Can SGLT2 Inhibitors Be Added in Primary Membranous Nephropathy?
Direct Recommendation
Yes, you should add an SGLT2 inhibitor (dapagliflozin 10 mg daily or empagliflozin 10 mg daily) to your patient with primary membranous nephropathy, sub-nephrotic proteinuria (~1 g/day), and eGFR ≥30 mL/min/1.73 m², as these agents provide robust renal protection independent of diabetes status and are now considered foundational therapy for proteinuric chronic kidney disease. 1, 2, 3
Evidence-Based Rationale
SGLT2 Inhibitors in Non-Diabetic Proteinuric CKD
The DAPA-CKD trial demonstrated that dapagliflozin reduces the composite of sustained eGFR decline ≥50%, end-stage kidney disease, or renal/cardiovascular death by 39% (HR 0.61,95% CI 0.51-0.72) in patients with chronic kidney disease and albuminuria, with 32.5% of participants having no diabetes. 2, 4
The kidney-specific composite outcome (sustained eGFR decline, end-stage renal disease, or renal death) was reduced by 44% (HR 0.56,95% CI 0.45-0.68), demonstrating clear renoprotection in non-diabetic CKD. 2, 5
SGLT2 inhibition is similarly efficacious in diabetic and non-diabetic CKD with proteinuria, making treatment of CKD rather than "diabetic nephropathy" the central paradigm. 6
Specific Evidence in Primary Glomerular Disease
The DAPA-CKD trial included more patients with IgA nephropathy than any previous IgA nephropathy trial, establishing dual renin-angiotensin/SGLT2 inhibition as the new standard for proteinuric glomerular disease. 6
A 2025 multicenter prospective study in Japanese patients with biopsy-confirmed IgA nephropathy showed that dapagliflozin reduces residual proteinuria even after treatment with corticosteroids and renin-angiotensin system inhibitors, with significant attenuation of the post-treatment eGFR slope. 7
A 2024 randomized controlled trial in non-diabetic primary nephrotic syndrome patients demonstrated that adding dapagliflozin 10 mg to standard immunosuppression resulted in significant weight loss and triglyceride reduction, with stable eGFR after 6 months. 8
The 2020 DIAMOND trial in non-diabetic proteinuric CKD patients showed that while 6-week dapagliflozin treatment did not reduce proteinuria, it induced an acute and fully reversible decline in measured GFR, establishing the safety profile for short-term use. 9
Guideline Support for Non-Diabetic CKD
The 2024 BMJ guideline panel issues a strong recommendation for SGLT2 inhibitors in all adults at high or very-high risk of CKD progression and related complications, regardless of diabetes status. 3
The KDIGO 2020 guideline gives a Grade 1A (highest level) recommendation for using SGLT2 inhibitors in adults with chronic kidney disease and eGFR ≥30 mL/min/1.73 m², with benefits extending to non-diabetic patients. 3
The 2019 ESC guidelines recommend SGLT2 inhibitors for patients with eGFR 30 to <90 mL/min/1.73 m² to reduce renal endpoints, with a Class I, Level B recommendation. 1
Practical Implementation for Your Patient
Initiation Protocol
Start dapagliflozin 10 mg once daily (or empagliflozin 10 mg once daily) as the standard dose for renal protection; no titration is required. 2, 5
Confirm eGFR ≥30 mL/min/1.73 m² before initiation, which your patient meets with eGFR ≥30 mL/min/1.73 m². 1, 2
Assess volume status before starting and correct any depletion; consider reducing concurrent diuretic doses if present. 2, 5
Continue ACE inhibitors or ARBs unchanged when initiating the SGLT2 inhibitor, as >99% of DAPA-CKD participants were on renin-angiotensin-aldosterone system blockers with additive renal protection. 2
Monitoring Strategy
Re-measure eGFR 1-2 weeks after starting dapagliflozin; expect a modest, reversible dip of 2-5 mL/min/1.73 m² that should not trigger discontinuation. 2, 5, 4
Patients who experienced an acute eGFR reduction >10% at 2 weeks in DAPA-CKD actually had better long-term renal outcomes with slower eGFR decline (-1.58 vs -2.44 mL/min/1.73 m²/year) compared to those without an initial dip. 4
Re-assess eGFR every 3-6 months if eGFR <60 mL/min/1.73 m², or annually if eGFR ≥60 mL/min/1.73 m². 2, 5
Integration with Membranous Nephropathy Management
All patients with primary membranous nephropathy and proteinuria should receive optimal supportive care, which now includes SGLT2 inhibitors as foundational therapy. 1
For your patient with sub-nephrotic proteinuria (~1 g/day), SGLT2 inhibition provides renal protection while you monitor for spontaneous remission or progression requiring immunosuppressive therapy. 1
If immunosuppressive therapy becomes indicated based on KDIGO risk stratification (Figure 3 and 4 in the guideline), continue the SGLT2 inhibitor as background therapy alongside rituximab, cyclophosphamide, or calcineurin inhibitors. 1
From now on, membranous nephropathy trials without SGLT2 inhibition as background therapy will be of limited value, as dual renin-angiotensin/SGLT2 inhibition becomes the new standard. 6
Safety Precautions Specific to Your Patient
Contraindication Assessment
Your patient has no recurrent genital or urinary tract infections, which is favorable as genital mycotic infections occur in approximately 6% of SGLT2 inhibitor users versus 1% with placebo. 2, 5
Your patient has no severe volume depletion or hypotension, meeting the safety criteria for initiation. 2, 5
Withhold dapagliflozin during acute illness with reduced oral intake, fever, vomiting, or diarrhea, and stop at least 3 days before major surgery or procedures requiring prolonged fasting. 2, 5
Patient Education
Counsel about euglycemic diabetic ketoacidosis (even in non-diabetic patients, though extremely rare) and advise immediate medical evaluation for unexplained malaise, nausea, vomiting, or abdominal pain. 2, 5
Emphasize daily hygiene to reduce the risk of genital mycotic infections. 2, 5
Critical Pitfalls to Avoid
Do not withhold SGLT2 inhibitors solely because your patient does not have diabetes; the DAPA-CKD trial demonstrated equivalent benefit in non-diabetic CKD. 2, 3, 6
Do not discontinue dapagliflozin if eGFR falls below 45 mL/min/1.73 m² after initiation; cardiovascular and renal benefits persist despite reduced glucose-lowering efficacy. 1, 2, 5
Do not stop dapagliflozin in response to the expected early eGFR dip in the first 2-4 weeks; this change is hemodynamic and reversible, not indicative of kidney injury. 2, 5, 4
Do not reduce the dapagliflozin dose below 10 mg for renal indications, even at lower eGFR levels; all outcome trials used the fixed 10 mg dose. 2, 5