Late Post-transplant Period Research Articles

PB2184: COURSE OF CORONAVIRUS INFECTION IN ONCOHEMATOLOGICAL PATIENTS IN THE POST-TRANSPLANT PERIOD

Background: In March 2020, specialists in the field of oncohematology faced the problem of severity of coronavirus infection in patients after high-dose course of chemotherapy and autologous or allogeneic bone marrow transplantation. This required a revision of a number of issues related to the selection of patients for bone marrow transplantation (BMT), the development of new preventive and therapeutic tactics aimed at the treatment of infectious and immunological complications in this category of patients, depending on the nature of the underlying disease, the status of the disease and the timing of the treatment. Aims: To assess the severity, the most typical complications and the COVID 19 severity aspects in patients in early and late post-transplant periods to develop the most optimal tactics for the prevention and treatment of COVID 19 in this group of patients. Methods: An analysis was made of patients after HSCT with active coronavirus infection from 2020 to 2021, hospitalized in the hematology department of the Moscow multidisciplinary hospital (the hospital was completely redesigned to work on the COVID19 profile). A total number of hospitalized patients after HSCT was 25: 4 patients after allogeneic transplantation, 21 - after autologous. According to the timing of HSCT, patients were divided into 2 groups - early post-transplant period (ETP) (2-90 days after HSCT) - 14 patients, and late post-transplant period (LTP) (3-24 months) - 11 patients. According to nosology, patients were divided into following groups: lymphomas - 72%, MM - 12%, AA and CML 8% each. All patients were admitted with a positive PCR test (0-7 days of COVID). COVID therapy was carried out according to the protocols adopted in the Russian Federation using antiviral drugs, biological therapy, corticosteroids, anticoagulants. If necessary, the required supportive therapy was carried out for this period of HSCT. Results: Severe COVID19 (CT 3-4 severity) was more often observed in patients in ETP (100%) than in LTP (45%) (p=0.021). The incidence of respiratory failure is 70% and 36% in ETP and LTP, respectively. According to the analysis in ETP, agranulocytosis was observed in 65% of cases, for LTP group - in 18% (p = 0.022). Development of severe infectious complications (bacterial, fungal and viral) was detected in 100% of patients in ETP, in 45% of patients in LTP (p = 0.002). Antifungal therapy was required in 100% of cases in ETP, and only in 27% of the LTP group (p=0.001). 90% of patients in both groups required biological therapy. Mortality in the group of patients in ETP was 35%, while no deaths were registered in the group of patients in LTP (p=0.027). Median of hospitalization period for ETP and LTP patients was 20 and 13 days, respectively. Summary/Conclusion: Patients in the early period after HSCT have a higher risk of developing lower respiratory tract infection, more likely to require antifungals, reserve group antibiotics, and have a greater risk of death from COVID-19. Biological therapy is not contraindicated in case of leukopenia and agranulocytosis in this group of patients.

Feasibility of a Home-Based Exercise Program for Managing Posttransplant Metabolic Syndrome in Lung and Liver Transplant Recipients: Protocol for a Pilot Randomized Controlled Trial.

BackgroundPosttransplant metabolic syndrome (PTMS) is a common contributor to morbidity and mortality among solid organ transplant recipients in the late posttransplant period (≥1 year). Patients diagnosed with PTMS are at a higher risk of cardiovascular disease and frequently experience decreased physical function and health-related quality of life (HRQL). Studies in the early posttransplant period (<1 year) have shown the benefits of facility-based exercise training on physical function and HRQL, but have not evaluated the effects on metabolic risk factors. It remains unclear whether home-based exercise programs are feasible and can be delivered at a sufficient exercise dose to have effects on PTMS. This protocol outlines the methodology of a randomized controlled trial of a partly supervised home-based exercise program in lung transplant (LTx) and orthotopic liver transplant (OLT) recipients.ObjectiveThis study aims to evaluate the feasibility (ie, recruitment rate, program adherence, attrition, safety, and participant satisfaction) of a 12-week individualized, home-based aerobic and resistance training program in LTx and OLT recipients initiated 12 to 18 months after transplantation, and to assess estimates of intervention efficacy on metabolic risk factors, exercise self-efficacy, and HRQL.MethodsIn total, 20 LTx and 20 OLT recipients with ≥2 cardiometabolic risk factors at 12 to 18 months after transplantation will be randomized to an intervention (home-based exercise training) or control group. The intervention group will receive an individualized exercise prescription comprising aerobic and resistance training, 3 to 5 times a week for 12 weeks. Participants will meet on a weekly basis (via videoconference) with a qualified exercise professional who will supervise exercise progression, provide support, and support exercise self-efficacy. Participants in both study groups will receive a counseling session on healthy eating with a dietitian at the beginning of the intervention. For the primary aim, feasibility will be assessed through recruitment rate, program adherence, satisfaction, attrition, and safety parameters. Secondary outcomes will be measured at baseline and 12 weeks, including assessments of metabolic risk factors (ie, insulin resistance, abdominal obesity, blood pressure, and cholesterol), HRQL, and exercise self-efficacy. Descriptive statistics will be used to summarize program feasibility and effect estimates (means and 95% CIs) for sample size calculations in future trials.ResultsEnrollment started in July 2021. It is estimated that the study period will be 18 months, with data collection to be completed by December 2022.ConclusionsA partly supervised home-based, individually tailored exercise program that promotes aerobic and resistance training and exercise self-efficacy may be an important intervention for improving the metabolic profile of LTx and OLT recipients with cardiometabolic risk factors. Thus, characterizing the feasibility and effect estimates of home-based exercise constitutes the first step in developing future clinical trials designed to reduce the high morbidity associated with PTMS.Trial RegistrationClinicalTrials.gov NCT04965142; https://clinicaltrials.gov/ct2/show/NCT04965142International Registered Report Identifier (IRRID)DERR1-10.2196/35700

Association between Long-Term Change in Arterial Stiffness and Cardiovascular Outcomes in Kidney Transplant Recipients: Insights from the TRANSARTE Study.

(1) Background: Increased arterial stiffness is associated with cardiovascular (CV) diseases in end-stage renal disease (ESRD) patients, and CV mortality remains higher in kidney transplantation (KT) recipients compared to in the general population. KT is associated with an improvement in arterial stiffness in the early post-transplant period, followed by a potential re-worsening in the late period. In a cohort of KT patients, we evaluated the associations of pulse-wave velocity (PWV) measured at different time-points (pre-transplant, and early and late post-transplant periods) with CV morbi-mortality, as well as the evolution between these measurements with CV morbi-mortality. (2) Methods: Forty KT recipients with a 10-year follow-up were included. The association of PWV with CV events was assessed with multivariable cox analysis. Backward linear regressions were conducted to identify the determinants of PWV at 1 year and those of the long-term evolution of PWV after KT (delta PWV at 1 year—latest PWV). (3) Results: The absence of arterial stiffening during the long-term follow-up after KT is associated with a lower CV outcome rate (HR for the delta PWV = 0.76 (0.58–0.98), p = 0.036). Age at KT is associated with the worsening of arterial stiffness in the late post-transplantation period (β for the delta PWV = −0.104, p = 0.031). A high PWV at 1 year was associated with a potential for recovery during follow-up (β = 0.744, p < 0.0001). (4) Conclusions: The absence of PWV worsening in the late post-transplantation period was significantly associated with a lower risk of CV events, whereas early changes in PWV were not. Finding an intervention capable of reducing long-term PWV could improve the prognosis of KT recipients.

POS-816 DE NOVO KIDNEY ALLOGRAFT RENAL CELL CARCINOMA: A RARE UNSALVAGEABLE CAUSE OF ALLOGRAFT LOSS IN A VERY LATE POST-TRANSPLANT PERIOD

Renal cell carcinoma (RCC) is a common malignancy in end-stage kidney disease (ESKD) from acquired cystic kidney disease (ACKD). With a net state of immunosuppression, kidney transplant recipients (KTR) are even at higher risk for RCC; however, RCC in the kidney allograft is uncommon unless it results from donor-derived disease. We report a case of old-aged woman with kidney allograft masses at the very late post-transplant period. Explanted transplant allograft revealed RCC.

Alterations of gut bacteria Akkermansia muciniphila and Faecalibacterium prausnitzii in late post-transplant period after liver transplantation

Introduction: Recent studies have shown that the intestinal microbiota can modulate certain systemic metabolic and immune responses, including liver graft function and the development of complications in patients after liver transplantation (LT). Akkermansia muciniphila (AKM) and Faecalibacterium prausnitzii (FAEP) are two of the most abundant gut commensal bacteria, with mucosa-protective and anti-inflammatory effects that are important for maintaining normal intestinal homeostasis and gut barrier function. Our objective was to quantify levels of Akkermansia muciniphila and Faecalibacterium prausnitzii in immunosuppressed patients with LT. Materials and methods: Fecal samples from 23 liver transplant patients (15 adults and 8 children) and 9 non-LT controls were examined. Bacterial DNA was isolated from the samples using the stool DNA isolation kit and the obtained DNA was analyzed with commercially available qPCR kit for AKM and FAEP. Results: We found a statistically significant decrease in the amount of AKM and FAEP compared to the control group. The median values were: for AKM 8.75 for patients and 10.25 for the control group (p = 0.030), and for FAEP 9.72 and 10.47, p = 0.003, respectively. In children after LT, this difference was also statistically significant: AKM (p = 0.051) and FAEP (p = 0.014). In contrast no statistically significant differences were found between adult patients and controls, AKM (p = 0.283) and FAEP (p = 0.056), although the amount of both bacteria showed tendency for reduction. Conclusions: In this pilot study, we found a reduction in the total amount of the two studied bacteria in transplanted patients compared to the control healthy group.

Incidence and mortality of post-transplant lymphoproliferative disorders after kidney transplantation: A real-world retrospective analysis in Japan.

Post-transplant lymphoproliferative disorder is a potentially life-threatening complication that has a greater risk of occurrence in the setting of immunosuppression and oncogenic viral infections after transplant surgery. Few studies have reported the cumulative incidence, histological subtypes and clinical outcomes of this disorder in kidney transplant recipients. We retrospectively investigated 34 post-transplant lymphoproliferative disorder patients diagnosed out of the 1210 kidney transplant recipients who had undergone the surgery at the two largest centers in Japan between January 1983 and December 2017. A total of 32 patients (94.1%) developed late-onset post-transplant lymphoproliferative disorder (diagnosed 1year after transplantation). The cumulative incidence rates were 0.76% and 1.59% at 5 and 10years post-transplantation, respectively. The central nervous system was the most common site (35.3%, 12/34). Overall survival was similar between patients with and without central nervous system lesions (P=0.676). Of all of the cases, 23.5% (8/34) were detected through cancer screening. Importantly, patients with screening-detected post-transplant lymphoproliferative disorder had better overall survival than those with the disorder who had been symptom detected (P=0.0215). Overall survival was significantly reduced in patients who developed the disorder compared with those who did not (P=0.0001). Post-transplant lymphoproliferative disorder was more likely to occur in the late post-transplantation period, which showed that long-term medical examination for transplant recipients is required. Based on our findings, we propose vigilant, long-term, cancer screening in kidney transplant recipients.

Parenteral nutritional support in children in the early period after hematopoietic stem cell transplantation: specifics and clinical aspects

Hematopoietic stem cell transplantation (HSCT) as a treatment modality is associated with nutritional problems that are mainly caused by eating difficulties and gastrointestinal complications occurring at different stages of HSCT: starting from conditioning until late post-transplant period. Nutritional problems have in turn a negative impact on the outcomes of HSCT which demonstrates the importance of preventive measures and timely correction of these problems. The majority of patients who underwent HSCT experience various problems at different stages of treatment leading to a situation when enteral nutrition is impossible. This is why parenteral nutrition is of utmost importance in these patients. This review describes the main clinical factors that may influence the prescription of nutritional support to patients after HSCT as well as possible problems and negative consequences of inappropriate prescribing of parenteral nutrition.

Iron Chelation With Deferasirox Increases Busulfan AUC During Conditioning Chemotherapy Prior to Allogeneic Stem Cell Transplantation

The negative effects of iron overload caused by repetitive blood transfusions and iron release during cytotoxic chemotherapy might be ameliorated by early treatment with an iron chelator. However, in the setting of allogeneic hematopoietic stem cell transplantation (HSCT), chelation therapy is often postponed until the late post-transplantation period because of potential drug interactions. Therefore we systematically investigated the influence of iron chelation with deferasirox on the pharmacokinetics of intravenous busulfan in adult patients in the context of routine therapeutic drug monitoring (TDM) before HSCT. We conducted a single-center, prospective, observational study in 25 adult patients with planned allogeneic HSCT after myeloablative, busulfan-based, TDM-guided conditioning chemotherapy. Busulfan was administered intravenously over 3 hours with an initial dose of 3.2 mg/kg once daily (based on adjusted ideal body weight [AIBW] in overweight patients). Four consecutive dosages were planned to achieve a cumulative area under the curve (AUC) of 80 mg · h/L. Patients received deferasirox for transfusional iron overload as per approval from the start of conditioning until day 3 after transplantation. Model-based calculation of the busulfan AUC was carried out by means of Bayesian prediction based on a population pharmacokinetic model after the first or second dose of busulfan, and dose adjustments were performed accordingly. Calculated median cumulative AUC before dose adjustment was 93.7 mg · h/L (65.1-151.4 mg · h/L), which was considerably above the target AUC of 80 mg · h/L ± 10%. Median dose adjustment was -17.1% (-50.0% to 18.2%), and patients ultimately received busulfan with a median cumulative dose of 10.60 mg/kg (6.38 - 15.62) mg/kg. A busulfan dose reduction was necessary in 19 patients (76%) whereas a dose increase was only needed in 1 patient. After dose adjustment the median AUC was 79.7 mg/L · h (62.5 - 84.2 mg/L · h). Median busulfan clearance was 0.134 L/h/kg (0.084 - 0.203 L/h/kg), which is significantly lower than the average clearance of 0.2 L/h/kg reported in the literature, whereas volume of distribution was not altered. We were able to demonstrate, that TDM is the key point to facilitate a safe co-administration of both medications, because the intake of deferasirox leads to a considerable increase in the busulfan AUC of about 35% to 40%. The reason for the increase in busulfan AUC is a reduction in busulfan clearance by about one third; therefore a lower initial dose of busulfan followed by TDM could be considered in patients with comedication with deferasirox.

Impact of Living Donor Liver Transplantation on COVID-19 Clinical Outcomes from a Quaternary Care Centre in Delhi.

Background and AimsThe anticipated fear of serious outcomes in coronavirus infected liver transplant recipients led to disruption of transplant services globally. The aim of our study was to analyze COVID-19 severity in transplant recipients and to compare the difference of COVID-19 clinical outcomes in early (<1 year) vs. late (>1 year) post-transplant period.Methods41 post-living donor liver transplant recipients with COVID-19 infection were studied retrospectively from 1st April 2020 to 28th February 2021.ResultsThe median age was 49.00 years with a male preponderance (80.49%). Fifteen patients had infection within 1 year of transplant and 26 were infected after 1 year of transplant. The overall median interval between transplantation and COVID-19 diagnosis was 816.00 days. Fever and malaise were the common presenting symptoms. The most common associated comorbidities were diabetes mellitus (65.85%) and hypertension (46.34%). The severity of illness was mild in 28 (68.29%), moderate in 4 (9.76%), severe in 6 (14.63%) and critical in 3 (7.32%). To identify associated risk factors, we divided our patients into less severe and more severe groups. Except for lymphopenia, there was no worsening of total bilirubin, transaminases, alkaline phosphatase, and gamma-glutamyl transferase in the more severe group. Eight (19.51%) patients required intensive care unit admission and three (7.32%) died, while none suffered graft rejection. In recipients with early vs. late post-transplant COVID-19 infection, there were similar outcomes in terms of severity of COVID-19 illness, intensive care unit care need, requirement of respiratory support, and death.ConclusionLiving donor liver transplantation can be performed during the COVID-19 pandemic without the fear of poor recipient outcome in cases of unfortunate contraction of severe acute respiratory syndrome coronavirus-2.

Incidence of herpes zoster in adult solid organ transplant recipients: A meta-analysis and comprehensive review.

Chronic immunosuppressive therapy in solid organ transplant (SOT) recipients can trigger latent varicella zoster virus reactivation even in those with stable graft function. The inactivated herpes zoster (HZ) vaccine can be effective in preventing post-transplant HZ, which can cause severe neuralgia or disseminated disease. This meta-analysis aims to assess the incidences of HZ across transplant organs in SOT recipients. We included 12 observational studies (6560 recipients) from a PubMed and EMBASE search of articles through October 2019 and collected data from single-center dating from January 2001 to December 2017 (3498 recipients). The pooled HZ incidence and its differences between subgroups were obtained from random-effect models and meta-analysis of variance tests using R package. The overall pooled crude incidence was 9.1% (95% confidence interval [CI], 7.6%-10.8%). The pooled incidence was similar between sexes but significantly different between transplanted organs (P<.001). Heart transplants (HT) (n=644) have the highest pooled incidence with 15.2% (95% CI, 12.7%-18.2%), followed by lung transplants (LTX) (n=780) with 11.0% (8.3%-14.4%). Kidney transplants (n=5435) have the lowest incidence of 6.7 (5.1%-8.8%). The meta-regression analysis revealed that HZ development had a relationship with past graft rejection (P=.024). These data support the need for subunit HZ vaccination in SOT recipients with a high risk for HZ, especially HT and LTX recipients, without respect to the late post-transplant period.

Cadaveric kidney allotransplantation at Krasnoyarsk Regional Clinical Hospital

Objective: to evaluate the early and long-term outcomes of cadaveric kidney allotransplantation (CKAT) based on a retrospective analysis of 71 cases treated at Krasnoyarsk Regional Clinical Hospital (KRCH).Materials and methods. From March 2014 to June 2019, 71 kidney transplants were performed at KRCH – 42 (59.15%) men and 29 (40.85%) women. The age of the patients varied from 20 to 59 years (mean age 39.6 ± 8.14 years). The causes of end-stage chronic kidney disease which subsequently led to CKAT were chronic glomerulonephritis, chronic tubulointerstitial nephritis, hypertensive nephropathy (HN), diabetic nephropathy resulting from type I diabetes (DN), nephropathy of mixed genesis (HN + DN), vesicoureteral reflux, congenital angiodysplasia of the kidneys, and Alport syndrome. The mean number of HLA mismatches was 4.5 ± 0.9.Results. Hospitalization lasted for an average of 34.05 ± 9.56 days. Primary function was observed in 32 (45.08%) patients, while 39 (54.92%) cases had delayed function. Post-transplant complications were noted in 23 (32.39%) patients, of whom 12 (16.9%) had early post-transplant complications, while 15 (21.13%) encountered complications in the late post-transplant period. The most frequently diagnosed were immunological, infectious, and urological complications. Vascular, surgical, oncological, and other complications were less frequent. The annual graft survival rate was 87.3%. Patient survival rate was 95.77%. One (1.4%) and 2 (2.81%) patients died in the early and late post-transplant periods, respectively. Hospital mortality – 1 case (1.4%).Conclusion. Kidney transplantation is the most effective treatment for patients with irreversible chronic kidney disease. About 87.33% of transplants were found to be effective. However, 32.39% of patients had postoperative complications. The vast majority of complications were reversible and were corrected conservatively or surgically. Nevertheless, graft loss occurred in 12.67% of cases. The success of transplantation depends on a number of factors related to both the donor and the recipient, as well as the immunological status and surgical technique. A personalized approach to recipients helps to reduce postoperative complications, prevent nephrotoxicity and rejection reactions.

Renal transplant evaluation: multimodality imaging of post-transplant complications.

With advancements in surgical techniques and immuno-suppression, renal transplantation is established as the most effective treatment option in patients with end-stage renal disease. Early detection of renal allograft complications is important for long-term graft survival. Late clinical presentation often causes diagnostic delays till the time allograft failure is advanced and irreversible. Imaging plays a key role in routine surveillance and in management of acute or chronic transplant dysfunction. Multimodality imaging approach is important with ultrasound-Doppler as the first-line imaging study in immediate, early and late post-transplant periods. Additional imaging studies are often required depending on clinical settings and initial ultrasound. Renal functional MRI is a rapidly growing field that has huge potential for early diagnosis of transplant dysfunction. Multiparametric MRI may be integrated in clinical practice as a noninvasive and comprehensive "one-stop" modality for early diagnosis and longitudinal monitoring of renal allograft dysfunctions, which is essential for guiding appropriate interventions to delay or prevent irreversible renal damage. With rapidly increasing numbers of renal transplantation along with improved patient survival, it is necessary for radiologists in all practice settings to be familiar with the normal appearances and imaging spectrum of anatomical and functional complications in a transplant kidney. Radiologist"s role as an integral part of multidisciplinary transplantation team continues to grow with increasing numbers of successful renal transplantation programs across the globe.

Analysis of survival and risk factors in recipients with coronary artery disease of a heart transplant

Objective: to conduct a comparative analysis of survival rate and development of heart transplant coronary artery disease risk factors during early and late post-transplantation periods. Materials and methods: a retrospective analysis of 58 patients with was conducted in S.V. Ochapovsky Region Clinical Hospital № 1, Krasnodar. Inclusion criteria were patients with vasculopathy; group № 1 — recipients with heart transplant coronary artery disease up until 3 years after heart transplantation; group № 1 — recipients with heart transplant coronary artery desease 3 years after heart transplantation. Endomyocardial biopsy, coronary angiography and immunological examination were used for monitoring heart recipients. Results: survival rate in group № 1 — 51,9%; in group № 2 — 64,5%. During studying the influence of age category on survival rate it was discovered that belonging to the age category influences on the survival rate in group № 1, p – 0,023. Death risk in group №1 is 1,7 (0,59 – 4,85) times higher in comparison with group № 2. When combined heart transplant coronary artery desease with cellular and humoral rejection in group №1 death risk is reliably 2,75 (1,58 – 4,78) times higher (p = 0,010). The frequency of heart transplant coronary artery desease recurrence does not have a meaningful impact on the survival rate of the recipients with heart transplant coronary artery desease n both groups. One of the meaningful risk factors in two groups, which affects heart transplant coronary artery desease development is cytomegalovirus infection. Cellular rejection is also a fact which influences lethal outcome.

Essentials in the diagnosis of postoperative myocardial lesions similar to or unrelated to rejection in heart transplant

Abstract Background, objectives: Histological diagnosis of control biopsies in patients with heart transplant represents a significant step of monitoring, with a great influence on adjusting immunosuppressive treatment. Histological lesions are usually related to ischemia and reperfusion, with varying degrees of intensity. This study aimed to highlight the most important aspects of the histological diagnosis and differential diagnosis of postoperative myocardial lesions associated or unrelated to rejection in heart transplant. Materials and Methods: This retrospective study involved 53 patients who received cardiac transplant between 2000 and 2017. Patients were monitored by lesion quantification of endomyocardial biopsies, with diagnoses established based on biopsy material in the early, medium and late post-transplant periods. Hematoxylin eosin, Masson’s trichrome, and Van Gieson stains were used; immunohistochemical determinations used CD4, CD20, CD45, CD68, HLA-DR, VEGF and CD31. Results: Ischemia and reperfusion lesions were diagnosed on all biopsies in the first 6 weeks post-transplant. Nine cases of the Quilty effect were identified, and in 12 cases, the biopsies were performed on the same spot as previous biopsies. A significant number of transplanted patients presented cytomegalovirus that was difficult to diagnose on endomyocardial biopsies. Conclusions: The detailed study of ischemia and reperfusion lesions, as well as of changes un-related to rejection becomes a major objective in the short, medium and late post-transplant period. Overdiagnosis of rejection induces changes of the immunosuppressive therapeutic protocol, with alarming repercussions on cytomegalovirus reactivation, and risks of potentiating inflammation, myocyte destruction and the recurrence of disorders related to both inducing and aggravating heart failure.

POS-738 SARS-CoV-2 INFECTION IN PEDIATRIC KIDNEY TRANSPLANT RECIPIENTS DURING EARLY AND LATE POST-TRANSPLANT PERIOD: A SINGLE-CENTER REPORT OF 2 CASES

Adult kidney transplant (KT) recipients with SARS-CoV-2 infection are susceptible to a more serious COVID-19 disease compared to immunocompetent patients, including more severe pneumonia, longer duration of illness and worse patient prognosis. Moreover, a high risk of allograft damage, possibly leading to allograft loss, has been reported. In contrast, data regarding the clinical course of infected pediatric KT recipients are scarce. Herein, we describe the clinical features, management and outcome of 2 deceased-donor KT pediatric recipients with SARS-CoV-2 infection, occurred during early and late post-transplant period.

POTENTIAL SIGNIFICANCE OF BRADYKININ 2 RECEPTOR GENOTYPING IN KIDNEY TRANSPLANT RECIPIENTS

Bradykinin (BK), a vasoactive peptide, is considered to exert the renoprotective and cardioprotective effects. Furthermore, most of its effects are mediated by the activation of BK type 2 receptor (B2R), whose level of expression is influenced by insertion/deletion (+9/-9) gene polymorphism. The aim of this study was to investigate the potential influence of B2R +9/-9 gene polymorphism on kidney function and blood pressure in kidney transplant recipients (KTRs) within the first post-transplantation year. Secondary, the study analyzed the correlation between hypertensive status and graft function, with respect to the B2R +9/-9 gene polymorphism. The pharmacogenetic study included 95 KTRs with clinical and biochemical parameters evaluated in three time-points (3rd, 6th, 12th month). The graft function was assessed using the estimated glomerular filtration rate (eGFR), while systolic (SBP), diastolic (DBP), and mean blood pressure (MAP) were used as parameters for the evaluation of blood pressure control. The carriers of -9/-9 genotype had more stable graft function compared to both, heterozygotes and homozygous for +9 allele, not only in the early (up to 6 months) but as well in the late post-transplantation period (beyond 6 months). Also, the -9/-9 genotype carriers showed a tendency to significantly decrease MAP, SBP, and DBP in the observed period, whereby only in this patient group the significant association between hypertensive status and graft function was demonstrated. In conclusion, genotyping of B2R +9/-9 gene polymorphism alongside with biochemical and clinical parameters may identify patients with respect to the risk of more prompt decline of graft function.

Recent Approaches and Strategies in the Generation of Anti-human Cytomegalovirus Vaccines.

Human cytomegalovirus is the largest human herpesvirus and shares many core features of other herpesviruses such as tightly regulated gene expression during genome replication and latency as well as the establishment of lifelong persistence following infection. In contrast to stereotypic clinical syndromes associated with alpha-herpesvirus infections, almost all primary HCMV infections are asymptomatic and acquired early in life in most populations in the world. Although asymptomatic in most individuals, HCMV is a major cause of disease in hosts with deficits in adaptive and innate immunity such as infants who are infected in utero and allograft recipients following transplantation. Congenital HCMV is a commonly acquired infection in the developing fetus that can result in a number of neurodevelopmental abnormalities. Similarly, HCMV is a major cause of disease in allograft recipients in the immediate and late posttransplant period and is thought to be a major contributor to chronic allograft rejection. Even though HCMV induces robust innate and adaptive immune responses, it also encodes a vast array of immune evasion functions that are thought aid in its persistence. Immune correlates of protective immunity that prevent or modify intrauterine HCMV infection remain incompletely defined but are thought to consist primarily of adaptive responses in the pregnant mother, thus making congenital HCMV a potentially vaccine modifiable disease. Similarly, HCMV infection in allograft recipients is often more severe in recipients without preexisting adaptive immunity to HCMV. Thus, there has been a considerable effort to modify HCMV specific immunity in transplant recipient either through active immunization or passive transfer of adaptive effector functions. Although efforts to develop an efficacious vaccine and/or passive immunotherapy to limit HCMV disease have been underway for nearly six decades, most have met with limited success at best. In contrast to previous efforts, current HCMV vaccine development has relied on observations of unique properties of HCMV in hopes of reproducing immune responses that at a minimum will be similar to that following natural infection. However, more recent findings have suggested that immunity following naturally acquired HCMV infection may have limited protective activity and almost certainly, is not sterilizing. Such observations suggest that either the induction of natural immunity must be specifically tailored to generate protective activity or alternatively, that providing targeted passive immunity to susceptible populations could be prove to be more efficacious.

Combined Effect of Inter- and Intrapatient Variability in Tacrolimus Exposure on Graft Impairment Within a 3-Year Period Following Kidney Transplantation: A Single-Center Experience.

Tacrolimus is a cornerstone of the most immunosuppressive protocols after kidney transplantation, but its use is complicated by notable interpatient and intrapatient variability (IPV). The goal of this studywas to evaluate whether or not tacrolimus IPV, or average dose-adjusted trough concentration (C0/D), during 6-12months post-transplantation might have contributed to graft function decline in a 3-year period following kidney transplantation. After primary evaluation of individual effects of tacrolimus IPV and C0/D, the study aimed to estimate the combined effect of tacrolimus IPVandC0/D on composite endpoint (consisting of graft failure, chronic allograft dysfunction, chronic rejection, and doubling of serum creatinine concentration) in the period between 13 and 36months after kidney transplantation. In addition, the goal was to analyze the impact of genetics on interpatient variability in tacrolimus exposure in the early and late post-transplantation periods. The study enrolled 104 Caucasian patients and included 2541 patient examinations up to 36months after kidney transplantation. All patients were genotyped on CYP3A5 6986A>G and ABCB1 3435C>T gene polymorphism. Patients were divided into groups based on the tacrolimus IPV tertiles and the median value of average C0/D during 6-12months post-transplantation. The results showed a more pronounced decline in estimated glomerular filtration rate values within the high IPV tertile group (p = 0.018), as well as within the low C0/D group (p = 0.013) in a 3-year period after kidney transplantation. The carriers of CYP3A5*1/*3 genotype had lower C0/D compared to the CYP3A5*3/*3 carriers during the entire study period, while the results for ABCB1 were inconsistent when considering tacrolimus C0/D. Patients with high IPV/low C0/D had significantly reduced graft survival compared to the other tacrolimus IPV/C0/D combination groups (i.e., high IPV/high C0/D, low IPV/low C0/D, low IPV/high C0/D) with the hazard ratio of 3.14 in Cox analysis for reaching the composite endpoint. The findings of this study suggest that combined assessment of tacrolimus IPV and tacrolimus C0/D may categorize patients towards risk of graft deterioration in the long-term post-transplantation period.

Β2-Microglobulin Post Kidney Transplantation as A Predictor of Subsequent Kidney Allograph Dysfunction

Background: Long-term outcome in renal transplantation is heterogeneous, and predicting success is challenging. Serum β2-microglobulin (β2MG), a novel marker of kidney function, predicts mortality and kidney failure in the general population, and its elevation following transplantation is a marker of acute rejection. Objective: To determine whether serum beta-2-micro-globulin one three-year post-transplant period could predict the decline in GFR over a follow-up period of six months. Patients and methods: This study was carried out at the National Institute of Nephrology and Urology, Cairo, Egypt. The patients were subjected to different demographic, clinical, biochemical, ultrasonographic, and endoscopic findings. In this study, 42 primary kidney transplant recipients were included. Results: The results showed a significant increase in serum β2-microglobulin level between renal transplant recipients with unstable kidney functions in comparison to renal transplant recipients with stable kidney function. The results showed serum β2-microglobulin level could be a good predictor of renal graft outcomes. Measurements of serum levels of beta 2 micro-globulin could be more sensitive and more specific than serum creatinine as renal function tests for early prediction of graft dysfunction. Conclusion: In this study, we found an association between serum level of β2MG in the late post-transplant period and a subsequent decline in kidney allograft function within a short time-frame. The overall results show that a higher serum level of β2MG after a single measurement at different intervals of the late post-transplant period independently predicts the lower eGFR. Thus, higher serum β2MG is a risk factor for graft function, particularly with longer follow-up.

Approach and Management of Hypertension After Kidney Transplantation.

Hypertension is one of the most common cardiovascular co-morbidities after successful kidney transplantation. It commonly occurs in patients with other metabolic diseases, such as diabetes mellitus, hyperlipidemia, and obesity. The pathogenesis of post-transplant hypertension is complex and is a result of the interplay between immunological and non-immunological factors. Post-transplant hypertension can be divided into immediate, early, and late post-transplant periods. This classification can help clinicians determine the etiology and provide the appropriate management for these complex patients. Volume overload from intravenous fluid administration is common during the immediate post-transplant period and commonly contributes to hypertension seen early after transplantation. Immunosuppressive medications and donor kidneys are associated with post-transplant hypertension occurring at any time point after transplantation. Transplant renal artery stenosis (TRAS) and obstructive sleep apnea (OSA) are recognized but common and treatable causes of resistant hypertension post-transplantation. During late post-transplant period, chronic renal allograft dysfunction becomes an additional cause of hypertension. As these patients develop more substantial chronic kidney disease affecting their allografts, fibroblast growth factor 23 (FGF23) increases and is associated with increased cardiovascular and all-cause mortality in kidney transplant recipients. The exact relationship between increased FGF23 and post-transplant hypertension remains poorly understood. Blood pressure (BP) targets and management involve both non-pharmacologic and pharmacologic treatment and should be individualized. Until strong evidence in the kidney transplant population exists, a BP of <130/80 mmHg is a reasonable target. Similar to complete renal denervation in non-transplant patients, bilateral native nephrectomy is another treatment option for resistant post-transplant hypertension. Native renal denervation offers promising outcomes for controlling resistant hypertension with no significant procedure-related complications. This review addresses the epidemiology, pathogenesis, and specific etiologies of post-transplant hypertension including TRAS, calcineurin inhibitor effects, OSA, and failed native kidney. The cardiovascular and survival outcomes related to post-transplant hypertension and the utility of 24-h blood pressure monitoring will be briefly discussed. Antihypertensive medications and their mechanism of actions relevant to kidney transplantation will be highlighted. A summary of guidelines from different professional societies for BP targets and antihypertensive medications as well as non-pharmacological interventions, including bilateral native nephrectomy and native renal denervation, will be reviewed.