KIDNEY PATHOLOGY

NORMAL

How many glomeruli needed for biopsy?

• § 3-5 glomeruli

3 functions of kidney

• § Excretion: urine formation and concentration
• § Homeostasis: acid excretion
• § Hormones: EPO, renin, prostaglandins

 

Normal kidney weight, number of major and minor calyces, normal cortical thickness*

• § 150g
• § 1 pelvisà 2-3 major calycesà 12 minor calyces
• § Normal cortex=1.2-1.5cm

 

4 compartments

Glomeruli

Composition of BM*

• § Lamina densa sandwiched by lamina rara.
• § Collagen IV (3 α-chains, glycoproteins (laminin, enactin, fibronectin), proteoglycans (heparin sulfate)[1]
• § Podocytes synthesize BM. Filtration slits 20-30nm*
• § More cationic, more permeable (albumin is anionic)

 

Tubules

• § Proximal tubules have long microvilli, numerous mitochondria, apical canaliculi, extensive intercellular interdigitations but prone to ischemia
• § Juxtaglomeurla apparatus: juxtaglomerular cells, macula densa, lacis cells

 

Interstitium

• § BM like material

 

BV***

• § Renal arteryà anterior or posteriorà interlobarà arcuateà interlobularà afferentà 20-40 capillary loopsà efferentà peritubular vascular network around tubules[2]
• § Only deeper juxtamedullary glomeruli have arterial vasa recta in medullaà venous vasa recta

How medulla more vulnerable to ischemia?***

• § Does not have its own supply; all derive from efferent arterioles which come from glomeruli

 

 

PRESENTATIONS

Clinical presentations of renal disease*

• § Nephritic (aka acute nephritis)
• § Nephrotic
• § Asymptomatic hematuria +/- proteinuria
• § ARF: acute onset of azotemia (increased BUN, creatinine), oliguria, anuria
• § CRF: uremia (uremia=azotemia with clinical signs and symptoms)
• § Renal tubular defect: polyuria, nocturia, electrolyte imbalance (metabolic acidosis)
• § UTI
• § Nephrolithiasis
• § Urinary obstruction

 

Name SSx of uremia[3]*

• § HyperK, edema, metabolic acidosis
• § HyperPO4, hypoCa, secondary hyperPTH (leading to renal osteodystrophy and nephrocalcinosis)
• § Anemia, bleeding
• § HTN (leading to LVH), CHF, uremic pericarditis
• § Inflammation of entire GI tube (uremic gastroenteritis), uremic pneumonitis
• § Myopathy, peripheral neuropathy, encephalopathy
• § Pruritus, dermatitis

Stages of renal failure and correlate with GFR*

• § Decreased reserve (>50% GFR)
• § Renal insufficiency (20-50% GFR)
• § Renal failure (<20% GFR)
• § End-stage renal disease (<5% GFR)

Once kidney function lowered down to 20-50%, decline progresses at constant rate by which 2 mechanisms?*

• § FSGS
• § Tubulointerstitial fibrosisà this correlates better with GFR than severity of glomerular injury*

 

 

 

 

 

CONGENITAL ANOMALIES

Types*

• § Dysplasia
• § Hypoplasia*: no scars, <6 lobes and pyramids
• § Agenesis: compensatory hyperplasia. Lethal if bilateral
• § Ectopic: ureteric kinkingà obstruction, infection
• § Horseshoe: anterior to aorta and IVC

RENAL CYSTS

CYSTIC RENAL DYSPLASIA

Complications

• § Sporadic
• § Obstruction of ureters and lower urinary tract
• § Unilateral or bilateral

 

Micro

• § Undifferentiated mesenchyme surrounding immature collecting ducts with cartilage

APKD

Genetics and chromosome?* What functions?*

• § PKD1 and PKD2 for polycystins 1 and 2 on chromosomes 16 and 4
• § Polycystins involved in cell-cell and cell-matrix interactions important in tubular epithelial cell growth and differentiation

 

When start seeing cysts?

• § Early childhood up to 80yo
• § Always bilateral
• § Entire kidney composed of cysts

Extrarenal disease

• § Berry aneurysms
• § Polycystic liver disease with bile duct proliferation
• § Mitral valve prolapse

 

Micro

• § Markedly distorted kidney by cysts with no obvious intervening parenchyma although there are function glomeruli

IPKD

Genetics*

• § PKHD (polycystic kidney and hepatic disease) on chromosome 6 coding for fibrocystin (remember fibro for liver fibrosis)

Variants*

• § Perinatal (no1)
• § Neonatal (no1)
• § Infantile
• § Juvenile

Where are cysts and present at birth? Always bilateral?

• § Liver cysts? + bile duct proliferation
• § Renal cysts present at birth
• § Cylindrical radially arranged cysts in both cortex and medulla
• § Hepatic fibrosis
• § Always bilateral

Micro

• § Dilation of tubules lined by cuboidal cells forming cysts
• § Bile ductular proliferation, hepatic fibrosis

 

MEDULLARY SPONGE KIDNEY MSK

Definition*

• § This term should limited to multiple cystic dilations of collecting ducts in medulla

Genetics

• § None

SSx

• § Stones, infections, hematuria

Gross

• § Dilation of collecting ducts leading to cysts in medulla, starting from adulthood

Px

• § Benign but stones

NEPHRONOPHTHISIS-MEDULLARY CYSTIC DISEASES

Juvenile	Adult
familial juvenile nephronophthisis	adult medullary cystic disease
NPH1-3* (nephrocystins) in AR variants	MCKD1-2*
Gross* -Small corticomedullary cysts, small kidney
Clinical Salt wasting, polyuria, nocturia, growth retardation, anemia, tubular acidosisà CRF
Variants Sporadic, familial (AR), renal-retina dysplasia (AR), adult-onset medullary cystic disease (AD)
Remember basic injury site is tubulointerstitium*à reason why aka hereditary tubulointerstitial nephritis Tubular atrophy, interstitial fibrosis
CRF starting at childhood	CRF starting at adulthood

 

SIMPLE

Gross

• § Rarely can be medullary

Micro

• § Cuboidal

ACQUIRED

Gross

• § Cortical and medullary

Micro

• § Lined by atypical hyperplastic epithelium

GLOMERULAR DISEASES

Mechanism*

• § Humoral: in situ, circulating, cytotoxic
• § Cellular
• § Alternative complement pathwayà type II MPGN

3 types of humoral reactions, sites of IC deposits and give exemples*

• § In situ: either intrinsic or planted
  • Ø Fixed intrinsic antigens (at GBM, subepithelial)
  • Ø GBM (α3 chain of collagen IV)
  • Ø Heymann nephritis (megalin, aka membranous GN)
  • Ø Planted exogenous antigens (subepithelial)
  • Ø Infections, ANA
• § Circulating IC (subendothelial or mesangial deposit)
  • Ø Complement activationà PMN release proteases, free radicals, arachidonic metabolites
  • Ø Macrophages, lymphocytes, NK cells release cytokines, GF
  • Ø PLT: eicosanoids, GF
  • Ø Mesangial cells:  can initiate inflammation
  • Ø Complement: MAC
  • Ø Coagulation proteins: fibrin can stimulate crescent formation
  • Ø Hemodynamics
• § Cytotoxic antibodies

 

Pathogenesis of glomerulonephritis

• § Humoralà ICà complementà PMN
• § Cellularà T, NKà injury

Locations of IC

• § Subendothelial (circulating IC): MPGN, SLE III-IV
• § GBM (intrinsic): Goodpasture
• § Subepithelial (intrinsic or planted): MGP, postinfectious, SLE V
• § Mesangial (planted): IgA, HSP

 

3 changes in glomerular diseases*

• § Hyalinization and sclerosis
• § BM thickening
• § Hypercellularity: cellular proliferation, leukocytic infiltration, crescent formation

MECHANISMS OF PROGRESSION IN GLOMERULAR DISEASES

When?

• § Starts once GFR below 50%

2 major micro findings?

GS (focal and segmental)

• Ø Loss of renal massà compensatory hypertrophy (often accompanied by systemic HTN)à proteinuria, GS

 

Tubulointerstitial inflammation and fibrosis

• Ø Better correlation with renal function decline than glomerular loss
• Ø Ischemia from sclerotic glomeruli, immune cross-reaction between glomeruli and tubules, ammonia retention, protein leaking into Interstitiumà activated tubular cells secrete cytokines and GFà interstitial fibrosis

 

 

NEPHRITIC SYNDROME

Definition

• § Hematuria
• § Azotemia
• § RBC casts
• § Oliguria
• § Mild HTN
• § Mild proteinuria
• § Mild edema

Pathogenesis of Nephritic Syndrome

Post-infectious
Group A Strep	Pharyngitis, impetigo
Other	Staph. endocarditis, HIV, HBV, HCV,  mumps, varicella, malaria, toxo
MPGN	Types based on LOCATION of immune deposits
Type I	subendothelial
Type II	intramembranous
Type III	not well defined
RPGN / Crescentic GN
Type 1 anti-GBM Ab	Isolated Goodpasture’s syndrome
Type 2 immune complex	IgA/HSP Postinfectious SLE
Type 3 pauci-immune	ANCA-associated Isolated/idiopathic Wegener Microscopic polyarteritis

 

Postinfectious glomerulonephritis

Most common infectious agent

• § Post-group A streptococcal (beta hemolytic)

SSx

• § Hematuria, RBC casts, moderate proteinuria, edema, 1 week to 1 month after pharyngeal or cutaneous infection (impetigo)

 

Other infectious agents

• Bacteria: staph endocarditis, pneumococcal pneumonia, meningococcemia
• Viruses: HBV, HCV, mumps, HIV, varicella, EBV
• Parasites: malaria, toxo

Mechanism*

• § Some strains of GABSà circulating or planted Ag (endostreptosin and other cationic antigens)à IC

Micro*

• § Diffuse and global hypercellularity due to proliferation of all cells (endothelial, mesangial, epithelials, PMN and monocytes)à large and cellular glomeruli
• § Leukocytic infiltration
• § Crescent in severe cases

IF*

• § Granular IgG, IgM, C3 in GBM and mesangium

EM*

• § Subepithelial humplike deposits

Lab

• § Elevated serum antistreptolysin O (ASO) Ab, decreased C3

 

Prognosis

• § 95% of children recover
• § 60% of adults recover

 

 

Membranoproliferative glomerulonephritis

Define (3)*

• § BM alteration, glomerular cell proliferation (also in mesangium), leukocytic infiltration

 

Type 1	DDD
SLE Hepatitis Cryoglobulinemia Schistosomiasis A1AT deficiency Chronic liver disease Malignancies Idiopathic
IC formation* Activation of both classic and alternative complement pathways*	Activation of alternative complement pathway*
	C3 nephritic factor* (AB against C3 convertase) in serum in all cases
Micro* Nodular glomeruli (due to mesangial proliferationà BM of capillary loops) Thickened (tram-track) with focal splitting (double-contour) Mesangial proliferation (increased black stain on silver)
IF* IgG+C3, C1q+C4 in mesangium*	IF* C3 alone*
EM* Subendothelial deposits	EM* Ribbon-like intramembranous deposit in GBM, +/-subepithelial humplike dense deposits
Slowed by CSTD but still 50% develop CRF, high recurrence after transplantation

 

 

 

 

Rapidly progressive/crescentic glomerulonephritis

Composition of crescents?

• § Parietal cells, monocytes, +/-lymphocytes, macrophages, fibrin between cellular layers

Common denominator?***

• § Rapid renal decline: acute nephritis, proteinuria, ARF

Range of microscopic findings based on severity?***

• § Mild: focal segmental necrosis of glomeruli
• § Severe: crescents (necrosis+ extensive fibrin and cellular component) in most glomeruli
• § Chronic: fibrous crescents (scar)

 

Variants

 

Anti-GBM (25%)

• § Linear IgG (and C3 in many cases)***
• § Idiopathic/isolated
• § Goodpasture: HLAà AB against noncollagenous domain of α3 chain of type IV collagen

IC-mediated (25%)

• § Idiopathic
• § Postinfectious
• § IgA/HSP
• § SLE

Pauci-immune (50%): lack*** of anti-GBM and IC but most have ANCA (anti-neutrophil cytoplasmic)

• § Isolated/idiopathic (most common)*
• § Wegnerà c-ANCA?
• § Microscopic polyarteritis nodosaà p-ANCA?

EM findings for all*

• § GBM rupture in many
• § Subepithelial deposits in some

 

How to workup?

• § Anti-GBM, ANA, ANCA

 

What’s ANCA?

• § Anti-neutorophil cytoplasmic Ab’s that have specificity for proteases located in granules of neutrophils and monocytes
• §

 

 

 

 

 

 

 

 

Goodpasture’s syndrome

Mechanism*

• § AB against NC1 domain of α₃ chain of collagen IV

Diagnosis

• § Proliferation, crescents

IF pattern*

• § Linear IgG and C3; fibrin in crescents

EM pattern?

• § No deposits on IF but GBM disruption, fibrin deposits in crescents

Treatment for Goodpasture

• § Intensive plasmapheresis, CTSD, cytotoxic agents

 

IC-mediated RPGN

Mechanism

• § IC formation following AB against GBM

Diagnosis

• § Same LM as Goodpasture, focal necrosis

IF?

• § Granular (lumpy bumpy) IgA or IgM or IgG

EM?

• § Variable deposit

 

ANCA-associated RPGN

Mechanism

• § ?

Diagnosis

• § Same LM as other two types
• § No deposits on IF or EM

 

Which vasculitis is c-ANCA vs p-ANCA?

• § Cytoplasmic: Wegener
• § Perinuclear: microscopic polyangiitis, Churg-Strauss
• § ANCA-related GN: no WG, no MP

 

 

IgA GN

What’s so special about its incidence?

• § No1 nephritic in world

Micro***

• § Normal on light microscope (or slight mesangial proliferation)
• § Mesangial proliferation with IgA deposit on IF
• § Mesangial and paramesangial deposits on EM

 

Mechanism

• § Genetic or acquired defect in immune regulation + inhaled antigen exposureà increased mucosal IgA production + decreased liver clearance of IgAà IgA deposit in mesangium

Secondary causes*

• § Liver (impaired IgA clearance) and intestinal (celiac disease) diseases

SSx*

• § Microscopic or macroscopic hematuria for several days, then recurs

Prognosis***

• § Up to 50% develop CRF over 20yrs. Older age onset, heavy proteinuria, HTN, crescents and vascular sclerosisà poor prognosis

EM***

• § Mesangial and paramesangila dense deopsits

DDx***

• § ???

 

 

 

 

Alport’s syndrome

Genetics*

• Ø X-linked, AD and ARà mutated α₃-chain of collagen IVà decreased α3 chain production

Demo

• § Males more severe
• § Present with micro/macro hematuria+family history of renal failure

SSx* (“I hear kidney”=eye, ear, kidney)

• § Eye disorders: cataracts, corneal dystrophy, lens dislocation
• § Nerve deafness
• § Nephritis

Micro

• § -Mild mesangial matrix proliferation + foamy epithelial cells in glomerulus or tubules

EM

• § -Irregular thickening and thinning of GBM; lamina densa split by interwoven lamellae (basket-weave appearance)

Prognosis*

• § -Males more severeà progresses to CRF

 

IF

• § -No change

How to diagnose?

• § -Skin biopsy

 

THIN BM DISEASE

Path

• § -ADà collagen IV mutation (α_{3 or 4} chain)à asymptomatic microscopic hematuria

Prognosis

• § -Excellent

Micro

• § -Diffuse thinning of GBM

BM thickness on EM?*

-200nm uniform (vs 400nm normal)

 

NEPHROTIC SYNDROME

Definition

• § Proteinuria: >3.5 g/24 hrs
• § Hypoalbuminemia: albumin <3 g/dL
• § Edema
• § Hyperlipidemia
• § Lipiduria: oval fat bodies

Differences in protein weights?

• § Selective (LMW proteins such as albumin)à non-selective (LMW+HMW proteins)

Main complications/risks?*

• § Prone to infections (Staph and pneumococcus)
• § Thromboembolism (renal vein thrombosis)

Incidence*

• § No1 cause of nephrotic syndrome in adults

Mechanism

• § Increased permeabilityà protein loss from serumà edema, hydrosodic retentionà lipid reabsorption and synthesisà hyperlipidemia, lipiduria

Pathogenesis of Nephrotic syndrome

Minimal change disease

Membranous glomerulonephropathy

FSGS

Membranoproliferative GN

Other proliferative GN: focal, pure mesangial, IgA

DM

Amyloidosis

SLE

Drugs: NSAIDs, penicillamine, heroin, gold

Infection: malaria, syphilis, HBV, HCV, HIV

Malignancy: carcinoma, lymphoma

Others: allergy, hereditary

 

 

Minimal Change Disease

EM and IF?

• § Diffuse effacement of processes of visceral epithelial cells
• § No deposits

Genetics*

• § Nephrin?

Mechanism

• § AI defects of T cellsà circulating cytokines affecting epithelial cellsà increased permeability

Treatment*

• § Dramatic response to CTSD

 

 

 

 

 

Membranous glomerulonephropathy

Mechanism*

• § Unknwon in situ Ag (megalin)à ICà capillary wall thickening

Micro***

• § Uniform and diffuse glomerular wall thickening (IC deposition)

EM***

• § Subepithelial deposit (spikes)à eventually intramembranous

IF***

• § Diffuse granular IgG and C3 along GBM

Etio*

• § Idiopathic
• § Malignancies (lung, colon, melanoma)
• § SLE
• § Drugs (penicillamine, captopril)
• § Infections (hepatitis, syphilis, schistosomiasis, malaria)
• § AI disorders such as thyroiditis

What % become CRF?

• § 40% CRF

 

 

Focal segmental glomerulosclerosis

Focal and segmental?*

• § Focal=some glomeruli; segmental=partial glomerulus

Etio?

• § Idiopathic
• § Another primary glomerulopathy like IgA
• § “Renal ablation FSGS” due to loss of renal mass such as from chronic reflux, analgesic, renal agenesis
• § Heroin, HIV, heavy weight,
• § Infections
• § Inherited such as proteins in podocytes (podocin, a-actinin) or in slit diaphragm between podocytes (nephrin)

Genetics*

• § Nephrin
• § Visceral epithelial damage is hallmark of FSGS

EM***

• § Podocyte injuryà visceral epithelial damage (effacement or detachment)

IF***

• § Focal IgM and C3 in glomeruli, tubules and BV walls

SSx

• § Nonselective proteinuria (vs selective in MCD), can have hematuria and HTN

Micro***

• § Normal glomeruli but lipid in tubules
• § Negative IF (some say focal IgM and C3 deposits)
• § Loss of foot processes on EM

When is it bad? Any recurrence?

• § Bad if idiopathic because poor response to CTSD
• § 25-50% recurrence after transplantation

1 variant. In who? EM finding?*

• § Collpasing
• § HIV
• § Tubuloreticular inclusions in endothelial cells

 

 

 

 

CHRONIC GLOMERULONEPHRITIS

• § Prognostic of main primary GN[4]
• § Postinfectious
• § 1-2% to CRF
• § RPGN
• § 90%
• § MGN
• § Up to 40%
• § FSGS
• § 50-80%
• § MPGN
• § 50%
• § IgA
• § 30-50%

Micro*

• § -Hyalinized glomeruli
• § -Tubular atrophy, interstitial fibrosis
• § -+/-arterosclerosis

What’s dialysis change?*

• § -Arterial intimal thickening
• § -Extensive deposition of calcium oxalate in tubules and interstitium
• § -Acquired cystic changes
• § IF
• § -Granular or no deposits on IF

 

 

SYSTEMIC GP (“BASH’D”)*

• § Bacterial endocarditis
• § Amyloidosis
• § Systemic lupus erythematosis

• § HSP (Henoch-Scholein purpura)
• § Diabetes mellitus
• § Others
• § Goodpasture, PAN, Wegener: same histology (foci of necrosis, crescents)
• § Allergic vasculitis
• § Cryoglobulinemia: HCV (no1 cause)à deposits of cryoglobulin (composed of IgG-IgM complexes) cause cutaneous vasculitis, synovitis, GN (MPGN mostly),
• § Plasma cell dyscrasias: amyloidosis (fibrillary light chain deposits), light chain disease (nonfibrillary light chain deposits)

 

BACTERIAL ENDOCARDITIS

• § Mechanism
• § -IC nephritis initiated by antigen-antibody complexes
• § SSx
• § -Mixture of hematuria and proteinuria
• § Micro if mild vs severe
• § -Mildà focal and segmental necrotizing GN
• § -Severeà diffuse proliferative GN (resembling postinfectious GN)+/-crescents
• § Classification of systemic vs localized forms.

AMYLOIDOSIS

 

• § Name FIVE types

 

Which types most commonly in kidneys?

• § AL and AA

Where do you find amyloid in kidney?

• § -Mesangium and BV wallsà leads to luminal obstructionà glomerular destructionà nephrotic

Characteristic about kidney size?

• § -Normal or increased!

What diseases are they associated with?

What are the precursor proteins?

 

Structure

• § beta pleated sheet comprised of numerous amyloid protein chains + serum amyloid P component, g-pr, proteoglycans, sulfated GAGs; resistant to proteases

Path

• § Kidney:
• § amyloid deposits in mesangium and BMà eventualy obsolescent
• § amyloid in arteries and arterioles and interstium too
• § proteinuria and nephrotic syndrome
• § Spleen: splenomegaly with 1) follicular deposits “sago spleen” (WHITE PULP)or map-like deposition from involvement of splenic sinuses “lardaceous spleen”
• § Liver: deposition in space of Disse causing pressure atrophy and replacement of parenchyma
• § Heart: b/w muscle fibres (senile)à ECG abN, CHF
• § Tongue: “tumor forming amyloid”à speech diff.

Diagnosis

• § Biopsy of gingival, rectum, abdominal fat pad. Biopsy of kidney if possible involvement.

Special studies

• § Congo red
• § IHC

 

SLE

Define. Which organs?

• § Chronic AI disease with variable course affecting skin, joints, kidneys and serosa

Mechanisms (2)

• § -Genetic self-tolerance failureà environmental triggers (unknown)à AB against DNAà type III HSà in glomeruli, tubules, capillary BM
• § -Antiphospholipid ABà hypercoagulabilityà thrombus in glomeruli

4 types of antibodies

• § Anti-nuclear
• § Anti-cytoplasm
• § Anti-RBC, PLT, lymphocytes
• § Anti-phospholipids: in 50% of patients, false syphilis test+, paradoxically makes patients hypercoagulable despite prolonged clotting time in vitroà venous and arterial thromboses, recurrent miscarriages, cerebral and ocular ischemia

What different types of ANA?

• § Anti-DNAà extremely sensitive but non-specific
• § Anti-histones
• § Anti-non-histone proteins
• § Anti-nucleolar antigens

Different ANA with different AI diseases

• § Anti-dsDNA, Anti-Smà SLE
• § Anti-histonesà drug-induced SLE
• § Anti-DNA topoisomerase I (aka Scl-70)à systemic scleroderma
• § Anti-centromere: limited scleroderma (CREST)
• § Anti-SS-A(Ro), anti-SS-B(La)à Sjogren
• § Anti-Jo1à inflammatory myopathies

Which ANA are diagnostic? Any significance?

• § Anti-dsDNAà correlates with activity
• § Anti-Sm (Smith)à inversely proportional to renal involvement risk

Usual onset age and race

• § -20-30 African women (more severe in blacks)

Possible presentations (5)

• § -Hematuria (asymptomatic, either micro or macro)
• § -Acute nephritis (nephritic)
• § -Nephrotic
• § -CRF
• § -HTN

4 different types of indirect IF patterns

• § Homogeneous
• § Rim
• § Speckled
• § Nucleoli

False ANA elevation

• § -AI diseases
• § -Normal (5-15%, increases with age)

Clinical criteria (MD BRING SOAP!)

• § Malar rash
• § Discoid rash
• § Blood (anemia, thrombocytopenia, leukopenia)
• § Renal: proteinuria, casts
• § Immunologic: anti-dsDNA, anti-Sm, anti-phospholipid
• § Neurologic (seizures and psychosis)
• § Genetic predisposition (↑risk w/family members)
• § Serositis
• § Oral ulcers (painless)
• § Arthritis
• § Photosensitivity

How to differentiate systemic vs localized?

• § -If ≥4/11 clinical criteria

WHO CLASSIFICATION***

• § I: Normal LM, IF, EM
• § II: Mesangial lupus (earliest change)
• § -Mild mesangial proliferationà mild hematuria or transient proteinuria
• § -Mesangial deposit of Ig and C always present on IF
• § -Glomeruli uninvolved
• § III. Focal proliferative GN
• § -<50% glomeruli (1-2 tufts) with endothelial, mesangial proliferation, +/-fibrinoid necrosis, +/-fibrin thrombi
• § -“Wire loop[5]” lesions
• § IV: Diffuse proliferative GN
• § -“Wire loop lesions”
• § -Most glomeruli.
• § -Entire glomerulus endothelial, mesangial proliferation, +/-fibrinoid necrosis, +/-fibrin thrombi
• § -Crescents
• § V. Membranous GN
• § -Widespread thickening of capillary walls “wire loops”
• § -Membranousà ie/ thickening of bv walls!

What’s hematoxylin body?

• § -Nuclei of injurged cells, in reaction with ANA, lose chromatin and become homogeneously eosinophilic
• § -Often engulfed by macrophages

Correlate pathology with clinical symptoms

Normal	None
Mesangial lupus	Mild hematuria or transient proteinuria
Focal proliferative GN	Hematuria, proteinuria
Diffuse proliferative GN	Gross hematuria, nephrotic, nephritic, HTN, renal failureà worst of all
Membranous GN	Nephrotic always

EM

• § -III and IV: subendothelialà wire loop when extensive deposits
• § -V: subepithelial deposits

IF staining

• § -Full house “IgG, M, A” and complements
• § -Variable deposition patterns including mesangium alone, along GBM or diffuse
• § -IC also deposits in tubular BM

Other organs

Skin: vacuolar interface dermatitis, vasculitis and fibrinoid necrosis, granular Ig and C deposit at BM

Joints: non-erosive synovitis

Heart

• § -Pericarditis: acute/subacute/chronic fibrinous exudate.
• § -Myocarditis. rare.
• § -Valve: Libman Sacks non-bacterial verrucous endocarditis

Splenomegaly with plasma cells

Lungs: pleuritis and pleural effusions

 

HENOCH-SCHOLEIN PURPURA

4 organs involved

• § Skin: purpura
• § Abdominal pain, N/V, bleeding
• § Arthralgia (non-migratory)
• § Kidney: either hematuria or proteinuria or mixed (remember IgA nephropathy sits in between). Some develop RPGN

Weird association

• § Atopia in 1/3, onset often after URTI

What’s so special about adult patients?

• § More severe

What do you see in kidney and skin? Can vasculitis occur elsewhere?

• § Kidney: variable severity (focal mesangial proliferationà diffuse mesangial proliferationà crescentic GN)
• § Skin: leukocytoclastic vasculitis
• § Vasculitis can occur in GI tract but rare in kidneys

IF*

• § IgA in mesangium (IgG and C3 to lesser extent)

How does it evolve?

• § Excellent prognosis except a few towards CRF (especially if diffuse, crescents or nephritic)

IgA nephropathy associated with

• § Celiac disease
• § Liver disease

 

DIABETES MELLITUS

Classes (3)

• § -Type I: polymorphism in genes encoding renin-angiotensin system
• § -Type II
• § -MODY (maturity-onset diabetes of the young)

3 glomerular syndromes

• § -Non-nephrotic proteinuria (starts with microalbuminuria)
• § -Nephrotic
• § -CRF

DM scleroses arterioles to cause what? (2)

• § -Pyelonephritis: acute or chronic inflammation spreads from interstitium to tubules (glomeruli spared)
• § -Papillary necrosis: tips and distal 2/3rds of papillae are necrotic

Gross***

• § -Nephrosclerosis (pitted surface)
• § -Small kidney in end stage

2 main mechanisms*

• § -Nonenzymatic glycosylationà advanced glycosylation end productsà thick GBM, increased mesangial matrix
• § -Increased GFR (associated with microalbuminuria)à glomerular hypertrophyà GS

Correlate urine abnormalities with different renal lesions***

Glomerular hypertrophy Thick GBM (earliest change) Thick tubular BM	No proteinuria
Diffuse mesangial sclerosis Nodular GS[6] Hyaline arteriolosclerosis	Microalbuminuria
	Nephrotic
Diffuse GS Tubular atrophy Interstitila fibrosis	CRF

Define microalbuminuria. What are 2 elements predictive of ominent diabetic nephropathy? What about death?*

• § -Albumin excretion of 30-300mg/day
• § -Increased GFR and microalbuminuria starts 10-20 years after diagnosis and predict CRF and death in 5 years

Findings in pancreas

• § -↓number and size islets
• § -Infiltration of the islets with lymphocytes

3 major findings in kidneys. Which ones affect all glomeruli?

• § Diffuse[7] BM thickening: GBM, tubular BMà starts 2 years after onset in DM1, occurs before proteinuria
• § Diffuse[8] mesangial sclerosis: increased mesangial matrix (not cell proliferation), PAS+à mesangial expansion correlates with worsening proteinuria
• § Nodular GS: same process as mesangial sclerosis
• § -Kimmelsteil Wilson nodules (PAS+)à obliterate glomerular capillary luminaà fibrin caps, capsular drops
• § -Mesangiolysis (loosening of glomerular capillaries from mesangium)à capillary microaneurysm

What accompanies nodular GS?

• § -Fibrin caps: hyaline material in capillary loops
• § -Capsular drops: if adherent to Bowman’s capsules

Vascular and tubulointerstitial changes*

• § -Arterioles: hyaline arterosclerosis, arteriolosclerosis (afferent and efferent arterioles)
• § -Tubulointerstitium: tubular atrophy and interstitial fibrosis
• § -Papillary necrosis*

Sequence of events

• § -Diffuse BM thickening (no proteinuria)à diffuse mesangial sclerosis, nodular GSà tubular atrophy, interstitial fibrosis, vascular changes

What can reverse diabetic nephropathy?

• § -Pancreatic transplant
• § -ACEI, ARB

IF***

• § -???

EM***

• § -BM thickening (even when invisible to light microscopy)
• § -Massive increase in mesangial matrix encroaching on glomerular capillary lumina

Is renal transplant curative?

• § -No, diabetic nephropathy recurs in transplant

 

FIBRILLARY AND IMMUNOTACTOID GN

• § -Not read

 

 

NAME 5 CAUSES OF ACUTE RENAL FAILURE

- organize into compartments -

• § Glomeruli: RPGN
• § Tublues: ATN
• § Interstitium: Pyelonephritis
• § Vascular: DIC, intrarenal disorders (PAN, HUS, malignant HTN)
• § Post-renal: Urinary tract obstruction

TUBULOINTERSTITIUM

2 main tubulointerstitial diseases*

• § ATN
• § Tubulointerstitial nephritis (inflammation of tubules and interstitium)

 

ACUTE TUBULAR NECROSIS

• § Acute decreased of renal function and urine output (<400cc/24h) due to destruction of tubular epithelium
• § Accounts for 50% of ARF

Name 5 causes***

• § Ischemic: PAN, malignant HTN, HUS, hypovolemia
• § Toxic: drugs, contrast, myoglobin, hemoglobin, radiation
• § Acute tubulointerstitial nephritis: mainly drug allergy
• § DIC
• § Urinary obstruction

Gross: Erythema at corticomedullary junction

Compare ischemic vs toxic

Ischemic	Toxic
	Causes Carbon tetrachloride, Ethylene glycol, Lead, Mercury, rhabdomyolysis, massive hemoglobinuria
Name 2 main components in pathogenesis* -Ischemiaà endothelial dysfunctionà increased endothelin, decreased NO and PGI2, activation of renin-angiotensin-aldosteroneà vasoconstriction -Ischemiaà tubule cell injuryà apoptotic epithelial cells and proteinsà cast formation, tubular back leak à tubular obstruction and decreased urine flowà oliguria
Acute -Tubular necrosis and apoptosis -Distal tubules and collecting ducts full of pigmented granular casts and eosinophilic Tamm-Horsfall protein casts Recovery -Regeneration: dark nuclei, mitoses, flat tubule cells
-Patchy distribution -Proximal tubule thick segment and ascending Henle -Less severe tubular injury: loss of brush borders, swelling, vacuolation, sloughing of non-necrotic tubule cells, no frank necrosis -Interstitial edema	-Mainly proximal tubules -More severe tubule injury but findings highly dependent on agents
What are 3 phases*? What’s special about non-oliguric ATN?* Initiation: first 36h, only slight urine decline with raising BUN Maintenance: severe oliguria[9] (<400cc/day), severe RF (edema, hyperK, metabolic acidosis). Recovery: polyuria (up to 3L/d), hypoK*
Worse prognosis	Better prognosis

TUBULOINTERSTITIAL NEPHRITIS

Name 5 tubulointerstitial nephritis*

• § -Toxins and drugs (analgesic abuse, allergic)
• § -Urate nephropathy: tumor lysis syndrome causes more ARF whereas gout more CRF. Lead exposure can also cause urate nephropathy
• § -HyperCa: nephrolithiasis (in urinary space) and nephrocalcinosis (in renal parenchyma)
• § -Infections (pyelonephritis)
• § -Multiple myeloma (cast nephropathyà peritubular inflammation) (nephrocalcinosis)
• § -Renal cysts (medullary cystic diseases)
• § -Chronic urinary obstruction

Acute and chronic tubulointerstitial nephritis

Acute	Chronic
Rapid clinical onset	Impaired urine concentrationà polyuria, nocturia, salt wasting, metabolic acidosis (due to impaired acid excretion -No glomerular symptoms (nephritis, nephrotic, GFR decrease)[10]
Micro -Acute inflammation (PMN, eosinophilis) -Interstital edema -Tubular necrosis	Micro[11]* -Mononuclear inflammation -Interstital fibrosis -Tubular atrophy

Differentiate glomerular vs tubular problems

Glomerular	Tubular
Nephritic, nephrotic	Inability to concentrate urineà polyuria, nocturia, salt wasting, metabolic acidosis

PYELONEPHRITIS

Define

• § -Infection of kidneys

SSx

• § -Flank pain and fever

Germs

• § -KEEPSà Klebsiella, E coli, Enterobacter, Proteus, Streptococcus faecalis, Staph
• § -Fungi
• § -Viruses: polyoma virus, CMV, adenovirus

Pathways

• § -Ascending infection from bladder
• § -Sometimes consequence of colonization of distal urethra and introitus
• § -Hematogenous from sepsis or endocarditis

Mechanism of chronic pyelonephritis*

• § -Cystitisà defective vesicoureteral junction (or valve)*à VUR due to incompetent vesicoureteral orificeà intrarenal reflux through open papillae
• § -Usually no pyelonephritis if no reflux unless hematogenous

RF*

• § -Age
• § -Women
• § -Catheter
• § -Urinary obstruction
• § -Pregnancy
• § -DM
• § -Incompetent vesicourethral valves (reflux)
• § -Immunocompromised

 

 

 

ACUTE PYELONEPHRITIS

Gross

• § -Focal abscesses or wedge infarct.

Micro: describe progression of inflammation*

• § -Patchy PMN in Interstitiumà PMN inside tubules, tubular necrosis, intratubular neutrophilic casts*à glomeruli usually resistant

Does pyuria indicate necessarily pyelonephritis?

• § -No, can be lower UTI. Pus casts more specifically indicates pyelonephritis

Outcome of most pyelonephritis

• § -Benign unless complicated

Etio*

• § -Directly from UTI (KEEPS=Klebsiella, E coli, Enterobacter, Proteus, Strep fecalis)

Name 3 complications*

• § Papillary necrosis: obstruction or DMà coagulative necrosis of tips of papillae (all at same stage!), usually bilateral
• § Pyonephrosis: partial or complete obstructionà pus in pelvis, calyx and ureter.
• § Perinephric abscess

Ischemic scar vs pyelonephritic scar*

• § -Pyelonephritic scar always associated with inflammation, fibrosis, severe deformation of pelvocalyceal system

 

 

 

 

HEALED ACUTE PYELONEPHRITIS

Gross

• § -Cortical depressions (scars), deformed calyces and pelvis

Micro

• § -Scar (interstitial fibrosis, tubule atrophy)+/-mononuclear infiltrate secondary to ongoing reflux.

 

CHRONIC PYELONEPHRITIS CPN

Define and how does chronic pyelonephritis differs from tubulointerstitial nephritis?*

• § -Chronic tubulointerstitial inflammation and renal scarring associated with pathologic involvement of calyces and pelvis (which is absent in tubulointerstitial nephritis)

Etio*

• § -UTI and also reflux

Name and compare 3 variants

Obstructive	Reflux (non-obstructive) (no1)	Xanthogranulomatous*
Enteric germs	Enteric germs	Proteus+obstruction
	Childhood onset,  Sometimes present with HTN	Clinically and radiographically mimic RCC
-Hallmark=irregular corticomedullary (involves both layers) scar overlying blunted calyx -Upper and lower poles mostly -Dilated ureters and thickened
-Tubulointerstitial chronic inflammation and fibrosis in cortex and medulla -Tubulointerstitial PMN only if ongoing infection -Tubular atrophy with focal tubule dilationà thyroidization with colloid casts -Normal glomeruli except periglomerular fibrosis. FSGS* (may be adaptive mechanism) when severe		-Mixture of foamy macrophages, plasma cells, lymphocytes, PMN, giants

RF for UTI

• § -Catheter
• § -VUR
• § -Pregnancy
• § -DM
• § -Immunosuppression
• § -Obstruction (congenital, BPH, calculi, tumors)

 

TUBULOINTERSTITIAL NEPHRITIS INDUCED BY TOXINS AND DRUGS

When does acute variant start? Acute clinical presentation?*

• § -2 days up to 40 days after exposure
• § -Fever*, eosinophilia*, rash*, acutely raising creatinine with oliguria*, leukocyturia (mostly eosinophils)

Can it be insidious?

• § -Yes, elvoves to CRF over years

Explain mechanism (hint: hapten theory)*

• § -Drugs secreted by tubulesà covalent bond to cytoplasmic or ECM components (acting as immunizing haptens)à immunogenicà type 1 (IgE, late phase) and type 4 HS (T-cell, giant cells)à attack against tubule cells and BM

Micro for acute

• § -Edema, patchy tubular necrosis and regeneration, tubulointerstitial mononuclear infiltrates (including eosinophils and plasma cells)
• § -Sometimes granulomas

 

ANALGESIC NEPHROPATHY

• § What meds? Characterized by what 2 features?*
• § -Aspirin and phenacetin at high doses together
• § -Papillary necrosis* leading to chronic tubulointerstitial nephritis*

Gross

• § -Cortical atrophy overlying necrotic papillae

Mechanism*

• § -Phenacetinà metabolized to acetaminophenà covalent bonds to tubule cells causing oxidative damage
• § -Aspirinà inhibits vasodilating prostaglandinà ischemia of papillae

Micro

• § -Early*: papillary necrosis of various stages of necrosis (unlike in DM) leading to secondary tubulointerstitial nephritis
• § -Late: ghost of tubules, dystrophic calcification and sloughing, interstitial fibrosis and tubule atrophy.

Name 2 major complications (hint: tumor)?*

• § -TCC of renal pelvis
• § -CRF

 

5 CAUSES OF PAPILLARY NECROSIS

• § -DM
• § -Analgesic abuse
• § -Obstruction (urinary tract)
• § -Hypotension
• § -Sickle

 

NSAID NEPHROPATHYà very common!

• § Mechanisms and micro***
• § -Inhibition of prostaglandin (anti-CO2 not protective!)
• § -Acute hypersensitivity interstitial nephritisà allergic
• § -Minimal change disease in combination with acute interstitial nephritisà must be in combo
• § -Membranous GN
• § -Papillary necrosis

 

URATE NEPHROPATHY

3 types of nephropathy associated with urate*

• § -Acute urate nephropathy: mostly in tumor lysis syndrome
• § -Chronic urate nephropathy: scarring, increased lead intake
• § -Nephrolithiasis

Micro of chronic uropathy*

• § -Tophus surrounded by giants cells within tubules and interstitium

 

HYPERCALCEMIA AND NEPHROCALCINOSIS

• § Name 5 causes of nephrocalcinosis (MMM…HD)
• § -Multiple myeloma
• § -Metastatic bone disease
• § -Milk-alkali syndrome
• § -HyperPTH
• § -D intoxication (vitamin D)
• § What’s earliest renal dysfunction?*
• § -Intracellular levels in tubular epitheliumà inability to concentrate urineà progressive CRF

 

MULTIPLE MYELOMA

Define

• § -Plasma cell neoplasm characterized by disease of bones and LN
• § SSx (hint: bones, kidney, LN)
• § -Older patients, bone pain & #
• § -Widespread skeletal lytic lesions
• § -HSM
• § -HyperCa
• § -Primary amyloidosis (ALà mostly lambda vs kappa in light chain deposition disease) and renal insufficiency due to toxicity of Bence Jones proteins
• § % of patients evolving to CRF? Why is bad?
• § -50%!
• § -Renal involvement correlates with worse prognosis

Characteristic bone lesion

• § -Currant jelly lytic lesions in diaphysis of skull and long bones

BM

• § -30% plasma cells

Which kidney compartment most commonly affected?

• § -Tubulointerstitial (hyperCa, hyperuricemia, obstruction, infection)

Micro

• § -Tubulointerstitial
• § -Plasma cell infiltrate with prominent nucleoli, perinuclear hof (Golgi)
• § -Russell bodies (cytoplasmic rods), Dutcher bodies (intranuclear rods)à pitcher

7 factors contributing to tubulointerstitial disease in MM? (Ben Casts Amy in Pus at HyperLight speed)***

• § -Bence Jones: direct toxicity
• § -Light chain deposition disease*: deposition of nonfibrillary light chain in glomeruli* (nodular glomerulopathy) or tubular BM* (tubulointerstitial nephritis)
• § -Cast nephropathy: BJ proteins can also mix with necrotic tubular epithelium and Tom Horsfallà casts ( “fractured”, surrounded by macrophages)à peritubular chronic inflammation and fibrosis (casts sometimes erode into interstitium causing granulomas)
• § -Amyloidosis*: deposition of fibrillary lambda light chain
• § -Pyelonephritis: casts or stonesà obstructionà pyelonephritis
• § -Hypercalcemia*
• § -Hyperuricemia*à nephrocalcinosis
• § -Vascular disease: what and how exactly???

Summarize micro of myeloma kidney

• § -BJ casts+/-giant cells within tubules
• § -Nonspecific peritubular chronic inflammation
• § -Amyloidosis
• § -Nonfibrillary light chainsà nodular GN, characteristic blue/pink amorphous casts with fractured appearance, surrounded by macrophagesà sometimes erode into interstitium causing inflammation
• § -Nephrocalcinosis

Special studies

• § -Monoclonal IgG spike in serum electrophoresis)
• § -Peripheral smearà rouleaux formation

IHC

• § -CD138+, light chain restriction

DDx

• § -Chronic osteomyelitis (will see other inflammation cells+­ vascularity)

What’s poeMs and where does it occur?

• Ø Osteosclerotic myelomaà polyneuropathy, organomegaly, endocrinopathy, monoclonal IgM gammopathy and skin lesions)

What are hints for light chain deposition disease and amyloidosis in multiple myeloma?

• § -When diverse proteins (including albumin) else than Bence Jones leak into urine (so no longer selective).

 

LIGHT CHAIN DEPOSITION DISEASE***

Which light chain?

• § -Kappa (vs lambda in amyloid!)

Always associated with myeloma?

• § -No

Nature?

• § -Nonfibrillary light chains

Where does it deposit in kidney and micro?*

• § -Glomeruli (causing nodular glomerular lesios)
• § -Tubular BM (causing tubulointerstitial nephritis)

 

HOW CAN TUMORS CAUSE RENAL FAILURE?

 

BLOOD VESSELS

BENIGN NEPHROSCLEROSIS

Mechanism and gross? Are kidney size often small?

• § -Narrowing of small arteries and arteriolesà diffuse ischemic atrophy of nephronsà small kidneys with granular surface due to scarring and contraction of individual glomeruli
• § -No, usually normal kidney size or only slightly smaller

Associated with?

• § -Age, HTN, DM

Always in hypertensive? Often causes renal failure? Who are at risk for rapid RF and how?

• § -Yes, can be in normotensive
• § -No! (remember it’s benign and only causes focal ischemia) but can cause mild proteinuria.
• § -Blacks, DM, severe HTN are at risk of rapid RF via malignant HTN (malignant nephrosclerosis)

Define and micro*. Origin of hyaline material?

• § -Diffuse glomerulosclerosis*
• § -Arterioles*: narrowing due to wall thickening and hyalinization* (plasma protein extravasation through injured endothelium and increased BM matrix)
• § -Small arteries (interlobar and arcuate): fibroelastic hyperplasia (onion-skinning) with thickening of both media and intima (from proliferating MFB)

Chronic complications

• § -Tubular atrophy, interstitial fibrosis
• § -Glomerular and periglomerular fibrosis

 

MALIGNANT HTN & ACCELERATED NS

Who are prone to develop this? Can this occur in normotensive (and which demographic group)?

• § -Chronic HTN, scleroderma, CRF (particularly GN or reflux uropathy)
• § -Sometimes in normotensive (usually young black men)

How often?

• § -1-5% of chronic HTN!

What are SSx and which end organs become damaged? What’s hypertensive crisis?

• § -DBP>130, edema, hematuria, marked proteinuria, headache, papilledema, scotomes, encephalopathy (due to increased ICP), cardiovascular abnormalities, renal failure
• § -Episodes of loss of consciousness and convulsions

Lab (think about what’s activated) in serum and in urine?*

• § -Increased serum renin*, angiotensine and aldosterone
• § -Proteinuria and hematuria, renal failure

Gross

• § -Petechial hemorrhages from vascular ruptureà “flea bitten” appearance

Mechanism for escalating BP. Which organ plays a main role?

• § -Arteritis, severe HTN, intravascular thrombosisà fibrinoid necrosis of BV wallsà renal ischemiaà activation of renin-angiotensin-aldosteroneà vicious cycle with escalating BP

2 major histologic findings in BV and changes in glomeruli?*

• § -Arterioles: fibrinoid necrosis[12] (fibrin demonstrable in wall)
• § -Arteries and arterioles: fibroelastic HP (onion-skinning, aka hyperplastic arteriolitis)
• § -Glomeruli: necrotizing GN, microangiopathic thrombopathy

 

RENAL ARTERY STENOSIS

When HTN occurs?*

• § -Unilateral stenosis leads to HTN whereas bilateral disease occur in normotensive

Causes and no1? Micro of no2 cause? Name 3 variants* of no2 cause.

• § Atheromatous plaque at origin of renal artery (no1): more in men, elderly, DM
• § Fibromuscular dysplasia: heterogeneous group, women at 20-30, nonarteriosclerotic intimal, medial (most common) or adventitial thickening are 3 variants. Very focal narrowing.

Micro of diffusely ischemic kidney. Any change on ipsilateral arterioles?

• § -Tubule atrophy, interstitial fibrosis, focal interstitial chronic inflammation
• § -Small kidney
• § -Crowded glomeruli (because last to undergo atrophy)
• § -No hypertensive change on ipsilateral arterioles (because protected) but severe arteriolosclerosis of controlateral arterioles
• § What’s so special about lab?*
• § -Most renovascular diseases have increased renin in serum or renal vein

 

HEMOLYTIC-UREMIC SYNDROME/THROMBOTIC THROMBOCYTOPENIC PURPURA (HUS/TTP)

Common pathologic finding*

• § -PLT-fibrin thrombus in capillaries and arterioles throughout body

4 common clinical SSx? (hint: HUS and TTP stand for what?)*

• § -Thrombocytopenia (due to thrombus formation)
• § -Microangiopathic hemolysis
• § -+/-Renal failure (due to thrombus in renal arterioles and glomeruli)
• § -Fever
• § -Hyperbilirubinemia
• § -Seizures

4 classes of thrombotic microangiopathies?* Name classic cause* of childhood and adult HUS

• § -Classic (childhood) HUS: bloody diarrhea due to verocytotoxin
• § -Adult HUS: infection, antiphospholipid AB, OCP, pregnancy, drugs, chemoradiation, scleroderma
• § -Familial HUS
• § -Idiopathic TTP

Do HUS and TTP have same pathophysiology?

• § -No

2 main components in mechanism which lead to similar ending*

• § -Endothelial injury (from verocytotoxin, drugs, antiphospholipid) + PLT aggregation (from lack of cleavage of vWF due to ADAMTS-13 loss)à vascular constriction and obstructionà distal ischemia

What do you see in micro in common?***

• § -PLT-fibrin thrombosis (key finding) throughout body including interlobular arteries, afferent arterioles, glomeruli in kidneys
• § -Thickening, fibrinoid necrosis, onion-skinning of capillaries and arterioles

What’s different from malignant HTN?

• § -Similar histology to malignant HTN but changes in HUS/TTP can precede onset of HTN. Also no thrombus in this latter

EM***

• § -???

Classic HUS

Cause

• § -Enterotoxic E.coli O157:H7à verocytotoxin

Classic presentation*

• § -Sudden onset of acute gastroenteritis or influenza-like symptoms, followed by GI hemorrhage, renal failure (oligouria, hematuria), HTN, microangiopathic hemolysis, +/-neurologic symptoms

Gross

• § -Patchy or diffuse cortical infarct

Micro

• § -PLT-fibrin thrombus in lumens but also in mesangium
• § -Mesangiolysis
• § -Fibrinoid necrosis, thickened arterioles with thrombus

Adult HUS

Name 4 common causes (hint: I AM PC)*

• § -Infection (E. coli, typhoid fever, viral infections, shigellosis)
• § -Antiphospholipid syndrome (primary or secondary to SLE which is aka lupus anticoagulant)
• § -Malignant HTN or other vascular renal diseases (such as scleroderma)
• § -Postpartum renal failure (on day 1 to several months, characterized by microangiopathic hemolysis, oliguria, anuria, HTN)
• § -Chemoradiation

Idiopathic TTP

Genetics for idiopathic TTP

• § -Acquired or genetic defect of ADAMTS-13 (protease that normally cleaves large vWF multimers)à uncleaved vWF enhances PLT aggregation

What’s dominant clinical SSx compared to HUS?

• § -CNS SSx dominates in adult TTP vs kidney in HUS

Treatment

• § -Exchange transfusion
• § -CTSD

 

 

 

 

 

SICKLE CELL DISEASE NEPRHOPATHY

Most common SSx* (4)

• § Hematuria
• § Inability to concentrate urine*
• § Proteinuria
• § Papillary necrosis

 

RENAL INFARCT

Complications

• § Most are clinically silent
• § HTN only when large infarct in one kidney

Detailed gross description

• § White (anemic)à hemorrhagic foci within 24 hoursà depressed fibrous scar with time
• § Wedge with base toward cortex
• § Narrow rim of preserved subcortical tissue (due to collateral cortical circulation)

 

TRANSPLANT REJECTION

Who rejects who?

• § -Host rejects graft (so not as bad as GVHD)

 

HYPERACUTE

Time?

• § -Within min-hours, recognized by surgeon

Gross (3)***

• § -Cyanotic and flaccid (no regain of color and tissue turgor), no urine excretionà frank infarct of cortex

Mechanism

• § -Preformed antidonor AB in circulation of recipientà IC and C deposition on BV wallsà fibrin-PLT thrombi (therefore, Ag-AB reaction at vascular endothelium)

Micro***

• § -Rapid accumulation of PMN in arterioles, glomeruli, peritubular capillaries (so any small BV)à BV wall fibrinoid necrosis and thrombosis

 

 

 

 

 

 

 

 

 

 

 

 

ACUTE

Time?

• § -Days if untreated but up to months or years with immunosuppressionà just remember it’s between hyperacute and chronic (so days up to years)

Humoral	Cellular
What’s no1 target of first formed AB? -Graft BV (not else)!!!	Mechanism -Interstitial mononuclear cells (mainly T cells)
-High creatinine
Micro*** -Severe: necrotizing vasculitis (endothelial necrosis, PMN infiltration, IC and C and fibrin deposition, thrombosis) -Less severe: BV wall thickening (proliferating FB, SM and foamy macrophages)	Micro*** -Edema -Interstitial mononuclear cells infiltrating Tubulesà focal tubular necrosis 2. Endothelium: confined to endothelium vs more diffuse in acute humoral responseà mimics arteriosclerosis
	Responds to cyclosporine

 

 

 

 

 

 

 

CHRONICà more and more frequently seen

Time?

• § -Years

Gross (3)***

• § -Progressive increase in creatinine over 4-6months

Mechanism

• § -Characterized by end-stage changes à small kidney

Micro*** (hint: end-stage changes in all 4 compartments). What’s chronic transplant nephropathy?

• § -Graft arteriosclerosis leading to occlusion by musculofibrous tissue
• § -Tubular atrophy
• § -Interstitial fibrosis and inflammation (abundant plasma cells, eosinophils)
• § -+/-GBM duplication (“chronic transplant nephropathy”)

 

CYCLOSPORINE&TACROLIMUS NEPHROPATHY***

Micro (hint: go through all compartments)

Acute

• § -Vasoconstriction (not visible on microscopy)
• § -Toxic tubulopathy (vacuolation)
• § -Acute arteriolopathy (thrombus, endothelial necrosis, giant cells,…)

Chronic

• § -Vascular: hyaline arteriolopathy
• § -Tubulointerstitial: fibrosis, tubular atrophy
• § -Glomerulopathy: secondary FSGS

 

BANFF 97 ClASSIFICATION

• § Normal
• § Antibody-mediated…

 

POLYOMA VIRUS

How to diagnose polyoma virus? Where do you can it?

• § -Intranuclear inclusion in tubular epithelium
• § -IHC
• § -EM showes crystalline-like lattices

 

URINARY OBSTRUCTION (REFLUX NEPHROPATHY)***

• § -Congenital (valves, strictures, bladder neck obstruction, ureteropelvic junction narrowing, severe VUR)
• § -Calculi
• § -Prostate problems
• § -Tumors (retroperitoneal lymphoma)
• § -Inflammation (prostatitis, ureteritis, urethritis, urethral stricture, retroperitoneal fibrosis)
• § -Sloughed papillae or blood clots
• § -Normal pregnancy
• § -Functional (neurogenic bladder)

What’s no1 cause in males and in females?

• § Males: BPH
• § Females: cystocele of bladder

Define hydronephrosis*. Mechanisms (2)

• § Pelvocalyceal dilation in association with progressive
• § renal atrophy
• § Urine backflow and compression of vasculature

Sequence of changes in macro, micro and correlate with clinic. Does obstruction affects glomeruli?

Early	Late
Dilated pelvis and calyces	Blunted, obliterated pyramids Thin-walled cystic kidney
Tubular dilation only Maybe some interstitial inflammation	Interstitial[13] fibrosis and inflammation Renal ablation GSGS*
Impaired urine concentrationà polyuria	Decreased GFR very late event

Earliest finding in bilateral partial obstruction?

• § Inability to concentrate urine (polyuria, nocturia), HTN, tubulointerstitial nephritis

When happens with unilateral vs bilateral partial vs bilateral complete obstruction?*

• § Unilateral: asymptomatic*
• § Bilateral incomplete: polyuria, nocturia, HTNà typical picture of chronic tubulointerstitial nephritis* (meaning tubular atrophy, interstitial fibrosis)
• § Bilateral complete: anuria, death shortly*

What happens when obstruction lifted*?

• § Diuresis of urine rich in sodium chloride

 

 

 

 

UROLITHIASIS

4 types and lab abnormalities*. Which radiolucent*?

• § Calcium oxalate+/-calcium phosphate (radiopaque): 70%, associated with hypercalciuria+/-hyperCa but some without any lab abnormality
• § Struvite (magnesium ammonium nitrate MAP) (radiolucent?): associated with infection by urea-splitting bacteria that convert urea to ammonia, forms staghorn calculi
• § Uric acid (radiolucent): associated with hyperuricemia or hyperuricosuria but not always
• § Cysteine

Name 4 metabolic disorders predisposing to stones

• § Hyperoxaluria
• § Hypercalciuria+/-hyperCa
• § Hyperuricosuria
• § Cystinuria
• § How postulated theory of deficiency in inhibitors of crystal formation in urine?* Which inhibitors?
• § Because many stone formers do not have metabolic disorders and many metabolic disorders do not form stones.
• § A lot including nephrocalcin

 

 

TUMOURS

RENAL CELL TUMOURS

4 benign tumors and their clinical SSx

• § Papillary adenoma
• § Fibroma or hamartoma
• § AML
• § Oncocytoma
• § Generally asymptomatic except oncocytoma

3 most common malignancies

• § RCC (no1)
• § Wilms (no2)
• § TCC (no3)

 

PAPILLARY ADENOMA

What color?

• § Yellow
• § <0.5cm by definition
• § WC
• § Always cortical

Micro

• § Tubules and complex branching papillae
• § Lining indistinguishable from LG papillary RCC

Similar genetics and IHC to what tumor

• § Same as papillary RCC (trisomies 7 and 17)

Micro

Papillary adenoma	Papillary RCC
-£0.5cm (Robbins says 3) -Papillary or tubulopapillary
Current philosophy is to treat all papillary adenomas as early papillary RCC regardless of size (Robbins)

 

RENAL FIBROMA OR HAMARTOMA

• § Renomedullay interstitial cell tumor

Gross

• § Medulla
• § <1cm

Micro

• § FB and collagen

EM

• § Resembling interstitial cells

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AML

Neoplastic or hamartomatous

• § Neoplastic (clonal)

Origin

• § Perivascular epithelioid cellsà differentiate into fat, spindle cells, epithelioid cells

Demo

• § Women (4:1) but equal in TS patients, rare before puberty

Benign or malignant

• § Most benign although rare cases of renal vein extension and LN spread reported (not worse prognosis)à excision is curative

Complications

• § Retroperitoneal hemorrhage (>4cm)
• § Renal failure!

Gross

• § WC, hemorrhagic, yellow (fat) depending on proportion of each componentsà may look like RCC, XGP, malakoplakia
• § Multipleà TS

Micro

• § Tortuous thickened BV
• § Mature fat
• § SM cells emanating from BV
• § High cellularity and atypia mimicking leiomyosarcoma
• § Epithelioid cells centered around BV
• § If prominent, may give rise to “epithelioid angiomyolipoma”

Variants

• § Monotypic
• § Epithelioidà resembling carcinoma with abundant eosinophilic cytoplasm, necrosis, mitoses, atypiaà problematic because mimics RCCà malignant
• § Cystic
• § Trabecular

IHC

• § SM markers+ (desmin, MSA, SMA): in SM cells
• § Melanocytic markers (HMB-45, MelanA): in epithelioid cells and spindle SM cells
• § C-kit
• § CK- (including EMA)

AML	Sarcomatoid RCC
AML	Sarcomatoid TCC

AML	Granular CRCC
	Vascular invasion
	Growth patterns
No	CK+, EMA+
SMA+, desmin+, HMB45+
AML	Eosinophilic AML

 

CYSTIC NEPHROMA

Presentation

• § Incidental radiographic finding
• § 8x more in females adults (not kids!)

Gross

• § WC, completely cystic (no solid area at all), thin septa

Micro (USCAP)

• § Adults
• § Expansile mass with pseudocapsule; entirely cystic
• § Flat, cuboidal to hobnail lining; focal areas often lacking lining
• § No mitoses
• § Septa may contain structures resembling mature renal tubules or ovarian-like stroma but should not have clear cells or SM or expansile nodules

Treatment

• § Radical or partial nephrectomyà recurrence if incomplete excision

 

CYSTIC PARTIALLY DIFFERENTIATED NEPHROBLASTOMA

Compare with cystic nephroma

CPDN	Cystic nephroma
Male infants (<2yo)	Adult females
Gross exactly same
Exactly same as cystic nephroma except septa contain blastema+/-embryonal stromal or epithelial components

Are they related?

• § No

 

MIXED EPITHELIAL AND STROMAL TUMOR OF KIDNEY

 

ONCOCYTOMA

Cell origin

• § Intercalated cells of collecting ducts

Genetics

• § Loss of 1 and Y

Gross

• § Mahogany brown with central scar (also in chromophobe and clear cell RCCs)
• § Variable size (small, large)

 

Micro and enumerate some “never” features***

• § Large polygonal cells with deeply eosinophilic granular cytoplasm (nucleoli)
• § Small round vesicular nuclei but prominent nucleoli
• § Finely stippled chromatin
• § Nests (archipelaginous), cords, tubules
• § NEVER: papillary, necrosis, mitoses, renal vein invasion, spindling

Would you grade it?

• § No

IHC

• § Hale’s colloidal iron- or luminal+
• § CK7- or focal+
• § EM
• § Abundant mitochondria with stacked lamellar cristae

Can it metastasize?***

• § Rarely but still considered benign because these were questionable cases

Oncocytoma vs chromophobe RCC

Oncocytoma	Chromophobe RCC
Must use IHC, EM, cytogenetics after thorough sampling
HCI- (or luminal+)	HCI+ (diffuse granular)
CK7- (or only focal+)	CK7+ (strong diffuse)
Mitochondria of normal size (>500µm) and shape	Microvesicles (150-300µm)
Loss of 1, Y
No	Hypodiploidy

Oncocytoma vs epithelioid AML

Oncocytoma	Epithelioid AML
	HMB45+
	Mart1+

 

 

 

 

 

 

 

 

 

 

 

 

 

 

RCC

Common cell origin

• § renal tubular epithelium (therefore adenocarcinomas)

Gender and age

• § 60-70, 2x in males

3 familial variants*

• § VHL: also involved in sporadic
• § Hereditary CRCC (non-VHL)
• § Hereditary PRCC: AD, MET mutation

Which pole?

• § Upper

Key to correct diagnosis in kidney tumor

• § Look at multiple slides

Can they invade into pelvis?

• § Start by bulging before breaking through into pelvis although renal vein still favorite pathway

Which variants can have sarcomatoid differentiation?

• § All possible

Clinical triad? Characteristic clinical presentation?

• § Hematuria (most reliable), mass, costovertebral pain
• § Widespread before any clinical SSx

Top 2 metastatic sites (hint: sarcoma sites)

• § Lung (50%)> bone (33%)> LN, liver, adrenals, brain

Paraneoplastic syndromes (hint: 3 hormones)

• § Polycythemia (EPO-stimulating substrate)
• § HyperCa (PTH-like hormone)
• § HTN (renin)
• § Hepatic dysfunction
• § Feminization or masculinization
• § Cushing syndrome
• § Eosinophilia
• § Leukemoid reaction
• § Amyloidosis

What causes huge drop in survival rate?

• § Renal vein or perinephric fat invasion

Which mostly bilateral?

• § PRCC

2 genes and associated tumours.

• § Clear cell RCC: VHL (tumor suppressor)
• § Papillary RCC: c-MET (proto-oncogene), PRCC

Cytogenetics of major RCC

 

Compare outcome of all RCC

• § Clear cell RCC > PRCC > CRCC = Xp11 translocation ca
• § Bad prognosis: collecting duct and renal medullary
• § Good prognosis: mucinous tubular, spindle cell ca

RF associated with RCC***

• § VHLà CRCC
• § Acquired cystic kidney diseaseà ESRD-associated RCCà PRCC
• § PCKD
• § Tuberous sclerosisà CRCC
• § Birt-Hogg-Dubeà ChRCC, oncocytoma
• § Hereditary PRCC

 

CLEAR CELL RCC (70-80%)

RF for CRCC***

• § VHL: at least 50% will develop renal cysts and bilateral multicentric RCC, in both sporadic and familial
• § Hereditary CRCC (non-VHL): confined to kidneys
• § Acquired cystic kidney disease
• § PCKD
• § Tuberous sclerosis
• § Acquired renal cystic disease

 

Smoking (no1, RR=2)	Males
HTN	Asbestos
Obesity	Metals
Petrol

Genetics

• § 3p loss (encodes for VHL tumour suppressor gene) (either by deletion, translocation or hypermethylation) in 98%, present in either sporadic or familial
• § VHL lossà loss of ubiquitin ligase complex assemblyà decreased HIF-1 degradationà increased transcription of VEGF, TGFb1à cell growth, angiogenesis

Relevance of hereditary tumors

• § -Younger, bilateral, multiple

Why bright yellow? Why other colors? How is border?

• § -Yellow (fat>glycogen), white (necrosis), red (hemorrhage), cystic (1/10)
• § Not encapsulated but WC, renal vein invasion (1/3), perinephric fat invasion

Cell origin

• § Proximal tubules

Micro

• § Polygonal cells, clear to eosinophilic granular cytoplasm
• § Clear cytoplasm (glycogen and fat) extending from nuclei to cell membrane, more eosinophilic granular in HG areas (decreased glycogen and fat)
• § Chicken wire vascularity separating nests (“acini”)
• § Glandular, cystic, pseudopapillary (degenerative due to ischemia), sarcomatous (sarcomatomatoid differentiation), rhabdoid in HG areasà important to look for LG areas for diagnosis
• § Geographic hemonecrosis, fibrosis

3 growth patterns*. What pattern is forbidden*?

• § Solid, cords, tubules
• § Papillary forbidden (can have pseudopapillae from degeneration)

Spread

• § Bulge into calyces and pelvis
• § Renal vein invasion

Prognosis***

• § Staging (size, extent of spread, vascular invasion)
• § Grade
• § Histologic type

IHC

• § CD10+ (membranous) vs cytoplasmic CD10+ in PRCC
• § CK7-

Treatment

• § -Targeted therapies: Rapamycin (mTOR), anti-VHL/HIF

 

Clear cell RCC	Papillary RCC
No FV cores	True papillae
No	Diffuse CK7+
	Foamy macrophages
	Psammomas
	Hemosiderin in tumor cells
3p loss	Trisomies 7, 17, t(X;1) TF3-PRCC, c-met

Clear cell RCC	Chromophobe RCC
	HCI+, CK7+?
EM	EM
3p loss	Hypodiploidy

C

Clear cell RCC	AML
CAM5.2+, EMA+	No
No	HMB45+, SMA+

Clear cell RCC	Mets

Clear cell RCC	ACC
EMA+	No
No	Inhibin+, Mart1+

 

MULTILOCULAR CYSTIC RCC

Median age

• § 50

Gross

• § Multicystic, WC, pseudocapsule
• § Thin fibrous cyst walls
• § Cyst of variable size
• § Serous or bloody fluid

Micro

• § Lined by single or multilayered epithelial cells
• § Papillary tufting sometimes
• § Clear cytoplasm, Furhman 1-2 nuclei
• § Small collections of tumor cells in septa or pseudocapsule but no solid or expansile massà do EMA or panCK

 

MCRCC	Cystic nephroma/MEST
Different lining	Single flat or hobnail lining
	More cellular ovarian-like stroma
	No clear cytoplasm
	Small tubules in septa reminiscent of renal tubules
MCRCC		Benign cysts

 

 

 

PAPILLARY RCC (10-15%)

3 mutations and respective genes

• § Sporadic (type 1, no1): trisomy of 7, 17, loss of Y
• § Sporadic (type 2): fumarate hydratase mutation
• § Familial (10%): trisomy 7à c-MET (proto-oncogene also in several other papillary cancers), which is TKR for HGF (aka cell scatter factor)

 

Cell origin

• § Distal tubules

Gross. What’s special about border?

• § Hemonecrosis common
• § Among all RCC, PRCC most likely to have pseudocapsule

How is distribution compared to clear cell RCC?

• § Like clear cell RCC (golden yellow and hemorrhage)
• § Often encapsulated, more often multifocal and bilateral

Micro

• § Papillary FV cores, lined by cuboidal cells
• § Foamy macrophages, occasional PMN
• § Hemosiderin in tumour cells
• § +/-psammoma bodies
• § Mainly papillary, tubular, tubulopapillary. Rarely solid, trabecular, glomeruloid
• § High vascularized, very little desmoplastic response (unlike collecting  duct carcinoma)
• § Geographic necrosis
• § Basophilic, eosinophilic or partially clear cytoplasm

IHC

• § CK7+: diffuse positivity (vs focal in other RCC except clear cell RCC which is completely negative)
• § VIM: inconsistent
• § RCC+ (also in CRCC)

Variants (2)

• § Type 1: Single layer
• § Type 2: Pseudostratified: worse prognosis

DDx

• § Clear cell RCC

PRCC	Collecting duct carcinoma
	Can have papillae
	Centered in medulla
	Always HG
	Desmoplastic stroma
	Intracytoplasmic and luminal mucin (CEA+)

PRCC vs translocation-associated RCC

PRCC	Translocation
	Younger
	Multifocal, bilateral
	HG
	Abundant cytoplasm
CK7+	CK focally+ or negative
	TFE3+, TFEB+

 

Xp11.2 TRANSLOCATION CARCINOMA

Genetics

• § Translocation of transcription factors E3 (TFE3) on Xp11.2 and EB (TFEB)à t(X;1) TFE3-PRCC

How to diagnose?

Demo	Mainly in kids and young adults (mean 25)
Micro	Mixed papillary and nested (alveolar, compact or mixed) patternsà pure form of either less common HG (Fuhrman 3-4) Mixed clear and eosinophilic cells with abundant cytoplasm Thin or thick FV cores with hyaline change in some Psammoma in 2/3
IHC	TFE3+ TFEB+ CD10+ Racemase+ MelanA+ HMB45+ E-cadherin+ CK- (including EMA, AE1/3, CK7)
Genetics	t(X;1) TFE3-PRCC -t(6;11) TFEB-?

• § DDx: PRCC

 

CHROMOPHOBE RCC (5%)

Prognosis

• § Better than clear cell RCC unless sarcomatoid differentiation

Genetics

• § 1 and Y loss and hypodiploidy
• § Thought to arise from the intercalated cells of the renal cortex, like oncocytomas

Can one use cytogenetics to DDx from oncocytoma?

• § No

Cell origin

• § Intercalated cells of collecting ducts

Gross

• § Dark brown, sometimes mahogany and sometimes central scar!
• § Lobulated, hemorrhage or necrosis, non-encapsulated

Micro

• § Thin fibrous septae, solid sheets
• § Plant-like round to polygonal cells with eosinophilic cytoplasm, peripheral granularity and perinuclear halo, thick cell membrane
• § Central, grooved, dark, wrinkled or angulated nuclei, binucleation common
• § May have focal cytologic atypia
• § DDx: Oncocytoma, eosinophilic clear cell RCC, papillary RCC (solid variant)

 

COLLECTING DUCT CARCINOMA

Where is it located?

• § -Medulla (because collecting ducts!), firm (desmoplastic)
• § -Poorly circumscribed, may extend into perihilar fat

Genetics

• § -Numerous but nothing consistent

Micro*

• § -Irregular ducts (lined by hobnail), papillae or nests
• § -Intense desmoplastic response
• § -HG nuclei with prominent nucleoli
• § -Sarcomatoid differentiation sometimes

IHC

• § -Cytoplasmic and luminal mucinà PAS, Alcian
• § blue+ and CEA+ (producing mucin)

 

MEDULLARY CARCINOMA

Clinical

• § Assoc. sickle cell trait
• § Young African-Americans

Micro

• § HG cells with prominent nucleoli

 

TCC

How common?

• § -10-15% of renal tumors are in renal pelvis!

What significance with bladder?

• § -50% also have bladder TCC (synchronous or metachronous)

Why is it bad despite small size?

• § -Common to invade through pelvis and calyces

 

METS

• § -Adrenal cortical carcinoma: inhibin and Melan-A +
• § -Clear cell carcinoma of ovary: CA-125 and 34BE12 +
• § -Clear cell carcinoma of thyroid: TTF-1 and thyroglobulin +

 

RENAL TUMORS WITH PAPILLARY FEATURES

• § -Clear cell RCC: pseudopapillae
• § -Chromophobe
• § -PRCC
• § -Collecting duct carcinoma
• § -TCC
• § -Translocation-associated carcinomas

 

RENAL TUMORS WITH SARCOMATOID FEATURES

• § -Clear cell RCC
• § -Chromophobe
• § -PRCC
• § -Collecting duct carcinoma
• § -TCC
• § -Mixed tubular and spindle cell carcinoma
• § -Sarcoma

 

RENAL TUMORS WITH GRANULAR FEATURES

• § -Clear cell RCC
• § -Chromophobe
• § -PRCC
• § -Oncocytoma
• § -Collecting duct carcinoma
• § -Birt-Hogg-Dube
• § -Epithelioid AML

 

LESIONS CONTAINING PSAMMOMA BODIES

• § -Papillary RCC
• § -PTC
• § -Serous borderline or malignant tumors of gynecologic tract (what about benign?)
• § -Mesothelioma
• § -?
• § -Hyaline
• § -Amyloid
• § -IC
• § -Thrombus
• § -Collagen

PINK MATERIAL

 

 

 

 

 

 

PEDIATRIC TUMOURS

NEPHROGENIC RESTS

When do you get it?

• § -Seen in kidneys resected for Wilms

Location

• § -Perilobar (beneath capsule) or intralobar (throughout cortex)

Micro

• § -Expansile masses resembling to Wilms to sclerotic rests composed of fibrous tissue admixed with immature tubules or glomeruli

 

WILMS TUMOUR (NEPHROBLASTOMA)

What age range?

• § 2-5yo, before 6yo (note rhabdoid tumor predominant <2yo)

Define

• § Malignant embryonal tumor derived from nephrogenic blastemal cells

Explain cytogenetics (hint: malformation). What precursor lesion?

• § Malformationsà premalignant (nephrogenic rests)à 2 hits of WT1

Special about gross? Cortex or medulla? How does it spread?

• § Unicentric, round, WC, very soft and grayà careful with displacement of tumor cells
• § Either cortical or medullary
• § Extensive vascular invasion

Micro

• § Blastemal: exactly similary to small cell NE carcinoma of lung
• § Primitive epithelial: glomeruli, tubules (no1), papillary
• § Stromal: skeletal muscle (no1),
• § Anaplasiaà indicator of poor prognosis

Mets

• § 3 “L” (Liver, Lungs, LN)

IHC (3) and which cells?

• § WT1+: blastemal and primitive epithelial only (so mature epithelium and stroma negative)
• § VIM+
• § P53+: anaplastic component

% of syndromic Wilms and which 3 syndromes?

• § 10%

1. WAGR syndrome (Wilms, aniridia, genital anomalies, retardation)à deletion of 11p (WT1 gene) and PAX6 (causing aniridia)

2. Denys-Drash syndrome (male pseudohermaphroditism, early-onset nephropathy, risk for gonadoblastoma)à gonadal dysgenesis and nephropathy with renal failureà inactivating point mutation in WT1

3. Beckwith-Wiedeman syndrome (organomegaly, macroglossia, hemihypertrophy, omphalocele, adrenomegaly)à maybe WT2…

Prognosis (hint: clinical-histo-stage)

• § Age<2à good prognosis (no time yet to develop anaplasia)
• § Stage
• § Size
• § Anaplasia (no1)
• § Chemotherapy resistance

How to stage?

 

Define anaplasia (2)

• § Markedly large dark nuclei
• § Multipolar mitoses (no1) (Mercedes sign)

 

DDx and tell how

• § Small round blue cells including neuroblastoma, metanephric adenoma, PNET/EWS, RMS, lymphoma: no tubules
• § Clear cell sarcoma: no tubules
• § Rhabdoid tumor (vs skeletal muscle stromal differentiation of Wilms)
• § DSRCT: desmin+

Wilms	Neuroblastoma
2-5	Younger
	Urine catecholamines
3L	Unusual mets other than 3L
WC	No WC
-Triphasic	-Homer-Wright -Non-overlapping nuclei -Salt-and-pepper
-WT1+	-NE markers
WT1 deletion/mutation	What cytogenetics?

 

 

METANEPHRIC ADENOMA

• § -Young to middle aged women
• § well-circumscribed and cortical
• § small round blue cells
• § compact tubules
• § CK and VIM +
• § benign (no mitoses, no nucleoli)

 

MESOBLASTIC NEPRHOMA

Clin: infants <3mo

Gross

• § -Unicentric, near hilusà medial margin very important!
• § -Looks like a LM on gross (white, whorled)

Micro: solid

• § spindle cells in classic or cellular pattern:

Classic: low cell density (looks like fibromatosis)

Cellular: high cell density with ↑mitoses (looks like sarcoma)

IHC: not helpful

Prog: good, only 5% recur local or w/ mets

 

 

 

 

 

 

 

 

CLEAR CELL SARCOMA

Clin: infants >1yr

• § -Mets widely to brain and bone

Gross: unicentric, irregular shape, large, solid with cysts

Micro

• § -nests separated by chicken wire bv
• § -sm cells, fine chromatin, NO nucleoli
• § -indistinct cell margins (only clear cytoplasm in 20%)
• § Dx: exlude other pediatric tumours first.
• § IHC (not same as clear cell sarcoma of soft tissue)
• § -Only VIM+
• § EM
• § -Elongated cytoplasmic processes

 

RHABDOID TUMOUR OF KIDNEY

Typical clinical presentation***

• § -Infants (<2yo, not kids), hyperCa

Significant associateon in brain?

• § -Posterior fossa PNET in 15%

Gross

• § -Unicentric, medulla

Micro***

• § -Solid sheets with infiltrative border
• § -Uniform cells with 1) large vesicular nuclei, 2) prominent nucleoli, 3) eosinophilic cytoplasmic inclusion pushing nucleus aside

What’s special about IHC? (hint: combined)***

• § -VIM+
• § -CK+/EMA+: patchy

Genetics

• § -Inactivation of hSNF5 gene

Prognosis***

• § -Very poor, death in 75% in 1 year

DDx (hint: pediatric tumors)***

• § -Nephroblastoma
• § -Neuroblastoma
• § -Clear cell sarcoma
• § -Mesoblastic nephroma
• § -Renal medullary carcinoma: older, sickle cell
• § -Mets

 

OSSIFYING RENAL TUMOUR OF INFANTS

Clin: very rare, medullary papilla

Micro: spindle cell stroma with large regions of osteoid

Prog: benign

 

NEUROBLASTOMA

HEREDITARY RENAL TUMORS

VON HIPPEL-LINDAU

• § -Multifocal and bilateral RCC
• § -VHL tumour suppresor gene is hypermethylated or mutated
• § -3p25

Features of VHL (hint: “PHEONA the HIPPO SQUISHES CYSTS and makes a BLOODY mess”)

• § -PHEONAà pheochromocytomas
• § -HIPPOà Hippel
• § -CYSTSà multiple bilateral renal cysts
• § -BLOODYà retinal and cerebellar hemangioblastomas
• § -RCC

 

HEREDITARY PAPILLARY RCC

• § -Activating mutations in proto-oncogene c-MET
• § -Causes activation of a tyrosine kinase receptor involved in cellular differentiation and proliferation

 

BIRT-HOGG-DUBE

• § -Multifocal and bilateral
• § -Assoc/ cutaenous lesions
• § -Assoc/ chromophobe RCC or oncocytomas
• § -BHD gene maps to 17p12à function unknown

 

 

 

TUBEROUS SCLEROSIS

SSx*

• § -Epilepsy
• § -Mental retardation
• § -Skin abnormalities
• § -Shagrain patch (fluorescent???)

Genetics

• § TSC1 (hamartin)

TSC2 (tuberin)
3 LESIONS OFTEN CONFUSED WITH RCC

AML

Xanthogranulomatous pyelonephritis

• § rare form of  acute pyleonephritis, assoc/ urinary obstruction

Gross: large yellow masses replace kidney

Micro: foamy mφ, lφ, nφ, giant cells.

• § assoc/ E. coli and Proteus infections

Malakoplakia

Gross

• § -Yellow masses in kidney, also seen as small nodules on bladder mucosa

Micro

• § -Foamy macrophages with targetoid inclusion Michaelis Gutman bodies (calcium and iron) “von Hanseman cells”

IHC

• § -PAS+, MG bodies secondary to lysosomal defect in destroying bacteria
• § -Von Kossa
• § -Prussian blue

 

 

 

 

 

RENAL EPITHELIAL TUMOURS

Clin features

• § adults, men >women
• § classic triad for presentation(10%): abdo mass & pain, hematuria

 

DIFFERENTIALS

Glomerular nodular lesions

• § -DM
• § -MPGN (lobular)
• § -Light chain deposition disease: nonfibrillary
• § -Amyloidosis: fibrillary

 

STAGE***

• § T1         < 7cm
• § T1a       < 4cmà cutoff for partial nephrectomy
• § T1b       4-7 cm
• § T2         > 7cm
• § T3         Perinephric fat (may include adrenal)
• § Into renal vein or into IVC below diaphragm
• § Into IVC wall or into IVC above diaphragm
• § T4         Beyond Gerota’s fascia

When is renal tumor upstaged?

• § -Size>7cmà T2
• § -Perinephric fat, adrenal gland, renal vein invasionà T3
• § -Gerota’s fasciaà T4

Important prognosticators in renal neoplasia

• § -Stage
• § -Histologic type
• § -Nuclear grade (sarcomatoid included here)

When partial nephrectomy feasible?

• § -<4cm tumor size

Define renal sinus invasion. What’s significance and what stage?

• § -Invasion of small BV and lymphatics in renal sinus
• § -Poor prognosis (probably comparable to perinephric fat invasion)à therefore T3

 

FURHMAN GRADING (USCAP)

How many grades? What are 3 criteria?

Grade	Diameter	Nuclear shape	Nucleoli
1	10µm	Round	Absent at 40x
2	15µm	Round	Visible at 40x
3	20µm	Oval	Visible at 10x
4	Giants, spindle, rhabdoid
-Grade based on worst area regardless of extent

• § -Chromatin pattern is 4^th criteria

Applicable on which tumors (update from USCAP)

• § -Furhman corresponds to outcome in CRCC
• § -Nuclear grading (not Furhman) better for PRCC
• § -Furhman not predictive of outcome for ChRCC

What other tumors can you use Furhman?

• § -Adrenocortical tumors

 

 

 

CLASSIFICATION

Pediatric	Adult
Nephrogenic rests	Papillary adenoma
Mesoblastic nephroma -Classic -Epithelial -Mixed	Metanephric adenoma
	Oncocytoma

 

Wilms -With favorable histology -With anaplasia	CRCC -Multilocular cystic RCC
Clear cell sarcoma	PRCC
Rhabdoid tumor	Chromophobe RCC
Papillary RCC	Collecting duct
Medullary RCC	Medullary
	Mucinous tubular and spindle cell carcinoma
	Translocation carcinomas
	Carcinoma associated with neuroblastoma
	Unclassified

 

 

DIFFERENTIALS

TWO hereditary isolated hematuria*

• § -Alport
• § -Thin BM diseaseà no1 benign familial hematuria*

Granulomas in kidney

• § -Malakoplakia
• § -Vasculitis: Churg-Strauss, Wegener
• § -Parasites
• § -TB
• § -Sarcoidosis

 

RENAL CYSTS: classify, gross, prognosis***

Non-neoplastic: infectious (abscess), non-infectious (congenital vs acquired)

Renal dysplasia (sporadic)	-*Cysts and solid (cartilage, undifferentiated mesenchyme), usually unilateral -Often other abnormalities (ureteropelvic obstruction, ureteral agenesis)	Bad because urinary obstruction
APKD (AD)	Cysts in kidneys (no solid areas), liver, berry aneurysms Huge kidney, bumpy surface	CRF by 40-60
IPKD (AR)	-Radial cysts in kidney at birth, smooth surface, large kidney -Hepatic fibrosis	Death in childhood
MSK (none)	-Cysts in medula	Benign except hematurai and infections
Juvenile MCD (AR or AD)	Corticomedullary cysts, small kidneys	CRF in childhood
Adult MCD (AD)		CRF in adulthood
Simple (none)	Normal-sized kidney	Benign except microscopic hematuria
Acquired	Cysts in cortex and medulla, small kidney	Dialysis
VHL	VHL on 3p[14]

• § Neoplastic: cystic nephroma, multiloculated cystic RCC