primary glomerular disease shokoufeh savaj associate professor of medicine firoozgar hospital,iums
TRANSCRIPT
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