Hydrocarbon exposure may cause glomerulonephritis and worsen renal function: evidence based on Hill's criteria for causality.

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.

Hydrocarbons may worsen renal function in glomerulonephritis: a meta-analysis of the case-control studies.

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.

Glomerular, tubular and interstitial nephritis associated with non-steroidal antiinflammatory drugs. Evidence of a common mechanism.

AIMS: To study the mechanisms behind NSAID-associated nephropathy. METHODS: Analysis of published case reports satisfying strict criteria for NSAID nephropathy. RESULTS: Ninety-seven cases with acute nephritis (AN; 19 patients), minimal change nephropathy (MC; 38 patients), membranous glomerulonephritis (MGN; 19 patients), focal sclerosis (FS; 13 patients) and other glomerulonephritis subgroups (8 patients) were identified. Hypersensitivity reactions were seen in all groups, most often in AN. Proteinuria was more severe in MC and FS than in MGN and unrelated to amount of glomerular deposits. The mean NSAID treatment time was 1.7 months in AN, 8.2 months in MC and 39 months in MGN and associated with amount of glomerular deposits, fusion of podocytes and proteinuria, and inversely associated with hypersensitivity, interstitial damage and renal failure. Rheumatic diseases were common in MGN. At follow-up 68 of 72 patients who had discontinued NSAID treatment had improved, 57 with normal renal function. CONCLUSIONS: NSAID nephropathy may be caused by hypersensitivity. The reaction is milder than in drug-induced acute tubulointerstitial nephritis, probably because the offending drug inhibits the inflammatory reaction it has started itself. Heavy proteinuria is probably due to lymphokines produced as a result of the immunological response. If the allergic reaction is strong, AN is produced rapidly with severe renal failure but little proteinuria; if it is less violent, immunocompetent cells may develop to produce lymphokines and proteinuria. Immune complexes may be formed eventually, secondary to the increased glomerular permeability, more easily in patients with a hyperactive immune system and with little consequence for renal function.

The subepithelial formation of immune complexes in membranous glomerulonephritis may be harmless and secondary to toxic or allergic factors.

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.

The questionable role of saturated and polyunsaturated fatty acids in cardiovascular disease.

A fat diet, rich in saturated fatty acids (SFA) and low in polyunsaturated fatty acids (PUFA), is said to be an important cause of atherosclerosis and cardiovascular diseases (CVD). The evidence for this hypothesis was sought by reviewing studies of the direct link between dietary fats and atherosclerotic vascular disease in human beings. The review included ecological, dynamic population, cross-sectional, cohort, and case-control studies, as well as controlled, randomized trials of the effect of fat reduction alone. The positive ecological correlations between national intakes of total fat (TF) and SFA and cardiovascular mortality found in earlier studies were absent or negative in the larger, more recent studies. Secular trends of national fat consumption and mortality from coronary heart disease (CHD) in 18-35 countries (four studies) during different time periods diverged from each other as often as they coincided. In cross-sectional studies of CHD and atherosclerosis, one group of studies (Bantu people vs. Caucasians) were supportive; six groups of studies (West Indians vs. Americans, Japanese, and Japanese migrants vs. Americans, Yemenite Jews vs. Yemenite migrants; Seminole and Pima Indians vs. Americans, Seven Countries) gave partly supportive, partly contradictive results; in seven groups of studies (Navajo Indians vs. Americans; pure vegetarians vs. lacto-ovo-vegetarians and non-vegetarians, Masai people vs. Americans, Asiatic Indians vs. non-Indians, north vs. south Indians, Indian migrants vs. British residents, Geographic Study of Atherosclerosis) the findings were contradictory. Among 21 cohort studies of CHD including 28 cohorts, CHD patients had eaten significantly more SFA in three cohorts and significantly less in one cohort than had CHD-free individuals; in 22 cohorts no significant difference was noted. In three cohorts, CHD patients had eaten significantly more PUFA, in 24 cohorts no significant difference was noted. In three of four cohort studies of atherosclerosis, the vascular changes were unassociated with SFA or PUFA; in one study they were inversely related to TF. No significant differences in fat intake were noted in six case-control studies of CVD patients and CVD-free controls; and neither total or CHD mortality were lowered in a meta-analysis of nine controlled, randomized dietary trials with substantial reductions of dietary fats, in six trials combined with addition of PUFA. The harmful effect of dietary SFA and the protective effect of dietary PUFA on atherosclerosis and CVD are questioned.