Acta Med Scand 200:427429, 1976

Nephrotic Syndrome due to Subacute Glomerulonephritis -Association with Hydrocarbon Exposure? Christian von SchCelel, Peter Althoff, Viktor Kempi and Ulf Schelin From the Departments of Medicine, Arvika Hospital, Arvika, and University Hospital, Uppsala, the Department of Radiophysics, Central Hospital. Ostersund, and the Department of Pathology, Central Hospital, Karlstad, Sweden

ABSTRACT. A 59-year-old man developed a nephrotic syndrome 40 days after hydrocarbon exposure of 3 days' duration. Renal biopsy gave evidence of a subacute proliferative glomerulonephritis. A lasting remission was obtained with immunosuppressive therapy. The case history is discussed in the light of recent studies indicating a causal relationship between hydrocarbon exposure and glomerulonephritis. The reversible nature of the disease in the present case is discussed in relation to the disease in experimental animals induced by a single administration of heterologous antigen.

Environmental factors have won increasing recognition as actual or possible causes of disease. The agents that provoke chronic glomerulonephritis are still obscure, but in the majority of patients there are reasons t o believe that immunological mechanisms are involved. T h e factors which trigger this abnormal immunological response are, however, largely unknown. During the last ten years there have been scattered reports of an association between hydrocarbon exposure and rapidly progressive glomerulonephritis ( 1 , 4, 6). Recently it was shown that patients with chronic proliferative glomerulonephritis had been exposed t o hydrocarbon significantly more than patients with other renal diseases (8). All patients hitherto described have had a chronically deteriorating disease course, resulting in end-stage renal failure. In contrast, the present patient developed a nephrotic syndrome due t o biopsy-proven subacute proliferative glo-

' Present address: Department of Medicine, Sjukhuset, S m e , Sweden.

merulonephritis 40 days after hydrocarbon exposure. The disease healed with immunosuppressive therapy and intermittent proteinuria has been the only sign of residual renal damage at subsequent controls.

CASEREPORT The patient, a post-office employee born in 1912, was well until 1970, when he was operated on for perforation of a duodenal ulcer. A gastric resection was performed. After that he was in excellent health until the end of Oct. 1971, at which time he spent three days painting a floor. He used 30 I of paint containing diacetone alcohol and ethanol as solvents. At the end of Nov. he first noted edema of the legs. The edema progressed rapidly and was generalized within four days. A diuretic was prescribed and some relief was experienced. During the first week of Dec. the edema could, however, no longer be controlled. There was again a rapid progression, resulting in pronounced and generalized edema. He gained about 12 kg in weight from the time of the first symptoms until the latter half of Dec. He was referred to the Medical Department in the end of Dec. 1971. On admission he was found to have anasarca, the edema being most pronounced in the lower half of the body. The breath sounds were diminished corresponding to the basal part of the right lung. His BP was 120/80 mmHg. Otherwise, physical examination showed normal results. HB was 15.0 g/l00 ml, WBC normal as a differential count, ESR 100 mmlhour. Total serum protein concentration was 4.3 gll00 ml, albumin 1.7 g/lW ml, globulins 2.6 gll00 ml. Fibrinogen was 0.8 g/lW ml. There was 11% protein in the urine, corresponding to a urinary excretion of 10 g/24 g hours. The 24-hour urine volume was 1000-1 500 ml. Within 16 hours after the administration of pitressin tannate the urine osmolality reached a maximum value of 980 mOsm/ kg. Urinary microscopy showed 5 red cells ger high power field and a moderate number of granular casts. Cholesterol was 540 mg/100 ml, triglycerides 306 mg/ 100 ml. Serum creatinine was 1.4 mg/100 ml, reaching Acta Med Scand 200

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a peak value of 2.2 mgll00 ml on the 10th day in hospital (Fig. I). Normal values were obtained at repeated serum estimations of sodium, potassium, calcium, standard bicarbonate and transaminases. A culture from the throat yielded no growth of streptococci. The antistreptolysin titer was normal. Chest X-rays revealed moderate, bilateral pleural effusions. A kidney biopsy was performed on the 8th day in hospital. The micro-

Fig. 2. Kidney biopsy. Three glomeruli showing hypercellularity, capsule proliferation and adhesion between glomerular tuft and capsule. Degenerative changes in the proximal convoluted tubules with swollen, vacuolated epithelial cells (v. Gieson, X 107). Acto

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scopic examination revealed changes compatible with the diagnosis of subacute proliferative glomerulonephritis (Fig. 2). Quantitative immune electrophoretic determinations of the plasma and urine proteins revealed increased plasma concentrations of macromolecular proteins, such as fibrinogen and cr-2-macroglobulin, and a pronounced reduction of albumin. IgG was 0.3, IgA 0.16 and IgM 0.17 gll00 ml, P-1,-globulin (C3) was within normal limits (IlO%), but P-IE(C,) was reduced to 76% of the normal value. The urinary protein pattern was compatible with that found in unselective proteinuria. No circulating antibodies against glomerular basement membrane (GBM) could be demonstrated with immunofluorescent studies. During the four-week stay in hospital the patient was normotensive. His weight reached a maximum of 88 kg at the end of the first week. The urine output was persistently in excess of one 1. Treatment with corticosteroids, azathioprine and furosemide was started on the 10th day. Within one week the proteinuria diminished to 2.8%0 and within two weeks to 0.5%0. His weight also normalized rapidly. The patient was discharged at the end of the 4th week on prednisolone and azathioprine. Frequent reinvestigations revealed a continued improvement. Trace amounts of protein were found intermittently in the urine. Serum proteins and serum creatinine returned to normal. The patient was persistently normotensive. In Aug. 1972 the creatinine clearance was 90 ml/min, the same value was obtained in Sept. 1973. The prednisolone and azathioprine therapy was gradually discontinued in Oct. 1973. In May 1975, BP was 140/80 mmHg, ESR 19 mmlhour, Hb 14.1 gll00 ml and serum creatinine 1.2 mg/lOO ml. There was a proteinuria of 0.8%0. Reportedly he was in excellent health.

Glomerulonephritis andhydrocarbons COMMENTS The evolution of a nephrotic syndrome due to a subacute proliferative glomerulonephritis 40 days after hydrocarbon exposure in the present case may well be a coincidence. However, the absence of other diseases or disease-provoking factors, known to be associated with glomerulonephritis, makes it necessary to consider such a causal relationship. An association of Goodpasture’s syndrome with exposure to petroleum products was suggested by Klavis and Drommer in 1970 (4). They described a 26-year-old painter, who, within two months after a single, heavy exposure to a gasoline-based paint spray, developed pulmonary infiltrates, pulmonary hemorrhages and a rapidly progressive glomerulonephritis. They were also able to induce a similar disease in rats by chronic exposure to gasoline vapors. In 1972 Beirne and Brennan ( I ) , on the basis of interviews, reported that six of eight patients with glomerulonephritis associated with GBM antibodies had a previous history of exposure to various hydrocarbon solvents. Accordingly, a theory was proposed implying chemical injury to the lung or the kidney as the first step, followed by autoimmune organ damage. The present case does not fit into the category of patients with rapidly progressive glomerulonephritis associated with GBM antibodies. The absence of such antibodies and the benign clinical course contradict the diagnosis of anti-GBM glomerulonephritis and would rather suggest an immune complex genesis. Before 1975, however, nearly all the cases in which hydrocarbons were suspected of being implicated, had the peculiarity of being examples of anti-GBM glomerulonephritis. Also in rats, fed with N,N’-diacetyl benzidine, a disease could be induced, which conformed to rapidly progressive glomerulonephritis in man (3). In 1975 Zimmerman et al. (8) were able to demonstrate that patients with proliferative glomerulonephritis had been exposed to hydrocarbon significantly more than patients with a variety of other renal diseases. Five of 12 patients with biopsyproven proliferative glomerulonephritis were found to have linear depositions of IgG suggesting GBM antibodies. Of the remaining patients, four had granular deposits of IgG, IgM and C,. This finding could indicate glomerular deposition of immune complexes. Immune complex deposition is sup-

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posed to be the most prevalent mechanism leading to glomerulonephritis. It is thought to occur with much higher frequency than anti-GBM antibodies in acute as well as in chronic glomerulonephritis (5,7). The benign and limited course of the disease in the present patient contrasts with the chronic and irreversible pattern in the patients described earlier. To explain this we suggest as an experimental model a self-limiting immune complex disease, called by Dixon (2) “one shot” serum sickness. In this disease, a single exposure to antigen is followed by production of antibodies, antigenantibody complexes are formed and there is a resulting deposition of immune complexes in the tissues. This phenomenon coincides with the appearance of an acute reversible glomerulonephritis. Admittedly, the proposed scheme of events leading to the subacute proliferative glomerulonephritis in the present case is highly hypothetical. Nevertheless, the possibility of hydrocarbon exposure as an important factor in the pathogenesis of glomerulonephritis, in whatever form it may appear, cannot be ignored. The prevalence of hydrocarbons and their recently recognized role as an OCcupational and environmental hazard warrant increased awareness and further exploration.

REFERENCES 1. Beirne, G. J. & Brennan, J. T.: Glomerulonephritis

2.

3. 4.

5. 6.

associated with hydrocarbon solvents. Arch Environ Health 25: 365, 1972. Dixon, F. J., Wilson, C. B. & Marquardt, H.: Experimental immunologic glomerulonephritis. In: Advances in nephrology, vol. 1 (ed. J. Hamburger, J. Crosnier and M. €1. Maxwell), pp. 1-10. Year Book Medical Publishers, Chicago 1971. Harman, J. W.: Chronic glomerulonephritis and the nephrotic syndrome induced in rats with N,N’-diacetyl benzidine. J Pathol 104: 119, 1971. Klavis, G. & Drommer, N.: Goodpasture-Syndrome und Benzineinwirkung. Arch Toxikol 26: 40, 1970. Merril, J. P.: Glomerulonephritis. Part one. N Engl J Med 290: 257, 1974. Seelinger, K. & Huland, H.: Kasuistischer Beitrag zur Atiologie des Goodpasture-Syndromes. Med Klin 68:

437, 1973. 7. Wilson, C. B. & Dixon, F. J.: Diagnosis of immunopathological renal disease. Kidney Int 5: 389, 1974. 8. Zimmerman, S . W.,Groehler, K. & Beirne, G. J.: Hydrocarbon exposure and chronic glomerulonephritis. Lancet 2: 199, 1975. Acra Med Scand 200