Nephrotic Syndrome Flashcards
What is the nephrotic syndrome?
Glomerular disease associated with heavy albuminurea (>3-3.5 g/day)
Also:
Hypoalbunimemia
Edema: periorbital and pedal
Hyperlipidemia
Thrombotic tendency
How does hypoalbuminemia develop in patients with nephrotic syndrome?
Glomerular disease –>
(1) proteinurea
(2) increased albumin catabolism bc it’s filtered, reabsorbed by the filters, and catabolized
Both lead to –> hypoalbumemia
What is the pattern of edema found in pt’s with nephrotic syndrome? Why do they develop characteristic pattern of edema?
Periorbital edema in the morning: bc they can sleep on their back unlike in CHF or ascites
Rings don’t fit their fingers
Pedal edema during the day
What is the pathogenesis of nephrotic edema?
Hypoalbuminema –> low oncotic pressure
Na and water retention –> high hydrostatic pressure
So there’s more pressure dirving it out of cells and less oncotic pressure pulling it into the cells
Note that there are 2 theories about the salt retention:
(1) primary renal salt retention: bc during glomerular dz, the kidney becomes a salt retaining organ immediately
(2) secondary renal sodium retention due to the loss of plasma oncotic pressure
What is the best treatment of edema in nephrotic syndrome?
Low Na diet
Oral loop diuretics: start with low dose, then double doses
IV diuretics, colloid rarely needed
Goal is 1-2# edema loss/day
Why do you get high lipids/cholesterol in nephrotic syndrome?
Glomerulus leaks protein –> low albumin –> liver perceives this & increases its production of albumin as well as other things i.e. lipids, cholesterol
What are maltese crosses? Where and why do you find them?
Cholesterol esters that under polarized light look like this
They escaped filtration barrier and come out in the urine
How do you treat hyperlipidemia in nephrotic syndrome?
Select high risk pt (high LDL, low HDL)
Atteempt to induce a remission o fthe proteinurea (ACEI, ARBs, specific immunosuppressors…)
Dietary therapy
Medical therapy (statins+)
What are the 3 main things you want to address in your treatment of nephrotic syndrome?
(1) Treat the primary dz i.e. with immune modulating meds
(2) Symptomatic treatment: diuretics, statins, diet, anticoag
(3) Reduction of proteinurea/slowing progression
- blood pressure reduction
- inhibiting the renin-angiotensin axis
What are the 5 major diseases in nephrotic syndrome?
- Minimal change dz (most common idiopathic type in kids)
- Focal segmental glomerulosclerosis (most common idiopathic in blacks)
- Membranous glomerulopathy (most common idiopathic in whites)
- Diffuse diabetic glomerulosclerosis
- Amyloidosis
Minimal change disease: findings, signs, symptoms, and course
- *Findings**: low serum albumin, normal 24h urine protein, high serum cholesterol, serologic tests normal
- 30% have high blood pressure
- 30% have microhematurea +/- low GFR
- Volume depletion
- *Histological patterns**:
- lipid nephrosis: pale, lipid rich kidneys
- tubules stuffed with lipids
- oval fat body: sloughed epithelial cells filled with lipid; hallmark of the urine analysis
- glomeruli appear normal!! hence the name of the dz
- no immune reactants
- it’s a podocyte dz:foot process effacement –> reduced filtration
Symptoms: general like nephrotic syndrome
Course: responds to steroids, relapse, no RF
What evidence supports the idea that there are immunologic derangements in MCD?
May follow viral infection, recent immunizations
Altered in vitro response to mitogens
Circulating lymphocytotoxins (permeability factors)
Association with Hodgkins’s Disease and other lymphoproliferative disease in some patients
Responds to steroids
** probably some factor is toxic to the podocytes –> debasement –> can’t maintain the normal glomerular barrier & size/charge selection
** highly selective proteinurea with albumin only –> tells liver to make more lipids
Do you need to biopsy in minimal change dz?
In adults: yes
In a kid: assume it’s MCD, bc 80% of kids with nephrotic syndrome have MCD. if they don’t respond, then you need a biopsy
How do you treat MCD?
Prednisone
Furosemide
Pt should get better!
Focal segmental glomerulosclerosis: signs, histology, symptoms, treatment, course
Signs: low albumin, normal creat, high cholesterol, proteinurea, negative serologic tests
- high blood pressure and microhematuria in 30%, renal dysfunction in 50%
Histology: sclerosis is focal (involves some of the glomeruli but not others) and segmental (portion of the glomerular tuft)
- debasement of the food processes in the whole glomerulus (not focal) –> podocyte effacement and detachment
- immuno staining: for IgM and C3
- can progress to global glomerulosclerosis –> extensive tubular atrophy & interstitial fibrosis –> ESRD
- in HIV: enlarged, hyperechoic kidneys, also can become global not segmental and lead to ESRF; you also get tubular microcysts
Treatment: 50% respond to steroids, reoccurs in 1/3 of transplant pt’s
Compare and contrast MCD and FSGS:
Similarities: might share the same permeability factor that leads to foot process debasement
Differences: FSGS - nonselective proteinurea; MCD - only albumin
- FSGS can progress to ESRF; MCD usually doesn’t
What can cause FSGS?
Primary FSGS: unknown cause, prob circulating permeability factors
Secondary FSGS: genetic (mutation in podocyte genes- nephrin, podocin)
- viral, esp HIV
- drugs (heroin, adriamycin in rodents)
- adaptive: in repsonse to elevated glomerular capillary pressures and flows i.e. if you’re born with one kidney, reflux nephropathy (if urine goes from bladder back to ureter and kidney causing damage & scarring –> hyperfiltration in remnant nephrons), any chronic renal dz, obesity
All cause podocyte injury and depletion –> glomerulosclerosis
When FSGS is adaptive, how does “stress” on kidneys lead to FSGS?
Loss of functioning nephrons –>
(1) increased glomerular volume –> increased capillary radius
(2) increased P and Q (increased cap radius also causes this)
–>
Tension of GCW
–> microaneurisms
–> segmental capillary collapse and mesangial sclerosis
This leads to a loss of functioning nephrons and creates a viscious cycle!
Who gets focal segmental glomerulosclerosis?
More common in blacks and they tend to do worse even with the same #s
Membranous glomerulopathy: signs, histology, symptoms, course, treatment
Signs: edema, proteinurea, normal GFR, low serum albumin, high cholest
- you can test for anti-PLA2R in blood (this helps you rule it in bc 70% of patients have circulating antibody)
- normal serologic tests
Histology:
- GBM thickening but no hypercellularity on H&E stain
- GBM spikes on silver stain, around the subepithelial deposits
- red staining subepithelial deposits on trichrome stain
- granular IgG and C3
- foot process effacement
Course: variable, but usually slow progressing; most common idiopathic NS in whites
Treatment: conservative therapy, not all pt’s need treatment - steroids, cyclosporine, anti C5 Ab, rituximab
In membranous glomerulopathy, what are the deposits from?
Antigen-antibody complexes composed of IgG bound to GP330/megalin are capped and shed from clathrin coated pits at soles of foot processes to form subepithelial deposits
Binding of complement –> formation of C5b9 complex –> activation of podocyte scavenging of C5b-9 & activation of cytochrome b558 –> formation of ROS –> deposition of ROS in GBM –> proteinurea
What is the target antigen in human primary membranous glomerulopathy?
Phospholipase A2 receptor (PLA2R)
What conditions are associated with secondary membranous glomerulopathy?
Infections: Hep B and C, secondary and congenital syphilis, malaria, schistosomiasis
Drugs: gold, penicillamine
Collagen vascular dz: SLE, Hashimoto’s thyroiditis, RA, mixed conn tiss disorder
Neoplasia: carcinoma- lung breast colon stomach
Which nephrotic syndrom dz do you see thrombosis most commonly?
Membranous glomerulopathy!!
It’s possible to get it in the other ones, but most commonly seen in MG!
Increased coagulation tendency
DVT, RVT, pulmonary emboli are possible
Membranous NS greatest risk (35%)
Most RVT asymptomatic but flank pain, microhematurea, low GFR
Sometimes you will see lots of collateral circulation if pt has total venous thrombosis
Diffuse Diabetic Glomerulosclerosis: signs, histoloty, treatment, course
- *Signs**: proteinurea, diabetes, edema (periorbital and pedal)
- microaneurisms, severe retinopathy: do opthalmic exam
- *Histology**:
- thickening of all the extracellular components in the glomerulus
- nodules made up of RBC; sometimes they can dilate and even burst –> hematuria; parallel to what’s happening in the retina!
- hyalinosis: lipid mixed with protinaceous material that gets trapped here
- arteries –> hyalinosis; thickening
- mesangial sclerosis and thick GBM; note there are no deposits; massive nodular areas of sclerosis obliterate teh glomerulus = mesantial nodule
Course: can progress to end stage kidney dz
Treatment: try to limit renal injury in diabetic nephropathy to prevent it; if they have proteinurea- treat symptoms with diuretic, reduce proteinurea
In diabetes mellitus, what happens to the basement membrane? Which body parts are affected?
Thickening due to glycation of basement membranes
Vascular BM: glomerular capillaries, muscle capillaries, retinal capillaries, and arterioles
Other: renal tubules, mammary ducts, schwann cells
What is the effect of nonenzymatic glycosylation of glomerular BM in diabetic glomerulsclerosis?
(1) accumulation of circulating plasma proteins –> gets trapped –> defective mesangial clearing –> mesangial sclerosis
(2) decrease in sialic acid content and increase in cationic charge –> protein can get thru more easily bc GBM becomes more + charged –> proteinurea
(3) increase in disulfide bonding GBM collagen –> decrease in GBM degradation and increase in GBM synthesis (altered homeostasis) –> GBM thickening
What are the 5 stages of diabetic renal dz in type 1 diabetes? (applies to type 2 but harder to characterize bc not a sudden onset)
1 hyperfiltration
2 clinically silent
3 incipient nephropathy: microalbuminemia you cant see on dipstick
4 overt nephropathy- overt proteinurea
5 ESRD
How can you limit renal injury in diabetic nephropathy?
blood pressure reduction
inhibition of the renin angiotensin aldosterone axis
blood sugar control
metabolic manipulation
Amyloidosis NS: signs, histology, course, treatment
Signs: another associated cause
- proteinurea, negative serologic tests
Histology: amyloid- pale staining infiltrate (paler staining than matrix)
- congo red polarization: apple green birefringence
- fibrils infiltrated at the glomerular basement membrane- this destroys the barrier
- immunostain tells you if you have amyloid (different type depending on the dz)
- lambda light chain in AL amyloidosis lights up in immunofluroesence
- end stage kidney is large and pale
Treatment: treat symptoms, reduce proteinurea, treat the underlying dz
What is amyloid?
homogenous, hyaline, eosinophilic proteinacious substance
- congo stain is the gold standard to see it
Fibrillar constituent: random arrays of non-branching fibrils
Nonfibrillar constituent: pentameric discs of protein in beta pleated sheet
What are teh 2 main types of amyloid and what are the causes?
Primary = AL = light chain
- dysproteinemias
Secondary = AA = acute phase reactant
- inflammatory or infectious states
What chronic dz’s are associated wtih AA amyloidosis?
TB
leprosy
chronic osteomyelitis
paraplegia
chronic bronchiectasis
CF
chronic heroin addiction
RA
psoriasis
familial mediterranean fever
