Acute Allograft Research Articles

Everolimus: an immunosuppressive agent in transplantation

Everolimus is a novel immunosuppressive agent related to sirolimus. It is a proliferation signal inhibitor with an improved pharmacokinetic profile and bioavailability compared with sirolimus. Everolimus has been shown to be as effective as mycophenolate mofetil in reducing acute rejection in renal transplantation. In cardiac transplant recipients, it is superior to azathioprine in reducing acute rejection and cardiac allograft vasculopathy. Its use is also associated with a decrease in cytomegalovirus infection. However, coadministration with calcineurin inhibitors requires careful dose adjustment to prevent renal toxicity. Antiproliferative effects of everolimus may abrogate the increased risk of malignancy seen in solid organ transplantation.

The long-term dialysis patient with purple-blue toes**This paper was written in memory of Gianni d'Angelo, a dear friend and teacher.

The article depicts the situation of a 57-year-old Caucasian man, on renal replacement therapy since 1979 because of membranous and proliferative glomerulonephritis, who came to the hospital dialysis ward complaining of severe foot pain. His long clinical history included about 17 years on dialysis and 8 years of transplantation (three kidney grafts, which failed because of various combinations of acute rejection and chronic allograft disease). He experienced a myocardial infarction at the age of 45 and angina at the time of the third graft. Three months before the episode described here, he suffered a worsening of claudicatio intermittens and was treated by angioplasty, with stenting of the left iliac artery and the right superficial femoral artery; the results of the intervention were considered highly satisfactory. However, severe diffuse vascular disease was present at all the levels examined (Figure 1). Despite an initial improvement, he experienced recurrence of local pain after a couple of months and, in the last few days, had noticed a bluish discolouration of his feet (Figure 2). The most likely clinical diagnosis is cholesterol crystal emboli syndrome, superimposed on severe diffuse peripheral vascular disease. The differential diagnosis of subacute painful vascular lesions, as presented by our patient, takes into account both the evolution of peripheral vascular disease and vasculitis or vasculitis-like lesions. The vascular echo Doppler, performed taking into account the hypothesis of closure of the previously treated vessels, was unchanged and revealed the presence of diffuse vessel lesions but no critical stenosis, thus ruling out ‘simple’ large/medium vessel occlusion. As shown in Figure 2, the patient presented diffuse livedo reticularis and two small necrotic lesions. Livedo is a generic sign, common to several systemic microvascular diseases including anti-phospholipid antibodies, calciphylaxis and vasculitis [1]. It is a major form of cutaneous involvement in cholesterol crystal emboli syndrome, together with ‘blue toes’, vasculitis-like lesions and necrotic lesions [1–4]. Concerning the necrotic lesions, an interesting diagnostic clue came from the location—while ‘pure’ obstructive diseases usually lead to very distal lesions, microembolic lesions often appear in more capricious ‘non-terminal’ sites, as seen in the figures [1].

Tracking Microchimeric DNA in Plasma to Diagnose and Manage Organ Transplant Rejection

One of the most promising areas of transplantation research is the recent discovery of biomarkers for rejection that are detectable in blood and urine. Biopsy-confirmed rejection, the current gold standard for diagnosis of allograft rejection, is invasive and subject to sampling errors. For example, diagnosis of episodes of rejection of pancreas allografts, which are frequent and can destroy the allograft, depends on conventional percutaneous biopsies that have a diagnostic sensitivity of only 79%–88% (1)(2) and are associated with a 2%–7% risk of serious complications (3). Development of noninvasive assays that detect molecular biomarkers for rejection could revolutionize management of transplant recipients by ( a ) detecting a prerejection profile that will allow therapeutic interventions before rejection causes graft dysfunction; ( b ) improving the sensitivity and specificity of rejection diagnosis; ( c ) developing new classification systems for rejection that will improve prognosis; and ( d ) providing information for designing individualized immunosuppressive regimens that could prevent rejection while minimizing drug toxicity. There have been several exciting reports of potential biomarkers for allograft rejection, with the most significant progress occurring in the area of renal transplantation. This work began by studying concentrations of particular mRNAs or proteins that were associated with immune activation or tissue stress (4). These studies have revealed several gene products that have altered expression in blood, urine, and/or biopsy tissue during rejection episodes. In the most recent contribution in this rapidly evolving field, Muthukumar et al. (5) demonstrated that urine concentrations of FOXP3 mRNA, a member of the forkhead family of cell differentiation genes and a lineage-specific transcript for graft-protecting regulatory T cells, can predict reversal of acute renal allograft rejection with 90% sensitivity and 73% specificity. Although measurement of the products of individual genes such as FOXP3 will probably not supplant conventional biopsies for diagnosis of rejection, development of panels of …

Value of radionuclide studies in cardiac transplantation

Effective noninvasive evaluation of acute and chronic allograft rejection remains an important challenge in patients with cardiac transplantation. Radionuclide studies have demonstrated utility because of their ease of use, giving relevant information about the pathophysiology of the transplanted heart, along with valuable diagnostic and prognostic indicators. This article focuses on reviewing the pathophysiological changes of the transplanted heart and implications for radionuclide studies.

Steroid preservation: the rationale for continued prescribing

Tailored immunosuppression according to risk stratification for optimal outcome for both immunological and non-immunological risk factors should be the ultimate objective for every child in whom renal transplantation is planned. Renal allograft survival is dependent on the appropriate use of immunosuppressive therapy to prevent acute rejection and chronic allograft nephropathy. Unfortunately, all immunosuppressive therapies, including corticosteroids, have unwanted side effects, including infections, malignancy, nephrotoxicity, hypertension, hyperlipidaemia and diabetes mellitus. However, the most worrying side effects of corticosteroids for children, adolescents and their parents are growth retardation and the cosmetic effects. Consequently, achieving immunosuppressive regimens without corticosteroids would be preferable. The major concern for paediatric nephrologists in the 21st century is no longer acute rejection, as the incidence appears to be decreasing, but infection, particularly EBV and the development of post-transplant lymphoproliferative disease (PTLD). With modern immunosuppressive agents in transplantation, rejection is being traded for infection. The long-term outcome data of PTLD with steroid-free and monoclonal antibody protocols is as yet unknown.

Effect of nifedipine on renal transplant rejection.

The effect of early nifedipine therapy on acute renal allograft rejection was studied in 170 adult cadaveric transplant recipients. Acute rejection occurring in the first 3 months after transplantation was diagnosed by Tru-cut biopsy and the severity of each rejection episode assessed histologically. The incidence of acute rejection was significantly lower in patients treated with nifedipine (29 of 80; 36 per cent) than in controls (52 of 90; 58 per cent) (P < 0.01) and there was a higher proportion of histologically mild rejection episodes in the former group (P < 0.01). Multivariate analysis confirmed that nifedipine exerted a significant independent effect on the incidence of early acute rejection. Other factors identified in the multivariate model as influencing rejection were human leucocyte antigen (HLA) matching at the DR locus, blood level of cyclosporin during the first week, HLA matching at the B locus, donor age and donor sex. The 1-year graft survival rate was 88.6 per cent in patients given nifedipine and 63.8 per cent in controls (P < 0.02). These data suggest that nifedipine therapy has a useful role in human renal transplantation.

Impacts of donor and recipient's SNP of cytokine and cytokine receptor on early acute renal allograft rejection

To investigate the impact of donor and recipient's SNP of cytokine and cytokine receptor on early acute rejection after renal transplantation. (1) 129 cases of cadaveric renal allograft recipients were divided into two groups according to the presence or absence of acute graft rejection. The distribution of 21 single nucleotide polymorphisms in cytokines and cytokine receptors gene were compared between two groups as well as latent factors affecting the development of acute rejection. (2) Based on the result of HLA-DR matching between donor and recipient, the recipients with AR were stratified into two conditions, 0-1 locus mismatched (0-1MM) and completely mismatched (2MM). By aids of SPSS 11.5 software, association analysis was assessed using Kruskal Wallis test, 2 x 2 or 2 x n contingency table, the Chi-square test. (1) Of 129 recipients of renal transplantation, 39 developed acute graft rejection (30.2%). (2) Compared with recipients without acute rejection, the number of HLA-DR mismatching was significantly higher in rejection group. (3) In rejection group and non-rejection group, the gene polymorphism distribution was significantly different. (4) 0-1MM group and 2MM group were various in the gene polymorphism distribution. In the whole, the susceptibility of acute rejection after renal transplantation may be predicted by the donor and recipient's SNP of cytokine and cytokine receptor.

Can urinary monokine induced by interferon-γ accurately predict acute renal allograft rejection?

Can urinary monokine induced by interferon-γ accurately predict acute renal allograft rejection?

47. Ex Vivo Hypothermic Recirculatory Adenoviral Gene Transfer to the Transplanted Pig Heart

Background: Heart transplantation is the most efficient and successful therapeutic procedure for end stage heart failure, but several limitations such as primary graft failure, acute graft rejection and chronic allograft vasculopathy still remain to be overcome. To facilitate the application of adenoviral gene therapy in clinical heart transplantation, we developed an ex vivo hypothermic recirculatory adenoviral gene transfer method to the transplanted pig heart.

Left ventricular systolic dysfunction is an independent predictor for cardiac death in heart transplant recipients

We retrospectively reviewed the incidence and risk factors for progression to irreversible left ventricular dysfunction (LVD) in stable heart transplant (HT) recipients and its relationship with posttransplant outcomes. Methods: The results of surveillance studies in 26,706 HT recipients between 1990 and 2004 in the United States were obtained from the Scientific Registry of Transplant Recipients. 17,968 patients were included in the analysis, who survived one year posttransplant and had available results of annual angiograms and assessment of LV function. Irreversible LVD was defined as LV ejection fraction 35% which did not improve in follow-up studies. Results: Irreversible LVD developed in 33% of HT recipients and was associated with increased risk of cardiac and sudden death (RR 2.5), irrespective of the results of annual angiograms. Patients with LVD were at increased risk of stroke (RR 1.6), renal failure (RR 1.9) and late graft rejection (RR 3.2). If the deterioration of LV function occurred within the first posttransplant year, it correlated with one-year survival of only 56% as opposed to 78% in patients who developed LVD later. The strongest single predictor of progression to irreversible LVD was an episode of LVD within the first posttransplant year, even if followed by temporary normalization of ejection fraction. Posttransplant events, such as acute rejection or cardiac allograft vasculopathy detected during the first posttransplant year doubled the risk of LVD. Recipients at highest risk for LVD included: African Americans, recipients 40 and 60 yrs of age, and recipients of hearts from donors of African American ethnicity and age 30 yrs. Conclusions: Early and aggressive management of the cardiac and non-cardiac complications of LVD may improve outcomes in high-risk HT recipients. Because of the high incidence of unexpected death in these patients, the adoption of SCD-HeFT and MADIT II indications should be considered in HT recipients with ejection fraction 35%.

Long-Term Beneficial Effect of Tacrolimus Conversion on Renal Transplant Recipients

Objective. Acute rejection, chronic allograft nephropathy, and cyclosporine (CsA) toxicity remain serious problems for renal transplant recipients and may lead to graft loss. We retrospectively analyzed 34 patients whose biopsies revealed acute and/or chronic allograft rejection, or CsA nephrotoxicity, and who converted from CsA to tacrolimus. Patients and Methods. From July 1996 through September 2003, CsA was converted to tacrolimus in 34 renal transplant recipients (26 male, 8 female) with renal biopsy at our hospital. Blood pressure and serum creatinine levels were checked monthly and serum cholesterol, triglyceride, and glutamic-pyruvic transaminase (GPT) levels were checked every three months. Results. A consistently stable and better function after conversion was obtained in a significant portion (24, 71%) of patients. A statistically significant decline in serum creatinine and an improvement in the glomerular filtration rate were found at 3 m, 6 m, 12 m, 36 m, and 72 m after tacrolimus conversion. In 85.7% (12/14) of patients with acute rejection and in 35.7% (5/14) of patients with chronic allograft nephropathy (concomitant with acute rejection in 5), improved or stabilized graft function was noted. In addition, the systolic blood pressure and diastolic BP dropped significantly (P< 0.05), while there was no significant change in cholesterol, triglyceride, and GPT levels. Conclusion. The beneficial effect of tacrolimus conversion on patients with acute rejection, chronic allograft nephropathy, or CsA nephrotoxicity was demonstrated in long-term follow up. The improvement in both renal function and blood pressure may be of paramount importance in reducing long-term cardiovascular morbidity and mortality.

Ultrastructure as a Diagnostic Adjunct in the Evaluation of Lung Allograft Biopsies

Humoral immunity contributes significantly to lung graft dysfunction. Recognizing a role of ultrastructural studies in the evaluation and diagnosis of chronic humoral allograft rejection in the kidney, the authors sought to explore its utility as a diagnostic adjunct in lung allograft biopsies. Ultrastructural studies were conducted on 44 biopsies from 26 lung transplant recipients. Endothelial cell activation and necrosis were seen in the setting of acute humoral allograft rejection. Septal chronic vasculopathic changes of thickening and lamellation of the basement membrane zone (BMZ) and BMZ collagen deposition were correlated with greater numbers of humoral allograft rejection episodes and with the development of chronic graft dysfunction/bronchiolitis obliterans syndrome. There was a positive correlation between the extent of septal fibrosis and certain chronic vasculopathic changes, namely collagen deposition in the BMZ and BMZ wrinkling. Patients with chronic graft dysfunction and multiple rejection episodes manifested low diffusion capacities (less than 50% predicted). The results indicate that ultrastructural analysis is useful in identification of septal fibrosis and chronic vasculopathy of the septal microvasculature, correlating with chronic graft dysfunction, encompassing not only fibrotic sequelae of the bronchial wall but also irreversible terminal lung parenchymal changes, the latter associated with repeated episodes of humoral rejection.

Gene therapy for heart transplantation-associated acute rejection, ischemia/reperfusion injury and coronary arteriosclerosis.

Acute cardiac allograft rejection is still a major complication after heart transplantation. Acute rejection usually responds to conventional immunosuppressants, however, the nonspecific nature of the immunosuppression and the toxicities of the drugs can be life threatening and may compromise the recipient's quality of life. In addition, cardiac allograft arteriosclerosis or chronic rejection limits the long-term survival of recipients. Such conditions cannot be prevented with conventional therapies. To overcome acute and chronic rejection of cardiac allograft as well as ischemia/reperfusion injury associated with organ preservation many novel approaches have been proposed. Gene transfection of the donor organ during organ preservation is an attractive method, because the transfected genes would not affect recipients and treatment could be delivered specifically to the site of inflammation. This method could be useful to prevent graft failure without systemic adverse effects. Here we shall review current advances in gene therapies to prevent and treat organ failure of transplanted allografts.

Prevention of acute and chronic allograft rejection by a novel retinoic acid receptor- -selective agonist

Prevention of acute and chronic allograft rejection by a novel retinoic acid receptor- -selective agonist

Prevention of acute and chronic allograft rejection by a novel retinoic acid receptor-alpha-selective agonist.

To investigate the involvement of retinoic acid receptor (RAR)-alpha in allograft rejection, we investigated the effect of a novel selective agonist to the receptor, ER-38925, in a mouse cardiac allograft model. Prophylactic treatment with ER-38925 inhibited the acute rejection of the mouse cardiac allograft (BALB/c --> C3H/HeN) at 0.3 and 3 mg/kg, and its effect was enhanced in combination with tacrolimus. In this model, ER-38925 remarkably inhibited cytotoxic T lymphocyte induction and alloantigen-stimulated production of cytokines, i.e. IL-2, IL-12 and IFN-gamma. In the chronic rejection model, combined treatment with tacrolimus and ER-38925 reduced the grade and incidence of arteriosclerosis in the cardiac allografts significantly more potently than tacrolimus monotherapy. ER-38925 inhibited the proliferation of rat aortic smooth muscle cells stimulated in vitro, presumably through the induction of a cyclin-dependent kinase inhibitor, p27(kip-1). Those results provide a rationale for using RAR-alpha agonists as immunosuppressants in human organ transplantation.

Elevated IL-15 in acute lung allograft rejection

Elevated IL-15 in acute lung allograft rejection

First evidence for B-lymphocyte/plasma cell participation in acute liver allograft rejection: B-cell expansion, expression of B-cell specific chemokines and IgVh gene diversification

First evidence for B-lymphocyte/plasma cell participation in acute liver allograft rejection: B-cell expansion, expression of B-cell specific chemokines and IgVh gene diversification

Correlation between Interleukin-15 and granzyme B expression and acute lung allograft rejection

Correlation between Interleukin-15 and granzyme B expression and acute lung allograft rejection

Histamine-degrading enzymes as cellular markers of acute small bowel allograft rejection.

Intestinal histamine-degrading enzymes diamine oxidase (DAO) and histamine N-methyltransferase (HNMT) activities are relatively constant per individual and bowel segment, and they reflect the functional integrity of the intestinal mucosa. It was, therefore, hypothesised that a decrease in these enzymes could be indicative of acute rejection of an intestinal allograft. Enzymatic activities of DAO and HNMT were determined in mucosal biopsies of isogeneic (Lewis-to-Lewis, n=48) and allogeneic (Brown Norway-to-Lewis, n=48) heterotopic small bowel transplants in a rat model at various time periods. Allograft recipients were not given any immunosuppression. While no changes in enzyme activities were observed in isografts up to day 8 following transplantation, significantly reduced activities of both enzymes were found in all allografts 6-8 days after transplantation. Activities of both DAO and HNMT exhibited a strong negative correlation with the histological rejection score ( P<0.01). We can conclude that DAO and HNMT activities in gut mucosa are reliable quantitative markers of acute intestinal allograft rejection in the rat that support histopathological analysis.

CXCR3, but not CCR5, +ve host T cells are predominant in lamina propria infiltrates in early acute small bowel allograft rejection

CXCR3, but not CCR5, +ve host T cells are predominant in lamina propria infiltrates in early acute small bowel allograft rejection