New approaches to the treatment of dense deposit disease

Abstract

The development of clinical treatment protocols usually relies on evidence-based guidelines that focus on randomized, controlled trials. For rare renal diseases, such stringent requirements can represent a significant challenge. Dense deposit disease (DDD; also known as membranoproliferative glomerulonephritis type II) is a prototypical rare disease. It affects only two to three people per million and leads to renal failure within 10 yr in 50% of affected children. On the basis of pathophysiology, this article presents a diagnostic and treatment algorithm for patients with DDD. Diagnostic tests should assess the alternative pathway of complement for abnormalities. Treatment options include aggressive BP control and reduction of proteinuria, and on the basis of pathophysiology, animal data, and human studies, plasma infusion or exchange, rituximab, sulodexide, and eculizumab are additional options. Criteria for treatment success should be prevention of progression as determined by maintenance or improvement in renal function. A secondary criterion should be normalization of activity levels of the alternative complement pathway as measured by C3/C3d ratios and C3NeF levels. Outcomes should be reported to a central repository that is now accessible to all clinicians. As the understanding of DDD increases, novel therapies should be integrated into existing protocols for DDD and evaluated using an open-label Bayesian study design.

Figure 1

Histopathology of dense deposit disease (DDD). (A) The classic light microscopic appearance showing a membranoproliferative pattern (seen in approximately 25% of patients; periodic acid-Schiff stain). (B) C3 in loops and mesangial areas. The prominent granular deposits in the mesangium result in rings of immunofluorescence that are characteristic of DDD (fluorescein-conjugated anti-C3 antibody stain). (C) Electron photomicrograph showing highly electron-dense transformation of the glomerular basement membranes diagnostic of DDD (unstained). Magnifications: ×400 in A and B; ×5000 in C.

Figure 2

Age at diagnosis versus outcome (stable or ESRD). Patients who are ≤10 yr of age are more likely to progress to ESRD than are older patients (P = 0.006). Progression to ESRD typically occurs within 4 yr of diagnosis.

Figure 3

The alternative pathway is constitutively active at low levels through the hydrolysis of the thioester in C3 to C3(H2O). Hydrolyzed C3 combines with factor B, and in the presence of factor D, C3(H2O)Bb is formed. This intermediate convertase leads to the production of C3a and C3b from C3, and C3b enters the C3bBb amplification loop. Amplification on soluble C3bBb occurs with low efficiency because free C3b is rapidly inactivated by factors H and I. However, if C3b binds covalently to surfaces or as a covalent dimer to fluid-phase IgG, then it is partially protected from inactivation. In its dimeric form (C3bC3bIgG), it is seven to 10 times more efficient in generating a C3 convertase than surface-bound monomeric C3b. The very same enzyme on surfaces or on IgG in the fluid phase becomes a C5 convertase by acquiring an additional C3b in its vicinity, which increases the affinity of the enzyme for C5. Here we show in red just one of the possible amplification routes, which seems to be the most relevant in DDD (see text). In the absence of factor H to control levels of C3b in the fluid phase, the Cfh^−/− mouse mutant develops DDD. Because factor B is critical to the formation of C3bBb, its absence in the Cfh^−/−.Cfb^−/− mutant rescues the disease phenotype and DDD does not develop. In the Cfh^−/−.C5^−/− mutant and the Cfh^−/− mutant treated with anti-C5 antibodies, the degree of kidney disease is decreased compared with the degree of kidney disease seen in the Cfh^−/− mutant.

Figure 4

Flow diagram illustrating the diagnostic evaluation and treatment of a patient with DDD. The diagnosis is made by renal biopsy. Serologic tests of complement should be obtained, C3NeF should be assayed, and CFH should be screened for mutations. In the presence of C3NeF, removal or dilution of the autoantibody should be considered via plasma exchange or infusion, and anti–B cell agents such as rituximab might be valuable. In the presence of pathologic mutations in CFH that lead to absent or dysfunctional factor H protein, plasma infusion should be considered (with the use of recombinant factor H in the future). In addition, nonspecific treatment should be aimed at controlling BP and proteinuria. Other treatments that should be considered include eculizumab (an anti-C5 antibody [see Figure 3]) and sulodexide (a heparanase inhibitor [see Figure 5]). The criterion for treatment success should be prevention of disease progression as determined by maintenance of or prevention of decrease in renal function. The secondary criterion should be normalization of activity levels of the alternative complement pathway as measured by C3/C3d ratios and C3NeF levels. After having reached a clinical steady state, reasonable follow-up steps could be monthly for the first 3 to 6 mo, every 2 mo for the rest of the first year, and subsequently every 6 mo, adjusting clinical monitoring if a flare in disease activity occurs.

Figure 5

In DDD, glomerular basement membrane staining of heparan sulfate is decreased and heparanase expression is enhanced. Staining for the agrin core protein remains unchanged. Tubular expression of heparanase is high in both DDD and controls.