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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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