Hypertension is a highly prevalent risk factor that affects a large, worldwide population [1,2]. It promotes the development of coronary heart disease (CHD), stroke, and renal and peripheral vascular disease, and largely contributes to increased cardiovascular (CV) morbidity and mortality . Regardless of the widespread knowledge about hypertension, the underlying mechanisms that contribute to the most common form of hypertension—essential hypertension—remain unclear, and individuals at the highest risk of developing hypertension must be identified in order to improve their CV status. Diverse studies support a basic role for the kidneys in the pathogenesis of essential hypertension. Cowley and Roman  reviewed six lines of evidence that show that renal dysfunction accompanies the development of all forms of hypertension in animal models. They described abnormal renal sodium excretion as one of the initial findings.
An adequate excretion of an increased sodium load due to high salt intake requires an elevation in glomerular pressure that when maintained can potentially lead to glomerular scarring and endothelial dysfunction. Frequently, a phase of glomerular hyperfiltration is observed in the early stage of arterial hypertension and diabetes. This phase can be followed by progressive renal damage with development of chronic kidney disease (CKD) to which a lower than normal number of nephrons at birth could contribute. Scarce data about the contribution of glomerular hyperfiltration to hypertension in humans are available, but during this phase of glomerular hyperfiltration, or later in patients with arterial hypertension and/or diabetes, microalbuminuria can develop .
CV diseases are a leading cause of death and serious morbidity or disabilities worldwide, and CV events rarely occur in patients without underlying disease; rather, they typically take place as the final stage of a pathophysiological process that results in progressive vascular damage. This stage is called the cardiorenal continuum . Figure 1, an overview of the cardiorenal continuum, illustrates a simplified version of the sequential occurrence of the atherosclerotic process from the first stage where CV risk factors are detected and prevention can be performed, if these conditions are appropriately controlled by implementing the optimal therapeutic approaches. Renal and CV disease share the same etiopathogenic risk factors, including hypertension, dyslipidemia, glucose metabolism disturbances, cigarette smoking, obesity, and physical inactivity. If these factors are controlled, then atherosclerotic process evolution and further target organ damage (TOD) development or CV events can be prevented. Therefore, prevention can be carried out not just at the first stage but along the whole continuum.
||Figure 1. The cardiorenal continuum.
As the cardiorenal process advances, atherosclerotic vascular damage progresses and subclinical organ damage can be detected. This is an intermediate stage in the continuum of vascular disease and a determinant of overall CV risk. CKD is included at this stage, and a number of conditions associated with renal function decline as anemia, secondary hyperparathyroidism, or accumulation of atherogenic substances become new CV risk factors and accelerate vascular disease. Therapeutic approaches at this point can regress CV damage, as shown in the Losartan Intervention For Endpoint reduction (LIFE) study, where reduced urine albumin/creatinine ratio (UACR), as well as regression of left ventricular hypertrophy (LVH), was associated with lower incidence of CV events . Therefore, strict objectives regarding CV risk factors must be set up.
A large body of evidence is now available concerning the crucial role of TOD in determining the CV risk of individuals with and without hypertension. If regression of CV damage is not achieved, the process advances to the development of CV events and progression of CKD to overt nephropathy and CV disease. Although prevention strategies must be present along the continuum, interventions at this point should only retard the occurrence of CV and renal events . This last stage represents the situation of further progression of vascular disease leading to the appearance of symptomatic TOD (myocardial infarction, angina, stroke, transient ischemic attack, advanced chronic renal failure, and peripheral artery disease), which eventually will lead to death or end-stage renal disease (ESRD). At this stage, the best we can do is to retard events.
CARDIOVASCULAR DISEASE ASSOCIATED WITH RENAL DISEASE: EVIDENCES ALONG THE CONTINUUM
Underlying the cardiorenal continuum is the pathophysiological continuum, which describes the progressive processes at molecular and cellular levels that manifest as clinical disease; a vast amount of research over the last two decades has provided a much understandable perception of the therapeutic interventions that are able to interrupt the continuum. Therefore, since CV risk factors can be evaluated, the process begins. At this first stage of cardiorenal disease, prevention approaches are the most relevant strategies in order to disrupt the progression of the disease . In this sense, some data have demonstrated that high-risk patients without evidence of renal damage may benefit from early therapeutic intervention.
The multicenter, double-blind, randomized BErgamo NEphrologic DIabetes Complications Trial (BENEDICT) was designed to assess whether a pharmacological intervention could prevent microalbuminuria in high-risk patients with no evidence of organ damage. The main results showed that the intervention decreased the incidence of microalbuminuria . Evidence from other ongoing trials will shed light on this issue, as will the Randomised Olmesartan And Diabetes MicroAlbuminuria Prevention (ROADMAP) study—a placebo-controlled, multicenter, double-blind, parallel group study investigating the effect of the angiotensin receptor blocker (ARB) olmesartan medoxomil on the incidence of microalbuminuria in hypertensive people with type 2 diabetes and an objective of blood pressure <130/80 mmHg. In addition, ROADMAP will also analyze effects of olmesartan medoxomil on retinopathy and other microvascular circulations . The results of the DIabetic REtinopathy Candesartan Trials (DIRECT) are designed to examine primary (incidence) and secondary (progression) prevention of diabetic retinopathy when blocking angiotensin II type 1-receptors with candesartan in patients with normoalbuminuric, normotensive type 1 diabetes, and secondary prevention only in patients with normoalbuminuric, normotensive, or treated hypertensive type 2 diabetes. This trial series will also support prevention strategies to block the advance of the atherosclerotic process that leads to the development of CV damage .
Optimal management in people with several risk factors is crucial, especially when hypertension is associated with other conditions. Awareness that several antihypertensive agents may exert undesirable metabolic effects has prompted investigation of the incidence of new diabetes in antihypertensive treatment trials. Almost all trials of antihypertensive therapy using new-onset diabetes as an end point have shown a significantly greater incidence in patients treated with diuretics and/or beta-blockers compared with angiotensin-converting enzyme inhibitors (ACEIs), ARBs, or calcium antagonists [13-16]. Angiotensin receptor antagonists  and ACEIs  have been shown to be associated with significantly less new diabetes than were calcium antagonists. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) is comparing telmisartan, ramipril, and their combination in the prevention of CV morbidity and mortality in patients at high risk . Telmisartan was the ARB selected for the ONTARGET Trial Programme because it provides sustained antihypertensive activity effect over the 24-hour period between doses . The comparator, the ACEI ramipril, was selected because in the Heart Outcomes Protection Evaluation (HOPE) trial ramipril was proved to reduce the incidence of CV events in a similar patient population . Patients enrolled in ONTARGET have vascular disease (coronary artery disease, peripheral arterial occlusive disease, or stroke) or diabetes with TOD. The primary outcome is a composite end point of CV, death, stroke, acute myocardial infarction, and hospitalization for chronic heart failure. A variety of renal end points have also been included. Telmisartan Randomized AssessmeNt Study in ACE-I-iNtolerant subjects with CV Disease (TRANSCEND) is a parallel study within the ONTARGET Trial Programme that is comparing the CV protective effect of telmisartan with placebo in patients intolerant of ACEIs . The first results of this trial have been published and emphasize that the ARB telmisartan was equivalent to ramipril in treating patients with vascular disease or high-risk diabetes and was better tolerated . The combination of these two drugs was associated with more adverse events without an increase in benefit. More evidence about prevention along the cardiorenal continuum is expected from this trial, including more than 150,000 patient-years of data.
The TRial Of Preventing Hypertension (TROPHY) hypothesized that early treatment with the ARB candesartan might prevent or delay the onset of hypertension. The main results showed that candesartan was better in preventing development of hypertension versus placebo . The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) evaluated the benefits associated specifically with the use of statins among patients with hypertension . Atorvastatin, which was added to the treatment therapy in over 10,000 patients with hypertension who have additional CV risk factors and a serum total cholesterol <6.5 mmol/L, reduced serum total cholesterol by 19.9% compared to placebo. This was accompanied by substantial benefits both with regard to total CV and renal events (36% reduction) and stroke (27% reduction).
Mechanical and chemical damage resulting from these interrelated CV risk factors promote a general progression of vascular damage that begins with endothelial dysfunction and atherosclerosis. This leads to end-organ damage as LVH, subclinical atherosclerotic vascular damage, and kidney injury that can be detected by microalbuminuria and renal function derangement (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2 or a slight increase in serum creatinine). At this second stage, vascular damage process may be regressed and inhibition of the renin-angiotensin system (RAS) has been shown to be the most efficient pharmacological intervention along with a strict control of CV risk factors.
The term CKD includes the development and evolution of chronic renal failure of many different origins . Current international guidelines devoted to arterial hypertension recognize microalbuminuria, elevation of serum creatinine values, and existence of a reduced value of eGFR as major CV risk factors that contribute to increase the risk afforded by other coexisting factors [25-27]. The diagnosis of hypertension-induced renal damage in a hypertensive patient is usually based on the finding of a reduced renal function and/or the detection of elevated urinary excretion of albumin. Renal function decline is classified in accordance with the eGFR calculated by the abbreviated modification of diet in renal disease (MDRD) formula that requires age, gender, race, and serum creatinine . Values of eGFR <60 mL/min/1.73 m2 indicate CKD stage 3, whereas values <30 and 15 mL/min/1.73 m2 indicate CKD stages 4 and 5, respectively (Table 1) . The other formula (the so-called Cockcroft-Gault formula) estimates creatinine clearance (CrCl) and is based on age, gender, body weight, and serum creatinine . This formula is applicable in the range >60 mL/min, but it overestimates CrCl in CKD stage 3 to 5 . Both procedures help to detect mild impaired renal function even though serum creatinine values are still in the normal range.
||TABLE 1. Description and estimation of the glomerular filtration rate at every stage of chronic renal disease
A reduction in GFR and an increase in CV risk may also be inferred from the increased serum levels of cystatin C . While patients may exhibit an elevated serum creatinine concentration or a low eGFR (or CrCl) point to a reduced rate of plasma filtered at the glomerular level, the finding of an increased rate of urinary albumin or protein excretion points to a derangement in the glomerular filtration barrier that allows an increased passage of albumin. Microalbuminuria has been shown to predict the development of overt diabetic nephropathy in those with either type 1 or type 2 diabetes . However, only about 40% of those with type 2 diabetes will develop microalbuminuria and, out of those, approximately 50% will develop microalbuminuria in the following 10 years . In contrast, in both diabetic and nondiabetic hypertensive patients, microalbuminuria, even below the threshold values currently considered , has been shown to predict CV events.
Several studies report a continuous relationship between CV—as well as non-CV—mortality and urinary protein/creatinine ratios >3.9 mg/g in men and 7.5 mg/g in women . Thus the term microalbuminuria may be misleading (because it falsely suggests a minor injury as well) and should in theory be substituted by low-grade albuminuria . Microalbuminuria can be determined in spot urine samples (24-hour or night urine samples are discouraged due to the inaccuracy of urinary sampling) by indexing the urinary albumin concentration to the urinary creatinine concentration. Initial evidence concluding that microalbuminuria increases CV risk came from observations involving high-risk patients .
The data from the HOPE study  confirmed the predictive value of microalbuminuria, which attained a predictive capacity similar to that of previous coronary artery disease and was equal for patients with and without accompanying diabetes. The relevance of urinary albumin excretion (UAE) as a CV risk factor in patients with hypertension without diabetes and in the general population has also been demonstrated . Some of these studies have described that the relationship between urinary albumin and CV risk is a continuum that starts below the currently established cut-off point indicated earlier. Definitely, both UAE and reduced GFR are independently associated with an increased CV risk, which is particularly elevated when both alterations coexist . In fact, the prevalence of microalbuminuria, either micro- or macro-, rises as eGFR falls below 60 mL/min/1.73 m2 .
Patients developing ESRD are a minority in the group developing different forms of CKD. They could be considered survivors because CV disease accounts for the majority of deaths of patients with CKD before the development of ESRD . In turn, advanced CV disease facilitates the development of CKD, and so the relationship between CKD and CV disease becomes a vicious circle. That CKD and CV disease are so closely related has resulted in increased interest in investigating the evolution of renal function in trials involving patients with hypertension, as well as heart failure and post-myocardial infarction. This interest is fully justified since, in all these situations, renal function alterations are predictive for the development of CV events or death.
Even from the early stages, CKD adds to the CV risk in any patient with hypertension and in any patient presenting with established forms of CV disease . Reduction of CV events in the CKD population requires the implementation of effective integral therapeutic interventions that protect both the kidney and the CV system. These interventions have to be implemented in the very initial stages of CKD, and the attainment of strict blood pressure control is imperative in any patient with an elevated global CV risk and high blood pressure. The presence of elevated blood pressure levels is required in the absence of other CV risk factors in order to consider patients as high added CV risks. In contrast, only high-normal blood pressure levels or even lower values are required for the same evaluation when patients present with three or more associated CV risk factors, TOD, diabetes, or associated clinical conditions. According to this, patients with hypertension and a high added level of CV risk can be found in any of the three stages of the CV and renal continuum. As soon as renal function exhibits minor derangements, CV risk starts a continuous rise until the development of ESRD.
As renal function declines, TOD appears and CKD adds several clinical characteristics that raise the possibility of suffering a CV event as atherosclerotic disease progresses. CKD-induced anemia and secondary hyperparathyroidism globally worsens outcomes in patients with and without myocardiopathies, and correction of these conditions is crucial to achieve the reduction of absolute CV risk [45,46]. Among patients who were referred to the authors' hypertension unit, 7.6% had a decreased renal function according to serum creatinine levels, and 25% had a decreased CrCl . Community-based longitudinal studies have demonstrated that CKD is an independent risk factor for the composite study outcome, including myocardial infarction, fatal CHD, stroke, and death . In patients with essential hypertension and normal renal function (defined as eGFR >90 mL/min/1.73 m2), those who developed CKD during 13 years of follow-up presented a rate of CV events 2.5 times higher than did those with preserved renal function . As widely evidenced in the hypertension population, the higher the CV risk the higher the prevalence of CKD (Table 2) .
||TABLE 2. Prevalence of mild renal insufficiency
Evidence for the relationship between renal dysfunction and adverse CV events was initially documented in the ESRD population in whom the incidence of CV death is elevated. Around 50% of individuals with ESRD die from a CV cause—a CV mortality that is much higher than is the age-adjusted CV mortality in the general population. This discrepancy is present across all ages, but it is most marked in the younger age group, where CV mortality is more than 300-fold greater in ESRD patients than compared with age-matched controls with normal renal function . When ESRD arrives, 40% of patients have evidence of CHD, and 85% of these patients have abnormal left ventricular structure and function. The relationship between renal disease and CV mortality has also been shown to extend to subjects with more moderate degrees of renal impairment. Indeed, the majority of patients with eGFR <60 mL/min/1.73 m2 die from CV causes rather than progress to ESRD. In addition, evidence of structural and functional cardiac abnormalities has been demonstrated.
Data about cardiac structure in the renal insufficiency population has been described with echocardiographic techniques and comparable criteria for the diagnosis of LVH, detecting a LVH prevalence of 16% in subjects with a CrCl of >30 mL/min and 38% in those with a CrCl <30 mL/min . Therefore, LVH is common in patients with renal insufficiency even before they progress to dialysis, and so prevalence of LVH correlates with the degree of renal functional deterioration. Many reports have shown that the relationship between renal impairment and increased CV mortality extends across the spectrum of renal dysfunction to cover the mildest degree of renal disease. Furthermore, this relationship appears to be maintained through populations with broadly diverse degrees of baseline CV health. LVH is an independent predictor of unfavorable prognosis in the hypertensive population, and, in the LIFE study, its relationship with albumin excretion was reported as independent of age, blood pressure, diabetes mellitus, race, serum creatinine level, or smoking .
The prevalence of microalbuminuria was approximately 2-fold higher in patients with hypertension and eccentric or concentric LVH and minimally elevated in the group with concentric LV remodelling compared with patients with normal LV geometry. Although the clinical significance of impaired renal function and LVH in patients with hypertension is not yet fully clarified, numerous reports link renal albumin leakage with morbidity and mortality. The LIFE study showed that the simple measurement of UACR further refines risk stratification by LV geometry and that patients with LVH have an increased risk of also having albuminuria, which should be further investigated to improve treatment and counselling.
The risk for CV end points increases in a stepwise trend with higher values for UACR in patients with diabetes. Data indicated that albuminuria at a lower level than what is usually utilized as a cut point in patients with diabetes defines patients at increased risk of CV morbidity and mortality. UACR did not predict risk of myocardial infarction. Perhaps diabetes itself is a strong predictor for CV morbidity and mortality, partly overlapping the influence of albuminuria as a risk factor in the present population with rather low levels of albuminuria. Other studies suggest that albuminuria at levels below established values is a risk factor for CHD in patients with and without diabetes, signifying that the relation between albuminuria and CV risk from other populations cannot be directly applied to nondiabetic hypertensive patients .
Global and strict control of the sum of CV risk factors and therapeutic action in order to regress already established vascular damage must be the cornerstone of the medical strategy, because, if not stopped, the cardiorenal continuum progresses to CKD (proteinuria, estimated GFR <30 mL/min/1.73 m2), overt CV disease, and stroke. Interventions at this point are focused on the delay of the development of CV and renal events . CV events and death are dramatically retarded when UACR is decreased and GFR decline is avoided. If renal decline progresses to the final stage, proteinuria will appear.
In type 2 diabetes, data from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial showed that changes in albuminuria in the first 6 months of therapy were approximately linearly related to the degree of long-term renal protection: every 50% reduction in albuminuria in the first 6 months was associated with a 45% reduction in the risk for ESRD during later follow-up . Furthermore, a secondary analysis of the Irbesartan in Diabetic Nephropathy Trial (IDNT) demonstrated that the risk for renal failure was reduced during the first year of the study when there were increases in proteinuria . Subsequently, these two studies (IDNT and RENAAL) demonstrated that an ARB (irbesartan or losartan) was more effective than was conventional therapy or a calcium channel blocker in slowing the progression of nephropathy, regardless of blood pressure control. Moreover, secondary analyses of these two large trials demonstrated that there was some interaction between the effect of the ARB and the levels of blood pressure that were achieved. It can also be concluded that optimal levels of blood pressure tended to magnify the renoprotective effects of ARB in both trials.
Greater efficacy was demonstrated for the ACEI compared with other treatments in reducing the incidence of overt nephropathy in a large cohort of patients with hypertension, microalbuminuria, and type 2 diabetes in the Microalbuminuria, Cardiovascular, and Renal Outcomes-Heart Outcomes Prevention Evaluation trial (MICRO-HOPE) . Furthermore, the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA-2) study showed that treatment with the ARB irbesartan was much more effective than was conventional therapy at both preventing the development of clinical proteinuria and favoring regression to normoalbuminuria in patients with microalbuminuria and type 2 diabetes, despite similar blood pressure control .
EPIDEMIOLOGICAL LINKS BETWEEN ALBUMINURIA, DECLINE IN GLOMERULAR FILTRATION RATE, AND CARDIOVASCULAR RISK
The prevalence of the CKD population is increasing worldwide. Perneger et al published an integrated analysis of data from several population studies showing a crude annual incidence of hypercreatininemia in patients with hypertension of 4.61 per 1000 subjects . On average, these results suggest that 1 in 13 patients with hypertension progresses to hypercreatininemia every year. Nevertheless, the study assessed renal function according to the serum creatinine level, a poor indicator of GFR . Ronstad et al  showed a deterioration of renal function in 15% of patients treated for hypertension, based on serum creatinine levels as well. Segura et al described a similar percentage (14.6%), but according to a more sensitive parameter: the CrCl rate . Furthermore, the mean follow-up was long enough (13.2 ± 4.8 years) to ensure a large enough number of renal events. The development of CKD, estimated as a CrCl level <60 mL/min/1.73 m2 in patients with hypertension who have a baseline normal renal function, is not an infrequent finding in follow-up: 14.6 per 100 patients included developed CKD during more than 13 years of mean follow-up .
In recent years a large body of information has come to confirm that as soon as renal function exhibits even minor derangements, CV risk starts a continuous rise until the development of ESRD, independently of renal etiology . The Hypertension Detection and Follow-up Program (HDFP)  showed for the first time that the presence of elevated serum creatinine values (41.7 mg/dL) at baseline was a very potent predictor of 5- and 8-year all-cause mortality. Data from the Hypertension Optimal Treatment (HOT) study  showed that serum creatinine levels >1.5 mg/dL were accompanied by an adjusted relative risk for major CV events of 2.05 and for CV mortality of 3.24. The capacity of serum creatinine was comparable to that of other well-established major CV risk factors such as diabetes or a previous myocardial infarction. Data from the Atherosclerosis Risk on Communities (ARIC) study showed that the level of GFR is an independent risk factor for atherosclerotic CV disease . The Hoorn study showed that mild to moderate loss of renal function is strongly associated with an increased risk of CV mortality .
Microalbuminuria is usually defined by an increased albumin excretion in urine (Table 3). However, the cut-off point to define microalbuminuria could be even lower if CV risk is considered . A continuous elevation in CV risk is observed with values of albuminuria less than generally established. Microalbuminuria is present in about 40% of middle-aged patients with either type 1 or type 2 diabetes mellitus . Microalbuminuria is a marker of risk even in apparently healthy normotensive nondiabetic people because it reflects vascular damage in the kidneys and systemic endothelial dysfunction. Indeed, microalbuminuria has been associated with increased incidence of CHD events and elevated risk of all-cause and CV mortality in some community-based samples .
||TABLE 3. Definitions of microalbuminuria
In the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) study, microalbuminuria was associated with increased risk of CHD. In this study, microalbuminuria was predictive of all-cause and CVD mortality in men and women independently of other established CVD risk factors: those with microalbuminuria had approximately a 50% increased risk of all-cause mortality and about twice the risk of CVD mortality compared with participants with normoalbuminuria. A dose-response relationship between degree of albuminuria and mortality risk was observed. A significant association was observed between microalbuminuria and non-CVD mortality in men only, which was largely attributed to non-CVD/noncancer causes of mortality, with no association seen with cancer mortality in either gender .
It is still difficult today to claim whether microalbuminuria represents a risk factor per se or rather reflects the effects of other CV risk factors frequently associated with albuminuria. In fact, increased levels of triglycerides, low-density lipoproteins (LDL), obesity, glucose intolerance, insulin resistance, LVH, and hyperuricemia frequently cluster with microalbuminuria, and such a correlation is particularly close with systemic blood pressure levels and, in particular, with ambulatory blood pressure levels .
Parving et al first described the essential hypertension and microalbuminuria association in 1974 . They observed that the presence of elevated levels of urinary excretion of albumin in patients who were unsatisfactorily treated for hypertension was directly correlated with blood pressure values and tended to be reduced whenever a better control of blood pressure was obtained. These results were later confirmed by diverse series . Microalbuminuria is detectable in up to 40% of the population with hypertension, predominantly in those patients inadequately controlled with medical treatment. The prevalence of microalbuminuria is associated with the duration and severity of hypertension .
The Hypertension and Ambulatory recording Venetia study (HARVEST) examined the association between UACR and office and ambulatory blood pressure and their relationship with other recognized CV risk factors in stage I middle-aged patients with hypertension. A 24-h systolic blood pressure profile was higher in patients with microalbuminuria than it was in those with levels <16 mg/day, emerging as the only determinant of microalbuminuria in the logistic regression analysis . An association between microalbuminuria and TOD has been reported previously. By means of echocardiographic examination, Redon et al found that patients with microalbuminuria show a large left ventricular mass and a high degree of LVH . Moreover, Bigazzi et al reported an increased thickness of the intima and media layers of the common carotid artery in a group of patients with essential hypertension and microalbuminuria; consequently a greater degree of vascular remodelling is suggested . Pontremoli et al reported that patients with microalbuminuria are characterized by signs of diffuse vascular and organ damage (ie, a high incidence of major echocardiographic abnormalities and vascular retinal changes), supporting the statement that microalbuminuria is a marker of early end-organ and CV damage in patients with essential hypertension .
The presence of microalbuminuria in patients with essential hypertension has been systematically interpreted as a sensitive marker of intrarenal vascular dysfunction, characterized by an impairment of renal function. It has also been shown to correlate with the presence of nephrosclerosis. While an elevated serum creatinine concentration points to a reduced GFR, an increased rate of albumin points to a derangement in the glomerular filtration barrier. Microalbuminuria might constitute the renal expression of a generalized disorder characterized by increased endothelial permeability, abnormalities of the fibrinolytic and coagulation pathways, and activation of the inflammatory process , explaining the link between microalbuminuria and CV risk. In essential hypertension, microalbuminuria can be considered a predictor of progressive deterioration of renal function . The presence of albuminuria serves as a powerful tool to identify those patients requiring an integrated intervention on multiple CV risk factors. Failure to regress albumin excretion in urine may indicate a clinician intervention inadequacy. Definitely, both proteinuria and reduced GFR are associated with an increased CV risk. However, the percentage of patients presenting both pathologies is not well established.
Segura and associates analyzed the prevalence of microalbuminuria and proteinuria according to GFR values in a cohort of 1047 patients with essential hypertension attended in a hospital-located hypertension unit . Both prevalences increased significantly at eGFR values <60 mL/min/1.73 m2 and were significantly associated with lower values of eGFR, diabetes mellitus, male gender, age >60 years, and presence of TOD or associated clinical conditions .
Microalbuminuria could be present in patients with hypertension and preserved GFR, including those presenting with hyperfiltration as an early marker of renal dysfunction. Urinary albumin excretion would increase progressively in association with an increased severity of hypertension and with the progressive decay in GFR values (Figure 2). Microalbuminuria has been shown to be a strong risk factor for the development of clinical proteinuria in nondiabetic people at high risk for CV events and was also confirmed to be the predictive value for overt nephropathy in type 2 diabetes . These findings help explain the exponential increase in CV risk observed with progressive decay in renal function. The clustering of CV risk factors describing the metabolic syndrome, especially its central component, that is, insulin resistance, has also been associated with the presence of elevated UAE .
||Figure 2. Evolution of cardiovascular risk factors in chronic renal disease stages.
GLOBAL THERAPEUTIC APPROACH FOCUSED ON RENAL OUTCOMES
Progression of CKD, that is, reduction in the GFR, occurs at a variable rate, with a faster rate of decline generally noted among patients with diabetic nephropathy due to the presence of proteinuria. Several therapeutic options have been shown efficient in slowing the rate of renal function decline. Among these therapeutic treatments are blood pressure reduction drugs—preferably using ACEIs and/or angiotensin II antagonists—low-salt and low-protein diets, and lipid-lowering drugs . Unfortunately, for such treatments to be most efficacious and in agreement with the European Society of Hypertension/ European Society of Cardiology guidelines, it is necessary to identify patients in an early stage of their disease, before significant loss of renal function has occurred. Such identification is simplified by the estimation of GFR and the measurement of microalbuminuria in any patient with hypertension. Urine albumin/creatinine ratio levels of approximately >2 mg/g or an estimated excretion rate of 2 mg/day are significantly associated with CV death, myocardial infarction, stroke, and elevation in blood pressure. As a result, reductions in levels of albuminuria during treatment translate to regression of a number of vascular abnormalities in hypertension, and so a decrease in risk in general.
In type 2 diabetes with diabetic nephropathy, and also in nondiabetic renal disease, there are data that point out that the extent of decreases in albuminuria during renin-angiotensin-aldosterone system intervention is associated with the degree of renal protection but also to the degree of reduction in CV risk . Both reductions in systolic and diastolic blood pressure are important in reducing levels of albuminuria. Despite the firm relationship between blood pressure values and albuminuria, ACEIs and ARBs seem to exhibit a more marked capacity to reduce microalbuminuria in patients with hypertension as compared to a number of different therapeutic interventions such as calcium antagonists, beta-blockers, or diuretics .
The results of the African American Study of Kidney Disease and Hypertension (AASK)  suggest that ramipril reduces UACR more effectively than does amlodipine in nondiabetic patients with hypertension and renal disease. This may directly and further enhance the potential causal role of angiotensin II in the pathogenesis of microalbuminuria in arterial hypertension, and drive the physician toward the use of specific classes of drugs, representing a compelling indication for the initial therapeutic choice.
These data demonstrate the importance of albuminuria monitoring in patients with hypertension before, as well as during, treatment as an integrated part of the management of arterial hypertension. Albuminuria should be assessed before treatment and measured at yearly intervals. If the level remains high regardless of antihypertensive treatment, it should be considered whether blood pressure is adequately controlled or whether other modifiable risk factors, such as smoking, lipid abnormalities, and glucose metabolism, require additional intervention to decrease patient risk.
Results from large trials with patients who have hypertension show that controlling blood pressure is the most important issue . However, there is general agreement in considering that patients with a high added CV risk require antihypertensive therapy to lead blood pressure to the expected goal of control, which is <130/80 mmHg in most cases. This blood pressure goal must be attained in any patient with high or very high added risk . All of the recently published trials in arterial hypertension have been reviewed in the Trialists meta-analysis . Data contained in this meta-analysis refer most importantly to the comparison between active therapy and placebo, lower and higher blood pressure goals, and different antihypertensive drug classes. All of these comparative data have been compiled by comparing the time elapsed to the development of one event or death in the required number of patients according to the initial sample size calculation. The main conclusion of this meta-analysis is that it is attainment of blood pressure control and not the type of therapy used that matters when antihypertensive therapy is concerned, albeit the inclusion of data from various trials are required to confirm that statement [18,87-93]. These trials include the following:
- Valsartan Antihypertensive Long-term Use Evaluation (VALUE)
- International Verapamil-Trandolapril Study (INVEST)
- Morbidity and Mortality After Stroke—Eprosartan vs Nitrendipine for Secondary Prevention (MOSES) trial
- A Coronary Disease Trial Investigating Outcome with Nifedipine GITS (ACTION)
- Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis (CAMELOT) trial
- Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) trial
- ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET)
- Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) study
ACCOMPLISH, a major morbidity and mortality trial, compared the effects of two forms of antihypertensive combination therapies on major fatal and nonfatal CV events. It ended early because treatment with antihypertensive combination therapy—the ACEI benazepril plus the calcium-channel blocker amlodipine—was more effective than was treatment with the ACEI plus a diuretic .
Benefits of antihypertensive therapy for renal protection
Significant evidence indicates that the unfavorable effects of hypertension on renal outcomes largely depend on the level to which systemic blood pressure increase is transmitted to the renal microvasculature. Hypertensive renal damage is substantially aggravated by the presence of damaged self-regulatory mechanisms, as in CKD, where the direct transmission of an elevated systemic blood pressure to the glomeruli is allowed . Agents that block the RAS should be preferred as initial therapy as they may provide additional risk reductions and diminish the potassium and magnesium depletion associated with the diuretic use, usually necessary to achieve the lower blood pressure targets.
RAS blockade is strongly recommended as the initial regimen of choice for renoprotection based on the results of several clinical trials and meta-analyses that have, with hardly any exceptions, revealed larger reductions in proteinuria, as well as enhanced progression on evaluating renal end points with RAS blockade, as compared with other antihypertensive regimens in both diabetic and nondiabetic nephropathies . The previously mentioned meta-analysis suggests that ACE inhibition was associated with overall relative risk reductions of 30 to 40% for doubling of serum creatinine and/or ESRD in nondiabetic nephropathy, with the greater benefits seen in patients with high levels of proteinuria . Such data may indicate that the greater renoprotection that is observed with RAS blockade is mediated by blood-pressure-independent mechanisms. Because of the known effect of thiazide diuretics and beta-blockers on glucose metabolism, use of these antihypertensive agents in patients with impaired glucose tolerance may require earlier and more intense antidiabetic medication . Further information on the CV beneficial effects of tight blood glucose control is available due to the latest results of two large-scale randomized trials on patients with type 2 diabetes, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial  and the ADVANCE trial , which examines the likely additional protective effects of tight blood pressure control, <120/70 mmHg. Preliminary data of the ACCORD study were released in view of the unexpected finding that patients with type 2 diabetes in the intensive blood-glucose-lowering treatment arm (target glycated hemoglobin [HbA1c] <6%) had an increased risk of CV death compared to those in the conventional treatment arm (target HbA1c 7-7.9%). Probably as a response to the concern raised by ACCORD, data from ADVANCE were released suggesting that, at least in this study, there was no evidence that intensive treatment to lower blood glucose levels in patients with type 2 diabetes increased their CV mortality risk. Yet, more data and analyses from these studies are needed before one can conclusively comment on the preliminary results.
Some deductions can de made from the benefits obtained with dual RAS blockade compared with monotherapy with either ACEIs or ARBs. Limited data suggest that combination therapy with an ACEI and an ARB may be superior to either agent alone in slowing progressive renal failure . The best data come from the Combination Treatment of Angiotensin Receptor Blocker and Angiotensin Converting Enzyme Inhibitor in Non-diabetic Renal Disease (COOPERATE) trial, which included 263 patients with nondiabetic renal failure who were randomly assigned to previously determined optimal antiproteinuric doses of losartan (100 mg/day), trandolapril (3 mg/day), or both . These fixed maximum doses were gradually reached by increasing the dose at intervals of 3 to 4 weeks. All 3 arms achieved similar blood pressure reduction. The most relevant findings showed that the incidence of the combined primary end point of time to doubling of the serum creatinine concentration or ESRD was significantly less common with combined therapy (11%) than it was with trandolapril (23%) or losartan alone (23%). Second, the largest decrease in proteinuria level was observed with combination therapy (-76% vs -42 and -44%, for losartan and trandolapril, respectively). The main inconvenience was that some patients were unable to tolerate maximum doses of ACEIs and ARBs as used in COOPERATE because of the collateral effects, such as hypotension, hyperkalemia, cough, and/or other effects. Among such patients, the administration of low doses of ACEIs and ARBs may provide greater antiproteinuric efficacy than that observed with greater (but not maximum) doses of either agent given alone.
As previously mentioned, ONTARGET has been designed to compare the effects of telmisartan and ramipril in high-risk patients with controlled blood pressure and a history of vascular events, or diabetes with TOD . ARBs have been less extensively studied than ACEIs in high-risk patients, but it is reasonable to predict that these agents may combine the protective effects of ACEIs with a superior tolerability profile . Hence, primary objectives of the ONTARGET study are to determine if the combination of the ARB telmisartan and the ACEI ramipril is more effective than ramipril alone, and if telmisartan is at least as effective as ramipril. TRANSCEND will determine if telmisartan is superior to placebo in patients who are intolerant of ACEIs.
The first published data show that despite a reduction in systolic blood pressure of 2 to 3 mmHg in the combination therapy group, as compared with the ramipril group, no significant benefit was seen in the primary outcome among patients receiving the 2-drug therapy. Still, combination therapy significantly increased the risk of hypotension, syncope, renal dysfunction, and hyperkalemia, with a trend toward an increased risk of renal dysfunction requiring dialysis .
There are a number of substudies within ONTARGET/ TRANSCEND that will help clarify the effect of telmisartan and ramipril, or a combination of both, on measures of TOD, such as arterial stiffness, magnetic resonance imaging determinations of cardiac muscle mass, and erectile dysfunction. Other substudies will examine the development of new-onset diabetes, changes in ambulatory blood pressure during treatment with telmisartan or ramipril, and health economics.
The benefit of the add-on ARB to an ACEI in slowing the progression of nephropathy in patients with hypertension and nondiabetic renal disease, as compared with monotherapy with an ACEI, has also been suggested . Special attention should be paid to uptitration of ARBs due to recent evidences that suggest a dose-dependent benefit by achieving a reduction of blood pressure and albuminuria. However, optimal reduction of albuminuria may require titration beyond the predefined blood pressure target. Evidence in favor of uptitration of either class of inhibitors of the RAS as compared with the combination of the two for the control of either blood pressure or proteinuria is increasing .
The Diabetics Exposed to Telmisartan And enalaprIL (DETAIL) study was designed to compare the long-term renal outcome of treatment with an ARB versus an ACEI, with titration to the higher dose after 4 weeks, in patients with type 2 diabetes, mild-to-moderate hypertension, and albuminuria . The main results show that the ARB offered comparable renoprotection to the ACEI. Renoprotective properties of ARBs are being tested in primary prevention in studies such as ROADMAP, designed to assess whether an ARB can prevent or delay the onset of microalbuminuria and whether this translates into protection against CV events and renal disease in patients with type 2 diabetes .
The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was designed to compare the effects of different antihypertensive agents on CV disease outcomes . Several factors need to be considered in interpreting the renal outcomes comparison between lisinopril and chlorthalidone. Patients who could not be withdrawn from their antihypertensive therapy (if they were taking any of the blinded class medications before enrollment) could not be entered into the study. Accordingly, patients with an established nephropathy who were already taking ACEIs may have been excluded.
The Systolic Hypertension in Europe (Syst-Eur) study included more than 4600 patients aged >60 years with isolated systolic hypertension. Antihypertensive treatment used in this study started with a calcium channel blocker, such as nitrendipine, and prevented proteinuria, especially in patients with diabetes. Active treatment also prevented mild renal dysfunction and slightly, but significantly, decreased the serum creatinine concentration in patients with initial proteinuria . In the active treatment group, serum creatinine did not change in patients on nitrendipine monotherapy, but was higher for patients who received the diuretic therapy alone or in combination with other study medication.
Kjeldsen and Julius published a meticulous analysis of the most relevant trials with CV end points  and reported that RAS inhibitors may confer protection to the vascular properties of the population with hypertension. They suggest that their effects may go beyond blood pressure reduction. But the ambiguous results of a meta-analysis have stimulated the debate about the benefits of RAS inhibitors on renal outcomes. Casas et al published a study analyzing the assumption that inhibition of the RAS has specific renoprotective effects beyond those resulting from lowering blood pressure alone . They included randomized, controlled, parallel-design studies and examined the effect of any drug treatment with a blood-pressure-lowering action on progression of renal disease, assessed by doubling of serum creatinine and ESRD and secondary continuous markers (GFR, serum creatinine, and UAE). Studies had to have a minimum follow-up of 1 year. The results of Kjeldsen and Julius confirmed the significance of blood pressure control to prevent renal disease development and progression, in the absence of evidence of a significant beneficial effect of RAS-blockade therapies. This meta-analysis included both trials devoted to investigate renal end points as the primary objective and trials where the primary end points were CV outcome. Differing number of follow-up periods (insufficient to investigate renal outcome) in those studies not primarily renal, and the absence of albuminuria estimation in most cases, impede an adequate evaluation of these conclusions.
A number of evidences support the benefit of ACEIs to CKD evolution. In the Prevention of Events with ACE inhibition (PEACE) trial, a significant interaction between eGFR and treatment was observed. It was suggested that the relation between eGFR and outcome was substantively modified by ACEI therapy and that patients with a reduced eGFR may be most likely to benefit from the CV protective effects of ACEIs . CKD is closely related to the development of CV events, but the association between these pathophysiological processes is not completely understood. It seems that patients with CKD are likely to have increased coronary microvascular disease even in early stages and without symptoms. A correlation between low eGFR and reduced coronary flow reserve, which suggests parallel modifications in the renal and coronary microcirculation, has been published, adding data to the increased propensity of patients with CKD for CV events . The effect of reduced eGFR on increased CV morbidity and mortality might be independent of UAE and metabolic control in populations with type 2 diabetes. This elevated risk associated with CKD is not fully explained by other accompanying risk factors. In the setting of a myocardial infarction, a graded inverse association has been observed between mild to moderate CKD and survival.
The Survival And Ventricular Enlargement (SAVE) trial randomized patients with acute myocardial infarction and LV dysfunction (LV ejection fraction 40%) to receive an ACEI or placebo. It demonstrated that ACEI therapy was associated with reductions in the risk of death, the development of heart failure, and recurrent myocardial infarction . Kidney disease has also emerged as a risk factor for mortality in populations with heart failure, and the rate of decline in renal function has proved to be a strong predictor of increased mortality in this population, independent of worsening heart failure and baseline kidney function.
Individuals with CKD usually have multiple risk factors for CV disease, in particular if type 2 diabetes is the etiology. A strict glycemic control is crucial, as well as the maintenance of CV risk factors in optimal parameters. Chronic, low-grade inflammation may be important in the development of microalbuminuria and diabetic nephropathy. ACEIs/ARBs and statins have anti-inflammatory properties that may contribute to reductions in CV morbidity and mortality independently of improvements in blood pressure or lipid profiles, respectively. Drugs such as the thiazolidinediones (TZDs) that achieve glycemic control and possess anti-inflammatory properties may also provide this benefit. TZDs are a class of agents that lower blood pressure and glucose through reduction of insulin resistance in patients with type 2 diabetes. A TZD such as rosiglitazone combined with metformin has proved to provide a greater reduction in microalbuminuria and blood pressure than has other oral antidiabetic combinations at comparable levels of glycemic control . The mechanisms through which TZDs reduce UAE and renal damage are under debate. Systemic actions of TZDs, such as reductions in glycemia and insulinemia, as well as blood pressure levels, could be involved in a renoprotective property. Additionally, functional peroxisome proliferator-activated receptor gamma (PPARγ) receptors have been identified in renal glomerular and tubular segments, suggesting that TZDs can also protect against renal injury through direct actions on these receptors .
A post hoc analysis from the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) investigated the relationship between CKD and incident CVD in a population of patients with diabetes and documented macrovascular disease, as well as the effects of pioglitazone treatment on recurrent CVD. They concluded that this population with CKD who were treated with pioglitazone were less likely to reach a composite end point of all-cause death, myocardial infarction, and stroke, independent of the severity of renal impairment .
In addition to antihypertensive therapies, recent evidence seems to indicate that a statin must be included in the treatment of a relevant percentage of high-risk hypertensive patients, at least in patients with diabetes in any of the three stages and in all of those in stage 3 . The beneficial effects of statins on CV morbidity and mortality are mostly derived from their effect on LDL-cholesterol levels and may involve an independent effect on endothelial dysfunction. Some investigators have observed that the effects of statins exceed those expected from simply lowering LDL levels. The nonlipid mechanisms that may be involved are called pleiotropic effects, such as lipid-independent plaque stabilization, reduced inflammation, decreased thrombogenicity, increased arterial compliance, and improved endothelial function .
Statins have proved to be of great value in patients with an elevated global CV risk, whether or not accompanied by elevated LDL-cholesterol levels. Moreover, the overall clinical benefits that are observed with statin therapy seem to be greater than what might be expected. Patients on statin therapy who present with CKD experience higher mortality and adverse CV event rates, which remain significant after adjustment for conventional CV risk factors, than do those who are not on statin therapy. Furthermore, CKD is common in patients with heart failure and coronary artery disease, and these patients have more advanced atherosclerosis. Nevertheless, there is a lack of appropriate risk factor modification and intervention, despite established awareness of their high CV risk and the evidence of better outcomes if they receive adequate therapy. In fact, pravastatin reduces CV event rates in people who have or are at risk for coronary disease and concomitant moderate CKD, many of whom have serum creatinine levels within the normal range. Indeed, there is controversial evidence about the effects of lipid-lowering therapy on the rate of kidney loss in people with CHD.
The Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study showed that in untreated dyslipidemic patients with CHD and normal renal function at baseline, CrCl declines over a period of 3 years, but statin treatment prevents this decline and significantly improves renal function . By contrast, a study that included 18,569 patients who had or were at risk for coronary disease, 3402 of whom had moderate CKD, showed that pravastatin modestly reduced the rate of kidney function loss . A meta-analysis examined the effect of statins in UAE and concluded that statins may have a beneficial effect on pathologic albuminuria. The validity of this finding—whether this effect translates into reduction of CV or ESRD—requires larger studies .
Aspirin has been reported to interfere with the blood-pressure-lowering effect of ACEIs, beta-blockers, and diuretics and to abolish the peripheral vasodilatory activity of ACEIs, which may deteriorate renal function in patients with heart failure. Information provided by the HOT trial helped answer this controversy, including more than 18,000 intensively treated patients with hypertension who received either aspirin 75 mg daily or placebo for 3.8 years. Reported data concluded that low-dose aspirin does not interfere with the blood-pressure-lowering effects of diverse antihypertensive agents, including ACEIs, or with renal function .
There is evidence concerning the efficacy and the safety of low-dose aspirin in patients with CKD, although this therapy is underused when CKD is associated with acute myocardial infarction. Therefore, the relevance of CKD in high-risk patients requires an integrative therapeutic approach to protect fully and simultaneously renal and CV systems (Table 4).
||TABLE 4. Global therapeutic strategies to prevent renal damage
Future evidence will be addressed by a number of ongoing outcome trials designed to evaluate a more complete inhibition of the RAS system with arenin inhibitor, for example, with aliskiren in the Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints (ALTITUDE) . Aliskiren is a drug that has showed efficacy, tolerability, and end-organ protection. Rimonabant, a drug that targets the endocannabinoid (CB) pathway by inhibiting the CB1 receptors and that demonstrates evidence as an effective agent for weight loss and smoking cessation, independently improves patients' CV risk profiles. In addition, further data will show if rimonabant offers end-organ protection and long-term CV end points in such trials as the Evaluation of the Rimonabant Impact on the Regression of Asymptomatic Damage Caused by Cardiovascular Risk Factors (RIALTO) and the Comprehensive Rimonabant Evaluation Study of Cardiovascular End Points and Outcomes (CRESCENDO) trial [119,120].
In conclusion, CKD creates high added CV risk in patients with hypertension. Strict blood pressure control must be obtained in most cases by combination therapy that must include an ACEI or an ARB. This must be accompanied by a statin and aspirin, the latter added once blood pressure control has been attained.
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