Glomerulonephritis

Question 1

Nephrotic syndrome - what?

Answer 1

1. Massive proteinuria (leads to)
2. Hypoalbuminemia (leads to)
3. Edema
4. Hyperlipidemia/hyperlipiduria

Question 2

Nephritic syndrome - what?

Answer 2

Inflammation related

1. Hematuria inflammation allows leak of rbc into filtrate
2. Haemodynamic changes lead to reduced GFR leads to Oliguria and
3. Azotemia (increased nitrogen containing compounds eg urea in blood)
4. Hypertension (due to water retention and increased renin from ischaemic kidneys)

Question 3

Basic pathophysiology

Answer 3

Diseases involving glomeruli largely immune mediated
Maybe be auto-antibody, antigen-antibody complexes may implant themselves in the glomerulus, T-cells don’t really play a role

Question 4

What is the glomerulus?

Answer 4

Cluster of capillaries in Bowman’s capsule at end of a nephron
3 layers - capillary endothelial cells, basement membrane, podocyte cells

Question 5

What does the glomerulus do?

Answer 5

Filtration
About 20% of blood volume that passes through
BIG molecules (eg protein) don’t pass through sieve
Glomerulus slightly negatively charged so quite small negative things also don’t pass through (eg albumin) positive things do
Very small things pass even if negative eg chloride
Also determined by the pressure

Question 6

Presentation of glomerular disease

Answer 6

Nephrotic or nephritic syndrome or rapidly progressive glomerulonephritis

Question 7

Causes of nephrotic syndrome

Answer 7

Minimal change disease
Focal segmental glomerulosclerosis
Membranous nephropathy
Membranoproliferative glomerulonephritis

Question 8

Basic pathophysiology of the nephrotic syndromes

Answer 8

Derangement in walls of the capillaries - proteins escape into filtrate
Usually relating to podocytes - often effaced (flattened) and as change shape the filtration slits between adjacent podocyes are damaged - proteins escape!

Question 9

Minimal change disease

Answer 9

More common in children
Not (m)any changes under microscope
On electron micrographs, podocytes appear flattened - foot processes are fewer and effaced
Most children with minimal change disease respond well to steroids, some relapse and a few develop CKD as adults

Question 10

Focal segmental glomerulosclerosis

Answer 10

Only some glomeruli involved (focal)
Usually only a portion of the glomerulus is damaged (segmental)
Can be primary (idiopathic) or related to other conditions (HIV/heroin), some arise from other forms of glomerulonephritis, rare cases are hereditary.
Exact mechanism unclear
Initiating event is podocyte injury
Proteins leak out of blood -> collect in places -> form masses of hyaline (pink) material -> encroach on or obliterate capillaries
Poor prognosis, poor response to steroids

Question 11

Membranous nephropathy aka membranous glomerulonephritis

Answer 11

Antibodies react to antigen in the glomerulus > antigen-antibody complexes > deposit selves in glomerular basement membrane
Capillary walls thicken as immune complexes accumulate
Damage > complement release > podocyte damage > protease and oxidant release > capillary wall damage > permeability
Most cases idiopathic
Clinical course variable
Often mild

Question 12

Membranoproliferative glomerulonephritis (MPGN)

Answer 12

Two types:
Type 1: characterised by subendothelial (and sometimes subepithelial/mesangial) immunoglobulin and complement deposits
Type 2: characterised by deposits of complement in basement membrane proper
Both: Thickened GBM on light microscopy, looks like GBM split in two in silver stain (due to mesangial and inflammatory cells stuck)
Associated with infection or idiopathic
Prognosis generally poor

Question 13

Causes of nephritic syndromes

Answer 13

Acute infectious (post-streptococcal) glomerulonephritis
IgA nephropathy (Berger disease)
Hereditary nephritis

Question 14

Basic pathophysiology of Nephritic syndromes

Answer 14

Proliferation of cells within glomeruli along with inflammation in the glomerulus.
Inflammatory cells damage capillary walls > red cells leak out
Requires more pressure to pump blood through glomerulus (cos it’s stuffed full of cells) > reduced GFR > oliguria

Question 15

Acute infectious (post-streptococcal) glomerulonephritis

Answer 15

Usually in children after group A strep
Body produces Ab to bacteria > forms Ag-Ab complex > gets stuck in glomerulus > immune response > cells proliferate
Light microscopy: glomeruli big and hypercellular
Most children recover, some develop rapidly progressive glomerulonephritis adults tend to be affected more seriously

Question 16

IgA nephropathy (Berger disease)

Answer 16

Most common glomerular disease worldwide
Usually child or young adult
Follows URTI > haematuria > resolves > comes back every few months
Overproduction of IgA (when get URTI) > stuck in mesangium > complement activation > damage
Immunofluorescence: lots of IgA (light microscopy: varied)
Prognosis good despite recurrent haematuria

Question 17

Hereditary nephritis

Answer 17

Group of hereditary diseases with mutations in GBM proteins.

Best known is Alport syndrome

Question 18

Alport syndrome

Answer 18

Glomerulonephritis, deafness and eye disorders
No microscopic changes til late, then interstitial cells look foamy, glomeruli become sclerotic, tubules atrophy, interstitium becomes fibrotic.
X linked. Mutation coding type IV collagen
Male: haematuria as child/young adult; renal failure 20-50yo

Question 19

Rapidly progressive (crescentic) glomerulonephritis causes

Answer 19

Type I (anti-GBM antibody)
Type II (immune-complex mediated)
Type III (pauci-immune)

Question 20

RPGN basic pathophysiology

Answer 20

Severely oliguric and develop renal failure within a few weeks or months
(Kinda like nephritic but faster)
Mostly immune mediated
Crescent shaped masses of proliferating cells and leukocytes within glomerular tuft

Question 21

Type I (anti-GMB antibody) RPGN

Answer 21

Linear deposition of IgG +/- complement on GBM.
Some patients: IgG also binds to basement membrane in lungs - Goodpasture syndrome
Plasmapheresis removes antibodies

Question 22

Type II (immune-complex mediated) RPGN

Answer 22

Immune complexes found along GBM +/- mesangium
Idiopathic or evolve from post-streptococcal GN, lupus, IgA nephropathy or HSP
Plasmapheresis doesn’t help

Question 23

Type III (pauci-immune)

Answer 23

Antineutrophil cytoplasmic antibodies (ANCAs).
Idiopathic or related to vasculitides that have ANCAs eg wegeners
Can have enough proteinuria to look like nephrotic syndrome
Plasmapheresis sometimes helpful

Question 24

Investigations: bedside

Answer 24

Urine dipstick and microscopy - haematuria, proteinuria, sometimes RBC casts
Also, urine protein quantification: 24hr sample or prot: creatinine ratio

Question 25

Investigations bloods

Answer 25

FBC, CRP, ESR
U&E: high K+, Low bicarb, high phosphate
GFR - eGFR
LFTs: low albumin in nephrotic syndrome
Glucose
Immunoglobulins, serum and urine electrophoresis: exclude myeloma
Complement and autoantibodies: ANA, dsDNA, ANCA, anti-GBM
Viral screen (hepatitis)

Question 26

Investigations: imaging and other

Answer 26

Renal US, CXR

Rebal biopsy unless very mild or nephrotic syndrome in children

Question 27

General management

Answer 27

Monitor haematuria and proteinuria
Treat oedema with diuretics and K+ supplements
Blood pressure control: with targets and using ACEi/ARBs
Dietary advice on protein content
Lipid lowering therapy

Question 28

Specific management

Answer 28

Dependent on type and degree of histological changes
Include:
- immunosuppression: steroids, alkylating agents (cyclophosphamide), cytotixics (azathioprine), levamisole, ciclosporine A
- antithrombotics: dipyridamole, warfarin, aspirin
- IVIG
- Dialysis