© 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder...

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© 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium

Transcript of © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder...

Page 1: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

© 2008 Universitair Ziekenhuis Gent

HEART AND KIDNEYS: TWO PARTNERS IN CRIME?

R Vanholder

University Hospital, Gent,

Belgium

Page 2: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

22© 2008 Universitair Ziekenhuis Gent

CARDIO-RENAL AXIS

Page 3: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

33© 2008 Universitair Ziekenhuis Gent

CARDIO-RENAL AXIS

Page 4: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

44© 2008 Universitair Ziekenhuis Gent

TYPES OF CARDIO-RENAL DISEASES

PRIMARY SECONDARY

Acute heart failure, acute coronary syndrome

Renal hypoperfusion, fluid retention, acute kidney injury, uremic retention

Chronic heart failure Renal hypoperfusion, fluid retention, acute or chronic kidney failure, uremic retention

Acute kidney injury Fluid retention, hypertension, heart failure, uremic retention

Chronic kidney disease Fluid retention, hypertension, heart failure, uremic retention, cardio-vascular damage

Simultaneous heart and kidney damage

Page 5: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

55© 2008 Universitair Ziekenhuis Gent

TYPES OF CARDIO-RENAL DISEASES

PRIMARY SECONDARY

Acute heart failure, acute coronary syndrome Renal hypoperfusion, fluid retention, acute kidney injury, uremic retention

Chronic heart failure Renal hypoperfusion, fluid retention, acute or chronic kidney failure, uremic retention

Acute kidney injury Fluid retention, hypertension, heart failure, uremic retention

Chronic kidney disease Fluid retention, hypertension, heart failure, uremic retention, cardio-vascular damage

Simultaneous heart and kidney damage

Page 6: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

66© 2008 Universitair Ziekenhuis Gent

SIMULTANEOUS CARDIAC AND RENAL DAMAGE

AcuteSepsis

Other acute inflammatory syndromes

ChronicDiabetes mellitus

Hypertension

Amyloidosis

Auto-immune disorders

Diffuse arteriosclerosis/atheromatosis

Page 7: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

77© 2008 Universitair Ziekenhuis Gent

CARDIO-RENAL INTERACTIONS

Heart failure Kidney failure

Fluid retention

Kidney hypoperfusion

Uremic retention

Vascular damage

Changes intestinal microbiota

Page 8: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

88© 2008 Universitair Ziekenhuis Gent

CARDIO-RENAL INTERACTIONS

Heart failure Kidney failure

Page 9: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

99© 2008 Universitair Ziekenhuis Gent

CARDIO-RENAL INTERACTIONS

Heart failure Kidney failure

Fluid retention

Page 10: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

1010© 2008 Universitair Ziekenhuis Gent

CARDIO-RENAL INTERACTIONS

Heart failure Kidney failure

Fluid retention

Kidney hypoperfusion

Page 11: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

1111© 2008 Universitair Ziekenhuis Gent

CARDIO-RENAL INTERACTIONS

Heart failure Kidney failure

Fluid retention

Kidney hypoperfusion

Page 12: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

1212© 2008 Universitair Ziekenhuis Gent

CARDIO-RENAL INTERACTIONS

Heart failure Kidney failure

Fluid retention

Kidney hypoperfusion

Uremic retention

Page 13: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

1313© 2008 Universitair Ziekenhuis Gent

CARDIO-RENAL INTERACTIONS

Heart failure Kidney failure

Fluid retention

Kidney hypoperfusion

Uremic retention

Page 14: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

1414© 2008 Universitair Ziekenhuis Gent

CARDIO-RENAL INTERACTIONS

Heart failure Kidney failure

Fluid retention

Kidney hypoperfusion

Uremic retention

Vascular damage

Page 15: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

1515© 2008 Universitair Ziekenhuis Gent

CARDIO-RENAL INTERACTIONS

Heart failure Kidney failure

Fluid retention

Kidney hypoperfusion

Uremic retention

Vascular damage

Page 16: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

1616© 2008 Universitair Ziekenhuis Gent

CARDIO-RENAL INTERACTIONS

Heart failure Kidney failure

Fluid retention

Kidney hypoperfusion

Uremic retention

Vascular damage

Changes intestinal microbiota

Page 17: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

1717© 2008 Universitair Ziekenhuis Gent

CARDIO-RENAL INTERACTIONS

Heart failure Kidney failure

Fluid retention

Kidney hypoperfusion

Uremic retention

Vascular damage

Changes intestinal microbiota

Page 18: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

© 2008 Universitair Ziekenhuis Gent

CARDIO-VASCULAR RISK FACTORS ARE ALSO RISK FACTORS FOR KIDNEY FAILURE

Page 19: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

1919© 2008 Universitair Ziekenhuis Gent

NORMALIZATION OF GLYCEMIA PROTECTS KIDNEYS

Fioretto et al, NEJM, 339:69-75; 1998

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2020© 2008 Universitair Ziekenhuis Gent

NORMALIZATION OF GLYCEMIA PROTECTS KIDNEYS

Fioretto et al, NEJM, 339:69-75; 1998

Page 21: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

2121© 2008 Universitair Ziekenhuis Gent Jafar et al, Ann Intern Med, 139:244-252; 2003

HYPERTENSION INCREASES RISK OF PROGRESSION

Page 22: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

2222© 2008 Universitair Ziekenhuis Gent

HYPERTENSION INCREASES RISK OF PROGRESSION

Relative risk for kidney disease progression based on current level of systolic blood pressure and current urine protein excretion.

Jafar et al, Ann Intern Med, 139:244-252; 2003

Page 23: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

2323© 2008 Universitair Ziekenhuis Gent

OBESITY

Page 24: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

2424© 2008 Universitair Ziekenhuis Gent

THE RISK FOR PROGRESSION TO ESRD INCREASES WITH BMI

Babayev et al, AJKD, 61:404-412; 2013

Page 25: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

2525© 2008 Universitair Ziekenhuis Gent

THE RISK FOR PROGRESSION TO ESRD INCREASES WITH BMI

Figure 3. Body mass index (BMI) and progression to end-stage renal disease (ESRD) in participants with chronic kidney disease (CKD) stages 3-4. Cumulative incidence curves for ESRD progression in (A) whites and (B) African Americans with CKD stages 3-4. There was a trend toward a higher incidence of ESRD with BMI >35 kg/m2, but it was not statistically significant in either cohort. Log-rank test P > 0.05 for both whites and African Americans.

Babayev et al, AJKD, 61:404-412; 2013

Page 26: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

2626© 2008 Universitair Ziekenhuis Gent

OBESE ADIPOSE TISSUE PRODUCES MORE PRO-INFLAMMATORY MEDIATORS AND IS INFILTRATED BY INFLAMMATORY CELLS

Han & Levings, J Immunol, 191:527-532; 2013

Page 27: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

2727© 2008 Universitair Ziekenhuis Gent

OBESITY

SMOKING

Page 28: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

2828© 2008 Universitair Ziekenhuis Gent Yacoub et al, BMC Public Health, 10:731; 2010

SMOKING INCREASES THE ODDS FOR CKD

Page 29: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

2929© 2008 Universitair Ziekenhuis Gent

SMOKING INCREASES THE ODDS FOR CKDTable 2: Smoking status and Odds ratio for chronic renal failure

  Cases Control OR† (CI 95%) P  n %* n %**    Ever regular smoking            No 112 56.5 251 67.7 1 (Reference) -Yes 86 43.4 120 32.3 1.6 (1.12-2.29) 0.009Regular smoking            Former 30 15.1 43 11.6 1.04(0.58-1.86) 0.8Current 56 28.2 77 20.8 1.63(1.08-2.45) 0.02No. of pack/years, cigarettes          jan/15 34 17.1 60 16.1 2.1(0.96-4.57) 0.0616-30 16 8 29 7.8 2.04(1.08-3.88) 0.028> 30 36 18.1 31 8.3 2.6(1.53-4.41) 0.000*Of cases (n = 198). **Of control (n = 371).† Adjusted by age and gender.

Yacoub et al, BMC Public Health, 10:731; 2010

Page 30: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

3030© 2008 Universitair Ziekenhuis Gent

SMOKING INCREASES THE ODDS FOR CKDTable 2: Smoking status and Odds ratio for chronic renal failure

  Cases Control OR† (CI 95%) P  n %* n %**    

Ever regular smoking            No 112 56.5 251 67.7 1 (Reference) -Yes 86 43.4 120 32.3 1.6 (1.12-2.29) 0.009Regular smoking            Former 30 15.1 43 11.6 1.04(0.58-1.86) 0.8Current 56 28.2 77 20.8 1.63(1.08-2.45) 0.02No. of pack/years, cigarettes          jan/15 34 17.1 60 16.1 2.1(0.96-4.57) 0.0616-30 16 8 29 7.8 2.04(1.08-3.88) 0.028> 30 36 18.1 31 8.3 2.6(1.53-4.41) 0.000*Of cases (n = 198). **Of control (n = 371).† Adjusted by age and gender.

Yacoub et al, BMC Public Health, 10:731; 2010

Page 31: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

3131© 2008 Universitair Ziekenhuis Gent

SMOKING INCREASES THE ODDS FOR CKDTable 2: Smoking status and Odds ratio for chronic renal failure

  Cases Control OR† (CI 95%) P  n %* n %**    Ever regular smoking            No 112 56.5 251 67.7 1 (Reference) -Yes 86 43.4 120 32.3 1.6 (1.12-2.29) 0.009Regular smoking            Former 30 15.1 43 11.6 1.04(0.58-1.86) 0.8Current 56 28.2 77 20.8 1.63(1.08-2.45) 0.02No. of pack/years, cigarettes          jan/15 34 17.1 60 16.1 2.1(0.96-4.57) 0.0616-30 16 8 29 7.8 2.04(1.08-3.88) 0.028> 30 36 18.1 31 8.3 2.6(1.53-4.41) 0.000*Of cases (n = 198). **Of control (n = 371).† Adjusted by age and gender.

Yacoub et al, BMC Public Health, 10:731; 2010

Page 32: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

3232© 2008 Universitair Ziekenhuis Gent

OBESITY

SMOKING

SEDENTARISM

SALT

Page 33: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

3333© 2008 Universitair Ziekenhuis Gent

OBESITY

ROKEN

SEDENTARISME

ZOUT

PHOSPHORUS: CURED MEAT

Page 34: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

3434© 2008 Universitair Ziekenhuis Gent

OBESITY

SMOKINGSEDENTARISME

ZOUT

PHOSPHORUS: CURED MEAT

PHOSPHFORUS: CHEESE

Page 35: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

3535© 2008 Universitair Ziekenhuis Gent

OBESITY

SMOKING

SEDENTARISME

ZOUT

FOSFOR: VLEESWAREN

FOSFOR: KAAS

PHOSPHORUS: COLA

Page 36: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

© 2008 Universitair Ziekenhuis Gent

CKD IS A CARDIOVASCULAR RISK FACTOR BY ITSELF

Page 37: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

3737© 2008 Universitair Ziekenhuis Gent Vanholder et al, NDT, 20: 1048-1056; 2005

CKD PRE-DIALYSIS IS ALSO LINKED TO CVD

Page 38: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

3838© 2008 Universitair Ziekenhuis Gent

CKD PRE-DIALYSIS IS ALSO LINKED TO CVD

Vanholder et al, NDT, 20: 1048-1056; 2005

y = (0.1262x) + 10.77, r = 0.645, P < 0.001; y = (–0.1018x) + 2.727, r = 0.574, P < 0.004

Page 39: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

3939© 2008 Universitair Ziekenhuis Gent

NEPHROPROTECTION REDUCES NUMBER OF PATIENTS NEEDING DIALYSIS

Palmer et al, Diabetes Care, 1897-1903; 2004

Page 40: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

© 2008 Universitair Ziekenhuis Gent

CLASSICAL RISK FACTORS DO NOT COVER THE WHOLE PICTURE

Page 41: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

4141© 2008 Universitair Ziekenhuis Gent

Weiner et al, JACC, 50: 217-224; 2007

FRAMINGHAM RISK DOES NOT PREDICT ALL MORTALITY IN CKD

Page 42: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

4242© 2008 Universitair Ziekenhuis Gent

FRAMINGHAM RISK DOES NOT PREDICT ALL MORTALITY IN CKD

Weiner et al, JACC, 50: 217-224; 2007

Page 43: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

4343© 2008 Universitair Ziekenhuis Gent

OTHER FACTORS AT PLAY

Neurohormonal disbalance

Anemia

Oxidative stress

Renal sympathetic activity

Inflammation

Uremic toxins

Page 44: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

© 2008 Universitair Ziekenhuis Gent

INFLAMMATION IN CKD AND NFκB AND CARDIOVASCULAR RISK

Page 45: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

4545© 2008 Universitair Ziekenhuis Gent Caravaca, NDT, 21: 1575-1581; 2006

INFLAMMATION IS ASSOCIATED TO MORTALITY OF CKD

Page 46: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

4646© 2008 Universitair Ziekenhuis Gent

INFLAMMATION IS ASSOCIATED TO MORTALITY OF CKD

Caravaca, NDT, 21: 1575-1581; 2006

Fig. 1. Kaplan–Meier analysis of survival according to C-reactive protein above or below 3.90 mg/l. Log-rank test = 13.65, P<0.0001.

Page 47: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

4747© 2008 Universitair Ziekenhuis Gent

↑NFκB

MITOCHONDRIALDYSFUNCTION

ROS UREMICSOLUTES-AGEs-ADMA- IS- PCS- TMAO- P

VASOACTIVEAGENTS-Angiotensin II-Noradrenaline-Endothelin I-Aldosterone

DIALYSIS-RELATEDFACTORS-Bioincompatibility-Dialysis fluid impurities

A

DYSLIPIDEMIA-OxLDL

RELEASECYTOKINES MCP-1 TGFβ-1

Vanholder et al, Lancet Diabetes Endocrinol, in preparation

Page 48: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

4848© 2008 Universitair Ziekenhuis Gent

LINKED TO CARDIO-VASCULAR TOXICITY

Small water solubleUrea

Phosphate

Potassium

Methylguanidine

Guanidinosuccinate

ADMA

SDMA

Uric acid

Oxalate

Protein boundP-cresyl sulfate

P-cresylglucuronide

Phenylacetic acid

Indoxyl sulfate

Indole acetic acid

TMAO

Middle moleculesβ2-microglobulin

Complement factor D

Endothelin

Leptin

resistin

FGF-23

Parathyroid hormone

Interleukin-1β

Interleukin-6

Tumor necrosis factor-α

Interleukin-18

AGES

Uridine adenosine triphosphateADMA: asymmetric dimethyl arginine; SDMA: symmetric dimethyl arginine; TMAO: trimethylamine-N-oxide; FGF-23: fibroblast growth factor-23; AGEs: advanced glycation end products

Page 49: © 2008 Universitair Ziekenhuis Gent HEART AND KIDNEYS: TWO PARTNERS IN CRIME? R Vanholder University Hospital, Gent, Belgium.

4949© 2008 Universitair Ziekenhuis Gent

CONCLUSIONS

The heart and kidneys are two organ systems that are intimately linked together.

Heart failure leads to kidney failure and vice versa, inducing a sort of vicious circle

Next to classical risk factors als non-traditional risk factors are at play

Among these, inflammation, but also coagulation pro-fibrotic factors and vaso-active substances play an important role

These mechanisms are at least in part induced by uremic retention solutes