Nephrotic syndrome: diagnosis, investigation, and GP management

Nephrotic syndrome is a clinical syndrome, not a diagnosis. It signals heavy glomerular protein loss — a failing filtration barrier — and requires urgent investigation to identify the underlying glomerulopathy. For the GP, the task is to recognise the clinical tetrad, arrange the correct baseline investigations, begin secondary-cause screening, and refer promptly to nephrology before serious complications (venous thromboembolism, acute kidney injury, or infection) develop.

A. Core clinical — the AU general-practice framework

The classic tetrad

Nephrotic syndrome is defined by the co-occurrence of four features:

1. Proteinuria > 3.5 g/24 hours (or spot urine protein-to-creatinine ratio [uPCR] ≥ 350 mg/mmol, equivalent to approximately 3.5 g of protein per gram of creatinine)
2. Hypoalbuminaemia < 30 g/L — severe hypoalbuminaemia below 20 g/L indicates a high-severity case
3. Generalised oedema — typically gravity-dependent (pedal, sacral) but periorbital oedema is characteristic and may be the presenting feature in children and adults who sleep supine
4. Hyperlipidaemia — predominantly elevated LDL-cholesterol and triglycerides; the liver synthesises excess lipoproteins to compensate for reduced plasma oncotic pressure

Each element follows causally from the glomerular leak: albumin is lost first, lowering oncotic pressure and provoking fluid redistribution into interstitium; compensatory hepatic lipoprotein synthesis drives hyperlipidaemia; lipiduria (oval fat bodies, “Maltese cross” doubly refractile fat in polarised microscopy) can be seen on urine microscopy.

History

Ask about:

• Onset and progression of oedema — rapid onset over days suggests minimal change disease; more insidious onset over weeks is typical of membranous nephropathy
• Frothy urine — a sensitive patient-reported sign of heavy proteinuria (protein causes surface tension changes)
• Recent upper respiratory tract infection — minimal change disease in children classically follows viral illness
• Systemic symptoms: malar rash, arthralgia, photosensitivity (lupus), fatigue, weight loss (malignancy-associated membranous nephropathy)
• Medication history: NSAIDs, gold, penicillamine, captopril, interferon — all implicated in secondary nephrotic syndrome
• Relevant history: diabetes (10–40% of type 2 diabetic patients develop nephropathy without biopsy), HIV, hepatitis B, hepatitis C

Examination

• Vital signs: blood pressure (hypertension common in FSGS and diabetic nephropathy; relative hypotension in severe hypoalbuminaemia from reduced intravascular volume)
• Bilateral pitting oedema — document depth and upper extent
• Periorbital oedema
• Ascites or pleural effusion in severe cases
• Fundoscopy for diabetic retinopathy (if present, nephropathy is diabetic until proven otherwise and may not require biopsy)
• Signs of systemic disease: malar rash, joint swelling, lymphadenopathy, organomegaly

Immediate investigations

Test	Purpose
Spot urine PCR (first void preferred)	Quantify proteinuria
Urine ACR	Sensitive if PCR not available; ≥ 300 mg/mmol = macroalbuminuria
Urine microscopy	Oval fat bodies, red cell casts (if nephritic overlap)
Serum albumin, total protein	Confirm hypoalbuminaemia
Renal function (creatinine, eGFR)	Baseline; baseline injury predicts prognosis
Electrolytes	Hyponatraemia common from SIADH-like physiology
Fasting lipids	Hypercholesterolaemia characterisation
LFTs	Hepatic synthetic function
Serum anti-PLA2R antibody	Positive in ~70% of primary membranous nephropathy (high specificity)
ANA, anti-dsDNA, complement (C3, C4)	Screen for lupus nephritis
Hepatitis B surface antigen, HCV antibody, HIV serology	Secondary causes
HbA1c and fasting glucose	Diabetic nephropathy
Serum protein electrophoresis, urine Bence Jones protein	Myeloma-associated (especially if age > 60)
FBC, coagulation screen	Thrombocytopenia in lupus; baseline before anticoagulation decisions

Renal biopsy

A kidney biopsy is required in almost all adults with nephrotic syndrome to establish the histological diagnosis, which determines treatment and prognosis. The major exceptions are children aged 1–12 years with classic minimal change disease presentation (where empirical steroids are used first) and adults with long-standing type 2 diabetes with diabetic retinopathy (where diabetic nephropathy is presumed). Arrange urgent nephrology referral — do not wait for the biopsy result to initiate referral.

B. Evidence basis — histological subtypes and their treatments

Membranous nephropathy (MN) — the most common primary cause in adults

Primary MN is an autoimmune disease mediated by IgG4 antibodies against podocyte surface antigens, most commonly M-type phospholipase A2 receptor (PLA2R) in 70–80% of primary MN cases. Anti-PLA2R antibody titre correlates with disease activity and can be used to monitor remission — a falling titre predicts clinical remission before proteinuria normalises.

Prognosis in untreated primary MN follows the “rule of thirds”: spontaneous complete remission in ~30%, partial stable remission in ~30%, and progressive disease to end-stage kidney disease in ~30–40% over 10–15 years.

MENTOR trial (Fervenza et al., NEJM 2019): In patients with primary MN who failed conservative therapy, rituximab (anti-CD20 monoclonal antibody, 1,000 mg IV × 2 doses, 6 months apart) achieved complete or partial remission at 24 months in 60% of participants versus 20% with cyclosporin. Crucially, all cyclosporin responders relapsed after the drug was stopped, while rituximab remissions were largely durable. Rituximab is now first-line immunosuppression for primary MN in KDIGO 2024.

The STARMEN trial compared tacrolimus plus rituximab versus the traditional cyclophosphamide-based Ponticelli regimen and confirmed that rituximab-containing regimes are non-inferior with better tolerability.

Focal segmental glomerulosclerosis (FSGS)

FSGS is a histological pattern, not a single disease. Primary (immune-mediated) FSGS often responds to high-dose corticosteroids (prednisone 1 mg/kg/day, maximum 80 mg) over 16–24 weeks. Secondary FSGS from obesity, hyperfiltration, or HIV does not respond to steroids. Calcineurin inhibitors (cyclosporin, tacrolimus) are second-line. Sparsentan (dual endothelin/angiotensin antagonist) has regulatory approval in some jurisdictions but is not yet PBS-listed in Australia at the time of writing.

Minimal change disease (MCD)

MCD predominantly affects children (accounts for >90% of childhood nephrotic syndrome) but occurs in adults. The hallmark is a complete response to corticosteroids (prednisone 1 mg/kg/day, maximum 60 mg) in 80–90% of children and 50–75% of adults. Relapses are common; steroid-dependent or frequently relapsing MCD may require calcineurin inhibitors or rituximab under nephrology supervision.

Diabetic nephropathy

The most common secondary cause globally. Characterised by glomerular hypertrophy, mesangial expansion, and eventually Kimmelstiel-Wilson nodules on biopsy. Management rests on three trial-supported pillars:

1. SGLT2 inhibitors: DAPA-CKD (dapagliflozin) and EMPA-KIDNEY (empagliflozin) demonstrated significant reductions in eGFR decline and ESKD progression across patients with CKD and proteinuria, including those without type 2 diabetes. PBS-listed for CKD with ACR ≥ 22.6 mg/mmol.
2. Finerenone: a non-steroidal mineralocorticoid receptor antagonist. In FIDELIO-DKD and FIGARO-DKD, finerenone reduced progression of CKD and cardiovascular events in patients with type 2 diabetes and proteinuric nephropathy already on a maximally-tolerated RAAS inhibitor. PBS-listed for this specific indication (diabetic CKD on RAAS blocker with eGFR ≥ 25 and ACR ≥ 30 mg/mmol).
3. RAAS blockade: ACE inhibitor or ARB to reduce intraglomerular pressure and proteinuria — first-line non-immunosuppressive intervention in all proteinuric nephropathies.

C. Thrombosis risk and prophylaxis

Nephrotic syndrome is a prothrombotic state. The urinary loss of antithrombin III, protein C, and protein S reduces natural anticoagulation; concurrent hepatic hypersynthesis of clotting factors VIII and V amplifies the coagulopathy. Venous thromboembolism — DVT, pulmonary embolism, and notably renal vein thrombosis — occurs in up to 25% of patients with membranous nephropathy with severe hypoalbuminaemia.

KDIGO 2024 guidance recommends considering prophylactic anticoagulation in primary MN when serum albumin is < 25 g/L, provided the bleeding risk is acceptable. The choice of agent (LMWH, warfarin, or direct oral anticoagulant — noting DOACs may have variable protein binding in hypoalbuminaemia) is a nephrology decision. GPs should maintain a low threshold for investigating new leg swelling or dyspnoea in nephrotic patients.

In diabetic nephropathy and FSGS (where thrombosis risk is lower), routine anticoagulation is not recommended; treat VTE if it occurs.

D. Australian operations — MBS and care pathways

Medicare rebates in nephrotic syndrome

MBS item	Description
66596	Urine protein-to-creatinine ratio (quantitative)
66500	Albumin (urine microalbumin assay)
65070	Serum albumin
65900	Serum lipids (total cholesterol, HDL, LDL, triglycerides)
66695	ANA screening
69412	Anti-double-stranded DNA antibody
66774	Complement C3 and C4
71155	Anti-PLA2R antibody (available in major state laboratory networks)
30618	Percutaneous renal biopsy (specialist)

PBS-listed medications relevant to nephrotic syndrome management

Drug	PBS indication
Dapagliflozin (Forxiga)	CKD with uACR ≥ 22.6 mg/mmol (diabetic or non-diabetic)
Empagliflozin (Jardiance)	CKD with persistent albuminuria ≥ 200 mg/g
Finerenone (Finerenox)	Type 2 diabetes + CKD on RAAS blocker with eGFR ≥ 25 and ACR ≥ 30 mg/mmol
Prednisone	Minimal change disease, FSGS — Authority (nephrology-initiated)
Cyclosporin	Steroid-resistant or dependent nephrotic syndrome — Authority
Rituximab	Primary MN and other glomerulopathies — access via s100 or hospital

Verify current PBS criteria at the PBS schedule as listings change. Most immunosuppressive therapy for nephrotic syndrome is initiated by a nephrologist.

Referral urgency

• Same-day / emergency referral: serum creatinine rising rapidly (AKI on nephrotic), signs of peritonitis, thrombotic event (renal vein thrombosis, PE, DVT), sepsis
• Urgent nephrology within 48 hours: confirmed nephrotic range proteinuria with hypoalbuminaemia (new diagnosis pending biopsy)
• Semi-urgent within 1–2 weeks: significant proteinuria (uPCR 200–350 mg/mmol) without full tetrad, or monitoring of established nephrotic syndrome

E. Special populations

Children

Childhood nephrotic syndrome (peak age 2–6 years) is predominantly minimal change disease. First-line treatment is empirical corticosteroids without biopsy in uncomplicated presentations in this age group. Biopsy is reserved for atypical features (haematuria, hypertension, impaired renal function, steroid resistance, or presentation before 1 year or after 12 years). Refer to a paediatric nephrologist. Kidney Health Australia provides resources for families.

Elderly patients

Primary MN is more common in older adults and may be paraneoplastic (secondary to occult solid-organ malignancy — particularly lung, gastrointestinal, and lymphoma). In any patient over 60 with primary MN and negative anti-PLA2R antibody, age-appropriate cancer screening should be performed before attributing the MN to idiopathic/immune aetiology.

Lupus nephritis

Systemic lupus erythematosus causes class V (membranous) lupus nephritis, which presents with nephrotic syndrome and may coexist with more active proliferative classes (III or IV). Biopsy classification drives immunosuppressive intensity. Standard induction therapy is mycophenolate plus hydroxychloroquine with low-dose glucocorticoid (EURO-LUPUS regime). Belimumab and voclosporin have PBS listings for specific class III/IV+V lupus nephritis indications.

IgA nephropathy with nephrotic-range proteinuria

IgA nephropathy typically causes low-grade proteinuria and haematuria (nephritic features) but can occasionally present with nephrotic-range proteinuria in aggressive variants. SGLT2 inhibitors have demonstrated benefit in IgA nephropathy in a pre-specified DAPA-CKD subanalysis; sparsentan is approved in some markets; the novel anti-complement approach (iptacopan) is being investigated.

When to escalate

Seek emergency assessment immediately for:

• Acute kidney injury overlying nephrotic syndrome (rising creatinine, oliguria)
• Suspected renal vein thrombosis (flank pain, haematuria, rising creatinine)
• Pulmonary embolism (dyspnoea, pleuritic chest pain, haemoptysis)
• Suspected bacterial peritonitis (abdominal pain, fever, ascites)
• Anasarca with respiratory compromise

Refer urgently to nephrology within 48 hours for:

• New nephrotic syndrome in any adult — biopsy required
• Albumin < 20 g/L — high short-term complication risk
• Creatinine elevated above baseline at presentation

Arrange non-urgent nephrology review for:

• Sub-nephrotic proteinuria (uPCR 150–349 mg/mmol) for risk stratification
• Established nephrotic syndrome with intercurrent illness or medication change

What this article is and is not

This article is educational material for patients and carers. It explains how nephrotic syndrome is diagnosed, investigated, and managed within the Australian health system. It is not individualised medical advice and does not substitute for assessment by a qualified clinician. Treatment decisions depend on individual biopsy results, eGFR, comorbidities, and patient preferences.

AHPRA prohibits testimonials, outcome promises, and claims that any treatment is superior for an individual patient. Nothing in this article implies a specific treatment outcome for any reader. Seek care from a qualified Australian GP or specialist for any health concern.

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Sources cited

• KDIGO 2024 Clinical Practice Guideline for Glomerular Diseases (specialty-society)
• eTG — Nephrotic syndrome (eTG)
• RACGP — Chronic kidney disease management in general practice (RACGP)
• Fervenza FC et al. Rituximab or cyclophosphamide in the treatment of membranous nephropathy (MENTOR). NEJM 2019;381:36–46 (peer-reviewed)
• Heerspink HJL et al. Dapagliflozin in patients with chronic kidney disease (DAPA-CKD). NEJM 2020;383:1436–1446 (peer-reviewed)
• EMPA-KIDNEY Collaborative Group. Empagliflozin in patients with chronic kidney disease. NEJM 2023;388:117–127 (peer-reviewed)
• Filippone EJ, Farber JL. Membranous nephropathy: PLA2R and the pathogenesis of disease. Kidney360 2020;1(12):1574–1582 (peer-reviewed)
• Fernández-Juárez G et al. The STARMEN trial indicates that switching treatment from tacrolimus to rituximab is superior to continuous treatment with tacrolimus in primary membranous nephropathy. Kidney Int 2021;99:1440–1448 (peer-reviewed)
• Bakris GL et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes (FIDELIO-DKD). NEJM 2020;383:2219–2229 (peer-reviewed)
• Kidney Health Australia — Patient information on nephrotic syndrome (AU-consumer)
• NPS MedicineWise — Managing proteinuria in CKD (NPS)
• MBS Online — Renal biopsy and pathology items (AU-specialty)