Inherited Kidney Complement Diseases

Abstract

In the past 20 years, we have witnessed tremendous advances in our ability to diagnose and treat genetic diseases of the kidney caused by complement dysregulation. Staggering progress was realized toward a better understanding of the genetic underpinnings and pathophysiology of many forms of atypical hemolytic uremic syndrome (aHUS) and C3-dominant glomerulopathies that are driven by complement system abnormalities. Many of these seminal discoveries paved the way for the design and characterization of several innovative therapies, some of which have already radically improved patients' outcomes. This review offers a broad overview of the exciting developments that have occurred in the recent past, with a particular focus on single-gene (or Mendelian), complement-driven aHUS and C3-dominant glomerulopathies that should be of interest to both nephrologists and kidney researchers. The discussion is restricted to genes with robust associations with both aHUS and C3-dominant glomerulopathies (complement factor H, complement component 3, complement factor H-related proteins) or only aHUS (complement factor B, complement factor I, and membrane cofactor protein). Key questions and challenges are highlighted, along with potential avenues for future directions.

Keywords: complement; genetic renal disease; glomerulopathy; hemolytic uremic syndrome; human genetics; immune complexes; membranoproliferative glomerulonephritis (MPGN).

Figure 1.

Activation of the complement system. The complement system may be activated via three distinct pathways illustrated here: the classic, lectin, and alternative pathways. All three converge to activate the complement component 3 (C3) amplification loop, ultimately leading to the formation of C5b9, also known as the membrane attack complex. The activation and regulation of the alternative pathway is presented in more detail because it is most relevant for aHUS and C3-dominant glomerulopathies. It involves a complex array of protein-protein interactions, and a series of proteolytic reactions that produce bioactive protein fragments that are labeled “a” or “b.” It also implicates a network of proteins that inhibit this cascade either in the fluid (serum) or solid (cell) phase, represented by lines with a black triangle or square, respectively. The composition of the various C3 and C5 convertases are also highlighted. C1*, C1 complex (includes C1q, C1r, and C1s). C1, complement component 1; C4BP, C4b-binding protein; CR1, complement receptor 1; DAF, decay-activating factor; FB, factor B; H₂O, water; MASP, mannan-binding lectin serine peptidase; MBL, mannose-binding lectin; MCP, membrane cofactor protein; VTN, vitronectin.

Figure 2.

Many genes encoding complement factors are implicated in atypical hemolytic uremic syndrome (aHUS) and C3-dominant glomerulopathies. (A) Breakdown of the various etiologies known to be causally linked to typical HUS and aHUS. (B) Approach to distinguish the various forms of C3-dominant glomerulopathies based on immunofluorescence (IF) signal and electron-microscopy (EM) findings. (C) Grading of the evidence level regarding the association of aHUS or C3-dominant glomerulopathies with genetic mutations on the basis of the analysis by Osborne et al. (50). Autoantibodies directed against proteins made by some of the same genes are also indicated when relevant to either aHUS or C3-dominant glomerulopathies. *CFHR indicates CFH-CFHRs hybrids. **Anti-CFB autoantibodies are also observed in many cases of postinfectious glomerulonephritis. CFB, complement factor B; CFHR, complement factor H–related protein; DGKE, diacylglycerol kinase ε; GBM, glomerular basement membrane; INF2, inverted formin-2; PLG, plasminogen; THBD, thrombomodulin; TMA, thrombotic microangiopathy; VEGF, vascular endothelial growth factor.

Figure 3.

Landscape of mutations in CFH and C3 associated with aHUS or C3-dominant glomerulopathies. (A and B) The mutational landscapes for disease-associated CFH and C3 mutations positioned on schematics of the proteins produced by these genes. The major functional domains for each protein are overlayed as light blue boxes. These data were extracted from Uniprot (factor H, P08603; C3, P01024). The black boxes over C3 indicate the position of the proteolytic cleavage site used to generate the bioactive protein fragments C3a and C3b. Mutations implicated in aHUS and/or C3-dominant glomerulopathies are located above or below the proteins, respectively. Mutations described in both aHUS and C3-dominant glomerulopathies are labeled with * and linked via dotted lines. Mutations that have been shown experimentally to cause quantitative (type 1) or qualitative (type 2) deficiencies are colored in red or blue, respectively. The mutation profiles were generated using data from the literature, the Human Gene Mutation Database (HGMD) database, and the complement.db database (50). Images were generated with the software Domain Graph, version 2.0 (http://dog.biocuckoo.org/).

Figure 4.

Dynamic changes at the CFH gene cluster are associated with aHUS and C3-dominant glomerulopathies. (A) Chromosome 1 harbors a cluster of genes that contains CFH and the five CFHRs. The relative positions of the genes were obtained from the University of California Santa Cruz Genome Browser (GRCh38/hg38 assembly); the vertical lines represent individual exons. (B) Phylogenetic alignment using the gene sequences reveals the relationships between CFH and the five CFHRs. (C) Gene conversion involves the swapping of short genomic segments between CFH and CFHR1, without a deletion event. In this case, two hybrid genes are created, CFH::CFHR1 and CFHR1::CFH (“::” is used to indicated hybrid genes). (D) Nonallelic homologous recombination between CFH (dark blue) and CFHR1 (red) leads to deletion of the terminal part of CFH, all of CFHR3, and the proximal part of CFHR1. After the large deletion event illustrated, the resulting CFH::CFHR1 hybrid gene encodes the normal CFH protein because only the untranslated region (UTR) is affected (77). (E) Duplication of the first two short consensus repeats (SCRs) of CFHR5 leads to the generation of a novel CFHR5 hybrid genes observed in Cypriots. (F) Other CFHR5 hybrid genes were observed where the first two SCRs of CFHR1 or CFHR2 were added to the amino-terminal of CFHR5 via deletion events.

Figure 5.

Landscape of mutations in CFB, CFI, and MCP associated with aHUS (or C3-dominant glomerulopathies). (A–C) The mutational landscapes for disease-associated CFB, CFI, and MCP, positioned on schematics of the proteins produced by these genes. The major functional domains for each protein are overlayed as light blue boxes. These data were extracted from Uniprot (factor B, P00751; factor I, P05156; MCP, P15529). Mutations implicated in aHUS and/or C3-dominant glomerulopathies are located above or below the proteins, respectively. Mutations described in both aHUS and C3-dominant glomerulopathies are labeled with * and linked via dotted lines. Mutations that have been shown experimentally to cause quantitative (type 1) or qualitative (type 2) deficiencies are colored in red or blue, respectively. The mutation profiles were generated using data from the literature, the HGMD database, and the complement.db database. Images were generated with the software Domain Graph, version 2.0 (http://dog.biocuckoo.org/).