Concept Map: Complement Testing for TMA(aHUS) made simple

 

What testing to order for complement evaluation for aHUS or TMA 

What do those results mean?

Based on Paper in Kidney International 2024

In the News: Dense Deposit Disease and ApoE- the new connection

C3 glomerulopathy arises from irregularities in the alternative pathway of complement. It manifests as two types: C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), identifiable by bright C3 staining in the glomeruli under immunofluorescence. EM distinguishes DDD by dense deposits along the glomerular basement membranes, contrasting with non-dense deposits in C3GN. A fascinating new study investigating 12 cases each of DDD, C3GN, and pretransplant kidney controls, laser microdissection (LCM) followed by mass spectrometry (MS) revealed a significant accumulation of complement proteins and regulatory factors in both C3GN and DDD compared to controls. Notably, DDD exhibited a much higher concentration of C5-9 and apolipoprotein E (ApoE) compared to C3GN. 

Image courtesy: pathologyoutlines.com 

ApoE staining aligned with dense deposit patterns in DDD but not in C3GN or controls, validated in 31 C3G cases. This is fascinating as perhaps ApoE staining may serve as a diagnostic tool for DDD, particularly when EM is unavailable, as it reflects the enriched presence of ApoE in dense deposits, distinguishing DDD from C3GN.

ApoE is a 34 kDa lipoprotein, that facilitates lipid transportation by binding to lipids. As we are aware, in various diseases like atherosclerosis, Alzheimer’s, and amyloidosis, ApoE plays pivotal roles in plaque formation and fibril assembly. Additionally, I learnt that it is also detected in fibrillary glomerulonephritis, immunotactoid glomerulonephritis, and monoclonal Ig deposition disease, potentially acting as a scaffolding protein. While its accumulation is significant in DDD, it's also found in other diseases but in lesser amounts. Staining for ApoE aids in diagnosing DDD alongside proliferative glomerulonephritis and bright C3 staining. Kidney accumulation of ApoE occurs predominantly in lipoprotein glomerulopathy and ApoE-related glomerulopathies. ApoE interacts with complement factors, inhibiting inflammation and regulating complement pathways. Moreover, it's a component of age-related macular degeneration but hasn't been previously identified in DDD dense deposits. This study suggests ApoE binds to heparan sulfate in the glomerular basement membrane, potentially acting as a chaperone for C5-9 proteins, contributing to dense deposit formation. Further investigation is warranted to confirm ApoE's interaction with C5-9 proteins and potential treatment strategies as a result. Kudos to the authors for making this connection. 

Hypocomplementemia and the Kidney

 When we are faced with AKI and classically low c3 and c4, certain diseases come to mind.

A classic figure that has been used for years is below:

I think we can divide the low complement diseases and the kidney with glomerular processes and non glomerular processes

The glomerular diseases that are classically associated with low complements are:

MPGN pattern( all forms, c3GN, DDD, immune complex related MPGN), Lupus related GN, Cyro related GN, infection associated GN( both post strep and endocarditis), but we should not forget Fibrillary GN ( especially if MPGN pattern of injury is noted) and heavy chain deposition disease(HCDD). Finally, we should not forget TMA with complement disorders can cause low c3 in some cases.  In other words, immune complex is the main pathology that is driving the hypocomplementemia. 

Non glomerular diseases that can be associated with low complements should be kept in mind- classically atheroembolic disease and IgG4 diseases( fair amount have low complements)

Here is a mnemonic that many use- CHAMPS ( created by NephSim)

Topic Discussion: Complement and the Kidney

The complement system can be attacked to help treat kidney disease. Complement activation contributes to the pathogenesis of acute and chronic kidney disease injury.  The aHUS and C3GN story has led us to believe that there might be hope for other potential targets in the complement system for patients with kidney disease.

A recent mini review in KI summarizes the role of the complement system in kidney disease and where future drugs hold promise. The complement activation is initiated via 3 pathways- classical, alternative and lectin.  Full activation leads to the generation of several biologically active fragments, namely C3a, C5a, C3b and C5b-9.  Drugs are currently being developed to block the classical pathway, the alternative pathway and the activation at the level of c3,c5 and c5a.

C1 inhibitors, TNT009( anti C1s) affect the classical pathway
Purified factor H, anti Factor D agents, CR2-factor H, affect the alternative pathway
Compstatin and soluble CR1 inhibits at level of C3
Eculizumab and other anti C5 inhibit at level of C5
and CCX168 inhibits at level of C5a

Check out two excellent reviews, one in KI and other in KIR
http://www.kidney-international.org/article/S0085-2538(16)30185-5/fulltext
http://www.kireports.org/article/S2468-0249(16)30031-6/fulltext

Complement Component Quiz Answers

Question:

Match the following complement components with their function in the complement cascade

C5a	Membrane attack complex
DAF	Initiates the alternative complement pathway
C5b-9	Initiates the classical complement pathway
Factor H	Byproduct of the classical complement pathway
C5	Potent inflammatory mediator
C1q	Membrane bound complement regulatory protein
C4d	Blockade of this complement component is the treatment for PNF
C3b	Deficiency results in atypical HUS

Answers:

C5a – Potent inflammatory mediator

DAF (decay accelerating factor) – membrane bound complement regulatory protein

C5b-9 – membrane attack complex (MAC)

Factor H – Deficiency results in atypical HUS (hemolytic uremic syndrome)

C5 - Blockade of this complement component is the treatment for PNF (paroxysmal nocturnal hematuria)

C1q – Initiates the classical complement pathway

C4d - Byproduct of the classical complement pathway

C3b - Initiates the alternative complement pathway

Post by

Vinay Nair 

Complement Component Quiz

Match the following complement components with their function in the complement cascade

C5a	Membrane attack complex
DAF	Initiates the alternative complement pathway
C5b-9	Initiates the classical complement pathway
Factor H	Byproduct of the classical complement pathway
C5	Potent inflammatory mediator
C1q	Membrane bound complement regulatory protein
C4d	Blockade of this complement component is the treatment for PNF
C3b	Deficiency results in atypical HUS

Good Luck
Answers provided in 1 week

Questions by Dr. Vinay Nair
Mt Sinai, Transplant Division
New York, USA