Allograft Nephropathy and Cardiovascular Disease: Important for Graft and Patient Survival Implicati

1
Allograft Nephropathy and Cardiovascular
DiseaseImportant 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

2
Leading Causes of Graft Failure

• CVD (also known as death with functioning graft)
• Allograft Nephropathy
• Are they related?

3
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

4

• 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
2000111735-1743
5
Observed and Expected Risk for Ischemic Heart
Disease after Renal Transplantation
1.00
0.90
0.80

0.70
10-year survival without IHD
0.60
0.50
0.40
Older Younger
Older Younger
Older Younger
Older Younger
--Diabetic--
-Non-Diabetic-
Diabetic
-Non-diabetic-
----------Smoker----------
----------Non-Smoker----------
6
This raises even more questions about the rigor
of our approach to CV risk reduction in
transplant patients, particular if they have
diabetes!
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Cardiovascular Risk Profile of the Renal
Transplant Recipient

• Hypertension
• Diabetes
• Dyslipidemia
• Renal Disease

8
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

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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)

11
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.

12
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

13
Renal function as an endpoint a historical
perspective

• 1978 Opelz et al examined all primary grafts at
  105 centers between 1971 and 1976 (n 4000)
• Renal function at all time points (d1, wk1, m1)
  was correlated with graft survival
• 33 of graft failed lt 30 days and 1 year graft
  survival 40-50

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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 (Scr4mg/dl)

Meier-Kriesche, Kaplan et al. Transplantation 2003
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Cardiovascular Death Events in 48,832 KTX by SCr
at One Year Post Transplant
100
98
Scr mg/dl _at_1 /RR
96
lt1.3
1.0 1.03 1.19 1.37 1.49 1.67 2.26
1.3-1.4
1.5-1.6
Cardiovascular death free survival
1.7-1.8
94
1.9-2.1
2.2-2.5
92
2.6-4.0
90
12
24
36
48
60
72
84
96
108
120
0
months post-transplant
Meier-Kriesche, Kaplan et al. Transplantation 2003
16
Conclusions

• independent association between decreased renal
  function and increased risk for cardiovascular
  death exists
• The degree of renal failure was strongly
  correlated to the risk for cardiovascular death

17
Renal function is a natural candidate for a
surrogate marker of graft loss
Era of 1988 to 1994, both acute rejection rates
and graft survival rates were improving
Functional cadaveric renal allograft survival
(censored for death with a functioning
graft) after the first year following
transplantation, by year of transplant. Harihara
n S. NEJM 2000 342605.
Better intercept or improving slope?
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Distribution of Serum Creatinine at 1 year post
deceased donor kidney transplantation (donor
agelt50 yrs)
N 54,388
lt1.5 1.6-2.5 gt2.5 NA

Transplant Year
Hariharan S. NEJM 2000 342605.
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ALTERNATIVE MECHANISMS FOREARLY KIDNEY GRAFT
FAILURE
Good Function
Ccr
Accelerated Slope
Reduced Intercept
Ccr at return to dialysis
Time
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The of patients with a negative slope of GFR
after 6m has decreased
Transplant year
1990- 93
1994-1996
1997-2000
0
Gourishankar, JASN 2003
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What is graph for the current population?
Transplant year
1990- 93
1994-1996
1997-2000
0
Gourishankar, JASN 2003
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A shift in conceptual frameworks challenging
traditional assumptions

• Early function (slope) predicts late function
  (slope) ie. worse early function results in more
  aggressive deterioration of function
• Graft loss is inevitable following kidney
  transplant as the average slope is decreasing

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There is no relationship between early and late
slope
The average early slope was -1.38 9.66
ml/min/year and subsequent slope was -1.62 9.81
ml/min/year
Gourishankar and Hunsicker 2007 ASN SU-PO438,
475, 219
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Stable over the years possible recent improvement
with long term positive slope increased to 50
of recipients experiencing slopes gt0 ml/min/yr
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Conclusions

• In over half of kidney and kidney-pancreas
  transplant recipients, the slope is less negative
  than -1 ml/min/year or even positive.
• These data show that the rate of loss of kidney
  function (GFR) for the first 3 years following
  kidney and kidney-pancreas transplant does not
  predict the subsequent rate of loss.
• The loss of GFR early or late following kidney
  and kidney-pancreas transplantation is not
  inevitable and any loss of GFR should be
  explained.

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Summary

• Renal function can be used as a new endpoint in
  kidney transplantation interpreted in the form of
  slopes and intercepts
• The majority of the action occurs after 6
  months baseline factors are poorly predictive of
  long-term outcomes
• The stability of renal function after kidney
  transplantation is improving
• Loss of graft function is not inevitable
  following kidney transplantation

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Renal Autoregulation

• How low should you go?
• What drugs should you use?
• Short-term, long-term concerns?

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Glomerular Structure
Capillary Loop
Mesangial Cell
Endothelial Cell
Afferent Arteriole
Efferent Arteriole
Juxtaglomerular Apparatus
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Implications of Microalbuminuria or Proteinuria?
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Schematic of Events With Microalbuminuria/Proteinu
ria
Decreased nephron mass
Glomerular-capillary hypertension
? Mechanical stretch and strain
Increased filtration of plasma proteins
Proteinuria
? Activation angiotensin II and transforming
growth factor ß1
Excessive tubular reabsorption of protein
Release of vasoactive and inflammatory substances
into the interstitium
Increased synthesis of Type IV collagen
Fibroblast proliferation
Interstitial inflammatory reaction
Glomerulosclerosis and fibrosis
32
Cardiovascular Events byDegree of Albuminuria in
HOPE
30
Microalbuminuria threshold
All participants
With diabetes
25
Without diabetes
20
Incidence ()
15
10
5
0
1 and 2
3
4
5
6
7
8
9
10
Albumin/Creatinine Ratio Deciles
Gerstein HC et al. JAMA. 2001286421-426.
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Multivariate Hazard Ratios forPrimary Outcome in
HOPE
Microalbuminuria
1.59
CAD
1.51
Diabetes
1.42
1.4
Creatinine ?1.4 mg/dL
Male
1.20
WHR (0.1)
1.13
Age (1y)
1.03
Ramipril
0.79
2
0
1
Hazard Ratio
HOPE Study Investigators. N Engl J Med.
2000342145-153.
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Microalbuminuria Resets the Focus on CV Risk
Reduction Strategies

• BP lt130/80 mmHg
• Evaluate lipids
• Extinguish microalbuminuria
• Reduction in dietary salt/saturated fat
• Intensify glycemic control
• ASA

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Opelz G, et al Kidney Int 199853217-222
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Allograft Nephropathy

• Hypertension/proteinuria/declining kidney
  function are the hallmarks of this disease
  process
• Need for specific antihypertensive,
  antiproteinuric approaches?
• Modification of immunosuppression

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Chronic Rejection of Renal Allografts
Impact of Early Events
Ischemia/Reperfusion
Acute Rejection
CMV and Other Infections
INJURY
LOSS OF NEPHRONMASS
Donor Factors
Adhesion Molecules, Cytokines, Growth Factors
CHRONIC GRAFTDYSFUNCTION
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Alloantigen-DependentMechanisms
Alloantigen-IndependentMechanisms
Brain deathIschemia/reperfusion
injuryInadequate renal mass(donor age, gender,
race, organ size)Hypertension and
hyperlipidemiaDrug nephrotoxicityCMV, other
infections
HLA matchingAcute rejectionOngoing subclinical
immunologic injury

• Allorecognition

APC

• Costimulation

T Cell
Cytokines
Macrophage
Cytokines Growth factors
B Cell
Antibodies
Effector mechanisms
Chronic rejection
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Lumenal Obliteration Due to Vasculopathy in
Chronic Allograft Nephropathy
40
Tubulointerstitial Fibrosis and Scarring in
Chronic Allograft Nephropathy
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Calcineurin Inhibitors

• CSA vs FK
• Mechanism of Action
• Calcineurin inhibition
• Sympathetic nervous stimulation
• Nephrotoxicity
• Glomerular hemodynamics
• Salt sensitivity

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Calcineurin inhibitors and hemodynamic effects
? extracellularmatrix deposition
.
? Ang II
? TG F-?
?? apoptosis
Direct effect ? ET-1 ? Sympathetic tone ?
Thromboxane A2 ? NO ? Prostaglandins ?
Prostacyclins
CsA
? Renal ischemia and injury
Vasoconstriction
interstitialcell proliferation followed
byApoptosis
Apoptosis gt gt Proliferation
Hypocellular lesions inareas of fibrosis
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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 200761572-1583
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Weir MR, et. al. Am J Nephrol 200424379-386
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Demographics (n125)
Wali RK, et al. Am J Transplant 200761572-1583
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Demographics (contd) (n125)
Wali RK, et al. Am J Transplant 200761572-1583
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Pre / Post Conversion BUN Creatinine
Wali RK, et al. Am J Transplant 200761572-1583
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Changes in GFR (Nankivell Formula) after
Conversion (? pre-post GFR ml/min)
Wali RK, et al. Am J Transplant 200761572-1583
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Demographic Factors
Wali RK, et al. Am J Transplant 200761572-1583
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Kaplan-Meier graph for graft loss Log Rank
p.0003
1.2
1.0
?gt16 (n79)
.8
Percentage survival
? 1-15 (n39)

.6
? zero or less (n7)

.4
.2
0.0
40
30
20
10
0
Graft Loss during the follow up
Wali RK, et al. Am J Transplant 200761572-1583
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Study Objective
To evaluate combination mycophenolate mofetil
(MMF) and sirolimus (SRL) as a calcineurin
inhibitor (CNI)-free regimen for renal function
preservation in renal allograft recipients
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Trial Design
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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

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Key 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

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Key Exclusion Criteria

• Corticosteroid-resistant, biopsy-proven acute
  rejection or treated for acute rejection with
  antibody therapy within 90 days prior to
  randomization
• Corticosteroid-sensitive acute rejection 30 days
  prior to randomization
• gt1 Biopsy-proven acute rejection prior to study
  entry
• SCr gt2.5 mg/dL or CrCl lt30 mL/min
  (Cockroft-Gault) at study entry
• Total cholesterol levels gt300 mg/dL or
  triglycerides gt350 mg/dL

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Endpoints

• Primary
• Mean percent change from baseline to 12 months of
  measured GFR (cold iothalamate)
• Secondary
• Biopsy-proven acute rejection at 12 months
• Treatment failure at 12 months
• graft loss
• death
• lost to follow-up/withdrawal of consent
• need to resume CNI therapy
• dialysis
• premature withdrawal due to adverse event
• Safety
• All adverse events with a focus on hyperlipidemia
  and new onset diabetes

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Patient Allocation (ITT)
Randomized N298
MMF/SRL N148
MMF/CNI N150
Tacrolimus Withdrawal N122
Cyclosporine Withdrawal N26
Tacrolimus N119
Cyclosporine N31
81 received tacrolimus and 19 received
cyclosporine
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Patient Demographics
P NS for MMF/SRL vs MMF/CNI and for MMF/TAC vs
MMF/CsA.
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Baseline Characteristics
P NS for MMF/SRL vs MMF/CNI and for MMF/TAC vs
MMF/CsA.
60
Induction Therapy, n ()
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Mycophenolate Mofetil Dose
MMF/SRL
MMF/CNI
Mean Dose (mg) SD
Baseline N140 N139
Post-Randomization
1 Month N114 N129
6 Months N116 N123
12 Months N122 N112
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Tacrolimus Trough Levels
Mean Tacrolimus Concentration ng/mL ( SEM)
Baseline N106
Post-Randomization
2 Weeks N92
6 Months N97
12 Months N88
63
Cyclosporine Trough Levels
Mean Cyclosporine Concentration ng/mL ( SEM)
Baseline N30
Post-Randomization
2 Weeks N23
6 Months N26
12 Months N26
64
Sirolimus Trough Levels
Mean Sirolimus Concentration ng/mL ( SEM)
Day 7 N123
Post-Randomization
1 Month N112
6 Months N104
12 Months N102
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Efficacy Outcomes, n ()
P NS for MMF/SRL vs. MMF/CNI.
66
Mean Change in Measured GFR
Baseline to Month 12
P0.013
35
MMF/SRL
30
MMF/CNI
25
25.7
20
Mean Percent Change SEM
15
10
7.8
5
0
N 118
N 109
-5
Baseline GFR mL/min/1.7 m2 ? SEM
59.5 ? 2.0
58.7 ? 2.2
67
Mean Change in Measured GFR,African Americans
Baseline to Month 12
P0.053
MMF/SRL
MMF/CNI
26.6
Mean Percent Change SEM
0.6
N 39
N 39
Baseline GFR (mL/min/1.7 m2) ? SEM
61.6 ? 3.8
58.1 ? 3.9
68
Other Renal Outcomes, Mean Change
69
Urinary Protein/Creatinine Ratio
MMF/SRL vs. MMF/CNI Baseline, PNS 12 Months,
P0.096 P0.043.
70
Treatment Failure, n ()
Events are mutually exclusive only the first
event counted per patient. P NS for MMF/SRL
vs. MMF/CNI.
71
Adverse Events Post-randomization in gt10 of
Patients, n ()

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Select Adverse Events Causing Withdrawal, n ()
73

• Why is there improvement in the renal histology
  with CSA or FK reduction or withdrawal?

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ACEI and ARB

• Preferred treatment strategies
• antihypertensive
• antiproteinuric
• antiproliferative

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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

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Study Design
Open label, randomized clinical trial to compare
the effects of ARB plus other drugs (non-ACE
inhibitor) versus CCB plus other drugs (non-ACE
inhibitor) on renal function and histology in
patients with CAN (who already were on reduced
dose calcineurin inhibitor).
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Interim Report

• 30 patients (ARB, n16 CCB (n14)
• Only reporting biopsy data
• Years post-TX 6.1
• Mean serum creatinine 3.5 mg/dl
• Mean blood pressure 127/78 mmHg

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BIOPSY RESULTS
plt0.05 vs 1 Bx
79
BIOPSY RESULTS
plt0.05 vs 1 Bx
80
Conclusions
Within 1 year of treatment, ARB attenuates renal
tissue expression of AII, TGF-beta, its receptor
and decreases DNA damage as well as apoptosis,
and increases DNA repair protein. This
therapeutic strategy may prove to be helpful in
preventing progression of CAN in a fashion
analogous to what has been described with ACE
inhibitor and AT1 blockers in patients with
diabetic and non-diabetic nephropathy.
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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

82
Conclusions

• Modification of immunosuppression is important in
  some patients to avoid progressive loss of kidney
  function.
• Protecting the kidney protects the heart!