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Joong Kyung Kim, MD. Division of Nephrology, Internal Medicine Bong Seng Memorial Hospital, Busan, Korea 2013.1.3. Thailand.

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Presentation on theme: "Joong Kyung Kim, MD. Division of Nephrology, Internal Medicine Bong Seng Memorial Hospital, Busan, Korea 2013.1.3. Thailand."— Presentation transcript:

1 Joong Kyung Kim, MD. Division of Nephrology, Internal Medicine Bong Seng Memorial Hospital, Busan, Korea Thailand

2

3 Three Major causes of ESRD Fig.1. Three major causes of end stage renal disease patients who were initiated renal replacement therapy in each year. (DM: diabetic nephropathy, CGN: chronic glomerulonephritis, HTN: hypertensive nephrosclerosis). Note increase of DM and decrease of CGN.

4 Prevalence of Renal Replacement Therapy

5 Patient Number of RRT Fig. 2. Patient numbers of renal replacement therapy at the end of each year.

6 RRT modalities Fig. 4. Proportion of renal replacement modalities, annual prevalence and incidence. HD: hemodialysis, PD: peritoneal dialysis, KT: kidney transplantation.

7 Kidney transplantation Fig.5. Annual number of kidney transplantation in Korea (including data from KONOS: Korean Network for Organ Sharing). * Survived KT waiting patient number at the end of each year.

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10 1. Pharmacology of Thymoglobulin 2. Clinical Indication of Thymoglobulin - Induction - Rescue Therapy - as a Bridge Therapy in delays of CNI administration

11 Thymoglobulin ® Production Thymoglobulin ® is a purified, pasteurized, gamma immune globulin obtained by immunization of rabbits with human thymocytes Data on file. Genzyme Corporation Rabbit Sera Production Purification and Viral Reduction of IgG Fill/Finish Thymus Immunogen Production

12 Granulocytes CD4, LFA-1, CD45, CD86, VLA-4, CD126, LPAM-1, HLA I B Lymphocytes T lymphocytes CD3/TCR, CD2, CD4, CD5, CD6, CD7, CD8, CD25,CD28, CD30, CD45, CD80, CD86, CTLA-4, VLA-4, LFA-1, LPAM-1, CCR5, CCR7, CXCR4, HLA I, β 2-M CD19, CD20, CD25, CD27, CD30, CD32, CD38, CD40, CD45, CD86, CD95, HLA-DR CD138 Monocytes Endothelium ICAM-1, ICAM-2, ICAM-3 NK cells CD2, CD45, CD56 Plasma cells Cellular Targets The polyclonal antibody contains cytotoxic antibodies directed against a broad array of antigens Bourdage JS, et al. Transplantation. 1995;59:1194 Rebellato LM, et al. Transplantation. 1994;57:685 Bonnefoy-Berard N, et al. Transplantation. 1991;51:669 The mechanism of action of Thymoglobulin is derived from nonclinical (in vitro or animal) data. The clinical relevance of these data is unknown.

13 The polyclonal nature of Thymoglobulin ® : multiple effects on the immune system 1 Thymoglobulin triggering - dose-dependent central and peripheral T cell depletion - complement-dependent lysis and/or T cell activation - apoptosis Preclinical investigation demonstrates that Thymoglobulin has functional effects on lymphocytes including modulation of key cell surface molecules 4 Following lymphocyte depletion, altered homeostasis can be observed with a resulta nt decreased ratio of CD4+/CD8+ T cells 5 and an increase in CD4 + CD25 + Foxp3 + T reg ulatory cells (as shown in ex vivo and in vitro studies) 6,7 1 Mohty M. Leukemia. 2007; Préville X, et al. Transplantation. 2001;71: Starlz et al. Lancet 2003; 361: Michallet M-C, et al. Transplantation. 2003;75: Mueller TF. Transplantation 1997;64: Lopez et al. J Am Soc Nephrol. 2006;17:2844– Lopez et al. Am J Transplant. 2008;8(s2):404. Pharmacodynamics of Thymoglobulin ®

14 Additional hematologic effects, including depletion of white blood cells (WBC) and platelets Note that anti-red blood cell antibodies are removed as a result of the hemoadsorption step in the manufacturing process of Thymoglobulin Cytokine release may also occur after Thymoglobulin therapy 1 Gaber et al. Transplantation 1998;66: Brennan et al. Transplantation 1999;67: Brennan et al. New Engl J Med 2006;355: Guttnann et al. Transpl Proc 1997;29:24. Pharmacodynamics of Thymoglobulin ® cont.

15 Half-life of Thymoglobulin ® Reported Half-lifeThymoglobulin® dosingPopulationReference days (active) From 3 doses x 2.5 mg/kg (7.5 mg/kg) to 4 doses x 10 mg/kg (40 mg/kg) prior to HSCT Pediatric Seidel, 2005 median of 15 days (total) 1 mg/kg on day -4, then 3mg/kg on days -3, -2, -1 prior to HSCT PediatricCall, hours (total - initial T 1/2 ) 13.8 days (total - terminal T 1/2 ) 2.5 mg/kg then 1.5mg/kg/day for 5 to 7 days after renal or cardiac transplant or 1.25 mg/kg/day for 10 days after renal transplant Adult Guttmann, days (total - initial T 1/2 ) 30 days (total - terminal T 1/2 ) 1.5mg/kg for 7-14 days for treatment of renal allograft rejection Adult Regan, days (total - initial T 1/2 ) 30 days (total - terminal T 1/2 ) 7 days (active-initial T 1/2 ) 29 days (active-terminal T 1/2 ) 2.5 mg/kg for 4 days (total of 10mg/kg; n=3) 1.5 mg/kg for 4 days (total of 6 mg/kg; n=22). Adult Waller, 2003

16 Factors Potentially Affecting Clearance: Plasma exchange Thymoglobulin’s depletional effects can be seen soon after treatment, so some level of T cell depletion is likely achieved in crossmatch-positive or ABO-incompatible adult kidney transplants have concomitantly administered thymoglobulin and plasma exchange Although some available Thymoglobulin would have been removed from the plasma 1 Gloor J, et al. Am J Transplant 2003;3: Gloor J, et al. Transplantation 2004;78: Gloor J, et al. Transplantation 2005;80: Stegall M, et al. Am J Transplant 2006;6: Thielke J, et al. Transplant Proc 2005;37: Thielke J, et al. Transplantation 2009;87: Akalin E, et al. Clin J Am Soc Nephrol 2008;3:

17 Factors Potentially Affecting Clearance: Plasma exchange Ipema H, et al. ATC Abstract 612. Day -5Day -3Day -1Day 0Day 1Day 3Day 5Day 7Day 9Day 30 2mg/kg ATG  Blood samples were collected 5 minutes before and 30 minutes after each plasmapheresis session on Days 1,5 and 9  Another blood sample was collected 30 minutes after the end of the ATG infusion on Days 1, 5, 9  A final blood sample was collected on post-operative day 30 PP 2mg/kg ATG 1.5mg/kg ATG Transplant ATG

18 Factors Potentially Affecting Clearance: Plasma exchange Day Pre-PPPlasma exchangePost-PPPost-ATG TotalActiveTotalActiveTotalActiveTotalActive Average ATG concentrations (ug/mL, n=5)  Total ATG levels decreased an average of 59.8 ± 13.9% after each PP session, and active ATG levels decreased by an average of 56.8 ± 17.1%. Ipema H, et al. ATC Abstract 612.

19 Factors Potentially Affecting Clearance Intravenous Immunoglobulin (IVIG) The co-administration of IVIG and Thymoglobulin ® have not reported any apparent drug-drug interactions Dialysis Gamma globulin proteins are typically not removed by dialysis; however, it is theoretically possible that some nonspecific protein binding to a dialysis membrane could occur It is recommended that the full dose of Thymoglobulin be administered after dialysis treatment 1 Glotz, et al. AJT 2002;2: Gloor, et al. AJT 2003;3: Akalin, et al. Transplantation 2003;76: Gallay et al. Clin Transplant 2004;18:

20 Mechanisms of T Cell Depletion by Thymoglobulin Apoptosis via Activation- Induced Cell Death (AICD) 1-4 Antibody-Dependent Cell Cytotoxicity (ADCC) 3,5 Complement-Dependent Cytotoxicity (CDC) 1,4,5 Lysis Killing FasFasL Effector Cell Target Cell Membrane Attack Complex Target Cell Complement Activation C1q Direct Killing by Effector Cell Activated NK Cell Juliusson G, et al. Bone Marrow Transplant. 2006;37(5):

21 Profound lymphopenia (>50% depletion) can be seen as early as 24 hours after infusion and can persist up to one year after treatment period Peripheral lymphocyte depletion is dose-dependent 4 In addition to peripheral lymphocyte depletion, central depletion(lymphoid tissue of the spleen and lymph nodes) 3,4 Thymoglobulin ® has been shown to target a broad range of different lymphocyte subsets 1,5 1 Gaber A, et al. Transplantation 1998; 66: Brennan D, et al. Transplantation 1999; 66: Starlz et al. Lancet 2003; 361: Preville X, et al. Transplantation 2001; 71: Guttmann R, et al. Transpl Proc 1997; 29:24. T Lymphocyte Depletion by Thymoglobulin

22 T-Lymphocyte Depletion by Thymoglobulin ® T Cells/mm 3 Thymoglobulin ® Atgam CD3 CD2 CD3 CD2 Days After Treatment Absolute Lymphocyte Count (x1000) Days After Treatment Thymoglobulin ® Atgam Thymoglobulin ® Dosing: 1.5 mg/kg for 7-14 days for treatment (Gaber) or prevention (Brennan) of renal allograft rejection The phase 3 study by Gaber et al (1998) reported more profound and more prolonged lymphocyte depletion with Thymoglobulin ® compared with ATGAM Similarly, a comparative trial by Brennan et al (1999) reported more profound and prolonged lymphocyte depletion with Thymoglobulin compared with ATGAM P=0.004 (CD2) P=0.004 (CD3) P< Gaber et al, Transplantation 1998;66(1):29-37 Brennan et al, Transplantation 1999;67(7):

23 T Lymphocyte Depletion by Thymoglobulin ® CD4 Cells (%) Thymo Atgam Days After Treatment MALG Days After Treatment CD3 Cells (%) Thymo Atgam MALG Days After Treatment CD8 Cells (%) Thymo Atgam MALG Thymoglobulin® Dosing: 2mg/kg for 5 days for prevention of renal allograft rejection in pediatric patients Similar to previous reports, a study in pediatric renal transplant patients by Brophy et al (2001) reported more profound and more prolonged lymphocyte depletion with Thymoglobulin ® compared with Atgam and Minnesota ALG (MALG) Brophy et al, Pediatr Transplant 2001; 5:

24 Lymphocyte Depletion by Thymoglobulin Peripheral DepletionCentral Depletion Percent of Lymphocyte Subsets Weeks After Treatment Guttmann et al 1997 reported profound decreases (absolute and relative) in a broad range of lymphocyte subsets in peripheral blood throughout the 3 months after Thymoglobulin ® treatment Starzl et al 2003 reported “striking” lymphocyte depletion following Thymoglobulin treatment in lymph nodes biopsied at the time of surgery Thymoglobulin ® Treatment: A single dose of 5mg/kg of Thymoglobulin was administered to solid organ transplant recipients several hours prior to transplant. CD45 CD3 CD8 CD25 CD4 CD16 CD2 Thymoglobulin ® Dosing: 1.25mg/kg for 10 days after renal transplant (French Center); 2.5mg/kg dose then 1.5mg/ kg/day for 5-7 days after renal or cardiac transplant (Canadian Center) W9W7W5W3WIW11 PRE Guttmann et al, Transplant Proc 29:24S-26S, 1997 Starzl et al, Lancet 361: , 2003

25 Hematologic Effects of Thymoglobulin Thymoglobulin ® Dosing: 1.5 mg/kg for 5 days for prevention of renal allograft rejection Consistent with previous reports, Brennan et al (2006) reported initial decreases in white blood cell (WBC) and platelet counts following Thymoglobulin ® therapy. In this study, counts returned to normal by day 14. Days After Treatment Mean WBC Count (x10 -3 /mm 3) Thymoglobulin ® Basiliximab Mean Platelet Count (x10 -3 /mm 3) Thymoglobulin ® Basiliximab Days After Treatment Brennan et al. N Engl J Med 355(19):

26 Thymoglobulin: Core Safety Information; Rev. 11/06 *Dose adjustments due to leukopenia and/or thrombocytopenia are not recommended when Thymoglobulin is used for hematologic indications Leukopenia and Thrombocytopenia: dosage adjustment WBC count (cells/mm 3 ) platelet count (cells/mm 3 ) Thymoglobulin Dose > 3,000> 75,000Full dose 2,000 to 3,00050,000 to 75,000Reduce dose by half < 2,000< 50,000Consider stopping treatment

27 Cytokine Release after Thymoglobulin ® Guttmann et al (1997) reported  Transient increases in the cytokines TNF  and IL-6 in the peripheral blood in the first 24 hours after Thymoglobulin ® infusion  Peak levels of TNF  and IL-6 were reported at approximately 3 hours after starting the infusion  Elevations in other cytokines, such as IL-1  and IFNγ were not observed in this study Thymoglobulin ® Dosing: 1.25mg/kg for 10 days after renal transplant (French Center); 2.5mg/kg dose then 1.5mg/ kg/day for 5-7 days after renal or cardiac transplant (Canadian Center) Guttmann et al, Transplant Proc 29:24S-26S

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29 PODThymoglobulinSteroidsMMFTacrolimus peri-op within 6 hours of transplant 1.5 mg/kg IV infuse peripherally over 12 hours M-PDS 500 mg IV given 1 hour prior to Thymoglobulin 1 gm IV/PO pre-op then 1 g PO/IV Q12h mg/kg IV infuse peripherally over 6 hours M-PDS 250 mg IV given 1 hour prior to Thymoglobulin 1 g PO Q12h 1-3mg PO q 12h within 48hours of transplant mg/kg IV infuse peripherally over 6 hours M-PDS 125 mg IV given 1 hour prior to Thymoglobulin. Adjust to trough levels of ng/ml 5 Prednisone 20 mg PO-daily.. Thymoglobulin induction Protocol

30 Thymoglobulin induction protocol in Bong-Seng Memorial Hospital 51 Tx. 4 MMF 1,5g/day FK 0.1mg/day Trough level 10~12 ng/ml 8~10 ng/ml 1M (Day) Steroid 500mg before thymo 250 mg 125 mg 20mg/day Thymoglobulin ( 1~1.5mg/kg ) 1.5/day ■ The following additives should be placed in 500ml 0.9% or 0.45% Nacl and the IV bag given by peripheral administration 1. Thymoglobulin 1.5mg/kg/day (max 150mg/day). 2. Heparin 1,000 units 3. Infuse peripherally over 12hrs at 1 st time ■ Premedicate with steroid dose, antihistamines and acetaminophen PO/IV 1hour prior to Thymoglobulin use 2 3 Start within 6 hours before transplant

31 CASE 1 F / 61 yr 1993 – ESRD d/t prob. CGN 1993 – CAPD OP – 1 st KTP with LUR (3 /6 mismatch ) 1998 – Acute cellular rejection (GK Bx.) PDS pulse & CsA/MMF -> FK/AZA 1999 – Hemodialysis via Lt. AVF shunt 2008 – 2 nd KTP with deceased donor (4/6 mismatch) PRA class I 67.9%, class II 91.7%, No present DSA

32 Induction Therapy in High Risk Kidney Transplantation 1. 2 nd KT 2. High PRA(PRA class I 67.9%, class II 91.7%, ) 3. History of intractable rejection in 1 st KT 4. Deceaced Donor 5. Old age(to avoid CNI toxicity)

33 Clinical course of CASE 1 Thymoglobulin (1.5mg/kg) FK trough level (ng/dL) MMF 1.5g/day PDS 500mg 250mg 125mg 30mg/day 60mg U/O (cc)

34 Thymoglobulin vs. ATGAM for Induction Therapy Acute Rejection through 10 Years P= Thymo Atgam Time after Transplant (years) Percent 42% Acute Rejection 11% Acute Rejection PLEASE SEE FULL THYMOGLOBULIN ® (ANTI-THYMOCYTE GLOBULIN [RABBIT]) PRESCRIBING INFORMATION INCLUDING BOXED WARNING Hardinger et al. Transplantation. 86(7): , 2008

35 Thymoglobulin vs. ATGAM for Induction Therapy Event-Free Survival through 10 years Time after Transplant (years) Percent Survival Thymo Atgam P=0.011 *Freedom from acute rejection, graft loss, and death 48% 29% Hardinger et al. Transplantation. 86(7): , 2008

36 Thymoglobulin vs. Basiliximab for induction therapy: Efficacy Endpoints at 12 Months P=0.34 P=0.02 P=0.68 P=0.90 P=0.54 The use of Thymoglobulin was associated with a 39% relative reduction in BPAR Quad = quadruple endpoint, BPAR, graft loss, death, DGF *Triple = Triple endpoint, BPAR, graft loss, death, calculated in an ad hoc analysis Brennan et al. N Eng J Med 355: , % 10% 20% 30% 40% 50% 60% QuadTriple*BPARGraft LossDeathDGF Thymoglobulin ® Basiliximab

37 Thymoglobulin vs. Basiliximab for induction therapy: Severity of Acute Rejection P=0.02 P= % 25.5% 8.0% 15.6% 0% 5% 10% 15% 20% 25% 30% BPARAntibody Treated AR Thymoglobulin ® Basiliximab Brennan et al. N Eng J Med 355: , 2006

38 Trends in the use of induction antibodies in the US from 1997 to Padiyar A. et al. Am J Kidney Dis 54: , 2009

39 Trends in the Thymoglobulin Use in US :Report of the TAILOR™ registry THYMOGLOBULIN DOSING mg/kg MEAN CUMULATIVE DOSE ± SD 5.29 ± 1.88 MEDIAN CUMULATIVE DOSE [range] 5.00 [ ] THYMOGLOBULIN ADMINISTRATION PRE-PERFUSION*2468 (87.8%) CENTRAL LINE2071 (89.2%) DOSING INTERUPTIONS PATIENTS REQUIRING DOSE INTERUPTION 821 (35.5%) INTERUPTIONS DUE TO LEUKOPENIA 258 (11.1%) INTERUPTIONS DUE TO THROMBOCYTOPENIA 75 (3.2%) 46.6% 35.4% 18.0% Cumulative Thymoglobulin Dose N=1081N=823 N=418 Gaber et al. Transplantation 94:4, 2012

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41 CASE 2 M / 62 yr 1991 – Colon cancer 2010 – Both ureteral stone remove 2010 – ESRD d/t prob. obstructive nephropathy 2010 – Hemodialysis via AVF shunt 2011 – KTP with LUR (5/6 mismatch) PRA class I 0 %, class II 0 % 2011 – 1 st GK Biopsy (Acute cellular rejection) 2012 – 2 nd GK biopsy (Acute cellular rejection)

42 Clinical course of CASE 2 FK MMF PDS 2 nd GK Bx. Thymoglobulin (1.5mg/kg for 5 days) 1 st GK Bx. Steroid pulse

43 CASE 3 F / 58 yr 1999 – DM, HTN 2008 – ESRD d/t diabetic nephropathy 2008 – CAPD start 2009 – KTP with younger brother (3/6 mismatch) 5 times episode of cross match positive PRA class I 78.6 %, class II 75.0 % Pre KTP plasma exchange (3 times) was done d/t high PRA Cyst of GK aspiration (30cc) & absorbable gelatin sponge add POD 4 – GK biopsy (Acute antibody mediated rejection)

44 Clinical course of CASE 3 GK Bx. Rituximab (375mg/mm 2 ) Plasma exchange (1.0 plasma volume) Thymoglobulin (1.0mg/kg ) PDS 500mg 250 mg 125 mg 30mg/day 60 mg MMF 1.5g/day FK trough level (ng/dL ) Plasma exchange (1.0 plasma volume) 2.0g/day

45 Thymoglobulin as a treatment of acute rejection

46 - To avoid CNI toxicity - To spare CNI - To delay of CNI administration - To early withdraw steroid

47 Thymoglobulin induction protocol for CNI sparing in Bong-Seng Memorial Hospital 51 Tx. 4 MMF 1.5g/day FK 0.1mg/day Trough level 8~12 ng/ml 8 ng/ml 1M (Day) Steroid 500mg before thymo 250 mg 120 mg 30mg/day Thymoglobulin (1.0 mg/kg) 1.0/day ■ The following additives should be placed in 500ml 0.9% or 0.45% Nacl and the IV bag given by peripheral administration 1. Thymoglobulin 1~1.5mg/kg/day (max 150mg/day). 2. Heparin 1,000 units ■ Premedicate with steroid dose, antihistamines and acetaminophen PO/IV 1hour prior to Thymoglobulin use mg 500mg

48 Thymoglobulin give chance to spare CNI use Single shot ATG induction can allow postoperative CNI holiday in patients with heart transplantation - renal sparing and safe strategy 1 A CD3+ count-based thymoglobulin induction regimen permits delayed introduction of CNI in KTP 2 Thymoglobulin can preserve renal function in patients with liver transplantation and delayed initiation of CNI 3 1 Thorac cardiovasc Surg 2009; 56 - V177 2 Wang et al. Clin Transplant 2012: 26: 900–909 3 Bajjoka et al. Liver Transplant 14:66-72, 2008

49 Conclusion. TMG seems to be a safe alternative induction strategy in patients for SF immunosuppression in pediatric renal transplantation. Extended follow-up and greater enrollment are necessary to fully explore the impact of TMG dosing on viral replication posttransplantation

50 Long-term Infectious Complications by Thymoglobulin Dose :Report of the TAILOR™ registry Cumulative Thymoglobulin Dose 1.5 to <5mg/kg5 to <7mg/kg7 to 15mg/kgTotal 12 Months Post-transplant -TAILOR n=862n=664n=290N=1816 CMV Infections 25 (2.9%)38 (5.7%)14 (4.8%)77 (4.2%) - Invasive CMV disease 01 (0.2%)01 (0.1%) EBV Infections 6 (0.7%)2 (0.3%)08 (0.4%) Fungal Infections 17 (2.0%)16 (2.4%)10 (3.4%)43 (2.4%) Bacterial Infections 179 (20.8%)189 (28.5%)83 (28.6%)451 (24.8%) 12 Months Post-transplant -UNOS N=2322 K-M Freedom from Infection-related Death % 5 Years Post-transplant -UNOS N=1174 K-M Freedom from Infection-related Death % Gaber et al. Transplantation 94:4, 2012

51 Viral Infections and Antiviral Prophylaxis :Report of the TAILOR™ registry The majority of recipients received antiviral prophylaxis Viral infections were more common among patients not receiving prophylaxis 103 / / 146 P=0.047 Received Prophylaxis Higher Incidence of Viral Infections at 6 months Among Patients Not Receiving Prophylaxis No Prophylaxis 90% Received Prophylaxis 10% None Percent Receiving Antiviral Prophylaxis Incidence of Viral Infections Gaber et al. Transplantation 94:4, 2012

52 PTLD by Thymoglobulin dose :Report of the TAILOR™ registry Cumulative Thymoglobulin Dose 1.5 to <5mg/kg5 to <7mg/kg7 to 15mg/kg Total 12 Months Post-transplant -per UNOS n=1081n=823n=418N=2322 PTLD incidence6 (0.6%)3 (0.4%)1 (0.2%)10 (0.4%) K-M Freedom from PTLD % 5 Year Post-transplant -per UNOS N=1174 K-M Freedom from PTLD % PTLD incidence did not correlate with Thymoglobulin dose PTLD was more common in EBV D+R- (known risk factor), than other combinations Of 58 EBV D+R- transplants in TAILOR, the majority (95%) did not develop PTLD Gaber et al. Transplantation 94:4, 2012

53 Summary 1. The pharmacodynamics of Thymoglobulin® are complex due to its polyclonal nature 2. Thymoglobulin® acts primarily by triggering dose-dependent central and peripheral T cell depletion 3. Thymoglobulin can be used in induction therapy in high risk renal transplantation 4. Thymoglobulin is alternative good choice in rescuing allograft rejection 5. With the aid of a Thymoglobulin, CNI sparing and early withdrawal of steroid regimen can be tried

54 Conclusion Thymoglobulin is an effective and generally well tolerated option for the prevention and treatment of acute renal graft rejection in renal transplantation

55 Thank you for your attention!

56 Dosage adjustment of Ganciclovir CcrInduction (mg/kg) IntervalMaintenance (mg/kg) Interval > <101.25X 3/wk, post HD 0.625X 3 /Wk Post HD Total Duration: 1wk Induction +2wk Maintenance 1 Ample =250mg or 500mg Use safely for 3 days(HD Pt give 70mg in one dose)


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