Stable Kidney Transplant Recipients Research Articles

Older age is associated with a distinct and marked reduction of functionality of both alloreactive CD4+ and CD8+ T cells

IntroductionOlder recipient age is associated with a significant decreased risk for rejection after kidney transplantation which is incompletely understood.MethodsIn a longitudinal study, circulating alloreactive T cells were assessed of young (≤45 years) and older (≥55 years) stable kidney transplant recipients. Alloreactive T-cells were identified by CD137-expression and phenotype, cytokine producing and proliferative capacity, were evaluated using multiparameter flowcytometry. ResultsThe results show that before transplantation frequencies of alloreactive CD4+ and CD8+ T-cells in older KT-recipients are significantly higher and shifted towards an effector memory-phenotype. However, the frequency of polyfunctional (≥2 pro-inflammatory cytokines) CD4+ T-cells was significantly lower and less IL2 was produced. The frequency of polyfunctional alloreactive CD4+ T-cells and proliferation of alloreactive T-cells donor-specifically declined after transplantation reaching a nadir at 12 months after transplantation, irrespective of age. A striking difference was observed for the proliferative response of alloreactive CD8+ T-cells. This was not only lower in older compared to younger recipients but could also not be restored by exogenous IL2 or IL15 in the majority of older recipients while the response to polyclonal stimulation was unaffected. ConclusionIn conclusion, older age is associated with a distinct and marked reduction of functionality of both alloreactive CD4+ and CD8+ T-cells.

Older age is associated with a distinct and marked reduction of functionality of both alloreactive CD4+ and CD8+ T cells.

Older recipient age is associated with a significant decreased risk for rejection after kidney transplantation which is incompletely understood. In a longitudinal study, circulating alloreactive T cells were assessed of young (≤45 years) and older (≥55 years) stable kidney transplant recipients. Alloreactive T-cells were identified by CD137-expression and phenotype, cytokine producing and proliferative capacity, were evaluated using multiparameter flowcytometry. The results show that before transplantation frequencies of alloreactive CD4+ and CD8+ T-cells in older KT-recipients are significantly higher and shifted towards an effector memory-phenotype. However, the frequency of polyfunctional (≥2 pro-inflammatory cytokines) CD4+ T-cells was significantly lower and less IL2 was produced. The frequency of polyfunctional alloreactive CD4+ T-cells and proliferation of alloreactive T-cells donor-specifically declined after transplantation reaching a nadir at 12 months after transplantation, irrespective of age. A striking difference was observed for the proliferative response of alloreactive CD8+ T-cells. This was not only lower in older compared to younger recipients but could also not be restored by exogenous IL2 or IL15 in the majority of older recipients while the response to polyclonal stimulation was unaffected. In conclusion, older age is associated with a distinct and marked reduction of functionality of both alloreactive CD4+ and CD8+ T-cells.

Longitudinal monitoring of Torque Teno virus DNAemia in kidney transplant recipients correlates with long-term complications of inadequate immunosuppression.

Optimization of individual immunosuppression, which reduces the risks of both graft loss and patients' death, is considered the best approach to improve long-term outcomes of renal transplantation. Torque Teno Virus (TTV) DNAemia has emerged as a potential biomarker reflecting the depth of therapeutic immunosuppression during the initial year post-transplantation. However, its efficacy in long-term monitoring remains uncertain. In a cohort study involving 34 stable kidney transplant recipients and 124 healthy volunteers, we established lower and upper TTV DNAemia thresholds (3.75-5.1 log10 cp/mL) correlating with T-cell activatability, antibody response against flu vaccine, and risk for subsequent serious infections or cancer over 50 months. Validation in an independent cohort of 92 recipients confirmed that maintaining TTV DNAemia within this range in >50% of follow-up time points was associated with reduced risks of complications due to inadequate immunosuppression, including de novo DSA, biopsy-proven antibody-mediated rejection, graft loss, infections, or cancer. Multivariate analysis highlighted "in-target" TTV DNAemia as the sole independent variable significantly linked to decreased risk for long-term complications due to inadequate immunosuppression (odds ratio [OR]: 0.27 [0.09-0.77]; p = 0.019). Our data suggest that the longitudinal monitoring of TTV DNAemia in kidney transplant recipients could help preventing the long-term complications due to inadequate immunosuppression.

Monocyte-derived dendritic cells can be detected in urine of kidney transplant recipients with pathogenic asymptomatic bacteriuria.

Urinary tract infections (UTI) are an important clinical problem in kidney transplant recipients (KTR). Asymptomatic bacteriuria (ASB) is frequent in these patients and often resolved by the immune system, but a significant proportion may progress to complicated UTI, which may compromise allograft function and survival. It is essential to determine the involvement of the immune system in the infectious process. Dendritic cells (DCs) are recognised as playing a pivotal role in initiating inflammatory responses capable of priming antigen-specific T cells, a crucial step in determining the fate of local inflammation. Little is known about their role in the control of UTI. In this brief communication, we report an incidental finding in a group of 16 stable KTR in which monocyte-derived dendritic cells (ModDCs), analysed by flow cytometry, were found in urine of patients with ASB and high bacterial counts >107 cfu/ml. Within this group, one patient developed pyelonephritis in the following days. These findings suggest that the immune system, in particular DCs, may be recruited during the course of a UTI and, to our knowledge, present for the first time evidence that inflammatory ModDCs can be detected in urine. Their frequency may reflect the degree of infection. This finding suggests the potential for exploring whether these cells may be useful in distinguishing between pathogenic ASB and those that can be resolved by the immune system.

Comparison of eGFR Equations to Guide Dosing of Medications for Kidney Transplant Recipients.

Clinicians caring for kidney transplant recipients (KTRs) most commonly use estimated glomerular filtration rate (eGFR) to guide medication dosing as it is the most readily available measure of kidney function. Which eGFR equations provide the most accurate medication dosing guidance for KTRs remains uncertain. We studied 415 stable KTRs in Canada and New Zealand. Participants completed same-day measurements of creatinine and cystatin C and measured GFR (diethylenetriaminepentaacetic acid). Chronic Kidney Disease Epidemiology Collaboration, European Kidney Function Consortium, and transplant-specific eGFR equations were compared with both Cockcroft-Gault creatinine clearance (CrCl) and measured GFR. eGFR equations were assessed both indexed to a standardized body surface area (BSA) of 1.73 m2 (milliliter per minute per 1.73 m2, as is conventional reporting from most clinical laboratories) and nonindexed (milliliter per minute) accounting for actual BSA. The primary outcome was the proportion of medication dosing discordance relative to Cockcroft-Gault CrCl or measured GFR for 8 commonly prescribed medications. Stratified analyses were performed on the basis of obesity status. Nonindexed eGFR equations (milliliter per minute) resulted in substantially lower medication dosing discordance compared with indexed eGFR equations (milliliter per minute per 1.73 m2). These findings were most pronounced among KTRs with obesity, in whom underdosing was frequent. When compared with Cockcroft-Gault CrCl, the lowest proportion of discordance was found with the nonindexed 2023 transplant-specific equation. When compared with measured GFR, the lowest proportion of discordance was found with the nonindexed 2021 Chronic Kidney Disease Epidemiology CollaborationCr/CysC equation. Nonindexed eGFR values accounting for actual BSA should be used by clinicians for medication dosing in KTRs. These findings may inform KT providers about which eGFR equations provide the safest, most accurate medication dosing guidance for KTRs.

#2586 Time to event prediction of new-onset diabetes after transplantation in kidney transplant recipients using machine learning models

Abstract Background and Aims New-onset diabetes after transplantation (NODAT) is a common and serious complication of kidney transplantation that contributes to long-term morbidity and mortality after the transplant procedure. Conventional methods may predict the risk of, but not time to developing NODAT. We aimed to develop a machine learning model that predicts the time to NODAT in kidney transplant recipients (KTR). Method Two large prospective cohort studies of stable KTR (inclusion >1 year after transplantation) from the University Medical Center Groningen were combined. Data collection took place between 2001 and 2003 for cohort A, and between 2008 and 2011 for cohort B, resulting in the inclusion of 750 KTR free of NODAT at baseline. To predict absolute time to NODAT, a bootstrap aggregating (bagging) approach was utilized which consisted of several extreme gradient boosting (XGBoost) models with the accelerated failure time (AFT) objective. The performance of the resulting bagging model was internally evaluated by assessing the concordance index (c-index) in 20% of the dataset not used for training. Results From the 750 KTR included, 76 (10.1%) developed NODAT during a median (interquartile range [IQR]) follow-up of 5.8 (4.7 to 9.2) years. The median (IQR) age was 51.2 (40.5 to 60.7) years and 342 (45.6%) of the KTR were female. During feature engineering, 18 features from 53 were selected. After hyperparameter tuning, model performance during internal validation was 0.84. Furthermore, SHapley Additive exPlanations (SHAP) values were used to estimate feature importance, which revealed that glucose, HbA1c, mean arterial pressure, cyclosporine concentrations and daily vegetable intake were the most important features. Conclusion The developed machine learning model shows good discriminative ability of time to NODAT prediction. Due to the methodology used, the model allows for flexible incremental learning, meaning that the bagging model can be retrained with additional data without compromising on performance.

#2751 CD14++CD16+ monocytes and CD8+ T cells are independently associated with annual change in eGFR and proteinuria in kidney transplant recipients

Abstract Background and Aims Immune cellular responses are implicated in all clinical aspects of kidney transplantation. There is little data regarding the additional value of regular monitoring of immune cells subsets expression in kidney transplant recipients (KTRs). The aim of our prospective study was a longitudinal follow-up analysis of monocytes subpopulations, natural killer (NK) cells and lymphocytes subsets including regulatory T cells (Tregs) in the circulation of KTRs and potential clinical correlations. Method 48 stable KTRs were initially enrolled. All KTRs were under immunosuppressive regimen with corticosteroids, mycophenolate mofetil or mycophenolate acid and calcineurin inhibitors (CNIs). Exclusion criteria were history or development during follow-up of acute rejection, cardiovascular disease, malignancy and active or chronic infections. Patients were followed for 12 months. The peripheral blood immune cell subsets CD14++CD16-, CD14++CD16+ and CD14+CD16++ absolute values and percentages out of total monocytes and NK cells (CD3+CD16+56+), CD3-CD19+ B lymphocytes, CD3+ CD4+ T cells, CD3+CD8+ T cells and Tregs (CD4+CD25+ FoxP3+) absolute values and percentages out of total lymphocytes were measured by flow cytometry at baseline (T0) and after 12 months (T1). Clinical and laboratory parameters were recorded at T0 and T1. Delta (Δ) eGFR and Δ spot urine protein to creatinine ratio (ΔUPCR) were defined as their respective differences between T1 and T0. Likewise, Delta (Δ) of immune cells subtypes or laboratory indices was defined as their respective difference between T1 and T0. Results 35 KTRs (mean age 53 ± 9.28 years, 71% males, mean transplant vintage 96 ± 66 months, 63% on Tacrolimus and 37% on Cyclosporine) were included in the final analysis. Significant differences were observed between T0 and T1 in monocytes number (653 ± 244 and 538 ± 197/μL respectively, p = 0.001), monocytes percentage (7.6 ± 2.9 and 6.6 ± 2.2% respectively, p = 0.006) as well as in the number of classical CD14++CD16- monocytes (534 ± 225 and 452 ± 185/μL respectively, p = 0.04). The rest immune cells subsets did not show any significant differences between T0 and T1. Mean eGFR declined from 58 ± 17 at T0 to 53 ± 18 ml/min/1.73 m2 at T1 (p = 0.004). No significant changes were observed between T0 and T1 in median UPCR [0.16 (IRQ, 0.09-0.56) at T0 and 0.16 (IQR, 0.10-0.70) gr protein/gr creatine at T1, p = 0.489], in median CRP [4.0 (IQR, 3-7) at T0 and 5 (IQR, 2.5-7.5) mg/L) at T1, p = 0.919], in mean ESR (20 ± 14 at T0 and 22 ± 19 mm/hour at T1, p = 0.381) or other parameters, including CNIs blood levels. ΔeGFR was correlated with the T0 percentage of monocytes (rho = 0.359, p = 0.037), the T0 number and T0 percentage of CD14++CD16+ monocytes (rho= 0.502, p = 0.003 and rho = 0.438, p = 0.008 respectively). On the other hand, a borderline inverse correlation was observed between ΔeGFR and ΔCD14++CD16+ monocytes number (rho = −0.339, p = 0.05). Additional correlates of ΔeGFR included serum albumin at T0 (rho = 0.395, p = 0.021) and Δuric acid (rho = 0.567, p = 0.000). At stepwise linear regression analysis, CD14++CD16+ monocytes (β = 0.338, p = 0.04) and Δuric acid (β = 0.477, p = 0.006) remained independent significant correlates of ΔeGFR. ΔUPCR was significantly correlated with the percentage of B-lymphocytes (rho = 0.385, p = 0.027) and CD4+ T-cells (rho = 0.352, p = 0.044) at T0, and inversely correlated with the T0 percentage of T-lymphocytes (rho = −0.402, p = 0.02) and CD8+ T cells (rho = −0.603, p = 0.000) as well as with Δhemoglobin (rho = −0.385, p = 0.027). At stepwise linear regression analysis, only the CD8+ T cells percentage at T0 remained independently correlated to ΔUPCR (β = –0.379, p = 0.03). Conclusion The results of our study indicate that intermediate CD14++CD16+ monocytes are associated with annual eGFR change whereas CD8+ T cells negatively correlate with the annual trend of proteinuria change in KTRs. Further research is needed to clarify underlying pathophysiological mechanisms for these findings. Finally, future studies including larger cohorts and with longer follow-up are required to specify the potential utility of immune subpopulations monitoring as potential prognostic biomarkers in KTRs.

#1462 Muscle mass, muscle strength, and health-related quality of life in kidney transplant recipients results of the TransplantLines Biobank & cohort study

Abstract Background and Aims Muscles play a vital role in nearly every aspect of daily living, and kidney transplant recipients (KTR) often experience reduced muscle mass and strength, potentially contributing to their diminished health-related quality of life (HRQoL). We aimed to investigate the potential relationship of muscle mass and muscle strength with physical HRQoL in KTR. Method Data of stable KTR (≥1 year after transplantation) enrolled in the TransplantLines Biobank and Cohort Studies were used. Muscle mass was assessed using both appendicular skeletal muscle mass (via bioimpedance analysis) indexed to height squared (ASMI) and 24-hour urinary creatinine excretion rate indexed to height squared (CERI). Muscle strength was assessed using handgrip strength indexed to height squared (HGSI). HRQoL was assessed using the physical component score derived from the Short Form 36 questionnaire. Results A total of 751 KTR (61% male, mean age 56 ± 13 years) at a median of 3 years after transplantation were included. Mean ASMI was 7.5 ± 1.2 kg/m2, mean CERI was 4.1 ± 1.1 mmol/24 h/m2 and mean HGSI was 12.4 ± 3.4 kg/m2. The mean physical HRQoL score was 70 ± 21. Lower ASMI, CERI and HGSI were all associated with lower physical HRQoL, independent of potential confounders. Both associations were best characterized by a significant non-linear relationship (see Figure). Below median values, ASMI, CERI and HGSI were each associated with physical HRQoL, whereas above median values, associations were far less pronounced. When associations of ASMI, CERI and HSGI were adjusted for each other, associations of below median values of ASMI and CERI with physical HRQoL materially weakened, while those of HGSI remained strongly associated. Compared to the 50th percentile, a decrease to the 10th percentile was associated with a decrease in physical HRQoL of 6.0% for ASMI (P = 0.006), of 5.1% for CERI (P = 0.006) and 13.2% for HGSI (P < 0.001), whereas an increase to the 90th percentile was associated with an increase in physical HRQoL of only 1.3% for ASMI (P = 0.22), of 3.6% for CERI (P = 0.05) and −0.4% for HGSI (P = 0.73). Conclusion Our findings suggest that low muscle mass and muscle strength are potentially modifiable risk factors for impaired physical HRQoL. Both muscle mass and muscle strength were complementarily associated with HRQoL. However, muscle strength was most strongly associated with physical HRQoL. The non-linear nature of the associations implies that KTR with low muscle mass or strength may particularly benefit from (p)rehabilitation interventions to improve HRQoL.

#2096 A randomized controlled study of telemonitoring in kidney transplantation: interim results of the Ap'TX trial

Abstract Background and Aims Telemedicine is a matter of growing interest in transplantation. However, its real added value is uncertain. In 2018, we have started to study the medico-economic impact of a less stringent on-site follow-up of our kidney transplant recipients (KTR) using Ap'Telecare®. We present here a preliminary report focusing on 500 KTR with a 2 years follow-up. Method The Ap'Tx study (NCT03750331) is a controlled randomized trial testing the hypothesis that monitoring stable KTR (at least 3 months after transplantation) with Ap'Telecare® is non inferior to a conventional follow-up in terms of the occurrence of graft dysfunction (defined as a decrease in eGFR of 20% or more). On-site consultation scheduling was 2 times less frequent for KTR followed by Ap'Telecare®. Secondary endpoints were the impact of a remote follow-up by Ap'Telecare® on medical workload, economic saving and quality of life. Results 688 KTR have been randomized so far with 500 of them having completed the 2 years follow-up. Among all KTR approached to participate in the study, 37% were not included mainly due to difficulties with accessing internet (44%) or to masterize the app (36%). After randomization, 27% of KTR were considered as non compliant in adequately using Ap'Telecare®. Over the 2 years study duration, graft dysfunction occurred in 16% and 18% of KTR in the Ap'telecare® and conventional arm, respectively (RR of 0.87 (0.56; 1.39), non-inferiority confirmed, superiority not significant). Medical time dedicated to handling daily lab results was decreased by a factor 3 for KTR using Ap'Telecare®. Rates of unplanned consultations and hospitalisations were reduced by 26% and 32% for patients using Ap'Telecare®, respectively (P < .05). Conclusion This preliminary report of Ap'Tx suggest that a partial and reasonable remote follow-up of selected KTR is feasible, safe and logistically beneficial. Determining the nature of factors associated with a wider implementation of Ap'Telecare® is underway.

#2831 A randomised controlled study of a Combined Home-based ExERcISe and Nutritional ApproacH to improve frailty in kidney transplant recipients (CHERISH)

Abstract Background and Aims Post-transplantation frailty is common, with a prevalence of up to 52% in kidney transplant recipients (KTRs), and is associated with increased mortality, recurrent hospitalisation and inferior quality of life (QoL). Resistance exercise training (RET) was found to improve frailty in this patient group. Both high and low protein intakes were associated with potential risk of graft failure. To date, no studies have evaluated the safety and efficacy of RET combined with protein supplementation (RETPS) in KTRs. The objectives of this study were to investigate the effect of RETPS on kidney function and frailty status in KTRs, and assess its impact on QoL. Method Forty clinically stable KTRs ≥1 year post-transplantation [mean age = 54 ± 14 years; 50% male, median time post-transplantation = 7 years] were enrolled and randomised to either RET (n = 20) or RETPS (n = 20). All participants completed a 30-minute home-based progressive RET regimen 2-3 times weekly for 12 weeks, guided by an exercise worksheet and a study-specific video link. Participants received weekly telephone call to ensure safety and compliance of the interventions. The RETPS group received additional body-weight adjusted whey protein supplementation 1-hour post exercise. Total daily dietary protein intake did not exceed 1.40 g/kg/day to confine to a safe level of protein consumption in KTRs. Kidney function was measured by estimated glomerular filtration rate (eGFR), creatinine, and albumin-creatinine ratio (ACR). Frailty was evaluated using Fried Frailty Phenotype (FFP), Short Performance Physical Battery (SPPB), 60-second Sit-to-Stand test (60s-STST), handgrip- (HG) and back-leg-chest- (BLC) derived muscle strength, bioimpedance-derived lean tissue index (LTI), and ultrasound-derived thigh muscle thickness (TMT). QoL was assessed using Short Form (SF) -36 questionnaire. All measurements were performed at baseline and at week 12. Results Kidney function did not differ significantly between baseline and week 12 in both RET [eGFR: 62.1 vs 59.7 ml/min; creatinine: 107.3 vs 111.5 μmol/L; ACR: 12.8 vs 10.4 mg/mmol] and RETPS [eGFR: 61.2 vs 60.7 ml/min; creatinine: 101.1 vs 102.2 μmol/L; ACR: 17.6 vs 20.9 mg/mmol] groups. Frailty status assessed by FFP and SPPB improved in both RET [FFP: 2.5 vs 1.3, P < .001; SPPB: 7.2 vs 11.6, P < .001] and RETPS [FFP: 2.8 vs 1.1, P < .001; SPPB: 6.4 vs 10.9, P < .001] groups, but the improvements did not differ significantly between groups (P > 0.23). Improvements in 60s-STST, HG-derived muscle strength, BLC-derived muscle strength, and ultrasound-derived TMT were observed in both RET [60s-STST: 23 vs 27, P < .001; HG-derived muscle strength: 24 vs 30 kg, P < .001; BLC-derived muscle strength: 62 vs 71 kg, P < .001; ultrasound-derived TMT: 15 vs 19 mm, P < .001] and RETPS [60s-STST: 20 vs 29, P < .001; HG-derived muscle strength: 24 vs 32 kg, P < .001; BLC-derived muscle strength: 57 vs 80 kg, P < .001; ultrasound-derived TMT: 14 vs 21 mm, P < .001] groups, with greater improvements in RETPS group for 60s-STST (P < .01), HG-derived muscle strength (P < .05), BLC-derived muscle strength (P < .05), and ultrasound-derived TMT (P < .001). For bioimpedance-derived LTI, improvement was observed only in RETPS group [12.8 vs 14.8 kg/m2, P < .05]. SF-36-derived overall-, physical- and mental- related QoL improved in both groups (P < .05 for all), with RETPS group reporting a greater improvement in physical-related QoL (P < .05). Conclusion This represents the first study demonstrating RET combined with protein supplementation is safe and effective in improving frailty and QoL in KTRs. Protein supplementation augments increased muscle mass and strength beyond RET effect, further enhancing improvement in physical-related QoL.

Phase angle and donor type are determinants of coronary artery calcification in stable kidney transplant recipients at twelve months after transplantation

Background and aimCoronary artery calcification (CAC) partially explains the excess cardiovascular morbidity and mortality after kidney transplantation. This study aimed to investigate determinants of CAC in stable kidney transplant recipients at 12 months post-transplantation. Methods and resultsCAC-score was quantified by the Agatston method using non-contrast enhanced computed tomography, and age- and sex-standardized CAC-percentiles were calculated. Univariable and multivariable multinomial logistic regression was performed to study potential determinants of CAC. The independent determinants were included in multivariable multinomial logistic regression adjusting for potential confounders. 203 KTRs (age 54.0 ± 14.7 years, 61.1% male) were included. Participants were categorized into four groups according to CAC percentiles (p = 0 [CAC-score = 0], n = 68; p ≥ 1%-p ≤ 50% [CAC score = 29.0 (4.0–166.0)], n = 31; p > 50 ≤ 75% [CAC score = 101.0 (23.8–348.3)], n = 26; and p>75% [CAC score = 581.0 (148.0–1652)], n = 83). Upon multivariable multinomial logistic regression, patients with a narrower phase angle and patients who had received a graft from a deceased donor had a higher risk of being in the >75th CAC-percentile. ConclusionsThis study identifies not only metabolic and transplant-related factors, but also phase angle, a composite marker of cell integrity, as an independent determinant of CAC at 12 months after kidney transplantation. This study offers new perspectives for future research into the value of bioelectrical impedance analysis in relation to vascular calcification in kidney transplant recipients.

Office or home versus 24-hour blood pressure measurement in stable kidney transplant recipients.

The aim of this study was to quantify hypertension control and evaluate concordance between all commonly available blood pressure modalities in kidney transplant recipients (KTR). For this prospective cross-sectional study 89 stable KTR were recruited at the Charité Transplant Outpatient Clinic. For each study participant office (manual office blood pressure 'MOBP' and automated office blood pressure 'AOBP'), 7-day home (HBPM) and 24-hour ambulatory blood pressure measurement (24h-ABPM) were performed. 80 of the 89 patients recruited had sufficient blood pressure recordings. Mean blood pressure for MOBP, AOBP, HBPM and 24h-ABPM was 129/73, 126/71, 131/85 and 130/81mmHg, respectively. Uncontrolled hypertension, as defined by 24h-ABPM (mean≥130/80mmHg), was present in 53 (66%) patients. MOBP, AOBP and HBPM classified 19 (24%), 22 (28%) and 41 (51%) patients respectively as 'uncontrolled hypertensive'. The Bland-Altman plot showed good agreement between systolic MOBP, AOBP, HBPM and Daytime-ABPM (mean bias±SD: -1±13mmHg, -4±13mmHg, 1±10mmHg, respectively). Uncontrolled nighttime hypertension was present in 74 (93%) KTR, with 71 (89%) patients showing a non-physiological dipping pattern. Moderate positive correlation between Daytime-ABPM/HBPM and Nighttime-ABPM (Pearson Correlation Coefficients: 0.62-0.73), followed by MOBP/AOBP (Pearson Correlation Coefficients: 0.49-0.59) was noted. eGFR and proteinuria displayed weak correlation with 24h-, Daytime- and Nighttime-ABPM (absolute values of Pearson Correlation Coefficients: 0.04-0.41). No robust association with either 24h-, Daytime- or Nighttime-ABPM was observed for volume status exams. Masked hypertension is highly prevalent in KTR, especially due to high rates of uncontrolled nighttime hypertension. HBPM shows the narrowest limits of agreement with Daytime-ABPM. Daytime-ABPM and HBPM show the highest, albeit clinically insufficient, correlation with Nighttime-ABPM. Systematic integration of 24h-ABPM into clinical practice, as proposed by the '2023 ESH Guidelines for the Management of arterial hypertension', should not be withheld for the KTR population. Clinical trials evaluating treatment of hypertension in KTR are urgently needed.

Only bioactive forms of PTH (n-oxPTH and Met18(ox)-PTH) inhibit synthesis of sclerostin – evidence from in vitro and human studies

Sclerostin (SOST) is produced by osteocytes and is known as a negative regulator of bone homeostasis. Parathyroid hormone (PTH) regulates calcium, phosphate as well as vitamin D metabolism, and is a strong inhibitor of SOST synthesis in vitro and in vivo. PTH has two methionine amino acids (positions 8 and 18) which can be oxidized. PTH oxidized at Met18 (Met18(ox)-PTH) continues to be bioactive, whereas PTH oxidized at Met8 (Met8(ox)-PTH) or PTH oxidized at Met8 and Met18 (Met8, Met18(di-ox)-PTH) has minor bioactivity. How non-oxidized PTH (n-oxPTH) and oxidized forms of PTH act on sclerostin synthesis is unknown. The effects of n-oxPTH and oxidized forms of PTH on SOST gene expression were evaluated in UMR106 osteoblast-like cells. Moreover, we analyzed the relationship of SOST with n-oxPTH and all forms of oxPTH in 516 stable kidney transplant recipients using an assay system that can distinguish in clinical samples between n-oxPTH and the sum of all oxidized PTH forms (Met8(ox)-PTH, Met18(ox)-PTH, and Met8, Met18(di-ox)-PTH). We found that both n-oxPTH and Met18(ox)-PTH at doses of 1, 3, 20, and 30 nmol/L significantly inhibit SOST gene expression in vitro, whereas Met8(ox)-PTH and Met8, Met18(di-ox)-PTH only have a weak inhibitory effect on SOST gene expression. In the clinical cohort, multivariate linear regression showed that only n-oxPTH, but not intact PTH (iPTH) nor oxPTH, is independently associated with circulating SOST after adjusting for known confounding factors. In conclusion, only bioactive PTH forms such as n-oxPTH and Met18(ox)-PTH, inhibit SOST synthesis.

High-Density Lipoprotein Particles and Torque Teno Virus in Stable Outpatient Kidney Transplant Recipients.

Torque teno virus (TTV) is emerging as a potential marker for monitoring immune status. In transplant recipients who are immunosuppressed, higher TTV DNA loads are observed than in healthy individuals. TTV load measurement may aid in optimizing immunosuppressive medication dosing in solid organ transplant recipients. Additionally, there is a growing interest in the role of HDL particles in immune function; therefore, assessment of both HDL concentrations and TTV load may be of interest in transplant recipients. The objective of this study was to analyze TTV loads and HDL parameters in serum samples collected at least one year post-transplantation from 656 stable outpatient kidney transplant recipients (KTRs), enrolled in the TransplantLines Food and Nutrition Cohort (Groningen, the Netherlands). Plasma HDL particles and subfractions were measured using nuclear magnetic resonance spectroscopy. Serum TTV load was measured using a quantitative real-time polymerase chain reaction. Associations between HDL parameters and TTV load were examined using univariable and multivariable linear regression. The median age was 54.6 [IQR: 44.6 to 63.1] years, 43.3% were female, the mean eGFR was 52.5 (±20.6) mL/min/1.73 m2 and the median allograft vintage was 5.4 [IQR: 2.0 to 12.0] years. A total of 539 participants (82.2%) had a detectable TTV load with a mean TTV load of 3.04 (±1.53) log10 copies/mL, the mean total HDL particle concentration was 19.7 (±3.4) μmol/L, and the mean HDL size was 9.1 (±0.5) nm. The univariable linear regression revealed a negative association between total HDL particle concentration and TTV load (st.β = -0.17, 95% CI st.β: -0.26 to -0.09, p < 0.001). An effect modification of smoking behavior influencing the association between HDL particle concentration and TTV load was observed (Pinteraction = 0.024). After adjustment for age, sex, alcohol intake, hemoglobin, eGFR, donor age, allograft vintage and the use of calcineurin inhibitors, the negative association between HDL particle concentration and TTV load remained statistically significant in the non-smoking population (st.β = -0.14, 95% CI st.β: -0.23 to -0.04, p = 0.006). Furthermore, an association between small HDL particle concentration and TTV load was found (st.β = -0.12, 95% CI st.β: -0.22 to -0.02, p = 0.017). Higher HDL particle concentrations were associated with a lower TTV load in kidney transplant recipients, potentially indicative of a higher immune function. Interventional studies are needed to provide causal evidence on the effects of HDL on the immune system.

Impact of Switching From Immediate- or Prolonged-Release to Once-Daily Extended-Release Tacrolimus (LCPT) on Tremor in Stable Kidney Transplant Recipients: The Observational ELIT Study.

Once-daily extended-release tacrolimus (LCPT) exhibits increased bioavailability versus immediate-release (IR-TAC) and prolonged release (PR-TAC) tacrolimus. Improvements in tremor were previously reported in a limited number of kidney transplant patients who switched to LCPT. We conducted a non-interventional, non-randomized, uncontrolled, longitudinal, prospective, multicenter study to assess the impact of switching to LCPT on tremor and quality of life (QoL) in a larger population of stable kidney transplant patients. The primary endpoint was change in The Essential Tremor Rating Assessment Scale (TETRAS) score; secondary endpoints included 12-item Short Form Survey (SF-12) scores, tacrolimus trough concentrations, neurologic symptoms, and safety assessments. Subgroup analyses were conducted to assess change in TETRAS score and tacrolimus trough concentration/dose (C0/D) ratio by prior tacrolimus formulation and tacrolimus metabolizer status. Among 221 patients, the mean decrease of TETRAS score after switch to LCPT was statistically significant (p < 0.0001 vs. baseline). There was no statistically significant difference in change in TETRAS score after switch to LCPT between patients who had received IR-TAC and those who had received PR-TAC before switch, or between fast and slow metabolizers of tacrolimus. The overall increase of C0/D ratio post-switch to LCPT was statistically significant (p < 0.0001) and from baseline to either M1 or M3 (both p < 0.0001) in the mITT population and in all subgroups. In the fast metabolizers group, the C0/D ratio crossed over the threshold of 1.05ng/mL/mg after the switch to LCPT. Other neurologic symptoms tended to improve, and the SF-12 mental component summary score improved significantly. No new safety concerns were evident. In this observational study, all patients had a significant improvement of tremor, QoL and C0/D ratio post-switch to LCPT irrespective of the previous tacrolimus formulation administered (IR-TAC or PR-TAC) and irrespective from their metabolism status (fast or slow metabolizers).

Changes in Cardiac Structure and Function Following Fistula Ligation in Kidney Transplant Recipients (Cohort Study)

Purpose: International guidelines recommend that haemodialysis access is provided by an arteriovenous fistula (AVF), which enables frequent, reliable access to the circulation, but there are no guidelines to suggest whether these AVFs need to be ligated after kidney transplantation. Cardiovascular morbidity and mortality remain high in recipients of a kidney transplant, the persistence of a patent arteriovenous fistula (AVF) after transplantation may contribute to ongoing maladaptive cardiovascular remodelling. The ability to reverse this maladaptive remodelling by ligation of this AVF is unknown. We conducted this trial to evaluate the effect of AVF ligation on cardiac structure and function in stable kidney transplant recipients. Also we studied the ability of preoperative echocardiographic and non-invasive hemodynamic measurements, including the effects of acute temporary occlusion of the fistula, to predict postoperative left ventricular diameter and mass reduction, by the closure of the fistula.&#x0D; Materials and Methods: Nonrandomized controlled trial. kidney transplant recipients (&gt;12 months after transplantation with stable graft function) were divided into 2 groups. The first referred for surgical arteriovenous fistula closure. The second group didn’t receive Fistula closure (control). Standard echocardiographic parameters, heart rate, and blood pressure were assessed preoperatively (fistula closure) at baseline. These measurements were repeated 6 months after surgical closure.&#x0D; Findings: Seventeen kidney transplant patients were prospectively studied with 11 case and 6 controls with no fistula closure. Surgical fistula closure decreased left ventricular end-diastolic diameter and mass indexes (29.9_2.4to 27.4_2.1 mm/m2, P&lt;0.001, and 141_37 to 132_39 g/m2, P&lt;0.05, respectively), whereas no changes were seen in controls after a similar delay. Postoperative left ventricular end-diastolic diameter and mass reductions correlated best with the increases in total peripheral resistance (r_0.85, P&lt;0.0001) and mean arterial blood pressure (r_0.64, P_0.006), respectively.&#x0D; Conclusions. Surgical closure of arteriovenous fistula reduces left ventricular diameter and mass in kidney transplant recipients. The best predictors of those morphological changes are the rise in blood pressure and total peripheral resistance induced by temporary occlusion of the fistula.&#x0D; Implications to Theory, Practice and Policy: Surgical closure of persistent AV fistula after renal transplantation to correct LV geometry and improve symptoms in terms of exertional dyspnea and palpitations.

Smoking, Alcohol Intake and Torque Teno Virus in Stable Kidney Transplant Recipients.

Torque Teno Virus (TTV) is a non-pathogenic virus that is highly prevalent among kidney transplant recipients (KTRs). Its circulating load is associated with an immunological status in KTR and is considered a promising tool for guiding immunosuppression. To allow for optimal guidance, it is important to identify other determinants of TTV load. We aimed to investigate the potential association of smoking and alcohol intake with TTV load. For this cross-sectional study, serum TTV load was measured using PCR in stable kidney transplant recipients at ≥1 year after transplantation, and smoking status and alcohol intake were assessed through questionnaires and measurements of urinary cotinine and ethyl glucuronide. A total of 666 KTRs were included (57% male). A total of 549 KTR (82%) had a detectable TTV load (3.1 ± 1.5 log10 copies/mL). In KTR with a detectable TTV load, cyclosporin and tacrolimus use were positively associated with TTV load (St. β = 0.46, p < 0.001 and St. β = 0.66, p < 0.001, respectively), independently of adjustment for potential confounders. Current smoking and alcohol intake of >20 g/day were negatively associated with TTV load (St. β = -0.40, p = 0.004 and St. β = -0.33, p = 0.009, respectively), independently of each other and of adjustment for age, sex, kidney function, time since transplantation and calcineurin inhibitor use. This strong association of smoking and alcohol intake with TTV suggests a need to account for the smoking status and alcohol intake when applying TTV guided immunosuppression in KTR.

Long-term clinical outcomes of late conversion to once-daily tacrolimus and sirolimus combination in stable kidney transplant recipients

Long-term clinical outcomes of late conversion to once-daily tacrolimus and sirolimus combination in stable kidney transplant recipients

Risks and Harms of Minimizing Total Immunosuppression in Stable Kidney Transplant Recipients

Risks and Harms of Minimizing Total Immunosuppression in Stable Kidney Transplant Recipients

Tacrolimus Pharmacokinetics is Associated with Gut Microbiota Diversity in Kidney Transplant Patients: Results from a Pilot Cross-Sectional Study.

Clinical use of tacrolimus (TAC), an essential immunosuppressant following transplantation, is complexified by its high pharmacokinetic (PK) variability. The gut microbiota gains growing interest but limited investigations have evaluated its contribution to TAC PKs. Here, we explore the associations between the gut microbiota composition and TAC PKs. In this pilot cross-sectional study (Clinicaltrial.gov NCT04360031), we recruited 93 CYP3A5 non-expressers stabilized kidney transplant recipients. Gut microbiota composition was characterized by 16S rRNA gene sequencing, TAC PK parameters were computed, and additional demographic and medical covariates were collected. Associations between PK parameters or diabetic status and the gut microbiota composition, as reflected by α- and β-diversity metrics, were evaluated. Patients with higher TAC area under the curve AUC/(dose/kg) had higher bacterial richness, and TAC PK parameters were associated with specific bacterial taxa (e.g., Bilophila) and amplicon sequence variant (ASV; e.g., ASV 1508 and ASV 1982 (Veillonella/unclassified Sporomusaceae); ASV 664 (unclassified Oscillospiraceae)). Building a multiple linear regression model showed that ASV 1508 (co-abundant with ASV 1982) and ASV 664 explained, respectively, 16.0% and 4.6% of the interindividual variability in TAC AUC/(dose/kg) in CYP3A5 non-expresser patients, when adjusting for hematocrit and age. Anaerostipes relative abundance was decreased in patients with diabetes. Altogether, this pilot study revealed unprecedented links between the gut microbiota composition and diversity and TAC PKs in stable kidney transplant recipients. It supports the relevance of studying the gut microbiota as an important contributor to TAC PK variability. Elucidating the causal relationship will offer new perspectives to predict TAC inter- and intra-PK variability.