Renal Pathology Review Medical Diseases of the Kidney Karlene Hewan-Lowe, MD Brody School of...

Renal Pathology Review

Medical Diseases of the Kidney

Karlene Hewan-Lowe, MDBrody School of Medicine at East Carolina University

Renal Pathology The Osler Institute Review Course

Normal Histology


Histology

Normal Glomerulus

• Anastamosing capillary networkArchitecture is defined with H and E, PAS and Methenamine silver stains

• Glomerular capillary wallFenestrated endothelial cellGlomerular Basement membrane 260 – 340 nmVisceral epithelial cell (Podocyte)

• MesangiumMesangial cellsMesangial matrix


Histology

TubuloInterstitium and Arteries

• Proximal convoluted tubules

• Distal convoluted Tubules

• Interstitium

Architecture defined by Masson’s trichrome stain

• Interlobular arteries

• Arterioles


Histologic Alterations in Glomerular Diseases

• The kidney has a limited reaction to a myriad of injurious agents

• Glomerular hypercellularity

Proliferative glomerulonephritides

• Thick glomerular basement membranes

• Hyalinization


Terms Used in the Evaluation of Glomerular Diseases

• Diffuse glomerular changes > 50%

• Focal glomerular changes < 50%

• Global involvement – single glomerulus

• Segmental involvement – single glomerulus


Immunofluorescence Microscopy

Linear capillary wall staining

Anti-GBM disease IgG, C3

MIDD kappa light chains

Diabetic nephropathy IgG, albumin

DDD C3

Granular mesangial staining

IgA Nephropathy IgA dominant

ISN/RPS Lupus Class I, II “Full house”

C1q nephropathy C1q



Granular mesangial and capillary wall staining

Membranous GN IgG,C3

MPGN C3

WHO Lupus III, IV Full house

Post infectious GN

Diffuse smudgy mesangial and capillary wall staining

Amyloidosis lambda light chains

Fibrillary GN IgG, C3, kappa > lambda

MIDD kappa light chains


Electron Microscopy

Subepithelial immune complex type dense deposits

Membranous GN Stage I - IV

MPGN

WHO Lupus IV

Post infectious GN “Humps”

Intramembranous (often with mesangial) immune complex type deposits

Dense deposit Disease


Electron MicroscopySubendothelial immune complex type deposits

MPGN

ISN/RPS Lupus III, IV Fingerprint, TRS

Cryoglobulinemia Tubular substructure

Pure mesangial immune complex type deposits

IgAN / HSP

ISN/RPS Lupus I, II

C1q nephropathy

Subendothelial immune complex type deposits

ISN/RPS Lupus class III, IV

MPGN Type III

Postinfectious GN


Clinical Patterns of Glomerular Disease


Clinical Patterns of Glomerular Diseases

Nephrotic Syndrome

• Edema

• Proteinuria > 3.5 gm/24 hours

• Hypoalbuminemia

• Hyperlipidemia

• Hyerplipiduria


Clinical Patterns of Glomerular Diseases

Nephritic Syndrome

• Hematuria

• Red cell casts

• Variable levels of proteinuria

• Acute or chronic renal failure

• Hypertension


Classification of Glomerular Diseases

• Primary renal disease: renal limited injury

• Secondary renal disease: systemic disease which involves the kidney

Nephrotic Syndrome Nephritic Syndrome

Primary Secondary Primary Secondary

Minimal ChangeFSGSMembranous GNMPGN

DiabetesAmyloid

Post Infectious GN

Crescentic GNIgA/HSP

SLEVasculitis


Nephrotic Syndrome


Minimal Change Disease (Nil Disease, Lipoid Nephrosis)

Clinical Features

• Peak age is 2 to 6 years• Severe proteinuria, nephrotic syndrome• Selective proteinuria• Normal renal function• Acute renal failure in adults• Associated with exposure to allergens or immunizations• Associated with Hodgkin’s disease, NSAID therapy


Minimal Change Disease (Nil Disease, Lipoid Nephrosis)

Pathogenesis

• Immune disorder• Circulating permeability factors• Loss of fixed, GCW polyanionic charge • Decreased and altered distribution of nephrin in

podocytes


Minimal Change Disease (Nil Disease, Lipoid

Nephrosis)

Light Microscopy

• Normal glomeruli• Foam cells• Resorbtion droplets in the

PCT


• No staining for G, A, M, C3, C1q, kappa, lambda


Minimal Change Disease

Electron Microscopy

• Foot process effacement and microvillous transformation

Prognosis

• Remission in 8 weeks with steroid therapy

• No tendency to progress to chronic renal disease


Focal Segmental Glomerulosclerosis

Clinical Features

• Heavy, non selective proteinuria• Nephrotic Syndrome• Microhematuria• Hypertension• Idiopathic FSGS• Secondary FSGS

HIVAN Heroin abuse

Morbid obesity Unilateral renal agenesis

Vesicoureteral reflux



Pathogenesis of FSGS

• Hyperfiltration/hyperperfusion injury• Circulating permeability factor• Most cases are sporadic• Few cases are associated with genetic abnormalities• Viral infections - HIV, parvovirus B19



Light Microscopy

• Juxta-medullary glomeruli• Focal glomerular involvement• Segmental glomerulosclerosis• Foam cells• Peripheral hyalinosis• Tubular atrophy and

interstitial inflammation



Columbia Classification

• FSGS, NOSTypical course

• Collapsing TypePoor prognosis

• Tip Lesion? Better prognosis

• Perihilar variant Secondary FSGS


Immunofluorescence Microscopy• IgM and C3 in the sclerosed

glomerular segments

Electron Microscopy

• Podocyte injury

• Protein droplets in podocytes

• Lamellar subepithelial reduplication of the glomerular basement membrane




HIV Associated Nephropathy

• HIV positive African American male• Short clinical history• Late manifestation of HIV infection• Rapid progression to end stage renal

disease• Collapsing variant of FSGS• Microcystic tubular dilatation• Mononuclear interstitial inflammation• Tubuloreticular structures in

endothelial cells



Membranous Glomerulonephritis

Clinical Features• Most common cause of nephrotic syndrome in

non-diabetic adults• Insidiuous onset of heavy proteinuria• Most common de novo glomerulonephritis in

renal allografts


Secondary MGNInfection

Hepatitis B, Hepatitis C, Syphilis, Parastic diseaseDrugs

Mercury, Gold, penicillamine, NSAID, Catopril, formaldehyeNeoplasms

Renal carcinoma, lung, stomach, breast, Hematolymphoid neoplasms, pancreas, melanoma, seminoma

Autoimmune DiseaseSLE, pemphigoid, MCTD, thyroiditis

OthersDiabetes, renal vein thrombosis, Sjogren’s, sarcoid, cryoglobulinemia, SCD



Light Microscopy• Normocellular glomerulus• Thickened glomerular

basement membranes• Spikes and rings seen on

Jones methenamine silver• Variable interstitial fibrosis• Interstitial foam cells may

be present


D’Agati Columbia-Presbyterian University


Immunofluorescence Microscopy• Granular IgG and C3 in the

peripheral capillary wall

Electron Microscopy

• Supepithelial electron dense deposits

• Subendothelial and mesangial deposits in secondary membranous GN

• Thickened basement membrane





Ehrenreich and Churg - Morphologic Classification• Stage I

Subepithelial electron dense deposits, normal GBM

• Stage II

Subepithelial electron dense deposits surrounded by cup-like extensions of the glomerular basement membranes

• Stage III

Subepithelial deposits, variable electron density, neomembranes are present on the surface of the deposit

• Stage IV

Irregularly thickened GBM and no deposits



Prognosis

• Slow deterioration to renal failure

• Corticosteroids and cytotoxic agents may be beneficial in idiopathic membranous GN

• Secondary membranous GN may regress


Membranoproliferative GN Type I

Clinical Features• More common in children• Uncommon in adults > 60 years of age• Prodrome of an upper respiratory infection• Hypertension• Proteinuria - always present, moderate to heavy , poorly

selective• Hematuria - macroscopic hematuria is uncommon• Nephritic Syndrome• Nephrotic Syndrome• Altered renal function - decrease GFR, Elevated BUN,

Creatinine• Hypocomplimentemia• Circulating immune complexes (20%)


GlomeruliEnlarged, hypercellular tuftLobular accentuationInfiltrating monocytes and neutrophils Crescents (2 - 10%)Thick peripheral glomerular membranesSilver stain - Double contours

TubulesHyaline (protein and lipid) droplets in tubular epitheliumTubular atrophy

InterstitiumInterstitial fibrosis, foam cellsIflammatory cells

VesselsArteriosclerosisVasculitis (Cryoglobulinemia)

Membranoproliferative GN Type I


MPGN Type II – Dense Deposit Disease

Clinical Features• Children and young adults• URI prodrome in ~50% of patients• Proteinuria with hematuria• Nephrotic syndrome is the most common presentation• Acute nephritic syndrome (16 – 38%)• Partial lipodystrophy• C3 – low, fluctuating, normal• C1q, C4 – normal• C3NeF - IgG autoantibody against complement inhibitory

proteins• Factor B, Properdin – low


PathologyGlomeruli

• Thick GBM• Hypercellular tuft• Leukocyte infiltration• Mesangial sclerosis

Immunofluorescence• C3, IgM - segmental

Electron Microscopy• Undulating ribbon-like

deposits in the GBM, mesangium and tubular basement membranes

MPGN Type II – Dense Deposit Disease


Membranoproliferative GN

Prognosis

• Uniformly poor

• Prognosis for Type II is generally worse than Type I

• Response to alpha interferon - MPGN associated with Hepatitis C

• Type II MPGN has 90% recurrence rate in allograft kidney


Glomerular Diseases with a Membranoproliferative Pattern• Diabetic glomerulosclerosis• Cryoglobulinemic Glomerulonephritis• Systemic Lupus nephritis (WHO Class IV)• Fibrillary glomerulonephritis• Hepatitis viral infection• Chronic liver disease• Light chain deposition disease• Lecithin-cholesterol acyltransferase deficiency


Diabetic Nephropathy

Clinical Features• Ten year or more history of diabetes mellitus• Microalbuminuria is an early clinical feature• Type I diabetes mellitus has good correlation

between renal disease and severity of fundoscopic findings

• Hypertension is common


Diabetic Nephropathy

Etiology and Pathogenesis• Irreversible glycosylation of the glomerular

basement membranes• Growth factors• Genetic susceptibility• Glomerular hyperperfusion or hyperfiltation injury


Diabetic NephropathyLight Microscopy

• Diffuse increase in mesangial matrix• Sclerotic mesangial nodules• Fibrin cap (peripheral hyalinosis)• Capsular drop• Hyaline arteriolosclerosis of the

afferent and efferent arterioles• Arteriosclerosis• Protein droplets in tubular epithelium• Glycogen in tubules - Armani Ebstein anomaly• Pyelonephritis• Papillary necrosis


Diabetic NephropathyImmunofluorescence Microscopy

• IgG - low intensity linear accentuation of the glomerular basement membrane

• Albumin - low intensity linear accentuation of the glomerular basement membrane

• IgM and C3 in sclerosed glomerular segmentsElectron Microscopy

• Podocytes show foot process effacement• Uniformly thick glomerular basement membrane • Expanded mesangial matrix


Diabetic NephropathyPrognosis

• Progression to end stage renal failure ranges from 3 to 20 years

• Renal failure 40% of Type I diabetics20% Type II diabetics

• Recurs in allograft kidney• Control of hyperglycemia and hypertension delays

the progression of diabetic nephropathy


AmyloidosisClinical Features

• AL Type amyloid - Plasma cell dyscrasia Most common is AL monoclonal light chain, l > kOvert myeloma is present in 10 – 20%

• AA Type amyloid - Chronic inflammatory diseases Osteomyelitis, TB, leprosy, rheumatoid arthritis

• Neoplasms - Renal cell carcinoma• Familial Mediterranean Fever • Severe proteinuria• Nephrotic syndrome


Light Microscopy• Smudgy, homogenous

deposits in glomeruli, tubular basement membranes, peritubular capillaries and blood vessels

• Deposits are weakly PAS positive and silver negative

• Detection: Congo Red, antibody to AA, Thioflavine T

Amyloidosis

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