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Nephrology
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General Medicine
EMERGENCY

Nephrotic Syndrome

High EvidenceUpdated: 2025-12-24

On This Page

Red Flags

  • Severe symptomatic oedema (pleural effusion, ascites)
  • Evidence of thrombosis (DVT/PE/Renal Vein Thrombosis)
  • Acute Kidney Injury (AKI)
  • Signs of infection (cellulitis, peritonitis)
  • Hypertension crisis (less common than in nephritic)
Overview

Nephrotic Syndrome

1. Clinical Overview

Summary

Nephrotic Syndrome is a clinical syndrome defined by the classic triad of classic triad: heavy proteinuria (>3.5g/24h), hypoalbuminaemia (less than 30g/L), and oedema. Hyperlipidaemia is also typically present. It results from injury to the glomerular filtration barrier (podocytes), causing massive protein leak. The underlying aetiology varies significantly by age: Minimal Change Disease predominates in children, whereas Membranous Nephropathy and Focal Segmental Glomerulosclerosis (FSGS) are common in adults, alongside secondary causes (Diabetes, SLE). Management focuses on treating the underlying cause (immunosuppression), controlling oedema (diuretics), reducing proteinuria (ACEi/ARB), and preventing complications (thrombosis, infection). [1,2]

Key Facts

  • Definition: Proteinuria >3.5g/24h (or PCR >300 mg/mmol) + Low Albumin + Oedema.
  • Top Cause (Child): Minimal Change Disease (>80%).
  • Top Cause (Adult): Membranous Nephropathy (Caucasian), FSGS (African descent), Diabetic Nephropathy (overall most common secondary).
  • Thrombosis Risk: Loss of Antithrombin III + thickened blood = Hypercoagulable. Can cause PE or Renal Vein Thrombosis.
  • Biopsy Rule: Children usually treated empirically with steroids first. Adults almost always require biopsy for diagnosis.

Clinical Pearls

Nephrotic vs Nephritic:

  • NephrOtic: Proteinuria (O-Protein), Oedema, Hypoalbuminaemia. (Podocyte injury).
  • NephrItic: Haematuria (Inflammation), HTN, Renal Impairment, less protein. (Glomerular inflammation).

The "Frothy" Urine: Patients may describe urine that looks like beer head or washing-up liquid foam. This is a specific sign of heavy proteinuria.

Renal Vein Thrombosis: Suspect if a nephrotic patient develops sudden flank pain, haematuria, or a varicocele (especially left-sided).

Morning Eyes, Evening Ankles: Oedema shifts with gravity. Patients wake up with puffy eyes (periorbital) which revolves, then develop ankle swelling by evening.

2. Epidemiology

Incidence

  • Children: 2-7 per 100,000. Peak age 2-6 years.
  • Adults: 3 per 100,000.

Aetiology by Age

Age GroupCommon CausesNotes
ChildrenMinimal Change Disease (85%)Highly steroid responsive. Good prognosis.
(Secondary)Genetic causes, infectionsRare.
AdultsMembranous Nephropathy (30%)Associated with Anti-PLA2R antibodies.
FSGS (20-25%)Primary or secondary (obesity, HIV).
Minimal Change (10-15%)NSAIDs, Hodgkin's lymphoma association.
SecondaryDiabetes MellitusCommonest cause of nephrotic-range proteinuria overall.
SLE (Lupus)Class V Lupus Nephritis is nephrotic.
AmyloidosisAL or AA amyloid.
InfectionsHepatitis B/C, HIV (HIVAN - causing FSGS variant).
3. Pathophysiology

Glomerular Filtration Barrier Injury

  • The barrier consists of Endothelium, Basement Membrane (GBM), and Podocytes.
  • Podocyte Injury: In nephrotic syndrome, podocyte foot processes are "effaced" (flattened) or detached.
  • Loss of Charge Selectivity: Normal barrier is negatively charged (repels albumin). Injury leads to loss of this charge = Albumin leak.

Consequences of Proteinuria

  1. Hypoalbuminaemia: Liver cannot keep up with urinary loss.
  2. Oedema:
    • Underfill Theory: Low albumin → Low oncotic pressure → Fluid leaks to interstitium → Hypovolaemia → RAAS activation → Salt/Water retention.
    • Overfill Theory (Now dominant): Primary renal sodium retention (ENaC activation) drives volume expansion.
  3. Hyperlipidaemia: Liver ramps up lipoprotein synthesis (LDL/VLDL) in response to low oncotic pressure and loss of regulatory proteins.
  4. Hypercoagulability: Urinary loss of Antithrombin III and Protein S + Liver synthesis of Fibrinogen.
  5. Infection Susceptibility: Urinary loss of Immunoglobulins (IgG) and Complement factors (B, D).
4. Clinical Presentation

Symptoms

Associated Symptoms (Secondary Causes)

Red Flags

  1. Breathlessness: Pulmonary oedema or Pulmonary Embolism.
  2. Flank Pain: Renal Vein Thrombosis.
  3. Fever/Pain: Spontaneous Bacterial Peritonitis (in ascites) or Cellulitis.
Oedema
Periorbital (morning), Ankles/Legs (evening), Genital, Ascites, Pleural effusions.
Frothy Urine
"Foamy".
Weight Gain
Fluid accumulation.
Fatigue/Lethargy.
Common presentation.
Anorexia (Gut oedema).
Common presentation.
5. Clinical Examination

General

  • Oedema: Pitting. Check sacrum if bedbound.
  • Nails: Muehrcke's lines (white bands due to hypoalbuminaemia) or Leukonychia.
  • Eyes: Xanthelasma (Hyperlipidaemia).

Systemic

  • BP: May be normal or high (depending on underfill vs overfill).
  • Chest: Pleural effusion (stony dullness).
  • Abdomen: Ascites (shifting dullness).
  • Urine Dip: Protein ++++ (Albumin). Often NO blood (or microscopic).
6. Investigations

Urine Tests

  1. Dipstick: +++ or ++++ Protein.
  2. PCR / ACR (Quantification):
    • PCR >300 mg/mmol usually indicates Nephrotic range.
    • ACR >250 mg/mmol.
  3. 24-hour Collection (Gold Standard): >3.5g protein.
  4. Microscopy: Hyaline casts, Fatty casts ("Maltese crosses"), Oval fat bodies.

Blood Tests

  • FBC: Haemoconcentration or anaemia.
  • U&E: Creatinine usually normal initially (unless hypovolaemia/ATN or progression).
  • Albumin: less than 30 g/L (often less than 20).
  • Lipid Profile: Cholesterol often >10 mmol/L.
  • Coagulation: Fibinogen high.

Nephrotic Screen (The "Glomerulonephritis Screen")

  • Autoantibodies: ANA, dsDNA (Lupus), Anti-PLA2R (Membranous).
  • Infection: Hep B, Hep C, HIV.
  • Complement: C3, C4 (Low in Lupus, MPGN).
  • Immunoglobulins / Electrophoresis: Myeloma/Amyloid.
  • HbA1c: Diabetes.

Renal Biopsy

  • Adults: Indicated in almost all cases (unless obvious diabetic nephropathy). Essential to distinguish Minimal Change vs FSGS vs Membranous.
  • Children: Not usually done initially. Empirical steroids started. Biopsy only if "Steroid Resistant" or atypical features (age less than 1 or >10, haematuria).
7. Management

Management Algorithm

           NEPHROTIC SYNDROME DIAGNOSED
           (Proteinuria + Low Albumin + Oedema)
                        ↓
            ┌───────────┴───────────┐
            ↓                       ↓
         CHILD (less than 10y)            ADULT
            ↓                       ↓
    Empirical Steroids          Renal Biopsy
    (Prednisolone)              (Determine Cause)
            ↓                       ↓
    ┌───────┴───────┐         ┌─────┴─────┐
    ↓               ↓         ↓           ↓
 RESPONSIVE     RESISTANT   PRIMARY     SECONDARY
(Typical MCD)   (Biopsy)   (Immunosupp) (Treat Cause)

General Management (Symptomatic)

  1. Oedema Control:

    • Salt Restriction: less than 2g/day. Crucial.
    • Fluid Restriction: 1-1.5L/day.
    • Diuretics: Furosemide (Loop). Often require high doses due to gut oedema and albumin binding. Add Spironolactone or Metolazone if resistant. Daily weights key.

  2. Antiproteinuric Therapy:

    • ACE Inhibitor / ARB: Reduce intraglomerular pressure. Reduce protein loss by 30-50%. Careful with AKI.

  3. Anticoagulation:

    • Prophylactic LMWH recommended if Serum Albumin less than 20 g/L.
    • High risk of VTE/Arterial thrombosis.

  4. Infection Prophylaxis:

    • Pneumococcal vaccination.
    • Penicillin V prophylaxis (sometimes in children).
    • Prompt treatment of sepsis.

  5. Lipids:

    • Statins (though hyperlipidaemia often resolves with remission).

Specific Immunosuppression (By Cause)

Minimal Change Disease (MCD)

  • 1st Line: High dose Prednisolone (1mg/kg) for 4-16 weeks.
  • Relapse: Frequent. Repeat steroids.
  • Frequent Relapsers/Steroid Dependent: Cyclophosphamide, Rituximab, CNIs (Tacrolimus).

Membranous Nephropathy

  • Rule of Thirds: 1/3 spontaneous remission, 1/3 stable, 1/3 progress.
  • Treatment: Based on risk (PLA2R levels, proteinuria).
  • Agents: Rituximab (Anti-CD20) is now 1st line. Ponticelli Protocol (Steroids + Cyclophosphamide) historic gold standard.

FSGS (Primary)

  • Difficult to treat.
  • High dose steroids (often extended) or Calcineurin Inhibitors (Tacrolimus/Cyclosporin).
8. Complications

Acute

  • Thromboembolism: DVT, PE, Renal Vein Thrombosis (10-40% risk).
  • Infection: Cellulitis (oedematous skin), Sepsis (Encapsulated bacteria - Strep pneumo).
  • Hypovolaemic Crisis: In children with severe low albumin. Abdo pain, shock. Requires Albumin infusion.
  • AKI: ATN or interstitial oedema.

Chronic

  • CKD: Progression to ESRD (FSGS is high risk).
  • Cardiovascular Disease: Accelerated atherosclerosis.
  • Malnutrition: Negative nitrogen balance.
9. Prognosis and Outcomes
ConditionPrognosis
Minimal ChangeExcellent renal survival. Relapses common but usually remit eventually.
MembranousVariable. 1/3 remission, 1/3 CKD, 1/3 ESRD.
FSGSpoorer. 50% reach ESRD in 5-10 years. Recurrence in transplant common.
DiabeticProgressive.
10. Evidence and Guidelines

Key Guidelines

GuidelineOrganisationKey Recommendations
Glomerular DiseasesKDIGO (2021)Comprehensive guide for MCD, Membranous, FSGS. Rituximab expanded role.
Renal AssociationUKManagement of oedema and thrombosis prophylaxis.

Landmark Studies

1. MENTALIST (2020)

  • Question: Rituximab vs Cyclosporin for Membranous?
  • Result: Rituximab non-inferior and safer long-term profile.
  • Impact: Shift towards Rituximab.

2. PREDNOS (2019)

  • Question: Short vs Long course steroids for MCD in kids?
  • Result: Long course did not reduce relapse rate.
  • Impact: Standard course preferred to reduce toxicity.

3. Beck et al. (2009)

  • Discovery: Identification of Anti-PLA2R antibody.
  • Impact: Revolutionised diagnosis and monitoring of Membranous Nephropathy.
11. Patient and Layperson Explanation

What is Nephrotic Syndrome?

It is a kidney condition where the filters (glomeruli) become leaky. Instead of keeping useful protein in the blood, the kidneys let huge amounts of it leak out into the urine.

Why does it make me swell up?

Protein (albumin) acts like a sponge to keep fluid inside your blood vessels. When you lose the protein in urine, the fluid leaks out into your tissues, causing swelling (oedema) in the legs, face, or tummy.

What causes it?

  • In Children: Usually "Minimal Change Disease". We don't know exactly why it starts, but it often responds very well to steroid medication.
  • In Adults: Often due to specific diseases of the kidney filter (like Membranous Nephropathy) or secondary to diabetes. A biopsy (taking a tiny piece of kidney) is usually needed to find the cause.

Treatment

  1. Reduce Swelling: Limiting salt and water, and taking water tablets (diuretics).
  2. Protect Kidneys: Blood pressure tablets (ACE inhibitors) reduce the leak.
  3. Treat the Cause: Strong medicines (steroids or immune suppressants) to stop the kidney inflammation.
  4. Prevent Clots: Because the blood becomes sticky, you might need blood thinners.
12. References

Primary Sources

  1. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1-S276.
  2. Floege J, et al. The Nephrotic Syndrome in Adults. Dtsch Arztebl Int. 2016;113:277-285.
  3. Eddy AA, Symons JM. Nephrotic syndrome in childhood. Lancet. 2003;362:629-639. PMID: 12944064.
  4. Hull RP, Goldsmith DJ. Nephrotic syndrome in adults. BMJ. 2008;336:1185-1189. PMID: 18497417.
13. Examination Focus

Common Exam Questions

  1. Paediatrics: "A 4-year-old has puffy eyes and 4+ protein. Next step?"
    • Answer: Prescribe Steroids (Prednisolone). Do NOT biopsy unless steroid resistant.
  2. Internal Medicine: "A nephrotic patient develops sudden left loin pain and haematuria. Diagnosis?"
    • Answer: Renal Vein Thrombosis.
  3. Pathology: "What is the specific antibody for Membranous Nephropathy?"
    • Answer: Anti-PLA2R (Phospholipase A2 Receptor).
  4. Complications: "Why are these patients infection prone?"
    • Answer: Urinary loss of Immunoglobulins and Complement.

Viva Points

  • Biopsy indications: Adult = Always (mostly). Child = Only if atypical (age less than 1 or >10, haematuria, resistant).
  • Thrombosis mechanism: Loss of ATIII + Liver production of fibrinogen.
  • Minimal Change EM findings: Effacement of podocyte foot processes. Normal light microscopy.

Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.

Last updated: 2025-12-24

At a Glance

EvidenceHigh
Last Updated2025-12-24
Emergency Protocol

Red Flags

  • Severe symptomatic oedema (pleural effusion, ascites)
  • Evidence of thrombosis (DVT/PE/Renal Vein Thrombosis)
  • Acute Kidney Injury (AKI)
  • Signs of infection (cellulitis, peritonitis)
  • Hypertension crisis (less common than in nephritic)

Clinical Pearls

  • **Nephrotic vs Nephritic**:
  • * **NephrOtic**: Proteinuria (O-Protein), Oedema, Hypoalbuminaemia. (Podocyte injury).
  • * **NephrItic**: Haematuria (Inflammation), HTN, Renal Impairment, less protein. (Glomerular inflammation).
  • **The "Frothy" Urine**: Patients may describe urine that looks like beer head or washing-up liquid foam. This is a specific sign of heavy proteinuria.
  • **Renal Vein Thrombosis**: Suspect if a nephrotic patient develops sudden flank pain, haematuria, or a varicocele (especially left-sided).

Guidelines

  • NICE Guidelines
  • BTS Guidelines
  • RCUK Guidelines