What is the best treatment approach for a patient with worsening proteinuria and microhematuria, and no C3 deposition, considering options such as iptacopan, low-dose steroids (e.g. Pozzi protocol with prednisone (prednisone) or alternatives like budesonide, nefacon (generic name not specified, possibly referring to a medication like nefamostate)), and additional Renin-Angiotensin-Aldosterone System (RAAS) blockade with medications like valasartan (valasartan) or atrasentan (atrasentan)?

Treatment Approach for Progressive IgA Nephropathy with Worsening Proteinuria

This patient requires immediate intensification of immunosuppression with targeted-release budesonide (Nefecon) combined with iptacopan, while maximizing RAAS blockade and adding an SGLT2 inhibitor if not already optimized.

Critical Assessment of Current Situation

Your patient demonstrates clear disease progression despite current therapy:

• Proteinuria has nearly doubled (UPCR from 628 to 1141 mg/g; UPCR from 1111 to 1821 mg/g) 1
• New microhematuria with dysmorphic RBCs indicates active glomerular inflammation 2
• Biopsy confirms IgA nephropathy (M1E0S0T0-C0) with mesangial IgA deposits and preserved podocyte foot processes 3
• Current therapy is inadequate: valsartan 80 mg is suboptimal dosing, and forxiga alone is insufficient 3, 1

Addressing Your Specific Questions

1. Will Iptacopan Help Without C3 Deposition?

Yes, iptacopan can still be beneficial despite negative C3 staining on immunofluorescence. The APPLAUSE-IgAN trial did not stratify results by C3 immunofluorescence staining because:

• Alternative complement pathway activation occurs systemically in IgA nephropathy, even when C3 deposits are not visible on standard immunofluorescence 4
• Electron microscopy showed small dense deposits in your patient, which may represent complement components below the detection threshold of immunofluorescence 5
• Iptacopan targets factor B systemically, blocking alternative pathway activation regardless of visible glomerular C3 deposits 5, 6
• Recent case reports demonstrate proteinuria reduction from >1 g/day to <0.3 g/day within 6 months in IgAN patients treated with iptacopan, independent of C3 staining status 6

The absence of C3 on IF does not exclude complement involvement—it may reflect timing of biopsy, technical factors, or rapid complement turnover 4.

2. Steroid Protocol Selection

Avoid systemic steroids entirely in this patient. Instead, use targeted-release budesonide (Nefecon) 16 mg once daily for 9 months 4. Here's why:

Contraindications to systemic steroids in your patient:

• Recent pregnancy (8 months postpartum) with possible breastfeeding considerations 3
• Atopic background (hay fever, nut allergy) increases infection risk 3
• Active smoking compounds cardiovascular and infection risks 7
• Elevated LDL (200 mg/dL) will worsen with systemic steroids 7
• History of psoriasis may flare with systemic corticosteroids 3

The Pozzi protocol (0.5 mg/kg every other day for 6 months) is outdated and toxic in Caucasian patients, showing no benefit in recent meta-analyses while causing significant adverse effects 4. This regimen should be abandoned 3.

Targeted-release budesonide advantages:

• Delivers drug to Peyer's patches in the distal ileum where Gd-IgA1 production occurs 4
• 90% first-pass hepatic metabolism minimizes systemic exposure and side effects 4
• Proven efficacy in reducing proteinuria and preserving eGFR in IgAN 4
• Better safety profile than systemic steroids, particularly for metabolic and infection complications 4

3. RAAS Blockade Optimization

Your current valsartan dose of 80 mg is grossly inadequate. Immediate actions:

• Uptitrate valsartan to maximum tolerated dose (320 mg daily) targeting proteinuria <1 g/day and blood pressure <120/80 mmHg 3, 1
• Monitor potassium and creatinine closely; accept up to 30% creatinine increase if stable 3
• Add potassium-wasting diuretics (hydrochlorothiazide or loop diuretic) if hyperkalemia limits RAAS blockade uptitration 3
• Intensify sodium restriction to <2 g/day to enhance RAAS blockade efficacy 3

Regarding atrasentan:

• Do not use atrasentan in this patient—it is not approved for IgAN and causes significant fluid retention requiring aggressive diuretic therapy 3
• Atrasentan data is limited to diabetic kidney disease, not primary glomerulonephritis 7
• The risk-benefit ratio is unfavorable given her recent preeclampsia history and cardiovascular risk factors 7

4. Forxiga (Dapagliflozin) Optimization

Continue forxiga 10 mg daily—this is already the maximum dose and provides nephroprotection independent of glucose-lowering effects 4. SGLT2 inhibitors reduce proteinuria and slow eGFR decline in IgAN 4.

Recommended Treatment Algorithm

Immediate Actions (Within 1 Week):

1. Uptitrate valsartan from 80 mg to 160 mg daily, then to 320 mg daily over 2-4 weeks as tolerated 3, 1
2. Start targeted-release budesonide (Nefecon) 16 mg once daily for 9 months 4
3. Start iptacopan 200 mg twice daily 5, 6, 4
4. Ensure meningococcal and pneumococcal vaccination before starting iptacopan 5, 8
5. Intensify dietary sodium restriction to <2 g/day 3
6. Counsel on smoking cessation urgently 3

Monitoring Schedule:

• Weeks 2,4,8,12: Check serum creatinine, potassium, UPCR, blood pressure 3
• Month 3: Assess proteinuria response; if <50% reduction, consider repeat biopsy to evaluate for progression 3
• Month 6: Reassess UPCR and eGFR; target UPCR <500 mg/g 1, 6
• Month 9: Complete budesonide course; continue iptacopan based on response 4

Expected Outcomes:

• Proteinuria reduction of 35-50% within 6 months with iptacopan 5, 6
• Additional proteinuria reduction from optimized RAAS blockade 3, 1
• Stabilization or improvement in eGFR 5, 4
• Resolution of microhematuria as inflammation subsides 2

Critical Pitfalls to Avoid

• Do not use systemic corticosteroids (prednisone, methylprednisolone)—the toxicity outweighs benefits in this patient 4
• Do not underdose valsartan—80 mg is inadequate; maximum tolerated dose is essential 3, 1
• Do not delay immunosuppression—progressive proteinuria despite RAAS blockade mandates treatment 3
• Do not use atrasentan—insufficient evidence in IgAN and high risk of fluid retention 7
• Do not forget vaccination—meningococcal infection risk with complement inhibition is real 5, 8
• Do not ignore cardiovascular risk—address LDL with statin therapy, smoking cessation, and blood pressure control 7

Special Considerations for This Patient

Recent pregnancy and preeclampsia history:

• Ensure contraception counseling—pregnancy should be avoided during immunosuppression 3
• Monitor blood pressure aggressively—preeclampsia history increases future hypertension risk 7
• Assess for residual preeclampsia-related kidney injury—though biopsy shows pure IgAN 2

Atopic background:

• Avoid systemic immunosuppression that increases infection risk (cyclophosphamide, high-dose steroids) 3
• Targeted-release budesonide is safer than systemic steroids in atopic patients 4

Smoking:

• Smoking accelerates IgAN progression independent of other risk factors 3
• Provide smoking cessation resources immediately—this is as important as medication 3

3, 1, 2, 5, 6, 4, 7