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
Abnormal reabsorption
(fluid/electrolyte loss, Fanconi’s syndrome – can’t reabsorb anything!)

CAUSES OF TUBULAR INJURY / DYSFUNCTION Primary
Ischemia Nephrotoxins Immunologic

Electrolyte / acid-base abnormalities GFR failure (fluid overload, hyperkalemia, toxins build up)

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

Sublethal Injury

Secondary

Normal: interconnected epithelium, PAS + brush border & more mitochondria in PT (vs DT)

Osmotic Injury: very swollen but still have PAS + brush border, some lacking mitochondria

Flattened cells, gaps in epithelium (arrowhead), apical blebbing of cytoplasm into lumen

EM: Loss of brush border & blebbing in lumen

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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
o junctions & adhesion molecules that keep apical & basolateral sides separate) Can’t generate gradients & now more permeable (leak stuff out into urine)

Note from picture: big vacuoles, less mitochondria, ultrastructural derangement

Lethal Injury
Cellular Coagulative necrosis Apoptosis Cell detachment
o Can see dead cells in tubules (drifted down from upstream site of injury) and in urine

Subcellular Major disruptions in Ca / electrolytes / ATP Proteins / organelles disrupted / dysfunctional Cell membrane disrupted Nuclear breakdown (karyorrhexis)

Normal: interconnected epithelium, PAS + brush border & more mitochondria in PT (vs DT)

Necrotic cells inside a relatively intact tubule: drifted down from upstream

Necrotic tubules: lots of dead tubule cells, disruption & clogging of tubules

Apoptotic figures in two tubular cells

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 like neoplasia) , mitotic figures with apoptosis Subcellularly: new genes expressed & new proteins formed (different markers)
Arrowhead: flatter cells, spread out, mesenchymal

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Inflammation plays a role too: marker of ischemic injury See RBC & WBC in vasa recta Probably attracted by chemotactic substances released from injured tubule cells & capillary endothelium Creates congestion & low flow (ischemia can result)

Endothelial dysfunction too: Edema from lack of endothelial integrity; NO lost, so less vasodilation Capillary “sludging” (RBC & WBC stuck in capillary b/c ↑adhesion molecules & ↑constriction) 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 Maybe bigger structural injury, more frank necrosis Can be generalized or segment-specific (e.g. PT only) Some path agents have distinctive lesions (see below) Effects from interference with oxidative metabolism ↑ free radicals  cell damage NEPHROTOXIC AGENTS Antibiotics (gentamicin, ampho B) Radiographic contrast Chemotherapy (cisplatin) Lithium, mushrooms, insecticides

Calcineurin Inhibitors: Isometric vacuolization (small, equal-sized vacuoles)

Aminoglycosides: Myeloid bodies (see these things on EM)

Indinivar: Crystalization (big crystal here – check out tubule size in comparison)

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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
Responsible for 15% acute RF, 25% chronic RF Can be 1° (± 2° tubule injury), or 2° to tubule injury – hard to tell which came first if you see them both o If huge inflammatory infiltrate (or if PMNs, eos, granulomas present) probably interstitial first

CAUSES OF INTERSTITIAL NEPHRITIS / FIBROSIS
Infection o Direct (incl. pyelonephritis) o Indirect (systemic inflammatory reaction – to drugs, parasites, viruses, etc.) Drugs Immune-mediated (Ab or cell-mediated) 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 (pyelonephritis) & streaking (pus in tubules), some hemorrhage too

Bigger cortical abscess

PMNs in a cast inside of a tubule, also in wall & interstitium (bacterial infection)

Cast with WBC and bacteria (in urine, seen here on EM) – can help with Dx

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 protein  new complex presented to T-cells  response

Offending drugs:
Abx (PCNs, sulfonamides) Thiazide diuretics NSAIDs Herbal meds Others (lots!)

Amplification via cytokine release
(from inflammatory & tubulointerstitial cells)

Sx: may have fever/rash/eos in blood
days/weeks post-exposure

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 6

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) Results: chronic renal failure, concentrating defects, fluid / electrolyte imbalances

Shrunken tubules, mononuclear cell infiltrate, zoom: would see fibrosis (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)

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Vesicouretral Reflux (VUR)
Retrograde propulsion of bladder urine into ureters Most often from abnormal implantation of ureters into bladder
o o more perpendicular angle between bladder wall & ureter 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 Infection
o o o o Complement activation Edema, Ischemia/Reperfusion Free radical release Tubular damage, ischemia (capillary compression)

Pathology:
Dilation (pelvis / calyces) Thinning of parenchyma Papillae flattened, cortical tubules atrophy Interstitial fibrosis CLASSIC FINDING: Coarse segmental scars over dilated calyces at POLES ± inflammation

Elevated pressure Hyperperfusion/Hyperfiltration in remaining
nephrons  more sclerosis

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

1) 2) 3) 4)

FAST FACTS: CHRONIC INTERSTITIAL NEPHRITIS / SCARRING Caused by prolonged interstitial inflammation, chronic ischemia, reflux, obstruction with back pressure from collecting system, (also, secondary to vascular, glomerular diseases). Characterized morphologically by fibrosis, inflammation (mononuclear) in tubulointerstitum; glomeruli often spared until late in course. Is the “pivotal lesion in nephrology,” correlating with prognosis in all renal diseases. 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
Diffuse vs Focal Global vs Segmental Sclerosing / sclerosis Proliferative / hypercellular % of glomeruli involved Extent of involvement of an individual glomerular tuft
only part or the whole thing?

The Nephrotic Syndrome • • • • • Proteinuria > 3.5 gm/24 hrs Hypoalbuminemia Edema (from ↓oncotic pressure) Increased serum lipids* (Doubly refractile fat bodies in urine - from ↑ serum lipids)

“Hard” (increase in matrix in the tuft)
proteinuria ± heme

Increase in intrinsic glomerular and/or inflammatory cells
hematuria ± proteinuria (Glomerular hematuria = GBM abnormality / injury)

*(liver cranking out more of everything to try to make more albumin)

Nephrosis vs Nephritis
Urine Inflammation & proliferation in glomeruli
Nope Yes – inflammation / complement cause capillary injury with blood, cells getting across GBM

In general
Nephrosis is COOL Nephritis is HOT

-osis / -otic -itis / -itic

Proteinuria, not hematuria, Cellular casts Hematuria ± renal failure Cellular casts

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. (more problems like CVD)

MAIN CAUSES OF NEPHROTIC SYNDROME:
1. Minimal Change Disease 2. Focal & Segmental Glomerulosclerosis (with hyalinosis) 3. Glomerulonephritis 4. Generalized systemic diseases (diabetes, amyloid, SLE)

Major problem is podocyte injury (can see hypertrophy, de-differentiation, or just loss of charge – but function is lost so filter messed up!)

Prevalence varies with race and age

Minimal Change Disease
Patient: Urine: Course: Treatment: Prognosis: mostly children (2-6yo) selective proteinuria (albuminuria ≫ other proteins) relapsing / remitting steroids (good response; give empirically to a kid with proteinuria) 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: Urine: Course: Treatment: Prognosis: both children & adults, more common in African Americans proteinuria poorly selective (not albuminuria like MCD) can recur in allografts, hematuria & HTN more frequent poor response to steroids; plasmapheresis post-transplant to avoid (remove unknown circulating factor)
ACEI may help too post-transplant (reduce glomerular capillary pressure)

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:
Capillaries collapse & large hypertrophic podocytes seen (dedifferentiating?) Podocyte loses its grip: detach from capillary loops; no structural support Esp in HIV pts; parvovirus B19 / viral involvement?

Left: Arrow: giant podocyte! Right: note big space on EM between damaged podocyte & GBM

“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: Urine: Course: Treatment: Prognosis: Adults (peak = middle age, M>F a bit) proteinuria poorly selective Sudden presentation, usually only trace hematuria. poor response to steroids; no good evidence supporting one therapy over another 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: Urine: Course: Diabetics (40% of patients!), associated with poor glucose control
Remember: type I = no insulin, type II = insulin resistance, CHO / fat / protein metabolism messed up

Microalbuminemia at first  gradual increase to nephrotic range proteinuria Five clinical stages (see box: hyperfiltration  ERSD). HTN can complicate
Diabetic Nephropathy Early Increased GFR Latent Asymptomatic Incipient Microalbuminuria Overt Proteinuria, decreasing GFR End stage Fibrosis, Sclerosis

Pathogenesis: Hemodynamic alterations (increased glomerular pressures, hyperfiltration  damage) Glycosylated collagen (↓degradation  ↑ECM, ↓heparan sulfate  ↑anion loss) Genetic predisposition

Stage I Stage II Stage III Stage IV Stage V

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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)
Age Presentation Minimal Change Kids Nephrotic Focal Segmental Glomerular Sclerosis Adults Nephrotic Foamy urine Obesity Heroin, HIV, Sickle Cell Focal, segmental, sclerosis Nothing (+/- secondary protein deposits) Membranous Adults Nephrotic Autoimmune Dz Lung / colon cancer Infection (esp. HBV, HCV, malaria) Drugs (NSAIDs) Cancer (esp. lung / colon) Thick capillary loops IgG & C3 Thick basement membrane Subepithelial deposits Most no response to steroids

Associations

Post-infection

LM IF EM Treatment

Nothing Nothing “Fusion” – simplification – of foot processes Excellent response to steroids

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

Immune complex-related Post-infectious IgA nephropathy Membranoproliferative
(e.g. cryoglobulinemia)

Anti-GBM Renal-limited Goodpasture’s Syndrome (pulmonary involvement too)

Renal-limited
(“idiopathic” crescentic GN)

Lupus nephritis Other uncommon forms

Systemic vasculitis
(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 Diffuse proliferative & exudative GN ± Crescents
(poor prognosis if many)

IF Granular IgG & C3 (in capillary loops, mesangium) C3 lasts longer

EM Subepithelial HUMPS characteristic (with
abnormal podocytes surrounding them)

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: Prognosis: Treatment: Other: 40-50%  ESRD over 20 yrs proteinuria > 1g/day & hypertension are bad ACEi/ARB, lots of others but not good evidence unknown etiology, probably related to henoch-schonlein purpura IF Granular IgA & C3 (in capillary loops, mesangium) IgG/M possible but ≪ IgA No C1q (lupus) EM Mesangial deposits (Subendothelial too in ~25%)

LM Focal, mesangial proliferative GN Diffuse / crescentic: worse prognosis Normal-looking: good prognosis

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 Subset of patients have mixed cryoglobulinemia (HCV +)

Other:

Etiology: Can be idiopathic (primary) or secondary to: Bacterial infection Viral infection (HCV / HBV) Neoplasia LM Diffuse, proliferative GN & hyperlobular glomeruli Double contours / TRAM TRACKS (PAS / silver) Cryoglobulinemia: Intracapillary pseudothrombi IF Granular IgG & C3 (± IgM, C1q) (in capillary loops, mesangium) Cryoglobulin coagula: IgG/IgM EM Subendothelial & mesangial deposits
“duplication” of GBM (separated because of deposits!)

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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

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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

C-ANCA

Pr3

Cytoplasmic

Wegener’s Granulomatosis
(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)
Crescentic antiGBM
(type I) Nephritic Goodpasture’s syndrome Crescents LINEAR IgG & C3 Ruptured GBM (other crescentic forms too) Granular IgG & C3 Subepithelial deposits Nothing

Membranoproliferative Pauci-immune
(type III) Nephritic ANCA (antineutrophil cytoplasmic Ab)

Acute( post-infectious) glomerulonephritis

Immune complex
(type II) Nephritic

Type I
Nephrotic > nephritic

Type II
Nephritic > nephritic C3NcF (C3 nephritic
factor – Ab that stabilizes C3 convertase)

Clinical LM IF EM

Membranoproliferative Tram-tracking Granular Granular IgG & C3, C4, C1q, etc C3 mainly (+/- IgM) Subendothelial deposits Intramembranous deposits

Nephritic Post-strep (GAS) pharyngitis or impetigo Proliferative PMNs in capillary loops Granular IgG & C3 Subepithelial and subendothelial deposits

Not much

Nephrotic Vs. Nephritic (from lecture notes)
Nephrotic
Proteinuria Urine Sediment Edema Hypertension Serum creatinine Glomerular Histology Specific diseases 3.5 grams/day +/- RBCs, no RBC casts present often absent (but may be present (especially in FSGS)) typically normal (but may be elevated (especially in FSGS)) normal cellularity Non-inflammatory glomerulopathies. including: Membranous Minimal change FSGS Diabetic nephropathy Amyloid

Nephritic
present, but typically <3.5 grams/day many RBCs, often RBC casts often present often present usually elevated hypercellular Glomerulonephritis. including: post-infectious GN IgA nephropathy membranoproliferative GN lupus nephritis (diffuse/focal proliferative) ANCA-associated (pauci-immune) GN anti-GBM nephritis

Pathologic Features

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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) Not rare, women ≫ men, AA > Caucasians Young adults most commonly (can see at any age) Circulating antibodies, especially ANA (ANTI-NUCLEAR ANTIBODIES) – directed against nuclear antigens
dsDNA, histones, nucleolar RNA, non-histone proteins, etc.

American Rheumatism Association SLE Diagnostic Criteria
1. Malar rash 2. Discoid rash- erythematous raised
patches with keratotic scaling 3. Photosensitivity – skin rash as a reaction to sunlight

Just about all SLE pts have ANA but POSITIVE ANA TITER NOT SPECIFIC FOR / DIAGNOSTIC OF SLE Clinical diagnosis (see box) – need ≥ 4, serially or simultaneously Renal failure and infection are top 2 causes of death

4. Oral nasopharyngeal ulcers 5. Arthritis – involving ≥2 peripheral joints 6. Pleuritis or pericarditis 7. Renal disease – proteinuria >0.5
grams/day or 4+ by dipstick, or RBC casts 8. Neurologic disorder – otherwise unexplained seizures or psychosis 9. Hematologic disorder – hemolytic anemia, leukopenia, or thrombocytopenia 10. Antibody to DNA, Smith antigen (anti-Sm), or phospholipid 11. Positive ANA titer – in absence of drugs known to be associated with this (e.g., hydralazine)

Lupus Nephritis
70% of pts with SLE  renal involvement (lupus nephritis) General features of lupus nephritis IF: “FULL HOUSE” staining (IgG/A/M + C3, C1q), esp. in class III/IV C1q is almost always present 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) Name Description Minimal mesangial lupus nephritis Normal glomeruli (LM), mesangial deposits (IF) Mesangial proliferative lupus nephritis Pure mesangial hypercellularity and/or mesangial matrix expansion Focal lupus nephritis < 50% glomeruli Diffuse lupus nephritis > 50% glomeruli Membranous lupus nephritis ± mesangial changes; can be in combination with III/IV Advanced sclerosing lupus nephritis ≥90% globally sclerosed glomeruli

Class I II III IV V VI

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

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↑ 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

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

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

Transformations: the different classes can transform from one to another Indices for prognosis of lupus Activity: how active is the disease Each scored 0-3
Glomerular cell proliferation Cellular crescents x2 (bad) Fibrinoid necrosis / karyorrhexis x 3 (really bad) Wire loops, hyaline thrombi Glomerular WBC infiltration Interstitial mononuclear cell infiltrate

Chronicity: how chronic is the disease? Each scored 0-3
Glomerular sclerosis Fibrous crescents Interstitial fibrosis 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 broken up, arrowhead) with cell reaction (maybe a multinucleated giant cell in tubule with arrow?)

IF: κ positive

IF: λ negative

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Amyloid
Two major types

AL (“primary”) amyloid
Amyloid protein derived from… In setting of… Light chains, λ > κ (L is for “light”) Conditions that overproduce light chains
85-90% monoclonal production 47% have myeloma Most common > 50yo

AA (“secondary”) amyloid
Plasma protein SAA (Type AA is SAA) Chronic inflammatory conditions
(e.g. rheumatoid arthritis, TB, osteomyelitis, Sub-Q-injection drug users)

Can only distinguish AL from AA by IF or IHC Renal amyloidosis: proteinuria (often nephrotic syndrome) o HTN & hematuria uncommon LM findings Mesangial expansion by : Eosinophilic, CONGO RED POSITIVE, acellular material Blood vessels also frequently involved EM findings Extracellular, randomly-oriented, thin, non-branching FIBRILS

Amyloid (arrow): fluffy, pink, acellular. Glomerulus looks hypocellular

Left: Congo red positive IF: positive for lambda light chain (primary / AL amyloid) Right: Congo-red-stained amyloid turns green under polarized light (both AL & AA, only amyloid has this birefringence)

Left: amyloid deposits eventually destroying entire structure here, pushing up & narrowing capillary lumen, replacing mesangium

Right:EM of amyloid deposit with fine, randomly oriented fibrils

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Light Chain Deposition Disease
Least common of 3 renal manifestations o 60% pts have multiple myeloma κ > λ (opposite of AL-amyloid) LM findings light chain deposits in tubular & glomerular BASEMENT MEMBRANES Clinical presentation & course Renal insufficiency & proteinuria Poor renal survival (35% @ 5yrs) EM findings finely granular deposits

Silver Stain 60%: nodular granulosclerosis (like diabetic nephropathy, but silver-stain negative 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 κlight chain in TUBULAR BASEMENT MEMBRANE near left: negative for λlight chain

Right: EM: continuous, granular, dense deposits in SUBENDOTHELIAL GBM

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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
Hemolytic-uremic syndrome (HUS) Thrombotic thrombocytopenic purpura (TTP) Anti-phospholipid syndrome (± SLE) Certain drugs (cyclosporine, etc.) Post-partum ARF (post-partum HUS)

Arteries / Arterioles > glomeruli
Scleroderma Malignant hypertension

Thrombotic microangiopathy: Hemolytic-uremic syndrome (HUS)
D+ (diarrhea positive) – “classic” / “epidemic”
Majority of cases, mainly in kids Some epidemics: infected meat (e.g. hamburgers) E. coli O157:H7 - shiga-like (vero-) toxin producing o Toxin binds to receptors on endothelial cells Renal disease follows several days of diarrhea Mainly glomerular involvement – good prognosis

D- (diarrhea negative) – “atypical” /“sporadic”
Adults & children Etiology unclear Often arterioles / small arteries involved – worse prognosis

One of main causes of ARF in children See box for symptoms

Symptoms of HUS microangiopathic hemolytic anemia 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 syndrome: see text box Significant renal insufficiency: only 50% pts Pathogenesis: vWF cleavage implicated 80% survival of acute dz with plasma exchange (formerly uniformly fatal) “Classic” TTP clinical syndrome Fever Microangiopathic hemolytic anemia Thrombocytopenic purpura Neurologic manifestations Renal failure

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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 with fragmented RBC

Focal loss of foot processes; swollen endothelial cells with subendothelial deposits

EM: widened subendothelial space with electrolucent material (double arrow), RBC (arrow)

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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 capillary collapse) Focal fibrinoid necrosis Can have HUS-like changes (capillary intima  “onionskin lesion”) Luminal thrombi thrombi, fragmented RBCs) Intima often has fibrin / RBC RBC/RBC fragments in vessel wall 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) – filled with smooth muscle cells from media!

Fibrinoid necrosis (arrows): 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

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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 o Understaging: 15-50% muscularis propria sampling 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
Majority (70-80%) only 5-10% progress to invasive (but 50% recur as non-invasive) Can be flat or papillary

Muscle invasive urinary carcinoma
Minority (20-30%) 15% have prior superficial urinary carcinoma 80-90% are “primary” muscle invasive UrCa 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 Cytologically malignant cells in any quantity Increased mitotic figures • • Dyscohesive – positive cytology By definition – High grade (risk for deeper muscle invasive disease)

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CIS in bladder – dark spots (flat lesions)

CIS: enlarged cells with ↑ N/C ratio, no maturation, ↓ organization, arrows = mitotic figures

Dyscohesion: structure falling apart

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 projections

Lower-grade lesion: cytology somewhat more regular; epithelial on outside; fibrovascular core

Higher-grade: still have fibrovascular core; some ugly nuclei, ↑ N/C ratio, abnormal hyperchromatic chromatin

Prognosis: generally better than CIS (only 3% papillary  invade)

Papillary vs CIS: Non-invasive Urothelial Carcinomas Risk of “recurrence” Risk of invasion into muscle

CIS 82% 75%

Papillary
50% 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 (invading muscle layers)

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

Renal Cell Carcinoma
Epidemiology Peak: 50s, 2:1 M:F Risk factors • Tobacco • Obesity: BMI >29 have double the risk? • Acquired and hereditary polycystic diseases • Familial RCC Syndromes Clinical features Symptom triad: PAIN, HEMATURIA, ABDOMINAL MASS Paraneoplastic syndromes:PTH, EPO, PG, ACTH Changing presentation: more imaging so seeing smaller masses now

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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! Sends out all kinds of vascular proliferation factors (VEGF, etc)  very vascular tumor

Clear cell carcinoma

60-80%

Intermediate
(stage dependent)

Yellow fat – clear cells filled with fat & glucagon

Papillary RCC

10-18%

Very good
(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 Medullary Sarcomatoid Rare Can see with any of above morphologies Aggressive Dismal Agrgressive

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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 o o Most often to lung & bones but predilection for unusual sites Can metastasize many years post-resection

Treatment: Local disease Radical or partial nephrectomy Wedge resection In-vivo ablation

Advanced disease Immunotherapy Anti-angiogenic agents Tyrosine kinase inhibitors

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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)

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Wilms’ tumor: morphology
Classic Wilms’ tumor is TRIPHASIC Tumor Element Recapitulates… Blastema Metanephric blastema Looks like… 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 Classic Wilm’s 80% Picture See above Looks aggressive but isn’t Lots of mitoses, spindlelooking cells, ↑ N/C ratio Has good prognosis even without chemo! Just resect! Other

Congenital mesoblastic nephroma

5%

Good

Clear cell sarcoma of the kidney

4%

Intermediate

Looks like Renal CCC No epithelial features Better prognosis these days (adriamycin)

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Tumor

%

Prognosis

Picture

Other Markedly enlarged nuclei with numerous mitotic figures Poor response to chemo p53 mutations (unlike classic Wilm’s)

Anaplastic Wilm’s Tumor

4%

Poor

Sheets of cells with pink cytoplasm & eccentric nuclei Lots of mitotic figures Bad & Sad: Very aggressive with poor prognosis & 90% <2 yrs old

Rhabdoid tumor of the kidney

2%

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 on gross pathology

Projections into lumen, actual location of tumor is more interior (arrow)

Arrows: rhabdomyoblasts (can even see some striations sometimes)

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Pathology of Hypertensive Nephrosclerosis
Primary / Essential HTN (no one specific cause)
Genetic & environmental factors Most adult HTN is essential HTN AA > Caucasians for incidence

Secondary HTN: results from specific abnormality
Renal parenchymal dz (Glomerulonephritis, FSGS) Renal artery stenosis Tumors (pheochromocytoma, adrenal cortical adenoma) 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
↓ kidney size cortical narrowing granular surface (untreated  scars) sometimes small cortical cysts

Arteries
intimal thickening narrowing of lumen duplication of internal elastic lamina (± mild medial hypertrophy) Tubular atrophy Interstitial fibrosis

Arterioles
Hyaline arteriolosclerosis

Glomeruli
↑ # globally sclerotic glomeruli (esp. subcapsular cortex) periglomerular fibrosis sometimes mild ↑ mesangial matrix

Tubules & Interstitium

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 (trying to protect self from ↑ pressure). Also another hyaline small vessel (diamond)

Above: special stain for elastic, see thickend intima with extra layers of elastic (response to ↑ luminal pressure)

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Malignant Hypertension
Pathophysiology: poorly understood (probably RAAS is important) ↑ renin (ischemic kidney produces), prominent JGA in ischemic kidney Return to normal BP after unclipping (surgery) Earliest renal sx: proteinuria ± hematuria Systemic symptoms:
Visual disturbances Headaches Nausea/vomiting Transient loss of consciousness

Malignant (accelerated) HTN:
DBP ≥ 130-140 mm Hg Associated retinal hemorrhages, exudates, papilledema Can be 1° or 2 Can be ± previous HTN Hx

Yearly incidence: 1-2/100k

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
Normal/swollen size, smooth surface (if no underlying benign nephrosclerosis) Shrunken / granular surface (if underlying benign neprhosclerosis) Small hemorrhages with areas of pallor (from ischemia) Occasionally small cortical infarcts (central pallor, hemorrhagic borders)

Arteries & Arterioles
Fibrinoid necrosis of vessel walls “ONION SKINNING”: Mucoid intimal hyperplasia

Glomeruli
Collapsed / wrinked capillary loops
(ischemia / poor perfusion) Segmental necrosis (from preglom. arteriole)

Tubules & Interstitium
Acutely: Focal ischemic ATN (acute tubular necrosis) with mild interstitial edema Over time: Tubular atrophy & interstitial fibrosis
(can also be from underlying benign nephrosclerosis)

Same changes as benign nephrosclerosis if underlying

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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), ONION SKINNING (arrowhead)

More onion skinning

Left: hypertrophied JGA (trying to improve perfusion by ↑ renin but can’t because of renal stenosis, for example)

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