Leukotriene Antagonist Use is Associated With Lower Systolic Blood Pressure in Adults

Introduction

Chronic kidney disease (CKD) is an increasingly prevalent and progressive disorder that affects many adults in the United States. This disorder is associated with significant health care costs, morbidity, and mortality because CKD leads to kidney failure and increased cardiovascular risk. With most forms of CKD, inflammation plays a central role in the progression of kidney and cardiovascular disease (CVD).¹ The severity of CKD correlates with the number of kidney macrophages promoting the induction of chronic inflammation, tubular injury, and fibrosis.² Specifically, proinflammatory lipid mediators called leukotrienes produced through the 5-lipoxygenase pathway by macrophages and neutrophils cause endothelial dysfunction and increased glomerular permeability to albumin.^S1 In addition, leukotrienes mediate CVD, and increased expression of leukotrienes is found in human atherosclerotic lesions.^S2 In animal studies, inhibition of the 5-lipoxygenase pathway significantly reduces kidney fibrosis and improves kidney function.³ Montelukast, a cysteinyl leukotriene receptor antagonist (CystLT₁R), also exhibits beneficial effects on vascular endothelial cell function in animal models.⁴ Even though CystLT₁R antagonists have been used extensively for the treatment of asthma and other diseases for decades, relatively little is known about their effects on kidney and cardiovascular outcomes in people with and without CKD. Using data from the National Health and Nutrition Examination Survey, we tested the hypothesis that the use of CystLT₁R antagonists (montelukast/zafirlukast) in adults would associate with lower albuminuria and systolic blood pressure (SBP).

Results

Among the 44,828 study participants from National Health and Nutrition Examination Survey, we identified 308 individuals that used montelukast or zafirlukast and propensity score matched them to 1232 individuals not using the medication (See Supplementary Methods). The characteristics of the study participants stratified by montelukast/zafirlukast prescription status are summarized in Table 1. Study participants were well matched. The mean age for all participants was 56.8 ± 18.0 years and the mean estimated glomerular filtration rate (eGFR) was 87.3 ± 23.5 ml/min per 1.73 m². The mean body mass index was in the obese range (31.4 ± 8.0 kg/m²). Table 2 shows the association of montelukast or zafirlukast use with kidney and cardiovascular outcomes. After adjusting for age, sex, race, diabetes status, hypertension, body mass index, eGFR, use of an angiotensin converting enzyme inhibitor or angiotensin receptor blocker, and serum C-reactive protein there was no association between montelukast/zafirlukast use and urine albumin-to-creatinine ratio (ACR), eGFR or CKD status (Table 2). Montelukast or zafirlukast use was associated with lower SBP after adjustment for age, sex, race, diabetes status, hypertension, body mass index, eGFR, urine ACR, use of antihypertensive medications and serum C-reactive protein (β [95% confidence interval]: −2.50 [−4.79, −0.20]).

Table 1.

Baseline characteristics of study participants

	Montelukast/Zafirlukast Use
Characteristic	Yes (N = 308)	No (N = 1232)
Age (yr)	55.7 ± 17.0	57.0 ± 17.7
Female (N, %)	199 (64.7)	796 (64.6)
Race
Non-Hispanic White (N, %)	168 (54.5)	703 (57.1)
Diabetes (N, %)	68 (22.1)	244 (19.8)
Hypertension (N, %)	163 (52.9)	675 (54.8)
Body mass index ≥ 30 (kg/m2)	155 (50.3)	616 (50.0)
eGFR (ml/min/1.73 m2)	87.7 ± 21.8	86.8 ± 23.5
Urine ACR (mg/g)	0.50 ± 5.4	0.66 ± 4.9

ACR, albumin-to-creatinine ratio; eGFR, estimated glomerular filtration rate.

Data are presented as mean ± SD.

Table 2.

Association of montelukast/zafirlukast use with albuminuria, blood pressure, and kidney disease

Montelukast use vs. no use	β-estimate (95% CI)	P-value
Urine ACRa	−0.10 (−0.21, 0.03)	0.14
eGFRb	0.53 (−1.50, 2.54)	0.60
SBPc	−2.50 (−4.79, −0.20)	0.033

	Odds ratio (95% CI)	P-value
CKDb	0.80 (0.47, 1.34)	0.38

ACE, angiotensin converting enzyme; ACR, albumin-to-creatinine ratio; CI, confidence interval; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; SBP, systolic blood pressure.

^aAdjusted for age, sex, race, diabetes status, hypertension, body mass index, eGFR, and use of ACE inhibitor or angiotensin receptor blocker and CRP.

^bAdjusted for age, sex, race, diabetes status, hypertension, body mass index, and use of ACE inhibitor or angiotensin receptor blocker and CRP.

^cAdjusted for age, sex, race, diabetes status, hypertension, body mass index, eGFR, urine ACR, and use of antihypertensive medications and CRP.

Discussion

The results of this analysis suggest that among a nationally representative sample, the use of montelukast or zafirlukast was related to SBP. We did not find an association between montelukast or zafirlukast use and eGFR, urine ACR or CKD status. Treatments that attenuate SBP are important, especially in individuals with chronic diseases such as diabetes and hypertension that can progress to kidney failure. Our findings suggest that CystLT₁R antagonists may be protective against kidney and CVD and warrant further testing.

The essential role of leukotrienes in promoting inflammation and recruiting neutrophils suggests that the use of CystLT₁R antagonists has protective benefits for kidney function. In some animal studies, elevated concentrations of leukotrienes such as leukotriene B₄ are a potent chemoattractant for neutrophils, which subsequently leads to the release of lysosomal enzymes and reactive oxygen species that increase tissue damage in the kidneys.⁵ Infusion of leukotrienes in animal models provoked vasoconstriction that led to a significant reduction in renal blood flow and attenuated GFR.⁶ Inhibition of leukotrienes also significantly reduces renal fibrosis in animal models.³ In a small study, children with minimal change disease using montelukast for 12 months showed a significant reduction in relapse rate during montelukast therapy and posttherapy.⁷ Thus, inhibition of leukotrienes using CystLT₁R antagonists may inhibit kidney damage and prevent development of CKD.

In addition to having kidney protective benefits, CystLT₁R antagonists have been implicated to have cardiovascular benefits as well. Elevated concentrations of leukotrienes, specifically leukotriene B₄ and cysteinyl leukotrienes, are associated with a greater degree of atherosclerosis.⁸ Animal studies have shown that montelukast improves vascular endothelial cell function and myocardial remodeling.⁴ More recently, an observational study of adults with asthma demonstrated a significant relationship between montelukast use and a reduction in major ischemic cardiovascular events, including myocardial infarction and ischemic stroke.⁹ Therefore, montelukast may target leukotriene-driven inflammation and have important benefits in reducing CVD.

Our study has limitations worth discussing. First, because this is an observational study, we are unable to imply causality. Second, we do not have information about adherence to the montelukast or zafirlukast prescription, which could have confounded our findings. Although we were able to adjust for C-reactive protein, we were not able to adjust for additional inflammatory markers because they were not available. In addition, albuminuria was based on a single random measure of ACR. We did not find any association with urine ACR, CKD, or eGFR in the current study. This may be due to a relative preservation of GFR throughout the participants and a very low prevalence of CKD overall. Finally, urine ACR was very low in the entire cohort. Accordingly, further study is needed in a population with a higher prevalence of CKD.

In summary, we found in National Health and Nutrition Examination Survey that participants using montelukast or zafirlukast had significantly lower SBP than participants not using montelukast or zafirlukast. Inhibiting leukotriene effects may prevent generalized inflammation that contributes to the advancement of both CKD and CVD. As a result, our analysis suggests that leukotriene inhibition may represent a novel therapeutic target for people with kidney disease and provide cardiovascular protection. Future investigations are needed to evaluate larger-scale cohorts, assess different populations, and further examine the relationship between montelukast use and kidney and CVD in mechanistic trials.

Disclosure

All the authors declared no competing interests.

Supplementary Material

Supplementary Methods.

Supplemental References.