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!!