Demographic, clinical characteristics and treatment outcomes of immune-complex membranoproliferative glomerulonephritis and C3 glomerulonephritis in Japan: A retrospective analysis of data from the Japan Renal Biopsy Registry

The reclassification of membranoproliferative glomerulonephritis (MPGN) into immune-complex MPGN (IC-MPGN) and C3 glomerulopathy (C3G) based on immunofluorescence findings in kidney biopsies has provided insights into these two distinct diseases. C3G is further classified into dense deposit disease and C3 glomerulonephritis (C3GN) based on electron micrographic findings. Although these diseases have poor outcomes, limited Japanese literature confined to small, single-center cohorts exist on these diseases. We retrospectively analyzed 81 patients with MPGN type I and III from 15 hospitals in the Japan Renal Biopsy Registry to compare demographic, clinical characteristics and treatment outcomes of patients with IC-MPGN to those with C3GN. Of the 81 patients reviewed by immunofluorescence findings in kidney biopsies, 67 patients had IC-MPGN and 14 patients had C3GN. Age at diagnosis and systolic and diastolic pressure were higher and proteinuria and impaired renal function were significantly more prevalent in patients with IC-MPGN than those with C3GN. About 80% of the patients in both groups were treated with immunosuppressive therapy. At last follow-up (median 4.8 years), complete remission rate of proteinuria was significantly higher in patients with C3GN (64.3%) than in those with IC-MPGN (29.9%; P = 0.015). The renal survival rate was lower in patients with IC-MPGN when compared to C3GN (73.1% vs. 100%; log-rank, P = 0.031). Systolic blood pressure and renal function at baseline were independent predictors of progression to end-stage kidney disease. The overall prognosis of patients with C3GN is more favorable than for patients with IC-MPGN.

Complete Renal Recovery in Pediatric Patient with C3 Glomerulonephritis: A Case Report

C3 glomerulonephritis (C3GN) is a rare kidney disease resulting from dysregulation of the alternative complement cascade. Without treatment, approximately 70% of affected children and 30–50% of affected adults will develop worsening of proteinuria and progress to end-stage renal disease within 10 years of diagnosis. Here, we describe a 9-year-old Sudanese girl with no significant past medical history who presented to the Emergency Department with a 2-month history of fatigue, poor oral intake, and worsening facial and lower extremity edema, and subsequently found to have anemia, hypoalbuminemia, microscopic hematuria, and proteinuria. Additional laboratory testing revealed that the patient had low C3, high C3 nephritic factor (C3NeF), and high factor H. Renal function was normal. The diagnosis of C3GN was confirmed by renal biopsy. The patient was treated with ACE inhibitor, mycophenolate mofetil (600 mg per m² per dose, every 12 h), in combination with “pulse” methylprednisolone at 30 mg/kg/day IV bolus (maximum 1 g) for 3 consecutive days, followed by 2 months of daily oral prednisolone (2 mg/kg/day) and alternate-day prednisolone weaning from 1 mg/kg to 0.1 mg/kg for additional 12 months. Mycophenolate was continued throughout her treatment course and for maintenance therapy. In response to treatment, anemia, microscopic hematuria, hypoalbuminemia, and proteinuria resolved. Complete complement profile before and at 6 months therapy showed normalization of C3NeF, complement regulatory factor H and C3. This present case provides evidence of the full responsiveness of a rare form of complement dysregulation C3GN to a combination of mycophenolate and corticosteroids. The disease has NOT recurred in >2 years after initial presentation.

Co-existence of Alport syndrome and C3 glomerulonephritis in a proband with family history

Background Alport syndrome and C3 glomerulonephritis (C3GN) are rare kidney diseases, frequently responsible for familial haematuria, proteinuria, and renal impairment. With the rapid development of molecular genetic testing, Alport syndrome causes have been restricted mostly to variants in the COL4A5 or COL4A3/COL4A4 genes. Moreover, a broad range of genetic contributors in the complement and complement-regulating proteins are definitely implicated in the pathogenesis of C3GN. Methods We sought a family with persistent microscopic haematuria associated with renal failure. Clinicopathologic and follow-up data were obtained, and molecular genetic testing was used to screen for pathogenic variants. Results We describe a three-generation family with Alport syndrome showing a dominant maternal inheritance. Notably, renal biopsy showed the concurrent histological evidence of C3GN in the proband harbouring an uncommon heterozygous variation in CFHR5, c.508G > A. The alteration leads to replacement of a highly conserved residue at position 170 of the β-strand subunit of CFHR5 (p.Val170Met). In silico analysis showed that the variation was predicted to deregulate complement activation by altering the structural properties and enhancing C3b binding capacity to compete with Complement Factor H (CFH), which was in line with experimental data previously published. Conclusions The comorbidity findings between Alport syndrome and C3GN indicate an underlying overlap and require further study.

C3 glomerulonephritis and systemic lupus erythematosus: A report of a patient treated with eculizumab and review of the literature

Introduction Activation of the complement pathway by immune complexes is a key feature of systemic lupus erythematosus (SLE) and SLE glomerulonephritis, which translates into low levels of C3 and C4 during active disease. C3 glomerulonephritis (C3GN) is part of a broader group of rare renal diseases, the C3 glomerulopathies, characterized by prominent C3 accumulation in the glomeruli with minimal to no immunoglobulin (Ig) deposition secondary to dysregulation of the alternative pathway of the complement system. Distinguishing lupus nephritis from other complement-mediated kidney disorders, including C3GN, represents a diagnostic challenge with potential therapeutic implications. Methods We report an unusual case of a 55-year-old woman with SLE and previous biopsy-proven class IV lupus nephritis, subsequently diagnosed with C3GN. Furthermore, we review the available literature published from January 2010—March 2021 on the clinical features and management of C3GN in the setting of SLE. Results In addition to our case, very few reports exist in the literature regarding C3GN in association with SLE. The underlying pathogenic mechanism of C3GN consists of dysregulation of the alternative pathway of the complement system, either due to genetic variation in complement-related genes or to acquired autoantibodies targeting C3 or C5 convertases; the latter mechanism could explain the occurrence of C3GN in the setting of autoimmune diseases, although it was not definitively identified in our patient or others with SLE. Similar to some of the previous reports, after suboptimal renal response on mycophenolate mofetil and rituximab, our patient has been successfully treated with eculizumab, thus far with >50% improvement in proteinuria. Conclusions C3GN represents an additional mechanism of renal injury in SLE mediated by alternative complement pathway dysregulation. Although rare, patients with SLE and persistent proteinuria with very low C3 would benefit from expedited renal biopsy to evaluate for C3GN as well as genetic testing, since this entity could require a different therapeutic approach.

Generation and Characterization of Mouse Models of C3 Glomerulonephritis With CFI D288G and P467S Mutations

C3 glomerulopathy (C3GP) is a disease entity caused by abnormality of the complement alternative pathway (AP) and characterized by C3 deposition in glomeruli. Many variations or mutations of complement factors are believed to underlie the susceptibility to C3GP, but there is a lack of experimental evidence. We have recently reported a patient with C3 glomerulonephritis (C3GN) and compound heterozygosity of two novel variations in the complement factor (CFI). Here, we generated a mouse model to mimic the CFI variations for studying pathogenicity of CFI variations in C3GN development. We used the CRISPR/Cas9 system to make mutant mouse lines that carried D288G and P467S mutations in CFI, respectively, and crossed them to generate mice with compound heterozygosity of CFI D288G and P467S. The mice were all normal in either SPF (specific pathogen free) or regular environment. When treated with lipopolysaccharides (LPS), a bacterial endotoxin that mimics infection and sepsis, the mice developed albuminuria, kidney function impairment, and C3 glomerular deposition at levels comparable with the wild-type mice. The mice with other genotypes concerning CFI D288G and P467S were also tested in parallel. Unexpectedly, we found that the D288G homozygotes all developed severe mesangial deposition of C3 in the LPS model, indicating that CFI D288G variation was involved in the C3 deposition, a key feature of C3GN. The mouse lines generated in the present study can be used to further study the role of CFI variations in C3GN development; in addition, they may be used to screen and test infections and environmental factors capable of triggering C3GN.