Urinary angiotensinogen and salt sensitivity of blood pressure

Beyond the ongoing controversy on salt and blood pressure (BP) and the unresolved question on whether a reduction of salt intake should be promoted in the entire population or only in selected patients, there are some strong clinical, epidemiological and scientific evidence regarding the relation between salt and BP which can hardly be questioned. The first is that salt intake is an important determinant of BP in the population. This was again confirmed in the recently published results of the Prospective Urban Rural Epidemiological (PURE) study involving 102 216 patients from 18 countries, in whom sodium intake was estimated based on a single morning urine sample, The results of this study show that every increase in 1 g of sodium is associated with an increment of 2.11 mmHg in SBP and 0.78 mmHg in DBP, and that the association between sodium intake and BP may even be steeper in hypertensive patients or elderly individuals [1]. Moreover, a high salt intake is associated with an increased risk of death and cardiovascular events [2]. The study by Mente et al.[1] has also demonstrated that a high potassium intake has a protective effect which tends to attenuate the negative cardiovascular impact of a high sodium intake. The second consistent observation is that we are not all equal in our response to changes in sodium intake. Indeed, whereas some individuals can eat very high amounts of salt without any modification of their BP, others experienced a significant rise in BP with a sodium-rich diet. This indicates that the BP response to changes in dietary sodium is heterogeneous and the observation has led to the development of the salt-sensitivity concept [3,4]. The validity of this concept has been challenged many times, but the clinical observation remains valid. One concern has been the arbitrary definition of salt sensitivity which had been defined by Weinberger [5] as an increase in BP of more than 10% on high sodium diet. Thereafter, many different definitions have been used to characterize sodium sensitivity, depending on whether the protocol assessed acute or chronic changes in BP measured by office or ambulatory BP. In this respect, it has been suggested that acute changes in sodium balance may not adequately reflect the situation obtained with long-term changes in sodium intake, and that ambulatory blood pressure monitoring could be a more reliable way of measuring the salt-induced changes in BP [6]. The arbitrary dichotomization of the population has also been questioned. Indeed, the distribution of salt-induced changes in BP is normal and there is no evidence for a bimodal distribution. Therefore, a salt-sensitive population could not be clearly defined. At last, there have always been some concerns about the reproducibility of the determination of salt-sensitivity [7,8]. Despite these criticisms, salt-sensitivity of BP remains a topic of clinical interest because of its public health impact as a high salt-sensitivity has been associated with an increased risk of cardiovascular events and death [9]. The Genetic Epidemiology Network of Salt Sensitivity (GENSALT) research program [10] is the largest clinical study performed in humans on the salt-sensitivity of BP. The main objectives of this family-based study were to localize and identify genes related to BP responses to dietary sodium and potassium interventions. The study involved more than 3000 Chinese participants from 658 families and used a very strict protocol to assess the sodium and potassium-sensitivity of BP. All participants were exposed to three 7-day dietary interventions: the first one was a 7-day low-sodium diet (about 50 mmol sodium/day) followed by a 7-day high-sodium feeding (about 300 mmol sodium/day) and a 7-day high-sodium feeding with an oral potassium supplementation (60 mmol/day). Blood pressure was measured several times using a random-zero sphygmomanometer. Importantly, none of the participants were treated for hypertension or diabetes, thereby excluding any interference of drugs with the analysis of the effect of sodium and potassium on BP. The adherence to dietary interventions was particularly exceptional in this study. Salt-sensitivity was defined as a change in absolute SBP by at least 5 mmHg or a change in percentage SBP by at least 5% from the low-sodium intervention to the high-sodium intervention, and potassium-sensitivity was defined as a change in absolute SBP by at least 5 mmHg or a change in percentage SBP by at least 5% from the high-sodium intervention to the potassium supplement intervention. Interestingly, a reproducibility sub-study was performed using the exact same protocol 4.5 years after the first one which confirmed the good reproducibility of the procedure [11]. It is in the context of the GENSALT study that Rebholz et al.[12] conducted their study published in this issue of the Journal of Hypertension. The goal of this sub-analysis was to investigate the association between urinary angiotensinogen and the salt and potassium-sensitivity of BP. Why angiotensinogen? Angiotensinogen is the main substrate of the renin–angiotensin cascade produced essentially in the liver. However, there is good evidence that angiotensinogen can be synthesized by renal proximal tubules. Experimental studies have demonstrated that the production of angiotensinogen in the kidney can be up-regulated in some circumstances and in particular in response to angiotensin II leading to a positive feedback loop [13]. Therefore, high intra-renal angiotensinogen levels may result in increased angiotensin II-mediated sodium reabsorption and the development of salt-sensitive hypertension. The detection of angiotensinogen in the urine may thus represent a useful biomarker of the intra-renal activity of the renin–angiotensin system [14]. Since the ability to modulate the activity of the renin–angiotensin system has been demonstrated as a major determinant of the salt-sensitivity of BP [15], the context of the GENSALT study was perfect to test the hypothesis of an association between the intra-renal renin–angiotensin system via urinary angiotensinogen and salt-sensitivity of BP. To this purpose, Rebholz et al. measured urinary angiotensinogen in the urines of 100 unselected participants to the GENSALT study. The association between baseline as well as diet-induced changes in urinary angiotensinogen was investigated in relation to the sodium and potassium-induced changes in BP. The main finding of this analysis was not only that urinary angiotensinogen correlates with BP in these participants but also that elevated baseline levels of urinary angiotensinogen, per se or corrected for urinary creatinine excretion, are positively associated with a higher BP during the high-sodium intervention. This observation suggests that the urinary excretion of angiotensinogen could be an indirect marker of sodium-sensitivity of BP. In contrast, the association of urinary angiotensinogen with potassium-sensitivity was much weaker and probably not useful. The data published by Rebholz et al. are interesting in several ways. Firstly, they confirm the role of the renin–angiotensin–aldosterone system in the pathophysiology of salt-sensitive hypertension – a role that has been demonstrated by numerous experimental and clinical studies [7,16,17]. The additional information gathered with these results is that the intra-renal activity of the renin–angiotensin system also contributes to the development of salt-sensitive hypertension. Secondly, although urinary angiotensinogen was measured only in 100 participants of the GENSALT study, it remains one of the largest studies evaluating urinary angiotensinogen and salt-sensitivity in humans without impaired renal function. Indeed, some earlier studies have reported an association between urinary excretion of angiotensinogen and salt-sensitivity, but patients enrolled were suffering from renal diseases which are known to affect sodium excretion [18,19]. Among the multiple mechanisms leading to the development of salt-sensitive hypertension, the ability of the kidney to excrete sodium was undoubtedly the key factor. A reduced capacity to excrete sodium can be the consequence of anatomic, hormonal, hemodynamic as well as genetic factors such as polymorphisms of channels affecting renal tubular sodium transport [20]. The third interest of the results presented by Rebholz et al. is the potential use of urinary angiotensinogen as a marker of salt-sensitivity that could help to distinguish salt-sensitive from salt-resistant individuals. Unfortunately, in their study, Rebholz et al. investigated only the association between urinary angiotensinogen excretion and salt-sensitivity of BP. In fact, they could have taken the opportunity of the large number of participants and patients included in the GENSALT study to evaluate the predictive values of urinary angiotensinogen to identify salt-sensitive patients. Today, the concept of salt-sensitivity of BP can hardly be applied in clinical practice because the protocols proposed to identify salt-sensitive patients are far too complex and limited to clinical research projects. Thus, although it is estimated that almost 50% of hypertensive patients are salt-sensitive, physicians can only suspect a salt-sensitive hypertension based on clinical characteristics such as the patients’ age (>65 years), the presence of a reduced renal function whatever its cause, or a clinical diagnosis associated with an increased likelihood of a salt-sensitive form of hypertension (e.g. primary hyperaldosteronism, obesity-associated hypertension, or obstructive sleep apnea). With this approach, physicians may miss many diagnoses of salt-sensitive hypertension developing, for example, in younger patients with a reduced number of nephrons because of a low birth weight or prematurity or a monogenic form of hypertension [21,22]. Thus, today there is a definite need to develop markers of salt-sensitivity that could be used clinically. These markers should be easy to obtain, cheap, reliable, and with a good positive predictive value. Measuring angiotensinogen in the urine might perhaps be one of these markers. However, today we do not have sufficient data to confirm the interest of measuring urinary angiotensinogen to detect salt-sensitivity in hypertensive patients. Yet, the GENSALT database with its very strict protocol probably contains all the necessary elements to study further the clinical utility of various new markers of salt-sensitivity of BP in humans, including urinary angiotensinogen. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.