Hypertension in autosomal dominant polycystic kidney disease: is renin acquitted as a culprit? (2006)

Autosomal dominant polycystic kidney disease (ADPKD) is one of the more common causes of endstage renal disease (ESRD). According to the data of United States Renal Data System. ADPKD accounts for approximately 2.9% of incident cases with ESRD or approximately 5.4 per 106 per year. The prevalence of ADPKD in the age group 55–59 years was estimated to be 261 per million population [1]. Recently, ADPKD has become extremely exciting as we move ever closer to understanding the molecular consequences of the two major mutations that account for this disease, PKD1 and PKD2 [2–5]. Following studies in Caenorhabditis elegans, it has been recognized that a malfunction of cilia in the tubular lumen underlies this condition, which is presumably a defect of sensing of the tubular fluid flow and, accordingly, adjustment of the tubular lumen [6]. Potential novel therapeutic approaches, either currently under investigation or on the drawing board, include antagonists of the vasopressin receptor type 2 [7–9] and inhibitors of the mTOR kinase (e.g. rapamycin) [10]. Nevertheless, practically the only handle on intervention is blood pressure control. Hypertension is usually the earliest clinical abnormality in this condition [11–14] and, when the stage of ESRD is reached, virtually all patients suffer from hypertension. Why is hypertension clinically important? In all types of renal disease, blood pressure is an important, if not the single most important, factor promoting the progressive loss of renal function [15,16]. This is true even for blood pressure values within the normotensive range [17]. Blood pressure values, and even a family history of essential hypertension, are powerful predictors of renal outcome [18] and of the rate of loss of glomerular filtration [19]. This was recently confirmed in a prospective study of patients with ADPKD [20]. Apart from the scientific interest in clarifying the pathogenesis of progression in ADPKD, documenting the role of activation, if any, of the renin–angiotensin system (RAS) potentially has consequences for the selection of the first-line antihypertensive agent in this disease. For proteinuric renal diseases, the guidelines state that pharmacological blockade of RAS is the first-line treatment [21], and we agree, despite some recent opinions to the contrary [22]. But what about ADPKD? The intensity of protein excretion predicts the rate of loss of renal function, although it remains usually, but not always [23], below the threshold of 1 g/day [14,24]. ADPKD differs from most other renal diseases with respect to target blood pressure. In the MDRD trial (modification of diet in renal disease), the benefit from lowering blood pressure below 140/90 mmHg could not be proven in patients with proteinuria < 1 g/day and these mostly comprised patients with ADPKD [25]. Apart from the target blood pressure, a further dilemma exists concerning the selection of the appropriate antihypertensive agent. There is no agreement as to whether RAS blockade in ADPKD patients, which was effective in one animal model [26], is the preferred treatment [13,27,28] or not. The latter case was suggested by one relatively short-term controlled prospective study in early ADPKD that failed to demonstrate a benefit with respect to loss of glomerular filtration rate (GFR) [29], although the potential impact of RAS blockade on cardiovascular risk must not be ignored [13]. All the available studies can be criticized on some methodological grounds or another. We will have to live with this unsatisfactory evidence because the unique evolution of renal function in ADPKD will render controlled comparisons extremely difficult: typically, a prolonged phase of stable GFR is usually followed by a sudden onset of fast GFR decline [30]. Then there are conflicting reports concerning whether or not RAS is activated in the first place, or at least inappropriately with respect to the prevailing blood pressure and sodium state. It is in this context that the study by Doulton et al. [31], as reported in the last issue of the journal, provides substantial, although not absolutely complete, clarification. The rationale for the present investigation goes back to the study of the Denver group [32]. These authors measured plasma renin activity (PRA) in ADPKD patients on their habitual salt intake, and found that PRA was no different from that in normotensive controls. However, when they compared PRA values in these patients with the PRA values of patients with essential hypertension, matched for blood pressure, they found that supine and upright values were inappropriately elevated. This finding would have been plausible given the severely stenosing vascular lesions seen in the kidneys of ADPKD patients [33]. Doulton et al. [31] argue correctly that the comparison is valid only if (apart from blood pressure) the sodium state is matched as well. To this end, they compared PRA in normotensive controls and in ADPKD patients who had normal renal function and no antihypertensive treatment. In all subjects, PRA was measured at two levels of sodium intake after the steady state had been reached. The outcome was clear: there was no significant difference, excluding absolute or relative [32] overactivity of the RAS in ADPKD. Their methodology is impeccable, but the study has certain limitations. Not surprisingly, in view of the complexity of the protocol, the sample size was somewhat small, raising the issue of statistical power. Indeed, the authors performed a beta error calculation showing that the study would fail to detect a difference in mean arterial pressure of 10.9 mmHg when changing from high salt to low salt. Thus, the statement of no difference is correct only within these limits. However, to put their finding into perspective, it should be mentioned that, in ADPKD, powerful alternative mechanisms have been documented that raise blood pressure. For example, sympathetic overactivity is found in ADPKD patients even when the GFR is still perfectly normal [34]. Furthermore, the study by Doulton et al. [31] only addressed the systemic RAS. The authors point out that they did not study renal haemodynamics, which would have been of interest for several reasons. There are conditions where the systemic RAS is suppressed and PRA is low, yet the intrarenal RAS system(s) is activated. For example, Price et al. [35] measured renal plasma flow (RPF) in patients with type 2 diabetes who typically had low PRA. After RAS blockade, the investigators observed an exaggerated increase of RPF, indicating that, before intervention by RAS blockade, RPF had presumably been constrained by angiotensin II, which was obviously generated by local intrarenal RAS systems [36,37]. As the authors acknowledge, this point is not trivial because local generation of angiotensin II may impact on progression by hemodynamic and non-hemodynamic actions [38]. Conceivably, such patients might benefit from RAS blockade even when the activity of the systemic RAS is low, as for example in type 2 diabetes. There is some evidence, although admittedly not overwhelmingly stringent, for activation of local intrarenal RAS. Most convincing is the demonstration of aberrant renin production within cyst walls [39] and by immortalized ADPKD cells [40], as well as angiotensin II production by ADPKD kidney extracts, albeit non-classically via chymase [41]. What conclusions can be drawn from this study? I agree with the authors that the finding softens the argument that RAS blockade is obligatory in ADPKD [21], although the issues of potentially activated intrarenal RAS systems and the potential effects of RAS blockade on cardiovascular events remain unresolved. A most impressive lesson taught by this study is that the authors have again documented an impressive lowering of blood pressure in both renal patients and controls, and an amplified blood pressure response to angiotensin-converting enzyme inhibition by the restriction of sodium intake. One must sadly admit that this intervention, which the investigators had proposed with much enthusiasm for decades, unfortunately had little impact in the renal community. This is the more surprising because sodium restriction not only lowers blood pressure, but also has blood pressure-independent beneficial effects [42–44] in animals, and presumably also in patients with renal disease, such as a decreased generation of reactive oxygen species. Such neglect is even more surprising because the beneficial effect of salt restriction on the course of renal disease has been known for almost a century [45].