1. Cardiovascular effects of anemia in ckd
Dr Racquel Gordon
Consultant Cardiologist

2. INTRODUCTION
Anemia is common among patients with chronic kidney disease (CKD).
In addition to causing disabling symptoms, severe anemia may affect cardiovascular function in non dialysis CKD and dialysis patients.
Among non dialysis CKD patients, severe anemia may accelerate the progression to end-stage renal disease (ESRD).

3. INTRODUCTION
Cardiovascular disease is a major cause of morbidity and mortality in patients with CKD, including those undergoing maintenance dialysis.
Even patients with mild CKD have a greater burden of prevalent cardiovascular disease compared with similar age controls. 

4. INTRODUCTION
Severe anemia is an important, independent risk factor for
the development and progression of left ventricular hypertrophy (LVH)
heart failure (HF)
adverse cardiovascular outcomes, including mortality.

5. definition WHO Anemia has been defined as a hemoglobin concentration:
<13.0g/dl for adult males and postmenopausal women.
<12.0g/dl for premenopausal women.

6. prevalence
Based upon these criteria, nearly 90% of patients with a glomerular filtration rate(GFR) <25 to 30 ml/min have anemia, many with hemoglobin levels <10g/dl.

7. Factors causing anemia in ckd
Decreased erythropoietin production.
Shorter life span of RBC’s.
Blood loss during dialysis.
Iron deficiency
Anemia of chronic disease.
Renal osteodystrophy

8. LEFT VENTRICULAR HYPERTROPHY
LVH is a major risk factor for cardiovascular morbidity and mortality in ESRD patients.
Among patients with ESRD or near ESRD, the reported prevalence of LVH is nearly 75 to 80 percent, with a higher prevalence among those of greatest dialysis vintage. 

10. ROLE OF ANEMIA
 Anemia has been identified as a risk factor for the development of LVH in dialysis and non dialysis CKD patients.
In an observational study including 432 hemodialysis and peritoneal dialysis patients, anemia was independently associated with an increase in left ventricular mass index.
In an analysis of data from the Atherosclerosis Risk in Communities Study (ARIC), among non dialysis CKD patients, anemia was predictive of left ventricular diameter after adjusting for kidney function and blood pressure.

11. PATHOPHYSIOLOGY
Potential mechanisms that may explain the relationship between anemia and the development of LVH among CKD patients include:
Effects of reduced oxygen delivery to the myocardium, perhaps leading to increased myocyte necrosis and apoptosis
Anemia-related increased cardiac output and reduced systemic vascular resistance
Increased oxidative stress
Activation of the sympathetic nervous system
A decrease in circulating endogenous erythropoietin caused by kidney disease may contribute to LVH among CKD patients. Erythropoietin receptors are present in cardiac tissue, and erythropoietin may have direct effects on myocardial function 

13. EFFECT OF TREATMENT OF ANEMIA
The treatment of severe anemia with erythropoesis stimulating agents (ESAs) is associated with improvement of LVH.
The best data are from a 2009 meta-analysis of 15 studies including 1731 patients. Among patients with baseline severe anemia (defined as hemoglobin [Hb] levels <10 g/dL with mean baseline Hb levels as low as 5.9 g/dL in individual studies), ESA treatment to increase Hb levels to ≤12 g/dL was associated with significant reductions in left ventricular mass index (-32.7 g/m2, 95% CI to -16.1).
The treatment of moderate anemia (ie, Hb ≥10 g/dL) to either Hb levels >12 g/dL or ≤12 g/dL was not associated with significant changes in the left ventricular mass index.

14. EFFECT OF TREATMENT OF ANEMIA
Whether the regression of LVH in CKD patients who are treated for severe anemia is associated with improved cardiac outcomes has not been well studied.
Any such analysis may be confounded by other factors that affect outcomes, such as ESA-induced increases in blood pressure and LVH geometry.

15. EFFECT OF TREATMENT OF ANEMIA
The effects of administered ESAs on myocardial function may be independent of effects on anemia.
Erythropoietin may have direct effects on myocardial function.
ESA administration reduced cellular damage and myocyte apoptosis and lowered infarct size and subsequent left ventricular dilatation and functional decline in some animal and in vitro models of ischemic reperfusion.
In another animal model of acute myocardial infarction, erythropoietin led to a small reduction in infarct size but also led to myocardial dilatation.

16. EFFECT OF TREATMENT OF ANEMIA
Additionally, a systematic review and meta-analysis concluded that short- term administration of ESAs (ie, immediately before or within three days after percutaneous coronary intervention) did not improve cardiac function, infarct size, or mortality in patients with myocardial infarction

17. HEART FAILURE
Severe anemia is an important, independent risk factor for the development of HF.
Prior to the availability of ESAs, one study of 432 dialysis patients (mean baseline Hb level of 8.8 g/dL) found that each 1 g/dL lower Hb was associated with an higher odds of left ventricular dilatation (odds ratio [OR] 1.46), de novo HF (OR 1.28), and recurrent HF (OR 1.20).

18. HEART FAILURE
Uncontrolled studies, none very recent, have described improvement in the clinical manifestations of HF after prolonged treatment of anemia in CKD patients.
As an example, in one study of 126 CKD patients with HF, an increase in the mean Hb level from 10.3 to 13.1 g/dL(with intravenous iron and ESAs) over a mean period of 12 months was associated with a rise in the mean left ventricular ejection fraction (33 to 40 percent), falls in the mean New York Heart Association (NYHA) class (3.8 to 2.7), and number of hospitalizations (3.7/patient to 0.2/patient).
An index of fatigue and shortness of breath also fell significantly. Similar results were noted in another uncontrolled study that included 179 CKD patients with severe HF studied over a mean of nearly 12 months.

19. HEART FAILURE
A systematic review of nine randomized trials of ESAs in HF, not all specifically in patients with CKD, concluded that anemia treatment improved exercise duration and capacity, ejection fraction, NYHA class, quality-of-life indicators, and HF-related hospitalizations.
Another, more recent meta-analysis of randomized, controlled trials found that ESA treatment improved dyspnea and NYHA class; there was no significant improvement in mortality or hospitalization, but there was increased risk of thromboembolic events.
Increased morbidity and/or mortality has been associated with attaining normal or near-normal Hb levels with ESAs

20. Coronary heart disease
Exercise-mediated cardiac ischemia is also ameliorated with partial correction of severe anemia.

21. Mortality
Anemia is an important, independent risk factor for mortality.
In one study of 432 dialysis patients with a mean baseline Hb level of 8.8 g/dL, after adjusting for age, diabetes, ischemic heart disease, blood pressure, and serum albumin, each 1 g/dL lower Hb was associated with increased mortality (OR 1.14) .

22. mortality
The combination of anemia and LVH may be associated with an even higher risk of adverse cardiovascular outcomes.
Among 2423 CKD patients in four population-based studies, the presence of anemia and LVH was correlated with the risk of the primary composite outcome of myocardial infarction, stroke, and death.
LVH was associated with an increased risk for composite and cardiac outcomes (hazard ratio [HR] 1.67, 95% CI and HR 1.62, 95% CI , respectively), while anemia was associated with increased risk for only the composite outcome (HR 1.51, 95% CI ).
The combination was associated with a higher increased risk for both study outcomes compared with individuals with neither risk factor (HR 4.15, 95% CI and HR 3.92, 95% CI ).

23. mortality
In a more recent study of 415 CKD patients, the combination of anemia and LVH also increased the risk of a cardiovascular event (defined as cardiovascular death, hospitalization for unstable angina or HF, nonfatal myocardial infarction, ventricular arrhythmia, or transient ischemic attack/stroke) (HR 4.3, 95% CI 1.4 to 13).
As noted above, however, treatment of anemia to normal or near-normal Hb levels with ESAs does not reduce morbidity or mortality among patients with CKD, including dialysis patients. 

24. PROGRESSION OF RENAL FAILURE
Anemia may be a risk factor for progression of kidney dysfunction to end- stage renal disease (ESRD).
As an example, one four-year study of over 1500 patients with diabetic nephropathy found that, compared with patients with the highest baseline hemoglobin (Hb) levels (>13.8 g/dL), patients with lower Hb levels had a nearly twofold increase in the adjusted risk of developing ESRD.

25. PROGRESSION OF RENAL FAILURE
In a more recent study of 415 CKD patients, the combination of anemia and left ventricular hypertrophy (LVH) was also associated with faster renal decline compared with patients with no anemia and no LVH.
(estimated glomerular filtration rate [eGFR] slope -2.66±0.23 versus ±0.23 mL/min/1.73 m2 per year) and compared with patients with LVH but no anemia (eGFR slope -1.05±0.26 mL/min/1.73 m2 per year).

26. PROGRESSION OF RENAL FAILURE
From animal models of ischemic and nephrotoxic renal injury, various mechanisms by which erythropoietin might have renoprotective effects have been proposed.
These include reduced apoptosis, increased tubular regeneration, decreased caspase activity, and decreased interstitial fibrosis.

27. PROGRESSION OF RENAL FAILURE
There is conflicting evidence concerning the effect of correction of anemia on the rate of progression of renal failure.
The most recent clinical trial data are from the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) trial, in which 4038 patients with type 2 diabetes and CKD (eGFR between 20 to 60 mL/min/1.73 m2) were randomly assigned to receive darbopoetin alfa to achieve a target Hb level of 13 g/dL or to placebo, with darbepoetin administered if the Hb level was <9 g/dL.
The mean achieved Hb level was 12.5 g/dL and 10.6 g/dL in the darbepoetin and placebo groups, respectively. At a median follow-up of 29 months, there was no difference between groups in the risk of ESRD (16.8 versus 16.3 percent in placebo, hazard ratio [HR] 1.02, 95% CI 0.87 to 1.18).

28. PROGRESSION OF RENAL FAILURE
A secondary analysis of the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial, however, found a greater risk of a CKD progression composite endpoint (doubling of the creatinine, initiation of renal replacement therapy [RRT], or death) and a greater rate of RRT initiation in the higher Hb target group

29. PROGRESSION OF RENAL FAILURE
Authors of one meta-analysis noted that larger trials of anemia treatment in patients with CKD suggested a trend for increased risk of CKD progression with a higher Hb targets; in the overall pooled analysis, however, no difference was detected between higher versus lower targets.
A more recent meta-analysis that included 19 studies and 993 participants concluded that, for most measures of CKD progression, erythropoiesis- stimulating agent (ESA) treatment was not different than placebo or no treatment.

30. Cardio-renal-anemia syndrome
Decline in glomerular filtration rate (GFR) is associated with a stepwise increase in all-cause mortality at all levels of kidney function.
The vast majority of individuals with CKD will experience death due to cardiovascular causes rather than progress to end-stage renal disease or dialysis.
The high burden of CVD in CKD cohorts, and vice versa, is a reflection of the fact that both disease processes share similar risk factors.

31. Cardio-renal-anemia syndrome
Having one disease increases an individual’s risk of having the other; the combination of both is associated with a higher mortality than either disease alone.
This observation is consistent across a number of studies including subgroup analyses from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
CV end points, including myocardial infarction, stroke, need for revascularization, the presence of coronary artery disease and all forms of atherosclerotic vascular disease, were increased in study participants as GFR decreased.

32. Cardio-renal-anemia syndrome
The presence or absence of anemia appears to add another layer of complexity to the relationship between CKD and CVD.
Among individuals with CKD, at all levels of GFR, anemia portends a poor prognosis and is associated with increased mortality compared with those individuals with preserved hemoglobin (Hgb).

33. Cardio-renal-anemia syndrome
Cardiovascular outcomes across a variety of cardiac disease states are similarly worse in the presence of anemia.
Potential hypotheses for this association suggest that: anemia is a marker of cardiac function/dysfunction due to the presence of inflammatory cytokines; anemia is a reflection of the metabolic milieu and occurs in the presence of other traditional and nontraditional risk factors for cardiac disease; anemia reduces oxygen carrying capacity and results in myocardial ischemia; and anemia contributes to maladaptive cardiac remodelling.

34. Cardio-renal-anemia syndrome
Anemia is common in HF patients; the prevalence of anemia increases with severity of New York Heart Association functional classification.
In reviewing a series of recently published major HF trials, anemia occurred in 9% to 25% of patients.
The presence of anemia in this patient population is associated with recurrent hospitalization and reduced survival.
Absolute Hgb levels correlate with one-year survival and an increase in mortality is observed when Hgb levels fall below 120 g/L; this relationship of poor outcomes and Hgb values less than 120 g/L is consistent across a variety of observational studies.

36. Effects of anemia on cv health
CV disease related mortality is 15 times more in patients with CKD.
50% of deaths in patients with CKD are due to CV disease.
LVH is the most common abnormality seen in patients with CKD and there is a strong correlation between anemia and LVH.
Tissue hypoxia due to anemia is principal stimuli triggering the compensatory changes that stresses the CV system.

37. Benefits of treating anemia
Decrease morbidity/mortality.
Reduce left ventricular hypertrophy.
Increase exercise tolerance.
Increase quality of life.

38. Treatment options Iron Erythropoietin stimulating agent
blood transfusion
Folic acid and vitamin B12

39. REFERENCES
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296–305. 
Canadian Organ Replacement Register Annual Data Report (Version current at May 22, 2008).
Go AS, Yang J, Ackerson LM, et al. Hemoglobin level, chronic kidney disease, and the risks of death and hospitalization in adults with chronic heart failure: the Anemia in Chronic Heart Failure: Outcomes and Resource Utilization (ANCHOR) Study. Circulation. 2006;113:2713–23. 
Wali RK, Henrich WL. Chronic kidney disease: a risk factor for cardiovascular disease. Cardiol Clin. 2005;23:343– 62. 
Al-Ahmad A, Rand WM, Manjunath G, et al. Reduced kidney function and anemia as risk factors for mortality in patients with left ventricular dysfunction. J Am Coll Cardiol. 2001;39:955–62. 
Rahman M, Brown CD, Coresh J, et al. The prevalence of reduced glomerular filtration rate in older hypertensive patients and its association with cardiovascular disease: A report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Arch Intern Med. 2004;164:969–76.
Astor BC, Coresh J, Heiss G, Pettitt D, Sarnak MJ. Kidney function and anemia as risk factors for coronary heart disease and mortality: The Atherosclerosis Risk in Communities (ARIC) Study. Am Heart J. 2006;151:492–500. 

40. THANK YOU