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

Mathieu Lemaire

Bradley P. Dixon

INTRODUCTION/GENERAL CONSIDERATIONS

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).

OVERVIEW OF THE ALTERNATIVE COMPLEMENT SYSTEM

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).

FIGURE 20.1: The cell-surface-bound and fluid-phase CAP. CAP, complement alternative pathway.

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

RELEVANCE OF COMPLEMENT ABNORMALITIES TO ATYPICAL HEMOLYTIC-UREMIC SYNDROME AND C3 GLOMERULOPATHY

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.

ATYPICAL HEMOLYTIC-UREMIC SYNDROME

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

Signs and Symptoms

Patients with aHUS present with acute kidney injury (AKI), usually accompanied by severe hypertension.⁷ aHUS can affect both children and adults.⁸ There is often a history of recent infection (eg, upper respiratory tract infection, diarrheal illness), which is presumed to trigger complement activation.⁷ Most patients with aHUS will experience recurrent episodes of thrombotic microangiopathy (TMA; microangiopathic hemolytic anemia, thrombocytopenia, and small-vessel thrombosis). If more than one sibling is affected, it is unusual for TMA episodes to occur simultaneously, which would be more consistent with Shiga toxin-mediated HUS (see below).

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).

FIGURE 20.2: Histopathologic appearance of atypical hemolytic-uremic syndrome. Clinical vignette: A 15-year-old female presented with intermittent headaches, vomiting, diarrhea, and hypertension, and was subsequently found to have severe acute kidney injury, microangiopathic hemolysis, thrombocytopenia, and mildly low serum C3 levels. Her biopsy demonstrated findings of thrombotic microangiopathy, and complement evaluation identified a variant of uncertain significance in one of the complement genes. A, The glomerulus stained with H&E demonstrates engorgement of the capillary loops with fibrin/microvascular thrombi (white arrow; 40×). B, Close-up of capillary loops stained with H&E demonstrating RBC fragments (white arrowhead, 40×). C, Electron microscopy demonstrates fibrin stranding associated with thrombus in the capillary loops (black arrow). D, Electron microscopy demonstrates endothelial cell injury, with focal widening of the subendothelial space as the endothelial cell lifts off the glomerular basement membrane (black arrowhead). H&E, hematoxylin and eosin; RBC, red blood cell. (Courtesy of Dr. Amy Treece.)

TABLE 20.1 Key Clinical Information to Distinguish aHUS From C3G

Characteristics	aHUS	C3G
Disease process	Thrombotic microangiopathy	Glomerulonephritis
Pathophysiology	Overactivation of cell-surface CAP	Overactivation of fluid-phase CAP
Signs and symptoms	Hypertension, proteinuria, hematuria (hemoglobinuria), acute kidney injury, anuria/oligoanuria	Proteinuria, hematuria, hypertension, acute kidney injury
Key laboratory findings	↓Hgb, ↓Plt, ↑creatinine/urea, ↑LDH, ↓↓haptoglobin, schistocytes on smear, ↓C3, ↑soluble C5b-9	↑creatinine/urea, ↓C3, ↑soluble C5b-9, ↓albumin, ↑proteinuria
Kidney biopsy	Typically not done because of ↓Plt but would show evidence of TMA	Required for diagnosis: shows predominant glomerular C3 staining
Genetic factors	Activating mutations in positive CAP regulators; loss-of-function mutations in negative CAP regulators	Mutations that result in overactivation of fluid-phase C3-convertase
Genes implicated	CFH, C3, MCP, CFB, CFI, THBD, CFHR1-5, DGKE	CFH, C3, CFB, CFI, CFHR1-5
Acquired factors	Autoantibodies directed against CFH (most common) or CFI (rare)	Autoantibodies against CFH or C3-convertase (C3 nephritic factor, C3NeF)
Disease-specific treatment options	Terminal pathway inhibition (eculizumab), plasma infusion/exchange, dialysis	Immunosuppression Unclear role for eculizumab
aHUS, atypical hemolytic-uremic syndrome; C3G, C3 glomerulopathy; CAP, complement alternative pathway; CFH, complement Factor H; CFHR1-5, Complement factor H related proteins 1-5; CFI, complement factor I; DGKE, diacylglycerol kinase epsilon (not part of the complement cascade, but implicated in some cases of aHUS); Hgb, hemoglobin; LDH; lactate dehydrogenase; Plt, platelet; THBD, thrombomodulin; TMA, thrombotic microangiopathy.

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

TABLE 20.2 Atypical Hemolytic-Uremic Syndrome: Characteristics of Kidney Biopsy

Microscopy Techniques	Salient Features
Light	Glomerular hypercellularity Split glomerular basement membranes (GBMs)
Immunofluorescence	Prominent fibrin-rich thrombi in kidney microvasculature Variable immune complex deposition No C3 deposition
Electron	Endothelial cell swelling GBM widening GBM devoid of electron-dense deposits
From Sethi S, Fervenza F. Pathology of renal diseases associated with dysfunction of the alternative pathway of complement: C3 glomerulopathy and atypical hemolytic uremic syndrome (aHUS). Semin Thromb Hemost. 2014;40: 416-421. © Georg Thieme Verlag KG.

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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