Nephrotic Syndrome: Symptoms, Causes and Treatment

Oedema that starts with puffy eyes in the morning and gradually spreads to the whole body, together with frothy urine and profound fatigue — this is the classic presentation of nephrotic syndrome. Behind this syndrome lies one fundamental disruption: the kidney filter has become permeable to protein. Everything else follows from that.

What Nephrotic Syndrome Is

Nephrotic syndrome is a clinico-laboratory complex defined by four classic features:

1. Massive proteinuria — urinary protein loss > 3.5 g/day in adults (> 40 mg/m²/hour in children). This is the defining, primary feature — all others derive from it.
2. Hypoalbuminaemia — blood albumin < 35 g/L (often < 25 g/L in fully developed syndrome).
3. Generalised oedema — soft, symmetrical, beginning periorbital, then spreading to ankles, legs, scrotum, ascites, pleural effusion.
4. Hyperlipidaemia — elevated total cholesterol, LDL, and triglycerides. The liver's compensatory response to falling oncotic pressure.

A fifth feature often included: lipiduria — fatty casts and "Maltese crosses" in urine sediment under polarised light.

Nephrotic syndrome is not a standalone diagnosis — it is always the expression of an underlying disease of the glomerular apparatus of the kidneys.

Mechanism: Why Protein Is Lost

The glomerular filter normally bars large molecules — albumin (69 kDa) is retained at three levels: the endothelium, the basement membrane, and podocytes (cells with "foot processes" covering the outer surface of the basement membrane). In nephrotic syndrome, podocytes are damaged — their foot processes flatten or fuse. The filter becomes permeable to albumin and other proteins.

Consequences of massive proteinuria:

• Fall in plasma oncotic pressure → fluid shifts from vessels into tissues → oedema
• Hypovolaemia → activation of the renin-angiotensin-aldosterone system → sodium and water retention → worsening oedema
• Protein deficit signal → liver compensatorily increases synthesis of all proteins including lipoproteins → hyperlipidaemia
• Loss of anticoagulant proteins (antithrombin III, protein C and S) → hypercoagulability — thrombosis risk

Causes of Nephrotic Syndrome

In children

Minimal change disease (MCD) — the cause of 90% of nephrotic syndrome in children under 8. Light microscopy shows no changes — only electron microscopy reveals podocyte foot process fusion. Responds excellently to glucocorticoids: remission in 90% of children. Prognosis is generally very good.

In adults

Primary (idiopathic) glomerulopathies:

• Minimal change disease (10–15%) — in adults often associated with Hodgkin's lymphoma and NSAIDs
• Focal segmental glomerulosclerosis (FSGS) — the most common primary cause in US adults; frequently treatment-resistant
• Membranous nephropathy — the leading primary cause in White adults; idiopathic (anti-PLA2R antibodies) or secondary
• Membranoproliferative glomerulonephritis

Secondary (systemic disease):

• Diabetes mellitus — diabetic nephropathy: the most common cause of nephrotic syndrome in adults globally
• Amyloidosis — amyloid fibril deposition in glomeruli; systemic AL-amyloidosis or reactive AA-amyloidosis
• Systemic lupus erythematosus (SLE) — lupus nephritis class V
• Infections — hepatitis B (membranous nephropathy), hepatitis C (MPGN), HIV (FSGS), syphilis, malaria
• Drugs — NSAIDs, gold salts, penicillamine, captopril, heroin

Nephrotic Syndrome Symptoms: Oedema, Proteinuria and Complications

Oedema — the hallmark of nephrotic syndrome. Unlike cardiac oedema (starting inferiorly — at the ankles), nephrotic oedema characteristically begins with the face: periorbital puffiness on waking is one of the earliest signs. Over time, oedema generalises: legs, scrotum, ascites, hydrothorax. The overlying skin is pale, soft, and pitting.

Frothy urine — the excess protein creates foam that persists long after the stream ends. One of the first symptoms patients notice.

General weakness and fatigue — consequence of hypoalbuminaemia and anaemia (urinary loss of transferrin and erythropoietin).

Hyperlipidaemia and xanthomas — with prolonged nephrotic syndrome, xanthoma deposits may appear on the skin.

Complications:

• Thrombosis and thromboembolism — renal vein thrombosis (classic complication of membranous nephropathy), deep vein thrombosis, pulmonary embolism. Driven by urinary loss of anticoagulant proteins and hyperfibrinogenaemia.
• Infections — loss of immunoglobulins and complement components → high susceptibility to encapsulated bacteria (pneumococcus, Haemophilus). Pneumococcal peritonitis is characteristic in children with MCD.
• Acute kidney injury — in 25–30% of patients; mechanisms: hypovolaemia, renal vein thrombosis, nephrotoxic drugs.
• Atherosclerosis — chronic hyperlipidaemia with prolonged nephrotic syndrome accelerates arterial disease.

Diagnosis: Key Lab Tests

Urine:

• 24-hour proteinuria > 3.5 g, or urine protein-to-creatinine ratio > 3.5 g/g — the diagnostic criterion
• Urinalysis: protein +++, fatty casts, "Maltese crosses" under polarised light
• Complete blood count with differential

Blood:

• Albumin — reduced (< 35 g/L); severity of hypoalbuminaemia correlates with syndrome severity
• Total protein — reduced
• Total cholesterol, LDL, triglycerides — elevated
• Creatinine, urea — kidney function assessment
• Coagulation panel — assess hypercoagulability
• C-reactive protein, ESR — inflammatory markers

Aetiological workup:

• Anti-dsDNA, ANA — SLE
• HBsAg, HCV, HIV
• Anti-PLA2R antibodies — membranous nephropathy
• Bence-Jones protein in urine, immunofixation — amyloidosis, multiple myeloma
• Kidney biopsy — the primary method of morphological diagnosis in adults

Treatment of Nephrotic Syndrome

Treatment is two-pronged: specific therapy for the underlying disease + symptomatic management.

Specific therapy:

• Minimal change disease: glucocorticoids (prednisolone 1 mg/kg/day) — remission in 80–90% of children and ~75% of adults. For relapses — tacrolimus, cyclophosphamide, rituximab.
• Membranous nephropathy: 30% undergo spontaneous remission. For progression — Ponticelli regimen (corticosteroids + chlorambucil), tacrolimus, rituximab.
• FSGS: glucocorticoids — first line; for resistance — calcineurin inhibitors.
• Diabetic nephropathy: RAAS inhibitors (ACEi/ARB) — reduce proteinuria; SGLT2 inhibitors — nephroprotective effect; glycaemic control (target HbA1c).

Symptomatic management:

• Oedema: sodium restriction (< 2 g/day), loop diuretics (furosemide). With hypovolaemia — use cautiously; risk of AKI.
• Hyperlipidaemia: statins — reduce cardiovascular risk in prolonged syndrome.
• Thrombosis prevention: at albumin < 20–25 g/L in membranous nephropathy — anticoagulant prophylaxis is considered.
• Dietary protein: moderate intake (0.8–1.0 g/kg/day) — high protein intake worsens proteinuria.
• Vaccination: pneumococcal and influenza vaccines — with prolonged nephrotic syndrome.

When to Seek Urgent Medical Attention

• Newly appeared generalised oedema + frothy urine — nephrology referral within days
• Dyspnoea with oedema — possible hydrothorax or pulmonary embolism
• Leg pain + swelling + redness — deep vein thrombosis; call emergency services
• Flank pain + blood in urine + worsening oedema — possible renal vein thrombosis
• Fever + abdominal pain in a child with nephrotic syndrome — rule out spontaneous peritonitis

This article is for informational purposes only and does not replace consultation with a qualified nephrologist.