KDIGO Clinical Practice Guideline for Acute Kidney Injury
Natriuretic peptides for the prevention or treatment of AKI: Recommendations and Rationale

Natriuretic peptides for the prevention or treatment of AKI

Several natriuretic peptides are in clinical use or in development for treatment of congestive heart failure (CHF) or renal dysfunction, and could potentially be useful to prevent or treat AKI.

Atrial natriuretic peptide (ANP) is a 28-amino-acid peptide with diuretic, natriuretic, and vasodilatory activity.²²⁴ ANP is mainly produced in atrial myocytes, and the rate of release from the atrium increases in response to atrial stretch.²²⁵ Early animal studies showed that ANP decreases preglomerular vascular resistance and increases postglomerular vascular resistance, leading to increased GFR.²²⁶ It also inhibits renal tubular sodium reabsorption. Increases in GFR and diuresis have also been confirmed in clinical studies.²²⁷ It could thus be expected that ANP might be useful for treatment of AKI, and several RCTs have been conducted to test this hypothesis.

• 3.5.3: We suggest not using atrial natriuretic peptide(ANP) to prevent (2C) or treat (2B) AKI.

Rationale

There have been several negative studies of prophylactic ANP therapy; for example, ANP failed in two studies to prevent primary renal transplant dysfunction^228,229 and ANP prophylaxis also failed to prevent CI-AKI.²³⁰ Based on the positive results of small clinical studies using ANP to treat AKI, a randomized placebo-controlled trial in 504 critically ill patients with AKI was conducted.²³¹ Patients received 24-hour i.v. infusion of either ANP (0.2 µg/kg/min) or placebo. The primary outcome was dialysis-free survival for 21 days after treatment. Despite the large size of the trial, ANP administration had no effect on 21-day dialysis-free survival, mortality, or change in plasma creatinine concentration. Of note, the mean SCr at enrollment (anaritide group: 4.4 mg/dl [389 µmol/l]; placebo group: 5.0 mg/dl [442 µmol/l]) in this study confirms that intervention in this trial was extremely late in the course of AKI. In subgroup analysis, dialysis-free survival was higher in the treatment group for patients with oliguria ( < 400 ml/d; ANP 27%, placebo 7%, P = 0.008). A subsequent trial in 222 patients with oliguric renal failure, however, failed to demonstrate any benefit of ANP.²³² The dose and duration of ANP treatment and primary outcome were the same as the previous study. The dose of ANP might have been too high (0.2 µg/kg/min) in both studies: hypotension (systolic blood pressure < 90mm Hg) occurred more frequently in the ANP groups of both trials (in the first study, 46% vs. 18%, P < 0.001; and in the second study, 97% vs. 58%, P < 0.001), and this may have negated any potential benefit of renal vasodilation in these patients. In addition to an excessive dose, the failure of these large studies has also been attributed in subsequent analyses to the late initiation of the drug to patients with severe AKI and an inadequate duration of infusion (only 24 hours).

A promising, but underpowered, study of ANP to treat AKI immediately following cardiac surgery showed a decreased rate of postoperative RRT compared to placebotreated patients.²³³ In this study, Sward et al. randomized 61 patients with AKI following cardiac surgery (defined as a SCr increase ≥ 50% from a baseline < 1.8 mg/dl [< 159 µmol/l]) to receive infusion of ANP or placebo until the SCr decreased below the baseline value at enrollment, the patient died, or one of four prespecified dialysis criteria was reached. Of note, all patients received infusions of furosemide (20–40 mg/h) and oliguria, defined as a urine output ≤ 0.5 ml/kg/h for 3 hours, was an exclusion criterion and an automatic dialysis indication. The primary end-point was the rate of dialysis within 21 days of enrollment. CrCl was significantly higher on the third study day in ANP-treated subjects (P = 0.04). Using prespecified dialysis criteria, 21% of patients in the ANP group and 47% in the placebo group were dialyzed within 21 days (hazard ratio [HR] 0.28; 95% CI 0.10–0.73; P = 0.009). The combined secondary end-point of death-ordialysis was similarly improved in the ANP group (28%) compared to placebo (57%; HR 0.35; 95% CI 0.14–0.82; P = 0.017). The incidence of hypotension during the first 24 hours was 59% in the ANP group and 52% in controls (P = NS).

It is intriguing to speculate on the potential reasons for the positive outcome of this trial, compared to larger prior studies of ANP for AKI prevention and therapy. Apart from the possibility that this is a false-positive, underpowered study, possible explanations include the use of ANP earlier in the course of AKI (the mean SCr in the prior ANP studies was much higher), and at lower doses (50 ng/kg/min vs. 200 ng/kg/min) that avoided the significant rate of hypotension observed in prior trials. The use of prespecified dialysis criteria was another strength of this trial. More recently, Sward et al.,²³⁴ compared the renal hemodynamic effects of ANP and furosemide in 19 mechanically ventilated post–cardiac surgery patients with normal renal function, measuring renal blood flow, GFR, and renal oxygen extraction. ANP infusion (25–50 ng/kg/min) increased GFR, filtration fraction, fractional excretion of sodium, and urine output, accompanied by a 9% increase in tubular sodium absorption and a 26% increase in renal oxygen consumption. Furosemide infusion (0.5 mg/kg/h) increased urine output 10-fold and fractional excretion of sodium 15-fold, while decreasing tubular sodium absorption by 28% and lowering renal oxygen consumption by 23%. Furosemide also lowered GFR by 12% and filtration fraction by 7%. Thus, although the balance of renal hemodynamic and tubular effects of the two drugs appears to favor furosemide for improving renal oxygen delivery-consumption balance, ANP is more likely to acutely improve GFR. One might speculate that the use of furosemide infusion in all of the subjects in the successful ANP trial may have provided an important protection against renal ischemia by reducing tubular sodium absorption and associated oxygen consumption, despite an increase in GFR in the ANP group. A larger prospective trial of ANP to improve dialysis-free survival in this setting is required, perhaps with and without furosemide infusion.

Pooled analysis of 11 studies involving 818 participants in the prevention cohort showed a trend toward reduction in the need for RRT in the ANP group (OR 0.45; 95% CI 0.21–0.99; P = 0.05). Restricting the analysis to studies that used low-dose ANP preparations did not change the overall effect for this outcome. There was no significant difference noted between the ANP and control groups for mortality in the prevention category (OR 0.67; 95% CI 0.19–2.35; P = 0.53), and this effect was unchanged by restricting the analysis to studies that used low-dose ANP preparations. However, these studies were generally of poor quality, several without reported baseline SCr values or clear definitions of AKI or RRT indications (Suppl Tables 10 and 11), and only one was of adequate quality.

Nigwekar et al., recently conducted a systematic review and meta-analysis of ANP for management of AKI.²³⁵ They found 19 relevant studies, among which 11 studies were for prevention and eight were for treatment of AKI. Pooled analysis of the eight treatment studies, involving 1043 participants, did not show significant difference for RRT requirement between the ANP and control groups (OR 0.59; 95% CI 0.32–1.08; P = 0.12). There was also no significant difference for mortality (OR 1.01; 95% CI 0.72–1.43; P = 0.89). However, low-dose ANP preparations were associated with significant reduction in RRT requirement (OR 0.34; 95% CI 0.12–0.96; P = 0.04). The incidence of hypotension was not different between the ANP and control groups for low-dose studies (OR 1.55; 95% CI 0.84–2.87), whereas it was significantly higher in the ANP group in the high-dose ANP studies (OR 4.13; 95% CI 1.38–12.41). Finally, a pooled analysis of studies that examined oliguric AKI did not show any significant benefit from ANP for RRT requirement (OR 0.46; 95% CI 0.19–1.12; P = 0.09) or mortality (OR 0.94; 95% CI 0.62–1.43; P = 0.79). Only two of the treatment studies included in the Nigwekar analysis ^231,232 were of adequate size and quality to meet the criteria for our systematic review (Suppl Tables 12 and 13), which found no significant inconsistencies in the findings of both trials that (combined) included 720 subjects (351 treated with ANP) (Suppl Table 12). Thus, although subset analyses separating low-dose from high-dose ANP trials suggest potential benefits, the preponderance of the literature suggests no benefit of ANP therapy for AKI. Therefore, the Work Group suggests that these agents not be used to prevent or treat AKI. This conclusion is based on placing a high value on avoiding potential hypotension and harm associated with the use of a vasodilator in high-risk perioperative and ICU patients, and a low value on potential benefit which is supported by relatively low-quality evidence from retrospective subset analyses from negative multicenter trials.

Urodilatin is another natriuretic peptide that is produced by renal tubular cells, and was found to have the same renal hemodynamic effect as ANP without systemic hypotensive effects.²³⁶ Limited data suggest that urodilatin improves the course of established postoperative AKI.²³⁷ Fifty-one patients who received orthotopic heart transplants received urodilatin (6–20 ng/kg/min) up to 96 hours postoperatively. AKI occurred in 6% of these patients, compared to 20% in a historical control group that did not receive urodilatin.²³⁷ However, in another small, placebo-controlled study of 24 patients who underwent orthotopic heart transplants, the incidence of AKI was unchanged,²³⁸ although duration of hemofiltration (HF) was significantly shorter and the frequency of intermittent hemodialysis (IHD) less in those who received urodilatin. Taken together, these data suggest that natriuretic peptides may have a role in the therapy of early AKI following cardiac surgery, but further prospective trials are needed to confirm this potential indication.

Nesiritide (brain natriuretic peptide) is the latest natriuretic peptide introduced for clinical use, and is approved by the Food and Drug Administration (FDA) only for the therapy of acute, decompensated CHF. Meta-analysis of outcome data from these and some other nesiritide CHF trials has generated some controversy.^239-241 Sackner-Bernstein et al.,²³⁹ analyzed mortality data from 12 randomized trials; in three trials that provided 30-day mortality data, they found a trend towards an increased risk of death in nesiritidetreated subjects. In another meta-analysis of five randomized trials that included 1269 subjects,²⁴⁰ the same investigators also found that there was a relationship between nesiritide use and worsening renal function, defined as a SCr increase > 0.5 mg/dl ( > 44.2 µmol/l). Nesiritide doses ≤ 0.03 µg/kg/min significantly increased the risk of renal dysfunction compared to non–inotrope-based controls or compared to all control groups (including inotropes). Even at doses ≤ 0.015 µg/kg/min, nesiritide was associated with increased renal dysfunction compared to controls. There was no difference in dialysis rates between the groups. Another retrospective study determined independent risk factors for 60-day mortality by multivariate analysis in a cohort of 682 elderly heart-failure patients treated with nesiritide vs. those who were not.²⁴² When patients were stratified according to nesiritide usage, AKI emerged as an independent risk factor for mortality only among patients who received the drug. Strikingly, among these heart-failure patients who developed AKI, nesiritide usage emerged as the only independent predictor of mortality.

The manufacturers of nesiritide convened an expert panel, which concluded that further trial data are needed to discern the effects of nesiritide therapy on renal function and survival in patients with decompensated CHF. The panel also reemphasized that the indication for nesiritide therapy is acute decompensated CHF, not chronic intermittent therapy or other uses, and in particular noted that the drug should not be used to improve renal function or in place of diuretic therapy in CHF patients, as there is no proof of the utility of the drug for these purposes. A 7000-patient multicenter RCT in acute decompensated heart failure is currently in progress to determine the clinical effectiveness of nesiritide therapy for acute decompensated heart failure (the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure; Clinicaltrials.gov identifier NCT00475852). Meanwhile, nesiritide is approved for treatment of symptomatic acute decompensated heart failure.

Uncontrolled studies using nesiritide for cardiovascular support of patients with CHF undergoing cardiac surgery have suggested beneficial effects on renal function. Mentzer et al.,²⁴³ conducted a 303-patient, multicenter, randomized, double-blind trial of a 24- to 96-hour infusion of 0.01 µg/kg/ min of nesiritide vs. placebo in patients with chronic left ventricular dysfunction (ejection fraction ≤ 40%) undergoing cardiac surgery using cardiopulmonary bypass. The Nesiritide Administered Peri-Anesthesia in Patients Undergoing Cardiac Surgery trial was an exploratory, safetyoriented study with five primary end-points, including three renal end-points and two hemodynamic end-points. There were no significant differences between the groups in baseline patient characteristics; SCr values were ~1.1 mg/dl (97.2 µmol/l), with eGFR ~80 ml/min per 1.73 m². The mean duration of study drug infusion was ~40 hours in both groups. Perioperative renal function quantified by the three renal primary end-points was better in the nesiritide group (peak SCr increase of 0.15 mg/dl [13.3 µmol/l] vs. placebo group 0.34 mg/dl [30.1 µmol/l]; P < 0.001; eGFR decrease of -10.2 ml/min per 1.73 m² vs. placebo -17.8 ml/ min per 1.73 m², P = 0.001; initial 24-hour urinary output 2.9 ± 1.2 l vs. placebo 2.3 ± 1 l; P < 0.001). The RR of AKI in the nesiritide group compared to placebo was 0.58 (0.27–1.21); the 180-day mortality was also reduced in the nesiritide group (RR 0.48 [0.22–1.05]; P = 0.046) (Suppl Table 9). These trends were more pronounced in the small, 62-patient subset with preoperative SCr values > 1.2 mg/dl ( > 106 µmol/l). Although SCr increased postoperatively in both groups, it returned to baseline within 12 hours in the nesiritide group, and remained elevated throughout hospitalization in the placebo group. Use of vasoactive drugs and hemodynamic parameters did not differ significantly between the groups. Adverse events also were similar between the groups, as was 30-day and 180-day mortality (although capture of mortality data was incomplete). Thus, it appears that administration of nesiritide infusion during and after cardiac surgery with cardiopulmonary bypass in patients with preoperative left ventricular dysfunction has favorable short-term effects on renal function, with short-term adverse effects comparable to placebo infusion; however, as mentioned earlier, this is not an FDA-approved indication for this drug. It is interesting to speculate that, based upon these results, any renoprotective effect of this vasoactive drug during and after cardiopulmonary bypass is not mediated by effects on systemic perfusion (similar in both groups), but rather suggesting an effect on regional perfusion or a pleiotropic phenomenon. Unfortunately, these promising pilot study findings have not been followed up with a confirmatory prospective clinical trial.

A prospective, randomized clinical trial (the Nesiritide Study), found no benefit of nesiritide for 21-day dialysis and/ or death in patients undergoing high-risk cardiovascular surgery.²⁴⁴ However, the study did demonstrate that the prophylactic use of nesiritide was associated with reduced incidence of AKI, the latter defined by the AKIN Group, in the immediate postoperative period (nesiritide 6.6% vs. placebo 28.5%, P = 0.004). Recently, Lingegowda et al.²⁴⁵ investigated whether the observed renal benefits of nesiritide had any long-term impact on cumulative patient survival and renal outcomes. Data on all 94 patients from the Nesiritide Study were obtained with a mean follow-up period of 20.8 ± 10.4 months. No differences in cumulative survival between the groups were noted, but patients with in-hospital incidence of AKI had a higher rate of mortality than those with no AKI (41.4% vs. 10.7%; P = 0.002). It seemed, thus, that the possible renoprotection provided by nesiritide in the immediate postoperative period was not associated with improved long-term survival in patients undergoing highrisk cardiovascular surgery.

In summary, although evidence from a variety of small studies suggests the potential for therapy with natriuretic peptides to be useful for the prevention or treatment of AKI in a variety of settings, there are no definitive trials to support the use of ANP, BNP, or nesiritide for these purposes. Thus, the Work Group suggests that these agents not be used for prevention or treatment of AKI.