Early cardiovascular risk markers and cardiac function in children with chronic kidney disease

Children with advanced chronic kidney disease (CKD) have an increased risk of premature death, foremost due to cardiovascular disease (CVD). The cardiovascular (CV) morbidity starts early in the disease process and renal transplanted children (CKD-T) are also at risk.

Aims: The overall aim of this thesis was to study CV morbidity and potential risk factors in pediatric CKD and CKD-T patients. The prevalence of various known biomarkers associated with increased risk of CVD was assessed (Papers I, II and IV). Furthermore, CV morbidity and associated risk factors were analyzed cross-sectionally (Paper II) and longitudinally (Papers III and IV). Associations between potential CV risk factors and CV outcome was explored in order to identify possible predicting factors (Papers III and IV).

Methods: In total 26 Italian (Paper I) and 34 Swedish CKD and 44 CKD-T patients (Paper II) were included. The Swedish cohort was followed prospectively every year for 3 years (Papers III-IV). Fasting blood samples were analyzed in regard to anemia, inflammation, abnormal glucose metabolism, dyslipidemia and altered mineral metabolism. The renal function and blood pressure levels were also assessed. Using echocardiography, the left ventricular mass index (LVMI) and left ventricular (LV) function were examined and, the carotid intima media thickening (cIMT) was further analyzed (Papers II-IV).

Results: Regarding biomarkers of CV risk, the dominant finding was high levels of insulin and insulin resistance (Papers I and II), but the lipid profile and inflammatory status were also altered (Paper II). In addition, high Fibroblast Growth Factor-23 (FGF23) and PTH revealed a disturbed mineral metabolism (Paper IV). Regarding CV morbidity, cardiac remodeling (increased LVMI) and markers of LV diastolic dysfunction were significantly altered in both patient groups, while the cIMT was normal (Papers II and III). Tissue Doppler Imaging (TDI) revealed early signs of LV diastolic dysfunction, present in 7.1% of CKD and 12.5% of CKD-T patients (Paper III). Furthermore, TDI was more sensitive in diagnosing subtle changes in cardiac function compared to conventional pulse wave Doppler (PWD). The most important risk factors for subclinical CVD were a young age, elevated BMI and systolic blood pressure z-scores as well as a low GFR and present albuminuria (Paper III). Increasing blood pressure and BMI over follow-up were also important cardiac risk factors longitudinally (Paper III). Both high FGF23 and low Klotho were associated with a worse LV diastolic function in CKD-T patients (Paper IV).

Conclusion: These results leads to the conclusion that an altered cardiac function and remodeling are a concurrent part of the CKD process, start early in the disease development, and persist after renal transplantation. The findings suggest that children with CKD or CKD- T are at high risk for future CVD where younger patients with elevated BMI and slightly increased blood pressures, as well as present albuminuria, are those at greatest risk, thus indicating targets for future interventions. The role of FGF23 and Klotho in cardiac morbidity is interesting and might be one of the missing pieces in this complicated puzzle of CKD- associated CVD.

List of scientific papers

I. Ylva Tranæus Lindblad, Jonas Axelsson, Peter Bárány, Gianni Celsi, Bengt Lindholm, Abdul Rashid Quershi, Alba Carrea, Alberto Canepa. Hyperinsulinemia and Insulin Resistance, Early Cardiovascular Risk Factors in Children with Chronic Kidney Disease. Blood Purification 2008; 26: 518-525.
https://doi.org/10.1159/000167799

II. Ylva Tranæus Lindblad, Jonas Axelsson, Rita Balzano, Georgios Vavilis, Milan Chromek, Gianni Celsi, Peter Bárány. Left ventricular diastolic dysfunction by tissue Doppler echocardiography in pediatric chronic kidney disease. Pediatric Nephrology 2013; 28: 2003-2013.
https://doi.org/10.1007/s00467-013-2504-x

III. Ylva Tranæus Lindblad, Georgios Vavilis, Jonas Axelsson, Maria Herthelius, Peter Bárány. Assessing longitudinal trends in cardiac function among pediatric patients with chronic kidney disease. [Accepted]
https://doi.org/10.1007/s00467-016-3371-z

IV. Ylva Tranæus Lindblad, Hannes Olausson, Georgios Vavilis, Ulf Hammar, Maria Herthelius, Jonas Axelsson, Peter Bárány. The FGF23 and Klotho axis in pediatric chronic kidney disease - a prospective cohort study. [Manuscript]