Renal ischemia regulates marinobufagenin release in humans

Abstract

Cardiotonic steroids, including marinobufagenin, are a group of new steroid hormones found in plasma and urine of patients with congestive heart failure, myocardial infarction, and chronic renal failure. In animal studies, partial nephrectomy induces marinobufagenin elevation, cardiac hypertrophy, and fibrosis. The objective of this study is to test the effect of renal ischemia on marinobufagenin levels in humans with renal artery stenosis (RAS). To test this, plasma marinobufagenin levels were measured in patients with RAS of the Prospective Randomized Study Comparing Renal Artery Stenting With or Without Distal Protection, non-RAS patient controls who were scheduled for coronary angiography, and normal healthy individuals. Marinobufagenin levels were significantly higher in patients with RAS compared with those of the other 2 groups. Multivariate analysis shows that occurrence of RAS is independently related to marinobufagenin levels. In addition, renal artery revascularization by stenting partially reversed marinobufagenin levels in the patients with RAS (0.77±0.06 nmol/L at baseline; 0.66±0.06 nmol/L at 24 hours; and 0.61±0.05 nmol/L at 1 month). In conclusion, we have found that marinobufagenin levels are increased in patients with RAS, whereas reversal of renal ischemia by stenting treatment reduces marinobufagenin levels. These results suggest that RAS-induced renal ischemia may be a major cause of marinobufagenin release.

Trial registration: ClinicalTrials.gov NCT00234585.

Figure 1

Plasma Marinobufagenin (MBG) levels in RAS patients and control subjects. The MBG concentration was measured in plasma samples from RAS patients or control subjects as described in the Methods section. Panel A shows a representative standard curve of MBG measurement using purified MBG compound; Panel B shows the distribution and mean MBG levels in normal healthy controls (Normal con.), hypertensive patient controls (Patients con.), and patients with renal artery stenosis (RAS patients).

Figure 2

Plasma MBG levels in patients categorized by the severity of RAS (0, stands for patients without RAS; 1 stands for patient with unilateral RAS; and 2 stands for patients with bilateral RAS or RAS patients with only a solitary kidney). The average MBG concentrations are 0.20±0.06 nM in patients without RAS, 0.69±0.07 nM in patients with unilateral RAS (n=32), and 0.88±0.12 nM in patients with bilateral RAS (n=16) respectively.

Figure 3

MBG levels at baseline, 24 hour and 1 month after renal artery stenting in RAS patients. The MBG levels were measured in the plasma samples collected from patients at three time points. The baseline sample was collected immediately before the patient receiving the renal artery stenting and the post stenting samples were collected at 24 hour and 1 month after receiving the renal artery stenting respectively.

Figure 4

MBG levels in the randomized groups at baseline, 24 hour, and 1 month. Patients were randomly assigned into 4 groups before receiving the renal artery stenting as previously described . The control group receives neither Angioguard^® nor abciximab); the Angioguard^® only group (AG) receives Angioguard during the stenting procedure; the abciximab only group (Abciximab) received abciximab treatment before the stenting procedure; and the Angioguard^® & abciximab group (Abciximab & AG) received both abciximab treatment before stenting and the Angioguard^® during the stenting procedure. The plasma MBG concentrations were analyzed in the above 4 groups at their baseline and 24 hour and 1 month post stenting.

Figure 5

Correlation between MBG and glomerular filtration rate (GFR) changes in RAS patients after renal artery stenting. The percentage change of MBG and GFR were calculated using the following formula: 24 h change (%) = (24 h value - baseline value)/baseline value × 100%. Negative values indicate a decrease in MBG or GFR after stenting. Panel A shows the correlation of 24 h change between MBG and GFR in patients with unilateral RAS; Panel B shows the correlation of 24 h change between MBG and GFR in patients with bilateral RAS.