Ameliorating Metabolic Profiles After Kidney Transplantation: A Protocol for an Open-Label, Prospective, Randomized, 3-Arm, Controlled Trial

Aim: High prevalence of metabolic disorders causes higher risk of cardiovascular diseases after kidney transplantation (KT), which remains the main burden impairing short-term and long-term survival. This open-label, prospective, randomized, 3-arm, controlled trial will evaluate the safety, tolerability and efficacy of metformin and empagliflozin in ameliorating metabolic profiles after KT.Methods: After a screening assessment, eligible patients with an estimated glomerular filtration rate (eGFR) >45 mL/min/1.73m2 are randomly assigned to standard triple immunosuppression alone, standard immunosuppression plus metformin (500 mg twice daily), standard immunosuppression plus empagliflozin (25 mg once daily) from discharge. The primary endpoint is the differences in the visceral-to-subcutaneous fat area ratio over 12 months, evaluated by magnetic resonance imaging (MRI). Secondary outcomes include kidney graft function, glycometabolism, lipid metabolism, and inflammatory parameters. The trial will enroll 105 kidney transplant recipients, providing 90% power to detect the difference at 5% significance.

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Relationship of Serum Bicarbonate Levels with 1-Year Graft Function in Kidney Transplant Recipients in Switzerland

Kidney & Blood Pressure Research ◽

10.1159/000502527 ◽

2019 ◽

Vol 44 (5) ◽

pp. 1179-1188 ◽

Cited By ~ 1

Author(s):

Anna Wiegand ◽

Nicole Graf ◽

Marco Bonani ◽

Diana Frey ◽

Rudolf P. Wüthrich ◽

...

Keyword(s):

Kidney Transplant ◽

Graft Function ◽

First Year ◽

Kidney Graft ◽

Serum Bicarbonate ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Open Label ◽

Post Hoc ◽

Relationship Of

Background: Metabolic acidosis (MA) is common in kidney transplant recipients (KTRs). Several studies have shown that MA is involved in the progression of chronic kidney disease. However, it is unclear if there is also a relationship between serum bicarbonate and graft function after kidney transplantation (KTx). We hypothesized that low serum bicarbonate is associated with a lower estimated glomerular filtration rate (eGFR) 1 year after KTx. Methods: We performed a post hoc analysis of a single-center, open-label randomized trial in 90 KTRs and investigated the relationship of serum bicarbonate and graft function in the first year after KTx. Results: Prevalence of MA was high after KTx (63%) and decreased to 28% after 1 year. Bicarbonate (20.6 ± 3.0 to 22.7 ± 2.7 mmol/L) increased in the first year after transplantation whereas eGFR (53.4 ± 15.8 to 56.9 ± 18.5 mL/min/1.73 m2) did not change significantly. Higher serum bicarbonate (p = 0.029) was associated with higher eGFR in the first year after KTx. Conclusion: Prevalence of MA is high in KTRs. In the first year after KTx, serum bicarbonate was positively correlated with eGFR, suggesting a potential role of MA in kidney graft function.

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Combined Immunotherapy With Belatacept and BTLA Overexpression Attenuates Acute Rejection Following Kidney Transplantation

Frontiers in Immunology ◽

10.3389/fimmu.2021.618737 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hengcheng Zhang ◽

Zijie Wang ◽

Jiayi Zhang ◽

Zeping Gui ◽

Zhijian Han ◽

...

Keyword(s):

Immune Response ◽

Kidney Transplantation ◽

Acute Rejection ◽

Serum Creatinine ◽

Graft Survival ◽

Rat Kidney ◽

Combined Therapy ◽

Graft Function ◽

Kidney Graft ◽

Term Survival

BackgroundCostimulatory blockade provides new therapeutic opportunities for ensuring the long-term survival of kidney grafts. The adoption of the novel immunosuppressant Belatacept has been limited, partly due to concerns regarding higher rates and grades of acute rejection in clinical trials. In this study, we hypothesized that a combined therapy, Belatacept combined with BTLA overexpression, may effectively attenuate acute rejection after kidney transplantation.Materials and MethodsThe rat kidney transplantation model was used to investigate graft rejection in single and combined therapy. Graft function was analyzed by detecting serum creatinine. Pathological staining was used to observe histological changes in grafts. The expression of T cells was observed by immunohistochemistry and flow cytometry. In vitro, we constructed an antigen-stimulated immune response by mixed lymphocyte culture, treated with or without Belatacept and BTLA-overexpression adenovirus, to observe the proliferation of receptor cells and the expression of cytokines. In addition, western blot and qRT-PCR analyses were performed to evaluate the expression of CTLA-4 and BTLA at various time points during the immune response.ResultsIn rat models, combined therapy reduced the serum creatinine levels and prolonged graft survival compared to single therapy and control groups. Mixed acute rejection was shown in the allogeneic group and inhibited by combination treatment. Belatacept reduced the production of DSA and the deposition of C4d in grafts. Belatacept combined with BTLA overexpression downregulated the secretion of IL-2 and IFN-γ, as well as increasing IL-4 and IL-10 expression. We also found that Belatacept combined with BTLA overexpression inhibited the proliferation of spleen lymphocytes. The duration of the elevated expression levels of CTLA-4 and BTLA differentially affected the immune response.ConclusionBelatacept combined with BTLA overexpression attenuated acute rejection after kidney transplantation and prolonged kidney graft survival, which suggests a new approach for the optimization of early immunosuppression after kidney transplantation.

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Day-Time Declamping Is Associated with Better Outcomes in Kidney Transplantation: The Circarein Study

Journal of Clinical Medicine ◽

10.3390/jcm10112322 ◽

2021 ◽

Vol 10 (11) ◽

pp. 2322

Author(s):

David Montaigne ◽

Nasser Alhawajri ◽

Mathilde Jacquelinet ◽

Amandine Coppin ◽

Marie Frimat ◽

...

Keyword(s):

Kidney Transplantation ◽

Ischemia Reperfusion ◽

Multivariable Analysis ◽

Graft Function ◽

Kidney Graft ◽

Cold Ischemia ◽

Night Time ◽

Term Survival ◽

Transplant Survival ◽

Post Transplant

Despite improvements in organ preservation techniques and efforts to minimize the duration of cold ischemia, ischemia–reperfusion (IR) injury remains associated with poor graft function and long-term survival in kidney transplantation. We recently demonstrated a clinically significant day-time variation in myocardial tolerance to IR, transcriptionally orchestrated by the circadian clock. Patient and graft post-transplant survival were studied in a cohort of 10,291 patients first transplanted between 2006 and 2017 to test whether kidney graft tolerance to IR depends on the time-of-the-day of clamping/declamping, and thus impacts graft and patient survival. Post-transplant 1- and 3-year survival decreased with increasing ischemia duration. Time-of-the-day of clamping did not influence outcomes. However, night-time (vs. day-time) declamping was associated with a significantly worse post-transplant survival. After adjustment for other predictors, night-time (vs. day-time) declamping remained associated with a worse 1-year (HR= 1.26 (1.08–1.47), p = 0.0028 by Cox multivariable analysis) and 3-year (HR= 1.14 (1.02–1.27), p = 0.021) outcome. Interestingly, the deleterious impact of prolonged ischemia time (>15 h) was partially compensated by day-time (vs. night-time) declamping. Compared to night-time declamping, day-time declamping was associated with a better prognosis of kidney transplantation despite a longer duration of cold ischemia.

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P0653THE USE OF URINARY EPIDERMAL GROWTH FACTOR FOR EVALUATION OF KIDNEY GRAFT FUNCTION

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0653 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Joe Chan ◽

Ivar Anders Eide ◽

Trond Geir Jenssen ◽

Bård Waldum-Grevbo ◽

Tone Møller Tannæs ◽

...

Keyword(s):

Kidney Transplantation ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Serum Creatinine ◽

Graft Function ◽

Kidney Graft ◽

Kidney Transplant Recipients ◽

Component Score ◽

Increased Risk ◽

Epidermal Growth

Abstract Background and Aims Follow-up after kidney transplantation requires repeated, reliable glomerular filtration rate (GFR) measurements. Measured GFR (mGFR), using urinary or plasma clearance of an exogenous filtration marker such as iohexol, provides precise measurements but are expensive and time consuming. Instead, estimated GFR (eGFR) based on serum creatinine is most commonly used in clinical practice. Epidermal growth factor is produced in the kidney and promotes tubular cell regeneration and recovery of kidney function after injury. Low levels of urinary epidermal growth factor (uEGF) are linked to progression of chronic kidney disease and increased risk of kidney graft failure. The aim of this study was to investigate uEGF as an additional marker to evaluate graft function in kidney transplant recipients (KTRs). Method Participants in the Omega-3 fatty acids in Renal Transplantation (ORENTRA) trial were examined with mGFR by iohexol clearance at 1 year after kidney transplantation. The concentration of iohexol in serum was measured 3 and 4 hours after iv injection. On the same day, fasting blood and urine samples were obtained in the morning. Serum creatinine was measured and eGFR calculated with the MDRD formula. uEGF and a pre-specified selection of inflammation and fibrosis markers were measured with multiplex immunoassay technique and normalized with urinary creatinine. Principal component analysis (PCA) was used to explore clustering of markers. Correlations were calculated with Pearson’s correlation coefficient R. Results Fifty-nine participants had complete measurements of mGFR (57.2 ± 15.2 mL/min/1.73m2), eGFR (68.6 ± 23.0 mL/min/1.73m2) and uEGF. The correlation between mGFR and eGFR was strong (R=0.783, P<0.001). Measurements of uEGF had a coefficient of variation below 10% for all participants, with a mean value of 22.0 ± 12.1 μg/g creatinine. There was a significant correlation between mGFR and uEGF (R=0.678, P<0.001). The component score of uEGF and eGFR calculated with PCA (74% of variance) had the strongest correlation with mGFR (R=0.845, P<0.001). Conclusion Combining uEGF with eGFR into one component score by PCA gives a greater correlation with mGFR compared to eGFR alone in this cohort of KTRs. These findings need to be validated in other patient populations.

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B-cell activating factor BAFF as a novel alert marker for the immunological risk stratification after kidney transplantation

Immunologic Research ◽

10.1007/s12026-021-09205-4 ◽

2021 ◽

Author(s):

Antonia Margarete Schuster ◽

N. Miesgang ◽

L. Steines ◽

C. Bach ◽

B. Banas ◽

...

Keyword(s):

Kidney Transplantation ◽

B Cell ◽

Graft Function ◽

Risk Profile ◽

Kidney Transplant Recipients ◽

Post Transplantation ◽

Antibody Mediated Rejection ◽

B Cell Activating Factor ◽

Medium Risk ◽

Patients At Risk

AbstractThe B cell activating factor BAFF has gained importance in the context of kidney transplantation due to its role in B cell survival. Studies have shown that BAFF correlates with an increased incidence of antibody-mediated rejection and the development of donor-specific antibodies. In this study, we analyzed a defined cohort of kidney transplant recipients who were treated with standardized immunosuppressive regimens according to their immunological risk profile. The aim was to add BAFF as an awareness marker in the course after transplantation to consider patient’s individual immunological risk profile. Included patients were transplanted between 2016 and 2018. Baseline data, graft function, the occurrence of rejection episodes, signs of microvascular infiltration, and DSA kinetics were recorded over 3 years. BAFF levels were determined 14 d, 3 and 12 months post transplantation. Although no difference in graft function could be observed, medium-risk patients showed a clear dynamic in their BAFF levels with low levels shortly after transplantation and an increase in values of 123% over the course of 1 year. Patients with high BAFF values were more susceptible to rejection, especially antibody-mediated rejection and displayed intensified microvascular inflammation; the combination of high BAFF + DSA puts patients at risk. The changing BAFF kinetics of the medium risk group as well as the increased occurrence of rejections at high BAFF values enables BAFF to be seen as an awareness factor. To compensate the changing immunological risk, a switch from a weaker induction therapy to an intensified maintenance therapy is required.

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Graft Pre-conditioning by Peri-Operative Perfusion of Kidney Allografts With Rabbit Anti-human T-lymphocyte Globulin Results in Improved Kidney Graft Function in the Early Post-transplantation Period—a Prospective, Randomized Placebo-Controlled Trial

Frontiers in Immunology ◽

10.3389/fimmu.2018.01911 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 2

Author(s):

Paul V. Ritschl ◽

Julia Günther ◽

Lena Hofhansel ◽

Anja A. Kühl ◽

Arne Sattler ◽

...

Keyword(s):

T Lymphocyte ◽

Controlled Trial ◽

Graft Function ◽

Kidney Graft ◽

Post Transplantation ◽

Human T Lymphocyte

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Effect of conversion from calcineurin inhibitors to everolimus on hepatitis C viremia in adult kidney transplant recipients

Brazilian Journal of Nephrology ◽

10.1590/2175-8239-jbn-3860 ◽

2018 ◽

Vol 40 (2) ◽

pp. 143-150 ◽

Cited By ~ 1

Author(s):

Larissa Sgaria Pacheco ◽

Valter Duro Garcia ◽

Ronivan Luis Dal Prá ◽

Bruna Doleys Cardoso ◽

Mariana Ferras Rodrigues ◽

...

Keyword(s):

Hepatitis C ◽

Controlled Trial ◽

Calcineurin Inhibitors ◽

Control Group ◽

P Value ◽

Kidney Transplant Recipients ◽

Positive Serology ◽

Open Label ◽

Adult Kidney ◽

Group 1

ABSTRACT Introduction: Currently, there is no specific immunosuppressive protocol for hepatitis C (HCV)-positive renal transplants recipients. Thus, the aim of this study was to evaluate the conversion effect to everolimus (EVR) on HCV in adult kidney recipients. Method: This is an exploratory single-center, prospective, randomized, open label controlled trial with renal allograft recipients with HCV-positive serology. Participants were randomized for conversion to EVR or maintenance of calcineurin inhibitors. Results: Thirty patients were randomized and 28 were followed-up for 12 months (conversion group, Group 1 =15 and control group, Group 2 =13). RT-PCR HCV levels reported in log values were comparable in both groups and among patients in the same group. The statistical analysis showed no interaction effect between time and group (p value G*M= 0.852), overtime intra-groups (p-value M=0.889) and between group (p-value G=0.286). Group 1 showed a higher incidence of dyslipidemia (p=0.03) and proteinuria events (p=0.01), while no difference was observed in the incidence of anemia (p=0.17), new onset of post-transplant diabetes mellitus (p=1.00) or urinary tract infection (p=0.60). The mean eGFR was similar in both groups. Conclusion: Our study did not show viral load decrease after conversion to EVR with maintenance of antiproliferative therapy.

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