Recent advances in understanding hypertension development in sub-Saharan Africa

Consistent reports indicate that hypertension is a particularly common finding in black populations. Hypertension occurs at younger ages and is often more severe in terms of blood pressure levels and organ damage than in whites, resulting in a higher incidence of cardiovascular disease and mortality. This review provides an outline of recent advances in the pathophysiological understanding of blood pressure elevation and the consequences thereof in black populations in Africa. This is set against the backdrop of populations undergoing demanding and rapid demographic transition, where infection with the Human Immunodeficiency Virus predominates, and where under and over-nutrition coexist. Collectively, recent findings from Africa illustrate an increased lifetime risk to hypertension from foetal life onwards. From young ages black populations display early endothelial dysfunction, increased vascular tone and reactivity, microvascular structural adaptions, as well as increased aortic stiffness resulting in elevated central and brachial blood pressures during the day and night, when compared to whites. Together with knowledge on the contributions of sympathetic activation and abnormal renal sodium handling, these pathophysiological adaptations result in subclinical and clinical organ damage at younger ages. This overall enhanced understanding on the determinants of blood pressure elevation in blacks encourages (a) novel approaches to assess and manage hypertension in Africa better, (b) further scientific discovery to develop more effective prevention and treatment strategies, and (c) policymakers and health advocates to collectively contribute in creating health-promoting environments in Africa

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

Paraoxonase-1: Characteristics and role in atherosclerosis and carotid artery disease

Paraoxonase-1 (PON-1) is a calcium-dependent enzyme that is synthesized in the liver and then secreted in blood where it is bound to High Density Lipoprotein (HDL). PON-1 is a hydrolase with a wide range of substrates, including lipid peroxides. It is considered responsible for many of the antia-therogenic properties of HDL. PON-1 prevents Low Density Lipoprotein (LDL) oxidation, a process that is considered to contribute to the initiation and development of atherosclerosis. PON-1 activity and levels are influenced by gene polymorphisms; of the 2 common variants, one is in position 192 (Q192R) and one in position 55 (M55L). Also, many drugs affect PON-1 activity. The role of PON-1 in carotid atherosclerosis is inconsistent. Some studies show an association of PON-1 polymorphisms with carotid plaque formation, whereas others do not. The aim of this review is to summarize the characteristics of PON-1, its interactions with drugs and its role in atherosclerosis and especially its relationship with carotid artery disease. © 2019 Bentham Science Publishers

Paraoxonase-1 and Symptomatic Status in Carotid Artery Disease

Background: Paraoxonase-1 (PON-1) is a high-density lipoprotein (HDL)-associated hydrolase that appears to have a protective action against atherosclerosis. The aim of our study is to identify whether PON-1 levels may be associated with the manifestation of symptoms in patients with carotid artery stenosis. Methods: We studied all patients who underwent carotid endarterectomy in the Vascular Surgery Department of Laikon Hospital, Athens, Greece, from July 2012 to July 2014. Medical history was recorded and PON-1 glucose, total cholesterol, HDL cholesterol, low-density lipoprotein cholesterol, and triglycerides levels were measured. Variables were compared between symptomatic and asymptomatic patients. A receiver operating characteristic (ROC) curve was constructed to evaluate the accuracy of PON-1 to predict symptoms. Results: A total of 74 patients were included, 41 were asymptomatic and the mean age was 68.5 years. The 2 groups appear to differ significantly with regards to the PON-1 levels, with the symptomatic group showing lower levels (5.3 ± 1.19 vs. 4.6 ± 1.36 ng/mL; P = 0.025). ROC analysis demonstrated an area under the curve of 0.654 (P = 0.023). Conclusions: Reduced PON-1 levels showed a significant association with symptomatic status, which was independent of other traditional cardiovascular factors. Further studies are required to prospectively assess the role of PON-1 in predicting cerebrovascular events in patients with carotid artery disease. © 2019 Elsevier Inc

Rapamycin induced ultrastructural and molecular alterations in glomerular podocytes in healthy mice

Background. In the normal kidney, rapamycin is considered to be non-nephrotoxic. In the present study, we investigated whether rapamycin is indeed non-nephrotoxic by examining the ultrastructural and molecular alterations of podocytes in healthy mice. Methods. Balb/c mice were given three different intraperitoneal doses of rapamycin for 1 week (dose model)low-dose group: 1 mg/kg/day, intermediate-dose (ID) group: 1.5 mg/kg/day and high-dose (HD) group: 3 mg/kg/day; four mice in each group. An ID of rapamycin was also given for three different periods (time model): 1, 4 and 8 weeks; four mice were in each group. Mice treated with dimethyl sulphoxide served as controls. Body weight was measured weekly. Renal function was assessed by serum creatinine at the time of sacrifice. For estimation of albuminuria, 24-h urine collections were performed before treatment and weekly thereafter. Glomerular content of nephrin, podocin, Akt and Ser473-phospho-Akt was estimated by western blot and immunofluorescence. Nephrin and podocin messenger RNA (mRNA) were measured by real-time polymerase chain reaction. Mean podocyte foot process width (FPW) was measured by electron microscopy. Results. Urine albumin levels increased in the HD and 4-week groups. Renal function was modestly deteriorated in the HD group. The mean FPW increased in a dose-dependant manner at Week 1, further deteriorated at Week 4 and finally improved at Week 8. Nephrin and podocin mRNA levels showed a significant decrease at Week 1 and were restored at Week 4 and 8. Nephrin and podocin protein levels were reduced at Week 4 and recovered at Week 8. Ser473-phospho-Akt significantly increased in all rapamycin-treated groups. Conclusion. sRapamycin induced significant ultrastructural and molecular alterations in podocytes in association with albuminuria. These alterations happened early during treatment and they tended to improve over an 8-week treatment period. © The Author 2012. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved

The P274S Mutation of Lecithin-Cholesterol Acyltransferase (LCAT) and Its Clinical Manifestations in a Large Kindred

Rationale & Objective: Lecithin-cholesterol acyltransferase (LCAT) catalyzes the maturation of high-density lipoprotein. Homozygosity for loss-of-function mutations causes familial LCAT deficiency (FLD), characterized by corneal opacities, anemia, and renal involvement. This study sought to characterize kidney biopsy findings and clinical outcomes in a family with FLD. Study Design: Prospective observational study. Setting & Participants: 2 (related) index patients with clinically apparent FLD were initially identified. 110 of 122 family members who consented to genetic analysis were also studied. Predictors: Demographic and laboratory parameters (including lipid profiles and LCAT activity) and full sequence analysis of the LCAT gene. Kidney histologic examination was performed with samples from 6 participants. Outcomes: Cardiovascular and renal events during a median follow-up of 12 years. Estimation of annual rate of decline in glomerular filtration rate. Analytical Approach: Analysis of variance, linear regression analysis, and Fine-Gray competing-risk survival analysis. Results: 9 homozygous, 57 heterozygous, and 44 unaffected family members were identified. In all affected individuals, full sequence analysis of the LCAT gene revealed a mutation (c.820C>T) predicted to cause a proline to serine substitution at amino acid 274 (P274S). Homozygosity caused a complete loss of LCAT activity. Kidney biopsy findings demonstrated lipid deposition causing glomerular basement membrane thickening, mesangial expansion, and “foam-cell” infiltration of kidney tissue. Tubular atrophy, glomerular sclerosis, and complement fixation were associated with worse kidney outcomes. Estimated glomerular filtration rate deteriorated among homozygous family members at an average annual rate of 3.56 mL/min/1.73 m2. The incidence of cardiovascular and renal complications was higher among homozygous family members compared with heterozygous and unaffected members. Mild thrombocytopenia was a common finding among homozygous participants. Limitations: The presence of cardiovascular disease was mainly based on medical history. Conclusions: The P274S LCAT mutation was found to cause FLD with renal involvement. Tubular atrophy, glomerular sclerosis, and complement fixation were associated with a worse renal prognosis. © 2019 National Kidney Foundation, Inc

Risk of COVID-19 Disease, Dialysis Unit Attributes, and Infection Control Strategy among London In-Center Hemodialysis Patients.

Background Patients receiving in-center hemodialysis treatment face unique challenges during the COVID-19 pandemic, specifically the need to attend for treatment that prevents self-isolation. Dialysis unit attributes and isolation strategies that might reduce dialysis center COVID-19 infection rates have not been previously examined. Methods We explored the role of variables including community disease burden, dialysis unit attributes (size, layout) and infection control strategies, on rates of COVID-19 among patients receiving in center hemodialysis in London, UK, between March 2nd 2020 and May 31st 2020. The two outcomes were defined as (i) a positive test for infection or admission with suspected COVID19 and (ii) admission to the hospital with suspected infection. Associations were examined using a discrete-time multi-level time-to-event analysis. Results Data on 5,755 patients, dialysing in 51 units were analysed. 990 (17%) tested positive and 465 (8%) were admitted with suspected COVID-19 between 2nd March and 31st May 2020. Outcomes were associated with age, diabetes, local community COVID-19 rates and dialysis unit size. Greater number of available side rooms and introduction of mask policies for asymptomatic patients were inversely associated with outcomes. No association was seen with sex, ethnicity, or deprivation indices nor with any of the different isolation strategies. Conclusions Rates of COVID-19 in the in center-hemodialysis population relate to individual factors, underlying community transmission, unit size and layout