Review of Renal Anatomy and Histology with Introduction to Renal Pathology (Robbins pp. 931-936)
Renal anatomy
Renal Histology Distribution of glomerular damage
CL – capillary lumen
MES – mesangium
END – endothelium
EP – visceral epithelial cells w/ foot processes

Pattern of glomerular injury
Injury Presentation Description capillary wall alterations proteinuria
GBM alterations proliferation proteinuria (permeable to albumin) hematuria may be thickened due to immune complexes may be thickened due to accumulation of structural proteins

in cells either intrinsic (e.g., mesangial cells) or extrinsic (e.g., e.g., inflammatory), may have deposits necrotizing cellular crescents fibrocellular crescent fibrous crescent dysmorphic rbcs w/ rbc casts in urine, acute renal failure clinically “RPGN” necrosis usually w/ disruption of capillary wall & fibrinoid change defn – 2 cellular layers occupying min 1/3 of circumference

in cells in Bowman’s space (parietal epithelial cells & m

), often see fibrin, if >80% glomeruli w/ crescents

“crescentic GN” same as above but w/ fibrosis fibrous scar which may or may not have arisen from cellular/fibrocellular crescents hyalinosis sclerosis proteinuria acellular, structureless material located in capillary lumen consisting of glycoproteins & sometimes lipids

in mesangial matrix or fibrosis w/ glomerular collapse or occlusion

glomerular scar; possible final pathway
IF patterns
 granular – due to discrete deposits of immune complexes, best seen on capillary loops
 linear – smooth, global staining of GBM
 mesangial – w/in mesangial matrix
EM patterns

 epithelial cell injury – effacement of foot processes and microvillous transformation subepithelial deposits – btw epithelial cells and GBM
 subendothelial deposits – btw endothelial cells and GBM
 mesangial matrix deposits – in mesangium
Immune complex deposition
In situ deposition
 antibodies to GBM deposit on GBM itself (linear IF pattern) (e.g., anti-GBM GN)
 antibodies to intrinsic glomerular antigens (granular IF pattern) (e.g., Heymann’s nephritis, , membranous GN)
 nonglomerular antigens bind to GBM, antibodies bind to planted antigen
Circulating immune complex deposition
 complexes trapped in glomerular filter

incite inflammatory response
Progression of renal injury
 end stage renal disease

compensatory hypertrophy,

glomerular pressure, systemic HTN
Clinical manifestations of renal disease

 acute nephritic syndrome – hematuria, mild to moderate proteinuria, HTN nephrotic syndrome – heavy proteinuria (> 3.5 g/d), hypoalbuminemia, severe edema, hyperlipidemia, lipiduria
 asymptomatic hematuria or proteinuria – subtle/mild glomerular abnormalities
 acute renal failure – oliguria or anuria, recent onset of azotemia
 chronic renal failure – prolonged symptoms and signs of uremia
 renal tubular defects – polyuria, nocturia, electrolyte disorders
 urinary tract infection – bacteriuria, pyuria
 nephrolithiasis (renal stones) – renal colic, hematuria, recurrent stone formation
 urinary tract obstruction and renal tumors – varied manifestations
Renal failure
 diminished renal reserve – GFR 50% of normal, serum BUN and Cr values normal, pts asymptomatic
 renal insufficiency – GFR 20% to 50% of normal, azotemia appears, anemia, HTN, polyuria, nocturia
 renal failure – GFR less than 20% to 25% of normal, edema, metabolic acidosis, hypocalcemia, overt uremia
 end-stage renal disease – GFR less than 5%, end stage of uremia

Medical Renal Disease (Robbins pp. 942-968)
Nephrotic Syndrome – proteinuria > 3.5 g/d, hypoalbumenia (< 3.5 g/dL), edema, hyperlipidemia/hypercholesterolemia, little or no hematuria
Disease
Minimal Change Dz
(Lipoid Nephrosis, Nil
Dz)
Focal & Segmental GN
(Focal Sclerosis, FSGS)
Membranous
Nephropathy
Diabetic Nephropathy
Amyloid
Epi
 children
(most)
 also adults

 freq in adults

African
 adults
 leading

 uncommon in children
Americans cause of nephrotic syndrome adults 10-20 yrs after onset of diabetes adults w/ multiple myeloma
 familial in others
Path
 cause: unknown

LM: nl glomeruli, lipids in tubular cells

IF: no staining

EM: diffuse effacement of epi foot processes, microvillous transformation of epi cell
 protein & lipid in prox tubule
 cause: 1 o (idiopathic)/2 o (HIV, morbid obesity,

renal mass)

LM: segmental sclerosis (

mesangial matrix), hyalinosis, atrophy of prox tubule

IF: passive trapping of IgM, C3

EM: diffuse effacement of epi foot processes, separation of epi cells from GBM (vacuolization), cell swelling, proliferation
 mech includes circulating factor, hemodynamic injury, glom hypertrophy, hyperlipidemia, 1 o injury or dysfxn of glom cells
 cause: 1 o (idiopathic)/2 o (HBV, SLE, gold therapy); immune-complex mediated

LM: uniform thickening of the GBM on H&E or PAS stains, silver stain will see spikes

IF: granular capillary-loop of IgG, C3

EM: subepi electron dense deposits (spikes = GBM rxn to deposits), effacement of epi foot processes, microvillous transformation
 little glom cell prolif or inflam exudate
 cause: poor metabolic control, hyperfiltration, genetic factors, HTN

LM: marked uniform thickening of GBM &

of mesangial matrix w/o

cells, periph spherical accumulations (Kimmelstiel-Wilson nodules), hyaline arteriosclerosis (aff and eff arterioles)

IF: linear Ig, albumin

EM: homogenous thickened GBM w/o deposits
 cause: deposition of light chains, chronic infxns, chronic dialysis, familial

LM: amorphous pink material in all 4 compartments, stains positively w/ Congo red & shows circular dichroism under polarized light

IF: kappa or lambda chains

EM: microfibrils
 manifestation of plasma cell dyscrasias
Clinical/Rx
 nephrotic syndrome, but nl renal fx
 diagnosis of exclusion
 rx w/ steroids, sometimes spontaneous remission
 nephrotic syndrome, renal insufficiency,
HTN, hematuria
 can progress to renal failure
 recurs in transplants at relatively high freq
 rx w/ steroids somewhat helpful

 chronic GN can occur
 rx w/ steroids,
 lower extremity edema, mild renal insufficiency sometimes spontaneous remission, sometimes nothing works microalbuminuria progressing to nephropathy (nephrotic syndrome & mild renal insufficiency)
 rx w/ good metabolic &
HTN control (slow progression)
 no rx

Nephritic Syndrome – inflamm damages glom capillaries

hematuria (rbc casts/smoky, brown urine), oliguria, azotemia, HTN, mild proteinuria, mild edema
Disease
IgA Nephropathy
(Berger’s Dz)
Post Infectious GN
(Post Strep GN)
Lupus Nephritis (LN)
Membranoproliferative
GN (MPGN)
Type I
Type II – Dense
Deposit Dz (DDD)
Epi
 young adults

> in males

Asia, W.
Eur,
Mexico

 women
 renal dz

 common in children young imp cause of morbidity, death in
SLE older children & young adults relatively rare
Path
 cause: unknown;

synthesis of IgA by gut, errors of IgA processing by liver

LM: mild to moderate diffuse proliferation of mesangial cells & matrix, cellular crescents rare

IF: granular IgA deposits in mesangium

EM: mesangial electron dense deposits, focal or no foot process effacement
 cause: serum sickness (Ag-Ab complexes

trapped in
 glom

accumulate & stimulate C’

inflamm
LM:

in mesangial cells & varying numbers of inflamm cells (PMNs) w/ endo cell swelling, cellular crescents, inflamm & edema in interstitium

IF: diffuse granular IgG, C3 (IgA, IgM) around cap loops

EM: electron dense material

“humps” subepi
 strep common; also staph, pneumo, others
 cause: SLE (autoimmune immune complexes)

LM/EM:
 normal glomeruli
 mesangial proliferative (nl/

cells) – LM shows

 matrix, EM shows mesangial deposits focal proliferative – segmental

cells < 50%, EM shows deposits in mesangium, subendo space
 diffuse proliferative – same as above, but > 50%
 membranous – spikes, subepi deposits, mesangial deposits

IF: full house mesangial or cap, IgG, IgA, IgM, C3, C1q

EM: tubuloreticular inclusions in endo cells
 cause: complement, 2 o causes (Hep C)

LM: diffuse global thickening of capillary loops accompanied by

numbers of mesangial cells & accumulation of mesangial matrix, double contours on silver stain (GBM split)
 IF: granular C’ (C3) in mesangium, periph cap loops

EM: Type I – excess matrix containing deposits, mesangial cells extend to subendo space, subendo deposits, endo cells make GBM

double contours, foot process effacement,
Clinical/Rx
 viral illness 1-2 d before
 recurrent microscopic or gross hematuria & proteinuria
 slowly prog HTN & renal insuff

20% lose renal fxn
 no rx, but usually no sequelae

 rx w/ steroids, other immunosuppressive type II worse prognosis
Anti-GBM Dz
(Goodpasture’s Dz)
GBM Dz:
Alport’s Hereditary
Nephritis (AHN)
GBM Dz:
Thin Basement
Membrane Disorder


2


> in young men, but at any age nd peak in elderly females mild
 males CRF by 40 children & adults
 familial microvillous transformation

EM: Type II – massive, very electron dense deposits in lamina densa of capillary GBM, GBM appears scalloped
 cause: circulating IgG Ab

interacts w/ Goodpasture’s Ag
(subunits of NC1 domain of collagen IV), viral infxn, smoking, hydrocarbons

LM: crescentic GN

IF: linear IgG, C3 in GBM

EM: collapse of cap loops, frag of GBM, no GBM deposits
 cause: lack Goodpasture’s Ag - 
mech fragility & breakage of GBM
 micro/macro hematuria; COL4A5 gene

LM: early nl, later focal sclerosis or proliferative GN, foam cells (glomeruli, interstitium)

IF: no staining

EM: (diagnosis) – segmental thickening & splitting of
GBM

layered, other segments show marked thinning
 cause: unknown

LM/IF: unremarkable

EM: marked thinning of GBM



 pulmonary hemorrhage followed by ARF rx w/ steroids, cytotoxic drugs, plasmaphoresis penetrance important deficits in hearing, mental retardation, platelet abnormalities
 renal transplants for
AHN pts

anti-GBM nephritis
 no rx

Nephrotic Syndromes
Minimal Change Disease FSGS
LM: looks normal
EM: foot effacement and microvillous transformation
LM: focal
Membranous Nephropathy
LM: segmental
LM: spikes on silver stain
LM: cellularity normal, thickened capillary loops
IF: granular, IgG, C3 EM: subepi deposits

Nephritic Syndromes
IgA nephropathy
LM: mesangial cellularity
Post Strep GN
LM: hypercellularity (epi, endo, mesan, PMNs), poorly defined capillary loops
IF: mesangial, IgA
No image available
EM: mesangial electron dense deposits, focal or no foot process effacement
IF: diffuse, granular, bumpy, IgG, C3, (IgA, IgM)
EM: subepithelial “humps”

A B
Goodpasture’s Disease
Membranoproliferative
GN (MPGN) on silver staining or
PAS staining, will see double contours of split
GBM
A = Type I subendo deposits in mesangium
B = Type II dense deposits in lamina densa, notice
“scalloped look”
Crescents
Crescentic GN caused by SLE (lupus nephritis)
IF: linear, IgG, C3
RPGN may idiopathic or caused by SLE, PSGN, vasculitis, Goodpasture’s
LM: crescent
LM: capillary wire loops seen in SLE

Male Reproductive System (Robbins pp. 1011-1034)
Prostate
Inflammations
 acute bacterial prostatitis – minute, dissemin’ abscesses; large necrotic areas; or diffuse edema, congestion, suppuration
 chronic prostatitis – aggregation of lymphocytes, plasma cells, macrophages, PMNs
Benign Prostatic Hypertrophy (Hyperplasia)
 epidemiology
 common in men over 50
 
w/ age (90% in 8 th decade)
 pathology/pathogenesis
 large hyperplastic nodules in central, periurethral region of prostate
 composed of glandular & stromal proliferation
 may be caused by testosterone (DHT) or advancing age
 clinical
 arise when nodules compress and narrow urethra

dysuria
 usually no rx, but 5-10% need surgery if serious urinary tract obstruction
 finasteride (anti-androgen) somewhat helpful
Carcinoma
 epidemiology

3 rd leading CA death in men (11% of CA deaths)
 
w/ age (peak in 8 th decade)

Af-Am > Caucasians > Asians
 occult CA common (9/10 remain undetected & clinically unimportant)
 pathology/pathogenesis
 most lesions adenocarcinoma (back-to-back acini w/ little stroma), in peripheral zone of gland
 gritty and firm tissue, felt best by palpation
 prostatic intraepithelial neoplasia (PIN) may be precursor to frank carcinoma (many of the same features)

Gleason grade

1 = well-differentiated (small to medium glands closely spaced)

3 = moderately differentiated (cribiform patterns)

5 = poorly differentiated (cords, nests, solid sheets, individual cells w/ anaplastic features)

Gleason score
 sum Gleason grades from 2 most prevalent types
 score < 4 = well differentiated, rx is conservative
 score > 5 = moderately to poorly differentiated, rx is aggressive

Staging – spread occurs by direct local invasion, lymphogenous spread, or hematogenous spread a occult or clinically unsuspected b palpable by rectal, but confined to prostate c local extension beyond prostate (seminal vesicles, bladder, lymph nodes) d metastases
 clinical

PSA = 4-10 (stage a/b)

localized prostate CA; PSA > 10 (stage c/d)

invasive/metastatic prostate CA
 virtually diagnostic if find osteoblastic metastases in bone
 rx w/ orchiectomy, radiation, or estrogen therapy
Testes
Cryptorchidism
 epidemiology – 0.3-0.8% of males, unilateral 75%, bilateral 25%
 pathology – congenital anomaly characterized by incomplete descent of one or both testes into scrotal sac
 clinical
 sequelae – 1.) infertility (

in interstitial stroma, Leydig cell hyperplasia), 2.) 10x-40x

risk of testicular CA
 rx w/ orchiopexy (surgical repositioning) at around 2 yrs of age
Torsion
 twisting of spermatic cord resulting in altered blood supply

hemorrhage/infarction

requires emergency surgery

Atrophy
 due to atherosclerosis, end stage inflamm orchitis, cryptorchidism, hypopituitarism, malnutrition/cachexia, obstruction to semen outflow, irradiation, estrogen rx to prostate CA, Klinefelter’s syndrome (XXY)
Inflammation
 epididymitis > orchitis
 in children, epididymitis associated w/ congenital genitourinary abnormalities
 in sexually active men, epididymitis associated w/ Chlamydia trachomatis & Neisseria gonorrhoeae infxn
 syphilis first affects the testis
 mumps orchitis unilateral & self-heals
Tumors

Germ Cell Tumors (95% of testicular CA)
 factors 1.) cryptorchidism, 2.) genetics, 3.) testicular dysgenesis

Seminoma (30% of germ cell tumors)
 typical variant (85% of seminomas)
 sheets of uniform cells w/ infiltration of septa by lymphocytes
 large individual cells, well-defined membranes, clear cytoplasm, large nuclei, prominent nucleoli
 anaplastic variant (5-10% of seminomas)
 greater cellularity, nuclear irregularity
 spermatocytic variant (4-6% of seminomas)
 slow growing that affects men > 65, does not metastasize, excellent prognosis
 not seen in children
 chemo and radiotherapy works for pure seminomas
 most AFP & HCG negative, but may see PLAP on tissue by immunoperoxidase staining

Embryonal carcinoma (3% of germ cell tumors in pure form, 45% of germ cell tumors in mixed form)
 has glandular, alveolar, tubular, or sheet-like growth patterns
 individual cells have indistinct borders, marked variation in cell and nuclear size and shape
 see AFP on immunoperoxidase staining or in serum

Yolk sac tumor (infantile embryonal carcinoma, endodermal sinus tumor)
 most common in infants and children
 contain AFP

Choriocarcinoma
 highly malignant arising from placenta, ovary, or totipotential cells in mediastinum or abdomen
 contains 2 cell types
 syncytiotrophoblast – large, multinucleate, contains HCG
 cytotrophoblast – regular, polygonal cells w/ distinct cell borders

Teratoma
 derivatives from more than one germ layer (ectoderm, mesoderm, endoderm)
 ectodermal only (skin, hair, sebaceous glands) – cystic, filled w/ sebaceous material & hair (dermoid cysts)
 benign (collection of mature tissue) usually occur in children
 malignant (contain embryonic tissue) usually occur in adults – lack of malignant cytologic features
 when contains areas of adenocarcinoma, squamous carcinoma, sarcoma

“teratoma w/ malignant transformation”

Mixed tumors

60% of testicular cancer is mixed
 most common mixture (14%) is teratoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma
 if seminoma part of MCGT (mixed cell germ cell tumor), then prognosis better than NS-MGCT (nonseminomatous mixed cell germ cell tumor)

Staging

Stage I – tumor confined to the testis

Stage II – tumor confined to the retroperitoneal nodes below the diaphragm

Stage III – tumor outside the retroperitoneal nodes above the diaphragm

Sex Cord-Gonadal Stromal Tumors (4-6% of testicular CA)

Leydig cell tumors
 epi – 2% of testicular CA
 path – cell cytoplasm may contain lipid granules, vacuoles, lipochrome pigment & characteristic rodshaped crystalloids of Reinke, most benign
 clinical – boys

precocious puberty; men

nothing or gynecomastia

Sertoli cell tumors (androblastoma) – most benign, freq in cryptorchid testes

Germ Cell Tumors
Seminoma showing poorly demarcated lobules and clear cells
Embryonal carcinoma showing sheets of undifferentiated cells and glandular elements
Choriocarcinoma w/ clear cytotrophoblastic cells w/ central nuclei and syncytiotrophoblastic cells w/ multiple dark nuclei

Neoplastic Disease of the Urinary Tract (Robbins pp. 991-994, 999, 1003-1008)
Neoplasms of the Urothelium normal histology – 5-7 layers thick (>7 abnl), lined by superficial “umbrella” cells (w/ asymmetric unit membrane)
Epithelial Tumors of the Bladder
 classification – based on pattern of growth, cell type, cytologic abnormalities, papillary vs. non-papillary, carcinoma-in-situ
 etiologic agents
 cigarette smoking is the most important factor
 industrial chemicals –

-naphthylamine & biphenyl compounds (both in dyes of textiles, paints, plastics, rubber, cable)
 environmental exposure – artificial sweeteners, Schistosoma may cause squamous bladder tumors
 genetic – chromosome 9 deletions (also 17 and 14)
 grading – based on epithelium thickness, mitosis, polarity, presence of umbrella cells, nuclear chromatin abnormalities

Grade 0 –

Grade I – urothelial papilloma urothelial neoplasm, low malignant potential
100% 5-yr survival
>90% 5-yr survival

Grade II –

Grade III –
 staging urothelial carcinoma, low grade urothelial carcinoma, high grade
>50% 5-yr survival
<10% 5-yr survival
Depth of Invasion Stage 5-yr survival
Noninvasive, papillary Ta 80%
Noninvasive, flat
Lamina propria
Superficial muscularis propria
TIS
T1
T2
40%
Deep muscularis propria
Perivesical fat
T3a
T3b 20%
Adjacent structures T4
Lymph node metastases (<2 cm) N1 6%
Lymph node metastases (2-5 cm) N2
Lymph node metastases (>5 cm) N3
Distant metastases M1
 subclassification
 papillary carcinoma (90% of all 1 o bladder tumors, will often recur in Grades I,II,III)
 clinical – males:females (3:1), older pts (6 th -7 th decade), painless gross or microscopic hematuria, frequency, urgency, dysuria, pyelonephritis, hydronephrosis
 gross – looks like red sea anemone, found in trigone & lateral walls, w/ narrow or broad stalk
 microscopic – well differentiated have delicate fronds while poorly differentiated may have invasion
 non-papillary (invasive, high grade)
 clinical – past hx of papillary neoplasia
 gross – flat, ulcerated, bulky lesions anywhere in bladder
 microscopic – high grade, squamous or glandular
 sessile carcinoma-in-situ (may give rise to non-papillary, may be near papillary CA, 4% of all bladder CA)
 clinical – 60% progress to invasive
 gross – red, velvety patch
 microscopic – full thickness mucosal involvement by undifferentiated cells, no invasion
 metastases – to regional lymph nodes then to liver and lungs
 prognosis – 90% recurrence rate, see grading and staging section
 treatment – local/radical surgery, local chemo/radiation
 special studies/techniques

Ag – ABH, Lewis A & B on normal, but Lewis X & T on neoplastic
 morphometry – quantify shape, abnormalities

DNA ploidy – diploid tumors better prognosis than aneuploid
 chromosomal structure – none
 genes/products – overexpression of ras family & mutations of p53 & Rb
 cell kinetics – use Ab

Primary Neoplasms of the Kidney
Tumor
Epidemiology
Clinical
Gross features
Histopathology
Nephroblastoma
(Wilm’s Tumor)
 peak during 2 yoa, 50% dx by 3 yoa, 75% dx by 5 yoa
 no sex, geographical, or racial difference
 tends to be familial (chromosome 11 abnormalities)
 assc’ w/ sporadic aniridia, hemihypertrophy, Beckwith-
Wiedemann syndrome (macroglossia, omphalocele, gigantism, adrenal cytomegaly, visceromegaly)
 abd mass (90%)

HTN, abd pain, anorexia, nausea, vomiting, fever, constipation, gross hematuria
 mets in 25% of presentations
 calcification rare
 
erythropoietin levels
 related to congenital mesoblastic nephroma & solitary multilocular cysts of kidney
 usually unilateral (5.8% bilateral)
 large (mean 12 cm, 540 g)
 on section, soft, gray-tan, bulging
 National Wilms’ Study Group

Group I – limited to kidney

Group II – beyond kidney, but totally removed

Group III – beyond kidney & tumor remains

Group IV – hematogenous spread
 may have epithelial, stromal, blastematous
 tubular/glandular differentiation

better prognosis
Pathogenesis
 persistent nodules of metanephric blastema (periphery of renal lobules & beneath capsule)
Renal Adenocarcinoma
(Hypernephroma, Grawitz Tumor)

6 mths to old age (peak in 6 th decade), adults
 males:females (3:1)
 pts w/ Von Hippel-Lindau dz (phakomatosis)
 nonpapillary

chromosome 3 deletions/ translocations
 papillary

show trisomies
 painless, gross or microscopic hematuria
 pain, renal mass, pyrexia, wt loss, fatigue, GI
& NM complaints
 erythrocytosis (sometimes

erythropoietin)
 anemia (normochromic, normocytic)
 hypercalcemia (make parthormone)
 amyloidosis (incidental)
 dx w/ x-ray, radioisotopic scan, CT, US, FNA
 both sides involved, bilateral 1-2%

<3 cm or >10 cm
 protrudes from cortical surface as yellow to gray mass
 bulging lobulated appearance
 tumor gray-yellow w/ hemorrhage, necrosis
 pseudocapsule many times
 papillary, cystic, sarcomatoid, tubular
 columnar/cuboidal in tubular/glandular pattern
 pleomorphism modest
 cytoplasm pale to eosinophilic
 highly vascular, w/ glycogen, lipid
 similar to prox convoluted tubules (both have tightly packed microvilli)
 causes include hydrocarbons, aromatic amines
& amides, aliphatic compounds, aflatoxins, lead compounds, obesity, unopposed estrogen
 strong association w/ tobacco use
 at dx, 95% w/ mets
 mets to lungs, lymph nodes, liver, bone, skin
Progression/Mets
 local extension, but usually spread via vessels,
Treatment
Prognosis lymphatics
 mets to lungs, liver, mediastinum (to bone rare)
 mets w/in 2 yrs of dx
 combined chemo, surgery, radiation
 younger pts (<2 yrs) do best
 current rx has led to

mortality in men
 pts w/ large tumors (>550 g) do poorly
 
stage
 
mortality
 surgery
 poor, 18-27% 10-yr survival
 staging

Stage I – confined to kidney

Stage II – invasion of perinephric fat

Stage III – regional nodes to vena cava

Stage IV – adjacent/distal organs
Causes of Hematuria
Hematologic
Coagulopathy
Hemoglobulinopathy
Renal
Glomerular vs. nonglomerular
Infection
Malformation
Ischemia
Trauma
Hypersensitivity
Post-Renal
Calculi
Mechanical
Inflammatory
Neoplasm
BPH
Exercise
False
Vaginal bleeding
Pigmenturia factitious

Epithelial Tumors of the Bladder
Normal bladder mucosa Grade I (low malignant potential)
Grade II (low grade)
Renal Adenocarcinoma (Renal Cell Carcinoma)
Grade III (high grade)
A: clear cell type sporadic/hereditary – translocations 3;6, 3;8, 3;11, deletions on chromosome 3, Loss of VHL, inactivated/mutated VHL, hypermethylation of VHL
B: papillary type sporadic – trisomy 7, 16, 17, loss of Y, mutated/activated MET, t(X;1)

PRCC oncogenes hereditary – trisomy 7, mutated/activated MET
C: chromophobe type excellent prognosis

Wilm’s Tumor
Gross: tan gray color, well-circumscribed margins
Microscopic: triphasic histology
 stromal (less cellular on left)
 epithelial (clear tubule in center)
 blastemic (tightly packed blue cells on right)

Tubulointerstitial and Vascular Diseases of the Kidney (Robbins pp. 968-990)
Tubulointerstitial Diseases
Acute Tubular Necrosis (ATN)

Types

Ischemic ATN
 etiology – shock, transfusion, hemorrhage, crush injuries, sepsis

hypoTN,

renal perfusion

tubular injury
 path – dilatation of tubules, single cell necrosis w/ skip areas, casts (hyaline or pigmented), interstitial edema, regenerating epi cells (after 3-5 d), mononuclear cells in vasa recta

Nephrotoxic ATN
 etiology
 drugs – antibiotics (gentamicin), contrast media, antineoplastic (cisplatin)
 chemicals – heavy metals (HgCl
2
, lead-see nuclear inclusions), organic solvents (CCl
4
, diethylene glycolsee oxalate deposition), poisons (herbicide)
 pigments – hemoglobin, myoglobin
 path – similar to ischemic (dilated tubules, interstitial edema, regenerating epi cells), but also w/ extensive epi necrosis affecting greater portion of tubule

Mechanism ischemia or nephrotoxins tubular damage ( epithelial injury/necrosis ) vasoconstriction obstruction by casts tubular back leak pathogenesis:
 tubule cell injury
 disturbances in blood flow

intratubular pressure
( dilated tubules )

tubular flow interstitial edema
?direct glomerular effect 
GFR oliguria

Clinical presentation
 rapid onset of oliguria or anuria w/ proportionate rise in serum Cr and BUN
 urinary sediment – granular, hyaline, pigmented casts
 pts recover w/ proper support if etiology is found & corrected
Interstitial Nephritis (IN) must show interstitial inflammatory infiltrate & tubular epithelial injury
Acute Hypersensitivity IN – immune-mediated injury
 etiology – drugs, esp synthetic penicillins (methicillin), diuretics (thiazides), NSAIDS (ibuprofen)
 path – inflamm infiltrate in interstitium comprising mononuclear cells, eos, PMNs; interstitial edema, tubular injury
 clinical – ARF w/ eos in urinary sediment, occurs w/in 2 wks of new drug, fever, eosinophilia, pyuria, skin rash
Pyelonephritis – infectious etiology
 acute pyelonephritis
 etiology – E. coli, Proteus, Klebsiella, Staph
 pathogenesis – ascending infxn associated w/ urinary obstruction, vesicoureteric reflux, intrarenal reflux, catheterization, pregnancy, sexual activity, diabetes, neurologic deficits
 pathology
 gross – yellow streaks (pus) from pelvis to cortex
 micro – shows inflamm infiltrate w/in tubular lumens & interstitium, interstitial edema, hematogenous infxn w/ small abscesses in cortex
 chronic pyelonephritis & reflux nephropathy
 etiology – chronic obstruction and/or reflux frequently associated w/ recurrent UTIs
 pathology
 gross – hydronephrosis, parenchymal atrophy, discrete cortical scar overlying damaged calyx most often at upper or lower pole
 micro – tubular atrophy, thyroidization, chronic interstitial inflamm & fibrosis, periglomerular fibrosis

Chronic IN – tubular atrophy & loss accompanied by chronic interstitial inflamm & fibrosis
 analgesic nephropathy
 etiology – phenacetin, NSAIDs [inhibition of PG synthesis

vasconstriction & ischemia]
 path – bland renal papillary necrosis w/ overlying cortical atrophy
 metabolic disturbances
 urate nephropathy (gout) & nephrocalcinosis
Hereditary Tubular Disease
 adult – autosomal dominant polycystic kidney dz
 infantile – autosomal recessive polycystic kidney dz
Vascular Disease
Hypertension
 benign – intimal thickening in larger arteries, hyaline arteriosclerosis, glomeruli collapsed, tubules atrophied
 malignant – fibrinoid necrosis in arterioles & onion skinning in medium sized arteries
Thrombotic Microangiopathy
 etiology – endothelial injury

local intravascular coagulation
 associated conditions – malignant HTN, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, scleroderma, pregnancy/delivery, drugs (cyclosporin, mitomycin C)
 path – intimal thickening, edema w/ marked narrowing of lumen; fibrin thrombi; erythrocyte fragmentation; fibrinoid necrosis; associated glomerular changes
Vasculitis
 hypersensitivity vasculitis, Wegener’s granulomatosis
Arterionephrosclerosis & Atheroembolic Renal Disease
 etiology – consequences of atherosclerosis
 path – result of chronic ischemia, glomerulosclerosis, tubular atrophy, interstitial fibrosis, intimal thickening, atheroemboli from aortic atherosclerotic plaques
Renal Transplantation
 intimal vasculitis – w/ or w/o necrosis of vascular walls

intimal thickening w/ encroachment on lumen, ischemia of renal parenchyma, loss of renal fxn
 tubulitis w/ interstitial inflammation

destruction of tubular epithelial cells results in destruction
Hyperacute Rejection
 timing – minutes to days
 etiology – preformed circulating Ab arising from previous blood transfusions
 path – massive vascular thrombosis & renal infarction
Acute Rejection
 timing – days to months or on abrupt cessation of immunosuppressive regimen
 etiology – predominantly cell-mediated immunity to foreign Ag
 path – interstitial immunoblastic infiltrates w/ tubulitis (lymphocytes btw tubular epi cells w/in TBM), intimal vasculitis, interstitial edema
Chronic Transplant Nephropathy
 timing – months to years
 etiology
 chronic rejection – end stage of acute rejection, characterized by effects of chronic ischemia

parenchyma loss & marked intimal thickening of large arteries
 drug toxicity – cyclosporin causes vasoconstriction

chronic ischemic changes
 hyperfiltration – reduction of renal mass

hypertrophy of remaining mass
 recurrence – varying frequency
 do novo dz

Developmental Pathology (Robbins pp. 459-471)
Concepts of Morphogenesis
Concept Definition Example
Malformation defect due to intrinsic process
Disruption defect due to extrinsic interference w/ originally nl process renal agenesis w/ no nephric development pulm stenosis following maternal rubella infxn
Deformation abnl form due to mechanical forces amputated digit following constriction by folds in amniotic membrane
Dysplasia
Sequence
Syndrome abnl organization of cells into tissue pattern of anomalies from single anomaly/mechanical factor pattern of related anomalies not known to be a sequence congenital adenomatoid malformation, cystic renal dysplasia oligohydramnios

renal agenesis

urethral atresia, bladder hypoplasia, clubbed foot, “Potter’s facies”, lung hypoplasia
Down syndrome

distinctive facies, congenital heart dz, musculoskeletal problems
Examples of Errors in Morphogenesis congenital adenomatoid malformation
 distinctive mass in developing lung, represents dysplastic, hamartomatous, neoplastic growth in one lobe
 detected on US as mass in lung, manifests as respiratory distress after birth
 path – solid w/ few cysts to largely cystic
 histo – multiple branched cuboidal or columnar epi-lined spaces resembling immature bronchioles
 rx by surgery congenital diaphragmatic hernia
 abd viscera enter thorax

mass effect crowds lungs

lung hypoplasia

small, immature lung & pulm HTN
 rx by surgery cystic renal disorders
 autosomal recessive polycystic kidney disease (infantile polycystic kidney disease)
 presents during infancy as respiratory distress due to lung hypoplasia (rare in older pts, but may present then as renal failure, HTN)
 dx by US – see very large reniform kidneys w/ tiny elongated cysts radiating outwards from renal pelvis
 cysts may also be in liver, pancreas
 autosomal dominant polycystic kidney disease (adult polycystic kidney disease)
 presents in adults as renal failure, but now can be dx during development
 path – kidneys enlarged by random cysts (grape-like clusters

bizarre kidney shapes)
 histo – cysts lined by collecting duct-type epithelium w/ intervening parenchyma
 liver cysts and/or berry aneurysms (Circle of Willis) present in 30% of cases
Intrauterine Infection of Fetus
 pathogenesis of fetal infections
 hematogenous spread (transplacental) – e.g., viruses, Listeria, T. palladium
 from amniotic fluid following ascending cervical infxn – e.g., bacteria
 through direct contact w/ vagina/cervix during delivery – e.g., HSV, HBV
 barriers to intrauterine infections
 maternal defenses – mucous membranes/secretions, placental villi, amniotic membranes/fluid
 fetal defenses – skin, immune system (after 1 st trimester
Infection Syndromes of Fetuses and Neonates
 transplacental route

disseminated infection w/ systemic consequences (e.g., syphillis)
 growth retardation, disruption, fetal anemia w/ edema (fetal hydrops), precocious development of lymphoid system
 in HIV, no neonatal syndrome (some membrane rupture, preemies), although some infants will develop AIDS
 membranes – usually ruptured (usually due to infxn then leads to chorioamnionitis), are opaque, contain abundant PMNs
 dx chorioamnionitis in mothers w/ fever and foul-smelling amniotic fluid

Acute Amniotic Infection Syndrome
 chorioamnionitis (may lead to sepsis), funisitis (inflamed umbilical cord)
 fetal lungs w/ exudate in airways (fetal pneumonia), fetal stomach containing exudate