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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2021  |  Volume : 32  |  Issue : 2  |  Page : 328-335
Could Omega 3 fatty acids reduce the risk of contrast-induced nephropathy in patients undergoing coronary angiography? A randomized controlled trial


1 Department of Medical Specialties, Nephrology Section, King Fahad Medical City, Riyadh, Saudi Arabia
2 King Salman Cardiac Center, King Fahad Medical City, Riyadh, Saudi Arabia
3 Research Center, King Fahad Medical City, Riyadh, Saudi Arabia

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Date of Web Publication11-Jan-2022
 

   Abstract 


Contrast medium-induced nephropathy (CIN) is a leading cause of acquired acute kidney injury and has been associated with prolonged hospitalization and adverse clinical outcomes. This study aimed to determine if omega 3 fatty acids reduce the risk of CIN in patients with chronic kidney disease undergoing coronary angiography. A total of 130 consecutive patients undergoing coronary angiography were randomly assigned to one of two groups as follows: 67 patients were assigned to the N-acetylcysteine (NAC; 1200 mg) and 63 patients were assigned to the omega 3 fatty acid (4 g). Both drugs were administered orally twice per day one day before and on the day of contrast administration. Of the 130 patients enrolled in this study, 10 (7.7%) experienced an increase of at least 0.5 mg/dL (44 μmol/L) in serum creatinine levels 48 h after administration of the contrast agent including 5 of the 67 patients in the NAC group (7.5%) and 5 of the 63 patients in the omega 3 fatty acids group (7.9%; P = 0.919). There were no significant differences in the need for renal replacement therapy (3.0% vs. 9.5%, P = 0.121) or in the mortality rate (3.0% vs. 6.3%, P = 0.361) between the two groups. Short-term prophylactic omega 3 fatty acid treatment with hydration does not reduce the risk of CIN in patients with chronic kidney disease undergoing coronary angiography.

How to cite this article:
Alrowaie FA, Almatham KI, Alsamadi F, Bashir MS, Munshi HH. Could Omega 3 fatty acids reduce the risk of contrast-induced nephropathy in patients undergoing coronary angiography? A randomized controlled trial. Saudi J Kidney Dis Transpl 2021;32:328-35

How to cite this URL:
Alrowaie FA, Almatham KI, Alsamadi F, Bashir MS, Munshi HH. Could Omega 3 fatty acids reduce the risk of contrast-induced nephropathy in patients undergoing coronary angiography? A randomized controlled trial. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2022 Jan 23];32:328-35. Available from: https://www.sjkdt.org/text.asp?2021/32/2/328/335443



   Introduction Top


Contrast-induced nephropathy (CIN) is a common cause of acquired acute kidney injury (AKI) in patients undergoing percutaneous coronary angiography and is associated with prolonged hospitalization and adverse clinical outcomes.[1],[2],[3],[4]

The incidence of CIN following coronary angiography varies from 7.5% in low-risk groups to over 50% in high-risk groups.[5] Patients at higher risk include those >75 years of age, patients with pre-existing renal impairment, diabetes mellitus, congestive heart failure, hypotension, and anemia, and patients requiring intra-aortic balloon pump and high contrast medium (CM) volume.[5]

The exact pathogenesis of CIN in humans is not well understood. Animal studies suggest that hypoxic medullary injury plays a critical role in the development of CIN.[6] Three possible mechanisms by which CM may lead to the development of CIN include hemodynamic effects of the CM, the effect of reactive oxygen species (ROS) and free radicals, and direct CM tubular cell toxicity.[7],[8],[9]

Intravascular hydration is the standard intervention used to prevent CIN.[10],[11],[12] Various protocols using both isotonic sodium chloride and isotonic bicarbonate are employed for pre- procedural prophylaxis, but no protocol has been reported to exert superior effects.[13]

Previous studies investigated the role of N-acetylcysteine (NAC), a potent antioxidant that scavenges a wide variety of oxygen-derived free radicals, on CIN prevention through its actions inhibiting direct oxidative tissue damage and improving renal hemodynamics.[14],[15] However, there is a conflicting evidence concerning the role of NAC.[13] Thus, we hypothesized that an alternative antioxidant molecule with anti-inflammatory properties may hinder the negative effects of CM on the kidney.

Omega 3 fatty acids are polyunsaturated fatty acids that have been shown to reduce inflammatory markers and oxidative stress, to improve endothelial function, and to reduce kidney dysfunction following reperfusion injury and chronic renal insufficiency in animal models.[16],[17],[18],[19],[20],[21],[22],[23],[24],[25]

Based on the assumption that ROS is involved in the pathogenesis of CIN, we studied the effects of prophylactic oral administration of omega 3 fatty acids in a prospective randomized controlled trial involving patients with chronic renal insufficiency undergoing coronary angiography.


   Methods Top


Study population

A total of 130 consecutive patients with chronic kidney disease who were scheduled for coronary angiography at King Fahad Medical City (KFMC) in Riyadh, Saudi Arabia, between March 1, 2017 and November 30, 2017 were enrolled in this study. Eligible participants were those with an estimated glomerular filtration rate (eGFR) <60 mL/min using the Chronic Kidney Disease Epidemiology Collaboration equation.[26],[27] Patients with an eGFR <15 mL/min, including those on hemodialysis or peritoneal dialysis, were excluded in addition to those on vasopressors, with cardiogenic shock, overt congestive heart failure, multiple myeloma, amyloidosis, recent major bleeding, an allergy to contrast CM, or those unwilling to provide informed consent were also excluded. The study was approved by the ethics committee at KFMC (IRB log number 16–273) and a written informed consent was obtained from each participant.

Study protocol

This trial is a single center randomized controlled trial supported by an intramural fund from the KFMC research center. Block randomization with a block size of four was used. Eligible patients were randomized to one of the following arms: (1) NAC (1200 mg) and intravenous isotonic sodium bicarbonate and (2) omega 3 fatty acids (Omacor®; 4 g) and intravenous isotonic sodium bicarbonate. Both drugs were orally administered twice per day on the day before and on the day of administration of the contrast agent, for a total of two days.

Omacor® (omega-3 acid ethyl esters; Abbott Laboratories, USA) was the only form of omega 3 fatty acids used in this study. The isoosmolar contrast media Visipaque (320 mg/mL; Iodixanol; GE Healthcare, USA) was used in all study participants. All patients received the same hydration protocol as follows: intravenous isotonic sodium bicarbonate at a rate of 3 mL/kg/h for 1 h before cardiac catheterization, followed by a rate of 1 mL/kg/h during contrast exposure and for 6 h after the procedure. Bicarbonate solution was prepared by adding 154 mL of 1000 mEq/L sodium bicarbonate to 846 ml of 5% dextrose in water.[28]

Clinical outcome

The primary end point of the study was the occurrence of CIN, defined as an increase in baseline serum creatinine (SCr) levels of at least 0.5 mg/dL (44 μmol/L) 48–72 h after coronary angiography or percutaneous coronary intervention. Another definition of CIN used in this study, which was assessed as a separate endpoint, was a 25% increase in SCr levels from baseline levels 48 to 72 h following CM administration.

The secondary endpoints were (1) the need for renal replacement therapy, (2) in-hospital death, (3) myocardial infarction, (4) stroke, and (5) length of hospitalization after contrast administration.


   Statistical Analysis Top


Categorical variables, including gender, ejection fraction, diabetes, and hypertension, are presented as frequencies and percentages, whereas continuous variables, including age, body mass index, and systolic blood pressure (BP), are expressed as means ± standard deviations. The independent sample t-test and Mann–Whitney U test were used to determine the mean and median significant differences between study groups and the clinical characteristics of the patients. The Chi-squared and Fisher’s exact tests were used to determine significant associations between categorical variables. A two-tailed P <0.05 was considered to indicate statistical significance. All statistical analyses were conducted using IBM SPSS Statistics software version 22.0 (IBM Corp., Armonk, NY, USA).


   Results Top


Patients

The participants’ baseline characteristics and biochemical values are presented in [Table 1]. Participants in the NAC group were significantly older (66.18 ± 10.69 years) compared to participants in the omega 3 fatty acids group (60.65 ±11.9 years; P = 0.006). All patients had chronic kidney disease, and the average eGFR was 40.42 ± 12.19 mL/min in the NAC group and 41.38 ± 11.29 mL/min in the omega 3 fatty acids group (P = 0.642). The number of patients with diabetes mellitus, hypertension, and previous history of ischemic heart disease or congestive heart failure was similar in each group. However, there was a significantly higher number of patients with hyperlipidemia in the NAC group compared with the omega 3 fatty acids group (38.8% vs. 17.5%; P = 0.007). There were no differences in the number of patients taking diuretics, calcium- channel blockers, statins, or anti-platelets between the two groups, but more patients in the omega 3 fatty acids group were treated with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers compared with the NAC group (54.0% vs. 34.3%; P = 0.024). The volume of contrast agent used and the Mehran score[5] in both groups were similar.
Table 1: Baseline patient characteristics.

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Clinical outcome

CIN, defined as an increase of at least 0.5 mg/dL (44 μmol/L) in the SCr concentration 48–72 h following administration of the contrast agent, occurred in 10 (7.7%) patients, including 5 (7.5%) patients in the NAC group, and 5 (7.9%) patients in the omega 3 fatty acids group (P = 0.919). No significant difference in the incidence of CIN was observed between the two groups, even when CIN was defined as a 25% relative increase in baseline SCr, which occurred in 9.1% of the NAC group and 14.3% (P = 0.358) of the omega 3 fatty acids group [Table 2] and [Figure 1].
Figure 1: Incidence of contrast-induced nephropathy, defined by an increase in serum creatinine levels >44 μmol/L (left) or by an increase >25% from baseline levels (right).

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Table 2: Primary and secondary endpoints.

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Eight patients required renal replacement therapy during the study period including two (3.0%) patients in the NAC group and six (9.5%) patients in the omega 3 fatty acids group (P = 0.121). There were six in-hospital deaths, of which two (3.0%) were in the NAC group and four (6.3%) were in the omega 3 fatty acid group (P = 0.361). All patients who died had low baseline ejection fractions ranging from 30% to 35%, but none developed CIN.

There were no significant differences between the NAC and omega 3 fatty acids groups in the rate of in-hospital myocardial infarction following coronary catheterization (6.0% vs. 9.5%; P = 0.447). Ischemic stroke occurred in only one patient in the omega 3 fatty acids group. Moreover, the length of in-hospital stay from initiation of the contrast study to discharge was similar in both groups (6.7 ± 8.73 days in the NAC group vs. 6.16 ± 7.82 days in the omega 3 fatty acids group; P = 714).


   Discussion Top


This is the first study assessing the effects of omega 3 fatty acids on the prevention of CIN in a high-risk population undergoing cardiac catheterization. Our findings indicate that the administration of omega 3 fatty acids with intravenous hydration using isotonic bicarbonate does not provide any additional benefit in reducing the incidence of CIN compared with NAC treatment in this patient population. NAC is a thiol-containing antioxidant used to attenuate CIN through its ability to scavenge oxygen free radicals, thereby preventing direct oxidative tissue damage, as well as its ability to counteract CM-induced renal vasoconstriction.[13],[14],[15] Conflicting evidence exists concerning the benefit of NAC in reducing CIN,[13] which led us to explore potential alternative antioxidant and anti-inflammatory treatments that may ameliorate the negative effects of CM on the kidney.

In animal models, dietary supplementation with omega 3 fatty acids at low doses reduces the severity of kidney disease following exposure to various nephrotoxic agents.[29],[30],[31],[32] Neumayer et al demonstrated the protective effect of fish consumption in an acute renal failure model.[23] After 120 min of complete renal ischemia in dogs pretreated with fish oil, they observed that the GFR remained stable and that renal blood flow and renal vascular resistance remained unchanged. A study by Ashtiyani et al[22] showed that, following renal reperfusion injury, rats fed omega 3 fatty acids had smaller increases in plasma creatinine and malondialdehyde, which is a marker of oxidative stress, and reduced evidence of histological damage compared with the acute kidney injury group not treated with omega 3 fatty acids.

In human studies, omega 3 fatty acid supplementation showed to modify inter-mediaries in the pathogenesis of kidney disease by lowering BP, oxidative stress, and inflammation and improving endothelial function.[33]

Based on the above data, we postulated that omega 3 fatty acids might exert a protective effect on kidney function after contrast administration, mainly through their antioxidant effect. Omacor capsules were used as the only source of omega 3 fatty acids in our study, which include 1000 mg of omega 3 fatty acid ethyl esters 90 comprising 460 mg eicosapentaenoic acid and 380 mg docosahexaenoic acid ethyl esters as well 4 mg d-alpha-tocopherol mixed with a vegetable oil (i.e., soya-bean oil).[34] A dose of 4 g was chosen based on previous IgA nephropathy studies.[35],[36]

In our study, short-term omega 3 fatty acid treatment with intravenous hydration using isotonic bicarbonate did not exert additional protective effects against CIN. The mean risk score in our study was 9.55 ± 4.94 and 11.57 ± 14.28 (P = 0.291) in the NAC and omega 3 fatty acid groups, respectively, which corresponds to a CIN incidence of 14%.

The observed overall CIN incidence was 7.7%, which is lower than the predicted CIN incidence and thus may have contributed to our negative findings. Another explanation for these results is the short duration of omega 3 fatty acid treatment before cardiac catheterization. In this study, we used an omega 3 fatty acid treatment protocol similar to that used for NAC treatment in a major CIN prophylaxis study, for a total treatment duration of two days. Ashtiyani et al[22] treated rats with omega 3 fatty acids for two weeks before inducing ischemic reperfusion injury, and showed preventive effects in the form of decreased histological damage, oxidative stress, and kidney dysfunction. It may be that these results could have been replicated in our study if the treatment timeline had been increased; however, this would not be practical for urgent contrast procedures such as cardiac catheterization. The dose of omega 3 fatty acid used may not have been adequate to attenuate the effect of contrast on the kidneys, and higher doses may be more protective in this regard.

The relative limitations of our study are those inherent to single-blind, single-center studies with small sample sizes. Therefore, our data require validation in a larger multicenter confirmatory trial. Another limitation of our study is that we did not compare omega 3 fatty acid use with a placebo, although the PRESERVE study did confirm that NAC treatment did not exert protective effects on CIN.[13] In addition, we did not use accurate laboratory methods such as neutrophil gelatinase associated lipocalin or cystatin C levels, in addition to SCr for early detection of CIN.


   Conclusion Top


Short-term prophylactic use of omega 3 fatty acids with hydration does not reduce the risk of CIN, the need for renal replacement therapy, hospitalization rates, or death in patients with chronic kidney disease undergoing coronary catheterization. Further studies are warranted to evaluate the optimal dose of omega 3 fatty acids for the prevention of CIN.

The OTCIN (Omega 3 fatty acids to reduce Contrast-Induced Nephropathy) trial is supported by a grant from King Fahad Medical City Research Center (IRF#017-005).

Conflicts of interest: None declared.



 
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Correspondence Address:
Fadel A Alrowaie
Department of Medical Specialties, Nephrology Section, King Fahad Medical City, P. O. Box 59046, Riyadh 11525
Saudi Arabia
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DOI: 10.4103/1319-2442.335443

PMID: 35017325

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