1. Pathology of Kidney Part II Dr. Sachin Kale, MD. Asso. Professor, Dept of Pathology.

2. Nephrotic syndrome Massive proteinuria (>3.5 gm/24 hrs) Massive proteinuria (>3.5 gm/24 hrs) Hypoalbuminemia Hypoalbuminemia Generalised edema Generalised edema Hyperlipidemia Hyperlipidemia Why? – derangement in glomerular capillary wall – Increased permeability Why? – derangement in glomerular capillary wall – Increased permeability

3. NS: pathophysiology Proteinuria –depletion of serum albumin Proteinuria –depletion of serum albumin Edema – results from loss of colloid pressure of blood – accumulation of fluid in interstitial tissue Edema – results from loss of colloid pressure of blood – accumulation of fluid in interstitial tissue Sodium/ H 2 O retention – Sodium/ H 2 O retention – Aldosterone, ADH, decreased ANP Aldosterone, ADH, decreased ANP Edema: soft and pitting – periorbital region Edema: soft and pitting – periorbital region

4. Largest proportion of protein lost is albumin Largest proportion of protein lost is albumin Highly selective proteinuria – low molecular wt proteins Highly selective proteinuria – low molecular wt proteins Poorly selective proteinuria : HMW in addition to albumin Poorly selective proteinuria : HMW in addition to albumin NS: pathophysiology

5. Genesis of Hyperlipidemia Increased levels of Cholesterol, TG, VLDL, LDL, LP(a), apolipoproteins Increased levels of Cholesterol, TG, VLDL, LDL, LP(a), apolipoproteins Increased synthesis of Lipoproteins in liver, abnormal transport of lipids, decreased catabolism. Increased synthesis of Lipoproteins in liver, abnormal transport of lipids, decreased catabolism. Lipiduria: lipoproteins leak across glomerular capillary wall. Lipiduria: lipoproteins leak across glomerular capillary wall. Oval fat bodies Oval fat bodies

6. Vulnerability towards infection Vulnerability towards infection Staph, peumococci, why? Loss of Immunoglobulins, LMW complement Staph, peumococci, why? Loss of Immunoglobulins, LMW complement Thrombotic/thomboembolic complications – loss of anticoagulant factors Thrombotic/thomboembolic complications – loss of anticoagulant factors Renal vein thrombosis Renal vein thrombosis

7. Primary glomerular diseases: Membranous GN (5, 40%), Lipoid Nephrosis (65, 15%), FSGS (10, 15%), MPGN (10, 7%), IgA nephropathy Primary glomerular diseases: Membranous GN (5, 40%), Lipoid Nephrosis (65, 15%), FSGS (10, 15%), MPGN (10, 7%), IgA nephropathy Systemic diseases: Diabetes, amyloidosis, SLE, Drugs (Gold, penicillamine, heroin), Infections (malaria, syphilis, Hepatitis B, AIDS), Malignancy (carcinoma, melanoma), Misc (bee sting, hereditary nephritis) Systemic diseases: Diabetes, amyloidosis, SLE, Drugs (Gold, penicillamine, heroin), Infections (malaria, syphilis, Hepatitis B, AIDS), Malignancy (carcinoma, melanoma), Misc (bee sting, hereditary nephritis) Causes of NS

8. Membranous GN Major cause of NS in adults Major cause of NS in adults Presence of electron dense, Ig containing deposits subepithelial side of BM Presence of electron dense, Ig containing deposits subepithelial side of BM Early: normal by light microscopy Diffuse: thickening of capillary wall Early: normal by light microscopy Diffuse: thickening of capillary wall

9. Secondary MGN Malignant epithelial tumors, carcinoma lung, colon and melanoma Malignant epithelial tumors, carcinoma lung, colon and melanoma SLE SLE Exposure to inorganic salts (Gold, mercury) Exposure to inorganic salts (Gold, mercury) Drugs (Penicillamine, Captopril) Drugs (Penicillamine, Captopril) Infections (Chr Hep B), syphilis, thyroiditis Infections (Chr Hep B), syphilis, thyroiditis Met. Disorders (GM, thyroidis) Met. Disorders (GM, thyroidis) 85% Idiopathic 85% Idiopathic

10. Etiology/Pathogenesis Chr antigen-antibody mediated disease Chr antigen-antibody mediated disease Secondary forms – specific antigens implicated – Exogenous/Endogenous (thyroglobulin) Secondary forms – specific antigens implicated – Exogenous/Endogenous (thyroglobulin) Majority of patients antigens unknown Majority of patients antigens unknown Genetic susceptibility Genetic susceptibility In situ immune reaction – glomerular or planted antigens In situ immune reaction – glomerular or planted antigens Heymann’s nephritis Heymann’s nephritis Why capillaries are leaky? Membrane attack complex complent Why capillaries are leaky? Membrane attack complex complent

11. Morphology Early stages: normal Early stages: normal Uniform, diffuse thickening of capillary wall Uniform, diffuse thickening of capillary wall

14. Clinical features Insidious NS, 15% non-nephrotic proteinuria Insidious NS, 15% non-nephrotic proteinuria Hematuria/Mild HT – (15 – 35%) Hematuria/Mild HT – (15 – 35%) Course: indolent Course: indolent Progression: increasing sclerosis, rising BUN, reduction of proteinuria, HT. Progression: increasing sclerosis, rising BUN, reduction of proteinuria, HT. Proteinuria persists 60%, 10% die, 40% develop renal insufficiency Proteinuria persists 60%, 10% die, 40% develop renal insufficiency

15. Minimal change disease Relatively benign disorder Relatively benign disorder Most frequent cause in children Most frequent cause in children Diffuse loss of foot processes of epithelial cells Diffuse loss of foot processes of epithelial cells Glomeruli virtually normal by light microscopy Glomeruli virtually normal by light microscopy Peak incidence: 2 – 6 yrs Peak incidence: 2 – 6 yrs

16. Etiology/ pathogenesis Immunologic basis – Immunologic basis – Clinical asso with respiratory infections and immunizations Clinical asso with respiratory infections and immunizations Response to steroid and immunosuppressive therapy Response to steroid and immunosuppressive therapy Asso with other atopic disorders Asso with other atopic disorders Increased prevalence of certain HLA haplotypes Increased prevalence of certain HLA haplotypes

17. Increased incidence in HD Increased incidence in HD Recurrence of proteinuria after transplantation Recurrence of proteinuria after transplantation

19. Minimal Change Disease: Loss of Foot processes

20. Clinical features Proteinuria Proteinuria Renal function good Renal function good No HT or Hematuria No HT or Hematuria 90% rapid response to steroids 90% rapid response to steroids May recur May recur Steroid dependent Steroid dependent Long term prognosis: excellant Long term prognosis: excellant

21. Focal segmental glomerulosclerosis Sclerosis of some (focal) but not all, glomeruli Sclerosis of some (focal) but not all, glomeruli Only a portion of capillary tuft (segmental) is involved. Only a portion of capillary tuft (segmental) is involved. A) Idiopathic A) Idiopathic B) FSG superimposed on other primary GN (IgA nephropathy) B) FSG superimposed on other primary GN (IgA nephropathy) C) Renal ablation FSG C) Renal ablation FSG Secondary FSG (HIV, Heroin) Secondary FSG (HIV, Heroin)

22. FSG.. 10 - 15 % cases of NS 10 - 15 % cases of NS Hematuria, GFR, HT Hematuria, GFR, HT Proteinuria: Non-selective Proteinuria: Non-selective Poor response to steroids Poor response to steroids Progress to Chr GN Progress to Chr GN IgM, C3 deposits IgM, C3 deposits

23. FSG.. Sclerotic segments: collapse of BM Sclerotic segments: collapse of BM Increased mesangial matrix Increased mesangial matrix Deposition of Hyaline masses (Hyalinosis) Deposition of Hyaline masses (Hyalinosis) Lipoid droplets Lipoid droplets Diffuse loss of foot processes Diffuse loss of foot processes Pronounced, focal detachment of epithelial cells Pronounced, focal detachment of epithelial cells Denudation of underlying GBM Denudation of underlying GBM Hyaline thickening of afferent arterioles Hyaline thickening of afferent arterioles Global sclerosis Global sclerosis Tubular atrophy and interstial fibrosis Tubular atrophy and interstial fibrosis

26. FSG: Clinical features No spontaneous remissions No spontaneous remissions Children : better prognosis. Children : better prognosis. Malignant focal sclerosis: 20% unusually rapid course Malignant focal sclerosis: 20% unusually rapid course HIV: Idiopathic FSG, focal cystic dilation of tubule segments, tubuloreticular inclusions HIV: Idiopathic FSG, focal cystic dilation of tubule segments, tubuloreticular inclusions

27. Membranoproliferative GN Alteration in BM & proliferation of glomerular cells Alteration in BM & proliferation of glomerular cells Mesangiocapillary GN Mesangiocapillary GN 5 – 10% idiopathic NS 5 – 10% idiopathic NS Hematuria/proteinuria Hematuria/proteinuria Asso with systemic disorders, Primary or secondary Asso with systemic disorders, Primary or secondary

28. MPGN Glomeruli: large, Hypercellular Glomeruli: large, Hypercellular Proliferation of mesangial cells, Proliferation of mesangial cells, Leukocytic infiltrate, parietal epithelial crescents Leukocytic infiltrate, parietal epithelial crescents Lobular appearance of glomeruli Lobular appearance of glomeruli GBM thickened GBM thickened

29. MPGN Gomerular capillary wall shows ‘double contour’ or ‘Tram track apperence” Gomerular capillary wall shows ‘double contour’ or ‘Tram track apperence” Splitting of BM due to extension of processes of mesangial cells : Mesangial interposition Splitting of BM due to extension of processes of mesangial cells : Mesangial interposition Type I: Subendothelial electron dense deposits Type I: Subendothelial electron dense deposits

30. MPGN Type II: Deposition of dense material of unknown composition in GBM proper Type II: Deposition of dense material of unknown composition in GBM proper C3 is present in granular linear foci and as mesangial rings. C3 is present in granular linear foci and as mesangial rings. IgG absent IgG absent Type III: Subendothelial and subepithelial deposits Type III: Subendothelial and subepithelial deposits

31. Membranoproliferative “tram-tracking”

32. MPGN

33. Type I: Immune complexes, activation of classic and alternate pathway of complement Type I: Immune complexes, activation of classic and alternate pathway of complement Type II: Activation of alternate pathway of complement Type II: Activation of alternate pathway of complement C3 Nephrtic Factor (C3NeF) in blood C3 Nephrtic Factor (C3NeF) in blood Presents as NS Presents as NS Progresses slowly but unremittingly Progresses slowly but unremittingly Some develop RPGN Some develop RPGN 50% develop CRF in 10 years 50% develop CRF in 10 years

34. Secondary MPGN Usually of Type I Usually of Type I SLE, Hepatitis B, C SLE, Hepatitis B, C Cryoglobulinemia Cryoglobulinemia Chronic liver disease Chronic liver disease Certain malignancies Certain malignancies Schistosomiasis Schistosomiasis

35. Chronic Glomerulonephritis End stage pool of gomerular disease - End stage pool of gomerular disease - RPGN RPGN Membranous GN Membranous GN Focal Glomerulosclerosis Focal Glomerulosclerosis MPGN MPGN IgA nephropathy IgA nephropathy Poststreptococcal is rare, others Poststreptococcal is rare, others

36. Morphology Symmetrically contracted kidneys Symmetrically contracted kidneys Diffuse granular cortical surface Diffuse granular cortical surface Cortex is thinned Cortex is thinned Peripelvic fat is increased Peripelvic fat is increased Hyaline obliteration of glomeruli Hyaline obliteration of glomeruli Acellular, eosinophilic PAS-positive masses Acellular, eosinophilic PAS-positive masses

38. Arterial arteriolar sclerosis: HT Arterial arteriolar sclerosis: HT Atrophy of tubules Atrophy of tubules Interstitial fibrosis Interstitial fibrosis Lymphocytic infiltrate Lymphocytic infiltrate Stigmata of uremia: pericarditis, gastroenteritis, renal osteodystrophy, LVH due to HT, Uremic pneumonitis Stigmata of uremia: pericarditis, gastroenteritis, renal osteodystrophy, LVH due to HT, Uremic pneumonitis

39. Clinical features Develops insidiously Develops insidiously Nonspecific GI complaints Nonspecific GI complaints Finding of azotemia, proteinuria, HT on routine check up Finding of azotemia, proteinuria, HT on routine check up Edema Edema HT – CNS, CVS problems HT – CNS, CVS problems Dialysis or transplantation Dialysis or transplantation

40. False about NS Proteinuria results from deranged capillary walls Proteinuria results from deranged capillary walls In selective proteinuria Albumin is lost In selective proteinuria Albumin is lost Hyperlipidemia Hyperlipidemia Vulnerability to infection Vulnerability to infection Bleeding complications Bleeding complications

41. False about MCD.. Frequent cause of NS between 2 – 6 yrs Frequent cause of NS between 2 – 6 yrs Glomeruli show thickening of GBM by light microscopy Glomeruli show thickening of GBM by light microscopy Immune deposits are not seen Immune deposits are not seen Tubules are ladden with lipids. Tubules are ladden with lipids.

42. FSGS: True or False Seen in Heroin abuse and HIV Seen in Heroin abuse and HIV Selective proteinuria Selective proteinuria Respond well to steroids Respond well to steroids Many Progress to chronic GN Many Progress to chronic GN Sclerotic segments show hyalinosis and lipoid droplets Sclerotic segments show hyalinosis and lipoid droplets There is no podocyte fusion There is no podocyte fusion Represents evolution of MCD Represents evolution of MCD True False True False True

43. False about MPGN.. Type I is common Type I is common Type I shows subendothelial electron dense deposits Type I shows subendothelial electron dense deposits Type I is called dense deposit disease Type I is called dense deposit disease In type II GBM is, irregular, ribbon-like structure In type II GBM is, irregular, ribbon-like structure Type I shows Immune complexes Type I shows Immune complexes Type II has activation of alternate complement pathway Type II has activation of alternate complement pathway Secondary MPGN is usually type I Secondary MPGN is usually type I

44. Following commonaly leads to Chronic Glomerulonephritis except RPGN RPGN Membranous GN Membranous GN MPGN MPGN Post-streptococcal GN in children Post-streptococcal GN in children

45. False about CGN Asymmetrically contracted kidneys Asymmetrically contracted kidneys Thinned cortex Thinned cortex Hyaline obliteration of glomeruli Hyaline obliteration of glomeruli Hypertension Hypertension Atrophy of tubules Atrophy of tubules Uremia Uremia

46. Which of the following is a clinical feature of CGN Loss of appetite, nausea, Loss of appetite, nausea, Proteinuria, HT Proteinuria, HT Edema Edema All of the above All of the above

47. Spot the diagnosis… FSGS

48. Spot the diagnosis… CGN

49. Spot the diagnosis… MGN

50. Spot the diagnosis… MCD

51. Spot the diagnosis… MPGN

52. Thought for the day… Life is like lemon & spoon race, if you drop the lemon there is no use coming first.. Life is like lemon & spoon race, if you drop the lemon there is no use coming first.. Same is with life, where health and family are your lemon! Same is with life, where health and family are your lemon!

53. Thank you! Contact: Contact: http://sachinkale1.tripod.com http://sachinkale1.tripod.com http://sachinkale1.tripod.com