Generic selectors
Exact matches only
Search in title
Search in content
Post Type Selectors
Search in posts
Search in pages
Filter by Categories
Author Reply
Book Review
Brief Communication
Case Report
Case Series
Clinical Case Report
Clinicopathological Conference
Commentary
Corrigendum
Current Issue
Editorial
Editorial – World Kidney Day 2016
Editorial Commentary
Erratum
Foreward
Guideline
Guidelines
Image in Nephrology
Images in Nephrology
In-depth Review
Letter to Editor
Letter to the Editor
Letters to Editor
Literature Review
Notice of Retraction
Obituary
Original Article
Perspective
Research Letter
Retraction Notice
Review
Review Article
Short Review
Special Article
Special Feature
Special Feature - World Kidney Day
Systematic Review
Technical Note
Varia
Generic selectors
Exact matches only
Search in title
Search in content
Post Type Selectors
Search in posts
Search in pages
Filter by Categories
Author Reply
Book Review
Brief Communication
Case Report
Case Series
Clinical Case Report
Clinicopathological Conference
Commentary
Corrigendum
Current Issue
Editorial
Editorial – World Kidney Day 2016
Editorial Commentary
Erratum
Foreward
Guideline
Guidelines
Image in Nephrology
Images in Nephrology
In-depth Review
Letter to Editor
Letter to the Editor
Letters to Editor
Literature Review
Notice of Retraction
Obituary
Original Article
Perspective
Research Letter
Retraction Notice
Review
Review Article
Short Review
Special Article
Special Feature
Special Feature - World Kidney Day
Systematic Review
Technical Note
Varia
View/Download PDF

Translate this page into:

Commentary
31 (
2
); 93-94
doi:
10.4103/ijn.IJN_224_20

C4d in Proliferative Glomerulonephritis

Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
Address for correspondence: Dr. Geetika Singh, Department of Pathology, All India Institute of Medical Sciences, New Delhi, India. E-mail: drsingh.geetika@gmail.com

Read COMMENTARY-ARTICLE associated with this -

Licence

This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

Disclaimer:
This article was originally published by Wolters Kluwer - Medknow and was migrated to Scientific Scholar after the change of Publisher.

There was a time when “diffuse proliferative and exudative pattern of glomerular injury” was considered synonymous with post infectious glomerulonephritis (PIGN). However, in recent years as we better understand underlying pathophysiology, it is clear that not all diffuse proliferative and exudative glomerulonephritis behave like the classical PIGN. It is a common discussion point between the renal pathologist and nephrologist whenever such glomerular injury pattern is noted, with the question being “Is this PIGN?” to which the most likely answer is— If the patient gets better, it is.

The diffuse proliferative and exudative pattern of glomerular injury is the response of the glomerulus to immune complexes in a subendothelial and mesangial location (subepithelial deposits are those that escape through the glomerular basement membrane).[1] An infectious trigger and its immunoglobulin response could cause such deposits, which set the ball rolling for the activation of the complement pathways including classical (CP), alternative (AP), and lectin pathways (LP). All the pathways would finally converge into the formation of C3, which deposits in the glomeruli. Along the way, activation of the CP would also result in the deposition of C1q and C4d, which can be detected, and LP activation would bring in C4d too.

What we expect in a classical PIGN is a transient deposition of immune complexes and complement components, which then clear out of the glomeruli with complete resolution of the glomerulonephritis (GN). Recent studies into patients who do not behave in this typical manner have resulted in the term “atypical post infectious GN” in whom underlying abnormality in the AP has been found in the majority of cases.[2] It is hypothesized that the abnormality may be mild and so ultimately the disease resolves, though it takes longer. What is even more ominous is that with a more severe AP abnormality some cases of dense deposit disease/C3 glomerulonephritis may present with a similar pattern of injury. These may represent the early phase of the GN, which will progress to a more usual membranoproliferative pattern of injury over time.[3] The infectious trigger with a history of febrile illness may also be present in these cases.

The role of the nephrologist and renal pathologist team is to, therefore, stratify the risk of progressive glomerular disease and advise AP evaluation in selected cases, which is itself challenging in the Indian context due to the lack of complement genetics and antibody testing in most centers. Practically, we rely on clinical parameters such as sustained low serum C3 (with normal C4 levels), lack of clinical remission; and pathology parameters such as an isolated C3 immunofluorescence pattern without accompanying immunoglobulins and abnormal electron microscopic findings inconsistent with the diagnosis of classical PIGN for risk stratification. Again, electron microscopy is not readily available in most centers.

Therefore in the hunt, for more tissue markers to help resolve the differential diagnosis Bansode et al.[4] have objectively evaluated C4d in 104 cases of diffuse proliferative and exudative GN, hypothesizing that low-intensity C4d staining (cut off of 1.45 defined by statistical modeling) would suggest AP activation. They found that these patients did poorly compared to cases with higher C4d staining. The caveat here is that a few cases with significant C4d staining also did not remit. A previous study on C4d in PIGN showed slightly less than 50% cases were C4d negative, however, no follow up data or complement testing was available.[5]

So will C4d (specifically the lack of it) be the marker for the renal pathologist to suggest underlying abnormality in AP and thus poor prognosis in patients with “diffuse proliferative and exudative pattern of glomerular injury?” The answer is complicated due to the following –

  1. An infectious trigger may likely result in a CP/LP activation even in a patient with an underlying AP abnormality such as dense deposit disease, which would give a C4d positivity (with or without immunoglobulins)

  2. The role of the lectin pathway is still unresolved in this form of glomerulonephritis. Abnormalities in this pathway may contribute to positive C4d with variable prognosis.

From Bansode et al.[4] and our own experience,[6] the value of the lack of C4d is significant in indicating a potential abnormality in the AP in proliferative glomerulonephritis, however, its presence should not give false reassurance. In our practice, based on a combination of clinical and pathology features including C4d, the first step is to perform electron microscopy in suspect cases and at the very least advise a close clinical follow-up with serial serum C3/C4 estimation.

We expect that more renal pathologists will use C4d in the evaluation of glomerulonephritis in combination with routine immunofluorescence in the future.

References

  1. , , . Infection-related glomerulonephritis: Understanding mechanisms. Semin Nephrol. 2011;31:369-75.
    [Google Scholar]
  2. , , , , , , . Atypical postinfectious glomerulonephritis is associated with abnormalities in the alternative pathway of complement. Kidney Int. 2013;83:293-99.
    [Google Scholar]
  3. , , . Membranoproliferative glomerulonephri.tis: Pathogenetic heterogeneity and proposal for a new classification? Semin Nephrol. 2011;31:341-8.
    [Google Scholar]
  4. , , . A novel glomerular C4d scoring system: A tool to prognosticate proliferative exudative pattern of glomerular injury. Indian J Nephrol. 2021;31:111-5.
    [Google Scholar]
  5. , , , , . C4d as a diagnostic tool in proliferative GN. J Am Soc Nephrol. 2015;26:2852-9.
    [Google Scholar]
  6. , , , , , , . Glomerular C4d staining does not exclude a C3 glomerulopathy. Kidney Int Rep. 2019;4:698-709.
    [Google Scholar]

    Fulltext Views
    122

    PDF downloads
    255
    View/Download PDF
    Download Citations
    BibTeX
    RIS
    Show Sections