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Please Help Us with the Following Prior to the start of the program, check your syllabus to ensure you have the following printed program materials: • Participant Survey and CME Evaluation – In the front of your syllabus – Remove from your packet – Fill out the demographic information at the top – Throughout the program, please take a moment to answer the corresponding Activity Survey questions on this form (slides will be marked as “Polling Questions” throughout the deck) CME Information Please note, all pertinent CME information, statements, and disclosures can be found in your program syllabus, including: • Faculty/Steering Committee and Non-faculty Planner/Reviewer Disclosures • Educational Objectives • Accreditation and Credit Designation Statements • Faculty/Steering Committee Bios Educational Objectives • Describe evidence supporting increased use of higher KDPI kidneys and optimizing allocation of donor kidneys • Apply current evidence regarding strategies to individualize and optimize immunosuppressive therapy to prevent chronic rejection and minimize immunosuppressantassociated toxicity • Identify patients at risk for non-adherence and implement strategies to maximize adherence in patients undergoing kidney transplant Polling Question 1 Activity Survey Please rate your level of confidence in your ability to individualize and optimize immunosuppressive therapy? A. Not confident B. Slightly confident C. Confident D. Very confident E. Expert Case Study • 65-year-old woman, with polycystic kidney disease (PKD) and prior mitral-valve replacement, no other coronary artery dissection (CAD), on waiting list for 2.5 years, expected waiting time in region is ~4 years for her blood type (B). Otherwise healthy. She has no living donors. cPRA = 56. • Called with a kidney offer. Polling Question 2 Activity Survey Which of the following kidneys would you consider for this patient? A. KDPI 98, DCD, CIT 28 hours, terminal creatinine 2.5 mg/dL B. KDPI 87, CIT 12 hours, terminal creatinine 1.1 mg/dL C. KDPI 40, malignant melanoma D. KDPI 37, prior heart transplant recipient on CyA for 20 years, terminal creatinine 3.6 mg/dL E. KDPI 9, HIV-viremia, terminal serum creatinine 1.1 mg/dL Case Study (cont) • Offered a kidney from deceased donor with KDPI 89; 1 DR match, blood type A2 • Deceased donor: 5’6” 180lb AA woman, PMH of HTN for <5 years, DBD due to CVA, terminal Cr 1.1 mg/dL; History of jail time in the past 36 months (no DM, no DCD, HCV negative) Polling Question 3 Activity Survey What advice would you give this patient? A. Decline the kidney, wait for a blood type O donor B. Decline the kidney, wait for a blood type A1 donor C. Decline the kidney, it has a 60% chance of working at 12 months D. Decline the kidney, wait for a PHS-increased donor kidney from a younger donor as national wait times are about 2.7 years E. Accept the kidney Organ Allocation Major New Components as of December 4, 2014 • Replaced SCD/ECD with KDPI • Broader sharing for high KPDI kidneys (>85) • Longevity matching – donor KDPI to recipient expected post-transplant survival (EPTS) • Increased priority for sensitized candidates/CPRA sliding scale • Included pre-registration dialysis time • Incorporated A2/A2B to B Overview of Policy Recipient Donor Allocation to those with “longest expected posttransplant survival” Allocation first to pediatric list, then according to waiting time Allocation according to waiting time Allocation to those who consent (similar to yesterday’s “ECD”) All allocation sequences to be based on KDPI OPTN kidney allocation system (KAS) https://optn.transplant.hrsa.gov/media/1200/optn_policies.pdf#nameddest=Policy_08 Donor and Recipient Factors to Determine Groups KDPI – – – – – – – – – – Donor age Race/ethnicity Hypertension Diabetes Serum creatinine COD CVA Height Weight DCD HCV Candidate Estimated Post Transplant Survival (EPTS) – Candidate age – Candidate diabetes – Prior transplant – ESRD time Sequence A Sequence B KDPI ≤20% KDPI >20% but <35% Highly sensitized 0-ABDRmm (top 20% EPTS) Prior living donor Local pediatrics Local top 20% EPTS 0-ABDRmm (all) Local (all) Regional pediatrics Regional (top 20%) Regional (all) National pediatrics National (top 20%) National (all) United Network for Organ Sharing. Highly sensitized 0-ABDRmm Prior living donor Local pediatrics Local adults Regional pediatrics Regional adults National pediatrics National adults Sequence C KDPI ≥35% but ≤85% Highly sensitized 0-ABDRmm Prior living donor Local Regional National Sequence D KDPI >85% Highly sensitized 0-ABDRmm Local + Regional National Regional sharing is prioritized to optimize utilization Kidney Donor Profile Index (KDPI) KDPI Variables • • • • • • • • • • Donor age Height Weight Ethnicity History of HTN History of diabetes Cause of death Serum creatinine HCV status DCD status United Network for Organ Sharing. Graft Survival and Discard Rates by KDPI 100% 91.5% 90% 80% 90.0% 89.0% 87.9% 86.6% 2-year graft survival 85.2% 83.7% 81.9% 78.9% 76.3% 71.9% 69.9% 70% 60% 55.0% 50% 46.1% 40% 36.3% Discard rate 30% 29.5% 24.5% (Pre-KDPI in DonorNet) 17.8% 20% 12.5% 7.2% 10% 1.6% 0% Kidney Donor Profile Index (KDPI) Gradual decline in graft survival, but steep increases in kidney discard rates. Provided by Alexander Wiseman, MD, FACP. Projected Results • >8000 additional life years annually • Increase in transplants to blood type B, PRA>98 A AB B O Pre-KAS Estimated 35.2 5.1 12.7 47.0 30.1 5.6 17.7 46.6 Diabetes, <50 Diabetes, ≥50 Hypertension Glomerular Polycystic 6.1 25.7 21.1 20.8 7.9 5.8 23.4 21.7 22.7 7.3 AA Hispanic White Other 34.1 14.5 44.3 7.1 35.0 15.2 42.9 7.0 Primary disease Race/ethnicity Israni AK et al. J Am Soc Nephrol. 2014;25:1842-1848. Age Distribution 50 Pre-KAS Estimated -4.1% 40 30 -2.7% 20 10 0 <18 18-34 35-49 50-64 65+ Survival Advantage of Kidney Transplant is Maintained in Elderly ≥70 Years Mortality RR (95% CI) for 2,078 first deceased donor kidney transplant recipients vs 5,667 wait-listed dialysis patients ≥70 years of age Rao PS et al. Transplantation. 2007;83:1069-1074. The Risk of NOT Being Transplanted is High in the Elderly “Almost half (46%) of candidates >60 years…are projected to die before receiving a DDTx” “Older candidates are now at significant risk for not surviving the interval in which a deceased-donor transplant would become available” Schold JD, Meier-Kriesche HU. Clin J Am Soc Nephrol. 2006;1:532-538. Schold J et al. Clin J Am Soc Nephrol. 2009;4:1239-1245. Should You Take a “High KDPI” Kidney or Wait for a “Better Offer”? • High-KDPI KTx • Increased short-term but decreased long-term mortality risk • “Break-even point” of cumulative survival at 7.7, 18.0, and 19.8 months post-KTx with survival benefit thereafter (P<0.01 for each comparison) Massie AB et al. Am J Transplant. 2014;14:2310-2316. Should You Take a “High KDPI” Kidney or Wait for the “Better Offer”? • Benefit of high-KDPI KT • Greatest for those >50 years old and for patients at centers with median wait time ≥33 months Massie AB et al. Am J Transplant. 2014;14:2310-2316. The Combined Risk of Donor Quality and Recipient Age: Higher-quality Kidneys May Not Always Improve Patient and Graft Survival UNOS analysis of 137,311 primary kidney transplant recipients 1995-2010 with follow-up through 2012 • Donor organ quality (by KDPI) was divided into quintiles (very high, high, medium, low, and very low quality) • Recipients 70 -79 years had comparable outcomes if they received low-quality kidneys compared to medium-quality kidneys. (HR death, 1.03, P=0.51; HR graft loss, 1.11; P=0.19) • “Transplanting medium-quality kidneys into elderly recipients does not provide significant advantage over low-quality kidneys” Hernandez RA et al. Transplantation. 2014;98:1069-1076. Peri-operative Risk in Elderly is Dramatically Reduced with Living Donor Transplant • Elderly recipients of LD, SCD, and ECD transplants vs all wait listed patients ≥65 yrs in the USRDS from 1995-2007 • Categorized patients as low, intermediate, or high risk based on presence of comorbidities (ischemic heart disease, congestive heart failure, stroke, peripheral vascular disease) • Zero = Low Risk; One = Intermediate Risk, ≥ Two or Diabetes = High Risk Living Donor SCD ECD Death rate/100 patient years in first year Days to equal Survival Death rate/100 patient years in first year Days to equal Survival Death rate/100 patient years in first year Days to equal Survival Low 3 0 8 203 10 264 Inter. 3 0 8 285 14 304 High 6 76 11 368 16 521 Gill JS et al. Am J Transplant. 2013;13:427-432. First Report on the OPTN National Variance Allocation of A2/A2B Deceased Donor Kidneys to Blood Group B Increases Minority Transplantation • Eligibility: Candidates with at least two consecutive, quarterly IgG anti-A titer <1:8. • Majority of donors were white (86%) and the majority of recipients (61%) were non-white • Rejection rates equivalent, patient survival equivalent to B to B transplants • As of April 23, 2015: – 30 A2/A2B to B transplants performed (vs. 6 in the 5 months before the new KAS policy was implemented) – Only 3.6% of active B candidates were registered to accept potential A2/A2B offers Williams W et al. Am J Transplant. 2015;15:3134-3142. n=101 A2/A2B to B transplants from 2002-2011 Graft Survival Public Health Service (PHS) High Risk Donors: ~10% of Donor Pool Categories of behavior leading to classification of High Risk Donor: MSM IDU Hemophiliac men who have had sex with another man in the preceding 5 years persons who report nonmedical intravenous, intramuscular, or subcutaneous injection of drugs in the preceding 5 years persons with hemophilia or related clotting disorders who have received human derived clotting factor concentrates CSW men and women who have engaged in sex in exchange for money or drugs in the preceding 5 years High Risk Sex persons who have had sex in the preceding 12 months with any person described in items 1-4 above or with a person known or suspected to have HIV infection HIV exposed persons who have been exposed in the preceding 12 months to known or suspected HIV-infected blood through percutaneous inoculation or through contact with an open wound, non-intact skin, or mucous membrane Incarcerated inmates of correctional systems MSM = men who have sex with other men, IDU = injection drug user, CSW = commercial sex worker, HIV = human immunodeficiency virus Seem DL et al. Public Health Rep. 2013;128:247-343. Risk of Window Period Hepatitis-C Infection in High Infectious Risk Donors Systematic Review and Meta-analysis • NAT testing reduces the the estimated window period (WP) for HCV and HIV infection to 7-10 days RISK BEHAVIOR HIV RISK % HIV RISK HEP C RISK % HEP C RISK 1:2000 0.05% risk 1:313 0.3% risk 1:2500 0.04% risk 1:3333 0.03% risk 1:3333 0.03% risk 1:833 0.12% risk Incarcerated 1:10,000 0.01% risk 1:12,500 0.008% Blood transfusion 1:20,000 0.005% risk 1:25,000 0.004% risk IV drug use Men having sex with men Commercial sex worker Kucirka LM et al. Am J Transplant. 2011;11:1188-1200. HCV Transmission Despite Modern Donor Screening Practices: Risks and Responses • 3 clusters (3 organ donors defined as PHS high risk, with negative NAT testing) resulted in 6 cases of acute HCV infection in transplant recipients – 2 with active IDU, one with a history of IDU • Advisable to screen recipients of PHS high risk donors for HCV and HIV 1-3 months after transplant • Recent studies indicate successful eradication of HCV following kidney transplant with direct-acting antivirals (DAA) – Need to consider access to DAA Suryaprasad A et al. Am J Transplant. 2015;15:1827-1835. Humar A et al. Am J Transplant. 2010;10:889-899. Sawinski D et al. Am J Transplant. 2015 Nov 25 (epub ahead of print). Seem DL, et al. Public Health Reports. 2013;128(4):247-343. Case Study • Patient accepts kidney offer • BMI 33, VSS, on BP meds, warfarin, statin, PPI, cPRA 49 • Admitted for transplant, cold ischemia time 21 hours Polling Question 4 Activity Survey Based on available clinical trial data, which of the following de novo regimens has the greatest efficacy (lowest rates of graft loss, rejection, or death) in the first two transplant years? A. Alemtuzumab-Tac-sirolimus-steroid withdrawal (day 5) B. rATG-Tac-MPA-prednisone C. rATG-Tac-MPA-steroid withdrawal (day 5) D. Basiliximab-belatacept-everolimus-prednisone E. Basiliximab-Tac-MPA-prednisone Case Study • Immediate graft function, discharged on day 4 on rATGtacrolimus, mycophenolate (MPA), prednisone • Month 1: Developed wound infection, tac C0 range 5-10 ng/mL, MPA 720 bid, prednisone tapered to 10 mg daily, creatinine remained stable (1.2-1.4) • Month 6: BK viremia on screening, 10K, MPA decreased to 360 bid, prednisone tapered to 2.5 daily Maintenance Immunosuppression Use in USA, 1998-2011 SRTR Annual Data Report, 2012 “Gold-standard” RATG Tac MPA Steroids Rationale for multi-agent regimen • Most efficacious • More immunological targets • Permits reduced dosing of each drug, with less drug-specific toxicity Chapter 1: Induction Therapy Limitations of induction trials No double-blind RCT No long-term outcomes No approved depleting agent Alemtuzumab on the way out Variable maintenance Rx Factors Influencing Selection of Therapies • Established efficacy – RCTs • Immunological risk – Highly sensitized – African-American • Medical risk – Comorbidities – Prior immunosuppressive burden • Potential drug toxicity – CNI – Steroid Chapter 2: Initial Maintenance Immunosuppressive Medications CNI Minimization SYMPHONY OPTICEPT ASSET CNI Elimination CTOT-9 ORION CENTRAL CONVERT ZEUS CNI Avoidance SYMPHONY ORION SYMPHONY: “Low Dose” Tacrolimus 4-7 ng/mL 12-month randomized open-label multicenter trial (n=1645) 4 arms (IL2R induction in “low” arms, MMF/Prednisone for all) At 12 months: Regimen GFR (mL/min) CSA “standard” 57.1 CSA “low” 59.4 TAC “low” 65.4 SRL “low” 56.7 Ekberg H et al. N Engl J Med. 2007;357:2562-2575. SYMPHONY and CNI Minimization Drug Trough: Tac (4-7) CSA (100-200) CSA (50-100) SRL (4-8) 12 months 6.4 142 101 7.5 36 months 6.5 114 103 7.0 Graft survival Ekberg H et al. Am J Transplant. 2009;9:1876-1885. Ekberg H et al. N Engl J Med. 2007;357:2562-2575. “Low-dose” tacrolimus GFR The ORION Study • Tacrolimus elimination [13 wks] • Tacrolimus avoidance • Standard tacrolimus-MMF RCT (n=443) 1. Tac Srl: 66% withdrawn 2. Srl-MMF: 60% withdrawn (arm terminated) 3. Tac-MMF: 37% withdrawn Primary endpoint: 1 year GFR: no difference between groups Adverse events • SRL arms had higher rates of: – withdrawal from study – Acute rejection (15% vs 32% vs 8%) Flechner SM et al. Am J Transplant. 2011;11:1633-1644. Tac Withdrawal in Immunologically Quiescent Recipients (CTOT9) • Prospective study, nonsensitized, primary live donor recipients • rATG-Tac-MMFprednisone for all, randomized at 6 months to continue, vs Tac withdrawal if DSA neg, no rejection/inflammation on protocol biopsy • 14 weaned, 6/14 developed rejection, 5/14 developed DSA Hricik DE et al. J Am Soc Nephrol. 2015;26:3114-3122. CNI Elimination Studies with mTOR Inhibitors Study Time to conversion (months) CONVERT (Srl)1 6-120 ZEUS (Evr)2 Followup Baseline (months) CNI CyA or 12 Tac GFR, mL/min Treatment Failure/ Graft Loss BPAR +4.9a ↑ ↑ 4.5 36 CyA +7.8a ↑ ↑ CENTRAL (Evr)3 2 12 CyA +8.0a ↑ ↑ ORION (Srl)4 3 12 Tac - ↑ ↑ 1-6 24 80% Tac +3.6a - (but 27% back to CNI) - SPARE THE NEPHRON (Srl)5 All intent-to-treat 1. 2. 3. 4. 5. Schena FP et al. Transplantation. 2009;2:233-224. Budde K et al. Lancet. 2011;2:837-847. Murbraech K et al. Transplantation. 2014;97:184-188. Flechner SM et al. Am J Transplant. 2011;2:1633-1644. Weir MR et al. Kidney Int. 2011;2:897-907. a P<0.05 Belatacept and CNI-Avoidance BENEFIT and BENEFIT-EXT – Simultaneous studies: Bela vs CyA – EXT: ECD, DCD, and prolonged cold time 7-year follow-up [BENEFIT] Acute rejection rates at 1 year 20 17.7 17 18 16 14.1 14 12 CsA 10 8 Bela 7 6 4 2 0 BENEFIT BENEFIT-EXT Vincenti F et al. Am J Transplant. 2010;10:535-546. Durrbach A et al. Am J Transplant. 2010;10:547-557. Vincenti F et al. N Engl J Med. 2016;374:333-343. What Are the Concerns about Belatacept? • Higher rejection rates • Histologically more severe rejection • Post-transplant lymphoproliferative disorder risk • IV administration and cost • Patient reluctance • No RCTs with tacrolimus as comparator agent Pestana JO et al. Am J Transplant. 2012;12:630-639. Vincenti F et al. Am J Transplant. 2012;12:210-217. Durrbach A et al. Am J Transplant. 2010;10:547-557. Vincenti F et al. Am J Transplant. 2010;10:535-546. Heher et al. N Engl J Med. 2016;374:388-389. Early Steroid Withdrawal RCT Summary at 5 Years 60-month randomized controlled, double-blinded, double-dummy, multicenter trial (n=386) 2 arms, RATG-Tac-MMF; steroid withdrawal within 7 days • Lipids a little better • No differences in: CV risk - weight gain - new diabetes - kidney function - • Increased - acute rejection - chronic graft dysfunction Woodle ES et al. Ann Surg. 2008;248:564-577. Case Study (cont) • Month 6 to year 2: BK virus clears; stable kidney function (Cr 1.2-1.4) (monthly-quarterly follow-up) with tac trough trending lower (range 3-7 ng/mL) • Consistent complaints of emotional lability, insomnia, tremor • At 2-year visit: she asks if she can decrease tacrolimus (level is 3.3 ng/mL despite no changes in dose); also informs you that sometimes she falls asleep before her evening meds Polling Question 5 Activity Survey Clinical studies suggest that which of the following treatment options would be associated with the lowest risk of acute rejection after conversion? A. Change twice-daily tacrolimus to once daily tacrolimus (MR4 or LCP)-MPA-prednisone B. Change to everolimus-MPA-prednisone C. Change to sirolimus-MPA-prednisone D. Change to belatacept-MPA with steroid elimination Once-a-Day Tacrolimus Tac-MR* LCP-Tac* Similar Similar Cmax Similar Lower Tmax Similar Delayed AUC Lower Higher Higher Lower C0 Required dose *compared to twice-daily tacrolimus Twice –daily Tac Provided by Roy D. Bloom, MD. Tac MR [Astagraf] LCP-Tac [Envarsus] Efficacy of LCP-Tacrolimus • Phase III, RCT, double-blind, double-dummy; primary endpoint: treatment failure • 543 subjects receiving de novo kidney transplants were randomized to one of two treatment arms: daily LCP-tacrolimus, twice daily tacrolimus • All subjects received basiliximab induction, mycophenolate mofetil; corticosteroids per local practice Grinyó JM, Petruzzelli S. Expert Rev Clin Immunol. 2014;10:1567-1579. Budde K et al. Am J Transplant. 2014;14:2796-806. Efficacy of Once-daily Tacrolimus • Phase III, open-label, comparative, non-inferiority study • 638 subjects receiving de novo kidney transplants were randomized to one of three treatment arms: daily tacrolimus extended-release, twice-daily tacrolimus, or twice-daily cyclosporine • All subjects received basiliximab induction, mycophenolate mofetil, and corticosteroids Silva HT et al. Transplantation. 2014;97:636-641. Case Study (cont) • Converted to tacrolimus MR4; month 26: serum creatinine 1.5 mg/dL; Tac level 5.1 ng/mL, despite stable dose; BK negative • Month 36: kidney function has declined (Cr 1.9 mg/dL); urine protein/creatinine 1.6, Tac level 2.3 ng/mL, despite stable dose • Also informs you that she stopped her prednisone 9 months ago because of fear of side effects • New DSA to DQ at 4500 MFI Polling Question 6 Activity Survey The most likely diagnosis at this point is: A. BK nephropathy B. CNI toxicity C. Late episode of acute kidney injury D. Chronic rejection secondary to non-adherence E. Recurrence of primary disease Improving Long-term Kidney Allograft Survival Progress in graft outcomes is due to improved short-term outcomes 2012 OPTN/SRTR Annual Data Report. Available at: http://srtr.transplant.hrsa.gov/annual_reports/2012/pdf/01_kidney_13.pdf. Lamb KE et al. Am J Transplant. 2011;11:450-462. Adjusted Rate of Allograft Failure in the USA Patients aged ≥18 years at transplant; adjusted by age, gender, and race United States Renal Data System; 2013 Annual Data Report. Available at: www.usrds.org/2013/slides/vol2_chap07_13.zip. Graft Survival in DeKAF Impact of Diagnosis of CAN or CNI Nephrotoxicity CAN Does not Predict Subsequent Graft Failure: DEKAF Study • n=440 “troubled grafts” • Baseline creatinine <2 mg/dL • Creatinine increase >25% Gaston RS et al. Transplantation. 2010;90:68-74. Gourishankar S et al. Am J Transplant. 2010;10:324-330. Why Do Kidneys Fail? Mayo Experience 1996-2006: 330 of 1317 KTX with graft loss at mean 50-month follow-up 138 (43.4%) due to death 39 (11.8%) due to 1° non-function 153 (46.3%) due to graft failure (biopsies mean 4.7 months prior to graft loss): • Of “glomerular disease” • Of “IF/TA” Med/Surg (16%) • 1/4 history of acute rejection • 40% “transplant glomerulopathy” (~HLA Ab?) Glomerular disease (37%) IF/TA (31%) Acute rejection (12%) • ONLY 1 GRAFT LOSS ATTRIBUTED SOLELY TO CNI TOXICITY El-Zoghby ZM et al. Am J Transplant. 2009;9:527-535. Late Graft Loss: A Changing Paradigm • Chronic rejection is the most frequent cause of deathcensored graft loss • Chronic rejection is commonly due to insufficient immunosuppression – Inappropriate prescription (minimizing or avoidance strategies) – Patient non-adherence Morath C et al. Transpl Int. 2012;25:633-645. The Role of Antibody-mediated Rejection and Non-adherence in Kidney Transplant Failure ABMR = antibody-mediated rejection Sellarés J et al. Am J Transplant. 2012;12:388-399. Strategies to Optimize Adherence • Monitoring drug levels • Tracking pharmacy refills • Supervised medication administration • Electronic notification (patient, center, other) – Bottle caps – Pill dispensers – Apps – Alarms/reminders • Simplified regimens Transplant Outcomes and Economic Costs Associated with Patient Noncompliance to Immunosuppression • Use of Medicare claims data to calculate compliance as medication possession ratio (MPR) • 15,525 KTx recipients with at least 1 year of graft function Pinsky BW et al. Am J Transplant. 2009;9:2597-2606. Transplant Outcomes Associated with Patient Noncompliance to Immunosuppression Medication possession ratio quartile cutpoints: Y1 Y2 Y3 Overall 25% 0.731 0.816 0.827 0.811 50% 0.896 0.951 0.962 0.951 75% 0.964 0.997 1.000 0.998 Compliance by quartiles: Graft failure HR Excellent (Ref.) Good 1.12 Fair 1.63 Poor 1.80 P-Value 0.2514 <0.0001 <0.0001 Pinsky BW et al. Am J Transplant. 2009;9:2597-2606. Compliance predicts graft and patient survival Predictive Patterns of Early Medication Adherence in Renal Transplantation MEMS (Medication Event Monitoring System): A microprocessor embedded in the cap of a medication bottle records every opening and closing of the cap 195 patients: • 44 (22.6%) decreased adherence by 7% or more in month 2 post treatment Acute Rejection Early Graft Loss Nevins TE et al. Transplantation. 2014;98:878-884. Use of Drug Level Monitoring (Intra-patient Variability) to Assess Under-immunosuppression/adherence • 356 patients, measured tacrolimus variability while on stable dose (“tacSD”=tacrolimus standard deviation), median follow-up 3.72 years • Composite end point: late allograft rejection, transplant glomerulopathy, or graft loss (including death) tacSD >1.5 tacSD ≤1.5 n=256; P=ns tacSD >2 tacSD ≤2 tacSD >2.5 tacSD ≤2.5 tacSD >3 tacSD ≤3 n=136; P=ns n=74; P=0.04 P<0.001; n=47 • For every 1-unit increase in TacSD, a 27% increase in composite end point [HR 1.27 (95% CI 1.03-1.56)] Sapir-Pichhadze R et al. Kidney Int. 2014;85:1404-1411. Persistence and Adherence in Kidney Recipients: Effect of Dosing Frequency • 219 patients randomized to once-daily tacro or twice-daily tacro 035. Persistence, 6 mos Adherence, 6 mos Once-daily (n=145) 82% 88% Twice-daily (n=74) 72% 79% • Doses were missed more frequently in the evening than in the morning (11.7% vs 14.2%; P=0.0035) Kuypers DRJ et al. Transplantation. 2013;95:333-340. P value 0.08 0.0009 Difficulty for Both Prediction and Intervention • There is not one single cause for non-adherence – Examples • Lack of understanding of the regimen • Forgetfulness • Financial problems with co-pays • Difficulty with regimen (work schedule/travel) • Therefore, it is difficult to have a single effective intervention Outcomes of Interest to Patients: The perspectives of kidney transplant recipients on medicine taking: Medication properties • • • • Large size Multiplicity of medicines Unpleasant taste and smell Stickiness (…and acute rejection, graft, and patient survival) Tong A et al. Nephrol Dial Transplant. 2011;26:344-354. Side effects • • • • • • • • • • • • • • Bone disease/joint pain Skin thinning Hirsutism Cancer Psychological (aggression, moodiness, memory loss) Hand tremor/shaking Gastrointestinal (diarrhea, nausea, stomach pain) Puffy face Weight gain Fatigue Infections Swollen gums Hair loss Dry mouth Conclusions • Anticipated benefits of the new kidney allocation system include improved equity and utility • Compared to remaining on dialysis for better quality organs, high KDPI kidneys and kidneys from PHS-increased donors are associated with better outcomes in patients who are older or are residents in regions with longer waiting times • Among currently used immunosuppressants: – tacrolimus-based therapy remains the efficacy “gold standard” – belatacept is an emerging alternative, though trials comparing it to tacrolimusbased therapy are needed • The leading cause of death-censored graft loss is chronic rejection, typically due to non-adherence • Several strategies to improve adherence are entering the transplant arena, including use of more simplified immunosuppression regimens CME Credit • Post-activity Survey – Now that the program has completed, please take a moment to answer the Post-activity Survey questions on your form – Your answers are important and will help us identify remaining educational gaps and shape future CME activities • CME Evaluation – If you’re seeking credit, ensure you’ve filled in your name and demographic information on page 1 and complete the CME Evaluation on your form (after the Post-activity Survey) – Return all forms to on-site CME staff Thank you for joining us today!