1. Cardiovascular Risk In Chronic Kidney Disease Dr Ginny Quan

2. Who Shall Live ? NBC documentary screened in the 70’s, USA

3. Cardiovascular Risk In Chronic Kidney Disease Chronic Kidney Disease Persistent Renal Damage on Biopsy or Imaging Persistant abnormal urinalysis Glomerular Filtration Rate <60mL/min/1.73m2

4. CHRONIC KIDNEY DISEASE Increased risk of Increased Risk of CARDIOVASCULAR DISEASE

5. Cardiovascular Risk In CKD 1.Is it important? 2.What factors are responsible? 3.What can be done about them?

6. Data from USRDS 2002 and USA National Vital Statistics Report 1999 Patients with End Stage Renal Disease Die Young

7. What Do Patients with Renal Disease Die Of ? UK renal registry 2002

8. What Do People With ERF Die Of ? Cardiac death slightly increased compared to the general population BUT Age related risk for Cardiac death is very different x200 age 25-29 x5 age 80-84

9. Early CKD Predicts Risk of Cardiovascular Disease HOORN Study: Population based cohort, n=631 Age 50-75 yrs Followed 10.2 yrs 5ml/min drop in GFR increased risk of CV death by 26%

10. Early CKD Predicts Risk of Cardiovascular Disease HOPE study : Patients at high risk of cardiovascular events. Mann JF Ann Intern Med 2001 134:629-36 6.6% 11.4% 15.1% 22.1% P<0.001

11. Early CKD Predicts Risk Of Cardiovascular Disease The hazard ratio for renal dysfunction in the HOPE study was as high as that conferred by diabetes

12. Microalbuminuria/Proteinuria Predicts Risk of Cardiovascular Disease Predicts CV risk in DM Predicts CV mortality in general population -PREVEND increase in cardiovascular mortality of 1.35 for each doubling of urinary albumin excretion Predicts CV risk in patients with other high risk factors -HOPE, Linear association between microalbuminuria and an increased risk of endpoint

13. Cardiovascular Risk In CKD Cardiovascular risk increases as soon as chronic kidney disease can be measured As renal function deteriorates risk of cardiovascular disease increases proportionally In ESRD cardiovascular risk up to 200 times the general population CKD associated with poorer outcome post cardiovascular events

14. Is It Important ? Prevalence diagnosed CKD estimated at 5554 pmp (0.5%) >80% will not develop ESRD Majority of these will die of CVD Population screening studies estimate up to 10% population with CKD

15. Cardiovascular Risk In CKD 1.Is it important? 2.What factors are responsible? 3.What can be done about them?

16. What factors are responsible? Longenecker JC :The CHOICE study J Am Soc Nephrol 2002 ;13;1918 1. Increased Prevalence of Conventional Risk Factors

17. What factors are responsible? 2. Non-conventional risk factors Cardiac disease is atypical in CKD CKD is a risk factor for Cardiovascular disease independent of known risk factors

18. Cardiac Disease is Atypical in Renal Disease General population: Cardiac death mostly due to Coronary Heart Disease 5% Have LVH on Echo Coronary artery calcification unusual ESRD: Cardiac death often due to Cardiomyopathy /arrhythmia/CHF 75% Have LVH on Echo High incidence of coronary artery calcification

19. What factors are responsible? 3. Lack of risk factor modification Failure to recognise early CKD as a risk factor for cardiovascular disease Lack of trials in CKD patients Fear of polypharmacy and side effects in patients with severe renal disease

20. Risk Factors for Cardiac Disease In CKD Conventional Hypertension Dyslipidaemia Smoking Diabetes ?Under treatment Kidney related Anaemia Calcium metabolism Vascular compliance Fluid shifts Homocysteine levels Inflammation (CRP) ?Under treatment LVH

21. Cardiovascular Risk In CKD 1.Is it important? 2.What factors are responsible? 3.What can be done about them?

22. What should go in a cardiovascular polypill for renal patients ?

23. Risk Factors for Cardiac Disease In CKD Conventional Hypertension Dyslipidaemia Smoking Diabetes Kidney related Anaemia Calcium metabolism Vascular compliance Fluid shifts Homocysteine levels Inflammation (CRP) LVH

24. An independent risk factor for CHD in the general population and in renal disease. CONCENTRIC LVH

25. Prevalence of LVH in HD patients Foley et al, KI 1995;47:186-192

26. Echo findings predict survival in HD patients Parfrey P et al. NDT. 1996;11:1277-85 0 6 12 18 24 30 36 42 48 54 60 66 72 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Months Normal Eccentric LVH Concentric LVH Systolic dysfunction Survival

27. LVH Develops Early in Renal Disease LVH on echo found in: 30% with creatinine clearance 50-75ml/min 50% with creatinine clearance <25ml/min Levin A Am J Kidney Disease 1999 34 125-34

28. LVH and Myocardial Dysfunction Risk factors for LVH: Hypertension is treatable Anaemia is preventable and treatable –>95% of patients will respond to Epo

29. Treatment of Hypertension leads to LVH regression in the General Population Regression of LVH in hypertension- meta analysis of 39 trials

30. Treatment of Hypertension leads to regression of LVH in ESRD LVH shown to regress with: –Treatment of hypertension in ESRD –Treatment of hypertension in Chronic renal failure –Treatment of anaemia in ESRD Regression of LVH in one study associated with improved cardiac outcome Foley RN; J Am Soc Nephrol 2000

31. Risk Factors for Cardiac Disease In CKD Conventional Hypertension Dyslipidaemia Smoking Diabetes ?Under treatment Kidney related Anaemia Calcium metabolism Vascular compliance Fluid shifts Homocysteine levels Inflammation (CRP) ?Under treatment LVH

32. Cardiovascular Disease and Hypertension in the general population Cardiovascular risk increases progressively as blood pressure increases ? Threshold: relationship holds for blood pressures above 110/75 Treating blood pressure <140/90 or lower reduces cardiovascular mortality and morbidity.

33. Data from prospective studies collabaration Lancet 2002: 360 CHD Mortality Related to Blood Pressure Early renal failure estimated to increase diastolic blood pressure 10-20mmHg if untreated

34. Cardiovascular Disease and Hypertension in CKD ESRD –BP>140/90 associated with increased cardiovascular risk –Duration of hypertension prior to dialysis correlates with mortality CKD –Subgroup analysis hypertension greater cardiovascular risk factor than general population No major trials looking at reduction cardiovascular risk with BP reduction in renal patients BUT Biggest reduction in general population is evident in subgroups –Other risk factors/Underlying target organ damage

35. HOT Study: 51% RR Reduction of CV Events in Diabetics Hansson L et al. Lancet. 1998;351:1755-1762. 0 5 10 15 20 25  90  85  80 Major cardiovascular events/1,000 patient-years p=0.005 for trend mm Hg Target Diastolic Blood Pressure

36. Hypertension in Renal Disease-The size of the problem CKD –50-90% hypertensive depending on stage /disease –Around 50% not adequately controlled ie >140/90 ESRD –80% of ESRD patients have hypertension –50%-70% DO NOT achieve BP<130/80

37. Treating Hypertension in Renal Disease Has Other Massive Advantages Lowering blood pressure slows progression of renal disease –Bp reduced from 130/80 to 125/75 reduces decline in GFR by 10.2ml/min/yr -6.7ml/min/yr (mdrd trial) In renal disease aim for –<125/75 with proteinuria –<130/80 without proteinuria

38. Which Antihypertensive Is Best For Renal Protection? 1993 Lewis EJ

39. Treatment of Hypertension leads to LVH regression in the General Population Regression of LVH in hypertension- meta analysis of 39 trials

40. Ramipril reduces cardiovascular endpoints in patients with mild renal impairment Mann JF Ann Intern Med 2001 134:629-36

41. Summary: Recommendations for BP Control in Renal disease If target organ damage (Renal+proteinuria) –Aim for BP<125/75 If possible ACE first line On haemodialysis renal association standards –pre-dialysis <140/90 –post-dialysis <130/80

42. Risk Factors for Cardiac Disease In CKD Conventional Hypertension Dyslipidaemia Smoking Diabetes ?Under treatment Kidney related Anaemia Calcium metabolism Vascular compliance Fluid shifts Homocysteine levels Inflammation (CRP) ?Under treatment LVH

43. Degree of Anaemia predicts survival of patients on dialysis Ma JZ; J Am Soc Nephrol 1999 Mar;10(3):610-9. Increased risk of death

44. Treatment of anaemia prior to ESRD Evidence now for correcting anaemia prior to dialysis: –Patients feel better –Reduces LVH –Improves survival after starting dialysis 4800 patients followed prospectively after starting dialysis EPO given prior to starting improved survival afterwards Fink J Am J Kidney Dis 2001 Feb;37(2):348-55

45. Summary: Treatment of Anaemia Treat anaemia with recombinant EPO otherwise Hb stabilises at 7.0g/dl in CRF –£5000 per patient/year Treat early-Anaemia can first develops at a GFR <30ml/min (creatinine of 200umol/l) Target Hb >11g/dl

46. Risk Factors for Cardiac Disease In CKD Conventional Hypertension Dyslipidaemia Smoking Diabetes ?Under treatment Kidney related Anaemia Calcium metabolism Vascular compliance Fluid shifts Homocysteine levels Inflammation (CRP) ?Under treatment LVH

47. Coronary Artery Disease is Atypical in Renal Disease

48. Dialysis patients age 20-30yrs –88% of dialysis patients had some coronary artery calcification –5% of controls Coronary Artery calcification related to: –Length of time on dialysis –Calcium -phosphate product –Daily dose of calcium Goodman WG Engl J Med 2000 May 18;342(20):1478-83.

49. Coronary Calcification In Renal Patients In CKD/ESRD AIM TO: Normalise phosphate Reduce parathyroid hormone levels Avoid hypercalcaemia UNTIL RECENTLY OPTIONS LIMITED: Aluminium binders –long term toxicity Calcium binders-risk of hypercalcaemia /metastatic calcification Vitamin D (alphacalcidol)-risk of hypercalcaemia and hyperphosphataemia

50. Coronary Calcification In Renal Patients New phosphate binder-Sevelamer Not absorbed Lowers lipids May halt progression of coronary calcification Initial trials suggest mortality benefit (DCOR) New Vit D compounds –Paricalcitol Reduce PTH levels Minimal increase in calcium and phosphate Calcimimetics-Cinacalcet Stimulates calcium receptor Lowers PTH without increasing calcium and phosphate

51. Risk Factors for Cardiac Disease In CKD Conventional Hypertension Dyslipidaemia Smoking Diabetes ?Under treatment Kidney related Anaemia Calcium metabolism Vascular compliance Fluid shifts Homocysteine levels Inflammation (CRP) ?Under treatment LVH

52. Graded Correlation Between Plasma Cholesterol and Coronary Risk in the general population Six yr coronary risk in men age 35-37 screened for MRFIT study Stamler J JAMA 1986 256;2823

53. Reduction in Total and LDL cholesterol reduces coronary events  25-35% coronary events shown in all trials Almost all trials used statins Reduction shown in primary and secondary prevention  1-2mmol/l LDL,  risk 25-40%

54. What Happens To Lipids In Renal Disease? Initially: –Rise in LDL cholesterol –Fall in HDL Cholesterol –Rise in triglycerides Endstage: –Total Cholesterol normal/low –LDL /HDL remains abnormal All Changes Begin Early In Renal Disease

55. ? Intersection of the risks of malnutrition/inflammation and the risks of CHD The relationship with cholesterol and CHD is atypical in ESRD

56. There Are No Trials Showing Cholesterol Lowering Works in Renal Disease

57. Treatment of Hyperlipidaemia is Based on an Assessment of Risk Joint British Societies

58. How Should Renal Patients be Assessed? Epidemiologically renal patients at high risk –most ESRD >30% 10yr risk of CHD BUT CHD is atypical in renal failure –Does cholesterol have the same significance?

59. Trials of cholesterol lowering in renal disease now beginning TRIALPATIENT NO PATIENT TYPEDRUGRESULT DUE SHARP9000Esrd and CKDSimvastatin and ezetimide 2009 AURORA2700HDRouvastatin2008 4D1252HD/type II diabetes Atorvastatin2005 ALERT2102TransplantFluvavstatin2003

60. Statins May Also Slow Disease Progression Trials suggest statins may reduce the rate of progression to renal impairment ? Secondary to cholesterol lowering ? Secondary to separate anti-inflammatory effects

61. Summary: Recommendations for Now  40% will be high risk for other reasons UK guidelines for high risk group –LDL < 3.0mmol/l or Total cholesterol < 5.0mmol/l NKF recommends Controlling the epidemic of CV disease in CRD 1998 –Renal dysfunction: highest risk group for coronary events –Aim for LDL<2.5mmol/l using statin No specific recommendation from Renal Association Standards

62. In Conclusion Renal patients die of cardiac disease at a young age Increased risk is present as soon as renal dysfunction is measurable Due to: –Increased incidence of traditional risk factors –Other renal related factors Strategies to decrease excessive cardiac death in renal patients should begin early

63. In a renal cardiac polypill I would put…. ACE/ARB Other antihypertensives to achieve BP lower than 130/80 Epo once Hb below 11.0 Statin if cholesterol >6.0 or if >5.0 and other risk factors ?Aspirin dependent on other risk factors

64. I WOULD BEGIN TREATMENT OR AS SOON AS CKD WAS IDENTIFIED

65. Risk Factors for Cardiac Disease In CKD Conventional Hypertension Dyslipidaemia Smoking Diabetes Kidney related Anaemia Calcium metabolism Vascular compliance Fluid shifts Homocysteine levels Inflammation (CRP) LVH UNDERTREATMENT

67. Meta-analysis of lipid lowering studies in CRF Statins most effective in lowering LDL cholesterol/total cholesterol Increased risk of myopathy Rhabdomyolysis (pain+CK>x10) almost always with drug combinations Massey Kidney Int 1995

68. Homocysteine High homocysteine levels associated with an increased cardiovascular risk in general population Homocysteine levels increased in CRF No evidence that treating homocysteine levels make a difference If treating: folate /B12 /B6 But to have an effect in renal failure may need high doses –eg 15mg folic acid (B6 100mg/day B12 1mg/day) did not normalise levels

69. Homocysteine High homocysteine levels associated with an increased risk of cardiovascular disease Homocysteine not as important as hypercholesterolemia, smoking, diabetes mellitus, and hypertension Homocysteine levels increased in CRF Observational data links homocsyteine to cardiovascular disease in ESRD No evidence that treating makes a difference If treating 5mg /day in CRF or if levels of >30umol/l +B12 and B6 But studies suggest that to have an effect in renal failure may need higher dose eg 15mg folic acid (B6 100mg/day B12 1mg/day) even then did not normalise levels

70. Patients with Renal Disease Die Young UK renal registry 2002