Renal disease in Zellweger s syndrome - Echo360 · The Spectrum When All Goes Wrong Active disease...

Renal Pathology from A to Z

IgA nephropathy

Renal disease in Zellweger’s syndrome

Pathologists “Read”

the Slides

BUT…..

Patients Do Not

Read

the Textbook

•Glomerulus

•Tubules

•Vessels

•Interstitium

•

•

•All of the above

What Can Go Wrong in the Kidney?

What can go wrong,

will go wrong

Murphy’s Law

The Spectrum When All Goes Wrong

Active disease End Stage Kidney

Proliferation

Necrosis

Sclerosis

Fibrosis

Glomerulus

Cells Processes

Podocyte

Endothelial

Mesangial

Proliferation

Necrosis

Sclerosis

Deposits

Mechanisms of Renal Disease

Glomerulus-

•podocyte/GBM injury

•immune complex deposition

Glomerulus and/or vessels-

•hemodynamic

•thrombotic

•metabolic

•deposition of abnormal proteins

Tubules-

•ischemia

•immune

•inflammation

•infection

•toxic

Mechanisms of Renal Disease

Glomerulus-

•podocyte/GBM injury

• Idiopathic (or associated with

e.g. drug reaction)

• Nephrotic range proteinuria

• Normal light microscopy

• Foot process effacement by EM

Minimal Change Disease

• Idiopathic

• Nephrotic range proteinuria

• Glomerulosclerosis in

focal/segmental pattern

• Foot process effacement

• No immune complexes

FSGS

• Juxtamedullary lesions early

• Focal - > 25 glomeruli optimal

sample

• Peripheral, hilar, and mixed

FSGS Distribution

• FSGS, nos

• FSGS, collapsing

• FSGS, cellular

• FSGS, tip

• FSGS, hilar

Columbia FSGS Classification

D’Agati, Fogo, Bruijn, Jennette, AJKD 2004

• Collapse glomerular tuft, with

overlying proliferating GVEC

• Disproportionately severe, cystic

tubular lesions

Collapsing Glomerulopathy

Collapsing Glomerulopathy

Possible Etiologies

• Pamidronate treatment

• Ischemia

• Calcineurin inhibitor

• HIV

• Parvovirus

• Idiopathic

• SLE

• Other

Tip Lesion

•Sclerosis/adhesion at

proximal tubular pole

•Varying endocapillary proliferation

• “Bad” immune complex disease-

• diagnose by IF, EM

• Healed, chronic pauciimmune GN-

• broad-based scars, fibrocellular crescents

• Secondary scarring linked to hypertension-

• severe vascular lesions, subtotal FPE

• Secondary scarring linked to hypertension-

• Chronic pyelonephritis- geographic scarring

Secondary Glomerulosclerosis

Mechanisms of Renal Disease

Glomerulus-

• Immune complex deposition: • mesangial

• subepithelial

• subendothelial

Immune Complex Location

Determines the Reaction

• Mesangial–

• mesangial proliferation (e.g. IgAN, mesangial

LN)

• Subepithelial-

• GBM reaction—spikes (e.g. MN)

• Subendothelial-

• endocapillary proliferation, new matrix next to

deposits , interposed cells, tramtracking (e.g.

MPGN)

IgA Nephropathy

•Mesangial deposits

•Varying mesangial expansion

±endocapillary proliferation

±sclerosis

±crescents

•Poor prognostic indicators:

•Mesangial hypercellularity

•Endocapillary proliferation

•Segmental sclerosis

•Tubulointerstitial fibrosis >25%

Robert I et al, Cattran D et al, KI 2009

Oxford Classification of

IgA Nephropathy

•Subepithelial deposits

•IgG, C3

•Varying GBM reaction, silver stain

with spikes, lucencies on tangential

sections

±sclerosis

Membranous Nephropathy

•Proliferative, exudative (PMNs)

•Subepithelial hump-type deposits

±crescents

•IgG/C3

•May be IgA dominant with Staph

infection

Postinfectious GN

Membranoproliferative GN, Type I

•Endocapillary proliferation

•GBM split appearance

•Subendothelial deposits

•IgG/C3

Lupus Nephritis

• Immune complexes

(anywhere!)

• All Igs, C3, C1q

• Reticular aggregates

The diagnosis of SLE is NOT

made by renal biopsy

RATHER

Renal biopsy defines the TYPE

of renal lesion in a patient with

SLE

Abbreviated ISN/RPS classification of

lupus glomerulonephritis

Class I Minimal mesangial LGN

Class II Mesangial proliferative LGN

Class III Focal LGN

Class IV Diffuse segmental (IV-S) or global (IV-G) LGN

Class V Membranous LGN

Class VI Advanced stage LGN

Activity vs. Chronicity

Endocapillary proliferation Glomerulosclerosis

Leukocyte infiltration

Necrosis

*Cellular crescents Fibrous crescents

Interstitial nephritis Tubular atrophy

*Interstitial fibrosis

Lupus Nephritis • Nephritic - proliferative form

(subendothelial deposits)

• Bad prognosis

• Nephrotic - membranous form

(mostly subepithelial deposits)

• Chronic, low grade

• Minor urinary abnormalities- mesangial

proliferation due to mesangial deposits

Mechanisms of Renal Disease

Glomerulus- • Complement dysregulation

C3 glomerulopathies: • Dense deposit disease

• C3 glomerulonephritis

Dense Deposit Disease

(membranoproliferative GN, Type II)

•Endocapillary proliferation

•GBM splitting

•C3

•Dense transformation by EM

•Mesangial/endocapillary proliferation

•Mesangial, subendothelial deposits

•C3 only/dominant by IF

•Underlying complement abnormality

C3 Glomerulonephritis

Crescentic GN • Rapidly progressive GN -to ESRD quickly

• Disease-specific IF findings:

-Immune complex GN-

disease specific IF +

typically BAD deposits

-Anti-GBM-

linear IgG along GBM

-Pauciimmune-

neg IF

Granulomatosis with polyangiitis vs

Microscopic polyangiitis vs renal limited

Dr. Ernest W. Goodpasture

Mechanisms of Renal Disease

Glomerulus-

•Abnormal protein deposition

• MIDD

• Amyloid (AL, other)

• Cryoglobulin

• Other substructured deposits

LCDD

• Nodular glomerulosclerosis

• Granular, amorphous deposits -

glomeruli and tubules

Amyloid

• Congo-Red positive randomly

arranged fibrils in glomeruli,

vessels

• AL >> AA in kidney

Classification of Amyloidoses

Abbreviation Subunit Disease

AL (AH) Light chain

(rarely heavy chain)

Plasma cell dyscrasias

AA Serum amyloid A protein

(SAA)

Chronic inflammatory

states

Beta2 microglobulin Ab2M CKD-dialysis-

associated

Afib Fibrinogen Familial

Ab b protein Alzheimer

ALect2 Leukocyte chemotactic

factor

Renal/liver

Alys Lysozyme Familial

Agel Gelsolin Familial

Acys Cystatin C Familial

Apo A I/II or IV Apolipoprotein Kidney/(medulla for

I/IV)

Varying Deposits Can Occur

in a Given Patient

• LCCN + LCDD

• LCCN + AL amyloid

• Very very rare:

LCDD + AL amyloid

Cryoglobulin

• Proliferative, mesangial or MPGN-

type

• Type I - organized

• Type II, III - short, fibrillar

substructure

Substructured Deposits

Fibrillary GN and Immunotactoid

Glomerulopathy

• Fibrillary GN-

mesangial/membranoproliferative, polyclonal

IgG, fibrils by EM

• Immunotactoid GP- mesangial proliferative,

often clonal Ig, microtubular substructure

Lesions of Renal Disease

•Thick GBM+ proteinuria

Diabetic Nephropathy

Lesions of Renal Disease

•Segmental sclerosis

•Proteinuria

•Hematuria

Lesions of Renal Disease

•Crescents

•Proteinuria

•Hematuria

Lesions of Renal Disease

•GBM splitting

•±Proteinuria

•±Hematuria

What is it?

London, Saturday, Nov. 1st, 1845

Dear Dr. Jones,

The tube contains urine of very high specific gravity; when

boiled it becomes highly opake; on the addition of nitric acid it

effervesces, assumes a reddish hue, becomes quite clear, but, as

it cools, assumes the consistence and appearance which you

see: heat reliquifies it. What is it?

Dr. Thomas Watson

Dr. William Mcintyre