Combination of Renal Biomarkers Predicts Acute Kidney Injury in Critically Ill Adults

Figures & data

Figure 1.  Study flowchart.

Notes: ESRD was defined according to KDIGO (CKD–MBD) Work Group definition: eGFR < 15 mL/h or hemodialysis.¹⁷ Chronic kidney diseases included glomerulonephritis, interstitial renal disease, and obstructive uropathy. AKI, acute kidney injury; ESRD, end-stage renal disease; ICU, intensive care unit; HDU, high-dependency unit.

Figure 2.  Receiver-operating characteristic (ROC) curves of the individual biomarkers and the two best combinations of them.

Notes: pNGAL, plasma neutrophil gelatinase-associated lipocalin; pCysC, plasma cystatin; uNGAL, urine neutrophil gelatinase-associated lipocalin; sCr, serum creatinine; AUC, area under curve. Open circle indicates the ideal cut-off point of each curve, according to the Youden’s index.²¹

Table 1.  Patient’s admission characteristics, renal parameters, and outcomes.

	No AKI (n = 64)		AKI (n = 36)		p-Value
Demographics
Age (years)	49	[35.0–66.3]	63	[50.3–80.8]	0.004
Gender (male)	34	(53.1)	23	(63.9)	0.40
Comorbidities
DM	9	(14.1)	6	(16.7)	0.77
Hypertension	20	(31.3)	10	(27.8)	0.82
CAD	5	(7.8)	7	(19.4)	0.11
COPD	4	(6.3)	3	(8.3)	0.70
HF	2	(3.1)	4	(11.1)	0.18
Cancer	16	(25.0)	9	(25.0)	1.0
Patient type
Medical	28	(43.8)	19	(52.8)	0.41
Elective surgery	14	(21.9)	3	(8.3)	0.10
Emergency surgery	19	(29.7)	12	(33.3)	0.82
Admission diagnosis
Neurologic	32	(50.0)	12	(33.3)	0.14
Respiratory	12	(18.8)	12	(33.3)	0.14
Cardiovascular	2	(3.1)	3	(8.3)	0.35
Polytrauma	8	(12.5)	6	(16.7)	0.56
Neurotrauma	9	(14.1)	3	(8.3)	0.53
Gastrointestinal	5	(7.8)	4	(11.1)	0.72
Admisson parameters
APACHE II (mean SD)	13.9	(5.6)	16.8	(5.2)	0.012
SOFA (mean SD)	6.2	(2.6)	7.2	(3.2)	0.206
SAPS III (mean SD)	54.2	(12.1)	64.6	(14.2)	0.000
INR	1.1	[1.1–1.2]	1.3	[1.1–1.5]	0.01
Glucose (mg/dL)	130	[112.0–168.0]	160.5	[125.5–205.5]	0.004
CRP (mg/L)	5.7	[2.8–15.9]	13.0	[3.4–22.8]	0.117
Lactate (mg/L)	1.3	[0.9–2.3]	1.7	[1.0–2.7]	0.185
WBC (×10^3/μL)	11.8	[9.5–15.3]	13.8	[11.4–20.9]	0.017
Nephrotoxic agents (pre-admission exposure)
Diuretics	3	(4.7)	2	(5.6)	1.0
Antibiotics	20	(31.3)	9	(25.0)	0.64
Contrasts	12	(18.8)	8	(22.2)	0.80
Chemotherapy	1	(1.6)	4	(11.1)	0.055
Shock	11	(17.2)	13	(36.1)	0.050
Baseline renal parameters
sCr (mg/dL)	0.7	[0.6–0.8]	0.8	[0.6–1.0]	0.016
eGFR (mL/min/1.73 m^2)	116.7	[88.7–138.4]	88.2	[68.3–125.1]	0.02
Admission renal parameters
sCr (mg/dL)	0.7	[0.5–0.8]	1.0	[0.7–1.3]	0.000
pUrea (mg/dL)	32.5	[22.0–44.5]	55.5	[40.0–90.8]	0.000
pNGAL (ng/mL)	60.0	[60.0–61.0]	152	[60.0–245.0]	0.000
uNGAL (ng/mL)	29.8	[7.3–80.7]	106.8	[61.0–343.6]	0.000
pCysC (mg/L)	0.8	[0.6–1.0]	1.3	[0.8–1.8]	0.000
Outcome
ICU mortality	12	(18.8)	21	(58.3)	0.000
RRT need (during ICU stay)	0	(0.0)	10	(27.8)	0.000
Sepsis (within first week)	23	(35.9)	17	(47.2)	0.29
ICU-LOS (days)	15.0	[6.3–23.8]	16.0	[11.3–31.0]	0.052
MV duration (days)	12.5	[4.0–20.0]	15.0	[9.3–27.8]	0.093

Notes: Values are expressed as n (%) or median [IQR], unless otherwise noted. Baseline eGFR was calculated according to MDRD equation.²⁵ AKI, acute kidney injury; IQR, interquartile range; DM, diabetes mellitus; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; HF, heart failure; APACHE, acute physiology and chronic health evaluation; SOFA, sequential organ failure assessment; SAPS III, simplified acute physiology score; INR, international normalized ratio; CRP, C-reactive protein; WBC, white blood cell count; eGFR, estimated glomerular filtration rate; sCr, serum creatinine; pUrea, plasma urea; pNGAL, plasma neutrophil gelatinase-associated lipocalin; uNGAL, urine neutrophil gelatinase-associated lipocalin; pCysC, plasma cystatin C; RRT, renal replacement therapy; LOS, length of stay; MV, mechanical ventilation.

Table 2.  Predictive performance of each individual biomarker and all their possible combinations for AKI development within 7 days post-admission.

Logistic regressionmodel	p-Value in the model	AUC	95% CI
Univariate models
pNGAL	0.0001	0.777	0.68–0.85
pCysC	0.0001	0.750	0.65–0.83
uNGAL	0.0003	0.743	0.64–0.82
sCr	0.0001	0.765	0.67–0.84
Multivariate models
pNGAL	0.0005	0.799	0.71–0.87
+pCysC	0.034
pNGAL	0.0002	0.814	0.72–0.88
+uNGAL	0.36
pNGAL	0.0001	0.823	0.73–0.89*
+sCr	0.0016
pCysC	0.0037	0.759	0.66–0.84
+uNGAL	0.13
pCysC	0.043	0.776	0.68–0.85
+sCr	0.015
uNGAL	0.014	0.805	0.71–0.87
+sCr	0.0005
pNGAL	0.0013	0.801	0.71–0.87
+pCysC	0.053
+uNGAL	0.85
pNGAL	0.0004	0.821	0.73–0.89
+pCysC	0.76
+sCr	0.012
pNGAL	0.0012	0.835	0.75–0.90*
+uNGAL	0.54
+sCr	0.0019
pCysC	0.29	0.807	0.71–0.88
+uNGAL	0.065
+sCr	0.008
pNGAL	0.0016	0.822	0.74–0.90
+pCysC	0.89
+uNGAL	0.58
+sCr	0.010

Notes: AKI, acute kidney injury; AUC, area under curve; CI, confidence interval; pNGAL, plasma neutrophil gelatinase-associated lipocalin; pCysC, plasma cystatin C; uNGAL, urine neutrophil gelatinase-associated lipocalin; sCr, serum creatinine. *p < 0.05 versus sCr_AUC, according to the test of DeLong et al.²⁰ for AUCs comparison.

Table 3.  Formula for fitted multiple logistic regression model for combining biomarkers.

For AKI (n = 36) vs. no AKI (64) combined
pNGAL, sCr	−9.1131 + 4.5981 × log10 pNGAL + 4.8566 × log10 sCr
pNGAL, uNGAL, sCr	−8.9421 + 4.2611 × log10 pNGAL + 0.2758 × log10 uNGAL + 4.7366 × log10 sCr

Note: AKI, acute kidney injury; pNGAL, plasma neutrophil gelatinase-associated lipocalin; pCysC, plasma cystatin C; uNGAL, urine neutrophil gelatinase-associated lipocalin; sCr, serum creatinine.

Table 4.  Predictive characteristics of admission biomarkers and their combinations for AKI development within 7 days post admission.

Variable	Cut-off ^a	Sn	(95% CI)	Sp	(95% CI)	(+) LR	(95% CI)	(−) LR	(95% CI)	PPV	(95% CI)	NPV	95% CI
pNGAL	62 ng/mL	72.2	(54.8–85.8)	78.1	(66.0–87.5)	3.3	(2.6–4.2)	0.36	(0.2–0.7)	65.0	(48.3–79.4)	83.3	71.5–91.7
pCysC	1.04 mg/L	61.1	(43.5–76.9)	81.2	(69.5–89.9)	3.2	(2.4–4.3)	0.48	(0.2–0.9)	64.7	(46.5–80.3)	78.8	67.0–87.9
uNGAL	58.5 ng/mL	77.8	(60.8–89.9)	71.8	(59.2–82.4)	2.7	(2.2–3.5)	0.31	(0.1–0.6)	60.9	(45.4–74.9)	85.2	72.9–93.4
sCr	0.86 mg/dL	72.2	(54.8–85.8)	79.7	(67.8–88.7)	3.5	(2.8–4.5)	0.35	(0.2–0.7)	66.7	(49.8–80.9)	83.6	71.9–91.8
pNGAL, +sCr	0.52^b	63.9	(46.2–79.2)	96.9	(89.2–99.6)	20.4	(15.9–26.2)	0.37	(0.09–1.6)	92.0	(74.0–99.0)	82.7	72.2–90.4
pNGAL, +uNGAL, +sCr	0.42^b	69.4	(51.9–83.7)	89.0	(78.8–95.5)	6.3	(5.0–8.0)	0.34	(0.1–0.8)	78.1	(59.7–90.9)	83.8	72.9–91.6

Notes: AKI, acute kidney injury; pNGAL, plasma neutrophil gelatinase-associated lipocalin; pCysC, plasma cystatin C; uNGAL, urine neutrophil gelatinase-associated lipocalin; sCr, serum creatinine; AUC, area under curve; CI, confidence interval; Sn, sensitivity; Sp, specificity; (+) LR, positive likelihood ratio; (−) LR, negative likelihood ratio; PPV, positive predictive value; NPV, negative predictive value.

^aIdeal cut-off value according to Youden’s index.

^bPredictive probability of the multivariate logistic regression model.

Table 5.  Category-free NRI and IDI of including biomarkers and their combinations in the risk factor model to predict AKI development within 7 days post-admission.

Reference clinical model	Added marker or combination	p-Value in the model	AUC	ΔAUC	p-Value vs. clinical model^a	NRI (SE), p-value (total)	NRI (SE), p-value (in AKI patients)	NRI (SE), p-value (in no AKI patients)	IDI (SE), p-value
SAPS III + INR AUC: 0.756 95% CI: 0.66–0.83	pNGAL	0.0002	0.852	0.097	0.03	0.78 (0.208), 0.0002	0.16 (0.167), 0.31	0.62 (0.125), 0.0001	0.16 (0.045), 0.0004
	pCysC	0.01	0.786	0.03	0.40	0.45 (0.208), 0.031	0.11 (0.167), 0.51	0.34 (0.125), 0.006	0.056 (0.028), 0.049
	uNGAL	0.058	0.781	0.025	0.37	0.38 (0.208), 0.068	0.16 (0.167), 0.31	0.22 (0.125), 0.08	0.032 (0.018), 0.09
	sCr	0.002	0.816	0.06	0.13	0.28 (0.208), 0.18	0.0 (0.167), 1.0	0.28 (0.125), 0.025	0.10 (0.034), 0.003
	pNGAL	0.0008	0.858	0.102	0.04	0.78 (0.208), 0.0002	0.22 (0.167), 0.18	0.56 (0.125), 0.0001	0.23 (0.051), 0.0001
	+sCr	0.01
	pNGAL	0.002	0.858	0.102	0.04	0.78 (0.208), 0.0002	0.22 (0.167), 0.18	0.56 (0.125), 0.0001	0.23 (0.051), 0.0001
	+uNGAL	0.98
	+sCr	0.01

Notes: NRI, net reclassification improvement; IDI, integrated discrimination improvement; SE, standard error; AKI, acute kidney injury; AUC, area under curve; CI, confidence interval; ΔAUC, difference in AUCs between the model including the added marker or combination and the reference clinical model; SAPS III, simplified acute physiology score III; INR, international normalized ratio; pNGAL, plasma neutrophil gelatinase-associated lipocalin; uNGAL, urine neutrophil gelatinase-associated lipocalin; pCysC, plasma cystatin C; sCr, serum creatinine

^aAccording to the method of DeLong et al.²⁰ for AUCs comparison.

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