In 1963, Berger and Galle (2
) described a type of glomerulonephritis with unique, extremely osmiophilic electron-dense deposits in the glomerular basement membranes (GBMs) as the major identifying characteristic (see Fig. 9.1
). Since that time, many additional reports of DDD have appeared (3
). Because DDD often has light microscopic features of a membranoproliferative glomerulonephritis (MPGN), it has also been referred to as MPGN type II. However, it is clear that many cases do not have an MPGN pattern on light microscopy, and therefore the name DDD is to be preferred. In some series, it has accounted for up to a third of cases of MPGN although the frequency compared to type I MPGN in most series is much lower. Appel et al. (19
) published an excellent review on DDD in 2005.
DDD has a prevalence of 2 to 3 per million population and is primarily a disease of children and young adults (11
). However, in a 2009 series from New York, 39% of the adult patients were over 60 years of age (16
). It affects males and females equally in many cohorts although some studies have shown a female predominance (15
). The clinical picture is not distinctive, and it is not possible to distinguish DDD from
immune complex MPGN type I on clinical grounds alone (5
TABLE 9.1 Pathologic classification of C3 glomerulopathy
Dense deposit disease (DDD) (formerly membranoproliferative GN type II)
Membranoproliferative GN pattern (type II)
Mesangioproliferative or proliferative GN pattern
C3 glomerulonephritis (C3GN)
Membranoproliferative GN pattern (types I and III)a
Mesangioproliferative or proliferative GN pattern
a Note that membranoproliferative GN types I and III may be either the result of a C3 glomerulopathy or an immune complex-mediated glomerulonephritis (see Chapter 8).
At presentation, almost all patients have proteinuria (6
) usually with hematuria (16
). Nephrotic-range proteinuria is present in two thirds of the patients (15
), and full nephrotic syndrome in 12% to 65% in different series (5
). In a large series of 98 patients from North America (18
), the commonest symptoms leading to health care referral were hematuria (42.9%) and peripheral (37.8%) and facial (31.6%) edema. About one fifth of these patients (21.4%) did not suspect a problem, and in this group, signs of kidney disease were detected as part of a routine annual examination. A number of patients have initial signs and symptoms of acute nephritic syndrome; this presentation is found in 16% (21
) to 38% (7
) of patients. There may be episodes of acute nephritis (gross hematuria, edema, hypertension) or renal insufficiency that are reversible and show complete clinical subsidence (7
). Renal insufficiency is common at presentation (6
) and is more common in adults (16
). Hypertension is commonly found either at clinical onset or during the course of the disease (18
FIGURE 9.1 Diagram depicting one normal glomerular capillary (A) and a diagram (B) and electron micrograph (C) of a glomerular capillary with DDD with extensive dense deposits within the GBM as well as dense deposits in the mesangial matrix. (Green, podocyte; dark gray, GBM; yellow, endothelial cell; red, mesangial cell; light gray, mesangial matrix.)
The clinical onset of DDD is preceded by acute infection, often an upper respiratory tract infection, in approximately one half of the patients (5
). Elevated antistreptolysin O (ASO) titers were noted in 21% to 45% of patients with infective episodes (5
); therefore, some were perhaps related to group A streptococcal infection.
Persistently, low serum levels of C3 are found in most patients (approximately 80%) (6
), whereas fluctuating levels are found in others. In the series reported by Nasr et al. (16
), the entire pediatric group had low C3 levels but significantly fewer of the adults (41%). In contrast to MPGN type I, serum levels of the early components of the classic pathway (C1q and C4) are usually normal. These complement profiles suggest that the complement is activated in DDD primarily through the alternative pathway, whereas MPGN type I arises through the classic and alternative pathways. Most patients with DDD are positive for serum C3 nephritic factor (C3NeF), an autoantibody directed against C3bBb, the convertase of the alternative pathway of complement activation. In more than 50% of patients, serum C3NeF persists throughout the clinical course (23
). However, C3NeF is not a specific serologic marker because it also occurs with MPGN type I, lupus nephritis, and poststreptococcal glomerulonephritis, although less frequently. Its role is discussed further in the section dealing with pathogenesis.
Patients with DDD may also develop ocular drusen (24
). These are lipoproteinaceous deposits of complement-containing debris within the Bruch membrane beneath the retinal pigment epithelium. This pathology is similar to age-related macular degeneration (AMD), but in contrast to AMD, drusen in DDD occur at an early age and may be found in the second decade of life. The long-term risk for visual problems is 10%. There is no correlation between the severity of the disease in the kidney and that in the eye.
A small minority of patients with DDD have acquired partial lipodystrophy (APL), a condition with symmetrical loss of adipose tissue from the face, arms, and upper portions of the trunk (27
). APL is often accompanied by low levels of serum C3, normal serum levels of the early components of the complement, and the presence of C3NeF in the serum (27
). Misra et al. (27
) reported that approximately 83% of APL patients have low C3 levels and polyclonal C3NeF and that approximately 20% go on to develop MPGN.
Recently, an intriguing familial association has been shown between DDD and type 1 diabetes mellitus. In a series of 98 patients from North America, 16% reported at least one family member with type 1 diabetes, which is far greater than expected on the basis of the prevalence of type 1 diabetes in the general population (18
). The significance of this observation remains to be determined.