L7- Nephrotic Syndrome

Question 1

list the signs and symptoms that characterize nephrotic syndrome

Answer 1

• heavy proteinuria (>3.5g/day)
• hypoalbuminemia
• edema
• hyperlipidemia, lipuria
• normal complement levels

Question 2

describe how hypoalbuminemia occurs in nephrotic syndrome and what it leads to in terms of clinical presentation

Answer 2

1) glomerular membrane damage –> proteinuria / albumin loss –> hypoalbuminemia
2a) hypoalbuminemia => dec oncotic pressure + dec GFR (–> RAAS activation –> fluid retention) => edema
2b) hypoalbuminemia => inc plasma protein synthesis in liver => inc lipoproteins => hyperlipidemia

Question 3

list the common nephrotic renal diseases (and their categories)

Answer 3

Immunoglobulin deposition: membranous nephropathy

No immunoglobulin deposition: minimal change disease, FSGS, diabetic nephropathy, amyloidosis

Question 4

minimal change disease is mostly common in (1) and is usually caused by (2) and is possibly seen in (3) and (4) conditions

Answer 4

1- children (15% in adults)
2- idiopathic
3- lymphoma
4- renal cell carcinoma

Question 5

what is the reason minimal change disease and FSGS are suspected to linked to circulating glomerular permeability factors

Answer 5

rapid recurrence of disease after renal transplantation into patients with the disease
(50% w/ FSGS)

Question 6

minimal change disease as a result of (1) injury causing (2); there is no (3) or (4) involved although there may be involvement of (5) because treatment with (6) resolves symptoms

Answer 6

1- glomerular epipthelial cells / podocytes
2- inc glomerular permeability –> massive proteinuria
3- immune complex deposition
4- inflammatory injury
5- immune system
6- steroid therapy (immune suppressors)

Question 7

effacement of foot processes = …..

Answer 7

flattening, therefore more likely to break from basement membrane (rara externa) and less likely to prevent protein filtration

Question 8

describe the microscopic changes observed in minimal change disease

Answer 8

LM: normal

IF: no IG deposits

EM**: fusion of foot processes with their effacement and detachment from basement membrane

Question 9

On physical exam in minimal change disease, BP pressure is (high/normal/low) and (2) is very evident. On labs, serum shows (3) and urine shows (4).

Answer 9

-normal BP
-edema (periorbital, pedal)
Labs: low albumin, normal creatinine
Urine: proteinuria, bland urine sediment

Question 10

Minimal change disease is treated with (1) and usually has a (good/bad) prognosis although (3) frequently occurs and there (is/is not) a tendency to progress to CRF/ESRD.

Answer 10

1- 8 wks steroids
2- good: >90% children have complete remission (1/3 no relapse, 1/3 few, 1/3 frequent), usually relapses in adults
3- relapse after stopping steroids
4- no progression to CRF/ESRD

Question 11

define the components of FSGS

Answer 11

• Focal: affects few/some glomeruli
• Segmental: affects segment/part of glomerulus
• Glomerulo: affects glomeruli
• Sclerosis: scarring

Question 12

FSGS is often a primary disease with (1) as its cause, but it can be a secondary disease to the following: (2).

Answer 12

1- idiopathic

2- HIV, obesity, chronic reflux nephropathy, heroin use, malignancies (lymphoma)

Question 13

describe the pathogenesis of secondary FSGS

Answer 13

‘renal ablation glomerulopathy’

1) i) reduction in renal mass (due to renal disease), ii) partial nephrectomy, iii) glomerularnephritis, iv) congenital unilateral renal agenesis/aplasia
2) compensatory hypertrophy + hyperfiltation of remaining glomeruli to maintain GFR
3) intraglomerular HTN + hyperfiltration injury
4) FSGS

Question 14

describe the microscopic changes observed in FSGS

Answer 14

LM: FSGS

IF: negative OR non-specific granular deposits of IgM/C3

EM: patchy foot process fusion and effacement

Question 15

The initial presenting feature of FSGS is (1) that will progress into (2). Many patients also have (3) and (4). There (is/is not) a tendency to progress into CRF/ESRD.

Answer 15

1- asymptomatic proteinuria
2- nephrotic syndrome (massive proteinuria, microscopic hematuria)
3/4- HTN, renal insufficiency
5- it will progress to ESRD n 5-20 yrs

Question 16

membranous nephropathy is usually caused by (1) via (2) or (3) [include examples for each]

Answer 16

1- idiopathic
2- endogenous Ags: DNA (SLE/tumors)
3- exogenous Ags: Hep B, syphilis, malaria, captopril, mercury, gold, penicillamine

Question 17

describe the process of immunoglobulin deposition in membranous nephropathy

Answer 17

1) Ab-Ag reaction
2) complement activation
3) C5b-C9 (MAC) insert onto podocyte membrane
4a) direct damage to cytoskeleton => podocyte detachment
4b) stimulation of epithelial / mesangial cells + protease, oxidant, CK release => GBM growth / thickening
5) GFM damage, inc permeability, massive proteinuria
[subepithelial deposition]`

Question 18

what are the two theories of immune complex deposition in membranous nephropathy

Answer 18

(localized to sub-epithelial zone)
in situ (favored theory, Heymann Nephritis): IC formation in the kidney / glomerulus

circulating: IC formation in blood

Question 19

describe the microscopic changes observed in membranous nephropathy

Answer 19

• LM: diffuse GBM thickening (little inc in cellularity)
• IF: fine IgG/C3 subepithelial deposits
• EM: subepithelial IC deposits, GBM spikes indicating proliferation / growth

Question 20

Patients with membranous nephropathy present with (1). At the 20 year follow up they can develop into (2), (3), or (4) [include % chance]. It is worse in patients that are/have (5).

Answer 20

1- nephrotic syndrome, microscopic hematuria (50%), HTN
2- spontaneous remission (25%)
3- persistant proteinuria, stable or loss of renal function (50%)
4- ESRD, renal vein thrombosis (25%)
5- males, >50 y/o, >10g proteinuria

Question 21

1 cause of ESRD in USA is…..

Answer 21

diabetic nephropathy (1/3 of all ESRD patients)

-seen in 25-40% of type 1/2 diabetics

Question 22

what is the main evidence that diabetic nephropathy results from systemic effects

Answer 22

(mainly systemic hyperglycemia)

1) normal kidney into diabetic patient => diabetic lesions
2) diabetic kidney into normal patient => resolution of diabetic lesions

Question 23

list the 5 general effects of hyperglycemia that starts the pathogenesis of diabetic nephropathy

Answer 23

• non-enzymatic glycosalation
• advanced glycosylation products
• inc GFs (TGF-β)
• activation of CKs
• O2 species formation

Question 24

Hyperglycemia has many effects in the blood that will lead to:
-increased (1) causing (2)
-(3) changes leading to GBM thickening
-(4) hemodynamic changes
all of which result in (5)

Answer 24

1/2- inc matrix formation –> mesangium expansion

3- inc type IV collagen, inc fibronectin, dec proteoglycan heparin sulfate

4- hyperfiltration, inc glomerular capillary pressure, glomerular hypertrophy

5- glomeruloscelerosis

Question 25

describe the initial and later presentation of diabetic nephropathy (microscopically)

Answer 25

Early lesions: mesangial matrix expansion, GBM thickening

Later lesions: diffuse global glomerulosclerosis: Kimmelstiel-Wilson nodules, plasma proteins, ischemia, hyaline atherosclerosis

Question 26

describe the progression of clinical changes in diabetic nephropathy

Answer 26

• initially: inc GFR + inc glomerular hydrostatic pressure
• 7-13 yrs: microalbuminuria
• 10-20 yrs: macroalbuminuria
• lastly: persistent/progressive proteinuria, HTN, GFR decline (1-24 ml/min/yr)

Question 27

Amyloidosis most commonly affects the (1) part of the (2) organ. This is usually the result of primary amyloidosis caused by (3) which occurs alone or in association with (4). It can also be from secondary amyloidosis, which results from (5).

Answer 27

1/2- glomerulus, kidney
3- AL (abnormal light chain from Ig via abnormal plasma cell clone)
4- multiple myeloma
5- AR (serum amyloid via inc plasma protein synthesis in liver during chronic inflammation / long-standing infection)

Question 28

list other related diseases resulting from secondary amyloidosis besides renal deposition

Answer 28

• RA
• Behcet syndrome
• Crohn’s
• osteomyelitis
• tuberculosis
• renal cell carcinoma
• Hodgkin’s disease

Question 29

describe the microscopic changes observed in amyloidosis nephropathy

Answer 29

• LM: nodular, amorphous hyaline material in mesangium / capillary loops –> narrowing of capillary lumens
• Congo Red: ‘salmon pink’ on LM, ‘apple-green’ under polarized light
• EM: subendothelial / mesangial fibrils

Question 30

describe the renal symptoms of amyloidosis

Answer 30

• proteinuria, edema, nephrotic syndrome
• 50% have renal insufficiency (at time of Dx)
• electrolyte abnormalities (Fanconi’s syndrome)

Question 31

describe the non-renal / systemic presentation of amyloidosis

Answer 31

• Heart: cardiomyopathy, CHF, arrhythmias, heart block
• GI: hepatomegaly, malabsorption, bleeding
• Neuro: ischemic stroke, neuropathy, orthostatic hypotension
• Skin: easily bruised, purpura

Question 32

prognosis of amyloidosis (by years since Dx)

Answer 32

• very poor prognosis
• 1 yr, 51% survival
• 5 yr, 16% survival
• 10 yr, 5% survival

Question 33

(1) is the main complication of nephrotic syndrome, more common in (2). (3) results from urinary loss of (4), (5) causing increased plasma protein synthesis in the liver including (6), and increased blood viscosity due to (7). (8) dysfunction also contributes due to proinflammatory CKs.

Answer 33

1- thrombosis, thromboembolism (venous, deep/renal vein --> possible PE OR arterial --> coronary, cerebral, periphery thrombosis)
2- membranous nephropathy
3- hypercoagulability
4- antithrombin-III
5- hypoalbuminemia
6- coagulation factors
7- intravascular volume depletion
8- endothelial dysfunction