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Table of Contents
ORIGINAL ARTICLE
Year : 2018  |  Volume : 7  |  Issue : 3  |  Page : 137-143

Nesiritide modulates inflammatory response during cardiac surgery: A pilot study


1 Division of Thoracic and Cardiovascular Surgery, University of Florida, Gainesville, Florida, USA
2 Division of Nephrology, Hypertension and Renal Transplantation, University of Florida, Gainesville, Florida, USA

Date of Web Publication10-Sep-2018

Correspondence Address:
Dr. Abutaleb A Ejaz
Division of Nephrology, Hypertension and Renal Transplantation, University of Florida, Gainesville, Florida
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/rcm.rcm_15_18

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  Abstract 


Objectives: We investigated the effects of nesiritide (NES) on inflammatory response during cardiac surgery. Materials and Methods: Twenty-nine cardiac surgery patients were randomized to an infusion of NES at 0.01 mcg/kg/min for 48 h versus placebo (Ctrl). A panel of candidate biomarkers and clinical parameters were measured at predetermined time points. Results: There were no significant differences between the groups with regard to urine neutrophil gelatinase-associated lipocalin (NES 230.3 + 71.5 ng/mL vs. Ctrl 554.4 + 263.3 ng/mL, P = 0.253) and urine interleukin (IL)-18 (NES 29.9 + 4.8 pg/mL vs. 254.5 + 118.3 pg/mL, P = 0.090), or to the incidence of acute kidney injury (NES 7.1% vs. Ctrl 13.3%, P = 0.374). A concerted biomarker kinetic pattern of time-differentiated peak concentrations was observed. IL-10, inflammatory protein (IP)-10, IL-6, IL-10, IP-10, monocyte IP (MIP)-1α, interferon (IFN)-α, IFN-α, IL-1a, IL-3, and IL-7 reached peak concentration at 0 h following the end of cardiopulmonary bypass; tumor necrosis factor (TNF)-α, endothelial growth factor (EGF), granulocyte macrophage-colony-stimulating factor (GM-CSF), IL-12p40, IL-17, MIP-1α, and monocyte chemoattractant protein-1 at 1 h; IL-18, vascular EGF (VEGF), IL-13 and IL-1ra at 2 h, TNF-α, G-CSF, IL-1b, IL-2, IL-4, IL-5, and IL-15 at 4 h; and endothelin (ET)-1 and IL-18 at 6 h. At 0 h, the NES group exhibited significant reduction of peak concentrations of IL-6 (P = 0.009), IL-10 (P = 0.009), IL-1α (P = 0.020), IP-10 (P = 0.001), and IFN-α (P = 0.032) compared to the Ctrl group. Significant reduction in peak concentrations of TNF-α (P = 0.007) and MIP1-α (P = 0.027) at 1 h and ET-1 (P = 0.020) at 6 h in the NES group compared to the Ctrl group was noted. Conclusion: NES modulated the concerted inflammatory response in cardiac surgery and also attenuated ET-1 response, thus suggesting that previously observed favorable renal effect may be linked to reduced renal vasoconstriction.

Keywords: Biomarker, cardiac surgery, natriuretic peptide


How to cite this article:
Beaver TM, Cobb JA, Koratala A, Alquadan KF, Ejaz AA. Nesiritide modulates inflammatory response during cardiac surgery: A pilot study. Res Cardiovasc Med 2018;7:137-43

How to cite this URL:
Beaver TM, Cobb JA, Koratala A, Alquadan KF, Ejaz AA. Nesiritide modulates inflammatory response during cardiac surgery: A pilot study. Res Cardiovasc Med [serial online] 2018 [cited 2018 Nov 18];7:137-43. Available from: http://www.rcvmonline.com/text.asp?2018/7/3/137/240989




  Introduction Top


Acute kidney injury (AKI) is a serious complication occurring in up to 30% of patients undergoing cardiac surgery.[1] The incidence is greater in patients undergoing complex valve and thoracic aortic aneurysm surgeries (49%–55%). When AKI is associated with requirement for renal replacement therapy, the mortality can exceed 50%.[2],[3] Several agents including dopamine, fenoldopam, and diuretics have not proven to be effective in preserving renal function, and currently there are no Food and Drug Administration-approved renal protective agents.[4] However, several studies have reported that natriuretic peptides such as nesiritide (NES), a human recombinant brain natriuretic peptide, may have renoprotective effects in cardiac surgery.[5],[6] In a prospective, randomized clinical trial, we demonstrated that prophylactic administration of NES resulted in a significant decrease in the incidence of AKI (NES 6.6% vs. control, Ctrl 28.5%, P = 0.007) as per the Acute Kidney Injury Network criteria.[7] Although the exact mechanism has not been defined, we speculated that the observed benefits were due to renal vasodilatory effects of NES, i.e., maintaining blood flow to the kidney in the face of hypotension from cardiopulmonary bypass (CPB) and inotropic agents. In experimental models, natriuretic peptides have been shown to increase glomerular filtration via renal afferent arteriole dilation. In addition, NES has been shown to reduce the level of the vasoconstrictor endothelin-1 (ET-1), in the setting of heart failure.[8] Others have postulated that the mechanism involves attenuation of the inflammatory response.[9],[10],[11] We therefore investigated the hypothesis that NES confers renoprotection by preserving renal blood flow and attenuating the inflammatory response related to CPB.


  Materials and Methods Top


Clinical study protocol

We investigated the effect of NES on inflammatory response by measuring a panel of candidate biomarkers and clinical parameters at predetermined time points and comparing them with a control group during cardiac surgery. This prospective, double-blinded, placebo-controlled, randomized clinical trial was approved by the Institutional Review Board of the University of Florida and was registered at the National Institutes of Health's ClinicalTrials.gov (NCT01440881). The study was performed under a grant from the State of Florida James and Esther King Biomedical Research Program. Participants were recruited from the Division of Thoracic and Cardiovascular Surgery outpatient clinic at the University of Florida in Gainesville. Adult patients aged between 18 and 80 years with an estimated baseline glomerular filtration rate (GFR) between 30 and 90 mL/min (calculated using the Modification of Diet in Renal Disease equation) who were undergoing complex thoracic aorta or valve surgery were eligible for the study. These patients represent a high-risk group for postoperative AKI as per previous studies.[6],[7] Patients with preoperative intra-aortic balloon pumps, ejection fraction <30%, those receiving aprotinin or dopamine (<5 mcg/kg/min), and organ transplant recipients were excluded from the study. Written informed consents were obtained for all patients.

Eligible patients were randomized to prophylactic NES (0.01 mcg/kg/min for 48 h) or an identical-appearing placebo starting in the operating room immediately prior to surgery [Figure 1].
Figure 1: Study flowchart

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Random allocation sequences were generated by two-factor randomized block design stratified by gender. Randomization was performed by the investigational drug services and concealed until the study was completed. The study participants, physicians, nurses, and data analysis teams were blinded to group assignment. Patients received routine postoperative supportive care including optimization of fluid and nutritional status, inotropic support, and adjustment of medication doses as appropriate for patients with renal dysfunction. Serial blood sampling for cytokines and ET-1 was done at baseline and post-CPB at 0, 1, 2, 4, 6, 8, and 24 h, respectively. AKI was defined according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria as an absolute increase in serum creatinine (SCr) of ≥0.3 mg/dL within 48 h of surgery; SCr >1.5 × baseline or a urine output <0.5 ml/kg/h for 6 h or more.[12] We calculated kinetic-estimated GFR (KeGFR) using the equation by Chan:[13] KeGFR = (steady-state plasma creatinine × creatinine clearance/mean plasma creatinine) × ([1 − (24Δ -h plasma creatinine/Δtime (h) × max Δplasma creatinine/day]). KeGFR allows for estimation of kinetically changing GFR in nonsteady states.

Laboratory methods

Cytokine multiplex assays: Peripheral blood was collected into ethylenediaminetetraacetic acid tubes (BD Vacutainer ®, BD Medical, USA). Plasma was isolated by centrifuging the tubes at 1500 g for 10 min at 4°C and subsequently stored at −80°C until batch cytokine analysis was performed. Twenty-nine cytokines were measured simultaneously using the Milliplex MAP Human Cytokine/Chemokine Magnetic Bead Panel-Immunology multiplex assay (EMD Millipore, Billerica, MA, USA).

ET-1 assay for patient samples: Serum was isolated by allowing peripheral blood to clot at room temperature and then centrifuging at 1500 g for 10 min at 4°C. Serum samples were stored at − 80°C until batch analysis of ET-1 levels was performed using enzyme-linked immunosorbent assay kits (R&D Systems, Minneapolis, MN).

Statistical analysis

Baseline patient characteristics are presented as mean ± standard error of mean. Continuous variables were compared with a two-sample t-test or Wilcoxon rank-sum test and dichotomous variables with Chi-squared test or Fisher's exact test and P < 0.05 was considered statistically significant. Frequencies of categorical variables were reported as a percentage and the Fisher's exact test was used to test independence between categorical variables. Continuous variables that did not satisfy the normality assumptions were reported as medians and 25th–75th percentiles, and the Mann–Whitney U-test was used for comparisons. Multiple comparisons of biomarkers in the two study groups were analyzed with two-way analysis of variance (ANOVA). Bonferroni correction was used to counteract the problem of multiple comparisons. All analyses were conducted using SPSS version 20 (IBM Corp., Chicago IL, USA). The study conception, design, execution, data collection, analysis, and manuscript preparation were performed in its entirety and independently by the investigators. All authors had independent access to data and analysis.


  Results Top


Patient characteristics and perioperative data

The baseline characteristics of the 29 study participants are shown in [Table 1]. All of the participants were Caucasians. They were predominantly males, had baseline mean eGFR consistent with Stage 2 chronic kidney disease, and cardiac valve surgery (n = 20) was the most common procedure performed [Table 2]. There were no significant differences in baseline characteristics between the groups with the exception that more patients in the Ctrl group were taking beta blockers. The NES group was associated with significantly reduced aortic cross-clamp and CPB time and also had shorter mechanical ventilation time than the placebo (Ctrl) group, despite similar types of surgeries being performed in each group.
Table 1: Patient characteristics

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Table 2: Perioperative and hospital data

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Acute kidney injury

There were no significant differences between the groups with regard to the early biomarkers of AKI: urine neutrophil gelatinase-associated lipocalin (NGAL) (NES 230.3 + 71.5 ng/mL vs. Ctrl 554.4 + 263.3 ng/mL, P = 0.253) and urine interleukin (IL)-18 (NES 29.9 + 4.8 pg/mL vs. Ctrl 254.5 + 118.3 pg/mL, P = 0.090). No significant differences in postoperative day 1 or day 2 or 48-h peak SCr or hospital peak SCr values could be demonstrated between the groups [Table 2]. The incidence of AKI, based on SCr, between the groups was not significantly different: NES 7.1% vs. Ctrl 13.3%, P = 0.374. Applying the KDIGO urine output criteria for AKI (i.e., urine output <0.5 ml/kg/h for 6 h), the incidence of AKI was NES 57% vs. Ctrl 80% but not statistically significant (P = 0.245). None of the patients required renal replacement therapy. There was one death in the control group. Urine NGAL and IL-18 were determined at 6 h.

Inflammatory response markers

To understand the relative changes in biomarker concentration over time and to investigate the effect of NES on biomarker kinetics during cardiac surgery, we plotted median biomarker concentrations at baseline, 0, 1, 2, 4, 6, 8, and 24 h [Figure 2]a.[14] To create this figure, the time points with the highest median value were set to 100% and all other time points were converted to a percentage of this maximum. The kinetics of the individual biomarkers demonstrated unique time-differentiated peak median concentrations. Inducible protein (IP)-10, IL-6, IL-10, monocyte IP (MIP)-1α, interferon (INF)-α, INF-γ, IL-1α, IL-3, and IL-7 reached peak concentration at 0 h following the end of CPB; tumor necrosis factor (TNF)-α, endothelial growth factor (EGF), granulocyte macrophage-colony-stimulating factor (GM-CSF), IL-12p40, IL-17, MIP-1β, and monocyte chemoattractant protein (MCP)-1 at 1 h; IL-18, vascular EGF (VEGF), IL-13, and IL-1ra at 2 h; TNF-α, G-CSF, IL-1β, IL-2, IL-4, IL-5, and IL-15 at 4 h; and ET-1 and IL-18 at 6 h. Multiple comparisons of biomarkers in the two study groups using two-way ANOVA with Bonferroni correction demonstrated significant mean differences between the following: ET-1 at baseline and 6 and 8 h, 1 and 8 h; IL-6 at baseline and 0, 1, 2, and 4 h, 2 and 8 and 24 h; IL-8 at baseline and 0, 1, and 2 h; IL-10 at baseline and 0, 1 and 2, 0 and 2, 4, 6, 8, and 24 h, 1 and 4, 6, 8, and 24 h, 2 and 8 and 24 h; TNF-α at 1 and 8 and 24 h, 2 and 8 and 24 h; G-CSF at baseline and 2, 4, 6, 8, and 24 h, 0 and 2, 4, and 6 h, 1 and 4 h, 4 and 24 h; IL-1ra at baseline and 2 and 4 h, 0 and 2 and 4 h, 2 and 8 24 h, 4 and 24 h; IP-10 at baseline and 0, 1 and 2, 0 and 2, 4, 6, 8, and 24 h, 1 and 4, 6, 8, and 24 h, 2 and 8 and 24 h, 4 and 24 h; MIP-1a at baseline and 0 and 1 h, 0 and 4, 6, 8, and 24 h, 1 and 4, 6, 8, and 24 h and; MIP-1b at baseline and 1, 1 and 6, 8, and 24 h. A generalized trend toward lower levels of biomarker concentration in the NES group (solid lines) compared to the Ctrl group (Ctrl, dotted lines) could be observed. The effect of NES at different time points was then investigated by converting the biomarker concentration data into fold change from baseline concentrations, necessitated by the extremely large differences in absolute concentration between different biomarkers (0.1–4400 pg/mL). At 0 h, the NES group exhibited significant reduction of peak concentrations of IL-6 (P = 0.009), IL-10 (P = 0.009) [Figure 2]b, IL-1α (P = 0.020), IP-10 (P = 0.001), and IFN-α (P = 0.032) [Figure 2]c compared to the Ctrl group. Significant reduction in peak concentrations of TNF-α (P = 0.007) and MIP1-β (P = 0.027) was observed in the NES group compared to the Ctrl group at 1 h. Significant reduction in peak concentrations of ET-1 (P = 0.020) was observed at 6 h in the NES group compared to the Ctrl group [Figure 2]d.
Figure 2: (a) Concerted kinetic changes in biomarker concentration during cardiac surgery. Dotted lines indicate the control group and solid lines indicate the nesiritide group. Texts show time of peak concentrations of individual biomarkers. (b-d) fold change from baseline concentrations

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There were differences in CPB time between the groups. To investigate the effect of CPB time on cytokine levels, especially ET-1, we performed regression analysis. There were no significant correlation with CPB time and ET-1 (r = 0.20, P = 0.143). The adjusted R2 was 0.007 (standard error of estimate 1.35), i.e., only 0.7% of the variability of ET-1 can be accounted for by CPB time. The unstandardized coefficient was 0.007, i.e., for every minute of prolonged CPB time, ET-1 concentrations will increase by 0.007 pg/mL. Similar trends were observed for IL-6, IL-10, and IP-10.

Endothelin-1, kinetic-estimated glomerular filtration rate, and urine output

A trend toward higher KeGFR was observed in the NES group; however, the KeGFR was not statistically different between the groups at baseline (NES 66.8 + 14.0 mL/min/1.73 m 2 vs. Ctrl 71.3 + 12.8 mL/min/1.73 m 2, P = 0.378), 24 h (NES 73.6 + 6.6 mL/min/1.73 m 2 vs . Ctrl 69.6 + 5.9 mL/min/1.73 m 2, P = 0.663), or at 48 h (NES 71.4 + 5.4 mL/min/1.73 m 2 vs . Ctrl 68.8 + 4.9 mL/min/1.73 m 2, P = 0.727). The NES group had significantly higher urine output at 24 h than the Ctrl group (NES 2245.7 + 537.9 mL vs. Ctrl 1807.1 + 481.8 mL, P = 0.029). We then compared the interaction between ET-1 and KeGFR in both groups. In the Ctrl group, ET-1 at 6 h did not demonstrate significant correlation with KeGFR at 24 h (r = −0.23, P = 0.413). However in the NES group, ET-1 at 6 h demonstrated significant inverse correlation with KeGFR at 24 h (r = −0.45, P = 0.025) [Figure 3]. Furthermore, ET-1 at 2 h and 4 h showed correlation with 6 h (r = −0.44, P = 0.019) and 24 h total urine output (r = −0.43, P = 0.020).
Figure 3: Inverse relationship of endothelin-1 and kinetic-estimated glomerular filtration rate in Ctrl (a) and nesiritide group (b)

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  Discussion Top


Cardiac surgery produces complex inflammatory responses which can lead to ischemia-reperfusion (I-R) injury that can disturb the functions of the kidney. Clinical data have shown that NES confers renoprotection during cardiac surgery, and experimental evidence suggests that the mechanism may involve anti-inflammatory pathways. This study was therefore performed to investigate the effects of NES on inflammatory response during cardiac surgery.

One of the major findings of the study was the demonstration of a concerted biomarker kinetic pattern of time-differentiated peak concentrations. Different biomarkers were observed to reach peak concentrations at different time points. These observations are better appreciated by considering that patients undergoing cardiac surgery with extracorporeal circulation frequently develop systemic inflammatory response. Induction of leukocytosis by CPB and secretion of the cytokines TNF-α and IL-1β by activated monocytes and macrophages are the initial events in inflammatory response in cardiac surgery. This is followed by an increase in IL-6 levels.[15],[16] The inflammatory response is produced by complex humoral and cellular interactions with numerous pathways including activation, generation, or expression of thrombin, complement, cytokines, neutrophils, adhesion molecules, mast cells, and multiple inflammatory mediators.[10],[17],[18],[19] Genome-wide transcriptional analysis after CPB has revealed that the inflammatory response involves activation of gene regulatory network of 50 genes and upregulation of toll-like receptor (TLR)-4/5, IL1R2/IL1RAP, IL6, IL18/IL18R1/IL18RAP, MMP9, hepatocyte growth factor (HGF)/HGF regulation, Calgranulin A/B, and coagulation factors F5/F12.[20]

The second major finding is that NES modulates inflammatory response. NES significantly reduced peak IL-6, IL-10, TNF-a, IL-1a, IP-10, and IFN-α concentrations and demonstrated a general trend toward lower peak concentrations of most biomarkers compared to the Ctrl group. Cytokines, including TNF-a, IL-1, stimulate vascular endothelial cells and the downstream leukocyte recruitment cascade. We have previously shown that the degree of inflammatory response as measured by circulating pro-inflammatory cytokines is associated with the severity of end-organ injury in complex cardiothoracic procedures.[21],[22],[23],[24],[25] Specifically, patients undergoing thoracic aneurysm repair who develop multiple organ failure have higher circulating levels of TNF-α and IL-6.[22] Furthermore, inflammatory mediators released from cardiac ischemia during cross clamp, including TNF-α, have been implicated in perpetuating renal dysfunction after CPB in a feedback loop termed “cardiorenal syndrome.”[10]

The third major finding was that NES significantly reduced peak ET-1 concentrations. ET-1 is vasoconstrictor that reduces renal blood flow and decreases GFR. In normal physiologic conditions, the balance between vasoconstrictors (including ET-1) and vasodilators maintains vascular tone and renal blood flow. ET-1 levels have been shown to be higher in patients with AKI (compared to healthy controls), an entity associated with renal vasoconstriction and reduced GFR.[25] It was shown that ET-1 levels are elevated after cardiac surgery for up to 24 h; and furthermore, 18% of patients with elevated ET-1 levels developed kidney injury.[19] Zager et al. have reported intrarenal elevations of ET-1 in a mouse I-R model of AKI and improvement in intrarenal lactate levels with ET-A receptor blockade.[26] In addition, a porcine model of AKI showed that endotoxin ETA receptor blockade maintained renal medullary blood flow independent of systemic blood pressure and overall renal blood flow.[27] Further, ET-1 blockade has been proposed as a strategy to prevent AKI progression to chronic kidney disease.[28] The observations that the NES group had reduced peak ET-1 concentrations and that ET-1 demonstrated negative correlations with KeGFR and urine output suggest that the mechanism of action of NES involves attenuation of renal vasoconstriction during cardiac surgery.

Limitations

The limitations of the pilot study were the small sample size and measurement of urine NGAL and IL-18 concentrations only at baseline and 6 h that may have compromised a more complete understanding of their role. Urine NGAL peaks approximately 6 h after injury and can remain elevated for longer period. Urine IL-18 on the other hand is elevated within the first 6 h and attains peak concentration 12–18 h after injury, i.e., during the extension phase of AKI. Parikh et al. have reported that urine IL-18 >60 pg/mL at 0–6 h had a sensitivity of 54% and specificity of 82% for prediction of severe AKI.[29] Interestingly, urine IL-18 was <60 pg/mL in the NES group and >250 pg/mL in the Ctrl group in our study, albeit with a nonsignificant P value. Additional complicating factor in the interpretation of the urine NGAL and IL-18 data was the low incidence of AKI in this study.


  Conclusion Top


Our study demonstrated a concerted inflammatory response in cardiac surgery that was modulated by NES. Furthermore, NES attenuated ET-1 response, thus suggesting that previously observed favorable renal effect may be linked to reduced renal vasoconstriction. Further studies are warranted.

Financial support and sponsorship

The authors acknowledge the State of Florida's James and Esther King Biomedical Research Program funding support for this project.

Conflict of interest

There are no conflicts of interest.



 
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