Impaired renal function is strongly related to cardiovascular disease and mortality [1]. One in every 200 adults suffers from chronic kidney disease, and with growing obesity epidemic, this is likely to increase. This means that since kidney disease takes a long time to develop, pre-clinical kidney dysfunction is much more prevalent, and estimates in the general population range from 5 to 11% [2, 3]. From 1985 to 2000, a tenfold increase in obesity-related glomerulopathy was found [4]. Other publications relate factors of the metabolic syndrome to renal function [5]. Insulin resistance and dyslipidemia are common factors in the early impairment of renal function [6, 7]. Obesity is recently acknowledged as an important independent risk factor for kidney disease, in which epidemiological evidence played a crucial role. Obesity is related to various forms of kidney disease [8], including chronic renal failure [9] and end-stage renal disease (ESRD) [10, 11]. These associations reported by Hsu et al. are presented in Table 1. In this paper we discuss this evidence and outline perspectives for future lifestyle intervention studies to protect the kidney and reduce related cardiovascular disease and mortality.

Table 1 Adjusted relative risk for end-stage renal disease (ESRD) by body mass index (BMI) in 320,000 US subjects
Full size table

Obesity as an independent factor

A novel aspect in the field of renal epidemiology is that obesity is in itself an independent risk factor for the development of kidney disease. Obesity and the metabolic syndrome increase the risk for chronic kidney disease up to three- to fourfold [9, 12]. At most half of this obesity-related risk is explained indirectly by traditional risk factors like hypertension and type 2 diabetes [9, 11, 12], leaving a large part unexplained.

Obesity is strongly related to hypertension and type 2 diabetes, and more in general to the metabolic syndrome. The metabolic syndrome describes the clustering of cardiovascular risk factors, including elevated blood pressure and impaired glucose metabolism, but also central obesity, elevated serum triglycerides and decreased serum HDL-cholesterol. An important characteristic of the metabolic syndrome is the excess lipid accumulation in organs other than adipose tissue, e.g., in liver, skeletal muscle, pancreas and possibly in the kidney.

Epidemiological studies have played an important role to identify the metabolic syndrome as a risk factor for impaired kidney function. In 10,096 nondiabetic participants from the Atherosclerosis Risk in Communities (ARIC) study who had normal baseline kidney function, 691 (7%) participants developed chronic kidney disease (CKD) after 9 years of follow-up [12]. For subjects with the metabolic syndrome, the multivariable adjusted odds ratio (OR) of developing CKD was 1.43 (95% CI 1.18–1.73). After adjusting for the subsequent development of diabetes and hypertension during the 9 years follow-up, the OR was 1.24 (95% CI 1.01–1.51). A case–control study showed that overweight (BMI ≥ 25 kg/m2) at age 20 was associated with a significant threefold excess risk for chronic renal failure, relative to BMI < 25 [9]. This risk was also threefold in individuals who were overweight at age 20 but did not develop hypertension or diabetes.

Assessment of kidney disease

In the ARIC study described above, incident CKD was defined as an estimated GFR (eGFR) <60 ml/min per 1.73 m2 after 9 years among those with an eGFR ≥60 ml/min per 1.73 m2 at baseline [12]. The eGFR is usually calculated with abbreviated Modification of Diet in Renal Disease (MDRD) study equation [13], derived from serum creatinine, age, sex and race. Serum creatinine can thus be used as a plasma markers for kidney function, but is also directly related to muscle mass and physical activity [14]. This may overestimate kidney function in physically inactive individuals, and thereby underestimate the true effect of obesity. Other studies report CKD or ESRD from medical records. However, these endpoints do not represent early kidney dysfunction due to competition with cardiovascular death. Additional measurements of urinary albumin may largely improve the identification of individuals at increased risk for progressive renal disease [15].

Pathophysiology

Already in the 70s it was reported that obesity is related to increased proteinuria [16]. Recently, an obesity-related form of glomerulopathy was described [4]. This obesity-related glomerulopathy was characterized by fewer lesions of segmental sclerosis, more glomerulomegaly, and less extensive foot process effacement (impaired glomerular basement membrane integrity) than patients with classical idiopathic focal segmental glomerulosclerosis.

Studies in mice show that intracellular lipid accumulation in the kidney plays a role in high-fat diet induced albuminuria, glomerular and tubular changes [17] and in the age-related decline in kidney function, including albuminuria and glomerulosclerosis [18]. The issue of lipotoxicity has become especially relevant in the current obesogenic society and the widely spread prevalence of a high total and saturated fat intake.

Peripheral insulin resistance leads to hyperinsulinemia, necessary to keep blood glucose levels within normal limits. Such hyperinsulinemia may lead to overstimulation in various other tissues that seem to preserve their normal responsiveness to insulin, like the kidney [19]. This can have harmful consequences. Animal experiments show that excess insulin is associated with decreased endothelial production of nitric oxide and increased oxidative stress. Furthermore, excess insulin may promote the proliferation of renal cells via growth factors and stimulation of growth factor receptors [20]. Another mechanism that has attracted renewed interest in the association between obesity and altered renal hemodynamics. A number of early studies in healthy subjects—performed in times that obesity was not yet considered a risk factor for chronic kidney disease—show that insulin may have detrimental effects on renal hemodynamics (blood circulation in the kidney) [21, 22]. Nowadays it is known that also in the non-obese range (BMI between 23 and 30 kg/m2), obesity is related to hemodynamic changes [23]. Hemodynamic changes are related to hyperfiltration and increased intraglomerular pressure, podocyte injury, albuminuria (of FFA-rich albumin), and tubular cell injury. Several obesity related factors are involved in hemodynamic changes, including hormonal changes in the renin-angiotensin system, increased sympathetic tone, and potentially increased circulating FFA and leptin [24].

Lifestyle

Lifestyle factors such as physical activity [25] and diet [26, 27] are important modifiable factors for insulin resistance, and have been associated with the risk of kidney disease [28]. In the second National Health and Nutrition Examination Survey (NHANES II, n = 9,082), the risk of chronic kidney disease was related to physical inactivity both with and without adjustment for age, sex, race and body-mass index [28]. The adjusted relative risk (RR) of inactive versus very active was 2.2 (CI 1.3–3.8). This risk was comparable to the RR in smokers of more than 20 cigarettes a day versus never smokers (RR = 2.3; CI 1.3–4.2).

Lifestyle can play a role in the development of kidney disease in several stages, as indicated in the Fig. 1. Obviously, lifestyle modulates the development of obesity and the metabolic syndrome. Lifestyle contributes to the development of type 2 diabetes and hypertension in several ways, including energy intake, intake of saturated fat, salt intake, and physical activity. Less clear is whether lifestyle is related to the development of diabetic nephropathy, once patients have developed type 2 diabetes, but it is very likely that it is of influence on the development of obesity-related glomerulopathy. After renal transplantation, the metabolic syndrome is a prominent risk factor for post-transplantation diabetes mellitus, chronic graft dysfunction, graft loss, and patient death in renal transplant recipients [29]. Behavioural changes to prevent weight gain may counteract the post-transplant development of the metabolic syndrome and thereby improve renal graft function and survival on the long-term [30, 31].

Fig. 1
figure 1

Lifestyle can play a role in the development of kidney disease in several stages

Full size image

A classical nutritional factor in renal function is salt intake [32]. The effect of salt on renal function is related to both high blood pressure and to a direct effect on renal function, i.e., hemodynamic changes. The effect of sodium intake on cardiovascular disease in Western societies remains to be established, but urinary sodium/potassium intake may be related to all-cause mortality in specific groups of overweight subjects [33]. An in-depth review on dietary salt intake and renal function reproduces that variations in salt consumption are directly correlated with albuminuria. Furthermore, an increase in salt consumption is associated with an acute increase in glomerular filtration rate, whereas a reduction in salt consumption may slow the rate of renal function loss [34].

Likewise, many other lifestyle changes may be beneficial. In nondialysis CKD, exercise can decrease microalbuminuria, protect from oxidative stress, reduce inflammation, help to maintain body weight, increase IGF-1 and increase renal function (for review by Moinuddin and Leehey see [35]). In summary, exercise in hemodialysis patients has been reported to enhance insulin sensitivity, improve lipid profile, increase hemoglobin, improve IGF-1 status, increase muscle strength, decrease blood pressure, increase physical functionality and improve quality of life. Combined aerobic exercise and resistance training during dialysis improves muscle strength, work output, cardiac fitness, and possibly dialysis adequacy [36]. Also the maintenance or reduction on body weight will be beneficial. Obesity in the early stages of renal disease, and an increase in BMI after renal transplantation are important risk factors for cardiovascular disease and decline in renal function [37]. Very little is known about other nutritional factors such as a high saturated fat intake, low fibre intake and glycemic index/glycemic load of the food.

Perspectives

Pharmacological intervention to correct individual components of the metabolic syndrome (including high blood lipids, high cholesterol and elevated blood pressure) has been proven beneficial to retard renal function decline. Lifestyle intervention is a powerful tool to prevent or delay progression from a healthy or prediabetic state to type 2 diabetes [38–41], with lifestyle being at least as effective as pharmaceutical intervention [39, 42, 43]. Despite the notification of lifestyle changes in the guidelines for treatment of end-stage renal disease, the prescription of physical activity or other lifestyle changes has been severely hampered, among others by lack of convincing evidence. The recent success of lifestyle changes in diabetes research has improved the support for lifestyle changes as a tool to prevent and reduce obesity-related morbidity, including chronic kidney disease.

The publication of the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines for the evaluation, classification, and stratification of chronic kidney disease in 2002 [44] has raised awareness of chronic kidney disease and greatly stimulated epidemiological research.

However, there are a number of unanswered questions in the relation between lifestyle and improvement of renal function. Whether lifestyle changes that benefit diabetes will also benefit kidney function is unknown, but interesting from a practical as well as an etiological point of view. The role of dietary fats is unknown but the substitution of saturated fats for unsaturated fats could have great potential to prevent kidney disease as well as related cardiovascular disease. Weight loss, or the prevention of weight gain, is a very promising strategy. Weight loss has been the centre of a lively debate, since in end-stage renal disease, an elevated BMI is associated with a higher life expectancy [37]. With the need for dialysis, a catabolic process with muscular atrophy and loss of stored fat begins. On the other hand, obesity in the early stages of renal disease, and an increase in BMI after renal transplantation are important risk factors for cardiovascular disease and a decline in renal function and should be prevented. It is very likely that nutritional risk factors for cardiovascular disease, such as a high saturated fat intake and low fibre intake are also relevant for renal function, and certainly relevant in renal patients due to their increased CVD risk.

At the same time, it is still unclear to what extent pre-clinical kidney dysfunction is related to cardiovascular events, and whether kidney-specific factors may increase CVD risk in the general population. Also the relationship between obesity-related factors such as inflammatory parameters and early development of renal dysfunction deserves attention. Decently designed epidemiological and intervention studies are needed to fill these gaps in our knowledge. A logistic obstacle in large scale studies might be the collection of 24 h urine samples, which is necessary to calculate creatinine clearance and quantitatively assess renal function. With the awareness that early renal dysfunction is relatively common, projects like the recently started LifeLines cohort study now include urine sampling and demonstrate that this is feasible in daily epidemiological practice [45]. In addition, especially in the current obesogenic society, we need effective and tailored lifestyle programs to prevent early renal dysfunction and related cardiovascular disease, as well as to improve the long-term success of renal transplantation.