In a 26‑year‑old man with biopsy‑proven IgA nephropathy, impaired renal function (eGFR ~60–70 mL/min/1.73 m²) and significant proteinuria, what is the role of sodium‑glucose cotransporter‑2 inhibitors (dapagliflozin, empagliflozin) and the mineralocorticoid‑receptor antagonist finerenone in his management?

Role of SGLT2 Inhibitors and Finerenone in IgA Nephropathy

In this 26-year-old man with biopsy-proven IgA nephropathy, eGFR 60–70 mL/min/1.73 m², and significant proteinuria, SGLT2 inhibitors (dapagliflozin or empagliflozin) should be added immediately to his RAS blockade regimen, while finerenone can be considered as an additional agent if proteinuria remains elevated after SGLT2 inhibitor initiation.

SGLT2 Inhibitors: First-Line Add-On Therapy

Evidence for Use in IgA Nephropathy

• SGLT2 inhibitors are now recognized as disease-modifying agents in IgA nephropathy and should be incorporated into the treatment algorithm alongside RAS blockade. 1, 2

• Dapagliflozin demonstrated superior efficacy in preventing end-stage renal disease compared to placebo (RR 0.30; 95% CI 0.11–0.80), immunosuppressants (RR 0.14; 95% CI 0.02–0.81), and RAS monotherapy (RR 0.10; 95% CI 0.01–0.69) in a network meta-analysis of IgAN patients at high risk of progression. 3

• Dapagliflozin had the lowest serious adverse event risk among all pharmaceutical treatments for IgAN while maintaining the best comparative therapeutic efficacy in preventing ESRD. 3

• The 2025 KDIGO guideline explicitly recommends SGLT2 inhibitors as part of the management strategy for IgAN-induced nephron loss, positioning them alongside RAS inhibitors as foundational therapy. 2

Practical Implementation

• Start dapagliflozin 10 mg daily or empagliflozin 10 mg daily (can increase to 25 mg if tolerated) in addition to maximally tolerated ACE inhibitor or ARB therapy. 4, 3

• Monitor for an initial eGFR dip of 5–10% within the first 2–4 weeks, which represents a benign hemodynamic effect and should not prompt discontinuation. 4

• Assess proteinuria response at 4–8 weeks; SGLT2 inhibitors typically reduce albuminuria by 8–10% as monotherapy but show greater effects when combined with other agents. 4

• Continue SGLT2 inhibitor therapy long-term regardless of proteinuria response, as renal protection extends beyond antiproteinuric effects through hemodynamic and metabolic mechanisms. 3, 2

Finerenone: Additive Antiproteinuric Agent

Evidence for Use in Non-Diabetic CKD

• Finerenone 20 mg daily reduced albuminuria by 24% (95% CI –36% to –11%) when added to RAS blockade in patients with non-diabetic CKD and eGFR 25–45 mL/min/1.73 m². 4

• The combination of finerenone plus dapagliflozin demonstrated additive effects, reducing albuminuria by 36% (95% CI –46% to –24%) after 8 weeks with minimal adverse effects. 4

• Finerenone's antiproteinuric effect appears more pronounced than dapagliflozin's when used as monotherapy (24% vs 8% reduction), suggesting complementary mechanisms of action. 4

When to Add Finerenone

• Consider adding finerenone 20 mg daily if proteinuria remains ≥1 g/day after 4–8 weeks of optimized RAS blockade plus SGLT2 inhibitor therapy. 4

• Finerenone is particularly appropriate in this patient given his relatively preserved eGFR (60–70 mL/min/1.73 m²), as the evidence base is strongest for eGFR 25–45 mL/min/1.73 m² but safety is established at higher eGFR levels. 4

• Monitor serum potassium closely (weekly for first month, then monthly) when initiating finerenone, as hyperkalemia is the primary dose-limiting adverse effect. 4

• Accept a modest eGFR decline of up to 7 mL/min/1.73 m² as an expected hemodynamic effect when combining these agents, provided it stabilizes within 4–8 weeks. 4

Algorithmic Approach for This Patient

Step 1: Optimize Foundational Therapy (Months 0–3)

• Uptitrate ACE inhibitor or ARB to maximally tolerated dose targeting proteinuria <1 g/day and blood pressure <120/70 mmHg. 1, 5, 2

• Implement dietary sodium restriction to <2 g/day, weight normalization, smoking cessation, and regular exercise. 1, 5

• Add SGLT2 inhibitor (dapagliflozin 10 mg or empagliflozin 10–25 mg daily) immediately, as this patient's significant proteinuria and biopsy-proven IgAN warrant disease-modifying therapy beyond RAS blockade alone. 3, 2

Step 2: Reassess at 3 Months

• If proteinuria remains ≥0.75–1 g/day despite RAS blockade plus SGLT2 inhibitor, add finerenone 20 mg daily for additional antiproteinuric effect. 4

• If proteinuria persists ≥0.75–1 g/day after adding finerenone, consider a 6-month course of glucocorticoids (Pozzi protocol: methylprednisolone 1 g IV for 3 days at months 1,3,5 plus oral prednisone 0.5 mg/kg every other day), provided the patient has no contraindications (diabetes, obesity BMI >30, active infection). 1, 5

• At age 26 without diabetes or obesity, this patient is an ideal candidate for glucocorticoids if proteinuria remains elevated, but SGLT2 inhibitor plus finerenone should be optimized first. 1

Step 3: Long-Term Monitoring

• Continue RAS blockade, SGLT2 inhibitor, and finerenone indefinitely as long as tolerated, targeting sustained proteinuria <1 g/day (ideally <0.5 g/day). 5, 2, 6

• Monitor proteinuria and eGFR every 3–6 months; assess serum potassium monthly while on finerenone. 5, 4

• Maintain strict blood pressure control <120/70 mmHg and continue lifestyle modifications throughout. 1, 2

Critical Nuances and Pitfalls

Timing of SGLT2 Inhibitor Initiation

• Unlike the traditional approach of waiting 3–6 months to assess response to RAS blockade alone, emerging evidence supports early SGLT2 inhibitor initiation as part of foundational therapy rather than as a sequential add-on. 3, 2

• The network meta-analysis demonstrating dapagliflozin's superiority in preventing ESRD justifies its use as first-line therapy alongside RAS blockade, not as a rescue agent. 3

Finerenone vs. Traditional Mineralocorticoid Receptor Antagonists

• Finerenone is a non-steroidal mineralocorticoid receptor antagonist with greater selectivity for the mineralocorticoid receptor and less potassium retention compared to spironolactone or eplerenone, making it safer in CKD. 4

• The additive effect of finerenone plus dapagliflozin on albuminuria reduction (36% combined vs. 24% + 8% = 32% calculated) suggests synergistic rather than merely additive mechanisms. 4

Avoiding Premature Immunosuppression

• Glucocorticoids carry significant toxicity risk (serious adverse events RR 2.91 vs. placebo; 95% CI 1.39–6.07) and should be reserved for patients with persistent high-risk proteinuria despite optimal supportive care including SGLT2 inhibitors and finerenone. 1, 3

• The TESTING trial demonstrated steroid-related mortality even with pneumocystis prophylaxis, reinforcing the need to exhaust safer alternatives first. 1

Monitoring for Hemodynamic Effects

• The combination of RAS blockade, SGLT2 inhibitor, and finerenone will cause an expected cumulative eGFR decline of 10–15 mL/min/1.73 m² over the first 2–4 months, which should stabilize and reverse partially over subsequent months. 4

• Do not discontinue these agents for eGFR decline unless it exceeds 30% from baseline, continues to worsen beyond 8 weeks, or is accompanied by refractory hyperkalemia (>6.0 mEq/L despite dietary restriction and diuretics). 5, 4

Proteinuria as a Surrogate Endpoint

• Achieving proteinuria <1 g/day is associated with favorable long-term prognosis regardless of baseline proteinuria level, validating proteinuria reduction as a treatment target. 5, 6

• Time-averaged proteinuria >1 g/day predicts approximately 3 mL/year GFR decline even with favorable histologic features, emphasizing the urgency of aggressive antiproteinuric therapy in this patient. 7, 6