Pathology: Renal

Diseases of the Tubulo-Interstitium........................................................................................................................................ 2

Nephrotic Syndrome ............................................................................................................................................................... 9
Glomerulonephritis ............................................................................................................................................................... 14
Renal Manifestations of Systemic Diseases .......................................................................................................................... 19
Tumors of Bladder & Kidney ................................................................................................................................................. 28
Pediatric Renal and Bladder Tumors..................................................................................................................................... 33
Pathology of Hypertensive Nephrosclerosis ......................................................................................................................... 36

1
 Diseases of the Tubulo-Interstitium
Some basic points:
Diseases affecting tubulointerstitium = commonest causes of
acute renal failure
Tubules & interstitium closely related
Diseases of arteries, arterioles, glomeruli can affect downstream
tubulointerstitium

What determines what part of nephron will be injured?

Function
Proximal tubule: lots of uptake, most susceptible to nephrotoxins
Distal tubule: injured by lithium (unknown why)
Location in renal parenchyma
Parts in outer medulla more susceptible to hypoxic injury
(less blood flow)
Ascending infections: renal pelvis  tubules in medulla  cortex
(works its way up)

Consequences of tubulointerstitial disease CAUSES OF TUBULAR

Abnormal reabsorption INJURY / DYSFUNCTION
(fluid/electrolyte loss, Fanconi’s syndrome – can’t reabsorb anything!) Primary
Electrolyte / acid-base abnormalities Ischemia
GFR failure (fluid overload, hyperkalemia, toxins build up) Nephrotoxins
Immunologic
Sublethal Injury Secondary
With glomerular / vascular injury
Morphologic changes (subtle)
With interstitial nephritis
(from changes in cell calcium, cytoskeleton, adhesion molecules, cell polarity)
Apical brush border lost
Blebbing of apical cytoplasm
Cell swelling / vacuolization
Cell exfoliation (individual cells slough off, leave gaps on epithelium) – can show up in urine
Can see changes on EM but also on light microscope

Normal: interconnected Osmotic Injury: very Flattened cells, gaps in EM: Loss of brush border &
epithelium, PAS + brush swollen but still have PAS + epithelium (arrowhead), blebbing in lumen
border & more brush border, some lacking apical blebbing of cytoplasm
mitochondria in PT (vs DT) mitochondria into lumen

2
 Intracellular Events in Acute Tubular Injury
Generally just what happens when cells get injured:
Oxidative metabolism messed up, ATP depleted
+
Intracellular [Ca ] ↑  phospholipases / proteases activated
Free radicals generated (direct toxicity, esp in reflow post-ischemia)
Cell membranes injured, cytoskeleton disrupted
Cell adhesion & polarization messed up
o Lose the normal zona adherens (tight
junctions & adhesion molecules that keep
apical & basolateral sides separate)
o Can’t generate gradients & now more
permeable (leak stuff out into urine)

Note from picture:

big vacuoles, less mitochondria, ultrastructural derangement

Lethal Injury
Cellular Subcellular
Coagulative necrosis Major disruptions in Ca / electrolytes / ATP
Apoptosis Proteins / organelles disrupted / dysfunctional
Cell detachment Cell membrane disrupted
o Can see dead cells in tubules (drifted down Nuclear breakdown (karyorrhexis)
from upstream site of injury) and in urine

Normal: interconnected Necrotic cells inside a Necrotic tubules: lots of Apoptotic figures in two
epithelium, PAS + brush relatively intact tubule: dead tubule cells, disruption tubular cells
border & more drifted down from & clogging of tubules
mitochondria in PT (vs DT) upstream

Regeneration / Repair
Epithelial cells transdifferentiate & assume a more mesenchyemal pattern: transition
back & forth along spectrum
Trying to regenerate & proliferate from this more primitive cell type
Not good: worse cell junctions, simplified surfaces without brush border, bad
polarization, pro-fibrotic

Cellular manifestations: flatter cells, heterogeneous cells / nuclei (↑N/C ratio, almost Arrowhead: flatter cells,
spread out, mesenchymal
like neoplasia) , mitotic figures with apoptosis

Subcellularly: new genes expressed & new proteins

formed (different markers)

3
Inflammation plays a role too: marker of ischemic injury Endothelial dysfunction too:
See RBC & WBC in vasa recta Edema from lack of endothelial integrity; NO
Probably attracted by chemotactic substances lost, so less vasodilation
released from injured tubule cells & capillary Capillary “sludging” (RBC & WBC stuck in
endothelium capillary b/c ↑adhesion molecules &
Creates congestion & low flow (ischemia can ↑constriction)
result) o Procoagulant state (loss of protective
surface factors too) ischemia  etc
How does this cause renal dysfunction?
Hemodynamic abnormalities
Vasoconstriction – tubuloglomerular feedback (& maybe RAAS,
etc)  afferent arteriole constriction
o Not absorbing & secreting normally  shut down glomerulus of
affected nephron!
Back-leak of filtrate into blood with disruption of tubule integrity
No net filtration! Putting it right back into capillaries
Obstruction of tubule
↑tubular pressure  ↑ Bowman’s space pressure  GFR
compromised

Nephrotoxic Acute Renal Failure

Clinically the above stuff (for ischemic injury) applies too
Small path differences NEPHROTOXIC AGENTS
Maybe bigger structural injury, more frank necrosis Antibiotics (gentamicin, ampho B)
Can be generalized or segment-specific (e.g. PT only) Radiographic contrast
Some path agents have distinctive lesions (see below) Chemotherapy (cisplatin)
Lithium, mushrooms, insecticides
Effects from interference with oxidative metabolism
↑ free radicals  cell damage

Calcineurin Inhibitors: Aminoglycosides: Indinivar:

Isometric vacuolization Myeloid bodies Crystalization
(small, equal-sized (see these things on EM) (big crystal here – check out
vacuoles) tubule size in comparison)
4
 Outcomes of Acute Tubular Injury
Whole range: from recovery without dialysis to recovery with dialysis or even patient death (MOF)
Can be partial or complete (severity, duration, patient factors like age/illness, etc)
Can have chronic sequelae

FAST FACTS - TUBULAR INJURY

1. Most common causes are ischemia/hypoperfusion and toxins, including drugs
2. Morphologic changes are often subtle - while necrosis and apoptosis occur,
sublethal injury and reactive/regenerative changes may predominate
3. Typical cell injury cascade, with altered cytoskeleton, polarization, adhesion
4. Renal failure ensues due to arteriolar vasconstriction, tubular back leak, obstruction
5. Some evidence for an inflammatory component – PMN, T and B cells, adhesion molecules
6. New focus on endothelium in ischemia, improving reflow

Interstitial Disease
Interstitial nephritis: an inflammatory infiltrate in interstitium CAUSES OF INTERSTITIAL NEPHRITIS / FIBROSIS
Responsible for 15% acute RF, 25% chronic RF Infection
o Direct (incl. pyelonephritis)
Can be 1° (± 2° tubule injury), or 2° to tubule injury – hard to tell o Indirect (systemic inflammatory reaction – to
which came first if you see them both drugs, parasites, viruses, etc.)
Drugs
o If huge inflammatory infiltrate (or if PMNs, eos, Immune-mediated (Ab or cell-mediated)
granulomas present) probably interstitial first Obstruction / reflux
Secondary (to glomerulonephritis or vasculitis)

Direct bacterial infection of the kidney

1. Ascending: “pyelonephritis” – transits urethra, bladder, has to pass through
uretral valves into ureter, etc.
o Papillae  cortex (coming in via ureters from renal pelvis!)

2. Hematogenous: with big time bacteremia, can enter via glomerular capillaries
o Glomerularcentric (coming in through glomerulus!)

Types of bacteria: usually from feces

E. coli is #1, (also Klebsiella, Proteus, Enterobacter, Pseudomonas, Serratia)

Risk Factors:
Instrumentation (catheters, etc.)
Renal calculi (kidney stones, place for bacteria to hang out)
Virulence factors (capsular Ag  ↓phagocytosis & C’, fimbriae to keep from being
swept away in urine)
Females (anatomy) & pregnancy
Vesiculouretral reflux (see below)

Histology: fibrosis separates chronic from acute

Acute: interstitial edema with inflammatory infiltrate
(often mononuclear with PMNs around / in tubules, can form casts because of ↑adhesion molecules)
Chronic: interstitial fibrosis with inflammatory infiltrate (can see germinal centers)
Can see mixed acute + chronic too
5
Bacterial infection of the kidney

Gross: cortical abscesses Bigger cortical abscess PMNs in a cast inside of a Cast with WBC and bacteria
(pyelonephritis) & tubule, also in wall & (in urine, seen here on EM)
streaking (pus in tubules), interstitium (bacterial – can help with Dx
some hemorrhage too infection)

Note that viruses can cause kidney infection too (big mononuclear infiltrate,)

Drug-induced Primary Acute Interstitial Nephritis

Allergic / immunologic reaction to drug
Example mechanism: drug binds to interstitial / peritubular Offending drugs:
protein  new complex presented to T-cells  response
Abx (PCNs,
Amplification via cytokine release sulfonamides)
(from inflammatory & tubulointerstitial cells) Thiazide diuretics
NSAIDs
Sx: may have fever/rash/eos in blood Herbal meds
days/weeks post-exposure Others (lots!)
Eos especially if hypersensitivity (look out for drug rxn!)

Immune-mediated AIN
Anti-basement membrane antibodies:
LINEAR deposits on IF
Ab against structural Ag that’s uniformly expressed on TBM (tubular BM)
Goodpasture’s syndrome (also glomerular BM), renal allografts, membranous nephropathy

Immune complex deposition:

GRANULAR deposits on IF
Ab to irregularly distributed (“planted”) Ag
Granules are aggregates of Ag-Ab complexes
Some drug rxns, systemic lupus erythematosus, membranous & IgA GN

Cell-mediated
Sarcoidosis, some drug rxns, TB infection, allograft rejection
T-cell mediated injury

Renal Dysfunction in AIN

Tubular dysfunction  altered distal fluid delivery  TG feedback mechanisms
Vasoconstriction (TGF, reflex, etc); tubular obstruction, Injury / compression / loss of peritubular capillaries,
cytokines / enzymes released  RENAL FAILURE
Can result in concentrating defects (polyuria / nocturia), renal tubular acidosis, salt-losing nephropathies too

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 FAST FACTS - INTERSTITIAL NEPHRITIS
1. Causes: infection (direct, indirect), hypersensitivity reactions to drugs, immune-mediated processes (immune
complexes, anti-TBM antibodies, cell-mediated).
2. Histologic hallmarks are edema and inflammation, often lymphocytic/monocytic;
3. The presence of neutrophils suggests infection; eosinophils suggest hypersensitivity reaction; granulomas may be
seen with certain infections and drug reactions;
4. Causes renal failure by damaging tubules, interfering with blood supply - cytokines may play a role.

Chronic interstitial nephritis

Interstitial FIBROSIS is key finding
from fibrogenic cytokine release: AT II & TGF β  ECM
synthesis, obliteration of capillaries
Tubular atrophy, mononuclear infiltrate seen too

Tubules shrink  more mesenchymal differentiation 

secrete more collagen  more fibrosis  cycle!

Causes: chronic stage of AIN, chronic ischemia

(atherosclerosis, obstruction, etc.), drug rxn (lithium)
Shrunken tubules,
mononuclear cell infiltrate,
Results: chronic renal failure, concentrating defects, fluid /
zoom: would see fibrosis
electrolyte imbalances (pink in interstitium)
Big, thick basement
membrane(PAS+) with
some epithelial -
mesenchymal transition

Obstructive Nephropathy
Alterations to kidney / collecting system from obstruction
o usually chronic obstruction  fibrosis
Can be unilateral or bilateral (how low is obstruction?)
Can be component of infection or not (increases infection risk)
MANY causes (uretropelvic: extrinsic, intrinsic, congenital, or vesicourethral: prostate
enlargement, spinal cord probs, etc.)

Hydronephrosis: dilation of collecting system (depends on site of obstruction)

Can see on imaging with parenchymal thinning & fibrosis
Calyceal dilation (calyxes dilated) is common – can go away with relief of obstruction
Pictures to right: R sided obstruction with dilation (top), big dilated calyces (bottom)

Caliculi can form (from increased stasis)

7
 Vesicouretral Reflux (VUR)
Retrograde propulsion of bladder urine into ureters
Most often from abnormal implantation of ureters into bladder
o more perpendicular angle between bladder wall & ureter
o orifice doesn’t close right during micturition – usually squeezed shut on contraction
Renal injury can happen early (need to recognize) but present as adult
o NEED EARLY REPAIR (or damage / scarring can result)
Unilateral or bilateral

Causes of Damage Pathology:

Infection Dilation (pelvis / calyces)
o Complement activation Thinning of parenchyma
o Edema, Ischemia/Reperfusion Papillae flattened, cortical
o Free radical release tubules atrophy
Elevated pressure Interstitial fibrosis
o Tubular damage, ischemia CLASSIC FINDING: Coarse
(capillary compression) segmental scars over
Hyperperfusion/Hyperfiltration in remaining dilated calyces at POLES
nephrons  more sclerosis ± inflammation

Can see reflux (little jets) with increased pressure (images to right)

Why scarring at poles?

Simple papillae (not at poles) close duct orifices with increased backpressure
Compound papillae (poles) open duct orifices with increased backpressure (reflux results!)

simple compound

FAST FACTS: CHRONIC INTERSTITIAL NEPHRITIS / SCARRING

1) Caused by prolonged interstitial inflammation, chronic ischemia, reflux, obstruction with back pressure from
collecting system, (also, secondary to vascular, glomerular diseases).
2) Characterized morphologically by fibrosis, inflammation (mononuclear) in tubulointerstitum; glomeruli often
spared until late in course.
3) Is the “pivotal lesion in nephrology,” correlating with prognosis in all renal diseases.
4) Occurs in discrete stages with potential for arrest or even reversal if the process is detected early.

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 Nephrotic Syndrome
Normal glomerulus
(review: fenestrated endothelium, podocyte feet, etc.)

Remember the podocyte:

Regulates permselectivity
Structural support for glomerulus, remodels GBM, endycytoses filterd proteins, counteracts pressure, etc.
COMPLICATED: mutations in various proteins of filtration slit can lead to hereditary proteinuria

Basement Membrane:
has lamina densa (dark on EM, middle zone; blocks based on size) & 2
x lamina rara (interna & externa, heparin sulfate, blocks by charge)

Right: EM of the glomerular filter

with labels (fenestrated
endothelium on bottom, foot
processes of podocytes & filtration
slits above)

The Nephrotic Syndrome (general points)

Nomenclature The Nephrotic Syndrome

Diffuse vs • Proteinuria > 3.5 gm/24 hrs
% of glomeruli involved
Focal • Hypoalbuminemia
Global vs Extent of involvement of an individual glomerular tuft • Edema (from ↓oncotic pressure)
Segmental only part or the whole thing? • Increased serum lipids*
Sclerosing / “Hard” (increase in matrix in the tuft) • (Doubly refractile fat bodies in
sclerosis proteinuria ± heme urine - from ↑ serum lipids)
Increase in intrinsic glomerular and/or inflammatory cells
Proliferative / *(liver cranking out more of everything to
hematuria ± proteinuria
hypercellular try to make more albumin)
(Glomerular hematuria = GBM abnormality / injury)

Nephrosis vs Nephritis
Urine Inflammation & proliferation in glomeruli In general
Proteinuria, not hematuria,
-osis / -otic Cellular casts
Nope Nephrosis is COOL
Hematuria ± renal failure Yes – inflammation / complement cause capillary injury
-itis / -itic Cellular casts with blood, cells getting across GBM
Nephritis is HOT

Proteinuria: loss of >150mg in 24h (much more in nephrotic syndr.)

o > 3.5g = “nephrotic range proteinuria”

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 What’s going on in the Nephrotic Syndrome?
A few main points:
Glomerulus is leaky & you’re losing proteins:
Hormones, vitamins, minerals  deficiencies
Coagulation factor balances altered 
thromboembolism
Proteins as nutrients  malnutrition
(kwashiorkor)
Igs  infections (turnover too fast)

Tubule has to try to reabsorb 

damage & dysfunction

Too little albumin:

Edema (reduced [protein] in blood)
Liver starts cranking up synthesis of
everything while trying to make more albumin
(not the brightest organ around)  more
coagulation factors,
more lipoproteins, etc. MAIN CAUSES OF NEPHROTIC SYNDROME:
(more problems like
1. Minimal Change Disease
CVD)
2. Focal & Segmental Glomerulosclerosis
(with hyalinosis)
Major problem is podocyte 3. Glomerulonephritis
injury (can see hypertrophy, 4. Generalized systemic diseases
de-differentiation, or just loss (diabetes, amyloid, SLE)
of charge – but function is lost
so filter messed up!) Prevalence varies with race and age

Minimal Change Disease

Patient: mostly children (2-6yo)
Urine: selective proteinuria (albuminuria ≫ other proteins)
Course: relapsing / remitting
Treatment: steroids (good response; give empirically to a kid with proteinuria)
Prognosis: favorable

Pathology
LM: normal! No glomerular changes!
EM: effacement of foot processes with
loss of negative charge
Need EM to make diagnosis
(see pic –arrows)
Smooth instead of nice foot
processes

Pathogenesis:
negatively charged surface proteoglycans altered
lymphokines & T-cells may play a role; cationic factor neutralizes negative charge,
thromboxane  hemodynamic changes?
can be secondary to drugs (NSAIDs), lymphoma, venom/toxins, viral infection

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 Focal Segmental Glomerulosclerosis
Name tells you what it is: focal(<50% glomeruli involved), segmental (only part of glomerulus), -sclerosis = hard

Patient: both children & adults, more common in African Americans

Urine: proteinuria poorly selective (not albuminuria like MCD)
Course: can recur in allografts, hematuria & HTN more frequent
Treatment: poor response to steroids; plasmapheresis post-transplant to avoid (remove unknown circulating factor)
ACEI may help too post-transplant (reduce glomerular capillary pressure)
Prognosis: worse than MGD

Pathogenesis: Variety of possibilities. Probably multiple diseases  one pathological syndrome

Primary (idiopathic FSGS) – generalized podocyte injury, cause unknown
o Recurs in 40% transplanted kidneys; plasmaphereis post-transplant helps avoid
Secondary: (“post-adaptive”) – many related to reduced # nephrons & increased filtration
Localized podocyte loss may be key; TGFβ & AT II  more ECM
o Adaptation to: reflux nephropathy, renal dysplasia, morbid obesity, SCD, primary glomerular dz
Also: 2° to hereditary nephropathies; heroin-associated FSGS (CONTAMINATED HEROIN), can be HIV-associated

Morphology: different variants. All possible in primary, * = can be seen in secondary / post-adaptive FSGS
Early / recurrent: EM changes only
(podocytes)
Collapsing glomerulopathy: Left: Arrow: giant
Capillaries collapse & large podocyte!
hypertrophic podocytes seen
(dedifferentiating?) Right: note big
space on EM
between
Podocyte loses its grip: detach from
damaged
capillary loops; no structural support
podocyte & GBM
Esp in HIV pts; parvovirus B19 / viral
involvement?

“Tip” lesions
Foam cells & solidification in segment
of capillary tuft opposite the hilum
May be more benign

Capillaries no longer patent, adhering to Bowman’s capsule. Hyalinosis (silver stain)

* Segmental sclerosis (often with
hyalinosis & foam cells; peri-hilar)

Hyalinosis: collections of eosiophilic

material (represent plasma proteins)
o inside  filling capillary lumen

Can see capillaries adhering to

Bowman’s capsule

* Segmental sclerosis (non-specific)

IF: can see IgM & C3 in sclerotic portions of affected glomeruli (where lesion is!)

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 Membranous Glomerulopathy

Patient: Adults (peak = middle age, M>F a bit)

Urine: proteinuria poorly selective
Course: Sudden presentation, usually only trace hematuria.
Treatment: poor response to steroids; no good evidence supporting one therapy over another
Prognosis: More variable. Worse with HTN or >10g/day proteinuria

Pathogenesis: Deposition of immune complexes

Primary / idiopathic: autoimmune
(Ag is probably podocyte glycoprotein M-type phospholipase A-2 receptor)
o Complexes can form in situ (glomerular Ag) or from preformed complexes
that get filtered
Secondary to: chronic infection, drugs, autoimmune disease, malignancy.
o Anything that causes chronic low levels of circulating immune complexes
can start the process

Pathology:
think SUBEPITHELIAL IMMUNE COMPLEX DEPOSITS

LM: thick capillary walls

(immune complexes thicken them up)
Silver stain: may see spikes (basement membrane
extending out from / perpendicular to GBM in
reaction to deposits) and domes (same reaction,
when it surrounds deposit)

EM: subepithelial deposits

(between podocyte & BM)

IF: granular IgG & C3 along capillary walls

(immune complexes = granular)

Diabetic Nephropathy
Patient: Diabetics (40% of patients!), associated with poor glucose control
Remember: type I = no insulin, type II = insulin resistance, CHO / fat / protein metabolism messed up
Urine: Microalbuminemia at first  gradual increase to nephrotic range proteinuria
Course: Five clinical stages (see box: hyperfiltration  ERSD). HTN can complicate

Pathogenesis:
Diabetic Nephropathy
Hemodynamic alterations (increased glomerular
Stage I Early Increased GFR
pressures, hyperfiltration  damage)
Stage II Latent Asymptomatic
Glycosylated collagen (↓degradation  ↑ECM, Stage III Incipient Microalbuminuria
↓heparan sulfate  ↑anion loss) Stage IV Overt Proteinuria, decreasing GFR
Genetic predisposition Stage V End stage Fibrosis, Sclerosis

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Pathology of Diabetic Nephropathy:
Can have nodular sclerosis ± hyalinosis
o Increased amounts of matrix /
membrane form nodules called
Kimmelstiel-Wilson lesions

Diffuse mesangial matrix increase

Arteriolar hyalinosis is KEY (almost

always can see hyalinosis in arterioles!)

Thickened glomerular capillary walls

Thick basement membranes on EM

May have superimposed ischemic injury

(via arteriosclerosis from DM)

Capsular drops: blobs of hyaline in

Bowman’s capsule

IF: may see linear IgG & albumin along glomerular

capillary loops
No immune-type deposits! This are just
nonspecific plasma proteins building up

Therapy for Proteinuric Glomerular Diseases

Treatment Strategies
Treat or remove inciting diseases/factors (drug, neoplasm, autoimmune dz, infection)
Rx with steroids, other immunosuppressive drugs
prevent glomerular HTN / hyperperfusion - ACEI, ARB
Important to reduce proteinuria - will lead to tubular atrophy, fibrosis in time

A really basic summary table (from our small group; not exhaustive but main points)
Minimal Change Focal Segmental Glomerular Sclerosis Membranous
Age Kids Adults Adults
Nephrotic
Presentation Nephrotic Nephrotic
Foamy urine
Autoimmune Dz
Lung / colon cancer
Obesity
Associations Post-infection Infection (esp. HBV, HCV, malaria)
Heroin, HIV, Sickle Cell
Drugs (NSAIDs)
Cancer (esp. lung / colon)
LM Nothing Focal, segmental, sclerosis Thick capillary loops
Nothing
IF Nothing IgG & C3
(+/- secondary protein deposits)
“Fusion” – simplification Thick basement membrane
EM
– of foot processes Subepithelial deposits
Excellent response to
Treatment Most no response to steroids
steroids

13
 Glomerulonephritis
Terminology: diffuse vs focal, segmental vs global; also:
THE NEPHRITIC SYNDROME:
Exudative: GN where PMNs are significant Hematuria (can have RBC casts)
proportion of glomerulus Decreased renal function
(↑BUN & ↑serum creatinine)
Crescentic: extracapillary cell / matrix Proteinuria (variable, <3.5g/day)
proliferation (crescents) Edema
Hypertension
RBC casts: recapitulate inside of tubule (see on U/A) Decreased urine output

FORMS OF GLOMERULONEPHRITIS
Immune complex-related Pauci-immune Anti-GBM
Post-infectious Associated with ANCA:
IgA nephropathy anti-neutrophil cytoplasmic antibody
Renal-limited
Membranoproliferative Renal-limited Goodpasture’s Syndrome
(e.g. cryoglobulinemia) (“idiopathic” crescentic GN) (pulmonary involvement too)
Lupus nephritis Systemic vasculitis
Other uncommon forms (Wegener’s, microscopic polyangitis)

Post-Infectious Glomerulonephritis
Clinical presentation:
Group A, β-hemolytic STREP infection is #1
o Present 1-2wk after recovery from pharyngitis
o Gross hematuria (dark urine) common, low serum C3

Prognosis: excellent for complete recovery in children (small % adults  ERSD)

LM IF EM
Diffuse proliferative & Granular IgG & C3 Subepithelial HUMPS
exudative GN (in capillary loops, characteristic (with
mesangium) abnormal podocytes
± Crescents surrounding them)
(poor prognosis if many) C3 lasts longer
Subendothelial &
mesangial deposits too

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 IgA Nephropathy

Patient: Most common GN in world but uncommon in African-Americans

Presentation:
Microscopic hematuria ± proteinuria on routine exam or
Gross hematuria post-URI

Course: 40-50%  ESRD over 20 yrs

Prognosis: proteinuria > 1g/day & hypertension are bad
Treatment: ACEi/ARB, lots of others but not good evidence
Other: unknown etiology, probably related to henoch-schonlein purpura

LM IF EM
Focal, mesangial proliferative GN Granular IgA & C3 Mesangial deposits
(in capillary loops, mesangium)
Diffuse / crescentic: worse prognosis (Subendothelial too in ~25%)
IgG/M possible but ≪ IgA
Normal-looking: good prognosis
No C1q (lupus)

Membranoproliferative Glomerulonephritis
Epidemiology: Uncommon, 3 types but forms other than type I very rare
Presentation: Mixed nephrotic / nephritic, low C3

Course: Progression to ESRD is common

HIGH recurrence in renal transplants

Other: Subset of patients have mixed cryoglobulinemia (HCV +)

Etiology: Can be idiopathic (primary) or secondary to:

Bacterial infection
Viral infection (HCV / HBV)
Neoplasia

LM IF EM
Diffuse, proliferative GN & hyperlobular glomeruli Granular IgG & C3 (± IgM, C1q) Subendothelial & mesangial
(in capillary loops, mesangium) deposits
Double contours / TRAM TRACKS (PAS / silver)
Cryoglobulin coagula: IgG/IgM “duplication” of GBM
Cryoglobulinemia: Intracapillary pseudothrombi (separated because of deposits!)

15
 MPGN: pathology

Crescents
NOT specific for a given disease: indication of SEVERE GLOMERULAR INJURY

Acute: cellular crescents

Proliferated parietal epithelial cells, Mϕ, fibrin
Adhere to Bowman’s capsule
Can form shape of crescent or extend around entire circumference

Chronic: fibrocellular  fibrous crescents

Crescents scar over time

Can see interstitial inflammation, disruption of GBM

16
 DDx of Crescentic GN
1. Immune-complex mediated
a. lupus, MPGN, post-infectious GN, IgA nephropathy
b. Crescents = bad prognosis
c. Dx: show immune-complex deposits (IF or EM)

2. Pauci-immune
a. Don’t see deposits on IF or EM
b. Triggering of pathogenesis: PMNS activated  azurophilic granules
exposed  Ab bind  PMNs start degranulating  vasculitis (see
picture to right – can see acute lesions of small vessels)
c. 90% are ANCA positive (anti-neutrophil cytoplasmic antibodies)
Ab against PMN Staining Diseases

Microscopic polyangitis (MPA)

P-ANCA Myeloperoxidase Perinuclear (more often; rarely C-ANCA)
Pauci-immune crescentic GN

Wegener’s Granulomatosis
C-ANCA Pr3 Cytoplasmic
(more often, rarely P-ANCA)

3. Anti-GBM Nephritis
a. Least common of 3 causes of crescentic GN
b. Auto-Ab to portion of type IV collagen α3 chain (“Goodpasture antigen)
c. Dx: need LINEAR IgG in GLOMERULAR CAPILLARIES by IF
i. Confirm: ELISA (pt serum vs Goodpasture Ag)
ii. No deposits by EM
iii. 20-30% also ANCA positive
d. Ab can cross-react with pulmonary alveolar BM
(GOODPASTURE’S DISEASE)

Two examples of GBM IgG deposits: Linear vs Granular

Linear (left): nice and smooth (along the whole GBM)
Granular (right): concentrated where immune complex Ag are
17
A few tables:
Proliferative Glomerulonephropathies (summary from small group)
Acute( post-infectious)
Crescentic Membranoproliferative
glomerulonephritis
antiGBM Immune complex Pauci-immune
Type I Type II
(type I) (type II) (type III)
Nephritic Nephritic > nephritic Nephritic
Nephritic
ANCA (anti- Nephrotic > nephritic C3NcF (C3 nephritic Post-strep (GAS)
Clinical Goodpasture’s Nephritic
neutrophil factor – Ab that pharyngitis or
syndrome
cytoplasmic Ab) stabilizes C3 convertase) impetigo
Membranoproliferative Proliferative
LM Crescents
Tram-tracking PMNs in capillary loops
Granular
LINEAR Granular Granular Granular
IF Nothing IgG & C3, C4, C1q, etc
IgG & C3 IgG & C3 C3 mainly IgG & C3
(+/- IgM)
Ruptured GBM
Subepithelial Subendothelial Intramembranous Subepithelial and
EM (other crescentic Not much
deposits deposits deposits subendothelial deposits
forms too)

Nephrotic Vs. Nephritic (from lecture notes)

Nephrotic Nephritic
Proteinuria 3.5 grams/day present, but typically <3.5 grams/day
Urine Sediment +/- RBCs, no RBC casts many RBCs, often RBC casts
Edema present often present
Hypertension often absent (but may be present (especially in FSGS)) often present
Serum creatinine typically normal (but may be elevated (especially in FSGS)) usually elevated
Pathologic Features
Glomerular Histology normal cellularity hypercellular
Specific diseases Glomerulonephritis. including:
Non-inflammatory glomerulopathies. including:
post-infectious GN
Membranous
IgA nephropathy
Minimal change
membranoproliferative GN
FSGS
lupus nephritis (diffuse/focal proliferative)
Diabetic nephropathy
ANCA-associated (pauci-immune) GN
Amyloid
anti-GBM nephritis

18
 Renal Manifestations of Systemic Diseases
Remember that other systemic diseases with kidney manifestations are in other lectures:
Wegner’s, microscopic polyangiitis, Henoch-Schonlein purpura, HIV, diabetes, etc.

Systemic Lupus Erythematosus

Autoimmune disease involving multiple organ systems (esp. skin, joints,
bone/blood marrow, kidney, CNS) American Rheumatism Association
SLE Diagnostic Criteria
Not rare, women ≫ men, AA > Caucasians
1. Malar rash
Young adults most commonly (can see at any age) 2. Discoid rash- erythematous raised
patches with keratotic scaling
Circulating antibodies, especially ANA (ANTI-NUCLEAR ANTIBODIES) – 3. Photosensitivity – skin rash as a
directed against nuclear antigens reaction to sunlight
dsDNA, histones, nucleolar RNA, non-histone proteins, etc. 4. Oral nasopharyngeal ulcers
Just about all SLE pts have ANA but 5. Arthritis – involving ≥2 peripheral joints
POSITIVE ANA TITER NOT SPECIFIC FOR / DIAGNOSTIC OF SLE 6. Pleuritis or pericarditis
7. Renal disease – proteinuria >0.5
Clinical diagnosis (see box) – need ≥ 4, serially or simultaneously
grams/day or 4+ by dipstick, or RBC
Renal failure and infection are top 2 causes of death casts
8. Neurologic disorder – otherwise
unexplained seizures or psychosis
Lupus Nephritis 9. Hematologic disorder – hemolytic
anemia, leukopenia, or
70% of pts with SLE  renal involvement (lupus nephritis) thrombocytopenia
10. Antibody to DNA, Smith antigen
General features of lupus nephritis (anti-Sm), or phospholipid
11. Positive ANA titer – in absence of drugs
IF: “FULL HOUSE” staining (IgG/A/M + C3, C1q), esp. in class III/IV known to be associated with this (e.g.,
C1q is almost always present hydralazine)
Tubular basement membrane deposits Need ≥ 4, serially or sequentially

Electron microscopy: tubulo-reticular inclusions (endothelial cell cytoplasm)

Not specific, but most often in lupus nephritis + HIV; from exposure to IFN-α

Classification of Lupus Nephritis (subclasses too for II and IV)

Class Name Description
I Minimal mesangial lupus nephritis Normal glomeruli (LM), mesangial deposits (IF)
II Mesangial proliferative lupus nephritis Pure mesangial hypercellularity and/or mesangial matrix expansion
III Focal lupus nephritis < 50% glomeruli
IV Diffuse lupus nephritis > 50% glomeruli
V Membranous lupus nephritis ± mesangial changes; can be in combination with III/IV
VI Advanced sclerosing lupus nephritis ≥90% globally sclerosed glomeruli

Key idea: Lupus can present in a LOT of different ways in the kidney. Path pics on next few pages.

19
 ↑ Lupus Nephritis TYPE II: mesangial proliferative ↑

↑ Lupus Nephritis TYPE III (focal) / IV (diffuse) ↑

Can also have crescents in either kind; note full house staining in capillary walls & mesangium

20
 ↑ Lupus Nephritis TYPE V (membranous)↑
Note that this looks like “Membranous Glomerulopathy” (page 12) from the nephrotic syndrome lecture

Summary table

Class II Class III Class IV Class V

Description mesangial focal proliferative diffuse proliferative membranous
Frequency (- class I) 15% 20% 50% 15%
hematuria,
hematuria and nephritic or
Clinical pres non-nephrotic nephrotic
proteinuria nephritic/nephrotic
proteinuria
mesangial cell & endocapillary GN in endocapillary GN in capillary loop
LM
matrix increase <50% glomeruli > 50% glomeruli thickening
subENDOthelial, subENDOthelial, subEPIthelial,
EM Deposits mesangial
mesangial mesangial usu. mesangial

Transformations: the different classes can transform from one to another

Indices for prognosis of lupus

Activity: how active is the disease Chronicity: how chronic is the disease?
Each scored 0-3 Each scored 0-3
Glomerular cell proliferation Wire loops, hyaline thrombi Glomerular sclerosis
Cellular crescents x2 (bad) Glomerular WBC infiltration Fibrous crescents
Fibrinoid necrosis / karyorrhexis x 3 Interstitial mononuclear cell Interstitial fibrosis
(really bad) infiltrate Tubular atrophy

Activity > 9 = ↑ renal failure; chronicity >4 = worse progression (more eventual renal failure)
Helps you decide how aggressive to be in treatment

21
 Light Chain Cast Nephropathy “myeloma kidney”
Most common renal manifestation of light chain disease
o Can be 1st presenting symptom of myeloma or monoclonal gammopathy
Usually presents as acute renal failure
Light chains (EITHER κ OR λ) + acidic urine + Tamm-Horsfall glycoprotein  large CASTS
o Casts obstruct tubules
o Casts have FRACTURED appearance (artifact of fixing) – if you hear “fractured cast,” think light chain cast
o Cast often surrounded by cells in tubule, including multinucleated giant cells
IF: either κ OR λ (light chain restriction)

Fractured casts (note how they’re IF: κ positive IF: λ negative

broken up, arrowhead) with cell
reaction (maybe a multinucleated
giant cell in tubule with arrow?)

22
 Amyloid
Two major types
AL (“primary”) amyloid AA (“secondary”) amyloid
Light chains, λ > κ Plasma protein SAA
Amyloid protein derived from…
(L is for “light”) (Type AA is SAA)
Conditions that overproduce light chains
Chronic inflammatory conditions
85-90% monoclonal production
In setting of… (e.g. rheumatoid arthritis, TB,
47% have myeloma
osteomyelitis, Sub-Q-injection drug users)
Most common > 50yo

Can only distinguish AL from AA by IF or IHC

Renal amyloidosis: proteinuria (often nephrotic syndrome)
o HTN & hematuria uncommon

LM findings EM findings
Mesangial expansion by :
Extracellular, randomly-oriented,
Eosinophilic, CONGO RED POSITIVE, acellular material
thin, non-branching FIBRILS
Blood vessels also frequently involved

Amyloid (arrow): fluffy, pink, Left: Congo red positive IF: positive for lambda light
acellular. Glomerulus looks Right: Congo-red-stained amyloid turns green chain (primary / AL amyloid)
hypocellular under polarized light (both AL & AA, only amyloid
has this birefringence)

Left: amyloid Right:EM of amyloid

deposits eventually deposit with fine,
destroying entire randomly oriented
structure here, fibrils
pushing up &
narrowing capillary
lumen, replacing
mesangium

23
 Light Chain Deposition Disease
Least common of 3 renal manifestations
o 60% pts have multiple myeloma Clinical presentation & course
Renal insufficiency & proteinuria
κ > λ (opposite of AL-amyloid) Poor renal survival (35% @ 5yrs)

LM findings Silver Stain EM findings

light chain deposits in tubular & 60%: nodular granulosclerosis (like diabetic finely granular
glomerular BASEMENT nephropathy, but silver-stain negative deposits
MEMBRANES deposits in LCDD)

Left: Nodular glomerular appearance. Need to ddx from diabetic nodular granulosclerosis using silver stain
(center: material is silver NEGATIVE in LCDD, right: silver positive in diabetic glomerulopathy)

Far left: IF
positive for κ-
light chain in
TUBULAR
BASEMENT Right: EM:
MEMBRANE continuous,
granular, dense
near left: deposits in
negative for λ- SUBENDOTHELIAL
light chain GBM

24
 Thrombotic Microangiopathy
Not a specific disease but a type of lesion
Endothelial cell injury in capillaries, arterioles, and/or small arteries
o Swelling of endothelial cells with detachment from BM
Subendothelial accumulation: fluid, fibrin cell debris
Intraluminal fibrin/platelet thrombi
Trauma to circulating RBCs – microangiopathic hemolytic anemia
o fragmented and distorted RBCs (“schistocytes”) – see picture

DDx of thrombotic microangiopathy involving kidney

Glomeruli / Arterioles > arteries Arteries / Arterioles > glomeruli
Hemolytic-uremic syndrome (HUS)
Thrombotic thrombocytopenic purpura (TTP) Scleroderma
Anti-phospholipid syndrome (± SLE) Malignant hypertension
Certain drugs (cyclosporine, etc.)
Post-partum ARF (post-partum HUS)

Thrombotic microangiopathy: Hemolytic-uremic syndrome (HUS)

D+ (diarrhea positive) – “classic” / “epidemic” D- (diarrhea negative) – “atypical” /“sporadic”
Majority of cases, mainly in kids
Some epidemics: infected meat (e.g. hamburgers) Adults & children
E. coli O157:H7 - shiga-like (vero-) toxin producing Etiology unclear
o Toxin binds to receptors on endothelial cells Often arterioles / small arteries involved – worse
Renal disease follows several days of diarrhea prognosis
Mainly glomerular involvement – good prognosis

Symptoms of HUS
One of main causes of ARF in children microangiopathic hemolytic anemia
See box for symptoms thrombocytopenia
renal failure
occasional CNS involvement
(cause of mortality in childhood HUS)

Thrombotic microangiopathy: Thrombotic Thrombocytopenic Purpura (TTP)

Most often adults < 40 yo, women > men “Classic” TTP clinical syndrome
Classic syndrome: see text box Fever
Significant renal insufficiency: only 50% pts Microangiopathic hemolytic anemia
Pathogenesis: vWF cleavage implicated Thrombocytopenic purpura
80% survival of acute dz with plasma exchange Neurologic manifestations
(formerly uniformly fatal) Renal failure

25
 Pathology of TTP & HUS
Fibrin/platelet thrombi in glomerular capillaries / arterioles (> arteries)
Glomeruli: RBC fragments, RBC stasis, or “bloodless” (due to endothelial swelling )
Separation of endothelial cell from GBM and production of new GBM – “Double contours”
Loss of mesangial cells and matrix (“mesangiolysis”)
RBC and RBC fragments within arterioles; may show focal fibrinoid necrosis
Best prognosis: glomerular involvement only (involvement of arteries = poor prognosis)

HUS glomerulus: Lots of red Congestion in glomerulus: fibrin thrombi &

(fragmented RBC in capillaries), fragmented RBC in capillary loops (all stuffed up)
lumen lost (endothelial swelling)

Glomerulus: diffusely simplified tuft Focal loss of foot processes; EM: widened subendothelial space with
with fragmented RBC swollen endothelial cells with electrolucent material (double arrow),
subendothelial deposits RBC (arrow)

26
 Scleroderma (systemic sclerosis)
Characterized by excessive collagen deposition at multiple sites
Skin, GI tract, kidney, blood vessels, musculoskeletal involvement common
Limited & more indolent forms exist

Etiology: unknown (abnormal T-cell activation, cytokine release, 1° injury to endothelium unknown)
Lab findings: ANA positive usually; <50% have anti-DNA-topo-I Ab (specific if present)
Major problem: SEVERE HTN with ARF (“SCLERODERMA RENAL CRISIS”)

Kidney involvement: up to 70% cases (not always renal crisis)

Small arteries: major findings here Arterioles: commonly involved Glomeruli: variable involvement
Mucoid intimal hyperplasia Endothelial swelling Ischemia-related changes (e.g.
(concentric proliferation of cells in Focal fibrinoid necrosis capillary collapse)
intima  “onionskin lesion”) Luminal thrombi Can have HUS-like changes (capillary
Intima often has fibrin / RBC RBC/RBC fragments in vessel wall thrombi, fragmented RBCs)
fragments too
VASCULAR CHANGES LOOK LIKE MALIGNANT HTN – but can happen in absence of HTN

Note huge space between endothelial cells (very

center) & internal elastic lamina (blue ring on outside) Fibrinoid necrosis (arrows):
– filled with smooth muscle cells from media! note both small arteries & arterioles are involved)

Left:

Ischemic glomerulus with capillary

collapse (arrow): wrinkled capillary
loop with ↓ # open capillaries

onion-skin lesion (arrowhead):

concentric narrowing in small artery

27
 Tumors of Bladder & Kidney
Urothelial (transitional cell) Cancer of the Bladder
Epidemiology: 70k cases, 14k deaths in 2008 (USA)
Male > Female (3:1) – esp. older males like most GU tumors
o Majority present in localized stages (early stage  good tx options)
Big health care cost burden – starts superficially, keep recurring, progress  more aggressive
o We don’t know who’s going to progress – keep monitoring!  $$$ ($4B/yr)
o Most expensive cancer per patient
Risk factors
Carcinogen exposure: carcinogens in urine, not via bloodstream
o Smoking: up to 2/3 M bladder ca, pack-years is big risk, slow acetylators ↑ smoking related risk (40%)
o Occupational exposure: up to 25% UrCa (aromatic amines, rubber, petroleum, paint, textile dye, etc)
o Iatrogenic cancers: chemo, phenacetin, X-ray Rx, cyclophos
o Arsenic in chlorinated water (China, Chile)
Familial: only 8% (not as much as some other cancers). Muir-Torre syndrome is one example
Schistosomes in Egypt

Clinical Presentation & Evaluation

Gross / microscopic hematuria (70%)
Irritation (10%): dysuria, urgency, frequency (esp CIS)
Cytoscopy & transurethral tesection (TUR) biopsy: gold standard of Dx
o Understaging: 15-50% muscularis propria sampling
o Overstaging: muscularis propria vs muscularis mucosa – need to discern where you are in bladder

Two groups of urothelial tumors (start in urothelium, can become invasive)

Superficial (non-muscle invasive) urinary carcinoma Muscle invasive urinary carcinoma
Majority (70-80%) Minority (20-30%)
only 5-10% progress to invasive 15% have prior superficial urinary carcinoma
(but 50% recur as non-invasive) 80-90% are “primary” muscle invasive UrCa
Can be flat or papillary Practically all are high grade
o Only 20-50% overall survival

“Recurrent urothelial tumor” – different from other tumors

Recurrence in other organs: incomplete resection  regrowth of tumor
Urothelial tumor: may be shed tumor cells from initial tumor  implant & grow in other areas of bladder
May be multifocal new tumors (from field effect of chemical carcinogens in urine)

Bladder cancer: Carcinoma In-Situ (CIS)

• Flat morphology • Dyscohesive – positive cytology
• Cytologically malignant cells in any quantity • By definition – High grade
• Increased mitotic figures (risk for deeper muscle invasive disease)

28
 CIS: enlarged cells with ↑ N/C ratio,
CIS in bladder – dark spots Dyscohesion: structure falling apart
no maturation, ↓ organization,
(flat lesions)
arrows = mitotic figures

Prognosis:
40-83% progress to muscle invasion with resection only
Variable course (protracted  rapid invasion)
With tx (BCG): 80% initial response, 50% 4-yr response, 30% dz-free @ 10yrs
If refractory: 30% have muscle invasion @ cystectomy

Bladder cancer: Papillary Urothelial Carcinoma

Classification
• Papilloma – Mostly cured with excision
• Papillary urothelial neoplasm of low malignant potential – May recur yet otherwise no morbidity
• Low grade papillary urothelial carcinoma – May recur and rarely lead to significant morbidity and death
• High grade papillary urothelial carcinoma – Frequently recur with significant morbidity and occasional mortality

Papillary structure: finger-like Lower-grade lesion: cytology Higher-grade: still have fibrovascular core; some ugly
projections somewhat more regular; epithelial nuclei, ↑ N/C ratio, abnormal hyperchromatic
on outside; fibrovascular core chromatin

Papillary vs CIS: Non-invasive Urothelial Carcinomas

Prognosis: generally better than CIS
(only 3% papillary  invade) CIS Papillary
Risk of “recurrence” 82% 50%
Risk of invasion into muscle 75% 3%
29
 Muscle Invasive Urothelial Carcinomas

Primary (most, present @ advanced stage) or secondary to non-invasive UrCa

Worse prognosis: only 20-40% @ 5 yrs

Lots of yellowy necrosis here Bundles of smooth muscle with invading urothelial
(invading muscle layers) carcinoma cells pushing into this deep muscular layer

Two phenotypes, two genetic pathways

Superficial & muscle-invasive urothelial (transitional cell) carcinomas have different genetic lesions!
Superficial TCC Muscle invasive TCC
Clinical phenotype Generally more limited 50% pts die in 5-10 yrs with tx
15% can progress to muscle invasive Distal metastasis kills you
Molecular pathway Tyrosine RK (H-RAS/FGFR3) P53 / RB

Treatment of urothelial carcinomas

Small, unifocal, non-invasive or
Transurethral resection (TUR) only
superficially invasive papillary
TUR
Larger, multifocal, recurrent,
Intravesical immunotherapy with BCG
high-grade non-invasive,
(attenuated M. bovis to ↑ local immune response & inflammatory reaction)
superficially invasive, or
Radical cystectomy (refractory to BCG or invasive into bladder muscularis propria)
CIS
o Men: take out the prostate too!

Renal Cell Carcinoma

Epidemiology Peak: 50s, 2:1 M:F

Risk factors Clinical features

• Tobacco Symptom triad: PAIN, HEMATURIA, ABDOMINAL MASS
• Obesity: BMI >29 have double the risk? Paraneoplastic syndromes:PTH, EPO, PG, ACTH
• Acquired and hereditary polycystic diseases Changing presentation: more imaging so seeing smaller
• Familial RCC Syndromes masses now

30
 RCC: types
Type % all RCC Picture Prognosis Other
Cell mutations interfere with H1F1α
(oxygen sensor in cell) – fools cell
into thinking that it’s hypoxic!
Clear cell Intermediate
60-80%
carcinoma (stage dependent) Sends out all kinds of vascular
proliferation factors (VEGF, etc) 
very vascular tumor
Yellow fat – clear cells filled with fat & glucagon

Very good
Papillary RCC 10-18%
(resect!)

Papillary (see cross-sections of the projections)

Excellent!
Chromophobe 2-6% Cure if confined to
kidney

Perinuclear halo, plant-like, thick cell membranes

Collecting duct Aggressive
Medullary Rare Dismal
Sarcomatoid Can see with any of above morphologies Agrgressive

31
 RCC: Prognosis & Treatment
Prognosis:
Age & gender of patient
Anatomy: pTNM staging (where is it?)
Histology: type (table above) & Furhman grade (cytology)

5 year survival
Localized: 70-90%
Regional: 40-50%
Distant metastasis: < 5%
o Most often to lung & bones
o but predilection for unusual sites
o Can metastasize many years post-resection

Treatment:
Local disease Advanced disease
Radical or partial nephrectomy Immunotherapy
Wedge resection Anti-angiogenic agents
In-vivo ablation Tyrosine kinase inhibitors

32
 Pediatric Renal and Bladder Tumors
Carcinomas ↓ in kids (don’t have chronic exposure of adults)
Most common pediatric cancers: lymphoma,
Most common pediatric…
leukemia, brain, sarcomas, neuroblastomas, etc.
Kidney tumor: WILMS’ TUMOR (nephroblastoma)
o Kidneys: 6% of pediatric cancers
Bladder tumor: RHABDOMYOSARCOMA

Wilms’ Tumor

Most common pediatric renal tumor: WILMS’ TUMOR (84%)

Can be favorable histology (80%) or anaplastic (4%)
Others: congenital mesoblastic nephroma (5%), clear cell sarcoma of kidney (4%), rhabdoid tumor of kidney (2%)

Embryonal tumors: microscopic appearance recapitulates the normal developmental histology of their organ
“-blastomas” – neuroblastoma, retinoblastoma, hepatoblastoma, etc.
Nephroblastoma = Wilms’ tumor

Quick embryology review

4th wk Metanephric duct (ureteric bud)
penetrates lateral mesoderm, induces it
to condense into the metanephric
blastema
th
4-8 Ureteric bud branches, dilates renal
wks pelvis, collecting ducts formed
th
8-36 Ureteric bud’s collecting ducts signal
wks metanephric blastema to form
glomeruli.

12 generations of glomeruli formed here

– this is the stage that Wilms’ tumor
recapitulates

Patient: YOUNG KIDS (median age 3.5yo, 90% ≤ 6yo)

Presentation: abdominal mass
5% bilateral: think of associated syndromes (WAGR, Denys-Drash, Beckwith-Wiedemann)
o Or if you have a pt with one of these, check their kidneys via imaging often!
Spread: LN, liver, lungs

Prognosis: very good for classic Wilm’s (95% overall survival)

33
 Wilms’ tumor: morphology
Classic Wilms’ tumor is TRIPHASIC
Tumor Element Recapitulates… Looks like…
Blastema Metanephric blastema Deep blue nuclei, scant cytoplasm
Like they’re trying to form structures but not quite getting there
Epithelium Glomerular / tubular epithelium Glomeruli & tubules
Stroma Surrounding renal mesenchyme Spindle cells, bunches, few nuclei
Can also differentiate  other tissues (blastema = primitive cell line!)
o Skeletal muscle, cartilage, squamous / mucous differentiation, etc.

Other Pediatric Renal Tumors

Prognosis: need to know stage & histopathology
Tumor % Prognosis Picture Other
Classic Wilm’s 80% See above
Looks aggressive but isn’t
Lots of mitoses, spindle-
Congenital
Good looking cells, ↑ N/C ratio
mesoblastic 5%
Has good prognosis even
nephroma
without chemo!
Just resect!

Looks like Renal CCC

Clear cell sarcoma No epithelial features
4% Intermediate
of the kidney Better prognosis these days
(adriamycin)

34
 Tumor % Prognosis Picture Other

Markedly enlarged nuclei

with numerous mitotic
Anaplastic Wilm’s figures
4%
Tumor Poor response to chemo
p53 mutations
(unlike classic Wilm’s)

Poor
Sheets of cells with pink
cytoplasm & eccentric nuclei

Rhabdoid tumor Lots of mitotic figures

2%
of the kidney
Bad & Sad: Very aggressive
with poor prognosis & 90%
<2 yrs old

Rhabdomyosarcoma (#1 pediatric bladder cancer)

Malignant tumor of primitive skeletal muscle cells
Q: Doesn’t make sense- bladder has smooth muscle around it?
A: Arises from primitive mesenchymal cell (differentiates skeletally in the tumor)
Prognosis: based on stage & histopathology type
Alveolar rhabdomyosarcoma – round cells
Embryonal rhabdomyosarcoma – spindled cells

Botryoid embryonal rhabdomyosarcoma is most common peds bladder cancer

Botryoid = “grape-like” (see pictures) – projects into bladder lumen like a bundle of grapes

Grape-like projections into bladder lumen Projections into lumen, Arrows: rhabdomyoblasts
on gross pathology actual location of tumor is (can even see some
more interior (arrow) striations sometimes)

35
 Pathology of Hypertensive Nephrosclerosis
Primary / Essential HTN (no one specific cause) Secondary HTN: results from specific abnormality
Renal parenchymal dz (Glomerulonephritis, FSGS)
Genetic & environmental factors Renal artery stenosis
Most adult HTN is essential HTN Tumors (pheochromocytoma, adrenal cortical adenoma)
AA > Caucasians for incidence Pregnancy-related (e.g. pre-eclampsia)
Drugs (e.g. oral contraceptives)

Hypertensive Nephrosclerosis: changes in the kidney as a result of HTN (1° or 2°)

Benign nephrosclerosis: renal changes resulting from chronic, mild, or moderate HTN
o maybe not so benign (can and does cause ESRD)
Malignant nephrosclerosis: renal changes resulting from malignant HTN (see description below)
Remember: changes in other organs too! (atherosclerosis / vascular dz / hemorrhagic stroke / LVH in heart)

Benign Nephrosclerosis
Gross Path Arteries Arterioles
↓ kidney size intimal thickening
cortical narrowing narrowing of lumen
Hyaline arteriolosclerosis
granular surface (untreated  scars) duplication of internal elastic lamina
sometimes small cortical cysts (± mild medial hypertrophy)
Glomeruli Tubules & Interstitium
↑ # globally sclerotic glomeruli (esp. subcapsular cortex)
Tubular atrophy
periglomerular fibrosis
Interstitial fibrosis
sometimes mild ↑ mesangial matrix

Above: Globally sclerotic glomeruli (left Above: Mesangial proliferation (like DM, but w/o
center), replaced by collagen; tubules & thickened BM), hyaline replacing wall in arteriole
interstitium OK in some places (lower L) (arrow), would be very PAS positive
shrunken / absent in others (lower R)

Above: L: HTN nephrosclerosis, R:

normal. Note shrinkage of kidney,
fine pitting pattern externally;
very thin cortex (arrow)
Right: Original internal elastic
lamina (arrowhead) & fibrotic
thickening of intima (arrow) with
incomplete loops & coils of elastica Above: special stain for elastic, see thickend intima with
(trying to protect self from ↑ extra layers of elastic (response to ↑ luminal pressure)
pressure). Also another hyaline
small vessel (diamond)

36
 Malignant Hypertension
Pathophysiology: poorly understood (probably RAAS is important)
Malignant (accelerated) HTN:
↑ renin (ischemic kidney produces), prominent JGA in ischemic kidney DBP ≥ 130-140 mm Hg
Return to normal BP after unclipping (surgery) Associated retinal hemorrhages,
exudates, papilledema
Earliest renal sx: proteinuria ± hematuria Can be 1° or 2
Systemic symptoms: Can be ± previous HTN Hx
Visual disturbances Yearly incidence: 1-2/100k
Headaches
Nausea/vomiting
Transient loss of consciousness

Can cause rapid & irreversible renal damage  ESRD (if not treated)
POTENTIALLY FATAL (prior to antiHTN Rx, majority died within months; much more uncommon today)

Gross Path Arteries & Arterioles

Normal/swollen size, smooth surface (if no underlying benign nephrosclerosis)
Fibrinoid necrosis of vessel walls
Shrunken / granular surface (if underlying benign neprhosclerosis)
“ONION SKINNING”: Mucoid
Small hemorrhages with areas of pallor (from ischemia)
intimal hyperplasia
Occasionally small cortical infarcts (central pallor, hemorrhagic borders)
Glomeruli Tubules & Interstitium
Acutely:
Focal ischemic ATN (acute tubular necrosis)
Collapsed / wrinked capillary loops
(ischemia / poor perfusion)
with mild interstitial edema
Segmental necrosis (from preglom. arteriole)
Over time:
Same changes as benign nephrosclerosis if underlying
Tubular atrophy & interstitial fibrosis
(can also be from underlying benign nephrosclerosis)

37
 Malignant Nephrosclerosis: Pathology

Lots of small hemorrhages (dark areas) on surface Would want to treat this patient to ↓ edema 
open lumen before damage becomes permanent

Thrombi / fibrin on damaged wall of small vessel (arrow), More onion skinning
ONION SKINNING (arrowhead)

Left: hypertrophied JGA (trying to

improve perfusion by ↑ renin but can’t
because of renal stenosis, for example)

38