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1
Minimizing Cardiovascular Concerns Posttransplant
Andrew D. Howard, MD, FACPMetropolitan
Nephrology Associates Alexandria, Virginia
2
Introduction

• Renal transplant recipients continue to
  experience improvements in short-term graft and
  patient survival
• Long-term outcomes have shown much slower rates
  of improvement
• Developments in immunosuppression which have been
  so critical in achieving short-term gains have
  likely contributed to the risk of cardiovascular
  disease (CVD)
• CVD remains the most important cause of mortality
  in renal transplant recipients

3
Number of Transplants And Patients on Waiting List
(113,866 as of 12/31/01)
(62,411 as of 8/20/04)
USRDS 2000 Annual Data Report
4
Distribution of RTR by CKD Stage
University of Wisconsin 1985-2001
Patients
RTR (N890)
CKD chronic kidney disease RTRrenal transplant
recipients Djamali et.al. Kidney Intern.
2003641800-1807.
5
Overall Survival Rates
Adjusted for Age, Gender and CKD Stage
Patients
CKD
RTR
CKD chronic kidney disease RTRrenal transplant
recipients Djamali et.al. Kidney Intern.
2003641800-1807.
6
Complications of CKDCardiovascular Disease
Mortality
General Population
AnnualMortality()
Hemodialysis Population
Peritoneal Dialysis Population
Renal Transplant Recipient
14.0
13.2
12.0
10.8
11.2
11.1
10.3
9.4
9.2
10.0
9.1
8.8
8.1
8.0
6.7
6.1
6.0
4.0
0.6
0.5
0.6
2.0
0.4
0.5
0.3
0.3
1.1
0.3
0.8
0.3
0.2
0.0
Adapted from Meyer KB, Levey AS. J Am Soc
Nephrol. 19989(suppl)S31-S42.
7
Survival After Myocardial Infarction by
Creatinine Clearance
Plt.001 by log-rank test for differences
Shlipak, M. G. et. al. Ann Intern Med.
2002137555-562.
8
In-hospital Mortality As a Function of Creatinine
Clearance
3106 consecutive patients with an acute MI at the
Mayo Clinic between 1988-2000
Plt.001
Wright, R S. et. al. Ann Intern Med.
2002137563-570.
9
Complications of CKDCardiovascular Disease

• Cardiovascular disease (CAD, cerebrovascular
  disease, PVD, CHF) more prevalent in patients
  with CKD than in the general population
• 40 of patients have CAD or CHF at start of
  dialysis
• Only 15 of patients have normal LV structure and
  function
• Framingham heart study SCr 1.4-3.0, CVD
  prevalence 18-20 vs 8-14
• HOPE study 980 pts with 1.4 ltSCrlt 2.3, higher
  incidence of CV death, MI, stroke
• Higher incidence of traditional risk factorsDM,
  HTN, hyperlipidemia, older age

CADcoronary artery disease CHFcongestive heart
failure CKDchronic kidney disease DMdiabetes
mellitus HTNhypertension PVDperipheral
vascular disease SCrserum creatinine
USRDS 1998 Annual Data Report Kidney Int
199547186-193. Kidney Int. 1999562214-2219.
Ann Intern Med. 2001134629-636. Arch Intern
Med 20011611207-1216.
10
Complications of CKDCardiovascular Disease

• Decreasing GFR proteinuria are independent risk
  factors for CVD
• The relative contribution of other CKD related
  risk factors to CVD is highly suggestive but is
  not yet conclusive
• RAS activity/volume overload
• Abnormal Ca and Phos metabolism
• Anemia
• Malnutrition
• Inflammation/infection
• Thrombogenic factors
• Oxidative stress
• Homocysteine

K/DOQI. Am J of Kidney Dis. 200035S1-S140.
11
Cause of Death in Renal Transplant Recipients
(1995-1997)
21
13
CVD 46
7
20
26
13
Excludes patients whose cause of death was
unknown USRDS 1999 Annual Data Report
12
Cardiovascular MortalityRTR vs General
Population
10
1
Annual Mortality ()
Renal transplant
0.1
recipients (1994-1996)
General population
0.01
(1993)
0.001
25-34
35-44
45-54
55-64
65-74
75-84
Age (years)
Cardiovascular mortality is underestimated in
transplant recipients because of incomplete
ascertainment of cause of death in these patients.
Foley RN, et al. Am J Kidney Dis. 199832(suppl
3)S112-S119
13
Cardiovascular Risk Factors General Population
1. Eckel RH. Circulation. 1997963248-3250 BPblo
od pressure CRP C-reactive protein
HDL-Chigh-density lipoprotein cholesterol
LDL-Clow-density lipoprotein cholesterol
Lp(a)lipoprotein (a) TGstriglycerides
Total-Ctotal cholesterol
14
Relative Risk for Cardiovascular Death in Renal
Transplant RecipientsCox Model
Meier-Kriesche H-U, et al. Transplantation.
2003751291-1295.
15
Classification of Blood Pressure for Adults 18
Years (JNC-VII)
JNC-VII. JAMA. 20032892560-2572.
16
Hypertension in Renal Transplant Recipients

• Present in gt95 of renal transplant recipients
  after 1 year (only 3.5 of patients had normal BP
  without medication)
• Associations with transplant-related hypertension
  include
• Male sex, age, diabetes BMI
• Native kidneys
• Immunosuppressive agents, such as corticosteroids
  and calcineurin inhibitors
• Acute rejection and delayed graft function

Kasiske BL, et al. Amer J Kid Dis.
200461071-1081.
17
HypertensionLong Term Control Posttransplant
JNC 7 hypertension stage at 5 years posttransplant
1976-92
1993-02
Patients
Normal
Stage 1
Pre-HTN
Stage 2
Kasiske BL, et al. Amer J Kid Dis.
200461071-1081.
18
HypertensionLong Term Control Posttransplant
Number of blood pressure medications at 5 years
posttransplant
1976-92
1993-02
0
2
4
1
3
Kasiske BL, et al. Amer J Kid Dis.
200461071-1081.
19
Treatment of Hypertension in Renal Transplant
Recipients

• No antihypertensive agent is absolutely
  contraindicated in renal transplantation
• Lifestyle modification
• Sodium restriction
• Weight reduction
• Smoking cessation
• Exercise
• Diuretics
• Volume overload and hyperkalemia
• Beta-blockers
• Cornerstone of therapy in CVD
• Overall usage remains low decreases with time
• Use of calcium channel blockers with appropriate
  adjustments in cyclosporin, tacrolimus, sirolimus

Midtvedt K, et al. Transplantation.
2001721787-1792.
20
Treatment of Hypertension in Renal Transplant
Recipients

• Reduction or elimination of corticosteroids
• Reduction or conversion of cyclosporin
• ACE inhibitors
• Risks reversible decline in GFR, hyperkalemia,
  anemia
• Usage increasing but remains only 30 after 1
  year
• Angiotensin receptor blockers
• Possible decrease in production of TGF-ß
• Usage 5 up to 5 years

Kasiske BL, et al. Amer J Kid Dis.
200461071-1081.
21
Treatment of Hypertension in Renal Transplant
Recipients
K/DOQI Clinical Practice Guidelines on HTN and
antihypertensive agents in chronic kidney disease

• Goals lt130/80 mm Hg
• No preferred agents
• Possible options
• Diuretics
• Necessary in most choice dependent on GFR
• Beta-blockers
• CCB
• ACEI/ARB
• First choice for all diabetics and non-diabetics
  with spot protein/creatinine 200 mg/g

K/DOQI. Amer J Kid Dis. 200443(Suppl 1)S16-S41.
22
Conversion From Cyclosporine to Tacrolimus
Improved hypertension in stable renal transplant
recipients
Cyclosporin
Following conversion to tacrolimus


Return to cyclosporin
Systolic BP (mm Hg)
Mean Day
Mean Night
Plt.05
Ligtenberg G, et al. J Am Soc Nephrol.
200112368-373.
23
Diabetes and Renal Transplant Recipients

• An estimated 16 million individuals in the U.S.
  have diabetes (diagnosed undiagnosed)
• Direct and indirect costs were estimated at 98
  billion in 1997
• 25 of renal transplant recipients have
  preexisting diabetes (33 increase since 1992)
• 15-20 of renal transplant recipients will
  develop new onset glucose intolerance after
  transplantation

Gaston RS, et al. Am J Kid Dis. 200444529-542.
24
ADA Guidelines for Diagnosis of Diabetes

• Diabetes mellitus
• FBS 126 mg/dL
• Symptoms casual glucose 200 mg/dL
• 2-h postprandial glucose 200 mg/dL after 75 g
  glucose load
• Impaired fasting glucose
• FBS gt100 lt126 mg/dL
• Impaired glucose tolerance
• 2-h postprandial glucose 140 and
• lt200 mg/dL

Diabetes Care 200326S33-S50.
25
Posttransplant Diabetes Mellitus

• De novo development of diabetes after transplant
  is common, appears to be increasing in frequency
  and compromises patient and graft survival
• Determining the true incidence of PTDM is
  difficult because of variable diagnostic criteria
• Most often develops during the initial 3-6 months
  posttransplant but can occur at any time
• PTDM likely exerts the same adverse consequences
  as preexisting diabetes over 8-10 years
  posttransplant (CVD risk)

Gaston RS, et al. Am J Kid Dis. 200444529-542.
26
Incidence of PTDM Multivariate Analysis Study
Cosio FG, et al. Kidney Int. 200159732-737.
27
Posttransplant Diabetes MellitusRisk Factors

• Older age of recipient
• Body weight
• Risk increases with rising BMI
• Ethnicity
• African American, Hispanic, Native American
• Preexistent diabetes or glucose intolerance
• Family history of type 2 diabetes
• Hepatitis C
• Dyslipidemia
• Immunosuppression
• Steroids,
• Calcineurin inhibitors

Gaston RS, et al. Am J Kid Dis. 200444529-542.
28
Diabetes Screening Posttransplant

• The American Society of Transplantation
  recommends posttransplant screening
• Weekly for months 1-3
• Every other week for months 4-6
• Monthly for months 6-12
• 3-4 months thereafter

Kasiske BL, et.al. J Am Soc Nephrol.
200011S1-S86.
29
Management After Transplantation

• Likely an expression of peripheral insulin
  resistance and low insulin production due to
  medication effect
• Complicated by the competing effects of changing
  renal function and diabetogenic
  immunosuppressants
• As renal function improves posttransplantation,
  insulin requirements increase
• Posttransplant infections profoundly impact
  therapeutic approaches to diabetes
• No superior immunosuppressive regimen exists
• Provision of immunosuppression adequate to
  prevent rejection and maintain allograft function
  is critical

30
Diabetes and Immunosuppressive Regimens
Number of patients not diabetic at time of
transplantation
31
Diabetes Long-term Treatment

• Tight glycemic control posttransplant is as
  important to patients with diabetes as in other
  settings
• DCCT UKPDS results
• Results of pancreatic transplants in kidney
  recipients
• Metformin may be problematic
• Early administration of insulin may preserve
  residual islet function
• HbA1c lt7 checked 4 times a year
• Glucose self-monitoring
• FBS 80-120 mg/dL
• postprandial glucose lt140-160 mg/dL
• Ophthalmologic foot examinations
• Microalbuminuria test unless frank proteinuria
  present

32
Hyperlipidemia

• Common in patients with chronic kidney disease
  and even more so in renal transplant recipients
• Characterized by a significant increase in
• total cholesterol (gt200 mg/dL)
• LDL cholesterol (gt130 mg/dL)
• Triglycerides (gt150 mg/dL)
• VLDL (gt35mg/dL)
• Other changes that occur in the lipid profile of
  the renal transplant recipient
• variable effects on HDL cholesterol and Lp(a)
• accumulation of atherogenic remnants (eg, IDL)

33
Hypercholesterolemia Independent Risk Factor
for Graft Loss
Wissing KM, et al. Transplantation.
200070464-472.
34
HypercholesterolemiaRisk Factor for Renal
Allograft Dysfunction
Probability of Doubling Serum Creatinine
1
3
5
7
Years Posttransplant
Carvalho MF, et al. Clin Transplant.
20011548-52.
35
HypertriglyceridemiaRisk Factor for Renal
Allograft Dysfunction
0.5
Probability of Doubling Serum Creatinine
0.25
0
Years Posttransplant
Carvalho MF, et al. Clin Transplant.
20011548-52.
36
Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults

• CHD risk equivalents
• Clinical CHD
• Symptomatic carotid disease
• Peripheral arterial disease
• Abdominal aortic aneurysm
• Diabetes mellitus
• Major risk factors
• Cigarette smoking
• Hypertension (?140/90)
• HDL lt40 mg/dL
• Family history of early CHD
• Age (men ?45 women ?55)

• The National Cholesterol Education Program
  recommendations include maintaining
• total cholesterol and LDL cholesterol below 200
  and 130 mg/dL, respectively
• HDL cholesterol above 35 mg/dL
• triglycerides below 200 mg/dL

National Cholesterol Education Program. Third
Report of the Expert Panel on Detection,
Evaluation, and Treatment of High Blood
Cholesterol in Adults (Adult Treatment Panel
III). Bethesda, Md National Heart, Lung, and
Blood Institute 2001. NIH publication 01-3670.
37
KDOQI GuidelinesManagement of Dyslipidemias in
Adults With Chronic Kidney Disease
Am J Kid Dis. 200341(Suppl 3)S39-S58.
38
Lipid Lowering Agents
LFT liver function test GI gastrointestinal.
39
Lipid Lowering Agents
40
Treatment for Hyperlipidemia in Renal Transplant
Recipients

• Diet
• Saturated fat lt 7 of total calories
• Polyunsaturated fat up to 10 of total calories
• Monounsaturated fat up to 20 of total calories
• Total fat 25-35 of total calories
• Complex carbohydrates 50-60 of total calories
• Fiber 20-30 g/day
• Cholesterol lt 200 mg/day

Am J Kid Dis 41(Suppl 3)S39-S58.
41
Treatment for Hyperlipidemia in Renal Transplant
Recipients

• BMI
• 25-28 kg/m2
• Moderate physical activity
• 20-30 minutes 3-4 x/week
• Alcohol in moderation
• Smoking cessation

Am J Kid Dis 41(Suppl 3)S39-S58.
42
Treatment for Hyperlipidemia in Renal Transplant
Recipients

• Statins are the drugs of choice to lower LDL
  cholesterol
• Begin with lower doses if on therapy with a CNI
  (esp CYA, ?TAC)
• No data on SRL
• Use caution if adding a fibrate and begin with
  reduced dosages with GFR lt90 unless using
  gemfibrozil

Am J Kid Dis 41(Suppl 3)S39-S58.
43
Treatment for Hyperlipidemia in Renal Transplant
Recipients

• If LDL remains 100 mg/dL despite maximal medical
  management, consider
• Tapering or discontinuing prednisone /- adding
  or increasing the dose of AZA or MMF
• Tapering or discontinuing CYA /- adding or
  decreasing the dose of AZA or MMF
• Replacing CYA with TAC
• Discontinuing or replacing SRL
• Bile acid sequestrants may interfere with the
  absorption of immunosuppressive agents (CNI)

44
Hyperlipidemia Post-Hoc Subgroup Analysis of the
ALERT Study

• 2102 renal transplant patients treated with
  fluvastatin (40-80 mg) for 5-6 years
• 32 reduction in LDL cholesterol vs placebo
• Incidence of cardiac death or nonfatal MI reduced
  from 104 to 70 events vs placebo
• (RR 0.65, P.005)
• Statistically significant in multiple subgroups
  including patients at lower CV risk

Jardine AG, et.al. Am J Trans. 20044988-995.
45
Use of Lipid Reducing Drugs Over TimeTacrolimus
vs Cyclosporine
Vincenti F, et al. Transplantation.
200273775-782.
46
Hypercholesterolemia After Conversion to
Tacrolimus
P.0005
P.0007
P.0098
300
250
200
150
Serum Lipid Levels (mg/dL)
100
50
0
Cholesterol
LDL Cholesterol
Apolipoprotein B
McCune TR, et al. Transplantation. 19986587-92
47
Hyperhomocysteinemia

• Common condition in renal transplant recipients
• Testing for fasting homocysteine level might be a
  useful tool to identify patients at increased
  risk for development of vascular disease
• Further long-term studies are needed to determine
  the best treatment
• Effects of immunosuppressive therapy on
  hyperhomocysteinemia are also under investigation
  

48
Cardiovascular Risks Associated With
Immunosuppressive Regimens
MMF mycophenolate mofetil, least
association, greatest association.
49
Conclusion

• Cardiovascular disease after renal
  transplantation is related to a high prevalence
  and accumulation of risk factors before and after
  transplantation
• Hypertension, diabetes and hyperlipidemia are
  well-recognized risk factors and are linked to
  immunosuppressive therapy
• Reducing cardiovascular risk can only be
  accomplished by reducing the impact of these
  defined risk factors early after the onset of
  chronic kidney disease and effectively after
  renal transplantation