Renal Pathology

1
Review Course

• Renal Pathology
• Stephen M. Bonsib, MD
• Professor and Chairman of Pathology, Director of
  Renal Pathology Consultative Services, Albert G.
  and Harriet G. Smith Professor of Pathology
• Louisiana State University Health Sciences Center
  in Shreveport, Louisiana

2
Challenges of Renal Pathology

• The diagnosis requires correlation of multiple
  studies LM special stains, IF and EM
• You may see the LM, but often the IF is not seen
  and the EM may not be timely
• Most gns are primary, but they may be secondary
  clinical information is crucial and influences
  the terms used in the final diagnosis.

3
Challenges of Renal PathologyExample 1

• Diseases that may be histologically identical
• Membranoproliferative gn, type 1
• Dense deposits disease/MPGN, type 2
• Hepatitis C-associated gn
• Cryoglobulinemic gn
• Diffuse proliferative lupus nephritis
• Other infectious disease-associated gns

4
Challenges of Renal PathologyExample 2

• Focal segmental glomerular scars
• Focal segmental glomerulosclerosis
• Collapsing gn
• HIV nephropathy
• IgA nephropathy
• Alports syndrome
• Other hereditary nephritis
• Inactive crescentic gn

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Pathogenic Mechanisms in Glomerulonephritis

• 1. Immune complex/antibody negative (cytokines
  or other circulating factors)
• Minimal change disease
• Focal segmental glomerulosclerosis
• 2. Immune complex formation/deposition
• Numerous forms of glomerulonephritis
• 3. Nephrotoxic autoantibodies
• AGBM and ANCA

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Major Types of Glomerulonephritis (patterns of
glomerular injury and secondary causes)

• LPD, NSIAD
• HIV, iv drugs, obesity, parvovirus B-19, Alports
• Infection, SLE
• SLE, Cryogl., Hep. B/C
• SLE, Hep B, neoplasms, drugs
• AGBM, ANCA, I.C.
• Henoch-Schonlein purpura
• Diabetes, paraprotein/amyloid

• Minimal change disease
• Focal segmental glomerulosclerosis
• Proliferative gns
• Membranoproliferative gn
• Membranous gn
• Crescentic gns
• IgA nephropathy
• Mesangial sclerosis

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Terminology

• Nephrotic syndrome 3.5 g proteinuria, edema,
  hypercholesterolemia
• Nephritic syndrome acute renal failure,
  hypertension, hematuria
• Focal some glomeruli (lt 80) involved
• Diffuse most glomeruli (gt80) involved
• Segmental portion of a glomerulus involved
• Global entire glomerulus involved

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Glomerulonephritidies to be Discussed and Major
Presentation

• Minimal change disease
• Focal-segmental GS
• Membranous gn
• Diabetic nephropathy
• Acute Post. Strept. gn
• Crescentic gns
• Membranoproliferative gns
• SLE
• IgA nephropathy
• Alports syndrome/thin BMS

• Nephrotic
• Nephrotic
• Nephrotic
• Nephrotic
• Nephritic
• Nephritic
• Nephrotic/Nephritic
• Nephrotic/Nephritic
• Nephrotic/Nephritic
• Nephrotic/nephritic

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Glomerulonephritidies not discussed

• Fibrillary gn
• Immunotactoid gn
• Collgenous/collagenofibrotic gn
• Fibronectin gn
• C1q nephropathy
• Idiopathic nodular glomerulosclerosis
• Congenital/hereditary gns - Finnish type CNS,
  diffuse mesangial sclerosis, nail-patella
  syndrome, oligomeganephronia

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Proteinuria / Nephrotic Syndrome

• Immune complex negative Children Adults
• Minimal change disease 95 20
• Focal segmental 5 20
• Immune complex positive
• Membranous gn. uncommon 20
• IgA nephropathy uncommon 20

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Minimal Change Disease

• 95 pediatric and 20 adult nephrotic syndrome,
  usually normal renal function
• Biopsy
• LM - normal
• IF - negative
• EM - loss of podocyte foot processes
• Steroid responsive with an excellent prognosis
• Most important secondary causes
• Non steroidal anti-inflammatory drugs
• Lymphoproliferative disorders

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Normal light microscopy HE stain
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Normal glomerulus
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Normal glomerulus
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EM-podocyte foot process effacement
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EM-normal capillary loop
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Focal Segmental Glomerulosclerosis

• 5 pediatric and 20 adult nephrotic syndrome,
  normal renal function or renal insufficiency
• Biopsy
• LM - segmental sclerosis is diagnostic lesion
• IF - no immune deposits are present
• EM - foot process loss /- segmental sclerosis
• Steroid resistant and progressive in 30-50
• Secondary causes, numerous, but remember HIV
  nephropathy

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Focal segmental glomerulosclerosis- PAS stain
19
Segmental scar - HE stain
20
Segmental scar-JMS stain
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IF- nonspecific IgM deposits in areas of sclerosis
22
EM-hyaline, foam cell and effacement of podocyte
foot processes
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Focal Segmental Glomerulosclerosis

• Primary/idiopathic FSGS
• Secondary/variants FSGS
• I.V. drugs
• Collapsing gn HIV, parvovirus B-19,
  pamidronate, CS2, Loa Loa
• Obesity-associated - reversible with weight
  reduction
• Familial FSGS - podocin, alpha-actinin-4
  mutations
• Congenital - Finnish type (nephrin mutation),
  DMS
• Cholesterol emboli
• Lithium
• Mitochondrial myopathies/cytopathies

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HIV Nephropathy

• A combination of glomerular, tubular, and
  interstitial abnormalities, often with an
  ultrastructural finding that predicts HIV
  seropositivity
• Collapsing focal segmental glomerulosclerosis
• Dilated tubular casts
• Prominent interstitial inflammation and
  fibrosis
• Endothelial reticulotubular inclusions on EM
• Clinical course - rapid progression to renal
  failure over several months

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HIV nephropathy with collapsing form of FSGS
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HIV nephropathy-capillary loop collapse and
epithelial proliferation
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HIV nephropathy endothelial cell
tubuloreticular inclusion
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Membranous Glomerulonephritis

• 20 adult nephrotic syndrome, rare in children,
  normal renal function or renal insufficiency
• Biopsy
• LM - normal to thick capillary loops,
• /- spikes or pinholes on silver stain
• IF - diffuse granular capillary loop IgG/C3
• EM - diffuse subepithelial deposits
• Variable course remission, progression, or
  prolonged proteinuria
• Secondary forms Hepatitis B, SLE, drugs

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Membranous gn
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Membranous gn thickened capillary loops
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Membranous gn spikes
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IF membranous gn - IgG
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IF membranous gn - IgG diffuse granular deposits
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Membranous gn diffuse subepithelial deposits
with spikes
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IgA Nephropathy

• The most common gn in the world
• 20 adult nephrotic syndrome, uncommon in
  children, usually with hematuria /- RI
• Biopsy
• LM - variable with proliferation /- sclerosis
• IF - IgA immune deposits, primarily mesangial
• EM - mesangial deposits
• Variable course
• Secondary form Henoch-Schonlein purpura

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IF IgA nephropathy diffuse mesangial deposits
of IgA
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IgA nephopathy mesangial proliferative pattern
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IgA nephropathy segmented proliferative pattern
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IgA Nephropathy crescentic pattern
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EM- mesangial deposits of IgA
41
Diffuse ProliferativeGlomerulonephritis
Multiple Forms

• Acute post streptococcal (post infectious) gn
• Membranoproliferative gn, types 1 and 2
• Cryoglobulinemic glomerulonephritis
• Diffuse proliferative lupus nephritis (WHO class
  IV)
• Diffuse proliferative IgA nephropathy

42
HypocomplementemicGlomerulonephritis

• Acute post infectious glomerulonephritis
• Membranoproliferative glomerulonephritis
• Proliferative lupus nephritis
• Cryoglobulinemic glomerulonephritis
• Complement deficiency syndromes

43
Acute Poststreptococcal (Postinfectious)
Glomerulonephritis

• Primarily in children, uncommon in adults
• Hypocomplementemic acute nephritic syndrome
  10d-2wks following an URI (or skin, other
  infection)
• Biopsy
• LM - diffuse glomerular hypercellularity
• IF - large capillary loop /- mesangial
  deposits IgG/C3
• EM - large, infrequent hump-like
  subepithelial deposits
• Children Favorable, self-limited
• Adults progressive with a poor prognosis

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Acute poststreptococcal glomerulonephritis
showing diffuse proliferation
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Acute poststreptococcal glomerulonephritis-diffuse
proliferation
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APSGN endocapillary proliferation
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IF - APSGN large subepithelial IgG deposits
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EMAPSGN large subepithelial deposits capillary
loop hypercellularity
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Membranoproliferative Glomerulonephritis, type 1

• Most pediatric cases primary, most adult cases
  secondary
• Hypocomplementemic acute nephritic syndrome
• Biopsy
• LM - diffuse glomerular hypercellularity with
  GBM duplication
• IF - numerous subendothelial and mesangial
  deposits
• EM - subendothelial and mesangial deposits with
  GBM duplication
• Chronic slowly progressive course
• Secondary forms hepatitis C /- type 2
  cryoglobulinemia

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Membranoproliferative glomerulonephritis (MPGA)
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MPGN notice capillary loop basement membrane
duplication
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IF - MPGN - heavy IgG deposits in capillary loop
and mesangium
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EM MPGM subendothelial deposits
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HEPATITIS C-ASSOCIATED MPGN (Johnson, et al.,
Kidney Int 461700, 1994)

• 75 nephrotic syndrome
• 66 elevated liver function test
• 59 cryoglobulins
• 44 extrahepatic manifestations of cryoglobulins
• Interferon therapy (3K units, 3x/wk)
• 100 decrease in proteinuria
• HCV RNA disappears from serum

55
MPGN secondary to essential mixed cryoglobulins
notice capillary loop
thrombi-like deposits
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MPGN cryoglobulin - notice microtubular
structure
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Prevalence of HCV Infection inVarious Types of
Glomerulonephritis(Yamabe, et al., JASN 1995)

• MPGN, Type I
• Membranous
• IgA nephropathy
• Lupus nephritis
• Minimal change disease
• Others

• 6/10 60
• 2/24 8.3
• 1/58 1.7
• 0/14 0
• 0/12 0
• 0/24 0

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Dense Deposit Disease (Membranoproliferative
Glomerulonephritis, type 2)

• Clinical presentation identical to MPGN, type 1
• Biopsy
• LM - usually indistinguishable from type 1
• IF - linear C3 with mesangial rings, IgG is
  negative
• EM - electron dense transformation of the GBM
  lamina densa
• Course identical to MPGN, type 1
• Secondary forms none

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Dense deposit disease (DDD)
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IF - Dense deposit disease C3
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IF DDD C3
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EM-DDD- dense transformation of capillary loop
basement membrane
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EM DDD
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Crescentic Glomerulonephritis(Rapidly
Progressive Gn)

• Rapidly progressive (renal failure developing
  over 2 weeks to 2 months)
• There are a variety of causes which are most
  easily resolved by IF and serologic data
• Three categories are defined by their IF features

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A cellular crescent
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Tubules containing red blood cell casts
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Capillary loop necrosis with fibrin
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Capillary basement membrane disruption with fibrin
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Circumferential crescent
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Crescentic Glomerulonephritis

• Type 1 - Linear immunoflourescence
• Goodpasture syndrome
• Anti-glomerular basement membrane disease
• Type 2 - Granular immunoflourescence
• Many primary and secondary immune complex
  diseases
• Type 3 - Negative (pauci immune)
  immunoflourescence
• Predominately anti-neutrophil cytoplasmic
  antibody associated systemic vasculitis and renal
  limited crescentic gn

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IF fibrin in a large crescent
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Anti-glomerular Basement Membrane Diseases

• Diseases mediated by circulating anti-glomerular
  basement antibody
• Goodpasture syndrome
• Pulmonary hemorrhage and rapidly progressive
  glomerulonephritis
• Anti-glomerular basement membrane disease
• Rapidly progressive glomerulonephritis

74
IF linear reactions for IgG in Goodpastures
syndrome
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IF linear reaction for IgG in Goodpastures
syndrome
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Anti-neutrophil Cytoplasmic Antibodies

• A family of autoantibodies that have specificity
  for proteases located in primary granules of
  neutrophils and monocytes
• Useful in the diagnosis and monitoring of
  patients with several forms of systemic
  vasculitis and renal-limited (pauci-immune)
  crescentic glomerulonephritis

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Anti-neutrophil CytoplasmicAntibodies

• C-ANCA - cytoplasmic pattern
• Major specificity - proteinase 3
• Major clinical association - Wegeners
  granulomatosis
• P-ANCA - perinuclear pattern
• Major specificity - myeloperoxidase
• Major clinical associations - microscopic
  polyangiitis and renal-limited crescentic gn

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C-ANCA
P-ANCA
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Systemic Lupus Nephritis(classification now
under revision)

• Pattern of injury
• Normal
• Mesangial proliferative
• Segmental proliferative
• Diffuse proliferative gn
• Membranous gn
• Chronic sclerosing
• Interstitial nephritis
• Vascular lesions

• WHO class
• I
• II
• III
• IV
• V
• VI
• No class designation
• No class designation

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WHO Class II lupu nephritis
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WHO Class II Mesangial IgG
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WHO Class III lupus nephritis
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WHO Class IV lupus nephritis
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WHO Class IV wire loops
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WHO Class IV - IgG
86
WHO Class IV IgG glomerular and
tubulointerstitial deposits
87
EM WHO Class IV wire loop subendothelial and
mesangial deposits
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EM SLE endothelial tubuloreticular inclusion
89
WHO Class V membranous lupus nephritis
90
WHO Class V membranous SLE
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Diabetic Nephropathy

• Gradually worsening proteinuria and renal
  insufficiency
• Leading cause of end stage renal disease
• Usually requires 8-10 years of diabetes
• Microalbuminuria indicates onset of nephropathy
• Biopsy
• LM - diffuse /- nodular mesangial sclerosis,
  arteriolar insudative lesions
• IF - negative (nonspecific linear IgG)
• EM - severe thickening of GBM, mesangial
  sclerosis

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Diabetes Kimmelstiel-Wilson nodule
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Diabetes afferent and efferent arteriolar
hyalinosis
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Diabetes mesangial sclerosis and capillary loop
basement membrane thickening
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Glomerular Type IV Collagen Diseases

• Alports hereditary nephritis mutations in the
  alpha-3, -4, or -5 chain of type IV collagen
• X-linked - most common, alpha-5 mutations
  (gt300)
• Autosomal recessive - alpha-3, or -4 mutations
• Autosomal dominant - rarest, alpha-3, or -4
  mutations
• Thin glomerular basement membrane disease
• Non progressive - alpha-3, or -4 mutations
• Progressive - alpha-5 mutations

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Alport syndrome

• Hematuria with progressive development of
  proteinuria and renal failure
• Complex genetics
• /- hearing loss, ocular changes
• Renal biopsy
• LM - normal or segmental/global sclerosis
• IF - negative
• EM - GBM thinning /- lamellation (splitting)

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Alport syndrome GBM lamellation
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Thin Glomerular Basement Membrane Disease

• Hematuria with normal renal function clinically
  referred to as benign familial hematuria
• Often a positive family history of hematuria
• Non progressive (with a rare exception)
• Renal biopsy
• LM - normal
• IF - negative
• EM - GBM thickness lt200-250 nm (nl 300-350 nm)

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Thin basement membrane disease
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Chronic Glomerulonephritis

• Not an entity, but a final outcome, of any form
  of glomerulonephritis that progresses to renal
  failure
• Defined by the presence of gt 2/3 sclerotic
  glomeruli

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Chronic gn diffuse glomerulosclerosis
102
Amyloidosis and Immunoglobulin (Light Chain)
Associated Diseases

• Amyloidosis
• AL-associated - primary and LPD
• Diverse secondary, familial, organ-isolated,
  and neoplasm-associated forms
• Immunoglobulin (light chain) deposition disease
• Light chain cast nephropathy

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Amyloid and Immunoglobulin (Light
Chain)-Associated Diseases

• Amyloidosis
• Immunoglobulin (light chain) deposition disease
• Light chain cast nephropathy

• Nephrotic syndrome
• Nephrotic syndrome
• Renal failure without proteinuria

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Amyloid
105
Amyloid silver negative deposits
106
Interstitial amyloid disposition
107
Congo Red (polarized)
Congo Red (not polarized)
108
IF - amyloid lambda reaction
109
EM amyloid fibrils
110
Light chain deposition disease
111
IF - Kappa
112
EM Subendothelial kappa light chain deposits
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Light chain cast nephropathy
114
IF Lambda light chain casts
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The End . . . .