matthew r. weir, m.d. professor and director division of nephrology

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!