Author: Prof. Michel Burnier

Hypertension is defined as resistant to therapy when the prescribed drug treatment fails to control blood pressure (BP) and to achieve recommended targets, and the inadequate BP control is confirmed by outof-office BP monitoring in patients whose adherence to therapy has been confirmed [1]. This definition implies that 3 antihypertensive drugs are prescribed at maximally tolerated doses with one of them being a diuretic. In recent years, additional definitions have appeared in the literature [2]. They include the concept of refractory hypertension, when BP remains uncontrolled with the use of 5 antihypertensive agents of different classes, including a long-acting thiazide-like diuretic and spironolactone, or controlled resistant hypertension, when BP falls below targets on 4 antihypertensive medications at maximal or maximally tolerated doses [2]. Frequently, however, uncontrolled hypertension is considered as ‘apparent’ rather than true resistant hypertension because BP has not been measured outside the office, drug adherence has not been assessed and other factors of pseudo-resistance have not been excluded [3].

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Abstract: In the general population, the prevalence of moderate and severe chronic kidney disease (CKD) is usually below 5% but this figure is often higher in specific groups of patients such as those with type 2 diabetes. Patients with advanced CKD (CKD stage 3b and 4) are at high or very high cardiovascular risk, and their risk of progressing towards endstage kidney disease (CKD stage 5) and the need of renal replacement therapy are elevated. Hypertension is a major cause of poor cardiovascular and renal outcomes in severe CKD. Therefore, an adequate control of blood pressure (BP) is mandatory. However, normalizing BP is often challenging in these patients because the clinical management of hypertension in advanced CKD is not well defined and rarely supported by large randomized controlled trials. In the present review, we discuss the characteristics of hypertension in advanced CKD, excluding dialysis, and its management integrating data from recent clinical studies and a pragmatic approach enriched by a long-standing clinical experience.

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According to current nutritional recommendations, patients with chronic kidney disease (CKD) should restrict their salt intake and eat <90–100 mmol sodium (Na) per day [5–6 g sodium chloride (NaCl)/day]. The scientific basis of this recommendation is the strong evidence of a beneficial effect of reducing salt intake on two major targets of CKD management, namely blood pressure (BP) and proteinuria. Indeed, when compared with patients with a high urinary Na excretion, CKD patients with a lower Na excretion (100 mmol/day) had better BP control and lower proteinuria [1, 2]. Experimentally there is also increasing evidence that a high Na intake may have a detrimental effect on renal function, independent of BP, through direct effects on inflammatory processes and immune balance [3, 4]. However, evidence that being on a low salt diet reduces mortality and slows the progression of renal diseases in CKD is still low, despite an increasing number of retrospective and prospective observational studies suggesting a favourable impact of low Na intake on mortality and on renal function decline as reviewed in a recent editorial [5].

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Abstract: As a part of the salt controversy, it has been suggested that people with a low sodium intake have an increased risk of cardiovascular events. However, there is no clear explanation for this increased risk. We examined the socio-demographic, clinical profile, and behavioral factors associated with a low sodium intake in the Swiss subjects who participated in the Swiss Survey on Salt. Only 13.3% of the Swiss population eat less than 5 g of salt daily and among them 78.2% are women. Subjects with a low sodium intake eat and drink less as reflected by lower intakes of proteins, potassium, and calcium and a smaller urine volume. In addition, a low blood pressure, a normal body mass index, a low prevalence of obesity, a low serum uric acid, and less alcohol and cigarette consumption characterized this group, suggesting a rather low cardiovascular risk profile. Being single and doing most of the cooking at home are associated with a low intake of sodium, as well as a less frequent consumption of meat and fish when eating less than 5 g salt per day. However, the awareness of the effects of salt on health and cardiovascular risk, health concerns, and physical activity are similar in subjects eating more or less salt. In conclusion, we could not evidence clinical or behavioral factors that could significantly increase the risk of developing cardiovascular events in low salt eaters.

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Hypertension is highly prevalent after the age of 65 years affecting more than 60% of individuals in developed countries. Today, there is sufficient evidence from clinical trials that treating elderly subjects with hypertension with antihypertensive medications has a positive benefit/risk ratio even in very elderly patients (>80 years). In recent years, partial or total non-adherence has been recognized as major issues in the long-term management of hypertension in all age categories. However, whether non-adherence is more frequent in hypertensive patients older than 65 years or not is still a matter of debate and the common belief is that adherence is lower in older than in younger patients. Are clinical data supporting this belief? In this brief review, we discuss the topic of drug adherence in elderly in the context of the medical treatment of hypertension. Studies show that drug adherence is actually better in patients aged 65 to 80 years when compared to younger hypertensive patients (<50 years). however, in very old patients (>80 years) the prevalence of non-adherence does increase. In this patients’ group, there are specific risk factors for non-adherence such as cognitive ability, depression, and health believes, in addition to classical risk factors for non-adherence. One important aspect in the elderly is the prescription of potentially inappropriate medications that will interfere with the adherence to necessary treatments. In this context, an interesting new concept was developed few years ago, i.e., the process of deprescribing. Thus, today, in addition to conventional guidelines recommendations (use of single pill combinations, individualization of treatments), the evaluation of cognitive abilities, the regular assessment of potentially inappropriate medications, and the process of deprescribing appear to be three new additional steps to improve drug adherence in the elderly and thereby ameliorate the global management of hypertension.

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Kidney transplant recipients have a 2-fold risk of cardiovascular (CV) disease compared with the general population [1]. Following transplantation, several factors have the potential to increase CV risk over time, including traditional risk factors [e.g. hypertension (HTN), diabetes], which are highly prevalent [2]. HTN, apart from being a primary CV risk factor, is the most common clinical problem among transplant patients, affecting at least 90% of this population [3]. Inadequate control of post-transplant HTN is associated with an increased risk of CV morbidity and mortality, other than being an independent risk factor for graft loss [4]. Several mechanisms, transplant-specific or not (e.g. elevated renin secretion by the recipients’ native kidneys, poor-quality donor kidneys, renal transplant artery stenosis [5]), are implicated in the pathogenesis of post-transplant HTN. In this context, immunosuppressive medications, essential to prevent acute rejection and graft loss, play a key role in promoting post-transplant HTN [6], as demonstrated in particular for calcineurin inhibitor use [7].

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Every 5 to 6 years, international and national guidelines provide updated recommendations for the standard management of hypertension in adults. Thus, within the last 18 months, societies from Europe (European Society of Cardiology and European Society of Hypertension), America (American College of Cardiology and American Heart Association), and Great Britain (National Institute for Health and Care Excellence) published their new guidelines. Despite the fact that all of them are supposedly based on the most recent clinical evidence, there are always some discrepancies between recommendations due to different interpretation of clinical trials. The purpose of the present review is to discuss 6 issues that have generated some controversies, namely, the definition of hypertension, identification of patients who should be treated, target blood pressure, pertinence of reducing salt intake, mono- or combination therapy as first-line treatment, and the role of renal denervation in resistant hypertension.

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A precise maintenance of sodium and fluid balance is an essential step in the regulation of blood pressure and alterations of this balance may lead to the development of hypertension. In recent years, several new advances were made in our understanding of the interaction between sodium and blood pressure regulation. The first is the discovery made possible with by new technology, such as 23Na-MRI, that sodium can be stored non-osmotically in tissues including the skin and muscles particularly when subjects are on a high sodium diet or have a reduced renal capacity to excrete sodium. These observations prompted the refinement of the original model of regulation of sodium balance from a two-compartment model comprising the extracellular fluid within the intravascular and interstitial spaces to a three-compartment model that includes the intracellular space of some tissues, most prominently the skin. In this new model, the immune system plays a role, thereby supporting many previous studies indicating that the immune system is a crucial co-contributor to the maintenance of hypertension through pro-hypertensive effects in the kidney, vasculature, and brain. Lastly, there is now evidence that sodium can affect the gut microbiome, and induce pro-inflammatory and immune responses, which might contribute to the development of salt-sensitive hypertension.

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The global epidemic of hypertension is largely uncontrolled and hypertension remains the leading cause of noncommunicable disease deaths worldwide. Suboptimal adherence, which includes failure to initiate pharmacotherapy, to take medications as often as prescribed, and to persist on therapy long-term, is a wellrecognized factor contributing to the poor control of blood pressure in hypertension. Several categories of factors including demographic, socioeconomic, concomitant medical-behavioral conditions, therapy-related, healthcare team and system-related factors, and patient factors are associated with nonadherence. Understanding the categories of factors contributing to nonadherence is useful in managing nonadherence. In patients at high risk for major adverse cardiovascular outcomes, electronic and biochemical monitoring are useful for detecting nonadherence and for improving adherence. Increasing the availability and affordability of these more precise measures of adherence represent a future opportunity to realize more of the proven benefits of evidence-based medications. In the absence of new antihypertensive drugs, it is important that healthcare providers focus their attention on how to do better with the drugs they have. This is the reason why recent guidelines have emphasize the important need to address drug adherence as a major issue in hypertension management.

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I n high-income countries, ≈1 in 4 adults have an elevated blood pressure (BP), when defined as an office BP >140/90 mmHg.1,2 In the United States, this prevalence reaches 40% in blacks and >60% in adults >60 years of age2 with the same definition. High BP put these individuals at greater risk of developing hypertension-mediated organ damages or dying prematurely from a cardiovascular event. During the last decades, many initiatives and campaigns have been set up to increase the awareness and the control of hypertension in the population. The last example is the May Measurement Month 2017, during which BP was measured in >1.2 million unselected adults around the world. This campaign showed that 17.3% of participants with an elevated BP were not treated and 46.3% of those receiving treatment did not have a well-controlled BP. Yet, in contrast to these disappointing results, several surveys have demonstrated very positive trends in terms of global cardiovascular protection. These include a decrease in age-standardized BP over years in high-income countries,1 a positive trend in age-adjusted percentage of controlled hypertension among treated US adults with an increase from 31.6% in 2000 to 53.9% in 2014,2 and a constant decrease in cardiac death in the US population during the last 40 years. Of course, this latter observation cannot be attributed to a better control of BP only. It rather reflects the benefits of the global efforts made to reduce the impact of major cardiovascular risk factors, that is, smoking, high cholesterol levels, diabetes mellitus, overweight, and high BP.

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