Acute Renal Failure

Urinary Biomarkers in the Early Detection of Acute Kidney Injury after Cardiac Surgery

Won K. Han, Gebhard Wagener, Yanqing Zhu, Shuang Wang and H. Thomas Lee
CJASN May 2009, 4 (5) 873-882; DOI: https://doi.org/10.2215/CJN.04810908

Article Figures & Data

Figures

  • Figure 1.
    Figure 1.

    Pattern of urinary biomarker expression. Graphs show mean normalized urinary kidney injury molecule-1 (KIM-1), N-acetyl-β-D-glucosaminidase (NAG), and neutrophil gelatinase associated lipocalin (NGAL) concentrations at multiple time points after cardiac surgeries. Error bars are SEM. AKI, acute kidney injury; early AKI, development of acute kidney injury within first 24 h after operation; late AKI, development of acute kidney injury between 24 and 72 h after operation; Ucr, urine creatinine concentration.

Tables

  • Table 1.

    Formula for fitted multiple logistic regression model for combining biomarkersa

    For AKI (n = 36) versus all non-AKI (n = 54) combined
        pre-OP[−0.9596 + 0.01386 × NAG + 0.3102 × KIM1 + 0.0006661 × NGAL]
        immediately post-OP[−2.0269 + 0.001718 × NAG + 0.7716 × KIM1 + 0.0001331 × NGAL]
        3 h post-OP[−2.0673 + 0.01182 × NAG + 1.0965 × KIM1 + 0.00009982 × NGAL]
        18 h post OP[−1.6097 + 0.03977 × NAG + 0.2894 × KIM1 + 0.0005103 × NGAL]
        24 h post-OP[−0.5933 + 0.007838 × NAG + 0.06978 × KIM1 + 0.0008006 × NGAL]
    For early AKI (n = 16) versus all non-AKI (n = 54) combined
        pre-OP[−2.0360 − 0.0005436 × NAG + 0.5281 × KIM1 + 0.0008857 × NGAL]
        immediately post-OP[−3.3182 + 0.00212 × NAG + 1.088 × KIM1 + 0.00009552 × NGAL]
        3 h post-OP[−3.4557 + 0.01294 × NAG + 1.4386 × KIM1 + 0.0001215 × NGAL]
        18 h post-OP[−3.8619 + 0.06381 × NAG + 0.5328 × KIM1 + 0.0008294 × NGAL]
        24 h post-OP[−2.2619 − 0.01722 × NAG + 0.2097 × KIM1 + 0.0007784 × NGAL]
    For late AKI (n = 20) versus all non-AKI (n = 54) combined
        pre-OP[−1.3241 + 0.01832 × NAG + 0.1329 × KIM1 + 0.0003802 × NGAL]
        immediately post-OP[−2.4918 + 0.002208 × NAG + 0.6224 × KIM1 + 0.0001534 × NGAL]
        3 h post-OP[−2.4066 + 0.01427 × NAG + 0.977 × KIM1 + 0.00006504 × NGAL]
        18 h post-OP[−1.3878 + 0.03679 × NAG + 0.08044 × KIM1 + 0.00009971 × NGAL]
        24 h post-OP[−0.5948 − 0.0148 × NAG - 0.2848 × KIM1 + 0.0008516 × NGAL]

    • ↵a AKI, acute kidney injury; OP, open-heart operation; KIM-1, kidney injury molecule-1; NAG, N-acetyl-β-D-glucosaminidase; NGAL, neutrophil gelatinase associated lipocalin.

  • Table 2A.

    Stability of urinary biomarkersa

    Collection and ProcessingMean Percentage Difference (95% confidence interval of mean % difference) when Compared to Immediate Storage at −80°C
    KIM-1, n = 6NAG, n = 6NGAL, n = 6
    Remain at RMb for 2 h, then storage at −80°C−0.26 (−5.52 to 5.01)0.05 (−3.09 to 3.20)−2.45 (−6.54 to 1.64)
    Remain at RM for 4 h, then storage at −80°C1.43 (−5.39 to 8.25)0.48 (−3.19 to 4.15)−5.3 (−14.89 to 4.30)
    Remain at RM for 6 h, then storage at −80°C−3.97 (−10.80 to 2.86)0.48 (−2.42 to 3.38)2.54 (−7.86 to 12.93)
    Remain at RM for 24 h, then storage at −80°C−6.52 (−11.73 to −1.30)−0.43 (−1.46 to 0.60)−9.78 (−22.55 to 3.00)
    Remain at 4°C for 2 h, then storage at −80°C1.25 (−4.98 to 7.48)0.04 (−4.10 to 4.17)−3.97 (−9.91 to 3.77)
    Remain at 4°C for 4 h, then storage at −80°C0.43 (−5.37 to 6.23)2.38 (−1.75 to 6.51)6.65 (0.46 to 12.84)
    Remain at 4°C for 6 h, then storage at −80°C0.16 (−5.61 to 5.92)2.07 (−0.69 to 4.83)−5.19 (−13.47 to 3.09)
    Remain at 4°C for 24 h, then storage at −80°C−2.33 (−7.94 to 3.27)2.26 (−1.90 to 6.42)−1.01 (−14.52 to 12.5)
    Protease inhibitor versus no protease inhibitor1.23 (−3.76 to 6.23)−0.21 (−4.53 to 4.11)−1.51 (−7.23 to 4.20)
    Prolonged storage at −80°C
        1 yr with 3 repeat freeze and thaw cycles−0.53 (−8.57 to 7.50)4.96 (1.51 to 8.41)−2.43 (−13.53 to 8.66)
        2 yr with 3 repeat freeze and thaw cyclesNA2.13 (−4.47 to 8.72)NA

    • ↵a Immediate storage at −80°C and place urine samples at −80°C within first 20 min after initial collection.

    • ↵b RM, room temperature; NA, not applicable.

  • Table 2B.

    Stability of urinary biomarkers at prolonged storage at −20°C

    Collection and ProcessingMean Percentage Difference (95% confidence interval of mean % difference)
    KIM-1, n = 32NAG, n = 32NGAL, n = 32
    Prolonged storage at −20 and −80°C
        2 yr with 3 repeat freeze and thaw cycles (−20 versus −80°C)−15.08 (−21.26 to −8.91)−8.88 (−16.03 to −1.74)−40.24 (−52.67 to −27.82)
        compared with initial biomarker levels 2 yr before at −20°C−6.75 (−16.99 to 3.49)−6.11 (−14.44 to 2.22)NA
  • Table 3.

    Patient's characteristic and clinical outcomea

    CharacteristicAKI (n = 36)Early AKIb (n = 16)Late AKI (n = 20)Non-AKI (n = 54)
    Age (yr)68.31 ± 2.3065.41 ± 4.1670.64 ± 2.4560.39 ± 1.98
    Gender (male/female)23/139/714/638/16
    Scr (mg/dl)
        baseline (pre-OP)1.06 ± 0.061.10 ± 0.111.02 ± 0.051.02 ± 0.04
        post-OP (immediately)0.99 ± 0.05d1.09 ± 0.10d0.93 ± 0.050.84 ± 0.04
        post-OP day 11.28 ± 0.08c1.59 ± 0.13ce1.04 ± 0.050.91 ± 0.04
        post-OP day 21.51 ± 0.10c1.66 ± 0.19c1.40 ± 0.08c0.92 ± 0.04
        post-OP day 31.52 ± 0.11c1.55 ± 0.21c1.50 ± 0.10c0.91 ± 0.05
        post-OP day 41.54 ± 0.14c1.50 ± 0.21c1.57 ± 0.21c0.93 ± 0.05
        post-OP day 51.57 ± 0.19c1.39 ± 0.21d1.76 ± 0.32c0.92 ± 0.06
    Delta Scr change (%)
        post-OP (immediately)−7.94 ± 2.60d−5.71 ± 4.41d−9.50 ± 3.20d−17.41 ± 2.07
        post-OP day 122.78 ± 4.95c49.38 ± 4.70ce1.50 ± 3.72d−10.37 ± 2.27
        post-OP day 245.83 ± 5.54c56.25 ± 10.04c37.50 ± 5.47c−11.30 ± 2.48
        post-OP day 344.24 ± 6.51c44.67 ± 10.59c43.89 ± 8.33c−11.60 ± 3.11
        post-OP day 446.56 ± 11.06c40.00 ± 10.69c52.35 ± 18.80c−15.20 ± 4.09
        post-OP day 548.89 ± 15.69c31.43 ± 10.73c67.69 ± 30.28c−14.58 ± 4.26
    Mean duration of AKI (days)3.31 ± 0.404.13 ± 0.642.65 ± 0.46NA
    Type of heart operation
        CABG-CPB63311
        OPCABG4317
        single valve104618
        multiple valve1011
        CABG + valve11384
        aneurysm (or aneurysm + valve)1107
        other3216
    Intraoperative
        number of patients with CPB31 (86%)12 (75%)19 (95%)47 (87%)
        CPB (min)147.1 ± 11.6d151.7 ± 21.1d144.3 ± 13.9d113.9 ± 6.7
        aortic cross clamp time (min)92.2 ± 6.3100.4 ± 12.686.8 ± 6.479.6 ± 5.0
    Postoperative
        ICU-free days within 30 d23.7 ± 1.4c21.3 ± 2.7c25.6 ± 1.2d27.8 ± 0.3
        hospital-free days within 30 d15.5 ± 1.6c14.2 ± 2.5c16.6 ± 2.0d21.5 ± 0.9
        renal replacement therapy1100
        mortality5320

    • ↵a Values are means (±SEM).

    • ↵b Early AKI, development of AKI within first 24 h after operation; Late AKI, development of AKI between 24 and 72 h after operation; CPB, cardiopulmonary bypass; CABG-CPB, coronary artery bypass grafting with CPG; OPCABG, off-pump coronary artery bypass grafting; ICU, intensive care unit; Scr, serum creatinine concentration; Delta Scr change, % change in Scr from baseline.

    • ↵c P < 0.005 versus non-AKI.

    • ↵d P < 0.05 versus non-AKI.

    • ↵e P < 0.005 versus late AKI.

  • Table 4.

    Comparison of various normalized urinary marker levels in patients with AKI and non-AKIa

    Pre-OPImmediately Post-OP3 h Post-OP18 h Post-OP24 h Post-OP
    Normalized KIM-1 (ng/mg Ucr)b
        AKI1.1 (0.7 to 1.4) (n = 36)1.4 (0.1 to 2.4)c (n = 35)0.7 (0.0 to 2.1)d (n = 28)2.6 (1.2 to 4.0) (n = 34)2.1 (1.4 to 3.9) (n = 34)
        early AKI1.3 (0.8 to 1.7)d (n = 16)2.5 (0.2 to 4.5)cf (n = 15)1.5 (0.0 to 3.6)d (n = 12)4.3 (1.1 to 8.2)d (n = 15)4.2 (1.5 to 10.2)de (n = 15)
        late AKI0.8 (0.5 to 1.4) (n = 20)0.5 (0.0 to 2.0) (n = 20)0.4 (0.0 to 1.5) (n = 16)2.5 (1.1 to 3.3) (n = 19)1.6 (1.1 to 2.2) (n = 19)
        non-AKI0.8 (0.6 to 1.0) (n = 54)0.0 (0.0 to 0.6) (n = 54)0.0 (0.0 to 0.3) (n = 51)1.7 (1.3 to 2.7) (n = 48)1.7 (1.0 to 2.7) (n = 42)
    Normalized NAG (U/gram Ucr)
        AKI4.7 (2.7 to 9.6) (n = 36)47.9 (28.5 to 93.9) (n = 35)19.8 (6.1 to 27.9) (n = 28)6.4 (5.3 to 9.2)d (n = 34)7.6 (4.4 to 13.9) (n = 34)
        early AKI7.6 (1.0 to 16.3) (n = 16)37.8 (18.0 to 132.3) (n = 15)20.9 (3.7 to 43.6) (n = 12)7.7 (5.1 to 12.5) (n = 15)7.3 (3.6 to 22.5) (n = 15)
        late AKI4.3 (2.4 to 9.6) (n = 20)51.9 (26.2 to 168.8) (n = 20)17.7 (5.3 to 97.8) (n = 16)5.6 (5.2 to 10.7) (n = 19)8.0 (3.5 to 13.9) (n = 19)
        non-AKI4.2 (2.1 to 5.6) (n = 54)24.9 (14.5 to 55.6) (n = 54)9.2 (5.5 to 16.5) (n = 51)4.0 (3.2 to 7.2) (n = 48)7.5 (4.7 to 10.2) (n = 42)
    Normalized NGAL (ng/mg Ucr)
        AKI6.1 (2.8 to 12.0) (n = 36)4579.0 (1544.8 to 8074.2) (n = 35)2071.4 (455.4 to 6211.0)d (n = 28)71.2 (31.7 to 255.6)c (n = 34)69.6 (9.9 to 323.1) (n = 34)
        early AKI9.5 (1.4 to 85.1) (n = 16)2044.1 (36.0 to 7247.3) (n = 15)1153.3 (1.1 to 8000.0) (n = 12)70.8 (6.4 to 1418.2)d (n = 15)73.3 (8.0 to 4752.1) (n = 13)
        late AKI5.4 (2.4 to 13.1) (n = 20)7151.1 (1704.2 to 9810.8)d (n = 20)3041.7 (324.5 to 7457.0)d (n = 16)75.6 (26.5 to 251.9)d (n = 19)70.1 (9.1 to 621.6) (n = 19)
        non-AKI3.8 (2.9 to 6.7) (n = 54)2308.5 (344.1 to 5044.8) (n = 54)130.6 (35.9 to 601.9) (n = 51)15.8 (9.0 to 22.0) (n = 48)20.9 (13.8 to 31.6) (n = 42)
    Delta Scr (%)
        AKI−10.00 (−10.00 to 0.00)d (n = 34)−20.00 (10.00 to 31.45)c (n = 36)
        early AKI0.00 (−20.00 to 7.60)d (n = 14)40.00 (30.00 to 70.00)c (n = 16)
        late AKI−10.00 (−20.00 to 0.00) (n = 20)5.00 (−10.00 to 15.50)d (n = 20)
        non-AKI−20.00 (−20.00 to −10.00) (n = 54)−10.00 (−20.00 to 0.00) (n = 54)

    • ↵a Values are medians (95% confidence interval for median).

    • ↵b Ucr, urine creatinine concentration.

    • ↵c P < 0.005 versus non-AKI.

    • ↵d P < 0.05 versus non-AKI.

    • ↵e P < 0.005 versus late AKI.

    • ↵f P < 0.05 versus late AKI.

  • Table 5.

    Areas under the curve (AUCs) for normalized urinary biomarkers at various time pointsa

    Time after CPB
    Pre-OPImmediately After3 h18 h24 h
    AKI (n = 36)
        KIM-10.61 (0.51 to 0.72)0.68 (0.58 to 0.78)0.65 (0.54 to 0.75)0.60 (0.49 to 0.71)0.59 (0.47 to 0.70)
        NAG0.56 (0.46 to 0.67)0.61 (0.50 to 0.71)0.63 (0.51 to 0.73)0.64 (0.52 to 0.74)0.56 (0.44 to 0.67)
        NGAL0.55 (0.45 to 0.66)0.59 (0.48 to 0.69)0.65 (0.54 to 0.76)0.70 (0.59 to 0.80)0.59 (0.47 to 0.70)
        Combined0.63 (0.52 to 0.73)0.75 (0.65 to 0.84)b0.78 (0.68 to 0.87)c0.70 (0.58 to 0.79)0.68 (0.56 to 0.78)
        Delta Scr (%)0.67 (0.56 to 0.77)0.83 (0.74 to 0.90)
    Early AKI (n = 16)
        KIM-10.72 (0.60 to 0.82)0.79 (0.67 to 0.88)d0.73 (0.60 to 0.83)0.69 (0.56 to 0.80)0.71 (0.57 to 0.83)
        NAG0.58 (0.45 to 0.69)0.60 (0.47 to 0.71)0.59 (0.46 to 0.71)0.65 (0.52 to 0.77)0.54 (0.40 to 0.68)
        NGAL0.55 (0.42 to 0.67)0.51 (0.38 to 0.63)0.58 (0.45 to 0.70)0.68 (0.56 to 0.79)0.64 (0.50 to 0.77)
        Combined0.75 (0.63 to 0.85)0.80 (0.69 to 0.89)b0.84 (0.72 to 0.92)e0.83 (0.72 to 0.92)c0.78 (0.65 to 0.88)f
        Delta Scr (%)0.72 (0.60 to 0.82)1.00 (0.95 to 1.00)
    Late AKI (n = 20)
        KIM-10.54 (0.42 to 0.65)0.61 (0.49 to 0.72)0.60 (0.47 to 0.71)0.54 (0.41 to 0.66)0.54 (0.40 to 0.67)
        NAG0.55 (0.43 to 0.67)0.62 (0.51 to 0.74)0.65 (0.52 to 0.76)0.62 (0.50 to 0.74)0.54 (0.41 to 0.67)
        NGAL0.56 (0.44 to 0.67)0.66 (0.54 to 0.76)0.71 (0.59 to 0.82)0.72 (0.60 to 0.82)0.62 (0.48 to 0.74)
        Combined0.54 (0.42 to 0.66)0.72 (0.60 to 0.82)0.74 (0.62 to 0.84)0.59 (0.46 to 0.71)0.65 (0.52 to 0.77)
        Delta Scr (%)0.64 (0.52 to 0.75)0.70 (0.58 to 0.80)

    • ↵a Values are AUC (95% confidence interval for AUC).

    • ↵b P < 0.05 versus NGAL, NAG.

    • ↵c P < 0.05 versus KIM-1, NAG.

    • ↵d P < 0.05 versus NGAL.

    • ↵e P < 0.05 versus KIM-1, NAG, NGAL.

    • ↵f P < 0.05 versus NAG.

  • Table 6.

    Performance of urinary KIM-1, NAG, and NGAL for diagnosis of AKI at various time points

    AKI (n = 36)SensitivitySpecificityPositive Likelihood RatioNegative Likelihood Ratio
    Urinary KIM-1 at Post Immediately
        >1.2 ng/mg Ucr51.4377.782.310.62
        >1.8 ng/mg Ucr42.8688.893.860.64
    Urinary KIM-1 at 3 h Post-OP
        >1.2 ng/mg Ucr35.7190.203.640.71
        >1.8 ng/mg Ucr32.1496.085.460.72
    Urinary NAG at Post Immediately
        >18.5 U/gram Ucr82.8644.441.490.39
        >25.0 U/gram Ucr74.2950.001.490.51
    Urinary NAG at 3 h Post-OP
        >18.5 U/gram Ucr53.5770.591.820.66
        >25.0 U/gram Ucr28.5780.391.460.89
    Urinary NGAL at Post Immediately
        >456.0 ng/mg Ucr71.4338.891.170.73
        >1900.0 ng/mg Ucr65.7150.001.310.69
    Urinary NGAL at 3 h Post-OP
        >456.0 ng/mg Ucr71.4362.751.920.46
        >1900.0 ng/mg Ucr50.0070.591.700.71
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Urinary Biomarkers in the Early Detection of Acute Kidney Injury after Cardiac Surgery
Won K. Han, Gebhard Wagener, Yanqing Zhu, Shuang Wang, H. Thomas Lee
CJASN May 2009, 4 (5) 873-882; DOI: 10.2215/CJN.04810908
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