Renal Transplantation

1. Renal Transplantation Daniel Shoskes MD, FRCS(C) Professor of Surgery/Urology Glickman Urological and Kidney Institute Cleveland Clinic

2. Topics to Cover • Basic Transplant Immunology • Immunosuppressive Drugs • Evaluation of Recipient and Donor • Surgical Techniques and Complications • Early and Late Patient Management Issues

3. Renal Transplantation • Usually preferred form of renal replacement therapy • Cost effective if transplant lasts more than 2 years • Exchange disease of renal failure with "disorder" of being a transplant recipient • infections, cancer, diabetes, HTN, cardiac

4. Laws of Transplantation • Isografts Succeed • Xenografts Fail Immediately • Allografts Fail • Self vs Non-Self • Safe vs Danger

5. How to Detect and Respond to Danger? • Innate Immunity • Macrophages, Monocytes, PMN's, complement, NK cells • Acquired Immunity • Cellular • T cells, B cell • Humoral • Antibodies

6. T cells see processed antigen receptor is "T cell Receptor" need antigen presenting cell second signals activation produces cytokines kill via cell surface molecules B cells see whole antigen (tertiary structure) receptor is antibody need T cell cytokine signal activation produces antibody kill via complement fixation Antigen Recognition

7. HLA (MHC) • Class I • HLA-A, B, C • most nucleated cells • binds to CD8 on T cells • presents intracellular peptides (eg viral) • Class II • HLA-DR, DP, DQ • Antigen Presenting Cells (APC's) (dendritic cells, macrophages, endothelial cells) • binds to CD4 on T cells • presents extracellular peptides (eg bacteria)

8. Polymorphism: Improves chance that population survives new pathogen

9. T cell Antigen Education • Thymus • positive selection for self HLA (MHC) • negative selection for self peptides • Periphery • may see foreign HLA antigen "directly" (altered self) or "indirectly" (processed antigen) • CD4-class II CD8-class I • failure of second signal ("harm, danger") leads to anergy or deletion

11. Immune Cell Activation • Macrophages, Dendritic cells - TNF, IL-1 in response to local trauma (cull the herd?) • CD4 T cells • IL-2, IFNg, clonal expansion, NK cells • activation->intracellular Ca++-> calcineurin -> NFAT->IL-2 transcription • B cells • antibodies, antigen presentation to T cells • CD8 T cells • perforin, granzyme

13. Immunosuppression • Required for the life of the kidney • Modern protocols have dropped rates of acute rejection to 10% and increased 1 year graft survival to near 90% • All immunosuppression increases risk of infections and certain malignancies • Other side effects specific for each agent

15. Antibody Agents • Non-Depleting (bind to IL-2 receptor, prevent but don't treat rejection) • basiliximab (Simulect) • 2 doses, minimal specific side effects • Depleting (Prevent and treat rejection) • thymoglobulin, OKT3 • cytokine release syndrome, ARDS, profound leukopenia • cover with anti-viral and anti-pneumocystis carinii drugs

16. Calcineurin Inhibitors • Used to prevent rejection • cyclosporine (Neoral, Gengraf) and tacrolimus (Prograf) • Similar modes of action • Both nephrotoxic, increase hypertension • More cosmetic changes with cyclosporine • More neurotoxicity and diabetes with tacrolimus • tacrolimus superior in high risk patients

17. CI Dosages and Levels • Cyclosporine • 8 mg/kg/day divided q12h • target trough 275-350 ng/ml, drop to 175-200 after 6 months, but 2hr post is better • Tacrolimus • 0.15 mg/kg/d divided q12h • target trough 10-15 ng/ml, drop to 6-10 after 6 months

18. Practical Considerations • Drug Levels • try to approximate area under the curve exposure with limited data • trough levels most common, C2 (2 hours post dose) increased usage • IV dosing -> 1/4 to 1/3 oral dose • Drug interactions (cyt P450) • Raise: diltiazem, verapamil, ketoconazole, fluconazole, erythromycins, allopurinol, Reglan, ciprofloxacin, grapefruit juice • Decrease: Dilantin, phenobarbitol, rifampin, St. John's wort

19. Anti-Metabolites • mycophenolate mofetil (Cellcept, Myfortic) has replaced azathioprine (Imuran) as agent of choice • Prevents and may treat rejection • Some evidence for long term benefit even if no rejection • Primary side effects reduced WBC and GI (diarrhea, nausea)

20. Steroids • Mainstay of immunosuppression since inception but significant side effects • conventional dose blocks IL-1, high dose blocks IL-2 • typical protocol starts 500 mg Solumedrol IV q12h x 3 then taper to 40 mg Prednisone qd by day 5, 20 mg qd by 1 month and 0.1 mg/kg qd long term

21. Sirolimus • Novel mechanism of action • Reduced rejection combined with cyclosporine • Most difficult side effects are increased lipids, wound complications and reduced white count • Almost no role early post transplant, may switch if calcineurin inhibitor toxicity

22. Early Immunosuppression Combinations: IL-2R blocker (basiliximab), tacrolimus, mycophenolate mofetil, steroids Thymoglobulin, delayed tacrolimus, MMF, steroids Thymoglobulin, tacrolimus, MMF (steroid free)

23. Acute Rejection Treatment • Cellular only (Banff I) • steroid pulse • Resistant or vascular (Banff II-III) • OKT3, thymoglobulin • plasmapheresis if antibodies • IV immunoglobulin, anti-B cell antibodies • off label bortezomib (Velcade) proteasome inhibitor

24. Recipient Evaluation • Active infection • Malignancy • Recurrence of primary disease • Early mortality • Technical complications • Noncompliance • Lack of social or financial resources

25. Malignancy • Renal • No waiting period if incidental lesion • 2 years if symptomatic • Best to remove complex cystic mass • Bladder, Prostate, Testis • 2 years • beware need for BCG • evolving data suggests prostate cancer not a barrier (treated or untreated)

26. Recurrence of Primary Disease • High risk, High consequence • focal segmental glomerular sclerosis (FSGS), oxalosis (liver), hemolytic uremic syndrome (HUS) • High risk, low consequence • diabetes, IgA Nephropathy • Low to zero risk • polycystic kidney disease, primary reflux

27. Technical Issues • Peripheral Vascular Disease • safe kidney location, risk of steal • Lower urinary tract • clean intermittent self catheterization safe and effective • transplant to augment or diversion similar long term outcome • "dry TURP" prone to strictures and contractures • bladders will expand unless fibrosis

28. Native Nephrectomy • Suspicion of malignancy • Massive size • Grade 4-5 reflux • Massive proteinuria • Intractable hypertension • Recurrent stones • Recurrent UTI

29. Kidney Donors • >50% now living donor source in USA • cadaveric criteria expanded to include double kidneys at extremes of age and non-heart beating donors • brain death -> organ dysfunction • well matched cadaveric fares worse than poorly matched LRD

30. Risks to the Living Donor • Mortality 0.03% • Morbidity • Major 0.2% • Minor 8% • No increased risk of renal failure or hypertension compared to siblings • Extensive medical investigations give net survival benefit

31. Pros possibly smaller incision shorter hospital stay less pain medication faster return to work increased donor acceptance so far, graft survival is equivalent Cons increased operative time shorter blood vessels right kidney may pose challenge, violate “leave donor with better kidney” rule increased ischemic injury to kidney, DGF more common Laparoscopic Kidney Donation

32. Cadaver List • National list for “zero mismatch” kidneys • Regional list for local donors • For each donor, a list is generated of patients with the same blood group according to points • waiting time • high antibody levels • degree of HLA antigen match (esp B-DR) • other local variances (eg children) • First 2 healthy recipients with negative cross-match get the kidneys

33. Tissue Typing • Panel reactive antibody (PRA) - risk of positive crossmatch • Crossmatch - look for preformed antibodies mixing donor cells and recipient serum plus complement • Flow cytometry more sensitive, less specific • Better matching = better long term results when all else equal but donor quality trumps HLA

34. Cross Match • “T Cell” = HLA class I target • “B Cell” = HLA class II target • T cell cytotoxic +ve • Never do the transplant • T cell neg, B cell cytotoxic +ve • first time recipient OK with antibody induction • re-do very high risk, esp if repeated DR donor • T cell flow +ve • first time OK with antibody unless high titer • do not transplant re-do • B cell flow +ve • only problem re-do with high titer

35. Ischemia-Reperfusion and DGF • Ischemia and reperfusion at surgery produce injury that can promote inflammation and rejection • Delayed graft function strong predictor of graft survival independent of rejection • Pulsatile perfusion can improve early function, especially with long cold ischemia times • Perioperative maneuvers • hydrate with colloid • mannitol • furosemide • intra-arterial verapamil • low dose dopamine

36. Intra-operative Decisions • Preserve lower pole arteries (ureter) • Right renal vein -> caval extension • Can use cadaveric iliac vessels • Conjoin arterial branches or end-side • Small lower pole vessel end-end to inferior epigastric artery • Can use ipsilateral native ureter end-end without native nephrectomy

37. Common Questions • Preserve lower pole artery, tie off small upper pole • 2 ureters conjoined or separate • 1 donor kidney has minor anomaly -> always transplant THAT kidney • may tie off any small venous branch • close ureteral gap • Boari, Psoas Hitch, U-U, U-P, P-C, ileal

41. Surgical Risks • Vascular leak or thrombosis (1-2%) • re-operation, high risk to lose kidney • Urine leak or obstruction (4-5%) • may need re-operation, low risk to lose kidney • many endoscopic approaches, surgery for early leaks, necrotic ureter or endo failure • Lymphocele (5-10%) • percutaneous drainage, sclerosis, peritoneal window • Wound infection / hernia

44. Early Graft Dysfunction • Check Foley, fluid bolus, Lasix, drug levels, ultrasound, renal scan, biopsy • Ddx: ATN, acute rejection, drug toxicity, vascular compromise • (ACE inhibitor, renal artery stenosis) • Acute Rejection • Steroids • Antibody (thymoglobulin or OKT3)

45. Long Term Issues • Chronic allograft nephropathy • Hypertension, Diabetes • Heart Disease (#1 cause of graft loss) • Infections • Erectile Dysfunction (vascular and hormonal)

47. CMV • “42 day fever” • may be transmission or reactivation • donor + to recipient - highest risk • prophylaxis with acyclovir, gancyclovir, valgancyclovir or Cytogam • disease • GI, liver, glomerulopathy, retinitis

48. BK Virus • Polyoma virus, latent in immunocompetent • Nephropathy in about 8% of recipients • Dx: Cytology, viuria, viremia, biopsy • Rx: minimize immunosuppression • GU Manifestations • nephropathy, graft loss • sterile pyuria (also in pregnancy) • ureteral stenosis • hemorrhagic cystitis

49. Expected Results • 1 year graft survival 87-94% • 3 year graft survival 76-87% • Graft half life 9-16 years • Risk of acute rejection episode 8-30%

50. A transplant patient has a baseline serum Cr of 1.8 mg/dl and takes tacrolimus, MMF and steroids. Because of persistent hypertension, he is started on an ACE inhibitor. One week later the Cr is 3.1 mg/dl. The most likely explanation is: • Acute rejection • Renal artery stenosis • Hypotension and acute tubular necrosis • Acute renal vein thrombosis • Tacrolimus toxicity since the ACE inhibitor raised the blood levels