The patient is a 39-year-old woman who presented 1 year ago with progressive proteinuria, renal failure, and hypertension. A biopsy was performed after development of significant renal dysfunction; serum creatinine was 3 mg/dL. The protein excretion rate was 1-2 g/24 h initially, which increased to 4-6 g/24 h with worsening renal function. The initial biopsy result at an outside institution was reported as non-diagnostic, with features of chronic autoimmune glomerulonephritis. The patient had a thorough infectious disease evaluation which was negative for hepatitis A, hepatitis B virus (HBV), and hepatitis C virus (HCV) serologies, negative for human immunodeficiency virus (HIV), negative for treponemal serologies, and with no evidence of tuberculosis, coccidiomycosis or other chronic infections. She did not have known diabetes, obesity, or malignancies.
Extensive serological evaluation was negative for lupus serologies [anti-nuclear antibody negative (<1:40 titer), anti-double stranded DNA (anti dsDNA) negative (<200 international units/ml), DNAase B antibody negative (<86 Units/ml), anti-histone antibody negative 0.4 units, anti-centromere <1, ribonucleoprotein <20 units, anti-smith antibodies <20 units, Sjogren's syndrome (SSA and SSB) antibodies <20 units, rheumatoid factor negative <1, scleroderma antibodies negative at 1 AU/ml, anti-citric citrulline peptide negative at 3 units, Cardiolipin IgA, IgG, IgM was negative, and ANCA panel (c-ANCA, p-ANCA, proteinase 3 and anti-myeloperoxidase were all negative <1:20 titer). Complement titers (CH 50) were near the lower limit of normal at 43 units/mL [Reference range 42-95 Units/mL], and there was isolated depression of C3 at 67 mg/dL [Reference range 76-165 mg/dL] but with normal C4 levels at 23 mg/dL [Reference range 16-48 mg/dL]. Serum and urine electrophoretic studies and immunofixation studies did not reveal a monoclonal spike. Free light chain kappa to lambda ratio was also normal with a ratio of 1.66.
On renal biopsy (Figure 1), the dominant finding by light microscopy was an MPGN pattern of injury that was predominantly chronic with segmental sclerosis, extensive global glomerulosclerosis, and parenchymal scarring. However, there was residual activity including focal cellular-to-fibrocellular crescents, karyorrhexis, and diffuse, and mild endocapillary hypercellularity. Along with prominent glomerular basement membrane double contours, there was also some suggestion of mesangiolysis and marked endothelial cell swelling raising the possibility of endothelial cell injury, although definitive morphologic features of TMA were not identified. Immunofluorescence studies showed segmental to global granular staining for IgG (2+), IgA (trace), IgM (trace), C1q (2+), C3 (3+), and kappa/lambda light chains (both trace). At least two glomeruli exhibited segmental fibrinogen staining (2-3+) in areas of capillary loop necrosis. Electron microscopy revealed amorphous electron dense deposits present in a predominantly subendothelial and mesangial distribution with occasional subepithelial and intramembranous deposits. Endothelial cell cytoplasm was swollen. There were no tubuloreticular inclusions or extra-glomerular deposits. A diagnosis of immune-complex mediated membranoproliferative glomerulonephritis was rendered.
Given the negative evaluation for underlying infectious, autoimmune diseases, and neoplastic disorders, the possibility of a complement-mediated disorder was investigated. Complement profile testing did not reveal C3Nef, C4Nef, anti-factor H, or factor B antibodies. Soluble C5b-9 levels were not elevated (within the normal range of <250 ng/mL), a finding which was compatible with the patient's glomerular disease having entered a quiescent stage. No known genetic mutations or variants of uncertain significance were found at the time (Iowa complement laboratory) in the 2017 panel that was sent. The panel sent included CFH, CFI, MCP (CD46), CFB, CFHR5, THBD, C3, ADAMTS13, PLG, DGKE, MMACHC, G6PD. Multiple Ligation Probe Amplification (MLPA) was included in the testing to determine copy number variants over the complete complement Factor H related region.
It should be noted that the rate of capture of genetic mutations remains only 41-60%, as not all mutations leading to complement mediated disorders are known at this point. However, C3 levels remained low at 67-75 mg/dL a year after the renal biopsy, supporting the presence of a complement-mediated disorder. The patient has remained off renal replacement therapy and is scheduled to undergo a preemptive renal transplant. Treatment with mycophenolate mofetil with the transplant may be able to prevent any complement mediated disease process recurrence; however, further therapy would depend on demonstration of recurrent glomerulonephritis in renal allograft biopsy.