Documents
Resources
Learning Center
Upload
Plans & pricing Sign in
Sign Out

Chronic kidney disease in solid organ transplant recipients

VIEWS: 2 PAGES: 60

									Strategies in transplant patients
  with chronic kidney disease
       Marcelo Cantarovich
   McGill University Health Center
                   Outline
•   Etiology of CKD
•   Impact of CKD on patient survival
•   Prevention of CKD
•   Management of CKD
    – Immunosuppressive strategies
    – Non-immunosuppressive strategies
NKF K/DOQUI. Am J Kidney Dis 2002;39:Suppl 2:S1-S246
                   Outline
•   Etiology of CKD
•   Impact of CKD on patient survival
•   Prevention of CKD
•   Management of CKD
    – Immunosuppressive strategies
    – Non-immunosuppressive strategies
 Causes of renal allograft loss
1 to 5 yrs post-renal transplant




                       Cecka JM. Clin Transplants. 2000;1-18
Causes of death with functioning
    graft in adult patients
          USRDS 2008



                          first-time, kidney-only
                          transplant recipients,
                          age 18 & older &
                          transplanted 1997–
                          2006, who died with a
                          functioning graft
                          (N=14,169). Cause of
                          death obtained from
                          OPTN when available,
                          otherwise taken from
                          ESRD Death
                          Notification form.
173 pts, 234 Bx, 6 days -31 yrs post-Tx
      Chronic allograft
     nephropathy (IFTA)
Immunological and non-immunological factors
 • Donor age          • CNI toxicity
                      • Acute rejection
 • Donor type
                      • Infection
   • Brain death
                           • CMV
   • DCD                   • Polyoma virus
• Ischemia /           •   Dyslipidemia
  Reperfusion injury   •   HTN
• Procurement          •   Cigarette
• Delayed graft        •   Other
  function
   Graft survival according to
immunosuppressive combinations
   SRTR: n = 58 131 recipients of first kidney transplant 2000-2005




                                                TR et TR et J Transplant 2007; 7:586-594
                                       SrinivasSrinivas al Amal Am J Transplant 2007; 7:586-594
    Significant Kidney Allograft Attrition
 Regardless of Immunosuppressive Regimen
 Collaborative Transplant Study Results 1998-2007




                                    Years Following Transplantation

CTS Database n=51,303 recipients of deceased donor organs
                                                                                                          10
                                                               Opelz G, Döhler B. Transplantation 2009;87: 795
    Impact of MMF or CNI dose
     reduction/discontinuation
            Data-base analysis (1996-2005)
        Renal Tx pts with acceptable renal function




↓CsA <100 mg/d, ↓Tac < 2 mg/d, ↓MMF <1000 mg/d + CsA or <500 mg/d + Tac
                                mg/d + Tac
                                           Opelz and Dohler, Transplantation 2008, 86:371-376
Etiology of ESRD in Nonrenal Organ
       Transplant Recipients†
                      Orthotopic Heart Recipients with                                Orthotopic Liver Recipients with
                                               1
                               ESRD (n=24)                                                     ESRD (n=45) 2

                      70                                                             80
                                                                                                    CNI toxicity (73%)
                                   CNI toxicity (60%)                                70
% of ESRD diagnosis




                      60           Hypertension (30%)
                                                                                                    HRS* (7%)




                                                               % of ESRD diagnosis
                                                                                                    FSGS (7%)
                                   FSGS (16%)                                        60             ADPKD (7%)
                      50           Diabetic nephropathy (6%)                                        Other (7%)
                                                                                     50
                      40
                                                                                     40
                      30
                                                                                     30
                      20                                                             20
                      10                                                             10

                      0                                                              0
1Adaptedfrom Coopersmith. Surgery. 2001;130:457-462 & Greenberg A. Am J Kidney Dis .1987;9:12-22.
2Adaptedfrom Gonwa TA. Transplantation. 2001;72:1934-1939.
*Nonrecovery from pretransplant hepatorenal syndrome.
†Some cases have multiple histologic diagnosis
                                                                            Courtesy by Dr. A. Ojo
                                                                                 Courtesy Dr. A. Ojo
Cumulative Risk of Stage 4-5 CKD
 in non-renal transplant recipients
      n=69,321   Predictors: ARF, age, women, DM, HTN




                                       Ojo AO. N Engl J Med 2003;349:9319-9340
                   Outline
•   Etiology of CKD
•   Impact of CKD on patient survival
•   Prevention of CKD
•   Management of CKD
    – Immunosuppressive strategies
    – Non-immunosuppressive strategies
Patient survival following renal
       transplant failure

           HR 3.39
           95% CI, 2.75-4.16
           P<0.0001




                                  • CORR
                                  • 1994-1999
                                  • n=4743
                                  • 607 (12.8%) graft failure
                                  • 411 (8.7%) died

                               Knoll G et al. Am J Transplant 2005; 5(7): 1719
  Outcomes in heart transplant patients with
 or without CrCl DROP >30% in the first year
           Chronic Dialysis                                                                   Patient Survival
                                                                                    100
                                                                                    90
                                   Logrank test p=0.004
                                                                                    80
                                   Logrank test p=0.004                                                                  Logrank test p=0.01




                                                                 Percent survival
                                                                                    70
                                                                                    60
                                         Logrank test p=0.004                       50
                                                                                    40
                                                                                    30
                                                                                    20
                                                                                    10
                                                                                     0
                                                                                          0         5          10                15        20



                                                                                               Years post heart transplantation
               Years post heart transplantation
                                                                Time (years)                              1         5       10        15   20
Time (years)                  1     5       10     15     20
                                                                -------DROP1-12 <30%, n                  166    131         86        37        5
______DROP1-12 <30%, n       165   131      88     34     14
- - - - - DROP1-12 >30%, n    34    23      11      6      1
                                                                - - - - DROP1-12 >30%, n                  34        24      11         7        1


238 HTx pts, 07/1982 – 08/2003
Survival >1-month                                                                             Cantarovich M et al. Am J Transplant 2009;9(2):348
Outcome of heart transplant recipients on
chronic dialysis: Analysis of the Canadian
      Organ Replacement Register

•   CORR data                                  Mortality
                                                               p < 0.001
•   2709 HTx pts                   70

                                   60           56.2

•   01/1981 – 12/2002              50




                         Percent
                                   40                                   35.9

•   105 (3.9%) on HD               30


•   Controls: 2 HD pts             20

                                   10

                                    0
                                        HTx Chronic Dialysis   HTx No Chronic Dialysis




                                                Alam A et al. Am J Transplant 2007;7(2):461
              Survival after the
             initiation of dialysis

                                                            DM    HTN
                                                  HTx (HD) 16.1% 70.3%
                                                  Controls 27.3%* 80.3%
Time elapsed between the initiation of chronic dialysis
                                                  *P=0.04
        and death: 1.6 1.8 yrs (median 0.9 yrs)
                                                 CVC death
                                                 45.8% vs. 31.8%
                                                 P<0.01




                                            Alam A. et al, Am J Transplant 2007;7(2):461
   Survival Post-kidney Tx
                                             100%
                                             n=30


                                            78.6%
                                            n=20


                                             35.2%
                                             n=171
                                              =

                                             15.7%
                                             n=85



      Time to kidney Tx after the initiation of dialysis
HTx 1.5 1.0 yrs (0.36-3.63), Controls 1.8 1.7 yrs (0.01-7.48)
                                            Alam A. et al, Am J Transplant 2007;7(2):461
Survival of liver transplant patients
   on chronic dialysis (CORR)
                          100

                           80
       Percent Survival




                           60

                           40                                                                       43%
                                                                                        Log Rank P<0.01

                           20
                                                                                                    17%
                            0
                                0          1          2             3               4           5
                                                     Time (years)
                                Matched dialysis cohort         OLT + chronic dialysis

                                                            Effective sample size
      Time (yrs)                               0-1        1-2       2-3       3-4        4-5        5+
      Matched dialysis cohort                  192        162       143       132        124        114
      OLT + chronic dialysis                   93         78        70        62.5       61         60

 01/1981 – 12/2002, 4186 LTx pts, 2.9% on chronic dialysis
                                                                        Al Riyami et al. Transplantation 2008, 15;85(9):1277
Survival post-kidney Tx
                                    90%
                                    80%


                                   36.5%

                                   11.5%




               al. Transplantation 2008,15;85(9):1277
               Al Riyami et al. Transplantation 2008,15;85(9):1277
                   Outline
•   Etiology of CKD
•   Impact of CKD on patient survival
•   Prevention of CKD
•   Management of CKD
    – Immunosuppressive strategies
    – Non-immunosuppressive strategies
           Prevention of CKD
•   Avoid SRL + CNI combination
•   Low-dose CNI
•   Low-dose CNI + ACE (ongoing trial)
•   CNI avoidance
•   Early conversion to SRL
                 SRL + CsA
       Am J Transplant 2004
                      •   SRTR, 23016 pts
                      •   Jan 1998 – July 2003
Graft survival
                      •   CsA-SRL vs. CsA-MMF
                      •   CsA-SRL
                          –  graft survival at 4-yr
                            74.6% vs. 79.3% (P=0.002)
                          –  death censored graft
                            survival 83.7% vs. 87.2%
Death censored              (P=0.003)
 graft survival




                                Am J Transplant 2004, 4(12):2058-66
                           Meier-Kriesche et al, Am J Transplant 2004; 4(12):2058
                         SRL + Tac
                                 Am
                                  • SRTR, 44915 pts
                                  • 2000 – 2004
                                  • Tac-SRL (3524 pts) vs.
    Graft survival
Death censored graft survival       Tac-MMF (27207 pts)
                                  • Tac-SRL
                                      – Graft loss at 3-yr HR 1.47,
                                        95% CI 1.32-1.63
                                        (P=0.002)
                                      –  death censored graft
 Death censored graft survival          survival: 83.6% vs. 90.4%
                                        (P<0.001)
 Graft survival in ECD                –  graft survival in ECD:
                                        74.5% vs. 57.5% (P<0.001)


                                       Meier-Kriesche et al. Am J Transplant 2005, 5(9):2273
                                            Am J Transplant 2005, 5(9):2273-80
                              Low-dose CNI - Symphony trial
                                  Measured and Calculated GFR
                                                                                                                P=0.007
                                         P=0.01          P=0.02
                             80                                                       70
                                                                                                            P<0.001        P<0.001
Mean Measured GFR (mL/min)




                                                  69.6




                                                                   Mean GFR (MDRD; mL/min)
                             70            65.3                                       60
                                  63.5                     64.4                                                        54.3
                             60                                                       50                     50.2                47.5
                                                                                                    46.2
                             50
                                                                                      40
                             40
                                                                                      30
                             30
                                                                                      20
                             20

                             10                                                       10

                             0                                                               0
                                    12-Month results                                                     12-Month results
                                                            Normal-Dose
                                                            CsA
                                                            Low-Dose CsA
                                                            Low-Dose TAC
                                                            Low-Dose SRL                              N Engl J Med J Med 2007; 357(25):2562
                                                                                                 Ekberg H. et al. N Engl2007;357(25):2562-75
Low-dose CNI - Symphony trial
      BPAR at 6 and 12 months

                                       50
                                                 P<0.001 for all pair-wise
                                                                                                 Normal-Dose CsA
   Biopsy-Proven Acute Rejection (%)


                                                 comparisons with TAC
                                                                                                 Low-Dose CsA
                                       40                                        37.2
                                                                              35.3               Low-Dose TAC
                                                                                                 Low-Dose SRL
                                       30       25.8
                                            24.0          24.0
                                                       21.9
                                       20
                                                                     12.3
                                                                  11.3
                                       10


                                        0   Hatched bars = BPAR at 6 months
                                            Solid bars = BPAR at 12 months
                                                                                 N H. et al. N Engl J Med 2007;357(25):2562
                                                                              EkbergEngl J Med 2007;357(25):2562-75
    CNI avoidance
Co-stimulatory blockade
Co-stimulatory blockade




                   Engl J et al. 353: J Med; 2005; 353:770
                 N Vincenti FMed N Engl 770-781, 2005
  High vs. low Tacrolimus ± ACE
• Ongoing Canadian RCT
• 4 groups
  – Tac 4-6 ng/mL ± ACE vs. No ACE
  – Tac 8-12 ng/mL ± ACE vs. No ACE
• Protocol biopsies
  – Pre-implantation, 6 and 24 months
                CNI avoidance
                   SRL vs. Tac
• RCT, 165 pts               • Acute rejection
  – SRL-MMF-Pred               Tac 10%
  – Tac-MMF-Pred               SRL 13%
                                          GFR
• 1-yr Bx
  – No difference in IFTA
    and glomerulopathy
  – Chronic vascular
    lesions (CV1)
     • Tac 43% vs. SRL 26%
       (P=0.03)

                                       Larson et al, Am J Transplant 2006;6(3):514
CNI avoidance
 SRL vs. CsA
               • SRL 31 pts (10-12
                 ng/mL) vs.
               • CsA 30 pts
               • Basiliximab/MMF/Pred
               • 5-yr pt survival
                   – SRL 87.1%
                   – CsA 90%
               • 5-yr death censored
                 graft survival
                   – SRL 96.4%
                   – CsA 76.7% (P=0.02)




           Flechner S et al, Transplantation 2007, 83(7):883
              CNI avoidance
          Daclizumab-MMF-Pred
           vs. CsA-MMF-Pred
• RCT                     • Acute rejection
• 54 pts, PRA 0%             – Dac 70.4%
• HLA-DR identical           – CsA 29.6%, P=0.006

• Daclizumab (5           • Similar graft survival
  doses), MMF (1.5 g      • rGFr (12 mo)
  bid), Pred vs.             – Dac 52±20 ml/min
• CsA, MMF (1.0 g bid),      – CsA 69±29 ml/min
  Pred


                                 Asberg et al , Transplantation 2006 ;15;82(1):62
CNI discontinuation <6 months
      The CAESAR study
              • RCT, 536 pts
              • Gr.1: daclizumab, MMF, Cs
                + low-dose CsA (trough l50-
                100 ng/mL),  from mo.4
                and D/C by mo.6
              • Gr.2: daclizumab, MMF, Cs
                + low-dose CsA
              • Gr.3: MMF, CS + standard-
                dose CsA




                       Ekberg H et al. Am J Transplant 2007;7(3):560
CNI discontinuation at 3 months
                •   525 (10%Re-Tx) pts (89% DD)
                •   SRL (>5 ng/mL) + CsA + Pred
                •   n=430 pts
                     – SRL + Cs
                     – CsA + SRL 20-30 ng/mL + Cs
                •   3-yr pt survival (94.4% vs. 96.3%)
                •   3-yr graft survival (91.2% vs.
                    93.5%)
                •   Pre-Rand AR (9.3% vs. 10.2%)
                •   Post-Rand AR (5.6% vs. 10.2%)




                           Kreis H et al. J Am Soc Nephrol 2004, 15(3):809
CNI avoidance and discontinuation at 13 wks




                 The Orion Trial
   CNI Conversion to SRL <6 months
           Spare the nephron – Kidney Tx
         n=298 pts were randomized, SRL/MMF 148, MMF/CNI 150 (81% Tac)
             30-180 days Post-Tx                          Post-randomization
                                              R
                                              a               MMF + TAC
                  MMF + TAC                   n
                                              d
                                              o               MMF + SRL
                                              m
                                              i
                                              z
                                              a                MMF + CsA
                                              t
                  MMF + CsA                   i
                                              o               MMF + SRL
                                              n
             Patient screening and
                  enrollment
SRL trough 5-10 ng/ml ( 2-10 mg load), MMF 1-1.5 mg bid                 1 year          2 years
Induction, CNIs and Pred as per center
First kidney Tx, DD or LD, CrCl >30 mL/min
No steroid resist AR <90 days or steroid sens <30 days    Pearson TC, et al. ATC 2008 (Abstract 129)
   CNI Conversion to SRL <6 months
                                                      STN – Kidney Tx
  Change in Measured GFR (baseline vs. 1-yr)
                                                35                 P=0.0247
                                                               P=0.052
                  Mean Percent Change (± SEM)


                                                30                                                      MMF/SRL
                                                                                                        MMF/CNI
                                                25     27.9                                             MMF/TAC*
                                                20

                                                15

                                                10
                                                                        11.0
                                                 5
                                                                                      6.1
                                                 0
                                                       n=116            n=115        n=91
                                                --5
      Baseline GFR
*Subgroup of (mL/m/1.7 m2)
       SEM MMF/CNI                                   59.5  2.0      59.4  2.3   61.3  2.7

                                                                                                                                        37
                                                                                                Pearson TC, et al. ATC 2008 (Abstract 129)
   CNI Conversion to SRL <6 months
                                                      STN – Kidney Tx
  Change in Measured GFR (baseline vs. 1-yr)
                                                35                  P=0.0247
                                                                P=0.052
                  Mean Percent Change (± SEM)


                                                30                                                     MMF/SRL
                                                      Mean difference in GFR at 2 yrs                  MMF/CNI
                                                25
                                                      MMF/SRL: 8.6%,
                                                       27.9                    59.5 mL/min
                                                                                       MMF/TAC*
                                                20    MMF/CNI: 3.4% (P=0.054), 58.8 mL/min
                                                      MMF/TAC: 0.2% (P=0.69), 60.5 mL/min
                                                15

                                                10
                                                                         11.0
                                                 5
                                                                                       6.1
                                                 0
                                                        n=116            n=115        n=91
                                                --5
      Baseline GFR
*Subgroup of (mL/m/1.7 m2)
       SEM MMF/CNI                                    59.5  2.0      59.4  2.3   61.3  2.7
                                                                                             Pearson TC et al. ATC 2008 (Abstract 129)
                                                                                             Weir M et al. Kind Int, Dec 2010          38
CNI conversion to SRL at 3 months
                     Concept trial
• RCT, n=192
• Daclizumab, CsA, MMF, Pred (D/C month 8)
• Conversion to SRL at 3 months vs. CsA
   – SRL 8-15 ng/mL 5-10 ng/mL (wk 39)
   – CsA C2 500-800 ng/mL
• Exclusion criteria
   – WBC <2500/mm3, PRA >30%, CIT >36 hr, donor >65 yrs
   – MMF 1.5 g, Prot >1 g/24 hr, Banff 1A, CrCl <40 mL/min




                                        Lebranchu Y et al. Am J Transplant 2009; 9(5): 1115
 CNI conversion to SRL at 3 months
                            Concept trial




• Patient survival 99.5%            Side-effects on SRL        Steroid withdrawal
• Graft survival 97.9%              Anemia,  PLT                  • SRL 72%
• No difference on IF at 12-mo Bx   Oral ulcers                    • CsA 78%
                                    Acne, diarrhea
                                                 Lebranchu Y et al. Am J Transplant 2009; 9(5): 1115
                                                 Servais A et al, Am J Transplant 2009; 9(11): 2552
    CNI conversion to SRL >6 months
                   Convert study
•   n=830, GFR >20 mL/min
•   6-120 mo post-Tx
•   Aza 50 or MMF 500 mg/d
•   No AR <3 mo.
•   Continue on CNI vs. SRL
•   SRL 12-20  4-8 mg/d
    (8-20 ng/mL)
•   Aza max 75 mg/d
•   MMF max 1500 mg/d
•    P/Cr ratio on SRL
•    malignancies on SRL


                                   Schena et al, Transplantation 2009: 87:233
       Reduced dose tacrolimus + MMF + daclizumab
             in de novo liver transplantation
                          Patients with Scr >200 mol/L were excluded


Group A                   Tac trough >10 ng/ml + corticosteroids
(Regimen in drug label)


Group B                   Tac trough ≤8 ng/ml
                          + MMF
                          + corticosteroids

Group C                   Tacrolimus (≤ 8 ng/ml) delayed until day 5
                          + IL2r blockade on days 0 & 7
                             (daclizumab 2 mg/kg & 1 mg/kg)
                          + MMF 1g bid
                          + corticosteroids
                                                                        Mayer D et al. ATC 2008
              Mean change in GFR




                           p = 0.128

                              p = 0.007


* Error bars show 95% CI



                                          Mayer D et al. ATC 2008
Acute rejection
             P = 0.0054
   P = 0.1576




                          Mayer D et al. ATC 2008
           Liver transplant
       Spare-the-Nephron (STN)
Pre-randomization       Stable               Post-randomization
                        4 – 12                MMF + tacrolimus
MMF + tacrolimus
 corticosteroids          W
                           E
                           E                   MMF + sirolimus
                           K
                           S
                           P
                           O                MMF + cyclosporine
MMF + cyclosporine         S
                           T
  corticosteroids         -
                           T                   MMF + sirolimus
                           X

     Screening        Enrollment

MMF 1.0-1.5 g bid                                                              2 years
                                                         1 year
CsA 100-250 ng/ml
                                              SRL 2-4 mg qd
Tac 3-10 ng/ml
                                              5-10 ng/ml


                     Sher L et al, ATC 2008; Roberts J et al, ATC 2009; Teperman L et al, ATC 2009
Liver STN: Mean %GFR Increase
         Baseline to Month 12




             P<0.0001




                           Teperman et al. ATC 2009; Abstract #132
Liver STN: Efficacy Endpoints

         P=0.609



                           P=0.014                             Lipid lowering drugs
                                                               MMF/SRL 24%
                                               P=0.072         MMF/CNI 8%
                                                                 Malignancies
                                                                 MMF/SRL 5%
                                                                 MMF/CNI 10%

                                                                  Withdrawals
                                                                  MMF/SRL 36%
                                                                  MMF/CNI 27%


   Treatment failure includes BPAR, graft loss, death or loss to follow-up

                                                         Teperman et al. ATC 2009; Abstract #132
                                                         Roberts et al. ATC 2009; Abstract #1204
                   Outline
•   Etiology of CKD
•   Impact of CKD on patient survival
•   Prevention of CKD
•   Management of CKD
    – Immunosuppressive strategies
    – Non-immunosuppressive strategies
                    Summary of RCT
                  Kidney transplantation
    Investigator       Study population         Intervention         Outcome
Saunders et al         n=31 pts             •  CsA 40% + SRL No change in GFR
Transplantation 2003   >1-yr post-Tx        (5-15 ng/ml) + Pred
                                            •  CsA 40% (50-75
                                            mg/ml) + Aza + Pred
Stoves et al           n=42 with CAN        • MMF +  CsA         GFR ↑ on MMF at
Nephrol Dial           >6 mo post-Tx        • Conversion to Tac   6 months
Transplant 2004                             • Continue on CsA
Stallone et al         n=84 pts with CAN    •  40% CNI + MMF     CrCl ↑, GS ↑
J Am Soc Nephrol       1-3 yrs post-Tx      • D/C CNI + SRL       Chronic changes 
2004                                                              on SRL at 2 yrs
Suwelack et al         n=30 with CAN        • Conversion to MMF   Slope of 1/Scr
Am J Transplant        >1-yr post-Tx        • CNI + MMF           improved on MMF
2004                                                              at 8 months
Watson et al           40 pts with CAD      • SRL + D/C CNI       GFR ↑ on SRL at
Am J Transplant        6-mo to 8-yr post-   • Continue on CNI     12 months
2004                   Tx
                 Summary of RCT
               Kidney transplantation
     Investigator          Study             Intervention          Outcome
                         population
Dudley et al           n=122 with CAD   • Conversion to MMF     Scr stabilized or
Transplantation 2005   >6-mo post-Tx    • Continue on CNI       improved on
                                                                MMF at 1 yr
Meier et al            n=46 with CAN    • Conversion to Tac     Scr ↓ on Tac at
Transplantation 2006   >1-yr post-Tx    • Continue on CsA       12 and 36
                                                                months
Frimat et al           n=106 with CAD   • MMF + half-dose CsA   CrCl ↑ on MMF
Am J Transplant 2006   >1-yr post-Tx    • Continue on CsA       at 24 months
          Conversion to SRL
                Meta-analysis
             Transplantation 2006
• 5 RCT (1040 pts), 25 non RCT (977 pts)
• In RCT CrCl ↑6.4 mL/min (95% CI 1.9 - 11.0)
• In non RCT renal function improved/stabilized in
  66% (95% CI 61% - 72%)
• Serum cholesterol and triglycerides increased
• SRL D/C 28% (95% CI 0% - 59%)
• Acute rejection 3.4%



                           Transplantationet2006, 82(9):1153-1162
                                     Mulay al.Transplantation 2006, 82(9):1153
 Clinical benefit of C2 monitoring
     in Heart Transplantation
               C2 300-600 vs. C0 100-200 ng/ml
          80
                         69 *
          70                                         64.5*
          60
                                     49
          50                              43
Percent




                                                                    Acute Rejection
          40                    33                                  Neg. Renal Outcome
          30                                        25              Clinical Benefit
                 18 18
          20                                   14
          10
           0
                 Period 1       Period 2       Period 3
      *P. 1 vs. P. 2, P<0.00001; P. 1 vs. P.3, P=NS; **P. 3 vs. P. 2, P=0.004
                                                         Cantarovich M et al. Transplantation 1999;68(12):1839
      CNI replacement strategies
        Heart Transplantation
                Randomized controlled study
Author               Gleissner et al.
                     Am J Transplant 2006; 6(11):2750
# of patients        39

Mean time post-Tx    8.2 4.3 years

Design               • Group 1: 19 pts
                       Start on SRL + D/C CsA + MMF
                     • Group 2: 20 pts
                       Low-dose CsA + MMF
Follow-up            6 months
Main results         Group 1: eGFR 48.5 21.4 to 61.7 21.4 mL/min
                     16% (3 pts) D/C SRL (diarrhea, skin rash)
                     No rejection
         CNI replacement strategies
           Heart Transplantation
                    Pilot and retrospective studies
# of studies analyzed     19
Date of review            2000-2010

# of patients             Range: 8-80

Mean time post-Tx         Range: 3 days-16 years

Design                    SRL/EVL ± MMF + ↓or D/CCNI: 11/19
                          MMF + Steroids + ↓CNI: 2/19
                          Aza, SRL or MMF + ↓CNI: 3/19
                          anti CD25 + MMF or SRL + ↓CNI: 1/19

Follow-up                 Range: 1 mo – 69 mo
Main results              Improvement in renal function
                          Acute rejection: 0-14%
                          Side effects: 30-76%
                          D/C: 8-75%
                          Chronic dialysis up to 5%
Clinical benefit C2 monitoring in
      Liver Transplantation
             100


                                                              82   *
             80                        77
                         73



             60
   Percent




                                                                        Acute Rejection


                          37.5                                          Neg. Renal
             40                                                         Outcome
                                                                        Clinical Benefit


             20                             18

                     9                                9   9

                                   0
              0
                    C0 100-200   C2 700-100          C2 300-600
                                                 0
                   C0: 100-200   C2: 700-1000        C2: 300-600
        *P=0.03 vs. C0 100-200 ng/ml
         *P=0.01 vs. C2 700-1000 ng/ml
                                                              Cantarovich M et al. Transplantation 1998, 66:1621
  CNI dose reduction and conversion
Summary of RCT in Liver transplantation
   Investigator             Study                   Intervention                            Outcome
                          population
Schlitt H et al         >6 mo post-Tx        Study group                      At 6 mo follow-up
Lancet.2001;357         Study group: 14      Initiation of MMF and            Scr decreased by 44.4 48.7 mol/L in
(9256):587-91           Control group: 14    reduction, and discontinuation   the study group vs. 3.1 14.3 in
                                             of CNI Control group             controls
                                             Continuation of CNI              Acute rejection: 3/14 study pts
                                                                              Side effects: 8/14 study pts
Stewart SF et al        RCT                  MMF replaced CNI vs.             Acute rejection in 3 of 5 pts, requiring
Lancet 2001; 357:609-                        continuation on CNI              re-Tx
10.
Pageaux G et al         OLT >1-yr            Study group                      CrCl at 1-yr
Liver Transpl 2006;     Scr >140 and         MMF + CNI reduction 50%          Study group: 42.6 10.9 to
12):1755-60.            <300                 Control group                                  51.7 13.8 mL/min
                        Study group: 27      No MMF                           Control group: 42.8 12.8 to
                        Control group: 29    CNI reduction (max 25%)                          44.8 19.7 mL/min
                                                                              (p=0.04)
                                                                              Rejection: 0 in study pts, 1 in controls
                                                                              Death: 1 in study pts, 0 in controls
                                                                              GI side-effects: 5 in study pts, 2 in
                                                                              controls
Cinncinnati VR et al    OLT pts with renal   Study group                      eGFR at 1-yr
                        dysfunction          MMF + CNI reduction              Study group:38.8 9.6 to 47.0 11.8
Aliment Pharmacol
                        Study group: 25      Control group                    mL/min
Ther 2007;26(9):1195-
                        Control group: 25    MMF + CNI No dose                Control group: No changes
208
                                             reduction
                   Outline
•   Etiology of CKD
•   Impact of CKD on patient survival
•   Prevention of CKD
•   Management of CKD
    – Immunosuppressive strategies
    – Non-immunosuppressive strategies
      Management of CKD
Non-immunosuppressive strategies

• Hypertension
• Microalbuminuria / Proteinuria
  – Ongoing Canadian RCT: ACE vs. placebo
• Anemia
• Hyperparathyroidism
• Evaluate pre-emptive kidney Tx
                 Conclusions
• CKD in SOT recipients is multi-factorial
• Prevention
  – Optimize immunosuppression
  – Treatment of co-morbidities
• Caution when converting pts
  – Renal Tx (AMR, side-effects)
  – Non-renal Tx (acute rejection, side-effects)
• RCT are needed in non-renal Tx pts
• Long-term results are required
Hyppocrates of Cos, 460-377 BC

 “There are in
 fact two things:
 Science and
 opinion; the
 former begets
 knowledge, the
 latter begets
 ignorance”

								
To top