Navigating the Challenges of IgA Nephropathy and IgA Vasculitis Nephritis in Children

Written by: Henny Adriani Puspitasari

Introduction:

IgA nephropathy (IgAN) and IgA vasculitis nephritis (IgAVN) are kidney diseases that can significantly impact children's health. While they share some similarities, understanding their distinct characteristics and management strategies is crucial for early diagnosis and effective treatment. This post aims to provide a clear overview of these conditions, drawing from the International Pediatric Nephrology Association (IPNA) guidelines.

What are IgAN and IgAVN?

• IgA Nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. It occurs when IgA1-IgG immune complexes deposit in the kidney's glomeruli (the filtering units), causing inflammation and damage. Children typically present with hematuria (blood in the urine), proteinuria (protein in the urine), and varying degrees of kidney dysfunction, often during or after an upper respiratory tract infection.

• IgA Vasculitis Nephritis (IgAVN) is a systemic small vessel vasculitis, which involves inflammation of small blood vessels throughout the body, including those in the kidneys. It often presents with palpable purpura (a raised, bruise-like rash), abdominal pain, and joint pain (arthritis/arthralgia). Kidney involvement is common, and when it occurs, it's termed IgAVN.

IgA Nephropathy:

Common definitions for IgA nephropathy (IgAN) 

Indications for kidney biopsy in primary IgAN:

• Presence of hematuria with proteinuria (UPCR ≥  20 mg/mmol or 0.2 mg/mg) persisting in over 2-3 weeks, at minimum 2 measurements 1-2 weeks apart, without lower urinary tract symptoms (LUTS) etiologies or features of systemic disease, with normal serum C3 level

• Persistent (>2-3 weeks) or recurrent (>2-3 times) gross hematuria during URTI

• Persistent or recurrent hematuria and nephrotic-range proteinuria (UPCR >200 mg/mmol or 2 mg/mg) and/or reduced eGFR

• Persistent or recurrent hematuria and UPCR >50 mg/mmol (0.5 mg/mg), at minimum two measurements 1-2 weeks apart

• Persistent or recurrent hematuria and UPCR between 20-50 mg/mmol (0.2-0.5 mg/mg), at minimum three measurements 1-2 weeks apart

• Diagnosis of primary IgAN requires dominant or co-dominant IgA glomerular staining among immunoglobulins, excluding differential diagnosis for clinical and/or pathologic reasons (e.g. IgAVN, secondary IgAN, IgA-dominant postinfectious GN).

Managing IgAN in Children

Management strategies for IgAN focus on slowing disease progression and managing complications.

• Supportive Care: This includes:

  • Salt restriction (less than 3-5 grams per day).

  • RASB therapy (ACE inhibitors or ARBs) to control blood pressure and reduce proteinuria.

  • Lifestyle modifications such as regular exercise, avoiding smoking/vaping, and weight management for those overweight or obese.

• Glucocorticoids (Steroids): These may be used for children with persistent proteinuria despite supportive care or those at higher risk of disease progression. The dosage and duration of treatment are carefully determined by a nephrologist.

• Other Immunosuppressants: In severe cases, other immunosuppressive medications like mycophenolate mofetil or cyclophosphamide may be used in addition to glucocorticoids.

• Regular Monitoring: Long-term follow-up is crucial to monitor kidney function, blood pressure, and urine abnormalities.

  
  

  

  
  
  
  

  Dose, monitoring, and adverse effects of main agents used to treat IgAN

	Therapeutic agents
Dose	Monitoring
Oral glucocorticoids: Prednisolone or Prednisone (PDN) 1-2 mg/kg/day (maximum dose 60 mg) for 4 weeks then alternate-day dosing tapered over 3-6 months IV glucocorticoids pulses: methylprednisolone, three doses given daily for 3 days at induction, 500 mg/m2 per dose (maximum dose 1000 mg). May be repeated	Quarterly: blood pressure, height, weight Yearly: ophthalmological examination
Mizobirine: Purine antimetabolite mainly available in Japan 4 mg/kg/day (maximum dose 150 mg)	Initially monthly, later quarterly: CBC Uric acid
Mycophenolate mofetil (MMF)/ mycophenolic sodium (MPS): MMF: 1200 mg/m2 per2day in two divided doses every 12 h (usually start at 600 mg/m in two doses for the first week to improve tolerance)MPS: 360 mg corresponds to 500 mg of MMFTherapeutic drug monitoring using a limited sampling strategy: The most effective MPA AUC is above 50 mg × h/L	Quarterly: CBC LFTs
Calcineurin inhibitors:CyclosporineStart: 3–5 mg/kg per day (maximum dose 250 mg) in two divided doses Target: C0 60–100 ng/mL or C2 300 two 550 ng/mL (aiming for the lowest possible dose to maintain remission) TacrolimusStart: 0.1–0.2 mg/kg per day (maximum dose 10 mg) in two divided dosesTarget: C0 level between 3 and 7 ng/mL (aiming for the lowest possible dose to maintain remission)	Quarterly: Blood pressure CBC, Creatinine,eGFR, K+ LFTs, lipids Uric acid (CsA) Mg+ (TAC) Fasting glucose (TAC) Drug levels Consider discontinuation or a kidney biopsy after 2-3 years to avoid/detect toxicity
Cyclophosphamide:IV pulses of 500 mg/1.73 m every 2 weeks for a maximum of six dosesNo more than two courses (max TCD 168 mg/kg)	CBC and urine culture every 14 days during therapy

CBC, complete blood count; LFT, liver function tests; CsA, cyclosporine; TAC, tacrolimus; eGFR, estimated glomerular filtration rate; K+, potassium; Mg, magnesium; CYC, cyclophosphamide

Differentiating IgAN in Children and Adults:

IgA nephropathy (IgAN) in children shares similarities with adult cases, but also shows distinct clinical variations and treatment responses. Children are more likely to have gross hematuria and proteinuria, while adults exhibit hypertension and reduced GFR. Histologically, children have more mesangial hypercellularity (M1) lesions, and adults have more segmental glomerulosclerosis (S1) and tubular atrophy/interstitial fibrosis (T1) lesions. Children with proteinuria over 1g/day treated with corticosteroids are more likely to achieve complete remission than adults. Therefore, pediatric IgAN has unique features and responds better to corticosteroid therapy.

IgA vasculitis nephritis:

Indications for kidney biopsy in children with suspected IgAVN

• A kidney biopsy is recommended. 

  • IgAV and nephrotic-range proteinuria (UPCR > 2 mg/mg or 200 mg/mmol).

  • IgAV and eGFR < 90 mL/min/1.73 m², regardless of proteinuria levels.

• A kidney biopsy is suggested.

  • IgAV and moderate proteinuria (UPCR 1–2 mg/mg or 100–200 mg/mmol) persisting for 2–4 weeks.

  • IgAV and mild proteinuria (UPCR 0.2–0.5 mg/mg or 20–50 mg/mmol) persisting for more than 4 weeks.

Follow-up and subsequent assessments

• Follow-up should occur at least monthly for the first 6 months, even if urinalysis remains normal.

• Patients with clinical nephritis should be closely monitored for at least five years. Extended follow-up for those with initially active disease may be conducted by primary care providers.

• For patients with kidney involvement, the suggested monitoring frequency is:

  • Monthly for the first 6 months.

  • Every 3 months for the subsequent 6 months.

  • Every 6 months thereafter for a minimum of 5 years

    
    

Indications for kidney biopsy in IgA vasculitis

Managing IgAVN in Children

Management for IgAVN focuses on controlling inflammation and managing complications.

• Monitoring: Regular monitoring of kidney function and urine protein is essential.

• Glucocorticoids: These are often used for children with nephrotic-range proteinuria or rapidly declining kidney function.

• Other Immunosuppressants: Additional immunosuppressants may be used if glucocorticoids are insufficient.

• RASB Therapy: This is used to manage proteinuria.

• Blood Pressure Control: Maintaining blood pressure within the normal range is important.

Treatment discontinuation

• Immunosuppressive treatment should be used in children with IgAVN for at least 8–12 weeks.

• Immunosuppressive treatment should be discontinued in children with IgAVN after at least 4 weeks of remission of proteinuria (PCR < 0.2 mg/mg or 20 mg/mmol) and absence of gross hematuria, with normal eGFR (> 90 mL/min/1.73 m²).

  
  

Follow-up

• Children with IgAVN should be monitored for at least five years after the initial episode, with evaluations of urinalysis, eGFR, and blood pressure. The primary care provider may conduct follow-up.

• Lifelong monitoring should be suggested for children who received therapy, individualized according to the severity and response to treatment.

  
  

Important Considerations for Both Conditions

• Remission and Relapse: IgA nephropathy (IgAN) and IgA vasculitis nephritis (IgAVN) in children are characterized by periods of remission, where the disease is inactive, and relapse, when symptoms reappear. Consistent monitoring is crucial for the early detection and effective management of these relapses.

• Long-term prognosis: Limited data exists regarding the long-term prognosis of both IgA Nephropathy (IgAN) and IgA Vasculitis Nephritis (IgAVN). Research conducted in China indicates that 10-20% of pediatric patients with IgAN and IgAVN will progress to renal failure during young adulthood. From the European cohort VALIGA, 15-year survival from a 50% eGFR decline or kidney failure was found in 93.7% of children. 

• Recurrence of IgAN after transplantation: Recurrence of IgA nephropathy (IgAN) after kidney transplantation in children is a significant concern, with reported rates ranging from 30% to 77%. The risk is lower in the case of IgAVN. While IgAN recurrence is more common in children than adults, factors like younger age at transplant, higher HLA mismatch, male sex, rapidly progressive course of IgAN leading to ESKD, and early steroid withdrawal are associated with increased risk. 

• Transition to Adult Care: As children with these conditions transition to adulthood, a structured plan is crucial to ensure continuity of care and support.

Key Takeaways

• IgAN and IgAVN are distinct kidney diseases affecting children, each with unique characteristics and management approaches.

• Early diagnosis and appropriate treatment are crucial for preventing long-term kidney damage.