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10.1080/0886022X.2024.2392844
2392844
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Research Article
Acute Kidney Injury
Early goal-directed renal replacement therapy in severe pneumonia associated acute kidney injury
A. Yusufu et al.
Early Gdrrt in Severe Pneumonia Associated Acute Kidney Injury
Yusufu Abuduxiukuer a*
Xie Yeqing a*
Shi Yanting b*
Jiang Wuhua a
Hu Jiachang a
Lv Wenlv a
Ding Xiaoqiang ab
Teng Jie ab
Shen Bo a
Bi Jing c
Zou Jianzhou a
Xu Jiarui a
a Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai Medical Center of Kidney, Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China
b Department of Nephrology, Xiamen Branch, Zhongshan Hospital, Fudan University, Nephrology Clinical Quality Control Center of Xiamen, Xiamen, Fujian, China
c Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
* Abuduxiukuer Yusufu, Yanting Shi, and Yeqing Xie contributed equally to this article.

Supplemental data for this article can be accessed online at https://doi.org/10.1080/0886022X.2024.2392844.

CONTACT Jiarui Xu xu.jiarui@zs-hospital.sh.cn
Jianzhou Zou zou.jianzhou@zs-hospital.sh.cn Division of Nephrology, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Xuhui District, Shanghai 200032, China
Jing Bi bi.jing@zs-hospital.sh.cn Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Xuhui District, Shanghai 200032, China
4 9 2024
2024
4 9 2024
46 2 239284410 12 2023
8 8 2024
10 8 2024
KnowledgeWorks Global Ltd.30 8 2024
published online in a building issue31 8 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

Introduction

Severe pneumonia is a crucial issue in the development of acute kidney injury (AKI). This study evaluated the efficacy of early goal-directed renal replacement therapy (GDRRT) for the treatment of severe pneumonia-associated AKI.

Methods

In this real-world retrospective cohort study, we recruited 180 patients with severe pneumonia who were hospitalized and received GDRRT in a third-class general hospital in East China between January 1, 2017, and December 31, 2021. Clinical data on baseline characteristics, biochemical indicators, and renal replacement therapy were collected. Patients were divided into Early and Late RRT groups according to fluid status, inflammation progression, and pulmonary radiology. We investigated in-hospital all-cause mortality (primary endpoint) and renal recovery (secondary endpoint) between the two groups.

Results

Among the 154 recruited patients, 80 and 74 were in the early and late RRT groups, respectively. There were no significant differences in the demographic characteristics between the two groups. The duration of admission to RRT initiation was significantly shorter in Early RRT group [2.5(1.0, 8.7) d vs. 5.0(1.5,13.5) d, p = 0.027]. At RRT initiation, the patients in the Early RRT group displayed a lower percentage of fluid overload, lower doses of vasoactive agents, higher CRP levels, and higher rates of radiographic progression than those in the Late RRT group. The all-cause in-hospital mortality was significantly lower in the Early RRT group than in Late group (52.5% vs. 86.5%, p < 0.001). Patients in the Early RRT group displayed a significantly higher proportion of complete renal recovery at discharge (40.0% vs. 8.1%, p < 0.001).

Conclusion

This study clarified that early GDRRT for the treatment of severe pneumonia-associated AKI based on fluid status and inflammation progression, was associated with reduced hospital mortality and better recovery of renal function. Our preliminary study suggests that early initiation of RRT may be an effective approach for severe pneumonia-associated AKI.

Keywords

Acute kidney injury
severe pneumonia
renal replacement therapy (RRT)
prognosis
Ethical Committee of Zhongshan Hospital affiliated to Fudan University B2018-175 Shanghai Federation of Nephrology Project SHDC2202230 Shanghai ‘science and technology innovation plan’ Technical Standard Project 19DZ2205600 Shanghai Shenkang Hospital Development Center Clinical Science and Technology Innovation Project SHDC12021608 This article was supported by grants from the Shanghai Federation of Nephrology Project supported by the Shanghai Shenkang Hospital Development Center (SHDC2202230); Shanghai ‘science and technology innovation plan’ Technical Standard Project (19DZ2205600) and Shanghai Shenkang Hospital Development Center Clinical Science and Technology Innovation Project (SHDC12021608).
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pmcIntroduction

Acute kidney injury (AKI) is common in hospitalized patients with community-acquired pneumonia (CAP), and results in increased mortality. Previous studies have indicated that approximately 20% of the patients with severe pneumonia develop AKI [1,2]. Recent reports have shown that the incidence of AKI can be as high as 40.9% in patients with severe pneumonia caused by COVID-19 in the intensive care unit (ICU) [3]. Therefore, it is crucial to develop a reliable approach to improve the prognosis of patients with severe pneumonia-associated AKI.

Renal replacement therapy (RRT) is a common treatment option in patients with severe pneumonia-associated AKI. However, the optimal timing for RRT initiation remains controversial [4]. The ELAIN randomized clinical trial showed that among critically ill patients with AKI, early RRT, compared with delayed initiation of RRT, reduced mortality over the first 90 days [5]. Previous studies conducted at our hospital have showed that preemptive RRT was associated with lower hospital mortality and faster and more complete recovery of renal function than standard RRT [6,7] which may benefit from the accelerated achievement of euvolemia, removal of inflammatory mediators, and correction of electrolyte imbalance.

In this study, early GDRRT was compared with late RRT to explore the timing of RRT in patients with pneumonia-associated AKI.

Methods

Study design and patient selection

This was a real-world study based on the medical record system of hospitalized patients who were diagnosed with severe pulmonary infection from January 1, 2017, to December 31, 2021, in a third-class general hospital in East China. The inclusion criteria were as follows: age > 18 years, diagnosis of severe pneumonia, and receipt of RRT treatment during hospitalization. Patients were excluded if they were < 18 years old, underwent maintenance hemodialysis or renal transplantation, had a hospital stay of < 24 h, had no serum creatinine (SCr) test, or had other severely missing biochemical tests. This study was approved by the institutional committee of our hospital.

Definition

AKI was defined according to the 2012 KDIGO guideline [8] as any of the following: an increase in SCr ≥ 0.3 mg/dL (≥ 26.5 μmol/L) within 48 h; or an increase in SCr to ≥ 1.5 times the baseline that is known or presumed to have occurred within the prior 7 days; urine volume of < 0.5 mL/kg/hour for 6 h and staged according to the SCr and urine output. Severe AKI was defined as KDIGO stage 2 or 3.

High dose of vasoactive agents was a definition which refer to: norepinephrine >0.4 µg/kg/min or epinephrine >0.2 µg/kg/min or epinephrine + (norepinephrine/2) >0.2 µg/kg/min or need for at least 3 vasoactive drugs.

The definitions of Early and Late RRT are presented in Table 1. If the patients met at least two of the items of the Early RRT shown in Table 1, they were assigned to the Early group; if patients met at least one of the items of the Late RRT, they were assigned to the Late group; if patients had characteristics of both groups, we allocated them to the Late group.

Table 1. Definition of early and late RRT.

 	Early RRT	Late RRT	
Basic renal function	CKD stage ≥3	 	
Fluid status	SCr criteria for AKI 1–2 stage;
UO ≤0.5 mL/kg/h ≥6 h;
PFO > 1%;
Mild to moderate pulmonary edema	Scr criteria for AKI 3 stage;
UO ≤0.3 mL/kg/h ≥24 h or anuria ≥12h;
Multiple cavity effusion; Congestive heart failure;
Severe pulmonary edema or refractory hypoxemia	
Inflammation	PCT ≥3 or CRP ≥90	 	
Radiology	Radiographic progression within 72h after treatment	 	
Metabolism	 	Serum potassium ≥6.5 mmol/L or severe metallic acidosis, pH ≤7.2	
Hemodynamics	 	Persistent hypotension with high dose vasoactive drugs: [norepinephrine >0.4 µg/kg/min, epinephrine >0.2 µg/kg/min or epinephrine + (norepinephrine/2) >0.2 µg/kg/min]	
Note: Scr, serum creatinine; AKI, acute kidney injury; UO, urine output; PFO, percent fluid overload; CRP, C-reactive protein; PCT, procalcitonin.

Pulmonary infection was diagnosed according to 2018 pneumonia guidelines [9], with typical clinical symptoms and signs as follows: temperature > 38.0 °C; recent onset of cough, sputum, or dyspnea; peripheral white blood cell count < 4 × 109/L or > 10 × 109/L; dry and wet rales or sputum rales can be heard from lung auscultation, and meet one of the following conditions: chest X-ray examination or CT has invasive lung inflammatory, or sputum or tracheobronchial secretion culture positive. Patients with one major criterion or ≥ 3 minor criteria were considered severe pneumonia [10]. These criteria are listed in Table 2. The percent fluid overload (PFO) = [total fluid input (L) − total fluid output (L)]/basal weight (kg) ×100% [11]. Chest radiography is important for assessing the severity of pulmonary edema.

Table 2. Infectious diseases society of America/American thoracic society criteria for defining severe community-acquired pneumonia.

Major criteria	
 Septic shock with need for vasopressors	
 Respiratory failure requiring mechanical ventilation	
Minor criteria	
 Respiratory rate ≥ 30 breaths/min	
 PaO2/FiO2 ratio ≤ 250	
 Multilobar infiltrates	
 Confusion/disorientation	
 Uremia (blood urea nitrogen level ≥ 20 mg/dl)	
 Leukopenia* (white blood cell count < 4,000 cells/μl)	
 Thrombocytopenia (platelet count < 100,000/μl)
 Hypothermia (core temperature < 36 °C)	
 Hypotension requiring aggressive fluid resuscitation	

Complete renal recovery was defined as an increase in the SCr level at discharge to within 25% of the baseline SCr level. Partial renal recovery was defined as failure to meet the criteria for complete renal recovery. No recovery was defined as SCr at discharge ≥ maximum SCr level during AKI episode, or a requirement for RRT [12,13].

All the RRT procedures were performed with Gambro Prisma with membranes made of polyacrylonitrile (1.5 m2 surface area, GAMBRO, Sweden). The blood flow was delivered from 150 mL/min to 180 mL/min. The majority modality was CVVHDF, with convective dose ≥ 35 mL/kg/h (rate of pre vs post dilution was about 4:1) and diffusion dose 20 ∼ 25 mL/kg/h. The ultrafiltration rate varied from 100 mL/h to 300 mL/h according to the hemodynamics of the patients. Anticoagulation was performed mostly with low doses of heparin.

We used GDRRT, which has been used to treat patients with AKI at our center since 2008. GDRRT comprises different modalities, including hemodialysis, hemofiltration, hemodiafiltration, and pure ultrafiltration. The goals of the GDRRT, which mainly involve metabolism, volume, and coagulation, are established at RRT initiation and evaluated every 6h during the RRT session. The modality, dose, duration, and frequency were adjusted according to the demand and tolerance of the patients to achieve their goals [14].

Data collection

Demographic characteristics, including age, sex, height, weight, and comorbidities (hypertension, diabetes mellitus, coronary heart disease, stroke, chronic kidney disease, and malignancy) were collected from the electronic medical record system.

The biochemical data of the patients within 24h of admission were collected as baseline variables, including renal function: blood urea (BUN), SCr, and uric acid; liver function: total bilirubin and direct bilirubin; electrolytes: blood sodium, potassium, chloride, calcium, magnesium, phosphorus, and CO2; Blood gas analysis: pH, partial pressure of CO2, O2, HCO3-, and base excess; and other biochemical data: white blood cell, B-type natriuretic peptide, C-reactive protein, procalcitonin, and albumin.

The primary endpoint was in-hospital all-cause mortality. Secondary endpoints included length of hospital stay and renal outcomes.

Statistical analysis

Statistical analyses were performed using SPSS version 24.0. The data of normal distribution is described by mean ± standard deviation, and the data of skew distribution is described by the median and interquartile range and was compared by Student t-test and Wilcoxon test. Categorical variables were described by frequency and compared using Pearson’s test. Cox regression was used to analyze the variables. All statistical tests were two-tailed, and statistical significance was set at p < 0.05.

Results

Baseline characteristics

Of the 180 hospitalized patients diagnosed with pneumonia and received RRT, 154 met the inclusion criteria and were enrolled (Figure 1). The mean age was 70 ± 13 years, 112 (72.7%) were male, and 127 (82.5%) were community-acquired pneumonia. Among them, 80 and 74 patients were included in the early and late RRT groups, respectively. Basic demographic data, including age, sex, body mass index, and comorbidities, including hypertension, malignancy, gastrointestinal bleeding, and coronary heart disease, showed no statistical significance between the two groups. The proportion of diabetes was significantly higher in the Early RRT group than in the Late-RRT group (52.5% vs. 29.7%, p = 0.004). Regarding echocardiography, there were no statistically significant differences in the diameters of the left atrium, ventricle, or pulmonary arterial pressure. The left ventricular ejection fraction of Early RRT group was significantly lower than in Late RRT group (56 ± 9 vs. 60 ± 9, p = 0.038). (Table 3).

Figure 1. Flow chart of the study.

Table 3. Baseline characteristics of the Early and Late RRT groups.

 	All (n = 154)	Early RRT (n = 80)	Late RRT (n = 74)	Statistics (U/χ2)	P	
Demographic characteristics	
 Age, year	70 ± 13	70 ± 12	70 ± 14	t= 0.097	0.923	
 Male, n (%)	112 (72.7)	56 (70)	56 (75.7)	χ2 = 0.624	0.429	
 BMI, kg/m2	22.86 [20.87, 25.89]	22.86 [21.06, 25.63]	23.76 [20.40, 26.31]	U = 1740	0.784	
 CAP, n (%)	127 (82.5)	69 (86.2)	58 (78.4)	χ2 = 1.647	0.199	
Comorbidities	
 Hypertension, n (%)	96 (62.3)	50 (62.5)	46 (62.2)	χ2 = 0.002	0.966	
 Diabetes, n (%)	64 (41.6)	42 (52.5)	22 (29.7)	χ2 = 8.206	0.004	
 CKD, n (%)	18 (11.7)	8(10)	10(13.5)	χ2 = 0.460	0.498	
 Malignancy, n (%)	38 (24.7)	18 (22.5)	20 (27.1)	χ2 = 0.424	0.515	
 Gastrointestinal bleeding, n (%)	36 (23.4)	16 (20.0)	20 (27.1)	χ2 = 1.060	0.303	
 Coronary heart disease, n (%)	38 (24.7)	20 (25.0)	18 (24.3)	χ2 = 0.009	0.923	
Echocardiography data	
 LVEF (%)	58 ± 9	56 ± 9	60 ± 9	t= −3.022	0.038	
 LAD, mm	38 ± 7	39 ± 8	37 ± 7	t= 0.394	0.344	
 LVEDD, mm	47 ± 5	47 ± 4	46 ± 5	t= 0.282	0.779	
 LVESD, mm	32 ± 5	33 ± 5	31 ± 6	t= 0.097	0.232	
 PAP, mmHg	37 ± 10	36 ± 7	39 ± 12	t= −1.909	0.059	
Laboratory indexes	
 BUN (mmol/L)	17 [10, 27]	17 [12, 28]	17 [8, 27]	U = 2252	0.106	
 SCr (µmol/L)	140 [90, 283]	140 [90, 283]	142 [81, 315]	U = 2492	0.922	
 eGFR (ml/min/1.73m2)	37 [15, 62]	39 [14, 74]	40 [16, 86]	U = 2956	0.988	
 Albumin (g/L)	30.99 ± 5.245	30.78 ± 5.88	31.22 ± 4.456	t= −0.488	0.626	
 Total bilirubin (µmol/L)	10 [6, 24]	10 [6, 28]	10 [7, 24]	U = 1950	0.701	
 Direct bilirubin (µmol/L)	6 [3, 13]	6 [3, 12]	6 [4, 14]	U = 1808	0.805	
Note: CAP, community-acquired pneumonia; BMI, body mass index; LVEF, left ventricular ejection fraction; LAD, left atrial diameter; LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter; PAP, pulmonary arterial pressure; BUN, blood urea nitrogen; Scr, serum creatinine; eGFR, estimated glomerular filtration rate.

Comparison at the initiation of RRT between the two groups

The duration of admission to RRT initiation was significantly shorter in Early RRT group than in Late RRT group [2.5(1.0, 8.7) d vs. 5.0(1.5,13.5) d, p = 0.027]. There were no significant differences in urinary output and SCr levels at RRT initiation between the two groups. The patients in Early RRT group displayed a lower level of BUN [26(16, 35) mmol/L vs. 30(23,39) mmol/L, p = 0.026], lower PFO [2(1, 3)% vs. 3(1,4)%, p < 0.001], and lower proportion of high dose of vasoactive agents(10.0% vs. 35.1%, p < 0.001) than in Late RRT group. There were no significant differences in the respiratory support mode, oxygenation index, or APACHE II score between the two groups. The patients in Early RRT group showed a higher rate of radiographic progression (60.0% vs 24.3%, p = 0.001) and higher CRP [91.6 (57.5, 176.1) mg/L vs. 83.3(39.4,129.1) mg/L, p = 0.050] than those in the Late RRT group. (Table 4).

Table 4. Comparison of clinical data at RRT initiation between the two groups.

 	All (n = 154)	Early RRT (n = 80)	Late RRT (n = 74)	Statistics (U/χ2)	P	
APACHE II score	19 ± 6	18 ± 6	20 ± 7	t= −0.55	0.583	
Duration between admission to RRT initiation (d)	4.0 [1.0, 11.5]	2.5 [1.0, 8.7]	5.0 [1.5, 13.5]	U = 2366	0.027	
RRT session	8.5 [4.5, 15.5]	8.5 [4.0, 14.5]	9.0 [4.5, 16.0]	U = 3426	0.235	
Average RRT duration per
session (h)	17 ± 6	17 ± 7	18 ± 5	t= −0.62	0.535	
Average ultrafiltration removal (ml/d)	2630 ± 790	2510 ± 760	2840 ± 830	t= −3.62	0.176	
Average RRT dose (ml/kg/h)	64 ± 20	64 ± 18	65 ± 22	t= −0.22	0.824	
Renal function	
 Urinary output, (mL/24h)	700 [300, 1200]	700 [350, 1300]	735 [223, 1025]	U = 1542	0.446	
 BUN, (mmol/L)	30 [20, 37]	26[ 16, 35]	30 [23, 39]	U = 2282	0.026	
 SCr, (umol/L)	238 [155, 366]	229 [142, 358]	250 [184, 376]	U = 2484	0.138	
AKI stage	 	 	 	χ2 = 96.53	<0.001	
 1	50 (32.5%)	44 (55.0%)	6 (8.1%)	 	 	
 2	51 (33.1%)	29 (36.2%)	22 (29.7%)	 	 	
 3	53 (34.4%)	7 (8.8%)	46 (62.2%)	 	 	
Hemodynamics	
 PFO, (%)	2 [1, 4]	2 [1, 3]	3 [1, 4]	U = 3948	<0.001	
 High dose of vasoactive agents, (%)	34 (22.1)	8 (10.0)	26 (35.1)	χ2 = 21.32	<0.001	
 Lactic acid, (mmol/L)	3.16 [1.70, 6.29]	2.95 [1.59, 5.35]	4.87 [1.70, 7.86]	U = 508	0.402	
 BNP	7112 [2703, 13735]	7572 [2988, 19173]	6480 [2347, 13319]	U = 6800	0.080	
Respiratory support (n, %)	152 (98.7)	78 (97.5)	74 (100)	χ2 = 2.64	0.497	
 NPPV	20 (13.2)	8 (10.3)	12 (16.2)	 	 	
 High-flow	0	0	0	 	 	
 Tracheal intubation	132 (86.8)	70 (89.7)	62 (83.8)	 	 	
CT/X-ray (n, %)	 	 	 	 	 	
 Exudative lesions in lung	148 (96.1)	74 (92.5)	74 (100)	χ2 = 8.08	0.029	
 Radiographic progression	66 (42.9)	48 (60.0)	18 (24.3)	χ2 = 19.98	<0.001	
Oxygenation index (mmHg)	133.50 ± 57.01	139.18 ± 60.86	126.88 ± 51.99	t = 1.098	0.275	
Inflammatory indicators	
 WBC, (109/L)	13.57 ± 8.85	13.37 ± 8.86	13.78 ± 8.89	t= −0.28	0.780	
 Platelet, (109/L)	126 [90, 192]	131 [93, 192]	120 [75, 192]	U = 2448	0.586	
 CRP (mg/L)	90.0 [42.8, 141.0]	91.6 [57.5, 176.1]	83.3 [39.4, 129.1]	U = 1584	0.050	
 PCT (ng/ml)	3.2 [1.1, 6.8]	3.3 [0.9, 6.5]	2.9 [1.2, 12.8]	U = 1960	0.526	
Arterial blood gas	
 PH	7.35 ± 0.09	7.36 ± 0.08	7.33 ± 0.11	t = 1.65	0.102	
 PO2(kPa)	89 [73, 111]	82 [71, 100]	98 [74, 139]	U = 1534	0.007	
 PCO2(kPa)	42 [32, 52]	42 [32, 51]	41 [32, 54]	U = 1968	0.938	
 HCO3-(mmol/L)	23.26 ± 5.93	23.83 ± 6.84	22.61 ± 4.84	t = 1.17	0.245	
 Base excess (mmol/L)	−2.39 [−5.75, 1.35]	−1.8 [−5.75, 1.73]	−2.39 [−5.95, 0.87]	U = 1712	0.897	
Electrolyte	
 Sodium (mmol/L)	142.77 ± 7.60	142.21 ± 7.52	143.47 ± 7.69	t= −0.986	0.326	
 Potassium (mmol/L)	4.45 ± 0.74	4.30 ± 0.69	4.66 ± 0.77	t= −2.85	0.005	
 Chlorine (mmol/L)	100.90 ± 12.68	101.86 ± 6.38	99.84 ± 17.11	t = 0.89	0.378	
Note: RRT, renal replacement therapy; BUN, blood urea nitrogen; Scr, serum creatinine; PFO, percent fluid overload; BNP, B type natriuretic peptide; CRP, C-reactive protein; PCT, procalcitonin; NPPV, noninvasive positive pressure ventilation; WBC, white blood cell; PO2: oxygen partial pressure; PCO2: carbon dioxide partial pressure; HCO3-: Bicarbonate ion.

Changes within 120 h after RRT initiation

There was a trend of decreasing SCr levels in the Early RRT group throughout the first 120 h after RRT initiation, whereas there were few changes in the Late RRT group. The CRP levels decreased significantly after RRT in the Early RRT group, with fewer changes in the Late RRT group. Changes in the doses of norepinephrine and vasopressin showed no distinct differences. The patients in Early RRT group displayed a lower PFO than in Late RRT group (Figure 2).

Figure 2. Evolution of hemodynamic parameters over time. Error bars are standard deviation. The asterisk (*) indicate p < 0.05, compared with 0 h.

Primary and secondary outcomes

The all-cause in-hospital mortality was significantly lower in the Early RRT group than in the Late RRT group (52.5% vs. 86.5%; p < 0.001). Kaplan-Meier curves for in-hospital mortality in the two groups are shown in Figure 3 (log-rank test, p < 0.001). Patients in the Early RRT group had a significantly higher proportion of complete renal recovery (40.0% vs. 8.1%, p < 0.001). Fewer patients in the Early RRT group had no renal recovery (50.0% vs. 83.8%, p < 0.001). There were no significant differences in the length of hospital stay between the two groups [22.5(13.2,33.0) d vs. 18.0(7.0,28.5) d, p = 0.203]. Patients in Early RRT group showed significantly lower SCr [125(78,204) μmol/L vs. 193(120,297) μmol/L, p = 0.002] and BUN [16(10,27) mmol/L vs. 26(10,32) mmol/L, p = 0.012] levels, and higher urinary output [430(55,1275) mL vs. 150(30,400) mL, p = 0.013] at discharge than those in Late RRT group (Table 5).

Figure 3. Kaplan-Meier Curves for in-hospital mortality.

Table 5. Comparison of clinical outcomes between the two groups.

 	Early RRT (n = 80)	Late RRT (n = 74)	Statistics (U/χ2)	P	
Primary end point	
All-cause of in-hospital mortality, n (%)	42(52.5)	64(86.5)	χ2 = 20.69	<0.001	
Secondary end point	
Kidney recovery, n (%)	 	 	χ2 = 22.62	<0.001	
Complete recovery	32(40.0)	6(8.1)	 	
Partial recovery	8(10.0)	6(8.1)	 	
No recovery	40(50.0)	62(83.8)	 	
Kidney function (discharge)	
Urinary output, (mL)	430 [55, 1275]	150 [30, 400]	U = 1856	0.013	
SCr, (μmol/L)	125 [78, 204]	193 [120, 297]	U = 2116	0.002	
BUN, (mmol/L)	16 [10, 27]	26 [10, 32]	U = 2268	0.012	
Inflammatory indicators (RRT weaning)	
CRP	47 [19.6, 127.08]	80.7 [46.1, 130.73]	U = 2378	0.035	
PCT	2.79 [0.67, 6.95]	2.58 [0.99, 15.12]	U = 2640	0.247	
Length of hospital stay (d)	22.5 [13.2, 33.0]	18.0 [7.0, 28.5]	U = 2360	0.203	
Note: BUN, blood urea nitrogen; Scr, serum creatinine; CRP, C-reactive protein; PCT, procalcitonin.

In the univariate Cox proportional hazards regression model, late initiation of RRT, radiographic progression of lung, high-dose vasoactive agents, PFO and renal recovery at discharge were significantly associated with worse in-hospital mortality. Further analysis using the forward multivariate Cox proportional hazards regression model revealed the significance between late initiation of RRT and in hospital mortality (Table 6).

Table 6. COX Analysis of risk factors for in-hospital mortality in patients with severe pneumonia-associated AKI.

 	Univariate	Multivariate	
HR (95%CI)	P	HR (95%CI)	P	
Late CRRT	1.81 (1.22–2.69)	0.003	2.08 (1.36–3.18)	0.001	
Male (male/female)	1.07 (0.69–1.66)	0.769	 	 	
Age	1.01 (0.99–1.02)	0.327	 	 	
AKI stage	1.39 (0.86–2.24)	0.183	 	 	
Diabetes	1.15 (0.77–1.71)	0.489	 	 	
Radiographic progression of lung	0.69 (0.46–1.04)	0.035	 	 	
High dose of vasoactive agents	2.03 (0.46–1.04)	0.001	1.72 (1.09–2.70)	0.019	
eGFR (ml/min/1.73m2)	1.00 (0.99–1.00)	0.835	 	 	
CRP (mg/L)	1.00 (1.00–1.00)	0.772	 	 	
PFO (%)	1.13 (0.98–1.30)	0.040	 	 	
Renal recovery	1.98 (1.96–2.00)	0.031	1.97 (1.95–1.99)	0.006	

Discussion

This study demonstrated that the in-hospital mortality of AKI patients with severe pneumonia in the Early RRT group was lower than that in the Late RRT group. Moreover, kidney recovery was much better in the early RRT group, and urine volume was notably higher than that in the Late RRT group, suggesting the superiority of the early RRT strategy in the treatment of pneumonia-associated AKI.

The optimal timing for RRT initiation remains debatable. Several trials on RRT initiation strategies have been published, and three largest trials (AKIKI, IDEAL-ICU, and ELAIN) [5,15,16] showed contradictory results. The ELAIN trial revealed that early initiation of RRT reduced in-hospital mortality compared to delayed RRT; AKIKI and IDEAL-ICU demonstrated no significant difference in mortality between early and late initiation of RRT. As the supplementary Table 1 shows, in large RCTs the criteria are often based on AKI staging, or days from hospital admission, and often included heterogeneous populations and diversity in RRT procedures in different clinical settings. Considering AKI associated with different diseases was characterized by distinct pathophysiological mechanisms. For example, AKI associated with heart failure is mainly influenced by hemodynamic and neuroendocrine factors, while AKI after major surgery is influenced by ischemic-reperfusion. In sepsis-associated AKI, infections and the inflammatory cascade was the major cause, and in the development of severe pneumonia, the lung-kidney crosstalk plays a crucial role (e.g. diuresis may alleviate pulmonary edema but could worsen prerenal AKI; sodium bicarbonate could correct acidosis but may increase CO2 accumulation). Therefore, our team has been dedicated to conduct serial studies to develop precise and individualized RRT strategies targeting for different diseases. Based on our previous findings, combined AKI severity with evaluation of fluid balance, hemodynamics status and metabolic disorders, we have found the optimal timing for patients after cardiac surgery or acute heart failure. Also in this study, we combined AKI severity with the mechanisms of lung-kidney crosstalk, including inflammatory status, assessments of pulmonary edema et al. to refine the optimal RRT timing for patients with severe pneumonia, aim to target the RRT treatment for this population in clinical settings.

In the present study, there may be two main explanations for the reduced in-hospital mortality. First, the PFO at RRT initiation was significantly lower in the Early RRT group than in the Late RRT group. We believe that this was because of the early initiation of RRT, which subsequently achieved fluid balance so that the Early group did not experience much volume overload. Numerous studies have confirmed the correlation between volume overload and poor prognosis, which prompts the choice of PFO as a significant indicator of early RRT. Therefore, the early initiation of RRT leads to better fluid balance, which may lead to better outcomes and renal recovery. Second, the present study demonstrated a trend of decreasing SCr and CRP levels and dependence on high doses of the vasoactive agent in the Early RRT group throughout the first 120 h after RRT initiation, which illustrates that earlier RRT also contributes to stabilizing metabolism, hemodynamics, and inflammation status, which may be helpful for kidney recovery and improved outcomes.

The present study showed that the complete renal recovery rate was significantly higher, and the SCr level at discharge was lower in the Early RRT group. Our potential explanation for this result is that there were more patients with AKI stages 1 and 2 in the Early RRT group at the initiation of RRT, which made better renal recovery possible. After RRT was initiated, diuretics were still used, and when urine output increased, discontinuation of GDRRT was considered. A previous study demonstrated that the use of diuretics during CRRT was related to successful CRRT discontinuation [17]. Furthermore, GDRRT has been widely applied at our center since 2008 and has been demonstrated to be effective in improving kidney outcomes and reducing the time and cost of RRT in critically ill patients [18].

This study had some limitations. As this was a single-center retrospective cohort study, the sample size was small. Data collection might have led to selection bias, and there was no validation in the multicenter cohort. Furthermore, more variables can be included, such as Kirby and oxygenation indices, to assess the severity of lung damage, as well as to include more ventilatory parameters and determine whether patients require lung protection strategies. Therefore, a multicenter prospective cohort study is needed to better elucidate the early RRT strategies for patients with pneumonia-associated AKI.

Conclusion

The present study demonstrates that early GDRRT for the treatment of patients with severe pneumonia-associated AKI is associated with a higher survival rate and better renal recovery. Our study suggests that early initiation of GDRRT is an effective approach in patients with severe pneumonia-associated AKI. Future studies on patients with severe pneumonia-associated AKI are needed to determine the optimal timing of RRT and unify the definitions.

Supplementary Material

Supplementary Table 1.docx

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Figure c.jpeg

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Author contributions

Abuduxiukuer Yusufu and Yanting Shi performed the literature search, performed the analysis, and drafted the manuscript. Yeqing Xie, Wuhua Jiang, and Jiachang Hu helped to collect the data and helped to do the revision. Jiarui Xu, Jianzhou Zou, Jing Bi, Yeqing Xie, and Xiao-qiang Ding conceived the idea and participated in manuscript writing and revision. Bo Shen, Wenlv Lv, and Jie Teng helped to revise the manuscript. All authors have read and approved the final manuscript.

Disclosure statement

The authors declare that they have no conflicts.

Ethics approval and consent to participate

This study was approved by the Ethical Committee of Zhongshan Hospital affiliated to Fudan University (No. B2018-175). All enrolled participants provided written informed consent in accordance with the World Medical Association Declaration of Helsinki.

Data availability statement

Data is not publicly available due to ethical reasons. Further enquiries can be directed to the corresponding author via email (xu.jiarui@zs-hospital.sh.cn).
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