Division of Nephrology, University Hospital, Verona, Italy
Correspondence and offprint requests to: Giuseppe Maschio, MD, Divisione Nefrologia, Ospedale Civile Maggiore, I-37126 Verona, Italy.
`It is easier to split an atom than a prejudice' (A. Einstein)
High blood pressure (BP) levels are unequivocally associated with increased risks of major cardiovascular events and stroke [1]. Significant progress in the control of hypertension over the years has also led to a true explosion of morbidity and mortality trials in hypertensive patients [2]. These studies have shown a significant reduction in the incidence of cardiovascular and cerebrovascular events. This has been obtained, almost without exception, with combinations of antihypertensive agents.
Despite the impressive results of the trials, most investigators document, even today, that BP continues to be poorly controlled in too many hypertensive patients [3,4]. This is not a new problem and the failure to control BP in many treated patients was observed several years ago (Table 1). It has been repeatedly confirmed that approximately 2040% of patients fail to achieve the goal of treatment. A notable exception is represented by the results of the recently published HOT study, in which 18 790 patients from 26 countries were followed for 38 years. Satisfactory control of BP (<90 mmHg diastolic) was achieved in approximately 90% of treated patients [10].
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Is the lack of aggressiveness in the pharmacologic treatment of patients with essential hypertension also seen in those with renal disease?
Physicians are reluctant to give up two major prejudices that interfere with the goal to achieve strict control of BP in chronic renal disease.
Error 1: hypertension does not cause progressive renal disease
The kidney has been largely neglected in almost all major clinical trials on pharmacologic treatment of essential hypertension: this lack of information on renal endpoints has led to the conclusion that renal failure is not a frequent outcome of long-lasting hypertension. Only a few prospective trials have examined the effect of systemic hypertension on the kidney. According to some large community-based studies, hypertensive patients tend to lose renal function faster than normotensive subjects. In addition, systolic and/or diastolic hypertension were reported to be independent risk factors for end-stage renal failure (ESRF) in treated hypertensive patients [1113].
Indirect evidence of the prominent role of hypertension in mediating renal damage is also provided by the results of pharmacological therapy. Progressive renal failure despite treatment was observed in some studies in which diastolic BP had been kept between 90 and 100 mmHg, whereas renal damage appeared to be slowed down or even prevented in other studies in which more aggressive lowering of blood pressure was achieved [14]. Physicians must be aware that high blood pressure is an important independent risk factor for incident renal damage and progression of pre-existing renal disease. In primary nephropathies, a positive correlation between hypertension and progression of renal damage is not regularly observed. This is probably due to several confounding factors, including age, gender and race which affect the rate of progression. Also, blood pressure may exhibit an abnormal circadian pattern. Unfortunately, the circadian blood pressure profile is seldom examined in renal patients.
A bone of contention is the issue of whether systolic, diastolic or mean BP is more injurious to the kidney. The central problem is obviously the impossibility to directly measure glomerular capillary BP which is mediating renal damage. The weight of evidence argues that systolic blood pressure is a more powerful predictor of renal injury.
Nephrologists acknowledge that systemic hypertension in conjunction with proteinuria is the leading factor in the genesis of progression. They are also well aware that benefit is obtained by lowering blood pressure and proteinuria [15,16]. In contrast, general practitioners are still hesitant to lower blood pressure satisfactorily and worry about the potential risks of blood pressure lowering in renal patients.
Error 2: strict blood pressure control results in underperfusion of vital organs including the kidney
The large majority of patients with hypertensive chronic renal disease are currently treated with multidrug therapy. The advantages of combination therapy are: (i) more marked lowering of BP and a greater response rate than with monotherapy; (ii) complementary (and mutually reinforcing) actions on different target processes in the kidney; and (iii) fewer side effects since smaller doses of each drug are administered.
In a recent report from Germany [17] more than 50% of 201 patients with chronic renal failure required at least three classes of antihypertensive drugs to control BP; yet, satisfactory BP control was only achieved in 15% of the patients. The recommended goal of a target BP of less than 130/80 mmHg in patients with renal disease [18,19] is much lower than was suggested in the past. For several reasons it is not easy to achieve. First, hypertension in patients with chronic renal disease may be more difficult to control because of the simultaneous presence of several powerful mechanisms that raise BP, i.e. expansion of the extracellular volume, activation of the reninangiotensin system, increased sympathetic tone and impaired vasodilatation, perhaps because the loss of vasodilator substances of renal origin. Secondly, as previously stated, physicians and patients have to face the problem of multidrug therapy that is not always easy to follow and may result in a relatively high rate of non-compliance. Thirdly, nephrologists are still reluctant to use the new drugs (such as ACE inhibitors) out of fear that they may adversely affect renal haemodynamics in addition to lowering blood pressure, so that occasionally renal function deteriorates.
If these concerns are raised even by nephrologists, they are definitely more virulent amongst family doctors or general physicians: as a result, blood pressure values are often kept unnecessarily high in renal patients. In the same report from Germany [17] a further lowering of 20 mmHg systolic and 10 mmHg diastolic was achieved when patients were switched from the care of their family physicians to that of the renal outpatient clinic.
It is surprising that ACE inhibitors are not used more widely in patients with chronic renal disease and renal failure. Evidence-based recommendations suggest that they should be the agents of first choice in patients with mild to moderate renal failure. The AIPRI trial evaluated the outcome of blood pressure and renal function in 583 patients with renal failure of various origin, i.e. the kind of patients who are usually seen in an outpatient renal clinic. Baseline serum creatinine concentrations ranged from 1.5 to 4.0 mg/dl. Three hundred patients were randomized to receive the ACE inhibitor benazepril and 283 to receive placebo, in addition to their usual antihypertensive therapy. The goal of the study was to achieve a diastolic blood pressure of less than 90 mmHg. The prevalence of uncontrolled hypertension fell from 28 to 18% in patients treated with benazepril and rose from 27 to 32% in those receiving placebo. Of note, the average number of drugs required to control BP was lower in the benazepril group. Diastolic BP decreased by 3.55.0 mmHg in the benazepril group and increased by 0.21.5 mmHg in the placebo group. This substantial decrease in BP, and the concomitant reduction in proteinuria, were associated with a significantly better outcome of renal function in benazepril-treated patients.
In a recent meta-analysis of the most important randomized trialsincluding 1688 patients followed for a mean period of 22.8 monthsit was concluded that ACE inhibitors are better than other antihypertensive agents in reducing BP and slowing the rate of progression of renal failure in patients with non-diabetic renal disease and mild to moderate renal failure [20].
Needless to say, there are some contraindications to the administration of ACE inhibitors. They should not be used without first examining the patient and his/her renal function. Today, nephrologists can choose among a variety of antihypertensive agents, all of which are to some extent renoprotective. It is the task of the nephrologists to instruct their colleagues, who may not be so familiar with the newer concepts and agents, about the drugs most appropriate to protect the patients' residual renal function. In addition, for their own patients they must translate into clinical practice the lessons which have been provided by clinical trials and suggest that blood pressure should be lowered to values much less than what had been accepted in the past for patients with renal disease.
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