Atrial natriuretic peptide for preventing and treating acute kidney injury

Sagar U Nigwekar; Sankar D Navaneethan; Chirag R Parikh; John K Hix

doi:10.1002/14651858.CD006028.pub2

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Figure 1

Funnel plot of comparison: 7 ANP in AKI, outcome: 7.1 Mortality.

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Figure 2

Funnel plot of comparison: 7 ANP in AKI, outcome: 7.2 Need for RRT.

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Figure 3

Flow chart of study selection

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Analysis 1.1

Comparison 1 ANP for preventing AKI, Outcome 1 Mortality ‐ low versus high dose studies.

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Analysis 1.2

Comparison 1 ANP for preventing AKI, Outcome 2 Mortality ‐ active versus placebo/no treatment control group.

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Analysis 1.3

Comparison 1 ANP for preventing AKI, Outcome 3 Need for RRT ‐ low versus high dose studies.

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Analysis 1.4

Comparison 1 ANP for preventing AKI, Outcome 4 Need for RRT ‐ active versus placebo/no treatment control group.

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Analysis 1.5

Comparison 1 ANP for preventing AKI, Outcome 5 Length of hospital stay (days) ‐ low versus high dose studies.

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Analysis 1.6

Comparison 1 ANP for preventing AKI, Outcome 6 Length of hospital stay (days) ‐ active versus placebo/no treatment control group.

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Analysis 1.7

Comparison 1 ANP for preventing AKI, Outcome 7 Length of ICU stay (days) ‐ low versus high dose studies.

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Analysis 1.8

Comparison 1 ANP for preventing AKI, Outcome 8 Length of ICU stay (days) ‐ active versus placebo/no treatment control group.

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Analysis 1.9

Comparison 1 ANP for preventing AKI, Outcome 9 Change in SCr (mg/dL) ‐ low versus high dose studies.

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Analysis 1.10

Comparison 1 ANP for preventing AKI, Outcome 10 Change in SCr (mg/dL) ‐ active versus placebo/no treatment control group.

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Analysis 1.11

Comparison 1 ANP for preventing AKI, Outcome 11 Hypotension ‐ low versus high dose studies.

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Analysis 1.12

Comparison 1 ANP for preventing AKI, Outcome 12 Hypotension ‐ active versus placebo/no treatment control group.

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Analysis 1.13

Comparison 1 ANP for preventing AKI, Outcome 13 Arrhythmias (atrial fibrillation) ‐ low versus high dose studies.

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Analysis 1.14

Comparison 1 ANP for preventing AKI, Outcome 14 Arrhythmias (atrial fibrillation) ‐ active versus placebo/no treatment control group.

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Analysis 1.15

Comparison 1 ANP for preventing AKI, Outcome 15 Arrhythmias (premature ventricular contractions) ‐ low versus high dose studies.

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Analysis 1.16

Comparison 1 ANP for preventing AKI, Outcome 16 Arrhythmias (premature ventricular contractions) ‐ active versus placebo/no treatment control group.

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Analysis 1.17

Comparison 1 ANP for preventing AKI, Outcome 17 Arrhythmias (ventricular tachycardia) ‐ low versus high dose studies.

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Analysis 1.18

Comparison 1 ANP for preventing AKI, Outcome 18 Arrhythmias (ventricular tachycardia) ‐ active versus placebo/no treatment control group.

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Analysis 2.1

Comparison 2 ANP for treating AKI, Outcome 1 Mortality ‐ low versus high dose studies.

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Analysis 2.2

Comparison 2 ANP for treating AKI, Outcome 2 Mortality ‐ active versus placebo/no treatment control group.

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Analysis 2.3

Comparison 2 ANP for treating AKI, Outcome 3 Need for RRT ‐ low versus high dose studies.

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Analysis 2.4

Comparison 2 ANP for treating AKI, Outcome 4 Need for RRT ‐ active versus placebo/no treatment control group.

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Analysis 2.6

Comparison 2 ANP for treating AKI, Outcome 6 Length of ICU stay (days) ‐ low versus high dose studies.

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Analysis 2.7

Comparison 2 ANP for treating AKI, Outcome 7 Length of ICU stay (days) ‐ active versus placebo/no treatment control group.

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Analysis 2.13

Comparison 2 ANP for treating AKI, Outcome 13 Hypotension ‐ low versus high dose studies.

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Analysis 2.14

Comparison 2 ANP for treating AKI, Outcome 14 Hypotension ‐ active versus placebo/no treatment control group.

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Analysis 2.15

Comparison 2 ANP for treating AKI, Outcome 15 Arrhythmias ‐ low versus high dose studies.

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Analysis 2.16

Comparison 2 ANP for treating AKI, Outcome 16 Arrhythmias ‐ active versus placebo/no treatment control group.

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Analysis 3.1

Comparison 3 Major surgery, Outcome 1 Mortality.

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Analysis 3.2

Comparison 3 Major surgery, Outcome 2 Need for RRT.

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Analysis 3.3

Comparison 3 Major surgery, Outcome 3 Mortality in cardiovascular surgery.

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Analysis 3.4

Comparison 3 Major surgery, Outcome 4 Need for RRT in cardiovascular surgery.

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Analysis 4.1

Comparison 4 Radiocontrast nephropathy, Outcome 1 Incidence of AKI.

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Analysis 5.1

Comparison 5 Oliguric AKI, Outcome 1 Mortality.

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Analysis 5.2

Comparison 5 Oliguric AKI, Outcome 2 Need for RRT.

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Analysis 6.1

Comparison 6 Sensitivity analysis based on methodological quality, Outcome 1 Mortality.

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Analysis 6.2

Comparison 6 Sensitivity analysis based on methodological quality, Outcome 2 Need for RRT.

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Analysis 7.1

Comparison 7 ANP in AKI, Outcome 1 Mortality.

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Analysis 7.2

Comparison 7 ANP in AKI, Outcome 2 Need for RRT.

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Comparison 1. ANP for preventing AKI

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality ‐ low versus high dose studies Show forest plot	11		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Low dose studies	10	794	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.21, 2.23]
1.2 High dose studies	1	24	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Mortality ‐ active versus placebo/no treatment control group Show forest plot	11		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 Active control group	2	57	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Placebo/no treatment control group	9	761	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.21, 2.23]
3 Need for RRT ‐ low versus high dose studies Show forest plot	11	818	Risk Ratio (M‐H, Random, 95% CI)	0.56 [0.32, 0.99]

3.1 Low dose studies	10	794	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.14, 0.71]
3.2 High dose studies	1	24	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.45, 2.23]
4 Need for RRT ‐ active versus placebo/no treatment control group Show forest plot	11	818	Risk Ratio (M‐H, Random, 95% CI)	0.56 [0.32, 0.99]

4.1 Active control group	2	57	Risk Ratio (M‐H, Random, 95% CI)	0.27 [0.06, 1.13]
4.2 Placebo/no treatment control group	9	761	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.35, 1.20]
5 Length of hospital stay (days) ‐ low versus high dose studies Show forest plot	3		Mean Difference (IV, Random, 95% CI)	Subtotals only

5.1 Low dose studies	3	201	Mean Difference (IV, Random, 95% CI)	‐9.50 [‐14.99, ‐4.02]
5.2 High dose studies	0	0	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
6 Length of hospital stay (days) ‐ active versus placebo/no treatment control group Show forest plot	3	201	Mean Difference (IV, Random, 95% CI)	‐9.50 [‐14.99, ‐4.02]

6.1 Active control group	1	37	Mean Difference (IV, Random, 95% CI)	3.0 [‐21.31, 27.31]
6.2 Placebo/no treatment control group	2	164	Mean Difference (IV, Random, 95% CI)	‐10.17 [‐15.80, ‐4.55]
7 Length of ICU stay (days) ‐ low versus high dose studies Show forest plot	4	219	Mean Difference (IV, Random, 95% CI)	‐0.90 [‐1.79, ‐0.01]

7.1 Low dose studies	4	219	Mean Difference (IV, Random, 95% CI)	‐0.90 [‐1.79, ‐0.01]
7.2 High dose studies	0	0	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
8 Length of ICU stay (days) ‐ active versus placebo/no treatment control group Show forest plot	4	219	Mean Difference (IV, Random, 95% CI)	‐0.90 [‐1.79, ‐0.01]

8.1 Active control group	1	37	Mean Difference (IV, Random, 95% CI)	‐1.40 [‐3.45, 0.65]
8.2 Placebo/no treatment control group	3	182	Mean Difference (IV, Random, 95% CI)	‐0.85 [‐1.88, 0.17]
9 Change in SCr (mg/dL) ‐ low versus high dose studies Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

9.1 Low dose studies	2	57	Mean Difference (IV, Random, 95% CI)	0.13 [‐0.15, 0.42]
9.2 High dose studies	0	0	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
10 Change in SCr (mg/dL) ‐ active versus placebo/no treatment control group Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

10.1 Active control group	2	57	Mean Difference (IV, Random, 95% CI)	0.13 [‐0.15, 0.42]
10.2 Placebo/no treatment control	0	0	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
11 Hypotension ‐ low versus high dose studies Show forest plot	10		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

11.1 Low dose studies	9		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
11.2 High dose studies	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
12 Hypotension ‐ active versus placebo/no treatment control group Show forest plot	10		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

12.1 Active control group	2		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
12.2 Placebo/no treatment control group	8		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
13 Arrhythmias (atrial fibrillation) ‐ low versus high dose studies Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

13.1 Low dose studies	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
13.2 High dose studies	0		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
14 Arrhythmias (atrial fibrillation) ‐ active versus placebo/no treatment control group Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

14.1 Active control group	0		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
14.2 Placebo/no treatment control group	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
15 Arrhythmias (premature ventricular contractions) ‐ low versus high dose studies Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

15.1 Low dose studies	2	272	Risk Ratio (M‐H, Random, 95% CI)	0.26 [0.14, 0.48]
15.2 High dose studies	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
16 Arrhythmias (premature ventricular contractions) ‐ active versus placebo/no treatment control group Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

16.1 Active control group	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
16.2 Placebo/no treatment group	2	272	Risk Ratio (M‐H, Random, 95% CI)	0.26 [0.14, 0.48]
17 Arrhythmias (ventricular tachycardia) ‐ low versus high dose studies Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

17.1 Low dose studies	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
17.2 High dose studies	0		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
18 Arrhythmias (ventricular tachycardia) ‐ active versus placebo/no treatment control group Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

18.1 Active control group	0		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
18.2 Placebo/no treatment control group	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 1. ANP for preventing AKI

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Comparison 2. ANP for treating AKI

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality ‐ low versus high dose studies Show forest plot	8	1103	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.90, 1.24]

1.1 Low dose studies	6	290	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.41, 1.49]
1.2 High dose studies	3	813	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.91, 1.29]
2 Mortality ‐ active versus placebo/no treatment control group Show forest plot	8	1103	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.90, 1.24]

2.1 Active control group	1	53	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.18, 1.27]
2.2 Placebo/no treatment control group	7	1050	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.92, 1.27]
3 Need for RRT ‐ low versus high dose studies Show forest plot	8	1103	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.68, 1.08]

3.1 Low dose studies	6	290	Risk Ratio (M‐H, Random, 95% CI)	0.54 [0.30, 0.98]
3.2 High dose studies	3	813	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.83, 1.14]
4 Need for RRT ‐ active versus placebo/no treatment control group Show forest plot	8	1103	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.68, 1.08]

4.1 Active control group	1	53	Risk Ratio (M‐H, Random, 95% CI)	0.45 [0.21, 0.95]
4.2 Placebo/no treatment control group	7	1050	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.74, 1.13]
5 Length of hospital stay (days)	0	0	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
6 Length of ICU stay (days) ‐ low versus high dose studies Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

6.1 Low dose studies	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
6.2 High dose studies	0		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
7 Length of ICU stay (days) ‐ active versus placebo/no treatment control group Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

7.1 Active control group	0		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
7.2 Placebo/no treatment control group	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
8 Change in SCr (mg/dL)	0	0	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
9 Change in serum BUN	0	0	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
10 Change in CrCl or GFR	0	0	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
11 Duration of AKI	0	0	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
12 Conversion from oliguric to non‐oliguric AKI	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
13 Hypotension ‐ low versus high dose studies Show forest plot	8	1103	Risk Ratio (M‐H, Random, 95% CI)	1.69 [1.29, 2.22]

13.1 Low dose studies	6	290	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.87, 1.81]
13.2 High dose studies	3	813	Risk Ratio (M‐H, Random, 95% CI)	1.92 [1.33, 2.77]
14 Hypotension ‐ active versus placebo/no treatment control group Show forest plot	8	1103	Risk Ratio (M‐H, Random, 95% CI)	1.69 [1.29, 2.22]

14.1 Active control group	1	53	Risk Ratio (M‐H, Random, 95% CI)	2.32 [0.10, 54.52]
14.2 Placebo/no treatment control group	7	1050	Risk Ratio (M‐H, Random, 95% CI)	1.68 [1.26, 2.23]
15 Arrhythmias ‐ low versus high dose studies Show forest plot	3	785	Risk Ratio (M‐H, Random, 95% CI)	1.65 [0.98, 2.77]

15.1 Low dose studies	1	59	Risk Ratio (M‐H, Random, 95% CI)	1.21 [0.83, 1.74]
15.2 High dose studies	2	726	Risk Ratio (M‐H, Random, 95% CI)	2.03 [1.25, 3.31]
16 Arrhythmias ‐ active versus placebo/no treatment control group Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

16.1 Active control group	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
16.2 Placebo/no treatment control group	3	785	Risk Ratio (M‐H, Random, 95% CI)	1.65 [0.98, 2.77]

Comparison 2. ANP for treating AKI

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Comparison 3. Major surgery

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	14	817	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.71, 1.37]

1.1 Prevention studies	9	551	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.21, 2.23]
1.2 Treatment studies	5	266	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.53, 1.65]
2 Need for RRT Show forest plot	14	817	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.37, 0.92]

2.1 Prevention studies	9	551	Risk Ratio (M‐H, Random, 95% CI)	0.56 [0.32, 0.99]
2.2 Treatment studies	5	266	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.22, 1.41]
3 Mortality in cardiovascular surgery Show forest plot	8	493	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.37, 1.43]

4 Need for RRT in cardiovascular surgery Show forest plot	8	493	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.18, 0.70]

Comparison 3. Major surgery

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Comparison 4. Radiocontrast nephropathy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of AKI Show forest plot	2	267	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.73, 2.03]

Comparison 4. Radiocontrast nephropathy

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Comparison 5. Oliguric AKI

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	5	535	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.84, 1.23]

1.1 Prevention studies	1	9	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 Treatment studies	4	526	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.84, 1.23]
2 Need for RRT Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 Prevention studies	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Treatment studies	4	528	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.70, 1.01]

Comparison 5. Oliguric AKI

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Comparison 6. Sensitivity analysis based on methodological quality

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	3	785	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.91, 1.29]

1.1 Low dose studies	1	59	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.38, 2.17]
1.2 High dose studies	2	726	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.92, 1.30]
2 Need for RRT Show forest plot	3	785	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.71, 1.14]

2.1 Low dose studies	1	59	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.20, 1.00]
2.2 High dose studies	2	726	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.80, 1.13]

Comparison 6. Sensitivity analysis based on methodological quality

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Comparison 7. ANP in AKI

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	19		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Low dose prevention studies	10	794	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.21, 2.23]
1.2 High dose prevention studies	1	24	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.3 Low dose treatment studies	6	290	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.41, 1.49]
1.4 High dose treatment studies	3	813	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.91, 1.29]
2 Need for RRT Show forest plot	19	1921	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.65, 1.01]

2.1 Low dose prevention studies	10	794	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.14, 0.71]
2.2 High dose prevention studies	1	24	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.45, 2.23]
2.3 Low dose treatment studies	6	290	Risk Ratio (M‐H, Random, 95% CI)	0.54 [0.30, 0.98]
2.4 High dose treatment studies	3	813	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.83, 1.14]

Comparison 7. ANP in AKI

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