Nephrosis I and II Flashcards
indicators of a nephritic state
hematuria
proteinuria
azotemia
oliguria
hypertension
edema
podocalyxin
a protein that covers the podocyte cell surface associated with sialoglycoprotein, SGP
components of the slit diaphragm
nephrin
P-cadherin
ZO-1
mesangial cells
centrally located phagocytic and contractile cells
contain angiotensin-II receptors, and thereby regulate intraglomerular blood flow, and lastly, they respond to various cytokines (IL-1) by producing reactive oxygen species, proteases, and growth factors
What are the four factors regulating ultrafiltration?
intrarenal blood flow
transcapillary hydraulic pressure difference
colloid concentration
capillary sieving coefficient
What proteins in the slit diaphragm determine charge selectivity?
HS-PG and SPGs
type IV collagen
laminin
minimal change disease
most common cause of nephrotic syndrome in children
normal glomeruli by light microscopy
podoctye process alterations by electron microscopy
What are the histological features of minimal change disease?
normal glomerular morphology
tubular protein absorption droplets
tubular lipid droplets (oil red o stain)
What are the electron micrograph features of minimal change disease?
fusion of podocyte foot processes
villous transformation
mechanisms of proteinuria
may be related to the loss of size and/or charge selectivity of the ultrafiltration unit
may be due to the injury to the capillary by antigen, antibody, immune complex, complement, proteolytic enzymes and reactive oygen species (ROS) or nascent oxygen radicals
may be related to the adverse influences of high protein diet damaging the glomerular mesangial cells
selective proteinuria
leakage of albumin only, seen in minimal change disease
nonselective proteinuria
leakage of albumin and globulins, seen in other nephritides
mechanism of nephrotic edema
glomerular injury (loss of charge/size selectivity) increases permeability to proteins
results in albuminuria and hypoalbuminemia
decreased plasma oncotic pressure
increase in interstitial fluid volume (anasarca)
edema
mechanism of nephritic edema
glomerular injury
decrease in ultrafiltration coefficient
decrease in GFR
decrease in fluid delivery to renal tubules
constant or increased distal tubular resorption (response to humoral factors
decrease in urinary Na while dietary Na is constant
sodium retention
increased extracellular volume
edema
diabteic nephropathy
10-15% of adult onset diabetes
higher among juvenile diabetics
superhyperfiltration (elevated GFR)
followed by nephrotic-range proteinuria and then declining GFR
may be initially slective with microalbuminuria
progression of disease becomes non-selective due to loss of both the charge- and size- selective properties of the renal glomerulus
mechanismtic findings in diabetes nephropathy
diffuse and/or nodular glomerulosclerosis
non-enzymatic glycations of proteins and decreased synthesis of proteoglycans
increased activity of TGF-beta and increased generation of reactive oxygen species (ROS)
thickening of renal basement membranes - non-specific trapping of proteins
morphological types of renal lesions in diabetes nephropathy
diffuse intercapillary glomerulosclerosis - characterized by thickened GBMs and increased nesangial matrix
nodular glomerulosclerosis (Kimmelstiel Wilson lesions) - characterized by nodularity with cellular
in advanced cases marked diabetic glomerulosclarosis is observed
Describe the histologicla features of diabetic nephropathy.
increased mesangial cells
extracellular mesangial matrix
thickened GBMs
four stages
Describe the electron micrograph findings of diabetic nephropathy.
thickened GBM
nodules in the mesangium
What is the result of non-enzymatic glycation in diabetes mellitus?
resistance to collagenase digestion
change in physiochemical properties
defective cross-linking of proteins
trapping of proteins in circulation
defective ECMs
What is the role of proteoglycans in diabetes mellitus?
decreased synthesis of PGs
decreased sulfation of PGs
excessive release of PGs
poor deposition of PGs and defective GBM
increased pore size, decreased negative charge in the GBM
What is the range of proteinuria for microalbuminuria?
30-300
high levels of damage and loss of negative charge allows large amounts of albumin to be released
hereditary nephritis (Alport’s Syndrome)
a disease with autosomal dominant inheritance, and mutations in gene encoding alpha5 chain of type-IV collagen
abnormalities in other chains of type IV-collagen may be seen
associated with hematuria and aminoaciduria
sensorineural deafness and occular abnormalities
morphology of hereditary nephritis (alport’s syndrome)
laminated-trabeculated appearance of the GBM, fetal glomeruli and foam cells
types of amyloidotic nephropathy
primary - nephrotic range proteinuria, related to multiple myeloma (cancer of the plasma cells - high Ig production), 75% of cases
Secondary - chronic infections, degenerative diseases, alzheimers, mutant proteins, renal lesions indistinguishable from secondary amyloidosis
no hypercellularity
histological findings of amyloidotic nephropathy
congo red stain
birefringent deposits
histological findings of amylodotic nephropathy under polarizing microscopy
birefringent nodules with two colors due to the presence of beta-pleated sheets
electron micrograph findings of amyloidotic nephropathy
amyloid deposits in mesangium and capillary wall
amyloid fibril deposits in capillary wall
fibrils are 8-10 nm in diameter and randomly arranged
immune-complex-mediated glomerular diseases
a disease state that results from the deposition of antigen-antibody complexes formed in situ or in circulation, and followed by activation of complement, elaboration of mediators of inflammation, and consequential glomerular injury
factors influencing the deposition of immune-complexes
valence of the antigen, affinity of the antibody, molar ratio, and reduction and alkylation status of the complex
charge on the complex
size
hemodynamics
monocytic regulation (Fc receptor-mediated immune-complex phagocytosis)
mechanism of immune-complex deposition
circulating immune-complex deposition
in situ immune-complex formation (2 scenarios)
circulating immune complex deposition
immune-complexes are formed in circulation and subsequently trapped in various regions of the glomerulus
best exemplified by lupus nephritis
in situ immune-complex formation
complexes are not formed in circulation but within the glomerular capillary wall
1) the antigen may be an intrinsic component of the glomerular capillary, the antibody or autoantibody in circulation complexes within the intrinsic agents of the glomerular capillary wall
2) the non-intrinsic foreign tissue antigen implants itself in the glomerular capillary, evokes an immune response, and subsequently the circulating antbody binds to the already implanted antigen
elements influencing the outcome of immune-complex mediated injury
complement
PMNs and monocytes
platelets and coagulation system
glomerular cells
How does the complement system influence the outcome of immune complex-mediated injury?
classical pathway is involved in glomerulonephritis in some and alternate in others
the terminal portion of the complement (C5-C9) causes lysis of glomerular cells via membrane attack complex (MAC) and results in the detachment of hte pithelial foot processes and proteinuria
Dense Deposit Disease (DDD)
an autoantibody to C3 convertase, nephritic factor (C3NeF), is found in the serum
causes slow and continued activation of complement and resultant hypocomplementemia
How doe PMNs and monocytes affect the outcome of immune-complex mediated injury?
releases proteases, metalloenzymes, lysosomes, cytokines, and free O2 radicals
these all damage the glomerulus and cause proteinuria
How do platelets and the coagulation system influence the outcome of immune-complex mediated injury?
aggregation of platelets and activation of coagulation system are seen in crescentic form of glomerulonephritis
How do glomerular cells influence the outcome of immune-complex mediated injury?
paracrine and autocrine effects of various cytokines and growth factors accentuate the extent of glomerular injury by stimulating the mesangial cells which in turn produce inflammatory mediators
general characteristics of focal segmental glomerulo-sclerosis (FSGS)
history of minimal change disease, heroin addiction, HIV, ureteral reflux uropathy
nephrotic - nonselective proteinuria
juxtamedullary glomeruli - FSGS, segmental hyalinosis, foam cells
effacement of foot processes and detachment
segmental deposits of IgM and C1q in hyalinotic segments
histologic findings of FSGS
predominant sclerosis of deeper glomeruli
loss of capillaries in segments and hyalinosis of the glomerulus
electron micrograph findings of FSGS
segmental large deposit in the glomerulus
foam cells in the glomerulus
general characteristics of idiopathic membranous nephropathy
most coommon cause of nephrotic syndrome in adults
history of neoplasms, prescriptions of gold or penicillamine, hepatitis
antigen excess disease, Heyman antigen complex
subepithelial deposits in various stages, IgG and C3 immune-complex deposits
What locations can immune complexes be deposited in the glomerulus?
subendothelial
mesangial
subepithelial
histological findings of IMN
thick capillary basement membranes without proliferation of cells
capillary deposits with granular appearance of IgG deposits
electron micrograph findings of IMN
subepithelial deposits
no deposits in mesangial matrix
membrane intrinsic-fluid-current hypothesis
more sheer forces in the inner layers of the capillary compared to the outer layers
since the sheer forces are much less in the outer layer, if the immune complexes are stuck on the outer layer, the inner layer becomes washed own
Heymann nephritis antigenic complex
related to the autoantibody directed against the Heymann Nephritis Antigen Complex
pathogenic epitope located in the smaller subunit
the epitope there is residing in the N-terminal 86 amino acids
these patients also have autoantibodies against the PLA2 receptor
thiscauses subepithelial deposits
redistribution-capping-shedding hypothesis
binding of ligand to a binding protein on a cell causes redistribution and shedding of the complexes on the cell
major diagnositc criteria for SLE
antinuclear and other antibodies
butterfly rash, photosensitivity, discoid lesions
migratory arthralgia
proteinuria/hematuria/casts
anemia/leukopenia/thrombocytopenia
Raynaud’s phenomenon
circulating mimmune complexes
pleuritis/pericarditis/endocarditis
psychosis/convulsions
alpecia
diffuse vs. membranous lupus nephritis
the nephritic form is minimal -> diffuse proliferative form
the nephrotic form is the membranous form
histologic findings of membranous lupus glomerulo-nephritis (MLGN)
thick membranes, karyorrhexis, and immune deposits
antibody - immunofluorescence of MLGN
electron-dense subepithelial and mesangial regions
IgG/C3 beaded immune complex disorders
electron micrograph findings of MLGN
membrane bound spherical virus C type particles
tubulo-vesicular myxovirus like elements
to make it a lupus disease - have a 90% of deposits in subepithelial space and 10% in the mesangium and also tubular vesicular elements
