The worldwide increase in the number of patients with chronic kidney disease is paralleled by the epidemic of obesity in the world, pointing to the overt causal relationship of obesity and renal disease (1). The prevalence of obesity in children has almost tripled since 1980, and this increase exceeds the rise recorded in adult population (2). The growing prevalence of obesity in the youngest age groups and the new increasing trend in the number of children with severe obesity at ever-younger age are the causes of deep concern (3). In obese children, pediatric nephrologist generally encounters three potential problems, i.e. progression of primary kidney disease, arterial hypertension, and obesity-related glomerulopathy.

Obesity exerts multiple effects on the kidney, which may cause primary (hemodynamic, structural and metabolic changes) or secondary (e.g., in diabetes mellitus type 2, which is frequently associated with obesity) kidney injury (4). Obesity favors progression of nearly all primary kidney diseases, as well as the onset of typical kidney lesions. For decades now, a special form of glomerular disease has been demonstrated in the population of obese individuals including children, which develops independently of diabetic or hypertensive nephropathy and is known as obesity-related glomerulopathy or secondary focal segmental glomerulosclerosis (FSGS) associated with obesity. As expected, the increased proportion of obese individuals is accompanied by the growing incidence of this disorder. Yet, obesity is not the only mediator in the onset of this nephropathy because not all overweight persons will develop this disease (5). It is believed that obesity most likely exerts additional burden upon the kidney in the individuals with congenital or acquired reduction in nephron number and/or inherited genetic vulnerability to metabolic sequels of the action of cytokines produced in adipose tissue (6). How does a reduced nephron number lead to kidney injury? In humans, nephron number is definitely defined at birth. Fetal kidney development is completed by 34^th-36^th week of gestation. After that, nephron mass can only decline as part of the aging process or due to disease, trauma or surgical ablation. Children born before 32 weeks of gestation will have a reduced nephron number proportionate to reduction in the length of gestation (7). Low birth weight children have a reduced nephron number, while the usual practice of feeding them with high-calorie formulas and consequential fast growth compensation result in greater susceptibility to early occurrence of insulin resistance, arterial hypertension and obesity, as well as to developing metabolic syndrome, making these children the main risk group for chronic kidney disease. On the other hand, greater birth mass, exposure to maternal diabetes and fast postnatal weight gain are also risk factors for developing obesity in childhood, which may result in the occurrence of proteinuria and renal disease later in life.

The main structural features of obesity-related glomerulopathy include kidney mass increase (up to 40%) and glomerulomegaly (8), while hyperfiltration is the major hemodynamic alteration. In obesity, metabolic requirements from the kidney are increased, resulting in adaptive glomerular hyperfiltration, which in turn leads to maladaptational glomerular lesions (9). As the number of nephrons is given at birth and cannot be increased, the state of greater metabolic requirements and hyperperfusion exerts additional burden upon each of the existing nephrons; then it undergoes enlargement to fulfill its role, which renders it more vulnerable to further damage and destruction. In his hyperperfusion injury hypothesis, Brenner was the first to point to the concept according to which hyperfiltrating glomeruli progress to glomerular sclerosis in the situation of reduced nephron number (10). It is hypothesized that in glomerular hyperfiltration, which may occur consequentially to different states such as reduced nephron number, unilateral kidney agenesis, post-unilateral nephrectomy state and metabolic changes, deterioration of renal function occurs along with glomerular and then systemic arterial hypertension. These states of increased risk for kidney disease are of particular importance in obesity. Clinical presentation of obesity-related glomerulopathy includes proteinuria, normal serum albumin and absence of edema, with mild clinical course and slower progression as compared with FSGS (5).

Clear association of arterial hypertension and excess body mass in children and adolescence was demonstrated in several pivotal studies as early as some 15 years ago (11-13). The risk of arterial hypertension in children was confirmed to increase linearly with body mass index (BMI) increase across the percentile range. The risk of systolic and diastolic arterial pressure elevation was 4.5-fold and 2.4-fold greater, respectively, in children with excess body mass. In obese adolescents, the prevalence of hypertension was 3-fold prevalence recorded in non-obese adolescents. Similar observations can also be found in recent literature reporting on strong, statistically significant correlation between BMI increase percentile and arterial pressure percentile, whereas large population-based studies have shown that body mass or BMI is a major predictor of arterial pressure level in children (14, 15). Environmental factors (diet, physical activity, stress, etc.), as well as some physiologic and genetic factors determine the extent to which obesity will influence arterial pressure. The mechanisms of arterial hypertension development related to obesity are complex and interacting, and include renal sodium retention, enhanced activity of the sympathetic nervous system, elevated level of circulating renin-angiotensin, and impaired endothelial function (16). Renal sodium retention is one of the confirmed mechanisms, while increased sodium tubular reabsorption is ascribed to the enhanced renal sympathetic activity. Elevated intrarenal pressure due to pressure exerted by the surrounding adipose tissue is also believed to interfere with natriuresis. The causes of sympathetic activation in obese persons have not yet been fully clarified, and are likely to be manifold. The potential mechanisms involve insulin resistance, renin-angiotensin system, leptin or other adipokines, obstructive sleep apnea, and psychological stress. Activation of the renin-angiotensin system probably results from enhanced sympathetic activity. Impaired endothelial function has been related to numerous cardiovascular risk factors including obesity.

The mechanisms by which obesity can cause kidney disease have not been fully elucidated and early clinical biomarkers of obesity-related glomerulopathy have not yet been standardized. One of the most frequently used methods for early detection of kidney injury is albuminuria, which primarily results from glomerular damage. However, studies show that tubular lesions are present even before the occurrence of proteinuria (17). Therefore, the values of several urinary enzymes are currently determined in the assessment of renal tubular lesion. One of the tubular lesion markers is N-acetyl-beta-D-glucosaminidase (NAG), which is used to determine the extent of tubular lesion caused by various noxae (18). Furthermore, the kidney injury molecule-1 (KIM-1) is a potentially useful tubular marker, as its level increases in proximal tubular cell damage (19). A recent study compared urinary levels of NAG and KIM-1 between the groups of obese children and control children with normal BMI values (20). The values of both markers were statistically significantly higher in the group of obese children, confirming them to be potentially useful markers of early kidney injury.

The basic therapeutic option for renal complications related to obesity is body mass normalization, primarily by lifestyle modifications that include dietary habits, intensified physical activity and reduction of salt intake. In persons with obesity-related glomerulopathy, the favorable effect of excess body mass reduction manifests as a decrease in albuminuria, creatinine clearance and hyperfiltration (21). Body mass normalization also is the basis of nonpharmacological treatment of arterial hypertension in obese children, and together with regular physical activity generally proven as an adequate therapeutic measure for arterial pressure regulation in these children (22, 23).