Side Effects of Medications and Therapies for IgA Nephropathy
All IgA nephropathy treatments carry significant risks that must be weighed against benefits, with glucocorticoids causing the most serious adverse events including infections and death, while ACE inhibitors and ARBs have a more favorable safety profile but still require monitoring for hyperkalemia and acute kidney injury. 1
ACE Inhibitors and ARBs (First-Line Supportive Therapy)
Common and Serious Side Effects
Hyperkalemia is the most important monitoring concern, particularly when combined with potassium-sparing diuretics, potassium supplements, or other agents that raise serum potassium 2, 3
Acute kidney injury and deterioration of renal function can occur, especially in elderly patients, volume-depleted patients, or those on concurrent NSAID therapy 2, 3
Hypotension and syncope may develop, particularly at treatment initiation or when combined with diuretics 3
Hypoglycemia risk increases when ACE inhibitors are combined with antidiabetic medications (insulin or oral agents) 3
Lithium toxicity can occur with concurrent lithium use, requiring serum lithium monitoring 2, 3
Dual RAS blockade (combining ACE inhibitors with ARBs or aliskiren) significantly increases risks of hypotension, hyperkalemia, and acute renal failure compared to monotherapy and should be avoided 2, 3
Critical Drug Interactions
NSAIDs (including COX-2 inhibitors) attenuate the antihypertensive effect and can cause reversible renal function deterioration 2, 3
Aliskiren should never be co-administered in patients with diabetes or renal impairment (GFR <60 mL/min) 2, 3
Nitritoid reactions (facial flushing, nausea, vomiting, hypotension) have been reported with injectable gold therapy and concurrent ACE inhibitor use 3
Glucocorticoids (Systemic Corticosteroids)
Serious Adverse Events and Mortality Risk
Infectious complications are the most serious concern, with the TESTING trial reporting 4 fatalities in the methylprednisolone arm despite pneumocystis prophylaxis 1
Significantly higher serious adverse event rates occurred in steroid-treated patients compared to placebo, with treatment-associated morbidity and mortality documented 1
Adverse event frequency increases with declining renal function: 2.3% in patients with GFR 90 mL/min, 5.7% with GFR 81 mL/min, and 15.4% in patients with GFR 34 mL/min 4
Major side effects occurred in 6.2% of patients (29 of 463) enrolled in randomized controlled trials 4
Specific High-Risk Populations Requiring Extreme Caution
The KDIGO guidelines explicitly state glucocorticoids should be avoided entirely or given with extreme caution in patients with: 1
- eGFR <30 mL/min per 1.73 m² (increased toxicity with minimal benefit)
- Diabetes (worsened glycemic control and infection risk)
- Obesity (BMI >30 kg/m²)
- Latent infections (viral hepatitis, tuberculosis, HIV)
- Secondary disease (liver cirrhosis)
- Active peptic ulceration
- Uncontrolled psychiatric disease
- Severe osteoporosis
- Advanced age (increased infection susceptibility)
- Metabolic syndrome (multiple compounding risk factors)
Common Steroid-Related Side Effects
- Opportunistic infections including pneumocystis pneumonia, even with prophylaxis 1
- Weight gain and cushingoid features 5
- Glucose intolerance and diabetes exacerbation 5
- Bone loss and fracture risk 5
- Psychiatric disturbances 5
- Gastrointestinal complications including peptic ulcer disease 5
Enteric-Coated Budesonide (Targeted-Release Formulation)
Favorable Safety Profile Compared to Systemic Steroids
Adverse events were not clinically relevant in the NEFIGAN trial, representing a major advantage over systemic corticosteroids 6
Infectious complications were minimal compared to systemic glucocorticoids, due to targeted intestinal delivery reducing systemic exposure 6
FDA accelerated approval granted in December 2021 for primary IgA nephropathy with UPCR >1.5 g/g, indicating acceptable safety profile 1, 7
Contraindications and Precautions
- Should be avoided in patients with eGFR <30 mL/min/1.73 m² 7
- Uncontrolled diabetes is a contraindication 7
- Inadequate trial of supportive care (must have at least 90 days of optimized RAS blockade first) 7
Immunosuppressive Agents (Generally Not Recommended)
Mycophenolate Mofetil (MMF)
Not recommended in non-Chinese patients due to lack of efficacy demonstrated in trials 1
May be used in Chinese patients as glucocorticoid-sparing agent at 1.5 g/day for proteinuria >1 g/day with active histologic features 1, 7
Common side effects include: gastrointestinal disturbances (diarrhea, nausea), leukopenia, increased infection risk, and teratogenicity 6
Calcineurin Inhibitors (CNIs)
Not recommended for IgA nephropathy per KDIGO guidelines 1
Nephrotoxicity is the primary concern, with potential for acute and chronic kidney injury 6
Other significant side effects: hypertension, hyperglycemia, neurotoxicity (tremor, headache), hirsutism, gingival hyperplasia 6
Cyclophosphamide
Only recommended for rapidly progressive IgAN with extensive crescent formation (>50% of glomeruli) and declining GFR 8
Serious toxicities include: bone marrow suppression, hemorrhagic cystitis, infertility (particularly in women), increased malignancy risk, and severe infections 6
Not recommended for routine IgAN treatment outside of crescentic disease 1
Azathioprine
Not recommended for IgA nephropathy per KDIGO guidelines 1
Side effects include: bone marrow suppression, hepatotoxicity, increased infection risk, gastrointestinal intolerance, and increased malignancy risk with long-term use 6
Rituximab
Not recommended for IgA nephropathy based on lack of efficacy in trials 1, 9
Potential side effects: infusion reactions, increased infection risk (including progressive multifocal leukoencephalopathy), prolonged B-cell depletion, and rare cases of severe mucocutaneous reactions 9
Emerging and Investigational Therapies
SGLT2 Inhibitors
Currently being evaluated for augmenting supportive care in high-risk IgAN patients 1
Known side effects from other indications: genital mycotic infections, urinary tract infections, diabetic ketoacidosis (in diabetics), volume depletion, acute kidney injury, and rare cases of Fournier's gangrene 1
Sparsentan and Atrasentan (Endothelin Receptor Antagonists)
Under investigation for IgA nephropathy treatment 1
Expected side effects based on drug class: fluid retention, edema, anemia, and potential hepatotoxicity 1
Complement Inhibitors
Various agents targeting complement system are in clinical trials 1, 6
Potential risks include: increased susceptibility to encapsulated bacterial infections (particularly meningococcal), infusion reactions, and immunogenicity 6
Hydroxychloroquine
Being evaluated as potential supportive therapy 1
Known side effects: retinal toxicity (requires ophthalmologic monitoring), QT prolongation, cardiomyopathy, hypoglycemia, and gastrointestinal disturbances 1
Critical Monitoring Recommendations
For ACE Inhibitors/ARBs
- Monitor serum potassium regularly, especially with concurrent medications that raise potassium 2, 3
- Monitor renal function periodically, particularly with NSAID co-administration 2, 3
- Monitor blood pressure to avoid excessive hypotension 3
- Monitor serum lithium levels if on concurrent lithium therapy 2, 3
For Glucocorticoids
- Screen for latent infections (tuberculosis, hepatitis B/C, HIV) before initiating therapy 1
- Provide pneumocystis prophylaxis during treatment, though this does not eliminate infection risk 1
- Monitor for signs of infection vigilantly, as this is the leading cause of serious morbidity and mortality 1
- Assess metabolic parameters including glucose, blood pressure, and bone density 5
For Budesonide
- Monitor proteinuria every 3 months with target of 50% reduction by 6 months and <1 g/day by 12 months 7
- Monitor eGFR every 3-6 months to assess renal function stability 7
Key Clinical Pitfalls to Avoid
Never combine multiple RAS inhibitors (ACE inhibitor + ARB + aliskiren), as this dramatically increases adverse event risk without additional benefit 2, 3
Do not use systemic glucocorticoids in patients with eGFR <30 mL/min due to unacceptable risk-benefit ratio with adverse events occurring in 15.4% of patients 4
Recognize that adverse treatment effects are more likely in patients with eGFR <50 mL/min per 1.73 m², requiring heightened vigilance 1
Avoid immunosuppression without adequate trial of optimized supportive care (minimum 90 days of maximal RAS blockade and blood pressure control) 1
Do not assume budesonide is risk-free—it still requires appropriate patient selection and monitoring, though it has a superior safety profile to systemic steroids 7, 6