A CASE OF IgA-ASSOCIATED MEMBRANOUS NEPHROPATHY WITH RECURRENT RELAPSES AND SUPERIMPOSED DIABETIC NEPHROPATHY: CLINICAL COURSE, PATHOLOGY, AND RESPONSE TO IMMUNOSUPPRESSION.

Primary membranous nephropathy (MN) is usually mediated by subepithelial IgG deposition against podocyte antigens such as PLA2R or THSD7A. IgA-associated MN (IgA-MN) is extremely rare and shows granular IgA deposits along the glomerular capillary walls. Its pathogenesis and response to therapy remain unclear. Here, we report a case of IgA-MN that showed responsiveness to steroid therapy but experienced repeated relapses and developed diabetic nephropathy during the clinical course. We present detailed pathological findings and the clinical course of this case. 

A 69-year-old male was diagnosed with nephrotic syndrome at another hospital six years prior, but without a kidney biopsy. He responded well to steroid therapy (methylprednisolone 500 mg × 3 days of pulse therapy, followed by oral prednisolone [PSL] 30 mg/day with gradual tapering), but a relapse was observed when PSL was tapered to 5 mg/day. Thereafter, relapses occurred repeatedly despite steroid treatment, and urine protein levels were maintained below 1 g/gCr with PSL adjusted to 5–15 mg/day. Steroid-induced diabetes developed during the treatment course, with HbA1c maintained around 7.0% with oral medication. His past medical history included bladder cancer, which was successfully treated with BCG and had not recurred. He was referred to our hospital for further investigation of the cause of nephrotic syndrome, and a kidney biopsy was performed. 

Pathological findings revealed changes consistent with MN in the glomeruli by light microscopy, including capillary wall thickening, spike formation, and bubble signs. In addition, changes consistent with diabetic nephropathy such as mild mesangial matrix expansion, exudative lesions (fibrin cap), and hyalinosis of the afferent arteriole were observed. Immunofluorescence showed granular deposition of IgA and C3 along the capillary walls, but no deposition in the mesangial region. Linear IgG deposition was also observed along the capillary walls. IgA subclass was positive for IgA1, and IgG subclasses (IgG1–4) were all negative. Immunostaining for PLA2R and galactose-deficient IgA1 were both negative. Electron microscopy showed small amounts of subepithelial and intramembranous deposits, while prominent foot process infolding was observed. Based on these findings, he was diagnosed with IgA-MN (Stage III) and diabetic nephropathy. To identify the causative antigen protein, proteins were extracted from glomeruli dissected by laser microdissection and analyzed by mass spectrometry. However, none of the known MN-related antigens were identified. After the kidney biopsy, steroid was adjusted as needed and controlled around 1 g/gCr, but since it gradually became resistant to treatment, cyclosporine was added, resulting in remission and allowing steroid reduction.

In this case, IgA-MN showed pathological features distinct from typical IgG-MN, including relatively small subepithelial electron-dense deposits and marked podocyte infolding on electron microscopy. Corticosteroids and cyclosporine were effective, as in IgG-MN. Mass spectrometry suggested that different proteins, and potentially their corresponding autoantibodies, may contribute to IgA-MN pathogenesis. Many aspects remain unclear, and further detailed studies are needed.