Renal pathology: Nephrotic and Nephritic Syndromes
John Higgins
Learning Objectives Morphology of renal injury Mechanisms of glomerular injury and clinicopathologic correlations of
prototype disease with a typical clinical presentation
◦ Nephrotic syndrome (minimal change nephrotic syndrome)
◦ Nephritic syndrome (Post streptococcal GN)
◦ RPGN (anti-GBM disease)
◦ Asymptomatic hematuria/Proteinuria (IgA nephropathy)
◦ Systemic disease (Lupus nephritis)
Medical renal pathologyoverview
Glomeruli◦ Glomerulonephritis
◦ Diabetes
◦ Amyloidosis
e.g. Crescentic glomerulonephritis
Medical renal pathologyoverview
Tubules◦ Acute tubular necrosis
◦ Pyelonephritis
◦ Myeloma kidney
e.g. Acute tubular necrosis
Medical renal pathologyoverview
Interstitium◦ Acute or chronic
interstitial nephritis
e.g. Tubulointerstitial nephritis
Medical renal pathologyoverview
Blood vessels◦ Classic polyarteritis
nodosa
◦ Malignant hypertension
◦ Atheroemboli
e.g. Necrotizing arteritis
Points not to be overlooked Tubulointerstitial diseases (such as ATN and pyelonephritis) and
vascular diseases (such as arteriolonephrosclerosis due to hypertension) are more common than glomerular diseases
Of the glomerular diseases, diabetes is much more common than glomerulonephritis
Nevertheless, we’re going to talk about rare glomerular diseases for the rest of this lecture
Medical kidney disease – New problems (why renal is hard)
Clinicopathologic correlation◦Clinical features◦Morphology◦Disease names
Immunofluorescence and EM◦Glomerular immune complex diseases
New terminology
Practice translating between light, IF, EM
Kidney DiseaseTerminology
Proliferation – more cells than normalNecrosisSclerosisDeposits
Normal: H&E
Visceral epithelial cells (podocytes)
Endothelial cells
Mesangial cells
Normal: PAS
Visceral epithelial cells (podocytes)
Endothelial cells
Mesangial cells
Mesangial proliferationIncrease in the number of cells in the
mesangium to four or more per zoneAs in mesangioproliferative
glomerulonephritis such as IgA
Mesangial proliferation
Epithelial proliferation(Crescent formation)
Increase in parietal epithelial cells together with infiltrating leukocytes
Often associated with fibrinoid necrosis50% or more glomeruli with crescents
defines crescentic glomerulonephritis
Cellular crescent
Bowman’s capsule
Capillary tuft
Crescent
NecrosisDeposition of fibrin (fibrinoid necrosis)
and/or karyorrhectic fragments
Fibrinoid necrosis
Bowman’s capsule
Crescent
Residual capillary tuft
Fibrin
SclerosisAbsolute or relative increase in the amount
of extracellular matrix◦Mesangial matrix increase◦Partial or complete capillary tuft collapse
Mesangial sclerosis
Diabetic glomerulopathy
ThickenedGBM
Mesangial cells
Mesangial matrix
Segmental sclerosis/hyalinosis
Residual normal tuft
Sclerosed segment
Global glomerulosclerosis
Deposits – Immune complex
Location◦Mesangial◦Subendothelial◦Subepithelial◦ Intramembranous
Quality (by immunofluorescence)◦Granular◦Linear
Subepithelial deposits
GBMEpithelial cell cytoplasm
Deposits
Subendothelial deposits
GBM
Endothelial cell cytoplasm
Subendothelial deposit
Intramembranous deposit
GBM replaced by electron dense deposit
Mesangial deposit
GBM
Mesangial cells
Deposit
Linear depositsIgG and C3 that outline the glomerular
basement membraneNot visible by EMSeen in the setting of crescentic
glomerulonephritisCharacteristic of Goodpasture’s disease
(anti-glomerular basement membrane disease)
Linear IgG by IF
Seen with glomerular crescents: anti-GBM nephritis
Granular IgG by IF
Mesangial deposits of IgA: Don’t look as much like a glomerulus
Distribution of glomerular lesions
Diffuse – involving >50% of the glomeruliGlobal – involving and entire glomerulusFocal – involving <50% of the glomeruliSegmental – involving only a portion of a
single glomerulus
Renal glomerular syndromescorresponding glomerular pathology
Nephritic (bleeding)◦ Increased cellularity
Mesangial Crescents
◦ Necrosis
◦ Immune complex deposits in the mesangium and subendothelial space
◦ Linear glomerular basement membrane deposits
Nephrotic (heavy proteinuria)◦ Podocyte injury
Foot process fusion Subepithelial immune complex
deposits Segmental glomerular basement
membrane collapse
Nephrotic syndrome causes
Children
◦ Primary diseases (95%) Membranous (5%) Minimal change (65%) FSGS (10%) MPGN (10%) Other proliferative GN (10%)
◦ Secondary (5%) SLE, drugs, Infections, malignancy, hereditary nephritis, bee-
sting allergy
Adults
◦ Primary diseases (60%) Membranous (30%) Minimal change (10%) FSGS (35%) MPGN (10%) Other proliferative GN (15%)
◦ Secondary diseases (40%) Diabetes, amyloidosis, SLE, drugs (gold, penicillamine, heroin),
Infections (malaria, syphilis, hep. B, HIV), malignancy, bee-sting allergy
Notice that:◦ Secondary causes are rare in children
but common in adults
◦ Secondary causes may resemble the primary lesions (e.g. malignancy associated membranous) or look nothing like them (e.g. amyloid)
◦ In children, the most common primary lesion is minimal change nephrotic syndrome. Because this is steroid responsive, children with NS are treated empirically
Minimal change nephrotic syndrome
Epithelial cell foot process effacement
Focal Segmental Glomerulo Sclerosis (FSGS)
Segmental sclerosis
Non-specific trapping of plasma proteins
Loss of capillary lumens with foam cells
Membranous glomerulopathy
Diffuse subepithelial deposits
Capillary wall thickening only if deposits are big enough
Granular loop deposits of IgG always present but not specific
Conditions associated with membranous nephropathy
Primary/idiopathic◦ most have antibodies against podocyte antigen
Phospholipase A2 receptor (PLA2R)
Malignancy: solid tumors Infection: hepatitis B/C, malaria, syphilisDrugs: penicillamine, goldAutoimmune diseases: SLESarcoidosis
Membranoproliferative Glomerulonephritis (MPGN) (type I)
Mesangial and endocapillary proliferation with lobular accentuation and double contoured capillary walls
Diabetic glomerulosclerosisGBM thickening and mesangial matrix increase
Visible by light microscopy only if advanced enough
AmyloidosisHaphazardly arranged 10nm fibrils
Amorphous material by light microscopy
Commonly light chain - associated with myeloma but does not have to be
Amyloidosis:
Congo red stain under polarized light
Clinical manifestations of glomerular disease
Nephrotic syndromeAcute nephritic syndrome: Post Streptococcal
GNRapidly progressive renal failure (RPGN)Asymptomatic hematuria and/or proteinuriaSystemic DiseaseChronic renal failure
Acute Post-Infectious GN
Group A hemolytic streptococci (types 12,4,1) eg. pharyngitis, impetigo
Staphylococcus (eg. subacute bacterial endocarditis, deep seated abscesses, infected ventriculo-atrial shunts);
pneumococcus, meningococcusViral infections: Hep B, C, HIV, varicella
Parasitic infections: malaria, toxoplasmosis
Acute Post-Streptococcal GNRenal symptoms 1-4 weeks after
streptococcal throat or skin infection>> ASO titers, low serum complement
levelsAtypical clinical presentation and course
prompt a renal biopsy in children
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Diffuse, proliferative, exudative glomerulonephritis
Neutrophils in capillary lumens (acute exudate)
Red blood cell casts
Granular C3, IgG
Glomerular basement membrane
Neutrophils
Deposits
Subepithelial “humps”
Epithelial cell
“hump”-likedeposit
GBM
Acute Post-Streptococcal GN
Pathogenesis: ◦Immune complex-mediated process◦the specific streptoccocal cationic
antigenic component responsible is unclear (exogenous antigen)
◦? cationic planted antigen versus circulating immune complexes
Acute Post-Streptococcal GN: Outcome
Spontaneous resolution in 95% of the children (& 60% of adults)◦1-2 % have crescents with rapid
deterioration of renal function◦1-3 % develop slow progression to
chronic renal failure
Crescentic GN
subdivided into 3 categories, based on IF:
-anti-GBM disease : linear IgG & C3; no deposits by EM
-Immune complex-mediated : abundant deposits eg. SLE, post-infectious GN, Henoch-Schönlein Purpura
-Pauci-Immune GN : No deposits by IF/EM eg. Granulomatosis polyangiitis (Wegener’s),
microscopic polyangiitis
Anti-GBM disease (Goodpasture’s syndrome)
Clinical presentation: RPGN If associated hemoptysis and dyspnea:
Goodpasture’s syndrome Pathogenesis: circulating auto-antibodies against
non-collagenous domain of 3 chain of collagen type IV (cross reacting with glomerular and alveolar basement membranes).
Glomerular necrosis
Glomeruli
Fibrinoid Necrosis
Fibrin extravasation, cellular crescent
Normal glomerular tuft
Fibrin
Crescent
EM: No deposits
Linear IgG; No deposits in EM
Alveolar hemorrhage
Alveolar septa
Blood
Anti-GBM disease: Clinical Course
Steroids, cytotoxic agents and plasmapheresis : Resolves pulmonary hemorrhages Renal function improves if intervened early (sCr 4-5
mg/dl) Irreversible renal failure if therapy is delayed May recur in renal transplants (anti-GBM antibody titers
monitored)
Clinical manifestations of glomerular disease
Nephrotic syndrome Acute nephritic syndrome Rapidly progressive renal failure (RPGN) Asymptomatic hematuria and/or proteinuria
◦ IgA nephropathy (Berger’s disease)◦ Alport syndrome, Thin basement membrane disease
Systemic Disease Chronic renal failure
IgA Nephropathy
Clinical presentation:◦ Recurrent gross/microscopic hematuria◦ Proteinuria usually non-nephrotic range◦ No systemic disease (vs Henoch-Schönlein Purpura)◦ Acute nephritic syndrome in 5-10% of cases◦ Hematuria often preceded by respiratory and
gastrointestinal infections
IgA Nephropathy LM:
◦ mesangioproliferative most common◦ endocapillary proliferative and/or sclerosing lesions may be
seen. ◦ Segmental crescents can be present.
IF: defining feature ◦ Dominant /co-dominant IgA stain (IgA /= IgG); C3, K, L +
EM: Mesangial deposits; segmental subendothelial deposits
Mesangial Proliferation
Expanded, hypercellularmesangium
Fibrocellular crescent
Crescent
Cellular areas
Less cellular, “Fibrous” areas
Mesangial IgA, C3
Mesangial deposits
Mesangial immune complex
GBM
Henoch-Schönlein Purpura
Most common in children (3-8 yrs), but also occurs in adults
Syndrome: systemic vasculitis◦ Purpuric skin rash (extensor surfaces of
extremeties) ◦ Abdominal pain, vomiting, melena◦ Arthralgias◦ Renal manifestations (IgA nephropathy)
Clinical manifestations of glomerular disease
Nephrotic syndrome Acute nephritic syndrome Rapidly progressive renal failure (RPGN) Asymptomatic hematuria and/or proteinuria Systemic Disease:
◦ Systemic lupus erythematosus, Henoch-Schönlein Purpura, Goodpasture’s syndrome, Wegener’s granulomatosis, cryoglobulinemic GN
Chronic renal failure
Systemic Lupus Erythematosus
Multisystem disease of autoimmune origin Predominantly seen in women of childbearing age (F:
M=9:1), > severe in AA, Hispanics Acute or insidious in onset; chronic remitting and relapsing
course Primary target organs: skin, joints, kidney, serosal
membranes
1997 Revised Criteria for SLE Classification (4 required for diagnosis)
1. Malar rash 8. Neurological disorder
2. Discoid rash 9. Hematological disorder
3. Photosensitivity 10. Immunological disorder: Anti-dsDNA
4. Oral ulcers Anti-Sm Ab
5. Arthritis Antiphospholipid Ab
6. Serositis
7. Renal disorder 11. Antinuclear Ab (ANA)
Systemic Lupus Erythematosus
Role of antibodies in the diagnosis:◦ ANA is highly sensitive , but not very specific◦ Anti-dsDNA and anti-Sm antibodies are less
sensitive but more specific Etiology and pathogenesis:
◦ Genetic factors◦ Environmental factors eg. Drugs◦ Immunological factors (dysregulation & loss of self
tolerance)
SLE and Kidney
The morphological changes in lupus nephritis (LN) are extremely variable
The lesions result from deposition of immune complexes (Ag-AB)
The clinical presentation, course and prognosis of various lesions differ◦ Nephrotic, nephritic-nephrotic, RPGN
Endocapillary proliferation
Too many cells and loss of capillary lumens
“Wire loops” (large subendothelial deposits)
Intraluminal hyaline thrombi
Cellular crescent
Different case: Membranous LN (nephrotic syndrome)
Diffusely thickened,Lumpy-bumpy capillary walls
IgG, IgM, IgA, C3, C1q, K, L: “full house”
Mesangial deposits
GBM
Deposit
Subendothelial deposits
GBM
Deposit
Deposit
Subepithelial deposits
GBM
Deposits
Tubuloreticular inclusions
CLASSIFICATION OF Lupus NephritisClass LM IF EM
I normal mesangial mesangial deposits
II mesangial hypercellularity
mesangial mesangial deposits
III focal proliferative GN (< 50% glomeruli)
mesangial + capillary wall
Mes + subendo dep
IV diffuse proliferative (> 50% glomeruli)
mesangial + capillary wall
Mes + subendo dep
V Membranous capillary wall (+/- mesangial)
Subepithelial +/- mes
VI Advanced sclerosis +/- +/-
Chronic Glomerulonephritis
Chronic end-stage damage to glomeruli, tubules and blood vessels
Bilateral kidneys symmetrically contracted Associated with hypertension Clinical features of chronic renal failure and uremia
develop
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Atrophic tubules
Atrophic tubules
Globally sclerosed glomeruli
Robbins..
