Calcineurin Inhibitor Reduction Research Articles

A comparative analysis of clinical outcomes between conversion to mTOR inhibitor and calcineurin inhibitor reduction in managing BK viremia among kidney transplant patients

BK virus-associated nephropathy (BKVAN) exerts a substantial impact on allograft survival, however, the absence of robust clinical evidence regarding treatment protocols adds to the complexity of managing this condition. This study aimed to compare the two treatment approaches. The study population consisted of patients who underwent kidney transplantation between January 2016 and June 2020 at two tertiary hospitals in Korea. Patients diagnosed with BK viremia were evaluated based on their initial viral load and the treatment methods. The ‘Reduction group’ involved dose reduction of tacrolimus while the ‘Conversion group’ included tacrolimus discontinuation and conversion to sirolimus. A total of 175 patients with an initial viral load (iVL) ≥ 3 on the log10 scale were evaluated within two iVL intervals (3–4 and 4–5). In the iVL 4–5 interval, the Reduction group showed potential effectiveness in terms of viral clearance without statistically significant differences. However, within the iVL 3–4 interval, the Reduction group demonstrated superior viral clearance and a lower incidence of biopsy-proven acute rejection (BPAR) than the Conversion group. The renal function over 12 months after BKV diagnosis showed no statistically significant difference. Reducing tacrolimus compared to converting to mTORi would be a more appropriate treatment approach for BK viral clearance in kidney transplantation. Further research is warranted in a large cohort of patients.

(57) - Randomized Controlled Trial Comparing Immediate versus Extended Release Tacrolimus; Reducing Calcineurin Inhibitor Related Toxicity in Lung Transplantation Patients; The Revolution Trial

(57) - Randomized Controlled Trial Comparing Immediate versus Extended Release Tacrolimus; Reducing Calcineurin Inhibitor Related Toxicity in Lung Transplantation Patients; The Revolution Trial

Utility of a fusion protein T-cell co-stimulation blocker Belatacept in heart transplant recipients: Real world experience from a high volume center.

Belatacept (BTC), a fusion protein, selectively inhibits T-cell co-stimulation by binding to the CD80 and CD86 receptors on antigen-presenting cells (APCs) and has been used as immunosuppression in adult renal transplant recipients. However, data regarding its use in heart transplant (HT) recipients are limited. This retrospective cohort study aimed to delineate BTC's application in HT, focusing on efficacy, safety, and associated complications at a high-volume HT center. A retrospective cohort study was conducted of patients who underwent HT between January 2017 and December 2021 and subsequently received BTC as part of their immunosuppressive regimen. Twenty-one HT recipients were identified. Baseline characteristics, history of rejection, and indication for BTC use were collected. Outcomes included renal function, graft function, allograft rejection and mortality. Follow-up data were collected through December 2023. Among 776 patients monitored from January 2017 to December 2021 21 (2.7%) received BTC treatment. Average age at transplantation was 53 years (±12 years), and 38% were women. BTC administration began, on average, 689 [483, 1830] days post-HT. The primary indications for BTC were elevated pre-formed donor-specific antibodies in highly sensitized patients (66.6%) and renal sparing (23.8%), in conjunction with reduced calcineurin inhibitor dosage. Only one (4.8%) patient encountered rejection within a year of starting BTC. Graft function by echocardiography remained stable at 6 and 12 months posttreatment. An improvement was observed in serum creatinine levels (76.2% of patients), decreasing from a median of 1.58 to 1.45 (IQR [1.0-2.1] to [1.1-1.9]) over 12 months (p=.054). eGFR improved at 3 and 6 months compared with 3 months pre- BTC levels; however, this was not statistically significant (p=.24). Treatment discontinuation occurred in seven patients (33.3%) of whom four (19%) were switched back to full dose CNI. Infections occurred in 11 patients (52.4%), leading to BTC discontinuation in 4 patients (19%). In this cohort, BTC therapy was used as alternative immunosuppression for management of highly sensitized patients or for renal sparing. BTC therapy when combined with CNI dose reduction resulted in stabilization in renal function as measured through renal surrogate markers, which did not, however, reach statistical significance. Patients on BTC maintained a low rejection rate and preserved graft function. Infections were common during BTC therapy and were associated with medication pause/discontinuation in 19% of patients. Further randomized studies are needed to assess the efficacy and safety of BTC in HT recipients.

Everolimus plus reduced calcineurin inhibitor prevents de novo anti-HLA antibodies and humoral rejection in kidney transplant recipients: 12-month results from the ATHENA study.

Studies prospectively monitoring de novo donor-specific antibodies (dnDSAs) and their clinical impact are sparse. This substudy of ATHENA was initiated to evaluate the effect of everolimus (EVR) or mycophenolic acid (MPA) in combination with reduced calcineurin inhibitor (CNI, tacrolimus [TAC] or cyclosporine [CsA]) on the formation of human leukocyte antibodies (HLA), including dnDSA, and the impact on clinical outcomes in kidney transplant (KTx) recipients. All eligible patients were randomized 1:1:1 to receive either EVR + TAC, EVR + CsA or MPA + TAC, with basiliximab induction plus steroids after transplantation up to Month 12. The incidence of dnDSA by treatment group and the association with clinical events were evaluated descriptively as an exploratory objective in the intent-to-treat (ITT) and per-protocol (PP) populations with at least one antibody assessment. Overall, none of the patients in the EVR + TAC group had either dnDSA or antibody mediated rejection (PP or ITT population) and only one patient with dnDSA in the TAC + MPA group had antibody mediated rejection. The EVR regimen was comparable to MPA regimen with an extremely low incidence of dnDSA over 1 year of treatment.

Cardiovascular Outcomes in De Novo Kidney Transplant Recipients Receiving Everolimus and Reduced Calcineurin Inhibitor or Standard Triple Therapy: 24-month Post Hoc Analysis From TRANSFORM Study.

The comparative impact of everolimus (EVR)-based regimens versus standard of care (mycophenolic acid+standard calcineurin inhibitor [MPA+sCNI]) on cardiovascular outcomes in de novo kidney transplant recipients (KTRs) is poorly understood. The incidence of major adverse cardiac events (MACEs) in KTRs receiving EVR+reduced CNI (rCNI) or MPA+sCNI from the TRANSplant eFficacy and safety Outcomes with an eveRolimus-based regiMen study was evaluated. The incidence of MACE was determined for all randomized patients receiving at least 1 dose of the study drug. Factors associated with MACEs were determined by logistic regression. Risk of MACE out to 3 y post-study was calculated using the Patient Outcome in Renal Transplantation equation. MACE occurred in 81 of 1014 (8.0%; EVR+rCNI) versus 89 of 1012 (8.8%; MPA+sCNI) KTRs (risk ratio, 0.91 [95% confidence interval [CI], 0.68-1.21]). The incidence of cardiac death, myocardial infarction, revascularization, or angina was similar between the arms. Incidence of MACE was similar between EVR+rCNI and MPA+sCNI arms with a higher incidence in prespecified risk groups: older age, pretransplant diabetes (15.1% versus 15.9%), statin use (8.5% versus 10.8%), and low estimated glomerular filtration rate (Month 2 estimated glomerular filtration rate <30 versus >60 mL/min/1.73 m2; odds ratio, 2.23 [95% CI, 1.02-4.86]; P = 0.044), respectively. Predicted risk of MACE within 3 y of follow-up did not differ between the treatment arms. Cardiovascular morbidity and mortality were similar between de novo KTRs receiving EVR+rCNI and MPA+sCNI. EVR+rCNI is a viable alternative to the current standard of care in KTRs.

European multicenter study on the real-world use and clinical impact of extracorporeal photopheresis after heart transplantation

Aim of this study was to describe the real-world use of extracorporeal photopheresis (ECP) and assess its impact on clinical outcomes in the modern era of heart transplantation. Seven transplant centers from 5 European countries participated in this retrospective, observational, single-arm chart review study. All patients received ECP after heart transplantation in 2015 or later. Data were extracted from medical records between November 2020 and December 2021. Overall, 105 patients were enrolled and followed for an average of 2 years after initiation of ECP. Reasons to start ECP were acute cellular rejection (35.2%), rejection prevention (32.4%), mixed rejection (18.1%), and antibody-mediated rejection (14.3%). Rejection ISHLT grades improved from start to end of ECP treatment in 92% of patients treated with ECP for rejection. Of patients who started ECP to prevent rejection, 88% remained free from any rejection despite a reduction of calcineurin inhibitors. Overall survival was 95%, and no deaths were related to ECP. Safety events occurred in 18 patients, of which 13 experienced complications with venous access. This study, the largest European ECP study in heart transplantation, demonstrates that ECP can effectively be used to treat different rejection types and to prevent rejection in the modern era of immunosuppression. Patients with rejections who have received ECP have shown high response as measured by histological improvements in ISHLT classification. A high percentage of patients in the prevention group remained free from rejection despite reduction in immunosuppression, in particular calcineurin inhibitors.

Research Highlights.

Research Highlights.

Basiliximab as maintenance immunosuppression in heart transplant recipients: A single pediatric center experience.

Pediatric heart transplant recipients are at risk for complications from prolonged exposure to immunosuppressive drugs, pharmacokinetic challenges in maintaining consistent immunosuppression, and medication non-adherence. Basiliximab (BAS), an interleukin-2 receptor antagonist, is used for induction therapy across many pediatric heart transplant centers, but use as maintenance immunosuppression has not been well described. This was a retrospective, single pediatric center cohort study of heart transplant recipients who received BAS for maintenance immunosuppression (defined as >2 monthly doses) from January 1, 2011, to December 31, 2021. Ten patients met study criteria with a median age of 17.5 (5-22)years and median 9.6 (1.2-18.9)years since transplant at time of BAS initiation. The primary indications for BAS use were recurrent rejection (n=4), fluctuating immunosuppression levels (n=3), and renal dysfunction (n=3). A median of 5.5 (3-32) monthly BAS doses were received. Three patients had a rejection event while on BAS. Calcineurin inhibitor exposure was reduced in 70% of patients. Three of the 10 patients were alive at last follow-up. There was one documented infection during BAS use, and no hypersensitivity reactions. Monthly BAS infusions were well tolerated and allowed for reduced calcineurin inhibitor exposure in most patients. Mortality commonly occurred despite BAS use, potentially reflecting the acuity of this patient cohort. BAS can be considered for maintenance immunosuppression in pediatric patients with fluctuating immunosuppressive levels and/or renal dysfunction. More studies are needed to determine long-term outcomes and explore expanded use of BAS in the pediatric heart transplant population.

COVID-19 Disease in Kidney Transplantation Recipients: A Single-Center Study (Experience of Dr. Shariati Hospital)

Background: Coronavirus disease 2019 (COVID-19 disease) is caused by SARS-CoV-2. In December 2019, several outbreaks of severe and life-threatening pneumonia with unknown organism were reported in Wuhan, China and the disease spread rapidly all over the world and caused the biggest pandemic. There was no clear information regarding incidence, morbidity, and mortality rate of COVID-19 disease in kidney transplant recipients or other solid organ transplant recipients. Therefore, we designed a study to evaluate the factors that can have any impact on kidney transplant recipients infected with SARS-Cov2.&#x0D; Methods: Our research was a retrospective cross-sectional study. The study population was all adult kidney transplant recipients (&gt; 18 years old) who were hospitalized due to COVID-19 disease according to national guidelines from 1st March, 2020 to 20th April, 2020 in Shariati Hospital, Tehran, Iran. Demographic data, common clinical complaints, vital signs, types and dose of immunosuppressive drugs, comorbidity diseases, and basic laboratory tests were extracted from the medical records using a data collection form.&#x0D; Results: According to the results of our investigation, mortality rate was 69.2% in kidney transplant recipients who were admitted in our hospital. No one died under the age of 47 years, while no one survived over the age of 58 years. As a result, age can be a reliable predictor of survival rate in kidney transplant recipients with COVID-19 pneumonia. All patients in non- survivors’ group were elderly and needed intubation, mechanical ventilation, and renal replacement.&#x0D; Conclusion: In addition to early referral and early start of appropriate and specific treatments of COVID-19 in patients with kidney transplantation, our general advice, is discontinuation of antimetabolite drugs at admission time, dose reduction of calcineurin inhibitors, and even withdrawal of all immunosuppressive drugs except steroids in critical cases.

COVID Infection in Heart Transplant Recipients: Experiences from an Epicenter

PurposeHeart transplant (HT) recipients are at significant risk from Covid-19 infection due to immunosuppression and potential effects on graft function. Currently no standard care management strategy exists for this population. We sought to describe our experiences as a single center caring for HT recipients with Covid-19 infection.MethodsRetrospective chart review of 250 adult HT recipients followed at the University of Southern California identified 46 individuals with PCR-proven Covid-19 infection between March 1st, 2020 and October 1st, 2021. Herein, we report on their baseline clinical characteristics, serial echocardiographic parameters, laboratory values and pharmacologic treatment regimens.Results46 HT patients were identified with Covid-19 infection. Patients were more likely to be male (74%), with a mean age of 52.0 years old, and average BMI of 28.71. The most common indications for HT included NICM (54%) and ICM (22%), and comorbidities included HTN (59%), HLD (59%), DM (39%), and CAD (26%). Over a third of patients (37%) had a history of smoking, and 7 patients (15%) were vaccinated against Covid-19. Patients were on average 6.53 (1.1-9.0) years post-transplant, and on three 3 classes of immunosuppressive medications (89%). The most common presenting symptoms were fever (24%), dyspnea (33%), hypoxic respiratory failure (26%), and GI symptoms (20%). Only 8 patients (17%) had evidence of graft injury with mean donor-derived cell free DNA levels of 0.41 (NL <0.12). Mean EF was 60.7% pre- and 59.0% post-infection. The most common treatment was supportive therapy (39%), followed by monoclonal antibody therapy (28%), steroids (24%; dexamethasone or solumedrol) and antibiotics (24%). Reduction in antimetabolites (33%), calcineurin inhibitors (15%), and prednisone (15%) was common. Half of the patients were admitted to the hospital with 11% requiring ICU level of care, and half were managed as outpatients. Only 4 patients died (1 from non-covid related illness 6 months post-infection) yielding a 91% overall survival rate.ConclusionIn a single-center experience over 18 months, 46 HT patients had proven Covid-19 infection. Overall survival was 91% with mainstays of treatment focusing on supportive care and monoclonal antibody therapy. Further research is needed to clarify optimal treatment strategies in HT patients with Covid-19 infection.

Effect of Itraconazole and Its Metabolite Hydroxyitraconazole on the Blood Concentrations of Cyclosporine and Tacrolimus in Lung Transplant Recipients.

Invasive Aspergillus infection is a major factor for poor prognosis in patients receiving lung transplantation (LT). An antifungal agent, itraconazole (ITCZ), that has antimicrobial activity against Aspergillus species, is used as a prophylactic agent against Aspergillus infection after LT. ITCZ and its metabolite, hydroxyitraconazole (OH-ITCZ), potently inhibit CYP3A and P-glycoprotein that metabolize or excrete calcineurin inhibitors (CNIs), which are the first-line immunosuppressants used after LT; thus, concomitant use of ITCZ and CNIs could induce an increase in the blood concentration of CNIs. However, no criteria for dose reduction of CNIs upon concomitant use with ITCZ in LT recipients have been defined. In this study, the effect of ITCZ and OH-ITCZ on the blood concentrations of two CNIs, tacrolimus and cyclosporine, after LT were retrospectively evaluated. A total of 39 patients who received LT were evaluated. Effects of ITCZ and OH-ITCZ on the concentration/dosage (C/D) ratio of tacrolimus and cyclosporine were analyzed using linear mixed-effects models. The plasma concentrations of OH-ITCZ were about 2.5-fold higher than those of ITCZ. Moreover, there was a significant correlation between the plasma concentrations of ITCZ and OH-ITCZ. Based on parameters obtained in the linear regression analysis, the C/D ratios of cyclosporine and tacrolimus increase by an average of 2.25- and 2.70-fold, respectively, when the total plasma concentration of ITCZ plus OH-ITCZ is 1000 ng/mL. In conclusion, the plasma levels of ITCZ and OH-ITCZ could be key factors in drawing up the criterion for dose reduction of CNIs.

Use of Basiliximab in Recipients Who Required Dose Reduction or Discontinuation of Calcineurin Inhibitors Early After Lung Transplantation

<h3>Purpose</h3> The standard immunosuppressive therapy after lung transplantation is a combination of calcineurin inhibitors (CNIs), antimetabolites, and corticosteroids. In the cases where CNIs need to be reduced or discontinued early after transplantation due to renal dysfunction or other side effects, basiliximab is used as an alternative at our hospital. In this study, we investigated the efficacy and safety of basiliximab administered early after transplantation as an alternative of CNIs. <h3>Methods</h3> All lung transplant recipients between April 2002 and April 2021 at our hospital were retrospectively reviewed. Among 272 lung transplant recipients (108 living-donor, 163 deceased-donor, and 1 hybrid), 18 recipients were treated with basiliximab due to the need for CNI reduction or discontinuation. We reviewed indications of basiliximab and the outcome. Acute rejection was diagnosed based on radiologic and clinical parameters without transbronchial biopsy. The incidence of clinically diagnosed acute rejection and that of chronic lung allograft dysfunction (CLAD) were compared between the basiliximab group (n = 18) and the non-basiliximab group (n = 254). <h3>Results</h3> The indications of basiliximab were preoperatively existing poor renal function (n = 11) postoperative acute kidney disease (eGFR < 50, n = 4), and posterior reversible encephalopathy syndrome (PRES, n = 3) due to CNIs. The first dose of basiliximab (20 mg for adults, 10 mg for children) was administered postoperatively (median 0, range 0-7 days) and the second dose was administered 4 days later. No apparent adverse effects were encountered. None of the recipients with poor renal function required dialysis in the perioperative period, and all the recipients with PRES showed complete recovery. The incidence of clinically diagnosed acute rejection before discharge was 44.4% in the basiliximab group and 41.3% in the non-basiliximab group (<i>p</i> = 0.81). Five-year CLAD-free survival was 50% in the basiliximab group and 60.6% in the non-basiliximab group (<i>p</i> = 0.41). <h3>Conclusion</h3> The use of basiliximab as an alternative of CNIs early after lung transplantation was safe and increased neither the risk of acute rejection nor CLAD.

Thymoglobulin Versus Alemtuzumab Versus Basiliximab Kidney Transplantation From Donors After Circulatory Death

IntroductionThe Campath, Calcineurin inhibitor (CNI) reduction, and Chronic allograft nephropathy (3C), a study comparing alemtuzumab versus basiliximab induction immunosuppression in kidney transplants, has found lower acute rejection rate with alemtuzumab but same graft survival. The aim of the current study is to evaluate the effect of induction immunosuppression (thymoglobulin, alemtuzumab, basiliximab) on the outcome of kidneys of donors after circulatory death (DCD).MethodsData of the 274 DCD patients of the 3C obtained from the sponsor were compounded with the 140 DCD patients who received thymoglobulin in a single center with the same entry criteria as the 3C, giving 414 patients on 3 induction regimes.ResultsThere were more male donors (P < 0.05) and human leukocyte antigen and DR mismatched patients in the thymoglobulin group (P < 0.001). Death-censored graft survival at 6 months was 98.6% in the thymoglobulin, 95.5% in the alemtuzumab (P = 0.08), and 95.7% in the basiliximab group (P = 0.09) and at 2 years 97.9% versus 94.8% (P = 0.13, hazard ratio [HR] 2.8, 95% CI 0.7–10.9) versus 94.3% (P = 0.06, HR 3.5, 95% CI 0.9–13.6), respectively.The 2-year overall graft survival was 95% in the thymoglobulin versus 88% in the alemtuzumab (unadjusted P = 0.038, adjusted HR 2.4, 95% CI 0.99–5.9) and 91.4% in the basiliximab group (P = 0.21). The 2-year patient survival was numerically less in the alemtuzumab compared with the thymoglobulin group (91.8% vs. 97.1%, P = 0.052, HR 2.90, 95% CI 0.93–9.2). Acute rejection was 17% in the basiliximab, 4.3% in the thymoglobulin, and 6% in the alemtuzumab group (P < 0.001).ConclusionIn DCD transplants, thymoglobulin induction may provide advantage over alemtuzumab in patient survival and the same advantage as alemtuzumab over basiliximab in terms of acute rejection. Differing maintenance immunosuppression may contribute to the difference found.

No Influence of Everolimus on Mycophenolic Acid Area Under the Concentration–Time Curve: Limited Sampling Strategy for Mycophenolic Acid in Japanese Kidney Transplant Recipients Treated With Tacrolimus, Mycophenolate Mofetil, Steroid, and Everolimus

Despite a growing need for everolimus (EVR) to reduce calcineurin inhibitor toxicity in kidney transplantation (KTx), the influence of EVR on the pharmacokinetics of mycophenolic acid (MPA), a mycophenolate mofetil (MMF) active metabolite, is obscure, and no suitable limited sampling strategy (LSS) for MPA when EVR is concomitantly present exists. We aimed to investigate the influence of EVR on MPA pharmacokinetics in KTx. This study complied with all principles of the Declaration of Helsinki. Twenty patients were initially administered tacrolimus, MMF, and methylprednisolone and then received EVR 4 months after KTx. Approximately 4 weeks before and after EVR administration, the estimated value of the area under the concentration-time curve for MPA from 0 to 12 hours (MPA-AUC0-12) was calculated using MPA blood concentration just before and 1, 2, 4, and 6 hours after MMF administration. We compared several MPA pharmacokinetics parameters before and after EVR addition and determined the best estimation equation for LSS of MPA-AUC0-12. Although MPA-C6 per dose (MPA-C6/D) significantly decreased after EVR addition (from 3.4 [±2.2] ng/mL/g to 2.5 [±0.9] ng/mL/g), MPA-C0/D, -C1/D, -C2/D, -C4/D, and MPA-AUC0-12/D showed no significant change. MPA-AUC0-12/D did not correlate with EVR-AUC0-12/D. The best estimation equation for LSS of MPA-AUC0-12 by 2 time points was [(2.94×C2)+(5.09×C4)+5.32] (R2=0.73) and [(5.70×C0)+(1.39×C1)+22.45] (R2=0.72) before and after EVR addition, respectively. EVR can be safely combined with MMF after KTx once our results have been reevaluated.

Reduced calcineurin inhibitor exposure with antibody induction and recurrent hepatocellular carcinoma after liver transplantation

Background Hepatocellular carcinoma (HCC) is a common indication for liver transplantation (LT), but post-LT tumor recurrence remains a concern. Early post-LT immunosuppression is suggested to affect recurrence risk. We evaluated the impact on HCC recurrence of an immunosuppression protocol introduced in 2010 with interleukin-2 receptor antibody (IL-2RA) induction and delayed-introduction of reduced-dose tacrolimus with mycophenolate. Methods We included consecutive HCC patients transplanted 2000–2017 in Gothenburg. The impact on HCC recurrence of IL-2RA induction and mean tacrolimus trough concentration during the first 20 post-LT days was analyzed by multivariable Cox regression and propensity score-adjusted analyses. Results The study comprised 235 patients (mean age 57 yrs, men 80%, mean MELD 13, within Milan criteria 57%). The cumulative 5-yr HCC recurrence rate among patients transplanted before and after 2010 were 28.6% and 19.7%, respectively. IL-2RA induction had no independent effect on HCC recurrence. High tacrolimus exposure (mean 20-day tacrolimus concentration ≥8ng/mL) was associated with increased HCC recurrence risk on univariable analysis (HR 2.22, 95% CI 1.23–4.01, p = .008), but was non-significant on multivariable analysis (p = .17). Outside Milan criteria, high tacrolimus exposure was significant for HCC recurrence (HR 3.68, 95% CI 1.34–10.11, p = .012) independently of tumor characteristics and AFP level. This was confirmed on multivariable propensity score-adjusted analysis. Conclusions Reduced early tacrolimus exposure, facilitated by IL-2RA induction, was associated with reduced risk for HCC recurrence among patients outside Milan criteria. Prospective studies are needed to confirm if early tacrolimus-minimization strategies can help reduce HCC recurrence rates and help extend transplant criteria.

Changes in glomerular filtration rate in liver recipients after reduced exposure to calcineurin inhibitors with concomitant everolimus administration within the first year after immunosuppression conversion

Objective: to compare changes in estimated glomerular filtration rate (eGFR) in liver recipients with initially normal and impaired eGFR within the first year after immunosuppression conversion.Materials and methods. Enrolled in the study were 215 recipients of deceased-donor livers from February 2009 to February 2020, who received everolimus with dose reduction or complete withdrawal of calcineurin inhibitors (immunosuppression conversion, ISxC) for varying periods of time. GFR was measured using the MDRD-4 formula immediately before ISxC, then 3, 6, and 12 months after orthotopic liver transplantation (LTx). One month was considered an acceptable temporary deviation from the corresponding point.Results. At the time of ISxC, 32 (15%) of 215 recipients had normal renal function. Chronic kidney disease (CKD) increased in 60% of the recipients with normal eGFR by the end of the first year following ISxC; the fall in eGFR was particularly pronounced in older recipients. In the group with a baseline eGFR of 60–89 mL/min/1.73 m2, eGFR normalized in 62% of cases within 12 months; 28% of cases had no changes in renal function. In the subgroup with a pronounced decrease in eGFR at the time of ISxC, increased eGFR was observed as early as 1 month after ISxC, and the maximum was recorded after 3–6 months. The mean eGFR relative to baseline by month 3 after eGFR were higher for ISxC that was done in the first 2 months after LTx (19.7 ± 15.7 ml/minute/1.73 m2) than for ISxC done in the long-term period after LTx (10.1 ± 8.7 ml/minute/1.73 m2, p &lt; 0.05).Conclusion. Changes in eGFR in liver recipients receiving EVR plus low-dose calcineurin inhibitor (CNI) depend on baseline eGFR and are multidirectional. The use of ISxC in the early post-LTx period led to a more pronounced improvement in eGFR. Maximal changes in eGFR were observed by 3–6 months after ISxC.

Everolimus‐facilitated calcineurin inhibitor reduction in Asian de novo kidney transplant recipients: 2‐year results from the subgroup analysis of the TRANSFORM study

ObjectiveWe analyzed the efficacy and safety of an everolimus with reduced‐exposure calcineurin inhibitor (EVR+rCNI) versus mycophenolic acid with standard‐exposure CNI (MPA+sCNI) regimen in Asian patients from the TRANSFORM study.MethodsIn this 24‐month, open‐label study, de novo kidney transplant recipients (KTxRs) were randomized (1:1) to receive EVR+rCNI or MPA+sCNI, along with induction therapy and corticosteroids.ResultsOf the 2037 patients randomized in the TRANSFORM study, 293 were Asian (EVR+rCNI, N = 136; MPA+sCNI, N = 157). At month 24, EVR+rCNI was noninferior to MPA+sCNI for the binary endpoint of estimated glomerular filtration rate (eGFR) < 50 ml/min/1.73 m2 or treated biopsy‐proven acute rejection (27.0% vs. 29.2%, P = .011 for a noninferiority margin of 10%). Graft loss and death were reported for one patient each in both arms. Mean eGFR was higher in EVR+rCNI versus MPA+sCNI (72.2 vs. 66.3 ml/min/1.73 m2, P = .0414) even after adjusting for donor type and donor age (64.3 vs. 59.3 ml/min/1.73 m2, P = .0582). Overall incidence of adverse events was comparable. BK virus (4.4% vs. 12.1%) and cytomegalovirus (4.4% vs. 13.4%) infections were significantly lower in the EVR+rCNI arm.ConclusionThis subgroup analysis in Asian de novo KTxRs demonstrated that the EVR+rCNI versus MPA+sCNI regimen provides comparable antirejection efficacy, better renal function, and reduced viral infections (NCT01950819).

Efficacy and safety of sirolimus early conversion protocol in liver transplant patients with hepatocellular carcinoma: A single-arm, multicenter, prospective study

Mammalian target of rapamycin (mTOR) inhibitor as an attractive drug target with promising antitumor effects has been widely investigated. High quality clinical trial has been conducted in liver transplant (LT) recipients in Western countries. However, the pertinent studies in Eastern world are paucity. Therefore, we designed a clinical trial to test whether sirolimus can improve recurrence-free survival (RFS) in hepatocellular carcinoma (HCC) patients beyond the Milan criteria after LT. This is an open-labeled, single-arm, prospective, multicenter, and real-world study aiming to evaluate the clinical outcomes of early switch to sirolimus-based regimens in HCC patients after LT. Patients with a histologically proven HCC and beyond the Milan criteria will be enrolled. The initial immunosuppressant regimens are center-specific for the first 4-6 weeks. The following regimens integrated sirolimus into the regimens as a combination therapy with reduced calcineurin inhibitors based on the condition of patients and centers. The study is planned for 4 years in total with a 2-year enrollment period and a 2-year follow-up. We predict that sirolimus conversion regimen will provide survival benefits for patients particular in the key indicator RFS as well as better quality of life. If the trial is conducted successfully, we will have a continued monitoring over a longer follow-up time to estimate indicator of overall survival. We hope that the outcome will provide better evidence for clinical decision-making and revising treatment guidelines based on Chinese population data.Trial register: Trial registered at http://www.chictr.org.cn: ChiCTR2100042869.

COVID-19 and Heart Transplantation. Initial Experience in a Tertiary Hospital

BackgroundCoronavirus disease 2019 (COVID-19) is a viral infectious disease caused by the severe acute respiratory syndrome coronavirus 2 virus that is affecting the entire world population. The objective of this study was to analyze the repercussion of the disease in a group of patients at risk such as heart transplant recipients.MethodsFrom February 2020 to February 2021, heart transplant recipients diagnosed with COVID-19 were consecutively included. The total number of transplant recipients in outpatient follow-up at that time was 381. Three levels of infection were determined: group A: asymptomatic patients or with trivial symptoms without the need for hospital admission (6 patients); group B: patients admitted to the hospital for respiratory symptoms (12 patients); and group C: patients with severe symptoms and need for admission to the critical care unit (2 patients). At each risk level, medical performance was different: group A: close control, no therapeutic modification; group B: reduction of calcineurin inhibitor and substitution of mycophenolate mofetil for everolimus; group C: reduction of calcineurin inhibitor and withdrawal of mycophenolate mofetil.ResultsThe prevalence of infection in the series was 5.2%. Most patients admitted had a pathologic chest x-ray with fever, cough, dyspnea, or vomiting. The change in immunosuppression performed in patients in group 2 was well tolerated and there was no graft rejection. Antiviral treatment was little used. However, boluses of steroids and some antibiotics were used frequently. The need for supplemental oxygen was 50% in group 2 and 100% in group 3.ConclusionsA significant number of transplant recipients will be affected by COVID-19 (5.3%). Management of the infection will depend on the severity of the infection and must be based on a balance between reduction and adjustment of immunosuppression, strict control of the cardiologic situation, and treatment of the infection.

SARS-CoV-2 in Solid Organ Transplant Recipients: A Structured Review of 2020

BackgroundThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is challenging health systems all over the world. Particularly high-risk groups show considerable mortality rates after infection. In 2020, a huge number of case reports, case series, and consecutively various systematic reviews have been published reporting on morbidity and mortality risk connected with SARS-CoV-2 in solid organ transplant (SOT) recipients. However, this vast array of publications resulted in an increasing complexity of the field, overwhelming even for the expert reader.MethodsWe performed a structured literature review comprising electronic databases, transplant journals, and literature from previous systematic reviews covering the entire year 2020. From 164 included articles, we identified 3451 cases of SARS-CoV-2–infected SOT recipients.ResultsInfections resulted in a hospitalization rate of 84% and 24% intensive care unit admissions in the included patients. Whereas 53.6% of patients were reported to have recovered, cross-sectional overall mortality reported after coronavirus disease 2019 (COVID-19) was at 21.1%. Synoptic data concerning immunosuppressive medication attested to the reduction or withdrawal of antimetabolites (81.9%) and calcineurin inhibitors (48.9%) as a frequent adjustment. In contrast, steroids were reported to be increased in 46.8% of SOT recipients.ConclusionsCOVID-19 in SOT recipients is associated with high morbidity and mortality worldwide. Conforming with current guidelines, modifications of immunosuppressive therapies mostly comprised a reduction or withdrawal of antimetabolites and calcineurin inhibitors, while frequently maintaining or even increasing steroids. Here, we provide an accessible overview to the topic and synoptic estimates of expectable outcomes regarding in-hospital mortality of SOT recipients with COVID-19.