Improving Human Life by Advancing the Field of Transplantation

Cardiovascular disease is the leading cause of mortality in kidney transplant recipients. Dyslipidemia is a common finding after renal transplantation and a significant risk factor in the development of coronary heart disease. Although a causal relationship with cardiovascular mortality has not been proven in the transplant population, it is reasonable to extrapolate data from the general population and aggressively treat posttransplant dyslipidemia. Statins are considered the agents of choice, though their use may be complicated by drug misadventures. Pravastatin, fluvastatin and pitavastatin are considered to be the safest statins to use in this population; however, given their low-potency, a high-potency statin, such as atorvastatin, may be necessary in patients with significant dyslipidemia. In this article, we discuss the etiology of and treatment strategies for dyslipidemia in renal transplant recipients based on a literature review of potential therapeutic adverse effects and benefits in this population. We will also evaluate the reasons for and consequences of the latest Food and Drug Administration (FDA) warnings regarding the use of simvastatin.

Murine CCR5−/− recipients produce high titers of antibody to complete MHC-mismatched heart and renal allografts. To study mechanisms of class I MHC antibody-mediated allograft injury, we tested the rejection of heart allografts transgenically expressing a single class I MHC disparity in wild-type C57BL/6 (H-2b) and B6.CCR5−/− recipients. Donor-specific antibody titers in CCR5−/− recipients were 30-fold higher than in wild-type recipients. B6.Kd allografts survived longer than 60 days in wild-type recipients whereas CCR5−/− recipients rejected all allografts within 14 days. Rejection was accompanied by infiltration of CD8 T cells, neutrophils and macrophages, and C4d deposition in the graft capillaries. B6.Kd allografts were rejected by CD8−/−/CCR5−/−, but not μMT−/−/CCR5−/−, recipients indicating the need for antibody but not CD8 T cells. Grafts recovered at day 10 from CCR5−/− and CD8−/−/CCR5−/− recipients and from RAG-1−/− allograft recipients injected with anti-Kd antibodies expressed high levels of perforin, myeloperoxidase and CCL5 mRNA. These studies indicate that the continual production of antidonor class I MHC antibody can mediate allograft rejection, that donor-reactive CD8 T cells synergize with the antibody to contribute to rejection, and that expression of three biomarkers during rejection can occur in the absence of this CD8 T cell activity.

Full-right-full-left split liver transplantation divides a donor liver into two grafts to be transplanted in adult-size patients. Major technical and organizational difficulties have limited its application to few single center series. We retrospectively analyzed the long-term results of the first multicenter series of this procedure with graft sharing. Between November 1998 and January 2005, 43 transplants were performed by five centers from 23 full-right-full-left in situ split liver procedures; 65% of the grafts were shared. A total of 31 (72%) patients had complications above grade II; 3 (6.9%) were retransplanted. Hospital mortality was 23% with sepsis as the main cause. Six patients died in the long term, two of them for a road accident. A total of 27 patients are alive after a median follow-up of 3200 days (2035–4256). Actuarial survival at 1 and 10 years were 72.1%, 62.6% and 65.1%, 57.9%, respectively for patients and grafts. These figures are similar to those reported for adult living donor liver transplantation by the European Registry over a similar period. Multicenter collaboration in sharing of these grafts is feasible and can help facing the organizational limits, thus increasing diffusion of full-right-full-left split liver transplantation.

Static cold storage (CS) is the most widely used organ preservation method for deceased donor kidney grafts but there is increasing evidence that hypothermic machine perfusion (MP) may result in better outcome after transplantation. We performed an economic evaluation of MP versus CS alongside a multicenter RCT investigating short- and long-term cost-effectiveness. Three hundred thirty-six consecutive kidney pairs were included, one of which was assigned to MP and one to CS. The economic evaluation combined the short-term results based on the empirical data from the study with a Markov model with a 10-year time horizon. Direct medical costs of hospital stay, dialysis treatment, and complications were included. Data regarding long-term survival, quality of life, and long-term costs were derived from literature. The short-term evaluation showed that MP reduced the risk of delayed graft function and graft failure at lower costs than CS. The Markov model revealed cost savings of $86 750 per life-year gained in favor of MP. The corresponding incremental cost-utility ratio was minus $496 223 per quality-adjusted life-year (QALY) gained. We conclude that life-years and QALYs can be gained while reducing costs at the same time, when kidneys are preserved by MP instead of CS.

Abstract Bronchiolitis obliterans syndrome (BOS), the clinical correlate of chronic rejection after lung transplantation, is the leading obstacle to better long-term outcomes. We previously instituted a clinical protocol to screen for donor-specific human leukocyte antigen (HLA) antibodies (DSA) and a preemptive antibody-directed therapy protocol consisting of rituximab and/or intravenous immune globulin. In this study, we retrospectively analyzed serum samples from lung transplant recipients (n = 108) for antibodies to self-antigens (K-α 1 tubulin and collagen V) before and after antibody-directed therapy and correlated the results with the subsequent development of BOS. Seventy-two of the 108 recipients developed antibodies to self-antigens. There was a correlation between the development of antibodies to self-antigens and DSA. Sixteen of the 54 patients who had antibodies to self-antigens and were treated with antibody-directed therapy cleared the antibodies, and they were significantly less likely to develop BOS than those who had persistent antibodies. Furthermore, those who cleared DSA after treatment but had persistent antibodies to self-antigens were significantly more likely to develop BOS than those who cleared these antibodies. We conclude that antibodies to self-antigens are an important risk factor for the development of BOS.

We hypothesized that Nox2, the classical phagocytic NADPH oxidase, plays an important role in calcineurin inhibitor (CNI)-induced renal fibrosis. We tested this hypothesis in vitro, in animal and in human studies. Cyclosporine A (CsA) and tacrolimus (TAC) were associated with greater levels of Nox2 mRNA and epithelial to mesenchymal transition (EMT) in NRK52E cells. CsA increased Nox2, α-SMA and phosphorylated-p38MAPK, Smad3 and NFκB proteins. Nox2 upregulation and EMT were inhibited in TGF-β1 knockout cells suggesting that TGF-β1 is required for Nox2 activation. Fisher344 rats treated with high dose CsA showed increased Nox2 in the tubulointerstitium and greater Nox2, α-SMA, phosphorylated Smad3 and nitrotyrosine by immunoblot analyses. Inhibition of Nox2 by coadministration of apocynin or diphenyleneiodonium was associated with reduced fibrogenesis. We validated these findings by treating wild type and Nox2 null (B6.129S-CybbTm1Din/J) mice with high dose CsA. Western blot analyses confirmed the absence of Nox2 and significantly lower levels of α-SMA and 4-hydroxynonenal (HNE) in CsA-treated knockout mice. These findings were clinically relevant since Nox2 and α-SMA were increased in the tubulointerstitium of kidneys from 15 liver transplant recipients with biopsy-confirmed chronic CsA or TAC nephrotoxicity. In conclusion, specific Nox2 inhibition strategies may improve chronic CNI nephrotoxicity in solid organ transplantation.

We conducted a cross-sectional study of patients who underwent pediatric liver transplant (LT) between 1988 and 1992 to evaluate long-term health status. Survivors completed socio-demographic, medical and Health-Related Quality of Life (HRQOL) surveys by mail including the SF-36v2, PedsQL™4.0 Generic Core Scale, PedsQL™ Cognitive Functioning Scale and PedsQL™3.0 Transplant Module. SF-36 scores were converted to SF6D-based utilities and risk factors for lower outcomes were assessed.

Eighty-five of 171 patients had survived. Fifty-six were contacted with a response rate of 66%. Median age at LT was 0.86 years (IQR 0.58–3.0) and 64.3% had biliary atresia. Mean age at survey was 23.0 ± 4.4 years: 62% attended college, 68% lived with parents and 80% of those over 23 were employed. Patient health utilities were lower than norms (0.75 ± 0.12 vs. 0.82 ± 0.18, p < 0.01) and correlated with unemployment (p < 0.042), hospitalizations (p < 0.005) and lower education level (p < 0.016). Lower PedsQL™3.0 Transplant Module and PedsQL™ 4.0 Generic Core Scale scores correlated with unemployment (p = 0.006, p = 0.009) and hospitalizations (p = 0.006, p = 0.02). Pediatric transplant recipients who survive to adulthood have lower physical HRQOL, measurable transplant-related disability and lower health utility. Transplantation is life saving; however, physical and psychological sequelae continue to affect health status up to two decades later.

The importance of CD40/CD154 costimulatory pathway blockade in immunosuppression strategies is well-documented. Efforts are currently focused on monoclonal antibodies specific for CD40 because of thromboembolic complications associated with monoclonal antibodies directed towards CD154. Here we present the rational development and characterization of a novel antagonistic monoclonal antibody to CD40. Rhesus macaques were treated with the recombinant anti-CD40 mAb, 2C10, or vehicle before immunization with keyhole limpet hemocyanin (KLH). Treatment with 2C10 successfully inhibited T cell-dependent antibody responses to KLH without significant peripheral B cell depletion. Subsequently, MHC-mismatched macaques underwent intraportal allogeneic islet transplantation and received basiliximab and sirolimus with or without 2C10. Islet graft survival was significantly prolonged in recipients receiving 2C10 (graft survival time 304, 296, 265, 163 days) compared to recipients receiving basiliximab and sirolimus alone (graft survival time 8, 8, 10 days). The survival advantage conferred by treatment with 2C10 provides further evidence for the importance of blockade of the CD40/CD154 pathway in preventing alloimmune responses. 2C10 is a particularly attractive candidate for translation given its favorable clinical profile.

In 2000, representatives of the transplant community convened for a meeting on living donation in an effort to provide recommendations to promote the welfare of living donors. One key recommendation included in the consensus statement was that all transplant centers which have performed living donor surgeries have an independent living donor advocate (ILDA) “whose only focus is on the best interest of the donor.” The aims of this study were to begin to understand the sociodemographic characteristics, selection and training, and clinical practices of ILDAs. All US transplant centers performing living donor surgeries were contacted to identify the ILDA at their center. One hundred and twenty ILDAs completed an anonymous survey. Results indicated considerable variability with regard to the sociodemographic characteristics of ILDAs, how the ILDA was selected and trained, and the ILDAs’ clinical practices, particularly ethical challenges encountered by ILDAs. The variability observed may result in differential selection of donors and could have a potential negative impact on the lives of both donors and transplant candidates. The variability in the background, training, and practice of ILDAs suggests the need for strategies, such as practice guidelines, to standardize the interaction between ILDAs and living donors.

Hepatitis E virus (HEV) infection is an underdiagnosed disease in the developed world. In pediatric and adult organ transplant patients HEV infection can cause chronic hepatitis, which can lead to cirrhosis. Extra-hepatic manifestations, such as neurological symptoms and kidney injury, have been also reported in transplant patients. In this comprehensive minireview, we summarize the current knowledge on HEV infection in transplant patients, that is, its prevalence, incidence, natural history and therapy.

With increasing short-term survival, the transplant community has turned its focus to delineating the impact of medical comorbidities on long-term outcomes. Unfortunately, conditions such as diabetes, hypertension and hyperlipidemia are difficult to track and often managed outside of the transplant center by primary care providers. We collaborated with Kaiser Permanente Northern California to create a database of 598 liver transplant recipients, which incorporates diagnostic codes along with laboratory and pharmacy data. Specifically, we determined the prevalence of diabetes, hypertension and hyperlipidemia both before and after transplant and evaluated the influence of disease duration as a time-dependent covariate on posttransplant survival. The prevalence of these comorbidities increased steadily from the time of transplant to 7 years after transplant. The estimated risk for all-cause mortality (hazard ratio = 1.07 per year increment, 95% CI 1.01–1.13, p < 0.02) and mortality secondary to cardiovascular events, infection/multisystem organ failure and allograft failure (hazard ratio = 1.08 per year increment, 95% CI 1.00–1.16, p = 0.05) increased for each additional year of diabetes. No associations were found for duration of hypertension and hyperlipidemia. Greater attention to management of diabetes may mitigate its negative impact on long-term survival in liver transplant recipients.

In lung transplant recipients (LuTRs), human cytomegalovirus (HCMV) DNAemia may be associated with HCMV disease and reduced survival of the allograft. Because T cells are essential for controlling HCMV replication, we investigated in this prospective study whether the kinetics of plasma HCMV DNA loads in LuTRs are associated with HCMV-specific CD8+ T-cell responses, which were longitudinally assessed using a standardized assay. Sixty-seven LuTRs were monitored during the first year posttransplantation, with a mean of 17 HCMV DNA PCR quantifications and 11.5 CD8+ T-cell tests performed per patient. HCMV-specific CD8+ T-cell responses displayed variable kinetics in different patients, differed significantly before the onset of HCMV DNAemia in LuTRs who subsequently experienced episodes of DNAemia with high (>1000 copies/mL) and low plasma DNA levels (p = 0.0046, Fisher's exact test), and were absent before HCMV disease. In HCMV-seropositive LuTRs, high-level DNAemia requiring preemptive therapy occurred more frequently when HCMV-specific CD8+ T-cell responses fluctuated, were detected only after HCMV DNA detection, or remained undetectable (p = 0.0392, Fisher's exact test). Thus, our data indicate that HCMV-specific CD8+ T cells influence the magnitude of HCMV DNAemia episodes, and we propose that a standardized measurement of CD8+ T-cell immunity might contribute to monitoring the immune status of LuTRs posttransplantation.

Although neurocognitive impairment is relatively common among patients with advanced lung disease, little is known regarding changes in neurocognition following lung transplantation. We therefore administered 10 tests of neurocognitive functioning before and 6 months following lung transplantation and sought to identify predictors of change. Among the 49 study participants, native diseases included chronic obstructive pulmonary disease (n = 22), cystic fibrosis (n = 12), nonfibrotic diseases (n = 11) and other (n = 4). Although composite measures of executive function and verbal memory scores were generally within normal limits both before and after lung transplantation, verbal memory performance was slightly better posttransplant compared to baseline (p < 0.0001). Executive function scores improved in younger patients but worsened in older patients (p = 0.03). A minority subset of patients (29%) exhibited significant cognitive decline (i.e. >1 standard deviations on at least 20% of tests) from baseline to posttransplant. Patients who declined were older (p < 0.004) and tended to be less educated (p = 0.07). Lung transplantation, like cardiac revascularization procedures, appears to be associated with cognitive decline in a subset of older patients, which could impact daily functioning posttransplant.

Many potential kidney transplant recipients are unable to receive a live donor transplant due to crossmatch or blood type incompatibility. Kidney paired donation increases access to live donor transplantation but has been significantly underutilized. We established a kidney paired donation program including consented incompatible donor/recipient pairs as well as compatible pairs with older non-human leukocyte antigen identical donors. Over a 3-year period, a total of 134 paired donor transplants were performed, including 117 incompatible pairs and 17 compatible pairs. All transplants were done with negative flow cytometry crossmatches and five were done with desensitization combined with paired donation. Kidney paired donation transplants included two-way and three-way exchanges as well as three chains initiated by nondirected donors. Of the sensitized recipients transplanted by paired donation, 44% had calculated panel reactive antibody levels greater than 80%. Transplantation of females and prior transplant recipients was significantly higher with paired donation. Only three episodes of rejection occurred and no transplants were lost due to rejection. These data highlight the potential of kidney paired donation and suggest that all transplant centers should be actively engaged in paired donation to increase access to live donor transplantation.

Rapidly progressing mucosal breakdown limits the intestinal preservation time below 10 h. Recent studies indicate that intraluminal solutions containing polyethylene glycol (PEG) alleviate preservation injury of intestines stored in UW-Viaspan. We investigated whether a low-sodium PEG solution is beneficial for intestines stored in histidine-tryptophane-ketoglutarate (HTK) preservation solution. Rat intestines used as control tissue (group 1) were perfused with HTK, groups 2 and 3 received either a customized PEG-3350 (group 2) or an electrolyte solution (group 3) intraluminally before cold storage. Tissue injury, brush-border maltase activity, zonula occludens-1 (ZO-1) and claudin-3 expression in the tight junctions (TJ) were analyzed after 8, 14 and 20 h. We measured epithelial resistance and permeability (Ussing chamber) after 8 and 14 h. Group 2 had superior morphology while maltase activity was similar in all groups. TJ proteins rapidly decreased and decolocalized in groups 1 3; these negative events were delayed in group 2, where colocalization persisted for about 14 h. Intestines in group 2 had higher epithelial resistance and lower permeability than the other groups. These results suggest that a customized PEG solution intraluminally reduces the intestinal preservation injury by improving several major epithelial characteristics without negatively affecting the brush-border enzymes or promoting edema.

This month, “The AJT Report” looks at the flat growth of NIH funding in recent years, and how the presidential election may impact future funding. Also this month, the concern of several researchers over the lung allocation system's effectiveness is examined.

A new report describes a fascinating chain of events in two different mouse models of obesity and nonalcoholic steatohepatitis that may fundamentally change thinking about many obesity-associated diseases, and have farreaching implications for transplantation.

The author provides historical and practical perspective for recently reported clinical advances in tolerance induction through mixed chimerism. See article by Scandling et al on page 1133.

This editorial summarizes the current evidence and the authors' perspective regarding the role of mTOR inhibitors and cancer in kidney transplant recipients. See article by Campbell et al on page 1146.

The authors describe the findings of Wiebe et al (page 1157) that de novo donor-specific HLA antibodies have adverse prognostic implications for long-term renal transplant survival and discuss how these findings may impact individual patient care and direct future research.