GSP F.01 Kidney Non-neoplastic Glomerular Diseases PDF

PCCSOM 2026 GENERAL AND SYSTEMIC PATHOLOGY F. 01 KIDNEY: NON-NEOPLASTIC GLOMERULAR DISEASES LECTURER: DR. AMERLITO NUESCA, MD, DPSP GENERAL AND SYSTEMIC PATHOLOGY LECTURE peripheral layers NUESCA, MD, DPSP LECTURER: AMERLITO DATE: MAY 2024 TOPIC OUTLINE Introduction Pathologic Response of Glomerulus...

PCCSOM 2026 GENERAL AND SYSTEMIC PATHOLOGY F. 01 KIDNEY: NON-NEOPLASTIC GLOMERULAR DISEASES LECTURER: DR. AMERLITO NUESCA, MD, DPSP GENERAL AND SYSTEMIC PATHOLOGY LECTURE peripheral layers NUESCA, MD, DPSP LECTURER: AMERLITO DATE: MAY 2024 TOPIC OUTLINE Introduction Pathologic Response of Glomerulus to Injury Histologic Patterns Pathogenesis of Glomerular Injury Mediators of Glomerular Injury Epithelial Cell Injury Mechanisms of Progression in GD INTRODUCTION proliferation - thin electron-lucent - laying down both matrix and collagen - secreting biologically active mediators Glomerular Basement Membrane - thick electron-dense central layer (lamina densa) - thin electron-lucent peripheral layers (lamina rara interna, lamina rara externa) - collagen, laminin, polyanionic proteoglycans (heparan sulfate), fibronectin, entactin - Type IV collagen forms a network suprastructure to which other glycoproteins attach - Collagen monomer: triple-helical molecule composed of one or more of six types of α chains (α1 to α6 or COL4A1 to COL4A6) - NC1 domain: helix formation and assembly of collagen monomers into BM suprastructure GLOMERULAR CAPILLARY WALL Endothelial cells: ~ 70 to 100 nm diameter fenestra Podocytes - visceral epithelial cells with interdigitating processes embedded in and adherent to lamina rara externa of BM - adjacent foot processes separated by 20 – 30 nm wide filtration slits Mesangium: composed of BM-like mesangial matrix that supports glomerular tuft Mesangial cells - contractile, phagocytic, and capable of NOTE TAKER: FERRER, NAMUHMUH, OLARTE, SANTIAGO Page 1 | 29 PCCSOM 2026 GENERAL AND SYSTEMIC PATHOLOGY F. 01 KIDNEY: NON-NEOPLASTIC GLOMERULAR DISEASES LECTURER: DR. AMERLITO NUESCA, MD, DPSP peripheral layers PATHOLOGIC RESPONSE OF GLOMERULUS TO - thin electron-lucent INJURY A. HYPERCELLULARITY proliferation of mesangial and endothelial cells infiltration of leukocytes glomerular epithelial cell proliferation to form crescents GLOMERULUS highly permeable to water and small solutes impermeable to proteins the size of albumin (3.6nm radius; 70 kilodaltons [kD] molecular weight) size- and charge-dependent barrier function visceral epithelial cell important for maintaining glomerular barrier function NEPHRIN transmembrane protein with a large extracellular portion made up of immunoglobulin (Ig)-like domains forms molecular connections with podocin, CD2associated protein, and actin cytoskeleton of visceral epithelial cells gene mutations encoding them give rise to defects in permeability and nephrotic syndrome B. BASEMENT MEMBRANE THICKENING Light microscopy: PAS stain to visualize capillary wall thickening EM: subendothelial or subepithelial depositions of immune complexes, fibrin, amyloid, and cryoglobulins, increased synthesis of BM components C. HYALINOSIS AND SCLEROSIS Hyalinosis: injury to endothelium and capillary walls → plasma proteins insudating in extravascular spaces Sclerosis: deposition of extracellular collagenous matrix NOTE TAKER: FERRER, NAMUHMUH, OLARTE, SANTIAGO Page 2 | 29 PCCSOM 2026 GENERAL AND SYSTEMIC PATHOLOGY F. 01 KIDNEY: NON-NEOPLASTIC GLOMERULAR DISEASES LECTURER: DR. AMERLITO NUESCA, MD, DPSP - thin electron-lucent peripheral layers HISTOLOGIC PATTERNS Diffuse - involving all glomeruli Focal - fraction of glomeruli Global - entire glomerulus Segmental - part of any given glomerulus Capillary or mesangial I. IN SITU FORMATION OF IMMUNE COMPLEXES immune complexes formed locally by antibodies reacting with intrinsic tissue antigens extrinsic antigens "planted" in the glomerulus from the circulation membranous nephropathy other possible planted antigens: viral, bacterial, and parasitic products and drugs Membranous nephropathy - local formation of immune complexes by antibodies reactive with endogenous antigens - LM: thickened BM - EM: numerous discrete subepithelial electrondense deposits (made up of immune reactants) ANTIBODIES DIRECTED VS COMPONENTS OF GBM anti-GBM antibody–induced glomerulonephritis antibodies intrinsic antigens homogeneously distributed along entire length of GBM → diffuse linear pattern of staining by IF < 5% of cases of human glomerulonephritis necrotizing and crescentic glomerular damage and clinical syndrome of RPGN PATHOGENESIS OF GLOMERULAR INJURY immune mechanisms underlie most forms of primary glomerulopathy and many secondary glomerular disorders Immune mechanisms of Glomerular Injury - In situ immune complex deposition - Circulating immune complex deposition - Cell-mediated immune injury NOTE TAKER: FERRER, NAMUHMUH, OLARTE, SANTIAGO II. DEPOSITION OF CIRCULATING IMMUNE COMPLEXES caused by trapping of circulating antigen-antibody complexes within glomeruli no immunologic specificity for glomerular Page 3 | 29 PCCSOM 2026 GENERAL AND SYSTEMIC PATHOLOGY F. 01 KIDNEY: NON-NEOPLASTIC GLOMERULAR DISEASES LECTURER: constituents DR. AMERLITO NUESCA, MD, DPSP peripheral localize within the glomeruli due to their layers physicochemical properties and hemodynamic factors peculiar to the glomerulus antigen trigger: endogenous or exogenous origin Microbial antigens: bacterial products, surface antigen of hepatitis B virus, hepatitis C virus antigens, and antigens of Treponema pallidum, Plasmodium falciparum, and viruses Tumor antigens might also cause immune complex–mediated nephritis inciting antigen unknown in majority of cases MECHANISMS OF GLOMERULAR INJURY - thin electron-lucent FOLLOWING IMMUNE COMPLEX FORMATION antigen-antibody complexes formed or deposited in the glomeruli → local inflammatory reaction → injury factors influencing immune-reactant deposition patterns: molecular charge and size of immune reactants changes in glomerular hemodynamics and mesangial function integrity of charge-selective barrier in the glomerulus may influence the variable pattern of immune-reactant deposition highly cationic antigens cross the GBM highly anionic macromolecules trapped subendothelially or not nephritogenic neutrally charged molecules and immune complexes containing neutral charge molecules accumulate in the mesangium most cases are consequences of deposition of discrete immune complexes → granular immunofluorescence staining along GBM or in mesangium in situ immune reactions, trapping of circulating complexes, and local hemodynamic and structural determinants → glomerulonephritis III. CELL MEDIATED IMMUNITY IN GLOMERULONEPHRITIS sensitized T cells cause glomerular injury and involved in the progression of some glomerulonephritides - presence of activated macrophages and T cells in the glomerulus - lymphocyte activation on exposure to antigen - dissolution of glomerular injury by lymphocyte depletion - experiments in which glomerular injury may be induced by transfer of T cells from nephritic animals to normal recipients NOTE TAKER: FERRER, NAMUHMUH, OLARTE, SANTIAGO Page 4 | 29 PCCSOM 2026 GENERAL AND SYSTEMIC PATHOLOGY F. 01 KIDNEY: NON-NEOPLASTIC GLOMERULAR DISEASES LECTURER: DR. AMERLITO NUESCA, MD, DPSP ACTIVATION OF ALTERNATIVE COMPLEMENT PATHWAY peripheral layers membranoproliferative glomerulonephritis (MPGN type II) - previously termed dense-deposit disease C3 glomerulopathies MEDIATORS OF GLOMERULAR INJURY: CELLS Neutrophils and monocytes - Proteases → GBM degradation - oxygen-derived free radicals → cell damage - arachidonic acid metabolites → reduction in GFR Macrophages and T lymphocytes - cytokines and growth factors Platelets aggregate - eicosanoids and growth factor Resident glomerular cells (mesangial cells) - cytokines, growth factors, chemokines, oxygen free radicals, eicosanoids, and endothelin NOTE TAKER: FERRER, NAMUHMUH, OLARTE, SANTIAGO MEDIATORS OF GLOMERULAR INJURY: SOLUBLE - thin electron-lucent MEDIATORS Complement activation - generation of chemotactic products → leukocyte influx and formation of MAC → cell lysis and stimulate mesangial cells → oxidants, proteases, and other mediators C3 glomerulopathies: alternative pathway Eicosanoids, nitric oxide (NO), angiotensin, and endothelin: vascular flow. Cytokines (IL-1, TNF) and chemokines (CCL5): influence inflammatory cell adhesion and recruitment Coagulation proteins (fibrin) → parietal epithelial cell proliferation (crescent formation) Chemokines - PDGF → mesangial cell proliferation - TGF-β and fibroblast growth factor → matrix deposition - VEGF maintains endothelial integrity and regulates capillary permeability EPITHELIAL CELL INJURY Podocyte injury common in both primary and secondary glomerular diseases as well as immune and nonimmune etiologies Podocytopathy - diseases with disparate etiologies whose principal manifestation is injury to podocytes Loss of podocytes feature of multiple types of glomerular injury, including FSGS and diabetic nephropathy loss of normal slit diaphragms is a key event in the development of proteinuria* Page 5 | 29 PCCSOM 2026 GENERAL AND SYSTEMIC PATHOLOGY F. 01 KIDNEY: NON-NEOPLASTIC GLOMERULAR DISEASES DR. AMERLITO NUESCA, LECTURER: mutation of components (podocin, nephrin) MD, DPSP cause of rare hereditary forms of nephrotic peripheral layers syndrome supply - thin electron-lucent Proteinuria: direct injury to and activation of tubular cells → adhesion molecule expression and proinflammatory cytokine, chemokine, and growth factor release → interstitial fibrosis MECHANISMS OF PROGRESSION IN GLOMERULAR DISEASE severity of renal damage nature and persistence of the antigens host immune status, age, and genetic predisposition destruction of functioning nephrons → reduction of GFR to ~ 30% to 50% of normal → end-stage renal failure or ESRD secondary factors - targets of therapy → delay or prevention two major histologic characteristics of progressive renal damage - glomerulosclerosis - tubulointerstitial fibrosis A. GLOMERULOSCLEROSIS Sclerosis involving portions of some glomeruli (secondary FSGS) develops after many types of renal injury → proteinuria → functional impairment Glomerular sclerosis may be seen even in nonglomerular primary disease END PART 1---------- B. TUBULOINSTERSTITIAL INJURY component of many glomerulonephritides fibrosis contributes to progression in both immune and nonimmune glomerular diseases correlation of decline in renal function with the extent of tubulointerstitial damage than with the severity of glomerular injury ischemia of tubular segments downstream from sclerotic glomeruli inflammation in adjacent interstitium damage or loss of the peritubular capillary blood NOTE TAKER: FERRER, NAMUHMUH, OLARTE, SANTIAGO Page 6 | 29 PCCSOM 2026 GENERAL AND SYSTEMIC PATHOLOGY F. 01 KIDNEY: NON-NEOPLASTIC GLOMERULAR DISEASES LECTURER: TOPIC OUTLINE DR. AMERLITO NUESCA, MD, DPSP peripheral layers Nephritic Syndrome I. Acute Proliferative (Postinfectious and InfectionAssociated) Glomerulonephritis II. Crescentic (Rapidly Progressive) Glomerulonephritis Nephrotic Syndrome I. Membranous Nephropathy II. Minimal Change Disease III. Focal Segmental Glomerulosclerosis IV. HIV-related Nephropathy V. Membranous Proliferative Glomerulonephritis Secondary Membranoproliferative Glomerulonephritis VI. Dense Deposit Disease VII. Fibrillary Glomerulonephritis NEPHRITIC SYNDROME Inflammation in the glomeruli Main clinical features: - Hematuria: Presence of RBC’s and red cell casts in urine - Proteinuria (subnephrotic range) With or without edema - Azotemia - Hypertension Clinical Presentation of most proliferative types of glomerulonephritis Caused by proliferation of cells w/in glomeruli and an inflammatory leukocytic infiltrate Inflammatory reaction->Capillary wall injury>Hematuria GFR reduction causes oliguria, fluid retention, and azotemia Fluid retention and renin release from ischemic kidneys will cause hypertension I. Acute Proliferative (Post infectious and Infectionassociated) Glomerulonephritis Diffuse proliferation of glomerular cells associated with influx of leukocytes Inciting antigen: - Exogenous: Postinfectious glomerulonephritis - Endogenous: Lupus nephritis Most common underlying infections are caused streptococcus species NOTE TAKER: FERRER, NAMUHMUH, OLARTE, SANTIAGO Appears 1-4 electron-lucent weeks after streptococcal infection of - thin pharynx or the skin (impetigo) Occurs most frequently in children ages 6 to 10 PATHOGENESIS: ✓ Caused by immune complexes containing streptococcal Ag and specific Ab ✓ Group A β-hemolytic streptococci - >90%: types 1,4, and 12 - identified by typing of bacterial cell wall M protein ✓ Immunologic basis is due to the following - Elevated antibodies against streptococcal antigens - Low serum complement levels - Granular immune deposits in the glomeruli ✓ Latent period between infection and onset of nephritis is compatible with the production of antibodies and the formation of immune complexes ✓ Streptococcal pyogenic exotoxin B (SpeB) - Principal antigenic determinant in most but not all cases of post streptococcal glomerulonephritis - Secreted by nephritogenic strains of streptococci - Can activate complement system ✓ Inciting antigens exogenously planted in subendothelial locations in glomerular capillary walls -> inflammatory responses -> Ag-Ab complexes dissociate -> Migration across glomerular basement membrane -> reform on the subepithelial side of the GBM -> “hump-like” deposits ✓ A similar form of glomerulonephritis occurs sporadically in association with other infections: - Bacterial: Staphylococcal endocarditis, Pneumococcal pneumonia, and Meningococcemia - Viral: Hep B, Hep C, mumps, HIV, Varicella and Infectious mononucleosis - Parasitic: Malaria, Toxoplasmosis MORPHOLOGY: ✓ LM (Light Microscopy): Enlarged, Hypercellular glomeruli caused by: - Infiltration of leukocytes - Proliferation of endothelial and mesangial cells - Crescent formation ✓ Proliferation and leukocyte infiltration global and Page 7 | 29 PCCSOM 2026 GENERAL AND SYSTEMIC PATHOLOGY F. 01 KIDNEY: NON-NEOPLASTIC GLOMERULAR DISEASES LECTURER: DR. AMERLITO NUESCA, MD, DPSP diffuse. peripheral layers ✓ IFM (Immunofluorescence Microscopy): Granular deposits of IgG and C3, Sometimes IgM in the mesangium along the GBM ✓ EM (Electron Microscopy): Discrete, Amorphous, Electron-dense deposits on the epithelial side of the membrane Ag-Ab complexes at the subepithelial cell surface “Humps” May also be present: Subendothelial, Mesangial, and intramembranous deposits NOTE TAKER: FERRER, NAMUHMUH, OLARTE, SANTIAGO - thin electron-lucent CLINICAL FEATURES: Child with sudden onset of malaise, fever, nausea, oliguria, and hematuria (smoky or cola-colored urine) 1 - 2 weeks after recovery from a sore throat Dysmorphic red cells or red cell casts in urine Mild proteinuria: 95% recover renal function with conservative therapy 90% have c-ANCA or p-ANCA in serum - c-ANCA: Neutrophil granule protein proteinase- Page 9 | 29 PCCSOM 2026 GENERAL AND SYSTEMIC PATHOLOGY F. 01 KIDNEY: NON-NEOPLASTIC GLOMERULAR DISEASES LECTURER: DR. AMERLITO NUESCA, MD, DPSP 3 (PR3-ANCA) - p-ANCA: Reactivity with neutrophil peripheral layers myeloperoxidase (MPO-ANCA) - Highly sensitive diagnostic marker for pauciimmune crescentic glomerulonephritis MORPHOLOGY Kidneys are enlarged and pale Petechial hemorrhages on cortical surfaces Focal and Segmental Necrosis of Glomeruli Diffuse or Focal endothelial proliferation Mesangial Proliferation Pauci-immune RPGN: Segmental glomerular necrosis and crescents adjacent to glomerular segments uninvolved by inflammatory or proliferation Most crescents undergo organization and foci of segmental necrosis resolve as segmental scars (segmental sclerosis) Restoration of normal glomerular architecture may be achieved with early aggressive therapy LM: Formation of crescents - Glomerular epithelial cell proliferation - Migration of monocytes and macrophages into urinary space - Prominent fibrin strands between cellular layers NOTE TAKER: FERRER, NAMUHMUH, OLARTE, SANTIAGO - thin electron-lucent Immunofluorescence Microscopy - Goodpasture syndrome: Linear GBM fluorescence for Ig and complements - Immune complex-mediated: Granular immune deposits - Pauci-immune: Little or no deposition of immune reactants Page 10 | 29 PCCSOM 2026 GENERAL AND SYSTEMIC PATHOLOGY F. 01 KIDNEY: NON-NEOPLASTIC GLOMERULAR DISEASES DR. AMERLITO NUESCA, MD, DPSP LECTURER: EM: GBM rupture -> Leakage peripheral layers of leukocytes, plasma proteins, and inflammatory mediators to urinary space -> triggers crescent formation CLINICAL FEATURES Crescentic glomerulonephritis - Hematuria - Moderate proteinuria - Variable Hypertension - Edema Goodpasture Syndrome - Recurrent hemoptysis leading to pulmonary hemorrhage Intensive plasmapheresis, steroids and cytotoxic agents will lead to recovery of renal function Many patients eventually require chronic dialysis or transplantation --Generalized edema thin electron-lucent - Hyperlipidemia and lipiduria Heavy Proteinuria and increased renal catabolism of filtered albumin will cause hypoalbuminemia - Protein lost in urine: Albumin and Globulins - Selectivity of proteinuria - Highly Selective: LMW proteins (albumin, transferrin) - Poorly Selective: HMW proteins (Globulins and Albumin) EDEMA - Decreased intravascular colloid osmotic pressure - sodium and water retention, compensatory aldosterone secretion, sympathetic system stimulation, natriuretic factor reduction - Physical Exam: Pitting Edema (periorbital regions, dependent portions of the body) - May lead to pleural effusion and ascites Hyperlipidemia: - Increased blood cholesterol, TG, VLDL, LDL, Lipoprotein(a), and apoproteins ○ Decreased HDL - Combination of increased synthesis of lipoproteins in the liver and abnormal transport of circulating lipid particles - Decreased lipid catabolism - Lipoproteins leak across glomerular capillary wall leading to lipiduria (Free fat or oval fat bodies) Loss of immunoglobulins will cause infections (staphylococcal, pneumococcal) Loss of endogenous anticoagulants leads to thrombotic and thromboembolic complications Membranous nephropathy: Hypercoagulable state leading to renal vein thrombosis NEPHROTIC SYNDROME PATHOPHYSIOLOGY Caused by derangement in glomerular capillary walls leading to increased permeability to plasma proteins - Massive Proteinuria: loss of ≥3.5g - Hypoalbuminemia: Plasma albumin Complement activation > Shedding of immune aggregates from cell surface -> subepithelial immune complex deposition Less common target antigens: THSD7A and CD10 - THSD7A: Thrombospondin type-1 domaincontaining 7A - NEP(CD10): Neutral endopeptidase (Neonatal membranous nephropathy) Lesions resemble to those of Heymann Nephritis - Experimental rat model for active and passive immune-mediated nephritis - Induced by antibodies to megalin antigenic complex (human counterpart: PLA2R) present in rat podocytes C5b-C9 (Membrane Attack Complex or MAC) - Activates epithelial and mesangial cells leading to protease and oxidant release which will lead to capillary wall injury and increased protein leakage IgG4 - Principal IgG deposited in most cases - Poor activator of classical complement pathway MORPHOLOGY LM: - Normal in early stages of the disease - Uniform and diffuse thickening of the glomerular capillary wall EM: - Glomerular capillary wall thickening - Irregular electron-dense deposits containing immune complexes between the BM and overlying Page 12 | 29 PCCSOM 2026 GENERAL AND SYSTEMIC PATHOLOGY F. 01 KIDNEY: NON-NEOPLASTIC GLOMERULAR DISEASES LECTURER: epithelial cellsDR. AMERLITO NUESCA, MD, DPSP - Effacement of podocyte foot processes BM peripheral layers material between deposits-> irregular spikes protruding from the GBM -> Spike thickening -> Dome Like protrusions->Close over immune deposits -> thickened irregular membrane - thin electron-lucent (EM showing electron-dense deposits (arrow) along the epithelial side of the basement membrane (B). Note the effacement of foot processes overlying deposits.) (Diagrammatic representation of membranous nephropathy) IFM: Granular deposits contain both immunoglobulin and complement NOTE TAKER: FERRER, NAMUHMUH, OLARTE, SANTIAGO IMMUNOHISTOCHEMICAL STAINING PLA2R or THSD7A glomerular positivity CLINICAL FEATURES Insidious onset of the nephrotic syndrome or with non-nephrotic proteinuria (15% of cases) Hematuria and mild hypertension present in 1535% of cases Treatment of underlying condition - Malignant neoplasm - Infection - SLE - discontinuance of the offending drug will lead to improvement Disease course variable but generally indolent Complete or partial remissions in 40% of patients 10% die or progress to renal failure within 10 years