Letter to the Editor: Finerenone and proteinuria in diabetic kidney disease

Abstract

Most patients with diabetic kidney disease (DKD) suffer from proteinuria. Finerenone, a novel nonsteroidal mineralocorticoid receptor antagonist acts as anti-inflammatory factor reducing the kidney inflammation and fibrotic pathways, which are overactive in patients with advanced proteinuria. The study by Pasari et al, published in the recent issue of the World Journal of Nephrology, correlated the greater reduction of albuminuria with the higher baseline albuminuria using finerenone. However, heterogeneity, disproportion and variability in response using finerenone for the reduction of proteinuria has been observed. Patients with persistent proteinuria despite the optimal renin-angiotensin-aldosterone system blockage, sodium-glucose co-transporter -2 inhibitors and finerenone, remain at high risk for renal and cardiovascular events. More factors including the novel functions of histone lactylation possibly are involved in the deterioration of albuminuria in DKD. It may need combined and intensive therapy with an additional healthy lifestyle. More pharmacogenomic trials, proteomic analyses in long-term real-world cohorts need to clarify the pathogenetic mechanisms related to proteinuria in DKD.

Key Words: Diabetic nephropathy; Proteinuria; Kidney inflammation; Finerenone; Cardiovascular events

Core Tip: Diabetic nephropathy is mainly characterized by proteinuria, which contributes to renal progression and cardiovascular complications. Finerenone, a novel nonsteroidal mineralocorticoid receptor antagonist, can reduce proteinuria with a dependance on initial baseline proteinuria, despite its effect may be disproportional and variant. More factors including genetics or epigenetics may be involved in diabetic kidney pathology, because of which proteinuria persists.

TO THE EDITOR

We have read with a great interest the original article by Pasari et al[1], efficacy of finerenone in reducing proteinuria in diabetic kidney disease (DKD) patients, who were treated with maximum tolerable doses of dapagliflozin [sodium-glucose co-transporter -2 (SGLT2) inhibitor] and telmisartan [renin-angiotensin-aldosterone system (RAAS), blockage] for at least 4 weeks before the inclusion in the study. The enrolled patients received 10 mg daily finerenone for 6 months according to accepting rules for the usage of finerenone [estimated glomerular filtration rate (eGFR) > 25 mL/minute/1.73 m², and serum potassium < 5 mg/mL]. Then, the change of proteinuria was observed in combination with changes of other potential parameters. As responders were considered the patients who showed a reduction of proteinuria after receiving finerenone, even though without statistically significant difference. The responders had a significantly higher baseline proteinuria compared with non-responders. However, when the responders were stratified in groups according to baseline proteinuria, the higher reduction of proteinuria was shown in the group with less baseline proteinuria than in the group with high baseline proteinuria in contrary to expectations. In addition, according to this study, the baseline proteinuria was the unique statistically significant predictor for the effective response on finerenone usage.

Finerenone, a novel nonsteroidal mineralocorticoid receptor antagonist acts as anti-inflammatory factor reducing the kidney inflammation and fibrotic pathways, which are very active in patients with advanced proteinuria. This pathophysiological mechanism can explain the achieved greater benefit from the therapy in patients with higher baseline albuminuria.

In consistent, finerenone in reducing kidney failure and disease progression in DKD (FIDELIO-DKD) and finerenone in reducing cardiovascular mortality and morbidity in DKD (FIGARO-DKD) clinical trials have correlated the greater absolute reduction of albuminuria with the higher baseline albuminuria using finerenone delaying renal and cardiovascular events in patients with diabetic nephropathy[2]. Proteinuria seen in DKD is not only an indicator of renal damage, but also an independent predictor for cardiovascular complications.

Nevertheless, in this study heterogeneity, disproportion and variability in response was observed. A differentiation in the group of responders has been shown regarding with reduction of proteinuria related with baseline proteinuria. Another previous study also reported a variability in albuminuria reduction using finerenone, even though the treatment among patients was similar[3]. The difference with the findings of FIDELIO-DKD and FIGARO-DKD clinical trials, which established an absolute albuminuria reduction connected with higher baseline albuminuria, could be attributed to limitations of current article by Pasari et al[1], mainly including the small sample size, population heterogeneity, the lack of comparable arm, the short duration of observation, non-randomized study design and ceiling effects. In the mean- time, in this study the difference of proteinuria reduction between responders and non-responders was not statistically significant. Moreover, the heterogeneity in response of finerenone regarding with proteinuria reduction may be connected with DKD stage and pre-existing reversible or irreversible renal fibrosis. On the other hand, in this study finerenone was used as concomitant therapy, in contrast to FIDELIO-DKD and FIGARO-DKD clinical trials, in which finerenone was used as unique therapy.

Previously, it has been reported an additive benefit with the usage of finerenone acting as anti-inflammatory and anti-fibrotic factor in patients with high proteinuria despite dual RAAS and SGLT2 inhibition[4]. Moreover, it has been reported modest declines in measured GFR when finerenone was combined with dapagliflozin, due possibly to transient hemodynamic effect rather than structural kidney injury[4].

However, patients with persistent proteinuria even though they are treated by the optimal RAAS blockage, SGLT2 inhibitors and finerenone, remain at high risk for renal and cardiovascular events. Previous study showed that a combination therapy including SGLT2 inhibitors, glucagon-like peptide 1 receptor agonists (GLP-1RA) and healthy lifestyle improved the survival from cardiovascular events and death in patients with DKD, due possibly to direct action on glucose, blood pressure, weight and on improving endothelial dysfunction and inflammation[5]. In discrepancy, recent Intervention review by Cochrane database of systematic reviews, that identified 42 studies evaluating GLP-1 RA in 48148 patients with chronic kidney disease and type 2 diabetes, concluded that GLP-1RA probably reduce cardiovascular events in patients with DKD, but these medications may have a little or no effect on kidney failure reporting an uncertain benefit on eGFR and proteinuria[6].

More factors possibly are involved in kidney pathology during diabetes, which could be implicated for heterogeneity in response on combined optimal therapy including finerenone. Genetics or epigenetics factors may be included in these pathways. The methylation of DNA, the novel functions of histone lactylation and regulation of non-coding RNA may be involved in the progress of cell dysfunction, inflammation and fibrosis in the kidney, which ultimately lead to the deterioration of diabetic nephropathy[7]. Some patients with DKD may never show proteinuria reduction.

CONCLUSION

In conclusion, in many cases finerenone reduces proteinuria depended on baseline level of proteinuria in DKD, despite heterogeneity and variability in response is observed. It may need combined and intensive therapy with an additional healthy lifestyle. However, more factors including genetics or epigenetics possibly are involved in diabetic kidney pathology, because of which proteinuria persists. More pharmacogenomic trials, proteomic analyses in long-term real-world cohorts need to clarify the pathogenetic mechanisms related to proteinuria in diabetic nephropathy.