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The original SARS-CoV-2 vaccination regimen (2 doses) induces insufficient short-term response in kidney transplant (KT) recipients. This study assessed the response to a third dose and the long-term immunogenicity after 2 doses in KT.We analyzed the dynamics of the humoral and cellular response by monitoring SARS-CoV-2 IgG antibodies against the Spike-protein (IgG-Spike) and QuantiFERON SARS-CoV-2 IFN-γ release assay 6 mo after the second dose (T2) and 28 d after the third dose of mRNA vaccines (T3) to KT and controls (dialysis patients and healthy individuals).At T2, the percentage of IgG-Spike+ KT and dialysis patients decreased (KT 65.8%-52.6%, hemodialysis 92.6-81.5%, and peritoneal dialysis 100%-90%), whereas 100% of healthy controls remained positive. About the cellular response, the percentage of responders decreased in all groups, especially in KT (22.4%-9.2%, P = 0.081). At T3, 92% of KT, 94%-98% of dialysis patients, and 100% of healthy controls were IgG-Spike+. In terms of antibody titers, patients and controls showed a reduction between T2 and T3 and about 80% of dialysis patients and 100% of controls achieved high titers after the third dose (1479.5 Binding Antibody Units/mL), whereas this percentage was only 50% in KT. With respect to the cellular response, only KT displayed a significant rise after the third dose.The third dose of mRNA vaccine improves both humoral and cellular responses, but less effectively in KT compared with dialysis patients and healthy controls.

Objective: To evaluate changes in multimodal retinal imaging of patients with chronic myeloid leukemia. Methods: Observational case series study. All patients underwent a complete ophthalmic examination and were imaged with multimodal imaging before and after therapy for CML. Results: Mean age at diagnosis was 15 years old. All patients were male. The retinal findings at diagnosis were foveal infiltrates in 66.6%, retinal infiltration in 66.6%, venous dilation and arterial tortuosity in 66.6%, retinal hemorrhages in 100%, pre-retinal hemorrhages 33.3%, cotton-wool spots in 66.6%, Roth’s spots in 100%. Mean follow-up was 94.6 weeks (range 20-150 weeks). Regression of LR was completed after 100 days (range 56-170 days), and regression of macular infiltrates, at day 19 (range 17-21 days). Conclusion: MRI can provide relevant information when monitoring clinical response for systemic conditions affecting the eyes. At first, foveal infiltrates tend to disappear once the induction therapy has started. Retinal hemorrhages, vascular dilation, retinal infiltrates, and cotton wool spots tend to gradually disappear associated to the reduction of mature cells into the blood stream and the achievement of a major molecular response (MMR) assessed by TR-PCR.

We evaluated outcomes of 18 patients with isolated extramedullary disease (iEMD) relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) treated with the CD19-directed CAR T cells ARI-0001 in two centers (adult and pediatric), including patients treated in the CART19-BE-01 trial and the consecutive compassionate use program. iEMD was detected by PET-CT in 78% (14/18), and/or by cerebrospinal fluid analysis in 28% (5/18). Patients received cyclophosphamide and fludarabine followed by 1 x 10(6) ARI-0001 cells/kg, initially as a single dose (first patient) and later split into three fractions (10%, 30%, and 60%). Cytokine release syndrome (CRS) occurred in 50% (9/18) of patients, with no cases of grade >= 3 CRS, and 1 case (6%) of grade 1 neurotoxicity. Tocilizumab was used in 6% of patients (1/18). Procedure-related mortality was 0% at 2 years. Objective responses were seen in 94% (95% confidence interval [CI]: 73%-99%) of patients, with complete responses (CR) seen in 78% (95% CI: 52%-94%) of them. Progression-free and overall survival were 49% (95% CI: 30%-79%) and 61% (95% CI: 40%-92%) at 2 years. In conclusion, the use of ARI-0001 cells in patients with R/R ALL and iEMD was associated with a safety and efficacy profile that is comparable with what is observed in patients with marrow involvement and in line with other CART19 products.

Studies are urgently needed to characterize immunogenicity, efficacy, and safety of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines in kidney transplant (KT) recipients, excluded from major clinical trials. Complex ELISPOT and other cellular response techniques have been applied, but simpler tools are needed. An easy-to-use real-world monitoring of SARS-CoV-2 IgG antibodies against the Spike protein and QuantiFERON® SARS-CoV-2 IFNI³ release assay (IGRA) were performed at baseline and 28 days after the second dose in KT recipients and controls (dialysis patients and healthy ones). All healthy controls and >95% dialysis controls became positive for anti-S IgG antibodies, while only 63.3% of KT patients seroconverted with a very low antibody level. A positive IGRA was documented in 96.9% of controls, 89.3% peritoneal dialysis, 77.6% hemodialysis, 61.3% of KT patients transplanted more than 1 year ago and only 36% of those transplanted within the previous 12 months. Overall, 100% of healthy controls, 95.4% of dialysis patients and 78.8% KT recipients developed any immune response (humoral and/or cellular) against SARS-CoV-2. KT patients showed low rates of immune responses to mRNA Coronavirus infectious disease 2019 vaccines, especially those with recent transplantations. Simple humoral and cellular monitoring is advisable, so that repeated doses may be scheduled according to the results.

Children with acute leukaemia (AL) are a high-risk population for infections and life-threatening conditions requiring paediatric intensive care unit (PICU) admission, presenting an increased mortality rate. A few literature exists about PICU outcomes in this kind of patients, especially with haematopoietic stem cell transplant (HSCT) background. We investigated the clinical and epidemiological characteristics of these patients as well as their outcomes. A retrospective, single-centre analytical/observational study was conducted from January 2011 to December 2018 in the PICU of a tertiary care hospital. AL patients from 28 days to 18 years old admitted to the PICU were included, excluding those with histories of HSCT or CAR T-cell therapy. We collected epidemiological and clinical characteristics, laboratory and microbiology results and outcomes. Forty-three patients with AL required urgent admission (35 lymphoblastic and 8 myeloblastic) for 63 different episodes. The main reasons were sepsis (21, 33.3%), hyperleukocytosis (12, 19%), respiratory failure (11, 17.5%) and seizures (8, 12.7%). Nineteen (30.2%) required inotropic support, and fifteen (23.8%) required mechanical ventilation. Three patients died at the hospital (3/43, 6.9%). Sixty-day mortality was 9.3%, and 1-year mortality was 13.9%. There was no differences regarding the type of AL and 60-day mortality (log-rank 2.652, p = 0.103). Conclusion: In our study, the main cause of admission for AL patients was infection, which was associated to more severity and longer hospital admission.

Asparaginase (ASP) is an essential component for the acute lymphoblastic leukemia (ALL) treatment, but toxicities, such as allergy, frequently limit its use. Although the potentially lower PEG-ASP formulation immunogenicity, few studies with conflicting results have compared the allergy incidence between Escherichia coli-ASP and PEG-ASP in the same protocol. We aimed at comparing the allergy incidence in children receiving native E. coli-ASP versus PEG-ASP within the same clinical protocol (Spanish Society of Pediatric Hematology and Oncology ALL-SEHOP-PETHEMA 2013). One hundred and twenty-six children (1-19 years) diagnosed with ALL from 2013 to 2020 were included. Patients in group 1 received a sequential scheme of native E. coli-ASP 10,000 IU/m2 intramuscularly (IM) followed by PEG-ASP 1000 IU/m2 IM. Patients in group 2 received PEG-ASP 1000 IU/m2 IM upfront. Clinical allergy incidence was compared between both groups. Serum ASP activity (SAA) was measured in a subgroup of patients, and silent inactivation was recorded. The cumulative incidence of clinical allergy was significantly higher in group 1 (native followed by PEG-ASP) than in group 2 (PEG-ASP upfront), 24.7% versus 4.1% (p = 0.0085). Adequate ASP activity was achieved with PEG-ASP 1000 IU/m2 dose in most patients (median SAA 412.5 and 453.0 IU/L at days 7 and 14). The incidence of silent inactivation in PEG-ASP upfront patients was very low. PEG-ASP-used upfront was associated with a lower incidence of clinical allergy than that observed in the sequential use of native E. coli-ASP followed by PEG-ASP. PEG-ASP at 1000 IU/m2 was effective in achieving enough ASP activity in most patients.

Background Post-transplantation diabetes mellitus (PTDM) might be preventable. Methods This open-label, multicenter randomized trial compared 133 kidney transplant recipients given intermediate-acting insulin isophane for postoperative afternoon glucose ≥140 mg/dl with 130 patients given short-acting insulin for fasting glucose ≥200 mg/dl (control). The primary end point was PTDM (antidiabetic treatment or oral glucose tolerance test-derived 2 hour glucose ≥200 mg/dl) at month 12 post-transplant. Results In the intention-to-treat population, PTDM rates at 12 months were 12.2% and 14.7% in treatment versus control groups, respectively (odds ratio [OR], 0.82; 95% confidence interval [95% CI], 0.39 to 1.76) and 13.4% versus 17.4%, respectively, at 24 months (OR, 0.71; 95% CI, 0.34 to 1.49). In the per-protocol population, treatment resulted in reduced odds for PTDM at 12 months (OR, 0.40; 95% CI, 0.16 to 1.01) and 24 months (OR, 0.54; 95% CI, 0.24 to 1.20). After adjustment for polycystic kidney disease, per-protocol ORs for PTDM (treatment versus controls) were 0.21 (95% CI, 0.07 to 0.62) at 12 months and 0.35 (95% CI, 0.14 to 0.87) at 24 months. Significantly more hypoglycemic events (mostly asymptomatic or mildly symptomatic) occurred in the treatment group versus the control group. Within the treatment group, nonadherence to the insulin initiation protocol was associated with significantly higher odds for PTDM at months 12 and 24. Conclusions At low overt PTDM incidence, the primary end point in the intention-to-treat population did not differ significantly between treatment and control groups. In the per-protocol analysis, early basal insulin therapy resulted in significantly higher hypoglycemia rates but reduced odds for overt PTDM-a significant reduction after adjustment for baseline differences-suggesting the intervention merits further study.Clinical Trial registration number: NCT03507829.

Non-adherence to treatment is a known factor for uncontrolled hypertension. We hypothesized that the detection of non-adherence to antihypertensive treatment plus the implementation of a specific nursing program would ameliorate treatment adherence and blood pressure (BP) control.An interventional, prospective, randomized, study of 44 consecutively attended patients (age 58.1±12.9yr, 30 men/14 women) with 24h-BP ≥130/80 mmHg while receiving ≥2 antihypertensive drugs was performed. Partially or fully non-adherent patients (confirmed by urine determination of antihypertensives) were randomized (1:1) to receive a specific 3 month nursing program (group I) to improve adherence - evaluation of knowledge on BP goals, complications of high BP, indicated treatment; detection of causes of non-compliance and proposal of measures to improve it, with fortnightly follow-up -, or to routine follow-up (group C). Urine antihypertensives and 24h-BP were determined at baseline, 3 and 12 months. Baseline office SBP/DBP (mmHg) was 150.4±16.3 / 91.1±15.5, and the number of prescribed non-detected drugs was 2±1.4. Between-groups differences in variation (Δ) of BP at 3 and 12 months are shown (Table). In addition, at 3 months, the percentage of patients with controlled BP was 50%( 11 of 22) and 18.2% (4 of 22) in the I and C groups, respectively (p=0.026), and at 12 months was 60% (12 of 20) and 26.3% (5 of 19), respectively (p=0.034).In conclusion, a specific 3 month nursing intervention improves control of BP in patients with uncontrolled hypertension and inadequate therapeutic compliance. Both the BP decrease and the improvement in therapeutic adherence were maintained at 12 months.

We evaluated the administration of ARI-0001 cells (chimeric antigen receptor T cells targeting CD19) in adult and pediatric patients with relapsed/refractory CD19+ malignancies. Patients received cyclophosphamide and fludarabine followed by ARI-0001 cells at a dose of 0.4–5 × 106 ARI-0001 cells/kg, initially as a single dose and later split into 3 fractions (10%, 30%, and 60%) with full administration depending on the absence of cytokine release syndrome (CRS). 58 patients were included, of which 47 received therapy: 38 with acute lymphoblastic leukemia (ALL), 8 with non-Hodgkin’s lymphoma, and 1 with chronic lymphocytic leukemia. In patients with ALL, grade ≥3 CRS was observed in 13.2% (26.7% before versus 4.3% after the amendment), grade ≥3 neurotoxicity was observed in 2.6%, and the procedure-related mortality was 7.9% at day +100, with no procedure-related deaths after the amendment. The measurable residual disease-negative complete response rate was 71.1% at day +100. Progression-free survival was 47% (95% IC 27%–67%) at 1 year: 51.3% before versus 39.5% after the amendment. Overall survival was 68.6% (95% IC 49.2%–88%) at 1 year. In conclusion, the administration of ARI-0001 cells provided safety and efficacy results that are comparable with other academic or commercially available products. This trial was registered as ClinicalTrials.gov: NCT03144583 .

BACKGROUND AND AIMS Frailty is associated with a higher rate of complications and mortality after kidney transplantation (KT). Physical frailty phenotype (PFP) is the most used frailty instrument among KT recipients, it comprises five criteria and classifies patients as frail if they have ≥3. We aimed to determine the impact of scoring 1 PFP criterion (mild frailty) on transplant outcomes. METHOD We have prospectively followed 449 KT candidates evaluated for frailty by PFP at the time of inclusion on the KT waiting list. Patients were classified as follows: 0, robust; 1, pre-frail-1; 2, pre-frail-2; and ≥3, frail. A prospective longitudinal study was performed in all patients in the cohort who underwent KT. Clinical outcomes and survival after transplantation according to frailty status at listing was assessed. RESULTS About 71.3% of total listed cohort resulted to be pre-frail (one criterion 41%, two criteria 19.8%) or frail (10.5%). Disparities were observed between sexes, with 5.2% of men and 21.9% of women being frail (P CONCLUSION Frailty is frequent in KT candidates, more frequent in women than men. Frail patients have less chances to receive a KT. KT candidates are frequently listed with one (out of five) frailty criterion, and this has an independent impact on patient survival after KT. A pre-transplant clinical framework for multimodal prehabilitation interventions to mitigate the effects of frailty and poor fitness after KT may be justified even in mildly pre-frail candidates.

Frailty is associated with poorer outcomes among patients waiting for kidney transplantation (KT). Several different tools to measure frailty have been used; however, their predictive value is unknown. This is a prospective longitudinal study of 449 KT candidates evaluated for frailty by the Physical Frailty Phenotype (PFP) and the FRAIL scale. During the study period, 296 patients received a KT, while 153 remained listed. Patients who did not get receive a transplant were more frequently frail according to PFP (16.3 vs. 7.4%, p = 0.013). Robust patients had fewer hospital admissions during the 1st year after listing (20.8% if PFP = 0 vs. 43.4% if ≥1, and 27.1% if FRAIL = 0 vs. 48.9% if ≥1) and fewer cardiovascular events (than FRAIL ≥ 1) or major infectious events (than PFP ≥ 1). According to PFP, scoring 1 point had an impact on patient survival and chance of transplantation in the univariate analysis. The multivariable analysis corroborated the result, as candidates with PFP ≥ 3 had less likelihood of transplantation (HR 0.45 [0.26–0.77]). The FRAIL scale did not associate with any of these outcomes. In KT candidates, pre-frailty and frailty according to both the PFP and the FRAIL scale were associated with poorer results while listed. The PFP detected that frail patients were less likely to receive a KT, while the FRAIL scale did not.

Children with acute leukaemia (AL) are a high-risk population for infections and life-threatening conditions requiring paediatric intensive care unit (PICU) admission, presenting an increased mortality rate. A few literature exists about PICU outcomes in this kind of patients, especially with haematopoietic stem cell transplant (HSCT) background. We investigated the clinical and epidemiological characteristics of these patients as well as their outcomes. A retrospective, single-centre analytical/observational study was conducted from January 2011 to December 2018 in the PICU of a tertiary care hospital. AL patients from 28 days to 18 years old admitted to the PICU were included, excluding those with histories of HSCT or CAR T-cell therapy. We collected epidemiological and clinical characteristics, laboratory and microbiology results and outcomes. Forty-three patients with AL required urgent admission (35 lymphoblastic and 8 myeloblastic) for 63 different episodes. The main reasons were sepsis (21, 33.3%), hyperleukocytosis (12, 19%), respiratory failure (11, 17.5%) and seizures (8, 12.7%). Nineteen (30.2%) required inotropic support, and fifteen (23.8%) required mechanical ventilation. Three patients died at the hospital (3/43, 6.9%). Sixty-day mortality was 9.3%, and 1-year mortality was 13.9%. There was no differences regarding the type of AL and 60-day mortality (log-rank 2.652, p = 0.103).Conclusion: In our study, the main cause of admission for AL patients was infection, which was associated to more severity and longer hospital admission. What is Known: • Acute leukaemia is the most common childhood cancer. Admission to a paediatric intensive care unit is required in 30% of children with acute leukaemia. • Regarding the outcomes of children with acute leukaemia that require admission to the intensive care unit data are scarce. What is New: • Mortality in acute leukaemia patients admitted to the paediatric intensive care unit is lower than that of patients with a history of stem cell therapy but higher than that of patients with solid tumours. • The main reason for admission was sepsis, which is related in literature to more severity and long length of stay.

The GenoDiabMar registry is a prospective study that aims to provide data on demographic, biochemical, and clinical changes in type 2 diabetic (T2D) patients attending real medical outpatient consultations. This registry is also used to find new biomarkers related to the micro- and macrovascular complications of T2D, with a particular focus on diabetic nephropathy. With this purpose, longitudinal serum and urine samples, DNA banking, and data on 227 metabolomics profiles, 77 immunoglobulin G glycomics traits, and other emerging biomarkers were recorded in this cohort. In this study, we show a detailed longitudinal description of the clinical and analytical parameters of this registry, with a special focus on the progress of renal function and cardiovascular events. The main objective is to analyze whether there are differential risk factors for renal function deterioration between sexes, as well as to analyze cardiovascular events and mortality in this population. In total, 650 patients with a median age of 69 (14) with different grades of chronic kidney disease—G1–G2 (eGFR > 90–60 mL/min/1.73 m2) 50.3%, G3 (eGFR; 59–30 mL/min/1.73 m2) 31.4%, G4 (eGFR; 29–15 mL/min/1.73 m2) 10.8%, and G5 (eGFR < 15 mL/min/1.73 m2) 7.5%—were followed up for 4.7 (0.65) years. Regardless of albuminuria, women lost 0.93 (0.40–1.46) fewer glomerular filtration units per year than men. A total of 17% of the participants experienced rapid deterioration of renal function, 75.2% of whom were men, with differential risk factors between sexes—severe macroalbuminuria > 300 mg/g for men OR [IQ] 2.40 [1.29:4.44] and concomitant peripheral vascular disease 3.32 [1.10:9.57] for women. Overall mortality of 23% was detected (38% of which was due to cardiovascular etiology). We showed that kidney function declined faster in men, with different risk factors compared to women. Patients with T2D and kidney involvement have very high mortality and an important cardiovascular burden. This cohort is proposed as a great tool for scientific collaboration for studies, whether they are focused on T2D, or whether they are interested in comparing differential markers between diabetic and non-diabetic populations.

The GenoDiabMar registry is a prospective study aims to provide data on demographic, biochemical and clinical changes, from a “real-world” population of Type 2 DM (T2D) patients. This registry is addressed to find new biomarkers related to the micro and macrovascular complications of T2D, especially focused on diabetic nephropathy. The registry includes longitudinal serum and urine samples, DNA bank, as well as data on 227 metabolomics profiles, 77 Immunoglobulin G glycomics traits and others emerging biomarkers. 650 patients aged 69.56 ±9.31 with different grades of chronic kidney disease; (G1-2 50.3%, G3 31.4%, G4 10.8% and G5 7.5%) were followed up for 4.96 (±0.43) years. Regardless of albuminuria, women lost 0.93 (0.40-1.46) glomerular filtration units per year less than men. 17% of the participant experienced rapid progression of renal function, 75.2% men, with differential risk factors between sexes; severe macroalbuminuria >300mg/g for men OR[IQ] 2.40 [1.29:4.44] and concomitant peripheral vascular disease 3.32 [1.10:9.57] for women. An overall mortality of 23% was detected (38% due to Cardiovascular aetiology).This cohort is postulated as a great tool for scientific collaboration for studies, whether they are focused on T2D, or whether they are interested in comparing differential markers between diabetic and non-diabetic populations.

Children with acute leukaemia (AL) are a high-risk population for infections and life-threatening conditions requiring paediatric intensive care unit (PICU) admission, presenting an increased mortality rate. A few literature exists about PICU outcomes in this kind of patients, especially with haematopoietic stem cell transplant (HSCT) background. We investigated the clinical and epidemiological characteristics of these patients as well as their outcomes. A retrospective, single-centre analytical/observational study was conducted from January 2011 to December 2018 in the PICU of a tertiary care hospital. AL patients from 28 days to 18 years old admitted to the PICU were included, excluding those with histories of HSCT or CAR T-cell therapy. We collected epidemiological and clinical characteristics, laboratory and microbiology results and outcomes. Forty-three patients with AL required urgent admission (35 lymphoblastic and 8 myeloblastic) for 63 different episodes. The main reasons were sepsis (21, 33.3%), hyperleukocytosis (12, 19%), respiratory failure (11, 17.5%) and seizures (8, 12.7%). Nineteen (30.2%) required inotropic support, and fifteen (23.8%) required mechanical ventilation. Three patients died at the hospital (3/43, 6.9%). Sixty-day mortality was 9.3%, and 1-year mortality was 13.9%. There was no differences regarding the type of AL and 60-day mortality (log-rank 2.652, p = 0.103).Conclusion: In our study, the main cause of admission for AL patients was infection, which was associated to more severity and longer hospital admission. What is Known: • Acute leukaemia is the most common childhood cancer. Admission to a paediatric intensive care unit is required in 30% of children with acute leukaemia. • Regarding the outcomes of children with acute leukaemia that require admission to the intensive care unit data are scarce. What is New: • Mortality in acute leukaemia patients admitted to the paediatric intensive care unit is lower than that of patients with a history of stem cell therapy but higher than that of patients with solid tumours. • The main reason for admission was sepsis, which is related in literature to more severity and long length of stay.

Frailty is common among advanced chronic kidney disease (CKD) patients who are kidney transplant (KT) candidates, and predisposes to poor outcomes after transplantation. However, frailty is not routinely measured during pretransplant work-up and it is unknown which metric should be used in this specific population. Our aim was to establish frailty prevalence in KT candidates according to different frailty scales.Prospective longitudinal study of 451 KT candidates evaluated for frailty by both Physical Frailty Phenotype (PFP) and FRAIL scale at the time of inclusion on the KT waiting list. Clinical and functional characteristics including sociodemographics, comorbidities, disability and nutritional status were recorded. Agreement between PFP and FRAIL scales as well as dissonant patients were analyzed.Mean age was 60.9 years and 31.7% were female. Comorbidity burden among patients was high, with 36.9% and 16.2% presenting with diabetes and ischemic coronary disease, respectively. Disabilities were also frequent. More than 70% of patients presented with ≥ 1 PFP criteria while this percentage for ≥ 1 FRAIL criteria was 45.4%. Agreement between PFP and FRAIL was not good (kappa index 0.317). There were 132 patients who were pre-frail or frail according to PFP but non-frail according to the FRAIL scale and they presented with fewer comorbidities and less disability.Frailty is frequent in advanced CKD patients, although its prevalence may vary according to different scales. Agreement between PFP and FRAIL scale is not good, and FRAIL scale might misclassify as robust patients those frail/prefrail patients who are in better health conditions.

Background: Since the beginning of SARS-CoV-2 pandemic, it has been widely recognized that children and adolescents seem to have milder clinical courses as compared to adult counterparts. However, there is concern that vulnerable collectives including pediatric patients treated for cancer or under immunosuppression may be at higher risk. Methods: We retrospectively collected Spanish COVID-19 cases in children and adolescents with solid and hematological malignancies, non-malignant chronic hematologic conditions, and post allogeneic-stem cell transplantation, from the beginning of the pandemic on January 31 to April 24, 2020. Results: We included 47 cases with RT-PCR positive COVID-19 from 41 centers in Spain, where 97.6% of pediatric patients are treated for cancer. In most cases (76.6%), infection was asymptomatic, or symptoms were mild. Severe illness was observed in 14.9% of cases with respiratory distress and/or hypoxemia, and 8.5% required admission to the PICU. Symptomatic patients received supportive care associated with antiviral and immunomodulatory agents depending upon severity. Anticancer therapy was withhold in the majority of cases during the infection course. Most patients recovered from COVID-19. Two deaths were reported. Conclusion: In our cohort, most children receiving anticancer chemotherapy presented a mild clinical course and had a good outcome. Highly immunosuppressed patients with major comorbidities were at higher risk of severe infections. Among this fragile collective, individualized expert discussion is critical for anti-infectious therapy and appropriate anticancer treatment.

We evaluated the administration of ARI-0001 cells (chimeric antigen receptor T cells targeting CD19) in adult and pediatric patients with relapsed/refractory CD19(+) malignancies. Patients received cyclophosphamide and fludarabine followed by ARI-0001 cells at a dose of 0.4–5 × 10(6) ARI-0001 cells/kg, initially as a single dose and later split into 3 fractions (10%, 30%, and 60%) with full administration depending on the absence of cytokine release syndrome (CRS). 58 patients were included, of which 47 received therapy: 38 with acute lymphoblastic leukemia (ALL), 8 with non-Hodgkin’s lymphoma, and 1 with chronic lymphocytic leukemia. In patients with ALL, grade ≥3 CRS was observed in 13.2% (26.7% before versus 4.3% after the amendment), grade ≥3 neurotoxicity was observed in 2.6%, and the procedure-related mortality was 7.9% at day +100, with no procedure-related deaths after the amendment. The measurable residual disease-negative complete response rate was 71.1% at day +100. Progression-free survival was 47% (95% IC 27%–67%) at 1 year: 51.3% before versus 39.5% after the amendment. Overall survival was 68.6% (95% IC 49.2%–88%) at 1 year. In conclusion, the administration of ARI-0001 cells provided safety and efficacy results that are comparable with other academic or commercially available products. This trial was registered as ClinicalTrials.gov: NCT03144583.

Background and Aims Protocol biopsies following kidney transplantation (KT) allow the histological diagnosis of antibody-mediated rejection (ABMR) with stable renal function (RF). Controversy arises when considering isolated proteinuria as a clinical biomarker. Currently, there is no effective treatment for ABMR and transplant units may decide on treatment independently of the clinical expression. Method KT recipients (1987-2017) with post-KT biopsies (2008-2018) showing ABMR graft lesions (category 2-Banff’2015) >1year post-KT were included. Cases were grouped into phenotypes of ABMR according to the clinical picture at biopsy : 1) acute RF impairment (↑creatinine >15% three weeks before biopsy) with/without proteinuria and with/without DSA detection. 2) sub-acute RF impairment (↑creatinine >15% six months before biopsy) with/without proteinuria and with/without DSA detection, 3) performed for DSA detection with stable RF and no proteinuria or 4) protocol biopsy, with stable RF, no proteinuria or DSA detection. We considered an additional category: 5) isolated proteinuria (↑>500 mg or x2 six months before biopsy). Categories 1), 2) and 5) were considered clinical ABMR. Categories 3) and 4) were considered subclinical ABMR. We aimed to evaluate graft outcomes in the different ABMR phenotypes. Results In a cohort of 105 KT recipients with histologic lesions of ABMR, biopsies corresponded to phenotypes 1) in 35 (33%), 2) 10 (9,5%), 3) 21 (20,3%), 4) 14 (13,4%) and y 5) in 25 23,8%). No differences between clinical and subclinical ABMR were found in baseline characteristics except for donors ‘age, who were older within the clinical group (51.8±18.8 vs. 43.88 ±16.1; p=0.04). At time of biopsy, subclinical had better RF than clinical ABMR (creatinine 1.3±0.4 mg/dl vs. 2.2±1.1 mg/dl; p=0.02) and less proteinuria (161 mg/g [IQR 93-269] vs 939 mg/g [IQR 412-2000]; p=0.001) Graft survival was worse in those patients with acute and sub-acute RF impairment, followed by those with isolated proteinuria (Figure 1). In comparison to subclinical ABMR, those with RF impairment and isolated proteinuria had an increased risk of graft lost; HR 9.4 (95% IC 2.2-40.7, p=0.002) and 4.8 (95% IC 1.01-23.2, P=0.05) respectively. DSA detection in these groups did not impact graft survival. Specific treatment was not different among groups, except for steroid pulses, which were more frequently applied in cases of ABMR with clinical manifestation. Conclusion The clinical phenotypes of ABMR influence long-term graft survival independently from treatment. Understanding graft evolution according to clinical phenotype at the time of histologic diagnosis should guide the therapeutic strategy, to balance risk-benefit ratio.

Classical immunosuppression based on steroids, calcineurin inhibitors, and mycophenolate results in several unwanted effects and unsatisfactory long-term outcomes in kidney transplantation (KT). New immunosuppressors search for fewer adverse events and increased graft survival but may have a distinct impact on graft function and immunological biomarkers according to their mechanism of action. This prospective study evaluates the immunological effect of tacrolimus to serine/threonine protein kinase mechanistic target of rapamycin inhibitors (mTORi) conversion in 29 KT recipients compared with 16 controls maintained on tacrolimus. We evaluated renal function, human leukocyte antigen (HLA) antibodies and peripheral blood lymphocyte subsets at inclusion and at 3, 12, and 24 months later. Twenty immunophenotyped healthy subjects served as reference. Renal function remained stable in both groups with no significant change in proteinuria. Two patients in the mTORi group developed HLA donor-specific antibodies and none in the control group (7% vs. 0%, p = 0.53). Both groups showed a progressive increase in regulatory T cells, more prominent in patients converted to mTORi within the first 18 months post-KT (p &lt, 0.001). All patients showed a decrease in na&iuml, ve B cells (p &lt, 0.001), excepting those converted to mTORi without receiving steroids (p = 0.31). Transitional B cells significantly decreased in mTORi patients (p &lt, 0.001), independently of concomitant steroid treatment. Finally, CD56bright and CD94/NK group 2 member A receptor positive (NKG2A+) Natural Killer (NK) cell subsets increased in mTORi- compared to tacrolimus-treated patients (both p &lt, 0.001). Patients switched to mTORi displayed a significant redistribution of peripheral blood lymphocyte subpopulations proposed to be associated with graft outcomes. The administration of steroids modified some of these changes.

There is scarce information regarding the complete renin-angiotensin-aldosterone system (RAAS) and its changes after bariatric surgery (BS) in patients with morbid obesity (MO). Objective: to analyze changes (Δ) in RAAS components in MO after BS at several follow-up time points. Methods: Fifty-five MO patients (78% women, 40% hypertensives, age 43.4±8.9yr, BMI 42.4±5.3Kg/m 2 ) were evaluated prospectively before and 1,3,6 and 12 months(m) after BS, with assessment of anthropometrics, RAAS components and 24h-systolic BP (SBP). Results: at 12m body weight (-35.1±9.7 Kg) and waist circumference (-27±9.2 cm) decreased (p There were correlations (p Conclusions: there are sequential changes in several components of the RASS after BS, with an increase in ACE and ACE2 activity as early as 1m after BS that lasts until 6m, and a decrease in PRA and plasma Aldosterone that initiates at 3m and remains 12m after BS. These changes correlate with the decrease of 24h-SBP. RAAS components, but not body weight, appear to correlate with changes in BP after BS.

Aim: to study changes in central and peripheral 24h-BP, as well as in estimated glomerular filtration rate (eGFR) and albuminuria (Alb), 12 months after bariatric surgery (BS). Methods: Sixty-two patients (39% hypertensives) with severe obesity (BMI 42.7±5.6 Kg/m 2 ) were evaluated prospectively before (0) and 1,3,6 and 12 months after undergoing BS. Peripheral and central BP parameters were determined by the Mobil-O-Graph device. Renal function was evaluated by eGFR and Alb. Generalized estimation equations were used to evaluate repeated measures in the variables analyzed. Results: at 12 months weight (-35.7±9.9 Kg) and waist circumference (-27 ± 9.2 cm) decreased (p0 , variation (Δ) of weight, Δ Ald and having or not HT at baseline, the only significant covariables in Δ 24h-SBP and Δ day-SBP were previous HT and Δweight. There was a decrease in eGFR (mean,95%CI: -5.6 mL/min/1.73m 2 , -9.4 to -1.8, p=0.005) and Alb (Z=-2.04,p=0.042). According to the constructed variance analysis models, the Δ Alb was dependent on Alb 0 and on Δ night-SBP, but not on the baseline hypertensive state, on the Δ eGFR nor on the Δweight (adjusted r 2 =0.606). Δ eGFR was independent of baseline eGFR and Δ weight. Conclusions: patients with morbid obesity significantly reduce heart rate and 24h- and day- SBP, both central and peripheral, 12 months after undergoing BS. In addition, there is a significant decrease in plasma Ald, eGFR and Alb.

Significant differences have been reported over the years in measuring physiological levels of free circulating serotonin (f5-HT) in platelet-poor plasma (PPP). This work shows that there are crucial pre-analytical factors in sample manipulation that can provoke an artifactual release of 5-HT from platelets, and that, even when the sample is accurately processed to obtain PPP, f5-HT levels are approximately 2.8 times higher than those of f5-HT in blood. An alternative methodology consisting of ex vivo blood microdialysis coupled to high-performance liquid chromatography–electrochemical detection is proposed and validated. It is considered the most accurate technique to measure physiological circulating f5-HT and its metabolite 5-hydroxyindoleacetic acid (f5-HIAA), owing to its sensitivity (limits of quantification of 0.08 ng/mL) and reliability since there is no sample manipulation. The f5-HT and f5-HIAA levels in blood and in PPP were studied in control subjects, hypertensive and end-stage renal disease patients, who have a deregulated serotonergic system. This work reveals that blood is the best matrix to determine f5-HT concentrations, and the clinical relevance of the accuracy of f5-HT determination is discussed. Copyright © 2014 John Wiley & Sons, Ltd.

Anti-HLA donor-specific antibodies (DSA) identified by single antigen bead array (SAB) are questioned for their excess in sensitivity and lack of event prediction after transplantation. Population and methods We retrospectively evaluated specific types of preformed DSA (class I, class II or C1q-fixing) and their impact on graft survival. Kidney transplantations performed across negative CDC-crossmatch were included (n = 355). Anti-HLA antibodies were tested using SAB to identify DSA and their capacity to fix C1q. Results Twenty-eight patients with pretransplant DSA + with MFI > 2000 were selected to assess C1q fixation. DSA were C1q + in 15 patients and C1q- in 13, without significant differences in demographics, acute rejection, graft loss or renal function. The maximum MFI of DSA in patients with C1q-fixing DSA was significantly higher (p = 0.008). Patients with DSA class-I suffered more antibody-mediated rejection (AMR) and had worse graft survival than class-II. The capacity of DSA I to fix C1q did not correlate with rejection, graft function or graft loss. Conclusions C1q testing in pretransplant sera with DSA was unable to predict acute antibody-mediated rejection or early graft loss, but the presence of DSA class I compared to DSA only class II did. Despite non-fixing complement in vitro, pretransplant C1q-negative DSA I can mediate rejection and graft loss.

Resumen Introducción: La malnutrición en la enfermedad renal crónica (ERC) está asociada al aumento del riesgo de mortalidad y complicaciones. Sin embargo, el estado nutricional de los pacientes con ERC en lista de espera (LE) de trasplante renal (TR), y su relación con el estado de fragilidad ha sido poco evaluado. Objetivo: Analizar el estado nutricional y funcional de una cohorte de pacientes en lista de espera de trasplante renal y su relación con la fragilidad. Pacientes y Método: Estudio retrospectivo de los pacientes incluidos en LE de TR desde Junio 2016 hasta Junio 2017. Se evaluaron a los pacientes mediante distintas escalas de valoración, recogiendo parámetros antropométricos, analíticos y de bioimpedanciometría (BCM). Resultados: De los 177 pacientes incluidos, 55 (31.1%) se definieron como frágiles. Dicho grupo eran de mayor edad (64.2 vs 61.2 años; p=0.08), sexo femenino (56.4% vs 32.8%, p

Summary Background and objectives Data are needed to assess safety and efficacy of the 2009 pandemic influenza A H1N1 vaccine in renal patients. Design, setting, participants, & measurements We prospectively evaluated seroconversion, predictors of response, and vaccine safety in renal patients. Hemagglutination inhibition tests to detect serum antibodies against a new influenza A-H1N1 virus were performed in 79 transplant patients, 48 hemodialysis patients, and 15 healthy workers before and 1 month after vaccination. Healthy controls and 88 of 127 renal patients were vaccinated. Seroconversion was defined as at least 2 dilutions increase in titer. Results We excluded 19 individuals seroprotected (≥1/40) against the novel H1N1 in the initial sample. Efficacy rate in the 96 vaccinated individuals was 43.7% (42 of 96 seroconverted versus four of 27 nonvaccinated patients, P = 0.007). For vaccinated subgroups, efficacy was 41.8% in transplant patients (P = 0.039 versus nonvaccinated), 33.3% in hemodialysis patients (P = 0.450), and 81.8% in controls. Healthy controls showed better response to vaccine than transplant (P = 0.021) and dialysis (P = 0.012) patients. For the transplant subgroup, longer time after transplantation (P = 0.028) was associated with seroconversion, but no influence was found for age, gender, renal function, or immunosuppression. In the hemodialysis subgroup, younger age was associated with response (55.7 ± 20.8 versus 71.6 ± 10.1 years, P = 0.042), but other specific variables, including Kt/V or time on dialysis, were not. No serious adverse events were reported, and kidney function was stable. Conclusion The novel influenza A 2009 H1N1 vaccine was safe in renal patients, although administration of a single dose of adjuvanted vaccine induced a poor response in these patients.

Aim: To compare the efficacy and safety between two therapeutic strategies to reduce 24h-SBP in patients with resistant hypertension: renal denervation or the addition of spironolactone. Methods: Twenty-one patients with office-SBP ≥150 mmHg and 24h-SBP≥140 mmHg despite receiving ≥3 full-dose antihipertensive drugs, one a diuretic, but without aldosterone antagonists, were randomized to renal denervation (by Simplicity®) or to spironolactone (25-50 mg), as add-on therapy. Changes in both office- (3 averaged readings) and 24h- BP (by Spacelabs®-90207) were evaluated at 6 months. Comparisons between treatment groups were performed using analysis of variance adjusted by age, gender and baseline values. Results: mean age was 62.7 ± 7.6 yr; men: 61.9% (13 of 21); diabetes: 47,6% (10 of 21). Mean BMI: 32.3 ± 6.1 Kg/m 2 . Duration of hypertension: 13.4 ± 7.2 yr. Number of antihypertensive drugs: 4,1 ± 0,7. Mean office-BP: 167,5 ± 20,1 / 91,7 ± 12,4 mmHg. Mean 24h-BP: 151,8 ± 9,1 / 81,7 ± 8,4 mmHg. Baseline characteristics were not different between groups (p=NS for all). Comparison between groups of main changes over time is shown in Table. Reduction of 24h-SBP was higher in the spironolactone group after adjusting by age, sex and baseline 24h-SBP (p=0.016). Reduction of eGFR was higher in the spironolactone group after adjusting by baseline eGFR (p=0.033). Conclusions: 1) As compared to renal denervation, spironolactone was more effective to reduce 24h-SBP after 6 months in patients with resistant hypertension. These differences were not significant as regards office-BP. 2) Spironolactone add-on treatment significantly decreased eGFR as compared to renal denervation treatment.

Background Atheromatous disease (AD) is a risk factor for death in renal patients. Traditional CV risk factors do not predict the presence of AD in this population. The aim of this study is to analyze whether the etiology of the primary renal disease influences in the risk of having silent AD. Study design Observational cross-sectional study in chronic kidney disease patients without previous cardiovascular events. Settings and Participants 2436 CKD subjects without any previous CV event included in the prospective Spanish multicenter NEFRONA study. Patients were classified according to primary renal disease: diabetic nephropathy (n = 347), vascular nephropathy (n = 476), systemic/glomerular disease (n = 447), tubulointerstitial and drug toxicity nephropathy (n = 320), polycystic kidney disease (n = 238), non-filiated nephropathy (n = 406) and other causes (n = 202). Predictors B-mode and Doppler ultrasonography analysis of the carotid arteries were performed to measure intima media thickness (IMT) and the presence of plaques. Clinical and laboratory parameters related to CV risk were also determined. Outcomes AD was scored according with the ultrasonography findings and the ankle-brachial index into two large groups: absence or incipient AD and severe AD. Results In multivariate regression analysis, older age (OR 1.09/year [1.088–1.108]), smoking habit (OR 2.10 [1.61–2.74]), male gender (OR 1.33 [1.09–1.64]), grade-5D of CKD (OR 2.19 [1.74–2.74]), and diabetic nephropathy (OR 2.59 [1.93–3.48]) are independent risk factors for severe AD. The prevalence of silent AD was highest for diabetic nephropathy with grade-5D of CKD (82.2%) and lowest with stages 2–3 CKD systemic/glomerular disease (36.6%). Limitations Observational study with the potential for confounding. Conclusion In CKD patients without any CV event in the background clinical history, diabetic nephropathy as primary renal disease is the most significant factor associated to severe silent AD. Furthermore, this difference was independent of other conventional risk factors for atherosclerosis and CV events.

Resumen Introduccion La practica clinica habitual nos muestra la gran variabilidad existente en las formas de tratar una misma patologia, asi como en los recursos utilizados y resultados obtenidos. Las vias clinicas constituyen una herramienta util para disminuir dicha variabilidad, ajustar los recursos y aumentar la calidad en la atencion de los pacientes. En el presente estudio presentamos nuestra experiencia y resultados de la implantacion de la via clinica para cirugia colorrectal electiva disenada con el fin de aplicarla en un hospital general basico. Pacientes y metodos Un total de 43 pacientes fueron intervenidos de forma programada de patologia colorrectal durante el periodo de febrero a diciembre de 2002. Los objetivos del presente estudio fueron: 1) elaboracion e implantacion de la via clinica de cirugia colorrectal electiva a todos los pacientes susceptibles; 2) definicion de criterios, indicadores, estandares de calidad y su evaluacion, y 3) mejora de la informacion al paciente. Resultados Se incluyo el 100% de los pacientes susceptibles de entrar en la via clinica para cirugia colorrectal electiva. La aparicion de complicaciones (28%; estandar Conclusiones Las vias clinicas constituyen un compromiso multidisciplinario pero de costosa implantacion en los actuales sistemas sanitarios de atencion al paciente. A pesar de las dificultades en su implantacion, estamos convencidos de que constituyen un sistema de control de calidad de dicha atencion, disminuyendo la variabilidad de la practica clinica, y aumentando la atencion personalizada y la informacion al paciente sobre su enfermedad. La mayor parte de los indicadores analizados en la via clinica se han aproximado a los estandares fijados previamente. Creemos necesario mejorar el porcentaje de entrega de hojas informativas graficas al paciente, la medicion de EVA, asi como el porcentaje de EVA inferior a 4 como criterio de eficacia analgesica.

Significant differences have been reported over the years in measuring physiological levels of free circulating serotonin (f5-HT) in platelet-poor plasma (PPP). This work shows that there are crucial pre-analytical factors in sample manipulation that can provoke an artifactual release of 5-HT from platelets, and that, even when the sample is accurately processed to obtain PPP, f5-HT levels are approximately 2.8 times higher than those of f5-HT in blood. An alternative methodology consisting of ex vivo blood microdialysis coupled to high-performance liquid chromatography-electrochemical detection is proposed and validated. It is considered the most accurate technique to measure physiological circulating f5-HT and its metabolite 5-hydroxyindoleacetic acid (f5-HIAA), owing to its sensitivity (limits of quantification of 0.08 ng/mL) and reliability since there is no sample manipulation. The f5-HT and f5-HIAA levels in blood and in PPP were studied in control subjects, hypertensive and end-stage renal disease patients, who have a deregulated serotonergic system. This work reveals that blood is the best matrix to determine f5-HT concentrations, and the clinical relevance of the accuracy of f5-HT determination is discussed.

Living donor kidney transplantation has become the option of preference for the treatment of endstage renal disease, whenever its performance is possible. The advantages of patient and graft survival should be balanced with risks associated with donation. Therefore, the evaluation of candidates for living donor kidney transplantation is mainly the comprehensive evaluation of these risks: medical, psychological, social and economic. Evaluating risks implies we are treating a controversial process, the medical progress, which is modifiable with time, even in the family and/or social environment of the donor-receptor couple. Short and long-term safety of living donor nephrectomy is directly engaged to the existence of a healthy donor. This he is the main objective of standard evaluation of candidates. Currently, with a growing demand of this option, minor abnormalities or risk factors detected during evaluation do not always become a formal contraindication, but we should try to establish a most objective threshold for the acceptance of donors in all evaluated spheres, for surgical risks and others directly related or not with renal mass reduction, and even for those engaged to the existence of a genetic link between donor and receptor, which might determine the presence of any future primary renal disease. As for other donation types, the process of evaluation should also ensure minimal risks for the receptor, with the same safety criteria applied to cadaver donors. We can conclude that careful evaluation of candidates for living kidney donation is the best guarantee for their safety and transplant success, and, in our opinion, it is the best instrument to offer an adequate informed consent.