The impact of one year weight loss treatment on renal circadian rhythm in obese adolescents

Pauwaert K1, Dejonckheere S2, Bruneel E1, Van Der Jeugt J1, Keersmaekers L3, Roggeman S1, De Guchtenaere A4, Vande Walle J2, Everaert K1

Research Type

Clinical

Abstract Category

Paediatrics

Abstract 423
Paediatric Lower Urinary Tract Symptoms and Urinary Incontinence
Scientific Podium Short Oral Session 19
Thursday 5th September 2019
14:52 - 15:00
Hall H2
Nocturia Nocturnal Enuresis Prospective Study
1.Department of Urology, Ghent University Hospital, 2.Department of Pediatric Nephrology, Ghent University Hospital, 3.Faculty of Medicine, Ghent University, 4.Zeepreventorium, Medical Pediatric Rehabilitation Center, De Haan, Belgium
Presenter
K

Kim Pauwaert

Links

Abstract

Hypothesis / aims of study
Adolescent obesity is a serious public health problem. Children with obesity have an increased risk of becoming obese adults and develop chronic conditions, such as cardiovascular disease, diabetes mellitus (DM), hypertension and kidney disease [1].

We hypothesize that obesity is associated with a disruption of renal circadian rhythm. Like many other biological processes, renal functions exhibit clear circadian variations. Urine production and voiding should predominate during the awake phase, whereas increased storage of urine and reduced micturition frequency must be ensured during the sleeping phase.  Renal circadian rhythm in obesity has not been investigated yet. Previous studies however, did observe obesity-related alterations in circadian rhythm of other biological functions. Macumber et al. [2] demonstrated that obesity is related to a relatively decreased dipping in nocturnal BP in children. Pagano et al. [3] discussed the deranged circadian rhythm of metabolic functions and glucose homeostasis in obese adults.

The aim of the study was to examine this renal circadian rhythm in obese adolescents before and after one year of weight loss therapy.
Study design, materials and methods
This prospective interventional study was performed at a medical pediatric rehabilitation center between July 2016 and June 2017. Obese adolescents aged between 10 and 19 years old were recruited at the beginning of a one year multidisciplinary obesity treatment program consisting of dietary restriction, psychological support and physical activity.  Exclusion criteria were: comorbidities (kidney failure, heart failure, liver failure, DM, and diabetes insipidus), pregnancy and intake of medication with a potential effect on urine output (diuretics, desmopressin, ACE-inhibitors, AngII receptor antagonists, non-steroidal anti-inflammatory drugs, corticosteroids, lithium and selective serotonin reuptake inhibitors).

Data were collected at the beginning and after completion of the residential program one year later. All patients performed a renal function profile (RFP) and a morning blood sample. A RFP is a 24 hour-urine collection in which urine samples are collected at fixed time points every 3 hours, starting 3 hours after the first morning void. Body weight was measured on a digital scale with a precision of 0.1 kg and height was measured to the nearest 0.01 m using a wall-mounted stadiometer. Body mass index (BMI) was calculated as weight/heigth2 (kg/m2). 

Overweight and obesity were defined as a BMI equal to or above the age- and gender-specific 85th and 97th percentile respectively according to regional charts in adolescents younger than 16 years. In adolescents older than 16 years overweight and obesity were defined as BMI ≥ 30 and ≥ 35 respectively. 

Statistical analysis was performed using SPSS®, version 25. The median, interquartile range (IQR) and frequency were recorded as descriptive parameters. Continuous variables were analysed using the non-parametric Wilcoxon matched-pairs signed ranks test. Statistical significance was considered at p < 0.05. The study was approved by the hospitals review board (EC 2015/1438). Written informed consent was obtained from both the parents and all individual participants included in the study.
Results
34 adolescents (73.5% female) with a median age of 15.7 (14.1 – 16.7) years were recruited in this prospective study. One year of treatment led to a median weight loss of 24.0 (17.9 – 33.5) kg or 21.9 (18.7 – 28.3) %. The median BMI z-score at baseline was calculated at 2.42 (2.23 – 2.73) and decreased significantly (p <0.001) after treatment (1.56 (1.28 – 1.92)). At the end of the treatment program 6 adolescents had a normal BMI, 12 were overweight and 16 remained obese. 

The day-night variation in diuresis rate (p = 0.013) , creatinine clearance (p < 0.001),  solute clearance (p < 0.001), sodium clearance (p < 0.001) and potassium clearance ( p < 0.001) was preserved before weight loss. These circadian rhythms did not change after one year (p <0.001, p < 0.043, p <0.001, p = 0.029, p <0.001 respectively), despite significant increase in diuresis rate, solute clearance, sodium clearance and potassium clearance. Creatinine clearance was not statistically different between baseline and after treatment measurements (p = 0.071). (Table 1)

At baseline nocturnal free water clearance (FWC) was significantly higher than daytime values (p < 0.001). However, this inversed circadian rhythm changed during the one year treatment program, as nighttime FWC did not differ from daytime levels (p = 0.091) after treatment. After 12 months of treatment no significant change in 24-hour FWC was observed (p = 0.321). However, we noted a trend toward lower FWC after weight loss (Figure 1).
Interpretation of results
Before treatment, an inverse circadian rhythm of FWC was observed. This inversion can be provoked by a deranged anti-diuretic hormone (ADH) activity with lower ADH levels during the night. Another possible explanation is the nocturnal mobilization of obesity-related peripheral edema when patients lay down during the sleeping phase. After 12 months of weight loss, no significant difference in day and nighttime FWC was reported, suggesting a normalizing circadian rhythm.

We observed clear circadian rhythm of diuresis rate and in the renal clearance of creatinine, solutes, sodium and potassium at the beginning and after completion of the weight loss program. We expected blunted renal circadian rhythms in accordance to disrupted daily rhythms of blood pressure and other metabolic functions in obese patients as described in previous studies [2,3]. Possible reasons for this largely preserved renal circadian rhythm are the short duration of obesity in our adolescent study population, or our study sample is a variant of the obese population. Lastly our theory suggesting that obesity disrupts renal circadian rhythm might be incorrect.
Concluding message
Renal circadian rhythm in obese adolescents is largely preserved. Before and after one year of weight loss, clear circadian rhythm of diuresis rate and of renal clearance of creatinine, solutes, sodium and potassium was observed. A normalization of the inverse circadian rhythm of free water clearance was noticed after one year weight loss.
Figure 1 Table 1: Interpretation of RFP: Day sample include the first 5 urine collections, whereas the night sample includes the last 3 urine samples.
Figure 2 Figure 1 Change in free water clearance (FWC) (ml/min) on different moments of the RFP before and after 12 months of weight loss-therapy
References
  1. Kovesdy CP, Furth S, Zoccali C, World Kidney Day Steering Committee on B of the WKDS. Obesity and kidney disease: Hidden consequences of the epidemic. Indian J Nephrol. 2017;27(2):85–92.
  2. Macumber IR, Weiss NS, Halbach SM, Hanevold CD FJ. The association of pediatric obesity with nocturnal non-dipping on 24-hour ambulatory blood pressure monitoring. Am J Hypertens. 2016;29(4):647–52.
  3. Pagano ES1, Spinedi E GJ. White Adipose Tissue and Circadian Rhythm Dysfunctions in Obesity: Pathogenesis and Available Therapies. Neuroendocrinology. 2017;104(4)::347-363.
Disclosures
Funding Ferring research grant; Astellas & Medtronic: honoraria for speaking at lectures Clinical Trial No Subjects Human Ethics Committee Ghent University Hospital review board (EC 2015/1438). Helsinki Yes Informed Consent Yes