Abstract
Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, exhibits anti-fibrotic and anti-inflammatory properties. While numerous studies have demonstrated its efficacy in reducing kidney and cardiovascular events in diabetic kidney disease, data on non-diabetic chronic kidney disease (CKD) remain limited. This retrospective study evaluated the safety and efficacy of finerenone in adult patients with non-diabetic CKD. The primary study parameters included estimated glomerular filtration rate (eGFR), 24-h proteinuria, serum potassium (sK+), and serum albumin. A total of 78 patients met the eligibility criteria. Following finerenone treatment, the overall efficacy rate was 61.5% (n = 48). Among responders, 24-h proteinuria significantly decreased (1.71 ± 0.32 g/d at baseline, 0.64 ± 0.14 g/d at 3 months, and 0.55 ± 0.14 g/d at 6 months), while eGFR showed a transient decline (88.34 ± 4.48 mL/min/1.73 m2 at baseline, 82.09 ± 4.69 mL/min/1.73 m2 at 3 months, and 87.05 ± 6.21 mL/min/1.73 m2 at 6 months). Serum potassium fluctuated slightly (4.23 ± 0.07 mmol/L at baseline, 4.46 ± 0.07 mmol/L at 3 months, and 4.41 ± 0.08 mmol/L at 6 months), whereas serum albumin progressively increased (39.17 ± 0.93 g/L at baseline, 41.80 ± 0.70 g/L at 3 months, and 42.24 ± 0.70 g/L at 6 months). Among patients with IgA nephropathy (IgAN), 50% (n = 20) achieved proteinuria reduction. Adverse effects were minimal. Finerenone effectively reduced proteinuria in non-diabetic CKD patients with minimal impact on eGFR and sK+, supporting its efficacy and safety in real-world clinical practice in China.
Keywords: Finerenone, non-diabetic, chronic kidney disease, 24-h urinary protein, estimated glomerular filtration rate
Introduction
Chronic kidney disease (CKD) has a poor prognosis and a prolonged course. In recent years, with an aging population, CKD has risen in the global ranking of causes of death [1]. It is projected to become one of the top five global causes of death by 2040 [2]. Without treatment, CKD patients face an increased risk of cardiovascular events and progression to end-stage renal disease (ESRD), with cardiovascular-related mortality exceeding the risk of kidney failure. This imposes a significant burden on both patients and healthcare systems.
Proteinuria is strongly associated with cardiovascular and kidney-related mortality as well as ESRD [3]. Moreover, studies have shown that albuminuria independently predicts cardiovascular events and mortality in CKD patients [4,5]. A meta-analysis of clinical trials demonstrated that a 30% reduction in proteinuria decreases the likelihood of CKD progression to ESRD by 23.7% [6]. Proteinuria-induced renal inflammation and fibrosis further damage glomerular and tubular function, creating a vicious cycle [7]. Thus, inflammation and fibrosis suppression represent key therapeutic targets.
Glomerular damage, vascular disease, and renal tubulointerstitial fibrosis are all linked to mineralocorticoid receptor (MR) activation [8]. Excessive MR activation by aldosterone promotes renal inflammation and fibrosis by increasing the synthesis of pro-inflammatory cytokines, reactive oxygen species (ROS), and connective tissue growth factors8. Mineralocorticoid receptor antagonists (MRAs) offer renal protection through multiple mechanisms. In animal models, MR blockade has been shown to reduce proteinuria, alleviate kidney damage, and prevent glomerulosclerosis [9–11]. In a study of CKD patients with persistent proteinuria (>1 g/d) despite enalapril treatment, four weeks of spironolactone therapy resulted in a 54% reduction in urinary protein excretion, independent of blood pressure effects [12]. In non-diabetic CKD, a trial evaluating eplerenone combined with conventional antihypertensive therapy demonstrated a significant reduction in the urine albumin-to-creatinine ratio (UACR) compared with placebo [13]. However, the clinical use of eplerenone and spironolactone is limited due to their association with an increased risk of hyperkalemia in CKD patients [14].
Finerenone is a novel nonsteroidal mineralocorticoid receptor antagonist (MRA) with greater affinity than eplerenone and higher selectivity than spironolactone [15]. Preclinical studies have shown that finerenone is more effective than eplerenone in reducing proteinuria and cardiac-renal damage [16]. In patients with heart failure and mild to moderate CKD, the ARTS study reported that oral finerenone (2.5–10 mg/day) reduced proteinuria while significantly lowering the incidence of hyperkalemia compared with spironolactone [17]. The phase III FIDELIO-DKD trial demonstrated that finerenone reduced the progression of diabetic kidney disease (DKD), decreasing the primary outcome (kidney failure, a sustained ≥40% reduction in eGFR for at least four weeks, or death from renal causes) by 18% in patients with eGFRs of 25–75 mL/min/1.73 m2 [18]. In FIGARO-DKD, which evaluated renal outcomes as a secondary endpoint, finerenone significantly reduced the urine albumin-to-creatinine ratio (UACR) within four months of treatment in type 2 diabetes (T2D) patients with varying renal function (30 ≤ UACR < 300 mg/g and 25 ≤ eGFR ≤ 90 mL/min/1.73 m2; or 300 ≤ UACR ≤ 5000 mg/g and eGFR ≥ 60 mL/min/1.73 m2) [19]. The FIDELITY analysis confirmed that finerenone slowed DKD progression by 23% and reduced the risk of ESRD by 20% [20]. Although finerenone is associated with a higher incidence and discontinuation rate due to hyperkalemia than placebo, this risk can be mitigated by monitoring serum potassium (sK+) levels and adjusting the dosage accordingly. The use of potassium-binding agents, such as sodium zirconium cyclosilicate, has been shown to effectively lower sK + levels and improve treatment safety [21]. Consequently, the American Diabetes Association (ADA) recommends finerenone to slow CKD progression [22], and the 2022 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline endorses its use in T2D patients with persistent albuminuria despite receiving the maximum tolerated dose of renin-angiotensin system inhibitors (RASi) [23].
While most clinical trials have focused on CKD with T2D, non-diabetic CKD also imposes a substantial burden on patients. However, data on the long-term effects of MRAs on renal function in non-diabetic CKD remain limited. Previous studies have included non-diabetic CKD cases. A meta-analysis of 26 studies involving 15,531 CKD patients with or without diabetes found that MRAs (including finerenone) significantly reduced UACR without increasing sK + levels [24]. A randomized controlled trial in stage 2 and 3 CKD (with diabetic kidney disease accounting for only 14.2% of cases) showed that eplerenone slowed eGFR decline, with eGFR levels remaining significantly higher in the eplerenone group than in the placebo group at 24 and 36 months [25]. Additionally, a small retrospective study found that low-dose spironolactone combined with an ARB reduced proteinuria in patients with glomerulonephritis (GN) after three months of treatment [26]. Further supporting evidence comes from a study comparing finerenone and spironolactone in patients with heart failure and reduced left ventricular ejection fraction (HFrEF) and moderate CKD, in which 66% of participants had non-diabetic CKD [17]. A recent small retrospective analysis of 16 patients with non-diabetic CKD also demonstrated that finerenone effectively reduced UACR while lowering the incidence of hyperkalemia by 34% [27]. These studies have provided preliminary insights into the use of MRAs in non-diabetic CKD. However, clinical evidence for finerenone in this population remains insufficient. The FIND-CKD trial [28], the first large phase 3 study designed to assess the efficacy and safety of finerenone in non-diabetic CKD, aims to expand its indications, but results are not yet available.
Given this background, this retrospective study aimed to evaluate the real-world safety and effectiveness of finerenone in non-diabetic CKD. Additionally, we further analyzed its efficacy in combination therapy and in specific pathological subgroups, such as immunoglobulin A nephropathy (IgAN) and non-IgAN cases.
Methods
Study patients
This study included patients aged ≥18 years with non-diabetic CKD who received finerenone at the First Affiliated Hospital of Xi’an Jiaotong University between January 1, 2023, and August 31, 2023. Exclusion criteria were as follows: eGFR <45 mL/min/1.73 m2 or serum potassium ≥4.8 mmol/L at the time of finerenone initiation. Immunosuppressive therapy or prednisone ≥10 mg (methylprednisolone ≥8 mg) for induction. Lack of follow-up after starting finerenone treatment (Figure 1).
Figure 1.
Study flowchart.
The etiology of CKD was determined by the treating physician based on medical history, clinical characteristics, and kidney biopsy findings. eGFR was calculated using the CKD-EPI formula.
This study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of the First Affiliated Hospital of Xi’an Jiaotong University. Given the retrospective study design and the complete anonymization of patient data, the requirement for informed consent was waived.
Data collection and definitions
Baseline demographic data, disease characteristics, laboratory parameters, and adverse events (AEs) were extracted from electronic medical records. Study outcomes were assessed within six months of finerenone treatment initiation. The follow-up period was defined as the time from prescription to the last recorded outpatient visit. For key follow-up points (three and six months), data recorded within one month of the target date were used if the exact time point was missing.
Baseline was defined as the time of the first finerenone prescription. Effective treatment was defined as meeting either of the following criteria within six months of treatment initiation: 24-h urinary protein <0.5 g/d, stable serum creatinine, and serum albumin >35 g/L. ≥30% reduction in 24-h urinary protein from baseline, regardless of serum albumin normalization. Proteinuria remission was defined as a ≥ 25% reduction in 24-h urinary protein from baseline, with a reduction to <1 g/d within six months of treatment initiation. Safety Definitions: Hypotension: SBP <90 mmHg or DBP <60 mmHg. Hyperkalemia: Serum potassium >5.5 mmol/L.
Outcomes
Primary outcomes: 1. Effective treatment rate following finerenone therapy. 2. In effective cases, changes in 24-h urinary protein, eGFR, sK+, and serum albumin from baseline to 3 and 6 months.
Secondary outcomes: 1. Effective treatment rate in combined medication subgroups. 2. Comparison of treatment effectiveness between pathological subgroups (IgAN vs. non-IgAN), including changes in 24-h urinary protein, eGFR, sK+, and serum albumin at 3 and 6 months, with a focus on proteinuria remission in IgAN. 3. AEs, including treatment discontinuation due to hyperkalemia.
Statistical analysis
This retrospective, single-center real-world cohort study analyzed quantitative data with a normal distribution as mean ± standard deviation (SD) and categorical variables as frequency and percentage. Categorical variables were compared using the χ2 test or Fisher’s exact test, while continuous variables were analyzed with the t-test. The time effect of a variable was defined as its change over time. Generalized estimation equations were used to analyze repeated measurements and assess the statistical significance of time effect differences within groups. Potential influencing factors, including combined medication (e.g. RASi), age, gender, and blood pressure, were adjusted as covariates. Data analysis was conducted using SPSS 27.0 (IBM) and GraphPad Prism v.9.5. A two-sided p < 0.05 was considered statistically significant.
Results
Baseline characteristics
A total of 364 non-diabetic CKD patients were screened based on the inclusion and exclusion criteria, of whom 78 were ultimately enrolled (Figure 1).
The 78 participants had a mean age of 41.53 ± 12.54 years, including 50 (64.1%) men. Cardiovascular disease was present in 34 (43.6%) cases. The mean height was 1.67 ± 0.12 meters, weight was 75.37 ± 15.56 kg, and BMI was 27.34 ± 6.26 kg/m2. After treatment, the 48 patients with effective outcomes had a mean age of 44.33 ± 12.75 years, with 31 (64.6%) men and 20 (41.7%) having cardiovascular disease. Regarding concomitant medications, the most frequently used drugs were RASi (n = 67, 85.9%), sodium-glucose cotransporter-2 inhibitors (SGLT2i) (n = 49, 62.8%), and statins (n = 33, 42.3%). Only 2 (2.6%) patients received glucagon-like peptide-1 receptor agonists (GLP-1RA), with one in combination with RASi and the other with both RASi and SGLT2i. Low-dose corticosteroids (<10 mg prednisone) were administered to 5 (6.4%) patients, all for IgAN. Other medications included diuretics, antiplatelet agents, and potassium binders (Table 1). Except for 5 patients who received low-dose corticosteroids, the rest of the patients did not receive immunosuppressants for at least 6 months before initiating finerenone treatment.
Table 1.
Baseline characteristics of all patients and the effective casesa.
| Characteristic | All patients (n = 78) | Effective cases (n = 48) |
|---|---|---|
| Age, y | 41.53 ± 12.54 | 44.33 ± 12.75 |
| Male sex, N (%) | 50 (64.1) | 31 (64.6) |
| Female sex, N (%) | 28 (35.9) | 17 (35.4) |
| Systolic blood pressure, mmHg | 124.52 ± 16.40 | 122.41 ± 14.95 |
| Serum potassium, mmol/L | 4.20 ± 0.05 | 4.23 ± 0.07 |
| Albumin, g/L | 39.76 ± 0.75 | 39.17 ± 0.93 |
| eGFR, mL/min/1.73 m² | 89.03 ± 3.53 | 88.34 ± 4.48 |
| eGFR, mL/min/1.73 m², N (%) | ||
| 45–60 | 18 (23.1) | 13 (27.0) |
| ≥60 | 60 (76.9) | 35 (73.0) |
| 24-h urine protein, g/d | 1.82 ± 0.27 | 1.71 ± 0.32 |
| 24-h urine protein, g/d, N (%) | ||
| <0.5 | 8 (10.3) | 7 (14.6) |
| Between 0.5 and 3.5 | 64 (82.0) | 38 (79.2) |
| ≥3.5 | 6 (7.7) | 3 (6.3) |
| Cardiovascular disease, N (%) | 34 (43.6) | 20 (41.7) |
| Concomitant medications, N (%) | ||
| RASib | 22 (28.2) | 14 (29.2) |
| ACEi | 1 (1.3) | 1 (2.1) |
| ARB | 21 (26.9) | 13 (27.1) |
| SGLT2ic | 5 (6.4) | 3 (6.3) |
| RASi + SGLT2id | 43 (55.1) | 27 (56.3) |
| Potassium binderse | 5 (6.4) | 3 (6.3) |
| Diuretics | 3 (3.8) | 3 (6.3) |
| Statins | 33 (42.3) | 24 (50.0) |
| Antiplatelets | 3 (3.8) | 3 (6.3) |
eGFR, estimated glomerular filtration rate; RASi, Renin–angiotensin system inhibitors; ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin-receptor blockers; SGLT2i, sodium-glucose cotransporter-2 inhibitors.
. Plus or minus values indicate mean ± standard deviation.
. RASi refers to the use of RASi alone without SGLT2i and glucagon-like peptide-1 (GLP-1) receptor agonists.
. SGLT2i refers to the use of SGLT2i alone without RASi and glucagon-like peptide-1 (GLP-1) receptor agonists.
. RASi + SGLT2i refers to the simultaneous use of RASi and SGLT2i.
. Potassium binder: sodium polystyrene sulfonate, calcium polystyrene sulfonate, sodium zirconium cyclosilicate.
In total, 69 of 78 patients (88.5%) underwent kidney biopsy, which excluded diabetic nephropathy (DKD). Among them, 26 had abnormal glucose metabolism, including 19 with type 2 diabetes (T2DM), 6 with impaired glucose tolerance (IGT), and 1 with impaired fasting glucose (IFG). Additionally, 6 (8%) patients with chronic glomerulonephritis (CGN) and 3 (4%) CKD patients who did not undergo renal biopsy had no history of diabetes. Figure 2 illustrates the main etiologic characteristics at the initiation of finerenone treatment: 40 (51%) had IgAN, 14 (18%) membranous nephropathy (MN), 6 (8%) CGN, 5 (6%) metabolic syndrome (MS), 3 (4%) CKD (unknown pathological type), and 3 (4%) mesangial proliferative glomerulonephritis (MsPGN). Other etiologies included hypertensive renal disease (HRD), lupus nephritis (LN), minimal change disease (MCD), anti-glomerular basement membrane disease (Anti-GBM), chronic interstitial nephritis (CIN), multiple myeloma (MM), and Henoch-Schönlein purpura nephritis (HSPN), each observed in one case (1%).
Figure 2.
Etiologic characteristics. MN, membranous nephropathy; CGN, chronic glomerulonephritis; MS, metabolic syndrome; CKD, chronic kidney disease (unknown pathological type); MsPGN, mesangial proliferative glomerulonephritis; HRD, hypertensive renal disease; anti-GBM, anti-glomerular basement membrane disease; LN, lupus nephritis; MM, multiple myeloma; MCD, minimal change disease; CIN, chronic interstitial nephritis; HSPN, Henoch-Schonlein purpura nephritis.
Effects of finerenone
Main outcomes
Of the 78 enrolled cases, 48 showed effective treatment, resulting in an effectiveness rate of 61.5%. The outcomes of these effective cases are shown in Figure 3. Within 6 months of finerenone initiation, 24-h proteinuria consistently decreased compared to baseline, with a statistically significant reduction (Figure 3(A)). eGFR initially declined at 3 months of treatment but rebounded by 6 months (Figure 3(B)). Serum K + remained stable, with values remaining below 4.8 mmol/L, indicating no severe hyperkalemia (Figure 3(C)). Serum albumin gradually increased (Figure 3(D)).
Figure 3.
Changes in 24-h urinary protein (a), eGFR (B), sK+ (C), and serum albumin (D) from baseline to 6 months in effective cases. **p < 0.05, ***p < 0.005 (statistically significant 3 or 6 months after treatment compared to baseline). Data are presented as mean ± standard deviation; sK+, serum potassium; eGFR, estimated glomerular filtration rate.
The average 24-h proteinuria at finerenone initiation was 1.71 ± 0.32 g/day (95% CI: 1.08–2.33), and the average eGFR was 88.34 ± 4.48 mL/min/1.73 m2 (95% CI: 79.56–97.12). At 3 and 6 months after initiation, average proteinuria levels were 0.64 ± 0.14 g/day (95% CI: 0.36–0.92, p = 0.002) and 0.55 ± 0.14 g/day (95% CI: 0.28–0.83, p < 0.001), respectively. The average percentage reductions from baseline were −63% (95% CI: −67%, −61%, p = 0.002) at 3 months and −68% (95% CI: −74%, −64%, p < 0.001) at 6 months. Mean eGFR values were 82.09 ± 4.69 mL/min/1.73 m2 (95% CI: 72.90–91.27, p = 0.016) at 3 months and 87.05 ± 6.21 mL/min/1.73 m2 (95% CI: 74.87–99.23, p = 0.759) at 6 months. Average serum K + levels were 4.23 ± 0.07 mmol/L (95% CI: 4.10–4.37) at baseline, 4.46 ± 0.07 mmol/L (95% CI: 4.33–4.59, p = 0.003) at 3 months, and 4.41 ± 0.08 mmol/L (95% CI: 4.25–4.57, p = 0.041) at 6 months. Average serum albumin levels were 39.17 ± 0.93 g/L (95% CI: 37.34–41.00) at baseline, 41.80 ± 0.70 g/L (95% CI: 40.43–43.17, p = 0.005) at 3 months, and 42.24 ± 0.70 g/L (95% CI: 40.87–43.61, p = 0.003) at 6 months.
Secondary outcomes
Figure 4 illustrates the efficacy of finerenone treatment in subgroups based on concomitant medications. The subgroups included RASi alone (n = 22, 28.2%), SGLT2i alone (n = 5, 6.4%), RASi plus SGLT2i (n = 43, 55.1%), and no RASi, SGLT2i, or GLP-1 receptor agonists (GLP-1RA) (n = 6, 7.7%). The effective rates for these subgroups were 64, 60, 63, and 50%, respectively. However, no statistically significant difference was observed in the effective rates across these groups (χ2 = 0.664, p = 0.952).
Figure 4.
Effective rates of subgroups according to concomitant medications. RASi, renin–angiotensin system inhibitors; SGLT2i, sodium-glucose cotransporter-2 inhibitors; RASi refers to the use of RASi alone without SGLT2i and glucagon-like peptide-1 receptor agonists (GLP-1RA); SGLT2i refers to the use of SGLT2i alone without RASi and GLP-1RA; RASi + SGLT2i refers to the simultaneous use of RASi and SGLT2i; "No" refers to the absence of combined use of RASi, SGLT2i, and GLP-1RA.
The pathological subgroups were IgAN and non-IgAN. Table 2 shows no significant differences in age, gender, systolic blood pressure, cardiovascular history, 24-h proteinuria, eGFR, or use of RASi or SGLT2i combinations between the IgAN and non-IgAN groups at the onset of finerenone treatment, for both all patients and effective cases.
Table 2.
Baseline characteristics of the IgAN and non-IgAN groupsa.
| Characteristic | ALL |
P | Effective |
P | ||
|---|---|---|---|---|---|---|
| IgAN (n = 40) |
Non-IgAN (n = 38) |
IgAN (n = 22) |
Non-IgAN (n = 26) |
|||
| Age, y | 38.90 ± 10.34 | 44.29 ± 14.11 | 0.060 | 40.77 ± 10.74 | 47.35 ± 13.71 | 0.075 |
| Sex, N (%) | 0.438 | 0.632 | ||||
| Male | 24 (60.0) | 26 (68.4) | 15 (68.2) | 16 (61.5) | ||
| Female | 16 (40.0) | 12 (31.6) | 7 (31.8) | 10 (38.5) | ||
| Systolic blood pressure, mm Hg | 125.21 ± 19.86 | 123.57 ± 10.24 | 0.706 | 122.24 ± 18.89 | 122.60 ± 9.35 | 0.946 |
| Serum potassium, mmol/L | 4.20 ± 0.08 | 4.17 ± 0.08 | 4.16 ± 0.14 | 4.20 ± 0.09 | ||
| Albumin, g/L | 41.33 ± 0.63 | 38.02 ± 1.41 | 40.15 ± 0.60 | 38.18 ± 1.57 | ||
| eGFR, mL/min/1.73 m² | 83.98 ± 4.71 | 102.29 ± 3.65 | 76.60 ± 7.71 | 101.54 ± 3.87 | ||
| eGFR, mL/min/1.73 m², N (%) | ||||||
| 45–60 | 10 (25.0) | 8 (21.1) | 0.681 | 7 (31.8) | 6 (23.1) | 0.502 |
| ≥60 | 30 (75.0) | 30 (78.9) | 0.681 | 15 (68.2) | 20 (76.9) | 0.502 |
| 24-h proteinuria, g/d | 1.54 ± 0.28 | 2.11 ± 0.52 | 1.11 ± 0.16 | 2.24 ± 0.63 | ||
| 24-h proteinuria, g/d, N (%) | ||||||
| <0.5 | 3 (7.5) | 5 (13.2) | 0.413 | 2 (9.1) | 5 (19.2) | 0.326 |
| 0.5−3.5 | 35 (87.5) | 29 (76.3) | 0.201 | 20 (90.9) | 18 (69.2) | 0.068 |
| ≥3.5 | 2 (5.0) | 4 (10.5) | 0.363 | 0 | 3 (11.5) | 0.103 |
| Cardiovascular disease | 17 (42.5) | 14 (36.8) | 0.610 | 7 (31.8) | 11 (42.3) | 0.454 |
| Baseline medications, N (%) | 0.377 | 0.521 | ||||
| RASib | 12 (30.0) | 11 (28.9) | 7 (31.8) | 7 (26.9) | ||
| ACEi | 0 | 1 (2.6) | 0 | 1 (3.8) | ||
| ARB | 12 (30.0) | 10 (26.3) | 7 (31.8) | 6 (23.1) | ||
| SGLT2ic | 1 (2.5) | 4 (10.5) | 0 | 3 (11.5) | ||
| RASi + SGLT2id | 24 (60.0) | 19 (50.0) | 13 (59.1) | 14 (53.8) | ||
| Potassium bindere | 1 (2.5) | 4 (10.5) | 1 (4.5) | 2 (7.7) | ||
| Diuretics | 2 (5.0) | 1(2.6) | 2 (9.1) | 1 (3.8) | ||
| Statins | 11 (27.5) | 22 (57.9) | 8 (36.4) | 16 (61.5) | ||
| Antiplatelets | 0 | 3 (7.9) | 0 | 3 (11.5) | ||
eGFR, estimated glomerular filtration rate; RASi, Renin–angiotensin system inhibitors; ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin-receptor blockers; SGLT2i, sodium-glucose cotransporter-2 inhibitors.
Plus or minus values indicate mean ± standard deviation.
RASi refers to the use of RASi alone without SGLT2i and glucagon-like peptide-1 (GLP-1) receptor agonists.
SGLT2i refers to the use of SGLT2i alone without RASi and glucagon-like peptide-1 (GLP-1) receptor agonists.
RASi + SGLT2i refers to the simultaneous use of RASi and SGLT2i.
Potassium binder: sodium polystyrene sulfonate, calcium polystyrene sulfonate, sodium zirconium cyclosilicate.
The χ2 test, Fisher’s exact test, or t-test was used to compare both groups.
The effective rate of treatment was higher in the non-IgAN group (n = 26, 68.5%) compared to the IgAN group (n = 22, 55.0%).
Follow-up analysis of the effective cases in both IgAN and non-IgAN groups revealed significant decreases in 24-h urinary protein levels at 3 and 6 months after finerenone initiation (p < 0.05 for all). The average percentage changes at 6 months from baseline were −63% (95% CI: −99%, −44%, p < 0.001) in the IgAN group and −77% (95% CI: −72%, −93%, p = 0.006) in the non-IgAN group. eGFR remained stable without significant decrease (p > 0.05 for all). Both groups showed a modest increase in serum K + at 3 and 6 months after finerenone initiation, with values remaining below 4.8 mmol/L. Serum albumin levels significantly increased in the non-IgAN group at 3 and 6 months (p = 0.034 and 0.002, respectively), while the IgAN group showed gradual increases, though without statistical significance compared to baseline (p > 0.05 for all) (Table 3). However, the temporal effects of treatment on 24-h urinary protein, eGFR, serum K+, and serum albumin showed no significant differences between the two groups (p = 0.255, 0.393, 0.135, and 0.494, respectively) (Figure 5).
Table 3.
Clinical measurements at baseline, 3 months, and 6 months in effective cases of the IgAN and non-IgAN groups.
| Baseline (T1) |
Month 3 (T2) |
P | Month 6 (T3) |
P | |||||
|---|---|---|---|---|---|---|---|---|---|
| Follow-up index | Group | Mean ± SD | 95% CI | Mean ± SD | 95% CI | Mean ± SD | 95% CI | ||
| 24-h proteinuria (g/d) | IgAN | 1.11 ± 0.16 | (0.78, 1.43) | 0.41 ± 0.17 | (0.08, 0.75) | <0.001 | 0.40 ± 0.20 | (0.01, 0.80) | <0.001 |
| Non-IgAN | 2.24 ± 0.63 | (1.01, 3.47) | 0.58 ± 0.25 | (0.10, 1.07) | 0.028 | 0.52 ± 0.23 | (0.07, 0.97) | 0.006 | |
| eGFR (mL/min/1.73 m²) | IgAN | 76.60 ± 7.71 | (61.47, 91.72) | 74.32 ± 7.05 | (60.51, 88.15) | 0.247 | 72.11 ± 8.29 | (55.86, 88.35) | 0.313 |
| Non-IgAN | 101.54 ± 3.87 | (93.97, 109.12) | 95.60 ± 5.73 | (84.38, 106.83) | 0.126 | 99.67 ± 5.63 | (88.63, 110.72) | 0.651 | |
| sK+ (mmol/L) | IgAN | 4.16 ± 0.14 | (3.89, 4.42) | 4.42 ± 0.15 | (4.12, 4.72) | 0.005 | 4.24 ± 0.16 | (3.92, 4.55) | 0.382 |
| Non-IgAN | 4.20 ± 0.09 | (4.01, 4.38) | 4.32 ± 0.07 | (4.18, 4.46) | 0.250 | 4.45 ± 0.10 | (4.25, 4.65) | 0.035 | |
| Albumin (g/L) | IgAN | 40.15 ± 0.60 | (38.97, 41.32) | 41.66 ± 0.52 | (40.65, 42.68) | 0.070 | 42.02 ± 0.96 | (40.13, 43.91) | 0.080 |
| Non-IgAN | 38.18 ± 1.57 | (35.11, 41.26) | 42.08 ± 1.09 | (39.95, 44.21) | 0.034 | 42.18 ± 0.76 | (40.68, 43.68) | 0.002 | |
Data are mean ± standard deviation. eGFR, estimated glomerular filtration rate; IgAN, immunoglobulin A nephropathy; sK+, Serum potassium.
Baseline (T1), month 3 (T2) (3 months after treatment), month 6 (T3) (6 months after treatment). Data at 3 months and 6 months were analyzed and compared with baseline using generalized estimation equations.
Figure 5.
Changes in 24-h urinary protein (a), eGFR (B), sK+ (C), and serum albumin (D) from baseline to 6 months in effective cases of the IgAN and non-IgAN groups. IgAN, immunoglobulin a nephropathy; sK+, serum potassium; eGFR, estimated glomerular filtration rate.
†Generalized estimation equations were used to analyze time-effects in both groups.
In IgAN, renal function progresses slowly in patients with proteinuria <1 g/day. Therefore, we conducted further analysis on IgAN patients with proteinuria remission to assess the effect of finerenone. Of the 40 IgAN patients, 20 achieved proteinuria remission, resulting in a remission rate of 50%. The median time to proteinuria remission was 3 months. The proteinuria remission results are shown in Figure 6. At 3 and 6 months after finerenone initiation, 24-h proteinuria significantly decreased compared to baseline (Figure 6(A)), while eGFR showed a slight decrease (Figure 6(B)). Serum K + slightly increased, with a high value remaining below 4.8 mmol/L (Figure 6(C)), and serum albumin increased compared to baseline (Figure 6(D)). Average 24-h proteinuria levels were 1.03 ± 0.11 (95% CI: 0.81–1.24) at baseline, 0.35 ± 0.06 (95% CI: 0.23–0.47, p < 0.001) at 3 months, and 0.63 ± 0.08 (95% CI: 0.48–0.78, p = 0.002) at 6 months after treatment. Average eGFR levels were 85.52 ± 4.68 (95% CI: 76.35–94.68) at baseline, 81.32 ± 5.11 (95% CI: 71.31–91.33, p = 0.077) at 3 months, and 82.96 ± 6.59 (95% CI: 70.05–95.88, p = 0.606) at 6 months after treatment. Average serum K + levels were 4.21 ± 0.05 (95% CI: 4.10–4.31) at baseline, 4.49 ± 0.07 (95% CI: 4.35–4.63, p = 0.003) at 3 months, and 4.35 ± 0.07 (95% CI: 4.21–4.50, p = 0.058) at 6 months after treatment. Average serum albumin levels were 40.47 ± 0.64 (95% CI: 39.22–41.72) at baseline, 41.96 ± 0.93 (95% CI: 40.14–43.79, p = 0.109) at 3 months, and 41.60 ± 0.98 (95% CI: 39.67–43.54, p = 0.282) at 6 months after treatment.
Figure 6.
Changes in 24-h urinary protein (a), eGFR (B), sK+ (C), and serum albumin (D) from baseline to 6 months in the IgAN proteinuria remission patients. **p < 0.05, *p < 0.005 (statistically significant at 3 or 6 months after treatment compared to baseline). Data are presented as mean ± standard deviation; IgAN, immunoglobulin a nephropathy; sK+, serum potassium; eGFR, estimated glomerular filtration rate.
In terms of safety, one patient (1.3%) with multiple myeloma-related kidney damage permanently discontinued treatment due to hyperkalemia, and one patient (1.3%) with IgAN temporarily discontinued treatment due to hyperkalemia. Three patients (3.8%) with chronic kidney disease of unknown etiology, metabolic syndrome kidney damage, and mesangial proliferative glomerulonephritis required concomitant use of potassium-lowering drugs due to hyperkalemia. Additionally, one patient (1.3%) experienced skin itching. No cardiovascular events, hypotension, acute kidney injury, or other adverse events were reported during the follow-up period.
Discussion
This study analyzed the anti-proteinuria effects and safety profile of finerenone in a Chinese single-center cohort of non-diabetic CKD patients, yielding several key findings. Firstly, finerenone treatment was associated with a clinically significant reduction in proteinuria, with over half of the patients (61.5%) showing effective treatment. The effective rates in the pathological subgroups were also above 50%. Secondly, proteinuria reduction persisted throughout the 6-month follow-up period. Thirdly, in the IgAN subgroup, half of the patients achieved proteinuria remission. Fourthly, the efficacy of finerenone was independent of the use of RASi and SGLT2i. Fifthly, in patients with preserved renal function, finerenone effectively reduced proteinuria with relatively minimal impacts on eGFR and sK+. Only one patient (1.3%) required permanent discontinuation of treatment due to hyperkalemia, and no hospitalizations or deaths attributable to hyperkalemia were observed.
Numerous studies have demonstrated that proteinuria serves as an independent predictor of kidney disease progression and is closely associated with the risk of ESRD and mortality due to kidney disease [3–5]. In this study, more than half of the patients (61.5%) showed efficacy after treatment with finerenone, with efficacy rates above 50% in both IgAN and non-IgAN subgroups, although individual response trajectories and follow-up durations varied. These findings suggest that finerenone may also be an effective protein-lowering treatment in non-diabetic CKD. Preclinical studies have shown that finerenone can delay the progression of kidney disease by reducing inflammatory markers, fibrosis, and perirenal macrophage deposition, as well as decreasing proteinuria and tubulointerstitial fibrosis [29]. Large clinical trials have confirmed that finerenone effectively reduces proteinuria and the occurrence of ESRD in T2D patients with CKD [18,19]. A phase II randomized controlled trial including patients with HFrEF and mild to moderate CKD found that finerenone reduced albuminuria levels to a degree comparable to spironolactone, with a significantly lower incidence of adverse events in the finerenone group (renal failure: 1.5 vs. 7.9%; hyperkalemia: 5.3 vs. 12.7%) [17]. A recent study showed a statistically significant decrease in UACR after 3 months of finerenone treatment, though the sample size was small [27]. Our study, focusing primarily on non-diabetic CKD, observed a significant reduction in proteinuria by the third month (p < 0.05), with continued decline at the sixth month (p < 0.05). These results provide further insight into the role of finerenone in non-diabetic CKD.
Previous studies have shown that early changes in proteinuria can reliably predict the long-term progression of kidney disease [30,31], and the greater the reduction in proteinuria during the early stages, the more significant the protective effect on the kidneys [32]. Furthermore, a reduction in proteinuria of more than 30% within the first six months is associated with reduced renal and cardiovascular risks [31]. In this study, proteinuria decreased by more than 60% (−68%, 95% CI: −74%, −64%) in the early stages of treatment compared to baseline. In the non-IgAN subgroup, a persistent reduction of over 70% (−77%, 95% CI: −72%, −93%) in proteinuria was observed compared to baseline. This finding confirms the anti-proteinuria effect of finerenone in non-diabetic CKD patients. IgAN, the most prevalent glomerular disease worldwide and a significant contributor to ESRD, represented more than half of the cases in this study. Proteinuria decreased significantly in the IgAN subgroup following finerenone initiation, with 50% of patients achieving proteinuria remission. A meta-analysis of clinical trials assessing IgAN found a 63% relative risk reduction in the composite endpoint of ESRD, serum creatinine doubling, or death, associated with a 24% reduction in proteinuria between the treatment and control groups [33]. Several observational studies have also indicated that IgAN patients with proteinuria <1 g/d exhibit very slow renal function progression, whereas those with proteinuria >3–3.5 g/d experience the most rapid progression. Although IgAN cases achieving proteinuria remission did not show a sustained reduction in proteinuria within 6 months of treatment, proteinuria was significantly reduced at both 3 and 6 months after finerenone initiation (p < 0.001, p = 0.002, respectively). Furthermore, proteinuria levels were below 1 g/d at both 3 and 6 months, consistent with the treatment goal for IgAN patients. This demonstrates the substantial proteinuria-reducing effect of finerenone in specific IgAN populations. Although the study’s overall follow-up period was insufficient to fully capture long-term trends regarding the protective effects of finerenone on eGFR and cardiorenal function, the findings provide clinical evidence supporting the use of finerenone in non-diabetic CKD patients, particularly those with IgAN.
Another finding of this study was that, at the initiation of finerenone treatment, the use of RASi alone, SGLT2i alone, or RASi + SGLT2i may enhance finerenone efficacy, which appears not to be influenced by concurrent use of RASi or SGLT2i. In all three treatment scenarios, the efficacy of finerenone was higher than in patients who did not receive either RASi or SGLT2i (64, 60, and 63 vs. 50%, p = 0.952). Furthermore, in most patients who received RASi or SGLT2i in combination (with only six patients not using them together), no hyperkalemia or other serious adverse events were observed, indicating that the combination is associated with acceptable safety. The FIDELIO-DKD study confirmed that finerenone significantly reduced the composite endpoint risk of major renal events by 18% in T2D and CKD patients treated with RASi at the maximum tolerated dose [18], providing novel targets for CKD treatment through anti-fibrotic and anti-inflammatory pathways. This may be attributed to the fact that, in patients using RASi, aldosterone levels may not be adequately controlled (a phenomenon known as aldosterone breakthrough) [34], while finerenone exerts complementary effects by selectively inhibiting MR and enhancing the RASi combination’s ability to reduce proteinuria. Regarding the renal benefits of SGLT2i, the CREDENCE trial [35] (which enrolled T2D patients with CKD who required stable RASi treatment for at least 4 weeks before enrollment) and DAPA-CKD [36] (where 32.5% of patients did not have T2D and there were no strict requirements for prior RASi treatment) demonstrated that SGLT2i improves renal function progression in CKD patients with or without diabetes. The renal benefits of SGLT2i may stem from both its hypoglycemic effects and its ability to reduce glomerular internal pressure independently of its hypoglycemic action. Peter Rossing et al. explored the impact of SGLT2i use on the treatment effect of finerenone, showing that finerenone reduced UACR by 25% in patients concurrently receiving SGLT2i [37]. This suggests that finerenone further lowers UACR in the context of SGLT2i therapy. These findings also indicate that, in non-diabetic CKD, the use of finerenone alone or in combination with SGLT2i or RASi can provide efficacy through multiple therapeutic targets.
eGFR is a key indicator of renal function. In this study, the mean eGFR showed no statistically significant decrease during follow-up. Although there was a temporary decline, this reduction was reversed as treatment continued. In a meta-analysis assessing the safety and efficacy of finerenone in CKD patients with T2D, the finerenone group exhibited a higher reduction in eGFR from baseline within the first 4 months of treatment compared to the placebo group. However, the proportion of patients with a ≥ 40% decrease in eGFR or progression to ESKD was significantly lower in the finerenone group [38]. The FIDELIO-DKD study also demonstrated that finerenone induced a rapid decrease in eGFR within the first four months, but the rate of decline slowed over time, and the benefits ultimately outweighed the initial acute decline [18]. This may be due to improvements in hemodynamics [39,40].
Regarding safety, finerenone increases sK + concentrations through MR antagonism [8] and is independently associated with hyperkalemia [41]. In this study, there was a modest increase in sK + levels after treatment with finerenone, but no clinically significant hyperkalemia-related adverse events (including hospitalization or death) were observed. The FIDELITY pooled analysis showed a permanent discontinuation rate due to hyperkalemia of only 1.7% [20], slightly higher than the 1.3% observed in our study. Furthermore, regular sK + monitoring and effective hyperkalemia management strategies can further mitigate the occurrence of severe hyperkalemia in clinical settings.
This study had several limitations. First, being a retrospective analysis, it could not establish causal relationships. Second, compared to clinical trials, it did not include unbiased controlled comparative studies. Third, the high heterogeneity of kidney disease and variations in follow-up might limit the generalizability of certain outcomes. The small sample size and short follow-up duration also restricted the ability to assess long-term renal outcomes, including renal failure. Fourth, there was a potential risk of underreporting safety signals. Fifth, due to the observational nature of real-world studies, medication adherence and adjustments during treatment were not assessable. However, the study also had several strengths. It laid the groundwork for the safe use of finerenone in non-diabetic CKD and provided insight into its potential combination with traditional anti-proteinuria drugs.
In conclusion, the results indicated that finerenone effectively reduced proteinuria in non-diabetic CKD patients with minimal effects on eGFR and sK+. It showed potential for inducing proteinuria remission and reducing the need for glucocorticoids in IgAN patients. Additionally, the combination of finerenone with RASi or SGLT2i may further enhance treatment efficacy. These findings suggest that finerenone may offer renal benefits to a broader patient population in clinical practice. Nonetheless, due to the limited sample size, further large-scale prospective studies and real-world research are needed to validate these findings.
Funding Statement
The study was supported by The Shaanxi Social Development Science and Technology Research Project (No. 2020SF-162).
Author contributions
Jiping Sun and Fang Li had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Jiping Sun and Fang Li were involved in the study concepts and design. All authors (Fang Li, Jing Han, Wenjing Zhang, Jia Lv, Zhigang Wang, Huixian Li, Li Jin, Jie Feng, Wanhong Lu, Jiping Sun) involved in the acquisition, analysis and interpretation of data. Wanhong Lu and Jiping Sun supervised the analysis. Fang Li involved in the draft of the manuscript. All authors read, critically revised and approved the manuscript. Fang Li and Jing Han contributed equally to this work.
Disclosure statement
All authors have no conflicts of interest to declare.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.