CL11 :Glomerular diseases-GN, NS, haematuria

and diabetic nephropathy

GLOMERULAR DISEASES • explain the syndrome of glomerular diseases – nephritic and

nephrotic syndrome

Assoc Prof. Dr Nordashima Abd Shukor

• classify glomerular diseases
Pathology Department
UKMMC
• explain the pathogenesis, clinicopathologic features of each
glomerulonephritis

Glomeruli Tubules

Kidney
diseases

Interstitium Blood vessels

 CLASSIFICATION OF GLOMERULAR DISEASES GLOMERULONEPHRITIS

➢Clinical presentation:
➢Proteinuria, hematuria MAJOR CLINICAL SYNDROMES
➢Nephrotic Syndrome
➢Nephritic Syndrome 1. Nephrotic syndrome
➢Immune/non-immune
mediated GN ➢Acute glomerulonephritis 2. Nephritic syndrome
➢Chronic glomerulonephritis
➢Primary / Secondary: 3. Rapidly progressive glomerulonephritis
➢Primary glomerular disease: ➢Chronic kidney disease
membranous nephropathy
➢Secondary: SLE, DM, HPT
4. Chronic glomerulonephritis (syndromes lasting
➢Morphological pattern: more than 3 months)
➢Membranoproliferative GN
➢FSGS
➢Membranous GN

Clinical manifestations: 4 major glomerular syndromes Clinical manifestations: 4 major glomerular syndromes

Glomerular syndromes Clinical features Glomerular syndromes Clinical features

Nephrotic syndrome Proteinuria > 3.5 g per per 24 h, hypoalbuminemia, Nephrotic syndrome Proteinuria > 3.5 g per 24 h, hypoalbuminemia,
generalized edema, hyperlipidemia, lipiduria generalized edema,hyperlipidemia, lipiduria

Nephritic syndrome Hematuria, RBC casts, azotemia, variable proteinuria,

oliguria, edema, hypertension
Clinical manifestations: 4 major glomerular syndromes Clinical manifestations: 4 major glomerular syndromes

Glomerular syndromes Clinical features Glomerular syndromes Clinical features

Nephrotic syndrome Proteinuria > 3.5 g per 24 h, hypoalbuminemia, Nephrotic syndrome Proteinuria > 3.5 g per 24 h, hypoalbuminemia,
generalized edema, hyperlipidemia, lipiduria generalized edema,hyperlipidemia, lipiduria

Nephritic syndrome Hematuria, RBC casts, azotemia, variable proteinuria, Nephritic syndrome Hematuria, hypertension and oliguria with azotemia,
oliguria, edema, hypertension variable proteinuria, edema, RBCs casts

Rapidly progressive Nephritic syndrome with rapid decline in GFR, within
glomerulonephritis hours to days/weeks. Medical emergency.
Accompanying proteinuria.Usually underlying
crescentic glomerulonephritis
Rapidly progressive Nephritic syndrome with rapid decline in GFR, within
glomerulonephritis hours to days/weeks. Medical emergency.
Accompanying proteinuria.Usually underlying
crescentic glomerulonephritis
Chronic renal failure Azotemia >>uremia progressing for years; Symptoms or
signs of renal osteodystrophy, Kidneys reduced in size
bilaterally

NEPHRITIC SYNDROME

Definition: hematuria, hypertension*, and oliguria with

azotemia* and proteinuria.
Nephrotic Syndrome is mediated by damage to the
podocytes and glomerular basement membrane. Clinical: edema, hypertension, elevated serum creatinine, and
oliguria.

Etiology and pathogenesis :

Nephritic Syndrome occurs as a result of An immune response triggered by an infection or other
inflammatory damage to basement membrane, disease. Triggers inflammation and proliferation of
mesangium or capillary endothelium. glomerular tissue that can result in damage to the basement
membrane, mesangium or capillary endothelium.

*azotemia:elevation of blood urea nitrogen and serum creatinine levels

*mild to moderate hypertension
 NEPHRITIC SYNDROME

NEPHRITIC SYNDROME
Common causes in children and adolescents:
IgA nephropathy
Poststreptococcal glomerulonephritis
Hemolytic uremic syndrome
Acute proliferative GN Crescentric GN Proliferative lupus GN Henoch-Schonlein purpura

Postinfectious Common causes in adults:

Membranoproliferative GN
Rapidly progressive (crescentic) glomerulonephritis
Infectious associated Goodpasture syndrome
SLE or lupus nephritis
Hepatitis B or C
Infective endocarditis
Vasculitis
Viral diseases such as measles, mumps, infectious mononucleosis

*GN: Glomerulonephritis

Nephrotic Syndrome

Massive proteinuria > 3.5 g per 24 h,

• Hypoalbuminemia,
• Generalised edema,
• Hyperlipidemia,
• Lipiduria
 Pathophysiology : Nephrotic Syndrome Nephrotic Syndrome
CAUSES
➢Hyperlipidemia and lipiduria
➢Increased synthesis of lipoprotein in liver, abnormal transport of circulating Primary glomerular diseases
lipid particles and decreased lipid catabolism - Minimal change disease (MCD)
➢ Increased blood levels of cholesterol , triglyceride, VLDL, LDL,lipoprotein and decreased - Membranous nephropathy
HDL
➢Lipoprotein leaks across glomerular capillary wall - Focal segmental glomerulosclerosis (FSGS)
➢Lipoprotein resorbed by tubular epithelial cells - Membranoproliferative glomerulonephritis (MPGN)
➢Shed into urine

Secondary causes
➢Increase vulnerability to infection due to loss of immunoglobulin in - Infections – HBV, HIV, endocarditis, streptococcal infection
urine - Neoplasms – lymphomas, leukaemias, carcinoma
- Drugs – gold, penicillamine, captopril, heroin
➢Thrombotic and thromboembolic plus renal vein thrombosis - Systemic diseases – SLE, amyloidosis, diabetes, sarcoidosis
complication due to loss of endogenous anticoagulant in urine - Etc

Nephrotic Syndrome Pathologic response to injury:glomerulus

• Hypercellularity:
COMPLICATIONS • Proliferation of mesangial or endothelial cells
• Infiltration of leucocytes: neutrophils/monocytes/lymphocytes
1. Hypoproteinaemia • Mesangial+leucocytes+/endothelial cells=endocapillary
hypercellularity/proliferation
2. Generalised edema, pulmonary edema • Formation of crescents:predominantly parietal cells
3. Reduced gamma globulin→Increased infection susceptibility • Basement membrane thickening
4. Increased lipoprotein synthesis and hypercholestrolaemia • deposition of electron-dense material e.g immune complexes, amyloid
• Increased synthesis of protein component of BM:diabetic glomerulosclerosis
5. Loss of anticoagulant factors eg reduced anti-thrombin III → thrombotic,
• Formation of additional layers of BM matrices e.f membranoproliferative GN
thromboembolic complications
• Hyalinosis and sclerosis
6. Acute renal failure
• Hyalinosis:accumulation of homogenous and eosinophilic material on LM
7. Growth retardation • Hyalin=extracellular, amorphous material of plasma protein(due to
endothelial or capillary wall injury
• end result of various glomerular damage
• Sclerosis:deposition of extracellular collagenous material
 Mesangial proliferation Cellular crescent

Pathologic response to injury:glomerulus

Hyalinosis Sclerosis

Normal glomerulus

Endocapillary hypercellularity Basement membrane thickening

Histologic distribution of affected glomerulus

• Diffuse: affecting all glomeruli Histologic distribution of affected glomeruli
• Focal: affecting a proportion of glomeruli
• Global: involving entire glomerulus
• Segmental: involving part of each glomerulus
• Mesangial: affecting the mesangial region

Global Segmental
 Normal glomerulus
Classification of glomerular diseases (based on causes)

Primary glomerular disease

(unknown etiology)

Secondary to
systemic disease

Secondary to
infections

Classification of glomerular diseases

Normal glomerulus

Primary glomerular disease

Minimal change disease

• no glomerular lesions by light microscopy
Diffuse lesion
• Diffuse proliferative glomerulonephritis
• Membranoproliferative GN
• Membranous glomerulonephritis
• Crescentic GN (with or without immune deposit)
Focal lesion
• IgA nephropathy
• Focal segmental glomerulosclerosis
 Classification of glomerular diseases
Classification of glomerular diseases

Secondary to systemic diseases

• Bacterial – Proliferative GN(post streptococcal)
Infective causes Membranoproliferative GN
• Sytemic Lupus erythematosus Crescentic GN
• Diabetes Mellitus • Parasitic – Filariasis – Membranous GN
- Scistosoma Mansoni – Focal
• Amyloidosis proliferative GN
• Goodpasture’s syndrome • Viral - AIDS – FSGS
• Henoch-Schonlein purpura - Hepatitis – Membranous and
MPGN
• Neoplasms – lymphomas,
leukaemia, carcinoma
• Drugs – gold, penicillamine

Pathogenesis of glomerular injury Pathogenesis of glomerular injury

1. Antibody-mediated injury
• Most primary and many secondary glomerular diseases are immune
mediated
1. Immune complexes formed locally by ab reacted with intrinsic
• Others remain unknown tissue antigen or extrinsic antigen “planted” in the glomerulus from
the circulation. Antibodies are directed against intrinsic fixed
• Two forms of antibody-associated injury: antigens that are normal components of GBM (anti-GBM antibody).
i)injury by antibodies reacting in situ within the glomerulus 2. Accounts for < 5% of cases of GN
ii)injury resulting from deposition of circulating antigen-antibody
complexes 3. Eg. Goodpasture syndrome (lung and kidney lesions)
4. Usually characterised by severe crescentic glomerular damage and
rapidly progressive GN.
5. Immunofluorescence microscopy shows a linear deposit along the
length of the glomerulus
 Pathogenesis of glomerular injury Minimal change disease GN

2. Deposition of circulating antigen-antibody complexes in the

glomerulus • Commonest cause of nephrotic syndrome in childhood
• 20% of adults with nephrotic syndrome
1. Glomerular injury is caused by trapping of circulating antigen-
antibody complexes within glomeruli.
2. The Ab have no specificities for glomerular constituents.
• Clinical presentation:
- proteinuria usually massive and severe oedema
3. Antigen may be endogeneous eg in SLE or exogenous as in GN
following infections (streptococcus, hepatitis B, hepatitis C, - Highly selective proteinuria (albuminuria)
Treponema pallidum etc) - Haematuria and hypertension are usually absent
4. Injury is mediated and amplified by binding of complement
• Good prognosis
• Respond to steroid therapy

Minimal change disease GN Minimal change disease GN

Morphology :
- normal by light microscopy
- no immune deposits by IF
- EM: fusion of foot processes of epithelial cells

Causes :
- idiopathic
- malignancy esp Hodgkin disease
- drugs ( NSAID, lithium, gold, ampicillin)

Pathogenesis
-Epithelial cell injury.
-Suggested by mutations of glomerular protein including nephrin
Normal light microscopy
 Minimal change disease GN Membranous glomerulonephritis

• Common cause of nephrotic syndrome in adults (20-

25%)
• Morphology :
- Thickened capillary basement membrane with ‘spikes’
on silver stain
- IgG and C3 Subepithelial deposits
• Complication :
- renal vein thrombosis
• Prognosis :
- 30% spontaneous complete remission and stable GFR for
up to 20 yrs
Effacement of the epithelial cell (podocyte) foot
- 25% spontaneous partial remission with stable GFR
processes and loss of the normal charge barrier such
that albumin selectively leaks out through the urine

Membranous glomerulonephritis Membranous glomerulonephritis

• 20-25% persistent nephrotic with stable or very slowly progressive loss

of GFR
• 20-25% progress to end stage renal failure over 20-30 yr
• Causes :
- Idiopathic
- SLE
- Malignancies ( carcinoma, leukaemia, lymphoma)
- Infections (HBV, syphilis, quartan, malaria, leprosy, schistosomiasis
- Drugs :Penicillamine, Gold, Mercury, Captopril
• Pathogenesis
- Idiopathic-Immune complexes develop in situ to an intrinsic glomerular
antigen Basement membranes are thickened and prominent,
- Secondary causes- extrinsic antigen but the cellularity is not increased.
 Membranous glomerulonephritis Membranous glomerulonephritis

A silver stain shows characteristic "spikes" with membranous

glomerulonephritis. Basement membrane material appears as IgG and complement collect in the basement membrane and
projections around the capillary loops. appear in a diffuse granular pattern by immunofluorescence,
as seen here.

IgA nephropathy IgA nephropathy

➢ Commonest form of primary glomerulonephritis ➢Prognosis :
➢ Clinical features (2 main pattern): ➢ - 80% renal survival at 5 yrs
➢ Macroscopic haematuria concurrent with upper respiratory ➢ - 1/3 go into CRF after 20-30 yrs
infection- synpharyngitic haematuria ➢Pathogenesis :
➢ Asymptomatic microscopic haematuria and variable proteinuria ➢ - Abnormality in IgA regulation (excess production or reduced
➢ Morphology : clearance)
➢ diffuse mesangial proliferative, focal proliferative, crescentic GN ➢Causes:
(rare) ➢ - Idiopathic
➢ Immunofluorescence: IgA and C3 in mesangium
➢ - Liver cirrhosis
➢ Nephrotic syndrome or mixed nephritic-nephrotic syndrome
➢ - Dermatitis herpetiformis
➢ Henoch-Scholein purpura in children with skin, joint and intestinal
involvement ➢ - Inflammatory bowel disease
➢ - Ankylosing spondylitis
 IgA nephropathy
Post infectious GN/ Post-streptococcal GN

• Group A beta-hemolytic Streptococcus (type 12, 4 and 1) infection causing

pharyngitis and impetigo
• Post-streptococcal GN common in childhood
• Others: Bacterial, viral, parasitic, rickettsial and fungal infections

• Morphology :
• Increased cellular proliferation with neutrophils, +/- crescents in the glomeruli
• IF: IgG and C3
• EM:subepithelial deposits (humps)

• Clinical presentation
• acute nephritic syndrome 7-21 days after primary infection
Increases mesangial Immunofluorescence pattern • Haematuria
cellularity as shown at the demonstrates positivity with • Oedema
arrow. antibody to IgA. Note that the • Hypertension
pattern is that of mesangial • oliguria
deposition in the glomerulus.

POSTSTREPTOCOCCAL GN: NEPHRITIC SYNDROME

POSTSTREPTOCOCCAL GN
-a prototypical glomerular disease of immune complex etiology.

--95% recover with conservative therapy; few may develop rapidly

progressive glomerulonephritis or chronic glomerulonephritis Etiology and pathogenesis :

Caused by immune complexes containing streptococcal antigens and specific

Children age 6 - 10: nephritic presentation with abrupt onset of hematuria, antibodies which are formed in situ.
oliguria, fever, malaise and nausea 1 - 4 weeks after strep infection of
pharynx or skin (impetigo); RBC casts, proteinuria, periorbital edema and Deposition of immune complexes triggers inflammation and proliferation of
hypertension glomerular tissue that can result in damage to the basement membrane,
Adults: may have atypical presentation with sudden hypertension, edema and mesangium, or capillary endothelium.
elevated BUN; 60% recover, others develop rapidly progressive
glomerulonephritis

Laboratory (children and adults): high antistreptococcal antibody titers

(ASOT), low C3 (due to consumption)
 Post infectious GN
Post infectious GN

• Prognosis :
- excellent in children
- haematuria persist for 6
months
- proteinuria up to 2 years
- less favourable in adults
• Pathogenesis :
- immune complex disease
The glomerulus is hypercellular (due to
infiltration by leucocytes and proliferation of
both endothelial and mesangial cells) which
leads to obliteration of capillary lumens.
Electron microscopy:Discrete, amorphous, electron-dense
subepithelial deposits (humps appearance) (black arrow)

Anti-GBM disease
Anti-GBM disease

• Goodpasture’s syndrome is a clinical syndrome of ❖Morphology :

glomerulonephritis and pulmonary haemorrhage ❖ Cellular crescent affecting
most/all glomeruli
• Uncommon- <5% of GN overall
❖Immunofluorescence
• Due to an autoimmune antibody against GBM and study (IF)
❖ : linear pattern of IgG along
pulmonary capillary basement membranes
GBM
 Diabetic glomerulosclerosis Diabetic glomerulosclerosis
• Diabetic nephropathy in long standing diabetes
mellitus complication
Pathological changes in glomelurus:
• Major cause of end stage renal disease (10% locally)
• Capillary basement membrane thickening
• Clinical presentation and complications :
• Increase mesangial matrix
• non-nephrotic proteinuria
• nephrotic syndrome • Nodular glomerulosclerosis (Kimmesteil Wilson’s
nodules)
• chronic renal failure
• Diffuse glomerulosclerosis
• Pathogenesis: • Vessels – hyaline arteriolosclerosis
• linked to hyperglycaemia
• Non-enzymatic glycosylation of proteins results in
accumulation of advanced glycosylation end products
(AGE)

Lupus nephritis

• Occurs in about 50 – 80% of patient with SLE

• Affect the kidney :

• Proliferation
• Glomerulosclerosis
• tubulointerstitial nephritis
• Vasculitis

• Pathogenesis :
• deposition of circulating immune complex in
 Histological classification of Lupus
Nephritis

•Class I – normal by light microscopy

THANK
•Class II – mesangial proliferative
•Class III – focal proliferative
YOU
•Class IV – diffuse proliferative
•Class V – membranous
•Class VI – diffuse sclerosis