Early Post-transplant Phase Research Articles

Progenitor effect in the spleen drives early recovery via universal hematopoietic cell inflation.

Hematopoietic stem cells (HSCs) possess the capacity to regenerate the entire hematopoietic system. However, the precise HSC dynamics in the early post-transplantation phase remain an enigma. Clinically, the initial hematopoiesis in the post-transplantation period is critical, necessitating strategies to accelerate hematopoietic recovery. Here, we uncovered the spatiotemporal dynamics of early active hematopoiesis, "hematopoietic cell inflation," using a highly sensitive invivo imaging system. Hematopoietic cell inflation occurs in three peaks in the spleen after transplantation, with common myeloid progenitors (CMPs), notably characterized by HSC-like signatures, playing a central role. Leveraging these findings, we developed expanded CMPs (exCMPs), which exhibit a gene expression pattern that selectively proliferates in the spleen and promotes hematopoietic expansion. Moreover, universal exCMPs supported early hematopoiesis in allogeneic transplantation. Human universal exCMPs have the potential to be a viable therapeutic enhancement for all HSC transplant patients.

Single Nucleotide Polymorphisms of CYP3A4 and CYP3A5 in Romanian Kidney Transplant Recipients: Effect on Tacrolimus Pharmacokinetics in a Single-Center Experience.

Background: This study examines the impact of CYP3A4 and CYP 3A5 genotypes on tacrolimus (Tac) pharmacokinetics in Romanian kidney transplanted patients. Methods: We included 112 kidney recipients genotyped for CYP3A5*3, CYP3A4*1.001, and CYP3A4*22. Patients were categorized into poor, intermediate, rapid, and ultra-rapid metabolizers based on the functional defects linked to CYP3A variants. Results: Predominantly male (63.4%) with an average age of 40.58 years, the cohort exhibited a high prevalence of the CYP3A4*1/*1 (86.6%) and CYP3A5*3/*3 (77.7%) genotypes. CYP3A4*1.001 and CYP3A5*1 alleles significantly influenced the Tac concentration-to-dose (C0/D) ratio in various post-transplant periods, while the CYP3A4*22 allele showed no such effect (p = 0.016, p < 0.001). Stepwise regression highlighted the CYP3A4*1.001's impact in early post-transplant phases, with hematocrit and age also influencing Tac variability. Conclusions: The study indicates a complex interaction of CYP3A4 and CYP3A5 genotypes on Tac metabolism, suggesting the necessity for personalized medication approaches based on genetic profiling in kidney transplant recipients.

Management of hypertension in heart transplant recipients: an ongoing conundrum.

Hypertension remains one of the most common clinical problems leading to significant posttransplant complications. This study reviews the pathophysiology of hypertension in the postcardiac transplant phase and provides an update on currently available antihypertensive therapies for heart transplant patients. The true prevalence of hypertension in the heart transplant population remains unknown. Effective blood pressure (BP) control is key to prevent left ventricular remodeling, diastolic dysfunction and stroke. Calcium channel blockers (CCBs) are the most commonly and preferred agents in the early posttransplant phase and may have renal protective effects. Angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) can all be used as second line antihypertensive agents and may have a role in preventing other long-term complications such as calcineurin-inhibitor induced nephropathy. Although more data are needed, sodium-glucose co-transporter 2 inhibitors (SGLT2i) appeared to be well tolerated and could be considered especially in the presence of type diabetes and chronic kidney disease. Conversely, angiotensin receptor-neprilysin inhibition (ARNI) have not been studied in the heart transplant population therefore cannot be recommended at this time. Hypertension is very common after heart transplant. Early steroid wean and traditional risk factor modification play an important part in the management of post-heart transplant hypertension. CCB, ACEI, ARB are the preferred antihypertensive agents to improve postcardiac transplant complications. Novel therapies such as SGLT2i appear well tolerated and may have benefits in both BP and glycemic control in heart transplant; however, larger trials are needed.

Imlifidase in kidney transplantation.

Kidney transplantation, the gold-standard therapeutic approach for patients with end-stage kidney disease, offers improvement in patient survival and quality of life. However, broad sensitization against human leukocyte antigens often resulting in a positive crossmatch against the patient's living donor or the majority of potential deceased donors in the allocation system represents a major obstacle due to a high risk for antibody-mediated rejection, delayed graft function and allograft loss. Kidney-paired donation and desensitization protocols have been established to overcome this obstacle, with limited success. Imlifidase, a novel immunoglobulin G (IgG)-degrading enzyme derived from Streptococcus pyogenes and recombinantly produced in Escherichia coli, is a promising agent for recipients with a positive crossmatch against their organ donor with high specificity towards IgG, rapid action and high efficacy in early pre-clinical and clinical studies. However, the rebound of IgG after a few days can lead to antibody-mediated rejection, making the administration of potent immunosuppressive regimens in the early post-transplant phase necessary. There is currently no comparative study evaluating the efficiency of imlifidase therapy compared with conventional desensitization protocols along with the lack of randomized control trials, indicating the clear need for future large-scale clinical studies in this field. Besides providing a practical framework for the clinical use of the agent, our aim in this article is to evaluate the underlying mechanism of action, efficiency and safety of imlifidase therapy in immunologically high-risk kidney transplant recipients.

Evaluating tixagevimab/cilgavimab prophylaxis in allogeneic haematopoietic cell transplantation recipients for COVID-19 prevention.

Allogeneic haematopoietic cell transplantation (allo-HCT) recipients exhibit an increased risk of COVID-19, particularly in the early post-transplant phase, due to insufficient vaccine responses. This retrospective study investigated the incidence of SARS-CoV-2 infection in allo-HCT recipients who received tixagevimab/cilgavimab pre-exposure prophylaxis (T/C PrEP) compared to those who did not. Logistic regression, adjusted for sex, age, SARS-CoV-2 vaccination status and immunosuppressive treatment, revealed a significant reduction in the likelihood of SARS-CoV-2 infection risk with T/C PrEP (adjusted odds ratio aOR = 0.26 [0.07, 0.91]). These findings suggest the potential efficacy of monoclonal antibody PrEP in protecting this vulnerable patient population from COVID-19.

Identification of Factors Influencing Donor-Derived Cell-Free DNA Levels up to One Year After Kidney Transplant.

Introduction: Donor-derived cell-free DNA (dd-cfDNA) in the peripheral blood of allograft recipients has shown to early identify allograft injury. In this study, we assessed the factors that influence the amount of circulating dd-cfDNA during the first month postkidney transplant as well as its longitudinal trend. Materials and Methods: A consecutive series of 98 adult kidney transplant recipients at a single center between July 2018 and January 2020 were included in this study. All demographic and operative details were collected for donors and recipients of the organ transplant. Median eGFR, dd-cfDNA, and serum creatinine were calculated at 1, 2, 3, 6, and 12 month posttransplant. Descriptive statistics were used for patient demographics. Nonparametric comparisons of dd-cfDNA cumulative distributions between dichotomized groupings were evaluated using Kruskal-Wallis or Mann-Whitney U tests. Results: The median age of recipients was 54.5 years (IQR: 42.7-62.2). The cause of ESRD among recipients was hypertension (43%) and Type II diabetes mellitus (29%). Eighty-two percentage of patients received a deceased donor allograft, 14% received a living unrelated allograft, and 4% received a living related allograft. Sixteen percentage of recipients experienced delayed graft function (DGF). Median creatinine level at 1 month posttransplant was 1.75 mg/dL (IQR: 1.34-2.26) and median eGFR at 1 month posttransplant was 49.6 mL/min/1.73 m2 (IQR: 35-65). The median dd-cfDNA score at 1 month posttransplant for all recipients was 0.4% (IQR: 0.15-5.3). Donor sex was a statistically significant differential for dd-cfDNA score. Recipients from male donors had a significantly higher median dd-cf DNA score at 1 month posttransplant versus those who received a female kidney (0.57% vs. 0.28%, p < 0.01). Highest median score was recorded at the first month posttransplant (0.4%, IQR: 0.26-0.74), and a sustained downward trend was observed through Month 2 (0.19%, IQR: 0.17-0.31) and Month 3 (0.19%, IQR: 0.15-0.26). Correlation between 1-, 2-, 3-, 6-, and 12-month posttransplant median dd-cfDNA scores between deceased donor and living donor (LRD and LURD) cohorts was not statistically significant. Conclusion: This study provides further insight into donor and recipient variables' effects on dd-cfDNA in the early posttransplant phase by analyzing a more diverse cohort of patients and adds to the knowledge around interpreting dd-cfDNA scores with clinical correlation for posttransplant management.

Targeting GD2 after allogeneic SCT: effector cell composition defines the optimal use of ch14.18 and the bispecific antibody construct NG-CU (GD2-CD3).

We investigated whether T cell-recruiting bispecific anti-CD3/GD2 antibody NG-CU might be an alternative to therapeutic anti-GD2 monoclonal antibody (mAb) ch14.18, mediating complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) through natural killer (NK) cells for immunotherapy in high-risk/relapsed neuroblastoma after autologous/allogeneic stem cell transplantation (auto/alloSCT). Different antibody concentrations and effector-to-target ratios (E:T) were evaluated using xCELLigence RTCA system, peripheral blood mononuclear cells (PBMCs) (healthy donors and patients after alloSCT), and neuroblastoma cell lines (LS/LAN-1). Mean specific lysis of LS cells utilizing PBMCs from healthy donors and ch14.18 (1µg/ml) was 40/66/75% after 12/24/48 h compared to 66/93/100% in the presence of NG-CU (100 ng/ml). NG-CU showed enhanced cytotoxicity compared to ch14.18, even at lower concentrations and E:T ratios, and completely eradicated LS cells after 72 h. To decipher the influence of effector cell subsets on lysis, different ratios of T and NK cells were tested. At a ratio of 1:1, ch14.18 was more effective than NG-CU. Using patient PBMCs taken at different time points posttransplant, significant lysis with both constructs was detectable depending on percentages and total numbers of T and NK cells; in the early posttransplant phase, NK cells were predominant and ch14.18 was superior, whereas later on, T cells represented the majority of immune cells and NG-CU was more effective. Our study highlights the importance of analyzing effector cell subsets in patients before initiating antibody-based therapy. Consequently, we propose an adjusted administration of both antibody constructs, considering the state of posttransplant immune recovery, to optimize anti-tumor activity.

Circulating microbial cell–free DNA is increased during neutropenia after hematopoietic stem cell transplantation

AbstractWe used a next-generation sequencing platform to characterize microbial cell–free DNA (mcfDNA) in plasma samples from patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT). In this observational study, we sought to characterize plasma mcfDNA in order to explore its potential association with the immunologic complications of transplantation. We compared serially collected patient samples with plasma collected from healthy control subjects. We observed changes in total mcfDNA burden in the plasma after transplantation, which was most striking during the early posttransplant neutropenic phase. This elevation could be attributed to a number of specific bacterial taxa, including Veillonella, Bacteroides, and Prevotella (genus level). For an additional cohort of patients, we compared the data of mcfDNA from plasma with 16s-ribosomal RNA sequencing data from stool samples collected at matched time points. In a number of patients, we confirmed that mcfDNA derived from specific microbial taxa (eg, Enterococcus) could also be observed in the matched stool sample. Quantification of mcfDNA may generate novel insights into mechanisms by which the intestinal microbiome influences systemic cell populations and, thus, has been associated with outcomes for patients with cancer.

Identifying Outcome Domains for Clinical Trials of Physical Rehabilitation Among Adults Undergoing Solid Organ Transplantation Using a Delphi Approach.

Introduction: A core outcome set (COS) improves the quality of reporting in clinical trials; however, this has not been developed for clinical trials of exercise training among adults undergoing solid organ transplant. Research Question: To explore the perspectives of transplant patients and healthcare professionals on the key outcomes domains that are relevant for clinical trials of exercise in all recipients of transplanted organs. Methods: A Delphi approach was employed with 2 rounds of online questionnaires. Participants rated the importance of outcome domains using a 9-point Likert scale ranging from "not important" to "very important". A score of 7 to 9 (very important) by 70% or more participants and a score of 1 to 3 (not important) by less than 15% participants were required to keep an outcome domain from the first to the second round. Results: Thirty-six participants completed 2 rounds of questionnaires (90% response rate). After Round 1, 8 outcome domains were considered very important in the pretransplant phase; 16 in the early posttransplant; and 17 in the late posttransplant. Only 1 outcome domain, organ rejection in the early posttransplant phase, met the criteria to be considered very important after Round 2. Conclusion: Although consensus was not reached on the core outcome domains, this study provides preliminary information on which domains are higher priority for patients and professionals. Future work should consider a meeting with key stakeholders to allow for deeper discussion to reach consensus on a core outcome set.

A Primed Neutrophil Subset Predicts the Risk of Bloodstream Infections in Allogenic Bone Marrow Transplant Patients: A Prospective Study

Background: Blood stream infections (BSIs) are the most common infectious complications in patients receiving allogenic hematopoietic stem cell transplants (allo-HSCT). Timing of polymorphonuclear neutrophil (PMN) recovery following allo-HSCT varies widely among patients. PMN counts are monitored to assess susceptibility of patients to BSIs. Even though allo-HSCT patients undergo a phase of severe neutropenia, some of these patients develop BSIs while others don't. Recent studies have emerged describing the heterogeneity of PMNs and the different functional phenotypes. This raises questions on whether susceptibility to BSIs is related to levels of specific PMN phenotypes rather than total PMN counts. Our previous work has identified a primed PMNs (pPMN) phenotype as a steady-state subset representing (~10%) of PMNs in the circulation. These pPMNs display enhanced transmigration and activation, making them the first cells to respond to bacterial insults. In this study, we explore the potential use of the levels of pPMNs as a biomarker for assessing BSI risk in allo-HSCT patients. Methods: This study was a prospective longitudinal assessment of PMNs in consecutive blood and oral samples collected from 76 patients who underwent an allo-HSCT at Princess Margaret Cancer Hospital between August 2020 and August 2021. Patients received the transplant on day 0 and blood and oral samples were collected from the patients on days (-5, +5, +7, +9, +11, +13, +15, +17, +19 and +21). Blood and oral samples were immediately processed, PMNs were counted, phenotyped with a seven CD marker panel of antibodies to identify pPMNs. Flow cytometry was performed, and data was analyzed by FlowJo software. Results: While all allo-HSCT patients displayed a decline in PMN counts during the early post-transplant phase, two patient subsets were identified by their opposing trends in pPMN frequency. Patients were divided into a high pPMN group (n=36) and a low pPMN group (n=40) based on having above or below the 10% threshold of average blood pPMN percentage on day +5 post-transplant. Patients in the low group had increased susceptibly to BSIs (Hazards ratio= 4.814, 95% CI= 2.086-11.11, P= 0.0013). This was not affected after adjusting for sex, age at transplant, diagnosis, conditioning regimen, mucositis, and the stem cell source and counts and remained statistically significant (P<0.01). We also show that patients in the low pPMN group had delayed oral repopulation of PMNs (19.81 days post-transplant) compared to patients in the high group (15.95 days post-transplant). Oral PMN repopulation helps in maintaining equilibrium between the host immune response in the oral cavity and the colonizing microorganisms which is crucial to preventing infections. Therefore, delays in oral repopulation might be one of the means by which deficiencies in pPMNs contribute to BSIs. Conclusion: In patients receiving an allo-HSCT, having less than 10% pPMNs early in the post-transplant phase can be used as an independent early predictor of BSI in allo-HSCT patients

Usefulness of Indocyanine Green Plasma Disappearance Rate in Liver Donors and Recipients: A Prospective Observational Study

Determination of indocyanine green (ICG) plasma disappearance rate (PDR) is a simple, inexpensive, and noninvasive tool to assess liver perfusion, absorption, and elimination. Its application in the liver transplant process has not been widely incorporated in clinical practice. This study aims to assess the usefulness of ICG PDR in the donor selection setting and in the early post-transplant phase and to analyze its variation between these 2 time points. We performed a single-center prospective observational study. ICG clearance test was performed in 50 brain-dead donors (T0-PDR) to assess concordance with graft suitability. Rejected grafts biopsy specimens were analyzed to correlate histology with T0-PDR. In the recipients, ICG PDR was performed before wound closure (T1-PDR). The association of T0, T1, and T0-T1 variation with the development of early allograft dysfunction (EAD) was investigated. A total of 23 of 50 grafts were discarded because of poor macroscopic quality. A T0-PDR below 15.5%/min could predict graft rejection with 100% specificity and 69.6% sensitivity. All the biopsy specimens from donors with PDR < 10 %/min showed liver fibrosis. A total of 25 of the remaining 27 grafts were implanted; 5 patients (20%) developed EAD. T1-PDR performed better than T0-T1 variation to predict dysfunction. ICG PDR could be used in the donors as a filter to discard poor-quality grafts before procurement and, in the early post-transplant phase, to predict EAD.

Model-Based Tacrolimus Follow-up Dosing in Adult Renal Transplant Recipients: A Simulation Trial.

Initial algorithm-based dosing appears to be effective in predicting tacrolimus dose requirement. However, achieving and maintaining the target concentrations is challenging. Model-based follow-up dosing, which considers patient characteristics and pharmacological data, may further personalize treatment. This study investigated whether model-based follow-up dosing could lead to more accurate tacrolimus exposure than standard therapeutic drug monitoring (TDM) in kidney transplant recipients after an initial algorithm-based dose. This simulation trial included patients from a prospective trial that received an algorithm-based tacrolimus starting dose followed by TDM. For every measured tacrolimus predose concentration (C 0,obs ), model-based dosing advice was simulated using the InsightRX software. Based on previous tacrolimus doses and C 0 , age, body surface area, CYP3A4 and CYP3A5 genotypes, hematocrit, albumin, and creatinine, the optimal next dose, and corresponding tacrolimus concentration (C 0,pred ) were predicted. Of 190 tacrolimus C 0 values measured in 59 patients, 121 (63.7%; 95% CI 56.8-70.5) C 0,obs were within the therapeutic range (7.5-12.5 ng/mL) versus 126 (66.3%, 95% CI 59.6-73.0) for C 0,pred ( P = 0.89). The median absolute difference between the tacrolimus C 0 and the target tacrolimus concentration (10.0 ng/mL) was 1.9 ng/mL for C 0,obs versus 1.6 ng/mL for C 0,pred . In a historical cohort of 114 kidney transplant recipients who received a body weight-based starting dose followed by TDM, 172 of 335 tacrolimus C 0 (51.3%) were within the therapeutic range (10.0-15.0 ng/mL). The combination of an algorithm-based tacrolimus starting dose with model-based follow-up dosing has the potential to minimize under- and overexposure to tacrolimus in the early posttransplant phase, although the additional effect of model-based follow-up dosing on initial algorithm-based dosing seems small.

232.2: High Levels of Donor Derived Cell-Free DNA in the Early Post-transplant Phase Indicates Injury Independent of Renal Function Status

232.2: High Levels of Donor Derived Cell-Free DNA in the Early Post-transplant Phase Indicates Injury Independent of Renal Function Status

Detectable Serum Concentration with Prophylactic Inhaled Tobramycin in Lung Transplant Recipients

<h3>Purpose</h3> Inhaled tobramycin (iTOBI) is used in bilateral lung transplant recipients (LTRs) to prevent PsA colonization. Pharmacokinetic studies show that iTOBI is not systemically absorbed, making it an alternative to intravenous formulations. Case reports exist of LTRs on iTOBI developing renal failure with detectable tobramycin troughs (DTTs). The purpose of this review is to describe the incidence of DTT in LTRs receiving iTOBI immediately post-transplant. <h3>Methods</h3> This single-center, retrospective review included patients in their index lung transplant admission who received iTOBI with a DTT (≥ 0.5 mg/L). All LTRs received iTOBI 300 mg q12hr prophylaxis for at least one month with levels drawn for cause when concerned for accumulation. Primary outcome was the number of LTRs with DTTs. Secondary outcomes included duration of therapy and incidence of SCr increase ≥ 0.3 mg/dL within 48 hours (AKI). Descriptive statistics were used to analyze baseline characteristics and outcomes. <h3>Results</h3> We reviewed 211 LTRs from January 2014 to August 2021. Twenty patients (9.5%) met inclusion criteria with 32 DTTs and 4 were excluded due to undetectable troughs. Median time to initial DTT was 10 (2-34) days of therapy. AKI occurred within a week prior to 84% of DTT, with a median of 3 days to elevated trough. Median time to DTT clearance (undetectable level or resumption of therapy) was 2 days. Therapy was discontinued in 10% of patients due to concern for nephrotoxicity (Table 1). <h3>Conclusion</h3> iTOBI therapy may cause systemic drug levels in the early post-transplant phase. Given known association of systemic tobramycin with nephrotoxicity, particularly in the presence of nephrotoxic medications, iTOBI trough surveillance may be prudent to guide therapy. Rapid DTT clearance may render repeat levels unnecessary. Larger studies are needed to assess the renal risk, timing of iTOBI accumulation in LTRs and thresholds for serum monitoring.

Pharmacologic Strategies for Post-Transplant Maintenance in Acute Myeloid Leukemia: It Is Time to Consider!

Simple SummaryAllogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapeutic procedure for patients with high risk acute myeloid leukemia. Its anti-leukemic activity is mainly derived from the intensity of the conditioning regimen used and the graft-versus-leukemia effect exerted by the donor T lymphocytes. Despite major progress in the allo-HCT procedure in recent years with the achievement of lower non-relapse mortality and long-term disease control. However, up to 45% of patients still experience relapse. Therapeutic strategies post-transplant aiming at preventing disease relapse are discussed in this review.Patients with high-risk acute myeloid leukemia are offered allogeneic hematopoietic cell transplantation (allo-HCT) in first remission to reduce risk of relapse. However, disease recurrence remains the major reason of allo-HCT failure, occurring in around 35–45% of patients, and leading to dismal outcomes. Strategies to reduce the risk of relapse are greatly needed, especially in the early post-transplant phase where the graft-versus-leukemia (GVL) effect is not yet activated. Some practices include the use of myeloablative conditioning regimens, close monitoring of measurable residual disease and donor chimerism, rapid tapering of immunosuppression, and implementation of pre-emptive strategies as the use of donor lymphocyte infusion. However, it’s time to consider prophylactic pharmacologic interventions post allo-HCT that aim at maintaining leukemic clones under control by both direct cytotoxic activity and by enhancing the GVL effect. In this current review, available data on drugs targeting epigenetic pathways like azacitidine, or actionable mutations like FLT3 and IDH1/2 inhibitors used as maintenance post allo-HCT, will be discussed.

Critical Considerations in Bioluminescence Imaging of Transplanted Islets: Dynamic Signal Change in Early Posttransplant Phase and Signal Absorption by Tissues.

In pancreatic islet transplantation studies, bioluminescence imaging enables quantitative and noninvasive tracking of graft survival. Amid the recent heightened interest in extrahepatic sites for islet and stem cell-derived beta-like cell transplantations, proper understanding the nature of bioluminescence imaging in these sites is important. Islets isolated from Firefly rats ubiquitously expressing luciferase reporter gene in Lewis rats were transplanted into subcutaneous or kidney capsule sites of wild-type Lewis rats or immunodeficient mice. Posttransplant changes of bioluminescence signal curves and absorption of bioluminescence signal in transplantation sites were examined. The bioluminescence signal curve dynamically changed in the early posttransplantation phase; the signal was low within the first 5 days after transplantation. A substantial amount of bioluminescence signal was absorbed by tissues surrounding islet grafts, correlating to the depth of the transplanted site from the skin surface. Grafts in kidney capsules were harder to image than those in the subcutaneous site. Within the kidney capsule, locations that minimized depth from the skin surface improved the graft detectability. Posttransplant phase and graft location/depth critically impact the bioluminescence images captured in islet transplantation studies. Understanding these parameters is critical for reducing experimental biases and proper interpretation of data.

Standardized Phase Angle for Predicting Nutritional Status of Hemodialysis Patients in the Early Period After Deceased Donor Kidney Transplantation.

BackgroundThis study was designed to verify whether early posttransplant standardized phase angle (SPhA) determines nutrition status of hemodialysis patients in regard to different nutritional markers and predicts handgrip strength (HGS) 6 months after kidney transplantation.MethodsA total of 82 kidney transplant recipients on maintenance hemodialysis treatment entered the study. Nutritional status was evaluated before kidney transplantation, at the hospital discharge date, and 6 months after. We used bioelectrical impedance analysis (BIA), three different malnutrition screening tools, HGS, and anthropometric measurements. Demographic profiles and biochemical nutritional markers were collected. SPhA values, adjusted for age and BMI, were used in our study.ResultsIn the early posttransplant period, kidney transplant recipients lost muscle mass, gained fat mass, and developed mostly negative SPhA, accompanied by significantly lower albumin levels. The subjects with lower than median (<-1.46) SPhAdis [the SPhA (at discharge) adjusted for hospitalization time and the baseline SPhA] displayed lower values of albumin concentration (43.4 vs. 45.1 g/l, p = 0.010), hemoglobin (124 vs. 133 g/l, p = 0.016), GNRI (113 vs. 118, p = 0.041), and HGS (30 vs. 33 kg, p = 0.043). These patients had higher ferritin concentrations (420 vs. 258 mkmol/l, p = 0.026), longer inpatient stays (32 vs. 21 days, p < 0.001), and higher MIS scores (3 vs. 1, p = 0.001).ConclusionAt the moment of hospital discharge, lower than the median SPhA is related to protein-energy wasting, represented as lower concentrations of nutrition biomarkers and an active inflammatory response. Higher SPhA before kidney transplantation predicts HGS 6 months after kidney transplantation, especially in women.

Glucagon-Like Peptide-1 Is Associated With Systemic Inflammation in Pediatric Patients Treated With Hematopoietic Stem Cell Transplantation.

Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are challenged with severe side effects, which are propagated by mucosal barrier disruption, and the related microbial translocation and systemic inflammation. Glucagon-like peptide-1 (GLP-1), a well-known incretin hormone, possesses anti-inflammatory properties and promotes regeneration of damaged intestinal epithelium in animal studies. We hypothesized that the immense inter-individual variation in the degree of mucosal damage and systemic inflammation, seen after HSCT is influenced by endogenous GLP-1 and could be related to acute post-transplant complications. In this prospective study we measured serial weekly fasting plasma GLP-1, along with C-reactive protein (CRP), and citrulline in 82 pediatric patients during allogeneic HSCT together with a fasting plasma GLP-1 in sex- and age-matched healthy controls. Overall, GLP-1 levels were increased in the patients during the course of HSCT compared with the controls, but tended to decrease post-transplant, most pronounced in patients receiving high-intensity conditioning regimen. The increase in CRP seen in the early post-transplant phase was significantly lower from day +8 to +13 in patients with GLP-1 above the upper quartile (>10 pmol/L) at day 0 (all P ≤ 0.03). Similar findings were seen for peak CRP levels after adjusting for type of conditioning (-47.0%; 95% CI, -8.1 – -69.4%, P = 0.02). Citrulline declined significantly following the transplantation illustrating a decrease in viable enterocytes, most evident in patients receiving high-intensity conditioning regimen. GLP-1 levels at day 0 associated with the recovery rate of citrulline from day 0 to +21 (34 percentage points (pp)/GLP-1 doubling; 95% CI, 10 – 58pp; P = 0. 008) and day 0 to day +90 (48 pp/GLP-1 doubling; 95% CI, 17 – 79pp; P = 0. 004), also after adjustment for type of conditioning. This translated into a reduced risk of acute graft-versus-host disease (aGvHD) in patients with highest day 0 GLP-1 levels (>10 pmol/L) (cause-specific HR: 0.3; 95% CI, 0.2 – 0.9, P = 0.02). In conclusion, this study strongly suggests that GLP-1 influences regeneration of injured epithelial barriers and ameliorates inflammatory responses in the early post-transplant phase.

Functional roles of graft‐infiltrating lymphocytes during early‐phase post‐transplantation in mouse cardiac transplantation models

Immunological behavior of graft-infiltrating lymphocytes (GILs) determines the graft fate (i.e., rejection or acceptance). Nevertheless, the functional alloreactivity and the phenotype of GILs at various times during the early post-transplantation phase have not been fully elucidated. We examined the immunological activities of early-phase GILs using a murine model of cardiac transplantation. GILs from 120-h allografts, but not 72-h allografts, showed robust activation and produced proinflammatory cytokines. In particular, a significant increase in CD69+ T-bet+ Nur77+ T cells was detected in 120-h allografts. Furthermore, isolated GILs were used to reconstitute BALB/c Rag2-/- γc-/- (BRG) mice. BRG mice reconstituted with 120-h GILs displayed donor-specific immune reactivity and rejected donor strain cardiac allografts; conversely, 72-h GILs exhibited weak anti-donor reactivity and did not reject allografts. These findings were confirmed by re-transplantation of cardiac allografts into BRG mice at 72-h post-transplantation. Re-transplanted allografts continued to function for >100 days, despite the presence of CD3+ GILs. In conclusion, the immunological behavior of GILs considerably differs over time during the early post-transplantation phase. A better understanding of the functional role of early-phase GILs may clarify the fate determination process in the graft-site microenvironment.

Production of growth factors, pro – and anti-inflammatory cytokines by postnatal MMSCs from various tissue sources during in vitro co-cultivation with immunoisolated pancreatic β-cells

The article presents the results of evaluating growth factors, pro – and anti-inflammatory cytokine production by multipotent mesenchymal stem cell cultures under the conditions of co-cultivation with immuno-isolated beta-cells of the pancreas. β-cell transplantation is a minimally invasive therapeutic approach (compared to transplantation of entire pancreas), and it provides better metabolic control with respect to insulin administration. However, when transplanting β-cells, there is always a risk of immune rejection of the grafted cells. It is generally recognized that encapsulation is an effective means of immunological protection against the recipient’s immune system during transplantation. Regulation of the autoimmune response to transplanted cells is crucial for the treatment of type I diabetes mellitus. In recent years, along with replacement of islet cells, much attention has been paid to the use of multipotent mesenchymal stem cells with immunomodulatory and/or immunosuppressive properties, aimed for the correction of diabetes mellitus. Either in vitro and in vivo, they impact not only T-lymphocytes, but also B-lymphocytes, dendritic and NK-cells. Mesenchymal stem cells are able to inhibit proliferation of immune cells and reduce their secretion of inflammatory cytokines, acting as auxiliary cells to improve the survival of islets in the early post-transplant phase. Combined transplantation of multipotent mesenchymal stem cells and pancreatic β-cells is a promising approach to the treatment of type I diabetes mellitus. Deeper study of the mechanisms that cause their cytoprotective effect upon the transplant may be helpful for implementation of this therapeutic approach and improve its efficiency. In our study, a 1% solution of low-viscosity sodium alginate with addition of saline solution (0.9% sodium chloride) was used to create immuno-insulating scaffolds, and a 2.2% BaCl2 solution was added for polymerization. Decreased production of proinflammatory cytokines (TNFα, IL-12, IL-5) and growth factor (GM-CSF) was registered in co-cultures of β-cells with mesenchymal stem cells of bone marrow origin, and those obtained from subcutaneous adipose tissue. Anti-inflammatory activity was more pronounced in adipose stem cells and their immunomodulatory effects were shown via changes of their cytokine-producing activity. Hence, the multipotent mesenchymal stem cells obtained from adipose tissue and bone marrow have shown to exert cytoprotective effect upon pancreatic beta-cells by shifting the cytokine-producing activity towards an antiinflammatory profile.