Current problems in hypertension and nephrology

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.     

Mechanisms responsible for renoprotective effects of renin-angiotensin inhibitors

In recent years, the focus of interest on the role of the renin-angiotensin system (RAS) in the pathophysiology of hypertension and organ injury has changed to a major emphasis on the role of the local RAS in specific tissues. In the kidney, all of the RAS components are present and intrarenal angiotensin II (Ang II) is formed by independent multiple mechanisms. Ang II is compartmentalized in the renal interstitial fluid and the proximal tubular compartments with much higher concentrations than those existing in the circulation. It has also been revealed that inappropriate activation of the intrarenal RAS is an important contributor to the pathogenesis of chronic kidney disease (CKD). Indeed, most national guideline groups now recommend the use of RAS inhibitors in preference to other antihypertensive agents for hypertensive patients with CKD. In this review, we will briefly summarize our current understanding of independent regulation of the intrarenal RAS. We will also discuss the impact of RAS inhibitors in preventing the progressive increases in the intrarenal RAS during the development of CKD.     

Which antihypertensive drugs are the most nephroprotective and why?

Importance of the field: Hypertension is a major independent risk factor for kidney disease and for faster renal function loss. Choice of antihypertensive strategies with highest nephroprotective effect is crucial to prevent or reverse progression to end stage renal disease (ESRD).

Areas covered in this review: The present review focuses on the role of hypertension in the progression of chronic kidney disease (CKD), the renoprotective effects of different antihypertensive therapies, and the blood pressure levels that should be targeted in different patient populations. To this end, the PubMed (1975 – 2010) database was searched for English-language articles, using the following keywords: hypertension, kidney disease, ACE-inhibitor, angiotensin receptor blocker, aldosterone antagonist, renin inhibitor, proteinuria.

What the reader will gain: A comprehensive review of data on the association between hypertension and progression of chronic nephropathies and on the antihypertensive treatments with highest nephroprotective effects.

Take home message: Blood pressure should be targeted to 140/90 mmHg or less in patients with hypertension but no renal injury and 130/80 mmHg or less in those with CKD. Amongst different antihypertensive drugs, renin angiotensin aldosterone system (RAAS) inhibitors have an incremental nephroprotective effect in proteinuric patients. Maximal RAAS inhibition should be aimed to optimize renoprotection in hypertensive patients with CKD and proteinuria.     

Hypertensive nephropathy: prevention and treatment recommendations

Importance of the field: A worldwide epidemic of chronic kidney disease (CKD) exists; hypertensive nephropathy is second only to diabetes as a leading cause of progressive CKD. Due to the increasing morbidity and mortality and escalating costs associated with end-stage renal disease (ESRD), novel therapeutic strategies are needed urgently to maximally reduce albuminuria, control blood pressure, and delay progression of hypertensive nephropathy to ESRD. In particular, rational use of renin–angiotensin–aldosterone (RAAS) blockers and achieving blood pressure targets are crucial to reduce cardiovascular and renal outcomes.

Areas covered in this review: We discuss the pathophysiology of hypertensive nephropathy and review current research evidence in support of i) albuminuria reduction as a key factor to maximally slow CKD progression, ii) the blood pressure (BP) goal of < 130 mmHg, and iii) strategies for prevention and optimal treatment of hypertensive nephropathy.

What will the reader gain: Insight into the complexity of treating patients with hypertensive nephropathy and the effective strategies required for reducing albuminuria, achieving BP goals and delaying progression of hypertensive nephropathy.

Take home message: Patients with hypertensive proteinuric nephropathy need aggressive BP-lowering with multiple agents that should include RAAS blockers, calcium antagonists and diuretics to maximally slow progression to ESRD.     

Reduction of blood pressure in patients with treatment-resistant hypertension

Background: Resistant hypertension is a common clinical problem, and patients with resistant hypertension have increased cardiovascular risk. It is a subset of the hypertensive population that is little studied and poorly characterized. Objective: The purpose of this review is to discuss resistant hypertension, its recognition and diagnostic workup and management, and to present current data about the disease from the latest research. Methods: We define resistant hypertension and differentiate it from pseudoresistance. We identify diagnostic tests that may be done on patients with resistant hypertension. Last, we discuss therapeutic approaches to resistant hypertension, focusing on pharmacological treatment, and present an algorithm that may be used by the clinician in treating a patient with resistant hypertension. Conclusion: Resistant hypertension is a significant clinical problem commonly encountered by clinicians. Patients with resistant hypertension have increased cardiovascular risk. In evaluating for resistant hypertension, it is important to recognize elements that contribute to pseudoresistance to treatment. Secondary causes of hypertension are common in patients with resistant hypertension and should be included in the diagnostic workup. Pharmacological treatment for resistant hypertension entails choosing medications with complementary mechanisms of action, optimizing diuretic use, and considering the use of mineralocorticoid antagonists as an add-on agent to the antihypertensive regimen.     

Is there a future for direct renin inhibitors?

Importance of the field: The renin-angiotensin-aldosterone system (RAAS) is a key regulator of blood pressure (BP), as well as volume and electrolytes, in both hypertensive and normotensive individuals. Inappropriate activation of the RAAS is important in hypertension-induced cardiovascular disease (CVD) and chronic kidney disease (CKD). Renin is the rate-limiting step in the RAAS cascade, which makes direct renin inhibitors (DRIs) an attractive target for RAAS suppression and treatment of hypertension. Current regimens using either angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) result in feedback upregulation of renin and aldosterone breakthrough, which contribute to incomplete suppression of the RAAS. Thereby, aliskiren – alone or in combination – might offer a novel therapeutic intervention to improve suppression of the RAAS, with potential to translate to improved CVD and CKD outcomes.

Areas covered in this review: Herein, we present the current state of knowledge of DRIs in the preclinical and clinical realm and their antihypertensive efficacy in relation to cardiovascular and renal risk. Recent clinical trials (2007 – 2009) support the efficacy of aliskiren, and studies suggest the potential for improved CVD and CKD outcomes.

What the reader will gain: An understanding of the mechanism of action of DRIs and a perspective of recent clinical trials.

Take home message: The DRI aliskiren is an effective antihypertensive agent that preliminary data suggests has a beneficial effect in CVD and CKD. Combination of aliskiren with an ACEi or ARB may be better tolerated than the ACEi–ARB combination. Future work is needed to further quantify aliskiren's impact on hard CVD and CKD end points.     

Evaluation of the impact of pharmaceutical care service on hospitalized patients with chronic kidney disease in Jordan

Objectives The primary goal of the present study was to implement and evaluate the impact of pharmaceutical care service for hospitalized chronic kidney disease (CKD) patients in Jordan. Setting Nephrology wards of one of the largest general hospitals in Jordan. Methods All patients who were previously diagnosed with CKD by their physician were eligible for inclusion in the study. Recruited patients were fully assessed for treatment related problems (TRPs) by a clinical pharmacist. Pharmaceutical care service was assessed through a systematic, prospective before–after design. Chi Square test was used to investigate association between categorical variables. P value <0.05 was considered to be statistically significant. Main outcome measures Study outcomes included: Process outcomes (prevalence and nature of identified TRPs, clinical significance of TRPs, associated diseases and drugs), General clinical outcomes (Therapeutic outcomes of TRPs) and CKD specific clinical outcomes (Change from baseline in the number of patients receiving appropriate progression modifying therapy and appropriate management of complications). Results 130 patients were included in the study. The average number of the identified TRPs was 5.31. Eighty-six percent of the recommendations were accepted by physicians. Efficacy related problems were the most common TRP category. Seventeen percent of all TRPs were resolved, 5.5 % were improved, and 37.4 % were prevented through the clinical pharmacist interventions. Conclusions The current study indicated that hospitalized patients with CKD suffer from multiple TRPs mostly related to efficacy of medications and patients monitoring. Clinical pharmacists substantially contributed towards the care of hospitalized CKD patients through optimizing progression modifying therapies, medications safety and management of CKD complications. Based on this study it is strongly recommended to implement pharmaceutical care services for hospitalized CKD patients.     

Combination drug versus monotherapy for the treatment of autosomal dominant polycystic kidney disease

Introduction: Despite progress in the understanding of pathogenetic mechanisms of organ cyst formation in autosomal dominant polycystic kidney disease, current treatment methods are insufficient. Experimental studies and clinical trials target at inhibition of cysts development and to slowing CKD progression.

Areas covered: The purpose of this analysis is to overview available literature regarding treatment of ADPKD. The most important recent events concerning ADPKD treatment are: the results of TEMPO 3/4 study and the registration of tolvaptan in the treatment of patients with CKD stage I-III and rapidly progressive ADPKD by EMA. ERA-EDTA recommendations for use of tolvaptan in ADPKD of 2016 will be useful for the identification of patients with rapid progression of disease who will benefit most from treatment. Clinical trials concerning inhibitors of mTOR and SSAs have not delivered convincing evidence of their effectiveness. Usefulness of statins in ADPKD require confirmation in adults. The HALT-PKD study confirmed that inhibition of RAA system slows progression of ADPKD.

Expert opinion: Current treatment of ADPKD involves: the optimization of life style and combined pharmacological treatment with ACE inhibitors or angiotensin receptor blockers, statins (patients with lipid disorders and cardiovascular disease) and tolvaptan (patients with stage I-III CKD and rapidly progressive ADPKD).     

Role and significance of statins in the treatment of hypertensive patients

ABSTRACT

Background: Statins are the first-line drug therapy in the treatment of hypercholesterolemia. The beneficial clinical impact of statins on the cardiovascular system results not only from their lipid-lowering action but also from other effects. Recently, it has been suggested that statins can reduce blood pressure, especially in hypertensive patients.

Aim: The role of the hypotensive action of statins and other mechanisms which reduce cardiovascular risk in hypertensive patients are discussed in this review.

Methods: Electronic databases searched were [MEDLINE (1966 – February 2009), EMBASE and SCOPUS (1965 – February 2009), DARE (1966 -- February 2009)]. Additionally, abstracts from national and international cardiovascular meetings were studied to identify unpublished studies. The main data search terms were: blood pressure, hypertension, hypercholesterolemia and statins.

Findings: At present, it is difficult to unequivocally assess the impact of statins on blood pressure. However, according to most authors, the impact of statins on the decrease in BP is slight, but significant, especially among patients with hypertension.     

Cardiovascular disease in patients with renal disease: the role of statins

ABSTRACT

Objectives: Atherosclerosis is common in patients with chronic kidney disease (CKD), and cardiovascular disease (CVD) represents a major cause of death. The National Kidney Foundation guidelines favour the use of statin therapy for treatment of dyslipidaemia in patients with CKD. Much evidence supports statin therapy for reducing CVD and improving outcomes in the general population, but there is less evidence in patients with CKD. Consequently, prevention of CVD in CKD is based primarily on extrapolation from non-CKD trials. Significantly, in trials specifically designed to investigate patients with CKD, evidence is emerging for improved cardiovascular outcomes with statin therapy. This review describes available data relating to cardiovascular outcomes and the role of statins in patients with CKD, including pre-dialysis, dialysis, and renal transplant patients.

Research design and methods: The PubMed database was searched (1998–present) to ensure comprehensive identification of publications (including randomised clinical trials) relevant to CKD patients, patterns of cardiovascular outcome in such patients and their relationship to lipid profile, and the role of statins for the prevention and treatment of cardiovascular complications.

Results: There are conflicting data on the relationship between dyslipidaemia and cardiovascular outcomes, with one major study of statin therapy (4D – Deutsche Diabetes Dialyse Studie) providing equivocal results. Further studies, including AURORA (A study to evaluate the Use of Rosuvastatin in subjects On Regular haemodialysis: an Assessment of survival and cardiovascular events; NCT00240331) in patients receiving haemodialysis, and SHARP (Study of Heart And Renal Protection; NCT00125593) in patients with CKD including those on dialysis, should help to clarify the role of statin therapy in these populations.

Conclusions: More studies are needed to elucidate the role of statins in improving cardiovascular outcomes for CKD patients. It is anticipated that ongoing clinical trials geared towards the optimal prevention and treatment of CVD in patients with CKD will help guide clinicians in the management of CKD.     

Angiotensin receptor blockers: RAAS blockade and renoprotection

ABSTRACT

Introduction: Chronic kidney disease (CKD) is an increasingly prevalent public health concern and is associated with a high risk of adverse cardiovascular outcomes. Renal impairment is frequently associated with hypertension and there is compelling evidence of the benefits of antihypertensive therapy for reducing progression of kidney disease. The central role of the renin-angiotensin-aldosterone system (RAAS) in hypertension and renal disease has led to interest in the ability of RAAS-blocking agents to provide benefits beyond blood pressure control.

Scope: This review explores the mechanisms involved in CKD development, assesses markers of CKD progression, explores the role of the RAAS in renal disease, and examines RAAS blockade as a therapeutic option for renoprotection. For this purpose, a non-systematic literature review was conducted using the Medline database.

Findings: Studies in patients with diabetic renal disease have shown that RAAS blockade with angiotensin converting enzyme (ACE)-inhibitors or angiotensin receptor blockers (ARBs) reduces progression of renal disease. Similarly, several studies have demonstrated the benefits of ACE inhibitors in non-diabetic renal disease, although few studies have been conducted with ARBs in this setting. At present, there is little evidence to determine the relative merits of ARBs and ACE inhibitors in terms of clinical outcomes, although ARBs appear to have advantages in terms of renal haemodynamics and measures of renal function.

Conclusions: The beneficial effects of ARBs, which result from a combination of antihypertensive, haemodynamic, antiproteinuric and pleiotropic mechanisms, provide a strong rationale for considering the use of these agents in the treatment of high-risk patients.     

Safety issues related to erythropoiesis-stimulating agents used to treat anemia in patients with chronic kidney disease

Introduction: Erythropoiesis-stimulating agents (ESAs) have been the main therapy for anemia in CKD patients since the late eighties. Since then, treatment indications have progressively changed, together with a progressive increase in therapeutic targets, in terms of hemoglobin levels.

Areas covered: This paper discusses possible concerns about ESA use and increased cardiovascular risk (in particular stroke), hypertension, cancer progression and the development of pure red cell aplasia. A literature search was done on PubMed to obtain studies about the adverse effects of ESA in the CKD population.

Expert opinion: The publication of the TREAT study has largely contributed to the concerns about ESA use, indicating that complete anemia correction may not be safe in the CKD population. This may be particularly true in high-risk patients, especially if hyporesponsive to ESA treatment. However, there is a gray area of no evidence either way for intermediate levels (11.5 – 13 g/dl), in comparison with higher or lower levels. New recommendations about ESA use in the CKD population by the Food and Drug Administration seem to move toward treatment individualization.     

Control of blood pressure in the community: an unsolved problem

Available data indicate that blood pressure (BP) is reduced below 140-90 mmHg in less than 30% of hypertensive patients. This poor control of BP derives from lack of diagnosis (unawareness of hypertension), lack of treatment of aware hypertensive patients and lack of efficacy of treatment. Systolic BP (SBP) is now considered as the most important parameter for diagnosis and stadiation of hypertension, above all in elderly patients, and the most frequent cause of unsatisfactory control of BP in the population. Lack of SBP control is caused both by physicians' attitude and difficulty in reducing SBP. Physicians are more prone to consider diastolic BP as the most important parameter for diagnosis and stadiation of hypertension, decision to treat and intensification of treatment and therefore SBP is often forgotten and-or misinterpreted in this decision making process. On the other hand, since current antihypertensive drugs are equally effective in lowering SBP and DBP and-or less effective in lowering SBP more than DBP, SBP is often uncontrolled in treated patients with isolated systolic hypertension or prevalent increase in SBP. The possibility of obtaining better control of SBP in the future is linked to better education of physicians, who need to pay greater attention to SBP as a parameter for diagnosing, treating and intensifying treatment, and to the development of new drugs more active in reducing SBP.     

Systemic hypertension and nondiabetic chronic kidney disease: the best evidence-based therapeutic approach today

Despite the high prevalence and significant morbidity and mortality associated with high chronic kidney disease (CKD) in patients with hypertension, it remains vastly under-diagnosed and under-treated. Consequently, many patients develop kidney failure requiring dialysis or kidney transplant. Moreover, patients with CKD represent the group at highest risk from cardiovascular complications, even greater than patients with diabetes mellitus. Therefore, management of hypertension in such patients needs to be more aggressive compared to those with normal kidney function. This review provides guidelines for treatment of hypertension in patients with non-diabetic CKD based on updated evidence from clinical trials data. Following these recommendations is likely to minimize the risk of development of kidney failure and cardiovascular disease.     

Biomarkers determining cardiovascular risk in patients with kidney disease

Cardiovascular disease (CVD) remains the leading cause of premature death in patients with chronic kidney disease (CKD). Recent evidence suggests that the interaction of "classic" and "non-classic" cardiovascular risk factors is an important contributor in excessive and accelerated CVD in patients with CKD. Indeed, the imposing cardiovascular morbidity and mortality of CKD patients corresponds to a significant extent in endothelial dysfunction, inflammation, oxidative stress, vascular calcification and volume overload. In addition, the kidney's function decline is independently associated with CVD in patients with chronic kidney disease. Currently, there is a growing interest in the role of new biomarkers that are closely correlated with CVD in CKD population. In current review, we summarize the so far acquired knowledge of the most promising biomarkers and we discuss the major clinical correlations of novel risk factors and new biomarkers of CVD in CKD patients, their predictive value for future cardiovascular events and their use in the treatment monitoring of this population.     

慢性肾脏病的流行病学及维生素D的缺乏

慢性肾脏病目前已成为全球威胁健康的公共卫生问题,维生素D在慢性肾病患者中普遍缺乏,慢性肾脏病的进展与矿物质和骨代谢紊乱、维生素D代谢均有密切的关系。活性维生素D在非透析和透析的慢性肾脏病患者的治疗中均有重要作用。     

Renal risk‐benefit determinants of recombinant human erythropoietin therapy in the remnant kidney rat model – hypertension,anaemia, inflammation and drug dose

Clinical studies showed that high doses of recombinant human erythropoietin (rHuEPO) used to correct anaemia in chronic kidney disease (CKD) hyporesponsive patients may lead to deleterious effects. The aim of this study was to analyze the effects of rHuEPO in doses usually used to correct CKD‐anaemia (100, 200 IU/kg body weight (BW) per week) and in higher doses used in the treatment of hyporesponsive patients (400, 600 IU/kg BW per week), focusing on renal damage, hypoxia, inflammation and fibrosis. Male Wistar rats with chronic renal failure (CRF) induced by 5/6 nephrectomy were treated with rHuEPO or with vehicle, over a 3‐week period. Haematological, biochemical and renal function analyses were performed. Kidney and liver mRNA levels were evaluated by quantitative real‐time polymerase chain reaction (qPCR) and protein expression by Western blot and immunohistochemistry. Kidney histopathological evaluations were also performed. The CRF group developed anaemia, hypertension and a high score of renal histopathologic lesions. Correction of anaemia was achieved with all rHuEPO doses, with improvement in hypertension, renal function and renal lesions. In addition, the higher rHuEPO doses also improved inflammation. Blood pressure was reduced in all rHuEPO‐treated groups, compared to the CRF group, but increased in a dose‐dependent manner. The current study showed that rHuEPO treatment corrected anaemia and improved urinary albumin excretion, particularly at lower doses. In addition, it is suggested that a short‐term treatment with high doses, used to overcome an episode of hyporesponsiveness to rHuEPO therapy, can present benefits by reducing inflammation, without worsening of renal lesions; however, the pro‐hypertensive effect should be considered, and carefully managed to avoid a negative cardiorenal impact.     

T102C genetic polymorphism of the 5-HT2A receptor in Chinese hypertensive patients and healthy controls

1. The 5-HT(2A) receptor belongs to the G-protein superfamily. It plays an important role in vascular regulation. 2. Previous reports in the UK have indicated that there is an association of the T102C genetic polymorphism of the 5-HT(2A) receptor with hypertension, but no studies have been made on the T102C genetic polymorphism in Chinese hypertensive patients. In the present study, we investigated the T102C genetic polymorphism of 5-HT(2A) receptors in Chinese hypertensive patients to determine whether there is an association of this polymorphism with hypertension in Chinese. 3. The present study was conducted on 198 hypertensive patients and 164 healthy controls. Polymerase chain reaction-restriction fragment length polymorphism was used to identify the T102C genetic polymorphism of the 5-HT(2A) receptor. 4. In the present study, the C allele frequency of the 5-HT(2A) receptor genetic polymorphism was 0.343 in hypertensive patients, which was not significantly different to that in healthy controls (0.393; chi(2) = 1.922; P = 0.166; odds ratio = 0.807, 95% confidence interval 0.596-1.093). In addition, no gender differences were observed. 5. In conclusion, to our knowledge, this is the first report on the T102C genetic polymorphism of the 5-HT(2A) receptor in Chinese hypertensive patients. We find that no correlation exists between the T102C genetic polymorphism and hypertension, which affords useful information on the pathogenesis of hypertension in the Chinese population.     

Treatment of hypertension and diabetes mellitus in patients with chronic kidney disease: a review

Hypertension and diabetes mellitus are the two leading causes of chronic kidney disease (CKD). The purpose of this paper is to provide an overview of the present pharmacologic and adverse events involved in the treatment of hypertension and diabetes mellitus in patients with CKD. Proper management of hypertension and diabetes mellitus, a common co-morbidity associated with CKD, would slow the progression of kidney disease and reduce healthcare expenditures. Awareness of potential side effects due to the medications or renal insufficiency could prevent unnecessary harm to the patient and provide cost-containment. Active involvement of all healthcare team members can reduce progression of CKD and improve quality of life outcomes in CKD patients.     

Treatment of hypertension and diabetes mellitus in patients with chronic kidney disease: a review

Hypertension and diabetes mellitus are the two leading causes of chronic kidney disease (CKD). The purpose of this paper is to provide an overview of the present pharmacologic and adverse events involved in the treatment of hypertension and diabetes mellitus in patients with CKD. Proper management of hypertension and diabetes mellitus, a common co-morbidity associated with CKD, would slow the progression of kidney disease and reduce healthcare expenditures. Awareness of potential side effects due to the medications or renal insufficiency could prevent unnecessary harm to the patient and provide cost-containment. Active involvement of all healthcare team members can reduce progression of CKD and improve quality of life outcomes in CKD patients.