Non Conventional cardiovascular risk factors in CKD

Transcription

1 Non Conventional cardiovascular risk factors in CKD

2 Death rates for major cardiovascular diseases have decreased in the United States Cooper, R, Cutler, J, Desvigne-Nickens, P, et al. Circulation 2000; 102:3137

3 Traditional Risk Factors for CVD

4 Influence of GFR on cardiovascular outcomes A lower estimated glomerular filtration rate (GFR) was associated with a higher incidence of various cardiovascular outcomes Go, AS, Chertow, GM, Fan, D, et al. N Engl J Med 2004

5 Lipids CKD - CVD Risk Factors

6 Trials of statin therapy: NEGATIVE! 4-D hemodialysis patients with type 2 diabetes and elevated serum LDL chol were randomly assigned to placebo or atorvastatin (20 mg/day) Wanner C N Engl J Med Aurora hemodialysis patients who were not being treated with a statin were randomly assigned to rosuvastatin (10 mg/day) or placebo Fellström BC et al. N Engl J Med SHARP - simvastatin plus ezetimibe compared with placebo in lowering cardiovascular morbidity in patients with CKD, approximately one-third of whom required maintenance dialysis 2010 American Society of Nephrology Annual Meeting

7 4-D Die Deutsche Diabetes Dialyse Estimated Cumulative Incidence of the Composite Primary End Point Median Level of Low-Density Lipoprotein (LDL) Cholesterol from Baseline to the End of the Study Wanner C N Engl J Med. 2005

8 4-D Die Deutsche Diabetes Dialyse Median Level of Low-Density Lipoprotein (LDL) Cholesterol from Baseline to the End of the Study Estimated Cumulative Incidence of the Composite Primary End Point CONCLUSIONS: Atorvastatin had no statistically significant effect on the composite primary end point of cardiovascular death, nonfatal myocardial infarction, and stroke in patients with diabetes receiving HD Wanner C N Engl J Med. 2005

9 Rosuvastatin and Cardiovascular Events in Patients Undergoing Hemodialysis AURORA study Changes in Levels of Lipids and C-Reactive Protein Kaplan Meier Curves for the Primary End Point in the Two Study Groups. Fellström BC et al. N Engl J Med * The primary end point was the first major cardiovascular event.

10 Rosuvastatin and Cardiovascular Events in Patients Undergoing Hemodialysis AURORA study Changes in Levels of Lipids and C-Reactive Protein Kaplan Meier Curves for the Primary End Point in the Two Study Groups. CONCLUSIONS: In HD patients the initiation of treatment with rosuvastatin lowered the LDL cholesterol level but had no significant effect on the composite primary end point of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke Fellström BC et al. N Engl J Med * The primary end point was the first major cardiovascular event.

11 Study of Heart and Renal Protection (SHARP) The largest-ever statin trial in renal patients 9438 CKD patients were randomized predialysis patients and 3056 dialysis patients, of whom 2540 were on hemodialysis and 496 on peritoneal dialysis 20 mg simvastatin plus 10 mg ezetimibe or placebo over 4.9 years of follow-up

12 Major atherosclerotic events 25 Proportion suffering event (%) Risk ratio 0.83 ( ) Logrank 2P= Placebo Eze/simva Years of follow-up Presented at the Am. Soc. Nephrology, Denver, Nov 20 th th 2010

13 Major atherosclerotic events Proportion suffering event (%) in dialysis 10 patients with CKD, about 20% versus Eze/simva about 10% 5 Risk ratio 0.83 ( ) Logrank 2P= Placebo It seems as if there may be a higher effect size in predialysis than Years of follow-up Presented at the Am. Soc. Nephrology, Denver, Nov 20 th th 2010

14 SHARP: Renal outcomes Main renal outcome End-stage renal disease (ESRD) Eze/simva (n=3117) 1057 (33.9%) Placebo (n=3130) 1084 (34.6%) Risk ratio (95% CI) 0.97 ( ) Tertiary renal outcomes ESRD or death 1477 (47.4%) 1513 (48.3%) 0.97 ( ) ESRD or 2 x creatinine 1190 (38.2%) 1257 (40.2%) 0.94 ( ) Eze/simva better Placebo better Presented at the Am. Soc. Nephrology, Denver, Nov 20 th th 2010

15 SHARP: Renal outcomes Main renal outcome End-stage renal disease (ESRD) Eze/simva (n=3117) 1057 (33.9%) Placebo (n=3130) 1084 (34.6%) Risk ratio (95% CI) 0.97 ( ) Tertiary renal outcomes ESRD or death 1477 No substantial effect on kidney disease progression (47.4%) 1513 (48.3%) 0.97 ( ) ESRD or 2 x creatinine 1190 (38.2%) 1257 (40.2%) 0.94 ( ) Eze/simva better Placebo better Presented at the Am. Soc. Nephrology, Denver, Nov 20 th th 2010

16 Non-Conventional CVD Risk Factors Lipids Adipokines CRP MIA-Malnutrition-Inflammation-Atherosclerosis Stiffness, PWV, VC Bone-ALP FGF-23 NT-proBNP, ctnt Volume status ft3, ft4, TSH Uric acid

17 Balagopal et al. Circulation 2011

18 Adiponectin Adipose-specific hormone that has antiinflammatory and insulin-sensitizing properties Protective against obesity and obesity-related disorders Secretion from adipocytes is regulated by PPARγ Abbasi F, et al. Diabetes Fernandez-Real JM, et al. J Clin Endocrinol Metab Pischon T et al. Clin Chem. 2006

19 . Adiponectin and survival in CKD: negative correlation Zoccali C et al. JASN 2002;13: by American Society of Nephrology

20 Adiponectin and survival in CKD: negative correlation (A) CVD events in all subjects and (B) IHD events in the subgroup with previous Subjects were stratified into 2 groups according to median adiponectin concentration by each gender. Hypoadiponectinemia is a predictor of CVD in CKD patients Iwashima Y et al. The American Journal of Cardiology 2006

21 CRP and adiponectin 101 consecutive male patients who underwent coronary angiogram. A. Relationship between the plasma CRP and adiponectin levels P<0.01 B. The plasma CRP and adiponectin levels in the CAD patients and control subjects. Columns and vertical bars denote mean and SEM. * P<0.05 versus control subjects. Ouchi N, et al. Circulation. 2003

22 High levels of leptin and CVD risk in general population Myocardial infarction - P. C. Schulze et al. European Journal of Heart Failure 2003 Coronary heart disease - S. Soderberg et al. Journal of Internal Medicine 1999 Stroke - J. Ren et al. - Journal of Endocrinology 2004 Chronic heart failure - Soderberg et al. Journal of Internal Medicine 1999 Left cardiac hypertrophy - A. M. Wallace et al. Circulation 2001

23 Leptin in CKD leptin levels are significantly higher in patients on dialysis conflicting data on leptin in CKD, particularly its association with CVD and mortality adverse cardiovascular profile in CKD patients in the clinical setting has been attributed to lower levels of leptin leptin may reflect a state of malnutrition, and hence contribute towards uremic cachexia Leptin levels are higher in healthier dialysis subjects, and are directly correlated with improved markers of nutrition

24 Low Serum Leptin Predicts Mortality in Patients with Chronic Kidney Disease Stage 5 Kaplan-Meier survival curves for death in 71 patients with CKD stage 5 Scholze et al. OBESITY 2007

25 Resistin Is an adipokine that belongs to a unique family of cysteine-rich C-terminal domain proteins In mice, resistin antagonizes insulin action, causing glucose intolerance There are various cross-sectional studies, both for and against a role for resistin in insulin resistance

26 Resistin Is an Inflammatory Marker of Atherosclerosis in Humans Conclusions: Plasma resistin levels are predictive of coronary atherosclerosis in humans, independent of CRP. Resistin may represent a novel link between metabolic signals, inflammation, and atherosclerosis Reilly MP et al. Circulation 2005

27 Elevated resistin level is significantly associated with the likelihood of CKD! The age- and sex-adjusted mean values of estimated glomerular filtration rate (egfr) according to quartiles of serum resistin concentrations (left panel), and the age- and sexadjusted mean values of serum resistin levels according to egfr (right panel). Kawamura R et al. Nephrol. Dial. Transplant. 2010;25: The Author Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

28 The positive relationship between plasma levels of resistin and TNF α in subjects with CKD resistin may play a role in the sub-clinical inflammation associated with CKD Brooks O et al. Cytokine 2007

29 Non-Conventional CVD Risk Factors Adipokines Lipids CRP MIA Stiffness, PWV, VC Bone-ALP FGF-23 NT-proBNP ctnt Volume status ft3, ft4, TSH Uric acid

30 Inflammation Plays a central role in developing atherosclerosis CRP is a downstream marker of inflammation that has multiple effects including: complement binding, augmentation of expression of adhesions molecules, decreased expression of the vasodilator enos. CRP may stimulate the expression of PAI 1 and may induce oxidative stress and the secretion of other cytokines. Adipocytes and macrophages release IL 6 and TNF, which stimulate the liver to produce CRP

31 CRP independent predictor of CV events CRP concentration has continuous associations with the risk of coronary heart disease, ischaemic stroke, vascular mortality, and non vascular mortality The Emerging Risk Factors Collaboration, Lancet 2010

32 CRP is predictors of all-cause and cardiovascular mortality in CKD stage 3 and 4 Menon, Kidney Int 2005

33 and also in hemodialysis patients Patients in the highest quartile had a 4.6-fold higher risk for all-cause and a 5.5-fold higher risk for cardiovascular mortality during follow-up than those in the lowest quartile Zimmermann, Kidney Int 1999

34 Rosuvastatin decreased CRP by 37% and lowered CVD event rates by 50%, independently of a reduction in low-density lipoprotein levels the presence of elevated CRP is able to identify a high-risk population that would benefit from statin treatment JUPITER convincingly demonstrated that elevated CRP is able to identify a high-risk population that would benefit from statin treatment Ridker PM et al. N Engl J Med. 2008

35 Non-Convention Risk Factors Adipokines Lpids CRP MIA-Malnutrition-Inflammation-Atherosclerosis Stiffnes, PWV, VC Bone-ALP FGF-23 NT-proBNP, ctnt Volume status ft3, ft4, TSH Uric acid

36 Schematic representation of the causes and manifestations of the protein energy wasting syndrome in kidney disease D Fouque, K Kalantar-Zadeh et al. Kidney Int. 2008

37 The phosphate and protein intake paradigm Mortality decreases when protein intake increases up to1.4 g/kg/day despite a slight increase in serum phosphate Shinaberger et al Am J Clin Nutr 2008

38 The phosphate and protein intake paradigm Mortality decreases when protein intake increases up to1.4 g/kg/day despite a slight increase in serum phosphate Conclusions: The risk of controlling serum phosphorus by restricting dietary protein intake may outweigh the benefit of controlled phosphorus and may lead to greater mortality. Shinaberger et al Am J Clin Nutr 2008

39 Survival, represented by Kaplan Meier survival curves in 204 ESRD patients with none, one, two, or all three of the complications malnutrition, inflammation and atherosclerosis. P< Pecoits-Filho R, Lindholm B, Stenvinkel P Nephrol Dial Transplant 2002

40 Association of Malnutrition-Inflammation Score With Mortality in 809 HD Patients: A 5-Year Prospective Cohort Study Kamyar Kalantar-Zadeh, AJKD 2009

41 The MIS could predict death similar to IL 6, slightly better than CRP, and significantly better than each of its 10 components (SGA, and serum prealbumin level Kamyar Kalantar-Zadeh, AJKD 2009

42 Non-Conventional CVD Risk Factors Adipokines Lipids CRP MIA-Malnutrition-Inflammation-Atherosclerosis Stiffness, PWV, VC Bone-ALP FGF-23 NT-proBNP, ctnt Volume status ft3, ft4, TSH Uric acid

43 Aortic Stiffness and Mortality in ESRD: PWV and AIx A) Probability of Overall Survival PWV < 9.4 m/s 9.4 PWV 12.0 m/s PWV > 12.0 m/s Duration of Follow-Up (Months) N = 241, F/U = 72+/-41 months N = 189, F/U = 52+/-36 months BlacherCirculation, 1999 (99): London et al, Hypertension, 2001, 38:

44 In younger dialysis pts. impact might be different

45 Presence and progression of aortic calcification is associated with mortality in chronic dialysis patients Noordzij M, Ketteler. NDT 2011

46 Non-Conventional CVD Risk Factors Adipokines Lipids CRP MIA-Malnutrition-Inflammation-Atherosclerosis Stiffness, PWV, VC Bone-ALP, FGF-23 NT-proBNP, ctnt Volume status ft3, ft4, TSH Uric acid

47

48 Bone Alkaline Phosphatase and Mortality in Dialysis Patients High levels of BAP were strongly associated with short-term mortality in dialysis patients Drechsler C et al. CJASN 2011

49 FGF-23 - Physiopathology

50 The ArMORR study in a multivariable adjusted model, subjects in the highest quartile of FGF- 23 levels had nearly a sixfold increase in risk as compared with subjects in the lowest quartile FGF-23 was a much stronger predictor of mortality than serum phosphate Gutierrez et al. N Engl J Med 2008

51 Impact of fibroblast growth factor (FGF)-23 on renal survival- MMKD trial Fliser et al J Am Soc Nephrol 2007

52 Non-Conventional CVD Risk Factors Adipokines Lipids CRP MIA-Malnutrition-Inflammation-Atherosclerosis Stiffness, PWV, VC Bone-ALP FGF-23 NT-proBNP, ctnt Volume status ft3, ft4, TSH Uric acid

53 Studies that evaluated the prognostic value of BNP and NT pro BNP in ESRD Angela Yee-Moon Wang, J Am Soc Nephrol. 2008

54 In reality, NT probnp, what for? Increase in structural heart abnormalities as well as in overhydration! AUTHOR PATIENTS END POINT AUC BEST CUT OFF Khan 2006 De Filippi 2005 Khan 2006 Sommerer 2007 Madsen 2007 Kharma 2007 SENSITIVITY SPECIFICITY 54, CKD CAD pg/ml 79% / 70% 207, CKD LVSD pg/ml 98% / 79% 54, CKD LVH pg/ml 63% / 67% 134, HD Hypervolemia pg/ml 77% / 77% 109, HD DEATH pg/ml 82% / 61% 50, HD 29, PD DEATH pg/ml 72% / 76%

55 Of course HUGE cut off values are highly discriminative. Sascha David, Nephrol Dial Transplant 2008 Inverse correlation between left ventricular ejection fraction (EF) and NTproBNP serum concentration (log-transformed data). The correlation was highly significant (Spearman s correlation: r= 0.77, P < ).

56 ctnt vs NT-proBNP C. Sommerer, European Journal of Clinical Investigation 2007 Sensitivity and specificity of receiver operator characteristic (ROC) curve of cardiac troponin T (ctnt) and N-terminal pro-natriuretic peptide (NT-proBNP) as predictor of hypervolaemia, n = 134 haemodialysis patients.

57 Cardiac biomarkers correlation with hydration status C. Sommerer, European Journal of Clinical Investigation 2007 ctnt < NT-proBNP for overhydration

58 Cardiac biomarkers and survival in hemodialysis patients C. Sommerer, European Journal of Clinical Investigation 2007 Patient survival according to cardiac troponin T (ctnt)and N-terminal pro-natriuretic peptide (NT-proBNP) levels. In 34 patients ctnt and NT-proBNP were above the threshold, in100 patients both parameters or at least one parameter was below the threshold (threshold: ctnt > ng ml 1, NT-proBNP > 5300 pg ml 1)

59 Non-Conventional CVD Risk Factors Adipokines Lipids CRP MIA-Malnutrition-Inflammation-Atherosclerosis Stiffness, PWV, VC Bone-ALP FGF-23 NT-proBNP, ctnt Volume status ft3, ft4, TSH Uric acid

60 The Game and the Holly Quest Obtain cross-sectional body composition

61 Euvolemia is a predictor of outcome in dialysis The European APD Outcome Study UF >750 ml/d UF<750 ml/d UF < 750 ml/d at baseline was associated with significantly worse patient survival on univariate analysis J Am Soc Nephrol 14: , 2003 Kaplan Meier patient survival according to baseline P

62 Bioimpedance Fluid Overload Mortality The Mortality Risk of Overhydration in HD Patients V. Wizemann, W. Zaluska, P. Wabel, D. Marcelli, NDT prevalent HD pts. 3,5 year follow up 1 OH<2.5 L Survival OH>2.5 L Months Is overhydration >2,5 L (>15%) associated with a higher 63

63 ULCs by chest sonography

64 a significantly better outcome for those patients without ULCs Frassi F. et al. J Card Fail. 2007

65 Non-Conventional CVD Risk Factors Adipokines Lipids CRP MIA-Malnutrition-Inflammation-Atherosclerosis Stiffness, PWV, VC Bone-ALP FGF-23 NT-proBNP, ctnt Volume status ft3, ft4, TSH Uric acid

66 Cappola A et al. JAMA 2006 Thyroid Status, Cardiovascular Risk, and Mortality in Older Adults

67 Subclinical hypothyroidism is frequent in CKD Chonchol M et al. CJASN 2008;3:

68 Only T3 was a significant predictor of all cause mortality, whilst ft3, T4, ft4 and TSH were not significantly associated with death Carrero, J Intern Med. 2007

69 perhaps due to an intimate association with inflammation perhaps due to an intimate association with inflammation Carrero, J Intern Med. 2007

70 Non-Conventional CVD Risk Factors Adipokines Lipids CRP MIA-Malnutrition-Inflammation-Atherosclerosis Stiffness, PWV, VC Bone-ALP FGF-23 NT-proBNP, ctnt Volume status ft3, ft4, TSH Uric acid

71 Is Hyperuricemia an Independent Risk Factor? Independent Atherogene CASTEL Chicago Heart Association Detection Framingham 1988 Study Gothenburg Heart Institute of Spokane Hypertension Detection Followup Program Honolulu Heart MONICA NHANES I PIUMA Rotterdam SHEP Syst-China Worksite Report Group Not Independent ARIC British Regional Heart Coronary Drug Project European Working Party Framingham 1999 Iceland Social Institute of Finland Syst Eur

72

73 Uric Acid and Mortality Basar, Kanbay, Covic. J ınvest Med, 2011

74 Uric Acid and Mortality Basar, Kanbay, Covic. J ınvest Med, 2011

75 CONCLUSIONS Despite the advances in our understanding of nontraditional risk factors/biomarkers for CVD, the clinical utility of many nontraditional risk factors/biomarkers for CVD is promissing but remains uncertain With the increasing connection between obesity and CVD, biomarkers produced from adipose tissue and those with roles in inflammation and oxidative stress are increasingly centerstage Nontraditional risk factors/biomarkers could be used to the development of more directed therapeutic strategies to prevent CVD (volume management, inflammation, CKD-MBD.)