Clinical and pathologic features of nephrotic syndrome Flashcards
1
Q
Terms used for evaluating glomerular disease
A
- Focal: 50% of glom involved
- Segmental: lesions affecting just a portion of the glom
- Global: lesions affecting the entire glom
- Sclerosis: increased amounts of basement membrane (GBM), mesangial matrix and collagen (leads to obliteration of glom)
- Crescent: macs, fibroblasts, epithelial cells aggregated in bowman’s space
2
Q
Nephrotic syndrome
A
- Collection of signs/Sx including edema, hypoalbuminemia, hypercholesterolemia, proteinuria (usual >3.5g/day)
- There is structural and/or charge barrier loss of GBM (fusion of podocyte foot processes)
- Pathologic features: obliteration and fusion of podocyte foot processes, changes in microvilli swelling of epithelial cells, protein reabsorption (hyaline) droplets in PT epithelial cells
- Lipid w/in tubular epithelial cells and peritubular macrophages, these are sloughed off as oval fat bodies seen in urine sed (Maltese cross- tells you its nephrotic syndrome but not what kind)
- Primary: issue is in the glom
- Secondary: glomerular injury is a feature of multi-organ disease
3
Q
Minimal change disease (MCD)
A
- Primary nephrotic syndrome w/ few or no glom abnormalities by light microscope but epithelial foot process obliteration by EM (only abnormality)
- Most common in children, incidence usually 2-3, but can occur in young adults
- MCD is primary (problem is in the glom), but it can be secondary to drugs (NSAIDs, penicillin), toxins (metals), infection, tumors (hodgkin lymphoma)
- Acute onset, usually after viral URTI, usually w/ heavy proteinuria, edema, and oval fat bodies (OFBs)
- GFR often normal, steroids should correct the problem (if not-> FSGS)
4
Q
Pathogenesis and pathologic features of MCD
A
- Thought that dysfxn of T cell immunity leads to production of a cytokine that induces podocyte damage, loss of foot processes and sialoproteins (loss of - charge)
- Under LM there is no abnormal findings
- EM shows loss of foot processes
- Lipid droplets intracellular and interstitium of PT epithelia (desquamate as OFBs) and protein reabsorption droplets in PT lumen (granular hyaline appearance)
5
Q
Focal segmental glomerulosclerosis (FSGS)
A
- Primary nephrotic syndrome that is rare in kids and most common in black adults
- Sclerosis of some glomeruli (focal) in which a portion of the glom (segmental) is affected
- Pts have heavy non-selective proteinuria and can be associated w/ microscopic hematuria, reduced GFR and HTN
- May be idiopathic or secondary to: HIV, heroin, SCD, unilateral renal agenesis, obesity, HTN, reflux nephropathy
- Often will progress to ESRD, will recur in Tx pts, may or may not respond to steroids
6
Q
FSGS pathology and pathogenesis 1
A
- Renal biopsy is required for Dx, but since it is focal and segmental the sample size is very important
- Lesions initially affect the juxtamedullary glomeruli
- Thought that a permeability factor produced by a rogue lymphocyte clone damages the podocytes leading to injury and depletion
- Genetic mutations (APOL1 gene) in podocyte structural proteins can causes FSGS
7
Q
FSGS pathology and pathogenesis 2
A
- HTN or loss of renal mass can produce glomerular hyper filtration and podocyte stress, leading to damage
- In LM, there is segmental collapse of the glom w/ exudative lesions (hyalinosis) and foam cells w/in the sclerosis from entrapment of large molecules in the scarred areas
- These lesions are positive for IgM and C3
- EM shows capillary collapse, sub endothelial and mesangial e- dense deposits and loss of foot processes
8
Q
Special variant of FSGS: collapsing glomerulopathy
A
- Severe proteinuria, rapid loss of renal function and not responsive to steroids (most blacks), does recur after Tx
- Segmental or global glom collapse w/ proliferation and hypertrophy of podocytes
- Can be primary or secondary to viral infection (HIV, parvo, CMV)
- Podocytes are infected by the virus or are damaged from cytokines released due to infection
- Podocytes become dedifferentiated and dysregulated
- APOL1 allelic variants (blacks) have increased resistance to infection but a greater risk of developing FSGS
9
Q
Membranous glomerulonephritis (MG) 1
A
- Primary nephrotic syndrome characterized by diffuse thickening of capillary walls of glom, produced by sub epithelial (btwn podocyte and GBM) immune deposits and associated GBM rxn
- Most frequent cause of nephrotic syndrome world-wide, can be idiopathic or secondary to systemic disease (MG signs/Sx may proceed manifestation of disease by months)
10
Q
Membranous glomerulonephritis (MG) 2
A
- Diseases that can cause MG: immunologic d/o (SLE, RA), neoplasms (non-hodgkin lymphoma), infections (hep B/C), drugs (NSAIDs)
- Clinical findings: nephrotic syndrome, mostly normal urine function, HTN uncommon, +/- renal vein thrombosis
- Can respond to steroids
11
Q
Pathology and pathogenesis of MG 1
A
- Diffuse uniformly thickened basement membranes (subepithelial deposits under BM) with thickening of capillary walls
- Silver stains show spikes protruding from the external surface of capillary walls w/ domes btwn spikes (spike dome appearance)
- Granular deposits of IgG and C3, w/ primary MG displaying mostly IgG4/IgG3 and secondary MG has all IgG subsets
- EM shows e- dense deposits (immune complexes) in the subepithelial area
- Thickening of GBM due to deposits and from podocytes over producing BM material (forms the spikes)
- These changes also result in loss of podocyte foot processes and microvillous changes
12
Q
Pathology and pathogenesis of MG 2
A
- The in situ immune complexes can be due to 2 mechanisms
- A local (intrinsic) Ag is released from podocytes in primary MG (Ag is PLAR) and is deposited in the GBM on the sub epithelial side
- IgG and C3 then pass thru the GBM (IgM can’t pass thru GBM) and bind to the PLAR resulting in immune complex deposition
- In secondary MG there is an extrinsic Ag that is planted in the subepithelial GBM location, based on its charge and size
- Then circulating IgG penetrate the GBM and complex w/ it (Ag is often from hep B)
13
Q
Diabetic glomerulosclerosis (DGS)
A
- A secondary nephrotic syndrome of sclerosed gloms/tubules secondary to thickened mesangial matrix and GBM, and arteriolar narrowing (hyaline arteriolosclerosis due to non enzymatic glycosylation of vascular BM)
- Process scars tubules b/c the BM gets so thick it cuts off blood supply to tubules, also increasing efferent artery pressure (selectively thickens efferent artery) will increase GFR and thus cause hyperfiltration and damage (ACEIs help prevent this)
- Clinical features: proteinuria, HTN, retinopathy
- Most frequent cause of ESRD in US
14
Q
Pathogenesis and pathology of (DGS)
A
- Biochemical abnormalities of BM: increased glc, galactose, glycosylations, increased collagen, fibronectin
- Hemodynamic factors: early in course there is increased GFR (hyperglycemia-> reduced mesangial contraction) leading to glomerular sclerosis and protein deposits
- Looks like MG but no immune depositions, often shows kimmelstiel wilson nodules from sclerosis of mesangium
- Early changes show mild thickening of GBM w/ increase in mesangial matrix 2-8 yrs after onset of diabetes
- Pathognomonic: hyaline deposits in both afferent and efferent arterioles (!)
- Generalized tubular BM thickening, lamina densa can be 6-10x thicker than normal
15
Q
Kimmelstiel Wilson syndrome
A
- Proteinuira, HTN and renal insufficiency
- Nodular mesangial matrix accumulations (kimmelstiel-wilson nodules) result from repeated damage to mesangial cells and augmented synthesis of mesangial matrix in response
- Is seen in diabetic pts and diabetic glomerulosclerosis
18
Q
37 yo african american w/ 1.7 Cr, 22 BUN, edema, and BP of 190/100. Urine sediment shows mild hematuria and 3.8g/day proteinuria
A
FSGS
Associated w/ APOL1 allelic variants
