Prognostic Biomarkers and AKI: Potential to Enhance the Identification of Post-Operative Patients at Risk of Loss of Renal Function

Figures & data

Table 1 Adapted KDIGO Criteria for AKI Diagnosis

Functional Criteria	AKI Stage	Damage Criteria
No change or SCr level increase <0.3 mg/dL and no UO criteria	1S	Biomarker Positive
Increase of sCr level by ≥0.3 mg/dL for <48 h or ≥150% for <7 days and/or UO <0.5 mL/kg/hr for >6 hr	1A	Biomarker Negative
	1B	Biomarker Positive
Increase of SCr level by >200% and/or UO <0.5 mL/kg/hr for > 12 hr	2A	Biomarker Negative
	2B	Biomarker Positive
Increase of SCr level bv >300% (24.0 mg/dL with an acute increase of ≥0.5 mg/dL) and/or UO <0.3 mL/kg/h for >24 h or anuria for >12 hr and/or acute RRT	3A	Biomarker Negative
	3B	Biomarker Positive

Notes: Functional markers include serum creatinine (SCr) and urine output (UO), but new functional markers may also be included. To convert sCr to millimoles per liter, multiply by 88.4. RRT indicates renal replacement therapy.

Figure 1 Outline of the results from the EPIS-AKI trial.^{4 a}Percentage of patients undergoing that surgery type who developed PO-AKI. ^bPatients who developed PO-AKI after 72 h and were therefore classified in the “No PO-AKI” group and received RRT (Renal Replacement Therapy).

Figure 2 Biomarkers of AKI implicated in PO-AKI.

Abbreviations: DKK-3, dickkopf-3; suPAR, soluble urokinase plasminogen activator receptor; IGFBP-7, insulin growth factor binding protein-7; TIMP-2, tissue inhibitor of metalloproteinases −2; PENK, proenkephalin A 119–159; NGAL, neutrophil gelatinase-associated lipocalin; KIM-1, kidney injury molecule-1; FABP, fatty acid binding protein; IL-18, interleukin 18.

Table 2 Significant Papers Investigating Biomarkers of AKI in Surgical Patients

Biomarker	Reference	Population	AKI Criteria	n	nAKI	Biomarker time	AUC	Cut-off	Comments
uNGAL	Nisula, Finland 2014^Citation23	Emergency ICU patients	KDIGO, UO and SCr	1042	379	ICU admission, 12/24 hours	0.733	157ng/mL	Sub analysis of septic patients, AUC 0.690
uNGAL, sNGAL	Mishra, USA 2005^Citation24	Paediatric, cardiac surgery	KDIGO, SCr only	71	20	2 hourly for 14 hours, 12 hourly	uNGAL 1.00 (4 hours), sNGAL 0.906 (2 hours)	25mcg/l 50mcg/l	Cut-offs chosen for optimum sensitivity and specificity
uNGAL	Siew, USA 2009^Citation25	Medical and surgical ICU	AKIN, SCr only	451	86	< 24 hours of ICU admission	0.71 (AKI at 12 hours)	N/A	AKI at 48 hours AUC 0.64
pNGAL, uNGAL	Bagshaw, Australia 2010^Citation26	Medical and surgical ICU	RIFLE (not specified)	83	83	12/24/48 hours	pNGAL 0.71, uNGAL 0.70	150/280 ng/mL	Assessing AKI progression. pNGAL septic AKI 0.77, non-septic 0.70.
pNGAL, uNGAL	Koyner, USA 2012^Citation27	Adults, cardiac surgery	AKIN, SCr only	1219	426	First day of AKI diagnosis	uNGAL 0.58, pNGAL 0.74 (unadjusted)	uNGAL - 141 ng/mL, pNGAL - 322 ng/mL	Assessing AKI progression, not AKI
uNGAL	Au, USA 2016^Citation28	Adults, mixed surgical population	AKIN, SCr only	510	17	Within 2–3 hours of admission to recovery	0.738 (0.851 for sustained AKI)	12.52ng/mL	Assessing prediction of sustained vs transient AKI
IGFBP-7/TIMP-2	Kashani, USA 2013^Citation29	Adults, medical and surgical ICU, high risk for AKI	KDIGO, stage 2 or 3, SCr and UO	728	101 / 218	<18 hours from enrolment	0.8	0.3/2 (moderate / high risk)	AKI assessed ‘within 12 hours of sample’. 101 AKI at 12 hours, 218 at 7 days
IGFBP-7/TIMP-2	Gunnerson, USA 2016^Citation30	Mixed surgical cohort	KDIGO, stage 2 or 3, SCr and UO	375	35	<18 hours from enrolment	0.84	0.3/2 (moderate / high risk)	AKI assessment as above
IGFBP-7/TIMP-2	Gocze, Germany 2015^Citation31	Adults, non-cardiac surgery, high risk for AKI	KDIGO, SCr only, within 48 hours of admission	107	45	4 hours post ICU admission after surgery	0.853 (all AKI), 0.848 (stage 2 and 3)	0.315	Included transplant, vascular patients
IGFBP-7/TIMP-2	Meersch, Germany 2014^Citation32	Paediatric, cardiac surgery	pRIFLE (↓ creatinine clearance), within 72 hours	51	12	Before, 4- and 24-hours post op	0.85	0.7	Paper also compared NGAL (0.87) and KIM-1 (0.64).
KIM-1	Koyner, USA 2010^Citation33	Adults, undergoing CPB	AKIN, unclear if using UO	123	46	Enrolment, induction, post op, ICU admission, 6 hours post admission	0.66 at 6 hours, 0.82 pre-operatively	Not provided	Also assessed Cys C - 0.64, uNGAL - 0.72
KIM-1	Nickolas, USA 2012^Citation34	Unselected Emergency Department patients	RIFLE, SCr only	1635	96	On presentation to ED	0.71	Upper - 2.817, Lower - 1.665	AUC specifically for Intrinsic AKI 0.81
KIM-1	Han, USA 2008^Citation35	Adults, cardiac surgery	AKIN, SCr only	90	36	Pre and postop, 3, 18, 24 hours postop	0.65 (at 3h)	1.2ng/mg, 1.8ng/mg	uNGAL - 0.65 at 3 hours
DKK-3	Schunk, Germany 2019^Citation36	Adults, cardiac surgery	KDIGO (UO/SCr)	733	193	preop	0.783	471 pg/mg creatinine	Assessing DKK: creatinine ratio

Figure 3 Outline of stages in the patient journey, preoperative, perioperative and postoperative where biomarkers could be employed.

Abbreviations: DKK-3, Dickkopf-3; suPAR, soluble urokinase plasminogen activator receptor; IGFBP-7, insulin growth factor binding protein-7; TIMP-2, tissue inhibitor of metalloproteinases −2; PENK, proenkephalin A 119–159; NGAL, neutrophil gelatinase-associated lipocalin; KIM-1, kidney injury molecule-1; FABP, fatty acid binding protein; IL-18, interleukin 18; CCL14, chemokine 14.

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