Early conversion to everolimus was assessed in kidney transplant recipients participating in the Eurotransplant Senior Program (ESP), a population in whom data are lacking. The SENATOR multicenter ...study enrolled 207 kidney transplant recipients undergoing steroid withdrawal at week 2 post-transplant (ClinicalTrials.gov NCT00956293). At week 7, patients were randomized (1:2 ratio) to continue the previous calcineurin inhibitor (CNI)-based regimen with mycophenolic acid (MPA) and cyclosporine or switch to a CNI-free regimen with MPA, everolimus (5-10 ng/mL) and basiliximab at weeks 7 and 12, then followed for 18 weeks to month 6 post-transplant. The primary endpoint was estimated GFR (eGFR). At week 7, 77/207 (37.2%) patients were randomized (53 everolimus, 24 control). At month 6, eGFR was comparable: 36.5±10.8ml/min with everolimus versus 42.0±13.0ml/min in the control group (p = 0.784). Discontinuation due to adverse events occurred in 27.8% of everolimus-treated patients and 0.0% of control patients (p = 0005). Efficacy profiles showed no difference. In conclusion, eGFR, safety and efficacy outcomes at month 6 post-transplant showed no difference between groups. The everolimus group experienced a higher rate of discontinuation due to adverse events. However, the high rate of non-randomization is highly relevant, indicating this to be a somewhat unstable patient population regardless of treatment.
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.
We assessed the prevalence, awareness, treatment and control of hypertension in patients with moderate chronic kidney disease (CKD) under nephrological care in Germany. In the German Chronic Kidney ...Disease (GCKD) study, 5217 patients under nephrology specialist care were enrolled from 2010 to 2012 in a prospective observational cohort study. Inclusion criteria were an estimated glomerular filtration rate (eGFR) of 30-60 mL/min/1.73 m2 or overt proteinuria in the presence of an eGFR>60 mL/min/1.73 m2. Office blood pressure was measured by trained study personnel in a standardized way and hypertension awareness and medication were assessed during standardized interviews. Blood pressure was considered as controlled if systolic < 140 and diastolic < 90 mmHg. In 5183 patients in whom measurements were available, mean blood pressure was 139.5 ± 20.4 / 79.3 ± 11.8 mmHg; 4985 (96.2%) of the patients were hypertensive. Awareness and treatment rates were > 90%. However, only 2456 (49.3%) of the hypertensive patients had controlled blood pressure. About half (51.0%) of the patients with uncontrolled blood pressure met criteria for resistant hypertension. Factors associated with better odds for controlled blood pressure in multivariate analyses included younger age, female sex, higher income, low or absent proteinuria, and use of certain classes of antihypertensive medication. We conclude that blood pressure control of CKD patients remains challenging even in the setting of nephrology specialist care, despite high rates of awareness and medication use.
Gene expression regulated by the transcription factor NFAT (nuclear factor of activated T-cells) has been proposed for monitoring the pharmacodynamic effect of calcineurin inhibitors. We aimed to ...correlate the pharmacokinetics of tacrolimus with the suppression of NFAT-regulated gene expression. Tacrolimus trough (C
) and peak concentrations (C
) were measured by LC-MS. The effect on NFAT-regulated gene expression at trough (E
) and at peak levels (E
) were determined by qRT-PCR. The pharmacodynamic concentration producing the half-maximum effect (CE
) and the Hill coefficient (H) were estimated from E
and from E
. Ten stable kidney transplant recipients on triple immunosuppression with prednisolone, mycophenolate, and tacrolimus were analyzed. Median age was 58 years, median time since transplant was 84 months, and median serum creatinine was 249 µmol/L. The immunosuppressive effect on NFAT-regulated genes at trough concentrations was 38% (E
), and the effect at peak concentrations was 59% (E
) of maximum immunosuppression (E
). The pharmacodynamic parameters of the action of tacrolimus were estimated with the Hill coefficient H at 1.5 and the CE50 at 6.7 ng/mL. Accordingly, the pharmacodynamic threshold concentration was estimated at 0.9 ng/mL and the ceiling concentration at 48 ng/mL, indicating a wide span between target trough and peak levels. The low Hill coefficient indicates concentration-dependent pharmacodynamics of tacrolimus on NFAT transcripts. Therefore, the extension of the administration interval to 24 hours is not likely to jeopardize the immunosuppressive effect of the prolonged-release tacrolimus preparations. .
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.
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.
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
= 0.046) and more opportunistic infections (log rank
= 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
and high CD19
CD24
CD38
transitional and CD19
CD24
CD27
memory B lymphocytes until year five after surgery.
MIC infusions together with reduced conventional immunosuppression were associated with good graft function during five years of follow-up, no
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.
https://clinicaltrials.gov/, identifier NCT02560220 (for the TOL-1 Study). EudraCT Number: 2014-002086-30.
The clinical outcome and health-related quality of life (HRQoL) of living kidney donors is mostly not detrimental, but some donors experience impairment after donation. Gender-specific effects of ...living kidney donors was evaluated.
Clinical outcome was assessed in living kidney donors and HRQoL was obtained by self-reporting validated test systems as the Multidimensional Fatigue Inventory (MFI-20), the Short Form 36 (SF-36), and the Patient Health Questionnaire (PHQ-9).
Two hundred and eleven (211) living renal donors were evaluated (female 62.2%). Response rate was 80.8%. In both genders, a decrease of renal function of 26% was observed after donation. De novo antihypertensives were introduced in 28.3% of women and 36.5% of men. HRQoL was comparable in female and male donors, except for mental HRQoL, which was lower in 51- to 60-year-old female donors, compared to age-matched male donors and to the female general population. Female donors aged 40-59 years demonstrated more fatigue than the age-matched general population. A low mental HRQoL (MCS; SF-36) was associated with higher values for fatigue (General Fatigue Score; MFI-20) in both genders. Multiple regression analysis detected the General Fatigue score of the MFI-20 questionnaire and depression identified by the PHQ-9 score as independent variables predicting MCS of the SF-36 in both genders. Lower age at time of donation contributed to a lower MCS in female donors.
Overall, HRQoL in living kidney donors exceeds that of the general population. Inferior mental health status and fatigue seem to be a problem, especially in middle-aged female donors, but not in all female donors. Psychological evaluation pre donation and psychological support post donation are required.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Therapeutic drug monitoring of mycophenolate mofetil is a promising tool for reducing acute rejection episodes after renal transplantation.
• Limited ...sampling algorithms of mycophenolic acid in mycophenolate mofetil‐treated renal transplant patients have been established.
• Recently published study results indicate that the intensity of early drug exposure might determine the risk of acute rejection episodes.
WHAT THIS STUDY ADDS
• This study provides pharmacokinetic and pharmacodynamic data of mycophenolic acid in enteric‐coated mycophenolate sodium‐treated renal transplant patients.
• Limited sampling algorithms are evaluated and a practical sampling strategy with five sampling time points within the first 4 h after oral drug intake is provided in renal transplant patients with combined immunosuppression consisting of enteric‐coated mycophenolate sodium and ciclosporin A.
• The association between pharmacokinetic and pharmacodynamic parameters and the risk of adverse events are evaluated.
• Both pharmacokinetic and pharmacodynamic parameters contribute to optimized individual immunosuppression.
AIMS Pharmacokinetic (PK) and pharmacodynamic (PD) monitoring strategies and clinical outcome were evaluated in enteric‐coated mycophenolate sodium (EC‐MPS)‐treated renal allograft recipients.
METHODS PK mycophenolic acid (MPA) and PD inosine monophosphate dehydrogenase (IMPDH) activity data were analysed in 66 EC‐MPS and ciclosporin A (CsA)‐treated renal allograft recipients. Adverse events were considered in a follow‐up period of 12 weeks.
RESULTS Analyses confirmed a limited sampling strategy (LSS) consisting of PK and PD data at predose, 1, 2, 3 and 4 h after oral intake as an appropriate sampling method (MPA r2= 0.812; IMPDH r2= 0.833). MPA AUC0–12 of patients with early biopsy‐proven acute rejection was significantly lower compared with patients without a rejection (median MPA AUC0–12 28 µg*h ml−1 (7–45) vs. 40 µg*h ml−1 (16–130), P < 0.01), MPA AUC0–12 of patients with recurrent infections was significantly higher compared with patients without infections (median MPA AUC0–12 65 µg*h ml−1 (range 37–130) vs. 37 µg*h ml−1 (range 7–120), P < 0.005). Low 12‐h IMPDH enzyme activity curve (AEC0–12) was associated with an increased frequency of gastrointestinal side‐effects (median IMPDH AEC0–12 43 nmol*h mg−1 protein h−1range 12–67) vs. 75 nmol*h mg−1 protein h−1 (range 15–371), P < 0.01.
CONCLUSIONS Despite highly variable absorption data, an appropriate LSS might be estimated by MPA AUC0–4 and IMPDH AEC0–4 in renal transplant patients treated with EC‐MPS and CsA. Regarding adverse events, the suggested MPA‐target AUC0–12 from 30 to 60 µg*h ml−1 seems to be appropriate in renal allograft recipients.
IntroductionDonor-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 analysisSixty-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 disseminationEthical 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 numberNCT05365672.
The cohort of senior renal allograft recipients is increasing. Age-related physiologic changes are believed to influence the pharmacokinetics and pharmacodynamics of immunosuppression. Measuring the ...residual nuclear factor of activated T-cell (NFAT)-regulated gene expression (RGE) is a promising pharmacodynamic tool to individually monitor cyclosporin A (CsA) therapy.
In stable senior renal allograft recipients (≥65 years), the expression of 3 calcineurin-dependent NFAT-regulated genes (interleukin-2, interferon-γ, and granulocyte-macrophage colony-stimulating factor) was measured in whole-blood samples before (C₀) and 2 hours (C₂) after oral drug intake. Clinical data on opportunistic infections were collected in a clinical observational period of 12 months.
Thirty-six senior patients 22 male, median age 70 years (65-77) were enrolled in this clinical study. Median daily CsA dosage was 150 mg (50-250), CsA C₀ concentration 102 mcg/L (range 33-157), and CsA C₂ concentration 551 mcg/L (range 254-1228). The NFAT RGE varied between 3% and 37% (median 10%). CsA peak concentrations and inhibition of gene expression correlated significantly (r = -0.737, P < 0.001). NFAT RGE in patients with opportunistic infections including atypical pneumonia, cytomegalovirus and herpes viral infections was lower compared with that in patients without infections 4% (3-13) versus 11% (3-37), P = 0.05, whereas the daily CsA dosage, CsA C₀, and CsA C₂ concentrations were comparable. Renal allograft function correlated inversely with NFAT RGE.
A higher degree of immunosuppression correlated with more infectious complications in a considerable proportion of senior renal allograft recipients treated with standard CsA therapy. Pharmacodynamic monitoring is an approach to individualize immunosuppression and could provide the opportunity to reduce complications caused by infections.
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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