L14 - Glomerular diseases Flashcards
Glomerular Diseases (Robbin's)
Glomerular diseases definition and importance
Glomerular diseases are disorders affecting the glomerulus; common cause of chronic renal failure
Glomerular diseases nomenclature and classifications
*** 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
Focal glomerular diseases defintion
< 50% of glomeruli are involved
Diffuse glomerular diseases definition
>50% of glomeruli are involved
Proliferative glomerular diseases definition
Hypercellularity observed
Membranous glomerular diseases definition
Thickening of glomerular basement membrane (due to subendothelial/epimembraneous deposits)
Membranoproliferative definition
AKA Mesangiocapillary; caused by deposits in the kidney glomerular mesangium and basement membrane (GBM) thickening (subendothelial deposits)
Primary glomerular diseases definition
Glomerular diseases in which the kidneys are the only or predominant organs involved; thus a primary disease of the kidney
Secondary glomerular diseases defintion
Secondary glomerular diseases are those in which the kidney is injured in the course of systemic diseases (secondary to systemic diseases)
Primary vs secondary glomerular diseases
- 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.
Examples of primary glomerular diseases
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)
Examples of secondary glomerular diseases
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
Hereditary glomerular disorders
1) Alport syndrome
2) Fabry disease
3) Thin membrane disease
4) Podocyte/slit-diaphragm protein mutations
Glomerulonephritis defintion
Inflammation of the glomeruli and kidney assumed
Crescentic definition
Pathological terminology; more than 50% glomeruli with crescent bodies formation
Diagnosis of glomerular diseases depend on
1) Morphology of glomerular lesion (histological alterations)
2) Cause and pathogenesis
3) Clinical manifestations
Glomerular diseases morphology (histological alterations)
1) Hypercellularity
2) Basement membrane thickening
3) Hyalinization and sclerosis
Hypercellularity explanation
– 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)
GBM Thickening (definition, histology)
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
Hyalinization and Sclerosis (definition)
- 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)
Pathogenesis of glomerular injury
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
Non-immunlogical pathogenesis of glomerular injury
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.
Types of In situ immune complex deposition in glomerular damage
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)
Anti-GBM nephritis
- 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
PLA2R and nephritis
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
Planted antigens
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
Circulatory immune complex nephritis
- 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
Localization sites of circulating immune complex in glomerular damage
- Subepithelial humps (post-streptococcal nephritis)
- Epimembranous deposits (membranous GN)
- Subendothelial deposits (membranoproliferative GN)
- Mesangial deposits (mesangial proliferative GN)
Types of Antigen in circulating immune complex nephritis
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)
Immunoflorescence microscopy of immune complex deposition in glomerular damage
A: Granular, characteristic of circulating and in-situ immune complex nephritis
B: Linear, characteristic of anti-GBM antibody nephritis
Glomerular functional disturbances in disease
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.
Clinical manifestations of glomerular diseases
(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.
Nephritic syndrome signs
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),
Nephrotic syndrome signs
Presents with massive proteinuria (>3.5g/day, frothy urine), as well as:
- hypoalbuminemia
- hyperlipidemia
- generalized oedema
Nephrotic syndrome risks and complications
- Loss of immunoglobulins and complement in urine
–> more susceptible to infections, esp. with staphylococci and pneumococci
- Contraction of circulatory volume and lose of anticoagulation factors in urine –> thrombosis and thromboembolism (Renal vein thrombosis aggravates proteinuria)
Pathophysiology of nephrotic syndrome
Glomerular diseases with nephritic and nephrotic syndromes
Causes of nephrotic syndrome
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)
Primary Causes of nephrotic syndrome in children and adults
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 (+++)
Post-streptococcalnephritis
- 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
