Presentation on theme: "Cardiovascular Disease in Dialysis and Renal Transplantation"— Presentation transcript:
1Cardiovascular Disease in Dialysis and Renal Transplantation Jeffrey Guardino, MD FACCStanford HospitalDivision of Cardiology
2Magnitude of CVD RiskCKD has reached epidemic proportions with ~650,000 patients requiring dialysisPrevalence of CAD in CKD patients is highPatients on HD have ~40-50% prevalence with 9% annual CV mortalityRenal Transplant Recipients (RTRs) have a lower CAD prevalence (15%) and annual CV mortality (0.54%)- Still 2X general population
4CKD tied to Early CV events National Kidney Foundation study screened 31,417 patients “at risk” for CKDAt 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)
569% woman, 23% had DMCKD was identified in 21% based on either albumin/creatinine ratio > 30 kg/g OR eGFR of <60 mL/min per 1.73 m2Premature CV disease defined as a H/O MI or CVA in Men <55 and Woman <65
6Other factors increasing the risk of Premature CV Disease Older AgeAfrican American raceDMHTN
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 riskIn 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
9Cardiovascular Disease in End Stage Kidney Disease (Dialysis)
10CVD 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)
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
13DiabetesPrimary cause of ESRD and strongly associated with CV disease
14Unique risk factors in CKD CKD itself (independent risk factor)AnemiaHyperhomocysteinemiaUremia and renal replacement therapy leading to oxidative stress (leading to accelerated atherosclerosis)Increased plasma fibrinogen levelsVascular Calcification
15Hyperhomocysteinemia Cleared by the kidneys, thus elevated in CKD.Associated with deficiency in Vit B6, B12 and FolateIndependent risk factor for CVD in renal transplant recepients:Hazards ratio of 2.44Despite 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 outcomesAsymmetrical 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 CVDBaseline ECG, Stress Test and ECHOAngiography should be considered for dialysis patients with unstable symptoms or positive non-invasive stress-testsSpecial attention to minimize contrast (only use iso-osmolar)
18Prevention of CAD Treat CKD patients as equivalent to prior H/O CAD Aggressive lipid loweringAggressive BP controlSurveillance of and treatment for DMSmoking cessationWeight lossEncourage 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 AcidsCorrection of Anemia (goal Hemoglobin g/dL)
21The 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.
22Risk Factors for Atherosclerosis in RTR’s John Vella, MD
23Determinants of atherosclerosis in Renal Transplant Recipients Traditional risk factors which can be exacerbated by immunosuppressive drugsUnique risk factors found only in Kidney Transplant population
25HyperlipidemiaPost-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.
26Hypertension after Renal Transplantation Hypertension develops in up to 80% of Renal allograft recipientsElevated Blood Pressure and Pulse Pressure results in decreased allograft survival and LVHLVH is an independent risk factor for CHF and CV mortality
27HypertensionPost-transplant hypertension results in a decline in long-term allograft and patient survival.Kidneys obtained from hypertensive donors result in lower graft survival ratesCyclosporine, 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 dysfunctionDonor with a FHX of HypertensionPresence of Native KidneysCyclosporine, Tacrolimus or Corticosteroid useRenal Artery StenosisObesity
29Role of Donor and Recipient FHX There is evidence that the transplanted kidney may have either pro-hypertensive or anti-hypertensive propertiesMultiple animal models suggest that the inherited tendency to hypertension resides primarily in the kidney
30In 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)
31In 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 timeIt 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 patientsCombination 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/ARB—best to wait for 6 months if possible to avoid potential anemia and obscuring acute-rejection detection (by mildly raising CR)
35Renal Artery StenosisIs a significant cause of Post-Transplantation hypertension, responsible for approximately 12-20% of the casesUsually occurs between 3-24 months post transplantImportant to detect early and correct
36Risk FactorsHarvesting and operative complications (mechanical damage from suturing or trauma)Atherosclerotic DiseaseCMV infectionDelayed allograft function
37Features of Graft Renovascular Disease Increased creatinine after ACE-I/ARB administration“Flash” Pulmonary EdemaUncontrolled HypertensionAcute rise in Blood Pressure
38Diagnostic Imaging Renal Arteriography– “Gold Standard” but InvasiveRisk of dye-induced renal dysfunctionAlternatives include:Ultrasound (highly dependent on center)MRA (caution using gadolinium with GFR of < 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 studyAssessment of Lescol (fluvastatin) in Renal Transplantation (Am J Kidney Dis 2005)Factors showing independent risk for MI and CV death included:Preexisting CADHypercholesterolemiaAcute rejectionAgeDMElevated serum creatinine (>1.5, significant >2.3)
41Pre-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 RTR’s Troponin T is a central marker for diagnosis, prognosis and risk-stratification of patients with ACSIt has been known that Troponin T elevations also occur in asymptomatic patients on dialysis and in RTR’sWhat role, if any does Troponin T play in this setting?
43Connolly, Nephrology Dialysis Transplant 2007 372 consecutive asymptomatic RTR’s were recruited betweenTroponin T was measured at baseline and prospective follow-up data collectedCV risk assessment questionnaire at enrollment recorded traditional CV risk factors
44Demographics: Of the 372 patients, 64% Male19% Smokers14% DM22% known vascular disease at enrollmentAt follow-up (median 1739 days), 311 were still alive and 61 (16%) had died24 died from CV disease28 died from non-CV disease9 other/unidentified
47ConclusionsTroponin T level is a strong independent predictor of all cause mortality in RTR’sAggressive 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 VCIncreased 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 VCCT 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++ supplementationAvoid Vitamin D useUse Non-Calcium based phosphate bindersAggressive Statin use to lower LDL? Early Transplantation for ESRD
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 >45, 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 CardiologistIf 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 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)
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 testingPatients with non-critical CAD on angiography maintained with appropriate medical therapyPatients S/P successful PCI/CABG
65Although 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)
66If possible, Primary PCI are the preferred modality in most patients with STEMI with CABG if necessaryNeed to be mindful of CINEven with the best care, mortality after CABG and complication rate after PCI are increased in patients with CKDRisk 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
68Valvular disease is common in CKD population Occurs as a consequence of secondary hyperparathyroidism with associated VC, hypercalcemia and hyperphospatemiaOther risk factors include:HTNDMAnemiaHigh CO state
69Valvular ASMost common obstructive abnormality among hemodialysis population with a prevalence of 15-20%Hemodynamically significant AS occurs in ~7% of HD patientsTrack AS yearly with ECHO
70Pre-operatively (on dialysis)- careful ultrafiltration to avoid reduction of end diastolic filling pressuresPost-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 treatmentRegular H/P, Labs, ECG and Non-invasive Stress testingAngiography for high risk, symptomatic patients or positive non-invasive testing
72Issue 2Are patients with CHF candidates for transplant?
73CHF 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
74LV dysfunction is not necessarily a contraindication to kidney transplantation. Uremic CHF may actually improve post-transplantationPatients 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 Wali, JACC 2005
76Followed 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 deathsAt 1 year, the mean LVEF increased from 32% to 52%
77More 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