L14 - Glomerular diseases

Question 1

Glomerular diseases definition and importance

Answer 1

Glomerular diseases are disorders affecting the glomerulus; common cause of chronic renal failure

Question 2

Glomerular diseases nomenclature and classifications

Answer 2

*** Nomenclature and characteristics can co-exist, even for nephritic and nephrotic syndromes***

1) Focal
2) Diffuse
3) Proliferative
4) Membranous
5) Membranoproliferative/mesangiocapillary
6) Primary
7) Secondary
8) Hereditary
9) Presented with nephritic syndrome
10) Presented with nephrotic syndrome
11) Glomerulonephritis

Question 3

Focal glomerular diseases defintion

Answer 3

< 50% of glomeruli are involved

Question 4

Diffuse glomerular diseases definition

Answer 4

>50% of glomeruli are involved

Question 5

Proliferative glomerular diseases definition

Answer 5

Hypercellularity observed

Question 6

Membranous glomerular diseases definition

Answer 6

Thickening of glomerular basement membrane (due to subendothelial/epimembraneous deposits)

Question 7

Membranoproliferative definition

Answer 7

AKA Mesangiocapillary; caused by deposits in the kidney glomerular mesangium and basement membrane (GBM) thickening (subendothelial deposits)

Question 8

Primary glomerular diseases definition

Answer 8

Glomerular diseases in which the kidneys are the only or predominant organs involved; thus a primary disease of the kidney

Question 9

Secondary glomerular diseases defintion

Answer 9

Secondary glomerular diseases are those in which the kidney is injured in the course of systemic diseases (secondary to systemic diseases)

Question 10

Primary vs secondary glomerular diseases

Answer 10

• Primary glomerular diseases are those in which the kidneys are the only or predominant organs involved
• Secondary glomerular diseases are those in which the kidney is injured in the course of systemic diseases.

Question 11

Examples of primary glomerular diseases

Answer 11

1) Acute diffuse proliferative glomerulonephritis (GN)
- Post-streptococcal & Non-post-streptococcal
2) Chronic glomerulonephritis (GN)
3) Rapidly-progressive (crescentic) glomerulonephritis (GN)
4) Membranoproliferative glomerulonephritis (mesangiocapillary GN)
5) Focal proliferative glomerulonephritis (GN)
6) Focal Segmental glomerulosclerosis
7) Membranous nephropathy (membranous glomerulopathy)
8) Minimal-change disease
9) IgA nephropathy (Berger’s disease)

Question 12

Examples of secondary glomerular diseases

Answer 12

1) Lupus nephritis (Systemic lupus erythematosus; SLE)
2) Diabetic nephropathy (Diabetes mellitus)
3) Amyloidosis
4) GN secondary to multiple myeloma
5) Goodpasture syndrome
6) Microscopic polyangiitis
7) Polyarteritis nodosa
8) Wegener granulomatosis
9) Henoch-Schönlein purpura
10) Bacterial endocarditis-related GN
11) Thrombotic microangiopathy

Question 13

Hereditary glomerular disorders

Answer 13

1) Alport syndrome
2) Fabry disease
3) Thin membrane disease
4) Podocyte/slit-diaphragm protein mutations

Question 14

Glomerulonephritis defintion

Answer 14

Inflammation of the glomeruli and kidney assumed

Question 15

Crescentic definition

Answer 15

Pathological terminology; more than 50% glomeruli with crescent bodies formation

Question 16

Diagnosis of glomerular diseases depend on

Answer 16

1) Morphology of glomerular lesion (histological alterations)
2) Cause and pathogenesis
3) Clinical manifestations

Question 17

Glomerular diseases morphology (histological alterations)

Answer 17

1) Hypercellularity
2) Basement membrane thickening
3) Hyalinization and sclerosis

Question 18

Hypercellularity explanation

Answer 18

– Cellular proliferation (increased number) of mesangial, endothelial, or less commonly, parietal epithelial cells in Bowman’s capsule

– Leukocytic infiltration (inflammation; accumulation of polymorphs observed)

– Formation of crescent: an accumulation of cells composed of proliferating epithelial cells and infiltrating leukocytes (cellular crescent will develop into fibrocellular crescent containing collagenous tissues if not resolved entirely and became chronic)

Question 19

GBM Thickening (definition, histology)

Answer 19

1) Thickening of the BM proper (lamina densa), as in diabetic glomerulosclerosis
- H&E stain reveals thickening of capillaries with hyaline deposits
-
2) Deposition of proteins on the endothelial or epithelial side of the BM or within the BM itself

** • Immune complexes**

• Fibrin
• Amyloid
• Cryoglobulins

Question 20

Hyalinization and Sclerosis (definition)

Answer 20

• Hyaline is formed by precipitated plasma protein, mixed with increased amounts of BM and/or mesangial matrix
• Obliteration of structure of the glomerular tuft (irreversible function loss)
• Usually the end result of various forms of glomerular damage
• Hyalin highly PAS positive as it is deprived from plasma proteins; homogeneous and eosinophilic (light microscopy)
• Hyalin electron dense, acellular, extracellular, and amorphous (electron microscopy)

Question 21

Pathogenesis of glomerular injury

Answer 21

IMMUNE MECHANISM

1) Antibody-mediated injury

– In situ immune complex deposition
– Circulating immune complex deposition
– Cytotoxic antibodies

2) Cell-mediated immune injury
3) Activation of alternative complement pathway

NON-IMMUNE MECHANISM

4) Various non-immunological causes

Question 22

Non-immunlogical pathogenesis of glomerular injury

Answer 22

For example:

(i) excess glycoxylation of GBM material occurs in diabetes leading to proteinuria and nephrotic syndrome,
(ii) hereditary defects in the production of collagen (e.g. Alport syndrome) and other structural components of glomeruli, and
(iii) amyloid deposition.

Question 23

Types of In situ immune complex deposition in glomerular damage

Answer 23

1) Antibody against fixed intrinsic tissue antigen

i) antibody against glomerular antigen (Heymann nephritis or membraneous nephritis; e.g. against PLA-2R)
ii) anti-GBM antibody (anti-GBM nephritis; against goodpaste antigen - intrinsic fixed antigens that are normal components of the GBM proper)

2) Antibody against planted antigens

i) Exogenous (infectious agents, drugs)
ii) Endogenous (DNA, immunoglobulins, immune complexes)

Question 24

Anti-GBM nephritis

Answer 24

• Antibodies are directed against intrinsic fixed antigens that are normal components of the GBM proper, which typically is a component of the noncollagenous domain (NC1) of the α3 chain of collagen type IV
• Complement fixation and activation leads to an intense inflammatory reaction with glomerular crescent formation. Usually a diffuse process affecting all glomeruli and clinically a rapidly progressive Gn.
• Anti-GBM nephritis is responsible for less than 5% of cases of human GN
• It may occur as a primary glomerulopathy or as part of Goodpasture syndrome
• characteristic linear pattern of deposition of immune complexes in immunoflorescence microscopy

Question 25

PLA2R and nephritis

Answer 25

Newly reported in 2009, that patients with membranous nephropathy had circulating autoantibodies against M-type phospholipase A2 receptor (PLA2R), which in the kidney is exclusively expressed on glomerular podocytes Binding of PLA2R autoantibodies to PLA2R is responsible for the induction of a large fraction of idiopathic membranous nephropathy

Question 26

Planted antigens

Answer 26

Antigens not intrinsic in the glomerulus but are planted there, which includes: i) cationic molecules that bind to the anionic components of glomerulus ii) DNA, nucleosides and other nuclear proteins (have an affinity for GBM) iii) Bacterial or parasitic products iv) Aggregated IgG v) Drugs Can be classified as endogenous or exogenous based on origin

Question 27

Circulatory immune complex nephritis

Answer 27

* Glomerular injury is caused by the trapping of circulating immune complexes within glomeruli * The immune complexes localize within the glomeruli because of their physicochemical properties and the hemodynamic factors peculiar to the glomerulus

Question 28

Localization sites of circulating immune complex in glomerular damage

Answer 28

* Subepithelial humps (post-streptococcal nephritis) * Epimembranous deposits (membranous GN) * Subendothelial deposits (membranoproliferative GN) * Mesangial deposits (mesangial proliferative GN)

Question 29

Types of Antigen in circulating immune complex nephritis

Answer 29

Types of antigens: 1) Endogenous (e.g. in lupus nephritis) 2) Exogenous (e.g. bacterial antigens in post- streptococcal nephritis, viral antigens such as HBsAg, hepatitis C, tumor antigens, Treponema pallidum, Plasmodium falciparum, and others)

Question 30

Immunoflorescence microscopy of immune complex deposition in glomerular damage

Answer 30

A: Granular, characteristic of circulating and in-situ immune complex nephritis B: Linear, characteristic of anti-GBM antibody nephritis

Question 31

Glomerular functional disturbances in disease

Answer 31

The major possible disturbances are: (1) **Loss of permeability barrier to plasma proteins**. Normally urine contains less than 20 mg/L of albumin. An increased amount of urinary albumin indicates glomerular disease. (2) **Decrease in glomerular filtration rate** (GRF). This leads to a rise in plasma creatinine and urea concentration. The acid-base, salt and water balance is also affected. (3) **Increased renin output** from the JG apparatus, leading to hypertension. (4) **Leakage of red blood cells into urine.** These disturbances may occur singly or in different combinations. A mild to moderate decrease in GRF does not lead to a decrease in urine volume. On the other hand, loss of urine concentration power in chronic renal disease leads to polyuria, especially noticeable at night time.

Question 32

Clinical manifestations of glomerular diseases

Answer 32

(1) **Persistent urinary abnormalities** (proteinuria and/or microscopic hematuria) constitute a typical presentation of IgA nephropathy. The abnormalities are usually picked up incidentally, e.g. at medical checks. The patients are otherwise asymptomatic.  (2) **Nephrotic syndrome**: when protein loss persistently exceeds 3 to 4 g a day, this will lead to hypoalbuminaemia, generalized edema (anasarca), and hyperlipidaemia. The source of blood albumin is the liver. Hyperlipidaemia in nephrotic syndrome is primarily a result of metabolic disturbance secondary to hypoalbuminaemia and is usually measured by the blood cholesterol concentration. It is the typical presentation of minimal change nephropathy, membranous glomerulonephritis (Gn), focal segmental glomerulosclerosis, and renal amyloidosis. (3) **Acute nephritis/nephritic syndrome**. Abrupt onset of oliguria, blood and proteins in the urine, drop in GFR (uraemia), with sodium & water retention, and hypertension. A typical presentation of post-streptococcal nephritis. (4) **Rapidly progressive Gn**. Rapid onset and progressive worsening of uraemia with abnormal urinary sediments. Symptoms are less abrupt than those of acute nephritis. A typical presentation of anti-GBM nephritis and ANCA-related pauci-immune crescentic Gn. (5) **Chronic renal failure**. (6) **Hypertension**. (7) **Gross haematuria.** An uncommon presenting symptom of IgA nephropathy and distinctly rare of other Gn.

Question 33

Nephritic syndrome signs

Answer 33

Characterised by **inflammation in the glomeruli**, along with Abrupt onset of: – Hematuria – Azotemia – Variable proteinuria (\< 3.5 g/day). – Oliguria – Edema – Hypertension (due to salt retention),

Question 34

Nephrotic syndrome signs

Answer 34

Presents with **massive proteinuria** (\>3.5g/day, frothy urine), as well as: - hypoalbuminemia - hyperlipidemia - generalized oedema

Question 35

Nephrotic syndrome risks and complications ## Footnote

Answer 35

1. Loss of immunoglobulins and complement in urine --\> **more susceptible to infections**, esp. with staphylococci and pneumococci 2. Contraction of circulatory volume and lose of anticoagulation factors in urine --\> **thrombosis and thromboembolism (**Renal vein thrombosis aggravates proteinuria)

Question 36

Pathophysiology of nephrotic syndrome

Answer 36

Question 37

Glomerular diseases with nephritic and nephrotic syndromes

Answer 37

Question 38

Causes of nephrotic syndrome

Answer 38

**Primary glomerular disease** – Membranous GN – Minimal change disease – Focal segmental glomerulosclerosis – Membranoproliferative GN – Other proliferative GN **Systemic diseases** – _Diabetes mellitus_ – _Amyloidosis_ – _SLE_ – Drugs (gold, penicillamine) – Infections (_hepatitis B_, malaria, syphilis, AIDS) – Malignant disease (_carcinoma_, lymphoma) – Misc. (bee-sting allergy, hereditary nephritis)

Question 39

Primary Causes of nephrotic syndrome in children and adults

Answer 39

Children – Membranous GN (+) – Minimal change disease (++++) – Focal segmental glomerulosclerosis (++) – Membranoproliferative GN (+) – Other proliferative GN (+) Adults – Membranous GN (++++) – Minimal change disease (++) – Focal segmental glomerulosclerosis (++) – Membranoproliferative GN (+) – Other proliferative GN (+++)

Question 40

Post-streptococcalnephritis

Answer 40

- Prototype of acute glomerulonephritis with acute nephritic syndrome - Only certain strains of group A Streptococci are nephritogenic - The time it takes from the onset of infection to the occurrence of nephritis is consistent with that for antibody build up - Present with endocapillary proliferation and polymorph infiltration and IgG deposition