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

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

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

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 YO’s (avg 47)

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

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

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

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

Cardiovascular Disease in End Stage Kidney Disease (Dialysis)

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)

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

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

Diabetes Primary cause of ESRD and strongly associated with CV disease

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

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

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.

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)

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

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)

Cardiovascular Disease in Renal Transplantation

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.

Risk Factors for Atherosclerosis in RTR’s John Vella, MD

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

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

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.

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

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.

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

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

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)

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)

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)

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)

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)

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

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

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

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

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

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)

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.

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?

Connolly, Nephrology Dialysis Transplant 2007 372 consecutive asymptomatic RTR’s 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

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

CV deaths

All-cause mortality

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.

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.

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.

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).

Detection and Treatment of Vascular Calcification

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.

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

Case Studies

Case 1 Pre-Transplant CV evaluation

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)

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.

Case 1 Is a negative DSE enough?

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)

Low Risk (44%) Proceeded to transplantation WITHOUT further testing

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

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)

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

Case 1 Thrombolysis, when is it safe?

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)

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.

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

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

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

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

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

Issue 2 Are patients with CHF candidates for transplant?

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

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?)

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

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%

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