding to a feed level of 1 mg per kg for 3 months. The only observable lesion developed was a kidney damage, identical to the naturally occurring porcine nephropathy. The changes of renal function was characterized by impairment of proximal tubular function, indicated by a decrease of the ratio TmPAH/CIn, of the ability to concentrate urine, and by an increased urinary excretion of glucose. The decrease of the ratio TmPAH/CIn is correlated with time of exposure to ochratoxin A. The changes of renal structure were characterized by degeneration of the proximal tubules, leading to tubular atrophy accompanied by interstitial fibrosis. At the end of the experiment the kidney, liver, adipose and muscular tissue of the slaughtered pigs contained sizable amounts of ochratoxin A residues. As the pigs would have passed the meat inspection this represents a possible health problem. The changes observed in this study are identical to those observed by feeding to pigs grains naturally contaminated with ochratoxin A.

Proteinuria was studied experimentally in pigs with renal damage induced by maleic acid, potassium dichromate and by 5/6 nephrectomy. The methods used were: analysis of total protein, immunochemical quantitation of a porcine low molecular weight (alpha-PLMW) protein, agarose gel electrophoresis, and gel chromatography of concentrated urine samples. The urinary clearance of the alpha-PLMW protein in normal pigs was considerably higher than LMW protein clearance in normal man. No increase was seen after surgery. The induction of proximal tubular damage resulted in an increased excretion of, above all, high molecular weight proteins (greater than or equal to albumin) but also of low molecular weight proteins. The highest increase in alpha-PLMW clearance was seen immediately after 5/6 nephrectomy, and the increased alpha-PLMW excretion in pigs with proximal tubular dysfunction was better correlated to creatinine clearance than to the degree of phosphaturia or glucosuria. The results suggest different renal handling of plasma proteins in pigs and humans.

Many observational and experimental studies point to hydrocarbon exposure as an important pathogenic factor in glomerulonephritis. The findings have made little impact on current concepts and patient care, possibly because the hypothesis of a direct causal effect of the exposure and the hypothesis that the exposure worsens renal function have not been considered separately. This review examines these two hypotheses using Hill's criteria for causality. The results from 14 cross-sectional, 18 case-control studies, two cohort studies, 15 experiments on laboratory animals and two on human beings together with many case reports satisfy all but one of Hill's criteria for both hypotheses. Of particular importance is the finding in the case-control and follow-up studies of an association between degree of exposure and stage of renal disease, and an inverse association between degree of exposure and renal function, indicating that the most important effect of hydrocarbon exposure is its effect on renal function. End-stage renal failure may be preventable in many patients with glomerulonephritis provided a possible exposure to toxic chemicals is discontinued.

Background Previous case-control studies of hydrocarbon exposure in glomerulonephritis may have given inconsistent results because the stage of disease has not been considered. Methods The association between stage of disease and degree of previous exposure was studied by a meta-analysis of all published case-control studies and by reviewing all follow-up studies. Results Odds ratios (OR) for exposure could be calculated for 16 patient groups from 14 case-control studies. After exclusion of four patient groups with 5–17% drop-outs due to death, the mean weighted OR for patient groups with acute or early glomerulonephritis, chronic renal failure, and end-stage renal failure were 0.95, 3.1, and 5.9, respectively. At follow-up, reported in four studies, renal failure was mainly seen in patients with extensive exposure, and improvement was seen only in patients who had discontinued the exposure. Conclusions Hydrocarbon exposure in glomerulonephritis is associated with the advancement of the disease and inversely associated with renal function. Early elimination of the exposure may, therefore, prevent the progress of renal failure in many patients. Am. J. Ind. Med. 37:599–606, 2000. © 2000 Wiley-Liss, Inc.

Introduction Glomerulonephritis is seen as a serious immunologic disease of the glomeruli. However, permanent renal damage has never been produced experimentally by immunisation without the concomitant use of Freund’s adjuvant or other tubulotoxic chemicals. Also contradictory is that renal failure is strongly associated with the degree of tubulointerstitial damage, both in experimental and human glomerulonephritis, whereas weak or no association at all has been found with the degree of glomerular damage. There is solid clinical and experimental evidence that the exposure to tubulotoxic chemicals alone is able to produce glomerulonephritis and renal failure, and there is increasing evidence that such exposure is a major cause of renal failure in other kidney diseases. The aim of this review was to discuss the role of tubulotoxic chemicals in renal failure. Conclusion As several studies have observed improvement of renal function after cessation of hydrocarbon exposure, it is reasonable to expect that avoiding other types of toxic exposure may be beneficial as well. It should therefore be mandatory to ask all the patients with renal failure about possible exposure to tubulotoxic chemicals, preferably by experienced occupational hygienists, and to support attempts to avoid such exposure. Introduction Glomerulonephritis (GN) is an innocent disease as long as renal function is normal. To prevent or to treat serious GN it is therefore necessary to know what causes renal failure. For many years, the interest has been focused on various immunological reactions, either between foreign antigens that arrive into the glomeruli after having reacted with circulating antibodies and complement; or between autologous anti-kidney antibodies and various kidney cells or membranes. In addition severe proteinuria has been considered noxious for the tubular cells. However, there are a host of contradictory observations. This review discusses the crucial role of tubulotoxic chemicals in renal failure. Discussion The author has referenced some of his own studies in this review. These referenced studies have been conducted in accordance with the Declaration of Helsinki (1964) and the protocols of these studies have been approved by the relevant ethics committees related to the institution in which they were performed. All human subjects, in these referenced studies, gave informed consent to participate in the studies. The role of the immunological processes If the immunological reactions in the glomeruli are the cause of renal failure, directly or indirectly, there should exist an association between the number of glomerular immune complexes (ICs) or the degree of glomerular damage, and renal function, but it is not so. Greater amount of glomerular ICs are often seen in sheep, steers, guinea pigs, horses, mice and rabbits with normal renal function and normal urine1. Patients with malignancies, alcoholic liver disease and essential hypertension may have such deposits as well, although their renal function and their urine are normal1. A single injection of a foreign antigen into experimental animals results in the production of circulating and glomerular ICs, but unless the animals are injected with Freund’s adjuvant (FA) as well, or unless the foreign antigen is injected repeatedly, no renal damage is seen apart from mild and transient proteinuria1,2. In accordance, most cases of human GN following an acute infection may heal without permanent damage of the kidneys, but renal failure may be seen in patients with chronic infections, or if the patients are exposed to tubulotoxic chemicals. Experimental GN can also be produced in rats by autologous antibrush border or anti-podocyte antibodies, either by immunisation with rat kidney cells (active Heymann nephritis), or by injecting rabbit antirat brush border antibodies into rats (passive Heymann nephritis). These models are used as an argument for the idea that serious GN is caused by immunologic mechanisms. However, without FA autologous anti-kidney antibodies do not produce more than mild and transient proteinuria. In passive Heymann nephritis injected heterologous rabbit antibodies bind to the glomerulus immediately, but no harm is produced until a few days later, when the autologous anti-rabbit Ig antibodies lead to complex formation in situ1,2. However, this model cannot be used as an argument for an immunologic mechanism, as the presence of heterologous antibodies is most unlikely in human GN. * Corresponding author Email: ravnskov@tele2.se Magle Stora Kyrkogata 9, S 22350 Lund, Sweden

The diet-heart idea is impossible because unbiased investigations have never demonstrated a correlation between the level of serum cholesterol and the degree, or the progress rate, of atherosclerosis.

Membranous glomerulonephritis (MGN) is said to be caused by circulating autoantibodies against antigen(s) located to the epithelial side of the glomerular capillaries. Membranous glomerulonephritis with severe renal damage can be produced experimentally by injections of heterologous antibodies, but this model is obviously of questionable relevance. It can also be produced by immunizing the animal with antigen mixed with Freund's adjuvant, but this model does not prove that the damage is exerted by antibodies because Freund's adjuvant is nephrotoxic and is itself able to produce MGN. It has not yet been demonstrated experimentally that autologous antibodies alone can produce more than trace or transient proteinuria; and kidney biopsies in unselected humans have shown that MGN is a frequent finding in individuals with normal urine and normal renal function, indicating that a subepithelial formation of immune complexes is also harmless to humans. Severe glomerulonephritis without immune complex formation can easily be produced experimentally with many nephrotoxic chemicals. It is therefore suggested that the primary event in MGN, and probably other subgroups, is a toxic or allergic tubulointerstitial reaction to chemicals or drugs and that the formation of glomerular immune complexes is a later and secondary phenomenon. In agreement, renal function and the course in MGN and other glomerulonephritides are strongly correlated with the degree of tubulointerstitial damage, but totally unrelated to the degree of glomerular damage. The hypothesis explains why a large number of patients with endstage renal failure owing to glomerulonephritis have been heavily exposed to environmental pollutants.

Several recent studies have suggested that a relation may exist between exposure to occupational organic solvents and diseases of the kidney--particularly malignancy and glomerulonephritis. Two case referent studies were undertaken in the West Midlands to investigate these possibilities. In the case of renal cancer 54 live cases of biopsy proved adenocarcinoma of the kidney were compared with an equal number of community based healthy referents matched for age, sex, place of residence, and socioeconomic and ethnic grouping. For glomerulonephritis, 50 biopsy proved cases were matched in the same manner with 50 referents. Fourteen other patients were also reviewed who, on biopsy, proved not to have glomerulonephritis. For both sets of cases and their referents each individual was interviewed and a detailed account obtained of medical history and environmental exposures. Exposure to solvents was assessed independently and "blind" in a semiquantitative way by an experienced occupational hygienist. Past exposure was estimated for 10 different solvent types and 17 material types. No relation was found between exposure to solvents and renal cancer or glomerulonephritis. In the case of renal cancer the numbers studied only precluded a fourfold excess risk. For glomerulonephritis, the study, although methodologically superior to most other published studies and of similar size, was of similar power to the renal cancer investigation.

Editor—We agree with Law and Wald that one must consider the cohort effect—the time lag—in investigating the association of levels of risk factors with mortality from coronary heart disease.1 Analysis of mortality from coronary heart disease in birth cohorts since the second world war is therefore important. We evaluated mortality from coronary heart disease in the United States, Japan, South Korea, and other countries, as well as within the United States by state, for men aged 35-44. We found that the very low mortality from coronary heart disease in Japan (5.5/100 000, compared with 11.4/100 000 in South Korea and 26.4/100 000 among American white men in 1992) might be an artefact. A substantial proportion of mortality from coronary heart disease among men aged 35-44 may be miscoded as heart failure (ICD-9, code 428) because in Japan more than 60%of mortality from diseases of the heart (codes 390-429) was coded as heart failure. This proportion is usually very low in this age group—1% among American white men. If half the mortality from heart disease was due to coronary heart disease in Japan there would be only a twofold difference in mortality from coronary heart disease between the United States and Japan: 26.4/100 000 among American white men versus 13.5/100 000 among Japanese men in 1992. In some states in the United States we found that mortality from coronary heart disease among white men aged 35-44 is similar to that in France (14.7/100 000): 13.8/100 000 in Washington, 14.7/100 000 in Connecticut, 15.4/100 000 in Kansas, 16.4/100 000 in Colorado, and 17.1/100 000 in California. The low rates in these states are not due to heavy alcohol consumption compared with that in other states; rather, they are strongly related to educational attainments of the population and the prevalence of cigarette smoking and perhaps other risk factors. Studies of recent birth cohorts by country provide better evaluation of causes of death and measurements of atherosclerosis. Focusing on smaller geographic areas as opposed to whole countries may improve understanding of geographic variation in mortality from coronary heart disease. Alcohol may be an important attribute for a lower rate of coronary heart disease in France but is not necessarily the only key factor. Atherosclerosis has a long incubation period. Diet measured 30 years before reported death may better predict the extent of atherosclerosis and mortality from coronary heart disease.

Glomerulonephritis is thought to be caused by immune complexes trapped or formed in the glomeruli. But immune complexes are found in the glomeruli of many normal mammals and of patients with non-renal diseases, and immune complexes trapped or formed experimentally in the glomeruli induce mild proteinuria at most suggesting that additional factors must be responsible. An induction of serious renal damage in experimental glomerulonephritis demands a chronic supply of antigen, rarely seen in human glomerulonephritis; or the use of heterologous antibodies, a design with questionable clinical relevance; or immuno- and nephrotoxic chemicals; or Freund's adjuvant which is also nephrotoxic. It is therefore suggested that the pathogenesis of human non- systemic glomerulonephritis includes exposure to nephro- and immunotoxic chemicals, the deposition of glomerular immune complexes being secondary. The hypothesis has clinical support: a majority of patients have been exposed to such chemicals, mainly hydrocarbons; and the tubulointerstitial changes in glomerulonephritis are better correlated to renal function and clinical course than are the glomerular changes. The chemicals enhance or derange immunizations and sensitize the kidneys to immunological reactions.

The renal extraction rates of β2-microglobulin (Eβ), p-aminohippurate (EPAH), and inulin (Ein) have been studied in 36 kidneys from 22 patients with different kidney diseases. A positive correlation was found between the ratio Eβ/Einand EPAH. In seven kidneys with a high EPAH, Eβexceeded Ein. At low EPAHvalues, Eβwas less than 40% of Ein. These findings indicate that a peritubular uptake may play a major role in renal elimination of β2-microglobulin and, possibly, other low molecular weight proteins.

The excretion of N-acetyl-beta-glucosaminidase (Nag) was studied in 109 patients with glomerulonephritis. A positive correlation was found between the concentration of albumin and Nag in the urine. Almost all the urinary Nag had the properties of the tissues, not of the serum isoenzyme. The ratio between Nag and albumin in the urine was significantly lower in patients with minimal lesions and in those with focal sclerosis than in those with proliferative, membrano-proliferative and membranous glomerulonephritis. The excretion of Nag per g creatinine differed significantly between the various histologic subgroups of glomerulonephritis but not between groups with various degrees of tubulointerstitial changes. The excretion of Nag in 9 patients with proximal tubular damage induced by exposure to cadmium in the past was only moderate. We suggest that urinary Nag excretion is not caused by an increased glomerular permeability to macromolecules but may instead reflect the activity of renal disease.

Nine pigs were fed crystalline ochratoxin A in amounts corresponding to a feed level of 1 mg per kg for 3 months. The only observable lesion developed was a kidney damage, identical to the naturally occurring porcine nephropathy. The changes of renal function was characterized by impairment of proximal tubular function, indicated by a decrease of the ratio TmPAH/CIn, of the ability to concentrate urine, and by an increased urinary excretion of glucose. The decrease of the ratio TmPAH/CIn is correlated with time of exposure to ochratoxin A. The changes of renal structure were characterized by degeneration of the proximal tubules, leading to tubular atrophy accompanied by interstitial fibrosis. At the end of the experiment the kidney, liver, adipose and muscular tissue of the slaughtered pigs contained sizable amounts of ochratoxin A residues. As the pigs would have passed the meat inspection this represents a possible health problem. The changes observed in this study are identical to those observed by feeding to pigs grains naturally contaminated with ochratoxin A.

Mental retardation in combination with proteinuria and a slight hyperlipoproteinemia was found in three brothers. The increased urinary protein excretion was dominated by albumin and the low molecular weight proteins retinol-binding protein (RBP) and beta2-microglobulin, indicating the presence of proximal tubular dysfunction. However, there was no glucosuria, phosphaturia or amino aciduria and the renal concentrating and acidification capacities were normal. A kidney biopsy in one of the patients revealed morphologic evidence of glomerular damage but a normal tubular structure. A mild hyper-beta-lipoproteinemia was found in the patients but not in their healthy siblings. The cause of this syndrome, hitherto not described, is unknown.

Nine pigs were fed crystalline ochratoxin A in their feed at a concentration of about 1 mg/kg. Three pigs and their controls were killed after 3 months and 6 pigs and controls were killed after 2 years. A decrease of the ratio TmPAH/CIn, increased urinary glucose excretion and decreased ability to concentrate urine, occurred within a few weeks and aggravated slightly during the 2-year period. Changes in renal structure, characterized by degeneration and atrophy of proximal tubules, interstitial fibrosis and hyalinization of glomeruli, were progressive during time of exposure, but terminal renal failure was not reached. The kidney, liver, muscular and adipose tissue contained 3 to 27 μg ochratoxin A/kg after 3 months of exposure. No further accumulation of ochratoxin A residue was found after 2 years of exposure.

Many hydrocarbons have properties which make them candidates for causing glomerulonephritis. They alter most immune functions and create a state of immunity deficiency; they damage the tubules which may lead to interstitial fibrosis and increased postglomerular capillary resistance furthering the trapping of macromolecules in the glomeruli; and they probably increase tissue permeability to macromolecules. The idea that hydrocarbons cause glomerulonephritis is supported by findings of an association between glomerulonephritis and hydrocarbon exposure, by findings of a relationship between tubulointerstitial damage and glomerular filtration rate in glomerulonephritis, and by findings of immunity deficiency in most subgroups of glomerulonephritis.

A patient with paroxysmal myoglobinuria presented with low molecular weight (LMW) proteinuria in association with an episode of exertional myoglobinuria. Since no signs of acute renal failure were present, the cause was probably competition between myoglobin and other LMW proteins for proximal tubular reabsorption. Agarose gel electrophoresis was found to be an excellent method for the investigation of myoglobinuria since this technique not only allowed the separation of myoglobin from hemoglobin but also myoglobin from metmyoglobin.

Proteinuria was studied experimentally in pigs with renal damage induced by maleic acid, potassium dichromate and by 5/6 nephrectomy. The methods used were: analysis of total protein, immunochemical quantitation of a porcine low molecular weight (alpha-PLMW) protein, agarose gel electrophoresis, and gel chromatography of concentrated urine samples. The urinary clearance of the alpha-PLMW protein in normal pigs was considerably higher than LMW protein clearance in normal man. No increase was seen after surgery. The induction of proximal tubular damage resulted in an increased excretion of, above all, high molecular weight proteins (greater than or equal to albumin) but also of low molecular weight proteins. The highest increase in alpha-PLMW clearance was seen immediately after 5/6 nephrectomy, and the increased alpha-PLMW excretion in pigs with proximal tubular dysfunction was better correlated to creatinine clearance than to the degree of phosphaturia or glucosuria. The results suggest different renal handling of plasma proteins in pigs and humans.

The occupations, as given in the national public census 1975, of 124 adult patients with non-systemic glomerulonephritis were compared with those of the general population in the catchment area of the hospital. Occupations assumed to be linked with exposure to organic solvents or fuels were commoner among patients than in the general population. The finding supports the idea that such exposure is causal in glomerulonephritis.