Renal transplant for medicine resident

Renal Transplant for the Medicine Resident Karin True Renal Transplant Fellow Introduction  Transplant patients are difficult to take care of in the hospital       Have nonspecific symptoms, often are very ill Lots of caregivers involved – surgeons, nephrologists, transplant coordinators Many different opinions on how to treat them Patients often very particular about their care Medications are not familiar – levels, interactions, etc. Usually have most of their labs elsewhere  Transchart a valuable tool, fellows/coordinators can help Kidney Transplantation is the Treatment of Choice for ESRD  Reduced morbidity    Improved quality of life Return to work Reduced hospitalization rates    Mortality Advantage Reduced cost to the health care system Female fertility Mortality in ESRD Deaths/100 Dialysis Patient Years 20 18 16 14 12 10 8 6 4 2 0 19.9 13.3 10.8 5.6 3 Cadaveric Transplant www.unos.org Diabetes No Diabetes 4.3 All dialysis Wait List Relative Risk of Death in Transplant vs. Dialysis (Marginal and Ideal Donors) J Am Soc Nephrol 12:589, 2001 “Marginal” donors    Better referred to as Extended Criteria Donors (ECD) Previously would have been discarded Age 50-59 with 2 of 3 of the following:    Terminal Cr > 1.5 CVA HTN  Age 60+ Waiting List/ Deceased Donor Kidney Disparity Am J Transplantation, 2(10): cover, 2002 Kidney Donation in US National Median Waiting Times 2000 1800 1600 1400 1200 1000 800 600 400 200 0 Type O Type A Type B Type AB Median Waiting Time www.unos.org UNOS Point System For Deceased Donor Kidney Allocation      Zero antigen mismatch = National mandatory sharing program Point System for Sharing Within Regional OPO  Time On List 1 point/year  O DR mismatch 2 points  1 DR mismatch 1 point  PRA >80% 4 points  Prior kidney donation 4 points  Child <11 years 4 points  Child 11-17 years 3 points Expanded criteria donor: Longest waiting patient NO points for medical urgency Latest revision 6/20/06, new allocation schema on its way T-cell Activation Three Signal Pathway NEJM 2004; 351: 2715 - 2729 T-cell Activation Three Signal Pathway     Signal 1  MHC/peptide antigen: TCR/CD3 Signal 2  CD80 (B7-1), CD86 (B7-2): CD28 Signal 1 + 2 pathway  Ca++-calcineurin, MAP kinase, Protein kinase C  Activate nuclear transcription factors (NFAT, AP-1, NF-kB)  IL-2, CD25 (IL-2R a chain), CD154 Signal 3  IL-2: IL-2R (incl gc chain:JAK3)  PI-3K, mTOR initiate cell cycle Immunosuppressive Rx Site Of Action NEJM 2004; 351: 2715 - 2729 Induction Therapy     Anti-thymocyte globulin (Thymoglobulin®) Alemtuzumab (Campath®) Basiliximab (Simulect®), Daclizumab (Zenapax ®) Corticosteroids Maintenance Therapy       Cyclosporine (Neoral®, Gengraf®, Sandimmune®) Tacrolimus (Prograf®) Mycophenolic acid (Cellcept®, Myfortic®) Azathioprine (Imuran®) Sirolimus (Rapamune®) Corticosteroids Treatment of Acute Rejection       Corticosteroids Anti-thymocyte globulin (Thymoglobulin®) OKT3 (Muromonab®) IVIG Plasmapheresis Rituximab (Rituxan®) First a word about drug levels….      Can measure trough levels of cyclosporine, tacrolimus, sirolimus and Cellcept/Myfortic Ideally drawn immediately prior to next scheduled dose Need to be drawn frequently when patients are ill as levels can change with N/V, diarrhea, etc. Double check MARs when levels not what you would expect Verify dose changes with renal service The Calcineurin Inhibitors Cyclosporine and Tacrolimus Origin of Species  Cyclosporine: small (11aa) cyclic polypeptide, fungal origin  Tacrolimus: macrolide isolated from Streptomyces spp. Mechanism of Action Bind to cytosolic receptor proteins:  Cyclophilin (cyclosporine)  FKBP12 (tacrolimus) Complex binds to and inhibits action of calcineurin Inhibits the transcription of cytokines essential for T-cell activation and proliferation (e.g., IL-2) The Calcineurin Inhibitors Cyclosporine and Tacrolimus The Calcineurin Inhibitors Adverse Effects Nephrotoxicity  Renal artery vasoconstriction  Enhanced TGF-b expression  Thrombotic microangiopathy Hypertension (csa > tac) Hypercholesterolemia (csa > tac) Post transplant diabetes mellitus (tac > csa) Neurotoxicity (tac > csa) Electrolyte abnormalities  Incr K+, Type IV RTA, decr Mg++  Hyperuricemia/gout (csa > tac) Cosmetic complications  Cyclosporine: hirsutism, gingival hyperplasia  Tacrolimus: alopecia The Calcineurin Inhibitors Drug Interactions    Increased CSA level Diltiazem, verapamil, nicardipine, +/-amlodipine Ketoconazole, fluconazole, itraconazole Erythromycin, clarithromycin Lansoprazole, rabeprazole Corticosteroids, OCP Allopurinol Metoclopramide Amiodarone Grapefruit juice Decreased CSA level            Rifampin, rifabutin Phenytoin, phenobarbital, carbamazepine Ticlodipine Cholestyramine, octreotide, orlistat St. John’s Wort Cyclosporine (Neoral®, Gengraf®, and Sandimmune®)      Dose: 2.0-2.5 mg/kg PO BID Microemulsion formulations (Neoral, Gengraf)  improved GI absorption  not bile dependent PO: IV conversion 3:1 dose ratio C-2 level more predictive of AUC vs. 12h trough level Target 12h trough [and C2] levels in kidney tx:  0 - 6 wks 200-250+ ng/ml [1200+]  6 - 12 wks 150-200 ng/ml [1200]  3 - 12 mo 100-150 ng/ml [1000]  12+ mo 100 ng/ml [800] Tacrolimus/ FK506   ®) (Prograf  Dose: 0.05 - 0.1 mg/kg PO BID Target 12h trough levels in kidney tx:  0 - 6 wks 8 - 12+ ng/ml  6 - 12 wks 6 - 8 ng/ml  3 - 12 mo 4 - 6 ng/ml  12+ mo 2-4 ng/ml Tacrolimus vs. Cyclosporine:  Tacrolimus +/- more effective vs. acute rejection  +/- increased BK nephropathy incidence  Side effect profiles Mycophenolic Acid ®) and Myfortic   ® (Cellcept Origin of Species  Mycophenolic acid (MPA): isolated from Penicillim spp. Mycophenolate mofetil (MMF): a prodrug of MPA Myfortic® (MYF): enteric-coated MPA preparation Mechanism of Action  Competitive, reversible inhibition of IMPDH, a critical ratelimiting enzyme in de novo purine synthesis   Lymphocytes dependent on de novo pathway vs. salvage pathway utilized by other cell types Inhibits proliferation of B + T lymphocytes Mycophenolic acid Mycophenolic acid Clinical Outcomes in Renal Transplantation Decreased incidence of acute rejection vs. azathioprine  18-20% acute rejection vs. 38% in CSA + steroid regimens No difference in patient + 1 yr graft survival  No difference b/w 2-3 gm/d MMF regimens MPA + calcineurin inhibitor regimens vs. azathioprine  Decreased early + late allograft rejection  Increased patient + renal graft survival  Mycophenolic acid Pharmacology Dose   MMF: 500-1000 mg PO BID to TID MYF: 360-720 mg PO BID (MYF 360 mg: MMF 500 mg) Drug Interactions  Antacids, cholestyramine, sevelamer, FeSO4: decr MPA level  Rifampin, phenytoin, phenobarbital: decr MPA level  Corticosteroids, cyclosporine: decr MPA level  Tacrolimus, sirolimus: no change MPA levels Therapeutic drug monitoring  MPA trough level +/- 1.7 – 2.7 mg/L Mycophenolic acid Adverse Effects Gastrointestinal:  Abdominal pain, gastritis, nausea, vomiting, diarrhea  Dose related, increased incidence > 2g MMF/d  GI side effect profile not significantly different b/w the MMF and MYF preparations  Increased patient tolerance + decreased MPA dose adjustments with MYF Hematologic:  Leukopenia, anemia, thrombocytopenia Infection:  Esp. viral infection (CMV, BKN) Azathioprine   ®) (Imuran   Purine analogue Metabolized in the liver to 6-mercaptopurine and then to thiosinosine monophosphate (TIMP) TMP decreases synthesis of DNA precursors and also incorporates into DNA More nonspecific effects than MMF  Effects on DNA synthesis not limited to lymphoid cells Sirolimus (Rapamune®) Sirolimus (Rapamune®) Origin of Species  Macrolide isolated from Streptomyces spp from Easter Island (Rapa Nui) Mechanism of Action  Sirolimus binds to FKBP12  complex binds and modulates the activity of mTOR (mammalian target of rapamycin)  blocks signal 3: inhibition of cytokine/IL-2 induced cell cycle progression from G1 to S phase Sirolimus ®) (Rapamycin Sirolimus    ®) (Rapamune Dose and Therapeutic Drug Monitoring 2-5 mg PO QD Initial loading dose of 6-15 mg PO x1 Target 24h trough levels 5-10 ng/ml Sirolimus increases cyclosporine +/- tacrolimus levels Sirolimus potentiates csa + tacrolimus nephrotoxicity Rifampin, phenytoin, phenobarbital, calcium channel blockers increase sirolimus levels Drug Interactions    Sirolimus (Rapamune®) Adverse Effects Nephrotoxity!  Sirolimus + tacrolimus regimen: increased creatinine and HTN c/w MMF + tacrolimus  Prolonged recovery from ATN, delayed graft function  Thrombotic microangiopathy  Increased proteinuria (?glomerular vs. tubular proteinuria)  ?Collapsing glomerulopathy Hematologic  Anemia, thrombocytopenia, leukopenia Hyperlipidemia, hypertriglyceridemia Pneumonitis Impaired wound healing, lymphocoeles Anti-Thymocyte Globulin ®) (Thymoglobulin Mechanism of action Polyclonal antibody (rabbit) vs. CD3 receptors on T lymphocytes Peripheral blood lymphocyte depletion Indication Induction therapy Treatment of acute rejection AntiThymocyte Globulin (Thymoglobulin®) UNC Infusion Protocol Premedication:  Methylprednisolone 500 mg IV 30+ min pre 1st + 2nd dose  Acetaminophen 650 mg PO  Diphenhydramine 25 mg PO/IV Thymoglobulin infusion:  1.5-2 mg/kg (round dose to nearest 25 mg) IV daily  central line infusion: 4-6 hrs  peripheral line infusion: 8-12 hrs, mix in 500 ml 0.45% NS w/ hydrocortisone 20 mg + heparin 1000 units  Telemetry monitoring with 1st and 2nd dose AntiThymocyte Globulin (Thymoglobulin®) UNC Infusion Protocol Monitoring Parameters  CBC w/ differential, CD3 count > 6hr post infusion  Redose thymoglobulin w/ ALC > 0.1, CD3 > 10  Decrease thymoglobulin dose by 50% for WBC < 2-3, platelets < 50-75K Immunosuppressive Medication Adjustment  decrease ½ dose vs. hold tacrolimus  decrease ½ dose MMF  Restart maintenance dose Rx @thymoglobulin day#5-7  Valganciclovir CMV prophylaxis 450 mg PO QD x 3 months Please call us with any questions – we are here to help!!