Childhood obesity and renal function 

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Varvara Askiti
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Evi Gole
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Elpis-Athina Vlachopapadopoulou
Dr Vlachopapadopoulou is a member of the Endocrine Society since 1994, of the European Society of Pediatric Endocrinology since 1997 and of the European Society of Endocrinology since 2006.
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Introduction 

Childhood obesity is a major healthcare issue worldwide. The prevalence of obesity in the pediatric population has significantly increased in the last decades, specifically in boys from 0.9% in 1970s to 7.8% currently, and in girls from 0.7% to 5.65% (1). In addition, the incidence of chronic kidney disease (CKD) has also increased by 41.5% in the last 3 decades (2). It seems that there is a strong association between obesity and both the development and progression of kidney disease. It is also apparent that renal dysfunction associated with obesity, starts early in childhood, before the other complications of obesity that are known to have an impact on kidney function, such as metabolic syndrome, diabetes and hypertension develop (3).  

One of the first reports examining the histologic changes in kidneys from children with obesity was published in 1975 (4). In this study, renal biopsy was performed in children with significant obesity and normal renal function. Histological examination of the renal tissue showed increased glomerular size, mild hypercellularity and enlargement of the mesangial areas. These changes were confirmed in later studies that showed that the primary renal histologic abnormality of children with obesity is secondary focal segmental glomerulosclerosis and this condition is currently known as obesity related glomerulopathy (5).  

Obesity related glomerulopathy very rarely might present with significant proteinuria and nephrotic syndrome leading to end stage renal disease (ESRD). However, in the majority of cases, children with obesity have subtle clinical symptoms and the disease is silent for many years. Usually, these children have only laboratory manifestations like microalbuminuria and very mild reduction of the glomerular filtration rate (GFR). A study in 242 adolescents undergoing bariatric surgery showed that 14% had only microalbuminuria, 3% had proteinuria and 3% had GFR below 60% (6). As these abnormalities are not associated with clinical symptoms, in most cases are unrecognized and lead to a delayed diagnosis of chronic kidney disease usually in adult life. 

 

Mechanisms of renal injury 

Obesity, as already known, is related to insulin resistance and hyperglycemia. It is also associated with hypertension and activation of the renin-angiotensin aldosterone system. All these alterations, along with the increased Na tubular reabsorption lead to increased blood flow in renal glomeruli and glomerular hyperfiltration. On the other hand, dyslipidemia as another complication of obesity, contributes also to the progression and development of renal disease. Adipokines, secreted by the adipose tissue, are cytokines that induce oxidative stress, inflammation and glomerular hypertrophy. In addition, obesity is associated with damage in renal tubular cells, podocytes and in the tubulointerstitial tissue causing both glomerular and tubular lesions (7). All the aforementioned mechanisms in combination, lead to significant renal damage and the entity known as obesity related glomerulopathy (8). 

Although the above mechanisms of obesity related glomerulopathy have been very well described, for many decades the metabolic syndrome was thought to be the only cause of renal damage in the population with obesity. However, studies have shown that obesity leads to renal damage independently of the presence of metabolic syndrome. In a study by Jung et al, the risk of kidney disease was assessed in both children with normal weight or obesity, with and without metabolic syndrome patients. It was shown that the highest risk was seen in patients with obesity and metabolic syndrome (HR 1.56), however the risk of chronic kidney disease was also elevated in patients with obesity, without metabolic syndrome (HR 1.38) compared with the general population (9).  

 

 

Figure 1: Mechanisms of obesity related renal injury (7). 

RAAS: Renin-Angiotensin Aldosterone System. 

 

Obesity related kidney disease in children without underlying renal problems 

Many studies have investigated the impact of obesity in the development of kidney disease in children without an underlying renal problem. One of the largest studies, including a population of 1.194.704 adolescents, was published by Vivante et al in 2012. In this study, body mass index (BMI) was recorded in all adolescents at the age of 17 and related to the risk of developing ESRD after 25 years of follow up. It was shown that children with overweight had an increased risk of developing ESRD (HR: 3.00; 95% CI 2.50-3.60) and children with obesity had even higher risk (HR: 6.89; 95% CI 5.52-8.59). In addition, when the population was divided to those that also developed diabetes or not, overweight (HR: 5.96; 95% CI 4.41-8.06) and obesity (HR: 19.37; 95% CI 14.13-26.55) were also strong risk factors for diabetic ESRD (10) 

However, not all children with obesity develop kidney disease, and it seems that other contributing factors play an additional role. Firstly, the impact of the age of onset of obesity was studied in a large British cohort study (11). In this study, the investigators divided the population on groups of those never with obesity, always with obesity, and groups with pubertal or prepubertal onset obesity. It was shown that at the age of 60-64, the group with pubertal onset obesity or those always with obesity had an increased risk of kidney disease identified by impaired GFR or microalbuminuria. The age of onset of obesity was an independent risk factor, regardless of the incidence of hypertension, diabetes, smoking, or low exercise activity. The children with obesity only at a prepubertal age, had a similar risk of kidney disease with the general population.  

Another contributing factor is the gestational age, with premature newborns being a high risk population for developing obesity related kidney disease. It is widely known that during embryogenesis nephrons develop until the 36th week of gestation and children born earlier have a lower nephron number. It is evident that if these kids develop obesity later in life, this has an additional impact in kidney function due to the increased hemodynamic pressure on the nephrons as explained previously. A study in proteinuric children that also included children with primary focal glomerular sclerosis, showed that children with obesity and a history of prematurity, had worse progression of their kidney disease and a 5-fold higher risk to develop ESRD compared to premature children without obesity. This risk was comparable to the risk of non obese children with focal glomerular sclerosis  (12).  

Figure 2: Renal survival of children non-obese and preterm (NO-PT), obese and term (Obese-T), non-obese with focal glomerular sclerosis (NO-FSGS) and children obese and preterm (Obese-PT) (12). 

As already mentioned, in the early stages, obesity related kidney disease is silent with no clinical symptoms until severe kidney damage has occurred. However, it has been shown that certain metabolic biomarkers can speculate the development of obesity related kidney disease. A recent study indicated that increased serum concentrations of cholesterol, triglycerides, uric acid and increased urine concentration of NGAL (neutrophil gelatinase associated lipocalin) might predict CKD development in adolescents with obesity. The assessment of these biomarkers might be a useful clinical tool in classifying patients with obesity according to the risk of developing kidney disease even if they have initially normal kidney function (13). 

 

Obesity related kidney disease in children with underlying renal problems, ESRD and renal transplantation 

Incidence and definition 

Obesity is present in a significant percentage of children with underlying renal problems. Specifically, data from the European Society for Pediatric Nephrology/European Renal Association-European Dialysis and Transplant Association Registry have demonstrated that in the population of dialysis and renal transplant patients, 20.8% are patients with overweight and 12.5% are patients with obesity. In most of the patients BMI increases post transplant, and a very short stature (OR: 1.64, 95% CI: 1.40–1.92) or treatment with steroids (OR: 1.23, 95% CI: 1.03–1.47) are associated with a higher risk of being overweight or obese after transplantation (14). 

Regarding terminology, the international Pediatric Renal Nutrition Taskforce consisting of a global group of Pediatric Nephrologist and Dieticians has defined overweight and obesity in children with CKD stages 2-5 as below (15):  

  1. Children with overweight 2-5 years: Weight-for-height for age > +2SD, using the World Health Organization (WHO) child growth standard chart.  
  1. Children with obesity 2-5 years: Weight-for-height for age > +3SD, using the WHO child growth standard chart. 
  1. Children with overweight aged > 5 years: BMI for age > +1SD, equivalent to BMI > 25 kg/m2 at 19 years, using the WHO growth reference chart or a country specific growth chart.  
  1. Children with obesity aged > 5 years: BMI for age > +2SD, equivalent to BMI > 30 kg/m2 at 19 years, using the WHO growth reference chart or a country-specific growth chart. 

Also, Metabolic syndrome in children with CKD stage 2-5 has also been defined as: Presence of overweight or obesity and at least 2 of 4 additional cardiovascular risk factors: 

  1. Systolic and/or diastolic office blood pressure (BP) ≥ 90th centile for age, sex and height or ≥ 130/80 mmHg, whichever is lower, or on anti-hypertensive medication
  2. Fasting triglycerides ≥ 100 mg/dL (1.1mmol/L) if age <10 years, or ≥ 130mg/dL (1.5 mmol/L) if age ≥ 10 years
  3. Fasting high-density lipoprotein (HDL) < 40 mg/Dl (1.03 mmol/L)
  4. Fasting serum glucose ≥ 100 mg/dL (5.6 mmol/L) or known type 2 diabetes mellitus (T2DM)

The impact of obesity in patients with underlying kidney disease has been specifically studied in patients with ESRD before and after renal transplantation as below: 

Impact of obesity before renal transplantation 

Obese patients with ESRD on hemodialysis have increased mortality and morbidity. This is firstly due to the inflammatory processes and the protein energy wasting that obesity predisposes them. On the other hand, a study investigating the association between BMI and patient centered outcomes in children with ESRD showed that children with obesity have a lower chance to proceed to transplantation and additionally have a lower probability of receiving a graft from a living donor (16). This is partly explained by the fact that usually obesity affects the whole family and parents with obesity are excluded from donation according to the international consensus that high BMI patients are not accepted as kidney donors. Therefore, with longer times on dialysis, children with obesity have a higher risk of morbidity and mortality because as it is widely recognized, kidney transplantation offers the best long term survival for children with ESRD. 

Impact of obesity after renal transplantation 

The adverse effects of obesity on patients after renal transplantation are well recognized. Firstly, patients with obesity face several surgical difficulties as prolonged operative time, delayed wound healing and also have a higher risk of venous‐thromboembolism. It is also evident, that the presence of obesity before or after transplantation has a negative impact in graft function. In a study that examined the effect of BMI in allograft function, it was demonstrated that one year post transplantation 40% of children were overweight and 29% were obese. Children with obesity before transplantation had lower GFR one year post transplant and an increased risk for graft failure (HR: 1.25, 95% CI 1.1, 1.42).  For every 1 point increase in BMI z-score, there was a 7% increased risk of allograft failure (HR 1.07; 95% CI 1.03-1.1, p < 0.001). Children with obesity had also increased incidence of hypertension post transplantation. In addition, the prevalence of delayed graft function and acute rejection immediately post transplantation was also correlated to higher BMI. On the long term, 5 years post transplant, children with high BMI had lower GFR and reduced graft function (17).  

 

Assessment of children with obesity 

As explained, obesity can lead to kidney damage in both children with and without underlying kidney disease. Therefore, it is crucial that children with obesity have careful monitoring of their renal function in regular timeframes to allow early detection and intervention. It is recommended that from the age of 6 years, microalbuminuria and serum creatinine should be assessed in all children with overweight or obesity.  Regarding microalbuminuria 3 assessments should be performed along with urine creatinine measurements to calculate the albumin to creatinine ratio that is a more reliable marker of early kidney injury. If these values are deranged, they should be referred to a pediatric nephrologist and renal function should be monitored every 6 months or earlier if there are other comorbidities (18).  

Assessment of serum creatinine is the first line kidney function screening method. It is inexpensive and widely available, however is influenced by diet, physical activity and muscle mass. On the other hand, serum cystatin C measurement is a more reliable and sensitive marker of renal function but is not routinely performed in all laboratories (18). A study in children with obesity showed that especially in children with metabolic syndrome cystatin C can be used as an early biomarker of kidney function in the early stages of renal damage before an increase in creatinine occurs (19).  

On the other hand, children with underlying renal disease, CKD stages 2-5 and after transplantation should have their BMI calculated and should be classified in groups of normal weight, of overweight or obesity as per the above terminology. They should also have regular measurements of blood pressure, lipid profile and glucose to assess for presence of metabolic syndrome. It is also crucial to have an evaluation of lifestyle habits including diet, physical activity, sleep and screen time (15). 

 

Management of obese children 

The cornerstone of obesity management remains the weight reduction through dietary intervention and physical activity. Therefore, lifestyle recommendations for a healthy diet and regular exercise are suggested to all children with obesity and preexisting or not kidney disease. Salt restriction is also recommended due to the very strong association between salt intake and BMI. A study in 231 elementary school children showed that salt intake was significantly different between children with healthy weight, obesity or overweight and there was a positive correlation between BMI and sodium intake (ρ = 0.45, p < 0.0001) (20). 

The Pediatric Renal Nutrition Taskforce recommends an individualized energy intake, adjusted for age, CKD stage and comorbidities in obese/overweight children with CKD. The nutrition care plan should include a high-quality diet consisting of fruits, vegetables, whole grains, fish and lean meat. Sugar-sweetened beverages, highly processed foods and foods high in saturated fat should be avoided. In order for this plan to be successful children should have a holistic approach including education, behavioral techniques and psychological support to achieve a healthy diet (15). In children with mild chronic kidney disease and obesity protein intake should not be significantly restricted but if needed can be carefully reduced towards the lower end of the suggested range. Low protein diets are not recommended as in childhood the goal is to promote normal growth, to preserve fat free mass, and there is no evidence to suggest that protein restriction ameliorates CKD progression (21). 

Emphasis is also given in the encouragement of physical activity that should include aerobic exercise daily and muscle reinforcement 2-3 times/week. The intensity and duration should be individualized according to age, physical tolerance, CKD stage and comorbidities.  

In children that develop proteinuria with underlying or not renal disease, angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II type I receptor blockers (ARBs) are recommended, both of which protect kidney function by reducing hyperfiltration and proteinuria. These medications have proven benefits in patients with kidney disease by slowing disease progression and reducing cardiovascular risk. On the other hand, anti-obesity medications are not recommended in children with chronic kidney disease or transplantation due to lack of evidence of their efficacy and side effects at present.  

Finally, regarding weight loss surgery, bariatric surgery can be considered when all the other interventions have failed. According to the recommendations by the Pediatric Renal Nutrition Taskforce (15) candidates for weight loss surgery are: 

  1. Adolescents with extreme obesity (BMI≥40 kg/m2) and other comorbidities associated with long-term risks  
  2. Adolescents with BMI≥35 kg/m2 with specific obesity related comorbidities including T2DM, severe steatohepatitis, pseudotumor cerebri, and moderate-to severe obstructive sleep apnea.  

In regards to the efficacy of the conservative measurements in ameliorating the impact of obesity in the progression of kidney disease, the results are impressive. A multicenter study in children with chronic kidney disease and mean GFR of 50 ml/min/1.73m2 showed that for every BMI reduction of 0.1 standard deviation (SD) the GFR increased by 0.62% (22). It is likely that weight loss reduces lipid toxicity and inflammation and also improves the other factors involved in obesity related glomerulopathy as RAAS activation and insulin resistance, hence overall reduces hyperfiltration and improves kidney function, blood pressure and albumin excretion. 

In conclusion, obesity in healthy children is associated with increased risk of developing chronic kidney disease and the damage starts early in life when only subtle markers like microalbuminuria or mild GFR decrease are evident. In children with underlying kidney disease, obesity deteriorates progression of kidney disease and is also associated firstly with lower access to transplantation and secondly to worse outcomes after renal transplantation. The cornerstone of management of these children includes lifestyle modification and close monitoring to detect and intervene early in the obesity related kidney implications.   

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