What's New and Hot in Clinical Organ Transplantation: Report From American Transplant Congress 2012

Authors


Corresponding author: Abhinav Humar

humara2@upmc.edu

Abstract

Innovative and exciting advances in the clinical sciences in organ transplantation were presented at the American Transplant Congress 2012. The full spectrum of transplantation was covered with important advancements in many topics. Key areas covered by presentations included living donor outcomes, organ preservation, optimal allocation of deceased donors, new immunosuppression regimens, antibody mediated rejection and the regulatory environment. This review will highlight some of the most interesting and innovative clinical presentations from the meeting.

Abbreviations
AR

acute rejection

ATC

American Transplant Congress

ATG

anti-thymocyte globulin

DCD

donation after cardiac death

DSA

donor-specific antibody

ECD

extended criteria donors

HCC

hepatocellular carcinoma

NAT

nucleic acid test

Introduction

The American Transplant Congress (ATC) has become one of the premiere and best-attended meetings in the area of solid-organ transplantation. ATC 2012 was held in Boston, June 2–6, 2012. It was attended by over 5000 delegates, representing all corners of the world where transplantation occurs. Over 1500 abstracts were featured in the form of oral presentations, posters, mini-symposia, lectures and state-of-the-art lectures. Outstanding work was distributed over a wide range of topics in both the basic and clinical sciences relevant to organ transplantation. This review will highlight some of the key presentation in the area of clinical sciences. Topics covered will include the individual organ types (including heart, liver, kidney and pancreas), as well as more general topics relevant to all the different organ types including areas such as regulatory oversight, allocation, immunosuppression and infectious complications.

Kidney Transplant

Living kidney donation and the impact on donors, both short and long term, is an important topic and was featured prominently at the meeting. Wainwright et al. [1], performed an analysis of the OPTN database looking at deaths postdonation in living kidney donors that had donated between October 25, 1999 and March 31, 2011 (n = 70 878). Of these, there were 96 (0.13%) deaths reported within 2 years of donation, divided into the following categories: accidental/homicide (n = 26), suicide (n = 10), cancer (n = 9), medical in nature (n = 28) and unknown (n = 23). Most concerning was that of the 96 deaths, 25 occurred early, within 0–90 days postdonation (n = 30 for 3–12 months postdonation and n = 41 for 1–2 years postdonation). The majority of these early deaths were classified as medical in nature (n = 17); the other causes were accidental/homicide (n = 6), suicide (n = 1) and unknown (n = 1). These data illustrate the importance of a thorough medical and psychosocial evaluation of donors prior to donating and the need for ongoing long-term follow-up.

Saunders et al. [2] similarly looked at the incidence of developing renal failure postdonation in living kidney donors in the United States and specifically at race and age disparities among these donors. Of the 92 672 living donors since 1994, 105 (0.11%) have subsequently been placed on a waitlist for transplantation. African American and younger donors had a higher rate of subsequent listing for kidney transplant compared to Caucasian and older donors. Additionally, the mean time from donation to being listed was significantly shorter in African Americans (AA) versus Caucasian donors (13 vs. 19 years, respectively).

Kidney donation was also associated with difficulty in obtaining insurance after donation. Boyarsky et al. [3] conducted a survey of 981 patients who had donated at a single center between 1970 and 2011, asking specifically regarding changes in health or life insurance after donation. Of these, 36% reported changing health insurance and 17% life insurance. Among those who changed health insurance, 4% had difficulty obtaining new insurance, 3% were denied altogether, 3% were charged a higher premium and 2% were told they had a preexisting condition because they were kidney donors. Among those who changed life insurance, 13% were denied, 16% were charged higher premiums and 10% were told they had a preexisting condition. The investigators concluded that a sizeable proportion of donors had problems with medical and life insurance after donation, especially the latter.

With regard to recipient outcomes, Reese et al. [4] demonstrated that functional status while on the waiting list was a strong predictor of mortality, regardless of age. They did this by linking OPTN data with data on pretransplant functional status (Physical Function [PF] scale of SF-36 score) from a national dialysis provider. This showed that a low PF score was strongly associated with inferior survival (HR = 2.0 for lowest vs. highest PF quartile, p< 0.001), and this was present in every age group. The differences in 3-year mortality between the highest and lowest PF groups ranged from 2% among recipients <35 years up to 11% for recipients ≥ 65 years.

Numerous abstracts dealt with outcomes after kidney transplant with ECD (extended criteria donors) and DCD (donation after cardiac death) donors. Singh et al. [5], in an analysis of the OPTN database, demonstrated that DCD did not have significant impact on outcomes with regards to graft survival. ECD/ DCD donor transplants had similar outcomes versus ECD/non-DCD donor transplants, while standard criteria/DCD donor transplants had similar outcomes to standard criteria/non-DCD donor transplants.

Leventhal et al. [6] presented exciting results from a phase 2 clinical trial of donor-specific tolerance induction in recipients of HLA disparate living donor kidney allografts by donor stem cell infusion. The protocol involved donor bone marrow collection 2 weeks before transplant, pretreatment of the recipient with Fludarabine, Cytoxan and 200 CGy total body irradiation. This was followed by living donor kidney transplant and then infusion of processed donor bone marrow cells enriched for specific cell lines on day 1 after the transplant. Patients had MMF discontinued at 6 months followed by tacrolimus at 12 months. Of eight patients with ≥ 18 months of follow-up, five are currently completely off immunosuppression with good graft function. There have been no cases of graft versus host disease.

With regard to specific immunosuppression protocol trials, a number of different studies were presented looking at induction and maintenance regimens in standard and high immunologic risk recipients. Farney et al. [7] presented long-term outcomes of a prospective randomized study of Alemtuzumab versus thymoglobulin for induction in kidney and kidney/pancreas transplant recipients. No differences were noted in patient or graft survival, but acute rejection (AR) was significantly lower in the Alemtuzumab group (at 5 years 29% vs. 18%, p = 0.03). The difference in AR was apparent by 1 year posttransplant (25% vs. 11%) and there was no difference in late acute rejection rates between the two groups. Between 1 and 5 years posttransplant the AR incidence increased by 6% only in both groups. There were also no differences in the two groups with regard to infectious or malignancy complications. Schmidt et al. [8] looked at various induction protocols in a group of high immunologic risk recipients. A total of 40 such recipients were randomized to one of four arms: thymoglobulin (rATG) alone versus rATG plus rituximab versus rATG plus bortezomib versus rATG plus rituximab plus bortezomib. Essentially no significant difference was seen in the groups with regard to acute rejection. Similarly, Amroche et al. [9] studied the impact of two different desensitization regimens (IVIG alone vs. IVIG/plasmapheresis/ rituximab) in a group of patients transplanted with significant preformed DSA (donor-specific antibody). They demonstrated that the regimen of IVIG/plasmapheresis/ rituximab was associated with better 1-year GFR (55.7 vs. 44.4, p = 0.003) and less histologic evidence of chronic antibody-mediated rejection (28% vs. 50%, p = 0.045).

Liver Transplant

Hallderion et al. [10] presented an interesting analysis on the impact of intercenter competition on liver transplant practices and outcomes. They noted that the competitive environment in the United States for liver organs varies from none (1 center in OPO) to heavy (7 centers in OPO). Posttransplant survival was lower in centers with high versus low competition, but the lab MELD at transplant and donor risk index were both significantly higher in high competition versus low competition centers. They concluded that low competition allowed for better control of donor/recipient risk matching but also perhaps resulted in risk aversion with decreased utilization of organs.

A number of abstracts dealing with devices pertaining to liver transplant were presented. Teperman et al. [11] provided the results of a phase 2b study of safety and efficacy of a liver support system using human cell-based biological liver (ELAD) in subjects with acute on chronic liver failure or acute alcohol-related liver failure. No benefit was observed in patients with acute liver failure due to nonalcohol-related disease, but there may have been a possible benefit in patients with acute alcohol hepatitis, either as a bridge to recovery or to transplant. Mesoheimer et al. [12] presented some animal data to show a possible benefit to the use of hypothermic oxygenated machine perfusion for liver preservation in a porcine model, while Guarrera et al. [13] demonstrated benefit in a phase 2 clinical trial using donors that had been turned down in a number of US UNOS regions. A total of 21 patients had been transplanted with these organs, with none having evidence of primary nonfunction. Of these 21, 18 (86%) were alive and well with a mean follow-up of 16.2 months.

While the finding of de novo donor-specific antibody (DSA) after kidney transplant has been shown to impact survival, a similar finding was shown after liver transplant by O'Leary et al. [14]. They analyzed 1 year post liver transplant serum samples in 760 consecutive patients and found de novo Class I DSA (MFI > 5000) occurred in 0.3% and class II DSA in 7%. Patients with de novo class II DSA had significantly lower survival versus those who did not (p < 0.001). On multivariate analysis, de novo class II DSA was a significant risk factor for patient survival (HR = 2.47, p<0.0001), as were HCV viremia (HR = 1.31, p = 0.04), recipient age>60 (HR = 1.58, p = 0.04) and donor age>50 (HR = 1.41, p = 0.04). Risk factors for developing DSA were cyclosporine-based immunosuppression (HR = 3.21, p <0.001) and African American race (HR = 2.74, p = 0.02).

A number of abstracts were presented on hepatocellular carcinoma (HCC) and transplantation in patients beyond Milan criteria. Motta et al. [15] presented on an exciting study on adoptive immunotherapy using donor-derived natural killer cells. In an adult-to-adult live donor model, perfusate obtained from flushing the liver graft was used to isolate donor lymphocytes which were then stimulated for 3 days with IL2 and then infused into the recipient. The HCC recurrence free rate in 13 patients that received this therapy was significantly lower compared to eight control recipients that did not (p < 0.005).

In the nontransplant hepatitis C literature there is significant interest and excitement raised by the new antiviral agents Boceprevir and Telaprevir. Similarly, there is interest in seeing if these agents can be used in a post liver transplant model to treat recurrence. Burton et al. [16] presented on 18 such patients treated with triple therapy including Telaprevir. All were prior nonresponders. Preliminary data demonstrated that all patients had significant viral load reductions (>2 log). Side effects including anemia and renal dysfunction were however common.

A number of abstracts detailing results of immunosuppression trials were presented including one which involved the use of Everolimus as a way to reduce or withdraw Tacrolimus in 719 de novo liver transplant recipients [17]. After 1 month of standard Tacrolimus-based therapy, patients were randomized to one of three arms—Tacrolimus withdrawal, Everolimus plus reduced dose Tacrolimus, or a control arm of ongoing Tacrolimus maintenance. Enrollment in the Tacrolimus withdrawal arm was stopped due to higher rejection rates. However, efficacy was similar in the Tacrolimus maintenance vs. Everolimus plus reduced dose Tacrolimus arms, but with significantly better renal function in the latter group (GFR at 12 months of 91 vs. 71, p < 0.05). Everolimus use in a heart transplant population (Koboshigawa et al. [18] also demonstrated equivalent efficacy compared to standard immunosuppression but with less coronary intimal thickening (0.03 mm vs. 0.07 mm, p = 0.001) and less cardiac allograft vasculopathy (12.5% vs. 26.7%, p = 0.02).

Islet and Pancreas Transplant

Islet cell transplantation (ICTx), and its promise as a treatment for diabetes, remained a hot topic with several single centers presenting their results. CITR investigators [19] presented results on behalf of the Collaborative Islet Transplant Registry (CITR). The registry included 752 islet allograft recipients and 333 islet autograft recipients. Results have continued to improve over the last 12 years with 3-year insulin independence rates of 30% (1999–2003), 37% (2004–2006) and 44% (2007–2010). The best results were seen in patients that received induction therapy with a T cell depleting agent in conjunction with TNF-alpha blockade, with results that were approaching results seen with isolated pancreas transplant.

Schnitzler et al. [20] analyzed the OPTN database and showed that high pretransplant insulin requirements correlated with pancreas failure risk in simultaneous pancreas–kidney (SPK) recipients. They also linked the OPTN database with a large pharmacy database to demonstrate that there was a discrepancy between the two, raising the question of if we had a consistent, validated definition of pancreas failure.

Allocation

Allocation of deceased donor organs in the United States and regulations impacting on allocation were widely discussed topics. Schold et al. [21] presented data on national kidney transplant volumes, demonstrating limited growth in numbers over the last 3 years. They hypothesized that this may in part be related to the increased emphasis on regulatory oversight of center performance. They demonstrated that change in kidney volume at an individual center was strongly related to center performance as reported by SRTR (Scientific Registry of Transplant Recipients). Centers without low performance had a slight increase in volume, but centers with low performance (“below expected”), either in patient or graft survival, had a significant decrease in kidney volume (between 25 and 30 kidney transplants/year). The investigators additionally showed that centers that were flagged for low performance had lower 1-year expected patient and graft survival rates versus nonflagged centers. These findings suggested that there were significant differences between flagged and nonflagged centers with regard to the risk status of donors and recipients at that center.

A number of abstracts looked at possible modifications to the current system of allocation. In liver transplant these included the addition of serum Na+ to the MELD score, methods to appropriately adjust the priority for HCC and assigning similar priority to patients with MELD >35 as status 1A candidates [22]. Proposed changes to kidney transplant included allocation of the top 20% of donor kidneys to recipients in the top 20% with regard to expected posttransplant survival.

Infections

Screening of donors for potential infectious disease transmission was a topic of much interest. Theodoropoulos et al. [23] looked at cases of discordant serology and nucleic acid test (NAT) results for HIV, HBV and HCV in 2010. There were 10 cases (0.3%) where NAT testing was positive for HIV but serology was negative. For HCV a similar scenario was seen in 5 (0.1%) cases. Furthermore, many of the HIV NAT results in serology negative donors were found to be nonreproducible on repeat testing. This highlights the importance of robust quality assurance to minimize nonreproducible positive results if NAT testing is used. Blumberg et al. [24] presented six cases where they proceeded with transplant with a presumably false-positive NAT for HIV (negative serology) with no evidence of disease transmission in the recipients.

Numerous abstracts were presented on CMV and BK viral infections. In a multivariate analysis, Limaye et al. [25] demonstrated that risk factors for the development of CMV viremia while on valganciclovir prophylaxis were delay in induction of valganciclovir >10 days posttransplant (p = 0.01), and under dosing of valganciclovir (p = 0.003). With regard to BK virus, Sood et al. [26] showed that as with the other types of viral infection, the serostatus of the recipient was an important risk factor for development of BK infection, with the D+R− subgroup having the highest risk for BK infection. Vue et al. [27] showed that IVIG therapy was effective in the treatment of BK infection in 43 patients who did not respond to standard treatment with reduction of immunosuppression and leflunomide. Mean viral load significantly decreased after IVIG treatment with patient and graft survival rates of 100% and 97.4%, 12 months posttreatment.

Finally, Kumar et al. [28] presented the results of a multicenter study of seasonal influenza in transplant recipients. Inclusion included a microbiological confirmed diagnosis of influenza infection during the 2010–2011 seasons. A total of 99 cases were identified in solid organ transplant recipients with hospitalization in 70.7%, ICU care in 11%, mechanical ventilation in 8% and death in 4%. Significant factors associated with increasing severity of infection were abnormal chest imaging at presentation, absence of immunization with the 2010–2011 influenza vaccine, and delay in the initiation of antiviral therapy beyond 48 h.

Disclosure

The author of this manuscript has no conflicts of interest to disclose as described by the American Journal of Transplantation.

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