Methods

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Four patients with membranous nephropathy were referred to us with possible exposure to toxic concentrations of formaldehyde. Air-borne formaldehyde concentrations were measured as recommended by the National Institute of Occupational Safety and Health [3]. Standard microcytotoxicity assays were used to serologically type histocompatibility leukocyte (HLA) antigens. We identified HLA-DR ß sequences from enzymatically amplified DNA by a modified reverse blot assay [4] that used sequence-specific oligonucleotide probes.

Results

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All four patients presented with the nephrotic syndrome. Biopsy specimens showed typical membranous nephropathy (Table 1). All had worked with materials that contained formaldehyde or had moved into new homes that had substantial amounts of formaldehyde in the insulation or cabinetry. In three of four cases, the patient or a family member had a history of eye or upper respiratory problems related to the formaldehyde fumes. No patient had evidence for any known cause of membranous nephropathy. However, atypical features included mild eosinophilia (two patients), low-positive antinuclear antibody levels with a negative anti-double-stranded DNA antibody test result (two patients), and borderline-low C4 (one patient) or CH₅₀ (one patient). Histocompatibility leukocyte antigen typing showed the A1 B8 DR3 haplotype in two patients and the B18 DR2 haplotype in one patient. These haplotypes have been associated with membranous nephropathy in Europe and Japan, respectively [1]. However, sequence-specific oligotyping showed that all four patients inherited an HLA-DR ß allele at either the DR ß 1 or DR ß 5 locus, which encodes an identical amino acid sequence (amino acids 35-39) in the peptide-binding region. Two of the patients are described below.

Patient 1

A 39-year-old male contractor built a cottage using wood paneling that was bonded with phenol formaldehyde resin. The floor consisted of urea formaldehyde-bonded particle board. While working, the patient noted a strong odor that was associated with "burning" eyes and headaches. Eight months later, hypertension and the nephrotic syndrome developed (serum creatinine level, 1.4 mg/dL; urine protein concentration, 9 g/d). A renal biopsy specimen showed membranous nephropathy.

Patient 2

The cottage built by patient 1 was intermittently occupied by a family of four in the year after construction. A strong odor was again noted, and several family members and visitors reported "burning" eyes, nausea, vomiting, diarrhea, or upper respiratory tract symptoms when in the house. After a year of intermittent exposure, the 13-year-old son developed the nephrotic syndrome (serum creatinine level, 0.6 mg/dL; urine protein concentration, 6 g/d). A renal biopsy specimen showed membranous nephropathy.

Discussion

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Formaldehyde is commonly used to bond particle board, fiber board, and plywood and was also used in the 1960s and 1970s for building insulation [5-7]. Whereas concentrations of formaldehyde in urban air are usually less than 0.01 parts per million (ppm), concentrations of formaldehyde in mobile homes or homes constructed with particle board are often increased (0.1 to 2 ppm or greater) [5-7]. Concentrations of 0.05 ppm may be associated with a strong odor and upper respiratory or eye irritation in exposed persons [5, 6]. Formaldehyde exposure may also be associated with dermatitis, urticaria, and possibly sinonasal cancer [5, 6].

Our patients developed membranous nephropathy after documented exposure to formaldehyde at a concentration of at least 0.1 ppm. A similar case has also been reported, although that patient was exposed to organic solvents as well [2]. Although specific epidemiologic studies are necessary to confirm this association, two recent studies showed a twofold increase in chronic nephritis as a cause of death in persons involved in the use [7] or manufacture [8] of formaldehyde.

Membranous nephropathy is probably an autoimmune disease induced by an antibody directed against an antigen on the glomerular epithelial cell [1]. Formaldehyde exposure may induce autoimmune reactions, including antinuclear autoantibody production and autoimmune hemolytic anemia [5, 9].

Because many people exposed to formaldehyde do not develop glomerular disease, other factors are probably involved. Although only two of four patients shared HLA-DR antigens, all four inherited one or more alleles that coded for the same amino acid sequence (amino acids 35-39) within a binding pocket of the DR molecule [10]. Although the frequency of these alleles in Caucasian and Japanese persons is not known, the frequency of the corresponding antigens is estimated not to exceed 35%. The DR ß polymorphism could be directly involved in the disease pathogenesis, or may be a marker for a susceptibility gene elsewhere. These data are consistent with the hypothesis that formaldehyde may act as a "triggering" agent to induce membranous nephropathy in genetically susceptible persons.