Acta Pædiatrica ISSN 0803-5253

REGULAR ARTICLE

Dyslipidaemia in overweight children and adolescents is associated with an increased risk of kidney stones J K Kirejczyk ([email protected])1, A Korzeniecka-Kozerska2, M Baran3, H Porowska4, T Porowski2, A Wasilewska2 1.Department 2.Department 3.Department 4.Department

of of of of

Paediatric Surgery, Medical University of Bialystok, Bialystok, Poland Paediatrics and Nephrology, Medical University of Bialystok, Bialystok, Poland Paediatrics, Endocrinology, Diabetology with Cardiology Division, Medical University of Bialystok, Bialystok, Poland Medical Chemistry, Medical University of Bialystok, Bialystok, Poland

Keywords Children, Lipid profile, Metabolic syndrome, Obesity, Urolithiasis Correspondence J K Kirejczyk, Department of Paediatric Surgery, Medical University of Bialystok, ul. Waszyngtona 17, 15-274 Bialystok, Poland. Tel: +48 85 7450922 | Fax: +48 85 7450920 | Email: [email protected] Received 14 March 2015; revised 3 May 2015; accepted 9 June 2015. DOI:10.1111/apa.13079

ABSTRACT Aim: There is conflicting evidence about the role of obesity in paediatric nephrolithiasis. This Polish study explored the influence of nutritional status and lipid disturbances on urinary lithogenic factors and the risk of kidney stone formation in children and adolescents from three to 18 years of age. Methods: We carried out serum lipid profile evaluations and 24-h urine chemistry analyses on 493 overweight/obese paediatric participants (mean age 13 years) without nephrolithiasis and 492 healthy normal weight sex and age-matched controls. Results: A third (33%) of the study group had blood lipid disturbances, with more acidic urine, lower urinary citrate excretion and a higher fraction of ionised calcium and higher Bonn Risk Index than the controls. The participants’ body mass index standard deviation score (BMI Z-score) was positively correlated with urinary oxalate and uric acid and negatively correlated with citrate excretion. Total cholesterol, low-density lipoprotein cholesterol and triglycerides correlated negatively with citraturia, while high-density lipoprotein cholesterol correlated positively. Conclusion: The main factor that predisposed overweight and obese children to kidney stones was hypocitraturia. Urinary citrate excretion was related to both BMI Z-scores and all lipid fraction abnormalities. However, hypercholesterolaemia and particularly low-density lipoprotein hypercholesterolaemia seemed to play a major role.

INTRODUCTION Over the last two decades, an increase in kidney stone disease in the paediatric populations has been observed in many countries, with the prevalence of urolithiasis estimated to be about 2–3% among children and adolescents. The reasons for this increase are not fully understood, but changes in lifestyle, eating habits and environmental factors are believed to play a significant role (1–3). Similarly, excessive body weight has become a serious public health problem in industrialised countries. It is estimated that 31.9% of children and teenagers in the USA are overweight and 11.3% are obese (4), while in the Cracow region of Poland, 16–28% of children and adolescents are overweight and 3.6–7% are obese (5). It has been well established that excessive weight underlies various cardiovascular and metabolic diseases. A growing body of

evidence suggests a possible link between being overweight or obese and kidney stone disease (6). The increased prevalence of urolithiasis and the coincidental epidemic of obesity has driven researchers to investigate whether these two health problems are related and whether they share pathophysiological mechanisms. An epidemiological study of adults revealed a statistically higher incidence of urolithiasis among overweight and

Key Notes 



 Abbreviations BMI, body mass index; BRI, Bonn Risk Index; Ca2+, Urinary ionised calcium; HDL cholesterol, High-density lipoprotein cholesterol; LDL cholesterol, Low-density lipoprotein cholesterol.

©2015 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2015 104, pp. e407–e413

Conflicting evidence about the role of obesity in paediatric nephrolithiasis prompted us to explore the factors linked to kidney stone formation. We compared 493 overweight and obese participants without nephrolithiasis and 492 healthy normal weight controls. The main factor predisposing overweight children and adolescents to kidney stone formation was low urinary citrate excretion, which, in turn, was related to both the body mass index standard deviation score and dyslipidaemia.

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Dyslipidaemia, weight and kidney stones

Kirejczyk et al.

obese participants compared to the overall population (7). Other investigations have shown that a higher body mass index (BMI) in adults was associated with increased excretion of urinary lithogenic promoters, such as oxalate, calcium, uric acid and decreased urinary citrate and pH values (8–10). Most of the studies performed on paediatric patients with kidney stones have failed to demonstrate an increased incidence of obesity compared to the normal paediatric population (11–13), but urolithiasis was associated with a higher odds ratio for obesity, compared to controls, in a study by Kokorowski et al. (14). Similarly, studies in children have not revealed whether nutritional status has a clear impact on 24-h urine chemistry (15–17). Studies have also suggested that metabolic syndrome may play a potential role in the development of nephrolithiasis. Metabolic syndrome, which often accompanies obesity, is a group of risk factors linked to the evolution of type 2 diabetes and cardiovascular diseases. These factors in the adolescent population include abdominal obesity, highdensity lipoprotein (HDL) cholesterol of less than 40 mg/ dL, triglycerides of more than 150 mg/dL, blood pressure above the 90th centile for age and reduced glucose tolerance (18). The study showed the presence of the above factors in 30.8% of the 415 obese adolescents who participated (19). Another investigation conducted on obese teenagers without urolithiasis demonstrated a relationship between the number of risk factors for metabolic syndrome and an increased risk of calcium oxalate urolithiasis (20). The aim of our study was to investigate the influence of the body mass index standard deviation score (BMI Zscore) of children and adolescents with excessive body weight on: (i) urinary pH and 24-h excretion of calcium, oxalate, citrate and uric acid (ii) the risk of calcium stone formation as determined by the Bonn Risk Index (BRI) and the calcium to citrate ratio. We also examined the associations between serum lipid fractions and urinary lithogenic risk factors.

PATIENTS AND METHODS This prospective cross-sectional study was undertaken in the Department of Paediatric Nephrology at the University Children’s Hospital in Bialystok, Poland, between 2004 and 2014. The study group consisted of 493 overweight or obese children and adolescents without a history of kidney stones. It included 238 boys and 255 girls aged from three to 18 years old (median 13.32). The participants were consecutively recruited from patients who were admitted to the hospital because of hypertension and obesity or overweight patients scheduled for minor surgical procedures. Inclusion criteria for the study were a BMI Z-score of one or more and the available of blood lipid profile: total cholesterol, HDL cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides and 24-h urine collection and its metabolic assessment. Children with a history of kidney stone disease were excluded from the study as well as children receiving diuretics, statins, fibrates, topiramate and other medications known to affect urinary electrolyte excretions or serum lipid

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profiles. We also excluded children on special diets, such as high-protein diets, the Atkins diet or a vegetarian diet. The reference group comprised 492 healthy children and adolescents, 237 boys and 255 girls, aged three to 18 years old (median 12.98) with a BMI Z-score of less than one and a normal plasma lipid profile. These subjects were volunteers with a past history of primary nocturnal enuresis or inguinal hernia or the children of hospital staff. Body weight and height were measured, and BMI Z-scores were calculated as previously described (21). The participants carried out 24-h urine collection at home while they were on their usual diet and carrying out their normal physical activities. Urine was stored at 4°C without the addition of preservatives, and all measurements were conducted within 24 h of the end of the collection period. Urine oxalate excretions were examined with an enzymatic–spectrophotometric method using a commercially available kit (Trinity Biotech, Berkeley Heights, NJ, USA). Urine calcium and creatinine were assessed using the Roche Cobas Integra 800 chemistry analyser (Roche Diagnostics, Mannheim, Germany). The urinary concentration of Ca2+ was measured using Rapidlab 855 calcium ion-selective electrodes (Bayer, Leverkusen, Germany). Urine citrate levels were determined by an enzymatic method using a commercial set (Boehringer Mannheim/R-Biopharm, Darmstadt, Germany). Urinary pH was measured using a CP-315 m microcomputer pH-meter (Elmetron, Zabrze, Poland). Serum lipid fractions were studied on the Roche Hitachi 912 chemistry analyser (Roche Diagnostics) from peripheral blood taken after overnight fasting. The Bonn Risk Index (BRI), which evaluates the risk for urinary calcium oxalate crystallisation, was carried out following the method described by Laube (22), using a modified analytical system that has previously been described (23). In brief, after the urinary ionised calcium was determined, the urine was titrated step-by-step with ammonium oxalate solution by a computer-operated analytical system. At the moment that crystallised particles of calcium oxalate caused a 2% decrease in light transmission, the computer application automatically stopped the titration process. The BRI value was then calculated as a ratio of urinary ionised calcium to the amount of titrated oxalate. In addition, the calcium to citrate index was calculated and expressed in mg/ mg. The protocol was approved by the Ethical Committee of The Medical University of Bialystok, Poland. Informed consent was obtained from the parents of all participants and from adolescents older than 16 years of age. Statistical analysis The statistical analyses were performed using Statistica software (StatSoft, Tulsa, OK, USA). The Mann–Whitney U-test was used for comparisons between two independent parameters. Spearman correlation coefficients were computed to estimate the linear relationship between selected measures. Multiple linear regression was performed to estimate the independent contributions of serum lipid fractions on selected urinary lithogenic metabolites. A p value 0.05). Calciuria was almost equal in both groups (2.40 vs 2.32 mmol/24 h, p = 0.607). The urine calcium and citrate excretion, adjusted for creatinine, was lower in the overweight group than the controls (102.11 vs 113.66 mg/g creat/24 h, p = 0.002 and 461.34 vs 523.91 mg/g creat/24 h, p < 0.001, respectively). As a consequence, the median urinary calcium/citrate ratio was comparable in both groups (0.21 and 0.20 mg/mg, p > 0.05). The 24-h fraction of Ca2+ excretion was statistically higher in the overweight group (0.32 vs 0.26 mmol/ 24 h, p < 0.001), but urinary Ca2+ concentrations were comparable in both the study and reference groups (0.35 and 0.33 mmol/L; p > 0.05). The BRI was significantly higher in the study group compared to the reference group (0.42 vs 0.29/L, p < 0.001). Correlations between the BMI Z-score and serum lipid fractions in the study group vs urinary pH and examined urinary lithogenic metabolites are presented in Table 3. The strongest correlations were found with citraturia, that is negative for BMI Z-score, total cholesterol, LDL

cholesterol and triglycerides (R = 0.2286, 0.2939, 0.3385, 0.3322, respectively) and positive for HDL cholesterol (R = 0.3146). In addition, the BMI Z-score was weakly correlated with urinary oxalate and uric acid (R = 0.1055 and R = 0.1116, respectively), and triglycerides showed a positive trend with Ca2+ (R = 0.1046) and a negative trend with uric acid (R = 0.1003). The remaining correlations did not reach statistical significance. Because of the high correlation between BMI Z-scores and serum lipid fractions in the study group, p < 0.05 for each fraction, we used multivariate linear regression to evaluate the relative importance of specific lipid fractions to predict urinary citrate excretion, adjusted for BMI Z-score, sex and age. The relationships between citraturia and HDL cholesterol became insignificant (p = 0.0808), whereas the relationships between citraturia and LDL cholesterol, total cholesterol and triglycerides remained important (p = 0.0002, 0.0016 and 0.0355, respectively) (Table 4). The associations between the BRI, the calcium/citrate ratio and specific blood lipid fractions are presented in Figs 2 and 3, respectively. Both urinary stone formation risk indices presented positive correlations with total cholesterol, LDL cholesterol and triglycerides and negative trends with HDL cholesterol.

DISCUSSION Identifying possible common biochemical mechanisms related to obesity and urolithiasis helps to prevent kidney stone disease and makes its treatment more effective. Dyslipidaemia is a frequent problem in overweight and obese patients and one of the components of metabolic syndrome. This study was designed to determine the impact of obesity and lipid disturbances on the potential urinary lithogenic factors and the risk of kidney stone formation in a large paediatric cohort without stones. We initially found one or more disturbances of serum lipid profile – total cholesterol >200, HDL cholesterol 130 and triglycerides >150 mg/dL – in 33.2% of the overweight and obese participants. Casavalle

Table 1 Comparison of anthropometric, urine volume and lipid profile between the study and reference groups

Number of participants Age (years) Weight (kg) Height (cm) BMI Z-score Urine volume (mL/24 h) Urine volume (mL/kg/24 h) Total cholesterol (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Triglycerides (mg/dL)

Study group: BMI Z-score ≥1

Reference group: BMI Z-score

Dyslipidaemia in overweight children and adolescents is associated with an increased risk of kidney stones.

There is conflicting evidence about the role of obesity in paediatric nephrolithiasis. This Polish study explored the influence of nutritional status ...
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