Novel mechanisms for buffering the haemodynamic effects of dietary salt and the relevance of skin sodium in humans

Background: Hypertension is one of the most common diseases in the United Kingdom and it remains an important risk factor for cardiovascular morbidity and mortality. Dietary sodium is an important trigger for hypertension and humans show a heterogeneous blood pressure (BP) response to salt intake. The mechanisms for this have not been fully explained, with renal sodium handling thought to play a central role. Animal studies have shown that dietary salt loading results in Na+ accumulation and lymphangiogenesis in skin mediated by vascular endothelial growth factor-C (VEGF-C), both attenuating the rise in BP. This represents an additional system for maintaining BP and volume homeostasis in response to salt load. The focus of this thesis is to determine whether these dermal mechanisms exist in humans. Methods: The technique of measuring skin Na+ and K+ using inductively coupled plasma optical emission spectrometry was developed in a pilot study of healthy adults. In a further study in healthy adults, the effects of dietary salt modulation on skin Na+, the effect of sex and the relationship between skin Na+ and haemodynamic parameters and plasma VEGF-C were studied. Skin Na+ concentrations were expressed as the ratio Na+:K+ to correct for variability in sample hydration. The effect of dietary salt intake on skin gene expression of factors that potentially influence BP such as VEGF-C and the hypoxia inducible factor (HIF) transcription system was assessed, exploring possible mechanisms linking skin Na+ to haemodynamic variables. Results: Skin Na+:K+ increased with dietary salt loading and this effect appeared to be greater in men while only women showed a rise in ambulatory mean BP. Skin Na+:K+ correlated with blood pressure, stroke volume and peripheral vascular resistance in men, but not in women. No change was noted in plasma vascular endothelial growth factor-C. Conclusions: These findings suggest that the skin may buffer dietary Na+, reducing the hemodynamic consequences of increased salt and this may be influenced by sex. Skin Na+ may influence blood pressure, stroke volume and PVR.British Heart Foundation National Institute for Health Researc

Comparison of Estimated Protein Output and Urine Protein: Creatinine Ratio in First and Second Voids with 24-Hour Urine Protein

Background: Current UK guidelines for the identification, management and referral of chronic kidney disease advise an early-morning urine sample for the albumin:creatinine ratio or the protein:creatinine ratio (PCR) in order to quantify proteinuria. Estimated protein output (EPO) is an alternative and possibly better method of quantifying proteinuria which takes lean weight into consideration. Methods: We carried out a single-centre study of 36 adult patients with proteinuric nephropathy over a period of 18 months. Urinary PCR and EPO estimates of 24-hour urine protein were compared with 24-hour urine collections by Bland-Altman analysis. Results: Average 24-hour urine protein was 1.6 g (range 0.2–5.1 g). Best agreement with 24-hour protein was for first-void EPO (limits of agreement 0.33–1.59) followed by a second-void EPO (0.40–1.76), then second-void PCR (0.40–2.08) and lastly first-void PCR (0.28–2.03). None of the differences between estimates of urine protein excretion and 24-hour urine protein were statistically significant. All estimates of protein output had wide confidence intervals confirming that spot urine samples, while simple and convenient to do, are imprecise measures of 24-hour urine protein excretion. Conclusion: When estimating 24-hour urine protein from a spot urine sample, EPO may be marginally more accurate than PCR, and first-void urine samples slightly better than second-void urine samples, but a first- or second-void PCR will suffice in most instances

Skin Sodium and Hypertension: a Paradigm Shift?

PURPOSE OF REVIEW: Dietary sodium is an important trigger for hypertension and humans show a heterogeneous blood pressure response to salt intake. The precise mechanisms for this have not been fully explained although renal sodium handling has traditionally been considered to play a central role. RECENT FINDINGS: Animal studies have shown that dietary salt loading results in non-osmotic sodium accumulation via glycosaminoglycans and lymphangiogenesis in skin mediated by vascular endothelial growth factor-C, both processes attenuating the rise in BP. Studies in humans have shown that skin could be a buffer for sodium and that skin sodium could be a marker of hypertension and salt sensitivity. Skin sodium storage could represent an additional system influencing the response to salt load and blood pressure in humans.British Heart Foundation NIHR Addenbrookes Charitable Trus

Clinical impact of tissue sodium storage

Abstract: In recent times, the traditional nephrocentric, two-compartment model of body sodium has been challenged by long-term sodium balance studies and experimental work on the dermal interstitium and endothelial surface layer. In the new paradigm, sodium can be stored without commensurate water retention in the interstitium and endothelial surface layer, forming a dynamic third compartment for sodium. This has important implications for sodium homeostasis, osmoregulation and the hemodynamic response to salt intake. Sodium storage in the skin and endothelial surface layer may function as a buffer during periods of dietary depletion and excess, representing an extra-renal mechanism regulating body sodium and water. Interstitial sodium storage may also serve as a biomarker for sodium sensitivity and cardiovascular risk, as well as a target for hypertension treatment. Furthermore, sodium storage may explain the limitations of traditional techniques used to quantify sodium intake and determine infusion strategies for dysnatraemias. This review is aimed at outlining these new insights into sodium homeostasis, exploring their implications for clinical practice and potential areas for further research for paediatric and adult populations

Prediction of cardiovascular risk factors from retinal fundus photographs: Validation of a deep learning algorithm in a prospective non-interventional study in Kenya

Aim: Hypertension and diabetes mellitus (DM) are major causes of morbidity andmortality, with growing burdens in low-income countries where they are underdiag-nosed and undertreated. Advances in machine learning may provide opportunities toenhance diagnostics in settings with limited medical infrastructure. Materials and Methods: A non-interventional study was conducted to develop andvalidate a machine learning algorithm to estimate cardiovascular clinical and labora-tory parameters. At two sites in Kenya, digital retinal fundus photographs were col-lected alongside blood pressure (BP), laboratory measures and medical history. Theperformance of machine learning models, originally trained using data from the UKBiobank, were evaluated for their ability to estimate BP, glycated haemoglobin, esti-mated glomerular filtration rate and diagnoses from fundus images. Results: In total, 301 participants were enrolled. Compared with the UK Biobankpopulation used for algorithm development, participants from Kenya were youngerand would probably report Black/African ethnicity, with a higher body mass indexand prevalence of DM and hypertension. The mean absolute error was comparable orslightly greater for systolic BP, diastolic BP, glycated haemoglobin and estimated glo-merular filtration rate. The model trained to identify DM had an area under thereceiver operating curve of 0.762 (0.818 in the UK Biobank) and the hypertensionmodel had an area under the receiver operating curve of 0.765 (0.738 in the UKBiobank). Conclusions: In a Kenyan population, machine learning models estimated cardiovas-cular parameters with comparable or slightly lower accuracy than in the populationwhere they were trained, suggesting model recalibration may be appropriate. Thisstudy represents an incremental step toward leveraging machine learning to makeearly cardiovascular screening more accessible, particularly in resource-limitedsettings

Clinical impact of tissue sodium storage

Abstract: In recent times, the traditional nephrocentric, two-compartment model of body sodium has been challenged by long-term sodium balance studies and experimental work on the dermal interstitium and endothelial surface layer. In the new paradigm, sodium can be stored without commensurate water retention in the interstitium and endothelial surface layer, forming a dynamic third compartment for sodium. This has important implications for sodium homeostasis, osmoregulation and the hemodynamic response to salt intake. Sodium storage in the skin and endothelial surface layer may function as a buffer during periods of dietary depletion and excess, representing an extra-renal mechanism regulating body sodium and water. Interstitial sodium storage may also serve as a biomarker for sodium sensitivity and cardiovascular risk, as well as a target for hypertension treatment. Furthermore, sodium storage may explain the limitations of traditional techniques used to quantify sodium intake and determine infusion strategies for dysnatraemias. This review is aimed at outlining these new insights into sodium homeostasis, exploring their implications for clinical practice and potential areas for further research for paediatric and adult populations

Clinical impact of tissue sodium storage

In recent times, the traditional nephrocentric, two-compartment model of body sodium has been challenged by long-term sodium balance studies and experimental work on the dermal interstitium and endothelial surface layer. In the new paradigm, sodium can be stored without commensurate water retention in the interstitium and endothelial surface layer, forming a dynamic third compartment for sodium. This has important implications for sodium homeostasis, osmoregulation and the hemodynamic response to salt intake. Sodium storage in the skin and endothelial surface layer may function as a buffer during periods of dietary depletion and excess, representing an extra-renal mechanism regulating body sodium and water. Interstitial sodium storage may also serve as a biomarker for sodium sensitivity and cardiovascular risk, as well as a target for hypertension treatment. Furthermore, sodium storage may explain the limitations of traditional techniques used to quantify sodium intake and determine infusion strategies for dysnatraemias. This review is aimed at outlining these new insights into sodium homeostasis, exploring their implications for clinical practice and potential areas for further research for paediatric and adult populations

Clinical impact of tissue sodium storage

Abstract: In recent times, the traditional nephrocentric, two-compartment model of body sodium has been challenged by long-term sodium balance studies and experimental work on the dermal interstitium and endothelial surface layer. In the new paradigm, sodium can be stored without commensurate water retention in the interstitium and endothelial surface layer, forming a dynamic third compartment for sodium. This has important implications for sodium homeostasis, osmoregulation and the hemodynamic response to salt intake. Sodium storage in the skin and endothelial surface layer may function as a buffer during periods of dietary depletion and excess, representing an extra-renal mechanism regulating body sodium and water. Interstitial sodium storage may also serve as a biomarker for sodium sensitivity and cardiovascular risk, as well as a target for hypertension treatment. Furthermore, sodium storage may explain the limitations of traditional techniques used to quantify sodium intake and determine infusion strategies for dysnatraemias. This review is aimed at outlining these new insights into sodium homeostasis, exploring their implications for clinical practice and potential areas for further research for paediatric and adult populations

Pre-Dialysis Systolic Blood Pressure-Variability Is Independently Associated with All-Cause Mortality in Incident Haemodialysis Patients

<div><p>Systolic blood pressure variability is an independent risk factor for mortality and cardiovascular events. Standard measures of blood pressure predict outcome poorly in haemodialysis patients. We investigated whether systolic blood pressure variability was associated with mortality in incident haemodialysis patients. We performed a longitudinal observational study of patients commencing haemodialysis between 2005 and 2011 in East Anglia, UK, excluding patients with cardiovascular events within 6 months of starting haemodialysis. The main exposure was variability independent of the mean (VIM) of systolic blood pressure from short-gap, pre-dialysis blood pressure readings between 3 and 6 months after commencing haemodialysis, and the outcome was all-cause mortality. Of 203 patients, 37 (18.2%) patients died during a mean follow-up of 2.0 (SD 1.3) years. The age and sex-adjusted hazard ratio (HR) for mortality was 1.09 (95% confidence interval (CI) 1.02–1.17) for a one-unit increase of VIM. This was not altered by adjustment for diabetes, prior cardiovascular disease and mean systolic blood pressure (HR 1.09, 95% CI 1.02–1.16). Patients with VIM of systolic blood pressure above the median were 2.4 (95% CI 1.17–4.74) times more likely to die during follow-up than those below the median. Results were similar for all measures of blood pressure variability and further adjustment for type of dialysis access, use of antihypertensives and absolute or variability of fluid intake did not alter these findings. Diastolic blood pressure variability showed no association with all cause mortality. Our study shows that variability of systolic blood pressure is a strong and independent predictor of all-cause mortality in incident haemodialysis patients. Further research is needed to understand the mechanism as this may form a therapeutic target or focus for management.</p></div