In a young female presenting with gross painless hematuria, nephrotic-range proteinuria, normal renal function, and renal biopsy showing IgA nephropathy with focal crescents and minimal interstitial fibrosis and tubular atrophy, what is the appropriate management?

Management of IgA Nephropathy with Focal Crescents and Nephrotic-Range Proteinuria

This young female with IgA nephropathy showing focal crescents (<50% of glomeruli), nephrotic-range proteinuria, and minimal chronicity should be treated with optimized RAS blockade (ACE inhibitor or ARB), SGLT2 inhibitor, blood pressure control to <120/70 mmHg, and consideration for targeted-release budesonide or sparsentan, but does NOT require aggressive immunosuppression with cyclophosphamide and systemic glucocorticoids since she does not meet criteria for rapidly progressive IgAN 1.

Risk Stratification: Focal vs. Rapidly Progressive Disease

The critical distinction here is that focal crescents (affecting a minority of glomeruli) with normal renal function does NOT constitute rapidly progressive IgAN. The KDIGO 2025 guideline specifically defines rapidly progressive IgAN as ≥50% decline in eGFR over ≤3 months with extensive glomerular crescent formation 1. Your patient has:

• Normal renal function (not declining rapidly)
• Focal crescents (not extensive)
• Minimal interstitial fibrosis and tubular atrophy (favorable chronicity)

This places her in the high-risk progressive disease category rather than the rapidly progressive category.

Stepwise Management Algorithm

1. Foundation Therapy (Mandatory for All)

• RAS blockade: Start ACE inhibitor or ARB at optimized maximally tolerated dose 1
• Blood pressure target: <120/70 mmHg 1
• Lifestyle modifications: Dietary sodium <2 g/day, smoking cessation, weight control, exercise 2

2. Add SGLT2 Inhibitor

The KDIGO 2025 guideline suggests SGLT2 inhibitors for patients at risk of progressive kidney function loss (2B recommendation) 1. Despite the caveat that landmark trials included patients with lower eGFR and longer disease duration, your patient's nephrotic-range proteinuria and crescents indicate high risk warranting this therapy.

3. Consider Sparsentan (Where Approved)

Sparsentan, a dual endothelin-angiotensin receptor antagonist, should replace (not add to) the RAS inhibitor 1. This is particularly relevant given:

• Nephrotic-range proteinuria
• Focal crescents indicating active disease
• Normal renal function allowing for optimal response

The 2B recommendation supports its use in high-risk patients 1.

4. Address the Nephrotic-Range Proteinuria

The guideline distinguishes between nephrotic syndrome (full syndrome with edema, hypoalbuminemia) and nephrotic-range proteinuria alone 1. Your patient likely has:

• Nephrotic-range proteinuria without full nephrotic syndrome: This commonly reflects the IgAN disease activity itself rather than coexistent minimal change disease
• Treatment approach: Treat as standard IgAN with the above therapies, not with high-dose systemic glucocorticoids as you would for MCD 1

5. Targeted Immunomodulation (Optional but Reasonable)

Given the focal crescents and active disease, consider:

• Targeted-release budesonide (Nefecon): Addresses the immunopathogenesis of IgAN with lower systemic steroid exposure 2
• NOT cyclophosphamide and systemic glucocorticoids: Reserved only for rapidly progressive IgAN with ≥50% eGFR decline over ≤3 months 1

Critical Pitfalls to Avoid

Do NOT Overtreat with Aggressive Immunosuppression

The presence of crescents does not automatically warrant cyclophosphamide. The guideline is explicit: cyclophosphamide and systemic glucocorticoids are for rapidly progressive IgAN with extensive crescents and rapid eGFR decline 1. Overtreatment exposes this young woman to:

• Gonadal toxicity and infertility risk
• Infection risk
• Malignancy risk
• Unnecessary morbidity

Preconception Counseling is Mandatory

As a young woman of childbearing potential, she must receive counseling about:

• Discontinuing RAS inhibitors, SGLT2 inhibitors, sparsentan, and Nefecon before conception 1
• Optimizing blood pressure control with pregnancy-compatible medications
• Considering a trial of immunomodulatory therapy to achieve disease control before pregnancy 1

Monitor for Disease Progression

With focal crescents and minimal chronicity, she has potential for good outcomes but requires:

• Serial proteinuria monitoring
• eGFR tracking every 3 months initially
• Repeat biopsy consideration if eGFR declines ≥50% over 3 months or proteinuria worsens despite therapy

Treatment Sequencing

Start immediately:

1. ACE inhibitor or ARB (or sparsentan if available and approved)
2. SGLT2 inhibitor
3. Blood pressure optimization
4. Lifestyle modifications

Add within 1-3 months if proteinuria remains >1 g/day: 5. Targeted-release budesonide (if available)

Reserve for true rapid progression only: 6. Cyclophosphamide + systemic glucocorticoids (only if eGFR declines ≥50% over ≤3 months) 1

This approach balances the need for aggressive treatment of high-risk disease against the substantial risks of overtreatment in a young woman with preserved renal function and favorable chronicity markers 1, 2.