After all those fat years: renal consequences of obesity

Our genetic background and physiological homeostasis, orchestrated through endocrine and neuronal networks, are optimized for a world with intermittent food supply and permit us to survive periods of starvation [1]. However, these systems are counterproductive in our current industrial society with fast-food restaurants, an abundance of high energy food and an increasingly sedentary life-style. The consequence is an alarming increase in obese adults and, even more disturbing, of overweight children [1]. The consequences of obesity such as the metabolic syndrome with its ultimate development of type 2 diabetes mellitus, cardiovascular diseases, an increased incidence of certain types of cancer, musculoskeletal disorders and pulmonary diseases are well known. What about renal diseases? Almost 30 years ago, Weisinger et al. [2] described focal-segmental glomerulosclerosis with nephrotic syndrome in four extremely obese patients. Only two of them exhibited hypertension by office blood pressure measurements [2]. In the following years, several case reports describing glomerulosclerosis in very obese patients have been published, but this entity was considered as rare and rather bizarre. However, a recent study showed a dramatic increase of histologically proven renal disease in obese patients in the absence of diabetes [3]. The patients had rapidly progressive renal disease [4]. Furthermore, obesity is an important risk factor for the progression of renal disease in IgA nephropathy [5], and is also associated with an enhanced risk of chronic graft dysfunction after renal transplantation [6]. On the other hand, overweight patients with a body mass index (BMI) >27 kg/m2 with various chronic renal diseases experienced a significant reduction in proteinuria after only moderate weight loss [7]. A problem with all these studies is the fact that confounding factors such as hypertension were not totally ruled out. Fat cells are much more than a passive store of excess energy. Adipose tissue is a source of various hormones that may very well influence renal function [8,9]. An incomplete list of these factors is shown in Table 1. Some of these hormones and growth factors could reach the kidney and exert their pathophysiological effects [8]. For example, transgenic mice with angiotensinogen expression restricted to adipose tissue have increased circulating angiotensinogen, and the angiotensin II thus generated has renal effects [10]. Overexpression of angiotensinogen in adipocytes leads to hypertension [10]. Thus, the adipose tissue renin–angiotensinogen system could exert direct effects on the kidney. The detrimental effects of continuously enhanced angiotensin II concentrations on renal function and structure are well appreciated [11]. Although not the subject of this review, an increase in local formation of angiotensin II in adipose tissue probably contributes to the development of insulin resistance and promotes the metabolic syndrome [12]. Renal effects of tumour necrosis factor-α (TNF-α) through the induction of proinflammatory cytokines and the profibrogenic role of plasminogen activator inhibitor-1 (PAI-1) have been studied in detail. Other factors such as adiponectin may inhibit some of TNF-α’s proinflammatory effects, but circulating adiponectin levels are paradoxically lower in obese individuals and patients with type 2 diabetes [9]. Some hormones, cytokines and growth factors produced in adipose tissue Some hormones, cytokines and growth factors produced in adipose tissue Leptin, the product of the ob gene, is a satiety factor produced in adipocytes. It acts on specific receptors localized in the hypothalamus and influences other neurohormones [13]. Leptin suppresses food intake by inhibiting neuropeptide Y and by increasing melanocyte-stimulating hormone (MSH), and decreasing agouti-related peptide, an antagonist of MSH at the MC4 receptor [14]. Interestingly, an experimentally induced disruption of the MSH system induces salt-sensitive hypertension, indicating a central role for these peptides in blood pressure regulation [15]. Leptin centrally stimulates sympathetic nerve action; transgenic mice overexpressing leptin are hypertensive and have elevated urinary catecholamine excretion [16]. However, despite high circulating leptin concentrations, obese individuals are characterized by a relative leptin resistance [17]. The molecular mechanisms of this leptin resistance are subject to active current research and may be heterogeneous. As a small peptide hormone, leptin is cleared by the kidney [14,18]. Consequently, patients with impaired renal function have high circulating leptin concentrations. Mice with a deficient leptin gene (ob/ob) as well as animals with a defect for the long leptin receptor (db/db) are both obese and develop type 2 diabetes. However, only db/db mice with high circulating leptin concentrations show histological changes reminiscent of diabetic nephropathy, whereas the kidneys of ob/ob mice appear relatively normal [18]. This provided the impetus for us to study whether leptin could have direct renal effects [18]. Leptin stimulates the proliferation of cultured rat glomerular endothelial cells [19]. Angiotensin II and leptin have additive proliferative effects on glomerular endothelial cells [19]. This proliferation is cell type specific because mesangial cells failed to replicate in the presence of leptin [19]. Glomerular endothelial cells express the short leptin receptor previously thought to act solely as a clearance receptor without signal transduction. However, leptin induces STAT1 phosphorylation, suggesting active signal transduction, but further studies are necessary to define whether the signals are indeed mediated through the short leptin receptor [19]. Moreover, leptin induces mRNA expression and protein secretion of transforming growth factor-β (TGF-β) in glomerular endothelial cells [19]. Leptin increases the expression of TGF-β type II receptors on mesangial cells from the rat and from db/db mice, suggesting that the long leptin receptor is not necessary for this effect [20]. In addition, exogenous leptin increases cellular glucose uptake and enhanced type I collagen synthesis [20]. The addition of both TGF-β and leptin increases mesangial cell type I collagen secretion more than either stimulus alone [20]. These findings suggest a paracrine TGF-β pathway between glomerular endothelial and mesangial cells that is mediated by leptin. Leptin-induced TGF-β from endothelial cells could easily reach mesangial cells where it binds to the leptin-induced upregulated TGF-β type II receptors [18]. The consequence is an increase in extracellular matrix deposition. To test a potential role for leptin in vivo, recombinant leptin was infused with osmotic minipumps into normal rats. Short-term infusion for 72 h stimulated glomerular TGF-β, expression and increased in parallel the number of cells expression proliferating cell nuclear antigen (PCNA). After 3 weeks of leptin infusion into rats, glomerular expression of type IV collagen was significantly enhanced compared with pair-fed controls [19]. Leptin did no influence blood pressure, but proteinuria was significantly enhanced in leptin-infused animals [19]. These studies provide for the first time evidence that leptin exerts pathophysiological effects in the kidney. However, retrospective measurements of serum leptin at a single time point did not correlate with the decline in renal function in non-diabetic patients from the Modification of Diet in Renal Disease Study (MDRD [21]). Obese patients without diabetes mellitus type 2 exhibit a significant increase in glomerular filtration rate (GFR), compared with controls with normal BMI [22]. This hyperfiltration is caused by dilation of the afferent arteriole [22]. One explanation for these haemodynamic changes could be an activated glomerulo-tubular feedback caused by enhanced sodium reabsorption in the proximal tubule. Leptin, through activation of the sympathetic nervous system as well as direct effects on angiotensin II and insulin, could contribute to the increase in sodium reabsorption. It is intriguing to speculate that fat tissue may contribute to the increase in angiotensin II that enhances sodium transport. Glomerular hyperfiltration is a well known pathophysiological link to glomerulosclerosis and proteinuria [11]. In addition, many animal studies demonstrated that chronic intravenous or intracerebroventricular infusion of leptin increases sympathetic activity in the kidneys and induces hypertension [23]. Fat tissue completely encapsulates the kidney of obese animals and increases intrarenal pressure [23]. This mechanism is similar to the well known wrap kidney model, originally developed by Grollmann in the 1940s. This mechanism may increase blood pressure further in obese individuals [24]. In addition, this observation may also explain why abdominal obesity correlates better with hypertension than BMI [23]. In an experimental study in dogs, Henegar et al. [25] found that a high calorie diet induces within no more than 7 weeks an increase in mean arterial blood pressure and GFR. Moreover, histological changes including glomerular cell proliferation, thickening of glomerular and tubular basement membranes, increased matrix expansion and glomerular TGF-β expression were present [25]. These structural findings are similar to those reported by us in leptin-infused rats [19]. It is obvious that life-style changes with weight loss are the key element of any successful therapy of obesity [26]. However, although it has been shown that initial successful weight loss is possible with several structured programmes, only a few patients maintain their reduced weight [26]. Many clinical diet trials have shown a high drop-out rate [27]. Treatment with anti-obesity substances such as orlistat and sibutramine have modest weight-reducing effects, but carry the definite risk of side effects [26]. A consistent effective treatment for hypertension is mandatory. First line therapies are angiotensin-converting enzyme (ACE) inhibitors because of the pathophysiological role of the renin–angiotensin system in obesity-mediated renal changes and hypertension [26]. Some clinical observations suggest that β-blockers are associated with additional weight gain [26]. Although it is premature to make general recommendations, clinical studies indicate that acarbose, metformin and ACE inhibitors may delay development of type 2 diabetes in obese subjects [28]. Consequently, an interdisciplinary management of type 2 diabetes is necessary to prevent nephropathy [29]. The family physician needs expert help for dealing with this important problem. Although the incidence of obesity-related glomerulosclerosis is increasing, which carries a poor renal prognosis, overweight is probably more important as a progression factor in patients with known primary chronic renal diseases. Certainly, more research is needed to understand better how obesity influences renal function. The adipocyte is a source of several hormones, including leptin, that may have detrimental effects on the kidney, indicating that fat tissue itself could be a major culprit. Our genetic hardwiring with neuronal–hormonal loops mainly fostering energy conservation served our ancestors in times of starvation well, but poses a major problem for successful weight reduction. Nevertheless, structured weight reduction and control programmes may help to overcome this difficulty. Good luck! Many of the views expressed in this article were developed together with my friend and colleague Fuad N. Ziyadeh, MD, University of Pennsylvania, Philadelphia, USA. Conflict of interest statement. None declared.