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

HEART AND KIDNEYS: TWO PARTNERS IN CRIME?

R Vanholder

University Hospital, Gent,

Belgium

CARDIO-RENAL AXIS

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

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

SIMULTANEOUS CARDIAC AND RENAL DAMAGE

AcuteSepsis

Other acute inflammatory syndromes

ChronicDiabetes mellitus

Hypertension

Amyloidosis

Auto-immune disorders

Diffuse arteriosclerosis/atheromatosis

CARDIO-RENAL INTERACTIONS

Heart failure Kidney failure

Fluid retention

Kidney hypoperfusion

Uremic retention

Vascular damage

Changes intestinal microbiota

Fluid retention

Uremic retention

Fluid retention

Uremic retention

Fluid retention

Uremic retention

Vascular damage

Fluid retention

Uremic retention

Vascular damage

Fluid retention

Uremic retention

Vascular damage

Fluid retention

Uremic retention

Vascular damage

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

NORMALIZATION OF GLYCEMIA PROTECTS KIDNEYS

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

NORMALIZATION OF GLYCEMIA PROTECTS KIDNEYS

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

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

OBESITY

THE RISK FOR PROGRESSION TO ESRD INCREASES WITH BMI

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

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

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

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

OBESITY

SMOKING

SMOKING INCREASES THE ODDS FOR CKD

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

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.

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.

OBESITY

SMOKING

SEDENTARISM

OBESITY

SEDENTARISME

PHOSPHORUS: CURED MEAT

OBESITY

SMOKINGSEDENTARISME

PHOSPHORUS: CURED MEAT

PHOSPHFORUS: CHEESE

OBESITY

SMOKING

SEDENTARISME

FOSFOR: VLEESWAREN

FOSFOR: KAAS

PHOSPHORUS: COLA

CKD IS A CARDIOVASCULAR RISK FACTOR BY ITSELF

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

NEPHROPROTECTION REDUCES NUMBER OF PATIENTS NEEDING DIALYSIS

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

CLASSICAL RISK FACTORS DO NOT COVER THE WHOLE PICTURE

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

FRAMINGHAM RISK DOES NOT PREDICT ALL MORTALITY IN CKD

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

OTHER FACTORS AT PLAY

Neurohormonal disbalance

Anemia

Oxidative stress

Renal sympathetic activity

Inflammation

Uremic toxins

INFLAMMATION IN CKD AND NFκB AND CARDIOVASCULAR RISK

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.

↑NFκB

MITOCHONDRIALDYSFUNCTION

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

VASOACTIVEAGENTS-Angiotensin II-Noradrenaline-Endothelin I-Aldosterone

DIALYSIS-RELATEDFACTORS-Bioincompatibility-Dialysis fluid impurities

DYSLIPIDEMIA-OxLDL

RELEASECYTOKINES MCP-1 TGFβ-1

Vanholder et al, Lancet Diabetes Endocrinol, in preparation

LINKED TO CARDIO-VASCULAR TOXICITY

Small water solubleUrea

Phosphate

Potassium

Methylguanidine

Guanidinosuccinate

Uric acid

Oxalate

Protein boundP-cresyl sulfate

P-cresylglucuronide

Phenylacetic acid

Indoxyl sulfate

Indole acetic acid

Middle moleculesβ2-microglobulin

Complement factor D

Endothelin

Leptin

resistin

FGF-23

Parathyroid hormone

Interleukin-1β

Interleukin-6

Tumor necrosis factor-α

Interleukin-18

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

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

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

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