Role of novel biomarkers in kidney transplantation

Table 12 Summary of biomarkers associated with graft survival and/or patient survival

Ref.	n	Sample	Biomarkers	Dysfunction	Study conclusion
de Holanda et al[16], 2018	73	Plasma	sCD30	Rejection; Graft survival	sCD30 at +7, +14 associated with ARa. No difference in 5 yr graft survival
Koo et al[63], 2016	94	Urine	microalbumin, NGAL, KIM-1, IL-18, L-FABP	DGF, slow graft function , 1 yr graft function	NGAL predicts AKI; NGAL + L-FABP predicts DGF, slow graft function (AUC 0.758, 0.704); NGAL + L-FABP + Cr better than DGF calculator and KDPI. L-FABP predictive of 1 yr graft functionb
Foster et al[68], 2017	508	Urine and plasma	Cystatin C, B2M, Cr	CV events, Mortality, Kidney failure	HR eGFRcys and HR eGFRB2M < 30 vs 60+ were 2.02c (1.09-3.76) and 2.56d (1.35-4.88) for CV events; 3.92e (2.11-7.31) and 4.09d (2.21-7.54) for mortality; and 9.49e (4.28-21.00) and 15.53d (6.99-34.51) for kidney failure
Bansal et al[69], 2016	1027	Urine	uNGAL, KIM-1, IL-18, L-FABP, Ucr	CV events, Graft failure, mortality	Each ↑ log in uNGAL/Cr associated with a 24% ↑ risk of CV events (aHR 1.24; 1.06 to 1.45), graft failure (1.40; 1.16 to 1.68), and risk of death (1.44; 1.26 to 1.65). uKIM-1/Cr and IL-18/Cr associated with higher risk of death (1.29; 1.03 to 1.61 and 1.25;1.04 to 1.49 per log increase)
O’Connell et al[89], 2016	204	Biopsy	Gene set of 13 genes	IFTA, Graft loss at 2/3 yr	Gene set prediction > clinicopathologic variables (AUC 0.967 > AUC 0.706, AUC 0.806) for IFTA; predicted graft loss at 2 and 3 years (AUC 0.842, 0.844), validated in 2 public datasets
Ix et al[90], 2017	748	Urine	Urine A1M, MCP-1, procollagen type III and type I amino-terminal amino pro-peptide	Graft failure	In adjusted models, ↑ concentrations of urine A1M (HR per doubling, 1.73; 1.43-2.08) and MCP-1 (HR per doubling, 1.60; 1.32-1.93) were associated with allograft failure. With the adjustment, urine A1M (HR per doubling, 1.76; 95%CI: 1.27-2.44)] and MCP-1 levels (HR per doubling, 1.49; 95%CI: 1.17-1.89) remained associated with allograft failure
Heylen et al[92], 2018	154	Biopsy	DNA methylation	1-yr graft function	↑ methylation risk scoref at transplant predicted chronic injury at 1 yr (OR 45; 98 to 499; P < 0.001; AUC 0.919) vs standard baseline clinical risk factors, including age, donor criteria, donor last SCr, CIT, anastomosis time, HLA mismatches (combined AUC 0.743) sensitivity, specificity, and PPV, NPV values of MRS-based ROC curves were 90%, 90%, 95%, and 82%
Park et al[70], 2017	1184 (300 CVD, 371 death, 513 random sub-cohort)	Urine	Urine A1M MCP-1, PINP and PIIINP	CV events, Mortality	In adjusted models, higher urine AlM (HR per doubling of biomarker = 1.40 (95%CI: 1.21 to 1.62), MCP-1 [HR = 1.18 (1.03 to 1.36)], and PINP [HR = 1.13 (95%CI: 1.03 to 1.23) were associated with CVD events. These three markers were also associated with death (HR per doubling A1M = 1.51 (95%CI: 1.32 to 1.72); MCP-1 = 1.31 (1.13 to 1.51); PINP = 1.11 (95%CI: 1.03 to 1.20)
Smedbråten et al[91], 2017	382	Plasma	CL-L1, CL-K1	CV mortality, Graft survival, Patient survival	↑CL-L1 (≥ 376 ng/mL) and ↑CL-K1 (≥ 304 ng/mL) levels at transplantation were associated with mortality in multivariate Cox analysesg [HR = 1.50 (95%CI: 1.09 to 2.07) and HR = 1.43 (95%CI: 1.02 to 1.99)] ↑CL-K1 levels were associated with CV mortality. No association between measured biomarkers and death-censored graft loss was found
San Segundo et al[93], 2019	133	Plasma	Abs number peripheral blood Treg cells	Death-censored graft survival	↑ Treg cells 1 yr post-KTh showed better DCGL (5-yr survival, 92.5% vs 81.4%). 1-yr Treg cellsh showed a ROC AUC of 63.1% (95%CI: 52.9 to 73.2) for predicting DCGL. After multivariate Cox regression analysis, an ↑ number of peripheral blood Treg cellsh was protective factor for DCGL (HR = 0.961 (95%CI: 0.924 to 0.998), irrespective of 1-yr proteinuria and renal function

^aP < 0.05 vs grafts without rejection.

^bP < 0.05 vs immediate function grafts.

^cP < 0.05 vs eGFR_cys > 60.

^dP < 0.005 vs eGFR_B2M > 60.

^eP < 0.005 vs eGFR_cys >60.

^fP < 0.005 vs low methylation risk score at transplant.

^gP < 0.05 vs KTRs with collectin levels below cutoff.

^hP < 0.05 vs KTRs with absolute number of peripheral blood Treg cells below threshold. sCD30: Soluble cluster of differentiation thirty; AR: Acute rejection; uNGAL: Urinary neutrophil gelatinase-associated lipocalin; KIM-1: Kidney injury molecule 1; IL-18: Interleukin eighteen; L-FABP: Liver fatty acid binding protein; DGF: Delayed graft function; AKI: Acute kidney injury; AUC: Area under the curve; KDPI: Kidney donor profile index; B2M: Beta-2-microglobulin; Cr: Creatinine; CV: Cardiovascular; HR: Hazard ratio; Abs: Absolute; eGFR: Estimated glomerular filtration rate; eGFR_cys: Estimated glomerular filtration rate based on cysteine; eGFR_B2M : Estimated glomerular filtration rate based on beta-2-microglobulin; u: Urine; UCr: Urine creatinine; aHR: Adjusted hazard ratio; IFTA: Interstitial fibrosis tubular atrophy; A1M: Alpha 1 microglobulin; MCP-1: Monocyte chemoattractant protein-1; PINP: Procollagen type I intact N-terminal peptide; PIIINP: Procollagen type III intact N-terminal peptide; DNA: Deoxyribonucleic acid; OR: Odds ratio; SCr: Serum creatinine; CIT: Cold ischemia time; HLA: Human leukocyte antigen; PPV: Positive predictive value; NPV: Negative predictive value; MRS: Methylation risk score; CI: Confidence interval; CL-L1: Collectin liver-1: CL-K1-collectin kidney-1; Treg: Regulatory T cells; KT: Kidney transplant; DCGL: 95% eath censored graft loss; ROC: Receiver operating characteristic.