Dense deposit disease

Abstract

Dense deposit disease (DDD) is an orphan disease that primarily affects children and young adults without sexual predilection. Studies of its pathophysiology have shown conclusively that it is caused by fluid-phase dysregulation of the alternative pathway of complement, however the role played by genetics and autoantibodies like C3 nephritic factors must be more thoroughly defined if we are to make an impact in the clinical management of this disease. There are currently no mechanism-directed therapies to offer affected patients, half of whom progress to end stage renal failure disease within 10 years of diagnosis. Transplant recipients face the dim prospect of disease recurrence in their allografts, half of which ultimately fail. More detailed genetic and complement studies of DDD patients may make it possible to identify protective factors prognostic for naïve kidney and transplant survival, or conversely risk factors associated with progression to renal failure and allograft loss. The pathophysiology of DDD suggests that a number of different treatments warrant consideration. As advances are made in these areas, there will be a need to increase healthcare provider awareness of DDD by making resources available to clinicians to optimize care for DDD patients.

Figure 1

A. Schematic showing cleavage of C3 by C3 convertase (C3bBb) to generate C3b. The generation of C3b is controlled by tight regulation of C3 convertase activity by a number of different proteins. In the fluid phase, the most important controlling protein is CFH (Factor H). C3b can be inactivated (iC3b) by CFI (Factor I). B. DDD is caused by fluid-phase dysregulation of the C3 convertase. The dysregulation can be caused by a number of different mechanisms. Illustrated are: C3 nephritic factors, which bind to and stabilize the C3 convertase, increasing its half-life from a few seconds to minutes or hours; CFH autoantibodies, which bind to the N-terminal SCRs of this protein and prevent CFH-mediated fluid-phase regulation of C3 convertase; gain-of-function mutations in C3, which render the mutant C3 convertase resistant to normal regulatory mechanisms; and genetic deficiency of CFH, which results in deficiency of CFH and C3 convertase control. The functional consequence of these different pathologies is consumption of plasma C3 and generation of vast amounts of C3 breakdown products, which are deposited in the GBMs and appear as the dense deposits. This observation suggests that therapies to prevent C3 convertase activity or to sequester iC3b in plasma should be evaluated as treatment possibilities for DDD.