Atrial Natriuretic Peptide for the Prevention of Contrast Induced Nephropathy: “What’s Old is New but at the Right Dose and Duration of Therapy!”

Contrast-induced nephropathy (CIN) is most commonly defined as a 25% increase in serum creatinine concentration from the baseline value, or an absolute increase of at least 0.5 mg/dL, which appears within 48 hours after the administration of radiographic contrast media in the absence of an alternative cause.(1) CIN is the third most common cause of new acute renal failure in hospitalized patients.(2) The incidence of CIN in the general population has been reported to be 2-5 %. However; the incidence may be as high as 25% in patients with pre-existing renal impairment or certain risk factors, such as diabetes, congestive heart failure, advanced age, and concurrent administration of nephrotoxic drugs.(3) Despite the fact that CIN most commonly manifests as a non-oliguric and asymptomatic transient decline in renal function, cohort studies have demonstrated that it is associated with significant morbidity and mortality rates independent of other risk factors. Specifically, Levy et al reported in a study of more than 16,000 patients undergoing contrast-enhanced examinations that in patients who developed CIN, there was a significantly higher mortality rate than in the patient group from the same population matched for age and baseline creatinine levels who underwent similar contrast-enhanced procedures but did not develop CIN (34% vs 7%).(4) CIN was thus found to result in excessive mortality rates, independent of other risk factors.

Although the exact underlying mechanisms of CIN have yet to be fully elucidated, it is most likely multi-factorial due to increased adenosine, endothelin, and free radical induced vasoconstriction with decreased local prostaglandin and nitric oxide (NO) mediated vasodilatation resulting in renal medulla ischemia.(5) Contrast agents also have direct toxic effects on renal tubular cells, resulting in vacuolization, altered mitochondrial function, and apoptosis.(6)

As with all medical conditions, the best treatment for CIN is to prevent it. General measures to minimize the incidence include using the minimal effective dose, eliminating potentially nephrotoxic drugs at least 24 hours before the study and adequate hydration. Several drug interventions include the use of N-acetylcysteine, theophylline, fenoldopam, and other agents have been investigated as preventive strategies in CIN however, the results have been heterogeneous and are difficult to compare across the different treatment strategies. In a recent meta-analysis by Kelly et al which included 33 CIN prevention trials involving 3622 patients, the authors reported that N-acetylcysteine is more renoprotective than hydration alone and theophylline may also reduce risk for contrast-induced nephropathy, although the detected association was not significant.(7) The remaining agents did not significantly affect risk. Importantly, the authors pointed out that the available studies used in the meta-analysis examined laboratory end points (such as an increase in serum creatinine levels) rather than clinical end points (such as dialysis or death).

In this issue of JACC, Morikawa et al reported a single center controlled, randomized trial designed to examine the protective effects of atrial natriuretic peptide (ANP) on CIN after coronary angiography.(8) They randomized 254 consecutive patients with serum creatinine concentrations of ≥1.3 mg/dL, where patients received either ANP or Ringer’s solution alone initiated 4 to 6 hours before angiography and continued during 48 hours. The authors reported that the prevalence of CIN, defined as a 25% rise in creatinine or an increase in creatinine of ≥0.5 mg/dl from baseline within 48 hours, was significantly lower in the ANP group than in the control group (3.2% versus 11.7%, respectively; p=0.015). Multivariate analysis revealed that the use of >155 ml of contrast medium (odds ratio, 6.89; p<0.001) and ANP treatment (odds ratio, 0.24; p=0.016) were significant predictors of developing CIN. The incidence of an increase in creatinine of ≥25% or of ≥0.5 mg/dl from baseline at 1 month was also significantly lower in the ANP group than in the control group (p=0.006).

The natriuretic peptides are a group of structurally similar but genetically distinct peptides which have diverse actions in cardiovascular, renal and endocrine homeostasis. ANP and B type natriuretic peptide (BNP) are of myocardial cell origin, and C type natriuretic peptide (CNP) is of endothelial origin. ANP and BNP bind to the natriuretic peptide-A receptor (NPR-A), which via 3’,5’-cyclic guanosine monophosphate (cGMP), mediates natriuresis, vasodilatation, enhances glomerular filtration rate (GFR), renin-inhibition and anti-ischemic properties.(9) Preclinical studies have demonstrated that ANP and BNP, via the NPR-A receptor, increases GFR and glomerular hydrostatic pressure by dilating afferent arterioles and constricting efferent arterioles, while blocking tubular reabsorption of sodium and disrupting the tubuloglomerular feedback mechanism.(10) Furthermore, they have direct action on the renal mesangial cells to increase glomerular ultrafiltration coefficient which in turn increases GFR.(11) These renal enhancing properties together with anti-ischemic and anti-inflammatory properties have resulted in clinical investigations to determine the therapeutic potential of ANP and BNP for acute renal failure (ARF) and the prevention of CIN. Despite encouraging experimental data, initial clinical trails with ANP in two multicenter, prospective randomized trials in patients with acute tubular necrosis or late oliguric ARF were disappointing.(12,13) In these studies, ANP, at a dose of 200 ng/kg/min for 24 hours had no effect on the need for dialysis, the rate of dialysis-free survival at 21 days after treatment, and overall mortality rate. Subsequently, Sward et al reported in a single center, randomized, double-blind, placebo controlled trial that there was a significant reduction of renal impairment, and of the need for dialysis following cardiopulmonary bypass, with the use of long-term infusion (5 days) of recombinant ANP at a dose of 50 ng/kg/min.(14) The two main differences which may account for the discrepancies of their results and previous studies are the dose of ANP used and the duration of ANP infusion. The earlier studies used high dose of ANP at 200 ng/kg/min while Sward et al used the low dose of 50 ng/kg/min which was associated with less hypotension as compared to the earlier high dose studies. Furthermore, in the earlier studies, the infusion duration was only for 24 hours while Sward et al infused ANP for 5 days. Similarly, Krunik et al reported that ANP infusion at 10, 50 and 100 ng/kg/min initiated at 30 minutes before and continued for 30 minutes after the angiographic procedure did not reduce the incidence of CIN in patients with chronic renal insufficiency.(15) Comparatively, the study by Morikawa et al in the current issue of JACC, the authors infused ANP at 42 ng/kg/min initiated at 4-6 hours before angiography and continued for 48 hours, demonstrated that it was effective in preventing CIN. More importantly, this strategy also prevented worsening renal function at 1 month. This supports the concept that in addition to the dose, the duration of infusion is an important determinant in the efficacy of ANP in preventing CIN. Hence, Morikawa et al should be commended for making the effort to review the previous studies and determining the appropriate dose and duration of infusion for their study. Despite the favorable renal enhancing actions of both ANP and BNP, the hypotension associated with higher doses that results in decreased renal perfusion pressure limits the renal enhancing actions and may even have detrimental renal effects. This is also demonstrated in the clinical investigations of BNP (Nesiritide), where studies have demonstrated that at the clinical dose or higher (2μg/kg bolus followed by continuous infusion of 0.01 μg/kg/min), there is little renal enhancing actions and may even be associated with worsening renal function.(16,17) In contrast, at lower doses (0.01 or 0.005 μg/kg/min without bolus), there are renal enhancing or preserving properties.(18,19) (20)

In summary, CIN is a common cause of hospital acquired acute renal failure and is associated with increased morbidity and mortality. There is currently no established optimal strategy for the prevention of CIN. The study by Morikawa et al in the current issue of JACC has demonstrated the potential of administration of ANP to prevent CIN. More importantly, the authors have carefully determined the effective dose and duration of intervention. A large multiple-center, randomized, placebo controlled trial that is adequately powered with clinical end-points such as reduction in dialysis, hospital stay, etc. is clearly warranted based on the promising results from this pilot study.