L1.2 Patho PDF

L1,2_patho L1: Glomerular disease I The kidney can be divided into four morphologic components: Damage to one component affects the others → the ultimate result of any chronic renal disease, whatever its origin is, would be destruction of all kidney components → End-sta...

L1,2_patho L1: Glomerular disease I The kidney can be divided into four morphologic components: Damage to one component affects the others → the ultimate result of any chronic renal disease, whatever its origin is, would be destruction of all kidney components → End-stage kidney. The nephron is the kidney unit. Glomerulonephritis Inflammation and damage to the filtering part of the kidneys (glomerulus) pathogenesis of glomerular injury: Glomerular injury is, mainly, immunologically mediated It is either secondary to some other disease or primary Mechanisms: 1-Anti-body mediated /in situ immune complex mediated (type II hypersensitivity) A-Antibodies react directly with tissue antigens (Anti-glomerular basement membrane nephritis): Antibodies directed against Glomerular BM → bind along entire length → Immunofluorescence: Diffuse, linear pattern Ex: Goodpasture syndrome Anti-GBM Ab cross react with BM of lung alveoli → simultaneous lung & kidney lesions. B- Antibodies against planted non-glomerular antigen: Linear deposits by I.Fl Viral, parasitic and bacterial products Drugs Cationic molecules (DNA, nucleosomes, microbial products, drugs, and aggregated proteins including immune complexes) all have affinity for the anionic glomerular basement membrane (GBM) and can become trapped. Ex: Membranous Glomerulonephritis Immunofluorescence: granular heterogeneous pa 1|Page  L1,2_patho 2-immune complex mediated / circulating immune complex mediated (type III hypersensitivity) Trapping of Ag-Ab complex within glomeruli Antigen: o Endogenous (SLE) o Exogenous (Infection {bacterial, viral}, Tumor Ag) Dense, granular deposits : Mechanism: Sub-endothelial o Ag-Ab in circulation→ trapped in glomeruli (subendothelial, Sub-epithelial Mesangial subepithelial, or mesangial) → bind with complement → activation of C → glomerular injury → proliferation of resident cells & poly-morphonuclear leukocyte infiltrate Ex: membranoproliferative GN type I 3-Cell-Mediated Immunity in Glomerulonephritis, (type IV hypersensitivity) released cytokines may cause: Loss of adhesion molecules → loss of epithelial foot processes → Retraction (effacement of podocytes) and detachment of cells from GBM → protein leakage → PROTEINURIA E.g. minimal change disease Nephrotic Syndrome The pathogenesis of Nephrotic Syndrome : 2|Page  L1,2_patho Point out the glomerular causes of nephrotic syndrome: Primary glomerular diseases and systemic causes Etiology of nephrotic syndrome: Primary glomerular disease Secondary to a systemic disease May be due to idiopathic, genetic, or SLE. Diabetes mellitus. unknown causes e.g. Amyloidosis. Bacterial endocarditis. Minimal change disease (Lipoid nephrosis) Drugs. Focal segmental glomerulosclerosis. Infection. Membranous glomerulopathy. Neoplasm. Membranoproliferative glomerulopathy Hereditary disorders. IgA nephropathy. Combine the pathogenesis of Nephrotic Syndrome with the clinical presentation. Diagnosis of Glomerulonephritis: -C/P (Nephretic vs Nephrotic) -L/M -Fluorescence microscopy. -E/M What is immunoflurescence? Immunofluorescence is a widely used example of immunostaining (using antibodies to stain proteins) a single antibody, chemically linked to a fluorophore. recognizes the target molecule (antigen) and binds to a specific region called the epitope fluorophore is a fluorescent chemical compound that can re-emit the absorbed light Examination is performed by a fluorescence microscope 1. Minimal change disease (lipoid nephrosis): C/P: Nephrotic syndrome The most common cause of nephrotic syndrome in children Pathogenesis: Unknown cause ?? increased cytokines (type IV hypersensitivity), podocyte injury (effacement of foot process) Light Microscopy: normal appearance of glomeruli lipid in tubules Needs EM for diagnosis 3|Page  L1,2_patho Minimal change disease Light microscope Normal glomeruli ▪The cells of proximal convoluted tubules are heavily laden with lipids (lipoid nephrosis). Immunofluoresence Negative Electron microscopy Diffuse foot process effacement 2. Focal segmental glomerulosclerosis (FSG): C/P: Nephrotic syndrome Pathogenesis: Unknown, Ablation nephropathy podocyte injury ?? Progression of minimal change disease Light Microscopy: FSG is characterized histologically by sclerosis affecting Some but not all glomeruli (focal) Involving only segments of each glomerulus (segmental). 3. Membranous glomerulonephritis (MGN): C/P: Nephrotic syndrome The most common cause of nephrotic C/P syndrome in adults Pathogenesis: In situ antibody-mediated (AB mediated against planted Ag) Type II hypersensitivity antigen unknown Light Microscopy: Glomeruli may appear normal at early stages Diffuse capillary wall thickening (due to subepithelial deposits along GBM) 4|Page  L1,2_patho Membranous glomerulonephritis silver stain of the glomerulus highlights in which the capillary loops are the proteinaceous basement thickened & prominent ,but the membranes in black.There are cellularity is not increased. characteristic" spikes "seen with membranous glomerulonephritis 4. Membranoproliferative glomerulonephritis (MPGN) Type I: C/P: Nephrotic syndrome Pathogenesis: (TypeI) Immune complex mediated/ circulating immune complex (type III hypersensitivity) Light Microscopy: 1-Mesangial proliferation 2-basement membrane thickening; splitting This splitting of GBM is caused by mesangial cells inclusion between GBM laminae 5|Page  L1,2_patho Glomerular Membranous Minimal change Focal segmental Membranoprolife Pathology glomerulopathy Disease glomerulosclerosis Rative glomerulonephritis (MPGN) Type I clinical Nephrotic Nephrotic Nephrotic Nephrotic syndrome presentation syndrome syndrome syndrome Most common Most common cause in adults cause in children pathogenesis In situ antibody- Unknown, Unknown, (I) Immune complex mediated; podocyte injury, Ablation (type III antigen effacement of nephropathy, hypersensitivity) unknown (type II foot process (type podocyte injury hypersensitivity) IV hypersensitivity) L/M Diffuse capillary Normal; lipid in Focal and Mesangial wall thickening tubules segmental proliferation; sclerosis and basement hyalinosis membrane thickening; splitting IF Granular IgG and Negative Focal; IgM and C3 (I): Occasional C3; diffuse Granular subepithelial and mesangial immunoglogulin and C3, C1q, and C4 deposits EM Subepithelial Loss of foot Loss of foot (I) Subendothelial deposits processes; no processes; electorn dense deposits epithelial deposits (the only positive denudation finding) 6|Page  L1,2_patho L2: Glomerular disease II Nephritic syndrome Glomerular disease manifested by: Acute onset of usually visible hematuria. Hypertension of variable degrees. Mild to moderate proteinuria. Oedema. Oliguria. Uremia (azotemia). Glomerular pathology 1. Proliferation 2. Inflammation Etiology: 1. Acute Diffuse proliferative GN 5. Primary: Berger’s disease (IgA Nephritis) 2. Rapidly progressive GN (or Crescentic) 6. Secondary IgA nephritis, Henoch- 3. Goodpasture’s syndrome Schonlein purpura, SBE. 4. Focal Glomerulonephritis Acute glomerulonephritis Definition: glomerular diseases characterized by inflammatory changes in the glomeruli manifested clinically as nephritic syndrome Mechanism: Immunological or non immunological Inflammatory alterations in renal glomeruli damage of glomerular capillary endothelial cells Damage of glomerular capillary endothelial cells Focal increase in capillary Partial glomerular capillary obstruction permeability Proteinuria Decreased blood flow Hematuria ↓ Casts(protein, RBCs, granular, Decreased glomerular filtration rate (GFR) epithelial) ↓ Fluid retention ↓ Oliguria. ↑ Blood urea (azotemia) Edema Hypertension due to ↓ blood flow & ischemia → stimulate the juxta-glomerular 7|Page  L1,2_patho Acute diffuse(proliferative)GN Definition: acute inflammatory process involving all glomeruli of both kidneys Incidence: all ages, more in children 3-7 y male: female =2:1 Etiology Post streptococcal GN 2-4 weeks following infection of group A beta hemolytic streptococci Non post streptococcal GN Bacterial: Staph aureus & meningiococci Viral: Hepatitis B,C, A, EBV, mumps Parasitic: malaria, toxoplasmosis, bilharziasis Other infectious organism: rickettsia, fungi Pathogenesis: It is an immunologically mediated disease (immune complex) Antigen :strep Antibodies: IgG, IgM, C3 Deposited in glomerular capillaries: subepithelial Antigen-antibody reaction ➡️ immune complex ➡️deposited in the glomerular capillaries mainly of IgG & IgM classes and C3 ➡️ endothelial cell injury and inflammatory reactions. Clinical features Nephritic syndrome Acute onset of usually visible hematuria (smoky urine or cola-colored urine). Mild to moderate proteinuria. Oliguria. Edema (periorbital) Uremia. Hypertension of variable degrees. Granular, RBCs, casts. Laboratory findings: Moderate proteinuria. Increase blood urea and creatinine Hematuria (smoky urine or coca cola Decrease renal function and GFR like). Increase streptolysin O titre (for RBC's cast. cause) 8|Page  L1,2_patho Morphology Gross Both kidneys enlarged , pale, smooth surface with petechial hemorrhage. Capsule tense, easily striped C/S: wide pale cortex, congested glomeruli (light gray dots) Decrease differentiation between cortex & medulla Microscopic examination Post-streptococcal Glomerulonephritis LM: Glomeruli: Diffuse uniform hyppercellularity (equality is the clue) due to 1.Proliferation of endothelial cells 2.Proliferation of mesangial cells 3.Inflammatory cells (PNLs & monocytes) GBM: not thickened Tubules: Convoluted: cloudy swelling Collecting: red cell cast, granular, hyaline Interstistium: interstitial edema and inflammation IF Subepithelial humps of IgG and C3 with a granular pattern. EM Humps or dome-shaped deposits of immune complex: subepithelial, subendothelial and mesangial , not pathognomonic but usually correlated Prognosis Children: good outcome 95% complete recovery 1%cresentic GN 1-3% CRD (chronic renal disease) 1-2% die of renal failure Adults and old age: 60% recover 40%cresentic GN 10% CRD 9|Page  L1,2_patho Rapidly progressive (crescentic) glomerulonephritis Definition Diffuse glomerulonephritis characterized by: ▪ Clinically: progressive decline in renal function resulting in renal failure in weeks or months. ▪ Histologically: Accumulation of cells in Bowman's space in the form of crescents. ✓ Diffuse ✓ Progressive ✓ Crescent Causes Primary Idiopathic Vasculitis Post streptcoccal GN Good pasture’s syndrome Secondary SLE Infective endocarditis Morphology As post streptococcal + Crescent (due to capsular epithelial proliferation, infiltration by macrophages, monocytes, & fibrin deposition). In severe cases, some lobules of glomeruli show rupture of the basement membrane, thrombosis, and hemorrhagic necrosis of the glomerular capillaries. Obliteration of Bowman’s space leads to fibrosis with glomerular scarring and hyalinization. Prognosis Bad (usually progressive into irreversible renal failure within days to months) Good pasture‘s syndrome Definition: acute fulminating disorder ch ch by pulmonary hemorrhage and acute glomerulonephritis commonly of rapidly progressive type Incidence: Young adult. male>female Cause: (autoimmune reaction) Anti glomerular membrane antibodies cross react with alveolar basement membrane ➡️Pulmonary Hge +acute glomerulonephritis 10 | P a g e  L1,2_patho Morphology : ▪ Gross, L/M: As crescentic GN ▪ E/M: crescent, disruption of GBM, cellular infiltration ▪ IF: characteristic linear deposit of IgG along GBM C/P - As in acute diffuse glomerulonephritis - Progressive , fatal Why fatal? Renal failure Pulmonary hypertension Hypertension leading to heart failure and cerebral he Increases K+ level lead to HF Primary IgA nephropathy (Berger‘s disease) Definition: Immunoglobulin A (IgA) nephropathy is characterized by predominant IgA deposition in the glomerular mesangium. Incidence: It is one of the most common causes of glomerulonephritis in the world. Usually affects children & young adults Pathogenesis It is associated with viral or bacterial inflammation of mucosa surface containing IgA e.g.: gluten entropathy, Crohn’s disease, and chronic bronchitis. A genetic or acquired abnormality of immune regulation occur Increased mucosal IgA synthesis Increased IgA1 and IgA1 containing immune complex in the serum that entrapped and deposited in mesangium Activation of alternative complement pathway Glomerular injury (although the Ag is unknown). L/M ▪ Glomeruli are more or less normal ▪ Mesangial widening and proliferation ▪ Focal segmental proliferation ▪ Diffuse mesangial proliferation → mesangio-proliferative glomerulonephritis. ▪ Crescent is rare IF, E/M ▪ Mesangial IgA deposit Fate: 30-50% progress to renal failure 11 | P a g e  L1,2_patho Chronic glomerulonephritis Definition: The end stage of glomerulonephritis Clinical presentation Early: Late: Polyurea due to decrease tubular Progressive oliguria. absorption. Uremia. Decrease specific gravity due to Anemia. decrease the ability to concentrate Hypertension the urine. Mild proteinuria. Hyaline and granular casts. Morphology Acute glomerulonephritis Chronic glomerulonephritis Gross Both kidneys enlarged , Kidneys are symmetrically uniformly pale, smooth surface reduced in size Capsule tense, easily striped Granular surface c/s: pale cortex, congested Capsule firmly adherent glomeruli c/s: cortex is thinned out, medullary Decrease differentiation between pyramids shrunken cortex & medulla Loss of demarcation between cortex and medulla L/M Glomeruli: diffuse uniform Glomeruli: sclerosed, hyalinozed , hypercellularity (equallity is the clue) may some are normal ,some may show of endothelial, mesangial and original disease inflammatory cells Tubules: casts(thyroidizati, atrophy Tubules: convoluted :cloudy Interstitial: fibrosis, chronic swelling. Collecting :red cell cast, inflammatory infiltrate granular ,hyaline BV: thickned Interstisium: interstitial edema and inflammation BV: dilated & congested 12 | P a g e  L1,2_patho Acute GN Chronic GN Chronic glomerulonephritis Glomerular Lesions associated with systemic disease Diabetic nephropathy Pathogenesis Metabolic (hyperglycemia) Hemodynamic Glucose attached to amino group of protein (collagen, BV) Glomerulosclerosis ⬇️ 1-thickned BM 2-mesangial cell activation 3-increase mesangial matrix 4- increase endothelial permeability Effect 1) Glomerular: 1- Non-nephrotic proteinuria. 2- Nephrotic syndrome. 3- Chronic renal failure. 4- Diabetic glomerulosclerosis ➡️Capillaries basement membraneickening. ➡️Nodular glomerulosclerosis ➡️ Diffuse diabetic glomerulosclerosis. 2) Arteriolar ➡️ arterio-sclerosis ➡️ benign nephrosclerosis. ➡️Malignant nephrosclerosis. 3) Increase susceptibility to pyelonephritis. 4) Increase susceptibility to papillary necrosis. 5) Variety of tubular lesions: 13 | P a g e  L1,2_patho Morphology Diffuse diabetic nephropathy Nodular diabetic nephropathy Entire basement membrane ➡️ thick and Intercapillary glomerulosclerosis = hyaline. Kimmelstiel-Wilson disease. Diffuse increase in mesangial matrix. Ovoid or spherical, laminated, hyaline Mild proliferation of mesangial cells. masses, situated in the periphery of the glomeruli, within the mesangial core ➡️ As the disease progresses ➡️ mesangial “focal” or segmental, areas expand & obliterate the mesangial Surrounded by peripheral patent capillary cells ➡️ gradually filling the glomeruli ➡️ loops. Obliterative diabetic glemerulosclerosis. The uninvolved lobules show diffuse glomerulosclerosis. As disease advanced: The individual nodules affected enlarge ➡️ compress & engulf the capillary ➡️obliterating the glomerular tuft ➡️ ischemia ➡️ increase glomerular loss + tubular atrophy + interstitial fibrosis ➡️ contracted kidney. 14 | P a g e