INVITED COMMENTARY
Insulin Resistance, Microalbuminuria, and Chronic Kidney Disease Pantelis A. Sarafidis, MD, MSc, PhD, and Luis M. Ruilope, MD, PhD
Corresponding author Pantelis A. Sarafidis, MD, MSc, PhD Section of Nephrology and Hypertension, First Department of Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636, Thessaloniki, Greece. E-mail: psarafi
[email protected] Current Hypertension Reports 2008, 10:249 –251 Current Medicine Group LLC ISSN 1522-6417 Copyright © 2008 by Current Medicine Group LLC
Introduction Since the early decades of the 20th century, clinicians have described the coexistence in some individuals of certain disorders—type 2 diabetes mellitus, elevated blood pressure, obesity, and dyslipidemia—using several terms to name this “syndrome” [1]. However, only in 1988 did the modern era begin for what we now call the “metabolic” or “insulin resistance” syndrome. That year, Reaven [2] described “syndrome X” and proposed that insulin resistance is the common etiologic factor for a group of disturbances: impaired glucose tolerance, hyperinsulinemia, high levels of very-low-density lipoprotein triglycerides, low levels of high-density lipoprotein cholesterol, and hypertension [2]. In subsequent years, an enormous number of studies investigated the possible epidemiologic and pathophysiologic associations between insulin resistance and other factors to determine which disturbances belonged to the clustering of the metabolic syndrome [1]. These research efforts were coupled from attempts to defi ne this entity, which helped to form a stable reference context for the metabolic syndrome [1] but also met with criticism, mainly regarding the prognostic utility for cardiovascular disease [3]. Today, it seems that the epidemiologic coexistence of the main disorders included in the metabolic syndrome and the central role of insulin resistance in its underlying pathogenesis cannot be denied [4]. Ongoing research is expected to further clarify these associations and help form a consensus defi nition that can be used as both a diagnostic and prognostic tool. Among the aforementioned studies on the metabolic syndrome, several focused on the relationship of insulin resistance and microalbuminuria. According to current defi nitions, the term microalbuminuria refers to abnormal urine albumin excretion (UAE) between 30 and 300
mg/d in a 24-hour urine collection. UAE levels below the lower limit are considered normal, whereas albumin or protein excretion above the upper limit represents macroalbuminuria or proteinuria [5,6]. Today, microalbuminuria is considered mainly a marker of endothelial dysfunction and increased vascular leakage and a risk factor for cardiovascular disease, whereas macroalbuminuria is a typical manifestation of overt nephropathy and is associated with faster deterioration of kidney function and increased cardiovascular risk [7,8]. However, until a few years ago, microalbuminuria was considered the fi rst sign of nephropathy and predictor of kidney disease progression in patients with diabetes [6,9]. Studies on insulin resistance and microalbuminuria were performed under these considerations, and microalbuminuria was examined mainly as a marker of underlying nephropathy. The first studies of the epidemiologic associations between insulin resistance and microalbuminuria were published in the mid-1990s and followed a case-control design. With few exceptions, most showed that insulin resistance was significantly higher in microalbuminuric than in normoalbuminuric subjects with various components of the metabolic syndrome [10–12]. Similar trends were observed in cross-sectional studies. In a cohort of nondiabetic subjects from the Insulin Resistance Atherosclerosis Study [13], subjects with microalbuminuria had lower insulin sensitivity and higher fasting insulin compared with subjects without microalbuminuria, whereas increased insulin sensitivity was related to decreased microalbuminuria prevalence. In a recent study in type 2 diabetic patients, men with increased insulin resistance were at higher risk for increased urinary albumin-to-creatinine ratio, whereas in women the correlation did not reach significance [14]. Other studies examined the relation between hyperinsulinemia and microalbuminuria, and had comparable findings; in cross-sectional studies from Korea, elevated fasting insulin was independently associated with microalbuminuria [15,16], whereas a small prospective study in type 2 diabetic patients showed that serum insulin concentration at baseline was an independent predictor of the UAE rate after 6 years of follow-up [17 ]. In parallel to the above, several observational studies have examined the relationship between the metabolic syndrome, as defined using various diagnostic tools, and
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Invited Commentary
microalbuminuria. In early case-control studies, UAE was found to be higher in patients with many traits of the metabolic syndrome and vice versa [18,19]. Subsequent cross-sectional studies in various populations using multiple regression techniques to control for potential confounders showed that the risk for the presence of microalbuminuria increased progressively with the number of metabolic syndrome traits present in an individual [20–23]. Not all the relevant population studies confi rm the independent associations between insulin resistance or hyperinsulinemia and microalbuminuria [24–26]; however, the evidence derived from most of them, along with evolving background data, resulted in microalbuminuria being included among the main components of the metabolic syndrome in the fi rst major effort to define it, by the World Health Organization [27 ]. Subsequent defi nitions of the metabolic syndrome (ie, National Cholesterol Education Program–Adult Treatment Panel III [NCEP-ATP III] or International Diabetes Federation proposals) did not include microalbuminuria in the major components. However, this was likely because they were developed as simple, ready-to-use tools for clinical practice, and focused primarily on the main components that were easily assessed (hyperglycemia, obesity, hypertension, and dyslipidemia); for much the same reason, these defi nitions did not include insulin resistance [1]. As the role of microalbuminuria in predicting chronic kidney disease (CKD) progressively faded, a question arose about the relationship of insulin resistance and CKD. Case-control studies showed that insulin resistance was higher in patients with CKD than in controls and that insulin resistance deteriorated with progression of renal injury [28, 29]. A cross-sectional study in 6453 adults without diabetes mellitus from the Third National Health and Nutrition Examination Survey (NHANES III) population [30] displayed very nicely the relationship of insulin resistance and fasting insulin with CKD. In this study, after adjustment for potential confounders, the odds ratios of CKD were significantly increased from the lowest to the highest quartiles of homeostasis model assessment-insulin resistance (HOMA-IR) and insulin levels, but not of blood glucose levels. Further, for one standard deviation higher level of HOMA-IR or insulin, the increase in the risk of CKD was 30% and 35%, respectively. Although restricted by its cross-sectional nature, this analysis displayed that insulin resistance and concomitant hyperinsulinemia are present in subjects without diabetes mellitus and could play a role in the development of CKD. Recent studies also examined the relationship between metabolic syndrome and CKD. In another cross-sectional analysis of a NHANES III subpopulation, the OR for CKD progressively increased with the number of traits of the metabolic syndrome, defi ned according to NCEP-ATP III criteria [23]. An increased risk of CKD in patients with the metabolic syndrome compared to those without it was also evident in other population studies [31, 32]. In con-
trast, in a cross-sectional analysis in a young hypertensive population, the presence of the metabolic syndrome was associated with increased risk of microalbuminuria but not with increased risk of CKD [33]. Such fi ndings suggest that these associations may not be uniform and can be modified by the population under study (ie, the combination of the metabolic syndrome traits present). Of note, the association between the metabolic syndrome and CKD was also examined in two recent prospective studies [34, 35]. The fi rst included 10,096 nondiabetic subjects with normal renal function from the Atherosclerosis Risk in Communities (ARIC) study. Results showed that the risk of CKD after 9 years of follow-up was progressively increasing with the number of the metabolic syndrome traits—an association that remained significant after adjusting for development of diabetes and hypertension during follow-up [34]. The second study included subjects from the Framingham Heart Study who were followed for an average of 7 years; after adjusting for multiple confounders, among participants without diabetes mellitus at baseline, the presence of the metabolic syndrome was almost significantly associated with the development of CKD during follow-up (OR 1.46; P = 0.06) [35]. In conclusion, existing epidemiologic data indicate a close association between insulin resistance and microalbuminuria, and suggest that microalbuminuria should be considered, if not as a primary, at least as a secondary component of the metabolic syndrome. However, the presence of microalbuminuria should not be viewed as a sign of CKD, but rather as a sign of the underlying endothelial dysfunction and atherosclerotic vascular injury. Background and clinical studies have clearly showed that insulin resistance is directly related to endothelial dysfunction, as discussed elsewhere [36], and that microalbuminuria is largely the result of abnormal vascular responsiveness, endothelial injury, and increased vascular permeability, evident in the product of the kidney (urine) [7 ]. This direct relationship of insulin resistance with microalbuminuria is also supported by several clinical studies in which reducing insulin resistance and hyperinsulinemia with the use of thiazolidinediones resulted in important reductions in UAE in subjects with micro- or normoalbuminuria [37, 38]. On the other hand, recent population studies strongly support that insulin resistance and hyperinsulinemia are related to increased risk of CKD, and several background mechanisms, presented in detail elsewhere [39], can be responsible for this association. Animal studies showing prevention of renal injury with reversal of insulin resistance add support to this notion [37 ], but there are no human studies on the effect of insulin resistance reduction on hard renal outcomes. As the prevalence of the metabolic syndrome is increasing worldwide, future research should further delineate the associations of insulin resistance with cardiovascular and renal injury and develop effective ways to interfere with the pathways involved, for benefit of the patients.
Invited Commentary
Disclosures
21.
No potential conflicts of interest relevant to this article were reported. 22.
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