Dapagliflozin in Non-Diabetic Kidney Disease (N-DKD): A Nephrologist's Practical Perspective

Non-diabetic chronic kidney disease (N-DKD) accounts for nearly half of the global CKD burden and comprises a heterogeneous group of disorders, including IgA nephropathy, focal segmental glomerulosclerosis, membranous nephropathy, hypertensive nephrosclerosis, and CKD of unknown etiology. In India, chronic glomerular diseases remain important contributors to N-DKD and progressive kidney dysfunction. Despite optimized supportive care with renin–angiotensin system blockade, many patients continue to experience progressive eGFR decline and remain at risk of kidney failure. ^1-3 The disease-trajectory modifying potential of widely experienced dapagliflozin has been scientifically reviewed in this context.

Dapagliflozin in Non-Diabetic Kidney Disease (N-DKD): Mechanistic Rationale

The renoprotective effects of SGLT2i including dapagliflozin extend beyond glycemic control and are mediated through complementary haemodynamic and molecular mechanisms. By inhibiting proximal tubular sodium-glucose reabsorption, dapagliflozin restores tubuloglomerular feedback, reduces intraglomerular hypertension and hyperfiltration, and lowers proteinuria. Furthermore, it activates AMPK while modulating HIF-1α, TGF-β, NF-κB, and RAAS signaling pathways, thereby improving tubular energy metabolism, reducing oxidative stress, suppressing inflammation and fibrosis, and preserving renal structure and function. Together, these pleiotropic actions provide a strong mechanistic rationale for dapagliflozin across diverse non-diabetic CKD etiologies, independent of its glucose-lowering effects. ⁴ (Figure 1)

**Abbreviations: AMPK: AMP-Activated Protein Kinase; HIF-1α: Hypoxia-Inducible Factor-1 Alpha; TGF-β: Transforming Growth Factor-Beta; NF-κB: Nuclear Factor Kappa B; RAAS: Renin–Angiotensin–Aldosterone System; SGLT2: Sodium-Glucose Cotransporter-2; CKD: Chronic Kidney Disease; N-DKD: Non-Diabetic Kidney Disease.

Dapagliflozin in Non-Diabetic Kidney Disease (N-DKD): Insights from Clinical Studies

Dapagliflozin - Landmark Evidence in Non-Diabetic CKD: The significant evidence supporting dapagliflozin in non-diabetic CKD comes from the prespecified analysis of the DAPA-CKD trial, which included 4,304 patients, of whom 1,398 did not have diabetes. Over a median follow-up of 2.4 years, dapagliflozin 10 mg once daily reduced the relative risk of the primary composite outcome of sustained ≥50% eGFR decline, end-stage kidney disease (ESKD), or kidney/cardiovascular death by 50% compared with placebo (HR 0.50; 95% CI 0.35–0.72). The benefits were consistent across chronic glomerulonephritis, hypertensive/ischaemic nephropathy, and CKD of other etiologies, with a safety profile comparable to placebo. The study concluded that dapagliflozin reduced major adverse kidney and cardiovascular outcomes in patients with CKD, irrespective of diabetes status. ⁵

Effect of Dapagliflozin in Advanced Non-Diabetic CKD: The ADAPT trial further extended the evidence to patients with advanced non-diabetic CKD. In this prospective, randomized, double-blind, placebo-controlled crossover study, 31 adults with stage IV CKD and persistent proteinuria (>0.5 g/day) received dapagliflozin 10 mg/day or placebo for six weeks. Dapagliflozin significantly reduced measured GFR by 1.88 mL/min/1.73 m² and proteinuria by 0.50 g/24 h compared with placebo, consistent with an expected hemodynamic response, without serious treatment-related adverse events. The study concluded that dapagliflozin was well tolerated and may reduce proteinuria in patients with advanced non-diabetic CKD, although larger and longer-term studies are needed to confirm sustained renoprotection. ⁶

Effect of Dapagliflozin in Focal Segmental Glomerulosclerosis: A prespecified DAPA-CKD subgroup analysis evaluated 104 patients with biopsy-confirmed focal segmental glomerulosclerosis (FSGS), a progressive non-diabetic glomerular disease, followed for a median of 2.4 years. Dapagliflozin slowed the chronic rate of eGFR decline compared with placebo (−1.9 vs −4.0 mL/min/1.73 m²/year) and demonstrated a favorable trend toward reduced kidney events despite the limited sample size. The incidence of adverse events and treatment discontinuations was similar between groups, supporting the safety of dapagliflozin in this high-risk population. ⁷

Guideline Recommendation and Clinical Implication

Recent clinical practice guidelines have expanded the role of SGLT2 inhibitors beyond diabetes, recognizing their benefits in slowing CKD progression across a broad spectrum of kidney diseases. The 2024 KDIGO CKD Guideline recommends SGLT2 inhibitor therapy for adults with CKD and proteinuria (UACR ≥200 mg/g) with an eGFR ≥20 mL/min/1.73 m², irrespective of diabetes status.

Dapagliflozin may be considered as an adjunct to optimized supportive care, including RAAS blockade, while clinicians should anticipate a modest early decline in eGFR that reflects a reversible haemodynamic effect rather than treatment-related kidney injury. ⁸

Practice Pearls for Clinicians

In clinical practice, dapagliflozin offers nephrologists an evidence-based option to strengthen kidney protection in proteinuric non-diabetic CKD. Its role is particularly relevant in patients with ongoing albuminuria or progressive eGFR decline despite optimized supportive care. Dapagliflozin may be viewed as a complementary renoprotective strategy across eligible N-DKD phenotypes. Careful follow-up of eGFR, proteinuria, blood pressure, volume status, and tolerability may help maximize long-term benefit while ensuring safe continuation of therapy.

Key Message

• Dapagliflozin provides renoprotection beyond glycemic control by reducing intraglomerular pressure, proteinuria, inflammation, and fibrosis.
• The benefits of dapagliflozin in Non-Diabetic Kidney Disease (N-DKD) appear consistent across glomerular disease, FSGS, and advanced proteinuric CKD populations.
• Dapagliflozin may complement RAAS blockade and disease-specific therapy in eligible CKD patients.
• Early initiation and regular monitoring may help preserve kidney function and delay CKD progression.