Toward a working definition of C3 glomerulopathy by immunofluorescence

Hou, Jean; Markowitz, Glen S.; Bomback, Andrew S.; Appel, Gerald B.; Herlitz, Leal; Stokes, Michael B.; D’Agati, Vivette D.

doi:10.1038/ki.2013.340

Cited by 163 publications

(173 citation statements)

References 23 publications

(24 reference statements)

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“…To our knowledge, the effect of eculizumab on leukocyturia in DDD GN has previously not been described. Although leukocyturia is not commonly reported as a presenting symptom in DDD (8,9,28), it was a consistent finding in all patients with urinary leukocyte counts available. In the absence of other causes of leukocyturia, the fact that leukocyturia disappeared almost completely and within 1 week after the first dose in all episodes of GN with leukocyturia strongly indicates a direct effect of eculizumab.…”

Section: Discussionmentioning

confidence: 85%

Eculizumab in Pediatric Dense Deposit Disease

Oosterveld¹,

Garrelfs²,

Höppe

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Dense deposit disease (DDD), a subtype of C3 glomerulopathy, is a rare disease affecting mostly children. Treatment options are limited. Debate exists whether eculizumab, a monoclonal antibody against complement factor C5, is effective in DDD. Reported data are scarce, especially in children.Design, setting, participants, & measurements The authors analyzed clinical and histologic data of five pediatric patients with a native kidney biopsy diagnosis of DDD. Patients received eculizumab as therapy of last resort for severe nephritic or nephrotic syndrome with alternative pathway complement activation; this therapy was given only when the patients had not or only marginally responded to immunosuppressive therapy. Outcome measures were kidney function, proteinuria, and urine analysis.Results In all, seven disease episodes were treated with eculizumab (six episodes of severe nephritic syndrome [two of which required dialysis] and one nephrotic syndrome episode). Median age at treatment start was 8.4 (range, 5.9-13) years. For three treatment episodes, eculizumab was the sole immunosuppressive treatment. In all patients, both proteinuria and renal function improved significantly within 12 weeks of treatment (median urinary protein-to-creatinine ratio of 8.5 [range, 2.2-17] versus 1.1 [range, 0.2-2.0] g/g, P,0.005, and eGFR of 58 [range, 17-114] versus 77 [range, 50-129] ml/min per 1.73 m 2 , P,0.01). A striking finding was the disappearance of leukocyturia within 1 week after the first eculizumab dose in all five episodes with leukocyturia at treatment initiation.Conclusions In this case series of pediatric patients with DDD, eculizumab treatment was associated with reduction in proteinuria and increase in eGFR. Leukocyturia resolved within 1 week of initiation of eculizumab treatment. These results underscore the need for a randomized trial of eculizumab in DDD.

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Section: Discussionmentioning

confidence: 85%

Eculizumab in Pediatric Dense Deposit Disease

Oosterveld¹,

Garrelfs²,

Höppe

et al. 2015

Clinical Journal of the American Society of Nephrology

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“…2 Although the original concept was based on the presence of isolated C3 it is clear that, in practice, this is too stringent a definition and that, if cases where the underlying pathology is alternative pathway activation are not to be missed, a wider net is needed. This was clearly shown by a study from Hou et al 3 They looked at cases of dense deposit disease in which it is generally accepted that the glomerular changes result from abnormal control of the alternative pathway of complement. They found that if they used a stringent criterion of only C3 with no immunoglobulins then 50% of cases diagnosed as dense deposit disease on electron microscopy would not be classified as C3 glomerulopathy.…”

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confidence: 98%

C4d Staining in the Diagnosis of C3 Glomerulopathy

Cook

2015

Journal of the American Society of Nephrology

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ally regulates an early-response gene containing homology to platelet proteins. Nature 315: 672-676, 1985 15. Farber JM: A macrophage mRNA selectively induced by gammainterferon encodes a member of the platelet factor 4 family of cytokines. Proc Natl Acad Sci U S A 87: 5238-5242, 1990 16. Kawai T, Takeuchi O, Fujita T, Inoue J, Mühlradt PF, Sato S, Hoshino K, Akira S: Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes.

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“…However, a proportion of C3 glomerulopathy biopsies may show small amounts of Igs on immunofluorescence. 9,10 As a result, the definition of C3 glomerulopathy now states that C3 staining should be dominant and at least 2 orders of magnitude more intense than any other immune reactants. 8 This can lead to interobserver variability.…”

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confidence: 99%

C4d as a Diagnostic Tool in Proliferative GN

Sethi¹,

Nasr²,

Vriese

et al. 2015

Journal of the American Society of Nephrology

110

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Proliferative GN is classified as immune complex-mediated or complement-mediated (C3 glomerulopathy). Immune complex-mediated GN results from glomerular deposition of immune-complexes/Ig and C3; the C3 is derived from activation of the classical and/or lectin pathways of complement. C3 glomerulopathy results from deposition of C3 and other complement fragments with minimal or no deposition of immune complexes/ Ig; the C3 is derived from activation of the alternative pathway of complement. C4d is a byproduct of activation of the classic and lectin pathways. Although widely used as a marker for antibody-mediated rejection, the significance of C4d in C3 glomerulopathy is undetermined. We studied glomerular C4d staining in 18 biopsy specimens of immune-complex GN, 30 biopsy specimens of C3 GN, and 13 biopsy specimens of postinfectious GN. All specimens of immune complex-mediated GN, except two specimens of IgA nephropathy and one specimen of sclerosing membranoproliferative GN, showed bright (2-3+) C4d staining. The staining pattern of C4d mirrored the staining patterns of Ig and C3. Conversely, C4d staining was completely negative in 24 (80%) of 30 specimens of C3 glomerulopathy, and only trace/1+ C4d staining was detected in six (20%) specimens. With regard to postinfectious GN, C4d staining was negative in six (46%) of 13 specimens, suggesting an abnormality in the alternative pathway, and it was positive in seven (54%) specimens. To summarize, C4d serves as a positive marker for immune complex-mediated GN but is absent or minimally detected in C3 glomerulopathy. On the other hand, complement-mediated GN, also termed C3 glomerulopathy, is caused by glomerular deposition of complement factors resulting from dysregulation of the alternative pathway (AP) of complement. 4-7 C3 glomerulopathy includes C3 GN and dense deposit disease (DDD). 8 Immunofluorescence is the key to the Mayo classification. Immune complex-mediated GN shows Ig on immunofluorescence, often along with C3, the latter because of activation of the CP by the immune complexes or LP by microbial surfaces. On the other hand, there is bright staining for C3, and Igs are typically negative in complement-mediated GN/C3 glomerulopathy. However, a proportion of C3 glomerulopathy biopsies may show small amounts of Igs on immunofluorescence. 9,10 As a result, the definition of C3 glomerulopathy now states that C3 staining should be dominant and at least 2 orders of

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Toward a working definition of C3 glomerulopathy by immunofluorescence

Cited by 163 publications

References 23 publications

Eculizumab in Pediatric Dense Deposit Disease

Eculizumab in Pediatric Dense Deposit Disease

C4d Staining in the Diagnosis of C3 Glomerulopathy

C4d as a Diagnostic Tool in Proliferative GN

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