Changes In Immunosuppressive Therapy Research Articles

Impact of COVID-19 on anti-HLA antibodies in kidney transplantation

The effects of COVID-19 on the immune profile of kidney transplant recipients are unknown. Immunosuppression adjustment during the illness can increase the risk for de novo donor-specific anti-HLA antibodies (DSA) and acute rejection episodes. This single-center retrospective study includes adult kidney transplant recipients diagnosed with COVID-19 between March 2020 and December 2022, screened for anti-HLA antibodies (AbHLA) pre-transplant and after COVID-19. Analyzed data comprised demographics, immunosuppressive therapy before and during the illness, hospitalization rate, and AbHLA specificity. Two hundred sixty-seven transplant recipients were included and divided according to the pre-transplant AbHLA profile: absent [PRA- (n = 206, 77%)], non-DSA (N = 46, 17%), and DSA+ (n = 15, 6%). The DSA+ group was younger (40.5 ± 16.5; PRA- 50.3 ± 13.4; non-DSA 49.3 ± 11.7 years; p = 0.02). The hospitalization rate was higher in groups with preformed AbHLA (DSA+ n = 8, 53%; non-DSA = 24, 52%; PRA- n = 54, 26%; p < 0.01). Immunosuppression was maintained in 222 (83%), withdrawn in 33 (12%), and reduced in 11 (4%) cases without difference among groups. Twenty-two (8%) cases of de novo DSA were observed after COVID-19 [PRA-, n = 16 (73%) and non-DSA, n = 6 (27%)]. In the DSA+ group, the AbHLA profile remained stable. There were 6 (2%) cases of post-COVID-19 antibody-mediated rejection (DSA+ n = 4, 66%; non-DSA n = 1, 17%, PRA- n = 1, 17%) without T cell-mediated rejection cases. Post-COVID-19 de novo DSA was more frequent in groups without pre-transplant AbHLA, not having association with changes in immunosuppressive therapy.

#3108 Rituximab in adult-onset IgA vasculitis

Abstract Background and Aims Adult-onset IgA Vasculitis (IgAV) is poorly responsive to glucocorticoids (GC) and conventional immunosuppressive therapies, such as cyclophosphamide. Rituximab has been successfully used in a few cases and may represent a safer and potentially more effective option [1]. Crescentic IgA Nephropathy (cIgAN), a rare entity that shares features of renal vasculitis with IgAV, is also frequently refractory to cyclophosphamide, while response to rituximab is unknown. We investigated outcomes after rituximab in a multicentre European cohort of adult-onset IgAV and cIgAN. Method We screened clinical records of patients followed at 18 European consorted centres who were ≥18 years old at the onset of IgAV and received ≥1 rituximab dose. Furthermore, we identified patients with cIgAN (≥25% crescentic glomeruli and rapidly progressive glomerulonephritis), who were treated with rituximab. Remission was defined as Birmingham Vasculitis Activity Score (BVAS) &amp;lt;3 at month 6 after rituximab and renal response as stable or improved eGFR and ≥50% proteinuria reduction. Relapse was defined as an increase in BVAS requiring a change in immunosuppressive therapy. Outcomes of IgAV with severe nephritis (eGFR &amp;lt;60 mL/min) were compared with those of cIgAN. Results We included 61 patients with IgAV and 15 with cIgAN (Table). Rituximab was administered as initial therapy in 23/61 (38%) patients with IgAV and 13/15 with cIgAN (87%), while the remainder had refractory or relapsing disease. Active skin involvement was present in 49 patients (80%) and nephritis in 55 patients (90%) with IgAV at the time of starting rituximab. This was given alone in 13/61 (21%) or combined with GC in 48 (79%) patients with IgAV and in all those with cIgAN. Furthermore, cyclophosphamide was used in 15% of patients with IgAV and 40% of those with cIgAN. Remission at 6 months was achieved by 52 (85%) patients with IgAV and 12/13 (92%) of those treated with rituximab alone. A renal response was observed among 49/55 (89%) of those with nephritis. Patients with IgAV and severe nephritis had similar eGFR to those with cIgAN at the time of starting rituximab, but the latter had lower rate of remission and a higher frequency of kidney failure. A relapse occurred in 15/52 patients (29%) who achieved remission a median of 13 months (10-15) after rituximab. Eight patients resumed rituximab and achieved again remission. Conclusion Rituximab alone or in combination with GC and immunosuppressants appeared to achieve a high rate of remission in this cohort of adult-onset IgAV. Renal response among those with severe nephritis was also good, while this was worse among patients with cIgAN, suggesting substantial differences among these conditions despite similar histological appearances.

Impact of Everolimus Initiation and Corticosteroid Weaning During Acute Phase After Heart Transplantation on Clinical Outcome: Data from the Korean Organ Transplant Registry (KOTRY).

The effect of changes in immunosuppressive therapy during the acute phase post-heart transplantation (HTx) on clinical outcomes remains unclear. This study aimed to investigate the effects of changes in immunosuppressive therapy by corticosteroid (CS) weaning and everolimus (EVR) initiation during the first year post-HTx on clinical outcomes. We analyzed 622 recipients registered in the Korean Organ Transplant Registry (KOTRY) between January 2014 and December 2021. The median age at HTx was 56years (interquartile range [IQR], 45-62), and the median follow-up time was 3.9years (IQR 2.0-5.1). The early EVR initiation within the first year post-HTx and maintenance during the follow-up is associated with reduced the risk of primary composite outcome (all-cause mortality or re-transplantation) (HR, 0.24; 95% CI 0.09-0.68; p < 0.001) and cardiac allograft vasculopathy (CAV) (HR, 0.39; 95% CI 0.19-0.79; p = 0.009) compared with EVR-free or EVR intermittent treatment regimen, regardless of CS weaning. However, the early EVR initiation tends to increase the risk of acute allograft rejection compared with EVR-free or EVR intermittent treatment.

Dynamics of torque teno virus load in kidney transplant recipients with indication biopsy and therapeutic modifications of immunosuppression.

Following kidney transplantation, lifelong immunosuppressive therapy is essential to prevent graft rejection. On the downside, immunosuppression increases the risk of severe infections, a major cause of death among kidney transplant recipients (KTRs). To improve post-transplant outcomes, adequate immunosuppressive therapy is therefore a challenging but vital aspect of clinical practice. Torque teno virus load (TTVL) was shown to reflect immune competence in KTRs, with low TTVL linked to an elevated risk for rejections and high TTVL associated with infections in the first year post-transplantation. Yet, little is known about the dynamics of TTVL after the first year following transplantation and how TTVL changes with respect to short-term modifications in immunosuppressive therapy. Therefore, we quantified TTVL in 106 KTRs with 108 clinically indicated biopsies, including 65 biopsies performed >12 months post-transplantation, and correlated TTVL to histopathology. In addition, TTVL was quantified at 7, 30, and 90 days post-biopsy to evaluate how TTVL was affected by changes in immunosuppression resulting from interventions based on histopathological reporting. TTVL was highest in patients biopsied between 1 and 12 months post-transplantation (N = 23, median 2.98 × 107 c/mL) compared with those biopsied within 30 days (N = 20, median 7.35 × 103 c/mL) and > 1 year post-transplantation (N = 65, median 1.41 × 104 c/mL; p < 0.001 for both). Patients with BK virus-associated nephropathy (BKVAN) had significantly higher TTVL than patients with rejection (p < 0.01) or other pathologies (p < 0.001). When converted from mycophenolic acid to a mTOR inhibitor following the diagnosis of BKVAN, TTVL decreased significantly between biopsy and 30 and 90 days post-biopsy (p < 0.01 for both). In KTR with high-dose corticosteroid pulse therapy for rejection, TTVL increased significantly between biopsy and 30 and 90 days post-biopsy (p < 0.05 and p < 0.01, respectively). Of note, no significant changes were seen in TTVL within 7 days of changes in immunosuppressive therapy. Additionally, TTVL varied considerably with time since transplantation and among individuals, with a significant influence of age and BMI on TTVL (p < 0.05 for all). In conclusion, our findings indicate that TTVL reflects changes in immunosuppressive therapy, even in the later stages of post-transplantation. To guide immunosuppressive therapy based on TTVL, one should consider inter- and intraindividual variations, as well as potential confounding factors.

EBV Reactivation in Transplant Recipients following SARS-CoV-2 Infection: A Retrospective Study.

Reactivation and primary infection with a high Epstein Barr Virus (EBV) DNA level in kidney transplant patients could cause severe complications, including the development of Post-Transplantation Lymphoproliferative Disease (PTLD). While in the general population the reactivation of EBV after SARS-CoV-2 infection has been reported, very few data are available in transplant recipients. Our retrospective study aimed to evaluate a possible EBV reactivation in kidney transplant patients following SARS-CoV-2 infection and a possible impairment of the immune system. In addition, the effects of changes in immunosuppressive therapy on EBV DNA reactivation and vaccination were also evaluated. A total of 166 kidney transplant patients followed at the Kidney-Pancreas Transplant Ambulatory Nephrology Unit at Padova University Hospital were retrospectively considered for an observation period of 6 months from January 2020 to April 2023. EBV DNA level was measured by Rt-PCR and evaluated 6 months before and after SARS-CoV-2 infection. Patients' serological states were established via quantification of anti-VCA and anti-EBNA (chemiluminescence). Patients' immune systems were characterized by CD4+/CD8+ lymphocyte ratio (flow cytometry). EBV DNA was reactivated in 50% of the 166 patients with COVID-19 who completed the study. Older patients with more severe forms of COVID-19 had higher EBV reactivation (p < 0.05). EBV reactivation significantly increased in patients with severe SARS-CoV-2 infection requiring hospitalization compared to patients managed at home (p < 0.001). CD4+/CD8+ lymphocyte ratio was reduced in patients with a younger age of transplant (p < 0.01) and on a higher dose of steroids (p < 0.01). The results of our study confirm the role of immunodepression, especially in recent transplant patients and those on high steroids, in EBV reactivation. These results combined with the few available in the literature might contribute to providing an optimal management of immunosuppressive treatment for these patients in order to obtain an immune state unfavorable to the activation of latent viruses, including EBV.

Quantification of Torque Teno Virus Load to Monitor Short-term Changes in Immunosuppressive Therapy in Kidney Transplant Recipients.

Quantification of torque teno virus (TTV) has been proposed as a surrogate parameter to monitor immunocompetence in kidney transplant recipients (KTRs) early after transplantation. However, its use in monitoring short-term changes of immunosuppression in KTRs late after transplantation requires further investigation. In this post hoc analysis, we quantified TTV load in sera of 76 KTRs, with 43 pausing mycophenolic acid (MPA) 1 wk before to 4 wk after COVID-19 vaccination to increase vaccine response. TTV load was quantified before, 4 wk, and 3 mo postvaccination. Results were compared to 33 KTRs with continued standard immunosuppressive therapy and with 18 hemodialysis as well as 18 healthy control subjects. TTV load before vaccination was with a median (interquartile range) of 1.39 × 10 4 copies/milliliter (c/mL) (9.17 × 10 1 -2.66 × 10 5 c/mL) highest in KTRs compared to 1.73 × 10 3 c/mL (1.07 × 10 3 -1.31 × 10 4 c/mL) in hemodialysis patients and 1.53 × 10 2 c/mL (6.38-1.29 × 10 3 c/mL) in healthy controls. In KTRs with MPA withdrawal, TTV load decreased significantly from a median (interquartile range) of 1.11 × 10 4 c/mL (4.75 × 10 2 -1.92 × 10 5 c/mL) to 5.24 × 10 3 c/mL (6.92 × 10 2 -6.91 × 10 4 c/mL) 4-5 wk after initiation of MPA withdrawal ( P = 0.003). In patients with MPA withdrawal, TTV load was significantly inversely correlated with COVID-19 or SARS-CoV-2-specific antibodies 4 wk and 3 mo postvaccination ( P = 0.009 and P = 0.004). TTV load reflects changes in immunosuppressive therapy even late after transplantation, supporting its use to monitor immunocompetence in KTRs.

Utility of microbiologic testing in surveillance bronchoscopy following lung transplantation: A retrospective cohort study.

The utility of surveillance bronchoscopy (SB) for the clinical management of lung transplant recipients (LTRs) is undefined. This study evaluates the role of SB in the monitoring and care of LTRs. We retrospectively analyzed all LTRs who had SB at Henry Ford Hospital in Detroit, Michigan between August 2014 and August 2019. Bronchoscopies performed for clinical symptoms, new radiographic abnormalities, and to assess stents or acute rejection were excluded. A total of 107 LTRs and 449 bronchoscopies were analyzed. The primary outcome was the rate of change in clinical care based on microbiologic and pathologic test results. Secondary outcomes were rates of microbiologic and pathologic test positivity and rates of adverse effects. The most common microbiologic tests performed on bronchoalveolar lavage were bacterial (96.9%), fungal (95.3%), and acid-fast bacillus (95.1%) stains and cultures. Of 2560 microbiologic tests, 22.0% were positive and resulted in therapy changes for 2.9%. Positive galactomannan, acid-fast bacillus tests, and Pneumocystis jirovecii antigen/polymerase chain reaction did not result in therapy changes. Of the 370 transbronchial biopsies performed, 82.2% were negative for acute rejection and 13% were positive for A1/A2 rejection. Immunosuppressive therapy changes occurred after 15.8% with reduction in immunosuppression due to positive microbiologic tests in 16.9%. Adverse events occurred in 8.0% of patients. Diagnostic stewardship is warranted when performing SB in LTRs.

SIGLEC-1 in Systemic Sclerosis: A Useful Biomarker for Differential Diagnosis.

Systemic Sclerosis (SSc) is a clinically heterogeneous disease that includes an upregulation of type I interferons (IFNs). The aim of this observational study was to investigate the IFN-regulated protein Sialic Acid–Binding Ig-like Lectin 1 (SIGLEC-1) as a biomarker for disease phenotype, therapeutic response, and differential diagnosis in SSc. Levels of SIGLEC-1 expression on monocytes of 203 SSc patients were determined in a cross-sectional and longitudinal analysis using multicolor flow cytometry, then compared to 119 patients with other rheumatic diseases and 13 healthy controls. SSc patients higher SIGLEC-1 expression on monocytes (2097.94 ± 2134.39) than HCs (1167.45 ± 380.93; p = 0.49), but significantly lower levels than SLE (8761.66 ± 8325.74; p < 0.001) and MCTD (6414.50 ± 1846.55; p < 0.001) patients. A positive SIGELC-1 signature was associated with reduced forced expiratory volume (p = 0.007); however, we were unable to find an association with fibrotic or vascular disease manifestations. SIGLEC-1 remained stable over time and was independent of changes in immunosuppressive therapy. However, SIGLEC-1 is suitable for differentiating SSc from other connective tissue diseases. SIGLEC-1 expression on monocytes can be useful in the differential diagnosis of connective tissue disease but not as a biomarker for SSc disease manifestations or activity.

Association of intraindividual tacrolimus variability with de novo donor-specific HLA antibody development and allograft rejection in pediatric kidney transplant recipients with low immunological risk

BackgroundTacrolimus (Tac) intraindividual variability (TacIPV) in pediatric kidney transplant patients is only poorly understood. We investigated the impact of TacIPV on de novo donor-specific HLA antibodies (dnDSA) development and allograft rejection in Caucasian pediatric recipients of a living or deceased donor kidney with low immunological risk.MethodsThis was a single-center retrospective study including 48 pediatric kidney transplant recipients. TacIPV was calculated based on coefficient of variation (CV%) 6–12 months posttransplant. TacIPV cutoff was set at the median (25%). Outcome parameters were dnDSA development and rejection episodes.ResultsIn total, 566 Tac levels were measured with median 11.0 (6.0–17.0) measurements per patient. The cutoff of 25% corresponded to the median CV% in our study cohort (25%, IQR 18–35%) and was comparable to cutoffs determined by receiver operating characteristic (ROC) curve analysis. High TacIPV was associated with higher risk of dnDSA development (HR 3.4, 95% CI 1.0–11.1, P = 0.047; Kaplan–Meier analysis P = 0.018) and any kind of rejection episodes (HR 4.1, 95% CI 1.1–14.8, P = 0.033; Kaplan–Meier analysis P = 0.010). There was a clear trend towards higher TacIPV below the age of 6 years. TacIPV (CV%) was stable over time. A TacIPV (CV%) cutoff of 30% or IPV quantification by mean absolute deviation (MAD) showed comparable results.ConclusionsHigh TacIPV is associated with an increased risk of dnDSA development and rejection episodes > year 1 posttransplant even in patients with low immunological risk profile. Therefore, in patients with high TacIPV, potential causes should be addressed, and if not resolved, changes in immunosuppressive therapy should be considered.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information.

S1140 Practical Consideration for Drug Monitoring of Tacrolimus in Liver Transplant Recipients With SARS-CoV-2 Infection

Introduction: Previous studies have shown that infection-related cytokine increase of interleukins can cause suppression of cytochrome P450.. SARS-CoV-2 infection has been associated with increased cytokine levels which may suggest suppression of CYP3A4 enzymes and downstream interaction with CYP-mediated drug metabolism including calcineurin inhibitors. Tacrolimus is a calcineurin inhibitor metabolized via CYP3A4. This potential effect of CYP3A4 inhibition on immunosuppression management with tacrolimus in liver transplant recipients with SARS-CoV-2 infection has yet to be evaluated. Methods: We retrospectively evaluated data between June 1, 2020 through December 31, 2020. All patients had confirmed SARS-CoV-2 and among those on tacrolimus-based therapy, serial tacrolimus trough levels were collected during the hospitalization were analyzed. Results: 18 OLT recipients were hospitalized with SARS-CoV-2.14 patients had tacrolimus trough levels throughout hospitalization, 12 of which were on stable immunosuppression therapy. 9 (64.3%) patients had elevated liver enzymes at time of admission. All patients experienced a decrease in baseline albumin levels and 7 out of 10 had an elevated ferritin level within 72 hours from admission.13 (92.8%) patients on tacrolimus had an increase from their baseline levels after testing positive, with an average increase of 105.6% (SD, 81%.7). 9 patients (64.3%) had at least a 50% increase from baseline trough levels. Among these patients, tacrolimus dose was subsequently reduced by an average of 45%. Steroid use did show a positive correlation (Pearson coefficient=0.57, P=0.03) with a rise above baseline tacrolimus trough. Conclusion: We found that most patients on tacrolimus had a supratherapeutic trough goals. There was an average two-fold increase in tacrolimus trough levels compared to baseline, with 64% (n=9) of patients experiencing at least a 50% increase. As expected, these supratherapeutic levels in trough levels in the setting of SARS-CoV-2 infection led to considerable change in immunosuppressive therapy with an approximately 50% reduction in daily tacrolimus dosing. These observations may suggest that SARS-CoV-2 infection in liver transplant recipients should be taken into special consideration when managing immunosuppression. This is the first study to describe these findings. Our study provides compelling evidence to closely monitor tacrolimus levels during acute infection and adjust dosing accordingly.Figure 1.: Pathophysiologic Mechanisms of Liver Injury in COVID-19Table 1.: Characteristics of Patients with Cirrhosis and Clinically Significant Portal Hypertension (CSPH) Based on SARS-CoV-2 Infection. Abbreviations: IQR, interquartile range; BMI, body mass index; CAD, coronary artery disease; BMI, body mass index; MELD-Na, Model for End-stage Liver Disease; CTP, Child Turcotte Pugh; HgbA1C, hemoglobin A1c; COPD, chronic obstructive pulmonary disease

Auswirkungen einer SARS-CoV-2-Infektion auf Symptomatik und Therapie chronisch-entzündlicher Darmerkrankungen

The influence of a SARS-CoV-2 infection on inflammatory bowel disease (IBD) has not yet been well characterized and it is unclear whether this requires an adaptation of the immunosuppressive therapy. A national register was established for the retrospective documentation of clinical parameters and changes in immunosuppressive therapy in SARS-CoV-2 infected IBD patients. In total, only 3 of 185 IBD patients (1.6 %) were tested for SARS-CoV-2 infection because of abdominal symptoms. In the course of COVID-19 disease, 43.5 % developed diarrhea, abdominal pain or hematochezia (risk of hospitalization with vs. without abdominal symptoms: 20.0 % vs. 10.6 %, p < 0.01). With active IBD at the time of SARS-CoV-2 detection, there was an increased risk of hospitalization (remission 11.2 %, active IBD 23.3 % p < 0.05). IBD-specific therapy remained unchanged in 115 patients (71.4 %); the most common change was an interruption of systemic therapy (16.2 %). New abdominal symptoms often appeared in SARS-CoV-2 infected IBD patients. However, these only rarely led to SARS-CoV-2 testing. A high IBD activity at the time of SARS-CoV-2 detection was associated with an increased risk of hospitalization.

A study on echocardiographic findings in hospitalized patients with connective tissue diseases

Objective To determine the prevalence of echocardiographic findings and their change over time in patients with connective tissue diseases (CTDs) and to analyse which findings were associated with escalation of immunosuppressive therapy. Method We conducted a retrospective cohort study of consecutive hospitalized patients from a tertiary rheumatology referral centre who received transthoracic echocardiography between 1 January 2006 and 31 December 2015. We tested for associations between echocardiographic findings and treatment escalation via Fisher’s exact test; p < 0.05 was considered significant. Escalation of therapy was defined by dosage of glucocorticoids and type of disease-modifying anti-rheumatic drug. The clinical relevance of echocardiographic findings concerning change in immunosuppressive therapy was recorded. Results In total, 1004 patients were included (865 females), with a total of 1660 echocardiographic examinations. The most frequent findings were mitral, tricuspid, and aortic valve regurgitation (found in 36.7%, 25.4%, and 17.7% of all patients), aortic valve sclerosis (20.1%), left ventricular dysfunction (21.5%), and left atrial dilatation (19.2%). Only pericardial effusions were more frequent in cases with treatment escalation (10.9% of cases with escalated therapy vs 6.9% of cases without, p = 0.007). In 314 patients who received follow-up examinations, echocardiographic findings were found to change between examinations. Only 73 of all 1660 examinations were discussed in depth considering the treatment strategy in the hospital discharge letter. Conclusion Patients with CTDs exhibited a wide, dynamically changing spectrum of echocardiographic abnormalities. Most findings neither reflected disease activity nor appeared to influence the therapeutic regimen.

Microsporidiosis after liver transplantation: A French nationwide retrospective study.

Microsporidiosis has been largely reported in patients with acquired immunodeficiency syndrome, but emerged as a cause of persistent diarrhea in solid organ transplant patients. Through the French Microsporidiosis Network and the Groupe français de recherche en greffe de foie, we collected all microsporidiosis cases identified in liver transplant patients between 1995 and 2020 in France. We identified 24 liver transplant recipients with microsporidiosis. Sex ratio was balanced and median age was 58.8 (3.5-83.5) years (there were 4 children). Microsporidiosis occurred at a median time of 3.9 (0.1-18.9) years post-transplant. Median duration of diarrhea before diagnosis was 22days (12-45). Therapeutic care included immunosuppressive therapy changes in 20 patients, as follows: stop cyclosporine or tacrolimus (n=2), dose reduction of cyclosporine or tacrolimus (n=12), stop MMF (n=5), and dose reduction of corticosteroids (n=1). In addition, 15 patients received specific therapy against microsporidiosis: fumagillin (n=11) or albendazole (n=4). Median duration of treatment was 14days (8-45days). Finally, 7 patients had immunosuppressive treatment tapering only. Microsporidiosis was complicated by renal failure in 15 patients, requiring dialysis in one case. Two patients had infection relapse. No patient presented proven rejection within the 3months after microsporidiosis. None of the patients died within the 3months after microsporidiosis. Microsporidiosis is a very rare infection after liver transplantation but can induce severe dehydration and renal failure. Therefore, it must be systematically sought in any case of persistent diarrhea after first line screening of frequent infectious causes.

FC 039RENAL OUTCOME AFTER RITUXIMAB IN ADULT-ONSET IGA VASCULITIS AND CRESCENTIC IGA NEPHROPATHY: A MULTICENTRE STUDY

Abstract Background and Aims Glucocorticoids (GC) and/or immunosuppressive agents are the mainstay of therapy for adult-onset IgA Vasculitis (IgAV), but their efficacy is often partial while their toxicity is relevant. Recently, rituximab (RTX) has been reported as a safe and effective option but only few data on renal outcome are available.1 RTX has also been used in a few cases of crescentic IgA Nephropathy (cIgAN), an IgAN subset with vasculitic lesions and poor response to conventional immunosuppressive regimens.2 We present the results of a multicentre cohort of patients with IgAV and cIgAN treated with RTX. Method The databases of 16 consorted European centres were investigated to screen for patients with adult-onset, biopsy-proven IgAV and cIgAN (crescents in ≥25% glomeruli and rapid eGFR worsening at presentation), who received RTX as induction therapy. We selected patients with active renal manifestations at the time of RTX. Remission was defined as a Birmingham Vasculitis Activity Score (BVAS)=0 or &amp;lt;5 if it was due to persistent proteinuria and relapse as an increase in BVAS requiring change in immunosuppressive therapy. Results We identified 38 patients with IgAV and 12 patients with cIgAN who received RTX and had active renal involvement at the time of treatment. The median age at onset was 40 years (interquartile range, IQR, 25-53) and more than two-thirds of patients were male (Table 1). The median follow-up after RTX was 41 months (IQR 18-60). Renal outcomes are reported in Table 2. At the time of treatment, 24 patients (48%) had eGFR ≥60 mL/min/1.73 m2. All had IgAV and their median BVAS was 17 (IQR 10-22). Furthermore, all had microhaematuria and proteinuria. Renal histology showed mesangial or focal endocapillary proliferation in 12/17 (71%) patients who underwent biopsy (class II-IIIA according to Pillebout3). Twenty patients (83%) achieved remission; after a median of 12 months (range 9-14), four experienced a minor relapse and one had a major relapse with significant renal disease progression. Renal function remained stable in all but two patients who developed end-stage renal disease (ESRD). Micro-haematuria subsided in 14/24 (58%) and median 24h proteinuria decreased from 1750 mg (IQR 865-3275) to 175 mg (IQR 100-800) at last follow-up (p=0.029). Of the 26 patients with eGFR &amp;lt;60 mL/min/1.73 m2, 14 had IgAV and 12 had cIgAN. All were biopsied and 20 (77%) had diffuse endo/extra-capillary proliferation (classes IIIB-IV). Five patients required dialysis but recovered soon after treatment start. Remission was achieved by 16/26 (61%); eight (50%) subsequently relapsed and two (12%) reached ESRD. At last follow-up, eGFR was ≥60 mL/min/1.73 m2 in 8/26 (31%), 10/26 (48%) had stable renal function as compared to the time of RTX, while 8/26 (31%) had developed ESRD. Median 24h proteinuria decreased from 3400 mg (IQR 2150-6500) to 770 mg (177-1315) (p=0.016). Remission rate and ESRD-free survival were respectively 86% and 92% in patients with IgAV, while they were respectively 42% and 42% in cIgAN patients. Furthermore, 21/24 (87%) patients who received RTX alone or combined to glucocorticoids but not to immunosuppressive agents achieved remission and 22/24 (92%) were ESRD-free at last follow-up. Of the 26 patients receiving immunosuppressive agents, 17 (65%) obtained remission and 18 (69%) were ESRD-free at last assessment. Over the whole follow-up, only one patient reported a severe adverse effect related to RTX (pneumonia). Conclusion Renal involvement in adult-onset IgAV and cIgAN is frequently severe. RTX, combined or not with other immunosuppressive agents, may improve renal manifestations and is well tolerated. IgAV patients show higher remission rates and a longer ESRD-free survival as compared to cIgAN patients.

Recommandations françaises du Comité de transplantation de l’association française d’urologie (CTAFU) : carcinome rénal sur reins natifs chez le patient transplanté rénal ou en attente de transplantation

To define guidelines for the management of renal cell carcinoma of the native kidney (NKRCC) in kidney transplant (KTx) recipients and renal cell carcinoma (RCC) in end-stage renal disease (ESRD) patients candidates for renal transplantation. A review of the literature following a systematic approach (Medline) was conducted by the CTAFU to report renal cell carcinoma epidemiology, screening, diagnosis and management in KTx candidates and recipients. References were assessed according to a predefined process to propose recommendations with the corresponding levels of evidence. ESRD patients are at higher risk of RCC with a standardized incidence ratio of approximately 4,5as compared with general population. NKRCC tumors occur in 1to 3% of KTx recipients with a 10to 15-fold increased risk as compared with general population, especially in patients with acquired multicystic kidney disease. Most authors suggest yearly monitoring of the native kidneys using ultrasound imaging. Radical nephrectomy (either open or laparoscopic approach) is the preferred treatment of NKRCC in KTx recipients and RCC in ESRD. Surveillance in a valid option in small or cystic renal masses. In the localized setting, change in immunosuppressive therapy is not recommended besides perioperative avoidance of mTOR inhibitor to limit morbidity. CTAFU does not recommend a mandatory waiting time after nephrectomy for RCC in ESRD patients candidates for renal tranplantation when tumor stage<T3and low ISUP grade. Follow-up modalities should follow recommendations in general population. The French recommendations should contribute to improve management of NKRCC in KTx recipients and RCC in ESRD candidates for KTx, integrating oncological objectives in the context of kidney transplantation.

148. Fungal Disease Mortality Trends, United States, 1999–2017

BackgroundFungal diseases can lead to substantial morbidity and mortality, although research funding has been disproportionately low compared with other infectious diseases. Despite dramatic changes in immunosuppressive therapy over the past two decades, the U.S. mortality burden of fungal diseases has not been recently assessed.MethodsWe analyzed fungal disease-associated mortality trends during 1999–2017 using multiple cause-of-death mortality records from the National Vital Statistics System. We calculated age-standardized rates for aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, mucormycosis, pneumocystosis, unspecified mycoses, and other mycoses based on the age distribution of the 2000 U.S. population.ResultsAmong over 47 million deaths, 86,058 (0.2%) people had one or more fungal diseases listed on the death certificate as an underlying or contributing cause of death (median 4,431 annually) (Figure 1). The age-standardized mortality rate was 2.2/100,000 population in 1999. By 2017, rates declined by 47% to 1.2. The largest declines occurred for pneumocystosis and cryptococcosis, diseases particularly associated with HIV, by 66–70% from 1999 to 2007 and by 3–6% from 2008 to 2017. During 1999–2017, rates for aspergillosis, candidiasis, and other mycoses declined by 46–56%, although rates for candidiasis and other mycoses increased (10% and 31%, respectively) from 2013 to 2017. Overall, the steepest declines were seen in infants and younger adults (Figure 2).Age-standardized mortality rates for fungal diseases as underlying and contributing cause of death, per 100,000 people, by year and fungal disease type, United States, 1999–2017 Age-specific mortality rates for fungal diseases as underlying and contributing cause of death, per 100,000 people, by year and age group, United States, 1999–2017 ConclusionFungal disease-associated mortality rates declined by half from 1999 to 2017. Improved treatment of HIV and availability of new antifungals likely influenced the decline. However, fungal diseases are still documented in thousands of deaths annually, and rates differed substantially by disease. Better prevention, diagnosis, and treatment are needed to reduce mortality from fungal diseases.Disclosures All Authors: No reported disclosures

Concomitant Immunosuppressive Therapy Use in Eculizumab-Treated Adults With Generalized Myasthenia Gravis During the REGAIN Open-Label Extension Study.

Introduction: Chronic, broad-spectrum immunosuppressive therapy (IST) can be associated with side effects in many people with generalized myasthenia gravis (gMG), and treatment guidelines recommend that the IST dose be tapered once patients achieve a stable treatment response. We therefore examined IST use in eculizumab-treated patients with refractory gMG.Methods: The REGAIN open-label extension (OLE) enrolled 117 adults with refractory anti-acetylcholine receptor antibody-positive gMG who had completed the 6-month, randomized, double-blind, placebo-controlled REGAIN study of eculizumab. Eligible patients had received ≥2 ISTs for ≥1 year or ≥1 IST with intravenous immunoglobulin or plasma exchange ≥4 times in 1 year, without symptom control. During REGAIN, changes in concomitant MG therapies were not permitted; during the OLE, they were permitted at the investigators' discretion. Participants received eculizumab 1,200 mg every 2 weeks for up to 4 years; concomitant prednisone and related corticosteroids (PRED), azathioprine (AZA), and mycophenolate mofetil (MMF) use was recorded. Changes in MG Activities of Daily Living and Quantitative MG total scores, MG exacerbations, and adverse events were also recorded.Results: At last OLE assessment, 88.0% (103/117) of participants were using ≥1 IST vs. 98.3% (115/117) at OLE baseline. During the OLE, 76.9% (90/117) of patients experienced a total of 719 IST changes. Almost half of participants [48.7% (57/117)] stopped or decreased ≥1 IST owing to MG symptom improvement, representing 38.9% (280/719) of all changes. In patients who decreased and/or stopped ≥1 IST, mean daily doses of PRED, AZA, and MMF decreased between OLE baseline and last assessment by 60.8% [standard deviation (SD), 28.07; P < 0.0001], 89.1% (SD, 25.77; P < 0.0001), and 56.0% (SD, 32.99; P < 0.0001), respectively. Improved clinical outcomes were observed with eculizumab regardless of IST changes during the OLE, and eculizumab's safety profile was similar in patients who used PRED, AZA, and MMF.Conclusions: Use of ISTs by patients with previously refractory gMG decreased during eculizumab treatment in the REGAIN OLE. Clinical improvements with eculizumab were maintained by patients in all groups, including those who decreased and/or stopped concomitant ISTs.Trial registration: www.clinicaltrials.gov: NCT01997229, NCT02301624.

Interactions between Immunosuppressive Therapy and Direct-Acting Antivirals in Kidney Transplant Recipient with Hepatitis C Infection

Hepatitis C virus (HCV) causes increased mortality and morbidity in kidney transplant patients. Interferon-based therapies are poorly tolerated and involve the risk of rejection. The new direct-acting antiviral drugs (DAAs) have revolutionized the treatment of HCV infection in transplant patients. This observational study evaluates changes in immunosuppressive therapy during treatment with DAA in renal transplant recipients.In our transplant center, we selected seven HCV-positive patients at the time of transplantation , four men and three women, with an average age of 61 ± 7 years, in therapy with DAA. The dose and the blood levels of the immunosuppressive drugs were evaluated at the beginning and end of antiviral therapy, together with creatinine and proteinuria.Viremia was negativized in all patients within the initial 8 weeks of therapy. Currently, the number of patients is too limited to perform a sta-tistical analysis and obtain significant results. In one patient, the dose of Cyclosporine was lowered to 10 mg, while for the remaining patients it was not necessary to change the dose of immunosuppressive drugs.DAAs give encouraging results in the eradication of HCV in renal transplant recipients, although they are associated with potential adverse drug interactions. The preliminary data of our study suggest that it is not necessary to change the dose of immunosuppressive drugs during therapy and that creatinine and proteinuria remain stationary. We will achieve more significant results in the future, adding more patients to our study. However, further randomized trials are necessary to confirm the safety of DAAs.

A multicenter study to define the epidemiology and outcomes of Clostridioides difficile infection in pediatric hematopoietic cell and solid organ transplant recipients.

Hematopoietic cell transplant (HCT) and solid organ transplant (SOT) recipients are at increased risk for Clostridioides difficile infection (CDI). We conducted a multicenter retrospective study to describe the incidence of CDI in children transplanted between January 2010 and June 2013. Nested case-control substudies, matched 1:1 by transplant type, institution, patient age, and time of year (quartile) of transplant, identified CDI risk factors. Cohorts included 1496 HCT and 1090 SOT recipients. Among HCT recipients, 355 CDI episodes were diagnosed in 265 recipients (18.2%). Nested case-control study identified prior history of CDI (odds ratio [OR] 2.6, 95% confidence interval [CI] 1.5-4.7), proton pump inhibitors (PPIs; OR 2.1, 95% CI 1.3-3.4), and exposure to third- (OR 2.4, 95% CI 1.4-4.2) or fourth-generation (OR 2.1, 95% CI 1.2-3.7) cephalosporins as risk factors. Notably, fluoroquinolone exposure appeared protective (OR 0.6, 95% CI 0.3-0.9). Ninety-two episodes of CDI were diagnosed among 79 SOT recipients (7.3%), and exposure to PPIs (OR 2.4, 95% CI 1.1-5.4) and third-generation cephalosporin therapy (OR 3.9, 95% CI 1.4-10.5) wereidentified as risk factors. Strategies to decrease PPI use and changes in the class of prophylactic antibiotics may impact CDI incidence and warrant further study.

Belatacept-based immunosuppression: A calcineurin inhibitor-sparing regimen in heart transplant recipients.

Belatacept (BTC) is indicated for prophylaxis of graft rejection in adults receiving a renal transplant (Tx). This retrospective observational study (three centers) included all heart transplant recipients receiving BTC between January 2014 and October 2018. Forty EBV+ patients mean GFR 35±20mL/min/m2 were identified, among whom belatacept was initiated during the first 3months after transplantation in 12 patients, and later in 28 patients. Several patients were multiorgan transplant recipients. Study outcomes were GFR, safety, and changes in immunosuppressive therapy. The main reason for switching to BTC was to preserve renal function, resulting in discontinuation of CNI and changes in immunosuppressive therapy in 76% of cases. At study closeout, 24/40 patients were still on BTC therapy. GFR was improved (+59%, P=.0002*) within 1month, particularly in the early group. More episodes of rejection were observed among "late" patients (1 death). Sixteen treatment discontinuations were recorded: GFR recovery (n=4), DSA no longer detectable (n=1), compliance issues (n=3), poor venous access (n=2), multiple infections (n=1), 1 death (fungal lung infection), and treatment failure (n=4). Median follow-up was 24months. Four patients developed de novo DSA (MFI<1500). BTC is an effective alternative immunosuppressive for postoperative transient kidney failure, stabilizing delayed renal function, with acceptable safety profile under careful monitoring.