Renal medullary blood flow and essential hypertension

In this issue of Acta Physiologica, Assersen et al report experiments assessing renal medullary blood flow as a potential determinant of essential hypertension.1 Specifically, using a highly sophisticated approach, the authors determined changes in renal medullary blood flow in response to acute volume expansion in mildly hypertensive patients and normotensive controls. Contrary to the proposed hypothesis, renal medullary blood flow was similar in both groups. The data argue against a crucial role of renal medullary blood flow in the pathogenesis of essential hypertension.1 Hypertension is one of the major risk factors for cardiovascular disease, which is the number one cause of death in the Western hemisphere. In approximately 10% of cases, hypertension is the consequence of other primary diseases, such as renal artery stenosis and hormone-producing tumours. Addressing this primary disease is key to causal treatment of hypertension in these patients. Conversely, 90% of hypertensive patients suffer from essential hypertension. The cause for essential hypertension is presumably multifactorial and, despite substantial research efforts, remains largely unknown. Consequently, the therapeutic options for treatment of essential hypertension are limited and interventions aim at lowering blood pressure rather than addressing the cause of hypertension. Arterial blood pressure is determined by the cardiac output in a given time and the total vascular resistance. As such, arterial blood pressure is a function of blood volume, respective of the extracellular volume. Homoeostasis of the extracellular volume is determined by a balanced intake of salt and water and concomitant excretion of the same amount of salt and water. The elimination of salt and water follows various pathways, including the skin, stool and urine, with elimination via the kidneys accounting for the bulk of salt/water excretion, and other excretion pathways are of minor relevance. If volume homoeostasis is challenged by changes in oral salt intake, healthy kidneys will adapt the reabsorption of salt to exactly counterbalance the intake. In an ideal situation, this adaptation of renal salt excretion does not imply any changes in arterial blood pressure. Consequently, in terms of blood pressure regulation, we would call such people salt-resistant. In one subpopulation, however, increased oral salt intake leads to the development of hypertension, which is commonly known as salt-sensitive hypertension. The percentage of people belonging to the salt-sensitive group is largely dependent on the ethnic background and accounts for approximately 25% of the population in the Western hemisphere. Thus, what is different in salt-sensitive compared with salt-resistant humans? According to the concept by Guyton and Coleman, salt-sensitive hypertension is caused by the (mechanistically undefined) inability of the kidney to excrete an adequate amount of salt at a given blood pressure. As a consequence, blood volume inevitably increases with salt intake, as do arterial pressure and renal perfusion pressure, which eventually promotes renal salt excretion. Although renal perfusion is normally well autoregulated, the autoregulation of the juxtamedullary nephrons was suggested to be less stringent, which results in alterations of medullary vasa recta perfusion. Increased perfusion of the vasa recta, in turn, promotes renal salt and water loss and, eventually, balances oral salt intake. In addition to the proposed passive changes of the vasa recta perfusion due to limited autoregulation, vasa recta perfusion is regulated directly by pericytes.2 Furthermore, the medullary thick ascending limb of Henle (mTAL) has the capacity to modulate vasa recta blood flow independent of the systemic pressure. In this context, a recent study in Dahl rats, an animal model of salt-sensitive hypertension, indicated that paracrine mTAL purinergic signalling modulated the tone of the vasa recta and that the vasodilatory component was compromised in salt-sensitive animals.3 On the other hand, the concept of a causal involvement of renal medullary blood flow in the pathogenesis of essential hypertension was recently questioned in a study using various rat models of hypertension, such as chronic angiotensin II infusion, uninephrectomy in combination with a high salt diet, and spontaneously hypertensive rats (SHR) respectively.4 When the renal medullary blood flow was increased by 50% by the infusion of bradykinin, renal medullary osmolyte concentrations declined but mean arterial pressure did not change. The results were similar in the three independent hypertensive models,4 which questioned the relevance of renal medullary perfusion in the context of salt-sensitive hypertension. It is somewhat surprising that, when challenged by an acute volume loading, hypertensive patients respond with an enhanced natriuresis compared with normotensive controls.1 The exact reason for this phenomenon remains unknown. Differences in endocrine regulatory networks between hypertensive and normotensive subjects may provide the basis for a more pronounced responsiveness to perturbation in the volume status of hypertensive patients. In this context, plasma atrial natriuretic peptide (ANP) concentrations were shown to be markedly increased in hypertensive vs normotensive subjects.5 Furthermore, depending on the degree of hypertension, an elevated blood pressure by itself will favour natriuresis, as mentioned above. The study by Assersen and colleagues adds important new insights to the yet unsolved patho-mechanisms of essential hypertension.1 The authors hypothesized that differences exist between normotensive controls and hypertensive patients regarding renal medullary blood flow, which may account for the exaggerated natriuresis of hypertensive patients in response to salt loading. In this context, studies in the Dahl salt-sensitive rat strain suggested that reactive oxygen species (ROS) are excessively generated in the hypertensive rat kidney and that ROS reduce renal medullary blood flow.6 From these data, and in view of the basic physiology of renal salt reabsorption and urinary concentrating ability, one would have predicted that the experiments by Assersen would confirm the hypothesis that there actually is a difference in renal medullary blood flow between normotensive controls and hypertensive patients. Surprisingly, this was not the case. In mildly hypertensive patients, acute volume expansion with saline (2.1% of body mass) caused an increase in mean arterial pressure by 7 mm Hg whereas no changes were observed in normotensive controls.1 Contrary to the hypothesis, renal medullary blood flow, as determined by combined PET/CT scanning, remained constant after volume loading, and this was the case for both hypertensive and normotensive subjects. Furthermore, there was no difference in baseline renal medullary blood flow between the groups, although there appeared to be some trend towards lower medullary blood flow in hypertensive compared with normotensive subjects. Even if this trend would have become significant with a larger number of patients, the absolute differences in medullary blood flow would be minor. Although differences between normotensive and mildly hypertensive subjects in renal medullary blood flow were clearly excluded from the present study, it should be noted that the patients who were enrolled in the study were mildly hypertensive.1 It appears reasonable to assume that the situation may be different when salt loading is applied to patients with severe hypertension. In these patients, renal autoregulation, and in particular the autoregulation of the juxtamedullary nephrons, likely reaches the upper limit of the regulatory range, and, consequently, may be more susceptible to additional perturbations, such as acute volume expansion. In addition, the renal autoregulatory capacity of hypertensive patients may be compromised due to hypertensive vascular damage. The latter, of course, again would be more relevant in patients with severe hypertension. Thus, what might be the reason for the exaggerated natriuresis in response to volume expansion in hypertensive compared with normotensive subjects? As the authors suggested, neurohumoral factors most likely account for this phenomenon. It should be noted that a recent study by the same authors, ANP plasma concentrations in patients with essential hypertension were almost twice those determined in normotensive controls, as mentioned above.5 Furthermore, after sodium loading, ANP levels increased in control subjects but nevertheless remained lower than in hypertensive patients.5 Increased ANP levels would eventually favour sodium excretion by reducing tubular sodium reabsorption. Similarly, rapid increases in vasopressin reduced sodium excretion, and the vasopressin plasma concentrations decreased during volume loading in hypertensive patients but not in normotensive controls,7 again favouring exaggerated natriuresis in hypertensive subjects. Although, as outlined by Assersen, the isolated effect of vasopressin on the exaggerated natriuresis in hypertensive patients is presumably minor, it may represent one contributing factor among several (mostly undefined) others. Although the results of the study by Assersen were largely negative, the data add an important piece to unraveling the puzzle of the pathogenesis of essential hypertension.1 Furthermore, the study is an excellent example of how our concerns regarding the publication of negative results are unfounded. Let us keep in mind that the rejection of a hypothesis is just as valuable as its confirmation! I have no conflicts of interest to declare.