Human herpesvirus-6 (HHV-6), which comprises of HHV-6A and HHV-6B, is a common infection after solid organ transplantation. The rate of HHV-6 reactivation is high, although clinical disease is not common. Only 1% of transplant recipients will develop clinical illness associated with HHV-6 infection, and most are ascribable to HHV-6B. Fever, myelosuppression, and end-organ disease, including hepatitis and encephalitis, have been reported. HHV-6 has also been associated with various indirect effects, including a higher rate of CMV disease, acute and chronic graft rejection, and opportunistic infection such as invasive fungal disease. All-cause mortality is increased in solid organ transplant recipients with HHV-6 infection. HHV-6 is somewhat unique among human viruses because of its ability to integrate into the host chromosome. The clinical significance of chromosomally integrated HHV-6 is not yet defined, although a higher rate of bacterial infection and allograft rejection has been suggested. The diagnosis of HHV-6 is now commonly made using nucleic acid testing for HHV-6 DNA in clinical samples, but this can be difficult to interpret owing to the common nature of asymptomatic viral reactivation. Treatment of HHV-6 is indicated in established end-organ disease such as encephalitis. Foscarnet, ganciclovir, and cidofovir have been used for treatment.

Absolute uterine factor infertility (UFI) refers to the refractory causes of female infertility stemming from the anatomical or physiological inability of a uterus to sustain gestation. Today, uterine factor infertility affects 3–5% of the population. Traditionally, although surrogacy and adoption have been the only viable options for females affected by this condition, the uterine transplant is currently under investigation as a potential medical alternative for women who desire to go through the experience of pregnancy. Although animal models have shown promising results, human transplantation cases have only been described in case reports and a successful transplant leading to gestation is yet to occur in humans. Notwithstanding the intricate medical and scientific complexities that a uterine transplant places on the medical minds of our time, ethical questions on this matter pose a similar, if not greater, challenge. In light of these facts, this article attempts to present the ethical issues in the context of experimentation and standard practice which surround this controversial and potentially paradigm-altering procedure; and given these, introduces “The Montreal Criteria for the Ethical Feasibility of Uterine Transplantation”, a set of proposed criteria required for a woman to be ethically considered a candidate for uterine transplantation.

Knowledge of the very long-term consequences of kidney donors has not been previously reported extensively. The 398 persons who had donated a kidney between 1952 and 2008 at Necker hospital were contacted. Among the 310 donors who were located, the survival probabilities for this population were similar to those of the general population and end stage renal disease incidence was 581 per million population per year. All located donors still alive were asked to complete a medico-psychosocial questionnaire and give samples for serum creatinine and urinary albumin assays. Among the 204 donors who responded to the questionnaire, mean eGFR was 64.4 ± 14.6 ml/min per 1.73 m² and mean microalbuminuria was 27.0 ± 83 mg/g. Most donors never regretted the donation and consider that it has no impact on their professional or social lives. Among the 59 donors who gave a kidney more than 30 years ago (mean 40.2 years, range 30–48 years) had a mean eGFR of 67.5 ± 17.4 μmol/l, a mean microalbuminuria level of 44.8 ± 123.2 mg/g and none was dialyzed. In conclusion, living kidney donation does not impact survival, kidney function, medical condition or psychological or social status over the very long-term.

The aim of this study was to analyze the clinical and immunological features of the 56 still alive patients at our institution harboring a functional first renal transplant since more than 30 years. The mean post-transplant graft survival in all patients was 35.4 ± 3.1 years, the mean serum creatinine concentration was 128.7 ± 7 μmol/l, and the mean urinary protein concentration was 0.6 ± 0.5 g/l. Fifty-one percent of the patients had experienced cancer involving the skin (46.1%) and/or other tissues (28%). Hepatocarcinoma was diagnosed in 11% of the patients with chronic viral hepatitis B and/or C (48%). The 5-year patient survival rate (considered after the 30th transplantation anniversary) was 27% in patients presenting a tumor versus 87% in those tumor-free (P < 0.0001). The thymic output, the proportions of the memory and naïve T cell subsets, and the frequencies of EBV- and CMV-reactive, IFN-γ-producing T cells did not differ from those observed in more recently transplanted patients. These results suggest that the impact of chronic immunosuppression on some immune functions does not worsen over time and that the observed high prevalence of cancer in these patients may be related to the synergistic effects of decreased immunosurveillance and the time required for carcinogenesis.

Clinical trials have pointed out the promising role of co-stimulation blocker Belatacept for improvement of graft function and avoidance of undesired side-effects associated with calcineurin-inhibitors (CNI). However, due to the worldwide limited availability of appropriate patients, almost no data exist to assess the effects of sustained application of this immunomodulator on the recipient’s immune system. The aim of this study was to reveal specific alterations in the composition of immunologic subpopulations potentially involved in development of tolerance or chronic graft rejection following long-term Belatacept therapy. For this, peripheral lymphocyte subsets of kidney recipients treated with Belatacept (n = 5; average 7.8 years) were determined by flow-cytometry and compared with cells from matched patients on CNI (n = 9) and healthy controls (n = 10). T cells capable of producing IL-17 and serum levels of soluble CD30 were quantified. Patients on CNI showed a higher frequency of CD4⁺CD161⁺ Th₁₇-precursors and IL-17-producing CD4⁺ T cells than Belatacept patients and controls. Significantly higher serum levels of soluble CD30 were observed in CNI patients, indicating a possible involvement of the CD30/CD30L-system in Th₁₇-differentiation. No differences were found concerning CD4⁺CD25⁺CD127^lowFoxP3⁺ regulatory T cells. In conclusion, patients on therapy with Belatacept did not show a comparable Th₁₇-profile to that seen in individuals with chronic intake of CNI. The distinct effects of Belatacept on Th₁₇-immunity might prove beneficial for the long-term outcome following kidney transplantation.

There has been an increase in the number of older patients on the transplant waiting list and acceptance of older donor kidneys. Although kidneys from older donors have been associated with poorer graft outcomes, whether there is a differential impact of donor age on outcomes in older recipients remains unclear. The aim of this study was to evaluate the effect of donor age on graft and patient survival in renal transplant (RT) recipients ≥60 years. Using the Australia and New Zealand Dialysis and Transplant Registry, outcomes of 1 037 RT recipients ≥60 years between 1995 and 2009 were analyzed. Donor age groups were categorized into 0–20, >20–40, >40–60, and >60 years. Compared with recipients receiving donor kidneys >60 years, those receiving donor kidneys >20–40 years had lower risk of acute rejection (odds ratio 0.46, 95% CI 0.27, 0.79; P < 0.01) and death-censored graft failure (HR 0.37, 95% CI 0.19, 0.72; P < 0.01). There was no association between donor age groups and death. With a corresponding growth in the availability of older donor kidneys and the observed lack of association between donor age and patient survival in RT recipients ≥60 years, preferential allocation of older donor kidneys to RT recipients ≥60 years may not disadvantage the life expectancy of these patients.

The aim of this work is to compare disabilities of the upper limb before and after hand allograft transplantation (HAT), and to describe the side effects of immunosuppressive (IS) agents given to recipients of hand allografts. Clinical cases of HAT published between 1999 and 2011 in English, French, or German were reviewed systematically, with emphasis on comparing disabilities of the arm, shoulder and hand (DASH) scores before and after transplantation. Duration of ischemia, extent of amputation, and time since amputation were evaluated for their effect on intrinsic musculature function. Infectious, metabolic, and oncological complications because of IS therapy were recorded. Twenty-eight patients were reported in 56 clinical manuscripts. Among these patients, disabilities of the upper limb dropped by a mean of 27.6 (±19.04) points on the DASH score after HAT (P = 0.005). Lower DASH scores (P = 0.036) were recorded after secondary surgery on hand allografts. The presence of intrinsic muscle function was observed in 57% of the recipients. Duration of ischemia, extent of transplantation, and time since amputation were not associated statistically with the return of intrinsic musculature function. Three grafts were lost to follow-up because of noncompliance with immunosuppression, rejection, and arterial thrombosis, respectively. Fifty-two complications caused by IS agents were reported, and they were successfully managed medically or surgically. HAT recipients showed notable functional gains, but most complications resulted from the IS protocols.

Severe and life-threatening donor-transmitted human T-cell leukemia virus type 1 (HTLV-1) infections after solid organ transplantation have been reported. However, in HTLV-1-infected recipients, graft and patient survival were not fully evaluated. A total of 140 patients underwent living donor liver transplantation (LDLT). Of these, 47 of 126 adult recipients showed indications of hepatitis C virus (HCV)-related liver disease. The HTLV-1 prevalence rate was 10 of 140 recipients (7.14%) and three of 140 donors (0.02%). In HCV-related LDLT, graft and patient survival was worsened by HTLV-1 infection in recipients (seven cases). The 1-, 3-, and 5-year survival rates in the HCV/HTLV-1-co-infected group were 67%, 32%, and 15%, respectively, and the corresponding rates in the HCV-mono-infected group were 80%, 67%, and 67%, respectively. Only the 5-year survival rates were statistically significant (P = 0.04, log-rank method). HTLV-1 infection in recipients is also an important factor in predicting survival in HTLV-1 endemic areas.

Renal allograft compartment syndrome is an under recognized cause of early allograft dysfunction which can be reversed by early intervention. It occurs early after renal transplantation where closure of the anterior abdominal wall seems to compress the transplant in the limited retroperitoneal space. The literature about this syndrome in renal transplantation is sparse. Our report describes the diagnostic criteria and the management of two renal transplant recipients with this syndrome. Its diagnosis depends upon duplex vascular scan findings of reversed or absent diastolic flow in the renal vasculature in the absence of any perigraft collection or severe acute tubular necrosis. In our hands emergency laparotomy, decompression of the transplant and closure with interposition mesh salvaged these kidneys.

The patients with end-stage liver disease (ESLD) on the liver transplant waiting list are prioritized for transplant based on the model for end-stage liver disease (MELD) score. We developed and used an innovative approach to compare MELD to six proposed alternatives with respect to waiting list mortality. Our analysis was based on United Network for Organ Sharing data of patients with ESLD on the waiting list between January 2006 and June 2009. We compared six allocation models to MELD. Two models were based on reweighting the variables used by MELD: an “updated” MELD, and ReFit MELD. Four models also included serum sodium: MESO, MeldNa, UKELD, and ReFit MELDNa. We estimated that UKELD and the updated MELD would result in significantly fewer lives saved. There were no significant differences between the other models. Our new approach can supplement standard methods to provide insight into the relative performance of liver allocation models in reducing waiting list mortality. Our analysis suggests that UKELD and the updated MELD score would not be optimal for reducing waiting list mortality in the United States.

Mesenchymal stromal cells (MSCs), a rare heterogeneous subset of pluripotent stromal cells that can be easily isolated from different adult tissues, in vitro expanded and differentiated into multiple lineages, are immune privileged and, more important, display immunomodulatory capacities. Because of this, they are the preferred cell source in tissue-engineered replacements, not only in autogeneic conditions, where they do not evoke any immune response, but especially in the setting of allogeneic organ and tissue replacements. However, more preclinical and clinical studies are requested to completely understand MSC’s immune biology and possible clinical applications. We herein review the immunogenicity and immunomodulatory properties of MSCs, their possible mechanisms and potential clinical use for tissue-engineered organ and tissue replacement.

This 24-week, open, single-arm, prospective, multicenter study evaluated the effects of conversion from ciclosporin to Tacrolimus QD in adult kidney transplant patients. Stable patients receiving ciclosporin were converted to Tacrolimus QD at 0.1 mg/kg/day. Relative change in renal function (primary endpoint) was assessed using estimated creatinine clearance (eCrCl) with a noninferiority margin set at −10%. A total of 346 patients were enrolled; and 301 patients were treated per protocol (PPS) in the hyperlipidemia (n = 42), hypertrichosis (n = 106), hypertension (n = 77) and gingival hyperplasia (n = 76) groups. Relative change in eCrCl was −0.6% in all PPS patients (95% CI, −2.2; 0.9) and −5.3% in the hyperlipidemia (CI, −9.59; −0.97), 0.9% in the hypertrichosis (CI, −2.59; 4.45), −0.1% in the hypertension (CI, −3.8; 3.68), and −1% in the gingival hyperplasia groups (CI, −4.63; 2.65) (PPS), meeting noninferiority criteria. There was no acute rejection. Decreases in serum lipids and blood pressure were moderate but without meaningful change in the number of treatment medications. Substantial decreases in severity of ciclosporin-related cosmetic side effects were evident from investigator and patient self-report of symptoms. Renal function remained stable after conversion to Tacrolimus QD. The effect of conversion on cardiovascular parameters was not clinically meaningful, however, marked improvement in ciclosporin-related cosmetic side effects was observed.

(ClinicalTrials.gov number: NCT00481481)

There is a growing shortage of size-matched organs and tissues for children. Although examples of substandard care are reported in the literature, there is no overview of the paediatric donation process. The aim of the study is to gain insight into the chain of events, practices and procedures in paediatric donation. Method; a survey of the 1990–2010 literature on paediatric organ and tissue donation and categorization into a coherent chronological working model of key events and procedures. Studies on paediatric donation are rare. Twelve empirical studies were found, without any level I or level II-1 evidence. Seventy-five per cent of the studies describe the situation in the United States. Literature suggests that the identification of potential donors and the way in which parental consent is requested may be substandard. We found no literature discussing best practices. Notwithstanding the importance of looking at donation care as an integrated process, most studies discuss only a few isolated topics or sub-processes. To improve paediatric donation, more research is required on substandard factors and their interactions. A chronological working model, as presented here, starting with the identification of potential donors and ending with aftercare, could serve as a practical tool to optimize paediatric donation.

Long-term corticosteroid treatment impairs growth in children after kidney transplantation (KTx). The impact of steroid withdrawal with respect to adult height remains to be elucidated. In this single-center retrospective analysis linear growth and graft function in 74 pediatric KTx patients transplanted between 1981 and 2001 was investigated. Mean follow up was 8.5 years. Steroids were weaned off between months 4 and 6. Steroid withdrawal resulted in sustained catch-up growth after KTx. Absolute and standardized height velocity in prepubertal patients during the first year post-KTx was 8.9 cm/year and +2.9 SD score (SDS), respectively (P < 0.001 versus healthy children). Mean adult height amounted to −0.5 ± 1.1 SDS and −1.0 ± 1.3 SDS in prepubertal and pubertal patients and was within the normal range (>−2 SD) in 94% and 80% of them. Multiple regression analysis revealed age and standardized height at KTx as independent predictors of adult height (model r² = 0.48). Overall graft survival at 5 and 10 years was 92% and 71%, respectively. Steroid withdrawal during month 4–6 after KTx in prepubertal patients results in an adult height within the normal range, whereas catch-up growth is limited in pubertal patients.

This multicenter, open-label, phase III study assessed renal function, safety, and efficacy in stable adult liver transplant recipients converted from tacrolimus twice-daily (BID) to once-daily (QD). Patients received tacrolimus BID for 6 weeks before conversion to tacrolimus QD (1:1 [mg:mg] total daily dose basis) for 12 weeks. Primary endpoint: change in steady state creatinine clearance (CrCl) between treatment phases. Of 112 patients enrolled, 98 were converted to QD dosing (full analysis set [FAS]). Mean (SD) tacrolimus dose was 3.7 (1.7) mg/day during BID and at conversion, and 3.9 (1.8) mg/day at Week 12. 74.5% of patients required no dose adjustment on conversion (FAS). Mean tacrolimus whole blood trough levels were at the lower end of the recommended range during tacrolimus BID and QD; the difference between mean steady-state trough levels was statistically significant (7.5 ng/ml vs. 6.5 ng/ml; P < 0.0001). Following conversion, mean tacrolimus trough levels were reduced by 15% (about 1 ng/ml) without any cases of acute rejection, remained stable during the remainder of the study, and were more consistent, showing reduced between- and within-patient variability in trough levels. Renal function remained stable, demonstrating noninferiority of tacrolimus QD versus BID (relative difference in mean calculated CrCl −0.1% [±6.3%]). Patient and graft survival were 100%. Adverse events incidence was low during both treatment phases.

Optimization of donor-recipient match is one of the exciting challenges in liver transplantation. Using algorithms obtained by the Italian D-MELD study (5256 liver transplants, 21 Centers, 2002–2009 period), a web-based survival calculator was developed. The calculator is available online at the URL http://www.D-MELD.com. The access is free. Registration and authentication are required. The website was developed using PHP scripting language on HTML platform and it is hosted by the web provider Aruba.it. For a given donor (expressed by donor age) and for three potential recipients (expressed by values of bilirubin, creatinine, INR, and by recipient age, HCV, HBV, portal thrombosis, re-transplant status), the website calculates the patient survival at 90 days, 1 year, 3 years, and allows the identification of possible unsustainable matches (i.e. donor-recipient matches with predicted patient survival less than 50% at 5 years). This innovative approach allows the selection of the best recipient for each referred donor, avoiding the allocation of a high-risk graft to a high-risk recipient. The use of the D-MELD.com website can help transplant surgeons, hepatologists, and transplant coordinators in everyday practice of matching donors and recipients, by selecting the more appropriate recipient among various candidates with different prognostic factors.

T-cell-depleting strategies are an integral part of immunosuppressive regimens used in the hematological and solid organ transplant setting. Besides prevention of alloreactivity, treatment with rabbit antithymocyte globulin (rATG) has been related to the induction of immunoregulatory T cells (Treg) in vitro and in vivo. To investigate Treg induced by rATG, we prospectively studied the effect of rATG induction therapy in liver-transplanted recipients in vivo (n = 28). Treg induction was further evaluated by means of Treg-specific demethylation region (TSDR) analysis within the FOXP3 locus. Whereas no induction of CD4⁺ CD25^highCD127⁻ Treg could be observed by phenotypic analysis, we could demonstrate an induction of TSDR⁺ T cells within CD4⁺ T cells exclusively for rATG-treated patients in the long-term (day 540) compared with controls (P = NS). Moreover, although in vitro experiments confirm that rATG primarily led to a conversion of CD4⁺ CD25⁻ into CD4⁺ CD25⁺ T cells displaying immunosuppressive capacities, these cells cannot be classified as bona fide Treg based on their FOXP3 demethylation pattern. Consequently, the generation of Treg after rATG co-incubation in vitro does not reflect the mechanisms of Treg induction in vivo and therefore the potential clinical relevance of these cells for transplant outcome remains to be determined.

Vitamin D receptor (VDR) polymorphisms may confer susceptibility to immunologically mediated liver diseases. We aimed to verify whether recipient VDR polymorphisms might affect the incidence of acute cellular rejection (ACR) of the graft after liver transplantation (LT). Two hundred and fifty-one liver-transplanted patients surviving at least 1 month were studied. ACR in the first post-LT year was graded according to the Banff score. Recipients genotyping for VDR polymorphic sites (FokI C>T, BsmI G>A, ApaI T>G, TaqI T>C) was performed. A significant difference was found between patients with and without ACR episodes in allele frequencies of BsmI (G: 0.660 vs. 0.545, P = 0.017) and TaqI (T: 0.667 vs. 0.543, P = 0.010). Patients carrying the G-*-T/G-*-T diplotypes of the BsmI G>A, ApaI T>G and TaqI T>C experienced more frequently ACR: 33/79 Vs 42/172, P = 0.005. Carriage of G-*-T/G-*-T diplotypes was an independent predictor of ACR (OR 2.41, P = 0.006), with CMV reactivation (OR 2.34, P = 0.033) and HCV aetiology (OR 1.86, P = 0.036). In conclusion, recipient VDR polymorphic loci are strongly associated with ACR occurrence during the first year after LT. The knowledge of VDR genetic polymorphisms may be helpful in identifying recipients at higher risk of ACR and in selecting them for a more aggressive immunosuppressive therapy.

Anemia is a common problem after renal transplantation. Therefore, the patients are treated with erythropoietin stimulating agents (ESAs). The varying response to treatment contributes to hemoglobin variability, which might be associated with mortality. We conducted a retrospective cohort study of first kidney allograft recipients between 1990 and 2008 represented in the Austrian Transplant Registry. We included 1441 patients of whom 683 received ESAs at any time after transplantation. Cox regression with cubic splines and linear estimates and the purposeful selection algorithm of covariables were used. The measure of variability was the moving standard deviation computed at three monthly intervals for the entire graft life. The hazard ratio (HR) of mortality and graft loss in the spline models increased with hemoglobin variability. The linear HR for mortality was 2.35 (95% confidence interval 1.75–3.17, P < 0.001) and functional graft loss 2.45 (1.76–3.40, P < 0.001). In an adjusted Cox model (ESA use, hemoglobin, age, diabetes, days on dialysis, eGFR, biopsy confirmed acute rejection and year of transplantation), hemoglobin variability was associated with mortality (HR: 2.11; 1.51–2.94; P < 0.001). No association with functional graft loss could be detected (HR: 1.34; 0.93–1.93; P = 0.121). These findings suggest that hemoglobin variability is associated with mortality of renal allograft recipients.

With an increasing demand, organs from elderly donors are more frequently utilized for transplantation. Herein, we analyzed the impact of donor age on CD4⁺ T-cell responses with regard to regulatory and effector mechanisms. Young (3 months) BM12 recipients were engrafted with young or old (18 months) B6 cardiac allografts. Systemic CD4⁺ T-cell responses and intragraft changes were monitored and compared to age-matched syngenic transplant controls. While elderly, nonmanipulated hearts contained significantly elevated frequencies of donor-derived leukocytes prior to transplantation, allograft survival was age-independent. T-cell activation, however, was delayed and associated with a compromised immune response in mixed lymphocyte cultures (MLR; P = 0.0002) early after transplantation (day 14). During the time course after transplantation, recipients of old grafts demonstrated an augmented immune response as shown by significantly higher frequencies of activated CD4⁺ T-cells and a stronger in vitro alloreactivity (MLR; ELISPOT; P < 0.01). In parallel, frequencies of regulatory T-cells had increased systemically and overall fewer CD4⁺ T-cells were detected intragraft. Interestingly, changes in the CD4⁺ T-cell response were not reflected by graft morphology. Of note, transplantation of young and old syngenic hearts did not show age-related differences of the CD4⁺ T-cells response suggesting that old grafts can recover from a period of short cold ischemia time. Our data suggest that donor age is associated with an augmented CD4⁺ T-cells response which did not affect graft survival in our model. These findings contribute to a better understanding of the immune response following the engraftment of older donor organs.

Immunosuppressants have been associated with increased cardiovascular disease risk. We determined the effects of calcineurin and mammalian target of rapamycin (mTOR) inhibitor administration on endothelial dysfunction and associated inflammation and oxidative stress in adult rats. Cyclosporine A (low and high dose), sirolimus, tacrolimus, everolimus and placebo were administered to 8-week-old male Wistar rats for 10 consecutive days. Aortic vascular endothelial and smooth muscle function were assessed ex vivo in organ baths. Maximal aortic contraction to noradrenaline in sirolimus-treated rats was significantly greater than cyclosporine groups, everolimus and placebo, whereas endothelial-dependent relaxation was significantly impaired with cyclosporine and tacrolimus compared with everolimus. Endothelial-independent relaxation was impaired in tacrolimus-treated rats compared with low dose cyclosporine, everolimus and sirolimus. Sirolimus was associated with a reduction in plasma interleukin (IL)-1β and tumour necrosis factor (TNF)-α and higher levels of catalase and total antioxidant status. In nontransplanted rats, vascular dysfunction was evident following administration of cyclosporine A, sirolimus and tacrolimus, whereas everolimus did not compromise aortic endothelial or smooth muscle function. At the doses administered in this model, the immunosuppressants exerted varying effects on vascular function.

One of the leading causes of long-term kidney graft loss is chronic allograft injury (CAI), a pathological process triggered by alloantigen-dependent and alloantigen-independent factors. Alloantigen-independent factors, such as cold ischemia (CI) may amplify the recipient immune response against the graft. We investigated the impact of prolonged cold ischemia and the subsequent delayed graft function on CAI in a fully MHC-mismatched rat model of kidney allotransplantation. Prolonged CI was associated with anticipation of proteinuria onset and graft function deterioration (ischemia: 90d; no ischemia: 150d), more severe tubular atrophy, interstitial fibrosis, and glomerulosclerosis, and increased mortality rate (180d survival, ischemia: 0%; no ischemia: 67%). In ischemic allografts, T and B cells were detected very early and were organized in inflammatory clusters. Higher expression of BAFF-R and TACI within the ischemic allografts indicates that B cells are mature and activated. As a consequence of B cell activity, anti-donor antibodies, glomerular C4d and IgG deposition, important features of chronic humoral rejection, appeared earlier in ischemic than in non-ischemic allograft recipients. Thus, prolonged CI time plays a main role in CAI development by triggering acceleration of cellular and humoral reactions of chronic rejection. Limiting CI time should be considered as a main target in kidney transplantation.

Danazol, a derivative of testosterone, is useful for treatment of endometriosis as well as pretreatment for in vitro fertilization and embryo transfer, although its mechanisms of action are unclear. The aim of this study was to investigate the effect of danazol on alloimmune responses in murine heart transplantation. CBA male mice (H2^k) underwent transplantation of C57BL/6 male (H2^b) hearts and received a single dose of danazol (0.4, 1.2 or 4 mg/kg/day) by intraperitoneal injection on the day of transplantation and for 6 days thereafter. An adoptive transfer study was performed to determine whether regulatory cells were generated. The median survival time (MST) of allografts in danazol-treated (1.2 and 4 mg/kg/day) mice was 28 and 63 days, respectively, compared with 7 days in untreated mice. Moreover, secondary CBA recipients given whole splenocytes or CD4⁺ cells from primary danazol-treated (4 mg/kg/day) CBA recipients 30 days after transplantation had prolonged allograft survival (MSTs, 29 and 60 days, respectively). Cell proliferation, interleukin (IL)-2 and interferon-γ were suppressed in danazol-treated mice, whereas IL-4 and IL-10 were up-regulated. Moreover, danazol directly suppressed allo-proliferation in a mixed leukocyte culture. Flow cytometry showed an increased CD4⁺ CD25⁺ Foxp3⁺ cell population in splenocytes from danazol-treated mice. Danazol prolongs cardiac allograft survival and generates regulatory CD4⁺ cells.

Embolic stroke is a common complication in patients on ventricular assist devices in both adults and children. The reported incidence of strokes in children supported by VAD’s varies from 7 to 38%. The rapid increase in recent years in the availability of both adult and pediatric VADs will likely add to the overall prevalence of strokes in patients being bridged to heart transplant. Strokes in this population can be lethal as they frequently necessitate withdrawal of the extracorporeal device support and withdrawal from the organ transplant waiting list. We present a case of a fully anti-coagulated 29-month-old supported on a Berlin EXCOR LVAD (Berlin, Germany) with embolic stroke which was treated successfully with direct thrombolysis with recombinant tissue plasminogen activator. This is the first report which uses intra-arterial thrombolytics while on a ventricular assist device in a pediatric patient.

Acute renal allograft dysfunction in the first weeks after transplantation primarily requires examination for acute rejection, drug-associated injury, pre-renal failure due to exsiccosis/dehydration, and post-renal problems such as urinary tract obstruction. In rare instances, main renal artery or vein thrombosis may be found, e.g. due to acute rejection of the vessels. Herein, we describe the clinical course of a patient with a recent renal transplantation who presented with an acute enigmatic renal allograft failure which, after intensive diagnostic efforts, emerged as paradoxical embolism with extensive allograft ischemia in consequence of a venous thrombosis and a patent foramen ovale − a so far unreported case.