Pediatric Nephrotic Syndrome

Based on Recent ISPN Guidelines (2021)

1. Definition & Classic Tetrad

Nephrotic Syndrome is a clinical syndrome characterized by a collection of findings resulting from massive renal protein loss.

The Classic Tetrad:

1. Heavy Proteinuria: Urine protein/creatinine ratio (UPCR) >2 mg/mg (or >200 mg/mmol) or 3+/4+ on urine dipstick.
2. Hypoalbuminemia: Serum albumin <3.0 g/dL.
3. Edema: Generalized edema (anasarca) is the clinical hallmark.
4. Hyperlipidemia: Elevated serum cholesterol and triglycerides.

2. Clinical Definitions & Course (ISPN 2021)

The response to steroid therapy defines the clinical course.

• Remission: Urine protein nil or trace (UPCR <0.2 mg/mg) for three consecutive days.
• Relapse: Urine protein ≥3+ (UPCR >2 mg/mg) for three consecutive days after being in remission.

Based on Steroid Response:

• Steroid-Sensitive (SSNS): Achieves complete remission within the initial 6 weeks of high-dose daily steroid therapy.
• Steroid-Resistant (SRNS): Fails to achieve remission despite 6 weeks of daily prednisolone (2 mg/kg/day). This applies to both initial (at first presentation) and late (in a subsequent relapse) resistance.
• Frequently Relapsing (FRNS):
  • ≥2 relapses in the first 6 months after initial therapy.
  • ≥3 relapses in any 6 months.
  • ≥4 relapses in any 12-month period.
• Steroid-Dependent (SDNS): Two consecutive relapses while on alternate-day steroids, or within 14 days of stopping steroid therapy.
• Difficult-to-Treat SSNS: Meets criteria for FRNS/SDNS and has failed treatment with at least two steroid-sparing agents (e.g., levamisole, MMF, cyclophosphamide).

3. Pathophysiology

The primary defect is an injury to the podocytes (glomerular epithelial cells). This leads to a loss of the glomerular filtration barrier's integrity, causing massive proteinuria, subsequent hypoalbuminemia, decreased plasma oncotic pressure, and the resultant edema and hyperlipidemia.

4. Clinical Presentation

• Edema: The hallmark sign, typically starting as periorbital edema and progressing to become generalized (anasarca), with ascites and pitting edema.
• Frothy Urine: Caused by heavy proteinuria.
• Other Symptoms: Fatigue, irritability, abdominal pain. Blood pressure is usually normal in Minimal Change Disease (MCD).

5. Diagnosis & Evaluation

Diagnosis is primarily clinical and biochemical, supported by a kidney biopsy in specific situations.

Initial Investigations:

• Urinalysis: Dipstick for proteinuria (3+/4+) and a spot UPCR to quantify (>2 mg/mg).
• Blood Tests: Serum albumin (<3.0 g/dL), lipid profile, serum creatinine (usually normal), and electrolytes.

Kidney Biopsy:

• Not performed routinely for typical SSNS in children aged 1-12 years (MCD is presumed).
• Key Indications:
  • Steroid Resistance (SRNS) is the chief indication.
  • Age <1 year or >12 years at onset.
  • Atypical features: persistent hypertension, gross hematuria, low complement C3, or significant renal failure not due to hypovolemia.
  • Prior to starting Calcineurin Inhibitors (CNIs) in SSNS (suggested, not mandatory).
  • Prolonged (>30-36 months) CNI therapy to assess for nephrotoxicity.

Genetic Testing (for SRNS):

• Recommended for:
  • Congenital or infantile (<1 year) onset.
  • Family history of SRNS.
  • Syndromic features.
  • Resistance to CNI therapy.
  • Pre-transplant evaluation.
• Patients with a confirmed monogenic cause generally do not respond to immunosuppression.

6. Management (ISPN 2021 Guidelines)

A. Steroid-Sensitive Nephrotic Syndrome (SSNS)

1. Initial Episode (Presumed MCD)

• Corticosteroids: Oral Prednisolone is first-line.
  • Induction: 60 mg/m²/day or 2 mg/kg/day (max 60 mg) for 6 weeks.
  • Taper: 40 mg/m² or 1.5 mg/kg (max 40 mg) on alternate days for 6 weeks, then stop.
  • Note: Recent trials show extending therapy beyond this 12-week course does not reduce relapse risk.

2. Relapses

• Treat with daily Prednisolone (60 mg/m²/day or 2 mg/kg/day) until remission is achieved (urine protein nil/trace for 3 days).
• Follow with alternate-day Prednisolone (40 mg/m²) for 4 weeks.
• For intercurrent infections (e.g., URI): Switch from alternate-day to daily prednisolone at the same dose for 5-7 days to prevent an infection-triggered relapse.

3. Frequently Relapsing / Steroid-Dependent (FRNS/SDNS)

graph TD
                        A[Diagnosis: FRNS / SDNS] --> B(Step 1: Confirm Dx & Assess Steroid Threshold);
                        B --> C{Step 2: Initiate Steroid-Sparing Therapy};
                        C -- First-Line --> D[Levamisole OR MMF];
                        D --> E{Response?};
                        E -- Yes --> F[Maintain Remission, Taper Steroids];
                        E -- 'No: Fails First-Line' --> G(Move to Second-Line);
                        C -- 'Second-Line / High Threshold' --> G;
                        G --> H[Cyclophosphamide OR CNIs];
                        H --> I{Response?};
                        I -- Yes --> F;
                        I -- 'No: Difficult-to-Treat SDNS 
 (Failed 2+ agents)' --> J(Step 3: Manage Difficult-to-Treat);
                        J --> K[CNIs if not already failed];
                        K --> L{Response?};
                        L -- Yes --> F;
                        L -- 'No: CNI Failure/Dependence' --> M[Rituximab];

• Goal: Maintain remission and reduce steroid toxicity. A stepwise approach is used.

Step 1: Confirm the Diagnosis & Assess Steroid Threshold

• Before starting steroid-sparing agents, confirm the diagnosis of SDNS.
• The dose of alternate-day prednisolone at which the patient relapses is known as the "steroid threshold." A high threshold (e.g., >0.7-1 mg/kg on alternate days) indicates more severe disease and a greater need for potent steroid-sparing therapy.

Step 2: Initiate Steroid-Sparing Therapy

The choice of agent depends on the disease severity (steroid threshold), patient age, and risk of side effects.

• First-Line Steroid-Sparing Agents:

  • Levamisole: An immunomodulator. It is often a first choice, especially for patients with a lower steroid threshold. It is generally well-tolerated.
  • Mycophenolate Mofetil (MMF): An immunosuppressant that is also a common first-line choice. ISPN guidelines suggest MMF may be more effective than levamisole in patients with SDNS.
  • Goal: These medications are added to the current steroid regimen, with the aim of slowly tapering and discontinuing the prednisolone over several months.

• Second-Line / More Potent Agents:

  Used for patients who fail or have an inadequate response to Levamisole or MMF, or for those with a very high steroid threshold and significant steroid toxicity from the outset.

  • Cyclophosphamide: An alkylating agent given as a single 8-12 week oral course. It can induce long-term remission but carries risks of gonadal toxicity (especially in peri-pubertal boys) and is therefore used cautiously.
  • Calcineurin Inhibitors (CNIs): Tacrolimus or Cyclosporine. These are highly effective for maintaining remission but require therapeutic drug monitoring and can cause nephrotoxicity with long-term use. They are a key therapy for "Difficult-to-Treat" cases.

Step 3: Management of "Difficult-to-Treat" SDNS

This category is for patients with SDNS who have failed treatment with at least two of the standard steroid-sparing agents (Levamisole, MMF, Cyclophosphamide).

• Calcineurin Inhibitors (CNIs): If not already used, CNIs are the next step.
• Rituximab: A monoclonal antibody that depletes B-cells. This is reserved for patients who have failed or are dependent on CNIs, or have significant toxicity from them. It can induce prolonged, drug-free remission but carries risks of infusion reactions and hypogammaglobulinemia.

B. Steroid-Resistant Nephrotic Syndrome (SRNS)

This follows a structured, stepwise algorithm:

graph TD
    A["Diagnosis: Steroid-Resistant 
 NS -SRNS"] --> B{"Genetic Testing Done?"};
    B -- "Yes: Monogenic SRNS" --> C["Supportive Care ONLY 
ACEi/ARB, KRT prep 
 No Immunosuppression"];
    B -- "No: Non-Genetic SRNS" --> D("Step 1: First-Line Therapy");
    D --> E["Calcineurin Inhibitor -CNI 
+ Prednisolone Taper"];
    E --> F("Step 2: Assess Response 
at 6 Months");
    F --> G{"Response?"};
    G -- "Complete/Partial Remission" --> H["Continue CNI for >= 24 Months"];
    H --> I{"Relapses on Taper? 
CNI-Dependent"};
    I -- "Yes" --> J["Continue low-dose CNI 
OR
 Switch to Rituximab/MMF"];
    I -- "No" --> K["Continue Taper / Stop"];
    G -- "No Response: CNI-Resistant SRNS" --> L("Manage CNI-Resistance");
    L --> M["First: Re-check/Rule 
out Genetic Cause"];
    M --> N{"Choose Add-On Therapy"};
    N --> O["Option 1: 
Add Rituximab"];
    N --> P["Option 2: 
Add MMF 
(Triple Therapy)"];
    O --> Q{"Response?"};
    P --> Q;
    Q -- "Yes" --> R["Continue Therapy"];
    Q -- "No: Continued Non-Response" --> S["Withdraw Immunosuppression, 
 Supportive Care (ACEi/ARB)"];

A. Management of Monogenic SRNS

• Immunosuppression is NOT recommended. These patients do not respond, and therapy only adds toxicity.
• Management is supportive:
  • ACE inhibitors or ARBs: To control proteinuria and blood pressure.
  • Nutritional support, edema management.
  • Eventual preparation for Kidney Replacement Therapy (KRT).

B. Management of Non-Genetic SRNS

This follows a structured, stepwise algorithm:

Step 1: First-Line Therapy

• Calcineurin Inhibitors (CNIs): This is the cornerstone of treatment.
  • Agent: Tacrolimus is generally preferred over Cyclosporine due to a better side-effect profile (no hirsutism or gum hypertrophy).
  • Dosing: Titrated to achieve target trough blood levels (Tacrolimus: 4-8 ng/mL).
  • Duration: If remission (complete or partial) is achieved, CNI therapy should be continued for at least 24 months.
  • Steroids: CNIs are given along with alternate-day prednisolone, which is slowly tapered over 6-9 months.

Step 2: Assessing Response & Managing CNI Resistance

• Response Assessment: Patients are assessed after 6 months of adequate CNI therapy.
  • Complete/Partial Remission: Continue CNI for at least 24 months.
  • Non-Response (CNI-Resistant SRNS): This is a critical branch point. First, rule out a genetic cause if not already done.
• Management of CNI-Resistant SRNS:
  • Option 1: Add Rituximab: Administer 2-4 doses of IV Rituximab while continuing the CNI.
  • Option 2: Add Mycophenolate Mofetil (MMF): Create a "triple therapy" regimen of CNI + MMF + low-dose steroids.
  • Note: These are intensive regimens for difficult-to-treat disease and should be managed by a pediatric nephrologist.

Step 3: Long-Term Management & Relapses

• For CNI-Dependent Patients: For those who achieve remission but relapse when the CNI is tapered, options include:
  • Continuing the CNI at the lowest effective dose.
  • Switching to Rituximab or MMF to reduce CNI exposure and toxicity.
• For Patients with Continued Non-Response: If the patient fails CNI therapy and subsequent add-on therapies (Rituximab/MMF), immunosuppression is generally withdrawn, and care becomes supportive, focusing on slowing CKD progression.

What about Cyclophosphamide?

• IV Cyclophosphamide: Considered an alternate therapy, but it is inferior to CNIs for inducing remission in SRNS. It may be used if CNIs are unavailable or contraindicated.
• Oral Cyclophosphamide: NOT recommended for the treatment of SRNS.

7. Supportive Care & Complications

Anti-Proteinuric Therapy:

ACE inhibitors or ARBs are recommended for ALL patients with SRNS to reduce proteinuria and for renoprotection.

Edema Management:*

• Assess for Hypovolemia: Check for tachycardia, poor perfusion, or postural hypotension before giving diuretics. If present, give IV normal saline or albumin.
• No Hypovolemia: Manage with salt restriction. For moderate/severe edema, use oral Furosemide. Refractory edema may require IV furosemide or adding a thiazide diuretic.
• Severe Refractory Edema: IV albumin infusion followed immediately by IV furosemide

Infection:

• High risk, especially for Spontaneous Bacterial Peritonitis (SBP) caused by Streptococcus pneumoniae.
• Immunizations are crucial. Give pneumococcal (PCV13 + PPSV23), varicella, and annual influenza vaccines, preferably during remission and on low-dose immunosuppression.

Thromboembolism:

• High risk due to a hypercoagulable state.
• Prophylactic anticoagulation is not routine, but consider non-pharmacologic measures (hydration, ambulation).

Hyperlipidemia & Cardiovascular Risk:

• Manage with diet and lifestyle changes.
• Statins may be considered for persistent severe hyperlipidemia, especially in SRNS.