Hypertension in Africa

Schutte et al.1 describe a timely, ambitious and promising study of hypertension in South Africa. In this paper, the Hypertension in Africa Team describe baseline results in 1202 healthy volunteers (606 black and 596 white men and women) who were normotensive by clinic blood pressure readings and were aged 20–30 years during recruitment between 2013 and 2017. They also describe their plans for five-yearly follow-up visits, including detailed measurements of health behavior, cardiovascular profile and organ damage, and biological sampling for “omics” and biomarkers. This will allow the assessment of differences between black and white people with regard to genetic and other factors predisposing to hypertension. As reviewed recently,2 there is substantial evidence that black people of African origin are more likely to have hypertension resulting from the retention of salt and water, and greater sensitivity to the increased secretion of aldosterone. African-Americans are more likely to have hypertension, more likely to have their hypertension diagnosed, more likely to have it treated more intensively, but less likely to have it controlled. The observation that African-Americans born in the USA are nearly twice as likely to be hypertensive as foreign-born African-Americans supports the African diaspora hypothesis3—that there was a natural selection for a genetic predisposition to salt and water retention because of the very high mortality of slaves from vomiting, diarrhea and sweating during transport across the Atlantic, and then during the first few years of work on plantations in the southern USA. Hypertensive phenotypes that identify the best treatment for resistant hypertension can be identified by measuring plasma renin and aldosterone. Although salt and water retention suppress plasma renin activity, there are two streams of low-renin hypertension for which the best treatment is different. The specific treatment for a low-renin/low-aldosterone (Liddle) phenotype is amiloride.4 In addition to actual mutations of the SCNN1B gene, there are variants of a few genes that affect the function of the epithelial sodium channel (ENaC), resulting in the Liddle phenotype. Many variants of these genes have been found among African patients with uncontrolled hypertension and a Liddle phenotype.5 The Liddle phenotype is far more common than most physicians suppose. Baker et al.4 found a variant of the SCNN1B gene among 5% of black patients in London, UK, mainly of Caribbean origin. Jones et al.6 described a different variant of the SCNN1B gene in South Africa; it was found in 5.9% of hypertensive patients in South Africa, including the Nguni-Zulu (9.1%), Sotho (6.4%), Nguni-Xhosa (6.3%) people and in 20% of unselected San people from the Kalahari Desert. Among patients attending a Veterans’ Administration hypertension clinic in Louisiana, USA, 6% had a Liddle phenotype. The reason this is important to recognize is that amiloride, an ENaC antagonist, is the specific treatment for this condition. The other stream of low-renin hypertension is due to primary aldosteronism/inappropriate aldosterone secretion, with high levels of aldosterone causing salt and water retention and suppressing renin activity. Among patients with that phenotype in the African study,5 there were 14 nonsynonymous variants of the CYP11B2 gene (for making aldosterone synthase); of these, nine variants were found in all nine patients sequenced. In addition to the CYP11B2 gene, there are a number of other genes that cause primary aldosteronism/inappropriate aldosterone secretion. The primary treatment for this phenotype is aldosterone antagonists, whereas for the renal phenotype (high renin/high aldosterone) the primary treatment would be an angiotensin receptor blocker (ARB) or a renin inhibitor. Among patients with uncontrolled hypertension in clinics in Nigeria and South Africa, physiologically individualized therapy (PhysRx) based on renin/aldosterone phenotyping was significantly better than usual care.7 At the Nigerian site, where care more closely resembled that in high-income countries and where patients were randomized to the two treatment strategies, systolic control was obtained in 15% of usual care (UC) vs. 85% of PhysRx (P = 0.0001), diastolic control in 45 vs. 75% (P = 0.11) and control of both systolic and diastolic pressure in 15 vs. 75% (P < 0.0001) even though the renal function of patients was poorer at that site.7 The most significant difference in medication in that study was with amiloride, which was used in only 2.8% of usual care vs. 19% of PhysRx. This finding suggests that the Liddle phenotype may be much more common than previously supposed. It is possible that although variants of the SCNN1B gene are not very common, there are variants of a few genes that increase the function of ENaC. Figure 1 summarizes the physiology underlying individualized treatment based on renin/aldosterone phenotyping. Schematic representation of sodium handling by the kidney, syndromes causing hypotension and hypertension, genetic factors influencing sodium reabsorption, and potential targeted therapeutic options. Red denotes syndromes causing sodium retention and hypertension; blue denotes syndromes causing sodium wasting and hypotension; orange denotes genes influencing sodium reabsorption; and green denotes specific antihypertensive drug classes. The approximate sodium reabsorption in segments of renal tubules is given in brackets. ACEi: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; AS: aldosterone synthase; CASR: calcium-sensing receptor; CT: collecting duct; CYP4A11: cytochrome P450, family 4, subfamily A, member 11; DCT: distal convoluted tubule; ENaC: epithelial sodium channel; GRA: glucocorticoid remedial aldosteronism; GRK–4: G protein-coupled receptor kinase 4; KCNJ1: potassium voltage-gated channel, subfamily J, member 1; NEDDL4: neural precursor cell expressed developmentally downregulated 4, E3 ubiquitin protein ligase; NEP: neutral endopeptidase; NR3C2: nuclear receptor subfamily 3, group C, member 2; PCT: proximal convoluted tubule; PHA: pseudohyperaldosteronism; ROMK: potassium inwardly-rectifying channel; SCNNB1: sodium channel epithelial 1 beta subunit; SCNN1G: sodium channel epithelial 1 gamma subunit; WNK 1,4: lysine deficient protein kinase 1, 4. The figure was prepared by Michael Wyeth of Imago-Visual, Cape Town, South Africa. Reproduced by permission of Wolters Kluwer Health from: Spence JD and Rayner BL. Hypertension in blacks: Individualized therapy based on renin/aldosterone phenotyping. Hypertension 2018; 72: 263–269. Salt and water retention suppresses renin, as do licorice and nonsteroidal anti-inflammatory agents (with the probable exception of sulindac). For this reason, it is important that plasma renin and aldosterone levels are measured in a stimulated state to aid in interpretation. Diuretics, ARBs and angiotensin-converting enzyme inhibitors (ACEi) all stimulate renin, but ACEi and ARB lower levels of aldosterone, thereby tending to mask primarly aldosteronism/inappropriate aldosterone secretion and therefore require thoughtful interpretation of the results. A novel mechanism by which salt and water retention may increase end-organ disease, including cardiac hypertrophy and myocardial fibrosis, as well as renal damage, is increased levels of marinobufogenin (MBG), an endogenous bufadienolide synthesized by the adrenal cortex in response to sodium-induced plasma volume expansion. In addition to its primary natriuretic function via the inhibition of renal α1-sodium–potassium-dependent adenosine triphosphate (Na+/K+-ATPase), MBG additionally induces pro-fibrotic signaling through Na+/K+-ATPase in cardiovascular tissue. Strauss et al.8 reported that higher levels of MBG were associated with increased left ventricular mass in young black patients, particularly in women. Although amiloride and spironolactone were, on average, equally effective in the PATHWAYS 2 trial, and spironolactone was more effective in patients with inappropriate aldosterone secretion, it is important to recognize that amiloride will be more effective in patients with the Liddle phenotype, as shown by Laffer et al.9 in patients with a variant of the CYP4A11 gene. The study of Schutte et al.1 gives an excellent opportunity to explore differences in genetic predisposition to hypertension between white and black patients, and also the opportunity to test the hypothesis (enunciated by the current author at the International Hypertension Society conference in Beijing in September 2018) that some patients may have variants that predispose to both a Liddle phenotype and a primary aldosteronism phenotype. This might explain the previous observation that black patients are more sensitive to high levels of aldosterone. Among participants who develop hypertension, plasma renin and aldosterone should be measured in a stimulated state (preferably with furosemide) and candidate genes that should be explored include: Variants that predispose to the inappropriate secretion of aldosterone/primary aldosteronism (CYP11B2, KCNJ5, ATP1A1, ATP2B3, CACNA1D and ARMC5)10,11 Variants of SCNN1B/ENaC (Liddle syndrome), as well as variants that increase the function of ENaC and therefore predispose to the Liddle phenotype (GRK, NEDD4L, CYP4A11, NPPA, UMOD and perhaps others).5,9 The results of such a study are eagerly anticipated because they will not only clarify genetic aspects of hypertension in black vs. white people, but will also inform treatment. The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author received no financial support for the research, authorship, and/or publication of this article.