The combination of kidney function variables with cell cycle arrest biomarkers identifies distinct subphenotypes of sepsis-associated acute kidney injury: a post-hoc analysis (the PHENAKI study)

Figures & data

Table 1. Characteristics of the study population.

Characteristics	Total cohort (n = 184)	Subphenotype A (n = 99)	Subphenotype B (n = 74)	Subphenotype C (n = 11)	^ap Value
Age (years)	69 [58–79]	67 [55– 77]	72 [62– 82]	63 [53–71]	0.024
Male sex	122 (66)	65 (66)	50 (68)	7 (64)	>0.9
Comorbidities
Hypertension	93 (66)	42 (42)	45 (61)	6 (55)	0.1
Diabetes mellitus	51 (28)	24 (24)	25 (34)	2 (18)	0.3
NYHA class III–IV chronic heart failure	15 (8)	7 (7)	8 (11)	0 (0)	0.5
Stage 3 chronic kidney disease	27 (15)	3 (3)	23 (31)	1(9)	<0.001
Prior e-GFR (mL/min per 1.73 m^2)	77 [72– 98]	86 [76– 118]	73 [52– 78]	77 [69–122]	<0.001
Renin–angiotensin system inhibitor	67 (37)	29 (30)	37 (50)	1 (9.1)	0.003
Chemotherapy	25 (14)	16 (16)	7 (9)	2 (18)	0.4
Source of admission to the ICU					0.4
The emergency department	82 (45)	44 (44)	31 (42)	7 (64)
Direct admission to the ICU	30 (16)	19 (19)	10 (13)	1 (9)
A hospital ward	48 (26)	26 (26)	19 (26)	3 (27)
Transfer from another hospital	24 (13)	10 (10)	14 (19)	0
Etiology/site of sepsis
Admission for a nonsurgical condition	168 (91)	94 (95)	64 (86)	10 (91)	0.13
Lung	105 (57)	63 (64)	36 (49)	6 (55)	0.14
Urinary tract	22 (12)	11 (11)	9 (12)	2 (18)	0.8
Abdomen	37 (20)	16 (16)	18 (24)	3 (27)	0.3
Soft tissue	15 (8)	7 (7)	7 (9)	1 (9)	0.7
Documented pathogen	112 (61)	54 (55)	51 (69)	7 (64)	0.14
Organ failure
Lactate concentration on inclusion (mmol/L)	2.00 [1.40–3.50]	1.90 [1.35–2.90]	2.50 [1.50–3.90]	4.10 [2.60–6.80]	0.009
SOFA score at inclusion	10 [8–12]	9 [7–11]	11 [9–12]	13 [11–16]	<0.001
Nonrenal SOFA score	8 [7–10]	8 [6–10]	8 [7–10]	11 [9–12]	0.014
SAPS II	55 [42–69]	48 [39–61]	60 [50–75]	64 [48–79]	<0.001
Mechanical ventilation	101 (55)	53 (54)	44 (59)	4 (36)	0.3
Norepinephrine dose (µg/kg/min) at 0 h	0.37 [0.20–0.75]	0.33 [0.20–0.68]	0.41 [0.18–0.70]	0.45 [0.20–2.00]	0.4
Dobutamine support over the first 24 h	17 (9.2)	5 (5)	9 (12)	3 (27)	0.031
Fluid administered over the first 24 h (ml/kg)	31 [15–52]	25 [14–45]	36 [17–59]	68 [32–80]	0.006
Kidney function on inclusion
Serum creatinine level (µmol/L)	150 [112–216]	118 [93–150]	216 [170–281]	127 [108–189]	<0.001
Serum blood urea nitrogen (mmol/L)	14 [9–19]	11 [8–15]	19 [14–25]	14 [10–15]	<0.001
Urine output (mL/kg)	0.86 [0.39–1.90]	1.21 [0.58–2.92]	0.56 [0.24–1.20]	0.30 [0.16–0.49]	<0.001
[TIMP–2]*[IGFBP7] at 0 h ([ng/mL]^2/1000)	1.26 [0.26–4.00]	0.75 [0.18–1.87]	2.11 [0.41–5.89]	6.37 [4.19–14.80]	<0.001
KDIGO status					<0.001
Stage 1 AKI (mild)	94 (51)	65 (66)	25 (34)	4 (36)
Stage 2 AKI (moderate)	55 (30)	26 (26)	22 (30)	7 (64)
Stage 3 AKI (severe)	35 (19)	8 (8.1)	27 (36)	0 (0)
Urine variables at 6 h
Urine output (ml/kg/h)	0.59 [0.27–1.09]	0.86 [0.54–1.74]	0.33 [0.20–0.68]	0.25 [0.09–0.31]	<0.001
[TIMP–2]*[IGFBP7] ([ng/mL]^2/1000)	0.71 [0.22–2.86]	0.37 [0.11–1.34]	1.43 [0.41–4.32]	13.80 [9.28–31.34]	<0.001
Urine variables at 12 h
Urine output (ml/kg/h)	0.68 [0.35–1.27]	0.96 [0.61–1.54]	0.40 [0.17– 0.86]	0.20 [0.05–0.36]	<0.001
[TIMP–2]*[IGFBP7] ([ng/mL]^2/1000)	0.50 [0.19–1.59]	0.29 [0.12–0.82]	0.82 [0.28–2.08]	10.45 [3.88–19.61]	<0.001
Kidney function at 24 h
Urine output (ml/kg/h)	0.72 [0.34–1.32]	1.06 [0.64–1.82]	0.47 [0.20–0.97]	0.05 [0.00–0.26]	<0.001
[TIMP–2]*[IGFBP7] ([ng/mL]^2/1000)	0.46 [0.16–1.18]	0.34 [0.13–0.99]	0.52 [0.22–1.20]	11.27 [5.28–22.05]	<0.001
Serum creatinine level (µmol/L)*	123 [88–181]	88 [72–115]	183 [156–255]	189 [159–228]	<0.001
KDIGO status					<0.001
Complete recovery	57 (32)	52 (54)	5 (7)	0 (0)
Stage 1 AKI (mild)	47 (27)	28 (29)	18 (26)	1 (11)
Stage 2 AKI (moderate)	31 (18)	14 (14)	16 (23)	1 (11)
Stage 3 AKI (severe)	41 (23)	3 (3)	31 (44)	7 (78)
Initiation of RRT within the first 24 h	19 (10)	1(1)	14 (19)	3 (27)	<0.001
Outcome
Death related to the initial septic shock	45 (24)	13 (13)	25 (34)	7 (63)	<0.001
In-hospital death	68 (37)	24 (24)	35 (47)	9 (82)	<0.001

Data are quoted as the median [interquartile range] or n ().

^aKruskal–Wallis rank sum test; Fisher’s exact test; Pearson’s chi-squared test.

AKI: acute kidney injury; eGFR: estimated glomerular filtration rate; NYHA: New York Heart Association; RRT, renal replacement therapy; SOFA: Sequential Organ Failure Assessment; SAPS II: Simplified Acute Physiology Score.

^aKruskal–Wallis rank sum test; Fisher’s exact test; Pearson’s chi-squared test.

*Excluding patients on renal replacement therapy at 24 h.

Figure 1. Cluster identification. The upper figure shows the hierarchical clustering dendrogram with three clusters. The lower figure shows the factor map from the principal component analysis. Each individual is represented by label, depending on the cluster: a green circle (subphenotype A), a blue triangle (subphentopye B), or a red square (subphenotype C).

Figure 2. Vtest graph, showing the variables that contribute to the different subphenotypes. The Vtest graph characterizes the groups in terms of the variables whose average is lower or higher than in the total sample. Each bar represents the distance (in multiples of the standard deviation) between the within-class mean value and the total cohort mean value. TIMP-2: tissue inhibitor of metalloproteinases-2; IGFBP-7: insulin-like growth factor-binding protein 7; SCr: serum creatinine; eGFR: estimated glomerular filtration rate.

Figure 3. Proportions of patients with in-hospital death, renal replacement therapy initiation, and reversible AKI in the different subphenotype groups.

Figure 4. Crude composite in-hospital survival (no death or RRT initiation) curve for the different subphenotypes.

Figure 5. Adjusted composite in-hospital survival (no death or RRT initiation) curve for the different subphenotypes. With subphenotype A as the reference, the adjusted hazard ratio (aHR) [95%CI] for the composite in-hospital survival was 3.77 [1.92–7.42] (p < 0.001) for subphenotype B and 4.80 [1.67–13.82] (p = 0.004) for subphenotype C. Adjusted for age, renin–angiotensin system inhibitors, the nonrenal SOFA score at inclusion, lactate at inclusion, SAPS II, dobutamine support over the first 24 h, and fluid administered over the first 24 h.