© 2013 direct one communications, inc. all rights reserved. 1 improving your practice: clinical...

© 2013 Direct One Communications, Inc. All rights reserved. 1

Improving Your Practice: Clinical Updates for Transplant Coordinators and Advanced-Practice Providers

Shree Patel, PharmD, BCPS

University of Illinois Hospital and Health Sciences System, Chicago, Illinois

A REPORT FROM THE 2013 AMERICAN TRANSPLANT CONGRESS


Modern Immunosuppressants

The unfavorable safety profile of modern immunosuppressants poses significant long-term challenges despite short-term survival benefits.

Infectious, metabolic, cardiovascular, renal, and hematologic toxicities ultimately impede graft and patient survival in the long run.

The clinical focus is therefore on:

» Enhancing currently available immunosuppressive agents

» Using drugs currently approved for other indications within the transplant setting

» Evaluating novel agents that target both cellular and humoral pathways.


Modern Immunosuppressants

Modern immunosuppressants have made significant progress in preventing acute cellular rejection (ACR) and improving short-term allograft survival.

When compared with the past decade, allograft survival at 1 and 3 years has increased by 5% and 6%, respectively.1

Longer-term survival rates have improved marginally over the past 20 years.

Modern desensitization agents have practically eliminated hyperacute rejection.


Current Issues

Antibody-mediated rejection (AMR) is a significant complication after highly sensitized transplantation, occurring in about 35% of all cases.2–5

Use of current immunosuppressants may cause considerable side effects and poor tolerability. » Cardiovascular and renal complications remain chronic

issues as transplant patients age.

» Cardiovascular disease is still the most common cause of death among patients with a functioning allograft.

The ideal immunosuppressant drug would be selectively effective, formulated for ease of administration and compliance, and associated with favorable safety and pharmacokinetic profiles.


Reformulating Immunosuppressants

The FDA recently approved once-daily, extended-release tacrolimus to improve pharmacokinetics and medication adherence in renal transplant patients.

The new formulation provides convenient once-daily dosing, improved systemic absorption or bioavailability, limited interpatient variability, and reduced peak-to-trough fluctuation.6

Switching to once-daily tacrolimus can be accomplished successfully while maintaining graft protection.7,8

Switching also can effectively manage tremors associated with twice-daily tacrolimus.9


Repurposing Other Drugs

Used off-label, intravenous immunoglobulin (IVIg), rituximab, bortezomib, and eculizumab effectively prevented and managed AMR in limited studies.3,10–12

Various agents (eg, fluoroquinolones, IVIg, and leflunomide) have been successful in managing BK virus infections in renal transplant recipients.13–16

The FDA recently approved everolimus for use in liver transplant patients.17

Belatacept labeling no longer recommends use with corticosteroid minimization within 6 weeks after transplant surgery.18


Immunosuppressants in the Pipeline

ASKP1240 is a fully human anti-CD40 monoclonal antibody that blocks binding of CD40 to its ligand.

» Safe in healthy volunteers19

» Promising in nonhuman species receiving renal, pancreatic islet-cell, and liver allografts.20,21

TOL101 is a murine-derived monoclonal antibody specific for the subunit of the T-cell receptor on CD3+ T cells.

» Inhibited effector T-cell function while promoting the expansion of T-regulatory cells in a phase II, dose-escalating trial in renal transplant patients.22



Voclosporin is a novel calcuineurin inhibitor (CNI) with efficacy comparable to that of tacrolimus in preventing acute rejection over 6 months.» Renal function is similar to tacrolimus.

» Incidence of new-onset diabetes after transplant (NODAT) may be less.23

Belimumab is a humanized monoclonal antibody against B-cell–activating factor (BAFF).» A clinical trial testing its effectiveness in decreasing

antibody levels in sensitized patients awaiting kidney transplantation was terminated due to lack of efficacy.

» A placebo-controlled phase II trial is assessing the drug when added to the standard of care to prevent rejection.



C1 esterase inhibitors, which inhibit the first component within the complement system and thereby may prevent complement-mediated allograft injury, are being tested as agents for preventing and treating AMR.

Tocilizumab, a humanized, monoclonal antibody that targets the interleukin-6 receptor, may be beneficial in pancreatic islet-cell transplantation.


Pre-transplant Risk Factors for Infection

Type of donor

Type of organ being transplanted

Underlying illnesses that lead to organ failure, such as cystic fibrosis, hepatitis C virus (HCV) infection, or hepatic cirrhosis

Severity of the underlying disease

Chronic malnutrition

Mechanical ventilation

Extremes in age

Lack of preexisting immunity and vaccination


Intraoperative Risk Factors for Infection

Prolonged operative time

Unexpected surgical complications

Excessive bleeding

Need for blood products


Post-transplant Risk Factors for Infection

Net state of immunosuppression

Technical complications affecting allograft integrity (abscesses, infections)

Prolonged placement of indwelling cannulae and nosocomial exposures


Infection Timeline

Early post transplant (0–30 days after surgery): Bacterial or yeast infections arise from

preexisting conditions or colonization in the recipient, donor factors, or complications of surgery.

Surgical-site infections and graft injuries may later serve as a nidus for abscesses.

Opportunistic infections are generally absent.


Infection Timeline

Intermediate interval post transplant (30–180 days after surgery): Fever is mostly attributed to latent pathogens

(polyomavirus, adenovirus, recurrent HCV, endemic fungi) that are reactivated within the recipient.

Opportunistic infections caused by Pneumocystis jirovecii, Listeria monocytogenes, and Toxoplasma gondii are no longer common.

Herpesvirus infections now occur infrequently.

Without prophylaxis, these and cytomegalovirus infections prevail.


Infection Timeline

Late phase post transplant (> 180 days after surgery)

Infectious risk is low due to minimization of immunosuppression and stable graft function.

Late CMV and opportunistic infections can appear.

Presence of community-acquired respiratory and GI viral pathogens also is common.

During the entire post-transplant course some infectious microorganisms, nosocomial pathogens, and Clostridium difficile colitis may present.


Infection Timeline24


Donor-derived Infections

Transmission of latent microorganisms (eg, herpesviruses, HCV, Toxoplasma sp, mycobacteria) linked to tuberculosis and endemic fungi from asymptomatic donors is most common

Infections typically present late post transplant.

Donor-derived bacteria, West Nile virus, and rabies virus generally lead to acute symptomatic infections.


Preventing Infection25

Educate transplant recipient about preventing infectious diseases and minimizing exposure (washing hands thoroughly and frequently, avoiding contact with sick persons or crowded areas)

Obtain exposure history and physical examination

Update patient’s immunization status

Vaccinate recipient and people in direct contact

Avoid unpasteurized, raw, or undercooked products

Discuss all travel arrangements at least 2 months before departure


Managing Hypertension

Only 5%–12% of renal transplant recipients are normotensive at 1 year.26,27

Kasiske and colleagues27 identified hypertension as an independent risk factor for allograft failure and reduced patient survival.

Controlling blood pressure can improve both allograft and patient survival.28,29


Risk Factors for Hypertension30,31

Allograft rejection

Delayed and/or chronic allograft dysfunction

Deceased donor allografts

Calcineurin inhibitor–induced vasoconstriction

Corticosteroid-induced sodium and fluid retention

Increased body weight

Presence of native kidneys

Pretransplant hypertension

Renal artery stenosis


Hypertension Guidelines and Goals

The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines32 are universally used to help control blood pressure after renal transplantation.

» Blood pressure should be reduced to a goal systolic blood pressure of < 130 mm Hg and a diastolic blood pressure of < 80 mm Hg.

Dietary modifications can lower blood pressure.33

» In this regard, the Dietary Approaches to Stop Hypertension, or DASH diet (http://dashdiet.org/), is particularly effective and recommended.


Hypertension Guidelines and Goals

For drug treatment of high blood pressure, at least two antihypertensive agents from different therapeutic classes are recommended34:

» Dihydropyridine-based calcium-channel blockers are the most widely used initial agents.

» Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers generally should be avoided immediately after renal transplant but are preferred in the setting of post-transplant erythrocytosis or proteinuria.

» In the setting of chronic fluid retention or increased sodium intake, diuretics are effective.


Alcohol Consumption

Help transplant recipients make informed decisions about drinking beer, wine, or other alcoholic beverages after surgery and long term.

» Stress that alcohol affects every organ of the body.

Following a liver transplant, resumption of heavy drinking does not affect short- or mid-term survival but can shorten long-term survival.35

Moderate alcohol consumption (10–30 g/d) may protect renal allograft function by reducing the prevalence of NODAT after transplantation and may reduce the risk of mortality in renal transplant recipients.36


Fighting Obesity

Nurses , transplant coordinators, pharmacists, and other healthcare practitioners involved in the long-term care of transplant recipients need to combat obesity via education and counseling.37

When obesity is identified, first-line therapy still consists of dietary and lifestyle modifications.

If necessary, pharmacologic therapy (appetite suppressants) may be used adjunctively.

When indicated, more extreme measures (gastric bypass surgery, banding, sleeve gastrectomy) have proven successful.38


References1. 2011 Annual Report of the US Organ Procurement and Transplantation Network and the

Scientific Registry of Transplant Recipients: Transplant Data 1998–2011. US Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation, Rockville, MD; United Network for Organ Sharing, Richmond, VA; University Renal Research and Education Association, Ann Arbor, MI.

2. Thielke JJ, West-Thielke PM, Herren HL, et al. Living donor kidney transplantation across positive crossmatch: the University of Illinois at Chicago experience. Transplantation. 2009;87:268–273.

3. Vo AA, Peng A, Toyoda M, et al. Use of intravenous immune globulin and rituximab for desensitization of highly HLA-sensitized patients awaiting kidney transplantation. Transplantation. 2010;89:1095–1102.

4. Stegall MD, Gloor J, Winters JL, et al. A comparison of plasmapheresis versus high-dose IVIG desensitization in renal allograft recipients with high levels of donor specific alloantibody. Am J Transplant. 2006;6:346–351.

5. Magee CC, Felgueiras J, Tinckam K, et al. Renal transplantation in patients with positive lymphocytotoxicity crossmatches: one center’s experience. Transplantation. 2008;86:96–103.

6. Nigro V, Glicklich A, Weinberg J. Improved bioavailability of MELTDOSE once-daily formulation of tacrolimus (LCP-Tacro) with controlled agglomeration allows for consistent absorption over 24 hrs: a scintigraphic and pharmacokinetic evaluation. Presented at the 2013 American Transplant Congress; May 18–22, 2013; Seattle, Washington. Abstract B1034.

7. Bunnapradist S, Ciechanowski K, West-Thielke P, et al. Conversion from twice-daily tacrolimus to once-daily extended release tacrolimus (LCPT): the phase III randomized MELT trial. Am J Transplant. 2013;13:760–769.

8. Gaber AO, Alloway RR, Bodziak K, Kaplan B, Bunnapradist S. Conversion from twice-daily tacrolimus capsules to once-daily extended-release tacrolimus (LCPT): a phase 2 trial of stable renal transplant recipients. Transplantation. 2013;96:191–197.


References9. Langone A, Gedaly R, Steinberg SM, Shah T, Nigro V. LCP-Tacro improves TAC induced tremors:

preliminary analysis of switching STudy of Kidney TRansplant PAtients with Tremor to LCP-TacrO (STRATO): an exploratory study. Presented at the 2013 American Transplant Congress; May 18–22, 2013; Seattle, Washington. Abstract B1022.

10. Lemy A, Toungouz M, Abramowicz D. Bortezomib: a new player in pre- and post-transplant desensitization? Nephrol Dial Transplant. 2010;25:3480–3489.

11. Stegall MD, Diwan T, Raghavaiah S, et al. Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am J Transplant. 2011;11:2405–2413.

12. Locke JE, Magro CM, Singer AL, et al. The use of antibody to complement protein C5 for the salvage treatment of severe antibody-mediated rejection. Am J Transplant. 2009;9:231–235.

13. Gabardi S, Waikar SS, Martin S, et al. Evaluation of fluoroquinolones for the prevention of BK viremia after renal transplantation. Clin J Am Soc Nephrol. 2010;5:1298–1304.

14. Josephson MA, Gillen D, Javaid B, et al. Treatment of renal allograft polyoma BK virus infection with leflunomide. Transplantation. 2006;81:704–710.

15. Faguer S, Hirsch HH, Kamar N, et al. Leflunomide treatment for polyomavirus BK-associated nephropathy after kidney transplantation. Transpl Int. 2007;20:962–969.

16. Sener A, House AA, Jevnikar AM, et al. Intravenous immunoglobulin as a treatment for BK virus-associated nephropathy: one-year follow-up of renal allograft recipients. Transplantation. 2006;81:117–120.

17. Masetti M, Montalti R, Rompianesi G, et al. Early withdrawal of calcineurin inhibitors and everolimus monotherapy in de novo liver transplant recipients preserves renal function. Am J Transplant. 2010;10:2252–2262.

18. Nulojix [package insert]. Princeton, NJ: Bristol-Myers Squibb; April 2013.


References19. Goldwater R, Keirns J, Blahunka P, et al. A phase I single ascending dose study of antagonist anti-

human CD40 ASKP1240 in healthy subjects. Am J Transplant. 2013;13:1040–1046.

20. Oura T, Yamashita K, Suzuki T, et al. Long-term hepatic allograft acceptance based on CD40 blockade by ASKP1240 in nonhuman primates. Am J Transplant. 2012;12:1740–1754.

21. Pearson TC, Trambley J, Odom K, et al. Anti-CD40 therapy extends renal allograft survival in rhesus macaques. Transplantation. 2002;74:933–940.

22. Getts DR, Mulgaonkar S, Melton LB, et al. Dose escalating anti-ab-TCR (TOL101) monoclonal therapy, induces robust naive and memory T inhibition whilst promoting post dosing regulatory T cell induction. Presented at the 2013 American Transplant Congress; May 18–22, 2013; Seattle, Washington. Abstract 184.

23. Busque S, Cantarovich M, Mulgaonkar S, et al. The PROMISE study: a phase 2b multicenter study of voclosporin (ISA247) versus tacrolimus in de novo kidney transplantation. Am J Transplant. 2011;11:2675–2684.

24. Fishman JA. Introduction: infection in solid organ transplant recipients. Am J Transplant. 2009;9:S3–S6.

25. Avery RK, Michaels MG. Strategies for safe living after solid organ transplantation. Am J Transplant. 2013;13:304–310.

26. Paoletti E, Gherzi M, Amidone M, Massarino F, Cannella G. Association of arterial hypertension with renal target organ damage in kidney transplant recipients: the predictive role of ambulatory blood pressure monitoring. Transplantation. 2009;87:1864–1869.

27. Kasiske BL, Anjum S, Shah R, et al. Hypertension after kidney transplantation. Am J Kidney Dis. 2004;43:1071–1081.

28. El-Amm JM, Haririan A, Crook ED. The effects of blood pressure and lipid control on kidney allograft outcome. Am J Cardiovasc Drugs. 2006;6:1–7.


References29. Opals G, Döhler, B. Improved long-term outcomes after renal transplantation associated

with blood pressure control. Am J Transplant. 2005;5:2725–2731.

30. Béji S, Abderrahim E, Kaaroud H, et al. Risk factors of arterial hypertension after renal transplantation. Transplant Proc. 2007;39:2580–2582.

31. Ducloux D, Motte G, Kribs M, et al. Hypertension in renal transplantation: donor and recipient risk factors. Clin Nephrol. 2002;57:409–413.

32. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009;9:S1–S155.

33. Van den Berg E, Geleijnse JM, Brink E Jr, et al. Sodium intake and blood pressure in renal transplant recipients. Nephrol Dial Transplant. 2012;27:3352–3359.

34. Olyaei AJ, de Mattos AM, Bennett WM. Nephrotoxicity of immunosuppressive drugs: new insight and preventive strategies. Curr Opin Crit Care. 2001;7:384–389.

35. Lucey MR, Carr K, Beresford TP, et al. Alcohol use after liver transplantation in alcoholics: a clinical cohort follow-up study. Hepatology. 1997;25:1223–1227.

36. Zelle DM, Agarwal PK, Ramirez JL, et al. Alcohol consumption, new onset of diabetes after transplantation, and all-cause mortality in renal transplant recipients. Transplantation. 2011;92:203–209.

37. US Preventive Services Task Force. Screening for obesity in adults: recommendations and rationale. Ann Intern Med. 2003;139:930–932.

38. Potluri K, Hou S. Obesity in kidney transplant recipients and candidates. Am J Kidney Dis. 2010;56:143–156.

© 2013 direct one communications, inc. all rights reserved. 1 improving your practice: clinical...

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