Kidney Disease Caused by Dysregulation of the Complement Alternative Pathway: An Etiologic Approach

Abstract

Kidney diseases caused by genetic or acquired dysregulation of the complement alternative pathway (AP) are traditionally classified on the basis of clinical presentation (atypical hemolytic uremic syndrome as thrombotic microangiopathy), biopsy appearance (dense deposit disease and C3 GN), or clinical course (atypical postinfectious GN). Each is characterized by an inappropriate activation of the AP, eventuating in renal damage. The clinical diversity of these disorders highlights important differences in the triggers, the sites and intensity of involvement, and the outcome of the AP dysregulation. Nevertheless, we contend that these diseases should be grouped as disorders of the AP and classified on an etiologic basis. In this review, we define different pathophysiologic categories of AP dysfunction. The precise identification of the underlying abnormality is the key to predict the response to immune suppression, plasma infusion, and complement-inhibitory drugs and the outcome after transplantation. In a patient with presumed dysregulation of the AP, the collaboration of the clinician, the renal pathologist, and the biochemical and genetic laboratory is very much encouraged, because this enables the elucidation of both the underlying pathogenesis and the optimal therapeutic approach.

Keywords: GN; complement; hemolytic uremic syndrome.

Figure 1.

The normal complement cascade. The complement system can be activated by the classic pathway, the lectin pathway, and the AP, all resulting in the formation of C3 convertases. The classic pathway is initiated by immune complexes that interact with C1q, ultimately leading to the formation of the classic pathway C3 convertase C4bC2a. The lectin pathway generates the same C3 convertase C4bC2a but is activated by the binding of mannose-binding lectins (MBLs) to carbohydrate moieties found primarily on the surface of microbial pathogens. The AP is capable of autoactivation by a mechanism called tick over of C3. Tick over occurs spontaneously at a low rate, generating a conformationally changed C3, which is referred to as C3(H₂O). C3(H₂O) is capable of binding CFB, resulting in the cleavage of CFB by complement factor D (CFD) and generating Ba and Bb and the formation of the AP C3 convertase C3 (H₂O)Bb. Any of the C3 convertases can cleave C3 to C3a and C3b. The C3b fragment can bind to CFB. After the cleavage of CFB by CFD, the C3 convertase C3bBb is formed. This C3 convertase cleaves more C3 to C3b to generate even more C3 convertase in a powerful amplification loop, resulting in the full activation of the complement system. The plasma protein properdin stabilizes C3bBb and provides a platform for its in situ assembly on microbial surfaces, apoptotic cells, and malignant cells. C3b also initiates the terminal complement cascade by the formation of the C5 convertase through association with either of the C3 convertases (C4bC2aC3b or C3bBbC3b). The C5 convertase then cleaves C5 to C5a and C5b. C5b subsequently binds to C6, facilitating the binding of C7, C8, and C9 and culminating in the formation of the C5b-9 terminal membrane attack complex (MAC). The latter forms pores in the membrane of pathogens and damaged self-cells, thus promoting cell lysis. C3a and C5a are anaphylatoxins and among the most powerful effectors of complement activation capable of inducing chemotaxis, cell activation, and inflammatory signaling. MASP, mannose-binding lectin–associated serine protease.

Figure 2.

Normal regulation of the complement AP. CFI is responsible for the proteolytic inactivation of C3b to iC3b (inactive C3b) and ultimately, the C3 breakdown products C3d and C3g, thus irreversibly preventing reassembly of the C3 convertase. MCP (CD46) is a surface-expressed regulator that has decay accelerating activity and acts as a cofactor for CFI. CFH is one of the most important regulators of the AP, controlling complement activation in several ways. It decreases the formation of C3b by competing with CFB in binding to C3b and accelerating the dissociation of the C3bBb convertase complex (decay accelerating activity). In addition, it acts as a cofactor for CFI in the cleavage of C3b to iC3b in concert with MCP. CFH protects against complement-mediated damage both in the fluid phase and on the host cell surface. Additional control of the cascade occurs through the CFHR protein family. CFHR consists of five proteins that are structurally and functionally related to CFH: CFHR1, CFHR2, CFHR3, CFHR4, and CFHR5. These CFHR proteins compete with CFH for binding to C3b but have no direct complement inhibiting actions. Although the CFH-C3b interaction prevents further C3b generation, the CFHR protein-C3b interaction enables C3b amplification to proceed unhindered. This process is termed CFH deregulation. The ratio between CFH and CFHR proteins is, thus, critical for fine tuning complement regulation.

Figure 3.

Representative kidney biopsy findings from a single patient with (A–C) DDD and (D–F) C3 GN. (A) Light microscopy shows a membranoproliferative pattern of injury with thickened GBMs and mesangial and endocapillary proliferation. Periodic acid–Schiff stain. Original magnification, ×40. (B) Immunofluorescence microscopy shows bright granular C3 staining in the mesangium and along capillary walls. Staining for all Igs and C1q was negative. Original magnification, ×40. (C) Electron microscopy features dense deposits along the GBMs (thick black arrow). Original magnification, ×4400. (D) Light microscopy shows a predominantly mesangial proliferative GN. Periodic acid–Schiff stain. Original magnification, ×40. (E) Immunofluorescence microscopy shows bright staining for C3 in the mesangium and along the capillary walls. Immunofluorescence studies for IgG, IgM, C1q, and κ- and λ-light chains were negative. Original magnification, ×40. (F) Electron microscopy shows numerous mesangial (black arrows) and few capillary wall deposits (white arrows). Original magnification, ×2900.

Figure 4.

Representative kidney biopsy findings in aHUS. (A) Fibrin thrombi in the glomerular capillary lumen (black arrow points to fibrin thrombi; silver methenamine stain). Original magnification, ×40. (B and C) Electron microscopy showing subendothelial expansion by fluffy granular material (white arrows), cellular debris, and fibrin (black arrows). Also note the endothelial injury with swelling and loss of fenestration. Original magnification, ×4800 in B; ×13,000 in C.

Figure 5.

Structure-function relationship of CFH. CFH consists of 20 short consensus repeats (SCRs) with two main functional domains positioned at the opposite ends of the protein. The N terminus (SCRs 1–4) is responsible for the fluid–phase complement regulatory functions (more specifically, the cofactor and decay-accelerating activity). The C terminus (SCRs 19 and 20) mediates the recognition of ligands and binding to cell surfaces and tissue matrices, thus distinguishing self from nonself. The CFH mutations in aHUS mainly affect the surface recognition sites in SCRs 19 and 20.

Figure 6.

Sites of complement pathway dysregulation. (A) Loss of CFH inhibition. Deficiency or dysfunction of CFH results in excessive generation of C3b, because the AP C3 convertase continuously produces C3b that is not degraded. (B) CFH deregulation. Abnormal CFHR proteins with higher affinity outcompete CFH, resulting in less inhibition of the C3 convertase and excessive generation of C3b. (C) Stabilization of the C3 convertase. Hyperfunctional C3 results in excessive generation of C3b, despite normal function of the regulatory mechanisms. (D) Impaired inactivation of C3b to iC3b. Deficiency or dysfunction of CFI or MCP impairs degradation of C3b, resulting in increased levels of C3b.