C4 glomerulopathy

INTRODUCTION — Glomerulonephritis (GN) can result from a number of pathogenic processes that cause glomerular deposition of immune complexes and/or complement [1]. Immune complex-mediated GN (due, for example, to chronic infections such as hepatitis C virus) is characterized by deposits of immunoglobulin, often accompanied by deposition of complement that includes C3 and/or C4 and, in some cases, C1q. Deposition of C3, C4, and C1q in immune complex-mediated GN is likely due to activation of the classical pathway of complement.

On the other hand, complement-mediated GN is usually characterized by deposition of C3 with minimal or no immunoglobulin deposits. The prototype of complement-mediated GN is C3 glomerulopathy, which includes C3 glomerulonephritis (C3GN) and dense deposit disease (DDD). Both C3GN and DDD result from overactivation of the alternative pathway of complement [2-5]. In C3 glomerulopathy, C4 is typically absent on immunofluorescence microscopy [6].

In 2014, a new type of complement-mediated GN was identified that was characterized by deposition of C4 in the absence of C3, C1q, and immunoglobulin. This disorder was called C4 dense deposit disease (abbreviated as C4 DDD; if there were dense C4 deposits along the glomerular basement membrane documented by electron microscopy) or C4 glomerulonephritis (abbreviated as C4GN; if there were C4 deposits primarily in the mesangium with few capillary wall deposits). Thus, complement-mediated GN can be subdivided into C3 glomerulopathy (C3GN and DDD) and C4 glomerulopathy (C4GN and C4 DDD) (figure 1).

C4 DDD and C4GN are discussed in this topic. C3 glomerulopathy and immune complex-mediated GN are presented elsewhere:

●(See "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis".)

●(See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis", section on 'Immune complex/monoclonal immunoglobulin-mediated MPGN'.)

PATHOGENESIS — Although the pathogenesis of C4 glomerulopathy has yet to be defined, overactivity of the lectin pathway of complement activation is likely involved. The lectin pathway, like the classical (immunoglobulin-dependent) pathway, activates C2 and C4 (and not C1q), but it does so without involvement of antibodies. Detailed discussions of the lectin pathway of complement activation are presented elsewhere. (See "Overview and clinical assessment of the complement system" and "Complement pathways", section on 'Lectin pathway'.)

Although it is unproven, genetic factors, acquired autoantibodies, or a paraprotein that interferes with the lectin pathway may play a role in the development of C4 glomerulopathy. Alternatively, there may be a mutation producing an abnormal C4 protein that resists degradation and is prone to accumulation in the glomerulus.

CLINICAL MANIFESTATIONS — Reported cases of C4 dense deposit disease (C4 DDD) and C4 glomerulonephritis (C4GN) are scarce and affect both males and females [7-9]. With the exception of low C3 levels, the clinical manifestations appear to overlap with C3 glomerulopathy and may include [7,8]:

●Proteinuria, which may exceed 3.5 g per day

●Hematuria, with or without red blood cell casts

●Hypertension

●A normal C3 level and a normal or slightly low C4

●A slowly progressive decline in glomerular filtration rate

Patients diagnosed with C4 glomerulopathy have presented in childhood, adolescence, and adulthood. As an example, the first reported case was a girl with C4 DDD who was noted to have proteinuria and hematuria at her 12-year-old well-child visit [7]. The protein-to-creatinine ratio was 1.5 g/g on a random urine; she had a normal serum creatinine, normal serum C3 and C4 levels, and normal renal anatomy by ultrasonography. The disease progressed, and, at age 17 years, she had hypertension and a urine protein-to-creatinine ratio of 5.2 g/g, although her serum creatinine remained normal [8].

C4 glomerulopathy has also been described in a 34-year-old woman with C4 DDD who presented with 10 g/day of proteinuria and hematuria and in a 43-year-old man with C4GN who presented with hematuria, hypertension, progressive kidney function decline, and subnephrotic proteinuria [8]. In both cases, C3 was normal and C4 was slightly low. A proliferative C4 DDD, with associated acute thrombotic microangiopathy, monoclonal gammopathy, and acute kidney failure, has also been reported [10].

Unlike C3 glomerulopathy, patients identified with C4 glomerulopathy have not had elevated levels of circulating C5b-9 (also called the membrane attack complex, or MAC). (See "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis".)

DIAGNOSIS — The diagnosis of C4 dense deposit disease (C4 DDD) or C4 glomerulonephritis (C4GN) is made by kidney biopsy.

In patients with C4 DDD, light microscopy shows a membranoproliferative pattern of injury with mesangial hypercellularity, endocapillary proliferation, and thickened glomerular basement membranes as well as double-contour formation (picture 1) [8]. Dense periodic acid-Schiff (PAS)-positive and silver-negative deposits along the glomerular basement membranes are also present. Light microscopy in patients with C4GN may also reveal a mesangial proliferative glomerulonephritis (GN), but without endocapillary proliferation or double-contour formation.

Immunofluorescence of the kidney biopsy demonstrates bright staining for C4d, which is a breakdown product of C4 (picture 1). By contrast, staining is negative for other complement components (C3 and C1q) and for immunoglobulins (immunoglobulin G [IgG], immunoglobulin M [IgM], and immunoglobulin A [IgA]).

With C4 DDD, electron microscopy shows distinctive findings of dense osmiophilic deposits lining the glomerular basement membranes (picture 1). In C4GN, electron dense deposits are seen primarily in the mesangium; few intramembranous and subendothelial electron dense deposits may also be seen. Although it is not a routinely performed procedure, laser microdissection of the glomeruli followed by mass spectrometry studies can confirm that such deposits consist of C4d [7,8].

Unlike patients with C3 glomerulopathies (C3 glomerulonephritis [C3GN] or dense deposit disease [DDD]), those with C4 glomerulopathy should not have congenital or acquired defects in the alternative pathway of complement. In the patient mentioned above, for example, special diagnostic assays for C3 nephritic factor, complement factor H, and other factors associated with alternative pathway dysregulation were all negative [7]. However, patients with C4 glomerulopathy may have an overactive lectin pathway of complement.

Adult patients diagnosed with C4 glomerulopathy should have a serum protein electrophoresis (SPEP), immunofixation, and measurement of serum-free light chains because a paraprotein may be responsible for the abnormal complement activation. In the limited number of patients with C4 glomerulopathy studied so far, serum levels of the soluble membrane attack complex (sMAC) have been in the normal range.

Differential diagnosis — The differential diagnosis of GN is broad, and many diseases can present with both proteinuria and a nephritic sediment. (See "Glomerular disease: Evaluation and differential diagnosis in adults".)

There are no clinical features that distinguish C4 glomerulopathy from other causes of GN such as IgA nephropathy or C3 glomerulopathy. However, C4 glomerulopathy has unique kidney biopsy findings and therefore will be identified in a patient with glomerular disease who undergoes biopsy.

TREATMENT — The optimal treatment of patients with C4 glomerulopathy is unclear. Angiotensin-converting enzyme (ACE) inhibitors have been used in known cases, with improvement in blood pressure, although proteinuria continued to progress.

Data supporting the use of immunosuppressive therapy are lacking. However, a trial of immunosuppression (eg, glucocorticoids and mycophenolate, or another combination) may be appropriate in patients with C4 glomerulopathy who present with proteinuria >1 g/day and/or an active urinary sediment, and whose biopsy demonstrates proliferative glomerulonephritis (GN) or crescentic GN.

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

●Overview – Complement-mediated glomerulonephritis (GN) characterized by deposition of C4 in the absence of C3, C1q, and immunoglobulin is referred to as C4 glomerulopathy (C4 dense deposit disease [C4 DDD] if there are dense C4 deposits along the glomerular basement membrane documented by electron microscopy, or C4 glomerulonephritis [C4GN] if there are C4 deposits primarily in the mesangium with or without a few capillary wall deposits). C4 glomerulopathy, which is a rare condition, is distinct from C3 glomerulopathy, and therefore complement-mediated GN can be subdivided into C3 glomerulopathy (C3 glomerulonephritis [C3GN] and dense deposit disease [DDD]) and C4 glomerulopathy (C4GN and C4 DDD) (figure 1). (See 'Introduction' above.)

●Clinical manifestations – Clinical manifestations of C4 glomerulopathy appear to overlap with other causes of GN, and they include proteinuria, hematuria, hypertension, a slowly progressive decline in glomerular filtration rate, and a normal or slightly low C4 with a normal C3. (See 'Clinical manifestations' above.)

●Diagnosis – The diagnosis of C4 DDD or C4GN is made by kidney biopsy. Light microscopy shows a membranoproliferative pattern of injury with mesangial hypercellularity; patients with C4 DDD also have endocapillary proliferation and thickened glomerular basement membranes as well as double-contour formation (picture 1). Immunofluorescence demonstrates bright staining for C4d (picture 1) and negative staining for other complement components and immunoglobulins. With C4 DDD, electron microscopy shows distinctive findings of dense osmiophilic deposits lining the glomerular basement membranes (picture 1). (See 'Diagnosis' above.)

●Treatment – We treat patients who have C4 glomerulopathy with angiotensin-converting enzyme (ACE) inhibitors or an angiotensin II receptor blocker if they have hypertension or proteinuria and with immunosuppressive therapy if their biopsy reveals a proliferative GN or crescentic GN. (See 'Treatment' above.)