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histopathology of the kidney (intro to histo of kidney (glomerulus ( image…

- - - - hypercellularity
        
        if you see a crescent, think aggressive renal disease
        
        endocapillary -- happening within the glomerular tuft (can be segmental or diffuse)
        
        mesangial proliferation --
  - - - brightly eosinophilic
      - tall cuboidal epithelium
      - circular profile, indistinct cell boundaries
      - "fuzzy" luminal surface (brush border) -- PAS positive
      - eosinophilic striations at base (mitochondria)
  - - - smaller diameter
      - open lumens
      - lower pale staining epithelium
      - lack brush border (no PAS + border)
  - - - collecting tubules begin in cortex and extend through medulla to tips of papillae
      - cells lining collecting tubules gradually change from low cuboidal to high columnar
      - cells of the thin loops of Henle are low and flattened
  - - - normally inapparent in the cortex
    - - supporting stroma
      - a few cells
- - - - increase albumin loss
      - increased transferrin
      - increased IgG
    - - most forms of glomerulopathy
    - - foot process effacement
      - other unclear mechanisms
  - - - usually less than 3g/24 hours
      - proteins limited to those that are normally filtered at the glomerulus
      - other signs of proximal tubular epithelial dysfunction (glucose, bicarb, amino acids, etc.)
    - - tubulointerstitial disease due to allergic interstitial nephritis, sickle cell disease, analgesic nephropathy, light chain deposition, etc.
      - Fanconi syndrome
  - - - increased concentration of small, abnormal filterable serum proteins
      - tubular epithelium toxicity/cast formation
    - - usually less than 3g/24h
      - normal urine dipstick for protein
      - Ig light chains (Bence Jones protein)
    - - plasma cell dysplasias (e.g. multiple myeloma)
- - - - protein composition predicts source of proteinuria
      - may provide specific diagnostic information (e.g. detection of Ig light chains -- Bence-Jones protein)
    - - urine protein electrophoresis (UPEP)
      - urine immuno-electrophoresis (UIEP)
  - - - greater than 3.5g/24 h means must be glomerular in origin
      - may provide prognostic information
      - allows assessment of response to therapy
    - - urinalysis - dipstick for protein
      - spot urine for protein-creatinine ratio (mimics 24 hr collection
      - 24 hour urine collection
- - - - microscopic hamaturia
      - proteinuria
      - hypertension
      - edema
    - - RBC casts
      - dysmorphic RBCs
  - - - replacement of glomeruli with scar tissue
      - irreversible loss of nephrons
      - permanent loss of kidney function
  - - - LM: extracapillary proliferation (crescents), fibrinoid necrosis
      - EM: compressed glomerular tuft, no electron dense deposits
      - IF: linear antibody and complement staining along GBM
  - - - post-streptococcal GN
        
        EM
        
        large discrete subepithelial deposits ("humps") are pathognomonic
        
        presentation
        
        21 days post-strep infection
        
        clinical spectrum ranges from asymptomatic to dark urine to RPGN
        
        supporting studies: positive anti-streptolysin O (ASO) serology, low C3
        
        LM
        
        diffuse proliferative and exudative (PMNs) GN , accentuation of lobar structure
        
        IF
        
        granular capillary loop and mesangial deposits of IgG and C3
        
        pathogenesis
        
        in situ immune complex formation due to nephritogenic bacterial antigen deposition in glomeruli
        
        Tx: supportive in most cases, steroids considered in severe cases
      - lupus nephritis
        
        IF
        
        EM
        
        subendothelial deposits
        
        prominent mesangial deposits
        
        clinical presentation
        
        affects multiple organ systems
        
        MSK: arthritis/arthralgias, myositis/myalgias
        
        fatigue, anorexia, fevers
        
        rash - malar, discoid)
        
        polyserositis (pleuritis, pericarditis)
        
        nervous system: cerebritis, peripheral neuropathy
        
        hematologic abnormalities (cytopenias)
        
        renal disease (occurs in 30-70% of patients with SLE)
        
        renal presentation
        
        isolated microscopic hematuria
        
        subnephrotic proteinuria
        
        RPGN
        
        nephrotic syndrome
        
        positive ANA, anti-dsDNA; hypocomplementemia
        
        Tx: corticosteroids, cyclophosphamide, mycophenolate mofetil, azathioprine
      - IgA nephropathy
        
        systemic form IgA vasculitis (Henoch-Schonlein purpura)
        
        EM: mesangial hypercellularity
        
        EM: focal crescents
        
        IF
        
        mesangial IgA and C3 deposits
        
        mesangial electron dense deposits
        
        clinical presentation
        
        most common GN worldwide
        
        most common in East Asian pts
        
        patients can have subclinical disease, episodes of gross hematuria/dark urine that occurs at the same time as upper respiratory infections ("syn-pharangytic"), and slowly progressive nephritic syndrome that can lead to ESRD
        
        less common: nephrotic syndrome, RPGN
        
        no additional studies currently helpful
        
        pathogenesis
        
        associated with elevated levels of misprocessed IgA molecule (galactose deficient IgA), but not sufficient to cause disease
        
        clinical management
        
        BP control with ACEis, ARBs --> RAAS blockade reduces proteinuria
        
        corticosteroids used in severe presentations
        
        tonsillectomy -- used in Japan
    - - LM: proliferative GN (mesangial/endocapillary/extracapillary)
      - EM: electron dense deposits
      - IF: granular staining for antibody and complement
  - - - extracapillary proliferation, necrosis, crescents
      - IF: no IgG
      - anti-neutrophil cytoplasmic antibodies (not immune complex)
      - EM: compressed glomerular tufts
      - LM: crescents
      - types: GPA, MPA, EGPA
- - - - idiopathic/primary
        
        unclear etiology, hypothesized circulating factor
        
        pts present with acute onset nephrotic syndrome
        
        associated with long term risk of CKD and ESRD
        
        remission in proteinuria is associated with improved renal outcomes
        
        initial tx: corticosteroids
      - genetic
        
        more than 30 "associated" genes described
      - secondary/adaptive
        
        low nephron mass, obesity, hyperfiltration, infections (HIV)
        
        HIV-associated nephropathy, "collapsing FSGS"
        
        podocyte hypertrophy and hyperplasia
        
        "collapsed" glomerular capillary lamina
        
        focal tubular distension/microcysts
        
        adjacent tubular degeneration
        
        HIVAN is unusual in HAART era
        
        histology findings
      - histology findings
        
        LM
        
        some parts (segmental) of some glomeruli (focal) have enhanced PAS stain (sclerosis)
        
        segmental collapse with adhesions to Bowman's capsule
        
        evidence of podocyte injury and loss
        
        no significant IF staining
        
        EM
        
        podocytes demonstrate extensive food effacement
        
        no capillary loop electron dense protein deposits
        
        normal GBM
        
        mesangium has normal cellularity, matrix, and no electron dense deposits
    - - LM: normal
      - EM: podocytes demonstrate extensive foot process effacement. No capillary loop electron dense protein (immune) deposits. Normal GBM. Mesangium has normal cellularity, matrix and no electron dense deposits.
      - etiologies
        
        primary
        
        unknown pathogenesis
        
        considered to be a "podocytopathy"
        
        ? circulating factor, B or T cell mediated
        
        secondary
        
        NSAIDs (may also have interstitial nephritis)
        
        lymphoma
        
        tx: stop offending agent, treat underlying condition, consider steroids
    - - anti-PLA2R + MN
        
        phospholipase A2 receptor is present in normal podocytes and in immune deposites in patients with idiopathic MN. PLA2R and IgG4 co-localize on biopsy specimen from pts with idiopathic MN in a typical granular pattern
        
        histology findings
        
        normal glomerular cellularity
        
        thickened glomerular capillary loops
        
        PAS/PAS-M reveals sclerosis with BM spikes; trichrome shows subepithelial proteinaceous deposits
        
        IF
        
        granular staining for IgG, C3, kappa and lambda (can also stain for PLA2R in kidney biopsy)
        
        EM
        
        subepithelial electron dense deposits and podocyte foot process effacement
      - natural history
        
        spontaneous remission in a 1/3 of pts
        
        persistent proteinuria without decline in GFR in 1/3
        
        progressive course in 1/3
        
        prognosis is associated with serum anti-PLA2R antibody level
      - tx: ACEI or ARB, immunosuppression (cyclophosphamide, calcineurin inhibitors, rituximab)