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

2. 2 2 © 2008 Universitair Ziekenhuis Gent CARDIO-RENAL AXIS

3. 3 3 © 2008 Universitair Ziekenhuis Gent CARDIO-RENAL AXIS

4. 4 4 © 2008 Universitair Ziekenhuis Gent TYPES OF CARDIO-RENAL DISEASES PRIMARYSECONDARY Acute heart failure, acute coronary syndromeRenal hypoperfusion, fluid retention, acute kidney injury, uremic retention Chronic heart failureRenal hypoperfusion, fluid retention, acute or chronic kidney failure, uremic retention Acute kidney injuryFluid retention, hypertension, heart failure, uremic retention Chronic kidney diseaseFluid retention, hypertension, heart failure, uremic retention, cardio-vascular damage Simultaneous heart and kidney damage

5. 5 5 © 2008 Universitair Ziekenhuis Gent TYPES OF CARDIO-RENAL DISEASES PRIMARYSECONDARY Acute heart failure, acute coronary syndromeRenal hypoperfusion, fluid retention, acute kidney injury, uremic retention Chronic heart failureRenal hypoperfusion, fluid retention, acute or chronic kidney failure, uremic retention Acute kidney injuryFluid retention, hypertension, heart failure, uremic retention Chronic kidney diseaseFluid retention, hypertension, heart failure, uremic retention, cardio-vascular damage Simultaneous heart and kidney damage

6. 6 6 © 2008 Universitair Ziekenhuis Gent SIMULTANEOUS CARDIAC AND RENAL DAMAGE Acute Sepsis Other acute inflammatory syndromes Chronic Diabetes mellitus Hypertension Amyloidosis Auto-immune disorders Diffuse arteriosclerosis/atheromatosis

7. 7 7 © 2008 Universitair Ziekenhuis Gent CARDIO-RENAL INTERACTIONS Heart failure Kidney failure Fluid retention Kidney hypoperfusion Uremic retention Vascular damage Changes intestinal microbiota

8. 8 8 © 2008 Universitair Ziekenhuis Gent CARDIO-RENAL INTERACTIONS Heart failure Kidney failure

9. 9 9 © 2008 Universitair Ziekenhuis Gent CARDIO-RENAL INTERACTIONS Heart failure Kidney failure Fluid retention

10. 10 © 2008 Universitair Ziekenhuis Gent CARDIO-RENAL INTERACTIONS Heart failure Kidney failure Fluid retention Kidney hypoperfusion

11. 11 © 2008 Universitair Ziekenhuis Gent CARDIO-RENAL INTERACTIONS Heart failure Kidney failure Fluid retention Kidney hypoperfusion

12. 12 © 2008 Universitair Ziekenhuis Gent CARDIO-RENAL INTERACTIONS Heart failure Kidney failure Fluid retention Kidney hypoperfusion Uremic retention

13. 13 © 2008 Universitair Ziekenhuis Gent CARDIO-RENAL INTERACTIONS Heart failure Kidney failure Fluid retention Kidney hypoperfusion Uremic retention

14. 14 © 2008 Universitair Ziekenhuis Gent CARDIO-RENAL INTERACTIONS Heart failure Kidney failure Fluid retention Kidney hypoperfusion Uremic retention Vascular damage

15. 15 © 2008 Universitair Ziekenhuis Gent CARDIO-RENAL INTERACTIONS Heart failure Kidney failure Fluid retention Kidney hypoperfusion Uremic retention Vascular damage

16. 16 © 2008 Universitair Ziekenhuis Gent CARDIO-RENAL INTERACTIONS Heart failure Kidney failure Fluid retention Kidney hypoperfusion Uremic retention Vascular damage Changes intestinal microbiota

17. 17 © 2008 Universitair Ziekenhuis Gent CARDIO-RENAL INTERACTIONS Heart failure Kidney failure Fluid retention Kidney hypoperfusion Uremic retention Vascular damage Changes intestinal microbiota

18. © 2008 Universitair Ziekenhuis Gent CARDIO-VASCULAR RISK FACTORS ARE ALSO RISK FACTORS FOR KIDNEY FAILURE

19. 19 © 2008 Universitair Ziekenhuis Gent NORMALIZATION OF GLYCEMIA PROTECTS KIDNEYS Fioretto et al, NEJM, 339:69-75; 1998

20. 20 © 2008 Universitair Ziekenhuis Gent NORMALIZATION OF GLYCEMIA PROTECTS KIDNEYS Fioretto et al, NEJM, 339:69-75; 1998

21. 21 © 2008 Universitair Ziekenhuis Gent Jafar et al, Ann Intern Med, 139:244-252; 2003 HYPERTENSION INCREASES RISK OF PROGRESSION

22. 22 © 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

23. 23 © 2008 Universitair Ziekenhuis Gent OBESITY

24. 24 © 2008 Universitair Ziekenhuis Gent THE RISK FOR PROGRESSION TO ESRD INCREASES WITH BMI Babayev et al, AJKD, 61:404-412; 2013

25. 25 © 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/m 2, 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

26. 26 © 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

27. 27 © 2008 Universitair Ziekenhuis Gent OBESITY SMOKING

28. 28 © 2008 Universitair Ziekenhuis Gent Yacoub et al, BMC Public Health, 10:731; 2010 SMOKING INCREASES THE ODDS FOR CKD

29. 29 © 2008 Universitair Ziekenhuis Gent SMOKING INCREASES THE ODDS FOR CKD Table 2: Smoking status and Odds ratio for chronic renal failure CasesControlOR † (CI 95%)P n%*n%** Ever regular smoking No11256.525167.71 (Reference)- Yes8643.412032.31.6 (1.12-2.29)0.009 Regular smoking Former3015.14311.61.04(0.58-1.86)0.8 Current5628.27720.81.63(1.08-2.45)0.02 No. of pack/years, cigarettes jan/153417.16016.12.1(0.96-4.57)0.06 16-30168297.82.04(1.08-3.88)0.028 > 303618.1318.32.6(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

30. 30 © 2008 Universitair Ziekenhuis Gent SMOKING INCREASES THE ODDS FOR CKD Table 2: Smoking status and Odds ratio for chronic renal failure CasesControlOR † (CI 95%)P n%*n%** Ever regular smoking No11256.525167.71 (Reference)- Yes8643.412032.31.6 (1.12-2.29)0.009 Regular smoking Former3015.14311.61.04(0.58-1.86)0.8 Current5628.27720.81.63(1.08-2.45)0.02 No. of pack/years, cigarettes jan/153417.16016.12.1(0.96-4.57)0.06 16-30168297.82.04(1.08-3.88)0.028 > 303618.1318.32.6(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

31. 31 © 2008 Universitair Ziekenhuis Gent SMOKING INCREASES THE ODDS FOR CKD Table 2: Smoking status and Odds ratio for chronic renal failure CasesControlOR † (CI 95%)P n%*n%** Ever regular smoking No11256.525167.71 (Reference)- Yes8643.412032.31.6 (1.12-2.29)0.009 Regular smoking Former3015.14311.61.04(0.58-1.86)0.8 Current5628.27720.81.63(1.08-2.45)0.02 No. of pack/years, cigarettes jan/153417.16016.12.1(0.96-4.57)0.06 16-30168297.82.04(1.08-3.88)0.028 > 303618.1318.32.6(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

32. 32 © 2008 Universitair Ziekenhuis Gent OBESITY SMOKING SEDENTARISM SALT

33. 33 © 2008 Universitair Ziekenhuis Gent OBESITY ROKEN SEDENTARISME ZOUT PHOSPHORUS: CURED MEAT

34. 34 © 2008 Universitair Ziekenhuis Gent OBESITY SMOKING SEDENTARISME ZOUT PHOSPHORUS: CURED MEAT PHOSPHFORUS: CHEESE

35. 35 © 2008 Universitair Ziekenhuis Gent OBESITY SMOKING SEDENTARISME ZOUT FOSFOR: VLEESWAREN FOSFOR: KAAS PHOSPHORUS: COLA

36. © 2008 Universitair Ziekenhuis Gent CKD IS A CARDIOVASCULAR RISK FACTOR BY ITSELF

37. 37 © 2008 Universitair Ziekenhuis Gent Vanholder et al, NDT, 20: 1048-1056; 2005 CKD PRE-DIALYSIS IS ALSO LINKED TO CVD

38. 38 © 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

39. 39 © 2008 Universitair Ziekenhuis Gent NEPHROPROTECTION REDUCES NUMBER OF PATIENTS NEEDING DIALYSIS Palmer et al, Diabetes Care, 1897-1903; 2004

40. © 2008 Universitair Ziekenhuis Gent CLASSICAL RISK FACTORS DO NOT COVER THE WHOLE PICTURE

41. 41 © 2008 Universitair Ziekenhuis Gent Weiner et al, JACC, 50: 217-224; 2007 FRAMINGHAM RISK DOES NOT PREDICT ALL MORTALITY IN CKD

42. 42 © 2008 Universitair Ziekenhuis Gent FRAMINGHAM RISK DOES NOT PREDICT ALL MORTALITY IN CKD Weiner et al, JACC, 50: 217-224; 2007

43. 43 © 2008 Universitair Ziekenhuis Gent OTHER FACTORS AT PLAY Neurohormonal disbalance Anemia Oxidative stress Renal sympathetic activity Inflammation Uremic toxins

44. © 2008 Universitair Ziekenhuis Gent INFLAMMATION IN CKD AND NFκB AND CARDIOVASCULAR RISK

45. 45 © 2008 Universitair Ziekenhuis Gent Caravaca, NDT, 21: 1575-1581; 2006 INFLAMMATION IS ASSOCIATED TO MORTALITY OF CKD

46. 46 © 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.

47. 47 © 2008 Universitair Ziekenhuis Gent ↑NFκB MITOCHONDRIAL DYSFUNCTION ROSUREMIC SOLUTES -AGEs -ADMA - IS - PCS - TMAO - P VASOACTIVE AGENTS -Angiotensin II -Noradrenaline -Endothelin I -Aldosterone INFECTIOUS AGENTS -Infections -Endotoxin (LPS) -Bacterial DNA -Peptidoglycan DIALYSIS-RELATED FACTORS -Bioincompatibility -Dialysis fluid impurities A DYSLIPIDEMIA -OxLDL RELEASE CYTOKINES MCP-1 TGFβ-1 Vanholder et al, Lancet Diabetes Endocrinol, in preparation

48. 48 © 2008 Universitair Ziekenhuis Gent LINKED TO CARDIO-VASCULAR TOXICITY Small water soluble Urea Phosphate Potassium Methylguanidine Guanidinosuccinate ADMA SDMA Uric acid Oxalate Protein bound P-cresyl sulfate P-cresylglucuronide Phenylacetic acid Indoxyl sulfate Indole acetic acid TMAO Middle molecules β2-microglobulin Complement factor D Endothelin Leptin resistin FGF-23 Parathyroid hormone Interleukin-1β Interleukin-6 Tumor necrosis factor-α Interleukin-18 AGES Uridine adenosine triphosphate ADMA: asymmetric dimethyl arginine; SDMA: symmetric dimethyl arginine; TMAO: trimethylamine-N-oxide; FGF-23: fibroblast growth factor-23; AGEs: advanced glycation end products

49. 49 © 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