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Disclaimer: CME certification for these activities has expired. All information is pertinent to the timeframe in which it was released.


Report from the 2007 American Transplant Congress: Evolving Challenges in Renal Transplantation


GOAL
To provide nephrologists and nephrology nurses with up-to-date information on the challenges of renal transplantation.

TARGET AUDIENCE
This activity is designed for nephrologists and nephrology nurses working in renal transplant centers, in addition to renal transplant coordinators. No prerequisites required.

LEARNING OBJECTIVES
The Johns Hopkins University School of Medicine, The Institute for Johns Hopkins Nursing, and the American Board for Transplant Certification take responsibility for the content, quality, and scientific integrity of this CE activity. At the conclusion of this activity, the participant should be able to:
  • Summarize the challenges of renal transplantation in ethnic renal transplant recipients and formulate strategies to overcome these challenges and improve outcomes.
  • Outline the emerging data from immunosuppression clinical trials to foster greater understanding of current and evolving therapeutic strategies.
  • Categorize immunologic obstacles to renal transplantation in the sensitized patient and evaluate the efficacy of therapeutic strategies to overcome these obstacles.
  • Restate pertinent data from select posters presented at the 2007 American Transplant Congress.
ACCREDITATION STATEMENT
This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of The Johns Hopkins University School of Medicine, The Institute for Johns Hopkins Nursing, and the American Board for Transplant Certification.

The Institute for Johns Hopkins Nursing is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation.

The American Board for Transplant Certification (ABTC) has established a continuing certification program whereby certified coordinators meeting the eligibility requirements may seek to maintain certification through the Continuing Education Points for Transplant Certification (CEPTC) program. The ABTC has approved this educational offering.

CREDIT DESIGNATION STATEMENT
The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 2 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

This 2 contact hour Educational Activity (Provider Directed/Learner Paced) is provided by The Institute for Johns Hopkins Nursing. Claim only those contact hours actually spent in the activity.

The American Board for Transplant Certification (ABTC) has approved this educational offering for up to 2.0 Category I Continuing Education Points for Transplant Certification (CEPTCs).

The estimated time to complete this educational activity: 2 hours.

Release date: August 15, 2007. Expiration date: August 15, 2009.

This program is supported by an educational grant from Wyeth Pharmaceuticals.
Full Disclosure Policy Affecting CME Activities
As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of the Johns Hopkins University School of Medicine to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a provider has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation.  The presenting faculty reported the following:

PROGRAM DIRECTORS
Hamid Rabb, MD
Physician Director, Kidney and Pancreas Transplantation
Associate Professor of Medicine
Division of Nephrology
Johns Hopkins School of Medicine
Baltimore, Maryland
Dr Rabb reports having no significant financial or advisory relationships with corporate organizations related to this activity.

Flavio G. Vincenti, MD
President, American Society of Transplantation
Professor of Clinical Medicine
University of California, San Francisco
San Francisco, California
Dr Vincenti reports receiving grants/research support from Bristol-Myers Squibb Company, Genentech, Inc, Novartis, and Roche Pharmaceuticals.
PARTICIPATING FACULTY

Lorenzo Gallon, MD
Associate Professor
Division of Nephrology/Hypertension
Director, Transplant Nephrology Program
Northwestern University Medical School
Chicago, Illinois
Dr Gallon reports having no significant financial or advisory relationships with corporate organizations related to this activity.

Howard M. Gebel, PhD
Professor of Pathology
Co-Director, Histocompatibility and Molecular Immunogenetics Laboratory
Emory University Hospital
Atlanta, Georgia
Dr Gebel reports receiving grants/research support from One Lambda, Inc.

James M. Gloor, MD
Associate Professor of Medicine
Department of Nephrology and Internal Medicine
Mayo Clinic
Rochester, Minnesota
Dr Gloor reports having no significant financial or advisory relationships with corporate organizations related to this activity.

Tawara D. Goode, MA
Director, National Center for Cultural Competence
Research Instructor
Department of Pediatrics
Georgetown University
Washington, DC
Ms Goode reports having no significant financial or advisory relationships with corporate organizations related to this activity.

Donald Hricik, MD
Professor of Medicine
Case Western Reserve University
Chief, Division of Nephrology
University Hospital of Cleveland
Cleveland, Ohio
Dr Hricik reports receiving grants/research support from Astellas Pharma Inc, Novartis, Roche, and Wyeth Pharmaceuticals.

Ross Isaacs, MD
Associate Professor
Department of Medicine
Nephrology Division
University of Virginia
Charlottesville, Virginia
Dr Isaacs reports receiving grants/research support from Abbott Laboratories, NIH, and NKF; and serving on the speakers’ bureau for Novartis.

Thomas C. Pearson, MD, DPhil
Professor of Surgery
Emory University School of Medicine
Co-Director Kidney/Pancreas Transplant Program
Emory University Hospital
Atlanta, Georgia
Dr Pearson reports receiving grants/research support from Bristol-Myers Squibb Company, JDRF, Livingston Foundation, Mason Trust, Mckelvey Lung Transplant Center, NIH, Novartis, NSF, Roche, and Wyeth Pharmaceuticals; serving as a consultant for Bristol-Myers Squibb Company, Genzyme Corporation, LifeLink Foundation, Novartis, Roche, Schering Plough, and Wellpoint; and owns the intellectual property for a combination CD28/CD40 blockade licensed by Bristol-Myers Squibb Company.

Mark D. Stegall, MD
Professor of Surgery
Mayo Clinic
Rochester, Minnesota
Dr Stegall reports receiving grants/research support from Genzyme Corporation.

Stephen J. Tomlanovich, MD
Clinical Professor of Medicine and Surgery
Medical Director, Renal Transplant Service
University of California at San Francisco
San Francisco, California
Dr Tomlanovich reports receiving grants/research support from Astellas Pharma Inc, Isotechnika, Novartis, and Roche; and serving as a consultant for Novartis.

Notice: The audience is advised that the articles in this CE activity may contain reference(s) to unlabeled or unapproved uses of drugs or devices.

Dr Pearson—belatacept.
Dr Stegall—rituximab and antithymocyte globulin (rabbit).

All other faculty have indicated that they have not referenced unlabeled or unapproved uses of drugs or devices.

Johns Hopkins Advanced Studies in Medicine provides disclosure information from contributing authors, lead presenters, and participating faculty. Johns Hopkins Advanced Studies in Medicine does not provide disclosure information from authors of abstracts and poster presentations. The reader shall be advised that these contributors may or may not maintain financial relationships with pharmaceutical companies.

Report from the 2007 American Transplant Congress: Evolving Challenges in Renal Transplantation
Hamid Rabb, MD,* and Flavio G. Vincenti, MD

As the modern era of transplantation has advanced, the challenges have also evolved. Today, short-term successes have become almost routine. One-year patient and graft survival rates for living donors are 98.0% and 95.1%, respectively.1 Acute rejection incidence has declined steadily from 51% in 1996 to 12% in 2004.1 Every year, more than 16 000 procedures are performed, and the population living with a functioning kidney graft now exceeds 90 000 and continues to grow.1

Many of the emerging challenges in renal transplantation now involve access, special populations, and long-term outcomes. Clearly, opening the door to life-saving transplantation to even more patients with renal failure must remain a top goal. The number of patients on the kidney transplant wait list increased to more than 62 000 in 2005, reflecting the increased demand for, and the continuing shortage of, all solid organs (Figure 1).1 However, care must be improved for the swelling population of recipients who have progressed past the 1-year post-transplant time period.

In meeting these challenges, nephrologists and nephrology nurses are on the front lines. To ensure that all patients get appropriate access and follow-up care, these specialists must remain aware of the current issues and evolving strategies in renal transplantation.

This monograph is based on the following proceedings from the 2007 American Transplant Congress (ATC) held May 5–9, 2007, in San Francisco, California.

Diversity Issues in Renal Transplantation
African American patients are at an increased risk of acute rejection and long-term graft failure compared to their white counterparts. The multifaceted reasons for this include cultural, socioeconomic, genetic, and pharmacokinetic factors. Studies suggest that outcomes in African American patients may be improved with the use of specific immunosuppressive regimens,2 and steroid-avoidance immunosuppression has been shown to be effective in this high-risk group.3,4 However, overall adherence rates with prescribed immunosuppressive regimens appear to be lower in African Americans, and this could partially account for the lower success rates seen in this population.5 It must also be mentioned that African American patients with end-stage renal disease are less likely than white patients to even reach the stage of renal transplantation.6 Myriad patient-related and healthcare-related barriers may account for this difference, including preexisting medical conditions, financial concerns, distrust of the medical community, fear of surgery, and lack of awareness about living donor kidney transplantation.7,8

To optimize care of African American patients undergoing renal transplantation, transplant clinicians must be cognizant of the special considerations involved in this population. Transplant nurses and nephrology nurses in particular can play a key role in developing and implementing culturally responsive interventions to enhance immunosuppressive medication adherence in African American patients.5 The role of the clinical nurse specialist is implemented differently in many organizations; however, in this environment, across all races, the clinical nurse specialist is paramount in assisting renal transplant recipients taking immunosuppressive medication and, consequently, in fostering better outcomes.9 The presentation by Tawara D. Goode, MA, Ross Isaacs, MD, and Donald Hricik, MD, provide insights and strategies for overcoming the unique challenges in African American transplant recipients, which will help nurses and physicians improve outcomes in this high-risk group.

Clinical Trials in Long-term Immunosuppression
Short-term patient and graft survival rates after renal transplantation have improved markedly over the past 30 years (Figure 2).10 Much of this improvement in outcomes is attributable to the number of new immunosuppressive agents introduced over this span of time. In fact, by the early 1990s the majority of renal transplant patients were being discharged on steroids (93.6%), mycophenolate mofetil (75.5%), and/or tacrolimus (56.4%), and many others were receiving maintenance immunosuppression involving cyclosporine (37.5%) and/or inhibitors of mammalian target of rapamycin (17.3%).1

Although these new options for immunosuppressive therapy have markedly reduced acute rejection rates in transplantation, they have not provided a similar increase in longer term graft survival.11 The main causes of chronic graft loss are chronic rejection and death caused by cardiovascular causes in a patient with a functioning graft (Figure 3).12 Studies have documented that the calcineurin inhibitors (CNIs) are associated with renal toxicity in nearly all renal transplant patients (Figure 4),13 in addition to a large proportion of those with nonrenal transplanted solid organs.14 Given the close association of cardiovascular deaths with chronic renal failure, as measured for example with serum creatinine at 1 year after transplant, it seems clear that the CNIs contribute to poor long-term outcomes at least in part through kidney-related cardiovascular complications.15 This is just one of the known complications linked to the immunosuppressives currently used for maintenance therapy.

Chronic corticosteroid therapy at doses typically employed post-transplantation is also associated with serious adverse events. In particular, the bone disease that is well documented in patients with rheumatoid arthritis is also seen in transplant patients.16-18 In fact, steroid withdrawal has been associated with increased bone formation, bone mineral density, and serum osteocalcin in renal transplant recipients.19 Increased risk of infection and cardiovascular risk are the other major risks of steroid use in transplant patients.20,21 These steroid-related side effects lead not only to higher healthcare costs for management of fractures, avascular necrosis, cataracts, and cardiovascular complications, but also to reduced patient compliance and related increases in rejection rates and graft loss.22

Historically, most attempts to limit or withdraw prednisone in kidney transplant recipients have produced poor results. For example, one multicenter randomized trial comparing maintenance prednisone with placebo found 5-year graft survival rates of 85% and 73%, respectively.23 Shorter term trials involving steroid withdrawal have found generally similar results with higher incidences of 6- and 12-month rejection, especially in African American patients and in those who did not receive induction therapy.24,25 Overall, the pooled data from pre-2000 trials indicate that removing prednisone increases acute rejection rates by 14% (Figure 5).26 Clearly, when steroids are stopped, there is an increased risk of rejection that is likely related to removal of the glucocorticoid upregulation of cytokine receptors.

Therefore, the question is: How do we achieve low rejection rates and yet minimize the longer term toxicity that is associated with these immunosuppressive agents? This question was revisited at the 2007 ATC in a session that provided updates on the most current trials in areas related to CNI-free trials, presented by Stephen J. Tomlanovich, MD; CNI-conversion trials, presented by Thomas C. Pearson, MD, DPhil; and steroid-sparing trials, presented by Lorenzo Gallon, MD.

New Strategies for the Sensitized Candidate
Today, many of the patients on the United Network for Organ Sharing wait list for a kidney are sensitized to human leukocyte antigens. These patients are highly disadvantaged in terms of finding an acceptable match, as indicated by their longer wait times and lower rates of receipt of deceased donor organs. The development of new strategies for sensitized candidates is motivated largely by the scarcity of donated kidneys and the related prolonged waiting times and poor outcomes. To ensure that patients lingering on dialysis have the best possible chance for transplantation and improved survival, nephrologists and nephrology nurses must maintain a current knowledge of these evolving protocols for sensitized patients. Recent desensitization protocols in combination with novel post-transplantation immunosuppression have made transplantation possible for many patients who otherwise might have remained on dialysis indefinitely.27

However, as outlined by Howard M. Gebel, PhD, James M. Gloor, MD, and Mark D. Stegall, MD, in their ATC presentations, it is imperative for transplant nephrologists and nurses to consider the individual needs of patients as they interpret the emerging data from these trials using new protocols. Some sensitized patients, for example, are in a truly desperate situation because of problems with dialysis. In that context, less than stellar outcomes with imperfect matches may be acceptable. On the other hand, it is premature to make the blanket statement that positive cross-match transplantations are equal in efficacy and safety to negative cross-match procedures. Long-term outcomes with these special screening and transplant protocols are required before even more of these sensitized patients on the wait lists can be considered for transplant.

This issue of Johns Hopkins Advanced Studies in Medicine highlights select proceedings and posters from the 2007 ATC that review the latest issues in renal transplantation. It is hoped that the discussion of these important ATC sessions will benefit renal transplantation specialists in a manner that informs their daily treatment decisions and patient interactions.

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

REFERENCES
1.    Health Resources and Services Administration, US Department of Health and Human Services. 2006 OPTN/SRTR annual report: transplant data 1996-2005. Available at: http://www.ustransplant.org/annual_Reports/current/default.htm. Accessed July 10, 2007.
2.    Podder H, Kahan BD. Individualization of immunosuppressive therapy: I. Sirolimus improves outcomes in African-American renal transplant recipients. Transplant Proc. 2005;37:3723-3726.
3.    Gaston RS, Deierhoi MH, Young CJ, Hunt SL. “High-risk" renal transplantation: evolving definitions at a single center. Clin Transpl. 2004;18:121-126.
4.    Gruber SA, West MS, Sillix DH, et al. Preliminary results with early corticosteroid withdrawal in African American renal allograft recipients. Surgery. 2005;138:772-779.
5.    Russell CL. Culturally responsive interventions to enhance immunosuppressive medication adherence in older African American kidney transplant recipients. Prog Transplant. 2006;16:187-195.
6.    Navaneethan SD, Singh S. A systematic review of barriers in access to renal transplantation among African Americans in the United States. Clin Transplant. 2006;20:769-775.
7.    Robinson BM, Joffe MM, Pisoni RL, et al. Revisiting survival differences by race and ethnicity among hemodialysis patients. J Am Soc Nephrol. 2006;17:2910-2918.
8.    Lunsford SL, Simpson KS, Chavin KD, et al. Racial differences in coping with the need for kidney transplantation and willingness to ask for live organ donation. Am J Kidney Dis. 2006;47:324-331.
9.    Russell CL, Kilburn E, Conn VS, et al. Medication-taking beliefs of adult renal transplant recipients. Clin Nurse Spec. 2003;17:200-208.
10.    Zand MS. Immunosuppression and immune monitoring after renal transplantation. Semin Dial. 2005;18:511-519.
11.    Meier-Kriesche HU, Schold JD, Kaplan B. Long-term renal allograft survival: have we made significant progress or is it time to rethink our analytic and therapeutic strategies? Am J Transplant. 2004;4:1289-1295.
12.    Ojo AO, Hanson JA, Wolfe RA, et al. Long-term survival in renal transplant recipients with graft function. Kidney Int. 2000;57:307-313.
13.    Nankivell BJ, Borrows RJ, Fung CL, et al. The natural history of chronic allograft nephropathy. N Engl J Med. 2003;349:2326-2333.
14.    Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med. 2003;349:931-940.
15.    Meier-Kriesche HU, Baliga R, Kaplan B. Decreased renal function is a strong risk factor for cardiovascular death after renal transplantation. Transplantation. 2003;75:1291-1295.
16.    Saag KG, Koehnke R, Caldwell JR, et al. Low dose long-term corticosteroid therapy in rheumatoid arthritis: an analysis of serious adverse events. Am J Med. 1994;96:115-123.
17.    Laan RF, van Riel PL, van de Putte LB, et al. Low-dose prednisone induces rapid reversible axial bone loss in patients with rheumatoid arthritis. A randomized, controlled study. Ann Intern Med. 1993;119:963-968.
18.    Van Staa TP, Leufkens HG, Abenhaim L, et al. Use of oral corticosteroids and risk of fractures. J Bone Miner Res. 2000;6:993-1000.
19.    Farmer CK, Hampson G, Abbs IC, et al. Late low-dose steroid withdrawal in renal transplant recipients increases bone formation and bone mineral density. Am J Transplant. 2006;6:2929-2936.
20.    Sawyer R. Effects of steroids on infection: comparison of transplant and non-transplant patients. Am J Transplant. 2005;5(suppl 11):abstract 1382.
21.    Rilke A. Global cardiovascular risk and cardiovascular events in renal transplant patients receiving early corticosteroids withdrawal versus chronic corticosteroids. Am J Transplant. 2005;5(suppl 11):abstract 519.
22.    Veenstra DL, Best JH, Hornberger J, et al. Incidence and long-term cost of steroid-related side effects after renal transplantation. Am J Kidney Dis. 1999;33:829-839.
23.    Sinclair NR. Low-dose steroid therapy in cyclosporine-treated renal transplant recipients with well-functioning grafts. CMAJ. 1992;147:645-657.
24.    Ahsan N, Hricik D, Matas A, et al. Prednisone withdrawal in kidney transplant recipients on cyclosporine and mycophenolate mofetil--a prospective randomized study. Transplantation. 1999;68:1865-1874.
25.    Vanrenterghem Y, Lebranchu Y, Hene R, et al. Double-blind comparison of two corticosteroid regimens plus mycophenolate mofetil and cyclosporine for prevention of acute renal allograft rejection. Transplantation. 2000;70:1352-1359.
26.    Kasiske BL, Chakkera HA, Louis TA, Ma JZ. A meta-analysis of immunosuppression withdrawal trials in renal transplantation. J Am Soc Nephrol. 2000;11:1910-1917.
27.    Magee CC. Transplantation across previously incompatible immunological barriers. Transpl Int. 2006;19:87-97.

*Physician Director, Kidney and Pancreas Transplantation, Professor of Medicine, Division of Nephrology, Johns Hopkins School of Medicine, Baltimore, Maryland.
†Professor of Clinical Medicine, University of California, San Francisco.
Address correspondence to: Hamid Rabb, MD, Physician Director, Kidney and Pancreas Transplantation, Professor of Medicine, Division of Nephrology, Johns Hopkins School of Medicine, East Baltimore Campus, Ross 970 Nephrology, 600 North Wolfe Street, Baltimore, MD 21287. E-mail: hrabb1@jhmi.edu.

The content in this monograph was developed with the assistance of a medical writer. Each author had final approval of his article and all its contents.



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