Physical activity and its impact on cardiovascular health in pediatric kidney transplant recipients.

BACKGROUND: Cardiovascular (CV) morbidity after kidney transplantation (KTx) in childhood is of increasing importance. In light of a high prevalence of CV risk factors, protective measures such as physical activity (PA) come into focus. Our aim was to comprehensively assess PA in pediatric KTx recipients and evaluate its impact on CV health. METHODS: Forty-eight patients were assessed for frequency, duration, intensity, and setting of PA using the "Motorik-Modul" PA questionnaire. Walking-based activity was measured by accelerometer in a subgroup (n = 23). CV risk factors and subclinical CV organ damage were determined. The impact of PA on CV parameters was analyzed using linear regression models. RESULTS: Fifty-two percent of pediatric KTx recipients did not reach WHO recommended PA level; 54% did not engage in PA with vigorous intensity (VPA). Twenty-nine percent indicated an extremely inactive lifestyle (< 120 min/week of moderate to vigorous intensity PA, MVPA). Compared to the healthy German KiGGS cohort, KTx recipients specifically lacked engagement in sport activities (KTx: 129 min/week; 95%CI, 97-162 vs. KiGGS, 242 min/week; 95%CI, 230-253). VPA was associated with lower systolic blood pressure (p = 0.024) and resting heart rate (p = 0.005), MVPA with fewer components of the post-transplant metabolic syndrome (p = 0.037), and better left ventricular diastolic function (p = 0.006). CONCLUSIONS: A considerable lack of PA, especially VPA, exists in young KTx recipients. PA was positively associated with important parameters of CV health. While long-term CV protection through PA seems promising in pediatric KTx recipients, specific educational approaches are most likely needed to increase patients' engagement in sport activities.

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.

Arterial stiffness and blood pressure increase in pediatric kidney transplant recipients.

BACKGROUND: Pulse wave velocity (PWV) is a measure of arterial stiffness. We investigated PWV and blood pressure (BP) to determine to what extent BP changes contribute to arterial stiffness, and secondly, to identify influencing factors on BP in children after kidney transplantation. METHODS: Seventy children ≥ 2.5 years post-transplantation with at least two PWV measurements were included. Changes of systolic (Δ SBP) and diastolic BP (Δ DBP) were classified into "stable/decreasing," "1-10 mmHg increase," and " > 10 mmHg increase." Linear mixed modeling for PWV z-score (PWVz) adjusted either for Δ SBP or Δ DBP was performed. An extended dataset with monthly entries of BP, immunosuppression, and creatinine was obtained in 35 participants over a median of 74 months to perform linear mixed modeling for SBP and DBP. RESULTS: PWVz increased with a rate of 0.11/year (95% CI 0.054 to 0.16). Compared to participants with stable BP, those with 1-10-mmHg SBP and DBP increase showed a higher PWVz of 0.59 (95% CI 0.046 to 1.13) and 0.86 (95% CI 0.43 to 1.30), respectively. A > 10-mmHg BP increase was associated with an even higher PWVz (SBP ß = 0.78, 95% CI 0.22 to 1.34; DBP ß = 1.37, 95% CI 0.80 to 1.94). Female sex and participants with lower eGFR showed higher PWVz. In the extended analysis, DBP was positively associated with cyclosporin A and everolimus trough levels. CONCLUSIONS: A higher increase of PWV is seen in patients with greater BP increase, with higher cyclosporin A and everolimus trough levels associated with higher BP. This emphasizes the role of BP as a modifiable risk factor for the improvement of cardiovascular outcome after transplantation. A higher resolution version of the Graphical abstract is available as Supplementary information.

Findings from 4C-T Study demonstrate an increased cardiovascular burden in girls with end stage kidney disease and kidney transplantation.

Mortality in children with kidney failure is higher in girls than boys with cardiovascular complications representing the most common causes of death. Pulse wave velocity (PWV), a measure of vascular stiffness, predicts cardiovascular mortality in adults. Here, PWV in children with kidney failure undergoing kidney replacement therapy was investigated to determine sex differences and potential contributing factors. Two-hundred thirty-five children (80 girls; 34%) undergoing transplantation (150 pre-emptive, 85 with prior dialysis) having at least one PWV measurement pre- and/or post-transplantation from a prospective cohort were analyzed. Longitudinal analyses (median/maximum follow-up time of 6/9 years) were performed for PWV z-scores (PWVz) using linear mixed regression models and further stratified by the categories of time: pre-kidney replacement therapy and post-transplantation. PWVz significantly increased by 0.094 per year and was significantly higher in girls (PWVz +0.295) compared to boys, independent of the underlying kidney disease. During pre-kidney replacement therapy, an average estimated GFR decline of 4 ml/min/1.73 m2 per year was associated with a PWVz increase of 0.16 in girls only. Higher diastolic blood pressure and low density lipoprotein were independently associated with higher PWVz during pre-kidney replacement therapy in both sexes. In girls post-transplantation, an estimated GFR decline of 4ml/min/1.73m2 per year pre-kidney replacement therapy and a longer time (over 12 months) to transplantation were significantly associated with higher PWVz of 0.22 and of 0.57, respectively. PWVz increased further after transplantation and was positively associated with time on dialysis and diastolic blood pressure in both sexes. Thus, our findings demonstrate that girls with advanced chronic kidney disease are more susceptible to develop vascular stiffening compared to boys, this difference persist after transplantation and might contribute to higher mortality rates seen in girls with kidney failure.

Telomere length is associated with intima-media thickness in pediatric liver transplant patients: A prospective cohort study.

Leukocyte telomere length (LTL) is a marker for biological age. Pediatric liver transplant recipients show a high rate of subclinical atherosclerosis, indicated by elevated intima-media thickness (IMT). We hypothesized that atherosclerosis is associated with biological age in these patients and investigated the course of LTL over time. We measured LTL from peripheral blood leukocytes by quantitative polymerase chain reaction and IMT from 97 pediatric patients after liver transplantation in a prospective cohort study. Of the patients, 71% (n = 69) had two or more assessments (total, 228 observations; median follow-up, 1.1 years). Lower LTL was associated with higher IMT (ß = -0.701, p = 0.01) and higher aspartate aminotransferase (ß = -0.001, p = 0.02), adjusted for age, sex, and age at transplantation. Of the patients, 45% showed decreasing LTL over time, whereas 55% exhibited stable LTL. Patients with stable LTL showed a decrease in IMT (median, -0.02 mm/year) and a decrease of tacrolimus trough levels (median, -0.08 µg/L/year). LTL is associated with IMT independent of age in pediatric liver transplant patients, suggesting that early aging contributes to the high burden of subclinical cardiovascular damage and may furthermore negatively affect the graft.

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.

Safety and efficacy of the Seraph® 100 Microbind® Affinity Blood Filter to remove bacteria from the blood stream: results of the first in human study.

BACKGROUND: Bacterial burden as well as duration of bacteremia influence the outcome of patients with bloodstream infections. Promptly decreasing bacterial load in the blood by using extracorporeal devices in addition to anti-infective therapy has recently been explored. Preclinical studies with the Seraph® 100 Microbind® Affinity Blood Filter (Seraph® 100), which consists of heparin that is covalently bound to polymer beads, have demonstrated an effective binding of bacteria and viruses. Pathogens adhere to the heparin coated polymer beads in the adsorber as they would normally do to heparan sulfate on cell surfaces. Using this biomimetic principle, the Seraph® 100 could help to decrease bacterial burden in vivo. METHODS: This first in human, prospective, multicenter, non-randomized interventional study included patients with blood culture positive bloodstream infection and the need for kidney replacement therapy as an adjunctive treatment for bloodstream infections. We performed a single four-hour hemoperfusion treatment with the Seraph® 100 in conjunction with a dialysis procedure. Post procedure follow up was 14 days. RESULTS: Fifteen hemodialysis patients (3F/12 M, age 74.0 [68.0-78.5] years, dialysis vintage 28.0 [11.0-45.0] months) were enrolled. Seraph® 100 treatment started 66.4 [45.7-80.6] hours after the initial positive blood culture was drawn. During the treatment with the Seraph® 100 with a median blood flow of 285 [225-300] ml/min no device or treatment related adverse events were reported. Blood pressure and heart rate remained stable while peripheral oxygen saturation improved during the treatment from 98.0 [92.5-98.0] to 99.0 [98.0-99.5] %; p = 0.0184. Four patients still had positive blood culture at the start of Seraph® 100 treatment. In one patient blood cultures turned negative during treatment. The time to positivity (TTP) was increased between inflow and outflow blood cultures by 36 [- 7.2 to 96.3] minutes. However, overall TTP increase was not statistical significant. CONCLUSIONS: Seraph® 100 treatment was well tolerated. Adding Seraph® 100 to antibiotics early in the course of bacteremia might result in a faster resolution of bloodstream infections, which has to be evaluated in further studies. TRAIL REGISTRATION: ClinicalTrials.gov Identifier: NCT02914132 , first posted September 26, 2016.

Clinical and biochemical endpoints and predictors of response to plasma exchange in septic shock: results from a randomized controlled trial.

BACKGROUND: Recently, a randomized controlled trial (RCT) demonstrated rapid but individually variable hemodynamic improvement with therapeutic plasma exchange (TPE) in patients with septic shock. Prediction of clinical efficacy in specific sepsis treatments is fundamental for individualized sepsis therapy. METHODS: In the original RCT, patients with septic shock of < 24 h duration and norepinephrine (NE) requirement ≥ 0.4 µg/kg/min received standard of care (SOC) or SOC + one single TPE. Here, we report all clinical and biological endpoints of this study. Multivariate mixed-effects modeling of NE reduction was performed to investigate characteristics that could be associated with clinical response to TPE. RESULTS: A continuous effect of TPE on the reduction in NE doses over the initial 24 h was observed (SOC group: estimated NE dose reduction of 0.005 µg/kg/min per hour; TPE group: 0.018 µg/kg/min per hour, p = 0.004). Similarly, under TPE, serum lactate levels, continuously decreased over the initial 24 h in the TPE group, whereas lactate levels increased under SOC (p = 0.001). A reduction in biomarkers and disease mediators (such as PCT (p = 0.037), vWF:Ag (p < 0.001), Angpt-2 (p = 0.009), sTie-2 (p = 0.005)) along with a repletion of exhausted protective factors (such as AT-III (p = 0.026), Protein C (p = 0.012), ADAMTS-13 (p = 0.008)) could be observed in the TPE but not in the SOC group. In a multivariate mixed effects model, increasing baseline lactate levels led to greater NE dose reduction effects with TPE as opposed to SOC (p = 0.004). CONCLUSIONS: Adjunctive TPE is associated with the removal of injurious mediators and repletion of consumed protective factors altogether leading to preserved hemodynamic stabilization in refractory septic shock. We identified that baseline lactate concentration as a potential response predictor might guide future designing of large RCTs that will further evaluate TPE with regard to hard endpoints. Trial registration Retrospectively registered 18th January 2020 at clinicaltrials.gov (Identifier: NCT04231994 ).

Students' age and parental level of education influence COVID-19 vaccination hesitancy.

Widespread vaccination in pursuit of herd immunity has been recognized as the most promising approach to ending the global pandemic of coronavirus disease 19 (COVID-19). The vaccination of children and adolescents has been extensively debated and the first COVID-19 vaccine is now approved in European countries for children aged > 12 years of age. Our study investigates vaccination hesitancy in a cohort of German secondary school students. We assessed 903 students between age 9 and 20 in the period between 17 May 2021 and 30 June 2021. 68.3% (n = 617) reported intention to undergo COVID-19 vaccination, while 7% (n = 62) did not want to receive the vaccine and 15% (n = 135) were not yet certain. Age and parental level of education influenced COVID-19 vaccine hesitancy. Children under the age of 16 as well as students whose parents had lower education levels showed significantly higher vaccine hesitancy.  Conclusion: Identifying subsets with higher vaccination hesitancy is important for targeting public information campaigns in support of immunization. What is Known: • The willingness to receive COVID-19 vaccination among adults in Europe is about 70%, but data for children and adolescents is lacking. • The lack of immunization in younger cohorts represents a significant barrier to achieving herd immunity, and also leaves children and adolescents vulnerable to acute and long-term morbidity from natural COVID-19 infections. What is New: • Intention-to-vaccinate among children and adolescents is high (~ 70%); conversely, vaccination hesitancy is low. • Age and parental level of education influenced COVID-19 vaccine hesitancy among children and adolescents.

Impact of Sex and Obesity on Echocardiographic Parameters in Children and Adolescents.

Subclinical alterations in left ventricular structure and function are detectable in adolescents with hypertension or obesity. However, data on early echocardiographic abnormalities in seemingly healthy children are lacking. Sex differences in cardiac structure and function have been previously reported, but sex-specific reference values are not available. Specifically, the potential interaction of sex and overweight has not been addressed at all. Anthropometric data, blood pressure and exercise tests were obtained in 356 healthy children. Echocardiographic parameters comprised peak early (E) and late (A) mitral inflow Doppler velocities, E/A ratio, tissue Doppler peak velocities of early (e') and late diastolic (a') excursion of mitral/septal annulus and isovolumetric relaxation time (IVRT). Left ventricular mass index (LVMI) and LVMI z-score were calculated. Interaction terms between BMI and sex and stratification by sex were used for analysis. We provide values for echocardiographic parameters for children of two age groups separated by BMI. Overweight/obese children had a significant higher LVMI, lower E/A ratio, higher E/e' ratios and a longer IVRT. For a given BMI in the upper ranges we demonstrated a higher LVMI in girls than in boys, the IVRT extended significantly more in girls than in boys with increasing BMI. There are sex differences in structural and functional echocardiographic parameters in children and adolescents. Our data not only confirms the importance of overweight and obesity, but demonstrates important interactions between sex and overweight. The greater susceptibility of overweight girls toward echocardiographic changes associated with potential long-term functional impairment needs further exploration and follow-up.Trial registration number DRKS00012371; Date 18.08.2017.

[Insulin autoimmune syndrome : A rare, but important differential diagnosis of hypoglycemia]. / Insulinautoimmunsyndrom : Eine seltene, aber wichtige Differentialdiagnose der Hypoglykämie.

A 69-year-old female patient was referred to the Medical University of Hanover for further diagnostic evaluation of recurrent severe hypoglycemia. The patient had previously been started on clopidogrel after arterial stenting for peripheral arterial obstructive disease (PAOD). The presence of an insulinoma and paraneoplastic syndrome was excluded. Increased serum insulin and insulin autoantibodies levels were confirmed, despite normal to low blood sugar levels. An insulin autoimmune syndrome was diagnosed, most likely induced by the prior intake of clopidogrel. Treatment with immunoadsorption was initiated, achieving a significant reduction in hypoglycemic events and a lasting response to treatment over 3 months.

Effect of Therapeutic Plasma Exchange on Immunoglobulin Deficiency in Early and Severe Septic Shock.

BACKGROUND: Deficiency of immunoglobulins of the classes IgG, IgG1, IgA and IgM is associated with severity of disease and mortality in sepsis and septic shock. Therapeutic plasma exchange (TPE) with fresh frozen plasma (FFP) has recently gained attention as an adjunctive therapeutic option in early septic shock. We hypothesized that TPE might modulate immunoglobulin deficiencies besides sole elimination of circulating injurious molecules. METHODS: We conducted a prospective single center study with TPE in 33 patients with early septic shock (onset < 12 h) requiring high doses of norepinephrine (NE > 0.4µg/kg/min). Clinical and biochemical data, including measurement of immunoglobulin subgroups IgG, IgG1, IgM and IgA were obtained before and after TPE. The following immunoglobulin cut-off values were used to analyze subgroups with low immunoglobulin concentrations at baseline (IgG ≤ 6.5, IgG1 ≤ 3, IgM ≤ 1.5 and IgA ≤ 0.35 g/L). RESULTS: At inclusion, median (IQR) SOFA score was 18 (15-20) and NE dose was 0.8 (0.6-1.2) µg/kg/min. The majority of patients demonstrated profound reductions in immunoglobulins levels of all classes. Globally, immunoglobulin levels were not significantly changed after a single TPE session. However, in patients with low baseline immunoglobulin levels a significant increase in all classes was observed (IgG 1.92 (0.96-3) g/L (+41%), IgG1 2.1 (1.46-2.32) g/L (+96%), IgA 0.44 (0.12-0.62) g/L (59%) and IgM 0.18 (0.14-0.34) g/L (+55%), p < 0.001 for comparison to patients above cut-off). CONCLUSIONS: The majority of early and severe septic shock patients had reduced immunoglobulin levels and a single TPE could attenuate immunoglobulin deficiencies of all classes. The clinical relevance of this observation has to be investigated in a proper designed trial.

Clinical outcomes after ABO-incompatible renal transplantation: a systematic review and meta-analysis.

BACKGROUND: ABO-incompatible renal transplantation (ABOi-rTx) is increasingly used to overcome organ shortage. Evidence about its non-inferiority in comparison with ABO-compatible renal transplantation (ABOc-rTx) needs to be analysed at early and late timepoints. We aimed to investigate differences in outcome after ABOi-rTX and ABOc-rTX. METHODS: We did a systematic review and meta-analysis of observational studies published up until Dec 31, 2017, that reported outcome data (≥1 year of follow-up) after ABOi-rTx and included an ABO-compatible control group, by searching the Cochrane Central Register of Controlled Trials (CENTRAL), Embase Ovid, MEDLINE Ovid, and PubMed. Trials on recipients of ABOi-rTx were assessed, if an ABO-compatible control group was included and if outcome data on at least graft or recipient survival with 1 year or more of follow-up were available. Exclusion criteria included case reports, editorials, reviews and letters, animal studies, meeting papers, studies unable to extract data, non-renal solid organ and bone-marrow transplant studies, and deceased donor ABOc-rTx. Data were extracted from published reports. Primary endpoints were all-cause mortality and graft survival at 1, 3, 5, and more than 8 years after transplantation. In the meta-analysis, we used a fixed-effects model if the I2 value was 0, and both a fixed-effects and random-effects model if I2 was more than 0. This study is registered with PROSPERO, number CRD42018094550. FINDINGS: 1264 studies were screened and 40 studies including 49 patient groups were identified. 65 063 patients were eligible for analysis, 7098 of whom had undergone ABOi-rTx. Compared with ABOc-rTx, ABOi-rTx was associated with significantly higher 1-year mortality (odds ratio [OR] 2·17 [95% CI 1·63-2·90], p<0·0001; I2=37%), 3 years (OR 1·89 [1·46-2·45], p<0·0001; I2=29%), and 5 years (OR 1·47 [1·08-2·00], p=0·010; I2=68%) following transplantation. Death-censored graft survival was lower with ABOi-rTx than with ABOc-rTx at 1 year (OR 2·52 [1·80-3·54], p<0·0001; I2=61%) and 3 years (OR 1·59 [1·15-2·18], p=0·0040; I2=58%) only. Graft losses were equivalent to that of ABOc-rTx after 5 years and patient survival after 8 years. No publication bias was detected and the results were robust to trial sequential analysis until 5 years after transplantation; thereafter, data became futile or inconclusive. INTERPRETATION: Despite progress in desensitisation protocols and optimisation of ABOi-rTx procedures, excess mortality and loss of kidney grafts was found compared with ABOc-rTx within the first 3 years after transplantation. Only long-term outcomes after 5 years yielded equivalent survival rates and organ function. Awareness of the increased risks of infection, organ rejection, and bleeding could improve care of patients and promote efforts towards paired kidney exchange programmes. FUNDING: None.

Effect of therapeutic plasma exchange on endothelial activation and coagulation-related parameters in septic shock.

BACKGROUND: A dysbalanced coagulation system is part of the pathological host response to infection in sepsis. Activation of pro-coagulant pathways and attenuation of anti-coagulant activity ultimately lead to microvascular stasis and consequent organ failure. No treatment approaches specifically targeting this axis are available. We explored the effects of therapeutic plasma exchange (TPE) on microvascular coagulation dysbalance in septic shock. METHODS: We conducted a prospective single-center study enrolling 31 patients with early septic shock (onset < 12 h) requiring high doses of norepinephrine (NE > 0.4 µg/kg/min). Clinical and biochemical data, including measurement of protein C; a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS13); and von Willebrand factor antigen (vWF:Ag), were obtained before and after TPE against fresh frozen plasma. RESULTS: Antithrombotic acting proteins such as antithrombin-III (ATIII) and protein C were markedly reduced in septic patients, but their activity increased after TPE (ATIII, 51% (41-61) vs. 63% (48-70), p = 0.029; protein C, 47% (38-60) vs. 62% (54-69), p = 0.029). Median ADAMTS13 activity was increased by TPE from 27 (21-42) % before to 47 (38-62) % after TPE (p < 0.001). In contrast, vWF:Ag was elevated and could be reduced by TPE (353 (206-492) IU/dL vs. 170 (117-232) IU/dL, p < 0.001). Regression analysis yielded a correlation between ADAMTS13 activity and platelet count (p = 0.001, R2 = 0.316). CONCLUSIONS: Septic shock was associated with activation of pro-coagulant pathways and simultaneous depletion of anti-coagulant factors. TPE partially attenuated this dysbalance by removing pro- and by replacing anti-coagulant factors. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03065751. Retrospectively registered on 28 February 2017.

Sex and age as determinants for high blood pressure in pediatric renal transplant recipients: a longitudinal analysis of the CERTAIN Registry.

BACKGROUND: High prevalence of arterial hypertension is known in pediatric renal transplant patients, but how blood pressure (BP) distribution and control differ between age groups and whether sex and age interact and potentially impact BP after transplantation have not been investigated. METHODS: This retrospective analysis included 336 pediatric renal transplant recipients (62% males) from the Cooperative European Pediatric Renal Transplant Initiative Registry (CERTAIN) with complete BP measurement at discharge and 1, 2 and 3 years post-transplant. RESULTS: At discharge and 3 years post-transplant, arterial hypertension was highly prevalent (84% and 77%); antihypertensive drugs were used in 73% and 68% of the patients. 27% suffered from uncontrolled and 9% from untreated hypertension at 3 years post-transplant. Children transplanted at age < 5 years showed sustained high systolic BP z-score and received consistently less antihypertensive treatment over time. Younger age, shorter time since transplantation, male sex, higher body mass index (BMI), high cyclosporine A (CSA) trough levels, and a primary renal disease other than congenital anomalies of the kidney and urinary tract (CAKUT) were significantly associated with higher systolic BP z-score. Sex-stratified analysis revealed a significant association between high CSA and higher systolic BP in older girls that likely had started puberty already. An association between BP and estimated glomerular filtration rate was not detected. CONCLUSIONS: BP control during the first 3 years was poor in this large European cohort. The description of age- and sex-specific risk profiles identified certain recipient groups that may benefit from more frequent BP monitoring (i.e. young children) or different choices of immunosuppression (i.e. older girls).

Therapeutic plasma exchange in acute on chronic liver failure.

BACKGROUND: Acute on chronic liver failure (ACLF) has been identified as a distinct syndrome due to acute decompensation of liver cirrhosis accompanied by extra-hepatic organ failure, primarily caused by an overwhelming systemic immune response. Therapeutic plasma exchange (TPE) has been demonstrated in a randomized controlled trial to improve transplant free survival in acute liver failure. Here we investigated if TPE might have comparable beneficial effects in patients with ACLF. METHODS: Thirty-one patients with ACLF that were treated with TPE were enrolled into this retrospective analysis and 1:1 matched to an ACLF cohort treated with standard medical therapy (SMT) only. RESULTS: Patients considered for a bridge to recovery (n = 21 each group) approach had a 30-day mortality >90% that was not improved by TPE (P = .185). Deaths occurred in the SMT group at significant earlier time points compared to the patients treated with TPE (mortality at 5 days: 33.3% for TPE and 66.7% for SMT, P = .048). However, patients who received TPE as a bridge to transplant strategy (n = 10) survived in 60% of cases and demonstrated 24 hours after study inclusion a stabilization of organ dysfunction (organ failures at inclusion: 4 (3-5) vs 24 hours after inclusion: 3 (2-4), P = .031 and CLIF-C-ACLF score: 64 (49-76) vs 54 (49-66), P = .043) not seen in SMT patients. CONCLUSIONS: Although these retrospective data need to be interpreted with caution, they suggest that TPE in ACLF patients is feasible but not suitable as a bridge to recovery strategy. In selected patients TPE might assist as bridge to transplant.

Acute kidney injury and adverse renal events in patients receiving SGLT2-inhibitors: A systematic review and meta-analysis.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2is) represent a new class of oral hypoglycemic agents used in the treatment of type 2 diabetes mellitus. They have a positive effect on the progression of chronic kidney disease, but there is a concern that they might cause acute kidney injury (AKI). METHODS AND FINDINGS: We conducted a systematic review and meta-analysis of the effect of SGLT2is on renal adverse events (AEs) in randomized controlled trials and controlled observational studies. PubMed, EMBASE, Cochrane library, and ClinicalTrials.gov were searched without date restriction until 27 September 2019. Data extraction was performed using a standardized data form, and any discrepancies were resolved by consensus. One hundred and twelve randomized trials (n = 96,722) and 4 observational studies with 5 cohorts (n = 83,934) with a minimum follow-up of 12 weeks that provided information on at least 1 adverse renal outcome (AKI, combined renal AE, or hypovolemia-related events) were included. In 30 trials, 410 serious AEs due to AKI were reported. SGLT2is reduced the odds of suffering AKI by 36% (odds ratio [OR] 0.64 [95% confidence interval (CI) 0.53-0.78], p < 0.001). A total of 1,089 AKI events of any severity (AEs and serious AEs [SAEs]) were published in 41 trials (OR 0.75 [95% CI 0.66-0.84], p < 0.001). Empagliflozin, dapagliflozin, and canagliflozin had a comparable benefit on the SAE and AE rate. AEs related to hypovolemia were more commonly reported in SGLT2i-treated patients (OR 1.20 [95% CI 1.10-1.31], p < 0.001). In the observational studies, 777 AKI events were reported. The odds of suffering AKI were reduced in patients receiving SGLT2is (OR 0.40 [95% CI 0.33-0.48], p < 0.001). Limitations of this study are the reliance on nonadjudicated safety endpoints, discrepant inclusion criteria and baseline hypoglycemic therapy between studies, inconsistent definitions of renal AEs and hypovolemia, varying follow-up times in different studies, and a lack of information on the severity of AKI (stages I-III). CONCLUSIONS: SGLT2is reduced the odds of suffering AKI with and without hospitalization in randomized trials and the real-world setting, despite the fact that more AEs related to hypovolemia are reported.

High Burden of Subclinical Cardiovascular Target Organ Damage After Pediatric Liver Transplantation.

Cardiovascular (CV) events account for 8%-13% of deaths after liver transplantation (LT) in adulthood. Although CV risk factors (RFs) are present, little is known about the prevalence of subclinical CV target organ damage (TOD) in children after LT. The aim of this prospective observational study was to assess the prevalence of subclinical CV TOD in children after LT and to identify RFs contributing to CV damage as potential targets for clinical intervention. In this study, 104 children after LT (54% female, 46% male; aged 11.5 ± 3.8 years) underwent cross-sectional assessment of subclinical TOD by carotid-femoral pulse wave velocity (PWV), carotid intima-media thickness (IMT), and left ventricular mass index (LVMI). Results were correlated with the presence of CV RFs (obesity, hypertension, dyslipidemia, renal impairment, anemia, and microinflammation). Of the patients, 22% were exposed to 2 CV RFs, and 36% displayed 3 or more CV RFs. Pathological results for PWV, IMT, and LVMI were found in 21.9%, 57.0%, and 11.1% of patients, respectively. In the multivariate analysis, diastolic blood pressure (P = 0.01) and estimated glomerular filtration rate (eGFR; P = 0.03) were independently associated with PWV, eGFR (P = 0.005), and age at LT (P = 0.048) with IMT and body mass index with LVMI (P = 0.004). In conclusion, patients after pediatric LT carry a substantial burden of subclinical CV TOD. Identification of modifiable CV RFs opens opportunities for targeted intervention in order to reduce CV morbidity and mortality in the future.

Therapeutic plasma exchange in acute liver failure.

BACKGROUND: Multi-organ dysfunction in acute liver failure (ALF) has been attributed to a systemic inflammatory response directly triggered by the injured liver. High-volume therapeutic plasma exchange (HV-TPE) has been demonstrated in a large randomized controlled trial to improve survival. Here, we investigated if a more cost-/ resource effective low-volume (LV) TPE strategy might have comparable beneficial effects. METHODS: This retrospective study evaluated the effect of LV-TPE on remote organ failure, hemodynamical and biochemical parameters as well as on survival in patients with ALF. Twenty patients treated with LV-TPE in addition to standard medical therapy (SMT) were identified and 1:1 matched to a historical ALF cohort treated with SMT only. Clinical and biochemical parameters were recorded at admission to the intensive care unit and the following 7 days after LV-TPE. RESULTS: Mean arterial pressure increased following first LV-TPE treatments (d0: 68 [61-75] mm Hg vs d7: 88 [79-98] mm Hg, P = .003) and norepinephrine dose was reduced (d0: 0.264 [0.051-0.906] µg/kg/min vs d3: 0 [0-0.024] µg/kg/min, P = .016). Multi-organ dysfunction was significantly diminished following LV-TPE (CLIF-SOFA d0: 17 [13-20] vs d7: 7 [3-11], P = .001). Thirty-day in-hospital survival was 65% in the LV-TPE cohort and 50% in the SMT cohort (Hazard-ratio for TPE: 0.637; 95% CI: 0.238-1.706, P = .369). CONCLUSIONS: Patients treated with LV-TPE showed improved surrogate parameters comparable with the effects reported with HV-TPE. These data need to be interpreted with caution due to their retrospective character. Future controlled studies are highly desirable.

Renal transplant recipients receiving loop diuretic therapy have increased urinary tract infection rate and altered medullary macrophage polarization marker expression.

Loop diuretics deplete the renal cortico-medullary salt gradient that has recently been established as a major modulator of immune responses. Renal transplant recipients suffer from a markedly increased rate of urinary tract infections (UTIs). Whether diuretic therapy affects renal macrophage polarization in the human kidney graft and the incidence of UTI have not been reported. In a cohort of 112 adult renal allograft recipients, loop diuretic therapy significantly correlated with the rate of UTI during five years after transplantation in uni- and multivariable regression analysis. The M1 macrophage marker human leukocyte antigen-DR (HLA-DR) and the M2 macrophage marker CD206 co-localized with the pan-macrophage marker CD68 in the kidney graft. Both were more common in renal medulla than cortex. With increasing loop diuretic dose, the renal medullary M1/M2 macrophage marker ratio decreased in early surveillance biopsies of this cohort. In vitro, the sodium chloride concentration dose-dependently increased monocyte chemotactic cytokine CCL2 production in human myeloid and renal tubular epithelial cells. More CCL2 was detected in the renal medulla than cortex of the kidney grafts. However, in patients receiving loop diuretic therapy, the renal cortico-medullary CCL2 gradient was diminished and CCL2 serum levels decreased significantly. Thus, diuretic therapy associated with increased bacteriuria and leukocyturia after kidney transplantation and a decreased M1/M2 macrophage marker ratio in the renal medulla. Hence, adjustment of diuretic therapy should be investigated further as a possible approach in patients with frequent UTIs.