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Glomerulonephritis Flashcards

1
Q

Basics of glomerulonephritis

A
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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

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3
Q

Broad classification schemas for glomerulonephritis

A
  • Clinical presentation patterns
  • Age at presentation
  • Complement abnormalities
  • Also pathological classification system
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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
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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

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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
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7
Q

Glomerulnephritis pathologic classification system

A
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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
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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

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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
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11
Q

Histology seen on renal biopsy of IgA nephropathy

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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

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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

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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
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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)
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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

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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

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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
  1. Infertiliy
  2. Malignancy
  3. Bladder toxicity
  4. Myelosupression
  5. Major infection
  6. 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
Q

Management of Anti-GBM glomerulonephritis

A
  • 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
Q

GN with complement consumption

A
  1. Post infectious 2. Lupus 3. Mesangioproliferative
27
Q

Classification of RPGN

A
  1. Immune complex mediated - post infectious, lupus, MCGN, IgA
  2. Anti-GBM
  3. Pauci immune - ANCA mediated (pANCA/anti MPO, cANCA/anti PR3)
28
Q

Notes on Monoclonal Ig Glomerulonephritis

A
  • 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
Q

Notes on monoclonal Ig deposition disease

A
  • 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
Q

Notes on proliferative GN with monoclonal Ig deposition

A
  • 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
Q

Notes on immunotactoid glomerulopathy

A
  • 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
Q

Notes on fibrillary glomerulonephritis

A
  • 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
Q

Notes on cryoglobulins

A
  • 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
Q

Notes on Cryoglobulinaemic Glomerulonephritis

A
  • 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
Q

Notes on crystal storing histiocytosis

A
  • 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
Q

Notes on crystalglobulinaemia

A
  • 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
Q

Classification of Complement mediated MPGN

A
38
Q

Notes on C3 glomerulopathy

A
  • 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
Q

Notes on Dense Deposit Disease

A
  • 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
Q

Notes on C3 glomerulonephritis

A
  • 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
Q

Typical biopsy findings at kidney transplant and associated disorders

A

Renal (7 decks)

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