Table 2:

Summary of Biomarkers of Acute and Chronic Renal Injury Evaluated in Chronic Kidney Injury and Disease

Biomarker	Regulatory Statusa	Comments	R	D	NP	MP	H
Acute Renal Injury Biomarkers
uKIM-1	Q (H)	Functions in tubular repair as epithelial scavenger receptor for phosphatidyl serine-mediated phagocytosis of apoptotic cells.67 Expression is upregulated with PT injury.87 Chronic PT upregulation was associated with interstitial inflammation and fibrosis in mice suggesting a link between acute and chronic injury.76 Current dog assays are problematic.117	X		X		X
uNGAL	LOS (R) / Q (H)	Transport protein originally found in neutrophil specific granules. Located primarily in distal nephron. Induced with injury, inflammation, and neoplastic transformation in many epithelia.127 Functions as Fe-binding siderophore involved in host defense and is involved in nephron development.130 AKI marker with a large dynamic range in many species.38,45,141,146 Good at predicting the progression of AKI to CKD.150 Systemic inflammation or sepsis can cause increased serum levels which can lead to increased urine levels in the absence of renal injury.146	X	X	X	X	X
Acute Renal Injury: LMW Biomarkers of PT Injury with Normal Glomerular Function
uB2M	Q	Found in every nucleated cell and forms the light chain component of class I histocompatibility antigens. Normally filtered through the glomerulus and almost entirely reabsorbed by the PT.357 Urine levels increase with glomerular and/or PT damage due to a variety of causes.362 Has poor stability at room temperature and in acid urine.369 Less useful than other LMW biomarkers such as CysC or retinol binding protein, particularly in dog.161,370	X	Xb	X		X
uCysC	Q (H)	Produced at a constant rate by all nucleated cells and functions as a lysosomal protease and cysteine proteinase.228 Normally filtered through the glomerulus and almost entirely reabsorbed by the PTs.229 Urine levels increase due to impairment or saturation of PT reabsorption.228 Demonstrated utility in clinic and in animals.31,33,227	X	X	X		X
Acute Renal Injury and Chronic Renal Dysfunction: Intermediate to HMW Biomarkers of Glomerular / Tubular Damage
uAlbumin	Q (H standard)	High specificity for renal injury. Parallels changes in total urinary protein levels in most species, except in male rats.55,58 Both intact and fragmented albumin is normally reabsorbed in PTs, but immunoassays can underestimate low level injury due to PT resorption/excretion of variably sized non-immunoreactive albumin fragments.51,64	X	X	X	X	X
uProtein	Q (H standard)	Common method for monitoring the progression of glomerular disease in humans and animals.55,56 Can have lower specificity than albumin due to post-renal inflammation or increased production of abnormal LMW proteins.52,53	X	X	X	X	X
Chronic Renal Dysfunction: Candidate Biomarkers
sCysC	NQ (H standard)	Recent eGFR calculations in humans have used cystatin in blood and urine rather than creatinine to more precisely calculate GFR.15 Outperforms creatinine in rats with subacute renal injury and in dogs with decreased mGFR.105,261	X	X	X		X
sSDMA	NQ	By-product of cellular arginine metabolism and continually released into the circulation.274 Depends on glomerular filtration for excretion and serum levels correlate with renal function.278 Increases progressively with increased renal impairment and progressive nephron loss in animals and humans with CKD.285,286	X	X			X
u/pDKK3	NQ	Member of a family of glycoproteins in the Wnt signaling pathway.309 Demonstrates promising utility as a urinary biomarker of ongoing tubular injury and progressing tubulointerstitial fibrosis.312,314 Another surrogate renal biomarker for GFR.315	X				X
Chronic Renal Dysfunction: Other Experimental Biomarkers
u/sUMOD	NQ	Also known as Tamm-Horsfall protein, is the most abundant protein in urine.319 Produced exclusively in the thick ascending limb and the early distal tubule.320 Several studies have reported positive correlations between serum/plasma UMOD levels and kidney function.331	X	X	X		X
sB2M	NQ	Accumulates in serum when GFR is impaired and increases with stage of renal disease, but use in humans and dogs as a non-creatinine renal filtration marker has been overshadowed by CysC.374,378	X	X			X
sBTP	NQ	Also known as lipocalin-type prostaglandin D synthase. Is not physiologically inert. Has ligand-binding, enzymatic properties, and is associated with multiple physiologic functions which can affect its levels.393 In humans, BTP levels have good correlation with mGFR and increase with decreased GFR in CKD especially in early stages.409,414 Limited use in animals.	X				X

^aRegulatory status refers to rat unless otherwise specified,

^bWestern blot, R: rat, D: dog, NP: nonhuman primate, MP: minipig, H: human, Q: qualified, NQ: not qualified, LOS: letter of support, LMW: low molecular weight, HMW: high molecular weight, u: urine, s: serum, p: plasma, KIM-1: kidney injury molecule-1, PT: proximal tubule, NGAL: neutrophil gelatinase-associated lipocalin, B2M: beta 2 microglobulin, BTP: beta trace protein, CysC: cystatin C, SDMA: symmetrical dimethyl arginine, DKK3: dickkopf homolog 3, UMOD: uromodulin, eGFR: estimated glomerular filtration rate, mGFR: measured glomerular filtration rate, CKD: chronic kidney disease