New Approaches to the Treatment of Dense Deposit Disease

Smith, Richard J.; Alexander, Jessy J.; Barlow, Paul N.; Botto, Marina; Cassavant, Thomas L.; Cook, H. Terence; Accent]rdoba, Santiago Rodriguez de[Combining Acute; Hageman, Gregory S.; Jokiranta, T. Sakari; Kimberling, William J.; Lambris, John D.; Lanning, Lynne D.; Levidiotis, Vicki; Licht, Christoph; Lutz, Hans; Meri, Seppo; Pickering, Matthew C.; Quigg, Richard J.; Rops, Angelique L.; Salant, David J.; Sethi, Sanjeev; Thurman, Joshua M.; Tully, Hope F.; Tully, Sean P.; Vlag, Johan van der; Walker, Patrick D.; Diaeresis]rzner, Reinhard Wu[Combining; Zipfel, Peter F.

doi:10.1681/asn.2007030356

Cited by 233 publications

(209 citation statements)

References 64 publications

(70 reference statements)

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“…11 DDD has a high rate of recurrence after kidney transplantation and results in graft failure in up to 50% of patients, with graft loss occurring within 2.5 years of transplantation. 10,12,13 With regards to C3GN, we noted a recurrence rate of 66.7%, with graft failure in 50% of rC3GN. Thus, the rates of recurrence and graft failure are comparable with DDD.…”

Section: Discussionmentioning

confidence: 77%

“…DDD is similar to C3GN in that it results from dysfunction of the alternative pathway of complement. 9,10 It is distinguished from C3GN on electron microscopy. Electron microscopy shows sausage-shaped large osmiophilic dense deposits within the glomerular basement membranes, whereas in C3GN, the deposits tend to be mesangial and subendothelial.…”

Section: Discussionmentioning

confidence: 99%

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Clinical Findings, Pathology, and Outcomes of C3GN after Kidney Transplantation

Zand

Lorenz

Cosio

et al. 2014

Journal of the American Society of Nephrology

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139

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C3 glomerulonephritis (C3GN) results from abnormalities in the alternative pathway of complement, and it is characterized by deposition of C3 with absent or scant Ig deposition. In many patients, C3GN progresses to ESRD. The clinical features, pathology, and outcomes of patients with C3GN receiving kidney transplantation are unknown. Between 1996 and 2010, we identified 21 patients at our institution who received a kidney transplant because of ESRD from C3GN. The median age at the time of initial diagnosis of C3GN at kidney biopsy was 20.8 years. The median time from native kidney biopsy to dialysis or transplantation was 42.3 months. Of 21 patients, 14 (66.7%) patients developed recurrent C3GN in the allograft. The median time to recurrence of disease was 28 months. Graft failure occurred in 50% of patients with recurrent C3GN, with a median time of 77 months to graft failure post-transplantation. The remaining 50% of patients had functioning grafts, with a median follow-up of 73.9 months. The majority of patients had hematuria and proteinuria at time of recurrence. Three (21%) patients were positive for monoclonal gammopathy and had a faster rate of recurrence and graft loss. Kidney biopsy at the time of recurrence showed mesangial proliferative GN in eight patients and membranoproliferative GN in six patients. All allograft kidney biopsies showed bright C3 staining (2-3+), with six biopsies also showing trace/1+ staining for IgM and/or IgG. To summarize, C3GN recurs in 66.7% of patients, and one half of the patients experience graft failure caused by recurrence.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Clinical Findings, Pathology, and Outcomes of C3GN after Kidney Transplantation

Zand

Lorenz

Cosio

et al. 2014

Journal of the American Society of Nephrology

Self Cite

139

109

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“…However, as the anti-CFH autoantibody disappeared after dexamethasone therapy in patient 2, early chemotherapy aimed at controlling the underlying clonal disorder should be discussed with regard to preventing progression toward ESRD (12). Eculizumab therapy, which may improve renal symptoms in DDD (38), also represents an interesting alternative (39).…”

Section: Discussionmentioning

confidence: 99%

Glomerulonephritis With Isolated C3 Deposits and Monoclonal Gammopathy

Bridoux

Desport

Frémeaux‐Bacchi

et al. 2011

Clinical Journal of the American Society of Nephrology

102

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SummaryBackground and objectives Glomerular deposition of monoclonal Ig has been exceptionally described as the cause of membranoproliferative glomerulonephritis, through activation of the complement alternative pathway (CAP).Design, setting, participants, & measurements We retrospectively studied six adults with monoclonal gammopathy and glomerulonephritis (GN) characterized by isolated C3 deposits.Results All patients presented with hematuria, associated with chronic renal failure and proteinuria in five patients, three of whom had nephrotic syndrome. Five patients had monoclonal gammopathy of undetermined significance and one had smoldering myeloma. The serum monoclonal IgG ( four of six, two of six) was associated with light chain (LC) proteinuria in five patients. Four patients had low serum C3 and/or factor B levels. C4, factor H (CFH), and I protein levels were normal in five of five patients; none had detectable C3NeF. IgG anti-CFH activity was positive in one case. No mutations in CFH, CFI, and MCP genes were identified in four of four patients. Deposits were intramembranous, subepithelial, and mesangial by electron microscopy, and stained positive for C3 (six of six), properdin, and CFH (two of two) but negative for Ig LC and heavy chains, C4, and C1q (6/6) by immunofluorescence. Five patients progressed to end-stage renal disease over a median period of 47 months, despite chemotherapy in four patients. In one patient, monoclonal LC deposits were observed on a follow-up kidney biopsy after 4 years.Conclusions GN with isolated glomerular C3 deposits might represent an unusual complication of plasma cell dyscrasia, related to complement activation through an autoantibody activity of the monoclonal Ig against a CAP regulator protein.

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“…2 Electron microscopy distinguishes DDD from C3GN, with the former characterized by pathognomonic electron-dense transformation of the lamina densa of the glomerular basement membrane (GBM). 3 In C3GN, the electron microscopy deposits are lighter in color, and are more often mesangial and/or subendothelial, intramembranous, and subepithelial in location. 4 In both diseases, mass spectroscopy of laser dissected glomeruli is highly enriched for proteins of the AP and terminal complement cascade.…”

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confidence: 98%

Soluble CR1 Therapy Improves Complement Regulation in C3 Glomerulopathy

Zhang

Nester

Holanda

et al. 2013

Journal of the American Society of Nephrology

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Dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are widely recognized subtypes of C3 glomerulopathy. These ultra-rare renal diseases are characterized by fluid-phase dysregulation of the alternative complement pathway that leads to deposition of complement proteins in the renal glomerulus. Disease triggers are unknown and because targeted treatments are lacking, progress to end stage renal failure is a common final outcome. We studied soluble CR1, a potent regulator of complement activity, to test whether it restores complement regulation in C3 glomerulopathy. In vitro studies using sera from patients with DDD showed that soluble CR1 prevents dysregulation of the alternative pathway C3 convertase, even in the presence of C3 nephritic factors. In mice deficient in complement factor H and transgenic for human CR1, soluble CR1 therapy stopped alternative pathway activation, resulting in normalization of serum C3 levels and clearance of iC3b from glomerular basement membranes. Shortterm use of soluble CR1 in a pediatric patient with end stage renal failure demonstrated its safety and ability to normalize activity of the terminal complement pathway. Overall, these data indicate that soluble CR1 re-establishes regulation of the alternative complement pathway and provide support for a limited trial to evaluate soluble CR1 as a treatment for DDD and C3GN. Dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are two widely recognized subtypes of C3 glomerulopathy (C3G). 1,2 These ultra-rare renal diseases are caused by fluid-phase dysregulation of the C3 convertase of the alternative pathway (AP) of complement, with variable concomitant dysregulation of the C5 convertase. Consistent with complement-mediated disease acting through the AP, C3G is strongly positive for C3 and notably negative for Igs by immunofluorescence microscopy. 2 Electron microscopy distinguishes DDD from C3GN, with the former characterized by pathognomonic electron-dense transformation of the lamina densa of the glomerular basement membrane (GBM). 3 In C3GN, the electron microscopy deposits are lighter in color, and are more often mesangial and/or subendothelial, intramembranous, and subepithelial in location. 4 In both diseases, mass spectroscopy of laser dissected glomeruli is highly enriched for proteins of the AP and terminal complement cascade. 4,5

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New Approaches to the Treatment of Dense Deposit Disease

Cited by 233 publications

References 64 publications

Clinical Findings, Pathology, and Outcomes of C3GN after Kidney Transplantation

Clinical Findings, Pathology, and Outcomes of C3GN after Kidney Transplantation

Glomerulonephritis With Isolated C3 Deposits and Monoclonal Gammopathy

Soluble CR1 Therapy Improves Complement Regulation in C3 Glomerulopathy

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