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.