Dense Deposit Disease Highlights
Available data on DDD support the following:
DDD is a rare disease primarily diagnosed in children between 5-15 years of age. The disease is equally represented among sexes. Within 10 years of diagnosis, end-stage renal disease develops in about 50% of these children. In contrast to other forms of MPGN, immune complexes are NOT found in glomeruli in DDD. For this reason, the disease is more correctly known as Dense Deposit Disease (DDD) as opposed to MPGNII. It has recently been placed under the umbrella term C3 Dominant Glomerulopathy. This term includes both DDD and C3 glomerulonephritis (C3GN).
The diagnosis of DDD requires renal biopsy, which by electron microscopy must show osmophilic dense deposits in the glomerular basement membrane. C3 must be demonstrable by immunofluorescence staining. Features of partial lipodystrophy and the development of ocular drusen can accompany DDD. Drusen may lead to decreased visual acuity in approximately 10% of patients with DDD and so all DDD patients should have a baseline ophthalmologic evaluation with periodic follow-up.
The pathophysiologic basis for DDD is uncontrolled systemic activation of the alternative pathway of the complement cascade. There are different triggers that result in alternative pathway dysfunction including mutations in factor H, antibodies directed against factor H, and autoantibodies directed against the convertase of the alternative pathway, C3bBb, known as C3 nephritic factors (C3Nefs).
C3Nefs are NOT identical. The triggers that lead to the appearance of C3Nefs are not known. There are several different assays that test for C3Nefs. Different assays have different sensitivity.
Most treatments for DDD are ineffective. Treatments to remove or suppress C3Nefs include plasmapheresis, IVIg and B cell suppression. The first has met with limited success; there is little experience with IVIg and B cell suppression. T-cell suppressants are not effective. There is an on-going trial looking at soluble CR1 in DDD. The trial will enroll five patients. For information on the trial visit ClinicalTrials.gov
About 30% of patients with DDD may respond to Eculizumab. Response can be predicted by assaying levels of soluble C5b-9 (sMAC) in the serum. This testing should be ordered if you are considering Eculizumab.
For relevant articles please see:
Appel GB, Cook HT, Hageman G, Jennette JC, Kashgarian M, Kirschfink M, Lambris JD, Lanning L, Lutz HU, Meri S, Rose NR, Salant DJ, Sethi S, Smith RJH, Smoyer W, Tully HF, Tully SP, Walker P, Welsh M, Wurzner R, Zipfel PF. Membranoproliferative Glomerulonephritis Type II (Dense Deposit Disease): An Update. J Am Nephrol Soc 16: 1392-1403, 2005.
Lu DF, Moon M, Lanning LD, McCarthy AM, Smith RJH. Clinical features and outcomes of 98 children and adults with Dense Deposit Disease. Pediatr Nephrol 2011 Nov 22 [Epub ahead of print]; 27(5):773-81, 2012.
Smith RJH, Harris CL, Pickering MC. Dense deposit disease. Mole Immunol 2011 May 21 [Epub ahead of print]; 48(14):1604-10, 2011. PMID: 21601923.
Zhang Y, Meyer NC, Wang K, Nishimura C, Frees K, Jones M, Katz LM, Sethi S, Smith RJH. Causes of alternative pathway dysregulation in Dense Deposit Disease. Clin J Am Soc Nephrol 2012 Jan 5 [Epub ahead of print]; 7:265-74, 2012.