Glomerulonephritis Flashcards
Membranous nephritis/nephropathy (MN)
Description:
- Membranous nephropathy (MN) is common cause of nephrotic syndrome in non-diabetic adults.
- mostly primary (idiopathic) or secondary (associated with Hep B, auto immune disease, thyroiditis, malignancy, NSAIDs) MN.
- Pathophys: Gradual accumulation of subepithelial deposits resulting in podocyte damage, subsequent nephrotic syndrome.
Presentation
- Nephrotic syndrome with unexplained proteinuria, hypoalbuminemia, oedema/weight gain. Proteinuria is usu present for several months before diagnosis of MN.
- Note, MN associated nephrotic syndrome develops much slower than minimal change disease or FSGS
History:
- NSAID overuse
- Hep B, C
- Autoimmune disease e.g. SLE
- Malignancy
Work up for MN
- Anti-PLA2R antibody (by ELISA). Presence of PLA2R antibody is a highly specific diagnostic biomarker, but also prognostic for MN.
- Biochem inc UEC, albumin, FBE. 70% patients have normal renal function / GFR and blood pressure on presentation. AKI is uncommon (unless due to other reasons e.g. aggressive diuresis).
- Urinalysis with examination of the urinary sediment. Urinalysis shows proteinuria, oval fat bodies, lipid droplets, fatty casts. Microscopic haematuria in 50% but red cell casts are rare.
- 24-hour urine collection for protein quantification and creatinine clearance
- ANA and, if positive, anti-double-stranded DNA (anti-dsDNA), anti-Sm, anti-Ro/SSA, and anti-La/SSB antibodies (indicates MN 2ndary to auto-imm dx)
- Serum C3 and C4 (low)
- Tests for hepatitis B and C viruses and HIV
- In patients older than 50 years – serum free light chains (SFLCs) and serum protein electrophoresis (SPEP) with immunofixation – to check for MM
- Chest radiograph (or computed tomography [CT] of the chest in patients with a history of smoking or asbestos exposure) (looking for malignancy or sarcoidosis)
Diagnosis MN
Primary MN: Presence of Anti PLA2R antibodies and no evidence of secondary cause (normal renal f^n, negative infective / autoimm/ malignancy scrn)
- Anti PLA2R antibody is present in 70-80% of patients with Primary membranous nephritis (PMN). Serology testing is first line (esp pts with contraindications for biopsy, in which case you would repeat serology in 3months if results are -ve)
- Presence of PLA2R antibody is a highly specific diagnostic biomarker, but also prognostic.
- High titres of PLA2R Ab are linked with lower chance of spontaneous remission or immunosuppressant-induced remission, and a higher risk of nephrotic syndrome and ESRF.
- Low titres of PLA2R antibody are linked with a higher rate of remission
Renal biopsy:
- warranted if anti-PLA2R is negative, or if pt has abnormal renal f^n, or if secondary cause, should proceed to renal bx.
- to investigate for changes consistent with CKD or secondary cause
- Histopathology shows glomerular basement membrane thickening with little or no cellular infiltration / proliferation.
- Electron microscopy shows deposits in the subepithelial space across the BM.
- Immunofluorescence shows diffuse, granular, IgG and C3 deposition along capillary walls.
Treatment MN
Rituximab.
Goal of treatment: complete disappearance of PLA2R antibody
Resources
UpToDate - membranous nephropathy clinical manifestations.
Focal segmental glomerulosclerosis (FSGS)
Description
- type of histological focal renal lesion that causes nephrotic syndrome
Histopath: segmental sclerosis that’s focal (involves at least one glomerulus; but it’s not really as focal as the name suggests)
Immunofluorescence usu shows NO immune deposits, or sometimes non-specific binding of IgM, C3, C1.
Classification:
Primary FSGS:
- toxic factor causes generalised podocyte dysfunction/damage
- acute onset nephrotic sydrome with oedema, low albumin, high grade proteinuria; haematuria (50%); HTN (20%); renal impairment (25-50%)
Secondary FSGS:
- podocyte damage from virus, drugs, reduction in nephron mass
- slow progressive proteinuria and renal impairment, no oedema, normal albumin. (except for HIV-associated or pamindronate-associated FSGS, they present w nephrotic syndrome)
- normal albumin
Genetic:
- resulting from autosomal recessive mutations
- Features present from childhood. Progress to massive proteinuria in adolescence. Slow progressing CKD
- often glucocorticoid resistant
Treatment: immunosuppression
Minimal change disease
Pathogenesis:
- podocyte is mainly affected (Podocytes are cells in Bowman’s capsule that wrap around capillaries of the glomerulus. Podocyte cells make up the epithelial lining of Bowman’s capsule.)
- not characterised by immune deposition
- underlying cause unclear. ?T cell dysfunction ?role of B cells
Presentation: sudden onset (days-weeks) nephrotic syndrome inc proteinuria, albuminuria, oedema, hypoalbuminemia , hyperlipidemia.
Diagnosis: renal biopsy to confirm
Epidemiology: major cause of nephrotic syndrome in children (90%), less so in adults (10%).
Histopath: diffuse effacement (fusion) of epithelial foot processess
Specific biomarkers: podocyte B7-1, angiopoetin-like 4, CD44, CLCF1
Factors associated with increased risk/incidence of MCD: drugs (NSAIDs, antibiotics, pamindronate), neoplasms (hodgkins L), infections (syphilis, TB, Hep C), allergy, other glomerular disease
Main other differential is FSGS, but that is slower progressing and has sclerotic and non-sclerotic lesions
Treatment: glucocorticoids
IgA nephropathy
Epi:
- most common primary GN globally
Pathophys:
- mediated by pathogenic galactose-deficient IgA1 bound antiglycan antibodies. 4 step process:
- 1st: high levels of polymeric galactose deficient IgA1 (lacking O-glycan molecules), which self-aggregate
- 2nd: Gd-IgA1 that don’t self aggregate, have exposed N-acetylgalactosamine component, which binds to IgA1 autoantibodies or IgG glycan specific Abs (targeting N-acetylgalactosamine)
- 3rd: formation of galactose-deficient–IgA1 immune complexes
- 4th: immune complex deposition in the mesangium of the kidney, leading to glomerular injury, precipitating CKD
_Complement involvemen_t:
- complement activation is key in IgA nephropathy. Specifically activation of alternate and MBL pathways.
- Galactase deficienct IgA1 antibody immune complexes activate C3. (Gd-IgA1 Ab binds to many different proteins to form immune complexes). This leads to generation of C3a, C5a, and eventual MAC. C3 deposition at mesangial cells is present in >90% ppl. low C3 levels may be poor prognostic marker of IgAN. MAC complexes deposit at the mesangium also.
- Alternative pathyway components inc properdin and factor H. Properdin co-deposited with IgA and C3 is present in 75-100% ppl, Factor H in 30-90% ppl. Some studies suggest Factor H and CFHR proteins results in increased alternative pathway activation and progressive IgAN disease.
- [image: involvement of complement in pathogenesis of IgN)
Causes
- certain infections may precipitate IgA nephropathy inc CMV, Haemophilus, S.aureus, toxoplasmosis.
- Genetics (familial IgA nephropathy)
Diagnosis:
- finding IgA as the dominant or codominant Ig in the glomerular immunodeposits
Prognosis:
- 40% pts get ESRF within 20yrs after diagnosis
Sources: https://jasn.asnjournals.org/content/26/7/1503, UpToDate - pathogenesis of IgA nephropathy
Membranoproliferative (aka mesangiocapillary) glomerulonephritis (MPGN)
Pathogenesis/cause/classification
- involves 1 of 3 mechanisms (based on immunofluorenscence - also refer to classification slide for algorithm)
1. immune complex deposition
- positive staining for Ig and complement seen in pts with immune-complement mixed MPGN
- precipitated by chronic infection (inc Hep C and B, endocarditis, fungal, parasitic inc schistosomiasis); auto-imm dx (inc SLE/SS/RA. Involves deposition of all immune components inc IgG, IgM, IgA, C1q, C3, C4, kappa, lambda); monoclonal gammopathy (involves deposition of either kappa or lambda light chains)
2. complement dysregulation leading to persistent activation of alternative complement pathway
- less common than immune complex mediated
- caused by monoclonal gammopathy (e.g. C3 convertase autoantibody aka C3 nephritic factor)
- positive C3 and no Ig seen in complement-mediated MPGN
- complement products deposit on capillary walls and mesangium
- types: C3 or C4 glomerulonephritis or dense deposit disease (with minimal/no immunoglobulin staining)
3. endothelial injury, followed by reparative changes
- no immunoglobulin or complement deposition
- causes: TTP, HUS, APL syndrome, nephropathy associated with BM transplant, chronic renal allograft nephropathy, radiation nephritis, malignant HTN
Presentation
- haematuria, renal impairment
Diagnosis/work-up
- renal biopsy shows MPGN lesion. Immunofluorescence allows further classification
- low C3/C4. CH50 and AH50 provide a measure of complement activation.
- urinalysis shows dysmorphic red cells with occasional casts, proteinuria
- should look for cause by testing HepC/B serology, auto-imm panel, SPEP (for monoclonal gammopathy)
Histopath changes of MPGN:
- Glomerular BM thickening (due to immune complex/complement deposits, and new BM formation
- mesangial hypercellularity (also due to influx from monocytes)
- endocapillary proliferation with double-contour glomerular capillary walls
Old classification (based on electron microscopy)
- type I MPGN: discrete immune deposits in mesangium and subendothelial space
- type II: Dense deposit disease (DDD)
- type III: discrete immune deposits in mesangium, subendothelial, and subepithelial spaces
Prognosis:
- MPGN associated with monoclonal immunoglobulin deposits has a high rate of disease recurrence (70%) post renal transplant, with high risk graft failure
Source: UpToDate - MPGN classification, features, diagnosis
MPGN (image - histopath)
MPGN histopath
- thickening of capillary walls with double contours (long arrow in image) and focal areas of cellular proliferation (short arrow in image). The double-contour or tram-track appearance represents interposition of mesangial cell elements with new glomerular basement membrane synthesis.
Classification of MPGN
In image, DDD means dense deposit disease
