The role of circulating endotoxaemia as a proinflammatory mediator of atherosclerosis in chronic kidney disease patients

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, 2015Atherosclerosis is increasingly recognized as a chronic inflammatory disease. Moreover, endotoxin release into the circulation is a potential source of inflammation, and represents an important target for intervention directed towards stemming of cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. Although previous studies have shown that elevated plasma endotoxin levels were associated with the risk of atherosclerosis, a direct link between endotoxaemia and atherosclerosis is yet to be fully elucidated. This study investigated endotoxaemia across the spectrum of South African CKD patients and also determined the pro-inflammatory effects of endotoxin that are relevant to the development of subclinical atherosclerosis in CKD patients. A prospective cross-sectional study of 120 CKD patients was carried out, comprising 40 each of peritoneal dialysis (PD), haemodialysis (HD) and stage 3 chronic kidney disease (CKD), attending the Charlotte Maxeke Johannesburg Academic Hospital, South Africa; and a comparator cohort of 40 age- and sex-matched controls. Endotoxin levels were measured and the results compared with serum lipopolysaccharide binding protein (LBP), serum CD14 (sCD14), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), oxidized LDL, interleukin-6 (IL-6), C-reactive protein (CRP), transforming growth factor-β (TGF-β), carotid intima media thickness (CIMT) and plaque occurrence (measured by B-mode ultrasound), and echocardiographic parameters. Bio-impedance spectroscopy was carried out using a body composition monitor (BCM) to assess fluid and nutritional status. Inflammatory cytokines including TGF-β1 and IL-6 were genotyped, and the genotype frequencies compared to the serum concentrations of the cytokines. Data was analysed using the statistical package for social sciences (SPSS) version 16. Volume overload and circulating endotoxaemia were common across the spectrum of CKD patients, and were aggravated by worsening kidney function. Endotoxins levels correlated with both absolute overhydration (r=0.513, p<0.001) and percentage overhydration to extracellular water (OH/ECW%) (r=0.490, p<0.001). Carotid intima media thickness was significant higher among CKD patients compared to the controls (0.58 ± 0.12 versus 0.45 ± 0.05 mm; p<0.001); CIMT was 0.63 ± 0.12; 0.56 ± 0.09 and 0.56 ± 0.12 mm in PD, HD and CKD stage 3 patients respectively. Carotid intima media thickness correlated with overhydration (r=0.442, p<0.001) and OH/ECW% (r=0.421, p<0.001). The risk of atherosclerosis was associated with serum levels of endotoxins (odds ratio: 2.34; confidence interval: 1.26-4.35, p=0.007), with excess risk confined to the group with high endotoxin levels. The risk of subclinical atherosclerosis was predicted by high concentrations of sCD14, IL-8 or MCP-1. Patients with high levels of circulating endotoxaemia in combination with high levels of sCD14, IL-8 or MCP-1 showed markedly elevated risk of atherosclerosis. The lowest Oxidized LDL levels were significantly higher in patients with carotid plaques compared to patients without carotid plaques (472.6 ± 104.6 versus 348.6 ± 110.9 ng/ml, p=0.012). Oxidized LDL showed a strong association with CIMT (r=0.664, p<0.001) among non-dialytic CKD patients. TGF-β isoform were present in lower concentrations in haemodialysis patients compared to the PD, CKD and controls. TGF-β concentrations were significantly lower in the patients with subclinical atherosclerosis compared to patients without atherosclerosis (TGF-β1: 4.1 × 104 ± 1.5 × 104 versus 5.9 × 104 ± 1.6 × 104 pg/ml, p<0.001; TGF-β2: 1.6 × 103 ± 0.3 × 103 versus 1.8 × 103 ± 0.2 × 103 pg/ml, p<0.001; and TGF-β3: 4.2 × 102 ± 0.9 × 102 versus 5.3 × 102 ± 1.1 × 102 pg/ml, p<0.001). TGF-β isoforms had an inverse relationship with CIMT (TGF-β1: r=−0.562, p<0.001; TGF-β2: r=−0.477, p<0.001; TGF-β3: r=−0.442, p<0.001). There was significant association between IL6 polymorphisms (−174G/G and −174G/C) and elevated serum IL-6 levels in CKD patients. Volume overload and circulating endotoxaemia were common across the spectrum of CKD patients. Volume overload was associated with the severity of kidney failure, inflammation, malnutrition, atherosclerosis and cardiac enlargement. Bio-impedance spectroscopy device is a more sensitive tool than IVCD measurement for the assessment of fluid status in clinically euvolaemic non-dialytic stage 3 CKD patients. The findings suggest that the atherogenic predictive power of endotoxin is significantly increased by the presence of high concentrations of immune mediators in CKD patients. The increased risk of atherosclerosis in CKD patients was demonstrated to be due to the inflammation mediated by endotoxin, with protection afforded by TGB-β. Furthermore, there is a close association between IL-6 polymorphisms (G/G and G/C) and elevated serum IL-6 levels in CKD patients

COVID-19 infection during pregnancy - maternal and perinatal outcomes: a tertiary care centre study

Background: With the exponential increase in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2/COVID-19) worldwide, an increasing proportion of pregnant women are now infected during their pregnancy. The knowledge gained from previous human coronavirus outbreaks suggests that pregnant women and their fetuses are particularly susceptible to poor outcomes. The aim of this study was to summarize the maternal and perinatal outcomes of pregnant women infected with COVID-19 during their pregnancy.Methods: Eligibility criteria included pregnant women positive for COVID-19 as detected by real-time polymerase chain reaction (PCR) or dual fluorescence PCR-confirmed SARS-CoV-2 infection.Results: A total of 38 pregnant women positive for COVID-19 as confirmed by RT-PCR, were included in the study. 21% cases had preterm deliveries and LSCS was the preferred mode of delivery in 23 of 38 i.e., 60.5% cases. There was a tendency for low Apgar score at birth, higher rates of fetal distress, meconium, NICU admissions. There was one IUD and one neonatal death. The treatment patterns of COVID-19 infection among pregnant women during their pregnancy or following delivery was mostly supportive in the form of oxygen and antibiotic therapy.Conclusions: Although the majority of mothers were discharged without any major complications, severe maternal morbidity as a result of COVID-19 and perinatal deaths were reported. Vertical transmission of the COVID-19 could not be ruled out. Pregnant infected women had different symptoms, and they were given mostly supportive treatments than the general infected population. Careful monitoring of pregnancies with COVID-19 and measures to prevent neonatal infection are warranted

Cholestasis of pregnancy: effects on maternal and fetal outcome

Background: Intrahepatic cholestasis of pregnancy (ICP) typically occurs in late pregnancy affecting 1.5-2% pregnancies. Limited data is available regarding its fetal and maternal implications. This study aims to assess the impact of ICP on maternal and fetal outcome.Methods: A total 200 patients with pruritus in later half of pregnancy were studied over a period of 18 months out of which 135 were diagnosed as ICP. Clinical and biochemical parameters like serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total protein, and gamma glutamyl transferase was recorded. Maternal and fetal outcome was noted in the form of LSCS rate, preterm births, fetal distress and neonatal ICU admissions.Results: In this study, most common symptom was pruritus. Most of cases had onset of symptoms between 32-36 weeks. High LSCS rates were seen among cases. Intrapartum complications viz. meconium staining of amniotic fluid (57.8%), preterm delivery (11.9%), fetal distress (42.2%) were significantly higher in study population and there was high incidence of NICU admissions (49. 6% neonates) among cases mostly due to meconium aspiration and prematurity.Conclusions: ICP increases maternal morbidity and is associated with adverse perinatal outcome viz. increased risk of fetal distress, preterm births and sudden IUD at term as evidenced in this study. A timely intervention at 37-38 weeks will reduce the adverse outcomes

Epidemiology of prediabetes and prehypertension-progression, regression and interaction

Background: The major portion of the non-communicable diseases is formed by cardiovascular diseases. The two major modifiable risk factors are hypertension and diabetes. The probable CVD risk with pre-hypertension and pre-diabetes, to some extent, is dependent on whether pre-HTN leads to hypertension and pre-DM leads to diabetes. Our aim was to study: the progression of prehypertension and prediabetes to overt hypertension and diabetes or to normal status, and the association of pre-obesity and obesity with prehypertension and prediabetes. Methods: A total of 1200 patients equally distributed among three groups were studied for progression or regression. Group A included 400 patients of pre-hypertension, and group B included 400 patients of pre-diabetes and group C included 400 patients of pre-diabetes and pre-hypertension. Results: Among the 400 studied patients with prediabetes 31 (7.8%) progressed to diabetes and only 9 (2.3%) progressed to hypertension over a period of two years. Patients with both prehypertension and prediabetes had a higher risk of progression to hypertension and diabetes (3% to hypertension and 15.5% to diabetes). Males were more prone to develop both pre-hypertension and pre-diabetes mellitus and progression. Obesity increased the risk of progression to hypertension and diabetes significantly. Conclusions: The screening of people for pre-diabetes mellitus and pre-hypertension should be carried out at mass levels so as to diagnose them at an early stage and hence, their progression can be either halted or modified

Cardiovascular disease in chronic kidney disease – a review of risk factors

Patients with chronic kidney disease (CKD) are at increased risk of cardiovascular disease (CVD), such that the risk of cardiovascular mortality is greater than the risk of progression to end-stage kidney disease. Despite the increased prevalence of traditional and non-traditional cardiovascular risk factors, patients with kidney disease have been mostly under-represented in previous cardiovascular outcome studies, thereby resulting in a paucity of data on the evidence-based management of CVD in CKD. In this review, we explore the evidence on the burden of CVD and its risk factors in patients with CKD, highlight various inflammatory biomarkers for predicting CVD and provide an overview on novel biomarkers for CVD

Metabolic Syndrome in Adults with Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is associated with insulin resistance, obesity, and other features of metabolic syndrome. It is identified as the most common cause of liver enzyme derangement. Lately, NAFLD has generated interest in exploring treatment options, including weight loss and dietary interventions. An association of NAFLD with metabolic syndrome has been suggested in contemporary literature. In this study, we attempted to look into the association of NAFLD with metabolic syndrome. In this study, 80 adult NAFLD patients were recruited from a tertiary care hospital. Among these, 42 were males and 38 females with a mean age of 44.46±13.146 years (range 18–82 years). Grades of fatty liver and presence or absence of metabolic syndrome were studied in this patient population. Patients who did not qualify for the criteria of metabolic syndrome were placed in Group 1 and those who fulfilled the stated criteria were considered in Group 2. There were 29 (36.25%) patients in Group 1 and 51 (63.75%) in Group 2. All the patients in Group 1 were having Grade I fatty liver whereas patients in Group 2 were found to having varying grades of fatty liver, with six patients having Grade III fatty liver. We found statistically significant difference in various parameters of study (liver enzymes, high-density lipoprotein (HDL), triglycerides, and blood pressure) between Group 1 and Group 2. Ultrasound evidence of a fatty liver should be considered as a predictor of metabolic syndrome, and these patients must be investigated for the different components of metabolic syndrome so as to have early diagnosis and intervention to alter development of long-term metabolic disorders and their inherent complications

Cost effective & energy efficient intelligent smart home system based on loT

Smart Home reduces the need for active involvement of users in the process of monitoring and regulating household appliances. This study provides a method for developing Smart Home Energy Efficiency applications through integration of IoT (Internet of Things) with IP-based switching of Web services as well as Cloud Technology. The methodology embeds intelligent systems and machine learning into the design in addition to using the Poisson process along with the actuators and sensors in Arduino environment. Moreover, we apply the use fault detection to validate the efficiency and feasibility of the Smart Home implementation by assessing the home environments, taking care of home equipment, appliances and regulating home access.Akıllı Ev, kullanıcıların ev aletlerini izleme ve düzenleme sürecinde aktif katılım ihtiyacını azaltır. Bu çalışma, IoT'nin (Nesnelerin İnterneti) Internet tabanlı IP servislerinin yanı sıra Bulut Teknolojisi ile entegrasyonuyla Akıllı Ev Enerjisi Verimliliği uygulamalarının geliştirilmesi için bir yöntem sunmaktadır. Metodoloji, Poisson sürecinin Arduino ortamındaki aktüatörler ve sensörler ile birlikte kullanılmasının yanı sıra, akıllı sistemler ve makine öğrenmesini tasarıma dahil eder. Ayrıca, Akıllı Ortam uygulamasının etkinliğini ve uygulanabilirliğini doğrulamak için, ev ortamlarını değerlendirerek, ev eşyalarına, cihazlara ve ev erişimini düzenleyerek kullanım hatası tespitini sağlar

Automobile Paint Reducer Induced Acute Kidney Injury: A Case Series

The various aspects of the automobile industry also carry with it the risk for occupational health hazards with it. Toluene has also evolved as a commonly used drug by substance abusers. Accidental exposure or self-poisoning with these substances has been reported in literature. These substances can also cause distal renal tubular acidosis (RTA), acute tubular necrosis, glomerulonephritis and interstitial nephritis, rhabdomyolysis and myoglobinemia. In this series, we report about three patients who developed renal manifestations because of organic solvents. Two of the three patients had ingested the paint reducer substance and the third one was addicted to sniffing the toluene based paint reducer. All the patients had in taken these substances s with suicidal intent and developed acute kidney injury (AKI) and severe metabolic acidosis. One of the patients had features of rhabdomyolysis as well. The third patient was a substance abuser and had inhaled higher than usual dose and developed severe and refractory acidosis and mild kidney injury and required Renal Replacement Therapy (RRT) for acidosis. All the patients eventually recovered their kidney functions and were doing well during their follow-up. Toluene based organic solvents lead to acute neurological symptoms, accompanied by severe metabolic alterations, organ injury and dysfunction. An association of the development of hypokalemic paralysis and metabolic acidosis with toluene intoxication has been observed. The management of acute toluene toxicity is mainly conservative, consisting of electrolytes correction, acid-base and fluid abnormalities and renal replacement therapy in severe AKI. Organic solvent exposure may result in acute tubular necrosis, rhabdomyolysis, RTA and AKI irrespective of the intake route. Clinical suspicion of organ dysfunction and failure and timely induction of supportive care leads to a good outcome

Reduced glomerular filtration rate is associated with ascending aortic dilatation in South African chronic kidney disease patients

Background: Ascending aortic dilatation (AAD) is an adverse prognostic cardiovascular marker in the general population. There are few data reporting its presence or clinical significance in chronic kidney disease (CKD) patients. The aim of this study was to evaluate ascending aorta dimensions and their correlates in a population of South African CKD patients.Methods: A total of 124 CKD patients and 40 healthy controls were enrolled. Cardiac dimensions, systolic and diastolic function indices, and aortic root diameters were assessed by transthoracic echocardiography. The ascending aorta was measured at four levels (aortic annulus, sinuses of Valsalva, sino-tubular junction, and ascending aorta) and was normalised for body surface area. The prevalence of AAD was assessed in CKD patients compared with the control group.Results: In CKD patients, the ascending aorta dimension was significantly larger than in controls at all four sites of the aorta that were measured. The prevalence of AAD was 6.5% at the annulus, 12.9% at the sinuses, 15.3% at the sino-tubular junction, and 8.9% at the ascending aorta. Overall, 29 patients (23%) had AAD. On multivariate analyses, eGFR was independently associated with AAD (odds ratio 0.980; 95% confidence interval 0.965–0.996; P = 0.014).Conclusion: AAD is a common cardiovascular phenotype in South African CKD patients. Low eGFR was independently associated with AAD, suggesting a direct link between CKD and the development of AAD in South African CKD patients

Evaluation of Quality during Construction Projects: A Case Study of Pakistan

Achieving and maintaining quality values are indispensable for attaining organizational and customer satisfaction. This research investigates different aspects of operationalize quality culture and factors affecting the quality of building construction in under developed countries like Pakistan. A qualitative and quantitative survey was circulated among different stakeholders including Clients, Consultants and Contractors to assess the level of the contractor’s performance, the project monitoring and controlling techniques, proper health and safety requirements, client satisfaction and workers experience in construction industry projects. The practice of professional quality management in building projects is increasing, however, many flaws and negligence are still found in local practices. This analysis also indicates that political and socio-economic factors play a significant role in maintaining the quality level in local industry. Therefore, the allocation of sufficient resources, proper training of workers, and recruitment of quality control staff and the use of advanced technologies are recommended for proper implementation of QMS (Quality Management System)