1. A 35-year-old CKD 5 female patient was referred to after her renal transplantation for suspected recurrence of her C3 nephropathy. See the biopsy below:
- Please comment on the biopsy shown above
- Is this enough to diagnose the recurrence of C3 glomerulopathy?
- How do you mange him based on the available evidence?
Dear All
There are essential criteria required to diagnose recurrent C3 GLONERULOPATHY highlighted in the document below. No one paid any interest to read it.
I will advise you to see the NHS England document. The link is: https://www.england.nhs.uk/wp-content/uploads/2017/02/clin-comms-policy-16054p.pdf
Recurrence of C3GN
that is good Dr. Mariamutu but please highlight your management plan
Criteria for initiation of Eculizumab (All should be met)
1- Biopsy of the native kidney: definite diagnosis of C3 glomerulopathy in the native kidney (LM, IF, and EM)
2- Biopsy of the graft: evidence of recurrent disease occurring at any time following the transplant with a picture of active GN with cellular crescents seen in LM and evidence of C9 deposition detected by IF
3- Evidence of graft dysfunction in the form of deterioration of GFR of > 20 % over 3 months period, and other causes of graft dysfunction is excluded
Criteria for stopping Eculizumab treatment
1- Graft failure or deterioration of graft function necessitates immediate stopping of the treatment
2- Stabilization or improvement of graft function necessitate stoppage of treatment after 4 months of treatment and reevaluation again, if deterioration occurs, treatment is resumed for another 4 months
Excellent very clear plan for use of Eculizumab which is the main reason of this question
The following clinical criteria of diagnosing recurrent C3 glomerulopathy are :
1. A primary renal diagnosis of C3 glomerulopathy confirmed by renal biopsy( LM, IF& EM)
2. Recurrent disease ( Bx an active glomerulonephritis with cellular crescents).
3. Evidence of glomerular C9 deposition on transplant biopsy.
4. Recurrent disease occurring at any time post-transplant.
5. Evidence at the time of recurrence of a significant decline of transplant function (>20% decline in eGFR) within the previous three months.
Thank You
1- confrimed the diagnosis of primary C3GN in native kidney including LM,IF,EM
2-recurrence of the disease confrimed by graft biopsy with active cresentic GN
3-postive glomerular C9 depsoition in graft biopsy
4-recurrence after transplant with > 20% reduction in graft function in the abscence of other causes at any time post transplant .
eculuzemab used for treatment for recurrence of C3GN in limited conditions and case by case according to above criteria they use same protocol for AHUS and duration for 4 months then either stop the treatmnet if no response with progressive garft loss .
while in case of good response to therapy with stable graft function after4months also consider stop treatment and keep on follow up and reassessmnet accordingly .
Thank You, this is an excellent conclusion
If the patient meets the criteria , Eculizumab can be considered for 4 months with follow up ;
NHS England will commission eculizumab for the treatment of recurrent disease post-transplant in patients with C3 glomerulopathy only if all the following clinical criteria are met:
a. A primary renal diagnosis of C3 glomerulopathy confirmed by renal biopsy including LM, IF & EM.
b. Recurrent disease characterised on biopsy by an active glomerulonephritis with cellular crescents. Histopathology will be reviewed by a single centre with expertise in the pathology of C3 glomerulopathy.
c. Evidence of glomerular C9 deposition on transplant biopsy.
d. Recurrent disease occurring at any time post-transplant.
e. Evidence at the time of recurrence of a significant decline of transplant function (>20% decline in eGFR) within the previous 3 months. This criterion will not be necessary if the recurrence occurs immediately after transplantation when transplant function has not yet been established.
f. No other cause for the decline in transplant function can be identified.
Clinical Commissioning Policy: Eculizumab in the treatment of recurrence of C3 glomerulopathy post-kidney transplant (all ages): NHS England: 16054/P
https://www.england.nhs.uk/wp-content/uploads/2017/02/clin-comms-policy-16054p.pdf
All these criteria should be met –
· Primary diagnosis of C3GN confirmed by LM,IF,EM
· Recurrent disease on biopsy showing active glomerulonephritis with cellular crescents.
· Glomerular C9 deposition on transplant biopsy
· Significant decline of graft function ->20 % decline of eGFR in last 3 months
criteria for starting eculizumab ( all are required):
Although the current biopsy with shows cellular crescents , it is not sufficient to fulfill criteria of recurrent C3 glomerulopathy to start ecluzimab treatment.
The following criteria are required:
_ diagnosis of C3 glomerulopathy as 1 ry disease by LM and presence of C3 deposits by IF and EM
_ presence of active nephritis in allograft biopsy ( crescents in L/M and evidence of C3 deposits by IF and EM) .
_ evidence of graft dysfunction ( decrease GFR by 20 % or more from base line).
_ if all criteria are fulfilled, start ecluzimab for 4 months and assess response:
_ if graft function improve …we can try withdraw ttt and follow up graft function. If worsens again, resume ttt for further 4 months.
_ if no improvement , discontinue it .
L/M stained with H&E showed that ;
lobulated pattern MPGN.
IF and EM are needed to diagnose C3 deposition so ; LM not enough.
,Required criteria for recurrent C3 GN include :
Recurrent disease come with active GN & cellular crescents, Significant decline in eGFR in previous 3 months. can occur at any-time post-transplantation
Management:
Mild disease : proteinuria < 1.5 gm/d only prescribed ACEI or ARBS.
Moderate disease ; proteinuria 1.5-3.5 gm/d : steroids 1 mg/kg/d for 3 months ,anti-proliferative ( MMF).Severe cases: RPGN or nephrotic range proteinutia :pulse steroids, MMF. In resistent cases soliris may have a role.
comment on the biopsy shown above
LM shows mesangial hypercellarity
LM not enough for diagnosis of recurrence C3G
management:
Control of BP, proteinuria by ACEi and ARBs
Steroids and MMF
Plasma exchange
Eculizumab
comment on the biopsy shown above
this slide LM shows mesangial hypercellarity, fibrin clots
it is not enough for diagnosis of recurrence C3G
which needs: 1- native kidney biopsy LM/IF/EM
2-Graft biopsy LM/IF/LM
bloods: C3, C4, C3nef,
management of C3G:
Control of BP, proteinuria
Steroids and MMF (supposedly the patient is already on them).
Plasma exchange
Eculizumab: special criteria should be fulfilled to use it and when to stop it.
Please comment on the biopsy shown above :
Glomerular lobulation and mesangial proliferation and microthrombi In light microscopy H&E staining.
Is this enough to diagnose the recurrence of C3 Glomerulopathy?
No, in addition to light microscopy, immunofluorescence and electromicroscopic
evaluation should be done. Reduction in graft function more than 20% eGFR compared to the last 3 months and deposition of C9 in glomeruli and cellular crescents are needed, too.
How do you manage him based on the available evidence?
NHS suggests that Eculizumab can be used in severe cases for 4 months
C3glomerulopathy is a subtype of MPGN which is result from complement dysregulation. Progression of C3 glomerulopathy to ESKD is common and patients who undergo transplantation, recurrence in kidney graft is common as well. Recurrence rate of C3 glomerulonephritis and DDD is greater than 50% and 80% respectively and typically present 1 to 2 years after kidney transplantation.
1) this biopsy depicts lobular accentuation of glomerular tuft, mesangial proliferative, membranoproliferative, and endocapillary proliferative glomerulonephritis.
2) for definite diagnosis it needs to IF and EM evaluation. IF is necessary for diagnosis of C3 nephropathy (C3GN and DDD) and EM is required to differentiate between C3GN and DDD.
3) treatment is based upon severity of disease:
Mild disease (proteinuria less than 1.5 gr/day and stable eGFR): conservative therapy with ACEi and ARB in both non-hypertensive and hypertensive patients in combination with statins without change in immunosuppressive regimen.
Moderate disease (proteinuria >1.5 gr/day but <3.5 gr/day with stable eGFR or slowly decline in eGFR): ACEi and ARB is considered as conservative therapy as well as mild disease. In addition, based on the etiology of complement dysregulation such as factor H defect or presence of monoclonal gammopathy, various therapeutic options including plasma exchange, infusion of FFP, rituximab, or eculizumab can be used. Immunosuppressive regimen generally can be continued without any change.
Severe disease (proteinuria ≥3.5 gr/day and rapidly decline in eGFR): treatment with MMF 1.5 gr twice a day in addition to three 500-mg methyl prednisolone pulses following by prednisolone 1g/kg/day until remission or for a maximum of 12 weeks. Plasma exchange with Alb replacement is considered as a therapeutic option. Similar to moderate disease, based on the etiology of complement dysregulation such as factor H defect or presence of monoclonal gammopathy, various therapeutic options including plasma exchange, infusion of FFP, rituximab, or eculizumab can be utilized.
LM shows mesangioproliferation
Not enough
– Need IF to check:
deposits of C3 along the glomerular, tubular, and Bowman’s capsule basement membranes, as well as mesangial rings
– EM to see:
to diagnose DDD. Electron microscopy in patients with DDD reveals pathognomonic abnormal electron-dense material within the GBM,
– Special tests:
C3 and C4,
●C3 nephritic factor (C3NeF) – C3NeF is an autoantibody that stabilizes the C3 convertase (C3bBb). Determination of C3NeF in the serum supports the diagnosis of C3GN or DDD.
●Serum factor H – factor H promotes the decay of the C3 and C5 convertases (C3bBb and [C3b]2Bb). If factor H activity is diminished or if factor H is deficient, evaluation of possible mutations in the factor H gene and autoantibodies to factor H should be performed.
●Complement factor H-related (CFHR) protein gene mutations
●Serum protein electrophoresis (SPEP), immunofixation, and serum-free light chains – A paraprotein may be responsible for activation of the alternative complement cascade . If a monoclonal gammopathy is discovered, specialized tests are required to determine whether or not the protein could be responsible for the C3 glomerulopathy
●Serum factor B, serum factor I, and membrane cofactor protein (MCP, or CD46) – Deficiency of serum factors B or I or MCP can be associated with activation of the alternative complement cascade. If low, mutations in these genes or autoantibodies against these proteins should be investigated.
●Soluble C5b-9 (soluble membrane attack complex, or sMAC) – Elevated levels of sMAC may indicate increased activity of the alternative pathway.
see the attached figure
Please comment on the biopsy shown above
The light microscopy of kidney tissue using PAS stain, showing a glomerulus with mesangial hypercellularity and fibrin clot indicating a possibility of thrombotic micro-angiopathy. There’s thickening of the basement membrane. There is no end-ocapillary proliferation nor crescent formation. Biopsy may not be adequate as no interstitium and no blood vessels.
Is this enough to diagnose the recurrence of C3 glomerulopathy?
This is not enough to diagnose C3G as recurrent or de novo. Immunoflouresence and electron microscopy are needed for accurate diagnosis beside detailed history looking for previous past history of possible C3G.
Criteria for diagnosis of recurrent C3G:
Evidence of glomerulonephritis on kidney biopsy with C3 staining on IF with or without dense deposits on EM.
How do you mange him based on the available evidence?
There’s no standard therapy for C3G post transplant.
Supportive therapy should be considered to control the blood pressure, proteinuria and concomitant problem if present.
The use of Eculizumab in the treatment of C3G was proved to be effective and superior to TPE and Rituximab.
NHS England recomend Eculizumab for the treatment of recurrent C3G when the following criteria are met:
Please comment on the biopsy shown above
The light microscopy of kidney tissue using PAS stain, showing a glomerulus with mesangial hypercellularity and fibrin clot indicating a possibility of thrombotic micro-angiopathy. There’s thickening of the basement membrane. There is no end-ocapillary proliferation nor crescent formation. Biopsy may not be adequate as no interstitium and no blood vessels.
Is this enough to diagnose the recurrence of C3 glomerulopathy?
This is not enough to diagnose C3G as recurrent or de novo. Immunoflouresence and electron microscopy are needed for accurate diagnosis beside detailed history looking for previous past history of possible C3G.
Criteria for diagnosis of recurrent C3G:
Evidence of glomerulonephritis on kidney biopsy with C3 staining on IF with or without dense deposits on EM.
How do you mange him based on the available evidence?
There’s no standard therapy for C3G post transplant.
Supportive therapy should be considered to control the blood pressure, proteinuria and concomitant problem if present.
The use of Eculizumab in the treatment of C3G was proved to be effective and superior to TPE and Rituximab.
NHS England recomend Eculizumab for the treatment of recurrent C3G when the following criteria are met:
1. The biopsy shows mesangial cell proliferation, cellular crescents, thickened glomerular basement membrane .
2. Sure, not sufficient for diagnosis of recurrent C3 glomerulopathy, as we need visualization of C3 deposits by IF and EM ( to be more than IgG deposits).
_ in addition to define recurrence:
a. We need diagnosis of C3 glomerulopathy in the native kidney by L/M,IF and EM
b. Presence of active nephritis in the graft biopsy, and diagnosis by LM, IF and EM.
3. The treatment in case of C3 glomerulopathy according to the severity of the disease:
_ mild protinuria and stable graft function: just supportive as antiprotinuric (ACEi and ARBS).
_ moderate protinuria may need steroids and MMF.
_ severe protinuria may needs plasmapheresis and cyclophosphamide (presence of crescents).
_ plasmapheresis may have a role in case of complement dysregulation as factor H deficiency .
_ ecluizimab use needs diagnosis of C 3 glomerulopathy in native kidney plus evidence of active nephritis in graft biopsy and graft dysfunction.
_ follow up response by follow up the degree of protinuria and graft function.
follow
full assessment for this patient to put him in which categoriry of the disease(mild,moderate or sever).
do full lab include 24 hour protien collection and eGFR
renal biopsy for IF and EM
Control the Bp.
supportive treatment
specifici treatment according to his protinurea and eGFR as we mention below
1- light microscopic examination of postrenal transplant revealed mesangial proliferation with lobular appearance and this finding cope with c3 glommuropathy (MPGN).
2-this finding not enough to diagnosis recurrence of c3 glommuropathy:
first the primary disease diagnosis should be biopsy proven including light ,immunofluroence and EM.
the recurrent disease characterized on biopsy by an active glommuronephritis with or without cresent formation,evidence of granular C9 deposit in transplant kidney and ocure at any time postrenal transplant .
in addition to examination of renal biopsy by immunoflorence which usually showed C3 mesangial deposit and EM(C3 deposit widespread involving the mesangial, subendothelial focal intermembranous,and occasional subepithelial areas)
3- treatment:
There is no controlled studies on which to base thearputic recommendation.for C3 GN
treat patient based on severity of the disease:
1-mild disease which charctized by protienurea less than 1.5gm/day eGFR is stable treat with ACE or ARBs targetBpless130/80 and protienurea less than 1gm/day.
2-moderate disease if protienurea > or equal 1.5gm/day but less than 3.5gm/day and eGFR stable or declining treat by ACE and ecluzimab if complement dysregulation confirm.
3- sever disease if protienurea .3.5gm/day or rapidly decline eGFR we treat mycophenolate 1.5 gm bid and D/C azathiopurine and methylpredinosolone 1mg/kg for 3 days followed by oral steroid 1 mg/kg for 12 weeks
If patient with identifed serum factor defeciency can be treated by FFP.
other medication use for treatment are eculizimab,rituximab and plsma exchange based on a case by case.
References
The biopsy picture provided shows light microscopy picture with H and E staining of a glomerulus with mesangial hypercellularity and lobular accentuation. This is an inadequate biopsy as there is absence of interstitium and tubular structures as well as artery in the biopsy. Also, there is lack of history.
This picture of lobular accentuation may be seen in Transplant glomerulopathy, diabetic nephropathy, HCV infection, recurrent or de-novo MPGN or C3 glomerulopathy
No. It is not enough to diagnose C3 glomerulopathy.
For a diagnosis of C3 glomerulopathy, it is essential to show a dominant C3 staining at least 2 times more in intensity than other immunoglobulins along the glomerular capillary walls and mesangium on immunofluorescence.(1)
Moreover, electron microscopy can help differentiating in the 2 different types of C3 glomerulopathy. On electron microscopy, C3 glomerulopathy will show “hump-like” mesangial, subendothelial, intramembranous or subepithelial deposits (in C3 glomerulonephritis) or highly dense deposits in the glomerular basement membrane extending into the subendothelial zones (in dense deposit disease).(2)
The clinical data in the index patient has not been provided.
As per KDIGO, management of C3 glomerulopathy depends on the severity of the disease.(1)
Blood pressure (using ACE inhibitors or ARBs) and dyslipidemia (using statins) should be controlled in patients.
Moderate disease (characterized by 24-hour urine protein more than 500 mg, or moderate inflammation with increased endo- or extra-capillary proliferation or crescents on biopsy, or recent increase in creatinine) should be treated with steroids and MMF.
Severe disease (characterized by 24-hour urine protein more than 2000 mg, or severe inflammation on biopsy, or recent increase in creatinine despite immunosuppression): Lack of data to recommend Eculimzumab.
But as per the review article, treatment with eculizumab decreases the risk of allograft loss.(3)
The indication for starting Eculizumab therapy in C3 glomerulopathy is on the basis of following criteria:(4)
a) A primary pre-transplant diagnosis of C3 glomerulopathy on basis of light microscopy, immunofluorescence and electron microscopy of native kidney biopsy
b) Recurrent disease characterized by active glomerulonephritis and crescents on biopsy, occurring any time after transplant.
c) Glomerular C3 deposition on biopsy
d) Significant (more than 20%) decline of glomerular function within prior 3 months (except in cases with immediate post-transplant recurrence), with no other explainable cause for graft function decline.
The treatment should be continued for 4 months and indications to stop Eculizumab include:
a) Improvement in graft function
b) Stabilization of graft function
c) Ongoing worsening of eGFR despite treatment
d) Loss of graft.
References:
1) Goodship TH, Cook HT, Fakhouri F, Fervenza FC, Frémeaux-Bacchi V, Kavanagh D, Nester CM, Noris M, Pickering MC, Rodríguez de Córdoba S, Roumenina LT, Sethi S, Smith RJ; Conference Participants. Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference. Kidney Int. 2017 Mar;91(3):539-551. doi: 10.1016/j.kint.2016.10.005. Epub 2016 Dec 16. PMID: 27989322.
2) Seshan S, V, Salvatore S, P: Recurrent Glomerular Diseases in Renal Transplantation with Focus on Role of Electron Microscopy. Glomerular Dis 2021;1:205-236. doi: 10.1159/000517259
3) Gonzalez Suarez ML, Thongprayoon C, Hansrivijit P, Kovvuru K, Kanduri SR, Aeddula NR, Pivovarova AI, Chewcharat A, Bathini T, Mao MA, Basu A, Cheungpasitporn W. Treatment of C3 Glomerulopathy in Adult Kidney Transplant Recipients: A Systematic Review. Med Sci (Basel). 2020 Oct 21;8(4):44. doi: 10.3390/medsci8040044. PMID: 33096866; PMCID: PMC7712822.
4) Clinical Commisioning Policy: Eculizumab in the treatment of recurrence of C3 glomerulopathy post-kidney transplant (all ages) accessed on 06.06.2022 on https://www.england.nhs.uk/publication/clinical-commissioning-policy-eculizumab-in-the-treatment-of-recurrence-of-c3-glomerulopathy-postkidney-transplant-all-ages/
Please comment on the biopsy shown above
The current biopsy micrograph shows H&E staining of one glomerulus see on high power.
The provided glomerulus findings are:
Findings of the biopsy are compatible with membranoproliferative glomerulonephritis
Is this enough to diagnose the recurrence of C3 glomerulopathy?
The findings of light microscopy alone is not enough for final diagnosis but guide us for possible/differential diagnosis.
MPGN IS A HISTOLOGIC DESCRIPTION OF FINDINGS IN BIOPSY, AND NOT A FINAL DIAGNOSIS.
MPGN could result from immune complex mediated injury such as hepatitis c and other viruses, monoclonal gammopathy or renal significance/plasma cell dyscrasia, autoimmune or idiopathic, and could be complement dependent such as DDD and C3 glomerulopathy
How do you mange him based on the available evidence?
There is no definite treatment for C3 nephropathy, and the management is usually supportive, and optimisation of immunosuppression.
Eculizumab may have a significant role in the treatment of C3 glomerular disease in cases with following criteria:
a. A primary renal diagnosis of C3 glomerulopathy confirmed by renal biopsy
including light microscopy, immunofluorescence and electron microscopy.
b. Recurrent disease characterised on biopsy by an active glomerulonephritis
with cellular crescents. Histopathology will be reviewed by a single centre with
expertise in the pathology of C3 glomerulopathy.
c. Evidence of glomerular C9 deposition on transplant biopsy.
d. Recurrent disease occurring at any time post-transplant.
e. Evidence at the time of recurrence of a significant decline of transplant
function (>20% decline in eGFR) within the previous three months. This
criterion will not be necessary if the recurrence occurs immediately after
transplantation when transplant function has not yet been established.
f. No other cause for the decline in transplant function can be identified.
-LM with Hamatoxylin and eosin stain showing glomerulus with mesangial and endocapillary hypercellularity with exudative features with lobulation and endocapillary wall thickening
-No LM is not enough
EM differentiates between C3GN and DDD mean while there could be some overlap particularly in early stages
C3 GN seen by EM is charecterised by glomerular staining of C3 and widespread deposits in the mesangium, subendothelial, focal intramembranous and occasional subepithelial areas, similar to “hump-like” deposits. The texture of the deposits are finely granular to waxy, and amorphous in character.
IF is needed as it reveals granular pattern of staining along the glomerular capillary walls and mesangial areas in C3GN
-Over 50% of patients with disease recurrence reported to experience allograft failure, The best treatment is unknown meanwhile the use of plasmapheresis and other immunosuppressive agents including cyclophosphamide, eculizumab, and rituximab were used
In a study Ecluzimab use in such cases resulted in stabilization of kidney function and proteinuria in some of the studied cases
No enough studies on the use of plasmapheresis and rituximab but one study with small number of cases demonstrated modest outcome for half of the studied group.
Another retrospective Spanish cohort study of 60 patients with C3GN of the native kidneys showed that , patients maintained on corticosteroids and mycophenolate were more likely to achieve clinical remission compared to untreated patients or those on other immunosuppressive regimens
Therefore in this case Ecluzimab can be used
As starting criteria includes
· C3 GN confirmed by renal biopsy underwent LM ,EM and IF with active lesions and cellular cresents.
· glomerular C9 deposition on transplant biopsy.
· More than 20% decline of GFR
Ecluzimab can be given for 4 months then revaluated if will need more 4 months
Reference
-V. Seshan S and P. Salvatore S. Recurrent Glomerular Diseases in Renal Transplantation with Focus on Role of Electron Microscopy. Glomerular Dis 2021;1:205–236
-Lim WH, Shingde M and Wong G . Recurrent and de novo Glomerulonephritis After Kidney Transplantation. Front. Immunol.2019; 10:1944.
-NHS England: 16054/P
Biopsy is suggestive of MPGN pattern evidenced by mesangial hypercellularity, lobulation though no definitive double contour.in view of clinical scenario there is possibility of C3 nephropathy recurrence however to prove it we need further work up.
IF and EM which will guide us further towards etiology of MPGN
Immune complex mediated OR
Complement driven
Further work up will be directed accordingly.
Available evidence is not enough to devise a management plan.
If it is C3 recurrence which fulfills the following criteria there is definitive role of Ecluzimab
Evidence of definitive C3 Nephropathy in Native kidney(Bx proven )
Evidence of recurrence in graft at any time post Tx showing
cellular crescents
Active GN
C9 deposition
Evidence of graft dysfunction with loss of GFR more than 20% in last three months
Please comment on the biopsy shown above
This slide shows micothrombi, hypercellularity , increased mesangial matrix. No mention of the technique used but looks H&E.
Is this enough to diagnose the recurrence of C3 Glomerulopathy?
NO.
Criteria for diagnosis of C3 Glomerulopathy.
All these criteria should be met.
· Primary diagnosis of C3GN confirmed by LM,IF,EM
· Recurrent disease on biopsy showing active glomerulonephritis with cellular crescents.
· Glomerular C9 deposition on transplant biopsy
· Significant decline of graft function ->20 % decline of eGFR in last 3 months
How do you mange him based on the available evidence?
There no definite treatment of C3 glomerulopathy. In milder form with proteinuria<1.5 gm/ day, ACEI or ARBS can help. If proteinuria is more than 3.5 gm/d then ACEI or ARBS, PE, Rituximab , Steroids and optimization of immune suppression may help.
Eculizumab can be used in severe cases upto 4 months and then re assess.
Indications for Use.
C3GN in native kidney by LM, IF and EM
Recurrent disease on biopsy showing active glomerulonephritis with cellular crescents.
Glomerular C9 deposition on transplant biopsy
Significant decline of graft function ->20 % decline of eGFR in last 3 months
Reference– Clinical Commissioning Policy: Eculizumab in the treatment of recurrence of C3 glomerulopathy postkidney transplant (all ages) Reference: NHS England: 16054/P
1 – There is mesangial proliferation and expansion with hypercellularity and capillary wall thickening.
2- No. We need to examine the biopsy with IF and EM beside light microscopy to distinguish C3 deposit from DDD .
3- Eculizumab for C3 disease, ACEi or ARB for proteinuria
Comment on the biopsy
Biopsy shows one glomerulus with H &E stain, by light microscopy showing increased basement membrane cellularity, diffuse mesangial cell proliferation and the thickening of capillary walls.
It is not enough to diagnose the recurrence of C3 glomerulopathy
It is a histopathological diagnosis. The disease is defined by the presence in renal biopsy samples of a glomerulonephritis with sole (or at least dominant) glomerular immunofluorescence staining for C3 of at least two orders of magnitude greater intensity than for any other immune reactant.
The panel of antibodies used for immunofluorescence studies in most renal pathology laboratories includes antisera to immunoglobulin heavy chains (IgG, IgM and IgA), immunoglobulin light chains (κ and λ) and the complement components C1q and C3. The antibody to C3 is specific for C3c, a stable C3 cleavage product.
Electron microscopy is necessary to distinguish the two major subtypes of C3 glomerulopathy, DDD and C3GN. In DDD, electron microscopy reveals highly electron-dense, osmiophilic deposits with a ‘sausage-shaped’ or ‘Chinese calligraphy-like’ appearance that thicken and transform the lamina densa of the glomerular basement membrane (GBM). Similar extremely electron-dense deposits can also be identified in Bowman’s capsules and some tubular basement membranes. In C3GN, by comparison, the electron density of deposits approaches that of the glomerular matrix components. These deposits often have an amorphous cloudy appearance within the mesangium and can appear as ill-defined, subendothelial (intramembranous and/or subepithelial) inclusions. Subepithelial humps can occur in both subtypes.
Findings on light microscopy are diverse, and range from no glomerular hypercellularity to mesangial proliferative, endocapillary proliferative, exudative, membranoproliferative, crescentic and sclerosing patterns. The deposits often stain negative on Jones methenamine silver stain and red on Masson trichrome stain.
True recurrence:
Post-transplant proteinuria or hematuria or elevated serum creatinine is found after transplantation. Biopsy-proven kidney disease is diagnosed in the native kidneys. The same disease is proven by biopsy in the transplanted kidney.
In such patients, if the graft is not doing well, a renal biopsy should be promptly performed and examined by light microscopy, immunofluorescence and electron microscopy. When the diagnosis of C3G is suspected, a complete workup should be undertaken. The diagnostic approach should include a comprehensive biochemical, genetic and pathologic analysis of the complement AP.
This approach should include complement factors and complement regulatory protein levels, measurement of MCP on peripheral blood leukocytes as well as screening for anti-CFH antibodies and C3NeFs.
The genetic investigation should include mutation screening of CFH, CFI, MCP, C3 and CFB. The screening requires an extensive sequencing of all coding exons. A study of recombination in the CFHR region should be made.
Management:
Routine complement studies (measurements of serum levels of complement proteins and their split products, and screening for autoantibodies).
Low serum C3 levels, high serum levels of soluble C5b-9 and high stabilizing capacity of C3 nephritic factors have been identified as biomarkers predictive of aggressive complement dysregulation and rapid progression.
Therapeutic plasma exchange (TPE), and rituximab.
The anti-C5 monoclonal antibody (eculizumab) has been used.
An exciting new approach to C3G treatment is the soluble complement receptor 1 (CR1), which promotes the breakdown of active C3b.
reference:
Med Sci (Basel). 2020 Dec; 8(4): 44.
Published online 2020 Oct 21. doi: 10.3390/medsci8040044
Light microscopy picture of a renal biopsy biopsy with H&E showing a lobular pattern with mesangial and endo-capillary proliferation, increased mesangial hyper cellularity, no clear evidence of double contour (new basement membrane formation by endothelial or mesangial cells). Accordingly, this is most likely a membrano- proliferative pattern of ICGN
The answer is NO. As we moved from the morphological towards the new etiological classification of MPGN. So, immunofluorescence staining is the key for diagnosis
IF classification:
1. In the presence of immunoglobulin and complement (immune complex mediated), check immunoglobulins , if polyclonal think about a triggering infections, autoimmune diseases, but if monoclonal we have to think monoclonal immune deposition disease which include a spectrum of (monoclonal gammopathies especially Multiple myeloma), smoldering multiple myeloma, ,monoclonal gammopathy of renal significance, chronic lymphocytic leukemia and lymphoma and cryoglobinemia.
2. In the presence of 2 fold greater intensity of complement in conjunction with absence of near absence immunoglobulins we have to think about C3 glomerulopathy (abnormalities in alternative pathy-way of complement regulatory proteins whether there is mutation or variants of factor H,I, MCP or there is auto-AB like C3NEF directed against the firepower point of the complement cascade resulting in accumulation of C3B with down activation of other steps complement cascade to the formation of MAC. Keep I mind that monoglobulin Ig can act as c3 NEF interfering with function of complement regulatory proteins like factor H.
3. In absence of immunoglobulins and complement we can think about about other diseases like aHUS
C3G is a rare disorder 1-2 cases /million that can recur at any time after renal transplant accounting for overall 50% allograft loss despite being on maintenance immunosuppression).More earlier to occur with DDD compared to C3 glomerulonephritis
· Criteria set by NHS England to confirm recurrence of C3G post transplantation are:
1. The primary renal diseas before transplantation was C3G confirmed by renal biopsy including(LM,IF,EM)
2. The recurrence of the disease at any time post-transplant and the post-transplant biopsy is showing active glomerulonephritis with cellular crescents and glomerular C9 deposition.
3. When the disease recurred it results in deterioration of eGFR> 20% within 3 months. However, this is not necessary if the disease occurred immediately after transplantation when graft functions is not yet stabilized.
4. Absence of other causes to explain decline of graft functions
We are moving now from non-targeted therapy to a more complement targeted therapy :
Sub-nephrotic range proteinuria with stable renal functions, use conservative non immunomodulatory agents like ACE or ARBS
For patients with nephrotic range proteinuria or declining renal functions use
Steroids
MMF
Rituximab, plasmapheresis is underlying defects in factor H
C5 targeted therapy: Eculizumab(best results in patients with increased sMAC).However, other groups of patients in whom the electron dense deposits are predominantly C3 would not benefit.
It has been licensed mainly for management of a-HUS and PNH and this treatment should proceed in selected cases if the above criteria are met .
According to meta-analysis published in CJASEN in 2020 for kidney transplant recipients
for KTX patients with C3G treated with eculizumab. They had the lowest incidence of allograft loss (33%) when compared to those treated with TPE and Rituximab
Eculizumab based therapy:
Indications to start therapy are the above criteria set by NHS England to confirm recurrence of C3G post transplantation
Adult Dose: According to national renal complement therapeutic Centre in Newcastle
Initial dose: 900 mg weekly 4 4 weeks given as IV infusion over 25-45 minutes
Maintenance dose :1200 mg on week 5 the 1200 mg every 2 weeks on
After 4 months the therapy is evaluated
1. No response, Graft loss, deterioration of graft function: stop treatment and do not re-introduce again.
2. Stabilization or improvement of graft function: Stop treatment and re-introduce for another 4 months if all criteria of treatment are met
REFERANCES:
· Up to date
· Clinical Commissioning Policy: Eculizumab in the treatment of recurrence of C3 glomerulopathy post-kidney transplant (all ages): NHS England
· Maria L Gonzalez Suarez et al. Treatment of C3 Glomerulopathy in Adult Kidney Transplant Recipients: A Systematic Review Med. Sci. 2020
L/M with H&E staining showing one glomerulus revealing lobulated pattern ;MPGN
It is not enough of C3 GN diagnosis as IF is needed to prove C3 deposition
,Required criteria for recurrent C3 GN include :
_ primary renal diagnosis of C3 GN proved by LM, IF& EM
_. Recurrent disease proved by active GN & cellular crescents.
_. Glomerular C9 deposition .
– Recurrent disease at any time post-transplant.
_ Significant decline of transplant function (>20% decline in eGFR) over previous 3 months.
Management according to severity:
_Mild disease : proteinuria < 1.5 gm conservative ttt with ACEI or ARBS
_ Moderate disease ; proteinuria 1.5-3.5 gm: steroids 1 mg/kg/d for up to 3 m till partial or complete remission followed by tapering , MMF 1.5 gm
_ Severe disease: RPGN or nephrotic syndrome :pulse steroids then oral steroids as before, MMF 1.5-2 gm or switch to oral cyclophosphamide
_ Eculizumab in refractory moderate to severe active cases
_ PE if there is a genetic mutation in factor H
REFERANCES
Uptodate
. Clinical Commissioning Policy: Eculizumab in the treatment of recurrence of C3 glomerulopathy post-kidney transplant (all ages): NHS England: 16054/P
.Maria L Gonzalez Suarez et al. Treatment of C3 Glomerulopathy in Adult Kidney Transplant Recipients: A Systematic Review Med. Sci. 2020,
Very good
Suboptimal biopsy , showed one glomeruli with increase mesangial matrix & hypercellularity, microthromibi , no mention of IF & EM findings .
there are criteria have to be met ,
The following clinical criteria of diagnosing recurrent C3 glomerulopathy are :
1. A primary renal diagnosis of C3 glomerulopathy confirmed by renal biopsy( LM, IF& EM)
2. Recurrent disease ( Bx an active glomerulonephritis with cellular crescents).
3. Evidence of glomerular C9 deposition on transplant biopsy.
4. Recurrent disease occurring at any time post-transplant.
5. Evidence at the time of recurrence of a significant decline of transplant function (>20% decline in eGFR) within the previous three months.
No definitive treatment of C3G.The disease is complement associated , literatures , considered the use of Eculizumab in recurrent C3G, for 4 months.
criteria to stop the treatment of eculizumab are the followings :
1-loss of the renal allograft .
2- deterioration of renal function despite of the treatment
Good
1- Comment on biopsy
One glomeruli, H&E stain show MPGN pattern
2- Not enough for diagnosing recurrence of C3 glomerulopathy . diagnosis requires
a- Histological diagnosis : IF that reveleals C 3 depostion and scanty or no Ig deposits in renal tissue . EM to differniate DDD from C3 glomerulopathy
b- Laboratory investigations including
A- genetic testing
b-Complement level
c-Excluding other causes of MPGN pattern of injury as malignancy , infection , drugs and autoimmune diseases.
3- There is no definite treatment for C 3 glomerulopathy , but as it’s a diseses of dysregulated complement pathway , so several studies investigated efficacy of eculizumapb in sever cases of C 3 glomerulopathy ( defined by decreasing e GFR , dense C 3 deposits more than 20 % or cresent GN ) with variable results . Other studies investigated rituximab and plasma exchange , but results were inferior compared with eculizumab.
1- Gonzalez Suarez ML, Thongprayoon C, Hansrivijit P, et al. Treatment of C3 Glomerulopathy in Adult Kidney Transplant Recipients: A Systematic Review. Med Sci (Basel). 2020;8(4):44. Published 2020 Oct 21. doi:10.3390/medsci8040044
2- Prevention of recurrence of C3 glomerulopathy post-transplant: eculizumab. NICE Guidance, 2015
LM:
Lobular pattern of mesangial expansion ,with increased cellularity i.e. mesngicapillary proliferation (MPGN).
C3 level elevated.
No IF is required for c3 and EM which confirm subendothelial and mesangial electron
dense deposit. and rule out DDD(Linear appearing ,electron dense ,ribbon like deposits
intramembranous.
Mild disease: If proteinuria is <1.5 g/day and the estimated glomerular filtration rate, is
stable, ACE inhibitors or ARBs.
Moderate disease :
proteinuria is ≥1.5 g/day but <3.5 g/day and eGFR is stable or declining slowly,
ACE inhibitors or ARBs plus PE and factors infusion .(specific factor deficiency), and rituximab.
Severe disease:
Among patients who have proteinuria ≥3.5 g/day or rapidly declining eGFR,
MMF (1500 mg orally twice daily) with glucocorticoids (intravenous methylprednisolone 500 mg daily for three days followed by oral prednisolone 1mg/kg.
Eculizumab used in moderate to severe case with variable results.
References:
Anuja Java et al .C3 glomerulopathies: Recurrence after
transplantation.uptodate.april.2022.
You mean C3 nephrotic factor is elevated not C3
Please revise your answer
YES, prof. low C3 and high c3nephritic factor.
Comment on biopsy:
Light microscopy with hematoxylin and eosin stain shows endocapillary proliferation with diffuse mesangial proliferation and increased mesangial matrix. Gives a lobular appearance to the glomerular tuft. No clear basement membrane duplication.
For me, it seems as if there is thrombotic microangiopathy??? Isn’t it?
Is this enough to diagnose the recurrence of C3 glomerulopathy?
NO.
1- IF is needed in order to stain C3 deposition for diagnosis of C3 GN. C3GN has only C3 deposition with no Ig deposition. The presence of Ig deposition is indicative of other aetiology.
2- EM also needed to differentiate between both subtypes of complement-mediated MPGN (C3 glomerulopathy and DDD).
3- C3 nephritic factor positive test is also needed for diagnosis.
How do you manage him based on the available evidence?
In order to manage this patient, we need to confirm the diagnosis. Exclude secondary causes like infection, monoclonal gammopathy etc.
Also to know about the clinical presentation like the severity of proteinuria, and time post-transplant.
If the criteria going with the diagnosis is C3 GN then Eculizumab can be given for 3 months and then re-evaluate the case.
Plasmapheresis, rituximab, and optimizing the immunosuppressive drugs, change mTOR to CNI based regime.
Non-specific anti-proteinuria drugs like ACE-
Need more precise indication for use of Eculizumab
Eculizumab indication criteria are;
1. Definitive diagnosis of C3GN in the native kidney by LM, EM, and IF.
2. biopsy proven recurrent C3GN in the real graft
3. Renal graft dysfunction with decline in eGFR < 20
Eculizumab given for 4 months then reassess the case
if the graft function improved stop and restart if deteriorate
If deteriorate stop the drugs
Your feedback is requested on the biopsy that was displayed above:
There was one glomerulus that had a picture of MPGN, which is insufficient for the etiological diagnosis of C3 golumerulopathy.
a picture of MPGN is characterized by an increase in the number of mesangial cells and an extension of the mesangial matrix with some intraglomerular capillary nearly occluded.
Is this sufficient to make a diagnosis of recurrent C3 glomerulopathy?
NO, it is not sufficient for the purposes of diagnosis or therapy.
It is essential to get a complete history of the recipient’s renal pathology and to know the original cause of renal failure.
After ruling out all possible secondary causes, serum complement factors and genetic tests are performed on autoimmune diseases, infection, and malignancy).
In order to diagnose C3G, immunofluorescence testing is required to demonstrate the presence of dominant C3 deposition on the renal biopsy, which is a hallmark of abnormal complement activation.
to distinguish between C3GN and DDD by detecting the location of the deposit by EM:
-The C3GN specimen reveals a GBM that is more mottled and has fewer osmiophilic deposits.
In DDD, the lamina densa of GBM is replaced by a very electron-dense deposition.
For the patient who had C3Gn and had a kidney transplant, the following criteria must be met to determine a recurrence:
Active glomerulonephritis and cellular crescents are the primary diagnostic features of C3GN.
Glomerular C9 deposition and a reduction in eGFR of more than twenty per cent in the preceding three months.
once confirmation of the diagnosis, we will start anti-complement 5(eculizumab) for 4 months and review the effect of the drug. If improvement in the GFR and proteinuria continues for another 4 months. If no improvement had been achieved, stop the medication.
The problem is the cost of the medication and getting approval for it.
Dear all
Please check this classification for MPGN and C3
Check the following links:
Read these carefully, and consider the following:
Such an entity needs a pragmatic approach with no diagnostic dogmas
Best Luck
Please comment on the biopsy shown above
The renal biopsy showed endocapillary proliferation which gives rise to lobulated appearances, capillary wall thickening with mesangial hypercellularity
Is this enough to diagnose the recurrence of C3 glomerulopathy?
No, light microscopy (renal biopsy) alone is not sufficient in diagnosing, managing and prognosticate MPGN, it requires EM historically but latest classification required immunofluorescence only.
The new classification, classify MPGN into
1- Immune deposited MPGN- Immunoglobulin+/- complement (from IF),
2- C3 GN – further classify into C3GN or Dense Deposit Disease(DDD)
Need further evaluation such as:
How do you manage him based on the available evidence?
No definitive therapy for C3G but as it is a complement-associated disease, case reports of the use of eculizumab in refractory disease can be found in the literature and were considered
Patient who had C3Gn and had kidney transplant, we have to confirm recurrence by:
(Histopathology confirming a recurrence to be reviewed by national centre with expertise in the pathology of C3 glomerulopathy)
All Starting criteria met – treat with eculizumab for 4 months
Response 1: Loss of Transplant OR Ongoing deterioration / no response-Withdraw Treatment Do Not reintroduce
Response 2 Stabilistaion of graft function OR Improvement of graft function-Treat for 4 months and
monitor response – if all criteria met reintroduce for further 4 months
References
Wai H. Lim, Meena Shingde and Germaine Wong. Recurrent and de novo Glomerulonephritis after Kidney Transplantation. Frontier In Immunology. August 2019. vol 10. 1942
NHS England document. The link is: https://www.england.nhs.uk/wp-content/uploads/2017/02/clin-comms-policy-16054p.pdf
Well done
Well described criteria to use Eculizumab.
1- The slide show glomeruli with HE stain with Increased mesangial and endocapillary cellularity leading to a lobular appearance of the glomerular tuft.
2- Further evaluation neeed to know classification of the the disease
Membranoproliferative glomerulonephritis (MPGN) is classified into subtypes including
1- immune complex-mediated
is characterized by both immunoglobulin and complement protein deposition in the kidney identified by immunofluorescence microscopy.
and result from
*infection like hepatitis C virus (HCV) infection typically shows granular deposition of immunoglobulin M (IgM), C3
* monoclonal gammopathy characterized by deposition of monotypic immunoglobulin with kappa or lambda light chain
* autoimmune diseases (SLE)
2- C3 glomerulopathy
is characterized by predominant or exclusive C3 deposition.
And result from dysregulation and persistent activation of the alternative complement pathway
Divided in to
* C3 dense deposit disease
* C3 glomerulonephritis
So in this scenario we need to do
*Immunofloresence study and EM of the biopsy
*Screen for infection (hepatitis B,C)
*Screen for autoimmune disease
*Serum level of (C3,C4)
Hypocomplementemia is common
In immune complex/monoclonal immunoglobulin-mediated MPGN, complement activation occurs via the classic pathway and is typically manifested by a normal or mildly decreased serum C3 concentration and a low serum C4 concentration.
In complement-mediated MPGN, there are usually low serum C3 and normal C4 levels due to activation of the alternate pathway
*C3 nephritic factor (C3NeF) is found in approximately 80 percent of patients with DDD and roughly 40 percent of patients with C3GN
*Genetic study for complements:- Testing for mutations in the genes encoding factor H, factor I, C3, and complement factor H-related (CFHR) proteins (CFHR1-5) should be performed
3-Treatment
treat patients based upon the severity of the presentation:
Mild disease – If proteinuria is <1.5 g/day and the estimated glomerular filtration rate (eGFR) is stable, treated with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs).
Moderate disease – If proteinuria is ≥1.5 g/day but 20% decline in eGFR) within the previous three months.
This criterion will not be necessary if the recurrence occurs immediately after transplantation when transplant function has not yet been established.
6-No other cause for the decline in transplant function can be identified.
Reference
1-Up to date
2-the NHS England document. The link is: https://www.england.nhs.uk/wp-content/uploads/2017/02/clin-comms-policy-16054p.pdf
Thanks, Dalia
There are essential criteria required to diagnose recurrent C3 GLONERULOPATHY and to use Eculizumab highlighted in the document below. What are these criteria?
Recurrence of C3GN
#Histopathology confirming a recurrence to be reviewed by national center with expertise in the pathology of C3 glomerulopathy
All Starting criteria met – treat with eculizumab for 4 months
Recurrence of C3 GLONERULOPATHY
1-Primary diagnosis of C3GN
2-Active glomerulonephitis & cellular crescents
3-Glomerular C9 deposition
4->20% decline in eGFR within previous 3 months
eculizumab used in following conditions
1-primary renal diagnosis of C3 glomerulopathy confirmed by renal biopsy including light microscopy, immunofluorescence and electron microscopy.
2-Recurrent disease characterised on biopsy by an active glomerulonephritis with cellular crescents.
3-Evidence of glomerular C9 deposition on transplant biopsy.
4-Recurrent disease occurring at any time post-transplant.
5-Evidence at the time of recurrence of a significant decline of transplant function (>20% decline in eGFR) within the previous three months.
This criterion will not be necessary if the recurrence occurs immediately after transplantation when transplant function has not yet been established.
6-No other cause for the decline in transplant function can be identified.
Very good the above criteria are important to decide treatment using Eculizumab alongside with the above medications.
◇Please comment on the biopsy shown above?
______________
▪︎ This light microscopic changes ( H& E stain) showed a lobular glomeruli with hypercellularity and thickening of the glomerular basement membrane (GBM) with mesangial matrix expansion and thick capillary wall.
▪︎The above picture goes with membranoproliferative glomerulonephritis ( MPHN)
♧Note:
▪︎MPGN is a pattern of glomerular injury on kidney biopsy which is characterized by thickening of the capillary walls accompanied by cellular, predominantly mesangial, proliferation in all or almost all the glomeruli. The increase in cellularity and mesangial matrix produces accentuation of the lobular aspect of the glomerular tuft (lobular GN). The thickening of the capillary walls is due to subendothelial deposits and mesangial interposition with formation of material similar to the glomerular basement membrane (GBM) in the internal aspect of the wall, or subendothelial space. In some cases the injury is focal and segmental.
◇Is this enough to diagnose the recurrence of C3 glomerulopathy?
____________________________
No, I think we need immunofluorescence (IF) and electron microscopy (EM) due to the following:
▪︎The diagnosis of C3 glomerulopathy is established by renal biopsy and requires a C3 dominant pattern on IF in a patient with active glomerulonephritis [2].
▪︎ EM can show the presence of strong glomerular staining for C3 and electron deposit.
▪︎ C3 glomerulopathy can potentially morphologically distinguished from Dense deposit disease by the nature and ultrastructural charactersistics of these electron dense deposits [3]
▪︎ EM can differentiate C3 glomerulopathy from Dense deposit disease.
▪︎We need to do serum complement level which is low
◇How do you mange him based on the available evidence?
____________________
▪︎Plasma pharesis
▪︎IS agents including cyclophosphamide , Eculizumab and Rituximab[3].
NOTE: anti-cellular immune suppression and plasma therapy have limited efficacy in C3G. Data suggest that eculizumab may ameliorate disease in some C3G patients [4].
_____________
Reference:
[1] Agnes B. Forgot, et al. “AJKD Atlas of Renal Pathology: Membranoproliferative Glomerulonephritis”. ATLAS OF RENAL PATHOLOGY II| VOLUME 66, ISSUE 3, E19-E20, SEPTEMBER 01, 2015
DOI:https://doi.org/10.1053/j.ajkd.2015.07.007
[2] Carla M Nester et al.”Diagnosis and treatment of C3 glomerulopathy”Clin Nephrol. 2013 Decem
[3] Wai H. Lim, Meena Shingde and Germaine Wong. Recurrent and de novo Glomerulonephritis after Kidney Transplantation. Frontier In Immunology. August 2019. vol 10. 1942-
[4] Carla M. Nester, Richard J. Smith.”Treatment Options for C3 Glomerulopathy”https://doi.org/10.1097/MNH.0b013e32835da24c
Thanks, Tahani
There are essential criteria required to diagnose recurrent C3 GLONERULOPATHY and to use Eculizumab highlighted in the document below. What are these criteria?
These are:
a.A primary renal diagnosis of C3 glomerulopathy confirmed by renal biopsy including LM, IF and EM.
b. Recurrent disease characterised on biopsy by an active GN with cellular crescents. Histopathology will be reviewed by a single centre with
expertise in the pathology of C3 glomerulopathy.
c. Evidence of glomerular C9 deposition on transplant biopsy.
d. Recurrent disease occurring at any time post-transplant.
e. Evidence at the time of recurrence of a significant decline of transplant
function (>20% decline in eGFR) within the previous three months. This criterion will not be necessary if the recurrence occurs immediately after transplantation when transplant function has not yet been established.
f. No other cause for the decline in transplant function can be identified.
Renal biopsy shows mesangial expansion and hypercellularity.
Evidence of double wall of glomerular basement membrane and fibrinoid necrosis
Is it enough to diagnose of C3 GN?
Not enough/ It’s need diagnosis by immunoflorescence to detect C3 staining in which area deposits in subepithelial or subendothelial or it’s deposits in basement membrane to differentiated between C3 glomerulitis and dense deposits disease.
C3 level in serum may be low
check level of soluble membrane complex attach complement
evidence of proteinuria and sometimes hematuria.
Eculizmab is anti C5 monoclonal antibody is effective to treat recurrence of C3 GN disease plus triple immunosuppressive agents (tacrolimus and steroid and MFF)
Thanks, Sahar
There are essential criteria required to diagnose recurrent C3 GLONERULOPATHY and to use Eculizumab highlighted in the document below. What are these criteria?
Please comment on the biopsy shown above:
One glomerulus shown picture of MPGN (mesangial cell number increasing and expansion of mesangial matrix without clear doubling of GBM) histological diagnosis which is not enough for etiological diagnosis .
Is this enough to diagnose the recurrence of C3 glomerulopathy?
NO it is not enough for the sake of diagnosis or the sake of treatment.
History of renal pathology of the recipient is important.
Serum complement factors and genetic testing after excluding all secondary causes (infection or malignancy).
For C3G diagnosis need IF to prove presence of dominant C3 deposition on renal biopsy, a marker of aberrant complement activity(1).
E/M: to differentiate between C3GN and DDD by detect location of deposition:
A-Highly electron-dense deposition replaces the lamina densa of GBM in DDD.
B-C3GN shows thickened GBM with mottled and less osmiophilic deposits (2).
How do you mange him based on the available evidence?
No strong randomized controlled studies recommend special treatment for C3G.
For patients with mild or low grade recurrent disease no need for ecluzimab and will be treated with conservative treatment with the ongoing immunosuppressive treatment +ACEI and following RFT.
For patients with (Primary diagnosis of C3GN Active glomerulonephritis & cellular crescents Glomerular C9 deposition >20% decline in eGFR within previous 3 months) All Starting criteria met – treat with ecluzimab for 4 months.(3).
References:
1-Nester CM, Smith RJ. Diagnosis and treatment of C3 glomerulopathy. Clinical Nephrology. 2013 Dec;80(6):395-403. DOI: 10.5414/cn108057. PMID: 23993166.
2-Ito, Naoko et al. “C3 glomerulopathy and current dilemmas.” Clinical and experimental nephrology vol. 21,4 (2017): 541-551. doi:10.1007/s10157-016-1358-5.
3-Clinical Commissioning Policy: Ecluzimab in the treatment of recurrence of C3 glomerulopathy post-kidney transplant (all ages), Prepared by NHS England Specialized Services Clinical Reference Group for Renal Services, First published: February 2017.
Thanks, Dalia
There are essential criteria required to diagnose recurrent C3 GLONERULOPATHY and to use Eculizumab highlighted in the document below. What are these criteria?
Thanks prof,
I think I mentioned it.
Please comment on the biopsy shown above
It seems to be a MPGN
Is this enough to diagnose the recurrence of C3 glomerulopathy?
No, it can be other causes of MPGN. Monoclonal, polyclonal (infection or autoimmune), dense deposit disease, C3, and TMA are other possible causes.
We need IF and EM to distinguish these diseases.
How do you manage him based on the available evidence?
Rituximab is an option for prevention and treatment. But if C3 component is the cause we can use eculizumab. The choice will depend on the disease’s severity.
Thanks, Dalia
There are essential criteria required to diagnose recurrent C3 GLONERULOPATHY and to use Eculizumab highlighted in the document below. What are these criteria?
Single glomerulus stained by the H&E staining method shows features of MPGN ( glomerular lobulation, hypercellular glomerulus with infiltration of capillary lumens with leukocytes, and some thickened capillary walls).
NO,
First: there should be a pre-transplant biopsy to confirm that the original disease is C3 GN.
Second: Exclusion of other causes of MPGN ( infectious MPGN, autoimmune MPGN, monoclonal MPGN).
Third: for the biopsy, we need IF, and EM.
By IF microscope, there will be granular C3 staining along the capillary walls and mesangial areas. No significant amount of immunoglobulins is noted in glomerular deposits.
C4d staining is negative because the alternative pathway is involved in the case of C3 GN.
EM is critical for distinguishing C3GN from DDD, in C3 GN the deposits are more widespread involving the mesangium, subendothelial, focal intramembranous, and occasional subepithelial areas, while in the DDD, the deposits are dense, homogenous and lie within the GBM.
There is no controlled studies for treatment of recurrent C3 GN post-transplant, treatment is based on the severity of presentation:
References:
Thank you
What is the role of Eculizumab in the management of this case?
I will advise you to see the NHS England document. The link is: https://www.england.nhs.uk/wp-content/uploads/2017/02/clin-comms-policy-16054p.pdf
Thanks for providing this useful document.
Criteria for diagnosing recurrent C3GN include the followings:
All of the above criteria should be met in order to diagnose recurrent C3GN. once the diagnosis has been made, eculizumab should be started.
Eculizumab may be a therapeutic option for a subset of C3GN patients. Dysregulation of the alternative complement cascade plays a primary role in the pathogenesis of C3GN.
Uncontrolled activation of the alternative complement pathway is driven by inherited mutations in complement proteins and cofactors (e.g. C3, CFB, CFH, CFI, CFHR1–5), or by acquired defects (e.g. CFH, CFB, C3 convertase autoantibodies).
Eculizumab is a monoclonal humanized antibody that binds C5 and prevents assembly of the membrane attack complex (C5b-9) thereby blocking the final complement cascade. Several case reports and one open-label study showed a potential benefit of eculizumab for patients with C3GN.
The response to eculizumab is heterogeneous. the relative degrees of upstream and downstream complement dysregulation (at the sites of the C3 convertase and the C5 convertase, respectively) vary in C3GN patients and may drive some of the observed phenotypic differences. These differences likely explain the variation in response to eculizumab therapy in C3GN transplant recipients that are reported in the literature. For example, in C3GN patients in whom the dominant process is the activation of C5 convertase and the terminal complement cascade, as evidenced by elevated levels of soluble C5b-9, eculizumab may be of therapeutic benefit. Conversely, in C3GN patients in whom the dominant process is upstream dysregulation at the level of C3 convertase, as evidenced by elevated levels of C3 split products, the effect of eculizumab therapy would be less dramatic and continued complement dysregulation with continuing renal injury would occur.
References:
Very good Hoda for clarifying that the action of Eculizumab is by controlling C5
So C5b-9 is blocked and subsequently C3 is down regulated here it’s action is obviously significant.
While if the situation C3 overproduction is not accompanied with C5b-9 then the effect will not be that significant.
Being an extremely expensive drug choice of the patient has to be restricted to the above rules with sophisticated study of the complement cascade (center with high expertise).
thank you
· Biopsy: This is hematoxylin and eosin staining showing MPGN pattern on light microscopy.
· Is this enough to diagnose the recurrence of C3 glomerulopathy?
No, we need C3 dominant staining on IF. Additionally, the presence on EM of mesangial deposits, subendothelial, subepithelial, and/or intramembranous locations suggests C3GN, which will differentiate between it & DDD.
· How do you mange him based on the available evidence?
Given the lack of a proven beneficial therapeutic intervention, the aggressiveness of treatment should match the aggressiveness of the disease process. In general, the treatment for MPGN syndromes is not well established.
Patients can be treated based upon the severity of the presentation:
· Mild disease – If proteinuria is <1.5 g/day and the estimated glomerular filtration rate (eGFR) is stable, treat with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). The dose is targeted to a decrease in protein excretion to <1 gram/day. Additionally,
Statin can be added, primarily for cardiovascular benefit.
In such patients, we do not change the antirejection immunosuppressive regimen.
· Moderate disease – If proteinuria is ≥1.5 g/day but <3.5 g/day and eGFR is stable or declining slowly, treat with ACE inhibitors or ARBs as described above. In addition, add treatment based upon the specific, underlying defect that causes complement dysregulation, if known.
The antirejection immunosuppressive regimen is generally continued unchanged and patients may receive plasma exchange or fresh frozen plasma (FFP) infusions, rituximab, or eculizumab.
· Severe disease – Among patients who have proteinuria ≥3.5 g/day or rapidly declining eGFR, mycophenolate (1500 mg orally twice daily) with glucocorticoids (intravenous methylprednisolone 500 mg daily for three days followed by oral prednisone, 1 mg/kg/day with a maximum dose of 60 mg per day), can be given until remission or for a maximum of 12 weeks.
Some clinicians also treat such patients with daily or alternate-day plasmapheresis with albumin replacement in addition to immunosuppressive therapy.
Other therapies, such as eculizumab, rituximab, or plasma exchange, can be used on a case-by-case basis in patients with recurrent C3 glomerulopathy, particularly in those with autoantibodies or complement gene variants; however, data supporting the use of these agents in this setting are very limited.
References:
· Masani N, Jhaveri KD, Fishbane S. Update on membranoproliferative GN. Clinical Journal of the American Society of Nephrology. 2014 Mar 7;9(3):600-8.
· Anuja Java, Daniel C Brennan. C3 glomerulopathies: Recurrence after transplantation. Up-to-date. https://www.uptodate.com/contents/c3-glomerulopathies-recurrence-after-transplantation?search=treatmt%20of%20c3%20in%20transplant&source=search_result&selectedTitle=3~150&usage_type=default&display_rank=3
Thank you
What is the role of Eculizumab in the management of this case?
You mentioned it briefly Fakhriya, we need more detail
I will advise you to see the NHS England document. The link is: https://www.england.nhs.uk/wp-content/uploads/2017/02/clin-comms-policy-16054p.pdf
Dear all please note:
After giving your answers for this case with the given information emphasis should be made regarding:
History as to differentiate between primary and secondary causes of MPGN.
Having reached a conclusion of primary cause notice that there are overlap cases of C3GN and Immune mediated MPGN which would modulate plan of therapy.
Any case of primary MPGN should under go screening of the cause prTx as this is a highly recurring disease specially in C3 and DDD.
Once diagnosed councelling of the patient is needed to inform about chances of recurrence.
Light microscopic biopsy showing a glomerulus with double contouring of basement membrane(tram track appearance) with mesangial cell proliferation , endocapillary proliferation and occlusion of capillary lumens These findings are consistent with MPGN like pattern which can occur in a wide variety of conditions for which Immunofluorescence ,electron microscopy and other workup needed.
Is this enough to diagnose the recurrence of C3 glomerulopathy?
NO, we need a detailed history including the cause of native kidney, treatment the patient gets before transplant, duration of transplant , and renal biopsy including histopathology, immunofluorescence (C3 deposits )and electron microscopy(sub-epithelial, sub-endothelial, mesangial),serum complement levels and genetic studies for detecting mutation in factor H, factor I and C3. complement factor H-related (CFHR) proteins,and antibodies against C3, 4, 5 nephritic factor (C3NeF) and factor H and B.
How do you mange him based on the available evidence?
Treatment is according to severity of the disease.
Mild disease-(proteinuria <1.5g/day and eGFR stable)-ACE or ARBs
Moderate disease:(proteinuria>1.5g/day but <3.5 g/day and eGFR is stable or declining) –ACE or ARBs,Eclizumab +,antirejection immunosuppressive therapy continued unchanged
Severe disease: (proteinuria>3.5g/day or rapidly declining eGFR) MMF (1500mg twice a day orally )with pulse methylprednisolone followed by oral prednisone 1mg/kg/day until remission or up to 12 weeks. Cyclophosphamide can also be used if no response to MMF or as an alternative to MMF. Eclizumab ,plasmapheresis or Rituximab can be used in refractory cases or in complement gene variants or in autoantibodies.
REFERENCE:
1- Le Quintrec M, Lapeyraque AL, Lionet A, et al. Patterns of Clinical Response to Eculizumab in Patients With C3 Glomerulopathy. Am J Kidney Dis. 2018 Jul;72(1):84-92.
2- McCaughan JA, O’Rourke DM, Courtney AE. Recurrent dense deposit disease after renal transplantation: an emerging role for complementary therapies. Am J Transplant. 2012 Apr;12(4):1046-51
Please comment on the biopsy shown above:
The light microscopy shows typical MPGN like pattern of glomerular injury with mesangial expansion and lobular glomerulopathy, which is nonspecific finding could be part of transplant glomerulopathy or recurrence of denovo glomerular disease , infection like HCV infection, monoclonal gammopathy and complement dysregulation like c3 nephropathy (1).
Is this enough to diagnose the recurrence of C3 glomerulopathy?
NO we need more comprehensive history about the case, the disease course how aggressive the disease was in the native kidney and previous treatment prior to transplantation, the duration of the transplant and the time of this biopsy usually c3 nephropathy relapse earlier post TX first two years and more aggressive if associated with monoclonal gammopathy, high level of C3 nephritic factor or /and factor H auto antibodies , low c3 level also need to know about any sensitization history, immunological risk status of the recipient the FXCM and DSA level, induction and current maintenance IS type any previous history of rejection or infection like HCV infection , type of the donor DD vs LD we need IF staining for c3 and C4D staining , EM looking for deposits or PTC multilayering as DDX IS wide including CABM with transplant glomerulopathy current l c3 nephritic factor (c3nef) assay and complement assay ,proteinuria hematuria urine p/c, ratio ,tacrolimus tough level ,and Viral screen.
How do your mange him based on the available evidence?
Treatment options of post transplant c3 nephropathy based on the available limited evidence from small observational studies and expert opinion and the direction of treatment depends on the severity and progress of the disease
Mild disease defined by proteinuria < 1.5g/day with stable gfr still can be treated with ACEI, ARBS with target proteinuria < 1gm /day even in normal BP and for hypertensive candidate we target BP < 130/80 mmhg ( 2C).
Statin for cardiovascular benefit
Same immunosuppressive medication including MMF, steriods , TAC.
Moderate disease
Proteinuria 1.5-< 3.5gm with slowly decline GFR
ACEI, ARS for proteinuria and HTN
Plasma infusion or plasmapheresis with rituximab / eculizumab
Same triple maintenance antirejection therapy including MMF, steroid, TAC
Sever aggressive disease, proteinuria > 3.5gm with rapid aggressive decline in GFR
MMF dose 1.5gm BID as tolerated with PMP 500mg for 3 doses followed by oral steroid 1mg/kg max 60mg /day until remission for 12weeks, plus plasmapheresis alternate day with albumin infusion in addition to immunosuppressive therapy. and plasmapheresis can be extended to period of time according to the response
Eculizumab can be used case by case it’s not yet FDA approved for c3 nephropathy in addition its use limited due to the high cost .and availability
References:
1–C3 glomerulopathy: recurrence after transplantation, up to date medicine accessed 22.05,2022.
Well done for attempting with the offered information to exclude other causes of mesngiocapillary GN.
Excellent
The current biopsy shows MPGN pattern of glomerulonephritis
MPGN (LM finding) is classified according to IF into three types :
C3 glomerulopathy is a rare disease occurring in 1-2 cases per million
Characterized by MPGN pattern in LM, deposition of C3 in IF and they are further classified by EM according to the location of dense deposits into DDD (intramembranous) and C3GN (subendothelial, mesangial and sometimes subepithelial)
C3 glomerulopathy can occur in children and adults but DDD typically starts in childhood, while C3 GN occurs in older age
C3 glomerulopathies are caused by dysregulation of the alternative pathway of the complement system due to either genetic mutation or acquired defect in complement protein (the presence of antibodies that either stabilize C3 convertase or inhibit complement regulatory proteins) leading to uncontrolled activation with subsequent deposition of C3 in glomeruli, thus it share the same pathogenesis of a HUS
A circulating factor (C3 nephritic factor) was found in around 80% of cases with DDD and 40 % of cases with C3 GN
For definite diagnosis of C3 glomerulopathy the following are required
A- Renal biopsy (LM, IF and EM)
B- Measurement of serum complements including C3, factor H, B, I
C- Searching for circulating autoantibodies including C3, 4, 5 nephritic factor (C3NeF) and antibodies against factor H and B
D- Genetic studies of the complement system (may be abnormal in 20 % of cases) including testing for mutation in the genes that encodes factor H, factor I and C3. complement factor H-related (CFHR) proteins
C3 glomerulopathy is an aggressive disease with most of the patients develop ESRD, risk factors for the development of ESRD include
C3 glomerulopathy recurs in half of the patients after transplantation
C3 glomerulopathy either present with
Options in the treatment of native and recurrent C3 glomerulopathy include:
Eculizumab
So … back to our case
REFERANCES
1. Smith RJH, Appel GB, Blom AM, et al. C3 glomerulopathy – understanding a rare complement-driven renal disease. Nat Rev Nephrol 2019; 15:129.
2. Fakhouri F, Le Quintrec M, Frémeaux-Bacchi V. Practical management of C3 glomerulopathy and Ig-mediated MPGN: facts and uncertainties. Kidney Int 2020; 98:1135.
3. Uptodate
Excellent
Going back to the offered HE it is not a full picture of Mesangiocapilary GN true there is extensive mesangial proliferation with exudative cellularity
But the BM shows no obvious thickness or double contour . But we’ll done.
The biopsy shows massive mesangeal expansion with mesangeal cells proliferation and infiltration of leukocytes. There’s thickening of glomerular basement membrane with obliteration of glomerular capillaries.there is periglomerular fibrosis,tubulat atrophy and interstitial fibrosis and interstitium leukocytes infiltration,However, the slide is limited in displaying the interstitium.
This picture is consistent with mesangiocapillary GN, a pattern of glomerular injury that can be caused potentially by C3GN. Its mostly consistent with recurrent C3GN , but other causes has to be excluded as follow:
first of all we need to prove the diagnosis of C3GN by having immunofluorescent study which is classically showing only C3 deposition with no immunoglobulins IgG or other types.Presence of immunoglobulins is indicative of other etiologies .
EM study would exclude Dense deposit disease DDD.
Other confirmatory tests include C3, and C4 complement system assessment.
Classically, alternative pathway with be activated with low C3 and normal C4 in C3GN.
C3 Nephritic factor is to be assessed as the main culprit in triggering C3GN as its inhibiting C3 convertase enzyme leading to persistent activation of C3 complement with subsequent glomerular damage.
Importantly, C3GN secondary to monoclonal gammopathy of renal significance has to be excluded as the Free light chain might inhibit the C3 convertase enzyme and trigger the whole picture of C3GN. Therefore urine immunoelectrophoresis and serum immunofixation study along with serum free light chain assay has to be carried out to exclude this differential diagnosis.
In the presence of other immunofluorescent findings in kidney biopsy , then we have to look for causes involving immune-complex disease , like post infective , Lupus nephritis, and Hepatitis C and B viral infection are some other causes we need to investigate accordingly.
Negative immunofluorescent on the back ground of this light microscopy finding is consistent with microangiopathic insult like antiphospholipid syndrome and chronic TTP which has to investigated as well.
So definite diagnosis of C3GN depend entirely on the demonstration of the sole C3 deposition on IF study and exclusion of DDD by EM study, on the background of C3 Nephritic factor positive test
Treatment:
as far as complement system involved with activation by an autoimmune antibodies.
then treatment has to involve targeting complement system and autoimmune antibodies.
Therefore Eculizumab is indicated to inhibit the activated complement system, soluble membrane attack complex sMAC is a marker of positive response that can be considered as a surrogate for positive response to Eculizumab.
PE might be indicated as well to remove the Nephritic factor when its positive.
Rituximab and Bortezomib are another potential factors that are anecdotally recommended to suppress the production of C3 Nephritic factor .
MMF has to be added if it was not a part of immunosuppressant medication
references:
1-Maria L. Gonzales suarez et al.Treatment ofC3 Glomerulopathy in Adult Kidney Transplant Reciepients:A systemic Review.Med Sci[Basel] Dec.2020.
2-A. Java. Kidney Transplant in Adults:Recurrences of C3 glomerrulonephritis..www.uptodate.com
The relatively newer classification of primary MPGN into
Immune mediated due to overproduction of immoglobulins by the plasma cells (gamopathies).
Complement mediated C3GN .
This would direct to a more diff choice of management.
Keeping in mind there are overlap cases.
Thank you prof. Dawlat,
Absolutely, if its secondary to plasma cell dyscrasia, then treatment is directed towards the underltong etiology.
Biopsy
Double contour to basement membrane, or “tram tracking” – characteristic of membranoproliferative glomerulonephritis (MPGN). This results from basement membrane duplication.
Diffuse increase in tuft cellular its with the increase in cellularity in mesangial region. “Lobulation” of the tuft can be prominent and capillary walls are thickened with decrease in capillary lumens.
Mesangial hypercellularity and lobulated aspect seen mainly.
Diagnosis
Management
References :
Thank you Nandita
I will advise you to see the NHS England document. The link is: https://www.england.nhs.uk/wp-content/uploads/2017/02/clin-comms-policy-16054p.pdf
Thank you professor.
I just went through the NHS document. Does it mean that Eculizumab is the go-to treatment method for C3GN recurrence?
No Nandita but it gives very strong ,restricted rules to choose Eculizumab as it is an extremely expensive drug.
– Please comment on the biopsy shown above
– This is a light microscopic biopsy stained by hematoxylin and eosin showed a glomerulus with a lobular pattern, with endocapillary proliferation, and mesangial hypercellularity, capillary membrane doubling. A typical picture of MPGN-pattern GN.
– Is this enough to diagnose the recurrence of C3 glomerulopathy?
– No not enough, further evaluation needed
a. Immunohistochemistry or immunofluorescence:
– study for type and intensity of deposit the deposition of C3 with two-fold intensity in absence or near absence of other Ig suggest the C3 glomerulopathy.
-also staining with lambda and kappa light chain to exclude monoclonal deposition disease as a trigger for complement dysregulation and C3 glomerulopathy
-C4d staining is mandatory for graft biopsy examination for associated ABMR
b. EM
– needed to localize the site of the deposits, so the diagnosis of the subtype of c3 g (deposits in the basement membrane (DDD) or subendothelial and few intramembranous (C3Gn).
C. serum membrane attack complex sMAC especially if eculizumab would be a line of TTT
– How do you manage him based on the available evidence?
– C3g is associated with a high recurrence rate post-transplant (50%) with poor treatment response and high graft failure 50% and reaching 80% in DDD.
– No approved treatment till now but eculizumab was associated with less graft loss rates
– If unavailable, so the next step would be total plasma exchange or rituximab
References
1- Smith RJH, Appel GB, Blom AM et al. C3 glomerulopathy—Understanding a rare complement-driven renal disease. Nat. Rev. Nephrol. 2019, 15, 129–143.
2- Suarez ML, Thongprayoon C, Hansrivijit P, et al. Treatment of C3 Glomerulopathy in Adult Kidney
Transplant Recipients: A Systematic Review. Med. Sci. 2020, 8, 44Article
Thank you
I will advise you to see the NHS England document. The link is: https://www.england.nhs.uk/wp-content/uploads/2017/02/clin-comms-policy-16054p.pdf
# Please comment on the biopsy shown
above
** The biopsy showed MPGN which refers to the features noted on light microscopy (LM) hypercellularity, endocapillary proliferation, capillary wall remodeling, double contour formation, and duplication of basement membrane (1)
# Is this enough to diagnose the recurrence of C3 glomerulopathy
** No, not enough to diagnose the recurrence of C3 glomerulopathy, because the newer classification of MPGN is dependent on
– Immunofluorescence (IF) staining. This pathophysiologybased classification is most useful to given recent advances in the role of the alternative pathway of complement in MPGN, as it either immune complex (occur when there are increased levels of circulating immune complexes),or complement mediated(occur because of dysregulation of the alternative pathway of complement) If neither of these causes is present then chronic thrombotic microangiopathy may be the cause of the MPGN
– C3G is associated with complement abnormalities in the alternative complement system pathway.
– And can be caused by acquired antibodies (most commonly C3 nephritic factor)
– Genetic mutations in complement or complement regulatory proteins, so both genetic and antibody testing to identify the underlying complement abnormality can help to establish a diagnosis and inform therapeutic decision making(2)
– Urine test: to see protein & blood in urine
Blood test: to see if complement proteins are normal
-GFR
# How do you mange him based on the available evidence?
** KTX patients with C3G treated with eculizumab had the lowest incidence of allograft loss (33%) when compared to those treated with TPE and rituximab. Among those who received no treatment for C3G due to stable allograft function, there was an incidence of allograft loss of 32% in C3GN and 53% in DDD.(3)
References
(1) Swaminathan S, Leung N, Lager DJ, Melton LJ 3rd, Bergstralh EJ,
Rohlinger A, Fervenza FC: Changing incidence of glomerular
disease in Olmsted County, Minnesota: A 30-year renal biopsy
study. Clin J Am Soc Nephrol 1: 483–487, 2006
(2) Barbour S and Gill JS (2015) Advances in the understanding of complement mediated glomerular disease: implications for recurrence in the transplant setting. American Journal of Transplantation 15: 312−9
(3) Pickering M.C., D’Agati V.D., Nester C.M., Smith R.J., Haas M., Appel G.B., Alpers C.E., Bajema I.M., Bedrosian C., Braun M., et al. C3 glomerulopathy: Consensus report. Kidney Int. 2013;84:1079–1089. doi: 10.1038/ki.2013.377. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Thank you
I will advise you to see the NHS England document. The link is: https://www.england.nhs.uk/wp-content/uploads/2017/02/clin-comms-policy-16054p.pdf
Please comment on the biopsy shown above:
This is a high magnification light microscopy image with H&E staining. It shows only one glomerulus.
There is lobulated pattern that is characteristic of membranoproliferative glomerulonephritis(MPGN).
C3 nephropathy is a type of membranoproliferative glomerulonephritis; alternative complement pathway dysregulation leads to C3 deposits in the kidney.
————————————————-
Is this enough to diagnose the recurrence of C3 glomerulopathy?
No, it is not enough.
We need to do immunofluorescence staining to show C3 deposits in the mesangium & capiallary walls.
Electron microscopy, if done, would show mesangial electron dense deposits & subepithelial deposits.
————————————————-
How do you mange him based on the available evidence?
It is a rare disease (1-2 per million in UK population).
Has high recurrence rates(30–50%) within the 1st2 years post-transplant.
It recurs despite maintenance of effective triple immunosuppressive treatments(CNI, MMF, & Prednisolone)
There is 30% rate of graft loss.
Because it is a rare disease it is difficult to do a randomized trials about what is the best treatment.
Treatments used include plasmapheresis, rituximab, and eculizumab.
The rates of allograft loss was the least with the use of eculizumab (33%) as compared to the recurrence after plasmapheresis(42%) or rituximab(81%).
References
1. Surya V. Seshan Steven P. SalvatoreRecurrent Glomerular Diseases in Renal Transplantation with Focus on Role of Electron Microscopy Glomerular Dis 2021;1:205–236 DOI: 10.1159/000517259
2. Clinical Commissioning Policy: Eculizumab in the treatment of recurrence of C3 glomerulopathy post-kidney transplant (all ages): NHS England: 16054/P
3.Maria L Gonzalez Suarez et al. Treatment of C3 Glomerulopathy in Adult Kidney Transplant Recipients: A Systematic Review Med. Sci. 2020, 8, 44; doi:10.3390 /medsci8040044
Thank you
I will advise you to see the NHS England document. The link is: https://www.england.nhs.uk/wp-content/uploads/2017/02/clin-comms-policy-16054p.pdf
-Renal Biopsy sample showing a glomerulus , stained with H&E stain with lobular appearance with increased mesangial matrix and mesangial cells and thickened capillary loops due to endocapillary proliferation(membranoproliferative pattern).
-The available image is not enough to diagnose C3 glomerulopathy:
Specimen needs to be examined with Immunofluorescence to check for diffuse C3 deposition and electron microscopy to demonstrate the dense deposits in the mesangium and capillary wall of a glomerulus.
How do you mange him based on the available evidence?
Basically membranoproliferative glomerulonephritis is the most recurrent GN post transplant which is presented with nephrotic- nephritic picture.
Studies revealed that treatment of post transplant C3 glomerulopathy patients with eculizumab had the lowest rate of allograft loss compared with treatment with plasma exchange and rituximab. However, Patients who received no treatment had an estimated graft loss of approximately 40%. The dose of Eculizumab 900 mg weekly for 4 weeks, followed by eculizumab every other week at a dose of 1200 mg (from week 5).
Thank you
I will advise you to see the NHS England document. The link is: https://www.england.nhs.uk/wp-content/uploads/2017/02/clin-comms-policy-16054p.pdf
biopsy showed membranoproliferative pattern of GN revealed mesangial and endocapillary proliferation with lobulation or double contour of GBM
not enough, we need IF picture, and genetic study to detect homozygous or heterozygous mutations in the regulatory complement proteins factor H (CFH), factor I (CFI), or C3. also, acquired alternative pathway dysregulation may be induced by C3 nephritic factor activity which is present in 45% of C3 glomerulopathy, also low serum C3 and normal C4 is found.
treatment :
control bl.p and proteinuria by ACEI or ARBs
lipid lowering drugs
rituximab
plasmapharesis
eculizumab
follow up
Maria L Gonzalez Suarez, Charat Thongprayoon, Panupong Hansrivijit, Karthik Kovvuru,Swetha R Kanduri, Narothama R Aeddula, Aleksandra I Pivovarova, Api Chewcharat, Tarun Bathini, Michael A Mao,8 Arpita Basu, and Wisit Cheungpasitporn. Treatment of C3 Glomerulopathy in Adult Kidney Transplant Recipients: A Systematic Review. Med Sci (Basel). 2020 Dec; 8(4): 44.
AJKD Atlas of Renal Pathology: Membranoproliferative Glomerulonephritis.
Aude Servais , Laure-Hélène Noël, Véronique Frémeaux-Bacchi, Philippe Lesavre. C3 glomerulopathy. Contrib Nephrol. 2013;181:185-93.
ATLAS
Thank you
I will advise you to see the NHS England document. The link is: https://www.england.nhs.uk/wp-content/uploads/2017/02/clin-comms-policy-16054p.pdf
The biopsy show one glomerulus ( H&E stain) with lobulated appearance, diffuse endocapillary proliferation & mesangial matrix expansion with no crescents.
Diagnosis of C3GN depends mainly on strong C3 staining by IF ( sub-endothelial & intra-membraneous deposit) in absence if immunoglobulin.
KDIGO guidelines recommend treatment of mild to moderate cases with supportive treatment( steroid & MF) & in sever cases ( proteinuria >2g/24hrs, diffuse endocapillary proliferation with or with out crescent) the success was limited with using Pulse MP & immunosuppressive agents.
Treatment of post transplant C3 GN recurrence with eculizumab shows 80% success rate ( 20-30% risk of graft loss), TPE associated with 42% of graft loss & rituxmab associated with high rate (80%) of graft loss.
References:
Suarez M., Thonghrayoon C., Hansrivijit P., Kuvvuru K., Kanduri S., et al. Treatment of C3 Gloerulopathy in Adult Kidney Transplant Recipients: As Systemic Review. 2020, Med Sci-Fi; 8:44.
Thank you
I will advise you to see the NHS England document. The link is: https://www.england.nhs.uk/wp-content/uploads/2017/02/clin-comms-policy-16054p.pdf
recurrent C3 glomerulopathy if :
a)Renal biopsy with light microscopy, immunofluorescence, and electron microscopy confirmed a primary renal diagnosis of C3 glomerulopathy.
b. Recurrent disease with an active glomerulonephritis and cellular crescents on biopsy.
c) On transplant biopsy, there was evidence of glomerular C9 deposition.
d. Recurrent disease that occurs any time after the transplant.
e) Evidence of a severe reduction in transplant function (>20 percent decline in eGFR) within the previous three months at the time of recurrence. If the recurrence occurs immediately after transplant then 20% decline not required.
management –
eculizumab to be started and given for 4 months and stopped after 4 months if-
1. Transplant fails despite therapy.
2. Continuous graft function deteriorates (eGFR) with no sign of therapeutic response.
3. Graft function stabilisation (eGFR).
4. graft function improves (eGFR).
biopsy
lobulated appearance
endocapillary hypercellularity
mesangial hypercellularity
no crescents