Immunosuppressive Doses Research Articles

Associations between dialysis modality and adherence to immunosuppression after kidney transplantation-A single-center study.

Patients with end-stage kidney disease often prefer home-based dialysis due to higher self-efficacy, which relates to improved medical treatment adherence. Kidney transplantation (KT) success depends on adhering to immunosuppressive medication post-transplant. To investigate whether adherence post-kidney transplantation (KT) and patients' attitudes toward immunosuppression were influenced by their prior dialysis type modality. Additionally, the study examined if adherence and patient's attitudes towards immunosuppression are associated with kidney graft survival. This cross-sectional single-center study included 201 KT patients. Adherence was assessed using BAASIS and the coefficient of variation of calcineurin inhibitors (COV-CNI). Patient attitudes towards medication were evaluated using the Q-method. Pill burden, comorbidity score and HRQoL and medication complexity, were scored. Cox regression was applied to determine KT survival outcomes over a 14-year follow-up period (until Dec 2021). Prior dialysis modality was not associated with adherence to immunosuppression post-KT evaluated by BAASIS on average 4.7 years post-KT. Previous in-center hemodialysis patients had a higher CNI-COV (p = 0.011). The Q-sort analysis identified fully adherent patients linked to profile 1 (organized, resilient) whereas profile 2 patients were more careless. Patients linked to profile 3 (challenging, nervous) had higher education, a higher pill burden, and experienced more immunosuppression side effects. Death-censored graft loss increased by 7.6% with each additional pill, quadrupled if one dose of immunosuppression was missed, and increased by 2.9% for each point of COV-CNI rise. Adherence to immunosuppression post-KT using BAASIS was not associated with prior dialysis type, despite in-center hemodialysis patients showing the highest COV-CNI. Taking COV-CNI into account, managing missed doses of immunosuppressants, and exploring patient attitudes could potentially enhance adherence and consequently improve KT survival.

Association between immunosuppressive medications and COVID-19 hospitalisation and death: a retrospective cohort study

ImportanceImmunocompromised status is a risk factor for severe SARS-CoV-2 infection. Little is known about how systemic corticosteroid dose and concurrent use of immunosuppressants are associated with COVID-19 outcomes.ObjectiveTo assess the...

Phenotypic patterns and response to immunotherapy in a group of Very Late Onset Myasthenia Gravis: a single center study.

The goal of this study was to assess the clinical profile of myasthenia gravis (MG) in patients diagnosed above 65-years of age (VLOMG) and identify clinical/serological parameters associated with their MG status and prognosis. This was a retrospective assessment of consecutive patients with VLOMG (n = 70) Demographics, clinical characteristics, medical comorbidities, the Myasthenia Gravis Foundation of America (MGFA) severity scale scores, and MGFA Post-Intervention Status (MGFA-PIS) were collected. The research population was diagnosed with MG at an average age of 73.16 ± 6.33years, a male/female ratio of 2.3/1 and a mean follow-up time of 53.09 ± 46.37months. The titer of acetylcholine receptor antibodies (AChR Abs) was positive at 95.71% of patients. The predominant distribution of myasthenic weakness was oculobulbar (63.79%). At the last follow-up, 75.71% of patients reached Pharmacological-Remission (PR) or Minimal-Manifestations (MM), 17% manifested improvement and 7.14% were clinically unchanged, worse or dead, according to MGFA-PIS. Most patients responded to low doses of steroids. Males and patients with generalized muscle involvement upon disease-onset were more likely to reach PR or MM than females or ocular presentation (OR = 3.84 and O.18, respectively). Six patients (8.57%) were treated with at least one cycle of rituximab due to disease severity. Five (83%) reached PR or MM and one improved (mean follow up time: 7.5months). We found that patients with VLOMG are usually males, with oculobulbar muscle involvement and positive titer of AChR Abs. The majority had a favorable prognosis and an adequate response to low doses of prednisolone and long-term immunosuppression.

Impact of Letermovir for Cytomegalovirus Primary Prophylaxis on Myelosuppression and Immunosuppression in Lung Transplant Recipients.

Cytomegalovirus (CMV) is associated with detrimental outcomes after lung transplantation (LTX); primary prophylaxis (PPX) with valganciclovir (VGC) is guideline-recommended. VGC is associated with myelosuppression, spurring interest in letermovir (LTV). Adults undergoing LTX between January 1, 2021, and July 30, 2022 at our institution who were converted from VGC to LTV for PPX were evaluated. Outcomes included antimetabolite dosing during PPX, the incidence and frequency of myelosuppressive events, and the time to the first myelosuppressive event. Twenty-nine LTX recipients met the inclusion criteria. Most patients received non-lymphocyte-depleting induction (96.6%) and had moderate risk CMV serostatus (D+/R+, 48.3%). Patients transitioned from VGC to LTV 177 days (IQR 102 days) post-transplant. After conversion to LTV, patients tolerated higher daily doses of mycophenolate (721mg vs. 1000mg, p = 0.008) or azathioprine (33.3mg vs. 62.5mg, p = 0.478). The incidence of myelosuppressive events was reduced (100.0%vs. 62.1%, p < 0.001) including leukopenia (96.6%vs. 58.6%, p = 0.001), severe leukopenia (82.8%vs 31.0%, p < 0.001) and neutropenia requiring GCSF (96.6%vs. 48.3%, p < 0.001) while on VGC compared to LTV. While on LTV, patients had a reduced rate of myelosuppressive events compared to VGC (1 event per 6.2 patient days vs. 1 event per 14.7 patient days, p < 0.001). While on LTV, one patient had breakthrough viremia (3.4%) that was treated with (val)ganciclovir. In this single-center study, patients tolerated higher doses of antimetabolite immunosuppression, and the incidence and frequency of myelosuppressive events were reduced while on LTV compared to VGC. This evidence expands upon the current literature demonstrating improved tolerability of LTV in LTX recipients.

Quality by Design (QbD)-Driven Development and Optimization of Tacrolimus-Loaded Microemulsion for the Treatment of Skin Inflammation.

Background: Skin inflammation represents a hallmark of many skin conditions, from psoriasis to eczema. Here, we present a novel microemulsion formulation for delivering a low dose of potent immunosuppressant, tacrolimus, to the skin for local inflammation control. The efficacy of topically delivered tacrolimus in controlling skin inflammation can be enhanced by packaging it into microemulsions. Microemulsions are small-size, thermodynamically stable, and surfactant-rich emulsions that can enhance tissue penetration and local tissue retention of poorly soluble drugs, which can reduce dosing frequency and potentially improve patient compliance. Methods: We present a novel approach for microemulsion manufacturing that uses a combination of both low and high-energy methods. The microemulsion composition and manufacturing parameters were optimized by adopting Quality by Design methodologies. The FMECA (Failure, Mode, Effects, Criticality Analysis)-based risk assessment, D-optimal Design of Experiment (DoE), and statistical analysis of parameters impacting responses through the multiple linear regression (MLR) was implemented for identifying critical formulation and process parameters. Results: Through QbD strategy, a stable microemulsion with optimized drug loading that met all critical quality attributes (CQAs) was identified. The optimal microemulsion candidate was successfully scaled up three-fold with retained CQAs. The presented microemulsion showed a slow and extended drug release profile in vitro. Conclusions: Presented findings suggest that microemulsions are a promising novel approach for tacrolimus delivery to the skin. Further, we also demonstrated that a combination of low-energy emulsification and microfluidization processes can produce stable and robust microemulsions with small droplet size that can be implemented in drug delivery of poorly soluble anti-inflammatory drugs. To the best of our knowledge, this is the first report of QbD-driven optimization of microemulsion manufacturing by microfluidization.

Association of PIRCHE-II score with anti-donor T-cell response and risk of de novo donor-specific antibody production in kidney transplant recipients

BackgroundDe novo donor-specific antibodies (dnDSAs) affect long-term outcomes of kidney transplantation (KT). A higher Predicted Indirectly ReCognizable Human Leukocyte Antigen (HLA) Epitopes (PIRCHE-II) score correlates with various clinical outcomes, including dnDSA formation. However, a detailed analysis of the relationship between the PIRCHE-II score and anti-donor T-cell response is lacking. Therefore, this study investigated the relationship between PIRCHE-II scores associated with dnDSA formation and mixed lymphocyte reaction results of anti-donor T-cell response. MethodsData of 105 adult living-donor KT recipients were retrospectively assessed. ResultsOf the 105 patients, 13.3 % developed dnDSAs during the observation period. The PIRCHE-II score at the HLA-DQ locus (PIRCHE-DQ) was significantly higher in patients with dnDSA formation than in those without. The incidence of dnDSA formation was significantly higher in the PIRCHE-DQ ≥ 77 group than in the PIRCHE-DQ < 77 group. The proportion of patients with increased anti-donor T-cell response was significantly higher in the PIRCHE-DQ ≥ 77 group than in the PIRCHE-DQ < 77 group before KT and at 4 and 5 years after KT. ConclusionsPIRCHE-DQ may predict dnDSA formation and anti-donor T-cell response. Reducing the immunosuppressive drug dose in cases of high PIRCHE-DQ might not be prudent.

Administration of gene replacement therapy in patients with spinal muscular atrophy 5q type 1 with chronic nosocomial bronchopulmonary infection

Introduction. Spinal muscular atrophy (SMA) 5q is a severe hereditary neuromuscular disorder, one of the serious manifestations of which is the development of progressive respiratory insufficiency. The administration of pathogenetic therapy leads to decreased symptoms of respiratory failure, which reduces the risk of lethal outcome and is fundamental for stabilizing the progression of physical development and new motor skills in SMA patients. The aim — to present experience of onasmenogen abeparvovec (OA) gene replacement therapy (GRT) in patients with SMA type 1 and severe respiratory failure combined with chronic bronchopulmonary infection caused by nosocomial multidrug-resistant microflora in real clinical practice. Materials and methods. Five patients with SMA type 1 and respiratory failure of second degree complicated by chronic bronchopulmonary infection were enrolled in this study. All patients were performed a comprehensive clinical, laboratory, and radiologic examination before and for two years after GRT OA administration toof evaluate the severity of respiratory disturbances. The efficiency of OA therapy was estimated with the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), and motor development was assessed by the Hammersmith Infant Neurologic Examination Part 2 (HINE-2). Results. The medical records of 5 (four boys and one girl ) patients with SMA type 1 at the mean age of 19 months (13 to 27 months) at the time of GRT OA administration were analyzed, of them. All patients had been treated with a different type of pathogenetic therapy before GRT OA. After the preventive, personalized antibacterial therapy, all patients experienced GRT OA administration without exacerbation of chronic bronchopulmonary infection, despite hormonal therapy in an immunosuppressive dose (1 mg/kg). There were no lethal outcomes during two years after GRT OA. Over the first year, patients demonstrated a progressive increase in motor skills with further stabilization, but during the second year of follow-up, two patients showed moderate regression of motor skills after pneumonia. One of five patients had a positive lung function dynamics and eradication of highly pathogenic bacterial microflora from the respiratory tract. Conclusions. It is comparatively safe to administer GRT OA in children with SMA type 1 and chronic respiratory infection. However, changing pathogenetic therapy to GRT OA in the cases we presented did not have clinically significant advantages and required more careful patient preparation. Additional risks associated with the occurrence of immune-mediated adverse events due to concomitant hormonal therapy, which can be avoided on other types of pathogenetic therapy, should be considered.

THE EFFECTS OF VALACYCLOVIR ON POLYOMAVIRUS INFECTION (BKV) IN KIDNEY TRANSPLANT RECIPIENTS

Abstract Polyomavirus-associatednephropathy(PVAN) is one of the most serious infectious complications in allograft recipients, with the BK virus (BKV) being the primary etiologic agent. This study was conducted to investigate the efficacy of valacyclovir on BK virus (BKV) infection and viremia control in infected patients in Iran. This quasi-experimental study involved 21Iranian patients. All kidney transplant recipients with a confirmed diagnosis of BKV infection based on renal biopsy and PCR were administered standard therapy (reduced doses of immunosuppressive drugs) with or without valacyclovir at a one-gram dose twice daily for one month. After collecting the data, the data was analyzed using SPSS 23. The K-S test confirmed the normality of the quantitative data. Chi-square for trend, independent-t, and Fisher's exact tests were used to examine group homogeneity in terms of socio-demographic characteristics. Before the intervention, a t-test was used to compare mean scores among the groups; and repeated measures independent sample test, pair sample test, chi square test and ANOVA. The significance level of P 0.05 was considered for all tests. The mean creatinine level, mean GFR(Glomerular Filtration Rate) level, and median viral load in the serum were not significantly different between the two groups at the time of graft rejection diagnosis. One month after treatment, the serum viral load decreased in 90.9% of patients in the intervention group and 50% of patients in the control group, with the difference being statistically significant(p=0.038). Also, in the two-month review, the results showed that the reduction of the virus serum load level was observed in 81.8% of patients in the intervention group and 40% of patients in the control group, and this difference was statistically significant (p=0.049). Mean age, body mass index, and transplant duration were comparable between the two groups. Neither creatinine nor GFR levels differed significantly between the two groups after the intervention(P=0.557 and P=0.387). Valacyclovir can effectively reduce the serum viral load in BKV-infected kidney transplant recipients. This reduction, however, is not accompanied by an improvement in renal function or prevention of rejection.

Prevention of post-transplant lymphoproliferative disorder in pediatric kidney transplant recipients

BackgroundPost-transplant lymphoproliferative disorder (PTLD) is a devastating complication of immunosuppressive treatment in both solid organ transplantations (SOT) and hematopoietic stem cell transplantations (HSCT). Epstein-Barr virus (EBV) infection precedes PTLD in 90% of patients. Rituximab, a monoclonal anti-CD20 antibody, depletes B-lymphocytes, which are the ultimate reservoir for EBV. Although rituximab therapy is commonly used as a preventive measure for PTLD in high-risk HSCT, it is not established in SOT.MethodsPediatric kidney transplant recipients (PKTR) underwent routine EBV-PCR surveillance. Patients with increasing viral loads, despite immunosuppressive dose reduction, were managed with preventive rituximab therapy.ResultsBetween 2012 and 2023, we identified eight episodes of asymptomatic EBV-PCR-positive blood tests in seven out of 65 PKTR (11%) under our care. EBV DNAemia emerged 120–720 days post-transplantation. Five of seven patients with EBV DNAemia (71%) were EBV-seronegative prior to transplantation. All five patients did not respond to MMF dose reduction and were therefore treated with preventive rituximab therapy. Following this treatment, EBV PCR clearance was observed in all patients with only minimal complications.ConclusionsPKTR who are EBV-naïve prior to transplantation are expected to have a higher prevalence of EBV DNAemia. We found that PKTR who were EBV seronegative prior to transplantation were less likely to achieve EBV clearance in response to immunosuppression dose reduction. We suggest that rituximab therapy in PKTR may be safe and effective in EBV clearance and PTLD prevention.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

Torque Teno Virus Loads as a Marker of Immunosuppression in Pediatric Kidney Transplant Recipients.

Long-term renal function and survival after kidney transplantation rely on appropriate immunosuppressive treatment to prevent the risk of rejection. New biomarkers are needed to accurately assess the degree of immunosuppression in renal transplant recipients in order to avoid organ rejection and the development of opportunistic infections. Highly prevalent in humans, torque teno virus (TTV), which belongs to the family Anelloviridae, is a small, nonenveloped, single-stranded DNA virus which has not been linked with any specific human illness, but which constitutes a major component of the human virome. Host antiviral responses allow TTV levels to be controlled; however, viral persistence remains, explaining the high prevalence in human populations, including healthy individuals. Important confounders of TTV load include time since transplantation, age, gender, obesity, and smoking status. TTV-based guidance of immunosuppressive drug dosing could help with risk stratification, reducing the risk of infection, graft rejection and oncologic disease on an individual level, enabling long-term patient and graft survival. Original studies were accessed by a systematic search from electronic databases including PubMed, ScienceDirect and Wiley Online Library. The presented data mainly derive from adult transplant recipients showing an association between TTV plasma levels and the immune status of the host: High-TTV load and high immunosuppression are associated with a risk of infection, and low-TTV load and low immunosuppression indicate a risk of rejection. However, there is minimal information on pediatric transplant recipients with further research required in this cohort. To date, it has been demonstrated that longer posttransplant times are significantly associated with lower TTV levels in children with renal transplant. Meanwhile, an association between lower TTV loads and increased risk of graft reject during the first year of transplantation was also reported. More recently, Eibensteiner etal. revealed a robust, independent association between TTV plasma load and the onset of Cytomegalovirus and BK virus infections. Data from randomized controlled trials are still missing, even in adults, but a multicenter randomized controlled trial for TTV-guided immunosuppression in adult kidney recipients (TTVguideIT) began in 2022. There is, therefore, great promise for TTV levels to be used as a biomarker that could potentially improve both graft and patient survival in transplantation.

Long-term evaluation of the initial response to therapy in 60 dogs with chronic inflammatory enteropathy.

Dogs with chronic inflammatory enteropathy (CIE) are typically classified into food-responsive enteropathy (FRE), antibiotic-responsive enteropathy (ARE), immunomodulator-responsive enteropathy (IRE), and nonresponsive enteropathy (NRE) based on response to therapy(ies). Reassessment of initial categorization (especially IRE and NRE) is lacking. Investigate validity of categorization scheme when reassessed at least 1 year after diagnosis. Sixty client-owned dogs with CIE. Retrospective study. Clinical information was gathered from records and owners from time of diagnosis (TD), time of initial response (TIR), and at least 1 year after diagnosis (T≥1y). Category change was defined as a switch between groups. Median disease activity index (CIBDAI) at TD was 9 and reduced significantly to 1 at T≥1y (P < .0001). At TIR, dogs were categorized as: FRE 27/60 (45%, 95% binomial confidence intervals [CI], 0.32-0.58), IRE 30/60 (50%, CI 0.37-0.63), ARE 0/60 (0%), NRE 3/60 (5%, CI -0.01 to 0.11). Seventeen of 27 (63%) FRE dogs had previously had at least 1 unsuccessful diet trial. At T≥1y, categorization changed to FRE 44/60 (73%, CI 0.62-0.85), IRE 14/60 (23%, CI 0.13-0.34), ARE 0/60 (0%), NRE 2/60 (3%, CI -0.01 to 0.08). Group changes were found for 24/60 (40%) dogs, largest change was from IRE to FRE (19/24, 79%). Immunosuppressive dosages were administered as sole treatment in 1/30 (3%) IRE dogs at TIR. Chronic inflammatory enteropathy categorization based on initial response to therapy needs reassessment after 1 year. Frequent change from IRE to FRE suggests that dogs initially categorized as IRE might have been initially categorized as FRE if multiple dietary trials had been performed. In our study, antibiotics were not needed to achieve satisfying clinical responses.

A narrative literature review of equine sarcoidosis

SummaryEquine sarcoidosis (ES) is a rare disease characterised by granulomatous inflammation of one or multiple organs. The skin is most frequently affected in horses and the clinical presentation can range from scaling and crusting lesions to nodular or tumour‐like masses. ES has been divided into three subtypes depending on the distribution of lesions in the body: the localised, partially generalised and generalised form. Overall, no breed or sex predilections have been consistently observed so far. Most affected horses are older than 3 years although the disease may occur at any age. While aetiology and pathogenesis of ES have not yet been fully determined, a chronic exaggerated immune response to one specific or multiple antigens is frequently hypothesised. Diagnosis is based upon history, clinical presentation, histopathology and exclusion of likely differential diagnoses. The treatment of choice in ES is initial anti‐inflammatory to immunosuppressive doses of corticosteroids with subsequent tapering doses. Reported treatment success seems to be highly variable and prospective studies on the efficacy of corticosteroids or other agents are currently lacking in ES. Prognosis for survival is good for the localised form and poor for the other forms of ES. Complete remission of lesions in the localised form following treatment is less frequent and response to treatment is typically characterised by a slowdown or cessation of disease progression. There are scarce reports of spontaneous remission of this disease.

Auxiliary Partial Orthotopic Liver Transplantation Is a Safe and Effective Option for Yellow Phosphorus Toxin-induced Acute Liver Failure.

Ingestion of yellow phosphorus-containing rodenticides (YPR) or firecrackers is an important cause of acute liver failure (ALF) in young adults and children, particularly in South and South-East Asia and South America. Emergency liver transplantation is indicated in cases refractory to intensive supportive therapy, including low-volume plasma exchange. There are no published reports on the feasibility of auxiliary partial orthotopic liver transplantation (APOLT) for YPR-induced ALF. Clinical details of patients undergoing APOLT for YPR-induced ALF in 1 unit are reported. Details of postoperative follow-up, native remnant regeneration, and immunosuppression withdrawal are also reported. Between January 2021 and December 2023, 3 patients (4 y, 1.5 y, and 26 y) underwent emergency living donor liver transplantation for YPR-induced ALF. All patients were refractory to supportive therapies, including therapeutic plasma exchange, and demonstrated progression of liver injury in the form of severe encephalopathy needing intubation, ventilation, and organ support. APOLT was considered because of their young age and minimal intraoperative inotropic requirement. All explants showed confluent parenchymal necrosis with microvesicular and macrovesicular steatosis. Patients were initially maintained on standard immunosuppression. Good remnant regeneration was noted on follow-up imaging in all cases, enabling gradual withdrawal of immunosuppression. Currently, 1 child has been off immunosuppression for 15 mo and 2 others are on reduced doses of immunosuppression. All patients demonstrated good liver function. APOLT procedure can be an appropriate transplant option in YPR-related ALF for children and young adults without severe hemodynamic instability.

Protocol biopsy of kidney allograft enables early detection of BK virus nephropathy to preserve kidney allograft function.

The Banff Working Group has updated the histological classification of BK virus nephropathy (BKVN), highlighting the importance of early detection. However, an early detection strategy for BKVN using biopsy has not yet been established. Our investigation aimed to assess the efficacy of protocol biopsy for the diagnosis of BKVN. We performed a retrospective cohort study of 314 patients who had undergone kidney transplantation between 2006 and 2021. Kidney allograft biopsies were performed as part of a protocol biopsy at 3 months and 1 year post-transplantation. Following the diagnosis of BKVN, the immunosuppressant dose was reduced. Twelve patients (3.8%) were diagnosed with BKVN by biopsy. Most diagnoses are established during the early stages of BKVN (polyomavirus nephropathy class 1 in six, class 2 in five, and class 3 in one). Following the reduction in immunosuppressant dose, kidney allograft function did not deteriorate in any patients. Additionally, test for BK virus DNA in the blood was negative. All but one patient demonstrated histological resolution of BKVN, and the other had a very slight positivity for the simian virus 40 large T antigen. The median follow-up time after BKVN diagnosis was 6 years. One patient developed de novo donor-specific antibody and subclinical acute antibody-mediated rejection that was successfully cured. Our analysis indicates that protocol biopsy may enable the early detection of BKVN, resulting in the preservation of kidney function.

Management and treatment of severe immune-related hepatotoxicity based on clinical and pathological characteristics

BackgroundThe management of severe immune-related hepatotoxicity (irH) needs to be further optimized. This study aims to analyze the clinical characteristics of severe irH; improve the therapeutic strategy, especially salvage treatment in steroid-refractory irH; and determine the safety of immune checkpoint inhibitor (ICPi)-rechallenge.MethodsThis multicenter retrospective study included patients who developed severe irH and those without irH after immunotherapy between May 2019 and June 2023. Propensity score matching was used to match these two cohorts with similar baseline characteristics.ResultsAmong 5,326 patients receiving ICPis, 51 patients developed severe irH. irH occurred after a median duration of 36 days and a median of two doses after the first ICPi administration. Patients receiving PD-L1 inhibitors faced a lower risk of developing severe irH. A higher dose of glucocorticoids (GCS) was administered to grade 4 irH than grade 3 irH. For steroid-sensitive patients, grade 4 irH individuals received a higher dosage of GCS than those with grade 3 irH, with no difference in time to resolution. Meanwhile, a significantly higher dose of GCS plus immunosuppression was needed in the steroid-refractory group. Liver biopsy of the steroid-refractory patients exhibited heterogeneous histological features. Twelve patients were retreated with ICPi. No irH reoccurred after a median follow-up of 9.3 months.ConclusionirH requires multidimensional evaluation. PD-L1 inhibitors correlated with a lower risk of severe irH. Grade 4 irH demands a higher dose of GCS than recommended. Pathology may guide the salvage treatment for steroid-refractory irH. ICPi rechallenge in severe irH is feasible and safe.

Cardio-Renal-Metabolic Outcomes Associated With the Use of GLP-1 Receptor Agonists After Heart Transplantation.

The use of glucagon-like-peptide 1 receptor agonists (GLP1-RA) has dramatically increased over the past 5 years for diabetes mellitus type 2(T2DM) and obesity. These comorbidities are prevalent in adult heart transplant (HT) recipients. However, there are limited data evaluating the efficacy of this drug class in this population. The aim of the current study was to describe cardiometabolic changes in HT recipients prescribed GLP1-RA at a large-volume transplant center. We retrospectively reviewed all adult HT recipients who received GLP1-RA after HT for a minimum of 1-month. Cardiometabolic parameters including body mass index (BMI), lipid panel, hemoglobin A1C, estimated glomerular filtration rate (eGFR), and NT-proBNP were compared prior to initiation of the drug and at most recent follow-up. We also evaluated for significant dose adjustments to immunosuppression after drug initiation and adverse effects leading to drug discontinuation. Seventy-four patients were included (28% female, 53% White, 20% Hispanic) and followed for a median of 383 days [IQR 209, 613] on a GLP1-RA. The majority of patients (n = 56, 76%) were prescribed semaglutide. The most common indication for prescription was T2DM alone (n = 33, 45%), followed by combined T2DM and obesity (n = 26, 35%). At most recent follow-up, mean BMI decreased from 33.3 to 31.5 kg/m2 (p < 0.0001), HbA1C from 7.3% to 6.7% (p = 0.005), LDL from 78.6 to 70.3 mg/dL (p = 0.018) and basal insulin daily dose from 32.6 to 24.8 units (p = 0.0002). HT recipients prescribed GLP1-RA therapy showed improved glycemic control, weight loss, and cholesterol levels during the study follow-up period. GLP1-RA were well tolerated and were rarely associated with changes in immunosuppression dosing.

Induction immunosuppression strategies and outcomes post-lung transplant: A single center experience

PurposeCurrently 80% of lung transplant centers use induction immunosuppression. However, there is a lack of standardization of induction protocols within and across lung transplant centers. This study explores the association of two different induction immunosuppression strategies used at our center [single dose rabbit antithymocyte globulin (rATG) vs. alemtuzumab] compared to no induction with immunologic and clinical outcomes after lung transplantation. MethodsA total of 174 consecutive lung transplant recipients (LTR) between 2016 and 2019 were included in the analysis. Twenty nine LTR (16.7%) received no induction, 22 LTR (12.6%) received alemtuzumab, 123 LTR (70.6%) received a single dose of rATG; 1.5 mg/kg within 24 h of transplant for induction. All LTR had a negative flow cytometry crossmatch on the day of the transplant. All LTR were assessed for de novo HLA donor-specific antibodies (DSA) development and clinical outcomes, including the risk of acute cellular rejection (ACR), antibody-mediated rejection (AMR), chronic lung allograft dysfunction (CLAD), and overall survival post-transplant. ResultsThe median lung allocation score (LAS) was significantly higher in LTR that did not receive Induction immunosuppression (76; range = 35.3–94.3) compared to induction with rATG (41.6; range = 31.6–91) and alemtuzumab (51; range = 33.1–88.2) (p < 0.001). De novo HLA DSA were detected in 50/174 (28.7%) LTR within 12 months post-transplant. They were detected in 13/29 (44.8%) LTR without induction immunosuppression compared to 28/123 (22.8%) and 9/22 (40.9%) LTR with rATG and alemtuzumab induction, respectively (p = 0.02). The percent freedom from ACR rates between LTR who received alemtuzumab induction was significantly higher compared to LTR who received rATG or no induction at 1 (p = 0.02), 2 (p = 0.01) and 3 (p = 0.05) years post-transplant. In addition, the overall 1-year survival rates were significantly higher in LTR who received rATG or alemtuzumab induction compared to LTR without induction immunosuppression (p = 0.02). ConclusionInduction immunosuppression strategies utilizing rATG or Alemtuzumab have unique and contrasting benefits in LTR. Combination of alemtuzumab induction and a lower dose of maintenance immunosuppression may reduce the incidence of ACR in LTR. Single-dose rATG or alemtuzumab induction immunosuppression may also improve the 1 year overall LTR survival compared to no induction.

Effect of Hydroxychloroquine Treatment on Kidney Allograft Rejection and Graft Failure

Kidney allograft rejection is a major issue because it causes graft failure and because immunosuppressive treatments used for its prevention increase the risk of infections and cancers. In systemic lupus patients, hydroxychloroquine is used to prevent immune flares with decreased doses of immunosuppressants. Hydroxychloroquine can be safely used in kidney transplant recipients when indicated for autoimmune disease, but its effect on allograft rejection is unknown. We hypothesized that it may prevent kidney allograft rejection. We conducted a nationwide retrospective propensity-matched study on kidney transplantations of patients treated with hydroxychloroquine in France between 2008 and 2018. We analyzed the incidence of allograft rejection or failure within the first year after transplantation. The rates of rejection or allograft failure were not different between the 188 patients treated with hydroxychloroquine at the time of transplantation and their propensity matched controls. Hydroxychloroquine treatment in association with standard immunosuppressive treatment does not prevent rejection in kidney allograft recipients.

II Brazilian Society of Rheumatology consensus for lupus nephritis diagnosis and treatment

ObjectiveTo develop the second evidence-based Brazilian Society of Rheumatology consensus for diagnosis and treatment of lupus nephritis (LN).MethodsTwo methodologists and 20 rheumatologists from Lupus Comittee of Brazilian Society of Rheumatology participate in the development of this guideline. Fourteen PICO questions were defined and a systematic review was performed. Eligible randomized controlled trials were analyzed regarding complete renal remission, partial renal remission, serum creatinine, proteinuria, serum creatinine doubling, progression to end-stage renal disease, renal relapse, and severe adverse events (infections and mortality). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to develop these recommendations. Recommendations required ≥82% of agreement among the voting members and were classified as strongly in favor, weakly in favor, conditional, weakly against or strongly against a particular intervention. Other aspects of LN management (diagnosis, general principles of treatment, treatment of comorbidities and refractory cases) were evaluated through literature review and expert opinion.ResultsAll SLE patients should undergo creatinine and urinalysis tests to assess renal involvement. Kidney biopsy is considered the gold standard for diagnosing LN but, if it is not available or there is a contraindication to the procedure, therapeutic decisions should be based on clinical and laboratory parameters. Fourteen recommendations were developed. Target Renal response (TRR) was defined as improvement or maintenance of renal function (±10% at baseline of treatment) combined with a decrease in 24-h proteinuria or 24-h UPCR of 25% at 3 months, a decrease of 50% at 6 months, and proteinuria < 0.8 g/24 h at 12 months. Hydroxychloroquine should be prescribed to all SLE patients, except in cases of contraindication. Glucocorticoids should be used at the lowest dose and for the minimal necessary period. In class III or IV (±V), mycophenolate (MMF), cyclophosphamide, MMF plus tacrolimus (TAC), MMF plus belimumab or TAC can be used as induction therapy. For maintenance therapy, MMF or azathioprine (AZA) are the first choice and TAC or cyclosporin or leflunomide can be used in patients who cannot use MMF or AZA. Rituximab can be prescribed in cases of refractory disease. In cases of failure in achieving TRR, it is important to assess adherence, immunosuppressant dosage, adjuvant therapy, comorbidities, and consider biopsy/rebiopsy.ConclusionThis consensus provides evidence-based data to guide LN diagnosis and treatment, supporting the development of public and supplementary health policies in Brazil.

Corticosteroids and other immunosuppressants for immune-related adverse events and checkpoint inhibitor effectiveness in melanoma

BackgroundRecent studies indicate an association between immunosuppression for immune-related adverse events (irAEs) and impaired survival in patients who received immune checkpoint inhibitors. Whether this is related to corticosteroids or second-line immunosuppressants is unknown. In the largest cohort thus far, we assessed the association of immunosuppressant type and dose with survival in melanoma patients with irAEs. MethodsPatients with advanced melanoma who received immunosuppressants for irAEs induced by first-line anti-PD-1 ± anti-CTLA-4 were included from 18 hospitals worldwide. Associations of cumulative and peak dose corticosteroids and use of second-line immunosuppression with survival from start of immunosuppression were assessed using multivariable Cox proportional hazard regression. ResultsAmong 606 patients, 404 had anti-PD-1 + anti-CTLA-4-related irAEs and 202 had anti-PD-1-related irAEs. 425 patients (70 %) received corticosteroids only; 181 patients (30 %) additionally received second-line immunosuppressants. Median PFS and OS from starting immunosuppression were 4.5 (95 %CI 3.4–8.1) and 31 (95 %CI 15-not reached) months in patients who received second-line immunosuppressants, and 11 (95 %CI 9.4–14) and 55 (95 %CI 41–not reached) months in patients who did not. High corticosteroid peak dose was associated with worse PFS and OS (HRadj 1.14; 95 %CI 1.01–1.29; HRadj 1.29; 95 %CI 1.12–1.49 for 80vs40mg), while cumulative dose was not. Second-line immunosuppression was associated with worse PFS (HRadj 1.32; 95 %CI 1.02–1.72) and OS (HRadj 1.34; 95 %CI 0.99–1.82) compared with corticosteroids alone. ConclusionsHigh corticosteroid peak dose and second-line immunosuppressants to treat irAEs are both associated with impaired survival. While immunosuppression is indispensable for treatment of severe irAEs, clinicians should weigh possible detrimental effects on survival against potential disadvantages of undertreatment.