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									Update on Renal Transplantation


          Clifford Miles, MD, MS
  University of Nebraska Medical Center
               Objectives

 Review national data for ESRD and kidney
  transplantation
 Current immune suppressants, trends in
  use, and glimpse of the future
 BK virus associated nephropathy

 Proposed changes in allocation system
Adjusted prevalent rates
& annual percent change
Figure 2.22




December 31 point prevalent ESRD patients; rates adjusted for age, gender, & race.


2007 ADR
ESRD and life expectancy




       N Engl J Med 1998; 338:20
Adjusted Relative Risk of Death:
Deceased-donor Txp recipients compared to Waitlisted candidates




                      Wolfe, et al. N Engl J Med 1999;
                                341:1725-30.
Number of transplants,
by donor type
Figure 7.1




                         Transplant counts as
                         known to the USRDS
                         (reconciled from
                         various sources).


2007 ADR
2007 ADR
Causes of graft loss
Immune suppression
    Current Immunosuppressive Agents
   Prednisone             Daclizumab
   Azathioprine           Basiliximab
   Cyclosporine           OKT3
   Tacrolimus             Polyclonal Anti-
                            Thymocyte Globulin
   Mycophenolic Acid      Rituximab†
   Sirolimus              Alemtuzumab†



                            † use is off-label in transplantation
         Calcineurin inhibitors

 Prevent rejection by inhibiting IL-2 gene
  transcription
 Cyclosporine (1983): Sandimmune,
  Neoral, Gengraf
 Tacrolimus (1994): Prograf, generic
  available outside US
    Calcineurin inhibitor side effects

 Both: hypertension, hyperlipidemia, renal
  vasoconstriction, interstitial fibrosis, Na+
  retention, hyperkalemia, Mg++ wasting,
  hyperuricemia, neuropathy
 CsA: hirsutism

 TAC: alopecia, GI distress, diabetes



   Both: drug interactions
Baseline calcineurin
inhibitor use
Figure 7.57




                       First-time, kidney-only
                       transplants, 1995–2005.
                       Immunosuppression as
                       identified to OPTN.


2007 ADR
         Mycophenolic acid (MPA)

   MPA inhibits de novo pathway for purine
    biosynthesis
   Lymphocytes rely on this pathway; other cell
    lines can utilize salvage pathway
   Compared to Azathioprine, less bone marrow
    suppression, fewer infections, better at
    preventing rejection
      Mycophenolic acid (MPA)


                     Mycophenolate
                        sodium




Mycophenolate
   mofetil
Baseline antimetabolite use
Figure 7.58




                              First-time, kidney-only
                              transplants, 1995–2005.
                              Immunosuppression as
                              identified to OPTN.


2007 ADR
                   Sirolimus

 Macrolide isolated from Streptomyces
  hydroscopicus, found in the soil of Easter
  Island (Rapa nui)
 FDA approval 1999 for use in
  transplantation
     Phase III trials showed SRL + CsA + steroids
      was effective at preventing rejection
     Expanded approval in 2003, as replacement
      for CsA >3 months post-transplant
                  Mechanism

   Proliferation signal inhibitor (PSI)
     Binds to FKBP12, inhibits key kinases in
      signal transduction pathway of IL-2, CD-28
     Cell cycle arrested at G1 → S




                                              www.nature.com
               What’s next?

 Numerous companies, compounds, trials
 Potential targets expand as knowledge of
  T cell activation increases




            Halloran PF. NEJM 2004.
               Everolimus

 2nd “mTOR inhibitor” in transplantation
 Differs in structure by just one
  hydroxyethyl group from sirolimus
 Shorter ½ life (28 vs. 62 hours)

 Approved for use in Europe
Potential benefits of mTor inhibitors

 Potent prophylaxis against acute cellular
  rejection
 Less vasoconstriction

 Not associated with acute or chronic renal
  insufficiency
     Less interstitial fibrosis: down-regulation of
      TGF-β and PDGF
     Sustained GFR
      Key toxicities of sirolimus

 Cytopenias
 Mouth sores, poor wound healing
 Hyperlipidemia
 Enhancement of CNI nephrotoxicity
 Pneumonitis
 Apparent association with proteinuria


Will everolimus have better profile??
                     Costimulation blockade

    Belatacept
       Engineered monoclonal antibody directed
        against CD80/CD86
       Prevents costimulation by blocking interaction
        between CD28 and CD80/CD86




Vincenti F. J Allergy Clin Immunol 2008.
      Non-inferiority to CsA in phase II




Vincenti et al. NEJM 2005
     Renal function and histology

 Measured GFR significantly better in
  belatacept groups than CsA
 Lesser degree of tubular atrophy and
  interstitial fibrosis with belatacept
 Phase III trial now underway in US
BK virus
     BK virus-associated nephropathy

        Double-stranded DNA polyoma virus
              JC → PML
              SV40 → renal disease in immunodeficient monkeys
        1971: BK virus first isolated from a kidney
         transplant recipient with ureteral stricture
        1st reported case of nephropathy in 1993 (Pitt),
         graft failure in 3 months*
        Affects ~8% of renal transplant recipients
        30-60% of affected allografts fail of BKVAN
         within 1 year

* Purighalla R, et al. Am J Kid Dis 1995.
                  Epidemiology

   Estimated that 80-90% of adult population has
    been exposed to BK virus
   Probably multiple routes of transmission, but
    respiratory secretions predominate
   Primary infection may be asymptomatic, mild
    URI, cystitis…
   Enters latent phase, in urogenital tract, lymphoid
    tissue, brain
                     Pathogenesis

   BK replication (viruria) occurs during states of
    immune suppression
       Pregnancy
       Malignancy
       HIV
       Diabetes
       Transplantation
   Viremia (13-20%) & nephropathy (5-8%) are
    unique to the post-kidney transplant setting
           Clinical manifestations

   Risk factors:
     Older, male, White, diabetic recipient
     More HLA mm, ACR, DGF

     Net state of immune suppression

 Asymptomatic allograft dysfunction
 Suspect BK when rejection does not
  resolve with usual therapy
                     Diagnosis

   Viruria precedes viremia and nephropathy
     Urine cytology
     Urine PCR

   Viremia
       More specific for nephropathy
 Screening protocols increasingly used
 Renal biopsy is gold standard
                          BK nephritis

                                   Variable degree of
                                    interstitial inflammation,
                                    fibrosis, atrophy
                                   Nuclear inclusions
                                   Similar in appearance
                                    to cellular rejection
                                   Immunohistochemistry
www.kidneypathology.com             useful
                    Treatment

   Reduce immune suppression
     Stop antiproliferative
     Stop steroids

     Cut CNI and antiproliferative doses by 50%

   Noteworthy that all other treatments for
    BKVAN include reducing IS…
     Cidofovir
     Leflunomide
Allocation
    Current Deceased Donor Kidney
         Allocation Algorithm
   Standard criteria donor (SCD) kidneys
       5% - kidney plus life saving organ
       15% - zero HLA-A,B,DR mismatched candidates
        (mandatory national sharing)
       65% - HLA mismatched candidates based upon a point
        system
          Time on waitlist

          0-2 points for degree matching at HLA-DR locus

          Points awarded to sensitized candidates, pediatric
           candidates, and previous kidney donors
   Expanded criteria donor (ECD) kidneys based on
    waitlist time alone
      Concerns with allocation system

    OPTN Kidney committee began reviewing
     performance of the current algorithm in
     2004
    3 principal areas of concern:
    1. Allocation system itself: inequitable,
       inefficient, suboptimal utility
    2. Donor organ supply limitations

    3. Effects of geography on allocation equity
                     Geographic disparity




                                            Median Waiting Time, Blood Group A

                                     6.0                         5.6

                                     5.0
                                     4.0                                                 3.5
                                                 3.2
                             Years


                                           2.8                               3.0                     2.8
                                     3.0               2.7 2.6
                                                                       2.2         2.2         2.4
                                     2.0
                                     1.0
                                     0.0
                                           1     2     3    4     5    6     7     8     9     10 11
Data source: www.optn.org
                                                                OPTN Region
    Life Years From Transplant (LYFT)
   LYFT is the difference between two
    predicted lifetimes:
       Expected lifetime without a transplant
       Expected lifetime with a transplant from a
        specific donor
   Example, a hypothetical 30 year old (otherwise
    average) candidate’s remaining life might be:
       18 years with a deceased donor kidney transplant
       12 years with dialysis
       LYFT = 6 extra years of life with transplant
   This hypothetical candidate’s LYFT would be
    greater if his or her expected survival
       on dialysis would be shorter, or
       post-transplant would be longer
                     Median Survival and LYFT:
     Hypothetical 55 year-old diabetic kidney transplant
                         candidate
          100%

                                  Post-
          75%                     Transplant
                 Waitlist
% Alive




                                                       Median
          50%


          25%


           0%
                 0                5               10            15
                            4.0             7.6
                                                       Years
                                      3.6
Comparison of the current allocation system
      and newly proposed system
 Current Kidney
                                             KAS Simulations*
Allocation System
       HLA Match
                             Medical    Life Years From Transplant (LYFT)
  - Increases allograft
         survival            Criteria      - Increases candidate survival

        Wait time
                                               Dialysis Years (DY)
- Starts at listing or GFR    Time
                                          - Starts at initiation of dialysis
           < 20
                                            Donor Profile Index (DPI):
 Binary: Standard vs.        Donor          - Continuous measure of
Expanded criteria donor      Quality            association with
                                                   graft failure

* Under consideration by the HHS Office of Civil Rights
                 Summary

 ESRD continues to be a growing problem
 Transplantation is the treatment of choice

 The development of new drugs and new
  ways to combine drugs continues
 BK virus is a relatively new concern, and is
  an important source of morbidity
 Changes in the allocation system for
  deceased donor kidneys are likely
Thanks!!

								
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