Abstract
Introduction
Currently, there is no specific treatment for post–acute kidney injury (AKI) survivors, one of the highest risk groups of the renal and nonrenal adverse long-term outcomes. This study aimed to determine whether the sodium-glucose cotransporter-2 inhibitor (SGLT2i) can decrease 1-year major adverse kidney events (MAKE365) in post-AKI setting.
Methods
Multicenter randomized controlled trial, involving severe AKI survivors from 3 tertiary care hospitals, who were dialysis independent, and had an estimated glomerular filtration rate (eGFR) ≥ 20 ml/min per 1.73 m2. The participants were randomized to receive empagliflozin 10 mg/d or matching placebo for 1 year after the incident AKI. The primary outcome was MAKE365, defined as a composite of persistent kidney dysfunction (a sustained decrease in eGFR ≥ 25% or increase in serum creatinine ≥ 200% of baseline), the need for long-term dialysis, or death at 1 year after the incident of AKI.
Results
A total of 200 participants were included in this study, 98 patients in empagliflozin group and 102 patients in placebo group; AKI stage 3 was predominant, with renal replacement therapy required for 30% and 23% of patients in each group, respectively. On modified intention-to-treat analysis, MAKE365 occurred in 35% in the empagliflozin group and 36% in the placebo group (P = 0.82). The incident rate ratio indicated a significant reduction in recurrent AKI in the empagliflozin group (34 vs. 66 per 100 person-years, respectively; incident rate ratio: 0.51, 95% confidence interval [CI]: 0.31–0.84; P = 0.008).
Conclusion
Empagliflozin could not show reduction in MAKE365 but showed potential benefits in reducing recurrent AKI.
Keywords: 1-year major adverse kidney event (MAKE365), acute kidney injury (AKI), modified intention-to-treat (mITT), post–-acute kidney injury, sodium-glucose cotransporter-2 inhibitor (SGLT2i)
Graphical abstract
AKI is a prevalent issue in clinical practice, particularly within critical care units, where it increases mortality rates in both the short- and long-term.1 Survivors of AKI face an elevated risk of developing recurrent AKI, rehospitalization, and cardiac events compared with the general population.1 At present, there are no specific treatments or interventions that have been proven beneficial in improving outcomes for patients following AKI.
SGLT2is represent a new and promising class of medications that have demonstrated efficacy in delaying the progression of chronic kidney disease (CKD) and improving cardiovascular outcomes.2, 3, 4, 5, 6, 7 Recent meta-analyses8,9 and randomized controlled trials10,11 have established the benefits of SGLT2is on cardiovascular and renal outcomes; however, data regarding their effects on post-AKI survivors remains insufficient. Our study aimed to investigate the effects of SGLT2is in post-AKI survivors, focusing on both renal and nonrenal outcomes. This study was registered on ClinicalTrials.gov (ID NCT05360615) on April 30, 2022.
Methods
Study Population
A multicenter randomized controlled trial was conducted across 3 tertiary care centers in Thailand, involving 200 severe post-AKI patients (stages 2 and 3, as defined by the Kidney Disease: Improving Global Outcomes criteria for AKI 201212) who exhibited an eGFR, calculated using the CKD Epidemiology Collaboration formula, ≥ 20 ml/min per 1.73 m2. Baseline serum creatinine was defined as the most recent value within a year before hospitalization.13 If unavailable, it was estimated using a back-calculated value from the Modification of Diet in Kidney Disease equation,14,15 assuming an eGFR of 75 ml/min per 1.73 m2.
The patients were randomly assigned to 2 groups, receiving either 10 mg/d of empagliflozin or a matching placebo. Individuals who were dependent on dialysis, had received a kidney transplant, had diabetes mellitus type 1 or had prior ketoacidosis, exhibited an allergy to empagliflozin, or were suffering from a moribund medical condition expected to result in death within 1 year were excluded from the study.
Participant Allocation
Eligible patients were screened during their hospital admission, and a run-in period of 2 to 4 weeks was implemented following their discharge to ensure stabilization of kidney function prior to randomization. The eGFR measured at the first visit must not have varied by > 25% compared with previous values recorded before inclusion. Blood and urine samples were collected at the initial visit before the administration of the intervention.
The patients were then centrally randomized by blocks of 4 and assigned to receive either empagliflozin 10 mg/d or a matching placebo. The intervention drug and placebo were prepared in white capsules by the pharmacist, labeled as “A” or “B.” Both the investigators and participants were blinded to the treatment assignments. The patients were followed-up with at 3-month intervals for a total of 5 visits (0, 3, 6, 9, and 12 months). At each visit, blood and urine samples were collected for analysis. MAKE365, recurrent AKI, hospital readmissions, new occurrences of heart failure, strokes, new-onset hypertension, ischemic heart disease, and CKD were recorded. Their kidney function, blood pressure, body weight, adverse events, and concomitant medications were reviewed. Compliance was assessed through pill counts. In addition, participants’ activities of daily living were evaluated using quality of life and frailty scores.
Operational Definition
MAKE365 was defined as a composite of persistent kidney dysfunction (a sustained decrease in eGFR ≥ 25% or serum creatinine ≥ 200% of baseline), the need for long-term dialysis, or death from any cause at 1 year after the incident of AKI. "De novo CKD" is defined as an eGFR persistently < 60 ml/min for 3 months among those with a baseline eGFR > 60 ml/min and no previous history of CKD. CKD progression is characterized by changes in CKD stages (stages 3–5) during the study period. In addition, “microalbumin-to-creatinine ratio (MAU/Cr) progression” refers to changes in stages of microalbuminuria/creatinine (A1-3) throughout the study. The "acute slope”16 is defined as the change in eGFR from the first visit, at randomization (month [M]0), to the second visit (M3) to assess the initial eGFR changes at the beginning of the study. The "chronic slope" refers to changes in eGFR from M3 to M12, whereas the "total slope" is the average rate of eGFR decline from the beginning, M0 (the first visit) to M12 (the fifth visit).
Recurrent AKI was defined as an increase of serum creatinine ≥ 0.3 mg/dl within 48 hours, or an increase of serum creatinine to ≥1.5 times baseline within 7 days or, urine output < 0.5 ml/kg/h for 6 hours using the Kidney Disease: Improving Global Outcomes criteria 2012.
Laboratory Measurement
Blood and urine samples were collected during each visit for central analysis at the Excellence Center for Critical Care Nephrology, King Chulalongkorn Memorial Hospital.
Statistical Analysis
According to FUSION trial,17 MAKE365 were expected to be 44%. A total of 71 participants in each group would provide the trial with 80% power to detect a difference in MAKE365, which was anticipated to be 22% lower in the empagliflozin group.18,19 To account for potential dropout patients, a total of 100 patients in each group were anticipated for this study. Continuous variables with a normal distribution were analyzed and expressed as mean ± SD. For variables with a skewed distribution, data were presented as median ± interquartile range (IQR). Baseline comparisons between patients in both groups were conducted using the chi-square test for categorical data and t test for continuous data. MAKE365 were compared between groups using a univariate logistic regression model. Univariable linear regression models were employed to estimate coefficients and 95% CIs. All reported P-values were 2-tailed, with P < 0.05 considered statistically significant. Analyses were performed according to the modified intention-to-treat that included every participant with ≥ 1 follow-up in the study. Completed case analysis included only those who completed 1-year follow up.
Exploratory subgroup analysis of participants with diabetes, CKD, renin-angiotensin-aldosterone system (RAS) inhibitor uses were planned to see potential benefits of SGLT2is.
Ethical Approval and Consent to participate
The study was conducted in accordance with the Declaration of Helsinki and received approval from the Chulalongkorn University Institutional Research Ethics Review Committee (IRB No. 0211/65, COA No. 0572/2024), as well as from the institutional review board committees of each participating hospital. The participants were informed and asked to sign consent form before participation.
Results
Baseline Characteristics
During July 2022 to May 2024, a total of 200 patients were ultimately included in this analysis, comprising 98 patients in the empagliflozin group and 102 patients in the placebo group. Twenty-two patients were lost to follow-up after the first visit at the post-AKI clinic, resulting in 89 subjects included in each group for this study. In Figure 1, we show the data flow and analysis group.
Figure 1.
Data flow and analysis group. mITT, modified intention-to-treat.
In terms of demographic characteristics, 54% of the empagliflozin group and 59% of the placebo group were male, with median ages of 65 and 63 years, respectively. The most common underlying conditions among patients included hypertension (89% in the empagliflozin group and 81% in the placebo group), dyslipidemia (76% vs. 75%), and diabetes mellitus (51% vs. 53%). CKD was present in 24% of the placebo group and 21% of the empagliflozin group. The predominant mechanism of AKI was attributed to prerenal or ischemic processes, observed in approximately 50% of patients in each group. The second most common causes were sepsis and nephrotoxic drugs, affecting 24% to 28% of patients, whereas about 21% to 24% were categorized as multifactorial. The baseline characteristics are shown in Table 1. AKI stage 3 was noted in 76% of the empagliflozin group and 69% of the placebo group, with renal replacement therapy required for 30% and 23% of patients in each group, respectively. Among patients with available baseline kidney function before the incident AKI, the empagliflozin group had serum creatinine and eGFR values of 1.01 (IQR: 0.88–1.31) mg/dl and 63.0 (IQR: 47.5–86.3) ml/min per 1.73 m2, respectively; whereas the placebo group had median baseline serum creatinine and eGFR values of 1.00 (IQR: 0.83–1.36) mg/dl and 67.6 (IQR: 48.3–88.7) ml/min per 1.73 m2. The median admission creatinine and eGFR in the empagliflozin group were slightly better than those in the placebo group but was not statistically significant (2.26 [IQR: 1.53–3.78]) mg/dl vs. 3.19 ([IQR: 1.73–5.16]) mg/dl; and 28 [IQR: 12.4–41.0] ml/min per 1.73 m2 vs. 18.4 [IQR: 9.7–35.5] ml/min per 1.73 m2).
Table 1.
Baseline characteristics
| Parameters | Placebo (n = 102) | Empagliflozin (n = 98) | P-value |
|---|---|---|---|
| Gender, n (%) | 0.50 | ||
| Female | 42 (41) | 45 (46) | |
| Male | 60 (59) | 53 (54) | |
| Age, median (IQR) | 63 (56–75) | 65 (58–73) | 0.74 |
| Body weight, median (IQR) | 59 (52–72) | 60 (53–70) | 0.70 |
| Height, median (IQR) | 161 (155–168) | 160 (155–165) | 0.48 |
| BMI, median (IQR) | 22.5 (20.7–26.1) | 23.4 (20.8–27.3) | 0.36 |
| Systolic blood pressure, mean (SD) | 127 (18) | 130 (19) | 0.30 |
| Diastolic blood pressure, mean (SD) | 73 (12) | 75 (13) | 0.27 |
| Underlying diseases, n (%) | |||
| Hypertension | 83 (81) | 87 (89) | 0.14 |
| Dyslipidemia | 77 (75) | 74 (76) | 1.00 |
| Diabetes mellitus | 54 (53) | 50 (51) | 0.79 |
| Ischemic heart disease | 34 (33) | 36 (37) | 0.61 |
| Chronic kidney disease | 14/66 (21) | 15/62 (24) | 0.69 |
| Cerebrovascular disease | 11 (11) | 8 (8) | 0.53 |
| Mechanism of AKI, n (%) | |||
| Prerenal/ischemic | 51 (50) | 48 (49) | 0.89 |
| Sepsis | 25 (25) | 24 (24) | 1.00 |
| Nephrotoxic | 24 (24) | 27 (28) | 0.51 |
| Multifactorial | 21 (21) | 24 (24) | 0.51 |
| Post renal/obstruction | 3/92 (3) | 4/89 (4) | 0.67 |
| AKI Stage, n (%) | (n = 96) | (n = 94) | 0.30 |
| Stage 2 | 30 (31) | 23 (24) | |
| Stage 3 | 66 (69) | 71 (76) | |
| RRT in admission, n (%) | 23/101 (23) | 29/96 (30) | 0.26 |
| Baseline serum creatinine (mg/dl), median (IQR) (True baseline) |
(n = 75) 1.00 (0.83–1.36) |
(n = 79) 1.01 (0.88–1.31) |
0.82 |
| Baseline GFR (ml/min per 1.73 m2), median (IQR) (True baseline) |
(n = 75) 67.6 (48.3–88.7) |
(n =79) 63.0 (47.5–86.3) |
0.56 |
| Admission serum creatinine (mg/dl), median (IQR) | (n = 101) 3.19 (1.73–5.16) |
(n = 97) 2.26 (1.53–3.78) |
0.070 |
| Admission GFR (ml/min per 1.73 m2), median (IQR) | (n = 101) 18.4 (9.7–35.5) |
(n = 97) 28.0 (12.4–41.0) |
0.070 |
| Serum creatinine at randomization (mg/dl), median (IQR) (M0) | (n = 100) 1.22 (0.96–1.60) |
(n = 98) 1.23 (0.99–1.67) |
0.68 |
| GFR at randomization (ml/min per 1.73 m2), median (IQR) (M0) |
(n = 99) 56.8 (41.6–74.7) |
(n = 98) 52.8 (37.0–71.0) |
0.37 |
| Current medications at randomization (M0), n (%) | |||
| RAS inhibitors | 31 (30) | 36 (37) | 0.34 |
| Calcium channel blocker | 38 (37) | 30 (31) | 0.32 |
| Mineralocorticoid antagonist | 11 (11) | 12 (12) | 0.75 |
| Beta blocker | 41 (40) | 50/97 (52) | 0.11 |
| Diuretics | 32 (31) | 38/97 (39) | 0.25 |
| Vasodilator | 24 (24) | 24 (24) | 0.87 |
| Alpha blocker | 9 (9) | 10 (10) | 0.74 |
| Statin, n (%) | 66 (65) | 63 (64) | 0.95 |
| ASA, n (%) | 32 (31) | 36 (37) | 0.42 |
| aCompliance, n (%) | 96 (94) | 96 (98) | 0.17 |
AKI, acute kidney injury; ASA, aspirin; GFR, glomerular filtration rate; IQR, interquartile range; M0, month 0; RAS, renin-angiotensin-aldosterone system; RRT, renal replacement therapy.
Compliance was defined by using pill counts and medical reconciliation by pharmacists in post-AKI clinic.
At randomization (month 0; M0), serum creatinine and eGFR were similar between both groups (median [IQR]: 1.23 [0.99–1.67] mg/dl vs. 1.22 [0.96–1.60] mg/dl; and 52.8 [37.0–71.0] ml/min per 1.73 m2 vs. 56.8 [41.6–74.7] ml/min per 1.73 m2. The usage of RAS inhibitors (37% vs. 30%), diuretics (39% vs. 31%), statins (64% vs. 65%), and aspirin (37% vs. 31%) were comparable between the 2 groups. Drug reconciliation was performed in > 90% of patients in this study.
Primary Outcomes
At the 1-year follow-up, no patients were dialysis-dependent, and MAKE365 occurred in approximately 40% of each group (35% in the empagliflozin group vs. 36% in the placebo group; P = 0.82), indicating no statistically significant difference, the analysis on those who completed 1-year follow-up showed similar results (38% in the empagliflozin group vs. 39% in the placebo group; P = 0.88). In Table 2, we show primary and secondary outcomes in this study. In Figure 2, we show MAKE365-free survival.
Table 2.
Primary and secondary outcomes
| Parameters | Placebo | Empagliflozin | P-value |
|---|---|---|---|
| Primary outcome | |||
| mITT analysis | |||
| MAKE365, n (%) | 37/102 (36) | 34/98 (35) | 0.82 |
| Complete case analysis | |||
| MAKE365, n (%) | 35/89 (39) | 34/89 (38) | 0.88 |
| Secondary outcomes | |||
| MAKE365 criteria, n (%) | (n = 89) | (n = 89) | |
| Dead | 10 (11) | 4 (5) | 0.095 |
| Persistent renal dysfunction | 25 (28) | 30 (34) | 0.42 |
| Dialysis dependent | 0 (0) | 0 (0) | NA |
| Clinical Assessment | |||
| Recurrent AKI, n (%) | 28/83 (34) | 18/87 (21) | 0.056 |
| 1-yr recurrent AKI rate (95% CI), per 100 person-yrs | 66 (48–89) | 34 (21–51) | 0.008a |
| Readmission, n (%) | 27/83 (33) | 23/87 (26) | 0.38 |
| 1-yr readmission rate (95% CI), per 100 person-yrs | 56 (40–77) | 48 (33–68) | 0.54 |
| Heart failure event, n (%) | 15/83 (18) | 11/87 (13) | 0.33 |
| 1-yr heart failure rate (95% CI), per 100 person-yrs | 34 (21–51) | 38 (25–56) | 0.68 |
| Stroke (new event) | (n = 79) 3/74 (4) |
(n = 80) 2/78 (3) |
0.68 (Fisher exact) |
| Hypertension (new event) | (n = 14) 3/14 (21) |
(n = 7) 1/7 (14) |
1.00 (Fisher exact) |
| Kidney function (M12) | |||
| Serum creatinine, median (IQR) | (n = 54) 1.2 (1.0–1.7) |
(n = 50) 1.4 (1.1–1.9) |
0.31 |
| eGFR, median (IQR) | (n = 54) 51 (36–70) |
(n = 49) 46 (35–55) |
0.12 |
| MAU/Cr, median (IQR) | (n = 23) 3.4 (1.2–12.4) |
(n = 25) 3.2 (2.6–17.4) |
0.45 |
| New CKD (any), n/N (%) | 13/38 (34) | 13/27 (48) | 0.26 |
| CKD progression (any), n/N (%) | 15/44 (34) | 24/56 (43) | 0.37 |
| MAU/Cr progression (any), n (%) | 21/57 (37) | 30/60 (50) | 0.15 |
| Reduction in MAU/Cr at M12/last visit (M0–M12), median (IQR) | (n = 18) 16.0 (−8.9 to 65.6) |
(n = 21) 17.5 (−35.3 to 56.6) |
0.60 (Mann-Whitney U exact test) |
| Acute GFR slope (M0, M3) unit/mo, mean (SD; 95% CI) |
n = 80 0.57 (SD: 5.79; 95% CI: −0.72–1.85) |
n = 78 −1.08 (SD: 4.54; 95% CI: −2.10 to −0.05) |
0.049 |
| Chronic GFR slope (M3, M6, M9, M12) unit/mo, mean (SD) |
n = 72 −0.36 (2.78) |
n = 72 0.13 (2.38) |
0.26 |
| Total GFR slope (M0, M3, M6, M9, M12) unit/mo, mean (SD) |
n = 82 −0.34 (2.01) |
n = 85 −0.19 (2.37) |
0.65 |
| Current medications at 1-yr follow-up | |||
| RAS inhibitors | 33/53 (62) | 38/56 (68) | 0.54 |
| Calcium channel blocker | 29/53 (55) | 23/56 (41) | 0.15 |
| Mineralocorticoid antagonist | 6/53 (11) | 9/56 (16) | 0.47 |
| Beta blocker | 26/53 (49) | 27/56 (48) | 0.93 |
| Diuretics | 22/52 (42) | 13/56 (23) | 0.034 |
| Vasodilators | 14/53 (26) | 8/56 (14) | 0.11 |
| Alpha blockers | 11/52 (21) | 5/56 (9) | 0.074 |
AKI, acute kidney injury; CI, confidence interval; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate; IRR, incident rate ratio; MAKE365, 1-yr major adverse kidney events; NA, not applicable; MAU/Cr, microalbumin-to-creatinine ratio; M0, month 0; M3, month 3; M6, month 6; M9, month 9; M12, month 12; mITT, modified intension-to-treat; RAS, renin-angiotensin-aldosterone system.
IRR empagliflozin vs. placebo = 0.51 (95% CI: 0.31–0.84).
Figure 2.
(a) MAKE365 free survival (mITT). (b) MAKE365 free survival (completed cases). MAKE365, 1-year major adverse kidney events; mITT, modified intention-to-treat.
Secondary Outcomes
At the 1-year follow-up, 14 patients had died: 4 in the empagliflozin group and 10 in the placebo group (11% vs 5%, P = 0.095). In the empagliflozin group, 3 participants died from severe sepsis, with none attributed to cardiovascular causes. In contrast, in the placebo group, 6 participants died from cardiovascular diseases (2 had ST-elevated myocardial infarction, 3 had heart failure, and 1 had a stroke).The empagliflozin group experienced lower rates of recurrent AKI, with a rate of 21% compared with 34% in the placebo group (18 in 87 participants vs. 28 in 83 participants, with 1-year recurrent AKI rate 34 vs. 66 per 100 person-years), resulting in an incidence rate ratio of 0.51 (95% CI: 0.31–0.84; P = 0.008.). Hospital readmission rates were 26% in the empagliflozin group and 33% in the placebo group (P = 0.38) (1-year readmission rate of 48 vs. 56 per 100 person-years, P = 0.54). New heart failure events occurred in 11 patients (13%) of the empagliflozin group and 15 patients (18%) of the placebo group (P = 0.33). Strokes were reported in 2 participants (3%) of the empagliflozin group and 3 participants (4%) of the placebo group (P = 0.68). Incidences of new-onset hypertension were similar between the 2 groups.
When examining kidney function at the 1-year mark, the median serum creatinine levels were 1.4 (IQR: 1.1–1.9) mg/dl in the empagliflozin group and 1.2 (IQR: 1.0–1.7) mg/dl in the placebo group (P = 0.31). In addition, the median eGFR was 46 (IQR: 35–55) ml/min per 1.73 m2 and 51 (IQR: 36–70) ml/min per 1.73 m2, respectively (P = 0.12). The median urine MAU/Cr was comparable, at 3.2 (IQR: 2.6–17.4) and 3.4 (IQR: 1.2–12.4). New CKD, CKD progression, and the MAU/Cr showed similar results between the 2 groups.
Incidences of new-onset CKD occur in 13 participants from each group, 48% in the empagliflozin group compared with 34% in the placebo group (P = 0.26). CKD progression was observed in 43% of the empagliflozin group and 34% of the placebo group (P = 0.37). MAU/Cr progression affected 50% in the empagliflozin group and 37% in the placebo group (P = 0.15). The delta changes in MAU/Cr between month 12 and the baseline were comparable between groups.
eGFR slopes were analyzed to observe changes in eGFR following the intervention. The data indicated a statistically significant acute change in eGFR slope between the empagliflozin and placebo groups, measuring −1.08 ± 4.54 ml/min per 1.73 m2/mo (95% CI: −2.10 to −0.05) and 0.57 ± 5.79 ml/min per 1.73 m2/mo (95% CI: −0.72 to 1.85), respectively, (P = 0.049). Although not statistically significant, the empagliflozin group demonstrated a slower decline in eGFR than the placebo group. The chronic glomerular filtration rate (GFR) slope was 0.13 ± 2.38 ml/min/1.73 m2/mo in the empagliflozin group and −0.36 ± 2.78 ml/min per 1.73 m2/mo in the placebo group (P = 0.26). Similarly, the total GFR slope was −0.19 ± 2.37 ml/min per 1.73 m2/mo in the empagliflozin group and −0.34 ± 2.01 ml/min per 1.73 m2/mo in the placebo group (P = 0.65).
At the 1-year follow-up, the rates of RAS inhibitors and mineralocorticoid antagonist usage were similar between the 2 groups. However, in the empagliflozin group, there was a lower usage of diuretics (23% vs. 42%, P = 0.034).
The adverse events reported by the participants were shown in Table 3. No participant had to stop intervention because of adverse events. Table 4 reported the subgroup analysis of CKD, DM, and using RAS inhibitors and the outcomes.
Table 3.
Reported adverse events
| Adverse events | Placebo | Empagliflozin |
|---|---|---|
| Orthostatic hypotension | 2 | 1 |
| Rashes | - | 1 |
| Amputations | - | - |
| Fractures | - | - |
| Ketoacidosis | - | - |
| Urinary tract infection | - | - |
Table 4.
Subgroup analysis
| Parameters | Total | Placebo | Empagliflozin | P-value |
|---|---|---|---|---|
| CKD | ||||
| CKD progression, n (%) | 10/24 (42) | 4/12 (33) | 6/12 (50) | 0.41 |
| Acute GFR slope, mean (SD) | −0.61 (3.50) | 0.17 (4.03) | −1.33 (2.90) | 0.29 |
| Chronic GFR slope, mean (SD) | 0.03 (1.28) | 0.29 (1.47) | −0.20 (1.07) | 0.35 |
| Total GFR slope, mean (SD) | −0.09 (1.24) | 0.43 (1.12) | −0.53 (1.20) | 0.047 |
| MAU/Cr progression, median (IQR) | 11/21 (52) | 5/10 (50) | 6/11 (55) | 0.83 |
| Reduction in MAU/Cr (M0–M12), median (IQR) | −2.9 (−176.5 to 65.6) | −2.9 (−228.5 to 31.6) | 163.9 (−176.5 to 504.3) | 0.64 |
| Diabetes mellitus | ||||
| CKD progression, n (%) | 23/54 (43) | 11/25 (44) | 12/29 (41) | 0.85 |
| Acute GFR slope, mean (SD) | −1.17 (4.36) | −0.22 (4.79) | −2.12 (3.71) | 0.048 |
| Chronic GFR slope, mean (SD) | 0.14 (2.31) | −0.31 (2.19) | 0.57 (2.36) | 0.10 |
| Total GFR slope, mean (SD) | −0.32 (1.66) | −0.23 (1.88) | −0.41 (1.43) | 0.62 |
| MAU/Cr progression, median (IQR) | 30/64 (47) | 12/30 (40) | 18/34 (53) | 0.30 |
| Reduction in MAU/Cr (M0–M12), median (IQR) | 1.9 (−35.3 to 62.1) | 6.7 (−8.9 to 748.9) | −11.4 (−111.4 to 62.1) | 0.21 |
| RAS inhibitors | ||||
| CKD progression, n (%) | 14/31 (45) | 6/13 (46) | 8/18 (44) | 0.92 |
| Acute GFR slope, mean (SD) | −1.55 (3.75) | −0.95 (3.47) | −2.04 (3.96) | 0.30 |
| Chronic GFR slope, mean (SD) | 0.16 (2.72) | −0.38 (2.40) | 0.66 (2.95) | 0.20 |
| Total GFR slope, mean (SD) | −0.60 (2.00) | −0.59 (2.08) | −0.61 (1.97) | 0.97 |
| MAU/Cr progression, median (IQR) | 17/40 (43) | 7/19 (37) | 10/21 (48) | 0.49 |
| Reduction in MAU/Cr (M0–M12), median (IQR) | 44.7 (−8.9 to 372.9) | 44.7 (−8.9 to 3534.7) | 47.1 (−54.7 to 324.2) | 0.70 |
CKD, chronic kidney disease; GFR, glomerular filtration rate; IQR, interquartile range; M0, month 0; M12, month 12; MAU/Cr, microalbumin-to-creatinine ratio; RAS, renin-angiotensin-aldosterone system.
Acute GFR slope is defined as the change in eGFR from the first visit, at randomization (M0), to the second visit (M3) of the study.
Chronic GFR slope refers to changes in eGFR from M3 to M12.
Total GFR slope is the average rate of eGFR decline from the beginning M0 (the first visit) to M12 (the fifth visit).
Discussion
This study included 200 severe AKI survivors randomized to receive either empagliflozin or placebo. MAKE365 occurred in 35% of the empagliflozin group and 36% of the placebo group (P = 0.82). Mortality was numerically lower in the empagliflozin group (5% vs. 11%, P = 0.095), with fewer cardiovascular deaths. Empagliflozin was associated with significantly lower rates of recurrent AKI (21% vs. 34%, P = 0.008), and nonsignificant trends toward fewer heart failure events, hospital readmissions, and stroke. Kidney function parameters, including serum creatinine, eGFR, and albuminuria were similar between groups at follow-up, although the empagliflozin group showed a slower, albeit statistically nonsignificant, decline in chronic and total eGFR slopes. A significant difference was observed in the acute eGFR slope post-intervention (P = 0.049). Medication use at follow-up was similar, except for a lower use of diuretics in the empagliflozin group (23% vs. 43%, P = 0.034).
MAKE365 did not differ between the groups. This may have been influenced by several factors. First, this study included only severe AKI survivors; most participants had AKI stage 3 (76% in the empagliflozin group and 69% in the placebo group), with 23% to 30% requiring dialysis during hospitalization. MAKE365 occurred in 40% of these subjects, underscoring the necessity for intervention in this high-risk population. Second, the study was conducted within post-AKI clinics at 3 tertiary care hospitals in Thailand, all of which were managed by nephrologists. The literature indicates that short- and long-term post-AKI risks significantly impact outcomes 1 year after the incident. By conducting this study, every patient was managed aggressively to mitigate risks20,21 and improve outcomes.22,23 This is indirectly supported by care processes, such as the rate of RAS inhibitor usage, which doubled at the 1-year follow-up; drug reconciliation; and incidences of other post-AKI complications—for example, recurrent AKI, heart failure events, and hospital readmissions—tended to be lower than previous studies.24,25 This may explain the absence of dialysis-dependent patients at the 1-year follow-up. Third, the follow-up period may not have been long enough to observe the effects of SGLT2is on patient outcomes. The primary studies on SGLT2i, including the EMPA-KIDNEY and DAPA-CKD trials,26,27 had mean follow-up durations of ≥ 2 years, and the effects of SGLT2is on the progression of kidney disease or death from cardiovascular causes became apparent after 1 year. Some small differences in mortality were suggested in this 1-year report; specifically, in the placebo group, 6 participants died from cardiovascular diseases; whereas in the empagliflozin group, 3 participants died from severe sepsis, with no deaths attributed to cardiovascular causes. Therefore, differences may become more prominent with longer follow-up.
Moreover, the number of recurrent AKI episodes may be underestimated in this study, because the general follow-up period was limited to every 3 months. Only episodes meeting the creatinine-based diagnostic criteria were included, potentially excluding subclinical AKI cases. In addition, in healthy participants, serum creatinine levels and urine output were not routinely monitored between follow-up visits. Nonetheless, a more favorable outcome was still observed in the empagliflozin group. The incident rate ratio indicated a significant reduction in recurrent AKI in the empagliflozin group (34 per 100 person-years in the empagliflozin group vs. 66 per 100 person-years in the placebo group, incident rate ratio: 0.51, 95% CI: 0.31–0.84, P = 0.008). The rate of diuretic usage was lower in the empagliflozin group (23% vs. 42%, P = 0.034). These findings are consistent with recent meta-analyses.28,29 The key possible mechanisms30, 31, 32, 33 through which SGLT2is may prevent AKI have been variously described, including the restoration of tubulo-glomerular feedback, reduction of glomerular hyperfiltration, attenuation of RAS activation, cessation of cortical hypoxia and oxidative stress, and inhibition of inflammation and fibrosis. Another important point is the potential efficacy of post-AKI clinics. As mentioned earlier, the involvement of a multidisciplinary team and nephrologists may significantly influence outcomes, which may further explain why there was no difference in kidney function between the 2 groups, despite higher rates of recurrent AKI in the placebo group.
Acute declines in GFR following initiation of SGLT2is have raised concerns, particularly in patients with CKD and post-AKI. This study addresses that concern in a post–severe AKI population. Analysis of the acute eGFR slope—from M0 to M3—showed a slightly greater decline in the empagliflozin group than in the placebo group, with a statistically significant difference (−1.08 ± 4.54 ml/min per 1.73 m2; 95% CI: −2.10 to −0.05; P = 0.049). This finding can be attributed to the ability of SGLT2is to decrease glomerular hyperfiltration and restore tubulo-glomerular feedback. The chronic GFR slope broadly represents how GFR changes throughout the phases of intervention. Although the data were not statistically significant, they suggested a more favorable outcome in the empagliflozin group than in the placebo group (0.13 ± 2.38 ml/min in the empagliflozin group vs. −0.36 ± 2.78 ml/min in the placebo group, P = 0.26). The data indicated a similar trend in total GFR slope, with values of −0.19 ± 2.37 ml/min in the empagliflozin group compared with −0.34 ± 2.01 ml/min in the placebo group (P = 0.65).
The adverse events reported by the participants were low (Table 3). Diabetic ketoacidosis was not reported in any participants, and none reported hypoglycemia in participants without diabetes. These findings are concordant with previous major SGLT2i trials.26, 27, 28
This study represents the first multicenter randomized double-blinded controlled trial to assess the effects of SGLT2i in survivors of severe AKI. Given the lack of specific treatments in the post-AKI setting, the results of this trial may pave the way for new therapeutic strategies. In addition, we have demonstrated the feasibility and favorable outcomes associated with applying a SGLT2 inhibitor in the setting of post-AKI.
However, this study had several limitations. Thirteen patients in the placebo group and 9 patients in the empagliflozin group were lost to follow-up at 1 year, resulting in an overall dropout rate of 11%, which still provided a post hoc power of 88.4%. Because enrollment commenced during the COVID-19 pandemic, the recruitment rate was limited, and many participants experienced readmissions due to COVID-19 infections rather than post-AKI-related events. The number of participants was notably low during the first 6 months of the study, leading to delays in outcome reporting and follow-up times from the initial plan. This affected the overall recruitment rate, because SGLT2is have emerged as transformative treatments in various settings in recent years, particularly among cardiologists and endocrinologists, making it challenging to avoid concomitant treatments from other specialists.
This trial was originally powered to detect the difference in MAKE365 from 44% in the control group to 22% in the empagliflozin group. In our study, MAKE365 occurred in 35% in the empagliflozin group and 36% in controls (P = 0.82). These results do not support a large treatment effect of the magnitude originally hypothesized. Our sample size was therefore adequate to exclude very large risk reductions but underpowered to detect small to moderate differences.
In conclusion, initiation of empagliflozin in post–severe AKI patients is feasible and safe and had better signals toward reducing recurrent AKI in this setting.
Disclosure
All the authors declared no competing interests.
Acknowledgments
This study is supported by Thailand Science Research and Innovation Fund, Chulalongkorn University, Bangkok, Thailand, The Kidney Foundation of Thailand, Bangkok, Thailand and Rachadaphiseksompotch Endorsement Fund, Chulalongkorn University, Bangkok, Thailand.
Funding
NS is funded by Thailand Science Research and Innovation Fund, Chulalongkorn University, Bangkok, Thailand, The Kidney Foundation of Thailand, Bangkok, Thailand, and Rachadaphiseksompotch Endorsement Fund (HEAF67300025), Chulalongkorn University, Bangkok, Thailand. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the funding institution.
Data Availability Statement
Data supporting the study are available within the article. Any additional data related to the study will be provided on request to the corresponding author.
Author Contributions
Conception and design were by NS, NL, SP, and WC. Acquisition of data was by AW, PT, VN, KY, NS, and AL. Analysis was by AW, KY, NS, and AL. Drafting of manuscript was by AW, NS, and NL. All the authors approved for the final manuscript.
Footnotes
Study protocol.
Supplementary Material
Study protocol.
References
- 1.Joana G., Filipe M., Jose A. Long-term consequences of acute kidney injury: narrative review. Clin Kidney J. 2021;14:789–804. doi: 10.1093/ckj/sfaa177. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Giorgino F., Vora J., Fenici P., Solini A. Renoprotetion with SGLT2 inhibitors in type 2 diabetes over a spectrum of cardiovascular and renal risk. Cardiovasc Diabetol. 2020;19:196. doi: 10.1186/s12933-020-01163-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Rabizadeh S., Nakhjavani M., Esteghamati A. Cardiovasular and renal benefits of SGLT2 inhibitors: a narrative review. Int J Endocrinol Metab. 2019;17:e843–e853. doi: 10.5812/ijem.84353. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Kuriyama S. A potential mechanism of cardio-renal protection with sodium-glucose cotransporter 2 inhibitors: amelioration of renal congestion. Kidney Blood Press Res. 2019;44:449–456. doi: 10.1159/000501081. [DOI] [PubMed] [Google Scholar]
- 5.Griffin M., Rao V.S., Ivey-Miranda J., et al. Empagliflozin in heart failure: diuretic and cardio-renal effects. Circulation. 2020;142:1028–1039. doi: 10.1161/CIRCULATIONAHA.120.045691. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Hallow K.M., Helmlinger G., Greasley P.J., McMurray J.J.V., Boulton D.W. Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes Obes Metab. 2018;20:479–487. doi: 10.1111/dom.13126. [DOI] [PubMed] [Google Scholar]
- 7.Voors A.A. American College of Cardiology (AHA); 2021. Empagliflozin in patients hospitalized for acute heart failure – EMPULSE trial. Presented by Dr. Adriaan A Voors at the American Heart Association Virtual Annual Scientific Sessions. [Google Scholar]
- 8.Tang H., Li D., Zhang J., et al. Sodium-glucose co-transporter-2 inhibitors and risk of adverse renal outcomes among patients with type 2 diabetes: a network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2017;19:1106–1115. doi: 10.1111/dom.12917. [DOI] [PubMed] [Google Scholar]
- 9.Nuffield Department of Population Health Renal Studies Group SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium. Nuffield Department of Population Health Renal Studies Group; SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet. 2022;400:1788–1801. doi: 10.1016/S0140-6736(22)02074-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.McMurray J.J.V., Solomon S.D., Inzucchi S.E., et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381:1995–2008. doi: 10.1056/NEJMoa1911303. [DOI] [PubMed] [Google Scholar]
- 11.Perkovic V., Jardine M.J., Neal B., et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380:2295–2306. doi: 10.1056/NEJMoa1811744. [DOI] [PubMed] [Google Scholar]
- 12.Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract. 2012;120:c179–c184. doi: 10.1159/000339789. [DOI] [PubMed] [Google Scholar]
- 13.Siew E.D., Ikizler T.A., Matheny M.E., et al. Estimating baseline kidney function in hospitalized patients with impaired kidney function. Clin J Am Soc Nephrol. 2012;7:712–719. doi: 10.2215/CJN.10821011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. 2013;3:1–150. doi: 10.1038/ki.2013.243. [DOI] [PubMed] [Google Scholar]
- 15.Bellomo R., Ronco C., Kellum J.A., Mehta R.L., Palevsky P., Acute Dialysis Quality Initiative Workgroup Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8:R204–R212. doi: 10.1186/cc2872. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Lees J.S., Mark P.B. GFR slope as a surrogate marker for future kidney failure. Nat Rev Nephrol. 2023;19:625–626. doi: 10.1038/s41581-023-00748-3. [DOI] [PubMed] [Google Scholar]
- 17.Silver S.A., Adhikari N.K., Bell C.M., et al. Nephrologist follow-up versus usual care after an acute kidney injury hospitalization (Fusion): a randomized controlled trial. Clin J Am Soc Nephrol. 2021;16:1005–1014. doi: 10.2215/CJN.17331120. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Bernard R. 5th ed. Thomson Learning; 2000. Fundamentals of Biostatistics; pp. 384–385. [Google Scholar]
- 19.Ngamjarus C., Chongsuvivatwong V. The Thailand Research Fund & Prince of Songkla University; 2014. n4Studies: Sample Size and Power Calculations for iOS. The Royal Golden Jubilee Ph.D. Program. [Google Scholar]
- 20.Gayat E., Hollinger A., Cariou A., et al. Impact of angiotensin-converting enzyme inhibitors or receptor blockers in post-ICU discharge outcome in patients with acute kidney injury. Intensive Care Med. 2018;44:598–605. doi: 10.1007/s00134-018-5160-6. [DOI] [PubMed] [Google Scholar]
- 21.Brar S., Ye F., James M.T., Hemmelgarn B., Klarenbach S., Pannu N. Association of angiotensin-converting enzyme inhibitors or receptor blocker use with outcomes after acute kidney injury. JAMA Intern Med. 2018;178:1681–1690. doi: 10.1001/jamainternmed.2018.4749. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Harel Z., Wald R., Bargman J.M., et al. Nephrologist follow up improves all-cause mortality of severe acute kidney injury survivors. Kidney Int. 2013;83:901–908. doi: 10.1038/ki.2012.451. [DOI] [PubMed] [Google Scholar]
- 23.Thanapongsatorn P., Chaikomon K., Lumlertgul N., et al. Comprehensive versus standard care in post-severe acute kidney injury survivors, a randomized controlled trial. Crit Care. 2021;25:322. doi: 10.1186/s13054-021-03747-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Silver S.A., Harel Z., McArthur E. 30-day readmission after acute kidney injury hospitalization. Am J Med. 2017;130 doi: 10.1016/j.amjmed.2016.09.016. 163.e4–172.e4. [DOI] [PubMed] [Google Scholar]
- 25.Go A.S., Hsu C.Y., Yang J., et al. Acute kidney injury and risk of heart failure and atherosclerotic events. Clin J Am Soc Nephrol. 2018;13:833–841. doi: 10.2215/CJN.12591117. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Heerspink H.J.L., Stefánsson B.V., Correa-Rotter R., et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383:1436–1446. doi: 10.1056/NEJMoa2024816. [DOI] [PubMed] [Google Scholar]
- 27.Herrington W.G., Staplin N., Wanner C., et al. Empagliflozin in patients with chronic kidney disease. N Engl J Med. 2023;388:117–127. doi: 10.1056/NEJMoa2204233. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Menne J., Dumann E., Haller H., Schmidt B. Acute kidney injury and adverse renal events in patients receiving SGLT2-inhibitors: a systematic review and meta-analysis. PLOS Med. 2019;16 doi: 10.1371/journal.pmed.1002983. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Delanaye P., Scheen A. Epidemiology of acute kidney injury adverse events with SGLT2 inhibitors: a meta-analysis of observational cohort studies. Diabetes Epidemiol Manag. 2021;3 doi: 10.1016/j.deman.2021.100021. [DOI] [Google Scholar]
- 30.Margonato D., Giuseppe G., Mazzeti S., et al. Renal protection: a leading mechanism for cardiovascular benefit in patients treated with SGLT2 inhibitors. Heart Fail Rev. 2021;26:337–345. doi: 10.1007/s10741-020-10024-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Leoncini G., Russo E., Bussalino E., Barnini C., Viazzi F., Pontremoli R. SGLT2is and Renal Protection: from biological mechanisms to real-world clinical benefits. Int J Mol Sci. 2021;22:4441. doi: 10.3390/ijms22094441. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Cowie M.R., Fisher M. SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. Nat Rev Cardol. 2020;17:761–770. doi: 10.1038/s41569-020-0406-8. [DOI] [PubMed] [Google Scholar]
- 33.Herat L.Y., Magno A.L., Rudnicka C., et al. SGLT2 inhibitor induced Sympathoinhibition a novel mechanism for cardiorenal protection. JACC Basic Transl Sci. 2020;5:169–179. doi: 10.1016/j.jacbts.2019.11.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Study protocol.
Data Availability Statement
Data supporting the study are available within the article. Any additional data related to the study will be provided on request to the corresponding author.