Renal pathology: Nephrotic and Nephritic Syndromes John Higgins

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..