Nephrotic Syndrome in Children: Case Discussion & Key Points
Model Case Presentation
Patient Demographics
Name: Master Rohan, Age: 4 years, Gender: Male, Informant: Mother (Reliable)
Chief Complaints
- Puffiness of face – 7 days
- Swelling of feet and abdomen – 5 days
- Decreased urine output – 5 days
History Summary
A 4-year-old boy presented with insidious onset puffiness of the face, first noticed by the mother as periorbital swelling that was worse in the morning and improved by evening. This was followed by swelling of both feet and progressive abdominal distension. The mother noticed frothy urine and a decrease in urine output. No fever at presentation. No gross hematuria, no dysuria. No joint pains or skin rash. Appetite reduced.
One episode of upper respiratory tract infection two weeks before current symptoms. No previous similar episodes. Born at term via NVD, uneventful antenatal period. No family history of kidney disease. Non-consanguineous marriage.
Examination Summary
| Parameter | Finding | Significance |
|---|---|---|
| Weight | 17 kg (baseline ~14 kg) | +3 kg fluid overload |
| BP | 90/60 mmHg | Low-normal (intravascular depletion) |
| HR | 100/min | Mild tachycardia |
| Temperature | Afebrile | No active infection at presentation |
| Periorbital edema | Present (+++) | Hallmark of NS in children |
| Pedal edema | Pitting (++++) | Hypoalbuminemia |
| Ascites | Present | Fluid transudation |
| Cyanosis / Clubbing | Absent | No cardiac / chronic disease |
| Pallor | Mild | Dilutional / nutritional |
Abdomen: Distended with shifting dullness positive. No organomegaly. Fluid thrill positive (gross ascites). Scrotal edema present.
Respiratory: Decreased breath sounds at right base (pleural effusion).
CVS: No murmur. Peripheral pulses — volume reduced (intravascular depletion).
Urine: Frothy. Dipstick — Protein ++++. No blood.
✅ Complete Diagnosis
Idiopathic Nephrotic Syndrome — First Episode (Steroid-Sensitive, Minimal Change Disease likely) with Anasarca (periorbital edema, pedal edema, ascites, right pleural effusion, scrotal edema) and Intravascular Volume Depletion.
📝 History — Exam Q&A
Nephrotic Syndrome is a clinical syndrome characterized by the tetrad of:
- Massive proteinuria: >40 mg/m²/hr or urine protein:creatinine ratio >200 mg/mmol (or >2 mg/mg), or 3+ on dipstick for 3 consecutive days
- Hypoalbuminemia: Serum albumin <2.5 g/dL (<25 g/L)
- Generalized edema (anasarca)
- Hyperlipidemia: Total cholesterol >200 mg/dL
💡 Mnemonic:EPH
Edema + Proteinuria (massive) + Hypoalbuminemia = Nephrotic Syndrome. Hyperlipidemia is a consequence, not a defining criterion in all guidelines.
Minimal Change Disease (MCD) — accounts for ~76–90% of idiopathic nephrotic syndrome in children between 1 and 8 years of age. It is also called "nil disease," "lipoid nephrosis," or "foot process disease."
| Histology | Frequency in Children | Typical Age |
|---|---|---|
| Minimal Change Disease | ~76–90% | 1–8 years |
| Focal Segmental Glomerulosclerosis (FSGS) | ~8% | Older children |
| Mesangioproliferative GN | ~5% | Variable |
| Membranoproliferative GN (MPGN) | ~6% | Older / secondary |
| Membranous Nephropathy | Rare in children | Older / secondary |
- Incidence: ~2 per 100,000 children per year (general population); ~6–8 per 100,000 per year in South Asian children
- Peak age: 2–6 years (median ~4 years)
- Male:Female ratio = 2:1 (more common in boys)
- Higher incidence in South Asians and Africans compared to Caucasians
Periorbital edema appears first because the periorbital tissue has loose connective tissue with low tissue oncotic pressure, making it most susceptible to fluid accumulation from hypoalbuminemia.
Worse in the morning because fluid accumulates in the dependent loose periorbital tissue during recumbency at night. During the day, gravity redistributes fluid downward (gravity-dependent edema), so pedal edema becomes prominent while periorbital swelling improves.
Two theories explain edema in NS:
1. Underfill theory (classical):
- Massive proteinuria → Hypoalbuminemia → ↓ Plasma oncotic pressure → Fluid shifts from intravascular to interstitial compartment → Edema
- ↓ Intravascular volume → Activates RAAS → ↑ Aldosterone → Na+ and water retention → Worsens edema
2. Overfill theory:
- Primary intrinsic renal Na+ retention → ↑ Plasma volume → Edema even without hypoalbuminemia
- Supported by: Normal or high plasma renin in some patients, hypertension during relapse
💡 Clinical relevance
Underfill → intravascularly depleted (low BP, cold peripheries, high renin) → hypovolemic crisis risk.
Overfill → hypertensive → diuretics safer to use.
- ↓ Serum albumin → ↓ Plasma oncotic pressure → Liver increases lipoprotein synthesis (VLDL, LDL) to raise oncotic pressure → Hyperlipidemia
- Lipoprotein lipase activity is reduced → Impaired lipid clearance → Further hyperlipidemia
- Loss of HDL in urine → Disturbed lipid metabolism
- Lipiduria (oval fat bodies, fatty casts): Lipoproteins filtered through damaged glomerulus appear in urine
| Category | Examples |
|---|---|
| Idiopathic (Primary) ~90% in children | Minimal Change Disease, FSGS, MPGN, Membranous |
| Secondary | SLE (Lupus nephritis), HSP nephritis, Hepatitis B/C, Malaria, Syphilis, HIV, Amyloidosis, Drugs (NSAIDS, penicillamine, gold) |
| Congenital (< 3 months) | Finnish type (NPHS1 mutation – nephrin), NPHS2 (podocin), Diffuse Mesangial Sclerosis (WT1 mutation) |
| Infantile (3–12 months) | Genetic mutations, infections (congenital syphilis, CMV, toxoplasmosis) |
- No gross hematuria — Hematuria suggests nephritic component (MPGN, HSP, SLE)
- No fever / rash / joint pain — Suggests secondary NS (SLE, HSP)
- No drug intake (NSAIDs, gold) — Drug-induced NS
- No abdominal pain or bloody diarrhea — Rules out HSP as a trigger
- No family history of renal disease — Genetic NS
- No consanguinity — Autosomal recessive genetic NS (Finnish type)
- Previous episodes? — To classify relapse type
The following features suggest secondary NS, FSGS, or MPGN — and warrant biopsy / specialist referral:
- Age <1 year or >12 years at onset
- Gross or persistent microscopic hematuria
- Hypertension at presentation (sustained)
- Low complement levels (C3, C4) — suggests MPGN, SLE, post-infectious GN
- Impaired renal function (↑ creatinine) at presentation
- Extra-renal features: rash, arthritis, purpura, lymphadenopathy
- Positive family history of renal disease / consanguinity
- Steroid resistance — no response at 4 weeks of full-dose prednisolone
The exact mechanism remains incompletely understood. Proposed mechanisms:
- T-cell dysfunction: Abnormal T-cell–mediated release of a circulating permeability factor (possibly anti-nephrin autoantibodies) that damages podocytes
- Podocyte injury: Effacement (fusion) of foot processes → loss of the glomerular charge barrier and size barrier → massive proteinuria
- Anti-nephrin autoantibodies (recent advance 2024): Anti-nephrin IgG4 autoantibodies found in a significant proportion of MCD patients, linking MCD closer to an autoimmune etiology
- Supports steroid/immunosuppressive responsiveness
Light microscopy: Normal (hence "minimal change"). Electron microscopy: Diffuse effacement (fusion) of podocyte foot processes — the pathological hallmark. Immunofluorescence: Negative.
🩺 Examination — Exam Q&A
General: Well-nourished child (unlike nephritic syndrome — pale, sick-looking). Mild pallor.
Edema (hallmark):
- Periorbital puffiness — worse in morning, may mimic "allergic facies"
- Pedal/pretibial pitting edema
- Scrotal / labial edema
- Ascites — shifting dullness, fluid thrill (in gross ascites)
- Pleural effusion — reduced breath sounds, stony dull on percussion (usually right-sided)
- Pericardial effusion — rare, muffled heart sounds
Skin: Striae, stretch marks (steroid side effect in relapsing cases). White nails (leukonychia) due to hypoalbuminemia.
BP: Normal or low (underfill) in first episode MCD. May be elevated in FSGS or MPGN.
No: Significant hypertension, gross hematuria, or renal failure in typical first episode MCD.
- Inspection: Distended abdomen, everted umbilicus, flanks full
- Percussion: Shifting dullness (most sensitive clinical sign) — dullness shifts to dependent side when position changed. Positive when >1500 mL fluid present
- Fluid thrill: Positive only in massive (tense) ascites. Requires an assistant to place the edge of the hand in the midline
- Puddle sign: Detects as little as 120 mL — patient in knee-elbow position, percuss flanks; positive if dull
- Ultrasonography: Most sensitive — detects >100 mL
| Feature | Nephrotic Syndrome | Cardiac Failure | Malnutrition (Kwashiorkor) | Hypothyroidism |
|---|---|---|---|---|
| Distribution | Generalized, periorbital prominent | Dependent, JVP elevated | Generalized, face spared early | Non-pitting, periorbital |
| Edema type | Pitting | Pitting | Pitting | Non-pitting (myxedema) |
| Protein in urine | Massive ++++ | Mild | Absent | Absent |
| Albumin | Very low | Normal/mildly low | Low (nutritional) | Normal |
| BP | Low/Normal | Elevated | Normal/low | Low |
| Key clue | Frothy urine, periorbital AM edema | Murmur, hepatomegaly, dyspnea | Hair changes, moon face, growth failure | Dry skin, constipation, slow reflexes |
Signs of intravascular depletion:
- Low blood pressure or postural hypotension
- Tachycardia, cold peripheries
- Reduced capillary refill time (>2 sec)
- Low volume pulse
- Reduced urine output
- Abdominal pain (from mesenteric ischemia / peritonitis)
Clinical importance: Despite peripheral edema, the intravascular compartment may be depleted (underfill). Aggressive diuretics in this state can precipitate a hypovolemic crisis → acute kidney injury. Albumin infusion may be required before diuretics in severe cases.
Refers to the characteristic facial appearance of a child with nephrotic syndrome, with marked bilateral periorbital puffiness (periorbital edema). The swelling is soft, pitting, and bilateral. It is most prominent in the morning after lying flat overnight and resembles "allergic eyes" initially, often leading to diagnostic delay.
| Complication | Mechanism | Clinical Signs |
|---|---|---|
| Infections | Loss of IgG, IgA, complement (factor B, D) in urine → immunosuppression | Fever, peritonitis (spontaneous bacterial), cellulitis, pneumococcal sepsis |
| Thromboembolism | Loss of anticoagulants (Protein C, S, antithrombin III) in urine + ↑ procoagulants (fibrinogen) + hemoconcentration | DVT, pulmonary embolism, renal vein thrombosis, cerebral venous sinus thrombosis |
| Hypovolemia | ↓ Plasma oncotic pressure (underfill theory) | Hypotension, tachycardia, AKI, abdominal pain |
| AKI | Hypovolemia, thrombosis, drugs (NSAIDs, diuretics), sepsis | Oliguria, rising creatinine |
| Hyperlipidemia | ↑ Hepatic lipoprotein synthesis, ↓ lipase activity | Xanthomas (rarely), ↑ cardiovascular risk long-term |
| Steroid complications | Long-term corticosteroid use | Cushingoid features, hypertension, growth suppression, cataracts, osteoporosis, infections |
| Hypothyroidism | Loss of thyroid-binding globulin and T4 in urine | Usually subclinical; check TFTs in prolonged NS |
SBP is a serious infectious complication of NS. Ascitic fluid is a culture medium, and low opsonins (due to urinary loss of complement) impair bacterial clearance.
Common organisms: Streptococcus pneumoniae (most common), E. coli, Klebsiella.
Presentation: Fever, abdominal pain and tenderness, worsening ascites, vomiting. May present as unexplained deterioration in NS.
Diagnosis: Ascitic tap → WBC >250 polymorphs/mm³, positive culture.
Treatment: IV Cefotaxime or Ceftriaxone. Prophylaxis: Oral Penicillin V (phenoxymethylpenicillin) during active nephrotic phase is used in some centers.
| Feature | Nephrotic Syndrome | Nephritic Syndrome |
|---|---|---|
| Proteinuria | Massive (>3.5 g/day in adults; >40 mg/m²/hr) | Mild to moderate |
| Hematuria | Absent (if pure) | Gross or microscopic — RBC casts |
| Hypertension | Usually absent (may be low) | Prominent |
| Edema | Severe (anasarca) | Mild to moderate |
| Albumin | Very low (<2.5 g/dL) | Normal or mildly low |
| Renal function | Usually normal at first episode MCD | Often impaired |
| Common cause | MCD (children), membranous (adults) | Post-streptococcal GN, IgA nephropathy |
💡 Key
MPGN can present as nephrotic-nephritic overlap — both massive proteinuria AND hematuria/hypertension.
🔬 Investigations — Exam Q&A
| Investigation | Expected Finding | Purpose |
|---|---|---|
| Urine dipstick / urinalysis | Protein 3+ to 4+; No significant hematuria | Confirm proteinuria; rule out nephritic |
| Urine protein:creatinine (UP:Uc) ratio | >200 mg/mmol (or >2 mg/mg) | Quantify proteinuria; random spot sample |
| Serum albumin | <2.5 g/dL | Confirm hypoalbuminemia |
| Serum cholesterol (lipid profile) | >200 mg/dL (hyperlipidemia) | Fourth criterion of NS |
| Serum creatinine / urea | Usually normal in first-episode MCD | Baseline renal function |
| Serum electrolytes | Na+ may be low (dilutional); K+ variable | Electrolyte balance, guide diuretics |
| FBC / CBC | Haemoglobin, WBC, platelets | Infection, anemia |
| Mantoux test / IGRA | Rule out TB before steroids | Mandatory before starting prednisolone |
| Urine microscopy | Oval fat bodies, fatty casts; No/few RBCs | Lipiduria; rule out nephritic |
| Blood pressure | Normal or low in MCD | Hypertension → atypical feature |
| Method | Threshold for NS | Notes |
|---|---|---|
| Urine dipstick | 3+ or 4+ (on 3 consecutive days) | Quick bedside test; false positives with concentrated urine |
| Spot urine protein:creatinine ratio (UP:Uc) | >200 mg/mmol or >2 mg/mg | Best practical method; first morning urine preferred |
| 24-hour urine protein | >40 mg/m²/hr or >3.5 g/day (adults) | Gold standard for quantification; inconvenient in children |
💡 Remission definition
Complete remission: Urine protein trace or nil on dipstick (or UP:Uc <20 mg/mmol) for 3 consecutive days.
Partial remission: Reduction in proteinuria by >50% AND UP:Uc 20–200 mg/mmol.
- Complement levels (C3, C4): Low C3 → MPGN, post-infectious GN, SLE; Low C4 → SLE, hepatitis C
- ANA, anti-dsDNA: For SLE (Lupus nephritis)
- ANCA: Vasculitis-associated nephritis
- ASOT / Throat swab: Post-streptococcal GN (if nephritic features)
- Hepatitis B surface antigen (HBsAg) and HCV antibody: Hepatitis-associated membranous nephropathy
- HIV test
- Syphilis serology (VDRL)
- Thyroid function tests (TFTs): Loss of TBG in urine; subclinical hypothyroidism
- Coagulation profile (PT, APTT, fibrinogen): Thromboembolism risk assessment
- Genetic testing: In congenital or infantile NS, and steroid-resistant NS — mutations in NPHS1 (nephrin), NPHS2 (podocin), WT1, LAMB2, etc.
Biopsy is NOT indicated routinely for a first episode of nephrotic syndrome in children aged 1–12 years with typical features (no hematuria, no hypertension, normal complement and renal function) — these are highly likely to be MCD and steroid-sensitive.
Indications for biopsy (KDIGO 2025 / IPNA):
- Steroid-resistant nephrotic syndrome (SRNS) — no response at 4–6 weeks of full-dose prednisolone
- Age <1 year (infantile NS) or >12 years at presentation
- Atypical features: gross/persistent hematuria, sustained hypertension, low complement, renal impairment
- Suspected secondary NS (SLE, vasculitis)
- Frequently relapsing or steroid-dependent disease — to guide choice of immunosuppressant
- Kidneys: Normal size or slightly enlarged. Increased echogenicity in some cases. Rules out anatomical abnormalities
- Detects ascites (sensitive, detects >100 mL)
- Detects pleural effusion
- Detects renal vein thrombosis (Doppler US — absent/reversed flow in renal vein)
- Helps guide biopsy (real-time ultrasound-guided)
| Modality | Finding |
|---|---|
| Light Microscopy | Normal — no glomerular changes visible. Tubular epithelial cell lipid droplets (lipoid nephrosis) |
| Immunofluorescence | Negative — no immune deposits |
| Electron Microscopy | Diffuse effacement (fusion) of podocyte foot processes — the pathological hallmark of MCD |
💡 Mnemonic
MCD = Normal on light, Negative on IF, Foot process fusion on EM → NNF
💊 Management — Exam Q&A
Standard steroid regimen for first episode (KDIGO 2025 / IPNA):
- Ensure TB is excluded (Mantoux / IGRA) before starting
- Daily prednisolone: 60 mg/m²/day or 2 mg/kg/day (maximum 60 mg/day) for 4 weeks
- Alternate-day prednisolone: 40 mg/m² or 1.5 mg/kg (maximum 40 mg) for 4 weeks
- Total duration: 8 weeks (an alternative 12-week regimen of 6+6 weeks is equally acceptable per KDIGO 2025 — no proven advantage of longer over 8 weeks in reducing relapse)
- Dose is given as a single morning dose
✅ KDIGO 2025 Update
KDIGO 2025 confirms: prolonged initial steroid therapy (beyond 12 weeks) does NOT reduce the risk of frequently relapsing disease compared to 8 weeks. Standard recommendation remains 8 weeks total.
| Term | Definition (KDIGO 2025 / IPNA 2022) |
|---|---|
| Complete Remission | Urine protein nil or trace on dipstick (UP:Uc <20 mg/mmol) for 3 consecutive days |
| Partial Remission | >50% reduction in proteinuria AND UP:Uc 20–200 mg/mmol |
| Relapse | Urine protein 3+ or 4+ on dipstick (UP:Uc >200 mg/mmol) for 3 consecutive days after remission |
| Frequently Relapsing NS (FRNS) | ≥2 relapses within 6 months of initial response, or ≥4 relapses within any 12-month period |
| Steroid-Dependent NS (SDNS) | 2 consecutive relapses during high-dose steroid therapy, or within 14 days of stopping high-dose steroid |
| Steroid-Sensitive NS (SSNS) | Complete remission within 4 weeks of standard-dose prednisolone |
| Late Responder | Achieves complete remission between 4–6 weeks (confirmation period) |
| Steroid-Resistant NS (SRNS) | No complete remission by 6 weeks of full-dose prednisolone (including confirmation period) |
Treatment of relapse (standard regimen):
- Daily prednisolone 60 mg/m²/day (max 60 mg) until 3 consecutive days of remission
- Then alternate-day prednisolone 40 mg/m² (max 40 mg) for 4 weeks, then stop
Intercurrent infection trigger: If relapse occurs during/immediately after URTI, increase prednisolone to 15 mg/m²/day (or full dose) for 5–7 days during the infection to prevent relapse (KDIGO recommendation for FRNS/SDNS).
When a child develops steroid toxicity or frequently relapses requiring high cumulative steroid doses, steroid-sparing agents are used:
| Drug | Mechanism | Notes |
|---|---|---|
| Levamisole | Immunomodulator, T-cell regulation | Preferred in FRNS; not available in USA; biweekly dosing; SE: neutropenia, vasculitis |
| Oral Cyclophosphamide | Alkylating agent | Preferred in FRNS; 8–12 weeks course (2–3 mg/kg/day); SE: bone marrow suppression, gonadal toxicity, hemorrhagic cystitis; cumulative dose limit |
| Mycophenolate Mofetil (MMF) | Inhibits de novo purine synthesis in lymphocytes | Preferred in SDNS; well tolerated; SE: GI symptoms |
| Calcineurin Inhibitors (CNI) — Cyclosporine / Tacrolimus | Inhibit T-cell activation (IL-2 suppression); also have direct podocyte stabilization effect | |
| Rituximab | Anti-CD20 monoclonal antibody → B-cell depletion | Preferred in SDNS/FRNS not responding to above; IV infusion; SE: infusion reactions, hypogammaglobulinemia |
💡 KDIGO 2025 Position
KDIGO 2025 lists steroid-sparing agents in an unbiased order — choice depends on patient factors (age, fertility concerns, resources, compliance, disease severity).
- Renal biopsy — mandatory (rule out FSGS, MPGN, other causes)
- Genetic testing — mutations in NPHS1, NPHS2, WT1 etc. (if genetic mutation found → calcineurin inhibitors often fail, transplant may be needed)
- First-line immunosuppression for non-genetic SRNS:
- Calcineurin Inhibitor (Cyclosporine 4–6 mg/kg/day or Tacrolimus) + low-dose alternate-day prednisolone for 6 months
- If partial/no response after 6 months of CNI → switch to MMF to reduce long-term CNI toxicity
- RASi (ACE inhibitor / ARB): Recommended in SRNS to reduce proteinuria and protect kidneys — monitor for AKI and hyperkalemia
- Rituximab — emerging evidence in SRNS; not yet standard first-line
- SRNS has significant risk of progression to ESRD (end-stage renal disease)
Edema management:
- Salt restriction: No added salt diet — avoid excess sodium to prevent worsening edema
- Fluid restriction: In gross edema with oliguria
- Diuretics: Furosemide (1–2 mg/kg/dose) — only if intravascularly replete (BP and pulse normal). NOT if hypovolemic. Spironolactone can be added for Na+ retention
- Albumin infusion (20% albumin, 0.5–1 g/kg over 4 hours): Used only if intravascular depletion is severe (not for low serum albumin per se). Must be discussed with nephrologist. Follow with furosemide post-infusion
Infection prevention:
- Pneumococcal vaccine (before immunosuppression if possible)
- Varicella vaccine if non-immune (give before steroids or during remission)
- Avoid live vaccines during active immunosuppression
- Prophylactic Penicillin V in some centers during the nephrotic phase
Nutrition: Normal protein diet. No high-protein supplements (increases proteinuria). Calcium and Vitamin D supplementation during steroid therapy.
Thromboprophylaxis: In high-risk situations (immobile, serum albumin <20 g/L, fibrinogen >6 g/L) — discuss anticoagulation with nephrologist.
| System | Complication | Monitoring |
|---|---|---|
| Endocrine | Cushing syndrome, adrenal suppression, growth failure, diabetes | Growth chart, blood glucose, morning cortisol |
| Bone | Osteoporosis, avascular necrosis of femoral head | DEXA scan, Calcium/Vit D levels |
| Eye | Posterior subcapsular cataracts, glaucoma | Annual slit-lamp examination |
| Hypertension | Steroid-induced hypertension | Regular BP monitoring |
| Immunosuppression | Increased susceptibility to infections (varicella, TB, PCP) | TB screening, varicella status |
| Skin | Striae, acne, hirsutism, thin skin | Clinical examination |
| GI | Peptic ulceration | Symptoms; consider PPI prophylaxis in high-dose/long-term |
| Neuropsychiatric | Mood changes, behavioral changes, insomnia | Clinical assessment |
- ~85–90% of children with idiopathic NS are steroid-sensitive (SSNS) → excellent prognosis
- Of SSNS: 70–80% will have at least one relapse
- ~50% will have frequently relapsing or steroid-dependent course
- SSNS — risk of progression to ESRD is very low (<1%)
- ~10–30% of SSNS may "grow out" of the disease after puberty
- SRNS — 30–40% risk of ESRD within 5–10 years (depends on histology and genetic mutation status)
- Genetic SRNS (NPHS1, NPHS2) — poor response to immunosuppression; frequent progression to ESRD
- Transplantation possible in ESRD; FSGS may recur in transplant (<MCD)
🔭 Recent Advances — Exam Q&A
Anti-nephrin autoantibodies (IgG4 class) have been identified in a significant proportion (~20–25%) of children with MCD. They target nephrin, a key structural protein of the podocyte slit diaphragm.
- Significance: Confirms MCD as an autoimmune disease (not just T-cell mediated), moving it closer to membranous nephropathy in pathomechanism
- Antibody levels correlate with disease activity (high in relapse, low/undetectable in remission)
- Therapeutic implication: Justifies use of B-cell depleting agents (rituximab) and anti-CD20 therapies in MCD
- May serve as a future biomarker for monitoring and predicting relapse
Reference: Hengel et al., NEJM 2024 — confirmed anti-nephrin IgG4 autoantibodies in podocytopathies
Rituximab is an anti-CD20 chimeric monoclonal antibody that depletes B-cells. Now an established steroid-sparing agent in NS.
Indications in pediatric NS:
- Frequently relapsing or Steroid-dependent NS — to induce and maintain remission and reduce steroid burden
- Failure or toxicity with other steroid-sparing agents (cyclophosphamide, MMF, CNI)
- Emerging evidence in SRNS (non-genetic)
Administration: IV infusion (375 mg/m², typically 1–2 doses). Pre-medication with antihistamine and paracetamol required to prevent infusion reactions.
Side effects: Infusion reactions, hypogammaglobulinemia (monitor serum immunoglobulins), increased infection risk, rare progressive multifocal leukoencephalopathy (PML)
KDIGO 2025: Listed as a first-line steroid-sparing option for SDNS/FRNS in an unbiased order with other agents.
PREDNOS trial (UK, published 2019): A large, multicenter, randomized controlled trial comparing 8 weeks vs 16 weeks (4 months) of prednisolone for the initial episode of SSNS in children.
Findings: There was no significant difference in the rate of relapse at 12 months between 8-week and 16-week treatment. This confirmed that prolonged initial steroid therapy beyond 8–12 weeks does not reduce the risk of subsequently developing frequently relapsing disease.
Impact: This provided high-quality evidence that supported the KDIGO 2025 recommendation for 8 weeks as the standard duration for first-episode NS, avoiding unnecessary prolonged steroid exposure.
| Gene | Protein | Phenotype | Response to Steroids |
|---|---|---|---|
| NPHS1 | Nephrin | Finnish congenital NS (<3 months) | None |
| NPHS2 | Podocin | SRNS, FSGS (1–6 years) | None |
| WT1 | Wilms tumor suppressor protein | Diffuse mesangial sclerosis, Denys-Drash syndrome, Frasier syndrome | None |
| LAMB2 | Laminin beta-2 | Pierson syndrome (NS + ocular abnormalities) | None |
| CD2AP, ACTN4, TRPC6 | Podocyte structural proteins | Adult-onset FSGS | Poor |
🚨 Important
In children with genetic mutations causing SRNS, immunosuppressive therapy is largely ineffective. Genetic testing guides avoidance of toxic immunosuppression. Transplantation is the treatment of choice — disease generally does NOT recur post-transplant (unlike primary FSGS).
Ofatumumab is a fully human anti-CD20 monoclonal antibody (compared to rituximab which is chimeric — part mouse/part human).
- Binds a different epitope of CD20 — potentially more effective B-cell depletion
- May be used in patients who have developed infusion reactions or resistance to rituximab
- KDIGO 2025 reviewed trials comparing rituximab vs ofatumumab in FRNS/SDNS — ofatumumab is an emerging alternative
- Not yet standard first-line; reserved for rituximab failures or hypersensitivity
Sparsentan is a novel dual antagonist of both the endothelin-A receptor (ERA) and the angiotensin II type-1 receptor (AT1R).
- Primary use studied in primary FSGS and IgA nephropathy (DUPLEX trial, PROTECT trial — mainly adult data)
- Reduces proteinuria more than irbesartan alone in FSGS
- FDA approved for adults with primary IgA nephropathy (2023)
- Pediatric data still limited; being evaluated
- Represents the emerging therapeutic approach of targeting proteinuria through non-immunosuppressive mechanisms
⚡ Key Points — Quick Revision
One-Liners for Exam
- Tetrad of NS: Massive proteinuria + Hypoalbuminemia + Generalized edema + Hyperlipidemia
- Most common cause in children 1–8 years: Minimal Change Disease (MCD) ~85%
- Peak age: 2–6 years; Male:Female = 2:1
- First sign: Periorbital puffiness — worse in morning, improves by evening
- Frothy urine: Due to massive proteinuria (protein lowers surface tension)
- Hypoalbuminemia mechanism: Urinary loss of albumin + reduced synthesis
- Edema mechanism: ↓ Oncotic pressure → fluid to interstitium (underfill) + primary Na+ retention (overfill)
- MCD on biopsy: Normal LM, Negative IF, Foot process effacement on EM
- Protein:creatinine threshold: >200 mg/mmol = nephrotic-range proteinuria
- Serum albumin threshold: <25 g/L (<2.5 g/dL) = hypoalbuminemia of NS
- Biopsy NOT needed: First episode, age 1–12 yrs, typical features, no atypical signs
- TB must be excluded before starting steroids: Mantoux or IGRA
- First episode treatment (KDIGO 2025): Prednisolone 60 mg/m²/day × 4 weeks, then 40 mg/m² alternate day × 4 weeks (8 weeks total)
- Remission = 3 consecutive urine protein-free days (nil/trace on dipstick)
- FRNS: ≥2 relapses in 6 months or ≥4 in 12 months
- SDNS: Relapse during or within 14 days of stopping high-dose steroid
- SRNS: No remission by 6 weeks of standard prednisolone
- SRNS — first-line: Calcineurin inhibitor (Cyclosporine or Tacrolimus) + low-dose alternate-day steroids
- Steroid-sparing agents (FRNS/SDNS): Levamisole, Cyclophosphamide, MMF, Calcineurin inhibitors, Rituximab
- Most dangerous infectious complication: Spontaneous Bacterial Peritonitis (pneumococcus)
- Most dangerous prothrombotic complication: Renal vein thrombosis, cerebral venous sinus thrombosis
- Hypovolemic crisis: Do NOT give diuretics — give IV fluids or 20% albumin infusion
- Vaccinations: Pneumococcal, Varicella — before steroids. No live vaccines during immunosuppression
- Anti-nephrin autoantibodies (2024): Found in MCD — confirms autoimmune B-cell mechanism, validates rituximab use
- PREDNOS trial: 8 weeks = 16 weeks for initial NS — no benefit to prolonging beyond 8–12 weeks
- Genetic SRNS (NPHS1, NPHS2): No response to immunosuppression; transplant is treatment
- Prognosis SSNS: Excellent; very low risk of ESRD. 10–30% "grow out" after puberty
💡 High-yield Calculations
Prednisolone Dose Calculator:
(If BSA not known, it will be estimated from weight using Mosteller formula — requires height)