C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis

INTRODUCTION — Dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are rare forms of glomerulonephritis that affect both children and adults. Both diseases result from abnormal regulation of the alternative complement pathway and are classified under the heading of "C3 glomerulopathies." The clinical presentation is variable, and the diagnosis is made by immunofluorescence examination of a kidney biopsy specimen, supplemented by studies of the complement system. Whenever possible, the pathogenic mechanism should be identified as this can help guide therapy.

The pathogenesis, clinical presentation, diagnosis, and treatment of the C3 glomerulopathies (DDD and C3GN) are discussed in this topic. C4 glomerulopathies, as well as general discussions of the differential diagnosis of glomerular disease and the classification of membranoproliferative glomerulonephritis (MPGN), are presented elsewhere:

●(See "C4 glomerulopathy".)

●(See "Glomerular disease: Evaluation and differential diagnosis in adults".)

●(See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis".)

MORPHOLOGICAL CLASSIFICATION OF C3 GLOMERULOPATHIES — The C3 glomerulopathies are a group of rare forms of glomerulonephritis characterized by dysregulation of the alternative complement pathway, which results in predominant C3 deposition within the glomeruli [1]. The C3 glomerulopathies can be further classified morphologically based upon ultrastructural features observed on electron microscopy:

●DDD – The term "dense deposit disease" reflects the characteristic appearance of linear-appearing, highly electron-dense material in the glomerular basement membrane (GBM) observed on kidney biopsy electron microscopic examination (picture 1). (See 'Pathology' below.)

Historically, DDD was classified as a subgroup of primary membranoproliferative glomerulonephritis (MPGN type II), but it has been reclassified as a complement-mediated glomerular disease [2]. (See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis", section on 'Complement-mediated MPGN'.)

●C3GN – First described in 2007 [3], C3GN is characterized by isolated deposits of C3 on immunofluorescence (picture 2), but instead of dense intramembranous deposits as in DDD (picture 1), electron microscopy reveals predominant subendothelial and mesangial electron-dense deposits of lesser intensity (picture 3). In some cases, subepithelial deposits can also be seen. (See 'Pathology' below.)

Dysregulation of the alternative complement pathway by genetic or acquired abnormalities (such as C3 nephritic factor [C3NeF]) may also be seen in some cases of immune complex-mediated MPGN. This is discussed in more detail elsewhere. (See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis", section on 'Complement-mediated MPGN'.)

EPIDEMIOLOGY — The C3 glomerulopathies are rare, with an estimated incidence of one to three cases per million and point prevalence of 14 to 140 cases per million [1].

DDD is primarily, although not exclusively, a disease of children. The age range at diagnosis extends into adulthood [4-7]. By contrast, patients with C3GN are generally older. C3 glomerulopathy is also occasionally diagnosed in older adults, the majority of whom have been found to have an underlying monoclonal gammopathy [8-14]. DDD appears to affect both sexes equally although the data vary from study to study [5,6,15-18]. (See "Diagnosis and treatment of monoclonal gammopathy of renal significance", section on 'Subsequent evaluation of patients with confirmed MGRS'.)

PATHOGENESIS — The major defect underlying DDD and C3GN is excessive activation of the alternative complement pathway. This results in the deposition of multiple complement components in the glomerulus. The mechanism by which complement deposition leads to dense deposit formation or to the clinical manifestations of glomerulonephritis has not been established but most likely involves chemotaxis of leukocytes and possibly the cytolytic effects of C5b-9 (also called the membrane attack complex of complement or MAC).

The alternative complement pathway is normally autoactivated by low-level, spontaneous cleavage of C3 to C3b, which leads to the formation of the C3 convertase by the binding of factor B and properdin (figure 1). The C3 convertase (C3bBb) amplifies the cascade by enzymatically cleaving more C3 in addition to generating the downstream C5 convertase ([C3b]₂Bb). The C5 convertase cleaves C5 to the potent chemoattractant C5a and initiates assembly of C5b-9.

Normally, the activity of this pathway is tightly regulated and directly related to the activity of the C3 convertase (figure 1). The serum protein factor H regulates the activity of the alternative pathway in the fluid phase by directly promoting the decay of the C3 and C5 convertases. Factor H also combines with the regulator factor I to bind and rapidly inactivate free C3b. The alternative pathway is tightly regulated on cell surfaces by membrane cofactor protein (MCP, also called CD46), complement receptor 1 (CR1), and decay accelerating factor (DAF, also called CD55). CR1 also combines with factor I to bind and inactivate cell surface C3b. Complement pathways are reviewed in greater depth elsewhere. (See "Complement pathways".)

Deregulation of the complement alternative pathway in C3 glomerulopathy is most commonly induced by autoantibodies that stabilize C3 convertase or are directed against other complement regulatory proteins and less commonly by an inherited defect. Some patients are found to have more than one abnormality. The activity of C3 convertase can be increased by one of the following mechanisms:

●C3 nephritic factors (C3NeFs) – Generation of C3 convertase stabilizing autoantibodies called C3NeFs, usually of the immunoglobulin G class [4,15,19,20]. C3NeF is found in 80 percent of patients with DDD and somewhat less often in patients with C3GN [21] but is not unique to these patients [4,19,20,22,23]. C3NeF has also been found in the serum of healthy individuals, in those with meningococcal disease, and in patients with acquired partial lipodystrophy (APL), also called Barraquer-Simons (or Dunnigan-Kobberling) syndrome [23,24]. C3 convertase stabilizing autoantibodies that bind factor B and C3b and that inactivate factor H have been described [1,22,25-27].

In some patients, the activity of the terminal complement pathway is increased by a C5 convertase stabilizing autoantibody called C5 nephritic factor (C5NeF) [28]. Patients may have C3NeF alone or a combination of C3NeF and C5NeF autoantibodies. C5NeF-positive patients are more likely to have higher levels of C5b-9 and are more likely to have C3GN than DDD [28].

●Loss of regulator activity – Factor H normally inhibits the C3 convertase and activated C3 (C3b). Loss of functional factor H activity can result from the following inherited or acquired defects [29-32]:

•Autoantibodies to factor H that inhibit its action on C3b

•Monoclonal immunoglobulins that inhibit factor H

•Hereditary deficiency of factor H from particular mutations

•Familial mutations in complement factor H-related proteins, which compete with factor H for binding to C3b

C3 mutations that render activated C3 resistant to factor H inhibition or decrease its binding to CR1 have also been described in patients with DDD and C3GN [33,34]. Mutations in factor I and CR1 have also been reported [34,35]. Although such defects are not commonly seen in patients with C3G, when taken together with data from animal studies [36-43], observations of such defects in patients have helped to establish the role of unregulated alternate pathway activation in the pathogenesis of DDD and C3GN.

Although case studies have implicated autoantibodies and genetic mutations in the pathogenesis of the C3 glomerulopathies, it is important to recognize that the causality of C3NeFs is still unresolved, that their presence does not always correlate with disease activity, and that most patients with DDD or C3GN do not have disease-causing mutations in the factor H, C3, or other complement genes [27,29,44].

It is possible that subtle differences in factor H levels or activity confer a risk for C3 glomerulopathy since several allelic variants of the factor H gene and a closely related gene, complement factor H related 5 (CFHR5), have been associated with DDD [32]. A genetic analysis of 66 patients with DDD demonstrated that, compared with healthy controls, allelic variants of factor H or C3 genes increased the risk of developing the disease by up to twofold [45].

C3GN and, less commonly, DDD have been reported in association with monoclonal gammopathies [8-14,44,46-50]. In one report, a monoclonal Ig lambda light chain dimer inhibited factor H, resulting in decreased factor H activity [8]. However, in many cases, the monoclonal immunoglobulin does not show antibody activity against complement regulatory proteins and is thought to activate the alternative pathway through other mechanisms [51]. C3NeF [14] and antibodies to factor H and factor B have also been detected [13,14,51]. (See "Diagnosis and treatment of monoclonal gammopathy of renal significance".)

PATHOLOGY — Immunofluorescence is necessary to make a diagnosis of C3GN and DDD, and electron microscopy is required to distinguish them from one another [52,53]. Light microscopic findings are not specific for C3GN or DDD.

●Light microscopy – There are no characteristic light microscopic findings in C3 glomerulopathy; mesangial proliferative, membranoproliferative, and endocapillary proliferative glomerulonephritis may be present, as may crescentic glomerulonephritis [2]. Although DDD was previously classified as type II membranoproliferative glomerulonephritis (MPGN), the "classical" membranoproliferative pattern, including lobular accentuation of the glomerular tuft and reduplication of the glomerular basement membrane (GBM; so-called "tram tracks"), occurs in only 25 to 55 percent of C3 glomerulopathy biopsy specimens [2,16,54].

●Immunofluorescence microscopy – Immunofluorescence microscopy almost always shows bright deposits of C3 along the glomerular, tubular, and Bowman's capsule basement membranes, as well as mesangial rings (picture 2) [2,52,55]. Immunoglobulin deposits, including kappa and lambda light chains, are typically absent, or present at lower intensity than C3, which indicates that DDD and C3GN are not immune complex deposition diseases. C3 predominance of at least two orders of magnitude by immunofluorescence compared with other immunoreactants has been adopted as a diagnostic criterion for C3 glomerulopathy [52,56].

●Electron microscopy – Electron microscopy should be used whenever possible to confirm the presence and distribution of glomerular deposits. It is required to distinguish between DDD and C3GN. Electron microscopy in patients with DDD reveals pathognomonic abnormal electron-dense material within the GBM, which replaces and widens the lamina densa (picture 1). The GBM changes may be uniform or vary from loop to loop in DDD. Electron-dense material may also be found in the mesangium, paramesangial areas, and the basement membranes of the renal tubules and Bowman's capsule [2,4,15,16].

Such intramembranous electron-dense material is absent in C3GN. Rather, patients with C3GN have predominant subendothelial, mesangial, and sometimes subepithelial deposits of lesser intensity (picture 3) [16,57].

Subepithelial "humps" may be seen in both DDD and C3GN that are identical to those present in poststreptococcal glomerulonephritis (picture 4). (See 'Differential diagnosis' below.)

In some cases, kidney biopsies of C3 glomerulopathy are difficult to label as either DDD or C3GN, as there is an overlap in ultrastructural findings, although one pattern may dominate over the other [58].

Mass spectroscopy of laser-dissected glomerular extracts may identify proteins of the alternative complement pathway and of the terminal complement complex [57]. However, such techniques cannot distinguish DDD from C3GN and are not routinely performed [59].

CLINICAL FEATURES

Clinical presentation — Initial clinical manifestations of DDD and C3GN may be preceded by upper respiratory tract infection, including streptococcal infections [4,6,7,18,54]. Some cases of what may be initially diagnosed as postinfectious glomerulonephritis are ultimately found to be consistent with C3GN [60]. (See 'Differential diagnosis' below.)

Clinical manifestations of DDD and C3GN include the following:

●Urinary abnormalities – All patients with DDD and C3GN have proteinuria and/or hematuria. The degree of proteinuria is variable and may be nephrotic range.

Patients with DDD may present with the acute nephritic syndrome (16 to 38 percent), isolated macroscopic hematuria (21 to 36 percent), nephrotic syndrome (12 to 55 percent), microscopic hematuria with sub-nephrotic-range proteinuria (15 percent), and isolated proteinuria (15 to 41 percent) [4-7,16,48]. DDD may also be associated with sterile pyuria [6,15].

Patients with C3GN may present with hematuria and proteinuria and preserved kidney function (41 percent), nephrotic syndrome (33 percent), or, less commonly, acute kidney injury or rapidly progressive glomerulonephritis (8 percent) [61].

●Complement abnormalities – Many, but not all, patients with C3 glomerulopathy have low serum C3 levels [4,5,7,16,48,54]. Low C3 levels are more common among patients with DDD than among those with C3GN (79 versus 48 percent, respectively, in one series) [54]. Among patients with DDD, low C3 levels are more commonly seen in children than in adults [48]. This variability may be related to the nature or severity of the defect or defects.

Other complement abnormalities may be present. Serum levels of classical pathway components C1, C2, and C4 are usually normal although a minority of patients can have low serum C4 levels at some point in the disease course [4,5,19,54]. Elevated serum levels of sC5b-9 (ie, soluble membrane attack complex or sMAC), the terminal complement complex, may be present and provide additional evidence of complement activation [62-64]. Elevated serum levels of sC5b-C9 are more commonly observed in C3GN than in DDD [27].

C3 nephritic factor (C3NeF) is found in approximately 80 percent of patients with DDD [4,19-22] and roughly 40 percent of patients with C3GN [3,21]. Other autoantibodies against complement proteins are less frequent. Decreased levels of factor H, which are more common in DDD than in C3GN, and deficiencies of membrane cofactor protein (MCP, CD46) may also be detected [3,65,66].

●Kidney function impairment and hypertension – Patients with DDD and C3GN have variable degrees of kidney function impairment at presentation and variable rapidity of kidney function decline [61]. Occasionally, patients with DDD or C3GN can develop rapidly progressive (crescentic) glomerulonephritis.

The presence of hypertension at the time of diagnosis is also variable. In two studies, for example, hypertension was present in 21 to 60 percent of patients with DDD and 38 percent of patients with C3GN [21,54].

Extrarenal abnormalities — The following extrarenal abnormalities may be observed in patients with C3 glomerulopathy:

●Drusen – Many patients with DDD, and some with C3GN, develop drusen in Bruch's membrane of the retina [67-69]. Drusen are macular deposits and are a prominent feature of age-related macular degeneration (AMD). In contrast to the drusen in AMD, DDD-associated drusen develop at a much younger age and infrequently lead to vision loss. (See "Age-related macular degeneration".)

There does not appear to be a close correlation between kidney disease activity and drusen formation in DDD [70]. Nonetheless, given the similarities of electron-dense deposits in the retinal basement membrane and those in the glomerular basement membrane (GBM) in DDD, the two disorders are thought to share a common pathogenesis [71]. In addition, studies have shown a strong genetic link between AMD and specific factor H gene polymorphisms [72-78]. (See "Age-related macular degeneration".)

●Acquired partial lipodystrophy (APL) – Patients with DDD may also have APL, also called Barraquer-Simons (or Dunnigan-Kobberling) syndrome. APL is characterized by loss of subcutaneous fat in the upper half of the body [24,79]. Up to 22 percent of patients with APL are also affected by DDD, which may develop years after the onset of APL [79]. Sixty-seven to 74 percent of patients with APL have low C3 levels, and up to 83 percent have C3NeF. The putative link between both disorders is believed to be dysregulation of the alternative pathway of complement affecting both kidney and adipose tissue. (See "Lipodystrophic syndromes".)

DIAGNOSIS AND EVALUATION

When to suspect C3 glomerulopathy — The diagnosis of C3 glomerulopathy should be suspected in any patient who presents with hematuria and/or proteinuria, particularly if accompanied by kidney function impairment, hypertension, and a low serum C3 level.

All patients presenting with proteinuria and hematuria should undergo a thorough evaluation for glomerular disease and other disorders, which generally involves laboratory testing and, in most patients, a kidney biopsy to obtain a definitive diagnosis. The general evaluation of glomerular hematuria and proteinuria is discussed in more detail elsewhere. (See "Glomerular disease: Evaluation and differential diagnosis in adults", section on 'Glomerulonephritis (hematuria with proteinuria, kidney function impairment, or other manifestations)' and "Glomerular disease: Evaluation in children", section on 'Glomerulonephritis'.)

Establishing the diagnosis — The diagnosis of DDD or C3GN is established by kidney biopsy demonstrating the characteristic findings on immunofluorescence microscopy in a patient with suspected glomerulonephritis. Electron microscopy is required to distinguish DDD from C3GN. (See 'Pathology' above and 'Differential diagnosis' below.)

In patients with biopsy-confirmed DDD or C3GN, additional testing should be performed to help identify the underlying etiology of the glomerulopathy since this knowledge may help determine therapy.

●Evaluation for monoclonal gammopathy – In all patients with DDD or C3GN, particularly those aged older than 50 years, monoclonal gammopathy should be excluded by serum protein electrophoresis and immunofixation, serum free light chains, and urine protein electrophoresis and immunofixation. A paraprotein, including an isolated monoclonal light chain, may be responsible for activation of the alternative complement cascade [80].

●Complement testing – Patients with DDD or C3GN should be evaluated for activation of the alternative pathway of complement. Most of the tests listed below cannot be performed by the majority of routine clinical laboratories, and referral to specialized laboratories is required. A list of such laboratories is included in the table (table 1) and at the following website: European Complement Network.

Complement testing includes the following steps:

•Measurement of serum complement proteins

-Serum C3 and C4 – A low serum C3 level supports the diagnosis of C3GN or DDD but is not specific. Serum C4 levels are usually normal but may be low in a minority of patients. (See 'Clinical presentation' above.)

-Soluble C5b-9 (soluble membrane attack complex or sMAC) – Elevated levels of sMAC reflect activation of the C5 convertase and are found in approximately 25 and 50 percent of patients with DDD and C3GN, respectively.

-Serum factor H – As noted above, factor H promotes the decay of the C3 and C5 convertases. If factor H activity is diminished, factor H levels should be measured and assays for possible mutations in the factor H gene and autoantibodies to factor H should be performed.

-Serum factor B, factor I, and membrane cofactor protein (MCP, CD46) – Deficiency of serum factors I or MCP or activating mutations or antibodies to factor B can be associated with activation of the alternative complement cascade. Mutations in these genes or autoantibodies against these proteins should be included in the search for the cause of alternative pathway activation.

•Testing for autoantibodies

-C3 nephritic factor (C3NeF) – C3NeF is an autoantibody that stabilizes the C3 convertase (C3bBb). C3NeF is detected in approximately 80 percent of patients with DDD and 40 percent of those with C3GN. Detection of C3NeF in the serum supports the diagnosis of C3GN or DDD but is not specific.

-C5 nephritic factor (C5NeF) – C5NeF is an autoantibody that stabilizes the C5 convertase ([C3b]₂Bb) in the presence of properdin [28,81,82]. It is found most commonly in C3GN and is associated with high sC5b-9 levels.

-C4 nephritic factor (C4NeF) – C4NeFs, autoantibodies that stabilize the classical and lectin pathway C3 convertase, have been identified in a small subset of patients with C3 glomerulopathy [83,84].

-Other autoantibodies – Testing for autoantibodies against factor H, factor B, and C3b may also be performed; however, such autoantibodies are less common among patients with C3 glomerulopathy [27].

•Genetic testing – The frequency of complement gene variants in C3 glomerulopathy is estimated at approximately 20 percent. Testing for mutations in the genes encoding factor H, factor I, C3, and complement factor H-related (CFHR) proteins (CFHR1-5) should be performed [27].

The CFHR proteins CFHR1, CFHR2, and CFHR5 are able to compete with factor H for binding to tissue-bound complement fragments, thereby deregulating the control of the alternative pathway by factor H [85]. This balance can be disturbed by CFHR mutations. As examples, mutations in the CFHR5 gene that produce an internal duplication are responsible for C3GN of Cypriot origin [86], and a hybrid CFHR3-1 gene mutation resulted in familial C3GN in an Irish family [87].

Rare and novel variants in both C3 convertase and complement regulator genes have been identified in up to 43 percent of patients with C3 glomerulopathies; however, several are still regarded as variants of unknown significance. Likewise, variants in genes known to be involved in thrombotic microangiopathies have been identified in a few patients with C3 glomerulopathies, including THBD, DGKE, ADAMTS13, and PLG, but their pathogenic significance has yet to be established [13,88,89].

A presumed cause of DDD and C3GN can be identified in many patients. In a series of 114 patients with biopsy-proven C3 glomerulopathy (102 with C3GN and 12 with DDD) [44], a history of infection, positive autoimmune findings (most commonly a positive antinuclear antibody and/or a positive anti-double stranded DNA test), and monoclonal gammopathy were identified in 29, 25, and 38 percent of patients, respectively. Of note, among the 43 patients who were 50 years of age or older, 65 percent had a monoclonal gammopathy. Among the 77 patients who underwent testing for abnormalities in the alternative complement pathway, a genetic variant in complement genes was present in 26 of 70 (37 percent), C3NeF in 30 of 69 (44 percent), and other autoantibodies in 9 of 67 (13 percent).

DIFFERENTIAL DIAGNOSIS — The diagnosis of glomerulonephritis is suggested by the presence of proteinuria, hematuria, kidney function impairment, or an active urine sediment with red or white cell casts. (See "Urinalysis in the diagnosis of kidney disease" and "Glomerular disease: Evaluation and differential diagnosis in adults".)

Given the nonspecific clinical presentation, the differential diagnosis of DDD and C3GN is broad and includes almost all causes of acute glomerulonephritis and nephrotic syndrome, including IgA nephropathy, lupus nephritis, fibrillary glomerulonephritis, vasculitis, poststreptococcal glomerulonephritis, and staphylococcus-associated glomerulonephritis. In addition, the differential diagnosis includes such conditions as atheroembolic disease and complement-mediated thrombotic microangiopathy (also known as atypical hemolytic uremic syndrome), which may also present with acute kidney injury and a low C3 level, and monoclonal immunoglobulin-related glomerular diseases in patients with monoclonal gammopathy. (See "Glomerular disease: Evaluation and differential diagnosis in adults" and "Clinical presentation, evaluation, and treatment of renal atheroemboli" and "Complement-mediated hemolytic uremic syndrome in children" and "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS".)

Decreased serum C3 and a normal C4 may help distinguish DDD and C3GN from other types of glomerulonephritis. However, poststreptococcal and, to a lesser extent, staphylococcus-associated glomerulonephritis are also characterized by this pattern of complement activation and can produce a similar clinical syndrome with proteinuria, hematuria, and azotemia.

●Distinction from postinfectious glomerulonephritis – Several features help distinguish DDD and C3GN from poststreptococcal and staphylococcus-associated glomerulonephritis:

•Persistent or recurrent glomerulonephritis over a prolonged period is common with DDD and C3GN, whereas poststreptococcal and IgA-dominant, staphylococcus-associated glomerulonephritis typically resolve, although signs of irreversible injury (ie, persistent azotemia and proteinuria) may be present.

•Depression of C3 usually persists in DDD and C3GN, whereas it is transient in poststreptococcal and staphylococcus-associated glomerulonephritis.

•Immunofluorescence microscopy usually demonstrates immunoglobulin deposition in poststreptococcal and IgA-dominant, staphylococcus-associated glomerulonephritis; by contrast, there is typically intense C3 staining with scant or no immunoglobulin staining in DDD and C3GN.

The term "atypical" postinfectious glomerulonephritis has been used to describe either cases of nonresolving urinary abnormalities or kidney function impairment following a documented infection or cases that are diagnosed as postinfectious glomerulonephritis on biopsy without evidence of preceding infection [90]. These patients have been shown to have underlying defects in the alternative pathway regulation and most likely are examples of C3GN in which the regulatory defect is unmasked when complement is triggered by infection. (See "Poststreptococcal glomerulonephritis", section on 'Pathology'.)

●Glomerular disorders with monoclonal immunoglobulin deposits misdiagnosed as C3GN – Some patients with a glomerular disease due to monoclonal immunoglobulin deposits may be mistakenly diagnosed as having a C3GN [80]. In one study, for example, 16 patients with a membranoproliferative pattern of glomerulonephritis had negative staining for immunoglobulin initially by routine immunofluorescence but were later found to have monoclonal immunoglobulin deposition after immunofluorescence was performed on paraffin-embedded tissue after pronase digestion [80]. Of these 16 patients, 10 were originally diagnosed with C3GN after routine immunofluorescence, and eight of these were found subsequently to have a plasma cell dyscrasia or lymphoproliferative disorder. (See "Diagnosis and treatment of monoclonal gammopathy of renal significance", section on 'When to suspect MGRS'.)

TREATMENT — There is no high-quality evidence to inform therapeutic decisions for patients with DDD or C3GN. Our treatment approach (algorithm 1) is based upon data from case series and reports, our present knowledge of disease pathogenesis, and the clinical expertise of the authors and editors. This approach is largely consistent with the 2021 Kidney Disease: Improving Global Outcomes Clinical Practice Guideline for the Management of Glomerular Diseases [91].

Monoclonal gammopathy present — Patients with DDD or C3GN who are found to have a monoclonal gammopathy should be evaluated further for underlying malignancy (such as multiple myeloma) or evidence of other end-organ involvement and treated accordingly. In the absence of an assay to confirm that the monoclonal gammopathy is responsible for the complement dysregulation, treatment is based upon this presumption given the unusually strong association between monoclonal gammopathy and C3 glomerulopathy in older patients. The treatment of C3 glomerulopathy associated with monoclonal gammopathy is primarily directed against the pathologic clone responsible for producing the monoclonal protein and is discussed in more detail separately (See "Diagnosis and treatment of monoclonal gammopathy of renal significance", section on 'Patients with C3 glomerulopathy with monoclonal gammopathy'.)

Monoclonal gammopathy absent

Initial therapy — In patients with DDD or C3GN who do not have a monoclonal gammopathy, our approach to initial therapy is based upon the severity of disease (algorithm 1). We base our clinical decisions upon an arbitrary proteinuria threshold of 1.5 g/day. There is no evidence to support this (or any other) proteinuria threshold in patients with C3 glomerulopathy, and this threshold is largely based upon clinical experience.

Mild disease — Patients with C3GN or DDD who have mild disease (characterized by proteinuria <1.5 g/day, hematuria, and normal kidney function) typically do not require immunosuppressive therapy and can be initially managed with supportive measures only. Such patients can also be encouraged to participate in a clinical trial, if available. (See 'Supportive measures in all patients' below.)

Patients with mild disease should be monitored periodically for disease progression that might warrant therapy. We monitor serum creatinine and urine protein excretion (initially by 24-hour urine collection and then by spot urine protein-to-creatinine ratio [UPCR] if stable) every three months for one year and then every six months if stable. If proteinuria and kidney function remain stable or improve, we continue supportive measures indefinitely with follow-up every six months. Patients who develop increasing proteinuria or worsening kidney function should be considered for immunomodulatory therapies, as discussed below. (See 'Moderate to severe disease' below.)

There are no high-quality studies to guide the optimal therapy of patients with C3GN or DDD who have mild disease. Although observational studies suggest that patients with C3 glomerulopathy who are treated with immunosuppressive agents generally have better preservation of kidney function and are more likely to enter remission than those treated conservatively [44,92,93], these studies did not distinguish between those with mild and more severe disease. In our experience, patients with mild disease who are not treated with immunosuppressive therapy may continue to have preserved kidney function for several years despite microscopic hematuria and moderate proteinuria.

Moderate to severe disease — For patients with C3GN or DDD who have moderate to severe disease (characterized by proteinuria ≥1.5 g/day and/or abnormal kidney function [but not rapidly progressive disease] considered to be due to active DDD or C3GN), we suggest initial therapy with mycophenolate mofetil (MMF) and oral glucocorticoids plus supportive measures, rather than supportive measures alone or combined with other immunosuppressive agents. Alternatively, such patients can be encouraged to participate in a clinical trial, if available. However, some clinicians would treat patients who have sub-nephrotic-range proteinuria (<3 g/day) and normal kidney function with supportive measures alone and would not administer immunosuppressive therapy unless kidney function deteriorates or proteinuria worsens substantially.

We administer MMF 1000 mg twice daily and prednisone 20 mg daily or 40 mg every other day. We monitor serum creatinine and urine protein excretion (by spot UPCR), initially on a monthly basis and then every three months if these parameters remain stable.

●If proteinuria improves and kidney function stabilizes, we continue treatment with MMF for a total of at least six months. We administer prednisone at the initial dose for a total of at least three months, followed by a gradual taper to discontinuation by nine months. The optimal duration of MMF therapy is uncertain, and up to 50 percent of patients relapse when the treatment is stopped [93,94]. If MMF is discontinued after six months of therapy, we monitor serum creatinine and urine protein excretion every three months to monitor for signs of relapse (eg, increasing proteinuria or worsening kidney function). In patients who develop relapsing disease, we restart MMF and glucocorticoids and continue treatment with MMF indefinitely after tapering off the glucocorticoids.

●If there is no improvement in proteinuria or kidney function after six months of MMF plus glucocorticoid therapy, or if kidney function rapidly deteriorates prior to the completion of six months of therapy, our subsequent approach differs depending on whether the patient has an identified genetic defect in factor H. If the patient has a genetic defect in factor H, we discontinue MMF and glucocorticoids and offer a trial of plasma infusion or plasma exchange. If the patient does not have a genetic defect in factor H, we discontinue MMF and glucocorticoids and either switch to eculizumab or encourage the patient to participate in a clinical trial, if available. (See 'Plasma infusion or exchange for factor H defects' below and 'Eculizumab for refractory disease' below.)

Data from observational studies suggest that the combination of MMF and glucocorticoids may improve kidney outcomes among patients with C3 glomerulopathy [92-94]. In a retrospective study of 97 patients with C3 glomerulopathy (81 with C3GN and 16 with DDD), 42 were treated with MMF plus glucocorticoids, 29 were treated with other immunosuppressive regimens (glucocorticoids alone, cyclophosphamide, calcineurin inhibitors, rituximab, or eculizumab), and 17 were treated without immunosuppression [93]. At baseline, 40 percent of patients had nephrotic syndrome, 30 percent had nephritic syndrome, and 30 percent had asymptomatic urinary abnormalities. Over a median of 46 months, treatment with MMF plus glucocorticoids was associated with a higher rate of remission and lower rate of end-stage kidney disease (ESKD) compared with other immunosuppressive regimens or no immunosuppression (36 versus 8 and 0 percent and 14 versus 60 and 65 percent, respectively). Of note, patients treated conservatively were older and had worse baseline kidney function than those treated with immunosuppression, which may have accounted for their worse kidney survival. Among patients who achieved remission with MMF plus glucocorticoids, 33 percent developed relapse after treatment discontinuation.

Other studies have also reported higher remission rates associated with MMF plus glucocorticoid therapy compared with other regimens [92]. However, some studies have not found a selective benefit with MMF [95].

Rapidly progressive glomerulonephritis — For patients with C3GN or DDD who have rapidly progressive glomerulonephritis (RPGN; ie, rapidly deteriorating kidney function and extensive crescentic glomerulonephritis on kidney biopsy), we suggest glucocorticoids in combination with either cyclophosphamide or MMF. The goal of therapy is to try to suppress the acute inflammatory response and halt or reverse the disease course. In such patients, we typically advocate inpatient admission for initial management.

●We typically give methylprednisolone 500 to 1000 mg daily for three days, followed by a tapering course of oral prednisone (eg, starting dose 60 mg/day until remission is achieved, then tapered to discontinuation by six months).

●If cyclophosphamide is used, we administer 1.5 to 2 mg/kg/day orally for three to six months, depending upon the clinical response. If MMF is used, we give 1.5 to 2 g/day orally in two divided doses as tolerated for at least six months. The decision between cyclophosphamide and MMF is determined by clinician and patient preference, and there is no evidence to support the use of one agent over the other in patients with C3 glomerulopathy who present with RPGN.

In addition to the combination therapy described above, some experts would also administer eculizumab, based upon the results of one case series suggesting a potential benefit in patients with RPGN [96]. If eculizumab is used, we administer 1200 mg IV every two to four weeks. If there is no evidence of disease stabilization or improvement after three months of therapy, eculizumab should be discontinued, and the patient should be encouraged to participate in a clinical trial. Dialysis dependence of less than two weeks' duration should not preclude the use of eculizumab in patients with extensive cellular crescents on kidney biopsy. (See 'Eculizumab for refractory disease' below.)

In patients who have a genetic defect in factor H, some of the contributors to this topic would use plasma exchange or plasma infusion in addition to glucocorticoids with cyclophosphamide or MMF, given the success of this therapy in two case reports [97,98]. Plasma exchange can be performed with three exchanges per week for two weeks. If there is evidence of disease stabilization or improvement at two weeks, plasma exchange can be continued; if not, plasma exchange should be discontinued, and the patient should be offered a trial of eculizumab. (See 'Plasma infusion or exchange for factor H defects' below.)

An overview of the pathogenesis and treatment of RPGN is presented elsewhere. (See "Overview of the classification and treatment of rapidly progressive (crescentic) glomerulonephritis".)

Supportive measures in all patients — General supportive measures in all patients with C3GN or DDD include dietary sodium and protein restriction, blood pressure control, reduction of proteinuria with renin-angiotensin inhibition, and treatment of dyslipidemia, if present. Other aspects of therapy include diuretics to control edema and maintenance of adequate nutrition. These issues are discussed in greater detail elsewhere:

●Dietary sodium and protein restriction (see "Dietary recommendations for patients with nondialysis chronic kidney disease", section on 'Salt intake' and "Dietary recommendations for patients with nondialysis chronic kidney disease", section on 'Protein intake')

●Antihypertensive therapy (see "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults")

●Renin-angiotensin system inhibition (see "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Renin-angiotensin system inhibitors')

●Lipid lowering (see "Overview of the management of chronic kidney disease in adults", section on 'Dyslipidemia' and "Chronic kidney disease in children: Complications", section on 'Dyslipidemia')

●Treatment of edema (see "Overview of the management of chronic kidney disease in adults", section on 'Volume overload' and "Chronic kidney disease in children: Complications", section on 'Sodium and water homeostasis')

Eculizumab for refractory disease — For patients with C3GN or DDD and moderate to severe disease (see 'Moderate to severe disease' above) who do not respond to initial therapy with MMF plus glucocorticoids, we suggest eculizumab rather than continuation of MMF plus glucocorticoid therapy. Alternatively, the patient can be encouraged to participate in a clinical trial, if available. Eculizumab is a monoclonal antibody that binds with high affinity to C5, preventing its cleavage and thereby inhibiting the formation of C5a and the terminal complement complex (C5b-9), which have been implicated in the pathogenesis of both DDD and C3GN. (See 'Pathogenesis' above.)

We administer eculizumab 900 mg intravenously (IV) per week for four to five weeks, followed by 1200 mg IV every two weeks. We monitor serum creatinine and urine protein excretion (by spot UPCR) on a monthly basis during therapy. The optimal duration of eculizumab therapy is uncertain.

●In patients who respond with an improvement or stabilization of kidney function and proteinuria within three months, we continue eculizumab for a total of approximately one year. Since some patients will relapse when the treatment is stopped or frequency of treatment is reduced, we monitor serum creatinine and spot UPCR monthly for three months, then every two months for six months, and then every three months for one year. Subsequent monitoring then varies on a case-by-case basis. In patients who experience a relapse, we restart eculizumab and continue treatment indefinitely.

●In patients who have no improvement or stabilization of kidney function or proteinuria after three months of eculizumab therapy, we discontinue treatment since the benefits of eculizumab are likely to be seen within a few weeks to months. Patients who do not respond to eculizumab should be encouraged to participate in a clinical trial, if available. Some clinicians would consider a trial of plasma infusion or plasma exchange in such patients; however, data to support this approach are limited to a few case reports of patients with C3 nephritic factor (C3NeF) or factor H defects [31,99]. (See 'Plasma infusion or exchange for factor H defects' below.)

Treatment with eculizumab may be associated with life-threatening and fatal meningococcal infections. Patients should receive meningococcal vaccination at least two weeks prior to initiation of eculizumab whenever possible. We also administer daily antimicrobial prophylaxis for prevention of meningococcal infection in patients treated with eculizumab, despite vaccination, due to increased infection risk with immunosuppression. (See "Treatment and prevention of meningococcal infection", section on 'Patients receiving C5 inhibitors'.)

Data on the efficacy of eculizumab are derived from one small, open-label, phase I clinical trial and several case reports and series. These suggest that some [62,96,100-106], but not all [96,107], patients with C3 glomerulopathy may benefit from treatment with eculizumab. In the small number of patients included, there were no reported adverse effects of eculizumab therapy. The patients who had posttreatment kidney biopsies appeared to have eculizumab deposition in kidney tissues. The long-term effects of this deposition are unknown.

The largest case series of patients with C3 glomerulopathy treated with eculizumab included 13 children/adolescents and 13 adults [96]. Most patients (85 percent) had received other immunosuppressive therapy prior to eculizumab, and three had rapid progression of their kidney disease despite treatment. At the time of eculizumab initiation, 11 patients (42 percent) had chronic kidney disease, 19 (73 percent) had nephrotic syndrome, seven (27 percent) had rapidly progressive disease, and three (12 percent) required dialysis. None of the patients had monoclonal gammopathy. Patients were treated with eculizumab 900 mg IV per week for four weeks, followed by 1200 mg every other week; median duration of eculizumab therapy was 14 months. Six patients (23 percent) had a global clinical response, six (23 percent) had a partial clinical response, and 14 (54 percent) had no response. Patients with a global response tended to have a more rapidly progressive disease course and more extracapillary proliferation on kidney biopsy. Other factors, including age, extent of kidney fibrosis, frequency of nephrotic syndrome, complement levels, and gene variants, did not differ between responders and nonresponders.

Plasma infusion or exchange for factor H defects — For patients with moderate to severe disease that does not respond to initial treatment with mycophenolate and glucocorticoids and who have identified genetic defects in factor H, we suggest a trial of plasma infusion of fresh frozen plasma (FFP) or plasma exchange to replace the missing or mutant protein. Plasma exchange (with FFP, not albumin) may be preferred to plasma infusion if there is concern about volume overload. Plasma exchange may also be of value in those patients with an acquired functional deficiency of factor H due to the presence of inactivating proteins, such as an autoantibody, to remove the antibody while replacing factor H.

A trial of plasma infusion or exchange once every 14 days may be continued for 6 to 12 weeks while monitoring for signs of kidney recovery as measured by a decline in proteinuria and serum creatinine. If the patient responds, plasma infusion or exchange should be continued indefinitely. If the patient does not respond after 6 to 12 weeks, plasma infusion or exchange should be discontinued, and the patient should be offered eculizumab or encouraged to participate in a clinical trial. (See 'Eculizumab for refractory disease' above.)

The data supporting the use of plasma infusion come from a case report of two siblings with C3NeF and defective factor H secretion; normal kidney function was maintained with a regimen of 10 to 15 mL per kg body weight of FFP infused regularly every 14 days [31].

Plasma exchange with albumin has also been shown to stabilize disease progression in some patients with circulating C3NeF, presumably by removal of the pathologic autoantibody [99].

Investigational agents — Several complement inhibitors are under investigation for the treatment of C3 glomerulopathy. In small, open-label, single-arm phase II trials, pegcetacoplan (a targeted C3 and C3b inhibitor administered by subcutaneous injection) [108] and iptacopan (an oral complement factor B inhibitor) [109] reduced proteinuria and increased serum C3 levels with overall favorable safety profiles. Phase III trials for these agents are in progress and open for enrollment (NCT05067127, NCT04817618).

Therapies of unclear benefit — Therapies directed against B lymphocytes (rituximab) or plasma cells (bortezomib) would appear to be a logical approach to reduce or eliminate C3NeF or anti-factor H autoantibodies. However, the few published studies have yielded mixed results [100,101,110,111].

KIDNEY TRANSPLANTATION — Kidney transplantation is an option for patients with DDD and C3GN, but disease recurrence and graft loss are common and may be refractory to treatment, mostly because standard immunosuppression does not correct the underlying abnormality. Thus, patients with C3 glomerulopathy who are being prepared for transplantation, and any potential living donors, must be informed of this possibility. There is no evidence that pretransplant immunosuppressive treatment for those with autoantibody-mediated C3 glomerulopathy or plasma exchange for those with regulatory factor deficiency is effective in preventing recurrence. Eculizumab has been used with variable success for those with recurrence [35,112-114]. These issues are discussed in more detail elsewhere. (See "C3 glomerulopathies: Recurrence after transplantation".)

Patients with C3 glomerulopathy associated with monoclonal gammopathy should undergo treatment of the dysproteinemia prior to transplantation. (See "Diagnosis and treatment of monoclonal gammopathy of renal significance", section on 'Patients with C3 glomerulopathy with monoclonal gammopathy'.)

PROGNOSIS — Rates of progression vary widely in reports of C3 glomerulopathy.

●DDD – Although earlier studies reported a generally poor outcome among children with DDD [20,29], subsequent studies have found a more favorable prognosis in approximately half of cases [48,115]. As examples:

•In one multicenter prospective study in children, end-stage kidney disease (ESKD) developed in over 70 percent of affected individuals with a median onset of nine years after diagnosis of DDD [20]. Similar findings were reported in a review of data from the North American Pediatric Renal Trials and Collaborative Studies although the rate of progression was not reported in this study [29].

•By contrast, the following observations were made in a review of native kidney biopsies from patients with DDD that included 13 children and 14 adults [48]:

-Over a mean follow-up of 79 months, six children (46 percent) had normal kidney function and less than 500 mg/day of proteinuria. One child progressed to ESKD, and the remainder had persistent kidney dysfunction.

-Over a mean follow-up of 49 months, one adult had normal kidney function and less than 500 mg/day of proteinuria. Six adults developed ESKD, and seven had persistent kidney dysfunction.

-Older age and serum creatinine at biopsy were independent predictors of progression to ESKD.

The reasons for these disparate outcomes in children between earlier and subsequent studies are unclear but may have to do with differences in disease severity at the time of diagnosis and treatment modalities. In addition, comparative data in adults are lacking because DDD was regarded as a disease of childhood until more proactive kidney biopsy practices in older patients were introduced.

●C3GN – The prognosis of C3GN is variable. Some patients have persistently low-grade proteinuria but maintain kidney function for a long time while other patients have severe nephrotic syndrome, and some can present with rapidly progressive glomerulonephritis (RPGN) and have a poor prognosis. While some studies suggest that the prognosis of C3GN is better than that of DDD [54,94], others have found comparable kidney outcomes between patients with C3GN and those with DDD [61,115,116]:

•In one study, 23 percent of patients with C3GN, compared with 47 percent of patients with DDD, progressed to ESKD at a median of 28 months [54].

•By contrast, in the largest North American cohort of 111 patients with C3 glomerulopathy (87 with C3GN and 24 with DDD), there was no significant difference in the rates of progression to ESKD between patients with C3GN and those with DDD (21 versus 29 percent, respectively) [61]. Similarly, no difference in kidney prognosis was observed between C3GN and DDD in a large Italian registry of 173 patients [116].

A standardized chronicity grading classification of lesions on kidney biopsy in patients with C3 glomerulopathy has been shown to predict poor kidney outcomes and response to therapy [91], suggesting that this histology index score should be incorporated into the kidney pathology report.

Simple biomarker profiles may be helpful in predicting prognosis. In a large C3 glomerulopathy cohort, the combination of low C3/normal soluble C5b-9 levels or normal C3/high sC5b-9 levels in the serum was associated with increased likelihood of progressing to ESKD, independent of baseline proteinuria levels [117]. Rare disease variants in complement genes C3, CFH, and CFI were also associated with poorer prognosis.

In older patients with monoclonal gammopathy-associated C3GN, achievement of deep hematologic response with chemotherapy has been reported to result in improved kidney function and outcomes as compared with treatment with symptomatic measures or conventional immunosuppressive drugs [13,14].

SCREENING FAMILY MEMBERS — Family members of affected patients should undergo genetic testing if a potentially causative mutation is identified in the patient (eg, factor H mutation in a patient with low serum factor H levels). If the family member is found to have the same mutation, they should be evaluated for the presence of hypocomplementemia and an abnormal urinalysis or elevated serum creatinine. A kidney biopsy should be done to exclude DDD and C3GN if there is clinical evidence of glomerular disease. (See 'Clinical features' above.)

Asymptomatic siblings and other young family members who have a demonstrated genetic mutation should be followed prospectively for signs of glomerular disease. There are no data to guide the frequency with which such individuals are followed. However, it is reasonable to perform urinalysis and assessment of kidney function in such patients annually and following infections that might trigger complement activation and precipitate the onset of glomerulonephritis. Periodic measurements of complement levels and C3 nephritic factor (C3NeF) should also be done.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults".)

SUMMARY AND RECOMMENDATIONS

●Classification – Dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are rare forms of glomerulonephritis that affect both children and adults. Both diseases result from defective regulation of the alternative complement pathway and are now classified as "C3 glomerulopathies." (See 'Morphological classification of C3 glomerulopathies' above and 'Pathogenesis' above.)

●Clinical features – Major manifestations of C3 glomerulopathies include proteinuria (ranging from mild to nephrotic range) and/or hematuria, persistently low serum C3 levels in most cases, and variable degrees of kidney function impairment and hypertension. (See 'Clinical presentation' above.)

●Diagnosis – The diagnosis of DDD or C3GN is made by kidney biopsy in a patient with suspected glomerulonephritis. Immunofluorescence is necessary to make a diagnosis of C3GN and DDD, and electron microscopy is required to distinguish them from one another. Whenever possible, special diagnostic tests should be performed to help identify the underlying etiology of the glomerulopathy since this knowledge may help determine therapy. (See 'Diagnosis and evaluation' above.)

●Treatment – There are no randomized trials to inform therapeutic decisions. We suggest the following approach (algorithm 1):

•Monoclonal gammopathy present – Patients who are found to have a monoclonal gammopathy should be evaluated further for an underlying malignancy or evidence of end-organ involvement. The treatment of C3 glomerulopathy associated with monoclonal gammopathy is discussed in more detail elsewhere. (See "Diagnosis and treatment of monoclonal gammopathy of renal significance", section on 'Patients with C3 glomerulopathy with monoclonal gammopathy'.)

•Monoclonal gammopathy absent – In patients who do not have a monoclonal gammopathy, our approach to initial therapy is based upon the severity of disease. All patients, regardless of disease severity, can also be encouraged to participate in a clinical trial, if available.

-Mild disease – In patients with mild disease (proteinuria <1.5 g/day, hematuria, and normal kidney function), immunosuppressive therapy is typically not necessary, and such patients can be initially managed with supportive measures only. Supportive measures include dietary sodium and protein restriction, blood pressure control, reduction of proteinuria with renin-angiotensin inhibition, and treatment of dyslipidemia if present. (See 'Mild disease' above and 'Supportive measures in all patients' above.)

-Moderate to severe disease – For patients who have moderate to severe disease (proteinuria ≥1.5 g/day and/or abnormal kidney function [but not rapidly progressive disease] considered to be due to active DDD or C3GN), we suggest initial therapy with mycophenolate mofetil (MMF) and oral glucocorticoids plus supportive measures rather than supportive measures alone or combined with other immunosuppressive agents (Grade 2C). (See 'Moderate to severe disease' above and 'Eculizumab for refractory disease' above.)

In patients whose proteinuria or kidney function fails to improve after six months of MMF therapy, or whose kidney function rapidly deteriorates prior to the completion of six months of therapy, our approach differs depending upon whether the patient has a genetic defect in factor H. For those who have a genetic defect in factor H, we suggest a trial of plasma infusion or plasma exchange, rather than continuing the MMF or switching to an alternative immunosuppressive drug (Grade 2C). For those who do not have a genetic defect in factor H, we suggest switching to eculizumab, rather than continuing the MMF or switching to an alternative immunosuppressive drug (Grade 2C). Alternatively, the patient can be encouraged to participate in a clinical trial, if available. (See 'Eculizumab for refractory disease' above and 'Plasma infusion or exchange for factor H defects' above.)

-Rapidly progressive glomerulonephritis (RPGN) – For patients who have RPGN, we suggest glucocorticoids in combination with either cyclophosphamide or MMF (Grade 2C). The decision between cyclophosphamide and MMF is determined by clinician and patient preference. Some experts would also treat such patients with eculizumab in addition to immunosuppressive therapy. If the patient has a genetic defect in factor H, some experts would add plasma exchange to immunosuppressive therapy. (See 'Rapidly progressive glomerulonephritis' above.)