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Improving Your Practice:
Clinical Updates for Transplant
Coordinators and AdvancedPractice Providers
Shree Patel, PharmD, BCPS
University of Illinois Hospital and Health Sciences System,
Chicago, Illinois
A REPORT FROM THE 2013 AMERICAN TRANSPLANT CONGRESS
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1
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.
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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.
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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.
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4
Reformulating Immunosuppressants

The FDA recently approved once-daily, extendedrelease 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
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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
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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, doseescalating trial in renal transplant patients.22
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Immunosuppressants in the Pipeline

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.
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Immunosuppressants in the Pipeline

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.
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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
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Intraoperative Risk Factors for Infection

Prolonged operative time

Unexpected surgical complications

Excessive bleeding

Need for blood products
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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
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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.
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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.
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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.
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Infection Timeline24
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16
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.
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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
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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
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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
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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.
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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 angiotensinreceptor 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.
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22
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
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23
Fighting Obesity

Nurses , transplant coordinators, pharmacists, and
other healthcare practitioners involved in the longterm 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
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References
1.
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 oncedaily extended release tacrolimus (LCPT): the phase III randomized MELT trial. Am J Transplant.
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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.
© 2013 Direct One Communications, Inc. All rights reserved.
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References
9.
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 virusassociated 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.
© 2013 Direct One Communications, Inc. All rights reserved.
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References
19. 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.
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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.
© 2013 Direct One Communications, Inc. All rights reserved.
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References
29. 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.
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31. Ducloux D, Motte G, Kribs M, et al. Hypertension in renal transplantation: donor and recipient risk factors.
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32. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice
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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
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