Plasma Renin Measurement in the Management of Hypertension: The V and R Hypothesis

The Express version of the Seventh Joint National Committee Report on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) ¹ does not include a recommendation for renin testing in the evaluation and treatment of patients with hypertension. This omission has generated a response from those who believe that knowledge of a patient's renin status is a fundamental requirement for the optimal management of hypertension. ²

THE DEBATE

Articulation of the effects of the renin‐angiotensin‐aldosterone system (RAAS) on blood pressure regulation and cardiovascular disease mechanisms has clearly influenced modern therapy. Despite this improved understanding, the value of renin testing in individual hypertensive patients has always been debated. Those in favor believe strongly that plasma renin activity is the key to optimal individualized management. ² , ³ On the other side of the argument is a much larger group that believes that the primary issue in the management of hypertension is the achievement of goal blood pressure, with the underlying disease mechanism and choice of agent being less important. ¹ , ⁴ , ⁵

PROPOSED RATIONALE FOR RENIN TESTING

“Pro‐renin” physicians have argued that renin profiling should be performed in all hypertensive patients because it aids in the diagnosis, prognosis, and therapy of patients with hypertension. ² , ³

The fundamental basis for this assertion is the belief that individuals with high blood pressure can be characterized physiologically into one of two classes: those with a specific increase in either extracellular volume (V‐type) or those with increased vascular resistance (R‐type). The primary value of this classification is proposed to be improved drug management that matches the individual pathophysiologic abnormality and the corresponding therapeutic choice. According to this school of thought, diuretics and calcium antagonists are especially effective in low‐renin (V‐type) individuals who are volume expanded and salt sensitive. In contrast, blockers of the RAAS are said to be preferentially effective in high‐renin (Rtype) individuals. Additional justifications for universal renin testing are based on studies suggesting that plasma renin activity is an independent prognostic indicator of cardiovascular risk. ⁶ The use of plasma renin testing as a screen for secondary forms of hypertension, ⁷ especially primary aldosteronism (a low‐renin condition) and renovascular hypertension (a high‐renin condition), is also strongly advocated by some investigators.

Initially, it was believed that renin levels could only be interpreted if the degree of salt‐loading (24‐hour urinary sodium excretion) was also known since plasma renin activity is inversely related to extracellular volume status. ⁸ Thus, if sodium intake is high, renin levels should be relatively low, but if renin is high‐normal or high, there may be a disorder of the homeostatic mechanisms that regulate renin. Data clearly demonstrating that plasma renin activity is affected significantly only by extremes of sodium intake (<50 or >300 mEq of sodium daily) ⁹ have finally been accepted, and the requirement for a concomitant 24‐hour urine sodium collection has been dropped. ²

THEORETICAL CONCERNS

The notion that hypertension can be defined functionally by renin status is simply not justifiable based on logistics, physiologic variability, and the absence of confirmatory epidemiologic or clinical trial results. Even if outcome data had confirmed the value of this test, the overall cost (highly variable but as low as about $14–$20 per determination) does not seem justifiable if this was done in 50+ million hypertensive individuals in the United States; the resulting cost of almost $1 billion represents money that could be far better spent in other areas.

Measurement and Variability

There are problems with renin testing. Accurate and reproducible determination of the enzymatic activity of renin released by the kidney into the circulation (plasma renin activity) is considerably more difficult to achieve than its advocates suggest. Specific blood drawing techniques and careful sample preservation must be fastidiously performed because renin is temperature sensitive. Even if correctly determined, there is substantial physiologic within‐individual variation of renin (several‐fold) and even greater between‐individual variation (>100‐fold). Major acute physiologic influences on plasma renin include essentially all factors that affect the sympathetic nervous system, especially time of day, posture, environmental stress, and physical activity, any of which can cause a doubling or tripling of renin activity. Often, seated plasma renin levels are employed for convenience despite the exquisite sensitivity of the test to posture. Demographically, there is a trend for lower mean plasma renin activity in African Americans and a strong inverse relationship between plasma renin and age. Given its high degree of variability, plasma renin activity is not an ideal disease indicator, in part because physiologic and demographic differences in renin levels can change the classification from normal to low or normal to high.

Pathophysiology

From a pathophysiologic perspective, the notion that hypertension is simply volume‐related or resistancerelated is a gross oversimplification of the problem. There are also additional inconsistencies that deserve mention, most notably the assertion that calcium antagonists are indicated for V‐type patients. It is well known that calcium antagonists tend to promote volume expansion, not volume depletion, and therefore would be expected to be exactly the wrong agents for V‐type individuals.

Even if it is assumed that hypertension can be reduced operationally to a model that includes V and R components, V cannot be realistically evaluated without knowing R (because of the strong mutual counter‐regulatory influences that exist between the two components) and the V component simply cannot be measured clinically. Furthermore, the construct would only apply to short‐term BP responses because of the chronic restorative effects of homeostatic mechanisms that defend arterial pressure. For example, a hypertensive kidney requires a higher perfusion pressure to excrete a salt and water load. As blood pressure is lowered with nondiuretic drugs, there is relative salt and water retention, which diminishes the degree of BP lowering and results in the need for a diuretic to be added to achieve a meaningful reduction in BP. A second major BP defense mechanism includes a systemic neurohumoral response induced by diuretic or vasodilator therapy that includes activation of the sympathetic nervous system and the RAAS, and in the case of vasodilators, volume expansion, all of which tend to return of BP toward pretreatment levels. Overall, given the physiologic tendency of the body to defend arterial pressure and the inadequate effects of V or R monotherapy, it can be seen why hypertension is so grossly misrepresented by the V or R model. The continuing dynamic interaction between “volume and vasoconstriction” can be better understood by assuming that instead of being V or R, blood pressure should be determined by a V plus R model in which case renin testing becomes irrelevant.

PRACTICAL IMPLICATIONS: V OR R REDUX

No clinical trial has been completed that confirms or denies the utility of the V or R model. It seems highly unlikely, however, that much additional useful clinical information could come from universal renin testing. The validity of this statement can also be illustrated by a full discussion of each of the purported reasons for renin testing.

Drug choices

A major reason that JNC 7, or any of the previous six JNCs, did not include renin testing in its recommendations is the absence of a proper clinical trial validating its use. The JNC 7 for recommendations the use of a diuretic as initial therapy in most cases is consistent with data from clinical trials including the Antihypertensive and Lipid Lowering to Prevent Heart Attack Trial (ALLHAT) ¹⁰ but not consistent with the V and R approach. Actually, the JNC 7 therapeutic guidelines are fully consistent with a V plus R model because of the strong statement that most hypertensive patients will require two or more drugs to control BP, one of which should usually be a thiazide‐type diuretic. Proponents of universal renin testing argue that low‐renin patients do not respond to anti‐RAAS drugs or that high‐renin patients do not respond to diuretics. In practical experience, diuretics may be somewhat more effective in low‐renin patients (elderly and black patients), but they may also be effective in high renin patients. Blockers of the RAAS system may work slightly better in high‐renin patients (younger white patients and patients with severe hypertension), ¹¹ but they may also be effective in low renin subjects. The variation in individual responses is large. Thus, renin status is not as reliable in predicting responses as its proponents have suggested.

The need for combination drug therapy in hypertension is another important argument against the V or R approach. Recent clinical trials have taught us that it is pure folly to assume that a single agent will achieve target BP in the majority of people. In ALLHAT and other recent studies, over 60% of participants required combination therapy to achieve and maintain goal blood pressure. Thus, as stated by JNC 7, combination therapy is required in a large number of hypertensives. It could be said, however, that ALLHAT and JNC 7 are consistent with the V plus R concept. There was somewhat better BP control in the diuretic and calcium antagonist arms of ALLHAT (two V plus R approaches) than the angiotensin‐converting enzyme inhibitor arm (which employed 2 “R‐agents”).

Following this line of thought further, a basic tenet from observational studies is that lower is better. This statement is derived from a very large meta‐analysis that included 12 years of follow‐up in over 1 million people and analyzed the risk attendant to hypertension over the range from 115/75 to 185/110 mm Hg and found that every 20/10 mm Hg decrease in BP halved the risk of cardiovascular disease. ¹² Antihypertensive drug monotherapy can be expected to lower BP by about 10/5 mm Hg, which is equivalent to a cardiovascular disease risk reduction of about 25%. Therefore, to achieve a 20/10 mm Hg BP reduction and a corresponding cardiovascular disease risk reduction of 50%, at least two drugs will usually be needed in many cases. This notion is reflected in the JNC 7 recommendations for stage 2 hypertension (>160/100 mm Hg), where two‐drug initial therapy is suggested, and in the recommendations for treating “compelling indications,” such as diabetes or renal diseases, where three or more drugs may be needed to reach the BP goal of <130/80 mm Hg. In these more advanced forms of hypertension, renin determinations are clearly superfluous before starting therapy.

Renin and Prognosis

From a prognostic perspective, renin testing is at best problematic and may be misleading. Plasma renin activity has been reported to be an independent predictor of myocardial infarction risk, ⁶ but it is important to recognize that the population studied was a convenience sample of primarily middle‐aged white patients, not a population‐based scientific sample. In fact, from a broad population perspective, low‐renin individuals are probably at higher overall risk than high‐renin individuals because older individuals and African Americans, who tend to have low‐renin hypertension, are at higher cardiovascular risk than younger individuals or whites, who tend to have higher renin levels. While it is true that patients with severe, malignant, or accelerated hypertension have extremely high renin levels, ¹³ no study has identified deleterious effects related to renin from those related directly to the level of BP, and renin determinations are not necessary to establish a poor prognosis in those with severe hypertension.

Renin as a Diagnostic Screening Test

Plasma renin activity is far from being an ideal diagnostic indicator for the identification of secondary hypertension as it has been touted by its supporters. The major problem is that plasma renin activity is quite sensitive but poorly specific. A high sensitivity/low specificity test is a poor screening vehicle in situations where the prevalence of the condition is very low because there will be far too many false positives. Thus, there is a significant accuracy problem when renin testing is used as a screening test for secondary hypertension, which is quite uncommon (less than 1% in most practices). Overall, most patients with low renin hypertension do not have hyperaldosteronism, and most patients with high renin levels do not have renovascular disease. Accurate assessment of renal and adrenal causes of hypertension depends on tests specific to the individual conditions. Plasma renin activity can be useful on occasion as a confirmatory test.

OVERVIEW

Elaboration of the actions of the RAAS by Laragh ² , ³ and others has been important in advancing the theories regarding hypertension and cardiovascular diseases. This statement, however, in no way justifies universal renin testing. Renin determinations have not been performed in the hypertension treatment clinical trials that have reported outcome benefit. In addition, after a careful review of the data, none of the JNCs have recommended this test as part of the initial evaluation of hypertension. Based on the arguments presented, there remains little reason to advocate the use of renin testing for the diagnosis, prognostic, or therapeutic guidance‐related indications. Research‐generated information, such as the information amassed for plasma renin activity, may help in making some decisions, but rational application of therapeutic principles does not always require the use of a specific test such as plasma renin activity.