Calcineurin Inhibitors Group Research Articles

Validation of the R3-AFP model for risk prediction of HCC recurrence after liver transplantation in the SiLVER randomized clinical trial.

Explant-based models for assessing HCC recurrence after liver transplantation serve as the gold standard, guiding post-liver transplantation screening and immunosuppression adjustment. Incorporating alpha-fetoprotein (AFP) levels into these models, such as the novel R3-AFP score, has notably enhanced risk stratification. However, validation of these models in high-evidence data is mandatory. Therefore, the aim of the present research was to validate the R3-AFP score in a randomized clinical trial. We analyzed the intention-to-treat population from the 2-arm SiLVER trial (NCT00355862), comparing calcineurin-based ([calcineurin inhibitors]-Group A) versus mammalian target of rapamycin inhibitors-based (sirolimus-Group B) immunosuppression for post-liver transplantation HCC recurrence. Competing risk analysis estimated sub-hazard ratios, with testing of discriminant function and calibration. Overall, 508 patients from the intention-to-treat analysis were included (Group A, n = 256; Group B, n = 252). The R3-AFP score distribution was as follows: 42.6% low-risk (n = 216), 35.7% intermediate-risk (n = 181), 19.5% high-risk (n = 99), and 2.2% very-high-risk (n = 11) groups. The R3-AFP score effectively stratified HCC recurrence risk, with increasing risk for each stratum. Calibration of the R3-AFP model significantly outperformed other explant-based models (Milan, Up-to-7, and RETREAT), whereas discrimination power (0.75 [95% CI: 0.69; 0.81]) surpassed these models, except for the RETREAT model ( p = 0.49). Subgroup analysis showed lower discrimination power in the mammalian target of rapamycin group versus the calcineurin inhibitors group ( p = 0.048). In conclusion, the R3-AFP score accurately predicted HCC recurrence using high-quality evidence-based data, exhibiting reduced performance under mammalian target of rapamycin immunosuppression. This highlights the need for further research to evaluate surveillance schedules and adjuvant regimens.

Efficacy and safety of calcineurin inhibitors (CNIs) for septic patients in ICU: a cohort study from MIMIC database.

Sepsis is marked by a dysregulated immune response to infection. Calcineurin inhibitors (CNIs), commonly used as immunosuppressants, have unique properties that may help mitigate the overactive immune response in sepsis, potentially leading to better patient outcomes. This study aims to assess whether CNIs improve prognosis in septic patients and to evaluate any associated adverse reactions. We utilized the Medical Information Mart for Intensive Care IV 2.2 (MIMIC-IV 2.2) database to identify septic patients who were treated with CNIs and those who were not. Propensity score matching (PSM) was employed to balance baseline characteristics between the CNI user group and the non-user group. The primary outcome was 28-day mortality, analyzed using the Kaplan-Meier method and Cox proportional hazard regression models to examine the relationship between CNI use and patient survival. From the MIMIC-IV database, 22,517 septic patients were identified. After propensity score matching, a sample of 874 patients was analyzed. The CNI group exhibited a significantly lower 28-day mortality risk compared to the non-user group (HR: 0.26; 95% CI: 0.17, 0.41) in the univariate Cox hazard analysis. Kaplan-Meier survival curves also demonstrated a significantly higher 28- and 365-day survival rate for CNI users compared to non-users (log-rank test p-value = 0.001). No significant association was found between CNI use and an increased risk of new-onset infection (p = 0.144), but an association with mild hypertension (P < 0.001) and liver injury (P < 0.001) was observed. The use of calcineurin inhibitors was associated with reduced short- and long-term mortality in septic patients without an increased incidence of new-onset infections, hyperkalemia, severe hypertension, or acute kidney injury (AKI). However, CNI use may lead to adverse effects, such as liver injury and mild hypertension.

Long-term follow-up of the randomized, prospective Scandinavian heart transplant everolimus de novo study with early calcineurin inhibitors avoidance (SCHEDULE) trial

IntroductionEarly substitution of calcineurin inhibitor (CNI) with mammalian target of rapamycin inhibitors has been shown to improve kidney function and reduce intimal hyperplasia in heart transplant (HTx) recipients but data on long-term outcome of such a regime are still sparse. MethodsIn the SCHEDULE trial, 115 de novo HTx recipients were randomized to a) everolimus with reduced exposure of CNI followed by CNI withdrawal at week 7-11 post-transplant or b) standard-exposure with CNI. Both groups received mycophenolate mofetil and corticosteroids. Herein we report on the 10-12 year long-term follow-up of the study. ResultsA total of 78 patients attended the follow-up visit at a median time of 11 years post-transplant. In the everolimus intention to treat (ITT) group 87.5% (35/40 patients) still received everolimus and in the CNI ITT group 86.8 % (33/38) still received CNI. Estimated glomerular filtration rate (eGFR) (least square mean (95% CI)) at the 10-12 years visit was 82.7 (74.2-91.1) ml/min/1.73m2 and 61.0 (52.3-69.7) ml/min/1.73m2 in the everolimus and CNI group, respectively (p<0.001). Graft function measured by ejection fraction, ECG, NT-proBNP and drug safety were comparable between groups. During the study period there was a total of 28 deaths, but there was no difference in survival between the everolimus and the CNI group (aHR 0.61 (95% CI 0.29-1.30) p=0.20). For the composite endpoint of death, re-transplantation, myocardial infarction, PCI, dialysis, kidney transplantation or cancer no between group differences were found (aHR 1.0 (95% CI 0.57-1.77) p=0.99). ConclusionsDe novo HTx patients randomized to everolimus and low dose CNI followed by CNI free therapy sustained significantly better long-term kidney function than patients randomized to standard therapy. The graft function at 10-12 years was similar in both groups and there was no difference in survival.

Early Conversion to Everolimus Within 180 Days of Living Donor Liver Transplantation.

Early conversion to Everolimus (EVR) post deceased donor liver transplant has been associated with improved renal function but increased rejection. Early EVR conversion has not been evaluated after living donor liver transplant (LDLT). A retrospective cohort study was conducted to compare the rate of rejection and renal function in patients converted to EVR early post-LDLT to patients on calcineurin inhibitors (CNIs). This was a single center retrospective cohort study of adult LDLT recipients between January 2012 and July 2019. Patients converted to EVR within 180 days of transplant were compared to patients on CNIs. The primary endpoint was biopsy proven acute rejection (BPAR) at 24 months posttransplant. Key secondary endpoints included eGFR at 24 months, change in eGFR, adverse events, and all-cause mortality. From a total of 173 patients involved in the study: 58 were included in the EVR group and 115 in the CNI group. Median conversion to EVR was 26 days post-LDLT. At 24 months, there was no difference in BPAR (22.7% EVR vs. 19.1% CNI, p = 0.63). Median eGFR at 24 months posttransplant was not significantly different (68.6 [24.8 to 112.4] mL/min EVR vs. 75.9 [35.6-116.2] mL/min CNI, p = 0.103). Change in eGFR from baseline was worse in the EVR group (-13.0 [-39.9 to 13.9] mL/min EVR vs. -5.0 [-31.2 to 21.2] mL/min CNI, p = 0.047). Median change from conversion to 24 months posttransplant (EVR group only) was -3.43mL/min/1.73 m2 (-21.0 to 9.6). Early EVR conversion was not associated with increased risk of rejection among LDLT recipients. Renal function was not impacted. EVR may be considered as an alternative after LDLT in patients intolerant of CNIs.

Risk Factors for CMV Infection, Including HLA Disparity and Ptcy Transplant in the Era of Letermovir Prophylaxis

Reports suggest that post-transplant cyclophosphamide (PTCy) for haploidentical and HLA-matched sibling donor allogeneic stem cell transplant (allo-SCT) is associated with a higher incidence of cytomegalovirus (CMV) infection than calcineurin inhibitor (CNI) for HLA-matched sibling donor allo-SCT. Prophylactic letermovir has been shown effective for CMV seropositive patients, based on the data mostly before the FDA approval of letermovir (2017). We reevaluated the risk of CMV infection in PTCy transplants. We retrospectively analyzed 175 patients after allo-SCT between May 2019-May 2022). CMV infection was monitored at least for the first year by serostatus, viral load over 500 IU/mL, and/or evidence of CMV end-organ disease. Univariate and multivariate Cox regression analyses were used for the factors, including CMV serostatus, use of letermovir, GVHD prophylaxis, and HLA disparities, to affect the risk of CMV infection and graft-versus-host disease (GVHD)-free relapse-free survival (GRFS). Cumulative incidence curves were used to visualize the incidence of CMV infection stratified by HLA match and PTCY use. A landmark analysis at Day +100 was used for GRFS, where patients who had CMV infection beyond Day +100 (N=13) were assigned to the no-infection group. Of the 175 patients, 108 received HLA-matched donors with GVHD prophylaxis, either CNI (N=70) or PTCy (N=38), while 67 received HLA mismatched donors with either CNI (n=6) or PTCy (N=66) ( Table). Letermovir was given to 137 patients (CMV IgG positive N=130, negative N=7) but not to 38 patients (CMV IgG positive N=12, negative N=26). CMV infection occurred in 28 patients (CMV IgG positive N= 28, CMV IgG negative N=0) before or after Day +100 (N=15 or N=13, respectively). CMV IgG positive recipients not receiving letermovir demonstrated a higher risk of infection by Day +100 than those receiving letermovir (Hazard ratio (HR) 10.1 (95% confidence interval (CI) 3.6-28.6), p&amp;lt;0.01). All 13 infections after Day +100 occurred after the cessation of letermovir (median: 82.9 days after cessation). On univariate analysis, PTCy and HLA mismatch donors increased the risk of CMV infection. The risk of infection by Day +100 increased with PTCy (p=0.07). The risk of infection after Day +100 increased with HLA mismatch donors (p=0.05). In addition, it was confirmed that HLA mismatch allo-SCT with PTCy increased the risk of CMV infection over matched allo-SCT with CNI ( Figure, HR 4.6 (95% CI 1.6-11.9), p&amp;lt;0.01), while HLA match allo-SCT with PTCy did not (p=0.3) (Figure 1). The trend was similar when analyzed only in the case of CMV infection by Day +100 (p&amp;lt;0.05) and after Day +100 (p=0.1). In the 130 CMV IgG seropositive patients who received letermovir, multivariate analysis showed that HLA mismatch donors with PTCy increased the risk of CMV infection over HLA match allo-SCT with CNI. When analyzed only for acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndrome with letermovir (N=91), HLA mismatch transplant with PTCy increased the risk of CMV infection over HLA match transplant with CNI (p=0.05), but not for HLA match transplant with PTCy. Landmark analysis demonstrated better GRFS in the PTCy group than the CNI group and in patients who received PTCy with CMV infection than those who received CNI without CMV infection (p&amp;lt;0.01). PTCy increased the incidence of CMV infection in HLA mismatch allo-SCT by D+100 but not HLA match allo-SCT in the era of letermovir prophylaxis. Patients with PTCy transplant who overcome CMV infection have improved GRFS, possibly due to the increased graft-versus-leukemia effect. Further analysis is required to confirm the difference in the incidence of CMV infection between HLA match and mismatch transplant with PTCy and to assess the significance of late CMV (after Day +100) infection on GRFS.

Calcineurin inhibitors or cyclophosphamide in the treatment of membranous nephropathy superimposed with FSGS lesions: a retrospective study from China

Background Cyclophosphamide (CTX) and calcineurin inhibitors (CNIs) based regimens are recommended as immunosuppressive therapies for patients with idiopathic membranous nephropathy (IMN). Focal and segmental glomerular sclerosis (FSGS) lesions, which are common in membranous nephropathy (MN), are poor predictors of outcome. This study compared the differences of prognosis between two regimens in patients with IMN combined with FSGS lesions. Methods This retrospective study enrolled 108 patients with biopsy-proven IMN, accompanied with FSGS lesions, nephrotic syndrome and an estimated glomerular filtration rate (eGFR)≥60 mL/min/1.73 m2 who were treated with CTX or CNIs. We used propensity score matching (PSM) for balancing the confounding variables. Results During follow-up, 10 patients (10/55 [18.2%]; nine males) in the CNIs group showed a 50% decline in eGFR; eight had a not otherwise specified variant. Patients initially treated with CNIs had a significantly higher risk of progression to the primary outcome and a lower probability of complete or total remission. The relapse rate was higher in patients who initially received CNIs- than in those who received CTX-based treatment. Before PSM, age and 24-h urine protein level differed significantly between the groups. The PSM model included data from 72 patients. Worse outcomes were also noted among patients who initially received CNIs than those who received CTX-based treatments after matching. Conclusions Patients with MN combined with FSGS lesions have a higher risk of renal functional decline and a higher rate of relapse after CNIs than after CTX therapy.

Comparative analysis of the efficacy of different treatments for idiopathic membranous nephropathy: a retrospectively real-world study

Background This study aimed to explore the clinical efficacy of different treatment regimens for idiopathic membranous nephropathy (IMN). Methods Patients with IMN were retrospectively analyzed by dividing into two groups: glucocorticoids combined with cyclophosphamide group (GC + CYC) and glucocorticoids combined with calcineurin inhibitor group (GC + CNIs). After 1 year of treatment, those who found that the initial treatment was not effective were switched to another regimen. Patients continued to be followed up for at least 1 year to observe the treatment effects of different treatment regimens. Results This study found that the rate of complete and partial remission (CR + PR) in the GC + CYC and GC + CNIs groups was 76.19 vs. 82.63% after 1 year of follow-up (p > .05). In the GC + CYC and GC + CNIs groups, 27.78 and 11.95% of the patients switched treatment regimens, respectively. After 2 years of follow-up, the CR + PR rate was significantly higher in the change to GC + CNIs group after the switch compared to before the switch (80.00 vs. 31.43%, p < .001). It was also significantly higher in the change to GC + CYC group compared to before the switch (68.42 vs. 31.58%, p = .023). The recurrence rate was significantly higher in the maintain GC + CNIs and change to GC + CNIs groups than in the maintain GC + CYC and change to GC + CYC groups (25.14 vs 6.36%, p < .001). The disengagement rate from immunotherapy was significantly higher in the maintain GC + CYC group and the change to GC + CYC group than in the maintain GC + CNIs group and the change to GC + CNIs group (76.36% vs 29.71%, p < .001). High titer of anti-phospholipase A2 receptor (anti-PLA2R) antibody (95%CI: 0.199–0.947, p = .036) and serum C3 (95%CI: 0.030–0.570, p = .007) were independent risk factors, while serum IgG (95%CI: 1.000–1.331, p = .050) was a favorable factor for achieving CR. Anti-PLA2R antibody was the independent risk factor that affected the worse renal condition (p = .023). Conclusions Timely change of treatment regimen can significantly enhance therapeutic effect. Compared with patients administered with CYC, those administered with CNIs were less likely to leave treatment and had a higher recurrence rate.

Combination therapy for managing chronic allergic dermatoses

Atopic dermatitis is an inflammatory skin disease that is most frequently occurred in children, but also common in adults. The disease is characterized as chronic, but only 20% of children have severe atopic dermatitis, while the other 80% achieve a longterm remission by the age of 8 and earlier. The article summarizes the main details about atopic dermatitis including statistical epidemiological and pathogenetic data, and places special emphasis on the issues of patients’ quality of life and steroidophobia. It is known that combination treatment regimens are often used in the treatment of atopic dermatitis. The article highlights approaches to the tactics of choosing topical therapy according to the European guidelines for the treatment of atopic dermatitis 2018. Despite the fact that topical calcineurin inhibitors were made available for the treatment about 15 years ago, this group of drugs take the lead in the treatment of atopic dermatitis due to a pronounced anti-inflammatory mechanism of action with a steroid-sparing effect. The review presents the main mechanisms of action of topical calcineurin inhibitors and their effect on the skin’s barrier function. Literature data on the proven efficacy and high safety profile of Tacrolimus, the very first drug from the topical calcineurin inhibitor group, are presented. In the article, the authors described examples of the successful use of Tacrolimus, which can suppress the T-lymphocyte activation and reduce the production of pro-inflammatory cytokines in patients with moderate to severe atopic dermatitis, as well as with other chronic allergic dermatoses. The use of Tacrolimus in the presented clinical cases led to a reduction of severity of subjective and objective symptoms of the inflammatory skin diseases.

MTORi-based immunosuppression reduces HCC recurrence at the expense of increased adverse side effects: A systematic review and meta-analysis.

Sirolimus and everolimus are mammalian target of rapamycin inhibitors (mTORi) that can reduce relapse rates following liver transplantation (LT) for hepatocellular carcinoma (HCC). Herein, we performed a systematic review and meta-analysis to investigate the efficacy of mTORi and calcineurin inhibitors (CNI) in reducing HCC recurrence and survival adverse effects (AEs) in HCC patients after LT. Systematic literature searches were conducted using MEDLINE, EMBASE, and Cochrane Library databases up to October 2021. The primary outcomes of interest were tumor recurrence rates and overall survival. The secondary outcomes were the characterization and incidence of AEs. A total of 38 trials involving 10,607 participants was included in the analysis. The incidence of recurrence and overall mortality was significantly lower in the mTORi than in the CNI group (relative ratio [RR]: .78, 95% confidence interval [CI]: .68-.89 and RR: .76, 95% CI: .67-.86, respectively). The incidence of some AEs and complications such as acne, anemia, abnormal healing, dyslipidemia, depression, diarrhea, edema, headache/migraine, hypercholesterolemia, incisional hernia, infection, leukopenia, mouth ulceration, pyrexia, proteinuria, pruritis, rash, and thrombocytopenia were higher in the mTORi than in the CNI group. mTORi reduced the recurrence incidence and overall 5-year mortality rate but increased many other incidences of AEs compared with that by CNI. Therefore, clinicians should be aware of the risks and benefits of mTORi use when managing patients undergoing LT for HCC.

Sarcoidosis incidence after mTOR inhibitor treatment

ObjectiveMechanistic target of rapamycin (mTOR) inhibitors are effective in animal models of granulomatous disease, but their benefit in sarcoidosis patients is unknown. We evaluated the incidence of sarcoidosis in patients treated with mTOR inhibitors versus calcineurin inhibitors. MethodsThis was a cohort study using the Optum Clinformatics® Data Mart (CDM) Database (2003–2019), IBM® MarketScan® Research Database (2006–2016), and Danish health and administrative registries (1996–2018). Patients aged ≥18 years with ≥1 year continuous enrollment before and after kidney, liver, heart, or lung transplant treated with an mTOR inhibitor or calcineurin inhibitor were included. Patients diagnosed with sarcoidosis before, or up to 90 days after, transplant were excluded. The incidence of sarcoidosis by treatment group was calculated. ResultsIn the Optum CDM/IBM MarketScan cohort, 1,898 patients were treated with an mTOR inhibitor (mean age 49 years; 34% female) and 9,894 patients were treated with a calcineurin inhibitor (mean age 50 years; 37% female). The mean follow-up in the mTOR inhibitor group was 1.1 years, with no incident sarcoidosis diagnosed. In the calcineurin inhibitor group, the mean follow-up was 2.2 years, with 12 incident sarcoidosis cases diagnosed. In the Danish cohort, 230 patients were treated with an mTOR inhibitor (mean age 49; 45% female), with no incident sarcoidosis diagnosed. There were 3,411 patients treated with a calcineurin inhibitor (mean age 45; 40% female), with 10 incident cases of sarcoidosis diagnosed. ConclusionsThis study indicates a potential protective effect of mTOR inhibitor treatment compared with calcineurin inhibitor treatment against the development of sarcoidosis.

Longitudinal evaluation of the impact of immunosuppressive regimen on immune responses to COVID-19 vaccination in kidney transplant recipients.

Immunocompromised patients have a high risk of death from SARS-CoV-2 infection. Vaccination with an mRNA vaccine may protect these patients against severe COVID-19. Several studies have evaluated the impact of immune-suppressive drug regimens on cellular and humoral responses to SARS-CoV-2 variants of concern in this context. We performed a prospective longitudinal study assessing specific humoral (binding and neutralizing antibodies against spike (S) and T-lymphocyte (cytokine secretion and polyfunctionality) immune responses to anti-COVID-19 vaccination with at least two doses of BNT162b2 mRNA vaccine in stable kidney transplant recipients (KTR) on calcineurin inhibitor (CNI)- or belatacept-based treatment regimens. Fifty-two KTR−31 receiving CNI and 21 receiving belatacept—were enrolled in this study. After two doses of vaccine, 46.9% of patients developed anti-S IgG. Anti-spike IgG antibodies were produced in only 21.4% of the patients in the belatacept group, vs. 83.3% of those in the CNI group. The Beta and Delta variants and, more importantly, the Omicron variant, were less well neutralized than the Wuhan strain. T-cell functions were also much weaker in the belatacept group than in the CNI group. Renal transplant patients have an impaired humoral response to BNT162b2 vaccination. Belatacept-based regimens severely weaken both humoral and cellular vaccine responses. Clinically, careful evaluations of at least binding IgG responses, and prophylactic or post-exposure strategies are strongly recommended for transplant recipients on belatacept-based regimens.

Belatacept rescue conversion in kidney transplant recipients with vascular lesions (Banff cv score>2): a retrospective cohort study.

Immunosuppression in kidney transplant recipients with decreased graft function and histological vascular changes can be particularly challenging. The impact of a late rescue conversion to belatacept on kidney graft survival in this context has never been studied. We report a bicentric retrospective cohort study comparing a calcineurin inhibitor (CNI) to belatacept switch versus CNI continuation in 139 kidney transplant recipients with histological kidney vascular damage (cv≥2, g+cpt≤1, i+t≤1) and low estimated glomerular filtration rate (≤40mL/min/1.73 m²). Primary outcome was death-censored graft survival. During the study follow-up, 10 graft losses (14.5%) occurred in the belatacept group (n=69) versus 26 (37.1%) in the matched CNI group (n=70) (P=.005). Death-censored graft survival was significantly higher in the belatacept group (P=.001). At 3 years, graft survival was 84.0% in the belatacept group compared with 65.1% in the control group. Continuing CNI was an independent risk factor for graft loss [hazard ratio (HR) 3.46; P<.005]. The incidence of cellular rejection after the conversion was low (4.3% in both groups) and not significantly different between groups (P=.84). Patients switched to belatacept developed significantly less donor-specific antibodies de novo. Belatacept was an independent risk factor for the occurrence of opportunistic infections (HR 4.84; P<.005). The replacement of CNI with belatacept in patients with decreased allograft function and vascular lesions is associated with an improvement in graft survival and represents a valuable option in a context of organ shortage. Caution should be exercised regarding the increased risk of opportunistic infection.

The Effects of CNI and Mtori-Based Regimens on Bone Mineral Density After Renal Transplantation.

Background: Since glucocorticoids are used in low maintenance doses today, the relationship between calcineurin inhibitors (CNI) and osteoporosis has become clinically significant in osteoporosis after solid organ transplantation. However, there is evidence that the mammalian target of rapamycin inhibitors (mTORi) may be beneficial via osteoclast inhibition. Objective: The bone mineral density (BMD) changes are investigated in renal transplant patients under CNI or mTORi-based maintenance regimens during the first five-year post-transplant course. Methods: This study consists of thirty-three renal allograft recipients with less than one year of dialysis history. The exclusion criteria were: being older than 50 years old, history of bisphosphonate use, parathyroidectomy, CNI-mTORi switch after the post-transplant third month, diuretic use, and history of malignancy. First and fifth-year BMD scores and simultaneous laboratory parameters were evaluated. Results: CNI (n=21) and mTORi group (n=12) had similar demographics, dialysis vintages, first and fifth-year serum parathormone, calcium, phosphate, magnesium, alkaline phosphatase, and 25-OH-vitamin D levels. The femur neck scores of the CNI group decreased from -0.82 (±0.96) to -1.52 (±0.92) (p=0.020). We observed a significant decrease in the CNI group compared to the mTORi group [-0.70 (±0.68) and 0.30 (±0.36), respectively; p<0.01] when the BMD score changes were evaluated among years. The mean femur neck score of the mTORi group increased insignificantly from -1.13 (±0.65) to -0.82 (±0.56) at the fifth-year DXA scan (p=0.230). Similar trends were also observed in L1-4 scores. Conclusion: Our study suggests that CNI-based treatment is associated with decreased femur neck BMD scores, and mTORi-based treatment tends to be beneficial in the post-transplant five-year follow-up.

Impact of calcineurin inhibitor-free immunosuppression on de novo donor-specific antibody formation in liver transplant recipients.

Low calcineurin inhibitor (CNI) levels expose liver transplant recipients to rejection episodes and potentially to antibody-mediated rejection. There are little data on the impact of CNI-free immunosuppression on de novo donor-specific HLA antibody (dnDSA) development. Here we evaluated the prevalence of dnDSA in liver transplant recipients on CNI-free maintenance regimens and their associations with histopathological abnormalities of allografts. Seven hundred and twenty-seven liver transplant recipients underwent a first liver transplant between 2000 and 2018 in three French transplant centres and had protocolized follow-up with dnDSA screening and allograft biopsy 1, 5 and 10years after transplantation. CNIs were withdrawn in 166 (22.8%) patients with or without conversion to mammalian target of rapamycin inhibitors and/or maintenance with mycophenolic acid. DSA were present after withdrawal in 30.1% (50/166) patients on CNI-free immunosuppression compared with 16% (90/561) on CNI maintenance therapy (p<0.001). The cumulative incidence of dnDSA 10years after transplant was 20% in the CNI group versus 28% in the CNI-free group (p<0.01). dnDSAs were associated with histological graft abnormalities (significant allograft fibrosis or rejection) (HR 2.24, 95% CI 1.2-4.1; p=0.01). In univariate Cox regression analysis, being on a CNI-free regimen did not impact graft histology. Patients on a CNI-free IS regimen have a higher prevalence of dnDSA than patients on a standard IS regimen. dnDSAs but not CNI-free immunosuppression were associated with abnormal allograft histology.

MO573CNI AND MTORI-BASED REGIMENS ON FIVE-YEAR COURSE OF BONE MINERAL DENSITY SCORES AFTER RENAL TRANSPLANTATION

Abstract Background and Aims Since glucocorticoids are used in low maintenance doses today, the relationship between calcineurin inhibitors (CNI) and osteoporosis after solid organ transplantation has gained clinical significance. In contrast, (mammalian target of rapamycin inhibitors) mTORi agents are shown to have an antiresorptive effect on bone by reducing osteoclastic activity in vitro and in vivo. We investigated the bone mineral density (BMD) changes on an extremely selective group of incident renal transplant recipients under CNI or mTORi-based maintenance treatment regimens during the first five-year posttransplant course. Method This study consists of renal allograft recipients with a dialysis history of less than one year. Patients older than 50 years old, using CNI - mTORi combinations, patients with a history of a prior renal transplant, acute rejection, CNI – mTORi switch after posttransplantation first three months, bisphosphonate treatment, parathyroidectomy, diuretic use, and malignancy excluded to eliminate all confounding factors for bone mineral loss. First and fifth-year BMD scores and simultaneous laboratory parameters were evaluated. Results CNI (n=21) and mTORi (n=17) groups had similar demographics, dialysis vintages, cumulative steroid doses, first and fifth-year parathormone, calcium, phosphate, magnesium, alkaline phosphatase, and 25-OH-vitamin D levels. The femur neck scores of the CNI group decreased from -0.82(±0.96) to -1.52(±0.92) (p=0.020). We observed a significant decrease in the CNI group compared to the mTORi group [-0.70(±0.68) and 0.30(±0.36), respectively; p&amp;lt;0.01] when BMD score changes evaluated among years. The mean femur neck score of the mTORi group insignificantly increased from -1.13(±0.65) to -0.82(±0.56) at the fifth-year DXA scan (p=0.230). Although statistically insignificant, similar trends were also observed in L1-4 scores. Conclusion Our study suggests that CNI-based treatment is associated with decreased femur neck and L1-4 BMD scores, and mTORi-based treatment tends to be beneficial presumably due to their antiresorptive effects in the posttransplant five-year follow-up. Our findings may shed light on long-term maintenance therapy management in renal transplant patients with bone disease if supported by future studies.

The Unique Difference Between Serum Level of Soluble Urokinase Plasminogen Activator Receptor (suPAR) in Steroid-Resistant Nephrotic Syndrome Children Treated with an Alkylating Agent and Calcineurin Inhibitors

Background: Steroid-resistant nephrotic syndrome (SRNS) is a leading contributor to chronic kidney disease (CKD), and calcineurin inhibitors (CNIs) or monoclonal antibodies are currently the best identified therapy. Meanwhile, some developing countries still use alkylating agents (AA) such as cyclophosphamide (CPA) to treat SRNS due to economic reasons. Objectives: This study aims to determine the employability of soluble urokinase plasminogen activator receptor (suPAR) as a biomarker for monitoring therapy in SRNS children and compare the clinical improvement with those treated with an AA and CNIs. Methods: This was a retrospective cohort study conducted at Hasan Sadikin Hospital, Indonesia. The data was collected from July 2019 to July 2020 from 70 children with FSGS. Clinical signs were evaluated monthly, and serum suPAR level was measured at the third and sixth months following therapy. Two-way repeated measures ANOVA was carried out to compare the differences in suPAR level at baseline with the third and sixth months in SRNS patients who received AA and CNIs. Results: The mean age was nearly similar between the two groups based on the t-test (P = 0.140). Steroid-resistant nephrotic syndrome was more frequent in boys than in girls (P = 0.020), according to the Chi-square test. Baseline serum suPAR level was not significantly different between the two groups. In the third month, the daily urinary protein level was higher in SRNS patients that received the AA compared to the CNIs group (P &lt; 0.001). There was a significant interaction between time and treatment (F(2,138) = 7.203, P = 0.001), with higher suPAR level in SRNS patients that received the AA compared to those administered with CNIs at the 3rd and 6th months, but this difference was not statistically significant (P &gt; 0.05). Conclusions: As a noninvasive tool, suPAR is a promising modality in monitoring SRNS therapy, and CNIs have a tendency to achieve faster remission than the AA.

Induction therapy with mesenchymal stromal cells in kidney transplantation: a meta-analysis

ObjectiveThe aim of this meta-analysis was to evaluate the therapeutic effects of mesenchymal stromal cells (MSCs) versus traditional regimens for induction therapy in kidney transplantation (KT), especially the safety of MSC infusion, practicability of MSCs as induction therapy agents, and posttransplant complications.MethodsPubMed, Embase, EBSCO, Ovid, and the Cochrane Library were searched for prospective clinical trials that compared MSCs with traditional regimens for induction therapy in KT.ResultsFour trials were included, including a total of 197 patients. The pooled results revealed that MSC therapy had a lower 1-year infection rate than did the traditional therapies (RR = 0.65, 95% CI: 0.46–0.9, P = 0.01). There were no significant differences between the two protocols regarding the 1-year acute rejection (AR) rate (RR = 0.77, 95% CI: 0.41–1.45, P = 0.42), 1-year graft survival rate (RR = 0.99, 95% CI: 0.95–1.03, P = 0.74), delayed graft function (DGF) rate (RR = 0.54, 95% CI: 0.21–1.38, P = 0.2) and renal graft function at 1 month (MD = −1.56, 95% CI: − 14.2–11.08, p = 0.81), 3 months (MD = 0.15, 95% CI: − 5.63–5.93, p = 0.96), 6 months (MD = − 1.95, 95% CI: − 9.87–5.97, p = 0.63), and 12 months (MD = − 1.13, 95% CI: − 7.16–4.89, p = 0.71) postsurgery. Subgroup analysis demonstrated that the 1-year AR rate, 1-year graft survival rate, DGF rate, and renal graft function at 12 months postsurgery did not significantly differ between the low-dose calcineurin inhibitor (CNI) group and the standard-dose CNI group, indicating the potential benefits of successful CNI sparing in combination with MSC treatment. Moreover, when MSCs were applied as an alternative therapy rather than an additional therapy or allogeneic MSCs were utilized instead of autologous MSCs, all of the outcomes mentioned above were comparable.ConclusionInduction therapy with MSCs is safe and has similar immune response modulation effects to those of traditional regimens in the short term in KT recipients. However, regarding the long-term effects, as suggested by the 1-year infection rate and the potential of CNI sparing, MSC therapy has significant advantages. However, these advantages should be further verified in more well-designed, multicenter randomized controlled trials (RCTs) with large sample sizes and long follow-up periods.

Delayed Calcineurin Inhibitor Introduction Without Antibody Induction in Liver Transplantation Is Safe and Helps Preserve Kidney Function

IntroductionAcute kidney injury (AKI) is common after liver transplantation and affects outcome after liver transplantation. Antibody induction is commonly used to reduce dose and/or to delay introduction of calcineurin inhibitor (CNI) but is very expensive. We propose a modified immunosuppressive protocol that delays administration of CNI for 48 to 72 hours without antibody induction. This study evaluates the results of our new protocol. Material and MethodsA retrospective case-control study was performed. Study patients had induction with steroid and mycophenolate mofetil without antibody induction, and CNI administration was delayed for 48 to 72 hours. Control patients received CNI and steroid induction without antibody induction, and CNI was continued posttransplant. AKI was defined as an increase in serum creatinine level of at least 1.5 times the pretransplant baseline within the first postoperative week. ResultsSixty liver transplant recipients from 2013 to 2015 were included in this study (30 in the delayed CNI group and 30 in the control group). The patient characteristics and intraoperative factors were comparable in both groups. AKI developed in 11 patients in the study group and in 20 patients in the control group (37% vs 66.7%; P = .02). There was no acute rejection observed in the first month in either group. ConclusionWe have demonstrated that delayed CNI introduction without antibody induction is safe and helps preserve kidney function. Antibody induction can be omitted safely in a delayed CNI introduction protocol to reduce the cost of liver transplantation without increasing the risk of acute rejection.

Impact of Sirolimus as a Primary Immunosuppressant on Myocardial Fibrosis and Diastolic Function Following Heart Transplantation.

BackgroundMyocardial fibrosis is an important contributor for development of diastolic dysfunction. We investigated the impact of sirolimus as primary immunosuppression on diastolic dysfunction and fibrosis progression among heart transplantation recipients.Methods and ResultsIn 100 heart transplantation recipients who were either treated with a calcineurin inhibitor (CNI) (n=51) or converted from CNI to sirolimus (n=49), diastolic function parameters were assessed using serial echocardiograms and right heart catheterizations. Myocardial fibrosis was quantified on serial myocardial biopsies. After 3 years, lateral e′ increased within the sirolimus group but decreased in the CNI group (0.02±0.04 versus −0.02±0.04 m/s delta change; P=0.003, respectively). Both pulmonary capillary wedge pressure and diastolic pulmonary artery pressure significantly decreased in the sirolimus group but remained unchanged in the CNI group (−1.50±2.59 versus 0.20±2.20 mm Hg/year; P=0.02; and −1.72±3.39 versus 0.82±2.59 mm Hg/year; P=0.005, respectively). A trend for increased percentage of fibrosis was seen in the sirolimus group (8.48±3.17 to 10.10±3.0%; P=0.07) as compared with marginally significant progression in the CNI group (8.76±3.87 to 10.56±4.34%; P=0.04). The percent change in fibrosis did not differ significantly between the groups (1.62±4.67 versus 1.80±5.31%, respectively; P=0.88).ConclusionsEarly conversion to sirolimus is associated with improvement in diastolic dysfunction and filling pressures as compared with CNI therapy. Whether this could be attributed to attenuation of myocardial fibrosis progression with sirolimus treatment warrants further investigation.

Efficacy of infliximab, cyclosporine and tacrolimus on ulcerative colitis: A meta-analysis.

Positioning infliximab (IFX), cyclosporine and tacrolimus (TAC) for treating ulcerative colitis (UC) is in great debate. A literature search identified studies that investigated IFX vs. cyclosporine or IFX vs TAC in UC patients. Short-term remission, short-term, 1-year and 3-year colectomy rate were employed as primary end-points to assess efficacy. Odds ratios (ORs) with 95% confidence intervals (CIs) were analyzed. Overall, 15 studies comprised 596 patients in IFX group and 866 in calcineurin inhibitors group (644 received cyclosporine and 222 received TAC). No significant difference was seen between IFX and calcineurin inhibitors with regard to short-term remission. IFX led to a lower short-term (OR: 0.59, 95% CI: 0.43-0.82, P:.001), 1-year (OR: 0.53, 95% CI: 0.38-0.73, P < .001), 3-year colectomy (OR: 0.41, 95% CI: 0.20-0.84, P:.02) than calcineurin inhibitors. IFX led to a lower short-term (OR: 0.51, 95% CI: 0.36-0.71, P < .001), 1-year (OR: 0.53, 95% CI: 0.37-0.74, P:.003) colectomy and a trend of lower 3-year colectomy (OR: 0.49, 95% CI: 0.22-1.06, P:.07) than cyclosporine while no significant difference was seen between IFX and TAC. Results of network meta-analysis showed that the order was cyclosporine, TAC and IFX from high rate to low with regard to short-term and 1-year colectomy. IFX treatment leads to a lower short-term, 1-year colectomy rate and a trend of lower 3-year colectomy rate in UC patients than cyclosporine while no significant difference is seen between IFX and TAC. TAC may be superior than cyclosporine with regard to efficacy based on indirect comparisons. Randomized trials with fixed protocol are warranted to identify the optimal medical strategy in patients with UC.