Title: Cardiovascular Disease in Dialysis and Renal Transplantation
1Cardiovascular Disease in Dialysis and Renal
Transplantation
- Jeffrey Guardino, MD FACC
- Stanford Hospital
- Division of Cardiology
2Magnitude 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
3Target 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
4CKD 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
6Other factors increasing the risk of Premature CV
Disease
- Older Age
- African American race
- DM
- HTN
7Prevalence of Premature Adverse Events at 3-Year
Follow-up
- Peter McCullough, MD Poster at AHA 11/2007
8Statistics 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)
11Traditional risk factors
- Increasing patient age
- Male sex
- Diabetes
- Smoking
- Hypertension
- Hypercholesterolemia
12Hypertension
- 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
13Diabetes
- 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
15Hyperhomocysteinemia
- 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
16Abnormal 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.
17CV 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)
18Prevention 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
19Novel 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)
20Cardiovascular 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.
22Risk Factors for Atherosclerosis in RTRs
John Vella, MD
23Determinants 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
24Unique Risk Factors
- Hyperhomocysteinemia
- Elevated LP (a)
- Elevated CRP
- Allograft loss
- Obesity
- Rejection
- Vascular Calcifications
25Hyperlipidemia
- 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.
26Hypertension 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
27Hypertension
- 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.
28Risk 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
29Role 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)
32Role 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)
33Role 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)
34Treatment 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)
35Renal 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
36Risk Factors
- Harvesting and operative complications
(mechanical damage from suturing or trauma) - Atherosclerotic Disease
- CMV infection
- Delayed allograft function
37Features of Graft Renovascular Disease
- Increased creatinine after ACE-I/ARB
administration - Flash Pulmonary Edema
- Uncontrolled Hypertension
- Acute rise in Blood Pressure
38Diagnostic 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
39Treatment 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
40ALERT 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.
42Value 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?
43Connolly, 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
45CV deaths
46All-cause mortality
47Conclusions
- 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.
48Vascular 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.
49Two 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.
50Implications 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).
51Detection and Treatment of Vascular Calcification
52Detection 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.
53Treatment 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
54Case Studies
55Case 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)
57Types 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.
58Case 1
- Is a negative DSE enough?
59Paucity 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)
60Low Risk (44)
-
- Proceeded to transplantation WITHOUT further
testing
61High Risk (56)
- Underwent Noninvasive testing and examination by
a Cardiologist -
- If stress test was positive ? angiography and
subsequent PCI/CABG were appropriate
62Results
- 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)
632005 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
64Case 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.
67Case 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
69Valvular 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
71Issue 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
72Issue 2
-
- Are patients with CHF candidates for
transplant?
73CHF 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?)
75Effect of Kidney Transplantation on LVSD and CHF
in ESRD
76Followed 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