Is dapagliflozin (SGLT2 inhibitor) effective for treating nephrotic syndrome or significant proteinuria?

Dapagliflozin for Nephrotic Syndrome/Proteinuria

Dapagliflozin is highly effective for treating proteinuria in patients with chronic kidney disease (CKD) and should be initiated at 10 mg daily in patients with eGFR ≥25 mL/min/1.73 m² and albuminuria (UACR ≥200 mg/g), regardless of diabetes status, to reduce kidney disease progression, cardiovascular events, and mortality. 1, 2

Evidence for Efficacy in Proteinuric Kidney Disease

Diabetic Kidney Disease with Proteinuria

• The DAPA-CKD trial demonstrated a 39% reduction in the primary composite outcome (≥50% sustained eGFR decline, ESKD, or renal/cardiovascular death) in patients with CKD and median baseline proteinuria of 949 mg/g 1, 3
• Dapagliflozin reduced albuminuria by 29.3% overall compared to placebo, with a 35.1% reduction in patients with type 2 diabetes 3
• The drug decreased the composite renal outcome (sustained ≥50% eGFR decline, ESKD, or renal death) by 44% 4
• Cardiovascular death or heart failure hospitalization was reduced by 29%, and all-cause mortality decreased by 31% 1, 5

Non-Diabetic Proteinuric CKD

• Dapagliflozin is equally recommended for non-diabetic CKD patients with proteinuria (UACR >200 mg/g), as the DAPA-CKD trial showed consistent benefits regardless of diabetes status 2, 3
• In non-diabetic CKD patients, dapagliflozin reduced albuminuria by 14.8% and decreased cardiovascular death or heart failure hospitalization (HR 0.79) 2, 3
• All-cause mortality was reduced by 48% (HR 0.52) in non-diabetic patients 2

Important Caveat: Short-Term vs. Long-Term Effects

• A critical distinction exists between short-term and long-term proteinuria effects: The DIAMOND trial showed that 6-week treatment with dapagliflozin did NOT significantly reduce proteinuria in non-diabetic CKD patients (0.9% difference vs. placebo, p=0.93) 6
• However, the long-term DAPA-CKD trial demonstrated sustained albuminuria reduction and improved clinical outcomes over extended follow-up 3
• This suggests the renoprotective benefits extend beyond simple proteinuria reduction and involve additional mechanisms 7

Initiation Criteria and Dosing Algorithm

When to Start Dapagliflozin

1. eGFR ≥25 mL/min/1.73 m² AND UACR ≥200 mg/g: Initiate dapagliflozin 10 mg daily 1, 4, 2
2. Background therapy: Ensure patient is on stable ACEI or ARB therapy before adding dapagliflozin 2
3. Special populations:
   • IgA nephropathy with proteinuria >0.5 g/day: Add dapagliflozin to ACEI/ARB 2
   • Podocytopathies with FSGS lesions: Consider dapagliflozin as standard therapy 7

Continuation at Lower eGFR

• If eGFR falls below 25 mL/min/1.73 m² during treatment, continue dapagliflozin 10 mg daily until dialysis initiation 4, 2
• The EMPA-KIDNEY trial demonstrated efficacy down to eGFR 20 mL/min/1.73 m² 1

Do NOT Use for Glycemic Control

• Below eGFR 45 mL/min/1.73 m², dapagliflozin is ineffective for glucose lowering but retains cardiovascular and renal protective benefits 4

Expected Clinical Course and Monitoring

Initial eGFR Decline

• Expect a reversible 3-5 mL/min/1.73 m² eGFR decline within the first 4 weeks 2, 6
• This acute decline is hemodynamic, fully reversible upon discontinuation, and does NOT indicate harm 6
• Check eGFR within 1-2 weeks after initiation 4
• Patients with initial eGFR decline >10% at 2 weeks actually had better long-term outcomes with slower subsequent eGFR decline (-1.58 vs -2.44 mL/min/1.73 m²/year) 4

Proteinuria Response

• Larger early reductions in albuminuria at day 14 predict greater attenuation of subsequent eGFR decline 3
• Dapagliflozin increased the likelihood of regression from macroalbuminuria to microalbuminuria (HR 1.81) 3
• Among patients with UACR <3000 mg/g at baseline, dapagliflozin decreased progression to nephrotic-range proteinuria (HR 0.41) 3

Safety Considerations and Risk Mitigation

Volume Status Management

• Assess volume status before initiation and correct any volume depletion 4
• Consider proactive diuretic dose reduction in patients at high risk for volume depletion 2
• If eGFR decreases >30% from baseline WITH signs of hypovolemia, reduce diuretics first before adjusting dapagliflozin 4

Perioperative Management

• Withhold dapagliflozin at least 3 days before major surgery or prolonged fasting to prevent postoperative ketoacidosis 4

Sick Day Protocol

• Hold dapagliflozin during acute illness to minimize risk of ketoacidosis and volume depletion 2

Infection Risk

• Genital mycotic infections occur more frequently; educate patients on daily hygiene measures 4, 2
• Monitor for urinary tract infections 4
• Rare but serious: necrotizing fasciitis of the perineum (Fournier gangrene) requires immediate treatment if suspected 4

Hyperkalemia Benefit

• Dapagliflozin reduces hyperkalemia risk, facilitating concurrent use of mineralocorticoid receptor antagonists (finerenone) for additional renoprotection 4

Clinical Bottom Line for Nephrotic Syndrome

For true nephrotic syndrome (proteinuria >3.5 g/day with hypoalbuminemia and edema):

• While one case report showed dramatic reduction in nephrotic-range proteinuria (10.8 to 2.6 g/day over 24 weeks) with tofogliflozin in diabetic nephropathy 8, this represents low-quality evidence
• The DAPA-CKD trial excluded patients with UACR >5000 mg/g 3, so evidence for severe nephrotic syndrome is limited
• However, given the 59% reduction in progression to nephrotic-range proteinuria (HR 0.41) in patients starting with UACR <3000 mg/g 3, dapagliflozin should be initiated early to prevent progression to nephrotic syndrome
• The drug's diuretic effect and weight reduction (mean 1.5 kg) 6 may provide symptomatic benefit for edema management

The renoprotective mechanism extends beyond proteinuria reduction alone, as evidenced by similar clinical benefits in diabetic and non-diabetic CKD despite different magnitudes of albuminuria reduction 3, 7, suggesting SGLT2 inhibition addresses fundamental CKD pathophysiology regardless of etiology 7.