Improvement of renal function after transcatheter aortic valve replacement in patients with chronic kidney disease.

BACKGROUND: Chronic kidney disease is commonly found in patients with aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR) and has marked impact in their prognosis. It has been shown however that TAVR may improve renal function by alleviating the hemodynamic barrier imposed by AS. Nevertheless, the predictors of and clinical consequences of renal function improvement are not well established. Our aim was to assess the predictors of improvement of renal function after TAVR.
METHODS: The present work is an analysis of the Brazilian Registry of TAVR, a national non-randomized prospective study with 22 Brazilian centers. Patients with baseline renal dysfunction (estimated glomerular filtration rate [eGFR] < 60mL/min/1.73m2) were stratified according to renal function after TAVR: increase >10% in eGFR were classified as TAVR induced renal function improvement (TIRFI); decrease > 10% in eGFR were classified as acute kidney injury (AKI) and stable renal function (neither criteria).
RESULTS: A total of 819 consecutive patients with symptomatic severe AS were included. Of these, baseline renal dysfunction (estimated glomerular filtration rate [eGFR] < 60mL/min/1.73m2) was present in 577 (70%) patients. Considering variance in renal function between baseline and at discharge after TAVR procedure, TIRFI was seen in 197 (34.1%) patients, AKI in 203 (35.2%), and stable renal function in 177 (30.7%). The independent predictors of TIRFI were: absence of coronary artery disease (OR: 0.69; 95% CI 0.48-0.98; P = 0.039) and lower baseline eGFR (OR: 0.98; 95% CI 0.97-1.00; P = 0.039). There was no significant difference in 30-day and 1-year all-cause mortality between patients with stable renal function or TIRFI. Nonetheless, individuals that had AKI after TAVR presented higher mortality compared with TIRFI and stable renal function groups (29.3% vs. 15.4% vs. 9.5%, respectively; p < 0.001).
CONCLUSIONS: TIRFI was frequently found among baseline impaired renal function individuals but was not associated with improved 1-year outcomes.

Introduction

Transcatheter aortic valve replacement (TAVR) is a well-established treatment for patients who cannot undergo surgery and those with intermediate to high surgical risk with symptomatic severe aortic stenosis [1-6]. More recently, TAVR indications have also been expanded for patients at low surgical risk, as well as for dysfunctional bioprosthesis [7, 8].

Among the patients currently undergoing TAVR, a high prevalence of non-cardiac comorbidities are frequently observed, including chronic kidney disease (CKD) that ranged from 52% to 72% in prior studies [9-11]. Moreover, renal function impairment at baseline also denotes worse clinical outcomes following TAVR, including higher mortality rates [10-14], particularly when acute kidney injury (AKI) after TAVR ensues [9, 15–17]. Of note, some patients may also experience renal function improvement after TAVR, regardless of the baseline renal condition, and also despite the various procedural factors that could jeopardize renal function such as hypotension during rapid pacing, use of iodinated contrast media, bleeding and athero-emboli. Yet, such adverse effects may be mitigated by the beneficial effects after the AS relief leading to improvement in cardiac output and better renal perfusion [9, 15, 16].

However, there is divergence in recent studies about the effects of the improvement in renal function after TAVR regarding better outcomes, and its real role still needs more investigation [9, 16].

This study aims to determine the predictors and prognosis of renal function improvement after TAVR using data from the Brazilian TAVR Registry.

Methods

Study population

From January 2008 to January 2015, 819 consecutive patients with symptomatic severe AS underwent TAVR and were included in the Brazilian TAVR Registry [18], which is a non-randomized prospective registry, including 22 Brazilian centers. Patients with baseline impaired renal function, defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2, were selected. eGFR was calculated using Chronic Kidney Disease Epidemiology formula (CKD-EPI) [19], expressed by GFR = 141 * min(Scr/κ,1)α * max(Scr/κ, 1)-1.209 * 0.993Age * 1.018 [if female] * 1.159 [if black], which Scr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1. Also, 25 patients who died within the first 24 hours and 60 patients with missing data (4 patients without baseline eGFR, 55 patients without eGFR at discharge and 1 patient without eGFR at both moments) were excluded, remaining 577 patients who were included in the study (Fig 1). The study protocol was conducted in accordance with the Declaration of Helsinki and was approved by each institution’s ethics committee under protocol number 05676012.4.1001.00701, and all participants had provided informed consent. The follow-up was performed by phone calls at 1 month, 1 year and then annually.

Fig 1

Study flowchart.

Selection of the study population. Abbreviations: AS indicates aortic stenosis; eGFR, estimated glomerular filtration rate; TAVR, transcatheter aortic valve replacement.

Procedure

Patients with symptomatic severe AS (aortic valve area < 1.0cm2 and mean aortic valve gradient of ≥ 40 mmHg or peak aortic jet velocity of ≥ 4.0 m/s) were submitted to TAVR with self-expandable CoreValve prosthesis (Medtronic, Minneapolis, MN, USA), balloon-expandable Sapien XT prosthesis (Edwards Lifesciences, Irvine, CA, USA) or balloon-expandable Inovare prosthesis (Braile Biomédica, São José do Rio Preto, SP, Brazil). TAVR procedures were performed according to standard techniques. Aspirin (100 mg/day) and clopidogrel (300 mg loading dose and 75 mg/day) were administered to patients for at least 1 month. The preferable access was the transfemoral approach. When it was not feasible, transapical or transarterial approaches (transubclavian, direct transaortic, transapical or transcarotid) were used according to the preference of the Heart Team. Clinical, procedural and echocardiographic data were prospectively gathered into a pre-set TAVR database. Outcomes were defined according to the Valve Academic Research Consortium 2 (VARC-2) [20]. All outcomes and adverse events were adjudicated by an independent committee.

Group definition

Serum creatinine was collected at baseline and daily after the procedure until discharge. The first creatinine (baseline) was collected on the day or the day before TAVR procedure. The second creatinine used to calculate variation on renal function was at discharge. The median length of stay was 7 days (1–368) and the mean hospitalization period was 13 days. The CKD-EPI formula was used to calculate the eGFR at baseline and at discharge after TAVR procedure. Patients were categorized according to renal function variation after TAVR: increase >10% in eGFR were classified as TAVR induced renal function improvement (TIRFI); decrease > 10% in eGFR were classified as AKI; and stable renal function (neither criteria) [9, 15].

Statistical analysis

Continuous variables were reported as mean ± standard deviation, and the comparison between the 3 groups was performed using the ANOVA test, except for contrast media volume which Kruskal-Wallis test was used. Post-hoc analysis was performed using Tukey’s test. Categorical variables were reported as frequencies and percentages, and were compared using the Pearson chi-square test. Cox proportional hazards models were used to test the impact of TIRFI and AKI on all-cause death and cardiovascular mortality, and the models were adjusted for age, male sex, New York Heart Association functional class III/IV, diabetes, hypertension, chronic obstructive lung disease, pulmonary hypertension, coronary artery disease, peripheral vascular disease, previous coronary artery bypass grafting, STS score, baseline eGFR, use of diuretics, Angiotensin-converting enzyme inhibitors or Angiotensin II receptor blockers, beta-blockers, statin, left ventricular ejection fraction, aortic valve area, mean aortic valve gradient, contrast media volume, procedural access (except transfemoral), Inovare prosthesis, AKI and TIRFI, myocardial infarction, stroke/transient ischemic attack, major or life-threatening bleeding, major vascular complication, new left bundle branch block, atrioventricular block, valve malpositioning and new pacemaker. Kaplan-Meier survival curves were created comparing TIRFI, stable renal function and AKI groups and the outcomes were compared using a log-rank test. A stepwise logistic regression analysis including all variables with a P value < 0.2 in the univariate analysis was used to identify the predictors of TIRFI and AKI after the procedure until discharge. The models were adjusted for age, male sex, New York Heart Association functional class III/IV, diabetes, hypertension, chronic obstructive lung disease, pulmonary hypertension, coronary artery disease, peripheral vascular disease, previous coronary artery bypass grafting, STS score, baseline eGFR, use of diuretics, Angiotensin-converting enzyme inhibitors or Angiotensin II receptor blockers, beta-blockers, statin, left ventricular ejection fraction, aortic valve area, mean aortic valve gradient, contrast media volume, procedural access (except transfemoral), Inovare prosthesis. All statistical tests were 2-sided, and the criteria for statistical significance was P < 0.05. All statistical analyses were performed using SPSS statistical software version 20.0 (IBM, Armonk, New York, USA).

Results

Baseline clinical characteristics

Baseline characteristics of the study population are presented in Table 1. A total of 577 (70%) patients had CKD and were the population of the present study. The overall median length of stay was 7 days (1–368) and the mean hospitalization period was 13 days. After TAVR, 197 (34.1%) patients had TIRFI, 177 (30.7%) maintained stable renal function and 203 (35.2%) had AKI. The overall mean age among CKD patients was 81.3 ± 6.8 years, 56.2% were male, 31.7% had diabetes, 74.5% had hypertension and the mean baseline eGFR was 39.1 ± 12.2 ml/min/1.73m2. The mean STS score was 10.6 ± 7.9% and the preferable access site was transfemoral (93.4%). Comparing baseline characteristics between the 3 groups, the mean eGFR was 37.3 ± 12.5 ml/min/1.73m2 in the TIRFI group, 39.6 ± 11.7 ml/min/1.73m2 in the stable renal function group and 40.2 ± 12.3 ml/min/1.73m2 in the AKI group, with significant statistical difference between the 3 groups (P = 0.043). This difference was related to TIRFI and AKI groups (post-hoc analysis, P = 0.044). Also, hypertension was present among 75.6% patients in TIRFI group, 66.1% in stable renal function group and 80.8% in AKI group, with significant difference between the 3 groups (P = 0.004). This difference was related to stable renal function and AKI groups (post-hoc analysis, P = 0.003). There was no difference related to contrast media volume and other baseline clinical, echocardiographic and procedural characteristics between the 3 groups. In order to evaluate the impact of the extended period of enrollment, we divided our study population into tertiles according to the year they underwent TAVR: 100 (17.3%) patients were submitted to TAVR from 2008 to 2010 (T1), 352 (61.0%) patients from 2011 to 2013 (T2), and 125 (21.7%) from 2014 to 2015 (T3), with no statistical differences between the 3 tertiles (p = 0.15).

Table 1

Baseline and procedural characteristics of the study population.

	TIRFI Group	Stable Renal Function Group	AKI Group	Overall
	(n = 197)	(n = 177)	(n = 203)	(n = 577)	P value a
Clinical data
Age, years	81.3 ± 7.1	81.7 ± 7.2	82.6 ± 6.2	81.3 ± 6.8	0.14
Male sex	105 (53.3)	111 (62.7)	108 (53.2)	324 (56.2)	0.10
NYHA class III/IV	166 (84.3)	146 (82.5)	169 (83.3)	481 (83.4)	0.89
Diabetes	55 (27.9)	59 (33.3)	69 (34.0)	183 (31.7)	0.36
Hypertension	149 (75.6)	117 (66.1)	164 (80.8)	430 (74.5)	0.004 b
COPD	38 (19.3)	36 (20.3)	37 (18.8)	111 (19.2)	0.87
Pulmonary hypertension	41 (20.8)	50 (22.8)	47 (23.2)	138 (23.9)	0.23
CAD	110 (55.8)	118 (66.7)	123 (60.6)	351 (60.8)	0.10
Peripheral vascular disease	35 (17.8)	26 (14.7)	35 (17.2)	96 (16.6)	0.69
Previous CABG	40 (20.3)	44 (24.9)	36 (17.7)	120 (20.8)	0.22
STS score, %	10.9 ± 8.4	10.2 ± 7.2	10.6 ± 8.1	10.6 ± 7.9	0.67
eGFR, mL/min/1.73m2	37.3 ± 12.5	39.6 ± 11.7	40.2 ± 12.3	39.1 ± 12.2	0.043 c
Diuretics	130 (66.0)	105 (59.3)	134 (66.0)	369 (64.0)	0.30
ACE inhibitors or ARB	109 (55.3)	80 (45.2)	108 (53.2)	297 (51.5)	0.12
Beta-blockers	77 (39.1)	68 (38.4)	75 (36.9)	220 (38.1)	0.90
Statin	117 (59.4)	101 (57.1)	128 (63.1)	346 (60.0)	0.48
Echocardiographic data
LVEF, %	56.8 ± 15.5	57.2 ± 16.0	58.4 ± 15.3	57.5 ± 15.6	0.54
Mean transaortic gradient, mmHg	49.8 ± 16.5	46.5 ± 15.9	48.1 ± 15.8	48.2 ± 16.1	0.15
AVA, cm2	0.68 ± 0.22	0.66 ± 0.17	0.66 ± 0.17	0.67 ± 0.19	0.55
Procedural data
Access site					0.12
Transfemoral approach	188 (95.4)	167 (94.4)	184 (90.6)	539 (93.4)
Other	9 (4.6)	10 (5.6)	19 (9.4)	38 (6.6)
Prosthesis type					0.80
Corevalve	147 (74.6)	128 (72.3)	151 (74.4)	426 (73.8)
Sapien XT	46 (23.4)	43 (24.3)	44 (21.6)	133 (23.1)
Inovare	4 (2.0)	6 (3.4)	8 (3.9)	18 (3.1)
Contrast media volume, mL	188 ± 120	186 ± 101	181 ± 91	185 ± 105	0.86
Period of TAVR procedure					0.15
T1 (2008–2010)	35 (17.8)	23 (13.0)	42 (20.7)	100 (17.3)
T2 (2011–2013)	112 (56.9)	118 (66.7)	122 (60.1)	352 (61.0)
T3 (2014–2015)	50 (25.4)	36 (20.3)	39 (19.2)	125 (21.7)

Values are n (%) or mean (± SD).

a Represents significant statistical difference (P<0.05) between TIRF, stable and AKI groups.

b Significant difference (P<0.05) between to stable and AKI groups.

c Significant difference (P<0.05) between TIRFI and AKI groups.

Abbreviations: ACE, angiotensin-converting enzyme; AKI, acute kidney injury; ARB, angiotensin receptor blocker; AVA, aortic valve area; CABG, coronary artery bypass graft; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; STS, Society of Thoracic Surgeons; T, tertile; TIRFI, TAVR induced renal function improvement.

Procedural and clinical outcomes

Procedural and clinical outcomes are described in Table 2. The occurrence of valve malpositioning was higher in the AKI group compared with TIRFI and stable renal function groups (8.4% vs. 2.0% vs. 2.8%, respectively; P = 0.004). Also, major or life-threatening bleeding was higher in AKI group (20.2% vs. 6.7% vs. 6.3%, respectively; P < 0.001) as well as major vascular complication (10.5% vs. 3.6% vs. 4.0%, respectively; P = 0.006).

Table 2

Procedural, 30-day and 1-year outcomes.

	TIRFI Group	Stable Renal Function Group	AKI Group
	(n = 197)	(n = 177)	(n = 203)	P value a
Procedural variables
Valve malpositioning	4 (2.0)	5 (2.8)	17 (8.4)	0.004(b,c)
Major of life-threatening bleeding	13 (6.7)	11 (6.3)	41 (20.2)	< 0.001(b,c)
Major vascular complication	7 (3.6)	7 (4.0)	21 (10.5)	0.006(b,c)
30-day outcomes
All-cause death	4 (2.0)	2 (1.2)	26 (13.0)	<0.001(b,c)
Cardiovascular death	3 (1.5)	1 (0.6)	22 (10.6)	<0.001(b,c)
All stroke/TIA	5 (2.6)	6 (3.4)	11 (5.6)	0.28
Myocardial infarction	-	-	1 (0.5)	0.39
New pacemaker	38 (19.5)	41 (23.3)	48 (23.5)	0.56
New persistent LBBB	51 (25.9)	40 (22.6)	63 (31.1)	0.15
1-year outcomes
All-cause death	30 (15.4)	17 (9.5)	59 (29.3)	<0.001(b,c)
Cardiovascular death	12 (6.0)	8 (4.5)	43 (21.0)	<0.001(b,c)
All stroke/TIA	5 (2.6)	6 (3.4)	10 (5.6)	0.21
Myocardial infarction	2 (0.8)	-	4 (1.8)	0.16
New pacemaker	45 (23.0)	48 (27.4)	51 (25.2)	0.12
New persistent LBBB	52 (26.5)	41 (23.2)	67 (32.9)	0.12

a Represents significant statistical difference (P<0.05) between TIRF, stable and AKI groups.

b Significant difference (P<0.05) between stable and AKI groups.

c Significant difference (P<0.05) between TIRFI and AKI groups.

Values are n (%).

Abbreviations: AKI, acute kidney injury; LBBB, left bundle branch block; TIA, transient ischemic attack; TIRFI, TAVR induced renal function improvement.

Impact of TIRFI and AKI on short-term outcomes

At 30 days, patients in AKI group had higher rates of all-cause mortality compared with TIRFI and stable renal function groups (13.0% vs. 2.0% vs. 1.2%, respectively; P < 0.001), and also had higher rates of cardiovascular death (10.6% vs. 1.5% vs. 0.6%, respectively; P < 0.001). There was no significant difference regarding all stroke/transient ischemic attack and myocardial infarction and there was no significant difference in outcomes between TIRFI and stable renal function groups.

Follow-up at 1 year and loss of follow-up

Of the 577 patients included in our study, 157 (27.2%) patients lost follow-up or did not complete 1 year of follow-up until the time for data collection for the Brazilian TAVR Registry. However, the median follow-up of the patients included in the present study was 385 [162-742] days. Data comparing the baseline characteristics of the patients with loss of follow-up and those with complete 1-year follow-up are shown as supplemental data (S1 Table).

Impact of TIRFI and AKI on long-term outcomes

At 1 year, AKI group remained with higher rates of all-cause mortality compared with TIRFI and stable renal function groups (29.3% vs. 15.4% vs. 9.5%, respectively; P < 0.001), and had higher rates of cardiovascular death (21.0% vs. 6.0% vs. 4.5%, respectively; P < 0.001). There was still no difference regarding stroke/transient ischemic attack and myocardial infarction and there was no significant difference in outcomes between TIRFI and stable renal function groups group. Kapplan-Meier curves for 1-year all-cause mortality are represented in Fig 2.

Fig 2

Kaplan-Meier curves for 1-year all-cause mortality.

Comparison of TIRFI group vs. AKI group (A), TIRFI group vs. stable renal function group (B) and stable renal function group vs. AKI group (C) 1-Year all-cause mortality rates. Abbreviations: AKI indicates acute kidney injury; SRFG indicates stable renal function group; TIRFI indicates TAVR induced renal function improvement.

Predictors of TIRFI and AKI

Multivariate analysis of TIRFI and AKI are shown in Tables 3 and 4, respectively. The absence of coronary artery disease was an independent predictor of TIRFI (OR: 0.69; 95% CI 0.48–0.98; P = 0.039) as well as lower baseline eGFR (OR: 0.98; 95% CI 0.97–1.00; P = 0.008). Otherwise, independent predictors of AKI were age (HR: 1.03; 95% CI, 1.00–1.05; P = 0.033), hypertension (HR: 1.69; 95% CI, 1.11–2.57; P = 0.014), non-transfemoral access sites (HR: 2.07; 95% CI, 1.06–4.07; P = 0.034) and higher baseline eGFR (HR: 1.01; 95% CI, 1.00–1.02; P = 0.053). The multivariable analysis of TIRFI and AKI including the procedure complications after TAVR in the model are shown in S2 and S3 Tables).

Table 3

Predictors of TIRFI after TAVR procedure.

Variable	Univariable Analysis		Multivariable Analysis
	OR (95% CI)	P value	OR (95% CI)	P value
Age, years	0.98 (0.95–1.00)	0.13	-	-
Male sex	0.84 (0.59–1.19)	0.32	-	-
NYHA class III/IV	1.11 (0.69–1.76)	0.67	-	-
Diabetes	0.76 (0.52–1.11)	0.15	-	-
Hypertension	1.09 (0.74–1.63)	0.65	-	-
COPD	1.01 (0.65–1.56)	0.98	-	-
Pulmonary hypertension	0.77 (0.51–1.16)	0.20	-	-
CAD	0.73 (0.51–1.04)	0.077	0.69 (0.48–0.98)	0.039
Peripheral vascular disease	1.13 (0.72–1.78)	0.60	-	-
Previous CABG	0.96 (0.62–1.46)	0.83	-	-
STS score, %	1.00 (0.98–1.03)	0.45	-	-
eGFR, mL/min/1.73m2	0.98 (0.96–0.99)	0.014	0.98 (0.97–1.00)	0.008
Diuretics	1.15 (0.80–1.64)	0.46	-	-
ACE inhibitors or ARB	1.27 (0.90–1.79)	0.18	-	-
Beta-blockers	1.06 (0.75–1.51)	0.73	-	-
Statin	0.96 (0.68–1.37)	0.83	-	-
LVEF, %	0.99 (0.98–1.00)	0.45	-	-
Mean transaortic gradient, mmHg	1.00 (0.99–1.02)	0.10	-	-
AVA, cm2	1.68 (0.64–4.38)	0.28	-	-
Contrast media volume, mL	1.00 (0.99–1.00)	0.71	-	-
Procedure access (except Transfemoral)	0.58 (0.27–1.25)	0.16	-	-
Prosthetic valve type	-	0.55	-	-
Corevalve	1.00	-	-	-
Sapien XT	1.00 (0.67–1.51)	-	-	-
Inovare prosthesis	0.54 (0.18–1.68)	-	-	-
Period of TAVR procedure		0.25	-	-
T1 (2008–2010)	1.00	-	-	-
T2 (2011–2013)	0.87 (0.54–1.38)	-	-	-
T3 (2014–2015)	1.24 (0.72–2.14)	-	-	-

95% CI, 95% confidence interval.

Abbreviations: ACE indicates angiotensin-converting enzyme; ARB, angiotensin receptor blocker; AVA, aortic valve area; CABG, coronary artery bypass graft; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; OR, odds ratio; STS, Society of Thoracic Surgeons; TAVR, transcatheter aortic valve replacement; TIRFI, TAVR induced renal function improvement.

Table 4

Predictors of AKI after TAVR procedure.

Variable	Univariable Analysis		Multivariable Analysis
	OR (95% CI)	P value	OR (95% CI)	P value
Age, year	1.02 (0.99–1.05)	0.06	1.03 (1.00–1.05)	0.033
Male sex	0.83 (0.59–1.17)	0.29	-	-
NYHA class III/IV	0.99 (0.63–1.56)	0.95	-	-
Diabetes	0.17 (0.82–1.69)	0.38	-	-
Hypertension	1.71 (0.13–2.59)	0.011	1.69 (1.11–2.57)	0.014
COPD	0.90 (0.58–1.40)	0.65	-	-
Pulmonary hypertension	0.94 (0.63–1.40)	0.75	-	-
CAD	0.99 (0.69–1.40)	0.93	-	-
Peripheral vascular disease	1.07 (0.68–1.69)	0.77	-	-
Previous CABG	0.74 (0.48–1.15)	0.18	-	-
STS score, %	1.00 (0.97–1.02)	0.98	-	-
eGFR, mL/min/1.73m2	1.01 (0.99–1.02)	0.008	1.01 (1.00–1.02)	0.053
Diuretics	1.15 (0.80–1.64)	0.44	-	-
ACE inhibitors or ARB	1.11 (0.79–1.57)	0.54	-	-
Beta-blockers	0.93 (0.65–1.34)	0.66	-	-
Statin	1.22 (0.86–1.74)	0.26	-	-
LVEF, %	1.00 (0.99–1.01)	0.28	-	-
Mean transaortic gradient, mmHg	1.00 (0.99–1.01)	0.97	-	-
AVA, cm2	0.71 (0.26–1.87)	0.49	-	-
Contrast media volume, mL	0.99 (0.99–1.00)	0.60	-	-
Non-transfemoral access	0.93 (1.00–3.73)	0.048	2.07 (1.06–4.07)	0.034
Prosthetic valve type	-	0.62	-	-
Corevalve	1.00	-	-	-
Sapien XT	0.90 (0.60–1.36)	-	-	-
Inovare prosthesis	1.46 (0.56–3.77)	-	-	-
Period of TAVR procedure		0.23	-	-
T1 (2008–2010)	1.00	-	-	-
T2 (2011–2013)	0.73 (0.47–1.15)	-	-	-
T3 (2014–2015)	0.63 (0.36–1.08)	-	-	-

95% CI, 95% confidence interval.

Abbreviations: ACE indicates angiotensin-converting enzyme; AKI, acute kidney injury; ARB, angiotensin receptor blocker; AVA, aortic valve area; CABG, coronary artery bypass graft; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; OR, odds ratio; STS, Society of Thoracic Surgeons. TAVR, transcatheter aortic valve replacement.

Predictors of 1-year all-cause mortality

Univariable and multivariable predictors of 1-year all-cause mortality are shown in Table 5. The presence of AKI was associated with an increase in 1-year all-cause mortality (HR: 3.42; 95% CI, 1.87–6.23; P < 0.001), as well as chronic obstructive pulmonary disease (HR: 1.72; 95% CI, 1.06–2.79; P = 0.028), baseline eGFR (HR 0.72; 95% CI, 0.61–0.86. P < 0.001) and stroke/transient ischemic attack (HR: 3.08; 95% CI, 1.74–5.44; P < 0.001).

Table 5

Multivariable predictors of 1-year all-cause mortality.

Variable	Univariable Analysis		Multivariable Analysis
	Hazard Ratio (95% CI)	P value	Hazard Ratio (95% CI)	P value
Age, years*	1.05 (0.90–1.22)	0.50	-	-
Male sex	0.77 (0.51–1.15)	0.21	-	-
NYHA class III/IV	2.16 (1.04–4.45)	0.038	1.74 (0.83–3.63)	0.14
Diabetes	1.46 (0.97–2.22)	0.07	-	-
Hypertension	1.45 (0.88–2.41)	0.14	-	-
COPD	2.14 (1.38–3.32)	0.001	1.72 (1.06–2.79)	0.028
Pulmonary hypertension	1.69 (1.09–2.60)	0.017	1.36 (0.86–2.16)	0.18
CAD	1.30 (0.85–1.99)	0.23	-	-
Peripheral vascular disease	1.89 (1.18–3,04)	0.008	1.58 (0.92–2.69)	0.09
Previous CABG	1.07 (0.65–1.76)	0.78	-	-
STS score, %	1.04 (1.02–1.06)	0.001	-	-
Baseline eGFR, mL/min/1.73m2**	0.69 (0.59–0.81)	< 0.001	0.73 (0.61–0.86)	< 0.001
Baseline eGFR < 30 mL/min/1.73m2	2.02 (1.33–3.09)	0.001	-	-
Diuretics	1.46 (0.93–2.30)	0.09	-	-
ACE inhibitors or ARB	0.80 (0.54–1.21)	0.30	-	-
Beta-blockers	0.79 (0.50–1.19)	0.25	-	-
Statin	0.97 (0.64–1.48)	0.91	-	-
LVEF, %**	0.92 (0.81–1.37)	0.18	-	-
Mean transaortic gradient, mmHg**	0.94 (0.82–1.07)	0.34	-	-
AVA, cm2	0.51 (0.15–1.73)	0.28	-	-
Contrast media volume, mL	1.09 (0.87–1.37)	0.44	-	-
Procedure access (except Transfemoral)	2.34 (1.25–4.39)	0.008	1.29 (0.53–3.17)	0.57
Sapien XT prosthesis	0.76 (0.44–1.31)	0.32	-	-
Inovare prosthesis	2.55 (1.03–6.34)	0.043	-	-
Myocardial infarction	4.47 (1.09–18.09)	0.037	-	-
Stroke/TIA	3.96 (2.34–6.71)	< 0.001	3.08 (1.74–5.44)	< 0.001
Major or life-threatening bleeding	1.72 (0.89–3.32)	0.10	-	-
Major vascular complication	1.80 (1.03–3.13)	0.037	1.25 (0.69–2.25)	0.45
New LBBB	1.03 (0.66–1.61)	0.89	-	-
AV block	0.85 (0.52–1.38)	0.51	-	-
Valve malpositioning	4.35 (2.31–8.18)	< 0.001	1.94 (0.92–4.07)	0.08
New pacemaker	0.88 (0.53–1.38)	0.38	-	-
TIRFI	1.40 (0.84–3.15)	0.14	1.45 (0.75–2.83)	0.27
AKI	3.82 (2.12–6.88)	< 0.001	3.42 (1.87–6.23)	< 0.001

95% CI, 95% confidence interval.

Abbreviations: ACE indicates angiotensin-converting enzyme; AKI, acute kidney injury; ARB, angiotensin receptor blocker; AV, atrioventricular; AVA, aortic valve area; CABG, coronary artery bypass graft; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; HR, hazard ratio; LBBB, left bundle branch block; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; STS, Society of Thoracic Surgeons; TIA, transient ischemic attack; TIRFI, TAVR induced renal function improvement.

* For each increase of 5 units in age.

** For each increase of 10 units in baseline eGFR, LVEF or mean transaortic gradient.

*** For each increase of 100 units in contrast media volume.

Discussion

The main findings of the present study can be summarized as: (1) CKD was extremely prevalent among our population, corresponding to 70% of the patients; (2) TIRFI was frequently found after TAVR; (3) predictors of TIRFI were the absence of coronary artery disease and lower eGFR at baseline; (4) patients with AKI after TAVR had higher all-cause mortality and cardiovascular death at 30 days and 1 year; (5) there was no differences comparing 30-day and 1-year outcomes between TIRFI and stable renal function groups.

Patients with severe AS often have multiple comorbidities, and impaired renal function is associated with poor outcomes with surgical aortic valve replacement [21] and TAVR procedure [10, 11, 22]. Beyond that, the high proportion of CKD among these patients, ranging from 52% to 72% in previous large studies [10, 11, 21] reflects the impact of these comorbidities. In our study, CKD was present in 577 (70%) of the patients from the Brazilian TAVR Registry, with an average age of 80 years and high-surgical risk according STS score.

An interesting point of our study is that TIRFI occurred similarly compared with those with AKI or stable renal function (34.1% vs. 35.2% vs. 30.7%, respectively), despite all the adverse procedural features, such as the use of contrast media, atherosclerotic particles renal embolization during catheter passage through the aorta and deployment of the valve prosthesis [23], and also the occurrence of low cardiac output during rapid ventricle pacing for balloon expandable prosthesis deployment or pre- or post-dilation of the aortic valve, which was associated with acute kidney injury and short- and long-term mortality if multiple (≥ 3 episodes) or prolonged rapid ventricular pacing duration (≥ 36 seconds) are performed [24].

Attempting to determine the predictors of TIRFI, we found that the absence of coronary artery disease and lower eGFR were independent predictors for renal function recovery after TAVR. Regarding to eGFR as a predictor of TIRFI, the lower the eGFR, the greater is the chance of improvement in renal function. It can suggest that improvement in renal function is primarily due to the hemodynamics effects after TAVR procedure to relief aortic stenosis, increasing the cardiac output and leading to a better renal perfusion, suggesting that a mechanism of type 2 cardiorenal syndrome may be involved [25]. In the present analysis, there was no difference between the 3 groups related to contrast volume, use of diuretics and other variables that may contribute to deterioration of renal function. Importantly, the baseline eGFR was slightly lower among patients in the TIRFI group when compared with the AKI group, corroborating for the hypothesis that low cardiac output may be the main mechanism of impaired renal function at baseline in these population and explain why the presence of lower eGFR was found as an independent predictor of TIRFI. Also, patients without coronary artery disease may have less peripheral artery disease incidence and lower rates of atherosclerotic emboli during the TAVR procedure, and that may partially explain the association with TIRFI.

The presence of hypertension and higher age were associated with AKI, and the endothelial dysfunction added to the occurrence of low cardiac output during the procedure could be more harmful for this population. Furthermore, the use of non-transfemoral access sites was associated with AKI after TAVR, as well as AKI group had also more procedure complications such as valve malpositioning, major or life-threatening bleeding and major vascular complication. Also, the higher eGFR at baseline, the greater is the chance of developing AKI after TAVR. This finding was probably related simply to the percentage variation of eGFR in a high-risk population with multiple comorbidities, since the results of the statistical analysis were borderline.

According to previous studies, AKI was associated with poor outcomes, including higher 1-year all-cause and cardiovascular mortality rates [9, 16, 26]. However, our study did not show association between TIRFI and lower 30-days and 1-year all-cause mortality or other outcomes when compared with stable renal function group. Our results also sustain the findings from the subanalysis of Partner 1 which included a similar population and showed no reduction in mortality rates and other outcomes in the TIRFI group [9].

A recent single-center prospective study showed that patients who had TIRFI after TAVR may also have better 30-day and 2-year outcomes, independently of the baseline kidney function [16]. The reason for discordance of our findings with this recent study could be in part because our study population surgical risk was slightly higher using the STS score, which may justify an increase in mortality even in the stable renal function and TIRFI groups.

Limitations

This is a prospective observational multicenter study using the Brazilian TAVR Registry and there are several inherent limitations. First, data was self-reported by each center and on-site source document verification was randomly performed in only 20% of cases. Registries studies usually do not perform source document verification, and therefore, we consider that 20% of random verification is a representative sample to validity of the data. Besides that, there is no data about measure of urine output, pre- and post-hydration strategies and proteinuria levels that might be important for AKI definition. Since there is no definition of TIRFI, we arbitrary used variation in eGFR between baseline and at discharge after TAVR of 10% for both TIRFI and AKI criteria. As most of the patients had high-surgical risk using STS score, we could not extrapolate our results for intermediate- and low-surgical risk patients. Also, despite coronary angiography are usually performed before admission for TAVR, as a routine, for evaluation of concomitant coronary artery disease in Brazilian centers which included patients in the Brazilian TAVR Registry, information on how many patients had coronary angiography and percutaneous coronary intervention during the admission for TAVR was not available. Finally, we had around 27% loss of follow-up at 1 year. However, the median follow-up of the patients included in the present study was 385 [162-742] days, and therefore, we have chosen to assess the outcomes at 1 year.

Conclusion

In our study, TIRFI was frequently found in patients with prior impaired renal function and promoted lower mortality when compared with patients with AKI. The absence of coronary artery disease and lower eGFR at baseline were independent predictors of TIRFI.

Baseline and procedural characteristics of patients with loss of follow-up versus patients with complete 1-year follow-up.

(DOCX)

Click here for additional data file.

Predictors of TIRFI after TAVR procedure (including outcomes).

(DOCX)

Click here for additional data file.

Predictors of AKI after TAVR procedure (including outcomes).

(DOCX)

Click here for additional data file.

(XLSX)

Click here for additional data file.

22 Jan 2021

PONE-D-20-31591

Improvement of renal function after transcatheter aortic valve replacement in patients with chronic kidney disease

PLOS ONE

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Additional Editor Comments:

The time interval between the first and second renal function records should be mentioned. The information on subjects with loss follow-up needed to be addressed in the study. An extended period of enrollment in this study, so controlling this potential confounding factor could be considered in the analysis process.

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Reviewer #1: The current study by de Silva et al. explores the impact of TAVR for severe AS on renal function. The authors report that of their total patient population undergoing TAVI from 2008-2015, 70% had CKD at baseline. Of these, after undergoing TAVI, about 1/3 patients had an improvement in renal function, 1/3 had worsening renal function, and the remaining 1/3 had stable renal function. The authors also note in their analysis the predictors of TIRFI and AKI post-TAVI, as well predictors of 30-day and 1-year mortality.

Comments:

1. The authors should not mention p values derived from 2 different comparisons within the same column as they do in Tables 1 and 2. This is confusing for readers to interpret. If they want to show results from both comparisons, they should put the p values in 2 different columns specifying the comparison.

2. Similarly, the authors should cross check the p value for correction for eGFR between TIRFI vs stable renal group as the numbers are different in the results text and table 1.

3. According to the tables, baseline eGFR was a predictor for both TIRFI and AKI post- TAVR. The authors must provide more clarification regarding this in their text.

4. Can the authors clarify how the data regarding follow-up was collected for their patients? Furthermore, can the authors provide information regarding patients lost to follow-up? Was data available for all subjects up to 1 year?

5. The authors state that source document verification was performed only in 20% of the patients. Can the authors clarify this further as this may have impact on the results and validity of the data

6. Furthermore, according to the data, these patients underwent TAVI procedures over a time period of 7 years, during which the techniques of the interventional procedure and device structure changed considerably. How do the authors account for this in their results?

Reviewer #2: This is multi-center prospective registration study to investigate the predictors of improvement of renal function after transcatheter aortic valve replacement (TAVR) by Lemes da Silva et al. The authors reported that 34.1% of patients presented with improvement of renal function after transcatheter aortic valve replacement. Absence of coronary artery disease and lower baseline eGFR were independent predictors of improvement of renal function after TAVR. However, TAVR induced renal function improvement was not associated with improved 1-year outcomes.

Comments and questions for the authors are as follows:

1. When was the second time point for determination of renal function(eGFR)? What was the time interval between the first and second renal function? Was there a standard protocol?

2. How many patients had coronary angiography during the admission for TAVR? Did patients with coronary artery disease undergo percutaneous coronary intervention during the admission for TAVR?

3. There were high procedure complications in CKD group. Did the authors put these variables in the analysis of predictors of CKD?

4. Page 6 line 124 “leak aortic jet velocity of ≥ 4.0 m/s” should be peak aortic jet velocity of ≥ 4.0 m/s.

**********

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Reviewer #2: No

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24 Mar 2021

Dear, Ping-Hsun Wu, M.D. PhD., Academic Editor, PLOS ONE. We thank for the positive comments and suggestions. We have implemented your suggestions in the revised manuscript and we hope that the new version will be to your satisfaction.

Response to Reviewers

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

- We thank the editor and reviewers for the positive comments on our work and the constructive suggestions that have contributed to the improvement of our manuscript. We have implemented your suggestions in the revised manuscript and we hope that the new version will be to your satisfaction. We are open to any additional suggestions.

1. The time interval between the first and second renal function records should be mentioned.

- The editor made a very important point. Following the recommendation, we described more clearly the time between the first and the second renal function record (Page 6, Lines 138-142). Therefore, we highlight that the first creatinine (baseline) was collected on the day or the day before TAVR procedure, and the second creatinine used to calculate variation on renal function was at discharge. Moreover, the median length of stay was 7 days (1-368) and the mean hospitalization period was 13 days.

2. The information on subjects with loss follow-up needed to be addressed in the study.

- We thank the editor and found the suggestion extremely pertinent. Thus, we included a Follow-up section on Results section describing the information on subjects with loss of follow-up (Page 13, Lines 237-243). Also, we compared baseline characteristic of patients with loss of follow-up with those who completed followed up in 1 year. The comparison of baseline characteristics was highlighted in Supplemental Table 1. The follow-up was performed by phone calls at 1 month, 1 year and then annually (Page 5, Lines 114-115). We had around 27% loss of follow-up at 1 year, however, the median follow-up of our study was 385 [162 – 742] days, and therefore, we have chosen to assess the outcomes at 1 year. This practice is already well recognized and was performed in large studies like EXCEL Trial (N Engl J Med 2016;375:2223-35), in which the authors used the median follow-up in 3 years to assess the primary composite endpoint of the study. We have highlighted this issue as a potential limitation on appropriate section (Pages 22-23, Lines 380-382).

3. An extended period of enrollment in this study, so controlling this potential confounding factor could be considered in the analysis process.

- The Editors raised an important aspect. Following the suggestion, we have divided the study population into tertiles according to the year they were submitted to TAVR procedure. This information is included in Table 1 and throughout the manuscript (Page 9, Lines 196-200): 100 patients underwent TAVR from 2008 to 2010(T1); 352 patients from 2011 to 2013 (T2); and 125 from 2014 to 2015 (n = 125) –(T3), with no statistical differences between the 3 tertiles (p = 0.15). However, neither tertiles was predictor for either TAVR induced renal function improvement (TIRFI) (p = 0.25) or Acute Kidney Injury (AKI) (p = 0.23), as shown in Tables 3 and 4.

Reviewer #1: The current study by de Silva et al. explores the impact of TAVR for severe AS on renal function. The authors report that of their total patient population undergoing TAVI from 2008-2015, 70% had CKD at baseline. Of these, after undergoing TAVI, about 1/3 patients had an improvement in renal function, 1/3 had worsening renal function, and the remaining 1/3 had stable renal function. The authors also note in their analysis the predictors of TIRFI and AKI post-TAVI, as well predictors of 30-day and 1-year mortality.

- We thank the Reviewer for his/her comments and for the constructive suggestions that have contributed to improving our work.

1. The authors should not mention p values derived from 2 different comparisons within the same column as they do in Tables 1 and 2. This is confusing for readers to interpret. If they want to show results from both comparisons, they should put the p values in 2 different columns specifying the comparison.

- The Reviewer made a good suggestion. We highlighted that the p value described is from comparison within the 3 groups using legends “a”, and legends “b” and “c” were used to describe difference between stable vs AKI groups and TIRFI vs AKI groups, respectively (Tables 1 and 2).

2. Similarly, the authors should cross check the p value for correction for eGFR between TIRFI vs stable renal group as the numbers are different in the results text and table 1.

- The Reviewer is right. We have corrected this information throughout the manuscript accordingly. We also informed P value for statistical difference between the 3 groups and the P value for the post-hoc analysis describing which groups the difference was related to (Page 8, Lines 190-191). The same has been done for Hypertension (Page 8, Lines 193-194).

3. According to the tables, baseline eGFR was a predictor for both TIRFI and AKI post- TAVR. The authors must provide more clarification regarding this in their text.

- The Reviewer made an important point. We have highlighted the potential mechanism throughout the “Discussion” section (as stated on Page 21, Lines 337-340). As previously described by Ronco et al (Eur Heart J 2010; 31(6):703-11), any chronic cardiac abnormality that could lead to a low cardiac output condition and chronic renal hypoperfusion may impact on renal function. The relief of aortic stenosis after TAVR could improve the hemodynamics and lead to a better renal perfusion, if this is the main condition leading to CKD. In our study, the eGFR was lower among patients in the TIRFI group, when compared to AKI group. It is possible that the patients in the TIRFI group may have benefited more of TAVR procedure due to worse hemodynamic condition caused by the aortic stenosis and, therefore, explain why the lower the eGFR is, the greater is the chance of TIRFI (as highlighted in Page 14, Line 262; and Pages 20-21, Lines 330-331). On the other hand, higher eGFR was a predictor of AKI in multivariable analysis, as shown in Table 4 (HR: 1.01; 95% CI, 1.00 – 1.02; P = 0.053). However, this result was borderline as shown by the results of our analysis, and was probably related simply to percentage variation of eGFR in a high-risk population with multiple comorbidities (Page 14, Lines 265-268; and Page 21, Lines 349-352).

4. Can the authors clarify how the data regarding follow-up was collected for their patients? Furthermore, can the authors provide information regarding patients lost to follow-up? Was data available for all subjects up to 1 year?

- The Reviewer raised an important point. The follow-up was performed by phone calls at 1 month, 1 year and then annually (Page 5, Lines 114-115). We included a Follow-up section on Results describing the information on subjects with loss of follow-up (Pages 13, Lines 237-243). Also, we compared baseline characteristic of patients with loss of follow-up with those who completed followed up in 1 year. The comparison of baseline characteristics was highlighted in a Supplemental Table 1. We had around 27% loss of follow-up at 1 year, however, the median follow-up of our study was 385 [162 – 742] days, and therefore, we have chosen to assess the outcomes at 1 year. This practice is already well recognized and was performed in large studies like EXCEL Trial (N Engl J Med 2016;375:2223-35), in which the authors used the median follow-up in 3 years to assess the primary composite endpoint of the study. We have highlighted this issue as a potential limitation on appropriate section (Pages 22-23, Lines 380-382).

5. The authors state that source document verification was performed only in 20% of the patients. Can the authors clarify this further as this may have impact on the results and validity of the data?

- The Reviewer raised an interesting point. The data verification was randomly performed in one-fifth of the patients included in the Brazilian TAVR Registry, as determined and allowed by our ethical committee, and was highlighted as a potential limitation of our study. Registries studies usually do not perform source document verification, and therefore, we consider that 20% of random verification is a representative sample to validity of the data (Page 22, Lines 369-370).

6. Furthermore, according to the data, these patients underwent TAVI procedures over a time period of 7 years, during which the techniques of the interventional procedure and device structure changed considerably. How do the authors account for this in their results?

- The Reviewer made an important point. Following the Reviewer and Editor’s suggestion, we have divided the study population into tertiles according to the year they were submitted to TAVR procedure. This information is included in Table 1 and throughout the manuscript (Page 9, Lines 196-200): 100 patients underwent TAVR from 2008 to 2010 (T1); 352 patients from 2011 to 2013 (T2); and 125 from 2014 to 2015 (T3), with no statistical differences between the 3 tertiles (p = 0.15). However, neither tertiles was predictor for either TAVR induced renal function improvement (TIRFI) (p = 0.25) or Acute Kidney Injury (AKI) (p = 0.23), as shown in Tables 3 and 4.

Reviewer #2: This is multi-center prospective registration study to investigate the predictors of improvement of renal function after transcatheter aortic valve replacement (TAVR) by Lemes da Silva et al. The authors reported that 34.1% of patients presented with improvement of renal function after transcatheter aortic valve replacement. Absence of coronary artery disease and lower baseline eGFR were independent predictors of improvement of renal function after TAVR. However, TAVR induced renal function improvement was not associated with improved 1-year outcomes.

- We thank the Reviewer for his/her comments and for the constructive suggestions that have contributed to improving our work.

1. When was the second time point for determination of renal function (eGFR)? What was the time interval between the first and second renal function? Was there a standard protocol?

- The editor made a very important point. Following the recommendation, we described more clearly the time between the first and the second renal function record (Page 6, Lines 138-142). Therefore, we highlight that the first creatinine (baseline) was collected on the day or the day before TAVR procedure, and the second creatinine used to calculate variation on renal function was at discharge. Moreover, the median length of stay was 7 days (1-368) and the mean hospitalization period was 13 days.

2. How many patients had coronary angiography during the admission for TAVR? Did patients with coronary artery disease undergo percutaneous coronary intervention during the admission for TAVR?

- This is an important issue raised by the Reviewers. The coronary angiography are usually performed before admission for TAVR, as a routine, for evaluation of concomitant coronary artery disease in all Brazilian centers which included patients in the Brazilian TAVR Registry. However, data on how many patients had coronary angiography and percutaneous coronary intervention during the admission for TAVR was not available. The only data available is that 32 (5.5%) of the patients have undergone percutaneous coronary intervention during TAVR procedure. We have included the lack of data about this subject on “Limitations” section (Page 22, Lines 376-380).

3. There were high procedure complications in CKD group. Did the authors put these variables in the analysis of predictors of CKD?

- The Reviewer raised a very important point. At first, our primary objective was to evaluate which clinical baseline characteristics could predict the improvement and worsening in renal function. Based on that, we could evaluate the risk of our patients develop worsening in renal function after TAVR procedure, as well as take stricter measures to minimize the impact of this condition. However, following the recommendation of the Reviewer, we made a new model including procedure complications as variables in both analyses of predictors of TIRFI and AKI, as supplemental tables 2 and 3. Yet, we have stated these supplemental materials in the revised manuscript (Page 14, Lines 265-268)

4. Page 6 line 124 “leak aortic jet velocity of ≥ 4.0 m/s” should be peak aortic jet velocity of ≥ 4.0 m/s.

- We the reviewer is correct. The typo was corrected (Page 6, Line 124).

Submitted filename: Response to Reviewers PONE-D-20-31591.docx

Click here for additional data file.

20 Apr 2021

Improvement of renal function after transcatheter aortic valve replacement in patients with chronic kidney disease

PONE-D-20-31591R1

Dear Dr. Antonio C. B. Nunes Filho,

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Kind regards,

Ping-Hsun Wu, M.D. PhD.

Academic Editor

PLOS ONE

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Reviewer #2: All comments have been addressed

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Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #2: No

4 May 2021

PONE-D-20-31591R1

Improvement of renal function after transcatheter aortic valve replacement in patients with chronic kidney disease

Dear Dr. Nunes Filho:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Ping-Hsun Wu

Academic Editor

PLOS ONE