PARADOXICAL PROTEINURIA INCREASE WITH KIDNEY FUNCTION STABILIZATION DURING DAPAGLIFLOZIN THERAPY IN ADVANCED IGA NEPHROPATHY: A CASE REPORT

IgA nephropathy (IgAN) is the most common primary glomerulonephritis globally, with proteinuria recognized as a key prognostic marker and therapeutic target. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as renoprotective agents, primarily through their ability to reduce intraglomerular pressure and proteinuria via tubuloglomerular feedback (TGF) activation. However, whether SGLT2 inhibitors can provide kidney benefits independently of antiproteinuric effects remains unclear, particularly in advanced IgAN. We present an illustrative case demonstrating estimated glomerular filtration rate (eGFR) slope improved despite increased proteinuria following dapagliflozin treatment in advanced IgAN.

A woman with a 29-year history of progressive IgA nephropathy was diagnosed with advanced IgAN in her late twenties. She received comprehensive management including an angiotensin receptor blocker, tonsillectomy, multiple courses of glucocorticoid therapy, and intensive lifestyle and blood-pressure management. Despite these interventions, kidney function progressively declined. At age 57, serum creatinine (Cr) 2.75 mg/dL, eGFR 15 mL/min/1.73 m², and urinary protein-to-creatinine ratio (UPCR) 2.42 g/g, dapagliflozin 10 mg once daily was initiated. Time-averaged UPCR during the three years pre-dapagliflozin was 1.65 g/g, but increased to 2.98 g/g in the period from 90 days post-initiation through three years without active urinary sediment changes or clinical relapse. In contrast, the eGFR slope improved from –0.949 mL/min/1.73 m²/year pre-treatment to –0.073 mL/min/1.73 m²/year post-treatment.

This case demonstrates a discordance between worsening proteinuria and stabilization of kidney function during SGLT2 inhibitor therapy. This dissociation may be explained by alternative renoprotective mechanisms of SGLT2 inhibitors. First, SGLT2 inhibitors exert renoprotective effects by ameliorating tubulointerstitial hypoxia. During sodium and glucose reabsorption in the proximal tubule, oxygen delivery to the renal medulla becomes depleted. By suppressing glucose reabsorption, SGLT2 inhibitors improve renal oxygen utilization, thereby contributing to kidney protection. Second, SGLT2 inhibitors have been associated with reductions in multiple markers of inflammation and fibrosis, suggesting that they may confer kidney protection through anti-inflammatory and antifibrotic mechanisms. These effects are thought to be mediated by improvements in mitochondrial function, attenuation of oxidative stress, and amelioration of hyperuricemia induced by SGLT2 inhibitors. In summary, the renoprotective mechanisms of SGLT2 inhibitors extend beyond the improvement of TGF and involve multiple pathways. Therefore, even in cases where proteinuria does not decrease, SGLT2 inhibitors may still exert renoprotective effects. These findings challenge the prevailing paradigm that proteinuria reduction is necessary for kidney protection in IgAN.

This case suggests that SGLT2 inhibitors may confer kidney protection even in the presence of persistent or increasing proteinuria. It highlights the importance of reassessing therapeutic endpoints in IgAN and supports a broader mechanistic understanding of SGLT2 inhibitor action.