Association between the levels of urinary cell cycle biomarkers and non-recovery of renal function among critically ill geriatric patients with acute kidney injury

Figures & data

Figure 1. The flow chart of this study. AKI: acute kidney injury; ICU: intensive care unit.

Table 1. Clinical characteristics of older adults with acute kidney injury in intensive care units.

Variables	Renal recovery (n = 117)	Renal non-recovery (n = 92)	p Value
Baseline characteristics
Age (years)	72 (72, 76)	73 (72, 75)	0.804
Age groups (n, %)
60–74 (years)	67 (57.3)	54 (58.7)	0.835
≥ 75 (years)	50 (42.7)	38 (41.3)	0.835
Female sex (n, %)	44 (37.6)	39 (42.4)	0.483
BMI (kg/m^2)	23.7 (18.5, 33.1)	23.5 (14.8, 20.1)	0.304
Parameter at the time of AKI diagnosis
MAP (mmHg)	89 (86, 93)	70 (69, 77)	<0.001
HR (beats/min)	89 (89, 97)	95 (92, 103)	0.118
Disease severity
APACHE II score	17 (15, 17)	22 (20, 24)	<0.001
Nonrenal SOFA score	4 (3, 4)	5 (5, 6)	0.001
Comorbidities (n, %)
Hypertension	66 (56.4)	60 (65.2)	0.196
Diabetes	31 (26.5)	34 (37.0)	0.105
Cardiovascular disease	33 (28.2)	36 (39.1)	0.095
COPD	15 (12.8)	18 (19.6)	0.184
Cerebrovascular disease	21 (17.9)	17 (18.5)	0.922
Chronic liver disease	16 (13.7)	8 (8.7)	0.262
Etiology of AKI (n, %)
Surgery	78 (66.7)	34 (37.0)	<0.001
Infections	29 (26.5)	37 (40.2)	0.036
Cardiovascular events	6 (5.1)	17 (18.5)	0.002
Hypovolemia	2 (1.7)	3 (3.3)	0.656
Nephrotoxicity drugs	2 (1.7)	1 (1.1)	1.000
Vasopressor requirement (n, %)	25 (21.4)	36 (39.1)	0.005
Mechanical ventilation (n, %)	97 (82.9)	73 (79.3)	0.512
Renal replacement therapy in ICUs (n, %)	11 (9.4)	26 (28.3)	<0.001
Serum lactate (mmol/L)	1.6 (2.0, 3.0)	2.1 (2.9, 4.8)	0.014
PaO2/FiO2 ratio	298.0 (290.0, 348.5)	217.5 (216.4, 283.7)	<0.001
Use of diuretics within 24 h of AKI diagnosis (n, %)	8 (6.8)	6 (6.5)	0.928
Baseline serum creatinine (µmol/L)	66.9 (65.4, 70.8)	71.2 (68.6, 74.5)	0.100
Baseline BUN (mmol/L)	8.2 (9.0, 11.1)	10.6 (10.1, 12.5)	0.082
Serum creatinine at the time of AKI diagnosis (µmol/L)	115.5 (122.6, 169.9)	172.5 (185.7, 277.1)	<0.001
AKI severity (n, %)			<0.001
Stage 1	82 (70.1)	25 (27.2)
Stage 2	29 (24.8)	42 (45.7)
Stage 3	6 (5.1)	25 (27.2)
Urinary [TIMP-2]*[IGFBP7] ((ng/mL)^2)/1000	0.2 (0.4, 0.8)	1.3 (2.3, 3.8)	0.000
Mechanical ventilation (hours)	19.0 (50.0, 91.7)	45.0 (78.8, 143.1)	0.017
Length of stay (days)
ICU	6 (8, 11)	8 (9, 13)	0.029
Hospital	19 (19, 22)	23 (24, 35)	0.041
Mortality (n, %)
In-hospital	17 (14.5)	25 (27.2)	0.024
30-day	17 (14.5)	27 (29.3)	0.009

Abbreviations: AKI: acute kidney injury; APACHE II: acute physiology and chronic health evaluation; BMI: body mass index; BUN: blood urea nitrogen; HR: heart rate; ICU: intensive care unit; COPD: chronic obstructive pulmonary disease; IGFBP7: insulin-like growth factor-binding protein 7; MAP: mean arterial pressure; SOFA: sequential organ failure assessment; TIMP-2: tissue inhibitor of metalloproteinases-2.

Figure 2. Survival curve analysis stratified by renal recovery status.

Table 2. Risk factors associated with renal non-recovery among participants.

Variables	Univariate			Multivariable
	OR	95% CI	p Value	OR	95% CI	p Value
Surgery	3.231	0.000–	1.000
Infections	0.821	0.072–9.371	0.874
Cardiovascular disease	2.552	0.220–29.546	0.453
[TIMP-2]*[IGFBP7]	1.682	1.348–2.099	< 0.001	1.747	1.350–2.261	< 0.001
APACHE II score	1.110	1.065–1.157	< 0.001	1.056	1.007–1.108	0.028
Nonrenal SOFA score	1.116	1.033–1.205	0.005
Lactate	1.120	1.023–1.227	0.014
PaO2/FiO2 ratio	0.997	0.995–0.999	0.003
Vasopressor requirement	2.366	1.287–4.349	0.006
AKI Stages 2–3	6.279	3.424–11.513	< 0.001	5.954	2.827–12.544	<0.001
Renal replacement therapy requirement in ICUs	4.003	1.861–8.611	< 0.001

Abbreviations: AKI: acute kidney injury; APACHE II: acute physiology and chronic health evaluation; IGFBP7: insulin-like growth factor-binding protein 7; MAP: mean arterial pressure; TIMP-2: tissue inhibitor of metalloproteinases-2; SOFA: sequential organ failure assessment.

Figure 3. The predictive value of urinary biomarkers and the associated model. The ROC curves of urinary [TIMP-2]*[IGFBP7] and the associated model for predicting renal non-recovery from AKI. The AUC of using urinary [TIMP-2]*[IGFBP7] only, clinical prediction model only, and the [TIMP-2]*[IGFBP7] combined with clinical prediction model. ROC: receiver operating characteristic; AUC: area under the ROC.

Table 3. Biomarkers and combination models for predicting non-recovery from AKI.

Variables	AUC (95% CI)	Cutoff	Sensibility % (95% CI)	Specificity % (95% CI)	p Value
Urinary [TIMP-2]*[IGFBP7] ((ng/ml)^2)/1000	0.774 (0.711–0.829)	0.81	62.0 (52.1–71.9)	83.8 (75.8–89.9)	< 0.001
Clinical model	0.771 (0.708–0.826)	0.31	83.7 (74.5–90.6)	63.3 (53.8–72.0)	< 0.001
Urinary [TIMP-2]*[IGFBP7] combined with clinical model	0.851 (0.795–0.896)	0.50	72.8 (62.6–81.6)	84.6 (76.8–90.6)	< 0.001

Note: Clinical model consists of the presence of AKI stages 2 to 3 and APACHE II score.

Abbreviations: AKI: acute kidney injury; AUC: area under the receiver operating characteristic; CI: confidence interval; IGFBP7: insulin-like growth factor-binding protein 7; TIMP-2: tissue inhibitor of metalloproteinases-2.

Figure 4. The predictive value of biomarkers for 30-day mortality. The ROC curves of urinary [TIMP-2]*[IGFBP7] for predicting 30-day mortality after AKI. ROC: receiver operating characteristic; AUC: area under the ROC.

Figure 5. Kaplan-Meier survival curves according to the cutoff value. Survival analysis regarding 30-day mortality using the Kaplan-Meier technique according to the cutoff value. (a) Survival curves of participants with urinary [TIMP-2]*[IGFBP7] ≥ 0.81 and those with < 0.81. (b) Survival curves of participants with high urinary [TIMP-2]*[IGFBP7] and high clinical risk model (≥ 0.50) and those with low clinical risk (< 0.50).

Data availability statement

All data generated and/or analyzed during this study are included in this published article.