MPGN II/DDD Information for Physicians

Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II: Highlights

Available data on DDD/MPGNII support the following:

DDD/MPGNII 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, DDD/MPGNII is not characterized by immune complex localization in glomeruli. For this reason, it is more correctly known as Dense Deposit Disease.

The diagnosis of DDD/MPGNII requires renal biopsy, which by electron microscopy shows osmophilic dense deposits in the glomerular basement membrane. C3, but not IgG, is demonstrable by immunofluorescence staining. Features of partial lipodystrophy and the development of ocular drusen can accompany DDD/MPGNII. Drusen may lead to decreased visual acuity in approximately 10% of patients with DDD/MPGNII, and a baseline ophthalmologic evaluation with periodic follow-up is recommended. In view of the fundus similarities between individuals with various forms of glomerulonephritis and age-related macular degeneration, it is conceivable that these disorders may share a common, or related, etiology.

The pathophysiologic basis for DDD/MPGNII appears to be the uncontrolled systemic activation of the alternative pathway of the complement cascade. There are different triggers that result in complement system dysfunction, including mutations in factor H, antibodies directed against factor H, and an autoantibody directed against the convertase of the alternative pathway, C3bBb, called C3 Nephritic Factor (C3NeF) that is present in most persons with DDD/MPGNII.

All C3NeFs are not identical. It is possible that C3NeF is normally present in many healthy persons. The trigger(s) that leads to increased and pathologic levels of C3NeF is(are) not known.

Most treatments for DDD/MPGNII are ineffective. Treatments to remove or suppress C3NeF activity 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. Consistent with this observation is the recurrence of disease in allografts with the long-term outcome being graft failure in up to half of transplants. In patients with factor H mutations, however, plasma exchange can control complement activation and prevent end stage renal disease. Although only a few patients will have factor H mutations, genetic screening of factor H should be offered to all patients with DDD/MPGNII.

Whether local control of the complement cascade in the kidney can prevent end stage renal disease in the face of ongoing systemic activation of the alternative pathway of the complement cascade is not known. If so, it may be possible to target therapy to the kidney. One example might be the use of heparinoids to protect the glomerular basement membrane from complement activation. Another example would be the development of therapies specifically directed at controlling the AP of the complement system. Studies focused of these modalities would appear to be among the best avenues to pursue to develop an effective treatment for DDD/MPGNII.

For an in depth review of DDD/MPGNII please see

Appel et al. Membranoproliferative Glomerulonephritis Type II (Dense Deposit Disease): An Update. J Am Nephrol Soc 16: 1392-1403, 2005.

Zipfel PF, Smith RJH, Heinen S. The role of complement in membranoproliferative glomerulonephritis. In Zipfel PF, ed. Complement and Kidney Disease. Birkhauser Verlag Basel, Switzerland, 2006.

Smith RJ, Sethi S, Zipfel PF. Dense Deposit/ DiseaseMembranoproliferative Glomerulonephritis Type II In: /GeneReviews /at GeneTests: Medical Genetics Information Resource [database online]. Copyright, University of Washington, Seattle. At www.genetests.org <http://www.geneclinics.org/> 2007.



		Visit the MPGN DATABASE

DEDICATED TO THE STUDY OF DENSE DEPOSIT DISEASE

For patients and families Research Fundraising FAQ Home	Physicians

	Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II: Highlights Available data on DDD/MPGNII support the following: DDD/MPGNII 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, DDD/MPGNII is not characterized by immune complex localization in glomeruli. For this reason, it is more correctly known as Dense Deposit Disease. The diagnosis of DDD/MPGNII requires renal biopsy, which by electron microscopy shows osmophilic dense deposits in the glomerular basement membrane. C3, but not IgG, is demonstrable by immunofluorescence staining. Features of partial lipodystrophy and the development of ocular drusen can accompany DDD/MPGNII. Drusen may lead to decreased visual acuity in approximately 10% of patients with DDD/MPGNII, and a baseline ophthalmologic evaluation with periodic follow-up is recommended. In view of the fundus similarities between individuals with various forms of glomerulonephritis and age-related macular degeneration, it is conceivable that these disorders may share a common, or related, etiology. The pathophysiologic basis for DDD/MPGNII appears to be the uncontrolled systemic activation of the alternative pathway of the complement cascade. There are different triggers that result in complement system dysfunction, including mutations in factor H, antibodies directed against factor H, and an autoantibody directed against the convertase of the alternative pathway, C3bBb, called C3 Nephritic Factor (C3NeF) that is present in most persons with DDD/MPGNII. All C3NeFs are not identical. It is possible that C3NeF is normally present in many healthy persons. The trigger(s) that leads to increased and pathologic levels of C3NeF is(are) not known. Most treatments for DDD/MPGNII are ineffective. Treatments to remove or suppress C3NeF activity 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. Consistent with this observation is the recurrence of disease in allografts with the long-term outcome being graft failure in up to half of transplants. In patients with factor H mutations, however, plasma exchange can control complement activation and prevent end stage renal disease. Although only a few patients will have factor H mutations, genetic screening of factor H should be offered to all patients with DDD/MPGNII. Whether local control of the complement cascade in the kidney can prevent end stage renal disease in the face of ongoing systemic activation of the alternative pathway of the complement cascade is not known. If so, it may be possible to target therapy to the kidney. One example might be the use of heparinoids to protect the glomerular basement membrane from complement activation. Another example would be the development of therapies specifically directed at controlling the AP of the complement system. Studies focused of these modalities would appear to be among the best avenues to pursue to develop an effective treatment for DDD/MPGNII. For an in depth review of DDD/MPGNII please see Appel et al. Membranoproliferative Glomerulonephritis Type II (Dense Deposit Disease): An Update. J Am Nephrol Soc 16: 1392-1403, 2005. Zipfel PF, Smith RJH, Heinen S. The role of complement in membranoproliferative glomerulonephritis. In Zipfel PF, ed. Complement and Kidney Disease. Birkhauser Verlag Basel, Switzerland, 2006. Smith RJ, Sethi S, Zipfel PF. Dense Deposit/ DiseaseMembranoproliferative Glomerulonephritis Type II In: /GeneReviews /at GeneTests: Medical Genetics Information Resource [database online]. Copyright, University of Washington, Seattle. At www.genetests.org <http://www.geneclinics.org/> 2007.		Factor H Genetic Testing Genetic testing for factor H is offered through the MORL. Information Sheet Clinical Data Sheet
Contact us			Useful References On-line renal pathology CME courses including MPGNII/DDD at: www.gamewood.net http://path.upmc.edu The National Organization for Rare Disorders entry on MPGNII/DDD at: www.rarediseases.org An E-Medicine information page on MPGN for Physicians at: www.emedicine.com