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 pathology overview Glomeruli ◦ Glomerulonephritis ◦ Diabetes ◦ Amyloidosis e.g. Crescentic glomerulonephritis

Medical renal pathology overview Tubules ◦ Acute tubular necrosis ◦ Pyelonephritis ◦ Myeloma kidney e.g. Acute tubular necrosis

Medical renal pathology overview Interstitium ◦ Acute or chronic interstitial nephritis e.g. Tubulointerstitial nephritis

Medical renal pathology overview 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 Disease Terminology Proliferation – more cells than normal Necrosis Sclerosis Deposits

Normal: H&E Visceral epithelial cells (podocytes) Endothelial cells Mesangial cells

Normal: PAS Visceral epithelial cells (podocytes) Endothelial cells Mesangial cells

Mesangial proliferation Increase in the number of cells in the mesangium to four or more per zone As 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 necrosis 50% or more glomeruli with crescents defines crescentic glomerulonephritis

Cellular crescent Bowman’s capsule Capillary tuft Crescent

Necrosis Deposition of fibrin (fibrinoid necrosis) and/or karyorrhectic fragments

Fibrinoid necrosis Bowman’s capsule Crescent Residual capillary tuft Fibrin

Sclerosis Absolute or relative increase in the amount of extracellular matrix ◦ Mesangial matrix increase ◦ Partial or complete capillary tuft collapse

Mesangial sclerosis

Diabetic glomerulopathy Thickened GBM Mesangial cells Mesangial matrix

Segmental sclerosis/ hyalinosis Residual normal tuft Sclerosed segment

Global glomerulo sclerosis

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 deposits IgG and C3 that outline the glomerular basement membrane Not visible by EM Seen in the setting of crescentic glomerulonephritis Characteristic 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 glomeruli Global – involving and entire glomerulus Focal – involving <50% of the glomeruli Segmental – involving only a portion of a single glomerulus

Renal glomerular syndromes corresponding 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 A 2 receptor (PLA2R) Malignancy: solid tumors Infection: hepatitis B/C, malaria, syphilis Drugs: penicillamine, gold Autoimmune diseases: SLE Sarcoidosis

Membranoproliferative Glomerulonephritis (MPGN) (type I) Mesangial and endocapillary proliferation with lobular accentuation and double contoured capillary walls

Diabetic glomerulosclerosis GBM thickening and mesangial matrix increase Visible by light microscopy only if advanced enough

Amyloidosis Haphazardly 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 syndrome Acute nephritic syndrome: Post Streptococcal GN Rapidly progressive renal failure (RPGN) Asymptomatic hematuria and/or proteinuria Systemic Disease Chronic 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, meningococcus Viral infections: Hep B, C, HIV, varicella Parasitic infections: malaria, toxoplasmosis

Acute Post-Streptococcal GN Renal symptoms 1-4 weeks after streptococcal throat or skin infection >> ASO titers, low serum complement levels Atypical clinical presentation and course prompt a renal biopsy in children

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”-like deposit 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, hypercellular mesangium

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 rash8.Neurological disorder 2. Discoid rash9.Hematological disorder 3. Photosensitivity10.Immunological disorder: Anti-dsDNA 4. Oral ulcersAnti-Sm Ab 5. ArthritisAntiphospholipid Ab 6. Serositis 7. Renal disorder11.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

Subepithelial deposits GBM Deposits

Tubuloreticular inclusions

CLASSIFICATION OF Lupus Nephritis ClassLMIFEM Inormalmesangialmesangial deposits IImesangial hypercellularity mesangialmesangial deposits IIIfocal proliferative GN (< 50% glomeruli) mesangial + capillary wall Mes + subendo dep IVdiffuse proliferative (> 50% glomeruli) mesangial + capillary wall Mes + subendo dep VMembranouscapillary wall (+/- mesangial) Subepithelial +/- mes VIAdvanced 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

Atrophic tubules Globally sclerosed glomeruli

Robbins..