Docstoc

Chronic kidney disease in solid organ transplant recipients

Document Sample
Chronic kidney disease in solid organ transplant recipients Powered By Docstoc
					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”

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:2
posted:8/23/2012
language:English
pages:60