Salt and Health M.R.ABBASI MD,Nephrologist NRC TUMS 1992

Salt and Health

M.R.ABBASIMD,Nephrologist

NRC

TUMS

1992

Natrium=Sodium(Na)a metalic element with

mol.Wt. 23gr

Chloride(Cl)a light green toxic gas with

mol. Wt. of 35.5gr

5TUMS-Nephrology Research

Center

6TUMS-Nephrology Research

Center

Forms of Sodium• 90% of sodium consumed as

sodium chloride (salt, common salt, table salt,Halite)

• Other forms:–sodium bicarbonate–sodium in processed foods, such as

sodium glutamate, sodium benzoate, sodium phosphate

Sodium Balance• The human body contains 1 gr Na / Kg of

BW• 70 gr Νa = ~ 3000 mmol = 3000 meq Na• Sodium is located to 95% extracellularly

and to 5% intracellularly.

Every 6 gr salt contains 2.3 gr( 100mmol=100meq ) of Na

Adverse Effects ofExcess Salt Intake• Established relationship

– Increased blood pressure• Probable relationship

– Gastric and Colorectal cancer• Suggestive relationship

– Increased risk of osteoporosis– Increased risk of nephrolithiasis– Increased left ventricular mass

• Hypothesized relationship– Overweight/obesity– asthma

→ CVD and Stroke

P. A. Gilbert* and G. Heiser: Salt and health

British Nutrition Fundation

• There is conclusive scientific evidence of the adverse effect of excessive dietary salt consumption on health, particularly on blood pressure,

leading to cardiovascular disease, gastric cancer, osteoporosis,

cataracts, kidney stones and diabetes (Cappuccio & MacGregor, 1997;

• Cappuccio et al., 2000).

Deaths fromStomach Cancer

(per 100,000Per year)

Adapted from Joossens, Int J Epi 1996;25:494-504

KOR

r=0.702P<0.001

JAPAN

CHI

POLCOL

HUN

POR

GDRITA

SPAFRG

CAN

FINNET

MALE.W

ARGDEN

BEL

USA

N.I

MEX

TOB

190

170

150

130

110

90

70

50

30

10

06 7 8 9 10 11 12 13 14

Salt Intake (grams/day)

ICE

Salt and Stomach Cancer: Ecological Analysis

15TUMS-Nephrology Research Center

Hihg Na excretion causes high Ca loss

JNEPHROL 2000; 13: 169-177

Na excretion and BMD

JNEPHROL 2000; 13: 169-177

JNEPHROL 2000; 13: 169-177

Healthy vs. Osteoporotic Trabecular Bones


The association between a high salt intake and hardened pulse was already known 4500 years ago .

Cirillo M, Capasso G, Di Leo VA, De Santo NG. A history of salt. Am J Nephrol 1994;14:426-431.


Magnitude of BP Problem:Population Perspective

• Worldwide, cardiovascular disease (heart disease and stroke) is the leading cause of death

• 62% of strokes and 49% of CAD events attributed to elevated BP*

• 26% of adults worldwide (972 million) have hypertension**

*WHO, World Health Report 2002: Reducing Risks, Promoting Healthy Life, **Kearney Lancet 2005;305:217

Genitourinary diseases

Leading Causes of Death, Worldwide in 2002

Cardiovascular diseases

Infectious and parasitic diseases

Cancer

Respiratory infections

Respiratory diseases

Unintentional injuries

Perinatal conditions

Digestive diseases

Intentional injuries

Neuropsychiatric conditions

Diabetes mellitus

Maternal conditions

Congenital anomalies

Nutritional deficiencies

Others0 2000 4000 6000 8000 10000 12000 14000 16000 18000

Number of deaths (x1000)22TUMS-Nephrology Research

Center

Major Underlying Factors causing Death - Worldwide

Ezzati et al. Lancet 2002:360:1347-60.

Underweight

Unsafe water, sani & hygiene

Alcohol

Physical inactivity

High BMI

Low fruit & vegetables intake

Unsafe sex

High cholesterol

Tobacco

Raised Blood Pressure

0 1 2 3 4 5 6 7

Millions of Deaths

7 million

Developing region

Developed region


Types of Evidence Relating Salt Intaketo Blood Pressure

Epidemiology Over 50 population studies

Migration Several

Genetic All defects identified so far impair the ability of the kidney to excrete salt.

Animal All forms of hypertension are caused or aggravated by salt [rats, chimpanzees]

Trials Children: ~10 trials, one trial in infantsAdults: > 50 trials

PopulationInterventions

several


• Primary hypertension is seen primarily in societies with average sodium intakes above 100 meq/day (2.3 g sodium(

• HTN is rare in societies with average sodium intakes of less than 50 meq/day (1.2 g sodium)

• • HTN requires a threshold level of sodium intake.

• This effect appears to be independent of other risk factors for hypertension, such as obesity.

SBP Slope with Age (mmHg/yr) by Median Na Excretion in 52 Communities

Worldwide

INTERSALT BMJ 1988;297:319

0 1,150 2,300 3,450 4,600 5,750

-0.4

-0.2

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

Syst

olic

blo

od p

ress

ure

slop

e w

ith a

ge(m

m H

g/ye

ar)

Median sodium excretion (mg/24h)

Populations with No Rise in SBP with Age


Sodium: Dose Response Trials

Luft, 1979 (14 non-hypertensive)

40

60

80

100

120

140

160

180

200

0.23(10)

6.9(300)

13.8(600)

18.4(800)

27.6(1200)

34.5(1500)

grams/day (mmol/day)

SBP (mm Hg)

DBP (mm Hg)

+7+2+5+1+1

+6+4+2+2+4


MacGregor, 1989 (20 hypertensive)

406080

100120140160180200

1.1 (50) 2.3 (100) 4.6 (200)


SBP (mm Hg)

DBP (mm Hg)

+8* +8*

+4* +5*


Johnson, 2001 (n=17 non-hypertensive elderly)

4060

80100120

140160

180200

0.92 (40) 2.1(90) 3.2(140) 5.5 (240) 7.8 (340)


SBP(mmHg)

DBP (mmHg)

+6.1

+7.6 +3.5

+0.3 +3.7 -0.1 +1.6

-0.7

0.001≤ P <0.01*

0.01≤ P <0.05*


Johnson, 2001 (n=15 elderly with isolated systolic hypertension)

40

60

80

100

120

140

160

180

200

0.92 (40) 2.1(90) 3.2(140) 5.5 (240) 7.8 (340)


SBP (mmHg)

DBP (mmHg)

+9.0 +1.8 +4.1 +6.0

-0.3+3.1 +0.3 +3.4

0.001≤ P <0.01*

0.01≤ P <0.05*

Johnson, 2001 (n=8 elderly with systolic-diastolic hypertension)

406080

100120140160180200

0.92 (40) 2.1(90) 3.2(140) 5.5 (240) 7.8 (340)


SBP (mmHg)

DBP (mmHg)

+8.0 +4.1 +5.4 +0.7

-0.41.

+1.2 +1.6+3.0

0.001≤ P <0.01*

0.01≤ P <0.05*


Population-Based Strategy SBP Distributions

Population-Based Strategy SBP Distributions

Stamler R. Hypertension1991;17:I-16–I-20.Stamler R. Hypertension1991;17:I-16–I-20.

Reduction in SBPmmHg

235

Reduction in SBPmmHg

235

% Reduction in Mortality % Reduction in Mortality

Before InterventionBefore Intervention

Reduction in BP

Reduction in BP

After Intervention

After Intervention

Stroke CHD Total

-6 -4 -3-8 -5 -4-14 -9 -7

Predicted Benefits of Reducing Sodium

on Stroke and Heart Attack Deaths

• Reducing sodium by 400 mg/day would reduce

strokes by 5%

heart attacks by 3%

• Reducing sodium by 2,400 mg/day would reduce

strokes by 24%

heart attacks by 18%

Hypertension 2003;42:1093-9933TUMS-Nephrology Research

Center

Effects of Reduced Na on CVD Events:

Results from 3 Randomized Trials

INTERVENTION OUTCOME FU

TONE1 (2001) 639 Elderly ↓ Na 21% ↓

CVD events 2.3 yrs

Taiwan Veterans2

(2006) 1,981 Elderly

↓ Na /↑ K Salt

41%* ↓CVD

Mortality2.6 yrs

TOHP Follow-up3 (2007) 3,126 Prehypertensives ↓ Na 30%* ↓

CVD events 10-15 yrs

*p<0.05

1Appel, Arch Int Med, 2001; 2Chang, AJCN, 2006; 3Cook, BMJ, 2007

Sodium Intake (Na)* by Body Mass Index (BMI)

BMI Category

Non-Overweight (n=44)

Overweight (n=238)

Obese (n=528)

Sodium (mg/d)

2,991 3,708 4,235

% with Na < 2,300 mg

32% 20% 11%

* as estimated from 24 Hour Urinary Sodium Excretion, Unpublished Data, PREMIER

Median Sodium Intake (mg/d) in US Children, Adolescents, and Adults

Men Women9–13 y 3,700 3,10014–18 y 4,500 2,90019–30 y 4,700 3,10031–50 y 4,300 2,90051–70 y 3,700 2,50071+ y 3,100 2,300SOURCE: NHANES III, 1988-1994; Environ International Corporation and Iowa State University Department of Statistics, 2003.

Effects of Sodium Reduction in Children: Results of a Meta-Analysis

He and MacGregor, HTN 2006

• 10 Trials• 966 Children• Mean age=14• Median

duration = 20wk

• 42% Reduction in Na

Opportunity to Reduce Racial Disparities in BP: Greater Effects of Sodium Reduction in African-Americans

-12

-10

-8

-6

-4

-2

0

Ch

ang

e in

BP

Systolic BP Diastolic BP

African-Americans Non-African-Americans

- 8.0†

P<.001

- 4.5†

P<.001 - 5.1

P<.001

- 2.2

P<.001

0 † P-interaction < 0.05Vollmer, Ann Int Med; 2001

Salt sensitivity

• BP responsiveness to variations in salt intake is known as

salt sensitivity.

Factors Associated with Increased Salt Sensitivity

• Fixed factors– African-Americans– Middle and older-aged persons– Genetic Factors – Individuals with:

• Hypertension• Diabetes• Chronic Kidney Disease• Low birth Wt

• Modifiable– Low potassium intake– Low Calcium intake– Poor quality diet

Na sensitivity associated with:

• Insulin resistance• Dyslipidemia• Microalbuminuria• Subtle renal injury

• In the rat model developed by Lewis K. Dahl, inbred salt-sensitive rats remain normotensive on a low-salt diet but develop hypertension on a highsalt diet, whereas salt-resistant rats remain normotensive even on high salt (Dahl & Heine, 1975).

Sources of Dietary Sodium

Inherent12%

FoodProcessing

77%

At the Table6%

During Cooking 5%

Mattes and Donnelly, JACN, 1991; 10: 383

(62 adults who completed 7 day dietary records)

Na/K cotent of food

Copyright 2005 Wadsworth Group, a division of Thomson LearningCopyright 2005 Wadsworth Group, a division of Thomson Learning

• There is a significant variation in the levels of salt consumption between

countries, and also significantly different patterns of consumption. In

European and North American countries the main sources of dietary salt

are processed foods, restaurant services, and catering, while in Asian

and African countries the main sources are the salt used in cooking and

sauces.

The food industry uses salt in every food category to enhance flavor, condition dough, preserve foods, and retain moisture

The fundamental defect in all hypertension is the kidneys' inability to excrete the excessive sodium load imposed by a high-salt diet. (He & MacGregor, 2007).

Sodium retention(mechanisms)

• Increase activity of the proximal Na-H exchanger

• Increase Na reabsorption in thick ascending limb of henle loop by Na-K-2Cl cotransporter

• Increase Na reabsorption by distal Na-Cl cotransporter

• Increase Na reabsorption by ENaC in the collecting tubule.

Effect of High Na and Low K diet in laboratory animals

Sodium and Potassium in the Pathogenesisof HypertensionHoracio J. Adrogué, M.D., and Nicolaos E. Madias, M.D.NEJM356;19. May10 2007


Hakuo Takahashi et al, The cntral mechanism underlyinh HTN: a revew of the role of Na ions, ENaC, the R-A-A system,

oxidative stress and endogenous digitalis in the brain:HTN research (2011)34,1147-1160



Vasodilation failure

• Na loading causes vasodilation in Na insensitive subjects(by NO release).

• In Na sensitives Na loading causes an increase in Asymmetrical dimethylarginine which is endogenous inhibitor of NO.

Effect of Na restriction on antiHTN drugs

• Na restriction potentiate effect of all AntiHTN except CCB.

Recommendations for Sodium Intake (mg/d): US and WHO

US 2005 Dietary Guidelines

General Population < 2,300

Hypertensives, blacks, adults (45+) <1,500

World Health Organization <2,000

Institute of medicine recommends:Na intake 65mmol(3.8gr NaCl) for<50yrs old, 55mmol(3.2gr salt) for 51-70yrs old, 50mmol(2.9gr)/day for>70 yrs old + 120 mmol K(4.7gr) /day . Sodium and Potassium in the Pathogenesis

of HypertensionHoracio J. Adrogué, M.D., and Nicolaos E. Madias, M.D.NEJM356;19. May10 2007

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Nephrology Research Center

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Salt and Health M.R.ABBASI MD,Nephrologist NRC TUMS 1992