Glomerular Disease of Complement Dysregulation (C3 Glomerulopathy, Atypical Hemolytic-Uremic Syndrome)

Glomerular Disease of Complement Dysregulation (C3 Glomerulopathy, Atypical Hemolytic-Uremic Syndrome)

Mathieu Lemaire

Bradley P. Dixon


Dysregulation of the complement alternative pathway (CAP) plays a key role in the pathogenesis of many glomerular diseases. The two rare kidney diseases that are triggered by complement overactivation are atypical hemolytic-uremic syndrome (aHUS) and C3 glomerulopathy (C3G). Research from several laboratories over the past 25 years led to remarkable advances in our understanding of the genetics and autoimmune defects driving these pathologies. In turn, this new knowledge was instrumental in implementing novel therapies that radically improved patient outcomes1 (Visual Abstract 20.1); it is also responsible for the recent revision of how membranoproliferative glomerulonephritis (MPGN) is defined2 (Visual Abstract 20.2). Our current understanding of these two conditions suggests that the pathogenesis of aHUS and C3G are caused by dysregulated activation of CAP in the solid phase (ie, at the endothelial cell surface) or in the fluid phase (ie, in plasma), respectively (Figure 20.1).


The complement system is a component of the innate immune system, with ancient evolutionary origins spanning back to a common ancestor of eumetazoan organisms over 500 million years ago.3 Over evolutionary time, the complement system developed three principal activating proximal pathways.4 The first one is the classical pathway, which is activated by immune globulins. The second is the mannose-binding lectin pathway; its activation depends on the presence of carbohydrate moieties on cellular surfaces of pathogens such as bacteria and fungi. The most ancient of the proximal pathways, the alternative pathway, can be activated by bacterial and fungal cell surfaces, threat molecules such as lipopolysaccharide or cobra venom factor, and is also autonomously active at a low level by spontaneous hydrolysis of C3 (tick-over mechanism).

Activation of these three proximal pathways converges on the pivotal protein C3 by the formation of C3 convertases (C4bC2a in the classical and lectin pathways and C3bBb in the alternative pathway), cleaving C3 to its active fragments C3a and C3b. By their incorporation of C3b, these convertase complexes (C4bC2a•C3b and C3bBb•C3b) subsequently can activate the lytic terminal pathway by cleaving C5 to C5a and C5b, and ultimately forming of the membrane attack complex C5b-9.5 Because of its potent protective and potentially destructive power, this system is highly regulated by a series of plasma proteins (eg, Factor H ([CFH], Factor I [CFI]) and membrane-bound proteins (eg, membrane cofactor protein [MCP]/CD46, CD55, CD59) that serve to limit activation particularly on self-surfaces.6


Hyperactivation of the CAP is central to the pathophysiology of C3G and most forms of aHUS. As described below, this may be because of genetic mutations, autoantibodies, or other serum proteins that conspire to keep this potent immune cascade locked in an unregulated, active state. Current understanding of these diseases suggests that their distinct pathologies are because of the different sites where complement is most activated. Indeed, C3G and aHUS are most strongly associated with activation of the complement system in the fluid and tissue-bound phases, respectively. This framework is congruent with the biopsy findings expected for both conditions; it also helps explain why certain therapies are more effective for aHUS or C3G. More disease-specific details are provided in the sections below.


Pathogenesis and Histopathology

Uncontrolled activation of the cell-surface-bound CAP dramatically increases the risks of aHUS (Figure 20.1). When the complement system causes injury to glomerular capillaries, it triggers a chain of events that culminate in the production of microthrombi (Figure 20.2). Why kidney glomeruli are the prime target of complement-driven damage remains unclear. These clots prevent kidney filtration from occurring normally.

Clinical Findings

Key Laboratory Findings

Laboratory investigations show findings associated with AKI, along with evidence of microangiopathic hemolytic anemia and thrombocytopenia (Table 20.1).9 A peripheral blood smear may show evidence of schistocytes. Active hemolysis
is also associated with high lactate dehydrogenase and very low haptoglobin (a surrogate marker for high free hemoglobin) serum levels. If urine is produced, urine dipstick is positive for protein and blood (mostly because of hemoglobinuria). Serum complement levels may show low or normal C3 and/or C4 levels: although routinely done, these tests are not helpful because more than 50% of patients with a confirmed diagnosis of aHUS do not have abnormal complement levels.10 Measurement of soluble C5b9 levels is a sensitive marker of activation of the terminal complement pathway,11 but it is an expensive test that is only done in specialized laboratories. CH50, which measures total complement activity, is typically used for routine monitoring of complement inhibition by eculizumab.12 Ideally, additional blood samples should be drawn before infusing blood products
or initiating blood-based therapies to ensure the reliability of tests done to identify genetic mutations, autoantibodies, or an enzymatic deficiency (see sections below).

Kidney Biopsy

A kidney biopsy is usually not performed during the acute phase of the disease because of bleeding concerns. It may be helpful for patients with an unusual clinical presentation once they are in remission. If performed, a typical biopsy shows pathognomonic evidence of TMA (see Figure 20.2 and Table 20.2).13 A recent study suggests that specific biopsy findings (glomerular necrosis, cortical necrosis, or glomerular sclerosis) may help predict long-term clinical outcomes in patients who do not recover kidney function.14

Genetics and Acquired Factors Implicated in Atypical Hemolytic-Uremic Syndrome

The identification of mutations in CFH as the cause for aHUS in 199815 (Visual Abstract 20.3) resulted in an intense search for mutations in other genes known to regulate CAP, leading to the identification of many additional aHUS genes (eg, MCP, CFB, C3, or CFI; see Table 20.1).16 Consanguinity or a positive family history of aHUS are highly suggestive of a genetic etiology. Shortly after that, investigators identified patients with autoantibodies directed against many of the negative CAP regulators (most notably, CFH; see Table 20.1).17 These discoveries were crucial to enhance our understanding of complement biology and improve patient outcomes.

Differential Diagnosis

A clinical diagnosis of aHUS requires the exclusion of many conditions that mimic its clinical presentation (Figure 20.3).18 The most important to rule out are thrombotic thrombocytopenic purpura (TTP) and Shiga toxin HUS. TTP is diagnosed when serum ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type-1 motif, 13) enzymatic activity is low or absent, either because of ADAMTS13 mutations or autoantibodies against ADAMTS13.19 The TMA phenotype of TTP, which is usually not restricted to the kidney, is because of higher levels of pro-thrombotic forms of von Willebrand factor that are normally cleaved by ADAMTS13.20 Compiling the “plasmic score” is useful in distinguishing cases of TMA associated with severe ADAMTS13 deficiency, but it is only applicable to adult patients.21 A stool sample should also be sent to determine if Shiga toxin or enteropathogenic E. coli strain is detected.22 Simultaneous identification of multiple patients with HUS is highly suggestive of an outbreak of Shiga toxin-producing E. coli via consumption of the same source of tainted food or water.23 In this case, renal TMA is because of the cytotoxic effects caused by the internalization of Shiga toxin subunits after binding to globotriaosylceramide (Gb3) on the surface of glomerular endothelial cells.24 The treating team must also exclude the other known causes of HUS (eg, pneumococcal infection, various medications, cancer, pregnancy, malignant hypertension, cobalamin C deficiency, or bone marrow transplantation).25

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Apr 18, 2023 | Posted by in NEPHROLOGY | Comments Off on Glomerular Disease of Complement Dysregulation (C3 Glomerulopathy, Atypical Hemolytic-Uremic Syndrome)
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