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

Observed and Expected Risk for Ischemic Heart Disease after Renal Transplantation

1.00

0.90

0.80

0.70

0.60

0.50

0.40

Older Younger --Diabetic- Older Younger Older Younger Older Younger -Non-Diabetic ----------Smoker--------- Diabetic -Non-diabetic ----------Non-Smoker----------

This raises even more questions about the rigor of our approach to CV risk reduction in transplant patients, particular if they 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

Cardiovascular Death Events in 48,832 KTX by SCr at One Year Post Transplant 100 98 96 94

Scr mg/dl @1 /RR <1.3

1.3-1.4

1.5-1.6

1.7-1.8

1.9-2.1

1.0

1.03

1.19

1.37

1.49

2.2-2.5

1.67

92 90

0 12 24 36 48 60 72 84 96 108 120 2.6-4.0

2.26

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.

Hariharan S. NEJM 2000; 342:605.

Better intercept or improving slope?

ALTERNATIVE MECHANISMS FOR EARLY KIDNEY GRAFT FAILURE

Good Function Ccr Reduced Intercept Ccr at return to dialysis Time Accelerated Slope

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 by Degree of Albuminuria in HOPE

30 25 All participants With diabetes Without diabetes Microalbuminuria threshold 20 Incidence (%) 15 10 5 0 1 and 2 3 4 5 6 7 8 Albumin/Creatinine Ratio Deciles Gerstein HC et al. JAMA. 2001;286:421-426.

9 10

Multivariate Hazard Ratios for Primary Outcome in HOPE

Microalbuminuria CAD Diabetes Creatinine



1.4 mg/dL Male WHR (0.1) Age (1y) Ramipril 0 1.20

1.13

1.03

1.59

1.51

1.42

1.4

0.79

1 Hazard Ratio 2 HOPE Study Investigators. N Engl J Med. 2000;342:145-153.

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 INJURY Donor Factors LOSS OF NEPHRON MASS

Adhesion Molecules, Cytokines, Growth Factors

CHRONIC GRAFT DYSFUNCTION

Alloantigen-Dependent Mechanisms Alloantigen-Independent Mechanisms

HLA matching Acute rejection Ongoing subclinical immunologic injury T Cell • Allorecognition • Costimulation Cytokines APC B Cell Macrophage Antibodies Cytokines Growth factors Endothelium Brain death Ischemia/reperfusion injury Inadequate renal mass (donor age, gender, race, organ size) Hypertension and hyperlipidemia Drug nephrotoxicity CMV, other infections Effector mechanisms Chronic rejection

Lumenal Obliteration Due to Vasculopathy in Chronic Allograft Nephropathy

Tubulointerstitial Fibrosis and Scarring in Chronic Allograft Nephropathy

Calcineurin inhibitors and

CsA  Ang II Direct effect  ET-1  Sympathetic tone  Thromboxane A 2  NO  Prostaglandins  Prostacyclins  TG F   extracellular matrix deposition ?

 apoptosis Vasoconstriction  Renal ischemia and injury interstitial cell proliferation followed by Apoptosis Apoptosis > > Proliferation Hypocellular lesions in areas of fibrosis

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

Mean age in years (±SD) Gender—Males, number (%) Ethnic origin—number (%) Caucasians African American Others Cause of ESRD—number (%) Diabetes mellitus Hypertension Others

(n=125)

50.3 ± 14.2

75 (60) 56 (44.8) 67 (53.6) 2 (1.6) 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

4 3 2 6 5 1 0 Pre 1 Pre 2 SRL initiation 3 6

Time in months

Cr BUN 12 18 24 50 40 30 20 10 0

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 Δ >16 Ml/min p (n=39) (n=79) 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 Factors

All (n=125) Δ 0 (n=7) Δ 1-15 ml (n=39) Δ >16 ml (n=79) Age p 50.3

± 14.2 48.2 ± 21 51.7

± 14.7 49.7

± 13.5

.72

Time post-tx (months) 5.4

± 5.6

22 (17.6) Acute rejection Follow up (months) 17.1 ± 7.8

10.2

± 1 (14) 7.2 5.9 ± 8 (20) 5.2

19.8

± 6.4 16.3 ± 8.1

4.6 ± 5.4

13 (16) 17.3 ± 7.7

.03

.07

.51

Wali RK, et al. Am J Transplant 2007;6:1572-1583

1.2

1.0

.8

.6

.4

.2

0.0

0

Kaplan-Meier graph for graft loss:

Log Rank p=.0003

Δ>16 (n=79) Δ 1-15 (n=39) Δ zero or less (n=7)

10 20 30 40 Graft Loss during the follow up

Wali RK, et al. Am J Transplant 2007;6:1572-1583

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

Trial Design

Pre-randomization MMF + tacrolimus MMF + cyclosporine 30 – 180 D A Y S P O S T T X Patient screening and enrollment Post-randomization MMF + tacrolimus MMF + sirolimus MMF + cyclosporine MMF + sirolimus 2 years 1 year

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 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 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 >1 Biopsy-proven acute rejection prior to study entry SCr >2.5 mg/dL or CrCl <30 mL/min (Cockroft Gault) at study entry Total cholesterol levels >300 mg/dL or triglycerides >350 mg/dL

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

Patient Allocation (ITT)*

Randomized N=298 MMF/SRL N=148 MMF/CNI N=150 Tacrolimus Withdrawal N=122 Cyclosporine Withdrawal N=26 Tacrolimus N=119 Cyclosporine N=31 *81% received tacrolimus and 19% received cyclosporine

Patient Demographics

MMF/CNI MMF/SRL N=148 Total N=150 MMF/TAC N=119 Sex, n (%)* Male Female Race, n (%)* Caucasian African American 93 (63%) 55 (37%) 74 (50%) 48 (32%) 95 (63%) 55 (37%) 74 (49%) 50 (33%) 75 (63%) 44 (37%) 58 (49%) 40 (34%) Other Age (years)* 26 (18%) 26 (17%) Mean



SD 48.7



12.9

48.7



12.7

*P = NS for MMF/SRL vs MMF/CNI and for MMF/TAC vs MMF/CsA.

21 (18%) 48.4



12.5

Baseline Characteristics

MMF/SRL N=148 Type of donor, n (%)* Living related Living unrelated 41 (28%) 19 (13%) Deceased donor 88 (60%) PRA level (highest assessment), n (%)* 0% 1-19% >20% Not known/missing 93 (63%) 31 (21%) 21 (14%) 3 (2%) Time posttransplant to randomization* Mean ± SD, Days 113 ± 54 MMF/CNI Total N=150 38 (25%) 21 (14%) 91 (61%) 91 (61%) 27 (18%) 27 (18%) 5 (3%) *P = NS for MMF/SRL vs MMF/CNI and for MMF/TAC vs MMF/CsA.

116 MMF/TAC ± N=119 29 (24%) 19 (16%) 71 (60%) 70 (59%) 24 (20%) 22 (19%) 3 (3%) 49

Induction Therapy, n (%)

MMF/SR L N=151 MMF/CNI Total N=150 MMF/TA C N=119 Antithymocyte globulin Basiliximab Daclizumab 53 (35%) 35 (23%) 20 (13%) 53 (35%) 44 (29%) 13 (9%) 44 (37%) 32 (27%) 8 (7%)

Mycophenolate Mofetil Dose

MMF/SRL MMF/CNI Post-Randomization Baseline N=140 N=139 1 Month N=114 N=129 6 Months N=116 N=123 12 Months N=122 N=112

Tacrolimus Trough Levels

Post-Randomization Baseline N=106 2 Weeks N=92 6 Months N=97 12 Months N=88

Cyclosporine Trough Levels

Post-Randomization Baseline N=30 2 Weeks N=23 6 Months N=26 12 Months N=26

Sirolimus Trough Levels

Post-Randomization Day 7 N=123 1 Month N=112 6 Months N=104 12 Months N=102

Efficacy Outcomes, n (%)

MMF/SRL* N=148 MMF/CNI Total* N=150 MMF/TA C N=119 Biopsy-proven acute rejection Death Graft loss 10 (7%) 0 (0%) 3 (2%) 9 (6%) 3 (2%) 4 (3%) 7 (6%) 2 (2%) 3 (3%) African Americans Biopsy-proven acute rejection *P = NS for MMF/SRL vs. MMF/CNI.

N=48* 4 (8%) N=50* 4 (8%) N=40 4 (10%)

Mean % Change in Measured GFR

Baseline to Month 12 P

=

0.013

35 30 25 20 15 10 5 0 -5 Baseline GFR mL/min/1.7 m 2



SEM 25.7

N = 118 59.5



2.0

7.8

N = 109 58.7



2.2

MMF/SRL MMF/CNI

Mean % Change in Measured GFR, African Americans Baseline to Month 12 P

=

0.053

MMF/SRL MMF/CNI 26.6

0.6

Baseline GFR (mL/min/1.7 m 2 )



SEM N = 39 61.6



3.8

N = 39 58.1



3.9

Other Renal Outcomes, Mean % Change MMF/SRL N=148 Calculated GFR, mL/min Baseline, Mean ± SEM 71.3

± 1.2

% change, baseline to month 12 (n) 6.2 (121) Serum creatinine, umol/L Baseline, Mean ± SEM % change, baseline to month 12 (n) 121.1

± 2.5

2.6 (122) Calculated creatinine clearance, mL/min Baseline, Mean ± SEM 59.7

± 1.4

% change, baseline to month 12 (n) 5.2 (122) MMF/CNI Total N=150 72.7

± 1.3

1.1 (120) 137.4

± 7.2

11.8 (120) 59.5

± 1.7

-2.3 (120) MMF/TAC N=119 74.1

± 1.5

-0.3 (94) 133.8

± 8.0

15.0 (94) 60.5

± 2.0

-3.9 (94) P-Value MMF/SRL vs Total 0.069

0.007

0.012

MMF/SRL MMF/CNI Urinary Protein/Creatinine Ratio

All Patients*

Total TAC WD Total MMF/TAC Baseline, Median 25 th , 75 th percentiles (n) 12 Months, Median 25 th , 75 th percentiles (n) 0.1

0.1, 0.2 (123) 0.2

0.1, 0.4 (106) 0.2 0.1, 0.2 (104) 0.2 0.1, 0.4 (87) 0.2 0.1, 0.2 (129) 0.1 0.1, 0.3 (110) 0.2 0.1, 0.2 (102) 0.1

0.1, 0.2 (88) African Americans** Baseline, Median 25 th , 75 th percentiles (n) 12 Months, Median 25 th , 75 th percentiles (n) 0.1

0.1, 0.2 (40) 0.2

0.1, 0.6 (34) 0.1 0.1, 0.2 (37) 0.2 0.1, 0.6 (29) 0.1 0.1, 0.3 (44) 0.1 0.1, 0.3 (40) 0.2 0.1, 0.3 (35) 0.1

0.1, 0.2 (33) MMF/SRL vs. MMF/CNI: Baseline, P=NS; 12 Months, *P=0.096; **P=0.043.

Treatment failure* Treatment Failure, n (%) MMF/CNI MMF/SRL N=148 Total N=150 MMF/TAC N=119 44 (30%) 35 (23%) 30 (25%) Reason for treatment failure Death Withdrawal due to AE Need to resume CNI Need to withdraw therapy 0 (0%) 23 (16%) 5 (3%) 5 (3%) Lost to follow-up 10 (7%) Withdrew consent *Events are mutually exclusive; only the first event counted per patient.

*P = NS for MMF/SRL vs. MMF/CNI.

1 (1%) 2 (1%) 10 (7%) 0 (0%) 11 (7%) 12 (8%) 0 (0%) 1 (1%) 8 (7%) 0 (0%) 11 (9%) 10 (8%) 0 (0%)

Adverse Events Post-randomization in >10% of Patients, n (%) Diarrhea Peripheral edema Hyperlipidemia Leukopenia Anemia Hypertension Mouth ulceration Hypokalemia Upper respiratory tract infection Cough Serum creatinine increased Urinary tract infections Opportunistic infections MMF/SRL N=148 50 (34%) 39 (26%) 35 (24%) 33 (22%) 23 (16%) 23 (16%) 21 (14%) 20 (14%) 19 (13%) 16 (11%) 13 (9%) 20 (14%) 16 (11%) MMF/CNI N=153 47 (31%) 20 (13%) 13 (8%) 29 (19%) 18 (12%) 12 (8%) 0 (0%) 6 (4%) 16 (10%) 16 (10%) 31 (20%) 30 (20%) 27 (18%)

Select Adverse Events Causing Withdrawal, n (%) Mouth ulceration Proteinuria Focal segmental glomerulosclerosis Leukopenia Diarrhea BK virus infection Blood creatinine increased Alopecia MMF/SRL N=148 7 (6%) 3 (2%) MMF/CNI N=153 2 (1%) 2 (1%) 1 (<1%) 1 (<1%) 2 (1%) 4 (3%) 3 (2%) 2 (1%) 2 (1%)

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

Conclusions

• Modification of immunosuppression is important in some patients to avoid progressive loss of kidney function.

• Protecting the kidney protects the heart!