Prevention of Renal Impairment in Liver Allograft Recipients

1
Prevention of Renal Impairment in Liver Allograft
Recipients

• James M. Neuberger
• Queen Elizabeth HospitalBirmingham, UK

2
Disclosure

• I have received support from
• Roche
• Astellas
• Novartis
• Bristol Myers Squibb

3
Kaplan-Meier estimates by year of transplant
4
Kaplan-Meier estimates by year of transplant
5
Overall average life expectancy
6
Average life expectancy by sex and age group
53.7
48.3
10.9 life-years lost
41.2
15.7 life-years lost
36.5
35.6
31.9
30.3
28.8
27.9
24.0
23.5
1.7 life-years lost
20.8
20.2
20.3
18.6
17.3
6.7 life-years lost
16.1
15.6
14.8
8.1
7
Average life expectancy by primary liver
disease
8
Average life expectancy for male recipients by
age group and primary liver disease
9
Life-years for male recipients by age group and
primary liver disease
10
Why is patient survival not corrected by
transplantation

• Cardiovascular and cerebrovascular disease (2-3
  fold increase)
• Malignancy
• Recurrent disease
• Renal disease

11
Overall cancer incidence (excluding NMSC)
Transplanted patients
adjusted for age group, gender and time period
12
Overall cancer incidence (excluding NMSC)
Transplanted patients
Population
adjusted for age group, gender and time period
13
Incidence rates
Number of cases per 1000 patients
Years since transplantation Transplant recipients British population
5 36 17
10 90 39
15 147 63
Transplant recipients have more than twice the
risk of a cancer other than NMSC
14
SIRs for malignancy
Cancer site Transplant type Transplant type Transplant type Transplant type
Kidney Liver Heart Lung
All cancers (exc NMSC) 2.4 2.2 2.5 3.6
Skin NMSC 16.6 6.6 18.5 16.1
Lip 65.6 20.0 60.0 -
Hodgkin's lymphoma 7.4 8.9 11.4 5.0
Non-Hodgkins lymphoma 12.5 13.3 19.8 30.0
Breast 1.0 0.8 0.8 0.3
Oral cavity 4.2 10.0 5.0 5.0
Colorectal 1.8 2.3 1.1 1.1
Anus 10.0 3.3 7.5 20.0
Liver 2.4 - 1.2 10.0
Lung and bronchus 1.4 1.6 2.1 5.9
Kaposi sarcoma 17.1 0.0 10.0 -
Kidney 7.9 1.8 4.4 2.5
Multiple myeloma 3.3 0.8 3.2 2.5

Entries in black plt0.05
15
Trends in SIRs - all cancers(excluding NMSC)
Lung Heart Kidney Liver
Different patterns for different transplant types
16
Graft loss from Recurrence
17
Causes of Renal Dysfunction in liver disease and
after transplantation

• Pretransplant renal damage
• Renal artery stenosis
• Glomerulonephritis
• Hepatitis C infection, IgA deposition
• Hypertension
• Diabetes mellitus
• Drugs
• Calcineurin inhibitors (CNIs)
• Non-steroid anti-inflammatory drugs (NSAIDs)
• Others

18
Assessment of Renal Function

• Serum Creatinine and Urea
• Cockcroft-Gault
• MDRD (Modification of Diet in Renal Disease)
• 24h urine creatinine excretion

19
Assessment of Renal Function

• Formulae that use creatinine, urea, body weight,
  albumin may be unreliable in liver disease and
  after transplantation
• Liver disease affects creatinine levels
• Ascites and fluid retention affects body weight
• Bilirubin may affect measurement of creatinine
• Interpretation uncertain in Females,
  Afro-Caribbean and Afro-American

20
Assessment of Renal Function

• Direct measurement is more accurate
• Cr EDTA
• Inulin
• Iothalamate
• Lohexol
• But more expensive and time consuming

21
Other measures

• ACR
• ACRgt30mg/mmol or urine protein gt0.5g/24h reflects
  parenchymal disease and is associated with
  increased cardiovascular morbidity and mortality
• In Diabetes, ACR gt2.5 in men or gt3.5 in women is
  significant
• Cystatin C
• Good correlation with GFR
• Independent of age, body weight, height or
  composition
• Affected by steroids, male gender, smoking, CRP

22
Renal Histology

• Main arbiter of cause of renal impairment
• Histological features of CNI nephrotoxicity not
  well defined
• Cost
• Risk

23
Renal function is associated with increased
mortality before and after transplant
24
Does pre-LT renal function predict outcome in LT?
(Gonwa 2006)

• 5 year survival (from UNOS data-base)
• Creatinine
• 0-0.99 mg/dL 79
• 1.0-1.99 mg/dL 72
• gt2.0mg/dL 63
• Renal support 64
• Kidneyliver 70

25
UKELD AND 3 MONTHS SURVIVAL WITHOUT
TRANSPLANTATION

• UKELD
• 5.775 x lnINR
• 3.195 x ln bilirubin µmol/L
• 1.145 x ln creatinine µmol/l
• 74.14 x ln sodium µmol/L
• 400

26
UKELD PREDICTS OUTCOME AFTER TRANSPLANTATION
27
Renal failure after LT is associated with a poor
outcome
28
Chronic Kidney Disease After Transplantation of
Nonrenal Organ

• Analyzed 69,321 patients in USA transplanted
  between 1990-2000

16.5
With RenalFailure
28
3 Years Posttransplantation
Ojo AO et al. N Eng J Med. 2003349931-940.
29
Renal failure and death

• Renal failure is associated with a 4 fold
  increase risk in death after liver
  transplantation (Ojo et al, Fisher et al)

30
What are the risk factors for renal failure
31
Cumulative Incidence of Chronic Renal Failure
(CrCl 29 mL/min/1.73 m2)

Relative risk of chronic renal failure
0.63 (0.61-0.66)
1.0 (reference group)
0.99 (0.93-1.06)
Ojo AO et al. N Eng J Med. 2003349931-940.
32
Pre-LT risk factors for advanced chronic renal
disease (Tome et al, 2007)

• 651 patients grafted at Wisconsin 1994-2005
• Adults, first graft, pre-LT sCrlt2.5mg/dL and no
  dialysis
• Cox multi-variate analysis for severe Chronic
  Renal disease (eGFRlt30mL/min)
• Age at LT HR 1.032/yr
• BMI 0.94/unit
• Caucasian race 0.5
• Male sex 0.31
• preLT eGFR 0.98 each mL/min
• protective

33
Risk Factors for Chronic Renal Failure
Multivariate Analysis
RelativeRisk
(M vs F)
P lt0.001. DM diabetes mellitus.Postop ARF
postoperative acute renal failure. Ojo AO et al.
N Eng J Med. 2003349931-940.
34
Chronic Renal Failure After Transplantation of
Non-Renal Organ

• Immunosuppression
• For liver recipients greater risk with
  cyclosporine than with tacrolimus, RR 1.25 (P
  lt0.001)
• No data on sirolimus or MMF

Ojo AO et al. N Eng J Med. 2003349931-940.
35
Risk factors for post-operative renal failure
(Cabezuelo 2006)

• Risk factors for early renal failure
• Acute Renal Failure OR 10.2
• Serum albumin 0.3
• Dopamine treatment 1.6
• Graft Dysfunction 5.6

36
Early renal function predicts late renal function
37
(No Transcript)
38
Risk factors (Fisher et al)

• Significant
• CMV infection .08
• CyA level
• 1 month .07
• Creatinine
• 1 month .06
• 3 months .001
• 6 months .004

• Non-significant
• Pre-op creatinine
• Pre-op dialysis
• Childs grade
• Diabetes mellitus
• Hypertension
• IgA levels

39

• 15/353 developed ESRD requiring
  dialysis/transplantation
• Prevalence of ESRD
• Nil before 2.5 years
• 6.25 at 10 years

40

• GFR at listing did not correlate with GFR at 3
  years (r0.35)
• GFR at 1 year did correlate with GFR at 3 years
  (r0.72)

41
Odds ratio estimate for risk of development of
CRF or ESRD
Variable Unit OR 95 CI
Creatinine4 weeks 1 mg/dl 1.598 1.076-2.372
Creatinine3 months 1 mg/dl 2.254 1.262-4.025
Creatinine1 year 1 mg/dl 2.582 1.633-4.083
Mean creatinine levels of entire group at 4 weeks, 3 months and 1 year were 1.37, 1.46 and 1.59 mg/dl Mean creatinine levels of entire group at 4 weeks, 3 months and 1 year were 1.37, 1.46 and 1.59 mg/dl Mean creatinine levels of entire group at 4 weeks, 3 months and 1 year were 1.37, 1.46 and 1.59 mg/dl Mean creatinine levels of entire group at 4 weeks, 3 months and 1 year were 1.37, 1.46 and 1.59 mg/dl
Gonwa TA et al. Transplantation 2001 721934-9.
42
Liver alone or liver kidney?

• Campbell (2005) did a retrospective analysis of
  69 patients with pre-LT creatinine gt1.5mg/dL
• 53 LT, 13 LKT
• Prediction of 6 and 12 months serum creatinine
• Duration of pre-transplant creatinine
• Etiology of renal failure may be associated with
  outcome rather than severity or duration
• HRS (71 recovery at 1 year) vs ATN (20 recovery
  at 1 year) (Nadim 2010)

43
Liver alone or liver kidney?

• Multivariate analysis predicting creatinine at 12
  months
• Duration of pre-LT renal disease -0.036 (-0.076-
• -0.0048)
• Pre-transplant creatinine 0.86 (0.43-1.28)
• Bilirubin 0.092 (0.032-0.15)
• The duration, not the cause, of renal impairment
  is the main determinant of later renal impairment
  post liver and liver/kidney transplant

44
AASLD Guidelines for SLK

• Liver failure with CKD (GFRlt30mL.min)
• Liver failure with AKI or HRS with creatinine
  gt2mg/dL or dialysis gt8 weeks
• Liver failure with CKD and biopsy showing gt50
  glomerusclerosis or gt30 fibrosis

45
How can the risk of early renal impairment be
reduced?
46
Strategies to prevent renal impairment post LT

• Peri-operative
• Avoid hypovolemia and hypotension
• Avoid nephrotoxic drugs
• Avoid ischemia/reperfusion injury
• Potential approaches
• Veno-venous by-pass
• Piggy back surgery
• N-acetyl cysteine

47
Adjust immunosuppression

• Late renal failure after liver Tx is a
  significant cause of morbidity and associated
  with premature mortality1,2,3
• CNI exposure in the first 6 months post-Tx is a
  risk factor for renal failure4

1. Cohen AJ et al. Liver Transplant 2002
8916-21. 2. Fisher NC et al. Transplantation
1998 6659-66. 3. Ojo AO et al. N Engl J Med
2003 349931-40. 4. Wilkinson A, Pham PT. Liver
Transplant 2005 11S47-51.
48

• Post-operative
• CNI avoidance
• CNI delay
• CNI minimisation

49
Aim

• Does mycophenolate mofetil (MMF) in combination
  with
• either reduced tacrolimus during the first month
• or with reduced tacrolimus delayed for five days
  post-transplant
• reduce nephrotoxicity in de novo liver transplant
  patients without compromising graft survival?
• IL2r blockade was given to bridge CNI-free period
  in the reduced and delayed tacrolimus group

50
Key inclusion and exclusion criteria

• Inclusion
• 16 years
• De novo, single-organ (liver) Tx
• Patient and graft survival expected to begt7 days
  post-Tx
• Exclusion
• Previous organ transplantation
• Patients requiring dialysis within 30 days prior
  to transplantation, or with serum creatinine gt200
  mmol/l on day of transplantation

51
Design Patients randomised to 3 groups

• Group A Standard dose tacrolimus
• Tacrolimus trough gt 10 ng/ml for 1st month
• corticosteroids as per centre practice

(As in Tac label)
52
Design Patients randomised to 3 groups

• Group A Tacrolimus trough gt 10 ng/ml
• corticosteroids
• Group B Tacrolimus trough 8 ng/ml
• MMF 1 g bid
• corticosteroids

(As in Tac label)
53
Design Patients randomised to 3 groups

• Group A Tacrolimus trough gt 10 ng/ml
• corticosteroids
• Group B Tacrolimus trough 8 ng/ml
• MMF
• corticosteroids
• Group C Tacrolimus ( 8 ng/ml) delayed until day
  5
• daclizumab on days 0 7 (2mg/kg 1mg/kg)
• MMF 1 g bid
• corticosteroids

(As in Tac label)
54
Primary endpoint

• Change in creatinine clearance from baseline to
  week 52
• Creatinine clearance calculated using the
• Cockcroft-Gault formula

55
Patient populations
Standard Tac Reduced Tac Reduced, delayed Tac
Randomised(n) 183 170 172
Safety(n) 182 169 169
Full analysis set (FAS population) (n) 181 168 168
56
Baseline characteristics
Standard Tac (n 181) Reduced Tac (n 168) Reduced, delayed Tac (n 168)
Age, yearsmedian (range) 53(19-69) 54(18-73) 55(26-70)
Gender, male 70 65 69
MELD score median (range) 14(6-49) 15(5-33) 15(5-41)
HCC () 20.4 22.6 22.6
CrClmean (ml/min SD) 102 44 104 37 97 35
Unadjusted for HCC
57
Mean change in GFR significantly smaller in the
reduced, delayed Tac arm (3-month data, FAS
population)
p 0.028
p lt 0.001
58
Mean change in GFR significantly smaller in the
reduced, delayed Tac arm (6-month data, FAS
population)
p 0.087
p lt 0.001
59
Mean change in GFR significantly smaller in the
reduced, delayed Tac arm (12-month data, FAS
population)
p 0.199
p 0.2198
p 0.012
60
Fewer patients in the reduced and reduced,
delayed Tac arms were withdrawn from the study
61
Reasons for withdrawal
Patients, n () Patients, n () Patients, n ()
Standard Tac Reduced Tac Reduced, delayed Tac
Unsatisfactory therapeutic response 6 ( 3.3) 1 ( 0.6) 0
AE or intercurrent illness 52 (28.7) 31 (18.5) 37 (22.0)
Death 7 ( 3.9) 6 ( 3.6) 3 ( 1.8)
Lost to follow-up 2 ( 1.1) 0 3 ( 1.8)
Non compliance/wish not to continue 4 ( 2.2) 8 ( 4.8) 6 ( 3.6)
Other 12 ( 6.6) 6 ( 3.6) 2 ( 1.2)
62
Adverse events
Patients () Patients () Patients ()
Standard Tac Reduced Tac Reduced, delayed Tac
All 182 (100.0) 167 (98.8) 166 (98.2)
SAEs 113 (62.1) 107 (63.3) 110 (65.1)
AEs leading to death 16 (8.8) 16 (9.5) 7 (4.1)
AEs leading to withdrawal 55 (30.2) 35 (20.7) 34 (20.1)
63
Selected AEs
Patients () Patients () Patients () p p
Standard Tac Reduced Tac Reduced, delayed Tac Standard vs Reduced Tac Standard vs Reduced, delayed Tac
Diarrhoea 39 (21.4) 52 (30.8) 41 (24.3) lt 0.02 ns
Hypertension 74 (40.7) 48 (28.4) 47 (27.8) lt 0.03 lt 0.03
Hyperlipidaemia 11 (6.0) 8 (4.7) 8 (4.7) ns ns
Diabetes 85 (46.7) 71 (42.0) 65 (38.5) ns ns
Leucopenia 12 (6.6) 18 (10.7) 27 (16.0) ns lt 0.003
64
Biopsy-proven or presumed acute rejection not
significantly different
p 0.0867
p 0.4347
65
Fewer patients in the reduced, delayed Tac arm
required renal support
p 0.0367
p 0.0558
66
Graft loss up to 12 months
Patients, n () Patients, n () Patients, n ()
Standard Tac Reduced Tac Reduced, delayed Tac
Total 11 (6.1) 10 (6.0) 12 (7.1)
During study 8 (4.4) 9 (5.4) 9 (5.4)
After withdrawal 3 (1.7) 1 (0.6) 3 (1.8)
p ns for Standard Tac vs Reduced Tac or
Reduced, delayed Tac
67
Patient death up to 12 months
Patients, n () Patients, n () Patients, n ()
Standard Tac Reduced Tac Reduced, delayed Tac
Total 17 ( 9.4) 19 (11.3) 11 ( 6.5)
During study 10 ( 5.5) 7 ( 4.2) 3 ( 1.8)
After withdrawal 7 ( 3.9) 12 ( 7.1) 8 ( 4.8)
p ns for Standard Tac vs Reduced Tac or
Reduced, delayed Tac
68
Patient death during study
Patients, n () Patients, n () Patients, n ()
Standard Tac Reduced Tac Reduced, delayed Tac
During study 10 ( 5.5) 7 ( 4.2) 3 ( 1.8)
Cardiovascular 3 2 0
Infection/sepsis 1 0 2
Primary graft non-function 1 0 0
Multi-organ failure 0 2 0
CVA / intracerebral haemorrhage 0 1 0
Malignancy 1 0 0
Other 4 2 1
69
Patient death after withdrawal
Patients, n () Patients, n () Patients, n ()
Standard Tac Reduced Tac Reduced, delayed Tac
After withdrawal 7 ( 3.9) 12 ( 7.1) 8 ( 4.8)
Infection/sepsis 2 5 4
Surgical complications post-transplant surgery 0 0 1
Primary graft non-function 0 1 0
Multi-organ failure 3 1 1
Malignancy 1 1 1
Other 1 4 1
70
Freedom from renal dysfunction, acute rejection,
graft loss and acute rejection
p lt 0.0001 for Reduced, delayed Tac vs Standard
Tac,p 0.4785 for Reduced Tac vs Standard Tac
1.0
0.8
Standard Tac
0.6
Reduced Tac
Probability of no event
Reduced, delayed Tac
0.4
0.2
0.0
0
180
360
Time (days)
Renal dysfunction decrease ( 20) from
baseline in calculated CrCl
71
Per-protocol set

• Patients included in the Full analysis set (FAS)
  population
• No inclusion/exclusion criteria violation
• At least one creatinine clearance value beyond
  the first 6 months of the study (from Day 0)
• Treated according to the protocol
• Did not receive prohibited medication during the
  first 14 days after Day 0, and for less than 1
  week at any time during the study

72
Patient populations
Standard Tac Reduced Tac Reduced, delayed Tac
Randomised(n) 183 170 172
Safety(n) 182 169 169
Full analysis set (FAS population) (n) 181 168 168
Per protocol set (PP population) (n) 69 67 67
73
Reasons for exclusion from PP population
Standard Tac Reduced Tac Reduced, delayed Tac
Any inclusion-exclusion criteria violation 5 4 7
Any prohibited concomitant medication 40 23 26
Any study medication violation 84 81 78
No creatinine clearance beyond first 6 months of study 23 19 18
Not in FAS 2 2 4
Withdrawn before day 6 10 8 13
Patients may have more than one reason for
exclusion
74
Mean change in GFR by MDRD-4 is consistent with
Cockcroft-Gault (12 months)
Cockroft-Gault Cockroft-Gault MDRD-4 MDRD-4
FAS PP FAS PP
Standard Tac -23.61 -22.37 -24.89 -26.17
Reduced Tac -21.22 -20.50 -22.60 -23.10
Reduced, delayed Tac -13.63 -10.68 -14.62 -10.52
75
Mean change in GFR significantly smaller in the
reduced, delayed Tac arm (12-month data, PP
population)
p 0.327
p 0.250
p 0.035
76
Correlation between MDRD-4 and Cockcroft-Gault
GFR at 12 months
200
150
MDRD-4
100
50
50
100
150
200
250
Cockcroft-Gault
77
Participating centres

• Belgium
• Hopital Erasme, Brussels UZ Ghent, Ghent UZ
  Gasthuisberg, Leuven CHU Sart-Tilman, Liege
• Finland
• Helsinki University Hospital, Helsinki
• France
• Hôpital Beaujon, Clichy Hôpital Claude Huriez,
  Lille Hôpital Edouard Herriot, Lyon CHU
  Rangueil, Toulouse Hôpital Paul Brousse,
  Villejuif
• Germany
• Charité, Berlin Universitätsklinikum Essen,
  Essen Goethe-Universität, Frankfurt a.M.
  Universitätsklinikum Heidelberg, Heidelberg
  Universitätsklinikum Kiel, Kiel
  Universitätsklinikum Leipzig, Leipzig Klinikum
  der Universität Regensburg, Regensburg

• Norway
• Rikshospitalet, Oslo
• Spain
• Cuitat Sanitaria i Universitaria de Bellvitge,
  Barcelona Hospital Clinic, Villaroel, Barcelona
  Hospital Juan Canalejo, La Coruña Hospital
  Puerta de Hierro, Madrid Hospital Gregorio
  Marañón, Madrid Hospital Clínico de Santiago,
  Santiago di Compostela Hospital Universitario
  Virgin del Rocio, Sevilla
• Sweden
• Sahlgrenska University Hospital, Goteburg
  Huddinge, Stockholm
• Switzerland
• Universitätsspital Zurich, Zurich
• UK
• Queen Elizabeth Medical Centre, Birmingham Royal
  Free Hospital, London

78
Yoshida (2005) Randomised 148 IL2RdTacMMFST vs TacMMFST Renal Function Improved renal function at 1 and 6m
Calmus (2010) Randomised 199 IL2RdTACMMF vsTacMMFST sCrgt130 at 6m No change
Langrehr (2002) Randomised 381 IL2RCsASTvs dCsASt ACR Reduced ACR
Baijola (2008) Retrospective 112 ATGdTacMMFST Higher eGFR
Soliman (2007) Retrospective 391 ATGdTacSt Higher eGFR
AUTHOR TRIAL N Therapy End-point Result
79
Conclusions

• Low-dose and delayed introduction of tacrolimus
  with mycophenolate mofetil and IL2r blockade is
  associated with less impairment of renal function
  12 months after liver Tx compared with standard
  treatment
• Patient death, graft loss and acute rejection
  were not adversely affected

80
Concerns

• End-point was change in eGFR
• Should those with renal impairment have been
  excluded
• What is the long term outcome?
• Levels of tacrolimus appropriate?
• Is IL2R needed?

81
How to monitor renal function post LT

• eGFR using MDRD-4 has many limitations but is
  probably the most effective form of monitoring
  changes in renal function in an individual
  patient
• Changes in eGFR should be corroborated by more
  objective measures
• Surrogate biomarkers not yet of proven value in
  this situation

82
Close collaboration with nephrologists

• Stage 4 CKD with diabetes
• Stage 5 CKD
• ACRgt70mg/mol
• Close attention to management of
• Hypertension
• Hyperlipidemia
• Hyperuricemia
• Life-style
• Bone disease

83
Management of patients on CNI

• What is the appropriate target level?
• Does combination therapy allow for lower doses of
  CNI?
• When to stop CNI
• What is the best IMS regime

84
Birmingham experience

• Retrospective analysis

85
p0.12
86
p0.5
87
p0.007
88
When should CNI be withdrawn?
89
When to change

• Suggested triggers for change
• Decline of eGFR of gt5ml/min/1.73m2 over 1 year
• Decline of eGFR of gt10ml/min/1.73m2 over 5 years
• eGFR of lt60ml.min/1.73m2

90
What do change to?

• Withdraw all IMS
• Sirolimus/Everolimus
• Mycophenolate monotherapy
• Steroids and Mycophenolate
• Steroids and Azathioprine
• Belatacept and steroids or MMF
• Newer agents

91

• Mycophenolate Monotherapy
• Has been associated with ACR, CR and graft loss
  in some studies
• Avoid if pregnancy is possible
• Sirolimus
• Variable findings
• Avoid if there is proteinuria
• Advantages if HCC

92
Conclusions

• Renal function remains a major issue pre and post
  liver transplantation
• Monitoring of liver function is problematic
• Early renal function is associated with late
  renal impairment
• Prevention with either delayed or no CNI
• Early withdrawal of CNI and switch to mTORi or
  Mycophenolate and Steroids