A Clinical Guide to Pediatric Weight Management and Obesity, 1st Edition
Adult obesity has been associated with an increase in end-stage renal disease (ESRD) (1). In a prospective study of adults 18 years and older, followed up for 15 to 35 years, elevated body mass index (BMI) at baseline was associated with a greater rate of ESRD, defined as disease requiring dialysis or renal transplantation (2). There was a 10-fold increase in ESRD between adults who were normal weight and those with morbid obesity (BMI ≥40). The risk for ESRD rose continuously with an increase in BMI. The relationship of ESRD to BMI persisted after controlling for gender, race, education level, smoking, diabetes, hypertension, and baseline renal disease (2). Microalbuminuria has also been associated with the development of early renal disease (3). Microalbuminuria is also considered an early indication of vascular damage, a precursor of atherosclerosis (4), and is associated with the development of cardiovascular disease (5).
Obesity in adults can result in distinct glomerulopathology consisting of glomerulomegaly with or without segmental sclerosis (6). In adolescents, hypertrophy of the glomerulus, focal segmental glomerulosclerosis, and increased mesangial matrix and cellularity with preservation of foot process were found in a review of renal biopsies in obese adolescents with proteinuria and mild hypertension in the absence of inflammatory or immunologic changes (7).
Studies in obese adults have shown that cardiac output and expanded extracellular and intravascular volume increase the renal perfusion rate (8). In a study of obese and lean adults, glomerular filtration rate and effective renal plasma flow were higher in overweight than in normal weight patients (8). Urinary albumin excretion was higher in both obese normotensive and obese hypertensive patients than in their normal weight counterparts (8).
In obese Zucker rats, glomerular filtration rates are increased along with an expansion of glomerular area and mesangial matrix (9). Glomerular lesions in obese Zucker rats have been correlated with cholesterol levels, proteinuria, triglyceride levels, insulin levels, creatinine levels, and glucose levels. Histologically, glomerular
damage involved early podocyte damage and tubulointerstitial injury. Use of an angiotensin-converting enzyme (ACE) inhibitor normalized proteinuria, cholesterol levels, glomerular lesions, and podocyte morphology (10).
Obese children have been found to have a higher urinary albumin/creatinine ratio and urinary β2-microglobulin/creatinine ratio than normal weight children, possibly indicating early renal glomerular and tubular dysfunction. The urinary albumin/creatinine ratio was associated with fasting hyperinsulinemia, impaired glucose tolerance, and hypercholesterolemia and significantly correlated with fasting glucose and 2-hour glucose during a 2-hour plasma glucose tolerance test. Urinary albumin/creatinine ratios also increased in accordance with the number of features of the metabolic syndrome in these obese children (11).
Obesity has been shown to worsen renal failure in adults and is one of the treatment factors targeted to slow progression of renal failure.
A study of pediatric patients with chronic renal disease showed that an increase in obesity coincided with a significant rise in the incidence of chronic renal insufficiency (12).
Hormonal changes and low-grade inflammation associated with obesity have also been suggested as mechanisms responsible for obesity-related renal damage (13).
Increased synthesis of vasoactive and fibrogenic substances, including angiotensin II, insulin, leptin, and transforming growth factor–β (TGF-β), which are increased in obesity, may affect glomerular hyperfiltration, mesangial cell hypertrophy, and matrix production (14). Leptin, which is produced in adipose tissue and is cleared principally by the kidney, stimulates cellular proliferation, TGF-β1 synthesis, and type IV collagen production in glomerular endothelial cells. In mesangial cells, leptin increases type I collagen production. Infusion of leptin into normal rats fostered the development of focal glomerulosclerosis and proteinuria. In addition, leptin has been shown to increase sodium excretion, increase sympathetic activity, and stimulate production of reactive oxygen species in the kidney, suggesting a direct pathophysiologic link between obesity and renal pathology (15).
Renal disease is one of the most serious complications of type 2 diabetes, and diabetic nephropathy secondary to type 2 diabetes is the most common cause of ESRD in adults (16).
The most characteristic renal lesion in diabetes is diffuse and nodular glomerulosclerosis (Kimmelstiel-Wilson lesion). Diffuse glomerulosclerosis was present in 65% of Pima Indians with type 2 diabetes on autopsy (17).
- Microalbuminuria—The excretion of albumin greater than normal but less than the detection limits of urine dipstick methods, albuminuria 30 to 300 mg per 24 hours (15–200 µg/minute) (16,18). The simplest screening measure is a random urine microalbumin/creatinine ratio (µg/mg), which should be less than or equal to 30 µg/mg (19).
- Proteinuria—Glomerular proteinuria, which usually follows microalbuminuria, is an early sign of diabetic nephropathy (16). It is usually first evident as a dipstick urine protein value greater than or equal to 1+ (30 mg/dL). Proteinuria is defined as levels of protein excretion greater than 300 mg per 24 hours or a urinary total protein (mg/dL)/creatinine (mg/dL) ratio greater than 0.2 (16).
The 24-hour urine collection is the standard measure of microalbuminuria. However, the use of microalbumin/creatinine ratio in a morning urine specimen is closely correlated with 24-hour albumin in adults (20).
Microalbuminuria can be considered a direct risk factor for progression of renal disease and an integrated risk marker for cardiovascular disease (20).
It is associated with hypertension, endothelial dysfunction, and hyperhomocysteinemia (20). Microalbuminuria is a marker for diabetic nephropathy in both type 1 and type 2 diabetes (18).
Diabetic nephropathy is similar in both type 1 and type 2 diabetes in adults and responds to glycemic control and treatment with ACE inhibitors. In adults with diabetes—and with hypertension and cardiovascular disease in first-degree relatives— glycemic control, hypertension, and smoking are predictors of nephropathy (21). Adults with type 1 and type 2 diabetes had similar rates of proteinuria after 20 years (27% and 28%, respectively). After 25 years of diabetes, these percentages increased to 46% in type 1 diabetes and 57% in type 2 diabetes. After 5 years of proteinuria, the rates of renal failure were 63% for type 2 diabetes and 59% for type 1 (22).
Poor glycemic control, lack of physical exercise, hypertension, heart failure, and nondiabetic renal disease can contribute to microalbuminuria. In adults with type 2 diabetes, proteinuria and microalbuminuria have been shown to predict subsequent clinical nephropathy and mortality from cardiovascular disease (16).
Microalbuminuria has been associated with increased cardiovascular mortality in adults without diabetes. Microalbuminuria was associated with impaired glucose tolerance and parental history of type 2 diabetes as well as a higher incidence of
hypertension, decreased high-density lipoprotein (HDL) cholesterol, elevated triglycerides, and increased 2-hour insulin (23). The association between microalbuminuria and cardiovascular morbidity increased in a linear fashion with the degree of albumin excretion in adults (24). A link has also been found between urinary albumin excretion in adults and left ventricular hypertrophy (20).
Microalbuminuria has been detected in slightly more than 10% of a cohort of obese children with a BMI greater than the 97th percentile. The presence of microalbuminuria was associated with higher glucose and insulin levels during an oral glucose tolerance test independent of BMI, age, gender, ethnicity, or fasting glucose. The increases in microalbuminuria were continuous throughout the range of postchallenge blood glucose (25).
Morbidly obese children, especially those with evidence of the metabolic syndrome, may be at particular risk for progression of renal pathology.
Studies in adult diabetic patients have shown that treatment of hypertension decreases the amount of protein excretion and slows the rate of renal impairment (16). Microalbuminuria correlates with blood pressure in adults, and reduction in microalbuminuria is achieved via use of antihypertensive drugs (20).
There are no specific guidelines for obese children with microalbuminuria. The American Academy of Pediatrics (AAP) guidelines for Native American children with type 2 diabetes recommend the following (26):
After confirmation of microalbuminuria by elevated microalbumin/creatinine ratio on two studies and ruling out other primary renal causes of microalbuminuria, consideration of treatment with ACE inhibitors is recommended, bearing in mind that ACE inhibitors are teratogenic. Low dose is recommended to start, with repeat testing to confirm reduction of microalbuminuria and titrate dose. Control of hyperglycemia, hypertension, and smoking cessation are recommended (26).
CB is a 17-year-old African American young woman who is new to your practice. On her first visit, you note her marked obesity and increased difficulty maneuvering around the office. Her weight is 275 lb (>95th percentile) and height is 5 ft 1 in (10th percentile), giving her a BMI of 52.0 (>99th percentile). She is mildly hypertensive, with a blood pressure of 128/82 mm Hg [>95th percentile (126/84 mm Hg) systolic and >90th percentile (122/79 mm Hg) diastolic]. She and her mother note that CB has been “large since birth” and that there are many large relatives in the family. CB is a senior in high school and hopes to graduate and pursue cosmetology as a career. She skips breakfast, and often skips lunch, and then usually eats fast food after school and may or may not eat dinner with the family. Her main beverage during the day is regular soda. The family
history is positive for morbid obesity and type 2 diabetes; in fact, her mother is taking insulin, and two of her grandparents passed away from diabetes-related cardiovascular disease.
Review of systems indicates sleep disturbance with snoring, orthopnea, and daytime somnolence; her periods are irregular; and she has noted an increase in fatigue over the past several months, which has prompted this visit to your office. On physical examination, you find that she has acanthosis nigricans of her neck and axilla and marked central obesity. You perform a random glucose by fingerstick in the office and it is 155 mg/dL. You order a 2-hour glucose tolerance test, a lipid panel, and spot urine for creatinine and albumin, along with liver function studies and an a.m. cortisol, blood urea nitrogen (BUN), and creatinine and androgens.
You tell CB she is at increased risk for diabetes and has elevated blood pressure; you explain the etiology and describe the laboratory studies you are ordering. You ask her what these findings mean to her, and CB says she is scared because she has seen what happened to her grandparents. You describe several options to start: lifestyle management, including eliminating soda and sugared beverages, decreasing the intake of fast food, and eating regular meals. She and her mother decide to eliminate soda by buying only diet drinks for the house. You ask her to have her laboratory tests done as soon as possible and schedule an appointment for 2 weeks. You also schedule a sleep study to evaluate her possible sleep apnea and make an appointment with the nutritionist.
CB returns in 2 weeks. Her weight is down about 2 lb, placing her at 273 lb. Her blood pressure is 127/85 mm Hg (>95th percentile systolic and diastolic pressure). Her test results have come back, showing that she has impaired glucose tolerance and insulin resistance with a 2-hour glucose of 164 mg/dL and elevated insulin. Her spot urine shows microalbuminuria, and the rest of her laboratory values are within normal limits.
She has stopped all but a few sodas and occasional juices. She also met with the nutritionist and has begun to keep diet records and decrease her fast food consumption, noting that they talked about her blood pressure and decreasing sodium in her diet.
Her blood pressure is still elevated and she has microalbuminuria. You start treatment with an ACE inhibitor, carefully explaining that this drug is contraindicated in pregnancy. She denies sexual activity, and you ask her to let you know immediately if this changes so you can stop the medicine. CB and her mother express interest in seeing the nutritionist again; you have them schedule this appointment and another appointment with you in 2 weeks.
CB and her mother return, and CB's weight is down another pound. She is taking her antihypertensive medication and following a lower sodium diet. Her blood pressure is 123/79 mm Hg. She has scheduled the sleep study for the following week
and, right before your visit with her, has met with the nutritionist, who gave her some meal plans and ideas for breakfast and lunch at school.
You begin to talk about exercise, and she asks what she should do. You suggest adding some walking to her after-school routine, and she is interested. You also talk about screen time and explore other activities she could engage in if she is not watching television. She is unsure but thinks she could call a friend, visit her aunt who lives in the neighborhood, or occasionally go to a friend's house. You schedule an appointment for 1 month and ask her to call you if she is having any shortness of breath or joint problems as she starts to increase her walking. You suggest she begin by walking several minutes per day and increase by 1 minute per day as a way of incorporating the walking into her schedule.
CB and her mother check in. She has lost 3 more pounds and is taking her ACE inhibitor; her blood pressure is 120/76 mm Hg. Her sleep study was positive for apnea, and she has been started on bilevel airway pressure (BiPAP). She has begun and continued walking and is feeling more energetic and is not napping regularly after school, as she did in the past. You congratulate her on taking charge of her health and ask what help she needs in “keeping on the right track.” She says her mother is helping her with food selection and she would like to come to your office every week to “weigh in.” You arrange this with your nurse and plan for CB to return in 2 months for a blood pressure check and follow-up with you. You give her a prescription for spot urine for creatinine and albumin to see if the medication and changes she has made have decreased her microalbuminuria.
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