New Immunosuppression Horizons in Kidney Transplanta on KDIGO Mumbai, India, February 9, 2014 New Immunosuppression Horizons
• “Golden Era” of RCTs • KDIGO Guideline 2009 • Current Clinical Prac ce • Recent Randomized Trials • New Drug Development KDIGO
Kidney Disease: Improving Global Outcomes Ini al Immunosuppression A empts Joseph Murray Murray & Calne used total body used azathioprine radia on in 14 in 6 transplants — transplants — all died. all died. Murray & Calne Murray & Calne used azathioprine & 6-mercaptopurine treated rejec on used in 2 transplants with steroids — — both died. Melvin Douce e went home! 1958-1960 1960 KDIGO1961 1962
Kidney Disease: Improving Global Outcomes Beginning the Era of RCTs
Equine ATG RCT Canadian CsA RCT (N=50) (N=209) Arch Surg 1976; N Eng J Med 1983; 111:680 309:809
European CsA RCT (N=232) Lancet 1983; 2:986
1976 KDIGO1983
Kidney Disease: Improving Global Outcomes New Immunosuppression Horizons
• “Golden Era” of RCTs • KDIGO Guideline 2009 • Current Clinical Prac ce • Recent Randomized Trials • New Drug Development KDIGO
Kidney Disease: Improving Global Outcomes KDIGO Clinical Prac ce Guideline for the Care of Kidney Transplant Recipients • Systema c reviews by the ERT: 1985 through January 2007 • Evidence updated through: November 2008 • GRADE system used Strength of Recommenda ons: 1 or 2 Strength of Evidence: A, B, C, D “Not Graded” recommenda onsKDIGO
Kidney Disease: Improving Global Outcomes Ques on 1 A 55 year old women with ESRD from diabetes has a living donor for her 1st kidney transplant. PRA 0%; no DSA. You would use the following induc on: A. No an body induc on B. IL-2 receptor antagonist C. Rabbit ATG D. Alemtuzumab E. Other KDIGO
Kidney Disease: Improving Global Outcomes Ques on 2 A 55 year old women with ESRD from diabetes has a living donor for her 2nd kidney transplant. PRA 50%; no DSA. You would use the following induc on: A. No an body induc on B. IL-2 receptor antagonist C. Rabbit ATG D. Alemtuzumab E. Other KDIGO
Kidney Disease: Improving Global Outcomes Induc on Therapy
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Kidney Disease: Improving Global Outcomes Am J Transplant Jan 2009; 9 (Suppl 3): S1 Maintenance Immunosuppression
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Kidney Disease: Improving Global Outcomes Am J Transplant Jan 2009; 9 (Suppl 3): S1 Maintenance Immunosuppression
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Kidney Disease: Improving Global Outcomes Am J Transplant Jan 2009; 9 (Suppl 3): S1 Treatment of Acute Cellular Rejec on
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Kidney Disease: Improving Global Outcomes Am J Transplant Jan 2009; 9 (Suppl 3): S1 Treatment of AMR
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Kidney Disease: Improving Global Outcomes Am J Transplant Jan 2009; 9 (Suppl 3): S1 Treatment of Chronic Allogra Injury
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Kidney Disease: Improving Global Outcomes Am J Transplant Jan 2009; 9 (Suppl 3): S1 New Immunosuppression Horizons
• “Golden Era” of RCTs • KDIGO Guideline 2009 • Current Clinical Prac ce • Recent Randomized Trials • New Drug Development KDIGO
Kidney Disease: Improving Global Outcomes Induc on Therapy
KDIGO
Kidney Disease: Improving Global Outcomes OPTN / SRTR Annual Data Report Am J Transplant Jan 2014 Maintenance CNI Use
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Kidney Disease: Improving Global Outcomes OPTN / SRTR Annual Data Report Am J Transplant Jan 2014 Maintenance An metabolite Use
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Kidney Disease: Improving Global Outcomes OPTN / SRTR Annual Data Report Am J Transplant Jan 2014 Maintenance mTOR Inhibitor Use
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Kidney Disease: Improving Global Outcomes OPTN / SRTR Annual Data Report Am J Transplant Jan 2014 Maintenance Cor costeroid Use
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Kidney Disease: Improving Global Outcomes OPTN / SRTR Annual Data Report Am J Transplant Jan 2014 Adult US Kidney Transplant Outcomes Deceased Donor Transplants
Living Donor Transplants
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Kidney Disease: Improving Global Outcomes OPTN / SRTR Annual Data Report Am J Transplant Jan 2014 New Immunosuppression Horizons
• “Golden Era” of RCTs • KDIGO Guideline 2009 • Current Clinical Prac ce • Recent Randomized Trials • New Drug Development KDIGO
Kidney Disease: Improving Global Outcomes Alemtuzumab: An -CD52 T-Cell & B-Cell– Deple ng Monoclonal An body
(N=164)
(N=171) BPAR
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Kidney Disease: Improving Global Outcomes MJ Hanaway, ES Woodle, et al. N Engl J Med 2011;364:1909 Alemtuzumab: An -CD52 T-Cell & B-Cell– Deple ng Monoclonal An body
* (N=70)
(N=69) BPAR
KDIGO *High-risk: repeat transplant, a peak or current value PRA > 20%, or black race.
Kidney Disease: Improving Global Outcomes MJ Hanaway, ES Woodle, et al. N Engl J Med 2011;364:1909 Acute Rejec on in BENEFIT & BENEFIT-EXT Belatacept MI Belatacept LI Cyclosporine (N=219) (N=226) A (N=221) Acute Rejec on 49 (22%) 39 (17%) 16 (7%) Banff grade IIA 17 (8%) 16 (7%) 6 (3%) Banff grade IIB 20 (9%) 10 (4%) 2 (1%)
Belatacept MI Belatacept LI Cyclosporine (N=184) (N=175) A (N=184) Acute Rejec on 33 (18%) 31 (18%) 26 (14%) Banff grade IIA 10 (5%) 17 (10%) 17 (9%) Banff grade IIB KDIGO16 (9%) 8 (5%) 5 (3%)
F Vincen , et al. Am J Transplant 2010; 10:535 Kidney Disease: Improving Global Outcomes A Durrbach, et al. Am J Transplant 2010; 10:547 Es mated GFR in BENEFIT-EXT
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Kidney Disease: Improving Global Outcomes JO Medina-Pestanta, et al. Am J Transplant 2012; 12:630 Safety Results in BENEFIT & BENEFIT-EXT
Belatacept Belatacept Cyclosporine A Complica on MI (N=403) LI (N=401) (N=405)
PTLD 5 6 2
Tuberculosis 6 6 1 KDIGO
Kidney Disease: Improving Global Outcomes C Larsen, et al. ATC May 2, 2011 Late Switch from CNI to Belatacept
• Randomized, open-label trial: - Stable 6-36 months post-transplant - Group 1 (N=89): continue CNI - Group 2 (N=84): change to belatacept
Belatacept Con nue CNI Complica on (N=84) (N=89) Acute rejec on 6 (7%) 0 Banff grade IIA 3 (4%) 0 Banff grade IIB KDIGO1 (1%) 0
Kidney Disease: Improving Global Outcomes L Rostaing, et al. Clin J Am Soc Nephrol 2011; 6:430 Ques on 3
A 40 year old 1 year a er a deceased donor kidney transplant is on tacrolimus, mycophenolate and prednisone 2.5 mg daily. You would consider switching tacrolimus to an mTOR inhibitor for decreasing eGFR from 60 to 50 mL/min/1.73m2 with Banff Grade 1-2 inters al fibrosis. A. Yes B. No C. Unsure KDIGO
Kidney Disease: Improving Global Outcomes Effect of Rapamycin Conversion at 1 Month on Inters al Fibrosis at 1 and 2 Years
100 90 TAC 80 SRL P=0.71 70 N=25 N=30 60
50 P=0.12 40 N=54 30 N=55 Percent with IFTA ≥ 2 20 P=0.22 10 N=54 N=56 0 1 Month KDIGO1 Year 2 Years
Kidney Disease: Improving Global Outcomes RL Heilman, et al. Transplanta on 2012;93: 47 Effect of Rapamycin Conversion on Cancer
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Kidney Disease: Improving Global Outcomes J Alberu et al. Transplanta on 2011; 92:303 Rapamycin in Pa ents with Skin Cancer
Drug discon nued: 10/64 (15.6%) SRL 3/56 (5%) CNI KDIGO Shaded boxes indicate 95% confidence intervals.
Kidney Disease: Improving Global Outcomes S Euvrard, et al. N Eng J Med 2012; 376(4):329 Ques on 4
A 40 year old 3 years a er a deceased donor kidney transplant is on tacrolimus, mycophenolate and prednisone 2.5 mg daily. You would consider switching tacrolimus to an mTOR inhibitor for new onset diabetes. A. Yes B. No C. Unsure KDIGO
Kidney Disease: Improving Global Outcomes Everolimus for CNI Minimiza on or Loss to follow-up Free from BPAR, Death, Gra loss, KDIGO
Kidney Disease: Improving Global Outcomes D Cibric, et al. Transplanta on 2013; 95:933 Late Conversion from CNI to Everolimus
EVR + CNI EVR + CNI Controls Elimina on Minimiza on (N=123) (N=127) (N=144) BPAR 7 (5.5%) 8 (5.6%) 3 (2.4%) Serious Adverse Events 72 (56.7%)* 78 (54.2%) 52 (42.3%) Proteinuria > 3.5 g/L 10 (7.9%) 15 (10.4%) 5 (4.1%) Hyperlipidemia 36 (28.3%)* 34 (23.6%)* 11 (8.9%) mGFR (mL/min/1.73m2) 48.0±22.0 46.6±21.1 46.0±20.4 KDIGO*P<0.05 v. Controls
Kidney Disease: Improving Global Outcomes H Holdass, et al. Transplanta on 2011 Ques on 5
A 32 year old with no rejec on 6 months a er a living donor kidney transplant, develops diarrhea. He is on tacrolimus, mycophenolate mofe l (MMF) and prednisone. Evalua on for treatable causes of diarrhea is nega ve. You would: A. Reduce the dose of MMF B. Change MMF to EC-mycophenolate sodium C. Change MMF to azathioprine D. Use symptoma c treatment only KDIGO
Kidney Disease: Improving Global Outcomes Effect on GI Symptoms of Conversion to Enteric-Coated Mycophenolate Sodium
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Kidney Disease: Improving Global Outcomes AJ Lagone, et al. Transplanta on 2011; 91:470 Intensified Mycophenolate
• 2 open-label RCTs (N=441) Incidence of BPAR − EC-MMF − 2w 2880/d; 4w 2160/d then 1440/d − Standard 1440/d • Other: − IL2-RA (74%), CsA, steroids 13.8% v. 19.3% P<0.034 • AEs causing dose reduction: − Intensified: 67 (31.5%) − Standard: 45 (20.5%) P=0.011 AUC-12 KDIGO
Kidney Disease: Improving Global Outcomes K Budde, et al. Transplanta on 2011; Conversion to Once Daily Tacrolimus
Once Daily Twice Daily Event at 12 Months P-Value (N=162) (N=162) Efficacy failure* 4(2.5%) 4 (2.5%) N.S. Discon nua on 20 (12.3%)* 4 (2.5%) 0.028 Adverse events 135 (82.7%) 133 (81.6%) N.S. Serious adverse events 36 (22.2%) 26 (16%) N.S. *Death, gra failure, locally read biopsy-proven acute rejec on , or loss to follow-up KDIGO
Kidney Disease: Improving Global Outcomes S Bunnapradist, et al. Am J Transplant 2013; 13(3): 760 Once v. Twice Daily Tacrolimus Adherence
QD (N=145)
BID (N=74)
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Kidney Disease: Improving Global Outcomes DRJ Kuypers, et al. Transplanta on 2013;95: 333 Key RCT Results since the KDIGO Guideline
Alemtuzumab: similar to rATG, possibly less expensive Belatacept: role unclear Rapamycin: role unclear except to prevent skin cancer Everolimus: similar to rapamycin Enteric-coated mycophenolate sodium: role unclear Intensified mycophenolate: role unclear Once daily tacrolimusKDIGO: may improve adherence
Kidney Disease: Improving Global Outcomes New Immunosuppression Horizons
• “Golden Era” of RCTs • KDIGO Guideline 2009 • Current Clinical Prac ce • Recent Randomized Trials • New Drug Development KDIGO
Kidney Disease: Improving Global Outcomes Ques on 6 A 40 year old 3 years a er a deceased donor kidney transplant on low-dose tacrolimus, mycophenolate and prednisone 2.5 mg daily, develops decreasing eGFR 60 to 50 mL/min/1.73m2 over 12 months. Biopsy shows Banff Grade 2 inters al fibrosis, inflamma on in areas of fibrosis, C4d(-), and arteriolar hyalinosis. A single DSA is posi ve in low ter. This is most likely: A. Chronic an body-mediated rejec on B. CNI toxicity C. Non-adherence D. A combina on of the above KDIGO
Kidney Disease: Improving Global Outcomes New Immunosuppression Horizons
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Kidney Disease: Improving Global Outcomes A Webber, et al. Transplanta on 2011; 91:1057 Tofaci nib versus CsA
CsA CP MI CP LI Complica on (N=109) (N=106) (N=107) BPAR at Month 12 18.8% 17.4% 15.4% mGFR (mL/min) 53.9 64.6* 64.7* CMV disease 4.5% 19.5%* 13.3%* PTLD 0 2# 1
# *p<0.05 vs. CsAKDIGO; 2 more cases of PTLD a er 12 mo.
Kidney Disease: Improving Global Outcomes F Vincen , et al. Am J Transplant 2012; 12(9):2446 Sotrastaurin with Tacrolimus Minimiza on
*
KDIGO *BPAR, gra loss, death or lost to follow-up .
Kidney Disease: Improving Global Outcomes K Budde, et al. Am J Transplant 2010; 10:571 Sotrastaurin versus Tacrolimus
*
*BPAR, gra loss, death or lost to follow-up at month 3. KDIGO
Kidney Disease: Improving Global Outcomes S Friman, et al. Am J Transplant 2011; 11(7): 1444 Alefacept Phase II RCT
Control A+Low Tac A+Tac A(qow)+Low Tac Parameter (N=79) (N=77) (N=75) (N=78) BPAR (%) 12.7 26.3* 18.8 16.7 CD4+ T memory 538.6 335.2* 330.9* 268.8* (cells/mm3) CD8+ T memory 146.3 84.8* 92.0* 56.2* (cells/mm3) *P<0.05 versus control KDIGO
Kidney Disease: Improving Global Outcomes J Bromberg, et al. ATC May 4, 2011 Alefacept Phase II RCT
KDIGO
Kidney Disease: Improving Global Outcomes L Rostaing, et al. Am J Transplant 2013; 13(7):1724 Rituximab Induc on
(N=1/7)
(N=5/6) KDIGO
Kidney Disease: Improving Global Outcomes MR Clatworthy, et al. N Eng J Med 2009; 360:2683 Rituximab Induc on
Rituximab Placebo P-Value (N=68) (N=68) Treatment failure* 10 (14.7%) 14 (20.6%) 0.348 at 6 months BPAR at 6 months 8 (11.6%) 12 (17.6%) 0.317
*Acute rejec on, gra loss, or death during the first 6 months KDIGO
Kidney Disease: Improving Global Outcomes G Tyden, et al. Transplanta on 2009;87: 1325 Rituximab Induc on
Rituximab Placebo P-Value (N=138) (N=142) BPAR at 6 mo. 15.9% 21.8% 0.15 BPAR at 6 mo. in N=62 with 17.9% 41.1% 0.039 PRA>6 or re-transplant Pa ent survival at 24 mo. 92.3% 92.8% 0.87 Gra survival at 24 mo. 88.7% 87.7% 0.93 KDIGO
Kidney Disease: Improving Global Outcomes M. van den Hoogen, et al. ATC 2013 (abstract 266.1) Systema c Review of AMR Treatment
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Kidney Disease: Improving Global Outcomes DM Roberts et al. Transplanta on 2012;94: 775 Rituximab Treatment of Acute Cellular Rejec on with B-Cell Infiltrates
• Rituximab in acute cellular tubulointers al rejec on with B-cell infiltrates (RIACT). • Randomized, double-blind, placebo-controlled, parallel group Phase III study. • Addi on to standard treatment with steroids • Endpoint: 1-year kidney func on • N=180 KDIGO
Kidney Disease: Improving Global Outcomes L Schiffer et al. Trials 2012; 13:199 Ongoing Phase II Bortezomib Trials
• Preven on of AMR in sensi zed pa ents • Treatment of late AMR
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Kidney Disease: Improving Global Outcomes Ongoing Phase II Eculizumab Trials
• Preven on of AMR in sensi zed pa ents • Preven on of AMR in XM(+) pa ents • Treatment of acute AMR
• Treatment of chronic AMR • World's most expensive drug? (Ma hew HerperKDIGO, Forbes, Feb. 22, 2010)
Kidney Disease: Improving Global Outcomes Promising Pipeline?
Tofaci nib: higher rate of PTLD versus CsA Sotrastaurin: more rejec on versus tacrolimus Alefacept: more rejec on versus tacrolimus Rituximab: phase III induc on & AMR treatment trials Bortezomib: phase II induc on & AMR treatment trials Eculizumab: phase II induc on & AMR treatment trials KDIGO
Kidney Disease: Improving Global Outcomes New Immunosuppression Horizons
• “Golden Era” of RCTs • KDIGO Guideline 2009 • Current Clinical Prac ce • Recent Randomized Trials • New Drug Development KDIGO
Kidney Disease: Improving Global Outcomes