Cardiovasular risk factors and their association with biomarkers in children with chronic kidney disease in Johannesburg, South Africa
Background: In spite of the contributions of cardiovascular disease (CVD) to morbidity and mortality in chronic kidney disease (CKD) worldwide, there are no studies that have looked at cardiovascular risk factors (CVRFs) and their association with cardiovascular changes in African children with CKD. Several CVRFs have been implicated in the initiation and progression of cardiovascular changes in children with CKD, and these changes have been reported even in early CKD. This study investigated CVRFs and their association with cardiovascular changes in South African children with CKD. Method: This comparative cross sectional study recruited children (5-18 years) with CKD being followed up at the Division of Paediatric Nephrology of the Charlotte Maxeke Johannesburg Hospital and the Chris Hani Baragwanath Academic Hospital. One hundred and six children with a spectrum of CKD including those on chronic dialysis (34 CKD I, 36 CKD II-IV and 36 CKD V-dialysis) were enrolled over a 12 month study period. All patients had a short history taken along with a physical examination. Blood samples for serum creatinine, urea, albumin, calcium, phosphorus, parathyroid hormone (PTH), alkaline phosphatase, total cholesterol, haemoglobin and C-reactive protein, Vitamin D, Fibroblast growth factor-23 (FGF-23), Fetuin-A and genomic DNA studies were taken. Where feasible, transthoracic echocardiography and high resolution ultrasonography of the common carotid artery was performed. Results: The overall median age of the patients was 11 years (8-14 years), with a male female ratio of 2.1:1. Several CVRFs detected include hypertension, proteinuria, anaemia, hypercholesterolaemia and dysregulated mineral bone metabolism. The most common CVRF detected was anaemia (39.6%) and its prevalence was highest in the dialysis group when compared with the other CKD groups. The overall median (range) cIMT was 0.505mm (0.380-0.675), and was highest in patients with dialysis dependant CKD (p=0.003). The distribution of left atrial diameter (LAD) and left ventricular mass (LVM) differed significantly (p<0.05) across the different CKD groups. Abnormal LAD was seen in 10% of patients; left ventricular hypertrophy (LVH) in 27%; left ventricular systolic dysfunction in 6% and diastolic dysfunction in one patient. Mean arterial pressure and haemoglobin levels were independently associated with cIMT; hypertension was independently associated with concentric LVH; and age and hypoalbuminaemia were independently associated with eccentric LVH. Overall, the dialysis group had the highest prevalence of vascular changes, cardiac changes and associated risk factors. A skewed pattern of Fetuin-A and FGF-23 levels with medians (range) of 57.7 (0.9-225.2) mg/dL and 28.9 (0-3893.0) pg/ml respectively, were observed. The levels of these two biomarkers varied significantly between the different CKD groups (p<0.05). Fetuin-A was independently associated with abnormal LAD but no similar relationship with other cardiovascular changes and plasma levels of Fetuin-A and FGF-23 was found. Plasma FGF-23 levels correlated better with markers of bone mineralization than Fetuin-A. Eight Fetuin-A SNPs were analysed; rs2248690, rs6787344, rs4831, rs4917, rs4918, rs2070633, rs2070634 and rs2070635. We found an association between log-transformed Fetuin-A levels and the SNP rs4918 G-allele compared to the rs4918 C-allele (p=0.046) and the rs2070633 T-allele when compared to the rs2070633 C-allele (p=0.015). Markers of MBD such as phosphate and PTH levels were associated with Fetuin-A SNPs. The rs6787344 G-allele was significantly associated with phosphate levels (0.042), and the rs4918 G-allele with PTH (p=0.044). Seven deaths were recorded in the dialysis group during the study period and severe hypertension and intracranial bleed were the most common causes of death. Modifiable risk factors such as increased total cholesterol (TC) and decreased albumin levels were more commonly seen among the deceased dialysis patients. Conclusion: A high prevalence of CVRFs and cardiovascular changes were observed in the study groups, even in those with mild to moderate disease. Information obtained from the study highlights the need to address modifiable CVRFs such as hypertension, anaemia and hypoalbuminaemia in children with CKD and also the need to determine new, population specific, paediatric reference values for cIMT in healthy African children. Finally, the study was able to demonstrate differences in the relationship between Fetuin A SNPs and Fetuin-A levels and cardiovascular changes in our study population when compared with previously published data. We postulate that these differences may be due to genetic differences between our population and other population groups previously studied.
A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfilment of the requirements for the degree of Doctor of Philosophy Johannesburg, 2017.