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Background C3 glomerulonephritis (C3GN) is a rare disease caused by inherited or acquired complement alternative pathway (CAP) dysregulation, which could also be secondary to monoclonal gammopathy of undetermined significance (MGUS). Herein, we described a patient presenting with C3GN and monoclonal gammopathy, and the pathogenic association between the two diseases was further explored in vitro. Case presentation A 76-year-old Chinese man presented with low serum C3 level, haematuria and nephrotic syndrome, and experienced rapid worsening of renal function over a period of 10 months. His serum and urine immunofixation electrophoresis both revealed a monoclonal IgGλ. A bone marrow puncture showed plasma cell dyscrasias with the highest plasma cell count of 5.25%. Kidney biopsy showed the presence of C3 glomerulonephritis, with exclusive deposits of C3 visible on immunofluorescence, a membranoproliferative pattern on light microscopy and electron dense deposits in sub-epithelial, intramembranous, sub-endothelial and mesangial regions by electron microscopy. The patient was positive for C3 nephritic factor (C3NeF) activity and anti-CFH autoantibodies, and all became negative during disease remission. The anti-CFH autoantibodies purified from the patient’s plasma exchange fluids were proven to be a monoclonal IgGλ, and could inhibit CFH binding to C3b and accelerate the formation of C3 convertase indirectly by interfering with the formation-impeding activity of CFH. No deficiency of candidate genes, especially variants in CFH, was detected in our patient. Based on the pathological and laboratory findings, the diagnosis of monoclonal gammopathy of renal significance (MGRS)-associated C3GN was finally made. Conclusions This is the first demonstration that intact monoclonal immunoglobulin (IgGλ) could act as an anti-CFH antibody and lead to MGRS-associated C3GN by activating the CAP.

Background Multiple myeloma (MM) is a plasma-cell derived hematologic malignant disease. The malignant proliferating plasma cells secrete massive monoclonal immunoglobulins which lead to various pathologic types of renal injury. Myeloma cast nephropathy (MCN) is the most common histopathologic lesion with the worst renal prognosis. Rarely, the free light chains in the protein casts can form amyloid fibrils. Here, we reported two rare cases of MCN with diffuse amyloid casts. Case presentation Case 1: A 54-year-old Chinese man presented with a 4-year history of multiple myeloma, proteinuria and hematuria. He had monoclonal IgAλ plus free λ spike in both serum and urine. He had been on chemotherapy for 4 years and maintained normal serum creatinine until 11 months ago. Then, his renal function deteriorated and he went on hemodialysis 4 months before admission. Renal biopsy showed diffuse amyloid casts in the tubular lumens, without any obvious amyloid deposits in other kidney compartments or signs of extra-renal amyloidosis. The amyloid fibrils formed around mononuclear cells which were CD68 negative. According to the morphology and location, these mononuclear cells were considered as tubular epithelial cells. The patient was maintained on chemotherapy and hemodialysis. He died 8 months after renal biopsy. Case 2: A 58-year-old Chinese man presented with a one-and-a-half-year history of proteinuria and slowly rising serum creatinine. He had monoclonal IgDλ spike in both serum and urine. Amyloid casts were observed in the tubular lumens and mononuclear cells could be identified in the center of some casts. There were no amyloid deposits in other kidney compartments and no sign of systemic amyloidosis. The patient also had fine granular deposits along the tubular basement membrane with λ linear staining along tubular basement membrane suggesting light chain deposition disease. He was treated with bortezomib-based chemotherapy followed by lenalidomide-based chemotherapy and achieved very good partial remission (VGPR). After 27 months of follow-up, the patient still showed no signs of systemic amyloidosis. Conclusions These 2 cases of MCN with diffuse amyloid casts have different histopathologic characteristics from the usual myeloma casts and tubular epithelial cells might play important roles in the pathogenesis.

BackgroundThe commonly used methods for amyloid typing include immunofluorescence or immunohistochemistry (IHC), which sometimes may come with diagnostic pitfalls. Mass spectrometry (MS)-based proteomics has been recognized as a reliable technique in amyloid typing.Case presentationWe reported two middle-aged patients who presented with proteinuria, hypertension and normal renal function, and both had a family history of renal diseases. The renal biopsies of both patients revealed renal amyloidosis with the similar pattern by massive exclusively glomerular amyloid deposition. The IHC was performed by using a panel of antibodies against the common types of systemic amyloidosis, and demonstrated co-deposition of fibrinogen Aα chain and apolipoprotein A-I in the glomerular amyloid deposits of each patient. Then the MS on amyloid deposits captured by laser microdissection (LMD/MS) and genetic study of gene mutations were investigated. The large spectra corresponding to ApoA-I in case 1, and fibrinogen Aα chain in case 2 were identified by LMD/MS respectively. Further analysis of genomic DNA mutations demonstrated a heterozygous mutation of p. Trp74Arg in ApoA-I in case 1, and a heterozygous mutation of p. Arg547GlyfsTer21 in fibrinogen Aα chain in case 2.ConclusionsThe current study revealed that IHC was not reliable for accurate amyloid typing, and that MS-based proteomics and genetic analysis were essential for typing of hereditary amyloidosis.

Background Proliferative glomerulonephritis with monoclonal Immunoglobulin (G) deposits (PGNMID) is a rare kind of MGRS with intact monoclonal IgG deposition. Seventy percent of PGNMID patients were negative for M-spike. Case presentation A 51-year-old Chinese woman presented with 16-month history of chronic nephritic syndrome. Her first biopsy showed a MPGN pattern, and the IF showed polyclonal IgG deposition but with IgG3λ dominance, MGRS was highly suspected. But the serum/urine IFE and bone marrow examination was negative for monoclonal gammopathy. She was treated with RAS inhibitors, and monitored carefully in the outpatient clinic. When the proteinuria was not controlled by RAS inhibitors, immunosuppressive agents were initiated. The second biopsy was done due to her acute kidney injury 9 months later, showing a MPGN pattern with acute tubulointerstitial disease, but the IF showed monoclonal IgG3λ deposition. The κ light chain, IgG1, IgG2 and IgG4 were absent. Electron microscopic examination revealed electron-dense deposits in the mesangial, subendothelial and subepithelial area which is the same as the first renal biopsy. The final diagnose of this patient was PGNMID (IgG3λ) with non-organized deposits. Repeated serum/urine IFE and free light chain still failed to identify monoclonal gammopathy. The patient was treated with steroid and cyclophosphamide, and her serum creatinine decreased. Conclusions Some of the PGNMID patients may be derived from polyclonal immune complex mediated glomerulonephritis.

Background Monoclonal gammopathy of renal significance (MGRS) is a recently defined group of renal diseases caused by monoclonal immunoglobulin secreted by nonmalignant proliferative B cell or plasma cell. Monoclonal immunoglobulin can form different types of structures deposited in renal tissue, including fibrils, granules, microtubules, crystals and casts, and has mostly been reported in multiple myeloma patients. Here we report a rare case with κ light chain crystals in both podocytes and tubular epithelial cells associated with MGRS, which adds more information to the spectrum of MGRS-related renal diseases. Case presentation A 53-year old woman presented with albumin–predominant moderate proteinuria and renal failure. She had monoclonal IgGκ in the serum and monoclonal IgGκ plus free κ in the urine. Multiple myeloma and lymphoproliferative disorders were excluded. Renal biopsy confirmed κ-restricted crystal-storing renal disease involving the podocytes and proximal tubular epithelial cells. The patient was treated with bortezomib followed by lenalidomide-based chemotherapy, and renal function was stable after 1 year of follow-up. Conclusions This is a rare case of combined crystalline podocytopathy and tubulopathy associated with MGRS, in which diagnosis was dependent on electron and immuno-electron microscopy.