Biomarkers in chronic kidney disease, from kidney function to kidney damage

Table 1 Performance comparison of creatinine-based estimated glomerular filtration rate in North America/Europe/Australia

Ref.	Country	Patients, n	mGFR	eGFR	Results
			(value mL/min×1.73 m2, SD)	(equation)	1Bias (95%CI) mL/min×1.73 m2	2Precision (95%CI)	3P30 (95%CI), %
Murata et al[180]	United States	5238	I-Iothalamate, urine (55.9, SD 29.7)	MDRD CKD-EPI	-4.1 -0.7	ND	77.6 78.4
Levey et al[62]	United States	3896	I-Iothalamate, urine and others (68, SD 36)	MDRD CKD-EPI	-5.5 (-5.0 to -5.9) -2.5 (-2.1 to -2.9)	0.274 (0.265-0.283)4 0.250 (0.241-0.259)4	80.6 (79.5-82.0) 84.1 (83.0-85.3)
Lane et al[181]	United States	425	I-Iothalamate, urine (50, IQR 29 to 69)	MDRD CKD-EPI	-1.0 -1.7	15.05 13.85	75 80
Michels et al[77]	The Netherlands	271	I-Iothalamate, urine (78.2, SD 33)	MDRD CKD-EPI	14.6 mL/min 12.3 mL/min	19.96 12.16	81.2 84.5
Tent et al[182]	The Netherlands	253 before donation, 253 after donation	I-Iothalamate, urine (115, SD 20) and (73, SD 13)	MDRD CKD-EPI MDRD CKD-EPI	-22 mL/min (20-25) -14 mL/min (11-16) -15 mL/min (14-16) -11 mL/min (9-11)	20 (14-26)5 18 (14-22)5 12 (9-15)5 12 (10-16)5	73 (68-79) 89 (85-93) 71 (65-76) 89 (85-93)
Kukla et al[183]	United States	107 on steroid-free early post tranplantation 81 on steroid-free at 1 yr	I-Iothalamate, urine (55.5, SD 17) and (56.8, SD 17.7)	MDRD CKD-EPI MDRD CKD-EPI	8.23 13.30 2.40 6.91	17.94 21.14 15.84 17.34	71.7 58.5 75.0 66.7
White et al[184]	Canada	207	Tc-DTPA, plasma (58, SD 22)	MDRD CKD-EPI	-7.4 -5.2	14.45 15.75	79 (73-84) 84 (78- 88)
Pöge et al[185]	Germany	170	Tc-DTPA, plasma (39.6, IQR 11.8 to 82.9)	MDRD CKD-EPI	4.49 8.07	10.06 10.96	71.8 64.1
Jones[186]	Australia	169	Tc-DTPA, plasma (75, IQR 5 to 150)	MDRD CKD-EPI	-37 -1.57	ND	81 86
Cirillo et al[187]	Italy	356	Inulina, plasma (71.5, SD 36.3)	MDRD CKD-EPI	-5.2 -0.9	14.96 13.26	87.4 88.2
Eriksen et al[188]	Norway	1621	Iohexol, plasma (91.7, SD 14.4)	MDRD CKD-EPI	1.3 (0.4-2.1) 2.9 (2.2-3.5)	18.2 (17.2-19.5)5 15.4 (14.5-16.3)5	93 (91-94) 95 (94-96)
Redal-Baigorri et al[189]	Denmark	185	Cr-EDTA, plasma (85.1, SD 20.3)	MDRD CKD-EPI	0.81 (IQR, -1.56 to 3.19) 1.16 (IQR, -0.76 to 3.09)	16.496 13.376	88.6 89.7

¹Computed as estimated GFR minus measured GFR. Positive numbers indicate overestimation and negative numbers indicate underestimation of measured GFR. Smaller absolute values indicate lesser bias;

²Lower values indicate greater precision; ³Higher values indicate greater accuracy. Among the 3 studies (14, 18, 19) that reported alternative measures of accuracy, results were consistent with P30 in all. In addition to P30, references 14, 18, and 19 reported P10; Reference 14 also reported P20;

⁴Evaluated as the root mean square error for the regression of estimated GFR on measured GFR;

⁵Evaluated as the IQR for the differences between estimated and measured GFR;

⁶Evaluated as the SD of the differences between estimated and measured GFR;

⁷Converted to raw scale by multiplying percentage of bias by measured GFR. CKD-EPI: Chronic Kidney Disease Epidemiology Collaboration; mGFR: Measure glomerular filtration rate; eGFR: Estimated glomerular filtration rate; IQR: Interquartile range; MDRD: Modification of diet in renal disease; ND: Not documented; P30: Percentage of estimated GFR values within 30% of measured GFR; Tc-DTPA: Technetium-diethylene-triamine-pentaacetate; Cr-EDTA: Chromium-ethylenediamine-tetraacetic-acid. Adapted from Earley et al[39].

Table 2 Novel biomarkers in chronic kidney disease

Biomarker source	Ref.	Population/type of study	Commentaries
u-LFABP Urinary	Nielsen et al[190]	227 newly diagnosed type 1 diabetic patients/longitudinal	Baseline u-LFABP levels predicted development of microalbuminuria (HR = 2.3, 95%CI: 1.1-4.6), and predicted mortality (HR = 3.0, 95%CI: 1.3-7.0)
NAG Urinary	Kern et al[191]	87 type 1 diabetics with microalbuminuria and 174 controls/longitudinal	Baseline NAG independently predicted microalbuminuria (OR = 1.86, P < 0.001) and macroalbuminuria (OR = 2.26, P < 0.001) but risk was attenuated in multivariate models
CTGF Urinary	Nguyen et al[192]	318 type 1 diabetic patients and 29 control subjects/cross sectional	U-CGTF was significantly higher in diabetic nephropathy than micro o normoalbuminuria. U-CGTF correlated with albuminuria and GFR
IL-18 Kidney tissue	Miyauchi et al[193]	12 type 2 diabetes with overt nephropathy and 7 patients with MCD/cross sectional	IL-18 expression in tubular cells was observed highly observed (83%) in patients with diabetes but only observed in 14.3% of MCD
ApoA-IV Plasma	Boes et al[194]	177 non-diabetic patients with mild to modetare renal CKD/longitudinal	Baseline ApoA-IV was a significant predictor of disease progression (HR = 1.062, 95%CI: 1.018-1.108) and patients with level above the median had significantly faster progression compared with patients with level below median (P < 0.0001)
CD14 mononuclear cells Urinary	Zhou et al[195]	16 patients with autosomal dominat polycystic kidney disease/longitudinal	Baseline urinary CD14 mononuclear cells correlated with 2 yr change in total kidney volume in males
NGAL	Bolignano et al[121]	33 patients with glomerulonephritis and proteinuria > 1 g per day/cross sectional	u-NGAL was higher in glomerulonephritis compared with controls and significantly correlated with serum creatinine and urinary protein excretion
Urinary	Smith et al[124]	158 patients with CKD stages 3 and 4/longitudinal	u-NCR was associated with a higher risk of death and initiation of renal replacement therapy
Urinary	Bolignano et al[125]	96 white patients with CKD/longitudinal	Baseline urinary and serum NGAL were predictors of CKD progression
Urinary/serum	Shen et al[119]	92 patients with chronic glomerulonephritis CKD stage 2-4, and 20 control subjects/longitudinal	s-NGAL levels were higher compared to controls and negatively correlated with the eGFR Patients with sNGAL level > 246 ng/mL had a poor 2 yr renal survival compared with the control group
Serum	Bhavsar et al[123]	286 participants from the ARIC and 143 matched controls/longitudinal	Higher quiartiles of NGAL (but no KIM-1) were associated with incident CKD
KIM-1 Serum	Krolewski et al[111]	107 diabetic type 1 with CKD 1-3 (AER > 500 mg/24 h)/longitudinal	Baseline plasma KIM-1 levels correlated with rate of eGFR decline KIM-1 levels (> 97 pg/mL) correlated with progression to ESRD
Urinary	Peters et al[109]	65 patients with Proteinuric IgAN and 65 control subjects/longitudinal	In patients with IgAN uKIM-1 excretion was significantly higher than controls uKIM-1 is independently predictor of ESRD
FGF-23	Nakano et al[134]	738 Japanese patients with CKD stages 1-5/longitudinal	Levels of FGF-23 associated with kidney function decline or initiation renal replacement therapy
Serum	Fliser et al[137]	227 non diabetic patients with CKD stages 1-4/longitudinal	FGF-23 was an independent predictor of CKD progression
	Lee et al[138]	380 patients with type 2 diabetes/longitudinal	Levels of FGF-23 was associated with increased risk of ESRD and was a significant risk factor for all cause mortality

u-LFABP: Liver-type fatty acid-binding protein; NAG: N-Acetyl-b-O-glucosaminidase; CTGF: Connective tissue growth factor; IL-18: Interleukin-18; ApoA-IV: Apolipoprotein A-IV; NGAL: Neutrophil gelatinase associated lipocalin; MCD: Minimal change disease; ARIC: Atherosclerosis Risk In communities; IgAN: IgA nephropathy; u-NCR: u-NGAL to creatinine ratio; eGFR: Estimated glomerular filtration rate; FGF-23: Fibroblast growth factor 23; CKD: Chronic kidney disease; KIM-1: Kidney injury molecule; AER: Albumin excretion rate; GFR: Glomerular filtration rate; U-CGTF: Urinary-connective tissue growth factor; u-NGAL: Urinary-NGAL; s-NGAL: Serum-NGAL; ESRD: End stage renal disease.

Table 3 Utility of new biomarkers in chronic kidney disease

Biomarker	Origin	Outcome assessed
Urinary liver-type fatty acid-binding protein	Proximal tubule	Diabetic Nephropathy: Microalbuminuria and mortality
Urinary N-Acetyl-b-O-glucosaminidase	Proximal tubule	Diabetic Nephropathy: Albuminuria
Urinary connective tissue growth factor	Proximal tubule	Diabetic Nephropathy: Glomerular filtration rate decline
Interleukin-18	Tubulointerstitial	Diabetic Nephropathy: Albuminuria
Apolipoprotein A-IV	Intestinal enterocytes	CKD: CKD Progression
Urinary CD14 mononuclear cells		Polycystic kidney disease: Kidney volume
Neutrophil gelatinase associated lipocalin	Proximal and distal tubule	Glomerulonephritis: GFR and proteinuria CKD: CKD progression, renal replacement therapy and mortality
Kidney injury molecule-1	Proximal tubule	CKD: CKD progression and renal replacement therapy
Fibroblast growth factor-23	Osteocytes and osteoblasts	Diabetic Nephropathy and others CKD: CKD progression and mortality
Urinary retinol binding protein 4	Proximal tubule	Congenital or acquired tubular dysfunction: Proximal tubule dysfunction

CKD: Chronic kidney disease.