nephrotic syndrome

Nephrotic syndrome — nephrotic-range proteinuria (≥3.5 g/day), hypoalbuminaemia (<30 g/L), and oedema — is a clinical syndrome with distinct aetiologies requiring biopsy-guided management. The three major primary causes in adults are membranous nephropathy, focal segmental glomerulosclerosis (FSGS), and minimal change disease (MCD). Anti-PLA2R antibody testing has transformed the workup of membranous nephropathy, and rituximab is now first-line immunosuppression for high-risk disease.

quick recognition

Classic triad: nephrotic-range proteinuria + hypoalbuminaemia + peripheral oedema
Frothy urine, periorbital oedema (especially morning), anasarca in severe cases
Hyperlipidaemia and lipiduria (oval fat bodies, maltese crosses on polarised microscopy)
Hypercoagulability — renal vein thrombosis, PE, DVT
Sudden flank pain + haematuria + rising creatinine → suspect renal vein thrombosis

thrombotic risk

Membranous nephropathy carries the highest thrombotic risk of all nephrotic aetiologies. VTE risk is inversely proportional to serum albumin — risk rises sharply when albumin <20–25 g/L

when to suspect

New oedema without cardiac or hepatic explanation
Urine dipstick ≥1+ protein — even +1 can represent nephrotic-range disease if urine is dilute
Unexplained hypoalbuminaemia, hyperlipidaemia, or VTE
Quantify with urine protein-to-creatinine ratio (UPCR) on a first-morning sample — preferred over urine ACR as it detects non-albumin proteins (e.g. myeloma light chains)

dipstick pitfall

Urine dipstick protein is affected by concentration — specific gravity matters. Always confirm with UPCR. A dilute sample can mask nephrotic-range proteinuria.

diagnosis / investigations

initial workup

Test	Purpose
UPCR (spot, first morning)	quantify proteinuria (≥350 mg/mmol ≈ 3.5 g/day)
serum albumin	<30 g/L confirms nephrotic
urinalysis + microscopy	RBC casts (nephritic overlap), oval fat bodies
serum creatinine / eGFR	baseline renal function
lipid panel	hypercholesterolaemia typical
CBC, electrolytes, glucose	baseline

targeted serologies

Test	Looking for
anti-PLA2R antibody	primary membranous nephropathy (~70% sensitive)
ANA, anti-dsDNA, C3/C4	lupus nephritis
hepatitis B & C serology	HBV → membranous, MPGN; HCV → MPGN ± cryoglobulinaemia
HIV	collapsing FSGS (HIVAN)
SPEP/UPEP, free light chains	amyloidosis, myeloma — see Multiple Myeloma
HbA1c	diabetic nephropathy (most common cause of nephrotic-range proteinuria overall)
syphilis serology	secondary membranous

anti-PLA2R antibody

PLA2R as the target antigen in ~70% of primary membranous nephropathy. Antibody titre correlates with disease activity and can be used for:

Diagnosis: positive anti-PLA2R in the right clinical context may defer biopsy in some centres, though KDIGO still generally recommends biopsy to confirm the diagnosis and exclude concurrent pathology — practice varies
Prognosis: higher titres predict worse outcomes
Monitoring: declining titres with treatment (immunological remission often precedes proteinuria remission)

kidney biopsy

Indications (KDIGO-GN-2021):

Nephrotic-range proteinuria without clear aetiology (e.g. non-diabetic)
Proteinuria >1 g/day on serial measurements without explanation
Diabetic patient with atypical features: rapid onset, absence of retinopathy, active sediment

biopsy in diabetes

30% of diabetic patients with nephropathy lack retinopathy. Biopsy if proteinuria seems disproportionate to disease duration/control or if there is rapid progression, active sediment, or absence of retinopathy.

referral criteria

Urgent: nephrotic syndrome (UPCR >300 mg/mmol, albumin <30 g/L, oedema, hyperlipidaemia) — triggers conversation with nephrology
Priority: unexplained urine ACR >30–70 mg/mmol regardless of eGFR

the “big three” primary causes

minimal change disease (MCD)

Most common nephrotic syndrome in children; still common in adults
Rapid onset (days to weeks) with dramatic anasarca
Light microscopy normal → diagnosis on electron microscopy (podocyte foot process effacement)
Screen for: NSAIDs, Lithium, haematological malignancies (Hodgkin lymphoma)
Treatment: prednisone 1 mg/kg/day (max 80 mg) for ≥4 weeks, then taper over 6 months
Most adults respond but ~50% relapse — frequent relapsers may need cyclophosphamide, CNIs, or rituximab

MCD vs FSGS

MCD and FSGS exist on a spectrum. MCD refractory to steroids may represent sampling bias — FSGS lesions are focal and can be missed if <10–20 glomeruli are sampled.

focal segmental glomerulosclerosis (FSGS)

Primary (idiopathic): circulating permeability factor → podocyte injury
Secondary causes — must exclude before immunosuppressing:
- obesity / metabolic syndrome (hyperfiltration injury)
- HIV → collapsing FSGS (HIVAN) — treat with ART + RAS blockade
- drugs: heroin, bisphosphonates, interferon, pamidronate
- reduced nephron mass: solitary kidney, reflux nephropathy
Treatment of primary FSGS: high-dose prednisone for a maximum of 16 weeks (not the prolonged courses used in MCD) — taper if responding; calcineurin inhibitors for steroid-resistant disease
Secondary FSGS → treat the underlying cause + maximise RAS blockade; immunosuppression not indicated

membranous nephropathy

Peak incidence 50–60 years; most common primary nephrotic syndrome in white adults
Anti-PLA2R positive (~70%) → primary
Anti-THSD7A positive (~3–5% of PLA2R-negative cases) → primary, but carries a strong malignancy association — warrants thorough cancer screening
Anti-PLA2R negative → search hard for secondary causes:
- malignancy (age-appropriate screening + CT chest in smokers, PSA in men >50)
- hepatitis B, syphilis, lupus
- drugs: NSAIDs, gold, penicillamine

Risk stratification (KDIGO-GN-2021):

Risk	Features	Management
low	proteinuria <3.5 g/day, normal renal function, low anti-PLA2R	supportive care + RAS blockade for 6 months
moderate	persistent nephrotic proteinuria after 6 months observation	immunosuppression
high	declining renal function, very high anti-PLA2R, severe hypoalbuminaemia	early immunosuppression

Immunosuppression: rituximab is now preferred first-line over cyclophosphamide for most patients — MENTOR (2019) showed rituximab non-inferior to cyclosporine with fewer relapses at 24 months; RI-CYCLO (2021) showed similar remission rates to cyclophosphamide.

malignancy screening

All patients with membranous nephropathy require age-appropriate malignancy screening. Secondary membranous can present months before cancer diagnosis. Repeat screening if anti-PLA2R is negative.

management

step 1: supportive care (all causes)

All patients with nephrotic syndrome benefit from supportive care regardless of aetiology:

Sodium restriction: <2 g/day (critical for oedema control)
RAS blockade: ACE-I or ARB at maximum tolerated dose — reduces proteinuria independent of blood pressure (KDIGO-CKD-2024)
SGLT2 Inhibitors: add if uACR ≥20 mg/mmol — DAPA-CKD (2020) showed 39% reduction in kidney composite endpoint in broad CKD population (glomerular disease subgroup was small but included)
Statin: treat hypercholesterolaemia (universal in nephrotic syndrome)
BP target: <120/80 mmHg per KDIGO-CKD-2024

step 2: oedema management

Loop Diuretics are first-line — higher doses needed due to:
- hypoalbuminaemia reduces furosemide delivery to tubular lumen
- gut oedema impairs oral absorption → use IV if poor response
Sodium restriction is essential — diuretics will not work if sodium intake is high
Sequential nephron blockade if resistant: add Thiazide Diuretics (metolazone) or Amiloride
IV albumin + furosemide co-infusion: may provide transient benefit in refractory oedema but no long-term outcome data — not routine

diuretic dosing in nephrotic syndrome

Start with furosemide 40–80 mg IV (or equivalent). Expect to need 2–3× usual doses. Monitor daily weights and aim for 0.5–1 kg/day fluid loss. Ototoxicity from high-dose furosemide is rare and reversible.

step 3: anticoagulation

Thrombotic risk is driven primarily by albumin level and aetiology:

Factor	Detail
highest risk	membranous nephropathy
albumin threshold	prophylactic anticoagulation when albumin <20–25 g/L
additional high-risk features	BMI >35, NYHA III–IV, immobilisation, proteinuria >10 g/day

Agent: warfarin or LMWH preferred
Avoid DOACs: highly protein-bound drugs have unpredictable pharmacokinetics in hypoalbuminaemia — free drug fraction increases, but overall levels may be erratic

DOACs in nephrotic syndrome

DOACs are not well studied in nephrotic syndrome. Hypoalbuminaemia alters protein binding and drug levels unpredictably. Warfarin or LMWH remain standard until better data emerge.

step 4: cause-specific immunosuppression

See sections under each primary cause above. Key principle: immunosuppression is for primary glomerular disease — secondary causes require treatment of the underlying condition.

step 5: infection prevention

Nephrotic syndrome causes urinary immunoglobulin loss → increased infection risk
Pneumococcal and influenza vaccination for all patients
Counsel about sick-day rules: hold ACE-I, ARB, SGLT2i, and diuretics during acute illness with dehydration

what NOT to do

Do not dismiss +1 dipstick proteinuria — specific gravity matters; always quantify with UPCR
Do not start immunosuppression for secondary FSGS — treat the cause
Do not use DOACs for anticoagulation in severe hypoalbuminaemia — use warfarin/LMWH
Do not skip malignancy screening in membranous nephropathy, especially if anti-PLA2R negative
Do not co-prescribe ACE-I + ARB — increases hyperkalaemia and AKI without benefit (KDIGO-CKD-2024)
Do not biopsy diabetic nephropathy with typical features (gradual proteinuria, retinopathy present, no active sediment) — biopsy when atypical

special populations

secondary causes to screen for

Cause	Glomerular pattern	Key action
diabetes	nodular glomerulosclerosis	most common cause of nephrotic-range proteinuria; treat with RAS blockade + SGLT2i + optimise glycaemia
HIV	collapsing FSGS (HIVAN)	ART + RAS blockade
hepatitis B	membranous, MPGN, polyarteritis nodosa	antiviral therapy; avoid immunosuppression if possible
hepatitis C	MPGN ± cryoglobulinaemia	direct-acting antivirals
lupus	multiple classes (WHO I–V)	biopsy-guided immunosuppression
amyloidosis	congo red positive deposits	see Multiple Myeloma for AL amyloid; treat underlying disorder
IgA nephropathy	mesangial IgA deposits	occasionally presents with nephrotic-range proteinuria; typically nephritic — biopsy distinguishes
preeclampsia	endotheliosis	delivery is definitive treatment

pregnancy

CKD of any stage increases risk of preeclampsia, preterm delivery, and CKD progression
Many immunosuppressants are teratogenic (cyclophosphamide, mycophenolate) — requires pre-conception planning
ACE-I and ARB are contraindicated in pregnancy

key trials summary

Trial	Year	N	Intervention	Key result
MENTOR	2019	130	rituximab vs cyclosporine in membranous	rituximab non-inferior; fewer relapses at 24 months
RI-CYCLO	2021	74	rituximab vs cyclophosphamide in membranous	similar complete/partial remission rates
GEMRITUX	2017	75	rituximab + supportive care vs supportive care in membranous	higher anti-PLA2R depletion rate; trend toward remission
DAPA-CKD	2020	4,304	dapagliflozin vs placebo in CKD	39% reduction in kidney composite endpoint (included glomerular disease)

safety and monitoring

Parameter	Frequency	Action
UPCR	every 1–3 months initially	track response to treatment
serum albumin	every 1–3 months	guides anticoagulation decisions
anti-PLA2R titre (if membranous)	every 3–6 months	immunological remission precedes proteinuria remission
renal function (creatinine/eGFR)	every 1–3 months	watch for progression
serum potassium	2–4 weeks after ACE-I/ARB change	hyperkalaemia risk
lipid panel	at diagnosis, then as indicated	statin titration
VTE symptoms	each visit	low threshold for imaging if symptomatic