Role for urinary biomarkers in diagnosis of acute rejection in the transplanted kidney

Table 1 Review of the described studies

Ref.	Event	Urinary markers	n	Endpoints
Li et al[21]	AR	Perforin, GRB	n = 151	Potential to predict AR
Yannaraki et al[22]	AR	Perforin, GRB and Fas-L	n = 162	Levels are increased in different clinical settings (AR, UTI, CMVi or CMVd, CAN, DGF)
Heng et al[23]	AR	GRB and Perforin	n = 680	Combined use of GRB and Perforin may lead to a better prediction of AR
Muthukumar et al[31]	AR	FOX-3mRNA	n = 83	Reversal of acute AR and lower risk of graft failure with high levels of FOXP3 mRNA
Aquino-Dias et al[35]	AR with DGF	Perforin, GRB, PI-9, Fas-L and Foxp-3 mRNA	n = 48	Urinary Foxp-3 with 100% sensitivity and 100% specificity for AR
Schaub et al[39]	Subclinical tubulitis	CXCL9/CXCL10, a-microglobulin/Cr, NGAL/Cr	n = 88	CXCL9/CXCL10 potential noninvasive biomarkers for subclinical tubulitis
Matz et al[40]	AR and prediction of short and long-term graft function	IP-10 mRNA and protein	n = 76 for IP-10 mRNA	Incidence of AR: Urinary IP-10 protein observed 2/3 d prior to biopsy with 71% sensitivity and 95% specificity
			n = 100 for IP-10 protein	Long term graft function: Urinary IP-10 predictive of GFR at 6 mo post-transplant
Ho et al[41]	Subclinical and clinical tubulitis	CXCL10:Cr	n = 102	CXCL10:Cr sensitivity of 73.3% and specificity of 72.7%
Jackson et al[42]	AR	CXCL9/CXCL10	n = 110 adults and 46 children	Elevated CXCL9/CXCL10 identified AR and BKI
Hricik et al[43]	CTOT-1: AR	Urinary protein and mRNACXCL9/CXCL10, GRB mRNA	n = 2095	CXCL9 protein with high NPV 92%
				CXCL9 detects subclinical tubulitis
				Stratification of patients with low vs high risk for future injury
				Utility of CXCL9 for ruling out acute rejection
Suthanthiran et al[44]	AR	Urinary mRNA based signatures	n = 4300	Three-gene signature of CXCL10 mRNA, 18S ribosomal RNA, CD3ε mRNA distinguish ACR from AMR and even from other etiologies of graft dysfunction
Matignon et al[45]	ACR vs AMR	Urinary mRNA based signatures	n = 84	mRNAs for CD3ε, CD105, CD14, CD46 and 18S rRNA may be able to differentiate between ACR and AMR
Lorenzen et al[48]	AR	miRNAs: miR-10a, -10b, -210	n = 88	Low Urinary miR-210 during AR
				Urinary miR-210 predict outcome of renal transplant
				Urinary miR-210 novel biomarker of AR

GRB: Granzyme B; PI-9: Proteinase inhibitor-9; NGAL: Urine neutrophil gelatinase-associated lipocalin; Cr: Creatinine; DGF: Delayed graft function; AR: Acute rejection; UTI: Urinary tract infection; CAN: Chronic allograft nehropathy; CTOT-1: Clinical trial of transplantation-1; IP-10: Interferon-g–inducible protein-10; BKI: Polyomavirus BK infection; ACR: Acute cellular rejection; AMR: Antibody mediated rejection; Fas-L: Fas-Fas ligand lytic pathway.