Current problems in hypertension and nephrology

Abstract

The aim of this issue of Expert Opinion on Pharmacotherapy is to present the most important and controversial problems in hypertension and nephrology. To this end, the most important points of the current (2009) recommendations of the European Society of Hypertension (ESH) are discussed, including aspects related to the treatment of hypertension – the role of beta-blockers, combined therapy with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) the treatment of hypertension in elderly patients, and role of destiffening therapy. The authors also present current recommendations for the management of dyslipidemia in hypertensive and chronic kidney disease (CKD) patients, and new strategies to prevent cardiovascular risk in CKD patients, the optimal level of blood pressure in patients with hypertensive nephropathy and which hypotensive drugs are the most nephroprotective. The Editors are aware that many other important problems have not been addressed in this issue of the journal; however, they hope the readers find it interesting and useful.

Keywords::

• chronic kidney disease
• current problems
• hypertension

In October 2009, the European Society of Hypertension (ESH) presented its updated recommendations, many points of which were crucial improvements on earlier statements [1]. Since then, there has been an increase in the number of papers on the subject of hypertension – raised blood pressure (BP) – and on a subject very closely connected to hypertension – chronic kidney disease (CKD). These two specializations complement one another and studies looking at either hypertension or nephrology alone are becoming much less common. This is completely understandable, as hypertension can cause kidney impairment and failure and kidney disease can cause hypertension and enhance the development of cardiovascular disease. It is therefore important to be up to date with the most current achievements in these subjects [2].

The aim of this issue of Expert Opinion on Pharmacotherapy is to present the most important and controversial problems in hypertension and nephrology. We found this to be difficult, as many extensive reviews that discuss these problems are already available. Nevertheless, we think that, with the great help of the invited experts, we have succeeded and that readers will be able to find the answers to many important questions in this issue. However, we are conscious that we have not discussed all the possible problems, and that the choice we made was very subjective. Nonetheless, we hope you find this issue interesting and useful.

The current recommendations of the ESH – as well as trials and meta-analyses that have been published since the recommendations were announced – are detailed extensively in the paper by Gaciong and Symonides [3], who emphasize the fact that, despite continuously accumulating data, many decisions about the hypertension management must still be taken without the support of evidence from clinical trials. For example, we still do not know the optimal strategy for dealing with patients with stage 1 hypertension and there is uncertainty about whether subjects with BP in the range 140 – 149/90 – 99 mmHg would benefit from antihypertensive treatment [1-3]. Conversely, available data from clinical trials do not support the view that lowering BP that is < 130 mmHg in high-risk patients provides an additional benefit [2,4] as this is also connected with the J-curve phenomenon, especially in patients with hypertension, diabetes, and coronary artery disease (and probably also with ventricular dysfunction) [4-6]. Gaciong and Symonides [3] also discuss the drug choice strategy in patients with hypertension [3]. Basic drug classes [diuretics, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), calcium antagonists and beta-blockers] can all be considered suitable for both initiation and maintenance of hypertension and the choice of antihypertensive drugs should be based on clinical condition [1,3,7]. Because most hypertensive patients require multiple drug therapy for effective control of their BP (in many European countries, BP is controlled effectively only in 25 – 30% of patients), treatment with a fixed-dose combination (and the current use of polypills) may offer a valuable option for more effective BP reduction, in consequence decreasing the therapeutic inertia and improving the patient's compliance [1-3,8].

This subject is also addressed by Ruilope and Segura [9], who present the current state of knowledge on the use of ACEIs and ARBs in the treatment of hypertension. In their interesting paper they suggest that suppression of the renin–angiotensin system (RAS) with ACEIs or ARBs in monotherapy is associated with beneficial cardiovascular effects, but that such treatment has several limitations due to angiotensin breakthrough [9,10]. They note that dual blockade with aldosterone receptor antagonists has beneficial effects in nephropathies and in heart failure in a small percentage of patients. Therefore, they highlight the need for further studies with direct renin inhibitors and aldosterone receptor antagonists, which will probably increase the benefits of dual blockade. They might also support the reduction of cardiovascular events with an adequate safety profile using these combinations [9].

The British recommendations on BP lowering (2004) resulted in beta-blockers being almost ‘cursed’ as hypotensive drugs. Fortunately, the 2007 ESH guidelines were not so restrictive and the current recommendations (2009) indicate beta-blockers (especially carvedilol and nebivolol) as drugs of preference in the treatment of hypertension [7]. This issue is presented in detail in the paper by Aronow [11], who concludes that, on the basis of the available data, beta-blockers should be used to treat hypertension especially in patients with prior myocardial infarction, acute coronary syndromes (ACS), angina pectoris, congestive heart failure, ventricular arrhythmias, supraventricular tachyarrhythmias, diabetes mellitus, and after coronary artery bypass graft surgery, as well as in patients who are pregnant, have thyrotoxicosis, glaucoma, migraine, essential tremor, perioperative hypertension, or an excessive BP response after exercise [11]. Aronow emphasizes that beta-blockers could be used as preferable therapy in patients with primary hypertension, but that atenolol should not be used in the treatment of hypertension [11]. He suggests the beta-blockers carvedilol and nebivolol should be used as the treatment of choice in hypertension [7,11]. However, further well-designed clinical trials are necessary to investigate the efficacy of carvedilol and nebivolol in reducing all main endpoints (mortality, myocardial infarctions, strokes, and congestive heart failures) in patients with primary hypertension [11,12].

Gąsowski et al. discuss another important subject – hypertension therapy in elderly patients [13], a problem that was controversial until the Hypertension in the Very Elderly Trial (HYVET) was published [14]. They show that treatment of hypertension in elderly patients is very beneficial, as it significantly reduces cardiovascular events [13]. However, date are still lacking; for example, none of the trials in elderly hypertensives includes patients with mild isolated systolic hypertension with systolic BP (SBP) in the range 140 – 150 mmHg, which means that there is a lack of trial evidence for the guideline recommendation to lower SBP in such individuals to < 140 mmHg [13-15]. This is connected with the fact that the only available trial that tested the above hypothesis – the Japanese Ttrial to Assess Optimal Systolic blood pressure in elderly hypertensive patients (JATOS) trial – yielded negative results [13,16]. Both issues need to be resolved as soon as possible to avoid unnecessary treatment or to avoid unnecessary cerebrovascular and cardiovascular morbidity and mortality [13].

Elisaf et al. [17] and Rysz and colleagues [18] discuss the very important subject of dyslipidemia treatment in patients with hypertension or chronic kidney disease (CKD), respectively. This is especially relevant because dyslipidemia often coexists with hypertension and CKD, significantly hastening the development of atherosclerosis and increasing the risk of cardiovascular events [19]. Elisat et al. suggest that statins might favorably affect BP in both normolipidemic and hyperlipidemic patients with hypertension [17]. They emphasize that the combination of statins with several categories of antihypertensive drugs, especially with those that improve vascular endothelial function, including ACEIs and calcium channel blockers, may offer a preferential BP-lowering effect [17]. However, when evaluating the antihypertensive effect of statins, one should take into account the small number of groups that were studied, the technical differences in BP measurements, and the possible heterogeneity of the effects of statins on BP in different subjects (e.g., male vs female, young vs old, normocholesterolemic vs hypercholesterolemic, and hypertensive vs normotensive), which may be responsible for the discrepancies in the findings [17]. What is more, no trials have evaluated blood pressure reduction with statins as a main endpoint [20]. All these things considered, appropriately designed, long-term, large-scale studies are necessary to assess the impact of BP lowering associated with statin treatment on clinical outcomes [17-20].

Similar doubts were listed by Rysz et al. [18] when evaluating the role of statins in CKD patients. It is therefore necessary to perform further, large, randomized clinical trials with well-designed study groups and endpoints [21]. Rysz et al. recommend that although the results of available studies are conflicting, the evidence suggests that the benefits of using statins outweigh the drawbacks in patients with CKD in the early stages when their benefits can be effectively predicted [18,21]. However, available large, randomized clinical trials suggest the lack of their efficacy in patients on renal replacement therapy, recent meta-analyses and other papers have confirmed these suggestions [18].

The subject of nephroprotection with other drugs used in the treatment of hypertension is discussed extensively in the review by Cravedi et al. [22]. The authors emphasize that hypertension is a major independent risk factor for renal disease progression and that effective BP reduction is therefore invariably nephroprotective [22]. However, they noticed that the best antihypertensive strategies were still not clearly defined and might vary across different patient populations [22]. There is a need for further large trials to answer all such questions on this subject, including the assessment of the ideal target BP levels for patients with CKD [22]. This is connected to the fact that available large trials showed that BP reduction under the currently suggested target of 130/80 mmHg does not offer any additional renoprotective effect, whether this is obtained by using antihypertensive drugs not affecting the RAS or in patients with limited proteinuria [22,23]. Conversely, in patients with a greater degree of proteinuria, further BP reduction with ACEIs and ARBs at maximum tolerated doses can further reduce the proteinuria and the rate of renal disease progression [22-25]. Finally, Cravedi et al. conclude that although clear data from the trials are missing, it seems reasonable that the treatment of hypertension in patients with proteinuric CKD should start with ACE inhibitors and ARBs at doses that are progressively up-titrated to blunt proteinuria [22]. The use of diuretics should be considered to maximize the antiproteinuric effect of these drugs, as should add-on therapy with aldosterone antagonists or renin inhibitors; dihydropyridine calcium channel blockers may have a role in patients with uncontrolled hypertension but are not recommended as the first-line therapy [22].

The above problem is further continued in the paper by Bakris et al. [26], who point out that effective therapeutic strategies and prevention of hypertensive nephropathy should be the focus so as to slow the inexorable decline in renal function and high incident rates of end-stage renal disease (ESRD) worldwide [26]. They recommend that the main points of such a strategy must include: i) adequate 24-h control of BP control; ii) at least a 30% reduction in albuminuria from initiation of therapy; iii) the use of agents that inhibit the RAS, such as ACEIs or ARBs; iv) enough antihypertensive medications at maximally tolerated doses to achieve a BP goal of < 130 mmHg; and v) restriction of sodium intake to 2.4 – 3 g/day [26]. They also emphasize that the BP goal should be achieved within 4 months in most patients with hypertensive nephropathy using the recommended strategies to decrease the risk of worsening of renal function and cardiovascular events [26].

Another important subject in contemporary hypertensiology is described in the paper by Safar and Jankowski [27], who present the achievements of destiffening therapy in hypertensive patients [27]. It has been found possible to produce a selective SBP reduction through a significant decrease of aortic stiffness and/or wave reflections [27]. Safar and Jankowski suggest that destiffening therapy is especially effective in decreasing central SBP and pulse pressure, which have been shown to be major determinants of long-term outcome [23,27]. Most of the protocols used to destiffen arteries require the administration of agents blocking the RAS, which is frequently combined with a diuretic or a calcium antagonist. Safar and Jankowski emphasize that the available trials on the subject have shown better cardiovascular outcome in patients prescribed the above destiffening therapy than in those who did not receive this treatment [23,27].

Finally, Rodriguz-Iturbe and Correa-Rotter [28] present new strategies to prevent cardiovascular risk in CKD; this is a summary of almost all the above papers. The authors present the most current data on the prevalence and incidence of cardiovascular disease in the different stages of CKD, summarize the risk factors of cardiovascular disease in patients with reduced renal function, and examine treatment strategies for nontraditional risk factors and lifestyle modifications that are important for patients with CKD [28]. They emphasize that lifestyle modifications – including weight control, cessation of smoking, and dietary salt restriction – might have a major impact on cardiovascular morbidity and mortality in patients with CKD [28]. An additional benefit may be gained by treating nontraditional cardiovascular risk factors that are characteristic of CKD [28].

We are aware that we could not present all the important problems of contemporary hypertensiology and nephrology. For example, there is still much discussion on whether we should treat high-risk patients with high normal BP (with prehypertension), although the current ESH guidelines do not recommend such therapy [1,29,30]. Many other important problems have not been addressed in this issue of the journal. However, we hope that you will find it interesting and useful. Finally, we would like to thank all the editors of Informa Science, and especially all the authors who agreed to take part in this project.

Declaration of interest

M Banach is the Guest Editor of this issue and declares no conflicts of interest with this paper or any of the themed papers in this issue. J Rysz declares no conflicts of interest with this paper.