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10.1080/0886022X.2024.2406403
2406403
Version of Record
Research Article
Clinical Study
Investigating an appropriate indicator of acute kidney injury for patient prognosis following lung transplantation
W. du et al.
https://orcid.org/0000-0002-9826-8405
Du Wenwen a
Zhang Dan a
Chen Wenqian a
Chen Wenhui b
Li Pengmei a
Wang Xiaoxing a
a Department of Pharmacy, China-Japan Friendship Hospital, Beijing, China
b 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; Department of Lung Transplantation, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
Supplemental data for this article can be accessed online at https://doi.org/10.1080/0886022X.2024.2406403.

CONTACT Xiaoxing Wang subpharm@163.com Department of Pharmacy, China-Japan Friendship Hospital, No.2 Yinghua East Street, Chaoyang District, Beijing 100029, China.
20 9 2024
2024
20 9 2024
46 2 240640318 7 2024
11 9 2024
14 9 2024
KnowledgeWorks Global Ltd.20 9 2024
published online in a building issue20 9 2024
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
2024
The Author(s)
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

Abstract

Objective

The purpose of this study was to investigate the correlation between different subtypes of acute kidney injury (AKI) and clinical outcomes following lung transplantation (LTx) and to identify a reliable indicator for predicting poor prognosis in the LTx population.

Methods

We retrospectively analyzed the clinical data of 279 LTx patients from August 2016 to March 2023. The AKI subtypes included AKI, persistent AKI on Day 7 (P7-AKI) and Day 14 (P14-AKI) after LTx, and AKI stages. The correlations of these factors with respiratory outcomes, mortality at 90 days, mortality at 1 year and data finalization were assessed, and the risk factors for the selected AKI subtypes were evaluated.

Results

AKI occurred in 215 patients (77.1%), with 129 (46.2%) experiencing P7-AKI and 95 (34.1%) experiencing P14-AKI. P7-AKI was associated with more respiratory and mortality outcomes than were AKI and AKI stages, and P7-AKI surpassed P14-AKI in terms of a shorter diagnostic time. After adjusting for age, sex, BMI, type of transplant, transplant diagnosis and comorbidities, P7-AKI independently correlated with increased mortality risk at 90 days [HR 12.312 (95% CI: 2.839–53.402)], 1 year [HR 3.847 (95% CI: 1.840–8.044)], and data finalization [HR 2.010 (95% CI: 1.331–3.033)]. Five variables were identified as independent predictors for P7-AKI, including preoperative body mass index, prothrombin activity, hemoglobin and serum creatinine, and intraoperative colloid administration.

Conclusion

P7-AKI has been identified as a reliable indicator for predicting adverse outcomes in LTx patients, which may assist healthcare professionals in identifying high-risk individuals.

Keywords

Acute kidney injury
persistent acute kidney injury
AKI stages
lung transplantation
mortality
National High Level Hospital Clinical Research Funding 2023-NHLHCRF-YYPPLC-TJ-22 CAMS Innovation Fund for Medical Science 2021-I2M-1-049 National Natural Science Foundation Project 82273523 The study was financed with National High Level Hospital Clinical Research Funding (2023-NHLHCRF-YYPPLC-TJ-22), CAMS Innovation Fund for Medical Science (2021-I2M-1-049), National Natural Science Foundation Project (82273523).
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pmcIntroduction

Lung transplantation (LTx) remains the primary therapeutic approach for patients suffering from end-stage lung disease [1,2]. However, despite advances in surgical techniques and immunosuppressive drugs, patients’ survival rates continue to be impacted by severe postoperative complications. One of the most common complications following LTx is acute kidney injury (AKI), with incidence rates ranging from 36.6% to 84.9% [3–6].

The presence of AKI has consistently been associated with poor prognosis, including a longer duration of mechanical ventilation and hospitalization as well as short-term and long-term mortality [7,8]. However, the association between AKI and mortality has shown variability across studies [9,10]. Severe stages of AKI may be more predictive of mortality risk, regardless of the AKI definition used [2,11,12]. Furthermore, several studies have identified persistent AKI as a reliable indicator of adverse clinical outcomes in LTx patients [6,13]. Nevertheless, there are currently no studies comparing these indicators to determine which is more appropriate for assessing the prognosis of patients after LTx.

Therefore, our objectives in this retrospective study were to (1) elucidate the prevalence of different subtypes of AKI in the LTx population; (2) compare the efficiency of predicting clinical outcomes among different AKI subtypes; and (3) explore potential risk factors associated with the identified AKI subtypes.

Materials and methods

Study design and population

In this single-center, retrospective study, patients who underwent LTx at China-Japan Friendship Hospital from August 2016 to March 2023 and survived the first 14 days were enrolled according to the study criteria. The inclusion criteria were as follows: (1) LTx for the first time and (2) aged between 18 and 70 years. The exclusion criteria were as follows: (1) received continuous renal replacement therapy (CRRT) before LTx; (2) had a pretransplantation history; (3) had missing data; and (4) had a diagnosis of chronic kidney disease (CKD) or AKI before LTx.

All procedures in this study were in accordance with the 1964 Helsinki Declaration and its amendments and were approved by the Ethics Committee of China-Japan Friendship Hospital in June 2022 (No. 2022-KY-056-1); a waiver of informed consent was obtained from the Ethics Committee.

LTx surgical protocol

LTx procedure was performed according to the anesthetic and surgical technique protocols at the China-Japan Friendship Hospital. In brief, single-lung transplantation typically involves a thoracotomy on either the side or front of the chest, removal of the recipient’s original lung, and implantation of the donor’s lung. Double lung transplantation was performed via bilateral anterolateral thoracotomies using the sequential LTx method. Anesthesia is administered via propofol, remifentanil, or atracurium. Extracorporeal membrane oxygenation (ECMO) is selectively used for patients with severe pulmonary hypertension (mean pulmonary artery pressure ≥45 mmHg) and/or right ventricular failure, as well as for patients who experience instability during the transplantation procedure.

Immunosuppressive regimens

For induction therapy, patients received methylprednisolone alone or in combination with basiliximab. Methylprednisolone was administered intraoperatively at a dose of 500–1000 mg. Basiliximab was given at a dose of 20 mg both before surgery and on postoperative day (POD) 4. The maintenance immunosuppressive regimen consisted of tacrolimus, mycophenolate mofetil and prednisone. Tacrolimus was initiated on POD1, and dose adjustments were made according to whole-blood trough concentration measurements. The starting dose of mycophenolate mofetil was 1 g/day. Prednisone was administered intravenously at a dosage of 1 mg/kg/day from POD 1 to POD 3, followed by oral administration at a dosage of 0.5 mg/kg/day, which gradually tapered down to a long-term maintenance dose ranging between 5–10 mg/day.

AKI definition

AKI was determined and staged according to the ‘Kidney Disease: Improving Global Outcomes’ (KDIGO) Clinical Practice Guideline, which is based on serum creatinine (SCr) obtained from the transplantation date until 7 days after transplantation [14]. According to the guidelines, AKI was defined as any of the following: (1) increase in SCr by ≥ 26.5 μmol/L within 48 h or (2) increase in SCr to ≥1.5 times baseline in the first 7 postoperative days. AKI was further staged as follows: (1) Stage 1, SCr increased to 1.5–1.9 times the baseline value; (2) Stage 2, SCr increased to 2.0–2.9 times the baseline value; and (3) Stage 3, SCr increased to ≥3.0 times the baseline value or to ≥353.6 μmol/L or initiated renal replacement therapy (RRT). Baseline SCr was defined as the SCr level obtained prior to LTx. Persistent AKI was defined as incomplete recovery from AKI (SCr above the KDIGO criteria) on POD7 (P7-AKI) and POD14 (P14-AKI) following LTx, regardless of when AKI initially occurred.

Data collection

The pertinent parameters, including demographic, preoperative laboratory and intraoperative data, were obtained through a retrospective manual chart review of all patients. The demographic parameters included age, sex, height, weight, comorbidities, diagnosis for LTx and American Society of Anesthesiologists (ASA) score. The preoperative laboratory data included alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein (TP), albumin (ALB), total bilirubin (TBIL), direct bilirubin (DBIL), serum creatinine (SCr), uric acid (UA), urea, glucose, white blood cell (WBC) count, neutrophil count, lymphocyte count, red blood cell (RBC) count, hemoglobin, hematocrit, potassium, sodium, calcium, chlorine, prothrombin time (PT), prothrombin activity (PTA), the international normalized ratio (INR), fibrinogen (Fib), activated partial thromboplastin time (APTT), thrombin time (TT), D-D dimer (DD), fibrin degradation products (FDP), myoglobin (Myo), creatinine kinase-MB (CKMB), cardiac troponin I (cTnI) and the N-terminal prohormone of brain natriuretic peptide (NTproBNP). Intraoperative fluid information, including the administration of colloids and crystalloids and the transfusion of blood products and autologous blood, was obtained by referring to anesthesia notes. Other intraoperative parameters included operation time, transplant type, use of basiliximab and ECMO, and furosemide dosage.

Outcome measures

The primary outcome was the incidence of different types of AKI (AKI, P7-AKI and P14-AKI) following LTx. The secondary outcomes consisted of short-term outcomes, including days spent on ECMO, invasive mechanical ventilation (IMV), intensive care unit (ICU) admission, first hospitalization, and 90-day mortality; and long-term outcomes, including 1-year mortality and survival status during the study. The median follow-up time of the study was 1266 days, and the final follow-up time was March 31, 2024.

Statistical analysis

The distribution of the data was assessed via the Shapiro–Wilk test. Descriptive statistics are expressed as the means ± standard deviations (SDs) for normally distributed continuous variables or medians (interquartile ranges, IQRs) for nonnormally distributed continuous variables. Categorical variables are presented as counts (percentages). Differences between groups were analyzed by the Mann–Whitney U test or the Kruskal–Wallis test. Survival rates at different time points stratified by AKI status were analyzed via Kaplan–Meier analysis and compared via the log-rank test. Associations between different AKI statuses and mortality rates were assessed via Cox proportional hazard models. For analysis of potential risk factors for AKI, variables with p < 0.20 in the univariate analysis were incorporated into the multivariate logistic regression. p < 0.05 was considered statistically significant. All of the data analyses were performed with the R software package (version 4.2.1) and SPSS (version 19.0).

Results

Population

Among the 319 patients who underwent LTx, 16 were excluded because of age criteria (younger than 18 years or older than 70 years), whereas another 14 were excluded because of missing data. Additionally, 9 patients were excluded on the basis of their pretransplantation history, and one patient was excluded for receiving CRRT before LTx. Consequently, a total of 279 patients remained for the final analysis. The median age (IQR) of the cohort was 60 (54–64) years, with males accounting for approximately 86% of the population.

Prevalence rates of type 2 diabetes mellitus, hypertension, hyperlipidemia, and cardiovascular disease prior to surgery were 29.8%, 19.7%, 5.4% and 16.8%, respectively. The most prevalent pulmonary diagnosis among these patients was interstitial lung disease (ILD; 76%), followed by chronic obstructive pulmonary disease (COPD; 12.2%). Other less common diagnoses included pulmonary hypertension (3.2%), bronchiectasis (3.2%), pneumoconiosis (2.5%), bronchiolitis obliterans (1.4%), cystic fibrosis (0.7%), Castleman disease (0.4%), and pulmonary alveolar proteinosis (0.4%).

Prevalence of AKI

The incidence of AKI is shown in Figure 1, which illustrates the distribution by year and POD. Among the 279 patients included in the analysis, 215 had AKI (77.1%), with 129 patients (46.2%) experiencing P7-AKI and 95 patients (34.1%) experiencing P14-AKI. Notably, the highest incidence of AKI was observed on POD 2, accounting for 40.6% of the population (Figure 1A). Among the identified stages, stage 1 was present in 86 cases (30.8%), stage 2 was present in 78 cases (28.0%), and stage 3 was present in 51 cases (18.3%). In terms of temporal distribution, only one patient’s data were available for analysis in 2016, and these data points were combined with those from 2017. Furthermore, the incidence of AKI did not significantly vary across different years (Figure 1B); however, the prevalence of persistent AKI, such as P7-AKI and P14-AKI, showed interyear variability (Supplementary Figure S1).

Figure 1. Incidence of AKI (A) per day and (B) per year after lung transplantation. Post-operative day refers to the day after lung transplantation surgery.

Short-term outcomes

Our findings suggest that patients with AKI had significantly longer durations of IMV (median (IQR), in days, 2 (1–3) vs. 2 (1–2) days, p = 0.011) and extended stays in the ICU (4 (3–6) vs. 3 (3–4) days, p = 0.025) than patients without AKI. Furthermore, P7-AKI and P14-AKI were associated with longer durations on ECMO (1 (1–2) vs. 1 (0–2) days, p = 0.040; 1 (1–2) vs. 1 (0–2) days, p = 0.025) than patients with transient AKI were (Table 2). However, neither AKI nor persistent AKI exhibited a significant correlation with hospital stay duration.

Table 2. Post-operative outcomes stratified by different AKI status.

Outcome	AKI status	Persistent AKI	AKI stages	
No AKI	AKI	p	No P7-AKI	P7-AKI	p	No P14-AKI	P14-AKI	p	No AKI	1	2	3	p	
ECMO days	1(0–2)	1(1–2)	0.182	1(0–2)	1(1–2)	0.040	1(0–2)	1(1–2)	0.003	1(0–2)	1(1–2)	1(1–2)	1(0–2)	0.130	
IMV days	2(1–2)	2(1–3)	0.011	2(1–2)	2(1–4)	<0.001	2(1–2)	2(2–5)	<0.001	2(1–2)	2(1–2)	2(1–4)	3(2–4)	<0.001	
ICU days	3(3–4)	4(3–6)	0.025	4(3–5)	4(3–6)	0.002	4(3–5)	5(3–7)	<0.001	3(3–4)	3(3–5)	4(3–6)	5(3–11)	<0.001	
Hospital days	42(35–62)	50(35–71)	0.128	46(35–60)	52(34–78)	0.069	46(35–63)	53(34–81)	0.067	42(35–62)	44(35–56)	52(38–80)	58(31–85)	0.052	
Data presented as median with inter-quartile range (med (IQR)).

Abbreviations: AKI, acute kidney injury; ECMO, extracorporeal membrane oxygenation; ICU, intensive care unit; IMV, invasive mechanical ventilation; P7-AKI, AKI persistent on day 7; P14-AKI, AKI persistent on day 14.

When comparing different stages of AKI, we observed that patients in stage 3 experienced significantly longer durations of IMV and ICU stay than did those without AKI (p = 0.001 and p = 0.034, respectively; Bonferroni correction) and stage 1 patients (p = 0.004 and p = 0.007, respectively; Bonferroni correction). No significant difference was observed among the other stages.

Survival outcomes

The 90-day, 1-year and overall survival rates of the study population after LTx were 92.5%, 86.4% and 64.2%, respectively. K-M analysis revealed that all 3 types of AKI were predictive of survival at both 90 days and 1 year (90 days: no AKI versus AKI, p = 0.041; no P7-AKI versus P7-AKI, p < 0.001; no P14-AKI versus P14-AKI, p < 0.001; 1 year: no AKI versus AKI, p = 0.019; no P7-AKI versus P7-AKI, p < 0.001; no P14-AKI versus P14-AKI, p < 0.001) (Figure 2). Furthermore, P7-AKI and P14-AKI were significantly associated with the overall survival rate (no-AKI versus AKI, p = 0.119; no-P7-AKI versus P7-AKI, p < 0.001; no-P14-AKI versus P14-AKI, p < 0.001).

Figure 2. Kaplan-Meier survival curves stratified by AKI and no-AKI at (A) 90-day, (B) 1-year and (C) data finalization; by P7-AKI and no P7-AKI at (D) 90-day, (E) 1-year and (F) data finalization; by P14-AKI and no P14-AKI at (G) 90-day, (H) 1-year and (I) data finalization. Post-operative day refers to the day after lung transplantation surgery.

Notably, only patients classified as AKI stage 3 presented significantly lower survival rates than did those without AKI or with stage 1 AKI during both the short-term (90-day) and long-term (1-year and whole) follow-up periods (Figure 3). No statistically significant difference in survival rates between patients with no AKI and those with stage 1 AKI was observed. The predictive power of stage 2 AKI was not stable since it was significantly different from that of stage 1 AKI and non-AKI patients in terms of the survival rate at 1 year (Supplementary Table S1).

Figure 3. Kaplan-Meier survival curves stratified by AKI stages and no-AKI at (A) 90-day, (B) 1-year and (C) data finalization. Post-operative day refers to the day after lung transplantation surgery.

According to our study, P7-AKI has potential as a robust clinical outcome indicator in comparison with AKI, offering the additional advantage of reduced diagnostic time compared with P14-AKI. Moreover, it has the ability to identify a greater number of individuals at risk for stage 3 AKI, rendering it suitable for prognostic assessment following LTx. In the Cox proportional hazard model (adjusted for age, sex, BMI, type of transplant, transplant diagnosis and comorbidities), P7-AKI exhibited independent predictive value for mortality at 90 days [HR 12.312 (95% CI: 2.839–53.402), p < 0.001], 1 year [HR 3.847 (95% CI: 1.840–8.044), p < 0.001], and data finalization [HR 2.010 (95% CI: 1.331–3.033), p < 0.001].

Risk factors for P7-AKI

In addition to the baseline demographic characteristics in Table 1, we added other preoperative and intraoperative variables listed in Supplementary Table S2 to the risk factor analysis. According to the univariate analysis, preoperative PTA, hematocrit, hemoglobin, Tbil, BMI and colloid administration were significantly associated with AKI occurrence (Table 2). Variables with p < 0.2 were further assessed via a multivariate model (Table 3). BMI [OR 1.101 (95% CI: 1.029–1.178)], PTA [OR 0.973 (95% CI: 0.955–0.991)], hemoglobin [OR 1.024 (95% CI: 1.009–1.038)], SCr [OR 0.974 (95% CI: 0.956–0.992)] and colloid administration [OR 0.999 (95% CI: 0.998–1.000)] were associated with an increased risk of P7-AKI.

Table 1. Baseline characteristics of the population.

Parameters	All	No-AKI	AKI	p-value	
Pre-operative demographics	 	 	 	 	
 Age (years)	60 (54–65)	60 (53–65)	60 (55–64)	0.803	
 Male, n (%)	238 (85.3)	55 (85.9)	183 (85.1)	1.000	
 BMI (kg/m2)	22.0 ± 4.0	21.7 ± 4.1	22.1 ± 4.0	0.426	
 Comorbidities,	 	 	 	 	
  Diabetes mellitus	83 (29.8)	21 (32.8)	62 (28.8)	0.649	
  Hypertension	55 (19.7)	8 (12.5)	47 (21.9)	0.141	
  Hyperlipidemia	15 (5.4)	7 (10.9)	8 (3.7)	0.051	
 Cardiovascular disease	47 (16.8)	10 (15.6)	37 (17.2)	0.915	
 Diagnosis, n (%)	 	 	 	0.170	
 ILD	212 (76.0)	46 (71.9)	166 (77.2)	 	
  COPD	34 (12.2)	12 (18.8)	22 (10.2)	 	
  Others	33 (11.8)	6 (9.4)	27 (12.6)	 	
Pre-operative laboratory data	 	 	 	 	
 ALT (IU/L)	21 (14–32)	25 (15–38)	20 (14–31)	0.053	
 AST (IU/L)	21 (17–26)	23 (18–28)	20 (16–25)	0.059	
 TP (g/L)	68.5 (64.0–73.0)	68.4 (63.2–72.0)	68.6 (64.0–73.0)	0.536	
 ALB (g/L)	39.6 (4.1)	39.7 (4.0)	39.6 (4.1)	0.885	
 Tbil (μmol/L)	7.06 (5.36–10.08)	6.62 (4.75–8.05)	7.27 (5.52–10.58)	0.020	
 Dbil (μmol/L)	2.04 (1.44–2.89)	1.83 (1.37–2.42)	2.05 (1.47–2.99)	0.113	
 SCr (μmol/L)	56.1 (46.8–66.0)	58.9 (49.7–66.2)	55.7 (45.4–66.0)	0.245	
 UA (μmol/L)	257 (194–333)	255 (188–320)	257 (196–336)	0.741	
 Urea (mmol/L)	5.50 (4.22–7.14)	5.18 (4.08–6.56)	5.60 (4.24–7.30)	0.131	
 Glucose (mmol/L)	6.82 (5.54–9.11)	6.91 (5.69–8.60)	6.77 (5.45–9.18)	0.778	
 WBC (×109 cells/L)	8.70 (6.94–10.55)	8.73 (6.79–10.86)	8.64 (7.00–10.53)	0.737	
 Neutrophil (×109 cells/L)	5.83 (4.69–7.63)	5.67 (4.66–7.39)	6.02 (4.69–7.69)	0.525	
 Lymphocyte (×109 cells/L)	1.59 (1.17–2.16)	1.77 (1.15–2.37)	1.58 (1.17–2.13)	0.384	
 RBC (×1012 cells/L)	4.37 (3.88–4.81)	4.30 (3.78–4.52)	4.39 (3.96–4.87)	0.025	
 Hemoglobin (g/L)	133 (121–145)	128 (114–138)	133 (123–148)	0.013	
 Hematocrit (%)	40.1 (36.9–43.9)	39.2 (35.3–42.4)	40.4 (37.5–44.4)	0.030	
Intra-operative parameters	 	 	 	 	
  Transplant type, n (%)	 	 	 	0.696	
   Single lung	127 (45.5)	31 (48.4)	96 (44.6)	 	
   Bilateral lung	152 (54.5)	33 (51.6)	119 (55.4)	 	
  Basiliximab use, n (%)	150 (53.8)	36 (56.2)	114 (53.0)	0.755	
 ECMO use, n (%)	206 (73.8)	44 (68.8)	162 (75.4)	0.372	
Categoric data are presented as number (%) (n (%)), continuous data presented as mean with standard deviation (mean (SD)) or median with inter-quartile range (IQR), depending on variable distribution.

Abbreviations: ALB, albumin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; COPD, chronic obstructive pulmonary disease; DBIL, direct bilirubin; ECMO, extracorporeal membrane oxygenation; ILD, interstitial lung disease; RBC, red blood cells; TBIL, total bilirubin; TP, total protein; TT, thrombin time; WBC, white blood cells.

Table 3. Multivariate analysis for risk factors of P7-AKI.

Covariate	Univariate	Multivariate	
OR (95% CI)	p value	OR (95% CI)	p value	
Pre-operative parameters	 	 	 	 	
Hypertension	1.661 (0.919–3.033)	0.095	 	 	
PTA	0.98 (0.964–0.996)	0.017	0.973 (0.955–0.991)	0.004	
PT	1.24 (0.987–1.569)	0.068	 	 	
Hematocrit	1.051 (1.009–1.096)	0.019	 	 	
Hemoglobin	1.017 (1.005–1.03)	0.007	1.024 (1.009–1.038)	0.001	
RBC	1.351 (0.973–1.899)	0.076	 	 	
MCH	1.099 (0.987–1.229)	0.089	 	 	
SCr	0.985 (0.969–1.001)	0.068	0.974 (0.956–0.992)	0.004	
Sodium	0.95 (0.887–1.002)	0.123	 	 	
Dbil	1.137 (0.962–1.352)	0.137	 	 	
Tbil	1.055 (1.001–1.114)	0.049	 	 	
AST	0.984 (0.962–1.005)	0.151	 	 	
Diagnosis-ILD	Ref	 	 	 	
Diagnosis-COPD	0.478 (0.215–1.01)	0.06	 	 	
Diagnosis-Others	0.571 (0.261–1.203)	0.148	 	 	
BMI	1.091 (1.027–1.162)	0.005	1.101 (1.029–1.178)	0.005	
Intra-operative parameters	 	 	 	 	
Colloid administration	0.999 (0.998–1.000)	0.013	0.999 (0.998–1.000)	0.043	
Abbreviations: AKI, acute kidney injury; BMI, body mass index; CI, confidence interval; COPD, chronic obstructive pulmonary disease; DBIL, direct bilirubin; Hb, hemoglobin; HCT, hematocrit; MCH, mean corpuscular hemoglobin; OR, odds ratio; P7, persistent for 7 days; PT, prothrombin time; PTA, prothrombin activity; RBC, red blood cells; TBIL, total bilirubin.

Discussion

The aim of this single-center, retrospective study was to investigate which subtype of AKI is most suitable for predicting clinical outcomes after LTx. Our findings demonstrate that both P7-AKI and P14-AKI, which are persistent forms of AKI, are associated with unfavorable respiratory outcomes, including prolonged ECMO and ventilator days, as well as longer ICU stays. Furthermore, they are also correlated with increased mortality rates at 90-day, 1-year, and data finalization points, surpassing the predictive value of AKI or stage 3 AKI alone. Given its shorter diagnostic time frame, P7-AKI is suggested to be the most suitable prognostic indicator for clinical outcomes in the LTx population.

The prevalence of AKI in our study was relatively high at 77.1% compared with that reported in previous studies but was consistent with the rate reported in the Chinese LTx population [2,6,10,13,15]. Early recovery from AKI occurred in 40% of patients within the first 7 days after LTx, and this rate increased to 56% by Day 14. When considering a 7-day evaluation period, Jing et al. reported persistent AKI in 49.2% of patients, whereas Fidalgo reported a similar occurrence rate of 33.5%, which aligns with our findings [6,16].

Possible explanations contributing to the variability across studies included divergent definitions of AKI, disparities in surgical and medical practices, and discrepancies in population demographics. We conducted an analysis of our study population demographics and reported that the majority of patients who underwent lung transplantation were males (85.3%). Bennett et al. reported a greater risk of AKI among male individuals and attributed this partly to data from the International Society for Heart and Lung Transplantation (ISHLT) registry, which suggested that male sex was associated with poorer outcomes following lung transplantation [15,17]. Similarly, recent studies conducted in other disease settings have also indicated higher rates of hospital-acquired AKI among males [18]. Animal models have proposed a potential mechanism suggesting a protective effect of female sex against the development of AKI after ischemia–reperfusion injury, possibly through the suppression of increased renal sympathetic nerve activity during renal ischemia and a reduction in postischemic glomerular endothelial hyperpermeability induced by estrogen production [19–21].

The current understanding of how AKI affects the clinical outcomes of the LTx population is limited and sometimes contradictory [22]. Previous studies have focused primarily on mortality and respiratory outcomes, such as reintubation, tracheostomy, nitric oxide inhalation, ECMO, IMV and ICU stay [6,10,15]. In our study, we found that AKI was associated with prolonged IMV and ICU stay, whereas persistent AKI was further linked to increased ECMO days. This is possibly because renal injury may impair lung function through changes in acid–base or fluid balance or by increasing cytokine/chemokine production, leukocyte trafficking, and oxidative stress [23,24]. Interestingly, Fryman et al. reported that MV was associated with AKI and severe AKI, but they did not find a significant correlation between MV and prolonged AKI [25]. In their study, intubation was performed due to acute cardiac failure, which can quickly recover through appropriate treatment, leading to renal recovery. On the other hand, for our patients who underwent LTx, intubation serves as an indicator of the recovery of respiratory function. Compared with cardiac failure patients, LTx patients take a relatively longer time to recover from surgery. Therefore, there may be a persistent interaction between MV and renal injury over an extended period in these patients.

We did not find a significant correlation between any subtype of AKI and the duration of hospital stay. However, patients with AKI and persistent AKI, as well as those in different stages of AKI, showed an increasing trend in the median length of hospital stay. In contrast, Chaudhry et al. reported that patients with AKI had a significantly longer hospital stay than did those without AKI (median: 12 days vs. 10 days, p < 0.001). The inconsistency in findings across studies may be attributed to various factors influencing the length of hospitalization after LTx, such as age, sex mismatch, and ethnicity [26].

Previous studies have demonstrated that in critically ill patients, even after apparent complete recovery, AKI is associated with an elevated mortality risk [22,27]. However, conflicting findings have also been reported [8,28,29]. In a study conducted by Kellum et al. the status of AKI recovery (early reversal, relapse, or no reversal) upon hospital discharge was associated with long-term mortality among 16,968 critically ill patients [30]. Similarly, Peerapornratana et al. reported that the recovery of AKI in 29,726 critically ill patients at hospital discharge has an impact on long-term mortality for up to 15 years [31]. Our findings also suggest that only severe subtypes of AKI (persistent AKI and AKI stage 3) consistently have a detrimental effect on long-term mortality in LTx patients since there was no statistically significant difference in survival rates between the No-AKI group and the AKI stage 1 group. To further support our findings, we conducted a literature review summarizing the results of published studies in the LTx population and confirmed our findings (Supplementary Table S3): patients with severe stages of AKI or persistent AKI or those requiring renal replacement therapy had poorer survival outcomes, regardless of the definition of AKI.

In testing risk factors for P7-AKI, we identified several rarely reported characteristics that differ from the risk factors reported in previous studies. We discovered a positive correlation between higher BMI and increased AKI risk. Obesity can significantly alter renal hemodynamics, leading to elevated renal plasma flow and potentially resulting in a higher filtration rate or high filtration syndrome, thereby increasing susceptibility to renal injury [32]. Similar to our previous findings, a lower preoperative SCr was found to be associated with P7-AKI [2]. The SCr levels in our study population ranged from 27.7 to 100.7 μmol/L, which generally fell within the normal range (35–106 μmol/L), indicating that our patients had normal renal function prior to surgery. We hypothesize that owing to the small baseline value, even minor fluctuations can lead to the classification of patients with lower preoperative SCr as having AKI.

In our study, intraoperative colloid administration had a protective effect on the incidence of AKI. However, it is worth noting that while albumin has been reported to decrease the occurrence of AKI, a review summarizing published studies suggested that there are no significant differences in renal function between the use of albumin and crystalloids [33]. Furthermore, anemia has been recognized as a risk factor for AKI; however, we observed that a higher hemoglobin level is associated with an increased risk for AKI in our LTx population [34]. Prior studies conducted in mice have shown the renal proinflammatory effects of heme proteins and hem [35,36]. Additionally, intravascular hemolysis, which causes the release of free hemoglobin, can lead to AKI [37]. These inconsistencies in data suggest that reported risk factors may be influenced by bias and residual confounding variables in retrospective studies. Therefore, further research is warranted to elucidate the true role of these factors in AKI incidence and explore potential underlying mechanisms.

The ultimate goal of identifying risk factors for AKI is to improve prognosis. It is crucial to recognize AKI promptly and implement preventive measures to limit its occurrence and progression, thereby reducing morbidity and mortality rates. These preventive measures may involve avoiding nephrotoxic substances, utilizing specific biomarkers for assessing risk or early damage, managing perioperative fluid balance, and potentially implementing e-alert systems for AKI if necessary [35]. For example, a comprehensive study demonstrated that the implementation of a renal care bundle in the cardiac ICU led to improved patient outcomes [38]. Given the high incidence of AKI after LTx, it is imperative to consider all available therapeutic regimens aimed at supporting renal function.

Our study has several limitations. First, male patients constituted more than 80% of the total sample, resulting in an imbalanced sex ratio. Therefore, caution should be exercised when these findings are generalized to populations with a more equitable gender distribution. Second, given that this was a retrospective study conducted over a substantial time period, there were instances where data from certain patients were missing during the collection process of electronic medical records. For example, the retrieval of some intraoperative data was not possible, potentially impacting subsequent results analysis.

In conclusion, the current study presented the prevalence of different AKI subtypes and compared their impact on prognosis after LTx. The incidence rates of AKI, P7-AKI and P14-AKI were 77.1%, 46.2% and 34.1%, respectively. Our findings demonstrate that P7-AKI could serve as an appropriate indicator for predicting clinical outcomes in the LTx population. P7-AKI was strongly correlated with respiratory outcomes, such as prolonged ECMO and ventilator days, as well as extended intensive care unit (ICU) stays and both short- and long-term mortality rates. Identifying an appropriate AKI subtype is essential for healthcare providers in risk stratification and improved prognosis of LTx patients.

Supplementary Material

Supplementary files.docx

Disclosure statement

No potential conflict of interest was reported by the author(s).
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