brian rayner, division of nephrology and hypertension...

Insights into hypertension in children and

adolescents in (South) Africa: the role of salt

sensitivity

Brian Rayner,

Division of Nephrology and Hypertension,

University of Cape Town

False Bay

Table Bay

Robben Island

Cape Point

Table Mountain

Satellite View of Cape Town

Whales,

great white sharks

Cape Floral Kingdom

100C

200C

Winelands

Slopes of Devil’s Peak

Main campus

Prevalence of HT in SA by Age

Bradshaw et al, NCDs: the race against time, MRC, 2013

Prevalence of

overweight/obesity

Young Hypertensives, Cape Town

DEMOGRAPHICS

• 113 records located

• Mean age 22 years

• 81% had a family history of hypertension

• Majority have primary hypertension

• Body mass index:

– 45% normal BMI; 29% overweight; 26% obese

Unpublished

• Found no cases of hypertension in 1800 natives examined

• No age treated rise in BP

• No cases of LVH at autopsy

Background

• Non-Hispanic blacks had the highest age adjusted

prevalence (44.4% men and 43.9% women)

• Pressure-related cardiovascular-renal complications

(stroke, LVH, HF, and CKD/end-stage renal disease)

occur excessively in blacks compared with whites

• In 2005, the death rate from HTN (per 100 000

population) was 15.1 in white men, 51.0 in black men,

15.1 in white women, and 40.9 in black women

• Blood pressure less well controlled despite2:– More likely to be diagnosed

– More likely to be treated

– More likely to be treated more intensively

2.Howard G et al. Stroke 2006;37:1171-11781. John M. Flack et al. Hypertension. 2010;56:780-800

First Author Country Sample

Size

LVH CCF Overt proteinuria/

CKD

Oladapo Nigeria 415 27.9 4.6 15.2

Ayodele Nigeria 203 31.0 10.8 18.2

Ekore Nigeria 124 17.7 2.4 26.1

Ayodele Nigeria 147 42.2 8.8 18.2

Addo Ghana 219 33.3 - 13.4

Rayner South

Africa

1091 18.9 - 4.1

Peer South

Africa

403 35 - 26

Salako Nigeria 68 5.6

Stewart South

Africa

761 39 54 24

TOD in selected SSA countries

Ogah, Rayner, Heart 2013

SBP Responses in Blacks

Class Mean (mmHg) CI P value

CCB -12.1 -21 - -3.19 P<0.00001

Diuretic -11.81 -14.07 - -9.55 P<0.00001

ACE inhibitor -6.96 -9.64 - -4.27 P<0.00001

ARB -3.63 - 5.47 - -1.78 P<0.0001

blocker -3.73 -6.8 - -0.66 P=0.02

Adapted Brewster et al, Intern Emerg Med (2016) 11:355–374

Non-RAS

drugs

RAS drugs

11

Combined CVD – Subgroup

Comparisons (32% Black)ALLHAT

Amlodipine Better Chlorthalidone Better

0.50 1 2

Non-Diabetic 1.02 (0.96, 1.09)

Diabetic 1.06 (0.98, 1.15)

Non-Black 1.04 (0.97, 1.10)

Black 1.06 (0.96, 1.16)

Women 1.04 (0.96, 1.13)

Men 1.04 (0.98, 1.11)

Age >= 65 1.05 (0.99, 1.12)

Age < 65 1.03 (0.94, 1.12)

Total 1.04 (0.99, 1.09)

Lisinopril Better Chlorthalidone Better

0.50 1 2

Non-Diabetic 1.12 (1.05, 1.19)

Diabetic 1.08 (1.00, 1.17)

Non-Black 1.06 (1.00, 1.13)

Black 1.19 (1.09, 1.30)

Women 1.12 (1.03, 1.21)

Men 1.08 (1.02, 1.15)

Age >= 65 1.13 (1.06, 1.20)

Age < 65 1.05 (0.97, 1.15)

Total 1.10 (1.05, 1.16)

P = .04 for interaction

Change in 24 hour uNa, and SBP and DBP in hypertensive

and normotensive individuals in Na by ethnic group

Trials Participants Mean effect P value

Ethnic group

Hypertensive-white

SBP (mmHg) 16 599 −5.12 <0.001

DBP (mmHg) 17 623 −2.66 <0.001

24h UNa 17 623 −77.44 <0.001

Hypertensive-black

SBP (mmHg) 5 171 −7.83 <0.001

DBP (mmHg) 5 171 −4.08 <0.001

24h UNa 5 171 −66.87 <0.001

Hypertensive-Asian

SBP (mmHg) 1 29 −5.41 0.008

DBP (mmHg) 1 29 −2.17 0.047

24h UNa 1 29 −68.42 <0.001

Table 2

BMJ 2013;346:f1325 doi: 10.1136/bmj.f1325 (Published 5 April 2013)

HISTORY

Almost 113 years ago, Ambard and Beaujard

explored the association between salt intake and

BP

“It seems to us that one can say that each

individual who is able to retain chloride

is, by that very fact, apt to develop

arterial hypertension”

• Ambard L, Beaujard E. Causes de l’hypertension artérielle. Arch Gén Méd. 1904;81:520–533

Salt Sensitivity

• Hereditary*

• Acquired

– Older age

– CKD

– Obesity*

– Diabetes

Copyright ©2010 American Heart Association

Wang, X. et al. Hypertension 2010;56:1035-1037

Percentage of variance explained in SBP by the top SNPs of 6 loci identified in 2 large GWA meta-analysis studies

40-50% attributable risk

Approximately 1% identified

CAUSAL ORIGINS

Genotype Environment

PHENOTYPES (observed expressions)

Close Intermediate Distant

Enzymes Hormones BP

Receptors Organ processes measurement

Cell process Provocative tests

Na

transporter

in kidney

↑ Na/↓K intake

Impaired Na

excretion

Na overload,

renin,

aldosteroneHypertension

GENOTYPE/PHENOTYPE

Impaired Na

reabsorbtion

Na depletion,

Renin

aldosterone

Hypotension Na

24,000 mmol

Na

10-200 mmols

Gordon’s syndrome

Gitelman’s syndrome

Na-Cl co-transporter,

WINK

Thiazide

Liddle syndrome

Pseudohypoaldosteronism

SCNN1B, SCNN1G

Na- K or H

Amiloride

Barter’s syndrome

KCNJ1

CASR

Uromodulin

ROMK

Na-K-2Cl

Furosemide

Torasemide

In experimental models kidney transplantation from hypertensive to normotensive rat causes hypertension, and vice versa

ENaC

GRK-4

Dopamine, ANP +ve

Ang II, norepinephrine –ve

NEP inhibitor

Common Variants in Genes Underlying

Monogenic Hypertension and Hypotension and

Blood Pressure in the General Population

Martin D. Tobin, Maciej Tomaszewski, Peter S. Braund, Cother Hajat, Stuart M. Raleigh,

Thomas M. Palmer, Mark Caulfield, Paul R. Burton, Nilesh J. Samani

(Hypertension. 2008;51:1658-1664.)

The findings show that common variants KCNJ1,

CASR, NR3C2, SCNN1B, and SCNN1G in genes

responsible for some Mendelian disorders of

hypertension and hypotension affect blood pressure in

the general population. Notably, variants in KCNJ1

Ethnic differences in proximal and distal tubular sodium

reabsorption are heritable in black and white populationsMurielle Bochuda, Jan A. Staessen, Marc Maillardd, Muzi J. Mazekoe,Tatiana Kuznetsova,

Angela Woodiwiss, Tom Richart, Gavin Norton,Lutgarde Thijs, Robert Elston and Michel

Burnier

J Hypertens 27:606–612,2009

Conclusion Segmental sodium reabsorption along the

nephron is highly heritable

Aldosterone and PRA in

normotensive populations in SA

0

1

2

3

4

5

6

PRA Aldosterone

Black

White

PRA = ng/ml/hr, aldosterone pmol/L x 10-2

Rayner et al, S Afr Med J 2002

No difference in Na intake

Molecular and clinical investigations in patients

with low-renin hypertension.

Isla S. Mackenzie Æ. Morris J. Brown.

Clin Exp Nephrol (2009) 13:1–8

P<0.001

P<0.001Liddle-like phenotype

24,000 mmol

Na

10-200 mols

ENaC – Liddle’s syndrome

SCNN1B, SCNN1G

Na- K or H

Renal epithelial Na+ channel

aldosterone

+

Na+

ga

activating

mutations cause

Liddle’s

syndrome

membrane

subunit

}C

N

}Inactivating

mutations cause

psuedohypo-

aldosteronism

Novel sodium channel mutation in SCNN1B

normal sequence

patient N.T.

R563Q (p.Arg563Gln)

Heterozygote, 3 base pairs

from the original Liddle

syndrome

RESULTSPopulatio

n group

Diagnosis n R563Q negative

R563Q positive

% p vs. Controlsd

p vs. normal-high

renin HTe

Black LRHTa 14 10 4 28.6 0.0001 0.027

normal-high renin HTb

55 52 3 5.5 0.041

unknown renin HTc 70 67 3 4.3% ns

Controls 103 103 0 0%

Mixed Ancestry

LRHT 36 32 4 11.1 0.0174 0.040

normal-high renin HT

104 102 2 1.9 ns

unknown renin HT 110 109 1 0.9 ns

Controls 100 99 1 1.0

White LRHT 3 3 0 0

normal-high renin HT

13 13 0 0

unknown renin HT 120 120 0 0

Rayner et al, J Hypertens, 2003

Prevalence of the R563Q mutation in patients with pre-eclampsia

compared to normotensive controls.

Normotensive

pregnant

Pre-

eclampsia

p value

All subjects n 192 230

age (y)

mean ± SD

25.7 ± 6.0 27.6 ± 6.8 p=0.0027a

R563Q +ve (%) 5 (2.6%) 18 (7.8%) p=0.014b

aStudent’s unpaired t-test (2-tailed)bFisher’s Exact test (1-sided)

Dhanjal et al, BJOG, 2006

Prevalence in Urban South Africans

Jones E, et al, Am J Hypertens 2013

Analyzed R563Q +ve

Hypertensives Normotensives Hypertensives Normotensives P value*

Total 1468 471 87 (5.9%) 8 (1.7%) <0.0005

RESPONSE TO AMILORIDE

• 22 heterozygous patients with resistant

hypertension

• Amiloride 5-10 mg was added to their

antihypertensive regimen

• The mean BP at initiation was 172/99

mmHg

• The average decrease in BP was

36/17mmHg (p<0.0001)


Bantu Migration

.Cape Town (Xhosa, Coloured)

San

Typical San People

OVERALL SAN

• In the Namibian and Khomani San 19% of

unselected subjects were R563Q positive

respectively including 4 homozygotes

• Hardy-Weinberg frequencies borderline

statistical significance, Χ2 = 2. 7908

(p=0.095)

• No association with hypertension


SAN Data

Khomani San Cape Town subjects

Mean ± SD (n) Mean (n) P value

Potassium, mmol l-1 3.9±0.4 (46) 4.4±0.4 (86) <0.005

Aldosterone*, pmol l-1 91.4; 53.2-191.2 (49) 310; 221.2-426.0 (86) <0.001

Urine Sodium-Creatinine* 7.3; 4.6-13.0 (31) 12.2; 7.5-18.1 (86) 0.016


The mean levels of PRA, plasma aldosterone in

normotensive blacks and in whites

Tu W et al. Hypertension. 2014;63:1212-1218

Copyright © American Heart Association, Inc. All rights reserved.

Children

Adults

Changes from baseline parameters in response to 2 week

of treatment with 9-α fludrocortisone (ENaC)

Tu W et al. Hypertension. 2014;63:1212-1218


Copyright ©2008 American Heart Association

Rossier, B. C. et al. Hypertension 2008;52:595-600

Model of aldosterone action in the principal cell of the ASDN

A Functional Variant of NEDD4L Is Associated With

Hypertension, Antihypertensive Response, and Orthostatic

Hypotension

Fang Luo, Yibo Wang, Xiaojian Wang, Kai Sun, Xianliang Zhou,

Rutai Hui

Hypertension. 2009;54:796-801

Genetic variation in NEDD4L, an epithelial sodium channel

regulator, is associated with cardiovascular disease and

cardiovascular death

Jonas Dahlberg, Marketa Sjogren, Bo Hedblad, Gunnar

Engstrom, and Olle Melander

Journal of Hypertension 2014, 32:294–299

24,000 mmol

Na

10-200 mols

GRK-4

Dopamine, ANP +ve

Ang II, norepinephrine -ve

Table 1. Ethnic distribution of genotypes of the p.Ala142Val and p.Arg65Leu in Black and White South Africans

p.Ala142Val Black White P value

AA 3.7% 41.7%

AV 30.2% 42.7%

VV 66.1% 15.6% P<0.0001

p.Arg65Leu

RR 3.3% 16.1%

RL 36.7% 51.6%

LL 60% 32.3 P=0.05

Baseline – A142V (Normotensive,

lean adolescents)

* AA vs AV and VV, p=0.04

Parameter AA (sd) AV (sd) VV (sd) P value

SBP (mmHg) 130.9 (12.7) 136.8 (12.3) 137.8 (12.4) 0.38

DBP (mmHg) 69.2 (4.8) 73.9 (5.4) 76.1 (9.2) 0.07*

MAP 89.7 (6.8) 94.9 (7.1) 96.6 (8) 0.1*

Pulse

(beats/min)

64.8 (15.4) 67 (12.7) 71.4 (13.2) 0.34

Aldosterone

(pmol/L)

341.1 (143.7) 242 (112.8) 161.5 (112.8) 0.002

Rayner et al, Nephrol Rev 2011

AA vs AV, p=0.004, AA vs VV, p =0.001

Rayner et al, Nephrol Rev 2011

AA

AV

VV

Reduced Na, High K,

Mg, Ca diet (N = 20)

Week 4 Week 8Randomization

3-week Run-in 8-week Intervention

Visit 1 Visit 2 Visit 3

•BP (Omron)

•24hr urine

•24hr dietary recall

•24hr ambulatory BP

Control diet (N = 20)

•BP (Omron)

•24hr urine


•24hr ambulatory BP

•Anthropometry

•DEXA

•Blood analyses

•BP (Omron)

•24hr urine


•BP (Omron)

Study design: RCT double-blind

0 2 4 6 8 10 76

78

80

82

84122

124

126

128

130

132

134

136

138

140

Dia

sto

lic B

P

(m

mH

g)

Systo

lic B

P

(m

mH

g)

Low salt

Control

Intervention (week)

Diastolic BP Between-diet difference (mean (SE)) = -0.59 (1.22) mmHg (ns) 95 % CI: -3.02 to 1.83 mmHg

Systolic BP Between-diet difference (mean (SE)) = -6.19 (2.63) mmHg (P<0.05) 95 % CI: -11.44 to -0.94 mmHg

Change in BP

(Pre to Post)

CONTROL

Figure 5.1. Changes in mean 24 systolic BP in the control group according to genotype

Rayner et al, J Hum Hypertens 2011

AA/AV VV RR/RL LL

Changes in mean 24 systolic BP in the

intervention group according to genotype

133 135.4138

133.4

123.3

134

127.4

134

60

70

80

90

100

110

120

130

140

150

1 2 3 4

mm

Hg

A142V

Pre SBP

Post SBP

R65L

p=0.023 P=0.004

Rayner et al, J Hum Hypertens 2011

AA/AV VV RR/RL LL

Effects of G protein–coupled receptor kinase 4 65L-142V haplotype on blood pressure (BP)

response in Pharmacogenomic Evaluation of Antihypertensive Response (PEAR) trial.

Vandell A G et al. Hypertension. 2012;60:957-964


GRK Variant Parameter Comment

p.Arg65Leu, p.Ala142Val, and

p.Val486Ala

Hypertension in rats p.Ala142Val shows greatest

activity

p.Ala142Val Enhanced activity of AT1 in

smooth muscle

p.Arg65Leu Impaired stress related Na

excretion in normotensive blacks

p.Ala142Val Impaired incremental Na excretion

in healthy men, and lower

aldosterone levels

p.Ala142Val significantly more

common in blacks compared to

whites


p.Val486Ala

Impaired Na excretion and higher

BNP levels in healthy Japanese

with 2 or more variants

p.Val486Ala Association with hypertension in

Australian population


p.Val486Ala

94.4% predictive of salt sensitive

renin hypertension in Japanese

population

p.Ala142Val 78.4% predictive

p.Arg65Leu, p.Ala142Val BP response to Na restriction in

black South Africans with

hypertension

p.142Ala genotype In AASK males less likely to

respond to metoprolol

Especially if co-inherited the

p.65Leu variant

65Leu/142Val haplotype In 2 major hypertension studies

predicted a reduced response to

atenolol and increased

cardiovascular outcomes Rayner, Ramesar, IJMS, 2015

Low-renin HT in African-AmericansDavid Spence, Robarts Institute, Canada

• ~6% of HT in blacks due to Liddle’s variant1,2

• more likely to have 1 hyperaldo3

• More likely to have bilateral adrenocortical hyperplasia4

• Despite greater awareness and Rx, less control5

• Stroke belt discrepancies could likely be reduced by individualized therapy.6

1.Baker EH et al. Hypertension 2002; 40:13-7.

2.Rayner BL, et al. J Hypertens 2003;21:921-926.

3. Spence JD. Am J Hypertens 1999; 12:1077-83.

4. Russell RP, Masi T. Ann Int Med 1970;73:195-205

5. Howard G et al. Stroke. 2006 May; 37(5):1171-8 .

6. Spence JD. Hypertension 2006 Mar; 47(3):e11.

Physiologically individualized therapy in resistant hypertension in Blacks

Spence JD. Nat. Rev. Neurol. 2010;6: 477–486

Spence JD Curr Cardiol Rev 2010; 6: 119-123.

Am J Hypertens 2017

• 94/105 participants completed the study (42 UC,

52 PhysRx)

• Control of both SBP and DBP was obtained in

11.1% of UC vs. 50.0% of PhysRx (P = 0.0001).

• SBP control was achieved in 13.9% of UC vs.

60.3% of PhysRx (P = 0.0001)

• DBP control in 36.1% of UC vs. 67.2% of

PhysRx (P = 0.003).

↓ Na excretion by the kidney e.g. ENaC or GRK-variants Na retention, renin,

aldosterone

LOW RENIN HYPERTENSION

Figure 1.Putative pathogenesis of salt sensitive hypertension in Blacks

? Na / K

Salt Intake in SA

• Blacks – 7.8 gm/day

• Coloureds – 8.5 gm/day

• Whites – 9.5 gm/day

• All had inadequate K+ intake

Charlton et al 2005

UN SUMMIT ON NCDs

• Smoke-free workplaces and public places

• Warnings about the dangers of tobacco

• Comprehensive bans on tobacco advertising, promotion and sponsorship

• Raising excise taxes on tobacco and alcohol

• Restricting access to retail alcohol

• Enforcing bans on alcohol advertising

• Reducing salt (5-6 gram/day) and sugar content in packaged and prepared foods and drinks

• Replacing trans-fats with unsaturated fat in food

• Promoting public awareness about diet and physical activity through education and consumer information, including through mass media

South African Situation

• Over 75 % of total salt intake from packaged and restaurant foods

• Reducing the sodium content of bread, margarine, soups and gravies, would decrease salt intake by 0.85 grams per day

• Resulting in 7,000 fewer deaths due to CVD and 4,000 less non-fatal strokes in the country per year

• Save ~40 million USD each year in health-care costs associated with non-fatal strokes alone

Rayner et al, Comprehensive Clinical Nephrology,

2013

Conclusions and recommendations

• Africans have a predisposition to salt sensitivity and salt sensitive

hypertension

• This probably has an underlying genetic predisposition compounded

by changes in diet from rural to urban ( Na K amongst other

factors)

• Genes that regulate Na balance in the kidney are a fertile source to

understand salt sensitivity and hypertension in diverse ethnic

populations of Southern Africa and Blacks in the rest of the World

• A population approach to regulation of dietary Na is recommended

to prevent hypertension especially in children and adolescents

• This also suggests a differential approach to treatment

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