Nephrotic Syndrome

Question 1

Nephrotic syndrome is a cluster of abnormal findings:
- Physical sign (1), laboratory abnormalities (3+1)

Contrary to popular belief, __ or __ are NOT defining feature of nephrotic syndrome in any age group

Answer 1

Oedema
Massive proteinuria
Hypoalbuminaemia
Hypercholesterolaemia
Hypercoagulable state

Not defining feature:
Reduced eGFR
Azotemia

Question 2

In nephrotic syndrome, oedema can develop by 2 distinct hypothesised mechanisms:

Answer 2

1. Underfill hypothesis
   - Hypoalbuminaemia -> decreased oncotic pressure
   - Reduced effective intravscular compartment size
   - Activation of RAAS and renal sodium resorption
2. Overfill hypothesis
   - Corin mediated activation of epithelial sodium channel causes abnormal sodium retention

Question 3

Hypercoagulable state in nephrotic syndrome is due to (3)

Answer 3

Urinary loss of antithrombin III
Increased platelet aggregation
Endothelial dysfunction

Question 4

Diagnosis of Nephrotic Syndrome

Answer 4

1. Massive proteinuria
   - uPCR > 2g/day in adults (some suggests 3.5g)
2. Excluded cirrhosis, congestive heart failure and protein losing enteropathy/malabsorption

Question 5

Causes of Nephrotic Syndrome

Answer 5

A. Primary
1. Minimal change disease (MCD)
2. Focal segmental glomerulosclerosis (FSGS)
3. Membranous nephropathy (MN)
4. Membranoproliferative GN (MPGN)

B. Secondary
1. Post-infectious GN
2. SLE
3. HSP
4. Medications
5. Infections - Hep B, Hep C, HIV
6. Malignancy - HL
7. Amyloidosis
8. Diabetes, hypertension

Question 6

Clincial presentation of nephrotic syndrome

Answer 6

1. Oedema - usually over lower limbs, some may progress to anasarca and periorbital oedema prior to presentation
   (painless, symmetric)
2. Frothy bubbly urine
3. Reduced urine output - severe involvement

Rarely presents as:
4. Peritonitis
5. Thromboembolic events
6. Premature atherosclerosis and cardiovascular disease

Question 7

AKI in nephrotic syndrome can be due to (3)

Answer 7

Intra-renal oedema
Tubular obstruction
Severe contraction of effective intravascular compartment (reduced perfusion)

Question 8

Natural progression of nephrotic syndroem depends on primary etiology

Answer 8

MCD: excellent long term prognosis, responsive to therapy. Occasional relapse, with eventual outgrow without permanent kidney injury

FSGS: 50% progress to ESRF over 5-10 years, and 25-50% recurrence after kidney transplant

MPGN: 50% progress to ESRF over 10-20 years, 20-25% recurrence after kidney transplant

Membranous: variable, 1/3 remission, 1/3 persistent proteinuria with stable function, 1/3 steady decline

Question 9

Nephrotic syndrome workup

Answer 9

A. Quantitation of urine protein
1. Urine protein:creatinine ratio (uPCR) > 2mg/mg
2. 24H urine collection > 2g/day (or 3.5g/day)

B. Metabolic profile
1. Renal function test - urea, creatinine
2. Ca Mg Phos, albumin, PTH
3. FBC - anaemia

C. Secondary workup
1. HIV, Hep B, Hep C - membranous, cryo, medication side effect, screening pre-treatment
2. Anti-streptolycin O titre - post-strep GN
3. ANA, dsDNA, C3, C4 - post-infx, SLE, MPGN
4. C3 nephritic factor - MPGN
5. Anti-PLA2R, phospholipase A M-type - idiopathic MN
6. Anti-thrombospondin (sent to Mayo) - malignancy immune mediated MN
7. US renal veins TRO renal vein thrombosis

D. Kidney biopsy - for definitive diagnosis
- See subsequent card for indications

Question 10

What should we perform kidney biopsy to assess nephrotic syndrome?

Answer 10

Criteria for children:
1. Age < 6 months, or adolescent onset Tanner 3 or more
2. Low C3 levels
3. Unusual clinical features
4. Resistance to steroids

Criteria for adults:
1. Done prior to initiation of steroids - due to diverse pathology and reduced tolerance to steroids
2. Distinguish between different causes of nephrotic syndrome

Question 11

What should kidney biopsy samples be sent for?

Answer 11

1. Light microscopy (LM)
2. Eletron microscopy (EM)
3. Immunofluorescence
4. Special staining for synaptopodin, dystroglycan

Question 12

Management of Nephrotic Syndrome

Answer 12

A. Treatment
First Line
1. Corticosteroids - MCD and FSGS
2. ACEi/ARBs only in MN

Second Line - steroid resistant
1. MMF
2. Cyclophosphamide
3. CNI - ciclosporin, tacrolimus

Emerging
1. Eculizumab - for type II MPGN
2. Rituximab (CD20i) + CNI - for MN
3. Abatacept (B7.1 Ab) - for FSGS
4. Thiazolidinediones (rosiglitazone) and adalimumab (anti-TNF) - prevention of kidney fibrosis

B. Supportive care
1. Sodium and fluid restriction
2. Judicious use of diuretics
3. Monitor for hyponatraemia, hypokalaemia, metabolic alkalosis
4. Statins for hypercholesterolaemia
5. Immunisations

C. Explore on kidney transplant if progression to ESRF