ABSTRACT. Renal damage as a consequence of uncontrolled arterialhypertension is well recognized. Antihypertensive therapy hascome to very significantly decrease the vascular damage in thekidneys of hypertensive patients. However, prevalence of mildrenal insufficiency remains present in a significant proportionof the hypertensive population. This is accompanied by a markedincrease in cardiovascular risk, as a consequence of the clusteringof other cardiovascular risk factors and of insufficiently controlledBP. Prevention and protection of renal and cardiovascular damagein these patients will be one of the most relevent tasks inthe future. E-mail: Luis_M_Ruilope@teleline.es
The kidney plays a relevant role in the origin of essentialhypertension in humans (1–3) and can suffer the consequencesof the subsequent elevation in systemic BP (4). Nephrosclerosisconstitutes together with diabetic nephropathy the most commonrenal substrates leading to the development of end-stage renaldisease (5). However, the literature published in the last decadetransmits the idea that, with an "adequate" BP control withstandard antihypertensive therapy, the kidney is well protectedand very few hypertensive patients, less than 2%, will developrenal damage as a consequence of arterial hypertension (6).A small percentage of patients suffering the renal consequencesof a very prevalent process (more than 20% of the populationis hypertensive) is enough to explain the high prevalence ofnephrosclerosis as a cause of end-stage renal disease (3). Theaim of this short review is to show that the prevalence of renaldamage is higher than previously thought in essential hypertensionand also that the presence of mild renal insufficiency constitutesan excellent predictor of increased global cardiovascular risk.
Prevalence of Mild Renal Insufficiency in Essential Hypertension
The diagnosis of renal dysfunction in clinical practice is usuallybased on the finding of an elevated serum creatinine level,or of a decrease in GFR usually measured as creatinine clearance,and/or in the detection of an elevated urinary excretion ofalbumin below (microalbuminuria) or above (macroalbuminuria)the usual laboratory methods to detect proteinuria. Mild renalinsufficiency has recently been defined as serum creatininevalues above 1.5 mg/dl (132 µmol/L) in men and 1.4 mg/dl(123 µmol/L) in women (7) or by the finding of estimatedcreatinine clearance values below 60 to 70 ml/min (8,9,10).
Table 1 summarizes the prevalence of renal damage defined asan increment in serum creatinine above normal limits or a decreasein estimated creatinine clearance in three recently publishedstudies, HOT (8), INSIGHT (9), and HOPE (10), and in a recentlypublished survey performed in 47 hospital-based hypertensionunits in Spain (11). The global cardiovascular risk of the populationincluded in the three studies differs, with the top correspondingto the HOPE study, in which patients on secondary preventionor diabetics with at least one accompanying risk factor wereincluded, followed by the INSIGHT study, in which hypertensivepatients with one or more associated risk factors were present,and finally the HOT trial, which may be said to represent thegenerality of the hypertensive population. Finally, most patientsfollowed in hypertension units present an elevated degree ofglobal cardiovascular risk (11). As can be seen in Table 1,the prevalence of mild renal insufficiency is higher than previouslythought; a direct relationship seems to exist between the levelof cardiovascular risk and the prevalence of the renal disorderbeing detected either as an elevation of serum creatinine oras a diminution of estimated creatinine clearance. This associationis not explained by the simultaneous existence of diabetes (8,9,10).
Recently, Culleton et al. (12) described an elevated prevalenceof mild renal insufficiency, around 8% in both men and women,defined as the finding of an elevated serum creatinine in theFramingham population. The authors did not relate their findingto the existence of arterial hypertension (defined as a BP inexcess of 140/90 mmHg) because the prevalence of elevated BPdid not greatly differ among those with and without a derangedrenal function. However, the article describes that the prevalenceof left ventricular hypertrophy in those patients with an augmentin serum creatinine levels was 3 to 4 times higher than in thegroup with preserved renal function. This finding indicatesthat the threshold BP to classify people with mild renal insufficiencyas being hypertensives cannot be 140/90 mmHg but must be lower.Probably in agreement with the consideration of the recent guidelines(13,14), this level must be 130/85 mmHg or even lower.
More recently, a prevalence of mild renal insufficiency definedby a serum creatinine in excess of 1.4 mg/dl of 3% has beendescribed (15) in the general population of United States. Theelevated serum creatinine levels strongly correlated with aninadequate BP control. Furthermore, the estimation of creatinineclearance in the same survey (NHANES III) has revealed thatwith a cut-off point of 70 ml/min the prevalence of a decreasedrenal function is surprisingly elevated in the US population,as can be seen in Table 2 (16).
In the Hypertension Detection and Follow-up Program trial (17),the presence of elevated serum creatinine values (> 1.7 mg/dl)at baseline was found to be a very potent predictor for 5-yrand 8-yr all-cause mortality. Data from the HOT Study (8) haveconfirmed this finding, demonstrating that serum creatininevalues above the cut-off point for mild renal insufficiencypredict an elevated cardiovascular risk even when BP controlis good. In fact, serum creatinine values in the HOT study werethe most powerful predictor of mortality, stronger than anyof the known accompanying risk factors (18). We also assessedthe prognostic value of estimated creatinine clearance valuesbelow 60 ml/min, which were associated with a significantlyelevated cardiovascular risk (8).
In the general population, the presence of an elevated serumcreatinine concentration is also associated with a high prevalenceof cardiovascular disease (12). This has been attributed tothe fact that elevated serum creatinine concentrations frequentlycoexist with several cardiovascular risk factors (3,12).
Some data indicate that nephrosclerosis, often found in hypertensivepatients, is associated with atherosclerosis of the large arteries.Nephrosclerosis is characterized by hyalinization of arteriolesand fibroplastic intimal thickening of small arteries. Interestingly,hyalinization of renal arterioles is more marked in patientswith coronary heart disease than in matched control subjects(19). Conversely, in autopsy studies, the presence of hyalinizationin the renal arterioles is a marker of the presence of advancedcoronary atherosclerosis in otherwise asymptomatic young individuals(20).
Proteinuria and Microalbuminuria as Predictors of Cardiovascular Risk
The relevance of proteinuria for cardiovascular prognosis inthe community was documented by the Framingham Heart Study (21).The presence of proteinuria in patients with treated essentialhypertension varies between 4 and 16% in different series oftreated hypertensive patients (22). The INSIGHT Study comparedthe capacity of a long-acting dihydropyridine and a diureticto diminish cardiovascular events and death in essential hypertension.This study assessed the role of proteinuria as a risk factorand confirmed that proteinuria was accompanied by a very significantincrease in cardiovascular risk similar to that accompanyingan elevated serum creatinine or the existence of a previousmyocardial infarction (23).
Attention has recently been drawn to microalbuminuria and itsrelevance as a predictor of cardiovascular disease (24). Itsprevalence varies between 20 and 30% of untreated patients andup to 25% in treated patients. Recently, it has been shown thatthe presence of microalbuminuria in primary hypertension carriesan elevated cardiovascular risk (10,25). According to a persuasivehypothesis, microalbuminuria constitutes the renal expressionof a generalized disorder characterized by increased endothelialpermeability. This hypothesis provides an explanation for thelink between increased urinary albumin excretion and elevatedcardiovascular risk (24). Some preliminary data indicate thatmicroalbuminuria is also a predictor of progressive deteriorationof renal function in primary hypertension (3,26).
Can We Prevent the Development of Mild Renal Insufficiency Related to High BP?
Development of renal damage can be the consequence of uncontrolledarterial hypertension (4), but it also seems to coexist withsmall elevations of BP in a percentage of the population characterizedby the simultaneous presence of several other cardiovascularrisk factors (3,12,15). In this case, the development of mildrenal failure is accompanied by a significant increase in globalcardiovascular risk mostly as a consequence of the clusteringof other cardiovascular risk factors. This situation mimicsdiabetes mellitus where renal and cardiovascular risk are veryhigh, and subtle elevations in BP can cause great microvascularand macrovascular damage.
Prevention of this disorder would then need an early identificationof the people at risk to develop renal damage in conjunctionwith small BP elevations in the presence of several associatedcardiovascular risk factors. This group of patients could constituteone of the intermediate phenotypes deserving genetic investigation(27).
Table 3 summarizes the therapeutic attitudes that must be consideredwhen renal insufficiency is present. They contemplate the simultaneousperformance of cardiovascular and renal protection. First arelifestyle changes; among them, three are of particular relevance:diminishing salt intake, avoidance of overweight and obesity,and withdrawal from smoking. A high salt intake makes BP controldifficult as soon as the renal function is slightly deranged(28); obesity can cause a further fall in renal function whilemaking more difficult the control of arterial hypertension (29);and smoking has been shown to clearly facilitate the progressionof renal damage (30).
Table 3. Therapeutic attitudes in patients with mild renal insufficiency and hypertension
Strict BP control (probably below 130/80 mmHg) is required andwill probably need the administration of a combination of drugs.We recently published (31) that the presence of an angiotensin-convertingenzyme inhibitor in this combination significantly improvesthe long-term renal outcome of patients with nephrosclerosis.
Strict control of the other cardiovascular risk factors presentis also required. The presence of mild renal insufficiency inhypertensives is accompanied by higher initial levels of bothsystolic and diastolic BP, a predominantly male gender, higherinitial levels of serum uric acid and triglycerides, and lowerlevels of HDL-cholesterol (3). A multivariate logistic regressionanalysis identified systolic and diastolic BP, as well as serumuric acid and triglycerides as independent predictors for thedevelopment of nephrosclerosis. Therapies such as statins withgood effects beyond the effects on serum cholesterol levels(32) and drugs improving insulin sensitivity (33) deserve tobe investigated in this disorder.
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Abstract
Introduction
