Allograft Nephropathy and Cardiovascular Disease: Important for Graft and Patient Survival – Implications for Diagnosis and Treatment Matthew R. Weir, M.D. Professor and Director Division of Nephrology University of Maryland School of Medicine
Dec 30, 2015
Allograft Nephropathy and Cardiovascular Disease:Important for Graft and Patient Survival –
Implications for Diagnosis and Treatment
Matthew R. Weir, M.D.
Professor and Director
Division of Nephrology
University of Maryland School of Medicine
Leading Causes of Graft Failure
CVD (also known as death with functioning graft)
Allograft Nephropathy
Are they related?
Overview• Cardiovascular risk profile in the kidney
transplant recipient vs the general population
• Renal autoregulation and microalbuminuria
• Risk reduction strategies: focus on blood pressure, cholesterol and glucose
• Optimal immunosuppression strategies
• Conclusions
• 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
1.00
0.90
0.80
0.70
0.60
0.50
0.40
Older Younger Older Younger Older Younger Older Younger--Diabetic-- -Non-Diabetic- Diabetic -Non-diabetic-
----------Smoker---------- ----------Non-Smoker----------
10-y
ear
surv
ival
with
out
IHD
Observed and Expected Risk for Ischemic Heart Disease after Renal Transplantation
This raises even more This raises even more questions about the rigor questions about the rigor of our approach to CV risk of our approach to CV risk reduction in transplant reduction in transplant patients, particular if they patients, particular if they have diabetes!have diabetes!
Cardiovascular Risk Profile of the Renal Transplant Recipient
• Hypertension
• Diabetes
• Dyslipidemia
• Renal Disease
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
Unmet Need
• We need better long-term immunosuppression strategies to avoid the metabolic stresses of diabetes, hypertension and dyslipidemia on both the heart and the kidney and the vascular tree
• Biggest focus: corticosteroids
calcineurin inhibitors (CNI)
Corticosteroid Withdrawal• Feasible, particularly with newer, more effective
drugs and biologicals
• Will result in fewer metabolic consequences
• Not for everyone!
• Perspective: how often does 2.5 – 5 mg/day prednisone cause problems?
• Avoidance protocols more successful than tapering: chronic use may condition immune system and increase the risk for rejection.
CNI Withdrawal or Minimization
• a more practical issue• define risk: benefit ratio• metabolic improvement
cyclosporine: BP, cholesterol, glucose, kidney function
tacrolimus: glucose, kidney function
• need to be sure no T cell- or antibody-medicated rejection
Decreased Renal Function is a Strong Risk Factor for Cardiovascular Death
following Renal Transplantation
• USRDS Registry– First Transplants– 1988-1998– Adults– Multi-organ Transplants excluded
• All with functioning graft at one year post transplant (Scr≤4mg/dl)
Meier-Kriesche, Kaplan et al. Transplantation 2003
12 24 36 48 60 72 84 96 108 120090
92
94
96
98
100
2.6-4.0
2.2-2.5
1.9-2.1
1.7-1.8
1.5-1.61.3-1.4<1.3
Scr mg/dl@1 /RR
months post-transplant
% C
ard
iova
scu
lar
dea
th f
ree
surv
ival
Cardiovascular Death Events in Cardiovascular Death Events in 48,832 KTX by SCr at One Year Post TransplantKTX by SCr at One Year Post Transplant
Meier-Kriesche, Kaplan et al. Transplantation 2003
1.01.031.191.371.49
1.67
2.26
Functional cadaveric renalallograft survival (censored for death with a functioning graft)after the first year following transplantation, by year oftransplant.
Hariharan S. NEJM 2000; 342:605.
Era of 1988 to 1994, both acute rejection
rates and graft survival rates were
improving
Better intercept or improving
slope?
Renal function is a natural candidate for a surrogate marker of graft loss
ALTERNATIVE MECHANISMS FOREARLY KIDNEY GRAFT FAILURE
Ccr
Time
Ccr at return to dialysisCcr at return to dialysis
Good FunctionGood Function
Accelerated Accelerated SlopeSlopeReduced Reduced
InterceptIntercept
A shift in conceptual frameworks: challenging traditional assumptions
1. Early function (slope) predicts late function (slope) ie. worse early function results in more aggressive deterioration of function
2. Graft loss is inevitable following kidney transplant as the average slope is decreasing
Summary
1. Renal function can be used as a new endpoint in kidney transplantation interpreted in the form of slopes and intercepts
2. The majority of the “action” occurs after 6 months; baseline factors are poorly predictive of long-term outcomes
3. The stability of renal function after kidney transplantation is improving
4. Loss of graft function is not inevitable following kidney transplantation
Implications of Microalbuminuria or Proteinuria?
Cardiovascular Events byDegree of Albuminuria in HOPE
Gerstein HC et al. JAMA. 2001;286:421-426.
Incidence(%)
30
25
20
15
10
5
0
All participants
With diabetes
Without diabetes
Microalbuminuriathreshold
Albumin/Creatinine Ratio Deciles
1 and 2 3 4 5 6 7 8 9 10
Multivariate Hazard Ratios forPrimary Outcome in HOPE
HOPE Study Investigators. N Engl J Med. 2000;342:145-153.
0 1 2
Microalbuminuria
CAD
Diabetes
Creatinine 1.4 mg/dL
Male
WHR (0.1)
Age (1y)
Ramipril
1.59
1.51
1.42
1.4
1.20
1.13
1.03
0.79
Hazard Ratio
Microalbuminuria Resets the Focus on CV Risk Reduction Strategies
• BP <130/80 mmHg
• Evaluate lipids
• Extinguish microalbuminuria
• Reduction in dietary salt/saturated fat
• Intensify glycemic control
• ASA
Opelz G, et al Kidney Int 1998;53:217-222
Allograft Nephropathy• Hypertension/proteinuria/declining
kidney function are the hallmarks of this disease process
• Need for specific antihypertensive, antiproteinuric approaches?
• Modification of immunosuppression
Chronic Rejection of Renal Allografts
Impact of Early Events
Acute Rejection Ischemia/Reperfusion
CMV and Other Infections
Donor Factors
Adhesion Molecules, Cytokines, Growth Factors
INJURY
LOSS OF NEPHRONMASS
CHRONIC GRAFTDYSFUNCTION
Chronic rejection
Effector mechanisms
Antibodies
Brain deathIschemia/reperfusion injuryInadequate renal mass(donor age, gender, race, organ size)Hypertension and hyperlipidemiaDrug nephrotoxicityCMV, other infections
Cytokines Growth factors
Cytokines
• Costimulation
• Allorecognition
HLA matchingAcute rejectionOngoing subclinical immunologic injury
Alloantigen-DependentMechanisms
Alloantigen-IndependentMechanisms
B Cell
T Cell
Macrophage
APC
Endothelium
Lumenal Obliteration Due to Vasculopathy in Chronic Allograft Nephropathy
Tubulointerstitial Fibrosis and Scarring in Chronic Allograft Nephropathy
Hypocellular lesions inareas of fibrosis
Apoptosis > > Proliferation
interstitialcell proliferation followed by
Apoptosis
Renal ischemia
and injury
TG F- ? apoptosis
extracellularmatrix deposition
.
Ang II
Direct effect
ET-1
Sympathetic tone
Thromboxane A2
NO
Prostaglandins
Prostacyclins
CsA Vasoconstriction
Calcineurin inhibitors and Calcineurin inhibitors and hemodynamic effectshemodynamic effects
University of Maryland Clinical Experience Trial in Patients with Allograft Nephropathy
• All patients were on triple immunosuppressive therapy: tacrolimus, mycophenolate mofetil and maintenance prednisone therapy.
• Patients were asked to discontinue tacrolimus after the first loading dose of sirolimus.
• Maintenance dose of sirolimus was adjusted to maintain goal trough level of 8-12 ng/ml. MMF used at 1g BID. Low dose prednisone 2.5-5 mg QD.
Wali RK, et al. Am J Transplant 2007;6:1572-1583
Weir MR, et. al. Am J Nephrol 2004;24:379-386
Demographics (n=125)
Mean age in years (±SD) 50.3 ± 14.2
Gender—Males, number (%) 75 (60)
Ethnic origin—number (%)
Caucasians
African American
Others
56 (44.8)
67 (53.6)
2 (1.6)
Cause of ESRD—number (%)
Diabetes mellitus
Hypertension
Others
52 (41.6)
42 (33.6)
31 (24.8)
Wali RK, et al. Am J Transplant 2007;6:1572-1583
Pre / Post Conversion BUN & Creatinine
0
1
2
3
4
5
6
Pre 1 Pre 2 SRLinitiation
3 6 12 18 24
Time in months
Cre
ati
nin
e (
mg
/dl)
0
10
20
30
40
50
BU
N (
mg
/dl)
Cr BUN
Wali RK, et al. Am J Transplant 2007;6:1572-1583
Changes in GFR (Nankivell Formula) after Conversion (Δ pre-post GFR ml/min)
All pts.
(n=125)
Δ zero
(n=7)
Δ 1-15 ml/min
(n=39)
Δ >16
Ml/min
(n=79)
p
Pre
(mean ± SD)
24.8 ±
13.6
31.4±
13.1
28.5 ±
13.2
22.5 ±
13.4
.03
Post
(mean ± SD)
47.8 ±
17.6
25.9±
9.8
38.4 ± 14.0
54.4 ± 16.1
.000
Wali RK, et al. Am J Transplant 2007;6:1572-1583
Demographic FactorsAll
(n=125)
Δ 0 (n=7)
Δ 1-15 ml
(n=39)
Δ >16 ml
(n=79)
p
Age 50.3±14.2 48.2 ±21 51.7±14.7 49.7±13.5 .72
Time post-tx
(months)
5.4± 5.6 10.2±7.2 5.9 ± 5.2 4.6 ±5.4 .03
Acute rejection
22 (17.6) 1 (14) 8 (20) 13 (16) .07
Follow up (months)
17.1 ±7.8 19.8±6.4 16.3 ±8.1 17.3 ±7.7 .51
Wali RK, et al. Am J Transplant 2007;6:1572-1583
Graft Loss during the follow up
403020100
Per
cent
age
surv
ival
1.2
1.0
.8
.6
.4
.2
0.0
Δ>16 (n=79)
Δ zero or less (n=7)
Δ 1-15 (n=39)
Kaplan-Meier graph for graft loss: Log Rank p=.0003
Wali RK, et al. Am J Transplant 2007;6:1572-1583
Study Objective
To evaluate combination mycophenolate To evaluate combination mycophenolate mofetil (MMF) and sirolimus (SRL) as a mofetil (MMF) and sirolimus (SRL) as a
calcineurin inhibitor (CNI)-free regimen for calcineurin inhibitor (CNI)-free regimen for renal function preservation in renal allograft renal function preservation in renal allograft
recipientsrecipients
Trial Design
MMF + MMF + tacrolimustacrolimus
MMF + cyclosporine
MMF + tacrolimusMMF + tacrolimus
MMF + cyclosporine
MMF + sirolimusMMF + sirolimus
MMF + sirolimusMMF + sirolimus
Post-randomizationPost-randomization
Patient screening Patient screening and enrollment and enrollment
1 year1 year 2 years2 years
30 – 18030 – 180
DDAAYYSS
PPOOSSTT--TTXX
Pre-randomizationPre-randomization
Dosing Regimens
• Mycophenolate Mofetil
– 1 to 1.5 g BID
• Sirolimus
– 2 to 10 mg loading dose
– Maintain trough levels of 5 to 10 ng/mL
• Calcineurin Inhibitors/Corticosteroids
– According to center practice
Key Inclusion CriteriaKey Inclusion Criteria
• Male/female, age 13 to 75 years
• Received a primary living or deceased donor renal allograft within the previous 30 to 180 days
• Maintained on MMF + CNI (TAC or CsA) with or without corticosteroids for 14 days pre-randomization
Key Exclusion CriteriaKey Exclusion Criteria
• Corticosteroid-resistant, biopsy-proven acute Corticosteroid-resistant, biopsy-proven acute rejection or treated for acute rejection with antibody rejection or treated for acute rejection with antibody therapy within 90 days prior to randomizationtherapy within 90 days prior to randomization
• Corticosteroid-sensitive acute rejection 30 days prior Corticosteroid-sensitive acute rejection 30 days prior to randomizationto randomization
• >1 Biopsy-proven acute rejection prior to study entry>1 Biopsy-proven acute rejection prior to study entry• SCr >2.5 mg/dL or CrCl <30 mL/min (Cockroft-SCr >2.5 mg/dL or CrCl <30 mL/min (Cockroft-
Gault) at study entryGault) at study entry• Total cholesterol levels >300 mg/dL or triglycerides Total cholesterol levels >300 mg/dL or triglycerides
>350 mg/dL>350 mg/dL
EndpointsEndpoints• PrimaryPrimary
– Mean percent change from baseline to 12 months Mean percent change from baseline to 12 months of measured GFR (cold iothalamate)of measured GFR (cold iothalamate)
• SecondarySecondary– Biopsy-proven acute rejection at 12 monthsBiopsy-proven acute rejection at 12 months– Treatment failure at 12 monthsTreatment failure at 12 months
• graft lossgraft loss• deathdeath• lost to follow-up/withdrawal of consentlost to follow-up/withdrawal of consent• need to resume CNI therapyneed to resume CNI therapy• dialysisdialysis• premature withdrawal due to adverse eventpremature withdrawal due to adverse event
– SafetySafety• All adverse events with a focus on hyperlipidemia and new All adverse events with a focus on hyperlipidemia and new
onset diabetesonset diabetes
Randomized Randomized N=298N=298
Patient Allocation (ITT)*Patient Allocation (ITT)*
MMF/CNIMMF/CNIN=150N=150
MMF/SRLMMF/SRLN=148N=148
TacrolimusTacrolimusWithdrawalWithdrawal
N=122N=122
CyclosporineCyclosporineWithdrawalWithdrawal
N=26N=26
TacrolimusTacrolimusN=119N=119
CyclosporineCyclosporineN=31N=31
*81% received tacrolimus and 19% received cyclosporine
MMF/CNIMMF/CNI
MMF/SRL MMF/SRL N=148N=148
TotalTotalN=150N=150
MMF/TACMMF/TACN=119N=119
Sex, n (%)*Sex, n (%)*
MaleMale FemaleFemale
93 (63%)93 (63%)55 (37%)55 (37%)
95 (63%)95 (63%)55 (37%)55 (37%)
75 (63%)75 (63%)44 (37%)44 (37%)
Race, n (%)*Race, n (%)*
CaucasianCaucasian 74 (50%)74 (50%) 74 (49%)74 (49%) 58 (49%)58 (49%)
African AmericanAfrican American 48 (32%)48 (32%) 50 (33%)50 (33%) 40 (34%)40 (34%)
OtherOther 26 (18%)26 (18%) 26 (17%)26 (17%) 21 (18%)21 (18%)
Age (years)*Age (years)*
Mean Mean SD SD 48.7 48.7 12.9 12.948.7 48.7
12.712.748.4 48.4 12.5 12.5
Patient DemographicsPatient Demographics
*P = NS for MMF/SRL vs MMF/CNI and for MMF/TAC vs MMF/CsA.
Baseline CharacteristicsBaseline Characteristics MMF/CNIMMF/CNI
MMF/SRL MMF/SRL N=148N=148
TotalTotalN=150N=150
MMF/TACMMF/TACN=119N=119
Type of donor, n (%)*Type of donor, n (%)*
Living relatedLiving related 41 (28%)41 (28%) 38 (25%)38 (25%) 29 (24%)29 (24%)
Living unrelatedLiving unrelated 19 (13%)19 (13%) 21 (14%)21 (14%) 19 (16%)19 (16%)
Deceased donorDeceased donor 88 (60%)88 (60%) 91 (61%)91 (61%) 71 (60%)71 (60%)
PRA level (highest assessment), n (%)*PRA level (highest assessment), n (%)*
0%0% 93 (63%)93 (63%) 91 (61%)91 (61%) 70 (59%)70 (59%)
1-19%1-19% 31 (21%)31 (21%) 27 (18%)27 (18%) 24 (20%)24 (20%)
>20%>20% 21 (14%)21 (14%) 27 (18%)27 (18%) 22 (19%)22 (19%)
Not known/missingNot known/missing 3 (2%)3 (2%) 5 (3%) 5 (3%) 3 (3%)3 (3%)
Time posttransplant to randomization*Time posttransplant to randomization*
Mean Mean ±± SD, Days SD, Days 113 113 ± 54± 54 116 ± 49116 ± 49
*P = NS for MMF/SRL vs MMF/CNI and for MMF/TAC vs MMF/CsA.
Induction Therapy, n (%)Induction Therapy, n (%)MMF/CNIMMF/CNI
MMF/MMF/SRLSRL
N=151N=151
TotalTotalN=150N=150
MMF/MMF/TACTAC
N=119N=119
Antithymocyte globulin Antithymocyte globulin 53 (35%)53 (35%) 53 (35%)53 (35%) 44 (37%)44 (37%)
BasiliximabBasiliximab 35 (23%)35 (23%) 44 (29%)44 (29%) 32 (27%)32 (27%)
DaclizumabDaclizumab 20 (13%)20 (13%) 13 (9%)13 (9%) 8 (7%)8 (7%)
Mycophenolate Mofetil DoseMycophenolate Mofetil Dose
MMF/SRL MMF/CNI
Mea
n D
ose
(m
g)
± S
D
BaselineN=140 N=139
Post-Randomization 1 MonthN=114 N=129
6 MonthsN=116 N=123
12 MonthsN=122 N=112
Tacrolimus Trough LevelsTacrolimus Trough LevelsM
ean
Tac
roli
mu
s C
on
cen
trat
ion
ng
/mL
(±
SE
M)
BaselineN=106
Post-Randomization 2 WeeksN=92
6 MonthsN=97
12 MonthsN=88
Cyclosporine Trough LevelsCyclosporine Trough LevelsM
ean
Cyc
losp
ori
ne
Co
nce
ntr
atio
nn
g/m
L (
± S
EM
)
BaselineN=30
Post-Randomization 2 WeeksN=23
6 MonthsN=26
12 MonthsN=26
Sirolimus Trough LevelsSirolimus Trough LevelsM
ean
Sir
oli
mu
s C
on
cen
trat
ion
ng
/mL
(±
SE
M)
Day 7N=123
Post-Randomization 1 MonthN=112
6 MonthsN=104
12 MonthsN=102
MMF/CNIMMF/CNI
MMF/SRL*MMF/SRL*N=148N=148
Total*Total*N=150N=150
MMF/MMF/TACTAC
N=119N=119
Biopsy-proven acuteBiopsy-proven acute rejectionrejection 10 (7%)10 (7%) 9 (6%)9 (6%) 7 (6%)7 (6%)
DeathDeath 0 (0%)0 (0%) 3 (2%)3 (2%) 2 (2%)2 (2%)
Graft lossGraft loss 3 (2%)3 (2%) 4 (3%)4 (3%) 3 (3%)3 (3%)
African AmericansAfrican Americans N=48*N=48* N=50*N=50* N=40N=40
Biopsy-proven acuteBiopsy-proven acute rejectionrejection 4 (8%)4 (8%) 4 (8%)4 (8%) 4 (10%)4 (10%)
Efficacy Outcomes, n (%)Efficacy Outcomes, n (%)
*P = NS for MMF/SRL vs. MMF/CNI.
Mean % Change in Measured GFRMean % Change in Measured GFR
Baseline to Month 12Baseline to Month 12
N = 118 N = 109
0
5
10
15
20
25
30
35
Mea
n P
erce
nt
Ch
ang
e ±
SE
M
MMF/SRL
MMF/CNI
7.8
Baseline GFRmL/min/1.7 m2 SEM 59.5 2.0 58.7 2.2
-5
P=0.013
25.7
Mean % Change in Measured GFR,Mean % Change in Measured GFR,African AmericansAfrican Americans
Baseline to Month 12Baseline to Month 12
N = 39 N = 39
Mea
n P
erce
nt
Ch
ang
e ±
SE
M
MMF/SRL
MMF/CNI
Baseline GFR(mL/min/1.7 m2) SEM 61.6 3.8 58.1 3.9
P=0.053
0.6
26.6
Other Renal Outcomes, Mean % ChangeOther Renal Outcomes, Mean % Change
MMF/CNIMMF/CNI P-ValueP-Value
MMF/SRLMMF/SRLN=148N=148
TotalTotal
N=150N=150MMF/TACMMF/TAC
N=119N=119
MMF/SRL MMF/SRL vsvs
TotalTotal
Calculated GFR, mL/minCalculated GFR, mL/min
Baseline, MeanBaseline, Mean±SEM ±SEM 71.371.3±1.2±1.2 72.772.7±1.3±1.3 74.174.1±1.5±1.5
% change, baseline to month 12 (n) % change, baseline to month 12 (n)
6.2 (121)6.2 (121) 1.1 (120)1.1 (120) -0.3 (94)-0.3 (94) 0.0690.069
Serum creatinine, Serum creatinine, umol/Lumol/L
Baseline, MeanBaseline, Mean±SEM±SEM 121.1121.1±2.5±2.5 137.4137.4±7.2±7.2 133.8133.8±8.0±8.0
% change, baseline to month 12 (n)% change, baseline to month 12 (n) 2.6 (122)2.6 (122) 11.8 (120)11.8 (120) 15.0 (94)15.0 (94) 0.0070.007
Calculated creatinine clearance, mL/minCalculated creatinine clearance, mL/min
Baseline, Mean±SEMBaseline, Mean±SEM 59.7±1.459.7±1.4 59.5±1.759.5±1.7 60.5±2.060.5±2.0
% change, baseline to month 12 (n)% change, baseline to month 12 (n) 5.2 (122)5.2 (122) -2.3 (120)-2.3 (120) -3.9 (94)-3.9 (94) 0.0120.012
Urinary Protein/Creatinine Ratio
MMF/SRL MMF/SRL MMF/CNIMMF/CNI
All Patients*All Patients* TotalTotal TAC WDTAC WD TotalTotal MMF/TACMMF/TAC
Baseline, MedianBaseline, Median2525thth, 75, 75th th percentiles (n)percentiles (n)
0.10.10.1, 0.2 (123) 0.1, 0.2 (123)
0.2 0.2 0.1, 0.2 (104) 0.1, 0.2 (104)
0.2 0.2 0.1, 0.2 (129)0.1, 0.2 (129)
0.2 0.2 0.1, 0.2 (102)0.1, 0.2 (102)
12 Months, Median12 Months, Median2525thth, 75, 75th th percentiles (n)percentiles (n)
0.20.20.1, 0.4 (106)0.1, 0.4 (106)
0.2 0.2 0.1, 0.4 (87)0.1, 0.4 (87)
0.1 0.1 0.1, 0.3 (110)0.1, 0.3 (110)
0.10.10.1, 0.2 (88)0.1, 0.2 (88)
African Americans**African Americans**
Baseline, MedianBaseline, Median2525thth, 75, 75th th percentiles (n)percentiles (n)
0.10.10.1, 0.2 (40) 0.1, 0.2 (40)
0.1 0.1 0.1, 0.2 (37) 0.1, 0.2 (37)
0.1 0.1 0.1, 0.3 (44)0.1, 0.3 (44)
0.2 0.2 0.1, 0.3 (35)0.1, 0.3 (35)
12 Months, Median12 Months, Median2525thth, 75, 75th th percentiles (n)percentiles (n)
0.20.20.1, 0.6 (34)0.1, 0.6 (34)
0.2 0.2 0.1, 0.6 (29)0.1, 0.6 (29)
0.1 0.1 0.1, 0.3 (40)0.1, 0.3 (40)
0.10.10.1, 0.2 (33)0.1, 0.2 (33)
MMF/SRL vs. MMF/CNI: Baseline, P=NS; 12 Months, *P=0.096; **P=0.043.
MMF/CNIMMF/CNI
MMF/SRLMMF/SRLN=148N=148
TotalTotalN=150N=150
MMF/TACMMF/TACN=119N=119
Treatment failure*Treatment failure* 44 (30%)44 (30%) 35 (23%)35 (23%) 30 (25%)30 (25%)
Reason for treatment failureReason for treatment failure
Death Death 0 (0%)0 (0%) 2 (1%)2 (1%) 1 (1%)1 (1%)
Withdrawal due to AEWithdrawal due to AE 23 (16%)23 (16%) 10 (7%)10 (7%) 8 (7%)8 (7%)
Need to resume CNINeed to resume CNI 5 (3%)5 (3%) 0 (0%)0 (0%) 0 (0%)0 (0%)
Need to withdraw therapyNeed to withdraw therapy 5 (3%)5 (3%) 11 (7%)11 (7%) 11 (9%)11 (9%)
Lost to follow-upLost to follow-up 10 (7%)10 (7%) 12 (8%)12 (8%) 10 (8%)10 (8%)
Withdrew consentWithdrew consent 1 (1%)1 (1%) 0 (0%)0 (0%) 0 (0%)0 (0%)
Treatment Failure, n (%)Treatment Failure, n (%)
*Events are mutually exclusive; only the first event counted per patient.*P = NS for MMF/SRL vs. MMF/CNI.
MMF/SRLMMF/SRLN=148N=148
MMF/CNIMMF/CNIN=153N=153
DiarrheaDiarrhea 50 (34%)50 (34%) 47 (31%)47 (31%)
Peripheral edemaPeripheral edema 39 (26%)39 (26%) 20 (13%)20 (13%)
HyperlipidemiaHyperlipidemia 35 (24%)35 (24%) 13 (8%)13 (8%)
LeukopeniaLeukopenia 33 (22%)33 (22%) 29 (19%)29 (19%)
AnemiaAnemia 23 (16%)23 (16%) 18 (12%)18 (12%)
HypertensionHypertension 23 (16%)23 (16%) 12 (8%)12 (8%)
Mouth ulcerationMouth ulceration 21 (14%)21 (14%) 0 (0%)0 (0%)
HypokalemiaHypokalemia 20 (14%)20 (14%) 6 (4%)6 (4%)
Upper respiratory tract infectionUpper respiratory tract infection 19 (13%)19 (13%) 16 (10%)16 (10%)
CoughCough 16 (11%)16 (11%) 16 (10%)16 (10%)
Serum creatinine increasedSerum creatinine increased 13 (9%)13 (9%) 31 (20%)31 (20%)
Urinary tract infectionsUrinary tract infections 20 (14%)20 (14%) 30 (20%)30 (20%)
Opportunistic infectionsOpportunistic infections 16 (11%)16 (11%) 27 (18%)27 (18%)
Adverse Events Post-randomization in >10% of Patients, n (%)Adverse Events Post-randomization in >10% of Patients, n (%)
MMF/SRLMMF/SRLN=148N=148
MMF/CNIMMF/CNIN=153N=153
Mouth ulcerationMouth ulceration 7 (6%)7 (6%)
ProteinuriaProteinuria 3 (2%)3 (2%)
Focal segmental Focal segmental glomerulosclerosisglomerulosclerosis
2 (1%)2 (1%)
LeukopeniaLeukopenia 2 (1%)2 (1%)
DiarrheaDiarrhea 1 (<1%)1 (<1%) 4 (3%)4 (3%)
BK virus infectionBK virus infection 3 (2%)3 (2%)
Blood creatinine increasedBlood creatinine increased 1 (<1%)1 (<1%) 2 (1%)2 (1%)
AlopeciaAlopecia 2 (1%)2 (1%) 2 (1%)2 (1%)
Select Adverse Events Causing Withdrawal, n (%)
ACEI and ARB
• Preferred treatment strategies
antihypertensive
antiproteinuric
antiproliferative
ACEI and ARB Trade-offs
• HCT lower by about 5-15%
• Increased K+ (0.3-0.5 meq/l)
• GFR reduced by 15-20%
• Fire Drill
Conclusions
• Need same standard for systolic/diastolic blood pressure control as indicated in JNC 7: less than 130/80 mmHg, or lower if evidence of clinical proteinuria
• Routine use of RAAS blockade drugs
• Effective anti-proteinuric strategies
• Careful attention to all CV risk reduction strategies; they also impact on renal function
ConclusionsConclusions
• Modification of immunosuppression is important in some patients to avoid progressive loss of kidney function.
• Protecting the kidney protects the heart!