Transcript Clinical Care of Renal Transplant Recipients: An Internist’s Guide Matthew R. Weir, M.D. Professor and Director Division of Nephrology University of Maryland School of Medicine.

Clinical Care of Renal Transplant
Recipients: An Internist’s Guide
Matthew R. Weir, M.D.
Professor and Director
Division of Nephrology
University of Maryland School of Medicine
Overview
• Short-term risks
• Long-term risks
– Erosion of graft function
– Cardiovascular disease
– malignancy
• Drug – Drug interactions
• Future opportunities
Overview
• Short-term risks
• Long-term risks
– Erosion of graft function
– Cardiovascular disease
– malignancy
• Drug – Drug interactions
• Future opportunities
What are the short-term
risks?
• Rejection
• Donor factors leading to poorer outcome
• Recipient death
–
–
–
–
Operative complications
Infection
Malignancy
Cardiovascular disease
• Complications of immunosuppressive
therapy
Short-Term Risks: Infection
• First 6 weeks: standard post-surgical issues
including UTI, line infection,
thrombophlebitis, pneumonia/atelectasis,
wound infection, thrush
• After 6 weeks: opportunistic infection
including CMV, EBV, PCP, listeria,
aspergillus, etc.
• Chemoprophylaxis: clotrimazole, TMS,
valganciclovir
Overview
• Short-term risks
• Long-term risks
– Erosion of graft function
– Cardiovascular disease
– malignancy
• Drug – Drug interactions
• Future opportunities
Acute rejection rates at one year have improved
considerably since the mid-1990s1,2
60
Incidence (%)
50
40
30
20
10
0
1996
1997
1998
1999
2000
Year
1. OPTN/SRTR 2006 Annual Report.
2. OPTN/SRTR 2007 Annual Report.
2001
2002
2003
2004
2005
Longer-term outcomes remain a challenge
in kidney transplantation
Primary graft survival of deceased donors by year of transplant to
31/12/07: Australia and NZ
ANZDATA 31st annual report 2008 (http://www.anzdata.org.au/anzdata/AnzdataReport/31stReport/Ch08Txpart2.pdf)
Possible reasons why short-term
improvements have not changed the longterm attrition rate
• Increased immunosuppression to prevent early
•
•
acute rejection generates subsequent graft loss from
over-immunosuppression
Long-term attrition rate is a separate process driven
by calcineurin inhibitors or other chronic injury
Late immunosuppression minimization and/or noncompliance may play a role
Meier-Kriesche H-U WTC 2006.
Why hasn't improved early graft
survival resulted in better late graft
survival?
• Immunosuppression may
have early benefits but late
adverse effects on graft
survival
• Late graft failure may
occur via mechanisms
unrelated to immune
injury
• Immunosuppression may
be inadequate late because
of nonadherence and
BK nephropathy, other late
infections, malignancies, CVD
CNI nephrotoxicity, recurrent
disease, senescence
Multiple and/or late acute rejection
episodes, subclinical rejection, AMR
ALTERNATIVE MECHANISMS FOR
EARLY KIDNEY GRAFT FAILURE
Good Function
Ccr
Accelerated
Slope
Reduced
Intercept
Ccr at return to dialysis
Time
Disease and medical trends: Keys to
long-term success
• Graft survival
– Acute rejection
– One year survival
renal function1
long-term survival2
• Patient survival
– Cardiovascular disease3
– Post-transplant malignancy4
1. Meier-Kreische HU, et al. Am J Transplant. 2004;4:378–383.
2. Hariharan S, et al. Kidney Intl. 2002;62:311–318.
3. Meier-Kreische HU, et al. Transplantation. 2003;75:1291–1295.
4. Campistol J, et al. JASN. 2006; 17: 581–589.
What are the important late
risks?
• Donor factors leading to poorer outcome
• Recipient death
– Cardiovascular disease
– Malignancy
– Infection
• Late graft loss
– Chronic allograft nephropathy
– Subclinical ACR or AMR
– Infection
Death with a functioning graft is the most common
cause of graft loss in kidney transplant recipients
beyond the first year after transplantation
Cause of graft loss*1
Other Recurrence
4%
Noncompliance 6%
Cause of death2
USRDS 1st kidney transplants 1995–2003
(excluding 30% unknown)
13%
Chronic
rejection
21%
*beyond the first year after transplantation
1.
Death
56%
Other
19.4%
Cardiovascular disease
43.5%
Malignancy
10.7%
Infection
26.3%
Peeters J, et al. Kidney Int. 1995;48(Suppl 52):S97S101.
2. Kasiske B L. et al. Coronary Artery Disease. Presented at the American Society of Nephrology Renal Week 2006 San Diego
November, 14-19, 2006.
Cardiovascular risk and kidney transplantation
• Cardiovascular disease is much more
common among renal transplant recipients
compared to the general population
• The greater incidence of CVD is not entirely
explained by traditional risk factors, (blood
pressure, cholesterol, glucose). Thus, other
factors may be involved
(immunosuppression, rejection, infection?)
Kasiske BL et al. J Am Soc Nephrol 2000;11:1735-1743
Observed and expected risk for ischemic
heart disease after renal transplantation
10-year survival without IHD
1.00
0.90
0.80
0.70
0.60
0.50
0.40
Older Younger
--Diabetic--
Older Younger Older Younger
-Non-Diabetic-
----------Smoker----------
Diabetic
Older Younger
-Non-diabetic----------Non-Smoker----------
Cardiovascular Death Events in 48,832 KTX by
SCr at One Year Post-Transplant
% Cardiovascular death free survival
100
98
Scr mg/dl
@1 /RR
96
1.0
<1.3
1.3-1.4 1.03
1.5-1.6 1.19
1.7-1.8 1.37
1.9-2.1 1.49
94
2.2-2.5 1.67
92
2.6-4.0 2.26
90
0
12
24
36
48
60
72
84
Months post-transplant
96
108 120
Meier-Kriesche, Kaplan et al. Transplantation 2003.
Relationship Between CKD and CVD1
CKD is a risk factor for CVD, and CVD may be a risk factor for the progr
CKD
Traditional
CV risk factors
Non-traditional
CV risk factors
CVD
CKD = chronic kidney disease; CVD = cardiovascular disease; CV = cardiovascular.
1. Menon V et al. Am J Kidney Dis. 2005;45:223–232.
Graded and Independent Relationship Between Estimated
Glomerular Filtration Rate (GFR) and CVD Outcomes*
*Adjusted for baseline age, sex, income, education, coronary disease, chronic heart failure, stroke or transient ischemic
attack, peripheral artery disease, diabetes, hypertension, dyslipidemia, cancer, hypoalbuminemia, dementia, liver
disease, proteinuria, prior hospitalizations, and subsequent dialysis requirement.
Shastri S et al. Am J Kidney Dis. 2010 Jul 2. [Epub ahead of print].
The key understanding is
that patients with CKD
benefit as much as non-CKD
patients with appropriate
medications and therapies, if
not more, because of their
increased risk!
Decreased GFR has consistently
been found to be an independent
risk factor for CVD outcomes and
all cause mortality!
Cardiovascular Mortality Is Higher in Patients
With ESRD
100
Annual mortality (%)
GP Male
GP Female
10
GP Black
GP White
1
Dialysis Male
0.1
Dialysis Female
Dialysis Black
0.01
Dialysis White
Transplant
0.001
25-34
35-44
45-54
55-64
65-74
75-84
Age (years)
Adapted from Foley RN et al. Am J Kidney Dis. 1998;32(5 Suppl 3):S112–S119.
≥85
Traditional and Nontraditional Risk Factors Increase CVD
Event Risk in Patients With CKD1
Traditional Risk Factors
Non-Traditional Risk Factors
Older age
Anemia
Male sex
Volume overload
Hypertension
Abnormal mineral metabolism
High LDL-C
Electrolyte imbalances
Low HDL-C
Albuminuria
Diabetes
Smoking
Lipoprotein(a) and Apo(A) isoforms
and lipoprotein remnants
Physical inactivity
Homocysteine
Menopause
Oxidative stress/inflammation
Family history of heart disease
Malnutrition
Left ventricular hypertrophy
Thrombogenic factors
White race
Sleep disturbances
High sympathetic tone
CVD = cardiovascular disease; CKD = chronic kidney disease;
LDL-C = low-density lipoprotein cholesterol;
HDL-C = high-density lipoprotein cholesterol; Apo = apolipoprotein.
1. Shastri S et al. Am J Kidney Dis. 2010;56:399-417.
Altered nitric oxide/endothelin balance
Particular to
individuals with CKD
The Transplant Kidney
• Optimal GFR 50-60 ml/min, less in
situations of ischemia/reperfusion injury,
marginal donors, nephrotoxic drugs or
rejection
• Risk for hyperfiltration injury
• Pre-existing milieu of hypertension,
diabetes and vascular disease
Cardiovascular Risk Profile of
the Renal Transplant
Recipient
•
•
•
•
Hypertension
Diabetes
Dyslipidemia
Renal Disease
Appreciate that we have no
prospective randomized
controlled trials to evaluate
optimal treatment regimens and
goals in patients with kidney
transplants!
Pathogenesis of Hypertension
in Renal Transplant Recipients
• Pre-existing essential hypertension
• General-population risk factors
(obesity, smoking, alcohol, excessive salt intake)
• Renal dysfunction/rejection
• Renal-transplant artery stenosis
• Effects of native kidneys
• Hypertensive donor
• Immunosuppressive drugs
Mailloux LU et al. Am J Kidney Dis. 1998;32(suppl 3):S120–S141.
Kew CE II et al. J Renal Nutrition. 2000;10:3–6.
Association of Hypertension at 1 Year
With Decreased Graft Survival
100
% grafts surviving
90
80
70
60
50
0
0
1
2
3
4
5
6
Years post-transplantation
SBP = systolic blood pressure
Opelz G et al. Kidney Int. 1998;53:217–222.
7
SBP
No. pts
< 120
120–129
130–139
140–149
2,805
4,488
5,961
6,670
150–159
4,443
160–169
170–179
2,925
1,217
³ 180
1,242
Does treatment of high blood
pressure in renal transplant
recipients reduce graft loss
and patient death?
Probably!
• No outcome studies have been
performed
• It is likely that these high risk patients
will derive benefit for the heart, brain
and transplant kidney
Drug Therapy: Treatment
Diuretics: As needed to control
volume: more studies need to
focus on the advantages of
thiazides vs loop diuretics
Beta-blockers: Heart rate
control, CAD
Alpha blockers: BPH, outflow
obstruction
ACEI and ARB
• Preferred treatment strategies
antihypertensive
antiproteinuric
antiproliferative
ACEI/ARB in Renal
Transplantation
• Retrospective open cohort study
• N=2031, University of Vienna
• 1990-2003, ACE use increased 9%-47%, ARB
0%-18% at the end of the observation period
• Medication and co-morbidities were analyzed as
time-dependent variables in cox regression
analyses.
• Ten year patient survival:74% ACE/ARB vs 55% in
no ACE/ARB, p<.001
• Ten year graft survival: 59% in ACE/ARB group vs
41% in no ACE/ARB, p=.002
Heinze G, et al. JASN 2006;17:889-899
Kaplan-Meier estimates of patient survival. Angiotensinconverting enzyme inhibitors/angiotensin II type 1 receptor
blockers (ACEI/ARB) users lived significantly longer compared
with noACEI/ARB patients (log rank: P < 0.001).
Kaplan-Meier estimates of actual graft survival
counting death as event. ACEI/ARB therapy was
associated with longer graft survival (log-rank: P =
0.002).
Systematic Review of RAS
Blockade in Kidney Transplantation
•
•
•
•
•
•
•
•
21 randomized trials
n=1549
Median follow-up: 27 months
eGFR decreased by 5.8 ml/min
Hct decreased by 3.5 %
Proteinuria decreased by 470 mg/day
No change in serum potassium
Not enough power to see an effect on patient
or graft survival
Hiremath S, et. al AmJ Transplant 2007; 7:2350-2360
Calcium Channel Blockers
• Robust antihypertensive properties,
despite salt consumption
• Afferent glomerular dilators
? Good effect with calcineurin
inhibitors
? Deleterious effect with glomerular
capillary pressure
• Best combined with ACEI or ARB
Diabetes in Kidney Transplant
Patients
• Associated with reduced patient
survival
• Associated with reduced graft
survival Histologic appearance of
diabetic kidney disease within 5
years.
Impact of Intensive Glycemic
Therapy
Summary of Major Clinical Trials
Study
Microvascular
CVD
Mortality
UKPDS1,2
DCCT/EDIC3,4
ACCORD5,8
ADVANCE6
VADT7
Initial trial
Long-term follow-up
1. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-865. 2. Holman RR, et al. N Engl J Med. 2008;359:1577-1589.
3. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329;977-986.
4. Nathan DM, et al. N Engl J Med. 2005;353:2643-2653. 5. Gerstein HC, et al. N Engl J Med. 2008;358:2545-2559.
6. Patel A, et al. N Engl J Med. 2008;358:2560-2572. 7. Duckworth W, et al. N Engl J Med. 2009;360:129-139.
8. Ismail-Beigi F, et al. Lancet. 2010;376:419-430.
Cumulative Incidence of the First Occurrence of
Nonfatal MI, Stroke, or Death From CVD, T1D
Cumulative Incidence
0.12
0.10
Risk reduction 42%
95% CI: 9% to 63%
P = 0.02
0.08
Conventional
0.06
Longer studies?
0.04
Earlier intervention?
Intensive
0.02
0.00
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
15
10
Years from Study Entry
Nathan DM et al. N Engl J Med. 2005:353:2643-2653.
16
17
18
19
20
20
Cumulative Incidence of an Impaired Glomerular Filtration Rate, According to Treatment Group.
The DCCT/EDIC Research Group. N Engl J Med 2011;365:2366-2376.
Rationale for Lipid Lowering Clinical Trials in the
CKD Population
• CKD and ESRD patients are at increased risk of
cardiovascular complications
• CKD and ESRD patients have abnormal lipid profiles
• Secondary analyses of lipid lowering studies indicated statin
treatment improved CV outcomes in CKD patients
• Secondary analyses of these studies also demonstrated
slowing of CKD progression
• Need for randomized placebo-controlled statin trials in
CKD and ESRD patients
1. Scandinavian Simvastatin Survival Study (4S). Lancet.1994;344(8934):1383–1389.
2. Shepherd J et al. N Engl J Med. 1995;333(20):1301–1307.
3. Heart Protection Study Collaborative Group. Lancet. 2002;360(9326):7–22.
4. Seliger SL et al. Kidney Int. 2002;61(1):297–304.
5. Liao JK. Am J Cardiol. 2005;96(5A):24F–33F.
6. Fellström BC et al. Kidney Int. 2003;63(Suppl 84):S204–S206.
Mechanism of CVD Development in
Patients With Uremia
Uremi
a
Dyslipidemia
Immuno-deficiency
(T- & B- cell,
phagocytosis,
Ig-formation
T
B
Ab
Oxidative stress
(ROS, AGE, AOPP)
(TG↑,
ApoB↑,
Malnutrition
Inflammatory
ApoA1 ↓,
activity
Atherogenic
HDL↓)
ADMA↑
lipid fractions
Endothelial
(ox_LDL,
dysfunction
small dense
Accelerated
LDL)
Atherosclerosis
TG, triglycerides; HDL, high density lipoprotein; LDL, low density lipoprotein; ROS, reactive oxygen species; AGEs, advanced
glycation end products; AOPP, advanced oxidation of plasma proteins; ADMA, asymmetric dimethylarginine
Fellström BC et al. Kidney Int. 2003;63(Suppl 84):S204–S206.
ALERT
• n = 2102 renal transplant recipients
• Randomized controlled trial (60 months)
• Primary endpoint: cardiac death, non-fatal MI,
or cardiac procedures
• Fluvastatin (40-80 mg) vs placebo
• 17% RRR (p = 0.139), but fewer cardiac
deaths and MI in treatment group (p = 0.005)
Holdaas et al. Lancet 2003;361:2024-2031.
SHARP: Eligibility
• History of chronic kidney disease
– not on dialysis: elevated creatinine on 2 occasions
• Men: ≥1.7 mg/dL (150 µmol/L)
• Women:
≥1.5 mg/dL (130 µmol/L)
– on dialysis: haemodialysis or peritoneal dialysis
• Age ≥40 years
• No history of myocardial infarction or coronary
revascularisation
• Uncertainty: LDL-lowering treatment not
definitely indicated or contraindicated
SHARP: Randomisation structure
Randomised
(9438)
Simva/Eze
(4193)
Simvastatin
(1054)
Placebo
(4191)
Not re-randomised
(168)
Randomised
(886)
Simv/Eze
(4650)
Median follow-up 4.9 years
Lost to mortality follow-up 1.5%
Placebo
(4620)
Proportion suffering event (%)
SHARP: Atherosclerotic Events(Lancet
2011;377:2181)
25
20
Risk ratio 0.83 (0.74-0.94)
Logrank 2P=0.0021
15
Placebo
Simv/Eze
10
5
0
0
1
2
3
Years of follow-up
4
5
Summary
Nevertheless, given the data from the HPS and the
SHARP study, we feel that there is a strong
argument to abandon a threshold-based algorithm
for treating hyperlipidemia. Rather it may be
advisable to treat those with high risk for
atherosclerotic cardiac events regardless of initial
LDL level, and to treat with a potent dose of a
statin alone or in combination with a second line
drug to achieve a marked (at least 40%) reduction
in LDL, at least to ATP-III LDL goal levels.
CKD Resets the Focus on CV Risk
Reduction Strategies
• BP <130/80 mmHg?
• Evaluate and treat lipids
• Extinguish
microalbuminuria/proteinuria?
• Reduction in dietary salt/saturated fat
• Intensify glycemic control
• Control anemia
• Control calcium / phosphorus balance
• Anti-platelet therapy
The increased risk of malignancy in kidney
transplant patients
Cancer rates
vs. general
population
Colon, lung, prostate, gastric,
esophagus, pancreas, ovary and
breast
Moderate Testes and urinary, bladder
Risk
Cutaneous melanoma, leukemia,
liver and gynecological tumors
High risk Kidney
Kaposi sarcoma, PTLD, skin cancer
Kasiske BL, et al. Am J Transplant. 2004;4:905–913.
2
3
5
15
>20
Cumulative tumor incidence after renal transplantation
Cumulative tumor incidence (%)
60
All tumors
Solid tumors (without skin cancer)
Age-adjusted normal population
50
49.3 %
39.7 %
38.8 %
31.2 %
28.8 %
26.9 %
40
19.7 %
17.9 %
30
10.6 %
8.4 %
20
21.7 %
14.9 %
10
9.5 %
5.2 %
0
2.2 %
0
5
10
15
Time after transplantation (years)
20
25
Based on 2419 renal transplant recipients from the Munich Großhadern transplantation center
Wimmer CD, et al. Kidney Int. 2007;71:1271–1278.
Overview
• Short-term risks
• Long-term risks
– Erosion of graft function
– Cardiovascular disease
– malignancy
• Drug – Drug interactions
• Future opportunities
Drug – Drug Infections
A Major Concern!
Reality Check
FK
MMF
Prednisone
Val GCV
Bactrim
Mycelex
Lipitor
FeSO4
Prevacid
Actos
Glipizide
ASA
Norvasc
Atenolol
Lisinopril
Lasix
Viagra
?
Clinically relevant drug interactions
with immunosuppressive medications
Interacting Agent
Effect of Interacting Agent
Recommendations/Monitoring
Calcineurin Inhibitors
Antifungals
Anidulafungin
No significant effect
Amphotericin B
Increased risk of nephrotoxicity
Appropriate hydration; monitor renal
function closely
Caspofungin
Increased hepatic enzymes with
cyclosporine
Monitor transaminases closely; Consider
alternatives if elevation in hepatic enzymes
occurs
Fluconazole
Inhibits metabolism
Monitor CNI levels closely
Ketoconazole
Inhibits metabolism
Monitor levels closely; Decrease CNI dose by
50-75%
Micafungin
No significant effect
Posaconazole
Inhibits metabolism
Monitor CNI levels closely; Decrease
cyclosporine by 25% and tacrolimus by 66%
Voriconazole
Inhibits metabolism
Monitor levels closely; Decrease CNI dose by
50-75%
Clinically relevant drug interactions
with immunosuppressive medications
Antibiotics
Azithromycin
Little effect
Clarithromycin
Inhibits metabolism
Empiric dose reduction; monitor CNI levels closely
Erythromycin
Inhibits metabolism
Empiric dose reduction; monitor CNI levels closely
Rifampin
Induces metabolism
Increase in dose; monitor CNI levels closely
Inhibits metabolism
Dose reduction; monitor CNI levels closely
Barbiturates
Induces metabolism
Increase in dose; monitor CNI levels closely
Benzodiazepines
No effect
Carbamazepine and
Oxcarbazepine
May induce metabolism
Levertiracetam
No effect
Modafanil
Induces metabolism
Dose reduction; monitor CNI levels
Phenytoin
Induces metabolism
Dose reduction; monitor CNI levels closely
Valproic acid
No direct effect
Monitor levels
Antiretrovirals
Protease inhibitors
Anticonvulsants
Monitor CNI levels; may require increase in dose
Clinically relevant drug interactions
with immunosuppressive medications
Antihypertensives
ACEIs/ARBs
May increase risk of hyperkalemia
Monitor Potassium
Beta-blockers
Carvedilol may inhibit
Monitor CNI levels
Diltiazem,
verapamil, and
nifedipine
Inhibit metabolism
Decrease CNI dose by 25%; monitor CNI levels
closely
Dihydropyridine
calcium channel
blockers
No effect
Colchicine and NSAIDS
Colchicine
Inhibition of colchicine
metabolism; competitive inhibition
of cyclosporine metabolism
Dose adjustment of colchicine per package
labeling required
NSAIDS
Increased risk of nephrotoxicity
Avoid if possible; use for short period of time if
necessary with close monitoring
Increased statin exposure with
cyclosporine No effect with
tacrolimus
Significant dose reductions of statin; monitor
CPK
Lipid Lowering Agents
HMG Co-A
reductase
inhibitors
Clinically relevant drug interactions
with immunosuppressive medications
Lipid Lowering Agents
HMG Co-A reductase
inhibitors
Increased statin exposure with
cyclosporine No effect with tacrolimus
Significant dose reductions of statin;
monitor CPK
Citalopram
No reports
Monitor CNI levels
Desvenlafaxine
No reports
Caution due to CYP 3A4 metabolism of
desvenlafaxine
Duloxetine
No reports
Monitor CNI levels
Fluvoxamine
Inhibits metabolism
Monitor CNI levels closely; dose
reductions may be necessary
Fluoxetine, paroxetine, and
citalopram
Little effect
Monitor CNI levels
Haloperidol
QT prolongation
Monitor QTc interval
Lithium
Increased risk of nephrotoxicity
Monitor renal function closely
Nefazodone
Inhibits metabolism
Avoid if possible
Quetiapine and olanzapine
QT prolongation
Monitor QTc interval
Sertraline
May inhibit metabolism
Conflicting reports-monitor levels
closely
Venlafaxine
Little effect
Monitor CNI levels
Psychiatric Drugs
Clinically relevant drug interactions
with immunosuppressive medications
Antimetabolites
MMF and MPA
Calcineurin inhibitors
Cyclosporine
Reduction in MPA AUC
Dose adjustment may be necessary
Acyclovir
Possible Increase in AUC
Monitor for adverse events
Ganciclovir
Decreased clearance of ganciclovir
Monitor for adverse events
Antacids
Decrease in AUC and Cmax
Avoid concomitant administration if
possible
Proton Pump Inhibitors
MMF-decrease in Cmax and Tmax
MPA—no effect
Caution with MMF
Decrease in AUC and Cmax
Administer 2 hours after MMF
Antivirals
Gastrointestinal Drugs
Phosphate Binders
Calcium-free phosphate
binders
Clinically relevant drug interactions
with immunosuppressive medications
Miscellaneous Drugs
Cholestyramine
Decrease in AUC
Concomitant use not recommended
Oral
contraceptives
Decrease in levonorgestrel AUC
Caution with levonorgestrel
Ciprofloxacin and
amoxicillin/
clavulanic acid
Decrease in trough levels
Caution
Norfloxacin and
metronidazole
Decrease in AUC
Concomitant use not recommended with
combination
Trimethoprin/
Sulfamethoxazole
Small reduction in AUC
Does not appear clinically significant
Rifampin
Increase in exposure
Monitor for adverse events
Increase in 6-mercaptopurine
Avoid concomitant use
Anti-infectives
Xanthine Oxidase
Inhibitors
Allopurinol
Clinically relevant drug interactions
with immunosuppressive medications
Mammalian Target of Rapamycin Inhibitors
Calcineurin Inhibitors
Cyclosporine
Increase in sirolimus AUC
Monitor levels; if given concomitantly,
give sirolimus 4 hours after cyclosporine
Ketoconazole
Increase in Cmax, Tmax, and
AUC
Monitor levels; significant dose reduction
required
Voriconazole
Increase in Cmax and AUC
Monitor levels; significant dose reduction
required
Increase in Cmax and AUC
Monitor levels; dose reduction may be
required
Erythromycin
Increase in Cmax and AUC
Monitor levels; consider azithromycin as
an alternative
Rifampin
Decrease in Cmax and AUC
Monitor levels; significant dose increase
required
Increase in AUC
Monitor levels: dose reduction may be
required
Antifungals
Calcium Channel Blockers
Non-dihydropyridine calcium
channel blockers
Antibiotics
Antiretrovirals
HIV protease inhibitors
Improved Graft Survival after Renal
Transplantation in the US
Half Life (Years)
1988
1996
CRT
7.9
13.8
LRT
12.7
21.6
Hariharan S, et al. N Eng J Med 2000; 342: 605-612.
Perspective
The old consideration that control of rejection
changes short-term outcomes but not long-term
outcomes is not correct.
Kidney transplants should serve their owners for
their life expectancy.
Perhaps the biggest problem is:
INADEQUATE FOLLOW-UP AND SURVEILLANCE
and
LACK OF RESPONSE TO CHANGE IN FUNCTION!
Conclusions
• Many kidney transplant patients in general
medical practice
• Always work with a transplant center and a
nephrologist who is well trained in
immunosuppression management
• Many new immunosuppression drugs
• When in doubt, ask for help!