Finerenone-related initial declines in eGFR and urinary biomarkers of tubular injury: mechanistic insights from the FIVE-STAR trial

Background Several classes of therapies recommended in the care of patients with cardio-kidney-metabolic syndrome may induce initial declines in estimated glomerular filtration rate (eGFR). Clinicians and patients may be concerned that these changes may represent acute kidney injury, which may in turn lead to premature discontinuation of effective therapies. Methods FIVE-STAR was a multi-center, double-blind trial of 24-weeks of finerenone (10mg or 20mg) vs. matching placebo specifically designed to evaluate cardiovascular and kidney biomarkers in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). Patients were required to have eGFR ≥25 to <90 mL/min/1.73 m2 and elevated urinary albumin-to-creatinine ratio (≥30 to <3500 mg/g.Cr). An initial decline in eGFR was defined from baseline to 4 weeks of >10%. We compared treatment responses (finerenone vs. placebo) on changes in a detailed panel of 7 urinary biomarkers from baseline to 24 weeks, separately in those who did and did not experience an initial eGFR decline. Results Among 101 participants enrolled in FIVE-STAR, 24 (24%) experienced an eGFR decline >10%, more frequently with finerenone (n=17) than placebo (n=7). The presence or not of an initial eGFR decline did not modify finerenone’s effects on any urinary biomarker level over time (all Pinteraction>0.05). Furthermore, among individuals who experienced an initial eGFR decline, finerenone (vs. placebo) did not significantly affect urinary levels of L-FABP, NAG, NGAL, β2-microglobulin, α1-microglobulin, type IV collagen, or pentosidine over 24 week follow-up (all P>0.05: Figure). Conclusions Detailed urinary profiling confirms that the non-steroidal mineralocorticoid receptor antagonist, finerenone, does not affect markers of renal tubular injury, even among those who experience initial declines in eGFR. These data provide further reassurance that early eGFR declines do not represent acute tubular injury, and should not automatically prompt drug interruption or discontinuation.