Role of novel biomarkers in kidney transplantation

Table 7 Summary of biomarkers associated with delayed graft function

Ref.	n	Sample	Biomarkers	Outcome	Study conclusion
Parikh et al[46], 2016	671	Perfusate	NGAL, IL-18, L-FABP	DGF	Base (NGAL) was significantly ↑ in allografts with DGFa. This was also observed in post values of IL-18a and base/post perfusate L-FABP levelsb. These biomarkers did not significantly correlate with DGF development on multivariate adjustment
van Smaalen et al[49], 2017	390	Perfusate	Extracellular histone concentration	DGF	Extracellular histone concentration was significantly ↑ in the DGF group (median 0.70 µg/mL (IQR 0.4 to 0.98) compared to grafts that functioned immediatelyc (median, 0.42 (IQR 0.07 to 0.78). Interestingly there was no significant difference in extracellular histone concentration in grafts with primary non-function vs DGF
van Balkom et al[57], 2017	40	Perfusate	Leptin, GM-CSF, periostin, plasminogen activator inhibitor-1, osteopontin	DGF	5 perfusate proteins/158 tested predicted DGF. Leptin and GM-CSF -> most predictive. Validation with 40 kidneys found that leptin, GM-CSF + BMI predict DGF (AUC = 0.89 (95%CI: 0.74 to 1.00), which performed better than KDRI and DGF risk calculator (AUC 0.55, 0.59)
Roest et al[58], 2019	48	Perfusate	microRNA mir-505-3p	DGF	In 8 DCD and DBD donors, ↑ levels of perfusate microRNA mir-505-3p correlated with DGFb (OR 1.12). This was confirmed via validation of 40 allografts, of which 20 developed DGFb. Interestingly, this predictive capability held true solely for DCD allograftsc
Truche et al[59], 2019	41	Urine and Plasma	uNGAL, uNAG, LDH, UCr	DGF	DGF -UNGAL, UNAG AUC 1, 0.96 (0.84-1.0) , urinary tubular injury biomarker-to-creatinine ratio, and LDH AUC = 1 and 0.92 (95%CI: 0.73 to 1.0)
Pianta et al[60], 2015	81	Urine	Urinary clusterin, IL-18, KIM-1, NGAL	DGF	Urinary clusterin predicted DGF at 4 h (AUC = 0.72 (95%CI: 0.57 to 0.97), as did IL-18 , KIM-1 and NGAL; eGFR at 90 d was inversely correlated with urinary clusterin at 12 hb (Pearson r = −0.26, and 7 db (Pearson r = −0.25)
Reese et al[61], 2016	1304	Urine	Microalbumin, NGAL, KIM-1, IL-18, L-FABP	AKI, DGF, 6-month eGFR	Microalbumin, NGAL, KIM-1, IL-18, L-FABP from deceased donors at procurement; predictive of AKI; NGAL associated with DGF (RR = 1.21 (95%CI: 1.02 to 1.43), NGAL and L-FABP associated with lower 6 mo eGFR
Nielsen et al[62], 2019	225	Plasma and urine	pNGAL, uNGAL uL-FABP, urine cystatin C, urine YLK-40	DGF, 1 yr mGFR/eGFR	pNGAL 1 d after tx -> associated with DGF. Did not correlate to 12-mo eGFR; no relation w L-FABP, cystatin C, and YLK-40
Koo et al[63], 2016	94	Urine	Microalbumin, NGAL, KIM-1, IL-18, L-FABP	DGF, 1 yr graft function	NGAL predicts AKI; NGAL + L-FABP predicts DGF (AUC 0.758, 0.704); NGAL + L-FABP + Cr better than DGF calculator and KDPI. L-FABP predictive of 1 yr graft functionb
Li et al[64], 2019	1036	Urine and plasma	uNGAL, pNGAL	DGF	Composite AUC for 24 hours uNGAL was 0.91 (95%CI: 0.89 to 0.94) and the overall DOR for 24 hours uNGAL was 24.17; sensitivity 0.88, specificity 0.81. The composite AUC for 24 hours pNGAL was 0.95 (95%CI: 0.93 to 0.97) with an overall DOR for 24 hours pNGAL = 43.11 with sensitivity 0.91 and specificity 0.86
Bank et al[65], 2019	74 (DCD KTRs)	Urine	Urinary TIMP-2	DGF	TIMP-2/mOsm on day-1 and day-10 identified patients with DGF (AUC = 0.91) and prolonged DGF (AUC = 0.80); Consecutive TIMP-2/mOsm values showed a ↓ in TIMP-2/mOsm before an ↑estimated glomerular filtration rate, predicting resolution of fDGF
McGuinness et al[66], 2016	94		hsa-miR-217; hsa-miR-125b	DGF	miRNA + donor age + type donation predicted DGF in 83% of cases (61% sensitivity, 91% specificity)
Ledeganck et al[21], 2019	11 studies	Allograft biopsy	microRNA	DGF	Upregulation of miR-21-3P and miR-182-5p associated with DGF

^aP < 0.005 vs non-DGF allografts.

^bP < 0.05 vs non-DGF allografts.

^cP < 0.001 vs immediately functioning grafts. NGAL: Neutrophil gelatinase-associated lipocalin; IL-18: Interleukin eighteen; L-FABP: Liver fatty acid binding protein; DGF: Delayed graft function; IQR: Interquartile range; GM-CSF: Granulocyte-macrophage colony-stimulating factor; BMI: Body mass index; AUC: Area under the curve; KDRI: Kidney donor risk index; RNA: Ribonucleic acid; mir: Pre-microRNA; DCD: Deceased cardiac death donor; DBD: Deceased brain death donor; OR: Odds ratio; u: Urinary; uNGAL: Urinary neutrophil gelatinase-associated lipocalin; uNAG: Urinary N-acetyl-β-glucosaminidase; LDH: Lactate dehydrogenase; UCr: Urine creatinine; KIM-1: Kidney injury molecule-1; CI: Confidence interval; eGFR: Estimated glomerular filtration rate; RR: Relative risk; pNGAL: Plasma neutrophil gelatinase-associated lipocalin; YLK-40: Chitinase-3-like protein mGFR: Measured glomerular filtration rate; KDPI: Kidney donor profile index; DOR: Diagnostic odds ratio; TIMP-2: Tissue inhibitor of metalloproteinases 2; mOsm: Milliosmoles; fDGF: Functional delayed graft function; hsa: Homo sapiens; miR: Mature form of microRNA.