Download this article's Factoid (PDF & PPT for Gold Subscribers)

Administering atrial natriuretic peptide (ANP) to patients with chronic kidney disease (CKD) who are undergoing on-pump coronary artery bypass graft (CABG) surgery helps to preserve kidney function and avoid dialysis both perioperatively and over 1 year, according to a study published in the August 23, 2011, issue of the Journal of the American College of Cardiology.

For the NU-HIT (Nihon University Working Group Study of Low-Dose hANP Infusion Therapy During Cardiac Surgery) trial, investigators led by Akira Sezai, MD, PhD, of Nihon University School of Medicine (Tokyo, Japan), randomized 285 patients with CKD who were undergoing on-pump CABG to low-dose infusion of recombinant human ANP (hANP; n = 141) or saline (n = 144). An initial hANP dose of 0.02 μg/kg/min was administered at the start of cardiopulmonary bypass, decreased to 0.01 μg/kg/min when oral medication was begun, and discontinued after another 12 hours.

There were no differences in baseline characteristics between the 2 groups.

Patients Spared Dialysis

The length of hospital stay was shorter in the hANP group than in the placebo group (13.1 ± 6.1 days vs. 17.4 ± 14.6 days; P = 0.0015). During the early postoperative period, only 1 patient in the hANP arm vs. 8 patients in the placebo arm required dialysis (P = 0.0060). And at 1 year the rate of those remaining free of dialysis (co-primary endpoint) was 98.6% in the hANP group compared with 91.6% in the placebo group (P = 0.0066).

Serum creatinine and estimated glomerular filtration rate (eGFR) were the other co-primary endpoints. Although baseline serum creatinine was equivalent between the groups, by the first postoperative day levels were lower in the hANP group than in the placebo group (1.34 ± 0.05 mg/dL vs. 1.49 ± 0.05 mg/dL), and the difference continued through 3 days, 1 week, 1 month, 6 months, and 1 year (P < 0.01 for all time points). The same pattern was seen for eGFR.

In addition, hANP patients experienced fewer in-hospital deaths (0 vs. 4) and complications (10 including 1 acute renal failure vs. 20 including 7 acute renal failures) than placebo patients, but the differences were not statistically significant. Between discharge and 1 year, 1 patient in the hANP group and 2 patients in the placebo group died, yielding Kaplan-Meier estimated survival rates of 99.3% and 95.8%, respectively. Over the first year, fewer hANP than placebo patients experienced cardiac events (25 vs. 55), mostly arrhythmias, for a cardiac event-free rate of 82.3% in the hANP group vs. 61.8% in the placebo group (P < 0.0001).

Peak creatinine value was lower in the hANP group compared with the placebo group, as were the percent increase in creatinine and the proportion of patients whose creatinine rose by at least 0.3 mg/dL. In addition, postoperative creatinine greater than 1.5 mg/dL was less frequent in hANP patients (table 1).

Table 1. Postoperative Serum Creatinine

 
From a pharmacodynamic perspective, while ANP levels immediately before surgery were similar for the 2 groups, by the first postoperative day they had increased almost tenfold in the hANP group and were markedly higher than in the placebo group (560.3 ± 417.9 pg/dL vs. 161.9 ± 308.2 pg/dL; P < 0.01). At 1 week, however, ANP levels in the hANP group had fallen below those in the placebo group; and by 1 month, there was no difference between the 2 arms.

Dr. Sezai and colleagues observe that although hANP is not thought to have any long-term pharmacological effects, its perioperative renal protection translated into reduced dialysis and cardiac events over the year after surgery.

Kidney Injury Not Measured

Drawbacks of the study are that it did not measure biomarkers of renal injury such as cystatin C and albuminuria or pin down the renal effects of hANP, the authors note, but a randomized trial now underway should fill those gaps.

Meanwhile, the findings suggest that “perioperative infusion of low-dose [hANP] may have a significant role in the management of patients with renal dysfunction undergoing on-pump CABG,” they conclude.

Currently hANP is only available in Japan, where it is known as carperitide (Daiichi-Sankyo Pharmaceutical, Tokyo, and Asubio Pharmaceuticals, Kobe, Japan). But the recombinant form of a similar hormone, B-type natriuretic peptide (BNP), is sold in the United States as nesiritide (Natrecor; Johnson & Johnson, New Brunswick, NJ) to treat acute decompensated heart failure. Earlier research found that the compound improves postoperative biomarker levels but does not reduce the need for dialysis, while results for survival have been mixed.

Optimal Peptide, Combination Unknown

In an accompanying editorial, Guido Boerrigter, MD, and John C. Burnett Jr, MD, of the Mayo Clinic (Rochester, MN), write that both ANP and BNP, which are guanylyl cyclase agonists, likely act through multiple mechanisms, including suppression of aldosterone and angiotensin as well as the sympathetic nervous system. In addition, guanylyl cyclase-A activation may improve renal perfusion and promote cell survival, thus inhibiting loss of functional renal tissue, they note.

According to the editorialists, however, several questions regarding optimal therapeutic use of these peptides need further investigation, including whether they exhibit clinical differences, especially in regard to hypotension risk, and if their activity might be improved by adding inhibitors of their degradation.

Nonetheless, Drs. Boerrigter and Burnett say, the current study is a reminder that guanylyl cyclase-A agonism “has shown promising cardiorenal protective effects in several studies, and that it remains an attractive therapeutic target worthy of continuing investigation.”

Study Details

CKD was defined as a preoperative eGFR less than 60 mL/min/1.73 m². Patients who were on dialysis or in cardiogenic shock were excluded.

Surgical procedures and postoperative management, including aortic cross-clamp time, cardiopulmonary bypass time, number of bypasses performed, and mechanical support were similar for the hANP and placebo groups.

 

---

Sources:
1. Sezai A, Hata M, Niino T, et al. Results of low-dose human atrial natriuretic peptide infusion in nondialysis patients with chronic kidney disease undergoing coronary artery bypass surgery: The NU-HIT (Nihon University Working Group Study of Low-Dose hANP Infusion Therapy During Cardiac Surgery) trial for CKD. J Am Coll Cardiol. 2011;58:897-903.

2. Boerrigter G, Burnett JC. Natriuretic peptides: Renal protective after all? J Am Coll Cardiol. 2011;58:904-906.

 

 

Related Story:

• Study Highlights Difficulty in Treating MI Patients with Kidney Disease