Proceedings of the Fourth Genoa Meeting on Hypertension, Diabetes, and Renal Diseases
Chronic Kidney Disease as a Situation of High Added Risk in Hypertensive Patients
Julian Segura,
Jose A. García-Donaire,
Manuel Praga and
Luis M. Ruilope
Hypertension Unit, Nephrology Department, Hospital 12 de Octubre, Madrid, Spain
Address correspondence to: Dr. Julian Segura, Hypertension Unit, Hospital 12 de Octubre, Av. Córdoba s/n, 28041 Madrid, Spain. Phone: +34-91-3908198; Fax: +34-91-3908035; E-mail: juliansegura{at}mi.madritel.es
Recent guidelines for the management of hypertension have recognizedthe relevance of renal function on cardiovascular prognosisof hypertensive patients. In fact, growing evidences have confirmedthat as soon as renal function exhibits minor derangements,cardiovascular risk starts a continuous rise until the developmentof end-stage renal disease. Both estimated glomerular filtrationrate and urinary albumin excretion are associated with an increasedincidence of cardiovascular events and death among hypertensivepatients and in general population. Consequently, hypertensivepatients presenting with chronic kidney disease are consideredby guidelines as high-risk patients, and strict blood pressurecontrol should be considered as a part of an integrative therapeuticapproach, including correction of anemia, treatment of dyslipidemia,cessation of tobacco use, and antiplatelet therapy. This paperbriefly reviews the most recent evidences about pharmacologictherapies in high-risk patients, focusing on benefits relatedto improvement of cardiovascular risk factors in hypertensivepatients with chronic kidney disease.
Recently, the Seventh Report of the Joint National Committee(JNC-7) has recognized microalbuminuria and an estimated GFR(eGFR) value <60 ml/min per 1.73 m2 as two major cardiovascularrisk factors (CVRF) (1). In the same line, the Guidelines ofthe European Society of Hypertension–European Societyof Cardiology (ESH-ESC) (2) define the existence of a high addedrisk in hypertensive patients by the presence of a given levelof BP accompanied or not by the presence of associated CVRF,target organ damage (TOD), diabetes, or associated clinicalconditions (ACC). These guidelines consider slight increasein serum creatinine (1.3 to 1.5 mg/dl in men, 1.2 to 1.4 mg/dlin women) and microalbuminuria as TOD, and higher values ofserum creatinine or the presence of proteinuria as ACC (2).The presence of very elevated BP levels is required in the absenceof other CVRF to consider that a patient has a high added CVrisk, whereas only high-normal BP levels or even lower valuesare required for the same recognition when the patient presentswith three or more associated CVRF, TOD, diabetes, or ACC. Accordingto this, hypertensive patients with a high-added level of CVrisk can be found in any of the three stages of the CV and renalcontinuum (Figure 1). Since the publication of the guidelines,growing evidence has been added to confirm that as soon as renalfunction exhibits minor derangements, CV risk starts a continuousrise until the development of ESRD (3,4).
The presence of chronic kidney disease (CKD) relies on the determinationof serum creatinine, creatinine clearance, and/or urinary albuminexcretion (UAE). The Framingham Heart Study showed a relevantprevalence of mild renal insufficiency in the general population,on the basis of serum creatinine values (8.7% in men and 8.0%in women) (5). The prevalence of a mild decrease in renal functionin the community could be even higher according to the valuesof estimated creatinine clearance seen in the Third NationalHealth and Nutrition Examination Survey (6,7). Among patientswho were referred to our hypertension unit, 7.6% have a decreasedrenal function according to serum creatinine levels, and oneof every four patients has a decreased creatinine clearance(8).
Recently, community-based longitudinal studies have demonstratedthat CKD is an independent risk factor for the composite studyoutcome, including myocardial infarction, fatal coronary heartdisease, stroke, and death (9). These results were confirmedrecently in a Japanese population (10) and in a population withpreexisting CV disease (11). In essential hypertensive patientswith normal renal function (defined as eGFR >90 ml/min per1.73 m2), those who developed CKD during 13 yr of follow-uppresented a rate of CV events 2.5 times higher than those withpreserved renal function (12).
Microalbuminuria is associated with an increased incidence ofCV events and death, as well as with all-cause mortality. Initialevidence came from observations involving high-risk patients(13–15). The data from the HOPE study (16) came to confirmthe predictive value of microalbuminuria that attained a predictivecapacity similar to that of previous coronary artery diseaseand was equal for patients with and without accompanying diabetes.The relevance of UAE as a CVRF in hypertensive patients withoutdiabetes (13,17–19) and in the general population (20,21)also has been demonstrated. Some of these studies (16,21) havedescribed that the relationship between urinary albumin andCV risk is a continuum that starts below the cutoff point of30 mg/d albumin (or 30 mg/g creatinine) that normally allowsthe classification of a given patient as having microalbuminuria.This fact has led to questioning whether the actual thresholdto define a normal value of this parameter is adequate (22).
Definitely, both UAE and reduced GFR are associated with anincreased CV risk. Nevertheless, the percentage of patientswho present both disturbances is not well established. We haveanalyzed the prevalence of microalbuminuria and proteinuriaaccording GFR values in a cohort of 1047 essential hypertensivepatients who attended our hospital-located hypertension unit.As can be seen in Table 1, the prevalences of microalbuminuriaand proteinuria increase significantly at eGFR values <60ml/min per 1.73 m2. Both microalbuminuria and proteinuria weresignificantly associated with lower values of eGFR, diabetes(42.4%), male gender (36.4%), age above 60 yr (33.2%), and thepresence of TOD or ACC (39.6%). These findings contribute toexplain the exponential increase in CV risk that was observedwith progressive decay in renal function (23). Moreover, CKDcould appear together with other TOD as left ventricular hypertrophy(LVH). In fact, the fall in GFR in hypertensive patients isparticularly accelerated when the elevated BP is accompaniedby the concentric pattern of LVH (24). Concentric LVH is a strongmarker of the severity of hypertension (25), and it could bean indicator that CV and renal damages are closely related.
Results from big trials in hypertensive patients show that controllingBP is the most important issue (26). However, there is generalagreement in considering that patients with a high-added CVrisk require antihypertensive therapy to lead BP to the expectedgoal of control, which is <130/80 mmHg in most cases. ThisBP goal must be attained in patients with ACC or any degreeof renal damage and also in patients with diabetes (2). Thepresence of other forms of TOD and/or three or more associatedCVRF require that BP levels be maintained at levels <140/90mmHg.
All of the recently published trials in arterial hypertensionhave been reviewed in the Trialists Meta-analysis (27). Datacontained in this meta-analysis refer most importantly to thecomparison of active therapy and placebo and of lower and higherBP goal and to the comparison between different antihypertensivedrug classes. All of these comparative data have been constructedby the comparison of the time elapsed until the developmentof one event or death in the required number of patients accordingto the initial sample size calculation. Practically, it canbe considered that the great majority of the events and deathconsidered in this meta-analysis took place in patients withhigh-added CV risk, for whom the greatest likelihood for CVmorbidity and mortality was present. The main conclusion ofthis meta-analysis is that it is attainment of BP control andnot the type of therapy used that matters when antihypertensivetherapy is concerned. It is true that the class of the angiotensinreceptor blocker showed positive differences when compared withother therapies, in particular diuretics and blockers. However,data from the VALUE trial (28) were not included. This factis relevant also for the analysis of the calcium channel blockersas will be the inclusion of the INVEST, MOSES, ACTION, and CAMELOTtrials (29–32). Considering these new trials, recent analysissuggests that antihypertensive drug treatment improves outcomemainly through lowering of systolic BP (33).
In addition to antihypertensive therapies, recent evidence seemsto indicate that a statin must be included in the treatmentof a relevant percentage of high-risk hypertensive patients,at least in patients with diabetes in any of the three stagesand in all of those in stage 3 (34,35). Once BP control is attained,antiplatelet therapy with aspirin must be contemplated at leastin patients at stage 3 (36). These added therapies could contributeto bias the effect of a given antihypertensive therapy (whethermonotherapy or a combination). Statins have proved to be ofgreat value in patients with an elevated global CV risk accompaniedor not by elevated LDL cholesterol levels (37). Moreover, theoverall clinical benefits that are observed with statin therapyseem to be greater than what might be expected from changesin lipid profile alone, suggesting that the beneficial effectsof statins may extend beyond their effects on serum cholesterollevels. In fact, much evidence has shown the pleiotropic effectsof statins in improving or restoring endothelial function, enhancingthe stability of atherosclerotic plaques, and decreasing oxidativestress and vascular inflammation (38). Recent data from theBrisighella Heart Study demonstrated that the use of lipid-loweringmeasures could significantly improve BP control in patientswith both hypercholesterolemia and hypertension, enhancing thereduction in BP in patients who are treated with statins (39).
Patients who present with CKD experience higher mortality andadverse CV event rates, which remains significant after adjustmentfor conventional CVRF (40). Moreover, CKD is common in patientswith heart failure and coronary artery disease, and these patientshave more advanced atherosclerosis (41,42). Nevertheless, thereis a lack of appropriate risk factor modification and intervention,despite established awareness of their high CV risk and theevidence of better outcomes if they receive adequate therapy(40,41,43). In fact, pravastatin reduces CV event rates in peoplewho have or are at risk for coronary disease and concomitantmoderate CKD, many of whom have serum creatinine levels withinthe normal range (43). Indeed, there is controversial evidenceabout the effects of lipid-lowering therapy on rate of kidneyloss in people with coronary heart disease. The Greek Atorvastatinand Coronary Heart Disease Evaluation (GREACE) study showedthat in untreated dyslipidemic patients with coronary heartdisease and normal renal function at baseline, creatinine clearancedeclines over a period of 3 yr, but statin treatment preventsthis decline and significantly improves renal function (44).By contrast, a recent study that included 18,569 patients whohad or were at risk for coronary disease, 3402 of whom had moderateCKD, showed that pravastatin modestly reduced the rate of kidneyfunction loss (45). Similarly, there is recent evidence aboutthe efficacy and the safety of low-dose aspirin in patientswith CKD (46), although this therapy is underused when CKD isassociated with acute myocardial infarction (47,48).
In CKD, there is good evidence about the benefits related toBP control, correction of anemia, treatment of dyslipidemia,cessation of tobacco use, and antiplatelet therapy (49). Therelevance of CKD in high-risk patients requires an integrativetherapeutic approach to protect fully and simultaneously renaland CV systems (50,51).
CKD is a situation of high added CV risk in hypertensive patients.Strict BP control must be obtained in most cases by combinationtherapy that must include an ACE or an angiotensin receptorblocker. This must be accompanied by statin and aspirin (thelater once BP control has been attained).
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Abstract
Introduction
blockers. However, data from the VALUE trial (28) were not included. This fact is relevant also for the analysis of the calcium channel blockers as will be the inclusion of the INVEST, MOSES, ACTION, and CAMELOT trials (29–32). Considering these new trials, recent analysis suggests that antihypertensive drug treatment improves outcome mainly through lowering of systolic BP (33). 
