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10.1136/bmjopen-2023-081295
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Original Research
Respiratory Medicine
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Risk factors for acute kidney injury and impact of earlier anticoagulation on renal function in patients with normotensive pulmonary embolism: a retrospective cohort study
http://orcid.org/0000-0002-5754-029X
Wang Dingyi 10wg_snake@163.com

Fan Guohui 120fanguohui08@163.com

Lyu Yanshuang 3lyu.ys@outlook.com

Xu Xiaomao 4xuxiaomao@163.com

Luo Qin 5luoqin2009@163.com

Wan Jun 6blueswan2013@yahoo.com

Liu Xin 7liuxin3368@bjhmoh.cn

Chen Yinong 18yinong9627@163.com

Zhang Yu 1zhangyuccmu2013@yeah.net

Yang Peiran 3peiran.yang@foxmail.com

http://orcid.org/0000-0002-7096-8792
Zhai Zhenguo 1zhaizhenguo2011@126.com

1 Center of Respiratory Medicine, China-Japan Friendship Hospital; National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
2 School of Population Medicine and Public Health, Chinese Academy of Medical Sciences & Peking Union Medical College; State Key Laboratory of Respiratory Health and Multimorbidity; Key Laboratory of Pathogen Infection Prevention and Control (Peking Union Medical College), Ministry of Education；Public Health Emergency Management Innovation Center, Beijing, People's Republic of China
3 Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China
4 Department of Pulmonary and Critical Care Medicine, Beijing Hospital; National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing, People's Republic of China
5 Department of Cardiology, Fuwai Hospital; National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China
6 Department of Respiratory and Critical Care Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing, People's Republic of China
7 Department of Nephrology, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
8 Peking University Health Science Center, Beijing, People's Republic of China
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None declared.

DrZhenguoZhai; zhaizhenguo2011@126.com
DW and GF are joint first authors.

2024
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Abstract

Objective

We aimed to investigate the risk factors for acute kidney injury (AKI) after normotensive pulmonary embolism (PE) and the impact of anticoagulation on renal recovery.

Design

Multicentred, retrospective cohort study.

Setting

Data from four tertiary hospitals in China were captured. All available measurements of serum creatinine (SCr) during hospitalisation and follow-up were collected.

Participants

Patients with acute PE and those without haemodynamic instability were enrolled. All recruited patients were followed up for up to 2 years.

Primary and secondary outcome measures

The primary outcome was the occurrence of AKI, defined by the Kidney Disease Improving Global Outcomes criteria. The secondary outcome was the recovery of renal function. The time interval between PE onset and the initiation of anticoagulation was analysed to obtain its influence on the recovery of renal function.

Results

A total of 461 patients with acute normotensive PE were enrolled. A transient elevation of SCr during hospitalisation was observed. The incidence of AKI among normotensive patients was 18.9%. Brain natriuretic peptide (BNP) NT-proBNP elevation (adjusted HR (aHR) 2.27, 95% CI 1.33 to 3.86) and history of chronic kidney disease (aHR 4.81, 95% CI 2.44 to 9.48) were associated with the development of AKI during hospitalisation. Earlier initiation of anticoagulation therapy (within 5 days after PE onset, compared with over 6 days) promoted an early recovery of renal function (adjusted OR 0.26, 95% CI 0.08 to 0.84, p=0.025).

Conclusions

Renal impairment and AKI were highly prevalent among patients with normotensive patients. The occurrence of AKI was associated with right heart function. Patients who developed AKI after PE would benefit from earlier anticoagulation therapy for an early recovery of renal function.

thromboembolism
acute renal failure
heart failure
anticoagulation
CAMS Innovation Fund for Medical Sciences 2021-I2M-1-061 The National Key Research and Development Program of China 2016YFC0905600, 2023YFC2507200 National High Level Hospital Clinical Research Funding; Elite Medical Professionals. Project of China-Japan Friendship Hospital ZRJY2023-QM20 CAMS Institute of Respiratory Medicine Grant for Young Scholars 2023-ZF-8
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pmcSTRENGTHS AND LIMITATIONS OF THIS STUDY

Precise identification of acute kidney injury (AKI) by dynamic serum creatinine (SCr) measurements was obtained in patients with pulmonary embolism (PE).

Locally weighted smoothing method was conducted to provide a visible SCr change after acute PE.

Renal function recovery was monitored through dynamic SCr measurements of each participant.

Only available SCr measurements were obtained that might result in underestimation of AKI prevalence.

Introduction

Acute kidney injury (AKI) is defined as an abrupt decrease in kidney function that could be induced by both kidney and extrarenal diseases.1 AKI after acute pulmonary embolism (PE) has been recently discussed owing to its potential high incidence and worse prognosis for those patients: the Registro Informatizado de la Enfermedad TromboEmbolica (RIETE) study reported an AKI incidence of approximately 25% to 30% after PE2 and the occurrence of AKI was independently associated with higher 30-day mortality and major bleeding.3 The diagnostic criteria of AKI, based on the Kidney Disease Improving Global Outcomes (KDIGO) guidelines, requires at least two serum creatinine (SCr) levels or constant measurement of urine output that brings difficulty in AKI identification, especially for large-scale multicentre registries.1 Thus, previous studies mostly estimated AKI according to the single SCr level on admission or collected suspected or confirmed AKI events based on judgement of physician or experience.2 4 Considering the latent progression of AKI, the AKI incidence after PE has been underestimated. Risk estimation and renal function recovery among these patients would be inaccurate.

According to the existing evidence, the higher risk of AKI among patients with PE is probably related to high-risk PE that could induce AKI due to hypofiltration of the systemic circulation. However, an AKI incidence of approximately 20% among patients with normotensive PE has been previously reported (31% in intermediate-risk and 14% in low-risk PE).3 The underlying mechanism was inferred that venous congestion induced by right ventricular (RV) dysfunction after PE might cause lower perfusion of the kidney. The RIETE study reported that nearly three quarters of the patients achieved an early recovery (within the first week), and a complete recovery rate of 73% was found among those with AKI after acute PE, while no further investigation has been performed.5 Therefore, we hypothesised that earlier anticoagulation therapy might contribute to earlier relief of clot burden and decreased tension of RV, thus improving renal function.

We performed a retrospective cohort study of patients with acute PE, using dynamic SCr levels to reveal the accurate incidence of AKI during hospitalisation, especially in normotensive patients. Afterwards, we investigated the potential risk factors for AKI and the impact of anticoagulation on renal function recovery.

Methods

Participants and study design

In this multicentre, retrospective cohort, patients who were subjectively confirmed PE with/without deep vein thrombosis (DVT) were consecutively recruited from four tertiary hospitals with high quality of PE management in Beijing, China: China-Japan Friendship Hospital, Beijing Hospital, Fuwai Hospital and Anzhen Hospital. Patients who were hospitalised from April 2015 to November 2021 and met the inclusion criteria were enrolled in this study and followed up for at least 2 years, based on an existing cohort. PE was confirmed by helical CT pulmonary angiography (CTPA), ventilation-perfusion lung scintigraphy (V/Q scan) or pulmonary angiography. Patients with an unclear history of acute onset or over 30 days from onset to PE diagnosis, haemodynamically unstable (high-risk) or without available SCr data on admission were excluded. Decisions on diagnosis and initiation, maintenance or change in the treatment pattern were at the discretion of the physicians and patients of the participating centres. Demographic data, medical history related to venous thromboembolism (VTE), risk factors for VTE, symptoms and signs on presentation, physical and laboratory examination results, imaging test results, types of diagnostic methods, diagnostic results, therapeutic management and clinical outcomes of PE during hospitalisation and the follow-up period (through telephone or outpatient clinic) were collected via an electronic data capture system. All recruited patients were followed up for up to 2 years.

The study was approved by institutional review boards and ethical committees of all the centres involved (the ethical committee of China-Japan Friendship Hospital, the ethical committee of Beijing Hospital, the ethical committee of Fuwai Hospital and the ethical committee of Anzhen Hospital). Written informed consent was obtained from all participants in the study according to the requirements of the ethical committee of each medical centre.

Definitions

Both PE severity and the simplified pulmonary embolism severity index (sPESI) score were estimated according to the 2019 ESC (the European Society of Cardiology) guidelines for acute PE.5 All available measurements of SCr after hospitalisation (including the follow-up period) for each enrolled participant were recorded for an identification of AKI (from the first time measured after hospitalisation and the last time before discharge, where available). AKI was diagnosed according to the KDIGO definition: increase in SCr by 0.3 mg/dL (26.5 µmol/L) within 48 hours; or increase in SCr to ×1.5-fold of baseline, which is known or presumed to have occurred within the prior 7 days. Baseline SCr levels were back-calculated from theoretical renal function according to the MDRD equation and in accordance with international KDIGO guidelines,6 assuming that baseline estimated glomerular filtration rate (eGFR) is 75 mL/min per 1.73 m2. For patients with only one SCr record, which was usually tested on admission, AKI and its severity were estimated by comparing this record with baseline SCr. Bleeding events included major bleeding and clinically relevant non-major bleeding were defined by the International Society on Thrombosis and Haemostasis criteria.7

According to KDIGO, AKI severity was defined as: stage 1, increase in SCr levels to ×1.5-fold of baseline SCr or ≥0.3 mg/dL (≥26.5 µmol/L) increase; stage 2, increase of more than 2.0–2.9 folds of baseline SCr; stage 3, increase of more than 3.0 folds of baseline SCr or ≥4.0 mg/dL (≥353.6 µmol/L). Contrast-induced nephropathy (CIN) was defined as an elevation of SCr of more than 25% or 0.5 mg/dL (44 µmol/L) from baseline within 48 hours following CTPA.8 The mean pulmonary arterial pressure, diameter of inferior vein (IV), the RV end-diastolic anteroposterior diameter and the transverse diameter of the RV were measured by echocardiography.

BNP/NT-proBNP elevation was determined by local clinicians, according to the cut-off value of local centre, patient’s age and other health conditions. RV failure was diagnosed by CTPA or echocardiography according to the 2019 ESC/ERS guidelines for acute PE (RV/LV diameter ratio ≥1.0 on echocardiography or CTPA).9

The day of AKI diagnosis referred to the first day that the KDIGO criteria of AKI was met. The day of AKI recovery referred to the day when SCr decreased to the baseline level. Early recovery of AKI was identified if the SCr level decreased to baseline within 7 days after AKI occurrence. The primary outcome of the study was AKI and the secondary outcome was the recovery of renal function.

Patient and public involvement

No patient involved.

Statistical analysis

Baseline characteristics were expressed in terms of descriptive statistics. Categorical variables were summarised as frequency (percentage). Continuous variables were presented as mean (SD) or median (IQR). P values were calculated by students’ t test, Mann-Whitney U test, χ2 test or Fisher exact test among different groups, where appropriate. Missing data were objectively recorded as shown in the tables. Imputation of missing values was not performed. To describe the temporal changes of SCr in high risk and patients with normotensive PE, a locally weighted smoothing method was used for the spline curves. Kaplan-Meier curves were portrayed to present the cumulative AKI rates in patients with normotensive PE by BNP/NT-proBNP elevation and/or RV failure and differences among strata were compared by Log-rank tests. Thereafter, univariable and multivariable COX regression models were performed to explore the risk factors for AKI. To estimate the effect of early anticoagulation (within 5 days, 6–10 days and more than 10 days after PE onset) during follow-up in this cohort, a logistic model was fitted to estimate the ORs and 95% CIs on AKI recovery. All tests were two sided and were considered statistically significant at a p value of <0.05. All analyses were performed using SAS V.9.4 software (Cary, North Carolina).

Results

Dynamic changes of renal function after an onset of acute PE

Of 604 patients diagnosed with PE who were identified during our study period, after screening for acute onset (less than 30 days), 115 patients were excluded due to a chronic characteristic. Consequently, a total of 461 patients with acute normotensive PE were enrolled in the final analysis (figure 1). A slight but significant increase of SCr was observed, peaking at around 20 days with an approximate elevation of 10 µmol/L, and then returned to baseline after 40 days after onset (online supplemental figure 1).

Figure 1 Flowchart of the study. ǂincluding major bleeding and clinically relevant non-major bleeding (CRNMB) defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria. AKI, acute kidney injury; PE, pulmonary embolism.

AKI incidence and risk factors

Based on the dynamic changes of SCr during hospitalisation, the incidence of AKI was 18.9% (87/461) in the normotensive patients. Among those who developed AKI, 72.4% (63/87) were at stage 1, 21.8% (19/87) were at stage 2 and 5.7% (5/87) were at stage 3. Comparisons of the baseline characteristics and outcomes between patients with and without AKI are shown in tables1 2. Those with AKI had older age (median 74.0 vs 66.6 years old, p<0.0001), higher SCr levels (median 81 vs 69 µmol/L, p<0.0001), BNP (median 137.9 vs 76.9 pg/mL, p=0.0454), NT-proBNP (median 1999.0 vs 239.5 ng/mL) and D-dimer levels on admission, and higher rates of BNP/NT-proBNP elevation (72.4% vs 43.0%, p<0.0001).

Table 1 Characteristics of patients with normotensive PE with/without AKI during hospitalisation

Characteristics	AKI (N=87)	Non-AKI (N=374)	Total (N=461)	P value	
Days from onset to admission	5.0 (1.0, 10.0)	5.0 (1.0, 14.0)	5.0 (1.0, 14.0)	0.3556	
Contrast-induced nephropathy	11/33 (33.3)	6/106 (5.7)	17/139 (12.2)	<0.0001	
Male	39 (44.8)	178 (47.6)	217 (47.1)	0.6415	
Age, years	74.0 (62.5, 79.4)	66.6 (56.6, 75.3)	67.8 (57.3, 76.6)	0.0001	
Comorbidities					
 DVT	54/86 (62.8)	181/370 (48.9)	235/456 (51.5)	0.0204	
 Cardiovascular disease	68 (78.2)	229 (61.2)	297 (64.4)	0.0030	
 Hypertension	56 (64.4)	178 (47.6)	234 (50.8)	0.0048	
 Atrial fibrillation	7 (8.0)	33 (8.8)	40 (8.7)	0.8165	
 Chronic heart failure	8 (9.2)	21 (5.6)	29 (6.3)	0.2154	
 Chronic lung disease	32 (36.8)	98 (26.2)	130 (28.2)	0.0483	
 Diabetes	21 (24.1)	60 (16.0)	81 (17.6)	0.0739	
 Active cancer	7 (8.0)	48 (12.8)	55 (11.9)	0.2146	
 Chronic nephritis	1 (1.1)	3 (0.8)	4 (0.9)	0.7616	
 Nephrotic syndrome	1 (1.1)	1 (0.3)	2 (0.4)	0.3207	
 Chronic kidney dysfunction	17 (19.5)	6 (1.6)	23 (5.0)	<0.0001	
 Trauma within 3 months	7/87 (8.0)	14/373 (3.8)	21/460 (4.6)	0.1076	
sPESI				0.0001	
 sPESI=0	34/86 (39.5)	229/367 (62.4)	263/453 (58.1)		
 sPESI≥1	52/86 (60.5)	138/367 (37.6)	190/453 (41.9)		
sPESI scores				0.0034	
 0	34/86 (39.5)	229/367 (62.4)	263/453 (58.1)		
 1	39/86 (45.3)	110/367 (30.0)	149/453 (32.9)		
 2	10/86 (11.6)	21/367 (5.7)	31/453 (6.8)		
 3	2/86 (2.3)	6/367 (1.6)	8/453 (1.8)		
 4	1/86 (1.2)	1/367 (0.3)	2/453 (0.4)		
CTPA	65/86 (75.6)	305/372 (82.0)	370/458 (80.8)	0.1740	
Serum creatinine on admission, μmol/L	81.0 (64.7, 121.0)	69.0 (58.0, 80.0)	70.7 (59.0, 83.8)	<0.0001	
BNP on admission, pg/mL	137.9 (46.4, 410.9)	76.9 (28.4, 227.0)	89.6 (33.7, 260.6)	0.0454	
NT-pro BNP on admission, ng/mL	1999.0 (421.0, 7993.0)	239.5 (72.0, 808.0)	318.2 (100.0, 1191.0)	<0.0001	
BNP/NT-proBNP elevation	63/87 (72.4)	159/370 (43.0)	222/457 (48.6)	<0.0001	
cTNI on admission, ng/mL	0.01 (0.008, 0.04)	0.01 (0.00, 0.03)	0.01 (0.00, 0.03)	0.0295	
WBC count, ×10 /L,	8.3 (6.1, 11.2)	6.7 (5.3, 8.6)	6.9 (5.5, 9.0)	<0.0001	
Haemoglobin, g/L	122.0 (108.0, 136.0)	128.0 (115.0, 142.5)	127.0 (113.0, 141.0)	0.0570	
Anaemia*	28/87 (32.2)	86/372 (23.1)	114/459 (24.8)	0.0781	
D-Dimer	mg/L	4.2 (2.3, 7.3)	2.6 (1.2, 5.7)	2.8 (1.5, 6.5)	0.0051	
ng/mL	1868.5 (856.5, 3026.0)	848.0 (193.0, 2131.0)	991.0 (274.0, 2308.0)	0.0049	
PaO2, mm Hg	78.0 (67.0, 91.2)	74.8 (66.4, 86.0)	75.3 (66.8, 86.2)	0.1236	
Notes. Data were expressed as median (interquartile rangeIQR) or number (proportion), where appropriate. P values were calculated by student’s t test, Mann-Whitney U test, χ2 test or Fisher exact test, where appropriate.

* Anaemia refers to haemoglobin<120 g/L for manale and<110 g/L for femalewoman, respectively.

AKI, acute kidney injury; BNP, brain natriuretic peptide; cTnI, cardiac troponin I; CTPA, CT pulmonary angiography; DVT, deep venous thrombosisNT-proBNP, N-terminal pro-brain natriuretic peptide; PE, pulmonary embolism; WBC, white blood cell

Table 2 RV structural parameters, treatment and outcomes of patients with PE with/without AKI

Characteristics	AKI (N=87)	Non-AKI (N=374)	Total (N=461)	P value	
Echocardiographic parameters					
 mPAP, mm Hg	48.0 (44.0, 67.0)	41.5 (30.0, 52.0)	43.5 (30.5, 56.5)	0.0251	
 IV diameter, mm	16.0 (14.5, 18.5)	14.0 (13.0, 16.3)	15.0 (13.0, 16.9)	0.0046	
 MPA, mm	27.0 (25.0, 31.0)	26.0 (23.0, 30.0)	27.0 (23.0, 30.0)	0.2141	
 RVED, mm	25.0 (21.0, 32.0)	24.0 (21.0, 28.0)	24.0 (21.0, 29.0)	0.2974	
 RVTD, mm	37.0 (31.0, 42.0)	35.0 (31.0, 40.0)	35.0 (31.0, 40.0)	0.3561	
 TRPG	34 (20, 45)	29 (21, 41)	30 (21, 42)	0.4506	
 RV failure detected by CT or echocardiography	24/78 (30.8)	69/343 (20.1)	93/421 (22.1)	0.0407	
Initial anticoagulant therapy					
 LMWH	53/82 (64.6)	284/369 (77.0)	337/451 (74.7)	0.0201	
 LMWH daily dose, IU×103 /day	12.0 (8.0, 60.0)	12.0 (10.0, 120)	12.0 (8.0, 120)	0.0552	
 DOACs	5/82 (6.1)	35/369 (9.5)	40/451 (8.9)	0.3291	
 UFH	14/82 (17.1)	20/369 (5.4)	34/451 (7.5)	0.0003	
 Fondaparinux	0/82 (0.0)	4/369 (1.1)	4/451 (0.9)	0.2040	
 Others	10/82 (12.2)	26/369 (7.0)	36/451 (8.0)	0.1197	
 Days from onset to anticoagulation	7.0 (3.0, 11.0)	8.0 (3.0, 18.0)	8.0 (3.0, 16.0)	0.0549	
 Anticoagulation within 5 days after PE onset	32/82 (39.0)	128/370 (34.6)	160/452 (35.4)	0.4479	
Outcomes					
 In-hospital all-cause death	5 (5.7)	3 (0.8)	8 (1.7)	0.0061	
 In-hospital bleeding*	7/86 (8.1)	7/373 (1.9)	14/459 (3.1)	0.0072	
 Recovery within 7 days after AKI diagnosis	44/87 (50.6)	–	44/87 (50.6)		
 1-month all-cause death	0/62 (0.0)	5/301 (1.7)	5/363 (1.4)	0.1695	
 1-month bleeding	4/62 (6.5)	4/300 (1.3)	8/362 (2.2)	0.0307	
 3-month all-cause death	3/62 (4.8)	10/298 (3.4)	13/360 (3.6)	0.5836	
 3-month bleeding	1/62 (1.6)	7/292 (2.4)	8/354 (2.3)	0.6940	
 AKI recovery during 24-month follow-up	54/85 (63.5)	–	54/85 (63.5)		
Notes. Data were expressed as median (interquartile rangeIQR) or number (proportion), where appropriate. P values were calculated by student’s t test, Mann-Whitney U test, χ2 test or Fisher exact test.

* iIncluding major bleeding and clinically relevant non-major bleeding (CRNMB) defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria.

AKI, acute kidney injury; CTPA, CT pulmonary angiography; DOACs, direct oral anticoagulants; IV, inferior vein; LMWH, low molecular weight heparin; mPAP, mean pulmonary arterial pressure; PE, pulmonary embolism; RVED, right ventricular end-diastolic anteroposterior diameter; RVTD, transverse diameter of right ventricle; TRPG, tricuspid regurgitation pressure gradient; UFH, unfractionated heparin

Echocardiography revealed a significant higher mPAP and larger diameter of the IV among patients with AKI and non-AKI (48.0 mm Hg vs 41.5 mm Hg, p=0.0251, 16.0 mm vs 14.0 mm, p=0.0046, respectively). Low-molecular weight heparin was used less in patients with AKI (64.6% vs 77.0%, p=0.0201) with a numerically lower dose and the use of direct oral anticoagulants was not significantly different between those with or without AKI (6.1% vs 9.5%, p=0.3291). The rates of in-hospital all-cause death and bleeding events were both higher among the patients with AKI (5.7% vs 0.8%, p=0.0061, and 8.1% vs 1.9%, p=0.0072, respectively).

BNP/NT-proBNP elevation (HR 2.27, 95% CI 1.33 to 3.86, p=0.0026) and the history of chronic kidney disease (CKD) (HR 4.81, 95% CI 2.44 to 9.48, p<0.0001) were associated with the development of AKI during hospitalisation (table 3). Patients with AKI had higher rates of BNP/NT-proBNP elevation and RV failure, thus survival analyses were performed to identify the associations between cardiac and renal function (online supplemental figure 2). BNP/NT-proBNP elevation, RV failure or both were associated with increased AKI rates during hospitalisation.

Table 3 Risk factors for in-hospital AKI of patients with normotensive PE

Risk factors	Univariable model	Multivariable model	
HR (95% CI)	P	HR (95% CI)	P	
Days from PE onset to anticoagulation therapy	≤5 days	reference	–	reference	–	
6–10 days	1.15 (0.62 to 2.11)	0.6608	1.05 (0.57 to 1.96)	0.8675	
≥11 days	0.77 (0.44 to 1.33)	0.3416	0.69 (0.39 to 1.25)	0.2241	
Age>65 years	1.83 (1.12 to 3.00)	0.0156	1.27 (0.75 to 2.16)	0.3694	
Chronic heart and lung disease	1.88 (1.05 to 3.36)	0.0341	1.24 (0.66 to 2.31)	0.4991	
BNP/NT-proBNP elevation	2.95 (1.75 to 4.97)	<0.0001	2.27 (1.33 to 3.86)	0.0026	
DVT	1.53 (0.96 to 2.46)	0.0754	1.22 (0.76 to 1.98)	0.4120	
Chronic kidney dysfunction	6.28 (3.68 to 10.69)	<0.0001	4.81 (2.44 to 9.48)	<0.0001	
Diabetes	1.63 (0.96 to 2.76)	0.0717	1.42 (0.83 to 2.46)	0.2042	
Notes. HRs and 95% CIs were estimated by Cox proportion hazard regression model.

AKI, acute kidney injury; BNP, brain natriuretic peptide; DVT, deep venous thrombosis; NT-proBNP, N-terminal pro-brain natriuretic peptide; PE, pulmonary embolism; RV, right ventricle

Earlier anticoagulation and recovery of renal function

Early recovery of renal function occurred in 44 of 87 (50.6%) among the patients with normotensive PE with AKI. After adjustment for cardiovascular diseases, CKD and age, anticoagulation administered within 5 days after the onset of acute PE (probably due to earlier diagnosis) was a protective factor for the early recovery of AKI (OR 0.258, 95% CI 0.079 to 0.844, p=0.025), indicating a reduction of approximately three fourths in the odds of unrecovered renal function, compared with those with delayed treatment (more than 10 days after PE onset) (figure 2).

Figure 2 Forest plot of multivariable logistic regression on the effects of earlier anticoagulation on AKI recovery. *The ORs of days to anticoagulation were estimated taking later anticoagulation (≥11 days after PE onset) as reference. OR<1 refers to earlier recovery. AKI, acute kidney injury; PE, pulmonary embolism.

Discussion

Based on a multicentre, retrospective cohort, our analysis revealed an incidence of AKI during hospitalisation among patients with acute PE and investigated the potential association between cardiac and renal function in patients with normotensive acute PE. Of note, we innovatively reported a more accurate incidence of AKI according to the dynamic laboratory examinations of SCr level and revealed the potential beneficial impact of earlier anticoagulation therapy on the early recovery of renal function. These findings provide important clues and possible rationale to explore the pathophysiology and potential management strategy of AKI after acute PE.

AKI secondary to non-renal diseases is of high incidence but tends to be ignored. Thus, the incidences of AKI varied across studies. Our analysis revealed that the incidence of AKI was 18.9% after acute normotensive PE, which was much higher than that in the general inpatient population in China (2.5% and 9.1% for community-acquired and hospital-acquired AKI, respectively).10 However, a study from Taiwan reported a lower incidence of AKI among patients with PE of 4.9%, most likely based on the International Classification of Diseases, Ninth Revision (ICD-9) in discharge diagnosis.4 The RIETE multicentre registry study, although consistent with our study, reported an AKI incidence of 29.5% at baseline according to the KDIGO criteria, based on data from 21 131 patients with PE with SCr levels only available on admission.2 The reasons may be multiple for the current differences in AKI incidences. First, the progression of AKI is latent in most cases, with a gradual escalation in creatinine or slow de-escalation in urine output during hospitalisation, especially for patients with CKD, older age, multiple comorbidities and PE of high risk.2 Thus, the application of dynamic SCr for the identification of AKI was vital in our study, and successfully provided a relatively accurate AKI incidence.

There were significant differences in baseline characteristics between the patients who developed AKI or not. Those with older age, DVT and cardiovascular and lung diseases were more likely to develop AKI. Those with AKI had higher cardiac troponin I, white cell counts and D-dimer levels than those without. This clinical finding was consistent with previous studies and indicated that patients with AKI had more severe condition of PE (including multiorgan damage and clot burden).

Except for the remarkable incidence of AKI, a significant trend of SCr elevation and recovery was observed among normotensive patients in our study. The mechanism was deduced as the lower perfusion of the kidney due to venous congestion induced by RV dysfunction after PE, and this was partly verified by the significant association between BNP/NT-proBNP, RV structural change by radiology and AKI in our study. The current opinion suggests that haemodynamically stable patients are at low risk of death, but those with signs of RV dysfunction would develop worse outcomes. Previous studies proved the association between renal failure/dysfunction and adverse outcomes of PE.11 It is widely accepted that a sudden pressure overload in the pulmonary circulation due to PE leads to RV dysfunction along with tricuspid regurgitation. High filling pressures secondary to volume overload in the RV would also result in the elevation of BNP/NT-proBNP, a marker for RV dysfunction.12 13 From our results, BNP/NT-proBNP elevation alone (without structural change in the RV) was associated with the occurrence of AKI, indicated that the cardiorenal interaction after acute PE may undermine renal function by RV dysfunction, not merely RV decompensation. Consequently, central venous pressure (CVP) rises and may lead to renal congestion and injury.14 Previous studies revealed that an elevation in right atrial pressure, which was correlated with CVP, but not a decrease in cardiac output and/or cardiac index, was associated with descending renal function.15 Renal venous hypertension can induce a decline in glomerular filtration rate (GFR),16 17 and persistent renal venous hypertension can result in the progression of kidney disease.1821 Therefore, we inferred that the indicator for ventricular functional indexes was related to the impairment of renal function, exemplified by diameters of IV and BNP levels. The diameters of IV, as measured by echocardiography, were higher in AKI than patients with non-AKI in our study, although their RV diameters were comparable in patients with normotensive acute PE.

However, for BNP or NT-proBNP levels, we used elevation judged by clinician rather than unified cut-off values. It was suggested that the cut-off values for BNP in PE prognostic should be lower than those for congestive heart failure, while the recommended BNP or NT-proBNP levels in the assessment of RV function of PE remain undetermined.9 Additionally, the extraction of BNP/NT-proBNP is easily affected by the GFR. More studies on BNP/NT-proBNP among patients with PE with renal impairment are warranted.22

Our study innovatively illustrated the association between earlier anticoagulation therapy and early recovery of AKI, indicating a potential benefit in the protection of renal function and the outcomes of patients with acute PE. In accordance with our results, the RIETE study reported that 73% patients with AKI achieved renal recovery and among those, 80% was observed in the first 7 days, half of them recovered in the first 48 hours after the onset of AKI.5 The results highlighted the importance of individualised monitoring and decision-making in patients with AKI, as many patients will have better outcome. Delayed initiation of anticoagulation, usually due to delayed diagnosis or misdiagnosis, has been discussed in patients with acute VTE and higher rates of mortality and major bleeding were observed at 90-day follow-up but failed to reach a significant association between delayed anticoagulation and poor outcomes.23

CTPA is the currently widely applied diagnosis technique for PE and CIN is a usual cause of hospital-acquired kidney injury. Among those with available SCr obtained after CTPA (139 patients) in our study, the incidence of CIN was 12.3%, and 11 cases met the AKI criteria at the same time. Previous studies have presented incidence of CIN after CTPA of 14%24 and 13.1%.8 The incidence of CIN among patients with PE was higher than that among other patient populations (13% vs 5%),25 indicating that patients with PE may be more vulnerable to contrast and thus calling for more aggressive measurements to prevent renal impairment. Unfortunately, we were unable to track every patient’s renal function after CTPA in our cohort, which leaves uncertainty in the development and possible cause of AKI. Further analysis of the interaction between CTPA and RV dysfunction is required.

We acknowledge several limitations of our study. First, although dynamic records of SCr during hospitalisation was obtained, only available results were calculated in our analysis due to the retrospective design. Those patients who lacked frequent SCr measurements might be misdiagnosed for AKI. The actual incidence of AKI after acute PE was inevitably underestimated using real-world data. Second, only half of the patients underwent echocardiography during hospitalisation, so the evaluation of structural function of the heart and its correlation to renal function and outcomes was limited. Third, despite that it was deduced that RV function may be associated with the occurrence and early recovery of AKI, the lack of ultrasonic data on RV function at different time points made it difficult to determine the chronological order of RV and kidney function decline.

Conclusions

Renal impairment and AKI were highly prevalent among patients with normotensive PE. The occurrence of AKI was associated with right heart function. Patients developed AKI would benefit from early anticoagulation therapy for an earlier recovery of renal function.

supplementary material

10.1136/bmjopen-2023-081295 online supplemental file 1

Acknowledgements

The authors wish to gratefully acknowledge all the study centres and study participants who have devoted their time and effort to this study.

Data availability statement

Data are available upon reasonable request.

Review Process File
29 08 2024

Funding: This study is supported by The National Key Research and Development Program of China (2016YFC0905600, 2023YFC2507200). National High Level Hospital Clinical Research Funding; Elite Medical Professionals. Project of China-Japan Friendship Hospital (NO.ZRJY2023-QM20). CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-1-061). CAMS Institute of Respiratory Medicine Grant for Young Scholars (2023-ZF-8).

Prepublication history and additional supplemental material for this paper are available online. To view these files, please visit the journal online (https://doi.org/10.1136/bmjopen-2023-081295).

Provenance and peer review: Not commissioned; externally peer-reviewed.

Patient consent for publication: Consent obtained directly from patients.

Ethics approval: This study was conducted in accordance with the Declaration of Helsinki and has been approved by the ethical committees of all participating centres (Approval Number 2012BJYYEC-050-02, 2017-24). Written informed consent was obtained from all recruited participants.

Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
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