Genomics of Kidney Disease
Open Access

Inherited Kidney Complement Diseases

Mathieu Lemaire, Damien Noone, Anne-Laure Lapeyraque, Christoph Licht and Véronique Frémeaux-Bacchi
CJASN June 2021, 16 (6) 942-956; DOI: https://doi.org/10.2215/CJN.11830720

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.

Introduction

A role for the complement system in the pathophysiology of various glomerular diseases dates back decades (1). It was initially mostly viewed as an acquired abnormality (2) until cases of membranoproliferative GN (MPGN), which had the hallmarks of a familial disease, were published in the early 1980s (3). Around the same time, systematic functional screening of the complement components in a large cohort of patients with MPGN (n=44) revealed that approximately 20% had inherited complement defects (4). That time period also witnessed the discovery of the link between complement abnormalities and hemolytic uremic syndrome (HUS) (5), and of the existence of inherited forms of HUS (6). These dots were connected shortly thereafter when a case of familial HUS was linked to a complement factor H (CFH) deficiency (7).

In the later 1990s, the identification of the first disease-causing mutations for complement-mediated GN (8) and HUS (9) was followed by intense efforts to dissect their broader genetic underpinnings. As a result, we have witnessed tremendous advances in our ability to diagnose and treat these conditions in the past 20 years. Meanwhile, staggering progress was realized toward a better understanding of disease pathophysiology, and many of these seminal discoveries paved the way for the design of innovative therapies, some of which have already radically improved patients’ outcomes (e.g., eculizumab).

This review offers a broad overview of these exciting developments, a discussion of the knowledge gaps that still exist, and an outlook on what lies ahead for patients and nephrologists alike. Herein, we will focus on two broad categories of genetic diseases of the complement system that affect the kidneys and are driven by rare variants, namely, atypical HUS (aHUS) and complement component 3 (C3)–dominant glomerulopathy. It is important to note that the influence of common risk alleles in complement-related genes, known as the complotype (10), will not be covered.

General Overview of Complement Physiology

The complement system plays a major role in the innate immune system’s response to bacterial infections. It is composed of an assortment of approximately 30 plasma and membrane proteins (11). It is activated by the classic, lectin, or alternative pathways, and all three converge to the same steps: activation of the enzymes C3 and C5 convertases (Figure 1) (11). This initiates a complex chain reaction that ultimately leads to the formation of factors with potent proinflammatory, chemoattractant, and cell-damaging properties. A variety of proteins, with positive or negative regulatory roles, regulate this potent system at many levels (12).

Figure 1.
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.

While the activation of the classic and the lectin pathways occurs after binding to immune complexes or microorganisms, respectively, the alternative pathway is constitutively activated (by a “tick-over” mechanism) (12). The constitutive activity of the alternative pathway is largely responsible for its ability to rapidly deal with threats: it is always primed to act and is revved up to full activity in a matter of seconds (13). Factors B, D, and P are proteins that are necessary to actuate this system, both at baseline and upon activation (Figure 1) (12). However, the alternative pathway is only beneficial to hosts if tightly policed; even slight dysfunction in its regulation may cause indiscriminate damage to host cells. This “friendly fire” is avoided because host cells express an array of proteins that downregulate the alternative pathway. Some of these factors are in the fluid phase of plasma (e.g., factors H or I), whereas others are membrane bound (membrane cofactor protein [MCP], decay-accelerating factor, protectin, or complement receptor-1 or complement receptor-2; Figure 1) (12).

Complement abnormalities are typically identified by integrating data from measurements of individual components of the complement cascade (e.g., factor H, C3, or C4), serum levels of activation products (e.g., C3d or soluble C5b9), functional complement assays (hemolytic and ELISA), and analysis of mutations found in complement-related genes (14). In isolation, each method has its limitations, and an abnormal result in one is rarely sufficient to confirm a diagnosis. For instance, low serum C3 levels may identify patients with hyperactive complement system, however, although specific, it lacks sensitivity (15). Functional assays need a specialized laboratory and may not detect properdin deficiencies (16).

Overview of Kidney Complement Genetics

Nowadays, a significant proportion of all incident patients with aHUS (approximately 50%–60%) (17) or C3-dominant glomerulopathy (approximately 20%–25%) (18) are expected to be caused by a Mendelian disease. The studies that led to the discovery of these single-gene kidney complement diseases have contributed enormously to our understanding of complement physiology, to the development of novel therapies, and to the improvement of patients’ outcomes. Generally, a confirmed molecular diagnosis can have a significant effect on patient care because it can help avoid invasive procedures (e.g., kidney biopsy), and is also invaluable for family planning (19). Specifically, pinpointing the genetic cause of aHUS can have immediate consequences on therapies that may be offered to patients on the basis of a few principles. First, dramatic improvements in the outcomes of patients with pathogenic mutations that result in activation of the alternative complement pathway is often observed with eculizumab treatment (it is a humanized monoclonal anti-C5 antibody that inhibits the terminal pathway) (20). Second, eculizumab is not beneficial for a subset of patients with aHUS with mutations in genes unrelated to the complement system (e.g., diacylglycerol kinase ε [DGKE] [21]). Third, chronic eculizumab infusions may be safely discontinued in patients who are in remission when no disease-causing mutation is found; in contrast, the risk of recurrence is high (>50%) for patients with MCP or CFH mutations (22). Fourth, uncovering a disease-causing genotype is invaluable to stratify patients into groups with high (e.g., CFH), moderate (e.g., complement factor I [CFI]), or low (e.g., DGKE) risk of aHUS recurrence after kidney transplantation (20). It is anticipated that the genotype of patients with a C3-dominant glomerulopathy will also prove useful to clinical management once effective treatments are available (23).

It is important to note there is significant variation in the number of relevant genes that are currently tested for both aHUS and C3 glomerulopathy (C3G); detailed data from recently published cohorts are compiled in Supplemental Tables 1 and 2. It is also important to acknowledge that, despite significant advances in tools and approaches (24), assessing the pathogenicity of nonrecurring mutations that cause rare disease remains a challenging art in most of medicine. For most novel variants gracing the genetic testing reports received by physicians, functional data are not available to determine its potential clinical effect. Instead, predictions are made on the basis of segregation analysis, assessment of minor allele frequency, and evaluation of the degree of evolutionary conservation at a specific locus (see Table 1 for definitions of key genetic terms). In that regard, the recent formation by ClinGen investigators of multiple Kidney Clinical Domain Working Groups, including one exclusively focused on assessing mutations causing kidney complement diseases, is a positive development for the nephrology community. ClinGen is a National Institutes of Health–funded collaborative effort with thousands of contributors from >30 countries that started operating in 2013 (25). This effort will undoubtedly lead to harmonization of the gene panels used and systematization of genetic variant interpretation.

View this table:
Table 1.

Important definitions

The task at hand for ClinGen’s Kidney Complement Disease Working Group is particularly challenging because they must take into account several additional sources of complexity when curating genetic variants. First, prototypic Mendelian conditions with clear familial cosegregation are rare; instead, incomplete penetrance and/or variable expressivity are the norm (26). Second, complexity is further compounded because all recognized forms of genetic heterogeneity (27) are at play: allelic, locus, phenotypic, and mode-of-inheritance heterogeneity. Allelic heterogeneity means that unrelated patients with the same kidney pathology have different mutations in the same gene. In contrast, locus heterogeneity describes patients with similar kidney lesions who have mutations in different genes, whereas phenotypic heterogeneity refers to the phenomenon by which the same pathogenic mutations can cause HUS in one patient or a GN in another. Finally, mode-of-inheritance heterogeneity refers to the situation where a disease can be caused by heterozygous or homozygous mutations in the same gene (28). It is also important for clinicians to be aware of the complex architecture of inherited, complement-mediated kidney diseases so they are in a better position to inform their patients when genetic testing results are returned (29).

Major Genetic Diseases of the Kidney Caused by Complement Dysregulation

The focus of this review will be on aHUS and C3-dominant glomerulopathies, the two major kidney diseases caused by mutations in genes that encode effectors or regulators of the complement system. Rare variants in the same genes are associated with many other conditions that can present with a kidney phenotype. These conditions will not be covered in this review because causality is not as firmly established and/or the pathology observed extends beyond the kidneys (e.g., age-related macular degeneration, antiphospholipid syndrome, or transplantation-associated thrombotic microangiopathy [TMA]). For a broader overview of “complementopathies,” readers are directed to a recent review (30).

Atypical Hemolytic Uremic Syndrome

All patients with HUS present with laboratory evidence of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney failure. The presence of lesions consistently restricted to the kidneys was key to distinguish HUS from thrombotic thrombocytopenic purpura (TTP), another TMA that affected many other organs besides the kidneys (e.g., the brain). It took nearly 20 years after Gasser et al.’s (31) original description of HUS for clinicians to notice “atypical” patients with characteristics suggesting a genetic etiology, including familial clustering (6) and disease relapses over time (32). These features contrasted sharply with those of “typical” HUS, a sporadic disease associated with bloody diarrhea that is caused by Shiga toxin–producing bacteria (33). Nowadays, aHUS is an umbrella term that includes all forms of HUS that are not caused by infections or coexisting medical conditions (Figure 2A). Collectively, aHUS is very rare (incidence of approximately 0.25–2 per million per year) and accounts for <10% of all incident cases of pediatric HUS (34).

Figure 2.
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.

The first step to diagnose aHUS is to rule out typical HUS and TTP, but this is not a trivial exercise because patients with aHUS often present with prodromal diarrhea or neurologic symptoms (35). In response to this conundrum, a new TMA classification primarily determined on the basis of etiology and/or pathophysiology was recently proposed (36). Current diagnostic workup usually includes detailed assessment of complement function, autoantibody detection, and testing for mutations in known aHUS genes (36). While a kidney biopsy is almost never done in the acute phase because of severe thrombocytopenia, it is instructive to contrast the histopathology of aHUS with that of C3-dominant glomerulopathies (discussed below). Briefly, light microscopy typically shows glomerular hypercellularity and split glomerular basement membranes (GBMs); immunofluorescence (IF) reveals prominent fibrin-rich thrombi in the kidney microvasculature, with variable immune complex deposits (but no C3 deposition); and electron microscopy shows endothelial-cell swelling and GBM widening, without electron-dense deposits (37).

Our understanding of aHUS pathophysiology has improved dramatically since the early 2000s. Constitutive activation of the alternative pathway of the complement system is implicated in approximately 60%–70% of all patients with aHUS, usually via dysfunction of a regulatory protein (35). Consistent with this idea, nearly all genes identified as causing aHUS encode one of the proteins of the alternative pathway (Figure 2B). Some patients harbor deleterious mutations in inhibitory factors (e.g., CFH, CFI, MCP, or THBD) or gain-of-function mutations in activating factors (e.g., complement factor B [CFB] and C3) (35). Autoantibodies directed against regulators of the complement explain approximately 10% of cases (e.g., anti-CFH antibodies) (38). The predominant mode of inheritance for most patients with genetic forms of aHUS is autosomal dominance, with incomplete penetrance (35). A subset of patients who have homozygous mutations in CFH or MCP typically have earlier disease onset and more severe phenotypes. Two other aHUS genes, DGKE and cblC, invariably have autosomal recessive disease transmission; neither exhibit overt complement dysfunction (21).

Complement Component C3–Dominant Glomerulopathies

Historically, MPGN was characterized by proteinuria, hematuria, kidney dysfunction, and/or persistent hypocomplementemia (39). It was diagnosed when a kidney biopsy specimen showed glomerular capillary wall thickening, increased mesangial matrix and cellularity, and glomerular deposition of complement and/or Igs (39). The three major MPGN subtypes were distinguished on the basis of the location of pathognomonic lesions documented by electron microscopy (subendothelial, subepithelial space, or both) (39). The realization that these lesions usually had predominant C3 deposition in combination with various Ig levels suggested a complement defect was central to disease pathophysiology (40). These insights suggested it would be helpful to distinguish these diseases on the basis of their mechanism as opposed to histomorphology (40). Within a few years, there was consensus in the community that reclassification of a subset of MPGN lesions as C3-dominant glomerulopathies was necessary because of the limitations of existing MPGN diagnostic criteria and major advances in testing for alternative complement (41). This new classification defined groups of patients for which the centrality of alternative complement hyperactivation in disease pathophysiology held promise as a fulcrum for targeted therapy (41).

C3-dominant glomerulopathy is now an umbrella term for any kidney biopsy specimen showing predominant glomerular C3 IF signals and, ideally, evidence of abnormal alternative complement on quantitative or functional tests (Figure 2C) (18). The presence of codominant Ig staining, also documented by IF, differentiates immune-complex GN from C3G (41). Electron microscopy is necessary to discern two C3G subtypes on the basis of distinct GBM lesions, namely, dense-deposit disease (DDD) and C3 GN (41).

C3-dominant glomerulopathy is an ultrarare disease with an incidence of approximately 1 per million (18). Historically, a genetic etiology for MPGN was suspected on the basis of descriptions of affected sibships with low serum CFH levels (42). This suspicion was confirmed when many patients with MPGN were found to have homozygous or heterozygous CFH mutations (8,43). The discovery of rare mutations in CFI, MCP, C3, CFH-related 5 (CFHR5), and CFB, and rare genomic rearrangements at the CFH-CFHR gene clusters in other patients with MPGN reinforced that concept (Figure 2C) (44). Of interest, mutations in most of these genes are found in aHUS, often implicating the exact same locus (Figure 3). The specific phenotype expressed is likely influenced by additional genetic, autoimmune, or environmental factors. For example, C3 nephritic factors, autoantibodies that enhance C3 convertase activity, are only ever documented in C3-dominant glomerulopathies (45). In fact, C3 nephritic factors are much more commonly found than genetic mutations, being identified in up to 50% and 80% of patients with C3G and DDD, respectively (18).

Figure 3.
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/).

Widespread use of the new classification in clinical practice and research studies is starting to uncover inconsistencies that will drive further refinements. For example, it is unclear why a subset of patients with a C3-dominant glomerulopathy (approximately 30%–50%)—almost all with rapidly progressive GN—benefited from eculizumab therapy because it is caused by fluid-phase complement dysregulation at the level of C3 (46). Application of mass-spectrometry proteomics to laser-dissected glomeruli from DDD and C3 GN biopsy specimens yielded results that remain unexplained: the same complement proteins were dominant in both set of samples (C3, C6, C7, C8, and C9) (47,48). These results are indeed inconsistent with the assumption that DDD and C3-GN lesions should be enriched with C3 fragments or terminal complement components, respectively. Proteome imaging may help clarify this question because it allows for near-cellular spatial resolution, without the need for laser dissection (49).

Genes Implicated in Complement Disorders of the Kidney

Screening panels to identify pathogenic point mutations in patients with aHUS or a C3-dominant glomerulopathy currently include nine genes; of these, six are directly related to the complement system (CFH, C3, CFI, MCP, CFB, CFP), whereas the others are implicated in coagulation (plasminogen [PLG], THBD) or intracellular lipid signaling (DGKE). For this review, we will focus our efforts on discussing the genes with the most robust associations with aHUS (CFH, C3, CFI, CFB, MCP) or C3G (CFH and C3) (Figure 2B). We will also briefly discuss the genomic rearrangements at the CFH-CFHR gene cluster and the genetic forms of aHUS that do not require the complement system (e.g., DGKE).

These genes were selected on the basis of data from a recent study that systematically assessed the strength of evidence linking rare variants to aHUS or C3-dominant glomerulopathies (50). To this end, the investigators screened hundreds of patients from six centers, looking for evidence of significant enrichment when compared with thousands of control exomes (51). These data are aggregated in the Database of Complement Gene Variants (www.complement-db.org/) (50).

To evaluate the number of affected patients and pathogenic alleles, we relied on complement-db, Online Mendelian Inheritance in Man, Human Gene Mutation Database (HGMD), and manual curation of the literature. Throughout, we will refer to mutations as either “type 1” or “type 2” to describe the major abnormality uncovered when characterizing mutant complement factors: defective factor secretion (type 1) or disruption of its enzymatic activity (type 2). For simplicity, articles describing patients using the old MPGN nomenclature will be labeled using the broadest term of the new classification, C3-dominant glomerulopathies, when they clearly fit the diagnostic criteria.

Validated Dual-Phenotype Genes

Complement Factor H.

A substantial body of knowledge regarding CFH function (52) was available by the time mutant CFH was recognized as the first genetic cause of aHUS in 1998 (9). The association between HUS and low plasma C3 was first reported >25 years before (53). A few years later, low plasma CFH levels were first reported in patients with HUS (7). At the time, it was already known that CFI and CFH worked together to inhibit C3 function (54), and that CFH deficiency led to C3 consumption (55). It is now clear that CFH is the gene most frequently mutated in patients with aHUS, accounting for approximately 20%–30% of all incident patients (56). More than approximately 250 pathologic CFH mutations are described, including missense, nonsense, splice-site, and frameshift mutations (Figure 3A and Supplemental Table 3) (50,56). Most patients with CFH-aHUS present either before the age of 4 years or between the ages of 20 and 40 years (56). Homozygous CFH mutations are almost exclusively observed in infants, and heterozygous mutations are found in all age groups, usually displaying incomplete penetrance (57). Among all patients with aHUS, those with CFH-aHUS have the highest risk of developing kidney failure, usually within a year of diagnosis (58). Historically, kidney transplantation for CFH-aHUS was associated with high recurrence rates and poor allograft survival (56); the introduction of eculizumab dramatically improved patient outcomes (20).

The first study correlating serum C3 levels and C3 staining on kidney biopsy specimens, to evaluate patients with GN, was published approximately 55 years ago (59). The link between CFH deficiency and C3-dominant glomerulopathy in humans was established approximately 20 years later (60), followed in 1997 by the discovery of the first homozygous CFH mutations associated with GN-type lesions (8). There are now >50 different CFH mutations described in patients diagnosed with a C3-dominant glomerulopathy, including missense, nonsense, and frameshift mutations (see Supplemental Table 3) (50). Similar to the situation in CFH-aHUS, both homozygous and heterozygous mutations are documented, often with incomplete penetrance. One of the most intriguing findings is the identification of several patients with a C3-dominant glomerulopathy harboring CFH mutations already described in patients with CFH-aHUS (Figure 3A) (61). Patients with C3-dominant glomerulopathy associated with homozygous CFH mutations present around approximately 10 years of age (43). Associations between CFH genotypes and clinical outcomes are not as robust for C3-dominant glomerulopathies when compared with CFH-aHUS.

In patients with aHUS, CFH mutations are found throughout the gene, but the bulk (40%–60%) are found in the carboxy terminus; both type-1 and -2 mutations are common (Figure 3A) (58). This region encodes the short consensus repeats (SCRs) 19 and 20 that bind C3b (62) and endothelia (63). In contrast, most CFH mutations found in patients with a C3-dominant glomerulopathy are clustered near the amino terminus, a region implicated in the regulatory activities of CFH (Figure 3A) (50). Type-1 mutations appear to be most common, resulting in low plasma CFH levels owing to decreased production or secretion. Only a few select, specialized laboratories can reliably test for impaired complement regulation in the fluid phase or the cell surface (14).

Complement Component 3.

Screening the French aHUS cohort led to the discovery that many patients had heterozygous C3 mutations (64). There are now approximately 90 distinct mutations reported in hundreds of patients with aHUS (Figure 3B, Supplemental Table 3) (50). The pattern of inheritance is usually autosomal dominance with incomplete penetrance (56). It is estimated that approximately 2%–10% of incident patients with aHUS will carry a C3 mutation (56). Although mutations are distributed throughout the protein, there is a clear cluster in the thioester-containing domain that is critical for C3 activation (Figure 3B) (56). Just like for patients with CFH-aHUS, kidney prognosis for C3-aHUS was guarded until the introduction of eculizumab (65).

Functional analyses revealed most C3 mutations result in an “indirect” gain-of-function phenotype: mutant C3 proteins have a reduced ability to bind its negative regulators, factor H, MCP, or complement receptor-1 (66). As a result, activation of the alternative pathway leads to enhanced production of C3bBb. This mechanism applies to nearly all C3 missense mutations that have been characterized thus far. C3 mutations p.R139W and p.V1636A were the exceptions: they display increased binding to factor B, leading to the formation of hyperactive C3bBb (67). The mechanism by which disease occurs in the few patients found to have heterozygous nonsense or frameshift C3 mutations remains unclear (Figure 3B) (50,64). It would be important to test if they result in an unexpected gain-of-function phenotype, a phenomenon that is possible if the mutant transcripts escape nonsense-mediated decay (68). Systematic functional testing of novel genotypes is particularly important when dealing with gain-of-function mutations because current bioinformatic tools used to infer pathogenicity are optimized for loss-of-function mutations.

Shortly after the discovery of the link between C3 mutations and aHUS, and nearly 30 years after the first evidence of inherited C3 defects in patients with MPGN (69), a group from Spain demonstrated that activating C3 mutations could also cause DDD (70). The mother and two affected sons all carried a deletion of two amino acids in C3 (923ΔDG) that caused increased complement activity restricted to the fluid phase. Indeed, mutant C3 proteins prevented the proteolysis of activated C3b by factor I in the presence of factor H but not MCP (70). Detailed functional testing was also done to characterize the first C3 mutation associated with a C3-dominant glomerulopathy (p.I734T) (71). The main result was a significant reduction of factor I–dependent C3 degradation in the presence of complement receptor-1 or (to a lesser extent) factor H, but not MCP (71). Altogether, these experiments suggest that the two mutants affect the alternative complement system in the fluid phase or on cell membranes, respectively. Although many other patients diagnosed with C3-dominant glomerulopathies were found to harbor rare C3 mutations (see Supplemental Table 3) (50,72), almost none were tested to confirm their functional effect. Interestingly, many of these mutations are also described in patients with aHUS (Figure 3B) (50).

Complement Factor H–Complement Factor H–Related Protein Gene Rearrangements in Atypical Hemolytic Uremic Syndrome and Complement Component 3–Dominant Glomerulopathies.

Chromosome 1 includes a cluster of genes closely related to CFH (Figure 4, A and B) (73); the five CFHR genes are a result of partial duplication events involving CFH (74). Recent data indicate the main function for the CFHRs is to antagonize the regulatory actions of CFH (i.e., they are positive regulators) (75). The high degree of identity between CFH and the CFHRs is fertile ground for gene rearrangements (76); many of these play important roles in aHUS and C3 GN.

Figure 4.
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.

In a few cases of aHUS, CFH mutations were shown to be due to a CFH::CFHR1 hybrid gene that arose from a gene conversion event (Figure 4C) (77). A much more common gene rearrangement associated with aHUS is a macrodeletion (84 kb) involving CFHR3-CFHR1 (Figure 4D) (78). Around the same time as this discovery, an association between the presence of anti-CFH autoantibodies and aHUS was reported (79). These anti-CFH autoantibodies were shown to target the carboxy-terminal of CFH proteins, precisely the domain that normally interacts with C3 (80). When complexed with this antibody, the cytoprotective properties of a CFH protein are reduced because CFH is unable to bind—and negatively regulate—C3 activity (81). These two discoveries were brought together in short order; indeed, the CFHR3-CFHR1 deletion was found in approximately 90% of patients with anti-CFH antibodies (82). The prevalence of anti-CFH antibodies shows a striking geographic pattern among incident patients with aHUS (approximately 10% [38] in Europe and 56% in India [83]) that is not explained by differences in allele frequency of the CFHR3-CFHR1 deletion in Europe (approximately 7%–22%) (78) or India (28%) (83). It is critical to clarify why only a subset of individuals with CFHR3-CFHR1 deletion(s) develop anti-CFH autoantibodies.

Anti-CFH antibodies were also identified in a few patients with C3-dominant glomerulopathies; these autoantibodies recognized a different epitope (amino-terminal of CFH) and appeared to perturb CFH’s regulatory activities (84,85). These specific epitopes for anti-CFH antibodies found in aHUS and C3-dominant glomerulopathies were, therefore, remarkably well aligned with the location of the mutation clusters noted in the CFH gene (Figure 3A). However, a study with a larger sample size published a few years later concluded that most of these anti-CFH antibodies did not interfere with CFH function (86). Interestingly, the presence of anti-CFH antibodies was not associated with the CFHR3-CFHR1 deletion. The relevance of these autoantibodies in the pathophysiology of C3-dominant glomerulopathies thus remains unclear.

Other complex genomic rearrangements at the CFH-CFHR gene cluster were later associated with C3-dominant glomerulopathies—the common denominator being the creation of novel CFHR fusion proteins. The first demonstration of this phenomenon emerged from studies on a large cohort of affected Cypriots with multiple unrelated kindreds: all had an extra copy of the first two SCRs of CFHR5 that encode segments involved in dimerization (SCRs are structural motifs present in all CFH-related proteins) (Figure 4E) (87). CFHR5 hybrid proteins display abnormal oligomerization because the extra SCRs lead to enhanced ability to complex with other CFHRs; this is likely driving complement activation via increased competition with CFH (75). Remarkably, all other hybrid proteins discovered thereafter caused the same defect, each in a single kindred; what differed was the identity of the CFHR genes involved and the underlying mechanism (deletion event) (Figure 4F) (18,88).

Validated Single-Phenotype Genes

Complement Factor B.

A key step in the activation and perpetuation of the alternative pathway is factor D–dependent cleavage of factor B, ultimately leading to the formation of C3bBb (Figure 1) (12). Therefore, a gain-of-function mutation would be required for mutant factor B proteins to cause aHUS. The first such report described two kindreds with autosomal-dominant aHUS caused by novel CFB mutations that resulted in overactive C3bBb (89). At last count, >30 distinct CFB mutations are reported in patients with aHUS (see Supplemental Table 3); almost all are novel and exhibit incomplete penetrance (Figure 5A) (50,90). Overall, aberrant CFB function is estimated to play a role in approximately 1%–2% of all patients with aHUS (90). There are only a few reports describing patients diagnosed with a C3-dominant glomerulopathy associated with CFB mutations (Figure 5A, Supplemental Table 3).

Figure 5.
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/).

In vitro assessment of the functional effect of the first two CFB mutations reported was consistent with a gain-of-function phenotype. It produced a hyperactive C3 convertase (C3bBb) via two distinct mechanisms: increased formation or decreased degradation (89). This abnormality may explain why many patients with aHUS who have CFB mutations exhibit permanent activation of the alternative pathway, with very low C3 levels (90). Out of 15 CFB mutations characterized in this way, six revealed a gain-of-function phenotype, three were reclassified as benign variants, and the significance of the others is unclear (Figure 5A) (90). This example illustrates the challenges inherent to assessing the pathogenicity of mutations, even when there are well-accepted functional assays.

Complement Factor I.

CFI was a logical candidate gene for aHUS because it plays a central role in the negative regulation of the complement cascade (Figure 1) (12). Sequencing of factor I in patients from the French and United Kingdom aHUS cohorts uncovered a heterozygous CFI mutation in five out of 101 patients (91,92). To date, >80 CFI distinct mutations are reported in patients with aHUS (Figure 5B, Supplemental Table 3), accounting for approximately 4%–8% of all patients with aHUS (56,58). Incomplete penetrance is almost always documented (56). After the first HUS episode, patients with CFI-aHUS either exhibit complete remission, experience additional relapses, or rapidly develop kidney failure. The presence of pathogenic variants in other complement genes confers a higher risk of poor outcomes (93). Up until the introduction of eculizumab, most patients requiring a kidney transplantation experienced post-transplant HUS recurrence (94).

Experimental assessment of CFI mutants revealed that both type-1 and -2 mutations were prevalent in patients with aHUS and C3-dominant glomerulopathies (Figure 5B) (93). In keeping with this framework, serum factor I levels were only low in patients with the type-1 mutation. The end result of both mutation types is reduced degradation of fluid-phase and cell-surface C3b (95). Of note, it remains unclear why most patients with recessive CFI mutations, which result in complete factor I deficiency and low serum C3, present with frequent infections but no kidney lesions (96). In a few rare cases where kidney dysfunction was noted, kidney biopsy specimens showed a pattern consistent with immune-complex GN (97). There is also growing evidence of a potential link between CFI mutations and C3-dominant glomerulopathies: more than ten distinct, incompletely penetrant heterozygous CFI mutations are described thus far, without evidence of clustering in any specific functional domain of the protein (Figure 5A, Supplemental Table 3) (50).

Membrane Cofactor Protein.

MCP (CD46) was long considered a candidate gene for aHUS because it is a well-established negative regulator of the alternative pathway (Figure 1) (12). Two teams were first to report MCP mutations in four out of 55 screened kindreds with aHUS (98,99). Overall, >100 different mutations in MCP have now been identified in patients with aHUS (Figure 5C, Supplemental Table 3) (50,56). More than 75% are consistent with autosomal dominance, with incomplete penetrance. Complete penetrance is observed only in patients who have recessive MCP mutations (98). MCP mutations account for approximately 10%–15% of patients with aHUS (58). Similar to CFI and CFB, the limited number of reports linking C3-dominant glomerulopathies to MCP mutations (45,50,72) precludes drawing definitive conclusions about causality (Figure 5C, Supplemental Table 3).

Functional characterization revealed that MCP with an in-frame deletion or a frameshift mutation were retained intracellularly (type-1 mutations), whereas missense substitutions resulted in deficient activity against surface-bound C3b (type-2 mutations) (98). Most characterized MCP mutations are type 1 (approximately 90%) (56). Whether quantitative or qualitative, MCP deficiency leads to inadequate control of the alternative pathway on the surface of endothelial cells. On that basis, risk of post-transplant disease recurrence would be predicted to be low, but it is higher than expected. This apparent contradiction may be due to endothelial chimerism, whereby recipient endothelial cells populate the vascular bed of the allograft (100).

Combined Complement Gene Mutations

When screening patients for mutations in all genes known to cause aHUS, many investigators have reported patients with more than one mutation in these genes (93). To study this phenomenon more systematically, European investigators pooled data from 795 patients with aHUS for five genes (CFH, MCP, CFI, C3, and CFB); of these, 40% (318) were cases of single-gene aHUS, and multigene aHUS was found in 3% (27 subjects from 22 kindreds) (101). MCP (14/22), CFH (14/22), and CFI (13/22) were the genes most frequently implicated in multigene aHUS. A more recent assessment drawing from 3128 patients with aHUS from many of the same centers—and including six more genes (CFHR1, CFHR5, CFP, DGKE, PLG, and THBD)—revealed that approximately 4% had two or three rare variants in distinct genes (50). Interestingly, approximately 4% of patients diagnosed with a C3-dominant glomerulopathy had rare variants in more than one gene when the same analysis was done (n=443) (50).

None of the eight distinct multigene combinations found in the aHUS study appeared to confer a worse prognosis, except for those implicating MCP (101) (unfortunately, the C3-dominant glomerulopathies study does not include outcome data [50]). Indeed, approximately 50% of these patients developed kidney failure within 3 years of diagnosis, compared with 19% for patients with an isolated MCP mutation (101). Multigene MCP-aHUS was also associated with higher probability of poor kidney allograft survival (101). The main conclusions from this study are that multigene aHUS is rare and, at least for MCP-aHUS, is associated with more severe outcomes. These data help explain the phenotype penetrance, but only in a limited number of kindreds segregating MCP mutations. Integration of data from a multitude of sources may provide more predictive models. In particular, it is known that environmental triggers appear to play an important role in determining phenotype expression and severity.

Another level of complexity is added when investigating the interplay of rare mutations expressed along with common variants or risk haplotypes linked to complement genes (58). However, a better understanding of the complex genetic underpinnings of aHUS will likely require extending the breadth of studies well beyond the list of genes with known roles in complement biology. To this end, it may be instructive to apply approaches that were successful in linking common variants to the phenotypic variability of rare neurodevelopmental conditions (102).

Perhaps one of the most promising approaches is a novel genetic test that identifies regulatory modifiers of phenotype penetrance (103): it uncovers the associations between regulatory haplotypes and rare coding variants using allelic expression data from the Genotype-Tissue Expression database (this database includes genomic and transcriptomic data from 44 tissues obtained from >7000 healthy individuals) (104). Harmful expression haplotype configurations, associated with increased expression of pathogenic alleles, were much more common in patients with cancer or autism than healthy subjects (103). Alternative approaches used polygenic-risk-score methodology adapted to study rare neurodevelopmental diseases (105). Maximization of study power would require cooperation from as many nation-based aHUS and C3-dominant glomerulopathies cohorts as possible, and would ideally include genomic data from patients, parents, and unaffected siblings.

Genetic Forms of Atypical Hemolytic Uremic Syndrome that Do Not Implicate the Complement System

Kidney TMA has been a known complication of cobalamin-C (cblC) deficiency for decades (106). Up until recently, it remained the lone exception to the rule that inherited forms of aHUS are complement-mediated diseases (107). The concept of complement-independent aHUS has gained traction in recent years after the description of its associations with homozygous mutations in DGKE (21), or heterozygous mutations in PLG (108) or inverted formin-2 (109). Other disease-causing genes may be discovered because approximately 40% of patients with aHUS remain without a clear etiology, although they will likely explain very few patients.

One Model to Explain the Differences between Atypical Hemolytic Uremic Syndrome and Complement Component 3–Dominant Glomerulopathies?

A major conundrum of the field is to explain how the same mutations in many complement genes (e.g., C3, CFH) are associated with such a wide array of kidney pathologies. The current hypothesis to explain this phenomenon is made on the basis of evidence from mutation analyses and animal models. It states that the difference in phenotypes between aHUS and C3-dominant glomerulopathies is due to aberrant complement regulation on tissue surfaces or in the fluid phase, respectively (110). Indeed, CFH mutations found in aHUS are mostly clustered in the surface-recognition domains responsible for the regulation of C3b for interactions with cell surfaces via binding to glycosaminoglycans or sialoglycoproteins (111,112). In contrast, a high proportion of CFH mutations causing C3-dominant glomerulopathies impair its inhibitory functions without preventing binding (50). A pair of elegant mouse models that closely mimic these specific functional defects are supportive: mice expressing factor H devoid of the binding domains develops spontaneous aHUS (113), whereas Cfh −/− mice exhibit kidney lesions with features characteristic of C3-dominant glomerulopathies (114). In contrast to patients, both mouse models require homozygosity to display the kidney phenotype (113,114).

Where the Current Model Falls Short

However compelling, this model fails to explain several key points. First, patients with homozygous loss of function (and Cfh −/− mice) should have defects in both tissue and fluid phases because they do not express the protein anywhere. Second, patients with homozygous loss-of-function CFH mutations are described for both diseases, and are much more frequent in aHUS (50). Third, there are many patients with a clear diagnosis of aHUS that have homozygous mutations in the CFH gene segment where mutations causing C3-dominant glomerulopathies are typically clustered, and vice versa (50). Fourth, the many examples of the same CFH mutations causing aHUS or C3-dominant glomerulopathies in unrelated patients (50), coupled to the fact that there is no report of affected siblings with discordant phenotypes, suggest that environmental factors and/or common variants at multiple loci must be key drivers of the process of “phenotypic decision.” Fifth, the model does not provide a framework to understand why both aHUS and C3-dominant glomerulopathies can be caused by heterozygous or homozygous CFH mutations (50), sometimes at the exact same locus (43). Right now, these inconsistencies are usually explained by invoking autoantibodies against complement factors, additional genetic variants with small effects, or environmental factors.

A Role for Intracellular Complement to Trigger Kidney-Specific Lesions?

In 2013, we witnessed a paradigm shift in our understanding of complement biology: widespread intracellular roles must now be integrated into a complex system long thought to be restricted to the intravascular tissue and fluid phases (115). Indeed, intracellular C3 cleaved by cathepsin L (CTSL) into bioactive fragments was shown to play a critical role in T cells by engaging C3aR (116). Although intracellular C3 helps maintain T cell homeostasis, it can also be externalized by activated T cells, thereby contributing to a local extracellular complement cascade (116). These novel roles are likely to extend well beyond T cells because intracellular C3 was found in most cells tested, including epithelial and endothelial cells (116). Of great interest was the recent demonstration that intestinal tissue injury, triggered in mice by mesenteric ischemia, is driven by intracellular C3 and C5 (117).

Given the preponderance of complement in a variety of glomerular diseases, it would be important to investigate if the intracellular complement is implicated in causing these diseases. Supporting this possibility is the fact that CTSL expression is high in diseased glomeruli in humans and mice, and glomerular injury is improved by CTSL deficiency or CTSL inhibitors (118). Because intracellular complement expression is likely to be regulated in a cell type–specific manner, it may even provide an explanation for the “why the kidney?” problem that has perplexed the complement community for so long. A similarly intriguing question is what would be the effect of expressing C3 harboring a gain-of-function mutation on cellular metabolism and local complement biology (assuming that it confers protection from cleavage by CTSL)?

Conclusions

The dramatic advances in our understanding of inherited kidney complement diseases gained over the past 20 years are great examples of intense and concerted efforts in clinical and basic science research leading to significant improvements in patient outcomes. It is clear that detailed genetic studies, based on large, carefully phenotyped cohorts, played a critical role in driving this process, especially when integrated with analyses of animal models that recapitulate many aspects of their human correlates. Several challenges that remain to be addressed were highlighted in this review. For example, uncovering the reason why the kidneys are one of the few key target organs for complement diseases could open new avenues for therapeutic development. Similarly, delineating the mechanisms responsible for the unusually fluid phenotypes exhibited by patients with mutations in the same genes (aHUS versus various shades of C3-dominant glomerulopathies) could unlock new approaches to modulate disease expression. Along the same line, it will be important to clarify if genetic information collected for patients diagnosed with a C3-dominant glomerulopathy will match the clinical utility of variants found in aHUS, particularly as the array of complement-targeting compounds expands. It may also be worthwhile to devote resources to in-depth studies of the large group of patients with aHUS who do not have mutations or autoantibodies; their clear and homogenous responses to eculizumab exposure (acute benefits but extremely low recurrence rates after discontinuation) are a remarkable—and hitherto unexplained—phenomenon (22). Answers to many of these questions may come from applying so-called “multiomics” to study patients who are negative for mutations (and also revisit those that already have a molecular diagnosis) by combining genomics, epigenomics, transcriptomics, proteomics, and/or metabolomics data (119). An integrated multiomics approach is being developed to study CKD, another area of nephrology with complex patient populations (120).

Disclosures

V. Fremeaux-Bacchi received fees from Alexion Pharmaceuticals, Apellis, Baxter, Biocryps, Novartis, and Roche for invited lectures and/or board membership, and is the recipient of a research grant from Alexion Pharmaceuticals. A.-L. Lapeyraque reports serving on advisory boards of Alexion Pharmaceuticals. She has received consultancy and speaker honoraria from Alexion Pharmaceuticals and Alexion Pharma Canada. C. Licht has received consultancy and speaker honoraria from Alexion Pharmaceuticals and Alexion Pharma Canada. All remaining authors have nothing to disclose.

Funding

This work was supported by a Canadian Institutes of Health Research/Kidney Research Scientist Core Education and National Training Program Early Career Investigators in Maternal, Reproductive, Child and Youth Health grant 2019KP-NIOG01 (to M. Lemaire).

Supplemental Material

This article contains the following supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.11830720/-/DCSupplemental.

Supplemental Table 1. Data on genetic testing from recently published cohorts that included patients with aHUS.

Supplemental Table 2. Data on genetic testing from recently published cohorts that included patients with C3G.

Supplemental Table 3. Locus level mutation data for all key genes implicated in aHUS or C3G.

Footnotes

  • Published online ahead of print. Publication date available at www.cjasn.org.

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Inherited Kidney Complement Diseases
Mathieu Lemaire, Damien Noone, Anne-Laure Lapeyraque, Christoph Licht, Véronique Frémeaux-Bacchi
CJASN Jun 2021, 16 (6) 942-956; DOI: 10.2215/CJN.11830720
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