Lucan · Conditions

Nephrotic syndrome

Australian guidance: CARI Guidelines — Nephrotic Syndrome

1. Definition and epidemiology

Nephrotic syndrome is a clinical syndrome defined by heavy proteinuria (greater than 3.5 g per day in adults or greater than 40 mg/m2/hour in children), hypoalbuminaemia (serum albumin below 25 g/L), generalised oedema, and hyperlipidaemia with lipiduria. It is not a single disease but a common endpoint of multiple glomerular injuries. In Australia, the most common cause in adults is focal segmental glomerulosclerosis (FSGS) and membranous nephropathy, while in children under five years minimal change disease accounts for approximately 90% of cases. Diabetic nephropathy is the leading systemic cause in the Australian adult population, consistent with the high burden of type 2 diabetes documented in the CARI CKD classification guidelines.

2. Pathophysiology

The core defect is disruption of the glomerular filtration barrier, which normally restricts passage of large negatively charged proteins such as albumin. The barrier comprises the fenestrated endothelium, the glomerular basement membrane (GBM), and the podocyte foot processes with their slit diaphragms. In minimal change disease, immune mediators cause effacement (flattening) of podocyte foot processes without visible glomerular structural change on light microscopy, producing massive selective proteinuria. In membranous nephropathy, immune complex deposition along the subepithelial surface activates complement, generating a membrane attack complex that injures podocytes and increases permeability. In FSGS, segmental scarring of glomeruli reflects repeated or ongoing podocyte injury from diverse causes including viral infection (HIV, parvovirus B19), obesity-related hyperfiltration, and genetic mutations in slit-diaphragm proteins such as nephrin (NPHS1) and podocin (NPHS2). Urinary loss of albumin drives the fall in oncotic pressure, promoting oedema. Compensatory hepatic lipoprotein synthesis and reduced lipoprotein lipase activity produce the hyperlipidaemia and lipiduria. Loss of urinary antithrombin III, protein C, and protein S creates a pro-thrombotic state (Robbins Ch 20).

3. Clinical presentation and diagnostic criteria

Patients typically present with insidious onset of peripheral oedema, periorbital puffiness (most prominent in the morning), ascites, and pleural effusions due to reduced oncotic pressure. Frothy urine from heavy proteinuria is a common reported symptom. On examination there is pitting oedema and, in severe cases, anasarca. Blood pressure may be normal or elevated. The diagnostic tetrad used in clinical practice is: proteinuria above 3.5 g per 24 hours (or urine protein to creatinine ratio above 350 mg/mmol), serum albumin below 25 g/L, oedema, and hyperlipidaemia. In Australia, the CARI guideline recommends that any patient with persistent urinary protein to creatinine ratio above 60 to 120 mg/mmol (approximately 1 to 2 g/day) should be referred to a nephrologist for consideration of renal biopsy, which will clearly encompass all nephrotic-range proteinuria.

4. Investigations and AU-specific cutoffs

First-line investigations follow the standard kidney disease workup recommended by the Kidney Health Australia CKD handbook and CARI guidelines:

1. Urine albumin to creatinine ratio (uACR) on a first-morning void: nephrotic range corresponds to uACR above 220 mg/mmol in males and above 310 mg/mmol in females, which translates to macroalbuminuria well beyond the macroalbuminuria threshold of greater than 25 mg/mmol (males) or greater than 35 mg/mmol (females) defined in the CARI staging table. A 24-hour urine protein collection is generally not warranted in routine practice in Australia; spot uACR or urine protein to creatinine ratio is the preferred method.
2. Serum urea, electrolytes, creatinine, and eGFR: eGFR less than 60 mL/min/1.73 m2 indicates concurrent glomerular dysfunction and elevates urgency of nephrology referral.
3. Serum albumin and full blood count.
4. Fasting lipids and glucose; HbA1c if diabetes is suspected.
5. Urine microscopy for dysmorphic red cells and red cell casts (their presence suggests a nephritic component).
6. Renal ultrasound to exclude structural causes and establish kidney size.
7. Serological workup where indicated: antinuclear antibodies (ANA), extractable nuclear antigens (ENA), anti-double-stranded DNA, and complement levels (C3/C4) for lupus nephritis; anti-phospholipase A2 receptor (anti-PLA2R) antibody for membranous nephropathy; hepatitis B, hepatitis C, and HIV serology if risk factors are present; serum and urine protein electrophoresis with free light chains if age is over 40 years or myeloma is suspected.
8. Renal biopsy: required in adults to establish the underlying histological diagnosis and guide disease-specific therapy. It is indicated once nephrotic-range proteinuria is confirmed and reversible secondary causes have been excluded.

5. Management

Management follows a two-track approach: supportive care for the syndrome itself and disease-specific treatment targeting the underlying glomerular pathology.

Supportive care includes oedema management with dietary sodium restriction (below 2 g sodium or below 5 g salt per day, consistent with KHA CKD recommendations) and loop diuretics such as frusemide titrated to symptom relief. Renin-angiotensin system (RAS) blockade with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) reduces intraglomerular pressure and proteinuria and is recommended for all patients with proteinuric CKD. Blood pressure target is below 130/80 mmHg per KHA and CARI recommendations. Statins are recommended to manage the secondary hyperlipidaemia; however, there is no specific serum LDL target per CARI, and the decision to treat is based on overall cardiovascular risk. Anticoagulation should be considered in patients with serum albumin below 20 g/L or additional VTE risk factors, as nephrotic syndrome is listed as an independent risk factor for venous thromboembolism in the eTG cardiovascular guidelines.

Disease-specific treatment is determined by biopsy result. Minimal change disease in adults: corticosteroids (prednisolone 1 mg/kg/day up to 80 mg/day) typically produce remission within 8 to 16 weeks. Membranous nephropathy: immunosuppression with cyclophosphamide plus corticosteroids or rituximab (increasingly preferred for reduced toxicity) is used in high-risk patients. FSGS secondary to an identifiable cause is managed by treating the cause; primary FSGS uses high-dose corticosteroids as first-line. Lupus nephritis: protocol-based immunosuppression per rheumatology guidance.

6. Pharmacology and AU PBS notes

Prednisolone: Standard oral corticosteroid. Listed on the PBS for nephrotic syndrome in children (PBS streamlined authority code 1334 for minimal change disease in paediatric patients). Adult use for glomerulonephritis is prescribed under PBS general benefit. Available as 5 mg and 25 mg tablets (AU brand: Panafcort, Solone).

Frusemide: Loop diuretic used for oedema management. PBS general benefit (no streamlined code required). AU brand: Lasix, Uremide. Dose is typically 40 to 80 mg orally once to twice daily, titrated to response.

ACE inhibitors / ARBs: Ramipril (Tritace, Ramace) and perindopril (Coversyl) are common AU choices. Listed on PBS for hypertension and heart failure; use in nephrotic syndrome is proteinuria-reduction driven and falls under general prescribing. Dose-reduce according to eGFR.

Rituximab: PBS Authority Required (Streamlined) for membranous nephropathy refractory to conventional therapy. Administered as intravenous infusion; dosing regimens include 375 mg/m2 weekly for four doses or two doses of 1000 mg two weeks apart.

Statins: Atorvastatin (AU brand: Lipitor, Crestor equivalent rosuvastatin) are first-line for secondary hyperlipidaemia per CARI lipid guidelines; PBS listed under cardiovascular risk indication.

7. Complications and monitoring

Key complications requiring active surveillance:

Venous thromboembolism: Risk is highest with serum albumin below 20 g/L due to urinary losses of antithrombin III and protein C/S. Deep vein thrombosis and renal vein thrombosis are the most clinically important. Prophylactic or therapeutic anticoagulation (low molecular weight heparin bridging to warfarin) is considered when albumin is below 20 g/L.

Infection: Loss of urinary immunoglobulins and complement factors impairs opsonisation. Encapsulated organisms (Streptococcus pneumoniae) pose particular risk, especially in children on corticosteroids. Pneumococcal vaccination is recommended per the Australian Immunisation Handbook.

Acute kidney injury: Volume depletion from aggressive diuresis and reduced oncotic pressure can precipitate AKI. Renal vein thrombosis may also cause sudden deterioration in GFR.

CKD progression: Persistent heavy proteinuria drives tubulo-interstitial fibrosis and progressive GFR loss. Target uACR reduction of at least 30% per KHA guidelines.

Monitoring schedule: Monthly uACR and serum albumin until remission is achieved, then 3-monthly. eGFR at each review. Lipid panel every 6 to 12 months or at each dose adjustment of lipid therapy. Blood pressure at every visit targeting below 130/80 mmHg. Weight and fluid balance at each outpatient review. Nephrology follow-up should be maintained for the duration of active disease and for at least 12 months after complete remission given the risk of relapse, particularly in minimal change disease.

Written for Australian practice and grounded in the guidance named above. Study material only — not medical advice. Always check against current guidelines.