Renal Pathology Lecture II Flashcards
Medullary Sponge Kidney
- -Disease of adults
- -Often incidental finding
- -Normal kidney function
- -Multiple cystic dilations of collecting ducts in medulla
Gross features of medullary sponge kidney
Dilated papillary ducts in the medulla
Micro features of medullary sponge kidney
Cysts lined by cuboidal or transitional epithelium
Dialysis-Associated (acquired) cystic disease
- -Most asymptomatic
- -Almost always develop cysts with dialysis
- -7% of dialysis patients will develop renal cell carcinoma within the cysts
Simple cysts
- -Multiple or single (typically cortical)
- -1-5 cm in size commonly
- -Filled with clear fluid (ultrafiltrate)
- -Pretty avascular on CT-angiography
- -Single layer of cuboidal or flattened epithelium line the cysts
- -No clinical significance, but will want to differentiate from possible tumor
Glomerulonephritis
IMMUNE MEDIATED DISEASE
–Primary or secondary
Histologic patterns of glomerular injury
- Hypercellularity (increase in glomerular cells, increase in WBCs, formation of crescents)
- Basement membrane thickening
- Hyalinization and sclerosis
Diffuse
All glomerular involved
Focal
Proportion of glomeruli involved (less than 50%)
Global
Entire single glom involved
Segmental
Part of single glom involved
Antibody-mediated injury
- -In situ immune complex deposition (Goodpasture, hemyann, planted antigens)
- -Circulating immune complex antigen
Immune mechanisms of glomerular injury
- Antibody-mediated injury
- Cell-mediated immune injury
- Activation of alt. complement path
Anti-GBM Glomerulonephritis
- -Abs directed against normal parts of GBM
- -Ab may cross-react w/other basement membranes (such as pulmonary alveoli)
- -Ag component of type IV collagen!
- -
Anti-GBM glomerulonephritis appearance on IF
Homogenous, linear/ribbon-like appearance. Diffuse.
Membranous nephritis
- -Antigen: M-type Phospholipase A2 receptor
- -IF: granular and interrupted pattern
- -EM: electron dense deposits along subepithelial aspect of GBM
“Planted” antigens
- -Non-glomerular origin, but localize in kidney
- -Abs form against them
Circulating immune complex nephritis
- -Glomerular injury from trapping of circulating Ag/Ab complexes within gloms
- -Type III hypersensitivity
- -Antigens endogenous (SLE) or exogenous (streptococci)
IF and EM findings with circulating immune complex nephritis
IF: granular deposits
EM: electron-dense deposits, mesangial, subepithelial, or subendothelial
Progression in glomerular disease
Once reduced to 30-50% of normal, progress to end-stage renal failure no matter what inciting event was
Histological findings in glomerular disease
- -Focal segmental glomerulosclerosis
- Tubulointerstitial fibrosis
Focal segmental glomerulosclerosis as an adaptive change
- -Compensatory hypertrophy occurs
- -Hemodynamic changes in ind. glomeruli (increases in flow, filtration, transcapillary pressure)
- -Leads to segmental sclerosis
Treatment of focal segmental glomerulosclerosis
Renin-angiotensin inhibitors
Tubulointerstitial fibrosis
- -Develops with glomerulonephritides over time
- -Ischemic tubules downstream from sclerotic glomeruli
- -Proteinuria directly toxic to downstream tubular cells
- -Increased acute and chronic inflammation occurs
Nephritic syndrome
- -INFLAMMATORY process
- -Hematuria
- -RBC casts in urine
- -Azotemia, oliguria, HTN (from salt retention), proteinuria
Nephrotic syndrome
- -Massive proteinuria (>3.5g/day)
- -Hypoalbuminemia leading to edema
- -Hyperlipidemia
- -Frothy urine w/fatty casts.
- -Podocyte damage disrupting filtration charge barrier.
- -Hypercoagulable state
Types of nephritic syndrome
- -Acute poststreptococcal glomerulonephritis
- -Rapidly progressive (crescenteric) glomerulonephritis (RPGN)
- -Diffuse proliferative glomerulonephritis (DPGN) (and nephroltic syndrome)
- -IgA nephropathy (Berger Disease)
- -Alport syndrome
- -Membrano-proliferative glomerulonephritis (MPGN) (often also nephrotic syndrome)
Types of nephrotic syndrome
- -Focal segmental glomerulosclerosis
- -Minimal change disease (lipoid necrosis)
- -Membranous nephropathy
- -Amyloidosis
- -Diabetic glomerulo-nephropathy
Acute poststreptococcal glomerulonephritis general characteristics
- -Occurs 1-4 weeks post-infection of pharynx or skin.
- -Resolves spontaneously
- -Type III hypersensitivity reaction
- -All ages, most common in children
Acute poststreptococcal glomerulonephritis lab findings
- -Decreased C3 serum levels
- -Seum antistreptolysisin O, antiDNase B titers high
- -Red cell casts
- -Mild proteinuria
Acute poststreptococcal glomerulonephritis LM, IF, and EM findings
- -LM: glomeruli enlarged and hypercellular w/proliferation of endothelial and mesangial cells. Infiltration of neutrophils and monocytes
- -IF: Granular IgG, IgM
- -EM: sub epithelial immune complex humps
What helps make diagnosis for acute poststreptococcal GN
EM
Clinical presentation for Acute poststreptococcal GN
- –Nephritic
- -“SMOKY URINE” hematuria
- -Malaise
- -Oliguria
- -PERIORIBITAL EDEMA
- -Mild HTN
- -Adults may have atypical presentation
Rapidly progressive (crescentic) GN (RPGN) general info
- -SEVERE injury to glomerulus
- -Not caused by specific entity
- -Poor prognosis
- ->50% of glomeruli will have crescents
Crescents
Proliferations of parietal epithelial cells of Bowmans capsule mixed with inflammatory cells
Type I RPGN
- -Anti-GBM GN
- -IF show LINEAR deposits of IgG ,C3, in GBM
Type II RPGN
- -Immune complex mediated
- -IF: GRANULAR pattern, “lumpy-bumpy)
- -Seen with PSGN, SLE, IgA nephropathy
Type III RPGN
- -Pauci-immune type
- -LACK OF IF STAINING
- -Most have P or C-ANCA
- -Some cases due to vasculitis, most are idiopathic
RPGN gross, micro, EM findings
- -Gross: large, pale kidneys w/petechiae
- -Micro: crescent formation w/fibrin strands
- -EM: ruptures in GBM +/- subepithelial deposits
Nephrotic syndrome pathophysiology
- -Increased permeability of GBM to plasma proteins
- -Massive proteinuria
- -Hypoalbuminemia
- -Loss of colloid osmotic pressure and edema
- -Increased liver synthesis of lipoproteins
- -Infections due to loss of Ig and complement
- -Hypercoaguable state due to loss of anticoags
Number one cause of nephrotic syndrome in children
Minimal change disease (75% of cases)
Most common causes of nephrotic syndrome in adults
Membranous and Focal segmental glomerulosclerosis
Membranous GN general info
–Can be primary (idiopathic) or secondary to other conditions (DM, NSAIDs, HBV, HCV, SLE, solid tumors, etc.)
Pathogenesis of membranous GN
- -Chronic Ag-Ab mediated disease
- -Antigens can be endogenous or exogenous
- -Damage to GBM is COMPLEMENT MEDIATED
What is often the autoantigen in membranous GN in adults?
Phospholipase A2
Microscopic findings of membranous GN
- -Normocellular gloms
- -Uniform, diffuse, thickening of capillary wall (capillary loops look like cheerios)!!!
- -“Spikes” on silver stain correspond to BM material between deposits
- -Deposits become part of very thickened GBM
- -Late mesangial sclerosis and glomerular hyalinization occur
IF of membranous GN
Granular deposits along GBM–Deposits contain IgG and C3. Nephrotic presentation of SLE
EM of membranous GN
–Subepithelial deposits
–“Spike and dome” appearance
Spikes of BM between deposits
–Thickened GBM w/lucent defects (deposits resorbed)
–Effacement of foot processes
Course of membranous GN
- -Chronic proteinuria and slow deterioration (40% chronic renal insufficiency, 10% die or have renal failure)
- -Highly variable! Can’t predict who will do well
- -Corticosteroids are +/-
- -If secondary treat the cause
Minimal change disease (Lipid nephrosis) (MCD) general info
- -Most common cause of nephrotic syndrome in children (peak 2-6 yrs old)
- -Associated w/atopy, may follow URI or routine immunization
- -Increased incidence in Hodgkin lymphoma!
- -RESPONDS TO CORTICOSTEROID TREATMENT
Pathogenesis of MCD
- -Visceral epithelial cell injury
- -T cell dysfunction and release of cytokines
- -May lead to loss of charge barrier or adhesion defects between epithelial cells
Microscopic findings of MCD
- -Normal glomeruli!!
- -Proximal tubules may be fill with lipid
IF findings in MCD
No staining
EM findings in MCD
- -DIffuse effacement (cytokine mediated) of foot processes of visceral epithelial cells (podocytes)
- -No deposits
Clinical course of MCD
- -Massive proteinuria (mostly albumin)
- -No renal failure, often no HTN
- ->90% of kids respond to corticosterioids
- -Can recur
- -Adults respond more slowly, still recover
- -Damage to visceral epithelial cells reversed by steroid therapy
Focal Segmental Glomerulosclerosis (FSGS) general info
- -Sclerosis of some gloms in portion of glomerulus
- -Associated with HIV, heroin addiction, sickle cell disease, morbid obesity
- -Secondary change in area of previous necrotizing lesion
- -Adaptive response to loss of renal tissue
- -Currently most common cause of nephrotic syndrome in adults
Pathogenesis of FSGS
- -Thought to be related to MCD
- -Damage to visceral epithelial cells
- -Genetic abnormalities of proteins which localize to slit diaphragm and lead to FSGS
LM findings of FSGS
- -Make diagnosis this way
- -Focal, need good biopsy
- -Collapse of GBM, increased mesangial matrix, hyalinization, +/- foam cells
- -Segmental sclerosis and hyalinization
EM findings of FSGS
- -Diffuse effacement of foot processes (similar to MCD)
- -Focal detachment of epithelial cells from GBM
IF findings of FSGS
Mesangial deposits of IgM and C3 (in sclerotic area)
Clinical course in FSGS
- -Doesn’t respond well
- -Nephrotic syndrome, HTN, reduced GFR
- -Poor response to corticosteroids
- -At least 50% have ESRD in 10 yrs
- -RECURS POST-TRANSPLANTATION
- -Worse prognosis with HIV nephropathy
HIV nephropathy
- -Most commonly FSGS, collapsing variant
- -See cystically dilated tubules filled with proteinaceous material and inflammation
- -EM: TUBULORETICULAR INCLUSIONS IN ENDOTHELIAL CELLS
- -5-10% of HIV positive patients, more commonly in African-Americans
Membranoproliferative GN (MPGN) general info
- -5-10% of nephrotic syndrome in children and young adults.
- -May present with nephritic syndrome
- -Proliferation of glomerular cells, leukocyte infiltration, changes in GBM
Associations w/MPGN
- -Chronic immune complex disease (SLE, Hep B, Hep C, endocarditis, infected ventriculoatrial shunts)
- -Partial lipodystrophy (type II)
- -Alpha-1 antitrypsin deficiency
- -Malignancy (CLL, lymphoma, melanoma)
Pathology of MPGN
–Type 1 and 2 distinguished by IF, EM. Microscopic (1 and 2 similar).
Microscopic findings of MPGN
- -Large, hypercellular glomeruli w/lobular architecture (“flower-like”)
- -Thickened GBM
- -Silver stain show “tram track” or “double contour” from mesangial cell interposition into GBM
Type I MPGN
- -2/3 of cases
- -IF: granular C3, IgG, C1q, C4
- -SUBENDOTHELIAL DEPOSITS +/- subepithelial and mesangial deposits
Pathogenesis of Type I MPGN
- -Immune complex disease
- -Activation of classic and alternative complement pathways
Type II MPGN or dense deposit disease
–IF: granular C3 only
EM: DENSE DEPOSIT DISEASE
Lamina densa RIBBON-LIKE and extremely dense from deposits
–Excess activation of alt complement pathway
Clinical course of MPGN
50% develop chronic renal failure in 10 years
- -steroids and immunosuppressive drugs not helpful
- -COMMONLY RECURS POST-TRANSPLANT
IgA nephropathy (Berger disease)
- -Most common type of GN worldwide
- -Causes recurrent hematuria w/RBC casts
- -+/- proteinuria (can be in nephrotic range)
- -HSP systemic disease w/overlapping features
- -Associated w/celiac sprue, liver disease
Pathogenesis of IgA nephropathy
- -Plasma polymeric IgA increased
- -IgA aberrantly glycosylated
- -Immune complexes deposit or are formed in mesangium
LM of IgA nephropathy
Mesangial proliferation
IF of IgA nephropathy
Mesangial deposition of IgA!!!
+/- C3, properdin, IgG, IgM
EM of IgA nephropathy
Paramesangial and mesangial immune complex deposits
Clinical course of IgA nephropathy
–Hematuria following respiratory, GI, UT infection
–Variable course presentation
15-40% develop chronic RF over 20 years
–Disease recurs post-transplantation
Types of hereditary nephritis
- -Alport Syndrome
- -Thin membrane disease
Alport syndrome presentation
- -Nephritis, eye problems, sensorineural deafness
- -Most cases X-linked dominant
- -Males affected more frequently and severely
Alport syndrome pathophysiology
–Mutation in type IV collagen–> thinning and splitting of GBM
Alport syndrome microscopic findings
- -Glomeruli w/segmental proliferation or sclerosis
- -Mesangial matrix increases
- -Persistance of fetal-like glomeruli
- -Foam cells
EM findings in Alport Syndrome
- -Splitting of the lamina densa
- -Changes are widespread
- -Diagnosis made based on EM findings
Clinical course of Alport Syndrome
- -Present w/hematuria at 5-20 yrs
- -+/- proteinuria (Can be nephrotic)
- -Renal failure by 20-50
Thin membrane disease (Benign familial hematuria)
- -Fairly common
- -Present w/hematuria
- -EM shows diffuse thinning of GBM
- -Abnormal genes encoding collagen chains
- -Excellent prognosis but homozygous patients may progress to RF
Chronic Glomerulonephritis
- -End result of specific types of GN
- -Some present at end stage w/no antecedent disease
Gross and micro findings of Chronic GN
Gross: small, diffusely granular kidneys
Micro: globally hyalinized glomeruli (hyaline material contains plasma proteins, mesangial matrix, GBM material, collagen) Atrophy and fibrosis of tubules/interstitium
Progression to Chronic GN (in order of those most likely to progress)
- RPGN (90%)
- FSGS (50-80%)
- Membranous (50%)
- Membranoproliferative (50%)
- IgA nephropathy (30-50%)
- Poststreptococcal (1-2%)
SLE general info
- -Autoimmune disease
- -Affects skin, joints, kidney, serosal membranes
Lupus nephritis
- -60-70% involvement based on LM exam
- -Nearly all SLE patients show kidney involvement on IF and EM eval
- -5 patterns of involvement
IF and EM findings in SLE nephritis
IF: “full house” stains with everything
EM: subendothelial and sometimes IgG-based immune complexes often with C3 deposition
LM: “WIRE LOOP” LESION (thickening of capillary wall by subendothelial deposits)
HSP clinical presentation
Purpuric skin lesions on arms, legs and buttocks, abdominal pain, vomiting, bleeding, arthralgia, renal abnormalities (1/3 of patients) (hematuria, proteinuria/nephrotic syndrome, renal issues worse in adults, may have crescentic GN)
Most common age of HSP
3-8 year old after URI
HSP pathophysiology in kidneys
IgA deposition in mesangium
Diabetic nephropathy general info
- -ESRD in up to 40% of Type I and II DM
- -Proteinuria in 50% (typically 12-22 yrs after diagnosis)
- -Micro: capillary BM thickening, diffuse mesangial sclerosis, nodular glomerulosclerosiss
Pathogenesis of diabetic nephropathy
- -Metabolic defect: increases type IV collagen, fibronectin, nonenzymatic glycosylation of proteins, leads to thickened GBM, increased mesangial matrix
- -Hemdynamic effects: increased GFR, glomerular hypertrophy early, leads to glomerulosclerosis
Pathology of diabetic nephropathy
- -Capillary basement membrane thickening (see on EM)
- -Diffuse mesangial sclerosis
- -Nodular glomerulosclerosis
Nodular glomerulosclerosis in DM nephropathy
Kimmelstiel-Wilson disease
- -Hyaline masses in periphery of glomerulus
- -15-30% of DM patients, assoc. w/ RF
Clinical course of diabetic nephropathy
- -Microalbuminuria
- -HTN
- -Diabetic nephropathy
- -ESRD
- -Treatment options: long-term dialysis, renal transplant, pancreas transplant
