Week 3: Nephrotic Syndrome Flashcards
Describe general pathologic features of nephrotic syndrome.
- obliteration of visceral epithelial cell foot processes and swelling of epithelial cells
- tubular protein reabsorption droplets in PT
- oval fat bodies: lipid within tubular epithelial cells and peritubular macrophages –maltese cross
List the diseases usually associated with nephrotic syndrome.
- primary
- minimal change
- focal segmental glomerulosclerosis
- membranous nephropathy - Secondary
- diabetic glomerulosclerosis
- amyloidosis
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
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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.
- Idiopathic 15-20%
- 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
- 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) - 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.
- Primary
- AL amyloid: multiple myeloma - 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
