Update on Renal Transplantation

1. Update on Renal Transplantation Clifford Miles, MD, MS University of Nebraska Medical Center

2. 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

3. Adjusted prevalent rates & annual percent change Figure 2.22 December 31 point prevalent ESRD patients; rates adjusted for age, gender, & race.

4. ESRD and life expectancy N Engl J Med 1998; 338:20

5. Adjusted Relative Risk of Death:Deceased-donor Txp recipients compared to Waitlisted candidates Wolfe, et al. N Engl J Med 1999; 341:1725-30.

7. Number of transplants, by donor typeFigure 7.1 Transplant counts as known to the USRDS (reconciled from various sources).

10. Causes of graft loss

11. Immune suppression

12. Prednisone Azathioprine Cyclosporine Tacrolimus Mycophenolic Acid Sirolimus Daclizumab Basiliximab OKT3 Polyclonal Anti-Thymocyte Globulin Rituximab† Alemtuzumab† Current Immunosuppressive Agents † use is off-label in transplantation

14. Calcineurin inhibitors • Prevent rejection by inhibiting IL-2 gene transcription • Cyclosporine (1983): Sandimmune, Neoral, Gengraf • Tacrolimus (1994): Prograf, generic available outside US

15. 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

16. Baseline calcineurin inhibitor use Figure 7.57 First-time, kidney-only transplants, 1995–2005. Immunosuppression as identified to OPTN.

17. 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

18. Mycophenolic acid (MPA) Mycophenolate sodium Mycophenolate mofetil

19. Baseline antimetabolite use Figure 7.58 First-time, kidney-only transplants, 1995–2005. Immunosuppression as identified to OPTN.

20. 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

21. 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

25. What’s next? • Numerous companies, compounds, trials • Potential targets expand as knowledge of T cell activation increases Halloran PF. NEJM 2004.

26. 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

27. 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

28. 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??

29. 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.

30. Non-inferiority to CsA in phase II Vincenti et al. NEJM 2005

31. 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

32. BK virus

33. 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.

34. 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

35. 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

36. 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

37. Diagnosis • Viruria precedes viremia and nephropathy • Urine cytology • Urine PCR • Viremia • More specific for nephropathy • Screening protocols increasingly used • Renal biopsy is gold standard

38. BK nephritis • Variable degree of interstitial inflammation, fibrosis, atrophy • Nuclear inclusions • Similar in appearance to cellular rejection • Immunohistochemistry useful www.kidneypathology.com

39. 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

40. Allocation

41. 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

42. Concerns with allocation system OPTN Kidney committee began reviewing performance of the current algorithm in 2004 3 principal areas of concern: Allocation system itself: inequitable, inefficient, suboptimal utility Donor organ supply limitations Effects of geography on allocation equity

43. Geographic disparity Data source: www.optn.org

44. 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

45. 4.0 7.6 3.6 Median Survival and LYFT:Hypothetical55 year-old diabetic kidney transplant candidate Post-Transplant Waitlist Median

46. Comparison of the current allocation system and newly proposed system * Under consideration by the HHS Office of Civil Rights

47. 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

48. Thanks!!