Should We Routinely Measure Renin Levels to Diagnose and Treat Patients With Hypertension? (Part I)

The Argument For

Phyllis August, MD, MPH

In This Article

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 angioten-sin-converting enzyme (ACE) inhibitors or ß 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.