Medical Care

Improvements in blood pressure (BP) control are closely linked to the decline in cardiovascular and cerebrovascular mortality rates that has occurred over the last 3 decades. Epidemiologic studies underscore that even modest decrements of kidney function, usually identified by a serum creatinine level of greater than 1.4 mg/dL or estimated glomerular filtration rate (eGFR) of less than 60 mL/min, magnify long-term cardiovascular risk. One interpretation of these findings is that nephrosclerosis is part of generalized vascular disease. The National Kidney Foundation has identified that a reduction in the cardiovascular risks associated with renal disease is a critical focus of the care of patients with kidney disease.

Treatment of hypertension in patients with parenchymal renal disease is also effective in preserving kidney function, particularly in proteinuric kidney diseases such as diabetic nephropathy. Similarly, positive evidence suggests that antihypertensive treatment protects kidney function in patients with malignant hypertension.

Remarkably, whether treating hypertension is effective to prevent end-stage renal disease (ESRD) attributed to hypertensive nephrosclerosis is not clear. This is surprising because the percentage of patients aware of their hypertension has increased from 51% to 84% over the last 20 years. At the same time, the percentage of patients on antihypertensive medications increased from 36% to 73%. However, studies have shown that BP is adequately controlled (< 140/90 mm Hg) in only 25-30% of patients taking antihypertensive medication.

Early data from large treatment surveys provide little information on the ability of antihypertensive treatment to prevent progressive deterioration in kidney function in patients with essential hypertension. For example, Beevers and Lip (1996) analyzed the combined results of 9 major treatment trials of mild hypertension, which included 21,826 patients.^[37]According to their analysis, the number of patients randomized to active treatment who subsequently developed kidney failure was the same (ie, 50) as those patients who were randomized to placebo treatment.

Similarly, among the 2125 cases of men with hypertension followed by Madhavan et al (1995), no evidence showed that controlling BP influenced kidney function.^[38]Patients with hypertension who were treated for up to 5 years exhibited GFRs and renal plasma flow rates similar to those obtained in patients who were not treated. In the Hypertension Detection and Follow-up Program (HDFP), kidney function was found to decline in some patients despite optimal antihypertensive treatment.

Zucchelli and Zuccalà (1998) followed the cases of 30 patients with essential hypertension for more than 20 years.^[39]In 15 of these patients, kidney function was maintained, while the other 15 patients showed the onset of renal impairment. Both groups were matched for age, sex, and treatment duration. At the end of the study, BP profiles indicated similar or better pressure control in patients with progressive kidney disease compared with patients with normal kidney function.

Similarly, Rostand et al (1989) retrospectively reviewed the records of 181 patients with hypertension.^[40]In patients with a primary kidney disease diagnosed based on either suggestive medical history or kidney biopsy findings, those with urinary protein excretion of 1.5 g/d or greater, or a serum creatinine level of 1.5 mg/dL or greater, were excluded from the analysis. Ninety-four patients were considered as having essential hypertension. Fourteen patients (15%) had an increase in their serum creatinine level greater than 0.4 mg/dL from baseline. However, kidney function declined and was independent of the degree of BP control. In addition, Whelton and Klag (1989) reviewed 6 large antihypertensive treatment trials and reported that the total number of renal events was small, with no statistical difference between the treated groups and the placebo groups.^[41]

Toto et al (1995) reported on a long-term, prospective, randomized trial of 87 patients with the clinical diagnosis of hypertensive nephrosclerosis to determine whether strict versus conventional BP control was associated with a slower decline in kidney function.^[42]In this trial, strict control of BP (ie, mean diastolic BP of 81 mm Hg ± 0.8) was not better than conventional BP control (ie, mean diastolic BP of 86.7 mm Hg ± 1.1) for preserving kidney function; however, both groups experienced a slow decline in the GFR.

Hsu (2001) conducted a meta-analysis of 10 randomized controlled trials of antihypertensive drug therapy of more than 1 year's duration that reported kidney dysfunction as an outcome.^[43]Trials enrolling only those patients with known kidney insufficiency or established renal parenchymal disease were excluded. Totals included 26,521 individuals, 114,000 person-years, and 317 renal outcomes. This meta-analysis failed to demonstrate a difference between treated and untreated subjects regarding the development of ESRD. Notable limitations of this study were that (1) the study did not address how stricter or longer-term control of BP would affect the incidence of kidney dysfunction, and (2) the study was unable to evaluate the effects of newer classes of antihypertensive medications, such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs).

Similarly, Ruilope et al (2001) reported on the kidney function effect of intensive lowering of BP in hypertensive participants of the Hypertension Optimal Treatment (HOT) study.^[44]Baseline serum creatinine values were available in 18,597 patients. Among them, 470 subjects had a serum creatinine value higher than 1.5 mg/dL. Their conclusion was that, in contrast to patients with normal kidney function, the frequency of major cardiovascular events did not differ in the 3 groups of patients with mild kidney insufficiency randomized to different diastolic BP targets. In most patients, no significant changes in serum creatinine values were noted at the end of the 3- to 9-year treatment period. However, a small group of patients (0.58% of the total study population) had deterioration of kidney function (increase of > 30% over baseline and final serum creatinine values >2 mg/dL) despite a satisfactory reduction in diastolic BP.

A criticism to the study is that systolic BP remained more than 10 mm Hg (mean) above the goal of less than 130 mm Hg, which has been recommended for patients with high serum creatinine levels, and the attained BP differed by only 4 mm Hg among the lowest and highest target groups (139.7-143.7 mm Hg). Whether tighter systolic BP control could have had an impact in this population with progressive renal impairment cannot be addressed with the available data. In any case, the group of hypertensive patients in whom kidney function progressively deteriorated was small.

Studies of black patients with hypertension have not consistently shown a benefit of BP control on the progression of kidney disease. Determining whether more intense BP control may slow kidney disease progression in black patients was the objective of the AASK trial. The study involved 1094 black people aged 18-70 years with GFRs from 20-65 mL/min/1.73 m² and no other identified causes of kidney insufficiency. Based on a 3 × 2 factorial design, participants were randomized equally to a usual mean arterial pressure goal of 102-107 mmHg or to a lower goal of 94 mmHg or lower and to treatment with 1 of 3 antihypertensive drugs (ie, beta-blocker, ACE inhibitor, calcium channel blocker). The primary analysis was based on the rate of change in GFR (GFR slope). Secondary outcome included confirmed reduction in GFR by 50% or by 25 mL/min/1.73 m² from the mean of the 2 baseline GFRs, ESRD, or death.

After randomization, BP decreased from 152/96 mm Hg to 128/78 mm Hg in the lower BP group and from 149/95 mm Hg to 141/85 mm Hg in the usual BP goal group. A mean separation of approximately 10 mm Hg mean arterial pressure was maintained throughout most of the follow-up period. However, the mean GFR decline did not differ significantly between the lower and the usual BP groups during the total follow-up period from baseline to 4 years. Similarly, the number of events (ie, rates/participant year) for the main clinical composite outcome (ie, declining GFR events, ESRD, death) was no different between the BP groups. As such, results of the AASK trial do not support additional BP reduction as a strategy to prevent progression of hypertensive nephrosclerosis.

These results are in agreement with previous findings in the MDRD study, which showed no effect on GFR decline in patients assigned to rigorous BP control (goal mean arterial pressure < 92 mm Hg in participants < 60 y or < 98 mm Hg in participants > 60 y) compared with the usual BP goal (ie, < 107 mm Hg in participants < 60 y or < 113 mm Hg in participants > 60 y). However, further analysis showed a protective effect of tight BP control in patients with proteinuria at baseline.

The combination of hypertension and diabetes can result in more rapid progression of kidney disease. The UK Prospective Diabetes Study (UKPDS) and few more recent studies have shown that adequate control of BP decreases microvascular complications, including nephropathy. The JNC VII guideline recommends a goal BP of less than 130/80 mm Hg for diabetic patients with hypertension.^[30]However, whether lowering systolic BP to less than 130 mm Hg would improve microvascular and macrovascular complications has remained in question.

The Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD-BP) trial was designed to answer this question.^[45]A subset of patients (4733) from the ACCORD trial were enrolled in the ACCORD-BP trial and were randomized to intensive (systolic < 120 mm Hg) or standard (systolic < 140 mm Hg) therapies. The participants had type 2 diabetes with cardiovascular risk factors and were an average age of 62.2 years. They were followed for a median of 5 years.

At the end of the study, no difference was noted between the 2 groups in the primary outcome defined as the first occurrence of a major cardiovascular event (composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death). The mean estimated GFR was lower in the group receiving intensive therapy, with more patients with an estimated GFR of less than 30 mL/min/SA compared with the standard-therapy group. The rate of macroalbuminuria was lower in the intensive-therapy group, but no difference in the frequency of ESRD or need for dialysis was reported. It should be emphasized patients with creatinine values greater than 1.5 mg/dL were excluded from this study. The rate of total and nonfatal stroke was higher in the standard-therapy group.

The authors concluded that no additional benefit was gained from more intensive therapy (systolic < 120 mm Hg) in diabetic patients. Even though it may be true that additional reduction in the systolic BP in diabetic patients may not further reduce the risk of coronary disease events, further reduction in systolic BP does seem to reduce the risk of stroke. Based on the ACCORD-BP trial, there does not appear to be any additional benefit from reducing the systolic BP in controlling the rate of kidney disease progression in diabetic patients with creatinine values less than 1.5 mg/dL. At this point, the question of what goal BP is optimal in diabetic patients remains unanswered.

The Systolic Hypertension in the Elderly Program (SHEP) prospectively studied the relationship between baseline BP and an incident decline in kidney function among 2182 participants older than 65 years with serum creatinine values less than 2 mg/dL enrolled in the placebo arm of the study. A decline in kidney function was defined as an increase in serum creatinine values of 0.4 mg/dL or more.

Over the 5 years of follow-up, 226 subjects experienced an increase in serum creatinine values of greater than or equal to 0.4 mg/dL. The incidence and relative risk of a decline in kidney function increased at higher levels of BP for all BP components (systolic, diastolic, pulse, and mean arterial pressure, independent of age, sex, ethnicity, smoking, diabetes, and history of cardiovascular disease). Systolic BP imparted the highest risk of decline in kidney function, with the risk tending to be greater in persons with diabetes and in black persons.

Among the limitations of this work is the failure to identify the relative contribution of patients in these 2 categories to the total of the 226 persons who showed evidence of declining kidney function. In addition, the absence of a comparison group of subjects with normal systolic BP makes it difficult to fully estimate the effect of systolic BP on kidney function.

Finally, the Hypertension in the Very Elderly Trial (HYVET) evaluated whether treatment of hypertension in patients aged 80 years or older is of any benefit.^[46]Close to 4000 patients were enrolled in the study and were divided into active treatment (indapamide +/- perindopril) versus placebo for a goal BP of less than 150/80 mm Hg and were followed for median of 1.8 years. The mean BP difference at 2 years between the 2 groups was 15/6 mm Hg. At the end of the study, patients undergoing active treatment had a lower rate of both fatal and nonfatal stroke and a reduction in overall rate of death. There was no difference in the creatinine values between the 2 groups. Those patients with creatinine values greater than 1.7 mg/dL were excluded. This study highlights the importance of treating BP in very elderly persons.

Taken together, in the universe of individuals with essential hypertension, a review of the evidence shows that (1) in patients with essential hypertensive nephrosclerosis, the absolute risk of developing renal insufficiency that will lead to ESRD is low (as opposed to hypertension being a promoter of existing kidney disease, which is well established), and (2) the progression of kidney disease is not clearly related to hypertension per se because therapeutical trials have failed to demonstrate that intensive antihypertensive therapy slows the progression of kidney diseases attributed to hypertensive nephrosclerosis.

The indications, effects, and adverse effects of the most commonly used antihypertensive medications are outlined below.