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Flashcards in Week 3: Nephrotic Syndrome Deck (22):

Describe general pathologic features of nephrotic syndrome.

1. obliteration of visceral epithelial cell foot processes and swelling of epithelial cells
2. tubular protein reabsorption droplets in PT
3. oval fat bodies: lipid within tubular epithelial cells and peritubular macrophages --maltese cross


List the diseases usually associated with nephrotic syndrome.

1. primary
-minimal change
-focal segmental glomerulosclerosis
-membranous nephropathy
2. Secondary
-diabetic glomerulosclerosis


Describe clinical features of minimal change disease.

-most common cause of nephritic syndrome in young children
-acute onset, usually follows URI. GFR normal.
-look for secondary causes in adults: NSAIDs, lithium, infectious mono, immunizations, Hodgkin disease
-Few or no glomerular abnormalities by light microscopy, electron microscopy shows epithelial foot process obliteration


Describe pathologic features of minimal change disease.

-EM shows obliteration of visceral epithelial cell foot proceses
-biopsy showing minimal changes doesn't exclude FSGS
-lipid droplets in PT epithelial cells, oval fat bodies, increased protein reabsorption droplets


Pathogenesis of minimal change disease.

-Targeted podocyte injury--Dysfunction in T cell immunity
-abnormal T lymphocyte clone produces cytokine that induces podocyte damage, reorganization of podocyte actin cytoskeleton, reversible effacement of podocyte foot processes
-loss of anionic charge of basement membrane


Clinical features of focal segmental glomerulosclerosis (FSGS).

-scarring of some glomeruli in which a segment or portion of glomerular tuft is affected
-5% of nephrotic children and 15% nephrotic adults
-non selective proteinuria, microscopic hematuria, reduced GFR, and HTN
-Definition: A sclerosing lesion, associating with proteinuria, typically involves segments of some glomeruli


Etiology of FSGS

-Primary and Secondary types
-Secondary: obesity, heroin nephropathy, HTN, reflux, HIV nephropathy, unilateral renal agenesis
-steroids are usually non effective
-ESRD develops 5-20 years after presentation


Pathological features of FSGS

-need renal biopsy for diagnosis
-sample size is important because it is focal
-usually affects juxtamedullary glomeruli
-segmental collapse of glomerular tuft
-hyaline lesions and foam cells may be present within sclerotic lesions
-IgM and C3 staining
-EM: capillary collapse, subendothelial and mesangial electron dense deposits, epithelial foot process obliteration


Pathogenesis of FSGS

-podocyte injury and depletion
-podocytes are highly differentiated, limited replication ability. Loss of podocytes leads to bare and leaky GBMs
-possibly due to circulating permeability factor (cytokine)
-genetic mutations in podocyte structural proteins: nephrin, podocin, a-actinin4
-secondary FSGS: glomerular hyperfiltration and secondary podocyte stress, e.g. HTN


Clinical features of collapsing glomerulopathy

-variant FSGS with poor prognosis and serve proteinuria, rapid loss of renal function, and non responsive to steroid treatment
-at least one glomerulus shows segmental or global glomerular tuft collapse or implosion, with overlying podocyte hypertrophy and hyperplasia
-preponderance in african americans: linked to allelic variants in Chromosome 22, MYH9 encoding myosin heavy chain 9 and APOL1
-Secondary lesion in : viral infection (HIV, Parvo, CMV), drug toxicities, renal allografts


Pathogenesis of collapsing glomerulopathy

-direct infection of podocytes by virus (e.g. HIV)
-indirect damage to podocytes by cytokines
-African Americans: allelic variants in chrom 22: MYH9 site encoding myosin heavy chain 9 and APOL1
-APOL1 gives resistance to trypanosomal infection
-allelec variants of APOL1 comes at cost of increased risk of FSGS


Clinical features of membranous nephropathy.

-diffuse thickening of capillary walls of glomeruli produced by subenpithelial immune deposits and associated basement membrane reaction
-frequent cause of nephrotic syndrome in adults
-age 40-60 yo, male>female
-Clinical findings: Nephrotic syndrome (80%), HTN uncommon, renal function usually normal at presentation, renal vein thrombosis that can lead to PE


Etiology of membranous nephropathy.

1. Idiopathic 15-20%
2. Secondary
-Immunological disorders: SLE, RA
-neoplasms: carcinoma, Non-Hodgkins lymphoma
-Infections: Hep B


Pathology of membranous nephropathy.

-early disease: may appear normal by light microscopy
-capillary walls become thickened by sub epithelial (betw podocytes making up visceral epithelium and BM) deposits and the BM reaction to them
-holes, "spikes" in silver stain from where BM is destroyed and new BM is being made
-podocytes try to manufacture BM by putting cytoplasm in between BM,
-deposits washed out by blood flow, and left with thickened BM
-effaced foot processes, microvillous changes
-rarely crescent formation, which can be seen in late stage or may be associated with anti-GBM disease
-granular capillary wall staining for IgG and C3-->immune complexes


Pathogenesis of membranous nephropathy

2 mechanisms
1. in situ: local antigen released from visceral epithelial cells in primary disease.
-antibodies to M type phopholipase A2 receptor (PLA2R) occur in 75% of patients with primary MN. PLA2R is receptor glycoprotein found on podocytes and type II pneumocytes and leukocytes
-Circulating IgG4 antibodies against (autoimmune)
2. Planted antigen: extrinsic circulating antigen that is trapped in sub endothelial location because of size and charge, a circulating antibody IgG penetrates the BM to complex with it. Known antigens: Hep B, CEA, DNA, thyroid antigens
-(note: IgG can pass the BM but IgM cannot)


Clinical features of diabetic glomerulosclerosis.

-sclerosis of glomeruli and associated nephrons secondary to thickened mesangial matrix and BM in glomeruli and to arteriolar narrowing
-Clinical features: proteinuria, nephrotic syndrome <10% cases, HTN, retinopathy
-Kimmelstiel-Wilson syndrome=severe proteinuria, HTN, renal insufficiency
=#1 cause of secondary nephrotic syndrome in adults and ESRD in uS
-occurs 10-15 years after diabetes


Pathological features of diabetic glomerulosclerosis.

-scarring lesion, tubule for glomerulus also scars b/c blood supply is cut off and it atrophies.
-early changes: glomerular hypertrophy, mild mesangial matrix increases, thickened GBM, 2-8 years after DM onset
-eventually: diffuse thickening of GBM
-mesangial matrix increases from repetitive damage to mesangial cells-->Kimmelsteiel-Wilson nodules (IgA can also cause KW nodules, so not pathognomonic of DM)
-Pathognomonic of diabetes: hyaline changes in afferent and efferent arterioles- from leakage of plasma proteins in glomeruli


Pathogenesis of diabetic glomerulosclerosis

-hyperglycemia leads to a BM biochemically abnormal-->increased glucose, galactose, hydroxylysine groups
-increased collagen IV and fibronectin synthesis, which may be due to high glucose levels
-hemodynamic factors: increased glomerular filtration early in disease+glomerular protein deposits (hyaline). Hyperfiltration may be due to reduce mesangial contractility secondary to hyperglycemic state (mesangial contraction decreases permeability and decreases GFR)


Clinical features of renal amyloidosis

-most common cause of death in patients with amyloidosis
Features: nephrotic syndrome common, HTN uncommon, adults 40-50 yrs, diagnosis made by rectal, fat pad biopsy (renal not preferred)
-enlarged kidneys are present
-renal vein thrombosis is a common supervening complication
-poor prognosis


Etiology of renal amyloidosis.

1. Primary
-AL amyloid: multiple myeloma
2. secondary:
-AA amyloid: chronic inflammation, e.g. RA


Pathology of renal amyloidosis.

-amyloid deposits are present initially in mesangial regions, appear as eosinophlic widening or nodules
-EM: amyloid shows characteristic randomly oriented non branching fibrils measuring 8-10
-may see amyloid in arteriole. arterial wall infiltrated too. If put needle through this artery wall, it will bleed and won't stop b/c muscle can't contract due to deposits. This is why renal biopsy is not preferred.


Pathogenesis of renal amyloidosis.

-typically from polymerized immunoglobulin light chains (AL). Internalization and proteolytic processing of light chains, mainly lambda chains, or serum protein A (acute phase protein from chronic infections) by mesangial cells
-amyloid is formed internally in mesangial lysosomes, and is extruded into mesangial matrix
-with accumulation of amyloid in mesangial and subendothelium (between fenestrated endothelium and BM), physical disruption of GBM and non-selective proteinuria