Nephrotic Syndrome in Children

Introduction to Nephrotic Syndrome in Children

Nephrotic syndrome is a kidney disorder characterized by heavy proteinuria, hypoalbuminemia, edema, and hyperlipidemia. It is one of the most common glomerular diseases in children, with an incidence of 2-7 per 100,000 children per year. The peak incidence occurs between 2-8 years of age, with a male predominance (2:1 ratio).

Nephrotic syndrome in children is typically classified into two main categories:

Primary (idiopathic) nephrotic syndrome: No identifiable underlying cause
Secondary nephrotic syndrome: Associated with systemic diseases, infections, or drug reactions

In children, about 90% of cases are primary, with minimal change disease (MCD) being the most common histological finding (80-90% of cases in children under 10 years).

Etiology of Nephrotic Syndrome in Children

The etiology of nephrotic syndrome in children varies depending on whether it is primary or secondary:

Primary (Idiopathic) Nephrotic Syndrome:

Minimal Change Disease (MCD): Most common cause in children (80-90%)
Focal Segmental Glomerulosclerosis (FSGS): 10-20% of cases
Membranous Nephropathy: Rare in children (<5%)
Membranoproliferative Glomerulonephritis: Rare in children

Secondary Nephrotic Syndrome:

Infections: Hepatitis B, Hepatitis C, HIV, Malaria
Systemic diseases: Systemic Lupus Erythematosus, Henoch-Schönlein purpura, Diabetes mellitus
Medications: NSAIDs, Penicillamine, Gold, Bismuth
Genetic disorders: Congenital nephrotic syndrome (Finnish type), Alport syndrome
Malignancies: Lymphoma, Leukemia
Allergies: Food allergies, Insect stings

Pathophysiology of Nephrotic Syndrome in Children

The pathophysiology of nephrotic syndrome involves complex interactions between the immune system, podocytes, and glomerular basement membrane:

Podocyte Injury: The primary event is damage to podocytes, specialized epithelial cells that form part of the glomerular filtration barrier. This leads to effacement of podocyte foot processes and alterations in the slit diaphragm.
Increased Glomerular Permeability: Podocyte injury results in increased permeability of the glomerular filtration barrier, allowing proteins (primarily albumin) to pass into the urine.
Proteinuria: Excessive protein loss in urine, typically >40 mg/m²/hour or a urine protein/creatinine ratio >2.0 mg/mg.
Hypoalbuminemia: As a result of protein loss, serum albumin levels decrease (<2.5 g/dL).
Edema: Decreased plasma oncotic pressure due to hypoalbuminemia leads to fluid shift from intravascular to interstitial space, causing edema.
Hyperlipidemia: Increased hepatic synthesis of lipoproteins and decreased catabolism of lipids contribute to elevated cholesterol and triglyceride levels.
Hypercoagulability: Loss of anticoagulant proteins in urine and increased production of procoagulant factors by the liver increase the risk of thrombosis.
Immune Dysregulation: In MCD, there's evidence of T-cell dysfunction leading to the production of a circulating factor that alters podocyte function.

In minimal change disease, the glomeruli appear normal under light microscopy, but electron microscopy reveals podocyte foot process effacement. In contrast, FSGS shows focal and segmental sclerosis of glomeruli, visible under light microscopy.

Clinical Presentation of Nephrotic Syndrome in Children

The clinical presentation of nephrotic syndrome in children typically includes:

Cardinal Features:

Edema: The most common presenting symptom
- Often starts periorbital, worse in the morning
- Progresses to lower extremities, genitalia, and can lead to anasarca
Proteinuria: >40 mg/m²/hour or urine protein/creatinine ratio >2.0 mg/mg
Hypoalbuminemia: Serum albumin <2.5 g/dL
Hyperlipidemia: Elevated cholesterol and triglycerides

Other Common Symptoms and Signs:

Weight gain due to fluid retention
Fatigue and lethargy
Decreased urine output (oliguria)
Anorexia and sometimes abdominal pain
Frothy urine due to high protein content
Pallor due to fluid retention and sometimes anemia
Respiratory distress if pleural effusions develop
Hypertension (in some cases)

Age-Specific Considerations:

Infants: May present with failure to thrive, irritability, and recurrent infections
Older Children: May report swelling, particularly around the eyes and legs

It's important to note that the severity of symptoms can vary, and some children may present with subtle signs that progress over time. Additionally, the clinical presentation may differ in cases of secondary nephrotic syndrome, where symptoms of the underlying condition may be present.

Diagnosis of Nephrotic Syndrome in Children

Diagnosis of nephrotic syndrome in children involves a combination of clinical assessment, laboratory tests, and sometimes imaging studies:

1. Clinical Evaluation:

Detailed history, including onset and progression of symptoms, family history, recent infections, and medication use
Physical examination, focusing on edema, blood pressure, and signs of underlying systemic diseases

2. Laboratory Tests:

Urinalysis:
- Dipstick: 3+ or 4+ protein
- Microscopy: Lipid droplets (oval fat bodies), fatty casts
Quantification of Proteinuria:
- 24-hour urine collection: >40 mg/m²/hour or >50 mg/kg/day
- Spot urine protein/creatinine ratio: >2.0 mg/mg
Serum Studies:
- Albumin: <2.5 g/dL
- Lipid profile: Elevated total cholesterol, LDL, triglycerides
- Renal function tests: BUN, creatinine
- Electrolytes, including calcium
Complement Levels (C3, C4): Usually normal in MCD, may be low in secondary causes
Infectious Disease Screening: Hepatitis B, Hepatitis C, HIV (as indicated)
Autoimmune Workup: ANA, anti-dsDNA (if systemic disease suspected)

3. Imaging Studies:

Renal Ultrasound: To assess kidney size and echogenicity, rule out structural abnormalities
Chest X-ray: If respiratory symptoms present, to evaluate for pleural effusions

4. Renal Biopsy:

Not routinely performed in all cases. Indications include:

Age <1 year or >12 years at onset
Persistent hypertension or hematuria
Low C3 complement level
Impaired renal function not attributable to hypovolemia
Steroid resistance or frequent relapses
Suspicion of secondary causes

5. Genetic Testing:

Considered in cases of congenital or familial nephrotic syndrome, or in steroid-resistant cases.

The diagnosis of nephrotic syndrome is typically made when a child presents with edema, heavy proteinuria (>40 mg/m²/hour), hypoalbuminemia (<2.5 g/dL), and hyperlipidemia. In most cases of primary nephrotic syndrome in children, especially those responsive to steroids, a presumptive diagnosis of minimal change disease is made without the need for a renal biopsy.

Treatment of Nephrotic Syndrome in Children

The treatment of nephrotic syndrome in children aims to induce remission, prevent complications, and minimize long-term side effects. The approach varies based on the underlying cause and response to initial therapy:

1. General Measures:

Fluid and sodium restriction
High-protein diet (2 g/kg/day) during active disease
Calcium and Vitamin D supplementation if on prolonged steroid therapy
Immunizations (avoid live vaccines if on immunosuppression)

2. Pharmacological Treatment:

A. Initial Treatment (Presumed Minimal Change Disease):

Corticosteroids: First-line therapy
- Prednisone 60 mg/m²/day or 2 mg/kg/day (max 60 mg/day) for 4-6 weeks
- Followed by 40 mg/m²/alternate day or 1.5 mg/kg/alternate day for 4-6 weeks
- Gradual taper over 2-3 months

B. Frequently Relapsing or Steroid-Dependent Nephrotic Syndrome:

Steroid-sparing agents:
- Cyclophosphamide: 2-3 mg/kg/day for 8-12 weeks
- Mycophenolate mofetil (MMF): 1200 mg/m²/day in two divided doses
- Calcineurin inhibitors (Cyclosporine, Tacrolimus)
- Rituximab: Consider in difficult cases

C. Steroid-Resistant Nephrotic Syndrome:

Calcineurin inhibitors (first-line for steroid resistance)
Consider renal biopsy if not done previously
Rituximab or other novel therapies in selected cases

3. Management of Complications:

Edema: Diuretics (furosemide, spironolactone) if severe
Infections: Prompt antibiotic treatment
Thromboembolism: Anticoagulation if high risk or symptomatic
Hypertension: ACE inhibitors or ARBs
Hyperlipidemia: Statins in persistent cases (usually in older children)

4. Supportive Care:

Regular monitoring of growth, blood pressure, and renal function
Psychosocial support for children and families
Education about disease management and when to seek medical attention

5. Treatment of Secondary Causes:

If a secondary cause is identified, treatment should be directed at the underlying condition in addition to managing the nephrotic syndrome.

The treatment approach should be individualized based on the child's age, disease severity, and response to therapy. Close monitoring is essential to assess treatment efficacy and detect potential side effects of immunosuppressive medications.

Complications of Nephrotic Syndrome in Children

Nephrotic syndrome in children can lead to various complications, both acute and chronic. Awareness and prompt management of these complications are crucial for improving outcomes:

1. Infections:

Bacterial infections: Particularly pneumococcal infections, peritonitis, cellulitis, and urinary tract infections
Viral infections: Increased susceptibility to varicella and other viral illnesses
Reasons for increased infection risk:
- Loss of immunoglobulins in urine
- Decreased complement activity
- Immunosuppressive therapy

2. Thromboembolism:

Increased risk due to loss of anticoagulant proteins, hyperviscosity, and immobilization
Common sites: Renal veins, deep veins of legs, pulmonary arteries
Risk factors: Severe hypoalbuminemia, infection, dehydration

3. Acute Kidney Injury (AKI):

Can occur due to hypovolemia, sepsis, or nephrotoxic medications
May be exacerbated by renal vein thrombosis

4. Cardiovascular Complications:

Hypertension: Due to fluid overload or as a complication of treatment
Hyperlipidemia: Increases long-term cardiovascular risk

5. Endocrine and Metabolic Complications:

Growth retardation: Due to chronic disease and prolonged steroid use
Hypothyroidism: Loss of thyroid-binding proteins in urine
Vitamin D deficiency and hypocalcemia: Loss of vitamin D-binding protein

6. Medication-related Complications:

Steroid-related: Cushing's syndrome, growth suppression, osteoporosis, cataracts
Calcineurin inhibitor-related: Nephrotoxicity, hypertension, hirsutism
Alkylating agent-related: Bone marrow suppression, increased cancer risk

7. Psychological and Social Complications:

Depression and anxiety
Poor school performance due to frequent absences
Body image issues related to edema and medication side effects

8. Progression to Chronic Kidney Disease (CKD):

More common in steroid-resistant cases or those with FSGS
Can lead to end-stage renal disease (ESRD) requiring dialysis or transplantation

Early recognition and appropriate management of these complications are essential for improving the quality of life and long-term outcomes in children with nephrotic syndrome. Regular follow-up, patient and family education, and a multidisciplinary approach are key to preventing and addressing these complications effectively.

Prognosis of Nephrotic Syndrome in Children

The prognosis of nephrotic syndrome in children varies depending on the underlying cause, response to treatment, and the occurrence of complications. Here's an overview of prognostic factors and outcomes:

1. Steroid-Sensitive Nephrotic Syndrome (SSNS):

Generally good long-term prognosis
80-90% of children with minimal change disease (MCD) respond to initial steroid therapy
About 60-70% experience relapses, with most occurring within the first year
Frequency of relapses typically decreases with age, with many achieving long-term remission by adulthood
Normal renal function is usually preserved in the long term

2. Frequently Relapsing and Steroid-Dependent Nephrotic Syndrome:

Higher risk of treatment-related complications due to prolonged or repeated courses of steroids
May require additional immunosuppressive agents
Generally maintain normal renal function but may have a more complicated course

3. Steroid-Resistant Nephrotic Syndrome (SRNS):

Poorer prognosis compared to SSNS
Higher risk of progression to chronic kidney disease and end-stage renal disease
About 50% of children with SRNS may progress to ESRD within 5-10 years
Prognosis varies based on underlying histology (e.g., FSGS has a worse prognosis than MCD)

4. Congenital and Infantile Nephrotic Syndrome:

Generally poor prognosis without aggressive management
Many require early nephrectomy and renal replacement therapy
Outcomes have improved with advances in supportive care and renal transplantation

5. Secondary Nephrotic Syndrome:

Prognosis depends on the underlying cause and its treatment
Some causes (e.g., postinfectious) may have a good prognosis with appropriate management

6. Factors Affecting Prognosis:

Age at onset (younger age at onset generally associated with better outcomes)
Initial response to steroids
Frequency of relapses
Presence of hematuria or hypertension
Development of complications
Adherence to treatment and follow-up

7. Long-term Considerations:

Growth and development: May be affected by disease course and treatment
Cardiovascular risk: Increased due to chronic inflammation and lipid abnormalities
Bone health: Risk of osteoporosis due to prolonged steroid use
Fertility: Generally preserved, but may be affected in some cases of genetic forms or after certain treatments

Overall, the majority of children with nephrotic syndrome have a favorable long-term prognosis, especially those with steroid-sensitive disease. However, the course can be unpredictable, and long-term follow-up is essential. Advances in understanding the genetic basis of the disease and new targeted therapies are expected to improve outcomes further in the future.

Minimal Change Disease (MCD)

Introduction

Minimal Change Disease is the most common cause of nephrotic syndrome in children, accounting for approximately 80-90% of cases in children under 10 years of age. It is characterized by the absence of visible changes in the glomeruli under light microscopy, hence the name "minimal change."

Etiology

The exact cause is unknown, but it is believed to involve immune system dysfunction
Proposed mechanisms include:
- T-cell dysfunction leading to the production of a circulating factor that alters podocyte function
- Direct podocyte injury
- Alterations in the glomerular basement membrane charge
Occasionally associated with:
- Allergies
- Viral infections
- Medications (e.g., NSAIDs)

Pathophysiology

Normal appearance under light microscopy
Electron microscopy reveals:
- Effacement (flattening) of podocyte foot processes
- No immune complex deposits
Immunofluorescence is typically negative
Increased permeability of the glomerular filtration barrier leads to proteinuria

Clinical Presentation

Sudden onset of edema, often first noticed around the eyes
Massive proteinuria (>40 mg/m²/hour or urine protein/creatinine ratio >2.0 mg/mg)
Hypoalbuminemia (<2.5 g/dL)
Hyperlipidemia
Generally normal blood pressure
Usually no hematuria (if present, it's typically microscopic)

Diagnosis

Clinical presentation and laboratory findings consistent with nephrotic syndrome
Urine protein electrophoresis showing selective proteinuria (predominantly albumin)
Normal complement levels
Renal biopsy is not routinely performed if:
- Age is between 1-10 years
- There's no hematuria or hypertension
- Normal complement levels
- Good response to initial steroid therapy

Treatment

Initial treatment: Corticosteroids
- Prednisone 60 mg/m²/day or 2 mg/kg/day (max 60 mg/day) for 4-6 weeks
- Followed by 40 mg/m²/alternate day or 1.5 mg/kg/alternate day for 4-6 weeks
- Gradual taper over 2-3 months
For frequent relapses or steroid-dependent cases:
- Cyclophosphamide
- Mycophenolate mofetil
- Calcineurin inhibitors (cyclosporine, tacrolimus)
- Rituximab (in selected cases)
Supportive care: Diuretics, ACE inhibitors, statins as needed

Prognosis

Excellent long-term prognosis
90-95% initial response rate to steroids
60-70% experience relapses, but frequency typically decreases with age
Most achieve long-term remission by adulthood
Very low risk of progression to chronic kidney disease

Focal Segmental Glomerulosclerosis (FSGS)

Introduction

Focal Segmental Glomerulosclerosis is the second most common cause of nephrotic syndrome in children, accounting for about 10-20% of cases. It is characterized by scarring (sclerosis) in some, but not all (focal) glomeruli, and only in parts (segmental) of the affected glomeruli.

Etiology

Primary (idiopathic) FSGS
Secondary causes:
- Genetic mutations (e.g., NPHS2, WT1, ACTN4)
- Viral infections (e.g., HIV, parvovirus B19)
- Drug toxicity (e.g., heroin, interferon, lithium)
- Adaptive responses (e.g., obesity, hypertension, reflux nephropathy)

Pathophysiology

Initial podocyte injury leads to:
- Detachment of podocytes from the glomerular basement membrane
- Adhesion of the capillary tuft to Bowman's capsule
- Progressive scarring and collapse of capillary loops
Light microscopy: Focal and segmental areas of sclerosis in glomeruli
Electron microscopy: Effacement of podocyte foot processes
Immunofluorescence: Usually negative or with non-specific IgM and C3 deposits

Clinical Presentation

Can present at any age, but more common in older children and adolescents
Nephrotic syndrome: Edema, proteinuria, hypoalbuminemia, hyperlipidemia
More likely to have hypertension compared to MCD
May have microscopic hematuria
Some patients may present with non-nephrotic proteinuria
Renal function may be impaired at presentation or decline over time

Diagnosis

Clinical presentation and laboratory findings consistent with nephrotic syndrome
Renal biopsy is required for definitive diagnosis, showing:
- Focal and segmental glomerulosclerosis
- Variants: Cellular, tip, perihilar, collapsing, and not otherwise specified (NOS)
Genetic testing may be indicated, especially in steroid-resistant cases or family history

Treatment

Initial treatment: Corticosteroids
- Similar regimen to MCD, but may require a longer course (up to 12 weeks)
For steroid-resistant cases:
- Calcineurin inhibitors (cyclosporine, tacrolimus) - first-line for steroid resistance
- Mycophenolate mofetil
- Rituximab (in selected cases)
Supportive therapy:
- ACE inhibitors or ARBs for proteinuria and hypertension
- Statins for hyperlipidemia
- Diuretics for edema management
Treatment of secondary causes if identified

Prognosis

Generally poorer prognosis compared to MCD
10-20% initial response rate to steroids
50-60% of patients may progress to end-stage renal disease within 5-10 years
Risk factors for poor prognosis:
- Steroid resistance
- Persistent proteinuria
- Hypertension
- Elevated serum creatinine at presentation
- Collapsing variant on histology
Recurrence rate of 30-50% after kidney transplantation

Membranous Nephropathy (MN)

Introduction

Membranous Nephropathy is an uncommon cause of nephrotic syndrome in children, accounting for less than 5% of cases. It is characterized by the uniform thickening of the glomerular basement membrane due to subepithelial immune complex deposits.

Etiology

Primary (idiopathic) MN:
- Associated with anti-PLA2R antibodies in some cases (more common in adults)
Secondary causes:
- Infections: Hepatitis B, malaria, syphilis
- Autoimmune diseases: Systemic lupus erythematosus (SLE)
- Medications: NSAIDs, gold, penicillamine
- Malignancies (rare in children)

Pathophysiology

Formation of immune complexes in situ or deposition of circulating immune complexes
Activation of complement cascade
Injury to the glomerular filtration barrier, leading to proteinuria
Light microscopy: Thickening of the glomerular basement membrane
Electron microscopy: Subepithelial electron-dense deposits, "spike and dome" appearance
Immunofluorescence: Granular deposits of IgG and C3 along the glomerular basement membrane

Clinical Presentation

Often presents with full nephrotic syndrome: Edema, proteinuria, hypoalbuminemia, hyperlipidemia
Can also present with asymptomatic proteinuria
Microscopic hematuria in about 50% of cases
Hypertension may be present
Renal function usually normal at presentation

Diagnosis

Clinical presentation and laboratory findings consistent with nephrotic syndrome
Renal biopsy is required for definitive diagnosis, showing:
- Thickened glomerular basement membrane
- Subepithelial immune complex deposits
- Granular IgG and C3 deposits on immunofluorescence
Serological tests:
- Anti-PLA2R antibodies (if positive, suggests primary MN)
- ANA, anti-dsDNA, complement levels (to rule out lupus)
- Hepatitis B and C serologies
Age-appropriate cancer screening in selected cases

Treatment

For secondary MN: Treat the underlying cause
For primary MN:
- Conservative therapy for 6-12 months in children with normal renal function and non-severe proteinuria
- Immunosuppressive therapy for persistent nephrotic syndrome or declining renal function:
  - Alternating months of corticosteroids and alkylating agents (cyclophosphamide)
  - Calcineurin inhibitors (cyclosporine, tacrolimus)
  - Rituximab (especially in anti-PLA2R positive cases)
Supportive therapy:
- ACE inhibitors or ARBs for proteinuria
- Statins for hyperlipidemia
- Anticoagulation if high risk of thrombosis

Prognosis

Variable course, generally better in children compared to adults
Spontaneous remission can occur in up to 50% of cases, especially in children
Factors associated with poor prognosis:
- Persistent heavy proteinuria
- Impaired renal function at presentation
- High levels of anti-PLA2R antibodies
Risk of progression to end-stage renal disease:
- Lower in children compared to adults
- Approximately 10-20% over 10 years in treated cases
Recurrence rate of about 40-50% after kidney transplantation
Long-term follow-up is essential due to the risk of relapse

Membranoproliferative Glomerulonephritis (MPGN)

Introduction

Membranoproliferative Glomerulonephritis, also known as Mesangiocapillary Glomerulonephritis, is a rare cause of nephrotic syndrome in children. It is characterized by mesangial hypercellularity and thickening of the glomerular basement membrane.

Etiology

Primary (idiopathic) MPGN
Secondary causes:
- Infections: Hepatitis B and C, chronic bacterial infections
- Autoimmune diseases: Systemic lupus erythematosus, Sjögren's syndrome
- Complement disorders: C3 glomerulopathy (C3 glomerulonephritis and dense deposit disease)
- Monoclonal gammopathies (rare in children)

Pathophysiology

Classified based on immune complex deposition and complement activation:
- Immune complex-mediated MPGN (with IgG deposits)
- Complement-mediated MPGN (C3 glomerulopathy)
Light microscopy: Mesangial hypercellularity, thickening of capillary walls, double contours ("tram-track" appearance)
Electron microscopy: Subendothelial deposits, mesangial interposition
Immunofluorescence:
- Immune complex MPGN: IgG, C3, and often IgM deposits
- C3 glomerulopathy: Dominant C3 staining with minimal or no immunoglobulin

Clinical Presentation

Can present with nephrotic syndrome, nephritic syndrome, or a mixed picture
Proteinuria (often in nephrotic range)
Hematuria (microscopic or macroscopic)
Hypertension
Edema
Renal insufficiency may be present at diagnosis

Diagnosis

Clinical presentation and laboratory findings
Renal biopsy is essential for diagnosis, showing:
- Characteristic light microscopy findings
- Electron microscopy to determine deposit location
- Immunofluorescence to differentiate immune complex vs. complement-mediated forms
Additional tests:
- Complement levels (C3, C4)
- Autoimmune markers (ANA, ANCA)
- Hepatitis B and C serologies
- Genetic testing for complement regulatory proteins in suspected C3 glomerulopathy

Treatment

For secondary MPGN: Treat the underlying cause
For primary MPGN:
- Corticosteroids
- Immunosuppressive agents: Cyclophosphamide, mycophenolate mofetil
- Rituximab in selected cases
For C3 glomerulopathy:
- Eculizumab (complement inhibitor) in some cases
- Plasma exchange for dense deposit disease
Supportive therapy:
- ACE inhibitors or ARBs for proteinuria and hypertension
- Statins for hyperlipidemia

Prognosis

Generally poor compared to other forms of nephrotic syndrome in children
Risk factors for poor prognosis:
- Persistent nephrotic-range proteinuria
- Hypertension
- Elevated creatinine at presentation
Progression to end-stage renal disease:
- 50% at 10 years for immune complex-mediated MPGN
- Higher rates for C3 glomerulopathy, especially dense deposit disease
Recurrence after kidney transplantation is common, especially in C3 glomerulopathy

Congenital Nephrotic Syndrome (CNS)

Introduction

Congenital Nephrotic Syndrome refers to nephrotic syndrome presenting within the first 3 months of life. It is a rare condition, often caused by genetic mutations affecting podocyte structure and function.

Etiology

Genetic causes:
- NPHS1 mutations (Finnish-type CNS)
- NPHS2 mutations (podocin)
- WT1 mutations
- LAMB2 mutations (Pierson syndrome)
Non-genetic causes (less common):
- Congenital infections: Syphilis, toxoplasmosis, cytomegalovirus
- Maternal systemic lupus erythematosus

Pathophysiology

Genetic mutations lead to structural or functional defects in podocytes or glomerular basement membrane components
Resulting in severe, persistent proteinuria from birth or early infancy
Light microscopy findings vary depending on the specific genetic cause
Electron microscopy typically shows extensive foot process effacement

Clinical Presentation

Proteinuria present at birth or within the first 3 months of life
Large placenta (25% or more of birth weight) in Finnish-type CNS
Edema, which may be present at birth or develop in early infancy
Failure to thrive
Recurrent infections
Hypothyroidism due to loss of thyroid-binding proteins
Associated extra-renal manifestations in some genetic forms (e.g., eye abnormalities in Pierson syndrome)

Diagnosis

Clinical presentation of nephrotic syndrome in early infancy
Laboratory findings:
- Massive proteinuria
- Hypoalbuminemia
- Hyperlipidemia
Genetic testing to identify specific mutations
Renal biopsy may be performed, but genetic testing is often more informative
Prenatal diagnosis possible in subsequent pregnancies if genetic mutation is identified

Treatment

Supportive care is the mainstay of treatment:
- Albumin infusions
- Nutritional support with high-protein, high-calorie diet
- Thyroid hormone replacement
- Immunoglobulin replacement
- Anticoagulation if indicated
Management of complications (infections, thrombosis)
Bilateral nephrectomy may be considered to control protein losses
Dialysis as a bridge to transplantation
Kidney transplantation is the definitive treatment

Prognosis

Generally poor without aggressive management and kidney transplantation
Most patients progress to end-stage renal disease in infancy or early childhood
Survival has improved significantly with advances in supportive care and transplantation
Post-transplant outcomes are generally good, with low recurrence risk for genetic forms
Long-term complications may include growth retardation and neurodevelopmental delays

Minimal Change Disease (MCD)

What is Minimal Change Disease (MCD)?
Answer: A kidney disorder characterized by nephrotic syndrome with minimal or no visible changes on light microscopy of kidney biopsy
What age group is most commonly affected by MCD?
Answer: Children aged 2-6 years
What is the most common presenting symptom of MCD in children?
Answer: Edema, particularly periorbital edema
What is the characteristic feature of MCD on electron microscopy?
Answer: Diffuse effacement of podocyte foot processes
What is the typical range of proteinuria in MCD?
Answer: >40 mg/m²/hour or >50 mg/kg/day
What is the first-line treatment for MCD in children?
Answer: Oral corticosteroids (prednisone or prednisolone)
What percentage of children with MCD respond to initial steroid therapy?
Answer: Approximately 80-90%
How long does it typically take for remission to occur after starting steroid therapy in MCD?
Answer: Within 2-4 weeks
What is the definition of steroid-sensitive nephrotic syndrome?
Answer: Complete remission achieved within 4 weeks of daily steroid therapy
What is the definition of steroid-resistant nephrotic syndrome in MCD?
Answer: Failure to achieve remission after 8 weeks of daily steroid therapy
What is the risk of relapse in children with MCD?
Answer: 60-80% of children experience at least one relapse
What is the most common complication of MCD in children?
Answer: Infections, particularly bacterial infections
What is the role of genetic testing in MCD?
Answer: Generally not indicated in typical cases, but may be considered in steroid-resistant or early-onset cases
How does MCD affect lipid metabolism?
Answer: It leads to hyperlipidemia, particularly hypercholesterolemia
What is the mechanism of edema formation in MCD?
Answer: Combination of hypoalbuminemia and sodium retention
What is the role of cyclophosphamide in treating MCD?
Answer: Used in frequently relapsing or steroid-dependent cases to induce longer remissions
How does MCD differ from focal segmental glomerulosclerosis (FSGS) on kidney biopsy?
Answer: MCD shows no glomerular scarring, while FSGS has focal and segmental scarring
What is the long-term prognosis for children with MCD?
Answer: Generally excellent, with most children outgrowing the disease by adulthood
What is the role of calcineurin inhibitors (e.g., cyclosporine, tacrolimus) in MCD treatment?
Answer: Used as steroid-sparing agents in frequently relapsing or steroid-dependent cases
How does MCD affect the immune system?
Answer: Associated with T-cell dysfunction and possibly increased IgE levels
What is the significance of selectivity index in MCD?
Answer: Highly selective proteinuria (mainly albumin) is characteristic of MCD
How does MCD affect vitamin D metabolism?
Answer: Can lead to vitamin D deficiency due to loss of vitamin D-binding protein in urine
What is the role of rituximab in treating MCD?
Answer: Used in some cases of frequently relapsing or steroid-dependent disease
How does MCD affect growth and development in children?
Answer: Repeated courses of steroids can lead to growth retardation; disease itself can affect nutrition
What is the significance of podocyte injury in the pathogenesis of MCD?
Answer: Podocyte foot process effacement is the hallmark of MCD, leading to proteinuria
How does MCD affect blood pressure in children?
Answer: Usually normal, but hypertension can occur due to fluid retention
What is the role of levamisole in MCD treatment?
Answer: Used as a steroid-sparing agent in frequently relapsing cases
How does MCD affect thromboembolic risk in children?
Answer: Increased risk due to loss of anticoagulant proteins in urine and hyperfibrinogenemia
What is the significance of CD80 (B7-1) in MCD pathogenesis?
Answer: Increased podocyte expression of CD80 may play a role in disease development
How does MCD differ in presentation between children and adults?
Answer: More common and typically more responsive to steroids in children compared to adults

Focal Segmental Glomerulosclerosis (FSGS)

What is Focal Segmental Glomerulosclerosis (FSGS)?
Answer: A kidney disease characterized by scarring (sclerosis) in some, but not all (focal) glomeruli, affecting only parts (segmental) of the affected glomeruli
What are the main types of FSGS?
Answer: Primary (idiopathic) and secondary FSGS
What is the most common presenting symptom of FSGS in children?
Answer: Nephrotic syndrome (edema, proteinuria, hypoalbuminemia)
How does FSGS differ from Minimal Change Disease (MCD) in terms of steroid response?
Answer: FSGS is generally less responsive to steroids compared to MCD
What are the five histological variants of FSGS?
Answer: Tip, cellular, collapsing, perihilar, and not otherwise specified (NOS)
Which FSGS variant has the worst prognosis?
Answer: Collapsing variant
What is the role of genetic testing in FSGS?
Answer: To identify genetic causes, particularly in steroid-resistant or familial cases
Name three genes commonly associated with genetic forms of FSGS.
Answer: NPHS1, NPHS2, WT1
What is the first-line treatment for primary FSGS in children?
Answer: High-dose corticosteroids
What percentage of children with primary FSGS typically respond to initial steroid therapy?
Answer: Approximately 20-30%
What is the role of calcineurin inhibitors in FSGS treatment?
Answer: Used as second-line therapy in steroid-resistant cases
How does FSGS affect kidney function in the long term?
Answer: Can lead to progressive kidney failure if not adequately controlled
What is the significance of suPAR (soluble urokinase plasminogen activator receptor) in FSGS?
Answer: Elevated levels may be associated with disease activity and recurrence after transplantation
How does obesity contribute to secondary FSGS?
Answer: Through increased glomerular hyperfiltration and mechanical stress on podocytes
What is the role of rituximab in treating FSGS?
Answer: Used in some cases of steroid-resistant or recurrent FSGS, particularly post-transplant
How does FSGS differ from MCD on electron microscopy?
Answer: FSGS shows areas of foot process effacement along with sclerosis, while MCD shows diffuse foot process effacement without sclerosis
What is the significance of proteinuria selectivity in FSGS compared to MCD?
Answer: FSGS typically shows less selective proteinuria compared to the highly selective proteinuria in MCD
How does FSGS affect blood pressure in children?
Answer: Often associated with hypertension, more commonly than in MCD
What is the role of ACE inhibitors or ARBs in FSGS management?
Answer: Used to reduce proteinuria and slow disease progression
What is the risk of FSGS recurrence after kidney transplantation?
Answer: Approximately 30-50% in primary FSGS
How does HIV infection contribute to FSGS?
Answer: HIV can directly infect podocytes, leading to the collapsing variant of FSGS
What is the role of plasmapheresis in FSGS treatment?
Answer: Used in some cases of recurrent FSGS post-transplant or treatment-resistant cases
How does FSGS affect growth and development in children?
Answer: Can lead to growth retardation due to chronic disease, proteinuria, and steroid treatment
What is the significance of podocin mutations in FSGS?
Answer: Associated with steroid-resistant FSGS and increased risk of progression to end-stage renal disease
How does FSGS affect lipid metabolism?
Answer: Often leads to hyperlipidemia, particularly in cases with nephrotic-range proteinuria
What is the role of kidney biopsy in diagnosing FSGS?
Answer: Essential for definitive diagnosis and determining the histological variant
How does the tip variant of FSGS differ from other variants in terms of prognosis?
Answer: Generally has a better prognosis and higher likelihood of response to treatment
What is the significance of APOL1 gene variants in FSGS?
Answer: Associated with increased risk of FSGS in individuals of African descent
How does FSGS affect vitamin D metabolism?
Answer: Can lead to vitamin D deficiency due to urinary loss of vitamin D-binding protein
What is the role of mycophenolate mofetil in FSGS treatment?
Answer: Used as a steroid-sparing agent or in combination therapy for resistant cases

Membranous Nephropathy (MN)

What is Membranous Nephropathy (MN)?
Answer: An immune-mediated kidney disease characterized by thickening of the glomerular basement membrane due to subepithelial immune complex deposits
What is the most common cause of primary MN in adults?
Answer: Autoantibodies against the M-type phospholipase A2 receptor (PLA2R)
How common is MN in children compared to adults?
Answer: Relatively rare in children, more common in adults
What is the typical presentation of MN in children?
Answer: Nephrotic syndrome (edema, proteinuria, hypoalbuminemia)
What are some common causes of secondary MN in children?
Answer: Systemic lupus erythematosus, hepatitis B infection, medications
What is the characteristic finding on light microscopy in MN?
Answer: Diffuse thickening of the glomerular basement membrane
What is the typical pattern seen on immunofluorescence in MN?
Answer: Granular deposits of IgG and C3 along the glomerular basement membrane
What is the hallmark finding on electron microscopy in MN?
Answer: Subepithelial electron-dense deposits with intervening spikes of basement membrane material
What is the role of anti-PLA2R antibodies in diagnosing MN in children?
Answer: Less common than in adults, but can be positive in some cases of primary MN
What is the significance of IgG subclass analysis in MN?
Answer: IgG4 predominance suggests primary MN, while other subclasses may indicate secondary causes
What is the natural history of MN in children?
Answer: More likely to undergo spontaneous remission compared to adults
What is the first-line treatment for MN in children with nephrotic syndrome?
Answer: Supportive care with close monitoring, as spontaneous remission is common
When should immunosuppressive therapy be considered in pediatric MN?
Answer: In cases of persistent nephrotic syndrome, declining kidney function, or severe complications
What immunosuppressive regimens are commonly used in treating MN in children?
Answer: Corticosteroids combined with cyclophosphamide or calcineurin inhibitors
What is the role of rituximab in treating MN in children?
Answer: Used in some cases of resistant disease, particularly in PLA2R-positive cases
How does MN affect the risk of thromboembolism in children?
Answer: Increased risk, particularly in cases with severe hypoalbuminemia
What is the significance of proteinuria selectivity in MN compared to other glomerular diseases?
A: Less selective proteinuria compared to minimal change disease
How does MN affect lipid metabolism in children?
A: Often leads to hyperlipidemia, particularly in cases with persistent nephrotic syndrome
What is the role of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) in MN management?
A: Used to reduce proteinuria and slow disease progression
How does MN affect growth and development in children?
A: Can lead to growth retardation if nephrotic syndrome persists or due to prolonged steroid use
What is the significance of anti-thrombospondin type-1 domain-containing 7A (THSD7A) antibodies in MN?
A: Associated with a subset of PLA2R-negative primary MN cases
How does MN differ from minimal change disease in terms of steroid responsiveness?
A: Generally less responsive to steroids compared to minimal change disease
What is the role of complement in the pathogenesis of MN?
A: Complement activation contributes to podocyte injury and proteinuria
How does the presence of crescents on kidney biopsy affect the prognosis of MN?
A: Associated with more aggressive disease and worse prognosis
What is the significance of IgA deposits in MN?
A: May indicate a secondary form, such as lupus nephritis or IgA nephropathy overlap
How does MN affect vitamin D metabolism in children?
A: Can lead to vitamin D deficiency due to urinary loss of vitamin D-binding protein
What is the role of serial anti-PLA2R antibody monitoring in managing MN?
A: Can help predict disease activity and guide treatment decisions
How does MN affect the risk of infections in children?
A: Increased risk due to urinary loss of immunoglobulins and complement factors
What is the significance of C3 deposits without IgG in apparent MN cases?
A: May indicate C3 glomerulopathy rather than true MN
How does the presence of mesangial deposits affect the diagnosis and prognosis of MN?
A: May suggest a secondary form of MN, often with worse prognosis

Membranoproliferative Glomerulonephritis (MPGN)

What is Membranoproliferative Glomerulonephritis (MPGN)?
A: A pattern of glomerular injury characterized by mesangial hypercellularity and thickening of the glomerular basement membrane
How is MPGN currently classified?
A: Based on immunofluorescence findings: immune complex-mediated and complement-mediated
What are the typical clinical presentations of MPGN in children?
A: Nephrotic syndrome, nephritic syndrome, or asymptomatic urinary abnormalities
What is the characteristic light microscopy finding in MPGN?
A: Mesangial hypercellularity with thickening and splitting of the glomerular basement membrane (tram-track appearance)
How does C3 glomerulopathy differ from immune complex-mediated MPGN?
A: C3 glomerulopathy shows predominant C3 deposition without significant immunoglobulin deposits
What are some common causes of secondary MPGN in children?
A: Infections (e.g., hepatitis B, C), autoimmune diseases (e.g., lupus), and monoclonal gammopathies
What is the role of genetic testing in MPGN evaluation?
A: To identify mutations in complement regulatory proteins, particularly in C3 glomerulopathy
How does MPGN affect complement levels in the blood?
A: Often associated with low C3 levels, particularly in complement-mediated forms
What is the significance of nephritic factors in MPGN?
A: Autoantibodies that stabilize C3 convertase, leading to persistent complement activation
How does MPGN differ from dense deposit disease (DDD) on electron microscopy?
A: DDD shows characteristic ribbon-like, highly electron-dense deposits within the GBM
What is the first-line treatment for idiopathic MPGN in children?
A: Typically includes corticosteroids and other immunosuppressants, depending on the underlying cause
What is the role of eculizumab in treating MPGN?
A: Used in some cases of C3 glomerulopathy to inhibit terminal complement activation
How does MPGN affect long-term kidney function in children?
A: Can lead to progressive kidney failure if not adequately controlled
What is the significance of cryoglobulins in MPGN?
A: Can cause secondary MPGN, often associated with hepatitis C infection
How does MPGN affect blood pressure in children?
A: Often associated with hypertension
What is the role of plasmapheresis in MPGN treatment?
A: May be used in cases with circulating factors (e.g., cryoglobulins) or as rescue therapy
How does MPGN affect growth and development in children?
A: Can lead to growth retardation due to chronic disease and treatment side effects
What is the significance of monoclonal gammopathy in MPGN?
A: Can cause secondary MPGN, more common in adults but rarely seen in children
How does MPGN affect lipid metabolism?
A: Often leads to hyperlipidemia, particularly in cases with nephrotic syndrome
What is the role of rituximab in treating MPGN?
A: Used in some cases of immune complex-mediated MPGN, particularly in resistant disease
How does MPGN differ from post-infectious glomerulonephritis?
A: MPGN tends to be chronic, while post-infectious GN is typically self-limiting
What is the significance of IgG subclass analysis in MPGN?
A: Can help differentiate between primary and secondary forms
How does MPGN affect the risk of thromboembolism in children?
A: Increased risk, particularly in cases with severe nephrotic syndrome
What is the role of mycophenolate mofetil in MPGN treatment?
A: Used as a steroid-sparing agent or in combination therapy for resistant cases
How does MPGN affect vitamin D metabolism in children?
A: Can lead to vitamin D deficiency due to urinary loss of vitamin D-binding protein
What is the significance of recurrent MPGN after kidney transplantation?
A: Can occur, particularly in genetic forms or those with persistent circulating factors
How does the presence of crescents on kidney biopsy affect the prognosis of MPGN?
A: Associated with more aggressive disease and worse prognosis
What is the role of anticoagulation in managing MPGN-associated thrombotic risk?
A: May be considered in high-risk cases, balancing potential benefits against bleeding risks
How does MPGN affect the immune system in children?
A: Can lead to increased susceptibility to infections due to complement dysfunction and immunosuppressive treatment
What is the significance of tubulointerstitial inflammation in MPGN?
A: Associated with worse prognosis and increased risk of progression to chronic kidney disease

Congenital Nephrotic Syndrome (CNS)

What is Congenital Nephrotic Syndrome (CNS)?
A: A rare kidney disorder characterized by nephrotic syndrome presenting within the first 3 months of life
What are the main genetic causes of CNS?
A: Mutations in NPHS1 (nephrin), NPHS2 (podocin), WT1, and LAMB2 genes
What is the most common genetic cause of CNS?
A: NPHS1 mutations (Finnish-type CNS)
What are the typical clinical features of CNS at birth?
A: Large placenta, prematurity, low birth weight, edema
How is CNS diagnosed?
A: Clinical presentation, genetic testing, and kidney biopsy if needed
What is the characteristic finding on kidney biopsy in Finnish-type CNS?
A: Microcystic dilatation of proximal tubules
How does CNS affect fetal development?
A: Can lead to oligohydramnios, pulmonary hypoplasia, and other complications
What is the role of prenatal genetic testing in CNS?
A: Can identify genetic mutations in high-risk families, allowing for early diagnosis and management
How is proteinuria managed in CNS?
A: Albumin infusions, nutritional support, and ACE inhibitors or ARBs
What is the significance of thyroid hormone replacement in CNS?
A: Essential due to urinary loss of thyroid-binding globulin and thyroid hormones
How does CNS affect growth and development?
A: Can lead to severe growth retardation and developmental delays if not adequately managed
What is the role of bilateral nephrectomy in managing CNS?
A: Considered in severe cases to control proteinuria and facilitate management
When is kidney transplantation typically considered in CNS?
A: When the child reaches a weight of 8-10 kg, usually around 1-2 years of age
What is the risk of disease recurrence after kidney transplantation in CNS?
A: Generally low, except in cases of anti-nephrin antibodies
How does CNS affect the immune system?
A: Increased risk of infections due to loss of immunoglobulins and complement factors
What is the role of indomethacin in managing CNS?
A: Can help reduce proteinuria and improve fluid balance
How does CNS affect vitamin D metabolism?
A: Leads to vitamin D deficiency due to urinary loss of vitamin D-binding protein
What is the significance of thrombosis risk in CNS?
A: Increased risk due to urinary loss of anticoagulant proteins and hyperfibrinogenemia
How is nutrition managed in infants with CNS?
A: High-protein, high-calorie diet, often requiring gastrostomy tube feeding
What is the role of genetic counseling in families affected by CNS?
A: Essential for understanding inheritance patterns and family planning
How does CNS affect cardiovascular health?
A: Can lead to hypertension and increased risk of atherosclerosis in the long term
What is the significance of extra-renal manifestations in some forms of CNS?
A: May indicate syndromic forms, such as Denys-Drash or Pierson syndrome
How does CNS affect bone health?
A: Can lead to rickets due to vitamin D deficiency and chronic acidosis
What is the role of erythropoietin in managing CNS?
A: Often required to treat anemia due to urinary losses and nutritional deficiencies
How does CNS affect lipid metabolism?
A: Leads to severe hyperlipidemia due to increased hepatic lipoprotein synthesis
What is the significance of podocyte-specific gene mutations in CNS?
A: Lead to structural and functional abnormalities of the glomerular filtration barrier
How does CNS affect the risk of infections in infants?
A: Significantly increased risk due to loss of immunoglobulins and complement factors
What is the role of anticoagulation in managing CNS?
A: May be considered in high-risk cases, balancing thrombotic risk against bleeding risk
How does CNS affect cognitive development?
A: Can lead to developmental delays if not adequately managed, particularly due to hypothyroidism and malnutrition
What is the significance of anti-nephrin antibodies in post-transplant management of CNS?
A: Can lead to recurrence of nephrotic syndrome in the transplanted kidney