Glomerulonephritis Flashcards
Basics of glomerulonephritis
Manifestations of glomerular disease
- 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
Broad classification schemas for glomerulonephritis
- Clinical presentation patterns
- Age at presentation
- Complement abnormalities
- Also pathological classification system
Clinical classification of glomerulonephritis
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
Common age of presentations for specific glomerular diseases
- 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
Glomerular disease classification based on complement levels
- _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
Glomerulnephritis pathologic classification system
Notes on immune complex glomerulonephritis
- 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
Typical presentation of IgA nephropathy
- 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
Conditions associated with IgA nephropathy
- 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
Histology seen on renal biopsy of IgA nephropathy
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
Markers of good and poor prognosis in IgA nephropathy
- *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
Management of IgA nepropathy and relevant trials
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
Lupus Nephritis - incidence, timing of presentation
- 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)
Poor prognostic indictors for lupus nephritis
Black, Hispanic, elevated serum creatinine at presentation, failure to achieve remission, high chronicity index on biopsy
Features of lupus nephritis
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
Stages of lupus nephritis
- *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
Histological features of lupus nephritis
- 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
Principles of treatment in lupus nephritis:
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
Manifestations of cyclophosphamide toxicity:
- Infertiliy
- Malignancy
- Bladder toxicity
- Myelosupression
- Major infection
- Herpes zoster
Notes on infection related glomerulonephritis
- 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
Features of Anti-GBM glomerulonephritis
- 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
Factors which increase liklihood of pulmonary haemorrhage in Goodpasture syndrome
- Smoking
- LRTI
- Pulmonary oedema
- Inhalation of hydrocarbons
- Young males
Finding on renal biopsy for Anti-GBM glomerulonephritis
Linear IgG deposits along basement membrane on immunofluroescence or immunohistochemistry. Also frequently C3 deposits.
Detection of circulating anti-GBM antibodies
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
GN with complement consumption
- Post infectious 2. Lupus 3. Mesangioproliferative
Classification of RPGN
- Immune complex mediated - post infectious, lupus, MCGN, IgA
- Anti-GBM
- Pauci immune - ANCA mediated (pANCA/anti MPO, cANCA/anti PR3)
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
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
- Light chain deposition disease
- Presentation
- Renal: proteinuria, nephrotic syndrome and renal insufficiency
- Urine: monoclonal FLCs and albumin
- Serum: abnormal FLC ratio
- Other: heart, liver, skin
- Renal: proteinuria, nephrotic syndrome and renal insufficiency
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
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
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
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
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
- Type 1
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
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
Classification of Complement mediated MPGN
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
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
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
Typical biopsy findings at kidney transplant and associated disorders
