RENAL FUNCTION TESTS

-Urinalysis
-Gross appearance - odor, color, clarity
-RBCs make urine opaque
-Protein (e.g. albumin) will make urine foamy
-Tubular disorders - protein is not reabsorbed (< 1-1.5 g/day)
-Glomerular diseases - protein > 3-3.5 g/day must be from glomerulus
-Overflow states - as in light chains from multiple myeloma
-Contamination - semen, mucus, etc.
-Basic chemistries, pH, specific gravity
-6-dipstick test: blood, bilirubin, ketone, glucose, protein, pH (BBKGPP)
-10-dipstick test - also specific gravity, urobilinogen, nitrite, leukocyte esterase
-Microscopic exam - cells, crystals, casts, organisms
-Cells
-Squamous cells appear polygonal w/ small nuclei
-Indicate contamination
-Transitional cells are rounded w/ slightly larger nuclei
-Dysmorphic RBCs come from the glomerulus
-They are traumatized by the variable tonicity of the nephron tubule
-Oval fat bodies - shed tubular cells containing lipid
-Lipid accompanies protein in the urine; tubular cells absorb it
-Polarized light gives them a cross or 4-leaf clover appearance
-Normal values
-0-2 RBCs per high power field
-0-5 WBCs/hpf
-Crystals
-Oxalate - like the backs of envelopes, seen in acid urine
-Triple phosphate - like coffin lids, assoc w/ infection, seen in alkaline urine
-Cystine - hexagonal
-Casts
-Cylindrical-shaped elements of urinary sediment molded by the renal tubule
-Tamm-Horsfall protein, made by the TAL, acts as "cement"
-Hyaline cast
-Does not contain a cellular component - mostly Tam-Horsfall protein
-May be seen in small numbers normally
-RBC cast
-RBCs are trapped within a proteinaceous matrix (e.g. T-H protein)
*Indicates glomerulonephritis (glomerular inflammation)
-WBC cast
-WBCs trapped within a proteinaceous matrix
-Seen in acute inflammatory processes – glomerulo- & pyelonephritis
-Renal tubular cast
-Renal tubular epithelial cells are trapped in a proteinaceous matrix
*Imply tubular damage - e.g. nephrotoxin, pyelo- or interstitial nephritis
-Granular cast
-Unidentifiable degenerated cells in a proteinaceous matrix
-Large numbers are seen in acute tubular necrosis
-Waxy cast
-Broad, translucent cast representing severe, long-standing renal disease
-Organisms
-Are contaminants unless accompanied by inflammatory cells

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 -Other tests must be ordered separately
-Measuring GFR (the best overall indicator of renal function)
-Requires measurement of a substance meeting the following criteria:
-Constantly produced/infused, freely filteres, not secreted/reabsorbed
-Creatinine is the best endogenous compound
-Creatinine clearance (CCr)
-CCr = (urine [creatinine]) * (urine flow rate) / (plasma [creatinine])
-CCr = UCr * V / PCr
-Yields volume of blood cleared of creatinine per unit time
-Creatinine is secreted by the tubules, so it overestimates GFR
-In addition, the PCr-GFR relationship is not linear
**Hence s[Cr] should NOT be the sole means of assessing kidney fxn
-Other variables must be considered when calculating GFR
-Assume steady state, so these eqns don't work for an acute condition
*Cockcroft-Gault (know)
-Men: Cr Cl = (140-age) * (weight) / (sCr*72)
-Women: Cr Cl = (140-age) * (weight) * 0.85 / (sCr*72)
-Modification of Diet in Renal Disease (MDRD)
-GFR = 186 * [sCr]^-1.154 * age^-0.203 * 0.742 if female * 1.21 if AA
-Results given as ml/min/1.73m^2
-Cytology, eosinophils & electrolytes, protein, or creatinine quantification
*Proteinuria may be the only indication of renal disease
-GFR & sCr may be normal
-Protein is the most important factor for future loss of kidney fxn
-CKD - proteinuria is an independent risk factor for CV disease & death
-Measuring protein excretion
-Dipstick is useful for screening, but imprecise (scale 0-4+)
-Misses small amounts of albumin, seen in early DM
*Send a separate urine sample for microalbumin testing
-Untimed, random "spot" urine for protein & creatinine
-Is as accurate as a 24 hr timed specimen
-[protein (mg/dL)]/[creatinine] = grams protein excreted per 24 hrs

-Chronic Kidney Disease Stages (according to NKF)

-1 - kidney damage w/ normal or increased GFR (>/=90 ml/min/1.73m^2)
-2 - kidney damage w/ mildly decreased GFR (60-89)
-3 - moderately decreased GFR (30-59)
-4 - severely decreased GFR (15-29)
-5 - kidney failure (< 15 or dialysis)

-Never do a 24 hour urine collection - it's not reliable. Just use equations.

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KIDNEY TUMORS
-Eipithelial Tumors
-Benign tumors
-Adenoma
-Tubulopapillary (fimbria-like) tumor of the renal cortex – often incidental find
-Same genetic findings as RCC, but smaller size (< 5mm)
-Oncocytoma
-Responsible for 5% of adult kidney tumors; majority are asymptomatic
-Derived from intercalated cells of collecting ducts
-Pathology
-Circumscribed, brown (cortex-colored), possibly w/ central scar
-May be multifocal and/or bilateral
-Histopathology - uniform sheets or nests of pink cells
-EM reveals numerous mitochondria
-Renal cell carcinoma
-Clear cell
-Comprise 70% of epithelial kidney tumors; 75% five year survival
-Associated w/ Von Hippel-Lindau disease
-Mutated/inactive VHL gene results in overactive HIV & VEGF
-Sx: angiomatosis & hemangiomas, polycythemia
-Hemangioblastoma in the cerebellum
-Pheochromocytoma & renal clear cell carcinoma
-Derived from the proximal tubule; usually a solitary, unilateral tumor
-Gross pathology (same for Papillary & Chromophobe)
-Solid or cystic; bright yellow appearance
-Variable hemorrhage/necrosis - pts may present with hematuria
-Tendency to grow into the renal vein & inferior vena cava
-Histopathology - islands of cells w/ round nuclei
-Clear cytoplasm b/c high lipid content has been washed out
-Intervening capillary network may separate islands
-Remember: "CC'd emails by Proxy, VHS images are Clear"
-Papillary
-Associated with acquired cystic kidney disease; 95% five year survival
-Caused by trisomy 7, 16, or 17; or loss of Y chromosome in men
-Derived from distal tubule
-Histopathology - cuboid-ish cells in papillary formations
-Papillary cores are often filled w/ foamy macrophages
-Remember: "take 3 (trisomY) Pills Distilled in Foam"
-Chromophobe
-100% 5-yr survival; caused by monosomy 1,2,6,10,13, or 17 (chroMo = mono)
-Derived from intercalated cell of collecting duct
-Histopathology - eosinophilic cells w/ a perinuclear halo
-Granular, pink cytoplasm may be outside of the perinuclear halo
-Remember: "Chromo & onCo = Collecting"
*Prognosis correlates strongly with nuclear grade & stage of cancer
-pT1/2 - tumor confined to kidney - 95% five yr survival -1/2-kidney
-pT2 is > 7cm
-pT3a - invading perinephric fat or adrenal - 75% -3a-fat
-Tumor has not gone through Gerrota's fascia
-pT3b - invading renal vein - 40% -3b-vein
-pT4 - invading adjacent structures - 20% -4-Gerrota's

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-Mesenchymal Tumors
-Angiomyolipoma
-Benign mesenchymal tumor
-Often seen in pts w/ Tuberous Sclerosis (~40%)
-AD disorder - hamartoma formation in skin, brain, eye, kidney, heart
*Renal angiomyolipoma and cardiac rhabdomyoma are associated
-Clinical features
-Sporadic - female predominance, solitary, larger
-Often incidental finding, can present w/ acute sx from hemorrhage
-Tuberous Sclerosis - presents at younger age, multiple/bilateral, smaller
-Often detected as part of work-up, may result in renal failure
-Histopathology
-Hemorrhage & necrosis
-Composed of fat, smooth muscle, & blood vessels
-Cartwheel pattern of SM can be seen coming off of vessel walls
-Remember: "Angio & Rhabdo fed Tubers to their children"

-Embryonal Tumors
-Wilms tumor
-Most common pediatric (age < 5) kidney neoplasm, often detected by the mother
-Presents as large abdominal mass, abdominal pain, GI obstruction
-Genetics
-Often a component of WAGR syndrome & Denys-Drash syndrome
-WT1 gene is implicated - critical for normal renal & gonadal formation
-Histopathology
-Triphasic w/ blastemal, epithelial, & mesenchymal elements
-Blastemal - small blue cells w/ little cytoplasm, in sheets
-Epithelial - forming glomeruli-ish or tubular structures
-Mesenchymal - spindle-shaped fibroblasts
-Anaplastic features indicate a worse prognosis
-We won't have to identify the histo

-Secondary Tumors
-Lymphoma
-Metastases

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GLOMERULAR PATHOLOGY
-Nomenclature: -Refer to # of glomeruli: -Diffuse is > 50% -Focal is < 50%
-Refer to a single glomerulus: -Segmental-portion is involved -Global-all involved
-Glomerular Anatomy
-Membrane: cap endothelial cell, glom basement membrane (GBM), epithelial podocyte feet
-Mesangium supports glomerular capillary loops

-Nephrotic Syndrome
-Features
-Marked proteinuria (> 3.0-3.5 g/day)
-Peripheral edema due to hypoalbuminemia
-Hyperlipidemia & lipiduria - to compensate for low protein?
-Hypercoagulability & increased propensity for infection - anticoag's & Ab's in urine
-Age influences the differential diagnosis
-Children: MCD (65%), FSGS, MPGN, membranous GN -2o causes: SLE (rare)
-Adults: FSGS (24%), membranous GN (23%), MCD, (also IgA nephropathy, MPGN)
-Secondary causes (40%): diabetes, SLE, amyloidosis
-Minimal change disease (MCD)
-Clinical
-Most common cause of nephrotic syndrome in children; also important to adults
-Albumin is the predominant protein in urine
-Responds well to steroids
-Etiology
-Primary podocyte injury of unknown cause - generally following URI or vaccine
-Incidence is increased in Hodgkin lymphoma patients
-Injury reduces the (-) charge on the GBM → albumin lost
-Microscopy
-Light microscopy (LM) - normal (capsule, open capillaries, nml cellularity, etc.)
-Immunofluorescence (IF) - no immune complexes (IC's) or antibodies
-Electron microscopy (EM) - podocyte injury resulting in lost foot processes
-Focal segmental glomeruloscerosis (FSGS)
-Clinical
-Most common cause in African Americans; 2nd leading cause in children
-Protienuria isn't selective
-Tx w/ transplant drugs (not steroids); progresses to chronic renal failure (yrs)
-Etiology
-Idiopathic resulting in primary podocyte injury
-Due to a non-antibody circulating factor - transferred serum induces it
-Secondary causes result from conditions of significant nephron loss
-Unilateral renal agenesis
-Chronic renal disease of any kind when pt is "close to the end"
-HTN, diabetes, vascular disease, etc.
-Remaining glomeruli try to compensate - increase flow & pressure
-HTN & hyperfiltration cause further injury - vicious cycle
-Microscopy
-LM - begins w/ < 50% of glomeruli showing partial sclerosis
-Over time all capillary loops collapse resulting in global sclerosis
-Other glomeruli begin to show segmental followed by global sclerosis
-Once glomerulus is scarred, tubule will atrophy & fibrose
-IF - negative, no immune deposits
-EM - like MCD, podocyte foot process effacement

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-Nephrotic Syndrome (cont.)
-Collapsing glomerulopathy (CG)
-Clinical
-Considered a virulent, rapidly progressive form of FSGS
-Massive proteinuria & end-stage kidney disease w/in 13 mo. of onset
-Associated w/ HIV, heroin users, & increased incidence in African Americans
**HIV-associated nephropathy (HIVAN)
-Collapsing glomerulopathy in HIV-infected patients
-Assoc w/ AA polymorphism in myosin heavy chain (MYH9/CD2AP)
-HIV infection in podocytes causes dedifferentiation
-Etiology - idiopathic
-Microscopy
-LM - global collapse of glomerular tufts
-Hypertrophy & hyperplasia of podocytes overlying the capsule
-Nuclei are increased & "lined up" around the exterior
-IF - negative, not due to IC's
-EM - like MCD, podocyte foot process effacement
-Membranous glomerulopathy (MG)
-Clinical
-Like FSGS, important cause of nephrotic syndrome in white adults (30s-40s)
-Renal failure is associated w/
-High levels of proteinuria at diagnosis
-Older age at onset, male sex, increased BUN & Cr at diagnosis
-May resolve, remain static, or slowly progress to renal failure
-Tx w/ transplant drugs (not steroids)
-Etiology
-Mostly idiopathic autoimmune disease
-Auto-Ab's react with podocyte phospholipase A2 receptor (PLA2R)
-IC's shed into SUBEPITHELIAL space, & GBM grows between them
-Secondary causes (15%) are largely treatable
*Chronic infections - malaria, syphilis, *Hepatitis B
-Autoimmune diseases - SLE, rheumatoid arthritis
-Paraneoplastic syndrome associated with cancer
-Medications - gold, penicillamine
-Microscopy
-LM - diffuse, uniform thickening of the GBM
-Deposits don't stain differently w/ H&E, so it looks like one big GBM
-Trichrome stain (red) differentiates b/t GBM & IC's
-Jones stain (black) shows GBM finges & bubbly holes
-Glomerulus is not hypercellular (only 1-2 nuclei in the mesangium)
-Anaphyactatoxins are washed into the urine - don't attract
-IF - regular, coarse, granular GBM w/ IgG & C3
-EM - innumerable dense subepithelial IC deposits
-Digitating "hair like" GBM progections & podocyte foot effacement

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-Nephrotic Syndrome (cont.)
-Membranoproliferative glomerulonephritis type I (MPGN)
-Clinical
-Affects primarily children & young adults
-Nephrotic range proteinuria
-Hypocomplementemia - decreased serum C3 & C4
-HTN, persistent hematuria, & evidence of renal failure (increased Cr)
-Also assoc w/ asymptomatic hematuria/proteinuria & acute nephritic syndrome
-Suspect in pts with nephrotic range proteinuria who also have
-Many RBC's in urine, &/or evidence of renal failure (inc Cr)
-Clinical course
-Idiopathic is usually progressive with poor prognosis
-Reversal is possible if secondary causes are treated
-Etiology
-Idiopathic - IC's deposit in MESANGIUM & SUBENDOTHELIAL space
-Activate complement & attract inflammatory cells
-Mesangial cells spread along GBM b/t original & new layer of GBM
-Hence IC's cause endothelial cell injury & GBM reduplication
-Secondary causes
**Chronic infection - Hep B, *Hep C, *bacterial endocarditis, etc.
-Immune disorders - SLE, cryoglobulinemia
-Paraneoplastic syndrome associated with malignancy
-Microscopy
-Light microscopy
-Mesangial hypercellularity - more than 2-3 nuclei
-Endocapillary proliferation - misnomer, PMN margination in the lumen
-Combined changes give glomeruli a lobated "cauliflower" appearance
-Special stains show duplicated GBM - "train tracks"
-IF - capillary loops & mesangium stain for IgG & C3
-EM - IC's seen in subendothelial space & mesangium
-Mesangial cells can be seen between GBM layers

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-Acute Nephritic Syndrome
-Features -Hematuria - gross or microscopic (but if microscopic, still significant)
-Proteinuria - mild to moderate (not in nephrotic range)
-Hypertension
-Poststreptococcal glomerulonephritis is the prototypic cause
-Clinical-Onset 1-3 wks after Grp A Strep throat infection, 3-6 wks after skin infection
-Features suggestive of renal inflamm/edema - hematuria, azotemia, oliguria, etc.
-Titers of anti-Streptolysin O or anti-DNAse B from Strep pyogenes
-Decreased complement levels early during disease (indicates glomerular cause)
-Immune complexes formed from Ab's to pyrogenic exotoxin B
-Prognosis
-95% children recover spontaneously or w/ minimal treatment
-60% adults recover, 40% develop rapidly progressive GN or chronic RF
-Microscopy
-LM - capillary loops occluded by marginated inflammatory cells (PMNs)
-Called "diffuse endocapillary proliferation" - a misnomer
-IF - "starry night" or "lumpy bumpy" capillary loop deposits - IgG, C3, C4, etc.
-Think "Starry Strep"
-EM - large randomly spaced SUBEPITHELIAL "humps" of IC deposits
-Lupus nephritis
-Seen in 2/3 of pts at diagnosis
-Renal biopsy is almost always indicated to guage activity & make diagnosis
-Clinical manifestations
-Nephrotic syndrome (membranous glomerulopathy)
-Acute nephritic syndrome
-Asymptomatic hematuria/proteinuria
-Acute renal failure due to severe glomerular damage
-Etiology
-Autoimmune disorder mediated by IC's
-Mesangial proliferation & deposits
-Endocapillary proliferation - subendothelial deposits damage GBM
-Inflammatory cells marginate
-GBM's may rupture, tissue may necrose
*Membranous glomerulopathy is seen in SLE
-Treatment - corticosteroids, cytotoxic agents like cyclophosphamide
-Do renal biopsy to confirm disease before treating young women
-Microscopy
-IF - deposits in capillary loops, but especially in mesangium
-"Full house" - IgG, IgA, IgM, C3, etc.

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-Acute Renal Failure
-Features
-Anuria or oliguria
-Occurs over short time (days-weeks)
-Azotemia - the biochemical abnormalities that lead to symptoms (increased Cr, etc.)
-Caused by Rapidly progressive GN (RPGN - clinical term) / Crescentic GN (path term)
-Caused by various diseases that severely damage the glomerulus
-The crescent - proliferation of cells w/in Bowman's space cause glomerulus to collapse
-Plasma proteins (fibrin, coag factors, C') leak and stimulate formation
-Cells are derived from monocytes & epithelial cells lining Bowman's space
-Pathogenesis
-Type I - Anti-GBM disease
-Anti-GBM Ab's; uncommon in African Americans
-Most cases are idiopathic, but many patients have HLA-DR2 haplotype
-Also assoc w/ hydrocarbon solvents, influenza A2, malaria, & Hodgkin
-Goodpasture's syndrome - also attack against pulm capillary BM (hemoptysis)
-Microscopy
-LM - crescents! also areas of necrosis w/ nuclear debris (karyorrhexis)
-IF - GBM's fluoresce for IgG - linear pattern (like crumpled paper)
-EM - no deposits; severe glomerular damage
-Type II - immune complex-mediated diseases
-Seen mostly in ages 10-40
-Diagnose with kidney biopsy - IC's deposit in the glomerulus
-Membranoproliferative GN - subendo deposits & "tram tracks"
-Lupus nephritis - "full house" on IF
-IgA nephropathy - IgA deposition by IF w/o vasculitis
-HS Purpura if vasculitis is seen
*Post-Strep GN - "Starry night" by IF, hx of Strep infection
-Type III - non-immune deposit diseases (PAN, Wgener's, idiopathic)
-Predominates at ages > 40
-ANCA(+) in > 90% of patients - anti-neutrophil cytoplasmic antibody
-Antibodies to myeloperoxidase & proteinase-3 components of granules
-Perinuclear (p-ANCA) - myeloperoxidase
-Cytoplasmic (c-ANCA) - PR3
-Myeloperoxidase & PR3 expression usually follows infection
-PMN-Ab complexes stick to glomerular endothelium
-Potential causes
ANCA Vascuitis Granuloma Asthma Comments
*Microscopic polyangiitis p&c yes no no
*Wegener’s granulomatosis c yes yes no Highly associated w/ lung
& ENT
Churg-Strauss syndrome p no yes yes Often involves lungs;
eos are seen
Pauci-immune crescentic GN p Renal involvement only

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-Asymptomatic Hematuria / Proteinuria
-A variety of diseases present this way, some of which are not related to the glomerulus
-IgA nephropathy (Berger's disease)
-Clinical
-Mostly children & young adults; high incidence in SE Asians, Nat Americans
-Hx of associated upper respiratory or GI infection (inflamed mucosa)
-Hx of intermittent macro hematuria, or hematuria/proteinuria on urinalysis
-Prognosis - benign disease or progressive to chronic renal failure (10-50%)
-Etiology
-Genetic & environmental components
-Genetic mutation → IgA Ab's w/ d/c # of galactose moieties at hinge regions
-Environmental trigger causes production of Ab's against abnormal IgA's
-IC's lodge in glomeruli - especially the mesangium
-Microscopy
-LM - mesangial hypercellularity, but capillary loops remain open
-IF - IC's containing IgA & C3 (not C1 or C4) in the mesangium
-EM - deposits in the mesangium, mesangial hypercellularity
-Basement membrane disorders
-Alport's disease
-Clinical
-Hematuria - most common presentation; episodic gross, persistent micro
-High frequency hearing loss
-Myopia & other visual changes
-Variable progression to end-stage renal disease
-Tx - symptomatic support, renal transplant (may cause anti-GBM)
-Etiology
-Hereditary defect in type IV collagen - glomerulus, cochlea, eye lens
-X-linked - missing alpha-5 isoform of type IV collagen
-Autosomal (AD/AR) - missing alpha-3 or alpha-4 isoforms
-Microscopy
-LM - most glomeruli look normal; some may be sclerosing
-IF - negative with conventional study; must look for collagen isoforms
*EM - thick GBM w/ irregular borders & "basket-weave" appearance
-GBM looks eroded like dirt after a hard rain
-Thin basement membrane disease
*Clnical - hematuria/proteinuria
-Relatively benign clinical course
-Etiology - AR defect in GBM production
-Microscopy
-LM - nonspecific (open loops, 2-3 cells in mesangium);
-IF - negative
-EM - characteristic thin GBM

-Other Glomerular Disorders

-Chronic Renal Failure - marked by progressive increase in Cr & BUN
-Renal Tubular Defects - manifests as electrolyte disturbances, polyuria, & nocturia
-Urinary Tract Infections - fever, pyuria, flank pain
-Nephrolithiasis (kidney stones)

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SYSTEMIC / HEREDITARY / VASCULAR RENAL DISEASES
-Systemic Renal Diseases
-Diabetes mellitus
*Diabetic nephropathy (DN) is leading cause of ESRD in the U.S.
-Clinical features
-Microalbuminuria progressing to proteinuria, nephrotic syndrome
-Decreased GFR & hypertension
-Other manifestations of DM - retinopathy, etc.
-Pathogenesis
*Primary lesion is excess ECM accumulation in the kidney
-Formation/degradation is disturbed, favoring formation
-Increased synthesis of TIMPs & decreased MMPs
-Disturbance involves growth factors - TGF-beta
-Renal biopsy is rarely indicated
-DIsease has a natural history
-Exceptions
-Early onset proteinuria (< 10 y/o in T1DM)
-Lack of other diabetic changes when renal disease develops
-Atypical features - unexplained hematuria, unusual pace
-Pathology
-Gross - enlarged kidneys due to ECM & growth factors
*LM - diffuse & nodular glomerulosclerosis - diagnostic lesion for DM renal dz
-Diffuse - progressive, even thickening of GBMs & mesangium
-Nodular - ECM in mesangium forms Kimmelstiel-Wilson nodules
-Mesangium compresses capillary lumens & leads to glomerulosclerosis
-Other changes
*Hyaline arteriolosclerosis - BOTH afferent & efferent arterioles
-Fibrin "caps" in the glomeruli & "drops" in Bowman's capsule
-Tubular atrophy & sclerosis following gomerular failure
*Accelerated atherosclerosis in all arteries
-IF - linear deposition of IgG & albumin along GBM & TBM
-Hypothesized that proteins stick to the abnormal GBM
-EM - uniformly thickened GBMs, expanded mesangium
-Podocyte foot process effacement, but no IC's
-Myeloma cast nephropathy
-Associated with multiple myeloma & light chain production
-Chemical reaction between light chains & Tamms-Horsfall protein produces casts
-Casts can obstruct cortical and medullary tubules & cause renal failure
-Pathology
-LM - glomeruli are normal, but tubules are clogged
-Large, irregular casts w/in tubules, often cracked or fractured
-Casts may appear lamellar (concentric rings)
-May be ringed by Mphages & multinucleated giant cells
-Treatment
-Reduce light chain production w/ chemotherapy
-Decrease light chain & TH protein aggregation
-Drink more water, alkalinize urine, avoid nephrotoxins (radiocontrast)

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-Amyloidosis
-Abnormally synthesized or processed proteins are deposited in tissue
-Results in proteinuria in the kidney
-Renal insfficiency also develops ~ 60% of pts have i/c Cr at time of dx
-Characteristics of amyloid
-Can be made from 21 different proteins
-All deposit as a beta-pleated sheet and stain w/ Congo Red
-Polarized light reveals characteristic apple-green birefringence
-Forms of amyloid
-AL - Primary amyloidosis
-Most common type, results from Ig light chains (multiple myeloma)
-Malignant plasma cells produce monoclonal Ig's & light chains
-Lambda light chains > kappa
-Detected as a monoclonal spike in SPEP
-Bence Jones proteinuria = free light chains in urine
-AA - Secondary amyloidosis
-Serum AA protein (SAA) - an acute phase reactant
-Inflammation increases its serum levels
-Normally metabolized by monocytes/macrophages
-Hereditary defect in metabolism may result in abnormal processing
-Associated w/ chronic inflammatory conditions
-Autoimmune diseases - e.g. Rheumatoid arthritis
-Chronic infections - e.g. TB, osteomyelitis
-Pathology
-LM - amorphous pink material, mainly in glomeruli & vasculature
-Glomerulus: amyloid deposits first in mesangium → d/c capillary lumen
-Subsequent deposition in GBM → protein loss
-Vasculature: amyloid compromises artery & arteriole lumens
-Congo Red + polarized light identifies amyloid
-IF - identifies light chains, SAA
-EM - masses of thin, non-branching fibrils

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-Vascular Renal Diseases (Thrombotic Microangiopathies)
-TMs cause direct damage to endothelium resulting in increased platelet aggregation & adherence
-Acute changes
-LM - Platelet/fibrin thrombi in glomerular capillaries & arterioles
-IF - glomerulus stains for fibrin deposition
-Chronic changes
-EM - GBM reduplicates - mesangial cell interposition & new GBM formation
-Similar to membranoproliferative GN - no IC's
-Hemolytic uremic syndrome (HUS)
-Diarrhea positive (D+) or Typical
*Most common cause of acute renal failure in children
-E. coli that produce Shiga toxin (O157:H7) are ingested
-Shiga toxin damages epithelium of gut & kidney
-Endothelial cells swell & detach
-Platelets activate & aggregate - thrombi in capillaries
-Results in bloody diarrhea & acute renal failure
-Diarrhea negative (D-) or Atypical
-Smaller # of cases, associated w/ hereditary C' disorder of Factors H & I
-Thrombotic thrombocytopenic purpura (TTP)
-Most commonly seen in adult women
-Clinical
-Fever, bleeding, hematuria, proteinuria, azotemia (elevated Cr, etc.)
-Note: diarrhea is occasionaly present, but not necessarily
-CNS encephalopathy - HA, confusion, aphasia, focal deficits, seizure, etc.
-Other organ systems like heart & lungs often hemorrhage as well
-Pathogenesis
-Hereditary or acquired deficiency in ADAMTS13
-Enzyme normally cleaves vWF pre-protein
-Defect leads to vWF multimers that favor platelet aggregation
-slide 48
-Malignant hypertension - direct barotrauma to endothelium triggers TM
-SLE - antiphospholipid syndrome (lupus anticoagnulant) may cause TM
-Renal transplant - anti-endothelial antibodies may develop
-Drugs - minocycline (antineoplastic), cyclosporin, tacrolimus
-Other - radiation, pre-eclampsia, eclampsia, scleroderma, paraneoplastic syndrome

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-Hereditary Renal Diseases
-Autosomal dominant Polycystic kidney disease (ADPKD)
-Inherited defect in either PKD1 or PKD2 gene
-PKD1 (polycystin 1) - membrane glycoprotein for cell & matrix interactions
-PKD2 (polycystin 2) - ion channel closely associated with polycystin 1
-Characterized by progressive development & enlargement of cysts in both kidneys
-Cysts balloon out of the nephron - may become infected, rupture, hemorrhage
-Hyperproliferation of tubular epithelial cells, fluid secretion, & abnormal ECM
-Cyst epithelium produces cytokines - provoke interstitial inflamm & fibrosis
-Associated with berry aneurysm - defects in basement membrane & ECM?
-Clinical manifestations
-Renal
-Hypertension, hematuria, acute & chronic pain
-Decreased ability to concentrate urine
-Cardiovascular
-Intracranial saccular aneurysms that may rupture and bleed
-Aneurysms of other vascular beds
-Cardiac valvular abnormalities
-Other extrarenal
-Liver cysts - may compress porta hepatis structures of IVC
-Pancreatic cysts
-Cysts in various organs
-Pathology
-Gross
-Markedly enlarged kidneys - fibrosis, cysts
-Large number of variably sized cysts distributed throughout parenchyma
-Micro
-Cysts lined by simple cuboidal epithelium
-Cysts may arise from any portion of the nephron
-Autosomal recessive Polycystic kidney disease (ARPKD)
-Much less common disorder
-Mutation in gene w/ unknown function on chromosome 6
*Cysts only arise from the collecting duct - radial distribution
-Liver undergoes a variable amount of fibrosis
-Clinical manifestation
-Pts usually diagnosed < 1 y/o
-Present w/ palpable abdominal mass, HTN, & UTI's
-ESRD may occur at any time - support and transplant are the only treatment
-In utero renal failure leads to oligohydramnios
-Insufficient amniotic fluid - compresses face & arms
-Respiratory hypoplasia due to compression by kidneys
-Pathology
-Gross
-Large kidneys filling the abdominal cavity
*Cut kidney surface shows radially oriented tubular cortical cysts
-Microscopic
-Cortical area filled with cysts
-Compressed intervening glomeruli & proximal nephron elements

14
TUBULO-INTERSTITIAL DISEASES & ACUTE RENAL FAILURE
-Development of Acute Renal Failure
-Oliguria (< 400 mL urine/day) is the earliest warning sign
-Most cases develop inside the hospital
-Causes: hypovolemia, d/c CO, surgery & anesthesia, nephrotoxic drugs (diuretics, contrast)

-Principal Causes of ARF

-Pre-renal events
-Absolute decrease in effective blood volume - hemorrhage, GI loss, diuresis
-Relative decrease in peripheral resistance - sepsis, anaphylaxis, shock
-Reduced cardiac output - MI, pulmonary embolism, CFH
-Post-renal events (obstruction)
-Ureteral obstruction of one or both kidneys - tumor, fibrosis, etc.
-Bladder outlet obstruction - calculi, tumor, prostate, etc.
*Renal (intrinsic) events
-Glomerular - RPGN/Crescentic GN
-Vasculature
*Interstitial/Tubule
-Acute tubular necrosis - results from ischemia (usually 2o to pre-renal cause)
-Acute tubulo-interstitial nephritis - related to drugs, infection, cancer

-Acute Tubular Necrosis (ATN)

-Results from injury and/or destruction of renal tubular epithelium
-Impaires synthetic fxn (low ATP) & activates destructive processes
-"Necrosis", however, rarely occurs - most cells are simply injured
-If the tubular basement membrane remains intact, then regeneration is possible
-Two categories of cause
-Ischemic injury - due to shock or hypotension caused by sepsis, hemorrhage, etc.
-Tubulo-toxic injury - due to a substance that is toxic to tubular cells
-Ex: aminoglycosides (e.g. gentamicin), mercury, radiocontrast dye
-Histopathology
-Normal histology
-Proximal tubule - less cylindrically shaped, less nuclei per x-section
-Pink line around lumen indicates brush border
-Distal tubule - cuboidal epithelium, more nuclei, no brush border
-Indicators of damage
-Vacuoles inside of the tubular epithelial cells
-Absent brush border in the proximal tubules
-Necrotic material filling tubule lumens
-Tubular epithelial cells may form casts & obstruct the tubule lumen
-Obstruction effectively decreases GFR
-Naked tubular basement membranes - mitoses indicate regeneration

-Acute Tubulo-Interstitial Nephritis (ATIN)

-Probably an immunological phenomenon - occurs in pts w/ clinical hx of hypersensitivity
*T-cell mediated hypersensitivity (type IV) is the most likely explanation
*Drug probably acts as a haptan & incites an immune reaction
-Beta-lactam antibiotics - penicillin, ampicillin, etc.
-Sulfonamides, NSAIDs, diuretics
-Also associated with systemic infections where antigens deposit in the tubulo-interstitium
-Group A Strep, diptheria, toxoplasmosis, Legionnaire's disease

15
 -Histopathology
-Interstitial nephritis - Lcytes in the interstitial tissue & attacking tubular BM
*Eosinophils in the interstitial tissue and urine - bilobed nucleus
-ATIN vs. GN
-Clinical Signs ATIN GN
-Fever, rash, eosinophilia + -
-Acidosis, hyperkalemia + -
-Hypertension - +
-Nephrotic syndrome - +
-Renal Signs
-Papillary necrosis + -
-Calyceal abnormality + -
-Urinary sediment Eos RBCs & RBC casts
-Proteinuria (g/day) <2 >2

-Acute Pyelonephritis
-Actual infection of the renal parenchyma
-Usually due to ascending UTI (95% of cases)
-Hence organisms are usually GI-related: E. coli, Klebsiella, Enterobacter, Enterococcus
-5% of cases due to hematogenous spread via bacteremia
-Predisposing factors for UTI
-Obstructed urine flow at any level - incomplete bladder emptying (DM), BPH, etc.
-Vesico-ureteral reflux
-Ureter normally enters bladder at an acute angle, contraction closes the ureters
-Interference with this mechanism predisposes to reflux
-Congenital defect, inflammation of bladder wall
-Instrumentation of GU tract - catheter
-Pregnancy - uterus obstructs ureters
-Immune dysfunction - AIDS, diabetes, steroids
-Age & sex are important
-Age < 1 yr - male infants more likely - due to congenital anomalies
-Age 1-50 yr - women more likely - short urethra, intercourse trauma, etc.
-Age > 50 yr - men more likely - secondary to prostatic hypertrophy
-Complications
-Pyonephrosis - kidney is a bag of pus
-Perinephric abscess - infection escapes the kidney
*Papillary necrosis - has 3 requirements
-Acute pyelonephritis
-Obstructed urine flow
-Vascular compromise
-Histopathology
-Hematogenous spread - many "seeded" areas in the cortex
-Ascending infection - spread through papillae into the medulla & cortex
-Tubules filled with PMN's; WBC casts in the urine
-Papillary necrosis - papillae degenerate into the renal pelvis

-Chronic Pyelonephritis
-Due to recurrent, repeated bouts of acute pyelonephritis
-Leads to severe scarring of renal parenchyma, calyces, & pelvis
-Commonly seen in patients with chronic reflux, numerous UTIs, & acute pyelonephritis
-Histopathology - asymmetric, scarred kidneys w/ markedly thickened & scarred calyces

16
LUNG PATHOLOGY OVERVIEW
-Lung Anatomy
-Lobes – 3 on Right, 2 on Left – each lung has 10 bronchopulmonary segments
-Airways
-Conductive zone - cartilagenous airways such as trachea & bronchi
-Respiratory zone - area where gas exchange occurs
-Includes the bronchioles, which have no cartilage
-Acinus is composed of respiratory bronchiole, alveolar ducts, & alveoli
-Pulmonary arteriole runs adjacent to the bronchiole
-3-30 acini form a lobule, which is the smallest gross compartment
-Negative intrapleural pressure keeps airways open
-Tissue compartments
-Airspaces - contain alveolar macrophages
-Interstitial space - contain supporting tissue
-These surround airways & alveolar walls
-Contain lymphoid cells, fibroblasts, lymphatic & blood vessels, etc.
-Interstitial tissues - primarily elastic tissue
-Located in the interstitial space between alveoli & bronchioles, arterioles
-Elasticity allows for recoil after expansion
-Surface epithelium
-Bronchus - columnar ciliated cells; Bronchiole - cuboidal cells w/ decreasing cilia
-Alveolus - type I & type II penumocytes
-Type I pneumocyte - squamous epithelial cell lining alveolar wall, no mitosis
-Component of blood-air barrier w/ capillary endothelium
-Type II pneumocyte - stem cell, secretes surfactant & DPPC
-Surfactant
-Type 2 pneumocytes become functional ~ 7 mo. of gestation
-Hyaline membrane disease - surfactant deficiency of newborn
-DPPC - dipalmitoyl phophatidylcholine; main component of surfactant
-Reduces surface tension & hence alveolar collapse
-Laplace: surface tension increases w/ radius
-Hence DPPC decreases the work of breathing
-Interrupts bonds between liquid molecules - keeps lung "dry"
-Production decreases in hypoxic states
-Collateral airflow maintains V/Q match, but also allows infection to spread
-Canals of Lambert - connections between alveolar ducts & terminal bronchioles
-Pores of Kohn - openings in interalveolar septae

-Respiratory Mechanics
-Compliance
-Change in volume produced by a change in pressure
-Thoracic expansion decreases intrapulmonary pressure to negative - air enters
-A low lung volume, a healthy lung is compliant - expands w/ little change in P
-Compliance decreases with increasing volume
-Disease states
-Emphysema increases compliance (more volume for a given pressure change)
-Fibrosis decreases compliance (less volume for a given pressure change)
-Elasticity
-Ability of the lung to recoil to resting volume after being stretched
-Facilitated by elastic tissue in lung & chest that supports small airways during expiration
-Emphysema decreases lung elasticity

17
-Pulmonary Vasculature
-Lungs receive a dual blood supply
-Pulmonary artery terminates in an anastomosing network of vessels around alveoli
-Bronchial artery supplies respiratory bronchioles
-Pulmonary lymphatics - composed of superficial pleural plexus & deep bronchovascular plexus
-Both drain → to intrapulmonary & hilar lymph nodes → mediastinal & tracheal LN's
-Pulmonary edema
-Defined as fluid accumulation in the alveolar space; exceeds lymphatic drainage
-Classification - cardiogenic (pump failure) or non-cardiogenic (in/c permeability)
-Cardiogenic - increased hydrostatic pressure creates protein-poor infiltrate
-Non-cardiogenic - damage to alveoli allows fluid, protein, & cells to enter

-Pleural Tissue
-Continuous membrane covering lungs & inner chest wall - visceral & parietal
-Visceral - elastic tissue & connective tissue underlying mesothelial cells
-Vascular supply is continuous w/ lung parenchyma
-Parietal - mesothelial cells w/ stomata
-Vascular supply is continuous w/ pleural space
-Pleural fluid fills the pleural space
-May contain transudative fluid in CHF
-Is continuous w/ interstitial fluid of parietal pleura through mesothelial cell stoma
-Fluid from systemic vessels leaks into interstitium of parietal pleura
-Fluid enters pleural space & is absorbed across visceral pleura into lymphatics
*Effusion - abnormal accumulation of lung in the pleural space
-Due to increased flow into space & decreased fluid exit
-CHF - increases systemic hydrostatic pressure
-Liver disease & nephrotic syndrome - decreased oncotic pressure
-Pleural lymphatic tumor - impaired lymphatic drainage
-Pneumonia - increased vessel permeability
-Lung appears smaller on X-ray
-Differential diagnosis is narrowed by distinguishing transudate from exudate
-Transudate - protein-poor fluid leakage through intact capillary
-Causes - in/c hydrostatic pressure (CHF), d/c oncotic pressure
-Exudate - protein-rich fluid leakage through altered capillary barrier
-Causes - pneumonia, PE, malignancy, etc.
-Pneumothorax - air in the pleural space
-Caused by communication between alveoli & pleural space
-Negative pressure of pleural space causes air to enter until pressures equalize
-Causes of secondary pneumothorax
-COPD - most common cause
-Penumocystis jiroveci (PCP), asthma, cystic fibrosis, mechanical ventilation
*2o pneumothorax is worse than 1o, since pt already has compromised fxn
-X-ray - lung is collapsed centrally against the mediastinum

-Pleuritis - inflammation of the pleura

-Pneumonia is the most common cause; pain intensifies w/ breathing

18
LUNG INFECTIONS
-Injury to Defense Mechanisms Increases Risk for Infection
-Tracheobronchial clearance (cough, mucociliary elevator), alveolar Mphages, surfactant, etc.
-Smoking, altered LOC, etc. can impair these mechanisms

-Pneumonia
-Definition - inflammation of the lung
-Classified by morphology (bronchial, lobar, etc.) or etiology (bacterial, fungal, etc.)
-Key points
-One type of pneumonia predisposes to another
-Inhalation is most often the portal of entry (hematogenous seeding can also occur)
-Many hospitalized patients acquire pneumonia - often terminal
-Tissue response
-Acute
-Bacteria & fungi - located in distal airspaces (bronchioles, alveoli, etc.)
-Present w/ L-cytes, Mphages, granulomas, PMNs, necrosis
-Viruses & mycoplasma - located in proximal airways & interstitium
-Present as bronchial epithelial necrosis, hemorrhage, L-cytes, Mphages
-Chronic
-Successful therapy leads to resolution & reorganization
-Presents as abscess, diffuse alveolar damage, hemorrhage, cavitation
-Superinfection & death are possible

-Bacterial Pneumonia
-Disease of the distal airspaces
-Symptoms - airspaces consolidate & fill w/ PMNs, fibrin, exudate
-Risk factors - damage to normal defense mechanisms
-Smoking, alcohol, viral pneumonia, aspiration, & underlying lung disease
-Cystic fibrosis - *Pseudomonas, Staph aureus
*Classification
-Lobar pneumonia - exudate & bacteria spread along lumen of broncus
-Inflammation confined by lobar barrier - entire lobe is grossly white
-Bronchopneumonia - inflammatory exudate originates in bronchioles & damages walls
-Pores of Kohn provide spread to adjacent alveoli - patchy gross appearance
-Etiology drives choice of therapy
*Histopathology
-Lobar - airspaces diffusely involved with acute inflammation, proteinaceous exudate
-Associated w/ Strep pneumoniae, Klebsiella pneumoniae, etc.
-Bronchopenumonia - patchy distribution of inflammation (adjacent areas are normal)
-Associated w/ Staph aureus, Haemophilus influenzae

-Lung Abscess
-Local suppurative process with tissue necrosis
-Causes/risk factors - aspiration is most common (altered LOC, poor oral hygiene, immune supp)
-Also prior pneumonia, post-obstructive pneumonia
-Pathology
-Anaerobic infection mix w/ oral flora - K. pneumoniae, P. aeruginosa, S. aureus
-Liquefactive necrosis, granulation tissue, fibrous capsule
-Cavity may form in the lung, surrounded by granulation/fibrous tissue
-Clinical course - generally manifests w/ worsening cough, foul-smelling sputum
-Histopathology - defined area of confluent PMNs, fibrin, and/or necrotic material

19
-Tuberculosis
-Airborne infectious disease caused by Mycobacterium Tuberculosis (MTB)
-Even talking can aerosolize the bacteria
-Symptoms
-Weight loss, low fever, night sweats, cough w/ bloody sputum, adenopathy
-Imaging may reveal a lung nodule
-Generally seen in foreign-born persons (e.g. migrant worker), homeless, etc.
-Tuberculin skin test
-Purified protein derivative (PPD) is MTB culture precipitate
-Mantoux test - usually in left arm (give in the arm you don't shake hands with)
-Any induration after 48-72 hrs = positive
-Size of induration is specific to population
-Tests delayed hypersensitivity (type IV) - at least 3 wks after exposure
-Does NOT differentiate infection from disease
-Infection - organisms present w/ or w/o clinical sx
-Disease - clinical symptoms of infection
-False negative (anergy) - seen in pts w/ sardoidosis, Hodgkin, viral inf,
overwhelming TB, old TB, young age, recent live virus vaccine
-False positive - infection by atypical mycobacteria, BCG vaccine pts
-BCG vaccine - prepared from Mycobacterium bovis
-Administered after birth in countries w/ high TB prevalence
-Protection is variable 5-80%
-PPD test may be (+), but CDC says to take it as actual infection
-BCG is used to tx bladder CA - pts may have (+) PPD test
-Interferon-gamma release assay is more specific for MTB infection
-Risk factors
-Primary infection - poverty, overcrowded living, debilitating disease, homelessness
-Secondary disease - DM, Hodgin lymphoma, chronic lung disease, CKD, malnutrition,
alcoholism, immunosuppression, head & neck cancer

20
 -Classification
-Primary infection
-Develops in unsensitized person
*Ghon complex - 1 cm focus of granulomatous inflammation in the lung
-Usually subpleural w/ granulomatous lesion in corresponding LN
-Clinical course
-Usually asymptomatic, but fibrosis & calcification in 90% of pts
-Progressive primary disease
*Seen mostly in immunosuppressed individuals
-Ghon focus undergos caseous enlargement, usually w/o cavitation
-Generally seen in middle & lower lobes
-Erosion of bronchial tree & spread to adjacent lung → tuberculous pneumonia
*May involve blood vessels → hematogenous dissemination (Milary TB)
-Secondary disseminated disease
-Reactivation of asymptomatic primary infection or re-infection
-Occurs at time of decreased immune function
-Pts may be asymptomatic or have insidious sx (malaise, wt loss, etc.)
-Increasing sputum & hemoptysis are more overt sx
-Lung "mass" is malignancy until proven otherwise
*Typically occurs in apical or posterior segments of upper lobes
-Oxygen tension is higher in these areas
-Forms a cavitory lesion
-Clinical course is variable
-Fibrosis & calcification can stop the infection
-Can spread beyond lungs - likes the reticuloendothelial system (spleen)
-Massive dissemination leads to Miliary TB (immunosuppressed pts)
-Differential diagnosis
-Fungal infection, vasculitis (Wegener), sarcoidosis, aspiration, etc.
-Pathology
-Gross - nodule/mass in the lung w/ or w/o lymph node enlargement
-Microscopic - granulomas w/ central caseous necrosis, multinucleated giant cells
-Sheets of histiocytes in immune suppressed individuals (can't form granuloma)
-Acid-fast baccilli w/ special stains
-Diagnosis
-Culture - gold standard, but takes 3-8 weeks; good for drug susceptibility test
-PCR is faster, but can't do drug testing
-Other manifestations
-Isolated sx of dissemination - meninges, kidney, adrenals, vertebrae
-Lymphadenitis - most common extrapulmonary site, often cervical
-Intestinal - due to swallowing coughed-up infected material

PPD & Granuloma (what it looks like) will be on the exam

21
OBSTRUCTIVE LUNG DISEASE
-Obstructive Lung Disease
-Is defined by spirometry values - decreased FEV1 & FVC
-FRC (=ERV + RV) and RV increase
-TLC increases over time

-Chronic Obstructive Pulmonary Disease (COPD)

-Preventable & treatable disease characterized by irreversible airflow limitation
-Airflow limitation is progressive, NOT fully reversible, & assoc w/ noxious gas/particles
-Causes
-Increased airflow resistance in small airways
-Mucus hypersecretion, SM constriction, fibrosis, remodeling
-Decreased outflow pressure due to loss of parenchymal elasticity
-Alveolar walls are disrupted
-Etiology
-Cigarette smoking
-Occupational exposures (dust, fumes) - coal workers, welders, fire fighters, etc.
-Pathogenesis
-Innate defense system damage - epithelial cell damage, infection, cytokines
-Chronic bronchitis - "blue bloater"
-Emphysema - "pink puffer"
-Diagnosis via spirometry - FEV1/FVC < 0.7 follwoing bronchodilator
-Normal FEV1/FVC ~ 0.8
-Restrictive lung disease is characterized by FEV1/FVC ~ 0.9
-Chronic Bronchitis
-CLINICALLY defined by a productive cough for 3+ months for 2 consecutive yrs
-Diagnosed by excluding other causes
-Early disease may be mild - slightly worse during the winter, etc.
-Each infection, exacerbation, leads to progression & worsening sx
-Acute exacerbation generally brings a patient to see the physician
-50% of cases are related to bacteria - H. flu, M. catarrhalis, S. pneumo
-Pathogenesis - small airway obstruction
-Cigarette smoke & other irritants influence epithelial cells
-Submucosal glands undergo hyperplasia & increase mucus production
-Irritants injure epithelium and impair ciliary mucus clearance
-Bronchiolar basement membrane thickens due to collagen deposition
-Bronchoconstriction in response to irritant exposure
-Small airway obstruction is structural - present on inspiration & expiration
-Histopathology
-Gross - mucus plugging
-Micro - increased submucosal glands
-Clinical disease
*Small airway obstruction leading to V/Q mismatch
-Post-obstruction alveoli do not participate in gas exchange
-Hypercarbia & hypoxemia result - may lead to erythrocytosis
-Pulmonary vascular constriction → pulmonary HTN, cor pulmonale, & edema
-Decreased chemoreceptor sensitivity to CO2 prohibits normal hyperventilation
-Body "chooses" hypercarbia over work of breathing → blue bloater

22
-COPD (cont.)
-Emphysema
-PATHOLOGICALLY defined by permanent airway distension distal to term. bronchiole
-Due to destruction of airspace walls; obvious fibrosis is NOT noted
-Results in decreased lung elasticity / increased lung compliance
-Sx - hyperventilation, pursed lips, accessory muscle use, barrel chest
-X-ray - flat hemi-diaphragm (hyperinflated lung) & thin mediastinum
-Types of emphysema
-Centriacinar
-Proximal - initially affects the respiratory bronchiole
-Due to cigarette smoking - leads to PMN & MΦ recruitment
-PMN’s & MΦ’s release elastase
-Free radicals in smoke inhibit anti-proteases
-MΦ elastase is not normally inhibited by A1AT
-Panacinar
-Distal - initially affects the acini
-Related to α-1-antitrypsin deficiency (an anti-protease), IV drug abuse
-A1AT deficiency permits overactive PMN elastase activity
-Pathogenesis
-Overactive elastase activity results in destruction of airspace walls
-Enlarged airspaces coalesce to form bullae & blebs
-Rupture may lead to pneumothorax
-Elastase activity on capillary beds may compromise perfusion of ventilated areas
-Increased dead space
-Inflammation around bronchi & bronchioles
-Histopathology
-Massive airspaces - centriacinar is worse in upper lobes
-Clinical disease
-Parenchymal destruction causes a dynamic outflow obstruction to expiration
-It's hard to breathe against the already expanded space
-Scaffolding that holds lungs open at low volume is lost
-Forced expiration causes airways to collapse → air trapping
-V/Q mismatch due to ventilation of areas that are not perfused → hypercarbia
-Hypoxemia may be mild, but chemoreceptors are sensitive to CO2
-Body "chooses" the increased work of hyperventilation → pink puffer
-Hence these patients expend enormous energy and are thin
-Try to breathe at a higher RV to decrease airway resistance
-Increasing RV & FRC resculpts the chest into a "barrel shape"

Age SOB Cough Infection Blood gas Chest XR Appearance

Chronic bronchitis 45 late early common hypoxemia large heart overweight
Emphysema 65 early scant occasional ~normal hyper-inflated emaciated

23
-Asthma
-Chronic inflammatory disorder of the airways
-Recurrent wheezing, breathlessness, chest tightness, cough - worst in morn & evening
-Variable bronchoconstriction & airflow limitation due to hyperreactivity
-REVERSIBLE spontaneously or w/ therapy
-Classification helps guide therapy
-Extrinsic - type I hypersensitivity rxn to extrinsic antigen
-Atopy - genetic predisposition to develop IgE response to common allergens
-Ex: dust mites, cat dander
-Intrinsic - diverse non-immune mechanisms (cold, infection, stress, exercise, etc.)
-Clinical
-Spirometry before & after bronchodilators to determine if obstruction is reversible
-Pathogenesis of atopic asthma
-Allergen is presented to Th2 cell → IL-3,4,5
-IL-4 causes IgE class switching in B-cells; IgE's bind to mast cells
-IL-3,5 recruit eosinophils & stimulates release of mediators
-Allergen binds & cross-links IgE's on mast cell → mediator release
-Mediators stimulate vagus n. → vascular permeability & bronchoconstriction
-Leukotrienes have been implicated
-PMN's are recruited & cause endothelial damage and mucus production
-Pathogenesis of intrinsic asthma
-Viral URTI is the most common trigger - lowers threshold of vagal receptors to irritants
-Drug-induced - aspirin
-Occupational - fumes, dust, etc.
-Pathology is similar to chronic bronchitis
-Gross - mucus plugging
-Micro - hyperplasia of mucus glands & smooth muscle

-Bronchiectasis
-Characterized by permanent dilation of bronchi & bronchioles
-Due to destruction of muscle & elastic tissue associated w/ necrotizing infections
-Now uncommon w/ antibiotics
-Sx: cough, fever, copious foul-smelling purulent sputum
-Associated conditions
-Congenital - cystic fibrosis (predisposed to Pseudomonas)
-Post-infectious
-Necrotizing bacteria - MTB, Staph, H. flu, Pseudomonas
-Viral - adenovirus, influenza, HIV
-Fungi - aspergillus
-Bronchial obstruction - tumor, foreign body
-Pathogenesis - obstruction followed by infection
-Pathology
-Gross - dilated airways can be traced to pleura, filled w/ mucopurulent secretion
-Big, dilated holes in the lungs
-Micro - enlarged airways, mucus plugging
-Clinical disease
-May progress to bloody sputum & life-threatening hemorrhage
-Obstructive pattern can lead to profound cyanosis & dyspnea
-Also cor pulmonale, brain abscess, amyloidosis

24
RESTRICTIVE (INTERSTITIAL) LUNG DISEASE
-Restrictive Lung Diseases
-Heterogenous group of lung diseases
-Both known and idiopathic etiologies
-Classified by clinical syndrome or histology
-Pathology = diffuse interstitial disease
-Restrictive vs. obstructive
-Obstructive - characterized by an increase in resistance to airflow
-Restrictive - characterized by reduced expansion of lung parenchyma
-Decreased total lung capacity & loss of lung compliance (in/c recoil)
-FEV1/FVC ~ 0.9 (normal = 0.8)
-Diffuse & chronic involvement of the interstitium
-Interstitium = fused epithelium, BM, & endothelium
-Gas exchange occurs through it

-Chronic Interstitial Lung Disease

-Overview
-Constitute 15% of non-infectious lung diseases seen by pulmonologists
-Fibrosis around pulmonary vessels may cause R-sided HF 2o to pulmonary HTN
-Diseases are progressive
-Distinctive pathology becomes generic "honeycomb" in end-stage lung
-Usual Interstitial Pneumonia (UIP)
-Clinical - age > 50; men > women; can hear end-inspiratory crackles (like velcro)
-Prognosis - 3-5 yr survival, *does not respond to steroids
-Known causes
-Collagen vascular diseases - rheumatoid arthritis, SLE, systemic sclerosis
-Radiation - breast CA, lung carcinomas, Hodgkin disease
-Drugs - bleomycin, amiodarone
-Environmental - asbestos
*Idiopathic cause is most common
-Pathogenesis
-Lung injury leads to macrophage activation & cytokine release
-PMN's are recruited, along w/ Mphages secrete proteases
-Fibroblast recruitment leads to fibrosis
-Pathology
-Gross - *subpleural-based, patchy, fibrotic disease
-Fibrosis gives pleural surface a "cobblestone" appearance
-Lesions seen predominantly in lower lobes
-Progresses to honeycomb lung
-Micro - *"temporally heterogenous fibrosis"
-Old collagenous scarring & loose new fibrosis right next to each other

25
-Sarcoidosis
-Multi-organ system disease of unknown etiology
-Clinical - 20-40 y/o; women > men; black > white - *young black woman
*Predominantly in southeast U.S., usually incidental finding on CXR
-Pts tend to be anergic - do not respond to either Candida test or PPD test
-Prognosis - varied progression & spontaneous resolution
*Responds to steroids, 70% recover fully w/ minimal manifestation
-Pathogenesis
-CD4+ cells accumulate → IL-2 & IFN-gamma → T-cell & Mphage prolif
-TNF, IL-8, & MIP recruit T-cells to form a granuloma
-Main pathology - non-caseating granulomas
-Lungs are most common site
-Gross - granulomas along lymphatics, bronchi, bronchioles, vessels, pleura
-Hilar & mediastinal lymphadenopathy
-Cross-section of lung reveals bronchioles surrounded by granulomas
-Micro - diffuse nodules centered around bronchioles
-Non-caseating epitheliod granulomas, multinucleated giant cells
-Calcifications may also be seen
-Hypersensitivity Pneumonitis
-Immunologically mediated interstitial lung disease due to prolonged exposure to Ag’s
-Occurs in genetically predisposed individuals
-Takes weeks to months of exposure for sensitization to occur
-Bizarre etiology - farm silo, pet bird, humidifier
-Immune complexes & delayed type IV (T-cell) hypersensitivity
-Involves alveoli, not airways (compare to asthma) - recognize early & prevent
-Clinical
-Acute attacks of fever, dyspnea, & couch 4-6 hrs after exposure
-Chronic exposure leads to progressive respiratory failure due to fibrosis
-Remove offending antigen and lung will recover
-Pathology
-Micro - Lcytes, plasma cells, & Mphages in a loose non-caseating granuloma
-Granulomas are centered around bronchioles
-Para-bronchiolar fibrosis occurs late
-Desquamative Interstitial Pneumonia (DIP)
*Interstitial lung disease in current/former smokers - "desquamative" is a misnomer
-Mononuclear cell infiltrate (Mphages) w/o prominent fibrosis or honeycombing
-Clinical - 40-50 y/o; men > women
-Subacute illness (cough, SOB) takes weeks-months to develop
-Prognosis - full recovery if pt stops smoking; steroids may be used
-Pathology
-Micro - hypercellular lung, Mphages fill the airspaces

26
-Acute Restrictive Lung Disease
-Overview
-Spectrum of pulmonary lesions initiated by numerous factors
-Causes include bacteremia, DIC, & many more
-Genetic susceptibility contributes
-Mediated by cytokines - TNF, IL-1, IL-6, IL-10, TGF-beta
-Sx - pulmonary edema, congestion, surfactant disruption, atelectasis
-Diffuse Alveolar Damage (DAD)
-Rapid, sudden onset in pt usually hospitalized for profound dyspnea w/ cyanosis,
hypoxemia, respiratory failure
-Clinical - evolves in days-weeks, may lead to death
-Prognosis - 50% overall mortality (sepsis, multiorgan failure, etc.)
-Provide supportive tx - maintain O2, avoid infection, treat hypotension
-Pathogenesis
-Damage to alveolar epithelial & capillary endothelial cells allows leakage
-May be a result of G(-) bacteremia & LPS
-Cells & fluid leak into alveoli - Mphages phagocytose debris, recruit fibrobasts
-Reorganization forms a hyaline membrane - impedes gas exchange
-Pathology
-Micro - dramatically thickened alveolar walls
-Looks like holes in tissue instead of alveoli
-Acute Interstitial Pneumonia (AIP)
-Same as DAD both histologically & clinically, but IDIOPATHIC cause
-Ex: pt thought to have CA pneumonia - treat w/ empiric antibiotics but doesn’t respond
-No organism is ever identified
-Clinical - 100% present w/ cough, 50% w/ fever; may lead to acute respiratory failure
-Only tx is mechanical ventilation
-Survival ~50%

-Hyaline Membrane Disease

*Most common cause of respiratory distress in the newborn
-Responsible for 1/3 of neonatal deaths
-Child makes insufficient surfactant due to prematurity or lung insult
-Hyaline membranes form as a result of hypoxemia & CO2 retention
-Hypoxemia & hypoperfusion lead to endothelial & epithelial damage → leakage
-Clinical
*Risk factors - premature birth (< 28 wks), white, male, gestational diabetes, C-section
-Sx w/in hours of birth - tachypnea, nostril flaring, subcostal retractions, cyanosis
-Expiratory grunting to open airways - alveolar collapse increases work of breathing
-Cases may be mild or severe
-Treatment - prevent premature birth, exogenous surfactant therapy
-Pathology
-Gross - heavy, condensed, stiff lungs
-Micro - hyaline membranes, increased cellularity, & thickened alveolar walls

27
PNEUMOCONIOSES & PULMONARY HYPERTENSION
-Pneumoconioses
-Definition - non-neoplastic lung reaction to inhalation & retention of dust, fumes, vapors
-Pathogenesis
-Depends on
-Amount of dust retained in airways
-Irritant conc. in air, duration of exposure, effective mucociliary elevator
-Size & shape of particles - 1-5um particles can reach the terminal air sacs
-Alveolar Mphages - dust may overwhelm capacity; Mphage rxns can injure cells
-Tobacco smoke - worsens the effects of inhaled irritants, particularly asbestos
-Only a small % of those exposed go on to develop pneumoconiosis
-Process
-Particles activate alveolar Mphages → release cytokines & proteases
-Generates inflammation & fibrosis
-Reaction patterns
-Inorganic particulate dust - silica, aspestos cause fibrogenesis
-Carbon/coal is not fibrogenic
-Fine dusts (beryllium) - causes sarcoid-like granulomas
-Vapors, chemical fumes - cause DAD, acute lung injury
-Organic dusts (animals, etc.) - hypersensitivity pneumonitis, bronchiololitis, granulomas

-Classification of Pneumoconioses
-Coal Workers Pneumoconiosis - Nodules with lots of dust & less fibrosis than other dz’s
-Interstitial lung disease caused by coal dust
-Since coal is not pure, findings may overlap (silicosis - but exam is 1:1)
-Diagnosis - based on clinical hx & radiologic findings
-In absence of smoking, does not in/c CA risk; no increased susceptibility to TB
-Types of CWP
-Anthracosis - harmless accumulation of carbon in lymphatics
-Simple CWP - asymptomatic or chronic cough w/ black-tinged sputum
*Coal nodules - black Mphages border bronchioles, upper lobes
-Pulmonary function test (PFT) is normal
-Histopathology
-Numerous bilateral nodules throughout lungs
-Carbon macules (dust-filled Mphages), but little fibrosis
-Complicated CWP - dyspnea & productive cough
-Rare - progressive dz after SCWP, even w/o continued exposure
-PFT shows a restrictive pattern
-Histopathology
-Large zones of scarring & anthracosis
-Dense fibrosis w/ anthracotic pigment-laden Mphages
-However, dust > fibrosis
-Treatment - only tx is prevention
-Silicosis - Nodules of fibrosis; little dust, but dust is polarizable*
-Progressive parenchymal nodules & fibrosis after inhaling silica crystals
-Risky occupations - quarrying, stone engraving, sandblasting, etc.
*Increases susceptibility to tuberculosis
-Nodules may undergo necrosis w/o epithelioid granulomatous rxn
-Necrosis + granulomatous rxn in a nodule = TB until proven otherwise
-Diagnosis - hx, radiologic findings, exclusion of other causes

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 -Clinical may be chronic, accelerated, or acute depending on exposure
-Acute - rare, due to heavy exposure as in sandblasting
-Sx develop w/in 3 yrs
-Chronic (classical) is the most common form
-Sx develop decades after exposure to low levels of dust
-Accelerated experience disease after 3-10 yrs
-Can be simple or complicated (like CWP)
-Lung nodules are present (like CWP), but more obvious fibrosis
-Predominantly in upper lobes
-Histopathology
-Firm, demarcated, bilateral nodules - Mphages cause fibrosis
-Radiology can't distinguish CWP from silicosis
-Histo - pink nodules of dense, lamellar fibrosis
**Birefringent silicates & collagen fibers
-Anthrocotic pigment may be seen
-Lymph nodes often calcify - "eggshell calcification"
-Peritoneum & pleura may experience fibrosis
-Gross cavitation may be seen in fibrotic nodules
-Asbestosis - Diffuse fibrosis, asbestos bodies
-Risks - mining, insulation, ship-yards, textile worker, floor tiles
-Types of fibers
-Chrysotile - flexible, gets caught in the URT
-Amphibole - straight & stiff, aligns w/ air to reach LRT
-Can penetrate epithelial cells & reach interstitium
-Amphibole exposure correlates with mesothelioma
-Asbestos bodies
-Asbestos fibers coated w/ iron by macrophages (ferruginous body)
-Appear straight w/ clubbed ends & beaded shaft
-Diagnostic for asbestosis, but not required for dx of asbestos exposure
-Asbestos exposure
-Increases the risk of lung carcinoma - 5x in non-smoker, 55x in smokers
-Increases relative risk of mesothelioma by 1000x
*Bronchogenic carcinoma is more common than mesothelioma
-Pathology: Pleural plaques - circumscribed plaques of dense collagen
-Asymptomatic, most common manifestation
-Pathognomonic for exposure; bodies need not be present
-Asbestosis
-Bilateral diffuse interstitial fibrosis of the lungs due to fiber inhalation
-Requires heavy exposure
-Diagnosis - hx of exposure, diffuse interstitial fibrosis, asbestos bodies
-Clinical - sx develop decades after exposure
-Restrictive pattern via PFT, dyspnea, non-productive cough
-Disease may be static or progress to resp. failure, cor pulmonale
-Radiology
-Bilateral, symmetric, linear opacities, mainly in lower lobes
-May appear similar to UIP
-Pleural involvement is a hallmark & sets it apart from other dz's
-Pathology
-Fibrosis beginning at bronchioles & spreading peripherally
*Subpleural fibrosis & diffuse interstitial fibrosis
-Asbestos bodies seen microscopically

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-Pulmonary Arterial Hypertension (PAH)
-General
-Pulmonary circulation is a low resistance system (pressure is 1/8 of systemic)
-Pressure increases due to increased blood viscosity or decreased vessel radius
-Secondary
-Most common cause of PAH; due to structural conditions
-Etiology
-COPD/interstitial lung disease (hypoxia) + destruction of alveolar capillaries
-Increases pulmonary arterial resistance & hence pressure
-Congenital or acquired heart disease
-Recurrent thromboemboli - reduce x-sectional area of pulmonary vascular bed
-Autoimmune disorders - cause inflammation & fibrosis of pulmonary vessels
-Ex: systemic sclerosis
-Obstructive sleep apnea
*Clinincal associations
-Hypoxia - causes vasoconstriction in pulmonary vessels
-Anorexigens (appetite suppressants)
-CNS stimulants - cocaine, methamphetamine
-HIV infection, portal HTN, thrombocytosis, hemoglobinopathies
*Pathogenesis is similar to atherosclerosis
-Endothelial cell dysfxn
-Vascular constriction & platelet adhesion
-Decreased prostacyclin & NO; increased endothelin
-Vascular remodeling - migration & proliferation of SM & production of ECM
-Primary (familial / idiopathic)
-Diagnosis of exclusion, 6% familial AD w/ incomplete penetrance
-Most common in children & women age 20-40
-Mutations in the BMPR2 signaling pathway
-Normally inhibits proliferation & favors apoptosis in vascular SM
-Morphology - histologic lesions are not specific to PAH
-Marked medial hypertrophy in vessels - concentric rings of SM cells
-Atheromatous changes - arterioles & small arteries are most affected
-Plexogenic pulmonary arteriopathy - primary PAH & R→L shunts
-Capillary formation in the arteriole lumen (recanalization?)
-Clinical
-Dyspnea, fatigue, cyanosis, respiratory distress, RVH due to lung disease
-80% generally die in 2-5 years

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LUNG AND PLEURAL TUMORS
-Carcinomas
-Overview
-Pathogenesis
-Stepwise accumulation of genetic abnormalities in bronchial epithelium
-Smoking, radon, genetic alterations, etc.
-Presentation
-Pts are generally 40-70 y/o
-May be an incidental finding, or may present w/ sx
-Sx - cough, wt loss, fatigue, dyspnea, paraneoplastic syndrome, etc.
-Metastases may cause the first sx - seizure, HA, bone pain/fracture
-Adrenals, liver, brain, & bone are most common sites of metastasis
-Overall 5-year survival is 15%
-Secondary pathology
-Bronchial obstruction can cause atelectasis, post-obstructive pneumonia
-Superior vena cava syndrome – compression or invasion of SVC (emergency)
-Sx - venous congestion; edematous face, head, arm, brain
-Pericarditis - CA may extend to pericardium & restrict cardiac filling
-Pleural effusions, pleuritis
-Paraneoplastic syndrome - any tumor can secrete hormone-like substances
-SmCC - hyponatremia from SIADH, Cushing from ACTH
-SCC - hypercalcemia from PTH-related peptide (PTHrP)
-Associated with bone resorption
-Lung cancer (mostly small cell) - Lamber-Eaton Myasthenic Syndrome
-Sx - lower prox muscle weakness, fatigue, dry mouth, ptosis
-LEMS often develops before diagnosis of cancer
-Small cell carcinoma
-Derived from dispersed neuroendocrine system; strong association w/ smoking
-Usually found in the hilum - central mass
-Commonly associated with paraneoplastic syndromes - ACTH, ADH
*Almost never associated with hypercalcemia
-Aggressive - generally metastasized widely at diagnosis
-Tx: chemotherapy - surgery isn't possible due to metastases
-Histopathology
-Sheets of "small" cells with scant cytoplasm
-Finely granular "salt & pepper" chromatin
-Frequent mitotic figures & necrosis - rapid cell turnover
-Squamous cell carcinoma
-Generally preceeded by metaplasia, dysplasia, carcinoma in situ, etc.
-Strong association with smoking
-Slower to spread outside of the thorax compared to other types of carcinoma
-However, locoregional recurrence is more common than w/ other types
**Strongly associated with paraneoplastic Hypercalcemia
-Tx: surgery, possible chemo/radiation
-Pathogenesis
-Smoking causes squamous metaplasia of the respiratory epithelium
-Evolves to squamous dysplasia & squamous cell carcinoma in situ
-Eventually becomes invasive - extends into stroma
-Histopathology
-Nests of polygonal cells w/ glassy pink cytoplasm, demoplastic stroma
-Keratin pearls, intercellular bridges

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 -Adenocarcinoma
-Most common histologic carcinoma
-Generally seen in women & non-smokers - EGFR(+)
-EGFR is a TK that signals kRas to regulate proliferation & apoptosis
*NSmCC's with somatic EGFR mutations may respond to TK inhibitors
-EGFR mutations are extremely rare in small, squamous, & large cell
-Less frequently associated with smoking (only 75%)
-Generally appear peripherally; smaller size than other carcinomas
-Earlier metastasis outside of thorax than SCC
-May appear in pleura or chest wall since they are peripheral
-Symptoms may appear before the primary tumor is identified
-Tx: surgery, possible chemo/radiation
-Histopathology - patterns vary; glandular structures lined by a single layer of epithelium
-Large cell carcinoma
-Undifferentiated malignant epithelial tumor - diagnosis of exclusion
-Tends to be large at diagnosis
-Usually peripheral location; necrosis is seen
-Tx: surgery, possible chemo/radiation
-Histopathology
-Sheets of cells with large nuclei & moderate cytoplasm - big, ugly cells
-Nuclei have open chromatin & prominent nucleoli

-Other Cancers of the Lung & Pleura

-Carcinoid
-Low grade malignant epithelial neoplasm w/ neuroendocrine differentiation
-Arises from dispersed NES in bronchogenic epithelium; ~3% of lung tumors
-Types - typical (no necrosis, < 2 mitotic figures); atypical (necrosis, 2-10 mitotic fig’s)
-Sx - usually an incidental finding; may present w/ cough & hempotysis
-Histopathology
-Gross appearance - polyploid mass protruding into the bronchial lumen
-Nests of homogenous cells with round nuclei
-Hamartoma
-A mature indigenous tissue in a disorganized mass
-Appears in lung as lobule of disorganized cartilage w/ clefts lined by epithelium
-Usually incidental - peripheral, solitary, circumscribed, looks like a "coin"
-Tx: excision is curative
-Lung Metastases
-Lungs are most common site for mets - carcinomas, sarcomas, melanomas, lymphomas
-May be a single "cannonball" lesion, or a multiple "buckshot" lesion
-Many lesions of various sizes is indicative of mets from a distant primary
-Malignant Pleural Tumors
-Metastases are also the most common tumor of the pleura
-Often obstruct lymphatics & cause a pleural effusion
-Other causes include lung CA, breast CA, & lymphoma
-Survival 3-6 months
-Mesothelioma
-Most common 1o pleural CA, but rare overall - very aggressive (2yr survival)
-Sx - pleural effusion, breathlessness, chest wall pain
-20% of pts have concurrent asbestosis
-However, asbestos is more likely to cause lung CA than mesothelioma
-Histopathology - diffuse pleural thickening, may appear like an orange rind

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LUNG CASES
-Asthma
-Airway remodeling in bronchioles - fibrosis & SM proliferation
-Also mucus gland proliferation & mucus plugs
-Curschmann sprial - mucus appears this way on a slide
-Charcot-Leyden crystals - remnants of eosinophil proteins
-Hyaline Membrane Disease & GBS Pneumonia (infant)
-Lungs look like liver - stiff, full of something besides air
-Hypercellular lungs - don't see airspaces or alveoli
-Hyaline membrane lining alveolar spaces
-Asbestos Exposure - lower lobe infiltrates, acellular fibrosis
-Mesothelioma - asbestos bodies, pleural effusion
-Diffuse pleural thickening (rind-like); most common primary tumor of the pleura
-Change in history – rapidly progressive dyspnea
-Differentiate from carcinoma
-Mesothelioma: Calretinin(+),

LUNG LAB
-Smoker w/ Shortness of breath
-Bronchopneumonia - PMN infiltrate in a PATCHY pattern
-Adenocarcinoma - single layer of cells lining a space, jagged orientation of spaces
-Well-formed cartilage indicates the cancer obstructed a bronchus → bronchopneumonia
*Panacinar emphysema
-Correlates with A1AT deficiency
-Upper lobes are affected worse - dilated airspaces

-Migrant Worker
-Diffuse Alveolar Damage (DAD)
-Hyaline membranes made of proteinacous debris & pneumocytes
-Clinical - acute respiratory distress syndrome from chlorine exposure
-Tuberculosis
-Caseating granuloma - pink material, central necrosis
-Surrounded by macrophages, giant cells, & outer layer of lymphocytes

-Other Points
-HA pneumonia occurs > 48 hrs after hospital admission - Enterobacteriaceae, Pseudomonas
-If alcoholic vomits & aspirates, can get Klebsiella pneumonia
-Multiple lung lesions - most likely mestastases
-Pathogenesis of emphysema - overactive elastases
-Panacinar - A1AT deficiency
-Centriacinar - smoking
-Causes of DAD
-Something damages epithelium or endothelium - chemicals, exotoxin (sepsis)
-Proteinacous fluid leaks & accumulates in alveoli; pneumocytes are damaged
-Debris forms hyaline membranes

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