Mark van Dam

Obesity is a chronic disease characterized by excessive fat deposits that harms health, and its prevalence in children has risen majorly over the last decades. As a major risk factor for chronic kidney disease (CKD), obesity is an important modifiable factor in the prevention and deterioration of CKD. The major aims of this thesis were to 1) improve understanding of serum creatinine (SCr) and SCr-based estimated glomerular filtration rate (eGFR) equations in children with overweight and obesity without kidney disease, 2) explore the relation between eGFR and obesity-related comorbidities in childhood obesity, and 3) assess the effect of a multidisciplinary lifestyle intervention on SCr and eGFR in children with overweight and obesity.

Estimation of GFR in children with overweight and obesity
As a key marker of kidney function, GFR is commonly estimated using SCr. Studies on SCr in children with overweight and obesity show inconsistent results, possibly due to confounding factors (e.g. age, height, and sex) and heterogeneous SCr-measurement methods. In Chapter 2 and 3, SCr and SCr-based eGFR were analysed in 600 children with overweight and obesity without CKD. Enzymatically measured SCr was ‘rescaled’ using Q-age and Q-height (the median SCr value of a child with corresponding age (and sex in case of an age >14 years) or height, respectively), resulting in SCr/Q. Most children (96.5%) had SCr values within the SCr/Q-age reference range of [0.67-1.33] (corresponding to the 2.5th and 97.5th percentile, which equals eGFR FAS-age of about 81-160 ml/min/1.73m2).

In Chapter 2, commonly used SCr-based eGFR equations in children were compared. Since SCr values of children with overweight and obesity are mostly within the reference range and measured GFR is known to remain stable from age 2 to 40 years in healthy individuals, a flat and sex-independent GFR-age relationship is expected in children with overweight and obesity. Considering the distribution of eGFR, absence of age dependency and order of magnitude of sex-dependency, eGFR FAS-age, FAS-height and LMR18 are suggested as the preferred eGFR equations in children with overweight and obesity aged 2 years and older.

In Chapter 3, SCr/Q is suggested to be a valuable add-on next to SCr-based eGFR equations. Advantages over eGFR equations include no modelling biases, a clear target value (SCr/Q = 1) and defined reference interval [0.67 - 1.33], independent from age and sex, and independence from BSA-adjustment.

Relation between eGFR and obesity-related comorbidities in childhood
In Chapter 3, correlations between eGFR, SCr/Q, and anthropometrical and metabolic variables were analysed in 600 children with overweight and obesity without CKD. SCr/Q and some eGFR equations showed weak correlations with BMI z-score, fat mass, waist to-hip ratio, HOMA-IR and HDL-cholesterol, triacylglyceride, serum uric acid and ALT concentrations (univariate correlation coefficients ranged from 0.1 to 0.3). Our findings support the role of disturbed body composition and other components of the metabolic syndrome in the pathogenesis of obesity-related kidney disease. Besides, it is clear that the choice of a SCr-based eGFR-equation influences observed correlations.

In Chapter 4, blood pressure (BP) was assessed in children with overweight and obesity, since hypertension is a common comorbidity in childhood obesity and a key risk factor for CKD. Less than half of the children had a normal BP measurement, and 24%, 25% and 6.0% of the children had an elevated BP measurement, stage 1 and stage 2 hypertensive BP measurement, respectively. Contrary to other studies, BMI z-score did not differ significantly between the BP categories. Weak positive correlations were found between eGFR and both systolic and diastolic BP percentile.

In Chapter 5, glucose dysregulation was examined in 106 children with overweight and obesity. Like hypertension, glucose dysregulation is common in children with overweight and obesity, and a key risk factor for CKD. Different stages of glucose dysregulation were already highly present: 56.6% of the children had a HOMA-IR > 2.5 (suggesting insulin resistance), and 23.6% and 3.8% of the children had prediabetes and impaired glucose tolerance, respectively. During 48-hour real-time continuous glucose monitoring (rtCGM), hyperglycemic sensor glucose excursions were present in 26.4% of the children with overweight and obesity. In children with overweight and obesity with suspected insulin resistance and hyperglycemic glucose excursions, time spent in hyperglycemic range in free living conditions is strongly positively correlated with SCr-based eGFR and the inverse of SCr/Q. These findings support the hypothesis of hyperglycemia-induced hyperfiltration in children with overweight and obesity.

Effect of lifestyle intervention on SCr, SCr/Q and eGFR in children with overweight and obesity
Lifestyle modification is the cornerstone in the treatment of childhood obesity and preventing CKD. While studies among adults suggest that obesity-related kidney disease and/or glomerular hyperfiltration may be reversible following weight loss, data in children are limited. In Chapter 6 and 7, the effect of the multidisciplinary lifestyle intervention program on SCr and eGFR in children with overweight and obesity are described.

After one year lifestyle intervention (Chapter 6), BMI z-score, waist-to-hip ratio, diastolic BP, HbA1c concentration and dyslipidemia improved significantly. SCr and SCr/Q increased, and eGFR (unit: ml/min/1.73m2) decreased significantly. De-indexing eGFR using actual BSA (unit: ml/min) negated this effect. In children with estimated glomerular hyperfiltration, de-indexed eGFR decreased significantly. Changes in eGFR were not associated with changes in BMI z-score or other parameters of the metabolic syndrome.

During 5 years lifestyle intervention (Chapter 7), SCr/Q increased slightly each year (0.01-0.04), corresponding a small eGFR-FAS reduction (1.1-4.1 ml/min/1.73m2). BMI z-score decreased in both females and males and this reduction was significantly higher in males. Changes in BMI z-score were not correlated with SCr/Q changes. Moreover, there was no difference in the change of SCr/Q during follow-up between children who achieved a significant reduction in BMI z-score and those who did not. The observed SCr/Q increase (and eGFR decrease) may reflect increased muscle mass, altered tubular handling of SCr, and/or reversal of glomerular hyperfiltration.

Conclusions
In this thesis, the majority of children with overweight and obesity had a normal SCr based eGFR and in these children aged 2 years and older, eGFR FAS-age, FAS-height and LMR18 can be allotted as the preferred eGFR equations. Associations were found between adiposity, eGFR, high blood pressure and impaired glucose regulation, supporting the role of disturbed body composition and other components of the metabolic syndrome in the pathogenesis of obesity-related kidney disease. During lifestyle intervention, a yearly SCr/Q increase of about 0.01-0.04 was demonstrated, which equals an eGFR-FAS reduction of about 1.1-4.1 ml/min/1.73m2. Whether this minor change in eGFR is a favorable outcome and has clinical consequences on the long-term, requires further research.

In conclusion, current evidence suggests that excess weight in children puts the kidneys under pressure. (Pediatric) nephrologists should consider obesity as a modifiable risk factor for the development and progression of kidney disease.