Lecture:20 [Path] Glomerular Pathology [Part 1] Objectives The objective of the lecture is to discuss the pathogenesis and criteria for diagnosis of glomerular disease, differences between nephritic and nephrotic syndromes and the common disease entities presenting with nephritic syndrome Learning Outcomes At the end of the lecture, students should be able to: – Define and discuss basic histopathological morphology and terms used in the diagnosis of renal glomerular diseases – Distinguish the diagnostic criteria between nephritic and nephrotic syndromes – Discuss the pathogenesis of glomerular disease – Discuss incidence, cause, morphology (including histopathological, electron microscopy and immunofluorescence) and prognosis of common disease entities presenting as nephritic syndrome

NEPHROTIC SYNDROME

Lecture:21 [Path] Glomerular Pathology [Part 2] Objectives The objective of the lecture is to discuss the classification of Nephrotic syndrome and disease entities associated with nephrotic syndrome Learning Outcomes At the end of the lecture, students should be able to: – Classify disease entities associated with nephrotic syndrome – Compare and discuss various disease entities presenting as nephrotic syndrome, in the context of clinical presentation with laboratory data; etiopathogenesis; light microscopy, immunofluorescence, electron microscopic morphology; clinical course and prognosis

Classification of Nephrotic Syndrome Primary Glomerular diseases DiseaseChildren(%) Adults(%) Minimal change GN Membanous GN 5 40 MembranoProl.GN I 5 5 Focal segmental Glomerulosclerosis(FSGS) 5 20

Secondary causes Diabetes Mellitus SLE Amyloidosis Drugs (gold,penicillamine,heroin) Infections (malaria,syphilis,AIDS,HBV) Malignancy Miscellaneous-bee sting allergy;hereditary nephritis

Minimal Change GN Most common cause of nephrotic syndrome in children ( Age=2-3 years) ETIOPATHOGENESIS: unknown ( ? disorder of T cells).T cell derived factors cause podocyte damage & effacement foot processes Morphology. MICRO : Glomerulus- normal. Prox. Convoluted tubule- cells heavily laden with lipids &protein droplet (lipoid nephrosis) EM:fusion of foot processes-obliterating network of arcade

Minimal Change Glomerulopathy

LIPID in Tubular Epithelium

Effacement of visceral epithelial foot processes - MCD

Fatty casts

Clinical course( MCD) Nephrotic syndrome in children is more common than in adults > 80% NS in children is caused by MCD. Insidious onset.Renal function is preserved Selective protenuria (chiefly albumin) 90% cases in children respond to corticosteroid therapy.

FOCAL SEGMENTAL GLOMERULOSCLEROSIS(FSGS)

Focal Segmental Glomerulosclerosis Focal and segmental glomerular Sclerosis Common cause of Nephrotic Syndrme in adults Important to distinguish FSGS from MCD in children, because clinical course is different.

Focal Segmental Glomerulosclerosis Pathogenesis.:- Not Known Injury to visceral podocytes of epithelial cell – Hallmark of FSG Permeability increasing factor produced by T cells in circulation is proposed as cause. Hyalinosis / sclerosis – due to entrapement of plasma protein & lipid in mesangium

FSGS changes are seen In --HIV, – I-V drug abuse (heroin) – Secondary to IgA nephropathy – Inherited –mutation in nephrin protein

MICRO:- Affects some glomeruli (Focal ). Some tufts of a single glomeruli are affected (Segmental) Deposition of hyaline masses & lipid droplets in mesangium & obliteration of capillary lumen Some glomeruli are completely sclerosed(global SCLEROSIS) IF – IgM & complement deposition in sclerotic area. EM -loss of foot process Fate -Diffuse sclerosis ---tubular atrophy----interstitial fibrosis –Chronic GN Morphology

Focal Segmental Glomerulosclerosis

FSGS

Membranous GN Most common cause of nephrotic syndrome in adults (40%). Characterised by ----Subepithelial deposits of immune complex Causes: Primary. (Idiopathic)-85% Secondary: Infection- Ch.hepatitis,syphilis,malaria Malignancy-Ca Lung, Colon SLE & Ch. Immunolical Disorder Metals-Hg.Gold Drugs-Penicillamine

Membranous GN(Pathogenesis) A Form of chronic immune-compelx nephritis Circulating immune complex against exogenous antigen-eg HBV In situ immune complex against intrinsic and planted Ag -There is no inflammation. -Damage is caused by Direct action of C5b-C9 (membrane attack complex) on glomerular epithelial cells (podocyte) and mesangial cells which liberate proteases &oxidants→damage cap, wall.

CLINICAL Protenuria non-seleective Does not respond to corticosteroid Overall, proteinuria persists in over 60% of individuals About 40% suffer progressive disease terminating in renal failure after 2 to 20 years. An additional 10% to 30% have a more benign course with partial or complete remission of proteinuria.

Membranous Nephropathy Morphology MICRO:- Diffuse thickening of GBM EM- Subepithelial deposits over GBM separated from each other by spikes (Spike & dome pattern) IF – granular deposit of IgM & complement.

Membranous GN

Membranous GN( Spikes and Dome)

Membranous GN - IF

Membranoproliferative Glomerulonephritis IT CAN PRESENT AS NEPHRITIC AND NEPHROTIC SYNDROME Occurs in children and adults Two Types:-TYPE I --80% TYPE II --20%

Etiopathogenesis Type I:- Persistence of circulating antigens(antigenaemia) essential for continuous formation of circulating immune complex which are deposited in glomeruli. Causes:- Ch serum sickness Circulating hepatitis B and C antigen SLE Extrarenal infections with persistent antigenemia Type II Excessive complement activation by alternate pathway Autoantibody against C3 convertase called C3 nephritic factor which causes uncontrolled cleavage of C3.

Morphology Light microscopic picture of both is same Glomeruli –large & lobular due to proliferation of mesangial and endothelial cells and infiltration of leukocytes GBM = Thickened Silver stain – Tram – track / double contour of capillary wall due to extension of mesangial cell processes in cap wall.

EM & IF TYPE I EM:-Sub endothelial electron dense deposit IF:-C3 &IgG –deposited in granular pattern Subendothelium(++++) Subepithelial & mesangial deposit (+++). TYPE II EM- Ribbon like electron dense structure in lamina densa-called dense deposit disease IF-C 3 present as segmental linear foci in BM

MPGN

Interposition of mesangial cytoplasm into the peripheral capillary loop-type I MPGN

Tram- TraCk

Dense Deposit Disease

Clinical features Common in children & young adults Presents as Nephrotic syndrome % Nephritic syndrome % Mild protenuria % Majority of patients progress to Renal failure

Diabetic Kidney Diseases Renal involvement is an imp. complication of DM >10% of all diabetics die due to renal disease. Renal complications are more severe in type I than in type II diabetes

Diabetic nephropathy Diabetic Glomerulosclerosis Vascular lesions-Arteiosclerosis Pyelonephritis and Papillary necrosis Tubular lesion (Armmani-Ebstein lesions)

Diabetic Glomerulosclerosis Etiopathogenesis : 1. Advanced non-enzymatic glycation end products of proteins lead to BM thickening and increased mesangial matrix. 2.Haemodynamic effect-↑GFR→↑glom. Cap. Pressor →glom hypertrophy.

Glomerular LESION 1.Diffuse Glomerulosclerosis Characterised by Diffuse thickening of BM Diffuse increase in mesangial matrix and mesangial cell proliferation and deposition of PAS +ve material in mesangium. 2.Nodular Glomerulosclerosis ( Kimmelstiel Wilson K.W.Lesion) Glomerular lesion take the form of spherical nodule at periphery of lobule.They are PAS +ve and located in mesangium surrounded by cap. Loop

Diffuse & Nodular

Diabetes Mellitus – KW lesion

KW Lesion - PAS

3.Fibrin cap Homogeneous brightly eosinophilic material in a peripheral capillary loop 4. Capsular drop Hyalin eosinophilic material adherrent to Bowman capsule

Capsular Drop

Fibrin Cap

Lupus glomerulonephritis

Lupus Glomerulonephritis- (pathogenesis) Deposition of DNA / anti-DNA Immune complex in glomeruli with complement- TYPE III HYPERSENSITIVITY Inflammatory response Proliferation of endothelial, mesangial, epithelial cells

Pathology Of SLE GN Highly variable Immune complexes vary in/size/location – Subendothelial – Intramembranous – Subepithelial – Mesangial Proliferation of Mesangeal, Endothelial, Epithelial cells (crescent); PMN and macrophages Fibrinoid necrosis IF-”full house” of Immune staining (i.e. IgG,IgM, IgA, IgE, complement components – Clq, C3, C4 )

Lupus Glomerulonephritis WHO classification of Kidney Lesions Class I: No or slight ↑ in mesangial matrix & cells Class II: moderate ↑ Class III: Focal proliferative GN Class IV: Diffuse proliferative GN Class V: Membranous GN Class VI : Advanced Sclerosing Nephritis

Lupus Nephritis-Focal Proli.

Lupus nephritis-Diffuse Proli.

Lupus nephritis- wire loop lesion (PAS)

Amyloidosis kidney

One of the most common & most serious involvement is in the kidney. AA and AL chains are deposited Gross – kidney may be abnormally large & pale Micro:- Deposits of amyloid In glomeruli (mesangial) In arterioles IN tubular BM Demonsted by Congo red stain  Renal failure (with large kidneys!)

Amyloidosis

Hereditary Nephritis Alport Syndrome Nephritis with Nerve Deafness Ocular changes:- Lense dislocation Post cataract Corneal dystrophy. Pathognesis:- Mutation in any one α chain of type IV collagen

Morphology:- Glomeruli- Early stage- normal. Late stage -sclerosed. interstitium --foam cells End stage-glomerulosclerosis. vascular sclerosis, tubular atrophy and interstitial fibrosis. EM: Early stage-BM is thin and attenuated Late stage;-Irregular thickening,splitting and lamination “Basket weave” appearance.

Alport Syndrome Clinical Age- 5—20 yrs Present with gross haematuria and proteinuria mostly x linked, males more frequently and severely affected Renal failure by yrs

Interstitial foam cells

Thin BM

Alport Syndome