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BACKGROUND AND HYPOTHESIS: Persons with chronic kidney disease (CKD) are at increased risk of adverse events, early mortality, and multimorbidity. A detailed overview of adverse event types and rates from a large CKD cohort under regular nephrological care is missing. We generated an interactive tool to enable exploration of adverse events and their combinations in the prospective, observational German CKD (GCKD) study. METHODS: The GCKD study enrolled 5217 participants under regular nephrological care with an estimated glomerular filtration rate of 30-60 or >60 mL/min/1.73m2 and an overt proteinuria. Cardio-, cerebro- and peripheral vascular, kidney, infection, and cancer events, as well as deaths were adjudicated following a standard operation procedure. We summarized these time-to-event data points for exploration in interactive graphs within an R shiny app. Multivariable adjusted Cox models for time to first event were fitted. Cumulative incidence functions, Kaplan-Meier curves and intersection plots were used to display main adverse events and their combinations by sex and CKD etiology. RESULTS: Over a median of 6.5 years, 10 271 events occurred in total and 680 participants (13.0%) died while 2947 participants (56.5%) experienced any event. The new publicly available interactive platform enables readers to scrutinize adverse events and their combinations as well as mortality trends as a gateway to better understand multimorbidity in CKD: incident rates per 1000 patient-years varied by event type, CKD etiology, and baseline characteristics. Incidence rates for the most frequent events and their recurrence were 113.6 (cardiovascular), 75.0 (kidney), and 66.0 (infection). Participants with diabetic kidney disease and men were more prone to experiencing events. CONCLUSION: This comprehensive explorative tool to visualize adverse events (https://gckd.diz.uk-erlangen.de/), their combination, mortality, and multimorbidity among persons with CKD may manifest as a valuable resource for patient care, identification of high-risk groups, health services, and public health policy planning.
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Background: Optimal initial tacrolimus dosing and early exposure of tacrolimus after renal transplantation is not well studied. Methods: In this open-label, 6 months, multicenter, randomized controlled, non-inferiority study, we randomly assigned 432 renal allograft recipients to receive basiliximab induction, mycophenolate and steroids and either standard prolonged-release tacrolimus (trough levels: 7-9 ng/ml; Standard Care arm), or an initial 7-day fixed 5 mg/day dose of prolonged-release tacrolimus followed by lower tacrolimus predose levels (trough levels: 5-7 ng/ml; Slow & Low arm). The primary end point was the combined incidence rate of biopsy-proven acute rejections (BPAR; including borderline), graft failure, or death at 6 months with a non-inferiority margin of 12.5%. (EudraCT-Nr: 2013-001770-19. Findings: The combined primary endpoint in the Slow & Low arm was non-inferior compared to the Standard Care arm (22.1% versus 20.7%; difference: 1.4%, 90% CI -5.5% to 8.3%). The overall rate of BPAR including borderlines was similar (Slow & Low 17.4% versus Standard Care 16.6%). Safety parameters such as delayed graft function, kidney function, donor specific HLA-antibodies, infections, or post-transplantation diabetes mellitus did not differ. Interpretation: This is the first study to show that an initial fixed dose of 5 mg per day followed by lower tacrolimus exposure is non-inferior compared to standard tacrolimus therapy and equally efficient and safe within 6 months after renal transplantation. These data suggest that therapeutic drug monitoring for prolonged release tacrolimus can be abandoned until start of the second week after transplantation. Funding: Investigator-initiated trial, financial support by Astellas Pharma GmbH.
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Introduction: We reported increased spleen tyrosine kinase (SYK) expression in kidney biopsies of patients with IgA nephropathy (IgAN) and that inhibition of SYK reduces inflammatory cytokines production from IgA stimulated mesangial cells. Methods: This study was a double-blind, randomized, placebo-controlled phase 2 trial of fostamatinib (an oral SYK inhibitor) in 76 patients with IgAN. Patients were randomized to receive placebo, fostamatinib at 100 mg or 150 mg twice daily for 24 weeks on top of maximum tolerated dose of renin-angiotensin system inhibitors. The primary end point was reduction of proteinuria. Secondary end points included change from baseline in estimated glomerular filtration rate (eGFR) and kidney histology. Results: Although we could not detect significant reduction in proteinuria with fostamatinib overall, in a predetermined subgroup analysis, there was a trend for dose-dependent reduction in median proteinuria (from baseline to 24 weeks by 14%, 27%, and 36% in the placebo, fostamatinib 100 mg, and 150 mg groups, respectively) in patients with baseline urinary protein-to-creatinine ratios (UPCR) more than 1000 mg/g. Kidney function (eGFR) remained stable in all groups. Fostamatinib was well-tolerated. Side effects included diarrhea, hypertension, and increased liver enzymes. Thirty-nine patients underwent repeat biopsy showing reductions in SYK staining associated with therapy at low dose (-1.5 vs. 1.7 SYK+ cells/glomerulus in the placebo group, P < 0.05). Conclusions: There was a trend toward reduction in proteinuria with fostamatinib in a predefined analysis of high risk patients with IgAN despite maximal care, as defined by baseline UPCR greater than 1000 mg/g. Further study may be warranted.
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Background: Diabetes mellitus (DM) and chronic kidney disease (CKD) are well-known cardiovascular and mortality risk factors. To what extent they act in an additive manner and whether the etiology of CKD modifies the risk is uncertain. Methods: The multicenter, prospective, observational German Chronic Kidney Disease study comprises 5217 participants (1868 with DM) with a baseline mean estimated glomerular filtration rate of 30-60 mL/min/1.73 m2 and/or proteinuria >0.5 g/day. We categorized patients whose CKD was caused by cardiovascular or metabolic diseases (CKDcvm) with and without DM, as opposed to genuine CKD (CKDgen) with and without DM. Recorded outcomes were first events of non-cardiovascular and cardiovascular death, 4-point major adverse cardiovascular events (4-point MACE) and hospitalization for heart failure (HHF). Results: During the 6.5-year follow-up 603 (12%) non-cardiovascular and 209 (4%) cardiovascular deaths, 645 (12%) 4-point MACE, and 398 (8%) HHF were observed, most frequently in patients with DM having CKDcvm. DM increased the risk of non-cardiovascular [hazard ratio (HR) 1.92; 95% confidence interval (CI) 1.59-2.32] and cardiovascular (HR 2.25; 95% CI 1.62-3.12) deaths, 4-point MACE (HR 1.93; 95% CI 1.62-2.31) and HHF (HR 1.87; 95% CI 1.48-2.36). Mortality risks were elevated by DM to a similar extent in CKDcvm and CKDgen, but for HHF in CKDcvm only (HR 2.07; 95% CI 1.55-2.77). In patients with DM, CKDcvm (versus CKDgen) only increased the risk for HHF (HR 1.93; 95% CI 1.15-3.22). Conclusions: DM contributes to cardiovascular and mortality excess risk in patients with moderate to severe CKD in both, CKDcvm and CKDgen. Patients with DM and CKDcvm are particularly susceptible to HHF.
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Introduction: Soluble urokinase plasminogen activation receptor (suPAR) is an immune-derived pathogenic factor for kidney and atherosclerotic disease. Whether the association between suPAR and cardiovascular (CV) outcomes is dependent on the severity of underlying kidney disease is unclear. Methods: We measured serum suPAR levels in 4994 participants (mean age 60 years; 60% men; 36% with diabetes mellitus; mean estimated glomerular filtration rate (eGFR) 49 ml/min per 1.73 m2, SD 18) of the German Chronic Kidney Disease (GCKD) cohort and examined its association with all-cause death, CV death, and major CV events (MACE) across the range of eGFR and urine albumin-to-creatinine ratio (UACR). Results: The median suPAR level was 1771 pg/ml (interquartile range [IQR] 1447-2254 pg/ml). SuPAR levels were positively and independently correlated with age, eGFR, UACR, and parathyroid hormone levels. There were 573 deaths, including 190 CV deaths and 683 MACE events at a follow-up time of 6.5 years. In multivariable analyses, suPAR levels (log2) were associated with all-cause death (hazard ratio [HR] 1.36, 95% confidence interval [CI] 1.21-1.53), CV death (HR 1.27, 95% CI 1.03-1.57), and MACE (HR 1.13, 95% CI 1.00-1.28), and were not found to differ according to diabetes mellitus status, baseline eGFR, UACR, or parathyroid hormone levels. In mediation analysis, suPAR's direct effect on all-cause death, CV death, and MACE accounted for 77%, 67%, and 60% of the total effect, respectively; whereas the effect mediated through eGFR accounted for 23%, 34%, and 40%, respectively. Conclusion: In a large cohort of individuals with chronic kidney disease (CKD), suPAR levels were associated with mortality and CV outcomes independently of indices of kidney function, consistent with its independent role in the pathogenesis of atherosclerosis.
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Background: The administration of modified immune cells (MIC) before kidney transplantation led to specific immunosuppression against the allogeneic donor and a significant increase in regulatory B lymphocytes. We wondered how this approach affected the continued clinical course of these patients. Methods: Ten patients from a phase I clinical trial who had received MIC infusions prior to kidney transplantation were retrospectively compared to 15 matched standard-risk recipients. Follow-up was until year five after surgery. Results: The 10 MIC patients had an excellent clinical course with stable kidney graft function, no donor-specific human leukocyte antigen antibodies (DSA) or acute rejections, and no opportunistic infections. In comparison, a retrospectively matched control group receiving standard immunosuppressive therapy had a higher frequency of DSA (log rank P = 0.046) and more opportunistic infections (log rank P = 0.033). Importantly, MIC patients, and in particular the four patients who had received the highest cell number 7 days before surgery and received low immunosuppression during follow-up, continued to show a lack of anti-donor T lymphocyte reactivity in vitro and high CD19+CD24hiCD38hi transitional and CD19+CD24hiCD27+ memory B lymphocytes until year five after surgery. Conclusions: MIC infusions together with reduced conventional immunosuppression were associated with good graft function during five years of follow-up, no de novo DSA development and no opportunistic infections. In the future, MIC infusions might contribute to graft protection while reducing the side effects of immunosuppressive therapy. However, this approach needs further validation in direct comparison with prospective controls. Trial registration: https://clinicaltrials.gov/, identifier NCT02560220 (for the TOL-1 Study). EudraCT Number: 2014-002086-30.
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Trasplante de Riñón , Humanos , Estudios de Seguimiento , Estudios Prospectivos , Estudios Retrospectivos , Anticuerpos , Progresión de la EnfermedadRESUMEN
BACKGROUND: We previously reported excellent efficacy and improved safety aspects of rapid steroid withdrawal (RSWD) in the randomized controlled 1-year "Harmony" trial with 587 predominantly deceased-donor kidney transplant recipients randomized either to basiliximab or rabbit antithymocyte globulin induction therapy and compared with standard immunosuppressive therapy consisting of basiliximab, low tacrolimus once daily, mycophenolate mofetil and corticosteroids. METHODS: The 5-year post-trial follow-up (FU) data were obtained in an observational manner at a 3- and a 5-year visit only for those Harmony patients who consented to participate and covered clinical events that occurred from the second year onwards. RESULTS: Biopsy-proven acute rejection and death-censored graft loss rates remained low and independent of RSWD. Rapid steroid withdrawal was an independent positive factor for patient survival (adjusted hazard ratio 0.554, 95% confidence interval 0.314-0.976; P = .041).The reduced incidence of post-transplantation diabetes mellitus in RSWD patients during the original 1-year study period was not compensated by later incidences during FU. Incidences of other important outcome parameters such as opportunistic infections, malignancies, cardiovascular morbidity/risk factors, donor-specific antibody formation or kidney function did not differ during FU period. CONCLUSIONS: With all the limitations of a post-trial FU study, the Harmony FU data confirm excellent efficacy and beneficial safety aspects of RSWD under modern immunosuppressive therapy over the course of 5 years after kidney transplantation in an immunologically low-risk, elderly population of Caucasian kidney transplant recipients. Trial registration: Clinical trial registration number: Investigator Initiated Trial (NCT00724022, FU study DRKS00005786).
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Trasplante de Riñón , Anciano , Humanos , Anticuerpos Monoclonales , Basiliximab , Estudios de Seguimiento , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/etiología , Rechazo de Injerto/prevención & control , Supervivencia de Injerto , Inmunosupresores/efectos adversos , Trasplante de Riñón/efectos adversos , Ácido Micofenólico/uso terapéutico , Esteroides , Tacrolimus/efectos adversosRESUMEN
OBJECTIVE: Adipose tissue contributes to adverse outcomes in chronic kidney disease (CKD), but there is uncertainty regarding the prognostic relevance of different adiposity measures. We analyzed the associations of neck circumference (NC), waist circumference (WC), and body mass index (BMI) with clinical outcomes in patients with mild to severe CKD. METHODS: The German Chronic Kidney Disease study is a prospective cohort study, which enrolled Caucasian adults with mild to severe CKD, defined as estimated glomerular filtration rate : 30-60 mL/min/1.73 m2, or >60 mL/min/1.73 m2 in the presence of overt proteinuria. Associations of NC, WC, and BMI with all-cause death, major adverse cardiovascular events (MACE: a composite of nonfatal stroke, nonfatal myocardial infarction, peripheral artery disease intervention, and cardiovascular death), and kidney failure (a composite of dialysis or transplantation) were analyzed using multivariable Cox proportional hazards regression models adjusted for confounders and the Akaike information criteria were calculated. Models included sex interactions with adiposity measures. RESULTS: A total of 4537 participants (59% male) were included in the analysis. During a 6.5-year follow-up, 339 participants died, 510 experienced MACE, and 341 developed kidney failure. In fully adjusted models, NC was associated with all-cause death in women (hazard ratio 1.080 per cm; 95% CI 1.009-1.155) but not in men. Irrespective of sex, WC was associated with all-cause death (hazard ratio 1.014 per cm; 95% CI 1.005-1.038). NC and WC showed no association with MACE or kidney failure. BMI was not associated with any of the analyzed outcomes. Models of all-cause death, including WC offered the best (lowest) Akaike information criteria. CONCLUSION: In Caucasian patients with mild to severe CKD, higher NC (in women) and WC were significantly associated with increased risk of death from any cause but BMI was not.
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Adiposidad , Insuficiencia Renal Crónica , Adulto , Humanos , Masculino , Femenino , Pronóstico , Estudios Prospectivos , Obesidad/complicaciones , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/complicaciones , Circunferencia de la Cintura , Índice de Masa Corporal , Factores de RiesgoRESUMEN
BACKGROUND: The comparative impact of everolimus (EVR)-based regimens versus standard of care (mycophenolic acid+standard calcineurin inhibitor [MPA+sCNI]) on cardiovascular outcomes in de novo kidney transplant recipients (KTRs) is poorly understood. The incidence of major adverse cardiac events (MACEs) in KTRs receiving EVR+reduced CNI (rCNI) or MPA+sCNI from the TRANSplant eFficacy and safety Outcomes with an eveRolimus-based regiMen study was evaluated. METHODS: The incidence of MACE was determined for all randomized patients receiving at least 1 dose of the study drug. Factors associated with MACEs were determined by logistic regression. Risk of MACE out to 3 y post-study was calculated using the Patient Outcome in Renal Transplantation equation. RESULTS: MACE occurred in 81 of 1014 (8.0%; EVR+rCNI) versus 89 of 1012 (8.8%; MPA+sCNI) KTRs (risk ratio, 0.91 [95% confidence interval [CI], 0.68-1.21]). The incidence of circulatory death, myocardial infarction, revascularization, or angina was similar between the arms. Incidence of MACE was similar between EVR+rCNI and MPA+sCNI arms with a higher incidence in prespecified risk groups: older age, pretransplant diabetes (15.1% versus 15.9%), statin use (8.5% versus 10.8%), and low estimated glomerular filtration rate (Month 2 estimated glomerular filtration rate <30 versus >60 mL/min/1.73 m 2 ; odds ratio, 2.23 [95% CI, 1.02-4.86]; P = 0.044), respectively. Predicted risk of MACE within 3 y of follow-up did not differ between the treatment arms. CONCLUSIONS: Cardiovascular morbidity and mortality were similar between de novo KTRs receiving EVR+rCNI and MPA+sCNI. EVR+rCNI is a viable alternative to the current standard of care in KTRs.
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Everolimus , Trasplante de Riñón , Humanos , Everolimus/efectos adversos , Inhibidores de la Calcineurina/efectos adversos , Inmunosupresores/efectos adversos , Trasplante de Riñón/efectos adversos , Nivel de Atención , Ácido Micofenólico/uso terapéutico , Tasa de Filtración Glomerular , Rechazo de Injerto/etiología , Tacrolimus/efectos adversosRESUMEN
BACKGROUND: Renal transplantation is the therapy of choice for kidney failure. The Eurotransplant Senior Program (ESP) has been established to allocate kidneys ≥65 years to recipients of the same age group considered a regional allocation with short cold ischemia (CIT) but not human-leukocyte-antigen (HLA)-matching. The acceptance of organs aged ≥75 years is also still controversial within the ESP. METHODS: In a multicenter approach, 179 kidney grafts ≥75 years (mean donor age 78 years) that were transplanted in 174 patients in 5 German transplant centers were analyzed. The primary focus of the analysis was long-term outcome of the grafts and the impact of CIT, HLA matching, and recipient related risk factors. RESULTS: The mean graft survival was 59 months (median 67 months) with a mean donor age of 78.3 ± 2.9 years. Grafts with 0 to 3 HLA-mismatches had a significantly better overall graft survival compared to grafts with ≥4 mismatches (69 months vs 54 months; P = .008). The mean CIT was short (11.9 ± 5.3 hours) and had no impact on graft survival. CONCLUSION: Recipients receiving a kidney graft from donors aged ≥75 years can benefit from nearly 5 years of survival with a functioning graft. Even minimal HLA matching may improve long term allograft survival.
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Trasplante de Riñón , Humanos , Trasplante de Riñón/efectos adversos , Riñón , Trasplante Homólogo , Donantes de Tejidos , Supervivencia de Injerto , AloinjertosRESUMEN
BACKGROUND: We recently demonstrated that donor-derived modified immune cells (MICs)-PBMCs that acquire immunosuppressive properties after a brief treatment-induced specific immunosuppression against the allogeneic donor when administered before kidney transplantation. We found up to a 68-fold increase in CD19 + CD24 hi CD38 hi transitional B lymphocytes compared with transplanted controls. METHODS: Ten patients from a phase 1 clinical trial who had received MIC infusions before kidney transplantation were followed to post-transplant day 1080. RESULTS: Patients treated with MICs had a favorable clinical course, showing no donor-specific human leukocyte antigen antibodies or acute rejections. The four patients who had received the highest dose of MICs 7 days before surgery and were on reduced immunosuppressive therapy showed an absence of in vitro lymphocyte reactivity against stimulatory donor blood cells, whereas reactivity against third party cells was preserved. In these patients, numbers of transitional B lymphocytes were 75-fold and seven-fold higher than in 12 long-term survivors on minimal immunosuppression and four operationally tolerant patients, respectively ( P <0.001 for both). In addition, we found significantly higher numbers of other regulatory B lymphocyte subsets and a gene expression signature suggestive of operational tolerance in three of four patients. In MIC-treated patients, in vitro lymphocyte reactivity against donor blood cells was restored after B lymphocyte depletion, suggesting a direct pathophysiologic role of regulatory B lymphocytes in donor-specific unresponsiveness. CONCLUSIONS: These results indicate that donor-specific immunosuppression after MIC infusion is long-lasting and associated with a striking increase in regulatory B lymphocytes. Donor-derived MICs appear to be an immunoregulatory cell population that when administered to recipients before transplantation, may exert a beneficial effect on kidney transplants. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: MIC Cell Therapy for Individualized Immunosuppression in Living Donor Kidney Transplant Recipients (TOL-1), NCT02560220.
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Linfocitos B Reguladores , Trasplante de Riñón , Humanos , Inmunosupresores/uso terapéutico , Terapia de Inmunosupresión , Tolerancia Inmunológica , Receptores de TrasplantesRESUMEN
OBJECTIVE: Psychosocial parameters play a pivotal role in organ recipient evaluation before wait-listing for transplantation because of their impact on organ and patient outcome. Patients in need of heart (HTx), liver (LTx), or kidney transplantation (KTx) face distinct physical and psychological challenges. This study compares the psychosocial characteristics and preferences for additional therapy for patients undergoing assessment for these three types of organ transplantation to optimize patient-tailored psychological, social, and other supportive interventions. METHODS: We conducted a cross-sectional, observational study with 1110 potential transplantation candidates (LTx, n = 544; KTx, n = 330; HTx, n = 236), psychosocial status was determined for depressive symptoms (Patient Health Questionnaire Depression Scale), anxiety symptoms (seven-item Generalized Anxiety Disorder Screener), health-related quality of life (36-Item Short Form Health Survey), perceived social support (Perceived Social Support Questionnaire), sense of coherence (SoC; short form of the Sense of Coherence Scale), self-efficacy (General Self-Efficacy Short Scale), and body image (German Body Image Questionnaire-20). Preferences for additional supportive therapy were assessed dichotomously. Data were analyzed using multivariate analysis of covariance and χ2 tests. RESULTS: Patient groups differed significantly regarding depression ( F (2,1107) = 35.283, p < .001, partial η2 = 0.01), anxiety ( F (2,1107) = 15.027, p < .001, partial η2 = 0.03), health-related quality of life (physical: F (2,1107) = 96.772, p < .001, partial η2 = 0.15; mental: F (2,1107) = 11.442, p < .001, partial η2 = 0.02), perceived social support ( F (2,1107) = 20.813, p < .001, partial η2 = 0.04), SoC ( F (2,1107) = 12.920, p < .001, partial η2 = 0.02), self-efficacy ( F (2,1107) = 17.308, p < .001, partial η2 = 0.03), and body image (rejecting body evaluation: F (2,1107) = 5.006, p = .007, partial η2 = 0.01; vital body dynamics: F (2,1107) = 40.216, p < .001, partial η2 = 0.07). Patients evaluated for HTx showed the highest psychosocial impairment and the highest inclination regarding additional supportive therapy. CONCLUSIONS: Patients evaluated for HTx, LTx, and KTx have distinct psychosocial characteristics and treatment preferences. HTx patients display the highest psychosocial impairment. We suggest psychocardiological treatment structures for optimal outcome.
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Trasplante de Corazón , Trasplante de Riñón , Trasplante de Hígado , Humanos , Estudios Transversales , Trasplante de Corazón/psicología , Riñón , Hígado , Calidad de Vida/psicología , Trasplante de Riñón/psicología , Trasplante de Hígado/psicología , Depresión , Ansiedad , Apoyo Social , Imagen Corporal , AutoeficaciaRESUMEN
BACKGROUND: Although therapeutic drug monitoring of calcineurin inhibitor (CNI) concentrations is performed routinely in clinical practice, an identical concentration may lead to different effects in different patients. Although the quantification of nuclear factor of activated T-cell-regulated gene expression (NFAT-RGE) is a promising method for measuring individual CNI effects, CNI pharmacodynamics are as of yet incompletely understood. METHODS: CNI concentrations and NFAT-RGEs were quantified in 24 healthy volunteers receiving either ciclosporin or tacrolimus in 2 clinical trials. NFAT-RGE was measured using quantitative reverse transcription polymerase chain reaction tests of whole-blood samples. Pharmacokinetics and pharmacodynamics were analyzed using compartmental modeling and simulation. In addition, NFAT-RGE data from renal transplant patients were analyzed. RESULTS: The average NFAT-RGE during a dose interval was reduced to approximately 50% with ciclosporin, considering circadian changes. The different effect-time course with ciclosporin and tacrolimus could be explained by differences in potency (IC 50 204 ± 41 versus 15.1 ± 3.2 mcg/L, P < 0.001) and pharmacokinetics. Residual NFAT-RGE at the time of maximum concentration (RGE tmax ) of 15% when using ciclosporin and of 30% when using tacrolimus was associated with similar average NFAT-RGEs during a dose interval. Renal transplant patients had similar but slightly stronger effects compared with healthy volunteers. CONCLUSIONS: Ciclosporin and tacrolimus led to similar average suppression of NFAT-RGE in a dose interval, despite considerably different RGE tmax . Pharmacodynamic monitoring of average NFAT-RGE should be considered. When using NFAT-RGE at specific time points, the different effect-time courses and circadian changes of NFAT-RGEs should be considered.
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Ciclosporina , Tacrolimus , Humanos , Tacrolimus/uso terapéutico , Ciclosporina/farmacocinética , Inmunosupresores/uso terapéutico , Voluntarios Sanos , Linfocitos T , Regulación de la Expresión Génica , Inhibidores de la Calcineurina/farmacología , Expresión Génica , Factores de Transcripción NFATC/genética , Factores de Transcripción NFATC/metabolismoRESUMEN
Background: Non-human leukocyte antigen (non-HLA) antibodies including antibodies targeting Angiotensin II type 1 (AT1R) and Endothelin-1 type A (ETAR) receptors represent a topic of interest in kidney transplantation (KTx). This exploratory substudy evaluated the impact of everolimus (EVR) or mycophenolic acid (MPA) in combination with tacrolimus (TAC) or cyclosporine A (CsA) in patients with preformed non-HLA antibodies, potentially associated rejections and/or their impact on renal function over 1 year. Methods: All eligible patients were randomized (1:1:1) before transplantation to receive either EVR/TAC, EVR/CsA, or MPA/TAC regimen. The effect of these regimens on the formation of non-HLA antibodies within one year post de novo KTx and the association with clinical events was evaluated descriptively in randomized (n = 268) population. Results: At Month 12, in EVR/TAC group, higher incidence of patients negative for AT1R- and ETAR-antibodies (82.2% and 76.7%, respectively) was noted, whereas the incidence of AT1R- and ETAR-antibodies positivity (28.1% and 34.7%, respectively) was higher in the MPA/TAC group. Non-HLA antibodies had no influence on clinical outcomes in any treatment group and no graft loss or death was reported. Conclusions: The studied combinations of immunosuppressants were safe with no influence on clinical outcomes and suggested minimal exposure of calcineurin inhibitors for better patient management. Clinical Trial Registration: https://clinicaltrials.gov/ (NCT01843348; EudraCT number: 2011-005238-21).
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Background: Studies prospectively monitoring de novo donor-specific antibodies (dnDSAs) and their clinical impact are sparse. This substudy of ATHENA was initiated to evaluate the effect of everolimus (EVR) or mycophenolic acid (MPA) in combination with reduced calcineurin inhibitor (CNI, tacrolimus [TAC] or cyclosporine [CsA]) on the formation of human leukocyte antibodies (HLA), including dnDSA, and the impact on clinical outcomes in kidney transplant (KTx) recipients. Methods: All eligible patients were randomized 1:1:1 to receive either EVR + TAC, EVR + CsA or MPA + TAC, with basiliximab induction plus steroids after transplantation up to Month 12. The incidence of dnDSA by treatment group and the association with clinical events were evaluated descriptively as an exploratory objective in the intent-to-treat (ITT) and per-protocol (PP) populations with at least one antibody assessment. Results: Overall, none of the patients in the EVR + TAC group had either dnDSA or antibody mediated rejection (PP or ITT population) and only one patient with dnDSA in the TAC + MPA group had antibody mediated rejection. Conclusion: The EVR regimen was comparable to MPA regimen with an extremely low incidence of dnDSA over 1 year of treatment.
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INTRODUCTION: Donor-derived modified immune cells (MIC) induced long-term specific immunosuppression against the allogeneic donor in preclinical models of transplantation. In a phase I clinical trial (TOL-1 Study), MIC treatment resulted in a cellular phenotype that was directly and indirectly suppressive to the recipient's immune system allowing for reduction of conventional immunosuppressive therapy. Here, we describe a protocol for a randomised controlled, multicentre phase-IIb clinical trial of individualised immunosuppression with intravenously administered donor MIC compared with standard-of-care (SoC) in living donor kidney transplantation (TOL-2 Study). METHODS AND ANALYSIS: Sixty-three living donor kidney transplant recipients from six German transplant centres are randomised 2:1 to treatment with MIC (MIC group, N=42) or no treatment with MIC (control arm, N=21). MIC are manufactured from donor peripheral blood mononuclear cells under Good Manufacturing Practice conditions. The primary objective of this trial is to determine the efficacy of MIC treatment together with reduced conventional immunosuppressive therapy in terms of achieving an operational tolerance-like phenotype compared with SoC 12 months after MIC administration. Key secondary endpoints are the number of patient-relevant infections as well as a composite of biopsy-proven acute rejection, graft loss, graft dysfunction or death. Immunosuppressive therapy of MIC-treated patients is reduced during follow-up under an extended immunological monitoring including human leucocyte antigen-antibody testing, and determination of lymphocyte subsets, for example, regulatory B lymphocytes (Breg) and antidonor T cell response. A Data Safety Monitoring Board has been established to allow an independent assessment of safety and efficacy. ETHICS AND DISSEMINATION: Ethical approval has been provided by the Ethics Committee of the Medical Faculty of the University of Heidelberg, Heidelberg, Germany (AFmu-580/2021, 17 March 2022) and from the Federal Institute for Vaccines and Biomedicines, Paul-Ehrlich-Institute, Langen, Germany (Vorlage-Nr. 4586/02, 21 March 2022). Written informed consent will be obtained from all patients and respective donors prior to enrolment in the study. The results from the TOL-2 Study will be published in peer-reviewed medical journals and will be presented at symposia and scientific meetings. TRIAL REGISTRATION NUMBER: NCT05365672.
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Trasplante de Riñón , Humanos , Trasplante de Riñón/efectos adversos , Donadores Vivos , Nivel de Atención , Leucocitos Mononucleares , Terapia de Inmunosupresión , Inmunosupresores/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Multicéntricos como Asunto , Ensayos Clínicos Fase II como AsuntoRESUMEN
Background: Infectious complications are a major cause of morbidity and mortality after kidney transplantation. Methods: In this transplant cohort study at the German Center of Infectious Diseases (DZIF), we evaluated all infections occurring during the first year after renal transplantation. We assessed microbial etiology, incidence rates, and temporal occurrence of these infections. Results: Of 804 renal transplant recipients (65.2% male, 51 ± 14 years), 439 (54.6%) had 972 infections within the first year after transplantation. Almost half of these infections (47.8%) occurred within the first 3 months. Bacteria were responsible for 66.4% (645/972) of all infections, followed by viral (28.9% [281/972]) and fungal (4.7% [46/972]) pathogens. The urinary tract was the most common site of infection (42.4%). Enterococcus was the most frequently isolated bacterium (20.9%), followed by E. coli (17.6%) and Klebsiella (12.5%). E. coli was the leading pathogen in recipients <50 years of age, whereas Enterococcus predominated in older recipients. Resistant bacteria were responsible for at least 1 infection in 9.5% (76/804) of all recipients. Viral infections occurred in 201 recipients (25.0%). Of these, herpes viruses predominated (140/281 [49.8%]), and cytomegalovirus had the highest incidence rate (12.3%). In the 46 fungal infections, Candida albicans (40.8%) was the most commonly isolated. Other fungal opportunistic pathogens, including Aspergillus fumigatus and Pneumocystis, were rare. Conclusions: Renal allograft recipients in Germany experience a high burden of infectious complications in the first year after transplantation. Bacteria were the predominating pathogen, followed by opportunistic infections such as cytomegalovirus. Microbial etiology varied between age groups, and resistant bacteria were identified in 10% of recipients.
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Introduction: Prospective data on impact of educational attainment on prognosis in patients with chronic kidney disease (CKD) are scarce. We investigated the association between educational attainment and all-cause mortality, major adverse cardiovascular (CV) events (MACEs), kidney failure requiring dialysis, and CKD etiology. Methods: Participants (N = 5095, aged 18-74 years) of the ongoing multicenter German Chronic Kidney Disease (GCKD) cohort, enrolled on the basis of an estimated glomerular filtration rate (eGFR) of 30 to 60 ml/min (stages G3, A1-A3) or overt proteinuria (stages G1-G2, A3), were divided into 3 categories according to their educational attainment and were followed for 6.5 years. Results: Participants with low educational attainment (vs. high) had a higher risk for mortality (hazard ratio [HR] 1.48, 95% CI: 1.16-1.90), MACE (HR 1.37, 95% CI: 1.02-1.83), and kidney failure (HR 1.54, 95% CI: 1.15-2.05). Mediators between low educational attainment and mortality were smoking, CV disease (CVD) at baseline, low income, higher body mass index, and higher serum levels of CRP, high-density lipoprotein cholesterol, uric acid, NGAL, BAP, NT-proBNP, OPN, H-FABP, and urea. Low educational attainment was positively associated with diabetic nephropathy (odds ratio [OR] 1.65, 95% CI: 1.36-2.0) and CKD subsequent to acute kidney injury (OR 1.56, 95% CI: 1.03-2.35), but negatively associated with IgA nephropathy (OR 0.68, 95% CI: 0.52-0.90). Conclusion: Low educational attainment is associated with adverse outcomes and CKD etiology. Lifestyle habits and biomarkers mediate associations between low educational attainment and mortality. Recognition of the role of educational attainment and the associated health-relevant risk factors is important to optimize the care of patients with CKD and improve prognosis.
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After solid-organ transplantation, reactivation of the cytomegalovirus (CMV) is often observed in seronegative patients and associated with a high risk of disease and mortality. CMV-specific T cells can prevent CMV reactivation. In a phase 1 trial, CMV-seronegative patients with end-stage renal disease listed for kidney transplantation were subjected to CMV phosphoprotein 65 (CMVpp65) peptide vaccination and further investigated for T-cell responses. To this end, CMV-specific CD8+ T cells were characterized by bulk T-cell-receptor (TCR) repertoire sequencing and combined single-cell RNA and TCR sequencing. In patients mounting an immune response to the vaccine, a common SYE(N)E TCR motif known to bind CMVpp65 was detected. CMV-peptide-vaccination-responder patients had TCR features distinct from those of non-responders. In a non-responder patient, a monoclonal inflammatory T-cell response was detected upon CMV reactivation. The identification of vaccine-induced CMV-reactive TCRs motifs might facilitate the development of cellular therapies for patients wait-listed for kidney transplantation.
Asunto(s)
Infecciones por Citomegalovirus/prevención & control , Fallo Renal Crónico/terapia , Receptores de Antígenos de Linfocitos T/genética , Proteínas de la Matriz Viral/administración & dosificación , Linfocitos T CD8-positivos/inmunología , Ensayos Clínicos Fase I como Asunto , Citomegalovirus/inmunología , Infecciones por Citomegalovirus/inmunología , Vacunas contra Citomegalovirus/administración & dosificación , Vacunas contra Citomegalovirus/inmunología , Humanos , Fallo Renal Crónico/inmunología , Trasplante de Riñón , Análisis de Secuencia de ARN , Imagen Individual de Molécula , Proteínas de la Matriz Viral/inmunologíaRESUMEN
The German living donor register Safety of the Living Kidney Donor - The German National Register (SOLKID-GNR) collects data of the medical and psychosocial outcome of living kidney donors. For the first time in Germany, a prospective data collection allows a scientifically based long-term analysis of how a living kidney donation influences the psychological and physical health of living kidney donors. This will contribute directly to improve the information and care of living kidney donors.