Transplant Rejection Episodes Research Articles

Successful use of therapeutic plasma exchange for the management of acute lung transplant rejection secondary to immune checkpoint inhibitor therapy

The use of immune checkpoint inhibitors (ICIs) in individuals with a history of solid organ transplantation is fraught with the emergence of solid organ transplantation rejection (SOTR). The current recommendations for the management of SOTRs secondary to ICI include the use of high-dose steroids along with the escalation of immunosuppressive therapy. Therapeutic Plasma Exchange (TPE) has been described to be effective in managing various immune-related toxicities, however, the data for using TPE in the setting of acute SOTRs induced by ICIs are limited. Herein, we describe the successful use of TPE in a patient with a history of bilateral lung transplantation who developed an episode of mixed acute cellular and antibody-mediated lung transplant rejection after a single dose of PD-1 inhibitor Pembrolizumab for the treatment of underlying melanoma.

Pregnancy management and outcome after uterus transplantation.

Uterus transplantation is a novel approach in women whose uterus is absent or severely abnormal. However, it is still an experimental procedure that poses risks to both mother and baby. To date, 32 live births after uterus transplantation have been reported in peer-reviewed journals, with several maternal, fetal and neonatal complications. The most common complications were preterm delivery, hypertensive disorders and placenta previa. Four patients experienced episodes of transplant rejection during pregnancy. The appropriate management of complicated and non-complicated pregnancies following uterus transplantation is still unresolved. In this review, obstetric outcomes after uterus transplantation and optimal management during pregnancy are discussed in light of the available data. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Pregnancy and childbirth in women with a kidney transplant (clinical observation)

The number of pregnant women with kidney transplant is growing and will continue to increase in Ukraine and all over the world, taking into account the development of transplantology. Such patients belong to the high-risk group, however, a clear understanding and adequate evaluation of the prognostic factors which are described in the literature will allow to transfer from prohibition and intimidation to the stage of supporting motherhood and providing highly qualified medical care to women with kidney transplants.This article presents two clinical cases of pregnancy and childbirth in women with kidney transplants, which occurred in the Department of Internal Pathology of Pregnant Women of the State Institution “Institute of Pediatrics, Obstetrics and Gynecology named after Acad. O. M. Lukyanova National Academy of Sciences of Ukraine”. Both patients with kidney transplants that functioned for 4 and 5 years, respectively, visited the doctor in early pregnancy.The anamnesis of the first pregnant woman was without peculiarities, while the second patient already had an episode of acute transplant rejection in the anamnesis and organ retransplantation from her mother. In addition, she had viral hepatitis B and C, as well as an insufficient level of immunosuppression. The function of the transplants in both women was satisfactory, each of the persons suffered from secondary nephrogenic anemia. Correction of immunosuppression in both patients was difficult, especially at 28 weeks, which is associated with hemodilution of pregnant women. Both women experienced an episode of urinary tract infection, which is experienced by about 40 % of pregnant kidney recipients.The first pregnant woman was practically healthy at full term pregnancy and had no indications for abdominal operation delivery, however, due to a clinically narrow pelvis she had cesarean section, which is a technically difficult surgery in such cases. In the second patient, the last weeks of pregnancy were complicated by hypertension of non-placental origin and transplant function disorders, which became an indication for cesarean section at 38 weeks. In the postpartum period kidney function began to recover. The condition of both newborns was satisfactory.Therefore, despite the reliable pregnancy outcomes in kidney transplant patients, an increased risk of obstetric complications and adverse perinatal outcomes remains. Interdisciplinary monitoring with timely correction of kidney transplant function disorders, monitoring of immunosuppressive therapy, prevention of premature births, careful control of blood pressure and adequate fetal monitoring allows to hope for favorable obstetric and perinatal outcomes in this group of patients.

Descemet Membrane Endothelial Keratoplasty in Vascularized Eyes: Outcome and Effect on Corneal Neovascularization

To report the outcomes after Descemet membrane endothelial keratoplasty (DMEK) in vascularized eyes. Consecutive cases of DMEK in vascularized eyes (involving ≥2 vascularized quadrants) were selected from a prospective database. Best corrected visual acuity, endothelial cell density (ECD), central corneal thickness, corneal transplant rejection episode, graft survival, and area of neovascularization (quantified using image analysis software) were evaluated. In this study, 24 eyes of 24 patients were selected [mean age, 65.0 years; mean follow-up duration, 14.8 months (6-36 months)], which consists of 14 vascularized eyes after failed penetrating keratoplasty and 10 vascularized eyes with bullous keratopathy. Best corrected visual acuity improved from 1.60 ± 1.02 LogMAR preoperatively to 0.47 ± 0.37 LogMAR 12 months postoperatively (P < 0.001). Central corneal thickness decreased from 824 ± 193 μm preoperatively to 544 ± 48 μm 12 months postoperatively (P = 0.001). The donor ECD decreased from 2272 ± 723 cells/mm2 preoperatively to 1570 ± 279 cells/mm2 12 months postoperatively. The total loss of ECD at the last visit was 40.7% ± 13.0%. Eight of 24 eyes (33.3%) required rebubbling, which resulted in final attachment. The corneal neovascularization area significantly regressed from 4.68% ± 3.26% preoperatively to 2.28% ± 1.58% (n = 18, P = 0.021). Corneal transplant rejection episodes occurred in 1 eye of 24 patients (4.2%). There was no primary graft failure. DMEK is a feasible option to treat endothelial dysfunction in vascularized eyes.

Urinary nitrate concentration as a marker for kidney transplant rejection

BackgroundEarly identification and treatment of kidney transplant rejection episodes is vital to limit loss of function and prolong the life of the transplanted kidney and recipient. Current practice depends on detecting a creatinine rise. A biomarker to diagnose transplant rejection at an earlier time point than current practice, or to inform earlier decision making to biopsy, could be transformative.It has previously been shown that urinary nitrate concentration is elevated in renal transplant rejection. Nitrate is a nitric oxide (NO) oxidation product. Transplant rejection upregulates NO synthesis via inducible nitric oxide synthase leading to elevations in urinary nitrate concentration. We have recently validated a urinary nitrate concentration assay which could provide results in a clinically relevant timeframe. Our aim was to determine whether urinary nitrate concentration is a useful tool to predict renal transplant rejection in the context of contemporary clinical practice.MethodsWe conducted a prospective observational study, recruiting renal transplant participants over an 18-month period. We made no alterations to the patients’ clinical care including medications, immunosuppression, diet and frequency of visits. We collected urine samples from every clinical attendance. We assessed the urinary nitrate to creatinine ratio (uNCR) between patient groups: routine attendances, biopsy proven rejection, biopsy proven no rejection and other call backs. uNCR was examined over time for those with biopsy proven transplant rejection. These four groups were compared using an ANOVA test.ResultsA total of 2656 samples were collected. uNCR during biopsy proven rejection, n = 15 (median 49 μmol/mmol, IQR 23–61) was not significantly different from that of routine samples, n = 164 (median 55 μmol/mmol, IQR 37–82) (p = 0.55), or biopsy proven no rejection, n = 12 (median 39 μmol/mmol, IQR 21–89) (P = 0.77).Overall uNCR was highly variable with no diagnostic threshold for kidney transplant rejection. Furthermore, within-patient uNCR was highly variable over time, and thus it was not possible to produce individualised patient thresholds to identify rejection. The total taking Tacrolimus was 204 patients, with no statistical difference between the uNCR of all those on Tacrolimus, against those not, p = 0.18.ConclusionThe urinary nitrate to creatinine ratio is not a useful biomarker for renal transplant rejection.

P1612CAN THE URINARY NITRATE TO CREATININE RATIO BE USED AS A MARKER FOR KIDNEY TRANSPLANT REJECTION?

Abstract Background and Aims Early identification and treatment of kidney transplant rejection episodes is vital to limit loss of function and prolong the life of the transplanted kidney and recipient. Current practice depends on detecting a creatinine rise. A biomarker to diagnose transplant rejection, either at an earlier time point, or to inform earlier decision making to biopsy, could be transformative. Urinary nitrate concentration is elevated in renal transplant rejection. Nitrate is a nitric oxide (NO) oxidation product. Transplant rejection upregulates NO synthesis via inducible nitric oxide synthase leading to elevations in urinary nitrate concentration. Historically, assays for measurement of inorganic nitrate in biological fluids have been too time consuming to be useful in a clinical setting. We have recently validated a urinary nitrate concentration assay which could provide results in a clinically relevant timeframe. Our aim was to determine whether urinary nitrate concentration is a useful tool to predict renal transplant rejection in the context of contemporary clinical practice. Method We conducted a prospective observational study, recruiting renal transplant participants over an 18 month period. We made no alterations to the patients’ clinical care including medications, immunosuppression, diet and frequency of visits. We collected urine samples from every clinical attendance including routine attendances, unscheduled attendances for acute clinical indications, and on the day of attendance for biopsy, for those who underwent biopsy. We measured the urinary nitrate to creatinine ratio (uNCR) between patient groups including routine attendances, biopsy proven rejection and biopsy proven “no rejection”. uNCR was examined over time for those with transplant rejection. Groups were compared using a 2 tail t-test of unequal variance, for statistical significance. Results A total of 2656 samples were collected. uNCR during biopsy proven rejection, median 49 µmol/mmol, IQR 23-61, was not significantly different from that of routine samples, median 55 µmol/mmol, IQR 37-82 (p=0.56), or biopsy proven “no rejection”, median 39 µmol/mmol, IQR 21-89, (P=0.77). Overall uNCR was highly variable; median 52 µmol/mmol, IQR 31-81, with no diagnostic threshold for kidney transplant rejection. Furthermore, within-patient uNCR was highly variable over time, and thus it was not possible to produce individualised patient thresholds to identify rejection. Conclusion The urinary nitrate to creatinine ratio is not a useful biomarker for renal transplant rejection.

SUN-573 Use of PCSK9 Inhibitors Post-Transplant

Background:Dyslipidemia is common in patients after transplant. While statins are the mainstay of therapy, interactions with immunosuppressants such as calcineurin inhibitors (CNIs) can limit dose titration or lead to intolerance of this important drug class. Withdrawal of statin therapy can precipitate hyperlipidemia and potentially accelerate cardiovascular disease in transplant recipients, including coronary allograft vasculopathy (CAV) in heart transplant (HT) patients. Proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i) may provide a safe, effective option for such patients. PCSK9i profoundly reduce low-density lipoprotein (LDL) and subsequently the risk of cardiovascular events in nontransplant patients. Further, these novel agents have no known interactions with CNIs. There is a paucity of data describing PSCK9i use post-transplant, with only a few small case series reported in HT recipients. Here, we summarize our experience along with available literature on this topic.Methods:In this retrospective case series we investigated adult recipients of heart transplant who were treated with PCSK9 inhibitors from July 2015 to 2019 because of statin intolerance or refractory hyperlipidemia. We compared the data of patients at baseline and after various durations of therapy with the PSCK9i evolocumab and alirocumab using the median and interquartile range (IQR). Specifically, we evaluated PCSK9i efficacy, effect on immunosuppressant levels, cardiac function and adverse events.Results:Five patients (4 men; median age 54, IQR 52-60) underwent heart transplant an average of 7.4 years ago. Median treatment duration of evolocumab or alirocumab was 12 months (IQR 7-17). This led to a reduction of total cholesterol by 94 mg/dl (p=0.04) (47% decrease) and LDL cholesterol by 83 mg/dl (p=0.04) (69% decrease). No statistically significant difference in HDL cholesterol, triglycerides or liver function tests (LFTs) were observed. There were no episodes of rejection. Immunosuppressant levels remained at goal. One patient noted a few days of fatigue after alirocumab injections but otherwise no side effects were reported.Conclusion:The PCSK9 inhibitors evolocumab and alirocumab are promising alternatives to statin therapy in transplant recipients with statin intolerance or refractory hyperlipidemia. Our study showed their potential to significantly reduce LDL cholesterol in heart transplant patients without altering IST levels. No episodes of transplant rejection were noted. Further long-term studies to establish the safety and efficacy of PSCK9 inhibitors post-transplant are needed.

A case of trichodysplasia spinulosa improving after an acute cellular heart transplant rejection episode

A case of trichodysplasia spinulosa improving after an acute cellular heart transplant rejection episode

Cytokine Profiles Associated With Angiotensin II Type 1 Receptor Antibodies

IntroductionAngiotensin II type 1 receptor antibody (AT1R-Ab), is a non–human leukocyte antigen (HLA) antibody implicated in poor renal allograft outcomes, although its actions may be mediated through a different pathway than HLA donor-specific antibodies (DSAs). Our aim was to examine serum cytokine profiles associated with AT1R-Ab and distinguish them from those associated with HLA DSA in serially collected blood samples from a cohort of pediatric renal transplant recipients.MethodsBlood samples from 65 pediatric renal transplant recipients drawn during the first 3 months posttransplant, at 6, 12, and 24 months posttransplant, and during suspected episodes of kidney transplant rejection were tested for AT1R-Ab, HLA DSA, and a panel of 6 cytokines (tumor necrosis factor [TNF]-α, interferon [IFN]-γ, interleukin [IL]-8, IL-1β, IL-6, and IL-17). Associations between antibodies and cytokines were evaluated.ResultsAT1R-Ab, but not HLA DSA, was associated with elevations in TNF-α, IFN-γ, IL-8, IL-1β, IL-6, and IL-17. This relationship remained significant even after controlling for relevant clinical factors and was consistent across all time points. In contrast to HLA DSA, AT1R-Ab was associated with elevations in vascular inflammatory cytokines in the first 2 years posttransplant.ConclusionsThis profile of vascular cytokines may be informative for clinical monitoring and designing future studies to delineate the distinct pathophysiology of AT1R-Ab–mediated allograft injury in kidney transplantation.

Enhanced Drug Delivery to the Skin Using Liposomes.

Background:Enhancing drug delivery to the skin has importance in many therapeutic strategies. In particular, the outcome in vascularized composite allotransplantation mainly depends on systemic immunosuppression to prevent and treat episodes of transplant rejection. However, the side effects of systemic immunosuppression may introduce substantial risk to the patient and are weighed against the expected benefits. Successful enhancement of delivery of immunosuppressive agents to the most immunogenic tissues would allow for a reduction in systemic doses, thereby minimizing side effects. Nanoparticle-assisted transport by low temperature–sensitive liposomes (LTSLs) has shown some benefit in anticancer therapy. Our goal was to test whether delivery of a marker agent to the skin could be selectively enhanced.Methods:In an in vivo model, LTSLs containing doxorubicin (dox) as a marker were administered intravenously to rats that were exposed locally to mild hyperthermia. Skin samples of the hyperthermia treated hind limb were compared with skin of the contralateral normothermia hind limb. Tissue content of dox was quantified both via high-performance liquid chromatography and via histology in skin and liver.Results:The concentration of dox in hyperthermia-treated skin was significantly elevated over both normothermic skin and liver. (P < 0.02).Conclusions:We show here that delivery of therapeutics to the skin can be targeted and enhanced using LTSLs. Targeting drug delivery with this method may reduce the systemic toxicity seen in a systemic free-drug administration. Development of more hydrophilic immunosuppressants in the future would increase the applicability of this system in the treatment of rejection reactions in vascularized composite allotransplantation. The treatment of other skin condition might be another potential application.

Sofosbuvir/velpatasvir for 12 weeks in genotype 1–4 HCV-infected liver transplant recipients

Sofosbuvir, an NS5B inhibitor, combined with velpatasvir, an NS5A inhibitor (SOF/VEL), produces high sustained virologic response rates 12 weeks after treatment (SVR12) in patients with genotype 1-6 HCV infection, and has no anticipated clinically relevant drug-drug interactions with immunosuppressants. This study evaluated the safety and efficacy of SOF/VEL in adults with recurrent chronic genotype 1-4 HCV infection after liver transplant. Patients received SOF/VEL 400/100 mg daily for 12 weeks. Patients could be treatment experienced or treatment naïve with no cirrhosis or with compensated cirrhosis. The primary endpoints were SVR12 and discontinuations due to adverse events. A total of 79 patients were enrolled and treated in this study (37 [47%] had genotype 1, 3 [4%] genotype 2, 35 [44%] genotype 3, and 4 [5%] genotype 4 HCV). Of these, 81% were male, 82% were white, 18% had compensated cirrhosis, and 59% were treatment experienced. The most commonly used immunosuppressants were tacrolimus (71%), mycophenolic acid (24%), cyclosporine (14%), and azathioprine (11%). Median (range) time from liver transplantation was 7.5 (0.3, 23.9) years. The SVR12 rate was 96%. By genotype, SVR12 rates were 95% (genotype 1), 100% (genotype 2), 97% (genotype 3), and 100% (genotype 4). Two patients experienced virologic relapse: one with genotype 1a infection was non-cirrhotic and treatment naïve, and one with genotype 3 infection was non-cirrhotic and treatment experienced. One patient discontinued SOF/VEL due to hyperglycemia. No serious or severe adverse events were deemed SOF/VEL-related by the investigator, and no liver transplant rejection episodes or deaths occurred during the study period. Treatment with SOF/VEL for 12 weeks was highly effective and well tolerated in genotype 1-4 HCV-infected liver transplant recipients with and without cirrhosis. Sofosbuvir/velpatasvir is a combination of two drugs in one tablet that is approved for the treatment of patients with chronic hepatitis C virus (HCV) infection. When patients with chronic HCV infection receive a liver transplant, the HCV infection usually recurs, and damages the transplanted liver. This study tested the effects of 12 weeks of sofosbuvir/velpatasvir treatment in patients who had HCV recurrence after a liver transplant. Three months following the end of treatment, 96% of patients were cured of HCV infection. Clinical trial number: NCT02781571.

Assessment of Arterial Stiffness in Stable Heart Transplant Recipients

IntroductionArterial stiffness depends on both genetic and environmental factors. The aim of this study was to assess arterial stiffness in patients after heart transplant. MethodsThe study was conducted between May and June 2017. Fifty patients from the Transplantology Clinic of the Institute of Cardiology in Anin, Warsaw, Poland, were enrolled in the study. Pulse wave velocity (PWV), central systolic blood pressure (CSBP), and central diastolic blood pressure (CDBP) were measured and patients' medical records were also analyzed. ResultsIn the study, 50 patients aged 57.9 years on average were evaluated, of whom 88% were male patients, with average PWV of 8.94 m/s and an average time after transplant of 9.7 years. The study has shown that age (R = 0.77), total cholesterol concentration (R = 0.22, P = .017) and creatinine concentration (R = 0.34; P = .15) show positive correlation with PWV. ConclusionsOur data indicates that age has significant impact on arterial stiffness and the type of immunosuppressive drugs and transplant rejection episodes do not impact an increase in arterial stiffness.

O-19 Incidence and risk factors of adverse events during immunosuppressive therapy after renal transplantation in children

Background Transplantation has become an important treatment option in children with end-stage renal dis-ease. In the last decades progress in immunosuppressive treatment options and surgical techniques have reduced the frequency of acute rejection, graft loss and mortality. However, adverse events occur in patients treated with immunosuppressive therapy. These adverse events are well described for adults but few data are available for children. Our objective was to describe the frequency of adverse events (AEs) under different immunosuppres-sive regimen including either ciclosporin or tacrolimus in children after renal transplantation. Secondary objectives include comparison of AEs with known adverse drug re-actions (ADRs) as described in the Summary of Product Characteristics. Furthermore, risk factors for AEs will be examined. Methods Children receiving a renal transplant at our institution between 2002 to 2015 were included in the study. Initial immunosuppression was obtained by thy-moglobulin or monoclonal antibody, calcineurin inhib-itors (tacrolimus or ciclosporin), mycophenolate mofetil, and corticoids. AEs reported after transplantation were collected from medical reports and coded using Med-DRA (version 19.1). Descriptive statistical analyses were performed using SAS 9.4. Data were stratified by tacrolim-us or ciclosporin treatment schedule at the time of the AE. Results A total of 164 children fulfilled the inclusion cri-teria. Finally, complete medical records were available for 125 children (53 girls and 72 boys). The median age was 12 (2 – 19) years old. The indication for renal transplan-tation included congenital, familial and genetic disorders for 61% of the patients and renal and urinary disorders for 39% (including 30% of nephritis). The median time of observation until last follow up was 2.7 (0.6–4.3) years. Initially, 91 patients were treated with tacrolimus and 34 with ciclosporin. During the observation period 6 patients switched from tacrolimus to ciclosporin and 14 switched from ciclosporin to tacrolimus. A total of 1520 AEs were reported. For patients receiving tacrolimus 1122 AEs (233.6 person-years of exposure) were reported and 372 AEs (71.4 person-years of expo-sure) for those treated with ciclosporin. Twenty-six AEs were reported in patients not receiving any calcineurin inhibitor. The most frequent medical AEs reported for pa-tients treated with tacrolimus and ciclosporin by system organ class were renal and urinary disorders (0.3 vs 0.3 AEs per person-year of exposure), infections (0.3 vs 0.4 AEs per person-year of exposure), vascular disorders (0.2 vs 0.3 AEs per person-year of exposure) and gastrointestinal disor-ders (0.2 vs 0.2 AEs per person-year of exposure). For 46 patients at least one episode of transplant rejection was reported. Conclusion This study describes AEs up to 4 years after renal transplantation in children treated with immuno-suppressive therapy. Our findings will contribute to the understanding of the benefit-risk balance of immuno-suppressive therapy following renal transplantation in children.

P216 Case of suspected hyperacute rental transplant rejection due to angiotensin II type 1 receptor antibodies

Though the majority of antibody-mediated renal transplant rejections are thought to be due to HLA antibodies, there is increasing evidence that non-HLA antibodies also can mediate rejection. For example, antibodies directed against the Angiotensin II type 1 receptor (AT1R) have been implicated in humoral renal transplant rejection episodes and impaired graft survival. While many cases of acute rejection potentially due to AT1R antibodies have been reported, there is little published evidence relating to AT1R antibodies causing hyperacute rejection. We report the case of a patient with pre-existing AT1R antibodies and no donor-specific HLA antibodies who experienced an episode of hyperacute rejection. The patient is a 47 year old female with a longstanding history of type 1 diabetes and end stage renal disease secondary to diabetic nephropathy. She had received 2 previous renal transplants approximately 21 and 22 years ago. Pre-transplant she was highly sensitized with a T-cell flow PRA of 99% and B-cell flow PRA of 100%, but did not demonstrate any donor- specific HLA antibody. The T- and B-cell flow and T-cell CDC crossmatches performed between the patient and donor were negative. She had a pre-transplant AT1R antibody level of 18.5 Units/ml measured 8 days before transplant. During the surgical procedure the patient experienced a hyperacute rejection episode. Biopsy of the organ demonstrated possible antibody-mediated rejection. The patient was treated with plasmapheresis and IVIG and her renal function stabilized over the following 6 weeks. The patient has also been maintained on Losartan, an AT1R inhibitor. The patient has now continued to demonstrate stable renal function for the previous 2 years. Our case highlights the importance of appreciating the possible peri-transplant risks of AT1R antibody particularly as treatment with the AT1R inhibitor, Losartan, has been shown by others to provide therapeutic benefits.

The influence of the microbiota on the immune response to transplantation.

In the past decade, appreciation of the important effects of commensal microbes on immunity has grown exponentially. The effect of the microbiota on transplantation has only recently begun to be explored; however, our understanding of the mechanistic details of host-microbe interactions is still lacking. It has become clear that transplantation is associated with changes in the microbiota in many different settings, although what clinical events and therapeutic interventions contribute to these changes remains to be parsed out. Research groups have begun to identify associations between specific communities of organisms and transplant outcomes, but it remains to be established whether microbial changes precede or follow transplant rejection episodes. Finally, results from continuing exploration of basic mechanisms by which microbial communities affect innate and adaptive immunity in various animal models of disease continue to inform research on the microbiota's effects on immune responses against transplanted organs. Commensal microbes may alter immune responses to organ transplantation, but direct experiments are only beginning in the field to identify species and immune pathways responsible for these putative effects.

The risk of cholelithiasis in patients after heart transplantation

IntroductionExtended immunosuppressive treatment in patients after heart transplantation modifies etiopathogenesis and occurrence of many diseases in this population. The aim of the present study was to evaluate the frequency and to define risk factors for cholelithiasis after heart transplantation (HTX).Material and methodsThe study population consisted of 176 subjects. Of them, 24 patients (group A) presented with symptomatic cholelithiasis. Another group of 24 patients without cholelithiasis (group B) served as controls. Both groups were similar with respect to age, gender and follow-up after the transplant. Clinical interview, surgical and hospitalization data were collected from medical records.ResultsThe groups did not differ in demographic features. There were statistical differences (p < 0.05) between group A and B in rejection reaction, doses of immunosuppressive drugs, type 2 diabetes, serum lipid disorders and acute rejection episodes. These events were caused by modification of treatment, especially the immunosuppressive regimen. Group A consisted of 75% men and 25% women. The frequency of symptomatic cholelithiasis was 11.7% in men and 27.3% in women, on average 19.5%. Mean time to cholelithiasis following HTX was 37.9 ±4.9 (Me = 41.5) months, 27.7 ±8.2 (Me = 30.0) months in women and 41.3 ±5.9 (Me = 41.5) months in men. The female to male ratio was 2.3: 1.ConclusionsCholelithiasis following HTX was significantly more frequent as compared with the non-transplant population. Patients with cholelithiasis required more aggressive immunosuppression because of more frequent episodes of acute transplant rejection. Patients with cholelithiasis significantly more frequently showed increased glycemia and blood lipids, which could be the side effect of intensive immunosuppressive therapy.

Mortality After Steroid-Resistant Acute Cellular Rejection and Chronic Rejection Episodes in Adult Intestinal Transplants: Report From a Single Center in Induction/Preconditioning Era

Steroid-resistant acute cellular rejection (ACR) and chronic rejection (CR) are still major concerns after intestinal transplantation. We report our experience from a single center on 48 adults recipients using 49 grafts from 2001 to 2011, immunosuppressing them initially with daclizumab initially and later Alemtuzumab. Overall patient survival was 41.9% at 10 years while graft survival was 38.5%. The steroid-resistant ACR population of 14 recipients (28.5%) experienced 50% mortality mainly due to sepsis, while the five (8%) CR recipients, included two survivors. All but 1 graft was placed without a liver. CR was often preceded by ACR episodes. Mortality related to steroid-resistant ACR and CR still affects the intestinal transplant population despite induction/preconditioning, especially in the absence of a protective liver effect of the liver. New immunosuppressive strategies are needed.

Influence of Cytokine Gene Polymorphisms on Graft Rejection in Turkish Patients with Renal Transplants from Living Related Donors

BackgroundCertain cytokine gene polymorphisms (CGPs) have been shown to be associated with renal transplant rejection episodes or graft outcomes. We sought to evaluate the relationships between gene polymorphisms and acute rejection episodes (RG, n = 19) versus stable graft function (NRG, n = 71) in transplant recipients compared with healthy control subjects (HCG, n = 150). The follow-up time period was 18 months. Using polymerase chain reaction sequence-specific primers with the Heidelberg kit we genotyped 22 single nucleotide polymorphisms distributed across 13 cytokine and cytokine receptor genes. ResultsInterleukin (IL)-2 TT/GT haplotype was found in 36.8% of RG patients and 6.7% of HCG but not among the NRG (P < .0001; .0007). The IL-2 GG/TT haplotype was observed among 13 NRG and nine HCG patients (P = .007); the IL-2 GG/GG haplotype, 18.7% HCG and 4.2% NRG patients (P = .0033); and the IL-2 TT/TT haplotype, five NRG and eight HCG patients, but none of the RG cohort (P > .05). The transforming-growth factor-beta 1 CG/CC haplotype was noted in 15 NRG (21.1%) and four HCG but no RG patients (P < .0001). The IL-2 +166 GT genotype was detected in 36.8% of RG, 8.5% of NRG, and 14.7% of HCG patients (P = .005, .0244). The IL-2 −330 GG genotype was demonstrated in 32 healthy controls and three nonrejection transplant patients (P = .0007). Significant differences were concluded between NRG and HCG for IL-6 565 AG, IL-1beta −511 TT and +3962 CC/CT/TT genotypes. DiscussionWe observed significant differences among the frequencies of IL-2 gene polymorphisms among RG and NRG subjects, which agreed with previous clinical, but not in vitro studies.

Multimodal Imaging in a Case of Central Serous Chorioretinopathy Following Renal Transplantation

A 33-year-old woman with a medical history of deceased donor renal transplant receiving immunosuppressive therapy with prednisone and sirolimus complained of progressive visual loss during hospitalization for an episode of recurrent transplant rejection a few months following transplantation. Dilated fundus examination revealed bilateral retinal pigment epithelium mottling, focal pigment epithelial detachments within the macula, and inferior serous retinal detachments. Fluorescein angiogram revealed multifocal expansile dots of leakage, consistent with multifocal central serous chorioretinopathy. Spectral-domain optical coherence tomography showed neurosensory detachments with subretinal deposits and well-defined hyperreflective membrane underlying elongated photoreceptor outer segments. This subretinal membrane, seen in the detached portion of retina, has not been described before in organ transplant patients with central serous chorioretinopathy. This finding may have relevance to the fibrinous deposits and septations described in patients with Vogt-Koyanagi-Harada syndrome.

Naturally occurring regulatory T cells: markers, mechanisms, and manipulation

Naturally occurring CD4(+)CD25(high) forkhead box protein 3 (FOXP3)(+) regulatory T cells (nTregs) are key mediators of immunity, which orchestrate and maintain tolerance to self and foreign antigens. In the recent 1.5 decades, a multitude of studies have aimed to define the phenotype and function of nTregs and to assess their therapeutic potential for modulating immune mediated disorders such as autoimmunity, allergy, and episodes of transplant rejection. In this review, we summarize the current knowledge on the biology of nTregs. We address the exact definition of nTregs by specific markers and combinations thereof, which is a prerequisite for the state-of-the-art isolation of defined nTreg populations. Furthermore, we discuss the mechanism by which nTregs mediate immunosuppression and how this knowledge might translate into novel therapeutic modalities. With first clinical studies of nTreg-based therapies being finished, questions concerning the reliable sources of nTregs are becoming more and more eminent. Consequently, approaches allowing conversion of CD4(+) T cells into nTregs by coculture with antigen-presenting cells, cytokines, and/or pharmacological agents are discussed. In addition, genetic engineering approaches for the generation of antigen-specific nTregs are described.