Attenuation of Torque teno viral load over time in kidney transplantation recipients treated with calcineurin inhibitors is mitigated after conversion to belatacept.

Torque Teno Virus (TTV) is a non-pathogenic anellovirus, highly prevalent in healthy populations. Variations in its viral load have been associated with states of diminished immunity, as occurs after organ transplantation. It is hypothesized that TTV-load might be used as a diagnostic tool to guide prescription and dosing of immunosuppressive drugs. Not much is known about the effects of combined immunosuppressive drugs on TTV replication in renal transplantation. Belatacept was introduced to counter side-effects of calcineurin inhibitors (CNI). It was never widely adopted, mainly because its association with increased risk of rejection. To investigate the differential effects of a regimen based on calcineurin inhibitors versus belatacept on TTV-loads, we measured TTV-levels in 105 patients from two randomized controlled trials in kidney transplant recipients (KTRs). We observed that time after transplantation was inversely related to TTV-levels of patients that remained on a CNI-containing regime, whereas this decline over time was diminished after conversion to belatacept. In addition, a correlation with tacrolimus-trough levels and age were found. Our study is the first report on the impact of conversion from CNI to belatacept on TTV-levels in KTR. In conclusion, the time-related decline in TTV-levels is mitigated after conversion from CNI to belatacept.

Immunosuppression in Kidney Transplant Recipients: An Update for the General Nephrologist.

Over the last 7 decades, kidney transplantation has evolved from an experiment between identical twins to becoming the gold standard treatment for end-stage kidney disease. To date, mycophenolate and calcineurin inhibitors, with or without prednisone, continue to constitute the backbone of modern maintenance immunosuppression. Despite major strides in improving acute rejection, long-term outcomes remain suboptimal with current regimens. Alternatives to calcineurin inhibitors such as belatacept and mammalian targets of rapamycin inhibitors exist; however, their wider-scale adoption remains relatively delayed due to concerns about increased rejection rates. In addition to continuing the investigation of steroid and calcineurin inhibitor sparing protocols, it is time to identify measurable surrogates for meaningful long-term graft survival. iBOX, a dynamic risk-prediction tool that predicts long-term death-censored graft failure could be a potential surrogate end point for future immunosuppression clinical trials. In this review, we summarize the landmark studies supporting current immunosuppression protocols and briefly discuss challenges and future directions.

Topical Therapy for Atopic Dermatitis: What is New and the New Paradigm.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder that requires a complex management strategy, which often involves multiple and diverse topicals and systemic treatment regimens. While topical steroids and more recently calcineurin inhibitors have been the mainstay therapy for mild-to-moderate disease, recent advances in the understanding of AD pathogenesis have led to the development of different new targets, rapidly widening our therapeutic armamentarium. This review summarizes their efficacy and safety data. We also review topical optimization strategies, including the recently published topical volume calculator, to maximize long-term disease control, especially when using multiple agents at the same time.

Pharmacogenetics of Calcineurin inhibitors in kidney transplant recipients: the African gap. A narrative review.

Calcineurin inhibitors (CNIs) are the mainstay of immunosuppression in kidney transplantation. Interpatient variability in the disposition of calcineurin inhibitors is a well-researched phenomenon and has a well-established genetic contribution. There is great diversity in the makeup of African genomes, but very little is known about the pharmacogenetics of CNIs and transplant outcomes. This review focuses on genetic variants of calcineurin inhibitors' metabolizing enzymes (CYP3A4, CYP3A5), related molecules (POR, PPARA) and membrane transporters involved in the metabolism of calcineurin inhibitors. Given the genetic diversity across the African continent, it is imperative to generate pharmacogenetic data, especially in the era of personalized medicine and emphasizes the need for studies specific to African populations. The study of allelic variants in populations where they have greater frequencies will help answer questions regarding their impact. We aim to fill the knowledge gaps by reviewing existing research and highlighting areas where African research can contribute.

Research on the pharmacogenetics of calcineurin inhibitors in kidney transplant recipients is truly wanting in data from the African continent. Given Africa's vast genetic diversity, it is necessary to intensify efforts to generate data from Africa in this field.

Comparison of Three Graft-versus-Host Disease Prophylaxis Strategies after T Cell-Replete Haploidentical Hematopoietic Transplantation: Tacrolimus versus Calcineurin Inhibitors + Mycophenolate Mofetil versus Sirolimus + Mycophenolate Mofetil.

Since the introduction of post-transplantation cyclophosphamide (PTCy), haploidentical hematopoietic stem cell transplantation (haploSCT) has become a real alternative for patients who lack other eligible donors. The standard graft-versus-host disease (GVHD) prophylaxis after PTCy has been a calcineurin inhibitor (CNI) plus mycophenolate mofetil (MMF) (up to day +35), but promising results with sirolimus (with or without MMF) and single-agent tacrolimus have been published recently. This multicenter retrospective study compared the outcomes of 372 adult haploSCT recipients who received conditioning with thiotepa, busulfan, and fludarabine (TBF), PTCy, and additional GVHD prophylaxis with 1 of 3 strategies: cohort A, single-agent tacrolimus (n = 222); cohort B, CNI + MMF (n = 49); or cohort C, sirolimus + MMF (n = 101). No differences among the 3 cohorts were found in terms of grade II-IV acute GVHD (20% in cohort A, 25% in cohort B, and 30% in cohort C) or grade III-IV acute GVHD (9%, 6%, and 15%, respectively) at 100 days; however, cohort A had the lowest incidence of overall chronic GVHD (24%, 47%, and 52%, respectively; P = .001) and moderate-severe chronic GVHD (13%, 35%, and 33%, respectively; P = .001). There were no differences in 3-year overall survival, progression-free survival, nonrelapse mortality, or relapse among the 3 cohorts. Overall, our study suggests that single-agent tacrolimus, CNI + MMF, and sirolimus + MMF GVHD prophylaxis lead to similar outcomes following haploSCT with TBF and PTCy, with a low incidence of grade III-IV acute GVHD, although possible differences in chronic GVHD require further investigation.

Topical calcineurin and mammalian target of rapamycin inhibitors in inflammatory dermatoses: Current challenges and nanotechnology­based prospects (Review).

Topical therapy remains a critical component in the management of immune­mediated inflammatory dermatoses such as psoriasis and atopic dermatitis. In this field, macrolactam immunomodulators, including calcineurin and mammalian target of rapamycin inhibitors, can offer steroid­free therapeutic alternatives. Despite their potential for skin­selective treatment compared with topical corticosteroids, the physicochemical properties of these compounds, such as high lipophilicity and large molecular size, do not meet the criteria for efficient penetration into the skin, especially with conventional topical vehicles. Thus, more sophisticated approaches are needed to address the pharmacokinetic limitations of traditional formulations. In this regard, interest has increasingly focused on nanoparticulate systems to optimize penetration kinetics and enhance the efficacy and safety of topical calcineurin and mTOR inhibitors in inflamed skin. Several types of nanovectors have been explored as topical carriers to deliver tacrolimus in both psoriatic and atopic skin, while preclinical data on nanocarrier­based delivery of topical sirolimus in inflamed skin are also emerging. Given the promising preliminary outcomes and the complexities of drug delivery across inflamed skin, further research is required to translate these nanotherapeutics into clinical settings for inflammatory skin diseases. The present review outlined the dermatokinetic profiles of topical calcineurin and mTOR inhibitors, particularly tacrolimus, pimecrolimus and sirolimus, focusing on their penetration kinetics in psoriatic and atopic skin. It also summarizes the potential anti­inflammatory benefits of topical sirolimus and explores novel preclinical studies investigating dermally applied nanovehicles to evaluate and optimize the skin delivery, efficacy and safety of these 'hard­to­formulate' macromolecules in the context of psoriasis and atopic dermatitis.

Significant Long-Term Prevention of High Sensitization After Kidney Allograft Failure by Maintaining Calcineurin Inhibitor-Based Immunosuppression.

INTRODUCTION: Broad national or international programs contribute to mitigating the expected longer waiting list (WL) time for sensitized patients but with minor benefits for highly sensitized subjects. Therefore, strategies to prevent high sensitization are urgently required. In this study, we investigated the risk of developing highly sensitized patients with different immunosuppressive (IS) handling after kidney allograft failure (KAF). METHODS: Data from 185 patients with KAF, retransplanted/relisted from 2010 to 2020 in two regions of Italy that share the same regional WL, were analyzed. Patients were categorized according to IS management at 12 months after KAF as follows: patients maintaining IS with calcineurin inhibitors (CNI) (late withdrawal group [LWG], n = 58) and those who withdrew all IS therapy or were on steroids only (early withdrawal group [EWG], n = 127). RESULTS: Patients in the LWG showed lower panel reactive antibodies (PRA) at 12 (29.0% vs. 85.5%, p < 0.001) and 24 months (61.0% vs. 91.0%, p = 0.001), reduced risk of high sensitization (PRA ≥90%) at 12 (9.4% vs. 40.7%, p < 0.001, OR = 0.15) and 24 months (25.6% vs. 57.3%, p = 0.001, OR = 0.26) and almost no very high sensitization (PRA ≥ 98%) at 12 months (1.9% vs. 18.6%, p = 0.003, OR = 0.08) after KAF. In the LWG subgroup analysis, patients who maintained IS for up to 24 months after KAF did not show very high sensitization. The LWG showed shorter active WL times (406 vs. 813 days, p = 0.001) without an increased risk of complications. CONCLUSIONS: CNI maintenance for at least 12 months after KAF could be a useful approach to prevent high sensitization and reduce WL times in patients who are offered retransplantation, without a higher burden of complications.

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

BACKGROUND: 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). METHODS: 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. RESULTS: 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 -3.43 mL/min/1.73 m2 (-21.0 to 9.6). CONCLUSIONS: 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.

Post-Transplant Cyclophosphamide-Based Graft-Versus-Host Disease Prophylaxis Attenuates Disparity in Outcomes Between Use of Matched or Mismatched Unrelated Donors.

PURPOSEAccess to allogeneic hematopoietic cell transplantation (HCT) remains limited among persons of non-European ancestry if human leukocyte antigen (HLA) matching is required. We evaluated whether post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis improved HCT outcomes with HLA-matched unrelated donor (MUD) and mismatched unrelated donor (MMUD) HCT when compared with calcineurin inhibitor (CNI)-based prophylaxis.METHODSThree-year overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were compared between adult recipients undergoing initial MUD or single HLA locus MMUD HCT with either PTCy- or CNI-based prophylaxis who were reported to the Center for International Blood and Marrow Transplant Research between 2017 and 2021.RESULTSIncluded were 10,025 HCT recipients (7,272 recipients of MUD with CNI, 1,681 MUD with PTCy, 613 MMUD with CNI, and 459 MMUD with PTCy) who underwent HCT for acute leukemia (70.9%) or myelodysplastic syndromes (29.2%). Median patient age was 60.7 years (range, 18.0-82.7) and median follow-up was 36.6 (range, 3.0-77.8) months. When compared with MUD HCT with PTCy, MMUD HCT with PTCy had similar OS (hazard ratio [HR], 0.96 [95% CI, 0.823 to 1.11]; P = .60) and GRFS (HR, 0.90 [0.79 to 1.02]; P = .1). When compared with MUD HCT with CNI, OS was improved after MUD HCT with PTCy (HR, 0.88 [0.80 to 0.96]; P = .004) and GRFS was improved with PTCy after either MUD (HR, 0.61 [0.57 to 0.66]; P < .0001) or MMUD (HR, 0.68 [0.60 to 0.76]; P < .0001) HCT. Benefit from PTCy was independent of patient ancestry. Global registry level analysis demonstrated that inclusion of MMUD increased donor availability regardless of recipient ancestry.CONCLUSIONUse of PTCy results in comparable OS and GRFS using either MUD or MMUD HCT, expanding access to HCT for patients from all racial and ethnic ancestry groups.

Nemolizumab with concomitant topical therapy in adolescents and adults with moderate-to-severe atopic dermatitis (ARCADIA 1 and ARCADIA 2): results from two replicate, double-blind, randomised controlled phase 3 trials.

BACKGROUND: Nemolizumab, an interleukin (IL)-31 receptor subunit α antagonist, inhibits the IL-31 pathway of itch and skin inflammation in atopic dermatitis. Two international phase 3 studies were done to assess the efficacy and safety of nemolizumab in atopic dermatitis. In this Article we report results for the 16-week initial treatment period of both trials. METHODS: ARCADIA 1 and ARCADIA 2 were identical 48-week randomised, double-blind, placebo-controlled phase 3 trials in adult and adolescent participants (aged ≥12 years) with moderate-to-severe atopic dermatitis, associated pruritus, and inadequate response to topical steroids. Participants were enrolled from 281 clinics, hospitals, and academic centres in 22 countries across both trials, and were randomly assigned (2:1) to receive nemolizumab 30 mg subcutaneously (baseline loading dose 60 mg) or matching placebo once every 4 weeks with background topical corticosteroids (TCS) with or without topical calcineurin inhibitors (TCI; ie, TCS-TCI background treatment). Randomisation was done via interactive response technology and stratified by baseline disease and pruritus severity. Study staff and participants were masked throughout the study, with outcome assessors masked until database lock. Coprimary endpoints at week 16 post-baseline were Investigator's Global Assessment (IGA) success (score of 0 [clear skin] or 1 [almost clear skin] with a ≥2-point improvement from baseline) and at least 75% improvement in Eczema Area and Severity Index score from baseline (EASI-75 response). Outcome rates were compared between groups with the Cochran-Mantel-Haenszel test adjusting for randomisation strata. The key secondary endpoints were the proportion of participants with Peak Pruritus Numerical Rating Scale (PP-NRS) score improvement of at least 4 points at weeks 1, 2, 4, and 16; PP-NRS score below 2 at weeks 4 and 16; Sleep Disturbance Numerical Rating Scale score improvement of at least 4 points at week 16; EASI-75 response plus PP-NRS score improvement of at least 4 points at week 16; and IGA success plus PP-NRS score improvement of at least 4 points at week 16. Efficacy analyses were done on an intention-to-treat basis; safety analyses included all participants who received one dose of nemolizumab or placebo. Both studies are completed (ClinicalTrials.gov: ARCADIA 1, NCT03985943 and ARCADIA 2, NCT03989349). FINDINGS: Between Aug 9, 2019, and Nov 2, 2022, 1728 participants were enrolled across both trials: 1142 were allocated to nemolizumab plus TCS-TCI (620 in ARCADIA 1 and 522 in ARCADIA 2) and 586 to placebo plus TCS-TCI (321 in ARCADIA 1 and 265 in ARCADIA 2). ARCADIA 1 included 500 (53%) male participants and 441 (47%) female participants, and ARCADIA 2 included 381 (48%) male participants and 406 (52%) female participants. Mean age ranged from 33·3 (SD 15·6) years to 35·2 (17·0) years across the treatment groups. Both trials met the coprimary endpoints; at week 16, a greater proportion of participants receiving nemolizumab plus TCS-TCI versus placebo plus TCS-TCI had IGA success (ARCADIA 1: 221 [36%] of 620 vs 79 [25%] of 321, adjusted percentage difference 11·5% [97·5% CI 4·7-18·3], p=0·0003; ARCADIA 2: 197 [38%] of 522 vs 69 [26%] of 265, adjusted difference 12·2% [4·6-19·8], p=0·0006) and an EASI-75 response (ARCADIA 1: 270 [44%] vs 93 [29%], adjusted difference 14·9% [7·8-22·0], p<0·0001; ARCADIA 2: 220 [42%] vs 80 [30%], adjusted difference 12·5% [4·6-20·3], p=0·0006). Significant benefits were observed with nemolizumab for all key secondary endpoints including improvement in itch, as early as week 1, and sleep improvement by week 16. The safety profile was similar between nemolizumab plus TCS-TCI and placebo plus TCS-TCI. In the safety sets, 306 (50%) of 616 participants (ARCADIA 1) and 215 (41%) of 519 participants (ARCADIA 2) who received nemolizumab plus TCS-TCI had at least one treatment-emergent adverse event (serious treatment-emergent adverse events in six [1%] and 13 [3%], respectively); and 146 (45%) of 321 (ARCADIA 1) and 117 (44%) of 263 (ARCADIA 2) who received placebo plus TCS-TCI had at least one treatment-emergent adverse event (serious treatment-emergent adverse events in four [1%] and three [1%], respectively). Ten serious treatment-emergent adverse events possibly related to nemolizumab were reported in five (1%) participants in ARCADIA 2. No deaths occurred. INTERPRETATION: Nemolizumab plus TCS-TCI was efficacious and showed statistically and clinically significant improvements in inflammation and itch in adults and adolescents with moderate-to-severe atopic dermatitis. Nemolizumab might offer a valuable extension of current therapies if approved. FUNDING: Galderma.

A Difficult Case of Calcineurin Inhibitor Neurotoxicity Post-Haploidentical HCT With a Successful Novel Solution: Cytotoxic T-Lymphocyte-Associated Protein 4-Immunoglobulin Blockade for GVHD Prophylaxis.

Post-allogeneic hematopoietic cell transplant (HCT) immunosuppression regimens are given as graft-versus-host disease (GVHD) prophylaxis. Most GVHD prophylaxis regimens are based on calcineurin inhibitors (CNIs). Unfortunately, CNIs are associated with significant associated morbidity, frequently cannot be tolerated, and often need to be discontinued. There is no consensus as to which alternative immunosuppression should be used in cases where CNIs have to be permanently discontinued. Cytotoxic T-lymphocyte-associated protein 4-immunoglobulin (CTLA4-Ig) blocking agents are well tolerated and have been used extensively in patients with autoimmune disease and as post-transplant immunosuppression. There are two CTLA4-Ig agents: belatacept and abatacept. Belatacept is routinely used in adult kidney transplantation to prevent rejection and abatacept has been approved by the Food and Drug Administration (FDA) for GVHD prophylaxis in patients undergoing a matched or one allele-mismatched unrelated allogenic HCT. Herein, we describe a case in which abatacept was given off-label to replace tacrolimus GVHD prophylaxis in a patient with neurotoxicity undergoing haploidentical HCT. This case suggests that CTLA4-Ig blockade may be a good alternative to a CNI in cases where the CNI needs to be discontinued and warrants further investigation.

Pearls for practice from the 2023 allergy immunology joint task force on practice parameters GRADE and institute of medicine based atopic dermatitis guidelines.

PURPOSE OF REVIEW: To review the updated 2023 Allergy Immunology Joint Task Force on Practice Parameters (JTFPP) GRADE and Institute of Medicine (IOM) Based Guidelines for the management of atopic dermatitis. RECENT FINDINGS: Topical corticosteroids and/or calcineurin inhibitors are recommended in individuals with atopic dermatitis refractory to moisturizer alone and may be used to maintain remission after acute flare control is achieved. Calcineurin inhibitors are a class of immunosuppressants used to effectively manage different autoimmune disorders. Bleach baths and allergen immunotherapy may be beneficial for individuals with moderate-to-severe disease, while elimination diets, azathioprine, methotrexate, mycophenolate, and systemic corticosteroids are not recommended. Dupilumab is strongly recommended for refractory atopic dermatitis. Oral Janus kinase (JAK) inhibitors carry significant risks; however, this class of medicines may be considered in cases of severe or refractory atopic dermatitis with intolerance to dupilumab. Patient preferences regarding cost, availability, feasibility, and tolerability should be integrated into all treatment plans using a shared decision-making approach. SUMMARY: The 2023 JTFPP Atopic Dermatitis Guidelines offer up-to-date guidance for the management of atopic dermatitis of varying severity in infants, children, and adults.

Optimization of immunosuppression strategies for the establishment of chronic hepatitis E virus infection in rabbits.

Chronic hepatitis E mostly occurs in organ transplant recipients and can lead to rapid liver fibrosis and cirrhosis. Previous studies found that the development of chronic hepatitis E virus (HEV) infection is linked to the type of immunosuppressant used. Animal models are crucial for the study of pathogenesis of chronic hepatitis E. We previously established a stable chronic HEV infection rabbit model using cyclosporine A (CsA), a calcineurin inhibitor (CNI)-based immunosuppressant. However, the immunosuppression strategy and timing may be optimized, and how different types of immunosuppressants affect the establishment of chronic HEV infection in this model is still unknown. Here, we showed that chronic HEV infection can be established in 100% of rabbits when CsA treatment was started at HEV challenge or even 4 weeks after. Tacrolimus or prednisolone treatment alone also contributed to chronic HEV infection, resulting in 100% and 77.8% chronicity rates, respectively, while mycophenolate mofetil (MMF) only led to a 28.6% chronicity rate. Chronic HEV infection was accompanied with a persistent activation of innate immune response evidenced by transcriptome analysis. The suppressed adaptive immune response evidenced by low expression of genes related to cytotoxicity (like perforin and FasL) and low anti-HEV seroconversion rates may play important roles in causing chronic HEV infection. By analyzing HEV antigen concentrations with different infection outcomes, we also found that HEV antigen levels could indicate chronic HEV infection development. This study optimized the immunosuppression strategies for establishing chronic HEV infection in rabbits and highlighted the potential association between the development of chronic HEV infection and immunosuppressants.IMPORTANCEOrgan transplant recipients are at high risk of chronic hepatitis E and generally receive a CNI-based immunosuppression regimen containing CNI (tacrolimus or CsA), MMF, and/or corticosteroids. Previously, we established stable chronic HEV infection in a rabbit model by using CsA before HEV challenge. In this study, we further optimized the immunosuppression strategies for establishing chronic HEV infection in rabbits. Chronic HEV infection can also be established when CsA treatment was started at the same time or even 4 weeks after HEV challenge, clearly indicating the risk of progression to chronic infection under these circumstances and the necessity of HEV screening for both the recipient and the donor preoperatively. CsA, tacrolimus, or prednisolone instead of MMF significantly contributed to chronic HEV infection. HEV antigen in acute infection phase indicates the development of chronic infection. Our results have important implications for understanding the potential association between chronic HEV infection and immunosuppressants.

Calcineurin Inhibitor in NEuRoloGically deceased donors to decrease kidney delayed graft function study: study protocol of the CINERGY Pilot randomised controlled trial.

INTRODUCTION: Most solid organ transplants originate from donors meeting criteria for death by neurological criteria (DNC). Within the organ donor, physiological responses to brain death increase the risk of ischaemia reperfusion injury and delayed graft function. Donor preconditioning with calcineurin inhibition may reduce this risk. METHODS AND ANALYSIS: We designed a multicentre placebo-controlled pilot randomised trial involving nine organ donation hospitals and all 28 transplant programmes in the Canadian provinces of Ontario and Québec. We planned to enrol 90 DNC donors and their approximately 324 organ recipients, totalling 414 participants. Donors receive an intravenous infusion of either tacrolimus 0.02 mg/kg over 4 hours prior to organ retrieval, or a matching placebo, while monitored in an intensive care unit for any haemodynamic changes during the infusion. Among all study organ recipients, we record measures of graft function for the first 7 days in hospital and we will record graft survival after 1 year. We examine the feasibility of this trial with respect to the proportion of all eligible donors enrolled and the proportion of all eligible transplant recipients consenting to receive a CINERGY organ transplant and to allow the use of their health data for study purposes. We will report these feasibility outcomes as proportions with 95% CIs. We also record any barriers encountered in the launch and in the implementation of this trial with detailed source documentation. ETHICS AND DISSEMINATION: We will disseminate trial results through publications and presentations at participating sites and conferences. This study has been approved by Health Canada (HC6-24-c241083) and by the Research Ethics Boards of all participating sites and in Québec (MP-31-2020-3348) and Clinical Trials Ontario (Project #3309). TRIAL REGISTRATION NUMBER: NCT05148715.

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.

Common Skin Conditions in Children and Adolescents: Atopic and Seborrheic Dermatitis.

Atopic dermatitis (AD) is a chronic, recurring, inflammatory skin condition. Xerosis, pruritus, and rash make the clinical diagnosis. Adequate skin care and regular emollient use are key in management. Topical corticosteroids are the first-line treatment for AD flare-ups. Wet wrap therapy can improve AD severity and extent. Topical calcineurin inhibitors are second-line treatments. Emollient use, topical corticosteroids and calcineurin inhibitors, and bleach baths can help prevent flare-ups. Patients with refractory AD that might require immunomodulatory treatments, such as dupilumab (Dupixent), Janus kinase inhibitors, or phototherapy, should be referred to a dermatologist. Seborrheic dermatitis (SD) is a common, chronic, relapsing, inflammatory condition that involves sebaceous skin areas. Infection with Malassezia species and the inflammatory response to it are the probable etiologies. The clinical diagnosis is made by the presence of hallmark greasy, yellow scales on the scalp or face. Infantile SD most commonly involves the scalp and forehead and typically is self-limited. In infants, application of emollients followed by hair brushing and shampooing may be effective. In infants and children, if the condition does not improve with this treatment, topical ketoconazole shampoo, gel, or lotion is safe and effective. Refractory cases of SD can be managed with topical corticosteroids and calcineurin inhibitors.

Tacrolimus Intrapatient Variability on Graft Outcomes in Adherent Renal Transplantation Patients: A Cross-Sectional Study.

INTRODUCTION: Tacrolimus is the mainstem of immunosuppressive therapy in kidney transplant patients. It has high intrapatient variability (Tac-IPV), which has been reported to affect graft function by predisposing patients to rejection or nephrotoxicity. We conducted this study with the aim of assessing the influence of Tac-IPV on 2-year graft function, biopsy-proven rejection, and infections in compliant renal recipients. METHODS: In this single-center retrospective analytic cross-sectional study, 250 patients who underwent transplantation from March 21, 2018, to March 20, 2020 and had at least three outpatient tacrolimus trough levels on the same daily dose 6 to 12 months after transplantation were recruited. Tac-IPV was defined as a coefficient variation of > 15%. Graft function, biopsy-proven rejection, cytomegalovirus (CMV) and BK virus viremia, and calcineurin inhibitor (CNI) toxicity were evaluated. RESULTS: Of 202 transplant recipients, 128 were included with a mean age of 45.48 ± 13.14 years. The median Tac-IPV was 13.28% with 43.75% of patients with Tac-IPV > 15%. There were no significant differences in graft function, rejection, CNI toxicity, and CMV viremia among the groups during the 24-month study (P > .05).  However, BK viremia was significantly higher among patients with Tac-IPV > 15% (13 vs. 2.9%, P = .042). The risk of antibody mediated rejection alone (22.7 vs. 2.9%) or any kind of rejection (22.7 vs. 11.8%) was significantly higher in patients with higher Tac-IPV, and in those who had mean trough levels below 7 ng/mL (P = .015, .032; respectively). CONCLUSION: Tac-IPV is low in adherent patients (with the median of 13.28%) and maintaining tacrolimus trough level above 7 ng/mL can overcome the adverse graft outcome of Tac-IPV in compliant kidney transplant recipients. DOI: 10.52547/ijkd.7815.

Successful treatment of fulminant and recurrent lymphocytic myocarditis with calcineurin inhibitors.

Lymphocytic myocarditis (LM) is primarily triggered by various factors including viral infections and subsequent immune responses. While rare, some patients with LM experience recurrence with a life-threatening fulminant form. Although combining steroids and immunosuppressants, such as azathioprine and mycophenolate mofetil, has demonstrated favourable outcomes in patients with LM, their efficacy is limited to the chronic phase. Indeed, various immunosuppressants have been used for LM with fulminant manifestation; however, their evidence remains lacking. In our case series, two patients with LM experienced fulminant relapses during steroid tapering, and another presented persistent cardiac enzymes elevation despite steroid therapies. Consequently, we initiated calcineurin inhibitors alongside steroids, resulting in well-controlled clinical courses without further recurrence of LM and significant adverse effects. Our cases suggest calcineurin inhibitors as therapeutic options for managing steroid-resistant LM with fulminant relapse.

Therapeutic management of atopic dermatitis.

ABSTRACT: Atopic dermatitis (AD), a chronic inflammatory, pruritic skin disorder, is seen primarily in the pediatric population but can be found among all age groups. The symptoms of AD can cause embarrassment in patients and can interrupt daily activities and productivity, potentially resulting in avoidance of social situations. In addition to nonpharmacologic management, mainstay pharmacologic treatments for AD are topical medications including corticosteroids, calcineurin inhibitors, phosphodiesterase-4 inhibitors, and topical Janus kinase (JAK) inhibitors. Promising new drugs-oral JAK inhibitors and monoclonal antibodies-have emerged as new treatment options for moderate-to-severe AD.

Topical Prescription Management.

With recent advances in topical therapies for atopic dermatitis (AD), steroid-sparing options like calcineurin inhibitors, Janus kinase (JAK) inhibitors, and phosphodiesterase-4 (PDE-4) inhibitors are becoming mainstays in therapy, underscoring the importance of careful selection and usage of topical corticosteroids (TCSs) to minimize side effects. Alongside the necessity of emollient use, these steroid-sparing alternatives offer rapid itch relief and efficacy in improving disease severity. While TCSs still hold a prominent role in AD management, promising novel topical treatments like tapinarof and live biotherapeutics to modulate the skin microbiome are also discussed. Overall, the recent addition of novel topical therapies offers diverse options for AD management and underscores the importance of topical treatments in the management of AD.