Nephrotic Syndrome in Children

Nephrotic syndrome is one of the commonest chronic glomerular disorders of childhood, defined by a quartet of heavy proteinuria, hypoalbuminaemia, oedema and hyperlipidaemia. In children it is overwhelmingly idiopathic, minimal change disease dominates, and the single most important prognostic question is whether the child responds to steroids.

Definition and diagnostic criteria

Nephrotic syndrome (NS) is a clinical state arising from increased glomerular permeability to plasma proteins. The classic tetrad is:

1. Nephrotic-range proteinuria → urine protein > 40 mg/m²/hour (or spot urine protein:creatinine ratio > 2 mg/mg, or 3+/4+ on dipstick).
2. Hypoalbuminaemia → serum albumin < 2.5 g/dL.
3. Oedema (the usual presenting complaint).
4. Hyperlipidaemia / hypercholesterolaemia (cholesterol typically > 200 mg/dL).

High-yield: The ISKDC (International Study of Kidney Disease in Children) defined cut-offs are the most tested: proteinuria > 40 mg/m²/h and albumin < 2.5 g/dL. Memorise both exact numbers.

The ISKDC remains the reference body whose definitions of remission, relapse, frequent relapse and steroid dependence are repeatedly examined.

Epidemiology

• Incidence ~2–7 per 100,000 children; cumulative prevalence ~16 per 100,000.
• Peak age 2–6 years; boys affected more than girls (≈2:1) in young children, ratio equalises by adolescence.
• Minimal change disease (MCD) accounts for ~90% of NS in children aged 1–6 years and ~50% in older children, hence "idiopathic nephrotic syndrome of childhood" is treated as MCD until proven otherwise.

Classification

By aetiology

Type	Examples
Idiopathic / primary (90%)	Minimal change disease, FSGS, membranoproliferative GN, membranous nephropathy
Congenital / infantile (<1 yr)	Finnish type (NPHS1/nephrin mutation), diffuse mesangial sclerosis (NPHS2/podocin, WT1), Denys-Drash, Pierson syndrome
Secondary	Henoch-Schönlein purpura, SLE (lupus nephritis), post-infectious (malaria, hepatitis B/C, HIV), Alport, diabetes (rare in children), drugs (penicillamine, NSAIDs)

By histology (idiopathic NS)

Histology	Frequency in children	Steroid response	Notes
Minimal change disease	~85–90%	Excellent (>90% respond)	Normal light microscopy; EM: foot process effacement
Focal segmental glomerulosclerosis (FSGS)	~10%	Often steroid-resistant	Commonest cause of steroid-resistant NS; segmental sclerosis
Membranoproliferative GN	<5%	Poor	Low complement (C3); "tram-track" basement membrane
Membranous nephropathy	Rare in children	Variable	Anti-PLA2R; subepithelial "spike and dome"

High-yield: Minimal change disease shows a normal glomerulus on light microscopy and negative immunofluorescence; the only abnormality is diffuse podocyte foot-process effacement on electron microscopy. This negative-light-microscopy/positive-EM combination is a favourite single-best-answer.

Etiology and pathophysiology

The unifying lesion is podocyte injury with disruption of the glomerular filtration barrier (fenestrated endothelium → glomerular basement membrane → podocyte slit diaphragm). In MCD a circulating permeability factor and T-cell dysfunction are implicated; cytokines reduce the anionic charge on the GBM.

Charge-selective barrier loss → selective proteinuria (mainly albumin). This selectivity is characteristic of MCD; non-selective proteinuria (loss of larger globulins too) points toward FSGS or other lesions.

Sequence of events:

Podocyte injury → loss of glomerular charge/size selectivity → massive albuminuria → hypoalbuminaemia → fall in plasma oncotic pressure → fluid shift into interstitium → oedema → reduced effective circulating volume → activation of RAAS and ADH → renal Na⁺ and water retention → worsening oedema.

An additional "overfill" mechanism (primary renal sodium retention via activated ENaC) operates in parallel, which is why some children are normo- or hypervolaemic rather than hypovolaemic.

Hyperlipidaemia: Low oncotic pressure stimulates hepatic lipoprotein synthesis and reduced lipoprotein lipase activity → raised LDL, VLDL and cholesterol → lipiduria with oval fat bodies and "Maltese cross" appearance under polarised light.

High-yield: The Maltese cross (cholesterol esters in oval fat bodies) seen under polarised microscopy is the classic urinary finding of nephrotic-range lipiduria.

Clinical features

• Oedema is the hallmark and presenting feature: starts periorbital (worse in mornings), becomes dependent (ankles, scrotum/labia), and may progress to anasarca with ascites and pleural effusions.
• Frothy urine (proteinuria), reduced urine output, weight gain.
• Blood pressure usually normal in MCD; significant hypertension, gross haematuria or impaired renal function suggest a non-MCD lesion.
• Children may present with abdominal pain (peritonitis, hypovolaemia, or thrombosis) or breathlessness (effusions).

Features that argue AGAINST simple MCD

High-yield — atypical features: age < 1 yr or > 8 yr, persistent hypertension, gross haematuria, raised creatinine, low C3, or extra-renal features (rash, arthritis). These mandate early biopsy and raise suspicion of FSGS, MPGN or secondary causes.

Investigation of choice and work-up

• Urinalysis: dipstick 3+/4+ proteinuria; microscopy for RBC casts (suggest nephritic component) and oval fat bodies.
• Quantification: early-morning spot urine protein:creatinine ratio is the practical investigation of choice (avoids cumbersome timed collection); nephrotic range > 2 mg/mg. 24-h/timed sample > 40 mg/m²/h is the gold reference.
• Blood: serum albumin, total protein, lipid profile, urea, creatinine, electrolytes.
• Complement (C3, C4): normal in MCD; low C3 suggests post-streptococcal GN, MPGN or lupus.
• Targeted serology when secondary cause suspected: ANA/anti-dsDNA, hepatitis B/C, HIV.

Renal biopsy — when is it indicated?

In a child 1–8 years with typical features, biopsy is NOT done first; empirical steroids are started assuming MCD.

High-yield — indications for renal biopsy in childhood NS:

• Age < 1 year or > 8–10 years at onset
• Steroid resistance (no remission after 4 weeks of daily steroids)
• Frequent relapses/steroid dependence before starting steroid-sparing agents (variable practice)
• Features of nephritis: persistent hypertension, gross/persistent haematuria, low complement, renal impairment
• Before/while on calcineurin inhibitors to assess nephrotoxicity

Management and drug of choice

Drug of choice — corticosteroids (oral prednisolone)

The drug of choice for first episode is oral prednisolone. The widely tested ISKDC/IAP regimen:

Prednisolone 60 mg/m²/day (max 60 mg) for 4–6 weeks → then 40 mg/m² on alternate days for 4–6 weeks → taper.

• ~90% of MCD children achieve remission, usually within 2 weeks.
• First relapse: prednisolone 60 mg/m²/day until remission (urine protein nil/trace × 3 days), then 40 mg/m² alternate-day for 4 weeks.

Definitions of response (ISKDC) — heavily examined

Term	Definition
Remission	Urine protein nil/trace (or PCR < 0.2) for 3 consecutive days
Relapse	Proteinuria 3+/4+ (or PCR > 2) for 3 consecutive days, having been in remission
Frequent relapser	≥ 2 relapses in 6 months of initial response, or ≥ 4 relapses in any 12 months
Steroid dependent	2 consecutive relapses during steroid taper, or within 14 days of stopping steroids
Steroid resistant	Failure to achieve remission after 4 weeks of daily prednisolone (some define 6–8 weeks ± IV methylprednisolone)

High-yield: Two consecutive relapses on tapering = steroid dependent; failure to remit after 4 weeks of daily steroids = steroid resistant. These exact definitions are repeatedly asked.

Steroid-sparing agents (frequent relapsers / steroid dependent)

• Levamisole (immunomodulator) — often first steroid-sparing agent.
• Cyclophosphamide — alkylating agent; risk of gonadal toxicity, marrow suppression, haemorrhagic cystitis.
• Calcineurin inhibitors — cyclosporin / tacrolimus.
• Mycophenolate mofetil (MMF).

Steroid-resistant nephrotic syndrome (SRNS)

High-yield: For steroid-resistant NS (usually FSGS on biopsy), the drug of choice is a calcineurin inhibitor — cyclosporin (or tacrolimus), often with low-dose alternate-day steroids and an ACE inhibitor for antiproteinuric effect. Genetic testing (NPHS1, NPHS2, WT1) is advised as monogenic SRNS responds poorly to immunosuppression.

Supportive measures

• Salt restriction during oedema; fluid restriction only if severe.
• Diuretics (furosemide ± albumin infusion) for symptomatic/refractory oedema — use cautiously to avoid precipitating hypovolaemia/thrombosis.
• Pneumococcal vaccination (and annual influenza); live vaccines deferred until off high-dose steroids.
• Albumin (20–25%) infusion for severe symptomatic hypovolaemia, often followed by furosemide.
• ACE inhibitors / ARBs as antiproteinuric agents, mainly in steroid-resistant disease.
• Vitamin D and calcium supplementation with prolonged steroids.

Complications

The exam loves the infective and thrombotic complications.

Infections

• Children are functionally immunosuppressed: urinary loss of immunoglobulins and complement factor B (properdin pathway) impairs opsonisation of encapsulated organisms.
• Spontaneous bacterial peritonitis is the classic complication; the commonest organism is Streptococcus pneumoniae (pneumococcus), followed by E. coli.

High-yield: The most characteristic infection in childhood NS is pneumococcal (spontaneous bacterial) peritonitis, due to loss of factor B/properdin and opsonising antibody. Present with fever, abdominal pain and guarding in an oedematous child.

• Also cellulitis, pneumonia, urinary infection.

Thromboembolism

• Hypercoagulable state from urinary loss of antithrombin III, raised fibrinogen, thrombocytosis and haemoconcentration.
• Renal vein thrombosis is classic (haematuria, flank mass); also DVT, pulmonary embolism, and cerebral venous (sagittal sinus) thrombosis.

Others

• Hypovolaemia / shock (especially with aggressive diuresis or during relapse).
• Acute kidney injury.
• Hyperlipidaemia → long-term atherosclerosis risk in chronic disease.
• Growth failure, osteoporosis, cataract, Cushingoid features from prolonged steroids.
• Protein malnutrition and anaemia (transferrin loss).

Key differentials

Condition	Distinguishing features
Acute post-streptococcal GN	Nephritic picture: hypertension, gross haematuria, low C3, oliguria, recent throat/skin infection
HSP nephritis	Palpable purpura on buttocks/legs, arthralgia, abdominal pain, IgA deposits
Lupus nephritis	Malar rash, arthritis, cytopenias, ANA/anti-dsDNA positive, low C3 and C4
Protein-losing enteropathy	Hypoalbuminaemia + oedema but no proteinuria; GI symptoms
Hepatic / cardiac oedema	Low albumin from liver failure or raised venous pressure; urine protein negative
Angio-oedema / allergic periorbital swelling	Transient, no proteinuria, normal albumin

High-yield: A nephrotic child with low C3 + haematuria + hypertension is not simple MCD — think MPGN, post-streptococcal GN or lupus, and biopsy.

Congenital nephrotic syndrome (special note)

• Onset < 3 months of age = congenital; 3–12 months = infantile.
• Finnish type (CNF): autosomal recessive NPHS1 / nephrin mutation; large placenta, raised maternal/amniotic alpha-fetoprotein, severe steroid-resistant proteinuria. Steroids/immunosuppression are ineffective; management is supportive (albumin, nutrition, nephrectomy and transplant).
• Diffuse mesangial sclerosis: NPHS2 (podocin), WT1; part of Denys-Drash (NS + Wilms tumour + ambiguous genitalia) and Pierson syndromes.

High-yield: Congenital nephrotic syndrome of the Finnish type is due to a nephrin (NPHS1) mutation and is steroid resistant — never expect a response to prednisolone.

Mnemonics and eponyms

• Nephrotic tetrad — "PALE": Proteinuria, Albumin low, Lipids high (lipiduria), Edema.
• MCD on biopsy — "Nil on LM, Foot on EM": nil disease on light microscopy, foot-process effacement on EM.
• Eponyms to recall: ISKDC (criteria), Denys-Drash and Pierson (congenital), Finnish type (CNF/nephrin), Maltese cross (lipiduria).

Recently asked / exam angle

• Drug of choice for first-episode childhood NS → oral prednisolone; for steroid-resistant NS → cyclosporin (calcineurin inhibitor). Both frequently paired in single-best-answer stems.
• Commonest cause of NS in children → minimal change disease; commonest cause of steroid-resistant NS → FSGS.
• Light microscopy normal, EM shows foot-process fusion → identify MCD.
• Spontaneous bacterial peritonitis organism → Streptococcus pneumoniae; mechanism via loss of factor B / properdin.
• Hypercoagulability mechanism → urinary loss of antithrombin III; classic event = renal vein thrombosis.
• ISKDC definition matching: remission (3 days nil/trace), steroid dependence (2 relapses on taper/within 14 days), steroid resistance (no remission at 4 weeks).
• Investigation of choice for quantifying proteinuria → spot urine protein:creatinine ratio (> 2 mg/mg = nephrotic range).
• Congenital NS, raised AFP, large placenta → Finnish type / nephrin (NPHS1) mutation.
• Maltese cross under polarised light → identify nephrotic lipiduria.
• Indications for biopsy in childhood NS (age extremes, steroid resistance, nephritic features) recur as multiple-true-false.

Rapid revision

1. Nephrotic tetrad = proteinuria (> 40 mg/m²/h) + albumin (< 2.5 g/dL) + oedema + hyperlipidaemia.
2. Commonest cause in children = minimal change disease (~90% in 1–6 yr group).
3. MCD biopsy = normal LM, negative IF, foot-process effacement on EM.
4. Investigation of choice to quantify proteinuria = early-morning urine protein:creatinine ratio (> 2 mg/mg).
5. Drug of choice, first episode = prednisolone 60 mg/m²/day × 4–6 wk → 40 mg/m² alternate days.
6. ~90% of MCD children are steroid-responsive; remission = nil/trace protein × 3 days.
7. Steroid dependent = 2 relapses on taper or within 14 days of stopping; steroid resistant = no remission after 4 weeks daily steroids.
8. Commonest cause of steroid-resistant NS = FSGS; drug of choice = cyclosporin (calcineurin inhibitor).
9. Classic infection = pneumococcal spontaneous bacterial peritonitis (loss of factor B/properdin).
10. Hypercoagulability from urinary antithrombin III loss → classic renal vein thrombosis.
11. Low C3 + haematuria + hypertension = NOT MCD → think MPGN/PSGN/lupus, biopsy.
12. Congenital NS, Finnish type = nephrin (NPHS1) mutation, raised AFP, steroid-resistant — supportive care only.