Incidence and Prognostic Impact of Acute Kidney Injury After Transcatheter Aortic Valve Replacement in Patients With Low-Flow and Low-Gradient Aortic Stenosis

Abstract

Background: Acute kidney injury (AKI) is a common and serious post-transcatheter aortic valve replacement (TAVR) complication that affects patient outcomes. Low-flow, low-gradient (LFLG) aortic stenosis (AS) and chronic kidney disease (CKD) represent a high-risk subset of patients undergoing TAVR. The objective of this study was to evaluate the prognostic impact of LFLG-AS and AKI in CKD patients undergoing TAVR.

Methods and Results: A retrospective analysis was conducted on 324 patients with CKD stage G3a-5 who underwent TAVR for severe AS between August 2015 and December 2022. Patients were stratified into 4 groups according to the presence of LFLG- AS and AKI. The primary endpoint was defined as all-cause mortality or heart failure during the 2-year follow-up period. During a median period of 13 months, 46 (14%) patients reached the primary endpoint. The difference between the baseline values for renal function of the patients with AKI or without AKI was not significant. The patients without either condition who had the most favorable outcomes were those without LFLG-AS or AKI. Patients with LFLG-AS only or AKI only had intermediate outcomes. The patients with LFLG-AS and AKI showed significantly higher mortality and adverse outcomes than the other groups (log-rank P<0.001).

Conclusions: This study highlighted the severe prognostic implications of AKI for patients with LFLG-AS who undergo TAVR.

Central Figure

Aortic stenosis (AS) is a common and progressive valvular disease that affects the elderly population. The advent of transcatheter aortic valve replacement (TAVR) has markedly transformed the management of severe AS, especially in patients who are at high surgical risk or inoperable because of comorbid conditions. Recent advances in TAVR techniques have expanded its indications not only to patients at intermediate and low surgical risk, but also to those with very severe AS.^1–4 While treatment techniques are advancing, further improvement of AS treatment outcomes requires attention to the occurrence of complications. Acute kidney injury (AKI) is a serious complication following TAVR. The incidence of AKI after TAVR has been reported to range from 8.3% to 57%, depending on the patient population and diagnostic criteria.⁵ AKI is defined as a sudden decrease in kidney function, which is typically recognized as an increase in the serum creatinine level.⁶ AKI is associated with a range of adverse outcomes, including increased in-hospital mortality, prolonged hospital stays, increased rates of readmission, and long-term mortality.^7–9 The pathophysiology of post-TAVR AKI involves multiple factors, including hemodynamic instability, the use of contrast agents, renal hypoperfusion, and systemic inflammation.^10,11 In addition, patients with chronic kidney disease (CKD) have been reported to have a higher risk of mortality and complications after TAVR.⁷ Furthermore, the development of AKI after TAVR in patients with CKD is of particular concern as it may further worsen their prognosis.

Moreover, the background of patients undergoing TAVR should also be considered. Among the patients undergoing TAVR, a subset of patients with low-flow, low-gradient (LFLG)-AS poses a particular clinical challenge. LFLG-AS is characterized by reduced stroke volume and a low transvalvular gradient despite severe aortic valve obstruction. Because of associated complex comorbidities, patients with LFLG-AS typically have a worse prognosis compared with patients with high-gradient AS.¹² Although it is well known that patients with LFLG-AS are at high surgical risk and that AKI has a negative impact on outcomes post-TAVR, data focusing on the effect of these conditions combined are limited. The objective of this study was to evaluate the prognostic impact of LFLG-AS and AKI in CKD patients undergoing TAVR.

Methods

Study Population

This retrospective study enrolled 457 patients who underwent TAVR for severe AS between August 2015 and December 2022. The exclusion criteria were an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m² or missing data. Patients who died during hospitalization were also included in the analysis. A total of 324 consecutive patients with CKD grade ≥3 (including 8 dialysis patients) were included in the final analysis (Figure 1). Patients were stratified into 4 groups according to the presence/absence of LFLG-AS and AKI. The study was conducted in accordance with the Declaration of Helsinki. This study was approved by Ethics Committee of Medical and Health Research Involving Human Subjects in Ryukyu University Hospital (IRB no. 23-2255-02-00-00). All patients provided informed consent for their data to be published.

Figure 1.

Flowchart of patient enrollment. AKI, acute kidney injury; AS, aortic stenosis; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; TAVR, transcatheter aortic valve replacement.

Laboratory Data

Blood tests were taken at the time of admission and 1 week after TAVR. The eGFR was calculated according to the following equation used for Japanese patients: eGFR (mL/min/1.73 m²) = 194 × Age^−0.287 × Cre^−1.094 (if female, ×0.739).¹³ The change in eGFR from baseline to within 1 week (5–7days) after TAVR was measured and designated as ∆eGFR. AKI was defined as ∆eGFR ≥5%.

Echocardiographic Assessments

Echocardiography was conducted within 3 months prior to TAVR and again at 1 week after TAVR by experienced sonographers who used a range of commercially available ultrasound machines (Vivid 7, Vivid E9, Vivid E95, Vivid S60, Vivid S70; GE [Vingmed], Horten, Norway; iE33, EPIQ 7; Philips, Amsterdam, The Netherlands). To ensure consistency and reliability in the assessments of cardiac structure and function before and after TAVR, the recordings and measurements were performed in strict accordance with the American Society of Echocardiography’s guidelines,^14,15 The stroke volume was calculated by measuring the left ventricular outflow tract diameter and the velocity-time integral of blood flow in the left ventricular outflow tract using echocardiography. The stroke volume index (SVi) was determined by dividing the stroke volume in mL by the body surface area in m². Low flow (LF) was defined as SVi ≤35 mL/m². Low gradient (LG) was defined as a mean pressure gradient ≤40 mmHg. The mean pressure gradient was obtained using echocardiography. Severe AS with both LF and LG was defined as LFLG-AS. Among patients with LFLG, we defined classical LFLG-AS as those with an LVEF <50% and paradoxical LFLG-AS as those with an LVEF ≥50%.

Clinical Outcomes

All patients underwent annual follow ups at University of the Ryukyus Hospital with clinical visits every 12 months. Outcomes were obtained from medical records during outpatient visits. The observation period was set to 2 years. To ensure a comprehensive evaluation of patient outcomes post-procedure, the primary endpoints were the incidences of all-cause death and hospitalizations for heart failure (HF).

Statistical Analysis

Continuous variables are presented as means±standard deviation (SD) for normally distributed values, and medians (interquartile range) for non-normally distributed values. The normality of continuous variables was assessed using the Shapiro-Wilk test. Differences between groups were evaluated using the Student’s t-test and Wilcoxon rank sum test for continuous variables, and the Pearson chi-squared test and Fisher›s exact test for small samples for categorical variables, with results expressed as percentages. To evaluate outcomes, a Kaplan-Meier analysis was performed separately for patients with or without AKI, and for patients with or without LFLG. Event-free survival rates were compared using a 2-tailed log-rank test. Associations of parameters with the primary endpoints ware identified using Cox proportional-hazards models in univariable and multivariable analysis. Sequential Cox models were performed to determine the incremental prognostic benefits of clinical parameters over the baseline model, with the incremental prognostic value being defined by a significant increase in global chi-squared values. Hazard ratios (HRs) with 95% confidence intervals (CI) were calculated for each variable. JMP Pro software (Version 17; SAS Institute Inc., Cary, NC, USA), MedCalc (Version 22; MedCalc Software, Mariakerke, Belgium), and SPSS Statistics (Version 20.0; SPSS, Inc., Chicago, IL, USA) were used to analyze the data. Statistical significance was defined as a P value <0.05.

Results

Patient Characteristics

Baseline characteristics are presented in Table 1. The study included 324 patients. There were 194 female and 130 male patients, with a median age of 86 years. Among the 324 patients, 80% had hypertension and 49% had dyslipidemia. The overall rate of diabetes was 27%. The proportion of patients with AKI who had diabetes was significantly greater than the proportion of patients without AKI who had diabetes (40% vs. 24%; P=0.028). The proportion of patients with AKI who had ischemic heart disease was greater than the proportion of patients without AKI who had ischemic heart disease, although the difference was not significant.

Table 1.

Baseline Characteristics of Patients

	All (n=324)	AKI group (n=42)	No AKI group (n=282)	P value
Demographics
Age (years)	86 (83–89)	86 (82–88.25)	86 (83–89)	0.190
Sex, male	130 (40)	19 (45)	111 (39)	0.469
BMI (kg/m2)	23.2 (21.1–26.2)	23.4 (21.0–26.8)	23.2 (21.3–26.2)	1.000
NYHA class III/IV	137 (42)	20 (48)	117 (41)	0.453
Hypertension	259 (80)	30 (71)	229 (81)	0.140
Diabetes	86 (27)	17 (40)	69 (24)	0.028
Dyslipidemia	159 (49)	24 (57)	135 (48)	0.262
Ischemic heart disease	127 (39)	22 (52)	105 (37)	0.061
Cerebrovascular disease	55 (17)	12 (29)	43 (15)	0.032
Chronic atrial fibrillation	44 (14)	6 (14)	38 (13)	0.886
Peripheral arterial disease	37 (11)	5 (12)	32 (11)	0.916
Prior hospitalization for HF	137 (42)	18 (43)	119 (42)	0.936
Medical treatment
ACEi/ARB	175 (54)	26 (63)	149 (53)	0.204
Calcium channel blocker	147 (46)	16 (39)	131 (46)	0.372
β-blocker	88 (27)	15 (37)	73 (26)	0.151
Loop diuretics	142 (44)	22 (54)	120 (43)	0.181
Statin	145 (45)	25 (61)	120 (43)	0.027
Laboratory data
Hemoglobin (g/dL)	11.3 (10.3–12.8)	11.9 (10.0–12.9)	11.3 (10.3–12.7)	0.790
Albumin (mg/dL)	3.7 (3.4–4.0)	3.7 (3.2–4.0)	3.7 (3.5–4.0)	0.239
Creatinine (mg/dL)	1.05 (0.86–1.39)	1.08 (0.85–1.55)	1.04 (0.86–1.38)	0.648
eGFR (mL/min/1.73 m2)	43.1 (31.9–52.1)	45.5 (29.8–51.5)	43.1 (32.1–52.1)	0.998
HbA1c (%)	5.8 (5.4–6.2)	5.9 (5.5–6.3)	5.8 (5.4–6.2)	0.811
NT-proBNP (pg/mL)	1,971 (929–5,321)	4,472 (1,245–10,134)	1,886 (904–4,275)	0.008
Echocardiographic indices
LVEF (%)	61.6 (50.5–70.2)	59.3 (44.2–73.2)	61.8 (50.9–69.7)	0.973
AV peak velocity (m/s)	4.33 (3.99–4.74)	4.18 (3.76–4.70)	4.37 (4.01–4.75)	0.320
AV mean PG (mmHg)	45.0 (36.5–54.6)	41.3 (32.7–54.3)	45.2 (36.9–54.6)	0.336
AVA (cm2)	0.59 (0.47–0.77)	0.59 (0.42–0.73)	0.59 (0.48–0.78)	0.550
LVOT-SV (mL)	60.0 (48.7–78.6)	62.3 (49.9–80.6)	60.0 (48.4–78.6)	0.907
SVi (mL/m2)	42.5 (33.4–52.5)	44.0 (30.3–51.4)	42.4 (33.4–52.7)	0.994
LFLG-AS	48 (15)	7 (17)	41 (15)	0.717
Classical LFLG-AS	35 (11)	7 (17)	28 (10)	0.189
Paradoxical LFLG-AS	13 (4)	0 (0)	13 (5)	0.388
Procedural parameters
Emergency TAVR	22 (7)	9 (21)	13 (5)	<0.001
Complication	44 (14)	6 (14)	38 (13)	0.886
Neurologic events	12 (4)	1 (2)	11 (4)	0.627
Pacemaker implantation	21 (6)	3 (7)	18 (6)	0.852
Vascular and access-related complication	5 (2)	1 (2)	4 (1)	0.637
Contrast media dose (mL)	40 (30–63)	36 (30–60)	40 (30–63)	0.574
Self-expandable valve use	45 (14)	6 (15)	39 (14)	0.890
Operation time (min)	50.5 (33.3–86)	66.5 (33.5–106.8)	49.5 (33–83)	0.138

Data are presented as n (%), or median (Q1–Q3). ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blocker; AV, aortic valve; AVA, aortic valve area; BMI, body mass index; eGFR, estimated glomerular filtration rate; HbA1c, hemoglobin A1c; HF, heart failure; LFLG-AS, low-flow, low-gradient aortic stenosis; LVEF, left ventricular ejection fraction; LVOT- SV, left ventricular outflow tract stroke volume; NT-proBNP, N-terminal pro B-type natriuretic peptide; NYHA, New York Heart Association; PG, pressure gradient; SVi, stroke volume index; TAVR, transcatheter aortic valve replacement.

Forty-two percent of all study patients had previous hospitalizations for HF. The proportions of patients with AKI who had cerebrovascular disease and used statins were significantly greater than the proportions of patients without AKI with cerebrovascular disease and used statins. The differences between the serum creatinine levels, eGFRs, and echocardiographic indices were not significant. LFLG-AS were compared separately for classical and paradoxical types, but there was no difference between the AKI and no-AKI groups. A significantly higher proportion of patients with AKI than without AKI underwent emergency TAVR (21%; P<0.001). There was only 1 hemorrhagic complication requiring blood transfusion. No significant differences were observed in the rates of neurological events, pacemaker implantation, or access-site injury between the AKI group and the no-AKI group. There were no differences in the volumes of contrast media, types of TAVR values, and operative times between the AKI and no-AKI groups.

Outcomes of Patients With AKI and LFLG-AS Who Underwent TAVR

During a median period of 383 days (13 months), 46 (14%) patients reached the primary endpoint. There was only 1 in-hospital death. AKI occurred in 42 (13%) patients. Figure 2A shows the event-free survival rates over time of patients with and without AKI. Patients who developed AKI after TAVR had a significantly shorter duration of event-free survival than those without AKI (log-rank P=0.003). LFLG-AS was present in 48 (15%) patients. Patients with LFLG-AS had a significantly shorter duration of event-free survival than patients without LFLG-AS (Figure 2B; log-rank P<0.001). Figure 3 shows the event-free survival rate over time by LFLG classification. Event-free survival was significantly shorter in the classical LFLG group (Figure 3A; log-rank P<0.001), but not in the paradoxical LFLG group (Figure 3B; log-rank P=0.555). Figure 4 shows the event-free survival rates for 4 patient groups stratified by the presence or absence of AKI and LFLG-AS. As no patients with paradoxical LFLG-AS developed AKI, all LFLG-AS cases in Figure 4 represent the classical subtype. Therefore, LFLG-AS was analyzed as a single group in this figure. Patients with LFLG-AS and AKI had the highest event rate and the shortest duration of event-free survival (log-rank P<0.001). Patients with either LFLG-AS or AKI alone had the next shortest durations of event-free survival. Patients with neither LFLG-AS nor AKI obtained the longest duration of event-free survival. The analysis that focused on classical LFLG revealed a significant difference, showing that the combination of classical LFLG and AKI is associated with the worst prognosis. The results shown in Figures 2–4 remained consistent when emergency TAVR cases and patients on hemodialysis were excluded from the analysis.

Figure 2.

Kaplan-Meier analysis for the primary endpoint. (A) Presence and absence of acute kidney injury (AKI). The green line indicates patients with AKI and the blue line indicates patients without AKI. (B) Presence and absence of low-flow, low-gradient aortic stenosis (LFLG-AS). The green line indicates patients with LFLG-AS and the blue line indicates patients without LFLG-AS.

Figure 3.

Kaplan-Meier curves for the primary endpoint by LFLG classification. (A) Presence and absence of classical LFLG. The green line indicates patients with classical LFLG and the blue line indicates the others. (B) Presence and absence of paradoxical LFLG. The green line indicates patients with paradoxical LFLG-AS and the blue line indicates the others. LFLG-AS, low-flow, low-gradient aortic stenosis.

Figure 4.

Kaplan-Meier curves for the primary endpoint in patients divided into 4 groups according to the presence/absence of AKI and LFLG-AS. The red line indicates patients with both AKI and LFLG. These patients had the worst outcome. The green line indicates patients with LFLG only. The orange line indicates patients with AKI only. The blue line indicates patients without AKI and LFLG-AS. AKI, acute kidney injury; LFLG-AS, low-flow, low-gradient aortic stenosis.

Related Factors of Outcome

Table 2 shows the results of univariate analysis using the Cox proportional hazards model for prognostic evaluations. AKI after TAVR (HR 2.44; 95% CI 1.32–4.52; P=0.005), serum albumin (HR 0.36; 95% CI 0.23–0.58; P<0.001), serum creatinine (HR 1.29; 95% CI 1.12–1.42; P<0.001), LFLG-AS (HR 2.67; 95% CI 1.54–4.63; P<0.001), and use of loop diuretics (HR 2.21; 95% CI 1.33–3.69; P=0.002) were significantly associated with the primary endpoint. Although not statistically significant, prior hospitalization for HF showed a trend toward an association with the primary outcome (HR 1.64; 95% CI 0.99–2.71; P=0.055). Table 3 shows the results of multivariate analysis for the primary endpoint during follow up across 3 different models. Considering the potential for multicollinearity and the limited number of events, age, sex, and heart failure classified as New York Heart Association class III or higher were included as basic clinical covariates in all models. Model 1 included the basic clinical variables plus serum albumin and creatinine levels. Model 2 added echocardiographic parameters, including left ventricular ejection fraction (LVEF) and the presence of LFLG-AS. Model 3 incorporated eGFR and the development of AKI after TAVR in addition to the basic variables. After adjustment for these background factors, serum albumin, serum creatinine, LFLG-AS, eGFR, and post-TAVR AKI remained significantly associated with clinical outcomes. The incremental benefits of clinical parameters to the prediction of events are shown in Figure 5. Prognostic models that included age, sex, and prior heart failure hospitalizations showed significantly improved prognostic ability with the addition of eGFR, presence of LFLG, and occurrence of AKI after TAVR (Model 1 – age, male, prior hospitalization for HF, global chi-squared: 7.3; Model 2 – plus eGFR, global chi-squared: 15.4, P=0.005; Model 3 – plus LFLG, global chi-squared: 23.3, P=0.024; Model 4 – plus AKI after TAVR, global chi-squared 31.8, P=0.014).

Table 2.

Univariate Associations of All-Cause Death and Hospitalization for HF During Follow up

	All patients, HR (95% CI)	P value
Demographics
Age	0.97 (0.92–1.02)	0.218
Sex, male	1.24 (0.75–2.06)	0.401
BMI (kg/m2)	0.97 (0.90–1.03)	0.313
NYHA class III/IV	1.16 (0.69–1.93)	0.575
Hypertension	0.98 (0.52–1.85)	0.960
Diabetes	1.32 (0.76–2.28)	0.326
Dyslipidemia	0.85 (0.52–1.41)	0.536
Ischemic heart disease	0.93 (0.56–1.55)	0.795
Cerebrovascular disease	1.65 (0.92–2.96)	0.090
Prior hospitalization for HF	1.64 (0.99–2.71)	0.055
AKI after TAVR	2.44 (1.32–4.52)	0.005
Laboratory data
Hemoglobin (g/dL)	0.84 (0.72–0.97)	0.018
Albumin (mg/dL)	0.36 (0.23–0.58)	<0.001
Creatinine (mg/dL)	1.29 (1.12–1.42)	<0.001
eGFR (mL/min/1.73 m2)	0.97 (0.95–0.99)	0.002
HbA1c	0.95 (0.66–1.30)	0.750
Echocardiography
LVEF (%)	0.98 (0.97–1.00)	0.024
AV peak velocity (m/s)	0.74 (0.52–1.08)	0.116
AV mean PG (mmHg)	0.99 (0.97–1.01)	0.169
AVA (cm2)	1.26 (0.36–3.90)	0.703
LVOT-SV (mL)	1.00 (0.99–1.01)	0.900
SVi (mL/m2)	1.00 (0.98–1.02)	0.809
LFLG-AS	2.67 (1.54–4.63)	<0.001
Medical treatment
Statin	1.08 (0.66–1.77)	0.767
Loop diuretics	2.21 (1.33–3.69)	0.002

AKI, acute kidney injury; AV, aortic valve; AVA, aortic valve area; BMI, body mass index; CI, confidence interval; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; HF, heart failure; HR, hazard ratio; LFLG-AS, low-flow, low-gradient aortic stenosis; LVEF, left ventricular ejection fraction; LVOT-SV, left ventricular outflow tract stroke volume; NYHA, New York Heart Association; PG, pressure gradient; SVi, stroke volume index; TAVR, transcatheter aortic valve replacement.

Table 3.

Multivariate Associations of All-Cause Death and Hospitalization for HF During Follow up

	Model 1			Model 2			Model 3
	HR	95% CI	P value	HR	95% CI	P value	HR	95% CI	P value
Clinical parameter
Age	0.97	0.92–1.03	0.305	0.98	0.93–1.04	0.500	0.98	0.93–1.04	0.531
Sex, male	1.03	0.60–1.75	0.923	1.10	0.65–1.86	0.733	1.08	0.63–1.83	0.788
NYHA class III/IV	0.90	0.53–1.53	0.705	1.06	0.62–1.83	0.823	1.09	0.65–1.84	0.743
Laboratory data
Albumin (mg/dL)	0.39	0.25–0.64	<0.001
Creatinine (mg/dL)	1.20	1.04–1.36	0.005
Echocardiography
LVEF				0.99	0.98–1.01	0.420
LFLG-AS				2.23	1.19–4.20	0.013
Renal function
eGFR							0.97	0.95–0.99	0.003
AKI							2.30	1.22–4.36	0.011

AKI, acute kidney injury; CI, confidence interval; eGFR, estimated glomerular filtration rate; HF, heart failure; HR, hazard ratio; LFLG-AS, low-flow, low-gradient aortic stenosis; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association.

Figure 5.

Changes in the global chi-squared values of sequential Cox models. This graph shows the incremental values of adding data on echocardiography, renal function, and the presence of acute kidney injury (AKI) after transcatheter aortic valve replacement (TAVR) to basic information and represents improvements in prognostic abilities. The table below the graph indicates hazard ratios, 95% confidence intervals, and P values. eGFR, estimated glomerular filtration rate; HF, heart failure; LFLG, low-flow, low-gradient.

Discussion

TAVR is an effective treatment for elderly patients who are unable to undergo open chest surgery. Elderly patients have a variety of comorbidities, and the prevalence of CKD increases with age. It has been reported that patients with preoperative moderate or increased CKD have worse outcomes after TAVR than patients with low or no CKD after TAVR.¹⁶ It has also been reported that patients who develop AKI after TAVR have increased mortality compared with those who do not develop AKI.¹⁷ From these points, this study focused on CKD patients and evaluated the incidence of AKI in AS patients who underwent TAVR in Japan, finding results similar to those of previous studies. Additionally, we also considered prognostic factors, focusing on LFLG-AS from the viewpoint of AKI. As shown in Figure 4, the best outcomes were observed in patients without LFLG-AS or AKI. The combination of both LFLG-AS and AKI was associated with the worst outcome. To our best knowledge, this study is among the first to focus on the cohort of high-risk patients with LFLG -AS who undergo TAVR. Its findings highlighted the compounded risks in this population that were associated with AKI.

Mechanisms of AKI

AKI following TAVR is a multifaceted complication, affected by a variety of hemodynamic and procedural factors.¹¹ An understanding of the underlying mechanisms can aid in the development of targeted strategies to mitigate this risk, especially in patients with LFLG-AS and pre-existing CKD. The heart and kidneys are considered to be strongly interrelated, leading to the concept of cardiorenal syndrome (CRS).¹⁸ CRS is classified according to whether it is caused by the heart or the kidneys and is acute or chronic. Among the patients with LFLG-AS and CKD, a high proportion has been considered to have CRS type 2, which is a type of chronic cardiac dysfunction that leads to renal damage.

Patients with LFLG-AS often have significantly reduced cardiac output and renal blood flow. Under these circumstances, patients undergoing TAVR are prone to hemodynamic instability, which may be one of the mechanisms leading to the development of AKI. Renal function is already declining in CKD patients. Therefore, hemodynamic instability due to cardiac disease is likely to cause further decline in renal function. Post-TAVR, renal perfusion may be enhanced by restoration of adequate cardiac output and increased eGFR, which results in improved renal function in some patients.¹⁹ Additionally, a subanalysis of the PARTNER-1 trial reported that among CKD patients with baseline eGFR <60 mL/min/1.73 m², more patients with improved eGFR after TAVR had low cardiac index.²⁰ These results suggest that renal function should improve because of the improved cardiac output after TAVR. An improved renal function is particularly important for patients whose renal function was maintained by an unstable cardiac output-dependent balance. Enhanced renal perfusion after TAVR can alleviate chronic ischemia of the renal microcirculation, thus improving kidney function overall. However, some patients unexpectedly develop AKI, and other factors that cause AKI, including contrast agents, cholesterol emboli and an inflammatory response to TAVR must also be considered.^21,22

AKI and Emergency TAVR

In this study, no significant differences were found between the AKI and no-AKI groups regarding contrast volume, device type, or operative time. In addition to the aforementioned risks of contrast agents and hemodynamics, previous literature suggests that rapid ventricular pacing, hemodynamic instability, embolic risk, vascular access complications during the procedure, postoperative bleeding, and paravalvular regurgitation may also contribute to the development of AKI.²³ Based on these findings, preventative strategies should include appropriate preoperative fluid management, optimization of intravascular volume, minimization of rapid pacing, reduction of bleeding and vascular complications, and avoidance of nephrotoxic agents, especially contrast media. In addition, given that loop diuretics are known to exacerbate volume-dependent worsening in patients with chronic heart failure,²⁴ appropriate diuretic management should also be emphasized.

A notable feature of this study is that a higher percentage of patients with AKI underwent emergency TAVR compared with those without AKI. The aforementioned strategies for preventing AKI are often insufficient in emergency TAVR cases. Most patients undergoing emergency TAVR require urgent treatment for acute heart failure, chest pain and syncope, often presenting with poor systemic status, including congestive complications and hypoxia. Preoperative syncope and heart failure have been reported to be associated with a poor prognosis.²⁵ In such patients, preoperative evaluation and the TAVR procedure itself may further compromise their condition. In clinical practice, we frequently encounter cases where patients consent to treatment only after symptoms have worsened, resulting in the need for emergency TAVR. Therefore, routine management strategies are necessary to assess and intervene in AS at the appropriate time to prevent the onset of decompensated heart failure and emergency TAVR.

Prognosis of Paradoxical LFLG-AS

Most notably in this study, the combination of LFLG-AS and AKI led to the worst outcome. The prognosis of paradoxical LFLG-AS varies among reports.^26,27 This study found no clear indicators of poor prognosis for paradoxical LFLG-AS. In the present study, no patients with paradoxical LFLG-AS developed AKI, which may partially explain the absence of a significant difference in event-free survival within this subgroup, as AKI was associated with worse outcomes in the overall cohort. Furthermore, previous studies have suggested that the prognosis of paradoxical LFLG-AS may vary by ethnicity. For example, the JUST-R registry, which investigated Japanese patients, reported that paradoxical LFLG-AS was associated with relatively favorable outcomes, similar to those of moderate AS.²⁸ Considering that our study population consisted entirely of Japanese patients, this may help explain the relatively benign prognosis observed in this subgroup.

Complexity of AKI and LFLG-AS

The combination of classical LFLG-AS with reduced LVEF and AKI constitutes a subset that warrants special attention. The strong association between AKI and poor outcomes in patients undergoing TAVR can be attributed to several factors. First, AKI itself can lead to a cascade of adverse effects, including fluid overload, electrolyte imbalance, and the accumulation of metabolic waste products, which can exacerbate cardiac dysfunction and overall clinical instability. This is the so-called CRS type 3 pattern, in which AKI leads to cardiac dysfunction and heart failure.¹⁸ Second, AKI often serves as a marker of the severity of underlying systemic disease, reflecting not only renal vulnerability but also broader cardiovascular and systemic health challenges. When such deterioration in overall condition contributes to classical LFLG-AS, the clinical complexity may further complicate therapeutic management and potentially lead to underestimation of AS severity requiring intervention. This complexity also complicates postoperative management of patients undergoing TAVR, necessitating increased monitoring and interventions. AKI increases the length of hospital stay and the risk of additional complications such as dialysis and prolonged mechanical ventilation.^7–9 The increased burden of care and the associated utilization of resources underscore the importance of preventing AKI and heart failure through optimized perioperative strategies, vigilant postoperative care, and timely therapeutic intervention for AS.

Study Limitations

First, this study was observational in nature, which limits the ability to establish causality. Additionally, because it focused on a specific patient population undergoing TAVR, the generalizability of the findings to other patient groups or clinical settings remains uncertain. Second, the definition of post-TAVR AKI warrants consideration. The diagnostic criteria for AKI after TAVR have undergone several revisions over time.^29–31 Although the Valve Academic Research Consortium-3 (VARC-3) criteria³¹ are currently the most widely accepted, we found that even the mildest category of this definition (Stage 1: increase in serum creatinine ≥150–200% within 7 days) identified AKI in only 2 patients in our cohort. One likely reason for this low incidence is that the majority of our study population consisted of elderly patients with pre-existing CKD and elevated baseline serum creatinine levels. In such patients, even clinically meaningful changes in renal function may not produce a ≥1.5-fold increase in serum creatinine, leading to underestimation of AKI when using creatinine-based definitions alone. Moreover, it has been previously reported that in elderly individuals, reduced muscle mass may result in lower baseline creatinine production, thereby masking the actual decline in kidney function and potentially delaying or missing the diagnosis of AKI.²³ Given these limitations, we were concerned that subtle but clinically meaningful renal impairment might be overlooked using the VARC-3 criteria. To address this issue and better detect early and mild changes in kidney function, we adopted a more sensitive criterion by defining AKI as a 5% or greater reduction in eGFR, calculated by comparing pre- and post-TAVR values. It has also been reported that a previous study demonstrated that even a modest decline in eGFR of approximately 5% was associated with a HR greater than 1.0 for all-cause mortality in CKD patients.³² This finding highlights the prognostic relevance of even minor eGFR reductions and supports our rationale for using a more sensitive definition in this context. Furthermore, the primary endpoints of this study were all-cause mortality and hospitalization for heart failure. The causes of death were not limited to cardiovascular disease, particularly given the presence of multiple comorbidities in the elderly population studied. Last, the sample size was relatively small. Although patients with both LFLG-AS and AKI exhibited the poorest outcomes, their number was limited to just 7 in our study population. Therefore, validation in larger cohorts is necessary to generalize these findings, and further research is warranted.

Conclusions

To our knowledge, this is the first study to show the relationship between AKI and LFLG-AS in patients undergoing TAVR. This study provides important insights into the association between LFLG-AS and AKI, as well as outcomes, in patients with CKD undergoing TAVR. The study results show that patients with both LFLG-AS and AKI have the poorest outcomes. These findings should contribute to improving the management and outcomes of this vulnerable population. It is essential to develop strategies to prevent the development of AKI.

Acknowledgments

We thank all members of the University of the Ryukyus Hospital, and staff of the Department of Cardiovascular Medicine, Nephrology and Neurology and the Department of Thoracic and Cardiovascular Surgery.

Sources of Funding

This work was partially supported by the JSPS Kakenhi Grant 23K07509, the AMED grant JP22uk1024007 and the EXT program for the advanced clinical resource development to K.K. The funding sources had no roles in the design and conduct of the study, the collection, management, analysis, and interpretation of the data, the preparation, review, and approval of the manuscript, and the decision to submit the manuscript for publication.

Disclosures

The authors declare that they have no conflicts of interest.

Author Contributions

H.N., Y.T. and K.K. conceived the idea for this study. H.N. conducted the data analyses. The initial draft of the manuscript was produced by H.N. and K.K. All authors were involved in interpreting the results and writing the manuscript. All authors read and approved the final manuscript.

IRB Information

The study was approved by the local ethics committee and Institutional Review Board of the University of the Ryukyus (protocol: 23-2255-02-00-00).

Data Availability

The data are not publicly available due to the inclusion of patient information.

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