Obesity and kidney disease

Nutrition, Metabolism & Cardiovascular Diseases (2007) 17, 757e762

www.elsevier.com/locate/nmcd

REVIEW

Obesity and kidney disease Mauro Cignarelli*, Olga Lamacchia Unit of Endocrinology and Metabolic Diseases, Department of Medical Sciences, University of Foggia, Via Luigi Pinto 1, 71100 Foggia, Italy Received 17 January 2007; received in revised form 7 March 2007; accepted 13 March 2007

KEYWORDS Obesity; Kidney; Metabolic syndrome; Remodeling; Oxidative stress

Abstract The prevalence of obesity worldwide has increased dramatically. Besides, an approximately two-fold higher rate of increase in mean BMI among the incident ESRD has been reported in the US population from 1995e2002. Chronic kidney disease (CKD) prevalence increases from 2.9% among adults with an ideal BMI to 4.5% among obese adults. The development of CKD is usually the culminating result of the interaction of multiple risk factors. Obesity represents one example of a multitoxicity state and given the background of genetic susceptibility and/or reduced nephron number, overweight may initiate renal remodeling and/or accelerate kidney failure. Obesity may be the number one preventable risk factor for CKD. Weight loss has indeed been shown to improve glomerular hemodynamics and reduce urine albumin excretion. Thus, obese patients with CKD should be counseled on the benefits of weight loss. ª 2007 Elsevier B.V. All rights reserved.

Background The development of CKD is commonly the culminating result of the interaction between multiple risk factors, and obesity is one example of a ‘‘multitoxicity’’ state; given the background of genetic susceptibility and/or reduced nephron number, it may initiate uncontrolled remodeling and then accelerate kidney failure [1,2]. * Corresponding author at: Unita ` Operativa di Endocrinologia e Malattie del Metabolismo, Via Luigi Pinto 1, 71100 Foggia, Italy. Tel.: þ39 0881 732212; fax: þ39 0881 733851. E-mail address: [email protected] (M. Cignarelli).

Here, we discuss the consistent association between CKD risk and increasing BMI noted in several observational studies. Potential mechanisms for obesity’s role in the development and progression of CKD are also discussed.

Epidemiology of CKD in overweight and obese adults Data from NHANES 1999e2000 demonstrated that the prevalence of obesity worldwide has increased dramatically from approximately 200 million adults in 1995 to over 300 in 2000 [3,4]. Besides,

0939-4753/$ - see front matter ª 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.numecd.2007.03.003

758 an approximately two-fold higher rate of increase in mean BMI among the incident ESRD has been reported in the US population from 1995 to 2002 [5]. Prevalence of subjects with a reduction in glomerular filtration rate (GFR <60 ml/min per 1.73 m2: stages 3e5 of CKD [6]) is reported to increase from 2.9% among adults with an ideal BMI (18.5e24.9 kg/m2) to 4.5% among obese adults (BMI 30 kg/m2) [7]. Compared to patients with an ideal BMI (18.5e24.9 kg/m2), the relative risk of ESRD has been reported to be 3.57 (95% CI 3.05e4.18) for those with BMI 30e34.9 kg/m2, 6.12 (95% CI 4.97e7.54) for those with BMI 35e 39.9 kg/m2 and 7.07 (95% CI 5.37e9.31) for those with BMI 40 kg/m2 [7]. Thus, the global obesity epidemic translates into markedly heightened CKD risk factors worldwide. The ten-fold increase in incidence of obesity related glomerulopathy (ORG) over 15 years suggests a newly emerging epidemic. Obesity may be the most preventable risk factor for CKD by virtue of its strong link with diabetes and hypertension, the two primary causes of CKD [8]. Aside from its link with traditional CKD risk factors, obesity itself may increase susceptibility to CKD via several potential mechanisms. The fact that central adiposity modifies the association between overweight and CKD points to the potential role of the metabolic syndrome [9e12]. Interestingly, the cross-sectional study by Chen et al. found a stepwise relationship between the number of metabolic syndrome traits and the risk of incident CKD, with individuals with five traits at the highest risk of developing CKD [13].

Clinical features of kidney dysfunction in obesity The so-called ‘‘obesity-related glomerulopathy’’ is the most accurately described type of renal involvement in obese individuals [14] (Fig. 1). By contrast with other clinical conditions leading to kidney dysfunction, obese patients commonly show a slowly progressive proteinuria, and its onset usually precedes that of GFR decline by several years [14e17]. Focal and segmental glomerulosclerosis (FSGS) and glomerulomegaly are the most significant and frequent findings in the setting of obesity [14,15,17]. However, unlike ‘primary’ or ‘idiopathic’ FSGS, obesity-related FSGS usually exhibits a slower progression of proteinuria and renal failure. In a series of 15 obese patients with biopsyproven FSGS, estimated probabilities of renal survival after 5 and 10 years were 77% and 51%,

M. Cignarelli, O. Lamacchia OBESITY Visceral Large Adipocytes Insulin Resistance Hyperleptinemia

Sympathetic and RAAS activation

Metabolic Multitoxicities

Low nephrons number genetically programmed

Altered Renal Redox Balance

Nephron load work TGF- 1 MMP AGE

Mesangial Expansion

Hyperfiltration Glomerulomegaly Podocyte detachement

RENAL REMODELING Focal and Segmental Glomerulosclerosis

CHRONIC KIDNEY DISEASE

Figure 1 Major players in the activation of pathogenetic mechanisms of kidney dysfunction in obesity.

respectively [15]. In a much larger review, the 5 year renal survival was almost 90% for patients with ORG [14]. However, an increased BMI is particularly harmful in patients with reduced renal functional mass (unilateral renal agenesis or nephrectomy) and other renal diseases (such as chronic graft dysfunction after kidney transplantation). Moreover, by contrast with classical nephrotic syndrome, nephrotic proteinuria in patients with obesity-related FSGS is characteristically not associated with edema, hypoalbuminemia or extreme hyperlipidemia, even in the presence of massive proteinuria levels [15,18]. On the other hand, these features are shared by other hyperfiltration-related nephropathies, such as reflux nephropathy or proteinuria associated with renal mass reduction [18].

Hemodynamic glomerular changes, renin-angiotensin-aldosterone system, inflammation, oxidative stress and nitric oxide An increase in GFR, renal plasma flow, glomerular pressure and filtration fraction through a dilated glomerular afferent arteriole has been repeatedly found in experimental models of obesity as well as in obese subjects [19,20]. Consistent with renal hemodynamic changes, glomerular hyperperfusion and hyperfiltration are a feature of obesity, and they have been demonstrated to improve markedly after drastic weight loss induced by bariatric surgery [21]. The mechanisms through which overweight induces these hemodynamic changes are

Obesity and kidney disease only partially known. Impaired natriuresis is likely to play an important role in the vasodilation of afferent glomerular arterioles and the consequent transmission of increased arterial pressure to the glomerular capillary [22]. Obese patients usually have increases in plasma renin activity, angiotensinogen, angiotensin-converting enzyme activity, circulating angiotensin II (renin-angiotensin-aldosterone-system: RAAS), and increased renal sympathetic activity, which are all important stimuli for obesity-related increased renal sodium reabsorption [22]. Activated RAAS is also very likely to play an important role in the hyperinsulinemia, oxidative stress and inflammation that typically accompany overweight, obesity metabolic syndrome and diabetes mellitus [23e25]. Interactions between angiotensin II and insulin with leptin could have deleterious cardiorenal effects in obesity. Additionally, leptin appears to stimulate vascular inflammation, oxidative stress. These actions may contribute to the pathogenesis of hypertension, atherosclerosis, and left ventricular hypertrophy, which are commonly associated with obesity as well as with kidney dysfunction [26].

Renal redox stress and matrix metalloproteinases and renal remodeling The metabolic syndrome, obesity and insulin resistance, accumulation of advanced glycation endproducts (AGE) either singly or in concert, constitute a milieu with multiple metabolic toxicities conducive to tissue redox stress [2]. Large abdominal adipocytes of obese individuals are active production sites of inflammatory cytokines (C-reactive protein, tumor necrosis factor a (TNF a), interleukin-6 (IL-6)), likely responsible for enhanced levels of oxidative stress, which is partially mediated by increased production of angiotensin II and augmented free fatty acid (FFA) flux [2,27,28]. Chander et al. provided conclusive evidence of the role of oxidative and nitrosative stress in obese Zucker rats [29]. The loss of redox homeostasis contributes to renal remodeling, which is a structural rearrangingeadaptive process that occurs long-term, as a chronic response to injurious stimuli. When there is loss of control of the process, the remodeling may become a disease entity resulting in fibrotic scarring, with the extracellular matrix (ECM) playing a pivotal role in this maladaptive process [2]. There is accumulating evidence that obesity contributes to glomerular remodeling. After 8 weeks on a high-fat diet there was considerable glomerular remodeling in an

759 obese canine model, leading to the following changes: an increase in kidney weight by 31  7%, a significant increase in the Bowman’s space, increased mesangial matrix and thickening of glomerular and tubular basement membranes, and an increase in the number of dividing cells within the glomerulus [30]. Wu et al. studied gene expression profiles in renal biopsies of six patients with obesity-related glomerulopathy [31]. Compared with normal controls, the expression of genes related to lipid metabolism, inflammation and insulin resistance (low density lipoprotein receptor, fatty acid binding protein 3, TNFa, IL-6 signal transducer, g-interferon, glucose-transporter 1, leptin receptor, peroxisome proliferator-activated receptor-gamma (PPAR-g), and vascular endothelial growth factor (VEGF)) was significantly higher in obese subjects. Even matrix metalloproteinases (MMP) are upregulated and activated from their inactive latent form when exposed to redox stress [32e36]. An increase in MMP-9 in response to heightened redox stress causes a complete disconnection of integrin matrix binding sites, after which the cell may undergo apoptosis. A robust activation of MMP-9 may result in a complete disconnection of the renal cells within the glomerulus (endothelial cell, mesangial cell and podocyte) and the proximal renal tubule, resulting in atrophy, dysfunction, apoptosis, cytoskeleton rearrangement and ECM remodeling [37].

Synergy of obesity and low nephron number Since nephron number is fixed at birth, weight gain increases the metabolic and hemodynamic load on each individual nephron. Therefore, increased metabolic demands on the kidney may also mediate increased CKD risk in overweight and obesity [20,38e41]. Both glomerular hypertrophy and increased glomerular capillary pressures are risk factors for glomerulosclerosis [42e46]. Since podocytes are unable to replicate in the setting of glomerular hypertrophy, for a given glomerular surface area the density of podocytes decreases, leading to detachment of the foot processes from the basement membrane [47]. Thus, in the setting of obesity, there are several activators for the expression of transforming growth factor-b1 (TGFb1), an important fibrogenic cytokine, including glomerular hypertrophy, increased insulin and angiotensin II levels and heightened glomerular volume and capillary pressures [48,49]. In the clinical context of overweight and obesity, individuals with reduced nephron mass possess a high risk for

760 CKD, since the reduction in the total number of functioning nephrons is compounded by the increased metabolic load in the remaining glomeruli and necessarily followed by a series of unspecific maladaptive hemodynamic changes [45]. Renal diseases, characterized by a reduction in renal mass, are considered to be the clinical translation of the experimental hyperfiltration models (3/4 or 5/6 nephrectomy). Some clinical studies suggest that obesity could be the key factor in explaining the discrepant evolution of some patients with these renal diseases who show progressively increasing proteinuria and renal insufficiency, in contrast to others who maintain a normal renal function and negative proteinuria over prolonged follow-up [50]. Gonza ´lez et al. [51] in a series of studies of 54 patients with unilateral renal agenesis or remnant kidneys, found indeed that BMI was the only clinical variable statistically associated with the risk of developing proteinuria and progression of renal failure. BMI was the most important difference between these patients and those who remained normal throughout follow-up: (27  3.6 kg/m2 compared with 21.6  2.6 kg/m2, respectively). The synergic interplay between obesity and reduction in nephron number has an apparently physiological basis. As already noted, obesity induces a series of renal hemodynamic changes that are almost identical to those induced by a significant reduction in the number of functioning nephrons. Interestingly, mechanisms by which poor early fetal growth programs type-2 diabetes, obesity, the metabolic syndrome and low nephron number have been also proposed [52]. On the basis of this hypothesis, suboptimal fetal environments due to poor or inadequate nutrition, (infection, anemia, hypertension, inflammation, gestational diabetes or hypoxia in the mother) expose the fetus to hormonal, growth factor, cytokine or adipokine cues which alter metabolic, immune system, vascular, hemodynamics, renal (low number of nephrons), and growth parameters, enhancing the risk in the later stages of life for poor glucose homeostasis, type 2 diabetes, hypertension, cardiorenal disease, obesity, likely because these events are compounded by overnutrition or lifestyle choices which are in conflict with the programming of the fetus [52]. Therefore, it is important for nephrologists to carefully evaluate in their patients the history and the duration of body weight increase, since the detrimental influence of obesity in patients with a reduced renal mass could also play an important role in renal transplant recipients. Ducloux et al. found indeed among 292 patients that those with an increase of more than 5% in BMI at 1 year post-transplant had

M. Cignarelli, O. Lamacchia an increased risk of graft loss [53]. However studies exploring the impact of obesity on graft survival have reached to conflicting results [54e57]. It seems that weight gain post-transplantation could predict graft loss independently of BMI [53]. In other words, pre-transplant obese patients do not necessarily have higher risk if their weight remains stable [55].

What is the renal benefit from weight reduction? Weight loss induces an important antiproteinuric effect in obese patients with proteinuria [58e60]. Importantly, the effect of weight loss is observed in type-2 diabetic patients with obesity and in obesity-related glomerulopathy, but also in obese patients suffering from renal diseases whose pathogenesis is unrelated to hyperfiltration [60], suggesting that overweight/obesity could also exert a detrimental influence on the evolution of chronic proteinuric nephropathies [61]. The mechanisms through which weight loss might reverse proteinuria are likely to be a reduction in multiple toxicities, such as a better control of blood pressure, hyperglycemia and dyslipidemia, improvement in insulin sensitivity [62,63], decrease in circulating leptin levels [64], reversal of glomerular hyperfiltration [19e22] and decrease in RAAS activation [65]. The reduction in proteinuria induced by weight loss is rapidly observed and shows a significant correlation with the percentage of weight reduction; even modest weight loss, less than 5% of the baseline weight, can induce reductions in proteinuria higher than 30% of baseline values in subjects with preexisting proteinuria, mainly because of diabetic nephropathy [60]. Palomar et al. studied the evolution of 35 morbidly obese patients who underwent bariatric surgery [66]. Excess weight loss was 67% at 1 year after intervention. All cardiovascular risk factors (hypertension, diabetes, dyslipemia) significantly improved during follow-up and microalbuminuria and proteinuria showed a drastic reduction [66]. All this evidence strongly suggests that weight loss is a potent but commonly underevaluated antiproteinuric therapeutic measure which, in addition, offers a generalized improvement of patients’ metabolic profile [60,61,63].

Conclusions Obesity is an important risk factor for CKD. Treatment of obese adults with CKD should include weight loss with right dietary modification,

Obesity and kidney disease because it may reduce the metabolic demands on the kidney, and simultaneously lower systemic and glomerular pressures, proteinuria, and oxidative stress as well as improving insulin sensitivity. The basic objective of dietary modification is to help the kidney maintain normal equilibrium of the body’s environment. Thus dietary modifications must be individualized and appropriate to the stage of CKD [67]. However, more studies are needed to further optimize the prevention and treatment of CKD associated with obesity.

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