| COMMENTARIES |
Resistin As an Inflammatory Marker in Subjects with Chronic Kidney Disease
This Commentary is based on the following article: Yaturu S, Reddy RD, Rains J, Jain SK. Plasma and urine levels of resistin and adiponectin in chronic kidney disease. Cytokine 2007;37(1):1-5.
Subhashini Yaturu, M.D., Department of Endocrinology, Overton Brooks VA Medical Center/LSUHSC,
Shreveport, LA 71101-4295
Please address correspondence to:
Subhashini Yaturu, M.D.
Department of Endocrinology
Overton Brooks VA Medical Center/LSUHSC
Shreveport, LA 71101-4295
Tel: 318-841-4707, 318-424-6076
Fax: 318-424-6179
E-mail address: Subhashini.Yaturu@med.va.gov , yaturu@yahoo.com
Cardiovascular disease (CVD) is the most common cause of mortality in patients with chronic kidney disease (CKD) and end-stage kidney disease (ESKD); subjects with CKD are considered as potential candidates for aggressive risk factor reduction. Recent studies show that even mild renal dysfunction is associated with an increased CVD risk. [1,2] Around 20 million adults in the United States have CKD, 8 million of whom are classified as having moderate or severe kidney disease. People with CKD have multiple metabolic abnormalities that may accelerate atherosclerosis, such as hypertension, insulin resistance, and dyslipidemia, along with other CKD-related risk factors.
Insulin resistance is an established culprit responsible for several metabolic abnormalities that lead to dyslipidemia, prediabetes, diabetes, atherosclerosis, non-alcoholic hepato-steatosis, polycystic ovarian syndrome, and so on. Adipose tissue, especially visceral adipocytes, secrete a number of proinflammatory adipokines, such as leptin, resistin, tumor necrosis factor-α, and interleukin-6, and anti-inflammatory adipokines such as adiponectin that are involved in energy metabolism, inflammation, insulin resistance, obesity, type 2 diabetes, and atherosclerosis. Among those that have received a lot of attention, are adiponectin and resistin, along with inflammatory markers TNF-α, IL-6, and CRP.
Decreased adiponectin levels have been reported in association with prediabetes, diabetes, obesity dyslipidemia, coronary artery disease, insulin resistance, increased waist-to-hip ratio, and increased levels of CRP and IL-6. The last two are inflammatory mediators and markers of increased cardiovascular risk, which can be affected by weight loss or pharmacotherapy, are thus reverse atherosclerosis or insulin resistance.
The retn gene encodes an adipocyte-derived hormone called resistin. Scientists have just begun to explore its complex biology. Increased resistin levels are noted in prediabetes, pregnancy-induced insulin resistance, diabetes, coronary artery disease [3,4], and in children with subclinical atherosclerosis. Circulating levels of resistin are proportional to the degree of adiposity, especially with abdominal adiposity [5], with multifold expression in visceral adipocytes. Insulin resistance is generally a polygenic disorder, and resistin is considered as an obvious candidate gene [6]. In earlier studies, we noted decreased adiponectin levels in subjects with prediabetes and diabetes and subjects with CAD with normal kidney function [7]. Resistin levels correlated with inflammatory markers even in patients with CAD or type 2 diabetes [8]. In the study under review, we measured the levels of adiponectin and resistin in subjects with CKD stages 3 and 4 with a mean GFR of 29.1 ± 7.1 (SD) ml/min/1.73 m². GFR was estimated in ml/min/1.73 m2 using MDRD study equation. Then we evaluated the relationship between adiponectin and resistin with GFR, body mass index (BMI), insulin resistance, and inflammatory markers such as C-reactive protein (CRP) and tumor necrosis factor alpha (TNF-α). Glomerular filtration rates in subjects with CKD inversely correlate with the plasma levels of adiponectin (r = -0.32; p < 0.05). Interestingly, although sixty percent of subjects with CKD have CAD, we did not observe any decrease in adiponectin levels [8]. It was not clear whether unaltered adiponectin levels reflect impaired adiponectin clearance by the kidney, or a compensatory mechanism aimed at counteracting increased cardiovascular risk factors, so we measured urinary adiponectin levels. We noted an inverse correlation with GFR for both plasma and urine adiponectin levels, which suggests probable impaired clearance [8]. Subjects with CKD had significantly higher insulin levels, increased insulin resistance indexes, and increased levels of inflammatory markers such as CRP and TNF-α, as well as resistin. We also noted a very strong correlation of TNF-α with resistin (r = 0.84; p < 0.000001) and CRP (r = 0.63; p = 0.00001). Urinary adiponectin levels (41.05 ± 24 µg/ml) correlated inversely with GFR (r = -0.40; p < 0.05) and plasma adiponectin levels (r = 0.9; p < 0.00001). Increased plasma levels of resistin and CRP in association with TNF-α suggest a role for resistin as a possible surrogate marker of inflammation in subjects with CKD. Our data support the previous finding by Kougias and co-workers in their porcine vascular studies that resistin may contribute directly to vascular disease by causing endothelial dysfunction in porcine coronary arteries through oxidative stress and down-regulation of eNOS [9]. TNF-α and IL-6 are also expressed in adipose tissues, which inhibit insulin signaling [10], tyrosine kinase phosphorylation of the insulin receptor [11], and may play a crucial role in the systemic insulin resistance [12]. Because resistin contributes to systemic insulin resistance along with insulin and obesity-induced cytokines [6], it is considered to represent a novel link between metabolic signals, inflammation, and atherosclerosis [13]. Our study supports the hypothesis and data of Lehrke et al. that inflammation is a hyper-resistinemic state and that cytokine induction of resistin may contribute to insulin resistance in obesity and other inflammatory states [14]. Studies to evaluate the potential benefit of alteration of resistin levels to modulate atherosclerosis or insulin resistance would be interesting. We conclude that resistin may have a role in sub-clinical inflammation associated with CKD.
Acknowledgements
Authors receive support from ¹Edward Stiles Grant from LSU health Sciences Center and Merit review grant¹ and a grant 4(RO1 DK064797) from NIDDK and the Office of Dietary Supplements of the National Institutes of Health.
References