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. Annual CV Mortality (%)
Target Population
CAD Prevalence (%)
Annual CV Mortality (%)
General Population
5-12
0.28
Mild-Moderate CKD
--- 1
Dialysis patients
40-50 9
RTR’s 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/ /2003 There were 560 screening events in 49 states screened YO’s (avg 47)

5. 69% woman, 23% had DM
CKD was identified in 21% based on either albumin/creatinine ratio > 30 kg/g OR eGFR of <60 mL/min per 1.73 m2
Premature CV disease defined as a H/O MI or CVA in Men <55 and Woman <65

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 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 g/dL)

20. Cardiovascular Disease in Renal Transplantation

21. The overall mortality associated with renal transplant has been stable since the 1960’s.
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 RTR’s
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 LDL<80, Trig<200, HDL>40)
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/ARB—best 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 < 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 (>1.5, significant >2.3)

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 RTR’s
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 RTR’s
What role, if any does Troponin T play in this setting?

43. Connolly, Nephrology Dialysis Transplant 2007
372 consecutive asymptomatic RTR’s were recruited between
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 RTR’s
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 >45, 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 PCI’s 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 > 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 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 EF<40% 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 >50%)
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 >50
Renal transplant should be considered as early as possible, as prolonged dialysis worsens uremic-induced CHF and outcomes after transplantation