Glomerulonephritis Flashcards
(41 cards)
1
Q
Basics of glomerulonephritis
A
2
Q
Manifestations of glomerular disease
A
- Haematuria and/or proteinuria
- Renal insufficiency
- Hypertension
- Oedema
- Hypercoaguability
- Systemic symptoms
Severity ranges from asymptomatic urinary findings → AKI or ESKD
2nd most common cause of CKD leading to RRT
3
Q
Broad classification schemas for glomerulonephritis
A
- Clinical presentation patterns
- Age at presentation
- Complement abnormalities
- Also pathological classification system
4
Q
Clinical classification of glomerulonephritis
A
Macroscopic glomerular haematuria
- IgAN, thin basement menbrane disease, Alport’s syndrome
Asymptomatic urinary abnormalities
- Microscopic glomerular haematuria → same causes as macroscopic
- Non-nephrotic proteinura (150mg - 3.5g in 24 hrs) → IgAN, FSGS
- Nephrotic range proteinuria w/o nephrotic syndrome (proteinrua >3.5g/day + albumin >3.5g/dL w/o oedema) → Secondary FSGS, diabetic nephropathy
Nephritic syndrome
- Mild (glomerular haemturia +/- proteinuria +/- HTN +/- presevered renal function) → Secondary FSGS, lupus nephritis, mesangioproliferative GN
- Severe (diminished renal function) → immune complex mediated GN, infection related GN, C3 glomerulopathy
- RPGN (renal failure over days → weeks + proteinuria + glomerular haematuria) → immune complex mediated, pauci-immune, anti-GBM
Nephrotic syndrome
- Proteinuria >3.5g/day + serum albumi <3.5g/dL +/- oedema +/- lipidaemia→ minimal change disease, membranous nepropathy, primary FSGS, lupus nephritis
Chronic kidney disease
- Evidence of chronic kidney damage + proteinuria +/- haematuria → secondary FSGS, diabetic nephropathy, monoclonal gammopathies
5
Q
Common age of presentations for specific glomerular diseases
A
- Younger (20s/30s) → IgA, lupus nephritis, FSGS
- Middle age → FSGS peaks, diabetic GS, membranous
- Older → diabetic, ANCA, Pauci-immune
MGPN and minimal change constant throughout
6
Q
Glomerular disease classification based on complement levels
A
- _C3/C4 above reference leve_l
- Minimal change, FSGS, membranous, IgA, ANCA-associated vasculitis, diabetic nepropathy, glomerular disease with organised deposits
-
Low C4, Variable C3
- Cryoglobulinaemic nephropathy
-
Low C3, variable C4
- Atypical HUS, C3 glomerulopathy, MPGN
-
Low C3, C4
- Acute post infectious GN, Infection associated glomerulonephritis, proliferative lupus nephritis
7
Q
Glomerulnephritis pathologic classification system
A
8
Q
Notes on immune complex glomerulonephritis
A
- Characterised by granular deposits of polyclonal Ig on immunoflurescence or immunohistochemistry
- Pattern of injury variable → no lesion by LM, mesangial proliferation, endocapillary proliferation, exudative, mebranoproliferative, necrotizing, crescentic, or combination
- Includes:
- IgA nephropathy
- Lupus nephritis
- Fibrillary glomerulonephritis
- Infection related glomerulonephritis
- Autoimmune diseases other than SLE
9
Q
Typical presentation of IgA nephropathy
A
- Most common cause primary GN
- Peak 2nd -3rd decade. 2:1 male to female predominance (NA and Western European populations)
- Incidence of mesangial IgA deposition in healthy individuals 3-16%
Typical presentation
Young male, recurrent episodes of macroscopic haematuria, typically assoicated with mucosal infections (URTI), nephrotic range proteinuria rare
Differentiating IgA nephropathy from post-streptococcal glomerulonephritis: ○ Post streptococcal glomerulonephritis - low complement levels, main symptom is proteinuria (although haematuria can occur), typically an interval between URTI and the onset of renal problems
10
Q
Conditions associated with IgA nephropathy
A
- Cirrhosis + CLD
- ETOH liver disease, HBV, HCV
- Coeliac disease
- HIV infection
- Membranous nephropathy - overlap picture with haematuria and proteinuria
- GPA - occuring when in remission with no other features of recurrent vasculitis
- Infrequent associations
- Dermatitis herpetiformis
- Seronegative arthritis (ank spond)
- Small cell carcinoma
- Lymphoma
- Disseminated TB
- Bronchiolitis obliterans
- IBD
11
Q
Histology seen on renal biopsy of IgA nephropathy
A
Indications for biopsy
- Persistent protein excretion >1000mg/day
- Elevated creatinine
- New onset hypertension
- Significant elevation in BP above a previous stable baseline that does not exceed 140/90
Mesangial hypercellularity, postitive immunofluorescence for IgA and C3
12
Q
Markers of good and poor prognosis in IgA nephropathy
A
- *Good:** frank haematuria
- *Poor:** Male, reduced GFR, proteinuria (pre and post treatment), HTN, smoking, hyperlipidaemia, ACE genotype DD
Prediction tools
Internation IgA Nephropathy Prediction Tool (IIgAN-PT) - risk of 50% decline in GFR or progression to ESKD 5.5 years from diagnosis
13
Q
Management of IgA nepropathy and relevant trials
A
STOP IgA Trial
- RCT, 6 month run in with supportive care, patients with persistent proteinuria after this point (>0.75g/day) assigned to supportive care alone or supportive care + immunosuppression
- Endpoints → full remission (PCR<0.2 + <5ml/min reduction in GFR), and decrease in GFR >15 ml/min
- Immunosuppression arm → increased rate of clinical remission (significant), no significant difference between groups in relation to decline in GFR
TESTING Trial
- High dose glucocorticoids vs supportive care in IgAN following 3/12 supportive care
- Had to be modified due to high rates serious infections/AE in methypred arm
- Concluded lower dose glucocorticoids combined with PJP prophylaxis lowers the risk of progressino to ESKD without SAEs A/W higher doses
- 75% Chinese population - might not be generalisable
General approach to treatment
- Goal is to prevent progression to ESKD primarily through non=immunosuppresive strategies
- Score kidney biopsy using Oxford classification MEST-C score
- Assess risk of progressive disease using IIgAN-PT
- Supportive care → BP control, maximally tolerated RAAS blockade, treat dyslipidaemia, lifestyle modifications - dietary Na and protein restriction, smoking cessations, weight control and exercise, consider SGLT2i if eGFR >30ml/min - for 3-6 months
- If high risk proteinuria >1g/day → consider immunosuppressants
14
Q
Lupus Nephritis - incidence, timing of presentation
A
- Most patients with SLE with have evidence of clinical renal disease at some point in course of illness
- European study → 16% have LN at diagnosis, 28% at 10 year follow up
- US → 32% LN within 1 year of dx, 47% at 9 year follow up
- Most LN presents within 6-36 months of diagnosis
- Elevated creatinine eventually develops in 30% → decreased renal function uncommon within first few years of diagnosis
- Highest risk of lupus nephritis early in time of course of SLE
- Male, younger age (<33 year at dx, non-whites)
15
Q
Poor prognostic indictors for lupus nephritis
A
Black, Hispanic, elevated serum creatinine at presentation, failure to achieve remission, high chronicity index on biopsy
16
Q
Features of lupus nephritis
A
All patients with SLE should have regular screening - urinalysis (haematuria + cellular casts), spot PCR, serum creatinine/eGFR, dsDNA and C3/C4
Kidney biopsy
- For most patients who develop evidence of renal involvement
- Not for <0.5g/day proteinuria + bland urne sediment unless worsening renal function
- Important to determine class as treatment is guided by this, clinical presentation may not accurately reflect severity of histologic findings
Features
Nephrotic syndrome
Microscopic haematuria
Acute renal failure
Lupus serology - DSDNA, C3, C4
17
Q
Stages of lupus nephritis
A
- *Stage I: minimal mesangial lupus nephritis**
- *Stage II: Mesangial proliferation** → microscopic haemturia +/- proteinuria (no specific therapy unless progression)
- *Stage III: Focal**, <50% glomeruli involved → microscopic haematuria, proteinuria, +/- HTN, +/- decreased GFR +/- nephrotic syndrome
- *Stage IV: Diffuse,** >50% glomeruli involved → microsopic haemturia, proteinuria, HTN, decreased GFR, nephrotic syndrome
- Most common → also A/W significant hypocomplementaemia and elevated dsDNA levels
- *Stage V: Pure membranous** → nephrotic syndrome +/- microscopic haematuria +/- HTN, usually have normal or only slightly elevated serum creatinine
- *Stage VI: Advanced sclerosing,** >90% glomeruli involved → Slowly progressive renal dysfunction + proteinuria, usually without microscopic haematuria. Immunosuppression unlikely to be of benefit
18
Q
Histological features of lupus nephritis
A
- Glomerular deposits - IgG and co-deposits IgA, IgM, C3 and C1q
- Glomerular deposits simulataneosly seen in mesangial, subendothelial, subepithelial locations
- Extragloerular immune type deposits within TBM, interstitium and vessels
- Tubuloreticular inclusions in the glomerular endothelial cells
19
Q
Principles of treatment in lupus nephritis:
A
Induction agents: - Cyclophosphamide, prednisone, mycophenolate, CNIs + MMF (advantage of voclosporin in that it does not require therapeutic drug monitoring compared to tacrolimus). Recent studies belimumab + MMF or cyclophosphamide.
Rituximab in refactory cases
Maintainence agents: Mycophenolate or azathioprine to continue for at least 2 years post remission
20
Q
Manifestations of cyclophosphamide toxicity:
A
- Infertiliy
- Malignancy
- Bladder toxicity
- Myelosupression
- Major infection
- Herpes zoster
21
Q
Notes on infection related glomerulonephritis
A
- Replaces post-infectious GN - previously mostly seen in children in the context of URT or skin infections → increasingly common in adults now (34% cases elderly)
- Risk factors
- Male, immunocompromised, alcoholism, malignancy, severe malnutrition, synthetic heart valve, IVDU, AIDS, TB
- In adult disease more likely to be related to non-strep infections e.g. staph
- Typically URTI in younger patients, skin in elderly
- Strep GN still more common in developing countries
- Diabetes major risk factor for staph GN
- Diagnosis → biopsy in most with preceding or concurrent infection with low c3
- Differential → SLE, cryoglobulinaemia, C3 glomerulopathy, IgA, ANCA
22
Q
Features of Anti-GBM glomerulonephritis
A
- Rare, small vessel vasculitis affecting the capillary beds of the kidneys and lungs, assoicated with pulmonary haemorrhage and rapidly progessive glomerulonephritis
- Caused by anti-GBM antibodies to type IV collagen (pathogenic antibodies)
- More common in men (2:1), bimodal age distribution (peaks in 20-30, and 60-70)
- Associated with HLA DR2, smoking, hydrocarbons, alemtuzumab
23
Q
Factors which increase liklihood of pulmonary haemorrhage in Goodpasture syndrome
A
- Smoking
- LRTI
- Pulmonary oedema
- Inhalation of hydrocarbons
- Young males
24
Q
Finding on renal biopsy for Anti-GBM glomerulonephritis
A
Linear IgG deposits along basement membrane on immunofluroescence or immunohistochemistry. Also frequently C3 deposits.
Detection of circulating anti-GBM antibodies
25
Management of Anti-GBM glomerulonephritis
* Plasma exchange, steroids, cyclophosphamide
* Relapse after transplant uncommon
* Can occur de novo after transplant for Alport's syndrome
* Co-presentation with ANCA-associated vasculitis and mebranous nephropathy
26
GN with complement consumption
1. Post infectious 2. Lupus 3. Mesangioproliferative
27
Classification of RPGN
1. Immune complex mediated - post infectious, lupus, MCGN, IgA
2. Anti-GBM
3. Pauci immune - ANCA mediated (pANCA/anti MPO, cANCA/anti PR3)
28
Notes on Monoclonal Ig Glomerulonephritis
* Monotypic Ig deposits in glomeruli and/or along tubular BM on immunoflurescence/immunohistochemistry
* A/W underlying monoclonal gammopathy/paraproteinaemia in many but not all
* Examples:
* Proliferative forms of monoconal Ig deposition disease
* Immunotactoid GN
* Fibrillary GN with monoclonal Ig deposits
* If none of the above distinct patterns → proliferative GN with monoclonal Ig depositis
**Monoclonal gammopathy of renal significance**
* Acknowledges a clonal plasma cell or b lymphocyte proliferation causing a renal lesion in the absence of haematological malignancy or other myeloma defining event
29
Notes on monoclonal Ig deposition disease
* Deposition of MIg alone the glomerular and tubular basement membrane
* Three types:
* Light chain deposition disease
* Most common
* 80-90% → deposits composed of k chains
* Heavy chain ‘’'
* Deposits of truncated y chains, rarely a and u
* Co-deposits of C3 and C1q can be seen → hypocomplementaemia
* Light heavy chain deposition disease
* Presentation
* Renal: proteinuria, nephrotic syndrome and renal insufficiency
* Urine: monoclonal FLCs and albumin
* Serum: abnormal FLC ratio
* Other: heart, liver, skin
30
Notes on proliferative GN with monoclonal Ig deposition
* Proliferative GN with exclusively glomerular MIg deposits on IF and ordinary granular electron dense deposits seen on EM
* Deposits
* Most often IgG 3 subclass
* IgM less common, rarely IgA
* Requires exclusion of cryoglobulinaemia
* Presentation
* Renal: significant proteinuria and often nephrotic syndrome. Variable degrees of haematuria and renal insufficiency
* HTN common, can be severe
* C3/C4 low in one third
* 20-30% detectable M protein in serum or urine
31
Notes on immunotactoid glomerulopathy
* Prolierfative GN on light microscopy, IgG deposits on IF, and capillary wall deposits with a microtubular structure on EM
* Deposits:
* IgG → 1 subclass most common
* Co-deposition of C1q and C3, IgM in some patients
* Transiently positive tests for serum cryoglobulins reported
* Presentation
* Renal: proteinuria often with NS, haematuria and variable levels of renal insufficiency
* HTN common
* Patients generally older
* Often have underlying lymphoproliferative disorder
32
Notes on fibrillary glomerulonephritis
* Glomerular deposition of nonamyloid fibrills
* Mesangial proliferative GN most common pattern, then membranoproliferative, endocapillary proliferative and diffuse sclerosing GN
* Crescents in up to 25%
* Deposits:
* IgG in all patients with C3 co-deposits
* IgA and IgM in some patients
* C1q codeposits in some
* Presentation
* Renal: proteinuria, haematuria, renal impairment
* HTN common
* \<20% have a momoclonal gammopatyh
* Also A/W malignancies, autoimmune disease, hepatitis C
33
Notes on cryoglobulins
* Circulating Igs that reversibly precipitate on cooling of the serum and redissolve on warming
**Type 1**
* Single MIg (IgG, IgM, less commonly IgA)
* Due to underlying haematological malignancy
* Often A/W hyperviscosity syndrome
**Type 2**
* Mixed cryoglobulin composed of MIg complexed to polyclonal Ig (usually IgG)
* A/W underlying viral infections, dysproteinaemias or autoimmune disease
**Type 3**
* Mixed cryoglobulin composed of polyclonal Ig (usually IgM, and IgG)
* Often secondary to autoimmune diseases or infections
34
Notes on Cryoglobulinaemic Glomerulonephritis
* Membranoproliferative pattern with abundant infiltrating macrophages and intraluminal PAS positive deposits on LM
* Deposits:
* Mostly IgM, less often IgG, co-deposition of C1q and C3
* Presentation
* Type 1
* Features of TMA common (Raynaud's, livedo reticularis, acrocyanosis)
* Type 2 and 3
* Meltzer triad: weakness, arthralgias and purpura, less commonly present with peripheral neuropathy
* RF activity
35
Notes on crystal storing histiocytosis
* Numerous enlarged histiocytes containing MIg noted in glomeruli and/or interstitium
* LM: glomerular capillary loops infilatrated with histiocytes, sometimes associated with membranoproliferative features and subendothelial deposits
* Deposits
* Typically k light chain restricted
* Presentation
* Proteinuria with or without NS + renal insufficiency
* Most frequently seen with MM and lymphoproliferative disorders
* Only rarely seen in MGRS
36
Notes on crystalglobulinaemia
* Extracellular deposition of large MIg crystals within systemic vascular lumens, including renal arteries and glomerular capillaries
* LM: crystals visible as eosinophilic, PAS positive and trichrome red
* Deposits:
* Usually IgG or IgA
* Less common light chain only
* Presentation:
* AKI, large vessel involvement can produce renal infarction
* Systemic → rash, polyarthralgias, neuroopathy
* Most frequently seen in setting of MM/lymphoproliferative disorders
* Rarely seen in MGRS
37
Classification of Complement mediated MPGN
38
Notes on C3 glomerulopathy
* Dominant C3 deposits in the glomeruli with minimal of no Ig deposits on IF or IH
* EM differentiates between Dense Deposit Disease and C3 glomerulonephritis
* Pattern of glomerular injury - variable → mesangial proliferative, diffuse endocapillary proliferative, membranoproliferative, necrotizing, and crescenteric or sclerosing
* A/W abnormalities in regulation of the alternate pathway of complement → C3 convertase activity increased by:
* Generation og C3 convertase stabilising autoantibodies called C3 nephritic factors
* Loss of functional Factor H activity → mutations or acquired
* C3 mutations that renders activated C3 resistant to factor H inhibition (DDD)
* C3 mutation leading to functional Factor H deficiency (C3GN)
* Others that you won't remember
39
Notes on Dense Deposit Disease
* Affects → children, young adults, older adults (A/W monoclonal gammopathies)
* Majority hae antibodies that stabilise C3 convertase in circulation (C3 nephritic factors)
* LM: MPGN or mesangial proliferative, diffuse proliferative, crescenteric and sclerosing
* IF - C3 deposits
* EM - sausage shaped, waxy, densly osmophilic deposits along the GBM and mesangium
* Drusen on fundoscopy
40
Notes on C3 glomerulonephritis
* Excessive activation of the alternate complement cascade
* Mutation in or antibodies to complement regulating proteins
* LM: MPGN, mesangial proliferative, diffuse proliferative, crescenteric, sclerosing
* IF: C3 deposition alongcapillary walls and mesangium with no Ig deposition
* EM: Deposits similar to those seen with IC mediated GN, no sausages like DDD
* Presentation
* Proteinuria, NS, haematuria, variable HTN, and renal impairment
* C3 levels low, normal C4
* Some patients present post nonstrep URTI with GN
* Treatment:
* Mild - supportive
* Moderate to severe - add GC and MMF
* RPGN - add cyclophosphamide or MMM + steroids +/- eculizumab +/- plasma exchange (if genetic factor H defect)
* Refactor disease - eculizumab
* Transplant
41
Typical biopsy findings at kidney transplant and associated disorders
