C3 glomerulopathy - understanding a rare complement-driven renal disease

Abstract

The C3 glomerulopathies are a group of rare kidney diseases characterized by complement dysregulation occurring in the fluid phase and in the glomerular microenvironment, which results in prominent complement C3 deposition in kidney biopsy samples. The two major subgroups of C3 glomerulopathy - dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) - have overlapping clinical and pathological features suggestive of a disease continuum. Dysregulation of the complement alternative pathway is fundamental to the manifestations of C3 glomerulopathy, although terminal pathway dysregulation is also common. Disease is driven by acquired factors in most patients - namely, autoantibodies that target the C3 or C5 convertases. These autoantibodies drive complement dysregulation by increasing the half-life of these vital but normally short-lived enzymes. Genetic variation in complement-related genes is a less frequent cause. No disease-specific treatments are available, although immunosuppressive agents and terminal complement pathway blockers are helpful in some patients. Unfortunately, no treatment is universally effective or curative. In aggregate, the limited data on renal transplantation point to a high risk of disease recurrence (both DDD and C3GN) in allograft recipients. Clinical trials are underway to test the efficacy of several first-generation drugs that target the alternative complement pathway.

Figure 1.. C3-dominant glomerulonephritis.

C3-dominant glomerulonephritis is a disease classification based on immunofluorescence findings of C3 staining that is at least 2 orders of magnitude more intense than that for any other immune reactant. Included in this definition are post-infectious glomerulonephritis and paraprotein-associated glomerulonephritis. In post-infectious glomerulonephritis, complement abnormalities are transient and C3 normalization typically occurs within 8 weeks; reclassification as C3 glomerulopathy is warranted if C3 levels remain abnormal at 12 weeks. Complement dysregulation occurs in a subset of patients with paraprotein-associated glomerulonephritis, perhaps because the paraprotein acts as a factor H autoantibody or nephritic factor. Paraprotein-targeted therapy improves the prognosis of C3 glomerulopathy in these patients. C3 glomerulopathy is a subtype of C3-dominant glomerulonephritis that can be subdivided into dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) on the basis of electron microscopy findings. In DDD, highly electron dense, osmiophilic sausage-shaped deposits thicken and transform the lamina densa of the glomerular basement membrane, and mass spectrometry reveals complement components in these deposits. In C3GN, the deposits have a similar electron density to matrix components, and mass spectrometry reveals that they contain terminal complement components. Patients with C3GN are more likely than those with DDD to have C5 convertase dysregulation. Light microscopy cannot distinguish C3 glomerulopathy from other forms of glomerulonephritis: findings are highly diverse, and include mesangial and endocapillary proliferative lesions, crescentic and membranoproliferative lesions. Complement dysregulation also underlies immune complex glomerulonephritis (ICGN), which can be distinguished from C3 glomerulopathy by pronase immunofluorescence, which unmasks immunoglobulin deposits. However, C3 glomerulopathy can transition to ICGN and vice versa.

Figure 2.. Dysregulation of the complement cascade in C3 glomerulopathy.

Complement is activated through the classical, lectin and alternative pathways, which lead to the formation of two C3 convertases. One C3 convertase (C4b2a) is associated with both the classical and lectin pathways, whereas the other (C3bBb) is associated with the alternative pathway. The two C3 convertases generate copious amounts of C3b, after which the pathways converge to generate large amounts of C3bBb. As more C3bBb forms, the terminal pathway is activated, primarily by generation of C3bBbC3b, a C5 convertase that cleaves C5 into C5a and C5b. However when the classical and lectin pathways are activated, C4b2aC3b, the C5 convertase of the classical and lectin pathways, is also formed. Complement activity results in generation of two potent anaphylatoxins, C3a and C5a (pink). In the majority (>90%) of patients with C3 glomerulopathy, dysregulation of the alternative pathway occurs in the fluid phase and in the glycocalyx overlying the glomerular endothelial pores (shown at the bottom of the figure). In the remainder (<10%) of patients with C3 glomerulopathy, dysregulation occurs at the level of the classical and/or lectin pathways. As a result of dysregulation, C3b deposited on the glycocalyx can serve as a substrate for C3 convertase formation and ultimately C5 convertase formation. Driving dysregulation are genetic changes (not shown) and/or autoantibodies to various pathway components and complexes. The targets of therapeutic agents currently under development are indicated by pink stars (the purple star is the site of action of eculizumab, which has already received approval); however, the complexity of the complement system and the heterogeneity of C3 glomerulopathy raise the possibility that no single treatment will be universally appropriate.

Figure 3.. Diagnosis, evaluation and treatment of C3 glomerulopathy.

This algorithm presents a step-wise approach to the diagnosis, evaluation and treatment of C3 glomerulopathy. In the absence of robust predictive biomarkers and data from randomized controlled trials, this algorithm is based on the best evidence available and/or expert consensus. Patients presenting with proteinuria as well as haematuria and features of glomerulonephritis (such as renal insufficiency, hypertension and possibly nephrotic syndrome) undergo a standard battery of pre-biopsy laboratory tests. A biopsy finding of C3 dominant glomerulonephritis means that C3 deposition is at least 2 orders of magnitude greater than that for any other immunoreactant. However, this pathological diagnosis does not necessarily result in the diagnosis of C3 glomerulopathy. For example, infection can trigger a first episode of C3 glomerulopathy, which might confound the diagnosis of post-infectious glomerulonephritis (PIGN). By consensus, however, if all features of glomerulonephritis resolve by 12 weeks, the patient is not considered to have C3 glomerulopathy. Patients >50 years of age should be evaluated for the presence of paraproteins, which can trigger a predominant C3-deposition glomerulonephritis. If paraproteins are present, clone-guided treatment might improve renal outcomes; thus, a haematology consultation might be warranted (of note, paraproteins might also be present in patients <50 years of age). Once the diagnosis of C3 glomerulopathy is made, complement levels and activity should be evaluated to determine the degree of complement dysregulation, conduct disease staging, establish disease quiescence or progression, and determine transplant readiness. In the future, complement biomarkers might be key to choosing targeted therapeutics. Clinicians are, therefore, encouraged to conduct full complement function testing (biomarker measurement and interpretation are offered by several commercial laboratories) for all patients enrolled in clinical trials. Treatment depends on inflammation severity. Patients with mild inflammation receive glomerulus-focused supportive care, including blood pressure control (to blood pressure <90th percentile in children and ≤120/80 mmHg in adults); use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, where possible, to control both blood pressure and urine protein excretion; optimal nutrition; and lipid control. In patients with moderate inflammation (that is, mesangial proliferative glomerulonephritis), treatment with mycophenolate mofetil (MMF) has been suggested by retrospective studies but is not uniformly successful. Severe inflammation (that is, marked membranoproliferative, endocapillary or crescentic glomerulonephritis) is treated by pulse methylprednisolone, perhaps with the addition of anti-complement agents. Although the evidence is insufficient to support a disease-specific versus an anti-inflammatory effect of eculizumab, isolated reports of some clinical benefit are associated with terminal complement blockade. No trials or other data consistently support a particular duration of prednisone therapy, but the authors of this Review caution against long-term steroid use and favour steroid-sparing agents. Finally, clinicians are encouraged to consider enrolling their patients in clinical trials of anti-complement therapies where safe and available. ANA, antinuclear antibodies; ANCA, antinuclear cytoplasmic antibodies; APH50, the serum dilution causing 50% lysis of rabbit erythrocytes in magnesium EGTA buffer; Bb, complement component; C, complement component; CBC, complete blood count; CH50, the serum volume or dilution causing 50% lysis of sensitized erythrocytes; GFR, glomerular filtration rate; UPC urinary protein:creatinine ratio; SCr, serum creatinine level.