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Cardiovascular Disease in Dialysis and Renal Transplantation

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Title: Cardiovascular Disease in Dialysis and Renal Transplantation


1
Cardiovascular Disease in Dialysis and Renal
Transplantation
  • Jeffrey Guardino, MD FACC
  • Stanford Hospital
  • Division of Cardiology

2
Magnitude of CVD Risk
  • CKD has reached epidemic proportions with
    650,000 patients requiring dialysis
  • Prevalence of CAD in CKD patients is high
  • Patients on HD have 40-50 prevalence with 9
    annual CV mortality
  • Renal Transplant Recipients (RTRs) have a lower
    CAD prevalence (15) and annual CV mortality
    (0.54)- Still 2X general population

3
Target Population CAD Prevalence () Annual CV Mortality ()
General Population 5-12 0.28
Mild-Moderate CKD --- 1
Dialysis patients 40-50 9
RTRs 15 0.54
Source Gupta, JACC V 44 No. 7
4
CKD tied to Early CV events
  • National Kidney Foundation study screened 31,417
    patients at risk for CKD
  • At risk defined as having HTN, DM or both or were
    first-degree relative of people with HTN or DM
    (or both)
  • 8/2000-12/2003 There were 560 screening events in
    49 states screened 18-64 YOs (avg 47)

5
  • 69 woman, 23 had DM
  • CKD was identified in 21 based on either
    albumin/creatinine ratio gt 30 kg/g OR eGFR of lt60
    mL/min per 1.73 m2
  • Premature CV disease defined as a H/O MI or CVA
    in Men lt55 and Woman lt65

6
Other factors increasing the risk of Premature CV
Disease
  • Older Age
  • African American race
  • DM
  • HTN

7
Prevalence of Premature Adverse Events at 3-Year
Follow-up
  • Peter McCullough, MD Poster at AHA 11/2007

8
Statistics for CVD in CKD
  • In dialysis patients over 75, there is a 5 fold
    increased mortality risk
  • In patients 25-35 on dialysis, there is a 375
    fold increased risk of CV mortality!!
  • In stage 5 CKD, CVA risk is 6 fold increased and
    CV disease is 2 fold increased and advances at
    twice the rate over time

9
  • Cardiovascular Disease in End Stage
    Kidney Disease (Dialysis)

10
  • CVD is the single best predictor of mortality
    in patients with ESRD, and accounts for 50
    of deaths
  • Risk factors are both traditional
  • - DM (54), Low HDL (33), HTN (85), LVH (22)
    and increased age (average age at commencement is
    60 years old)

11
Traditional risk factors
  • Increasing patient age
  • Male sex
  • Diabetes
  • Smoking
  • Hypertension
  • Hypercholesterolemia

12
Hypertension
  • Complicated risk factor due to comorbid
    conditions
  • Low BP also portends a worsened survival (perhaps
    a sicker population)
  • Increased mortality likely driven by hypertension
    induced LVH (with studies showing that regression
    of LVH via BP control reduces mortality)
  • London G, J Am Soc Nephrol 2001

13
Diabetes
  • Primary cause of ESRD and strongly associated
    with CV disease

14
  • Unique risk factors in CKD
  • CKD itself (independent risk factor)
  • Anemia
  • Hyperhomocysteinemia
  • Uremia and renal replacement therapy leading to
    oxidative stress (leading to accelerated
    atherosclerosis)
  • Increased plasma fibrinogen levels
  • Vascular Calcification

15
Hyperhomocysteinemia
  • Cleared by the kidneys, thus elevated in CKD.
  • Associated with deficiency in Vit B6, B12 and
    Folate
  • Independent risk factor for CVD in renal
    transplant recepients
  • Hazards ratio of 2.44
  • Despite risk, lowering levels has NOT been shown
    to reduce CV mortality

16
Abnormal NO metabolism
  • Inhibition of Nitric Oxide synthesis is a common
    finding in dialysis patients.
  • Leads to vasoconstriction, hypertension and
    adverse CV outcomes
  • Asymmetrical dimethylarginine (ADMA) has been
    targeted for study as it is significantly
    increased in ESRD and is the most specific
    endogenous compound with inhibitory effects on NO
    synthesis.

17
CV surveillance in ESRD
  • All patients should undergo evaluation for CVD
  • Baseline ECG, Stress Test and ECHO
  • Angiography should be considered for dialysis
    patients with unstable symptoms or positive
    non-invasive stress-tests
  • Special attention to minimize contrast (only use
    iso-osmolar)

18
Prevention of CAD
  • Treat CKD patients as equivalent to prior H/O CAD
  • Aggressive lipid lowering
  • Aggressive BP control
  • Surveillance of and treatment for DM
  • Smoking cessation
  • Weight loss
  • Encourage daily exercise

19
Novel approaches for ESRD
  • Vitamin E (for Homocysteine/oxidative stress
    lowering)
  • In one trial of 200 dialysis patients with known
    CAD, 800 IU/day significantly lowered rate of MI,
    CVA, PAD and USA (Boaz, Lancet 2000)
  • Omega-3 Fatty Acids
  • Correction of Anemia (goal Hemoglobin 11-12 g/dL)

20
Cardiovascular Disease in Renal Transplantation
21
  • The overall mortality associated with renal
    transplant has been stable since the 1960s.
  • Despite a significant decrease in
    infection-related deaths, a proportionate
    increase in CV deaths has occurred.
  • 50-60 of deaths are attributable to CV disease.

22
Risk Factors for Atherosclerosis in RTRs
John Vella, MD
23
Determinants of atherosclerosis in Renal
Transplant Recipients
  • Traditional risk factors which can be exacerbated
    by immunosuppressive drugs
  • Unique risk factors found only in Kidney
    Transplant population

24
Unique Risk Factors
  • Hyperhomocysteinemia
  • Elevated LP (a)
  • Elevated CRP
  • Allograft loss
  • Obesity
  • Rejection
  • Vascular Calcifications

25
Hyperlipidemia
  • Post-transplant patients are considered CHD risk
    equivalent (target LDLlt80, Triglt200, HDLgt40)
  • Despite advances in short-term allograft survival
    due to immunosupressive regimens, Hyperlipidemia
    remains a significant problem.
  • Corticosteroids, Cyclosporin, Tacrolimus and
    Rapamycin all raise serum lipids, including
    triglycerides.

26
Hypertension after Renal Transplantation
  • Hypertension develops in up to 80 of Renal
    allograft recipients
  • Elevated Blood Pressure and Pulse Pressure
    results in decreased allograft survival and LVH
  • LVH is an independent risk factor for CHF and CV
    mortality

27
Hypertension
  • Post-transplant hypertension results in a decline
    in long-term allograft and patient survival.
  • Kidneys obtained from hypertensive donors result
    in lower graft survival rates
  • Cyclosporine, Steroids and Tacrolimus (FK-506)
    use result in new onset or exacerbation of
    hypertension.

28
Risk factors for Post-transplant Hypertension
  • Delayed and/or chronic allograft dysfunction
  • Donor with a FHX of Hypertension
  • Presence of Native Kidneys
  • Cyclosporine, Tacrolimus or Corticosteroid use
  • Renal Artery Stenosis
  • Obesity

29
Role of Donor and Recipient FHX
  • There is evidence that the transplanted kidney
    may have either pro-hypertensive or
    anti-hypertensive properties
  • Multiple animal models suggest that the inherited
    tendency to hypertension resides primarily in the
    kidney

30
  • In a study of 85 patients, it was found that
    elevations in blood pressure and increased
    antihypertensive requirements post-transplant
    occurred much more frequently in recipients
    WITHOUT a family history of hypertension who
    received a kidney from a donor WITH a family
    history of hypertension (Guidi E, J Am Soc
    Nephrol 1996)

31
  • In a follow-up study, donor kidneys from
    patients with a family history of hypertension
    into a patient without a family history of
    hypertension were associated with a greater
    hypertensive response during acute rejection
    compared to all other groups (Guidi, E- J Am Soc
    Nephrol 1998)

32
Role of Corticosteroids
  • Corticosteroids have been a known precipitant of
    hypertension in the general population for some
    time
  • It has been shown that gradual withdrawal of
    corticosteroid therapy from stable renal
    transplant recipients results in a fall in blood
    pressure. The effect is greatest in those with
    preexisting hypertension (Hricik DE
    Transplantation 1992)

33
Role of Cyclosporine and Tacrolimus
  • Limited data post renal transplantation, but
    information from BMT and Cardiac Transplantation
    suggest hypertension in 70 of patients
  • Combination of Tacrolimus and Sirolimus has been
    shown to worsen pre-existing hypertension (Gonwa,
    Transplantation 2003)

34
Treatment of Post-Transplantation Hypertension
  • Reduction or elimination of offending drug (in
    cases of immunosuppresive cause)
  • Calcium Channel Blockers (particularly
    nifedipine)
  • Diuretics with salt restricted diet
  • ? ACE-I/ARBbest to wait for 6 months if possible
    to avoid potential anemia and obscuring
    acute-rejection detection (by mildly raising CR)

35
Renal Artery Stenosis
  • Is a significant cause of Post-Transplantation
    hypertension, responsible for approximately
    12-20 of the cases
  • Usually occurs between 3-24 months post
    transplant
  • Important to detect early and correct

36
Risk Factors
  • Harvesting and operative complications
    (mechanical damage from suturing or trauma)
  • Atherosclerotic Disease
  • CMV infection
  • Delayed allograft function

37
Features of Graft Renovascular Disease
  • Increased creatinine after ACE-I/ARB
    administration
  • Flash Pulmonary Edema
  • Uncontrolled Hypertension
  • Acute rise in Blood Pressure

38
Diagnostic Imaging
  • Renal Arteriography Gold Standard but
  • Invasive
  • Risk of dye-induced renal dysfunction
  • Alternatives include
  • Ultrasound (highly dependent on center)
  • MRA (caution using gadolinium with GFR of lt
    30-60)
  • CTA- most data in native kidneys, but promising

39
Treatment Modalities for RAS
  • PTCA successful in up to 80 of patients, but not
    useful with mechanical causes (arterial kinking,
    anastomotic strictures or long lesions)
  • Surgery useful only for cases not amenable to PTCA

40
ALERT study
  • Assessment of Lescol (fluvastatin) in Renal
    Transplantation (Am J Kidney Dis 2005)
  • Factors showing independent risk for MI and CV
    death included
  • Preexisting CAD
  • Hypercholesterolemia
  • Acute rejection
  • Age
  • DM
  • Elevated serum creatinine (gt1.5, significant gt2.3)

41
  • Pre-transplant CV disease in the single
    largest determinant of post-transplant CV disease
  • Pre-transplant uremic state is associated with
    accelerated atherogenesis via hyperfibrinogenemia,
    increased calcium ingestion, mineral metabolism
    abnormalities and modification of LDL by
    glycosylation end-products (AGE) in DM.

42
Value of Biomarkers in RTRs
  • Troponin T is a central marker for diagnosis,
    prognosis and risk-stratification of patients
    with ACS
  • It has been known that Troponin T elevations also
    occur in asymptomatic patients on dialysis and in
    RTRs
  • What role, if any does Troponin T play in this
    setting?

43
Connolly, Nephrology Dialysis Transplant 2007
  • 372 consecutive asymptomatic RTRs were recruited
    between 2000-2002
  • Troponin T was measured at baseline and
    prospective follow-up data collected
  • CV risk assessment questionnaire at enrollment
    recorded traditional CV risk factors

44
  • Demographics Of the 372 patients,
  • 64 Male
  • 19 Smokers
  • 14 DM
  • 22 known vascular disease at enrollment
  • At follow-up (median 1739 days), 311 were still
    alive and 61 (16) had died
  • 24 died from CV disease
  • 28 died from non-CV disease
  • 9 other/unidentified

45
CV deaths
46
All-cause mortality
47
Conclusions
  • Troponin T level is a strong independent
    predictor of all cause mortality in RTRs
  • Aggressive CV risk factor modification should be
    targeted at patients with elevated Tropnin T
    levels.

48
Vascular Calcification
  • Presence of vascular calcifications detected
    radiographically by CT (particularly Coronary
    Artery Calcification) pre-transplant is a major
    risk factor for CVD post-transplant.
  • Presence of CAC is associated with calcium
    supplementaion, CA-containing Oral Phosphate
    Binders, Vitamin D therapy, increasing age and
    length of dialysis.

49
Two types of VC medial and intimal deposition.
  • -Medial deposition is more common, associated
    with vascular stiffness resulting in downstream
    CV disease.
  • -Intimal deposition is less common, and although
    clearly associated with CVD in patients with
    normal renal function its role CKD patients is
    unclear. It is associated with plaque
    vulnerability and rupture.

50
Implications of VC
  • Increased stiffness of large conduit arteries
    resulting in increased pulse pressure, reduced
    coronary perfusion and impaired endothelial
    function.
  • Impact on smaller arteries include vascular
    anastomoses failure and difficulty with coronary
    artery interventions (PTCA, Stenting and CABG).

51
Detection and Treatment of Vascular Calcification
52
Detection of VC
  • CT scanning is gold standard because it permits
    both detection and quantification of VC (although
    does not distinguish between medial/intimal).
  • Plain films and Vascular ultrasound sometimes
    helpful.

53
Treatment and Prevention
  • Avoidance of marked or prolonged positive calcium
    balance.
  • Minimize Ca supplementation
  • Avoid Vitamin D use
  • Use Non-Calcium based phosphate binders
  • Aggressive Statin use to lower LDL
  • ? Early Transplantation for ESRD

54
Case Studies
55
Case 1
  • Pre-Transplant CV evaluation

56
  • History
  • PE
  • ECG
  • CXR
  • Non-Invasive CV testing (patients with
    signs/symptoms of CAD or multiple traditional
    risk factors)
  • Angiography for H/O CAD, DM or High risk of CAD
    (caution with dye and volume use)

57
Types of Non-Invasive studies
  • Stress ECHO
  • Dobutamine ECHO
  • Nuclear Stress
  • -The determination of which strategy to use is
    dependent on the expertise of the individual
    center.

58
Case 1
  • Is a negative DSE enough?

59
Paucity of data exists regarding the
effectiveness of risk-stratification for CVD
pre-transplant
  • The largest study looked at outcomes of 514
    consecutive patients (Kasiske, Transplantation
    2005)
  • Stratified into low and high risk groups based on
    clinical features
  • High risk DM, H/O or symptoms of CAD,
    Multiple risk factors (age gt45, smoking,
    hyperlipidemia, HTN, CVA, PAD)
  • Low risk everyone else (44 of group)

60
Low Risk (44)
  • Proceeded to transplantation WITHOUT further
    testing

61
High Risk (56)
  • Underwent Noninvasive testing and examination by
    a Cardiologist
  • If stress test was positive ? angiography and
    subsequent PCI/CABG were appropriate

62
Results
  • Among the High risk group, PCI was performed 6.2
    and CABG 3
  • For those on the waitlist, 25 low risk and 36
    high risk were tested/retested resulting in 6
    PCIs and 1 CABG.
  • Among the Low risk group, incidence of CV events
    after waitlisting was low (0.5, 3.5 and 5.3
    for 1, 3 and 5 years respectively-includes pre
    and post)

63
2005 Canadian Society for Transplantation
  • Based on this study, the guidelines were revised
    to indicate that those eligible for kidney
    transplantation are
  • Asymptomatic low risk patients, including those
    with negative non-invasive testing
  • Patients with non-critical CAD on angiography
    maintained with appropriate medical therapy
  • Patients S/P successful PCI/CABG

64
Case 1
  • Thrombolysis, when is it safe?

65
  • Although it is still unclear whether CKD patients
    with an STEMI obtain the same benefit with
    thrombolytics as those with normal renal
    functions (most trials excluded CR gt 1.5 gm/dL),
    they should be used when needed.
  • Two studies have looked at this issue
  • Sorrell (Semin Nephrol 2001)
  • Fernandez (Am J Kidney Dis 2003)

66
  • If possible, Primary PCI are the preferred
    modality in most patients with STEMI with CABG if
    necessary
  • Need to be mindful of CIN
  • Even with the best care, mortality after CABG and
    complication rate after PCI are increased in
    patients with CKD
  • Risk of in-hospital mortality after CABG was
    markedly increased compared to non-CKD (odds
    ratio 3.38) Charytan, Nephrol Dial Transplant
    2007.

67
Case 2
  • Renal Transplantation in patients with Aortic
    Stenosis
  • Post-Op monitoring issues

68
  • Valvular disease is common in CKD population
  • Occurs as a consequence of secondary
    hyperparathyroidism with associated VC,
    hypercalcemia and hyperphospatemia
  • Other risk factors include
  • HTN
  • DM
  • Anemia
  • High CO state

69
Valvular AS
  • Most common obstructive abnormality among
    hemodialysis population with a prevalence of
    15-20
  • Hemodynamically significant AS occurs in 7 of
    HD patients
  • Track AS yearly with ECHO

70
  • Pre-operatively (on dialysis)- careful
    ultrafiltration to avoid reduction of end
    diastolic filling pressures
  • Post-operatively avoid dehydration,
    tachycardia, anemia and diuretics

71
Issue 1
  • CV evaluation in chronic dialysis patients
  • Addressed previously, patients are treated as
    being equivalent to CAD patients in terms of HTN,
    Lipids and DM surveillance and treatment
  • Regular H/P, Labs, ECG and Non-invasive Stress
    testing
  • Angiography for high risk, symptomatic patients
    or positive non-invasive testing

72
Issue 2
  • Are patients with CHF candidates for
    transplant?

73
CHF in ESRD
  • Both systolic and diastolic function is impaired
    with ESRD
  • Prevalence of CHF is 10-30 fold higher among
    dialysis patients than in the general population

74
  • LV dysfunction is not necessarily a
    contraindication to kidney transplantation.
  • Uremic CHF may actually improve
    post-transplantation
  • Patients with a severe (non-uremic) CM, should
    generally not be listed for renal transplant
    alone (perhaps combined heart-kidney in selected
    patients?)

75
Effect of Kidney Transplantation on LVSD and CHF
in ESRD
  • Wali, JACC 2005

76
Followed 103 patients with EFlt40 and CHF
post-transplant
  • Conclusions
  • Kidney transplantation resulted in increased
    LVEF, improved NYHA functional class and survival
    (but only for the group that had a
    post-transplant LVEF gt50)
  • There were no perioperative deaths
  • At 1 year, the mean LVEF increased from 32 to 52

77
  • More than 2/3 of patients achieved an LVEF of gt50
  • Renal transplant should be considered as early as
    possible, as prolonged dialysis worsens
    uremic-induced CHF and outcomes after
    transplantation
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