Current role of biomarkers in the initiation and weaning of kidney replacement therapy in acute kidney injury

Table 1 Kidney biomarkers of practical utility KRT in AKI

Kidney biomarker	Biological role	Sample	Type of marker	Role in KRT practice	Limitations	Advantages
NGAL	At least 3 different types. Monomeric: 25-kDa glycoprotein produced by neutrophils and epithelial tissues, including tubular cells. Homodimeric: 45-kDa protein produced by neutrophils. Heterodimeric: 135-kDa protein produced by tubular cells	Urine and plasma	Damage	Predicting need for KRT with high sensitivity and specificity. Mortality in patients on KRT. Prediction of successful weaning from KRT: Not assuring	Confounding factors: Sepsis, malignancy, CKD, urinary tract infection, pancreatitis, chronic obstructive pulmonary disease, endometrial hyperplasia.	As urinary NGAL is not removed via CVVHDF, serial measurement is a real-time indicator of kidney damage
CyC	13-kDa cysteine protease inhibitor produced by nucleated human cells; freely filtered	Plasma and urine (plasma CyC: May be a marker of GFR. Urine CyC: Marker of Tubular injury)	Functional	Controversial results on the diagnostic ability for the need for KRT. Independent predictor of successful weaning from continuous KRT in AKI	Lack of specific cutoff values	Less likely to be affected by CVVHDF
PenKid	5-kDa stable fragment of endogenous opioid enkephalin	Plasma	Functional	Reliably predict AKI and need for KRT in patients with sepsis. Low pre-KRT penKid levels: Predict successful, earlier termination of KRT	Confounded by age, sex, inflammatory state, diabetes, low albumin, muscle mass, high-dose steroids	Potential to dynamically guide kidney function, prior and during ongoing KRT: Thus facilitates early and successful termination of KRT
TIMP-2 × IGFBP7	Metalloproteinases released during tubular cell cycle arrest (cell cycle arrest biomarker)	Urine	Stress	TIMP-2: More predictive of need for KRT in septic AKI patients. IGFBP-7: Performs better in surgical patients; Combined predictive ability: Better than individual biomarkers	Elevated in diabetes
suPAR	A multifaceted, glycosylphosphatidylinositol-anchored three domain protein acting as a receptor for urokinase-type plasminogen activator	Plasma	Functional	Levels at intensive care unit admission: Promising in predicting AKI progression to KRT	Since neutrophils can serve as a major source, elevated levels occur in inflammatory conditions, acute respiratory distress syndrome or different cancers. Confounding factors: CKD, polycystic kidney disease, liver disease, sepsis
FABP	Low molecular weight proteins of 14–15 kDa, belonging to lipid-binding proteins superfamily. Nine types identified: FABP-1 expressed in the proximal tubular cells; FABP-3 in the distal tubular cells	Urine and plasma	Damage	A positive prediction of KRT with use of urinary FABP-1 and FABP-3 levels	Validation of the cutoff value required. Associated with anemia in nondiabetic patients
KIM-1	Transmembrane glycoprotein produced by proximal tubular cell; released into urine after tubular cell damage; no systemic source	Urine	Damage	A good predictability for the need for KRT	Elevated in kidney cell carcinoma, chronic proteinuria, CKD, sickle cell nephropathy
Mid-regional pro-adrenomedullin	A 52 amino acid peptide with natriuretic and vasodilatory properties, and antimicrobial activity	Plasma	Damage	Prediction of requirement of KRT in children with coronavirus disease 2019 and AKI	Paucity of literature

AKI: Acute kidney injury; KRT: Kidney replacement therapy; NGAL: Neutrophil gelatinase-associated lipocalin; CKD: Chronic kidney disease; CVVHDF: Continuous veno-venous hemodiafiltration; GFR: Glomerular filtration rate; TIMP-2: Tissue inhibitor of metalloproteinase-2; IGFBP7: Insulin-like growth factor-binding protein 7; suPAR: Soluble urokinase plasminogen activator receptor; FABP: Fatty acid-binding proteins; KIM-1: Kidney injury molecule 1; PenKid: Proenkephalin 119–159.

Table 2 Summary of studies on role of biomarkers for initiation of kidney replacement therapy

Ref.	Biomarker studied	Type of study	No. of patients	AUROC (95%CI)	Cutoff	Sensitivity (95%CI)	Specificity (95%CI)	Positive predictive value (95%CI)	Negative predictive value (95%CI)
Klein et al[5]	Urine output	Meta-analysis	604	0.614 (0.389-0.840)
Klein et al[5]	Fractional excretion of sodium	Meta-analysis	240	0.718 (0.619-0.816)
Klein et al[5]	Blood urea nitrogen	Meta-analysis	283	0.732 (0.661-0.802)
Klein et al[5]	Plasma/serum Cr	Meta-analysis	2969	0.764 (0.732-0.796)
Hjortrup et al[6]	Plasma Cr	Prospective	222	0.74 (0.67–0.82)	166	63	75	36	90
Pipili et al[7]	UNGAL	Prospective	310	0.727	106.7			66	86
Klein et al[5]	UNGAL	Meta-analysis	3195	0.720 (0.638-0.803)
Klein et al[5]	PNGAL/SNGAL/whole-blood NGAL	Meta-analysis	4391	0.755 (0.706–0.803)
Tiranathanagul et al[8]	PNGAL	Prospective	47	0.813 (0.66-0.90)	960	72.2	9.6	81.25	83.8
Tiranathanagul et al[8]	UNGAL	Prospective	47	0.806 (0.63-0.98)	2600	54.5	90.9
Haase et al[9]	PNGAL/UNGAL	Meta-analysis	2538	0.782 (0.648-0.917)	278.3 (141.9-381.6)	76.0 (65.1-84.4)	80.3 (59.5-91.9)
Cruz et al[10]	PNGAL	Prospective	301	0.82 (0.70-0.95)	150	0.87 (0.60–0.98)	0.65 (0.60–0.71)	0.12 (0.06–0.19)	0.99 (0.96–1.00)
Cemil et al[11]	PNGAL	Prospective	60	0.84 (0.74-0.94)	615	82	80
Nisula et al[12]	UNGAL	Prospective	1042	0.839 (0.797-0.880)	449	83.1	78.5	30	90
Hjortrup et al[6]	PNGAL	Prospective	211	0.70 (0.61-0.78)	641	69	64	28	88
Hjortrup et al[6]	UNGAL	Prospective	162	0.62 (0.51-0.73)	641	46	77
Hanson et al[13]	UNGAL	Prospectivecohort–acute falciparum malaria	163	0.68 (0.55-0.80)	1832
Lukasz et al[14]	SNGAL	Prospective Cohort-Shiga toxin	39	0.76 (0.61-0.91)	330	83.3	60	76.9	69.2
Senthilkumaran et al[15]	PNGAL	Prospective and Russell’s Viper bite	309	1.0	493.75	98	100	79	98
Albert et al[16]	UNGAL	Meta-analysis	5454	0.74 (0.66–0.82)	83	78	67

AUROC: Area under the receiver operating characteristic curve; CI: Confidence interval; Cr: Creatinine; PNGAL: Plasma neutrophil gelatinase-associated lipocalin; SNGAL: Serum neutrophil gelatinase-associated lipocalin; UNGAL: Urinary neutrophil gelatinase-associated lipocalin.

Table 3 Summary of studies on role of biomarkers for weaning of KRT

Ref.	Biomarker studied	Type of study	No. of patients	AUROC (95%CI)	Cutoff	Sensitivity (95%CI)	Specificity (95%CI)
Chen et al[52]	SNGAL	Prospective	110	0.81	403	91	61
Chen et al[52]	SNGAL	All AKI, prospective nonseptic AKI	70	0.89	403	81	89
Chen et al[52]	SNGAL	Prospective and septic AKI	40	0.65	782	63	67
Komaru et al[53]	UNGAL	Prospective	105	0.81 (0.71-0.88)	186	94	60
Kim et al[54]	SNGAL	Prospective	110	0.654 (0.539-0.768)	-	90.5	44.9
von Groote et al[55]	PenKid–pre-KRT	Post hoc analysis	210	0.582 (0.505–0.660)	95.25	50	67
von Groote et al[55]	PenKid at day 10	Post hoc analysis	210	0.681 (0.594–0.767)	77.1	60	71
von Groote et al[55]	PenKid at day 28	Post hoc analysis	210	0.660 (0.570–0.750)	74.9	52	75
Kim et al[54]	Serum CyC	Prospective	110	0.739 (0.624-0.853)	-	76.2	62.9
Yang et al[56]	Serum CyC	Prospective	69	0.525 (0.408-0.643)	-	-	-
Aregger et al[57]	Kynurenic acid on day 1	Prospective	92	0.72 (0.59-0.85)	-	-	-
Aregger et al[57]	Kynurenic acid on day 2	Prospective	92	0.80 (0.69-0.93)	-	-	-
Aregger et al[57]	Kynurenic acid on day 3	Prospective	92	0.78 (0.66-0.90)	-	-	-
Pan et al[58]	Liver-fatty acid-binding proteins/creatinine	Prospective	140	0.79	-	-	-

AUROC: Area under the receiver operating characteristic curve; CI: Confidence interval; KRT: Kidney replacement therapy; SNGAL: Serum neutrophil gelatinase-associated lipocalin; AKI: Acute kidney injury; UNGAL: Urinary neutrophil gelatinase-associated lipocalin; CyC: Cystatin C; PenKid: Proenkephalin 119–159