Gemma Currie

Proteinuria and its relation to cardiovascular disease

Chronic kidney disease (CKD) and its associated morbidity pose a worldwide health problem. As well as risk of endstage renal disease requiring renal replacement therapy, cardiovascular disease is the leading cause of premature death among the CKD population. Proteinuria is a marker of renal injury that can often be detected earlier than any tangible decline in glomerular filtration rate. As well as being a risk marker for decline in renal function, proteinuria is now widely accepted as an independent risk factor for cardiovascular morbidity and mortality. This review will address the prognostic implications of proteinuria in the general population as well as other specific disease states including diabetes, hypertension and heart failure. A variety of pathophysiological mechanisms that may underlie the relationship between renal and cardiovascular disease have been proposed, including insulin resistance, inflammation, and endothelial dysfunction. As proteinuria has evolved into a therapeutic target for cardiovascular risk reduction in the clinical setting we will also review therapeutic strategies that should be considered for patients with persistent proteinuria.

Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy in TYpe 2 diabetic patients with normoalbuminuria (PRIORITY): essential study design and rationale of a randomised clinical multicentre trial

Introduction Diabetes mellitus affects 9% of the European population and accounts for 15% of healthcare expenditure, in particular, due to excess costs related to complications. Clinical trials aiming for earlier prevention of diabetic nephropathy by renin angiotensin system blocking treatment in normoalbumuric patients have given mixed results. This might reflect that the large fraction of normoalbuminuric patients are not at risk of progression, thereby reducing power in previous studies. A specific risk classifier based on urinary proteomics (chronic kidney disease (CKD)273) has been shown to identify normoalbuminuric diabetic patients who later progressed to overt kidney disease, and may hold the potential for selection of high-risk patients for early intervention. Combining the ability of CKD273 to identify patients at highest risk of progression with prescription of preventive aldosterone blockade only to this high-risk population will increase power. We aim to confirm performance of CKD273 in a prospective multicentre clinical trial and test the ability of spironolactone to delay progression of early diabetic nephropathy. Methods and analysis Investigator-initiated, prospective multicentre clinical trial, with randomised double-masked placebo-controlled intervention and a prospective observational study. We aim to include 3280 type 2 diabetic participants with normoalbuminuria. The CKD273 classifier will be assessed in all participants. Participants with high-risk pattern are randomised to treatment with spironolactone 25 mg once daily, or placebo, whereas, those with low-risk pattern will be observed without intervention other than standard of care. Treatment or observational period is 3 years. The primary endpoint is development of confirmed microalbuminuria in 2 of 3 first morning voids urine samples. Ethics and dissemination The study will be conducted under International Conference on Harmonisation – Good clinical practice (ICH-GCP) requirements, ethical principles of Declaration of Helsinki and national laws. This first new biomarker-directed intervention trial aiming at primary prevention of diabetic nephropathy may pave the way for personalised medicine approaches in treatment of diabetes complications. Trial registration number NCT02040441; Pre-results.

Biomarkers in diabetic nephropathy: present and future

Diabetic nephropathy (DN) is the leading cause of end stage renal disease in the Western world. Microalbuminuria (MA) is the earliest and most commonly used clinical index of DN and is independently associated with cardiovascular risk in diabetic patients. Although MA remains an essential tool for risk stratification and monitoring disease progression in DN, a number of factors have called into question its predictive power. Originally thought to be predictive of future overt DN in 80% of patients, we now know that only around 30% of microalbuminuric patients progress to overt nephropathy after 10 years of follow up. In addition, advanced structural alterations in the glomerular basement membrane may already have occurred by the time MA is clinically detectable.Evidence in recent years suggests that a significant proportion of patients with MA can revert to normoalbuminuria and the concept of nonalbuminuric DN is well-documented, reflecting the fact that patients with diabetes can demonstrate a reduction in glomerular filtration rate without progressing from normo-to MA. There is an unmet clinical need to identify biomarkers with potential for earlier diagnosis and risk stratification in DN and recent developments in this field will be the focus of this review article.

Disorders of Blood Pressure Regulation—Role of Catecholamine Biosynthesis, Release, and Metabolism

Catecholamines (epinephrine and norepinephrine) are synthesised and produced by the adrenal medulla and postganglionic nerve fibres of the sympathetic nervous system. It is known that essential hypertension has a significant neurogenic component, with the rise in blood pressure mediated at least in part by overactivity of the sympathetic nervous system. Moreover, novel therapeutic strategies aimed at reducing sympathetic activity show promise in the treatment of hypertension. This article reviews recent advances within this rapidly changing field, particularly focusing on the role of genetic polymorphisms within key catecholamine biosynthetic enzymes, cofactors, and storage molecules. In addition, mechanisms linking the sympathetic nervous system and other adverse cardiovascular states (obesity, insulin resistance, dyslipidaemia) are discussed, along with speculation as to how recent scientific advances may lead to the emergence of novel antihypertensive treatments.

Systematic Review of Micro-RNA Expression in Pre-Eclampsia Identifies a Number of Common Pathways Associated with the Disease.

Background Pre-eclampsia (PE) is a complex, multi-systemic condition of pregnancy which greatly impacts maternal and perinatal morbidity and mortality. MicroRNAs (miRs) are differentially expressed in PE and may be important in helping to understand the condition and its pathogenesis. Methods Case-control studies investigating expression of miRs in PE were collected through a systematic literature search. Data was extracted and compared from 58 studies to identify the most promising miRs associated with PE pathogenesis and identify areas of methodology which could account for often conflicting results. Results Some of the most frequently differentially expressed miRs in PE include miR-210, miR-223 and miR-126/126* which associate strongly with the etiological domains of hypoxia, immunology and angiogenesis. Members of the miR-515 family belonging to the imprinted chromosome 19 miR cluster with putative roles in trophoblast invasion were also found to be differentially expressed. Certain miRs appear to associate with more severe forms of PE such as miR-210 and the immune-related miR-181a and miR-15 families. Patterns of miR expression may help pinpoint key pathways (e.g. IL-6/miR-223/STAT3) and aid in untangling the heterogeneous nature of PE. The detectable presence of many PE-associated miRs in antenatal circulatory samples suggests their usefulness as predictive biomarkers. Further progress in ascertaining the clinical value of miRs and in understanding how they might contribute to pathogenesis is predicated upon resolving current methodological challenges in studies. These include differences in diagnostic criteria, cohort characteristics, sampling technique, RNA isolation and platform-dependent variation in miR profiling. Conclusion Reviewing studies of PE-associated miRs has revealed their potential as informants of underlying target genes and pathways relating to PE pathogenesis. However, the incongruity in results across current studies hampers their capacity to be useful biomarkers of the condition.

Urinary Proteomics for Diagnosis and Monitoring of Diabetic Nephropathy

The last decade has seen a surge in publications describing novel biomarkers for early detection of diabetic nephropathy (DN), but as yet none have outperformed albuminuria in well-designed prospective studies. This is partially attributable to our incomplete understanding of the many complex interrelated mechanisms underlying DN development, a heterogeneous process unlikely to be captured by a single biomarker. Proteomics offers the advantage of simultaneously analysing the entire protein content of a biological sample, and the technique has gained attention as a potential tool for a more accurate diagnosis of disease at an earlier stage as well as a means by which to unravel the pathogenesis of complex diseases such as DN using an untargeted approach. This review will discuss the potential of proteomics as both a clinical and research tool, evaluating exploratory work in animal models as well as diagnostic potential in human subjects.

Placental expression of the angiogenic placental growth factor is stimulated by both aldosterone and simulated starvation

Aldosterone is an important factor supporting placental growth and fetal development. Recently, expression of placental growth factor (PlGF) has been observed in response to aldosterone exposure in different models of atherosclerosis. Thus, we hypothesized that aldosterone up-regulates growth-adaptive angiogenesis in pregnancy, via increased placental PlGF expression. We followed normotensive pregnant women (n = 24) throughout pregnancy and confirmed these results in a second independent first trimester cohort (n = 36). Urinary tetrahydroaldosterone was measured by gas chromatography-mass spectrometry and corrected for creatinine. Circulating PlGF concentrations were determined by ELISA. Additionally, cultured cell lines, adrenocortical H295R and choriocarcinoma BeWo cells, as well as primary human third trimester trophoblasts were tested in vitro. PlGF serum concentrations positively correlated with urinary tetrahydroaldosterone corrected for creatinine in these two independent cohorts. This observation was not due to PlGF, which did not induce aldosterone production in cultured H295R cells. On the other hand, PlGF expression was specifically enhanced by aldosterone in the presence of forskolin (p < 0.01) in trophoblasts. A pronounced stimulation of PlGF expression was observed with reduced glucose concentrations simulating starvation (p < 0.001). In conclusion, aldosterone stimulates placental PlGF production, enhancing its availability during human pregnancy, a response amplified by reduced glucose supply. Given the crucial role of PlGF in maintaining a healthy pregnancy, these data support a key role of aldosterone for a healthy pregnancy outcome.

The Future of “Omics” in Hypertension

Despite decades of research and clinical practice, the pathogenesis of hypertension remains incompletely understood, and blood pressure is often suboptimally controlled. “Omics” technologies allow the description of a large number of molecular features and have the potential to identify new factors that contribute to blood pressure regulation and how they interact. In this review, we focus on the potential of genomics, transcriptomics, proteomics, and metabolomics and explore their roles in unraveling the pathophysiology and diagnosis of hypertension, the prediction of organ damage and treatment response, and monitoring treatment effect. Substantial progress has been made in the area of genomics, in which genome-wide association studies have identified > 50 blood pressure–related, single-nucleotide polymorphisms, and sequencing studies (especially in secondary forms of hypertension) have discovered novel regulatory pathways. In contrast, other omics technologies, despite their ability to provide detailed insights into the physiological state of an organism, have only more recently demonstrated their impact on hypertension research and clinical practice. The majority of current proteomic studies focus on organ damage resulting from hypertension and may have the potential to help us understand the link between blood pressure and organ failure but also serve as biomarkers for early detection of cerebrovascular or coronary disease. Examples include signatures for early detection of left ventricular dysfunction or albuminuria. Metabolomic studies have the potential to integrate environmental and intrinsic factors and are particularly suited to monitor the response to treatment. We discuss examples of omics studies in hypertension and explore the challenges related to these novel technologies.

Healthy Vascular Aging

See related article, pp 267–274 Decisions on preventative treatments can be based on single parameters, but in most cases, clinicians take more than one risk factor into account, as some negative indicators of risk can be outbalanced by other more favorable factors. This concept has led to the development of risk scores that integrate a multitude of cardiovascular risk factors; the Framingham Risk Score is one notable example.1 Although these scores work well on the population level, they are of limited use for individual risk prediction. A tendency to overestimate risk; differences in risk between populations, ethnicities, and social classes; general changes in population health from derivation of scores in historic samples and application to modern societies; and the fact that not all damaging and protecting factors that could play a role in an individual patient are taken into account explain why as clinicians we are often confronted with patients at seemingly high risk who do perfectly well even at advanced age and with patients at seemingly low risk who are struck by premature cardiovascular disease. In this era of precision medicine,2 we would like to offer not only individualized treatment options but also individualized preventative strategies to our patients. An alternative approach is, therefore, based on early detection of cardiovascular disease rather than prediction of cardiovascular disease risk. The concept of the cardiovascular continuum where advanced disease develops not without earlier functional and structural subclinical changes forms the theoretical basis of this approach.3 One can assume that an individual’s position on the continuum from health to overt cardiovascular disease is determined by the integrated action of genetic, environmental, and other risk factors and could, therefore, inform decision rules on initiation of preventative and therapeutic strategies.4 Assessment of vascular function and structure is a key element …

Use of Biomarkers in the Evaluation and Treatment of Hypertensive Patients.

The current definition of hypertension is based on blood pressure values, and blood pressure also drives treatment decisions, is the most important treatment monitoring tool and helps estimating risk of hypertension-related organ damage. In an era of precision medicine, additional biomarkers are needed in the diagnosis and management of patients with hypertension. In this review, we outline the areas in which functional, imaging and circulating biomarkers could help in a more individualised definition of hypertension and associated risk. We will cover biomarkers for diagnosis; of pathophysiology and prediction of hypertension; response to treatment, organ damage; and to monitor treatment. A clear focus is on the vasculature, the heart and the kidneys, whereas we see a need to further develop biomarkers of cerebral function in order to diagnose cognition deficits and monitor changes in cognition in the future to support addressing the growing burden of hypertension-associated vascular dementia.