Incidence, risk factors, management strategies, and outcomes of antibody-mediated rejection in pediatric kidney transplant recipients-a multicenter analysis of the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN).

BACKGROUND: This study by the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) was designed to determine the incidence, risk factors, current management strategies, and outcomes of antibody-mediated rejection (ABMR) in pediatric kidney transplant recipients (pKTR). METHODS: We performed an international, multicenter, longitudinal cohort study of data reported to the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry. Three hundred thirty-seven pKTR from 21 European centers were analyzed. Clinical outcomes, including kidney dysfunction, rejection, HLA donor-specific antibodies, BK polyomavirus-associated (BKPyV) nephropathy, and allograft loss, were assessed through 5 years post-transplant. RESULTS: The cumulative incidence of de novo donor-specific class I HLA antibodies (HLA-DSA) post-transplant was 4.5% in year 1, 8.3% in year 3, and 13% in year 5; the corresponding data for de novo class II HLA-DSA were 10%, 22.5%, and 30.6%, respectively. For 5 years post-transplant, the cumulative incidence of acute ABMR was 10% and that of chronic active ABMR was 5.9%. HLA-DR mismatch and de novo HLA-DSA, especially double positivity for class I and class II HLA-DSA, were significant risk factors for ABMR, whereas cytomegalovirus (CMV) IgG negative recipient and CMV IgG negative donor were associated with a lower risk. BKPyV nephropathy was associated with the highest risk of graft dysfunction, followed by ABMR, T-cell mediated rejection, and older donor age. CONCLUSIONS: This study provides an estimate of the incidence of de novo HLA-DSA and ABMR in pKTR and highlights the importance of BKPyV nephropathy as a strong risk factor for allograft dysfunction.

Dyslipidemia in children with chronic kidney disease-findings from the Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study.

BACKGROUND: Dyslipidemia is an important and modifiable risk factor for CVD in children with CKD. METHODS: In a cross-sectional study of baseline serum lipid levels in a large prospective cohort study of children with stage 3-5 (predialysis) CKD, frequencies of abnormal lipid levels and types of dyslipidemia were analyzed in the entire cohort and in subpopulations defined by fasting status or by the presence of nephrotic range proteinuria. Associated clinical and laboratory characteristics were determined by multivariable linear regression analysis. RESULTS: A total of 681 patients aged 12.2 ± 3.3 years with a mean eGFR of 26.9 ± 11.6 ml/min/1.73 m2 were included. Kidney diagnosis was classified as CAKUT in 69%, glomerulopathy in 8.4%, and other disorders in 22.6% of patients. Nephrotic range proteinuria (defined by a urinary albumin/creatinine ratio > 1.1 g/g) was present in 26.9%. Dyslipidemia was found in 71.8%, and high triglyceride (TG) levels were the most common abnormality (54.7%). Fasting status (38.9%) had no effect on dyslipidemia status. Except for a significant increase in TG in more advanced CKD, lipid levels and frequencies of dyslipidemia were not significantly different between CKD stages. Hypertriglyceridemia was associated with younger age, lower eGFR, shorter duration of CKD, higher body mass index (BMI-SDS), lower serum albumin, and higher diastolic blood pressure. CONCLUSIONS: Dyslipidemia involving all lipid fractions, but mainly TG, is present in the majority of patients with CKD irrespective of CKD stage or fasting status and is significantly associated with other cardiovascular risk factors.

LMS-based continuous pediatric reference values for soluble receptor activator of nuclear factor kappa B ligand (sRANKL) and osteoprotegerin (OPG) in the HARP cohort.

Soluble RANKL (sRANKL) and osteoprotegerin (OPG) are regulators of osteoclast differentiation and activation, but adequate pediatric reference values are lacking. Here we provide LMS (Lambda-Mu-Sigma)-based continuous pediatric reference percentiles for sRANKL, OPG and sRANKL/OPG ratio that will allow calculation of standardized patient z-scores to assess bone modeling in children. PURPOSE: Soluble receptor activator of nuclear factor kappa B ligand (sRANKL) and osteoprotegerin (OPG) are regulators of osteoclast differentiation and activation and thus bone metabolic turnover in children. Adequate pediatric reference values for their serum/plasma concentrations are lacking. The development of Lambda-Mu-Sigma (LMS)-based continuous reference percentiles for laboratory parameters allow improved data interpretation in clinical practice. METHODS: A total of 300 children aged 0.1-18 years (166 boys) were enrolled in the HAnnover Reference values for Pediatrics (HARP) study. sRANKL and OPG were assessed by ELISA. LMS-based continuous reference percentiles were generated using RefCurv software. RESULTS: LMS-based percentiles were established for sRANKL, OPG and sRANKL/OPG ratio, which were all found to be age-dependent. sRANKL and sRANKL/OPG associated with sex. In boys, sRANKL percentiles were highest during infancy, followed by a continuous decline until the age of 7 years and a second peak around age 12-13 years. In girls, a continuous, slow decline of sRANKL percentiles was noticed from infancy onwards until the age of 13 years, followed by a rapid decline until adulthood. OPG percentiles continuously declined from infancy to adulthood. The percentiles for sRANKL/OPG ratio paralleled those of sRANKL. Serum concentrations of sRANKL correlated with OPG and serum phosphate z-scores, while OPG concentrations inversely associated with standardized body weight, BMI, and urinary phosphate to creatinine ratio (each p < 0.05). CONCLUSION: This is the first report of LMS-based continuous pediatric reference percentiles for sRANKL, OPG and sRANKL/OPG ratio that allows calculation of standardized patient z-scores to assess bone metabolic turnover in children.

Psychosocial and environmental risk factors of obesity and hypertension in children and adolescents-a literature overview.

Childhood obesity has become a worldwide epidemic in the 21st century. Its treatment is challenging and often ineffective, among others due to complex, often not obvious causes. Awareness of the existence and meaning of psychosocial and environmental risk factors seems to be an essential element in the prevention and treatment of obesity and its complications, especially arterial hypertension. In this review, we will discuss the role of that risk factors linking obesity and increased cardiovascular disorders including the role of nutritional factors (including the role of unhealthy diet, inadequate hydration), unhealthy behaviors (e.g. smoking, alcohol and drugs, sedentary behavior, low physical activity, disrupted circadian rhythms, sleep disorders, screen exposure), unfavorable social factors (such as dysfunctional family, bullying, chronic stress, mood disorders, depression, urbanization, noise, and environmental pollution), and finally differences in cardiovascular risk in girls and boys.

Efficacy of CytoSorb®: a systematic review and meta-analysis.

INTRODUCTION: Cytokine adsorption using the CytoSorb® adsorber has been proposed in various clinical settings including sepsis, ARDS, hyperinflammatory syndromes, cardiac surgery or recovery after cardiac arrest. The aim of this analysis is to provide evidence for the efficacy of the CytoSorb® adsorber with regard to mortality in various settings. METHODS: We searched PubMed, Cochrane Library database and the database provided by Cytosorbents™ (01.1.2010-29.5.2022). We considered randomized controlled trials and observational studies with control groups. The longest reported mortality was defined as the primary endpoint. We computed risk ratios and 95%-confidence intervals and used DerSimonian and Lairds random effects model. We analysed all studies combined and divided them into the subgroups: sepsis, cardiopulmonary bypass surgery (CPB), other severe illness, SARS-CoV-2 infection and recovery from cardiac arrest. The meta-analysis was registered in advance (PROSPERO: CRD42022290334). RESULTS: Of an initial 1295 publications, 34 studies were found eligible, including 1297 patients treated with CytoSorb® and 1314 controls. Cytosorb® intervention did not lower mortality (RR [95%-CI]: all studies 1.07 [0.88; 1.31], sepsis 0.98 [0.74; 1.31], CPB surgery 0.91 [0.64; 1.29], severe illness 0.95 [0.59; 1.55], SARS-CoV-2 1.58 [0.50; 4.94]). In patients with cardiac arrest, we found a significant survival advantage of the untreated controls (1.22 [1.02; 1.46]). We did not find significant differences in ICU length of stay, lactate levels, or IL-6 levels after treatment. Of the eligible 34 studies only 12 were randomized controlled trials. All observational studies showed moderate to serious risk of bias. INTERPRETATION: To date, there is no evidence for a positive effect of the CytoSorb® adsorber on mortality across a variety of diagnoses that justifies its widespread use in intensive care medicine.

A multi-faceted approach to sex and gender equity in solid organ transplantation: The Women in Transplantation Initiative of The Transplantation Society.

The advancement of women's careers in transplantation continues to be challenging. Academic careers in both basic and clinical disciplines in transplantation, such as surgery and management of end organ failure in medical specialties, have been underrepresented by diverse genders and ethnicities. Over the last decade, the Women in Transplantation Initiative (WIT) has solidified to becoming an internationally recognized organization with activities focused on diversity and inclusion in terms of the sexes. The WIT organization is divided into 3 pillars that address career advancement and networking (Pillar 1), scientific investigation and presentations on sex and gender in transplantation (Pillar 2) and investigating and facilitating equitable access to transplantation for women throughout the world (Pillar 3). By taking this multipronged approach of collaborating across continents, leveraging virtual platforms for information dissemination and discussion, and providing financial support for research, WIT has become a highly visible grass roots organization that aims to improve the experience of women as transplant professionals as well as transplant donors and recipients.

Induction of ferroptosis selectively eliminates senescent tubular cells.

The accumulation of senescent cells is an important contributor to kidney aging, chronic renal disease, and poor outcome after kidney transplantation. Approaches to eliminate senescent cells with senolytic compounds have been proposed as novel strategies to improve marginal organs. While most existing senolytics induce senescent cell clearance by apoptosis, we observed that ferroptosis, an iron-catalyzed subtype of regulated necrosis, might serve as an alternative way to ablate senescent cells. We found that murine kidney tubular epithelial cells became sensitized to ferroptosis when turning senescent. This was linked to increased expression of pro-ferroptotic lipoxygenase-5 and reduced expression of anti-ferroptotic glutathione peroxidase 4 (GPX4). In tissue slice cultures from aged kidneys low dose application of the ferroptosis-inducer RSL3 selectively eliminated senescent cells while leaving healthy tubular cells unaffected. Similar results were seen in a transplantation model, in which RSL3 reduced the senescent cell burden of aged donor kidneys and caused a reduction of damage and inflammatory cell infiltration during the early post-transplantation period. In summary, these data reveal an increased susceptibility of senescent tubular cells to ferroptosis with the potential to be exploited for selective reduction of renal senescence in aged kidney transplants.

Renal events in patients receiving neprilysin inhibitors: a systematic review and meta-analysis.

BACKGROUND: While it is well known that angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARBs) increase the risk of acute renal failure, the role of neprilysin inhibition (NEPi) is unclear and some physicians are reluctant to prescribe sacubitril/valsartan because of safety concerns. This meta-analysis aimed to examine the risk for renal events, progression of chronic kidney disease (CKD) or progression to dialysis on combined NEPi and ACEi/ARBs compared with ACEi or ARBs. METHODS: We performed a systematic meta-analysis including 17 randomized controlled trials (study drug sacubitril/valsartan or omapatrilat), involving a total of 23 569 patients, after searching PubMed, Cochrane, ClinicalTrials.org and Embase for eligible studies. From the included trials, all renal endpoints, including long- and short-term outcomes and hyperkalemia, were extracted. Pooled odds ratios (ORs) were calculated using the DerSimonian and Laird method. The study was registered at PROSPERO. RESULTS: Overall, treatment with sacubitril/valsartan or omapatrilat showed a slightly lower risk of any renal event [OR 0.82 (0.7-0.97)] compared with treatment with an ACEi or ARB alone. Also, there was a decreased risk of severe acute renal events [OR 0.8 (0.69-0.93)] and a decrease in estimated glomerular filtration rate decline [mean difference -0.58 mL/min (-0.83 to -0.33 mL/min)]. There was no difference in chronic renal events [OR 0.92 (0.8-1.05)] or hyperkalemia [OR 1.02 (0.84-1.23)]. CONCLUSION: NEPi + ACEi/ARBs are safe in terms of renal adverse events. Longer trials focusing on CKD are needed to evaluate the effect of NEPi on decreasing progression of CKD.

Molecular imaging of inflammation crosstalk along the cardio-renal axis following acute myocardial infarction.

Rationale: Acute myocardial infarction (MI) triggers a systemic inflammatory response including crosstalk along the heart-kidney axis. We employed radionuclide-based inflammation-targeted whole-body molecular imaging to identify potential cardio-renal crosstalk after MI in a translational setup. Methods: Serial whole-body positron emission tomography (PET) with the specific CXCR4 ligand 68Ga-Pentixafor was performed after MI in mice. Tracer retention in kidneys and heart was compared to hematopoietic organs to evaluate systemic inflammation, validated by ex vivo analysis and correlated with progressive contractile dysfunction. Additionally, 96 patients underwent 68Ga-Pentixafor PET within the first week after MI, for systems-based image analysis and to determine prognostic value for adverse renal outcome. Results: In mice, transient myocardial CXCR4 upregulation occurred early after MI. Cardiac and renal PET signal directly correlated over the time course (r = 0.62, p < 0.0001), suggesting an inflammatory link between organs. Ex-vivo autoradiography (r = 0.9, p < 0.01) and CD68 immunostaining indicated signal localization to inflammatory cell content. Renal signal at 7d was inversely proportional to left ventricular ejection fraction at 6 weeks after MI (r = -0.79, p < 0.01). In patients, renal CXCR4 signal also correlated with signal from infarct (r = 0.25, p < 0.05) and remote myocardium (r = 0.39, p < 0.0001). Glomerular filtration rate (GFR) was available in 48/96 (50%) during follow-up. Worsening of renal function (GFR loss >5 mL/min/1.73m2), occurred a mean 80.5 days after MI in 16/48 (33.3%). Kaplan-Meier analysis revealed adverse renal outcome for patients with elevated remote myocardial CXCR4 signal (p < 0.05). Multivariate Cox analysis confirmed an independent predictive value (relative to baseline GFR, LVEF, infarct size; HR, 5.27). Conclusion: Systems-based CXCR4-targeted molecular imaging identifies inflammatory crosstalk along the cardio-renal axis early after MI.

Induction of Stress-Induced Renal Cellular Senescence In Vitro: Impact of Mouse Strain Genetic Diversity.

Cellular senescence, a stress-induced state of irreversible cell cycle arrest, is associated with organ dysfunction and age-related disease. While immortalized cell lines bypass key pathways of senescence, important mechanisms of cellular senescence can be studied in primary cells. Primary tubular epithelial cells (PTEC) derived from mouse kidney are highly susceptible to develop cellular senescence, providing a valuable tool for studying such mechanisms. Here, we tested whether genetic differences between mouse inbred strains have an impact on the development of stress-induced cellular senescence in cultured PTEC. Kidneys from 129S1, B6, NOD, NZO, CAST, and WSB mice were used to isolate PTEC. Cells were monitored for expression of typical senescence markers (SA-ß-galactosidase, γ-H2AX+/Ki67-, expression levels of CDKN2A, lamin B1, IL-1a/b, IL-6, G/M-CSF, IFN-g, and KC) at 3 and 10 days after pro-senescent gamma irradiation. Clear differences were found between PTEC from different strains with the highest senescence values for PTEC from WSB mice and the lowest for PTEC from 129S1 mice. PTEC from B6 mice, the most commonly used inbred strain in senescence research, had a senescence score lower than PTEC from WSB and CAST mice but higher than PTEC from NZO and 129S1 mice. These data provide new information regarding the influence of genetic diversity and help explain heterogeneity in existing data. The observed differences should be considered when designing new experiments and will be the basis for further investigation with the goal of identifying candidate loci driving pro- or anti-senescent pathways.

Cellular senescence inhibits renal regeneration after injury in mice, with senolytic treatment promoting repair.

The ability of the kidney to regenerate successfully after injury is lost with advancing age, chronic kidney disease, and after irradiation. The factors responsible for this reduced regenerative capacity remain incompletely understood, with increasing interest in a potential role for cellular senescence in determining outcomes after injury. Here, we demonstrated correlations between senescent cell load and functional loss in human aging and chronic kidney diseases including radiation nephropathy. We dissected the causative role of senescence in the augmented fibrosis occurring after injury in aged and irradiated murine kidneys. In vitro studies on human proximal tubular epithelial cells and in vivo mouse studies demonstrated that senescent renal epithelial cells produced multiple components of the senescence-associated secretory phenotype including transforming growth factor ß1, induced fibrosis, and inhibited tubular proliferative capacity after injury. Treatment of aged and irradiated mice with the B cell lymphoma 2/w/xL inhibitor ABT-263 reduced senescent cell numbers and restored a regenerative phenotype in the kidneys with increased tubular proliferation, improved function, and reduced fibrosis after subsequent ischemia-reperfusion injury. Senescent cells are key determinants of renal regenerative capacity in mice and represent emerging treatment targets to protect aging and vulnerable kidneys in man.

High-intensity interval training in allogeneic adoptive T-cell immunotherapy - a big HIT?

BACKGROUND: Adoptive transfer of virus-specific T cells (VSTs) represents a prophylactic and curative approach for opportunistic viral infections and reactivations after transplantation. However, inadequate frequencies of circulating memory VSTs in the T-cell donor's peripheral blood often result in insufficient enrichment efficiency and purity of the final T-cell product, limiting the effectiveness of this approach. METHODS: This pilot study was designed as a cross-over trial and compared the effect of a single bout (30 min) of high-intensity interval training (HIT) with that of 30 min of continuous exercise (CONT) on the frequency and function of circulating donor VSTs. To this end, we used established immunoassays to examine the donors' cellular immune status, in particular, with respect to the frequency and specific characteristics of VSTs restricted against Cytomegalovirus (CMV)-, Epstein-Barr-Virus (EBV)- and Adenovirus (AdV)-derived antigens. T-cell function, phenotype, activation and proliferation were examined at different time points before and after exercise to identify the most suitable time for T-cell donation. The clinical applicability was determined by small-scale T-cell enrichment using interferon- (IFN-) γ cytokine secretion assay and virus-derived overlapping peptide pools. RESULTS: HIT proved to be the most effective exercise program with up to fivefold higher VST response. In general, donors with a moderate fitness level had higher starting and post-exercise frequencies of VSTs than highly fit donors, who showed significantly lower post-exercise increases in VST frequencies. Both exercise programs boosted the number of VSTs against less immunodominant antigens, specifically CMV (IE-1), EBV (EBNA-1) and AdV (Hexon, Penton), compared to VSTs against immunodominant antigens with higher memory T-cell frequencies. CONCLUSION: This study demonstrates that exercise before T-cell donation has a beneficial effect on the donor's cellular immunity with respect to the proportion of circulating functionally active VSTs. We conclude that a single bout of HIT exercise 24 h before T-cell donation can significantly improve manufacturing of clinically applicable VSTs. This simple and economical adjuvant treatment proved to be especially efficient in enhancing virus-specific memory T cells with low precursor frequencies.

Should kidney allografts from old donors be allocated only to old recipients?

In several deceased donor kidney allocation systems, organs from elderly donors are allocated primarily to elderly recipients. The Eurotransplant Senior Program (ESP) was implemented in 1999, and since then, especially in Europe, the use of organs from elderly donors has steadily increased. The proportion of ≥60-year-old donors reported to the Collaborative Transplant Study (CTS) by European centers has doubled, from 21% in 2000-2001 to 42% in 2016-2017. Therefore, in the era of organ shortage it is a matter of debate whether kidney organs from elderly donors should only be allocated to elderly recipients or whether <65-year-old recipients can also benefit from these generally as "marginal" categorized organs. To discuss this issue, a European Consensus Meeting was organized by the CTS on April 12, 2018, in Heidelberg, in which 36 experts participated. Based on available evidence, it was unanimously concluded that kidney organs from 65- to 74-year-old donors can also be allocated to 55- to 64-year-old recipients, especially if these organs are from donors with no history of hypertension, no increased creatinine, no cerebrovascular death, and no other reasons for defining a marginal donor, such as diabetes or cancer.

SerpinB2 Regulates Immune Response in Kidney Injury and Aging.

BACKGROUND: Expression of SerpinB2, a regulator of inflammatory processes, has been described in the context of macrophage activation and cellular senescence. Given that mechanisms for these processes interact and can shape kidney disease, it seems plausible that SerpinB2 might play a role in renal aging, injury, and repair. METHODS: We subjected SerpinB2 knockout mice to ischemia-reperfusion injury or unilateral ureteral obstruction. We performed phagocyte depletion to study SerpinB2's role beyond the effects of macrophages and transplanted bone marrow from knockout mice to wild-type mice and vice versa to dissect cell type-dependent effects. Primary tubular cells and macrophages from SerpinB2 knockout and wild-type mice were used for functional studies and transcriptional profiling. RESULTS: Cultured senescent tubular cells, kidneys of aged mice, and renal stress models exhibited upregulation of SerpinB2 expression. Functionally, lack of SerpinB2 in aged knockout mice had no effect on the magnitude of senescence markers but associated with enhanced kidney damage and fibrosis. In stress models, inflammatory cell infiltration was initially lower in knockout mice but later increased, leading to an accumulation of significantly more macrophages. SerpinB2 knockout tubular cells showed significantly reduced expression of the chemokine CCL2. Macrophages from knockout mice exhibited reduced phagocytosis and enhanced migration. Macrophage depletion and bone marrow transplantation experiments validated the functional relevance of these cell type-specific functions of SerpinB2. CONCLUSIONS: SerpinB2 influences tubule-macrophage crosstalk by supporting tubular CCL2 expression and regulating macrophage phagocytosis and migration. In mice, SerpinB2 expression seems to be needed for coordination and timely resolution of inflammation, successful repair, and kidney homeostasis during aging. Implications of SerpinB2 in human kidney disease deserve further exploration.

Survival after Kidney Transplantation during Childhood and Adolescence.

BACKGROUND AND OBJECTIVES: Survival in pediatric kidney transplant recipients has improved over the past five decades, but changes in cause-specific mortality remain uncertain. The aim of this retrospective cohort study was to estimate the associations between transplant era and overall and cause-specific mortality for child and adolescent recipients of kidney transplants. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data were obtained on all children and adolescents (aged <20 years) who received their first kidney transplant from 1970 to 2015 from the Australian and New Zealand Dialysis and Transplant Registry. Mortality rates were compared across eras using Cox regression, adjusted for confounders. RESULTS: A total of 1810 recipients (median age at transplantation 14 years, 58% male, 52% living donor) were followed for a median of 13.4 years. Of these, 431 (24%) died, 174 (40%) from cardiovascular causes, 74 (17%) from infection, 50 (12%) from cancer, and 133 (31%) from other causes. Survival rates improved over time, with 5-year survival rising from 85% for those first transplanted in 1970-1985 (95% confidence interval [95% CI], 81% to 88%) to 99% in 2005-2015 (95% CI, 98% to 100%). This was primarily because of reductions in deaths from cardiovascular causes (adjusted hazard ratio [aHR], 0.25; 95% CI, 0.08 to 0.68) and infections (aHR, 0.16; 95% CI, 0.04 to 0.70; both for 2005-2015 compared with 1970-1985). Compared with patients transplanted 1970-1985, mortality risk was 72% lower among those transplanted 2005-2015 (aHR, 0.28; 95% CI, 0.18 to 0.69), after adjusting for potential confounders. CONCLUSIONS: Survival after pediatric kidney transplantation has improved considerably over the past four decades, predominantly because of marked reductions in cardiovascular- and infection-related deaths.

Indoxyl sulfate associates with cardiovascular phenotype in children with chronic kidney disease.

BACKGROUND: Cardiovascular disease is the leading cause of death in children with chronic kidney disease (CKD). Serum levels of gut-derived uremic toxins increase with deterioration of kidney function and are associated with cardiac comorbidities in adult CKD patients. METHODS: Indoxyl sulfate (IS) and p-cresyl sulfate (pCS) were measured by high-performance liquid chromatography in serum of children participating in the Cardiovascular Comorbidity in Children with CKD (4C) Study. Results were correlated with measurements of the carotid intima-media thickness (cIMT), central pulse wave velocity (PWV), and left ventricular mass index (LVMI) in children aged 6-17 years with initial eGFR of 10-60 ml/min per 1.73 m2. RESULTS: The median serum levels of total IS and of pCS, measured in 609 patients, were 5.3 µmol/l (8.7) and 17.0 µmol/l (21.6), respectively. In a multivariable regression model, IS and pCS showed significant positive associations with urea and negative associations with eGFR and uric acid. Furthermore, positive associations of pCS with age, serum albumin, and non-Mediterranean residency and a negative association with glomerular disease were observed. By multivariable regression analysis, only IS was significantly associated with a higher cIMT SDS at baseline and progression of PWV SDS within 12 months, independent of other risk factors. CONCLUSIONS: Serum levels of gut-derived uremic toxins IS and pCS correlated inversely with eGFR in children. Only IS was significantly associated with surrogate markers of cardiovascular disease in this large pediatric CKD cohort.

Functionality and Cell Senescence of CD4/ CD8-Selected CD20 CAR T Cells Manufactured Using the Automated CliniMACS Prodigy® Platform.

Clinical studies using autologous CAR T cells have achieved spectacular remissions in refractory CD19+ B cell leukaemia, however some of the patient treatments with CAR T cells failed. Beside the heterogeneity of leukaemia, the distribution and senescence of the autologous cells from heavily pretreated patients might be further reasons for this. We performed six consecutive large-scale manufacturing processes for CD20 CAR T cells from healthy donor leukapheresis using the automated CliniMACS Prodigy® platform. Starting with a CD4/CD8-positive selection, a high purity of a median of 97% T cells with a median 65-fold cell expansion was achieved. Interestingly, the transduction rate was significantly higher for CD4+ compared to CD8+ T cells and reached in a median of 23%. CD20 CAR T cells showed a good specific IFN-γ secretion after cocultivation with CD20+ target cells which correlated with good cytotoxic activity. Most importantly, 3 out of 5 CAR T cell products showed an increase in telomere length during the manufacturing process, while telomere length remained consistent in one and decreased in another process. In conclusion, this shows for the first time that beside heterogeneity among healthy donors, CAR T cell products also differ regarding cell senescence, even for cells manufactured in a standardised automated process.

Greater Susceptibility for Metabolic Syndrome in Pediatric Solid Organ and Stem Cell Transplant Recipients.

BACKGROUND: Cardiovascular comorbidity is of increasing importance after transplantation. Metabolic syndrome (MS) contributes to the risk for cardiovascular sequelae. Our aim was to assess the risk for MS in pediatric solid organ and stem cell transplant recipients by comparing them with matched untransplanted peers in a multicenter study. METHODS: We prospectively assessed MS in 295 pediatric transplant recipients and compared them with 1475 age- and sex-matched controls. RESULTS: Posttransplant metabolic syndrome (PTMS) was most frequent in lung (43%) and kidney (39%), followed by liver (16%) and stem cell (13%) recipients, compared with nontransplanted peers (4%; P < 0.01). The risk of displaying PTMS was almost 22-fold higher after lung (95% confidence interval, CI, 8.2-57.4), 16-fold higher after kidney (95% CI, 9.1-28.9), 5-fold higher after liver (95% CI, 2.1-10.1), and 4-fold higher after stem cell (95% CI, 1.4-9.5) transplantation. The contribution of individual components leading to MS differed depending on transplant type. In the combined analysis of all transplant groups, older age, less physical activity, calcineurin or mammalian target of rapamycin inhibitor-based immunosuppression, and hypovitaminosis D were associated with PTMS. CONCLUSIONS: By investigating a large group of patients, our study not only shows a high prevalence of PTMS but also identifies kidney and lung transplant patients as being at a particularly high risk. Moreover, knowledge on the factors associated with PTMS allows for individualized treatment approaches as well as potential preventive measures.

Time-dependent p53 inhibition determines senescence attenuation and long-term outcome after renal ischemia-reperfusion.

Inhibition of p53 has been shown to be an efficient strategy for ameliorating kidney ischemia-reperfusion (I/R) injury in experimental models. The therapeutic value of p53 siRNA-based inhibition for I/R in renal transplantation is currently being evaluated in clinical studies. While the major rationale for these studies is the suppression of proapoptotic properties, there are more equally important injury response pathways regulated by p53. A p53-dependent pathway shown to be crucial for renal long-term outcome is cellular senescence. In this study, we tested the hypothesis that p53 siRNA reduces I/R-induced senescence and thereby improves kidney outcome. By comparing the impact of different treatment durations in a mouse model of renal I/R, we found that repetitive administration of p53 siRNA during the first 14 days after I/R reduced the senescence load and ameliorated the postischemic phenotype. Prolonged application of p53 siRNA over a 26-day period after I/R, however, did not provide any additional benefit for senescence reduction but reversed some of the renoprotective effects of the early treatment. These data suggest a time-dependent role of p53 activity supporting the current therapeutic concept of a short-term inhibition, while advocating against a prolonged treatment after I/R.

Equally Interchangeable? How Sex and Gender Affect Transplantation.

Organ transplantation as an option to overcome end-stage diseases is common in countries with advanced healthcare systems and is increasingly provided in emerging and developing countries. A review of the literature points to sex- and gender-based inequity in the field with differences reported at each step of the transplant process, including access to a transplantation waiting list, access to transplantation once waitlisted, as well as outcome after transplantation. In this review, we summarize the data regarding sex- and gender-based disparity in adult and pediatric kidney, liver, lung, heart, and hematopoietic stem cell transplantation and argue that there are not only biological but also psychological and socioeconomic issues that contribute to disparity in the outcome, as well as an inequitable access to transplantation for women and girls. Because the demand for organs has always exceeded the supply, the transplant community has long recognized the need to ensure equity and efficiency of the organ allocation system. In the spirit of equity and equality, the authors call for recognition of these inequities and the development of policies that have the potential to ensure that girls and women have equitable access to transplantation.