Abstract and Introduction
Concurrent with the global obesity epidemic, there is an increasing number of people of all ages developing chronic kidney disease associated with obesity. In adults, the definition of obesity is a BMI greater than 30 kg/m2. Whereas, in children, a BMI greater than the 85th percentile for age is considered overweight and greater than the 95th percentile is classified as obese. Clinical and pathologic characteristics of a distinct nephropathy have emerged independent of that of diabetic or hypertensive glomerulosclerosis. These include a silent presentation in an obese individual with heavy proteinuria, normal serum albumin and the absence of edema. Renal pathologic findings are notable for mesangial matrix expansion, glomerular hypertrophy and reduced density of podocytes with detachment of foot processes from the glomerular basement membrane. These findings are frequently associated with the development of secondary focal segmental glomerulosclerosis. Obesity alone does not appear to be the sole mediator of this nephropathy. It is most likely the ‘second hit’ for individuals who have congenital or acquired reduced nephron mass as well as an inherited genetic vulnerability to the metabolic consequences imposed by cytokines released by adipose tissue. In children, those born of low birthweight, whether small for gestational age and/or preterm, are likely to have reduced nephron mass as well as an increased tendency for early insulin resistance and the development of obesity and the metabolic syndrome. This in turn is perpetuated by the practice of feeding high-calorie fortified formulas to low-birthweight infants. Rapid catch-up growth, early obesity and insulin resistance are major contributors to the emergence of obesity-related glomerulopathy in children and adolescents. Early detection requires recognizing the demographics of high-risk infants and monitoring them for the development of hypertension, elevated glomerular filtration rate, hyperfiltration and proteinuria. After 6 months of age, angiotensin-blocking agents may be used to control blood pressure, glomerular hyperfiltration and proteinuria. If obesity is present, a comprehensive program of weight loss, including diet and exercise, should be the mainstay of treatment. In older children and adolescents, lipid-lowering medications may be indicated. With morbid obesity, bariatric surgery may be an option.
During the past decade, the obesity epidemic has extended around the world and has affected all populations and all ages including our children.[1,201] The impact of obesity on world health has become astronomical, both socially and financially, with an estimated 1 billion adults overweight and 300 million obese worldwide accounting for over 7% of healthcare costs in developed nations. In children, the incidence of overweight has tripled since the 1960s. The impact of the problem in developing countries, such as China, India and South America, has reached catastrophic proportions.[2,3,202] With the obesity epidemic, the rise in co-morbidities of Type 2 diabetes mellitus (T2DM) and hypertension have paralleled the rise in chronic kidney disease. Once considered rare, obesity-related glomerulopathy (ORG) without diabetes and often independent of systemic hypertension, has emerged as a unique clinical and pathologic entity. Moreover, subtle increments in BMI are now recognized as a major contributor to the progression of primary kidney diseases as well as renal allograft dysfunction.[5,6,7,8,9,10,11,12] Individuals with congenital or acquired decrease in nephron mass appear to be most vulnerable, particularly those from certain ethnic populations.[12,13,14,15,16,17]
Importantly, as the epidemic has affected younger individuals, it has become increasingly evident that the origins of this disease lie in an individual's earliest exposures, which extend as far as the moment of conception. The now seminal epidemiologic works of Barker et al., with his concept of the fetal origins of adult disease hypothesized that the increase of cardio-renal diseases among recent generations originated in adverse intrauterine exposures. Expansions of this research suggest that both genetic and epigenetic alterations may lead to transmission of traits beyond a single generation and may propagate population characteristics and vulnerabilities.[18,19,20,21,22,23,24] This seems to be particularly apparent in groups emerging from impoverished or foraging environments. With the 'fetal programming' of physiologic and metabolic needs discordant with the extrauterine environment of food abundance and sedentary lifestyles, we see decades of worsening obesity.[24,25,26,27,28,29] This has extended to progressively earlier manifestations of disease in children, especially those born at low birthweight.[30,31,32,33,34,35,36]
The obesity epidemic has coincided with the recognition of an increase in the incidence of the nephropathy typical of the natural aging process in the kidneys.[37,38,39,40,41] The lesion is called secondary focal segmental glomerulosclerosis (FSGS) and is characterized by focal scarring of the renal glomeruli, subtle loss of kidney function and a concurrent increase in proteinuria.[37,38,39,40,41] Although aging individuals typically develop FSGS, acceleration in the process has been noted in some populations of individuals and is associated with the histological appearance of enlarging glomeruli.[14,15,16,17,32,42] Brenner et al. has postulated that increasingly large glomeruli (glomerulomegaly) are a consequence of glomerular hyperfiltration.[43,44] Similarly, glomerulomegaly and hyperfiltration are commonly preceded by a nephron deficit, which occurs with aging or as a consequence of disease or surgical ablation (Figure 1).[13,45,46] Hence, the common denominator may be an individual's nephron mass, which is ultimately determined by genetic and/or environmental experiences.
Hematoxylin and eosin.
(A) Age-matched non-obese control with secondary focal segmental glomerulosclerosis. Observe a normal-sized glomerulus. (B) Obese patient of normal birthweight presenting with heavy proteinuria. The glomerulus is larger than the control.
This review is intended to provide a comprehensive summary of the evolution of ORG in children with a focus on early recognition, prevention and treatment.
No writing assistance was utilized in the production of this manuscript.
Pediatr Health. 2009;3(2):141-153. © 2009 Future Medicine Ltd.