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