3. Electronic Theses and Dissertations (ETDs) - All submissions
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Item Cardiovasular risk factors and their association with biomarkers in children with chronic kidney disease in Johannesburg, South Africa(2017) Mudi, AbdullahiBackground: 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.Item Hypertension : Experimental and clinical pharmacological studies(1985-09-08) Leary, William, Peregrine, PepperrellThe publications forming this submission cover two broad fields. A series of papers deal with experimental hypertension ; possible roles for angiotensin and prostanoid substances in the pathogenesis of hypertension were investigated. The results indicated that the capacity of kidney to inactivate angiotensin II could be quite profoundly altered by inducing hypertension using the one and two-clip Goldblatt methods or by altering the sodium chloride content of the diet.Item Biomarkers in acute kidney injury due to contrast induced nephropathy(2016) Banda, JustorBackground: Despite preventive guidelines, iatrogenic contrast-induced nephropathy (CIN) ranks third as a cause of hospital acquired acute kidney injury (AKI), and impacts significantly on morbidity and mortality and is associated with high hospital costs. In Sub-Saharan Africa, the rates and risk factors for CIN remain unexplored. Despite the positive association of genetic polymorphisms in the TNFα and IL10 genes with CIN in Asian populations, the CIN genetic susceptibility in other races is unknown. Serum creatinine is a sub-optimal biomarker for the early diagnosis of CIN resulting in delayed interventions. This study investigated rates, risk factors and outcomes of CIN, the influence of genetic susceptibility to CIN in the black population and lastly, the accuracy of novel biomarkers in the early diagnosis of CIN and prognosticating patient outcomes. Methods: This was a prospective case-controlled study conducted at Charlotte Maxeke Johannesburg Academic Hospital, in South Africa from January 1, 2014 to December 30, 2015.Hospitalized patients undergoing enhanced computed tomography and angiography were consecutively recruited to the study and followed up for development of CIN. CIN was defined as an increase in serum creatinine >25% or an absolute increase of >44 μmol/l from baseline at 48-72 hours after exposure to contrast media. In the second part of the study, a nested case-controlled cohort that included 30 CIN patients and 60 controls (those undergoing contrast administrations and not meeting CIN criteria) were ethnically matched for gender, and age in a case: control ratio of 1:2 at all-time intervals. Sera for neutrophil gelatinaseassociated lipocalin-2 (NGAL), cystatin C, beta-2 microglobulin (β2M), interleukin 18 (IL18), IL10, and tumor necrosis factor alpha (TNFα) were collected at four time points: baseline (pre-contrast), 24 hours, 48 hours and ≥5-7 days after contrast administration and their concentrations were determined using luminex assays and an enzyme linked immunosorbent assay for β2M as per manufacturer’s instructions. The areas under receiver operating characteristic curves (AUROC) were generated to determine accuracy of novel biomarkers to diagnose CIN and CIN mortality. Genomic DNA was extracted from peripheral blood samples of 208 black South Africans using the Maxwell DNA purification kit (Promega AS1010, USA) and their genotypes for - 308(rs1800629) and -857(rs1799724) in the TNFα gene and -592(rs1800872), - 819(rs1800871), -1082 (rs1800896) and +1582(rs1554286) in the IL10 gene were determined by restriction fragment length polymorphism (RFLP). Results: We recruited 371 hospitalized patients (mean age 49.3±15.9); the rates of CIN were4.6% and 16.4% respectively, using an absolute or relative increase in serum creatinine from baseline. Anaemia was an independent predictor for the development of CIN (RR 1.71, 95% 1.01-2.87; p=0.04). The median serum albumin was 34 g/l (IQR: 29-39.5) vs. 38 g/l (IQR: 31-42), p=0.01 in the CIN and control groups respectively.Mortality was significantly increased in the CIN group (22.4% vs. 6.8%; p<0.001), and CIN together with anaemia predicted mortality with a 2-fold (p=0.01) and a 3-fold (RR p=0.003) riskrespectively. The median cystatin C at 24 hours (p<0.001) and β2M(at all-time points)levels were significantly higher in the CIN group compared to controls. The median cystatin C at 24 hours and β2Mlevels at 48 hours were 856.59 ng/ml (IQR 620.75-1002.96) vs. 617.42 ng/ml (IQR 533.11-805.20); p<0.001 and 5.3 μg/ml (IQR 3.8-6.9) vs. 3.3 μg/ml (IQR 2.7-4.5); p<0.001 with AUROCs of 0.75 and 0.78 respectively for early CIN discrimination.Pre-contrast IL18 (p <0.001), β2M (p=0.04) and TNFα (p<0.001) levels were significantly higher in the nonsurviving group and their AUROC were 0.83, 0.82 and 0.94 for CIN+ mortality. Baseline NGAL was a better marker for excluding patients at higher risk of developing CIN with negative predictive and positive predictive values of 0.81 and 0.50 respectively. The frequency of TNFα -308 AA genotype was significantly increased in the CIN group compared to controls (13.3% vs.1.82%, p=0.016) and the presence of the TNFα-308 AA (high producer) vs. GA genotypes was associated with a 9-fold CIN risk (9.24, 95% CI, 1.88-45, p=0.006). The IL10-1082 AA-allele (low producer) was significantly higher in the non-surviving CIN+ patients compared to controls (p=0.01). Conclusions:CIN occurred at a relatively high rate in our study and predicted poorer clinical outcomes. The presence of CIN and anaemia positively predicted mortality. Caution should be exercised in patients with anaemia and hypoalbuminaemia undergoing contrast studies. Serumcystatin C was the best novel biomarker for the early diagnosis of CIN and while baseline NGAL is superior as a biomarker for excluding patients at higher risk for CIN. IL18, β2M and TNFα are the best novel biomarkers for predicting the prognosis of patients with CIN. Increased frequency of the TNFα-308 AA genotype is a predisposing factor for CIN development. The low producer IL10-1082 AA genotype decreases survival in patient with CIN.