Causes of alternative pathway dysregulation in dense deposit disease

Yuzhou Zhang, Nicole C. Meyer, Kai Wang, Carla Nishimura, Kathy Frees, Michael Jones, Louis M. Katz, Sanjeev Sethi, Richard J.H. Smith

Research output: Contribution to journalArticlepeer-review

138 Scopus citations


Background and objectives This study was designed to investigate the causes of alternative pathway dysregulation in a cohort of patients with dense deposit disease (DDD). Design, setting, participants, & measurements Thirty-two patients with biopsy-proven DDD underwent screening for C3 nephritic factors (C3Nefs), factor H autoantibodies (FHAAs), factor B autoantibodies (FBAAs), and geneticvariants in CFH.C3Nefs were detected by: ELISA,C3 convertase surface assay (C3CSA), C3CSA with properdin (C3CSAP), two-dimensional immunoelectrophoresis (2DIEP), and immunofixation electrophoresis (IFE). FHAAs and FBAAs were detected by ELISA, and CFH variants were identified by Sanger sequencing. Results Twenty-fivepatients(78%) were positivefor C3Nefs. Three C3Nef-positivepatientswerealso positive for FBAAs and one of these patients additionally carried two novel missense variants in CFH. Of the seven C3Nef-negativepatients, one patient was positiveforFHAAs andtwopatientscarriedCFH variants that maybecausally related to their DDD phenotype. C3CASP was the most sensitive C3Nef-detection assay. C3CASP and IFE are complementary because C3CSAP measures the stabilizing properties of C3Nefs, whereas IFE measures their expected consequence-breakdown of C3b. Conclusions A test panel that includes C3CSAP, IFE, FHAAs, FBAAs, and genetic testing for CFH variants will identify a probable cause for alternative pathway dysregulation in approximately 90% of DDD patients. Dys-regulation is most frequently due to C3Nefs, although some patients test positive for FHAAs, FBAAs, and CFH mutations. Defining the pathophysiology of DDD should facilitate the development of mechanism-directed therapies.

Original languageEnglish (US)
Pages (from-to)265-274
Number of pages10
JournalClinical Journal of the American Society of Nephrology
Issue number2
StatePublished - Feb 1 2012

ASJC Scopus subject areas

  • Epidemiology
  • Critical Care and Intensive Care Medicine
  • Nephrology
  • Transplantation


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