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Glomerular diseases are a heterogeneous group of kidney disorders that can be primary, secondary, or hereditary in nature. They involve pathological changes to the glomeruli, such as injury to the mesangial cells, endothelial cells, basement membrane, or podocytes. This can lead to clinical manifestations like proteinuria, hematuria, edema, hypertension, and renal failure. The mechanisms of glomerular injury are complex, often involving the immune system through immune complex deposition, complement activation, or cytotoxic antibodies. Glomerular diseases have diverse clinical presentations and outcomes depending on the specific cause and severity of involvement.

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Glomerular diseases
Glomerular diseases (glomerulopathy)  heterogeneous group of diseases Dividing: a) Primary glomerulopathy b) Secondary glomerulopathy c) Hereditary glomerulopathy – can be manifestation of systemic diseases, vascular, metabolic or genetic disorders affecting also other organs The mechanisms for glomerular injury are complex  more often are iniciated by an immune response exclude
• A group of diseases: pathological changes:glomerular injury clinical manifestation:protenuria/ hematuria complicated causes/mechanisms various clinical manifestation different prognosis multiple treatment
What kind of nephritis does Alport syndrome belong to？ 1 Primary glomerular diseases 2 Secondary glomerular diseases 3 Hereditary glomerular diseases
Drugs and poisons product of metabolism Special capillary bulb structure The renal blood supply is abundant Vasculitis
Clinical manifestation of GN initiation hematuria proteinuria Edema,hyp ertention Renal failure Acute GN acute 100% 100% frequent resumable rapid progressive GN acute 100% 100% frequent ARF Chronic GN latent frequent frequent frequent CRF Latent GN latent frequent <1g/d - - Nephrotic syntrome
Diffuse Membranous nephropathy proliferative glomerulonephritis Sclerosing glomerulonephritis Mesangial proliferative glomerulonephritis endocapillary proliferative glomerulonephritis Mesangial capillary glomerulonephritis Crescentic and necrotizing glomerulonephritis Minor glomerular abnormalities Focal segmental lesions
Fig. Glomerular basement membrane (GBM) negative charge barrier Immunopathologic mechanisms
Immunopathologic mechanisms Damage of kidney depend on: - mechanism and intensity of immune reaction - collocation of antigens (Ag) Mechanisms:  Damage by immunocomplexes  Damage by cytotoxic antibodies (Ab)  Cell-mediated immune injury = delayed-type hypersensitivity  Damage by complement and proinflammatory mediators
Cytotoxic (Type II) reaction – antibody mediated cytotoxicity (ADCC) These occur when antibodies interact with antigens found on cell surface 2 mechanisms of cytotoxicity: 1. Ab mediate cell destruction via mechanism ADCC (cell cytotoxicity dependent on Ab) 2. Ab directed against cell- surface antigens mediate cell destruction via complement activation
Type III reaction – immune complex- mediated hypersensitivity - The reaction of antibody with antigen generates immune complexes. In some cases, large amounts of immune complexes can lead to tissue damage They deposited in various tissues  induce complement activation and ensuing inflammatory response Antigens can be: a) Endogenous – for example DNA in SLE b) Exogenous – bacteria, viral, parasitical Ag
The magnitude of the reaction depends on the quantitity of immune complexes as well as distribution within the wall of glomerular capillary
Location of immune deposits in the glomerular capillary wall
Delayed – type hypersensitivity (Type IV) T lymphocytes may also recognize antigen When they do, a mononuclear cell infiltrate may accumulate at the site of Ag concentration and lead to the elaboration of toxic products and tissue injury
Immune mechanisms Humoral Cell mediated Non immune mechanisms inflammation Glomerular diseases
• Immune mechanisms deposits of immuno- complex(IC) antigen+antibody kidney deposits
• Extrinsic drug:nonhomologous serum,penicilin Foods:xenogenic protein Pathogens:specific serotypes streptococci,HBV,HCV • Intrinsic Nucleus(SLE) Cytoplasm(ANCA) Cellular membrane Antigen of tumor Antigen of thyroid
Why does IC deposit in the glomeruli • Large area of glomurular capallaries More chances of contact • Net structure of CIC Easy to deposit and settle down • Decrease clearance of CIC clearance dysfunction of mesangial cells Disability of mononuclear macrophage Component or function defect of complements
Balance of deposit and clearance of IC determines thd situation of the diseases • Persistence of antigen • Clearance dysfunction of mesangial cells • Disability of mononuclear macrophage • Component or function defect of complements IC deposit>clearance
• Non immune mechanisms Glomerular hypertension Hyperlipidemia(LDL-Cho) Advanced glycosylation end products protein glomerulosclerosis
inflammation • Mediators of inflammation A group of molecules which act as mediators of inflammation and complicated biological function • Original mediators in kidney Extrinsic cells in kidney Infiltrative neutrophil,lymphocyte,mononuclear macrophage,platelet intrinsic cells in kidney Mesangial cells,tubular cells,endothelial cells
Mediators of inflammation • Active oxygen and active nitrogen • Lipids • Complements • Cytokines • Adhension molecules • Growth factors • Vasoactive substances
Effects of inflammation mediators • To arouse or promote Proliferation of cells Accumulation of extracellular matrix Changes of histological structure Expression of immunomodulating molecules and adhension molecules
Mechanism of primary GN Immune Mesangial cells,tubular cells,endothelial cells Essential in the initiation Essential in the progressive period inflammation Inflammation cells Extrinsic cells Intrinsic cells Infiltrative neutrophil,lymphocyte,mononucl ear macrophage,platelet Inflammation mediators Active oxygen and active nitrogen,cytokines,growth factors,chemotatic factors, complments,vasoactive subtances,coagulation and fibrolysis system,enzyme Glomerular injuries Non immune
Sites of pathological changes • Mesangium mesangial cell mesangial matrix • Basement membrane Podocyte Endothelial cell
Pathogenesis Normal glomerular structure • Glomerular tuft composed 4 major components – Endothelial cells – Visceral epithelial cells or Podocytes – Mesangium – Capillary loop basementmembrane • Capillary wall – carries a net negative charge – acts as both – charge-selective – size-selective filter
Glomerular capillary wall: Size selective filter The capillary wall restricts the passage of large molecules into Bowman's space, while there is less restriction of smaller molecules. As radii increase, filtration decreases, approaching zero at radii > 4.2 nm
Glomerular capillary wall: Charge-Selective Filter The capillary wall restricts the passage of negatively charged molecules such as albumin while neutral substances pass more freely and are restricted by size from passing into Bowman's space.
Pathological changes • LM Mesangial cells,matrix of mesangium Endothelial cells Epithelial cells Basement membrane Loops of glomeruli • EM（Electron microscope） • Foot process Basement membrane Hyperplasy of mesangium(electron dense deposits) • IF Sites,appearances,type of deposits（IG or C）
Basical changes • Proliferation • Fibrosis and sclerosis • Necrosis • Infiltration of inflammation cells
Extents of injury • Primary GN:glomerular injury-only or dominating injury • Secondary GN: glomerular injury-a part of systematic diseases • Diffuse:impaired glomeruli>50% • Focal: impaired glomeruli>50% • Global:impaired capillary loops of a glomerule>50% • Segmental:impaired capillary loops of a glomerule<50%
Pathological types of primary GN • Minimal change of glomerulonephritis • Focal segmental lesions • Diffuse glomerulonephritis • Unclassified glomerulonephritis
Minimal Change Disease (MCD) • Most common cause of nephrotic syndrome in childhood – In a prospective study of untreated children with N.S.: • minimal change disease was found in 76.6%. • Only 10% to 30% of adult cases of nephrotic syndrome – Percentages vary in different parts of the world • The clinical onset of nephrotic syndrome associated with: – upper respiratory infection – with routine prophylactic immunizations – Other genetic and environmental factors may also be important
Morphologic Features (LM & IF) • LM: normal in glomeruli, tubules and interstitium • IF: No immune deposits
• diffuse effacement of the epithelial cell (podocyte) foot processes Morphologic Features (EM)
Clinical Course • Most patients with MCD develop mild periorbital edema as initial complaint • Proteinuria: to be "selective“ – primarily of albumin – Microscopic hematuria is rare (13 to 36%) – Hypertension: also unusual • Treatment: – Most patients (90%) respond to an 8 week course of steroids – Cytotoxic agents: may be used in steroid resistant cases (~10%) – Renal failure: rare – Relapses are common
Focal Segmental Glomerulosclerosis (FSGS) (a ) often present with severe proteinuria (b ) 30-50% combine with hypertension (c ) HIV may associated with FSGS (d ) subepithelial “ hump” of glomuerulus in electron microscopy
Focal Segmental Glomerulosclerosis (FSGS) • Prevalence in idiopathic nephrotic syndrome : – 10% of childhood – 15-20% of cases of adult • Symptoms and signs: common with – proteinuria – microscopic hematuria – Hypertension • Pathogenesis: – sclerosing lesions and their progressive nature are debated • hyperfiltration, • increased intracapillary glomerular pressure
Morphologic Features • LM: focal and segmental glomerular sclerosis with capillary loop collapse, hyaline and lipid deposition and often adhesion to Bowman's capsule – The remainder of the glomerular tuft is normal in appearance; thus the term 'segmental'. The lesions are considered to begin or to be more common near the corticomedullary junction. • IF: Deposition of IgM and C3 in the mesangium or in the areas of segmental sclerosis may be seen, but no immune complex deposition is present. • EM: effacement of podocyte foot processes. Podocyte denudation may be present focally as an early lesion, and segmental sclerosis may also be seen
Clinical Course • FSGS may be : – primary (idiopathic) – secondary to a number of etiologic agent : • Unilateral renal agenesis • Renal ablation • Sickle cell disease • Morbid obesity (with or without sleep apnea) • Congenital cyanotic heart disease • Heroin nephropathy • HIV nephropathy • Aging kidney
Membranous Glomerulonephritis（MGN） • Antibody mediated disease – ICs localize to subepithelial of the capillary loop • between outer aspect of GBM and podocyte • Immune complexes – develop in situ – deposition of circulating ICs (less likely) – antibody may bind to • intrinsic glomerular antigen • exogenous antigen planted on the capillary wall – Serum complement level was normal
Clinical Manifestation • more common in adults (peak 40-50 y/o) • mostly older than 30 years at diagnosis • 35-50% of cases of adult nephrotic syndrome • Most patients present with: – heavy proteinuria: most commonly in nephrotic range – insidious in onset – few patients accompanying microscopic hematuria
Morphologic Features Capillary walls are thickened and numerous subepithelial "spikes" are present on capillaries of this glomerulus, representing elaboration of basement membrane between subepithelial immune deposits. LM
Immunofluorescence Microscopy Direct immunofluorescence microscopy of frozen tissue demonstrates bright granular staining of the subepithelial aspect of the capillary loops with antibody to IgG
Electromicroscopy Ultrastructurally numerous subepithelial electron dense deposits are present. The deposits are separated by basement membrane correlating with the "spikes" seen by light microscopy.
Membranoproliferative Glomerulonephritis (MPGN) (mesangiocapillary glomerulonephritis) • Chronic progressive glomerulonephritis – occurs in older children and adults • Circulating immune complexes (CIC) have been identified in 50% of patients • activation of the complement system with hypocomplementemia, is a hallmark of MPGN.
MPGN (IF) Type I: subendothelial and mesangial deposits of IgG and C3
MPGN (EM) Electron microscopy Electron microscopy Type I: deposits in subendothelial and mesangial Duplication of the capillary loop basement membrane between the deposits and interposed mesangium, and the endothelial cells.
Clinical Course of MPGN Clinical manifestation: • Nephrotic syndrome • Abnormal urinary sediment with non- nephrotic proteinuria • Acute nephritis • Lab. Data: – depressed serum complement levels
In summary • Proliferation of mesangium can presents in various types of GN • Proliferation and subsequent stiffness of mesangium may be the results of various types of GN • FSGS:primary—later phase of the disease itself secondary—later phase of other type of GN • Crescents can presents in different types of GN
Clinical menifestation • Proteinuria Urinary protein test—positive Urinary protein excretion rate>150mg/24h
• Quantity: • Mild:<1.5g/d • Moderate:1.5-3.5g/d • Severe:>3.5g/d
• Hematuria RBC>3/HP(fresh,10ml/sample,1500rmp centrifuge for 5min,sediment observation) • Gross hematuria Red color of urine,1ml blood/1L urine
RBC from glomeruli Squeezing through GBM Changing when passing tubule with different osmosis Dismorphic RBC Phase contrast microscopy Dismorphic RBC>50%,hypothesis of glomerular bleeding Dismorphic RBC>50%,final diagnosis of glomerular bleeding Urinary RBC volume distribution curve Dissymmetry curve MCV of urinary RBC<that in blood
edema Glomerular diseases GFR↓ Intrinsic RAS or aldosterone↑ Water sodium filtration↓ Water sodium readsorpation↑ Primary Water and sodium retention Effective circulation blood volumn↑ edma Effective circulation blood volumn↓ Large ammount of urinaryprotein lost hypoalbuminemia Colloid osmotic pressure↓ secondary water and sodium retention
hypertention Glomerular diseases Primary Water and sodium retention Volumn dependent hypertension Stimulus,such as ischemia Vessoconstrictive substances↑ RAS ALD Vessoactive substances dependent Vessodilatory substances↓ PGI2,PGE2
Clinical types of GN • Glomerulonephropathy Confined concept Leading manifestation: proteinuria /hematuria Extensive concept Glomerular diseases • Glomerulonephritis Leading manifestation:hematuria /proteinuria
Clinical manifestation of GN initiation hematuria proteinuria Edema,hyp ertention Renal failure Acute GN acute 100% 100% frequent resumable rapid progressive GN acute 100% 100% frequent ARF Chronic GN latent frequent frequent frequent CRF Latent GN latent frequent <1g/d - -
Acute glomerulonepritis • Etiology:streptococcus others:bacteria viruses parasites • antigen:components of cytoplasm/ membrane • frequently CIC •
Pathological changes • Endocapillary proliferative GN Acute phase Proliferation of endothelial /mesangium Recovery phase Only mesangium proliferation,sometimes minor injure
Clinical manifestation • Epidemiology:primarily children,sometimes adult/aged • Preliminary infection Frequently tonsillitis,upper respiratory infection • Latent period:1-3w Occasionally skin infection Latent period:longer,less than 4w
Nephritis syndrome • Hematuria:100%,40% are gross hematuria • Proteinuria:frequently,<20% are NS • Edema:>90% • Hypertension:80% • Renal failure:mild,ARF
Laboratory finding • Acute phase of infection of strep. Elevated ASO titer Only the marker of infection,not nephritis • Acute phase of immune reaction Serum C3/total complement↓,return normal within 8w Blood CIC↑
Natural history • Edema and hypertention Disappear in one month • Hematuria,proteinuria Usually reduce in one month,resolve in2- 3 months Some resolve in 6-8 months • C3:return to normal in two months
diagnosis • Points: • Preliminary infection/latent period • Acute onset • Surely hematuria,frequently edema and hypertention • ASO↑c3↓--dynamic change • Self limitation
Indications of renal biopsy • Oligouria>1w,except ECBV,insufficient,urinary tract obstruction,etc • Progressive renal failure Unresolved in 2 months Untypical manifestation,or with NS
treatment • Supportive treatment • Rest • Food and water • Restrictive intake of NaCL<5g/d If moderate to severe edema or hypertention • Water If decreased urine volumn • Protein Renal failure,but not dialysis yet
Treatment of infection • Penicilin for 2w • Tonsillectomy if recurrent attacks of tonsillitis • Patient is stable:U pro<1g/d,Urbc<10/HP • Penicilin for 2w before and after the surgery • Symptomatic treatment Diuresis Antihypertention dialysis
prognosis • Hematuria,proteinuria Usually reduce in one month,resolve in 2-3 months Some resolve in 6-12months • 1% ARF death • 6-18% CGN?
Rapidly progressive glumerulonephritis • Rapidly progressive glumerulonephritis syndrome • Some induced by respiratory infection • Acute onset,rapidly progressive • Renal failure within a few weeks to a few months
• Primary RPGN:crescentic GN • Other primary GN:other pathological changes with lots of crescents • Secondary RPGN:SLE,SHP,etc
Type 1 Anti GBM Type 2 IC Type 3 Pauci-immune Linear GBM deposits Granular GBM/mesangium deposits - Anti-GBM+ C3↓CIC↑ 70-80%small vessel ANCA+ The young/middle aged The middle aged/aged The middle aged/aged
diagnosis • Acute onset • Rapidly progressive • Renal failure within a few weeks to a few months • Acute renal failure-chronic renal failure
Treatment-early!!! • Aim to humoral immune mechanism • Plasmapheresis discard the antibodies plasm exchange immoadsorption,type1 typ2 • Drugs:glucocorticoid+cytotoxic drugs MP05.-1.0g/d,repeat if necessary CTX type2-type3
Symptomatic treatment • Renal failure Balance of fluid,electrolytes and acid base Dialysis • Infection • hypertension
prognosis • Hardly relieve • Mostly CRF-death • Risk factors:type1 worst,type2 worse,type 3 bad Treatment:not progressive,not prompt Age:the aged
Chronic glomerulonephritis • Clinical manifestation:chronic nephritis syndrome • Pathological change:except MCD,MmRPN,crescentic GN
Clinical manifestation • Age:any age,frequently young • Priliminary infection:upper respiratory infection,intestinal tract,latent period<1w • Nephritis syndrome: Hematuria,proteinuria,edema hypertention,Renal failure uremia
Prognosis factor • Pathological properties • Treatment • Hypertension • Infection,prerenal factors(hypertension etc) • Nephrotoxic drugs
Point of diagnosis • Chronic onset • proteinuria and/or hematuria • Protracted and progressive
AGN CGN age children Young/middle-aged Preliminary infection frequently sometimes Latent period 1-3w <1w onset acute Chronic,insidious hematuria 100% Sometimes no edema frequently Sometimes no hypertension frequently Sometimes no ASO frequently↑ normal Blood C3 ↓,<8W persistent↓/normal prognosis <1y protracted and
Secondary GN • SLE:sysmetic presentation Immune abnormality Pathological changes
Treatment • Target Inhibit immune reaction Halt the progression of disease • Restrictive intake of protein <0.5-0.8g/kg/d Protein of high biological value ↓Pressure in glomeruli
antihypertention • Less than 140/90mmHg Ideal target125/83mmHg • ACEI/ARB:dialation of efferent glomerular Arteriole>dialation fo afferent Pressure in glomeruli↓ Upro↓ Postpone glomerulosclerosis
• Antiplatelet • Immunosuppression • Glucocorticoid
Four major pathogenetic forms of glomerular injury In non-proliferative glomerulopathy:  Damage by antibodies  Damage mediate by complement In proliferative glomerulopathy:  Damage by circulating proinflammatory cells (especially neutrophils and macrophages)  Damage by localy activating resident cells (for example mesangial cells)
Classification of glomerulopathies • Clinical: primary x secondary • According time period: acute x subacute x chronic • According renal biopsy: focal x segmental x diffuse • According number of cells: non-proliferative x proliferative • According imunofluorescence:
Pathogenic mechanisms of glomerular diseases  NEPHRITIC NEPHROTIC Chronic glomerulonephritis
Pathogenesis of nephritic diseases
Histologic pattern • May not correlate with the clinical presentation • Various histological types of glomerulonephritis
B: “Minimal changes” GN = lipoid nephrosis: some mesangial proliferation, edematous podocytes, fusion (“loss”) of their foot processes C: Intracapillary mesangial proliferative GN: proliferation of endothelia and mesangium, peeling off of enthelial cells from the GBM, duplication of GBM, “humps” formed by immunocomplexes D: Crescentic GN: proliferation of all components (aggressive white cells, endo- and epithelia, mesangium, epitheloid and giant cells), leakage of fibrin. Hypersensitivity reaction type II or IV E: Membranous GN: Precipitation of immunoglobulins on the outer surface of the GBM (“spikes”  complete incorporation of Ig into the membrane) F: Proliferative sclerotizing GN: advanced mesangial proliferation  narrowing and destruction of capillaries
Acute glomerulonephritis (poststreptococcal GN)  Is commonly caused by infection by certain strains of group A beta-hemolytic Streptococci (pharyngitis, pyoderma)  Ab against streptococci react with vimentin  imunokomplexes  nephritis develop after a latent period of about 2-3 weeks  Clinical syndrome: nephritic syndrom  Histologic pattern: intracapillary proliferation of mesangial and endothelial cells with subepithelial („humps“) and subendothelial deposits (C3, or IgG) Acute diffuse proliferative GN
Postinfectional non-streptococcus glomerulonephritis  Acute glomerulonephritis can develope also in the course of other infections: - stafylococci - herpes virus - pneumococci - EBV - Klebsiella pneumonie - virus hepatitis B  GN in infection endocarditis  GN in visceral abscessus (especially lung) Histologic pattern and clinical syndrome – similar one as in poststreptococcal GN
Focal proliferative glomerulonephritis - different etiology:  IgA nefropathy  Nephritis in systemic lupus erythematodes (SLE)  Nephritis in bacterial endocarditis  Henoch-Schölein purpura
Rapidly progressive glomerulonephritis (RPGN)  Heterogeneous group of diseases, it is characterised by intense proliferation of glomerular/capsular epithelial cells in the form of a crescent.  crescemt = accumulation and proliferation of extracapillary cells.  The glomerular capillaries collapse and are bloodless, and fibrin can be identified within the capsule  it can stimulate proliferation of parietal epithelial cells  deposits of fibrin compress the glomerula capillaries tuft ( GFR and destruction of glomerulus)
Three forms of RPGN  GN with creation of antiobdies (IgG, IgA) agains GBM (anti-GBM) - linear deposits of Ig (+ alveolocapillary BM) Goodpastures´ syndrome  GN with granular deposits of Ig and complemen - formation of crescent is complication less serious intracapillary proliferative GN (IgA nefropathy, SLE, acute GN e.g.)  GN with ANCA antibodies - ANCA ab (Ab agains cytoplasma of neutrophiles) 2 forms – systemic disorders (Wegener granulomatosis) - only renal disease Crescent GN
Goodpastures´ syndrome  It is charecterised antibodies against basal membrane of glomeruli (alveolocapillary membrane)  Etiology: combination of exogenous factors (smoking, infection, toxines) with genetic predisposition (HLA B7, DR2)  Pathogenesis: GBM is composed by collagen IV with proteins (laminine, entaktine, tenascine) and proteoglycans Goodpastures antigen (localised in C-terminal non-collagen globular domain (NC1) of the molecule 3 chain of collagen IV  formation of Ab (IgG1 – can activate complement)  damage of BM  Clinical manifestation: typically presents with crescentic glomerulonephritis + pulmonary hemorrhage
Slowly progressive glomerulonephritis  Group of GN called membrane-proliferative GN  2 forms: in 1 form : -  levels of complements in plasma - subendothelial and mesangial deposits are present findings: proteinuria or picture of nephrotic syndrom in 2 form: - activation of complement is due to nephritic factor C3 - intramembranous deposits are present findings: proteinuria or picture of nephritic syndrom (similary as in RPGN)
Pathogenesis of nephrotic diseases