Renin and Antihypertensive Drug Therapy in African Ancestry Patients

In 1898, the Finnish physiologist Robert Tigerstedt described in the paper “Niere und Kreislauf” (Kidney and Circulation) his experiments with his student Bergman in the year before: “In der Niere wird eine den Blutdruck steigernde Substanz gebildet und dem Blute übergeben” (a blood pressure enhancing substance is synthesized by the kidney and transmitted to the blood).1 In series of experiments on the “inner secretions” of organs using kidney extracts, Tigerstedt found that the renal cortex synthesizes a substance that increases blood pressure through actions on the peripheral vessels. He concludes that this substance is probably a protein not previously described, and names it “renin.”1 However, others do not succeed in isolating the protein and Tigerstedt’s work is not acknowledged for more than 30 years, when Goldblatt in his classic experiments, inducing renal ischemia through clamping renal arteries in dogs, concludes that ischemia causes the kidneys to produce an “internal secretion” that increases blood pressure through vasoconstriction.2 In the decades thereafter, many scientist contributed to the science of what would become known as the renin–angiotensin–aldosterone system, as summarized in detail by Cleland and Reid,3 and others.4–6 It becomes clear that renin itself has no pressor effect, but is an enzyme catalyzing the first step of a cascade resulting in the vasoconstrictive protein angiotensin II. With methods for renin measurement now widely available, one of the first notions of an ethnic difference in renin comes in 1966, from the group of Brown et al. reporting low renin in hypertensive pregnant women of African ancestry.4 A year later, Creditor et al.5 find that renin levels are too low to measure in the majority of hypertensive African ancestry women and men studied, stating: “The studies herein described further dampen the enthusiastic expectation that levels of circulating pressor substance might parallel blood pressure and be of pathogenetic significance.” Thus, despite an understanding of the renin–angiotensin system (RAS), there is still doubt about its role in hypertension, until Laragh et al. report the blood pressure lowering effect of angiotensin converting enzyme (ACE) inhibitors in patients with high levels of circulating renin.7 Laragh forwards the idea that hypertensive patients with low plasma renin activity (PRA) have volume-dependent hypertension which is responsive to diuretics, while in patients with high PRA, renin–angiotensin vasoconstriction is dominant in the pathophysiology, with a better response to renin–angiotensin system blockers.7 Many studies have been published thereafter that assess the effect of RAS inhibitors related to renin activity and also ethnicity. Quickly, it became clear that drugs affecting the RAS system have low efficacy in hypertensive patients of African ancestry, who generally have a suppressed RAS system.8 Furthermore, clinical trials produced mixed results as to whether renin levels predict individual responses to antihypertensive drugs.9 Profiling based on age and ancestry was superior to renin levels in predicting response to ACE inhibitors and other antihypertensive drugs.9 Elsewhere in this journal, Mehanna et al.10 used a step-wise methodology to assess whether PRA would predict the blood pressure lowering response to chlorthalidone vs. metoprolol in 134 European ancestry and 102 African ancestry patients aged 17–65 years, included in the Pharmacogenomics Evaluation of Antihypertensive Responses-2 (PEAR-2) trial. With a well-evidenced cut point of PRA<0.65 ng/ml/hour vs. PRA≥0.65 ng/ml/hour, the authors first assessed the association of PRA with blood pressure reduction, before analyzing whether PRA predicts drug responses. The Pharmacogenomics Evaluation of Antihypertensive Responses-1 (PEAR-1) study, where participants were randomized to atenolol followed by hydrochlorothiazide (HCTZ), or HCTZ followed by atenolol; and the Genetic Epidemiology of Responses to Antihypertensives (GERA-1 and GERA-2) studies, where participants received HCTZ (GERA-1) or candesartan (GERA-2) were used as independent validation cohorts. Indeed, both European and African ancestry patients in PEAR-2 with PRA<0.65 ng/ml/hour had a significantly greater reduction in systolic blood pressure (SBP) to chlorthalidone than to metoprolol, of respectively −15.9 and −12.4 mmHg. But in those with PRA≥0.65 ng/ml/hour, the difference was modest. European ancestry patients had a 3.3 mmHg greater reduction in SBP to metoprolol than to chlorthalidone, and African ancestry patients had similar responses to both drugs. The area under the receiver operating characteristic (ROC) curve (0.69, P<0.05) showed that PRA can predict SBP response among European ancestry patients. Using PEAR-2 as a discovery cohort, the authors derived a new cut-off point for PRA levels in African ancestry patients, where metoprolol and chlorthalidone induced similar effect, at 1.3ng/ml/hour. In the meta-analysis of PEAR-1 and GERA, African-Americans with PRA<1.3 ng/ml/hour had a better SBP response to HCTZ than to atenolol or candesartan, whereas those with PRA≥1.3 ng/ml/hour had a greater reduction (−7.6 mmHg) to atenolol or candesartan than to HCTZ. However, PRA at the 1.3ng/ml/hour cut-off point had only 10% sensitivity to identify African ancestry patients who would be atenolol or candesartan responders. The ROC curve indicated that PRA could not predict SBP response to atenolol in African ancestry patients. The authors conclude that the PRA cut-off point of 0.60–0.65 ng/ml/hour is useful to guide antihypertensive drug therapy in European ancestry patients, but not in African ancestry patients.10 Conflicting results on renin as a predictor of the response to antihypertensive drug therapy have been reported previously in the African ancestry group.9 In our systematic review, renin as a continuous measure did not predict the response of African ancestry patients to diuretics (hydrochlorothiazide, furosemide, or spironolactone) in four out of six studies.9 This does not exclude that low renin may predict the presence of volume-dependent hypertension as defined by Laragh,7 with an adequate response to diuretics. This is also the finding of Mehanna et al., regardless of ethnicity.10 However, although high renin might lead to high vascular contractility as in the experiments of Tigerstedt and Goldblatt, relatively low renin is frequently observed in African ancestry patients, while this group has high vascular contractility and sodium retaining ability.9,11 Importantly, low renin does not cause or explain the greater occurrence of hypertension, nor the enhanced vascular contractility and sodium retention reported in this group.9,11 Therefore, other factors than renin are probably relevant for the pathophysiology of hypertension and drug responses in African ancestry patients. New views have developed, pointing to a central role of low NO bioavailability and greater activity of ATPases involved in pressor responses, including sodium/potassium ATPase, which is the driving force of sodium retention throughout the kidney,11,12 and calcium-ATPase and myosin ATPase involved vascular contractility, leading to higher blood pressure levels, with low renin as a result of volume expansion (Figure 1).9,11 Renin and new causal pathways in hypertension. Primary hypertension is characterized by enhanced renal sodium retention and arterial vasoconstriction. With an increase in blood pressure, renal perfusion generally increases, and this leads to lower renin secretion. Hence, low renin might reflect relative volume overload that is responsive to diuretics.9,10 Importantly, greater tendency towards salt retention and high vascular contractility are often found in hypertensive African ancestry patients, while renin and aldosterone are generally not increased.9 Thus, other pathophysiological mechanisms than the renin–angiotensin–aldosterone system have been implicated. Increasing evidence indicates that perturbations of nitric oxide (NO) metabolism and enhanced ATPase activity might be involved in the enhanced pressor responses.9,11 This includes Ca2+- and myosin ATPase for contractility responses and Na+/K+-ATPase involved in sodium retention.9,11,12 The demand for creatine involved in ATP regeneration might further compromise L-Arginine and NO bioavailability.9,11,13 This causal model better explains the clinical characteristics of low-renin hypertension and the efficacy of drugs including calcium blockers (CAB), which induce NO-independent vasodilation, and diuretics, which promote sodium excretion. In addition, hyper-contractile resistance arteries might be more susceptible to vasoconstriction induced by beta-adrenergic blockers, while the stimulating of effect of angiotensin converting enzyme on NO bioavailability might be attenuated.9 However, currently there are no validated markers for drug response in African ancestry. Until further data become available, self-defined African ethnicity remains the best predictor of response to antihypertensive drugs.9 (−) inhibition; (+) stimulation. Red dotted line, inhibition. These causal factors have also been associated with the blood pressure lowering efficacy of drugs.9,11 The lower efficacy of ACE inhibitors and beta-adrenergic blockers in the African ancestry group is thought to be related to the repressed RAS system.9,10 Aside the effect of ACE inhibitors on the conversion of angiotensin I to angiotensin II (thereby reducing vasoconstriction, hypertrophy, and endothelial dysfunction), improved bradykinin availability probably contributes to the effect of these drugs.14 The molecular mechanisms involved in the effect of ACE inhibitors include upregulation of endothelial cell NOS activity and an increase in NO bioavailability.14 Therefore, perturbations in NO metabolism as seen in African ancestry patients are perceived to contribute to the attenuated effect of ACE inhibitors.8,9,11,14,15 As renin lowering contributes to the antihypertensive effect of beta-adrenergic blockers, these drugs are expected to be less effective in subjects of African ancestry,9,10 but inhibition of beta-2-mediated vasodilation may also induce peripheral vasoconstriction.9 This effect might be enhanced with pre-existent vascular hypercontractility as found in the African population.8,9,11,15 Antihypertensive drugs that promote sodium excretion such as thiazide diuretics, or enhance NO-independent smooth muscle relaxation such as calcium blockers are effective in this population subgroup. Thus, the presented causal model expands the renin model to include other pathways involved in hypertension, and may help explain responses to specific blood pressure lowering strategies beyond renin levels.9 In summary, the pathophysiology of hypertension in African ancestry indicates that low renin may be associated with volume expansion and response to diuretics. However, the predictive value of renin as a continuous measure is hampered in subpopulations where other (non-RAS) causal factors for vascular hypercontractility and sodium retention may contribute to high blood pressure. New biomarkers have been suggested to predict the effect of antihypertensive drugs,9,11 but these have not yet been clinically validated. Hitherto, African ancestry remains the best predictor of responses to antihypertensive drugs.9 L.M.B. is an inventor on patent WO/2012/138226 (filed).