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ISSN: 2168-9857
Medical & Surgical Urology
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Blood Pressure in Renal Disease: Objectives, Surrogate Markers and Treatment

Robles NR*

Cardiovascular Risk Chair, Universidad de Salamanca, Salamanca, Spain

*Corresponding Author:
Nicolás Roberto Robles
Unidad de HTA, Hospital Infanta Cristina
Carretera de Portugal s/n, 06080, Badajoz, Spain
E-mail: [email protected]

Received date: November 30, 2012; Accepted date: December 28, 2012; Published date: December 30, 2012

Citation: Robles NR (2013) Blood Pressure in Renal Disease: Objectives, Surrogate Markers and Treatment. Med Surg Urol S11:002. doi:10.4172/2168-9857.S11-002

Copyright: © 2013 Robles NR. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Despite decades of trials, we still are uncertain as to what level we should lower BP to achieve maximalcardiovascular protection in hypertensive patients. Even more, nowadays the target for reducing blood pressure inrenal disease is under discussion; there is scanty evidence from randomized clinical trials to support a straight bloodpressure control for proteinuric patients.

On the other hand the value of microalbuminuria as surrogate marker of renal disease progression is controversialin hypertensive non diabetic patients. Furthermore, frequently the effects of treatment on glomerular filtration rate themore used and useful test for chronic kidney disease- are opposite in several clinical trials.

The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension(ACCOMPLISH) trial showed that initial antihypertensive therapy with benazepril plus amlodipine was superior to benazepril plus hydrochlorothiazide in reducing progression of chronic kidney disease as well as cardiovascular morbidityand mortality in renal patients. The renal results of the ACCOMPLISH trial strongly support the recommendation ofusing calcium channel blockers as second antihypertensive agent added to renin-angiotensin axis blocking drugs. Thevalidity of this data and its relationship with the cumulated evidence on the effects of calcium antagonists (especially new calcium channel blockers which reduce proteinuria) on renal disease progression will be discussed.

Keywords

Blood Pressure (BP); Chronic Kidney Disease (CKD); Surrogate markers

Introduction

Chronic kidney disease (CKD) is a growing public health problem that currently affects over 20 million adults in the United States [1]. Globally, the increasing incidence and prevalence of CKD is associated with adverse health outcomes and high health-care costs [2]. Two major outcomes of patients with CKD stages 1–4 are progression of kidney disease including development of kidney failure, and mortality predominantly attributable to the development of cardiovascular disease [3].

Current Recommended Blood Pressure Targets in CKD

The 2007 European Guidelines for management of hypertension recommended for patients with CKD a blood pressure (BP) goal lesser than 130/80 mmHg [4]. However, on 2009 these recommendations were clearly modified [5] due to:

• There was limited trial support for treatment initiation at high normal BP (130/85 mmHg) to be recommended in the presence of kidney damage (e.g. microalbuminuria)

• The <130/80 BP goal was not supported by trial evidence and, in clinical settings, it was very difficult to achieve

• It seems not realistic to pursue a sizeable BP reduction indicating a goal which is unproven by adequated randomized clinical trials.

So that the general BP objective (<140/90 mmHg) is now also the goal for CKD patients in these guidelines. In this regard, a systematic review of randomized clinical trials in adults with CKD did not find conclusive evidence favoring a blood pressure target of less than 125/75 to 130/80 mm Hg rather than a target of less than 140/90 mm Hg [6]. After a mean 2- to 4-year follow-up, the main trial results did not show benefit for clinical outcomes. Only the post-trial follow-up report from the MDRD Study showed benefit of the lower target for kidney failure after about a 6-year follow-up [7]. Subgroup analyses by baseline proteinuria levels in the MDRD Study and AASK Trial [8], but not in the REIN-2 trial [9], suggest benefit for the lower target only in patients with proteinuria greater than 1000 mg/d and urinary proteincreatinine ratio greater than 0.22 g/g, respectively.

The ACCOMPLISH trial

Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial showed that initial antihypertensive therapy with benazepril plus amlodipine was superior to benazepril plus hydrochlorothiazide in reducing cardiovascular morbidity and mortality [10]. More recently a second report has assessed the effects of these drug combinations on progression of chronic kidney disease. ACCOMPLISH was a double-blind, randomized trial which recruited 11,506 patients with hypertension who were at high risk for cardiovascular events. They were randomly assigned to receive benazepril (20 mg) plus amlodipine (5 mg; n=5744) or benazepril (20 mg) plus hydrochlorothiazide (12.5 mg; n=5762), orally once daily. There were 113 (2.0%) events of chronic kidney disease progression in the benazepril plus amlodipine group compared with 215 (3.7%) in the benazepril plus hydrochlorothiazide group (HR 0.52, 0.41–0.65, p<0.0001). The combined endpoint of progression of chronic kidney disease and all-cause mortality was also lower in the benazepril plus amlodipine group (6.0%) than in the benazepril plus hydrochlorothiazide group (8.1%, p<0.0001). There was a slower decline in EGFR in the benazepril plus amlodipine group (–0.88 mL/min/1.73 m2) than in the benazepril plus hydrochlorothiazide group (–4.22 mL/min/1.73 m2, p=0.01). Also in patients with chronic kidney disease (i.e., those with a mean EGFR at baseline of 45.1 mL/ min/1.73 m2, progression of chronic kidney disease was slower in the benazepril plus amlodipine group [11].

Surprisingly, in 446 of those patients with base line microalbuminuria there was a reduction in UACR from baseline in the benazepril plus hydrochlorothiazide group (median change –63·8%, n=217) compared with a median change of –29.0% (n=229) in the benazepril plus amlodipine group (p<0.0001). In 409 patients in the chronic kidney disease subgroup who were assessed at the final visit, a reduction in UACR from baseline was noted in the benazepril plus hydrochlorothiazide group (–26.8%, n=202) whereas an increase was seen in the benazepril plus amlodipine group (2.9%, n=207; p=0.0001). Of the 2207 patients with baseline microalbuminuria, a smaller proportion in the benazepril plus amlodipine group became normoalbuminuric than in the benazepril plus hydrochlorothiazide group (n=463, 41.7%, vs. n=750, 68.3%; p=0.0016). Similarly, in 585 patients who had baseline albuminuria in excess of 33.9 mg/mmol, the proportion of patients that reverted to microalbuminuria or became normoalbuminuric differed between groups (n=146, 49.7%, vs. n=251, 89.6%; p=0·0012) [12].

It has recently published a sub-study of the ACCOMPLISH trial where 573 subjects underwent 24-hour ambulatory blood-pressure monitoring. Subjects were recruited from the U.S. cohort and did not differ in baseline clinical characteristics from the overall study population. The study groups did not differ significantly in mean 24-hour, daytime, or nighttime systolic blood-pressure levels. This supports the original interpretation of the investigators that the difference in the primary composite cardiovascular end point that favored the amlodipine-based regimen could not be explained by between-group differences in blood-pressure levels [13].

Proteinuria and Classic Calcium Channel Blockers

There is an enormous amount of reports on the anti-proteinuric or anti-microalbuminuric effect of dihydropiridinic calcium antagonist compared with ACE inhibitor or angiotensin receptors blockers. Taken altogether the conclusion is clearly unfavourable to first and second generation calcium channel blockers, since the anti-proteinuric effect of renin-angiotensin axis blocking drugs have been usually higher. Angiotensin axis blocking drugs are reputed to minimize the hypertension- induced renal damage by preserving renal blood flow in the face of systemic blood pressure reduction [13-15]. It have documented that calcium antagonists cause a preferential dilation of the glomerular afferent arteriole, with only modest action on the efferent arteriole [16-18]. Thus, it is inferred that whereas the depressor action of the calcium antagonist favours an attenuation of glomerular hypertension and the subsequent renal protection [19-22], the predominant activity of this agent on preglomerular vessels might cause glomerular hypertension that could finally be associated with the progression of renal diseases [23-26].

New Calcium Antagonists

In contrast with this large amount of investigations suggesting that first and second generation of calcium antagonists have predominant action on preglomerular vessels, a growing body of evidence has been accumulated demonstrating that the new type of these agents may affect postglomerular as well as preglomerular vessels. The intravenous administration of manidipine caused a greater increase in RPF than that in GFR in spontaneously hypertensive rats (SHR), resulting in decreased filtration fraction [27]. Nilvadipine and efonidipine may elicit similar GFR in humans [28,29]. In humans manidipine, as benidipine, elicits both afferent and efferent arteriolar dilation [30-32]. Hayashi et al. have demonstrated that several calcium antagonists including manidipine, nilvadipine, benidipine, and efonidipine, cause substantial dilation of efferent arterioles in the isolated perfused rat hydronephrotic kidney. In contrast, in the same preparation, both dihydropyridine-class (nifedipine, nicardipine, and amlodipine) and non-dihydropyridine-class calcium antagonists (diltiazem) cause predominant afferent arteriolar dilation [33-36].

There is an growing number of reports on the clinical renal effects of new calcium antagonist and they have rendered promising results. Bellinghieri et al. compare the effects of manidipine and nifedipine, on blood pressure, and renal function. Creatinine blood levels and creatinine clearance significantly increased in the manidipine group. Proteinuria did not significantly change in the manidipine group but increased in the nifedipine group [37] The effect of long-term monotherapy with manidipine or lisinopril on albumin excretion rate (AER) has been compared. Both drugs provided a significant decrease in AER, but it was significantly more pronounced with lisinopril [38] Del Vecchio et al. [39] evaluate the efficacy and tolerability of manidipine in comparison with enalapril in patients with chronic renal disease secondary to primary renoparenchymal disease. Proteinuria remained unchanged with manidipine and decreased significantly with enalapril. No significant difference was observed in the rate of renal function decline in the two groups. The DIAL (Diabetes Ipertensione Albuminuria Lercanidipina) evaluated the effectiveness of lercanidipine in comparison with ramipril in mild-to-moderate hypertensive patients with Type 2 diabetes and persistent microalbuminuria. A reduction in AER was observed in both groups, without differences between the groups [40]. More recently the ZAFRA study has shown a positive effect on overt proteinuria by the combination of the new calcium channel blocker lercanidipine and renin-angiotensin axis blocking drugs [41]. A more recent report with higher dose of lercanidipine associated to renin-angiotensin axis blockers showed that this combination got a deeper reduction of proteinuria [42].

Calcium Channel Types

Recent advances in basic research have emphasized that new dihydropyridine calcium channel blockers can inhibit other types of Ca2+ channels including the T-type, the P/Q type and the neuronal N-type Ca2+ channels. In parallel, these Ca2+ channels subtypes have been localized in renal vascular and tubular tissues (T-type, P/Q-type). The presence of the N-type Ca2+ channel at perivascular sympathetic nerve terminals may also impact on vascular tone. The lack of functional expression of the L-Type Ca2+ channel in renal efferent arterioles and their DHP-insensitivity to most CCBs support the hypothesis of a critical role of the T-type Ca2+ channel (and possibly the N-type) to vascular tone in these arterioles. Therefore, the effect of mibefradil and of new DHPs on the non-L type Ca2+ channels may account for the divergent actions of CCBs on afferent and efferent arterioles and for the beneficial effect on glomerular hemodynamics [43].

Conclusions

• A BP target <140/90 reduces kidney disease progression.

• Deeper reductions (a target around 130/80 mmHg) may improve the treatment results.

• BP <130/80 mmHg could be the objective for proteinuric patients.

• There is scanty evidence for this target in microalbuminuria.

• Calcium channel blockers should be preferred after RAS blocker as second line therapy for CKD hypertensive patients.

• New calcium channel blockers may reduce microalbuminuria and proteinuria.

References

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