Tacrolimus-based Immunosuppression Research Articles

α- or β-Adrenergic blockade does not affect transplanted islet cell responses to hypoglycemia in type 1 diabetes.

Type 1 diabetes recipients of intrahepatic islet transplantation exhibit glucose-dependent suppression of insulin and activation of glucagon secretion in response to insulin-induced hypoglycemia associated with clinical protection from hypoglycemia. Whether sympathetic activation of adrenergic receptors on transplanted islets is required for these responses in defense against hypoglycemia is not known. To evaluate the adrenergic contribution to post-transplant glucose counterregulation, we performed a randomized, double-blind crossover study of responses during a hyperinsulinemic euglycemic-hypoglycemic clamp under phentolamine (α-adrenergic blockage), propranolol (β-adrenergic blockage), or placebo infusion. Participants (5 female/4 male) were median (range) age 53 (34-63) years, diabetes duration 29 (18-56) years, post-transplant 7.0 (1.9-8.4) years, HbA1c 5.8 (4.5-6.8)%, insulin in-/dependent 5/4, all on tacrolimus-based immunosuppression. During the clamp, blood pressure was lower with phentolamine and heart rate lower with propranolol vs. placebo (P <0.05). There was no difference in suppression of endogenous insulin secretion (derived from C-peptide measurements) during the euglycemic or hypoglycemic phases, and while levels of glucagon were similar with phentolamine or propranolol vs. placebo, the increase in glucagon from eu- to hypoglycemia was greater with propranolol vs. placebo (P < 0.05). Pancreatic polypeptide was greater with phentolamine vs. placebo during the euglycemic phase (P < 0.05), and free fatty acids were lower and the glucose infusion rate higher with propranolol vs. placebo during the hypoglycemic phase (P < 0.05). These results indicate that neither physiologic α- nor β-adrenergic blockade attenuates transplanted islet responses to hypoglycemia, suggesting sympathetic re-innervation of the islet graft is not necessary for post-transplant glucose counterregulation.

#2047 Trough-level guided dosing is reliable for mycophenolate mofetil but not for enteric-coated mycophenolic sodium

Abstract Background and Aims While trough level (TL) guided dosing is usus for calcineurin inhibitors, mycophenolic acid (MPA) was marketed as a one-size-fits-all drug. TL has been reported to be a poor surrogate marker of MPA exposure by reason of complex pharmacokinetics. Measurement of area under the curve (AUC) remains the gold-standard for MPA dosing. Method We measured MPA TL and AUC in 299 KTRs at the University Hospital of Zurich. KTRs with agreement between TL and AUC target range of 40-60 mg/Lxh were compared to KTRs with missing agreement between TL and AUC for differences regarding baseline characteristics and co-medication. Results For mycophenolate mofetil (MMF, n = 218) a high correlation between TL and AUC was observed, p &amp;lt; 0.0001, r = 0.85, while correlation was only low for enteric-coated mycophenolate sodium (EC-MPS, n = 81), p = 0.002, r = 0.34, Fig. 1. However, a high correlation between MPA level 4 hours after EC-MPS intake (C4L) and AUC was found, p &amp;lt; 0.0001, r = 0.94. ROC analysis defined an MMF-TL range of &amp;gt;2.05 mg/l (sensitivity 68%, specificity 89%) and &amp;lt;3.05 mg/l (sensitivity 70%, specificity 81%) correlating with an AUC of 40-60 mg/Lxh. Lack of proton pump inhibitors (PPI) use was significantly associated with incorrect classification (n = 71/218). For EC-MPS C4L a range of &amp;gt;1.25 mg/l (sensitivity 98, specificity 100) and &amp;lt;4.4 mg/l (sensitivity 93, specificity 91) was defined for an AUC of 40-60 mg/Lxh. Here, non-tacrolimus-based immunosuppression was significantly associated with incorrect classification (n = 7/81). Conclusion MMF dosing according to TL highly correlates with AUC especially in KTRs treated with PPI. In contrast, EC-MPS dosing according to C4L is preferred especially in context of tacrolimus-based immunosuppression.

Human MuStem cells are competent to fuse with nonhuman primate myofibers in a clinically relevant transplantation context: A proof-of-concept study.

We previously reported that human muscle-derived stem cells (hMuStem cells) contribute to tissue repair after local administration into injured skeletal muscle or infarcted heart in immunodeficient rodent models. However, extrapolation of these findings to a clinical context is problematic owing to the considerable differences often seen between in vivo findings in humans versus rodents. Therefore, we investigated whether the muscle regenerative behavior of hMuStem cells is maintained in a clinically relevant transplantation context. Human MuStem cells were intramuscularly administered by high-density microinjection matrices into nonhuman primates receiving tacrolimus-based immunosuppression thereby reproducing the protocol that has so far produced the best results in clinical trials of cell therapy in myopathies. Four and 9 weeks after administration, histological analysis of cell injection sites revealed large numbers of hMuStem cell-derived nuclei in all cases. Most graft-derived nuclei were distributed in small myofiber groups in which no signs of a specific immune response were observed. Importantly, hMuStem cells contributed to simian tissue repair by fusing mainly with host myofibers, demonstrating their capacity for myofiber regeneration in this model. Together, these findings obtained in a valid preclinical model provide new insights supporting the potential of hMuStem cells in future cell therapies for muscle diseases.

Effects of Antithymocyte Globulin, Basiliximab, and Induction-Free Treatment in Living Donor Kidney Transplant Recipients on Tacrolimus-Based Immunosuppression.

Induction treatment in renal transplant is associated with better graft survival. However, intensified immunosuppression is known to cause unwanted side effects such as infection and malignancy. Furthermore, the effects of the routine use of immunosuppressants in low-risk kidney transplant recipients are still not clear. In this study, we assessed the first-year safety and efficacy of induction treatment. We examined first living donor kidney transplant patients who were on tacrolimus based immunosuppression therapy. We formed 3 groups according to the induction status: antithymocyte globulin induction, basiliximab induction, and no induction. We collected outcome data on delayed graft function, graft loss, creatinine levels, estimated glomerular filtration rates, acute rejection episodes, hospitalization episodes, and infection episodes, including cytomegalovirus infection and bacterial infections. We examined a total of 126 patients (age 35 ± 12 years; 65% male). Of them, 25 received antithymocyte globulin, 52 received basiliximab, and 49 did notreceive any induction treatment. We did not observe any statistically significant difference among the 3 groups in terms of acute rejection episodes, delayed graft function, and first-year graft loss. The estimated glomerular filtration rates were similar among the groups. Overall bacterial infectious complications and cytomegalovirus infection showed similar prevalence among all groups. Hospitalization was less common in the induction-free group. In low-risk patients, induction-free regimens could be associated with a better safety profile without compromising graft survival. Therefore, induction treatment may be disregarded in first living donor transplant patients who receive tacrolimusbased triple immunosuppression treatment.

Tacrolimus-induced leukopenia in a kidney transplant recipient: A case study

Introduction: Leukopenia occurs in 10%-55% of patients after kidney transplant and neutropenia occurs in approximately 28% of patients after kidney transplant. Resolution of leukopenia and neutropenia is done through treatment of the pathogen, such as cytomegalovirus, or removing the offending medication. Medications that are first thought to contribute to leukopenia include Valganciclovir, Sulfamethoxazole-Trimethoprim, and Mycophenolic Acid. Tacrolimus rarely contributes to leukopenia and neutropenia post kidney transplantation.Case presentation: This case study presents a patient who developed leukopenia and neutropenia 13 weeks after solitary kidney transplantation.Management: Mycophenolate Mofetil, Valganciclovir, Ergocalciferol, Aspirin, Famotidine, and Sulfamethoxazole-Trimethoprim were all discontinued. Filgrastim was used intermittently to increase white blood cell count. Ultimately, Tacrolimus was switched to Cyclosporine.Outcome: Leukopenia was resolved by switching Tacrolimus to Cyclosporine-based immunosuppression.Discussion: A systematic approach should be taken to resolve leukopenia post-kidney transplant. When a kidney transplant recipient is on Tacrolimus-based immunosuppression, Tacrolimus should be the last medication changed when attempting to resolve leukopenia.

Influence of Cyp3A4, Cyp3A5 and ABCB1 Polymorphisms on Tacrolimus Concentrations and Rejection Risk in Indian Kidney Transplant Recipients

Background: Tacrolimus metabolism is known to be determined by gene polymorphisms. Cyp3A5 genotype has most widely been seen to be associated with tacrolimus metabolism. Studies on other genes have produced mixed results. Objective: We studied the association of three polymorphisms CYP3A4*1B (-392 G&gt;A), CYP3A5 (6986 A&gt;G), and ABCB1 (3435 T&gt;C) on tacrolimus levels and their association with either rejection or nephrotoxicity (infection or tacrolimus toxicity) in renal transplant recipients from India. Materials and Methods: In this prospective cohort study, patients who underwent kidney transplantation between July 2018 and July 2023 were studied. Inclusion criteria: Patients who underwent Kidney Transplantation and were (i) on tacrolimus-based immunosuppression and (ii) not on medications known to interact with calcineurin inhibitors, such as ketoconazole, phenytoin, and diltiazem, were studied. Tacrolimus levels, tacrolimus concentration/dose (C/D) and tacrolimus C/D per kg body weight, at monthly time points posttransplant for 6 months and biopsy-proven rejection, infection, tacrolimus toxicity, and acute tubular necrosis data were collected. Results: Three hundred and twenty-seven patients were included in the study. Two hundred and fifty-seven were male and 70 were female. A total of 1402 tacrolimus samples were collected, with an average of 3.2 ± 2.1 samples per patient. Tacrolimus levels were significantly lower in the Cyp3A5 AG and AA GG genotypes versus GG (5.27 ± 2.95 and 6.22 ± 2.79 vs. 8.05 ± 4.83, P &lt; 0.001) as were C/D (3.45 ± 2.29 and 3.37 ± 1.91 vs. 6.47 ± 4.44, P &lt; 0.001) and C/D/W (52.45 ± 33.98 and 52.19 ± 32.61 vs. 98.09 ± 73.80, P &lt; 0.001). Cyp3A5 AA and AG had higher rejection rates than GG (20% vs. 13 vs. 8%, P = 0.03). The relative risk of rejection with A versus G polymorphism was 1.9 (confidence interval: 1.03–3.58), P = 0.03. Cyp3A4 and ABCB1 polymorphism studies did not show any association with the parameters studied. Conclusion: Our study showed that Cyp3A5 gene polymorphisms were significantly associated with tacrolimus metabolism, rejection episodes, and rejection risk. Cyp3A4 and ABCB1 were not significantly associated with the parameters studied.

Tacrolimus Interaction with Azole Antifungals in Kidney Transplant Recipients: Is Fluconazole or Clotrimazole a Worse Offender?

The utilization of rabbit ant thymocyte globulin induction with tacrolimus-based maintenance immunosuppression may increase the risk for opportunistic fungal infections, particularly oral-esophageal candidiasis. Both are commonly prescribed for deceased donor kidney transplant recipients Tacrolimus (TAC), a calcineurin inhibitor, is metabolized hepatically by cytochrome P450 3A4/5 enzymes. Due to this, a drug interaction can occur with TAC and either fluconazole (FCZ) or clotrimazole (CTMZ). Both are commonly used for antifungal prophylaxis. While both FCZ and CTMZ inhibit CYP3A4/5, systemic absorption of CTMZ is minimal, theoretically limiting the interaction with TAC and reducing the need for dose readjustments. Medical records for adult patients receiving a renal transplant between March 2009 and September 2011 were retrospectively reviewed for TAC dose adjustments following discontinuation of the antifungal agent required to maintain therapeutic TAC blood levels. The change in TAC dose: trough ratio 4-8 weeks after azole discontinuation was greater in patients receiving FCZ compared to CTMZ (FCZ +92.9% vs CTMZ +43.4%, p=0.004). In addition, the proportion of patients requiring ≥30% TAC dose increase was 70% with FCZ versus 45% with CTMZ (p=0.006). The choice of antifungal also did not affect the number of sub-therapeutic TAC levels, the number of patients with sub-therapeutic levels pre- or post-discontinuation, or incidence of biopsy-proven allograft rejection.

Evaluation of Humoral Response following SARS-CoV-2 mRNA-Based Vaccination in Liver Transplant Recipients Receiving Tailored Immunosuppressive Therapy.

Background: The role of tailored immunosuppression (IS) in the development of the humoral response (HR) to SARS-CoV-2 mRNA-based vaccination in liver transplant (LT) recipients is unknown. Methods: This is a single-centre prospective study of patients who underwent LT between January 2015 and December 2021 and who have received three doses of mRNA-based SARS-CoV-2 vaccination. Patients undergoing Tacrolimus-based immunosuppression (TAC-IS) were compared with those undergoing Everolimus-based immunosuppression (EVR-IS). Patients receiving the TAC-EVR combination were divided into two groups based on trough TAC concentrations, i.e., above or below 5 ng/mL. HR (analysed with ECLIA) was assessed at 30 to 135 days after vaccination. The primary outcome was the presence of a positive antibody titre (≥0.8 U/mL). Secondary outcomes were the presence of a highly protective antibody titre (≥142 U/mL), median antibody titre, and incidence of COVID-19. Results: Sixty-one participants were included. Twenty-four (40%) were receiving TAC-IS and thirty-seven (60%) were receiving EVR-IS. At the median follow-up of 116 (range: 89-154) days, there were no significant differences in positive antibody titre (95.8% vs. 94.6%; p = 0.8269), highly-protective antibody titre (83.3% vs. 81.1%; p = 0.8231), median antibody titre (2410 [IQ range 350-2500] vs. 1670 [IQ range 380-2500]; p = 0.9450), and COVID-19 incidence (0% vs. 5.4%; p = 0.5148). High serum creatinine and low estimated glomerular filtration rate were risk factors for a weak or absent HR. Conclusions: Three doses of mRNA-based SARS-CoV-2 vaccination yielded a highly protective HR in LT recipients. The use of TAC or EVR-based IS does not appear to influence HR or antibody titre, while renal disease is a risk factor for a weak or null HR.

Belatacept with time-limited tacrolimus coimmunosuppression modifies the 3-year risk of eplet mismatch in kidney transplantation

Solid organ transplant donor-recipient eplet mismatch has been correlated with donor-specific antibody (DSA) formation, antibody-mediated rejection, and overall rejection rates. However, studies have been predominantly in patients on tacrolimus-based immunosuppression regimens and have not fully explored differences in ethnically and racially diverse populations. Evidence indicates that patients on belatacept have lower rates of DSA formation, suggesting mediation of the immunogenicity of mismatched human leukocyte antigen polymorphisms. We performed a retrospective, single-center analysis of class II eplet disparity in a cohort of kidney transplant recipients treated using belatacept with tacrolimus induction (Bela/TacTL) or tacrolimus regimens between 2016 and 2019. Bela/TacTL (n = 294) and tacrolimus (n = 294) cohorts were propensity score-matched with standardized difference <0.15. Single-molecule eplet risk level was associated with immune event rates for both groups. In Cox regression analysis stratified by eplet risk level, Bela/TacTL immunosuppression was associated with a decreased rate of DSA (hazard ratio [HR] = 0.4), antibody-mediated rejection (HR = 0.2), and rejection (HR = 0.45). In the low-risk group, cumulative graft failure was lower for patients on Bela/TacTL (P < .02). Analysis of eplet mismatch burden may be a useful adjunct in identifying high-risk populations with increased immunosuppression requirements and should encourage the design of allocation rules to incentivize lower-risk pairings without negatively impacting equity in access.

Voclosporin and the Antiviral Effect Against SARS-CoV-2 in Immunocompromised Kidney Patients

Immunocompromised kidney patients are at increased risk of prolonged SARS-CoV-2 infection and related complications. Preclinical evidence demonstrates a more potent inhibitory effect of voclosporin on SARS-CoV-2 replication than tacrolimus invitro. We investigated the potential antiviral effects of voclosporin on SARS-CoV-2 in immunocompromised patients. First, we conducted a prospective, randomized, open-label, proof-of-concept study in 20 kidney transplant recipients (KTRs) on tacrolimus-based immunosuppression who contracted mild to moderate SARS-CoV-2 infection. Patients were randomized to continue tacrolimus or switch to voclosporin. Second, we performed a post hoc analysis on SARS-CoV-2 infections in 216 patients with lupus nephritis (LN) on standard immunosuppression who were randomly exposed to voclosporin or placebo as part of a clinical trial that was conducted during the worldwide COVID-19 pandemic. The primary end point was clearance of SARS-CoV-2 viral load and that did not differ between voclosporin-treated KTRs (median 12 days, interquartile range [IQR] 8-28) and tacrolimus-treated KTRs (median 12 days, IQR 4-16) nor was there a difference in clinical recovery. Pharmacokinetic analyses demonstrated that, when voclosporin trough levels were on-target, SARS-CoV-2 viral load dropped significantly more (ΔCt 7.7 [3.4-10.7]) compared to tacrolimus-treated KTRs (ΔCt 2.7 [2.0-4.3]; P= 0.035). In voclosporin-exposed patients with LN, SARS-CoV-2 infection was detected in 6% (7/116) compared to 12% (12/100) in placebo-exposed patients (relative risk [RR] 1.4 [0.97-2.06]). Notably, no voclosporin-exposed patients with LN died from severe SARS-CoV-2 infection compared to 3% (3/100) in placebo-exposed patients (RR 2.2 [1.90-2.54]). This proof-of-concept study shows a potential positive risk-benefit profile for voclosporin in immunocompromised patients with SARS-CoV-2 infection. These results warrant further investigations on voclosporin to establish an equipoise between infection and maintenance immunosuppression.

Cost-Effectiveness of Tacrolimus Compared With Cyclosporine for Immunosuppression Therapy in Patients Who Underwent Heart Transplant in Colombia

ObjectivesTo evaluate the cost-effectiveness of pharmacological treatment in maintenance therapy for adult heart transplant recipients from the Colombian health system perspective. MethodsWe constructed a decision tree model with a 1-year time horizon. A review of the clinical literature was performed to extract probabilities of health events and acute rejections avoided were used as the health outcome. Costs were calculated from the base-case approximation and were obtained from administrative databases in Colombia (Sistema de Información de Precios de Medicamentos 2020 and Suficiencia 2012-2019), and the prices were adjusted to US dollar 2021. ResultsTwo evaluation results were presented. The first evaluates the tacrolimus + azathioprine + corticosteroid (TAC) scheme compared with cyclosporine + azathioprine + corticosteroid (CAC), in which the incremental cost-effectiveness ratio indicates that 1 additional rejection avoided has a cost of US dollar $5461.09 which, compared with the cost-effectiveness threshold in the base case, indicates that the TAC scheme is not a cost-effective (CE) strategy with respect to the CAC scheme. The second result shows the comparison of tacrolimus + mycophenolate mofetil + corticosteroid (TMC) with cyclosporine + mycophenolate mofetil + corticosteroid (CMC) in which TMC was found to be a dominant alternative to CMC. ConclusionsThe tacrolimus-based immunosuppression scheme is not CE in its TAC scheme, versus CAC, and is dominant in its TMC scheme, versus CMC, sensitivity analyses show that tacrolimus could become a CE alternative in any scheme used against higher cost-effectiveness threshold.

Long-term outcomes and health-related quality of life 20 years after pediatric liver transplantation

Pediatric liver transplantation is a challenging surgical procedure requiring complex post-transplant patient management. Liver transplantation in children should ensure long-term survival and good health-related quality of life (HR-QOL), but data in the literature are conflicting. With the aim of investigating survival and psychosocial outcomes of patients transplanted during childhood, we identified 40 patients with ≥ 20-year follow-up after liver transplantation regularly followed up at our Institution. Clinical charts were reviewed to retrieve patients’ data. Psychosocial aspects and HR-QOL were investigated by an in-person or telephonic interview and by administering the WHOQOL-BREF questionnaire through an online form. Ten- and 20-year patient survival was 97.5% (95% CI 92.8–100%), whereas 10- and 20-year graft survival was 77.5% (65.6–91.6%) and 74.8% (62.5–89.6%), respectively. At last follow-up visit, 31 patients (77.5%) were receiving a tacrolimus-based immunosuppression. Twelve (32.4%) patients obtained a university diploma or higher, whereas 19 (51.4%) successfully completed high school. 81.1% of patients were active workers or in education, 17.5% had children, and 35% regularly practiced sport. 25 patients answered to the WHOQOL-BREF questionnaire. More than 60% of respondents did not report any disability and the perceived physical status was invariably good or very good. Median scores for physical health, psychological health, social relationships, and environment were 16.6, 14.7, 16, and 15, respectively. Pediatric liver transplantation is associated with excellent long-term survival and good HR-QOL. Psychological health and environment represent areas in which support would be needed to further improve HR-QOL.

Pediatric Lung Transplant Outcomes Based on Immunosuppressive Regimen at Discharge: Retrospective Cohort Study Using Real-World Evidence From the US Scientific Registry of Transplant Recipients

This retrospective analysis of the US Scientific Registry of Transplant Recipients was undertaken to obtain real-world evidence concerning the efficacy and safety of tacrolimus-based immunosuppression in pediatric lung transplant recipients to support a supplemental New Drug Application. Overall, 725 pediatric recipients of a primary deceased-donor lung transplant between January 1, 1999, and December 31, 2017, were followed for up to 3 years post-transplant based on an immunosuppressive regimen at hospital discharge: immediate-release tacrolimus (TAC)+mycophenolate mofetil (MMF), TAC+azathioprine (AZA), cyclosporine (CsA)+MMF, or CsA+AZA. The primary outcome was the composite endpoint of graft failure or death (all-cause) at 1 year post-transplant, calculated by Kaplan-Meier analysis. The use of TAC+MMF increased over time. During 2010 to 2017, 91.7% of pediatric lung transplant recipients were receiving TAC+MMF at the time of discharge. The proportion of recipients continuing their discharge regimen at 1 year post-transplant was 83.7% with TAC+MMF and 40.4% to 59.7% with the other regimens. Cumulative incidence of the composite endpoint of graft failure or death at 1 year post-transplant was 7.7% with TAC+MMF, 13.9% with TAC+AZA, 8.9% with CsA+MMF, and 9.1% with CsA+AZA. There was no significant difference in the risk of graft failure or death at 1 year post-transplant between groups from 1999 to 2005 (the only era when adequate numbers on each regimen allowed statistical comparison). No increase in hospitalization for infection or malignancy was seen with TAC+MMF. The real-world evidence from the US database of transplant recipients supported the Food and Drug Administration's approval of tacrolimus-based maintenance immunosuppression in pediatric lung transplant recipients.

Desensitization and belatacept-based maintenance therapy in pregnancy-sensitized monkeys receiving a kidney transplant.

Among sensitized patients awaiting a transplant, females are disproportionately represented, partly because of pregnancy-induced sensitization. Using female NHPs sensitized by pregnancy alone, we examined the efficacy of costimulation blockade and proteasome inhibition for desensitization. Three animals received no desensitization (control), and seven animals received weekly carfilzomib (27 mg/m2) and belatacept (20 mg/kg) before kidney transplantation. All animals received renal allografts from crossmatch-positive/maximally MHC-mismatched donors. Controls and three desensitized animals received tacrolimus-based immunosuppression. Four desensitized animals received additional belatacept with tacrolimus-based immunosuppression. Multiparous females had less circulating donor-specific antibody when compared to skin-sensitized males before transplantation. While females receiving desensitization showed only a marginal survival benefit over control females (MST = 11 days versus 63 days), additional belatacept to posttransplant maintenance significantly prolonged graft survival (MST > 164 days) and suppressed posttransplant DSA and circulating follicular helper T-like cells. This combination of therapies demonstrates great potential to reduce antibody-mediated rejection in sensitized recipients.

(757) Prolonged-Release Tacrolimus-Based Immunosuppression in Heart Transplant Recipients: 5-Year Follow-Up

(757) Prolonged-Release Tacrolimus-Based Immunosuppression in Heart Transplant Recipients: 5-Year Follow-Up

A multicentre, patient- and assessor-blinded, non-inferiority, randomised and controlled phase II trial to compare standard and torque teno virus-guided immunosuppression in kidney transplant recipients in the first year after transplantation: TTVguideIT

BackgroundImmunosuppression after kidney transplantation is mainly guided via plasma tacrolimus trough level, which cannot sufficiently predict allograft rejection and infection. The plasma load of the non-pathogenic and highly prevalent torque teno virus (TTV) is associated with the immunosuppression of its host. Non-interventional studies suggest the use of TTV load to predict allograft rejection and infection. The primary objective of the current trial is to demonstrate the safety, tolerability and preliminary efficacy of TTV-guided immunosuppression.MethodsFor this purpose, a randomised, controlled, interventional, two-arm, non-inferiority, patient- and assessor-blinded, investigator-driven phase II trial was designed. A total of 260 stable, low-immunological-risk adult recipients of a kidney graft with tacrolimus-based immunosuppression and TTV infection after month 3 post-transplantation will be recruited in 13 academic centres in six European countries. Subjects will be randomised in a 1:1 ratio (allocation concealment) to receive tacrolimus either guided by TTV load or according to the local centre standard for 9 months. The primary composite endpoint includes the occurrence of infections, biopsy-proven allograft rejection, graft loss, or death. The main secondary endpoints include estimated glomerular filtration rate, graft rejection detected by protocol biopsy at month 12 post-transplantation (including molecular microscopy), development of de novo donor-specific antibodies, health-related quality of life, and drug adherence. In parallel, a comprehensive biobank will be established including plasma, serum, urine and whole blood. The date of the first enrolment was August 2022 and the planned end is April 2025.DiscussionThe assessment of individual kidney transplant recipient immune function might enable clinicians to personalise immunosuppression, thereby reducing infection and rejection. Moreover, the trial might act as a proof of principle for TTV-guided immunosuppression and thus pave the way for broader clinical applications, including as guidance for immune modulators or disease-modifying agents.Trial registrationEU CT-Number: 2022-500024-30-00

Long-term prolonged-release tacrolimus outcomes in living donor kidney transplantation: The Japan Academic Consortium of Kidney Transplantation study-II.

To evaluate the 10-year efficacy and safety of a prolonged-release tacrolimus-based combination immunosuppressive regimen on longer-term outcomes in living donor kidney transplantation. Data from Japanese living donor kidney transplant recipients (n= 410) maintained on continuous prolonged-release tacrolimus-based immunosuppression from 2009-2013 were analyzed with a median follow-up of 9.9 years. A prolonged-release, tacrolimus-based combination regimen provided death-censored graft failure and all-cause death rates at 10 years of 7.0% and 6.8%, respectively. In multivariable analyses, acute and chronic rejection and 'throughout' (new-onset plus preexisting) diabetes mellitus were risk factors for death-censored graft failure. Recipient age ≥ 65 years, throughout diabetes mellitus and malignancy were common risk factors for all-cause death. Throughout diabetes mellitus was the most common risk factor for both death-censored graft failure and all-cause death. Additional analyses showed 10-year cumulative rates of death-censored graft failure were 14.0% and 5.4% for recipients with or without preexisting diabetes mellitus, respectively (log-rank test: p= 0.009). All-cause death rates were 12.7% and 5.4% in the preexisting and non-diabetes mellitus groups, respectively (log-rank test: p= 0.023). In this real-world, retrospective, living donor kidney transplantation study, a prolonged-release tacrolimus-based immunosuppressive combination regimen provided 10-year death-censored graft failure rates of 14.0% and 5.4% in diabetes mellitus and non-diabetes mellitus patients, respectively; Similarly, 10-year all-cause death rates were 12.7% and 5.4% in diabetes mellitus and non-diabetes mellitus patients, respectively. To our knowledge, the data in this study are the first to provide 10-year transplant outcomes in living donor kidney transplant recipients under prolonged-release tacrolimus-based regimen.

Long-term Prolonged-release Tacrolimus-based Immunosuppression in De Novo Kidney Transplant Recipients: 5-Y Prospective Follow-up of Patients in the ADVANCE Study.

ADVANCE was a 24-wk, randomized, open-label, phase-4 study. De novo KTPs received PR-T with basiliximab and mycophenolate mofetil and were randomized to receive an intraoperative corticosteroid bolus plus tapered corticosteroids until day 10 (arm 1) or an intraoperative corticosteroid bolus (arm 2). In this 5-y, noninterventional follow-up, patients received maintenance immunosuppression according to standard practice. The primary endpoint was graft survival (Kaplan-Meier). Secondary endpoints included patient survival, biopsy-confirmed acute rejection-free survival, and estimated glomerular filtration rate (4-variable modification of diet in renal disease). Follow-up study included 1125 patients. Overall graft survival at 1 and 5 y posttransplantation was 93.8% and 88.1%, respectively, and was similar between treatment arms. At 1 and 5 y, patient survival was 97.8% and 94.4%, respectively. Five-year graft and patient survival rates in KTPs who remained on PR-T were 91.5% and 98.2%, respectively. Cox proportional hazards analysis demonstrated similar risk of graft loss and death between treatment arms. Five-year biopsy-confirmed acute rejection-free survival was 84.1%. Mean ± standard deviation values of estimated glomerular filtration rate were 52.7 ± 19.5 and 51.1 ± 22.4 mL/min/1.73 m2 at 1 and 5 y, respectively. Fifty adverse drug reactions were recorded, probably tacrolimus-related in 12 patients (1.5%). Graft survival and patient survival (overall and for KTPs who remained on PR-T) were numerically high and similar between treatment arms at 5 y posttransplantation.

Improved Arterial Stiffness Indices 3 and 6 Months after Living-donor Renal Transplantation.

Arterial stiffness is a non-traditional risk factor of cardiovascular disease and may explain part of the excess cardiovascular risk in chronic kidney disease patients. Successful renal transplantation (RT) may restore renal function and improve several metabolic abnormalities involved in arterial stiffness. This prospective study conducted non-invasive assessments of arterial stiffness indices [the augmentation index (AI) and pulse wave velocity (PWV)] in end-stage kidney disease (ESKD) patients before RT and 3 and 6 months after living-donor RT, alongside the effects of age and calcineurin inhibitors on arterial stiffness. The study included 26 ESKD patients (22 males and 4 females; mean age, 34.07 years; median duration of dialysis, 10 months) scheduled for RT and followed up for three visits (within 1 week before transplantation, and 3 and 6 months after transplantation). Six months after successful RT, the patients had nearly normal serum creatinine and significantly improved serum phosphate and intact parathyroid hormone levels. The pretransplant AI was 21.53% ± 13.61% which reduced significantly 6 months after RT to 16.19% ± 10.74% (P <0.05). Although there was a reduction in PWV 6 months after RT from the pre-transplant PWV, it was not significant. A significant correlation between age and the augmentation index was noted 3 and 6 months after RT. Patients on tacrolimus-based immunosuppression after RT showed significant improvements in the AI compared with patients on a cyclosporine-based regimen. RT helped to improve arterial stiffness indices, resulting in reduced cardiovascular risk.

Real-world utilization and acceptance of tacrolimus-based immunosuppression in solid organ transplant recipients in India

&lt;p&gt;&lt;strong&gt;Background:&lt;/strong&gt; The objectives of the study were to describe the demographics and utilization pattern of tacrolimus (TAC)-based immunosuppressive regimens in recipients with solid organ transplant in India.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods:&lt;/strong&gt; This real-world, multicenter (134 centers), retrospective analysis included data of solid organ transplant recipients between 2010 and 2022 who had received TAC-based immunosuppressive therapy. The study data was collected between April 2021 and March 2022.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results:&lt;/strong&gt; Data of a total of 1022 recipients with kidney transplant (KT, n=899) or liver transplant (LT, n=123) who received TAC-based immunosuppression was analyzed. The mean age of recipients among KT and LT was 41.04±10.62 and 42.88±11.32 years, respectively. The most common diseases leading to end stage organ failure were diabetes (24.7%), hypertension (15.8%), concomitant diabetes and hypertension (14.9%), chronic kidney disease (9.2%), nephrotic syndrome (5%), and end stage renal disease (ESRD, 4.4%) in KT recipients, whereas for LT, the common indications were liver cirrhosis (32.5%), hepatitis B viral infection (11.4%), alcoholic liver disease (10.6%), fatty liver disease (12, 9.8%) and non-alcoholic steatohepatitis (NASH, 5.7%). The source of transplant was living donor in majority of both KT (91.2%) and LT (77.2%) recipients. The most common induction regimen in KT was anti-thymocyte globulin (ATG), TAC, mycophenolate mofetil (MMF), and steroid (ATG+TAC+MMF+steroid, 42.3%) whereas in LT, it was TAC+MMF+steroid (67.5%); TAC+MMF+steroid was most common maintenance regimen (KT: 91.1%, LT: 78%).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt; Tacrolimus-based immunosuppression is widely used in the recipients of solid organ transplantation, including KT or LT in real‑world clinical practice in India.&lt;/p&gt;