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Clinical Epidemiology
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Phosphate May Promote CKD Progression and Attenuate Renoprotective Effect of ACE Inhibition

Carmine Zoccali, Piero Ruggenenti, Annalisa Perna, Daniela Leonardis, Rocco Tripepi, Giovanni Tripepi, Francesca Mallamaci and Giuseppe Remuzzi
JASN October 2011, 22 (10) 1923-1930; DOI: https://doi.org/10.1681/ASN.2011020175
Carmine Zoccali
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Piero Ruggenenti
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Annalisa Perna
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Daniela Leonardis
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Rocco Tripepi
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Giovanni Tripepi
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Francesca Mallamaci
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Giuseppe Remuzzi
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    Figure 1.

    Distribution of baseline serum phosphate in the study population.

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    Figure 2.

    Cumulative incidence of ESRD alone and in combination with doubling serum creatinine in patients stratified according to serum phosphate quartiles. I/II quartile: < 3.45 mg/dl. III quartile: 3.45 to 4.00 mg/dl. IV quartile: > 4.00 mg/dl.

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    Figure 3.

    Effect modification of serum phosphate on the efficacy of ramipril for reducing the incidence rate of ESRD. Data are expressed as hazard ratio, 95% confidence interval, and P-value (see box). °Crude data. *Data adjusted for all variables listed in Table 4. **Shrinkage corrected.24

Tables

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    Table 1.

    Main clinical and biochemical characteristics of study patients according to serum phosphate quartiles

    1st and 2nd Phosphate QuartilesP3rd Phosphate QuartileP4th Phosphate QuartileP
    Ramipril (n = 81)Placebo (n = 85)Ramipril (n = 48)Placebo (n = 44)Ramipril (n = 36)Placebo (n = 37)
    Age (years)51 ± 1352 ± 120.5548 ± 1449 ± 160.9246 ± 1345 ± 150.63
    Male sex, n (%)68 (84%)72 (84.7%)0.8936 (75%)30 (68.2%)0.4728 (77.8%)18 (50.0%)0.01
    Urinary sodium (mEq/24 h)98 ± 3989 ± 470.2585 ± 3688 ± 400.7475 ± 2778 ± 410.71
    Urinary urea (mg/24 h)1067 ± 583984 ± 4700.351017 ± 4281010 ± 4490.94811 ± 392844 ± 2300.69
    On treatment with Ca supplements, n (%)2 (2.5%)2 (2.4%)0.961 (2.1%)0 (0%)0.340 (0%)1 (2.7%)0.32
    On treatment with Vit. D analogs, n (%)1 (1.2%)1 (1.2%)0.972 (4.2%)2 (4.5%)0.935 (13.9%)2 (5.4%)0.22
    Smokers, n (%)19 (23.5%)10 (11.8%)0.058 (16.7%)9 (20.5%)0.6410 (27.8%)7 (18.9%)0.37
    Diabetes, n (%)4 (4.9%)5 (5.9%)0.796 (12.5%)5 (11.4%)0.873 (8.3%)2 (5.4%)0.62
    Cholesterol (mg/dl)241 ± 56240 ± 530.96236 ± 53248 ± 620.34258 ± 109250 ± 550.71
    Albumin (g/dl)3.9 ± 0.53.9 ± 0.50.703.9 ± 0.53.9 ± 0.40.783.6 ± 1.23.8 ± 0.40.53
    Glucose (mg/dl)104 ± 26105 ± 340.89116 ± 55110 ± 470.5798 ± 23105 ± 380.34
    Calcium (mg/dl)9.1 ± 1.49.3 ± 1.00.539.4 ± 0.59.4 ± 0.60.719.2 ± 0.69.1 ± 0.60.85
    Phosphate (mg/dl)2.8 ± 0.52.9 ± 0.40.073.8 ± 0.23.7 ± 0.20.364.6 ± 0.64.5 ± 0.40.15
    Hemoglobin (g/dl)14.2 ± 1.314.0 ± 1.70.5513.7 ± 2.012.9 ± 1.60.0412.6 ± 1.912.2 ± 1.70.38
    Systolic pressure (mmHg)145 ± 22146 ± 170.86147 ± 15145 ± 180.56146 ± 18148 ± 190.69
    Diastolic pressure (mmHg)91 ± 1191 ± 120.7291 ± 1487 ± 100.1389 ± 1191 ± 110.58
    Mean arterial pressure (mmHg)109 ± 14110 ± 130.77110 ± 13107 ± 110.20108 ± 12110 ± 110.57
    Urinary protein (g/24 h)2.3 (1.3–3.7)3.0 (1.5–4.3)0.112.7 (1.5–4.0)2.6 (1.4–3.9)0.573.8 (2.2–7.8)4.0 (2.0–6.6)0.61
    Iohexol GFR (ml/min/1.73m2)52 ± 2047 ± 170.0545 ± 2040 ± 170.1535 ± 1631 ± 130.27
    • 1st and 2nd quartiles, serum phosphate <3.45 mg/dl; 3rd phosphate quartile, 3.45–4.00 mg/dl; 4th phosphate quartile, >4.00 mg/dl. Data are expressed mean ± SD or as percent frequency, as appropriate.

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    Table 2.

    Multivariate Cox regression analyses

    ESRD occurrenceCrude Hazard ratio, 95% CI, and P-valueAdjusted for confounders, gender, and systolic BP Hazard ratio, 95% CI, and P-value
    Phosphate (1 mg/dl)3.30 (2.46–4.43), P < 0.0011.84 (1.27–2.67), P = 0.001
    Treatment with Ramipril (0 = no; 1 = yes)0.48 (0.29–0.79), P = 0.004
    Albumin (1 g/dl)0.43 (0.26–0.73), P = 0.002
    Hemoglobin (1 g/dl)0.90 (0.78–1.02), P = 0.11
    Iohexol GFR (1 ml/min/1.73m2)0.94 (0.92–0.96), P < 0.001
    Urinary Protein (1 g/24 h)1.11 (1.02–1.21), P = 0.01
    Gender (0 = M; 1 = F)1.71 (0.94–3.10), P = 0.08
    Systolic pressure (1 mmHg)1.03 (1.01–1.04), P = 0.001
    Combined end point (ESRD/creatinine doubling)Crude Hazard ratio, 95% CI, and P-valueAdjusted for confounders, gender, and systolic BP Hazard ratio, 95% CI, and P-value
    Phosphate (1 mg/dl)2.87 (2.18–3.77), P < 0.0011.66 (1.18–2.33), P = 0.004
    Treatment with Ramipril (0 = no; 1 = yes)0.49 (0.31–0.79), P = 0.003
    Albumin (1 g/dl)0.50 (0.31–0.82), P = 0.006
    Hemoglobin (1 g/dl)0.92 (0.81–1.05), P = 0.20
    Iohexol GFR (1 ml/min/1.73m2)0.95 (0.93–0.97), P < 0.001
    Urinary protein (1 g/24 h)1.11 (1.02–1.20), P = 0.01
    Gender (0 = M; 1 = F)1.51 (0.87–2.63), P = 0.14
    Systolic pressure (1 mmHg)1.02 (1.01–1.03), P = 0.002
    • The approach to multivariate Cox's regression analysis is described in detail in the Methods section. Data are expressed as hazard ratio, 95% CI, and P-values.

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    Table 3.

    Crude incidence rate of ESRD and (a) combined renal end point, and (b) according to serum phosphate quartiles and study arms (Ramipril versus placebo)

    (a) Incidence rate of end stage renal disease (ESRD)
    Crude Incidence Rate of ESRD Occurrence (events/100 person-years)*Crude Hazard Ratio, 95% CI, and P-value (Ramipril versus placebo)
    Placebo groupRamipril group
    First two quartiles (<3.45 g/dl)6.9 (4.0–11.2)0.42 (0.01–2.4)0.13 (0.04–0.39), P < 0.0001
    Third quartile (3.45–4.00 mg/dl)13.8 (7.6–23.2)6.5 (3.0–12.3)0.32 (0.18–0.59), P < 0.001
    Fourth quartile (> 4.00 mg/dl)26.8 (16.1–41.7)20.7 (11.6–34.2)0.82 (0.44–1.55), P = 0.54
    P for effect modification = 0.008
    (b) Incidence rate of the combined renal end point (ESRD and doubling of serum creatinine)
    Crude Incidence Rate of Renal Outcomes (events/100 person-years)*Crude Hazard ratio, 95% CI, and P-value (Ramipril versus placebo)
    Placebo groupRamipril group
    First two quartiles (<3.45 g/dl)8.8 (5.3–13.7)1.3 (0.3–3.8)0.15 (0.06–0.39), P < 0.0001
    Third quartile (3.45–4.00 mg/dl)18.6 (10.8–29.7)6.7 (3.1–12.7)0.37 (0.22–0.62), P < 0.001
    Fourth quartile (> 4.00 mg/dl)27.9 (16.8–43.8)25.2 (14.7–40.4)0.90 (0.49–1.66), P = 0.73
    P for effect modification = 0.004
    • Data are incidence rate and 95% confidence intervals.

    • *The crude hazard ratios of Ramipril treatment for study outcomes across serum phosphate quartiles were derived by Cox models including Ramipril treatment, serum phosphate strata, and their interaction term.

    • View popup
    Table 4.

    Interaction analysis between Ramipril treatment and serum phosphate strata for (a) ESRD alone and (b) in combination to doubling of serum creatinine levels

    (a) End stage renal disease (ESRD)
    Adjusted for Confounders, Gender, and Systolic BP Hazard ratio, 95% CI, and P-value
    Treatment with Ramipril (0 = no; 1 = yes)P for interaction = 0.034
    Phosphate strata [1 = I/II quartile; 2 = III quartile; 3 = IV quartile]
    Treatment * phosphate strata
    Albumin (1 g/dl)0.46 (0.27–0.77), P = 0.003
    Hemoglobin (1 g/dl)0.89 (0.78–1.02), P = 0.10
    Iohexol GFR (1 ml/min/1.73m2)0.94 (0.92–0.96), P < 0.001
    Urinary protein (1 g/24 h)1.13 (1.04–1.23), P = 0.003
    Gender (0 = M; 1 = F)1.56 (0.85–2.85), P = 0.15
    Systolic pressure (1 mmHg)1.03 (1.01–1.04), P < 0.001
    (b) ESRD/doubling of serum creatinine
    Adjusted for confounders, gender and systolic BP Hazard ratio, 95% CI, and P-value
    Treatment with Ramipril (0 = no; 1 = yes)P for interaction = 0.021
    Phosphate strata [1 = I/II quartile; 2 = III quartile; 3 = IV quartile]
    Treatment * phosphate strata
    Albumin (1 g/dl)0.53 (0.33–0.88), P = 0.01
    Hemoglobin (1 g/dl)0.91 (0.80–1.04), P = 0.17
    Iohexol GFR (1 ml/min/1.73m2)0.95 (0.93–0.96), P < 0.001
    Urinary protein (1 g/24 h)1.12 (1.04–1.21), P = 0.003
    Gender (0 = M; 1 = F)1.34 (0.76–2.36), P = 0.23
    Systolic pressure (1 mmHg)1.02 (1.01–1.04), P = 0.001
    • Data are expressed as hazard ratio, 95% CI, and P-values.

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Journal of the American Society of Nephrology: 22 (10)
Journal of the American Society of Nephrology
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1 Oct 2011
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Phosphate May Promote CKD Progression and Attenuate Renoprotective Effect of ACE Inhibition
Carmine Zoccali, Piero Ruggenenti, Annalisa Perna, Daniela Leonardis, Rocco Tripepi, Giovanni Tripepi, Francesca Mallamaci, Giuseppe Remuzzi
JASN Oct 2011, 22 (10) 1923-1930; DOI: 10.1681/ASN.2011020175

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Phosphate May Promote CKD Progression and Attenuate Renoprotective Effect of ACE Inhibition
Carmine Zoccali, Piero Ruggenenti, Annalisa Perna, Daniela Leonardis, Rocco Tripepi, Giovanni Tripepi, Francesca Mallamaci, Giuseppe Remuzzi
JASN Oct 2011, 22 (10) 1923-1930; DOI: 10.1681/ASN.2011020175
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