In recent years, the prevalence of end stage renal disease (ESRD) , including ESRD in the pediatric population, has been increasing in parallel with the rise of obesity and insulin-resistance. The clustering of cardiovascular risk factors (higher BMI, type 2 diabetes mellitus (T2DM), dyslipidemia, hypertension and insulin resistance (IR), has been well documented in obese children and adolescents, suggesting that the effects of obesity on target organs in adults, including the kidneys are initiated during childhood.
by Dr A. Savino, Dr P. Pelliccia, Dr F. Chiarelli and Dr A. Mohn

The increasing prevalence of ESRD and childhood obesity
The prevalence of end stage renal disease (ESRD) has approximately doubled over the past three decades [1], in parallel with the increasing prevalence of obesity and insulin-resistance, which also occur in the pediatric population throughout the world [2]. Currently approximately one-fifth of children and adolescents in industrialised countries are overweight or obese; obesity is thus a real threat not only to the health of children and adolescents, , but also for adults since the metabolic, cardiovascular and renal impacts of obesity, although generally not presenting symptomatically until adulthood, have their origins in childhood [3]. This is alarming, since in most cases the condition of being overweight/obese earlier in life continues into adulthood, thus representing a major contributor to the adult obesity epidemic and to increased cardiovascular and renal morbidity and mortality in adult life.

Even if the vast majority of studies that have examined the association between obesity and kidney disease (KD) have been carried out in adults, a growing body of evidence suggests that childhood obesity also increases the risk of KD and its consequences, and that renal dysfunction may start long before the appearance of hypertension or diabetes in adulthood [4].

From obesity and its metabolic complication to renal involvement and injury
The so-called “obesity-related glomerulopathy” is clinically characterised by a higher serum albumin, moderate proteinuria (with a lower incidence of nephrotic-range proteinuria), lower serum cholesterol and minimal edema; morphologically it is defined as glomerulomegaly with or without focal segmental glomerulosclerosis, due to functional and structural renal changes [5].
Currently there is increasing evidence that obesity may also damage the kidneys; in particular, central adiposity seems to be important for renal function abnormalities, as it is strongly associated with diabetes and hypertension, the two most common causes of ESRD [6]. Moreover, the metabolic syndrome (MS), a major consequence of obesity, also seems to be an independent risk factor for both chronic kidney disease (CKD) and ESRD [4], with accumulating data supporting the hypothesis that increased insulin resistance (IR) and hyperinsulinemia are among the most important factors of MS contributing to renal injury [7] [Figure 1].

Insulin resistance/hyperinsulinemia
Accumulating data suggest that IR, as well as compensatory hyperinsulinemia, are independently associated with an increase prevalence of CKD [8], and support the existence of several pathways linking IR and hyperinsulinemia with KD [Figure 2]. Insulin has been related to the development of glomerular hyperperfusion and hyperfiltration, promotion of mesangial renal cell proliferation, increasing urinary albumin excretion rate, and augmented activity of the renin-angiotensin-aldosterone system, thus contributing to hypertension. Moreover, insulin stimulates the production of pro-inflammatory cytokines by the adipose tissue and seems to be related to an impaired nitric oxide production or action, and to the altered oxidant/antioxidant status observed in obese subjects [9, 10].

Impaired glucose tolerance (IGT)
Elevated plasma glucose levels were found to be significantly associated with an increased prevalence of both CKD and microalbuminuria, and with increased odds ratios of microalbuminuria [11]. Hyperglycemia is directly related to hyperfiltration and renal hyperperfusion, and it has been causally linked to vascular and glomerular dysfunction [12]. GFR values increase across the spectrum of hyperglycemia among patients with IGT and newly diagnosed diabetes. The decline in GFR was greatest in patients with diabetes whereas it was only modest in those with normal or impaired glucose tolerance.

High blood pressure
Obesity is associated with the activation of the renin-angiotensin-aldosterone system, increased sympathetic nervous system activity, IR and hyperinsulinemia, all of which contribute to tubular sodium reabsorption, associated fluid retention and hypertension. A compensatory lowered renal vascular resistance, elevated renal plasma flow, increased GFR and higher blood pressure are important in overcoming increased sodium reabsorption. In the presence of other risk factors, such as hyperlipidemia and hyperglycemia, these adaptive changes may provoke glomerulosclerosis, proteinuria and loss of nephron function, even before structural changes are evident [13]. Furthermore, in obese subjects, visceral adipose tissue almost completely encapsulates the kidneys and penetrates into the sinuses of the medulla, causing compression and increased intrarenal pressure. Both increased intrarenal and abdominal pressure may contribute to obesity-associated hypertension [14, 15].

Hyperlipidemia
Obesity is commonly associated with hyperlipidemia and there is growing evidence that abnormalities in lipid metabolism contribute to renal disease progression. The mechanism has not been fully elucidated, but triglyceride-rich lipoproteins, free fatty acids (FFA) and metabolites, and albumin-loaded FFA seem to play a major role in renal cell injury. Hyperlipidemia also causes mesangial proliferation and expansion due to LDL cholesterol, development of glomerulosclerosis and progressive renal failure [16]. CKD patients also suffer from a secondary form of dyslipidemia, which contributes to the rate of progression of renal disease.

Metabolic syndrome (MS)
Several studies investigating the relationship between factors of the MS and KD showed that it can to a large extent be explained by the fact that most of the components of the metabolic syndrome, namely T2DM, hypertension, obesity and low HDL-cholesterol levels, apart from predisposing to cardiovascular disease are also strong independent risk factors for CKD [8]. Prospective data also suggest that the presence of the MS is independently related to a greater risk of developing CKD and microalbuminuria [17].

Obesity-related renal injury in childhood
The sequelae of obesity, such as hypertension, dyslipidemia and hyperinsulinemia are increasingly being recognised in childhood. Clustering of cardiovascular risk factors is seen in children and adolescents, suggesting that adult consequences of obesity on target organs, including the kidney, are more likely to develop in young people. Growing evidence also suggests that childhood obesity may put young people at increased risk for KD and its consequences.One of the most important consequences of obesity is the development of a state of insulin resistance (IR). Obese children with a similar BMI can differ in their risk for complications on the basis of the degree of IR [18]. Hyperinsulinemia influences blood pressure and serum lipoprotein concentrations, and often results in hypertension and dyslipidemia. The presence of these conditions, in addition to obesity, is thought to play key roles in the pathogenesis of obesity-related glomerulopathy. It is alarming that metabolic and cardiovascular complications are already found in obese prepubertal children, as IR and related consequences might be further exacerbated by the influence of puberty, due to the physiological decrease in insulin sensitivity associated with normal development in puberty [19].

The association between hypertension and childhood overweight and obesity has been documented in several studies [9]. In general, blood pressure values have been increasing in young people over the last decade, in parallel with the rise in obesity [20], and more children and adolescents are falling into hypertensive ranges. The risk of hypertension increases across the entire range of BMI values and is not defined by a simple threshold effect [21, 22]. Compared with normal weight children, those with a BMI >90th percentile were about three times more likely to have hypertension [23]. Low insulin sensitivity is also a well-known contributor to high blood pressure in children: an insulin-mediated effect on renal sodium reabsorption and on the sympathetic nervous system (SNS), with a state of hyperactivity characterised by increased heart rate, BP variability, increased levels of catecholamines and increased peripheral sympathetic nerve traffic, are the main mechanisms that have been suggested and described in obese
children [24, 25].

The prevalence of microalbuminuria among severely obese children was found to be 10%, which is consistent with previous findings in obese adults. This was not related to BMI or classical cardiovascular risk factors, but there were significant associations with post-challenge glucose, insulin levels and whole body insulin sensitivity index (WBISI), suggesting that even slight abnormalities in glucose metabolism may be a driving force for early vascular damage in the toxic environment of pediatric obesity [26]. Increased levels of microalbuminuria and ß2-microglobulinuria were also observed in obese children compared to those of normal weight, indicating early renal glomerular and tubular dysfunction as a consequence of childhood obesity [27]. The urinary albumin/creatinine ratio was associated with metabolic disorders linked to obesity, and also with the clustering of features of the MS. The relationship between microalbuminuria and excess weight is more complicated in adolescents, since overweight adolescents, with presumably more coexisting cardiovascular risk factors, had a lower prevalence of microalbuminuria [28, 29], probably due to the existence of important confounding variables, e.g. orthostatic proteinuria. In any case, the association of microalbuminuria with cardiovascular risk factors differed according to BMI category, being strongly modified by overweight.

The increasing prevalence of overweight closely parallels the rise in type 2 diabetes among children and adolescent [30]. In 1994, T2DM accounted for one third of the newly diagnosed diabetes cases among 10 to 19 year olds [31], 90% of these subjects having BMI values at or above the 90th percentile for age and gender. IGT and IR are presenting early in life among overweight and obese children and adolescents [32, 33], suggesting that the metabolic process is accelerated in these individuals and that the transition between IGT and diabetes is shortened.

Obese children and adolescents have consistently been observed to have a more unfavorable lipid and lipoprotein profile than children and adolescents with a normal body weight, with significantly elevated total cholesterol concentrations, higher LDL cholesterol and TG concentrations and significantly lower HDL cholesterol concentrations [34]. At-risk lipoprotein concentrations are of particular concern during the years of growth because they tend to continue into adulthood [35]. The best predictor of young adult total cholesterol concentration is a measurement taken 12 years earlier; approximately fifty percent of children and adolescents who had total cholesterol or LDL-cholesterol concentrations above the 75th percentile had elevated concentrations at follow-up in young adulthood [36].

Conclusions
Excess body weight is significantly associated with an increased risk for KD, not only in adults, which is well documented, but also in obese children and adolescents. A higher BMI, the presence of T2DM, hypertension and, of particular importance, IR, are strong independent risk factors for CKD and ESRD, which may be present even among overweight and obese children and adolescents.

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The authors
Alessandra Savino MD, Piernicola Pelliccia MD, Francesco Chiarelli MD, PhD, Angelika Mohn MD, PhD.
Department of Pediatrics
University of Chieti
Chieti, Italy

Correspondence to:
Alessandra Savino, MD
University Department of Pediatrics
Ospedale Policlinico
Via dei Vestini 5, 66013 Chieti, Italy
Tel. +390871358015 
e-mail: alessavino@katamail.com