Should We Routinely Measure Renin Levels to Diagnose and Treat Patients With Hypertension?

THE ARGUMENT FOR—

Phyllis August, MD, MPH, Weill Medical College, Cornell University, New York, NY

The validity as well as the usefulness of measuring components of the renin‐angiotensin‐aldosterone system in the diagnosis and treatment of patients with elevated blood pressure (BP) has been debated for many years. Advocates of measuring plasma renin activity argue that this approach leads to individualized treatment, which is more likely to lower BP in a timely manner with fewer drugs. ¹ Additionally, curable forms of secondary hypertension will be identified earlier. Opponents argue that tailoring antihypertensive therapy based on renin sodium profiling, compared with a conventional approach to treatment, has never been demonstrated to lead to improved clinical outcomes such as reduction in stroke, coronary artery disease, and cardiovascular mortality. ² Both arguments clearly have merit, and I propose a reasonable approach to using the renin sodium profile based on available data. I also support the idea of further clinical investigation of the use of renin profiling to better establish its utility.

It is worth emphasizing some widely publicized, yet nevertheless disheartening, facts regarding treatment of hypertension. Hypertension is the most treatable and prevalent risk factor for cardiovascular disease. It has been more than adequately demonstrated that lowering BP reduces cardiovascular morbidity and mortality. Nevertheless, only 36% of patients with hypertension have adequately controlled BP. ² There remain some major unresolved issues regarding the treatment of hypertension. For example, the optimum BP treatment targets have not been adequately identified. Although the cumulative evidence suggests that the most important determinant of cardiovascular outcome in patients with hypertension is achieving lower BP, there is a large body of reasonably persuasive evidence that specific antihypertensive agents may have benefits beyond BP lowering. Considerable resources have been consumed in an attempt to determine the ideal approach to initial treatment of hypertension, despite the realization that to achieve BP targets, many, if not most, patients will require more than one drug, thus diminishing the importance of this question.

The treatment of the individual patient with hypertension is not as straightforward as implied by guidelines. Patients with hypertension may present to the physician with a variety of different situations, making application of guidelines less helpful. For example, patients may present untreated with newly diagnosed hypertension—the easiest scenario to deal with. They may present with inadequately controlled BP on one or more drugs, in which case the physician must decide whether to add additional medication or to switch from one drug to another. Patients may present with resistant hypertension on multiple drugs, or they may present with intolerable adverse effects of therapy. Each of these scenarios presents unique challenges.

THE UNTREATED PATIENT WITH NEWLY DIAGNOSED HYPERTENSION

These individuals are more likely to be younger (<50 years of age) and more likely to have stage 1 or 2 hypertension. The ideal approach to treatment remains uncertain. Most agree that the goal of treatment is to prevent cardiovascular morbidity and mortality, lower BP, and rule out secondary hypertension. Most would also agree that lifestyle modification is advisable and has little down side. Unfortunately, lifestyle modification is frequently not sufficient to achieve BP targets, and pharmacologic therapy is required. ³ The most widely accepted strategy for selecting pharmacologic therapy is that endorsed by the Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7). ² This is an evidence‐based strategy that recommends using drugs that have been shown to reduce adverse clinical outcomes, e.g., cardiovascular morbidity and mortality, taking into consideration important comorbidities such as established heart disease, renal disease, or diabetes. Another approach is to select initial antihypertensive therapy based on either demographic characteristics or hormonal/biochemical profiling. For example, the Veterans Affairs Cooperative study ⁴ demonstrated that younger white patients respond well to angiotensin‐converting enzyme (ACE) inhibitors or β blockers and older black patients will respond better to diuretics and/or calcium channel blockers. The observation has been made that African Americans have a higher prevalence of salt sensitivity, are thus more sensitive to diuretics, and often require higher doses of ACE inhibitors and angiotensin receptor blockers compared with other groups. ⁵ Choosing therapy based on hormonal profiling, particularly on renin sodium profiling, has been advocated most strenuously by Laragh and colleagues. ¹ Their underlying premise is that essential hypertension is heterogeneous and involves different mechanisms in different people; patients with similar degrees of hypertension respond quite differently to similar drug treatments. Over 30 years ago, these investigators studied 330 patients with essential hypertension on a metabolic ward and observed that untreated hypertensive patients could be distinguished by baseline renin levels while ingesting a controlled sodium diet. ⁶ Approximately 30% of patients were distinguished by a low plasma renin activity despite sodium restriction. This form of hypertension is characterized by volume excess and a favorable response to either diuretics or calcium channel blockers. Approximately 15% of patients were categorized as “high renin” and despite a high sodium diet, failed to suppress plasma renin activity. The majority (55%) of patients were in the “normal or medium” renin subgroup and have a combination of volume and vasoconstrictive factors contributing to their elevated BP. There are several underlying assumptions to the renin‐based strategy. First, the assumption is that measurement of renin accurately identifies hypertensive patients who will have a predictable response to specific antihypertensive therapy. The second underlying assumption is that specific therapy is more effective in different subgroups, e.g., diuretics and calcium channel blockers are more effective in low‐renin patients and ACE inhibitors or angiotensin receptor blockers are more effective in high‐renin patients. Combination therapy is usually necessary in patients with medium‐renin levels, since both vasoconstrictive and volume mechanisms may be involved in the pathogenesis of their elevated BP.

How strong are the data supporting this approach to therapy? Unfortunately, although this approach appeals to reason and a mechanistic approach to treatment, there have been surprisingly few studies that have tested and validated this approach. The largest is the Veterans Affairs Cooperative study. ⁴ In this trial of 1292 subjects, therapeutic responses were consistent with baseline renin; however, age and race were better predictors of response to treatment. Other smaller studies have been conducted; however, none have rigorously addressed the issue of whether renin profiling leads to better outcomes of hypertensive patients.

In spite of the lack of clinical trials that have addressed this question, there would be potential advantages to a screening test that could intelligently guide antihypertensive therapy. Such an approach could lead to earlier recognition of secondary hypertension and mechanistically based therapy that might lower BP in a shorter period of time, with fewer drugs per patient, and hopefully fewer adverse effects. Whether such an approach would also lead to better clinical outcomes (reduced stroke, reduced cardiovascular morbidity and mortality) remains to be established.

MEASURING RENIN IN PATIENTS ALREADY ON THERAPY

More common than the newly diagnosed, untreated patient with hypertension is the individual on therapy with inadequately treated hypertension. In such cases the physician must decide whether to increase the medication that the patient is already taking, add a second or third drug, or stop the current medication and switch to another medication. If the clinical history is not helpful (e.g., there is no documentation of the efficacy of drug “A”), then measuring a renin level (either plasma renin activity or direct renin) can be helpful, provided the known effects of various drugs on renin levels are taken into consideration. For example, an individual with uncomplicated essential hypertension is taking lisinopril 40 mg daily and has a BP of 160/95 mm Hg. Measuring a plasma renin level can guide your response in this situation. If the renin level is very low, then it is unlikely that the lisinopril is having much of a therapeutic effect, since patients with a reactive renin system should have an increased renin while on ACE inhibitor therapy. A reasonable strategy would be to stop the ACE inhibitor and start a diuretic. If the renin level is high, then it might be reasonable to add either a β blocker or an angiotensin receptor antagonist. Similarly, if a patient taking a diuretic still has elevated BP and the renin level is high, then an ACE inhibitor or angiotensin receptor blocker should be considered. If the renin level is low while on a diuretic, then an aldosterone antagonist could be considered.

MEASURING RENIN IN PATIENTS WITH RESISTANT HYPERTENSION

Patients with true resistant hypertension should be carefully evaluated for secondary hypertension. Resistant hypertension is rare and is operationally defined as elevated BP despite three antihypertensive agents including a diuretic. For example, a 50‐yearold male was referred to the Cornell Hypertension Center for treatment of “resistant hypertension.” He had hypertension for 15 years, treated with amlodipine with suboptimal control (150–160/80–90 mm Hg). He had an acute myocardial infarction with a subsequent coronary artery bypass operation. He was treated postoperatively with lisinopril, metoprolol, verapamil, Hyzaar (losartan potassium and hydrochlorothiazide; Merck & Co., Whitehouse Station, NJ) and terazosin and had a BP of 200/110 mm Hg. His serum potassium was 3.8 mEq/L. He was switched from verapamil to amlodipine, and a plasma renin and 24‐hour urine aldosterone excretion were measured. His plasma renin was 0.15 ng/mL/h, and his urine aldosterone excretion was 35 μg/d. A computed tomography scan demonstrated an adrenal nodule. Spironolactone 25 mg daily was added to his regimen, and Hyzaar was discontinued. His BP is 120/80 mm Hg and he is considering adrenalectomy. This case illustrates that in cases where secondary hypertension is a consideration, measurement of renin can be invaluable, particularly when mineralocorticoid hypertension is present.

SHOULD A TRIAL OF RENIN‐GUIDED THERAPY BE CONDUCTED?

Given the lack of adequate BP control in the population and the unequivocal importance of BP control in preventing morbidity, a clinical trial evaluating a renin‐based strategy for treating hypertension could be considered. Such a trial would necessitate clear delineation of the hypothesis to be tested. Possible questions that could be answered by such a trial include: Will renin‐guided therapy compared with standard of care (JNC 7 approach) lead to: 1) fewer cardiovascular events; 2) lower BP after 1 year of treatment; 3) reduced cost of treating hypertension; 4) better patient satisfaction (fewer adverse reactions); or 5) greater number of cases of curable (secondary) hypertension diagnosed? In view of the expense and duration of a trial that evaluated “hard clinical outcomes” (i.e., stroke, coronary disease), such a trial may simply be too costly; however, other outcomes such as BP control, cost, and side effects are important. Any trial that evaluates the utility of renin‐based treatment of hypertension should take into consideration the cost effectiveness of this approach, since a plasma renin profile would not only add to the expense of treatment, but may also lead to additional expensive diagnostic tests. On the other hand, more effective and timelier BP control could control health care costs considerably. The logistics of conducting a clinical trial of renin‐based treatment are not trivial. Should only untreated patients be studied? Should high‐risk patients be studied (diabetics, elderly)? What would be appropriate inclusion/exclusion criteria?

CONCLUSIONS

Measuring renin levels can be helpful in the management of hypertension. Although baseline renin measurements may lead to better BP control and the use of fewer medications, this hypothesis has never been formally tested in a large clinical trial. A clinical trial measuring surrogate end points such as BP control, cost, and time to control BP would provide useful information and should be considered. Renin measurement may also be useful in the management of patients already on treatment in whom BP is not at target. Measurement of renin levels is also a first step in the investigation of secondary hypertension, particularly mineralocorticoid hypertension.