Primary Glomerular DiseaseSHOKOUFEH SAVAJ

ASSOCIATE PROFESSOR OF MEDICINE

FIROOZGAR HOSPITAL ,IUMS

• Albumin has a negative charge with a physical radius of 3.6 nm.• GBM and slit-pore membranes have a radius of 4 nm• Albumin is reabsorbed in proximal tubule• Normal urine albumin :8-10 mg/d.

Glomerulonephritis :Glomerular Injury with

Inflammation ( Leukocyte infiltration ,

Complement activation & Antibody deposition )

Primary :Limited to kidney

Secondary : Part of Systemic disorder

Acute :Injury occur in days or weeks

Subacute or rapidly progressive : in

Weeks or months

Chronic : Injury in years

Nephrotic syndrome : > 3.5gr proteinuria in 24 hours/1.73 M2

Nephritic syndrome : proteinuria ,decrease in GFR,

hypertension,hematuria and cellular casts

Proliferative : Increase in glomerular cell number

( intracapillary & Extracapillary )

Sclerosis:Deposition of homogenous non fibrillar material

Fibrosis:Deposition of collagen type I and III

Nephrotic Syndrome

Proteinuria

Hypoalbuminemia

Hyperlipidemia

hypercoagulable state

Hypertension

Decrease in GFR

Minimal Change Disease

Pathogenesis

T cell dysfunction

Permeability Factor : immune origin (IL13)

Genetic ??

70–90% in childhood &10–15% of nephrotic syndrome in adults.

Acellular urinary sediment

Hypertension (30% in children, 50% in adults)

Microscopic hematuria (20% in children, 33% in adults)

Atopy or allergic symptoms (40% in children, 30% in adults)

Decreased renal function (<5% in children, 30% in adults).

Causes of minimal change disease Allergy : bee stings, house dust, pollens..

Cancer :Lymphoma ,leukemia

Infection : syphilis, tuberculosis, HIV, Hepatitis C virus, and

Echinococcus

Drugs : NSAID, Lithium, ampicillin,rifampin pamidronate

Membranous Nephropathy

C5-9

Neutral endopeptidase expressed by podocytes

Hepatitis antigens B/C

Helicobacterpylori antigens

Tumor antigens.

Autoantibodies against the M-type phospholipase A2 receptor

(PLA2R) circulate and bind to a conformational epitope present in

the receptor on human podocytes

Primary/idiopathic membranous glomerulonephritis

Secondary membranous glomerulonephritis

Infection: Hepatitis B and C, syphilis, malaria, schistosomiasis,

leprosy, filariasis

Cancer: Breast, colon, lung, stomach, kidney, esophagus,

neuroblastoma

Drugs: gold, mercury, penicillamine, nonsteroidal anti-inflammatory

agents, probenecid

Autoimmune diseases: systemic lupus erythematosus, rheumatoid

arthritis, primary biliary cirrhosis, dermatitis herpetiformis, bullous

pemphigoid, myasthenia gravis, Sjögren's syndrome, Hashimoto's

thyroiditis

Other systemic diseases: Fanconi's syndrome, sickle cell anemia,

diabetes, Crohn's disease, sarcoidosis, Guillain-Barré syndrome,

Weber-Christian disease, angiofollicular lymph node hyperplasia

30% of nephrotic syndrome Adult

The male to female ratio :2 to 1

80% nephrotic syndrome

Microscopic hematuria in 50%

Highest incidence of renal vein

thrombosis

Focal segmental Glomerulosclerosis

Primary focal segmental glomerulosclerosis

Secondary focal segmental glomerulosclerosis

Viruses: HIV/Hepatitis B/Parvovirus

Hypertensive nephropathy

Reflux nephropathy

Cholesterol emboli

Drugs: Heroin/analgesics/pamidronate

Oligomeganephronia

Renal dysgenesis

Alport's syndrome

Sickle cell disease

Lymphoma

Radiation nephritis

Familial podocytopathies

NPHS1 mutation/nephrin

NPHS2 mutation/podocin

TRPC6 mutation/cation channel

ACTN4 mutation/actinin

-Galactosidase A

deficiency/Fabry's disease

N-acetylneuraminic acid hydrolase

eficiency/nephrosialidosis

Collapsing glomerulosclerosis

Clinical Presentation

Hematuria

Hypertension

A level of proteinuria

Renal insufficiency

African-American raceare associated with a poor outcome, with

50% of patients reaching renal failure in 6–8 years

Alport Syndrome

The most common hereditary nephrits

Genetic defect of α5 chain of type IV collagen

Gene on long arm of chromosome X

Males presented with :

Hematuria, Proteinuria, Progressive renal

insufficiency

Immune Mechanisms of Glomerular Injury

Non inflammatory

• Podocyte

Inflammatory

• Neutrophil, Monocyte

• Proliferating glomerular cells

Inflammatory Mechanisms of

Immune Glomerular Injury

Antibody – Mediated Injury

1- Reactivity of circulatory autoantibodies with

intrinsic autoantigens

2-Insitu formation of immune Complex

( with extrinsic antigens )

3- Intraglomerular trapping of immune complex

Generation of nephritogenic Antibodies :

1. Similarity with foreign antigen

2. Expression MHC II ( which were

invisible)

3. Problem in tolerance

Deposition of Nephritogenic antibodies within Glomerus

Site of antibody deposition

Size

Charge

Quantity

Site of antigen

Local hemodynamics factor

Problem in clearance mechanisms for immune complexes

Mechamism of glomerular Damage

Post Streptococcal Glomerulonephritis

Pathogenesis

Children 4-12 Decreased incidence rate Throat infections infection:1-3 weeks after

with M types of streptococci (nephritogenic strains) antedate glomerular disease and M types 1, 2, 4, 3, 25, 49, and 12 with pharyngitis

Skin: 2-6 weeks after infection ; M types 47, 49, 55, 2, 60, and 57 are seen following impetigo .

IgA nephropathy

Pathogeneis

Immune complex mediated GN with diffuse

mesangial IgA deposit

Abnormal IgA production

Abnormal IgA clearance (liver ,mesangial )

O-glycosylation of hinge region of IgA

Clinical Presentation

Microscopic hematuria

Subnephrotic proteinuria

Nephrotic syndrome (rare)

Gross hematuria

Acute renal failure

Rapidly progressive GN

Membranoproliferative GN type I

 lobular appearance of the glomerular tuft with focal areas of increased glomerular cellularity (large arrows), mesangial expansion (*), narrowing of the capillary lumens, and diffuse thickening of the glomerular capillary walls

Electron Microscopy In MPGN I

Membranoproliferative Type II

Basement membrane thickening, double contour, mesangial

interposition

C3 deposition on capillary wall and

mesangium

Electron microscopy in MPGN II DDD

Pathogensis

Type I MPGN : secondary to glomerular deposition of

circulating immune complexes or their in situ formation

Types II and III MPGN :"nephritic factors," (autoantibodies

that stabilize C3 convertase).

Clinical Findings

Proteinuria, hematuria, and pyuria (30%)

Systemic symptoms of fatigue and malaise

An acute nephritic picture with RPGN and a

Speedy deterioration in renal function in up to

25% of patients.

Low serum C3 levels are common

Prognosis

50% with MPGN develop ESRD in10 years after

diagnosis,

90% have renal insufficiency after 20 years.

Nephrotic syndrome, hypertension, and renal

insufficiency all predict poor

Rapidly Progressive Glomerulonephriris