© 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
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22© 2008 Universitair Ziekenhuis Gent
CARDIO-RENAL AXIS
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33© 2008 Universitair Ziekenhuis Gent
CARDIO-RENAL AXIS
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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
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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
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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
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77© 2008 Universitair Ziekenhuis Gent
CARDIO-RENAL INTERACTIONS
Heart failure Kidney failure
Fluid retention
Kidney hypoperfusion
Uremic retention
Vascular damage
Changes intestinal microbiota
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88© 2008 Universitair Ziekenhuis Gent
CARDIO-RENAL INTERACTIONS
Heart failure Kidney failure
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99© 2008 Universitair Ziekenhuis Gent
CARDIO-RENAL INTERACTIONS
Heart failure Kidney failure
Fluid retention
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1010© 2008 Universitair Ziekenhuis Gent
CARDIO-RENAL INTERACTIONS
Heart failure Kidney failure
Fluid retention
Kidney hypoperfusion
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1111© 2008 Universitair Ziekenhuis Gent
CARDIO-RENAL INTERACTIONS
Heart failure Kidney failure
Fluid retention
Kidney hypoperfusion
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1212© 2008 Universitair Ziekenhuis Gent
CARDIO-RENAL INTERACTIONS
Heart failure Kidney failure
Fluid retention
Kidney hypoperfusion
Uremic retention
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1313© 2008 Universitair Ziekenhuis Gent
CARDIO-RENAL INTERACTIONS
Heart failure Kidney failure
Fluid retention
Kidney hypoperfusion
Uremic retention
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1414© 2008 Universitair Ziekenhuis Gent
CARDIO-RENAL INTERACTIONS
Heart failure Kidney failure
Fluid retention
Kidney hypoperfusion
Uremic retention
Vascular damage
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1515© 2008 Universitair Ziekenhuis Gent
CARDIO-RENAL INTERACTIONS
Heart failure Kidney failure
Fluid retention
Kidney hypoperfusion
Uremic retention
Vascular damage
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1616© 2008 Universitair Ziekenhuis Gent
CARDIO-RENAL INTERACTIONS
Heart failure Kidney failure
Fluid retention
Kidney hypoperfusion
Uremic retention
Vascular damage
Changes intestinal microbiota
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1717© 2008 Universitair Ziekenhuis Gent
CARDIO-RENAL INTERACTIONS
Heart failure Kidney failure
Fluid retention
Kidney hypoperfusion
Uremic retention
Vascular damage
Changes intestinal microbiota
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© 2008 Universitair Ziekenhuis Gent
CARDIO-VASCULAR RISK FACTORS ARE ALSO RISK FACTORS FOR KIDNEY FAILURE
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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
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2121© 2008 Universitair Ziekenhuis Gent Jafar et al, Ann Intern Med, 139:244-252; 2003
HYPERTENSION INCREASES RISK OF PROGRESSION
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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
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2323© 2008 Universitair Ziekenhuis Gent
OBESITY
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2424© 2008 Universitair Ziekenhuis Gent
THE RISK FOR PROGRESSION TO ESRD INCREASES WITH BMI
Babayev et al, AJKD, 61:404-412; 2013
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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
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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
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2727© 2008 Universitair Ziekenhuis Gent
OBESITY
SMOKING
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2828© 2008 Universitair Ziekenhuis Gent Yacoub et al, BMC Public Health, 10:731; 2010
SMOKING INCREASES THE ODDS FOR CKD
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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
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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
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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
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3232© 2008 Universitair Ziekenhuis Gent
OBESITY
SMOKING
SEDENTARISM
SALT
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3333© 2008 Universitair Ziekenhuis Gent
OBESITY
ROKEN
SEDENTARISME
ZOUT
PHOSPHORUS: CURED MEAT
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3434© 2008 Universitair Ziekenhuis Gent
OBESITY
SMOKINGSEDENTARISME
ZOUT
PHOSPHORUS: CURED MEAT
PHOSPHFORUS: CHEESE
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3535© 2008 Universitair Ziekenhuis Gent
OBESITY
SMOKING
SEDENTARISME
ZOUT
FOSFOR: VLEESWAREN
FOSFOR: KAAS
PHOSPHORUS: COLA
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© 2008 Universitair Ziekenhuis Gent
CKD IS A CARDIOVASCULAR RISK FACTOR BY ITSELF
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3737© 2008 Universitair Ziekenhuis Gent Vanholder et al, NDT, 20: 1048-1056; 2005
CKD PRE-DIALYSIS IS ALSO LINKED TO CVD
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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
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3939© 2008 Universitair Ziekenhuis Gent
NEPHROPROTECTION REDUCES NUMBER OF PATIENTS NEEDING DIALYSIS
Palmer et al, Diabetes Care, 1897-1903; 2004
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© 2008 Universitair Ziekenhuis Gent
CLASSICAL RISK FACTORS DO NOT COVER THE WHOLE PICTURE
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4141© 2008 Universitair Ziekenhuis Gent
Weiner et al, JACC, 50: 217-224; 2007
FRAMINGHAM RISK DOES NOT PREDICT ALL MORTALITY IN CKD
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4242© 2008 Universitair Ziekenhuis Gent
FRAMINGHAM RISK DOES NOT PREDICT ALL MORTALITY IN CKD
Weiner et al, JACC, 50: 217-224; 2007
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4343© 2008 Universitair Ziekenhuis Gent
OTHER FACTORS AT PLAY
Neurohormonal disbalance
Anemia
Oxidative stress
Renal sympathetic activity
Inflammation
Uremic toxins
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© 2008 Universitair Ziekenhuis Gent
INFLAMMATION IN CKD AND NFκB AND CARDIOVASCULAR RISK
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4545© 2008 Universitair Ziekenhuis Gent Caravaca, NDT, 21: 1575-1581; 2006
INFLAMMATION IS ASSOCIATED TO MORTALITY OF CKD
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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.
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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
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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
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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