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Antibodies against Planted Antigens

  • Ab react in situ with antigens that are not normally present in glomerulus but planted there.
  • planted antigens: cationic molecules binding to anionic components of glomerulus; DNA, nucleosomes, nuclear proteins (affinity for GBM); bacterial products; immunoglobulins; immune complexes
  • induce Ig deposition
  • IF: granular deposition


Anti-GBM Antibody-induced Glomerulonephritis

  • Ab directed against intrinsic fixed antigens that are normal components of GBM proper.
  • IF: diffuse linear pattern
  • cross-reactivity in the lungs ⇒ simultaneous lung and kidney lesions = Goodpasture syndrome
  • GBM antigen = component of noncollagenous domain of the alpha3 chain of collagen type IV (for GBM suprastructure).  also the antigen in Goodpasture syndrome.
  • features: severe crescentic glomerular damage and rapidly progressive glomerulonephritis.


Circulating Immune Complex Glomerulonephritis

  • caused by trapping of circulating Ag-Ab complexes within glomeruli.
  • localize not from affinity but from the physicochemical properties and hemodynamic factors of the glomerulus.
  • antigens can be endogenous or exogenous
  • microbial antigens: Hep B, Hep C, T. pallidum, Plasmodium falciparum.
  • glomerular lesions have leukocytic infiltrate and proliferation of mesangial and endothelial cells
  • EM: immune complexes in mesangium = subendothelial deposits, or subepithelial deposits = outer surface of GBM and podocytes.
  • IF: granular deposits
  • highly cationic antigen ⇒ subepithelial deposit;
  • highly anionic antigen ⇒ subendothelial deposit.  
  • neutral ⇒ mesangial deposits


Antibodies to Glomerular Cells

  • Ab to mesangial cell ⇒ mesangiolysis then mesangial cell proliferation.
  • Ab to endothelial cell ⇒ endothelial injury and intravascular thrombosis
  • Ab to visceral epithelial cell ⇒ proteinuria.
  • IF: granular deposits along GBM or in mesangium.


Role of Cell Mediated Immunity in Glomerulonephritis

  • sensitized T cells may injure glomerulus.
  • clues: activated macrophages and T cells, injury by transpanting T cells.
  • T lymphocytes propogate the inflammation.


Membranoproliferative Glomerulonephritis

  • aka MPGN type II or dense deposit disease.  
  • through activation of alternative complement pathway


Cell causing Glomerular Injury

  • neutrophils/monocytes: from activating complement and from Fc-mediated adherence/activation.  release proteases ⇒ GBM degradation; O2 free radicals; arachidonic acid metabolites.
  • macrophages/T lymphocytes/NK cells: in Ab and cell mediated rxn.
  • platelets: in immune-mediated injury. release eicosanoids and growth factors.
  • resident glomerular cells: mesangial cells.  make: ROS, cytokines, chemokines, growth factors, eicosanoids, NO, and endothelin.  


Soluble Mediators of Glomerular Injury

  • chemotactic complement components: cause leukocyte influx ⇒membrane attack complex ⇒ stimulate mesangial cells to make oxidants, proteases, etc.  without neutrophils ⇒ proteinuria.
  • eicosanoids/NO/angiotensin/endothelin: cause hemodynamic changes.
  • cytokines: IL-1 and TNF ⇒ leukocyte adhesion, etc. 
  • chemokines: monocyte chemoattractant protein 1 and CCL5 promote monocyte and lymphocyte influx.
    • PDGF in mesangial cell proliferation.
    • TGF-beta, CTGF, and FBGF important for ECM deposition and hyalinization ⇒ glomerulosclerosis.
    • VEGF maintains endothelial integrity, helps regulate capillary permeability.
  • coagulation system: fibrin stimulates parietal epitheial cell proliferation (crescent formation).  mediated by macrophage procoagulant activity.
    • Plasminogen activator inhibitor-1 ⇒ ↑ thrombosis and fibrosis, inhibits degradation of fibrin and matrix proteins.


Tubulointerstitial Fibrosis

  • tubular damage and interstitial inflammation. 
  • from ischemia downstream of sclerotic glomeruli, acute/chronic inflammation, loss of peritubular capillary blood supply.
  • proteinuria ⇒ direct injury to and activation of tubular cells from iron, Ig, complement products, cytokines, lipid moieties, oxidated plasma proteins.
  • active tubular cells ⇒ cytokines, chemokines, growth factors ⇒ interstitial fibrosis


Acute Proliferative Glomerulonephritis

  • includes Poststreptococcal and Postinfectious glomerulonephritis.
  • diffuse proliferation of glomerular cells, influx of leukocytes.
  • caused by immune complexes


Poststreptococcal Glomerulonephritis

  • appears 1-4 weeks after beta hemolytic strep infection of pharynx or skin. identify by M protein.
  • usually kids 6-10 yrs.
  • low serum complement levels (used up), elevated titers of antibodies against strep.
  • IF: granular deposits IgG, IgM, and C3 in mesangium and along GBM.  focal and sparse.
  • EM: discrete, amorphous, electron-dense deposits on epithelial side of GBM, look like humps.  Subendothelial and intramembranous deposits common.
  • antigens: NAPlr, strep pyogenic exotoxin (SpeB), zSpeB.
  • morphology: enlarged hypercellular glomeruli from infiltration by leukocytes, proliferation of mesangial and endothelial cells, crescent formation in severe cases.  involves all glomeruli.  swelling of endothelial cells.  interstitial edema, inflammation, red cell casts.
  • prognosis: most kids recover. 1% ⇒ rapidly progressive glomerulonephritis. some ⇒ chronic glomerlonephritis.  60% adults recover, the rest have persistent proteinuria, hematuria, and HTN which may ⇒ chronic glomerulonephritis or rapidly progressive glomerulonephritis.
  • bad prognosis: prolonged and persistent heavy proteinuria and abnormal GFR.


Clinical Case:

Young child presents with: malaise, fever, nausea, oliguria, and hematuria.  Had sore throat 1-2 weeks ago.  Red cell casts in urine, mild proteinuria, periorbital edema, mild-mod HTN.

What does this child have?

Poststreptococcal Glomerulonephritis


Clinical Case:

Adult presents with sudden appearance of HTN or edema with an elevated BUN.  He is found to have a decreased serum concentration of C3 complement and other complement factors and upon microscopic examination of his urine he has hematuria.

What does this patient have?

Poststreptococcal Glomerulonephritis


Rapidly Progressive (Crescentic) Glomerulonephritis

  • rapid and progressive loss of renal function with severe oliguria and nephritic syndrome.
  • most commonly has crescents in most glomeruli
  • group 1: anti-GBM antibody induced disease.
    • IF: linear deposits of IgG and C3 in GBM.
    • Goodpasture's Syndrome if also cross-react with pulmonary alveolar basement membrane.
    • tx: plasmapheresis
  • group 2: immune complex deposition.   like from IgA nephropathy, lupus nephritis, postinfectious GN, Henoch-Schonlein purpura.
    • IF: granular pattern
    • cellular proliferation within glomerulus tuft and crescent formation.
    • tx: treat underlying disease.
  • group 3: pauci-immune type.  lack of anti-GBM or immune complexes.  have circulating antineutrophil cytoplasmic antibodies (ANCAs) ⇒ cytoplasmic or perinuclear staining patterns.
    • play a role in vasculitides.  ex: Wegener granulomatosis or microscopic polyangiitis
  • morphology: kidneys enlarged and pale, petechial hemorrhages.
    • can have focal necrosis, diffuse or focal endothelial proliferation, and mesangial proliferation.
    • have crescents = proliferating parietal cells with monocytes and macrophages in urinary space.  eventually obliterate Bowman space and compress glomerular tuft. later undergo sclerosis but can go away with early aggressive treatment.
    • prominent fibrin strands between layers in crescents.
    • EM can show rupture in GBM ⇒ leukocytes, proteins, and inflammatory mediators into urinary space for crescent formation.
  • features: hematuria, RBC casts in urine, mod proteinuria, variable HTN and edema.
  • tx: steroids and cytotoxic agents.  may require chronic dialysis or transplantation


Goodpasture Syndrome

  • rapidly progressive glomerulonephritis with anti-GBM antibody and C3 deposits that affect both the kidney and lungs ⇒ pulmonary hemorrhage with renal failure.
  • antigen = peptide in noncollagenous portion of the alpha3 chain of type IV collagen
  • features: recurrent hemoptysis or life-threatening pulmonary hemorrhage.
  • tx: plasmapheresis and steroids.


Clinical Case:

A 40 y/o man presents to the ER for bloody urine and puffy legs.  Upon examination he is found to have 2+ edema to his knees and a BP of 145/85.  His U/A showed 2+ proteinuria and RBC casts.  On H&E stain, crescents are visible from the biopsy sample.

What does he have?  What further tests need to be run to confirm the diagnosis?

  • Rapidly Progressive GN.
  • to differentiate we need to run anti-GBM antibody tests, ANCA tests, and antinuclear antibodies (immune complexes as well).


Clinical Case:

A 24 y/o male presents to the ER with shortness of breath and coughing up blood for the past few days.  On U/A he is found to have 1+proteinuria, hematuria, and rare RBC casts.  Kidney biopsy was done and he was found to have crescents in 65% of his kidneys. 

What is his diagnosis?

Goodpasture Syndrome that is rapidly progressive.


Membranous Nephropathy

  • in adults.  has diffuse thickening of glomerular capillary wall from accumulation of electron-dense, Ig deposits along subepithelial GBM.  
  • 2° membranous glomerulopathy when in association to other systemic diseases: SLE, infections (Hep B/C, syphilis, schistosomiasis, malaria), autoimmune disorders, malignant tumors, drugs (penicillamine, captopril, gold, NSAIDs).
  • 85% is idiopathic. 
  • paucity of neutrophils, monocytes, platelets in glomeruli.  MAC (C5b-C9) activates glomerular epithelial and mesangial cells ⇒ proteases and oxidants ⇒ capillary wall injury and ↑ protein leakage.
  • morphology: light microscopy = normal or diffuse thickening of glomerular capillary wall.
    • EM: thickening from irregular dense deposits of immune complexes between GBM and epithelial cells with effaced foot processes.  irregular spikes of matrix protein from GBM on silver stain.  thicken to domelike protrusions and close over deposits.
    • IF: granular deposits containing Ig and complement
    • sclerosis can occur, proximal tubules have protein reabsorption droplets, may be considerable interstitial mononuclear cell inflammation.
  • features: insidious onset nephrotic syndrome.  hematuria and mild HTN, proteinuria not fixed by steroids, ↑ sclerosis, ↑ serum creatinine.
  • prognosis: sclerosis = bad, non-nephrotic proteinuria = good, women = good.


Clinical Case:

35 y/o female presents to the ER with hematuria with no past medical history.  On examination she is found to have a BP of 155/90, hypercholesterolemia, hyperlipidemia,  and 3+ proteinuria (>3.5mg/day).  EM shows domelike protrusions and spikes as well as a thickened glomerular capillary wall.

What is the diagnosis?

Membranous glomerulopathy.


Minimal Change Disease

  • most frequent cause of nephrotic syndrome in children (peak btw 2-6).
  • diffuse effacement of foot processes of visceral epithelial cells in glomeruli on light microscopy.
  • absence of immune deposits.
  • associations: mostly visceral epithelial cell injury
    • sometimes follows respiratory infection or immunization.
    • has a dramatic response to corticosteroid therapy.
    • associated with atopic disorders (rhinitis, eczema)
    • ↑ certain HLA haplotypes
    • ↑ incidence of Hodgkin's lymphoma (defects in T-cell mediated immunity)
    • proteinuria-inducing factors in plasma or lymphocyte supernatants
  • morphology: normal on light microscopy and EM.
    • visceral epithelial cells show uniform and diffuse effacement of  foot processes
    • rim of cytoplasm showing vacuolization, swelling, and hyperplasia of villi = fusion of foot processes
    • cells of proximal tubules laden with lipid and protein = lipoid nephrosis
  • features: massive proteinuria but good renal function.  protein is mostly albumin.
  • tx: corticosteroids


Clinical Case:

A 6 y/o girl presents today for a routine physical and upon U/A was found to have high levels of urine protein, predominantly albumin.  Kidney function appears normal on analysis.  Biopsy shows normal glomerular anatomy with lipid deposits in some tubular cells.

What does this child have?

Minimal Change Disease


Focal Segmental Glomerulosclerosis (FSGS)

  • sclerosis of some glomeruli (focal) and in the glomeruli only part of the capillary tuft is involved.
  • types: primary disease
    • associated with HIV, heroin addiction, sickle-cell disease, massive obesity
    • secondary event, scarring of previously active necrotizing lesions
    • adaptive to loss of renal tissue from reflux nephropathy, HTN nephropathy, unilateral renal agenesis.
    • inherited forms: like with slit diaphragm proteins.
  • initiated by adaptive change in unaffected glomeruli: compensatory hypertrophy.

  • hemodynamic changes = ↑ glomerular blood flow, filtration, and transcapillary pressure (glomerular HTN), systemic HTN.

  • podocytes can't proliferate ⇒  can't maintain filtration barrier ⇒ abnormal protein filtration and loss of support of GBM ⇒ segmental loop dilation and fibrous attachment to Bowman capsule and sclerosis.

  • sequence: endothelial/epithelial cell injury, ↑ glomerular permeability to proteins, accumulation of proteins in mesangial matrix, proliferation of mesangial cells, infiltration by macrophages↑ accumulation of ECM, segmental and global sclerosis of glomeruli, ↓ nephron mass, activate compensatory mechanisms.

  • proteinuria and sclerosis ⇒ uremia and sclerosis.

  • tx: renin-angiotensin inhibitors

  • idiopathic FSGS: 10% nephrotic cases in kids, 35% in adults. ↑ incidence in Hispanics and African Americans.
    • ↑ incidence hematuria, ↓ GFR, HTN, non-selective proteinuria, poor response to steroids, progression to chronic kidney disease.
    • hallmark is epithelial damage from cytokines, genetic defects of slit diaphragm.
    • hyalinosis and sclerosis from entrapment of plasma proteins in hyperpermeable foci and ↑ ECM deposition.
  • morphology: initially involve juxtamedullary glomeruli. sclerotic areas have collapsed capillary loops, ↑ matrix, segmental deposition of plasma proteins along capillary wall (hyalinosis).
    • lipid droplets and foam cells.
    • light microscopy: ↑ matrix.
    • EM: diffuse effacement of foot processes, denudation of underlying GBM.
    • IF: IgM and C3 in sclerotic areas or mesangium
    • profuse hyalinosis and thickening of afferent arterioles.
    • leads to profuse sclerosis, tubular atrophy, and interstitial fibrosis.
    • collapsing glomerulopathy - variant of FSGS with retraction or collapse of entire glomerular tuft. has proliferation and hypertrophy of glomerular visceral epithelial cells.
      • characteristic of HIV nephropathy.
      • prominent tubular injury with cyst formation.
  • genetic basis: NPHS1 (nephrin); NPHS2 (podocin) ⇒ kid onset steroid resistant nephrotic syndrome aut recessive.  alpha actinin 4 mutation is aut dominant.  TRPC6 mutation affects podocytes.
  • renal ablation FSGS = complication of glomerular diseases (reflux nephropathy, unilateral agenesis). may ⇒ progressive glomerulosclerosis and renal failure. 
  • features: kids better prognosis. 20% pts have rapid course with intractable proteinuria and failure in 2 yr.


Clinical Case:

A 45 y/o Hispanic male presents to his primary care physician with a complaint of bloody urine.  Physical exam reveals a blood pressure of 145/88.  U/A reveals gross hematuria, and severe proteinuria.  He was previously seen for the same reason and has not responded to corticosteroid therapy.  A biopsy was performed which revealed sclerosis with IgM and C3 deposits.  Light microscopy shows sporadic involvement of glomeruli that are only partially affected.

What does this patient have?



HIV-associated Nephropathy

  • occurs with: acute renal failure, acute interstitial nephritis from drugs/infection, thrombotic microangiopathies, postinfectious glomerulonephritis, collapsing variant of FSGS (most common).
    • more frequent in African Americans.
  • EM: large numbers of tuberloreticular inclusions within endothelial cells caused by IFN-alpha.
  • caused by HIV products: vpr and nef.


1° Membranoproliferative Glomerulonephritis

  • alterations in GBM, proliferation of glomerular cells, and leukocyte infiltration
  • aka mesangiocapillary glomerulonephritis.
  • 1° MPGN: type I and type II.
    • type I MPGN: evidence of immune complexes in glomerulus, activation of both classic and alternative complement pathways.
      • antigens unknown.  associated with Hep C and B.  
    • type II MPGN: aka dense-deposit disease.  rare.  abnormalities suggest activation of alternative complement pathway.  ↓ serum C3, normal C1 and C4. ↓ factor B and properdin.
      • C3 and properdin deposited in glomeruli.
      • 70% have C3 nephritic factor (C3NeF) - circulating antibody that binds to alternate pathway C3 convertase ⇒ ↑ C3 activation and hypocomplementemia.  ↓ synthesis C3 from liver
  • morphology:  light microscopy: large, hypercellular glomeruli from proliferation of mesangial cells and capillary endothelial cells and infiltrating leukocytes.  may have crescents.  lobular appearance from proliferating mesangial cells and ↑ mesangial matrix.  GBM thickened, glomerular capillary wall looks 'double-contour' or 'tram-track' on silver or PAS stain.
    • type I: presence of subendothelial electron-dense deposits.
      • IF: granular pattern.  C3 deposits, some IgG and early complement (C1q and C4).
    • type II: lamina densa is irregular, ribbon-like, extremely electron-dense with dense deposits in GBM.
      • IF: C3 deposits irregular granular or linear foci in GBM but not in dense deposits. also in mesangium = mesangial rings.  IgG absent as well as C1q and C4. 
  • presentation: kid or young adult with nephrotic syndrome, hematuria, mild proteinuria, mixed nephrotic-nephritic component.  slowly progressive.  some get crescents and look like RPGN. 50% ⇒ chronic renal failure.  high recurrence in transplant kidneys.
  • tx: steroids, immunosuppressive agents, antiplatelet drugs (none effective)



  • more common in adults.
  • found with: chronic immune comlex disorders (SLE, Hep B, Hep C, endocarditis, chronic visceral abscesses, HIV, schistosomiasis); alpha1 antitrypsin deficiency; malignant diseases; hereditary deficiencies of complement regulatory proteins.
  • presentation: nephrotic syndrome.


IgA Nephropathy

  • aka Berger Disease
  • prominent IgA deposits in mesangial regions on IF.
  • frequent cause of recurrent gross or microscopic hematuria, most common type of glomerulonephritis****
  • 2° IgA nephropathy in pts with liver and intestinal diseases.
  • ↑ plasma polymeric IgA, circulating IgA immune complexes.  IgA1 ⇒ nephritogenic deposits in mesangium.  uses alternative pathway (C3 with no C1q or C4).  
  • genetic influence.
  • ⇒ ↑ IgA synthesis ⇒ trapped in mesangium ⇒ activate alternative complement pathway ⇒ glomerular injury
  • more common with gluten enteropathy (Celiac disease) and liver disease
  • morphology: can look normal, have mesangial widening and endocapillary proliferation, or rarely have crescents.  may have leukocytes.
    • healing ⇒ 2° focal segmental sclerosis.
    • IF: mesangial depositition of IgA, some  C3 and properdin, less IgG and IgM.
    • EM: presence of electron-dense deposits in mesangium.
  • presentation: older children and young adults, gross hematuria after respiratory, GI, or urinary tract infection, microscopic hematuria with or without proteinuria, few have acute nephritic syndrome.  hematuria lasts a few days and returns every few months.
    • slow progression to chronic renal failure over 20yrs.  
    • ↑ risk of progression: old age, heavy proteinuria, HTN, ↑ glomerulosclerosis.
    • recurs in transplants.  


Clinical Case: A 20 year old male presents to the ER with a complaint of blood in his urine.  Blood analysis shows 4+ proteins, hyperlipidemia, ↓ C3, ↓ factor B, and normal levels of C1 and C4.  He is C3NeF positive.  On light microscopy of a renal biopsy crescents are visible, and there is a tram-track appearance on silver stain.  IF shows irregular ribbon-like deposits in the GBM.

What does this patient have?



Clinical Case: An 18 y/o female presents to the ER with a lot of blood in her urine.  She was seen here last week for a UTI.  She complains that this has been occuring on and off for the past year with the hematuria lasting a few days each time.  IF showed mesangial deposition of IgA.  Mesangial widening was also noted.

What does she have?

IgA Nephropathy


Alport Syndrome

  • a hereditary nephritis.  X-linked.
  • females typically limited to hematuria
  • due to abnormal alpha3 (COL4A3), alpha4 (COL4A4), or alpha5 (COL4A5) of type IV collagen.
    • COL4A5 is the X-linked.  COL4A3 and COL4A4 are autosomal recessive.
    • defective assembly type IV collagen, defective assembly of collagen network 
  • morphology: early lesion EM: diffuse GBM thinning, interstitial foam cells filled with neutral fats and mucopolysaccharides.
    • later see focal segmental and global glomerulosclerosis, vascular sclerosis, tubular atrophy, interstitial fibrosis.
    • EM late: irregular foci of thickening alternates with thinning and splitting of lamina densa ⇒ basket-weave appearance.
    • antibodies to alpha3, alpha4, alpha5 don't stain both glomerular and tubular basement membranes.  alpha5 staining absent in skin biopsy specimens.
  • presentation: onset age 5-20 year, gross hematuria with progression to chronic renal failure, red cell casts, nerve deafness, eye disorders (lens dislocation, posterior cataracts, and corneal dystrophy).