Il rischio Cardiovascolare : aspetti patogenetici Il rischio Cardiovascolare : aspetti patogenetici e diagnosticie diagnostici

Il ruolo del SodioIl ruolo del Sodio

Carmine Zoccali Carmine Zoccali

Huang Ti, 2698–2598 BC (the Yellow Emperor)

What really defined the decade was What really defined the decade was the rise of China.the rise of China. By Fareed ZakariaBy Fareed Zakaria

‘Hence if too much salt is used for food, the pulse hardens ...’

Alderman MH, Cohen H, Madhavan S. Dietary sodium intake and mortality: the National Health and Nutrition Examination Survey (NHANES I). Lancet 1998; 351: 781-785.

Death Death (x1000 person years)(x1000 person years)

3030

2525

2020

1515

1010

55

00

1° 2° 3° 4° 1° 2° 3° 4° sodiumsodium

……. these results do not support current recommendations for routine reduction of sodium consumption, nor do they justify advice to increase salt intake or to decrease its concentration in the diet…..

2008: 23(9):1297–302

CV death

-5 mmHg-5 mmHg

-2 mmHg-2 mmHg

.......Absent convincing scientific evidence of a benefit to eating less .......Absent convincing scientific evidence of a benefit to eating less salt, much less an assurance of safety, it might be wiser for the NY dpt. salt, much less an assurance of safety, it might be wiser for the NY dpt. of Health to press for the research that could provide a solid scientific of Health to press for the research that could provide a solid scientific basis for action……basis for action……

The New York TimesThe New York Times

A Pinch of ScienceA Pinch of Science

by Michael Aldermanby Michael Alderman9 February 20099 February 2009

New York City Health Department.New York City Health Department.

20082008Salt reduction (-40%) in processed foodSalt reduction (-40%) in processed food

& Carmine Zoccali

End Stage Renal DiseaseEnd Stage Renal Disease

Systolic BPSystolic BP(mmHg)(mmHg)

160160

150150

140140

130130

120120

110110

0 1 2 3 4 5 60 1 2 3 4 5 6Time (months)Time (months)

Extracellular VolumeExtracellular Volume(L)(L)

2424

1818

1212

66

00

““Lag phenomenon” Lag phenomenon”

New hypothesis.New hypothesis.

The lag phenomenon depnds on a peculiar The lag phenomenon depnds on a peculiar inhability in ESRD patients for removing “stored” inhability in ESRD patients for removing “stored” Na. i.e. Na which accumulates in connective tissue Na. i.e. Na which accumulates in connective tissue bound to proteoglycansbound to proteoglycans

16-18 L16-18 L

Blood Volume Blood Volume 5.6 L5.6 L ( (~30% extracellular volume)~30% extracellular volume)

Extracellular Fluids Extracellular Fluids Volume Volume (sodium space)(sodium space)

Blood Pressure Blood Pressure

Na+

Na+

Na+

Na+

Na+

Na+

Na+

Na+Na+

Na+

Na+

Na+

Na+

Na+

Lymphatic vessels

tonicitytonicityenhanced binding protein enhanced binding protein

((TonEBPTonEBP))

VEGFVEGFNa+

Na+

Na+

Na+

Na+

Na+

Na+

Na+Na+

Na+

Na+

Na+

Na+

Na+

Machnik, A. et al. Nat. Med. 15, 545–552 (2009).Machnik, A. et al. Nat. Med. 15, 545–552 (2009).

150 mmMol/ L

150 mmMol/ L

Iso-osmotic sodium poolIso-osmotic sodium poolNaNaNaNa

Systolic BPSystolic BP(mmHg)(mmHg)

160160

150150

140140

130130

120120

110110

0 1 2 3 4 5 60 1 2 3 4 5 6Time (months)Time (months)

Extracellular VolumeExtracellular Volume(L)(L)

2424

1818

1212

66

00

““Lag phenomenon” Lag phenomenon”

Restoration of a disturbed Regulation? Restoration of a disturbed Regulation?

Na+

Na+

Na+

Na+

Na+

Na+

Na+

Na+Na+

Na+

Na+

Na+

Na+

Na+

Lymphatic

vessels

tonicitytonicityenhanced binding protein enhanced binding protein

((TonEBPTonEBP))

VEGFVEGFNa+

Na+

Na+

Na+

Na+

Na+

Na+

Na+Na+

Na+

Na+

Na+

Na+

Na+

Albumin > 4 g/dlAlbumin > 4 g/dl

Ca x P <55 mgCa x P <55 mg22/dl/dl22

Kt/V Kt/V >> 1.2 1.2

Hb Hb >> 11 g/dl 11 g/dl

Access type, fistulaAccess type, fistula

MortalityMortality%%

100100

7575

5050

2525

000 1 2 3 4 5 60 1 2 3 4 5 6

years on dialysisyears on dialysis

MortalityMortality%%

100100

7575

5050

2525

00

0-10-1 targets targets

22 targets targets

33 targets targets

4-5 4-5 targets targets-30%-30%

Even among patients achieving the top Even among patients achieving the top number of performance targets mortality rate number of performance targets mortality rate remains quite high, about 50% at 6 years or remains quite high, about 50% at 6 years or 8 % /year, i.e. a mortality at least 16 times 8 % /year, i.e. a mortality at least 16 times higher than in age and sex matched general higher than in age and sex matched general population. population.

Albumin > 4 g/dlAlbumin > 4 g/dl

Ca x P <55 mgCa x P <55 mg22/dl/dl22

Kt/V Kt/V >> 1.2 1.2

Hb Hb >> 11 g/dl 11 g/dl

Access type, fistulaAccess type, fistula

No clinical indicator No clinical indicator reflecting reflecting fluids volume fluids volume

andand cardiac status cardiac status

Clinically assessing fluids volumeClinically assessing fluids volume

BIABIA

Measurement of Plasma or Blood Volume orExtracellular Volume Measurement of Plasma or Blood Volume orExtracellular Volume by radio-isotopic methods.by radio-isotopic methods.

Vena Cava diameter Vena Cava diameter

Either not sufficiently reliable or unpractical.

Either not sufficiently reliable or unpractical.

None of these m

ethods is actually incorporated in

None of these m

ethods is actually incorporated in

the clinical decision process in the vast majority

of

the clinical decision process in the vast majority

of

dialysis centres.

dialysis centres.

SymptomsSymptoms

Poor discriminatory Poor discriminatory power of body fluids power of body fluids

volume measurements volume measurements for guiding therapy for guiding therapy

1+ 2+ 3+ 4+1+ 2+ 3+ 4+Clinically estimated edemaClinically estimated edema

Total Na SpaceTotal Na Space(L/m(L/m22))

2222

2020

1818

1616

1414

1212

1010

Old normal adultsOld normal adults

Warner GF et al., Circulation 5:915, 1952Warner GF et al., Circulation 5:915, 1952

the modest discriminatory value of body the modest discriminatory value of body fluids volume estimates for identifying fluids volume estimates for identifying volume expanded patients in clinical volume expanded patients in clinical practice is not a surprisepractice is not a surprise

Extracellular Volume (sodium space)Extracellular Volume (sodium space)16-18 L16-18 L

Blood Volume Blood Volume 5.6 L5.6 L ( (~30% extracellular volume)~30% extracellular volume)

LV filling PressureLV filling Pressure8-10 mmHg8-10 mmHg

Cardiac Extracellular Fluids Cardiac Extracellular Fluids function Volumefunction Volume

The fundamental parameter for The fundamental parameter for defining the loading conditions of defining the loading conditions of the CV system, i.e. the relationship the CV system, i.e. the relationship

between circulating volume and CV between circulating volume and CV

function function

Extracellular Volume (sodium space)Extracellular Volume (sodium space)

LV filling PressureLV filling Pressure8-10 mmHg8-10 mmHg

Externally, intermittently Externally, intermittently regulated ECVregulated ECV

Like in other conditions, LV filling Like in other conditions, LV filling pressure in ESRD reflects the pressure in ESRD reflects the loading conditions of the left loading conditions of the left ventricle, i.e. a fundamental factor ventricle, i.e. a fundamental factor for central hemodynamicsfor central hemodynamics

kidney is central in regulating the kidney is central in regulating the blood volume –LV filling pressure blood volume –LV filling pressure

relationshiprelationship

Capillary Pressure at Capillary Pressure at alveolar levelalveolar level

Atrial PressureAtrial Pressure

LV Diastolic (filling) LV Diastolic (filling) PressurePressure

LV filling pressure depends on 2 components:LV filling pressure depends on 2 components:

1) volume component 1) volume component 2) LV function component2) LV function componenttherefore it reflects the loading conditions of the LV at a therefore it reflects the loading conditions of the LV at a given BVgiven BV

Capillary Wedge PressureCapillary Wedge Pressure a very reliable indicator of a very reliable indicator of LV filling pressureLV filling pressure

However highly reliable, However highly reliable, this is an invasive this is an invasive technique and therefore it technique and therefore it is employed in the acute is employed in the acute setting only.setting only.

Capillary Pressure at Capillary Pressure at alveolar levelalveolar level

Pulmonary WaterPulmonary Water

normalnormal

Pulmonary edemaPulmonary edema

Lung cometsLung comets

! the number of lung comets is strictly ! the number of lung comets is strictly proportional to lung waterproportional to lung water

Lung water

CHESTCHEST127:1690, 2005127:1690, 2005

Severe lung Severe lung congestioncongestion

Moderate lung Moderate lung congestioncongestion

<14 14-30 >30<14 14-30 >30Lung Comets numberLung Comets number

PrevalencePrevalence(%)(%)5050

4040

3030

2020

1010

00

35%35%

28%28%

Hypo Normal HyperHypo Normal HyperHydration Status by BIAHydration Status by BIA

Lung CometsLung Comets(n)(n)

6060

5050

4040

3030

2020

1010

00

17172020

1515

PredialysisPredialysis

Detection of pulmonary congestion by chest ultrasound (US) in dialysis patients.Mallamaci F, Benedetto A, Tripepi R, Rastelli S, Castellino P, Tripepi G, Picano E, Zoccali CIn Press

Median # of Median # of comets: 18comets: 18

Detection of pulmonary congestion by chest ultrasound (US) in dialysis patients.Mallamaci F, Benedetto A, Tripepi R, Rastelli S, Castellino P, Tripepi G, Picano E, Zoccali CIn Press

Severe lung Severe lung congestioncongestion

Moderate lung Moderate lung congestioncongestion

<14 14-30 >30<14 14-30 >30Lung Comets numberLung Comets number

PrevalencePrevalence(%)(%)5050

4040

3030

2020

1010

00

33%33%

30%30%

PostdialysisPostdialysisMedian # of Median # of comets: 10comets: 10

Pulmonary PressurePulmonary Pressure(mmHg)(mmHg)

Left atrial VolumeLeft atrial Volume

r=0.33, P=0.002

r=0.32, P=0.006

70

60

50

40

30

20

10

0200150100500

Lung comets (n)

r=0.39, P<0.001

r=0.30, P=0.0130

25

20

15

10

5

0

(mL/m2.7)

200150100500Lung comets (n)

r=-0.73, P<0.001

r=-0.64, P<0.001

80

70

60

50

40

30

20

10200150100500

Lung comets (n)

Detection of pulmonary congestion by chest ultrasound (US) in dialysis patients.Mallamaci F, Benedetto A, Tripepi R, Rastelli S, Castellino P, Tripepi G, Picano E, Zoccali CIn Press

LV Ejection LV Ejection Fraction (%)Fraction (%)

200180160140120100806040200

Pre-dialysis lung comets (n)

140

120

100

80

60

40

20

0

-20

Lungcomets changes (n)

r=0.75P<0.001

Detection of pulmonary congestion by chest ultrasound (US) in dialysis patients.Mallamaci F, Benedetto A, Tripepi R, Rastelli S, Castellino P, Tripepi G, Picano E, Zoccali CIn Press

+ 2SD

- 2SD

Average

Concordance index=0.96, 95% CI: 0.90-0.98

Inter-observer agreement60

40

20

0

-20

-40

[Lu

ng

co

met

s (1

st O

bs)

- L

un

g c

om

ets

(2n

d O

bs)

]

200150100500[Lung comets (1st Obs)+ Lung comets (2nd Obs)]/2

Concordance index=0.98, 95% CI: 0.97-0.99

[Lung comets (3.5 MHz)+ Lung comets (3.0 MHz)]/210080604020

[Lu

ng

co

met

s (3

.5 M

Hz)

-

Lu

ng

co

met

s (

3.0

MH

z)]

0

15

10

5

0

-5

-10

-15

Agreement between probes / machines

The measurement of lung comets is a reliable technique for the measurement of pulmonary water

Peritoneal DialysisPeritoneal Dialysis

Volume expansion : often a major problemVolume expansion : often a major problem

Hemodialysis Hemodialysis Peritoneal DialysisPeritoneal Dialysis n=201 n=201 n=51n=51

Systolic BPSystolic BPmmHgmmHg

180180

140140

100100

Left Atrial volumeLeft Atrial volumemlml

8080

6060

4040

2020

9090

7070

5050

3030

LVH (%)

62%62%

86%86%

P <0.001PD patients obviously volume PD patients obviously volume expanded.expanded.

A change in local clinical policies A change in local clinical policies clearly needed clearly needed

60%60%

Systolic BPSystolic BPmmHgmmHg

180180

140140

100100

9090

7070

5050

3030

LVH (%)

New New policypolicy

Multiply efforts for educating patients at carefully Multiply efforts for educating patients at carefully monitoring BP on a daily basis to aim at GLs monitoring BP on a daily basis to aim at GLs recommended systolic BP target (<140 mmHg).recommended systolic BP target (<140 mmHg).

Systematic use of icodextrin in patients in Systematic use of icodextrin in patients in whom BP is insufficiently controlled or with whom BP is insufficiently controlled or with clinical evidence of volume expansion.clinical evidence of volume expansion.

Clinical policies vary much across centres

Clinical experience and background errors make a difference

Peritoneal DialysisPeritoneal Dialysis

Systolic BPSystolic BPmmHgmmHg

140140

100100

9090

7070

5050

3030

LVH (%)

New New policypolicy

RCRC

60%60%

4545

3030

1515

00

Systolic BPSystolic BPmmHgmmHg

140140

100100

9090

7070

5050

3030

LVH (%)

Centre Centre with less with less experiencexperiencee

57%57%

Left atrium by the 10% larger

Different emphasis on volume-Different emphasis on volume-salt control may translate into salt control may translate into occult volume overload in occult volume overload in patients being treated in centres patients being treated in centres with less stringent salt-volume with less stringent salt-volume policies.policies.

Lung comets monitoring may be Lung comets monitoring may be useful to achieve salt-volume useful to achieve salt-volume balance appropriate to individual balance appropriate to individual cardiac / hemodynamic profilecardiac / hemodynamic profile

Lung comets monitoring may be Lung comets monitoring may be useful to achieve salt-volume useful to achieve salt-volume balance appropriate to individual balance appropriate to individual cardiac / hemodynamic profilecardiac / hemodynamic profile

late eightieslate eighties

BIA bielectrical impedance analysisBIA bielectrical impedance analysis

enthusiasmenthusiasm

disappointementdisappointement

controversycontroversy

NO APPROPRIATE CLINICAL TRIAL NO APPROPRIATE CLINICAL TRIAL TESTING THE USEFULNESS OF TESTING THE USEFULNESS OF THIS TECHNIQUE OVER 20 YEARS THIS TECHNIQUE OVER 20 YEARS OF CLINICAL APPLICATION.OF CLINICAL APPLICATION.

A clinical trial based on a A clinical trial based on a management strategy guided by management strategy guided by lung comets neededlung comets needed

S S & & C C

La storia dei rapporti tra sale e rischio cardiovascolare a livello di La storia dei rapporti tra sale e rischio cardiovascolare a livello di popolazione è lunga e controversa ma è assodato che un eccesso di sale / popolazione è lunga e controversa ma è assodato che un eccesso di sale / volume pone alti rischi nell’insufficienza renale. volume pone alti rischi nell’insufficienza renale.

L’eccesso di volume innescato dal sale è difficilmente quantificabile nei L’eccesso di volume innescato dal sale è difficilmente quantificabile nei pazienti in dialisi. D’altra parte, per l’alta frequenza di disfunzione pazienti in dialisi. D’altra parte, per l’alta frequenza di disfunzione ventricolare sinistra, la sola misura del volume è insufficiente per guidare ventricolare sinistra, la sola misura del volume è insufficiente per guidare l’ultrafiltrazione in questi pazienti. l’ultrafiltrazione in questi pazienti.

La misura dell’acqua polmonare con gli US è una tecnica promettente in La misura dell’acqua polmonare con gli US è una tecnica promettente in quanto fornisce informazioni affidabili sul grado di congestione polmonare, quanto fornisce informazioni affidabili sul grado di congestione polmonare, cioè su un fenomeno da prevenire o correggere tempestivamente nei cioè su un fenomeno da prevenire o correggere tempestivamente nei pazienti in dialisi.pazienti in dialisi.

L’utilità di questa tecnica deve essere testata in uno specifico trial clinico. L’utilità di questa tecnica deve essere testata in uno specifico trial clinico.

16-18 L16-18 L

Blood Volume Blood Volume 5.6 L5.6 L ( (~30% extracellular volume)~30% extracellular volume)

Extracellular Fluids Extracellular Fluids Volume Volume (sodium space)(sodium space)

Blood PressureBlood Pressurecontrol control

Na+

Na+

Na+

Na+

Na+

Na+

Na+

Na+Na+

Na+

Na+

Na+

Na+

Na+

Lymphatic vessels

tonicitytonicityenhanced binding protein enhanced binding protein

((TonEBPTonEBP))

VEGFVEGF

Na+

Na+

Na+

Na+

Na+

Na+

Na+

Na+Na+

Na+

Na+

Na+

Na+

Na+

Machnik, A. et al. Nat. Med. 15, 545–552 (2009).Machnik, A. et al. Nat. Med. 15, 545–552 (2009).

& Carmine Zoccali

Luik AJ Blood Purif. 1998;16:197-209 Luik AJ Blood Purif. 1998;16:197-209

mmHgmmHg

180180

160160

140140

120120

100100

8080

6060

4040

mmHgmmHg

180180

160160

140140

120120

100100

8080

6060

4040

……Short Short dialysisdialysis

5 yr Survival5 yr Survival%%

<35 35-44 45-54 55-64 >64<35 35-44 45-54 55-64 >64Age at start of dialysis Age at start of dialysis (years)(years)

100100

8080

6060

4040

2020

00

Tassin

EDTA

USRDS

……Clinical policies adopted in Clinical policies adopted in Tassin make a difference…. Tassin make a difference….

All cause mortalityAll cause mortalityHRHR

1.51.5

1.41.4

1.31.3

1.21.2

1.11.1

1.01.0

0.80.8

0.5-1.0 1.0-1.5 1.5-2.0 2.5-3.0 3.0-3.5 3.5-4.0 >4.0 Kg.2.0-2.5

High body weight gain, High body weight gain, Better appetite and nutrition status!Better appetite and nutrition status!

Adjusted for malnutrition/inflammationAdjusted for malnutrition/inflammation

Alderman MH, Cohen H, Madhavan S. Dietary sodium intake and mortality: the National Health and Nutrition Examination Survey (NHANES I). Lancet 1998; 351: 781-785.

Death Death (x1000 person years)(x1000 person years)

3030

2525

2020

1515

1010

55

00

1° 2° 3° 4° 1° 2° 3° 4° sodiumsodium

……. these results do not support current recommendations for routine reduction of sodium consumption, nor do they justify advice to increase salt intake or to decrease its concentration in the diet…..

Death Death (x1000 person years)(x1000 person years)

3030

2525

2020

1515

1010

55

00

1° 2° 3° 4° 1° 2° 3° 4° caloriescalories

2008: 23(9):1297–302

CV death