KARDIYORENAL HASTALIKTA ANEMININ ROL Cardiorenal disease: The pivotal role of anemia

1
KARDIYORENAL HASTALIKTA ANEMININ
ROLÜCardiorenal disease The pivotal role of
anemia

• Dr. Sehsuvar Ertürk
• Ankara Üniversitesi Tip Fakültesi
• Nefroloji Bilim Dali
• Ankara University School of Medicine
• Department of Nephrology

2
Goals of the lecture

• To consider anemia as a major component
  not an innocent bystander- of cardiorenal
  disease.
• To know impact of anemia on clinical outcomes in
  patients with cardiorenal disease.
• To approach management of anemia of cardiorenal
  disease in terms of evidence-based
  medicine.

3
Plan

• Cardio-renal interactions
• Anemia as an emerging risk factor
• Epidemiological aspects
• Pathophysiology
• Observational and interventional studies

4
Richard Bright-1836
Kidney disease
Cardiac hypertrophy
Constitutional abnormalities in blood
Increased resistance in microcirculation
5
Traube-1856
RENAL FAILURE
HYPERTENSION
Oliguria
Hypervolemia
6
Guyton-1985 Basic factors in overall circulatory
function
Renal output of water and electrolytes
Arterial pressure
ECC fluid volume
Total peripheral resistance
Net intake of water and electrolytes
Local vascular regulation
Mean circulatory filling pressure
Venous return and cardiac output
Blood volume
Guyton AC. (In Sodemans Pathologic Physiology
Mechanisms of Disease, W.B.Saunders, 1985, p 202)
7
Evolution of CKD and CVD
ESRD
CHF CRF (GFR )

CAD compl. Proteinuria

CAD, LVH HT, DM, Age
HT,
DM, Age Chronic kidney disease
Cardiovascular disease


End stage
Progression
Initial
Increased risk
8
The true risk of CKD is cardiovascular rather
renal
Zoccali
C. Kidney Int 7026-33, 2006
Patients with mild and moderate renal
insufficiency
1 19 24
Developed ESRD
Died because of atherosclerotic complications in
5 years
Go AS, et al. N Engl J Med 231296-1305, 2004
9
Emerging cardiovascular and renal risk factors

• Anemia
• Hyperphosphatemia and SHPT
• Hyperhomocysteinemia
• C-reactive protein
• Proinflammatory cytokines
• Symphatetic overreactivity
• Endothelial dysfunction (NO/ADMA)
• Zoccali C. Kidney Int 7026-33, 2006

10
Anemia (WHO criteria)

• Male
• Postmenopausal
• female
• lt13 g/dL

• Female
• lt12 g/dL

11
Bright-1830s

• Anemia is a characteristic manifestation
• of chronic kidney disease

12
High prevalence of anemiaCKD

• 1.058 patient
• Age 66 y
• CKD Stage 3,4,5 (predialysis)
• Anemia 16, 32, 51, respectively.
• De Nicola L, et al (TABLE in CKD Study Group).
  Kidney Int 69538-545, 2006

13
High prevalence of anemiaMedicare population

• 1.136.201 patient
• Age gt67 y
• 14.8 Anemia
• 13.2 CHF
• 3.2 CKD
• Herzog CA, et al. J Card Fail 10467-472, 2004

14
High prevalence of anemiaAcute MI

• 559 patient
• Age 74 (range, 32-97) y
• Anemia 27.7
• Langston RD, et al. Kidney Int 641398-1405, 2003

15
High prevalence of anemiaCAD (ARIC Study)

• 14.971 patient
• Age 45-64 y
• GFRgt29 mL/min
• Follow-up 12 y
• Anemia 9.6(male), 12.8(female)
• Astor BC, et al. Am Heart J 151492-500, 2006

16
High prevalence of anemiaCHF (ANCHOR Study)

• 59.772 patient
• Age 72 y
• Anemia 42.6
• Go AS, et al. Circulation 1132713-2723, 2006

17
High prevalence of anemiaDM Type 2

• 503 patients
• Age 65 y
• GFRgt30 mL/min
• Follow-up 5 y
• Anemia 12.7 (baseline)
• 12.5 (during follow-up)
• Thomas MC, et al. Am J Kidney Dis 48537-545, 2006

18
Predictors of anemia in cardiorenal disease

• Age
• Gender (female)
• Diabetes mellitus
• Severity of CHF (NHYA Class)
• Low GFR
• Proteinuria

19
Levin A. Kidney Int 61 (Suppl 80)S35-S38, 2002
20
Mean change in Hb levels during the 5-year
follow-up stratified according to (A) AER and
(B) baseline GFR.
Thomas MC, et al. Am J Kidney Dis 48537-545, 2006
21
Etiology of anemia in cardiorenal disease

• Bone marrow depression
• CKD, Inflammatory cytokines
• Apopitosis, decreased eryhtroid progenitors
• Relative EPO deficiency/resistance to EPO
• ACE inhibitor/ARA
• Reduced availability of iron
• Malnutrition
• Decreased absorption
• GIS losses (ASA, NSAID)
• Iatrogenic (repeated blood testing)
• Hemodilution (water and sodium retention)

Rao M and Pereira BJG. Kidney Int 681432-38,
2005 Lewis BS, et al. Nephrol Dial Transplant
20(Suppl 7)vii3-6, 2005
22
Adaptive mechanisms in response to hypoxemia
secondary to chronic anemia

• Non-hemodynamic
• (Increased O2 extraction)
• Increased EPO production (?)
• Increased 2,3-DPG

• Hemodynamic
• (Increased Cardiac Output)
• Systemic arterial dilatation
• Decreased TPR
• Reduced afterload
• Increased stroke volume
• Decreased blood viscosity
• Increased venous return
• Increased preload
• Symphatetic activation
• Increased heart rate

Pereira AA and Sarnak MJ. Kidney Int 64(Suppl
87)S32-S39, 2003 Silverberg D. Nephrol Dial
Transplant 18(Suppl 2)ii7-12, 2003 Levin A.
Kidney Int 61(Suppl 80)S35-S38, 2002
23
Pathophysiological interactions between anemia
and cardiorenal disease
Felker GM, et al. J Am Coll Cardiol 44959-66,
2004
24
Cardio-renal anemia syndrome
CHF
CKD
Anemia
Silverberg D. Nephrol Dial Transplant 18(Suppl
2)ii7-12, 2003
25
Possible consequences of anemia in cardiorenal
disease

• Decreased
• Exercise capacity
• Coagulation
• Immune response
• Cognitive funtion
• Sexuel function
• Appetite/Nutrition
• Quality of life
• Growth (in children)

• Increased
• Depression
• Angina
• LVH
• Cardiac failure
• Myopathy
• Renal disease progression
• Morbidity
• Mortality

Adapted from Gomez JML and Carrera F. Kidney
Int 61 (Suppl 80)S39-S43, 2002
26
Impact of anemia on clinical outcomes in
cardiorenal disease

• gt1 Million Medicare subjects, agegt67y
• 1-y mortality
• Anemia 8
• CKD 8
• CHF 13
• None 4
• All 23

Herzog CA, et al. J Card Fail 10467-72, 2004
27
59.792 patients with CHF, age 72y

• Baseline 42.6 anemia
• Hazard Ratio (HR) for mortality
• Hblt13 1.16
• Hblt9 g/dL 3.48
• Hbgt17 1.42

Go AS, et al. Circulation 1132713-23, 2006
28
1.061 patients with CHF
Hb 1g/dL Mortality
13
Horwich TB, et al. J Am Coll Cardiol 391780-86,
2002
29
5.549 patients post-AMI
Hblt9g/dl Mortality
38
Keough-Ryan TM, et al. Am J Kidney Dis 46845-55,
2005
30
Economic issues

• Administrative claims data from a US population
• Prevalence of anemia 6.9-26.1
• Cost difference between anemic and nonanemic
  patients
• CHF 29.511 USD/patient/year
• CKD 20.529
• Cancer 18.418

Ershler WB, et al. Value Health 8629-38, 2005
31
Anemia is not an independent predictor of
mortality or CVD events

• Patients of 4 studies (ARIC, Framingham,
  Framingham offspring, CV Health study) 3.015
  patients with DM, age 62.5y
• Vlagapoulos PT, et al. J Am Soc Nephrol
  163403-10, 2005
• ARIC Study 14.971 patients, 45-64y
• Astor BC, et al. Am Hearth J 151492-500, 2006
• 552 patients with CHF
• Kalra PR, et al. Lancet 362211-2, 2003
• Blue Mountains Eye Study 3.654 patients, age
  45-97y
• Leeder SR, et al. J Am Soc Nephrol 17279-84,
  2006

32
Impact of anemia on clinical outcomes in CKD
(pre-dialysis)

• Increased risk for
• Mortality
• CVD (LVH, LVD, CHF)
• Progression

33
Anemia and Clinical Outcomes CKD (pre-dialysis)

• 246 patients, 12 months follow-up,
• Pr. Outcome gt20 increase in LVMI Hb
  0.5 g/dL OR 1.32
• 853 male patients,
• Composite outcome (Mortality and ESRD)
• Hblt12 g/dL 1.97
• Hblt11 g/dL 2.57

Levin A, et al. Am J Kidney Dis 27347-54, 1996
Kovesdy CP, et al. Kidney Int 69560-64, 2006
34
Post-hoc analysis of RENAAL Study
Risk of ESRD associated with baseline hemoglobin.
Patients DM, Type 2 with overt nephropathy.
Shahinfar S, et al. Kidney Int 67(Suppl
93)S48-S51, 2005
35
Anemia and Clinical Outcomes ESRD

• 93.087 patients (mortality)
• Hblt10 g/dL HR 1.64
• Hb 12-13 g/dL HR 0.79
• Roberts TL, et al. Nephrol Dial Transplant
  211652-62, 2006.
• 432 patients
• Hb 1 g/dL Mortality 14
• Foley RN, et al. Am J Kidney Dis 2853-61, 1996.

36
Potential benefits/risks of anemia treatment in
cardiorenal disease

• Potential Benefits
• Improved oxygen delivery
• Improved exercise tolerance
• Improved quality of life (QOL)
• ?Decrease in LVMI
• ?Slowing the progression of renal disease
• ?Decrease in hospitalizations
• ?Improved survival

• Potential Risks
• Hypertension
• Thrombosis
• ?Increase in mortality

37
Effect of treatmentExperimental

• Doxorubicin induced cardiorenal insufficiency in
  rats
• Darbepoetin
• Creatinine
• Progression
• Interstitial fibrosis
• LV weight

Decreased
38
Effect of treatmentCHF (EPO and/or IV Iron)

• 32 patients
• Decreased hospitalization
• Decreased NHYA Class
  
• Silverberg DS, et al. J Am Coll Cardiol
  371775-80, 2001.
• 26 patients
• Increased exercise capacity
• Increased peak O2 consumption
• Mancini DM, et al. Circulation 107294-99, 2003.

39
Effect of treatmentCKD-predialysis (RCTs)

• Increased exercise capacity, QOL
• Revicki DA, et al. Am J Kidney Dis 25548-54,
  1995
• Teehan BP, et al. Am J Kidney Dis 1850-9, 1991
• No effect on LVMI (155 patients, Hb 12.1 vs 10.8)
• Roger SD, et al. J Am Soc Nephrol 15148-56,
  2004
• Decrease in LVMI (101 patients, Hb 11.3 vs 9.1)
• Ayus JC, et al. Kidney Int 68788-95, 2005

40
Median change in left ventricular mass index over
a 6-month follow-up period comparing anemic
patients who received recombinant human
erythropoietin (r-HuEPO) with nonanemic control
subjects.
Ayus JC, et al. Kidney Int 68788-95, 2005
41
Effect of treatmentESRD-dialysis (RCTs)

• Increase in mortality (1236 pts., Hb 14 vs 10)
• Besarab A, et al. N Engl J Med 339, 584-90,
  1998.
• No effect on LVMI Prevention of
  new LVD (146 pts., Hb 13 vs 10)
• Foley RN, et al. Kidney Int 581325-35, 2000.
• No effect on LVMI Improvement in QOL
  (596 pts., Hb 13.3 vs 10.9)
• Parfrey PS, et al. J Am Soc Nephrol 162180-89,
  2005.

42
Potential effect of EPO on progression

Rossert J, et al. Kidney Int 68(Suppl
99)S76-S81, 2005
43
Ongoing studies

• CHF
• STAMINA-HFP (Study of Anemia in Heart failure)
• CKD
• CREATE (Cardiovascular Risk Reduction by Early
  Anemia Treatment with Epo beta)
• CHOIR (Correction of Hemoglobin and Outcomes in
  Renal Insufficiency)
• TREAT (Trial to Reduce Cardiovascular Events
  with Aranesp Therapy)
• ACORD (Anemia Correction in Diabetes)

44
Current practice DOPPS
Time trend in rHuEpo use and mean hemoglobin
concentration by time since starting hemodialysis
(Locatelli F, et al. Am J Kidney Dis 44(Suppl
2)S27-S33, 2004)
45
Current practice

• 1.353 patients, CKD Stage 3-5
• EPO was omitted in 78 of anemics.
• De Nicola L, et al (TABLE Study Group). Kidney
  Int 69538-45, 2006.
• 24.778 patients, agegt67
• Claims for anemia testing lt50
  during 2 years prior to dialysis
  Kausz AT, et al. J Am Soc Nephrol
  163092-101, 2005.

Anemia is insufficiently treated
46
Conclusion

• Anemia is a common component of cardiorenal
  disease, and is associated with higher
  morbidity and mortality rates.
• Individualized treatment with ESA and iron to
  keep hemoglobin between target levels of the
  currently available guidelines (Hb, 11-12
  g/dL) (until RCTs are completed)
  may improve the clinical outcomes in
  these patients.