Calcineurin Inhibitor Therapy Research Articles

Association between everolimus combination therapy and cancer risk after liver transplantation: A nationwide population-based quasi-cohort study.

The potential of everolimus (EVR) in reducing hepatocellular carcinoma (HCC) among recipients following liver transplantation has been reported. This nationwide population-based quasi-cohort study investigated whether combining EVR with calcineurin inhibitor therapy affects the risk of HCC and extrahepatic cancers compared to a time duration-matched cohort of recipients not receiving EVR. Using data covering the entire population from Korea, liver transplant recipients who had initiated immunosuppressants between June 2015 and February 2020 were included, and divided into 2 groups: the EVR combination and noncombination groups. We calculated adjusted hazard ratios (aHRs) and absolute risk reduction for the risk of HCC and extrahepatic cancer with EVR combination therapy using a Cox regression model. A time duration-matched retrospective cohort of 932 recipients in both of the groups was identified. The EVR combination group showed a lower risk of HCC (aHR, 0.53; 95% confidence interval, 0.30-0.94) and extrahepatic cancers (aHR, 0.30; 95% confidence interval, 0.14-0.63) compared to the noncombination group. The absolute risk reduction was 0.004 for HCC and 0.012 for extrahepatic cancer. The findings suggest that adding EVR to calcineurin inhibitor therapy reduces cancer risk in liver transplant recipients, highlighting the importance of considering cancer risk when choosing immunosuppressive therapies.

Effectiveness of Topical Treatment of Steroid and Calcineurin Inhibitor Combination Therapy for Atopic Dermatitis in Children at Skopje Hospital, Macedonia

Introduction: Atopic dermatitis (AD) is a chronic inflammatory skin disease that often occurs in children. Topical treatments, including steroids and calcineurin inhibitors (CNI), are the main line of AD therapy. This study aimed to evaluate the effectiveness of topical treatment of combination steroid and CNI therapy for AD in children at Skopje Hospital, Macedonia. Methods: This research was a retrospective study involving 60 children with AD who were treated with combination therapy of steroids and CNIs for 8 weeks. Clinical data, including SCORAD (Severity of Atopic Dermatitis) score and extent of eczema, were collected before and after treatment. Results: Steroid and CNI combination therapy showed significant improvement in SCORAD score (p<0.001) and eczema extent (p<0.001) after 8 weeks of treatment. Reported side effects are minimal. Conclusion: Combination therapy of steroids and CNIs is an effective and safe treatment for AD in children.

Tacrolimus-Associated Thrombotic Microangiopathy Presenting with Ischemic Colitis After Kidney Transplantation: A Case Report

Calcineurin inhibitors (CNIs) are a significant component of the immunosuppressive regimen after kidney transplantation. By inhibiting cytokine gene transcription, CNIs suppress T cell and T cell-dependent B cell activation. Tacrolimus is preferred in most patients undergoing kidney transplantation. Thrombotic microangiopathy (TMA) is a severe but rare complication of CNIs therapy. TMA defines a specific pathologic lesion of arterioles and capillaries that leads to microvascular thrombosis. A 45-year-old male underwent kidney transplantation five months ago due to autosomal dominant polycystic kidney disease (ADPKD). His triple-maintenance immunosuppressive therapy includes tacrolimus. Abdominal pain and bloody diarrhea occurred in the fifth month of posttransplant. The edematous and erythematous mucosa of the ascending colon was detected on the colonoscopy. The foci of microthrombi inside the vessel lumen in the lamina propria were shown biopsy. The thrombosis or occlusion was excluded with computerized tomography (CT) angiography in abdominal vessels. The fragmented red blood cells and moderate thrombocytopenia were detected on the peripheral blood smear. Eventually, TMA diagnosis was established through laboratory and histological findings. Tacrolimus was suspected as the trigger of the pathological process and promptly switched to the everolimus. Afterward, laboratory abnormalities and clinical symptoms were improved. In this case, we intend to emphasize drug-associated TMA and atypical presentations, such as colonic microvasculature involvement.

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

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

#3670 THE ROLE OF CALCINEURIN INHIBITORS IN MONOGENIC PEDIATRIC STEROID RESISTANT NEPHROTIC SYNDROME: A RETROSPECTIVE, MULTICENTER STUDY

Abstract Background and Aims Response to calcineurin inhibitors (CNI) is associated with a significant improvement in long-term kidney survival of children with non-genetic steroid resistant nephrotic syndrome (SRNS). On the contrary, these agents are considered non-efficacious in monogenic SRNS and are contraindicated according to the latest International Pediatric Nephrology Association (IPNA) Clinical Practice Recommendations for SRNS. However, there is evidence suggesting that remission with CNI therapy in this subgroup of children with SRNS is possible, but no studies to date have assessed this question in a systematic way. We aimed to study the incidence of response to CNI in children with monogenic SRNS, factors predictive of remission and the effect of treatment on kidney survival. Method Retrospective cohort study of children 0–18 years with genetically confirmed SRNS treated with a CNI for at least 3 months. Demographic, clinical, genetic, biochemical, histopathologic and treatment data were collected at various time points; at clinical diagnosis, 6, 12, 24 months from CNI onset, and last available follow-up. Pathogenicity of all reported variants was assessed by a dedicated geneticist according to the American College of Medical Genetics guidelines and only patients with a pathogenic genotype were included in the analysis[1]. Patients were classified according to their response to CNI as complete, partial or non-responders based on the IPNA Clinical Practice Recommendations for SRNS[2]. Results 141 patients from 37 international paediatric nephrology centers were included in the study. At 6 months from CNI initiation and at last visit, 27.6% and 22.5%, respectively, demonstrated either complete or partial response (“at least partial response”). Median observation time between CNI initiation and last visit was 42.1 months (IQR 20.1–65.6) and was comparable between patients with no response and at least partial response (42.3 vs 41.6 months; P&amp;gt;0.05). No serious adverse effects mandating treatment discontinuation were reported. Children demonstrating at least partial response at 6 months had a lower risk of progression to kidney failure at last visit versus non-responders (hazard ratio [95%CI] 0.25, [0.10–0.62]; P = 0.003). Subgroup analysis of patients with a follow-up of at least 2 years revealed similar results with a hazard ratio of 0.35 (95%CI 0.14–0.91; P = 0.03). Of the various clinical, biochemical, genetic, histopathologic and treatment parameters tested in a multivariable logistic regression model only higher serum albumin at CNI onset was associated with higher likelihood of response at 6 months (odds ratio [95% CI] 1.16, [1.08–1.24]; P &amp;lt; 0.001). Conclusion Our findings suggest that CNI use could be considered in monogenic SRNS and that achievement of response in this setting can alter an otherwise dismal long-term kidney outcome.

Rituximab/Mycophenolate Combination Therapy in Children with Calcineurin Inhibitor-Resistant FSGS.

There is a paucity of data and therapeutic options nationally and internationally on calcineurin inhibitor (CNI)-resistant forms of focal segmental glomerulosclerosis (FSGS) in children. CNI (tacrolimus or cyclosporine) are proven monotherapy in children with FSGS with a steroid-dependent (SD) or steroid-resistant (SR) course. We analyzed a novel therapeutic option in CNI-resistant FSGS by using the dual therapy of rituximab and mycophenolate to maintain remission. This is a retrospective analysis of clinical, therapeutic profile, and treatment outcomes (sustained remission versus no remission) in subjects with CNI-resistant FSGS who received dual rituximab therapy along with mycophenolate as maintenance therapy for a minimum of 1 year. The median age of presentation of 13 recruited children was 7.8 years (range: 2.4-17.6 years); nine (69.2%) were males. Ten (76.9%) of them had an SD course and three (23.1%) had an SR course. Four (30.7%) had evidence of acute/chronic CNI toxicity, and the remaining nine (69.3%) showed no response to CNI therapy despite adequate trough levels. Post dual therapy, 11 (84.6%) had sustained remission for at 1 year and two (15.4%) children did not show remission. None reported adverse reactions or infections, and all had preserved renal functions. Dual combination therapy with rituximab and mycophenolate among children with CNI-resistant FSGS can emerge as a promising and efficacious treatment strategy to ensure sustained remission in this subset of patients.

Clinical characteristics and prognosis of patients with idiopathic membranous nephropathy with kidney tubulointerstitial damage

Background To investigate the clinical and kidney pathological features and prognosis of idiopathic membranous nephropathy (IMN) with kidney tubulointerstitial damage (TID). Methods Based on the presence or absence of kidney TID by kidney biopsy, 300 patients diagnosed with IMN were categorized into non-TID (TID−) and tubulointerstitial injury (TID+) groups. The clinical and pathological data were analyzed retrospectively. All patients were followed up for 6–24 months after treatment with glucocorticoids (GCs) combined with cyclophosphamide or GCs combined with calcineurin inhibitors (CNIs) to observe treatment effects on patient prognosis. Results The patients in the TID + group were older and more likely to be male. The 24-h urine protein, blood urea nitrogen, serum creatinine, cystatin C, β2-microglobulin, and antiphospholipase A2 receptor antibody levels were higher than those in the TID − group and the pathological manifestations were more severe. After 1 year of follow-up, the overall response rate (complete response + partial response) in the TID + group was lower (66.67% vs. 80.89%, p = .022) than in the other. After combined GC and CNI therapy, the complete remission rate in the TID + group was significantly lower than that in the TID − group (13.79% vs. 35.46%, p = .022). The 24-h urine protein level was an independent risk factor for worsening kidney condition (p = .038). Conclusion Patients with IMN with TID have more severe clinical manifestations and pathological damage and lower remission rates. IMN with TID is a risk factor for worsening kidney condition; however, it is not an independent risk factor.

Donor-Derived Cell-Free DNA for Kidney Allograft Surveillance after Conversion to Belatacept: Prospective Pilot Study

Donor-derived cell-free DNA (dd-cfDNA) is used as a biomarker for detection of antibody-mediated rejection (ABMR) and other forms of graft injury. Another potential indication is guidance of immunosuppressive therapy when no therapeutic drug monitoring is available. In such situations, detection of patients with overt or subclinical graft injury is important to personalize immunosuppression. We prospectively measured dd-cfDNA in 22 kidney transplant recipients (KTR) over a period of 6 months after conversion to belatacept for clinical indication and assessed routine clinical parameters. Patient and graft survival was 100% after 6 months, and eGFR remained stable (28.7 vs. 31.1 mL/min/1.73 m2, p = 0.60). Out of 22 patients, 2 (9%) developed biopsy-proven rejection-one episode of low-grade TCMR IA and one episode of caABMR. While both episodes were detected by increase in creatinine, the caABMR episode led to increase in absolute dd-cfDNA (168 copies/mL) above the cut-off of 50 copies/mL, while the TCMR episode did show slightly increased relative dd-cfDNA (0.85%) despite normal absolute dd-cfDNA (22 copies/mL). Dd-cfDNA did not differ before and after conversion in a subgroup of 12 KTR with previous calcineurin inhibitor therapy and no rejection (12.5 vs. 25.3 copies/mL, p = 0.34). In this subgroup, 3/12 (25%) patients showed increase of absolute dd-cfDNA above the prespecified cut-off (50 copies/mL) despite improving eGFR. Increase in dd-cfDNA after conversion to belatacept is common and could point towards subclinical allograft injury. To detect subclinical TCMR changes without vascular lesions, additional biomarkers or urinary dd-cfDNA should complement plasma dd-cfDNA. Resolving CNI toxicity is unlikely to be detected by decreased dd-cfDNA levels. In summary, the sole determination of dd-cfDNA has limited utility in the guidance of patients after late conversion to belatacept. Further studies should focus on patients undergoing early conversion and include protocol biopsies at least for patients with increased dd-cfDNA.

Membrane-bound IL-2 improves the expansion, survival, and phenotype of CAR Tregs and confers resistance to calcineurin inhibitors.

Regulatory T cells (Tregs) play an important role in the maintenance of immune homeostasis and the establishment of immune tolerance. Since Tregs do not secrete endogenous IL-2, they are especially dependent on external IL-2. IL-2 deficiency leads to lower Treg numbers, instability of the Treg phenotype and loss of immune regulation. After organ transplantation, patients are treated with calcineurin inhibitors (CNIs), which further limits available IL-2. Application of low-dose IL-2 expands Tregs but also activates NK and CD8+ T cells. It was recently shown that graft-specific Tregs recognizing mismatched MHC I molecules via a chimeric antigen receptor were far more potent than polyclonal Tregs in the regulation of immune responses after solid organ transplantation in a humanized mouse model. Therefore, our aim was to enhance the function and stability of transferred CAR-Tregs via expression of membrane-associated IL-2 (mbIL-2). mbIL-2 promoted higher survival, phenotypic stability, and function among CAR-Tregs than observed in clinical trials. The cells were also more stable under inflammatory conditions. In a preclinical humanized mouse model, we demonstrated that mbIL-2 CAR Tregs survive better in the Treg niche than control CAR Tregs and are even resistant to CNI therapy without affecting other Tregs, thus acting mainly in cis. The functional and phenotypic improvements observed after membrane-attached IL-2 expression in CAR-Tregs will be important step for enhancing CAR-Treg therapies currently being tested in clinical trials for use after kidney and liver transplantation as well as in autoimmune diseases.

Short-term decreased post transplant lymphoproliferative disorder risk after kidney transplantation using two novel regimens

BackgroundBelatacept is employed alongside calcineurin inhibitor (CNI) therapy to prevent graft rejection in kidney transplant patients who are Epstein-Barr virus (EBV) seropositive. Preliminary data suggested that rates of post-transplant lymphoproliferative disorder (PTLD) were higher in individuals treated with belatacept compared to CNI therapy alone. MethodsThe records of 354 adults who underwent kidney only transplantation from January 2015 through September 2021 at one medical center were evaluated. Patients underwent treatment with either low-doses of mycophenolate, tacrolimus and sirolimus (B0, n = 235) or low-doses of mycophenolate, tacrolimus and belatacept (B1, n = 119). All recipients underwent induction with antithymocyte globulin and a rapid glucocorticosteroid taper. Relevant donor and recipient information were analyzed and endpoints of PTLD were assessed. ResultsThere were no cases of PTLD in either cohort within the study period. Recipients in the belatacept cohort experienced lower estimated glomerular filtration rates at 12 months (B0: 67.48 vs. B1: 59.10, p = 0.0014). Graft failure at 12 (B0: 1.28% vs. B1: 0.84%, p = 1.0) and 24 months (B0:2.55% vs. B1: 0.84%, p = 0.431) were similar. There was no difference in rejection rates at 12 (B0: 1.27% vs. B1: 2.52%, p = 0.408) or 24 months (B0: 2.12% vs. B1: 2.52%, p = 1.000). Both groups had similar rates of malignancy, mortality and CMV/BK viremia. ConclusionNon-belatacept (MMF, tacrolimus and sirolimus) and belatacept-based (MMF, tacrolimus and belatacept) regimens do not appear to pose any increased risk of early onset PTLD. Both cohorts benefited from low rates of rejection, malignancy, mortality and graft failure. Recipients will continue to be monitored as PTLD can manifest as a long-term complication.

Stepwise Reduction of Mycophenolate Mofetil with Conversion to Everolimus for the Treatment of Active BKV in Kidney Transplant Recipients: A Single-Center Experience in Vietnam.

Background: No specific antiviral drug can effectively treat BKV reactivation after kidney transplantation. Thus, we evaluated stepwise-reduced immunosuppression to treat BKV reactivation. Methods: 341 kidney-transplant recipients were monitored for BKV infection (BKV-viremia, BKV-viruria). Positive samples with a significant virus load were nested PCR-genotyped in the VP1 region. In 97/211 patients presenting BKV viremia ≥104 copies/mL and/or BKV viruria ≥107 copies/mL, or BKV-nephropathy immunosuppression (i.e., mycophenolate mofetil [MMF]) was reduced by 50%. If viral load did not decrease within 28 days, MMF dose was further reduced by 25%, although calcineurin-inhibitor (CNI) therapy remained unchanged. If BKV viral load did not decrease within another 28 days, MMF was withdrawn and replaced by everolimus combined with reduced CNIs. Results: Only 41/97 BKV (+) cases completed the 6-month follow-up. Among these, 29 (71%) were in the BKV-I group and 12 (29%) were in BKV-IV. BKV viruria and BKV viremia were significantly decreased from 9.32 to 6.09 log10 copies/mL, and from 3.59 to 2.45 log10 copies/mL (p < 0.001 and p = 0.024, respectively). 11/32 (34.4%) patients were cleared of BKV viremia; 2/32 (6.3%) patients were cleared of BKV in both serum and urine, and 9/9 (100%) only had BKV viruria but did not develop BKV viremia. eGFR remained stable. No patient with BKV-related nephropathy had graft loss. There was a significant inverse relationship between changes in eGFR and serum BKV load (r = −0.314, p = 0.04). Conclusions: This stepwise immunosuppressive strategy proved effective at reducing BKV viral load in kidney transplant recipients that had high BKV loads in serum and/or urine. Renal function remained stable without rejection.

Chronic CD40L blockade is required for long-term cardiac allograft survival with a clinically relevant CTLA4-Ig dosing regimen.

In de-novo kidney transplantation, the CTLA4-Ig fusion protein belatacept is associated with improved graft function but also an increased risk of acute rejection compared to calcineurin inhibitor therapy. The combination with a second costimulation blocker could potentially improve outcome while avoiding calcineurin inhibitor toxicity. The aim of this study was to define the conditions under which the combination of CTLA4-Ig and CD40L blockade leads to rejection-free permanent graft survival in a stringent murine heart transplantation model. Naïve wild-type or CD40L (CD154) knock-out mice received a fully mismatched BALB/c cardiac allograft. Selected induction and maintenance protocols for CTLA4-Ig and blocking αCD40L monoclonal antibodies (mAB) were investigated. Graft survival, rejection severity and donor-specific antibody (DSA) formation were assessed during a 100-day follow-up period. Administering αCD40L mAb as monotherapy at the time of transplantation significantly prolonged heart allograft survival but did not further improve the outcome when given in addition to chronic CTLA4-Ig therapy (which prolongs graft survival to a median of 22 days). Likewise, chronic αCD40L mAb therapy (0.5mg) combined with perioperative CTLA4-Ig led to rejection in a proportion of mice and extensive histological damage, despite abrogating DSA formation. Only the permanent interruption of CD40-CD40L signaling by using CD40L-/- recipient mice or by chronic αCD40L administration synergized with chronic CTLA4-Ig to achieve long-term allograft survival with preserved histological graft integrity in all recipients without DSA formation. The combination of α-CD40L and CTLA4-Ig works most effectively when both therapeutics are administered chronically.

EE204 Cost-Effectiveness of Everolimus Combination Therapy in Patients After Liver Transplantation Focusing on Cancer Risk: A Markov Model Using Real-World Data

The potential of everolimus (EVR) in reducing hepatocellular carcinoma (HCC) among the patients on immunosuppressants after liver transplantation (LT) has been reported. Thus, we aimed to investigate whether combining EVR with standard calcineurin inhibitor (CNI) therapy affects the risk of HCC and extrahepatic cancers and assess its cost-effectiveness.

Single-cell profiling reveals distinct adaptive immune hallmarks in MDA5+ dermatomyositis with therapeutic implications

Anti-melanoma differentiation-associated gene 5-positive dermatomyositis (MDA5+ DM) is an autoimmune condition associated with rapidly progressive interstitial lung disease and high mortality. The aetiology and pathogenesis of MDA5+ DM are still largely unknown. Here we describe the immune signatures of MDA5+ DM via single-cell RNA sequencing, flow cytometry and multiplex immunohistochemistry in peripheral B and T cells and in affected lung tissue samples from one patient. We find strong peripheral antibody-secreting cell and CD8+ T cell responses as cellular immune hallmarks, and over-stimulated type I interferon signaling and associated metabolic reprogramming as molecular immune signature in MDA5+ DM. High frequency of circulating ISG15+ CD8+ T cells at baseline predicts poor one-year survival in MDA5+ DM patients. In affected lungs, we find profuse immune cells infiltration, which likely contributes to the pro-fibrotic response via type I interferon production. The importance of type I interferons in MDA5+ DM pathology is further emphasized by our observation in a retrospective cohort of MDA5+ DM patients that combined calcineurin and Janus kinase inhibitor therapy show superior efficacy to calcineurin inhibitor monotherapy. In summary, this study reveals key immune-pathogenic features of MDA5+ DM and provides a potential basis for future tailored therapies.

Postreperfusion Syndrome in Liver Transplant: A Risk Factor for Acute Kidney Failure: A Retrospective Analysis

The maximum expression of hemodynamic instability during liver transplant is the so-called postreperfusion syndrome (PRS) that increases both overall mortality and postoperative complications. It was first defined by Aggarwal et al in 1987, but the results are still conflicting when establishing the relationship between PRS and acute kidney failure (AKF). We conducted a retrospective observational study of transplant recipients with deceased-donor liver grafts between January 2002 and December 2018. We analyzed the incidence of PRS and its potential negative impact over kidney function. A total of 551 transplants were analyzed. PRS was recorded in 130 patients (23.6%). The incidence of AKF was 61.5%. A total of 111 patients required kidney replacement therapy (32.7%). Regarding the severity of AKF, 128 patients were classified as acute kidney injury (AKI) 1 (23.2%), 76 as AKI 2 (13.8%), and 135 as AKI 3 (24.5%). In the group with PRS, 75.4% (n=98) developed AKF vs 57.2% (n=241) in the group without PRS. In the multivariate analysis we found a relationship between PRS and AKF with an odds ratio of 2.18 (95% CI, 1.30-3.64; P=.003), once adjusted by the length of the anhepatic phase, donor age, Model for End-Stage Liver Disease score, history of ascites, and need for early surgical reintervention. The incidence of AKF decreased (44.5%) ever since the implementation of delayed calcineurin inhibitors therapy and piggyback surgical technique, but a clear influence of the occurrence of PRS on the development of AKF is still observed, with an OR of 3.78 (95% CI, 1.92-7.43; P < .001), once adjusted by albumin and hemoglobin levels, Model for End-Stage Liver Disease score, and Child classification.

COVID-19 vaccination antibody responses in patients with aplastic anaemia and paroxysmal nocturnal haemoglobinuria

COVID-19 vaccination antibody responses in patients with aplastic anaemia and paroxysmal nocturnal haemoglobinuria

Determinants and Clinical Significance of Musculoskeletal Symptoms in Patients With Chronic Graft-Versus-Host Disease.

Musculoskeletal symptoms in chronic graft-versus-host disease (cGVHD) are rare manifestations contributing to disease burden. This study assesses the frequency of muscle cramps, joint and muscle aches, and muscle weakness in a cohort of patients severely affected by cGVHD. Three hundred thirty-four patients participated in the NCI natural history study of cGVHD (NCT00092235) from October 2004 to March 2017. Five-point Lee cGVHD Symptom Scale was dichotomized (less symptom bother—0, 1, 2; severe symptom bother—3, 4) and tested for associations with: Short Form 36 (SF36), 2-minute walk test, grip strength, joint range of motion, and human activity profile, clinical and laboratory data. Seventy-five point four percent of patients reported joint and muscle aches (36.8% severe, Lee Symptom Scale score 3–4), 74.3% muscle cramps (33.5% severe), and 82.34% muscle weakness (45.51% severe), which were associated with reduced functional capacity (SF36 Physical Component Scale, P < 0.0001). Muscle cramps were associated with limited joint movement (P < 0.0001) and skin manifestations (skin thickening, P = 0.0008; itchy skin, P = 0.0003). Muscle cramps did not show association with potential causative agents, such as concomitant calcineurin inhibitors therapy, statins, or use of antidiabetic drugs. Joint and muscle aches showed associations with multiple variables (including strong associations with mood symptoms and fatigue, P < 0.0001). Muscle weakness was not associated with steroid dose, but was significantly associated with depression (P < 0.0001) and anxiety (P = 0.0009). This study documents a high frequency of musculoskeletal symptoms in a cohort of adult patients with cGVHD. The multivariable logistic regression models showed that a joint set of factors were moderately well associated with musculoskeletal symptoms in this study.

P36 THE ELDEST HEART TRANSPLANTED PATIENT IN EUROPE: 36 YEARS SURVIVAL AND STILL GOING ON

Development of endomyocardial biopsy for acute rejection monitoring in the early Seventies, and above all use of cyclosporine in the clinical practice starting from 1980, introduced the modern era of heart transplantation. Following the initial positive outcomes, the first Italian transplant was performed in Padua by V.Gallucci on November 15th 1985. This pioneering success was rapidly repeated in Pavia, where M.Viganò performed the second transplant on Novembre 17th. Recipient was 20 years old man, suffering from dilated cardiomyopathy, on urgent transplant list. Cardiac index was 1.38 l/min/m2 and pulmonary vascular resistance 1.6 WU. Donor was a 14 years old boy died of brain injury. Total ischemic time was 125 minutes. Induction immunosuppression consisted of horse anti–lymphocyte immunoglobulins, whereas maintenance therapy included cyclosporine, azathioprine and steroids. Postoperative course was complicated by pericardial effusion and cholestatic jaundice. Later pulmonary aspergillosis occurred and due to the profound immunodepression was complicated by fungal localization at L2 vertebral body. The infection was treated with surgical removal of the secondary localization and amphotericin B administration. On December 6th severe acute rejection was found at biopsy and treated with i.v. steroid pulse. Length of ICU and hospital stay was 28 and 72 days, respectively. In 1998 HCV infection was detected and eradicated in 2017 with elbasvir/grazoprevir therapy. Complications of long term immunosuppressive treatment included dyslipidemia, myeloma and basal cell carcinoma. Due to long–term calcineurin inhibitors therapy progressive chronic renal failure occurred, leading to replacement therapy in 2015 and kidney transplantation in 2016. In 2015 the patient underwent percutaneous coronary intervention with stents implantation in two marginal branches and in the anterior descending artery in 2021. Everolimus was introduced to slow down progression of cardiac allograft vasculopathy. In 2020 he suffered from Covid–19, but the course of infection was uneventful being cough the only symptom. We report the eldest survivor after heart transplant in Europe. Our case demonstrates that despite early and long–term complications of immunosuppressive therapy, a careful and patient tailored management allowed an amazing outcome. Nowadays heart transplant remains the best treatment for end stage heart failure and allows to resume a nearly normal quality of life.

Tacrolimus induces ligand independent TGFβ receptor signaling to promote renal fibrosis

BackgroundAlthough calcineurin inhibitors (CNIs) such as tacrolimus and cyclosporin have dramatically improved the quality of patient care, long‐term therapy causes irreversible damage to the kidneys in the form of renal fibrosis. These morphologic changes ultimately lead to a decline in renal function and can progress to end‐stage renal failure. These detrimental outcomes present a critical need to identify the driving mechanisms by which CNIs cause renal damage.ObjectiveIt is well established that TGFb is a major contributor to CNI‐induced renal fibrosis. However, the underlying mechanisms remain unknown. The objectives of this study are to 1) investigate whether TGFb secretion is required to stimulate TGFb receptor signaling in a model of CNI‐induced renal fibrosis and 2) investigate whether calcineurin plays a critical role in regulating TGFb receptor activity.Experimental DesignTo examine the role of calcineurin inhibition in altered TGFb receptor signaling, wild type mice were treated with either vehicle (0.01% ethanol) or 10 mg/kg tacrolimus for 7 days. To confirm in vivo findings, wild‐type mouse renal cortical fibroblasts were treated with either vehicle (0.01% ethanol) or 1nM tacrolimus for 24 hours in the presence and absence of anti‐TGFb neutralizing antibodies. TGFb receptor expression and activation, TGFb receptor downstream signaling mediators, profibrotic markers and calcineurin activity were analyzed.ResultsFindings demonstrate that tacrolimus‐induced loss of calcineurin activity is accompanied with enhanced TGFb receptor activation and signaling. Notably, increasing concentrations of anti‐TGFb neutralizing antibodies failed to abolish aberrant TGFb signaling and increased expression of profibrotic markers.ConclusionsTogether, these results demonstrate that 1) CNIs promote ligand‐independent TGFb signaling and 2) calcineurin plays a functional role in regulating TGFb receptor activity.SignificanceThis study elucidates a direct pharmacological mechanism by which CNIs promote renal fibrosis and provides a physiological role of calcineurin in regulating TGFb receptor activity. Further insight into the role of calcineurin in regulating TGFb receptor activity could improve the long‐term outcomes of patients on chronic CNI therapy.

Atypical HUS Unmasked by Infection and Calcineurin Inhibitors Post Lung Transplant

<h3>Introduction</h3> Lung transplant recipients are maintained on multiple lifelong immunosuppressive medications including steroids, calcineurin inhibitors (CNI), and antimetabolite (AM) medications. We report a unique case of a double lung transplant (DLT) recipient developing thrombotic microangiopathy (TMA) from atypical hemolytic uremic syndrome (aHUS) unmasked by infection and CNI therapy. <h3>Case Report</h3> 63-year-old male developed delirium and thrombocytopenia after initiation of CNI therapy with tacrolimus post DLT. Evaluation was otherwise negative and patient improved with cessation of therapy. CNI was switched to cyclosporine without further issues. Four-week biopsy was negative for acute cellular rejection. Five days later, he presented with hypoxia, dyspnea, dizziness, confusion, and impaired gait. His immunosuppressive regimen included prednisone & cyclosporine. His AM therapy was held for leukopenia. All testing and imaging were negative apart from bronchial lavage cultures positive for pseudomonas, klebsiella, and parainfluenza. Appropriate antibiotics and antiviral therapies were started. He developed delirium, acute kidney injury, hemolysis, and thrombocytopenia. Impression was CNI-induced TMA, and CNI was held. All additional work up was negative including shiga-like toxin producing E.Coli. He failed to improve with removal of offending agent and concern was for aHUS given complement panel was suggestive of alternative pathway dysregulation (absent AH50, normal C4 and decreased factors B and H). Patient did not respond to plasmapheresis, and eculizumab was started. He remained thrombocytopenic with positive hemolytic parameters despite 2 doses of therapy. Complement genetic panel testing is pending. Treatment is now held due to respiratory failure and septic shock. <h3>Summary</h3> aHUS is a rare form of TMA, associated with excess activation of the alternate complement pathway which is part of innate immunity. It usually responds to treatment with eculizumab, an anti-C5 monoclonal antibody that inhibits terminal complement complex generation. Our case is inconsistent with secondary HUS from drugs or solid organ transplant and has failed standard aHUS therapy. This is a complex and uniquely challenging case, limited second line options are available including a recently approved long-acting C5 complement inhibitor, which is under review at our institution.